abstract	label
TRPV4, a nonselective calcium permeable ion channel, is expressed broadly in many organs including bone and neurons. Pathogenic variants in TRPV4 are known to cause both a spectrum of skeletal dysplasias and neuropathies. Recent publications have documented a few patients who have a combined phenotype of skeletal dysplasia and neuropathy secondary to TRPV4 pathogenic variants. We present an additional patient who has an overlapping neuromuscular and skeletal phenotype secondary to a TRPV4 pathogenic variant. The patient has spondylometaphyseal dysplasia-Kozlowski type and Charcot-Marie-Tooth disease type 2C. This and prior reports illustrate that TRPV4-related skeletal dysplasias and TRPV4-related neuropathies are not fully distinct disorders secondary to unique sets of pathogenic variants as originally postulated, but rather are 2 phenotypes on the same spectrum that may or may not overlap. We suggest that evaluation for patients presenting with any TRPV4-related disorder include assessment for both skeletal and neurological findings.	0
OBJECTIVE:We present prenatal diagnosis of mosaicism for double trisomies of trisomy 11 and trisomy 12 in a single colony at amniocentesis with a favorable outcome. CASE REPORT:A 23-year-old woman underwent amniocentesis at 24 weeks of gestation because of congenital bowel dilation in the fetus. Amniocentesis revealed a karyotype of 48,XX,+11,+12[1]/46,XX[24]. In 25 colonies of cultured amniocytes, all five cells in one colony had the karyotype of 48,XX,+11,+12, while the rest 24 colonies had the karyotype of 46,XX. The parental karyotypes were normal. Repeat amniocentesis was performed at 26 weeks of gestation. Interphase fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH) and quantitative fluorescent polymerase chain reaction (QF-PCR) were applied on the uncultured amniocytes, and conventional cytogenetic analysis was applied on cultured amniocytes. Interphase FISH analysis showed no trisomy 11 signal and no trisomy 12 signal in 102 uncultured amniocytes. QF-PCR analysis excluded uniparental disomy (UPD) 11 and UPD 12. aCGH analysis showed no genomic imbalance. The cultured amniocytes at repeat amniocentesis had the karyotype of 46,XX in 13/13 colonies. At term, a healthy 3445-g female baby was delivered with no phenotypic abnormality except imperforate anus and a perianal fistula. The cord blood had a karyotype of 46,XX in 40/40 lymphocytes. Postnatal interphase FISH analysis of buccal cells and urinary cells revealed trisomies 11 and 12 signals in 11/111 (9.9%) buccal cells compared with 3% in normal control, and in 3/103 (2.9%) urinary cells compared with 0.98% in normal control. CONCLUSION:Mosaicism for double trisomies of trisomy 11 and trisomy 12 in a single colony at amniocentesis without UPD 11 and UPD 12 can be associated with a favorable outcome.	0
This study aimed to determine the relationships between the quality of life, health condition, and caring in terms of health practice behaviors of parents of children with developmental disabilities. Two hundred forty-three parents of children with developmental disabilities participated. We examined the quality of life; the health practice behavior questionnaire comprised details of health condition, caring behavior, and diet, and it used a 10-point scale for scoring. The data were analyzed using a one-way analysis of variance; linear regression was conducted using IBM SPSS Statistics ver. 23.0. The results indicated that there were associations between quality of life, relations with family members, relations with neighbors, living standards, physical condition, and function among the subfactors. There were significant differences between exercise practice behavior, quality of life, relations with family, relations with neighbors, living standards, physical condition and functioning, emotional state, and self-esteem among subfactors. It was found that there were significant differences between diet behavior and quality of life, and physical condition and function, emotional state in sub factor of quality of life. Based on the results of this study, if a health promotion behavior program is developed and applied systematically, it will contribute to improving the quality of life for parents' children with developmental disabilities.	0
Biallelic pathogenic variants in mitochondrial aminoacyl-tRNA synthetase (mt-aaRS) PARS2 are associated with mitochondrial cytopathy. Here, we report the tenth case of an individual with biallelic PARS2 pathogenic variants, detected by exome sequencing (ES), and a literature review of ten cases of PARS2 mutations. Our patient displayed symptoms and clinical and laboratory findings similar to those reported previously with normal lactate levels. These symptoms included seizure disorder (which was managed with antiepileptics), developmental delay, and progressive cardiomyopathy which manifested at 19 years of age. The patient received a vitamin regimen including antioxidants as part of his treatment regimen. While further studies are required to conclusively establish the beneficial role of vitamin and cofactor administration on the mitochondria in PARS2-associated mitochondrial disease, these factors may have delayed the onset of cardiomyopathy.	0
BACKGROUND:Both maternal uniparental disomy 14 (UPD(14)mat) and mosaic trisomy 14 are rare events in live individuals. A combination of the two events in one individual is rarely encountered. Only six live-born cases have so far been reported. CASE PRESENTATION:Here we reported a case of concomitant UPD(14)mat and mosaic trisomy 14 in a 10-year-old Chinese patient. Most clinical features of our patient were consistent with those previous reported for UPD(14)mat cases, which include prenatal and postnatal growth retardation, neonatal hypotonia, feeding difficulty, intellectual disability, truncal obesity, small hands and feet, short stature, and mild facial dysmorphism, but our patient showed more severe intellectual disability and no sign of precocious puberty. SNP array analysis revealed a mixture of chromosome 14 maternal isodisomy with heterodisomy and a low level trisomy mosaicism of whole chromsome 14 in blood and hyperpigmented skin samples, whereas only UPD(14)mat was detected in normal skin sample. Cytogenetic analysis identified one trisomy 14 cell in 100 metaphase of peripheral blood lymphocytes (47,XX, +14[1]/46,XX[99]). CONCLUSIONS:To our knowledge, this is the first case of a patient with UPD(14)mat and mosaic trisomy 14 reported in a Chinese patient. The definitive genetic diagnosis is beneficial for genetic counseling and clinical management of our patient, and for improving our understanding of the genotype-phenotype correlations of concomitant UPD(14)mat and mosaic trisomy 14.	0
Autosomal recessive axonal neuropathy with neuromyotonia (ARANNM) is a rare disease caused by mutations of histidine triad nucleotide binding protein 1 (HINT1) gene. ARANNM has been reported mainly in European countries but little reported so far in China. We describe novel mutations of HINT1 in three Chinese patients with ARANNM from unrelated families. Patient 1 was a 14-year-old girl who presented with progressive distal weakness of upper limbs at two years of age. After that, she reported weakness of both feet, and difficulty in muscle relaxation after making a fist. Patient 2 was an 18-year-old boy, who presented with progressive distal weakness of all limbs with foot drop at the age of ten with loss of ambulation at age 15. Patient 3 was a 26-year-old man who had been afflicted with weakness and atrophy of distal lower limbs since the age of 16 complaining about muscle stiffness of the lower limbs when standing and walking, and contraction of finger flexion muscles when releasing a forced grip. Electrodiagnostic testing revealed an axonal motor or sensorimotor neuropathy with or without myokymic discharges. Sural biopsy showed no pathological changes in patient 1 and mild axonal neuropathies with demyelination in patients 2 and 3. Genetic analysis revealed HINT1 with novel compound heterozygous c.112T > C (p.C38R) and c.171G > C (p.K57N) mutations in patient 1, homozygous c.112T > C (p.C38R) mutation in patient 2, as well as compound heterozygous c.112T > C (p.C38R) and c.98T > C (p.F33S) mutations in patient 3. Our study, for the first time, confirms ARANNM in the Chinese population. These genetic findings can help expand the genotypic spectrum of HINT1 mutations.	0
Transformation of Fonsecaea pedrosoi into muriform cells enhances the resistance against phagocytosis and elimination by host immune cells, and links to the chronicity of chromoblastomycosis. Here, we aim to determine whether the muriform cells can reproduce in tissue without reverse transformation into hyphal form by using an experimental nu/nu-BALB/c mouse model of chromoblastomycosis due to F. pedrosoi. During the whole 81-day observation period, most of the hyphal inocula had transformed into muriform cells at 75 days postinoculation and maintained as this parasitic morphology till 81 days postinoculation simultaneously with increased fungal loads in tissue and the worsening of footpad lesion. Scanning and transmitting electronic microscope examinations showed that the muriform cells obtained in tissue or induced in vitro can reproduce daughter cells by dividing, and, meanwhile, the daughter cells had the potential to produce buds and grow into hyphae reversely. Furthermore, exoenzyme examination suggested that the profile of exoenzymes constituted by muriform cells was quite different from that constituted by hyphae although the assay showed both of them had obvious metabolic activity. By contrast, most muriform cells in the footpad gradually transformed into the elongated hyphae without obvious infiltration of inflammatory cells during repeated intraperitoneal administration of cyclophosphamide (50 mg/kg, per every other day) from 50 to 80 days postinoculation. Therefore, we infer that F. pedrosoi can reproduce by dividing as muriform cells in mouse tissue, and the morphological transformation between hyphal form and muriform cells is possibly associated with the host immune status.	0
We report a rare congenital limb defect with combined features of both fibular aplasia, tibial campomelia, and oligosyndactyly (FATCO) and Fuhrmann's syndromes. A female newborn infant, born to nonconsanguineous Egyptian parents, presented with isolated abnormalities of the lower limbs comprising bilateral shortening and anterior bowing of the lower limbs at the distal third of the tibia and split foot. Radiographic examination revealed complete absence of both fibulae, anterolateral bowing and shortening of the tibia, bowing of the femora, and absence of several metatarsal and phalangeal bones. The upper limbs were clinically and radiologically normal, and the infant had neither facial dysmorphism nor other associated visceral anomalies. The presented case highlights an extremely rare limb deficiency syndrome, and together with additional case reports, it could be useful to further delineate this condition.	0
Stormorken syndrome is a rare autosomal-dominant disease with mild bleeding tendency, thrombocytopathy, thrombocytopenia, mild anemia, asplenia, tubular aggregate myopathy, miosis, headache, and ichthyosis. A heterozygous missense mutation in STIM1 exon 7 (c.910C>T; p.Arg304Trp) (NM_003156.3) was found to segregate with the disease in six Stormorken syndrome patients in four families. Upon sensing Ca(2+) depletion in the endoplasmic reticulum lumen, STIM1 undergoes a conformational change enabling it to interact with and open ORAI1, a Ca(2+) release-activated Ca(2+) channel located in the plasma membrane. The STIM1 mutation found in Stormorken syndrome patients is located in the coiled-coil 1 domain, which might play a role in keeping STIM1 inactive. In agreement with a possible gain-of-function mutation in STIM1, blood platelets from patients were in a preactivated state with high exposure of aminophospholipids on the outer surface of the plasma membrane. Resting Ca(2+) levels were elevated in platelets from the patients compared with controls, and store-operated Ca(2+) entry was markedly attenuated, further supporting constitutive activity of STIM1 and ORAI1. Thus, our data are compatible with a near-maximal activation of STIM1 in Stormorken syndrome patients. We conclude that the heterozygous mutation c.910C>T causes the complex phenotype that defines this syndrome.	0
We report two Hong Kong children with severe generalized epidermolysis bullosa simplex (EBS), the most severe form of EBS, without a family history of EBS. EBS is a rare genodermatosis usually inherited in an autosomal dominant fashion although rare autosomal recessive cases have been reported. Genetic studies in these patients showed that the first case was due to a novel de novo heterozygous variant, c.377T>G (NM_000526.5 (c.377T>G, p.Leu126Arg)) in the KRT14 gene and the second case was due to a rare de novo heterozygous variant c.527A>G (NM_000424.4, c.527A>G, p.Asn176Ser) in the KRT5 gene. To our knowledge, the c.377T>G variant in the KRT14 gene has not been previously reported, and the c.527A>G variant in the KRT5 gene is a rare cause of severe generalized EBS. In severe generalized EBS, infants exhibit severe symptoms at the onset; however, they tend to improve with time. A precise genetic diagnosis in these two cases aided in counseling the families concerning the prognosis in their affected children and the recurrence risk for future pregnancies.	0
Glanzmann thrombasthenia (GT) is an autosomal recessive disorder of platelet aggregation caused by quantitative or qualitative defects in integrins αIIb and β3. These integrins are encoded by the ITGA2B and ITGB3 genes and form platelet glycoprotein (GP)IIb/IIIa, which acts as the principal platelet receptor for fibrinogen. Although there is variability in the clinical phenotype, most patients present with severe mucocutaneous bleeding at an early age. A classic pattern of abnormal platelet aggregation, platelet glycoprotein expression and molecular studies confirm the diagnosis. Management of bleeding is based on a combination of hemostatic agents including recombinant activated factor VII with or without platelet transfusions and antifibrinolytic agents. Refractory bleeding and platelet alloimmunization are common complications. In addition, pregnant patients pose unique management challenges. This review highlights clinical and molecular aspects in the approach to patients with GT, with particular emphasis on the significance of multidisciplinary care.	0
We report the anesthetic management of a 16-year-old woman with Fowler's syndrome who became pregnant three years after sacral neuromodulation was initiated for treatment of the condition. Multidisciplinary consensus was to switch off the neurostimulator during pregnancy, and attempt vaginal delivery with a neuraxial block. When the patient was admitted for labor, an epidural catheter was placed successfully. The patient had a normal vaginal delivery. Sacral neuromodulation was restarted uneventfully in the early puerperium and the Fowler's syndrome remains well controlled. The baby continues to develop normally three years after delivery.	0
OBJECTIVE:To detect mutation of NDP gene in a pedigree affected with Norrie disease. METHODS:Sanger sequencing was used to analyze the NDP gene at Xp11.3. Prenatal diagnosis was performed on amniotic fluid sample after the causative gene was detected. RESULTS:Sanger sequencing has revealed a c.2T>C (p.M1T) missense mutation of the NDP gene in the proband and the fetus. The same variation was not found in ClinVar and HGMD database. CONCLUSION:The c.2T>C mutation of the NDP gene probably underlies the Norrie disease in this pedigree.	0
Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a congenital disorder characterised by macrocephaly, multiple hamartomas, lipomas, and pigmented macules of the glans penis. Intermediate uveitis is characterised by chronic inflammatory cells aggregates on the pars plana (snowbanks) and within the vitreous cavity (snowballs). We describe what we believe to be the first case of intermediate uveitis associated with BRRS. Early examination under anaesthesia should be considered in the management of young children diagnosed with this syndrome in order to provide appropriate ocular evaluation, treatment and follow-up. Further research is needed to establish a better understanding of the ophthalmic manifestations of this syndrome.	0
Pyruvate kinase deficiency (PKD) is the most common enzyme defect of glycolysis and an important cause of hereditary, nonspherocytic hemolytic anemia. The disease has a worldwide geographical distribution but there are no verified data regarding its frequency. Difficulties in the diagnostic workflow and interpretation of PK enzyme assay likely play a role. By the creation of a global PKD International Working Group in 2016, involving 24 experts from 20 Centers of Expertise we studied the current gaps in the diagnosis of PKD in order to establish diagnostic guidelines. By means of a detailed survey and subsequent discussions, multiple aspects of the diagnosis of PKD were evaluated and discussed by members of Expert Centers from Europe, USA, and Asia directly involved in diagnosis. Broad consensus was reached among the Centers on many clinical and technical aspects of the diagnosis of PKD. The results of this study are here presented as recommendations for the diagnosis of PKD and used to prepare a diagnostic algorithm. This information might be helpful for other Centers to deliver timely and appropriate diagnosis and to increase awareness in PKD.	0
Chronic myocarditis is sometimes difficult to diagnose using several clinical diagnostic modalities. A 43-year-old Japanese man was admitted to our hospital with heart failure due to a diffusely hypokinetic left ventricle. No abnormal accumulation was seen on 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. Coronary angiography showed no abnormalities. Endomyocardial biopsy was performed on suspicion of dilated cardiomyopathy, revealing diffuse cell infiltration (more T lymphocytes associated with macrophages than B cells on immunohistochemical staining), myocyte damage, and replacement fibrosis. The pathological diagnosis of biopsy specimen was difficult to differentiate between chronic myocarditis and inflammatory dilated cardiomyopathy without immunohistochemistry. Endomyocardial biopsy offers one of the most useful methods for diagnosing chronic myocarditis.	0
The successful treatment of prosthetic joint infection (PJI) is difficult, requiring coordination across multiple specialties. In 2017, we formed a collaboration between our infectious disease clinicians and our orthopaedic arthroplasty surgeons in an effort to optimize care, accommodate patients, and expedite clinical decision-making in the treatment of PJI. The model consisted of combined infectious disease and arthroplasty clinics, standardized lab results, and planned staged revision procedures. We named this the arthroplasty infection service. Our early experience with a defined multidisciplinary approach to PJI was positive. Although the impact of the arthroplasty infection service on PJI outcomes is yet to be determined, we believe this is a step forward in the management of this complex patient population. With an increasing burden of PJI in the United States, this model could be emulated at many institutions that regularly treat these challenging cases.	0
Pathogenic mutations in DPAGT1 are manifested as two possible phenotypes: congenital disorder of glycosylation DPAGT1-CDG (also known as CDG-Ij), and limb-girdle congenital myasthenic syndrome (CMS) with tubular aggregates. UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosamine phosphotransferase (GPT), the protein encoded by DPAGT1, is an endoplasmic reticulum (ER)-resident protein involved in an initial step in the N-glycosylation pathway. The aim of the present study was to examine the effect of six variants in DPAGT1 detected in patients with DPAGT1-CDG, and the role of endoplasmic reticulum stress, as part of the search for therapeutic strategies to use against DPAGT1-CDG. The effect of the six mutations, i.e., c.358C>A (p.Leu120Met), c.791T>G (p.Val264Gly), c.901C>T (p.Arg301Cys), c.902G>A (p.Arg301His), c.1154T>G (p.Leu385Arg), and of the novel mutation c.329T>C (p.Phe110Ser), were examined via the analysis of DPAGT1 transcriptional profiles and GTP levels in patient-derived fibroblasts. In addition, the transient expression of different mutations was analysed in COS-7 cells. The results obtained, together with those of bioinformatic studies, revealed these mutations to affect the splicing process, the stability of GTP, or the ability of this protein to correctly localise in the ER membrane. The unfolded protein response (UPR; the response to ER stress) was found not to be active in patient-derived fibroblasts, unlike that seen in cells from patients with PMM2-CDG or DPM1-CDG. Even so, the fibroblasts of patients with DPAGT1-CDG seemed to be more sensitive to the stressor tunicamycin. The present work improves our knowledge of DPAGT1-CDG and provides bases for developing tailored splicing and folding therapies.	0
Movement disorders in childhood comprise a heterogeneous group of conditions that lead to impairment of voluntary movement, abnormal postures, or inserted involuntary movements. Movement disorders in children are frequently caused by metabolic disorders, both inherited and acquired. Many of these respond to vitamin supplementation. Examples include infantile tremor syndrome, biotinidase deficiency, biotin-thiamine-responsive basal ganglia disease, pyruvate dehydrogenase deficiency, aromatic amino acid decarboxylase deficiency, ataxia with vitamin E deficiency, abetalipoproteinemia, cerebral folate deficiency, and cobalamin metabolism defects. Recognition of these disorders by pediatricians and neurologists is imperative as they are easily treated by vitamin supplementation. In this review, we discuss vitamin-responsive movement disorders in children.	0
Palmoplantar keratoderma (PPK) is a defect in cornification that is characterized by progressive hyperkeratosis of palms and soles. Many phenotypes are linked with PPK, making exome-based diagnosis increasingly efficient. In this report, we identified tyrosinemia type II on whole-exome sequencing in a 7-year-old Syrian refugee that presented with PPK. Dietary therapy helped improve her overall symptoms.	0
BACKGROUND: Postaxial polydactyly (PAP) is one of the commonest congenital malformations and usually is associated to several syndromes. There is no primary investigational strategy for PAP cases with single gene disorder in literature. PAP cases with single gene disorder can be classified according to common pathways and molecular basis. Molecular classification may help in diagnostic approach. MATERIALS AND METHODS: All single gene disorders associated with PAP reported on PubMed and OMIM are analyzed and classified according to molecular basis. RESULTS: Majority of genes related to cilia structure and functions are associated with PAP, so we classified them as ciliopathies and non-ciliopathies groups. Genes related to Shh-Gli3 pathway was the commonest group in non-ciliopathies. CONCLUSION: Genes related to cilia are most commonly related to PAP due to their indirect relationship to Shh-Gli3 signaling pathway. Initially, PAP may be the only clinical finding with ciliopathies so those cases need follow up. Proper diagnosis is helpful for management and genetic counseling. Molecular approach may help to define pleiotropy.	0
AIMS:To document the long term course of chronic idiopathic intestinal pseudo-obstruction syndrome (CIIPS) in children with defined enteric neuromuscular disease, and the place and type of surgery used in their management; in addition, to identify prognostic factors. METHODS:Children with CIIPS were investigated and treated prospectively. RESULTS:Twenty four children presented congenitally, eight during the 1st year of life, and 10 later. Twenty two had myopathy and 16 neuropathy (11 familial). Malrotation was present in 16 patients, 10 had short small intestine, six had non-hypertrophic pyloric stenosis, and 16 had urinary tract involvement. Thirty two patients needed long term parenteral nutrition (TPN): for less than six months in 19 and for more than six months in 13, 10 of whom are TPN dependent; 14 are now enteral feeding. Prokinetic treatment improved six of 22. Intestinal decompression stomas were used in 36, colostomy relieved symptoms in five of 11, and ileostomy in 16 of 31. A poor outcome (death (14) or TPN dependence (10)) was seen with malrotation (13 of 16), short small bowel (eight of nine), urinary tract involvement (12 of 16), and myopathic histology (15 of 22). CONCLUSIONS:In CIIPS drugs are not helpful but decompression stomas are. Outcome was poor in 24 of 44 children (15 muscle disorder, 10 nerve disease).	0
The human X and Y chromosomes evolved from a pair of autosomes approximately 180 million years ago. Despite their shared evolutionary origin, extensive genetic decay has resulted in the human Y chromosome losing 97% of its ancestral genes while gene content and order remain highly conserved on the X chromosome. Five 'stratification' events, most likely inversions, reduced the Y chromosome's ability to recombine with the X chromosome across the majority of its length and subjected its genes to the erosive forces associated with reduced recombination. The remaining functional genes are ubiquitously expressed, functionally coherent, dosage-sensitive genes, or have evolved male-specific functionality. It is unknown, however, whether functional specialization is a degenerative phenomenon unique to sex chromosomes, or if it conveys a potential selective advantage aside from sexual antagonism. We examined the evolution of mammalian orthologs to determine if the selective forces that led to the degeneration of the Y chromosome are unique in the genome. The results of our study suggest these forces are not exclusive to the Y chromosome, and chromosomal degeneration may have occurred throughout our evolutionary history. The reduction of recombination could additionally result in rapid fixation through isolation of specialized functions resulting in a cost-benefit relationship during times of intense selective pressure.	0
Bloom syndrome is characterized by severe pre- and postnatal growth deficiency, immune abnormalities, sensitivity to sunlight, insulin resistance, and a high risk for many cancers that occur at an early age. The diagnosis is established on characteristic clinical features and/or presence of biallelic pathogenic variants in the BLM gene. An increased frequency of sister-chromatid exchanges is also observed and can be useful to diagnose BS patients with weak or no clinical features. For the first time, we derived an induced pluripotent cell line from a Bloom syndrome patient retaining the specific sister-chromatid exchange feature as a unique tool to model the pathology.	0
Ganglioside GM3 synthase is a key enzyme involved in the biosynthesis of gangliosides. GM3 synthase deficiency (GM3D) causes an absence of GM3 and all downstream biosynthetic derivatives. The affected individuals manifest with severe irritability, intractable seizures, and profound intellectual disability. The current study is to assess the effects of an oral ganglioside supplement to patients with GM3D, particularly on their growth and development during early childhood. A total of 13 young children, 11 of them under 40 months old, received oral ganglioside supplement through a dairy product enriched in gangliosides, for an average of 34 months. Clinical improvements were observed in most children soon after the supplement was initiated. Significantly improved growth and development were documented in these subjects as average percentiles for weight, height, and occipitofrontal circumference increased in 1-2 months. Three children with initial microcephaly demonstrated significant catch-up head growth and became normocephalic. We also illustrated brief improvements in developmental and cognitive scores, particularly in communication and socialization domains through Vineland-II. However, all improvements seemed transient and gradually phased out after 12 months of supplementation. Gangliosides GM1 and GM3, although measureable in plasma during the study, were not significantly changed with ganglioside supplementation for up to 30 months. We speculate that the downstream metabolism of ganglioside biosynthesis is fairly active and the potential need for gangliosides in the human body is likely substantial. As we search for new effective therapies for GM3D, approaches to reestablish endogenous ganglioside supplies in the affected individuals should be considered.	0
Sea-blue histiocytosis is one of the six types of Niemann-Pick disease. It is characterized by childhood onset of hepatosplenomegaly, lack of neurological involvement and diminished sphingomyelinase activity. Pulmonary system is rarely involved sea-blue histiocytosis. In this paper, we present a 39-years-old male who had previously diagnosed as sea-blue histiocytosis at the age of 15. He was admitted to our clinic due to productive cough, hemoptysis, fever and weight loss. His symptoms did not resolve with the antibiotic treatment and further investigations revealed pulmonary involvement of sea-blue histiocytosis. After diagnostic bronchoalveolar lavage, his symptoms were improved, interestingly. This rare entity was discussed with literature survey.	0
For many patients with atrial fibrillation, ventricular rate control with atrioventricular (AV) nodal blockers is considered first-line therapy, although response to treatment is highly variable. Using an extreme phenotype of failure of rate control necessitating AV nodal ablation and pacemaker implantation, we conducted a genome-wide association study (GWAS) to identify genomic modulators of rate control therapy. Cases included 95 patients who failed rate control therapy. Controls (n = 190) achieved adequate rate control therapy with ≤2 AV nodal blockers using a conventional clinical definition. Genotyping was performed on the Illumina 610-Quad platform, and results were imputed to the 1000 Genomes reference haplotypes. A total of 554,041 single-nucleotide polymorphisms (SNPs) met criteria for minor allele frequency (>0.01), call rate (>95%), and quality control, and 6,055,224 SNPs were available after imputation. No SNP reached the canonical threshold for significance for GWAS of p <5 × 10(-8). Sixty-three SNPs with p <10(-5) at 6 genomic loci were genotyped in a validation cohort of 130 cases and 157 controls. These included 6q24.3 (near SAMD5/SASH1, p = 9.36 × 10(-8)), 4q12 (IGFBP7, p = 1.75 × 10(-7)), 6q22.33 (C6orf174, p = 4.86 × 10(-7)), 3p21.31 (CDCP1, p = 1.18 × 10(-6)), 12p12.1 (SOX5, p = 1.62 × 10(-6)), and 7p11 (LANCL2, p = 6.51 × 10(-6)). However, none of these were significant in the replication cohort or in a meta-analysis of both cohorts. In conclusion, we identified several potentially important genomic modulators of rate control therapy in atrial fibrillation, particularly SOX5, which was previously associated with heart rate at rest and PR interval. However, these failed to reach genome-wide significance.	0
To describe the profile of Enthesitis Related Arthritis' (ERA) patients, in the era of biologic DMARDs (bDMARDs). This retrospective cohort study included patients with ERA monitored on a 3-month schedule for at least 1 year. Their metric assessment included the disease status and damage by applying the contemporary tools clinical-Juvenile Arthritis Disease Activity Score (c-JADAS), Juvenile Spondyloarthritis Disease Activity Index (JSpADA), clinical remission (CR) on/off medication and Juvenile Arthritis Damage Index (JADI). 43 patients (males 26) were enrolled, with a mean disease onset of 10.75 years. Median lag time from diagnosis to bDMARDs was 8.5 months. Patients with sacroiliitis received earlier bDMARDs (hazard ratio, HR 3.26). 36/43 patients achieved CR on medication (median time 11 months), which was correlated with compliance (HR: 3.62). The percentage of CR in patients with or without sacroiliitis was 35% and 63% respectively (p = 0.02). Twenty patients (47%) experienced a flare following CR (75%). The median flare-free survival following CR on/off medication was 42 and 34 months, respectively. At the last evaluation, both median baseline cJADAS and JSpADA dropped to 0, 13/43 patients had a persistent disease activity, while 17/43 and 13/43 patients were in CR on/off medication, respectively. The median patient percentage of CR was 54% and no patient had a JADI > 0. Increased lag time to bDMARDs was associated with increased CR (Odds ratio: 1.48). Early administration of bDMARDs and compliance improved long-term outcome of ERA. Sacroiliitis was a negative prognostic factor with an increased need for bDMARDs and diminished rates of CR.	0
A 3-month-old female Maltese puppy was hospitalized with persistent diarrhea in a local veterinary clinic. Blood chemistry and hematology profile were analyzed and fecal smear was examined. Diarrheal stools were examined in a diagnostic laboratory, using multiplex real-time polymerase chain reaction (PCR) against 23 diarrheal pathogens. Sequence analysis was performed using nested PCR amplicon of 18S ribosomal RNA. Coccidian oocysts were identified in the fecal smear. Although multiplex real-time PCR was positive for Cyclospora cayetanensis, the final diagnosis was Cystoisospora ohioensis infection, confirmed by phylogenetic analysis of 18S rRNA. To our knowledge, this the first case report of C. ohioensis in Korea, using microscopic examination and phylogenetic analysis.	0
Gorlin-Chaudhry-Moss syndrome (GCMS) is a rare disorder consisting of craniofacial dysostosis, hypertrichosis, underdeveloped genitalia, and ocular and dental anomalies. Recently, GCMS has been reclassified together with Fontaine syndrome as Fontaine progeroid syndrome (FPS), after a common genetic basis was found. It was previously thought that GCMS/FPS was not associated with aortopathy, but in recent years 3 patients with aortic disease have been described. We describe the fourth case, who is the oldest patient with GCMS/FPS reported in the medical literature: a 45-year-old patient who presented with acute aortic dissection. We therefore recommend screening patients previously diagnosed with GCMS/FPS for aortic pathology to aid early detection and avoid patient presentation in an acute setting.	0
BACKGROUND:Progressive encephalopathy, hypsarrhythmia and optic atrophy (PEHO) has been described as a clinically distinct syndrome. It has been postulated that it is an autosomal recessive condition. However, the aetiology is poorly understood, and the genetic basis of the condition has not been fully elucidated. Our objective was to discover if PEHO syndrome is a single gene disorder. METHOD:Children with PEHO and PEHO-like syndrome were recruited. Clinical, neurological and dysmorphic features were recorded; EEG reports and MRI scans were reviewed. Where possible, exome sequencing was carried out first to seek mutations in known early infantile developmental and epileptic encephalopathy (DEE) genes and then to use an agnostic approach to seek novel candidate genes. We sought intra-interfamilial phenotypic correlations and genotype-phenotype correlations when pathological mutations were identified. RESULTS:Twenty-three children were recruited from a diverse ethnic background, 19 of which were suitable for inclusion. They were similar in many of the core and the supporting features of PEHO, but there was significant variation in MRI and ophthalmological findings, even between siblings with the same mutation. A pathogenic genetic variant was identified in 15 of the 19 children. One further girl's DNA failed analysis, but her two affected sisters shared confirmed variants. Pathogenic variants were identified in seven different genes. CONCLUSIONS:We found significant clinical and genetic heterogeneity. Given the intrafamily variation demonstrated, we question whether the diagnostic criteria for MRI and ophthalmic findings should be altered. We also question whether PEHO and PEHO-like syndrome represent differing points on a clinical spectrum of the DEE. We conclude that PEHO and PEHO-like syndrome are clinically and genetically diverse entities-and are phenotypic endpoints of many severe genetic encephalopathies.	0
Benign recurrent intrahepatic cholestasis represents a rare class of autosomal recessive chronic cholestasis disorders, usually presenting with recurrent episodes of intense pruritus and jaundice. We report a 27-year-old woman presenting with benign recurrent intrahepatic cholestasis type 2 due to heterozygosity in ABCB11. Interestingly, she was also found to be heterozygous in cystic fibrosis transmembrane conductance regulator, NPHP4, and A1ATD (SERPINA1), which may explain the severe nature of her disease expression because heterozygosity in each of these genes has been associated with cholestasis. Finally, she exhibited a response to steroids that may have implications for future treatment of bile salt export pump-related diseases.	0
OBJECTIVE:Since 2010, we have mainly performed surgical treatment following radiotherapy and concomitant intraarterial cisplatin (RADPLAT) for locally advanced maxillary sinus cancer (MSC). The present study investigated treatment results and pathological evaluations following RADPLAT for MSC. METHODS:Pathological response to RADPLAT was evaluated using surgical specimens. Pathological response was graded in accordance with the classification method that Shimosato reported in 1964, as grade V (no tumor cells remain in any of section), grade IV, III, II, I, and 0. Five-year overall and disease-specific survival rates were estimated using Kaplan-Meier methods. Univariate analyses of correlations between recurrence of MSC and other clinicopathological parameters were evaluated using the chi-square or Fisher's exact tests. RESULT:19 patients were enrolled in this study, 5 patients showed T3 disease and 14 had T4 disease. One patient demonstrated local recurrence and 3 patients experienced distant metastasis. The 5-year overall survival rate was 67.1% (T3, 50.0%; T4, 69.6%), and the 5-year disease-specific survival rate was 81.9% (T3, 100%; T4, 76.0%). Histological response was categorized as grade V in 9 cases. No significant risk factors for residual cancer were identified. CONCLUSION:Our study suggested that RADPLAT not only has a low risk of side effects, but also could represent an effective procedure for locally advanced MSC by pathological evaluation. Increasing the therapeutic intensity of RADPLAT might provide an effective modality to avoid highly invasive surgery.	0
Two new cases with the Tel-Hashomer camptodactyly syndrome have been ascertained in an Indian family. This report emphasizes the autosomal recessive nature of disease and documents an additional feature of hirsuitism not previously described. The gene for Tel-Hashomer camptodactyly syndrome is present in all populations around the world.	0
L-carnitine transports fatty acids into the mitochondria for oxidation and also buffers excess acetyl-CoA away from the mitochondria. Thus, L-carnitine may play a key role in maintaining liver function, by its effect on lipid metabolism. The importance of L-carnitine in liver health is supported by the observation that patients with primary carnitine deficiency (PCD) can present with fatty liver disease, which could be due to low levels of intrahepatic and serum levels of L-carnitine. Furthermore, studies suggest that supplementation with L-carnitine may reduce liver fat and the liver enzymes alanine aminotransferase (ALT) and aspartate transaminase (AST) in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). L-carnitine has also been shown to improve insulin sensitivity and elevate pyruvate dehydrogenase (PDH) flux. Studies that show reduced intrahepatic fat and reduced liver enzymes after L-carnitine supplementation suggest that L-carnitine might be a promising supplement to improve or delay the progression of NAFLD.	0
Many genes, including odd-skipped related 1 (Osr1), are involved in regulation of mammalian kidney development. We describe here a new recessive mutation (kidney adysplasia and variable hydronephrosis, kavh) in the mouse that leads to downregulation of Osr1 transcript, causing several kidney defects: agenesis, hypoplasia, and hydronephrosis with variable age of onset. The mutation is closely associated with a reciprocal translocation, T(12;17)4Rk, whose Chromosome 12 breakpoint is upstream from Osr1. The kavh/kavh mutant provides a model to study kidney development and test therapies for hydronephrosis.	0
The SLC30A2 gene encodes zinc transporter ZnT2, which is indispensable for the transport of zinc into the breast milk in the mammary gland. Transient neonatal zinc deficiency (TNZD) is caused by a mutation in the maternal SLC30A2 gene and has a clinical presentation similar to that of acrodermatitis enteropathica (AE). We described the case of a Chinese infant who presented with AE-like lesions 10 days after birth. Sanger sequencing of the AE-causing gene SLC39A4 revealed no mutations in genomic DNA from the infant, excluding the possibility of AE. Detection of the mother's breast milk showed a significantly lower zinc level. Thus, SLC30A2 sequencing was performed on her genomic DNA and a previously unreported homozygous c.262G > A (p.E88K) mutation was disclosed. Functional analysis suggested the novel mutation could lead to a strong disruption of zinc secretion, which indicated a complete loss of function in the ZnT2 protein. We finally diagnosed the infant with TNZD. To the best of our knowledge, this is the first case of TNZD caused by a homozygous mutation in the maternal SLC30A2 gene. Compared to the heterozygous condition, a homozygous mutation seems to result in a more significant decrease in zinc secretion and a more rapid onset of TNZD.	0
BACKGROUND:The notable discrepancy between platelet count and bleeding manifestations in immune thrombocytopenia (ITP) patients with acquired Glanzmann thrombasthenia (GT) has been described. OBJECTIVES:We aimed to examine the mechanisms responsible for thrombocytopenia and the bleeding phenotype in a patient with acquired GT. PATIENT, METHODS, AND RESULTS:A patient with primary ITP underwent splenectomy due to steroid intolerance. Despite platelet count normalization, bleeding continued. Platelet aggregometry was abnormal with all agonists except for ristocetin. Flow cytometry demonstrated the presence of antiplatelet antibody, which caused dose-dependent inhibition of fibrinogen and PAC-1 binding, induction of neuraminidase-1 expression as well as platelet desialylation in donor platelets. Indirect monoclonal antibody immobilization of platelet specific antigen assay (MAIPA) confirmed specificity to αIIb β3 only, corroborated by binding on Chinese hamster ovary (CHO) cells expressing human glycoprotein αIIb β3 but not GP Ib/IX. Both desialylation and neuraminidase expression were observed with plasma adsorbed on Ib/IX CHO cells and with the immunoglobulin G (IgG) fraction. Desialylation was inhibited in the presence of anti-Fc-gamma receptor IIa (FcγRIIa) antibody. A nonobese diabetic/severe combined immunodeficient ITP murine model was established, which showed rapid hepatic donor platelet clearance in the presence of patient IgG. Treatment of mice with the neuraminidase inhibitor oseltamivir significantly reduced antibody-induced platelet destruction. CONCLUSIONS:We report the first case of a patient with acquired GT due to ITP with FcγRIIa mediated platelet desialylation, independent of platelet activation. Treatment with neuraminidase inhibitor may prevent platelet clearance by anti-αIIb β3 antibodies.	0
To highlight the clinical features and diagnosis of cranio-osteoarthropathy, an extremely rare disease.Case report and literature review.A 2.3-year-old child presented with mild swelling of his distal phalanges at the age of 5 months that became pronounced gradually. His parents were consanguineous and his 14-year-old sister had albinism. Physical examination showed normal height and weight. A mild prominent nose, patent cranial sutures and anterior and posterior fontanel, clubbing of the digits without cyanosis, finger joint laxity, large nails, and mild knock-knee were noted. Radiographs showed wormian bones, patent cranial sutures, anterior and posterior fontanels, periostosis and wide diaphyses of long bone, abnormal curvature tibia.Cranio-osteoarthropathy is an extremely rare occurrence and may be an autosomal-recessive inheritance. This diagnosis should be considered while a patient presented digital clubbing, periosteal new bone formation and decreased neurocranium ossification.	0
BACKGROUND:Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). OBJECTIVE:To identify pathogenic mutation in the Korean patients with CMT and distal hereditary motor neuronopathy (dHMN). METHODS:We screened AARS1 mutations in 373 unrelated CMT families including 318 axonal CMT, 36 dHMN, and 19 intermediate CMT (Int-CMT) who were negative for 17p12 (PMP22) duplication or deletion using whole exome sequencing and targeted sequencing of CMT-related genes. RESULTS:This study identified an early onset Int-CMT family harboring an AARS1 p.Arg329His mutation which was previously reported as pathogenic in French and Australian families. The mutation was located in the highly conserved tRNA binding domain and several in silico analyses suggested pathogenic prediction of the mutations. The patients harboring p.Arg329His showed clinically similar phenotypes of the early onset and electrophysiological intermediate type as those in Australian patients with same mutation. We also found a novel c.2564A>G (p.Gln855Arg) in a CMT2 patient, but its' pathogenic role was uncertain (variant of uncertain significance). CONCLUSION:This study suggests that the frequency of the AARS1 mutations appears to be quite low in Korean CMT. This is the first report of the AARS1 mutation in Korean CMT patients and will be helpful for the exact molecular diagnosis and treatment of Int-CMT patients.	0
BACKGROUND:Rituximab (RTX) provides significant clinical benefits in active rheumatoid arthritis (RA) patients with inadequate response to DMARDs and anti-TNF. There is no data regarding efficacy of RTX in seropositive Palindromic Rheumatism (PR), a forerunner of RA. AIM:To determine the efficacy and safety of RTX treatment in active PR patients exhibiting inadequate response to conventional synthetic DMARDs (csDMARDs). METHODS:The retrospective study, over a period of 3 years, included seropositive (RF ± antiCCP) PR patients with inadequate control of PR (> 4 attacks per months) despite combination csDMARDs and were treated with RTX. All the patients were treated with an initial dose of 500 mg RTX and later with a second infusion after 2 weeks' period in those who did not achieve adequate/ complete disease control. Patients were continued on csDMARDS and retreated with RTX on relapse of symptoms. RESULTS:Thirty-three seropositive PR patients with a mean age of 48.15 ± 14.2 years, mean disease duration of 68.4 ± 68.2 months, mean follow up period of 24.3 ± 10.8 months, were treated with RTX. 88% patients were on combination DMARDS and 79% patients were females. All patient achieved rapid and complete control of palindromic attacks with RTX. Fifteen patients had a relapse after a mean duration of 10.4 ± 5.5 months and needed repeat RTX infusions following which remission was achieved. None of the patients progressed to RA till the end of the follow-up. No serious adverse effects were recorded. CONCLUSION:RTX treatment could be effective in achieving disease control in active palindromic rheumatism not responding to csDMARDs. KEY POINTS:• PR is thought to be a forerunner of RA and rituximab (RTX) has been found to be effective in RA. • Our study supports the hypothesis that B cells play an important role in the pathophysiology of PR and that the combination (RTX+ conventional drugs) can prevent the disease evolution into RA. • This 3-year retrospective study showed that rituximab was found to be effective in those who responded poorly to conventional drugs and remission was achieved in all patients. • Although it is a rare disease, we see palindromic rheumatism patients in India more often. As the symptoms are very debilitating in these patients, in those patients, not controlled on conventional drugs, rituximab offers newer promise in controlling the attacks and prevents further progression to RA.	0
A previously independent 66-year-old right-handed male presented with right-sided weakness, preferring the lower-extremities with additional impaired gait and dysarthria for 1-day duration. Imaging found a large left hemispheric anterior cerebral artery ischemic infarction with multiple lacunar infarcts. He exhibited frontal, callosal, and posterior variants of Alien Hand Syndrome which impeded activities of daily living. Although limited in evidence, a trial of clonazepam was initiated based on previous case reports describing suspected efficacy. Botulinum toxin A was not used given the patient's immediate need and limited hospital length of stay. Right upper extremity constricting therapies improved intermanual conflict and spontaneous grasping and levitation (arm elevation in retroflexion) activity; however, concomitant left upper extremity motor apraxia complicated task-oriented activities. The combination of pharmaceutical and therapeutic interventions improved the patient's quality of life as assessed by clinical observation, functional independence measures from 41 to 57, and patient-reporting. This case report aims to increase awareness of a potential barrier to rehabilitation of a debilitating and rare condition and to discuss current assessment tools and treatment options supported by available evidence.	0
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder caused by defects in the NADPH oxidase complex. Mutations in NCF2 encoding the cytosolic factor p67phox result in autosomal recessive CGD. We describe three patients with a novel c.855G>C NCF2 mutation presenting with diverse clinical phenotype. Two siblings were heterozygous for the novel mutation and for a previously described exon 8-9 duplication, while a third unrelated patient was homozygous for the novel mutation. Mutation pathogenicity was confirmed by abnormal DHR123 assay and absent p67phox production and by sequencing of cDNA which showed abnormal RNA splicing. Clinically, the homozygous patient presented with suspected early onset interstitial lung disease and NCF2 mutation was found on genetic testing performed in search for surfactant-related defects. The two siblings also had variable presentation with one having history of severe pneumonia, lymphadenitis, and recurrent skin abscesses and the other presenting in his 30s with discoid lupus erythematosus and without significant infectious history. We therefore identified a novel pathogenic NCF2 mutation causing diverse and unusual clinical phenotype.	0
BACKGROUND:Genomic variations have shown an ethnic-specific pattern within various cohorts. Genetic variants of KCNQ1, KCNH2, SCN5A and KCNE1 causing LQT syndrome have been described in many populations. In this article the spectrum of variants of these genes is presented in Iranian patients. METHODS:102 unrelated individuals diagnosed with LQT were enrolled in this study. Clinical and electrocardiogram (ECG) data of 95 patients were documented, and analyzed by expert pediatric cardiologists. Coding regions and exon-intron boundaries were amplified and sequenced. Segregation analysis was done for novel variants as well as in silico analyses. RESULTS:Sixty nine of 95 cases (73%) had Schwartz score of ≥3.5. The causal variants were found in 31 cases (9 novel variants). 21 patients had KCNQ1 (LQTS1) of which15 patients were homozygous for KCNQ1 variants, 9 of these patients (29%) had a Jervell and Lange-Nielsen phenotype. 4 patients had KCNH2 (LQTS2) variants, 7 cases had SCN5A had heterozygous variants, and 2 cases had heterozygous variants in KCNE1 (LQTS5). 19 variants were missense, 3 were nonsense, and 3 were frameshifts. There was one large deletion and 3 intronic variants. CONCLUSION:The yield of genetic testing and the genotype profile of LQTS patients in Iran is different from reports elsewhere, with lower overall yield and with 48% having homozygous states.	0
Dystroglycan (DG) is a cell adhesion complex composed by two subunits, the highly glycosylated α-DG and the transmembrane β-DG. In skeletal muscle, DG is involved in dystroglycanopathies, a group of heterogeneous muscular dystrophies characterized by a reduced glycosylation of α-DG. The genes mutated in secondary dystroglycanopathies are involved in the synthesis of O-mannosyl glycans and in the O-mannosylation pathway of α-DG. Mutations in the DG gene (DAG1), causing primary dystroglycanopathies, destabilize the α-DG core protein influencing its binding to modifying enzymes. Recently, a homozygous mutation (p.Cys699Phe) hitting the β-DG ectodomain has been identified in a patient affected by muscle-eye-brain disease with multicystic leucodystrophy, suggesting that other mechanisms than hypoglycosylation of α-DG could be implicated in dystroglycanopathies. Herein, we have characterized the DG murine mutant counterpart by transfection in cellular systems and high-resolution microscopy. We observed that the mutation alters the DG processing leading to retention of its uncleaved precursor in the endoplasmic reticulum. Accordingly, small-angle X-ray scattering data, corroborated by biochemical and biophysical experiments, revealed that the mutation provokes an alteration in the β-DG ectodomain overall folding, resulting in disulfide-associated oligomerization. Our data provide the first evidence of a novel intracellular mechanism, featuring an anomalous endoplasmic reticulum-retention, underlying dystroglycanopathy.	0
A 33-year-old man presented to us with slowly progressive dyspnea. At the physical examination we found pleural effusion on the right side, lymph edema of the left lower limb and foot and blotchy map-like skin changes. The pleural puncture revealed a chylous effusion. In whole body MRI we saw the pleural effusion on the right, an increase in lymph vessels in the pelvis and paraaortic, and prominent chylous vessels. There was no bone involvement. The abdominal thoracic duct was enlarged by up to 3 mm. We diagnosed a general lymphatic anomaly (GLA) - lymphangiomatosis. GLA is a rare disease of unknown origin with dysplasia of the lymphatic system. The thoracic manifestation is often the development of chylous pleural effusions. However, many other organs can also be involved. Therapy includes in most cases symptomatic relief and the attempt to slow the progression of the disease.	0
Introduction:Pre-axial foot polydactyly has been termed as mirror foot, otherwise known as diplopodia. Association of a hypoplastic trapezoid shaped tibia makes the condition extremely uncommon. Whatever limited literature is available, most of it is focused on the preliminary reconstruction of deformity which again may not be feasible in late presentation. Case Report:We present a 17-year-old girl having mirror foot with dysplastic trapezoid shaped tibia. She had mild equinovarus deformity of the right foot with three pre-axial extra digits that represent a mirror foot. There was also a gross shortening of the right leg with 20° fixed flexion deformity of the knee, but she could walk around with limited disability. Her chief complaint was difficulty in outdoor ambulation and poor cosmesis of the foot. Limb reconstruction may not have a predictable outcome with so much of shortening and she was also reluctant for amputation. A course of therapy was given with a treatment objective of improvement of knee flexion deformity and quadriceps control. She was fitted with an extension prosthesis which accommodates the deformed foot and also corrected the limb length discrepancy. Conclusion:Mirror foot with dysplastic tibia reported at an adolescent age may not be benefitted from surgical reconstruction. Functional rehabilitation is better than an anatomic correction in case of late presentation.	0
We report a case of a 16-year-old adolescent girl who presented to the pediatric emergency department for worsening abdominal pain and vomiting and had significant weight loss over the previous 4 months. Point-of-care ultrasound was used to assess for signs of superior mesenteric artery syndrome.	0
BACKGROUND: The prevalence of acquired angioedema (AAE) is hitherto unknown and, to date, less than 200 patients have been reported worldwide. AAE is associated with lymphoproliferative conditions and autoantibodies against C1 inhibitor (C1INH). Rituximab (RTX) is increasingly used in the treatment of AAE patients. METHODS: A nationwide study of AAE patients was performed in Denmark. Clinical features, associated disorders, treatments and outcomes were registered. RESULTS: Eight AAE patients were identified. The diagnostic delay was on average 1 year and 8 months. Patients were treated with C1INH concentrate or icatibant on demand. Six patients were diagnosed with a clonal B-cell disorder during follow-up, on average 2.5 years after the first swelling. Two patients had monoclonal B-cell lymphocytosis (MBL). Two patients received RTX. CONCLUSIONS: AAE is a rare condition occurring in less than 10% of patients with C1INH deficiency in Denmark. AAE is highly associated with haematologic disorders, and we recommend yearly follow-up visits with clinical examination and blood tests including flow cytometry to diagnose B-cell conditions at an early stage. We report 2 patients with AAE and associated MBL, which is a benign expansion of clonal B lymphocytes. MBL can be the precursor of chronic lymphocytic leukaemia or is associated with non-Hodgkin's lymphoma. If angioedema is poorly controlled with standard treatment regimens, we suggest treatment of the associated haematologic disorder. Based on a review of the literature and our own data, we recommend therapy with RTX, especially in patients with anti-C1INH autoantibodies.	1
Background:Endocardial Fibroelastosis is diffuse, accentuated proliferation of ventricular endocardium causing a rare form of restrictive cardiomyopathy in both children and adults. It is an incompletely understood cause of heart failure predominantly in Sub-Saharan Africa associated with high morbidity and mortality. Atrial fibrillation and thrombus formation are common accompanying complications and portend a poor prognosis. Due to rarity of the condition in the developed countries and lack of evidence based options, the optimal strategy for anticoagulation is unclear. Case presentation:Herein, we describe a relatively asymptomatic patient with endocardial fibroelastosis who has been found to have atrial fibrillation and a large thrombus in the right atrium. Currently, there is no evidence-based strategy in the management of endocardial fibroelastosis-associated intracardiac thrombus. This case report illustrates a scenario by which the use of apixaban potentially benefited or prevented the thrombus formation compared with warfarin as demonstrated by imaging findings. Conclusions:The patients with endocardial fibroelastosis are at risk of developing intracardiac thrombus due to sticky substrate lining cardiac chambers while being relatively asymptomatic. No directed therapy is known for the management of heart failure and any complications of subsequent arrhythmias. The general recommendations follow those of same conditions in other hosts. Novel oral anticoagulant agents can be considered in the treatment of atrial thrombus in the appropriate settings.	0
PURPOSE:Schnyder corneal dystrophy (SCD) is a rare inherited disease that leads to gradual vision loss by the deposition of lipids in the corneal stroma. The aim of this study is to report a novel pathogenic variant in the UBIAD1 gene and present clinical and molecular findings in Polish patients with SCD. METHODS:Individuals (n = 37) originating from four Polish SCD families were subjected for a complete ophthalmological check-up and genetic testing. Corneal changes were visualized by slit-lamp examination, anterior segment optical coherent tomography (AS-OCT), and in vivo confocal microscopy (IVCM). RESULTS:In a proband with primarily mild SCD that progressed rapidly at the end of the fifth decade of life, a novel missense pathogenic variant in UBIAD1 (p.Thr120Arg) was identified. The other studied SCD family represents the second family reported worldwide with the UBIAD1 p.Asp112Asn variant. SCD in the remaining two families resulted from a frequently identified p.Asn102Ser pathogenic variant. All affected subjects presented a crystalline form of SCD. The severity of corneal changes was age-dependent, and their morphology and localization are described in detail. CONCLUSION:The novel p.Thr120Arg is the fourth SCD-causing variant lying within the FARM motif of the UBIAD1 protein, which underlines a high importance of this motif for SCD pathogenesis. The current study provides independent evidence for the pathogenic potential of UBIAD1 p.Asp112Asn and new information useful for clinicians.	0
SUMMARYTaenia solium neurocysticercosis (NCC) is endemic in most of the world and contributes significantly to the burden of epilepsy and other neurological morbidity. Also present in developed countries because of immigration and travel, NCC is one of few diseases targeted for eradication. This paper reviews all aspects of its life cycle (taeniasis, porcine cysticercosis, human cysticercosis), with a focus on recent advances in its diagnosis, management, and control. Diagnosis of taeniasis is limited by poor availability of immunological or molecular assays. Diagnosis of NCC rests on neuroimaging findings, supported by serological assays. The treatment of NCC should be approached in the context of the particular type of infection (intra- or extraparenchymal; number, location, and stage of lesions) and has evolved toward combined symptomatic and antiparasitic management, with particular attention to modulating inflammation. Research on NCC and particularly the use of recently available genome data and animal models of infection should help to elucidate mechanisms of brain inflammation, damage, and epileptogenesis.	0
PURPOSE:To report the clinical course and high resolution images of autosomal recessive retinitis pigmentosa (RP) associated with a variant of the RP1 gene (c.4052_4053ins328/p.Tyr1352Alafs*9; m1), a high frequency founder variant in Japanese RP patients. STUDY DESIGN:Retrospective case series. METHODS:Nine patients from 5 unrelated Japanese families were studied. Five patients had the m1 variant homozygously, and 4 patients had the m1 variant compound heterozygously with another frameshift variant (c.4196delG/p.Cys1399Leufs*5). Ophthalmic examinations including adaptive optics (AO) fundus imaging were performed periodically. RESULTS:The fundus photographs, fundus autofluorescence (FAF) images, and optical coherence tomographic (OCT) images indicated severe retinal degeneration in all the patients involving the macula even at a young age (20 s). The areas of surviving photoreceptors in the central macula were seen as hyper-autofluorescent regions in the FAF images and preserved outer retinal structure in the OCT images; they were identifiable in the AO fundus images in 8 eyes. The borders of the surviving photoreceptor areas were surrounded by hyporeflective clumps, presumably containing melanin, and the size of these areas decreased progressively during the 4-year follow-up period. The disappearance of the surviving photoreceptor areas was associated with complete blindness. CONCLUSION:Patients with RP associated with the m1 variant have a progressive and severe retinal degeneration that begins at an early age. Monitoring the surviving photoreceptor areas by AO fundus imaging can provide a more precise pathological record of retinal degeneration.	0
PURPOSE:To report the 30-months' course of macular dystrophy in a patient with genetically confirmed spinocerebellar ataxia type1 (SCA1). METHODS:Detailed ophthalmological examinations including best-corrected visual acuity (BCVA), perimetry, multimodal fundus imaging, and electrophysiological recordings were performed on a 52-year-old woman with SCA1. The number of CAG sequence repeats of the candidate gene was verified. RESULTS:The baseline decimal BCVA was 0.2 OD and 0.3 OS. Goldman perimetry showed relative central scotomas and slight enlargements of Mariotte blind spot bilaterally. Ophthalmoscopy revealed no abnormalities in the macula and optic disk. Fundus autofluorescence (FAF) showed a circular hyperautofluorescence and round-shaped hypoautofluorescence in the macula. Optical coherence tomography (OCT) showed a loss of the interdigitation zone and ellipsoid zone (EZ) in the macula. Full-field scotopic and photopic Full-field electroretinograms (ERGs) were normal, and multifocal ERGs were decreased in the central area. After 30 months, the BCVA had not changed, but the FAF showed a spark-like hypoautofluorescence in the macula. The abnormal area of the EZ had expanded toward the periphery, and the rate of EZ loss was 199.7%/year OD and 206.8%/year OS. Genetic examinations revealed an increase in the number of heterozygous CAG repeats in the ATXN1 gene, and the CAG repeat number of the mutant allele ranged from 43 to 48. CONCLUSIONS:The full-field scotopic and photopic ERGs were normal. The mfERGs were significantly smaller in the central region. OCT demonstrated bilateral photoreceptor atrophy in the macula, and the rate of EZ loss was more rapid than in other macular dystrophies. Spark-like hypoautofluorescence appeared during the course of the disease process which might be a specific feature of SCA1-related retinopathy.	0
The association between umbilical cord ulceration and intestinal atresia has been previously established. Umbilical cord ulceration is a seemingly rare, potentially life threatening complication of intestinal atresia. The exact etiological mechanism is unknown and recent literature indicates more intensive prenatal monitoring may alter fetal outcome. In this paper we will review the previously reported cases of intestinal atresia complicated by umbilical cord ulceration and comment on the pathophysiological mechanism of umbilical cord ulceration, with emphasis on the unique location of the atresia at the gastroduodenal junction in our case.	0
PURPOSE OF REVIEW:The purpose was to review the most recent literature on neuroimaging in the Kleine-Levin syndrome (KLS). We aimed to investigate if frontotemporal and thalamic dysfunction are key KLS signatures, and if recent research indicates other brain networks of interest that elucidate KLS symptomatology and aetiology. RECENT FINDINGS:In a comprehensive literature search, we found 12 original articles published 2013-2018. Most studies report deviations related to cerebral perfusion, glucose metabolism, or blood-oxygen-level-dependent responses in frontotemporal areas and/or the thalamus. Studies also report dysfunction in the temporoparietal junction and the oculomotor network that also were related to clinical parameters. We discuss these findings based on recent research on thalamocortical networks and brain stem white matter tracts. The hypothesis of frontotemporal and thalamic involvement in KLS was confirmed, and additional findings in the temporoparietal junction and the oculomotor system suggest a broader network involvement, which can be investigated by future high-resolution and multimodal imaging.	0
Hereditary gingival fibromatosis (HGF) is a rare genetic condition characterized by slow and progressive gingival enlargement. The gingival overgrowth often delays teeth eruption and may cause serious functional and aesthetic problems. We reported a case of a 10-year-old female child presenting a generalized gingival enlargement covering almost all the maxillary and mandibular teeth and resulted in problems for swallowing, speaking, and poor aesthetics. An incisional biopsy was performed and revealed a hypocellular and hypovascular dense collagenous tissue covered by squamous epithelium exhibiting acanthosis and elongated rete ridges. The diagnosis was HGF. The treatment instituted was an association of gingivectomy with a rigorous program of oral hygiene and follow-up. Herein, we describe a rare non-syndromic case of generalized HGF, including clinical and microscopical features, as well as highlighting the importance of correct diagnosis of this genetic condition.	0
Since its cloning more than 30 years ago, the thyrotropin receptor (TSHR) has emerged as a pivotal player in thyroid physiology and pathophysiology. In particular, hyperthyroidism due to autoimmune disease or thyroid autonomy is linked with TSHR activation via autoantibodies or mutations respectively. This review summarises clinical aspects of constitutive TSH receptor activation by naturally occurring somatic or germline TSHR mutations resulting in TSH-independent thyroid function and cell proliferation.	0
Frontonasal dysplasia is a rare congenital anomaly affecting the eyes, nose and forehead, and occurs sporadically in most of the cases. A 24-year-old woman was referred to our unit at 27 weeks gestation due to the preliminary diagnosis of encephalocele. The sagittal and axial sonography of the fetal face depicted a midline mass measuring 3.8 × 4.2 cm, projecting anteriorly between the fetal orbits and extending from the the upper aspects of the forehead to the nasal bridge, which was consistent with the frontal (anterior) encephalocele. There were prominent hypertelorism and two facial clefts, and the nostrils were extremely separated. Following genetic counseling, the couple requested termination of pregnancy. Fetal pathologic examination confirmed the diagnosis of frontonasal dysplasia and anterior encephalocele with no additional major malformation. The fetal karyotype was normal and no mutation in the ALX1 gene was found, excluding ALX1-related frontonasal dysplasia in the differential diagnosis. Fetuses with neural tube defect may suffer from associated syndromes and disorders, as with our case. The presence of frontonasal dyplasia should be considered when an anterior encephalocele is detected by ultrasonography.	0
Cerebral cavernous malformations (CCMs) are common brain vascular dysplasias that are prone to acute and chronic hemorrhage with significant clinical sequelae. The pathogenesis of recurrent bleeding in CCM is incompletely understood. Here, we show that central nervous system hemorrhage in CCMs is associated with locally elevated expression of the anticoagulant endothelial receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR). TM levels are increased in human CCM lesions, as well as in the plasma of patients with CCMs. In mice, endothelial-specific genetic inactivation of Krit1 (Krit1 ECKO ) or Pdcd10 (Pdcd10 ECKO ), which cause CCM formation, results in increased levels of vascular TM and EPCR, as well as in enhanced generation of activated protein C (APC) on endothelial cells. Increased TM expression is due to upregulation of transcription factors KLF2 and KLF4 consequent to the loss of KRIT1 or PDCD10. Increased TM expression contributes to CCM hemorrhage, because genetic inactivation of 1 or 2 copies of the Thbd gene decreases brain hemorrhage in Pdcd10 ECKO mice. Moreover, administration of blocking antibodies against TM and EPCR significantly reduced CCM hemorrhage in Pdcd10 ECKO mice. Thus, a local increase in the endothelial cofactors that generate anticoagulant APC can contribute to bleeding in CCMs, and plasma soluble TM may represent a biomarker for hemorrhagic risk in CCMs.	0
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. Mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene have been found to cause X-linked dominant CMT type 6 (CMTX6). This study identified the p.R158H PDK3 mutation after screening 67 probable X-linked CMT families. The mutation fully segregated with the phenotype, and genotyping the family indicated the mutation arose on a different haplotype compared with the original Australian CMTX6 family. Results of bisulphite sequencing suggest that methylated deamination of a CpG dinucleotide may cause the recurrent p.R158H mutation. The frequency of the p.R158H PDK3 mutation in Koreans is very rare. Magnetic resonance imaging revealed fatty infiltration involving distal muscles in the lower extremities. In addition, fatty infiltrations were predominantly observed in the soleus muscles, with a lesser extent in tibialis anterior muscles. This differs from demyelinating CMT1A patients and is similar to axonal CMT2A patients. The clinical, neuroimaging, and electrophysiological findings from a second CMTX6 family with the p.R158H PDK3 mutation were similar to the axonal neuropathy reported in the Australian family.	0
Tracheobronchomegaly or Mounier-Kuhn syndrome is a rare disorder characterized by the widening of the trachea and the main bronchi. It is a form of tracheomalacia called 'cartilaginous malacic' and is characterized by deformation of the tracheal cartilages and intrusion of the redundant membranous wall into the lumen of the airway. We present a patient with Mounier-Kuhn syndrome managed like patients with tracheomalacia of other aetiologies-a tracheobronchoplasty with a reconstructed D-shaped trachea and stabilization of the posterior membranous wall by attaching a polypropylene mesh to the posterior membranous wall of the trachea and the main bronchi after a trial period with a tracheobronchial Y-shaped silicone stent.	0
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is associated with mutations in the cardiac ryanodine receptor (RyR2). These result in stress-induced ventricular arrhythmic episodes, with clinical symptoms and prognosis reported more severe in male than female patients. Murine homozygotic RyR2-P2328S (RyR2S/S ) hearts replicate the proarrhythmic CPVT phenotype of abnormal sarcoplasmic reticular Ca2+ leak and disrupted Ca2+ homeostasis. In addition, RyR2S/S hearts show decreased myocardial action potential conduction velocities (CV), all features implicated in arrhythmic trigger and substrate. The present studies explored for independent and interacting effects of RyR2S/S genotype and sex on expression levels of molecular determinants of Ca2+ homeostasis (CASQ2, FKBP12, SERCA2a, NCX1, and CaV 1.2) and CV (NaV 1.5, Connexin (Cx)-43, phosphorylated-Cx43, and TGF-β1) in mice. Expression levels of Ca2+ homeostasis proteins were not altered, hence implicating abnormal RyR2 function alone in disrupted cytosolic Ca2+ homeostasis. Furthermore, altered NaV 1.5, phosphorylated Cx43, and TGF-β1 expression were not implicated in the development of slowed CV. By contrast, decreased Cx43 expression correlated with slowed CV, in female, but not male, RyR2S/S mice. The CV changes may reflect acute actions of the increased cytosolic Ca2+ on NaV 1.5 and Cx43 function.	0
The transcription factor peroxisome proliferator-activated receptor gamma (PPARG) is essential for placental development, and alterations in its expression and/or activity are associated with human placental pathologies such as pre-eclampsia or IUGR. However, the molecular regulation of PPARG in cytotrophoblast differentiation and in the underlying mesenchyme remains poorly understood. Our main goal was to study the impact of mutations in the ligand-binding domain (LBD) of the PPARG gene on cytotrophoblast fusion (PPARGE352Q ) and on fibroblast cell migration (PPARGR262G /PPARGL319X ). Our results showed that, compared to cells with reconstituted PPARGWT , transfection with PPARGE352Q led to significantly lower PPARG activity and lower restoration of trophoblast fusion. Likewise, compared to PPARGWT fibroblasts, PPARGR262G /PPARGL319X fibroblasts demonstrated significantly inhibited cell migration. In conclusion, we report that single missense or nonsense mutations in the LBD of PPARG significantly inhibit cell fusion and migration processes.	0
The aim of this work is to report the distribution of clinical phenomenology, demographic variables, and delay of diagnosis in a cohort of patients with childhood-onset movement disorders. Personally examined patients with childhood-onset movement disorders apart from those with cerebral palsy are reported. A total of 606 patients were included. The majority had tic disorders (346; 57%) followed by dystonia (72; 12%); other movement disorders were less frequent (<5%). Mean onset age of patients with tics was 7.4 years ± 3.8 standard deviation; mean delay of diagnosis was 9.9 ± 11 years. Mean onset age of other movement disorders was 8.6 ± 5.7 years; mean delay of diagnosis was 11.1 ± 12.5 years. Psychogenic movement disorders had a later onset than all other movement disorders (P < 0.01) apart from tremor and "other movement disorders." Dystonias had a longer delay of diagnosis than psychogenic movement disorders (P < 0.038). The diagnostic delay of childhood-onset movement disorders is considerable, indicating that they are probably under-recognized.	0
Hydrolethalus syndrome is a lethal malformation syndrome with a severe brain malformation, most often hydrocephaly and absent midline structures. Other frequent findings are micrognathia, polydactyly, and defective lobation of the lungs. Hydrolethalus syndrome is inherited in an autosomal recessive manner and is caused by a missense mutation in the HYLS1 gene. Here, we report the neuropathologic features of 21 genetically confirmed cases. Typically, 2 separated cerebral hemispheres could be identified, but they lacked midline and olfactory structures and were situated basally with a massive accumulation of cerebrospinal fluid. Temporal and occipital lobes were hypoplastic, and normally developed hippocampi were not found. Primitive thalami and basal ganglia were fused in the midline. A hypothalamic hamartoma was a frequent finding, and brainstem and cerebellum were hypoplastic. Three cases were hydranencephalic, and 1 was anencephalic. A midline "keyhole" defect in the skull base was a constant finding. Histologically, the cortex was dysplastic. This pattern of brain pathology, clearly belonging to the midline patterning defects, seems to be unique for the hydrolethalus syndrome and combines features of disturbed neurulation, prosencephalization, and migration. Despite variation in the clinicopathologic phenotype, all cases in the series carried the same homozygous missense mutation in HYLS1.	0
We herein report a case of a 28-year-old man with generalized lipodystrophy-associated progeroid syndrome treated by leptin replacement. He showed symptoms of generalized lipodystrophy around onset of puberty. His body mass index was 11.9 kg/m2, and he had a short stature, birdlike facies, dental crowding due to micrognathia, partial graying and loss of hair, and a high-pitched voice, all of which are typical features of the progeroid syndrome. Laboratory examinations and abdominal ultrasonography revealed diabetes mellitus, insulin-resistance, dyslipidemia, decreased serum leptin levels (2.2 ng/mL), elevated serum hepatobiliary enzyme levels and fatty liver. Whole exome sequencing revealed de novo heterozygous LMNA p.T10I mutation, indicating generalized lipodystrophy-associated progeroid syndrome, which is a newly identified subtype of atypical progeroid syndrome characterized by severe metabolic abnormalities. Daily injection of metreleptin [1.2 mg (0.04 mg/kg)/day] was started. Metreleptin treatment significantly improved his diabetes from HbA1c 11.0% to 5.4% in six months. It also elevated serum testosterone levels. Elevated serum testosterone levels persisted even 1 year after the initiation of metreleptin treatment. To the best of our knowledge, this is the first Japanese case report of generalized lipodystrophy-associated progeroid syndrome. Furthermore, we evaluated short and long-term effectiveness of leptin replacement on generalized lipodystrophy by monitoring metabolic and endocrine profiles.	0
Objective:To report a case of Fowler's syndrome after oocyte retrieval. Design:Case report. Setting:Tertiary referral center, King Fahad Medical City. Patients:A 23-year-old nulligravida with polycystic ovarian syndrome and primary infertility underwent oocyte retrieval for intracytoplasmic sperm injection (ICSI), and developed Fowler's syndrome (FS). Interventions:Intermittent self-catheterization, insertion of sacral neuromodulator (SNM). Main outcome measures:Restoration of normal voiding. Results:Immediate resolution of patient's symptoms after installation of SNM. Conclusions:Fowler's syndrome, although rare, may occur post routine oocyte retrieval; Successful restoration of voiding and resolution of symptoms is possible with SNM installation in similar patients.	0
Neuro-ichthyotic syndromes are a group of rare genetic diseases mainly associated with perturbations in lipid metabolism, intracellular vesicle trafficking, or glycoprotein synthesis. Here, we report a patient with a neuro-ichthyotic syndrome associated with deleterious mutations in the ALDH1L2 (aldehyde dehydrogenase 1 family member L2) gene encoding for mitochondrial 10-formyltetrahydrofolate dehydrogenase. Using fibroblast culture established from the ALDH1L2-deficient patient, we demonstrated that the enzyme loss impaired mitochondrial function affecting both mitochondrial morphology and the pool of metabolites relevant to β-oxidation of fatty acids. Cells lacking the enzyme had distorted mitochondria, accumulated acylcarnitine derivatives and Krebs cycle intermediates, and had lower ATP and increased ADP/AMP indicative of a low energy index. Re-expression of functional ALDH1L2 enzyme in deficient cells restored the mitochondrial morphology and the metabolic profile of fibroblasts from healthy individuals. Our study underscores the role of ALDH1L2 in the maintenance of mitochondrial integrity and energy balance of the cell, and suggests the loss of the enzyme as the cause of neuro-cutaneous disease.	0
The cardinal virulence factor of human-pathogenic enterohaemorrhagic Escherichia coli (EHEC) is Shiga toxin (Stx), which causes severe extraintestinal complications including kidney failure by damaging renal endothelial cells. In EHEC pathogenesis, the disturbance of the kidney epithelium by Stx becomes increasingly recognised, but how this exactly occurs is unknown. To explore this molecularly, we investigated the Stx receptor content and transcriptomic profile of two human renal epithelial cell lines: highly Stx-sensitive ACHN cells and largely Stx-insensitive Caki-2 cells. Though both lines exhibited the Stx receptor globotriaosylceramide, RNAseq revealed strikingly different transcriptomic responses to an Stx challenge. Using RNAi to silence factors involved in ACHN cells' Stx response, the greatest protection occurred when silencing RAB5A and TRAPPC6B, two host factors that we newly link to Stx trafficking. Silencing these factors alongside YKT6 fully prevented the cytotoxic Stx effect. Overall, our approach reveals novel subcellular targets for potential therapies against Stx-mediated kidney failure.	0
The absence of neuroendocrine (NE) cells in the intestinal mucosa in autoimmune enteropathy (AIE) has been occasionally reported. However, the status of NE cells has not been studied in detail in AIE. Small bowel and colonic biopsies were retrospectively retrieved from 18 AIE patients (26 baseline [18 small bowel and 8 colon]; and 15 follow-up [11 duodenum and 4 colon] biopsies in 11 patients). Thirty-three common variable immunodeficiency (CVID) patients (30 small bowel and 16 colon), 15 inflammatory bowel disease patients (5 duodenum and 10 colon), 13 immunoglobulinA deficiency patients (13 duodenum and 5 colon), and 10 normal controls (5 colon and 5 duodenum) were selected as control groups. Histologic features (villous atrophy, intraepithelial lymphocytosis, acute inflammation, crypt apoptosis, and absence or presence of goblet cells, Paneth cells and plasma cells) were recorded. Chromogranin immunostain was performed and chromogranin-positive NE cells were counted per 10 consecutive, well-oriented crypts. On the basis of the number of chromogranin-positive NE cells, cases were graded as being absent (≤3 NE cells), markedly decreased (≤15), and intact (>15). The NE cell status correlated with histologic features. The median age of 18 AIE patients was 38.5 years (range: 11 to 74 y) and 14 patients were male. Fourteen of 18 (78%) patients showed loss (absent or markedly decreased) of NE cells in the small bowel and/or colon in the baseline biopsies including 12 (of 18) small bowel and 6 (of 8) colon biopsies. Follow-up biopsy was available in 11 patients. Six of 7 (85%) patients who showed loss of NE cells in the baseline biopsies regained NE cells in the follow-up biopsies, and 1 patient continued to show loss of NE cells. Four patients who showed intact NE cells in the baseline remained unchanged in the follow-up. Among the control groups, 3 of 33 (9%) CVID patients showed loss of NE cells. NE cells were not lost in the biopsies of all 15 and 13 patients with inflammatory bowel disease and immunoglobulinA deficiency, respectively, or the 10 normal controls. In all 41 biopsies (26 baseline plus 15 follow-up) with AIE, NE cell loss was significantly associated with increased crypt apoptosis and loss of goblet cells (P=0.001, both) but not with other histologic findings. In conclusion, our study suggests that NE cells may also be the target cells in AIE and commonly lost in the intestinal crypts in AIE, and consequently loss of NE cells can be used as an adjunct histologic feature for diagnosis of AIE.	0
Congenital hypothyroidism (CH) occurs in approximately 1:2,000 to 1:4,000 newborns. The clinical manifestations are often subtle or not present at birth. This likely is due to trans-placental passage of some maternal thyroid hormone, while many infants have some thyroid production of their own. Common symptoms include decreased activity and increased sleep, feeding difficulty, constipation, and prolonged jaundice. On examination, common signs include myxedematous facies, large fontanels, macroglossia, a distended abdomen with umbilical hernia, and hypotonia. CH is classified into permanent and transient forms, which in turn can be divided into primary, secondary, or peripheral etiologies. Thyroid dysgenesis accounts for 85% of permanent, primary CH, while inborn errors of thyroid hormone biosynthesis (dyshormonogeneses) account for 10-15% of cases. Secondary or central CH may occur with isolated TSH deficiency, but more commonly it is associated with congenital hypopitiutarism. Transient CH most commonly occurs in preterm infants born in areas of endemic iodine deficiency. In countries with newborn screening programs in place, infants with CH are diagnosed after detection by screening tests. The diagnosis should be confirmed by finding an elevated serum TSH and low T4 or free T4 level. Other diagnostic tests, such as thyroid radionuclide uptake and scan, thyroid sonography, or serum thyroglobulin determination may help pinpoint the underlying etiology, although treatment may be started without these tests. Levothyroxine is the treatment of choice; the recommended starting dose is 10 to 15 mcg/kg/day. The immediate goals of treatment are to rapidly raise the serum T4 above 130 nmol/L (10 ug/dL) and normalize serum TSH levels. Frequent laboratory monitoring in infancy is essential to ensure optimal neurocognitive outcome. Serum TSH and free T4 should be measured every 1-2 months in the first 6 months of life and every 3-4 months thereafter. In general, the prognosis of infants detected by screening and started on treatment early is excellent, with IQs similar to sibling or classmate controls. Studies show that a lower neurocognitive outcome may occur in those infants started at a later age (> 30 days of age), on lower l-thyroxine doses than currently recommended, and in those infants with more severe hypothyroidism.	0
INTRODUCTION:Chromosome 6pter-p24 deletion syndrome (OMIM #612582) is a rare genetic disorder characterized by deletion of the distal part of 6p. Human 6p deletion syndromes result in a variety of congential malformations. PATIENT CONCERNS:The fetus was the fourth child born to healthy non-consanguineous parents with no relevant family history. DIAGNOSIS:The fetus was diagnosed with 6pter-p24 deletion syndrome through prenatal ultrasound, magnetic resonance imaging, and chromosomal microarray analysis. The fetus had brain, skeletal, and heart malformations. The fetus was cytogenetically normal. Chromosomal microarray analysis detected an interstitial 7.999Mb deletion within the 6p25.1p24.3 region of chromosome 6. INTERVENTIONS:There was no treatment for the fetus. OUTCOMES:Pregnancy was terminated. CONCLUSIONS:To the author's knowledge, the present case is one of the first to report the prenatal diagnosis of 6pter-p24 deletion syndrome in a fetus. No published reports have described the diagnosis of 6pter-p24 deletion syndrome using multiple technologies during the antenatal period; therefore, our findings may provide a reference for other clinicians. The clinical features and pathophysiology of this prenatal diagnosis are discussed.	0
SIGNIFICANCE:Serpiginous choroiditis is a rare yet visually debilitating condition. To date, there is no established consensus on treatment protocol. This article presents a case report of macular serpiginous choroiditis and reviews supporting data for immunosuppressive treatment plans. PURPOSE:The purpose of this study was to examine a case of atypical serpiginous choroiditis with emphasis on diagnostic testing and treatment options. CASE REPORT:A 62-year-old man presented with new, bilateral, yellow chorioretinal placoid lesions within the posterior pole. Optical coherence tomography revealed focal hyperreflective retinal pigment epithelium lesions with disruption of outer retinal layers. Fundus fluorescein angiography demonstrated stable hyperfluorescent lesions with the absence of fluid leakage. Further testing ruled out possible systemic correlation. CONCLUSIONS:Macular serpiginous choroiditis is infrequently encountered; however, various differentials must be considered before making the diagnosis. Optical coherence tomography and fundus fluorescein angiography serve as useful tools in aiding the diagnosis. Treatment of serpiginous choroiditis must be initiated with caution given the high risk of adverse effects.	0
Background Denosumab is an inhibitor of receptor activator of nuclear factor kappa-B ligand, which strongly suppresses osteoclasts. Cherubism is a rare autosomal dominant disorder characterized by symmetrical swelling of the jaws, in which the bone is replaced by a fibrous granuloma containing osteoclast-like giant cells. Case presentation We report the efficacy and safety of denosumab treatment in a prepubertal boy with progressive cherubism. The treatment consisting of eight subcutaneous denosumab injections (120 mg/dose) in 6 months not only suppressed the expansion of the osteolytic lesions but also dramatically ossified them. However, a transiently decreased growth rate and rebounded asymptomatic hypercalcemia were associated with the treatment. Conclusions The present case demonstrated the therapeutic potential of denosumab for treatment of cherubism, although adverse effects, especially those on childhood growth, remain obscure. Further studies are needed to establish a safe and effective protocol for denosumab treatment of children.	0
GM1 gangliosidosis is a storage disorder with autosomal recessive inheritance caused by deficiency of β-galactosidase (GLB1), which is a lysosomal hydrolase, due to mutations in GLB1. We describe here an autopsy case of GM1 gangliosidosis in a female patient who survived for 38 years with a long period of artificial respiratory support (ARS). She was born after a normal pregnancy and delivery. Although development was normal until one year old, she was unable to walk at two years old and started having seizures by nine years old. At 21 years old, she became unable to communicate and was bed-ridden. At 36 years old, she suffered from pneumonia and required ARS. She died of pneumonia at 40 years old. Neuropathological examination revealed severe atrophy, predominantly found in the frontal lobes. Microscopically, severe gliosis and neuronal loss were observed in the cerebral cortex, putamen, cerebellum, the latter including Purkinje cell and granule cell layers. The hippocampus was relatively preserved. Severe neuronal swelling was observed in the limbic regions and stored a material in these neurons negative for periodic acid-Schiff (PAS). A PAS-positive granular storage material in neurons and macrophages was mainly observed in the brainstem and limbic regions. Exome analysis showed a known c.152T>C (p.I51T) variant that has been described in type III patients and a novel c.1348-2A>G variant in GLB1. Detailed analysis of reverse transcription-polymerase chain reaction products of GLB1 mRNA revealed that these variants were present in a compound heterozygous state. In our case, clinical features and neuropathological findings were most consistent with type II, although the entire course was longer than any previously reported cases. This may be explained by the residual enzyme activity in this patient whose severity lay between types II and III. Our finding of relative preservation of the limbic regions suggests that neuronal loss in GM1 gangliosidosis has regional selectivity.	0
PHARC syndrome is a rare neurodegenerative disorder caused by mutations in the ABHD12 gene. It is a genetically heterogeneous and clinically variable disease, which is characterized by demyelinating polyneuropathy, hearing loss, cerebellar ataxia, retinitis pigmentosa, and early-onset cataract and can easily be misdiagnosed as other neurologic disorders with a similar clinical picture, such as Charcot-Marie-Tooth disease and Refsum disease. We describe the genotype-phenotype correlation of two siblings with a novel genotype underlying PHARC syndrome. The genotype was identified using next-generation sequencing. We examined both patients by means of thorough history taking and clinical examination, nerve conduction studies (NCS), brain imaging, and optical coherence tomography to establish a genotype-phenotype correlation. We identified a novel homozygous point mutation (c.784C > T, p.Arg262*) in the ABHD12 gene. This mutation was detected in both siblings, who had bilateral hearing loss and cataracts, signs of cerebellar ataxia, and neuropathy with a primarily demyelinating pattern in NCS. In one case, retinitis pigmentosa was also evident. As PHARC syndrome is a rare autosomal recessive disorder, our findings highlight the importance of an interdisciplinary diagnostic workup with clinical and molecular genetic testing to avoid a misdiagnosis as Charcot-Marie-Tooth disease or Refsum disease.	0
A 33-year-old Japanese woman was referred for hoarseness. She had been diagnosed with Charcot-Marie-Tooth disease at age 3 and bilateral optic atrophy at age 15. Laryngoscopy revealed left vocal fold palsy. These findings suggested Charcot-Marie-Tooth disease type 2; the diagnosis was confirmed by a mitofusin 2 mutation analysis. Her symptoms remained stable for almost 10 years. Although vocal fold palsy and optic atrophy have been previously reported in patients with mitofusin 2 mutations, detailed clinical information and clinical course have never been documented. These data might contribute to the elucidation of the pathological conditions associated with mitofusin 2 mutations.	0
Acrocallosal syndrome (ACLS) is a rare autosomal recessive disorder characterized by agenesis of the corpus callosum, facial dysmorphism, postaxial polydactyly of the hands as well as preaxial polydactyly of the feet, and developmental delay. Mutations in the KIF7 gene, encoding a molecule within the Sonic hedgehog (SHH) pathway, have been identified as causative for ACLS but also for the fatal hydrolethalus syndrome and some cases of Joubert syndrome. We report here on a Tunisian boy who shows the clinical characteristics of ACLS and was found to have a novel homozygous KIF7 nonsense mutation. Further, we summarize the current knowledge about the clinical spectrum associated with KIF7 mutations as well as genetic and/or phenotypic overlap with ciliopathies and other mutations in the SHH pathway.	0
BACKGROUND:Alien Hand Syndrome (AHS) is an uncontrollable, involuntary, but in appearance, purposeful motor control disorder of the upper extremity. CASE REPORT:A 42-year-old male patient was admitted to our clinic complaining of involuntary motor activity in his right hand. He had a previous history of migraine with visual aura. The uncontrollable motor control disorder was compatible with Alien Hand Syndrome, which was appearing immediately after the visual aura and before the beginning of headache. CONCLUSION:Alien Hand Syndrome is usually observed with anterior cerebral artery infarction, midline tumors, trauma and several neurodegenerative diseases, but is rarely seen in paroxysmal conditions such as migraine with aura.	0
OBJECTIVE:Evidence links trait hostility with components of the metabolic syndrome (MetS), a clustering of cardiometabolic risk factors, but which hostility dimensions (e.g., expressive or cognitive hostility) relate to MetS are not well known. Further, there may be age and sex differences in the extent to which hostility dimensions relate to MetS. The present study evaluated associations between dimensions of hostility and the metabolic syndrome and its individual components as well as the moderating effects of sex and age. METHODS:In a cross-sectional sample of 478 employed adults, a principal component analysis from common trait hostility questionnaires yielded a two-factor solution: expressive hostility (anger and aggression) and cognitive hostility (cynicism). Each of these two components of hostility was examined as predictors of each of two aggregated MetS outcomes: a dichotomous measure of MetS, based upon the NCEP-ATP III definition, and a continuous measure based upon the average of standardized scores for each component; and they were examined as predictors of individual MetS components as well. RESULTS:Expressive hostility was associated with MetS severity (b = 0.110, p = 0.04) and waist circumference (b = 2.75, p = 0.01). Moderation analyses revealed that elevated expressive hostility was associated with elevated waist circumference in women but not men. Cognitive hostility was not related to any metabolic syndrome component or aggregated outcome, and no moderation was observed. CONCLUSIONS:Among multiple individual components and two aggregated scores, only trait dispositions to expressed hostile affect and behavior were associated with MetS severity and waist circumference. The effects were small but statistically significant. The association between cognitive hostility and metabolic syndrome measures may not be robust in a large sample of healthy, midlife adults.	0
Sjögren's syndrome (SS) is an autoimmune disease that involves the nervous system in about 20% of cases. In 25-92% of patients affected by Sjögren's syndrome, neurological symptoms may precede the sicca syndrome. A 65-year-old male presented with a seven-month history of episodes of near-syncope, constipation, anhidrosis, disabling fatigue and asthenia. Physical examination was unremarkable, whilst the ECG revealed sinus bradycardia. Laboratory tests showed lymphopenia and normal inflammatory markers. In order to assess a potential autonomic neuropathy, "Deep Breathing Test" (E/I 1.02), "Lying to Standing Test" (R/R' 0.95), and "Orthostatic Hypotension Tests" (T 120s Systolic reduction >20 mmHg and Diastolic reduction >10 mmHg) were performed, all of which were abnormal. ECG Holter monitoring revealed sinus bradycardia, and right bundle branch block with 24-h blood pressure monitoring revealing a diurnal hypotensive profile. The patient reported a three-month history of worsening dry mouth. On physical examination, the patient had anisocoria in response to light stimulation. Auto-antibody testing was performed to evaluate the presence of any autoimmune disease. The results of these studies included an abnormal elevation of ANA (1:320 speckled pattern), Ro/SS-a (>240U/l), and La/SS-b (162 U/ml) antibodies. The patient was discharged with a diagnosis of "Autonomic Neuropathy Most Likely Due to Primary Sjögren's Syndrome (SS)" and started the immunotherapy. After one month, he reported a significant improvement in his symptoms with a concomitant normalization of his "Orthostatic Hypotension Tests." This case underlines the potential for dys-autonomic symptoms to precede the onset of sicca syndrome in patients with Sjogren's Syndrome.	0
Myriad conditions may affect both the neurologic system and the thorax, while other diseases primarily affecting the thorax may manifest with neurologic abnormalities. Correlation of signs, symptoms, and imaging findings in the neurological system with those in the thorax can help diagnose certain conditions and/or guide further diagnostic work-up and treatment. We will review and illustrate the imaging appearance of several systemic/neurological diseases with thoracic manifestations as well as discuss conditions in the thorax that can lead to neurologic symptoms.	0
Background:Methylmalonic acidaemia with homocystinuria type C (cblC defect) is an inherited error of cobalamin metabolism. Cobalamin deficient processing results in high levels of methylmalonic acid and homocysteine. The latter is considered to be a risk factor for multiple sclerosis (MS). We report on the first case of a patient with comorbid cblC defect and MS. Case report:This young male presented at the age of 14 with a relapsing-remitting neurological disorder associated with imaging alterations suggestive of MS. Treatment resulted in a partial clinical improvement with vanishing of white matter lesions. Later on, the emergence of unexpected clinical features led to a metabolic work-up, revealing a cobalamin intracellular defect. Genetic analysis disclosed a single variant in MMACHC (c.482G > A; p.Arg161Gln) and another splicing variant in PRDX1 (c.1-515G > T) that cause the silencing of the wild-type MMACHC allele, so confirming the diagnosis of cblC defect. Although cblC treatment was effective, when 17-year-old he experienced a relapse of neurological symptoms. Further imaging and laboratory studies eventually supported the diagnosis of MS. Discussion:While the comorbid association of MS and cblC in our patient may remain anecdotic, we suggest measuring Hcy and MMA levels in young patients with a relapsing-remitting demyelinating disorder, in order not to miss a cblC defect, that requires a specific and effective treatment.	0
Potocki-Shaffer syndrome (PSS) is a rare contiguous gene deletion syndrome caused by heterozygous deletion of 11p11.2p12. Typical features described in patients with PSS include developmental delay, intellectual disability, multiple cartilaginous exostoses, biparietal foramina, craniofacial abnormalities, and genitourinary anomalies. While hypertension has been noted in three patients with PSS, it has not been described in most patients with this syndrome. This report details the evaluation and treatment of a teenager with PSS who presented on several occasions during childhood with elevated blood pressure measurements. The renin level was elevated, likely indicating a secondary cause for the HTN. The patient's BP responded to monotherapy with Angiotensin Converting Enzyme Inhibitor (ACEI).	0
Insulin plays an important role during adipogenic differentiation of animal preadipocytes and the maintenance of mature phenotypes. However, its role and mechanism in dedifferentiation of adipocyte remains unclear. This study investigated the effects of insulin on dedifferentiation of mice adipocytes, and the potential mechanisms. The preadipocytes were isolated from the subcutaneous white adipose tissue of wild type (WT), TNFα gene mutant (TNFα-/-), leptin gene spontaneous point mutant (db/db) and TNFα-/-/db/db mice and were then induced for differentiation. Interestingly, dedifferentiation of these adipocytes occurred once removing exogenous insulin from the adipogenic medium. As characteristics of dedifferentiation of the adipocytes, downregulation of adipogenic markers, upregulation of stemness markers and loss of intracellular lipids were observed from the four genotypes. Notably, dedifferentiation was occurring earlier if the insulin signal was blocked. These dedifferentiated cells regained the potentials of the stem cell-like characteristics. There is no significant difference in the characteristics of the dedifferentiation between the adipocytes. Overall, the study provided evidence that insulin plays a negative regulatory role in the dedifferentiation of adipocytes. We also confirmed that both dedifferentiation of mouse adipocytes, and effect of the insulin on this process were independent of the cell genotypes, while it is a widespread phenomenon in the adipocytes.	0
BACKGROUND Primary effusion lymphoma (PEL) is a rare and aggressive non-Hodgkin lymphoma (NHL) that is responsible for 1% of all lymphomas not related to human immunodeficiency virus (HIV). PEL is characterized by human herpesvirus-8 (HHV-8) positivity in the absence of overt tumor burden that does not exhibit typical B cell or T cell immunophenotype characteristics. The exact mechanism of development is unknown, but it is hypothesized to develop from post-germinal B cell origin. Although it is most common in HIV patients, other immunocompromising comorbidities can be seen in conjunction with PEL, including liver cirrhosis. CASE REPORT We present the case of a 73-year-old HIV-seronegative man with alcohol-induced liver cirrhosis who was found to have T cell PEL of the pleural space diagnosed by thoracentesis. CONCLUSIONS Little is known regarding oncogenesis of T cell PEL, and few studies exist regarding appropriate treatment regimens for PEL as a whole, prompting need for further investigation and discussion to improve survival rates. Even in the absence of active HIV infection, PEL should be considered as a potential cause of pleural effusion in cirrhotic patients in order to prompt earlier treatment for the best chance of survival.	0
HELLP syndrome is a rare complication of pregnancy that may result in serious consequences such as hepatic rupture, one of the most feared and potentially life-threatening complications. This article aims to carry out a literature review on hepatic rupture in the context of HELLP syndrome as well as to present two clinical cases.	0
Grebe syndrome (OMIM-200700) is a very rare type of acromesomelic dysplasia with autosomal recessive inheritance. We studied a Pakistani family with two affected individuals having typical features of Grebe chondrodysplasia. Patients were observed with short and deformed limbs having a proximo-distal gradient of severity. Hind-limbs were more severely affected than fore-limbs. Digits on autopods were very short and nonfunctional. Index subject also had nearsightedness. However, symptoms in the craniofacial and axial skeleton were minimal. Genetic analysis revealed four base pair insertion mutation (c.1114insGAGT) in gene coding cartilage-derived morphogenetic protein-1 (CDMP1). This mutation was predicted to cause premature stop codon. The clinical presentation in this study broadens the range of phenotypes associated with CDMP1 mutation in Pakistani population.	0
Epidermal barrier integrity could be influenced by various factors involved in epidermal cell differentiation and proliferation, cell-cell adhesion, and skin lipids. Dysfunction of this barrier can cause skin disorders, including eczema. Inversely, eczema can also damage the epidermal barrier. These interactions through vicious cycles make the mechanism complicated in connection with other mechanisms, particularly immunologic responses. In this article, the molecular mechanisms concerning epidermal barrier abnormalities are reviewed in terms of the following categories: epidermal calcium gradients, filaggrin, cornified envelopes, desquamation, and skin lipids. Mechanisms linked to ichthyoses, atopic dermatitis without exacerbation or lesion, and early time of experimental irritation were included. On the other hand, the mechanism associated with epidermal barrier abnormalities resulting from preceding skin disorders was excluded. The molecular mechanism involved in epidermal barrier dysfunction has been mostly episodic. Some mechanisms have been identified in cultured cells or animal models. Nonetheless, research into the relationship between the causative molecules has been gradually increasing. Further evidence-based systematic data of target molecules and their interactions would probably be helpful for a better understanding of the molecular mechanism underlying the dysfunction of the epidermal barrier.	0
OBJECTIVE:To assess the long-term safety, tolerability and monitor benefits of extended use of bimagrumab in individuals with sporadic inclusion body myositis (sIBM) who completed a single-dose core study. METHODS:In this multicenter, open-label extension study, 10 adults received bimagrumab 10 mg/kg IV every 4 weeks up to 2 years (104 weeks). Safety (primary endpoint) was assessed by recording adverse events (AEs). Clinical benefits were assessed by changes from baseline in thigh muscle volume (TMV), lean body mass (LBM), 6-minute walk distance (6MWD), handgrip and quadriceps strength. RESULTS:Participants had a mean (standard deviation [SD]) age of 70.1 (10.4) years. All participants (n = 10) discontinued the treatment due to early termination of the study (n = 7) or AEs (n = 3; myocardial infarction, esophageal carcinoma, and dementia, none of which were treatment-related). The most common AEs were muscle spasms and falls (both 9/10, 90%), followed by diarrhea (6/10, 60%), acne and skin eruption (both 5/10, 50%). At weeks 8 and 16, mean (SD) TMV increased from baseline by 4.1% (4.3) and 4.5% (6.3). Mean LBM increased from baseline and was sustained at 6.9% (3.9) at week 76. Means of 6MWD showed a progressive decline from baseline to week 76, during which there was a modest numerical increase in handgrip strength and no significant changes in quadriceps strength. CONCLUSIONS:Long-term treatment up to 2 years with bimagrumab had good safety profile and was well-tolerated in individuals with sIBM. An increase in muscle mass was noted on a group level, however, there was no evidence of clinical improvement. CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that for patients with sIBM, long-term bimagrumab treatment was safe and well-tolerated and did not lead to functional improvement.	0
SHORT syndrome is a rare genetic congenital defects condition. The frequency of the disease still remains unknown.We report the two-year-four-month old female with SHORT syndrome who present growth retardation and dysmorphic features (triangular-shaped face, prominent forehead, ocular depression, lipodystrophy at the lumbar region and around elbows), consistent with the phenotype described for this syndrome. The molecular analysis showed the presence of heterozygous variant c.1956dupT (p.Lys653*) in exon 15 of PIK3R1.The frequency of the disease still remains unknown; solely several dozen cases have been described worldwide.	0
There are several entities that combine a skeletal dysplasia with a retinal dystrophy. Recently, another possibly autosomal recessive entity was added to this group characterized by a specific spondylometaphyseal dysplasia and a cone-rod dystrophy, without other significant impairments. The entity was named SMD-CRD. We further delineate this disorder by reporting on a 16-year-old boy and a pair of twins with this entity. Possible etiologies are discussed. The boy showed low alpha-neuraminidase activity levels in fibroblasts, but normal levels in leucocytes. The meaning of this finding remains as yet unknown.	0
Purpose: SPG76 is one of the rare forms of hereditary spastic paraplegia (HSP) which causes by mutations in the CAPN1 gene. The mode of inheritance of SPG76 is autosomal recessive (AR) and so far, only 24 families and 25 mutations in this gene have been reported worldwide. These mutations have been associated with a spectrum of disorders from pure HSP to spastic ataxia. HSP genetically is one of the most heterogeneous neurological disorders and to date, 79 types of HSP (SPG1-SPG79) have been identified, however, it has been suggested that many HSP-genes, particularly in AR-HSPs, remained unknown. AR-HSPs clinically overlap with other neurodegenerative disorders, making an accurate diagnosis of the disease difficult. Therefore, in addition to clinical examination, a high throughout genetic method like whole exome sequencing (WES) may be necessary for the diagnosis of this type of neurodegenerative disorders.Methods and Results: Herein, we present the clinical features and results of WES in the first Iranian family with a novel CAPN1 variant, c.C853T:p.R285* and pure HSP.Conclusion: Some of the previous studies have mentioned that the "spasticity-ataxia phenotype might be conducted to the diagnosis of SPG76" but recently the number of pure HSP patients with CAPN1 mutation is increasing. The present study also expands the mutation spectrum of pure CAPN1-related SPG76; emphasizing that CAPN1 screening is required in both pure HSP and spasticity-ataxia phenotypes. As noted in some other literature, we suggest the clinical spectrum of this disorder to be considered as "CAPN1-associated neurodegeneration".	0
Schneckenbecken dysplasia (SBD) is an autosomal recessive lethal skeletal dysplasia that is classified into the severe spondylodysplastic dysplasias (SSDD) group in the international nosology for skeletal dysplasias. The radiological hallmark of SBD is the snail-like configuration of the hypoplastic iliac bone. SLC35D1 (solute carrier-35D1) is a nucleotide-sugar transporter involved in proteoglycan synthesis. Recently, based on human and mouse genetic studies, we showed that loss-of-function mutations of the SLC35D1 gene (SLC35D1) cause SBD.To explore further the range of SLC35D1 mutations in SBD and elucidate whether SLC35D1 mutations cause other skeletal dysplasias that belong to the SSDD group.We searched for SLC35D1 mutations in five families with SBD and 15 patients with other SSDD group diseases, including achodrogenesis type 1A, spondylometaphyseal dysplasia Sedaghatian type and fibrochondrogenesis. We identified four novel mutations, c.319C>T (p.R107X), IVS4+3A>G, a 4959-bp deletion causing the removal of exon 7 (p.R178fsX15), and c.193A>C (p. T65P), in three SBD families. Exon trapping assay showed IVS4+3A>G caused skipping of exon 4 and a frameshift (p.L109fsX18). Yeast complementation assay showed the T65P mutant protein lost the transporter activity of nucleotide sugars. Therefore, all these mutations result in loss of function. No SLC35D1 mutations were identified in all patients with other SSDD group diseases.Our findings suggest that SLC35D1 loss-of-function mutations result consistently in SBD and are exclusive to SBD.	0
Endosalpingiosis is a benign condition characterized by the presence of tubal epithelium outside the fallopian tube and the absence of endometrial stroma. Florid cystic endosalpingiosis is a very rare form of endosalpingiosis that presents as a tumor-like lesion. We report the case of a 67-year-old woman who presented with a cystic lesion of the uterus. Macroscopically, a cut section revealed a multicystic, whitish mass in the myometrium of the fundus. Histologically, the lesion consisted of numerous variably sized glands that were lined with a single or stratified layer of ciliated columnar cells similar to tubal epithelium.	0
Transient erythroblastopenia of childhood is a self-limited anemia occurring in previously healthy children, secondary to temporary cessation of erythrocyte production. Although the precise etiology is unclear, most cases are associated with a viral illness. The anemia may be severe, with associated pallor, tachypnea, and tachycardia; treatment is supportive. We present an unusual case of a child with viral-induced transient erythroblastopenia of childhood and associated ectopic atrial tachycardia, requiring therapy with antiarrhythmics.	0
Anti-idiotypic antibodies (anti-IDs) were discovered at the very beginning of the 20th century and have attracted attention of researchers for many years. Nowadays, there are five known types of anti-IDs: α, β, γ, ε, and δ. Due to the ability of internal-image anti-IDs to compete with an antigen for binding to antibody and to alter the biologic activity of an antigen, anti-IDs have become a target in the search for new treatments of autoimmune illnesses, cancer, and some other diseases. In this review, we summarize the data about anti-IDs that mimic the structural and functional properties of some bioregulators (autacoids, neurotransmitters, hormones, xenobiotics, and drugs) and evaluate their possible medical applications. The immune system is potentially able to reproduce or at least alter the effects of any biologically active endogenous or exogenous immunogenic agent via the anti-idiotypic principle, and probably regulates a broad spectrum of cell functions in the body, being a kind of universal remedy or immunacea, by analogy to the legendary ancient goddess of universal healing Panacea (Πανάκεια, Panakeia in Greek) in the treatment and prevention of diseases, possibly including non-infectious somatic and even hereditary ones.	0
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Prognosis is highly variable, ranging from few months to more than 30 years. 25OH vitamin D (25OH VD) blood levels have been associated with worse prognosis of ALS, but these results remain in dispute. We addressed this controversy with a prospective study and multivariate analysis to study the influence of known clinical prognostic factors of the disease and 25OH VD levels on Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) severity score (ALS-SS), as defined by the monthly rate of decline of ALSFRS-R score, to identify the factors most closely linked to the risk of worsening of the disease. Results:This prospective cohort of ALS patients recruited 127 individuals, and 105 of them met inclusion criteria. Mean age of onset was 62.2 ± 12.1 years, 32% of subjects had bulbar onset, and gender ratio was 1.44 (male/female). Mean 25OH VD level was 26.8 ± 10.8 ng/ml and was similar between males and females. Patients with 25OH VD levels <15 ng/ml had significantly higher ALS-SS at inclusion (ALS-SSi) than those with normal levels (>30 ng/ml), p = 0.011. The study of ALS-SS as calculated at the end of follow-up (ALS-SSe) was not found correlated to initial 25OH VD levels (r = -0.19; p = 0.084). Univariate analysis showed that ALS-SSe correlated with 25OH VD levels, ALS duration at inclusion, slow vital capacity (SVC) at inclusion, and SVC loss. Multivariate model showed that 25OH VD levels were independently associated with ALS-SSe: r = -0.0125, p = 0.033. Log rank test with Kaplan-Meier curves did not show significant differences of survival between the groups defined by 25OH VD levels: <15, >15 and <30, and > 30 ng/ml, p = 0.88. Conclusions: This prospective study in ALS patients confirmed previous retrospective results: ALS-SSi is significantly higher in patients with severe VD deficiency. For the first time, multivariate analysis showed that 25OH VD level was an independent prognostic factor correlated to ALS-SSe, suggesting that discrepancies between previous works could be due to confounders. It would be important that the present work be replicated in larger samples to confirm the present findings.	0
To describe and discuss otologic manifestations of Larsen syndrome, based on a case report and a systematic review of the literature.We performed a PubMED database search, and we selected studies reporting otolaryngologic manifestations secondary to Larsen syndrome. The selected articles were read in full, and three researchers independently extracted data from the studies. In parallel, we report the case of a 14-year-old patient who had hearing loss secondary to Larsen syndrome.Fifteen studies met our selection criteria. Seven studies reported hearing loss in patients with Larsen syndrome (4 had conductive hearing loss and 3 had mixed hearing loss). The conductive hearing loss may be secondary to ossicular malformations and/or middle ear effusions. Other causes for conductive hearing loss are mesenchymal remnants in the middle ear, Eustachian tube dysfunction, and cleft palate. Surgical management of the hearing loss is possible in selected cases, although the surgical and anesthetic risks should be considered. Hearing aids seem to be safe and effective treatment options for the hearing loss secondary to Larsen syndrome.Although rare, patients with Larsen syndrome may have hearing loss. The most frequent type of deficit is conductive, either secondary to malformation of the ossicles or middle ear effusion. Possible surgical correction of these abnormalities should be weighed against the anesthetic risks of these patients.	0
Pleuropulmonary blastoma (PPB), the most common primary malignant neoplasm of the lung in childhood, occurs in the same early age group (0-6 years) as the other more common solid tumors such as neuroblastoma and Wilms tumor. The tumor begins as a cystic lung lesion with the potential over a period of 3-5 years to progress to a high grade multipatterned primitive sarcoma in the absence of a malignant epithelial component. Several years after its initial description as a unique clinicopathologic entity, this and other tumors appeared to have a familial predilection which was later confirmed with the discovery of a heterozygous germline mutation in DICER1 whose protein is a member of ribonuclease III family of enzymes. It is estimated that 75%-80% of children with a PPB have the germline mutation. The other notable finding from our studies is the identification of a family of extrapulmonary neoplasms, including cystic nephroma and Sertoli-Leydig cell tumor of the ovary as two examples, also with DICER1 mutations.	0
Primary cilia are generally solitary organelles that emanate from the surface of almost all vertebrate cell types. Until recently, details regarding the function of these structures were lacking; however, extensive evidence now suggests that primary cilia have critical roles in sensing the extracellular environment, and in coordinating developmental and homeostatic signalling pathways. Furthermore, disruption of these functions seems to underlie a diverse spectrum of disorders, known as primary ciliopathies. These disorders are characterized by wide-ranging clinical and genetic heterogeneity, but with substantial overlap among distinct conditions. Indeed, ciliopathies are associated with a large variety of manifestations that often include distinctive neurological findings. Herein, we review neurological features associated with primary ciliopathies, highlight genotype-phenotype correlations, and discuss potential mechanisms underlying these findings.	0
We describe a patient with palatal abnormalities-cleft palate and bifid uvula; distinctive facial features-long and triangular face, large ears and nose, thin lips and dental crowding; musculoskeletal abnormalities-severe scoliosis, joint laxity, long digits, flat feet, decreased muscle mass, and diminished muscle strength; and cardiac features-a dilatated ascending aorta at the level of Valsalva sinuses and a patent foramen ovale. Sequence analysis and deletion/duplication testing for a panel of genes involved in connective tissue disorders revealed the presence of a novel homozygous deletion of exons 2-7 in TGFB3 gene. Heterozygous pathogenic mutations in TGFB3 have been associated with Loeys-Dietz syndrome 5 (LDS5) and Arrhythmogenic Right Ventricular Dysplasia type 1. Here, we report the first case of a homozygous TGFB3 variant associated with a severe LDS5 and Marfan-like presentation.	0
Introduction Burkholderia pseudomallei is an environmental intracellular Gram-negative bacterium that causes melioidosis, a severe infectious disease affecting humans and animals. An increase in melioidosis cases worldwide and the high mortality rate of the disease makes it a public health concern. Melioidosis is known as the 'great mimicker' because it presents with a wide range of disease manifestations. B. pseudomallei is naturally resistant to antibiotics and delay in diagnosis leads to ineffective treatment. Furthermore, there is no approved vaccine to prevent melioidosis infection in humans. Therefore, it is a priority to license a vaccine that can be used for both high-risk endemic areas and for biodefense purposes. Areas covered In this review, we have focussed on recent progress in the USA for the development and advancement of lead B. pseudomallei vaccine candidate(s) ready for testing in pre-clinical trials. Those candidates include live-attenuated vaccines, glycoconjugate vaccines, outer-membrane vesicles, and gold nanoparticle vaccines. Expert opinion Side-by-side comparison of the leading B. pseudomallei vaccine candidates will provide important information to further advance studies into pre-clinical trials. The likelihood of any of these current vaccines becoming the selected candidate that will reduce the occurrence of melioidosis worldwide is closer than ever.	0
Tubular aggregates and cylindrical spirals are 2 distinct ultrastructural abnormalities observed in muscle biopsies that have similar histochemical staining characteristics on light microscopy. Both are found in a wide range of disorders. Recently, a number of genetic mutations have been reported in conditions with tubular aggregates in skeletal muscle. It is widely accepted that tubular aggregates arise from the sarcoplasmic reticulum, but the origin of cylindrical spirals has been less clearly defined. We describe the histopathological features of myopathies with tubular aggregates, including a detailed immunohistochemical analysis of congenital myasthenic syndromes with tubular aggregates due to mutations in GFPT1 and DPAGT1, and myopathies with cylindrical spirals. Our findings support the notion that cylindrical spirals, like tubular aggregates, derive primarily from the sarcoplasmic reticulum; however, immunohistochemistry indicates that different molecular components of the sarcoplasmic reticulum may be involved and can be used to distinguish between these different inclusions. The immunohistochemical differences may also help to guide genetic testing.	0
Congenital myasthenic syndromes comprise a rare heterogeneous group of diseases that impair neuromuscular transmission and are characterized by muscle fatigability and transient or permanent weakness. Symptoms are often present from birth or early childhood. These syndromes have a wide range of phenotypes and severity. Caused by genetic mutations in any of the numerous genes encoding for components of the neuromuscular junction. They are classified by where in the neuromuscular junction the mutated component is located: presynaptic, synaptic, or postsynaptic. Mutations in about 30 genes have been implicated. Diagnosis can be difficult. Treatment options vary depending on the specific genetic type.	0
The treatment of choice for dermatitis herpetiformis (DH), a cutaneous manifestation of coeliac disease, is a life-long gluten-free diet (GFD). In a GFD, wheat, rye and barley should be strictly avoided, but the role of oats is more controversial. This study aimed to investigate the safety and long-term quality of life and health effects of oat consumption in 312 long-term treated DH patients. Baseline data were gathered from patient records and follow-up data from questionnaires or interviews, and validated questionnaires were used to assess quality of life. We found that altogether 256 patients (82%) were consuming oats as part of their GFD at the follow-up. Long-term follow-up data showed that there were no differences in the presence of long-term illnesses, coeliac disease complications or the usage of medication between those consuming and not consuming oats. However, oat consumers had a better quality of life and reported ongoing gastrointestinal symptoms less frequently (4% vs 19%, p = 0.004) at the follow-up than those not consuming oats. The study established that oats are safe for DH patients and in the long-term seem to improve the quality of life of DH patients.	0
Dengue's increasing trends raise concerns over global health and pose a challenge to the Brazilian health system, highlighting the necessity of a strong surveillance system to reduce morbidity, mortality, and the economic burden of this disease. Although the Brazilian surveillance system reports more dengue cases than any other country, recent studies suggest that non-reported cases are the majority. The aim of the study is to explore the strengths and weaknesses of the Brazilian surveillance system, particularly looking at the functioning of data collection and reporting. This was done through qualitative semi-structured interviews with 17 experts in dengue surveillance, supported by quantitative data from the official notification system. To select the interviewees, purposive and theoretical sampling were used. Data were analyzed through thematic analysis. The research highlighted that a lack of human and technological resources in healthcare units and surveillance departments slows down the notification process and data analysis. Due to a lack of integration in the private sector, the surveillance system fails to detect the socioeconomic profile of the patients. Investments in public healthcare, human and technological resources for surveillance and better integration in the private healthcare system, and vector surveillance may improve dengue surveillance.	0
Inner hair cells (IHCs) and outer hair cells (OHCs) are the two anatomically and functionally distinct types of mechanosensitive receptor cells in the mammalian cochlea. The molecular mechanisms defining their morphological and functional specializations are largely unclear. As a first step to uncover the underlying mechanisms, we examined the transcriptomes of IHCs and OHCs isolated from adult CBA/J mouse cochleae. One thousand IHCs and OHCs were separately collected using the suction pipette technique. RNA sequencing of IHCs and OHCs was performed and their transcriptomes were analyzed. The results were validated by comparing some IHC and OHC preferentially expressed genes between present study and published microarray-based data as well as by real-time qPCR. Antibody-based immunocytochemistry was used to validate preferential expression of SLC7A14 and DNM3 in IHCs and OHCs. These data are expected to serve as a highly valuable resource for unraveling the molecular mechanisms underlying different biological properties of IHCs and OHCs as well as to provide a road map for future characterization of genes expressed in IHCs and OHCs.	0
This report is concerned with gingival manifestations associated with a case of dermochondrocorneal dystrophy (DCCD) or François syndrome occurring in a 42-year-old woman. Our Department treated this patient for 15 years. Oral examination of this case revealed a diffuse enlargement and severe inflammation of the attached gingiva. Systemic findings were similar to those reported in the literature for patients with DCCD. Firm papules 3 mm wide, localized on the face and on the dorsal surface of the hands, were associated with corneal involvement and progressive and severe articular disorder. Because they recurred after surgical ablation, the gingival lesions became an important problem in the management of the patient. After 10 years of unsuccessful treatment limited to scaling, oral hygiene control and mouth rinses with 0.2% chlorexidine solution, the patient was submitted to extraction of the remaining teeth, remodelling osteoplasty and cutaneous graft. An acrylic full denture was inserted. In a follow-up of 7 years, good results for the oral health of the patient were seen.	0
PURPOSE:The aim of this study was to assess the genetic evaluation of a three-generation consanguineous family with isolated oligodontia. MATERIALS AND METHODS:A 16-year-old male patient who had been referred for orthodontic treatment due to the presence of oligodontia, and his family members who presented several missing teeth had been enrolled in the study. Clinical and radiological assessments and genetic analysis including whole-exome sequencing were performed. RESULTS:Genetic evaluations revealed both homozygous and heterozygous mutations (c.T682A:p.F228I) in the WNT10A gene of six affected members of the family. Higher frequency of agenesis of mandibular second molar was found in homozygous relative to heterozygous WNT10A mutations. CONCLUSION:The present findings have provided evidence for a known variant in the WNT10A gene in a three-generation consanguineous family with isolated oligodontia, while the results confirmed that cases with homozygous mutation revealed clinical heterogeneity.	0
Collagen VI-related dystrophies (COL6-RDs) and Duchenne muscular dystrophy (DMD) cause progressive muscle weakness and disability. COL6-RDs are caused by mutations in the COL6 genes (COL6A1, COL6A2 and COL6A3) encoding the extracellular matrix protein collagen VI, and DMD is caused by mutations in the DMD gene encoding the cytoplasmic protein dystrophin. Both COL6-RDs and DMD are characterized by infiltration of the muscles by fatty and fibrotic tissue. This study examined the effect of disease pathology on skeletal muscles in lower extremity muscles of COL6-RDs using timed functional tests, strength measures and qualitative/ quantitative magnetic resonance imaging measures (MRI/MRS) in comparison to unaffected (control) individuals. Patients with COL6-RD were also compared to age and gender matched patients with DMD.Patients with COL6-RD presented with a typical pattern of fatty infiltration of the muscle giving rise to an apparent halo effect around the muscle, while patients with DMD had evidence of fatty infiltration throughout the muscle areas imaged. Quantitatively, fat fraction, and transverse relaxation time (T2) were elevated in both COL6-RD and DMD patients compared to unaffected (control) individuals. Patients with COL6-RD had widespread muscle atrophy, likely contributing to weakness. In contrast, patients with DMD revealed force deficits even in muscle groups with increased contractile areas.	0
Amino acids serve as key building blocks and as an energy source for cell repair, survival, regeneration and growth. Each amino acid has an amino group, a carboxylic acid, and a unique carbon structure. Human utilize 21 different amino acids; most of these can be synthesized endogenously, but 9 are "essential" in that they must be ingested in the diet. In addition to their role as building blocks of protein, amino acids are key energy source (ketogenic, glucogenic or both), are building blocks of Kreb's (aka TCA) cycle intermediates and other metabolites, and recycled as needed. A metabolic defect in the metabolism of tyrosine (homogentisic acid oxidase deficiency) historically defined Archibald Garrod as key architect in linking biochemistry, genetics and medicine and creation of the term 'Inborn Error of Metabolism' (IEM). The key concept of a single gene defect leading to a single enzyme dysfunction, leading to "intoxication" with a precursor in the metabolic pathway was vital to linking genetics and metabolic disorders and developing screening and treatment approaches as described in other chapters in this issue. Amino acid disorders also led to the evolution of the field of metabolic nutrition and offending amino acid restricted formula and foods. This review will discuss the more common disorders caused by inborn errors in amino acid metabolism.	0
Introduction:Anion exchanger 1 (AE1) (SLC4A1 gene product) is a membrane protein expressed in both kidney and red blood cells (RBCs): it exchanges extracellular bicarbonate (HCO3 -) for intracellular chloride (Cl-) and participates in acid-base homeostasis. AE1 mutations in kidney α-intercalated cells can lead to distal renal tubular acidosis (dRTA). In RBC, AE1 (known as band 3) is also implicated in membrane stability: deletions can cause South Asian ovalocytosis (SAO). Methods:We retrospectively collected clinical and biological data from patients harboring dRTA due to a SLC4A1 mutation and analyzed HCO3 - and Cl- transports (by stopped-flow spectrophotometry) and expression (by flow cytometry, fluorescence activated cell sorting, and Coomassie blue staining) in RBCs, as well as RBC membrane stability (ektacytometry). Results:Fifteen patients were included. All experience nephrolithiasis and/or nephrocalcinosis, 2 had SAO and dRTA (dRTA SAO+), 13 dominant dRTA (dRTA SAO-). The latter did not exert specific RBC membrane anomalies. Both HCO3 - and Cl- transports were lower in patients with dRTA SAO+ than in those with dRTA SAO- or controls. Using 3 different extracellular probes, we report a decreased expression (by 52%, P < 0.05) in dRTA SAO+ patients by fluorescence activated cell sorting, whereas total amount of protein was not affected. Conclusion:Band 3 transport function and expression in RBCs from dRTA SAO- patients is normal. However, in SAO RBCs, impaired conformation of AE1/band 3 corresponds to an impaired function. Thus, the driver of acid-base defect during dominant dRTA is probably an impaired membrane expression.	0
Childhood obesity is a modern worldwide epidemic with significant burden for health. It is a chronic metabolic disorder associated with multiple cardiovascular risk factors such as dyslipidemia, hypertension, stroke, and insulin resistance. Many obese adolescents remain obese into adulthood, with increased morbidity and mortality. As childhood obesity is a risk factor for adult obesity, the childhood obesity-related disorders account for an increased risk of cardiovascular consequences in adults, in addition to the effects already exerted by the fat mass in adulthood. Several papers have already described the cardiovascular implications of idiopathic obesity, while few data are available about syndromic obesity, due to the small sample size, not homogeneous phenotypes, and younger age at death. The aim of this mini-review is to give a comprehensive overview on knowledge about cardiovascular implications of idiopathic and syndromic obesity to allow the reader a quick comparison between them. The similarities and differences will be highlighted.	0
Ankyrin-B is a multifunctional adapter protein responsible for localization and stabilization of select ion channels, transporters, and signaling molecules in excitable cells including cardiomyocytes. Ankyrin-B dysfunction has been linked with highly penetrant sinoatrial node (SAN) dysfunction and increased susceptibility to atrial fibrillation. While previous studies have identified a role for abnormal ion homeostasis in ventricular arrhythmias, the molecular mechanisms responsible for atrial arrhythmias and SAN dysfunction in human patients with ankyrin-B syndrome are unclear. Here, we develop a computational model of ankyrin-B dysfunction in atrial and SAN cells and tissue to determine the mechanism for increased susceptibility to atrial fibrillation and SAN dysfunction in human patients with ankyrin-B syndrome. Our simulations predict that defective membrane targeting of the voltage-gated L-type Ca(2+) channel Cav1.3 leads to action potential shortening that reduces the critical atrial tissue mass needed to sustain reentrant activation. In parallel, increased fibrosis results in conduction slowing that further increases the susceptibility to sustained reentry in the setting of ankyrin-B dysfunction. In SAN cells, loss of Cav1.3 slows spontaneous pacemaking activity, whereas defects in Na(+)/Ca(2+) exchanger and Na(+)/K(+) ATPase increase variability in SAN cell firing. Finally, simulations of the intact SAN reveal a shift in primary pacemaker site, SAN exit block, and even SAN failure in ankyrin-B-deficient tissue. These studies identify the mechanism for increased susceptibility to atrial fibrillation and SAN dysfunction in human disease. Importantly, ankyrin-B dysfunction involves changes at both the cell and tissue levels that favor the common manifestation of atrial arrhythmias and SAN dysfunction.	0
BACKGROUND:To describe the clinical phenotype of paroxysmal extreme pain disorder, an autosomal dominant condition in four members in one family with the mutation NM_002977.3:c.3892G > T (p.Val1298Phe) in the SCN9A gene. Clinical examinations and details from members of one Polish family were collected, including age at onset, features of attacks, problems between attacks, investigational results, treatments tried, and evolution over time. CASE PRESENTATION:Twenty two individuals from this family with paroxysmal extreme pain disorder were identified. Seven of them presented clinical manifestation of paroxysmal extreme pain disorder, of which and in four were identified missens mutations in the SCN9A gene (NM_002977.3:c.3892G > T). The onset of the disorder took place in the neonatal period or infancy and persists throughout life. Autonomic manifestations predominate with extreme pain, skin flushing and harlequin colour change were observed in all. Attacks of excruciating deep burning pain often appear in the rectal, or jaw areas, but also diffuse in the body. Attacks are triggered by factors such as: defecation, eating, pressure and emotion. Carbamazepine and other antiepileptic drugs were only partly effective in almost all, but the response was incomplete. CONCLUSIONS:Paroxysmal extreme pain disorder is a hereditary sodium channelopathy with pain and an autonomic nervous system dysfunction. Paroxysmal extreme pain disorder is rare, so far only 500 cases of both women and men have been described in world literature.	0
Glycosylation is an essential process by which sugars are attached to proteins and lipids. Complete lack of glycosylation is not compatible with life. Because of the widespread function of glycosylation, inherited disorders of glycosylation are multisystemic. Since the identification of the first defect on N-linked glycosylation in the 1980s, there are over 40 different congenital protein hypoglycosylation diseases. This review will include defects of N-linked glycosylation, O-linked glycosylation and disorders of combined N- and O-linked glycosylation.	0
Spondylothoracic dysostosis is a rare congenital disorder characterised by multiple vertebral malformations, shortening of the spine and fusion of the ribs at the costovertebral junction. These abnormalities create anaesthetic challenges due to difficult airway, severe restrictive lung disease and spine deformity necessitating a multidisciplinary approach and careful perioperative planning. We present the perianaesthetic management of a parturient with spondylothoracic dysostosis who successfully underwent preterm caesarean delivery under general anaesthesia with awake videolaryngoscopy-assisted tracheal intubation.	0
3-Hydroxy-3-methylglutaric aciduria (HMGA) is an inherited metabolic disorder caused by 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. It is biochemically characterized by predominant tissue accumulation and high urinary excretion of 3-hydroxy-3-methylglutarate (HMG) and 3-methylglutarate (MGA). Affected patients commonly present acute symptoms during metabolic decompensation, including vomiting, seizures, and lethargy/coma accompanied by metabolic acidosis and hypoketotic hypoglycemia. Although neurological manifestations are common, the pathogenesis of brain injury in this disease is poorly known. Astrocytes are important for neuronal protection and are susceptible to damage by neurotoxins. In the present study, we investigated the effects of HMG and MGA on important parameters of redox homeostasis and cytokine production in cortical cultured astrocytes. The role of the metabolites on astrocyte mitochondrial function (thiazolyl blue tetrazolium bromide (MTT) reduction) and viability (propidium iodide incorporation) was also studied. Both organic acids decreased astrocytic mitochondrial function and the concentrations of reduced glutathione without altering cell viability. In contrast, they increased reactive species formation (2'-7'-dichlorofluorescein diacetate (DCFHDA) oxidation), as well as IL-1β, IL-6, and TNF α release through the ERK signaling pathway. Taken together, the data indicate that the principal compounds accumulating in HMGA induce a proinflammatory response in cultured astrocytes that may possibly be involved in the neuropathology of this disease.	0
A 13-year-old child diagnosed with neurofibromatosis type 1 who on a routine control presented with rhegmatogenous retinal detachment associated to dialysis of the ora serrata in the left eye (OS). There were no clinical signs or history of contuse ocular trauma. Neurofibromatosis produces alterations in fibroblasts of the cortex of the vitreous base. This results in deficient production of the collagen fibers that anchor the vitreous base to the pars plana and the peripheral neurosensory retina. Thus, suboptimal function of the fibroblasts explains spontaneous avulsion of the vitreous base. Such avulsion in turn is related to dialysis of the ora serrata.	0
INTRODUCTION:Spinocerebellar Ataxia 38 (SCA38) is caused by ELOVL5 gene mutation, with significant reduction of serum docosahexaenoic acid (DHA) levels. DHA supplementation has been proven effective at short-term follow-up. In the present paper, we evaluated long-term safety and efficacy of 600 mg/day oral DHA in SCA38 by a 2-year open label extension study. METHODS:Nine SCA38 patients underwent standardised clinical assessment at 62 (T1), 82 (T2) and 104 (T3) weeks, and compared to pre-treatment scores (T0). Brain 18-Fluorodeoxyglucose Positron Emission Tomography and electroneurography were performed at T0 and T3. RESULTS:We found a significant maintenance of clinical symptom improvement at each follow-up time-point (p < 0.001) as compared to T0, a sustained increase of cerebellar metabolism at T3 as compared to T0 (p = 0.013), and no worsening of neurophysiological parameters. No side effect was recorded. CONCLUSIONS:Long-term DHA supplementation is an eligible treatment for SCA38.	0
Eosinophilic fasciitis (EF) is a rare connective tissue disease characterized by increased peripheral blood eosinophils and diffuse fasciitis, generalized morphea (GM) is a subtype of localized scleroderma, and IgA nephropathy is a chronic glomerulonephritis caused by abnormal deposition of IgA in the mesangial area of the glomeruli. We describe a 49-year-old male patient with hard skin, cutaneous hyperpigmentation, and proteinuria. The patient had suffered from a long disease course of hard skin, while urine protein was newly detected. Finally, the clinical presentation and physical examination, limb MRI, skin biopsy, and renal biopsy confirmed the diagnosis of eosinophilic fasciitis associated with generalized morphea and IgA nephropathy. This case is the first report of EF associated with GM and IgA nephropathy.	0
Segmental infantile hemangiomas (IH) can be associated with congenital anomalies in a regional distribution. PHACE refers to large cervicofacial segmental IH in association with congenital anomalies of the aortic arch and medium-sized arteries of the head and neck, as well as structural anomalies of the posterior fossa and eye. A subset of PHACE patients have arterial anomalies that progress to moyamoya vasculopathy (MMV). MMV is defined as stenosis of the supraclinoid segment of the internal carotid arteries and/or their major branches, with subsequent development of a compensatory collateral vessel network. We describe a patient with MMV and segmental IH on the back and lower body who meets diagnostic criteria for PHACE based on a posterior segment eye anomaly and cerebral arterial anomalies. Whole exome sequencing demonstrated two inherited heterozygous variants in RNF213. Variants in RNF213 are associated with increased susceptibility to MMV. Our findings suggest that RNF213 variants may play a role in the development of MMV in patients with hemangioma syndromes associated with congenital cerebral arterial anomalies.	0
Chromosome 6q24-related transient neonatal diabetes mellitus is characterized by intrauterine growth restriction and low birth weight, with neonatal hyperglycemia resolving by 18 months and an increased risk for type 2 diabetes in adulthood. Molecularly, it is caused by overexpression of the 6q24 imprinted chromosomal region due to a duplication, uniparental disomy, or abnormal methylation. Conventional testing for this condition analyzes methylation patterns at the 6q24 locus but does not evaluate for the presence of other surrounding chromosomal abnormalities. We report a female with a history of neonatal hyperglycemia due to a paternally inherited duplication at chromosomal location 6q24. She subsequently presented to the pediatric genetics clinic at 15 months of age with developmental delay and abnormal balance. Microarray analysis identified a larger 14 Mb chromosomal duplication from 6q24 to 6q25.2, consistent with a diagnosis of duplication 6q syndrome. This case highlights the clinical importance of pursuing further genetic evaluation in patients diagnosed with chromosome 6q24-related neonatal hyperglycemia via targeted methylation-specific multiplex ligation-dependent probe amplification analysis identifying a duplication in this region. Early identification and intervention can improve developmental outcomes for patients with larger chromosome 6q duplications.	0
Osteopetrosis (OP) is a group of rare sclerosing bone dysplasia characterized by increased bone density. The benign autosomal dominant form is the most common type. It typically carries a full life expectancy, despite increased propensity for fractures and other musculoskeletal problems, particularly hip osteoarthritis. In the current literature, the youngest OP patient having hip osteoarthritis is 16 years of age and treated with total hip arthroplasty. Within the present study, a 16-year-old female patient with early-onset hip osteoarthritis treated with hip joint debridement and femoral head reshaping is presented. The pain relieved and hip joint movements recovered to almost normal range. At the final follow-up at 2 years after the surgery, the patient was still free of pain and ambulating without restriction. Hip joint debridement and femoral shaping may be beneficial in hip osteoarthritis secondary to OP in adolescents, and may delay hip arthroplasty in a young age.	0
Sjögren-Larsson syndrome (SLS) is a rare inborn error of lipid metabolism. The syndrome is caused by mutations in the ALDH3A2 gene, resulting in a deficiency of fatty aldehyde dehydrogenase. Most patients have a clearly recognizable severe phenotype, with congenital ichthyosis, intellectual disability, and spastic diplegia. In this study, we describe two patients with a remarkably mild phenotype. In both patients, males with actual ages of 45 and 61 years, the diagnosis was only established at an adult age. Their skin had been moderately affected from childhood onward, and both men remained ambulant with mild spasticity of their legs. Cognitive development, as reflected by school performance and professional career, had been unremarkable. Magnetic resonance spectroscopy of the first patient was lacking the characteristic lipid peak. We performed a literature search to identify additional SLS patients with a mild phenotype. We compared the clinical, radiologic, and molecular features of the mildly affected patients with the classical phenotype. We found 10 cases in the literature with a molecular proven diagnosis and a mild phenotype. Neither a genotype-phenotype correlation nor an alternative explanation for the strikingly mild phenotypes was found. New biochemical techniques to study the underlying metabolic defect in SLS, like lipidomics, may in the future help to unravel the reasons for the exceptionally mild phenotypes. In the meantime, it is important to recognize these mildly affected patients to provide them with appropriate care and genetic counseling, and to increase our insights in the true disease spectrum of SLS.	0
OBJECTIVES: The aim of this study was to investigate the period prevalences of ANCA-associated vasculitides (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic GPA (EGPA)/Churg-Strauss and GCA, in an urban and rural population in northern Germany in 2006 and to compare the data with our previous study performed in 1994. METHODS: We identified of all patients with AAV or GCA via questionnaires to all hospital departments, physicians, health insurance providers, pension funds, reference laboratories for autoimmune diseases and death registries in Luebeck (city) and the rural region of Segeberg (population 468 962) between January and December 2006. The type of vasculitis, gender, year of birth, postal code and death were documented and re-evaluated. RESULTS: One-hundred and fifty patients were identified, indicating a prevalence of 320 per million inhabitants for the complete catchment area (95% CI 285, 355). GCA was more prevalent than AAV: 171 (146, 197) vs 149 (126, 174). GCA and AAV have almost doubled since 1994. GCA increased from 240 (164, 315) to 440 (399, 481) per million in the population ≥ 50 years of age and AAV increased from 74 to 149 cases per million. GCA and AAV were more prevalent in the urban compared with the rural region. CONCLUSION: The prevalence rates of AAV and GCA almost doubled from 1994 to 2006 for this region with a stable population and using an identical study design. Increased awareness has led to an earlier diagnosis of systemic vasculitis and improved activity-adapted treatment mostly based on randomized controlled trials has led to longer survival. Aspects such as environmental factors and exposure to certain substances need further research.	1
Short stature is a common and heterogeneous condition that is often genetic in etiology. For most children with genetic short stature, the specific molecular causes remain unknown; but with advances in exome/genome sequencing and bioinformatics approaches, new genetic causes of growth disorders have been identified, contributing to the understanding of the underlying molecular mechanisms of longitudinal bone growth and growth failure. Identifying new genetic causes of growth disorders has the potential to improve diagnosis, prognostic accuracy, and individualized management, and help avoid unnecessary testing for endocrine and other disorders.	0
BACKGROUND:The 18p terminal deletion with inverted duplication is an extremely rare chromosome structure abnormality and the common clinical manifestations include intellectual disability and speech delay, etc. Up to now, only three confirmed cases were reported in Europe, and here, for the first time in the Asian population, we report a case of de novo 18p inv-dup-del in a Chinese pregnant woman. This structural variation was accidentally discovered by the noninvasive prenatal testing (NIPT) during her prenatal examination. METHODS:Next generation sequencing (NGS) based copy number variations (CNVs) screening and karyotype analysis were performed to verify the type and heredity of the rearrangement, and the fluorescent in situ hybridization (FISH) analysis was also used to confirm the terminal deletion and inverted duplication. RESULTS:The patient has a de novo 18p11.31-18p11.1 inverted duplication with a 6.2 Mb 18p terminal deletion. This rare chromosome imbalance, most likely caused by the U-type exchange mechanism, resulted in the aberrant phenotype of mental disability, speech delay, seizure, and strabismus. However, the rearrangement was not inherited by her unborn child. CONCLUSION:This report added a new type of variation to the spectrum of 18p terminal deletion with inverted duplication, and demonstrated that the maternal chromosome rearrangement discovered in NIPT should not just be consider as an interference factor but also a potential indicator of previously undiscovered pathogenic chromosome structure variations in pregnant women.	0
OBJECTIVE:To analyze the clinical features and pathogenesis of a fetus with holoprosencephaly. METHODS:The findings of prenatal ultrasonography was reviewed. Following elective abortion, whole exome sequencing (WES) was carried out to identify potential pathogenic variant. Copy number variants (CNVs) of the abortus and its parents were detected by low-depth high-throughput sequencing. The parents were also analyzed by chromosomal karyotyping. RESULTS:Prenatal ultrasound suggested that the fetus had holoprosencephaly. WES revealed that it had approximately 33 Mb deletion at chromosome 13 involving ZIC2, a haploid dose sensitive gene. The results of low-depth high-throughput sequencing confirmed that the fetus carried a de novo 32.32 Mb deletion at 13q31.1-34. Karyotyping analysis has excluded gross chromosomal aberration in both parents. CONCLUSION:The fetus was diagnosed with holoprosencephaly, which may be attributable to the 13q31.1-34 deletion involving the ZIC2 gene.	0
Peruvians currently preserve in their DNA the history of 2.5 million years of human evolution and 150,000 years of migration from Africa to Peru or the Americas. The development of Genetics and Genomics in the clinical and academic field is shown in this review.	0
Aim:To demonstrate the demographic data, subgroup distributions, responses to treatment and outcomes of long-term follow-up in patients who were followed up and treated in our clinics with a diagnosis of juvenile idiopathic arthritis, and to compare these data with national and international data. Material and Methods:The files of 116 patients who had been diagnosed as having juvenile idiopathic arthritis, were initiated on treatment and presented for regular follow-up visits between January 2012 and January 2018, were examined. Their demographic findings, treatments, active/inactive disease states (on-medication and off-medication) and treatment response states were evaluated. Results:According to the International League of Associations for Rheumatology criteria, the subtypes were specified as enthesitis-related arthritis (n=38), oligoarticular (n=37), rheumatoid factor (-) polyarticular (n=17), systemic (n=15), rheumatoid factor (+) polyarticular (n=5), and psoriatic juvenile idiopathic arthritis (n=4). In total, the female/male ratio was found to be 1.5. The mean delay time between the first complaint and the diagnosis was found to be 5.7±5.2 months. The patients with systemic type were diagnosed at the earliest, while the patients with polyarticular and enthesitis-related subtypes were diagnosed at the latest. Thirty-two percent of the patients were treated with methotrexate alone, and 38% were given additional biologic drugs. In both treatment groups, the time to achieve inactive disease was the shortest in the oligoarticular group and the longest in the enthesitis-related arthritis group. In the study period, 38 patients were in remission off-medication (the highest rate (53.3%) was observed in the systemic group) and 71 patients were in remission on-medication (the highest rate (70.2%) was observed in the oligoarticular group). Remission was obtained in 94% of the patients. Conclusion:Enthesitis which is the remarkable finding of enthesitis-related arthritis, should not be overlooked in routine physical examination. Awareness of enthesitis can contribute to the prevention of diagnostic delay in children with enthesitis-related arthritis.	0
Spastic paraplegia type 7 (SPG7), which represents one of the most common forms of autosomal recessive spastic paraplegia (MIM#607259), often manifests with a complicated phenotype, characterized by progressive spastic ataxia with evidence of cerebellar atrophy on brain MRI. Recent studies have documented the presence of peculiar dentate nucleus hyperintensities on T2-weighted images and frontal executive dysfunction in neuropsychological tests in SPG7 patients. Therefore, we decided to assess whether any particular MRI pattern might be specifically associated with SPG7 mutations and possibly correlated with patients' cognitive profiles. For this purpose, we evaluated six SPG7 patients, studying the cerebello-cortical network by MRI voxel-based morphometry and functional connectivity techniques, compared to 30 healthy control subjects. In parallel, we investigated the cognitive and social functioning of the SPG7 patients. Our results document specific cognitive alterations in language, verbal memory, and executive function in addition to an impairment of social task and emotional functions. The MRI scans showed a diffuse symmetric reduction in the cerebellar gray matter of the right lobule V, right Crus I, and bilateral lobule VI, together with a cerebral gray matter reduction in the lingual gyrus, precuneus, thalamus, and superior frontal gyrus. The evidence of an over-connectivity pattern between both the right and left cerebellar dentate nuclei and specific cerebral regions (the lateral occipital cortex, precuneus, left supramarginal gyrus, and left superior parietal lobule) confirms the presence of cerebello-cortical dysregulation in different networks involved in cognition and social functioning in SPG7 patients.	0
BACKGROUND:Pulmonary hypertension (PH) causes increased morbidity and mortality in patients with interstitial lung diseases (ILD). Classification schemes, while well-characterised for the vasculopathy of idiopathic PH, have been applied, unchallenged, to ILD-related PH. We evaluated pulmonary arterial histopathology in explanted human lung tissue from patients who were transplanted for advanced fibrotic ILD. METHODS:Lung explants from 38 adult patients who underwent lung transplantation were included. Patients were divided into three groups: none, mild/moderate and severe PH by mean pulmonary artery pressure (mPAP) measured at pre lung transplantation right heart catheterisation (RHC). Grading of pulmonary vasculopathy according to Heath and Edwards scheme, and prelung transplantation evaluation data were compared between the groups. RESULTS:38 patients with fibrotic ILDs were included, the majority (21) with idiopathic pulmonary fibrosis. Of the 38 patients, 18 had severe PH, 13 had mild/moderate PH and 7 had no PH by RHC. 16 of 38 patients had severe pulmonary arterial vasculopathy including vascular occlusion with intimal fibrosis and/or plexiform lesions. There were no correlations between mPAP and lung diffusion with the severity of pulmonary arterial pathological grade (Spearman's rho=0.14, p=0.34, rho=0.11, p=0.49, respectively). CONCLUSIONS:Patients with end stage ILD had severe pulmonary arterial vasculopathy in their explanted lungs irrespective of the presence and/or severity of PH as measured by RHC. These findings suggest that advanced pulmonary arterial vasculopathy is common in patients with advanced fibrotic ILD and may develop prior to the clinical detection of PH by RHC.	0
STUDY OBJECTIVE:Mayer-Rokitansky-Küster-Hauser Syndrome (MRKH) is a female reproductive disorder characterised by absence or underdevelopment of the uterus, cervix and vagina. Limited research has examined factors related to psychological adjustment in MRKH. This study aimed to explore associations between illness representations, self-concept, psychological distress and self-esteem in MRKH. DESIGN:Cross-sectional. SETTING:Participants were recruited globally online and from patient meetings. PARTICIPANTS:263 people with MRKH (ages 16.1-74.4; M=31.7) completed questionnaires INTERVENTION: None. MAIN OUTCOME MEASURES:Validated self-reported measures of psychological distress and self-esteem (outcomes) and illness representations, self-concept, social support-seeking, and positive affect (hypothesised correlates) were explored in correlation and hierarchical regression analyses alongside demographic and clinical variables. RESULTS:Younger age and shorter time since diagnosis was associated with higher distress and lower self-esteem. People with MRKH reported significantly higher distress and lower self-esteem than the general population. Higher distress and lower self-esteem were associated with higher reported engulfment (defining one's identity or feeling consumed by MRKH) and beliefs about the serious consequences of MRKH, and lower reported MRKH coherence, enrichment (positive changes to self-identity because of MRKH) and positive affect. CONCLUSIONS:Findings suggest that the impact of MRKH on identity plays an important role in adjustment. High perceived coherence and maintenance of positive affect may play a protective role in psychological adjustment. A 12-month follow-up study is planned to examine associations between these variables longitudinally. Baseline data suggest that early availability of psychological support would be beneficial, and interventions focused on identity and psychoeducation about MRKH would be valuable.	0
X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare congenital immunodeficiency disease. We report the case of an 18-year-old male who developed hemophagocytic lymphohistiocytosis (HLH) with neurologic complications after primary Epstein-Barr virus (EBV) infection and subsequently developed EBV-related central nervous system lymphoma (CNSL). Given the vulnerability to EBV, he was finally diagnosed with XLP1 and treated with whole-brain irradiation along with chemotherapy and subsequent allogeneic hematopoietic stem cell transplantation from a SH2D1A wild-type sibling donor. Although the prognosis for CNSL is generally dismal, reconstitution of the immune system from a normal donor contributed to the patient remaining in remission for 30 months.	0
Background: Granulomatous interstitial nephritis (GIN) is uncommon in native kidneys, and descriptions in allografts are few. We report clinical and pathologic findings in 22 allograft recipients with GIN identified in renal allograft biopsies and nephrectomies. Methods: Renal allografts with GIN were retrieved from the pathology files of two academic medical centers. Available clinical and pathologic data were compiled retrospectively for a 23-year period. Results: GIN was present in 23 specimens from 22 patients (15 males and 7 females) with allograft dysfunction [serum creatinine averaged 3.3 mg/dL (range 1.4-7.8)], at a mean age of 48 years (range 22-77). GIN was identified in 0.3% of biopsies at a mean of 552 days post transplantation (range 10-5898). GIN was due to viral (5), bacterial (5) and fungal (2) infections in 12 (54.5%), and drug exposure was the likely cause in 5 cases (22.7%). One had recurrent granulomatosis with polyangiitis. In 4 cases, no firm etiology of GIN was established. Of 18 patients with follow up data, 33.3% had a complete response to therapy, 44.5% had a partial response and 22.2% developed graft loss due to fungal and E. coli infections. All responders had graft survival for more than 1 year after diagnosis of GIN. Conclusions: Allograft GIN is associated with a spectrum of etiologic agents and was identified in 0.3% of biopsies. Graft failure occurred in 22% of this series, due to fungal and bacterial GIN; however, most had complete or partial dysfunction reversal and long-term graft survival after appropriate therapy.	0
BACKGROUND:Tracheal agenesis (TA) is a rare disorder usually diagnosed prenatally when a congenital high airway obstruction syndrome (CHAOS) is identified. We present a case of unexpected TA in a neonate without prenatal diagnosis of airway obstruction, with a difficult management at birth. Moreover, we discuss about differential diagnosis, classification and treatment issues. CASE PRESENTATION:A 2280 g female neonate was born at 35 week gestational age (GA) with prenatal diagnosis of aortic coarctation, polyhydramnios and diffuse hyperechogenicity of the right lung. At birth, the neonate had no audible cry, no air entry to the lungs, and hypotonia. Tracheal intubation was unsuccessful, and no visualization of the trachea was obtained when tracheostomy was attempted. Post-mortem examination showed tracheal agenesis associated with tracheoesophageal fistula and revealed no cardiologic malformations. Aortic coarctation had been suspected prenatally because of the first portion of the descendent thoracic aorta being compressed by a fibrous band connecting the proximal and distal tracheal branches. CHAOS had not developed due to the tracheoesophageal fistula (TOF). CONCLUSIONS:TA is not always diagnosed in the fetus and it may present unexpectedly making the neonate's management at birth critical. An effective rescue temporary oxygenation may be obtained with mask ventilation or oesophageal intubation in those cases of TA associated with a TOF. We suggest to consider a fetal magnetic resonance imaging (MRI) when the association polyhydramnios/lung hyperechogenicity occurs, even in the absence of CHAOS or other malformations. Once a diagnosis is provided, the mother should be transferred to selected centres where an ex-utero intrapartum procedure (EXIT) can be attempted. Moreover, despite high mortality, different surgical management are described to improve survival.	0
OBJECTIVE:To identify concepts and constructs important to parents of children with Pierre Robin Sequence (PRS). DESIGN:Qualitative study. SETTING:All children received some care at a tertiary hospital with additional care at outside facilities. Interviews were conducted in nonclinical locations, including remote locations. PARTICIPANTS:Parents of children <5 years old with a diagnosis of PRS. Prior treatments included observation, positioning, nasal trumpet, mandibular distraction osteogenesis, tracheostomy, and gastrostomy. INTERVENTION:Semi-structured interviews with individuals (4) and with groups (focus groups, 4) were conducted using open-ended questions and non-leading prompts. Transcripts were analyzed with iterative open and axial coding. Concepts and constructs were identified and refined into codes and central themes. Interviews were conducted until thematic saturation was achieved. RESULTS:Sixteen parents were interviewed. Their experiences were coded into 5 main themes, which can be summarized as: (1) child's symptoms/well-being, (2) parents' grief/isolation, (3) family stress, (4) relationships with providers, and (5) psychological and technical growth. Difficulty with feeding, weight gain, and breathing problems were core physical issues described by participants with associated intense fear. Participants described frustration from not only lack of care coordination, slow diagnoses, and poor communication but also gratitude for providers who served as advocates. Participants described gradual development of knowledge/competencies. CONCLUSIONS:Families of children with PRS have experiences that profoundly affect their lives. Child's physical symptoms/well-being and parents' psychosocial well-being provide content for a future PRS-specific quality-of-life instrument. Concepts that emerged also provide a framework to improve parents' experience and enhance their children's quality of care.	0
OBJECTIVE:Large, population-based assessments of systemic sclerosis (SSc) prevalence and comorbidity in the United States (US) are rare. We explored autoimmune disease and other comorbidity patterns among SSc patients in the US from 2001 to 2002 and compared these with controls. RESEARCH DESIGN AND METHODS:Two US datasets with patient-level medical and drug claims were used to assess SSc prevalence and comorbidity: IMS Health Integrated Administrative Claims Database (IMS Health) and the MarketScan Commercial Claims and Encounters Database (MarketScan). SSc patients and comorbidities were identified by International Classification of Diseases (ICD), 9th revision diagnostic codes appearing on medical claims. Patients without SSc diagnostic codes (controls) were selected and matched 4:1 to SSc patients based on sex, age, Census Bureau region, and previous insurance coverage. The prevalence relative risk (RR) statistic compared comorbidity occurrence between SSc patients and controls, with 95% confidence intervals estimated using the Mantel-Haenszel method. Several sensitivity analyses tested methods used for identifying SSc cases and the prevalence of comorbidities. RESULTS:In both databases, SSc prevalence was 0.05% using the standard population model, 0.03% under sensitivity analysis. Among SSc patients the risks for inflammatory bowel disease (IBD) and multiple sclerosis (MS) were notably higher across datasets than for those without SSc: RR 3.2-6.6 for MS, RR 2.1-2.2 for IBD, in MarketScan and IMS Health, respectively (p < 0.05 for all). The chronic disease burden of SSc patients was much higher than that of controls, as confirmed by two chronicity measures (Chronic Disease Score, Elixhauser Comorbidity Index). The risks for cardiovascular, renal, liver and several neuropsychiatric diseases were higher for SSc patients across both datasets. Sensitivity analyses supported these findings. CONCLUSIONS:These data provide a population-based estimate of US prevalence of SSc and document the higher risk for certain other autoimmune diseases among SSc patients when compared to controls. Patients with SSc also had a higher chronic disease burden than those without SSc. These findings are limited by the unknown validity of ICD-9 codes for SSc case identification, unbalanced regional representation, and a likely 'healthy worker' effect in these databases.	1
Graham Little-Piccardi-Lassueur syndrome (GLPLS) is a rare variant of lichen planopilaris, characterized by a triad of clinical signs including follicular spinous papules on the body area, scarring alopecia of the scalp and non-scarring alopecia of the groin and/or axilla. To date, fewer than 50 cases have been described in the literature. We first report a case of GLPLS investigated with non-invasive techniques such as dermoscopy and in vivo reflectance confocal microscopy (RCM) and successfully treated with narrowband-UVB (NB-UVB) phototherapy.	0
Skin color is determined by the number of melanin granules produced by melanocytes that are transferred to keratinocytes. Melanin synthesis and the distribution of melanosomes to keratinocytes within the epidermal melanin unit (EMU) within the skin of vitiligo patients have been poorly studied. The ultrastructure and distribution of melanosomes in melanocytes and surrounding keratinocytes in perilesional vitiligo and normal skin were investigated using transmission electron microscopy (TEM). Furthermore, we performed a quantitative analysis of melanosome distribution within the EMUs with scatter plot. Melanosome count within keratinocytes increased significantly compared with melanocytes in perilesional stable vitiligo (P < 0.001), perilesional halo nevi (P < 0.01) and the controls (P < 0.01), but not in perilesional active vitiligo. Furthermore, melanosome counts within melanocytes and their surrounding keratinocytes in perilesional active vitiligo skin decreased significantly compared with the other groups. In addition, taking the means-standard error of melanosome count within melanocytes and keratinocytes in healthy controls as a normal lower limit, EMUs were graded into 3 stages (I-III). Perilesional active vitiligo presented a significantly different constitution in stages compared to other groups (P < 0.001). The distribution and constitution of melanosomes were normal in halo nevi. Impaired melanin synthesis and melanosome transfer are involved in the pathogenesis of vitiligo. Active vitiligo varies in stages and in stage II, EMUs are slightly impaired, but can be resuscitated, providing a golden opportunity with the potential to achieve desired repigmentation with an appropriate therapeutic choice. Adverse milieu may also contribute to the low melanosome count in keratinocytes.	0
Gastrointestinal tract is the most common extranodal site for childhood non-Hodgkin lymphomas (NHLs). However, primary gastric lymphoma (PGL) is very rare. We report our experience with PGL. Between 1972 and 2019, patients with PGL among 1696 NHL cases were evaluated retrospectively. Patient characteristics, treatments, and survival rates were recorded. We also reviewed the cases reported in literature. There were 16 PGL (11 males, five females) cases with a median age of 10 years. Most frequent complaints, similarly to the literature, were pain and vomiting. Hematemesis/melena and anemia were present in 20% of patients. Most common tumor location was antrum. Histopathological subtypes were Burkitt and non-Burkitt B-cell lymphoma in 43.75% and marginal zone lymphoma (MZL) in 6.25% of cases while mucosa-associated lymphoid tissue (MALT) and low-grade lymphomas constitute 15.3% of cases reported in the literature. In our series, Helicobacter pylori (H. pylori) was analyzed in only the case with MZL and found to be positive. However, H. pylori positivity was reported in 75% of the cases in the literature. H. pylori eradication, chemotherapy, and radiotherapy were applied in one, 14, and five patients. Subtotal gastrectomy with gastroduodenostomy/jejunostomy was performed in three patients. Gastrojejunostomy was done without tumor resection in two patients. Nine patients lived without disease for a median of 59 (12-252) months. Five-year EFS and OS were 69.6% and 64.3%, respectively. PGL constitutes 0.94% of our NHL cases. Interestingly, most of the cases in the literature were from Turkey. While adult PGL is mostly MALT lymphoma, most pediatric cases had high-grade histopathology. Although surgery and radiotherapy were applied earlier, chemotherapy alone is sufficient.	0
To enhance understanding of the metabolic indicators of type 2 diabetes mellitus (T2DM) disease pathogenesis and progression, the urinary metabolomes of well characterized rhesus macaques (normal or spontaneously and naturally diabetic) were examined. High-resolution ultra-performance liquid chromatography coupled with the accurate mass determination of time-of-flight mass spectrometry was used to analyze spot urine samples from normal (n = 10) and T2DM (n = 11) male monkeys. The machine-learning algorithm random forests classified urine samples as either from normal or T2DM monkeys. The metabolites important for developing the classifier were further examined for their biological significance. Random forests models had a misclassification error of less than 5%. Metabolites were identified based on accurate masses (<10 ppm) and confirmed by tandem mass spectrometry of authentic compounds. Urinary compounds significantly increased (p < 0.05) in the T2DM when compared with the normal group included glycine betaine (9-fold), citric acid (2.8-fold), kynurenic acid (1.8-fold), glucose (68-fold), and pipecolic acid (6.5-fold). When compared with the conventional definition of T2DM, the metabolites were also useful in defining the T2DM condition, and the urinary elevations in glycine betaine and pipecolic acid (as well as proline) indicated defective re-absorption in the kidney proximal tubules by SLC6A20, a Na(+)-dependent transporter. The mRNA levels of SLC6A20 were significantly reduced in the kidneys of monkeys with T2DM. These observations were validated in the db/db mouse model of T2DM. This study provides convincing evidence of the power of metabolomics for identifying functional changes at many levels in the omics pipeline.	0
Breast reconstruction patients frequently desire consecutive or simultaneous contralateral breast reduction. When combining the requirements of both autologous breast reconstruction with symmetrizing breast reduction, a 2-staged contralateral pedicled breast sharing is a dignified alternative. We present a 60-year-old woman with a radical mastectomy and adjuvant radiotherapy. On the contralateral side, she had a hypertrophic breast with a desire for reduction mammaplasty. A 2-stage procedure for breast sharing was planned. A preoperative computed tomography scan, to assess the status of the fourth intercostal mammary perforator (IMAP), was performed. After the first procedure, symmastia was evident. Water-assisted liposuction and quilting sutures to the sternal periosteum were applied in a second procedure to correct the symmastia. We preserved the fourth intercostal perforator to provide optimal vascularization. Water-assisted liposuction and quilting sutures were used to correct the remaining symmastia and contributed to the aesthetics of both breasts. A drawback of this procedure is the need for multiple stages. Furthermore, oncological safety should be considered and surgeons should be aware of the risk for venous congestion. Breast-sharing could be a feasible alternative reconstruction for women seeking unilateral breast reconstruction with contralateral breast hypertrophy. It reduces the need for free-flap surgery and subsequent donor-site morbidity. Considering the fact that the contralateral breast must be of significant size, the indication for this type of reconstruction is limited.	0
BACKGROUND:Nondiarrheal or Streptococcus pneumoniae-related hemolytic uremic syndrome (HUS) represents a heterogeneous group of disorders. This study was performed to: (1) describe the current incidence, causes, demographic features, hospital courses, and short-term outcomes of non-enteropathic HUS; (2) compare findings in patients with non-enteropathic HUS with those obtained from a contemporaneous cohort of children with enteropathic or diarrhea-associated HUS (D+ HUS) diagnosed and treated at the same clinical sites; and (3) identify clinical or laboratory features that differentiate these 2 groups and predict disease severity and the short-term outcome in patients with non-enteropathic HUS. METHODS:Data were collected from patients screened between 1997 and 2001 for enrollment in a multicenter trial of SYNSORB Pk (SYNSORB Biotech Inc, Calgary, Alberta, Canada) in D+ HUS, but who were ineligible because of lack of a diarrhea prodrome. The following features were recorded: age; sex; ethnicity; prodromal symptoms; cause; nadir values for hemoglobin, hematocrit, and platelet count; use of dialysis; and length of hospitalization. RESULTS:Twenty-seven of 247 children with HUS had non-enteropathic HUS (11%). Twenty-four patients (15 boys, 9 girls), whose medical records were complete and available for review, comprise the study cohort. Mean age at onset was 4.2 +/- 0.9 (SE) years. Infection caused by S pneumoniae was diagnosed in 9 patients (38%). Dialysis was performed in 17 patients (71%) for 40 +/- 27 days. Median length of hospitalization was 22 days (range, 2 to 71 days). Children with S pneumoniae-related HUS had a longer hospital stay than those with other causes of non-enteropathic HUS, but all patients with S pneumoniae-related HUS recovered kidney function. Dialysis therapy was required more often (17 of 24 versus 59 of 145 children; P = 0.025) and hospital stays were longer (median, 22 versus 9 days; P = 0.002) in children with non-enteropathic HUS compared with patients with D+ HUS who were enrolled in the SYNSORB Pk clinical trial. CONCLUSION:(1) The incidence of non-enteropathic HUS is approximately one tenth that of D+ HUS; (2) patients with non-enteropathic HUS require dialysis therapy more often and are hospitalized more than twice as long during the acute episode compared with those with D+ HUS; (3) infection caused by S pneumoniae accounts for nearly 40% of cases of non-enteropathic HUS; and (4) although S pneumoniae-related HUS is associated with a less favorable short-term course than other types of non-enteropathic HUS or D+ HUS, the long-term prognosis for recovery of renal function appears to be good in these patients.	1
Gastric lactobezoars are a result of the inability to digest milk and mucous. Formulas that contain high casein concentrations, medium triglyceride oils, or high caloric density can increase the risk of bezoar formation by decreasing gastric secretion or delaying gastric emptying. N-acetylcysteine (NAC) is used to clear thick mucus secretions and is hypothesized to be effective in the treatment of gastric lactobezoars due to the cleavage of disulfide bonds in mucoproteins. We describe the use of NAC in a 1-month-old full term male (4.5 kg) who was diagnosed with a gastric lactobezoar following an upper gastrointestinal series that showed a large persistent filling defect in the distal body, which was suggestive of a gastric lactobezoar. A dose of 45 mg (10 mg/kg) of 10% NAC was diluted in 50 mL of normal saline and given every 6 hours via a nasogastric (NG) tube. Administration was followed by clamping of the NG tube for 2 hours and aspiration of the stomach contents. NAC was discontinued when aspirates were a clear mucus consistency. The patient's gastric lactobezoar was successfully treated with a 10 mg/kg/dose of NAC that was given every 6 hours for a total of 4 doses.	0
Immune thrombocytopenia (ITP), an acquired autoimmune disorder of low platelets and risk of bleeding, has a substantial impact on health-related quality of life (HRQoL). Patients with ITP often report significant fatigue, although the pathophysiology of this is poorly understood. In this observational cohort of 120 children receiving second-line therapies for ITP, we assessed reports of fatigue using the Hockenberry Fatigue Scale. Children and adolescents with ITP reported a similarly high level of fatigue with 54% (29/54) of children and 62% (26/42) of adolescents reporting moderate-to-severe fatigue. There was no correlation between fatigue and age or gender. Adolescents with newly diagnosed and persistent ITP had higher mean fatigue scores than those with chronic ITP (P = 0·03). Fatigue significantly improved in children and adolescents by 1 month after starting second-line treatments, and this improvement continued to be present at 12 months after starting treatment. Fatigue scores at all time-points correlated with general HRQoL using the Kids ITP Tool, but did not correlate with bleeding symptoms, platelet count, or platelet response to treatment. Fatigue is common in children and adolescents with ITP and may benefit from ITP-directed treatment even in the absence of bleeding symptoms.	0
A national distribution of 66 French patients, from 49 sibships, has been studied. Segregation analysis, using the maximum likelihood method, was found to agree with the theoretical values expected in recessive autosomal inheritance. The birthplaces of these patients show an unequal geographic distribution of cystinosis, the incidence being higher in Western France. Compared with the total number of live births during the period 1959 to 1972, the minimum incidence of the condition in the province of Brittany is 1 per 25 909, and the gene frequency 0.0062. In the rest of France, the minimum incidence is 1 per 326,440 and the gene frequency 0.0018. Application of Dahlberg's formula gives a similar result. The mean inbreeding coefficient is 530 X 10(-5), a figure 23 times higher than the mean coefficient of France. An indirect test of inbreeding, the distance between parental birthplaces, was studied, first using the French administrative boundaries, second by using kilometers. This distance was constantly smaller for the parents of patients than for the parents of controls. Analysis of two erythrocyte polymorphisms (ABO and Rh) showed a large excess of group A patients when compared with overall French data. These findings are difficult to interpret on genetic grounds. The genetic reasons for the unequal geographic distribution of cystinosis in France are discussed.	1
We delivered plasmid DNA encoding therapeutic genes to the muscles of mouse models of limb girdle muscular dystrophy (LGMD) 2A, 2B, and 2D, deficient in calpain3, dysferlin, and alpha-sarcoglycan, respectively. We also delivered the human follistatin gene, which has the potential to increase therapeutic benefit. After intramuscular injection of DNA, electroporation was applied to enhance delivery to muscle fibers. When plasmids encoding the human calpain3 or dysferlin cDNA sequences were injected into quadriceps muscles of LGMD2A and LGMD2B mouse models, respectively, in 3-month studies, robust levels of calpain3 and dysferlin proteins were detected. We observed a statistically significant decrease in Evans blue dye penetration in LGMD2B mouse muscles after delivery of the dysferlin gene, consistent with repair of the muscle membrane defect in these mice. The therapeutic value of delivery of the genes for alpha-sarcoglycan and follistatin was documented by significant drops in Evans blue dye penetration in gastrocnemius muscles of LGMD2D mice. These results indicated for the first time that a combined gene therapy involving both alpha-sarcoglycan and follistatin would be valuable for LGMD2D patients. We suggest that this non-viral gene delivery method should be explored for its translational potential in patients.	0
Studies on the association of maternal exposure to polychlorinated dibenzo-p-dioxin (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) with decreased birth weight in humans have produced conflicting results. In Japan in 1968, an accidental human exposure to rice oil contaminated with PCDDs, PCDFs, and PCBs, led to the development of Yusho disease.The Yusho cohort was used to evaluate the effect of maternal exposure to PCDDs, PCDFs, and PCBs on birth weight.Blood samples, obtained from 101 Yusho women (190 births) who gave birth after exposure, were analyzed for congeners of seven PCDDs, ten PCDFs, and four non-ortho PCBs.Total PCDD TEQ (adjusted beta=-161.9g; 95% CI, -265.3 to -58.6), total PCDF TEQ (adjusted beta=-105.9g; 95% CI, -179.5 to -32.2), and total non-ortho PCBs (adjusted beta=-178.4g; 95% CI, -318.3 to -38.5) levels were inversely associated with birth weight. Significant inverse associations with birth weight were also found for total PCDD TEQ, total PCDF TEQ, and total non-ortho PCB TEQ levels among male, but not female, infants. Significant inverse associations with birth weight were also found for nine congeners among all infants; the adjusted beta coefficients were largest for 1,2,3,6,7,8-HxCDD and smallest for 2,3,4,7,8-PeCDF.In the setting of exposure to high levels of dioxins, maternal blood levels of PCDDs, PCDFs and PCBs are associated with lower birth weight in Yusho patients. The association exhibited gender-specific differences, as male infants are more susceptible than females to growth restriction induced by in utero dioxin exposures.	0
Myopathies are a heterogeneous group of disorders that can be challenging to diagnose. This review provides a diagnostic approach based predominantly on the clinical history and neurologic examination. Laboratory testing that can be used to confirm the suspected diagnosis based on this pattern recognition approach is also discussed. Careful consideration of the distribution of muscle weakness and attention to common patterns of involvement in the context of other aspects of the neurologic examination and laboratory evaluation should assist the clinician in making a timely and accurate diagnosis and can sometimes minimize the expense of further testing.	0
Dehydrodolichyl diphosphate synthase (DHDDS) is required for protein N-glycosylation in eukaryotic cells. A K42E point mutation in the DHDDS gene causes an autosomal recessive form of retinitis pigmentosa (RP59), which has been classified as a congenital disease of glycosylation (CDG). We generated K42E Dhdds knock-in mice as a potential model for RP59. Mice heterozygous for the Dhdds K42E mutation were generated using CRISPR/Cas9 technology and crossed to generate DhddsK42E/K42E homozygous mice. Spectral domain-optical coherence tomography (SD-OCT) was performed to assess retinal structure, relative to age-matched wild type (WT) controls. Immunohistochemistry against glial fibrillary acidic protein (GFAP) and opsin (1D4 epitope) was performed on retinal frozen sections to monitor gliosis and opsin localization, respectively, while lectin cytochemistry, plus and minus PNGase-F treatment, was performed to assess protein glycosylation status. Retinas of DhddsK42E/K42E mice exhibited grossly normal histological organization from 1 to 12 months of age. Anti-GFAP immunoreactivity was markedly increased in DhddsK42E/K42E mice, relative to controls. However, opsin immunolocalization, ConA labeling and PNGase-F sensitivity were comparable in mutant and control retinas. Hence, retinas of DhddsK42E/K42E mice exhibited no overt signs of degeneration, yet were markedly gliotic, but without evidence of compromised protein N-glycosylation. These results challenge the notion of RP59 as a DHDDS loss-of-function CDG and highlight the need to investigate unexplored RP59 disease mechanisms.	0
Congenital progressive kyphoscoliosis associated with split spinal cord malformation (SSCM) is a very rare disease.Here, we present the case of a 23-year-old woman who was found kyphoscoliosis when she was 10 years old and developed rapidly. Thereafter, no management was proposed before her consultation at our center. On examination, numbness was found in the right low limbs, kyphoscoliosis was detected in thoracolumbar, the trunk deviated to the right on standing view and curvature of the thoracolumbar spine was left-sided, the left rib hump was severe and there was little muscle tissue felt under the right side paravertebral area, the pelvis was oblique with the right side higher than the left side, the right arcus costarum was 5 cm below the right iliac crest. One-stage corrective surgery was determined, at first, halo-wheelchair traction gradually with increased traction weights out of hospital for a month; then, after a reasonable correction achieved without any neurological deficits. The one-stage operation was taken through single posterior segmental pedicle screw instrumented fusion with VCR between T12 and L1. Post-operative recovery was uneventful and there were no complications, she was discharged 10 days post operation. At 2 years follow-up, the patient's outcome is excellent with balance and correction of the deformity.Based on the Grand Round case and relevant literature, we discuss the different options for the treatment of congenital kyphoscoliosis associated with type I SSCM. In the patient whose kyphoscoliosis is severe and rigid, we recommend an initial release followed by halo-wheelchair traction gradually to correct the deformity, once optimal correction acquires during the traction, the posterior instrumented fusion with VCR upper the bony spur could be done safely without the resection of bony spur.	0
To identify the underlying genetic cause in a two generation German family diagnosed with isolated aniridia.All patients underwent full ophthalmic examination. Mutation screening of the paired box gene 6 (PAX6) was performed by bidirectional Sanger sequencing. A minigene assay was applied to analyze transcript processing of mutant and wildtype PAX6 variants in HEK293 cells.We identified a PAX6 sequence variant at the splice donor site (+5) of intron 12. This variant has been described before in another family with aniridia but has not been characterized at the transcript level. We could demonstrate that the mutant allele causes the skipping of exon 12 during transcript processing. The mutation is predicted to result in a 'run on' translation past the normal translational stop codon.A splice site mutation resulting in exon skipping was found in a family with autosomal dominant aniridia. The mutation is predicted to result in an enlarged protein with an extra COOH-terminal domain. This very likely affects the transactivation properties of the PAX6 protein.	0
PURPOSE:Short stature in children is a significant medical problem which, without proper diagnosis and treatment, can lead to long-term consequences for physical and psychological health in adult life. Since human height is a polygenic and highly heritable trait, numerous variants in the genes involved in growth-including the growth hormone (GH1) gene-have been identified as causes of short stature. METHODS:In this study, we performed for the first time molecular analysis of the GH1 gene in a cohort (n = 186) of Polish children and adolescents with short stature, suffering from growth hormone deficiency (GHD) or idiopathic short stature (ISS), and a control cohort (n = 178). RESULTS:Thirteen SNP variants were identified, including four missense variants, six in 5'UTR, and three in introns. The frequency of minor missense variants was low (<0.02) and similar in the compared cohorts. However, two of these variants, Ala39Val (rs151263636) and Arg42Leu (rs371953554), were found (heterozygote status) in only two GHD patients. These substitutions, according to databases, can potentially be deleterious. CONCLUSIONS:Mutations of GH1 causing short stature are very rare in the Polish population, but two potentially causative variants need further studies in a larger cohort of GHD patients.	0
BACKGROUND:Microtia is a congenital defect characterized by disturbances in the size and form of the ear lobe. Anotia corresponds to the absence of the ear lobe. AIM:To study the prevalence of microtia and anotia at the Maternity of the University of Chile Clinical Hospital. MATERIAL AND METHODS:Analysis of the database of the Latin American Collaborative Study of Congenital Defects (ECLAMC). All newborns and stillborns with congenital defects are incorporated to this database. RESULTS:The prevalence of microtia-anotia in the period 1982-2001 was 8.7 per 10,000 born alive. Chilean hospitals have an uniform prevalence of 5.2 per 10,000 born alive. Thirty seven percent presented as isolated malformations and the rest were associated to other defects. Eighty six percent of non isolated cases were part of a syndrome. Sixty eight percent were mild or moderate forms and the rest, severe forms. Two cases were stillborns and two newborns died before hospital discharge. CONCLUSIONS:The prevalence of microtia in this hospital and in the rest of Chilean hospitals is significantly higher than in the rest of non Chilean hospitals participating in the ECLAMC, that is 4.1 per 10,000 born alive.	1
In the 1980s, after the mitochondrial DNA (mtDNA) had been sequenced, several diseases resulting from mtDNA mutations emerged. Later, numerous disorders caused by mutations in the nuclear genes encoding mitochondrial proteins were found. A group of these diseases are due to defects of mitochondrial carriers, a family of proteins named solute carrier family 25 (SLC25), that transport a variety of solutes such as the reagents of ATP synthase (ATP, ADP, and phosphate), tricarboxylic acid cycle intermediates, cofactors, amino acids, and carnitine esters of fatty acids. The disease-causing mutations disclosed in mitochondrial carriers range from point mutations, which are often localized in the substrate translocation pore of the carrier, to large deletions and insertions. The biochemical consequences of deficient transport are the compartmentalized accumulation of the substrates and dysfunctional mitochondrial and cellular metabolism, which frequently develop into various forms of myopathy, encephalopathy, or neuropathy. Examples of diseases, due to mitochondrial carrier mutations are: combined D-2- and L-2-hydroxyglutaric aciduria, carnitine-acylcarnitine carrier deficiency, hyperornithinemia-hyperammonemia-homocitrillinuria (HHH) syndrome, early infantile epileptic encephalopathy type 3, Amish microcephaly, aspartate/glutamate isoform 1 deficiency, congenital sideroblastic anemia, Fontaine progeroid syndrome, and citrullinemia type II. Here, we review all the mitochondrial carrier-related diseases known until now, focusing on the connections between the molecular basis, altered metabolism, and phenotypes of these inherited disorders.	0
Urinary dysfunctions are not considered symptoms of spinocerebellar ataxias (SCAs). However, given that a patient with SCAs without a family history might be misdiagnosed as MSA-C when having urinary dysfunctions, characterization of urinary dysfunctions in SCAs is needed not only to understand SCAs but also to correctly diagnosis patients with ataxia. We retrospectively reviewed medical records of 143 patients with genetically confirmed SCA1, 2, 3, 6, 7, 17, and DRPLA. Twenty-two patients (men n = 9; age 62.1 ± 10.9; disease duration 8.2 ± 2.9 years) who had lower urinary track symptoms (LUTS) were included in this study. Six patients underwent urodynamic study (UDS), and 2 underwent uroflowmetry. LUTS was present in 1 of 11 patients with SCA1, in 4 of 51 with SCA2, in 2 of 26 with SCA3, in 3 of 20 with SCA6, in 2 of 4 with SCA7, in 8 of 26 with SCA17, and in 2 of 5 with DRPLA. Overall, urinary frequency was the most common symptom (16 patients, 72.7%) followed by voiding difficulty. In three of the 6 patients with UDS, post-micturition residuals were > 100 ml. Detrusor overactivity was noted in three patients. Detrusor areflexia was observed in one. Four patients were diagnosed with a neurogenic bladder, 3 with a storage problem, and 1 with both storage and voiding problems. Fifteen percent of the patients with SCAs had LUTS, and LUTS occurred in various types of SCAs. Our results indicate that SCAs should be considered in patients with progressive cerebellar ataxia and urinary dysfunctions.	0
Phenylalanine hydroxylase (PAH) deficiency is an autosomal recessive disorder of phenylalanine metabolism that is characterized by insufficient activity of PAH, a hepatic enzyme. Throughout this document, PAH deficiency is used instead of the older nomenclature of phenylketonuria, in order to reflect the spectrum of PAH deficiency and in accordance with the terminology established by the American College of Medical Genetics and Genomics. Aspects of PAH deficiency management that are particularly relevant to obstetrician-gynecologists or other obstetric care providers include the prevention of embryopathy associated with maternal hyperphenylalaninemia and PAH deficiency and the risk of genetic transmission of PAH deficiency. Family planning and prepregnancy counseling are recommended for all reproductive-aged women with PAH deficiency. The fetal brain and heart are particularly vulnerable to high maternal concentrations of phenylalanine. The crucial role played by maternal dietary restriction before and during pregnancy should be stressed in counseling patients with PAH deficiency; the goal should be to normalize blood phenylalanine levels (less than 6 mg/dL) for at least 3 months before becoming pregnant and to maintain at 2-6 mg/dL during pregnancy, in order to optimize developmental outcomes for the fetus. Although phenylalanine levels are increased in the breast milk of patients with PAH deficiency, breastfed infants who do not have PAH deficiency have normal enzyme levels and no dietary restriction. Breastfeeding is safe for infants born to women who have PAH deficiency provided the infants do not have PAH deficiency. Coordinated medical and nutritional care, as well as follow-up with the patient's metabolic geneticist or specialist, are important in the postpartum period. Because newborns with PAH deficiency appear normal at birth and early detection can improve developmental outcomes for children, newborn screening for PAH deficiency is mandated in all states. This Committee Opinion has been revised to include updates on advances in the understanding and management of women with PAH deficiency and recommendations on prepregnancy counseling, serial fetal growth assessments, and fetal echocardiography.	0
PURPOSE OF THE REVIEW:This review will provide an overview of the microcephalic primordial dwarfism (MPD) class of disorders and provide the reader comprehensive clinical review with suggested care guidelines for patients with microcephalic osteodysplastic primordial dwarfism, type II (MOPDII). RECENT FINDINGS:Over the last 15 years, significant strides have been made in the diagnosis, natural history, and management of MOPDII. MOPDII is the most common and well described form of MPD. The classic features of the MPD group are severe pre- and postnatal growth retardation, with marked microcephaly. In addition to these features, individuals with MOPDII have characteristic facies, skeletal dysplasia, abnormal dentition, and an increased risk for cerebrovascular disease and insulin resistance. Biallelic loss-of-function mutations in the pericentrin gene cause MOPDII, which is inherited in an autosomal recessive manner.	0
Biliary atresia (BA) is a childhood disease which manifests with abnormal narrowing, blockage or complete absence of bile ducts within the liver. Many possible etiologies have been reported for the development of BA, including congenital, perinatal and acquired conditions. Since the 1970's, there has been increasing evidence linking BA development to viral perinatal infections. The viral vectors most commonly implicated include members of the herpesviridae family (cytomegalovirus and Epstein-Barr virus) as well as those of the reoviridae family (reovirus and rotavirus). While extensive work has been done on a murine model of disease, the current review focuses primarily on evidence from human studies of viral vectors in children afflicted with BA.	0
Frontal fibrosing alopecia (FFA) entails a progressive recession of the frontotemporal hairline resulting in smooth, uniformly-pale skin without follicular openings, in contrast to the sun-damaged skin of the forehead. Skin atrophy and depression of the frontal veins have been described in the alopecic band (AB) in patients with FFA without prior corticosteroid treatment. Despite the remarkable clinical appearance, the histopathological features of the AB have not been studied previously.	0
Mediastinal gray-zone lymphoma (MGZL, lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma) was declared as a separate entity in WHO classification of Tumors of Haematopoetic and Lymphoid Tissues in 2008 and 2017 years. Despite of similar pathomorphological characteristics between primary mediastinal B-cell lymphoma and Hodgkin lymphoma, clinical features and optimal therapeutic approach to MGZL are not clearly defined. Usually MGZL manifests with mediastinal lymphadenopathy, although extranodal lesions often occur (grey-zone lymphoma, GZL). Patients with MGZL have unfavorable prognosis, taking into account high rate of relapse. This article describes two cases of MGZL. First case manifested by arrhythmias due to primary heart involvement. In spite of cardiac failure antracycline-containing chemotherapy (6 courses of R-DA-EPOCH) it allowed to achieve a complete remission and resolving of arrhythmias. Second case was represented by metachronous tumors: primary mediastinal B-cell lymphoma at the time of disease onset and classical Hodgkin lymphoma, NS II, diagnosed after disease progression. Thus, we demonstrated two examples of MGZL that differ by clinical manifestation, response to chemotherapy, which emphasizes an importance of pathogenesis studying, and using of new therapeutic approaches.	0
OBJECTIVE: To assess the prevalence of systemic sclerosis (SSc) in a French multi-ethnic population and to examine ethnic differences. METHODS: This survey was conducted in Seine-Saint-Denis County, a suburb of Paris, home to 1,094,412 adults (>/=15 yr), among whom 26% are of non-European background with mainly northern and sub-Saharan African, Asian and Caribbean ancestries. The study period comprised the entire calendar year 2001. Patients were ascertained through four sources: public and private hospitals, general practitioners and community specialists, the French SSc patient support group, and the National Public Health Insurance System database. Only cases meeting either the 1980 ACR and/or LeRoy and Medsger's classification criteria were included and assigned to three clinical subsets: limited (normal skin) (l), limited cutaneous (lc) or diffuse cutaneous (dc) SSc. Capture-recapture (CR) analyses using log-linear modelling were performed to correct for incomplete case finding. RESULTS: We retained a total of 119 patients with SSc, including 15 extrapolated from inaccessible files. CR analysis estimated that 54.2 additional cases were missed by all the sources. The overall SSc prevalence (per million adults) was 158.3 (95% confidence interval, 129-187); those of lSSc, lcSSc and dcSSc were, respectively, 32.3 (16-48), 83.1 (66-101) and 42.9 (25-60); and respective values for Europeans and non-Europeans were 140.2 (112-170) and 210.8 (128-293). CONCLUSION: Regarding the heterogeneity of previously published estimates, this population-based survey using CR analysis might contribute to obtaining a better appraisal of SSc prevalence. Despite overlapping confidence intervals, the higher prevalence observed for non-Europeans could support potential influences of ethnic origin on the pathogenesis of SSc.	1
To describe the characteristic optical coherence tomography (OCT) findings of the iris in Cogan-Reese syndrome.A 63-year-old woman was referred for consultation due to diffuse pigmentation of the iris and elevated intraocular pressure (IOP) in the left eye. The clinical examination revealed Cogan-Reese syndrome with pedunculated iris outcroppings on the entire iris surface, and no peripheral anterior synechia. The right eye was normal with normal IOP.Imaging the left iris with the CAM-L cornea lens adapter of the Optovue Fourier-domain OCT (RTVue-OCT) showed a folded iris surface, an increased total iris thickness, and an increased distance between the anterior and posterior iris layers, compared to those of the healthy right eye.Traction by the pathological endothelial cell layer that covers the iris surface in Cogan-Reese syndrome causes characteristic OCT signs in the iris. Detection of the folded iris surface, increase of iris thickness, and increase of the distance between the anterior and posterior iris layers with RTVue-OCT anterior segment examination may promote the correct diagnosis and may help the clinician to discriminate Cogan-Reese syndrome from true iris nevi or iris melanoma.	0
Neuralgic amyotrophy is characterized by recurrent, painful, unilateral neuropathy involving mainly the upper brachial plexus followed by muscle weakness and muscle wasting. There are two forms: idiopathic and hereditary. Hereditary neuralgic amyotrophy is an autosomal dominant disease that is often linked to a mutation of SEPT9, a gene of the Septin family. The phenotypic spectrum of the disease may include hypotelorism, cleft palate, and other minor dysmorphisms. The age of onset is from infancy to adulthood. Hereditary neuralgic amyotrophy can be triggered by external stimuli such as infections, vaccinations, cold, stress, surgery, and strenuous exercise. Here, we report a six-year-old girl who was found to have mutation in the SEPT9 gene when she presented with recurrent attacks of painful brachial plexopathy following vaccinations, and was diagnosed as having hereditary neuralgic amyotrophy.	0
Despite being a rare congenital limb anomaly, triphalangeal thumb is a subject of research in various scientific fields, providing new insights in clinical research and evolutionary biology. The findings of triphalangeal thumb can be predictive for other congenital anomalies as part of an underlying syndrome. Furthermore, triphalangeal thumb is still being used as a model in molecular genetics to study gene regulation by long-range regulatory elements. We present a review that summarizes a number of scientifically relevant topics that involve the triphalangeal thumb phenotype. Future initiatives involving multidisciplinary teams collaborating in the field of triphalangeal thumb research can lead to a better understanding of the pathogenesis and molecular mechanisms of this condition as well as other congenital upper limb anomalies.	0
Ovarian cancer currently is the fifth leading cause of cancer-related deaths among women in the United States, and approximately 140 000 women die globally per year of ovarian cancer. This debilitating disease presents subtly, and when it is diagnosed, treatment options often are limited. To provide care that is most favorable for the patient, health care professionals must have a basic understanding of the signs and symptoms of ovarian cancer and the imaging tools and treatment options available. This article provides a succinct overview of ovarian cancer, including diagnostic imaging.	0
Angiomyomatous hamartoma of lymph nodes (AMH-LN) is an uncommon benign proliferation of smooth muscle, blood vessels, collagenous stroma, and adipocytes, most commonly affecting inguinal LN. A similar constellation of cell types constitutes various members of the perivascular epithelioid cell tumor (PEComa) family, including lymphangioleiomyomatosis (LAM), which can involve LN in women. Because some LN-LAM patients have tuberous sclerosis complex and/or other PEComa family lesions, it is clinically relevant to distinguish LN-LAM from AMH-LN. Given their similar features, however, the possibility that AMH-LN is a morphologic variant of LN-LAM merits inquiry. The dual melanocytic and myoid immunophenotype distinguishes the PEComa family from its mimics. Cathepsin K has recently emerged as a more sensitive marker for the PEComa family than HMB-45, which can be weak and focal, but cathepsin K has not been studied in AMH-LN. This study evaluated 21 AMH-LNs for clinical, morphologic, and immunophenotypic features of LN-LAM. None (0/21) had tuberous sclerosis complex or PEComas. Thirteen (62%) were male, unlike LN-LAM, which is restricted to women. All cases exhibited intraparenchymal proliferation of variable-sized, thick-walled blood vessels within collagenous stroma containing a sparse to focally cellular population of haphazardly distributed smooth muscle cells. Admixed adipocytes were commonly present. None exhibited classical features of LN-LAM such as subcapsular localization, extranodal extension, intralymphatic growth, compact nests, branching lymphatic channels, plump cell shape, or foamy/clear cytoplasm. None exhibited any staining for cathepsin K, HMB-45, or microphthalmia transcription factor. There is no clinical, morphologic, or immunohistochemical evidence to suggest that AMH-LN is a variant of LN-LAM.	0
Short bowel syndrome (SBS) is a malabsorptive state that may occur either after surgical bowel resection or as the result of congenital bowel anomalies. SBS can incur significant morbidity and mortality including intestinal failure, cholestasis, sepsis, and death. For patients with SBS, management involves a multidisciplinary approach that begins with neonatology, pediatric surgery, nutritionists, pharmacists, and nurses in the NICU and also includes the transition to an intestinal rehabilitation program. The aim of this review is to provide the neonatologist with an overview of the common causes of neonatal SBS, anticipated nutritional deficiencies, complications associated with SBS, and the surgical and medical management of SBS to assist in counseling affected families.	0
Spinocerebellar ataxia type 14 (SCA-PRKCG, formerly SCA14) is a rare, slowly progressive disorder caused by conventional mutations in protein kinase Cγ (PKCγ). The disease usually manifests with ataxia, but previous reports suggested PRKCG variants in retinal pathology. To systematically investigate for the first time visual function and retinal morphology in patients with SCA-PRKCG. Seventeen patients with PRKCG variants and 17 healthy controls were prospectively recruited, of which 12 genetically confirmed SCA-PRKCG patients and 14 matched controls were analyzed. We enquired a structured history for visual symptoms. Vision-related quality of life was obtained with the National Eye Institute Visual Function Questionnaire (NEI-VFQ) including the Neuro-Ophthalmic Supplement (NOS). Participants underwent testing of visual acuity, contrast sensitivity, visual fields, and retinal morphology with optical coherence tomography (OCT). Measurements of the SCA-PRKCG group were analyzed for their association with clinical parameters (ataxia rating and disease duration). SCA-PRKCG patients rate their vision-related quality of life in NEI-VFQ significantly worse than controls. Furthermore, binocular visual acuity and contrast sensitivity were worse in SCA-PRKCG patients compared with controls. Despite this, none of the OCT measurements differed between groups. NEI-VFQ and NOS composite scores were related to ataxia severity. Additionally, we describe one patient with a genetic variant of uncertain significance in the catalytic domain of PKCγ who, unlike all confirmed SCA-PRKCG, presented with a clinically silent epitheliopathy. SCA-PRKCG patients had reduced binocular vision and vision-related quality of life. Since no structural retinal damage was found, the pathomechanism of these findings remains unclear.	0
BACKGROUND:Thrombotic thrombocytopenic purpura (TTP) is a rare but serious complication in pregnancy that places the mother and fetus at high risk for morbidity and mortality. This case illustrates novel pregnancy complications associated with this rare medical condition. CASE PRESENTATION:A 31-year-old G3P0020 at 28 weeks and 1 day was admitted with severe thrombocytopenia and was ultimately diagnosed with TTP. With therapeutic plasma exchange (TPE), maternal status improved. At 28 weeks 6 days, however, non-reassuring fetal testing prompted cesarean delivery with placental abruption noted intraoperatively. Pathology examination confirmed placental abruption and also revealed multiple placental infarcts. CONCLUSION:While medical management of TTP can significantly improve the health of the mother, this case highlights the potential role of TTP in abruption and other placental pathology and thus, the need for close fetal surveillance throughout an affected pregnancy.	0
OBJECTIVE:Human genome-wide association studies and animal models suggest a role for TGFB2 in contributing to the corneal thickness phenotype. No specific mutations, however, have been reported in this gene that affect corneal thickness. We sought to determine if haploinsufficiency of TGFB2 in humans associated with Loeys-Dietz syndrome type 4 is associated with corneal thinning. DESIGN:Observational cohort study of families with Loeys-Dietz syndrome type 4, caused specifically by TGFB2 mutations, in a tertiary care setting. PARTICIPANTS:Three probands with pathogenic mutations in TGFB2 and family members underwent comprehensive ophthalmic examination. METHODS:Clinical assessment included Scheimpflug imaging, specular microscopy, and slit-lamp biomicroscopy. We measured visual acuity, axial length, refractive error, and central corneal thickness. RESULTS:Clinical evaluation of 2 probands identified corneal thinning and cornea guttata, despite a young age and distinct mutations in TGFB2 (c.905G>A, p.Arg302His; c.988C>A, p.Arg330Ser). In the third family, corneal thinning co-segregated with a TGFB2 mutation (c.1103G>A, p.Gly368Glu), although without apparent guttae. CONCLUSIONS:In this series, participants with TGFB2 mutations associated with Loeys-Dietz syndrome type 4 demonstrated decreased corneal thickness, and in 2 cases with splice site mutations, also demonstrated cornea guttata. The data demonstrate the importance of considering distinct phenotype-genotype correlations within this condition.	0
Skeletal dysplasias result from disruptions in normal skeletal growth and development and are a major contributor to severe short stature. They occur in approximately 1/5,000 births, and some are lethal. Since the most recent publication of the Nosology and Classification of Genetic Skeletal Disorders, genetic causes of 56 skeletal disorders have been uncovered. This remarkable rate of discovery is largely due to the expanded use of high-throughput genomic technologies. In this review, we discuss these recent discoveries and our understanding of the molecular mechanisms behind these skeletal dysplasia phenotypes. We also cover potential therapies, unusual genetic mechanisms, and novel skeletal syndromes both with and without known genetic causes. The acceleration of skeletal dysplasia genetics is truly spectacular, and these advances hold great promise for diagnostics, risk prediction, and therapeutic design.	0
We report the first case of autoimmune pulmonary alveolar proteinosis (PAP) associated with and preceding myelodysplastic syndrome. A 74-year-old female with a history of polymyalgia rheumatica presented with six months history of progressive exertional breathlessness. Examination revealed bilateral chest crackles and exertional desaturation. A diagnosis of autoimmune PAP was made based on the presence of autoantibodies to granulocyte-macrophage colony-stimulating factor and characteristic findings on chest computed tomography, bronchoalveolar lavage, and transbronchial biopsies. Bilateral whole lung lavage was performed with prompt improvement in symptoms. Fourteen months later, she presented with new breathlessness and was diagnosed with myelodysplasia on bone marrow biopsy. No recurrence of alveolar proteinosis was detected. This case highlights the importance of follow-up and screening of patients with autoimmune PAP for haematological conditions.	0
Imerslund-Grasbeck syndrome (IGS, OMIM 261100) is a rare autosomal recessive disease characterized by vitamin B12 malabsorption resulting in megaloblastic anemia and asymptomatic proteinuria. IGS is caused by bi-allelic mutations in either CUBN or AMN that respectively encode the cubilin and amnionless subunits of the cobalamin-intrinsic factor receptor. We report four siblings (three boys, one girl) of non-consanguineous parents of Jewish background, aged 10 months to 12 years, with homozygous CUBN frameshift c.2614_2615deIGA p.(Asp872LeufisTer3) mutation and typical features of IGS. The two older brothers presented in early infancy with lethargy, mouth ulcerations, eosinophilic enterocolitis, megaloblastic anemia and failure to thrive. Investigations revealed low serum cobalamin levels. Intramuscular hydroxycobalamin supplementation resulted in dramatic resolution of all symptoms including lethargy. A positive impact on their growth curve was seen. Prospective early treatment in the younger siblings prevented these manifestations. Proteinuria with proximal tubulopathy was seen in all patients, plasma protein level and renal function were normal. All children had pronounced vitamin D deficiency and required high doses of oral supplementation. Vitamin B12 treatment could be individually adjusted; requirement decreased with age. Tubulopathy showed improvement over time. Low vitamin D could be explained by cubilin being involved in reabsorption of vitamin carriers.	0
Proximal deletion of 6q is a relatively rare chromosomal abnormality. Reported patients have deletions of different sizes but share partial overlap and present with similar clinical features, and some of them were described prior to the introduction of chromosome microarrays. We describe a male patient with prenatal sonographic findings of nuchal edema, intrauterine growth restriction, renal pelvis dilatation, and oligohydramnios. At birth, facial dysmorphism, retro/micrognathia, a short and wide neck as well as cardiovascular and renal anomalies were noted. His clinical evolution has been marked by failure to thrive, severe developmental delay, and cognitive impairment. The diagnosis of Toriello-Carey syndrome (TCS) was based on his "gestalt." aCGH identified a de novo proximal deletion of 17 Mb in 6q (6q12q14.3). Deletion 6q13q14 seems to be responsible for the main facial features and should be considered within the differential diagnosis of TCS.	0
An inverted duplication with a terminal deletion (inv-dup-del) is one of the complex constitutional structural rearrangements that can occur in a chromosome. Although breakages of dicentric chromosome have been suggested, the precise mechanism of this is yet to be fully understood. In our present study, we investigated the genomic structure of 10 inv-dup-del cases to elucidate this mechanism. Two recurrent 8p inv-dup-del cases harbored a large copy-number-neutral region between the duplication and deletion in common. Although the other non-recurrent cases did not appear to have this copy-number-neutral region, refined sequencing analysis identified that they contained a small intervening region at the junction between the inverted and non-inverted segment. The size of this small intervening region ranged from 1741 to 3728 bp. Combined with a presence of microhomology at the junction, a resolution of the replication fork stalling through template switching within the same replication fork is suggested. We further observed two cases with mosaicism of the dicentric chromosome and various structural rearrangements related to the dicentric chromosome. Refined analysis allowed us to identify different breakpoints on the same chromosome in the same case, implicating multiple rounds of U-type formation and its breakage. From these results, we propose that a replication-based mechanism generates unstable dicentric chromosomes and that their breakage leads to the formation of inv-dup-dels and other related derivative chromosomes.	0
Autosomal dominant hyper-IgE syndrome (AD-HIES), characterised by eczema, increased susceptibility to skin and lung infections, elevated IgE and skeletal abnormalities is associated with heterozygous STAT3 mutations. The autosomal recessive variant (AR-HIES) has similar immunological findings but mainly lacks extraimmune manifestations. Several AR-HIES patients have recently been shown to harbour mutations in the gene for dedicator of cytokinesis 8 (DOCK8). Here, we present the long-term outcome of a girl having received a hematopoietic stem cell graft for an at that time genetically undefined combined immunodeficiency associated with severe eczema, multiple food allergies, excessively elevated serum IgE levels and eosinophilia. She was recently found to carry a homozygous nonsense mutation in the DOCK8 gene. HSCT resulted in complete immunological correction, even though mixed donor chimerism occurred. Clinically, the outcome was characterised by disappearance of skin manifestations and severe infections, improvement of pulmonary function and constant decline of IgE levels. Outcome in untransplanted DOCK8 deficient patients is poor because of frequent life-threatening infections, CNS bleeding and infarction, and increased susceptibility to malignancy. This argues for early curative therapeutic approaches, supported by this report of successful long-term outcome after HSCT.	0
Ependymosarcomas are rare, biphasic tumors composed of ependymal and sarcomatous components. Due to their rarity, their biologic basis is not well understood. We report the case of a 38-year-old male with anaplastic ependymoma (WHO grade III) that progressed to ependymosarcoma in less than 2 years after multiple resections, chemoradiotherapy, and anti-PD1 immunotherapy. Next-generation sequencing was performed on both high-grade anaplastic ependymoma and ependymosarcoma samples to detect small base changes, insertions, and deletions in exons and splice junctions from a panel of over 400 genes. We identify genetic variants in the tumor suppressors RB1, TP53, and TSC2 in these samples and discuss the potential significance of an additional TSC2 genetic variant in the progression to ependymosarcoma.	0
Introduction: Even though Fetal and Neonatal Alloimmune Thrombocytopenia (FNAIT) has been recognized as the main cause of primary hemorrhagic morbidity and mortality in fetuses and newborns, screening programs to detect pregnancies at risk have not yet been implemented in any country. Moreover, in spite of increased concerns about maternal, fetal and neonatal health care in general, this potentially lethal disease is still underdiagnosed. The aim of this report is to highlight the importance of considering FNAIT in fetal and perinatal health-care settings and show the usefulness of molecular tools in early diagnosis of this clinical entity.Methods: DNA was extracted from whole blood from parents and newborns; genotyping was performed by in house PCR using sequence-specific primers for typing Human Platelet Antigens (HPA)-1 to -6, -9, and -15, and with commercial HPA-TYPE (BAG HealthCare, Lich, Germany). Anti-HPA antibodies in the maternal serum were detected by the Monoclonal Antibody Solid Phase Platelet antibody Test (MASPAT). Chloroquine-treated platelets were used for the discrimination of platelet-specific antibodies from anti-HLA antibodies.Results: Patients 1 and 2 had severe thrombocytopenia due to incompatibility in HPA-1 and HPA-15, respectively. The third case was a thrombocytopenic neonate with severe bleeding complications other than ICH and in whom differential diagnosis between FNAIT and Von Willebrand congenital disease was necessary; incompatibility in HPA-15 was also demonstrated. Case 4 represents a missed diagnostic opportunity.Conclusion: This is the first report of FNAIT cases confirmed by molecular evidence and anti-HPA antibodies detection in Argentina. This report reinforces the relevance of early diagnosis of this clinical entity. Since the delay in FNAIT diagnosis could lead to severe consequences in the fetus and neonates, strategies to approach maternal, fetal, and perinatal health, as well as prevention policies aimed to reduce fetal and neonatal morbidity and mortality should focus on implementing programs to identify high-risk pregnancies and thus reduce thrombocytopenia-related complications in fetuses and newborns.	0
BACKGROUND:Intellectual disability (ID) is a heterogeneous neurodevelopmental disorder with a complex genetic underpinning in its etiology. Chromosome microarray (CMA) is recommended as the first-tier diagnostic test for ID due to high detection rate of copy number variation (CNV). METHODS:To identify an appropriate clinical detection scheme for ID in Han Chinese patients, whole genome low-coverage sequencing was performed as the first-tier diagnostic test, and medical exome sequencing (MES) as the second-tier diagnostic test for patients with negative results of CNVs. RESULTS:A total of 19 pathogenic CNVs in 16/95(16.84%) ID patients and 10 pathogenic single-nucleotide variations (SNVs), including 6 novel mutations in 8/95(8.42%) ID patients were identified on whom no pathogenic CNVs were discovered. The detection rate of CNVs in ID with multiple congenital anomalies (MCA) subgroup was significantly higher than ID with autism spectrum disorders and other IDs subgroups. And the single-nucleotide variations showed a higher occurrence rate in the other IDs subgroup. CONCLUSIONS:There were differences in the diagnostic yields of different variation types among the three ID subgroups. Our findings provided a new perspective on appropriate clinical detection scheme in different ID subgroups based on statistically significant differences among the three ID subgroups. The application of whole genome low-coverage sequencing as the first-tier diagnostic test for ID with MCA subgroup and MES as the first-tier diagnostic test for other ID subgroup was considered as an efficient clinical detection scheme.	0
Objective:Atypical parathyroid adenoma is a rare neoplasm, showing atypical histological features intermediate between classic benign adenoma and the rarest parathyroid carcinoma, whose the clinical behaviour and outcome is not yet understood or predictable. Up to date only two cases of atypical adenoma were found associated to a MEN1 syndrome, and only one was proved to carry a pathogenic variant of the MEN1 gene. Design:We report the clinical, histologic, and molecular findings of a 44-year-old woman, presenting with a histologically proved atypical parathyroid adenoma with an apparent aggressive behaviour. Methods and Results:CDC73 gene was screened at germline and somatic levels with no results. Whole exome sequencing performed on DNA extracted from blood leukocytes and tumour tissue revealed a somatic MEN1 gene heterozygous variant, c.912+1G > A, of the splicing donor site of exon 6. On immunohistochemistry, downregulation of the menin protein expression in the neoplastic cells was also observed. Conclusions:We report the second case of a rare association of a somatic MEN1 gene mutation in a patient with atypical parathyroid adenoma. We suggest that MEN1 gene could be an underestimate genetic determinant of these rare histological entities, and we highlight the utility of a complete genetic screening protocol, by the use of next-generation sequencing technology in such undetermined clinical cases with no frank clinical presentation.	0
BACKGROUND:Glioma is the most common and deadliest malignant primary intracranial brain tumor in adults. It remains unclear whether the pre-treatment peripheral blood test parameters might serve as biomarkers for treatment outcome. The purpose of the current study was to investigate the predictive and prognostic value of pre-treatment peripheral blood test parameters in glioma. METHODS:In total, 288 glioma patients with complete results of pre-operation peripheral blood test, clinical information and tumor transcriptome data from Chinese Glioma Genome Atlas (CGGA project) were enrolled in our study. Receiver operating characteristic (ROC) curve, Kaplan-Meier analysis and Cox proportional hazards models were performed to evaluate the diagnostic and prognostic value of pre-treatment peripheral blood test parameters in glioma patients. RESULTS:The white blood cells (WBC) and neutrophils (NEU) counts and neutrophil to lymphocyte ratio (NLR) were positively correlated with tumor grade. IDH mutation and 1p/19q codeletion occurred frequently in patients with higher NEU counts and NLR. We also found that glioma patients with higher NEU or NLR were more likely to have a significantly decreased overall survival. Meanwhile, NEU count was a prognostic marker for TMZ standard treatment GBM patients or IDH wild-type GBM patients. Further biological and functional analysis revealed that NEU count was positively associated with cell cycle and DNA duplication. CONCLUSION:Our study was first to highlight the clinical significance of NEU count in GBM clinical treatment, which should be fully valued for clinical prediction and precise management.	0
Topical imiquimod is a medication approved for the treatment of external genital and perianal warts, actinic keratosis, and superficial basal cell carcinoma. There have also been reports of its successful use in patients with lentigo maligna melanoma in situ. An 80-year-old female patient was diagnosed with lentigo maligna melanoma in situ which was then surgically removed. After several recurrences, nonsurgical treatment using topical 5% imiquimod was introduced. At 9-month follow-up the skin was completely healed with no evidence of cancer recurrence. In select cases, topical imiquimod seems to be an effective alternative to surgical treatment of melanoma in situ (MIS). Further studies are necessary to assess the successfulness of this treatment method.	0
Acrodermatitis continua of Hallopeau (ACH) is a rare, sterile pustular eruption of one or more digits. The condition presents with tender pustules and underlying erythema on the tip of a digit, more frequently arising on a finger than a toe. As far as classification, ACH is considered a localized form of pustular psoriasis. The eruption typically occurs after local trauma or infection, but such a history is not always present and various other etiologies have been described including infectious, neural, inflammatory, and genetic causes. The natural progression of ACH is chronic and progressive, often resulting in irreversible complications such as onychodystrophy that can result in anonychia, as well as osteitis that can result in osteolysis of the distal phalanges. Because of the rarity of ACH, there have been no randomized controlled studies to evaluate therapies, resulting in an absence of standardized treatment guidelines. In clinical practice, a wide variety of treatments have been attempted, with outcomes ranging from recalcitrance to complete resolution. In recent years, the introduction of biologics has provided a new class of therapy that has revolutionized the treatment of ACH. Specifically, rapid and sustained responses have been reported with the use of anti-tumor necrosis factor agents like infliximab, adalimumab, and etanercept; IL-17 inhibitors like secukinumab; IL-12/23 inhibitors like ustekinumab; and IL-1 inhibitors like anakinra. Nevertheless, there remains a considerable need for more research into treatment for the benefit of individual patients with ACH as well as for the clinical knowledge gained by such efforts. The purpose of this review is to provide a comprehensive overview of the key features of ACH as well as a discussion of clinical management strategies for this unique and debilitating condition.	0
Urea cycle disorders (UCDs) are an unusual genetic condition that may lead to hyperammonemia in catabolic situations such as surgery, infections or chemotherapy administration. Without specific treatment, it causes life-threatening encephalopathy. We present the case of a young woman, heterozygous carrier of ornithine transcarbamylase deficiency (OTCD) with breast cancer, who was treated with surgery, chemotherapy, radiotherapy and hormone therapy while following a protocol to minimize the risk of metabolic decompensation due to her condition.	0
Cutaneous blastomycosis is the most common extrapulmonary manifestation of disseminated blastomycosis, a disease caused by Blastomyces dermatitidis, a dimorphic fungus endemic of North America. Initially, the organism enters the respiratory system by inhalation of the infectious conidia and produces an acute pulmonary infection that may eventually disseminate if it is left untreated. Blastomycosis may represent a diagnostic challenge and its definitive diagnosis requires direct visualization of the distinctive yeast or a positive fungal culture. The objective of this case report is to highlight the importance of the skin exam and tissue biopsy in the diagnosis of blastomycosis. We present a previously healthy patient with chronic pneumonia, evaluated at Pulmonary clinic with non-diagnostic thoracentesis and bronchoscopy, found to have disseminated blastomycosis after biopsy of a scalp lesion in Dermatology clinic.	0
INTRODUCTION: Spinal muscular atrophy (SMA) causes muscle weakness and fatigue. Better understanding of the relationship between weakness and fatigue may help identify potential targets for rehabilitation. METHODS: Gait and surface electromyography (EMG) from 4 muscle groups were measured during the Six-Minute Walk Test (6MWT) in 10 ambulatory participants, aged 9-49 years. Average root mean square amplitude (RMS) of muscle activity was calculated. Strength was assessed using manual and quantitative methods. RESULTS: RMS, stride length, and velocity decreased during the 6MWT. Knee flexor and hip abductor strength was associated with fatigue-related changes; overall strength correlated with disease duration; and leg strength was associated with 6MWT distance. CONCLUSIONS: Clinical measures are valid in assessing fatigue and function in SMA, and these assessments can be enhanced by use of gait analysis and EMG. Disease duration and strength measures may represent further stratification refinements when enrolling patients in clinical trials.	0
Metatropic dysplasia (MD) is a rare skeletal dysplasia associated with heterozygous mutations in the TRPV4 gene. We describe a 28-month-old boy with knock-knees referred for metabolic investigation suspected of carrying vitamin D-resistant rickets. He has received regular vitamin D prophylaxis at the usual dose. Laboratory investigations revealed normal values for calcium, phosphorus and alkaline phosphatase. He was short (-3.5 SDS), his mental development was normal, and he started to walk at the age of 22 months. The diagnostic clue for the diagnosis of metatropic dysplasia was the presence of the hump back in the upper lumbar and lower thoracic vertebrae, in addition to a long and narrow chest. An X-ray survey of the skeleton revealed platyspondyly, dysplastic metaphyses with dumbbell appearance of the long bones, kyphoscoliosis, and narrow and elongated thorax with short ribs. This is the first patient with MD in the Republic of Macedonia. Knock-knees were the cause of his referral, as a peculiarity of his phenotype. The very presence of the hump back, and the dumbbell appearance of the long bones distinguished the MD from other bone dysplasias with similar characteristics. We believe that the presence of those two features can shorten the path to accurate diagnosis in the crowded field of overlapping skeletal dysplasias. The diagnosis of MD in this patient was further confirmed by the discovery of the mutation c.2396C>T; p.Pro799Leu (P799L) of the TRPV4 gene.	0
BACKGROUND:Balantidium coli, a parasitic unicellular ciliate, often causes asymptomatic balantidiasis of the colon, but extraintestinal disease may occur rarely in immunosuppressed individuals. Renal balantidiasis associated with systemic lupus erythematosus has not been reported before. CASE PRESENTATION:We present a case of a 48-year-old Thai woman who presented with nephrotic syndrome due to systemic lupus erythematosus-related nephritis. Initially, few B. coli cysts were found in urine sediment, but these increased substantially following treatment with prednisolone. She made an uneventful recovery with 10 days of oral tetracycline therapy. No B. coli cysts were found in her stool. CONCLUSION:The route of infection in our patient was unclear but is likely to have been orofecal. Neither her infection nor its treatment caused a deterioration in her renal function.	0
Chronic lithium therapy in patients with bipolar disorder and other psychiatric illnesses can lead to a very common side effect of complete or partial nephrogenic diabetes insipidus. After confirmation of hypotonic polyuria, water deprivation test with desmopressin injection is used to make the diagnosis. Incomplete response to desmopressin suggests partial nephrogenic diabetes insipidus. We report a rare case of a 58-year-old patient who presented with hypernatremia and hypotonic polyuria secondary to chronic lithium therapy. She was diagnosed with partial nephrogenic diabetes insipidus secondary to chronic lithium therapy and was treated with amiloride resulting in improvement.	0
Background:Renal involvement in patients with the m.3243A>G mutation may result in end-stage renal disease (ESRD) requiring renal replacement therapy. Although kidney transplantations have been performed in a small number of patients, short- and long-term follow-up data are lacking. Methods:We describe five patients with the m.3243A<G mutation who received a kidney transplant, including follow-up data up to 13 years. We also summarize all cases (n = 13) of kidney transplantation in m.3243A>G carriers described in the literature. Results:Proteinuria with or without renal failure was the first clinical presentation of renal involvement in 13 of 18 (72%) patients. Focal segmental glomerulosclerosis (FSGS) was found in 9 of 13 (69%) biopsies. Sixteen of 18 (84%) patients developed hearing loss. All patients were diagnosed with diabetes mellitus, of whom eight (44%) developed the disease after transplantation. All patients with reported follow-up data (13/18) had stable kidney function from 6 months to 13 years of follow-up after transplantation. Conclusions:Renal involvement in carriers of the m.3243A>G mutation most commonly leads to proteinuria and FSGS and may lead to ESRD. Proper recognition of the mitochondrial origin of the renal disease in these patients is important for adequate treatment selection and suitable supportive care. This case series and review of the available literature on long-term follow-up after kidney transplantation shows it is feasible for non-mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes phenotype carriers of the m.3243A>G mutation to be considered for kidney transplantation in case of ESRD. These patients should not be excluded from transplant solely for their mitochondrial diagnosis.	0
In 1993, Suthers et al. reported on a child with an undiagnosed syndrome associating developmental delay, brachycephaly, deafness and cataracts. They discussed the possibility that this child had the same dysmorphic syndrome as the patient reported by Fine and Lubinsky in 1983. Twenty years ago, we examined a very similar patient who has been followed up to now. When she was a baby, she looked extremely similar to another patient, reported by Preus et al. in 1984. We now think that these four patients have in fact the same syndrome, the patient reported by Fine and Lubinsky being an example of a very severe expression of this condition, the other patients expressing different anomalies depending on the age at examination.	0
Pure red cell aplasia (PRCA) is a rare syndrome that only affects the erythroid lineage. It is defined by a normocytic, normochromic anemia with a marked reticulocytopenia and severe reduction or absence of erythroid precursors in the bone marrow. Treatment of primary, idiopathic PRCA is immunosuppressive therapy. Although it is rare, isolated cytogenetic abnormalities can be seen in PRCA, and abnormal karyotype is associated with poor response to immunosuppressive therapy and poor prognosis. We describe a 77-year-old male with primary, idiopathic PRCA and a deletion of chromosome 20q, del(20q), in the bone marrow cells. He was successfully treated with immunosuppressive therapy and became transfusion-independent. The same cytogenetic abnormality has also been described in a few other reports; taken together, these observations suggest that del(20q) may represent a recurrent cytogenetic abnormality in PRCA. Our case report clearly illustrates that even patients with primary PRCA and an abnormal karyotype can respond to immunosuppression and become transfusion-independent.	0
PURPOSE OF REVIEW:Peripheral T cell lymphomas (PTCLs) are a heterogeneous group of diseases and represent approximately 10-15% of all non-Hodgkin lymphomas. Multiagent chemotherapy with a CHOP (cyclophosphamide, adriamycin, vincristine, prednisone)-like regimen is the current standard of care in the frontline setting, but outcomes for PTCL patients generally remain poor. Strategies used to improve survival and reduce the risk of relapse in PTCL patients include autologous hematopoietic cell transplant (autoHCT) and allogeneic HCT (alloHCT). Due to the relative rarity of these diseases, the evidence supporting the use of autoHCT and alloHCT is based on retrospective and single-arm prospective studies. Novel targeted therapies are now being incorporated into the treatment of PTCL, and they may play important roles in improving upon current standards of care. Herein, we summarize the evidence supporting HCT for the treatment of the most common PTCL histologic subtypes and highlight novel treatment strategies aimed at improving outcomes for these patients, including cutting-edge approaches using chimeric antigen receptor T cells (CAR-T). RECENT FINDINGS:Given recent improvements in OS and PFS in CD30+ PTCL using the drug-antibody conjugate brentuximab vedotin (BV), new questions arise regarding the impact of BV on consolidative autoHCT, and its role as a maintenance therapy. Multiple histone deacetylase inhibitors (HDACis) have been approved for the treatment of relapsed/refractory PTCL, and these agents are being incorporated into HCT approaches, both in the frontline and maintenance settings. Early data incorporating these agents into novel conditioning regimens have been reported, and emerging evidence from recent trials suggests that CART cell therapies may prove effective in relapsed/refractory PTCL. The recommended treatment strategy in non-ALK+ PTCL remains induction with a CHOP-like regimen followed by consolidative autoHCT in first remission. In the relapsed/refractory setting, salvage chemotherapy followed by HCT (autoHCT or alloHCT depending on histologic subtype and HCT history) offers the only potential for cure or long-term remission. Ample room for improvement remains in the treatment of patients with PTCL, and novel treatment strategies incorporating targeted agents and CAR-T therapy may help to address the unmet needs of this patient population.	0
Children with osteogenesis imperfecta (OI) type VI often have high fracture rates despite the current standard treatment with bisphosphonates. Subcutaneous injections of denosumab have been proposed as an alternative treatment approach, but safety data on denosumab in children are limited. Here we describe fluctuations in bone and mineral metabolism during denosumab treatment in four children with OI type VI who started denosumab (basic protocol: 1 mg per kg body mass every 3 months) between 1.9 and 9.0 years of age, after having received intravenous bisphosphonates previously. All four children developed hypercalciuria during active denosumab therapy. In two children aged 3.9 and 4.6 years, episodes of hypercalcemia were observed between 7 and 12 weeks after the preceding denosumab injection. During times when the interval between denosumab injections was increased to 6 months for clinical reasons, lumbar spine bone mineral density z-scores decreased rapidly. It appears that the duration of action of denosumab is short and variable in children with OI type VI. These observations call into question the concept that denosumab can be used as a stand-alone alternative to bisphosphonates to treat children with OI.	0
Previously obtained data suggests that noradrenaline (NE) released from the efferent locus coeruleus (LC) endings in hippocampal formation (HPC) may serve as an important modulating signal involved in the pharmacological mechanisms responsible for the production of type 2 theta rhythm in rats. Hence, two distinct hypotheses were tested in the present study: 1/ if the decrease in HPC level of NE is correlated with the desynchronization of HPC field potential, then the inhibition of LC would be expected to abolish HPC type 2 theta rhythm; 2/ if the increase in HPC NE level is correlated with synchronization of HPC field potential, then the stimulation of LC would be expected to produce type 2 theta. The experiments were performed using an experimental model of HPC type 2 theta rhythm recorded in urethanized rats. It was demonstrated that electrical stimulation of LC produced type 2 theta rhythm whereas procaine injection into LC, in contrast, reversibly abolished type 2 theta. The possible relation of type 2 theta rhythm with some disturbances of Alzheimer disease are addressed.	0
Objectives:This article reviews the current role of genetics in pediatric hearing loss (HL). Methods:A review of the current literature regarding the genetic basis of HL in children was performed. Results:To date, 119 nonsyndromic genes have been associated with HL. There are also hundreds of syndromic causes that have HL as part of the clinical phenotype. Conclusions:Identifying HL genes coupled with clinical characteristics ("genotype-phenotype") yields a more accurate diagnosis and prognosis. Although the complexity of the auditory apparatus presents challenges, gene therapy is emerging and may be a viable management option in the future.	0
BACKGROUND: In 1972, Fuhrmann et al. (Humangenetik 1972;14:196-203) described a novel syndrome consisting of cleft palate (CP) and lateral synechiae (LS) between the palate and the floor of the mouth. This constellation of malformations, since denoted as cleft-palate lateral synechiae syndrome (CPLS), is a rare syndrome; only five cases have been reported since the original description. Because of the paucity of recognized cases, little is known regarding the phenotypic spectrum of this presumably autosomal dominant condition. CASES: We report two unrelated patients who presented with remarkably similar phenotypic features, including multiple intraoral synechiae (filiforme intraalveolar bands), cleft palate, micrognathia, and redundant lower lip tissue. Their phenotypic findings indicate a diagnosis of CPLS; however, case 3 (the monozygotic twin of case 2) had classic phenotypic features of Fryns syndrome. CONCLUSIONS: This report presents two new cases of CPLS, and suggests that the CPLS phenotype may represent the mild end of the Fryns syndrome phenotypic spectrum. Supplementary material for this article can be found on the Birth Defects Research (Part A) website (http://www.interscience.wiley.com/ jpages/1542-0752/suppmat/67/fig5.xls).	0
Purpose:Cone rod dystrophy (CRD) is a group of inherited retinopathies characterized by the loss of cone and rod photoreceptor cells, which results in poor vision. This study aims to clinically and genetically characterize the segregating CRD phenotype in two large, consanguineous Pakistani families. Methods:Funduscopy, optical coherence tomography (OCT), electroretinography (ERG), color vision, and visual acuity assessments were performed to evaluate the retinal structure and function of the affected individuals. Exome sequencing was performed to identify the genetic cause of CRD. Furthermore, the mutation's effect was evaluated using purified, bacterially expressed ADP-ribosylation factor-like protein 3 (ARL3) and mammalian cells. Results:Fundus photography and OCT imaging demonstrated features that were consistent with CRD, including bull's eye macular lesions, macular atrophy, and central photoreceptor thinning. ERG analysis demonstrated moderate to severe reduction primarily of photopic responses in all affected individuals, and scotopic responses show reduction in two affected individuals. The exome sequencing revealed a novel homozygous variant (c.296G>T) in ARL3, which is predicted to substitute an evolutionarily conserved arginine with isoleucine within the encoded protein GTP-binding domain (R99I). The functional studies on the bacterial and heterologous mammalian cells revealed that the arginine at position 99 is essential for the stability of ARL3. Conclusions:Our study uncovers an additional CRD gene and assigns the CRD phenotype to a variant of ARL3. The results imply that cargo transportation in photoreceptors as mediated by the ARL3 pathway is essential for cone and rod cell survival and vision in humans.	0
Cutaneous symptoms in some patients with clinical picture of Schimmelpenning-Feuerstein-Mims syndrome can include a speckled lentiginous nevus, also known as nevus spilus. Recent investigations show that somatic heterozygous HRAS mutations are present in the sebaceous and speckled lentiginous nevus tissues of patients with combination of two nevi.	0
Acromicric dysplasia (AD) and geleophysic dysplasia 2 (GD2) belong to the category of acromelic dysplasia syndromes, consisting of severe short stature, short hands and feet and skin thickening. Both can result from missense mutations in the transforming growth factor beta 5 domain of the fibrillin-1 gene (FBN1).Two patients (P1 age 10, and P2 age 7) from unrelated families presented to their endocrinologist with severe short stature (approx. -4 SDS). They were otherwise asymptomatic and only had mild facial dysmorphisms. Extensive endocrine work-up did not reveal an underlying etiology. Exome sequencing was performed in each family.Exome sequencing identified the presence of the same heterozygous missense variant c.C5183T (p.Ala1728Val) in the FBN1 gene in both P1 and P2. This variant was previously reported in a patient with GD2 and associated cardiac valvulopathy and hepatomegaly. Detailed clinical re-examination, cardiac and skeletal imaging did not reveal any abnormalities in P1 or P2 other than mild hip dysplasia.This report broadens the phenotypic spectrum of growth disorders associated with FBN1 mutations. Identical mutations give rise to a wide phenotypic spectrum, ranging from isolated short stature to a more classic picture of GD2 with cardiac involvement, distinct facial dysmorphisms and various skeletal anomalies.	0
Bispecific antibodies (BsAbs) are designed to recognize and bind to two different antigens or epitopes. In the last few decades, BsAbs have been developed within the context of cancer therapies and in particular for the treatment of hematologic B-cell malignancies. To date, more than one hundred different BsAb formats exist, including bispecific T-cell engagers (BiTEs), and new constructs are constantly emerging. Advances in protein engineering have enabled the creation of BsAbs with specific mechanisms of action and clinical applications. Moreover, a better understanding of resistance and evasion mechanisms, as well as advances in the protein engineering and in immunology, will help generating a greater variety of BsAbs to treat various cancer types. This review focuses on T-cell-engaging BsAbs and more precisely on the various BsAb formats currently being studied in the context of B-cell malignancies, on ongoing clinical trials and on the clinical concerns to be taken into account in the development of new BsAbs.	0
Terminal 17q trisomy is very rare but a recognizable genetic syndrome. The majority of cases reported are inherited from a balanced translocation carrier. This syndrome involves many organs and the severity ranges from mild to severe depending on the size of the 17q gain.	0
BACKGROUND:Noonan syndrome is a common genetic syndrome caused by pathogenic variants in genes in the Ras/MAPK signaling pathway. The medical literature has an abundance of studies on Noonan syndrome, but few are from the African continent. METHODS:The medical literature was searched for studies on Noonan syndrome from the African continent and these reports were added to our experience in Africa. Facial analysis was reviewed from two previous reports from our group using a support vector machine (SVM) algorithm and an analysis using the Face2Gene convolutional neural network technology. RESULTS:Individuals with Noonan syndrome from reports in African populations have the classic phenotype characteristics including typical minor facial anomalies such as widely spaced eyes (31-100%), short stature (71-100%), and congenital heart disease with pulmonary stenosis found in 24-100% of patients. Similarly, the genotypes are similar with the majority of variants occurring in the gene PTPN11 (72%) and 36% of these variants occurred in the amino acid residue Asn308, which is most commonly found in other populations. The two separate facial analysis algorithms successfully discriminated Africans with NS from unaffected matched individuals with area under the curve (AUC) of the receiver operator characteristic of 0.94 (SVM) and 0.979 for the Face2Gene research methodology. CONCLUSION:Few studies characterizing Noonan syndrome in Africans have been conducted, highlighting the need for more genetic and genomic research in African populations. Available clinical data, genotypes, and facial analysis technology data show that individuals of African descent with NS can be efficiently diagnosed using available standards.	0
Dissecting cellulitis of the scalp represents a disease of follicular occlusion that may be worsened by tight-fitting clothing, such as the patrol cap or advanced combat helmet used by military service members. Treatment poses a challenge to the clinician, and the treatment of choice, oral retinoids, may not improve the condition sufficiently to maintain active duty status. Early treatment augmentation with tumor necrosis factor-alpha inhibitors may improve efficacy of oral retinoids and prevent medical separation of the active duty service member.	0
INTRODUCTION:De Morsier syndrome, or septo-optic dysplasia, is a rare, heterogeneous, complex condition with a highly variable phenotype. It is characterized by optic nerve hypoplasia, pituitary gland hypoplasia, and midline brain abnormalities, including absence of septum pellucidum and corpus callosum dysgenesis. Diagnosis is made clinically by the presence of any two or more features from the clinical triad. CASE PRESENTATION:We report a case of a premature African newborn male baby born to nonconsanguineous parents who presented to our institution with agenesis of the septum pellucidum, unilateral optic nerve hypoplasia, and pituitary stalk hypoplasia. However, he had intact central endocrine function. He also presented with limb defects due to constricting amniotic band syndrome. Other dysmorphic features were low-set ears, microcephaly, and bilateral talipes equinovarus. He otherwise had a normal neurological examination result. Over time, he had an adequate weight gain and was managed by a multidisciplinary team. CONCLUSION:De Morsier syndrome still represents a diagnostic challenge, despite advances in neuroimaging and genetic studies, due to the heterogeneous nature of the disorder. This case adds to existing knowledge on the vascular pathogenesis of septo-optic dysplasia.	0
Importance:Impairment of dopaminergic transmission may contribute to cognitive dysfunction in Alzheimer disease (AD). Objective:To investigate whether therapy with dopaminergic agonists may affect cognitive functions in patients with AD. Design, Setting, and Participants:This phase 2, monocentric, randomized, double-blind, placebo-controlled trial was conducted in Italy. Patients with mild to moderate AD were enrolled between September 1, 2017, and December 31, 2018. Data were analyzed from July 1 to September 1, 2019. Interventions:A rotigotine 2 mg transdermal patch for 1 week followed by a 4 mg patch for 23 weeks (n = 47) or a placebo transdermal patch for 24 weeks (n = 47). Main Outcomes and Measures:The primary end point was change from baseline on the Alzheimer Disease Assessment Scale-Cognitive Subscale. Secondary end points were changes in Frontal Assessment Battery, Alzheimer Disease Cooperative Study-Activities of Daily Living, and Neuropsychiatric Inventory scores. Prefrontal cortex activity was evaluated by transcranial magnetic stimulation combined with electroencephalography. Results:Among 94 patients randomized (mean [SD] age, 73.9 [5.6] years; 58 [62%] women), 78 (83%) completed the study. Rotigotine, as compared with placebo, had no significant effect on the primary end point: estimated mean change in Alzheimer Disease Assessment Scale-Cognitive Subscale score was 2.92 (95% CI, 2.51-3.33) for the rotigotine group and 2.66 (95% CI, 2.31-3.01) for the placebo group. For the secondary outcomes, there were significant estimated mean changes between groups for Alzheimer Disease Cooperative Study-Activities of Daily Living score (-3.32 [95% CI, -4.02 to -2.62] for rotigotine and -7.24 [95% CI, -7.84 to -6.64] for placebo) and Frontal Assessment Battery score (0.48 [95% CI, 0.31 to 0.65] for rotigotine and -0.66 [95% CI, -0.80 to -0.52] for placebo). There was no longitudinal change in Neuropsychiatric Inventory scores (1.64 [95% CI, 1.06-2.22] for rotigotine and 1.26 [95% CI, 0.77-1.75] for placebo group). Neurophysiological analysis of electroencephalography results indicated that prefrontal cortical activity increased in rotigotine but not in the placebo group. Adverse events were more common in the rotigotine group, with 11 patients dropping out compared with 5 in the placebo group. Conclusions and Relevance:In this randomized clinical trial, rotigotine treatment did not significantly affect global cognition in patients with mild to moderate AD; however, improvement was observed in cognitive functions highly associated with the frontal lobe and in activities of daily living. These findings suggest that treatment with the dopaminergic agonist rotigotine may reduce symptoms associated with frontal lobe cognitive dysfunction and thus may delay the impairment of activities of daily living. Trial Registration:ClinicalTrials.gov Identifier: NCT03250741.	0
We describe the neurological, electrophysiological, and genetic features of autosomal dominant distal hereditary motor neuronopathy (HMN) in a three-generation Dutch family, including 12 patients with distal muscle weakness and atrophy. The severity of disease ranged from disabling muscle weakness to a subclinical phenotype. Neurologic exams of nine patients and nerve conduction studies (NCS) and myography in five endorsed the variable presentations of HMN in this family, including patients with only lower (four), upper (one), or both upper and lower extremities involvement (four). Asymmetrical or strictly unilateral disease was noted in three patients. Three also showed pyramidal features. A genome-wide search combining SNP arrays (250K) with parametric linkage analysis identified a novel locus on chromosome 16p (mLOD = 3.28) spanning 6 Mb (rs6500882-rs7192086). Direct sequencing excluded mutations in the SIMPLE/LITAF gene (mapping to the 16p locus) and identified a pathogenic mutation (p.N88S) in BCLS2 (11q12-q14). All 12 affected relatives had the BSCL2 mutation and the chromosome 16p haplotype and showed features of motor neuron degeneration. One patient had a very mild phenotype with bilateral pes cavus, normal concentric needle electromyography but signs of motor neuron involvement at electrophysiological muscle scan (EMS). Similar EMS abnormalities in addition to abnormal NCS and myography were observed in a clinically unaffected person (carrying only the 16p haplotype). These results expand the clinical spectrum of HMN and suggest a digenic inheritance of HMN in this family with a BSCL2 mutation and a chromosome 16 locus likely contributing to the phenotype.	0
BACKGROUND:Pseudodiastrophic dysplasia (PDD) is a severe skeletal dysplasia associated with prenatal manifestation and early lethality. Clinically, PDD is classified as a 'dysplasia with multiple joint dislocations'; however, the molecular aetiology of the disorder is currently unknown. METHODS:Whole exome sequencing (WES) was performed on three patients from two unrelated families, clinically diagnosed with PDD, in order to identify the underlying genetic cause. The functional effects of the identified variants were characterised using primary cells and human cell-based overexpression assays. RESULTS:WES resulted in the identification of biallelic variants in the established skeletal dysplasia genes, B3GAT3 (family 1) and CANT1 (family 2). Mutations in these genes have previously been reported to cause 'multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects' ('JDSCD'; B3GAT3) and Desbuquois dysplasia 1 (CANT1), disorders in the same nosological group as PDD. Follow-up of the B3GAT3 variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstream in vitro functional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of the CANT1 variant showed impaired nucleotidase activity, which results in inhibition of glycosaminoglycan synthesis through accumulation of uridine diphosphate. CONCLUSION:For the families described in this study, the PDD phenotype was caused by mutations in the known skeletal dysplasia genes B3GAT3 and CANT1, demonstrating the advantage of genomic analyses in delineating the molecular diagnosis of skeletal dysplasias. This finding expands the phenotypic spectrum of B3GAT3-related and CANT1-related skeletal dysplasias to include PDD and highlights the significant phenotypic overlap of conditions within the proteoglycan biosynthesis pathway.	0
BACKGROUND:Congenital left ventricular diverticulum is a rare cardiac malformation usually requiring total resection. CASE PRESENTATION:This report describes an infant presenting with a large apical diverticulum with a wide ventricle connection. Given the vicinity of the left anterior descending coronary artery to the diverticulum and its wide ventricular connection, partial resection was undertaken. The patient remained asymptomatic with good heart function 8 months after surgery. The last follow-up echocardiography did not demonstrate any significant left ventricular outpouching. CONCLUSIONS:We advocate early treatment of left ventricular diverticulum in children given the risk of spontaneous rupture of diverticulum, sudden death, and other serious complications if left untreated. For small patients with a wide connection of diverticulum to ventricle, partial resection is a safe option with favorable short-term outcomes.	0
Kaposi sarcoma (KS) is a vascular neoplasm caused by human herpesvirus-8 (HHV-8) infection. KS is most often seen in individuals with acquired immunodeficiency syndrome but can occur in patients who are on immunosuppressive therapy. While the skin and oral mucosa are the typical sites for KS, lesions of the tonsil are quite rare with only a few reported cases. Here, we present a case of tonsillar KS occurring in a renal transplant patient. He presented with dysphagia, odynophagia, and weight loss. Oral examination revealed tonsillar hypertrophy with purple discoloration. Imaging revealed diffuse enlargement of Waldeyer's ring with enlarged right cervical lymph nodes, worrisome for post-transplant lymphoproliferative disorder. Microscopic examination of the tonsillectomy specimen showed a vascular proliferation positive for HHV-8, consistent with KS. The patient was subsequently treated with immunosuppression reduction and the addition of sirolimus, which resulted in complete resolution of oropharyngeal and cervical lesions.	0
Unverricht-Lundborg disease (ULD), an autosomal recessive progressive myoclonus epilepsy, is due to an expansion, or less commonly a mutation, of the cystatin B (CSTB) gene. We report a clinical and molecular study of a Tunisian ULD family with five affected members presenting with a juvenile myoclonic epilepsy (JME)-like phenotype. The expansion of dodecamers was detected by a deamination/PCR assay. The expression profiles of CSTB and other candidate modifying genes, cathepsin B and cystatin C, were established by quantitative RT-PCR, and their respective transcription levels were compared with those from patients with a classic picture of ULD. Three patients had a fixed phenotype mimicking JME after 29 years of evolution. Only a discrete dysarthria was noticed in the two other patients. No correlation was observed between transcription level and severity of disease. Genetic screening should be performed in patients with a JME-like phenotype, when careful examination reveals discrete atypical signs of JME. This particular phenotype may be due to modifying genes and/or gene-environment interactions which require further clarification.	0
Cerebrotendinous xanthomatosis is an autosomal recessive inborn error of metabolism that is an often missed but treatable cause of hereditary ataxia. We report a case of cerebrotendinous xanthomatosis (CTX) that was diagnosed only after the development of cognitive decline and adult onset ataxia in a 35-year-old man. He had poor scholastic performance in childhood followed by gradually progressive cognitive decline. He presented to us with severe cerebellar ataxia and oculomotor apraxia. The key features that led to the diagnosis of CTX were the history of cataracts in childhood and Achilles tendon xanthoma. His brain magnetic resonance imaging showed characteristic features of CTX, and the diagnosis was confirmed by demonstrating the mutation in exon 2 of the CYP27A1 gene. The recognition of CTX earlier could have prevented his significant disabilities. The definitive treatment is oral chenodeoxycholic acid, which will prevent the accumulation of the cholestanol, which is thought to be responsible for the neurotoxicity.	0
OBJECTIVE:To report a case of rhizomelic chondrodysplasia punctata and present a brief literature review. DESCRIPTION:The authors report the case of a 52-day-old child presenting the main findings of the syndrome: rhizomelic micromelia, characteristic facies, suction difficulty and anthropometric measures below the expected indexes for his age. Skeletal radiographies showed humeri and femora shortening and calcifications stippling on shoulders, hips and knees joints. The patient also presented heart malformation, a less common manifestation of the syndrome. COMMENTS:The rhizomelic form of chondrodysplasia punctata is rare, with only 72 cases reported until 1995. The prognosis is bad and death usually occurs within the first year of age. The case presented here was diagnosed based on clinical and radiological criteria, due to the impossibility of searching for the peculiar biochemical markers.	0
We report a baby with aprosencephaly, preaxial limb defect and ambiguous genitalia. This combination of abnormalities have been reported previously and constitute the XK aprosencephaly syndrome.	0
Alzheimer's disease is a severe neurodegenerative brain disorder and characterized by deposition of extracellular toxic β-amyloid (42) plaques and the formation of intracellular tau neurofibrillary tangles. In addition, β-amyloid peptide deposits are found in the walls of small to medium blood vessels termed cerebral amyloid angiopathy (CAA). However, the pathogenesis of CAA appears to differ from that of senile plaques in several aspects. The aim of the present study was to analyze different lipids [phosphatidylcholines (PCs) and lysoPCs] in platelets and plasma of a novel mouse model of sporadic CAA (1). Our data show that lipids are significantly altered in plasma of the CAA mice. Levels of eight diacyl PCs, two acyl-alkyl PCs, and five lysoPCs were significantly increased. In extracts of mouse blood platelets, four diacyl and two acyl-alkyl PCs (but not lysoPCs) were significantly altered. Our data show that lipids are changed in CAA with a specific pattern, and we provide for the first time evidence that selected platelet and plasma PCs may help to characterize CAA.	0
X-Linked intellectual disability (XLID) accounts for 5%-10% of intellectual disability in males. Over 150 syndromes, the most common of which is the fragile X syndrome, have been described. A large number of families with nonsyndromal XLID, 95 of which have been regionally mapped, have been described as well. Mutations in 102 X-linked genes have been associated with 81 of these XLID syndromes and with 35 of the regionally mapped families with nonsyndromal XLID. Identification of these genes has enabled considerable reclassification and better understanding of the biological basis of XLID. At the same time, it has improved the clinical diagnosis of XLID and allowed for carrier detection and prevention strategies through gamete donation, prenatal diagnosis, and genetic counseling. Progress in delineating XLID has far outpaced the efforts to understand the genetic basis for autosomal intellectual disability. In large measure, this has been because of the relative ease of identifying families with XLID and finding the responsible mutations, as well as the determined and interactive efforts of a small group of researchers worldwide.	0
Hypertension and brachydactyly syndrome (HTNB; MIM 112410) is a rare, recently described, autosomal dominant syndromic disease characterized by the triad of brachydactyly type E (BDE), short stature, and hypertension. HTNB is caused by a heterozygous mutation in the PDE3A (MIM 123805) gene on chromosome 12p12; this gene encodes a member of the cGMP-inhibited cyclic nucleotide phosphodiesterase family. PED3A plays a role in many signal transduction pathways, including those involved in vascular smooth muscle proliferation and contraction, cardiac contractility, platelet aggregation, and hormone secretion. Here, we present a new case of HTNB in a 42-year-old patient who experienced recurrent ischemic strokes in various vascular territories; these strokes were caused by intracranial multiarterial dissection, and were experienced for 2 weeks. She was found to harbor a de novo heterozygous in-frame deletion, c.1333_1335del p.(Thr445del), in exon 4 of the PDE3A gene. Our finding is expected to contribute to the elucidation of the pathophysiology of stroke in HTNB patients. We further review all clinical and molecular genetic features of this rare disease described in the literature to date.	0
We present the findings of a prospective cohort study of babies born with antenatally detected urinary tract abnormalities (AUTAs) between 1999-2003 and compare the outcomes with those of an earlier cohort born between 1989 and 1993. All infants with a fetal anteroposterior renal pelvic diameter (APRPD) > or =7 mm in the third trimester or other urinary tract abnormality underwent a detailed postnatal ultrasound scan and other investigations as indicated. The incidence of AUTAs was significantly greater in the more recent cohort (7.6/1000 vs. 3/1000 live births; p<0.05). Of the 350 infants on which we had data, 48.6% (170/350) were in the non-specific dilatation (NSD) category, and vesicoureteric reflux (VUR) was detected in 12%. Restricting investigations to those who had an APRPD > or =10 mm at >30 weeks of gestation could have reduced the number with NSD in the more recent cohort (26/115; 25%), but 25% of those with pelviureteric junction hold-up and 50% with VUR would have been missed. Significantly fewer patients in the more recent cohort underwent surgery (7 vs. 21%; p<0.001). There is a trend towards larger APRPDs on third trimester scans being associated with more significant pathology, but there is a lot of clinical overlap. The study highlights the need for cautious antenatal counselling combined with an assurance to prospective parents that postnatal investigations will be performed in a stepwise manner based on the initial postnatal ultrasound scan and clinical findings.	1
Electroconvulsive therapy (ECT) is an increasingly popular treatment for drug-resistant depression that may have utility for some patients with neuroleptic malignant syndrome (NMS) who are unresponsive to pharmacotherapy. Using a case study as an example, this article discusses the diagnosis of a patient with NMS, the use of ECT as a treatment for NMS, and the importance of nursing care for these patients.	0
Hermansky-Pudlak syndrome (HPS) associates oculo-cutaneous albinism and systemic affections including platelet dense granules anomalies leading to bleeding diathesis and, depending on the form, pulmonary fibrosis, immunodeficiency and/or granulomatous colitis. So far 11 forms of autosomal recessive HPS caused by pathogenic variants in 11 different genes have been reported. We describe three HPS-8 consanguineous families with different homozygous pathogenic variants in BLOC1S3 (NM_212550.3), one of which is novel. These comprise two deletions leading to a reading frameshift (c.385_403del, c.338_341del) and one in frame deletion (c.444_467del). All patients have moderate oculo-cutaneous albinism and bleeding diathesis, but other HPS symptoms are not described. One patient diagnosed with HPS-8 suffered from lymphocyte predominant Hodgkin lymphoma. The mild severity of HPS-8 is consistent with other HPS forms caused by variants in BLOC-1 complex coding genes (HPS-7, DTNBP1; HPS-9, BLOC1S6, HPS-11, BLOC1S5).	0
OBJECTIVES:Coarctation of the aorta (CoA) in adolescents and adults is relatively rare. Several operative techniques have been reported, but there is no consensus. METHODS:From November 1994 to July 2018, a total of 24 adolescents and adults underwent CoA repair. The mean age at operation was 29.9 ± 15.1; 19 (79%) patients were older than 18. Sixteen (67%) patients had arterial hypertension, 5 (21%) patients had bicuspid aortic valve, 4 (17%) patients had descending aneurysm, 2 (8%) patients had ascending aneurysm, 2 (8%) patients had patent ductus arteriosus and 1 (4%) patient had atrial septal defect. Three patients had prior surgery (2 CoA repair, 1 ventricular septal defect repair). RESULTS:Surgical corrections included extra-anatomical bypasses in 12 (50%) patients (9: left subclavian artery to descending aorta bypass, 2 proximal-to-distal coarctation bypasses, 1 ascending-to-descending aortic bypass), end-to-end anastomosis in 6 (25%) patients, resections and interpositions of a tube graft in 5 (21%) patients and arch augmentation with a tube graft in 1 (4%) patient. The mean follow-up duration was 6.2 ± 5.1 years. No mortality was observed. No patient required reoperation or reintervention. The mean upper extremity systolic pressure significantly decreased from 142.4 ± 30.3 mmHg preoperatively to 121.1 ± 15.9 mmHg postoperatively (P = 0.002). Arterial pressure gradient between upper and lower extremities significantly decreased from 50.0 ± 21.8 mmHg preoperatively to 9.7 ± 13.5 mmHg postoperatively (P < 0.001). Among patients undergoing left subclavian artery to descending aorta bypass, 8 patients underwent ankle brachial pressure index evaluation. Postoperative mean right- and left-sided ankle brachial pressure index were 0.96 ± 0.16 and 0.94 ± 0.11, respectively. All grafts were patent at the last follow-up. CONCLUSIONS:CoA repair in adolescents and adults showed good outcomes. Left subclavian artery to descending aorta bypass grafting is safe and effective for managing CoA in adolescents and adults.	0
Despite being the second most common malignant bone tumor, Ewing's sarcoma remains uncommon in younger children and seldom seen in neonates and infants. Extraskeletal locations are even rarer, hardly ever suspected, and often misdiagnosed, causing delays in management. The histologic similarities of Ewing's sarcoma to more common pediatric small-blue-round-cell tumors such as lymphoma and neuroblastoma necessitate immunohistochemistry and molecular genetics for clinching the diagnosis. We report a soft-tissue Ewing's sarcoma in a 4-month-old female infant masquerading as a benign neck mass clinically, radiologically, cytologically, and intraoperatively. We also reviewed literature for any existing guidelines on when to biopsy neck masses in the pediatric population.	0
N-glycans provide structural and functional stability to asparagine-linked (N-linked) glycoproteins, and add flexibility. Glycan biosynthesis is elaborative, multi-compartmental and involves many glycosyltransferases. Failure to assemble N-glycans leads to phenotypic changes developing infection, cancer, congenital disorders of glycosylation (CDGs) among others. Biosynthesis of N-glycans begins at the endoplasmic reticulum (ER) with the assembly of dolichol-linked tetra-decasaccharide (Glc3Man9GlcNAc2-PP-Dol) where dolichol phosphate mannose synthase (DPMS) plays a central role. DPMS is also essential for GPI anchor biosynthesis as well as for O- and C-mannosylation of proteins in yeast and in mammalian cells. DPMS has been purified from several sources and its gene has been cloned from 39 species (e.g., from protozoan parasite to human). It is an inverting GT-A folded enzyme and classified as GT2 by CAZy (carbohydrate active enZyme; http://www.cazy.org ). The sequence alignment detects the presence of a metal binding DAD signature in DPMS from all 39 species but finds cAMP-dependent protein phosphorylation motif (PKA motif) in only 38 species. DPMS also has hydrophobic region(s). Hydropathy analysis of amino acid sequences from bovine, human, S. crevisiae and A. thaliana DPMS show PKA motif is present between the hydrophobic domains. The location of PKA motif as well as the hydrophobic domain(s) in the DPMS sequence vary from species to species. For example, the domain(s) could be located at the center or more towards the C-terminus. Irrespective of their catalytic similarity, the DNA sequence, the amino acid identity, and the lack of a stretch of hydrophobic amino acid residues at the C-terminus, DPMS is still classified as Type I and Type II enzyme. Because of an apparent bio-sensing ability, extracellular signaling and microenvironment regulate DPMS catalytic activity. In this review, we highlight some important features and the molecular diversities of DPMS.	0
The muscular dystrophies are a broad group of hereditary muscle diseases with variable severity. Population-based prevalence estimates have been reported but pooled estimates are not available. We performed a systematic review of worldwide population-based studies reporting muscular dystrophies prevalence and/or incidence using MEDLINE and EMBASE databases. The search strategy included key terms related to muscular dystrophies, incidence, prevalence and epidemiology. Two reviewers independently reviewed all abstracts, full text articles and abstracted data using standardized forms. Pooling of prevalence estimates was performed using random effect models. 1104 abstracts and 167 full text articles were reviewed. Thirty-one studies met all eligibility criteria and were included in the final analysis. The studies differed widely in their approaches to case ascertainment, resulting in significant methodological heterogeneity and varied data quality. The pooled prevalence of DMD and BMD was 4.78 (95% CI 1.94-11.81) and 1.53 (95% CI 0.26-8.94) per 100,000 males respectively. The incidence of DMD ranged from 10.71 to 27.78 per 100,000. This is the first meta-analysis of worldwide prevalence estimates for muscular dystrophies. There is a need for more epidemiological studies addressing global estimates on incidence and prevalence of muscular dystrophies, utilizing standardized diagnostic criteria as well as multiple sources of case ascertainment.	1
OBJECTIVE: To test the possible multifactorial-threshold model in the origin of isolated microtia/anotia (IMA). METHOD: The observed number of IMA in the first degree relatives of cases affected was compared with the expected number of affected first degree relatives based on the multifactorial-threshold model in the population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. RESULTS: Of 354 cases with IMA, 14 (4.0%) had the affected first degree relatives with IMA. There was a low and similar rate of familial occurrence of IMA in parents and siblings of cases. The observed numbers of affected first degree relatives of cases with IMA and their expected numbers did not show significant difference (p=0.47). Some other findings (e.g. male excess and the interaction of triggering environmental factors with polygenic predisposition) confirmed this hypothesis. CONCLUSIONS: The familial pattern of cases with IMA does not reject the hypothesis that the multifactorial-threshold model, i.e. gene-environmental interaction, may be the explanation for the origin of this congenital abnormality group, although the number of familial cases was quite small in the study.	0
Objective: To investigate the mutation characteristics and clinical relevance of Gilbert syndrome (GS) and Crigler-Najjar syndrome (CNS) in relation to uridine diphosphate glucuronosyltransferase A1 (UGT1A1) gene. Methods: The characteristics of UGT1A1 gene mutation and their clinical relevance were analyzed by searching PubMed and Human Gene Mutation Databases. Results: A total of 163 mutation sites were found in the UGT1A1 gene since November 16, 2018. The following patterns existed at the above sites: (1) the numbers of gene mutations occurring between different exons of UGT1A1 was related to GS or CNS phenotypes, and were positively correlated with the length of the exon; (2) nonsense point mutations was mainly occurred in type I of CNS; (3) GS, Crigler-Najjar syndrome type II compound heterozygous mutation sites had a certain combination and distribution, among which - 3279t > G mutation was found in all four GS complex heterozygous compositions; (4) UGT1A1 gene mutation sites reported in Asia had marked aggregation in c.211-c.558. Conclusion: UGT1A1 gene mutation characteristics and clinical relevance varies with different mutation sites, reporting areas and populations. This study has reference value for basic research and clinical diagnosis and treatment of GS and CNS.	0
A short review of literature data on the pathogenesis and clinical presentations of spinal muscular atrophies is provided. We report two cases of Werdnig-Hoffmann's disease in one family and present a diagnostic search strategy which allows the ordinary neurologist to distinguish this pathology.	0
BACKGROUND: Blueberry Muffin Baby is a rare neonatal cutaneous syndrome for purpuric lesions reflective of extramedullary hematopoiesis. Many causes are known, examples are congenital infections, malignancy and hematologic disorders. Langerhans' cell histiocytosis is a clonal proliferation of dendritic histiocytes. This has very rarely been associated with a Blueberry Muffin Baby presentation. CASE REPORT: We report the case of a newborn presenting with Blueberry Muffin Baby syndrome related to congenital Langherans' cell histiocytosis. At birth, he had multiple purpuric lesions on the trunk, limbs and face. Skin biopsy showed a dermal proliferation of histiocytes staining positive for S100 and CD1a. Chest and bone radiographs, and abdominal ultrasound were normal. Skin lesions have resolved in 8 weeks, the patient is in complete remission at 18 months of follow-up. DISCUSSION: A Blueberry Muffin Baby syndrome may reveal neonatal Langerhans' histiocytosis.	0
Pulmonary arterial hypertension (PAH) is a rare disease caused by pulmonary vascular remodeling. Current vasodilator treatments have substantially improved patients' survival. This improved survival has led to the appearance of complications related to conditions previously underdiagnosed or even ignored, such as pulmonary artery aneurysm (PAA). The presence of a dilated pulmonary artery has been shown to be related to an increased risk of sudden cardiac death among PAH patients. This increased risk could be associated to the development of left main coronary artery compression or pulmonary artery dissection. Nevertheless, very little is currently known about the molecular mechanisms related to PAA. Thoracic aortic aneurysm (TAA) is a well-known condition with an increased risk of sudden death caused by acute aortic dissection. TAA may be secondary to chronic exposure to classic cardiovascular risk factors. In addition, a number of genetic variants have been shown to be related to a marked risk of TAA and dissection as part of multisystemic syndromes or isolated familial TAA. The molecular pathways implied in the development of TAA have been widely studied and described. Many of these molecular pathways are involved in the pathogenesis of PAH and could be involved in PAA. This review aims to describe all these common pathways to open new research lines that could help lead to a better understanding of the pathophysiology of PAH and PAA and their clinical implications.	0
We report a 16-year-old man with disorders of tetrahydrobiopterin metabolism due to dihydropteridine reductase (DHPR) deficiency. He revealed moderate mental retardation, parkinsonism, and spastic paralysis with levodopa and 5-hydroxytryptophan (5-HTP) supplementation from the age of 2 months. Brain MRI showed high intensity areas in bilateral frontal and posterior deep white matter on fluid-attenuated inversion recovery (FLAIR). Coronal FLAIR image showed a high signal in bilateral pyramidal tracts. Single photon computed tomography (SPECT) imaging of the dopamine transporter was normal. This imaging indicates no dopaminergic cell loss. Our patient had no motor fluctuations or dyskinesias. Early diagnosis and replacement treatment might lead to a favorable outcome.	0
ABSTRACT: We present here a unique case of humeroradial synostosis. These anomalies are due to longitudinal failure of differentiation. Approximately 150 cases of humeroradial synostosis have been reported worldwide, the majority of which are familial in nature or associated with syndromes. The case presented here involves an infant aged 1½ months, born with bilateral humeroradial synostosis without familial or syndromic association. To the best of our knowledge, no such case has been reported in Asia.	0
BACKGROUND:Neuromuscular disorders (NMDs) comprise a group of heterogeneous genetic diseases with a broad spectrum of overlapping the clinical presentations that makes diagnosis challenging. Notably, the recent introduction of whole-exome sequencing (WES) is introducing rapid changes on the genetic diagnosis of NMDs. We aimed to investigate the diagnostic value of WES for pediatric-onset NMDs. METHODS:We applied integrated diagnostic approach and performed WES in 50 Chinese subjects (30 males, 20 females) with undiagnosed pediatric-onset NMDs despite previous specific tests. The patients were categorized in four subgroups according to phenotyping and investigation findings. Variants on NMDs gene list and open exome analysis for those with initial negative findings were identified. RESULTS:WES identified causative variants in ACTA1 (n = 2), POMT1, COL6A1 (n = 2), MTMR2, LMNA, SELENON, DNM2, TGFB1, MPZ, IGHMBP2, and LAMA2 in 13 patients. Two subjects have variants of uncertain significance (VUSs) in TTN and SCN11A, unlikely to be pathogenic due to incompatible phenotypes. The mean interval time from symptom onset to genetic diagnosis was 10.4 years (range from 1 month to 33 years). The overall diagnostic yield of WES in our cohort was 26%. Open exome analysis was necessary to identify the pathogenic variant in TGFB1 that caused skeletal dysplasia with neuromuscular presentation. CONCLUSION:Our study shows a clear role of WES in the pathway of integrated diagnostic approach to shorten the diagnostic odyssey in patients with rare NMDs.	0
Intestinal lactase is required for the hydrolysis of lactose that is the most essential carbohydrate in milk and the primary diet source of newborn.  Congenital lactase deficiency [CLD (MIM 223000)] is a severe gastrointestinal disorder and is characterized by watery diarrhea due to an extremely low or the lack of lactase activity in the intestinal wall from birth.  CLD is a rare disease and occurs more frequently in Finland.  Recent studies have shown that mutations in the coding region of the lactase (LCT) gene underlie CLD in patients from Finland and other European countries.  Here, we report two novel mutations in the LCT gene in a Japanese female infant with clinical features consistent with those of CLD.  She suffered from severe watery diarrhea from the age of 2 days on breast milk/lactose containing cow's milk formula.  With the lactose-free hydrolyzed cow's milk formula, diarrhea was stopped, and she has now developed well on a lactose-free diet.  She shows a lactose-intolerance pattern on the lactose challenge test.  Sequence analysis revealed the two mutations in her LCT gene: c.4419C>G (p.Y1473X) in exon 10 transmitted from her mother and c.5387delA (p.D1796fs) in exon 16 transmitted from her father.  Both mutations cause premature truncation of lactase polypeptide and are supposed to be responsible for CLD.  To our knowledge, this is the first report on mutations in the LCT gene in Japan.  We suggest that an increased awareness is required regarding CLD.	0
Clozapine is known as one of the atypical antipsychotics which is placed in the second line of medical treatment for schizophrenia due to its hematologic complications. It is used in cases of resistance to treatment. Some side effects of clozapine include leukopenia, granulocytopenia, fever, hepatotoxicity, sedation, dizziness, hypotension, weight gain, constipation, and seizure. Neutropenia and hepatotoxicity have been separately reported after taking atypical antipsychotics, including clozapine. However, simultaneous occurrence of these two complications is rare and has not been reported with clozapine use. This study reports a case of concurrent hepatotoxicity and neutropenia induced by clozapine. The patient was a 58-year-old man who started taking clozapine for the first time in March 2017, about seven weeks before his recent admission, because of a history of treatment-resistant schizophrenia. He had been referred to the emergency department of a general hospital with symptoms of weakness, lethargy, fever, and chills. The laboratory results showed neutropenia with a frequency of 352 × 103 (17.5%) and hepatotoxicity with alanine transferase (ALT) = 139 u/L, aspartate transferase (AST) = 214 u/L, total bilirubin = 11.5 mg/dL, and direct bilirubin = 9.3 mg/Dl, caused by taking clozapine. The symptoms were attenuated within eight days after discontinuation of clozapine. Moreover, the patient's para-clinical complications including neutropenia, and raised transaminases and bilirubin returned to normal. It was concluded that clozapine can simultaneously cause neutropenia and hepatotoxicity; physicians are recommended to be aware of this issue to prevent mortality through appropriate and timely diagnosis.	0
We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.	0
Cell proliferation and release from the bone marrow have been demonstrated to be controlled by circadian rhythms in both humans and mice. However, it is unclear whether local circadian clocks in the bone marrow influence physiological functions and life span of erythrocytes. Here, we report that loss of the clock gene Per2 significantly decreased erythrocyte life span. Mice deficient in Per2 were more susceptible to acute stresses in the erythrocytes, becoming severely anemic upon phenylhydrazine, osmotic, and H2O2 challenges. 1H NMR-based metabolomics analysis revealed that the Per2 depletion causes significant changes in metabolic profiles of erythrocytes, including increased lactate and decreased ATP levels compared with wild-type mice. The lower ATP levels were associated with hyperfunction of Na+/K+-ATPase activity in Per2-null erythrocytes, and inhibition of Na+/K+-ATPase activity by ouabain efficiently rescued ATP levels. Per2-null mice displayed increased levels of Na+/K+-ATPase α1 (ATP1A1) in the erythrocyte membrane, and transfection of Per2 cDNA into the erythroleukemic cell line TF-1 inhibited Atp1a1 expression. Furthermore, we observed that PER2 regulates Atp1a1 transcription through interacting with trans-acting transcription factor 1 (SP1). Our findings reveal that Per2 function in the bone marrow is required for the regulation of life span in circulating erythrocytes.	0
We present a residency curriculum for Ophthalmology in India. The document derives from a workshop by the All India Ophthalmological Society (AlOS) which adapted the International Council of Ophthalmology residency curriculum and refined and customized it based on inputs by the residency program directors who participated in the work shop. The curriculum describes the course content, lays down the minimum requirements of infrastructure and mandates diagnostic and therapeutic procedures required for optimal training. It emphasises professionalism, management, research methodology, community ophthalmology as integral to the curriculum. The proposed national ophthalmology residency curriculum for India incorporates the required knowledge and skills for effective and safe practice of ophthalmology and takes into account the specific needs of the country.	0
PURPOSE:To investigate complex and different phenotypes in seven Chinese patients diagnosed with Bardet-Biedl syndrome (BBS) and carrying pathogenic mutations. METHODS:Seven unrelated BBS patients were enrolled. Their medical and ophthalmic histories were reviewed, and comprehensive clinical examinations, such as fundus photography, optical coherence tomography, and medical imaging, were performed. A specific hereditary eye disease enrichment panel based on exome-capture technology was used to collect and amplify the protein-coding regions of 441 targeted hereditary eye disease genes, followed by high-throughput sequencing using the Illumina HiSeq platform. RESULTS:All patients exhibited the primary clinical phenotype of BBS. Seven BBS mutations were found in five patients (BBS7 in two patients, BBS10 in two patients, BBS12 in one patient), for a detection rate of 71% (5/7). The ratio of novel to known BBS mutations was 5:2. CONCLUSIONS:This study showed the phenotypic and genotypic spectrum of BBS patients from China, and the findings underscore the importance of obtaining comprehensive clinical observations and molecular analyses for ciliopathies.	0
Background:Glycogen storage disease type IV (GSD IV; Andersen's disease) is a rare autosomal recessive disease caused by mutation in the GBE1 gene. Presentation of GSD IV varies on a continuum of severity and symptomatology ranging from neonatal death to mild adult-onset disease with variable involvement of hepatic, muscular, neurologic, dermatologic, and cardiac systems. Cardiomyopathy seen in GSD IV is also heterogeneous and its appearance on cardiac magnetic resonance imaging (CMR) is rarely described. Case summary:A 29-year-old man without previous medical history was admitted to our facility multiple times over 2 years for focal sensorimotor deficits, gout arthropathy, chronic hyperlactataemia and hyperuricaemia, and severe decompensated non-ischaemic cardiomyopathy complicated by episodes of thromboembolic organ infarction. Echocardiography and CMR showed severe biventricular failure with the presence of intraventricular thrombi with increased right ventricular trabeculation and absent late gadolinium enhancement. He underwent muscle biopsy which showed prominent glycogen in skeletal muscle followed by genetic testing showing a single heterozygous splicing mutation c.993-1G>T found at the junction of intron 7 and exon 8 of the GBE1 gene which had not previously been reported and was predicted to be pathologic. He was referred to a tertiary care centre with glycogen storage disease specialists but expired prior to establishing care at that facility. Discussion:Discovery of GSD IV in our patient was unexpected due to a highly variant clinical presentation. Our case stresses the clinical heterogeneity of GSD IV and the importance of genetic sequencing studies in the evaluation of potential glycogen storage disease.	0
Cartilage-hair hypoplasia (CHH) is a skeletal dysplasia with combined immunodeficiency, variable clinical course and increased risk of malignancy. Management of CHH is complicated by a paucity of long-term follow-up data, as well as knowledge on prognostic factors. We assessed clinical course and risk factors for mortality in a prospective cohort study of 80 patients with CHH recruited in 1985-1991 and followed up until 2016. For all patients we collected additional health information from health records and from the national Medical Databases and Cause-of-death Registry. The primary outcome was immunodeficiency-related death, including death from infections, lung disease and malignancy. Standardized mortality ratios (SMRs) were calculated using national mortality rates as reference. Half of the patients (57%, n = 46) manifested no symptoms of immunodeficiency during follow-up while 19% (n = 15) and 24% (n = 19) demonstrated symptoms of humoral or combined immunodeficiency, including six cases of adult-onset immunodeficiency. In a significant proportion of patients (17/79, 22%), clinical features of immunodeficiency progressed over time. Of the 15 patients with non-skin cancer, eight had no preceding clinical symptoms of immunodeficiency. Altogether 20 patients had deceased (SMR = 7.0, 95%CI = 4.3-11); most commonly from malignancy (n = 7, SMR = 10, 95%CI = 4.1-21) and lung disease (n = 4, SMR = 46, 95%CI = 9.5-130). Mortality associated with birth length below -4 standard deviation (compared to normal, SMR/SMR ratio = 5.4, 95%CI = 1.5-20), symptoms of combined immunodeficiency (compared to asymptomatic, SMR/SMR ratio = 3.9, 95%CI = 1.3-11), Hirschsprung disease (odds ratio (OR) 7.2, 95%CI = 1.04-55), pneumonia in the first year of life or recurrently in adulthood (OR = 7.6/19, 95%CI = 1.3-43/2.6-140) and autoimmunity in adulthood (OR = 39, 95%CI = 3.5-430). In conclusion, patients with CHH may develop adult-onset immunodeficiency or malignancy without preceding clinical symptoms of immune defect, warranting careful follow-up. Variable disease course and risk factors for mortality should be acknowledged.	0
Charcot-Marie-Tooth disease type 4D (CMT4D) is an autosomal-recessive demyelinating form of CMT characterized by a severe distal motor and sensory neuropathy. NDRG1 is the causative gene for CMT4D. To date, only four mutations in NDRG1 -c.442C>T (p.Arg148*), c.739delC (p.His247Thrfs*74), c.538-1G>A, and duplication of exons 6-8-have been described in CMT4D patients. Here, using targeted next-generation sequencing examination, we identified for the first time two homozygous missense variants in NDRG1, c.437T>C (p.Leu146Pro) and c.701G>A (p.Arg234Gln), in two Chinese CMT families with consanguineous histories. Further functional studies were performed to characterize the biological effects of these variants. Cell culture transfection studies showed that mutant NDRG1 carrying p.Leu146Pro, p.Arg148*, or p.Arg234Gln variant degraded faster than wild-type NDRG1, resulting in lower protein levels. Live cell confocal microscopy and coimmunoprecipitation analysis indicated that these variants did not disrupt the interaction between NDRG1 and Rab4a protein. However, NDRG1-knockdown cells expressing mutant NDRG1 displayed enlarged Rab4a-positive compartments. Moreover, mutant NDRG1 could not enhance the uptake of DiI-LDL or increase the fraction of low-density lipoprotein receptor on the cell surface. Taken together, our study described two missense mutations in NDRG1 and emphasized the important role of NDRG1 in intracellular protein trafficking.	0
Peroxisomal biogenesis disorders (PBDs) represent a spectrum of autosomal recessive metabolic disorders that are collectively characterized by abnormal peroxisome assembly and impaired peroxisomal function. The importance of this ubiquitous organelle for human health is highlighted by the fact that PBDs are multisystemic disorders that often cause death in early infancy. Peroxisomes contribute to central metabolic pathways. Most enzymes in the peroxisomal matrix are linked to lipid metabolism and detoxification of reactive oxygen species. Proper assembly of peroxisomes and thus also import of their enzymes relies on specific peroxisomal biogenesis factors, so called peroxins with PEX being the gene acronym. To date, 13 PEX genes are known to cause PBDs when mutated. Studies of the cellular and molecular defects in cells derived from PBD patients have significantly contributed to the understanding of the functional role of the corresponding peroxins in peroxisome assembly. In this review, we discuss recent data derived from both human cell culture as well as model organisms like yeasts and present an overview on the molecular mechanism underlying peroxisomal biogenesis disorders with emphasis on disorders caused by defects in the peroxisomal matrix protein import machinery.	0
Paraneoplastic neurological syndromes are nonmetastatic complications of malignancy secondary to immune-mediated neuronal dysfunction or death. Pathogenesis may occur from cell surface binding of antineuronal antibodies leading to dysfunction of the target protein, or from antibodies binding against intracellular antigens which ultimately leads to cell death. There are several classical neurological paraneoplastic phenotypes including subacute cerebellar degeneration, limbic encephalitis, encephalomyelitis, and dorsal sensory neuropathy. The patient's clinical presentations may be suggestive to the treating clinician as to the specific underlying paraneoplastic antibody. Specific antibodies often correlate with the specific underlying tumor type, and malignancy screening is essential in all patients with paraneoplastic neurological disease. Prompt initiation of immunotherapy is essential in the treatment of patients with paraneoplastic neurological disease, often more effective in cell surface antibodies in comparison to intracellular antibodies, as is removal of the underlying tumor.	0
First reported in 1956, hereditary fructose intolerance (HFI) illustrates vividly how interactions between genes and nutrients can influence taste preferences; the disease also reflects the ascendancy of sucrose and fructose as energy sources and as the world's principal sweeteners. However, HFI is not the only genetic ill to have emerged from our obsession with sugar: the slave trade, which had such a key part in the development of the sugar industry, also included major genetic consequences in its haunting legacy.	1
A boy, aged 4 months, had the major clinical manifestations of prolonged jaundice and hepatomegaly. Multiple biochemical tests revealed abnormal liver function along with elevated alpha-fetoprotein and lactate. Genetic analysis confirmed that the boy had the mutations of c.589C>T(p.Gln197Ter) and c.687G>C(p.Trp229Cys) in the DGUOK gene, both of which were novel mutations and were determined to be pathogenic and likely pathogenic respectively, by a variety of bioinformatics tools and the ACMG standard. Therefore, the boy was confirmed to have DGUOK-related mitochondrial DNA depletion syndrome. Literature review showed that onset of liver disease in infancy was the main clinical feature of this disease, and some children presented with nervous system manifestations. Abnormal laboratory results included abnormal liver function, increases in blood lactate, serum ferritin and alpha-fetoprotein, and hypoglycemia. Such children had marked heterogeneity of DGUOK gene mutations, with missense mutations as the most common type. This disease tended to have a poor prognosis, and 79.6% of the children died before the age of 3 years.	0
PURPOSE:The main cause of carpal tunnel syndrome (CTS) is pathological changes in the flexor synovium, which is a known cause of pressure elevation in the carpal tunnel. The importance of the transverse carpal ligament (TCL) in the pathogenesis of CTS has hitherto been overlooked. However, the TCL significantly affects carpal biomechanics; the TCL is known to affect the carpal bone to a greater extent when intra carpal tunnel pressure is high. In addition, the effect of TCL properties on the progression course of idiopathic CTS is unknown.Therefore, we hypothesized that TCL thickness, measured using ultrasonography, would influence the results of conservative treatment for CTS patients with mild to moderate symptoms. We aimed to investigate the relationship between the ultrasound-measured TCL thickness and idiopathic carpal tunnel conservative treatment surgery rate. MATERIALS AND METHODS:We analyzed the wrists of 127 patients with mild to moderate symptoms of CTS. The patients were diagnosed on the basis of electrophysiological assessment outcomes, median nerve cross-sectional area in the carpal tunnel, and clinical symptoms. The Boston carpal tunnel questionnaire score was also measured. Patients with a TCL thinner than 1.5 mm were classified into group A (n = 62), and those with a TCL thicker than 1.5 mm were classified into group B (n = 65). Patients with severe symptoms or other diseases were excluded. The patients were initially treated with night splinting after diagnosis. If symptoms were not ameliorated, steroid injection and surgical treatment were performed consecutively. The procedures were determined by a single surgeon. RESULTS:The mean TCL thickness was 1.51 mm: 0.98 mm in group A and 2.28 mm in group B. The percentages of patients who underwent surgery were 43.0% in group A and 67.7% in group B. Group B was 1.77 times more likely to have surgery, and the interval between diagnosis and surgery and/or steroid injection was shorter. The TCL thickness in group B was also related to cross-sectional area and symptom duration. CONCLUSIONS:Transverse carpal ligament thickness affects disease progression and may affect treatment efficacy, depending on the treatment method. Transverse carpal ligament thickness may be a criterion for deciding between surgical and conservative treatments based on a thickness threshold of 1.5 mm.	0
BACKGROUND:Surgical resection of maxillary tumors can result in defects that can be difficult to reconstruct by conventional means due to the complex functional and anatomic nature of the midface and lack of regional bone flap options in the head and neck. Many reconstructive methods have been used to repair maxillary defects, but the ideal technique for the reconstruction of hemi-maxillectomy defects in growing pediatric patients has yet to be determined. METHODS:The authors present a rare pediatric patient with melanotic neuroectodermal tumor of infancy resulting in a hemi-maxillectomy defect after resection that was reconstructed using a pedicled vascularized composite flap consisting of temporalis muscle, pericranium, and parietal bone. RESULTS:The patient achieved successful long-term bony reconstruction of his right maxilla with this flap. Stable skeletal fixation with adequate orbital support was maintained over a >3-year follow-up period. CONCLUSION:A vascularized composite parietal bone flap is a reliable reconstructive option for reconstruction of large maxillectomy defects providing low donor-site morbidity, adequate globe support, excellent long-term skeletal stability, and malar symmetry in rapidly growing pediatric patients. Successful reconstruction for a rare patient with maxillary melanotic neuroectodermal tumor of infancy requiring hemi-maxillectomy was demonstrated with >3-year follow-up.	0
Background: Progressive pseudorheumatoid dysplasia (PPRD) inherited in an autosomal recessive fashion, is a disabling disease, characterized by platyspondyly, irregularities of the vertebral bodies, narrowing of the intervertebral discs and intraarticular spaces, widening of the epiphysis-metaphysis, polyarthralgia, multiple joint contractures, and disproportionate short stature. A number of studies have been performed on this deformity in various populations around the globe, including the Arab population. Mutations in CCN6, located on 6q22, are reported to cause this anomaly. Case Presentation: The present study describes the investigation of a consanguineous family of Yemeni origin. Clinical examination of the patient revealed short stature with progressive skeletal abnormalities, stiffness and enlargement of small joints of the hands along with restriction of movements of proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints with weakness and gait disturbance. Sanger sequencing revealed a novel homozygous frameshift deletion mutation (c.746delT; p.Val249Glyfs*10) in CCN6 which may lead to NMD (Nonsense mediated decay). This mutation expands the spectrum of pathogenic variants in CCN6 causing PPRD.	0
Lipodystrophies are a heterogeneous group of congenital or acquired disorders, characterized by partial or generalized loss of adipose tissue. Familial partial lipodystrophy (FPLD) presents with genetic and phenotypic variability with insulin resistance, hypertriglyceridemia and hepatic steatosis being the cardinal metabolic features. The severity of the metabolic derangements is in proportion with the degree of lipoatrophy. The underpinning pathogenetic mechanism is the limited capacity of adipose tissue to store lipids leading to lipotoxicity, low-grade inflammation, altered adipokine secretion and ectopic fat tissue accumulation. Advances in molecular genetics have led to the discovery of new genes and improved our knowledge of the regulation of adipose tissue biology. Diagnosis relies predominantly on clinical findings, such as abnormal fat tissue topography and signs of insulin resistance and is confirmed by genetic analysis. In addition to anthropometry and conventional imaging, new techniques such as color-coded imaging of fat depots allow more accurate assessment of the regional fat distribution and differentiation of lipodystrophic syndromes from common metabolic syndrome phenotype. The treatment of patients with lipodystrophy has proven to be challenging. The use of a human leptin analogue, metreleptin, has recently been approved in the management of FPLD with evidence suggesting improved metabolic profile, satiety, reproductive function and self-perception. Preliminary data on the use of glucagon-like peptide 1 receptor agonists (GLP1 Ras) and sodium-glucose co-transporter 2 (SGLT2) inhibitors in cases of FPLD have shown promising results with reduction in total insulin requirements and improvement in glycemic control. Finally, investigational trials for new therapeutic agents in the management of FPLD are underway.	0
OBJECTIVES:The study evaluated the driving habits and risk of traffic accidents among people with Ménière's disease (MD) in Finland. MATERIALS AND METHODS:The study used a cross-sectional survey design. Members of the Finnish Ménière Federation (FMF) were contacted and requested to participate in an online survey. In total, 558 FMF members (58.7% response rate) responded to the survey. RESULTS:People with MD were responsible for significantly fewer traffic accidents (0.8%) annually than individuals in the general population (1.7%). In addition, the lifetime risk of car accidents was lower among subjects with MD (8.3%) than that among individuals in the general population (24 to 28%). Nearly half of the total participants had either reduced the frequency of driving or had given up driving because of their condition. Factors such as gender, balance problems, visual problems with visual aura, and syncope during vestibular drop attacks can help explain the reasons for giving up car driving. One third (35.9%) of the participants were able to anticipate the MD attack before they decided to drive a car. Participants with falls during a vestibular drop attack, attacks of rotary vertigo, syncope during vestibular drop attacks, and those who were of a younger age were at a higher risk of experiencing a vertigo attack while driving a car. The most common strategies to avoid car accidents were selective driving and not driving when symptoms appeared. CONCLUSION:The results show that people with MD are at a lower risk of traffic accidents than individuals in the general population, which can be explained by selective driving.	0
This state-of-the art manuscript highlights our current understanding of maternal immunization-the practice of vaccinating pregnant women to confer protection on them as well as on their young infants, and thereby reduce vaccine-preventable morbidity and mortality. Advances in our understanding of the immunologic processes that undergird a normal pregnancy, studies from vaccines currently available and recommended for pregnant women, and vaccines for administration in special situations are beginning to build the case for safe scale-up of maternal immunization. In addition to well-known diseases, new diseases are emerging which pose threats. Several new vaccines are currently under development and increasingly include pregnant women. In this manuscript, targeted at clinicians, vaccinologists, scientists, public health practitioners, and policymakers, we also outline key considerations around maternal immunization introduction and delivery, discuss noninfectious horizons for maternal immunization, and provide a framework for the clinician faced with immunizing a pregnant woman.	0
OBJECTIVE:To better evaluate the imaging spectrum of subcortical heterotopic gray matter brain malformations (subcortical heterotopia [SUBH]), we systematically reviewed neuroimaging and clinical data of 107 affected individuals. METHODS:SUBH is defined as heterotopic gray matter, located within the white matter between the cortex and lateral ventricles. Four large brain malformation databases were searched for individuals with these malformations; data on imaging, clinical outcomes, and results of molecular testing were systematically reviewed and integrated with all previously published subtypes to create a single classification system. RESULTS:Review of the databases revealed 107 patients with SUBH, the large majority scanned during childhood (84%), including more than half before 4 years (59%). Although most individuals had cognitive or motor disability, 19% had normal development. Epilepsy was documented in 69%. Additional brain malformations were common and included abnormalities of the corpus callosum (65/102 [64%]), and, often, brainstem or cerebellum (47/106 [44%]). Extent of the heterotopic gray matter brain malformations (unilateral or bilateral) did not influence the presence or age at onset of seizures. Although genetic testing was not systematically performed in this group, the sporadic occurrence and frequent asymmetry suggests either postzygotic mutations or prenatal disruptive events. Several rare, bilateral forms are caused by mutations in genes associated with cell proliferation and polarity (EML1, TUBB, KATNB1, CENPJ, GPSM2). CONCLUSION:This study reveals a broad clinical and imaging spectrum of heterotopic malformations and provides a framework for their classification.	0
SUCLA2 encodes for a subunit of succinyl-coenzyme A synthase, the enzyme that reversibly synthesises succinyl-coenzyme A and ATP from succinate, coenzyme A and ADP in the Krebs cycle. Disruption of SUCLA2 function can lead to mitochondrial DNA depletion. Patients with a SUCLA2 mutation present with a rare but distinctive deafness-dystonia syndrome. Additionally, they exhibit elevated levels of the characteristic biochemical markers: methylmalonate, C4-dicarboxylic carnitine and lactate are increased in both plasma and urine. Thus far, eight different disease-causing SUCLA2 mutations, of which six missense mutations and two splice site mutations, have been described in the literature. Here, we present the first patient with an intragenic deletion in SUCLA2 and review the patients described in literature.	0
Spinocerebellar ataxia type 14 (SCA-PRKCG, formerly SCA14) is a rare, slowly progressive disorder caused by conventional mutations in protein kinase Cγ (PKCγ). The disease usually manifests with ataxia, but previous reports suggested PRKCG variants in retinal pathology. To systematically investigate for the first time visual function and retinal morphology in patients with SCA-PRKCG. Seventeen patients with PRKCG variants and 17 healthy controls were prospectively recruited, of which 12 genetically confirmed SCA-PRKCG patients and 14 matched controls were analyzed. We enquired a structured history for visual symptoms. Vision-related quality of life was obtained with the National Eye Institute Visual Function Questionnaire (NEI-VFQ) including the Neuro-Ophthalmic Supplement (NOS). Participants underwent testing of visual acuity, contrast sensitivity, visual fields, and retinal morphology with optical coherence tomography (OCT). Measurements of the SCA-PRKCG group were analyzed for their association with clinical parameters (ataxia rating and disease duration). SCA-PRKCG patients rate their vision-related quality of life in NEI-VFQ significantly worse than controls. Furthermore, binocular visual acuity and contrast sensitivity were worse in SCA-PRKCG patients compared with controls. Despite this, none of the OCT measurements differed between groups. NEI-VFQ and NOS composite scores were related to ataxia severity. Additionally, we describe one patient with a genetic variant of uncertain significance in the catalytic domain of PKCγ who, unlike all confirmed SCA-PRKCG, presented with a clinically silent epitheliopathy. SCA-PRKCG patients had reduced binocular vision and vision-related quality of life. Since no structural retinal damage was found, the pathomechanism of these findings remains unclear.	0
BACKGROUND:Pseudoduplication of the optic disc is a rare clinical condition that is characterized by a circumscribed, disc-like lesion with radiating vessels but only one normal optic nerve. We report a rare case that initially resembled a bifurcated optic nerve in a strabismus child. CASE PRESENTATION:A 6-year-old female child was initially referred to our hospital due to perceptual exotropia of 15 degrees with poor fixation of the left eye. The visual acuity of the left eye was 3/100 with a refraction of + 1.75/- 1.25 × 175. Fundus images of her left eye revealed a circumscribed and disc-like lesion located one disc diameter (DD) below the true optic disc that showed profound central cupping resembling a second optic disc with a vascular supply. B scan ultrasonography showed an optic nerve with a bifurcated weak-echo region, suggesting that two strands originated from the optic nerve. Optic coherence tomography (OCT) demonstrated a large crater-like depression of the lesion, indicating a colobomatous defect covered by a mysterious membranous structure, a disturbed nerve fibre layer and the absence of regular outer retinal layers. A perimetric examination revealed a relatively superior defect. Magnetic resonance imaging (MRI) revealed the left eye globe showed an abnormal morphology and that the optic nerve was abnormally shaped and shifted nasally in the left eye. Fundus fluorescein angiography (FFA) of the left eye revealed the absence of independent vascular vessels in the disc-like lesion. Hyperfluorescence with patchy fluorescence was evident in the inferotemporal area of the disc. Vascular loops surrounding the temporal region were evident in both eyes. Her right eye was normal except for the vascular loop. We proposed that this represented a case of pseudoduplication of the optic disc. The patient did not undergo any treatment, and her visual acuity remained stable during the follow-up period. CONCLUSIONS:Our patient presented with a deep and ectatic coloboma below the optic disc that communicated with the true optic nerve and was originally thought to indicate a bifurcated optic nerve. This case suggests that atypical ectatic colobomas should be considered before diagnosing malformations related to the optic nerve in double optic disc cases.	0
BACKGROUND:The aim of this study was to identify the genetic causes of patients with hypertrophic cardiomyopathy (HCM) within a family. Most of the previous studies found point mutations as the genetic causes for HCM, whole-gene deletion was rarely reported. METHODS:Although, clinical genetic testing has been widely used for identifying variants in HCM patients, structural variations are understudied, partly owing to the inadequacy of the available methodology. In the present study, whole-exome sequencing (WES) and Sanger sequencing validation was used to identify the genetic causes in patients with familial HCM. RESULTS:A genomic deletion in Chromosome 19 containing the whole of troponin I3 gene (TNNI3), and the p.Ile736Thr variant in the myosin heavy chain 7 gene (MYH7) were identified in two patients with familial HCM by WES. The p.Ile736Thr variant is further validated by Sanger sequencing and is predicted as a pathogenic variant by in silico analysis. CONCLUSION:We added the notion that not only p.Ile736Thr variant of MYH7, but also TNNI3 deletion might potentially contribute to HCM pathogenesis. Our study also suggested WES was a powerful tool to identify the genetic variants causing HCM.	0
Angiotensin-converting enzyme inhibitors (ACEIs) represent an important group of pharmacological compounds, largely prescribed for more than 30 years. They have been extensively evaluated in clinical trials, demonstrating significant reduction of morbidity and mortality of patients with cardiovascular diseases, mainly high blood pressure, myocardial infarction, heart failure and stroke. Besides their beneficial effects and a general good safety profile, it was proven that ACEIs might also induce adverse effects in some patients, most notably angioedema (AE) and chronic cough. The occurrence rate of adverse events induced by ACEIs is low, but the number of suffering patients is relatively high, since ACEIs is one of the most frequently prescribed medication worldwide. The aim of our study was to evaluate clinical pattern, risk factors and general management of ACEI-induced angioedema in a cohort of patients addressed for allergist evaluation in one university hospital in Romania, during a period of 32 months. It was found that ACEI-induced angioedema (ACEI-AE) represented more than half of the total number of patients addressed for angioedema without urticaria, with variable clinical and time-patterns. Most of the patients were referred by general practitioners (GPs) with diagnosis of urticaria or other skin allergy and continued to take ACEIs for months and years after onset of angioedema. We concluded that the awareness of acquired, non-allergic angioedema induced by ACEI therapy in medical practice is still low and there is a need for improved knowledge and interdisciplinary collaboration in this field.	0
Joubert syndrome is a rare autosomal recessive neurodevelopmental disease characterized by abnormal breathing patterns composed of episodic tachypnea/apnea, hypotonia, ataxia, developmental delay, intellectual impairment, ocular impairment, renal cysts, and hepatic fibrosis. We report the case of a 4-year-old boy who presented with global developmental delay, bilateral nystagmus, and gaze instability with difficulty walking and maintaining an upright posture. A detailed examination revealed facial dysmorphic features with a depressed nasal bridge and deepened orbital sockets. Neurological examination yielded positive results for hypotonia, gait ataxia, bilateral horizontal pendular nystagmus, and a grade 1 ptosis more prominent in the right eye. However, no abnormal breathing patterns were observed in our case. Magnetic resonance imaging revealed the characteristic molar tooth sign and a batwing appearance of the fourth ventricle.	0
Although amyotrophic lateral sclerosis (ALS) has been considered as a disorder of the motor neuron (MN) cell body, recent evidences show the non-cell-autonomous pathogenic nature of the disease. Axonal degeneration, loss of peripheral axons and destruction of nerve terminals are early events in the disease pathogenic cascade, anticipating MN degeneration, and the onset of clinical symptoms. Therefore, although ALS and peripheral axonal neuropathies should be differentiated in clinical practice, they also share damage to common molecular pathways, including axonal transport, RNA metabolism and proteostasis. Thus, an extensive evaluation of the molecular events occurring in the peripheral nervous system (PNS) could be fundamental to understand the pathogenic mechanisms of ALS, favoring the discovery of potential disease biomarkers, and new therapeutic targets.	0
The corpus callosum is the largest fibre tract in the brain, connecting the two cerebral hemispheres, and thereby facilitating the integration of motor and sensory information from the two sides of the body as well as influencing higher cognition associated with executive function, social interaction and language. Agenesis of the corpus callosum is a common brain malformation that can occur either in isolation or in association with congenital syndromes. Understanding the causes of this condition will help improve our knowledge of the critical brain developmental mechanisms required for wiring the brain and provide potential avenues for therapies for callosal agenesis or related neurodevelopmental disorders. Improved genetic studies combined with mouse models and neuroimaging have rapidly expanded the diverse collection of copy number variations and single gene mutations associated with callosal agenesis. At the same time, advances in our understanding of the developmental mechanisms involved in corpus callosum formation have provided insights into the possible causes of these disorders. This review provides the first comprehensive classification of the clinical and genetic features of syndromes associated with callosal agenesis, and provides a genetic and developmental framework for the interpretation of future research that will guide the next advances in the field.	0
Wilson disease (WD) is an autosomal recessive disorder resulting in pathological progressive copper accumulation in liver and other tissues. The worldwide prevalence (P) is about 30/million, while in Sardinia it is in the order of 1/10,000. However, all of these estimates are likely to suffer from an underdiagnosis bias. Indeed, a recent molecular neonatal screening in Sardinia reported a WD prevalence of 1:2707. In this study, we used a new approach that makes it possible to estimate the allelic frequency (q) of an autosomal recessive disorder if one knows the proportion between homozygous and compound heterozygous patients (the homozygosity index or HI) and the inbreeding coefficient (F) in a sample of affected individuals. We applied the method to a set of 178 Sardinian individuals (3 of whom born to consanguineous parents), each with a clinical and molecular diagnosis of WD. Taking into account the geographical provenance of the parents of every patient within Sardinia (to make F computation more precise), we obtained a q=0.0191 (F=7.8 × 10(-4), HI=0.476) and a corresponding prevalence P=1:2732. This result confirms that the prevalence of WD is largely underestimated in Sardinia. On the other hand, the general reliability and applicability of the HI approach to other autosomal recessive disorders is confirmed, especially if one is interested in the genetic epidemiology of populations with high frequency of consanguineous marriages.	1
A 41-year-old woman presented to our dermatology clinic in February 2005 with a chief complaint of numerous flesh-colored nodules on her back and abdomen. She initially noticed the lesions at age 17 years. The plaques had increased in size and number over time, but remained asymptomatic. The patient reported multiple similar lesions on a maternal uncle and a cousin. Her family history was also notable for cardiomyopathy, resulting in the death of her mother. The patient's past medical history was notable for poorly controlled type I diabetes, currently managed with an insulin pump; and coronary artery disease. The patient had undergone multiple cardiac procedures before the age of 40 years, including quadruple coronary artery bypass grafting surgery and placement of 9 cardiac stents. Her ejection fraction on cardiac catheterization in November 2004 was 65% with no wall motion abnormalities. On physical examination, numerous spongy, discrete, flesh-colored plaques and nodules were seen concentrated across the upper part of her back between the scapulae as well as underneath the breasts and across the flanks (Figure 1). All lesions were asymptomatic. Prior workup of this patient had included plain films of the long bones and hands, which were within normal limits. A biopsy from lesional skin on the back highlighted by trichome stain showed an increased number of markedly thickened and eosinophilic dermal collagen bundles compared with adjacent normal skin. Immunohistochemical studies with anticollagen type I and type III antibodies confirmed that the increased collagen material consisted of type I collagen fibers, which is the same type of collagen found in normal dermis. The elastic fibers, highlighted by Verhoeff-van Gieson stain (Figure 2), were diminished and haphazardly arranged. No increased cellular component or inflammatory infiltrate was observed. These findings were consistent with a collagenoma. Further analysis of the lesional tissue by electron microscopy revealed that the ultrastructural appearance of the collagen fibers, including arrangement and diameters, were not significantly different from that of the normal tissue (Figure 3).	0
Routine diagnostic screening of inborn errors of metabolism (IEM) is currently performed by different targeted analyses of known biomarkers. This approach is time-consuming, targets a limited number of biomarkers and will not identify new biomarkers. Untargeted metabolomics generates a global metabolic phenotype and has the potential to overcome these issues. We describe a novel, single platform, untargeted metabolomics method for screening IEM, combining semi-automatic sample preparation with pentafluorophenylpropyl phase (PFPP)-based UHPLC- Orbitrap-MS. We evaluated analytical performance and diagnostic capability of the method by analysing plasma samples of 260 controls and 53 patients with 33 distinct IEM. Analytical reproducibility was excellent, with peak area variation coefficients below 20% for the majority of the metabolites. We illustrate that PFPP-based chromatography enhances identification of isomeric compounds. Ranked z-score plots of metabolites annotated in IEM samples were reviewed by two laboratory specialists experienced in biochemical genetics, resulting in the correct diagnosis in 90% of cases. Thus, our untargeted metabolomics platform is robust and differentiates metabolite patterns of different IEMs from those of controls. We envision that the current approach to diagnose IEM, using numerous tests, will eventually be replaced by untargeted metabolomics methods, which also have the potential to discover novel biomarkers and assist in interpretation of genetic data.	0
The ridged skin of the palms and soles has several unique features: (i) presence of dermatoglyphics created by alternating ridges and grooves forming a unique pattern, (ii) presence of the highest density of eccrine sweat glands and absence of pilosebaceous units, and (iii) differential expression of keratins compared to the glabrous skin. These features explain the preferential localization of palmoplantar keratoderma (PPK) and several of its characteristic clinical features. PPK develops as a compensatory hyperproliferation of the epidermis and excessive production of stratum corneum in response to altered cornification of the palmoplantar skin due to mutations in the genes encoding several of the proteins involved in it. PPK can manifest as diffuse, focal, striate, or punctate forms per se or as a feature of several dermatological or systemic diseases. There is a wide genetic and phenotypic heterogeneity in hereditary PPK, due to which reaching an accurate diagnosis only on the basis of clinical features may be sometimes challenging for the clinicians in the absence of molecular studies. Nevertheless, recognizing the clinical patterns of keratoderma, extent of involvement, degree of mutilation, and associated appendageal and systemic involvement may help in delineating different forms. Molecular studies, despite high cost, are imperative for accurate classification, recognizing clinical patterns in resource poor settings is important for appropriate diagnosis, genetic counseling, and management. This review intends to develop a practical approach for clinical diagnosis of different types of hereditary PPK with reasonable accuracy.	0
OBJECTIVES:To evaluate the safety, pharmacokinetics, and preliminary efficacy of NT-814, a dual neurokinin 1,3 antagonist, in postmenopausal women with vasomotor symptoms (hot flashes). METHODS:We completed a double-blind, randomized, placebo-controlled trial in three US clinical research units in 76 postmenopausal women with moderate/severe hot flashes. Participants were randomized to 14 days of once-daily NT-814 or placebo within each of four sequential dose cohorts; 50, 100, 150, and 300 mg. Participants completed diaries of hot flash frequency and severity and waking due to night sweats before (baseline) and during treatment. RESULTS:All prespecified efficacy parameters (24-h hot flash frequency and severity, frequency of waking due to night sweats) decreased in all groups (including placebo). Mean reduction from baseline at week 2 in moderate/severe hot flash frequency was 37% in the placebo group and, respectively, 24% (P = 0.048 vs placebo), 59% (P = 0.155), 84% (P < 0.001) and 66% (P = 0.022) in the 50 mg, 100 mg, 150 mg, and 300 mg NT-814 groups; in waking due to night sweats reduction was 20% (P = 0.059), 55% (P = 0.135), 81% (P < 0.001), and 63% (P = 0.031) in the NT-814 groups and 32% in the placebo group. The improvement with NT-814 ≥150 mg was also evident in the first week of treatment. The most common treatment-related adverse events were mild somnolence and headache, more frequently in the 300 mg group. Safety monitoring identified no concerns. CONCLUSIONS:Once-daily NT-814 (≥150 mg/d) resulted in a rapid, marked improvement in hot flashes and waking due to night sweats. No safety concerns were identified. Doses up to 300 mg were well tolerated.	0
Sarcoidosis is a multisystem granulomatous disease with a myriad of clinical manifestations and a predilection to involve the lungs, eyes, lymph nodes, and skin. A 38-year-old man presented to dermatology with a history of progressive dyspnea, pulmonary consolidations on chest X-ray, and hilar adenopathy on computed tomography scan. Skin exam revealed asymptomatic, yellow to brown macules on the right lower extremity. Biopsy of a lesion showed diminutive syringotropic granulomas and perivascular hemosiderin; stains for bacteria, mycobacteria, and fungi were negative. Subsequent fine needle aspiration of a hilar mass revealed non-necrotizing epithelioid granulomas further supporting a diagnosis of sarcoidosis. The patient was placed on systemic steroids and had improvement of his pulmonary symptoms and stabilization of his hilar lymphadenopathy without resolution of his pigmented purpuric dermatosis (PPD) like lesions. Only three prior cases of syringotropic sarcoidosis have been reported; however, the biopsies had revealed conspicuously large granulomas in contrast with the small granulomas in our case, and none of the prior patients had clinical examination findings that mimicked PPD. Recognition of rare dermatologic and histopathological appearances of sarcoidosis is paramount as cutaneous sarcoidosis may be the harbinger of a systemic illness, which requires a timely diagnosis.	0
•LHON cases can show brainstem lesions without visual impairment.•There can be inconsistency between MRI finding and clinical symptom in LHON cases.•Auditory pathways may be often involved in LHON cases.	0
Members of the mitochondrial carrier (MC) protein family transport various molecules across the mitochondrial inner membrane to interlink steps of metabolic pathways and biochemical processes that take place in different compartments; i.e., are localized partly inside and outside the mitochondrial matrix. MC substrates consist of metabolites, inorganic anions (such as phosphate and sulfate), nucleotides, cofactors and amino acids. These compounds have been identified by in vitro transport assays based on the uptake of radioactively labeled substrates into liposomes reconstituted with recombinant purified MCs. By using this approach, 18 human, plant and yeast MCs for amino acids have been characterized and shown to transport aspartate, glutamate, ornithine, arginine, lysine, histidine, citrulline and glycine with varying substrate specificities, kinetics, influences of the pH gradient, and capacities for the antiport and uniport mode of transport. Aside from providing amino acids for mitochondrial translation, the transport reactions catalyzed by these MCs are crucial in energy, nitrogen, nucleotide and amino acid metabolism. In this review we dissect the transport properties, phylogeny, regulation and expression levels in different tissues of MCs for amino acids, and summarize the main structural aspects known until now about MCs. The effects of their disease-causing mutations and manipulation of their expression levels in cells are also considered as clues for understanding their physiological functions.	0
Three children who presented with two rare conditions, nephrogenic diabetes insipidus and intracerebral calcification, were studied. The lack of evidence for the presence of a metabolic defect other than nephrogenic diabetes insipidus suggests that it can lead to the development of intracerebral calcification. Perhaps the main risk factor is inadequate fluid intake during early infancy.	0
Urocanic aciduria is caused by a deficiency in the enzyme urocanase (E.C. 4.2.1.49) encoded by the gene UROC1. In the past, deficiency of urocanase has been associated with intellectual disability in a few case studies with some suggestion that the enzyme deficiency was the causative etiology. Here, we describe two phenotypically normal siblings with compound heterozygous pathogenic variants in UROC1 and characteristic biochemical evidence of urocanase deficiency collected utilizing untargeted metabolomic analysis. These findings suggest that urocanic aciduria may represent an otherwise benign biochemical phenotype and that those individuals with concurrent developmental delay should continue to be evaluated for other underlying causes for their symptoms.	0
In this chapter, we describe the history, presentation, diagnosis and treatment of pure autonomic failure (PAF). The pathology underlying this condition is thought to involve the deposition of alpha synuclein in the autonomic ganglia leading to diminished norepinephrine release and progressive autonomic dysfunction. We focus on various neurophysiological tests that may be used to evaluate the function of the peripheral autonomic nervous system including quantitative sudomotor axon reflex testing, thermoregulatory sweat testing, and others. These may help evaluate and diagnose various disorders of autonomic failure and neurogenic orthostatic hypotension including multiple system atrophy and Parkinson's disease dysautonomia. Management of PAF, including the therapeutic role of recent advances in pharmacologic treatment, is discussed.	0
The present study aimed to identify the molecular basis of the arthrogryposis‑renal dysfunction‑cholestasis (ARC) syndrome, which is caused by mutations in the vacuolar protein sorting 33 homolog B (VPS33B) gene. The microarray dataset GSE83192, which contained six liver tissue samples from VPS33B knockout mice and four liver tissue samples from control mice, was downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were screened by the Limma package in R software. The DEGs most relevant to ARC were selected via weighted gene co‑expression network analysis to construct a protein‑protein interaction (PPI) network. In addition, module analysis was performed for the PPI network using the Molecular Complex Detection function. Functional and pathway enrichment analyses were also performed for DEGs in the PPI network. Potential drugs for ARC treatment were predicted using the Connectivity Map database. In total, 768 upregulated and 379 downregulated DEGs were detected in the VPS33B knockout mice, while three modules were identified from the PPI network constructed. The DEGs in module 1 (CD83, IL1B and TLR2) were mainly involved in the positive regulation of cytokine production and the Toll‑like receptor (TLR) signaling pathway. The DEGs in module 2 (COL1A1 and COL1A2) were significantly enriched with respect to cellular component organization, extracellular matrix‑receptor interactions and focal adhesion. The DEGs in module 3 (ABCG8 and ABCG3) were clearly associated with sterol absorption and transport. Furthermore, mercaptopurine was identified to be a potential drug (connectivity score=‑0.939) for ARC treatment. In conclusion, the results of the current study may help to further understand the pathology of ARC, and the DEGs identified in these modules may serve as therapeutic targets.	0
Several genetic disorders caused by defective nucleotide excision repair that affect the skin and the nervous system have been described, including Xeroderma Pigmentosum (XP), De Sanctis-Cacchione syndrome (DSC), Cockayne syndrome, and Trichothiodystrophy. Cutaneous photosensitivity with an increased risk of skin malignancy is a common feature of these disorders, but clinical manifestations commonly overlap these syndromes. Several genes have been found to be altered in these pathologies, but we lack more genotype-phenotype correlations in order to make an accurate diagnosis. Very few cases of DSC syndrome have been reported in the literature. We present a case of a 12-year-old Colombian male, with multiple skin lesions in sun-exposed areas from the age of 3 months and a history of 15 skin cancers. He also displayed severe neurologic abnormalities (intellectual disability, ataxia, altered speech, and hyperreflexia), short stature, and microcephaly, which are features associated with DSC. Genetic testing revealed a novel germline mutation in the XP-C gene (c.547A>T). This is the first case of an XP-C mutation causing De Sanctis-Cacchione syndrome. Multigene panel testing is becoming more widely available and accessible in the clinical setting and will help rapidly unveil the molecular etiology of these rare genetic disorders.	0
Renal involvement is occasionally observed in Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT). It has been reported that galactose-deficient IgA is a closely linked to IgA nephropathy (IgAN), suggesting that patients with XLT/WAS associated with reduced galactosylation on serum IgA are susceptible to IgAN. It is necessary to pay more attention to patients with IgAN due to the potential complication with XLT/WAS. We here present a patient of XLT complicated with mild IgAN who underwent tonsillectomy combined with steroid pulse therapy to achieve complete clinical remission.	0
Aortic valvular atresia is a congenital condition in which the aortic valvular cusps are fused at birth. It frequently forms as a spectrum of malformations of the left ventricular outflow tract (LVOT). The atresia can be characterized as sub-valvular, valvular, or supra-valvular, depending on the site of the anomaly. Most commonly, the defect presents as aortic stenosis, though in rare cases, it can manifest as complete atresia. When atretic, the valve can be dome-shaped, monocuspid, bicuspid, or even quadricuspid, and the associated leaflets are dysplastic or fused, not permitting flow through the abnormal valve. It is sometimes but not always associated with congenital ventricular hypoplasia, which can be part of hypoplastic left heart syndrome (HLHS). In this condition, there is abnormal or under-development of the left heart as well as aortic structures. In HLHS, there is often underdevelopment of the mitral valve as well, though there is a universal association with aortic valve abnormalities. Isolated aortic valvular atresia is exceedingly rare, and in context, total aortic valvular atresia can be regarded as the most advanced manifestation of hypoplastic left heart syndrome. In a classic case of aortic valve atresia, there is generally an anatomic connection between the right and left sides of the heart, usually in the form of either a patent foramen ovale, another form of atrial septal defect, or in cases with a functioning mitral valve: a ventricular septal defect. The right ventricle is generally dilated rather than thickened, and the left ventricle is hypoplastic and thick-walled, being much smaller than the right ventricle. The mitral valve has been noted to usually be small, and in some cases, there is associated mitral valve atresia as well.[1] No pathological case report in the literature has shown transposition of the great vessels, and the pulmonary trunk arises normally from the right ventricle with appropriate branching. Due to the lack of an aortic valve, the aortic root generally arises from the base of the heart. The coronary arteries arise normally from the aortic root, but the ascending aorta and arch of the aorta are generally hypoplastic. The branches of the aorta are normal in caliber, and all studied cases report a large ductus arteriosus that empties into the descending aorta, providing mixed-oxygenation blood for the fetus. 	0
Kawasaki disease (KD) is an acute vasculitis of unknown etiology that predominantly affects children < 5 years of age. It is now the leading cause of acquired heart disease in the pediatric age in developed countries1.	0
The current phase I/II clinical trial for human glycogen storage disease type-Ia (GSD-Ia) (NCT03517085) uses a recombinant adeno-associated virus (rAAV) vector expressing a codon-optimized human glucose-6-phosphatase-α (G6Pase-α or G6PC). DNA sequence changes introduced by codon-optimization can negatively impact gene expression. We therefore generated a novel variant in which a single amino acid change, S298C, is introduced into the native human G6PC sequence. Short term gene transfer study in G6pc-/- mice showed that the rAAV-G6PC-S298C vector is 3-fold more efficacious than the native rAAV-G6PC vector. We have shown previously that restoring 3% of normal hepatic G6Pase-α activity in G6pc-/- mice prevents hepatocellular adenoma/carcinoma (HCA/HCC) development and that mice harboring <3% of normal hepatic G6Pase-α activity are at risk of tumor development. We have also shown that G6Pase-α deficiency leads to hepatic autophagy impairment that can contribute to hepatocarcinogenesis. We now undertake a long-term (66-week) preclinical characterization of the rAAV-G6PC-S298C vector in GSD-Ia gene therapy. We show that the increased efficacy of rAAV-G6PC-S298C has enabled the G6pc-/- mice treated with a lower dose of this vector to survive long-term. We further show that mice expressing ≥3% of normal hepatic G6Pase-α activity do not develop hepatic tumors or autophagy impairment but mice expressing <3% of normal hepatic G6Pase-α activity display impaired hepatic autophagy with one developing HCA/HCC nodules. Our study shows that the rAAV-G6PC-S298C vector provides equal or greater efficacy to the codon optimization approach, offering a valuable alternative vector for clinical translation in human GSD-Ia.	0
OBJECTIVE:To create reference charts for Sitting height to standing height ratio (SitHt/Ht) for children in the United States, and to describe the trajectory of SitHt/Ht during puberty. STUDY DESIGN:This was a cross-sectional study using data from the 1988-1994 National Health and Nutrition Examination Survey III, a strategic random sample of the United States population. Comparison between Non-Hispanic White (NHW), Non-Hispanic Black (NHB) and Mexican American groups was performed by analysis of variance (ANOVA) to determine if a single population reference chart could be used. ANOVA was used to compare SitHt/Ht in pre-, early and late puberty. RESULTS:NHANES III recorded sitting height and standing height measurements in 9,569 children aged 2 to 18 years of NHW (n=2,715), NHB (n=3,336), and Mexican American (n=3,518) ancestry. NHB children had lower SitHt/Ht than NHW and Mexican American children throughout childhood (p < 0.001). In both sexes, SitHt/Ht decreased from prepuberty to early puberty and increased in late puberty. Sex-specific percentile charts of SitHt/Ht vs age were generated for NHB and for NHW and Mexican American youth combined. CONCLUSIONS:SitHt/Ht assessment can detect disproportionate short stature in children with skeletal dysplasia, but age-, sex- and population-specific reference charts are required to interpret this measurement. NHB children in the United States have significantly lower SitHt/Ht than other children, which adds complexity to interpretation. We recommend the use of standardized ancestry-specific reference charts in screening for skeletal dysplasias and have developed such charts in this study.	0
Pierre-Robin sequence, radial deviation, and ulnar clinodactyly of the index fingers due to an additional phalangeal bone, as well as heart defects are the key features of Catel-Manzke syndrome. Although mutations in TGDS were identified as the cause of this disorder, the pathogenetic mechanism remains unknown. Here, we report on a fetus with severe heart defect, nuchal edema, talipes, Pierre-Robin sequence, and bilateral deviation and clinodactyly of the index and middle fingers. Pregnancy was terminated at the 22nd week of gestation. Postmortem radiographs showed hypoplasia and V-shaped displacement of the second and third proximal phalanges of both hands as well as hypoplasia of the first metatarsals and the phalangeal bones of the halluces. The suggested diagnosis Catel-Manzke syndrome was confirmed by the detection of two compound heterozygous mutations in TGDS: The known variant c.298G>T; p.(Ala100Ser) and the so far undescribed variant c.895G>A; p.(Asp299Asn), located in the predicted substrate binding site of TGDS. This is the first report on the association of mutations in TGDS with additional anomalies of the middle fingers and halluces. We provide a detailed phenotypic characterization of the only fetus with molecularly confirmed Catel-Manzke syndrome, which is relevant for prenatal diagnosis. Our findings widen the phenotype spectrum caused by TGDS mutations and underline the phenotypic overlap with Temtamy preaxial brachydactyly syndrome. This improves our understanding of the prenatal development and the pathogenetic mechanism of Catel-Manzke syndrome.	0
RATIONALE:Pelvic lipomatosis (PL) is a benign disease characterized by overgrowth of adipose tissue in pelvic space. Hydronephrosis and ureterectasis are common complications caused by PL in urinary system. But PL accompanied with upper urinary tract calculi is rare. Also there has been no report of PL with ureteral calculi managed by flexible ureteroscopy (fURS). PATIENT CONCERNS:A 62-year-old man who has been diagnosed of PL was found to have a right-side ureteral calculi by ultrasound in the routine health examination. In addition, the patient has a history of open surgery of uretero-vesical reimplantation in the left side 13 years ago because of heavy hydronephrosis in the left side. DIAGNOSES:The diagnosis was PL with ureteral calculi in the right side and heavy hydronephrosis in the left side. INTERVENTIONS:FURS was performed to remove the right ureteral calculi. OUTCOMES:A follow-up of 1 year showed that there was no progression of the hydronephrosis in right side and serum creatinine was stable. LESSONS:FURS is a suitable option for the upper urinary tract calculi accompanied with anatomical abnormality such as horseshoe kidney, pelvic ectopic kidney and so on. For patient of PL accompanied with upper urinary tract calculi, fURS is suitable and indicated.	0
The molecular basis for cornea guttata and anterior polar cataract remains idiopathic in most cases. In this study, our aim was to identify the disease-associated gene in Chinese patients with these conditions. Patients with the conditions from two Chinese families, and ten sporadic patients, were investigated. Genome-wide linkage and exome sequencing analyses showed transmembrane and coiled-coil domain 3 (TMCO3) as the disease candidate gene for a coding heterozygous mutation c.41C > T, resulting in a P14L amino acid change that co-segregated with the disease phenotype as discovered in Family A. TMCO3 belongs to the monovalent cation: protein antiporter 2 transporter family, a moderately large group whose members all share a very similar function under normal physiological conditions. The gene is expressed in the human cornea, lens capsule, and choroid-retinal pigment epithelium. This study reveals, for the first time, that mutations in TMCO3 are associated with cornea guttata and anterior polar cataract, warranting further investigation into the pathogenesis of this disorder.	0
We present patient characteristics and follow-up results of cases with anterior chamber dexamethasone implant migration. The common feature of all six presented cases was vitrectomized eyes. Four of the patients had sutured intraocular lens (IOL) implantation due to complicated cataract surgery, one had combined retinal detachment surgery with sutured IOL implantation, and one had vitrectomy for diabetic intravitreal hemorrhage cleaning and uncomplicated cataract surgery. Anterior chamber implant migration caused corneal edema in all cases and elevated intraocular pressure in three cases. In two cases, the dexamethasone implant was directed into the vitreous cavity after maximum pupillary dilation and corneal manipulation with cotton tip applicator with the patient in reverse Trendelenburg position. There was no other complication until dexamethasone implant degradation, with clear cornea at final examination. In two cases, the implant was removed from the anterior chamber by aspiration, but keratoplasty surgery was planned due to endothelial cell loss and persistent corneal edema during follow-up. In the last two cases, the dexamethasone implant was redirected into the vitreous chamber with a 23-gauge catheter and anterior chamber maintainer but they migrated into the anterior chamber again. In one of these patients, the implant was aspirated by catheter and corneal transplantation was performed due to corneal edema, while the other patient's implant was redirected into the vitreous chamber with no further anterior migration. The risk of dexamethasone implants migrating into the anterior chamber of vitrectomized eyes and those with sutured IOL implantation should be kept in mind and the patient should be informed and advised to see an ophthalmologist immediately before permanent corneal endothelial damage occurs.	0
Animals that accurately model human disease are invaluable in medical research, allowing a critical understanding of disease mechanisms, and the opportunity to evaluate the effect of therapeutic compounds in pre-clinical studies. Many types of animal models are used world-wide, with the most common being small laboratory animals, such as mice. However, rodents often do not faithfully replicate human disease, despite their predominant use in research. This discordancy is due in part to physiological differences, such as body size and longevity. In contrast, large animal models, including sheep, provide an alternative to mice for biomedical research due to their greater physiological parallels with humans. Completion of the full genome sequences of many species, and the advent of Next Generation Sequencing (NGS) technologies, means it is now feasible to screen large populations of domesticated animals for genetic variants that resemble human genetic diseases, and generate models that more accurately model rare human pathologies. In this review, we discuss the notion of using sheep as large animal models, and their advantages in modelling human genetic disease. We exemplify several existing naturally occurring ovine variants in genes that are orthologous to human disease genes, such as the Cln6 sheep model for Batten disease. These, and other sheep models, have contributed significantly to our understanding of the relevant human disease process, in addition to providing opportunities to trial new therapies in animals with similar body and organ size to humans. Therefore sheep are a significant species with respect to the modelling of rare genetic human disease, which we summarize in this review.	0
Nephronophthisis is an autosomal recessive cystic kidney disease and one of the most common genetic disorders causing end-stage renal disease in children. Nephronophthisis is a genetically heterogenous disorder with more than 25 identified genes. In 10%-20% of cases, there are additional features of a ciliopathy syndrome, such as retinal defects, liver fibrosis, skeletal abnormalities, and brain developmental disorders. This review provides an update of the recent advances in the clinical features and related gene mutations of nephronophthisis, and novel approaches for therapy in nephronophthisis patients may be needed.	0
BACKGROUND:Peters plus syndrome (PPS) is a combination of congenital Peters anomaly and systemic abnormalities. It is inherited most commonly in an autosomal recessive pattern with homozygous B3GLCT mutations. Ocular findings consist predominantly anterior segment abnormalities without posterior segment involvement. CASE PRESENTATION:In this presentation, we report a case of PPS with homozygous pathogenic variant in B3GLCT who presented with classic anterior segment findings, systemic abnormalities, as well as atypical bilateral chorioretinal atrophy. The chorioretinal findings were characterized with spectral-domain optical coherence tomography. CONCLUSIONS:Our report expands the phenotypic descriptions of PPS by characterizing posterior segment findings.	0
AIM:Gitelman syndrome (GS) is a rare inherited salt-losing renal tubulopathy. Data on clinical features and the pregnancy outcome for female GS patients in a large cohort are lacking. The study was aimed to explore the phenotype and pregnant issue for female GS patients. METHODS:GS cases from the National Rare Diseases Registry System of China (NRSC) were collected, and detailed clinical, laboratory and genetic data were analysed. Articles on pregnancy in GS were also systemically reviewed. RESULTS:A total of 101 GS patients were included; among them, 42.6% were female and 79.2% showed hypomagnesaemia. A lower proportion of female patients presented before 18 years of age, with less frequently reported polyuria, higher serum potassium and less urine sodium and chloride excretions. There was no gender difference in the sodium-chloride cotransporter (NCC) dysfunction evaluated by hydrochlorothiazide test. Twelve of the 43 female GS patients delivered after disease symptom onset, and their pregnancies were generally uneventful. As a group, pregnant GS patients had lower potassium levels in the first-trimester (P = .002) requiring higher potassium supplementation. After delivery, serum potassium (P = .02) and magnesium (P = .03) increased significantly. Both caesarean section and vaginal delivery were safe. CONCLUSION:Female GS patients may have a less severe phenotype with generally favourable outcomes of pregnancy. Intensive monitoring and increased potassium supplementation are necessary during pregnancy, especially in the first-trimester.	0
PURPOSE:To assess the safety and efficacy of cyclosporine A cationic emulsion (CsA CE) 0.1% eye drops in pediatric patients with severe active vernal keratoconjunctivitis (VKC). DESIGN:Multicenter, double-masked, randomized controlled trial 8-month safety analysis. METHODS:Of 169 patients (age range, 4-17 years) initially randomized in the 4-month VErnal KeratoconjunctiviTIs Study (VEKTIS), 142 entered the 8-month follow-up period during which CsA CE patients remained on their original regimen (CsA CE 4 times daily [QID, high-dose] or CsA CE twice daily [BID, low-dose] + vehicle BID) and vehicle patients were allocated to one of these 2 active regimens. Main outcome measures were safety, including treatment-emergent adverse events, and efficacy, including corneal fluorescein staining (CFS) score. RESULTS:Improvements in CFS score, rescue medication use, key VKC symptoms (photophobia, tearing, itching, and mucous discharge), and quality of life (QoL) assessed by QUICK questionnaire observed with CsA CE compared with vehicle during the 4-month evaluation period remained stable during the 8-month follow-up period, with the high-dose regimen continuing to provide greater benefits in most efficacy measures. CsA CE was well tolerated. Treatment-related treatment-emergent adverse events during the 12-month study were reported in 15 (20.8%) and 11 (15.7%) of the CsA CE high-dose and low-dose patients, respectively, most commonly instillation site pain (13.9% and 7.1%, respectively). Laboratory data, vital signs, slit lamp examination, best-corrected distance visual acuity, and intraocular pressure raised no safety concerns. CONCLUSIONS:Improvements in keratitis, symptoms, and QoL achieved after CsA CE treatment for 4 months remained stable over the 8-month follow-up period. CsA continued to maintain a favorable safety profile.	0
Objective:To investigate the expression of the ABCC3 gene in human glioma and its correlation with the patient's prognosis. Methods:The cancer genome atlas (TCGA) database was used to analyze the differential expression of the ABCC3 gene in human glioma. The STRING database was used to construct the protein-protein interaction (PPI) network of the ABCC3 gene coding protein. The co-expression genes relevant to the ABCC3 gene were analyzed by the Pearson correlation test. A log-rank test was used to analyze the difference of overall survival (OS) and disease-free survival (DFS) between the high and low ABCC3 gene expression groups. Results:The expression level of the ABCC3 gene in glioma tissues was lower than that of corresponding normal brain tissues. The PPI network contains 51 nodes with the average node degree of 13.3 and the local clustering coefficient of 0.72 which indicated that the PPI enrichment was significant (p<0.001). Ten hub genes (ABCC3,NR1I2,NR1H4,-CYP7A1,SLC10A1,CYP3A4,UGT1A1,UGT1A8,UGT1A6 and ALB) were identified by the cytoscape software. The KEGG analysis was enriched in drug metabolism - cytochrome P450 and PPAR signaling pathway. CFI gene expression level was positive correlated with the ABCC3 expression level (r=0.71, p<0.05). And the CNRIP1 gene expressed was negative correlated with ABCC3 expression (r=-0.43, p<0.05). The overall survival (HR=2.8, P<0.05) and disease-free survival rates (HR=2.0, P<0.05) of patients with ABCC3 low expression glioma were significantly higher than those of patients with high expression of ABCC3. Conclusion The expression level of the ABCC3 gene in glioma was decreased compared to normal brain tissue. The overall survival and disease-free survival of in the ABCC3 low-expression group was significant decreased.	0
BACKGROUND:Diffuse intrinsic pontine gliomas (DIPGs) are highly lethal childhood brain tumors. Their unique genetic makeup, pathological heterogeneity, and brainstem location all present challenges to treatment. Developing mouse models that accurately reflect each of these distinct features will be critical to advance our understanding of DIPG development, progression, and therapeutic resistance. The aims of this study were to generate new mouse models of DIPG and characterize the role of specific oncogenic combinations in DIPG pathogenesis. METHODS:We used in utero electroporation (IUE) to transfect neural stem cells in the developing brainstem with PiggyBac DNA transposon plasmids. Combinations of platelet-derived growth factor B (PDGFB), PdgfraD842V, or PdgfraWT, combined with dominant negative Trp53 (DNp53) and H3.3K27M expression, induced fully penetrant brainstem gliomas. RESULTS:IUE enabled the targeted transfection of brainstem neural stem cells. PDGFB + DNp53 + H3.3K27M induced the rapid development of grade IV gliomas. PdgfraD842V + DNp53 + H3.3K27M produced slower forming grade III gliomas. PdgfraWT + DNp53 + H3.3K27M produced high- and low-grade gliomas with extended latencies. PDGFB, PdgfraD842V, and PdgfraWT DIPG models display unique histopathological and molecular features found in human DIPGs. H3.3K27M induced both overlapping and unique gene expression changes in PDGFB and PdgfraD842V tumors. Paracrine effects of PDGFB promote disruption of pericyte-endothelial interactions and angiogenesis in PDGFB DIPG mouse models. CONCLUSION:Brainstem-targeted IUE provides a rapid and flexible system to generate diverse DIPG mouse models. Using IUE to investigate mutation and pathohistological heterogeneity of DIPG will provide a valuable tool for future genetic and preclinical studies.	0
The generation and homeostasis of bone tissue throughout development and maturity is controlled by the carefully balanced processes of bone formation and resorption. Disruption of this balance can give rise to a broad range of skeletal pathologies. Lethal osteosclerotic bone dysplasia (or, Raine syndrome) is an autosomal recessive disorder characterized by generalized osteosclerosis with periosteal bone formation and a distinctive facial phenotype. Affected individuals survive only days or weeks. We have identified and defined a chromosome 7 uniparental isodisomy and a 7p telomeric microdeletion in an affected subject. The extent of the deleted region at the 7p telomere was established by genotyping microsatellite markers across the telomeric region. The region is delimited by marker D7S2563 and contains five transcriptional units. Sequence analysis of FAM20C, located within the deleted region, in six additional affected subjects revealed four homozygous mutations and two compound heterozygotes. The identified mutations include four nonsynonymous base changes, all affecting evolutionarily conserved residues, and four splice-site changes that are predicted to have a detrimental effect on splicing. FAM20C is a member of the FAM20 family of secreted proteins, and its mouse orthologue (DMP4) has demonstrated calcium-binding properties; we also show by in situ hybridization its expression profile in mineralizing tissues during development. This study defines the causative role of FAM20C in this lethal osteosclerotic disorder and its crucial role in normal bone development.	0
Myotonic dystrophies (DM) are slowly progressing multisystemic disorders caused by repeat expansions in the DMPK or CNBP genes. The multisystemic involvement in DM patients often reflects the appearance of accelerated aging. This is partly due to visible features such as cataracts, muscle weakness, and frontal baldness, but there are also less obvious features like cardiac arrhythmia, diabetes or hypogammaglobulinemia. These aging features suggest the hypothesis that DM could be a segmental progeroid disease. To identify the molecular cause of this characteristic appearance of accelerated aging we compare clinical features of DM to "typical" segmental progeroid disorders caused by mutations in DNA repair or nuclear envelope proteins. Furthermore, we characterize if this premature aging effect is also reflected on the cellular level in DM and investigate overlaps with "classical" progeroid disorders. To investigate the molecular similarities at the cellular level we use primary DM and control cell lines. This analysis reveals many similarities to progeroid syndromes linked to the nuclear envelope. Our comparison on both clinical and molecular levels argues for qualification of DM as a segmental progeroid disorder.	0
The inherited bone marrow failure syndromes (IBMFS) are a rare yet clinically important cause of neonatal hematological and non-hematological manifestations. Many of these syndromes, such as Fanconi anemia, dyskeratosis congenita and Diamond-Blackfan anemia, confer risks of multiple medical complications later in life, including an increased risk of cancer. Some IBMFS may present with cytopenias in the neonatal period whereas others may present only with congenital physical abnormalities and progress to pancytopenia later in life. A thorough family history and detailed physical examination are integral to the work-up of any neonate in whom there is a high index of suspicion for an IBMFS. Correct detection and diagnosis of these disorders is important for appropriate long-term medical surveillance and counseling not only for the patient but also for appropriate genetic counselling of their families regarding recurrence risks in future children and generations.	0
The diagnosis of cutaneous lupus erythematosus (CLE) presents a challenge due to its heterogeneous nature. This is especially true in cases of discoid lupus erythematosus (DLE), which in the past has not had clearly defined diagnostic criteria. The recent development of classification criteria for DLE has made its diagnosis more straightforward; however, some cases previously called DLE must now be reclassified.	0
Hypereosinophilic syndrome (HES) is a rare clinical disease that affects 0.036/100,000 patients, with a minority of patients having associated genetic markers which can encompass PDGFRA/B or FGFR1 mutations. The prognosis is dependent on the timing of diagnosis and early treatment, with a mortality rate ranging from 48% to 75% if there is a delayed diagnosis. Eosinophilic myocarditis is characterized by invasion of the myocardium with eosinophils. Myeloid neoplasms are a rare, but known cause of HES induced myocarditis. Signs and symptoms can range from being asymptomatic to retrosternal pain, arrhythmias, and even sudden death. HES myocarditis is a diagnosis of exclusion that is made via endomyocardial biopsy. Peripheral eosinophilia is the only specific sign to suggest eosinophilic myocarditis with traditional biomarkers, electrocardiogram, and echocardiogram. Treatment modalities include systemic corticosteroids and symptomatic management. Complications from HES myocarditis may include embolic events, eosinophilic vegetations, and dysrhythmias, or conduction disturbances. We present a case of a 62-year-old male who initially presented with epigastric pain, and then suffered a myocardial infarction. After testing, the probable diagnosis of eosinophilic myocarditis was made. His clinical course was complicated by the development of shower thrombus associated with acute encephalopathy. Although HES has classically been treated with imatinib, in this case, an alternative biologic agent was used, resulting in a good prognosis and ultimate patient survival. This case details the importance of early clinical suspicion, diagnosing the condition, and early initiation of treatment to prevent worsening clinical status.	0
BACKGROUND:Neurotropic B vitamins play crucial roles as coenzymes and beyond in the nervous system. Particularly vitamin B1 (thiamine), B6 (pyridoxine), and B12 (cobalamin) contribute essentially to the maintenance of a healthy nervous system. Their importance is highlighted by many neurological diseases related to deficiencies in one or more of these vitamins, but they can improve certain neurological conditions even without a (proven) deficiency. AIM:This review focuses on the most important biochemical mechanisms, how they are linked with neurological functions and what deficits arise from malfunctioning of these pathways. DISCUSSION:We discussed the main role of B Vitamins on several functions in the peripheral and central nervous system (PNS and CNS) including cellular energetic processes, antioxidative and neuroprotective effects, and both myelin and neurotransmitter synthesis. We also provide an overview of possible biochemical synergies between thiamine, pyridoxine, and cobalamin and discuss by which major roles each of them may contribute to the synergy and how these functions are inter-related and complement each other. CONCLUSION:Taking into account the current knowledge on the neurotropic vitamins B1, B6, and B12, we conclude that a biochemical synergy becomes apparent in many different pathways in the nervous system, particularly in the PNS as exemplified by their combined use in the treatment of peripheral neuropathy.	0
Primary hyperoxaluria type 2 is a rare inherited disorder of glyoxylate metabolism causing nephrocalcinosis, renal stone formation and ultimately kidney failure. Previously, primary hyperoxaluria type 2 was considered to have a more favorable prognosis than primary hyperoxaluria type 1, but earlier reports are limited by low patient numbers and short follow up periods. Here we report on the clinical, genetic, and biochemical findings from the largest cohort of patients with primary hyperoxaluria type 2, obtained by a retrospective record review of genetically confirmed cases in the OxalEurope registry, a dataset containing 101 patients from eleven countries. Median follow up was 12.4 years. Median ages at first symptom and diagnosis for index cases were 3.2 years and 8.0 years, respectively. Urolithiasis was the most common presenting feature (82.8% of patients). Genetic analysis revealed 18 novel mutations in the GRHPR gene. Of 238 spot-urine analyses, 23 (9.7%) were within the normal range for oxalate as compared to less than 4% of 24-hour urine collections. Median intra-individual variation of 24-hour oxalate excretion was substantial (34.1%). At time of review, 12 patients were lost to follow-up; 45 of the remaining 89 patients experienced chronic kidney disease stage 2 or greater and 22 patients had reached stage 5. Median renal survival was 43.3 years, including 15 kidney transplantations in 11 patients (1 combined with liver transplantation). Renal outcome did not correlate with genotype, biochemical parameters or initially present nephrocalcinosis. Thus, primary hyperoxaluria type 2 is a disease with significant morbidity. Accurate diagnosis by 24-hour urine analysis and genetic testing are required with careful follow-up.	0
OBJECTIVE:This study aims to investigate the value and determine the accuracy of two kinds of scoring models in predicting the degree of esophageal varices (EV) and esophageal variceal bleeding (EVB) in patients with liver cirrhosis (LC). PATIENTS AND METHODS:A total of 189 patients with LC, who underwent esophagogastroduodenoscopy (EGD), color Doppler ultrasound (CDU), and computed tomography (CT), were retrospectively analyzed. Then, the routine blood examination, liver function test, M-index of the spleen in CT, EGD, and CDU results were recorded. According to the EGD result, these patients were divided into five groups: varicose bleeding group, severe varices group, moderate varices group, mild varices group, and no varices group. Then, the receiver operating characteristic curves of all predicting parameters studied were respectively drawn, the area under the receiver operating characteristic curves were calculated, and the predictive value of EV and EVB was evaluated. RESULTS:The area under the receiver operating characteristic curve of the VAP score model and Plt/S-D score model was 0.901 and 0.835, respectively. The VAP score model cut-off value of 461.5 for predicting moderate esophageal varices (MoEV), severe esophageal varices (SEV), and EVB has a specificity and sensitivity of 100% and 68.7%, respectively, while the Plt/S-D score model cut-off value of 835.5 for predicting MoEV, SEV, and EVB has a specificity and sensitivity of 95.1% and 58.2%, respectively. CONCLUSIONS:These two kinds of scoring models can predict the degree of esophageal varices and bleeding in liver cirrhosis patients and has good predictive accuracy.	0
MiR-1 and myostatin are markers for muscle growth and regeneration. Myostatin has a key role in the regulation of muscle mass. Myotonic dystrophy type 1(DM1) patients have a disease-specific serum miRNA profile characterized by upregulation of miR-1, miR-206, miR-133a, and miR-133b (myomiRNAs).This study aims to evaluate the possible utility of myomiRs and myostatin as biomarkers of rehabilitation efficacy in DM1, supporting clinical outcomes that are often variable and related to the patient's clinical condition.In 9 genetically proven DM1 patients, we collected biological samples before (T0) and after (T1) exercise rehabilitation training as biological measurement. We measured serum myomiRNAs by qRT-PCR and myostatin by ELISA test. The clinical outcomes measures that we utilized during a 3-6 week rehabilitation controlled aerobic exercise period were the 6-min walking test (6MWT) that increased significantly of 53.5 m (p < 0.0004) and the 10-m walk test (10MWT) that decreased of 1.38 s.We observed, after physical rehabilitation, a significant downregulation of myomiRNAs and myostatin that occurred in parallel with the improvement of clinical functional outcome measures assessed as endurance and gait speed, respectively.The modulation of biomarkers may reflect muscle regeneration and increase muscle mass after aerobic exercise. miRNAs and myostatin might be considered as circulating biomarkers of DM1 rehabilitation. The efficacy of physical rehabilitation in counteracting molecular pathways responsible for muscle atrophy and disease progression and the role of these biomarkers in DM1 and other neuromuscular diseases warrant further investigation.	0
Bronchopulmonary dysplasia is a common disease of prematurity that presents along a wide spectrum of disease severity. Infants with high severity require prolonged hospitalizations and benefit from multidisciplinary care. We describe our approach to the evaluation of infants with severe bronchopulmonary dysplasia. Important considerations include the phenotypic heterogeneity in clinical presentation that necessitates individualized care, the common presence of comorbidities and importance of a comprehensive multisystem evaluation, and the value of applying a chronic care model that prioritizes long-term respiratory and neurodevelopmental goals. Key features of the history, physical examination, and diagnostic studies are discussed with these considerations in mind.	0
Ankyloblepharon is defined by partial or complete adhesion of the ciliary edges of superior and inferior eyelids. It is usually a sporadic isolated malformation in which the upper and lower lids are joined by tags. Although it is an uncommon and benign condition, its presence should alert the clinician to the possibility of other important disorders. We report a case of a new born who had a sporadic ankyloblepharon, treated one day after birth.	0
Phenylalanine hydroxylase (PAH) deficiency is an autosomal recessive disorder of phenylalanine metabolism that is characterized by insufficient activity of PAH, a hepatic enzyme. Throughout this document, PAH deficiency is used instead of the older nomenclature of phenylketonuria, in order to reflect the spectrum of PAH deficiency and in accordance with the terminology established by the American College of Medical Genetics and Genomics. Aspects of PAH deficiency management that are particularly relevant to obstetrician-gynecologists or other obstetric care providers include the prevention of embryopathy associated with maternal hyperphenylalaninemia and PAH deficiency and the risk of genetic transmission of PAH deficiency. Family planning and prepregnancy counseling are recommended for all reproductive-aged women with PAH deficiency. The fetal brain and heart are particularly vulnerable to high maternal concentrations of phenylalanine. The crucial role played by maternal dietary restriction before and during pregnancy should be stressed in counseling patients with PAH deficiency; the goal should be to normalize blood phenylalanine levels (less than 6 mg/dL) for at least 3 months before becoming pregnant and to maintain at 2-6 mg/dL during pregnancy, in order to optimize developmental outcomes for the fetus. Although phenylalanine levels are increased in the breast milk of patients with PAH deficiency, breastfed infants who do not have PAH deficiency have normal enzyme levels and no dietary restriction. Breastfeeding is safe for infants born to women who have PAH deficiency provided the infants do not have PAH deficiency. Coordinated medical and nutritional care, as well as follow-up with the patient's metabolic geneticist or specialist, are important in the postpartum period. Because newborns with PAH deficiency appear normal at birth and early detection can improve developmental outcomes for children, newborn screening for PAH deficiency is mandated in all states. This Committee Opinion has been revised to include updates on advances in the understanding and management of women with PAH deficiency and recommendations on prepregnancy counseling, serial fetal growth assessments, and fetal echocardiography.	0
BACKGROUND:Tubulinopathies result from mutations in tubulin genes, including TUBG1, responsible for cell microtubules, are characterized by brain development abnormalities, microcephaly, early-onset epilepsy, and motor impairment. Only eleven patients with TUBG1 mutations have been previously described in literature to our knowledge. Here we present two new patients with novel de novo TUBG1 mutations and review other cases in the literature. CASE PRESENTATIONS:Both patients have microcephaly and intellectual disability. Patient B further fits a more typical presentation, with well-controlled epilepsy and mild hypertonia, whereas Patient A's presentation is much milder without these other features. CONCLUSION:This report expands the spectrum of TUBG1 mutation manifestations, suggesting the possibility of less severe phenotypes for patients and families, and influencing genetic counselling strategies.	0
A meta-analysis was conducted to estimate the prevalence of patients with molecularly confirmed Leber hereditary optic neuropathy (LHON) carrying any of the 3 primary mtDNA mutations (m.11778G>A, m.14484T>C, m.3460G>A) which cause this inherited form of blindness.A literature search was conducted to identify primary reports with LHON prevalence data reported for Europe. The overall prevalence of LHON with molecularly confirmed diagnosis was evaluated by weighting the prevalence estimates of the individual studies by the inverse of their variance.Based on this meta-analysis of 5 European studies providing appropriate information, the estimated prevalence of LHON disease associated with the combined m.11778G>A, m.14484T>C, m.3460G>A mutations was ~1:45,000 (2.23 x 10(-5); 95% confidence interval [CI] 2.01-2.44 x 10(-5)). Patients with LHON carrying either the m.11778G>A or the m.3460G>A mutation have a more severe clinical presentation and a much lower chance of spontaneous recovery from vision loss compared to patients with the m.14484T>C mutation. The estimated prevalence for patients with LHON in Europe carrying either of these severe mutations (m.11778G>A or m.3460G>A) was ~1:65,000 (1.54 x 10(-5); 95% CI 1.33-1.74 x 10(-5)).Although this meta-analysis summarizes the existing prevalence data for the primary, disease-causing mitochondrial DNA mutations of LHON in Europe, there is still a clear lack of reliable primary epidemiologic data for this devastating ophthalmologic disease.	1
Erythrokeratodermia variabilis et progressiva (EKVP) is a rare inherited skin disease characterized by fixed hyperkeratotic plaques and transient erythematous patches. EKVP is most often transmitted in an autosomal dominant manner. Causal mutations were found in the GJB3, GJB4 and GJA1 genes encoding connexins 31, 30.3 and 43, respectively. Approximately 50% of affected individuals develop palmoplantar keratoderma. Connexins are components of gap junctions, which are intercellular channels that are found in almost all tissues including the skin. Treatment of EKVP usually involves use of topical keratolytics and emollients resulting in some improvement in hyperkeratosis. Low-dose systemic retinoid may be beneficial. Novel therapies targeting connexin hemichannels and gap junctions may become available in the future.	0
Aseptic metacarpal head necrosis or 'Dieterich disease' is a rare condition, especially in children or adolescents, not routinely described in hand surgery literature reviews. This case report presents course and treatment of a teenage boy with the exceptional fifth ray involved.	0
There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers.	0
Asphyxiating thoracic dystrophy, also known as Jeune syndrome, is included in a group of syndromic skeletal ciliopathies associated with mutations in genes encoding proteins involved in the formation or function of motile cilia. Herein, we report a 6-mo-old male admitted to hospital with recurrent lung infections, thoracic dystrophy, and respiratory distress that was diagnosed as Jeune syndrome; DYNC2H1 mutation was detected via genetic analysis and ciliary dysfunction was noted via high-speed video microscopy.	0
In a screen for human kinases that regulate Xenopus laevis embryogenesis, we identified Nagk and other components of the UDP-GlcNAc glycosylation salvage pathway as regulators of anteroposterior patterning and Wnt signaling. We find that the salvage pathway does not affect other major embryonic signaling pathways (Fgf, TGFβ, Notch, or Shh), thereby demonstrating specificity for Wnt signaling. We show that the role of the salvage pathway in Wnt signaling is evolutionarily conserved in zebrafish and Drosophila. Finally, we show that GlcNAc is essential for the growth of intestinal enteroids, which are highly dependent on Wnt signaling for growth and maintenance. We propose that the Wnt pathway is sensitive to alterations in the glycosylation state of a cell and acts as a nutritional sensor in order to couple growth/proliferation with its metabolic status. We also propose that the clinical manifestations observed in congenital disorders of glycosylation (CDG) in humans may be due, in part, to their effects on Wnt signaling during development.	0
BACKGROUND:Non-invasive prenatal testing (NIPT) has been established as a routine prenatal screening to assess the risk of common foetal aneuploidy disorder (trisomy 21, 18, and 13). NIPT has high sensitivity and high specificity, but false positive and false negative results still exist. False negative NIPT results involving Down syndrome are rare, but have a high clinical impact on families and society. CASE PRESENTATION:We described a case of a foetus that tested "negative" for trisomy 21 (Z-score was 0.664) by NIPT based on the semiconductor sequencing platform (SSP). The foetal fraction of cell-free DNA was 16.9%; this percentage was much larger than the threshold of 4% for obtaining accurate NIPT results. However, postnatally, the newborn was diagnosed with Down syndrome with the 46,XY,der(21;21)(q10;q10),+ 21 karyotype. CONCLUSIONS:We presented a case of false negative NIPT results, which may occur through biological mechanisms rather than poor quality, technical errors or negligence. It is imperative for clinical geneticists and their patients to understand that NIPT is still a screening test.	0
BACKGROUND:Nevus of Ota and nevus of Ito are hyperpigmentary dermal melanocytoses which develop as a consequence of disturbances or failures during migration of melanocytes from the neural crest towards the epidermis; they have a relatively unknown aetiopathogenesis and may be congenital or acquired. CASE REPORT:This case involves a male patient with a simultaneous diagnosis of nevus of Ota and nevus of Ito at birth. He attended the Neurosurgery department at Carlos Andrade Marín hospital (Quito) with sudden severe headache associated with left brachio-crural hemiparesis. PROGRESS:Investigations revealed two extra-axial space-occupying lesions, one parasagittal at the right frontal and parietal lobes and the other located at the right temporal lobe pole. A surgical resection was planned for the parasagittal lesion and the histopathological diagnosis was meningeal melanocytosis. The temporal pole lesion was referred for treatment with Gamma Knife®. CONCLUSION:Primary melanocytic neoplasms are extremely rare. There is evidence of their association with dermal melanocytosis and, in particular, with nevus of Ota. This highly unusual case describes the coexistence of two very rare dermal melanocytoses (nevus of Ota and nevus of Ito) and a primary melanocytic neoplasms in the same patient.	0
An 11-month-old female Japanese macaque (Macaca fuscata), born in captivity in a research institute, suddenly died without clinical signs. Necropsy examination revealed a nodular mass protruding from the left ventral aspect of the larynx, compressing the epiglottis anteriorly. Histopathologically, the laryngeal mass was comprised of medium- to large-sized atypical cells. Immunohistochemically, these were positive for CD20 and partially positive for CD79α. Among the atypical cells were CD3+ T cells and CD68+ histiocytes. Based on the findings, this case was diagnosed as T-cell/histiocyte-rich large B-cell lymphoma. Epstein-Barr virus (EBV)-encoded small RNAs were frequently detected in the atypical cells by in-situ hybridization, which was consistent with the finding that the macaque was seropositive for EBV antigen. This is the first report showing the potential association of simian lymphocryptovirus, the simian homologue of EBV, with lymphoma in a juvenile non-human primate.	0
Hereditary gingival fibromatosis (HGF) is a rare disorder characterized by progressive and varying degrees of gingival overgrowth. Oral manifestations may vary from minimal involvement of only tuberosity area and the buccal gingiva around the lower molars to a generalized gingival enlargement. It can occur as an isolated disorder but can be one feature of a syndrome. Although the clinical and histopathological characteristics of HGF are well known and described, the pathogenic mechanism remains unknown. The goal of this article is to describe a family with three generations afflicted with a syndromic form of HGF known as gingival fibromatosis with distinctive facies, and discuss the diagnosis and treatment of the disease.	0
Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19) and imino acid (proline) transporter SIT1 (SLC6A20) are expressed at the luminal membrane of small intestine enterocytes and proximal tubule kidney cells where they exert key functions for amino acid (re)absorption as documented by their role in Hartnup disorder and iminoglycinuria, respectively. Expression of B(0)AT1 was shown in rodent intestine to depend on the presence of the carboxypeptidase angiotensin-converting enzyme 2 (ACE2). This enzyme belongs to the renin-angiotensin system and its expression is induced by treatment with ACE-inhibitors (ACEIs) or angiotensin II AT1 receptor blockers (ARBs) in many rodent tissues. We show here in the Xenopus laevis oocyte expression system that human ACE2 also functionally interacts with SIT1. To investigate in human intestine the potential effect of ACEIs or ARBs on ACE2, we analysed intestinal biopsies taken during routine gastroduodenoscopy and ileocolonoscopy from 46 patients of which 9 were under ACEI and 13 ARB treatment. Analysis of transcript expression by real-time PCR and of proteins by immunofluorescence showed a co-localization of SIT1 and B(0)AT1 with ACE2 in the brush-border membrane of human small intestine enterocytes and a distinct axial expression pattern of the tested gene products along the intestine. Patients treated with ACEIs displayed in comparison with untreated controls increased intestinal mRNA levels of ACE2, peptide transporter PEPT1 (SLC15A1) and AA transporters B(0)AT1 and PAT1 (SLC36A1). This study unravels in human intestine the localization and distribution of intestinal transporters involved in amino acid absorption and suggests that ACEIs impact on their expression.	0
Hepatitis E virus (HEV) infection is primarily manifesting as acute hepatitis, but extra-hepatic replication and injury are frequently reported. During the study period, we discovered two acute myeloid leukaemia (AML) patients infected with HEV genotype 3 and 4, respectively, and HEV RNA and/or viral proteins were persistently detected in the bone marrow of both patients. The finding suggests that HEV can replicate in human bone marrow as it may serve as a new target site and reservoir of HEV persistence.	0
Branchiootorenal syndrome is a rare autosomal dominant disorder characterised by branchial arch anomaly, hearing loss, renal anomalies and other otologic manifestations. We report a case of apparent de novo mutation that presented with hearing loss, branchial sinus and other manifestations of the disease. It is extremely rare in the West African region, and we suggest a high index of suspicion in a patient presenting with branchial sinus and/or hearing loss.	0
Hypertrophic radiculopathy is a rare feature of neuropathies. Single cases of enlarged nerve roots have been described in hereditary motor sensory neuropathies (HMSN) and chronic inflammatory demyelinating diseases (CIDP). This is the first description of hypertrophied nerve roots in a patient with Roussy-Lévy syndrome. MRI did not show contrast enhancement of the enlarged nerve roots or nodular lesions.	0
Sequences of long-interspersed elements (LINE-1, L1) make up ∼17% of the human genome. De novo insertions of retrotransposition-active L1s can result in genetic diseases. It has been recently shown that the homozygous inactivation of two adjacent genes SLCO1B1 and SLCO1B3 encoding organic anion transporting polypeptides OATP1B1 and OATP1B3 causes a benign recessive disease presenting with conjugated hyperbilirubinemia, Rotor syndrome. Here, we examined SLCO1B1 and SLCO1B3 genes in six Japanese diagnosed with Rotor syndrome on the basis of laboratory data and laparoscopy. All six Japanese patients were homozygous for the c.1738C>T nonsense mutation in SLCO1B1 and homozygous for the insertion of a ∼6.1-kbp L1 retrotransposon in intron 5 of SLCO1B3, which altogether make up a Japanese-specific haplotype. RNA analysis revealed that the L1 insertion induced deleterious splicing resulting in SLCO1B3 transcripts lacking exon 5 or exons 5-7 and containing premature stop codons. The expression of OATP1B1 and OATP1B3 proteins was not detected in liver tissues. This is the first documented case of a population-specific polymorphic intronic L1 transposon insertion contributing to molecular etiology of recessive genetic disease. Since L1 activity in human genomes is currently seen as a major source of individual genetic variation, further investigations are warranted to determine whether this phenomenon results in other autosomal-recessive diseases.	0
Gaucher disease (GD), the most common lysosomal storage disease, results from a deficiency of the lysosomal enzyme glucocerebrosidase. GD has been classified into 3 types, of which type 2 (the acute neuronopathic form) is the most severe, presenting pre- or perinatally, or in the first few months of life. Traditionally, type 2 GD was considered to have the most uniform clinical phenotype when compared to other GD subtypes. However, case studies over time have demonstrated that type 2 GD, like types 1 and 3, manifests with a spectrum of phenotypes. This review includes case reports that illustrate the broad range of clinical presentations encountered in type 2 GD, as well as a discussion of associated manifestations, pathological findings, diagnostic techniques, and a review of current therapies. While type 2 GD is generally associated with severe mutations in the glucocerebrosidase gene, there is also significant genotypic heterogeneity.	0
Proboscis lateralis (PL) is a rare malformation, reported for the first time in 1861 by Forster in his monograph on congenital malformations of the human body. The abnormal side of the nose is represented by a tube-like rudimentary nasal structure, attached at any point along the embryonic fusion line between the anterior maxilla and the frontonasal processes. As clefts of the lip (and alveolus) are bilateral or unilateral, an arrhinia can be bilateral (total) or unilateral. In this case it is a 'hemi-arrhinia' (or heminasal agenesis. The arrhinias represent three groups of anomalies, each with different levels of clinical severity, some involving association with the labio-palatal cleft or agenesia of the premaxilla (1). In PL the nasal cavity on the affected side is replaced by a tubular appendage located off-center from the midline of the face, arising commonly from the medial aspect of the roof of the orbit (2). It is usually associated with heminasal aplasia or hypoplasia, microphthalmia, and - less commonly - with midline clefting. Associated brain and cranial vault anomalies are seen in 19% of these patients. PL is usually unilateral, with very few symmetrical/bilateral cases being reported (3). Morpho-aesthetic and psychological problems are frequent concerns for the patients and their families. In this study, the authors describe a clinical case and the chosen surgical technique, as well as reviewing the alternative techniques present in the literature.	0
Inborn errors of metabolism (IEMs) are rare diseases produced by the accumulation of abnormal amounts of metabolites, toxic to the newborn. When not detected on time, they can lead to irreversible physiological and psychological sequels or even demise. Metabolomics has emerged as an efficient and powerful tool for IEM detection in newborns, children, and adults with late onset. In here, we screened urine samples from a large set of neonates (470 individuals) from a homogeneous population (Basque Country), for the identification of congenital metabolic diseases using NMR spectroscopy. Absolute quantification allowed to derive a probability function for up to 66 metabolites that adequately describes their normal concentration ranges in newborns from the Basque Country. The absence of another 84 metabolites, considered abnormal, was routinely verified in the healthy newborn population and confirmed for all but 2 samples, of which one showed toxic concentrations of metabolites associated to ketosis and the other one a high trimethylamine concentration that strongly suggested an episode of trimethylaminuria. Thus, a non-invasive and readily accessible urine sample contains enough information to assess the potential existence of a substantial number (>70) of IEMs in newborns, using a single, automated and standardized 1H- NMR-based analysis.	0
OBJECTIVE:To analyze the available literature on papilledema in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), report the first detailed pediatric case, and explore the underlying pathophysiology. METHODS:First, we conducted a comprehensive literature review of all cases of papilledema in CIDP. Next, we reviewed each case, incorporating only those including cerebrospinal fluid analysis into the results. Finally, we present our pediatric patient. RESULTS:Our literature review yielded a total of 9 adult and no pediatric cases. Cerebrospinal fluid protein and opening pressures were elevated in all cases. They were also elevated in our pediatric case. CONCLUSION:Prolonged periods of active immune-mediated inflammation is likely a cause of papilledema in adult CIDP, and possibly also in our pediatric case.	0
OBJECTIVES:Survivors of childhood brain tumors experience neurological sequelae that disrupt everyday adaptive functioning (AF) skills. The Neurological Predictor Scale (NPS), a cumulative measure of tumor treatments and sequelae, predicts cognitive outcomes, but findings on its relation to informant-reported executive dysfunction (ED) and AF are mixed. Given known effects of frontal-subcortical system disruptions on AF, this study assessed the NPS' relationship with AF as mediated by frontal systems dysfunction, measured by the Frontal Systems Behavior Scale (FrSBe). METHODS:75 participants (Mage = 23.5, SDage = 4.5) were young adult survivors of childhood brain tumors at least 5 years past diagnosis. FrSBe and Scales of Independent Behavior-Revised (SIB-R), a measure of AF, were administered to informants. Parallel multiple mediator models included Apathy and ED as mediators, and age at diagnosis and time between diagnosis and assessment as covariates. RESULTS:More complex treatment and sequelae were correlated with poorer functioning. Mediation models were significant for all subscales: Motor Skills (MS), p = .0001; Social Communication (SC), p = .002; Personal Living (PL), p = .004; Community Living (CL), p = .007. The indirect effect of ED on SC and CL was significant; the indirect effect of Apathy was not significant for any subscales. CONCLUSIONS:More complex tumor treatment and sequelae were associated with poorer long-term AF via increased ED. Cognitive rehabilitation programs may focus on the role of executive function and initiation that contribute to AF, particularly SC and CL skills, to help survivors achieve comparable levels of independence in everyday function as their peers.	0
Meiotic maturation and fertilization are metabolically demanding processes, and thus the mammalian oocyte is highly susceptible to changes in nutrient availability. O-GlcNAcylation-the addition of a single sugar residue (O-linked β-N-acetylglucosamine) on proteins-is a posttranslational modification that acts as a cellular nutrient sensor and likely modulates the function of oocyte proteins. O-GlcNAcylation is mediated by O-GlcNAc transferase (OGT), which adds O-GlcNAc onto proteins, and O-GlcNAcase (OGA), which removes it. Here we investigated O-GlcNAcylation dynamics in bovine and human oocytes during meiosis and determined the developmental sequelae of its perturbation. OGA, OGT, and multiple O-GlcNAcylated proteins were expressed in bovine cumulus oocyte complexes (COCs), and they were localized throughout the gamete but were also enriched at specific subcellular sites. O-GlcNAcylated proteins were concentrated at the nuclear envelope at prophase I, OGA at the cortex throughout meiosis, and OGT at the meiotic spindles. These expression patterns were evolutionarily conserved in human oocytes. To examine O-GlcNAc function, we disrupted O-GlcNAc cycling during meiotic maturation in bovine COCs using Thiamet-G (TMG), a highly selective OGA inhibitor. Although TMG resulted in a dramatic increase in O-GlcNAcylated substrates in both cumulus cells and the oocyte, there was no effect on cumulus expansion or meiotic progression. However, zygote development was significantly compromised following in vitro fertilization of COCs matured in TMG due to the effects on sperm penetration, sperm head decondensation, and pronuclear formation. Thus, proper O-GlcNAc homeostasis during meiotic maturation is important for fertilization and pronuclear stage development.	0
Chagas disease causes the highest burden of any parasitic disease in the Western hemisphere. By applying published seroprevalence figures to immigrant populations, we estimate that 300,167 individuals with Trypanosoma cruzi infection live in the United States, with 30,000-45,000 cardiomyopathy cases and 63-315 congenital infections annually. T. cruzi causes a substantial disease burden in the United States.	1
OBJECTIVES:To present the clinical picture, the associated complications and the genetic findings of Jordanian patients diagnosed with Congenital insensitivity to pain with anhidrosis (CIPA). PATIENTS AND METHODS:This is a retrospective study including 7 patients diagnosed with CIPA presenting to Jordan University Hospital neurology clinic between 2001 and 2017. RESULTS:Among five families, seven patients were diagnose with CIPA and followed for a period ranging from one month to 6 years. The initial symptom observed in all patients was high fever in the first few days after birth, decreased sensation to pain and decreased sweating were later noted. Poor weight gain, microcephaly and global developmental delay were present in most cases. All patients had tongue ulcerations. Fingers/toes ulcerations were present in 6/7 (86.0 %), hip joint dislocation in 3/7 (43.0 %), chronic arthritis and joint swelling in 6/7 (86.0 %), corneal ulcers in 4/7 (57.1 %) and kidney amyloidosis in 1/7 (13.0 %) of all patients. Death occurred in 4/7 (57.1 %) patients. Consanguinity was present in all families. Mutation analysis revealed three variants in NTRK1 gene. The frameshift (c.1860_1861insT; p.Pro621fs) mutation was common in our series. One patient carried a novel missense mutation (c.2170 G > A; p.Gly724Ser). The third missense mutation (C2125 G > T; p.Val709Leu) was reported in a previous study in one patient. CONCLUSION:This cohort reveals a severe CIPA phenotype necessitating thorough multidisciplinary care and follow up.	0
Complete gonadal dysgenesis (CGD) or Swyer syndrome is characterised by sexual infantilism in a phenotypic female with 46, XY karyotype. Patients with gonadal dysgenesis and Y-chromosome material are at a high risk of developing gonadoblastoma and dysgerminoma. A 16-year-old girl presented with progressive virilisation, poor breast development and primary amenorrhea. On evaluation, she was found to have male-range serum testosterone, large abdominopelvic mass lesion, elevated germ cell tumour markers and 46, XY karyotype. She underwent surgical excision of left gonadal mass and right streak gonad, histopathology of which revealed dysgerminoma and gonadoblastoma, respectively. A diagnosis of virilising germ cell tumour arising in the setting of 46, XY CGD was, therefore, made. This case highlights a rare presentation of 46, XY CGD and the need to consider early prophylactic gonadectomy in patients affected with this rare condition. The presence of dysgerminoma/gonadoblastoma should be suspected if a hitherto phenotypic female with CGD undergoes virilisation.	0
BACKGROUND AND AIMS:Data show that vitamin D deficiency may play a role in patients with diabetes mellitus and COVID-19 infection. In this article, we review evidence of vitamin D deficiency and COVID-19 infection in context of diabetes mellitus. METHODS:A literature search was carried out by using the key term 'COVID 19' combined with 'Diabetes', 'Vitamin D', 'Extra skeletal effects', 'immunity', 'infection', 'India' from Pub Med (National Library of Medicine, Bethesda, MD and Google Scholar from December 2019 to May 2020. A manual search of the references was also carried out. RESULTS:Vitamin D deficiency has been linked to increased morbidity and mortality in COVID -19 infections but convincing data on diabetic subgroup of patients in particular is still awaited. CONCLUSION:Robust studies are required to ascertain if Vitamin D supplementation could be beneficial in patients with diabetes and COVID-19.	0
INTRODUCTION:Charles Bonnet syndrome is characterized by simple or complex visual hallucinations (VH) due to damage along the visual pathways. We report a functional MRI study of brain correlates of VH in the context of a severe optic atrophy in a patient with Leber's Hereditary Optic Neuropathy (LHON). CASE REPORT:A 62-year-old man was diagnosed with LHON (11778/ND4 mtDNA mutation) after subacute visual loss in left eye (right eye was amblyopic). One month later, he experienced VH of a few seconds consisting in "moving red and blue miniature cartoons". One year later VH content changed in colored mosaic (10-15 s duration), usually stress-related, and blue and white flashes (2-5 s), triggered by unexpected auditory stimuli. Audiometry revealed mild sensorineural hearing loss. Three block design functional MRI paradigms were administrated: 1) random "clap", 2) "checkerboard" and 3) non-random "beep". After random "claps" simple flashes were evoked with bilateral activation of primary and secondary visual cortex, cuneus, precuneus and insula. Neither hallucinations nor cortex activation were registered after "checkerboard" stimulation, due to the severe visual impairment. Primary and secondary auditory cortices were "beep"-activated, without eliciting VH by non-random "beep". CONCLUSIONS:The peculiarity of our case is that VH were triggered by random auditory stimuli, possibly due to a cross-modal plasticity between visual and auditory networks, likely influenced by the sensorineural deafness. Functional alterations of both networks in resting conditions have been demonstrated in LHON patients, even without an auditory deficit. Finally, the absence of VH triggered by expected stimuli is consistent with the "expectation suppression theory", based on increased neural activations after unexpected but not by predicted events.	0
A 14-year-old boy presented with several months of increasing abdominal girth and fatigue. Imaging confirmed massive ascites and hepatic congestion secondary to central hepatic venous obstruction. Several large intrahepatic collateral veins were seen draining via caudate and emissary veins. After an unsuccessful attempt at retrograde recanalization utilizing intravascular ultrasound, the right hepatic vein was recanalized in an antegrade fashion by way of a prominent caudate collateral vein, and subsequently stented. We herein discuss the established treatment options for Budd-Chiari syndrome and describe our experience employing a single-access liver floss technique.	0
Hand oligodactyly refers to a developmental defect which results in the presence of less than 5 digits on a hand. It presents as a component of 4 main categories of congenital upper limb malformations. Herein, we present a 50-year-old man with an unusual form of hand oligodactyly which is characterized by atypical cleft hand accompanied by complex syndactyly between the thumb and the index finger. Accurate characterization of hand oligodacticity can sometimes be challenging due to unusual phenotypic appearances accompanying the abnormality. Radiological evaluation is of great importance for correct identification and classification of such complex hand anomalies, and the treatment should be highly individualized in these patients.	0
Although Crohn's Disease (CD) usually occurs between the second and third decade of life, it also may develop in older adults. Treating elderly patients may be challenging due to other comorbidities, including diverticular disease or intestinal ischemia. PURPOSE:The purpose of this case study was to describe successful treatment of atypical and life-threatening CD due to enterocutaneous fistulas with short-bowel syndrome and multiorgan failure after partial colectomy. CASE REPORT:After an urgent colectomy for an inflammatory colon tumor, a 64-year-old woman with a history of CD and multiple comorbidities developed acute small bowel ischemia. Following an extended bowel resection, she developed a severe surgical site infection, entero- and gastrocutaneous fistulas, multiorgan failure, and short bowel syndrome. Her care included intensive medical and nutritional treatment as well as negative pressure wound therapy (NPWT) using continuous negative pressure of -80 mm Hg. She not only survived, but she also achieved complete wound closure and restoration of digestive tract continuity and metabolic control. She was discharged with a central venous catheter on total parenteral nutrition. CONCLUSION:In this case study, a good outcome was observed using intensive medical treatment, nutritional therapy, and conservative surgical treatment that included NPWT for a patient with CD and major comorbidities who developed postoperative complications.	0
This study investigated the formation of angiotensin-converting enzyme (ACE) inhibitory peptides from koro kratok beans tempe during gastrointestinal digestion. The absorption of bioactive peptides was also investigated in this study. Koro kratok was fermented by commercial culture including Rhizopus oligosporus for 48 h. Gastrointestinal digestion was simulated sequentially by hydrolysis of tempe protein extract with pepsin and pancreatin for 240 min. The peptide content, degree of hydrolysis, molecular weight distribution, and ACE inhibitory activity were analyzed. The absorption of ACE inhibitory peptides was evaluated using the inverted gut sac of Sprague Dawley rats. Results showed that some amino acids, such as Arg, Lys, Asp, Glu, Phe, and Leu, were predominantly found in tempe. After the hydrolysis process, cooked tempe exhibited the highest ACE inhibitory activity (90.05%). Although the ACE inhibitory activity of nonfermented koro kratok was lower than that of tempe, the increase in its inhibitory activity was too large (23.03%). The ACE inhibitory peptides from tempe showed a predominance of peptides with a molecular weight of < 1 kDa and could inhibit ACE activity by 84.34%. The majority of ACE inhibitory peptides from tempe was absorbed in the jejunum and exhibited an ACE inhibitory activity of 81.59%. Based on these results, it can be concluded that the fermentation and boiling process of koro kratok beans improved the release of ACE inhibitory peptides during the gastrointestinal digestion process and had an impact on its absorption.	0
Hyperinsulinism-hyperammonemia (HI/HA) syndrome is a rare autosomal dominant disease characterized by recurrent hypoglycemia and persistent mild elevation of plasma ammonia. HI/HA syndrome is one of the more common forms of congenital hyperinsulinism (CHI), caused by activating mutations within the GLUD1 gene that encodes the mitochondrial enzyme glutamate dehydrogenase (GDH). We report here on monozygotic twin girls presented with fasting- and protein-induced hypoglycemia and mild persistent hyperammonemia. Genetic analysis revealed that both girls were heterozygous for a novel missense mutation within exon 11 [c.1499A>T, p.(R443W)] of the GLUD1 gene. Despite early treatment with diazoxide and a low protein diet, they both developed non-hypoglycemic seizures in early childhood followed by cognitive impairment. In addition to their clinical course, a review of the literature on HI/HA syndrome is provided.	0
Hennekam lymphangiectasia-lymphedema syndrome is an autosomal recessive disorder characterized by congenital lymphedema, intestinal lymphangiectasia, facial dysmorphism, and variable intellectual disability. Known disease genes include CCBE1, FAT4, and ADAMTS3. In a patient with clinically diagnosed Hennekam syndrome but without mutations or copy-number changes in the three known disease genes, we identified a homozygous single-exon deletion affecting FBXL7. Specifically, exon 3, which encodes the F-box domain and several leucine-rich repeats of FBXL7, is eliminated. Our analyses of databases representing >100,000 control individuals failed to identify biallelic loss-of-function variants in FBXL7. Published studies in Drosophila indicate Fbxl7 interacts with Fat, of which human FAT4 is an ortholog, and mutation of either gene yields similar morphological consequences. These data suggest that FBXL7 may be the fourth gene for Hennekam syndrome, acting via a shared pathway with FAT4.	0
Werdnig-Hoffmann disease is a type of spinal muscular atrophy (SMA), a rare form of motor neuron disease. It is the most common type of SMA and accounts for about 80% of individuals with this condition. There are 4 types of SMA, Werdnig-Hoffmann disease, also known as SMA1 is the most severe form, and infants with this condition experience severe muscle weakness with onset before 6 months of age and presenting symptoms include severe motor weakness, poor muscle tone and lack of motor development. Motor neuron disease is a condition that affects anterior horn cells of the motor neurons.[1] These are the neurons that control voluntary muscle control. These are rare conditions that are often very severe, and no cure is available. Examples of motor neuron diseases include amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), SMA, progressive bulbar palsy (PBP), primary lateral sclerosis (PLS), etc., These conditions spare sensory nerves and individuals do not have sensory involvement. Individuals often have a combination of upper and lower motor neuron symptoms. SMA is a type of motor neuron disease. SMA presents four subtypes.[2]: Werdnig-Hoffmann disease, also known as acute spinal muscular atrophy, is SMA 1. SMA2, also known as intermediate SMA and chronic infantile SMA, have less severe symptoms than SMA1 and can sit without support, but are unable to stand or walk. SMA2 symptom onset is in infanthood. SMA3, also known as Kugelberg-Welander disease, presents after the age of 1, and the child is able to walk initially, but later has the regression of motor abilities. They often develop poor balance, falls, and scoliosis. Individuals with SMA4 have minimal symptoms compared to the other forms, and symptom onset is after the age of 10 years. They usually have a normal lifespan. They usually have normal motor milestones and mobility.	0
GM1-gangliosidosis, a lysosomal storage disorder, is associated with ~ 161 missense variants in the GLB1 gene. Affected patients present with β-galactosidase (β-Gal) deficiency in lysosomes. Loss of function in ER-retained misfolded enzymes with missense variants is often due to subcellular mislocalization. Deoxygalactonojirimycin (DGJ) and its derivatives are pharmaceutical chaperones that directly bind to mutated β-Gal in the ER promoting its folding and trafficking to lysosomes and thus enhancing its activity. An Emirati child has been diagnosed with infantile GM1-gangliosidosis carrying the reported p.D151Y variant. We show that p.D151Y β-Gal in patient's fibroblasts retained < 1% residual activity due to impaired processing and trafficking. The amino acid substitution significantly affected the enzyme conformation; however, p.D151Y β-Gal was amenable for partial rescue in the presence of glycerol or at reduced temperature where activity was enhanced with ~ 2.3 and 7 folds, respectively. The butyl (NB-DGJ) and nonyl (NN-DGJ) derivatives of DGJ chaperoning function were evaluated by measuring their IC50s and ability to stabilize the wild-type β-Gal against thermal degradation. Although NN-DGJ showed higher affinity to β-Gal, it did not show a significant enhancement in p.D151Y β-Gal activity. However, NB-DGJ promoted p.D151Y β-Gal maturation and enhanced its activity up to ~ 4.5% of control activity within 24 h which was significantly increased to ~ 10% within 6 days. NB-DGJ enhancement effect was sustained over 3 days after washing it out from culture media. We therefore conclude that NB-DGJ might be a promising therapeutic chemical chaperone in infantile GM1 amenable variants and therefore warrants further analysis for its clinical applications.	0
Purpose:The purpose was to identify and describe patients with new-onset vernal keratoconjunctivitis-like (VKC-like) disease after puberty. Methods:The study consisted of two parts: a prospective observational descriptive study of patients with new-onset VKC-like disease, and a case-control study to determine the relationship of a CD4 count with VKC-like disease in adults, in the setting of human immunodeficiency virus (HIV). Patients were recruited between January 2016 and November 2017 from a Provincial Eye hospital, one of two large referral hospitals in KwaZulu-Natal, South Africa. Patients presenting to the eye clinic were screened and diagnosed at the Primary Eye Care Unit. Inclusion criteria: age 15 years and older with signs and symptoms of new-onset VKC-like disease. Exclusion criteria: a history of childhood atopic diseases, atopic keratoconjunctivitis and patients who declined HIV testing. Data collected included HIV status, CD4 count, antinuclear antibodies and total serum immunoglobulin E. Results:Thirty-three patients were included; females n = 16 and males n = 17. The mean age at presentation was 32.45 ± 9.93 years, 95% CI = 28.94-35.97. Twenty-six patients (78.8%) were HIV positive, 95% CI (62-89). The proportion of HIV positive patients was statistically different from the HIV negative group, Chi-squared = 21.866, P value <0.0001. In the group of HIV positive patients, 72% were classified as immunodeficient according to their CD4 counts. An association was proven between severely immunodeficient patients and the risk of VKC-like disease (Chi-squared = 4.992, P value = 0.0255). Conclusion:In this cohort, a statistically significant association was found between VKC-like disease in adults and an HIV positive status. This association calls for more research on the subject.	0
Pseudo-Pelger-Huët anomaly (PHA) refers to mono- or bi-lobed granulocytes, reportedly observed in patients with severe infections and inflammation or hematological malignancies including myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Dysplastic changes in granulocytes are typical manifestations in MDS and granulocytic leukemias. Here, we report the unique case of a patient found to have human granulocytic anaplasmosis (HGA), a tick-borne disease caused by Anaplasma phagocytophilum, a Gram-negative coccobacillus. This patient showed striking hematological manifestations including a large number of pseudo-PHA, a severe degree of left shift, and dysplastic granulocytes. These hematological presentations on the peripheral smear all resolved with doxycycline treatment, implying that the changes were most likely reactive manifestations secondary to HGA, rather than underlying hematological malignancies such as MDS or AML.	0
Swallowing function in long-term survivors with Creutzfeldt-Jakob disease (CJD) remains unknown. Herein, we demonstrated serial evaluation of swallowing function in a case with V180I genetic CJD (gCJD) using videofluoroscopic examination of swallowing (VF). A 69-year-old woman was admitted to our hospital because of bradykinesia and memory disturbances 4 months after the onset of symptoms. Neurological examination revealed dementia, bradykinesia and frontal signs. Diffusion-weighted MRI revealed bilateral cortical hyperintensity in the frontal, temporal, and parietal cortices, and PRNP gene analysis indicated a V180I mutation. Her dysphagia gradually progressed, and she received percutaneous gastrostomy 42 months after the onset. VF was performed at 27, 31, 39, and 79 months after the onset. Although bolus transport from oral cavity to pharynx gradually worsened and initiation of the pharyngeal swallow was gradually delayed, the pharyngeal swallowing function was preserved even at 72 months after onset. MRI revealed no apparent atrophy of brainstem, and single photon emission computed tomography showed preserved regional cerebral blood flow in the brainstem. These findings suggest that the pathophysiology of dysphagia in a long-term survivor of V180I gCJD is that of pseudobulbar palsy, likely owing to preserved brainstem function even in the akinetic mutism state.	0
BACKGROUND:Supravalvular aortic stenosis (SVAS) is one of the congenital cardiovascular diseases characterized by stenosis of the aorta. The stenotic lesions occur anywhere above the aortic valve in the aortic tree as well as pulmonary arteries and eventually leads to circulatory failure. The disease gene has been identified on the elastin gene (ELN) and two types of SVAS have been categorized; a familial type and an isolated type with the de novo mutation. METHODS:Fluorescent In situ hybridization (FISH) analysis and gene sequencing were performed in a two-generation family in which severe form of SVAS was diagnosed. RESULTS:None of the patients tested showed microdeletion of ELN, LIMK1, and D7S613. A novel nonsense mutation of ELN (c.160G>T (p.(Gly54*)), RNA not analyzed) was found in exon 3 in three members; two of them died suddenly due to rapid progression of SVAS with possible arrhythmia in early infancy. A point mutation in the 5' untranslated region, which was previously suggested to be associated with SVAS, did not co-segregate with the SVAS phenotype and found to be SNPs. CONCLUSION:Our report shows a broad spectrum of clinical features in family members sharing the identical mutations, suggesting a potential contribution of modifier gene(s) or interactions with environmental factors.	0
Nail diseases in children do not account for a significant proportion of pediatric consultations, and most of the time the nails are not observed by the clinician, overlooking their importance. Specific examination of the nails is neglected, while localization to the nails could be an initial sign of a syndrome or a systemic disorder. Nail diseases in the pediatric population differ from those in adults in terms of diagnostic approach and management; some of them even are manifested mainly or exclusively in children. Pediatric patients with underlying systemic disorders are more likely to manifest acquired disorders of the nails. Although rare, nail diseases in children are a source of anxiety for the parents. Examination of the nails is an essential part of pediatric physical examination. A correct clinical history and careful examination help the clinician to distinguish the different conditions and to decide on the correct management of nail diseases in young patients. A classification of nail dystrophies according to age is somewhat arbitrary and a unique classification does not exist. Nail diseases in the pediatric population can be divided according to age groups where a predilection appears in most of the cases. Moreover, certain abnormalities may be lifelong once acquired, but their presentation may be modified by age, worsening or improving during life. This review describes many of the nail conditions that are seen in the pediatric population aging from newborn to toddler, starting with physiological aspects to better recognize the pathological conditions.	0
Objective  To determine the rate of unsuspected noncardiac abnormalities in newborns suspected to have isolated cardiac abnormalities in the second trimester. Study Design  A review of the ultrasound database from the Weill Cornell Medical Center identified fetuses with a suspected cardiac abnormality from January 2006 to November 2016. Cases with prenatally suspected noncardiac structural abnormalities, abnormal fetal or neonatal karyotype or microarray, and those who delivered at an outside institution or underwent abortion were excluded. Neonatal records were reviewed to confirm prenatal findings and to identify anomalies not suspected in the second trimester. Results  Sixty-eight live births met the inclusion criteria. Five newborns (7.4%) had major abnormalities not identified in the second trimester. Three newborns had an imperforate anus. One newborn had left hydronephrosis and absent right lung, and one had hemifacial microsomia and fused ribs. All five newborns with unsuspected anomalies were in the group with suspected conotruncal anomalies, with a 11.9% rate of unsuspected anomalies versus 0% in those with nonconotruncal cardiac anomalies ( p  = 0.15). Conclusion  Patients with a suspected isolated fetal cardiac anomaly on ultrasound should be aware of the possibility of other major structural abnormalities, especially in cases of conotruncal cardiac anomalies.	0
The highly conserved and ubiquitously expressed transcription factor Yin Yang 1 (Yy1), was named after its dual functions of both activating and repressing gene transcription. Yy1 plays complex roles in various fundamental biological processes such as the cell cycle progression, cell proliferation, survival, and differentiation. Patients with dominant Yy1 mutations suffer from central nervous system (CNS) developmental defects. However, the role of Yy1 in mammalian CNS development remains to be fully elucidated. The isthmus organizer locates to the mid-hindbrain (MHB) boundary region and serves as the critical signaling center during midbrain and cerebellar early patterning. To study the function of Yy1 in mesencephalon/ rhombomere 1 (mes/r1) neuroepithelium development, we utilized the tissue-specific Cre-LoxP system and generated a conditional knockout mouse line to inactivate Yy1 in the MHB region. Mice with Yy1 deletion in the mes/r1 region displayed cerebellar agenesis and dorsal midbrain hypoplasia. The Yy1 deleted neuroepithelial cells underwent cell cycle arrest and apoptosis, with the concurrent changes of cell cycle regulatory genes expression, as well as activation of the p53 pathway. Moreover, we found that Yy1 is involved in the transcriptional activation of Wnt1 in neural stem cells. Thus, our work demonstrates the involvement of Yy1 in cerebellar agenesis and the critical function of Yy1 in mouse early MHB neuroepithelium maintenance and development.	0
BACKGROUND:Autosomal recessive dystrophic epidermolysis bullosa (RDEB) is an incurable and severe inherited skin disorder characterized by recurrent blistering at the sublamina densa beneath the cutaneous basement membrane. It is caused by biallelic loss-of-function mutation in the gene encoding type VII collagen (COL7A1). This study aimed to identify the causative variants of a Chinese RDEB patient and further provide prenatal diagnosis for the ongoing risk pregnancy of the proband's mother. METHODS:Clinical exome sequencing (CES) has been performed and an in-house pipeline was used to conduct a phenotype-driven data analysis. A minigene assay was used to verify the pathogenicity of a novel splice site variant in the COL7A1. RESULTS:Here we report two compound heterozygous variants in COL7A1, c.3867delT (p.G1290Efs*35) and c.5532+4_5532+5delAG, identified in a RDEB patient by CES. The minigene assay confirmed that thec.5532+4_5532+5delAGchange was a noncanonic splice site variant leading to in an in-frame deletion of exon 64. Prenatal diagnosis indicated that the present pregnancy of the patient's mother was not affected. CONCLUSION:Our study expands the mutation spectrum of COL7A1 and demonstrated that CES and minigene assays were efficient tools for RDEB molecular diagnoses.	0
BACKGROUND:Preaxial polydactyly type IV, also referred as polysyndactyly, has been described in a few syndromes. We present three generations of a family with preaxial polydactyly type IV and other clinical features of Greig cephalopolysyndactyly syndrome (GCPS). METHODS AND RESULTS:Sequencing analysis of the GLI3 coding region identified a novel donor splice site variant NC_000007.14(NM_000168.6):c.473+3A>T in the proband and the same pathogenic variant was subsequently identified in other affected family members. Functional analysis based on Sanger sequencing of the proband's complementary DNA (cDNA) sample revealed that the splice site variant c.473+3A>T disrupts the original donor splice site, thus leading to exon 4 skipping. Based on further in silico analysis, this pathogenic splice site variant consequently results in a truncated protein NP_000159.3:p.(His123Argfs*57), which lacks almost all functionally important domains. Therefore, functional cDNA analysis confirmed that the haploinsufficiency of the GLI3 is the cause of GCPS in the affected family members. CONCLUSION:Despite the evidence provided, pathogenic variants in the GLI3 do not always definitely correlate with syndromic or nonsyndromic clinical phenotypes associated with this gene. For this reason, further transcriptomic and proteomic evaluation could be suggested.	0
Arthrogryposes - multiple joint contractures - are a clinically and etiologically heterogeneous class of diseases, where accurate diagnosis, recognition of the underlying pathology and classification are of key importance for the prognosis as well as for selection of appropriate management. This treatment remains challenging and optimally in arthrogrypotic patients should be carried out by a team of specialists familiar with all aspects of arthrogryposis pathology and treatment modalities: rehabilitation, orthotics and surgery. In this comprehensive review article, based on literature and clinical experience, the authors present an update on current knowledge on etiology, classifications and treatment options for skeletal deformations possible in arthrogryposis.	0
BACKGROUND: Van der Woude syndrome (VWS) is the most common clefting syndrome in humans. It is characterized by the association of congenital lower lip fistulae with cleft lip and/or cleft palate. VWS individuals have a high prevalence of hypodontia. Although caused by a single gene mutation, VWS has variable phenotypic expression. This study aimed to describe the range of clinical presentations in 22 individuals with VWS to facilitate its diagnosis. METHODS: A retrospective study of 22 patients with a diagnosis of VWS was undertaken at the Australian Craniofacial Unit (ACFU) in Adelaide. Three extended families with affected members were included in the study cohort. RESULTS: The overall prevalence of lip pits in this study cohort was 86%. Cleft phenotypes included bilateral cleft lip and palate (32%); unilateral cleft lip and palate (32%); submucous cleft palate (23%); and isolated cleft hard and soft palate (9%). Missing permanent teeth were reported in 86% of affected individuals. CONCLUSIONS: Submucous cleft palate in VWS may go undiagnosed if the lower lip pits are not detected. Associated hypodontia and resultant malocclusions will also require management by a dental team.	1
To determine an accurate estimate of the prevalence of congenital heart defects (CHD) using current standard diagnostic modalities.We obtained data on infants with CHD delivered during 1998 to 2005 identified by the Metropolitan Atlanta Congenital Defects Program, an active, population-based, birth defects surveillance system. Physiologic shunts in infancy and shunts associated with prematurity were excluded. Selected infant and maternal characteristics of the cases were compared with those of the overall birth cohort.From 1998 to 2005 there were 398 140 births, of which 3240 infants had CHD, for an overall prevalence of 81.4/10 000 births. The most common CHD were muscular ventricular septal defect, perimembranous ventricular septal defect, and secundum atrial septal defect, with prevalence of 27.5, 10.6, and 10.3/10 000 births, respectively. The prevalence of tetralogy of Fallot, the most common cyanotic CHD, was twice that of transposition of the great arteries (4.7 vs 2.3/10 000 births). Many common CHD were associated with older maternal age and multiple-gestation pregnancy; several were found to vary by sex.This study, using a standardized cardiac nomenclature and classification, provides current prevalence estimates of the various CHD subtypes. These estimates can be used to assess variations in prevalence across populations, time, or space.	1
The different types of drug resistance encountered in chronic lymphocytic leukemia (CLL) cannot be fully accounted for by the 17p deletion (and/or TP53 mutation), a complex karyotype (CK), immunoglobulin heavy-chain variable region genes (IGHV) status and gene mutations. Hence, we sought to assess the associations between recurrent genomic abnormalities in CLL and the disease's development and outcome. To this end, we analyzed 64 samples from patients with CLL and gain of the short arm of chromosome 2 (2p+), which is frequent in late-stage and relapsed/refractory CLL. We found that fludarabine/cyclophosphamide/rituximab (a common first-line treatment in CLL) is not effective in removing the 2p+ clone - even in samples lacking a CK, the 17p deletion or unmutated IGHV. Our results suggest strongly that patients with CLL should be screened for 2p+ (using karyotyping and fluorescence in situ hybridization) before a treatment option is chosen. Longer follow-up is now required to evaluate bendamustine-rituximab, ibrutinib, and idelalisib-rituximab treatments.	0
Background: 6-Pyruvoyl-tetrahydropterin synthase (PTS) is the key enzyme in BH4 synthesis. PTS deficiency is classified as severe type and mild type, and the prognosis and treatment differ for these types. Distinguishing between two types in the early stage is difficult. Reference to reported cases is needed for interpretation of the correlation between genotype and prognosis. Case report: We report a full-term female newborn with mild PTS deficiency. On the day 21 after birth, the phenylalanine level was 859.6 mmol/L (reference range: 30-117 mmol/L). After 1 year of observation, the patient was found to be in a healthy condition without treatment. Conclusions: Although the phenylalanine level is high in mild PTS deficiency patients after birth, some of them may have few symptoms with no treatment. We review 19 cases and find 8 mutations of PTS that may be associated with mild PTS deficiency.	0
Dopa-responsive dystonia (DRD) is a complex genetic disorder with either autosomal dominant or autosomal recessive inheritance, with autosomal dominant being more frequent. Autosomal dominant DRD is known to be caused by mutations in the GCH1 gene, with incomplete penetrance frequently reported, particularly in males. Here, we report a male patient with DRD caused by exon 1 deletion in the GCH1 gene inherited from the asymptomatic mother. The patient had an atypical presentation, notably with no dystonia, and underwent extensive workup for a myriad of neuromuscular disorders before a low-dose L-dopa trial and confirmatory genetic testing were performed. Our experience with this family highlights an atypical presentation of DRD and prompts us to consider the genetic complexity of DRD.	0
OBJECTIVES:To determine the characteristics of juvenile idiopathic arthritis (JIA) patients seen during the transition period in order to compare paediatric classification criteria with those for adults. METHODS:Patients with JIA according to the ILAR classification and who had a consultation at transition between 2010 and 2017 were included in a retrospective bi-centre (Lyon, Lausanne) study. JIA classification criteria were compared to ACR/EULAR 2010 criteria for rheumatoid arthritis (RA), Yamaguchi criteria for adult-onset Still's disease (AOSD), ASAS criteria for spondyloarthritis and CASPAR criteria for psoriatic arthritis. RESULTS:130 patients were included: 13.9% with systemic JIA, 22.3% with polyarticular JIA, 22.3% with oligoarticular JIA, 34.6% with enthesitis-related arthritis (ERA) and 6.9% with psoriatic arthritis. 13.1% had suffered from uveitis. 14.5% of patients had erosions or carpitis, mainly those with psoriatic arthritis, polyarticular or systemic JIA. 37.5% of patients with ERA displayed radiological sacroiliitis. When comparing paediatric JIA criteria with adult classifications, we found that: 66.6% of patients with systemic JIA fulfilled the criteria for AOSD, 87.5% of rheumatoid factor-positive polyarticular JIA and 9.5% of rheumatoid factor-negative polyarticular JIA met the criteria for RA, and 34.5% of oligoarticular JIA fulfilled the criteria for spondyloarthritis. Finally, 77.7% of patients with ERA met the criteria for spondyloarthritis, and 100% of patients with psoriatic arthritis JIA met the criteria for psoriatic arthritis. CONCLUSION:Oligoarticular JIA and rheumatoid factor-negative polyarticular JIA seem to be paediatric entities, whereas the other types of JIA tended to meet the respective adult classification criteria.	0
INTRODUCTION:Duplication of long arm of chromosome 7(q) is uncommon. It may occur as "pure", isolated anomaly or in association with other mutations involving the same or other chromosomes. "Pure" chromosome 7q duplication has recently been classified by segment involved: the interstitial, proximal, or distal segment of the arm. Attempts to correlate genotype with phenotype in each group has yielded questionable results even though intellective disability and minor dysmorphic features of variable types are typically seen. MATERIAL AND METHODS:In a young boy showing minor facial dysmorphism, language delay, autistic spectrum disorder, epileptic seizures, behavioral disturbances and irritability an array-CGH analysis was carried out. RESULTS:Array-CGH analysis found in the proband a de novo variant of partial duplication of 7q31.32 (122.254.792-122.376.908). DISCUSSION:A very few cases of partial 7q duplication have been reported thus far mainly presenting with clinical signs of dysmorphic features, large head, developmental delay, epileptic seizures and skeletal anomalies. To our knowledge, this is the first report of a case of a de novo variant of 7q31.32 duplication, showing dysmorphic anomalies and neurologic impairment including ASD and seizures. In the 7q31.32 region is located the gene CADPS2, which has been associated to autistic spectrum disorder and other neurologic disorders. In the child, a genotype-phenotype correlation may be hypothesized. Further similar reports may be useful to confirm this observation.	0
Caffey disease is a rare and self-limiting condition characterised by cortical hyperostosis with inflammation of adjacent fascia and muscles. It usually presents in infancy and clinical features include hyperirritability, acute inflammation with swelling of overlying soft tissues and subperiosteal new bone formation. Awareness of the existence of this rare condition and its typical clinical and radiological profile will avoid unnecessary investigations and treatment and help the physician to explain its good prognosis to parents of affected children. We report a three-month-old male infant who presented to the Outpatient Paediatrics Department at Moti Lal Nehru Medical College, Allahabad, India, in 2018 with a right shoulder mass, decreased upper limb movements and irritability. The patient was treated with ibuprofen and paracetamol. Irritability and limitation of movement improved over a treatment period of two weeks.	0
A systematic literature review and meta-analyses (where appropriate) were performed to update the previous AASM practice parameters on the treatments, both dopaminergic and other, of RLS and PLMD. A considerable amount of literature has been published since these previous reviews were performed, necessitating an update of the corresponding practice parameters. Therapies with a STANDARD level of recommendation include pramipexole and ropinirole. Therapies with a GUIDELINE level of recommendation include levodopa with dopa decarboxylase inhibitor, opioids, gabapentin enacarbil, and cabergoline (which has additional caveats for use). Therapies with an OPTION level of recommendation include carbamazepine, gabapentin, pregabalin, clonidine, and for patients with low ferritin levels, iron supplementation. The committee recommends a STANDARD AGAINST the use of pergolide because of the risks of heart valve damage. Therapies for RLS secondary to ESRD, neuropathy, and superficial venous insufficiency are discussed. Lastly, therapies for PLMD are reviewed. However, it should be mentioned that because PLMD therapy typically mimics RLS therapy, the primary focus of this review is therapy for idiopathic RLS.	0
Purpose:There have been many efforts to develop generalizable severity markers in children with acute pancreatitis (AP). Expert opinion panels have developed consensus guidelines on management but it is unclear if these are sufficient or valid. Our study aims to assess the effect of clinical and laboratory variables, in addition to treatment modality on hospital length of stay (LOS) as a proxy variable for severity in pediatric patients admitted with AP. Methods:We conducted a retrospective chart review of patients between ages of 0-18 years, who were admitted with AP at 2 institutions between 2013-2018, John R. Oishei Children's Hospital (Buffalo, NY, USA) and Medical University of South Carolina Children's Hospital (Charleston, SC, USA). We constructed three linear regression models to analyze the effect of clinical signs of organ dysfunction, laboratory markers and fluid intake on hospital LOS. Results:Ninety-two patients were included in the study. The mean age was 12 years (range, 7.6-17.4 years), 55% were females, and median LOS was 3 days. The most frequent cause of AP was idiopathic. Our study showed that elevated blood urea nitrogen (BUN) on admission (p<0.005), tachycardia that lasted for ≥48 hours (p<0.001) and need for fluid resuscitation were associated with increase LOS. Total daily fluid intake above maintenance did not have a significant effect on the primary outcome (p=0.49). Conclusion:Elevated serum BUN on admission, persistent tachycardia and need for fluid resuscitation were associated with increase LOS in pediatric AP. Daily total fluid intake above recommended maintenance did not reduce LOS.	0
The 8p inverted duplication/deletion is a rare chromosomal rearrangement clinically featuring neurodevelopmental delay, mild to severe cognitive impairment, heart congenital defects and brain abnormalities. Patients affected also present typical facial dysmorphisms and skeletal malformations, and it is thought that the composite clinical picture may fall into the chromosomal rearrangement architecture. With the major aim of better framing its related clinical and diagnostic paths, we describe a patient carrying a de novo invdupde[8p] whose clinical features have not been described so far. Hence, through an extensive genotype-phenotype correlation analysis and by reviewing the dedicated scientific literature, we compared our patient's features with those reported in other patients, which allows us to place our proband's expressiveness in an intermediate area, widening the scope of the already known invdupde[8p] genotype-phenotype relationship.	0
Brain arteriovenous malformations (AVMs) are congenital vascular abnormality in which arteries and veins connect directly without an intervening capillary bed. So far, the pathogenesis of brain AVMs remains unclear. Here, we found that Wilms' tumour 1-associating protein (WTAP), which has been identified as a key subunit of the m6A methyltransferase complex, was down-regulated in brain AVM lesions. Furthermore, the lack of WTAP could inhibit endothelial cell angiogenesis in vitro. In order to screen for downstream targets of WTAP, we performed RNA transcriptome sequencing (RNA-seq) and Methylated RNA Immunoprecipitation Sequencing technology (MeRIP-seq) using WTAP-deficient and control endothelial cells. Finally, we determined that WTAP regulated Desmoplakin (DSP) expression through m6A modification, thereby affecting angiogenesis of endothelial cells. In addition, an increase in Wilms' tumour 1 (WT1) activity caused by WTAP deficiency resulted in substantial degradation of β-catenin, which might also inhibit angiogenesis of endothelial cells. Collectively, our findings revealed the critical function of WTAP in angiogenesis and laid a solid foundation for the elucidation of the pathogenesis of brain AVMs.	0
Epidermolysis bullosa acquisita (EBA) is a rare, acquired, chronic subepidermal bullous disease of the skin and mucosa characterized by autoantibodies to type VII collagen (C7) structures, a major component of anchoring fibrils, which attach the epidermis to the dermis. EBA patients have tissue-bound and circulating antitype C7 autoantibodies that attack type C7 and result in a reduction or perturbation of normally functioning anchoring fibrils. Patients with EBA have skin fragility, blisters, erosions, scars, milia, and nail loss, all features reminiscent of genetic dystrophic epidermolysis bullosa. These immunoglobulin G antitype C7 antibodies are pathogenic, because when they are injected into mice, the mice develop an EBA-like blistering disease. In addition to the classical mechanobullous presentation, EBA also has several other distinct clinical syndromes similar to bullous pemphigoid, Brunsting-Perry pemphigoid, or cicatricial pemphigoid. Although treatment for EBA is often unsatisfactory, some therapeutic success has been achieved with colchicine, dapsone, plasmapheresis, photopheresis, infliximab, and intravenous immunoglobulin.	0
The eosinophilia-myalgia syndrome (EMS) outbreak of 1989 that occurred in the USA and elsewhere was caused by the ingestion of l-Tryptophan (L-Trp) solely manufactured by the Japanese company Showa Denko K.K. (SD). Six compounds present in the SD L-Trp were reported to be case-associated contaminants. However, "one" of these compounds, Peak AAA has remained structurally uncharacterized, despite the fact that it was described as "the only statistically significant (p=0.0014) contaminant". Here, we employ on-line microcapillary-high performance liquid chromatography-electrospray ionization mass spectrometry (LC-MS), and tandem mass spectrometry (MS/MS) to determine that Peak AAA is in fact two structurally related isomers. Peak AAA1 and Peak AAA2 differed in LC retention times, and were determined by accurate mass-LC-MS to both have a protonated molecular ion (MH+) of mass 343.239Da (Da), corresponding to a molecular formula of C21H30N2O2, and possessing eight degrees of unsaturation (DoU) for the non-protonated molecule. By comparing the LC-MS and LC-MS-MS retention times and spectra with authentic synthetic standards, Peak AAA1 was identified as the intermolecular condensation product of L-Trp with anteiso 7-methylnonanoic acid, to afford (S)-2-amino-3-(2-((S,E)-7-methylnon-1-en-1-yl)-1H-indol-3-yl)propanoic acid. Peak AAA2 was determined to be a condensation product of L-Trp with decanoic acid, which produced (S)-2-amino-3-(2-((E)-dec-1-en-1-yl)-1H-indol-3-yl)propanoic acid.	0
Background:A large deletion in Xp22.3 can result in contiguous gene syndromes, including X-linked ichthyosis (XLI) and Kallmann syndrome (KS), presenting with short stature, chondrodysplasia punctata, intellectual disability, and strabismus. XLI and KS are caused by the deletion of STS and ANOS1, respectively. Method:Two KS patients with XLI were screened to identify possible pathogenic mutations using whole exome sequencing. The clinical characteristics, molecular genetics, treatment outcomes, and genotype-phenotype association for each patient were analyzed. Results:We identified a novel 3,923 kb deletion within the Xp22.31 region (chrX: 5810838-9733877) containing STS, ANOS1, GPR143, NLGN4X, VCX-A, PUDP, and PNPLA4 in patient 1, who presented with KS, XLI, obesity, hyperlipidemia, and strabismus. We identified a novel 5,807 kb deletion within the Xp22.31-p22.33 regions (chrX: 2700083-8507807) containing STS, ANOS1, and other 24 genes in patient 2, who presented with KS, XLI, obesity, and strabismus. No developmental delay, abnormal speech development, or autistic behavior were noticed in either patient. Conclusion:We identified two novel microdeletions in the X chromosome leading to KS and XLI. These findings contribute to the understanding of the molecular mechanisms that drive contiguous gene syndromes. Our research confirmed that the Kallmann-Ichthyosis phenotype is caused by microdeletions at the chromosome level.	0
BACKGROUND:Shigellosis is a highly contagious enteric bacterial disease transmitted through the fecal-oral route. It is primarily transmitted through person-to-person contact, and via contaminated food and water. Outbreaks of shigellosis among men who have sex with men (MSM) attributed to sexual person-to-person contact have been reported. These outbreaks are of concern because they are often caused by multidrug-resistant strains of Shigella. Little is known about shigellosis-related knowledge, attitudes, and practices (KAPs) among gay, bisexual, and other MSM. METHODS:Six focus groups were conducted among self-identified gay or bisexual men in Atlanta, GA in Fall 2017. Participants were asked about shigellosis-related KAPs. Focus groups were audio recorded and the transcribed audio was analyzed using inductive and deductive thematic coding. RESULTS:Among the 24 focus group participants, most perceived that diarrheal illness was caused by contaminated food. Knowledge of shigellosis and Shigella was low, with most never having heard of the disease or bacteria. Participants did not perceive shigellosis to be a serious health concern, especially when compared with HIV; however, they did perceive gay and bisexual men to be at risk for Shigella infection. Participants reported mixed intentions to change sexual behaviors to prevent shigellosis or talk with sexual partners about diarrhea. CONCLUSION:Health communication and education efforts could be used to increase knowledge about shigellosis and shift perceptions about the severity of shigellosis among gay, bisexual, and other MSM. Additional work is needed to identify effective ways to promote shigellosis-related prevention behaviors among gay, bisexual, and other MSM.	0
PURPOSE:To report a case of linezolid-induced reversible retinopathy. METHODS:Case report with literature review. RESULTS:Clinical examination and imaging are presented over a 7-month interval, from initial presentation to subsequent follow-up (6 months after discontinuation of linezolid). The subject was found to have not only an optic neuropathy but also severe reversible photoreceptor dysfunction as demonstrated by electrophysiologic testing. Upon discontinuation of linezolid, not only did the patient's visual acuity, visual fields, and visual evoked potential significantly improve, but the electroretinogram did as well. CONCLUSIONS:Linezolid has previously been reported to cause a toxic optic neuropathy. Reversible photoreceptor dysfunction on full-field electroretinography has never been reported in conjunction with linezolid toxicity. This novel case suggests that linezolid toxicity should be considered in cases of photoreceptor dysfunction.	0
Almost no epidemiological data are available on a worldwide basis on the prevalence, incidence or relative frequency of interstitial lung diseases (ILD). We report the results of a registration of ILD by 23 centers of pulmonary medicine in Spain over one year (from October 2000 to September 2001).A standardized questionnaire was sent to the centers, together with guidelines for classification and diagnostic evaluation. This questionnaire included questions about the explorations performed to establish the diagnosis.A total of 511 cases were registered. The mean age of the patients was 61 +/- 0.7 (x +/- SEM) yrs. The male to female ratio was 1.2:1. The estimated incidence of ILD was 7.6 per 100,000/year. The most frequent disease was idiopathic pulmonary fibrosis (38.6%), followed in decreasing order by sarcoidosis (14.9%), cryptogenic organizing pneumonia (10.4%), ILD associated with collagen vascular diseases (9.9%) and hypersensitivity pneumonitis (6.6%). In 5.1% of cases ILD was unclassified. HRCT scan was performed in 91.9% of cases, bronchoalveolar lavage in 67.9%, transbronchial lung biopsy in 59.9%, and surgical lung biopsy in 22.7%.This registration provides interesting information on the occurrence of ILD in Spain and on the procedures used to establish the diagnosis.	1
Epidermal barrier integrity could be influenced by various factors involved in epidermal cell differentiation and proliferation, cell-cell adhesion, and skin lipids. Dysfunction of this barrier can cause skin disorders, including eczema. Inversely, eczema can also damage the epidermal barrier. These interactions through vicious cycles make the mechanism complicated in connection with other mechanisms, particularly immunologic responses. In this article, the molecular mechanisms concerning epidermal barrier abnormalities are reviewed in terms of the following categories: epidermal calcium gradients, filaggrin, cornified envelopes, desquamation, and skin lipids. Mechanisms linked to ichthyoses, atopic dermatitis without exacerbation or lesion, and early time of experimental irritation were included. On the other hand, the mechanism associated with epidermal barrier abnormalities resulting from preceding skin disorders was excluded. The molecular mechanism involved in epidermal barrier dysfunction has been mostly episodic. Some mechanisms have been identified in cultured cells or animal models. Nonetheless, research into the relationship between the causative molecules has been gradually increasing. Further evidence-based systematic data of target molecules and their interactions would probably be helpful for a better understanding of the molecular mechanism underlying the dysfunction of the epidermal barrier.	0
Bethlem myopathy represents the milder form of the spectrum of Collagen VI-related dystrophies, which are characterized by a clinical continuum between the two extremities, the Bethlem myopathy and the Ullrich congenital muscular dystrophy, and include less defined intermediate phenotypes. Bethlem myopathy is mainly an autosomal dominant disorder and the causing mutations occur in the COL6A genes encoding for the α1 (COL6A1), α2 (COL6A2) and α3 (COL6A3) chains. However, few cases of recessive inheritance have been also reported. We here describe clinical, genetic and functional findings in a recessive Bethlem myopathy family harbouring two novel pathogenic mutations in the COL6A2 gene. Two adult siblings presented with muscle weakness and wasting, elbows and Achilles tendon retractions, lumbar hyperlordosis, waddling gait and positive Gowers' sign. Muscle biopsy showed a dystrophic pattern. Molecular analysis of the COL6A2 gene revealed the novel paternally-inherited nonsense p.Gln889* mutation and the maternally-inherited p.Pro260_Lys261insProPro small insertion. Fibroblast studies in both affected patients showed the concomitant reduction in the amount of normal Collagen VI (p.Gln889*) and impairment of Collagen VI secretion and assembly (p.Pro260_Lys261insProPro). Each of the two variants behave as a recessive mutation as shown by the asymptomatic heterozygous parents, while their concomitant effects determined a relatively mild Bethlem myopathy phenotype. This study confirms the occurrence of recessive inherited Bethlem myopathy and expands the genetic heterogeneity of this group of muscle diseases.	0
Inherited heart disease represent a very heterogenous group of cardiac disorders, characterized by inherited, acquired, and often rare disorders affecting the heart muscle (cardiomyopathies) or the cardiac electrical system (ion channel disease). They are often familial diseases, and are among the leading cause of juvenile sudden death and heart failure. The aim of this paper is to give a perspective on how to run a clinical service during an epidemic or pandemic emergency and to describe the potential COVID-19 associated risks for patients affected by inherited heart diseases.	0
Long-term outcomes in solid organ transplantation are constrained by the development of donor-specific alloantibodies (DSA) against human leukocyte antigen (HLA) and other targets, which elicit antibody-mediated rejection (ABMR). However, antibody-mediated graft injury represents a broad continuum, from extensive complement activation and tissue damage compromising the function of the transplanted organ, to histological manifestations of endothelial cell injury and mononuclear cell infiltration but without concurrent allograft dysfunction. In addition, while transplant recipients with DSA as a whole fare worse than those without, a substantial minority of patients with DSA do not experience poorer graft outcome. Taken together, these observations suggest that not all DSA are equally pathogenic. Antibody effector functions are controlled by a number of factors, including antibody concentration, antigen availability, and antibody isotype/subclass. Antibody isotype is specified by many integrated signals, including the antigen itself as well as from antigen-presenting cells or helper T cells. To date, a number of studies have described the repertoire of IgG subclasses directed against HLA in pretransplant patients and evaluated the clinical impact of different DSA IgG subclasses on allograft outcome. This review will summarize what is known about the repertoire of antibodies to HLA and non-HLA targets in transplantation, focusing on the distribution of IgG subclasses, as well as the general biology, etiology, and mechanisms of injury of different humoral factors.	0
A wedge-shaped anterior hairline extension is a very rare skin manifestation usually associated with congenital anomalies including a Tessier number 10 cleft. Other associated conditions are the Tessier number 9 cleft, the Fraser syndrome, and the Manitoba oculotrichoanal syndrome (MOTA syndrome). The Tessier number 10 cleft features include a coloboma of the middle third of the upper eyelid, and an eyebrow divided into two portions. The medial eyebrow portion may be absent and the lateral portion is angulated vertically, joining the hairline of the scalp. This creates a wedge-shaped anterior hairline extension. Herein we report on a case of a wedge-shaped anterior hairline extension associated with the Tessier number 10 cleft.	0
The birth prevalence of Robin sequence (RS) is frequently cited to be 1 in 8,500 to 14,000 live births (range: 7,1-11,8 per 100.000), which is based on just a few epidemiological studies. The objective of this study is to contribute to the limited knowledge of the epidemiology of RS by determining the frequency of RS in a cleft palate (CP) population and the estimated birth prevalence in live births in the Netherlands, using distinct diagnostic criteria. A retrospective population-based analysis of the National Cleft Registry was performed in order to obtain all CP patients registered in the Netherlands from 2000-2010, in addition to a thorough review of the medical records in three Dutch Academic Pediatric Hospitals for the same period. Furthermore, a systematic search of the literature was conducted to allow for comparison of our findings. The Dutch birth prevalence of RS was estimated to be 1:5,600 live births (or 17.7 per 100,000), with a slight female predominance. RS was estimated to occur in a third of the CP population and patients with RS had a more severe cleft grade than the general CP population. The literature search yielded 42 studies reporting the birth prevalence for RS, which varied between 1:3,900 and 1:122,400 (0.8-32.0 per 100,000), with a mean prevalence of 1:24,500 (8.0 per 100,000). The birth prevalence of RS in the Netherlands was higher than reported for most other countries when similar diagnostic criteria were used, with a slight female predominance. A third of the general CP could be classified as RS.	1
UNLABELLED:We reviewed of a number of genetic diseases known or at risk for sedation or anesthesia complications. Some of these conditions are relatively common (e.g., Down's syndrome) whereas others are rare or present with multiple congenital anomalies that have an impact on health care delivery. We listed complications, recommended presedation evaluations, and included checklist items to assist the health care provider administering sedation and anesthesia. A better recognition and awareness of risk factors associated with specific genetic diseases should lessen the likelihood of complications during these procedures. IMPLICATIONS:This article provides a brief description of potential problematic genetic disorders and associated complications that may manifest during sedation or anesthesia. Recommendations for presedation evaluation and checklist items are given that may impact on the delivery of care for these patients.	0
Primary biliary cholangitis is a cholestatic, chronic autoimmune liver disease with a wide individual variation in disease progression. The diagnosis is predominantly based on chronic elevation of alkaline phosphatase and the presence of anti-mitochondrial antibodies or other specific antinuclear antibodies (i.e. anti-gp210 and anti-sp100). Even in early-stage disease, health-related quality of life can be severely impaired by symptoms such as pruritus, fatigue, and sicca syndrome and metabolic bone disease should be assessed and treated. The prognosis of the disease is, however, largely determined by the development of cirrhosis and its complications. Ursodeoxycholic acid is associated with an improved prognosis and should be initiated and continued in all patients. Clinical outcome is related to the biochemical response to ursodeoxycholic acid, but the prognosis of those with an incomplete response is still better than those who remain untreated. Obeticholic acid was recently approved as second-line treatment and bezafibrate may serve as an adequate off-label alternative, particularly in patients with pruritus. Preliminary data suggest an additive effect of triple therapy with ursodeoxycholic acid, obeticholic acid, and bezafibrate, whereas other promising drugs are being evaluated in clinical trials.	0
PURPOSE:To compare the visual and anatomical outcomes of two different treatment strategies (non-internal limiting membrane (ILM) peeling and fovea-sparing ILM peeling) for retinoschisis with foveal detachment (FD) in highly myopic eyes. DESIGN:A retrospective cohort study. METHODS:Ninety-five eyes from 92 highly myopic patients with retinoschisis with FD were divided into two groups, including 44 eyes from 43 patients who received 23-gauge, 3-port vitrectomy without ILM peeling (group A) and 51 eyes from 49 patients who received vitrectomy with fovea-sparing ILM peeling (group B). All eyes also underwent cataract surgery. RESULTS:There were no significant differences between the two groups in terms of sex, age, diopters, axial length (AL), or central foveal thickness (CFT) before surgery (P > 0.05). One month after surgery, foveoschisis and FD were resolved in 74.47% of the eyes in group B and in only 12.50% of those in group A. Six months after surgery, foveoschisis and FD were resolved in 96.08% of the eyes in group B and in only 72.73% of those in group A (P < 0.05). There were no significant differences between the two groups in terms of BCVA 6 months after surgery. The postoperative complication was macular holes, which were found in seven eyes (15.90%) in group A and in one eye (1.96%) in group B (P < 0.05). CONCLUSION:Highly myopic eyes with FD that underwent fovea-sparing ILM peeling appeared to obtain a better anatomical outcome than those that did not undergo non-ILM peeling. The two procedures obtained similar results in terms of visual function.	0
RATIONALE:Malignant mixed Müllerian tumor (MMMT) of extragenital organs is rare, especially in male. To our knowledge, this is the first reported case of primary MMMT at the mediastinum in male. PATIENT CONCERNS:A 54-year-old male was admitted to the hospital due to repeated stimulating dry cough for 2 years. His systemic examination was unremarkable. Laboratory workup revealed that all blood indicators were within normal limits. But subsequent computerized tomography (CT) scans of chest showed an abnormal soft tissue density in the area of its left, measuring approximately 4 cm in anterior-posterior dimension and 7 cm in maximum transverse dimension. DIAGNOSES AND INTERVENTIONS:The pathogenesis of these tumors remains controversial. The diagnosis is combined with biopsy and immunohistochemical staining. So, the patient underwent radical surgical resection and pathologic examination of the excised specimen was consistent with the diagnosis of MMMT. After surgery, he was treated by sequential chemoradiotherapy. OUTCOMES:The patient died from tumor recurrence 16 months later. LESSONS:MMMT is a rare, highly aggressive tumor associated with interesting embryological origin, a definite diagnosis of which is only confirmed on pathological assessment. Due to its high degree of malignancy and high rate of recurrence, complete macroscopic excision of the tumor is recommended as soon as possible.	0
Purpose:The aim of this study is to compare the outcome and complications in patients who underwent double-head pterygium excision with split conjunctival autograft with and without limbus to limbus orientation. Methods:In this retrospective, comparative study, 99 eyes with double-head pterygium which underwent split conjunctival autograft with limbus to limbus orientation (Group 1) and 93 eyes which underwent without limbus to limbus orientation (Group 2) during the period of 2011-2016 were included in this study. The primary outcome compared was the recurrence rate. Other complications were included as secondary outcomes. Results:Mean age in group 1 and group 2 were 46.84 +/- 10.78 years and 54.38 +/- 11.44 years respectively. M:F was 36:63 in group 1 and 45:48 in group 2 with a mean follow up of 18.30 +/- 7.48 months in group 1 and 17.04 +/- 9.98 months in group 2. Recurrence was seen in 4 cases in each of the 2 groups with the mean time of recurrence being 7 +/- 2.34 months in group 1 and 6 +/- 2.01 months in group 2. Other complications included graft edema, SCH, graft retraction, granuloma, dellen and graft loss with only graft loss being statistically significant between 2 groups. Conclusion:This study provides data that recurrence rates are not different among patients who undergo split conjunctival graft with and without limbal orientation. The strict adherence to maintaining limbus to limbus orientation while managing double-headed pterygia may not be necessary in all cases, especially in those with large defects following excision.	0
Detailed phenotypic information on the spectrum of fundus abnormalities and clinical variability of all phenotypes associated with sequence variations in BEST1 is limited. To report a detailed phenotypic and genetic analysis of a patient cohort with sequence variations in BEST1. This retrospective case series took place at the Oxford Eye Hospital in Oxford, UK. Thirty-six patients from a single center with disease-causing sequence variations in BEST1 from 25 different families were analyzed. Data were collected from November 2017 to June 2018, and analysis began April 2018. Results of ocular phenotyping and genetic testing using targeted next-generation sequencing to identify BEST1 sequence variations. Thirty-six patients from 25 families with disease-causing sequence variations in BEST1 were included. Of 36 patients, 20 (55.6%) were female. Three distinct clinical phenotypes were identified: autosomal recessive bestrophinopathy (ARB), best vitelliform macular dystrophy (BVMD), and adult-onset vitelliform macular dystrophy. The ARB phenotype group comprised 18 patients from 9 families with age in years at symptom onset ranging from less than 10 to 40s. All patients showed a common phenotype of fundus autofluorescence abnormalities, and spectral-domain optical coherence tomography features were similar in all patients with schitic and cystoid changes. A phenotype of a beaten metallic retinal appearance extending from the mid periphery to the far periphery was identified in 8 patients. Four patients from 1 family with ARB were previously reported to have autosomal recessive retinitis pigmentosa but were reclassified as having ARB as part of this study. The BVMD phenotype group comprised 16 patients from 14 families with age at symptom onset ranging from less than 10 to 70s. Fundus features were localized to the macula and consistent with the stage of BVMD. In the adult-onset vitelliform macular dystrophy phenotype group, the age in years at symptom onset varied from 50s to 70s in 2 patients from 2 families. Fundus features included small vitelliform lesions. Where available, electro-oculogram results demonstrated a reduced or absent light rise in all patients with ARB and BVMD. Genetic testing identified 22 variants in BEST1. These findings support the notion that ARB, BVMD, and adult-onset vitelliform macular dystrophy are clinically distinct and recognizable phenotypes and suggest that the association of autosomal recessive retinitis pigmentosa with sequence variations in BEST1 should be rereviewed.	0
BACKGROUND:Turner syndrome (45,X), accounts for 1-2% of conceptions which typically miscarry early in the first trimester. Cases detected prenatally often present with cystic hygroma, which is an ultrasound marker for aneuploidy generally, but Turner syndrome particularly. In this study, we report a second trimester intrauterine fetal demise (IUFD), complicated by a marked cystic hygroma and bilateral syndactyly of the fingers and toes. CASE PRESENTATION:A 25-year-old woman presented for her first prenatal visit at 22-week gestation with IUFD. Color Doppler ultrasound revealed a septated nuchal lymphatic hygroma and hydrops fetalis, characterized by edema of the whole body, substantial pleural effusion and abdominal fluid. Pregnancy was further complicated by oligohydramnios. Following labor induction, a stillborn female baby was delivered at 22 weeks gestation. Autopsy confirmed the presence of huge nuchal cystic hygroma (10 cm × 10 cm × 6 cm) and generalized edema. Bilateral, partial syndactyly involving digits 2-5 of the fingers and toes were also observed. Chromosomal analysis revealed a 45,X karyotype. CONCLUSIONS:We investigated an unusual case of severe septated nuchal cystic hygroma associated with bilateral syndactyly of the fingers and toes in a stillborn infant with Turner syndrome. Although cystic hygroma has been frequently reported in 45,X the severity is marked in this case. In addition, syndactyly is not a typical complication of Turner syndrome. This case emphasizes the importance of early ultrasound in pregnancy.	0
Spinocerebellar ataxia (SCA) types 13 and 25 are two genetic entities among the autosomal dominant cerebellar ataxias, initially mapped in two French families to chromosomes 19q and 2p, respectively. The SCA13 locus was confirmed by the identification of a second kindred of Filipino ancestry. SCA13 patients have cerebellar ataxia of adult onset, or of early onset when associated with mental impairment. SCA25 patients present with cerebellar ataxia with sensory neuropathy and frequent gastrointestinal features. While the gene responsible for SCA25 is still unknown, missense mutations affecting the potassium channel KCNC3 function have been identified.	0
A 44-year-old woman with seronegative polyarthritis presented with a 2-year history of a solitary, bluish-red, oedematous, nonscaly, annular and partially reticulated macule on her right thigh. Histopathological findings revealed perivascular and periadnexal lymphocytic infiltrate in the dermis. Alcian blue and colloidal iron stains highlighted mucinous deposit in the upper and mid dermis. Direct immunofluorescence showed a linear deposit of IgG and C3 along the basement membrane zone. Antinuclear antibody was positive at a titre of 1 : 80, with homogenous and speckled patterns. Except for its unusual localization and lack of photosensitivity, our case had the clinical and histopathological features of lupus erythematosus tumidus. These characteristics were also reminiscent of reticular erythematous mucinosis and erythema annulare centrifugum, both of which are considered to be associated with cutaneous lupus erythematosus (CLE). Hydroxychloroquine 200 mg daily led to improvement of the skin lesion. The unusual clinical presentation of our case emphasizes the heterogeneity of clinical manifestations of CLE.	0
The features of a child with osteogenesis imperfecta type III (OI III) resulting from the heterozygous substitution of glycine 1006 by alanine in the pro alpha 2(I) chain of type I procollagen were studied. He was born at term with the clinical features of severe OI, including deep grey-blue sclerae. He had severe osteopenia and all long bones were smaller than normal with cortical thinning, metaphyseal expansion, poor metaphyseal modelling, and multiple fractures. However, the vertebrae, pelvis, and shoulder girdle were of normal shape and there were few rib fractures. Histological examination of the calvarium and tibial shaft showed woven bone without lamellar bone or Haversian systems. The shafts of the long bones were widened owing to repeated fractures. Progressive enlargement of the calvarium occurred between 3 and 4.5 months of age owing to bilateral chronic subdural haematomata and a large arachnoid cyst in the Sylvian fissure. The cyst was probably developmental in origin while the subdural collections were probably the result of perinatal skull trauma. The cyst and the subdural collections resolved following drainage but ventricular dilatation with normal cerebrospinal fluid pressure followed. The proband is the first reported case of OI with a glycine substitution by alanine in the pro alpha 2(I) chain of type I procollagen.	0
Glucocorticoids are typically prescribed for the treatment of idiopathic nephrotic syndrome of childhood. In selected patients with refractory focal segmental glomuerulosclerosis (FSGS), adrenocorticotropin (ACTH) can be used to induce remission and decrease the progression of the disease. We report a 6 8/12-year-old girl with recurrent proteinuria, resistant to standard immunotherapy. She underwent related renal transplant but again developed proteinuria and was started on ACTH. She subsequently developed peripheral precocious puberty (PPP), presumably from peripheral aromatization of adrenal androgens. She was started on an aromatase inhibitor, and her ACTH dose was slowly decreased. She then developed central precocious puberty (CPP). We hypothesize that treatment of her peripheral precocious puberty with an aromatase inhibitor may have triggered central precocious puberty.	0
Background: Bruck syndrome is a rare autosomal recessive condition that presents with many of the symptoms of osteogenesis imperfecta. In addition to defective type I collagen, manifesting as bone fragility, osteoporosis, and blue sclera, Bruck syndrome is additionally characterized by arthrogryposis with pterygia. Joint contractures are frequently bilateral and severe. Case Report: We report the medical record and radiographic data for 2 siblings with Bruck syndrome type 2-a male (age 6 years) and a female (age 5 years)-born to nonaffected parents. The male has experienced more than 45 fractures, developed severe scoliosis, and has debilitating flexion contractures. The female has minimal flexion contractures, a history of 15 fractures, and severe scoliosis. Conclusion: The dramatic difference between the phenotypes of these 2 cases is significant because it is the largest known variability of phenotypic presentation in siblings. Previous cases of siblings with differing presentations at birth have been reported, but the extent of these differences is not as extreme as in our cases. Because Bruck syndrome presents similarly to osteogenesis imperfecta and could be clinically mistaken for a form of osteogenesis imperfecta if contractures are minimal, a reasonable focus for research efforts is the development of genetic diagnostic protocols for osteogenesis imperfecta with the goal of ruling out Bruck syndrome.	0
Background/aim:To define the cytomorphologic findings leading to difficulties in diagnosis of Warthin tumors (WTs). Materials and methods:Forty-eight histopathologically diagnosed WT patients who had fine needle aspiration cytology preoperatively were reevaluated for defining the presence or absence of lymphocytes, oncocytic cell layer, oncocytic cell papillae, granular debris background, mucoid background, macrophages, polymorphonuclear cells, mast cells, squamous-like cells, atypical vacuolated cytoplasmic cells, and giant cells. Results:Forty-seven tumors were in the parotid gland and one in the submandibular gland. There were 37 (77%) male and 11 (23%) female patients. Cytopathologically in 36 patients the diagnosis was benign neoplasm (WT); in 6, other benign entities; and in 6, suspicious for malignancy. The main characteristic cytomorphologic features of WTs were as follows: 92% lymphoid cells, 83% oncocytic cell layers, and 67% granular debris background. These percentages were 67%, 17%, and 17% in the benign cytology group and 67%, 50%, and 17% in the suspicious for malignancy group, respectively. Conclusion:Absence or lack of main features of WTs with or without presence of squamous-like cells, vacuolated cytoplasmic cells, and inflammatory reaction may cause diagnostic dilemma. The presence of the mast cells accompanied by epithelial tissue was striking for WT diagnosis.	0
Pearson syndrome is a genetic disorder caused by mutations in the mitochondrial genome, characterized by failure to thrive with hematological and gastrointestinal abnormalities. Individuals with Pearson syndrome may develop the symptoms and signs of Kearns-Sayre syndrome with multisystem involvement. Spontaneous recovery of hematological problems is reported as is the situation in the present case. The child reported here was born out of in-vitro fertilization. She was maintaining normal hemoglobin level for more than three and a half years but had been detected to have hypoparathyroidism. The diagnosis of Pearson syndrome was confirmed by presence of deletion in mitochondrial genome. Awareness about this rare disorder will help clinicians to broaden their differentials when dealing with common presentations like failure to thrive and anemia.	0
Anton syndrome is characterised by visual anosognosia. It results from damage to both occipital lobes, while the anterior visual pathways remain intact. We describe four cases of Anton's syndrome. First case is that of a 73-year-old woman, who presented with two separate events of intraparenchymal brain haemorrhage, 4 years apart. Her first stroke affected the left and second affected the right occipital lobe. Bilateral occipital lobe damage resulted in cortical blindness. Second case is an 88-year-old man, who suffered from two ischaemic strokes, 2 days apart. Each stroke involved one posterior cerebral artery. This resulted in bilateral occipital and temporal lobe infarcts. Third case is a 64-year-old woman with chronic renal failure, who suffered bilateral occipital lobe infarction after haemodialysis, due to posterior reversible encephalopathy syndrome. Last case is that of an 80-year-old woman who suffered a basilar artery stroke, resulting in bilateral thalamic, temporal and occipital lobe infarction.	0
BACKGROUND:The development of the face occurs during the early days of intrauterine life by the formation of facial processes from the first Pharyngeal arch. Derangement in these well-organized fusion events results in Orofacial clefts (OFC). Van der Woude syndrome (VWS) is one of the most common causes of syndromic cleft lip and/or palate accounting for 2% of all cases. Mutations in the IRF6 gene account for 70% of cases with the majority of these mutations located in the DNA-binding (exon 3, 4) or protein-binding domains (exon 7-9). The current study was designed to update the list of IRF6 variants reported for VWS by compiling all the published mutations from 2013 to date as well as including the previously unreported VWS cases from Africa and Puerto Rico. METHODS:We used PubMed with the search terms; "Van der Woude syndrome," "Popliteal pterygium syndrome," "IRF6," and "Orofacial cleft" to identify eligible studies. We compiled the CADD score for all the mutations to determine the percentage of deleterious variants. RESULTS:Twenty-one new mutations were identified from nine papers. The majority of these mutations were in exon 4. Mutations in exon 3 and 4 had CADD scores between 20 and 30 and mutations in exon 7-9 had CADD scores between 30 and 40. The presence of higher CADD scores in the protein-binding domain (exon 7-9) further confirms the crucial role played by this domain in the function of IRF6. In the new cases, we identified five IRF6 mutations, three novel missense mutations (p.Phe36Tyr, p.Lys109Thr, and p.Gln438Leu), and two previously reported nonsense mutations (p.Ser424*and p.Arg250*). CONCLUSION:Mutations in the protein and DNA-binding domains of IRF6 ranked among the top 0.1% and 1% most deleterious genetic mutations, respectively. Overall, these findings expand the range of VWS mutations and are important for diagnostic and counseling purposes.	0
INTRODUCTION:Exercise pulmonary hypertension is common in patients with chronic thromboembolic pulmonary hypertension (CTEPH) who experience shortness of breath during exercise and reduced exercise capacity despite normalised pulmonary arterial pressure (PAP) at rest; however, the relationship between exercise pulmonary hypertension and exercise capacity remains unclear. Here we aimed to determine whether exercise pulmonary hypertension is related to exercise capacity and ventilatory efficiency in CTEPH patients with normalised resting haemodynamics after pulmonary balloon angioplasty (BPA). PATIENTS AND METHODS:In total, 249 patients with CTEPH treated with BPA (mean±sd age 63±14 years; male:female 62:187) with normal mean PAP (mPAP) (<25 mmHg) and pulmonary arterial wedge pressure (≤15 mmHg) at rest underwent cardiopulmonary exercise testing with right heart catheterisation. mPAP-cardiac output (CO) during exercise was plotted using multipoint plots. Exercise pulmonary hypertension was defined by a mPAP-CO slope >3.0. RESULTS:At rest, pulmonary vascular resistance was significantly higher in the exercise pulmonary hypertension group (n=116) than in the non-exercise pulmonary hypertension group (n=133). Lower peak oxygen consumption (13.5±3.8 versus 16.6±4.7 mL·min-1·kg-1; p<0.001) was observed in the former group. The mPAP-CO slope was negatively correlated with peak oxygen consumption (r= -0.45, p<0.001) and positively correlated with the minute ventilation versus carbon dioxide output slope (r=0.39, p<0.001). CONCLUSIONS:Impaired exercise capacity and ventilatory efficiency were observed in patients with CTEPH who had normalised PAP at rest but exercise pulmonary hypertension.	0
Roberts syndrome (RBS; OMIM 268300) is a rare autosomal recessive disease characterized by retardation before and after birth, cranial and maxillofacial deformities, limb anomalies and intellectual disability. Mutations in the establishment of cohesion 1 homologue 2 (ESCO2) gene on chromosome 8p21.1 have been found to be causative for RBS. We describe two patients with RBS with physical deformities and ll. One is an 8-year-old Yemeni male, and the other is his 13-year-old sister. These patients were diagnosed with RBS and underwent surgeries during their first to third years of life. Here, we present the cases for the two patients, focusing specifically on their surgical management and outcomes. Additionally, by reviewing the literature on RBS, we also summarize the proper surgical interventions for this rare disease. This paper describes the long-term follow-up of two patients with severe deformities who benefitted from corrective surgeries. The findings of this study indicate that patients who survive infancy and reach adulthood, even patients who present with severe disease symptoms, can benefit from corrective surgeries and lead better lives.	0
The clinical, electrophysiological, histological and ultrastructural features of a patient with chronic spinal muscular atrophy of adolescent onset associated with hypertrophied calf-muscle are described. This recently recognised entity must be distinguished from other types of spinal muscular atrophy.	0
AIM:To describe beneficial effects of callosotomy on KCNQ2-related intractable epilepsy. CASE REPORT:Our patient was a 10-year-old girl who had developed epilepsy during the neonatal period, accompanied by a suppression-burst pattern on the electroencephalography (EEG). The patient showed profound psychomotor developmental delay since early infancy. Daily seizures of versive posturing and ocular deviation were transiently controlled by carbamazepine and valproate at the age of 1 year; however, the seizures gradually increased to up to 50 times per day. Ictal EEG and positron emission tomography revealed an epileptic focus in the left frontal lobe at age 5 years. Total callosotomy resulted in marked reduction of epileptic seizures thereafter, as well as improved responses to external auditory and visual stimuli. Whole exome sequencing at age 9 identified a de novo missense variant in KCNQ2 (NM_172107.3:c.563A > C:p.(Gln188Pro)). CONCLUSION:This case supports that epilepsy surgery could benefit children with epileptic encephalopathy, even with the etiology of channelopathy.	0
A 10-year-old boy with unilateral cryptorchidism and renal aplasia displayed features of unilateral congenital pupil sparing third cranial nerve palsy with exotropia manifesting novel dysinnervation encompassing synergistic divergence with upshoot, convergence on attempted upgaze, gaze-evoked phasic conjugate torsion, and gaze-evoked nystagmus. Congenital third nucleus/nerve hypoplasia with secondary dysinnervation is classfied as congenital cranial dysinnervation disorder (CCDD). It is speculated that miswiring between prenuclear structures, otolithic pathways, interstitial nucleus of Cajal (INC), nucleus prepositus hypoglossi, and third and sixth nerve nuclei likely resulted in this novel dysinnervation. Cryptorchidism and renal aplasia if seen may point towards an overlapping phenotype with Duane-radial ray syndrome and acro-renal-ocular/IVIC syndromes.	0
PURPOSE:To describe the clinical, laboratory, neuroimaging, electroencephalographic features, etiology, treatment, as well as short-term and long-term outcomes of adults with new-onset refractory status epilepticus (NORSE). METHOD:A retrospective, single institution cohort study (2010-2018) of consecutive adult patients with NORSE. RESULTS:Among 20 patients with NORSE, nine (45 %) had prodromal febrile illness, 12 (60 %) had evidence of inflammation on CSF profile. Six patients (30 %) met criteria for definite autoimmune encephalitis (AE) while 8 patients (40 %) had probable AE. Eleven out of 13 (85 %) patients had an abnormal FDG-PET scan with the most common finding being regional hypermetabolism. Fourteen patients (70 %) received immunotherapy and ten (50 %) received the ketogenic diet (KD). Fifteen patients (75 %) progressed to super-refractory status epilepticus (SRSE) and seven patients (35 %) died in the hospital or within six months of discharge. Among the surviving patients, eight (40 %) had a good outcome (i.e., modified Rankin Scale score 0-2); 12 (80 %) received a diagnosis of epilepsy of which nine (75 %) developed drug-resistant epilepsy. CONCLUSIONS:New-onset refractory status epilepticus is a syndrome associated with multiple complications, high mortality, and subsequent intractable epilepsy. There are multiple causes, some of which are autoimmune encephalitides; however, in this series the majority of patients had no clear etiology identified after extensive evaluation. Prospective studies are needed to determine optimal evaluation and treatment.	0
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized. cause of end-stage kidney disease, primarily due to mutations in UMOD and MUC1. The lack of clinical recognition and the small size of cohorts have slowed the understanding of disease ontology and development of diagnostic algorithms. To expand on this, we analyzed two registries from Europe and the United States to define genetic and clinical characteristics of ADTKD-UMOD and ADTKD-MUC1 and develop a practical score to guide genetic testing. Our study encompassed 726 patients from 585 families with a presumptive diagnosis of ADTKD along with clinical, biochemical, genetic and radiologic data. Collectively, 106 different UMOD mutations were detected in 216/562 (38.4%) of families with ADTKD (303 patients), and 4 different MUC1 mutations in 72/205 (35.1%) of the families that are UMOD-negative (83 patients). The median kidney survival was significantly shorter in patients with ADTKD-MUC1 compared to ADTKD-UMOD (46 vs. 54 years respectively), whereas the median gout-free survival was dramatically reduced in patients with ADTKD-UMOD compared to ADTKD-MUC1 (30 vs. 67 years respectively). In contrast to patients with ADTKD-UMOD, patients with ADTKD-MUC1 had normal urinary excretion of uromodulin and distribution of uromodulin in tubular cells. A diagnostic algorithm based on a simple score coupled with urinary uromodulin measurements separated patients with ADTKD-UMOD from those with ADTKD-MUC1 with a sensitivity of 94.1%, a specificity of 74.3% and a positive predictive value of 84.2% for a UMOD mutation. Thus, ADTKD-UMOD is more frequently diagnosed than ADTKD-MUC1, ADTKD subtypes present with distinct clinical features, and a simple score coupled with urine uromodulin measurements may help prioritizing genetic testing.	0
BACKGROUND:No specific or curative therapy exists for hereditary palmoplantar keratoderma (hPPK), which can profoundly alter patient quality of life, leading sometimes to severe functional impairment and pain. The rarity and the aetiological diversity of this group of disorders can explain the difficulty in comparing the efficacy of available treatments. OBJECTIVES:To review the different treatments tried in patients with hPPK since 2008, their efficacy and safety, with an evaluation of the various therapeutic modalities that can be used to treat hPPK. METHODS:We undertook a comprehensive review of the literature data published since 2008. RESULTS:Only a few case series and individual case reports were identified. Topical (emollients, keratolytics, retinoids, steroids) and systemic treatments (mostly different retinoids), often combined, are used to relieve symptoms. Oral retinoids appear to be the most efficient treatment, but not in all PPK forms, and with variable tolerance. New targeted treatments, according to the specific mechanisms of hPPK, appear promising for the future. CONCLUSIONS:More studies using robust methodology and involving larger cohorts of well-characterized patients (phenotype-genotype) are necessary and should be prioritized by structured networks, such as the European Network for Rare Skin Diseases (ERN-Skin), with the aim of better management of patients with rare skin diseases.	0
Progressive familial intrahepatic cholestasis (PFIC) is a chronic cholestasis syndrome that begins in infancy and usually progresses to cirrhosis within the first decade of life. There are three varieties of PFIC described: PFIC-1 occurs due to mutations in the ATP8B1 gene mapped to 18q21.31, PFIC-2 due to mutations in ABCB11 mapped to 2q24, and PFIC-3 due to mutations in ABCB4 located on 7q21.12. We report an Indian child whose mutation analysis was suggestive of PFIC-2. He underwent a biliary diversion at 3½ years of age but subsequently died secondary to massive hematemesis.	0
BACKGROUND:Sturge-Weber syndrome (SWS) is caused by a somatic mutation in GNAQ leading to capillary venous malformations in the brain presenting with various neurological, ophthalmic, and cognitive symptoms of variable severity. This clinical variability makes accurate prognosis difficult. We hypothesized that the greater extent of physical factors (extent of skin, eye, and brain involvement), presence of possible genetic factors (gender and family history), and age of seizure onset may be associated with greater symptom severity and need for surgery in patients with SWS. METHODS:The questionnaire was collected from 277 participants (age: two months to 66 years) with SWS brain involvement at seven US sites. RESULTS:Bilateral brain involvement was associated with both learning disorder and intellectual disability, whereas port-wine birthmark extent was associated with epilepsy and an increased likelihood of glaucoma surgery. Subjects with family history of vascular birthmarks were also more likely to report symptomatic strokes, and family history of seizures was associated with earlier seizure onset. Learning disorder, intellectual disability, strokelike episodes, symptomatic stroke, hemiparesis, visual field deficit, and brain surgery were all significantly associated with earlier onset of seizures. CONCLUSION:The extent of brain and skin involvement in SWS, as well as the age of seizure onset, affect prognosis. Other genetic factors, particularly variants involved in vascular development and epilepsy, may also contribute to neurological prognosis, and further study is needed.	0
Cav1.2 L-type calcium channels play key roles in long-term synaptic plasticity, sensory transduction, muscle contraction, and hormone release. De novo mutations in the gene encoding Cav1.2 (CACNA1C) causes two forms of Timothy syndrome (TS1, TS2), characterized by a multisystem disorder inclusive of cardiac arrhythmias, long QT, autism, and adrenal gland dysfunction. In both TS1 and TS2, the missense mutation G406R is on the alternatively spliced exon 8 and 8A coding for the IS6-helix of Cav1.2 and is responsible for the penetrant form of autism in most TS individuals. The mutation causes specific gain-of-function changes to Cav1.2 channel gating: a "leftward shift" of voltage-dependent activation, reduced voltage-dependent inactivation, and a "leftward shift" of steady-state inactivation. How this occurs and how Cav1.2 gating changes alter neuronal firing and synaptic plasticity is still largely unexplained. Trying to better understanding the molecular basis of Cav1.2 gating dysfunctions leading to autism, here, we will present and discuss the properties of recently reported typical and atypical TS phenotypes and the effective gating changes exhibited by missense mutations associated with long QTs without extracardiac symptoms, unrelated to TS. We will also discuss new emerging views achieved from using iPSCs-derived neurons and the newly available autistic TS2-neo mouse model, both appearing promising for understanding neuronal mistuning in autistic TS patients. We will also analyze and describe recent proposals of molecular pathways that might explain mistuned Ca2+-mediated and Ca2+-independent excitation-transcription signals to the nucleus. Briefly, we will also discuss possible pharmacological approaches to treat autism associated with L-type channelopathies.	0
BACKGROUND:The objective of this prospective, multidisciplinary and multicenter study was to explore the effect of a cleft lip, associated or not with a cleft palate, on parents, on parent-infant relationship, and on the baby's relational development. It also highlighted how the type of cleft and the timing of the surgery could impact this effect. METHOD:158 infants, with Cleft lip with or without Palate, and their parents participated in this multicenter prospective cohort. Clinical evaluations were performed at 4 and 12 months postpartum. The impact on the parents and on the parent-infant relationship was evaluated by the Parenting Stress Index (PSI), the Edinburgh Post-partum Depression Scale (EPDS) and the Impact-on-Family Scale (IOFS). The relational development of the infant was assessed using the Alarm Distress Baby Scale (ADBB). The main criteria used to compare the infants were the severity of cleft and the time of surgery. RESULTS:The timing of surgery, the type of malformation or the care structure had no effect on social withdrawal behaviors of the child at 4 and 12 months postpartum (ADBB). Furthermore, early intervention significantly decreased maternal stress assessed with the PSI at 4 months. Parents for whom it had been possible to give a prenatal diagnosis were much better prepared to accept the waiting time between birth and the first surgical intervention (IOFS). Higher postpartum depression scores (EPDS) were found for both parents compared to the general population. CONCLUSION:A joint assessment of the mental health of both infants and parents is required in the follow-up of cleft lip and palate. Even if most families are remarkably resilient faced with this major cause of stress, a significant proportion of them could require help to deal with the situation, especially during this first year of follow-up. An assessment of the child's social withdrawal behaviour and of the parental stress and depression appears useful, in order to adapt care to infant and parent's needs. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT00993993. Registered 10/14/2009 <.	0
The 8p inverted duplication/deletion is a rare chromosomal rearrangement clinically featuring neurodevelopmental delay, mild to severe cognitive impairment, heart congenital defects and brain abnormalities. Patients affected also present typical facial dysmorphisms and skeletal malformations, and it is thought that the composite clinical picture may fall into the chromosomal rearrangement architecture. With the major aim of better framing its related clinical and diagnostic paths, we describe a patient carrying a de novo invdupde[8p] whose clinical features have not been described so far. Hence, through an extensive genotype-phenotype correlation analysis and by reviewing the dedicated scientific literature, we compared our patient's features with those reported in other patients, which allows us to place our proband's expressiveness in an intermediate area, widening the scope of the already known invdupde[8p] genotype-phenotype relationship.	0
BACKGROUND:Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that is characterized by motor symptoms such as tremor, rigidity, slowness of movement and problems with gait. Large-scale meta-analyses of genome-wide association studies (GWAS) have identified few susceptibility loci in patients with sporadic PD. The aim of this study was to investigate the association between NMD3 single nucleotide polymorphism (SNP) and symptoms in PD patients in South China. METHODS:A total of 217 PD patients were recruited in this study and genotyped by using the SNaPshot technique and the polymerase chain reaction. All subjects were evaluated by the Mini-Mental State Examination (MMSE), Beijing version Montreal Cognitive Assessment (MoCA), Sniffin' Sticks 16 (SS-16), Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, 39-item Parkinson's Disease Questionnaire (PDQ-39) and MDS Unified PD Rating Scale (MDS-UPDRS). RESULTS:NMD3 rs34016896 (C > T) carriers have worse cognitive function than wild types (MMSE: p = 0.042, NMD3 wild type: 27.44 ± 2.89, NMD3 carriers: 26.31 ± 3.79; MoCA: p = 0.005, NMD3 wild type: 23.15 ± 4.20, NMD3 carriers: 20.75 ± 6.68). CONCLUSIONS:The recessive and overdominant model of NMD3 rs34016896 was associated with cognitive impairment in PD patients.	0
BACKGROUND:Myopia is a good model for understanding the interaction between genetics and environmental stimuli. Here we dissect the biological processes affecting myopia progression. METHODS:Human Genetic Analyses: (1) gene set analysis (GSA) of new genome wide association study (GWAS) data for 593 individuals with high myopia (refraction ≤ -6 diopters [D]); (2) over-representation analysis (ORA) of 196 genes with de novo mutations, identified by whole genome sequencing of 45 high-myopia trio families, and (3) ORA of 284 previously reported myopia risk genes. Contributions of the enriched signaling pathways in mediating the genetic and environmental interactions during myopia development were investigated in vivo and in vitro. RESULTS:All three genetic analyses showed significant enrichment of four KEGG signaling pathways, including amphetamine addiction, extracellular matrix (ECM) receptor interaction, neuroactive ligand-receptor interaction, and regulation of actin cytoskeleton pathways. In individuals with extremely high myopia (refraction ≤ -10 D), the GSA of GWAS data revealed significant enrichment of the HIF-1α signaling pathway. Using human scleral fibroblasts, silencing the key nodal genes within protein-protein interaction networks for the enriched pathways antagonized the hypoxia-induced increase in myofibroblast transdifferentiation. In mice, scleral HIF-1α downregulation led to hyperopia, whereas upregulation resulted in myopia. In human subjects, near work, a risk factor for myopia, significantly decreased choroidal blood perfusion, which might cause scleral hypoxia. INTERPRETATION:Our study implicated the HIF-1α signaling pathway in promoting human myopia through mediating interactions between genetic and environmental factors. FUNDING:National Natural Science Foundation of China grants; Natural Science Foundation of Zhejiang Province.	0
BACKGROUND:Primary hypoparathyroidism (HPT) is rarely seen in the clinic, and it can be combined with rhabdomyolysis. There are few reports about this phenomenon. Therefore, it is significant to explore the etiology that is conducive to early diagnosis, timely treatment, and preventing the recurrence. CASE SUMMARY:A 63-year-old man was admitted to our hospital with a severe upper respiratory tract infection and progressing decreased myodynamia of the lower limbs. Blood tests showed creatine kinase > 32000 U/L, creatinine 207.8 µmol/L, calcium 1.28 mmol/L, myoglobin 558.7 ng/mL, and parathyroid hormone 0 pg/mL. He was diagnosed with primary HPT with rhabdomyolysis, and severe upper respiratory tract infection was considered to be the initial trigger. He responded well to supplementation of intravenous calcium gluconate and oral calcium as well as bedside hemodialysis, fluid hydration, infection control, protecting the liver, etc. Creatine kinase, myoglobin, and serum calcium returned to normal, and muscle strength improved significantly. Symptoms improved after symptomatic treatment. CONCLUSION:Severe infection should be prevented, which is the key cause of rhabdomyolysis in patients with HPT.	0
Allan-Herndon-Dudley syndrome (AHDS) is a rare, X-chromosome-linked inherited disorder that affects brain development and is caused by a mutation in SLC16A2. Herein, we generated an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells of a one-year-old male infant with AHDS using Sendai-virus-mediated reprogramming. These iPSCs exhibited stable amplification, expressed pluripotent markers, and differentiated spontaneously into three germ layers in vitro. Additionally, this iPSC line was found to maintain a normal karyotype and retain the pathogenic mutation in SLC16A2, facilitating the study of disease mechanisms and development of new therapies of AHDS.	0
Discovered by Louis Pasteur in 1880, Pasteurella multocida is the most common cause of zoonotic infection in humans which is transmitted via pet bites and/or scratches. However, animal contact may be absent or not identified in up to 40% of cases which usually occur in individuals with comorbidities. Despite having a low virulence, PM can cause serious and life threatening infections in rare instances. In such cases, prompt diagnosis and appropriate treatment can lead to miraculous recovery.	0
Graft-versus-host disease (GVHD) is a major complication of bone marrow transplantation. Polymyositis with myonecrosis is a rare manifestation of GVHD. Here, we report the case of a 32-year-old man with acute myeloid leukemia who developed GVHD after transplant. He subsequently developed polymyositis, which was diagnosed on PET/CT and confirmed on pathology. Treatment with corticosteroids resulted in the resolution of the symptoms. Abnormal muscular FDG uptake resolved on the follow-up PET/CT.	0
BACKGROUND:Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) for intrahepatic cholangiocarcinoma (ICC) demonstrated good long-term outcomes1 and can increase the rate of resectability in locally advanced ICC;2 however, the rates of postoperative complications (Clavien-Dindo grade III) and mortality range between 13.6 and 44% and 0 and 29%, respectively.3 Minimally invasive strategies may reduce the risk of postoperative morbidity, with the same oncologic outcomes.4,5 We report the first case of full robotic ALPPS for advanced ICC. METHODS:The patient was a 61-year-old male diagnosed with a 6.5 cm ICC involving segments IV, V, and VIII. The total clean liver volume was 1553 cc3, with a future liver remnant (FLR) volume of 21.6% (segments I, II, and III: 337 cc3). The procedure was performed by a senior hepato-pancreato-biliary (HPB) surgeon at the robotic console and a junior HPB surgeon at the table side. RESULTS:Computed tomography scan on postoperative day (POD) 9 after stage 1 showed that FLR increased up to 38%. The indocyanine green clearance test showed a plasma disappearance rate of 19.8%/min and a retention rate at 15 min of 5.1%; complete blood tests are available at the end of the video. ALPPS was completed on POD 14, the postoperative course was uneventful, and the patient was discharged in good general condition on POD 5. Final pathology showed a 6 cm ICC, G3, R0 margin (10 mm), T2-N0-M0. The patient started adjuvant capecitabine, and after 6 months was in good general condition without signs of local or systemic recurrence. CONCLUSIONS:Robotic ALPPS combines the opportunity to perform a curative resection in patients presenting with insufficient FLR with the advantages of a minimally invasive approach. It is feasible and oncologically accurate for ICC when performed in fully trained HPB centers.	0
Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, due to impaired protein and lipid glycosylation. We identified two patients with defective serum transferrin glycosylation and mutations in the MAGT1 gene. These patients present with a phenotype that is mainly characterized by intellectual and developmental disability. MAGT1 has been described to be a subunit of the oligosaccharyltransferase (OST) complex and more specifically of the STT3B complex. However, it was also claimed that MAGT1 is a magnesium (Mg2+) transporter. So far, patients with mutations in MAGT1 were linked to a primary immunodeficiency, characterized by chronic EBV infections attributed to a Mg2+ homeostasis defect (XMEN). We compared the clinical and cellular phenotype of our two patients to that of an XMEN patient that we recently identified. All three patients have an N-glycosylation defect, as was shown by the study of different substrates, such as GLUT1 and SHBG, demonstrating that the posttranslational glycosylation carried out by the STT3B complex is dysfunctional in all three patients. Moreover, MAGT1 deficiency is associated with an enhanced expression of TUSC3, the homolog protein of MAGT1, pointing toward a compensatory mechanism. Hence, we delineate MAGT1-CDG as a disorder associated with two different clinical phenotypes caused by defects in glycosylation.	0
Almost one decade ago, etoposide, doxorubicin, cisplatin and mitotane (EDP-M) has been established as first-line systemic therapy of metastatic adrenocortical carcinoma (ACC). Although heterogeneous, the prognosis of advanced stage ACC is still poor and novel treatments are urgently needed. This article provides a short summary of current systemic ACC treatment and provides a comprehensive overview of new therapeutic approaches that have been investigated in the past years, including drugs targeting the IGF pathway, tyrosine kinase inhibitors, radionuclide treatment, and immunotherapy. The results of most of these trials were disappointing and we will discuss possible reasons why these drugs failed (e.g. drug interactions with mitotane, disease heterogeneity with exceptional responses in very few patients, and resistance mechanisms to immunotherapy). We then will present potential new drug targets that have emerged from many molecular studies (e.g. wnt/β-catenin, cyclin-dependent kinases, PARP1) that may be the foundation of next-generation therapies of ACC.	0
The oromandibular limb hypogenesis syndrome is a group of anomalies affecting the mandible, tongue, and maxilla with or without reductive limb anomalies. It was first described by Hanhart in 1950. In severe syndromic cases of mandibular hypoplasia, a number of techniques have been described for mandibular advancement including sagittal split osteotomies, segmental osteotomies, or distraction osteogenesis just to name a few. A 25-year-old male patient presented to our clinic with symptoms including difficulty in speech and eating, disability in opening the mouth, together with hand and foot abnormalities; we want to describe a modification in the technique of mandibular advancement and the patient's late postoperative results. The design of the step osteotomy is modified by softening the angles of the steps and elongating the horizontal segment of the step to approximately 25 mm to allow for a more efficient advancement of the mandible. The postoperative period was uneventful, with no signs of inferior alveolar nerve disturbance. The patient showed an increase of the mouth opening distance immediately after surgery. We believe that this tongue-in-groove-like modified mandibular step osteotomy technique is a good alternative in patients where advancement greater than 15 mm is required, preserving the nerve and achieving solid bony intact surfaces.	0
OBJECTIVE:Bardet-Biedl syndrome is a genetic, multisystem disorder that causes severe visual impairment. This condition is characterized by retinal dystrophy, obesity, digit anomalies, renal disease, and hypogonadism. The purpose of this study was to analyze visual acuity and full-field electroretinogram findings in patients with the Bardet-Biedl syndrome phenotype. METHODS:The visual acuity of a group of 23 patients (15 males) with ages ranging from 6-36 years (mean = 15.8 ± 6.4; median = 14.7) was assessed. Retinal function was evaluated by full-field electroretinography, and dark-adapted thresholds were assessed. RESULTS:Visual acuity in the better-seeing eye was 20/40 or better in 5 patients (21.7%), 20/50-20/150 in 13 (56.5%) patients, 20/200-20/400 in 2 (8.7%) patients and worse than 20/400 in one (4.3%) patient. The mean acuity in the better-seeing eye was 0.7 ± 0.6 logMAR (20/100, Snellen equivalent). Scotopic rod and maximal responses were nondetectable in 21 (91.3%) patients, and cone responses were non-detectable in 15 (65.2%) patients. Elevated dark-adapted visual thresholds were observed in all 19 patients who were able to be assessed, with 10 (52.6%) patients having thresholds greater than 30 dB. CONCLUSIONS:In a relatively young cohort of patients with Bardet-Biedl syndrome, only 21% had 20/40 or better vision. ERG scotopic responses were absent in the majority of cases, with cone responses being observed in less than half of cases. These findings showed the early deleterious effects in retinal function and visual acuity caused by this condition.	0
Mesenchymal hamartoma is a benign tumor of the liver with a poorly understood pathogenesis. It is uncommon in older children, especially after 2 years of age. The signs and symptoms may be nonspecific; therefore, a high index of suspicion is required for diagnosis and treatment. We report a 5-year-old previously healthy male who presented with acute abdominal pain, fatigue, and fever. He was diagnosed with pneumonia initially and treated with antibiotics. A computed tomography (CT) scan done for evaluation of his persistent abdominal pain demonstrated a hepatic mass. Follow-up magnetic resonance imaging (MRI) of the liver demonstrated multiple serpiginous tubular-type structures, read as possible Caroli syndrome. He had a normal abdominal examination and normal biochemistries including alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, and alpha-fetoprotein. He was referred to our institution for second opinion. On further review of his imaging studies, the lesion was thought to be a mesenchymal hamartoma. He subsequently underwent resection of the mass. Pathology confirmed the diagnosis of mesenchymal hamartoma.	0
A rare syndrome was first described in 1997 in a 17-year-old male patient presenting with Retinitis pigmentosa, HYpopituitarism, Nephronophthisis and Skeletal dysplasia (RHYNS). In the single reported familial case, two brothers were affected, arguing for X-linked or recessive mode of inheritance. Up to now, the underlying genetic basis of RHYNS syndrome remains unknown. Here we applied whole-exome sequencing in the originally described family with RHYNS to identify compound heterozygous variants in the ciliary gene TMEM67. Sanger sequencing confirmed a paternally inherited nonsense c.622A > T, p.(Arg208*) and a maternally inherited missense variant c.1289A > G, p.(Asp430Gly), which perturbs the correct splicing of exon 13. Overall, TMEM67 showed one of the widest clinical continuum observed in ciliopathies ranging from early lethality to adults with liver fibrosis. Our findings extend the spectrum of phenotypes/syndromes resulting from biallelic TMEM67 variants to now eight distinguishable clinical conditions including RHYNS syndrome.	0
Diagnosis of bone marrow failure (BMF) disorders is challenging but essential for optimal patient management. Here, we report a young adult from nonconsanguineous parents with progressive pancytopenia since childhood, bone pain, increased bone density, and haphazard ossification replacing hematopoiesis within the bone marrow. Sequencing revealed two novel biallelic variants of unknown significance within the thromboxane A synthase gene, TBXAS1 (c.266T > C; c.989T > C), bioinformatically predicted to disrupt the protein. TBXAS1 mutations result in Ghosal hematodiaphyseal dysplasia (OMIM 231095), the autosomal recessive syndrome associated with abnormal bone structure and BMF. Identification of the genetic defect prompted steroid therapy leading to resolution of symptoms.	0
Hyperechogenic bowel (HB) is a nonspecific ultrasound finding that can be associated with human cytomegalovirus (CMV) congenital infection. In this study, we investigated HB pathophysiology in CMV-infected fetuses. We examined small and large intestine as well as pancreas in 8 fetuses at 22 weeks of gestation with congenital CMV infection. Ultrasound findings showed 4 fetuses with HB and 4 without. As negative group, 4 fetuses without CMV infection and without HB were studied. Immunohistochemistry for CMV, lymphocytic infiltrate, B-cell leukemia/lymphoma-2 (bcl-2), CD-117, cystic fibrosis transmembrane regulator (CFTR) were performed. HB fetuses showed multiple and sequential CMV-positive ganglion cells of Auerbach's myenteric plexus. In the ganglia, bcl-2 was weakly expressed representing a reduced neuronal functionality. CD-117 revealed a regular distribution of Cajal cells, the pacemakers of intestinal contractility. Pancreas showed normal CFTR staining, indicating a preserved exocrine secretion, thus unlikely a contributory factor in HB. In CMV-infected fetuses without HB, CMV-positive cells were scatteredly found in ganglion cells and bcl-2 was strongly expressed. Intestinal CD-117 and pancreatic CFTR expression were similar to fetuses with HB. In conclusion, fetal CMV infection of the bowel may lead to peristalsis impairment (paralytic ileus) due to intestinal plexus involvement, which at ultrasound appeared as HB.	0
The H3 subtype of avian influenza virus (AIV) is widespread in avian species and is frequently isolated in surveillance projects; thus, we have developed a more effective diagnostic approach of a monoclonal antibody (mAb)-based sandwich ELISA for the H3 AIV detection. First, we have produced the essential reagent of mAb against AIV H3 strains with the development of an mAb-Mouse immunization with a purified H3-subtype AIV strain and cell fusion to generate hybridoma cells. These cells were screened with hemagglutination inhibition (HI) tests, and optimal cells were subcloned. We chose a hybridoma cell line that steadily secreted a specific H3-subtype AIV mAb, designated 9F12, that belongs to the IgG1 subclass and has a K-type light chain. 9F12 was shown to bind specifically to the H3-subtype AIV antigen by both immunofluorescence assay and Western blot analysis. Finally, a 9F12-based sandwich ELISA was successfully developed and used to specifically test for this antigen. The sandwich ELISA conditions were optimized, and the specificity and sensitivity were validated. The results for clinical sample detection were consistent with viral isolation. Consequently, the 9F12-based sandwich ELISA is a specific, sensitive, robust, rapid and versatile diagnostic tool for H3-subtype AIV and provides a promising strategy for effective influenza virus prevention and control.	0
Objective:We systematically evaluated CNS manifestations in patients with inherited telomere biology disorders (TBDs) to better understand the clinical and biological consequences of germline aberrations in telomere biology. Methods:Forty-four participants with TBDs (31 dyskeratosis congenita, 12 Hoyeraal-Hreidarsson syndrome, and 1 Revesz syndrome) enrolled in an institutional review board-approved longitudinal cohort study underwent detailed clinical assessments, brain MRI, and genetic testing. Lymphocyte telomere length Z-scores were calculated to adjust for age. Results:In this cohort, 25/44 (57%) patients with a TBD had at least 1 structural brain abnormality or variant, most commonly cerebellar hypoplasia (39%). Twenty-one patients (48%) had neurodevelopmental disorder or psychomotor abnormality. Twelve had psychiatric diagnoses, including depression and/or anxiety disorders. Other findings such as hypomyelination, prominent cisterna magna, and cavum septum pellucidum were more frequent than in the general population (p < 0.001). Shorter lymphocyte telomere length was associated with an increased number of MRI findings (p = 0.02) and neurodevelopmental abnormalities (p < 0.001). Patients with autosomal recessive or X-linked TBDs had more neurologic findings than those with autosomal dominant disease. Conclusions:Structural brain abnormalities and variants are common in TBDs, as are neurologic and psychiatric symptoms. The connection between neurodevelopment and telomere biology warrants future study.	0
GM1-gangliosidosis, a lysosomal storage disorder, is associated with ~ 161 missense variants in the GLB1 gene. Affected patients present with β-galactosidase (β-Gal) deficiency in lysosomes. Loss of function in ER-retained misfolded enzymes with missense variants is often due to subcellular mislocalization. Deoxygalactonojirimycin (DGJ) and its derivatives are pharmaceutical chaperones that directly bind to mutated β-Gal in the ER promoting its folding and trafficking to lysosomes and thus enhancing its activity. An Emirati child has been diagnosed with infantile GM1-gangliosidosis carrying the reported p.D151Y variant. We show that p.D151Y β-Gal in patient's fibroblasts retained < 1% residual activity due to impaired processing and trafficking. The amino acid substitution significantly affected the enzyme conformation; however, p.D151Y β-Gal was amenable for partial rescue in the presence of glycerol or at reduced temperature where activity was enhanced with ~ 2.3 and 7 folds, respectively. The butyl (NB-DGJ) and nonyl (NN-DGJ) derivatives of DGJ chaperoning function were evaluated by measuring their IC50s and ability to stabilize the wild-type β-Gal against thermal degradation. Although NN-DGJ showed higher affinity to β-Gal, it did not show a significant enhancement in p.D151Y β-Gal activity. However, NB-DGJ promoted p.D151Y β-Gal maturation and enhanced its activity up to ~ 4.5% of control activity within 24 h which was significantly increased to ~ 10% within 6 days. NB-DGJ enhancement effect was sustained over 3 days after washing it out from culture media. We therefore conclude that NB-DGJ might be a promising therapeutic chemical chaperone in infantile GM1 amenable variants and therefore warrants further analysis for its clinical applications.	0
Virus-associated hemophagocytic syndrome (VAHS) in the neonatal period has a high mortality. Although clear diagnostic criteria and treatment methods have not been established, early diagnosis and treatment are critical. However, treatments for VAHS have potentially serious side effects, especially during the neonatal period. Echovirus type 7 can cause maternal infection around parturition and be vertically transmitted to the neonate and induce VAHS. Intravenous immunoglobulin (IVIG) therapy could be a first-line therapy for neonatal VAHS, so that treatments with potentially serious side effects, including cyclosporine A and etoposide, could be avoided. A case of VAHS associated with echovirus type 7 that was successfully treated with IVIG therapy is reported.	0
We present a case of a 38+1 weeks pregnant patient (G1P0) with a proven COVID-19 infection, who was planned for induction of labour because of pre-existent hypertension, systemic lupus erythematosus, respiratory problem of coughing and mild dyspnoea without fever during the COVID-19 pandemic in March 2020. To estimate the risk of vertical transmission of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) during labour and delivery, we collected oropharyngeal, vaginal, urinary, placental and neonatal PCRs for SARS-CoV-2 during the period of admission. All PCRs, except for the oropharyngeal, were negative and vertical transmission was not observed. Labour and delivery were uncomplicated and the patient and neonate were discharged the next day. We give a short overview of the known literature about SARS-CoV-2-related infection during pregnancy, delivery and outcome of the neonate.	0
We studied 28 Polish hereditary fructose intolerant (HFI) patients (26 unrelated) by direct sequencing of the ALDOB coding region/splice sites. Eight different mutations were found including two novel ones (each found in two unrelated individuals): c.250delC (frameshift) and c.522 C > G (p.Y174X). The most frequent mutation c.448 G > C (p.A150P, 67% of chromosomes) was screened for in a group of 1049 randomly selected unrelated individuals. Eight (1:131) carriers were found allowing to estimate the HFI prevalence in Poland as 1:31,000.	1
BACKGROUND:Noonan syndrome is an autosomal dominant disorder secondary to RASopathies, which are caused by germ-line mutations in genes encoding components of the RAS mitogen-activated protein kinase pathway. RIT1 (OMIM *609591) was recently reported as a disease gene for Noonan syndrome. METHODS AND RESULTS:We present a patient with RIT1-associated Noonan syndrome, who in addition to the congenital heart defect, had monocytosis, myeloproliferative disorder, and accelerated idioventricular rhythm that was associated with severe hemodynamic instability. Noonan syndrome was suspected given the severe pulmonary stenosis, persistent monocytosis, and "left-shifted" complete blood counts without any evidence of an infectious process. Genetic testing revealed that the patient had a heterozygous c.221 C>G (pAla74Gly) mutation in the RIT1. CONCLUSION:We report a case of neonatal Noonan syndrome associated with RIT1 mutation. The clinical suspicion for Noonan syndrome was based only on the congenital heart defect, persistent monocytosis, and myeloproliferative process as the child lacked all other hallmarks characteristics of Noonan syndrome. However, the patient had an unusually malignant ventricular dysrhythmia that lead to his demise. The case highlights the fact that despite its heterogeneous presentation, RIT1-associated Noonan syndrome can be extremely severe with poor outcome.	0
Branchio-oculo-facial syndrome (BOFS), a rare, multiple-malformation congenital disorder, is characterized by facial anomalies, including associated cutaneous and ocular abnormalities. We report a new case of BOFS in an 11-year-old male child with bilateral cervical erythematous scaly linear plaque associated with scar formation and erosion. Although BOFS is very rare, physicians, especially dermatologists, should be aware of the cutaneous and histopathological features of BOFS due to impacts of the associated anomalies.	0
A 9-year old country boy developed blepharitis with inflammation of the face and, 1 month later, eosinophilic meningitis with paralysis of 3 limbs and of an abducent nerve. Nuclear magnetic resonance imaging of the central nervous system disclosed a lesional signal beneath the floor of the 4th ventricle, which was compatible with the presence of a larva of fly. Treatment with thiabendazole was tried, and the clinical signs regressed. Six months later, an asymmetrical hydrocephalus due to obstruction of Monroe's foramen by an inflammatory granuloma was discovered. Human hypodermyasis, due to migration in tissues of larvae of flies, is not rare in cattle-breeding areas. Neuromeningeal disorders are observed in 12% of the cases, consisting of eosinophilic meningitis sometimes associated with neurological deficit or seizures. Such complications as intracerebral haematoma or meningeal haemorrhage may occur during the usually benign course of the disease.	0
AIMS:Citrin is an aspartate/glutamate carrier that composes the malate-aspartate reduced nicotinamide adenine dinucleotide (NADH) shuttle in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), failure to thrive and dyslipidemia (FTTDCD) and adult-onset type II citrullinemia (CTLN2). Hepatic glycolysis is essentially impaired in citrin deficiency and a low-carbohydrate diet was recommended. The lethal effect of infusion of glycerol- and fructose-containing osmotic agents was reported in these patients. Hyperalimentation was also reported to exacerbate CTLN2; however, glucose toxicity was unclear in citrin deficiency. METHODS:We studied two CTLN2 patients complicated with type 2 diabetes mellitus (DM), Case 1 presented with hyperammonemic encephalopathy accompanied with DM, while Case 2 presented with hyperammonemic encephalopathy relapse upon the onset of DM after several years' remission following supplementation with medium-chain triglycerides (MCT) and adherence to a low-carbohydrate diet. RESULTS:Insulin therapy with MCT supplementation and a low-carbohydrate diet improved hyperammonemia and liver function in Case 1. Additional insulin therapy improved hyperammonemia in Case 2. CONCLUSION:Glucose is not toxic for citrin deficiency in normoglycemia because glucose uptake and metabolism by hepatocytes are limited in normoglycemia. However, glucose becomes toxic during persistent hyperglycemia and antidiabetic therapy is indispensable for CTLN2 patients with DM.	0
José María ("Chema") Cantú (1938-2007), born in Mexico, was a pioneering, loved and respected leader in medical and human genetics and bioethics in Latin America. He graduated as a physician in Mexico and then trained in medical and human genetics in France and the United States. He was instrumental in developing a first-rate research, training and genetic services program in medical and human genetics in Guadalajara, in northwestern Mexico. He acted forcefully at national, regional and international levels to promote scientific development through collaboration and education in science and humanities, while he simultaneously strived for justice, peace, love and human rights. He attained some of the highest honors a scientist and humanist could aspire to as well as the recognition of the communities he served. Hundreds of disciples throughout Latin America and the world have been inspired by his vision of a better world through the conjunction of science, respect for humankind, ethics and love.	0
Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide.	0
We describe additional phenotypic features in a boy and his mother. Both manifested the phenotypic/genotypic correlation of oto-palato-digital syndrome type II. The mother's radiographs showed wormian bones of the skull, and paranasal bossing, her feet showed bilateral fusion of the cuboid with the lateral cuneiform bone with subsequent development of metatarsus varus associated with dysplastic distal phalanges.	0
As the leading cause of impaired vision, congenital cataracts, particularly autosomal dominant congenital cataract (ADCC), have been considered as a hereditary disease. The present study aimed to identify genetic defects in Chinese pedigrees with ADCC. A total of 6 Chinese families with ADCC were included, comprising 103 members and 27 patients assessed in total. Genomic DNA samples were extracted from the peripheral blood of probands; mutations were determined using a specific eye disease enrichment panel with next-generation sequencing. Following pathogenicity prediction, sites with notable pathogenicity were screened for further validation. Sanger sequencing was performed in the remaining individuals of the families and 100 normal controls. The pathogenic effects of the mutations, including amino acid substitutions, as well as structural and functional alterations of proteins linked to ADCC, were investigated via bioinformatics analysis. A total of seven mutations in six candidate genes associated with ADCC were identified in the 6 families: Myosin heavy chain 9 (MYH9) c.4150G>C, β-crystallin A4 (CRYBA4) c.169T>C, RPGR-interacting protein 1 (RPGRRIP1) c.2669G>A, wolframin (WFS1) c.1235T>C, CRYBA4 c.26C>T, Ephrin receptor subfamily 2 (EPHA2) c.2663+1G>A and paired box 6 (PAX6) c.11-2A>G. The seven mutations were only detected in affected individuals. Among them, there were three novel mutations (MYH9: c.4150G>C; CRYBA4: c.169T>C; RPGRRIP1: c.2669G>A) and four previously reported ones. Mutations in RPGRIP1 (c.2669G>A) and CRYBA4 (c.26C>T) were predicted to be benign according to bioinformatics analysis. Conversely, other mutations in EPHA2, PAX6, MYH9, CRYBA4 (c.169T>C) and WFS1 were determined to be pathogenic. The present study reported two novel heterozygous mutations (MYH9 c.4150G>C and CRYBA4 c.169T>C) identified by analyzing 6 Chinese families with ADCC, supporting their important roles in the development of the disease.	0
BACKGROUND:Hereditary spastic paraplegia is a heterogeneous group of clinically and genetically neurodegenerative diseases characterized by progressive gait disorder. Hereditary spastic paraplegia can be inherited in various ways, and all modes of inheritance are associated with multiple genes or loci. At present, more than 76 disease-causing loci have been identified in hereditary spastic paraplegia patients. Here, we report a novel mutation in SPAST gene associated with hereditary spastic paraplegia in a Chinese family, further enriching the hereditary spastic paraplegia spectrum. METHODS:Whole genomic DNA was extracted from peripheral blood of the 15 subjects from a Chinese family using DNA Isolation Kit. The Whole Exome Sequencing of the proband was analyzed and the result was identified in the rest individuals. RaptorX prediction tool and Protein Variation Effect Analyzer were used to predict the effects of the mutation on protein tertiary structure and function. RESULTS:Spastic paraplegia has been inherited across at least four generations in this family, during which only four HSP patients were alive. The results obtained by analyzing the Whole Exome Sequencing of the proband exhibited a novel disease-associated in-frame deletion in the SPAST gene, and this mutation also existed in the rest three HSP patients in this family. This in-frame deletion consists of three nucleotides deletion (c.1710_1712delGAA) within the exon 16, resulting in lysine deficiency at the position 570 of the protein (p.K570del). This novel mutation was also predicted to result in the synthesis of misfolded SPAST protein and have the deleterious effect on the function of SPAST protein. CONCLUSION:In this case, we reported a novel mutation in the known SPAST gene that segregated with HSP disease, which can be inherited in each generation. Simultaneously, this novel discovery significantly enriches the mutation spectrum, which provides an opportunity for further investigation of genetic pathogenesis of HSP.	0
BACKGROUND:Joubert syndrome and related disorders are a group of ciliopathies characterized by mid-hindbrain malformation, developmental delay, hypotonia, oculomotor apraxia, and breathing abnormalities. Molar tooth sign in brain imaging is the hallmark for diagnosis. Joubert syndrome is a clinically and genetically heterogeneous disorder involving mutations in 35 ciliopathy-related genes. We present a large cohort of 59 patients with Joubert syndrome from 55 families. Molecular analysis was performed in 35 families (trio). METHODS:Clinical exome analysis was performed to identify causal mutations, and genotype-phenotype correlations were evaluated. RESULTS:All of the cases were stratified into pure Joubert syndrome (62.7%), Joubert syndrome with retinal disease (22.0%), polydactyly (8.5%), and liver (1.7%) and kidney (1.7%) involvement. Joubert syndrome-related disorders include Meckel-Gruber syndrome in 5.1% cases and Leber congenital amaurosis (1.7%). Of the 35 Joubert syndrome-related genes, 11 were identified in these patients, i.e., CEP290, C5ORF, TCTN1, CC2D2A, RPGRP1L, TCTN3, AHI1, INPP5E, TCTN2, NPHP1, and TMEM237. For the first time, we identified a ciliopathy gene, CCDC28B, as a causal gene in Joubert syndrome in one family. CEP290 accounted for 37.8% cases of pure Joubert syndrome, Joubert syndrome with retinal and renal disease, and Meckel-Gruber syndrome. The p.G1890∗ allele in CEP290 is highly recurrent. Of the six families with Joubert syndrome who had a prenatal diagnosis, one fetus was normal, two were carriers, and three were affected. CONCLUSIONS:This is the largest study of Joubert syndrome from India. Although a high degree of locus and allelic heterogeneity was observed, CEP290 variants were the most common among these patients.	0
Thyroid storm (TS) is a rare hyperthyroidism associated multisystem decompensation and can mimic a systemic inflammatory response syndrome. It is diagnosed in the presence of fever with cardiovascular, central nervous system, and gastrointestinal complications. Only a few reports of acute flaccid quadriplegic thyrotoxic myopathy (TM) with TS have been reported. However, muscle magnetic resonance imaging (MRI) findings in TM have not been yet been reported. Our patient underwent muscle MRI and showed some unusual features. These are discussed in this article.	0
BACKGROUND:Numerous studies have shown visuoperceptual/visuospatial deficits in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). Visual texture recognition is also impaired in patients with DLB and AD. Although patients with DLB often exhibit visual misidentifications of objects, there are few studies on the relationships between visual texture recognition and viewpoints for object recognition. OBJECTIVES:The aim of this study was to clarify how viewpoints, textures, and visual cognitive functions affect object recognition and result in visual misidentifications in patients with DLB or AD. METHODS:A total of 37 patients with probable DLB and 58 with probable AD and 32 age-matched healthy controls underwent neuropsychological and visuoperceptual assessments, and performed object identification tasks under four conditions (non-canonical view + blurry texture, non-canonical view + clear texture, canonical view + blurry texture, canonical view + clear texture). The relationship between object identification and other visuoperceptual functions was analyzed. RESULTS:Patients with DLB and AD exhibited significantly impaired object recognition under non-canonical viewing with blurry texture conditions, with the DLB patients exhibiting a significantly worse performance than the AD patients. Patients with DLB and AD exhibited visual misidentifications during object identification tasks under non-canonical viewing. In patients with DLB, the number of visual misidentifications was significantly correlated with the scores of visual texture recognition. CONCLUSIONS:The present study showed that significantly impaired object recognition in patients with DLB under the influences by both viewpoint and visual texture and in those with AD under the influence by viewpoint. Visual misidentification in object recognition could be associated with impaired visual texture recognition in DLB.	0
Glycogen storage disease type IV (GSD IV) is a rare inborn metabolic disorder characterized by the accumulation of amylopectin-like glycogen in the liver or other organs. The hepatic subtype may appear normal at birth but rapidly develops to liver cirrhosis in infancy. Liver pathological findings help diagnose the hepatic form of the disease, supported by analyses of enzyme activity and GBE1 gene variants. Pathology usually shows periodic acid-Schiff (PAS) positive hepatocytes resistant to diastase. We report two cases of hepatic GSD IV with pathology showing PAS positive hepatocytes that were mostly digested by diastase, which differ from past cases. Gene analysis was critical for the diagnosis. Both cases were found to have the same variants c.288delA (p.Gly97GlufsTer46) and c.1825G > A (p.Glu609Lys). These findings suggest that c.1825G > A variant might be a common variant in the non-progressive hepatic form of GSD IV.	0
Objectives: The Chudley-McCullough Syndrome (CMS) is a rare autosomal-recessively inherited disorder caused by mutations in the GPSM2 gene, characterised by deafness and brain anomalies. The purpose of this paper is to report about a case of cochlear implant (CI) procedure in a subject affected by CMS. Methods: A 31-year-old subject affected by CMS referred to our centre requiring an evaluation for a CI, as the results with her hearing aids, which she had been using since she was 2-years-old, were unsatisfactory. A profound bilateral sensorineural hearing loss was pointed out. Pure tone audiometry in free field with hearing aids and speech perception results were poor. The subject was counselled about the surgical procedure and the surgery was performed with no complications. Results: The cochlear implant was switched on 22 days after surgery and the subject began speech therapy training. After 1 year, hearing and speech perception results were satisfactory. The hearing threshold in free field with the CI was around 30 dB, and the open set speech perception score reached 55% in silence. Conclusions: The reported case demonstrates that CI is a feasible and safe procedure in subjects with CMS. Furthermore, since satisfactory hearing and speech perception results were achieved we recognise that cochlear implant should be considered the best option for hearing restoration in subjects with CMS and profound sensorineural hearing loss.	0
Cutis laxa (CL) is a rare connective tissue disease characterized by a loose, wrinkled, and inelastic skin. Here, we report an unusual presentation in a 15-year-old male patient who is a known patient of CL who presented with bilateral pneumothorax. He was successfully managed initially by chest tube insertion and then he was treated surgically with bilateral staged thoracoscopy, apical bullectomy, and pleurodesis with full uneventful recovery.	0
Gnathodiaphyseal Dysplasia (GDD) is a rare, often misdiagnosed, autosomal-dominant disorder due to point mutations in the ANO5 gene. GDD combines craniofacial fibro-osseous lesions, dental loss and progressive curvature and cortical thickening of long bones and vertebra, causing pathological fractures. Diagnosis is based on bone pathology and mutation screening. Here we report three GDD cases within a single family with a novel ANO5 mutation: c.1790 G > T (p.Arg597Ile, i.e. R597I) on exon 16. Microsurgical mandibular reconstructions were performed in the three cases. We reviewed the literature on jaw reconstruction in this condition and discussed the challenges of craniofacial reconstruction in GDD due to the diffuse bone anomalies affecting potential flap donor zones and a specific risk for jawbone osteomyelitis.	0
The identification of rare disease-causing variants in humans by large-scale next-generation sequencing (NGS) studies has also provided us with new insights into the pathophysiological role of de novo missense variants in the CACNA1D gene that encodes the pore-forming α1-subunit of voltage-gated Cav1.3 L-type Ca2+ channels. These CACNA1D variants have been identified somatically in aldosterone-producing adenomas as well as germline in patients with neurodevelopmental and in some cases endocrine symptoms. In vitro studies in heterologous expression systems have revealed typical gating changes that indicate enhanced Ca2+ influx through Cav1.3 channels as the underlying disease-causing mechanism. Here we summarize the clinical findings of 12 well-characterized individuals with a total of 9 high-risk pathogenic CACNA1D variants. Moreover, we propose how information from somatic mutations in aldosterone-producing adenomas could be used to predict the potential pathogenicity of novel germline variants. Since these pathogenic de novo variants can cause a channel-gain-of function, we also discuss the use of L-type Ca2+ channel blockers as a potential therapeutic option.	0
Junctional epidermolysis bullosa inversa is an autosomal recessive blistering skin disease with an ultrastructural hemidesmosome defect similar to that of the Herlitz disease, yet with a non-lethal and different course of the disease. Its delineation is based on five geographically associated Norwegian families where all parents are likely to carry a mutant EBR2A allele identical in descent. Three informative families show a lod score of +1.65 at zero recombination to a trinucleotide repeat marker in intron 20 of the laminin gamma 1 (LAMC1, previously LAMB2) locus on 1q31. The four patients of these families are all homozygous for the 146 bp LAMC1 allele present only on 5% of random Norwegian chromosomes. The daughter of a deceased patient in a fourth family carries the same 146 bp allele. This extreme association confirms that the disease locus, EBR2A, is at or closely linked to LAMC1. Localized and generalized Mitis types as well as the majority of tested families with the Herlitz type of junctional epidermolysis bullosa appeared not to be similarly linked or associated to LAMC1. The MspI and AluI RFLPs of LAMC1 showed absolute allelic association. Each of the two RFLP haplotypes showed association to either 'long' or 'short' intron 20 STR alleles.	0
BACKGROUND: The aim of this study was to determine prevalence and 15-year survival in Charcot-Marie-Tooth disease (CMT). METHODS: The study covers the period from 1 January 1988 to 31 December 2007 in the territory of Belgrade. Data on a number of CMT-affected persons and their basic demographic characteristics as well as data on the disease were collected from medical records. Data on the course and outcome of the disease were obtained through direct contact with patients, their families and their physicians. RESULTS: We registered 161 patients with CMT in the population of Belgrade. The most frequent type was CMT1. The crude prevalence of CMT disease in the Belgrade population on 31 December 2007 was 9.7/100,000 for all subtypes, 7.1/100,000 for CMT1, and 2.3/100,000 for CMT2. Gender-specific prevalence was 11.2/100,000 for males and 8.3/100,000 for females. The highest age-specific prevalence was registered in the oldest age group (75+ years; 19.1/100,000), and the lowest one in patients aged 5-14 years (5.0/100,000). The cumulative probability of 15-year survival for CMT patients in Belgrade was 85.6 ± 7.8% (44.9 ± 31.8% for males and 98.2 ± 1.8% for females). CONCLUSIONS: The prevalence of CMT found in Belgrade is similar to the prevalence registered in Southern European countries.	1
Wernicke-Korsakoff syndrome is a type of brain disorder caused by the lack of thiamine, most commonly because of chronic alcohol misuse. It consists of two separate conditions including Wernicke's encephalopathy and Korsakoff syndrome. Various levels of cognitive impairments are associated with the severity of the syndrome. Although the effectiveness of thiamine replacement in the early phases of the syndrome is proven, the efficacy of subsequent treatments, which mainly include rehabilitation protocols after the development of Korsakoff syndrome, is not clear. This is the first report showing the positive effects of physical rehabilitation in a 48-year-old male patient with Wernicke-Korsakoff syndrome.	0
Background:A new variant of endemic pemphigus foliaceus in El Bagre (El Bagre-EPF), Colombia, South America, shares features with Senear-Usher syndrome and occurs in an endemic fashion. Patients affected by El Bagre-EPF have heterogeneous antigenic reactivity not only to the skin but to other organs, including the heart. Here we test for autoantibodies to the areae compositae of the heart (structure consisting of typical desmosomal amalgamated fascia adherens molecules) and evaluate any possible clinical correlation. Methods:A case-control study comparing 45 patients and 45 controls from the endemic area, matched by demographics including age, gender, weight, work activities, and comorbidities, was performed. Direct and indirect immunofluorescence, immunohistochemistry, confocal microscopic studies, and echocardiogram studies were completed. Results:The main clinical abnormally seen in the El Bagre-EPF patients was left ventricular hypertrophy in 15/45 patients, compared with no such findings in the control population (P < 0.1). Seventy percent of El Bagre-EPF patients and none of the controls displayed polyclonal autoreactivity using different immunoglobulins and complement to the areae compositae of the heart using different methods and antibodies (P < 0.1). Conclusions:Patients affected by El Bagre-EPF demonstrated autoantibodies to the areae compositae of the heart. This finding was associated with left ventricular hypertrophic cardiomyopathy. The areae compositae may play a role in cell junction tension and the El Bagre-EPF patients' autoantibodies possibly disrupting these junctions and thereby contributing to the left ventricular hypertrophy.	0
OBJECTIVE:Cytochrome c oxidase (COX) deficiency is a major mitochondrial respiratory chain defect that has vast genetic and phenotypic heterogeneity. This study aims to identify novel causative genes of COX deficiency with only striated muscle-specific symptoms. METHODS:Whole exome sequencing was performed in 2 unrelated individuals who were diagnosed with congenital myopathy and presented COX deficiency in muscle pathology. We assessed the COX6A2 variants using measurements of enzymatic activities and assembly of mitochondrial respiratory chain complexes in the samples from the patients and knockout mice. RESULTS:Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness. One patient had cardiomyopathy. Neither patient exhibited involvement from other organs. Whole exome sequencing identified biallelic missense variants in COX6A2, which is expressed only in the skeletal muscle and heart. The variants detected were homozygous c.117C > A (p.Ser39Arg) and compound heterozygous c.117C > A (p.Ser39Arg) and c.127T > C (p.Cys43Arg). We found specific reductions in complex IV activities in the skeletal muscle of both individuals. Assembly of complex IV and its supercomplex formation were impaired in the muscle. INTERPRETATION:This study indicates that biallelic variants in COX6A2 cause a striated muscle-specific form of COX deficiency. ANN NEUROL 2019;86:193-202.	0
We live and to do so we must breathe and eat, so are we a combination of what we eat and breathe? Here, we will consider this question, and the role in this respect of the AMP-activated protein kinase (AMPK). Emerging evidence suggests that AMPK facilitates central and peripheral reflexes that coordinate breathing and oxygen supply, and contributes to the central regulation of feeding and food choice. We propose, therefore, that oxygen supply to the body is aligned with not only the quantity we eat, but also nutrient-based diet selection, and that the cell-specific expression pattern of AMPK subunit isoforms is critical to appropriate system alignment in this respect. Currently available information on how oxygen supply may be aligned with feeding and food choice, or vice versa, through our motivation to breathe and select particular nutrients is sparse, fragmented and lacks any integrated understanding. By addressing this, we aim to provide the foundations for a clinical perspective that reveals untapped potential, by highlighting how aberrant cell-specific changes in the expression of AMPK subunit isoforms could give rise, in part, to known associations between metabolic disease, such as obesity and type 2 diabetes, sleep-disordered breathing, pulmonary hypertension and acute respiratory distress syndrome.	0
Pseudohyperaldosteronism, or Liddle syndrome, is a rare, autosomal dominant condition characterized by early-onset hypertension, often associated with hypokalemia and metabolic alkalosis. Martorell hypertensive ischemic leg ulcer is a rare, underdiagnosed ulcer characterized by subcutaneous arteriolosclerosis, classically appearing over the dorsolateral lower extremity or Achilles tendon in patients with hypertension and diabetes. It presents an important diagnostic challenge because it can appear grossly similar to other entities such as pyoderma gangrenosum or venous stasis ulcers, but requires surgical intervention. This article presents a case study of surgical management of a Martorell ulcer in a 69-year-old woman with Liddle syndrome. To the authors' knowledge, this is the first case reported in the literature of this rare ulcer occurring secondary to this rare cause of hypertension.	0
Primary cutaneous amyloidosis (PCA) is a form of localized amyloidosis. It is characterized by the deposition of a fibrillar material in the superficial dermis, without affecting other systems or organs. The diagnosis can be made clinically, but usually a skin biopsy is performed in order to exclude other skin diseases with similar appearance. Reflectance confocal microscopy (RCM) is a novel imaging tool that enables in vivo characterization of various skin changes with a high, quasi-microscopic resolution. This technique might have an important role in the differential diagnosis of cutaneous amyloidosis, by the in vivo assessment of epidermal changes and dermal amyloid deposition. Moreover, it is completely non-invasive and can be safely repeated on the same skin area. However, to date, there is only one published paper presenting the confocal features of primary cutaneous amyloidosis. Hereby, we describe the in vivo RCM features of PCA lesions from a patient with diabetes and correlate them with histologic findings. This strengthens the clinical usefulness of in vivo RCM examination for the non-invasive diagnosis of cutaneous amyloidosis, especially in patients that might associate diseases with impaired wound healing.	0
The oral-facial-digital syndrome belongs to a group of hereditary diseases, manifested by multiple birth defects (usually, the face and fingers). At the current stage, there are 14 genetic variations of the oral-facial-digital syndrome. The presence of various abnormalities of the oral cavity, face and fingers is common for all of them, but each syndrome has a specific phenotype or type of inheritance. The etiology of this syndrome is unknown. It is inherited in an X-linked dominant pattern. Aim of the study: to describe and analyze the clinical case of oral-facial-digital syndrome. Data of the patient (Kira M., 11 months old): clinical-anamnestic examination, chest radiography, ultrasound investigation, molecular-genetic testing OFD1. Results Numerous miliae are detected on the face and ears of the child. Facial dysmorphy (large wide eyes, epicantus, wide nose bridge, telecantus, small mouth, small beak shaped nose, hypoplasia of the wings of the nose, small chin). The large fontanel is closed. Focal alopecia and dry hair are noted. Syndactyly of 2nd-3rd toes, asymmetrical shortening of the index finger of the right hand. Oral cavity examination reveals cleft palate, ankyloglossy and tongue lobulation. Transcranial ultrasonography: M echodex = 50.0 mm. M echosin = 52.0 mm. VIII = 6.9 mm (N up to 3.0 mm). V latdex = 24.4 mm, V latsin = 25.0 mm (N up to 16.0 mm). Neurologist's consultation: "Congenital brain malformation: agenesis of corpus callosum, congenital cerebral cysts." Ultrasound examination of the abdominal organs detected liver enlargement (anteroposterior size of the right lobe: 78 mm (N up to 65 mm), left lobe: 0.38 mm (+1.5 cm) Conclusion Oral-facial-digital syndrome type I is an inherited pathology, which in most cases is diagnosed immediately after birth on the basis of oral, facial and digital anomalies. Molecular genetic study makes it possible to confirm this disease and provide counseling to family members. Elimination of some developmental defects (hard palate plastic, correction of frenulum hyperthrophy), as well as a properly selected complex of therapeutic and rehabilitation measures greatly improves the quality of life of the patient and contributes to a favorable forecast.	0
A 73-year-old man presented with multiple liver nodules on an abdominal echogram. Fluorine-18-fluorodeoxyglucose (FDG)-positron emission tomography computed tomography (PET-CT) showed multiple nodules in his anterior and posterior mediastinum, and liver. Following thymothymectomy with lymph node dissection, the liver nodules were completely resected. Finally, he was diagnosed with combined thymic tumor (small cell carcinoma and type B3 thymoma) with multiple mediastinal lymph nodes and liver metastases by type B3 thymoma. Follow-up PET-CT scan revealed multiple rib and celiac lymph node metastases, six courses of chemotherapy (paclitaxel and carboplatin) were administered, and the patient survived without any recurrence for 15 years after initial surgery.	0
BACKGROUND AND OBJECTIVES:Leiomyosarcoma of skin (LMS) can be sub-classified on pathology appearances as Dermal or Subcutaneous. The aim of this study was to provide treatment recommendations for these uncommon tumours. METHODS:A retrospective review of all patients with dermal and subcutaneous leiomyosarcoma managed at the Peter MacCallum Cancer Centre, Australia from January 2003 to December 2018 was performed. Eighty-three patients were identified (64 dermal leiomyosarcoma, 19 subcutaneous leiomyosarcoma). RESULTS:Subcutaneous leiomyosarcoma were larger (median size 14 mm dermal, 49 mm subcutaneous, P = 0.01). No patient with a dermal leiomyosarcoma developed metastatic disease compared to 4 of the 19 subcutaneous leiomyosarcoma (5-year overall survivals, 98% and 88%, respectively, P = 0.03). The most common site of metastasis was to the lung. No difference in risk of local recurrence was apparent (5-year recurrence-free survivals were 85% and 78%, respectively, P = 0.17). Adjuvant radiotherapy was used in 16 (25%) dermal leiomyosarcoma patients and 13 (68%) subcutaneous leiomyosarcoma patients (P < 0.001). Local recurrence was uncommon in both tumour subtypes when patients received definitive surgical excision (minimum histological margins of 10 mm as per institutional protocol) regardless of whether radiotherapy was used. The 5-year local recurrence-free survival for dermal leiomyosarcoma treated with radiotherapy was 93% versus 83% without radiotherapy (P = 0.7) and for subcutaneous leiomyosarcoma was 69% and 100%, respectively (P = 0.9). CONCLUSIONS:Dermal leiomyosarcoma have an excellent prognosis, particularly after definitive surgical excision with margins of at least 10 mm. Subcutaneous leiomyosarcoma has poorer outcomes and should be managed by wider excision and considered for adjuvant radiotherapy.	0
AIMS:To establish current epidemiological data, risks, and interventional outcomes of newly diagnosed sympathetic ophthalmia (SO). METHODS:Prospective surveillance took place of all permanently employed ophthalmologists in the UK and Republic of Ireland by a monthly reporting card through the British Ophthalmological Surveillance Unit. Case ascertainment was made of newly diagnosed SO from July 1997 and questionnaire data were returned at baseline, 6 months, and 1 year after diagnosis. RESULTS:23 patients with newly diagnosed SO were recruited over 15 months, corresponding to a minimum estimated incidence of 0.03/100 000. Baseline data were available on 18 patients, in whom SO occurred after surgery in 11 patients, after retinal surgery alone in six patients, and after accidental trauma in seven patients. 12 of the 16 patients with 1 year follow up had a visual acuity of 6/12 or better. Good visual outcome was related to prompt and adequate systemic immunosuppressive therapy. CONCLUSIONS:The incidence of sympathetic ophthalmia is very low. The main current risk is surgery, particularly retinal surgery, but visual prognosis is good if early diagnosis is made and rapid, adequate immunotherapy is commenced.	1
Naegeli-Franceschetti-Jadassohn syndrome is a rare autosomal dominant form of ectodermal dysplasia affecting sweat glands, nails, teeth, and skin. We report a case of 16-year-old female who had generalized reticulate pigmentation, dental changes, nail changes, and absence of dermatoglyphics and hypohydrosis.	0
Succinate dehydrogenase (SDH) is a crucial metabolic enzyme complex that is involved in ATP production, playing roles in both the tricarboxylic cycle and the mitochondrial respiratory chain (complex II). Isolated complex II deficiency is one of the rarest oxidative phosphorylation disorders with mutations described in three structural subunits and one of the assembly factors; just one case is attributed to recessively inherited SDHD mutations. We report the pathological, biochemical, histochemical and molecular genetic investigations of a male neonate who had left ventricular hypertrophy detected on antenatal scan and died on day one of life. Subsequent postmortem examination confirmed hypertrophic cardiomyopathy with left ventricular non-compaction. Biochemical analysis of his skeletal muscle biopsy revealed evidence of a severe isolated complex II deficiency and candidate gene sequencing revealed a novel homozygous c.275A>G, p.(Asp92Gly) SDHD mutation which was shown to be recessively inherited through segregation studies. The affected amino acid has been reported as a Dutch founder mutation p.(Asp92Tyr) in families with hereditary head and neck paraganglioma. By introducing both mutations into Saccharomyces cerevisiae, we were able to confirm that the p.(Asp92Gly) mutation causes a more severe oxidative growth phenotype than the p.(Asp92Tyr) mutant, and provides functional evidence to support the pathogenicity of the patient's SDHD mutation. This is only the second case of mitochondrial complex II deficiency due to inherited SDHD mutations and highlights the importance of sequencing all SDH genes in patients with biochemical and histochemical evidence of isolated mitochondrial complex II deficiency.	0
Experimental allergic encephalomyelitis (EAE) is considered to be a useful animal model of human multiple sclerosis (MS). However, among the various symptoms of MS, the mechanisms contributing to inflammatory anorexia remain unclear. In the present study, we used an EAE rat model to examine changes in expression levels of hypothalamic feeding-related peptide genes and neuroendocrine responses such as the hypothalamo-neurohypophysial system and the hypothalamo-pituitary-adrenal (HPA) axis. The weight gain and cumulative food intake in EAE rats in the early days after immunization was significantly lower than that of the control group. The expression of orexigenic peptide genes Npy and Agrp were significantly increased, whereas the levels of anorectic peptide genes (Pomc and Cart) were significantly decreased in the hypothalamus of EAE rats. There was also a significant increase in the mRNA and plasma oxytocin (OXT) but not of arginine vasopressin (AVP) in the supraoptic and paraventricular nuclei (PVN) of EAE rats at days 12 and 18 after immunization. The expression of corticotropin-releasing hormone (Crh) and Avp was downregulated and upregulated, respectively, in the parvocellular division of the PVN at day 12 after immunization. The expression level of Pomc in the anterior pituitary significantly increased, accompanied by increased plasma corticosterone levels, at days 6, 12, and 18 after immunization. These results suggest that inflammatory anorexia in rat EAE may be caused by activation of the OXT-ergic pathway and HPA axis via changes in the expression of hypothalamic feeding-related peptides, including Avp but not Crh.	0
Regulatory T cells (Tregs) have been shown to be critical in the balance between autoimmunity and tolerance and have been implicated in several human autoimmune diseases. However, the small number of Tregs in peripheral blood limits their therapeutic potential. Therefore, we developed a protocol that would allow for the expansion of Tregs while retaining their suppressive activity. We isolated CD4+CD25 hi cells from human peripheral blood and expanded them in vitro in the presence of anti-CD3 and anti-CD28 magnetic Xcyte Dynabeads and high concentrations of exogenous Interleukin (IL)-2. Tregs were effectively expanded up to 200-fold while maintaining surface expression of CD25 and other markers of Tregs: CD62L, HLA-DR, CCR6, and FOXP3. The expanded Tregs suppressed proliferation and cytokine secretion of responder PBMCs in co-cultures stimulated with anti-CD3 or alloantigen. Treg expansion is a critical first step before consideration of Tregs as a therapeutic intervention in patients with autoimmune or graft-versus-host disease.	0
The human X and Y chromosomes evolved from a pair of autosomes approximately 180 million years ago. Despite their shared evolutionary origin, extensive genetic decay has resulted in the human Y chromosome losing 97% of its ancestral genes while gene content and order remain highly conserved on the X chromosome. Five 'stratification' events, most likely inversions, reduced the Y chromosome's ability to recombine with the X chromosome across the majority of its length and subjected its genes to the erosive forces associated with reduced recombination. The remaining functional genes are ubiquitously expressed, functionally coherent, dosage-sensitive genes, or have evolved male-specific functionality. It is unknown, however, whether functional specialization is a degenerative phenomenon unique to sex chromosomes, or if it conveys a potential selective advantage aside from sexual antagonism. We examined the evolution of mammalian orthologs to determine if the selective forces that led to the degeneration of the Y chromosome are unique in the genome. The results of our study suggest these forces are not exclusive to the Y chromosome, and chromosomal degeneration may have occurred throughout our evolutionary history. The reduction of recombination could additionally result in rapid fixation through isolation of specialized functions resulting in a cost-benefit relationship during times of intense selective pressure.	0
Frank-ter Haar syndrome (FTHS) is an autosomal recessive disorder characterized by abnormalities that affect the development of bone, heart, and eyes. We report a sibling pair with FTHS caused by a homozygous, novel mutation pLys133Glnfs*13 in the SH3PXD2B gene: one sibling had bilateral ocular hypertension and unilateral colobomas of iris, choroid and retina; the other, unilateral myelinated nerve fiber layer of the optic disk and papilledema due to idiopathic intracranial hypertension. Both children had refractive amblyopia and megalocornea.	0
Complex neurodevelopmental syndromes frequently have an unknown etiology, in which genetic factors play a pathogenic role. This study utilizes whole-exome sequencing (WES) to examine four members of a family with a son presenting, since birth, with epileptic-like crises, combined with cerebral palsy, severe neuromotor and developmental delay, dystonic tetraparexia, axonal motor affectation, and hyper-excitability of unknown origin. The WES study detected within the patient a de novo heterozygous in-frame duplication of thirty-six nucleotides within exon 7 of the human KCNQ2 gene. This insertion duplicates the first twelve amino acids of the calmodulin binding site I. Molecular dynamics simulations of this KCNQ2 peptide duplication, modelled on the 3D structure of the KCNQ2 protein, suggest that the duplication may lead to the dysregulation of calcium inhibition of this protein function.	0
Clinical glycomics comprises a spectrum of different analytical methodologies to analyze glycan structures, which provides insights into the mechanisms of glycosylation. Within clinical diagnostics, glycomics serves as a functional readout of genetic variants, and can form a basis for therapy development, as was described for PGM1-CDG. Integration of glycomics with genomics has resulted in the elucidation of previously unknown disorders of glycosylation, namely CCDC115-CDG, TMEM199-CDG, ATP6AP1-CDG, MAN1B1-CDG, and PGM1-CDG. This review provides an introduction into protein glycosylation and presents the different glycomics methodologies ranging from gel electrophoresis to mass spectrometry (MS) and from free glycans to intact glycoproteins. The role of glycomics in the diagnosis of congenital disorders of glycosylation (CDG) is presented, including a diagnostic flow chart and an overview of glycomics data of known CDG subtypes. The review ends with some future perspectives, showing upcoming technologies as system wide mapping of the N- and O-glycoproteome, intact glycoprotein profiling and analysis of sugar metabolism. These new advances will provide additional insights and opportunities to develop personalized therapy. This is especially true for inborn errors of metabolism, which are amenable to causal therapy, because interventions through supplementation therapy can directly target the pathogenesis at the molecular level.	0
Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating disorder of the central nervous system characterized by nystagmus, motor developmental delay, ataxia, and progressive spasticity. The gap junction protein gamma-2 gene (GJC2), encoding the gap junction protein connexin 47, is one of the genes responsible for this condition. In this study, a novel homozygous mutation in GJC2 (c.746C>G; p.P249R) was identified in a 21-year-old female patient with PMLD. Although her mother was a carrier of this mutation, the Mendelian inheritance pattern could not be determined because the paternal sample was unavailable. Alternatively, chromosomal microarray testing together with single nucleotide polymorphism typing (CGH+SNP) was performed to determine the gene copy number and analyze the haplotype in the 1q42.13 region in which GJC2 is located. The result showed no deletion, but the GJC2 region was involved in the loss-of-heterozygosity region. Furthermore, haplotype of chromosome 1, in which GJC2 is located, revealed that both copies of chromosome 1 were derived from the patient's mother, indicating maternal uniparental disomy of chromosome 1. This study showed the advantage of the SNP genotyping microarray for detecting the origin of the mutation.	0
BACKGROUND:Inflammatory myofibroblastic tumor (IMT) is a rare type of soft-tissue neoplasm. IMT of the urinary tract is more common in the bladder and kidneys. Prostatic IMT is extremely rare. CASE REPORT:We present a rare case of IMT of the prostate and a literature review on this condition. The patient was a 72-year-old man who presented with urinary symptoms. Transrectal needle biopsy of the prostate revealed prostatic adenocarcinoma with nodular hyperplasia. Radical prostatectomy revealed IMT without residual adenocarcinoma. On immunohistochemical examination, the tumor cells showed positive immunoreactivity for α-smooth muscle actin, CD10, CD34, and desmin but negative immunoreactivities for anaplastic lymphoma kinase (ALK), receptor tyrosine kinase (c-KIT), and S-100 protein. The patient underwent regular follow-up examination. No recurrence was observed 4 months after the diagnosis. CONCLUSION:This was a case of IMT arising in the prostate. Pathologists should be aware of such an entity whenever they see spindle-cell lesions in the transrectal needle biopsy of the prostate.	0
Children affected by dentinogenesis imperfecta (DI) require restorative techniques or prosthodontic management to minimize the functional and psychosocial impacts of the condition. In cases of excessive wear of the deciduous dentition and moderate cooperation from the child, removable complete overdenture prostheses are the most suitable treatment option. However, limited restorative space is a technical challenge for the placement of such prostheses. Advances in digital technologies can help assist in the fabrication of monolithic prostheses with reduced thickness. The present clinical report describes the management of a moderately cooperative 7-year-old patient suffering from DI with severe tooth wear, reduced restorative space, and a high smile line. The design and fabrication of complete overdentures were performed using a digital workflow. This innovative monochromatic monolithic approach combined with the use of gingiva-shade composite resin respected the available restorative space while obtaining a natural esthetic appearance. Such a strategy requires regular denture replacement according to the child's growth and loss of deciduous dentition. An additional aim is to obtain the cooperation needed for a future global fixed rehabilitation over time.	0
BACKGROUND:Immune checkpoint inhibitors have improved clinical outcomes including survival in several malignancies but have also been associated with a range of immune-related adverse events (irAEs). Neurological irAEs are rare compared to the more typical skin, gastrointestinal, and endocrine toxicities, and are often underrecognized and challenging to diagnose. Here, we report a case of seronegative autoimmune autonomic ganglionopathy (AAG) induced by dual immune checkpoint inhibitor therapy (ICI) in a patient with metastatic melanoma. CASE PRESENTATION:A patient with metastatic melanoma was treated with ipilimumab and nivolumab. He developed a constellation of new symptoms including nausea, fatigue, and severe orthostatic hypotension refractory to fluid resuscitation. An infectious, cardiac, neurologic, and endocrine workup were unrevealing. Cardiovascular autonomic testing revealed poor sympathetic nervous system responses. He was diagnosed with seronegative AAG and significantly improved with immunomodulatory therapies including IVIG and steroids as well as varying doses of midodrine and fludrocortisone. He was able to restart nivolumab without recurrence of his symptoms. However, the AAG reoccurred when he was re-challenged with ipilimumab and nivolumab due to disease progression. While the AAG was manageable with steroids at that time, unfortunately his melanoma became resistant to ICI. CONCLUSIONS:Immune checkpoint inhibitors can have a wide range of unusual, rare irAEs, including neurotoxicity such as AAG. Clinicians should maintain suspicion for this toxicity so that treatment can be rapidly provided to avoid disability.	0
Progressive Myoclonus Epilepsies (PMEs) are a group of uncommon clinically and genetically heterogeneous disorders characterised by myoclonus, generalized epilepsy, and neurological deterioration, including dementia and ataxia. PMEs may have infancy, childhood, juvenile or adult onset, but usually present in late childhood or adolescence, at variance from epileptic encephalopathies, which start with polymorphic seizures in early infancy. Neurophysiologic recordings are suited to describe faithfully the time course of the shock-like muscle contractions which characterize myoclonus. A combination of positive and negative myoclonus is typical of PMEs. The gene defects for most PMEs (Unverricht-Lundborg disease, Lafora disease, several forms of neuronal ceroid lipofuscinoses, myoclonus epilepsy with ragged-red fibers [MERRF], and type 1 and 2 sialidoses) have been identified. PMEs are uncommon disorders, difficult to diagnose in the absence of extensive experience. Thus, aetiology is undetermined in many patients, despite the advance in molecular medicine. Treatment of PMEs remains essentially symptomaticof seizures and myoclonus, together with palliative, supportive, and rehabilitative measures. The response to therapy may initially be relatively favourable, afterwards however, seizures may become more frequent, and progressive neurologic decline occurs. The prognosis of a PME depends on the specific disease. The history of PMEs revealed that the international collaboration and sharing experience is the right way to proceed. This emerging picture and biological insights will allow us to find ways to provide the patients with meaningful treatment.	0
We report the case of a male 22-month-old child, with atypical presentation of Gianotti-Crosti syndrome after infection with Epstein-Barr virus.	0
RATIONALE:Lymphangioleiomyomatosis (LAM) is a metastatic neoplasm of reproductive age women associated with mutations in tuberous sclerosis complex (TSC) genes. LAM causes cystic remodeling of the lung and progressive respiratory failure. The sources and cellular characteristics of LAM cells underlying disease pathogenesis remain elusive. OBJECTIVES:Identification and characterization of LAM cells in human lung and uterus using single cell approach. METHODS:Single cell/nuclei RNA sequencing on LAM (n=4) and control (n=7) lungs, immunofluorescence confocal microscopy, ELISA, and aptamer proteomics were used to identify and validate LAMCORE cells and secreted biomarkers, predict cellular origins, define molecular and cellular networks in LAM. MEASUREMENTS AND MAIN RESULTS:A unique cell type termed LAMCORE was identified, which was distinct from, but closely related to, lung mesenchymal cells. LAMCORE cells expressing signature genes included known LAM markers such as PMEL, FIGF, CTSK and MLANA, and novel biomarkers validated by aptamer screening, ELISA, and immunofluorescence microscopy. LAM cells in lung and uterus are morphologically indistinguishable and share similar gene expression profiles and biallelic TSC2 mutations, supporting a potential uterine origin for the LAMCORE cell. Effects of LAM on resident pulmonary cell types indicated recruitment and activation of lymphatic endothelial cells. CONCLUSION:A unique population of LAMCORE cells was identified in lung and uterus of LAM patients, sharing close transcriptomic identity. LAM cell selective markers, secreted biomarkers, and the predicted cellular molecular features provide new insights into the signaling and transcriptional programs which may serve as diagnostic markers and therapeutic targets to influence the pathogenesis of LAM.	0
Progressive transformation of germinal centers (PTGCs) is a benign disease of the lymph nodes that is rarely associated with Hodgkin disease. We reviewed the clinical and pathologic features of PTGCs and the relationship of PTGCs with lymphoid neoplasia in an adult population. The data from 33 patients who were diagnosed with PTCGs were retrospectively analyzed. Of the 33 PTGC patients, 48.5% were men and 51.5% were women, with a mean age of 43.8 years at diagnosis. Most of the enlarged and excised lymph nodes were cervical and axillary. Diffuse large B-cell lymphoma and nodular lymphocyte predominant Hodgkin lymphoma was detected concurrent with PTGC in 2 patients. Also, PTGCs was detected 3 years after the diagnosis of diffuse large B-cell lymphoma, nodular lymphocyte predominant Hodgkin lymphoma, and T-cell-rich B-cell lymphoma in 3 patients. No relapse was found in the patients with lymphoma, and no progression to lymphoma was detected during the follow-up of the other patients. PTGCs is not considered a premalignant entity; however, the development of lymphoma has been reported rarely. If PTGCs occurs in the follow-up process of patients with lymphoma, the follow-up intervals should be shortened.	0
Bullous pemphigoid (BP) is a senile autoimmune blistering disease with autoantibodies against the basement membrane. Less than 20 cases of localized BP in young adults have been reported and the understanding of localized BP is very limited. An unusual location of localized BP is here described. A 30-year-old woman presented with a 4-month history of itchy erythema on her trunk. The lesion, well-demarcated erythema and maculopapules in bra's shape, had been misdiagnosed as contact dermatitis. Laboratory finding was notable for serum autoantibodies to BP antigen 180 (BP180). Histopathological examination revealed a subepidermal blister with eosinophils and neutrophils infiltration. Salt-split indirect immunofluorescence revealed linear deposition of IgG at the dermoepidermal junction. After treating her with minocycline 200 mg and nicotinamide 1,500 mg per day, all lesions resolved within 1 month. Localized BP is usually misdiagnosed. It starts from various triggers and has a more benign disease course. It should be emphasized that a long-term follow-up of patients with localized BP may be important for management of the chronic disease, given a relatively high risk of developing generalized BP.	0
Skeletal dysplasias are a diverse group of heritable diseases affecting bone and cartilage growth. Throughout the years, the molecular defect underlying many of the diseases has been identified. These identifications led to novel insights in the mechanisms regulating bone and cartilage growth and homeostasis. One of the pathways that is clearly important during skeletal development and bone homeostasis is the Wingless and int-1 (WNT) signaling pathway. So far, three different WNT signaling pathways have been described, which are all activated by binding of the WNT ligands to the Frizzled (FZD) receptors. In this review, we discuss the skeletal disorders that are included in the latest nosology of skeletal disorders and that are caused by genetic defects involving the WNT signaling pathway. The number of skeletal disorders caused by defects in WNT signaling genes and the clinical phenotype associated with these disorders illustrate the importance of the WNT signaling pathway during skeletal development as well as later on in life to maintain bone mass. The knowledge gained through the identification of the genes underlying these monogenic conditions is used for the identification of novel therapeutic targets. For example, the genes underlying disorders with altered bone mass are all involved in the canonical WNT signaling pathway. Consequently, targeting this pathway is one of the major strategies to increase bone mass in patients with osteoporosis. In addition to increasing the insights in the pathways regulating skeletal development and bone homeostasis, knowledge of rare skeletal dysplasias can also be used to predict possible adverse effects of these novel drug targets. Therefore, this review gives an overview of the skeletal and extra-skeletal phenotype of the different skeletal disorders linked to the WNT signaling pathway.	0
Gaucher disease is the most common sphingolipid storage disease and is present in all ethnic groups. Its symptoms span all systems including the cardiovascular system. The health care provider should be vigilant regarding this potentially fatal complication. Gaucher disease type IIIC has been linked to causing oculomotor apraxia and cardiac calcification. We report a Saudi girl who developed valvular and aortic calcification in late childhood and died as a result of her cardiovascular complications. This report further strengthens the association and reminds the clinicians that patients with D409H mutation need echocardiographic evaluation annually.	0
Juvenile Paget disease (JPD1), an autosomal-recessive disorder, is characterized by extremely rapid bone turnover due to osteoprotegerin deficiency. Its extra-skeletal manifestations, such as hypertension and heart failure, suggest a pathogenesis with shared skeletal and cardiovascular system components. In spite of this, the effects of anti-hypertensive drugs on bone morphometry remain unknown. We administered an angiotensin II type 1 receptor blocker, olmesartan (5 mg/kg/day) to 8-week-old male mice lacking the osteoprotegerin gene, with and without 1 μg/kg/min of angiotensin II infusion for 14 days. Olmesartan treatment decreased systolic blood pressure, and echocardiography showed increased left ventricular systolic contractility. Three-dimensional micro-computed tomography scans demonstrated that olmesartan treatment increased trabecular bone volume (sham, +176%; angiotensin II infusion, +335%), mineral density (sham, +150%; angiotensin II infusion, +313%), and trabecular number (sham, +407%; angiotensin II infusion, +622%) in the tibia. Olmesartan increased cortical mineral density (sham, +19%; angiotensin II infusion, +24%), decreased the cortical bone section area (sham, -16%; angiotensin II infusion, -18%), decreased thickness (sham, -18%; angiotensin II infusion, -31%), and decreased the lacunar area (sham, -41%; angiotensin II infusion, -27%) in the tibia. Similar trend was observed in the femur. Moreover, olmesartan decreased angiotensin II-induced increases in tartrate-resistant acid phosphatase concentrations in plasma, but it affected neither type I procollagen N-terminal propeptides, nor the receptor activator of nuclear factor kappa-B ligand. Our data suggest that blockade of the angiotensin II type 1 receptor improves bone vulnerability, and helps to maintain the heart's structural integrity in osteoprotegerin-deficient mice.	0
The aim of this case presentation is to describe ocular findings of a 22-year-old patient with Best vitelliform macular dystrophy accompanied by pachychoroid neovasculopathy. Color fundus photography, fundus autofluorescence (FAF), optical coherence tomography (OCT), and optical coherence tomography angiography (OCTA) images were reviewed. Funduscopic examination showed bilateral yellowish vitelliform-like submacular deposits. FAF revealed these deposits as hyperautofluorescent spots. OCT showed flat irregular pigment epithelial detachments corresponding to these submacular deposits. OCT showed choroidal thickening and dilatation of the large outer oval choroidal vessels. Fundus fluorescein angiography could not be performed because the patient was pregnant. En face OCTA images of the choriocapillaris illustrated the choroidal neovascular network. In this case report, we describe for the first time the coexistence of Best vitelliform macular dystrophy and pachychoroid neovasculopathy with OCTA images enabling visualization of the neovascular network in a patient with contraindication for fluorescein angiography.	0
The etiology and pathogenesis of oligomeganephronic renal hypoplasia (OMN) are not known. In the present paper a second case of monozygotic twins non-concordant for OMN is described. It is hypothesized that one of the mechanisms which have been proposed to explain structural defects in monozygotic twins, namely placental artery-vein shunting, may have been involved in the pathogenesis of OMN in these patients. In OMN in general vascular abnormalities may have to be considered as a pathogenetic mechanism.	0
A 10-year retrospective review was conducted to ascertain the prevalence of inclusion body myositis (IBM) in Western Australia. Seventeen patients with sporadic IBM aged 45-90 years were identified and the prevalence of IBM was calculated to be 9.3 x 10(-6). The prevalence was higher in men (10.9 x 10(-6)) than in women (7.7 x 10(-6)). The mean age of onset of IBM was 56.6 years, and the mean delay between onset of symptoms and diagnosis was 4.4 years. The age-adjusted prevalence over the age of 50 years was 35.3 x 10(-6). The results suggest a higher prevalence of IBM than has previously been reported.	1
BACKGROUND:Primary hyperoxaluria type 3 (PH3) is a rare autosomal recessive disorder that affects glyoxylate metabolism. PH3 is caused by defects in 4-hydroxy-2-oxoglutarate aldolase, which is encoded by the HOGA1 gene. However, only 3 cases of PH3 have been described in Asians until today. This study aimed to determine the clinical and mutation spectra of patients from mainland China with PH3. METHODS:We applied targeted next-generation sequencing to four non-consanguineous, unrelated Chinese families with PH3 to identify the genes hosting disease-causing mutations. This approach was confirmed by Sanger sequencing. RESULTS:Five patients (2 boys and 3 girls) from four unrelated Chinese families were admitted because of kidney stones. Five HOGA1 gene sequence mutations were detected, including two novel mutations, c.811C>T (p.R271C) and c.812G>A (p.R271H). These compound heterozygous mutations were detected in a female PH3 patient (patient 4). Other patients included 2 boys who had heterozygous c.834_834+1GG>TT and c.834G>A (p.A278A) mutations (patients 1 and 2), a girl with homozygous c.834G>A (p.A278A) mutation (patient 3), and a girl with heterozygous c.834_834+1GG>TT and c.346C>T (p.Q116X) mutations (patient 5). The mutations in the c.834_834+1 region, including c.834G>A, c.834+1G>T, and c.834_834+1GG>TT, account for 5/8 of alleles in our study and 3/4 of alleles reported among Chinese patients. All patients in this study received hyperhydration and urine alkalinization treatment. CONCLUSION:Five PH3 cases were reported. Potential mutation hot spot region (c.834_834+1) in the Chinese population and two novel mutations were found.	0
The term "spondyloperipheral dysplasia" (SPD) has been applied to the unusual combination of platyspondyly and brachydactyly as observed in a small number of individuals. The reported cases show wide clinical variability and the nosologic status and spectrum of this condition are still ill defined. Zabel et al. [1996: Am J Med Genet 63(1):123-128] reported an individual with short stature and SPD who was heterozygous for a frameshift mutation in the C-propeptide domain of COL2A1. To explain the additional finding of brachydactyly that is not an usual feature of the type II collagenopathies, it was postulated that the nature of the mutation induced precocious calcification and premature fusion of metacarpal and phalangeal growth plates. The C-propeptide of collagen II had previously been found to promote calcification ("chondrocalcin"). We have ascertained two further individuals with clinical and radiological findings of a type II collagenopathy in infancy who developed brachydactyly type E like changes of fingers and toes in childhood. In both individuals, heterozygosity for novel, distinct mutations in the C-propeptide coding region of COL2A1 were found. Although all three mutations (the one previously reported and the two novel ones) predict premature termination, their location close to the 3'-end of the mRNA probably protects them from nonsense-mediated decay and allows for synthesis of mutant procollagen chains. However, loss of crucial cysteine residues or other sequences essential for trimerization prevents these chains from associating and participating in procollagen helix formation, and thus leads to accumulation in the ER-consistent with EM findings. The mechanism leading to precocious fusion of phalangeal epiphyses remains to be explored. The consistency of clinical, radiographic, and molecular findings in these three unrelated individuals confirms SPD as a distinct nosologic entity. The diagnosis of SPD is suggested by the appearance of brachydactyly in a child who has clinical and radiographic features of a collagen II disorder.	0
The identification of cellular targets for antifungal compounds is a cornerstone for the development of novel antimycotics, for which a significant need exists due to increasing numbers of susceptible patients, emerging pathogens, and evolving resistance. For the human pathogenic mold Aspergillus fumigatus, the causative agent of the opportunistic disease aspergillosis, only a limited number of established targets and corresponding drugs are available. Among several targets that were postulated from a variety of experimental approaches, the conserved thioredoxin reductase (TrxR) activity encoded by the trxR gene was assessed in this study. Its essentiality could be confirmed following a conditional TetOFF promoter replacement strategy. Relevance of the trxR gene product for oxidative stress resistance was revealed and, most importantly, its requirement for full virulence of A. fumigatus in two different models of infection resembling invasive aspergillosis. Our findings complement the idea of targeting the reductase component of the fungal thioredoxin system for antifungal therapy.	0
African green monkey (AGM) spumaretroviruses have been less well-studied than other simian foamy viruses (SFVs). We report the biological and genomic characterization of SFVcae_FV2014, which was the first foamy virus isolated from an African green monkey (AGM) and was found to be serotype 3. Infectivity studies in various cell lines from different species (mouse, dog, rhesus monkey, AGM, and human) indicated that like other SFVs, SFVcae_FV2014 had broad species and cell tropism, and in vitro cell culture infection resulted in cytopathic effect (CPE). In Mus dunni (a wild mouse fibroblast cell line), MDCK (Madin-Darby canine kidney cell line), FRhK-4 (a fetal rhesus kidney cell line), and MRC-5 (a human fetal lung cell line), SFVcae_FV2014 infection was productive resulting in CPE, and had delayed or similar replication kinetics compared with SFVmcy_FV21 and SFVmcy_FV34[RF], which are two Taiwanese macaque isolates, designated as serotypes 1 and 2, respectively. However, in Vero (AGM kidney cell line) and A549 (a human lung carcinoma cell line), the replication kinetics of SFVcae_FV2014 and the SFVmcy viruses were discordant: In Vero, SFVcae_FV2014 showed rapid replication kinetics and extensive CPE, and a persistent infection was seen in A549, with delayed, low CPE, which did not progress even upon extended culture (day 55). Nucleotide sequence analysis of the assembled SFVcae_FV2014 genome, obtained by high-throughput sequencing, indicated an overall 80-90% nucleotide sequence identity with SFVcae_LK3, the only available full-length genome sequence of an AGM SFV, and was distinct phylogenetically from other AGM spumaretroviruses, corroborating previous results based on analysis of partial env sequences. Our study confirmed that SFVcae_FV2014 and SFVcae_LK3 are genetically distinct AGM foamy virus (FV) isolates. Furthermore, comparative infectivity studies of SFVcae_FV2014 and SFVmcy isolates showed that although SFVs have a wide host range and cell tropism, regulation of virus replication is complex and depends on the virus strain and cell-specific factors.	0
As a specialized subset of intestinal epithelial cells (IECs), goblet cells (GCs) play an important role during the antibacterial response via mucin production. However, the regulatory mechanisms involved in GC differentiation and function during infection, particularly the role of immune cell-IEC cross-talk, remain largely unknown. In this study, using Villin∆Ltbr conditional knockout mice, we demonstrate that LTβR, expressed on IECs, is required for GC hyperplasia and mucin 2 (MUC2) expression during Listeria infection for host defense but not homeostatic maintenance in the naive state. Analysis of single gene-deficient mice revealed that the ligand lymphotoxin (LT), but not LIGHT, and type 3 innate lymphoid cells (ILC3s), but not conventional T cells, are required for MUC2-dependent Listeria control. Conditional deficiency of LT in ILC3s further confirmed the importance of LT signals derived from ILC3s. Lack of ILC3-derived LT or IEC-derived LTβR resulted in the defective expression of genes related to GC differentiation but was not correlated with IEC proliferation and cell death, which were found to be normal by Ki-67 and Annexin V staining. In addition, the alternative NF-κB signaling pathway (involving RelB) in IECs was found to be required for the expression of GC differentiation-related genes and Muc2 and required for the anti-Listeria response. Therefore, our data together suggest a previously unrecognized ILC3-IEC interaction and LT-LTβR-RelB signaling axis governing GC differentiation and function during Listeria infection for host defense.	0
OBJECTIVE:To study the epidemiology of pyridoxine dependent seizures and other forms of pyridoxine responsive seizures. DESIGN:Monthly notifications to the British Paediatric Surveillance Unit over two years. Questionnaire follow up. SETTING:UK and the Republic of Ireland. PATIENTS:Children aged 15 years or younger whose seizures respond to pyridoxine. INTERVENTIONS:None. MAIN OUTCOME MEASURES:Numbers of children with definite, probable, and possible pyridoxine dependent seizures or other seizures responsive to pyridoxine. RESULTS:Point prevalence and birth incidence: 1/687 000 and 1/783 000, respectively (definite and probable cases); 1/317 000 and 1/157 000, respectively (all types of pyridoxine responsiveness). NOTIFICATIONS: Pyridoxine dependency: 14 definite, 9 probable, and 10 possible cases; neonatal seizures not meeting case definitions: 7; infantile spasms: 5. Eight of 18 families of definite/probable cases had 2 affected siblings. Just over a third had atypical presentations and just under a third had features and/or initial diagnoses of birth asphyxia and neonatal hypoxic ischaemic encephalopathy. CONCLUSIONS:Pyridoxine dependency is rare. Atypical presentations are relatively frequent. A trial of pyridoxine is justified in all cases of early onset intractable seizures or status epilepticus, whatever the suspected cause.	1
BACKGROUND:Chorea-acanthocytosis (ChAc; OMIM #200150) is a rare autosomal recessive condition with onset in early adulthood that is caused by mutations in the vacuolar protein sorting 13A (VPS13A) gene encoding chorein. Several diagnostic genomic DNA (gDNA) sequencing approaches are widely used. However, their limitations appear not to be acknowledged thoroughly enough. METHODS:Clinically, we deployed magnetic resonance imaging, blood smear analysis, and clinical chemistry for the index patient's characterization. The molecular analysis of the index patient next to his parents covered genomic DNA (gDNA) sequencing approaches, RNA/cDNA sequencing, and chorein specific Western blot. RESULTS:We report a 33-year-old male patient without functional protein due to compound heterozygosity for two VPS13A large deletions of 1168 and 1823 base pairs (bp) affecting, respectively, exons 8 and 9, and exon 13. To our knowledge, this represents the first ChAc case with two compound heterozygous large deletions identified so far. Of note, standard genomic DNA (gDNA) Sanger sequencing approaches alone yielded false negative findings. CONCLUSION:Our case demonstrates the need to carry out detection of chorein in patients suspected of having ChAc as a helpful and potentially decisive tool to establish diagnosis. Furthermore, the course of the molecular analysis in this case discloses diagnostic pitfalls in detecting some variations, such as deletions, using only standard genomic DNA (gDNA) Sanger sequencing approaches and exemplifies alternative methods, such as RNA/cDNA sequencing or qRT-PCR analysis, necessary to avoid false negative results.	0
Greig cephalopolysyndactyly syndrome (GCPS) is one of the autosomal dominant-inherited syndromes, caused by haploinsufficiency of the GLI3 gene. It is a rare, multiple congenital syndrome with an estimated rate of 0.009%. With the classic clinical triad of preaxial polydactyly with cutaneous syndactyly of at least one limb, hypertelorism, and macrocephaly, presumptive diagnosis of GCPS is made. The purpose of this article is to report a case of GCPS with emphasis on craniofacial and oral features.	0
The purpose of this pilot study was to analyze treatment pathways of pediatric epilepsy using the common data model (CDM) based on electronic health record (EHR) data. We also aimed to reveal whether CDM analysis was feasible and applicable to epilepsy research. We analyzed the treatment pathways of pediatric epilepsy patients from our institute who underwent antiseizure medication (ASM) treatment for at least 2 years, using the Observational Medical Outcomes Partnership (OMOP)-CDM. Subgroup analysis was performed for generalized or focal epilepsy, varying age of epilepsy onset, and specific epilepsy syndromes. Changes in annual prescription patterns were also analyzed to reveal the different trends. We also calculated the proportion of drug-resistant epilepsy by applying the definition of seizure persistence after application of two ASMs for a sufficient period of time (more than 6 months). We identified 1,192 patients who underwent treatment for more than 2 years (mean ± standard deviation: 6.5 ± 3.2 years). In our pediatric epilepsy cohort, we identified 313 different treatment pathways. Drug resistance, calculated as the application of more than three ASMs during the first 2 years of treatment, was 23.8%. Treatment pathways and ASM resistance differed between subgroups of generalized vs. focal epilepsy, different onset age of epilepsy, and specific epilepsy syndromes. The frequency of ASM prescription was similar between onset groups of different ages; however, phenobarbital was frequently used in children with epilepsy onset < 4 years. Ninety-one of 344 cases of generalized epilepsy and 187 of 835 cases of focal epilepsy were classified as medically intractable epilepsy. The percentage of drug resistance was markedly different depending on the specific electro-clinical epilepsy syndrome [79.0% for Lennox-Gastaut syndrome (LGS), 7.1% for childhood absence epilepsy (CAE), and 9.0% for benign epilepsy with centrotemporal spikes (BECTS)]. We could visualize the annual trend and changes of ASM prescription for pediatric epilepsy in our institute from 2004 to 2017. We revealed that CDM analysis was feasible and applicable for epilepsy research. The strengths and limitations of CDM analysis should be carefully considered when planning the analysis, result extraction, and interpretation of results.	0
The management of Amelogenesis imperfecta often poses a challenge for the dentists. It not only includes aesthetic and functional rehabilitation of the patient, but also requires a positive rapport building with the patient due to psychosocial issues. The treatment plan is driven by patient demands, age, cost-affordability, severity of the disease and the presenting condition. The present case report elucidates step by step management of a 20 year-old female who presented with generalized hypersensitivity, intermittent pain associated with multiple decayed posterior teeth, poor dental aesthetics and anterior deep bite. The management consisted of endodontic treatments in all teeth, crown lengthening to gain ferrule in some teeth, provision of provisional bridges at an increased vertical dimension for six weeks followed by full mouth all ceramic crowns on all teeth. The prosthetic management aimed at reorganized occlusal scheme. There was a significant improvement in the aesthetics, deep bite, and along with correction of the vertical dimension of occlusion. Key words:Amelogenesis imperfecta, hypoplastic enamel, mouth rehabilitation, dental esthetics.	0
Purpose:Oral nitisinone has been shown to increase fur and ocular pigmentation in a mouse model of oculocutaneous albinism (OCA) due to hypomorphic mutations in tyrosinase (TYR), OCA1B. This study determines if nitisinone can improve ocular and/or fur pigmentation in a mouse model of OCA type 3 (OCA3), caused by mutation of the tyrosinase-related protein 1 (Tyrp1) gene. Methods:Mice homozygous for a null allele in the Tyrp1 gene (C57BL/6J-Tyrp1 b-J/J) were treated with 8 mg/kg nitisinone or vehicle every other day by oral gavage. Changes in fur and ocular melanin pigmentation were monitored. Mature ocular melanosome number and size were quantified in pigmented ocular structures by electron microscopy. Results:C57BL/6J-Tyrp1 b-J/J mice carry a novel c.403T>A; 404delG mutation in Tyrp1, predicted to result in premature truncation of the TYRP1 protein. Nitisinone treatment resulted in an approximately 7-fold increase in plasma tyrosine concentrations without overt toxicity. After 1 month of treatment, no change in the color of fur or pigmented ocular structures was observed. The distribution of melanosome cross-sectional area was unchanged in ocular tissues. There was no significant difference in the number of pigmented melanosomes in the RPE/choroid of nitisinone-treated and control groups. However, there was a significant difference in the number of pigmented melanosomes in the iris. Conclusions:Treatment of a mouse model of OCA3 with oral nitisinone did not have a favorable clinical effect on melanin production and minimally affected the number of pigmented melanosomes in the iris stroma. As such, treatment of OCA3 patients with nitisinone is unlikely to be therapeutic.	0
OBJECTIVE:To explore the genetic basis for a child with clinically suspected nephronophthisis (NPHP). METHODS:Peripheral blood samples of the patient and her parents were collected subjected to high-throughput sequencing. Sanger sequencing was used to verify the gene variants. RESULTS:The patient, a 7-year-old girl with congenital blindness, was admitted to a local hospital due to repeated vomiting for 7-8 days and then transferred to author's hospital due to renal failure. Her urine occult bloods (3+) and urine protein (1+) were abnormal. Her blood urea nitrogen and creatinine showed a significant progressive increase. Renal ultrasound showed a mild enlargement in bilateral renal, increased echogenicity, loss of corticomedullary differentiation, and the presence of cysts in both kidneys. No familial genetic history was found in the family of patient and the child was clinically diagnosed with nephronophthisis. The proband was found to harbor compound heterozygous variants of the CEP290 gene, namely c.2587-2A>T and c.2251C>T, which were inherited from her mother and father, respectively. Based on the ACMG guidelines, both variants were predicted to be pathogenic. CONCLUSION:The patient was diagnosed with NPHP type 6 due to variants of the CEP290 gene. Above finding has provided new evidence for the genotype-phenotype correlation of this disease.	0
INTRODUCTION:A paucity of literature exists on genotype- phenotype correlates of 'unknown-etiology' infantile-onset developmental-epileptic encephalopathies (DEE) from India. The primary objective was to explore the yield of genetic testing in identifying potential disease causing variants in electro-clinical phenotypes of DEE METHODS: An observational hospital-based study was undertaken on children with unexplained refractory seizure-onset ≤12 months age and developmental delay, whose families consented and underwent genetic testing during a three year time period (2016-2018) by next-generation sequencing (NGS) or multiplex ligand protein amplification. Yield was considered based on demonstration of pathogenic/likely pathogenic variants only and variants of unknown significance (VUS) were documented. RESULTS:Pathogenic/likely pathogenic variants were identified in 26 (31.7 %) out of 82 children with DEE. These included those variants responsible for primarily DEE- 21(76.7 %); neuro-metabolic disorders- 3(18.6 %) and chromosomal deletions- 2(4.7 %). Of these patients, early-infantile epilepsy onset ≤ 6 months age was noted in 22(84.6 %). The DEE studied included Ohtahara syndrome associated with STXBP1 and SCN8A variants with yield of 50 % (2/4 tested); early myoclonic encephalopathy (no yield in 2); West syndrome with CDKL5, yield of 13.3 % (2/15 tested); epilepsy of infancy with migrating partial seizures due to CACNA1A and KCNT1 variants, yield of 67 % (2/3 tested); DEE-unclassified with KCNQ2, AP3B2, ZEB2, metabolic variants (SUOX, ALDH7A1, GLDC) and chromosome deletions (chr 1p36, chr2q24.3); yield of 32 % (8/25 tested). Patients with Dravet syndrome/Dravet-like phenotypes (N = 33) had variants in SCN1A (N = 10), SCN1B, CHD2; yield of 36.4 % (12/33 tested; 57.1 % from NGS). Eighteen patients with potential variants (SCN1A, SCN2A, SCN8A, KCNQ2, ALDH7A1 which also included VUS) could be offered targeted therapy. CONCLUSIONS:Our study confirms a good yield of genetic testing in neonatal and infantile-onset DEE provided robust phenotyping of infants is attempted with prognostic and therapeutic implications, particularly relevant to centres with resource constraints.	0
Two Turkish sibs, products of a second cousin marriage, with tetramelic syndactyly, ectodermal dysplasia, cleft lip and palate, renal anomalies, and mental retardation are reported. Similarities between these two brothers and previously reported cases and their mode of transmission are discussed.	0
Opisthorchis felineus is a trematode flatworm that parasitises mammals, including humans, and is mainly spread throughout Eastern Europe and Western Siberia. The main drug used in treatment of opisthorchiasis and other trematode and cestode infestations is praziquantel (PZQ). We provide a possible explanation of PZQ-mediated tegument disruption. The idea is that the nature of tegument disruption is related to failure of surface renovation due to insufficiency of microtubule transport of vesicles. This insufficiency arises from microtubule destabilisation, which in the medium term leads to the decrease in tubulins alpha, beta and dynein mRNA amounts and deficiency of the corresponding proteins. We also found the upregulation of cGMP-dependent protein kinase gene, and we concluded that its protein product helped to overcome the effect of praziquantel and might be a promising target for combined anthelmintic therapy with PZQ. We concluded that function of saposin-like protein 2 (SAP2) is unlikely associated with membrane fusion, and SAP2 is probably able to bind some type of hydrophobic compounds including praziquantel.	0
BACKGROUND:Porphyria cutanea tarda (PCT) occurs in sporadic (sPCT) and familial (fPCT) forms, which are generally clinically indistinguishable and have traditionally been differentiated by erythrocyte uroporphyrinogen decarboxylase (UROD, EC 4.1.1.37) activity. We used UROD gene sequencing as the reference standard in assessing the diagnostic accuracy of UROD activity, evaluating the mutation spectrum of the UROD gene, determining the frequency and disease attributes of PCT and its subtypes in Norway, and developing diagnostic models that use clinical and laboratory characteristics for differentiating fPCT and sPCT. METHODS:All consecutive patients with PCT diagnosed within a 6-year period were used for incidence calculations. UROD activity analysis, UROD gene sequencing, analysis of hemochromatosis mutations, and registration of clinical and laboratory data were carried out for 253 patients. RESULTS:Fifty-three percent of the patients had disease-relevant mutations, 74% of which were c.578G>C or c.636+1G>C. The UROD activity at the optimal cutoff had a likelihood ratio (LR) of 9.2 for fPCT, whereas a positive family history had an LR of 19. A logistic regression model indicated that low UROD activity, a high uroporphyrin-heptaporphyrin ratio, a young age at diagnosis, male sex, and low alcohol consumption were predictors of fPCT. The incidence of PCT was 1 in 100 000. CONCLUSIONS:Two commonly occurring mutations are responsible for the high frequency of fPCT in Norway. UROD activity has a high diagnostic accuracy for differentiating the 2 PCT types, and a model that takes into account both clinical information and laboratory test results can be used to predict fPCT.	1
Introduction. Acute rheumatic fever (ARF) is a manifestation of the nonsuppurative sequelae of Streptococcus pyogenes infection. Herein, two cases of ARF are presented to highlight that this disease is present in urban cities, can be diagnosed in otherwise healthy children, and that its diagnosis may be challenging, or marred with confounders, leading to delays in diagnosis. Case Report. Two unrelated children, age 7 and 9, presented to an urban hospital in Canada with unique manifestations of ARF. Diagnosis of ARF in the first patient was interrupted by a course of steroids which masked symptoms leading to therapeutic delays. The second patient presented with facial droop and symptoms thought to be viral, thus leading to misdiagnosis as Bell's palsy. Discussion/Conclusion. ARF is more common in underserviced and marginalized populations, which may lead clinicians in urban centers to overlook signs or symptoms suggestive of ARF because they no longer see this condition routinely, or they believe it is a disease of the past.	0
BACKGROUND/AIM:Although chemotherapy agents, such as oxaliplatin, cisplatin, paclitaxel and bortezomib frequently cause severe peripheral neuropathy, very few studies have reported the effective strategy to prevent this side effect. In this study, we first investigated whether these drugs show higher neuropathy compared to a set of 15 other anticancer drugs, and then whether antioxidants, such as sodium ascorbate, N-acetyl-L-cysteine, and vitamin B12 have any protective effect against them. MATERIALS AND METHODS:Rat PC12 cells were induced to differentiate into neuronal cells by repeated overlay of serum-free medium supplemented with nerve growth factor. The cytotoxic levels of anticancer drugs against four human oral squamous cell carcinoma cell lines, three normal oral cells, and undifferentiated and differentiated PC12 cells were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Cells were sorted for apoptotic cells (distributed into subG1 phase) and cells at different stages of cell cycle (G1, S and G2/M). RESULTS:All 19 anticancer drugs showed higher cytotoxicity against PC12 compared to oral normal cells. Among them, bortezomib showed the highest cytotoxicity against both undifferentiated and differentiated PC12 cell and, committed them to undergo apoptosis. Sodium ascorbate and N-acetyl-L-cysteine, but not vitamin B12, completely reversed the cytotoxicity of bortezomib. CONCLUSION:Bortezomib-induced neuropathy might be ameliorated by antioxidants.	0
Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterised by impaired glucose liver homeostasis and proximal renal tubular dysfunction. It is caused by pathogenic variants in SLC2A2 coding for the glucose transporter GLUT2. Main clinical features include hepatomegaly, fasting hypoglycaemia, postprandial hyperglycaemia, Fanconi-type tubulopathy occasionally with rickets, and a severe growth disorder. While treatment for renal tubular dysfunction is well established, data regarding optimal nutritional therapy are scarce. Similarly, detailed clinical evaluation of treated FBS patients is lacking. These unmet needs were an incentive to conduct the present pilot study. We present clinical findings, laboratory parameters and molecular genetic data on 11 FBS patients with emphasis on clinical outcome under various nutritional interventions. At diagnosis, the patients' phenotypic severity could be classified into two categories: a first group with severe growth failure and rickets, and a second group with milder signs and symptoms. Three patients were diagnosed early and treated because of family history. All patients exhibited massive glucosuria at diagnosis and some in both groups had fasting hypoglycaemic episodes. Growth retardation improved drastically in all five patients treated by intensive nutritional intervention (nocturnal enteral nutrition) and uncooked cornstarch with final growth parameters in the normal range. The four severely affected patients who were treated with uncooked cornstarch alone did not catch up growth. All patients received electrolytes and l-carnitine supplementation to compensate for the tubulopathy. This is one of the largest series of FBS on therapeutic management with evidence that nocturnal enteral nutrition rescues growth failure.	0
BACKGROUND:Alveolar macrophages (AMs) are the primary targets of silicosis. Blockade of autophagy may aggravate the apoptosis of AMs. Trehalose (Tre), a transcription factor EB (TFEB) activator, may impact the autophagy-lysosomal system in AMs during silicosis. However, the mechanism by which Tre acts upon AMs in silicosis is unknown. METHODS:We collected AMs from twenty male workers exposed to silica and divided them into observer and silicosis patient groups. AMs from the two groups were then exposed to Tre. Western blot was used to measure the expression of autophagy-associated proteins. Lysosomal-associated membrane protein 1 (LAMP1) expression was observed using immunofluorescence and western blot. Apoptosis of the AMs was detected by TUNEL assay and western blot. RESULTS:Tre induced localization of TFEB to the nucleus in the AMs of both groups. After Tre exposure, LAMP1 levels increased and LC3 levels decreased in the AMs of both groups, suggesting that Tre may increase the function of the autophagy-lysosomal system. The LC3-II/I ratio in the Tre-exposed AMs was lower than in the AMs not exposed to Tre. The LC3-II/I ratio in AMs subjected to Tre plus Bafilomycin (Baf) was higher than the ratio in cells exposed to Tre or Baf individually. Additionally, p62 levels decreased after Tre stimulation in the AMs of both groups. This indicates that Tre may accelerate the process of autophagic degradation. We also found decreased levels of cleaved caspase-3 after Tre treatment in the AMs of both groups. However, p-mTOR (Ser2448) and p-mTOR (Ser2481) levels did not change significantly after Tre treatment, suggesting that the mTOR signaling pathway was not affected by Tre treatment. CONCLUSION:Our findings suggest that the restoration of autophagy-lysosomal function by Tre may be a potential protective strategy against silicosis.	0
Maturity-onset diabetes of the young (MODY) is the most common monogenetic diabetes, which is easily misdiagnosed. We describe the first Chinese MODY4 family with a novel mutation, indicating that MODY4 cannot be excluded in early-onset obese diabetes, and pancreatic exocrine dysfunction could be present in MODY4.	0
BACKGROUND:Disseminated superficial actinic porokeratosis (DSAP) is a rare autosomal dominant disease. In our previous research, we found that a linkage region of DSAP in a large family is located at 12q23·2-q24·1. Subsequently, the mevalonate kinase gene (MVK) was shown to be pathogenic in DSAP. OBJECTIVES:To elucidate the mechanism by which MVK mutations lead to keratinocyte apoptosis and DSAP, and to report a new missense mutation, c.566 C>T (p.A189V), in MVK in a Chinese DSAP pedigree. METHODS:The half-life of wild-type (WT) MVK protein and mutants was assessed using cycloheximide treatment of cells. Dimerization of MVK was analysed by coimmunoprecipitation and glutathione S transferase pull-down assay. MVK kinase activity, production of cell cholesterol, mitochondrial complex activity and apoptosis were detected, using the corresponding commercial kits, in cells overexpressing MVK WT and mutants. RESULTS:Mechanically, we demonstrated that both the pathogenic p.A189V mutant and a sporadic mutation p.H312R (c.935A>G), which we reported previously, have rapid degradation, decreased kinase activity and reduced production of cell cholesterol. Also, we found the p.H312R mutation confers on the MVK protein an inability to dimerize. Further, we demonstrated that the mutants are impaired in mitochondrial function and lead to increased apoptosis. CONCLUSIONS:Our results provide an important basis for elucidating the mechanism by which MVK missense mutations contribute to DSAP.	0
BACKGROUND:Likely pathogenic variants in SLC17A5 results in allelic disorders of free sialic acid metabolism including (1) infantile free sialic acid storage disease with severe global developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; (2) intermediate severe Salla disease with moderate to severe global developmental delay, hypotonia, and hypomyelination with or without coarse facial features, and (3) Salla disease with normal appearance, mild cognitive dysfunction, and spasticity. PATIENT DESCRIPTION:This five-year-old girl presented with infantile-onset severe global developmental delay, truncal hypotonia, and generalized dystonia following normal development during her first six months of life. Brain magnetic resonance imaging showed marked hypomyelination and a thin corpus callosum at age 19 months, both unchanged on follow-up at age 28 months. Urine free sialic acid was moderately elevated. Cerebrospinal fluid free sialic acid was marginally elevated. Sequencing of SLC17A5 revealed compound heterozygous likely pathogenic variants, namely, a known missense (c.291G>A) variant and a novel truncating (c.819+1G>A) variant, confirming the diagnosis of Salla disease at age 3.5 years. CONCLUSION:We report a new patient with intermediate severe Salla disease. Normal or marginally elevated urine or cerebrospinal fluid free sialic acid levels cannot exclude Salla disease. In patients with progressive global developmental delay and hypomyelination on brain magnetic resonance imaging, Salla disease should be included into the differential diagnosis.	0
Neuroblastoma is a clinically heterogenous pediatric cancer of the sympathetic nervous system that originates from neural crest cells. It is the most common extracranial solid tumor in childhood and prognosis ranges from spontaneous tumor regression to aggressive disease resistant to multimodal therapy. Prognosis depends on patient characteristics and tumor biology that determine risk classification. Advancements in therapy reductions are merited for low- and intermediate-risk neuroblastoma patients, who generally have excellent outcomes. Of the patients with high-risk disease, only 50% achieve long-term survival, and therapeutic advancements are needed. Over the past several decades, genomic features such as germline mutations, somatic genetic aberrations, chromosome copy number, transcriptomics, and epigenetics have proven to contribute to the pathogenesis of neuroblastoma. The primary predisposition genes in familial neuroblastoma are ALK and PHOX2B. Sporadic neuroblastoma arises with complex pathogenesis, but chromosomal abnormalities and single-nucleotide polymorphisms have been identified to cooperatively lead to oncogenesis. These advances have led to new therapeutic approaches with the potential to improve outcomes for children with neuroblastoma.	0
Purpose:To report a severe phenotype of retinitis pigmentosa associated with novel mutations in CNGB1. Observations:Six siblings, age range 50-75 years old, were examined using optical coherence tomography and fundus autofluorescene, electroretinogram testing, Goldman visual field testing, and genetic testing using next generation sequencing.In four affected siblings, two novel compound heterozygous variants in CNGB1 were detected: in exon 26 the missense variant c.2603G > A (p.(Gly868Asp)), and in exon 21, the in-frame 12-bp duplication c.2093_2104dupGCGACCTCATCT (p.(Cys698_lle701dup)). One sibling was unaffected and carried neither of the variants, while another sibling had mild macular degeneration changes and carried the latter variant in heterozygous status. The affected siblings presented with a phenotype showing markedly constricted visual field, flat scotopic and photopic electroretinogram responses and generalized retinal atrophy. Conclusions and importance:This is the first report of a 12bp in-frame duplication and a missense variant (in compound heterozygous status) in CNGB1, being associated with a severe form of retinitis pigmentosa featuring extensive peripheral and central retinal degeneration. This study expands the molecular genetic basis of CNGB1-related disease.	0
Synpolydactyly type 1 (SPD1, OMIM 186000) is inherited as autosomal dominant and is caused by HOXD13 mutations. The condition is rare and is known for its phenotypic heterogeneity. In the homozygous state, the phenotype is generally more severe and is characterized by three main features: a more severe degree of syndactyly, a more severe degree of brachydactyly, and the frequent loss of the normal tubular shape of the metacarpals/metatarsals. Due to the phenotypic heterogeneity and the phenotypic overlap with other types of syndactyly, no pathognomonic feature has been described for the homozygous phenotype of SPD1. In the current communication, the author reviews the literature on the phenotypes of SPD1 in homozygous patients. The review documents that not all homozygous patients show a severe hand phenotype. The review also defines the "relatively long and medially deviated big toe with/without cupping of the forefoot" as a pathognomonic feature in the phenotype. Illustration of this feature is done through a demonstrative clinical report in a multigeneration family with SPD1 and HOXD13 polyalanine repeat expansion. Finally, the pathogenesis of the clinical features is reviewed.	0
Hydroxychloroquine (HCQ) suppresses an interleukin-1β-granulocyte-macrophage colony-stimulating factor cytokine axis, reported to be dysregulated in peripheral blood mononuclear cells of acute rheumatic fever patients ex vivo. We describe HCQ treatment for 2 patients with rheumatic carditis and a protracted inflammatory course. HCQ was associated with control of inflammatory markers, control of pericarditis in first patient and stabilization of progressive carditis in the second patient.	0
Genetic medicine applied to the study of hemochromatosis has identified the systemic loop controlling iron homeostasis, centered on hepcidin-ferroportin interaction. Current challenges are to dissect the molecular pathways underlying liver hepcidin synthesis in response to circulatory iron, HFE, TFR2, HJV, TMPRSS6 and BMP6 functions, and to define the major structural elements of hepcidin-ferroportin interaction. We built a first 3D model of human ferroportin structure, using the crystal structure of EmrD, a bacterial drug efflux transporter of the Major Facilitator Superfamily, as template. The model enabled study of disease-associated mutations, and guided mutagenesis experiments to determine the role of conserved residues in protein stability and iron transport. Results revealed novel amino acids that are critical for the iron export function and the hepcidin-mediated inhibition mechanism: for example, tryptophan 42, localized in the extracellular end of the ferroportin pore and involved in both biological functions. Here, we propose a strategy that is not limited to structure analysis, but integrates information from different sources, including human disease-associated mutations and functional in vitro assays. The first major hypothesis of this PhD thesis is that ferroportin resistance to hepcidin relies on different molecular mechanisms that are critical for ferroportin endocytosis, and include at least three fundamental steps: (i) hepcidin binding to ferroportin, (ii) structural reorganization of the N- and C-ter ferroportin lobes, and (iii) ferroportin ubiquitination.	0
Untreated progressive familial intrahepatic cholestasis (PFIC) type 2, or bile salt exporter protein deficiency, frequently leads to severe pruritus, impaired growth and progressive liver fibrosis with risk of organ failure. We describe a 15-month-old male patient with severe pruritus diagnosed with PFIC type 2 enrolled in an open-label phase 2 study who received 4 weeks of treatment with odevixibat, an ileal bile acid transporter inhibitor under development for cholestatic liver disease treatment. The patient experienced reductions in serum bile acids and improvement in itching and sleep scores, and odevixibat was well tolerated. After the odevixibat study, symptoms returned and the patient underwent partial external biliary diversion (PEBD). Odevixibat treatment and PEBD produced similar normalisation of serum bile acid levels and improvements in pruritus and sleep disruptions. Thus, odevixibat appeared to be as effective as invasive PEBD in treating serum bile acids and cholestatic pruritus in this patient.	0
Acalvaria is described as a rare congenital malformation in a 1-month-old female baby who presented with classical clinical features of soft, lax skull as a result of absent skull bones and associated muscles. Acalvaria is usually a fatal anomaly and is rarely discussed in English literature. Thus, we herein report a living case of acalvaria along with a review of the literature.	0
BACKGROUND AND OBJECTIVES:Rapid-onset dystonia-parkinsonism (RDP) is caused by mutations in the ATP1A3 gene, which codes for the α-3 subunit of the Na+ /K+ ATPase. It has been characterized by rapid-onset bulbar dysfunction, limb dystonia, bradykinesia, and a rostrocaudal spatial gradient of expression, usually after a physiologic trigger. We reexamined whether these features were in fact characteristic. METHODS:We characterized phenotypic variation within a cohort of 50 ATP1A3 mutation-positive individuals (carriers) and 44 mutation-negative family members (noncarriers). Potential participants were gathered through referral for clinical suspicion of RDP or alternating hemiplegia of childhood. Inclusion criteria were having a ATP1A3 mutation or being a family member of such an individual. RESULTS:We found RDP is underdiagnosed if only "characteristic" patients are tested. Rapid onset and bulbar predominance were not universally present in carriers. Among those with at least mild symptoms of dystonia, rostrocaudal severity gradient was rare (7%). Symptoms began focally but progressed to be generalized (51%) or multifocal (49%). Arm (41%) onset was most common. Arms and voice were typically most severely affected (48% and 44%, respectively). Triggers preceded onset in 77% of the participants. Rapid onset, dystonia, parkinsonism, bulbar symptoms, headaches, seizures, frontal impairment, and a history of mood disorder and a history of psychosis were more common in carriers. Approximately half of the proband mutations occurred de novo (56%). CONCLUSIONS:Our findings suggest that patients should not be excluded from ATP1A3 testing because of slow onset, limb onset, absent family history, or onset in middle adulthood. RDP should be strongly considered in the differential for any bulbar dystonia. © 2019 International Parkinson and Movement Disorder Society.	0
Background: REEP1 is a common cause of autosomal dominant hereditary spastic paraplegia (HSP) but is rare in China. The pathological mechanism of REEP1 is not fully understood. Methods: We screened for REEP1 mutations in 31 unrelated probands from Chinese HSP families using next-generation sequencing targeting pathogenic genes for HSP and other related diseases. All variants were validated by Sanger sequencing. The proband family members were also screened for variants for the segregation analysis. All previously reported REEP1 mutations and cases were reviewed to clarify the genetic and clinical features of REEP1-related HSP. Results: A pathogenic mutation, REEP1c. 125G>A (p.Trp42*), was detected in a pure HSP family from North China out of 31 HSP families (1/31). This locus, which is located in the second hydrophobic domain of REEP1, is detected in both Caucasian patients with complicated HSP phenotypes and Chinese pure HSP families. Conclusion: REEP1-related HSP can be found in the Chinese population. The 42nd residue is a novel transethnic mutation hotspot. Mutations in this spot can lead to both complicated and pure form of HSP. Identification of transethnic hotspot will contribute to clarify the underlying pathological mechanisms.	0
Congenital disorders of glycosylation (CDG) represent an expanding family of metabolic disorders with a wide range of biochemical, molecular and clinical phenotypes. ALG3-CDG (CDG-Id), due to a defect in endoplasmic reticulum (ER) mannosyltransferase VI, is one of the less common types of CDG-I. We describe two Vietnamese siblings with confirmed ALG3-CDG (CDG-Id) by molecular testing. As far as we are aware, they are the oldest reported patients in the literature at 15 and 21years. They share similar clinical features with previously reported patients including facial dysmorphism, severe psychomotor retardation, microcephaly, seizures, and gastrointestinal symptoms. Furthermore, our sibling pair highlights the intrafamilial variability, the natural clinical course of ALG3-CDG (CDG-Id) and the benefit of reassessing patients with undiagnosed and complex syndromes, particularly when they present with neurological deterioration.	0
To evaluate the role of neoadjuvant chemotherapy and radiotherapy in the treatment of central nervous system germinomas in 38 patients who received definitive treatment and were followed-up >5 years between 1980 and 2009.The median age at diagnosis and follow-up period were 16.5 years and 128.3 months, respectively. Treatment was irradiation alone or adjuvant platinum-based chemotherapy followed by reduced-dose local irradiation. Seven patients progressed at 12.9-133.9 months and 1 died of disease 89.3 months after therapy initiation.The treatment strategies were divided into 3 groups: group A (1980-1988, n = 5), whole brain with local irradiation; group B (1989-2002, n = 16), chemotherapy with or without reduced irradiation dose; and group C (2003-2009, n = 17): neoadjuvant chemotherapy (3 courses) followed by 30.6 Gy of whole ventricle irradiation for patients with localized complete response, and additional local boost of 19.8 Gy for others. There were 7 recurrent cases, all in group B. The progression-free survival was significantly longer in groups A and C versus group B (P < 0.001). Decreased Karnofsky performance status was observed in 2 (40%), 6 (37.5%), and 0 cases in groups A-C, respectively. The main reasons for the good results in group C might be the neoadjuvant chemotherapy with whole ventricle radiotherapy and introduction of neuroendoscopy, especially for pineal lesions, resulting in a substantial reduction of time from the diagnosis to first treatment.Chemotherapy followed by whole ventricle radiotherapy, with or without local boost, and with use of neuroendoscopy results in good disease control without late complications in patients with germinomas.	0
BACKGROUND:Store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ channels is an essential signaling pathway in many cell types. Ca2+ release-activated Ca2+ channels are formed by ORAI1, ORAI2, and ORAI3 proteins and activated by stromal interaction molecule (STIM) 1 and STIM2. Mutations in the ORAI1 and STIM1 genes that abolish SOCE cause a combined immunodeficiency (CID) syndrome that is accompanied by autoimmunity and nonimmunologic symptoms. OBJECTIVE:We performed molecular and immunologic analysis of patients with CID, anhidrosis, and ectodermal dysplasia of unknown etiology. METHODS:We performed DNA sequencing of the ORAI1 gene, modeling of mutations on ORAI1 crystal structure, analysis of ORAI1 mRNA and protein expression, SOCE measurements, immunologic analysis of peripheral blood lymphocyte populations by using flow cytometry, and histologic and ultrastructural analysis of patient tissues. RESULTS:We identified 3 novel autosomal recessive mutations in ORAI1 in unrelated kindreds with CID, autoimmunity, ectodermal dysplasia with anhidrosis, and muscular dysplasia. The patients were homozygous for p.V181SfsX8, p.L194P, and p.G98R mutations in the ORAI1 gene that suppressed ORAI1 protein expression and SOCE in the patients' lymphocytes and fibroblasts. In addition to impaired T-cell cytokine production, ORAI1 mutations were associated with strongly reduced numbers of invariant natural killer T and regulatory T (Treg) cells and altered composition of γδ T-cell and natural killer cell subsets. CONCLUSION:ORAI1 null mutations are associated with reduced numbers of invariant natural killer T and Treg cells that likely contribute to the patients' immunodeficiency and autoimmunity. ORAI1-deficient patients have dental enamel defects and anhidrosis, representing a new form of anhidrotic ectodermal dysplasia with immunodeficiency that is distinct from previously reported patients with anhidrotic ectodermal dysplasia with immunodeficiency caused by mutations in the nuclear factor κB signaling pathway (IKBKG and NFKBIA).	0
Branchio-oto-renal syndrome is characterized by branchial defects, hearing loss, preauricular pits, and renal anomalies. Mutations in EYA1 are the most common cause of branchio-oto-renal and branchio-otic syndromes. Large chromosomal aberrations of 8q13, including complex rearrangements occur in about 20% of these individuals. However, submicroscopic deletions and the molecular characterization of genomic rearrangements involving the EYA1 gene have rarely been reported. Using the array-comparative genomic hybridization, we identified non-recurrent genomic deletions including the EYA1 gene in three patients with branchio-oto-renal syndrome, short stature, and developmental delay. One of these deletions was mediated by two human endogenous retroviral sequence blocks, analogous to the AZFa microdeletion on Yq11, responsible for male infertility. This report describes the expanded phenotype of individuals, resulting from contiguous gene deletion involving the EYA1 gene and provides a molecular description of the genomic rearrangements involving this gene in branchio-oto-renal syndrome.	0
AIMS:Nakajo-Nishimura syndrome (NNS) is an autosomal recessive disease caused by biallelic mutations in the PSMB8 gene that encodes the immunoproteasome subunit β5i. There have been only a limited number of reports on the clinicopathological features of the disease in genetically confirmed cases. METHODS:We studied clinical and pathological features of three NNS patients who all carry the homozygous p.G201V mutations in PSMB8. Patients' muscle specimens were analysed with histology and immunohistochemistry. RESULTS:All patients had episodes of typical periodic fever and skin rash, and later developed progressive muscle weakness and atrophy, similar to previous reports. Oral corticosteroid was used for treatment but showed no obvious efficacy. On muscle pathology, lymphocytes were present in the endomysium surrounding non-necrotic fibres, as well as in the perimysium perivascular area. Nearly all fibres strongly expressed MHC-I in the sarcolemma. In the eldest patient, there were abnormal protein aggregates in the sarcoplasm, immunoreactive to p62, TDP-43 and ubiquitin antibodies. CONCLUSIONS:These results suggest that inflammation, inclusion pathology and aggregation of abnormal proteins underlie the progressive clinical course of the NNS pathomechanism.	0
Frontonasal dysplasia is an unusual congenital condition with a wide phenotypic range. Because of this, only a small number of cases and their management have been reported in the literature. The ideal surgical procedures to correct mild cases of frontonasal dysplasia, and the time to perform them, are still controversial. The case of a 9-month-old girl with a mild form of this condition (a congenital bifid nose and a duplicated frenulum), and its surgical management, is presented. The surgery achieved an early improvement of the patient's appearance and she had no complications. In the future, it is probable that she will need secondary rhinoplasty to aid in the projection of the tip and refine the shape of the nose.	0
PURPOSE OF REVIEW:The discovery of new disease-causing genes and availability of next-generation sequencing platforms have both progressed rapidly over the last few years. For the practicing neurologist, this presents an increasingly bewildering array both of potential diagnoses and of means to investigate them. We review the latest newly described genetic conditions associated with dystonia, and also address how the changing landscape of gene discovery and genetic testing can best be approached, from both a research and a clinical perspective. RECENT FINDINGS:Several new genetic causes for disorders in which dystonia is a feature have been described in the last 2 years, including ZNF142, GSX2, IRF2BPL, DEGS1, PI4K2A, CAMK4, VPS13D and VAMP2. Dystonia has also been a newly described feature or alternative phenotype of several other genetic conditions, notably for genes classically associated with several forms of epilepsy. The DYT system for classifying genetic dystonias, however, last recognized a new gene discovery (KMT2B) in 2016. SUMMARY:Gene discovery for dystonic disorders proceeds rapidly, but a high proportion of cases remain undiagnosed. The proliferation of rare disorders means that it is no longer realistic for clinicians to aim for diagnosis to the level of predicting genotype from phenotype in all cases, but rational and adaptive use of available genetic tests can certainly expedite diagnosis.	0
BACKGROUND:Hereditary ataxia is a group of neurodegenerative diseases with progressive cerebellar ataxia of the gait and limbs as the main symptoms. The genetic patterns of the disease are diverse but it is mainly divided into autosomal dominant cerebellar ataxia (ADCA) and autosomal recessive cerebellar ataxia (ARCA), and about 45 pathogenic loci have been found in ADCA. The purpose of this study was to explore the genetic defect in a Chinese family with ADCA. METHODS:A three-generation Chinese family with ADCA was enrolled in this study, Exome sequencing was conducted in four family members, including the proband, and verified by Sanger sequencing. RESULTS:The rs779393130 mutation of the CACNA1C gene co-segregated with the ataxia phenotype in this family. The mutation was not detected in 50 unaffected controls. CONCLUSIONS:The rs779393130 mutation of CACNA1C may be associated with the phenotype of the disease. The CACNA1C gene encodes the Cav1.2 (alpha-1) subunit of an L-type calcium channel and this subunit may be related to the ADCA phenotype. These findings may have implications for family clinical monitoring and genetic counseling and may also help in understanding pathogenesis of this disease.	0
Chondrodystrophy results in predictable and progressive biochemical and structural changes to the intervertebral disc, resulting in early onset degeneration and dystrophic mineralization of the disc. Accelerated degeneration and mineralization of the intervertebral disc are common in multiple dog breeds and can result in compromised function, herniation, pain, and a variety of neurological sequelae. A mutation responsible for chondrodystrophy in dogs has been identified as an aberrant fibroblast growth factor 4 (FGF4) retrogene insertion on chromosome 12 (CFA12) and is associated with short stature of the Nova Scotia Duck Tolling Retriever. Segregation of the CFA12 FGF4 retrogene in this dog breed provides an opportunity to examine the effect of retrogene presence on radiographic and histologic appearance of chondrodystrophic disc degeneration within a single breed. Here we found that in the intervertebral discs isolated from 2 dogs with the CFA12 FGF4 genotype, the nucleus pulposus was largely replaced by cartilaginous tissue, and physaliferous notochordal cells were rarely if ever identified. These findings are in contrast to the normal histologic findings in 2 breed-matched dogs lacking the mutation. The findings are consistent with premature chondroid degeneration of the intervertebral disc and suggest that the presence of the CFA12 FGF4 retrogene is sufficient to cause the chondrodystrophic phenotype.	0
BACKGROUND:Brachydactyly, a developmental disorder, refers to shortening of hands/feet due to small or missing metacarpals/metatarsals and/or phalanges. Isolated brachydactyly type E (BDE), characterized by shortened metacarpals and/or metatarsals, consists in a small proportion of patients with Homeobox D13 (HOXD13) or parathyroid-hormone-like hormone (PTHLH) mutations. BDE is often accompanied by other anomalies that are parts of many congenital syndromes. In this study, we investigated a Chinese family presented with BDE combined with pectus carinatum and short stature. METHODS:A four-generation Chinese family was recruited in June 2016. After informed consent was obtained, venous blood was collected, and genomic DNA was extracted by standard procedures. Whole-exome sequencing was performed to screen pathogenic mutation, array comparative genomic hybridization (Array-CGH) analysis was used to analyze copy number variations, and quantitative real-time polymerase chain reaction (PCR), stride over breakpoint PCR (gap-PCR), and Sanger sequencing were performed to confirm the candidate variation. RESULTS:A 3.06-Mb deletion (chr12:25473650-28536747) was identified and segregated with the phenotype in this family. The deletion region encompasses 23 annotated genes, one of which is PTHLH which has been reported to be causative to the BDE. PTHLH is an important regulator of endochondral bone development. The affected individuals showed bilateral, severe, and generalized brachydactyly with short stature, pectus carinatum, and prematurely fusion of epiphyses. The feature of pectus carinatum has not been described in the PTHLH-related BDE patients previously. CONCLUSIONS:The haploinsufficiency of PTHLH might be responsible for the disease in this family. This study has expanded the knowledge on the phenotypic presentation of PTHLH variation.	0
This study aimed to evaluate the outcomes and described the recovery process of cryopreserved limbal lamellar keratoplasty (CLLK) for peripheral corneal and limbal diseases. Thirteen eyes of 12 patients with a mean age of 41±23.9y were included. The average follow-up was 12.1±5.6mo. Stable ocular surface was achieved in all eyes at last follow-up. Epithelialization originated from both recipient and graft in 9 eyes. We conclude that CLLK compensates for the shortage of donor corneas and cryopreserved limbal grafts provide epithelialization sources in ocular surface reconstruction.	0
Inheritable and de novo variants in the cardiac voltage-gated sodium channel, Nav1.5, are responsible for both long-QT syndrome type 3 (LQT3) and Brugada syndrome type 1 (BrS1). Interestingly, a subset of Nav1.5 variants can cause both LQT3 and BrS1. Many of these variants are found in channel structures that form the channel fast inactivation machinery, altering the rate, voltage dependence, and completeness of the fast inactivation process. We used a series of mutants at position 1784 to show that the most common inheritable Nav1.5 variant, E1784K, alters fast inactivation through two separable mechanisms: (1) a charge-dependent interaction that increases the noninactivating current characteristic of E1784K; and (2) a hyperpolarized voltage dependence and accelerated rate of fast inactivation that decreases the peak sodium current. Using a homology model built on the NavPaS structure, we find that the charge-dependent interaction is between E1784 and K1493 in the DIII-DIV linker of the channel, five residues downstream of the putative inactivation gate. This interaction can be disrupted by a positive charge at position 1784 and rescued with the K1493E/E1784K double mutant that abolishes the noninactivating current. However, the double mutant does not restore either the voltage dependence or rates of fast inactivation. Conversely, a mutant at the bottom of DIVS4, K1641D, causes a hyperpolarizing shift in the voltage dependence of fast inactivation and accelerates the rate of fast inactivation without causing an increase in noninactivating current. These findings provide novel mechanistic insights into how the most common inheritable arrhythmogenic mixed syndrome variant, E1784K, simultaneously decreases transient sodium currents and increases noninactivating currents, leading to both BrS1 and LQT3.	0
This case report depicts the clinical course of a female patient with unilateral retinitis pigmentosa (RP), who presented first in 1984 at the age of 43 years. At the beginning, there were cells in the vitreous leading to the diagnosis of uveitis with vasculitis. Within 30 years, the complete clinical manifestation of RP developed with bone spicule-shaped pigment deposits, pale optic disc, narrowed arterioles, cystoid macular oedema, posterior subcapsular cataract, concentric narrowing of the visual field and undetectable electroretinogram signal. At the age of 72 years, there are still no signs of retinal dystrophy in the other eye.	0
BACKGROUND:The Houge type of X-linked syndromic mental retardation is an X-linked intellectual disability (XLID) recently recorded in the Online Mendelian Inheritance in Man (OMIM) and only 8 cases have been reported in literature thus far. CASE PRESENTATION:We present two brothers with intractable seizures and syndromic intellectual disability with symptoms consisting of delayed development, intellectual disability, and speech and language delay. The mother was a symptomatic carrier with milder clinical phenotype. Whole exome sequencing identified a small fragment deletion spanning four exons, about 9.5 kilobases (kb) in length in the CNKSR2 gene in the patients. The mutation co-segregation revealed that exon deletions occurred de novo in the proband's mother. CONCLUSION:Although large deletions have been reported, no small deletions have yet been identified. In this case report, we identified a small deletion in the CNKSR2 gene. This study enhances our knowledge of the CNKSR2 gene mutation spectrum and provides further information about the phenotypic characteristics of X-linked syndromic intellectual disability.	0
Spinal muscular atrophy (SMA) is caused by a deletion or mutation of the survival motor neuron 1 (SMN1) gene. Reduced SMN levels lead to motor neuron degeneration and muscular atrophy. SMN protein localizes to the cytoplasm and Cajal bodies. Moreover, in myofibrils from Drosophila and mice, SMN is a sarcomeric protein localized to the Z-disc. Although SMN participates in multiple functions, including the biogenesis of spliceosomal small nuclear ribonucleoproteins, its role in the sarcomere is unclear. Here, we analyzed the sarcomeric organization of SMN in human control and type I SMA skeletal myofibers. In control sarcomeres, we demonstrate that human SMN is localized to the titin-positive M-band and actin-positive I-band, and to SMN-positive granules that flanked the Z-discs. Co-immunoprecipitation assays revealed that SMN interacts with the sarcomeric protein actin, α-actinin, titin, and profilin2. In the type I SMA muscle, SMN levels were reduced, and atrophic (denervated) and hypertrophic (nondenervated) myofibers coexisted. The hypertrophied myofibers, which are potential primary targets of SMN deficiency, exhibited sites of focal or segmental alterations of the actin cytoskeleton, where the SMN immunostaining pattern was altered. Moreover, SMN was relocalized to the Z-disc in overcontracted minisarcomeres from hypertrophic myofibers. We propose that SMN could have an integrating role in the molecular components of the sarcomere. Consequently, low SMN levels might impact the normal sarcomeric architecture, resulting in the disruption of myofibrils found in SMA muscle. This primary effect might be independent of the neurogenic myopathy produced by denervation and contribute to pathophysiology of the SMA myopathy.	0
AD-HIES or Job's syndrome is a primary immunodeficiency, caused by dominant negative mutations in signal transducer and activator of transcription (STAT) 3. The syndrome is characterized by infectious, immunologic, and non-immunologic manifestations and is associated with significant morbidity, mortality, and development of lymphomas. What has not yet been elucidated is the role of HSCT in the disease treatment spectrum. We review published cases of patients with AD-HIES that underwent HSCT and attempt to clarify at what stage HSCT should be considered and what are the complications.	0
Pulmonary vein stenosis is a rare and poorly understood condition causing obstruction of the large pulmonary veins and of blood flow from the lungs to the left atrium. This results in elevated pulmonary venous pressure and pulmonary edema, pulmonary hypertension, potentially cardiac failure, and death. Clinical signs of the disease include failure to thrive, increasingly severe dyspnea, hemoptysis, respiratory difficulty, recurrent respiratory tract infections/pneumonia, cyanosis, and subcostal retractions. On chest radiograph, the most frequent finding is increased interstitial, ground-glass and/or reticular opacity. Transthoracic echocardiography with pulsed Doppler delineates the stenosis, magnetic resonance imaging and multislice computerized tomography are used for further evaluation. Interventional cardiac catherization, surgical techniques, and medical therapies have been used with varying success as treatment options.	0
This study explores the potential usefulness of EEG for patient diagnosis by analyzing SCA3 and wt mice. Self-made implantable electrodes were constructed and implanted to extract EEG signals from the cerebral motor cortex and the cerebellar areas that are affected by the disease. Nonlinear dynamic analysis and EEG energy were used to distinguish between SCA3 and WT mice, and we found that all four were increased in SCA3 mice. The alpha and theta bands of LZ complexity were significantly higher in SCA3 mice than in the control group. Therefore, it was possible to distinguish between the two groups by the LZ complexity of their alpha and theta bands. Analysis of C0 complexity and approximate entropy showed that the random part in the disease group was larger than in the control group, and that in addition the randomness was increased in SCA3 mice. The spatial learning and memory were analyzed by means of the Morris water maze test (MWM), The results showed that the swimming velocity, distance traveled and latency to reach the platform in SCA3 mice were increased when compared with WT mice during the 4 training days (p < 0.05, 0.01 or 0.001). And the results are conform to the results of EEG signals. In conclusion, EEG signals could be used to identify SCA3 in mice. They may also be clinically useful for the diagnosis of cerebellar ataxia in patients, and for additional studies aimed at gaining a deeper understanding of spinal cerebral ataxia.	0
Gaucher Disease (GD) type 3 is a neurological form of a multisystemic autosomal recessive disorder belonging to the group of lysosomal storage diseases. Causal mutations in the glucocerebrosidase 1 (GBA1) commonly lead to abnormal protein and GD, heterozygosity is a genetic risk factor for Parkinson's disease. This work describes the use of a non-integrative approach using Sendai Virus delivery to establish induced Pluripotent Stem Cells (iPSCs) from fibroblasts from a GD type 3 patient. Differentiation of iPSCs can be employed to generate a variety of complex cell types with a high degree of genetic complexity that would otherwise be unattainable.	0
BACKGROUND:Noonan syndrome is an autosomal dominant disorder secondary to RASopathies, which are caused by germ-line mutations in genes encoding components of the RAS mitogen-activated protein kinase pathway. RIT1 (OMIM *609591) was recently reported as a disease gene for Noonan syndrome. METHODS AND RESULTS:We present a patient with RIT1-associated Noonan syndrome, who in addition to the congenital heart defect, had monocytosis, myeloproliferative disorder, and accelerated idioventricular rhythm that was associated with severe hemodynamic instability. Noonan syndrome was suspected given the severe pulmonary stenosis, persistent monocytosis, and "left-shifted" complete blood counts without any evidence of an infectious process. Genetic testing revealed that the patient had a heterozygous c.221 C>G (pAla74Gly) mutation in the RIT1. CONCLUSION:We report a case of neonatal Noonan syndrome associated with RIT1 mutation. The clinical suspicion for Noonan syndrome was based only on the congenital heart defect, persistent monocytosis, and myeloproliferative process as the child lacked all other hallmarks characteristics of Noonan syndrome. However, the patient had an unusually malignant ventricular dysrhythmia that lead to his demise. The case highlights the fact that despite its heterogeneous presentation, RIT1-associated Noonan syndrome can be extremely severe with poor outcome.	0
Muscle-eye-brain disease (MEB) is a recessively inherited rare disease. Sixteen different gene mutations are known, with the most common mutations in the POMGNT1 gene. The disease is now called congenital muscular dystrophy-dystroglycanopathy type A3 (MDDGA3). It manifests itself as muscular dystrophy with eye and brain anomalies and intellectual disability. Previous clinical reports describe young patients. We have been able to follow two patients for almost 40 years. Their clinical picture has remained quite stable since adolescence, appearing as severe intellectual and motor disability, extremely limited communication skills, visual impairment, epilepsy, joint contractures, repeated bowel obstructions, teeth abrasion due to bruxism, an irregular sleep pattern and as a previously unreported feature hypothermic periods manifesting as excessive sleepiness.	0
Shah-Waardenburg syndrome or Waardenburg syndrome type 4 (WS4) is a neurocristopathy characterized by the association of deafness, depigmentation and Hirschsprung disease. Three disease-causing genes have been identified so far for WS4: EDNRB, EDN3, and SOX10. SOX10 mutations, found in 45-55% of WS4 patients, are inherited in autosomal dominant way. In addition, mutations in SOX10 are also responsible for an extended syndrome involving peripheral and central neurological phenotypes, referred to as PCWH (peripheral demyelinating neuropathy, central dysmyelinating leucodystrophy, Waardenburg syndrome, Hirschsprung disease). Such mutations are mostly private, and a high intra- and inter-familial variability exists. In this report, we present a patient with WS4 and a second with PCWH due to SOX10 mutations supporting again the genetic and phenotypic heterogeneity of these syndromes. Interestingly, the WS4 family carries an insertion of 19 nucleotides in exon 5 of SOX10, which results in distinct phenotypes along three different generations: hypopigmentation in the maternal grandmother, hearing loss in the mother, and WS4 in the proband. Since mosaicism cannot explain the three different related-WS features observed in this family, we propose as the most plausible explanation the existence of additional molecular events, acting in an additive or multiplicative fashion, in genes or regulatory regions unidentified so far. On the other hand, the PCWH case was due to a de novo deletion in exon 5 of the gene. Efforts should be devoted to unravel the mechanisms underlying the intrafamilial phenotypic variability observed in the families affected, and to identify new genes responsible for the still unsolved WS4 cases.	0
We report about a patient with infantile-onset neurodegenerative disease associated with isolated mitochondrial respiratory chain complex III (cIII) deficiency. The boy, now 13 years old, presented with language regression and ataxia at 4 years of age and then showed a progressive course resulting in the loss of autonomous gait and speaking during the following 2 years. Brain MRI disclosed bilateral striatal necrosis. Sequencing of a panel containing nuclear genes associated with cIII deficiency revealed a previously undescribed homozygous rearrangement (c.782_786delinsGAAAAG) in TTC19 gene, which results in a frameshift with premature termination (p.Glu261Glyfs(*)8). TTC19 protein was absent in patient's fibroblasts. TTC19 encodes tetratricopeptide 19, a putative assembly factor for cIII. To date TTC19 mutations have been reported only in few cases, invariably associated with cIII deficiency, but presenting heterogeneous clinical phenotypes. We reviewed the genetic, biochemical, clinical and neuroradiological features of TTC19 mutant patients described to date.	0
Gallbladder cancer (GBC) is associated with various nongenetic and genetic factors. Lack of specific and sensitive diagnostic markers has significantly impacted the mortality of this disease. Here we discuss the recent discovery of epigenetic changes that show great promise as diagnostic biomarkers as well as potential therapeutic targets for GBC.	0
Background:Multiple sclerosis (MS) is a chronic central nervous system inflammatory demyelinating disease characterized by multiple lesions disseminated in time and space. The lesions often have characteristic imaging findings on magnetic resonance (MR) imaging and cerebrospinal fluid findings that lead to their diagnosis. At times, these lesions may resemble tumors due to their large size (>2 cm), significant vasogenic edema, and ring-enhancing MR imaging findings. Such lesions are described as tumefactive demyelinating lesions or tumefactive MS, and they are generally seen in aggressive forms of MS associated with rapid progression. Case Description:We report an uncommon but clinically significant case of transtentorial brain herniation secondary to malignant cerebral edema from tumefactive MS in a 50-year-old woman. After the initial diagnosis of MS, the patient continued to have progression of her white matter lesions suggesting evolution of her MS despite treatment with intravenous (IV) steroids, IV immunoglobulin, and plasmapheresis. She was admitted to the hospital with a new, large, ring-enhancing lesion that displayed significant mass effect from vasogenic edema and progressed, necessitating a decompressive hemicraniectomy. Conclusion:Tumefactive MS presents a unique pathology that can often mimic primary brain tumors. Although these lesions affect white matter and infrequently cause a significant amount of mass effect, they can act like a tumor, causing edema that generates sufficient intracranial pressure to cause transtentorial herniation.	0
Spinal muscular atrophy is an autosomal-recessive degenerative neuromuscular disease that has historically been categorized into 5 types based on the individual's best functional ability. Two rather remarkable treatments have recently been approved for commercial use, and both have markedly changed the natural history of this disease. Here the authors report several cases of individuals, ranging from infants to adults, to highlight diagnostic considerations, along with initial and long-term treatment considerations in these individuals who now have the potential for stabilization to significant improvement in functional outcomes.	0
Mutations in the guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) gene are rare. To date, 72 cases with GMPPB gene mutations have been reported. Herein, we reported a case of a 29-year-old Chinese male presenting with limb-girdle muscular dystrophy (LGMD) who was found to have two heterozygous GMPPB mutations. The patient had a progressive limb weakness for 19 years. His parents and elder brother were healthy. On examination he had a waddling gait and absent tendon reflexes in all four limbs. Electromyography showed myogenic damage. Muscle magnetic resonance imaging (MRI) showed fatty degeneration in the bilateral medial thigh muscles. High-throughput gene panel sequencing revealed that the patient carried compound heterozygous mutations in the GMPPB gene, c.553C>T (p.R185C, maternal inheritance) and c.346C>T (p.P116S, paternal inheritance). This case provides additional information regarding the phenotypic spectrum of GMPPB mutations in the Chinese population.	0
Coronary artery fistulas are rare and half of them are symptomatic. Diagnosis is confirmed by echocardiography and coronarography and can be precisely located by multislice CT-scan. We report the case of a 56-year-old female patient with congestive heart failure caused by a coronaro-cardiac fistula established between the proximal circumflex coronary artery and the right atrium. Surgical exclusion of the fistula was achieved by ligation of both extremities and a running suture on the aneurysmal vessel. Follow-up at 6 months was satisfactory with an asymptomatic patient and absence of recurrence of the fistula on echocardiography.	0
Alpers syndrome is a progressive encephalopathy of early onset, characterized by rapid and severe developmental delay, intractable seizures and liver involvement in a previously healthy child. Here, we report on respiratory chain enzyme deficiency in the liver of four unrelated children presenting with epileptic encephalopathy and liver involvement diagnosed as Alpers syndrome. Interestingly, oxidative phosphorylation in skeletal muscle was normal in 4/4 and blood and CSF lactate in 3/4 patients. Liver involvement had a late clinical onset in patients with previously isolated epileptic encephalopathy. Based on these observations, we suggest 1. to give consideration to respiratory chain deficiency in the diagnosis of severe epileptic encephalopathy in childhood, even when no clinical or biological evidence of liver involvement or lactic acidosis is noted, and 2. to investigate the respiratory chain in a needle biopsy of the liver in children with epileptic encephalopathy prior to valproate administration if biochemical indications for respiratory chain disease or hepatic disturbance are noted, as this drug is believed to occasionally trigger hepatic failure and fatal outcome.	0
In the disease familial amyloidosis, Finnish type (FAF), also known as AGel amyloidosis (AGel), the mechanism by which point mutations in the calcium-regulated actin-severing protein gelsolin lead to furin cleavage is not understood in the intact protein. Here, we provide a structural and biochemical characterization of the FAF variants. X-ray crystallography structures of the FAF mutant gelsolins demonstrate that the mutations do not significantly disrupt the calcium-free conformations of gelsolin. Small-angle X-ray-scattering (SAXS) studies indicate that the FAF calcium-binding site mutants are slower to activate, whereas G167R is as efficient as the wild type. Actin-regulating studies of the gelsolins at the furin cleavage pH (6.5) show that the mutant gelsolins are functional, suggesting that they also adopt relatively normal active conformations. Deletion of gelsolin domains leads to sensitization to furin cleavage, and nanobody-binding protects against furin cleavage. These data indicate instability in the second domain of gelsolin (G2), since loss or gain of G2-stabilizing interactions impacts the efficiency of cleavage by furin. To demonstrate this principle, we engineered non-FAF mutations in G3 that disrupt the G2-G3 interface in the calcium-activated structure. These mutants led to increased furin cleavage. We carried out molecular dynamics (MD) simulations on the FAF and non-FAF mutant G2-G3 fragments of gelsolin. All mutants showed an increase in the distance between the center of masses of the 2 domains (G2 and G3). Since G3 covers the furin cleavage site on G2 in calcium-activated gelsolin, this suggests that destabilization of this interface is a critical step in cleavage.	0
The porphyrias are genetically heterogeneous diseases, and each mutation is exclusive to one or two families. Among the mutations responsible for variegate porphyria in our country, c.1042_1043insT stands out, since it was described only in Argentina and is present in about 40% of genetically diagnosed families. Thus, we hypothesized the possible existence of a common ancestor for the mutation in our population.We conducted a study based on microsatellite (short tandem repeats) haplotypes.We found a common haplotype in all of the patients carrying the common mutation. The age of the mutation was estimated to be about 375 years.There is a recent founder effect in our population for this particular genetic alteration in variegate porphyria.	0
Purpose:The purpose of this study was to investigate the inflammatory response of cornea and conjunctiva to topically applied lipopolysaccharide (LPS) in mice with and without antibiotic (antibiotic cocktail, ABX) induced dysbiosis. Methods:Dysbiosis was induced by oral antibiotics for 14 days in a group of conventional female C57BL/6J (B6) mice. 16S rRNA sequencing investigated microbiome composition. Intestinal microbiome differences were assessed using 16S rRNA sequencing of fecal pellet DNA. Blood was collected after euthanasia. CD86 expression in draining nodes was examined by flow cytometry. At day 15, a single dose of LPS or vehicle was topically applied to ABX and naïve mice. Corneal epithelium and conjunctiva were obtained after 4 hours and processed for gene expression analysis. A separate group of germ-free (GF) B6 mice was also topically challenged with LPS. Results:Antibiotic treatment significantly decreased intestinal diversity and increased serum levels of LPS. This was accompanied by a significant increase in CD86+MHC II+CD11c+CD11b+ cells in draining nodes. Compared to vehicle, topically applied LPS increased IL-1β, TNF-α, and CXCL10 mRNA transcripts in cornea and IL-1β, TNF-α, and CXCL10 in the conjunctiva in conventional and antibiotic-treated groups. However, there was higher TNF-α, CXCL10, and IL-12 expression in the cornea of LPS-treated ABX mice compared to LPS-treated mice with intact microbiota. LPS stimulation on GF conjunctiva mirrored the results in ABX mice, although greater IL-12 and IFN-γ expression was observed in GF conjunctiva compared to conventional LPS-treated mice. Conclusions:Acute depletion of commensals through antibiotics or germ-free environment worsens the inflammatory response to LPS.	0
OBJECTIVE:Peripartum cardiomyopathy (PPCM) is a rare life-threatening cardiomyopathy of unknown cause that occurs in the peripartum period in previously healthy women. In April 1997, the National Heart, Lung, and Blood Institute (NHLBI) and the Office of Rare Diseases of the National Institutes of Health (NIH) convened a Workshop on Peripartum Cardiomyopathy to foster a systematic review of information and to develop recommendations for research and education. PARTICIPANTS:Fourteen workshop participants were selected by NHLBI staff and represented cardiovascular medicine, obstetrics, immunology, and pathology. A representative subgroup of 8 participants and NHLBI staff formed the writing group for this article and updated the literature on which the conclusions were based. The workshop was an open meeting, consistent with NIH policy. EVIDENCE:Data presented at the workshop were augmented by a MEDLINE search for English-language articles published from 1966 to July 1999, using the terms peripartum cardiomyopathy, cardiomyopathy, and pregnancy. Articles on the epidemiology, pathogenesis, pathophysiology, diagnosis, treatment, and prognosis of PPCM were included. RECOMMENDATION PROCESS: After discussion of data presented, workshop participants agreed on a standardized definition of PPCM, a general clinical approach, and the need for a registry to provide an infrastructure for future research. CONCLUSIONS:Peripartum cardiomyopathy is a rare lethal disease about which little is known. Diagnosis is confined to a narrow period and requires echocardiographic evidence of left ventricular systolic dysfunction. Symptomatic patients should receive standard therapy for heart failure, managed by a multidisciplinary team. If subsequent pregnancies occur, they should be managed in collaboration with a high-risk perinatal center. Systematic data collection is required to answer important questions about incidence, treatment, and prognosis.	1
WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), a primary immunodeficiency disorder involving panleukopenia, is caused by autosomal dominant gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Myelokathexis is neutropenia caused by neutrophil retention in bone marrow. Patients with WHIM syndrome are often treated with granulocyte colony-stimulating factor (G-CSF), which can increase neutrophil counts but does not affect cytopenias other than neutropenia. In this investigator-initiated, open-label study, three severely affected patients with WHIM syndrome who could not receive G-CSF were treated with low-dose plerixafor, a CXCR4 antagonist, for 19 to 52 months. Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus-associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly. Adverse events were mainly infections attributable to the underlying immunodeficiency. One patient died from complications of elective reconstructive surgery. (Funded by the National Institutes of Health.).	0
Purpose:To report a rare case of Vogt-Koyanagi-Harada disease likely secondary to post-infectious Mycoplasma pneumoniae autoimmune response in a 14-year-old Hispanic female. Observations:On presentation, visual acuity was 20/400 in the right eye and 20/20 in the left eye. The patient also had bilateral hyperemia, subretinal fluid, and vitreous cell graded at 1+. Fluorescein angiography and indocyanine green chorioangiography showed bilateral peripapillary hypofluorescence consistent with blocking and hyperflourescence consistent with staining. Laboratory testing showed elevated M. pneumoniae IgM and rising IgG antibodies. Topical steroids and oral steroids helped mitigate the systemic disease process and fully restore visual acuity through the 7-week mark. Conclusions and Importance:The patient had elevated M. pneumoniae IgM and rising IgG antibodies resulting in ocular inflammation likely secondary to an autoimmune response. In this case of post-infectious M. pneumoniae, topical corticosteroids were beneficial in mitigating ocular manifestations initially, although oral steroids were needed and tapered over 6 weeks.	0
OBJECTIVES:Congenital diarrheal disorders is a group of inherited enteropathies presenting in early life and requiring parenteral nutrition. In most cases, genetics may be the key for precise diagnosis. We present an infant girl with chronic congenital diarrhea that resolved after introduction of fructose-based formula but had no identified mutation in the SLC5A1 gene. Using whole exome sequencing (WES) we identified other mutations that better dictated dietary adjustments. METHODS:WES of the patient and her parents was performed. The analysis focused on recessive model including compound heterozygous mutations. Sanger sequencing was used to validate identified mutations and to screen the patient's newborn sister and grandparents. Expression and localization analysis were performed in the patient's duodenal biopsies using immunohistochemistry. RESULTS:Using WES we identified a new compound heterozygote mutation in sucrase-isomaltase (SI) gene; a maternal inherited known V577G mutation, and a novel paternal inherited C1531W mutation. Importantly, the newborn offspring carried similar compound heterozygous mutations. Computational predictions suggest that both mutations highly destabilize the protein. SI expression and localization studies determined that the mutated SI protein was not expressed on the brush border membrane in the patient's duodenal biopsies, verifying the diagnosis of congenital sucrase-isomaltase deficiency (CSID). CONCLUSIONS:The novel compound heterozygote V577G/C1531W SI mutations lead to lack of SI expression in the duodenal brush border, confirming the diagnosis of CSID. These cases of CSID extend the molecular spectrum of this condition, further directing a more adequate dietary intervention for the patient and newborn sibling.	0
Ravitch repair is a common surgical procedure to correct chest wall deformities. In this procedure, a subperichondreal cartilage resection of the deformed parasternal cartilage, and if necessary a repositioning of the sternum, is performed. Insufficient regeneration of the resected cartilage may result in sternocostal instability or even floating sternum. This rare complication presents with symptoms of pain and exercise intolerance. Methods:We describe sternocostal instability in 3 adolescent patients after the Ravitch procedure for pectus carinatum and reviewed the literature on this topic. Results:Our patients suffered different degrees of instability. In all cases, we eventually achieved a satisfactory outcome. There is little literature on sternocostal instability. It is a rare complication, mainly occurring after reoperation by damaging the perichondrium. Conclusions:Malunion of costal cartilage is a rare complication of open pectus repair. To achieve the best regeneration and stability of the sternum, less extended resection of cartilage should be performed and the number of cartilages resected should be limited. The perichondrium must be kept intact. Autologous grafts, growth-enhancing materials, and metal or bioabsorbable struts may contribute to stabilization and regeneration of the cartilage.	0
We decided to evaluate the efficacy and complications of uterine artery embolization (UAE) in patients with symptomatic uterine fibroids. Sixty-five premenopausal patients, without considering the fibroids size and its location, were treated by bilateral UAE. At baseline and after 3, 6, and 12 months MRI was obtained to determine the uterine length and fibroid diameter. In addition, symptoms of the patients were documented at these follow-up schedules. UAE was successful in 62 (95.4%) cases. Complete infarction rate of the fibroid was 83.1%. After 12 months, the uterine length showed a decrease of 55.7% (mean of 9.4 cm) and the diameter of the dominant fibroid revealed a decrease of 52.1% (mean of 3.4 cm). Menorrhagia improved in 45 cases (91.8%), abdominal mass in 24 cases (82.28%), urinary symptoms in 17 cases (85%), pelvic pain in 21 cases (84%), and dysmenorrhea in 25 cases (80.6%). At final follow-up performed after one year, complete infarction of the fibroma was demonstrated in 49 patients (83.1%). Two cases achieved successful pregnancy in the one year follow-up period. Five patients developed post-embolization syndrome which necessitated admission to the hospital. Twenty-two patients presented and complained of pain for which outpatient pain management was done. UAE was a successful treatment for uterine fibroids that preserved the uterus, had minimal complications, and required short hospitalization and recovery.	0
Rubella is a systemic virus infection that is usually mild. It can, however, cause severe birth defects known as the congenital rubella syndrome (CRS) when infection occurs early in pregnancy. As many as 8%-13% of children with CRS developed autism during the rubella epidemic of the 1960s compared to the background rate of about 1 new case per 5000 children. Rubella infection and CRS are now rare in the U.S. and in Europe due to widespread vaccination. However, autism rates have risen dramatically in recent decades to about 3% of children today, with many cases appearing after a period of normal development ('regressive autism'). Evidence is reviewed here suggesting that the signs and symptoms of rubella may be due to alterations in the hepatic metabolism of vitamin A (retinoids), precipitated by the acute phase of the infection. The infection causes mild liver dysfunction and the spillage of stored vitamin A compounds into the circulation, resulting in an endogenous form of hypervitaminosis A. Given that vitamin A is a known teratogen, it is suggested that rubella infection occurring in the early weeks of pregnancy causes CRS through maternal liver dysfunction and exposure of the developing fetus to excessive vitamin A. On this view, the multiple manifestations of CRS and associated autism represent endogenous forms of hypervitaminosis A. It is further proposed that regressive autism results primarily from post-natal influences of a liver-damaging nature and exposure to excess vitamin A, inducing CRS-like features as a function of vitamin A toxicity, but without the associated dysmorphogenesis. A number of environmental factors are discussed that may plausibly be candidates for this role, and suggestions are offered for testing the model. The model also suggests a number of measures that may be effective both in reducing the risk of fetal CRS in women who acquire rubella in their first trimester and in reversing or minimizing regressive autism among children in whom the diagnosis is suspected or confirmed.	0
Freeman-Sheldon and Sheldon-Hall syndromes (FSS and SHS) and distal arthrogryposis types 1 and 3 (DA1 and DA3) are rare, often confused, congenital syndromes. Few studies exist. With reported diagnosis unreliable, it would be scientifically inappropriate to consider articles describing FSS, SHS, DA1, or DA3, unless diagnoses were independently verified, rendering conventional systematic review and meta-analysis methodology inappropriate and necessitating patient-level data analysis (PROSPERO: CRD42015024740).As part of a clinical practise guideline development process, we evaluate (1) diagnostic accuracy from 1938-2017, using the Stevenson criteria; (2) the most common physical findings, possible frequency clusters, and complications of physical findings amongst patients with FSS; and (3) treatment types and outcomes. All papers reporting diagnosis of FSS, SHS, DA1, and DA3 are included in searching PubMed and Google Scholar from December 2014 to July 2015 and again before final analyses. Patients with FSS are divided into four phenotype-defined sub-types; all patients are grouped by published diagnosis and medical speciality. Significance of physical findings and historical data is evaluated by chi-square. Associations of physical findings and history with diagnosis and treatment outcome are evaluated by Pearson correlation and linear regression analysis. Two-tailed alpha level of 0.05 is used throughout.The need for detailed patient-level data extraction may limit the types of articles included and questions able to be answered. For treatment and psychosocial health outcomes, we anticipate enhanced difficulties, which may limit significance, power, and results' usability. We hope to outline knowledge gaps and prioritise areas for clinical investigation.CRD42015024740 Universal Trial Number: U1111-1172-4670.	0
Background. A novel mutation in the ACTG2 gene is described in a pregnant patient followed up for chronic intestinal pseudoobstruction (CIPO) during pregnancy and her fetus with megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS). Case. 24-year-old gravida 1 para 1 with CIPO and persistent nausea and vomiting in pregnancy, admitted at 28 weeks of gestation. Ultrasound revealed a fetus measuring greater than the 95th percentile, polyhydramnios, and megacystis. At delivery, the newborn was noted to have an enlarged bladder, microcolon, and intolerance of oral intake. Genetic testing of mother and child revealed a novel mutation in the ACTG2 gene (C632F>A, p.R211Q). Conclusion. This is the first case in the literature describing a novel mutation in ACTG2 associated with visceral myopathy affecting both mother and fetus/neonate. Visceral myopathy should be included in the differential diagnosis of megacystis diagnosed by ultrasound, and suspicion should increase with family history of CIPO or MMIHS.	0
BACKGROUND:Although recurrent anaplastic ependymoma in pediatric patients is not uncommon, recurrent disease leading to widespread metastases to the peritoneum is extremely rare. CASE REPORT:We present a case of an 18-month old male who initially presented with posterior fossa anaplastic ependymoma, who then proceeded to present 1 year later with spinal recurrence, and then 2 years after that with widespread disease involving the intracranial ventricular system and peritoneum. CONCLUSION:We posit that surgical interventions to treat primary and recurrent presentations in combination with a conduit to the peritoneum via a ventriculoperitoneal shunt contributed to the mechanisms of this complex case.	0
Hemophagocytic lymphohistiocytosis (HLH) is an uncommon, aggressive hematological syndrome. It is caused by an increased and unchecked proliferation of T lymphocytes and histiocytes. These cells secrete a large number of inflammatory cytokines and infiltrate various tissues causing multi-organ system failure. HLH may be primary or associated with different types of infections, autoimmune disorders, or malignancies. Primary or familial HLH is fatal and is frequently considered a disorder of infants and young children. Only a few cases of primary HLH have been reported in adults. We present a case of a 37-year-old man who presented with fever, pancytopenia, and hepatosplenomegaly. Lymph node biopsy showed collections of histiocytes with lymphoplasmacytic cells. After excluding all the secondary causes a final diagnosis of primary HLH was made. The patient was started on HLH-2004 protocol (etoposide, cyclosporin A, dexamethasone) along with empiric antituberculous drugs as necrotic granulomas were also noted in the biopsy. HLH has a very poor prognosis and familiarity with clinical symptoms, and diagnostic criteria can aid in timely diagnosis.	0
TDP2 encodes a 5'-tyrosyl DNA phosphodiesterase required for the efficient repair of double-strand breaks (DSBs) induced by the abortive activity of DNA topoisomerase II (TOP2). To date, only three homozygous variants in TDP2 have been reported in six patients from four unrelated pedigrees with spinocerebellar ataxia 23 (SCAR23). By whole-exome sequencing, we identified a novel TDP2 splice-site variant (c.636 + 3_636 + 6del) in two Italian siblings (aged 40 and 45) showing progressive ataxia, intellectual disability, speech delay, refractory seizures, and various physical anomalies. The variant caused exon 5 skipping with consequent nonsense-mediated mRNA decay and defective repair of TOP2-induced DSBs, as demonstrated by the functional assays on the patients' fibroblasts. Our findings further demonstrate the pathogenic role of TDP2 biallelic loss-of-function variants in SCAR23 pathogenesis. Considering the age of our patients, the oldest reported to date, and their extensive follow-up, our study delineates in more detail the clinical phenotype related to the loss of TDP2 activity.	0
Febrile ulceronecrotic Mucha-Habermann disease (FUMHD), a severe form of pityriasis lichenoides et varioliformis acuta, is an inflammatory dermatosis of unknown etiology manifested by ulcerative and necrotic lesions accompanied by systemic manifestations. The mortality rate of FUMHD is about 15%. It is reported here a case of FUMHD presenting as toxic epidermal necrolysis that resulted in multiple organ failure and death.	0
BACKGROUND Incomplete closure of the neural tube results in congenital anomalies called neural tube defects (NTD). These defects are rarely multiple, and are characterized by loss of central nervous system soft tissue and bony coverings, along with herniation of the involved part of the CNS through the defect. CASE REPORT A newborn female infant was delivered through planned cesarean section due to large occipital encephalocele diagnosed antenatally. The pregnancy was unplanned and the mother did not take folic acid prior to conception. Birth weight was 3.41 Kg. Upon delivery, the newborn was healthy, with an Apgar score of 8. The physical examination revealed 2 large pouches; one was over the occiput, and the other swelling was located over the nape of the neck. Brain MRI revealed large occipital encephalocele and cervical myelomeningocele. The 2 defects were repaired separately, with an uneventful postoperative course. CONCLUSIONS We report the rare occurrence of multiple NTD. Early repair, either as single or multiple procedures, is mandatory to avoid dramatic complications.	0
Waldenström macroglobulinemia is a lymphoplasmacytic lymphoma with bone marrow involvement and a monoclonal IgM gammopathy. Infiltration of the skin by neoplastic cells is very rare, and it can be difficult to distinguish from marginal zone lymphoma. The MYD88 L265P mutation is strongly associated with Waldenström macroglobulinemia, and it may be helpful in differentiating the two disorders, although the presence of this mutation is not specific, and other factors must be considered when making the final diagnosis. We present a diagnostically challenging case of cutaneous Waldenström macroglobulinemia in which the MYD88 L265P mutation was identified in the skin but not in the bone marrow, due to a low tumor burden.	0
Autoimmune pulmonary alveolar proteinosis (APAP) is caused by macrophage dysfunction due to anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody. We experienced 2 cases of APAP complicated with sarcoidosis in a 42-year-old woman and a 51-year-old man (age at the sarcoidosis diagnosis). APAP preceded sarcoidosis in the woman, and both diseases were diagnosed simultaneously in the man. Sarcoidosis lesions were observed in the lung, skin, and eyes, and the pathological findings of APAP were not marked at the diagnosis of sarcoidosis in either case. Low-grade positive serum anti-GM-CSF autoantibody was suspected to be correlated with the occurrence of sarcoidosis and resolution of APAP.	0
Hereditary folate malabsorption (HFM) is an autosomal recessive disease caused by mutations in SLC46A1 encoding the proton-coupled folate transporter (PCFT). HFM patients present with various clinical features including megaloblastic anemia, thrombocytopenia, combined immunodeficiency and neurodevelopmental disorders. In this study, we report the same deep intronic mutation of c.1166-285 T > G shared by four unrelated Japanese patients with HFM. This mutation was shown to generate a cryptic splice donor site for a 168-bp insertion of intron 3 sequences, leading to premature termination in the middle of this insertion. This mutation could be a founder mutation in the Japanese population, but also could be a hot-spot and could be present in undiagnosed HFM patients worldwide because of the difficulty to detect this mutation.	0
BACKGROUND: Atypical teratoid/rhabdoid tumors are highly malignant embryonal central nervous system (CNS) tumors that were defined as an entity in 1996. As compared with other malignant CNS tumors, their biological behavior is particularly aggressive, but patients may benefit from an intensified treatment. Atypical teratoid/rhabdoid tumors display a complex histomorphology, which renders them prone to misdiagnosis. They occur predominantly in young children, with an estimated prevalence of 1% to 2% among all pediatric CNS tumors. However, population-based data on the incidence of these tumors are not yet available. METHODS: A nation-wide survey of malignant high-grade CNS tumors (World Health Organization grade III/IV), diagnosed in children (aged birth to 14 years) from 1996 to 2006 was conducted by the Austrian Brain Tumor Registry. A central histopathology review was performed including the assessment of SMARCB1 (INI1) protein status. RESULTS: A total of 311 newly diagnosed, malignant CNS tumors were included. Atypical teratoid/rhabdoid tumors constituted the sixth most common entity (6.1%), referring to an age-standardized incidence rate of 1.38 per 1,000,000 person-years in children. Peak incidence was found in the birth to 2 years age group, where they were as common as CNS primitive neuroectodermal tumors and medulloblastomas. A total of 47.4% of atypical teratoid/rhabdoid tumors were initially diagnosed, whereas 52.6% were retrospectively detected by the central review. The 5-year survival of atypical teratoid/rhabdoid tumor patients was 39.5%, with 66.7% in the correctly diagnosed group versus 15.0% in the not recognized group (P = .0469). CONCLUSIONS: Clinicians and pathologists should be aware of the high incidence of atypical teratoid/rhabdoid tumors in young children to optimize diagnostic and therapeutic management of patients with these tumors.	1
OBJECTIVE: To estimate the prevalences of polyarteritis nodosa (PAN), microscopic polyangiitis (MPA), Wegener's granulomatosis (WG), and Churg-Strauss syndrome (CSS). METHODS: Cases were collected in Seine-St. Denis County, a northeastern suburb of Paris, which has 1,093,515 adults (> or =15 years), 28% of whom are of non-European ancestry. The study period encompassed the entire calendar year 2000. Cases were identified by general practitioners, the departments of all the public hospitals and 2 large private clinics, and the National Health Insurance System. The Chapel Hill nomenclature was used to define MPA, and American College of Rheumatology criteria to define WG and CSS; PAN was diagnosed based on clinical laboratory, histological and/or angiographic findings. Three-source capture-recapture analysis was performed to correct for incomplete case ascertainment. RESULTS: A total of 75 cases were retained and capture-recapture analysis estimated that 23.8 cases had been missed by any 1 of the 3 sources. Accordingly, prevalences per 1,000,000 adults (95% confidence interval [95% CI]) were estimated to be 30.7 (95% CI 21-40) for PAN, 25.1 (95% CI 16-34) for MPA, 23.7 (95% CI 16-31) for WG, and 10.7 (95% CI 5-17) for CSS. The overall prevalence was 2.0 times higher for subjects of European ancestry than for non-Europeans (P = 0.01). CONCLUSIONS: This study provides the first prevalence estimates for these 4 vasculitides for a multiethnic, urban population. The significantly higher prevalence observed for Europeans may infer a genetic susceptibility of Caucasians. Compared with previous estimates based mostly on rural populations, the higher frequency of PAN and the lower frequency of WG might suggest specific environmental etiologic factors.	1
Background:The intrathecal contrast-enhanced magnetic resonance cisternography (MRC) is a diagnostic method that has been proven effective in selected patients with various disorders of the cerebrospinal system, including the detection of cerebrospinal fluid (CSF) leaks. The Mondini dysplasia is a malformation of the inner ear characterized by an incomplete cochlear development. The cerebrospinal fistula associated with Mondini dysplasia usually occurs in the first 5-10 years. Case Description:The case of a 34-year-old woman with CSF rhinorrhea and recurrent meningitis associated with CSF fistula into the right inner ear, which was detected by MRC with intrathecal gadolinium, is presented. The computed tomography (CT) cisternography failed to detect the exact location of the leak. The right Mondini dysplasia was identified on CT of the temporal bone. A subtotal right-sided petrosectomy and fistula closure into the bony labyrinth were performed. After the procedure the patient no longer presented meningitis or CSF leak. Conclusions:The radiological identification of the site of CSF leak through sensitive imaging studies such as MRC with intrathecal gadolinium is crucial for surgical approach.	0
We describe a newborn boy one of triplets, whose karyotype was 46,XY, t(8;12)(q22;q21). Prenatal diagnosis of multiple craniofacial anomalies had been made. Following delivery, the patient was thought to exhibit findings consistent with a diagnosis of frontofacionasal dysostosis. We hypothesize that one of the break points of this translocation may involve a gene essential to craniofacial development.	0
BACKGROUND:Ovarian cancer is one of the most common malignant tumors in the female reproductive system with the highest mortality rate. Cul4B participates in the oncogenesis and progression of several malignant tumors. However, the role of Cul4B in ovarian cancer has not been studied. RESULTS:High expression of intratumor Cul4B was associated with poor patient survival. Cul4B expression was associated with FIGO stage and Cul4B was independent risk factor of ovarian cancer disease-free survival and overall survival. In vitro studies revealed that overexpression of Cul4B promoted tumor proliferation while knockdown of Cul4B significantly inhibited the proliferation capacity of ovarian cancer cells. Mechanistically, Cul4B was found to promotes cell entering S phase from G0/G1 phase by regulating the expression of CDK2 and CyclinD1. Cul4B regulates the expression of CDK2 and CyclinD1 by repressing miR-372. CONCLUSIONS:The results revealed that high expression of Cul4B is associated with poor ovarian cancer prognosis and Cul4B may serve as a potential treating target for an adjuvant therapy.	0
It can be clinically challenging to distinguish dry age-related macular degeneration (AMD) from AMD-mimicking dystrophies, and sometimes misdiagnosis occurs. With upcoming therapies for dry AMD it is important to exclude patients with a different retinal disease from clinical trials. In this study we evaluated the occurrence of AMD-mimicking dystrophies in an AMD cohort. Whole-exome sequencing (WES) was performed in 218 patients with intermediate AMD or geographic atrophy secondary to AMD and 133 control individuals. WES data was analyzed for rare variants in 19 genes associated with autosomal dominant and recessive macular dystrophies mimicking AMD. In three (1.4%) of 218 cases we identified a pathogenic heterozygous variant (PRPH2 c.424C > T; p.R142W) causal for autosomal dominant central areolar choroidal dystrophy (CACD). Phenotypically, these patients all presented with geographic atrophy. In 12 (5.5%) of 218 cases we identified a heterozygous variant of unknown clinical significance, but predicted to be highly deleterious, in genes previously associated with autosomal dominant macular dystrophies. The distinction between AMD and AMD-mimicking dystrophies, such as CACD, can be challenging based on fundus examination alone. Genetic screening for genes associated with macular dystrophies, especially PRPH2, can be beneficial to help identify AMD-mimicking dystrophies.	0
Cystinosis is an autosomal recessive disorder, characterized by an accumulation of intralysosomal cystine, with an incidence of 1 in 100,000 to 200,000 live births. A higher incidence of cystinosis, 1 in 26,000 live births, has been reported in the western French province of Brittany. PCR amplification and sequencing has identified a 27-bp deletion starting 3 bp before the end of exon 8 and continuing into intron 8, 898-900+24del27, which has only been detected in families from this region. Reverse transcription-PCR amplification of RNA from an affected individual has shown that this mutation is indeed a splice-site mutation and results in the production of aberrant transcripts. These transcripts are predicted to either severely truncate cystinosin or alter its topology, thus accounting for the severe phenotype of these individuals. The mutation 898-900+24del27 has been identified in 7 of 18 alleles studied. This mutation is likely to be a founder mutation and would account for the higher incidence of cystinosis in Brittany.(1)	1
AIM:To evaluate presence and severity of social impairments in alternating hemiplegia of childhood (AHC) and determine factors that are associated with social impairments. METHOD:This was a retrospective analysis of 34 consecutive patients with AHC (19 females, 15 males; mean age: 9y 7mo, SD 8y 2mo, range 2y 7mo-40y), evaluated with the Social Responsiveness Scale, Second Edition (SRS-2). RESULTS:SRS-2 scores, indicating level of social impairment, were higher than population means (75, SD 14 vs 50, SD 10, p<0.001). Of these, 27 out of 34 had high scores: 23 severe (>76), four moderate (66-76). All subscale domains, including social cognition, social communication, social awareness, social motivation, restricted interests, and repetitive behavior, had abnormal scores compared to population means (p<0.001). High SRS-2 scores were associated with the presence of autism spectrum disorder (ASD) and epilepsy (p=0.01, p=0.04), but not with other scales of AHC disease symptomatology. All nine patients who received formal evaluations for ASD, because they had high SRS-2 scores, were diagnosed with ASD. INTERPRETATION:Most patients with AHC have impaired social skills involving multiple domains. ASD is not uncommon. High SRS-2 scores in patients with AHC support referral to ASD evaluation. Our findings are consistent with current understandings of the pathophysiology of AHC and ASD, both thought to involve GABAergic dysfunction. WHAT THIS PAPER ADDS:Most patients with alternating hemiplegia of childhood (AHC) have impaired social skills involving multiple domains. These impairments are significant compared to population means. Most patients with AHC have high Social Responsiveness Scale, Second Edition (SRS-2) scores. Patients with AHC with high SRS-2 scores are likely to have autism spectrum disorder.	0
The measurement of band 3 (AE1, SLC4A1, CD233) content of red cells by eosin-5- maleimide (EMA) staining is swiftly replacing conventional osmotic fragility (OF) test as a tool for laboratory confirmation of hereditary spherocytosis across the globe. Our group has systematically evaluated the EMA test as a method to screen for a variety of anemias in the last 10 years, and compared these results to those obtained with the osmotic gradient ektacytometry (osmoscans) which we have used over three decades. Our overall experience allowed us to characterize the distinctive patterns with the two tests in several congenital erythrocyte membrane disorders, such as hereditary spherocytosis (HS), hereditary elliptocytosis (HE), Southeast Asian Ovalocytosis (SAO), hereditary pyropoikilocytosis (HPP) variants, erythrocyte volume disorders, various red cell enzymopathies, and hemoglobinopathies. A crucial difference between the two methodologies is that osmoscans measure red blood cell deformability of the entire sample of RBCs, while the EMA test examines the band 3 content of individual RBCs. EMA content is influenced by cell size as smaller red cells have lower amount of total membrane than larger cells. The SAO mutation alters the EMA binding site resulting in a lower EMA MCF even as the band 3 content itself is unchanged. Thus, EMA scan results should be interpreted with caution and both the histograms and dot plots should be analyzed in the context of the clinical picture and morphology.	0
OBJECTIVE:To document the clinical presentation of scurvy in children with autism spectrum disorder (ASD) and summarize the contemporary approaches to assessment and management in this population. Scurvy is a disease caused by vitamin C deficiency most often detected in populations at high risk for nutrition insufficiency (e.g., extreme poverty). Children with ASD and severe food selectivity consistent with avoidant-restrictive food intake disorder may also be at risk for scurvy. METHOD:We searched MEDLINE, CINAHL, and PsycINFO databases (1990-2018) in peer-reviewed journals for studies of children with ASD and scurvy. Inclusion criteria required confirmed diagnosis of ASD and scurvy in children (birth to 18 years) with a clear description of restrictive dietary patterns. Cases of scurvy due to other causes were excluded. We used a standardized protocol to independently code information; agreement between coders was high. RESULTS:The systematic search identified 20 case reports involving 24 children (mean age = 9 ± 3.5; 22 boys/2 girls). The eventual diagnosis of scurvy followed a wide range of negative diagnostic testing; treatment with ascorbic acid and/or a multivitamin resulted in rapid improvement. CONCLUSIONS:Symptoms of scurvy mimic other pediatric conditions (e.g., cancer). The range of diagnostic testing increased costs and healthcare risks (radiation, sedation) and delayed the diagnosis of scurvy. In children with ASD and severe food selectivity, a nutrition evaluation and laboratory testing are warranted before a more elaborate testing.	0
With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross-species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in ataxic and preataxic subjects of two independent multicentric SCA3 cohorts and in a SCA3 knock-in mouse model. Ataxic SCA3 subjects showed increased levels of both NfL and pNfH. In preataxic subjects, NfL levels increased with proximity to the individual expected onset of ataxia, with significant NfL elevations already 7.5 years before onset. Cross-sectional NfL levels correlated with both disease severity and longitudinal disease progression. Blood NfL and pNfH increases in human SCA3 were each paralleled by similar changes in SCA3 knock-in mice, here also starting already at the presymptomatic stage, closely following ataxin-3 aggregation and preceding Purkinje cell loss in the brain. Blood neurofilaments, particularly NfL, might thus provide easily accessible, cross-species validated biomarkers in both ataxic and preataxic SCA3, associated with earliest neuropathological changes, and serve as progression, proximity-to-onset and, potentially, treatment-response markers in both human and preclinical SCA3 trials.	0
Huwe1 is a highly conserved member of the HECT E3 ubiquitin ligase family. Here, we explore the growing importance of Huwe1 in nervous system development, function and disease. We discuss extensive progress made in deciphering how Huwe1 regulates neural progenitor proliferation and differentiation, cell migration, and axon development. We highlight recent evidence indicating that Huwe1 regulates inhibitory neurotransmission. In covering these topics, we focus on findings made using both vertebrate and invertebrate in vivo model systems. Finally, we discuss extensive human genetic studies that strongly implicate HUWE1 in intellectual disability, and heighten the importance of continuing to unravel how Huwe1 affects the nervous system.	0
PURPOSE:Spinal cord involvement in Kearns-Sayre (KSS) syndrome could be more frequent than commonly thought. Our aims were to evaluate the involvement of the spinal cord in patients with KSS by means of MRI and to investigate possible correlations of spinal and brain disease with patient disability. METHODS:Eleven patients with KSS disease and spinal cord MRI were retrospectively recruited. The severity of spinal disease was defined as follows: grade 0 (none), grade 1 (focal), and grade 2 (extensive). We calculated a radiologic score of brain involvement based on typical features. We performed a chi-square test to correlate spinal cord and brain MRI involvement to patient disability. For significant variables, a contingency coefficient, phi factor, and Cramer's V were also computed. RESULTS:Spinal cord lesions were detected in 6/11 patients, showing four patterns: involvement of gray matter, gray matter and posterior columns, posterior columns, and anterior columns. The severity of spinal disease was grade 1 in two and grade 2 in four patients. All patients showed brain involvement (9-point average for patients with spinal involvement and 10 for the others). A significant correlation was found between disability score and spinal cord involvement (χ2 = 7.64; p = 0.022) or brain score (χ2 = 26.85; p = 0.043). Significance for brain score-disability correlation increased with the spinal cord as a cofactor (χ2 = 24.51; p = 0.017, phi factor = 1.201, Cramer's V = 0.849, contingency effect = 0.767; p = 0.017). CONCLUSION:Spinal cord lesions are common in KSS. Patients with spinal disease show higher disability than patients without spinal cord lesions, supporting the inclusion of dedicated acquisitions to routine MRI of the brain in patients with KSS.	0
Soft tissue calcifications associated with various connective tissue diseases such as dermatomyositis and scleroderma have been well documented Plaque-like sheets of subcutaneous calcifications presenting as an indurated soft tissue mass in a patient with primary Sjogren syndrome have been rarely documented in the literature. We present the magnetic resonance and conventional radiographic findings of calcinosis cutis and calcinosis circumscripta of a 47-year-old woman with biopsy proven Sjogren syndrome. We also delineate various types of soft tissue calcification, histopathology of calcinosis cutis, and current treatment options. Recognizing the magnetic resonance characteristics of this phenomenon may prove useful to radiologists, especially in the absence of clinical history and conventional radiographs.	0
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by absence or deficient activity of α-galactosidase A (α-Gal A) due to mutations in the α-galactosidase A gene (GLA), leading to progressive accumulation of globotriaosylceramide (Gb3) in tissues and organs including heart, kidney, the eyes, vascular endothelium, the nervous system and the skin. Cardiac involvement is leading to fatal complications and reduced life expectancy. FD is treatable with disease-specific treatment (enzyme replacement therapy (ERT) or with chaperone therapy). Therefore, the early diagnosis of FD is crucial for reducing the morbidity and mortality. Screening of high-risk populations (eg, patients with unexplained left ventricular hypertrophy (LVH), young patients with unexplained stroke, and patients with unexplained renal failure proteinuria or microalbuminuria) yields good results. The diagnostic algorithm is gender-specific. Initially, the measurement of α-Gal A activity is recommended in males, and optionally in females. In males with non-diagnostic residual activity (5-10%) activity, genetic testing is afterwards done for confirming the diagnosis. In fact, diagnosis of FD is not possible without genetic testing for both males and females. Globotriaosysphingosine (lyso-Gb3) for identification of atypical FD variants and high- sensitive troponin T (hsTNT) for identification of cardiac involvement are also important diagnostic biomarkers. The aim of this review was to provide an update on diagnosis and screening of patients with FD.	0
The most common form of spinal muscular atrophy (SMA) is a recessive disorder caused by deleterious SMN1 mutations in 5q13, whereas the genetic etiologies of non-5q SMA are very heterogeneous and largely remain to be elucidated. In a Bulgarian family affected by autosomal-dominant proximal SMA, we performed genome-wide linkage analysis and whole-exome sequencing and found a heterozygous de novo c.320C>T (p.Ser107Leu) mutation in bicaudal D homolog 2 (Drosophila) (BICD2). Further analysis of BICD2 in a cohort of 119 individuals with non-5q SMA identified a second de novo BICD2 mutation, c.2321A>G (p.Glu774Gly), in a simplex case. Detailed clinical and electrophysiological investigations revealed that both families are affected by a very similar disease course, characterized by early childhood onset, predominant involvement of lower extremities, and very slow disease progression. The amino acid substitutions are located in two interaction domains of BICD2, an adaptor protein linking the dynein molecular motor with its cargo. Our immunoprecipitation and localization experiments in HeLa and SH-SY5Y cells and affected individuals' lymphoblasts demonstrated that p.Ser107Leu causes increased dynein binding and thus leads to accumulation of BICD2 at the microtubule-organizing complex and Golgi fragmentation. In addition, the altered protein had a reduced colocalization with RAB6A, a regulator of vesicle trafficking between the Golgi and the endoplasmic reticulum. The interaction between p.Glu744Gly altered BICD2 and RAB6A was impaired, which also led to their reduced colocalization. Our study identifies BICD2 mutations as a cause of non-5q linked SMA and highlights the importance of dynein-mediated motility in motor neuron function in humans.	0
The aim of this review is to summarize and discuss recent findings and new insights in the etiology and phenotype of metabolic myopathies. The review relies on a systematic literature review of recent publications. Metabolic myopathies are a heterogeneous group of disorders characterized by mostly inherited defects of enzymatic pathways involved in muscle cell metabolism. Metabolic myopathies present with either permanent (fixed) or episodic abnormalities, such as weakness, wasting, exercise-intolerance, myalgia, or an increase of muscle breakdown products (creatine-kinase, myoglobin) during exercise. Though limb and respiratory muscles are most frequently affected, facial, extra-ocular, and axial muscles may be occasionally also involved. Age at onset and prognosis vary considerably. There are multiple disease mechanisms and the pathophysiology is complex. Genes most recently related to metabolic myopathy include PGM1, GYG1, RBCK1, VMA21, MTO1, KARS, and ISCA2. The number of metabolic myopathies is steadily increasing. There is limited evidence from the literature that could guide diagnosis and treatment of metabolic myopathies. Treatment is limited to mainly non-invasive or invasive symptomatic measures. In conclusion, the field of metabolic myopathies is evolving with the more widespread availability and application of next generation sequencing technologies worldwide. This will broaden the knowledge about pathophysiology and putative therapeutic strategies for this group of neuromuscular disorders.	0
Pituitary stalk interruption syndrome is a congenital disease with isolated growth hormone deficiency or multiple anterior pituitary hormone deficiencies. Here, the authors report a 22-year-old female presenting with growth retardation for 13 years. Growth hormone replacement therapy was performed when the patient was young, so her height improved. Besides, she had no secondary sexual characteristics development.	0
Idiopathic generalized epilepsy is a group of epilepsies accounting for about 20 to 40% of all epilepsies. This group of epilepsies is clinically characterized by the presence of absence seizures, generalized tonic-clonic seizures, and myoclonic seizures with an electroencephalographic pattern of generalized epileptiform spike and wave or polyspike and wave discharge, at times with a shifting predominance on a normal background.[1] Based on the latest International League Against Epilepsy (ILAE) classification, idiopathic generalized epilepsies include childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and generalized tonic-clonic seizures alone.[2]  Juvenile absence epilepsy is an idiopathic generalized epilepsy syndrome that is recognized by the ILAE (International League Against Epilepsy) that typically starts in adolescence around puberty and is characterized by absence seizures and generalized tonic-clonic seizures. In some patients, there may be additional myoclonic jerks as well.[3]	0
PURPOSE OF THE STUDY:High intensity interval training (HIIT) is able to improve the endothelial-dependent microvascular function is people with limited cutaneous systemic sclerosis (lcSSc). Resistance training (RT) alone has shown significant improvements in the function of the vasculature; moreover, a combination of aerobic and RT have shown both in the past and recently to significantly improve the vascular function and the microcirculation. Therefore, the purpose of this study is to explore the effectiveness of a combined exercise protocol (aerobic and resistance training) on microvascular function in people with lcSSc. METHODS:Thirty-two lcSSc patients (66.5 ± 12 years old) were randomly allocated in two groups (exercise and control group). The exercise group underwent a 12-week exercise programme twice per week. All patients performed the baseline, three- and six-month follow up measurements where microvascular function, transcutaneous oxygen tension (ΔTcpO2) and body composition were assessed. RESULTS:The time to peak endothelial-dependent reactivity was significantly improved (91 ± 42 s, d = 1.06, p = 0.007) when compared to control group after the exercise intervention. Endothelial-independent function was also significantly improved (3.16 ± 2, d = 1.17, p = 0.005) when compared to the control group. Baseline (5.71 ± 4.4, p < 0.05)) and peak (15.4 ± 7.5, p < 0.05) transcutaneous oxygen pressure were also significantly improved compared to the control group. CONCLUSIONS:Our results suggest that a combined exercise protocol (aerobic and RT) was effective in improving endothelial-dependent reactivity in people with lcSSc. The next step would be to explore its clinical- and cost- effectiveness. Therefore, we recommend a large, community-based intervention against standard pharmacotherapy only, which would assess these important factors and support a change in therapeutic protocols and guidelines for this clinical population. Trial registration ClinicalTrials.gov (NCT number): NCT03058887, February 23, 2017, https://clinicaltrials.gov/ct2/show/NCT03058887?term=NCT03058887&rank=1.	0
BACKGROUND:Since the establishment of chromosomal microarrays in clinical practice, many new microdeletion/microduplication syndromes have been identified, including 18q11.2 microdeletion. Chromosome 18q deletion syndrome is commonly classified into distal deletion and a much rarer proximal interstitial deletion spanning the 18q11.2-q21.1 region. METHODS:We report two new patients and review 27 additional cases in DECIPHER/ClinGen databases and four cases from the literature, with more proximal 18q deletions involving 18q11-q12 (band 1 only; 17.2-43.5 Mb position) deletion. RESULTS:Common presentations of 18q11-q12 deletions include developmental delay/intellectual disability (DD/ID) (82%); speech delay/autism/attention deficit and hyperactivity/other behavioral problems (30%); conotruncal heart defects (15%); and subtle/non-specific facial dysmorphism. The deletion in four out of five cases with cardiac defect was distal to GATA6, suggesting an alternative mechanism other than haploinsufficiency of GATA6 as an underlying cause of cardiac malformations. Precocious puberty with advanced skeletal age was first observed in one patient, suggesting a unique and expanded phenotype of proximal 18q deletion. When comparing genotype-phenotype correlations from the present study with previous reports, the critical regions for selected phenotypes of 18q11-q12 deletion syndrome could be narrowed down as follows: 38.8-43.5 Mb for moderate to severe DD/ID, 19.6-24.4 Mb and 26.9-28.6 Mb for conotruncal heart defect. CONCLUSION:The detailed clinical delineation of the proximal 18q deletions identified in this study should contribute to better understanding of the genotype-phenotype correlations and better long-term care of patients with this rare syndrome.	0
Klüver-Bucy syndrome (KBS) comprises a set of neurobehavioral symptoms with psychic blindness, hypersexuality, disinhibition, hyperorality, and hypermetamorphosis that were originally observed after bilateral lobectomy in Rhesus monkeys. We investigated two siblings with KBS from a consanguineous family by whole-exome sequencing and autozygosity mapping. We detected a homozygous variant in the heparan-α-glucosaminidase-N-acetyltransferase gene (HGSNAT; c.518G>A, p.(G173D), NCBI ClinVar RCV000239404.1), which segregated with the phenotype. Disease-causing variants in this gene are known to be associated with autosomal recessive Mucopolysaccharidosis type IIIC (MPSIIIC, Sanfilippo C). This lysosomal storage disease is due to deficiency of the acetyl-CoA:α-glucosaminidase-N-acetyltransferase, which was shown to be reduced in patient fibroblasts. Our report extends the phenotype associated with MPSIIIC. Besides MPSIIIA and MPSIIIB, due to variants in SGSH and NAGLU, this is the third subtype of Sanfilippo disease to be associated with KBS. MPSIII should be included in the differential diagnosis of young patients with KBS.	0
To identify the proteins that are relevant to eye research and develop assays for the study of a set of these proteins.We conducted a bibliometric analysis by merging gene lists for human and mouse from the National Center for Biotechnology Information FTP site and combining them with PubMed references that were retrieved with the search terms "eye" [MeSH Terms] OR "eye" [All Fields] OR "eyes" [All Fields].For human and mouse eye studies, respectively, the total number of publications was 13,525 and 23,895 and the total number of proteins was 4050 and 4717. For proteins in human and mouse eye studies, respectively, 88.7 and 81.7% had five or fewer citations. The top 50 most intensively studied proteins for human and mouse eye studies were generally in the areas of photoreceptors and phototransduction, inflammation, and angiogenesis, neurodevelopment, lens transparency, and cell-cycle and cellular processes. We proposed selected reaction monitoring assays that were developed in silico for the top fifty most intensively studied proteins in human and mouse eye research.We conclude that scientists engaged in eye research tend to focus on the same proteins. Newer resources and tools in proteomics can expand the investigations to lesser-known proteins of the eye.	0
Benign recurrent intrahepatic cholestasis (BRIC), a rare cause of cholestasis, is characterized by recurrent episodes of cholestasis without permanent liver damage. BRIC type 2 (BRIC2) is an autosomal recessive disorder caused by ABCB11 mutations. A 6-year-old girl had recurrent episodes of jaundice. At two months of age, jaundice and hepatosplenomegaly developed. Liver function tests showed cholestatic hepatitis. A liver biopsy revealed diffuse giant cell transformation, bile duct paucity, intracytoplasmic cholestasis, and periportal fibrosis. An ABCB11 gene study revealed novel compound heterozygous mutations, including c.2075+3A>G in IVS17 and p.R1221K. Liver function test results were normal at 12 months of age. At six years of age, steatorrhea, jaundice, and pruritus developed. Liver function tests improved following administration of phenylbutyrate and rifampicin. Her younger brother developed jaundice at two months of age and his genetic tests revealed the same mutations as his sister. This is the first report of BRIC2 confirmed by ABCB11 mutations in Korean siblings.	0
Histidemia, first described by Ghadimi in 1961, is caused by a defect in histidase. The defect results in elevated urinary excretion of histidine and its transamination products, and in high blood histidine. Blood histidine levels in histidinemic patients range from 290 to 1420 microM (normal 70-120 microM). The clinical picture of histidinemia varies from complete normality to severe retardation, with many patients being asymptomatic. No correlation has been found between clinical and biochemical data. Most reported cases have been identified in newborn screening programs. Frequency of histidinemia ranges from 1 in 8000 (Japan) to 1 in 37,000 (Sweden). Histidinemia is inherited as an autosomal recessive trait. Maternal histidinemia is believed to be benign. Studies in animal models have shown similar metabolic changes in animals and humans, but clinical changes differ. Histidinemia may be treated with a low-histidine diet, which reduces elevated histidine levels, although in most cases no improvement of clinical symptoms has been observed.	1
Systemic capillary leak syndrome is a rare disorder characterized by dysfunctional inflammatory response, endothelial dysfunction, and extravasation of fluid from the vascular space to the interstitial space leading to shock, hemoconcentration, hypoalbuminemia, and subsequent organ failure. The condition may be idiopathic or secondary to an underlying cause, which can include viral infections. Here we describe a patient with acute coronavirus disease 2019 (COVID-19) infection who presented with hemoconcentration, shock, and hypoalbuminemia. The patient subsequently developed rhabdomyolysis and compartment syndrome of all four extremities, requiring fasciotomies. This is the first reported case of systemic capillary leak syndrome associated with COVID-19 infection. This case adds to the evolving spectrum of inflammatory effects associated with this viral infection.	0
A 5-year-old boy presented with worsening headaches for 3 months. On examination, he was found to have a hairless fatty tissue nevus of the scalp (nevus psiloliparus), subcutaneous soft tissue masses on the right side of his face, neck, mandible and right buttock and epibulbar dermoid of the right eye (choristoma) (). Magnetic resonance imaging revealed a large suprasellar mass, which was debulked and found to be a pilocytic astrocytoma. Testing was not performed for the BRAF/KIAA1549 fusion or BRAFV600E mutation. Seven years later, he was started on adjuvant chemotherapy for gradual tumor progression. Over the ensuing 3 years, he had further disease progression despite treatment with 3 frontline chemotherapy regimens: vinblastine, carboplatin/vincristine, and irinotecan/bevacizumab. Targeted sequencing of tissue from the right gluteal mass, revealed a mosaic activating FGFR1 c.1966A>G (p.Lys656Glu) mutation, absent in normal left gluteal tissue, confirming the diagnosis of encephalocraniocutaneous lipomatosis (ECCL), belonging to the family of RASopathies (including neurofibromatosis type I, Noonan syndrome, Costello syndrome), with constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, and an increased risk of developing neoplasms. He was started on trametinib, a MEK inhibitor, off-label, targeting the MAPK pathway downstream from FGFR1, with stable tumor size at last follow-up, after 6 months on therapy.	0
This mini-review presents an update on the direct immunofluorescence (DIF) for diagnosing dermatitis herpetiformis. The DIF of uninvolved, perilesional skin is a crucial laboratory procedure in diagnosing dermatitis herpetiformis (DH). IgA deposits at the dermal-epidermal junction (DEJ) of perilesional skin with DIF can also be found in coeliac patients with inflammatory skin diseases different from DH. In certain patients presenting with the rash resembling DH, the deposition of exclusively C3 at DEJ can be found. The term "granular C3 dermatosis" was proposed to name such a rash. Recent data on DH suggest that perhaps the very concept of DH that we are universally accepting now is misleading and should be revised.	0
Birth injuries are a diverse set of traumas afflicting a newborn during labor and/or delivery. These range from temporary paralysis to hematomas. Herein, a comprehensive review of the birth injuries is presented, including the risk factors, classification of various paralyzes and nerve damage, as well as bleeding complications. The predicted outcomes and complications, as well as the treatment options for various birth injuries, are also discussed.	0
Takotsubo cardiomyopathy (TTC) is reversible stress-induced cardiomyopathy featuring symptoms of acute myocardial infarction without significant coronary artery abnormalities. TTC is frequently precipitated by stressful emotional events but it also has been reported as a result of substance withdrawal, non-cardiac events, and dangerous drug-to-drug interaction. The plasma levels of both epinephrine and norepinephrine were significantly elevated in TTC patients, suggesting that elevated catecholamine levels might be the main contributing factor. However, the mechanisms underlying susceptibility to development and recurrence are not completely understood. It has been suggested that even a therapeutic dose of antidepressant could be a cause of drug-induced tachycardia and TTC. Moreover, some cases have been reported in which the development of TTC was associated with the serotonin syndrome, neuroleptic malignant syndrome, and similar fatal consequences. The aim of this article is to explore the association between underlying psychiatric disorders and TTC and to determine the role of various psychotropic medications in the progression of stress-induced cardiomyopathy. This article also notes and discusses the current theories underlying the pathophysiology of TTC. This review suggests a serious side effect of antidepressants, and to avoid life-threatening cardiovascular events, such as TTC, for patients with affective and anxiety disorders, prior screening for cardiovascular conditions by ECG with close monitoring might be necessary.	0
Persistent Mullerian duct syndrome has been described as a disease of internal male pseudohermaphroditism, a rare autosomal recessive disease, characterised by persistent Mullerian derivatives in patients with male pattern 46, XY karyotype and normal pattern virilisation. We present a case of an elderly man, who on evaluation for bilateral undescended testes was found to have a pelvic mass suggestive of malignant transformation of an undescended testis on imaging. On surgical exploration, uterus with multiple fibroids, bilateral fallopian tubes, cervix and bilateral atrophic testes were identified. Interestingly, in this case, imaging (contrastCT and MRI) had missed Mullerian structures due to varied presentation, but exploration and excision of the structures followed by their histopathology revealed uterine leiomyomas and confirmed other Mullerian structures (bilateral fallopian tubes, cervix) with bilateral testes.	0
BACKGROUND: The epidemiology of congenital small intestinal atresia (SIA) has not been well studied. This study describes the presence of additional anomalies, pregnancy outcomes, total prevalence and association with maternal age in SIA cases in Europe. METHODS: Cases of SIA delivered during January 1990 to December 2006 notified to 20 EUROCAT registers formed the population-based case series. Prevalence over time was estimated using multilevel Poisson regression, and heterogeneity between registers was evaluated from the random component of the intercept. RESULTS: In total 1133 SIA cases were reported among 5126, 164 registered births. Of 1044 singleton cases, 215 (20.6%) cases were associated with a chromosomal anomaly. Of 829 singleton SIA cases with normal karyotype, 221 (26.7%) were associated with other structural anomalies. Considering cases with normal karyotype, the total prevalence per 10 000 births was 1.6 (95% CI 1.5 to 1.7) for SIA, 0.9 (95% CI 0.8 to 1.0) for duodenal atresia and 0.7 (95% CI 0.7 to 0.8) for jejunoileal atresia (JIA). There was no significant trend in SIA, duodenal atresia or JIA prevalence over time (RR=1.0, 95% credible interval (CrI): 1.0 to 1.0 for each), but SIA and duodenal atresia prevalence varied by geographical location (p=0.03 and p=0.04, respectively). There was weak evidence of an increased risk of SIA in mothers aged less than 20 years compared with mothers aged 20 to 29 years (RR=1.3, 95% CrI: 1.0 to 1.8). CONCLUSION: This study found no evidence of a temporal trend in the prevalence of SIA, duodenal atresia or JIA, although SIA and duodenal atresia prevalence varied significantly between registers.	1
Despite intensive multimodal therapy, the survival rate for high risk neuroblastoma (HR-NB) remains <50%. Most cases initially respond to treatment but almost half will subsequently relapse with aggressive treatment resistant disease. Novel treatments exploiting the molecular pathology of NB and/or overcoming resistance to current genotoxic therapies are needed before survival rates can significantly improve. DNA damage response (DDR) defects are frequently observed in HR-NB including allelic deletion and loss of function mutations in key DDR genes, oncogene induced replication stress and cell cycle checkpoint dysfunction. Exploiting defects in the DDR has been a successful treatment strategy in some adult cancers. Here we review the genetic features of HR-NB which lead to DDR defects and the emerging molecular targeting agents to exploit them.	0
INTRODUCTION:Jacobsen syndrome (JS) is caused by a deletion at the terminus of the long arm of chromosome 11. There are few reports of JS associated with cerebral white matter abnormalities (WMA), and the etiology, pathophysiology, and time-dependent changes in WMA with JS still remain unclear. CASE REPORT:The patient was a 2-month-old female with several morphological anomalies, including trigonocephaly, ectropion, flat nasal bridge, low-set ears, and sparse eyebrows. Chromosome analysis (G-banding karyotyping) of 46,XX,del(11)(q23.3) led to the diagnosis of JS. Head MRI performed at age 9 months indicated diffuse WMA with hyperintense signals on T2-weighted imaging. MRI at age 2.5 years demonstrated a decrease in the WMA and progressive myelination. DISCUSSION:These findings suggested that the WMA in the present patient were due to chronic white matter edema associated with a deletion in the 11q terminal region of HEPACAM/GlialCAM, a causative gene for megalencephalic leukoencephalopathy with subcortical cysts type 2B (MLC2B). As with some of MLC2B patients, the WMA in the present patient improved over time. The present report is the first to document dramatic changes in WMA in JS visualized by serial MRI examinations from the neonatal period through early childhood. CONCLUSION:The findings of the present study suggested that WMA in JS are due to chronic white matter edema associated with HEPACAM/GlialCAM deletion and show gradual improvement over time, as seen in some MLC2B patients.	0
The development of BCR-ABL1 tyrosine kinase inhibitors (TKIs) markedly improved the prognosis of patients with chronic myeloid leukemia (CML). Approximately 50% of patients who achieve deep molecular response (DMR) remain in treatment-free remission (TFR) even after discontinuation of TKIs. Although TKIs may achieve clinical "cure" after TKI treatment for specific periods, there are no reliable biomarkers for predicting the response to TKIs and the probability of TFR in CML. An increase in natural killer (NK) cells in the peripheral blood of TKI-treated CML patients is correlated with better outcomes, suggesting that TKIs induce antitumor NK cell immunity against CML cells. Killer immunoglobulin-like receptors (KIRs) are highly polymorphic NK cell receptors that play important roles in the regulation of immune responses. The identification of allelic polymorphisms of KIRs by next-generation sequencing uncovered novel aspects of KIRs. Here we summarize the current knowledge of the genetic and immunological aspects of KIRs and discuss the association between allelic polymorphisms of KIRs and TKI-treated CML.	0
Orofaciodigital syndrome 1 (OFD-1) is a rare, X-linked, dominantly inherited disorder caused by an OFD1 mutation that can cause polycystic kidneys. A 37-year-old woman on hemodialysis therapy was admitted to our hospital for trans-catheter arterial embolization therapy for enlarged polycystic kidneys. Lobulated tongue and brachydactyly were noticed, prompting an OFD1 sequencing analysis. Sequencing revealed a causal four-base-pair deletion in exon 13, both in the patient and in her mother, whose renal function had been retained. The peripheral leukocyte X chromosome inactivation pattern was skewed in the patient but not in her mother, suggesting some role in their phenotypic difference.	0
Developmental and epileptic encephalopathies (DEEs) are a group of severe, early onset epilepsies characterized by refractory seizures, developmental delay or regression associated with ongoing epileptic activity, and generally poor prognosis. DEE is genetically and phenotypically heterogeneous, and there is a plethora of genetic testing options to investigate the rapidly growing list of epilepsy genes. However, more than 50% of patients with DEE remain without a genetic diagnosis despite state-of-the-art genetic testing. In this review, we discuss the major advances in epilepsy genomics that have surfaced in recent years. The goal of this review is to reach a larger audience and build a better understanding of pathogenesis and genetic testing options in DEE.	0
Glycosylphosphatidylinositol biosynthesis defects cause rare genetic disorders characterised by developmental delay/intellectual disability, seizures, dysmorphic features, and diverse congenital anomalies associated with a wide range of additional features (hypotonia, hearing loss, elevated alkaline phosphatase, and several other features). Glycosylphosphatidylinositol functions as an anchor to link cell membranes and protein. These proteins function as enzymes, adhesion molecules, complement regulators, or co-receptors in signal transduction pathways. Biallelic variants involved in the glycosylphosphatidylinositol anchored proteins biosynthetic pathway are responsible for a growing number of disorders, including multiple congenital anomalies-hypotonia-seizures syndrome; hyperphosphatasia with mental retardation syndrome/Mabry syndrome; coloboma, congenital heart disease, ichthyosiform dermatosis, mental retardation, and ear anomalies/epilepsy syndrome; and early infantile epileptic encephalopathy-55. This review focuses on the current understanding of Glycosylphosphatidylinositol biosynthesis defects and the associated genes to further understand its wide phenotype spectrum.	0
Dyschromatosis universalis hereditaria (DUH) is a rare genodermatosis, which presents as hyper- and hypopigmented macules all over the body. Although a benign condition, rarely DUH is associated with abnormalities of dermal connective tissue, nerve, and systemic conditions. We report a case of DUH associated hypospadias and complicated with hydronephrosis that has not been described earlier.	0
Background: Congenital Hyperinsulinism (CHI) is the most common cause of recurrent and severe hypoglycaemia in childhood. Feeding problems occur frequently in severe CHI but long-term persistence and rates of resolution have not been described. Methods: All patients with CHI admitted to a specialist center during 2015-2016 were assessed for feeding problems at hospital admission and for three years following discharge, through a combination of specialist speech and language therapy review and parent-report at clinical contact. Results: Twenty-five patients (18% of all patients admitted) with CHI were prospectively identified to have feeding problems related to sucking (n = 6), swallowing (n = 2), vomiting (n = 20), and feed aversion (n = 17) at the time of diagnosis. Sixteen (64%) patients required feeding support by nasogastric/gastrostomy tubes at diagnosis; tube feeding reduced to 4 (16%) patients by one year and 3 (12%) patients by three years. Feed aversion resolved slowly with mean time to resolution of 240 days after discharge; in 15 patients followed up for three years, 6 (24%) continued to report aversion. The mean time (days) to resolution of feeding problems was lower in those who underwent lesionectomy (n = 4) than in those who did not (30 vs. 590, p = 0.009) and significance persisted after adjustment for associated factors (p = 0.015). Conclusion: Feeding problems, particularly feed aversion, are frequent in patients with CHI and require support over several years. By contrast, feeding problems resolve rapidly in patients with focal CHI undergoing curative lesionectomy, suggesting the association of feeding problems with hyperinsulinism.	0
Mal de Meleda, also known as keratoderma palmoplantaris transgrediens, is a rare type of autosomal recessive palmoplantar keratoderma. A 19-year-old male presented with a congenital yellowish discoloration and thickening of both palms and soles of the feet. His family history revealed that there was no consanguinity between the mother and the father and that the patient had three healthy brothers. The second- and third-degree relatives, five females and one male, also exhibited similar skin findings. From the isolated DNA samples, the extrinsic regions of the SLURP1 gene were screened using the sequence analysis and the Sanger sequencing was performed with the 3130 Sequence Analyzer. Results of this analysis show that a p.Arg 96 Pro (R96P) (c.287 CGA>CCA) homozygous missense point mutation was detected on the SLURP 1 (a secreted toxin-like mammalian lymphocyte antigen 6/urokinase-type plasminogen activator receptor-related protein 1) gene of the patients, while heterozygous p.Arg 96 Pro (R96P) (c.287 CGA>CCA) mutation was detected in the mother, father, and brothers. Our search of the Human Genome Mutation Database and previous literature revealed no reports of this mutation in mal de Meleda. We report this case due to the identification of a novel gene mutation in a patient with mal de Meleda, a palmoplantar keratoderma.	0
Fibrotic hypersensitivity pneumonitis is a complex interstitial lung disease that is not entirely understood. In its chronic and fibrotic form, hypersensitivity pneumonitis is one of the main mimickers of idiopathic pulmonary fibrosis (IPF). Distinguishing between these two conditions is challenging but is of particular clinical relevance. Two approved therapies are available for IPF, and a considerable number of clinical trials are now exploring newer pharmacological options. This impressive research effort is a consequence of new pathogenetic understanding, updated diagnostic criteria and a long history of pharmacological trials. Conversely, current knowledge gaps on pathogenesis of chronic hypersensitivity pneumonitis, coupled with lack of validated diagnostic criteria, make the management of this disease an unsolved clinical challenge. This also reflects the paucity of therapeutic clinical trials in this field. In this review, we describe the current evidence and the possible future options to approach this complex disease.	0
Otofaciocervical syndrome (OTFCS) is described as a single gene disorder of both autosomal dominant and autosomal recessive inheritance. The major clinical features of OTFCS include ear malformations (external/middle/inner ear), facial dysmorphism, shoulder girdle abnormalities, vertebral anomalies, and mild intellectual disability. The autosomal recessive form of OTFCS syndrome (OTFCS2) has been recently reported to be caused due to homozygous mutations in PAX1 gene. Here we report a third family of OTFCS2 phenotype wherein whole exome sequencing identified a novel homozygous small insertion in PAX1 as the underlying genetic cause.	0
Lhermitte-Duclos disease is a rare condition with less than 250 cases reported in the literature. It was considered a neoplastic or hamartomatous growth in the cerebellum. It commonly presents with symptoms of high intracranial pressure or obstructive hydrocephalus. Surgical resection is often curative. The lesion is associated with PTEN gene mutation, and it is considered to be one of the diagnostic criteria of Cowden's syndrome. Vascular tumors are reported in this syndrome, including glioblastomas and meningiomas. Furthermore, central nervous system vascular lesions were also reported in Lhermitte-Duclos disease, such as deep venous anomalies and brain arteriovenous fistulas. A report of an asymptomatic spinal cervical AVF in a patient with Lhermitte-Duclos disease was published in 2006. We present the second case of Lhermitte-Duclos disease associated with an asymptomatic spinal cervical AVF in a 17-year-old young woman with literature review of central nervous system vascular lesions in Lhermitte-Duclos disease.	0
Lithium carbonate is an effective mood stabilizer. We treated a patient for hypertrophic cardiomyopathy due to chronic unsupervised lithium carbonate use. We noted: a) a previously normal ECG; b) the absence of any familiarity for sudden cardiac death; c) the associated nephrogenic diabetes insipidus; d) probable exaggerated lithium plasma concentrations, which had not been monitored over the past few years; and e) the unusual traits of the right ventricle. We would like to stress the need for regular cardiologic follow-up in psychiatric patients treated with lithium carbonate, to minimize its potential cardiac untoward consequences.	0
BACKGROUND:Intellectual disability (ID) is a heterogeneous neurodevelopmental disorder with a complex genetic underpinning in its etiology. Chromosome microarray (CMA) is recommended as the first-tier diagnostic test for ID due to high detection rate of copy number variation (CNV). METHODS:To identify an appropriate clinical detection scheme for ID in Han Chinese patients, whole genome low-coverage sequencing was performed as the first-tier diagnostic test, and medical exome sequencing (MES) as the second-tier diagnostic test for patients with negative results of CNVs. RESULTS:A total of 19 pathogenic CNVs in 16/95(16.84%) ID patients and 10 pathogenic single-nucleotide variations (SNVs), including 6 novel mutations in 8/95(8.42%) ID patients were identified on whom no pathogenic CNVs were discovered. The detection rate of CNVs in ID with multiple congenital anomalies (MCA) subgroup was significantly higher than ID with autism spectrum disorders and other IDs subgroups. And the single-nucleotide variations showed a higher occurrence rate in the other IDs subgroup. CONCLUSIONS:There were differences in the diagnostic yields of different variation types among the three ID subgroups. Our findings provided a new perspective on appropriate clinical detection scheme in different ID subgroups based on statistically significant differences among the three ID subgroups. The application of whole genome low-coverage sequencing as the first-tier diagnostic test for ID with MCA subgroup and MES as the first-tier diagnostic test for other ID subgroup was considered as an efficient clinical detection scheme.	0
Objective:Retinitis pigmentosa-related retinal detachment (RPRD) is rare, and the full spectrum of retinal complications is not well defined. To describe the types of retinal detachment in patients with retinitis pigmentosa and the surgical outcomes of RPRD. Methods:This is a non-comparative, retrospective case series. An electronic database search was performed using Moorfields OpenEyes electronic health records. We identified 90 patients with RPRD between January 2000 and August 2017. Main outcome and measures are visual acuity (VA), surgical outcomes and classification of RPRD. Results:Of the 90 patients/detachments, 61 (67.8%) were rhegmatogenous retinal detachment (RRD), 19 (21.1%) were exudative, 3 (3.3%) were tractional retinal detachment (TRD) and 7 (7.8%) had combined. 37.5% (9/24) of patients with exudative retinal detachment were treated with either cryotherapy or laser, and one patient underwent vitrectomy for vitreous haemorrhage. 56/90 patients underwent surgical intervention. Nine patients presented late and were deemed inoperable (two exudative and seven RRD). Of the RRD patients with full operative record, the primary attachment rate was 76.2% (16/21) and final reattachment rate was 85.7% (18/21) over a mean 15.4-year follow-up period. Mean VA for RRD surgery improved from 6/190 (1.51 logMAR) to 6/120 (1.31 logMAR) (p=0.194). In the TRD group, the mean VA was 6/300 (1.66 logMAR) at baseline and improved after surgery to 6/48 (0.90 logMAR) (p=0.421). Conclusions:We demonstrated a final reattachment rate of 85.7% with a trend toward better vision following intervention for patients with RPRD. However, the final long-term vision may be poor due to the natural progression of retinitis pigmentosa-associated macular degeneration.	0
The recent report of the International Union of Immunological Societies (IUIS) has provided the categorized list of 354 inborn errors of immunity. We performed a systematic analysis of genes and diseases from the IUIS report with the use of the OMIM, ORPHANET, and HPO resources. To measure phenotypic similarity we applied the Jaccard/Tanimoto (J/T) coefficient for HPO terms and top-level categories. Low J/T coefficients for HPO terms for OMIM or ORPHANET disease pairs associated with the same genes indicated high pleiotropy of these genes. Gene ORGANizer enrichment analysis demonstrated that gene sets related to HPO top-level categories were most often enriched in immune, lymphatic, and corresponding body systems (for example, genes from the category "Cardiovascular" were enriched in cardiovascular system). We presented available data on frequent and very frequent clinical signs and symptoms in inborn errors of immunity. With the use of DisGeNET, we generated the list of 25 IUIS/OMIM diseases with two or more relatively high score gene-disease associations, found for unrelated genes and/or for clusters of genes coding for interacting proteins. Our study showed the enrichment of gene sets related to several IUIS categories with neoplastic and autoimmune diseases from the GWAS Catalog and reported individual genes with phenotypic overlap between inborn errors of immunity and GWAS diseases/traits. We concluded that genetic background may play a role in phenotypic diversity of inborn errors of immunity.	0
BACKGROUND:Sjögren-Larsson syndrome (SLS) is a rare genetic neurocutaneous disease caused by mutations in ALDH3A2 that results in deficiency of fatty aldehyde dehydrogenase and accumulation of fatty aldehydes and alcohols. The disease is associated with ichthyosis, spasticity, and intellectual disability. Patients exhibit a characteristic retinopathy with macular crystalline inclusions that first appear in early childhood and increase with age. Once formed, the inclusions are thought to be inert and irreversible. We sought to document how the crystalline inclusions change over time. MATERIALS AND METHODS:Serial retinal photographs of 4 SLS subjects (9-23 years old) were taken over a period of 1-3 years. Images were compared by visual inspection and analyzed using ImageJ/Fiji software to observe changes. RESULTS:Visual inspection of retinal photographs of SLS subjects taken over time demonstrated distinctive changes in crystalline inclusions. New inclusions were formed and some established inclusions regressed. These changes were conveniently demonstrated with software-based photographic image analysis. CONCLUSIONS:We conclude that macular inclusions in SLS are not simply inert deposits, but are dynamic structures that form over time and are subject to remodeling. This conclusion provides new insight into the interplay between the metabolic defect and retinal pathology in SLS, and raises the potential for new therapeutic approaches to reverse some aspects of the maculopathy.	0
Megalencephaly-capillary malformation syndrome (MCAP) is a brain overgrowth disorder characterized by cortical malformations (specifically polymicrogyria), vascular anomalies, and segmental overgrowth secondary to somatic activating mutations in the PI3K-AKT-MTOR pathway (PIK3CA). Cases of growth failure and hypoglycemia have been reported in patients with MCAP, raising the suspicion for unappreciated growth hormone (GH) deficiency. Here we report an observational multicenter study of children with MCAP and GH deficiency. Eleven participants were confirmed to have GH deficiency, all with very low or undetectable circulating concentrations of insulin-like growth factor-1 and insulin-like growth factor binding protein-3. Seven underwent GH stimulation testing and all had insufficient responses with a median GH peak of 3.7 ng/ml (range 1.1-8.6). Growth patterns revealed a drastic decline in length z-scores within the first year of life but then stabilized afterward. Five were treated with GH; one discontinued due to inconsolability. The other four participants continued on GH with improvement in linear growth velocity. Other endocrinopathies were identified in 7 of the 11 participants in this cohort. This study indicates that GH deficiency is associated with MCAP and that children with MCAP and hypoglycemia and/or postnatal growth failure should be evaluated for GH deficiency and other endocrinopathies.	0
Spondylocarpotarsal synostosis is a very rare skeletal disorder characterized by vertebral malsegmentation defects. Apart from severe vertebral defects, the disease is associated with carpal and tarsal synostosis which is quite characteristic for the disease. We report a case of young child who presented with short stature and congenital scoliosis. The radiological and clinical findings were compatible with the above diagnosis. Apart from the classical findings, the patient had evidence of odontoid aplasia which has not earlier been described in association with this disorder. We report this case for rarity of this disorder and the associated novel finding.	0
Gangliosidoses are caused by monogenic defects of a specific hydrolase or an ancillary sphingolipid activator protein essential for a specific step in the catabolism of gangliosides. Such defects in lysosomal function cause a primary accumulation of multiple undegradable gangliosides and glycosphingolipids. In reality, however, predominantly small gangliosides also accumulate in many lysosomal diseases as secondary storage material without any known defect in their catabolic pathway. In recent reconstitution experiments, we identified primary storage materials like sphingomyelin, cholesterol, lysosphingolipids, and chondroitin sulfate as strong inhibitors of sphingolipid activator proteins (like GM2 activator protein, saposin A and B), essential for the catabolism of many gangliosides and glycosphingolipids, as well as inhibitors of specific catabolic steps in lysosomal ganglioside catabolism and cholesterol turnover. In particular, they trigger a secondary accumulation of ganglioside GM2, glucosylceramide and cholesterol in Niemann-Pick disease type A and B, and of GM2 and glucosylceramide in Niemann-Pick disease type C. Chondroitin sulfate effectively inhibits GM2 catabolism in mucopolysaccharidoses like Hurler, Hunter, Sanfilippo, and Sly syndrome and causes a secondary neuronal ganglioside GM2 accumulation, triggering neurodegeneration. Secondary ganglioside and lipid accumulation is furthermore known in many more lysosomal storage diseases, so far without known molecular basis.	0
Little is known about the impact of blood rheology on the occurrence of retinopathy in sickle cell disease (SCD). Fifty-nine adult SCD patients in steady-state condition participated to the study: 32 with homozygous SCD (sickle cell anemia; SCA) and 27 with sickle cell hemoglobin-C disease (SCC). The patients underwent retinal examination and were categorized according to the classification of Goldberg: 1) no retinopathy (group 1), 2) non-proliferative or proliferative stage I-II retinopathy (group 2) and 3) proliferative stage III-IV-V retinopathy (group 3). Hematological and hemorheological (whole blood viscosity, RBC deformability and aggregation properties) measurements were performed for each patient. In the whole SCD group (SCA + SCC patients) and in SCC patients, the group 3 had higher platelets count than group 2 but the difference between group 3 and group 1 did not reach statistical significance. No difference was observed for the other parameters between the three groups. SCC patients from the group 3 exhibited higher whole blood viscosity than SCC patients from the group 1. No significant difference was observed between the three groups in SCA patients. This study revealed that severe sickle proliferative retinopathy is associated with blood hyperviscosity in SCC patients but not in SCA patients.	0
Referral for an assessment of tall stature is less common than for short stature. Tall stature is defined as a height more than two standard deviations above the mean for age. The majority of subjects with tall stature show a familial tall stature or a constitutional advance of growth (CAG), which is a diagnosis of exclusion. After a careful physical evaluation, tall subjects may be divided into two groups: tall subjects with normal appearance and tall subjects with abnormal appearance. In the case of normal appearance, the paediatric endocrinologist will have to evaluate the growth rate. If it is normal for age and sex, the subject may be classified as having familial tall stature, CAG or obese subject, while if the growth rate is increased it is essential to evaluate pubertal status and thyroid status. Tall subjects with abnormal appearance and dysmorphisms can be classified into those with proportionate and disproportionate syndromes.A careful physical examination and an evaluation of growth pattern are required before starting further investigations. Physicians should always search for a pathological cause of tall stature, although the majority of children are healthy and they generally do not need treatment to cease growth progression.The most accepted and effective treatment for an excessive height prediction is inducing puberty early and leading to a complete fusion of the epiphyses and achievement of final height, using testosterone in males and oestrogens in females. Alternatively, the most common surgical procedure for reducing growth is bilateral percutaneous epiphysiodesis of the distal femur and proximal tibia and fibula.This review aims to provide up-to-date information and suggestions about the diagnosis and management of children with tall stature.	0
The EuroFlow PID consortium developed a set of flow cytometry tests for evaluation of patients with suspicion of primary immunodeficiency (PID). In this technical report we evaluate the performance of the SCID-RTE tube that explores the presence of recent thymic emigrants (RTE) together with T-cell activation status and maturation stages and discuss its applicability in the context of the broader EuroFlow PID flow cytometry testing algorithm for diagnostic orientation of PID of the lymphoid system. We have analyzed peripheral blood cells of 26 patients diagnosed between birth and 2 years of age with a genetically defined primary immunodeficiency disorder: 15 severe combined immunodeficiency (SCID) patients had disease-causing mutations in RAG1 or RAG2 (n = 4, two of them presented with Omenn syndrome), IL2RG (n = 4, one of them with confirmed maternal engraftment), NHEJ1 (n = 1), CD3E (n = 1), ADA (n = 1), JAK3 (n = 3, two of them with maternal engraftment) and DCLRE1C (n = 1) and 11 other PID patients had diverse molecular defects [ZAP70 (n = 1), WAS (n = 2), PNP (n = 1), FOXP3 (n = 1), del22q11.2 (DiGeorge n = 4), CDC42 (n = 1) and FAS (n = 1)]. In addition, 44 healthy controls in the same age group were analyzed using the SCID-RTE tube in four EuroFlow laboratories using a standardized 8-color approach. RTE were defined as CD62L+CD45RO-HLA-DR-CD31+ and the activation status was assessed by the expression of HLA-DR+. Naïve CD8+ T-lymphocytes and naïve CD4+ T-lymphocytes were defined as CD62L+CD45RO-HLA-DR-. With the SCID-RTE tube, we identified patients with PID by low levels or absence of RTE in comparison to controls as well as low levels of naïve CD4+ and naïve CD8+ lymphocytes. These parameters yielded 100% sensitivity for SCID. All SCID patients had absence of RTE, including the patients with confirmed maternal engraftment or oligoclonally expanded T-cells characteristic for Omenn syndrome. Another dominant finding was the increased numbers of activated CD4+HLA-DR+ and CD8+HLA-DR+ lymphocytes. Therefore, the EuroFlow SCID-RTE tube together with the previously published PIDOT tube form a sensitive and complete cytometric diagnostic test suitable for patients suspected of severe PID (SCID or CID) as well as for children identified via newborn screening programs for SCID with low or absent T-cell receptor excision circles (TRECs).	0
Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is a rare condition associated with mutations in the genes RASA1 and EPHB4. We present a challenging case of CM-AVM in a 17-month-old boy with permanent diplegia from an undiagnosed arteriovenous malformation underlying a large atypical capillary malformation over the lower thoracic spine. This case demonstrates that clinicians should have a low threshold for neuroimaging in the context of new neurologic symptoms in patients with atypical capillary malformations.	0
Pyomyositis commonly presents with fever, muscle pain and abscess formation involving deep soft-tissue compartments. Staphylococcus aureus is the main causative organism and diagnosis is usually established clinically, supported by imaging, but confirmation may be achieved by histopathological examination. Broad-spectrum antibiotic therapy and surgical debridement are the cornerstone of treatment. Its prognosis is good but, as in all soft-tissue infections, it depends on early intervention, directed antibiotics and, if indicated, prompt surgery. In this paper, we describe a case of pelvic pyomyositis complicated with bacteraemia and bilateral septic pulmonary emboli in a young man in Colombia.	0
INTRODUCTION:Congenital infundibulopelvic stenosis (IFPS) is a rare renal dysmorphism marked by dilated calyces proximal to diminutive infundibulum and renal pelvises. The entity is theorized to exist on the spectrum of congenital obstructive renal diseases between ureteropelvic junction obstruction and multicystic dysplasia. OBJECTIVE:This case series sought to review and present the surgical management of three cases of IFPS with progressive renal insufficiency. MATERIALS AND METHODS:After Institute Review Board approval, we reviewed three cases of IFPS treated by a single surgeon over a 20-year period. All cases displayed evidence of progressive renal decline. The first case of a 16-year-old female had IFPS in a solitary kidney, with previous contralateral nephrectomy of a multicystic dysplastic kidney. The second case, a 17-year-old male, presented after blunt trauma to the ipsilateral flank. The third case of a 10-year-old female presented with microhematuria, mild azotemia and bilateral IFPS. RESULTS:Our current surgical management has evolved from renal sinus exposure and multiple infundibuloplasties in the first case to preoperative three-dimensional mapping of the dilated calyceal system with intraoperative ultrasonography for selective calicocalicostomies draining to a lower pole ureterocalicostomy in the third case. Our first case, treated with multiple infundibuloplasties experienced slow renal decline into her 20s, and the later cases, treated with calicocalicostomies, have experienced stable to mild loss of renal function with ongoing nephrological follow-up. DISCUSSION:IFPS is a complex pediatric urology problem without a clear treatment algorithm. The goal of surgical intervention is to offer an opportunity to halt or reduce progressive renal insufficiency. Our current surgical approach utilizes preoperative three-dimensional modeling via magnetic resonance urography to guide placement of multiple calicocalicostomies draining to a lower pole ureterocalicostomy. CONCLUSIONS:Not all cases of IFPS require surgical intervention. We have intervened in cases of IFPS with progressive hydronephrosis or worsening renal insufficiency with acceptable results.	0
BACKGROUND:Segmental progeroid syndromes (SPS) are rare hereditary diseases in which the affected individuals show signs of premature aging in more than one organ or type of tissue. We review the clinical and genetic features of some of these syndromes and discuss the extent to which their study affords a complementary opportunity to study aging processes in general. METHODS:This review is based on publications retrieved by a selective search in PubMed. RESULTS:Segmental progeroid syndromes are a clinically and genetically heterogeneous group of hereditary diseases. They can be categorized, for example, by the age of onset of manifestations (congenital vs. infantile vs. juvenile/adult forms). They are diagnosed on clinical grounds supplemented by genetic testing on the basis of next-generation sequencing, which is of central importance in view of the marked heterogeneity and complexity of their overlapping clinical features. The elucidation of the genetic and molecular causes of these diseases can lead to causally directed treatment, as shown by the initial clinical trials in Hutchinson- Gilford progeria syndrome. The molecular features of SPS are identical in many ways to those of "physiological" aging. Thus, studying the molecular mechanisms of SPS may be helpful for the development of molecularly defined treatment approaches for age-associated diseases in general. CONCLUSION:Segmental progeroid syndromes are a complex group of diseases with overlapping clinical features. Current research efforts focus on the elucidation of the molecular mechanisms of these diseases, most of which are very rare. This should enable the development of treatments that might be applicable to general processes of aging as well.	0
Keratosis follicularis spinulosa decalvans (KFSD; OMIM 308800) is an X-linked disorder characterized by widespread hyperkeratotic follicular papules (including keratosis pilaris-like lesions), facial erythema, hypotrichosis and scarring alopecia. KFSD results from mutations in the MBTPS2 gene. Mutations in this gene also underlie ichthyosis follicularis, alopecia and photophobia syndrome. We report a British pedigree with KFSD resulting from the mutation p.Asn508Ser. This particular mutation has been reported in three other pedigrees with KFSD (Dutch, American, British) and is the only pathogenic mutation reported in this disorder to date. However, the same mutation has also been reported in a Chinese pedigree with IFAP syndrome, highlighting the clinical heterogeneity and overlapping molecular pathology of these two disorders.	0
We report an original association of complex genetic defects in a patient carrying both an 11p paternal duplication, resulting in the double expression of insulin-like growth factor 2 (IGF2), as reported in Beckwith-Wiedemann syndrome, and a 15q terminal deletion, including the type 1 IGF receptor gene (IGF1R), resulting in haploinsufficiency for this gene. The patient was born with measurements appropriate for her gestational age but experienced growth retardation in early childhood, allowing a better comprehension of the IGF system in the pathophysiology of growth. It is possible that IGF-II plays a key role in fetal growth, independently of IGF1R signaling, and that its role is less important in post-natal growth, leaving IGF-I and growth hormone as the main actors.	0
The RECQL4 helicase gene is a member of the RECQL gene family, mutated in some Rothmund-Thomson syndrome (RTS) patients. Other members of this gene family are BLM mutated in Bloom syndrome, WRN mutated in Werner syndrome and RECQL and RECQL5. All polypeptides encoded by RECQL genes share a central region of seven helicase domains. The function of RECQL4 remains unknown, but based on the domain homology it possesses ATP-dependent DNA helicase activity such as BLM and WRN. Rothmund-Thomson, Bloom and Werner syndromes have overlapping clinical features, of which high predisposition to malignancies is the most remarkable feature. Here we report a fourth syndrome resulting in mutations in the RECQL genes. RAPADILINO syndrome is an autosomal recessive disorder characterized by short stature, radial ray defects and other malformations, as well as infantile diarrhoea, but not by a significant cancer risk. Four mutations in the RECQL4 gene were found in the Finnish patients, the most common mutation representing exon 7 in-frame deletion saving the helicase domain and showing dominant effect over other three nonsense mutations. The tissue expression of Recql4 in mouse well agrees with the tissue symptoms of RAPADILINO. The skeletal malformations in RAPADILINO and RTS patients as well as the high osteosarcoma risk in RTS propose a special role for RECQL4 in bone development.	0
Sphingolipidoses are inherited genetic diseases characterized by the accumulation of glycosphingolipids. Sphingolipidoses (SP), which usually involve the loss of sphingolipid hydrolase function, are of lysosomal origin, and represent an important group of rare diseases among lysosomal storage disorders. Initial treatments consisted of enzyme replacement therapy, but, in recent decades, various therapeutic approaches have been developed. However, these commonly used treatments for SP fail to be fully effective and do not penetrate the blood-brain barrier. New approaches, such as genome editing, have great potential for both the treatment and study of sphingolipidoses. Here, we review the most recent advances in the treatment and modelling of SP through the application of CRISPR-Cas9 genome editing. CRISPR-Cas9 is currently the most widely used method for genome editing. This technique is versatile; it can be used for altering the regulation of genes involved in sphingolipid degradation and synthesis pathways, interrogating gene function, generating knock out models, or knocking in mutations. CRISPR-Cas9 genome editing is being used as an approach to disease treatment, but more frequently it is utilized to create models of disease. New CRISPR-Cas9-based tools of gene editing with diminished off-targeting effects are evolving and seem to be more promising for the correction of individual mutations. Emerging Prime results and CRISPR-Cas9 difficulties are also discussed.	0
N-acetylaspartate is produced by neuronal aspartate N-acetyltransferase (NAT8L) from acetyl-CoA and aspartate. In cholinergic neurons, acetyl-CoA is also utilized in the mitochondrial tricarboxylic acid cycle and in acetylcholine production pathways. While aspartate has to be shared with the malate-aspartate shuttle, another mitochondrial machinery together with the tricarboxylic acid cycle supports the electron transport chain turnover. The main goal of this study was to establish the impact of toxic conditions on N-acetylaspartate production. SN56 cholinergic cells were exposed to either Zn2+ overload or Ca2+ homeostasis dysregulation and male adult Wistar rats' brains were studied after 2 weeks of challenge with streptozotocin-induced hyperglycemia or daily theophylline treatment. Our results allow us to hypothesize that the cholinergic neurons from brain septum prioritized the acetylcholine over N-acetylaspartate production. This report provides the first direct evidence for Zn2+-dependent suppression of N-acetylaspartate synthesis leading to mitochondrial acetyl-CoA and aspartate shortages. Furthermore, Zn2+ is a direct concentration-dependent inhibitor of NAT8L activity, while Zn2+-triggered oxidative stress is unlikely to be significant in such suppression.	0
Gangliogliomas are well-differentiated, slow-growing tumors. The majority are gradeI of WHO. It appears predominantly in children and young adults. Most are located at the temporal lobe, and as symptomatology more frequent epileptic seizures of difficult pharmacological control. In general, they have a good prognosis after surgical resection. The anaplasic variant, considered to be gradeIII of the WHO, presents greater clinical and radiological aggressiveness. Leptomeningeal dissemination is exceptional in these types of tumors, but when diagnosed it presents a rapidly progressive and fatal course for the patient.	0
Distal arthrogryposis (DA) is a skeletal muscle disorder which can be classified under a broader term as Arthrogryposis multiplex contractures. DA is characterized by the presence of joint contractures at various parts of the body, particularly in distal extremities. It is identified as an autosomal dominant and a rare X-linked recessive disorder associated with increased connective tissue formation around joints in such way that immobilizes muscle movement causing deformities. DA is again classified into various types since it manifests as a range of conditions representing different etiologies. Myopathy is one of the most commonly listed etiologies of DA. The mutations in sarcomeric protein-encoding genes lead to decreased sarcomere integrity, which is often associated with this disorder. Also, skeletal disorders are often associated with cardiac disorders. Some studies mention the presence of cardiomyopathy in patients with skeletal dysfunction. Therefore, it is hypothesized that the congenitally mutated protein that causes DA can also lead to cardiomyopathy. In this review, we will summarize the different forms of DA and their clinical features, along with gene mutations responsible for causing DA in its different forms. We will also examine reports that list mutations also known to cause heart disorders in the presence of DA.	0
The role of X-inactivation is often ignored as a prime cause of sex differences in disease. Yet, the way males and females express their X-linked genes has a major role in the dissimilar phenotypes that underlie many rare and common disorders, such as intellectual deficiency, epilepsy, congenital abnormalities, and diseases of the heart, blood, skin, muscle, and bones. Summarized here are many examples of the different presentations in males and females. Other data include reasons why women are often protected from the deleterious variants carried on their X chromosome, and the factors that render women susceptible in some instances.	0
OBJECTIVES:Fluorinated steroids are largely the therapeutic approach of autoimmune mediated congenital heart block (CHB). We performed a meta-analysis to assess the efficacy of fluorinated steroids for the treatment of CHB. METHODS:Studies evaluating the efficacy of fluorinated steroids versus no treatment in CHB patients were identified in electronic databases. Random-effects model was used to pool odds ratio (OR) (with 95% CI) of live births as the primary outcome. ORs of CHB progression, pacemaker implantation and extranodal disease were the secondary outcome. Subgroup analysis according to CHB grade and study type was performed. RESULTS:Data from nine studies involving 747 patients were analysed. The overall live birth rates were 86.8% and 86.7%, respectively, in the fluorinated steroids exposed foetuses and in the non-exposed ones. Fluorinated steroids did not ameliorate overall survival in CHB (OR 1.02; 95% CI: 0.65-1.61) with any significant statistical heterogeneity between studies (I2 0%, p=0.45). No significant differences for the progression of CHB, the pacing and the presence of extranodal disease were observed. Subgroup analysis revealed a significant protective role of fluorinated steroids for survival in 3rd degree CHB and for pacing in monocentric studies, OR 4.07; 95% CI: 1.10-15.08 and OR 0.15; 95% CI: 0.02-0.99, respectively. CONCLUSIONS:This meta-analysis shows that fluorinated steroids are not superior to any treatment in patients with CHB in terms of live birth, prevention of progression of incomplete CHB, pacemaker implantation and extranodal disease. Thus, considering their side effects, their use in CHB patients should be discouraged.	0
Hereditary hemochromatosis (HH) type 3 is an autosomal recessive disorder of iron metabolism characterized by excessive iron deposition in the liver and caused by mutations in the transferrin receptor 2 (TFR2) gene. Here, we describe three new HH type 3 Spanish families with four TFR2 mutations (p.Gly792Arg, c.1606-8A>G, Gln306*, and Gln672*). The missense variation p.Gly792Arg was found in homozygosity in two adult patients of the same family, and in compound heterozygosity in an adult proband that also carries a novel intronic change (c.1606-8A>G). Two new nonsense TFR2 mutations (Gln306* and Gln672*) were detected in a pediatric case. We examine the functional consequences of two TFR2 variants (p.Gly792Arg and c.1606-8A>G) using molecular and computational methods. Cellular protein localization studies using immunofluorescence demonstrated that the plasma membrane localization of p.Gly792Arg TFR2 is impaired. Splicing studies in vitro and in vivo reveal that the c.1606-8A>G mutation leads to the creation of a new acceptor splice site and an aberrant TFR2 mRNA. The reported mutations caused HH type 3 by protein truncation, altering TFR2 membrane localization or by mRNA splicing defect, producing a nonfunctional TFR2 protein and a defective signaling transduction for hepcidin regulation. TFR2 genotyping should be considered in adult but also in pediatric cases with early-onset of iron overload.	0
This special issue intends to review and update our understanding of the antimicrobial defense mechanisms of the skin and oral cavity. These two environments are quite different in terms of water, pH, and nutrient availability, but have some common antimicrobial factors. The skin surface supports the growth of a limited range of microorganisms but provides a hostile environment for others. The growth of most microorganisms is prevented or limited by the low pH, scarcity of some nutrients such as phosphorus and the presence of antimicrobial peptides, including defensins and cathelicidins, and antimicrobial lipids, including certain fatty acids and long-chain bases. On the other hand, the oral cavity is a warm, moist, nutrient rich environment which supports the growth of diverse microflora. Saliva coating the oral soft and hard surfaces determines which microorganisms can adhere to these surfaces. Some salivary proteins bind to bacteria and prevent their attachment to surfaces. Other salivary peptides, including defensins, cathelicidins, and histatins are antimicrobial. Antimicrobial salivary proteins include lysozyme, lactoferrin, and lactoperoxidase. There are also antimicrobial fatty acids derived from salivary triglycerides and long-chain bases derived from oral epithelial sphingolipids. The various antimicrobial factors determine the microbiomes of the skin surface and the oral cavity. Alterations of these factors can result in colonization by opportunistic pathogens, and this may lead to infection. Neutrophils and lymphocytes in the connective tissue of skin and mucosa also contribute to innate immunity.	0
OBJECTIVE:To identify a pharmacological compound targeting macrophages, the most affected immune cells in inflammatory X-linked adrenoleukodystrophy (cerebral X-ALD) caused by ABCD1 mutations and involved in the success of hematopoietic stem cell transplantation and gene therapy. METHODS:A comparative database analysis elucidated the epigenetic repressing mechanism of the related ABCD2 gene in macrophages and identified the histone deacetylase (HDAC) inhibitor Vorinostat as a compound to induce ABCD2 in these cells to compensate for ABCD1 deficiency. In these cells, we investigated ABCD2 and pro-inflammatory gene expression, restoration of defective peroxisomal β-oxidation activity, accumulation of very long-chain fatty acids (VLCFAs) and their differentiation status. We investigated ABCD2 and pro-inflammatory gene expression, restoration of defective peroxisomal ß-oxidation activity, accumulation of very long-chain fatty acids (VLCFA) and differentiation status. Three advanced cerebral X-ALD patients received Vorinostat and CSF and MRI diagnostics was carried out in one patient after 80 days of treatment. RESULTS:Vorinostat improved the metabolic defects in X-ALD macrophages by stimulating ABCD2 expression, peroxisomal ß-oxidation, and ameliorating VLCFA accumulation. Vorinostat interfered with pro-inflammatory skewing of X-ALD macrophages by correcting IL12B expression and further reducing monocyte differentiation. Vorinostat normalized the albumin and immunoglobulin CSF-serum ratios, but not gadolinium enhancement upon 80 days of treatment. INTERPRETATION:The beneficial effects of HDAC inhibitors on macrophages in X-ALD and the improvement of the blood-CSF/blood-brain barrier are encouraging for future investigations. In contrast with Vorinostat, less toxic macrophage-specific HDAC inhibitors might improve also the clinical state of X-ALD patients with advanced inflammatory demyelination.	0
Hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS) syndrome, a rare developmental disorder, involves the first and second branchial arches and is characterized by hemimaxillary enlargement, abnormal appearance of skin and teeth, and facial asymmetry. It is generally detected at birth or during early childhood and is associated with unilateral abnormalities of the face, including the bones, teeth, gums, and skin. Becker nevus is the most common cutaneous manifestation of HATS syndrome. Although patients with HATS syndrome have been treated with various therapeutic regimens, no standard or definitive treatment regimen has been established. This study describes this rare condition in a 12-year-old girl.	0
Pulmonary tissue obtained at thoracotomy or autopsy from 5 kaolin workers with complicated pneumoconiosis was studied by optical light and scanning electron microscopy. Premortem or preoperative chest roentgenograms demonstrated small irregular shadows and large opacities typical of kaolin pneumoconiosis. On gross examination, there were firm, grey-brown nodules and masses in the parenchyma and in the hilar lymph nodes. Histologically, there was extensive pulmonary kaolinite deposition associated with formation of peribronchiolar macules and nodules. The latter were comprised of kaolinite aggregates traversed by bands of fibrous tissue rather than dense whorled collagen, as seen in silicosis. Crystallographic studies confirmed the presence of kaolinite in the lungs, but silica was not demonstrable by either analytical scanning electron microscopy or X-ray diffractometry. These findings illustrate the pathology of human kaolin pneumoconiosis, confirm the fibrogenic potential of kaolinite, and emphasize differences in pulmonary responses to kaolinite and to silica.	0
Focal acral hyperkeratosis is a rare genodermatosis with an autosomal dominant pattern of inheritance. It is characterized by usually asymptomatic keratotic papules along the borders of the hands and/or feet. The main differential diagnosis is acrokeratoelastoidosis of Costa, which differs from the former only by not presenting elastorrhexis in histopathological examination, thus requiring this exam for a correct diagnosis.	0
Muscle loss due to fibrotic or adipogenic replacement of myofibers is common in muscle diseases and muscle-resident fibro/adipogenic precursors (FAPs) are implicated in this process. While FAP-mediated muscle fibrosis is widely studied in muscle diseases, the role of FAPs in adipogenic muscle loss is not well understood. Adipogenic muscle loss is a feature of limb girdle muscular dystrophy 2B (LGMD2B) - a disease caused by mutations in dysferlin. Here we show that FAPs cause the adipogenic loss of dysferlin deficient muscle. Progressive accumulation of Annexin A2 (AnxA2) in the myofiber matrix causes FAP differentiation into adipocytes. Lack of AnxA2 prevents FAP adipogenesis, protecting against adipogenic loss of dysferlinopathic muscle while exogenous AnxA2 enhances muscle loss. Pharmacological inhibition of FAP adipogenesis arrests adipogenic replacement and degeneration of dysferlin-deficient muscle. These results demonstrate the pathogenic role of FAPs in LGMD2B and establish these cells as therapeutic targets to ameliorate muscle loss in patients.	0
Joubert syndrome is a group of rare disorders that stem from defects in a sensory organelle, the primary cilia. Affected patients often present with disorders involving multiple organ systems, including the brain, eyes, and kidneys. Common symptoms include breathing abnormalities, mental developmental delays, loss of voluntary muscle coordination, and abnormal eye movements, with a diagnostic "molar tooth" sign observed by magnetic resonance imaging (MRI) of the midbrain. We reviewed the ocular phenotypes that can be found in patients with Joubert syndrome. Ocular motor apraxia is the most frequent (80% of patients), followed by strabismus (74%) and nystagmus (72%). A minority of patients also present with ptosis (43%), chorioretinal coloboma (30%), and optic nerve atrophy (22%). Although mutations in 34 genes have been found to be associated with Joubert syndrome, retinal degeneration has been reported in only 38% of patients. Mutations in AHI1 and CEP290, genes critical to primary cilia function, have been linked to retinal degeneration. In conclusion, Joubert syndrome is a rare pleiotropic group of disorders with variable ocular presentations.	0
Phosphoinositides (PIPs) are a ubiquitous group of seven low-abundance phospholipids that play a crucial role in defining localized membrane properties and that regulate myriad cellular processes, including cytoskeletal remodeling, cell signaling cascades, ion channel activity and membrane traffic. PIP homeostasis is tightly regulated by numerous inositol kinases and phosphatases, which phosphorylate and dephosphorylate distinct PIP species. The importance of these phospholipids, and of the enzymes that regulate them, is increasingly being recognized, with the identification of human neurological disorders that are caused by mutations in PIP-modulating enzymes. Genetic disorders of PIP metabolism include forms of epilepsy, neurodegenerative disease, brain malformation syndromes, peripheral neuropathy and congenital myopathy. In this Review, we provide an overview of PIP function and regulation, delineate the disorders associated with mutations in genes that modulate or utilize PIPs, and discuss what is understood about gene function and disease pathogenesis as established through animal models of these diseases.	0
Walker-Warburg syndrome is a rare congenital disorder. Several features, including muscular dystrophy, hydrocephalus, and oropharyngeal abnormalities, have important implications in the perioperative setting. We present a case of general anesthesia in an infant and discuss perioperative considerations to guide clinicians faced with the management of patients with this syndrome.	0
Mitochondrial chronic progressive external ophthalmoplegia (CPEO) is a major manifestation of human mitochondrial encephalomyopathies. Previous studies have shown cognitive deficits in patients with mitochondrial diseases. However, these studies often included patients with heterogeneous subtypes of mitochondrial diseases. Here, we aimed to provide a better cognitive profile of patients with CPEO by applying a comprehensive battery of neuropsychological assessments in a pure sample of patients with CPEO. We recruited 28 patients with CPEO (19 women, age 16-62 years) and 38 age- and education-matched healthy control subjects (25 women, age 16-60 years). The neuropsychological assessments covered global cognition and five cognitive domains (executive functions, language, working memory, memory, and visuospatial functions). We found that the patients were impaired in global cognition [Montreal Cognitive Assessment (MoCA)], executive functions [Trail Making Test Part B (TMT-B)], and language [Boston Naming Test (BNT)], but not in working memory, memory or visuospatial functions. Moreover, individual patients' performances in the TMT-B (completion time) were predicted by the severity of non-ophthalmoplegia mitochondrial symptoms/signs [Newcastle Mitochondrial Disease Adult Scale (NMDAS)] and duration of the mitochondrial disease (years). Namely, patients with more severe non-ophthalmoplegia mitochondrial symptoms/signs and a longer disease duration took a longer time to complete the TMT-B. No clinical measures predicted individual patients' performances in the BNT.	0
An eight-yr-old female with a history of multifocal lymphangioendotheliomatosis and thrombocytopenia presented for MVT. The patient had multiple vascular lesions in the skin and stomach in infancy. Although her cutaneous lesions resolved with vincristine and methylprednisolone, her gastric lesions persisted. Eight yr later, she was diagnosed with portal hypertension and decompensating liver function despite therapy with bevacizumab, propranolol, furosemide, and spironolactone. Upon presentation, she was found to have a Kasabach-Merritt-like coagulopathy in association with multiple lesions in her GI tract and persistent gastric lesions. Although treatment with methylprednisolone and sirolimus normalized her coagulation factors and d-dimer levels, she never developed sustained improvement in her thrombocytopenia. Her liver function continued to deteriorate and she developed hepatorenal syndrome. Given better outcomes after OLT in comparison with MVT, she underwent OLT, with the plan to manage her GI lesions with APC post-transplant. Post-transplant, her liver function and coagulopathy normalized, and GI tract lesions disappeared upon screening with capsule endoscopy. The patient is doing well, without recurrence of either GI lesions or thrombocytopenia, at 18 months after transplantation.	0
Dihydrolipoamide dehydrogenase (DLD, E3) is a flavoprotein common to pyruvate, α-ketoglutarate and branched-chain α-keto acid dehydrogenases. We found two novel DLD mutations (p.I40Lfs*4; p.G461E) in a 19 year-old patient with lactic acidosis and a complex amino- and organic aciduria consistent with DLD deficiency, manifesting progressive exertional fatigue. Muscle biopsy showed mitochondrial proliferation and lack of DLD cross-reacting material. Riboflavin supplementation determined the complete resolution of exercise intolerance with the partial restoration of the DLD protein and disappearance of mitochondrial proliferation in the muscle. Morphological and functional studies support the riboflavin chaperon-like role in stabilizing DLD protein with rescue of its expression in the muscle.	0
BACKGROUND:Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia that is characterized by hyperinsulinemia, hypoglycemia, and a high autoantibody titer. About 50% of patients with IAS have taken a medication containing sulfhydryl (-SH) groups. We present a case of IAS that developed after taking clopidogrel, a drug with an active metabolite that contains an SH-group. CASE REPORT:IAS was suspected in a 63-year-old Chinese man because of high concentrations of insulin and C-peptide during hypoglycemic episodes, and positivity for anti-insulin autoantibody (IAA). During his first episode of hypoglycemia, no trigger medication was identified and prednisone therapy was effective. However, imaging examination revealed a colonic carcinoma and the patient was discharged to undergo surgery. He had no episodes of hypoglycemia for 10 weeks after discontinuation of the prednisone, but then hypoglycemia recurred. Review of his medication revealed that he had taken a 10-day course of clopidogrel just before the recurrence. Therefore, a specialized multidisciplinary team consisting of endocrinologists, dieticians, and clinical pharmacists took charge of his management. Prednisone therapy was restarted and tapered off over 16 weeks. The patient also consumed small, frequent, low-carbohydrate meals and was instructed to avoid trigger medications. No further episodes of hypoglycemia were detected. His insulin and C-peptide concentrations and his anti-IAA index normalized during the follow-up period. CONCLUSION:SH-group-containing drugs might induce or exacerbate hypoglycemia in patients with a history of IAS. Furthermore, patients with IAS can benefit from multidisciplinary team management. We suggest herein an evaluation process for patients suspected of IAS.	0
Hereditary cerebellar ataxias are genetically heterogeneous disorders. Autosomal recessive spinocerebellar ataxia-21 (SCAR21) is a neurologic disorder characterized by the onset of cerebellar ataxia, recurrent episodes of liver failure, peripheral neuropathy, and learning disabilities. Herein, we reported a case presented with gait and balance problems, swallowing difficulties, mild delayed motor development, and mild learning disability with SCAR21 that confirmed by mutation analysis in a Turkish child. To the best of our knowledge, this is the first case of SCAR21 from Turkey.	0
Chronic granulomatous disease (CGD) is a rare primary immune deficiency caused by a defect in the phagocyte nicotinamide adenine dinucleotide phosphate oxidase enzyme complex and is X-linked recessive or autosomal recessive (AR) inherited. X-linked CGD is found most commonly in outbred populations, while AR-CGD is more common in areas with high consanguinity. In children, the hallmark clinical manifestation of CGD is a severe life-threatening bacterial or fungal infection, especially caused by catalase-positive organisms or Aspergillus species and also from complications due to the Bacillus Calmette-Guérin (BCG) vaccination in developing countries.2 However, granulomas consisting of lymphocytes and histiocytes may develop instead of overt pyogenic infections when stalemates occur between the pathogen and the CGD patient's leucocytes. Although typical clinical manifestations combined with small gene panel analysis or next-generation sequencing can provide relatively rapid and accurate diagnoses of CGD in children, there has been a lag between onset and diagnosis of CGD, especially in developing countries.	0
Preconception care (PCC) is acknowledged as a vital preventive health measure aiming to promote health today and for subsequent generations. We aimed to describe the content and context of PCC delivery in a very remote Australian Aboriginal Community Controlled Health Service setting. A retrospective audit was undertaken to identify what PCC was delivered between 2011 and 2018 to 127 Aboriginal women who had at least one pregnancy during this period. Of 177 confirmed pregnancies, 121 had received PCC prior to the pregnancy. Sexually transmissible infection screening (71%) was the most common care delivered, followed by folic acid prescription (57%) and smoking cessation support (43%). Younger women received PCC less often, particularly screening for modifiable pregnancy risk factors. Rates of prediabetes/diabetes, albuminuria, overweight/obesity and smoking were high amongst those screened (48-60%). PCC was usually patient-initiated and increased significantly over the audit period. Presentation for antenatal care in the first trimester of pregnancy was high at 73%. Opportunities to increase PCC delivery include integration with routine health checks, pregnancy tests and chronic disease programs. PCC programs codesigned with young people are also recommended. All primary care providers should be supported and assisted to provide opportunistic PCC and health promotion.	0
Introduction:Spondylo-epi-metaphyseal dysplasia (SEMD) represents a group of osteo-chondrodysplasias characterized by vertebral, epiphyseal as well as metaphyseal abnormalities. Several genes have been identified underlying the different forms. Methodology and results:Two relatives (cousins) in a family were found to have disproportionate short stature with clinical and radiological features suggestive of SEMD. Metabolic bone profile was normal including parathyroid hormone and 25(OH)vitamin D3. Exome sequencing revealed a missense mutation (p. T120M) in the von-Willebrand factor A-domain of the Matrilin 3 (MATN3) gene that segregates with the disease in the family. Conclusion:We identified a homozygous missense mutation in MATN3, an important structural component of the extracellular matrix of cartilage, as the genetic cause of SEMD in this pedigree. MATN3 mutations have been more commonly associated with multiple epiphyseal dysplasia than SEMD. Recognition of this mutation will aid in enhancing the understanding and expanding the spectrum of this particular skeletal dysplasia.	0
The endoplasmic reticulum is primarily recognized as the site of synthesis and folding of secreted, membrane-bound, and some organelle-targeted proteins. An imbalance between the load of unfolded proteins and the processing capacity in endoplasmic reticulum leads to the accumulation of unfolded or misfolded proteins and endoplasmic reticulum stress, which is a hallmark of a number of storage diseases, including neurodegenerative diseases, a number of metabolic diseases, and cancer. Moreover, its contribution as a novel mechanistic paradigm in genetic skeletal diseases associated with abnormalities of the growth plates and dwarfism is considered. In this review, I discuss the mechanistic significance of endoplasmic reticulum stress, abnormal folding, and intracellular retention of mutant collagen types II and X in certain variants of skeletal chondrodysplasia.	0
BACKGROUND:Jaffe-Campanacci syndrome is characterized by multiple non-ossifying fibromas, café-au-lait macules and giant cell granulomas of the jaw. Even if the association between all these peculiar features and neurofibromatosis type 1 have been described, it has not yet been clarified whether Jaffe-Campanacci syndrome represents a distinct entity or it can be regarded as a neurofibromatosis type 1 subtype. CASE PRESENTATION:The patient here described is a young boy, who fulfilled the clinical diagnostic criteria for both syndromes. He had a complex clinical history with café-au-lait macules, axillary and inguinal freckling, multiple non-ossifying fibromas, giant-cell granuloma of the jaw, neurofibromas, plexiform fibroma, ocular Lisch nodules, optic chiasmatic- hypothalamic glioma, pseudarthrosis, scoliosis, short stature, vascular anomalies, seizures. Molecular analysis of the NF1 gene both on blood cells and non-ossifying fibroma's biopsy tissue allowed the detection of a novel variant within the coding region, NM_000267.3:c.2789_2791delATC(p.Tyr930_Pro931delinsSer), with loss of heterozygosity (second hit mutation) in the non-ossifying fibroma. CONCLUSION:This result indicates that every patient with clinical features of Jaffe-Campanacci syndrome should be further evaluated to detect features related to neurofibromatosis type 1 and genetically investigated for mutations in the NF1 gene, since this could lead to a definite diagnosis, but also could clarify and quantify the real genotype-phenotype overlap between neurofibromatosis type 1 and Jaffe-Campanacci syndrome.	0
Annular atrophic lichen planus (AALP) is a rare variant of lichen planus. The clinical presentation of AALP shows distinct atrophic plaques with elevated borders on the trunk and extremities. Histopathologic findings generally reveal a lichenoid dermatitis in active lesions with a distinct loss of elastic fibers in the center of the lesions. We report a unique case of AALP, which highlights the chronicity of the eruption. Our patient showed early signs of improvement with hydroxychloroquine and acitretin, suggesting a role for systemic therapy in the treatment of AALP.	0
Niemann-Pick disease type C (NPC) is a fatal autosomal recessive lipid storage disease associated with impaired trafficking of unesterified cholesterol and glycolipids in lysosomes and late endosomes. This disease is commonly characterized by hepatosplenomegaly and severe progressive neurological dysfunction. There are two defective genes that cause this illness. One of these genes is NPC1 gene which is the cause of illness in 95% of the patients. The other gene is the rare type NPC2 which is the cause of illness in 5% of the patients. Patients with NPC2 usually present with respiratory distress in early infancy, which is rather unusual with NPC1. This article discusses about a patient who died at an early age from pulmonary involvement and who subsequently was found to have a novel homozygous mutation of NPC2 gene.	0
Purpose: To characterize the potential therapeutic effects of idebenone on Leber hereditary optic neuropathy (LHON) in terms of visual acuity (VA), visual field (VF) defects, visual evoked potential (VEP) and retinal nerve fibre layer (RNFL) thickness using optical coherence tomography (OCT) measurements.Methods: This was a retrospective case-controlled study of the effect of idebenone (900 mg/d) on 30 patients with LHON due to m.3460 G > A, m.11778 G > A and m.14484 T > C mutations. The primary end-point was the recovery in VA after 3 and 6 mon. The main secondary end-point was the change in VF, VEP and RNFL thickness. The other secondary end-point was the correlation between visual changes after 6 mon and the VF, VEP and RNFL thickness at baseline of the groups.Results: Idebenone was shown to be safe and well tolerated. The primary end-point reached statistical significance. The VA in the idebenone group improved in both the best eye and worst eye. The mean defect of VF decreased and amplitude of VEP increased. There was no significant difference in latency and RNFL thickness between the groups. The treatment, together with the VA and amplitude at baseline, had a significant effect on the improvement in VA at 6 mon.Conclusion: This case-controlled study of LHON provides evidence that idebenone treatment may be beneficial in cases of LHON and that the influential factors governing outcomes are the VA and amplitude of the VEP at baseline.	0
It is not unusual for patients with "rare" conditions, such as skeletal dysplasias, to remain undiagnosed until adulthood. In such cases, a pregnancy may unexpectedly reveal hidden problems and special needs. A 28 year old primigravida was referred to us at 17 weeks for counselling with an undiagnosed skeletal dysplasia with specific skeletal anomalies suggesting the collagen 2 disorder, spondyloperipheral dysplasia (SPD; MIM 156550).She was counselled about the probability of dominant inheritance and was offered a prenatal diagnosis by sonography. US examination at 17, 18 and 20 weeks revealed fetal macrocephaly, a narrow thorax, and shortening and bowing of long bones. The parents elected to continue the pregnancy. At birth the baby showed severe respiratory distress for four weeks which then resolved. Mutation analysis of both mother and child revealed a hitherto undescribed heterozygous nonsense mutation in the C-propeptide coding region of COL2A1 confirming the diagnosis of SPD while reinforcing the genotype-phenotype correlations between C-propeptide COL2A1 mutations and the SPD-Torrance spectrum. This case demonstrates the importance of a correct diagnosis even in adulthood, enabling individuals affected by rare conditions to be made aware about recurrence and pregnancy-associated risks, and potential complications in the newborn.	0
Hypoplastic right heart syndrome is a rare cyanotic congenital heart disease with under-development of the right ventricle, tricuspid, and pulmonary valves leading to right-to-left shunting of the blood through inter-atrial septal defect. Perinatal mortality is high with very few patients surviving to adulthood without corrective surgery. This report describes a 26-year-old young woman, who had recurrent abortions and stillbirths and detected to have marked cyanosis with hypoplastic right heart, sub-arterial ventricular septal defect, absent pulmonary valve, non-compaction of the left ventricle, and bicuspid aortic valve with aortic regurgitation. The patient died owing to progressive heart failure 4 years after the diagnosis was made.	0
INTRODUCTION:Amniotic band syndrome (ABS) includes limb deficiencies accompanied by fibrous strands originating from the amniotic lining. Terminal transverse limb deficiencies (TTLD) appear to be similar but lack fibrous strands. Both are hypothesized to result from vascular disruption. For ABS, limb deficiencies are considered secondary to amnion rupture. We explored an alternative possibility-that TTLD is the primary defect and ABS is secondary. METHODS:Using data from the National Birth Defects Prevention Study, we expanded on a previous study. We examined smoking, alcohol, and medications categorized by indicated vasoactivity as markers of vascular disruption. Logistic regression models with Firth's penalized likelihood were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS:Use of bronchodilators and aspirin appeared to increase the risk of ABS, while decongestants and nonaspirin NSAIDs increased the risk of TTLD. The risk of ABS was markedly increased in cases reporting combinations of vasoactive exposures, particularly alcohol and aspirin (aOR 3.7, 95% CI 1.6, 7.8), and alcohol and bronchodilators (aOR 3.4, 95% CI 1.4, 7.5). Increased risk of TTLD due to combinations of vasoactive exposures was only observed for smoking and decongestants (aOR 2.3, 95% CI 1.4, 3.6). CONCLUSIONS:Exposures associated with increased risk of ABS had no apparent association with TTLD, supporting previous evidence that these may be distinct phenotypes. ABS appears to be associated with combined exposures with vasodilation properties, such as alcohol and bronchodilators, while increased risk of TTLD may be associated with smoking and decongestants, both vasoconstrictive exposures.	0
A case report of an apparently unique progeroid syndrome is reported here. Major clinical characteristics included growth failure with onset of senility in the early teens, atrophic skin, hypogonadism, and retinal and vascular sclerosis. Mental retardation was present, but could have been attributable to trauma. The replicative life spans of several lines of cultured skin fibroblasts were within the normal range, in contrast to the limited life-spans of such cultures from patients with Werner's syndrome, whom our patient most closely resembles. Also, in contrast to Werner's syndrome, our patient did not have white or gray hair or cataracts.	0
Titanium dioxide (TiO2) nanoparticles have shown success as photosensitizers in the form of light-based cancer therapy called Cerenkov radiation induced therapy (CRIT). While TiO2 nanoparticles have been reported to be an effective therapeutic agent, there has been little work to control their functionalization and stability in aqueous suspension. In this work, the controlled coating of 25 nm diameter TiO2 nanoparticles with the glycoprotein transferrin (Tf) for application in CRIT was demonstrated using an electrospray system. Monodisperse nanoscale droplets containing TiO2 and Tf were dried during flight, coating the proteins on the surface of the metal oxide nanoparticles. Real-time scanning mobility particle sizing, dynamic light scattering, and transmission electron microscopy show efficient control of the Tf coating thickness when varying the droplet size and the ratio of Tf to TiO2 in the electrospray precursor suspension. Further, the functionality of Tf-coated TiO2 nanoparticles was demonstrated, and these particles were found to have enhanced targeting activity of Tf to the Tf receptor after electrospray processing. The electrospray-coated Tf/TiO2 particles were also found to be more effective at killing the multiple myeloma cell line MM1.S than that of nanoparticles prepared by other reported functionalization methods. In summary, this investigation not only provides a single-step functionalization technique for nanomaterials used in Cerenkov radiation induced therapy but also elucidates an electrospray coating technique for nanomaterials that can be used for a wide range of drug design and delivery purposes.	0
INTRODUCTION:Heterozygous mutations or haploinsufficiency of NKX2-1 are associated with the brain-lung-thyroid syndrome incorporating primary hypothyroidism, respiratory distress, and neurological disturbances. CASE PRESENTATION:We report a patient presenting in the neonatal period with multiple pituitary hormone deficiency including central hypothyroidism and hypoadrenalism, growth hormone deficiency, undetectable gonadotrophins, and a small anterior pituitary on MRI. CGH microarray revealed haploinsufficiency for NKX2.1 and during subsequent follow-up, she has exhibited the classic triad of brain-lung-thyroid syndrome with undetectable tissue on thyroid ultrasonography. Whilst the role of NKX2-1 is well described in murine pituitary development, this report constitutes the first description of multiple pituitary dysfunction in humans associated with the syndrome and haploinsufficiency NKX2-1. CONCLUSION:The report highlights a potential need for pituitary screening in patients with established brain-lung-thyroid syndrome and implicates NKX2.1 in human pituitary disease.	0
Langerhans cell histiocytosis (LCH) is a rare, clonal disease of the monocyte-macrophage system, varying in its clinical presentation from mere self-healing skin and bone lesions to life-threatening multi-system disease. In descending order of frequency, the disease is known to involve the skeleton, skin, lymph nodes and lesser often, the liver, spleen, lungs, hematopoietic and central nervous systems. Here, we present a pediatric case of multi-system LCH in a five-year-old child, unique in its evident cardiac and renal involvement alongside other organ systems and important in how the diagnosis was aided by a fine needle aspiration cytology instead of the costlier histopathological procedures, in a setting with limited resources.	0
Biochemical and biological properties of glycoconjugates are strongly determined by the specific structure of its glycan parts. Glycosylation, the covalent attachment of sugars to proteins and lipids, is very complex and highly-coordinated process involving > 250 gene products. Deficiency of glycosylation enzymes or transporters results in impaired glycosylation, and consequently pathological modulation of many physiological processes. Inborn defects of glycosylation enzymes, caused by the specific mutations, lead to the development of rare, but severe diseases - congenital disorders of glycosylation (CDGs). Up today, there are more than 45 known CDGs. Their clinical manifestations range from very mild to extremely severe (even lethal) and unfortunately, only three of them can be effectively treated nowadays. CDG symptoms highly vary, though some are common for several CDG types but also for other unrelated diseases, especially neurological ones, leaving the possibility that many CDGs cases are under- or misdiagnosed. Glycan analysis of serum transferrin (by isoelectric focusing or more sophisticated methods, such as HPLC (high-performance liquid chromatography) or MALDI (matrix-assisted laser desorption/ionization)) or serum N-glycans (by MS), enzyme activity assays and DNA sequence analysis are the most frequently used methods for CDG screening and identification, since no specific tests are available yet. In this review we summarize the current knowledge on the clinical, biochemical and genetic characteristic of distinct CDGs, as well as existing diagnostic and therapeutic procedures, aiming to contribute to the awareness on the existence of these rare diseases and encourage the efforts to elucidate its genetic background, improve diagnostics and develop new strategies for their treatment.	0
BACKGROUND:Ebola virus (EBOV) and Middle East respiratory syndrome coronavirus (MERS-CoV) have been identified as potential threats to blood safety. This study investigated the efficacy of the THERAFLEX UV-Platelets and THERAFLEX MB-Plasma pathogen inactivation systems to inactivate EBOV and MERS-CoV in platelet concentrates (PCs) and plasma, respectively. STUDY DESIGN AND METHODS:PCs and plasma were spiked with high titers of cell culture-derived EBOV and MERS-CoV, treated with various light doses of ultraviolet C (UVC; THERAFLEX UV-Platelets) or methylene blue (MB) plus visible light (MB/light; THERAFLEX MB-Plasma), and assessed for residual viral infectivity. RESULTS:UVC reduced EBOV (≥4.5 log) and MERS-CoV (≥3.7 log) infectivity in PCs to the limit of detection, and MB/light decreased EBOV (≥4.6 log) and MERS-CoV (≥3.3 log) titers in plasma to nondetectable levels. CONCLUSIONS:Both THERAFLEX UV-Platelets (UVC) and THERAFLEX MB-Plasma (MB/light) effectively reduce EBOV and MERS-CoV infectivity in platelets and plasma, respectively.	0
This paper aims to investigate the temporal dynamics within the dorsal anterior cingulate cortex (dACC) and the rostral-ventral (rv) ACC during the interaction of emotional valence and arousal with cognitive control in patients with Schizophrenia (SZ). Although cognitive deficits in SZ are highly relevant and emotional disturbances are common, the temporal relationship of brain regions involved in the interaction of emotional and cognitive processing in SZ is yet to be determined. To address this issue, the reaction time (RT), event-related potential (ERP) and temporal dynamics of the dACC and rvACC activity were compared between SZ subjects and healthy controls (HC), using a modified emotional Stroop experiment (with factors namely congruence, arousal and valence). EEG was recorded with 64 channels and source localisation was performed using the sLORETA software package. We observed slower initial increase and lower peaks of time course activity within the dACC and rvACC in the SZ group. In this particular group, the dACC activity during late negativity was negatively correlated with a significantly higher RT in the high arousal conflict condition. In contrast to HC subjects, at the N450 window, there was no significant valence (ERP and rvACC ROI) modulation effect in the SZ subjects. Using high density EEG and source localisation, it was possible to distinguish various disturbances within the dACC and rvACC in patients with SZ, during emotion-cognition processing.	0
Variants in genes encoding ribosomal proteins have thus far been associated with Diamond-Blackfan anemia, a rare inherited bone marrow failure, and isolated congenital asplenia. Here, we report one de novo missense variant and three de novo splice variants in RPL13, which encodes ribosomal protein RPL13 (also called eL13), in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477+1G>T, c.477+1G>A, and c.477+2 T>C) result in partial intron retention, which leads to an 18-amino acid insertion. In contrast to observations from Diamond-Blackfan anemia, we detected no evidence of significant pre-rRNA processing disturbance in cells derived from two affected individuals. Consistently, we showed that the insertion-containing protein is stably expressed and incorporated into 60S subunits similar to the wild-type protein. Erythroid proliferation in culture and ribosome profile on sucrose gradient are modified, suggesting a change in translation dynamics. We also provide evidence that RPL13 is present at high levels in chondrocytes and osteoblasts in mouse growth plates. Taken together, we show that the identified RPL13 variants cause a human ribosomopathy defined by a rare skeletal dysplasia, and we highlight the role of this ribosomal protein in bone development.	0
Mirror foot is a rare abnormality which presents as a preaxial, postaxial, or central polydactyly of the foot. The latter is encountered infrequently. We describe the case of a central mirror foot. Our patient had eight digits of a central ray pattern type with fully developed metatarsal, proximal, middle, and distal phalanges, as well as a medial toe syndactyly. He had no tarsal bone duplications. He was treated by central ray resection via double V-shaped incisions on the dorsal and plantar aspects of the foot, while preserving the medial and lateral rays. The results were satisfactory. We describe the technique and attempt a review of the literature.	0
Minimal change disease (MCD) is a main cause of the nephrotic syndrome. Thin basement membrane disease (TBMD) is another disease characterized by microscopic hematuria. The present case is a young adult female who presented with classic nephrotic syndrome, but she had microscopic hematuria as well. Hematuria can be part of MCD in 21% of patients, but in this case, histopathological diagnosis confirmed MCD with concurrent TBMD. This was reported only in two cases, up to our literature review. Using steroids resulted in nephrotic syndrome improvement, but microscopic hematuria has persisted, which is mostly related to TBMD rather than a primary part of MCD. Up to our knowledge, this is the first case report of MCD with concurrent TBMD in Arab countries.	0
BACKGROUND: Combined Malonic and Methylmalonic Aciduria (CMAMMA) is a rare recessive inborn error of metabolism characterised by elevations of urine malonic acid (MA) and methylmalonic acid (MMA). Nearly all reported cases are caused by malonyl-CoA decarboxylase (MCD) deficiency. Most patients have metabolic acidosis, developmental delay, seizures and cardiomyopathy. CMAMMA was also described in symptomatic patients with normal MCD activity, suggesting heterogeneity in this disorder. METHODS AND RESULTS: We identified two probands with a non-classical CMAMMA variant through the Quebec newborn urine screening program. While they share the biochemical phenotype of elevated MA and MMA, the MMA excretion was higher than MA, the clinical courses were benign, MYLCD gene sequencing was normal and MCD activity, measured in one proband, was normal. Using exome sequencing in the single consanguineous proband, we identified a homozygous missense allele in the ACSF3 gene, encoding an Acyl-CoA Synthetase (ACS) with unknown substrate and function. The second proband was homozygous for a different ACSF3 missense allele. Both substitutions were in conserved residues and were identified in less than 0.5% of their respective ethnic control populations. CONCLUSION: These results suggest that ACSF3 is a candidate gene for non-classical CMAMMA observed in our patients and document the value of exome sequencing of a limited number of patients for the identification of novel disease genes.	0
Canavan disease, a leukodystrophy caused by loss-of-function ASPA mutations, is characterized by brain dysmyelination, vacuolation, and astrogliosis ("spongiform leukodystrophy"). ASPA encodes aspartoacylase, an oligodendroglial enzyme that cleaves the abundant brain amino acid N-acetyl-L-aspartate (NAA) to L-aspartate and acetate. Aspartoacylase deficiency results in a 50% or greater elevation in brain NAA concentration ([NAAB]). Prior studies showed that homozygous constitutive knockout of Nat8l, the gene encoding the neuronal NAA synthesizing enzyme N-acetyltransferase 8-like, prevents aspartoacylase-deficient mice from developing spongiform leukodystrophy. We now report that brain Nat8l knockdown elicited by intracerebroventricular/intracisternal administration of an adeno-associated viral vector carrying a short hairpin Nat8l inhibitory RNA to neonatal aspartoacylase-deficient AspaNur7/Nur7 mice lowers [NAAB] and suppresses development of spongiform leukodystrophy.	0
Acetaminophen and flucloxacillin both interfere with the γ-glutamyl cycle. Long-lasting concomitant use of flucloxacillin and acetaminophen can lead to 5-oxoproline accumulation and severe high anion gap metabolic acidosis. Females and patients with sepsis, impaired kidney and/or liver function, malnutrition, advanced age, congenital 5-oxoprolinase deficiency and supratherapeutic acetaminophen and flucloxacillin dosage are associated with increased risk. Therefore, a critical attitude towards the prescription of acetaminophen concomitant with flucloxacillin in these patients is needed. We present the case of a 79-year-old woman with severe 5-oxoprolinaemia after long-lasting treatment with flucloxacillin and acetaminophen, explaining the toxicological mechanism and risk factors, and we make recommendations for acetaminophen use in patients with long-lasting flucloxacillin treatment. LEARNING POINTS:Although rare, long-lasting treatment with flucloxacillin concomitant with acetaminophen can lead to severe high anion gap metabolic acidosis.When prescribing long-lasting flucloxacillin therapy in combination with acetaminophen, regular blood gas analysis is needed to evaluate pH and the anion gap.In cases of 5-oxoproline-induced high anion gap metabolic acidosis in patients with long-lasting acetaminophen and flucloxacillin therapy, acetaminophen prescription should be stopped immediately. Replacing flucloxacillin with another antibiotic agent should be considered.	0
Background: Black women have greater than a three-fold risk of pregnancy-associated death compared to White women; cardiomyopathy is a leading cause of maternal mortality.Objectives: This study examined racial disparities in health outcomes among women with peripartum cardiomyopathy.Study design: Retrospective cohort of women with peripartum cardiomyopathy per the National Heart, Lung, and Blood Institute definition from January 2000 to November 2017 from a single referral center. Selected health outcomes among Black and White women were compared; primary outcome was ejection fraction at diagnosis. Secondary outcomes included cardiovascular outcomes, markers of maternal morbidity, resource utilization, and subsequent pregnancy outcomes.Results: Ninety-five women met inclusion criteria: 48% Black, 52% White. Nearly all peripartum cardiomyopathy diagnoses were postpartum (95.4% Black, 93% White, p=.11). Ejection fraction at diagnosis was not different between Black and White women (26.8 ± 12.5 vs. 28.7 ± 9.9, p=.41). Though non-significant, fewer Black women had myocardial recovery to EF ≥55% (35 vs. 53%, p=.07); however, 11 (24%) of Black women vs. 1 (2%) White woman had an ejection fraction ≤35% at 6-12 months postpartum (p<.01). More Black women underwent implantable cardioverter defibrillator placement: n = 15 (33%) vs. n = 7 (14%), p=.03. Eight women (8.4%) died in the study period, not different by race (p=.48). Black women had higher rates of healthcare utilization. In the subsequent pregnancy, Black women had a lower initial ejection fraction (40 vs. 55%, p=.007) and were less likely to recover postpartum (37.5 vs. 55%, p=.02).Conclusions: Black and White women have similar mean ejection fraction at diagnosis of peripartum cardiomyopathy, but Black women have more severe left ventricular systolic dysfunction leading to worse outcomes, increased resource use, and lower ejection fraction entering the subsequent pregnancy.	0
Retinitis pigmentosa 1-like 1 (RP1L1) is a component of the photoreceptor cilium. Pathogenic variants in RP1L1 lead to photoreceptor disease, suggesting an important role for RP1L1 in photoreceptor biology, though its exact function is unknown. To date, RP1L1 variants have been associated with occult macular dystrophy (a cone degeneration) and retinitis pigmentosa (a rod disease). Here, we summarize reported RP1L1-associated photoreceptor conditions and disease-causing RP1L1 variants. We also discuss novel associations between RP1L1 and additional photoreceptor conditions-besides occult macular dystrophy and retinitis pigmentosa-and fit RP1L1 into the broader scope of photoreceptor disease. RP1L1 appears to have a complex relationship with other photoreceptor proteins and may modify disease phenotype. Ultimately, further exploration of the relationship between RP1L1, other cilium components, and their impact on photoreceptor health is needed.	0
Background: The C34T polymorphism (rs 17602729) in adenosine monophosphate deaminase 1 gene (AMPD1) is associated with muscular energy metabolism in exercise. However, the role of its potential modifying impact on exercise-induced changes in obesity related parameters is unknown. The aim of the study was to determine if the C34T polymorphism influences the effects of an exercise training. METHODS:This study examines a group of one hundred and sixty-eight, young, non-obese Caucasian women in Poland who took part in a 12-week aerobic training program to determine the impact of allele and genotype distribution on training outcomes. RESULTS:A two-way analysis of variance ANOVA was conducted assuming a dominant model by pooling rare homozygotes and heterozygotes (TT + CT, n = 79) and comparing against common homozygotes (CC, n = 89). Our results showed that the AMPD1 C34T polymorphism was not related with selected parameters in study group. After completing the 12-week training program, a wide array of parameters (body mass, body mass index, fat mass, free fat mass, total body water) were significantly changed in the study participants with the exception of AMPD1 genotypes, among whom no significant changes were observed. CONCLUSIONS:The results did not confirm that harboring the rs 17602729 T allele influences the effects of the training program.	0
Background: The GNAT1 gene encodes the alpha-subunit of transducin in rod photoreceptors and is an important part of the phototransduction cascade. Defects in GNAT1 are very rare but have been identified in autosomal dominant and recessive congenital stationary night blindness (CSNB) and autosomal recessive rod-cone dystrophy. The purpose of this study was to determine the phenotype-genotype relationship in a non-consanguineous Japanese family with a GNAT1 mutation.Methods: Detailed ophthalmic examinations were performed on the patients and their family members. Whole exome sequencing (WES) was applied to the DNA obtained from the family members. Sanger sequencing and co-segregation analyses were performed to identify the most likely pathogenic variant.Results: Two female (13- and 11-years) and one male (15-years) patients from a family had night blindness from their childhood. The fundus had a mild golden appearance regardless of the state of light- or dark-adaptation. Electroretinographic (ERG) analyses showed that the scotopic a-wave was extinguished, and the mixed rod-cone responses were severely reduced with an electronegative form in patients. The shapes of the dark-adapted ERGs were similar to those recorded from patients with Oguchi disease. We identified a homozygous in-frame deletion c.818_820delAGA, p.Lys273del in the GNAT1 gene. Variants were verified by Sanger sequencing and co-segregated with the disease in five members of the family.Conclusions: Our findings indicate that a recessive GNAT1 mutation found in this family could be the cause of the golden appearance of the fundus and negative ERGs with reduced a-waves, and nearly absent b-waves in the mixed rod-cone ERGs.	0
BACKGROUND:Joubert syndrome (JBTS) is a genetically heterogeneous group of neurodevelopmental syndromes caused by primary cilia dysfunction. Usually the neurological presentation starts with abnormal neonatal breathing followed by muscular hypotonia, psychomotor delay, and cerebellar ataxia. Cerebral MRI shows mid- and hindbrain anomalies including the molar tooth sign. We report a male patient with atypical presentation of Joubert syndrome type 23, thus expanding the phenotype. CASE PRESENTATION:Clinical features were consistent with JBTS already from infancy, yet the syndrome was not suspected before cerebral MRI later in childhood showed the characteristic molar tooth sign and ectopic neurohypophysis. From age 11 years seizures developed and after few years became increasingly difficult to treat, also related to inadequate compliance to therapy. He died at 23 years of sudden unexpected death in epilepsy (SUDEP). The genetic diagnosis remained elusive for many years, despite extensive genetic testing. We reached the genetic diagnosis by performing whole genome sequencing of the family trio and analyzing the data with the combination of one analysis pipeline for single nucleotide variants (SNVs)/indels and one for structural variants (SVs). This lead to the identification of the most common variant detected in patients with JBTS23 (OMIM# 616490), rs534542684, in compound heterozygosity with a 8.3 kb deletion in KIAA0586, not previously reported. CONCLUSIONS:We describe for the first time ectopic neurohypophysis and SUDEP in JBTS23, expanding the phenotype of this condition and raising the attention on the possible severity of the epilepsy in this disease. We also highlight the diagnostic power of WGS, which efficiently detects SNVs/indels and in addition allows the identification of SVs.	0
Lysinuric protein intolerance (LPI) is caused by dysfunction of the dibasic amino acid membrane transport owing to the functional abnormality of y+L amino acid transporter-1 (y+ LAT-1). LPI is associated with autosomal recessive inheritance and pathological variants in the responsible gene SLC7A7 are also observed. The pathophysiology of this disease had earlier been understood as a transport defect in polarized cells (e.g., intestinal or renal tubular epithelium); however, in recent years, transport defects in non-polarized cells such as lymphocytes and macrophages have also been recognized as important. Although the former can cause death, malnutrition, and urea cycle dysfunction (hyperammonemia), the latter can induce renal, pulmonary, and immune disorders. Furthermore, although therapeutic interventions can prevent hyperammonemic episodes to some extent, progression of pulmonary and renal complications cannot be prevented, thereby influencing prognosis. Such pathological conditions are currently being explored and further investigation would prove beneficial. In this study, we have summarized the basic pathology as revealed in recent years, along with the clinical aspects and genetic features.	0
BACKGROUND: Bazex-Dupré-Christol syndrome (BDCS) is an X-linked dominantly inherited disorder affecting hair follicle structures. Currently, hypotrichosis, follicular atrophoderma and basal cell carcinomas are considered frequent symptoms of the disorder whereas milia are supposed to reflect infrequent clinical signs. Usually, basal cell carcinomas in this disease manifest from the second decade of life onwards. CASE REPORT: Here, we studied a novel multigeneration family of German origin with BDCS. Interestingly, two family members developed pigmented basal cell carcinomas in early childhood, at the age of 3 and 5 years, respectively. The differentiation from other pigmented lesions was accomplished by both dermoscopy and histopathology. A thorough survey of the current literature revealed that milia were present in almost all patients with BDCS reported, as is the case in our family. CONCLUSIONS: We suggest that milia should also be considered frequent symptoms in BDCS. For the first time, to the best of our knowledge, we describe the occurrence of pigmented basal cell carcinomas in BDCS during the first decade of life. Our observation emphasizes the importance of screening for cutaneous malignancies in this disorder already at young age.	0
BACKGROUND:Papillon-Lefévre syndrome (PLS; OMIM 245000) and Haim-Munk syndrome (HMS; OMIM 245010), which are both characterized by palmoplantar hyperkeratosis and periodontitis, are phenotypic variants of the same disease caused by mutations of the cathepsin C (CTSC) gene. AIM:To identify putative genetic modifying factors responsible for the differential development of the PLS or HMS phenotypes, we investigated two Hungarian patients with different phenotypic variants (PLS and HMS) but carrying the same homozygous nonsense CTSC mutation (c.748C/T; p.Arg250X). METHODS:To gain insights into phenotype-modifying associations, whole exome sequencing (WES) was performed for both patients, and the results were compared to identify potentially relevant genetic modifying factors. RESULTS:WES revealed two putative phenotype-modifying variants: (i) a missense mutation (rs34608771) of the SH2 domain containing 4A (SH2D4A) gene encoding an adaptor protein involved in intracellular signalling of cystatin F, a known inhibitor of the cathepsin protein, and (ii) a missense variant (rs55695858) of the odorant binding protein 2A (OBP2A) gene, influencing the function of the cathepsin protein through the glycosyltransferase 6 domain containing 1 (GLT6D1) protein. CONCLUSION:Our study contributes to the accumulating evidence supporting the clinical importance of phenotype-modifying genetic factors, which have high potential to aid the elucidation of genotype-phenotype correlations and disease prognosis.	0
A 5-year-old boy with the history of intractable seizure for the past 2 years was transferred to the emergency room for cardiopulmonary resuscitation because of the prolonged seizure and profound cyanosis. He was intubated and resuscitated by cardioversion for a bizarre shape ventricular tachycardia (VT). After noxious stimulation, he showed multiple polymorphic ventricular premature beats that were followed by a bidirectional VT in favor of catecholaminergic polymorphic VT. The genetic assessment was positive for CASQ2 mutation. In the follow-up, the arrhythmia was controlled by nadolol, however with a prominent neurological sequela.	0
Summary:Sodium/glucose co-transporter 2 (SGLT2) inhibitors are novel oral hypoglycaemic agents that are increasingly used in the management of type 2 diabetes mellitus (T2DM). They are now recommended as second-line pharmacotherapy (in conjunction with metformin) in patients with type 2 diabetes and established atherosclerotic heart disease, heart failure or chronic kidney disease due to their favourable effects on cardiovascular and renal outcomes. We report a case of a 69-year-old man who developed muscle pain, weakness and wasting after commencing the SGLT2 inhibitor empagliflozin. This persisted for 1 year before he underwent resistance testing, which confirmed muscle weakness. His symptoms resolved within weeks of ceasing empagliflozin, with improvement in muscle strength on clinical assessment and resistance testing and reversal of MRI changes. No other cause of myopathy was identified clinically, on biochemical assessment or imaging, suggesting that empagliflozin was the cause of his myopathy. Learning points:Empagliflozin, a commonly used SGLT2 inhibitor, was associated with myopathy. A high degree of suspicion is required to diagnose drug-induced myopathy, with a temporal relationship between starting the medication and symptom onset being the main indicator. Recognition of drug-induced myopathy is essential, as discontinuation of the offending drug typically improves symptoms.	0
Pulmonary atresia with ventricular septal defect (PA/VSD) is a complex cyanotic congenital heart disease with a wide-range of presentations and treatment strategies, depending on the source of pulmonary circulation, anatomy of pulmonary arteries (PAs), and major aortopulmonary collateral arteries (MAPCAs). Data about the outcomes in developing countries is scarce. We therefore conducted a retrospective study to assess survival rates and mortality risks of 90 children with PA/VSD at Siriraj Hospital, Thailand during 2005-2016. Patients with single ventricle were excluded. Survival and mortality risks were analyzed at the end of 2018. The median age of diagnosis was 0.5 (0-13.8) years. The patients' PAs were categorized into four groups: 1) PA/VSD with confluent PAs (n = 40), 2) PA/VSD with confluent PAs and MAPCAs (n = 21), 3) PA/VSD with non-confluent PAs and MAPCAs (n = 12), and 4) PA/VSD with small native PAs and MAPCAs (n = 17). Of the 88 patients who underwent operations, 32 patients had complete repair at 8.4 ± 4.6 years old. During the follow-up [median time of 5.7 years (7 days-13.6 years)], 17 patients (18.9%) died. The survival rates at 1, 5, and 10 years of age were 95%, 83.7%, and 79.6%, respectively. Significant mortality risks were the presence of associated anomalies and non-confluent PAs.	0
PURPOSE:To compare disease severity in detail between patients carrying variants in exons 1-14 and ORF15 of retinitis pigmentosa GTPase regulator (RPGR). METHODS:Systematic next-generation sequencing data analysis, Sanger sequencing validation and segregation analysis were utilised to identify the pathogenic variants. Detailed ophthalmic examinations, including electroretinograms, fundus photography, fundus autofluorescence and optical coherence tomography were performed. Statistical analysis, including age adjustment and comparison, were performed based on cross-sectional level to compare disease severity between variants in the two RPGR variant groups. RESULTS:Sixty-two variants were identified in RPGR in 86 patients from 77 unrelated families. Twenty-nine (37.7%) had variants in RPGR-exons 1-14 (group 1) and 48 (62.3%) in RPGR-ORF15 (group 2). Eighty-four patients were diagnosed with X-linked retinitis pigmentosa and only two patients with cone-rod dystrophy. LogMAR visual acuity increased 0.035 and 0.022 each year on average in group 1 and group 2, respectively. Group 2 patients had better visual acuity with a mean logMAR difference of 0.4378, which is significant after age adjustment (P < 0.01). Neither the value of log (ellipsoid zone width) nor central retinal thickness was significantly correlated with variant grouping after considering the effect of the age variable (P = 0.56 and 0.40, respectively). Spherical refractive error did not differ significantly between the two variant groups (P = 0.17). Patterns of autofluorescence included a hyperfluorescent ring at the posterior pole, diffuse hyperfluorescence in the macular area, and dark macular autofluorescence with or without fovea hyperfluorescence. The age and proportion of fundus autofluorescence patterns between the two variant groups were significantly different (P < 0.01). CONCLUSIONS:Patients with variants in exons 1-14 retained less visual acuity than patients with ORF15 variants and deteriorated faster. However, the ellipsoid zone widths, central retinal thickness and refractions were comparable between the two groups. Autofluorescence pattern relates to the age and the variant grouping.	0
BACKGROUND:Hereditary spastic paraplegia is a heterogeneous group of clinically and genetically neurodegenerative diseases characterized by progressive gait disorder. Hereditary spastic paraplegia can be inherited in various ways, and all modes of inheritance are associated with multiple genes or loci. At present, more than 76 disease-causing loci have been identified in hereditary spastic paraplegia patients. Here, we report a novel mutation in SPAST gene associated with hereditary spastic paraplegia in a Chinese family, further enriching the hereditary spastic paraplegia spectrum. METHODS:Whole genomic DNA was extracted from peripheral blood of the 15 subjects from a Chinese family using DNA Isolation Kit. The Whole Exome Sequencing of the proband was analyzed and the result was identified in the rest individuals. RaptorX prediction tool and Protein Variation Effect Analyzer were used to predict the effects of the mutation on protein tertiary structure and function. RESULTS:Spastic paraplegia has been inherited across at least four generations in this family, during which only four HSP patients were alive. The results obtained by analyzing the Whole Exome Sequencing of the proband exhibited a novel disease-associated in-frame deletion in the SPAST gene, and this mutation also existed in the rest three HSP patients in this family. This in-frame deletion consists of three nucleotides deletion (c.1710_1712delGAA) within the exon 16, resulting in lysine deficiency at the position 570 of the protein (p.K570del). This novel mutation was also predicted to result in the synthesis of misfolded SPAST protein and have the deleterious effect on the function of SPAST protein. CONCLUSION:In this case, we reported a novel mutation in the known SPAST gene that segregated with HSP disease, which can be inherited in each generation. Simultaneously, this novel discovery significantly enriches the mutation spectrum, which provides an opportunity for further investigation of genetic pathogenesis of HSP.	0
Double-outlet left ventricle (DOLV) is a rare cardiac malformation in which both great arteries originate from the morphological left ventricle. DOLV is associated with high mortality, generally due to heart failure, myocardial infarction, or aortic thrombosis. With surgery, the 5-year survival rate is estimated at 70%-75%. Most patients will continue to present with residual cardiac anomalies, such as aortic or mitral valve regurgitation, arrhythmias, or hypertension. Here, we report a 25-year-old male with DOLV with pulmonary stenosis and patent ductus arteriosus who presented to us with hemoptysis, which was due to respiratory tract infection. He improved with standard therapy.	0
Background:In patients with phaeochromocytomas or paragangliomas (PPGLs), 24-h urine collections for metanephrines (uMNs) are cumbersome. Objective:To evaluate the diagnostic utility of ratios to creatinine of 'spot' uMNs. Methods:Concentrations of uMNs and plasma metanephrines (pMNs) were measured by HPLC-mass-spectrometry. We retrospectively compared correlations of 24-h-urine output and ratio to creatinine in historical specimens and prospectively assessed 24-h and contemporaneous spot urines and, where possible, pMNs. Using trimmed log-transformed values, we derived reference intervals based on age and sex for spot urines. We used multiples of upper limit of normal (ULNs) to compare areas under curves (AUCs) for receiver-operator characteristic curves of individual, and sum and product of, components. Results:In 3143 24-h-urine specimens on 2416 patients, the correlation coefficients between the ratios and outputs of metanephrine, normetanephrine and 3-methoxytyramine in 24-h urines were 0.983, 0.905 and 0.875, respectively. In 96 patients, the correlations between plasma concentrations, urine output and ratios in spot specimens were similar to those for raw output or ratios in 24-h specimens. Of the 160 patients with PPGLs, the CIs for AUCs for individual metabolites overlapped for all four types of measurement, as did those for the sum of the multiple ULNs although these were slightly higher (AUC for spot urine: 0.838 (0.529-1), plasma: 0.929 (0.874-0.984) and output: 0.858 (0.764-0.952)). Conclusions:Ratios of fractionated metanephrines to creatinine in spot urine samples appear to have a similar diagnostic power to other measurements. The ease of spot urine collection may facilitate diagnosis and follow-up of PPGLs through improved patient compliance.	0
Plummer-Vinson syndrome (PVS) is characterized by a triad of symptoms comprising microcytic hypochromic anemia, esophageal webs, and dysphagia. PVS is commonly found in women of middle age especially in the fourth and fifth decade of life and is rarely reported in males. We report a case of a 39-year-old female patient who had a classic presentation of PVS. PVS is precancerous with high malignant potential; early diagnosis is of utmost importance for better prognosis and surveillance endoscopy is recommended. Iron repletion oftentimes improves the dysphagia; seldom esophageal dilatation is used to provide symptomatic relief.	0
Chromosome 6q24-related transient neonatal diabetes mellitus is characterized by intrauterine growth restriction and low birth weight, with neonatal hyperglycemia resolving by 18 months and an increased risk for type 2 diabetes in adulthood. Molecularly, it is caused by overexpression of the 6q24 imprinted chromosomal region due to a duplication, uniparental disomy, or abnormal methylation. Conventional testing for this condition analyzes methylation patterns at the 6q24 locus but does not evaluate for the presence of other surrounding chromosomal abnormalities. We report a female with a history of neonatal hyperglycemia due to a paternally inherited duplication at chromosomal location 6q24. She subsequently presented to the pediatric genetics clinic at 15 months of age with developmental delay and abnormal balance. Microarray analysis identified a larger 14 Mb chromosomal duplication from 6q24 to 6q25.2, consistent with a diagnosis of duplication 6q syndrome. This case highlights the clinical importance of pursuing further genetic evaluation in patients diagnosed with chromosome 6q24-related neonatal hyperglycemia via targeted methylation-specific multiplex ligation-dependent probe amplification analysis identifying a duplication in this region. Early identification and intervention can improve developmental outcomes for patients with larger chromosome 6q duplications.	0
A 27-year-old Caucasian female was hospitalized three times over a four-month period for recurrent, intermittent abdominal pain associated with nausea and diarrhea. No signs or symptoms of gastrointestinal (GI) bleeding were present. A stool occult blood test and stool enteric pathogen tests were negative. A complete blood count (CBC) revealed a peripheral blood eosinophil count of 1080 cells /µL without any inflammatory reaction. An upper endoscopy showed grossly normal-appearing esophageal and duodenal mucosa; however, a gastric mucosal biopsy showed an eosinophil infiltration of ≥20 eosinophils/high power field (HPF). Based on these findings, she was diagnosed with eosinophilic gastroenteritis (EGE). A definitive diagnosis of EGE should be confirmed with both an analysis of gastrointestinal mucosal biopsy and an elevated peripheral blood eosinophil count. Specifically, histological evaluation of the mucosal tissue must show an eosinophilic infiltration rate of 20 eosinophils/HPF. The diagnosis should be followed by an extensive review of the patient's allergic disease history.	0
Mutations in RAB18, a member of small G protein, cause Warburg micro syndrome (WARBM), whose clinical features include vision impairment, postnatal microcephaly, and lower limb spasticity. Previously, our Rab18-/- mice exhibited hind limb weakness and spasticity as well as signs of axonal degeneration in the spinal cord and lumbar spinal nerves. However, the cellular and molecular function of RAB18 and its roles in the pathogenesis of WARBM are still not fully understood. Using immunofluorescence staining and expression of Rab18 and organelle markers, we find that Rab18 associates with lysosomes and actively traffics along neurites in cultured neurons. Interestingly, Rab18-/- neurons exhibit impaired lysosomal transport. Using autophagosome marker LC3-II, we show that Rab18 dysfunction leads to aberrant autophagy activities in neurons. Electron microscopy further reveals accumulation of lipofuscin-like granules in the dorsal root ganglion of Rab18-/- mice. Surprisingly, Rab18 colocalizes, cofractionates, and coprecipitates with the lysosomal regulator Rab7, mutations of which cause Charcot-Marie-Tooth (CMT) neuropathy type 2B. Moreover, Rab7 is upregulated in Rab18-deficient neurons, suggesting a compensatory effect. Together, our results suggest that the functions of RAB18 and RAB7 in lysosomal and autophagic activities may constitute an overlapping mechanism underlying WARBM and CMT pathogenesis in the nervous system.	0
BACKGROUND:Oculo-auriculo-vertebral spectrum (OAVS) is a craniofacial developmental disorder that affects structures derived from the first and second pharyngeal arches. The clinically heterogeneous phenotype involves mandibular, oral, and ear development anomalies. Etiology is complex and poorly understood. Genetic factors have been associated, evidenced by chromosomal abnormalities affecting different genomic regions and genes. However, known pathogenic single-nucleotide variants (SNVs) have only been identified in MYT1 in a restricted number of patients. Therefore, investigations of SNVs on candidate genes may reveal other pathogenic mechanisms. METHODS:In a cohort of 73 patients, coding and untranslated regions (UTR) of 10 candidate genes (CRKL, YPEL1, MAPK1, NKX3-2, HMX1, MYT1, OTX2, GSC, PUF60, HOXA2) were sequenced. Rare SNVs were selected and in silico predictions were performed to ascertain pathogenicity. Likely pathogenic variants were validated by Sanger sequencing and heritability was assessed when possible. RESULTS:Four likely pathogenic variants in heterozygous state were identified in different patients. Two SNVs were located in the 5'UTR of YPEL1; one in the 3'UTR of CRKL and one in the 3'UTR of OTX2. CONCLUSION:Our work described variants in candidate genes for OAVS and supported the genetic heterogeneity of the spectrum.	0
Spondyloenchondrodysplasia (SPENCD) is a rare skeletal dysplasia characterized with platyspondyly and metaphyseal lesions of the long bones mimicking enchondromatosis, resulting in short stature. SPENCD often coexists with neurologic disorders and immune dysregulation. Spasticity, developmental delay and intracranial calcification are main neurologic abnormalities. Large spectrum of immunologic abnormalities may be seen in SPENCD, including immune deficiencies and autoimmune disorders with autoimmune thrombocytopenia and systemic lupus erythematosus as the most common phenotypes. SPENCD is caused by loss of tartrate-resistant acid phosphatase (TRAP) activity, due to homozygous mutations in ACP5, playing a role in non-nucleic acid-related stimulation/regulation of the type I interferon pathway. We present two siblings, 13-year-old girl and 25-year-old boy with SPENCD, from consanguineous parents. Both patients had short stature, platyspondyly, metaphyseal changes, spastic paraparesis, mild intellectual disability, and juvenile-onset SLE. The age at disease-onset was 2 years for girl and 19 years for boy. Both had skin and mucosa involvement. The age at diagnosis of SLE was 4 years for girl, and 19 years for boy. The clinical diagnosis of SPENCD was confirmed by sequencing of ACP5 gene, which revealed a homozygous c.155A > C (p.K52T), a variant reported before as pathogenic. Juvenile-onset SLE accounts for about 15-20% of all SLE cases. But, the onset of SLE before 5-years of age and also monogenic SLE are rare. Our case report and the literature review show the importance of multisystemic evaluation in the diagnosis of SPENCD and to remind the necessity of investigating the monogenic etiology in early-onset and familial SLE cases.	0
INTRODUCTION:BK virus (BKPyV) nephropathy occurs in 1%-10% of kidney transplant recipients, with suboptimal therapeutic options. CASE:A 54-year-old woman received a transplant in March 2017. BKPyV was detected at 1.5 × 102  copies/mL within a month, necessitating halving of mycophenolate and addition of leflunomide. Allograft histology in December showed polyomavirus nephropathy treated with intravenous immunoglobulin and cessation of mycophenolate. In February 2018, cidofovir and ciprofloxacin were commenced. In April, tacrolimus was reduced while introducing everolimus. A second graft biopsy in August showed increasing polyoma virus infection and a subsequent biopsy in September for worsening renal function showed 30% of tubular reactivity for simian virus 40 (SV40). Allogeneic BKPyV-reactive T cells were generated from the patient's daughter and infused over 10 sessions starting late September. The fourth allograft biopsy in November 2018 demonstrated involvement of BKPyV in 50% of tubules. Allograft function continued to decline, requiring hemodialysis from December 2018. Allograft nephrectomy after 6 months showed <1% SV40 in preserved tubules and 80% interstitial fibrosis. DISCUSSION:We conclude that the T-cell adoptive immunotherapy reduced BKPyV load significantly despite extensive infection, but attendant fibrosis and tubular atrophy led to graft failure. Early intervention with T-cell therapy may prove efficacious in BKPyV nephropathy.	0
There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers.	0
Corneal dystrophy is a common type of hereditary corneal diseases. It includes many types, which have varied pathology, histology and clinical manifestations. Recently, the examination techniques of ophthalmology and gene sequencing advance greatly, which do benefit to our understanding of these diseases. However, many aspects remain still unknown. And due to the poor knowledge of these diseases, the results of the treatments are not satisfoctory. The purpose of this review was to summarize the clinical, histological and genetic characteristics of different types of corneal dystrophies.	0
BACKGROUND:Cockayne syndrome (CS) is a rare autosomal recessive disorder which displays multiorgan dysfunction, especially within the nervous system including psychomotor retardation, cerebral atrophy, microcephaly, cognitive dysfunction, mental retardation, and seizures. Many genetic variations reported were related to this syndrome, but splicing mutations with cardiac anomalies have not been found in previous studies. METHODS:Herein, we described a pair of brothers and sisters who present essential manifestations of CS including premature feature, developmental delay, growth failure, microcephaly, and characteristic facial features, such as sunken eyes and a beaked nose. Interestingly, the brother also presented with atypical features which included cardiac anomalies such as left atrioventricular enlargement and cardiac dysfunction such as dilated cardiomyopathy. In addition, whole exome sequencing and RNA sequencing were employed to analyze their genetic landscape. RESULTS:WES analysis showed that these two cases carried double unreported heterozygous spliced mutations in the excision repair cross-complementing group 8 (ERCC8, also known as CSA, NM_000082) gene, which were c.78-2 (IVS1) A>T and c.1042-1 (IVS10) G>A, respectively. Moreover, transcript sequencing analysis validated these mutation sites. In this study, Gene Ontology enrichment and KEGG pathway analyses from RNA sequencing demonstrated similarities but some differences when compared with previous studies. CONCLUSION:For patients with Cockayne syndrome, cardiac changes need to be monitored carefully, especially for cases with splicing mutations of the ERCC8 gene.	0
BACKGROUND:Fraser syndrome or "cryptophthalmos syndrome" is a rare autosomal recessive disease. It is characterized by a group of congenital malformations such as: crytophthalmos, syndactyly, abnormal genitalia, and malformations of the nose, ears, and larynx. Although cryptophthalmos is considered as a main feature of Fraser syndrome, its absence does not exclude the diagnosis. Clinical diagnosis can be made by Thomas Criteria. Here we present the first documented case of Fraser Syndrome in Aleppo, Syria that is characterized by bilateral anophthalmia and intrahepatic biliary atresia. CASE PRESENTATION:During pregnancy, several ultrasound scans revealed hyperechoic lungs, ascites, and unremarkable right kidney at the 19th-week visit; bilateral syndactyly on both hands and feet at the 32nd-week visit. On the 39th week of gestation, the stillborn was delivered by cesarean section due to cephalopelvic disproportion. Gross examination showed bilateral anophthalmia, bilateral syndactyly on hands and feet, low set ears, and ambiguous genitalia. Microscopic examination of the lung, spleen, liver, ovary, and kidneys revealed abnormalities in these organs. CONCLUSION:The diagnosis of Fraser syndrome can be made prenatally and postnatally; prenatally by ultrasound at 18 weeks of gestation and postnatally by clinical examination using Thomas criteria. Moreover, intrahepatic biliary atresia was not described previously with Fraser syndrome; this recommends a more detailed pathologic study for Fraser syndrome cases.	0
BACKGROUND:X-linked recessive chondrodysplasia punctate (CDPX1) is a rare congenital disorder of bone and cartilage development, caused by a mutation in the arylsulfatase E (ARSE) gene located on chromosome Xp22.3. Although most of the affected men had mild symptoms, some had more severe symptoms, and had a poor prognosis. CASE PRESENTATION:We present the case of a male fetus diagnosed with CDPX1. Ultrasound clearly showed that hypoplasia of the midface, flatness of face, low flatness of the nose, collapse of the tip of the nose, accompanied by severe spinal stenosis and secondary ossification center of the femoral metaphysis appeared in advance. Chromosome analysis of the amniotic fluid cells revealed 46, XY. Whole exome sequencing showed that there was a novel missense mutation of c.640G > A in ARSE gene on X chromosome. Three protein function prediction software FATHMM、Polyphen-2、PROVEAN have shown that the novel missense mutation of c.640G > A in this study was pathogenic. CONCLUSIONS:Our case is a novel mutation and presents a typical characterization of the disease, which can expand the spectrum of mutations of the ARSE gene and is helpful for prenatal ultrasound diagnosis of this disease.	0
Ectopic pregnancy (EP) is most frequently located in the fallopian tube. Risk factors that have been identified so far include a history of pelvic inflammatory disease, a smoking habit, genital/pelvic surgery, previous ectopic pregnancy, endometriosis and infertility (Hendriks et al. Am Fam Physician.2020;101:599-606). These factors act through anatomical or functional (motility) alterations caused by mechanical defects, inflammation or local immunity disturbances, which are sometimes also responsible for subfertility and for the need for IVF. Maternal underweight per se is not associated with any of these conditions.	0
Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis with a putative neoplastic and inflammatory nature. The disease is driven by mutations in proto-oncogenes such as BRAF and MEK, while immune-mediated mechanisms contribute to disease development and progression. The clinical presentation of ECD is highly heterogeneous, ranging from smouldering unifocal forms to multiorgan life-threatening disease. Almost any organ can be involved, but the most common lesions include long-bone involvement, retroperitoneal fibrosis, interstitial lung disease, pericardial and myocardial infiltration, CNS, retro-orbital, and large-vessel involvement. These manifestations may mimic those of neoplastic and systemic immune-mediated diseases. Overlap with these conditions represents an emerging challenge for the clinician. A variety of treatments are efficacious for ECD, targeting both the MAPK-pathway and the immune-mediated pathomechanisms. The traditional approach is based on immunomodulatory agents (interferon-α), but recent alternatives-including anti-cytokine therapies (IL1- and TNFα-blockers) and immunosuppressants (mTOR-inhibitors)-showed promising results. However, since the detection of MAPK pathway activation in most patients and the dramatic efficacy of BRAF and MEK inhibitors, these targeted treatments represent the first-line approach in patients with severe disease forms. High rates of radiologic responses do not often mean clinical remission, especially for CNS involvement, which often results in chronic disability. This review will outline the main clinical features of ECD, with emphasis on the emerging challenges in pathogenesis and management, and on the role of recent targeted approaches.	0
We report on a boy with RAPADILINO syndrome. Including this report seven children with this syndrome have been described. The patient developed a poikilodermatous skin rash, suggesting overlap with the Rothmund-Thompson syndrome.	0
INTRODUCTION:The Pierre-Robin sequence (PRS) is a pattern of congenital facial abnormalities comprising micrognathia, glossoptosis, and airway obstruction. Associated spinal pathologies have rarely been reported with PRS. METHODS:We explore the molecular genetic basis of this association through a systematic review of spinal disease in patients with PRS. We also present an illustrative case of a PRS patient with tethered cord in the setting of chromosome 10q terminal deletion. RESULTS:Our systematic literature review of spinal disease in patients with PRS revealed several patterns in the underlying genetic syndromes causing these conditions to co-occur. These principles are illustrated in the case of a 6-month-old female with PRS and a 14.34-Mb terminal deletion of chromosome 10q, who was found to have a sacral dimple during a routine outpatient checkup. Magnetic resonance imaging of the spine revealed a lumbar syrinx associated with tethered spinal cord. Surgical de-tethering was undertaken, with subsequent improvement in motor function and decrease in the size of the syrinx. The deletion of chromosome 10q in our patient had not previously been described in association with tethered cord or PRS. CONCLUSION:Spinal pathologies are understudied contributors to disease burden in patients with PRS. The range of predisposing syndromes and mutations in patients with both PRS and spinal disorders remains poorly characterized but may be more defined than previously conceived. Clinical screening is most critical during neonatal and adolescent developmental periods with continued neurological assessment. This study emphasizes the need for early genetic testing and counseling in this patient population, in parallel with research efforts to develop molecular classifications to guide clinical management.	0
Muenke syndrome (MIM #602849), the most common syndromic craniosynostosis, results from the recurrent pathogenic p.P250R variant in FGFR3. Affected patients exhibit wide phenotypic variability. Common features include coronal craniosynostosis, hearing loss, carpal and tarsal anomalies, and developmental/behavioral issues. Our study examined the phenotypic findings, medical management, and surgical outcomes in a cohort of 26 probands with Muenke syndrome identified at the Children's Hospital of Philadelphia. All probands had craniosynostosis; 69.7% had bicoronal synostosis only, or bicoronal and additional suture synostosis. Three male patients had autism spectrum disorder. Recurrent ear infections were the most common comorbidity, and myringotomy tube placement the most common extracranial surgical procedure. Most patients (76%) required only one fronto-orbital advancement. de novo mutations were confirmed in 33% of the families in which proband and both parents were genetically tested, while in the remaining 66% one of the parents was a mutation carrier. In affected parents, 40% had craniosynostosis, including 71% of mothers and 13% of fathers. We additionally analyzed the medical resource utilization of probands with Muenke syndrome. To our knowledge, these data represent the first comprehensive examination of long-term management in a large cohort of patients with Muenke syndrome. Our study adds valuable information regarding neuropsychiatric and medical comorbidities, and highlights findings in affected relatives.	0
OBJECTIVE:To determine whether congenital arhinia/Bosma arhinia microphthalmia syndrome (BAMS) and facioscapulohumeral muscular dystrophy type 2 (FSHD2), 2 seemingly unrelated disorders both caused by heterozygous pathogenic missense variants in the SMCHD1 gene, might represent different ends of a broad single phenotypic spectrum associated with SMCHD1 dysfunction. METHODS:We examined and/or interviewed 14 patients with FSHD2 and 4 unaffected family members with N-terminal SMCHD1 pathogenic missense variants to identify BAMS subphenotypes. RESULTS:None of the patients with FSHD2 or family members demonstrated any congenital defects or dysmorphic features commonly found in patients with BAMS. One patient became anosmic after nasal surgery and one patient was hyposmic; one man was infertile (unknown cause) but reported normal pubertal development. CONCLUSION:These data suggest that arhinia/BAMS and FSHD2 do not represent one phenotypic spectrum and that SMCHD1 pathogenic variants by themselves are insufficient to cause either of the 2 disorders. More likely, both arhinia/BAMS and FSHD2 are caused by complex oligogenic or multifactorial mechanisms that only partially overlap at the level of SMCHD1.	0
Holt-Oram syndrome (HOS) is a rare monogenic disorder characterized by upper limb abnormalities, congenital heart defects and/or conduction abnormalities. It is determined by mutations of TBX5 gene and is inherited in an autosomal dominant manner. Penetrance is complete, but variable expressivity is present, which gives sometimes diagnostic difficulties. Our case is a young adult with a personal history of preaxial polydactyly operated in infancy, multiple cardiac malformations (atrial septal defect, bicuspid aortic valve, left ventricular non-compaction) and radiologic findings consistent with HOS. Family history is negative for HOS. In conclusion, we present a case of HOS diagnosed in the adult period to highlight the diagnostic problems for the proband and the family and the importance of an early diagnostic.	0
Nodular lymphocyte-predominant Hodgkin lymphoma is an uncommon variant of Hodgkin lymphoma. Progressive transformation of germinal centers has been associated with and can develop prior to, concurrent with, or after the diagnosis of nodular lymphocyte-predominant Hodgkin lymphoma. We present a patient with a history of progressive transformation of germinal centers of the right parotid who presented 4 years later with ipsilateral parotid mass and cervical adenopathy. Knowledge of her previous diagnosis raised our concern for lymphoma, influenced our surgical management, and spared the patient additional surgery with risk of facial nerve injury inherent in revision parotidectomy.	0
Erythema elevatum diutinum (EED) is a rare skin disease caused an Arthrus-type immunological reaction to antigen with immune complex deposition in the cutaneous microvasculature, which leads to tissue damage secondary to the effects of complement and leukocytes. It presents as brown or red cutaneous nodules, papules, or plaques, often on the extensor surfaces of the hands, knees, or elbows. Onset usually occurs in the fourth to sixth decades but possibly younger in patients with human immunodeficiency virus. Medical treatment is usually successful; however, surgical treatment can be used when chemotherapy fails. We present a case of a 29-year-old man with EED treated with excision and skin grafting.	0
Xeroderma pigmentosum is an orphan hereditary photosensitive human disorder that is recognized by the development of skin lesions in sun-exposed regions of the body due to severe photosensitivity. Patients with this condition have an abnormal DNA repair process due to a genetic mutation. Xeroderma pigmentosum is considered as a risk factor of cancer since the affected population may develop various cutaneous cancers including both melanoma and non-melanoma cutaneous malignancies even at a younger age than the general population. This risk concerns also asymptomatic heterozygote individuals. Here, we present a case of 46 years old man with a familial history of Xeroderma pigmentosum who developed a microscopically confirmed squamous cell carcinoma of the lip.	0
Background:Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, autosomal dominantly inherited disorder characterized by myoclonus, epilepsy, ataxia, and dementia. Diagnosis is challenging due to the heterogeneous presentation and symptomatic overlap with other spinocerebellar ataxias. Symptoms vary according to age of onset, with a mean age at onset of 31 years. A CAG repeat expansion in the ATN1 gene results in neuronal intranuclear inclusions, variable neuronal loss, and astrocytosis in the globus pallidus, dentate and red nuclei. No disease-modifying or curative treatments are currently available. Methods:We performed an online literature search using PubMed for all articles published in an English Language format on the topics of DRPLA or ATN1 over the last 10 years. Where these articles cited other research as support for findings, or statements, these articles were also reviewed. Contemporary articles from related research fields (e.g., Huntington's Disease) were also included to support statements. Results:Forty-seven articles were identified, 10 were unobtainable and 10 provided no relevant information. The remaining 27 articles were then used for the review template: seven case reports, seven case series, six model system articles (one review article), four population clinical and genetic studies (one review article), two general review articles, and one human gene expression study. Other cited articles or research from related fields gave a further 42 articles, producing a total of 69 articles cited: 15 case series (including eight family studies), 14 model systems (one review article), 14 population clinical and genetic studies (two review articles), 10 case reports, eight clinical trials/guidelines, four genetic methodology articles, three general review articles, and one human gene expression study. Discussion:DRPLA remains an intractable, progressive, neurodegenerative disorder without effective treatment. Early recognition of the disorder may improve patient understanding, and access to services and treatments. Large-scale studies are lacking, but are required to characterize the full allelic architecture of the disorder in all populations and the heterogeneous phenotypic spectrum, including neuroimaging findings, possible biomarkers, and responses to treatment.	0
Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is a high-mortality form of EBV infection. However, chronic hypoxemia is rare in these patients. We herein reported a case of severe hypoxemia due to intrapulmonary shunting in CAEBV. A 17-year-old girl presented with fever, dyspnea, cyanosis, and hepatosplenomegaly. Laboratory tests showed mild liver dysfunction and high copy numbers of EBV-DNA in the peripheral blood. A left supratrochlear lymph node biopsy showed infiltration of highly proliferative T lymphocytes with positive EBV encoded small RNA by in situ hybridization. Technetium-99m-labeled macroaggregated albumin and contrast-enhanced echocardiography confirmed the existence of intrapulmonary shunting, which was probably related to hepatopulmonary syndrome. The final diagnosis was CAEBV with intrapulmonary shunting. The patient was treated with cyclosporine A, etoposide, and dexamethasone. Finally, the patient died of respiratory failure. Intrapulmonary shunting is a rare complication of CAEBV. Early recognition and exploring the cause of hypoxemia should be highlighted in patients with CAEBV.	0
Staphylococcal scalded skin syndrome (SSSS) is a blistering skin disorder caused by Staphylococcus aureus. The "Dokumentationszentrum schwerer Hautreaktionen", a unique population-based registry for severe skin reactions, included SSSS during a time period of 2 y in Germany. Statistical calculations indicated a low overall incidence between 0.09 and 0.13 cases per 1 million inhabitants per year with 95% confidence interval of [0-4]. The age distribution showed two clusters; one in young children and one in adults. The mortality rate was much lower in children than in adults. Young age was the main risk factor, whereas immunosuppression and consumptive infectious disease were the detected risk factors in adults.	1
Circulating strains of Staphylococcus aureus (SA) have changed in the last 30 years including the emergence of community-associated methicillin-resistant SA (MRSA). A report suggested staphylococcal toxic shock syndrome (TSS) was increasing over 2000-2003. The last population-based assessment of TSS was 1986.Population-based active surveillance for TSS meeting the CDC definition using ICD-9 codes was conducted in the Minneapolis-St. Paul area (population 2,642,056) from 2000-2006. Medical records of potential cases were reviewed for case criteria, antimicrobial susceptibility, risk factors, and outcome. Superantigen PCR testing and PFGE were performed on available isolates from probable and confirmed cases.Of 7,491 hospitalizations that received one of the ICD-9 study codes, 61 TSS cases (33 menstrual, 28 non-menstrual) were identified. The average annual incidence per 100,000 of all, menstrual, and non-menstrual TSS was 0.52 (95% CI, 0.32-0.77), 0.69 (0.39-1.16), and 0.32 (0.12-0.67), respectively. Women 13-24 years had the highest incidence at 1.41 (0.63-2.61). No increase in incidence was observed from 2000-2006. MRSA was isolated in 1 menstrual and 3 non-menstrual cases (7% of TSS cases); 1 isolate was USA400. The superantigen gene tst-1 was identified in 20 (80%) of isolates and was more common in menstrual compared to non-menstrual isolates (89% vs. 50%, p = 0.07). Superantigen genes sea, seb and sec were found more frequently among non-menstrual compared to menstrual isolates [100% vs 25% (p = 0.4), 60% vs 0% (p<0.01), and 25% vs 13% (p = 0.5), respectively].TSS incidence remained stable across our surveillance period of 2000-2006 and compared to past population-based estimates in the 1980s. MRSA accounted for a small percentage of TSS cases. tst-1 continues to be the superantigen associated with the majority of menstrual cases. The CDC case definition identifies the most severe cases and has been consistently used but likely results in a substantial underestimation of the total TSS disease burden.	1
Campomelic dysplasia is an autosomal dominant skeletal dysplasia caused by heterozygous SOX9 mutations. Most patients are sporadic due to a de novo mutation. Familial campomelic dysplasia is very rare. We report on a familial campomelic dysplasia caused by maternal germinal mosaicism. Two siblings showed the classic campomelic dysplasia phenotype with a novel SOX9 mutation (NM_000346.3: c.441delC, p.(Asn147Lysfs*36)). Radiological examination of the mother showed mild skeletal changes. Then, her somatic mosaicism of the mutation was ascertained. This is the first report of molecularly confirmed maternal germinal mosaicism for a SOX9 mutation. We suggest that a meticulous clinical examination of the parents, even if they are superficially healthy, is needed to avoid overlooking germinal mosaicism of SOX9 mutations.	0
OBJECTIVE:To investigate the effectiveness of targeted next-generation sequencing (NGS) panels in achieving a molecular diagnosis in Charcot-Marie-Tooth disease (CMT) and related disorders in a clinical setting. METHODS:We prospectively enrolled 220 patients from 2 tertiary referral centers, one in London, United Kingdom (n = 120), and one in Iowa (n = 100), in whom a targeted CMT NGS panel had been requested as a diagnostic test. PMP22 duplication/deletion was previously excluded in demyelinating cases. We reviewed the genetic and clinical data upon completion of the diagnostic process. RESULTS:After targeted NGS sequencing, a definite molecular diagnosis, defined as a pathogenic or likely pathogenic variant, was reached in 30% of cases (n = 67). The diagnostic rate was similar in London (32%) and Iowa (29%). Variants of unknown significance were found in an additional 33% of cases. Mutations in GJB1, MFN2, and MPZ accounted for 39% of cases that received genetic confirmation, while the remainder of positive cases had mutations in diverse genes, including SH3TC2, GDAP1, IGHMBP2, LRSAM1, FDG4, and GARS, and another 12 less common genes. Copy number changes in PMP22, MPZ, MFN2, SH3TC2, and FDG4 were also accurately detected. A definite genetic diagnosis was more likely in cases with an early onset, a positive family history of neuropathy or consanguinity, and a demyelinating neuropathy. CONCLUSIONS:NGS panels are effective tools in the diagnosis of CMT, leading to genetic confirmation in one-third of cases negative for PMP22 duplication/deletion, thus highlighting how rarer and previously undiagnosed subtypes represent a relevant part of the genetic landscape of CMT.	0
Anterior segment dysgenesis (ASD) encompasses a spectrum of ocular disorders affecting the structures of the anterior eye chamber. Mutations in several genes, involved in eye development, are implicated in this disorder. ASD is often accompanied by diverse multisystemic symptoms and another genetic cause, such as variants in genes encoding collagen type IV. Thus, a wide spectrum of phenotypes and underlying genetic diversity make fast and proper diagnosis challenging. Here, we used AMELIE, an automatic text mining tool that enriches data with the most up-to-date information from literature, and wANNOVAR, which is based on well-documented databases and incorporates variant filtering strategy to identify genetic variants responsible for severely-manifested ASD in a newborn child. This strategy, applied to trio sequencing data in compliance with ACMG 2015 guidelines, helped us find two compound heterozygous variants of the B3GLCT gene, of which c.660+1G>A (rs80338851) was previously associated with the phenotype of Peters plus syndrome (PPS), while the second, NM_194318.3:c.755delC (p.T252fs), in exon 9 of the same gene was noted for the first time. PPS, a very rare subtype of ASD, is a glycosylation disorder, where the dysfunctional B3GLCT gene product, O-fucose-specific β-1,3-glucosyltransferase, is ineffective in providing a noncanonical quality control system for proper protein folding in cells. Our study expands the mutation spectrum of the B3GLCT gene related to PPS. We suggest that the implementation of automatic text mining tools in combination with careful variant filtering could help translate sequencing results into diagnosis, thus, considerably accelerating the diagnostic process and, thereby, improving patient management.	0
Interstitial and terminal deletions of chromosome 4q have been described for many years and have variable phenotypes depending on the size of the deletion present. Clinical features can include developmental delay, growth difficulty, digital differences, dysmorphic features, and cardiac anomalies. Here, we present an infant with pseudohypoaldosteronism found to have a deletion of 4q31.21q31.23, including NR3C2. Heterozygous mutations in NR3C2 have been reported to cause autosomal dominant pseudohypoaldosteronism type 1 (PHA1A). This represents a rare case of PHA1A due to a contiguous interstitial deletion and highlights the importance of evaluating patients with overlapping deletions for PHA1A.	0
We report on a 12-year-old girl who presented with generalized enamel hypoplasia, cataracts, and enlargement of the cerebral ventricles secondary to aqueductal stenosis. Previously described syndromes of enamel defects with or without cataracts were excluded on the basis of clinical criteria and appearance of the dentition. Metabolic conditions which could have caused cataracts were excluded clinically and by biochemical tests. The combination of signs in this patient may represent a new syndrome.	0
Glycogen storage disease type 1b (GSD-1b) is an autosomal-recessive disease caused by mutation of glucose-6-phosphate transporter and characterized by altered glycogen/glucose homeostasis. A higher frequency of autoimmune diseases has been observed in GSD-1b patients, but the molecular determinants leading to this phenomenon remain unknown. To address this question, we investigated the effect of glucose-6-phosphate transporter mutation on immune cell homeostasis and CD4+ T cell functions. In GSD-1b subjects, we found lymphopenia and a reduced capacity of T cells to engage glycolysis upon TCR stimulation. These phenomena associated with reduced expression of the FOXP3 transcription factor, lower suppressive function in peripheral CD4+CD25+FOXP3+ regulatory T cells, and an impaired capacity of CD4+CD25- conventional T cells to induce expression of FOXP3 after suboptimal TCR stimulation. These data unveil the metabolic determinant leading to an increased autoimmunity risk in GSD-1b patients.	0
Mutations in hydroxymethylbilane synthase (HMBS) cause acute intermittent porphyria (AIP), an autosomal dominant disease where typically only one HMBS allele is mutated. In AIP, the accumulation of porphyrin precursors triggers life-threatening neurovisceral attacks and at long-term, entails an increased risk of hepatocellular carcinoma, kidney failure, and hypertension. Today, the only cure is liver transplantation, and a need for effective mechanism-based therapies, such as pharmacological chaperones, is prevailing. These are small molecules that specifically stabilize a target protein. They may be developed into an oral treatment, which could work curatively during acute attacks, but also prophylactically in asymptomatic HMBS mutant carriers. With the use of a 10,000 compound library, we identified four binders that further increased the initially very high thermal stability of wild-type HMBS and protected the enzyme from trypsin digestion. The best hit and a selected analog increased steady-state levels and total HMBS activity in human hepatoma cells overexpressing HMBS, and in an Hmbs-deficient mouse model with a low-expressed wild-type-like allele, compared to untreated controls. Moreover, the concentration of porphyrin precursors decreased in liver of mice treated with the best hit. Our findings demonstrate the great potential of these hits for the development of a pharmacological chaperone-based corrective treatment of AIP by enhancing wild-type HMBS function independently of the patients' specific mutation.	0
Pfeiffer syndrome (MIM: #101600) is a rare autosomal dominant disorder classically characterized by limb and craniofacial anomalies. It is caused by heterozygous mutations in the fibroblast growth factor receptors types 1 and 2 (FGFR1 and FGFR2). We applied a next generation sequencing (NGS) panel approach comprising all 2877 genes currently known to be causative for one or more Mendelian diseases combined with the phenotype based computational tool PhenIX (Phenotypic Interpretation of eXomes). We report on a patient presenting with multiple anomalies of hands and feet including brachydactyly and symphalangism. No clinical diagnosis could be established based on the clinical findings and testing of several genes associated with brachydactyly and symphalangism failed to identify mutations. Via next generation sequencing (NGS) panel approach we then identified a novel de novo missense FGFR2 mutation affecting an amino acid reported to be mutated in Pfeiffer syndrome. Since our patient shows typical radiological findings of Pfeiffer syndrome in hands and feet but at the same time lacks several characteristic features such as clinical signs of craniosynostosis and prominent eyes we suggest introducing the term "FGFR2 associated phenotypes" for similar cases. Our results highlight the emerging role of combined NGS and phenotype based bioinformatics strategies to establish clinical diagnoses.	0
BACKGROUND: The incidence of sarcoidosis in Australia is unknown. The clinical features, diagnostic strategy and treatment of sarcoidosis in Australia have been poorly documented. METHODS: We analysed the medical records of 122 patients with sarcoidosis presenting to a respiratory service, between 1995 and 2005, which serves a regional southeastern Australian population of approximately 200,000. RESULTS: The incidence of sarcoidosis from 2000 to 2005 remained static and ranged from 4.4 to 6.3 patients per 100,000 population. The data showed that 55% were women and 28% were current smokers. Systems involved included lung parenchyma (66%), thoracic adenopathy (58%), skin (22%), ocular (18%), joint (11%), gastrointestinal tract (5%), central nervous system (3%) and hypercalcaemia (3%). Fifty-one per cent of patients had an increased serum angiotensin-converting enzyme level. The diagnosis was secured based on histological confirmation in 69%. Forty-three per cent of the patients were treated with oral corticosteroids and 10% with inhaled steroids. CONCLUSION: Sarcoidosis in Australia is a multi-system disease of unknown aetiology. This is the first reported incidence of sarcoidosis in Australia. The incidence is similar to another US-based epidemiological study of a predominately white population. The development of a larger multicentre database would assist in the identification, clinical description and treatment of sarcoidosis.	1
Studies utilizing large animal models of inherited retinal degeneration (IRD) have proven important in not only the development of translational therapeutic approaches, but also in improving our understanding of disease mechanisms. The dog is the predominant species utilized because spontaneous IRD is common in the canine pet population. Cats are also a source of spontaneous IRDs. Other large animal models with spontaneous IRDs include sheep, horses and non-human primates (NHP). The pig has also proven valuable due to the ease in which transgenic animals can be generated and work is ongoing to produce engineered models of other large animal species including NHP. These large animal models offer important advantages over the widely used laboratory rodent models. The globe size and dimensions more closely parallel those of humans and, most importantly, they have a retinal region of high cone density and denser photoreceptor packing for high acuity vision. Laboratory rodents lack such a retinal region and, as macular disease is a critical cause for vision loss in humans, having a comparable retinal region in model species is particularly important. This review will discuss several large animal models which have been used to study disease mechanisms relevant for the equivalent human IRD.	0
INTRODUCTION:Maturity Onset Diabetes of the Young (MODY) is a rare form of diabetes mellitus resulting from single nucleotide polymorphisms. There is a lack of evidence describing their periodontal condition and the management of these patients. The objective of this case report is to present the 6-month outcomes following non-surgical periodontal treatment of a patient diagnosed with MODY 5, the Renal Cyst and Diabetes Syndrome. CASE PRESENTATION:This case report describes the periodontal presentation and non-surgical management of a 21-year-old patient, diagnosed with hyperglycemia (HbA1c >14%) and stage 4 chronic kidney disease. She presented with generalized severe chronic periodontitis and multiple periodontal abscesses. She was treated with quadrant debridement with adjunctive systemic amoxicillin and metronidazole and 0.2% chlorhexidine mouth rinse. Significant improvement was observed after treatment, remaining stable 6-month post-treatment, with only 2 sites with probing depths ≥5mm. This was consistent with a reduction of the periodontal inflamed surface area from 3165mm2 to 500mm2. HbA1c was also reduced to 8.7% six months after treatment. CONCLUSIONS:MODY patients presenting with periodontitis can be successfully treated non-surgically, concurrent with diabetic management. This article is protected by copyright. All rights reserved.	0
The erythrokeratodermas are a distinct but clinically variable group of rare geno-dermatoses, characterized by circumscribed erythematous and hyperkeratotic lesions. All attempts to establish a valid classification have been based on purely clinical and morphologic criteria. Erythrokeratoderma en cocardes, also known as genodermatose en cocardes or Degos' syndrome, was first described by Degos in 1947. The condition is characterized by large round plaques with concentric erythema and scaling having a target configuration, which remit and recur, in addition to scaly plaques as seen in erythrokeratoderma variabilis. A case of this rare genodermatosis is described.	0
Retinitis pigmentosa (RP) is a common inherited retinal disease for which effective treatment is not yet known. This review sought to analyze the available medical literature covering the efficacy of different forms of laser treatment for RP in laboratory and clinical trials. The PubMed database was searched using the following phrases: "laser photocoagulation", "subthreshold laser", "nanolaser", "micropulse laser", "retinitis pigmentosa", "rod-cone dystrophy", and "retinal dystrophy". Results were stratified as clinical or experimental studies. Six studies involving animal models and three studies involving human subjects that examined laser treatment in RP were found. Laboratory studies on rodents favored classic laser photocoagulation as the most effective therapy for slowing the progression of proto-oncogene tyrosine-protein kinase MER-related RP. Two clinical studies on humans suggested transient but robust functional benefits of subthreshold micropulse laser treatment in RP. The available material is too scarce to define laser treatment as a standard procedure to treat RP in humans. Nondamaging retinal laser therapy should be tested more intensively in clinical trials as there is no proven negative side effect of that treatment and the theoretical background, especially the chaperone and reparative roles of heat shock proteins elicited during the procedure, supports this form of RP management.	0
Pediatric cataract is clinically and genetically heterogeneous and is the most common cause of childhood blindness worldwide. In this study, we aimed to identify disease-causing variants in three large British families and one isolated case with autosomal dominant congenital cataract, using whole exome sequencing. We identified four different heterozygous variants, three in the large families and one in the isolated case. Family A, with a novel missense variant (c.178G>C, p.Gly60Arg) in GJA8 with lamellar cataract; family B, with a recurrent variant in GJA8 (c.262C>T, p.Pro88Ser) associated with nuclear cataract; and family C, with a novel variant in GJA3 (c.771dupC, p.Ser258GlnfsTer68) causing a lamellar phenotype. Individual D had a novel variant in GJA3 (c.82G>T, p.Val28Leu) associated with congenital cataract. Each sequence variant was found to co-segregate with disease. Here, we report three novel and one recurrent disease-causing sequence variant in the gap junctional protein encoding genes causing autosomal dominant congenital cataract. Our study further extends the mutation spectrum of these genes and further facilitates clinical diagnosis. A recurrent p.P88S variant in GJA8 causing isolated nuclear cataract provides evidence of further phenotypic heterogeneity associated with this variant.	0
Usher syndrome encompasses a group of genetically and clinically heterogeneous autosomal recessive disorders with hearing deficiencies and retinitis pigmentosa. The mechanisms underlying the Usher syndrome are highly variable. In the present study, a Chinese family with Usher syndrome was recruited. Whole exome sequencing (WES), Sanger sequencing, homozygosity mapping, short tandem repeat (STR) analysis and segregation analysis were performed. Functional domains of the pathogenic variant for USH2A were analysed. We identified a homozygous frameshift variant c.99_100insT (p.Arg34Serfs*41) in the USH2A gene in the proband that showed discordant segregation in the father. Further homozygosity mapping and STR analysis identified an unusual homozygous variant of proband that originated from maternal uniparental disomy (UPD). The p.Arg34Serfs*41 variant produced a predicted truncated protein that removes all functional domains of USH2A. The variant was not included in the 1000 Human Genomes Project database, ExAC database, HGMD or gnomAD database, but was included in the ClinVar databases as pathogenic. Although USH2A is an autosomal recessive disease, the effects of UPD should be informed in genetic counselling since the recurrence risk of an affected child is greatly reduced when the disease is due to the UPD mechanism. To test potential patients, WES, combined with STR analysis and homozygosity mapping, provides an accurate and useful strategy for genetic diagnosis. In summary, our discoveries can help further the understanding of the molecular pathogenesis of Usher syndrome type IIA to advance the prevention, diagnosis and therapy for this disorder.	0
Background/Aims:Rosai-Dorfman disease (RDD) is a rare, self-limited disorder of unknown etiology that affects children and young adults worldwide and typically manifests as chronic, painless cervical lymphadenopathy. Orbital involvement is very rare and may be an isolated extranodal manifestation or associated with concurrent systemic disease. Adjacent bone involvement is most exceptional, and secondary optic neuropathy has never been reported. Methods:This is a case report with review of the literature. Results:We present a 32-year-old man who, over a 3-month period, developed worsening vision, headache, and vertical diplopia. On examination, there was decreased vision with dyschromatopsia, proptosis, and hypotropia of the left eye. CT scan of the orbits revealed a soft tissue mass inseparable from the lacrimal gland with adjacent bone erosion. Histopathologic evaluation revealed a diffuse infiltrate of histiocytes, lymphocytes, plasma cells, and neutrophils with peripolesis and emperipolesis (tunneling of lymphocytes and plasma cells in the histiocytes' cytoplasm without destruction), consistent with RDD. Resolution of symptoms as well as of the optic neuropathy was achieved with oral corticosteroids. Conclusion:RDD is an important diagnosis that must be considered in the differential diagnosis of an orbital mass.	0
We report a 7-year-old boy with infantile spasms caused by a novel mutation in the Aristaless-related homeobox (ARX) gene. He showed infantile spasms and hypsarrhythmia on electroencephalogram from early infancy. Brain MRI did not reveal severe malformation of the brain except mild hypoplasia of the corpus callosum. Two-fold adrenocorticotropic hormone (ACTH) therapy failed to control the seizures, and ketogenic diet therapy and multi-antiepileptic drug therapy were required as he showed intractable daily tonic-clonic seizures. Exome sequencing identified a hemizygous mutation in the ARX gene, NG_008281.1(ARX_v001):c.1448 + 1 G > A, chrX: 25025227 C > T (GRCh37). To our knowledge, this mutation has not been reported previously.	0
This case illustrates a rare and unique case of a 73-year-old woman who presents with a rapidly developing digital ischaemia, superior mesenteric artery thrombus with positive-lupus anticoagulant. She then developed avascular necrosis of the femoral head. Discussion of the process of diagnosis and management of antiphospholipid syndrome and catastrophic antiphospholipid syndrome are reported.	0
Bowman's layer lies immediately posterior to the epithelial basement membrane (EBM) and anterior to the stroma proper in humans, chickens, quail, zebra fish, deer, giraffe, antelope, California sea lions, guinea pig and several other species. It is not found in dog, wolf, cat, tiger, lions, rabbit, pigs, cows, goats, or horses. Developmental anomalies of Bowman's layer are rare, but acquired damage to Bowman's layer, or even complete destruction, is frequently seen in advanced bullous keratopathy or Fuchs' endothelial dystrophy. No detrimental effects of removal of Bowman's layer over the central 6-7 mm of central cornea have been noted in millions of patients who've had photorefractive keratectomy (PRK). Recent studies have suggested the randomly-oriented collagen fibrils that make up Bowman's layer do not have a significant barrier function in modulating the passage of moderate- to large-sized proteins. It is hypothesized that Bowman's layer develops in the corneas of those species that have one because of cytokine-mediated interactions occurring between corneal epithelial cells and underlying keratocytes, including negative chemotactic and apoptotic effects on the keratocytes by low levels of cytokines such as interleukin-1α that are gradually released as epithelial cells die and slough during their normal development. A "Bowman's like layer" can generate around stromal epithelial plugs after radial keratotomy, and possibly beneath the central corneal epithelial basement membrane many years after PRK.	0
BACKGROUND:Congenital femoral deficiency (CFD) is one of the most challenging and complex conditions for limb lengthening. We focused on the problem of hip instability during femoral lengthening because subluxation and dislocation are potentially catastrophic for hip function. METHODS:We assessed for hip stability in 69 children (91 femoral lengthenings) who had CFD Paley type 1a (43 children) and 1b (26 children). The mean age at first lengthening was 6.4 years. RESULTS:Hip subluxation/dislocation occurred during 14 (15 %) of 91 lengthenings. Thirty-three pelvic osteotomies were performed before lengthening in an attempt to stabilize hips. Thirteen patients (type 1a, eight; type 1b, five) had acetabular dysplasia at initiation of lengthening. One of the eight with type 1a experienced mild femoral head subluxation; four of the five with type 1b experienced three dislocations and one subluxation. Eight patients (type 1b) experienced hip instability although they had pelvic osteotomies. Proximal femoral lengthening was a significant factor for hip subluxation. Patients with hip subluxation more likely underwent monolateral fixation and the original superhip procedure. Age ±six years was not a contributing factor for hip instability. CONCLUSIONS:Important risk factors for hip instability during femoral lengthening are severity of CFD, residual acetabular dysplasia, and proximal femoral lengthening. We recommend routine performance of pelvic osteotomy for patients with Paley type 1b CFD and distal lengthening. LEVEL OF EVIDENCE:Therapeutic Level IV.	0
INTRODUCTION:Diffuse Large B-Cell lymphoma (DLBCL) is the most commonly diagnosed form of non-Hodgkin lymphoma (NHL) in adults. Most patients receive an initial treatment with chemo-immunotherapy, which includes rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone (R-CHOP). Cure rates are high but those who relapse, or do not respond to initial therapy, have a poor prognosis. Polatuzumab vedotin, an anti-CD79b monoclonal antibody conjugated to the cytotoxic payload monomethyl aurostatin-E (MMAE), in combination with bendamustine and rituximab (polatuzumab-BR) is a new, effective therapeutic option to add to the treatment of relapsed/refractory (R/R) DLBCL Areas covered: This review covers the clinical development of polatuzumab for the treatment of lymphoma, its current and future use in patients with DLBCL and identifies its place in the treatment of R/R DLBCL. A search of PubMed and oncology/hematology congresses using "polatuzumab" as the search term was undertaken to identify the most pertinent clinical reports. Expert opinion: Polatuzumab-BR is an effective and safe option for transplant-ineligible patients with R/R DLBCL either before or after CAR-T (chimeric antigen receptor T-cell therapy). Ongoing combination trials with polatuzumab will expand its applications in the treatment of this disease.	0
Flexor Digitorum Profundus avulsion injury associated with an enchondroma at the level of the distal phalanx is extremely rare. There have been few cases reported to date and most have been surgically managed using a screw and/or Bunnell pull-out wire technique with or without bone grafting. We describe the first case using a simple interosseus fixation technique for the reattachment of FDP tendon without bone grafting. The patient made an excellent post-operative recovery. This technique is a simple, effective, patient-friendly and internalised solution which, in addition, may prevent the need for bone grafting.	0
Multifocal, extraosseous, and surface aneurysmal bone cysts are rare variants of the primary lesions. The clinicopathological features are similar, and the optimal treatment is surgical. Although local recurrences may occur, the prognosis is excellent. This review article introduces the readers to a rare diagnosis which they may have been previously unfamiliar with, presents the clinicopathological and imaging features of these rare aneurysmal bone cyst variants, and discusses their diagnosis and treatment. The clinicians who treat patients with aneurysmal bone cysts should be familiar with these uncommon entities and their differential diagnosis.	0
In hemifacial microsomia (HFM), the correlations between mandibular dysplasia and maxillary deformities in HFM patients have not yet been assessed. The objective of the present study was to examine the association of maxillary volumetric and linear measurements with mandibular ramus height or corpus length on the affected side in children with unilateral HFM.In this retrospective research, a total of 70 children with unilateral HFM were enrolled at our department from 2010 to 2019. Demographic information was recorded, and computed tomographic scan were reconstructed and analyzed by segmentation, volumetric, and cephalometric measurements. Analyses involved independent sample t-test, univariable, and multivariable linear regression.In the overall population, mandibular ramus height (MRH) was positively associated with the maxillary bone volume (MBV) (r = 0.484, P < 0.001) and maxillary total volume (MTV) (r = 0.520, P < 0.001). Similarly, mandibular corpus length (MCL) was significantly associated with the MBV (r = 0.467, P < 0.001) and MTV (r = 0.520, P < 0.001). Multivariate regression analysis revealed that the MRH or MCL were significantly and independently associated with MBV or MTV (MRH/MBV β = 0.420, P < 0.001; MRH/MTV β = 0.391, P < 0.001; MCL/MBV β = 0.403, P < 0.001; MCL/MTV β = 0.307, P < 0.01).These results demonstrated that the MBV and MTV are independently associated with MRH or MCL on the affected side in children with unilateral HFM, suggesting a potential interaction between mandibular dysplasia and maxillary deformities.	0
Gürbüz G, Mutlu Albayrak H. Schwartz Jampel syndrome responding positively to carbamazepine therapy: a case report and a novel mutation. Turk J Pediatr 2019; 61: 967-970. Schwartz Jampel syndrome was first described in 1962. It is an autosomal recessive disease with generalized myotonic myopathy and skeletal dysplasia. A mutation in the HSPG2 gene occurs. Approximately 150 cases have been reported in literature. A 4-year-old girl presented to the pediatric neurology clinic due to difficulty in walking. The patient had difficulty opening her mouth and swallowing. She was unable to eat solid foods and was bottle fed. She was able to stand leaning forward, with her legs open and with one hand supported. Bilateral blepharospasm, posterior cleft palate, microstomia, pursed lips, kyphoscoliosis, contracture in the elbows, long thin fingers and campodactyly in the bilateral 5th fingers were present. Myotonic contraction with thenar percussion was observed. Previously undescribed mutation was determined in HSPG2 gene in the genetic study. Oral carbamazepine therapy was initiated and 1.5 months later the patient`s muscle rigidity had decreased and her motor skills had improved. This report contributes to the literature by defining a new mutation in HSPG2 gene and showing the importance of early diagnosis of the disease.	0
BACKGROUND:Mesenteric fibromatosis is a benign locally-aggressive mesenchymal neoplasm that lacks the potential for metastasis. It is related to Gardner's Syndrome, previous trauma, abdominal surgery, and prolonged intake of oestrogen. Differentially diagnosing this from similar tumours is crucial in order for establishing the appropriate treatment and only immunohistochemical features can be used for a definitive diagnosis. Although medical therapies play a role in the treatment of mesenteric fibromatosis, surgical resection is the gold-standard procedure. METHODS:Our case study is a 40-year-old male with a concomitant diagnosis of non-Hodgkin lymphoma and mesenteric fibromatosis, not associated with any of the risk factors mentioned above. We performed CT and PET scans and observed a vascularised and well-defined mesenteric centre-abdominal hypermetabolic solid mass in contact with the gastric body, duodenum, body and tail of the pancreas, transverse colon, and spleen. An ultrasound-guided tru-cut biopsy revealed features suggestive of mesenteric fibromatosis. RESULTS:An elective laparotomy was carried out and a giant mass, arising from mesentery, was excised, including a partial gastrectomy and segmental resection of the transverse colon. Distal pancreatectomy, small bowel resection and successive splenectomy were performed due to a large hypertensive component. The postoperative period was uneventful. The histopathology of the surgical pieces was compatible with intra-abdominal desmoid fibromatosis. CONCLUSION:As far as we know from the literature, this is the largest mesenteric fibromatosis tumour ever to be excised. We also noticed that this is the first reported case of the concomitant presence of mesenteric fibromatosis and non-Hodgkin lymphoma that is not related to any of the described risk factors. Further research is needed to establish what type of association this presentation may indicate.	0
Introduction:Obstructed hemivagina ipsilateral renal agenesis (OHVIRA) is a rare anomaly of the urogenital system. The characteristic triad of this syndrome, which was initially reported in 1950, is didelphys uterus, obstructed hemivagina, and ipsilateral renal agenesis (Embrey, 1950 [1]). Case:A 17-year-old girl was referred with a 6-month history of offensive vaginal discharge. Magnetic resonance imaging (MRI) established the diagnosis of OHVIRA. She underwent surgery for drainage of the hematocolpos and excision of the vaginal septum followed by an uncomplicated recovery and the patient had normal menstrual cycles after surgery. Conclusion:There should be a high suspicion of OHVIRA syndrome when encountering adolescent patients with non-specific abdominal or pelvic symptoms.	0
Background:Chordoid glioma of the third ventricle is a rare neuroepithelial tumor characterized by a unique histomorphology within the third ventricular region, but with radiological and histopathological features mimicking benign lesions such as meningioma. We report a case of chordoid glioma of the third ventricle and suggest a useful indicator for accurate diagnosis. Case Description:A previously healthy 46-year-old woman was admitted to our hospital with mild headache. Neuroimaging revealed a large tumor measuring approximately 18 mm in the suprasellar region, and perifocal edema in the optic tract and internal capsule on magnetic resonance imaging. Laboratory findings revealed no pituitary dysfunction including diabetes insipidus. Gross total resection of the tumor was performed by the interhemispheric translamina terminalis approach. Histological findings revealed nests of regular epithelioid cells with large nuclei and abundant eosinophilic cytoplasm within myxoid stroma. Immunohistochemical studies demonstrated diffuse cytoplasmic expression of glial fibrillary acidic protein (GFAP) and CD34, and strong nuclear staining for thyroid transcription factor 1 (TTF-1). We, therefore, histologically classified the tumor as chordoid glioma of the third ventricle. Headache improved immediately postoperatively, and follow-up neuroimaging after 12 months showed no signs of recurrence. Conclusions:Chordoid glioma of the third ventricle is a very rare tumor that is difficult to diagnose on routine neuroimaging. Accurate diagnosis requires detailed analysis of neuroimaging and immunohistochemical studies using CD34 and TTF-1 staining.	0
SRY-negative 46,XX testicular disorders of sex development (DSD) are very rare conditions. Recently, we identified a novel heterozygous NR5A1 mutation, p.Arg92Trp (c.274C>T, p.R92W), in 2 unrelated cases of 46,XX testicular/ovotesticular DSD. We report the clinical course from infancy to puberty in a Japanese male with SRY-negative 46,XX testicular DSD, carrying this p.Arg92Trp mutation in NR5A1. The patient naturally acquired the development of a penis and pubic hair during puberty. However, hypergonadotropic hypogonadism subsequently developed. More clinical cases will be needed to fully understand the effects of the p.Arg92Trp mutation on the ability to maintain testosterone secretion in 46,XX testicular DSD.	0
Amino acid transporters play very important roles in nutrient uptake, neurotransmitter recycling, protein synthesis, gene expression, cell redox balance, cell signaling, and regulation of cell volume. With regard to transporters that are closely connected to metabolism, amino acid transporter-associated diseases are linked to metabolic disorders, particularly when they involve different organs, cell types, or cell compartments. To date, 65 different human solute carrier (SLC) families and more than 400 transporter genes have been identified, including 11 that are known to include amino acid transporters. This review intends to summarize and update all the conditions in which a strong association has been found between an amino acid transporter and an inherited metabolic disorder. Many of these inherited disorders have been identified in recent years. In this work, the physiological functions of amino acid transporters will be described by the inherited diseases that arise from transporter impairment. The pathogenesis, clinical phenotype, laboratory findings, diagnosis, genetics, and treatment of these disorders are also briefly described. Appropriate clinical and diagnostic characterization of the underlying molecular defect may give patients the opportunity to avail themselves of appropriate therapeutic options in the future.	0
Context:Congenital generalized lipodystrophy, type 4 (CGL4) is a rare autosomal recessive disorder caused by mutations in caveolae-associated protein 1. Patients with CGL4 also have myopathy and cardiomyopathy with a predisposition for sudden death due to ventricular arrhythmias. However, the underlying pathology for these morbidities remains unknown. Therefore, we report on an autopsy of a Hispanic boy with CGL4. Case Description:Our patient had early-onset generalized lipodystrophy, feeding difficulties, myopathy, atlanto-axial dislocation, and learning disabilities. He was diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) at age 8 years, had poor compliance with medications, and died suddenly at age 15.3 years. Autopsy showed marked loss of subcutaneous and omental fat with no inflammatory cells in adipose tissue and normal adipocytes in the parathyroid glands. There were adipocytes interdigitating cardiac muscle fibers, with fibro-fatty infiltration in the right ventricle, near coronary sinus, and atrioventricular node. There was no evidence of coronary heart disease. The quadriceps femoris muscle did not show adipocyte infiltration, inflammation, or fibrosis. The muscularis mucosa layer was thickened in the esophagus and at the gastro-duodenal junction, and the esophagus had prominent, large nerves in the subserosa. The liver weighed 3000 g, with minimal chronic inflammation and steatosis in 40% of parenchyma, primarily in zones 2 and 3. There was no spermatogenesis in the spermatic tubules. Conclusions:Our data suggest that fibro-fatty infiltration of the right ventricle may contribute to CPVT in patients with CGL4. Thick muscularis mucosa and large nerves in the esophagus likely contributed to dysphagia and dysmotility. A lack of spermatids suggests infertility in affected male patients.	0
Primary intracranial malignant melanoma(PIMM)is a rare neoplasm of the central nervous system, accounting for 1% of cases of malignant melanomas and 0.1% of cases of brain tumors. Here, we report a case of PIMM that was initially considered to be a traumatic brain contusion. A 44-year-old man was transferred to a local hospital because of general tonic convulsion after falling while riding a bike. CT showed an irregular high-density area in the left temporal pole, which was diagnosed as a traumatic contusion. MRI performed 3 months after the initial episode revealed an enlarged temporal lesion with surrounding edema, suggestive of a neoplasm. The MRI showed the lesion as mixed signal intensity, suggesting both solid and cystic components. Subtotal resection was performed, except for the tumor adhering to the peripheral middle cerebral arteries(MCAs). The definitive diagnosis was made based on pathological findings and no evidence of extracranial lesions. Gamma knife surgery was performed for the remnant tumor adjacent to MCAs. The radiologically positive tumor chronologically regressed, and the patient remained progression-free for 18 months. Radiological findings of PIMM vary but typically include high density on CT and hyperintensity on T1-weighted MRI. Close observation enabled early diagnosis based on the suspicion of a neoplasm according to atypical radiological findings. PIMM has a poor prognosis with an overall survival of 12.0 months without confirmative treatment. Gamma knife surgery might achieve suppression of this highly progressive tumor.	0
OBJECTIVES:The aim of this study is to explore the effectiveness and safety of oral corticosteroids (prednisone) in the treatment of early stage SARS-Cov-2 pneumonia in patients who do not yet meet hospital admission criteria. TRIAL DESIGN:Randomized clinical trial, controlled, open, parallel group, to evaluate the effectiveness of steroids in adult patients with confirmed COVID-19, with incipient pulmonary involvement, without hospital admission criteria. Patients will be stratified by the presence or not of radiological data on pneumonia. PARTICIPANTS:We will include patients with early stage SARS-Cov-2 pneumonia who do not meet hospital admission criteria from the reference hospital, the Hospital Universitario de Burgos, in the region of Castilla y León, Spain. Patients will be followed-up by specialist physicians and Primary Health Care professionals. INCLUSION CRITERIA:- Men and women. - Age between 18 and 75 years old. - Diagnosed SARS-CoV-2 infection, by PCR and/or IgM+ antibody test and/or antigen test. - Clinical diagnosis of lung involvement: (respiratory symptoms +/- pathological auscultation +/- O2 desaturation) - Chest X-ray with mild-moderate alterations or normal. - Patients who give their verbal informed consent in front of witnesses, which will be reflected in the patients' medical records. EXCLUSION CRITERIA:- Oxygen desaturation below 93% or P02 < 62. - Moderate-severe dyspnea or significant respiratory or general deterioration that makes admission advisable. - Chest X-ray with multifocal infiltrates. - Insulin-dependent diabetes with poor control or glycaemia in the emergency room test greater than 300 mg/ml (fasting or not). - Other significant comorbidities: Severe renal failure (creatinine clearance < 30 mL/min); cirrhosis or chronic liver disease, poorly controlled hypertension. - Heart rhythm disturbances (including prolonged QT). - Severe immunosuppression (HIV infection, long-term use of immunosuppressive agents); cancer. - Pregnant or breast-feeding women. - Patients under use of glucocorticoids for other diseases. - History of allergy or intolerance to any of the drugs in the study (prednisone, azithromycin or hydroxychloroquine). - Patients who took one or more of the study drugs in the 7 days prior to study inclusion. - Patients taking non-suppressible drugs with risk of QT prolongation or significant interactions. - Patients unwilling or unable to participate until study completion. - Participation in another study. INTERVENTION AND COMPARATOR:Eligible patients will be randomized to receive standard outpatient treatment only (group 1) or standard outpatient treatment plus prednisone (group 2). - Group 1: paracetamol 1 g/8 h (on demand) + hydroxychloroquine 400 mg/12h the first day, 200 mg/12 h for 4 days + azithromycin 500 mg/24h for 5 days. - Group 2: paracetamol 1 g/8 h (on demand) + hydroxychloroquine 400 mg/12h the first day, 200 mg/12 h for 4 days + azithromycin 500 mg/24h for 5 days + prednisone 60 mg / 24 h for 3 days, 30 mg / 24 h for 3 days and 15 mg / 24 h for 3 days. MAIN OUTCOMES:If the patient requires ambulatory observation, according to the protocol established in this respect in the Emergency Department, meets all the criteria for inclusion and none for exclusion, data will be taken by the person responsible on the data collection sheet. The main result is admission after 30 days. Secondary outcomes are 30-day ICU admission and hospital stay. The safety variable will be the occurrence of clinical symptoms or delirium related to the steroids. Also, the possible decompensations of diabetes will be measured. All tests will be on an intention-to-treat basis. RANDOMISATION:Treatment will be assigned according to stratified randomization by the presence or absence of radiological data of lung involvement (previously performed by random sequence 1:1 generated with Epidat and kept hidden by opaque, sealed envelopes, which will only be opened after inclusion and basal measurement). BLINDING (MASKING):Participants, caregivers and personnel responsible for outcomes measurement will not be blinded to group assignment, once the patient is included and the basal measurement performed, as per protocol design. NUMBERS TO BE RANDOMISED (SAMPLE SIZE):The percentage of patients with incipient lung involvement is unknown, but given that pulmonary involvement already exists it is estimated to be around 20%. We consider that the intervention could reduce this percentage to 5%, so the necessary sample size would be 200 subjects (100 per group), with a power of 80% and an estimated loss percentage of 10%. TRIAL STATUS:The protocol with code TAC-COVID-19, version 2.0 on date: April 16, 2020 is approved by the Spanish Drug Agency (AEMPS) and the local Ethics Committee. The trial is in the recruitment phase. Recruitment began 19 April, 2020 and is anticipated to be complete by April 2021. TRIAL REGISTRATION:The trial was registered under the title "OUTPATIENT TREATMENT OF EARLY PULMONARY COVID19 WITH CORTICOSTEROIDS AS AN OPPORTUNITY TO MODIFY THE COURSE OF THE DISEASE" with EudraCT number 2020-001622-64 , registered on 3 April 2020. FULL PROTOCOL:The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.	0
Little information is available on the incidence of splanchnic vein thrombosis and on mortality rates during the acute phase of the disease. We performed a large epidemiologic study on hospital admissions for portal vein thrombosis (PVT) and the Budd-Chiari syndrome (BCS) between 2002 and 2012 in Northwestern Italy. Primary and secondary discharge diagnoses of PVT and BCS were identified using the 9th edition International Classification of Diseases codes 453.0, 572.1 and 452. Hospitalisations for recurrent events were not included. Information was collected on age and gender, vital status at discharge, duration of hospitalisation, and up to five secondary discharge diagnoses. Comorbidity was evaluated using the Charlson comorbidity index (CCI). A total of 3535 patients with PVT and 287 with BCS were hospitalized. The overall gender-specific incidence rates for PVT were 3.78 per 100,000 inhabitants in males and 1.73 per 100,000 inhabitants in females; for BCS 2.0 and 2.2 per million inhabitants, respectively. In-hospital case fatality was 7.3 % in patients with PVT and 4.9 % in patients with BCS. Age, non-abdominal solid cancer, and CCI were independently associated with in-hospital mortality in both PVT and BCS after stepwise regression analysis, male gender and haematologic cancer were associated with mortality in BCS patients only. In this large study we confirmed the low incidence of BCS and we found an incidence of PVT higher than previously reported. This incidence was stable during the period of observation. In-hospital mortality is not negligible, in particular in PVT patients.	1
Localized scleroderma (LoSc) is rare connective tissue disease that manifests with inflammation and fibrosis of the skin. Depending on the LoSc subtype, adjacent structures such as subcutaneous tissue, fascia, muscles, bones may be affected. The hallmark of fibrosis is tissue remodelling with excess deposition of extracellular matrix proteins (ECM), principally collagens. MicroRNAs (miRNAs) are small, noncoding RNA molecules that consist of 19-24 nucleotides and act as negative regulators of gene expression at the posttranscriptional level. Based on the current articles, approximately 40 microRNAs have been linked to fibrosis in different organs and diseases. The majority of these molecules promote or inhibit fibrosis by targeting connective tissue growth factor (CTGF), extracellular matrix proteins, TGF-β pathway and MAPK (mitogen-activated protein kinase) pathway. Further, particular microRNAs regulate fibrogenesis by altering epithelial-to-mesenchymal transition (EMT) or activating proliferation of myofibroblasts. MiRNAs are relatively stable, detectable in tissues and body fluids (serum, plasma) which suggest that they may serve as beneficial biomarkers to monitor the course of the disease and response to treatment. Herein, we report the present state of knowledge on microRNA expression in localized scleroderma.	0
The formation of human enamel is highly regulated at the molecular level and involves thousands of genes. Requisites for development of this highly mineralized tissue include cell differentiation; production of a unique extracellular matrix; processing of the extracellular matrix; altering of cell function during different stages of enamel formation; cell movement and attachment; regulation of ion and protein movement; and regulation of hydration, pH, and other conditions of the microenvironment, to name just a few. Not surprising, there is a plethora of hereditary conditions with an enamel phenotype. The objective of this review was to identify the hereditary conditions listed on Online Mendelian Inheritance in Man (OMIM) that have an associated enamel phenotype and whether a causative gene has been identified. The OMIM database was searched with the terms amelogenesis, enamel, dental, and tooth, and all results were screened by 2 individuals to determine if an enamel phenotype was identified. Gene and gene product function was reviewed on OMIM and from publications identified in PubMed. The search strategy revealed 91 conditions listed in OMIM as having an enamel phenotype, and of those, 71 have a known molecular etiology or linked genetic loci. The purported protein function of those conditions with a known genetic basis included enzymes, regulatory proteins, extracellular matrix proteins, transcription factors, and transmembrane proteins. The most common enamel phenotype was a deficient amount of enamel, or enamel hypoplasia, with hypomineralization defects being reported less frequently. Knowing these molecular defects allows an initial cataloging of molecular pathways that lead to hereditary enamel defects in humans. This knowledge provides insight into the diverse molecular pathways involved in enamel formation and can be useful when searching for the genetic etiology of hereditary conditions that involve enamel.	0
Biallelic mutations in the neuroblastoma amplified sequence (NBAS) gene have been reported to cause two different clinical spectra: short stature with optic nerve atrophy and Pelger-Huët anomaly (SOPH) syndrome and infantile liver failure syndrome 2 (ILFS2). Here, we describe a case of a 3-year-old Japanese boy who presented with fever-triggered recurrent acute liver failure (ALF). The clinical characteristics were considerable elevation of liver enzymes, severe coagulopathy, and acute renal failure. In addition to the liver phenotype, he had short stature and Pelger-Huët anomaly in the peripheral granulocytes. Whole-exome and Sanger sequencing of the patient and his parents revealed that he carried novel compound heterozygous missense mutations in NBAS, c.1018G>C (p.Gly340Arg) and c.2674 G>T (p.Val892Phe). Both mutations affect evolutionarily conserved amino acid residues and are predicted to be highly damaging. Immunoblot analysis of the patient's skin fibroblasts showed a normal NBAS protein level but a reduced protein level of its interaction partner, p31, involved in Golgi-to-endoplasmic reticulum retrograde vesicular trafficking. We recommend NBAS gene analysis in children with unexplained fever-triggered recurrent ALF or liver dysfunction. Early antipyretic therapy may prevent further episodes of ALF.	0
Reports of constitutional ring chromosome 22, r(22) are rare. Individuals with r(22) present similar features as those with the 22q13 deletion syndrome. The instability in the ring chromosome contributes to the development of variable phenotypes. Central nervous system (CNS) atypical teratoid rhabdoid tumors (ATRTs) are rare, highly malignant tumors, primarily occurring in young children below 3 years of age. The majority of ATRT cases display genetic alterations of SMARCB1 (INI1/hSNF5), a tumor suppressor gene located on 22q11.2. The coexistence of a CNS ATRT in a child with a r(22) is rare. We present a case of a 4-month-old boy with 46,XY,r(22)(p13q13.3), generalized hypotonia and delayed development. High-resolution microarray analysis revealed a 3.5-Mb deletion at 22q13.31q13.33. At 11 months, the patient had an ATRT (5.6 cm×5.0 cm×7.6 cm) in the cerebellar vermis, which was detected in the brain via magnetic resonance imaging.	0
Background:Sellar cysts are common in neurosurgery. Around 90% of these are diagnosed as pituitary adenomas. The other 10% are nonadenomatous, inflammatory, infective, metastatic, or cystic in nature. Some rare cysts include dermoid, epidermoid, colloid, and arachnoid. They all have different histological features. The case we present demonstrates a unique cyst with features that are not previously documented. Case Description:A 60-year-old female presented to the neurosurgical department complaining of blurring of vision and severe headache for more than ½ year. Imaging was done which revealed a bony erosive lesion in the region of sella. Magnetic resonance imaging with contrast showed high signals with no contrast enhancement. A clear diagnosis could not be made based on radiology. Surgery was done and sample was sent for histopathology. Based on histopathological report findings, a diagnosis of benign atypical sellar cyst was made. Post procedure, the patient recovered and was discharged. Conclusion:Sellar cysts present similarly. They are differentiated based on their histological features. The sellar cyst we encountered had features different from the ones already described in the literature.	0
OBJECTIVE:The clinical data on olfactory neuroblastomas (ONBs) are scarce owing to their rarity. This study aimed to assess the potential prognostic factors, outcomes, and optimal treatment strategies in patients with ONB. METHODS AND MATERIALS:The data of 217 patients with ONB between 1991 and 2019 were retrospectively reviewed. Long-term survival, potential prognostic factors, and outcomes with combined treatment strategies were analyzed. RESULTS:All patients received radiotherapy (RT); 185 patients underwent surgery, and 139 patients received chemotherapy. The 5-year overall survival (OS), progression-free survival (PFS), locoregional failure-free survival (LRFS), and distant metastasis-free survival (DMFS) of the entire cohort were 80.0%, 79.0%, 79.3%, and 80%, respectively. On univariate analyses, R0/R1 resection, early Kadish stage, negative lymph nodes, absence of orbital invasion, and administration of surgery with RT were found to be favorable factors. Conversely, combined sequential treatment with surgery, RT, and chemotherapy was not associated with survival. Multivariate analysis demonstrated lymph node status, orbital invasion, and the combination of surgery and RT to be independent prognostic factors. CONCLUSIONS:Patients with ONB, who had lymph node metastases, orbital invasion diseases, advanced Kadish stages, R2 resection margins, and received RT alone, had poor outcomes. Combined administration of surgery and RT may be a potentially useful strategy in patients with advanced Kadish stages; the role of chemotherapy in these stages requires further evaluation.	0
Background: Spinocerebellar ataxia type 3 (SCA3) is an inherited form of ataxia that leads to progressive neurodegeneration. Fatigue is a common non-motor symptom in SCA3 and other neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Although risk factors to fatigue in these diseases have been thoroughly studied, whether or not fatigue can affect clinical phenotypes has yet to be investigated. Methods: Ninety-one molecularly confirmed SCA3 patients and 85 age- and sex-matched controls were recruited for this study. The level of fatigue was measured using the 14-item Fatigue Scale (FS-14), and the risk factors to fatigue and how fatigue correlates with clinical phenotypes were studied using multivariable linear regression models. Results: We found that the severity was significantly higher in the SCA3 group than in the control group (9.30 ± 3.04% vs. 3.94 ± 2.66, P = 0.000). Daytime somnolence (β = 0.209, P = 0.002), severity of ataxia (β = 0.081, P = 0.006), and poor sleep quality (β = 0.187, P = 0.037) were found to have a positive relationship with fatigue. Although fatigue had no relationship with age at onset or ataxic progression, we found that it did have a positive relationship with the severity of ataxia (β = 7.009, P = 0.014). Conclusions: The high level of fatigue and the impact of fatigue on the clinical manifestation of SCA3 patients suggest that fatigue plays a large role in the pathogenesis of SCA3, thus demonstrating the need for intervention and treatment options in this patient cohort.	0
OBJECTIVE:Amyotrophic lateral sclerosis type 8 (ALS8) is a familial form of motor neuron disease, with predominance of lower motor neuron degeneration, and is caused by mutation of the vesicle-associated membrane protein-associated protein B (VAPB). We aimed to compare the cognitive profile of patients with ALS8 and healthy controls (HC), and to screen for behavioural features in ALS8 patients. METHODS:The sample was composed of ALS8 patients (n = 22; 14 men; median age 48 years old; median disease duration 6.5 years) and HC (n = 33; 19 men; median age 48 years old). Patients and HC were matched for sex, age and educational level. Participants underwent behavioural, psychiatric (Hospital Anxiety and Depression Scale and Cambridge Behavioural Inventory-Revised) and neuropsychological assessments, focused on executive functions, visual memory, and facial emotion recognition. RESULTS:ALS8 patients exhibited subtle deficits in executive functions. Compared to controls, ALS8 patients were significantly impaired in measures of flexibility and inhibitory control. ALS8 patients and HC did not differ in scores of facial emotion recognition. There was clinically relevant anxiety and depression in 36% and 27% of ALS8 patients, respectively. Behavioural disorders such as stereotypic and motor behaviours were present in more than 30% of patients. CONCLUSIONS:ALS8 patients present mild executive dysfunction and behavioural changes such as mood disorders, apathy and stereotypic behaviour. Our findings suggest that ALS8 is not a pure motor disorder and it is associated with subtle cognitive and behavioural impairments.	0
Staphylococcus infection-associated glomerulonephritis (SAGN) is characterized by the presence of IgA and C3 as the predominant components present in the glomerular immune deposits. Glomerulonephritis frequently resolves after effective treatment of the staphylococcal infection. However, there have been few studies of repeat kidney biopsy after resolution of glomerulonephritis. We present a combined kidney-pancreas transplant patient who developed SAGN due to Staphylococcus aureus bacteremia from an old infected arteriovenous (AV) graft, which occurred after a long period of stable allograft function. Clinical improvement occurred following surgical debridement and appropriate antibiotics with subsequent clearance of bacteremia. However, 3 weeks later he presented with severe acute kidney injury related to rapidly progressive glomerulonephritis. Renal allograft biopsy revealed immune complex glomerulonephritis with predominance of IgA and C3 in subendothelial and mesangial deposits, consistent with SAGN. There was no evidence for recurrent staphylococcal infection. High-dose steroid therapy was followed by resolution of hematuria and improvement in allograft function with gradual return of serum creatinine concentration to near baseline levels. However, 1 year after the diagnosis of SAGN, he developed gradually worsening allograft function with persistent proteinuria. Repeat allograft biopsy showed sclerosing glomerular changes and extensive interstitial fibrosis and tubular atrophy. There was complete resolution of proliferative changes, and IgA and C3 deposits were no longer detectable. Despite transient allograft function stabilization, the patient progressed to end-stage renal disease (ESRD), and maintenance hemodialysis was reinitiated 2.5 years after the diagnosis of SAGN. Pancreatic allograft function remained normal.	0
During local small measles outbreak in Japan, 3 adolescents with febrile skin rash suspected as having measles were diagnosed with primary human herpesvirus (HHV)-7 infection. Primary HHV-7 infection can cause exanthem subitum in not only young children but also adolescents. HHV-7 should be considered as a possible causative agent for adolescent febrile skin rash during the measles outbreak.	0
Background: BRAFV600E mutation is present in a subset of pediatric brain tumors. Vemurafenib is an oral, selective ATP-competitive inhibitor of BRAFV600E kinase. The goal of this multi-center study conducted through the Pacific Pediatric Neuro-Oncology Consortium (PNOC) was to determine the recommended phase 2 dose (RP2D) and dose limiting toxicities (DLTs) in children < 18 years with recurrent or progressive BRAFV600E mutant brain tumors. Results: Nineteen eligible patients were enrolled. Eleven patients had received three or more prior therapies. Data reported are from the start of treatment for the first patient (April 30 2014) through August 31 2019. The RP2D was defined as 550 mg/m2 twice daily after DLT criteria adjustment for rash. Related grade ≥ 3 adverse events included secondary keratoacanthoma (n = 1); rash (n =16); and fever (n = 5). Subjects received a median of 23 cycles (range 3-63). Four patients remain on treatment. Centrally reviewed best radiographic responses included 1 complete response, 5 partial responses, and 13 stable disease. The steady-state area under the curve (AUC0-∞median) was 604 mg*h/L (range 329-1052). Methods: Vemurafenib was given starting at 550 mg/m2, twice daily which corresponds to the adult RP2D. Adverse events were graded using the NIH Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Central imaging review was performed. Pharmacokinetic sampling was performed. Conclusions: Vemurafenib has promising anti-tumor activity in recurrent BRAF V600E-positive brain tumors with manageable toxicity. A phase 2 study is ongoing (NCT01748149).	0
Research on polycystic ovarian syndrome (PCOS) remains intense due to its evolving impact on metabolism, reproduction and cardiovascular function. Changes in metabolic pathways can also significantly impact renal function including the development of Focal Segmental Glomerulosclerosis (FSGS), one of the most highly investigated renal diseases. In FSGS, scarring of the glomerulus vascular tuft damages the kidneys. Onset of FSGS may either be congenital or due to other disorders that affect the metabolism and normal kidney function. Both PCOS and FSGS appear to be associated with Transforming Growth Factor-β (TGF-β) signalling. Over-expression of TGF-β may be due to the activation of the thrombospondin 1 (TSP1) gene, which increases the probability of developing renal disorders. Higher androgen levels in PCOS may also cause podocyte damage thus directly impacting development of FSGS. This article reviews the role of TGF-β's in PCOS and FSGS and explores the inter-relationship between these two disorders.	0
Pathogenic variants in the Glycyl-tRNA synthetase gene cause the allelic disorders Charcot-Marie-Tooth disease type 2D and distal hereditary motor neuropathy type V. We describe clinical features in 8 unrelated patients found to have Glycyl-tRNA synthetase variants by Next Generation Sequencing. In addition to upper limb predominant symptoms, other presentations included failure to thrive, feeding difficulties and lower limb dominant symptoms. Variability in the age at testing ranged from 14 months to 59 years. The youngest being symptomatic from 3 months and ventilator-dependent. Sequence variants were reported as pathogenic, p.(Glu125Lys), p.(His472Arg); likely pathogenic, p.(His216Arg), p.(Gly327Arg), p.(Lys510Gln), p.(Met555Val); and of uncertain significance, p.(Arg27Pro). Our case series describes novel Glycyl-tRNA synthetase variants and demonstrates the clinical utility of Next Generation Sequencing testing for patients with hereditary neuropathy. Identification of novel variants by Next Generation Sequencing illustrates that there exists a wide spectrum of clinical features and supports the newer simplified classification of neuropathies.	0
There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers.	0
The second 360° European Meeting on Growth Hormone Disorders, held in Barcelona, Spain, in June 2017, included a session entitled Pragmatism vs. Curiosity in Genetic Diagnosis of Growth Disorders, which examined current concepts of genetics and growth in the clinical setting, in terms of both growth failure and overgrowth. For patients with short stature, multiple genes have been identified that result in GH deficiency, which may be isolated or associated with additional pituitary hormone deficiencies, or in growth hormone resistance, primary insulin-like growth factor (IGF) acid-labile subunit deficiency, IGF-I deficiency, IGF-II deficiency, IGF-I resistance, and primary PAPP-A2 deficiency. While genetic causes of short stature were previously thought to primarily be associated with the GH-IGF-I axis, it is now established that multiple genetic anomalies not associated with the GH-IGF-I axis can result in short stature. A number of genetic anomalies have also been shown to be associated with overgrowth, some of which involve the GH-IGF-I axis. In patients with overgrowth in combination with an intellectual disability, two predominant gene families, the epigenetic regulator genes, and PI3K/AKT pathway genes, have now been identified. Specific processes should be followed for decisions on which patients require genetic testing and which genes should be examined for anomalies. The decision to carry out genetic testing should be directed by the clinical process, not merely for research purposes. The intention of genetic testing should be to direct the clinical options for management of the growth disorder.	0
Anomalies of the corpus callosum are the most frequent malformations of the central nervous system. The triad of spontaneous periodic hypothermia and hyperhydrosis with the agenesis of corpus callosum is described as Shapiro syndrome. Shapiro syndrome is a very rare condition and it can occur in every age group. The presence of agenesis of corpus callosum is not a strict criteria of the syndrome; the most important presenting symptom is paroxysmal hypothermia. Although the definite cause of recurrent hypothermia is unknown, dysfunction of the hypothalamus is suspected. From therapeutic aspects, only supportive therapy is available. In this report the authors present the first Shapiro syndrome case diagnosed in Hungary. The main symptoms of the 21-year-old male patient were recurrent hyperhydrosis with hypothermia resulting in severe general malaise. The skull magnetic resonance imaging demonstrated agenesis of corpus callosum. The patient was treated with clonidine resulting in significant improvement of symptoms.	0
We describe a case of a 44-year-old male with a history of Wolf-Hirschorn syndrome (WHS) with seizures and mental retardation who was evaluated for what was thought to be a seizure. He was found to be severely bradycardic with a heart rate of 24 bpm. The electrocardiogram revealed third-degree atrioventricular block and he subsequently underwent an uncomplicated single-chamber pacemaker implantation procedure. This is a unique report given its status as the first described case of bradycardic rhythm abnormalities in a patient with WHS.	0
BACKGROUND AND AIMS:Endoplasmic reticulum (ER) stress is associated with liver inflammation and hepatocellular carcinoma (HCC). However, how ER stress links inflammation and HCC remains obscure. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress-inducible secretion protein that inhibits inflammation by interacting with the key subunit of nuclear factor kappa light chain enhancer of activated B cells (NF-κB) p65. We hypothesized that MANF may play a key role in linking ER stress and inflammation in HCC. APPROACH AND RESULTS:Here, we found that MANF mRNA and protein levels were lower in HCC tissues versus adjacent noncancer tissues. Patients with high levels of MANF had better relapse-free survival and overall survival rates than those with low levels. MANF levels were also associated with the status of liver cirrhosis, advanced tumor-node-metastasis (TNM) stage, and tumor size. In vitro experiments revealed that MANF suppressed the migration and invasion of hepatoma cells. Hepatocyte-specific deletion of MANF accelerated N-nitrosodiethylamine (DEN)-induced HCC by up-regulating Snail1+2 levels and promoting epithelial-mesenchymal transition (EMT). MANF appeared in the nuclei and was colocalized with p65 in HCC tissues and in tumor necrosis factor alpha (TNF-α)-treated hepatoma cells. The interaction of p65 and MANF was also confirmed by coimmunoprecipitation experiments. Consistently, knockdown of MANF up-regulated NF-κB downstream target genes TNF-α, interleukin (IL)-6 and IL-1α expression in vitro and in vivo. Finally, small ubiquitin-related modifier 1 (SUMO1) promoted MANF nuclear translocation and enhanced the interaction of MANF and p65. Mutation of p65 motifs for SUMOylation abolished the interaction of p65 and MANF. CONCLUSIONS:MANF plays an important role in linking ER stress and liver inflammation by inhibiting the NF-κB/Snail signal pathway in EMT and HCC progression. Therefore, MANF may be a cancer suppressor and a potential therapeutic target for HCC.	0
BACKGROUND:Neurocutaneous melanosis is a rare disorder in which children with large cutaneous melanotic nevi have associated melanosis in the brain. Although many affected children have structurally normal brains, some have associated developmental disorders or brain anomalies. OBJECTIVES:To determine the range of extent of brain melanosis as assessed by magnetic resonance imaging (MRI) and to investigate the frequency and types of associated brain anomalies. MATERIALS AND METHODS:We retrospectively reviewed brain and spine MRIs of 80 patients with congenital melanocytic nevi (range: 1 day to 22 years of age) affiliated with Nevus Outreach Inc. from 1998 to 2017. Central nervous system (CNS) melanosis was diagnosed when a mass with abnormal parenchymal T1 hyperintensity was seen. The locations of abnormal signal, associated malformations, the presence of contrast enhancement and, in patients with more than one MRI, changes over time were recorded. Associations among findings were analyzed using chi-square test or Fisher exact test. RESULTS:Brain abnormalities were identified in 33 patients. The most common finding was melanosis in the amygdala, which was found in 31 patients (an isolated finding in 14 patients). Nineteen patients had melanosis in the brainstem, cerebellum, cerebral cortex or thalamus. Cerebral and/or spinal leptomeningeal enhancement was uncommon (five patients). Hindbrain melanosis was associated with cerebellar and pontine hypoplasia (P=0.012). Brain melanosis was most easily seen on T1 images prior to myelination; reduced/loss of visibility was noted as the CNS matured. CONCLUSION:Brain melanosis is a common manifestation in children with large cutaneous melanotic nevi, most commonly found in the anterior temporal lobes (amygdala), brainstem, cerebellum and cerebral cortex. Hindbrain melanosis is associated with hypoplasia of the affected structures. Early imaging is optimal to provide the greatest sensitivity for diagnosis and to guide proper management.	0
OBJECTIVE:Cushing's disease arises from functioning adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. These tumors can be very small and evade detection by MRI. Empty sella syndrome is a phenomenon by which an arachnoid outpouching of CSF into the sella leads to compression of the pituitary, likely due to intracranial hypertension (a common issue in Cushing's disease), further leading to difficulty in visualizing the pituitary gland that may contribute to difficulty in finding a tumor on MRI, so-called MRI-negative Cushing's disease. The authors sought to examine the association between empty sella syndrome and MRI-negative Cushing's disease. METHODS:A single-institution database of Cushing's disease cases from 2000 to 2017 was reviewed, and 197 cases were included in the analysis. One hundred eighty patients had a tissue diagnosis of Cushing's disease and 17 had remission with surgery, but no definitive tissue diagnosis was obtained. Macroadenomas (tumors > 1 cm) were excluded. The degree of empty sella syndrome was graded on the degree of CSF visualized in the sella on midline sagittal T1-weighted MRI. RESULTS:Of the 197 cases identified, 40 (20%) presented with MRI-negative disease, and empty sella syndrome was present in 49 cases (25%). MRI-negative disease was found in 18 (37%) of 49 empty sella cases versus 22 (15%) of 148 cases without empty sella syndrome present. Empty sella syndrome was significantly associated with MRI-negative disease (OR 3.32, 95% CI 1.61-6.74, p = 0.0018). Decreased thickness of the pituitary gland was also associated with MRI-negative disease (mean thickness 5.6 vs 6.8 mm, p = 0.0002). CONCLUSIONS:Empty sella syndrome is associated with an increased rate of MRI-negative Cushing's disease. Pituitary compression causing a relative reduction in the volume of the pituitary for imaging is a plausible cause for not detecting the tumor mass with MRI.	0
BACKGROUND:In 1969, Hecht and Beals described for the first time a rare dominant autosomal syndrome characterised by reduced mouth opening, pseudocamptodactyly, short stature, and foot deformities. Recent studies have confirmed that TPS is caused by a mutation of MYH8 that is common to another disease called Carney syndrome. CASE REPORT:The authors describe the long term follow-up of a case presented in 2003, ten years after the first surgical procedure: a 14-year-old girl, affected by this rare syndrome, had underwent an early (at 4 years) surgical treatment of bilateral coronoidotomies to ensure safe airway management to allow subsequent surgical treatment to correct foot deformities. After six years, a complete relapse of the trismus occurred. Three years later, the patient underwent a second surgery of bilateral coronoidotomies to definitely solve trismus. At the 18 months follow-up, the mouth opening was stable.	0
BACKGROUND:Communicating syringomyelia can develop in association with hydrocephalus, with communication between syringomyelia and the fourth ventricle a representative neuroimaging finding. CASE DESCRIPTION:A 51-year-old woman presented with slowly progressive bladder dysfunction and scoliosis. She had a nonfunctioning cerebrospinal fluid shunt that had been placed after birth for neonatal hydrocephalus. Tetraventricular enlargement and a holocord syrinx were noted in neuroimaging findings, while phase contrast magnetic resonance imaging and ventriculography revealed communication between the syrinx and fourth ventricle via a dilated central canal. Placement of a de novo ventriculoperitoneal shunt led to collapse of the syringomyelia, though apparent improvement of clinical symptoms was not obtained. CONCLUSIONS:Communicating syringomyelia can develop as a late complication in patients with shunted hydrocephalus. In the majority of reported cases, shunt revision has been shown to be effective, though some cases require posterior fossa decompression and exploration.	0
The aim of this study was to delineate the spectrum of muscle involvement in patients with a myopathy due to mutations in SEPN1 (SEPN1-RM).Whole-body magnetic resonance imaging (WBMRI) was used in 9 patients using T1-weighted turbo spin-echo (T1-TSE) sequences and short tau inversion recovery (STIR) in 5 patients.Analysis of signal and volume abnormalities by T1-TSE sequences in 109 muscles showed a homogeneous pattern characterized by a recognizable combination of atrophy and signal abnormalities in selected muscles of the neck, trunk, pelvic girdle, and lower limbs. Severe wasting of sternocleidomastoid muscle and atrophy of semimembranosus were detected. Selective paraspinal, gluteus maximus, and thigh muscle involvement was also observed. The lower leg was less constantly affected.WBMRI scoring of altered signal and atrophy in muscle can be represented by heatmaps and is associated with a homogeneous, recognizable pattern in SEPN1-RM, distinct from other genetic muscle diseases.	0
Hemimegalencephaly is known to occur in Proteus syndrome, but has not been reported, to our knowledge, in the other PTEN mutation-related syndrome of Bannayan-Riley-Ruvalcaba. Here, we report a patient with Bannayan-Riley-Ruvalcaba syndrome who also had hemimegalencephaly and in whom the hemimegalencephaly was evident well before presentation of the characteristic manifestations of Bannayan-Riley-Ruvalcaba syndrome. An 11-year-old boy developed drug-resistant focal seizures on the fifth day of life. MRI revealed left hemimegalencephaly. He later showed macrocephaly, developmental delay, athetotic quadriplegic cerebral palsy, and neuromuscular scoliosis. Freckling of the penis, which is characteristic of Bannayan-Riley-Ruvalcaba syndrome, was not present at birth but was observed at 9 years of age. Gene analysis revealed a c.510 T>G PTEN mutation. This patient and his other affected family members, his father and two siblings, were started on the tumour screening procedures recommended for patients with PTEN mutations. This case highlights the importance of early screening for PTEN mutations in cases of hemimegalencephaly not otherwise explained by another disorder, even in the absence of signs of Proteus syndrome or the full manifestations of Bannayan-Riley Ruvalcaba syndrome.	0
Trigeminal trophic syndrome (TTS) is a rare facial/cranial affection that arises in ulcerations, itch and paresthesia. Etiology is debated, however trigeminal nerve damage seems to be frequent in pathogenetic patterns. The disease may affect any region innervated by the trigeminal nerve, especially the maxillary branch. A case of TTS, trigged by allergic reaction to osteosynthetic materials and involving infraorbital nerve, was presented. The feature that makes this case one-off in the literature is the association with osteolytic lesion surrounding infraorbital nerve. Diagnosis and treatment were difficult and multidisciplinary approach was required. Treatments administered were satisfying and signs and symptoms remitted, however patient quitted follow-up. TTS is a rare disease, diagnosis is difficult to be performed and it is often a diagnosis of exclusion. Treatment is challenging and it requires a multidisciplinary approach and a great compliance of patients.	0
Objective: Gastrostomy tubes (GTs) are one of the most common procedures in neonatal surgery, and their malfunction represents one of the most common complaints in the emergency room and clinic. Complications can occur in up to one-third of patients and include pain, peristomal leak, and infection, but can range in severity. We hypothesize that a preventative strategy employing a GT fixation dressing at the time of operation minimizes these postoperative complications in neonates. Approach: All patients less than 1 year of age who underwent laparoscopic GT placement by a single surgeon in the study period were reviewed. All tubes were secured in place on the external abdominal wall for 2 weeks postoperatively. Demographics and outcomes were evaluated. Results: Fifty-three percent of our cohort were male, and 47% were premature. The most common indication for placement was failure to thrive (59%), and common comorbid conditions were characterized as neurologic (71%), and cardiac (59%). The dressing did not prevent hypertrophic granulation tissue formation, but no patient experienced surgical site infection or device-related pressure injury at 30 and 120 days postoperatively. No patient required reoperation or readmission. Innovation: This simple, one-time, cost-effective fixation dressing has the potential to reduce some of the most common postoperative surgical issues in neonatal patients and can be applied in almost any health care setting. Conclusions: A dressing aimed at tube fixation and immobilization for the first two postoperative weeks averts some of the major complications of GT placement over a standard follow-up period as compared with the literature.	0
PURPOSE:To review existing literature about fertility and sexuality of boys born with complex congenital genitourinary anomalies. METHODS:A Pubmed review was performed in December 2018 to identify the most relevant original manuscripts regarding male complex congenital conditions affecting the urogenital system in male patients including spina bifida (SB), bladder exstrophy-epispadias complex (BEEC) and hypospadias. A comprehensive review was drafted exploring sexual dysfunction from a medical, psychosexual, surgical and reproductive point of view during transition from childhood (or adolescence) to adulthood. RESULTS:About 75% of men with SB have erectile dysfunction (ED) (Gamé et al. in Urology 67(3):566-570, 2006; Diamond et al. in 58(4):434-435, 1986). Most SB patients have impaired sexual development mainly due to diminished self-esteem, dependence on caregivers and lack of privacy (Blum et al. in Pediatrics 88(2):280-285, 1991). Men with BEEC have fewer intimate relationships than women because of the greater difficulties with issues regarding their genitalia and sexual activities (Deans et al. in Am J Obstet Gynecol 206(6):496.e1-496.e6, 2012). However, a good quality of life is achievable with the effective use of coping strategies (Deng et al. in Transl Androl Urol 7:941, 2018; Rikken et al. in BMC Womens Health 18(1):163, 2018; Friedler et al. in Reprod Biomed Online 32(1):54-61, 2016). Chordee occurs in 25% of all hypospadias patients. More severe hypospadias is related to a greater risk for complications. The long-term sexual quality of life (QoL) in men who underwent hypospadias surgery is influenced by a lot of factors. Therefore, an interactive and dynamic biopsychosocial model of sexual QoL was proposed. CONCLUSIONS:The care of patients with congenital urologic conditions becomes a challenge especially in the period of 'transition'. The goal of follow-up is a holistic management viewed from a medical, psychosexual, surgical end reproductive point. All patients should be asked for specific urinary, fecal or sexual concerns.	0
Alsace is a region in eastern France with a population of ∼2 million. All residents have high access to health care and an accredited referral center for SSc. Seeking care outside of this region is difficult because of the peculiar geography. The aim of this study was to assess the prevalence and spatial variation of systemic sclerosis (SSc) in eastern France.Data for SSc patients were obtained from 3 sources (all general practitioners and community specialists, capillaroscopy centers, and all public and private hospital records) and were used to estimate the prevalence of SSc. Surviving patients who resided in Alsace on January 1, 2008 and fulfilled the American College of Rheumatology and/or the LeRoy and Medsger criteria were included in this study. The clinical characteristics of the patients were also assessed. Potentially incomplete case ascertainment was corrected by capture-recapture analyses. Geographic disparities were assessed by spatial cluster analysis and by comparing our results with those for other geographic areas in the world for which data derived using similar methodology were available.The review of 499 potential cases identified a total of 244 SSc patients. A trend toward a west-to-east gradient was observed but did not reach statistical significance. According to log-linear modeling, an estimated 83.87 additional cases were missed. Thus, the SSc prevalence was 228.42 cases per million adult inhabitants of Alsace (95% confidence interval 203.70-253.14); this prevalence was significantly higher than that in 2 other regions of France and comparable with the reported prevalence in Detroit, Michigan.The stringent methodology used in the current study is very likely to provide an accurate estimation of the prevalence of SSc. Design similarity with 3 other surveys extends the scope of the results by identifying geographic disparities that were previously indistinguishable due to methodologic differences.	1
Wilson's disease is characterized by hepatic and extrapyramidal movement disorders (EPS) with variable manifestation primarily between age 5 and 45. This variability often makes an early diagnosis difficult. A classification defines different clinical variants of Wilson's disease, which enables classifying the current clinical findings and making an early tentative diagnosis. Until the unequivocal proof or an autosomal recessive disorder of the hepatic copper transporter ATP7B has been ruled out, differential diagnoses have to be examined. Laboratory-chemical parameters of copper metabolism can both be deviations from the norm not related to the disease as well as other copper metabolism disorders besides Wilson's disease. In addition to known diseases such as Menkes disease, occipital horn syndrome (OHS), Indian childhood cirrhosis (ICC) and ceruloplasmin deficiency, recently discovered disorders are taken into account. These include MEDNIK syndrome, Huppke-Brendel syndrome and CCS chaperone deficiency. Another main focus is on differential diagnoses of childhood icterus correlated with age and anaemia as well as disorders of the extrapyramidal motor system. The Kayser-Fleischer ring (KFR) is qualified as classical ophthalmologic manifestation. The recently described manganese storage disease presents another rare metabolic disorder with symptoms similar to Wilson's disease. As this overview shows, Wilson's disease fits into a broad spectrum of internal and neurological disease patterns with icterus, anaemia and EPS.	0
We present a 44-year-old female with an initial presentation with distal renal tubular acidosis (RTA) after she presented with hypokalaemia and normal anion gap acidosis. Three years following the diagnosis, she presented with progressive renal impairment. In the absence of any clinical, biochemical and radiological clues, she underwent a renal biopsy which showed severe tubulitis secondary to lymphocytic infiltration. Serological investigations subsequently revealed positive anti-nuclear, anti-Sjögren's syndrome related antigen A (SS-A), and anti-Sjögren's syndrome related antigen B (SS-B) antibodies, supporting the diagnosis of Sjögren's syndrome. This case is unique in that distal RTA was the presenting clinical manifestation of Sjögren's syndrome. We hope that a consideration for Sjögren's syndrome is made in patients with seemingly idiopathic RTA.	0
We present a case report that entails prenatal ultrasonography, postnatal characteristics, and molecular genetic analysis of a newborn who presented with thanatophoric dysplasia type I (TDI) with a mutation in the fibroblast growth factor receptor 3 gene (FGFR3). A malformed newborn with tachypnea, delivered by caesarean at the gestational age of 39 weeks, was the first child of nonconsanguineous parents by a spontaneous pregnancy. Features in prenatal ultrasonography and postnatal radiography were consistent with the diagnosis of TDI, presenting with short body length (38 cm, <3rd percentile), redundant skin folds, a narrow thorax with a bust of 29.5 cm (3-5th percentile), and macrocephaly with a head circumference of 36 cm (>97th percentile). The proposita had postnatal dyspnea and unfortunately died of respiratory failure at the age of 13 days. Molecular genetic analysis revealed a mutation of c.2419 T > C (p. Ter807Arg) (X807R) in FGFR3. Live-born infants with TDI are exceedingly rare, and we hereby report a newborn with a c.2419 T > C mutation in FGFR3, emphasizing phenotype with clinical characteristics and ultrasonographic and X-ray findings, to raise awareness about the heterogeneous patterns of TD.	0
Myosin storage myopathy (MSM) is a congenital skeletal muscle disorder caused by missense mutations in the β-cardiac/slow skeletal muscle myosin heavy chain rod. It is characterized by subsarcolemmal accumulations of myosin that have a hyaline appearance. MSM mutations map near or within the assembly competence domain known to be crucial for thick filament formation. Drosophila MSM models were generated for comprehensive physiological, structural, and biochemical assessment of the mutations' consequences on muscle and myosin structure and function. L1793P, R1845W, and E1883K MSM mutant myosins were expressed in an indirect flight (IFM) and jump muscle myosin null background to study the effects of these variants without confounding influences from wild-type myosin. Mutant animals displayed highly compromised jump and flight ability, disrupted muscle proteostasis, and severely perturbed IFM structure. Electron microscopy revealed myofibrillar disarray and degeneration with hyaline-like inclusions. In vitro assembly assays demonstrated a decreased ability of mutant myosin to polymerize, with L1793P filaments exhibiting shorter lengths. In addition, limited proteolysis experiments showed a reduced stability of L1793P and E1883K filaments. We conclude that the disrupted hydropathy or charge of residues in the heptad repeat of the mutant myosin rods likely alters interactions that stabilize coiled-coil dimers and thick filaments, causing disruption in ordered myofibrillogenesis and/or myofibrillar integrity, and the consequent myosin aggregation. Our Drosophila models are the first to recapitulate the human MSM phenotype with ultrastructural inclusions, suggesting that the diminished ability of the mutant myosin to form stable thick filaments contributes to the dystrophic phenotype observed in afflicted subjects.	0
BACKGROUND:Maternally inherited complex I deficiencies due to mutations in MT-ND genes represent a heterogeneous group of multisystem mitochondrial disorders (MD) with a unfavourable prognosis. The aim of the study was to characterize the impact of the mutations in MT-ND genes, including the novel m.13091 T > C variant, on the course of the disease, and to analyse the activities of respiratory chain complexes, the amount of protein subunits, and the mitochondrial energy-generating system (MEGS) in available muscle biopsies and cultivated fibroblasts. METHODS:The respiratory chain complex activities were measured by spectrophotometry, MEGS were analysed using radiolabelled substrates, and protein amount by SDS-PAGE or BN-PAGE in muscle or fibroblasts. RESULTS:In our cohort of 106 unrelated families carrying different mtDNA mutations, we found heteroplasmic mutations in the genes MT-ND1, MT-ND3, and MT-ND5, including the novel variant m.13091 T > C, in 13 patients with MD from 12 families. First symptoms developed between early childhood and adolescence and progressed to multisystem disease with a phenotype of Leigh or MELAS syndromes. MRI revealed bilateral symmetrical involvement of deep grey matter typical of Leigh syndrome in 6 children, cortical/white matter stroke-like lesions suggesting MELAS syndrome in 3 patients, and a combination of cortico-subcortical lesions and grey matter involvement in 4 patients. MEGS indicated mitochondrial disturbances in all available muscle samples, as well as a significantly decreased oxidation of [1-14C] pyruvate in fibroblasts. Spectrophotometric analyses revealed a low activity of complex I and/or complex I + III in all muscle samples except one, but the activities in fibroblasts were mostly normal. No correlation was found between complex I activities and mtDNA mutation load, but higher levels of heteroplasmy were generally found in more severely affected patients. CONCLUSIONS:Maternally inherited complex I deficiencies were found in 11% of families with mitochondrial diseases in our region. Six patients manifested with Leigh, three with MELAS. The remaining four patients presented with an overlap between these two syndromes. MEGS, especially the oxidation of [1-14C] pyruvate in fibroblasts might serve as a sensitive indicator of functional impairment due to MT-ND mutations. Early onset of the disease and higher level of mtDNA heteroplasmy were associated with a worse prognosis.	0
Hereditary hearing loss is one of the most common sensory disabilities worldwide. Mutation of POU domain class 4 transcription factor 3 (POU4F3) is considered the pathogenic cause of autosomal dominant nonsyndromic hearing loss (ADNSHL), designated as autosomal dominant nonsyndromic deafness 15. In this study, four novel variants in POU4F3, c.696G>T (p.Glu232Asp), c.325C>T (p.His109Tyr), c.635T>C (p.Leu212Pro), and c.183delG (p.Ala62Argfs∗22), were identified in four different Chinese families with ADNSHL by targeted next-generation sequencing and Sanger sequencing. Based on the American College of Medical Genetics and Genomics guidelines, c.183delG (p.Ala62Argfs∗22) is classified as a pathogenic variant, c.696G>T (p.Glu232Asp) and c.635T>C (p.Leu212Pro) are classified as likely pathogenic variants, and c.325C>T (p.His109Tyr) is classified as a variant of uncertain significance. Based on previous reports and the results of this study, we speculated that POU4F3 pathogenic variants are significant contributors to ADNSHL in the East Asian population. Therefore, screening of POU4F3 should be a routine examination for the diagnosis of hereditary hearing loss.	0
Papillon-Lefèvre syndrome (PLS) is a rare genetic disease that causes dermatological and dental symptoms that usually start from early age. Dermatological findings include hyperkeratoderma over the palms and soles that are usually thought of as persistent psoriasis at first. Dental findings include severe caries in the teeth that lead to premature dental loss. We present a case of an otherwise healthy seven-year-old child with classical presentation of PLS with both dermatological and dental findings. He first presented to the dermatology clinic when he was five years old brought by his parents complaining of dry scaly patches on the palm of the hands and soles of the feet. On further history it was found that he is a child of first-degree consanguinity, and he had these patches since he was four months old. On examination, he was found to have an erythematous hyperkeratotic skin plaques and papules with scales over the planter and palmar aspect of both hands with similar lesions observed on both feet, legs, scalp, and ears with nail pitting. The diagnosis of PLS was confirmed by whole-exome sequencing (WES) and the patient was started on acitretin capsules and started to show improvement.	0
Coffin-Lowry syndrome is expressed as different phenotypes in males and females. In males, it is characterized by facial abnormalities, marked developmental disability, and skeletal changes. Approximately 80% of cases are associated with kyphoscoliosis, which can be quite severe, as seen in our patient, causing paraplegia and restrictive lung disease. In this article, we present the third oldest documented male case of Coffin-Lowry syndrome with severe kyphoscoliosis, paraplegia, and restrictive lung disease.	0
Pontocerebellar hypoplasia (PCH) is a diverse group of autosomal recessive genetic conditions presenting with hypoplastic changes in the brainstem, cerebellum, and spinal cord. It clinically manifests with neurological symptoms, respiratory failure, and often in a combination with other malformations of the internal organs and musculoskeletal system. In this report, we present an autopsy case report of a two-month-old female patient with blood-relative parents. The patient presented clinically with neonatal-onset respiratory failure, mild neurological symptoms, facial dysmorphism, and developmental delay. On autopsy, the cerebellum and brainstem were severely hypoplastic, and the diagnosis of PCH was established grossly. The central nervous system (CNS) revealed specific hypoplastic changes in the structures, with a decreased neuronal count, stratification disturbances of the cortex of the cerebellum, and cellular misarrangement. The morphological findings in the CNS and their associated parenchymal organ changes, even in the absence of a genetic test, were specific enough to identify PCH type 1B as the main condition.	0
We present the first Romanian study on the epidemiological characteristics of MDS, based on the data existing in Fundeni Clinical Institute, Hematological Department, Bucharest. The files at diagnosis of the adult patients with primary MDS admitted during the period 1982-2005, recorded in the registration forms provided by the MDS Foundation (USA), represented the primary database. This study indicates an increase in the number of new MDS cases over the period of time investigated. Also, a 10 years lower median age of the patients, a noticeable proportion of young patients and a low proportion of patients >or=81 years have been found, which situates our findings in the middle between the Eastern and Western epidemiological reported data on MDS.	1
Paediatric splenic abscesses are rare, but can be fatal. An 8-year-old boy developed recurrent fever and abdominal pain 5 months after undergoing an appendectomy. A CT scan showed splenic and rectovesical pouch abscesses. The patient was successfully treated with antibiotics, and laparoscopic drainage and debridement of pus from the rectovesical pouch abscess. Eggerthella lenta was cultured from the latter lesion. Early diagnosis and treatment resulted in the satisfactory resolution of the infection.	0
BACKGROUND:The Neacomys genus is predominantly found in the Amazon region, and belongs to the most diverse tribe of the Sigmodontinae subfamily (Rodentia, Cricetidae, Oryzomyini). The systematics of this genus and questions about its diversity and range have been investigated by morphological, molecular (Cytb and COI sequences) and karyotype analysis (classic cytogenetics and chromosome painting), which have revealed candidate species and new distribution areas. Here we analyzed four species of Neacomys by chromosome painting with Hylaeamys megacephalus (HME) whole-chromosome probes, and compared the results with two previously studied Neacomys species and with other taxa from Oryzomyini and Akodontini tribes that have been hybridized with HME probes. Maximum Parsimony (MP) analyses were performed with the PAUP and T.N.T. software packages, using a non-additive (unordered) multi-state character matrix, based on chromosomal morphology, number and syntenic blocks. We also compared the chromosomal phylogeny obtained in this study with molecular topologies (Cytb and COI) that included eastern Amazonian species of Neacomys, to define the phylogenetic relationships of these taxa. RESULTS:The comparative chromosome painting analysis of the seven karyotypes of the six species of Neacomys shows that their diversity is due to 17 fusion/fission events and one translocation, pericentric inversions in four syntenic blocks, and constitutive heterochromatin (CH) amplification/deletion of six syntenic autosomal blocks plus the X chromosome. The chromosomal phylogeny is consistent with the molecular relationships of species of Neacomys. We describe new karyotypes and expand the distribution area for species from eastern Amazonia and detect complex rearrangements by chromosome painting among the karyotypes. CONCLUSIONS:Our phylogeny reflects the molecular relationships of the Akodontini and Oryzomyini taxa and supports the monophyly of Neacomys. This work presents new insights about the chromosomal evolution of this group, and we conclude that the karyotypic divergence is in accord with phylogenetic relationships.	0
Aim:To demonstrate the demographic data, subgroup distributions, responses to treatment and outcomes of long-term follow-up in patients who were followed up and treated in our clinics with a diagnosis of juvenile idiopathic arthritis, and to compare these data with national and international data. Material and Methods:The files of 116 patients who had been diagnosed as having juvenile idiopathic arthritis, were initiated on treatment and presented for regular follow-up visits between January 2012 and January 2018, were examined. Their demographic findings, treatments, active/inactive disease states (on-medication and off-medication) and treatment response states were evaluated. Results:According to the International League of Associations for Rheumatology criteria, the subtypes were specified as enthesitis-related arthritis (n=38), oligoarticular (n=37), rheumatoid factor (-) polyarticular (n=17), systemic (n=15), rheumatoid factor (+) polyarticular (n=5), and psoriatic juvenile idiopathic arthritis (n=4). In total, the female/male ratio was found to be 1.5. The mean delay time between the first complaint and the diagnosis was found to be 5.7±5.2 months. The patients with systemic type were diagnosed at the earliest, while the patients with polyarticular and enthesitis-related subtypes were diagnosed at the latest. Thirty-two percent of the patients were treated with methotrexate alone, and 38% were given additional biologic drugs. In both treatment groups, the time to achieve inactive disease was the shortest in the oligoarticular group and the longest in the enthesitis-related arthritis group. In the study period, 38 patients were in remission off-medication (the highest rate (53.3%) was observed in the systemic group) and 71 patients were in remission on-medication (the highest rate (70.2%) was observed in the oligoarticular group). Remission was obtained in 94% of the patients. Conclusion:Enthesitis which is the remarkable finding of enthesitis-related arthritis, should not be overlooked in routine physical examination. Awareness of enthesitis can contribute to the prevention of diagnostic delay in children with enthesitis-related arthritis.	0
The ridged skin of the palms and soles has several unique features: (i) presence of dermatoglyphics created by alternating ridges and grooves forming a unique pattern, (ii) presence of the highest density of eccrine sweat glands and absence of pilosebaceous units, and (iii) differential expression of keratins compared to the glabrous skin. These features explain the preferential localization of palmoplantar keratoderma (PPK) and several of its characteristic clinical features. PPK develops as a compensatory hyperproliferation of the epidermis and excessive production of stratum corneum in response to altered cornification of the palmoplantar skin due to mutations in the genes encoding several of the proteins involved in it. PPK can manifest as diffuse, focal, striate, or punctate forms per se or as a feature of several dermatological or systemic diseases. There is a wide genetic and phenotypic heterogeneity in hereditary PPK, due to which reaching an accurate diagnosis only on the basis of clinical features may be sometimes challenging for the clinicians in the absence of molecular studies. Nevertheless, recognizing the clinical patterns of keratoderma, extent of involvement, degree of mutilation, and associated appendageal and systemic involvement may help in delineating different forms. Molecular studies, despite high cost, are imperative for accurate classification, recognizing clinical patterns in resource poor settings is important for appropriate diagnosis, genetic counseling, and management. This review intends to develop a practical approach for clinical diagnosis of different types of hereditary PPK with reasonable accuracy.	0
BACKGROUND:Neural tube defects (NTDs) are failure of neural tube closure, which includes multiple central nervous system phenotypes. More than 300 mouse mutant strains exhibits NTDs phenotypes and give us some clues to establish association between biological functions and subphenotypes. However, the knowledge about association in human remains still very poor. METHODS:High throughput targeted genome DNA sequencing were performed on 280 neural tube closure-related genes in 355 NTDs cases and 225 ethnicity matched controls, RESULTS: We explored that potential damaging rare variants in genes functioning in chromatin modification, apoptosis, retinoid metabolism and lipid metabolism are associated with human NTDs. Importantly, our data indicate that except for planar cell polarity pathway, craniorachischisis is also genetically related with chromatin modification and retinoid metabolism. Furthermore, single phenotype in cranial or spinal regions displays significant association with specific biological function, such as anencephaly is associated with potentially damaging rare variants in genes functioning in chromatin modification, encephalocele is associated with apoptosis, retinoid metabolism and one carbon metabolism, spina bifida aperta and spina bifida cystica are associated with apoptosis; lumbar sacral spina bifida aperta and spina bifida occulta are associated with lipid metabolism. By contrast, complex phenotypes in both cranial and spinal regions display association with various biological functions given the different phenotypes. CONCLUSIONS:Our study links genetic variant to subphenotypes of human NTDs and provides a preliminary but direct clue to investigate pathogenic mechanism for human NTDs.	0
β4GalT7 is a transmembrane Golgi enzyme, encoded by B4GALT7, that plays a pivotal role in the proteoglycan linker region formation during proteoglycan biosynthesis. Defects in this enzyme give rise to a rare autosomal recessive form of Ehlers-Danlos syndrome (EDS), currently known as 'spondylodysplastic EDS (spEDS-B4GALT7)'. This EDS subtype is mainly characterized by short stature, hypotonia and skeletal abnormalities, thereby illustrating its pleiotropic importance during human development. Insights into the pathogenic mechanisms underlying this disabling disease are very limited, in part due to the lack of a relevant in vivo model. As the majority of mutations identified in patients with spEDS-B4GALT7 are hypomorphic, we generated zebrafish models with partial loss of B4galt7 function, including different knockdown (morphant) and mosaic knockout (crispant) b4galt7 zebrafish models and studied the morphologic, functional and molecular aspects in embryonic and larval stages. Morphant and crispant zebrafish show highly similar morphological abnormalities in early development including a small, round head, bowed pectoral fins, short body-axis and mild developmental delay. Several craniofacial cartilage and bone structures are absent or strongly misshapen. In addition, the total amount of sulfated glycosaminoglycans is significantly diminished and particularly heparan and chondroitin sulfate proteoglycan levels are greatly reduced. We also show impaired cartilage patterning and loss of chondrocyte organization in a cartilage-specific Tg(Col2a1aBAC:mcherry) zebrafish reporter line. The occurrence of the same abnormalities in the different models confirms these are specifically caused by B4galt7 deficiency. A disturbed actin pattern, along with a lack of muscle tone, was only noted in morphants in which translation of b4galt7 was blocked. In conclusion, we generated the first viable animal models for spEDS-B4GALT7, and show that in early development the human spEDS-B4GALT7 phenotype is faithfully mimicked in these zebrafish models. Our findings underscore a key role for β4GalT7 in early development of cartilage, bone and muscle. These models will lead to a better understanding of spEDS-B4GALT7 and can be used in future efforts focusing on therapeutic applications.	0
BACKGROUND:Polyomavirus-associated nephropathy (PVAN) remains a relevant complication following kidney transplantation with allograft loss rates of up to 50%. Reduction in overall immunosuppression is a cornerstone of therapy, whereas no specific antiviral regimen has shown conclusive benefit to date. The present case series demonstrates the efficacy of a dual therapeutic approach with low-dose cidofovir and conversion to mTOR-based immunosuppression in PVAN. METHODS:Patients with biopsy-proven PVAN having received low-dose cidofovir (0.25 mg/kg) according to the Tübingen Cidofovir Protocol and been converted to mTOR-based immunosuppression were analyzed retrospectively. RESULTS:Twenty-three patients with a median follow-up of 2.24 [IQR 1.55-5.01] years were included in the analysis. Median time to PVAN diagnosis was 268 [IQR 153-869] days after transplantation. Polyomavirus clearance from plasma was achieved in 78% of patients after a median of 118 [IQR 76-293] days. Of the 23 patients, nine patients (39%) lost their allograft function during follow-up, but only three of these (13%) due to PVAN. Fourteen patients (61%) stabilized or improved allograft function. The cidofovir protocol allowed for specific antiviral therapy without adverse nephrotoxicity, even in patients with low allograft function. CONCLUSIONS:Low-dose cidofovir and conversion to mTOR-based immunosuppression allow for effective virus clearance and preservation of allograft function in a high proportion of patients with PVAN and progressive allograft dysfunction and may prolong allograft survival in these patients.	0
BACKGROUND:Pulmonary hypoplasia (PH) and congenital lobar emphysema (CLE) are very rare congenital pulmonary anomalies in veterinary medicine. PH refers to the incomplete pulmonary development due to embryologic imbalance of bronchial development between the lung buds, while CLE is defined as alveolar hyperinflation due to bronchial collapse during expiration caused by bronchial cartilage dysplasia, external bronchial compression, and idiopathic etiology. CLE may develop into pulmonary blebs or bullae that may rupture and induce a spontaneous pneumothorax. There are no reports on concurrent PH and CLE in animals. CASE PRESENTATION:A 7-month-old castrated male Italian Greyhound weighing 5.5 kg presented with vomiting and acute onset of severe dyspnea without any previous history of disease. After emergency treatment including oxygen supplementation and thoracocentesis, plain radiology and computed tomography scanning were performed and lobar emphysema with multiple bullae in the left cranial lung lobe associated with tension pneumothorax was identified. Since the pneumothorax was not resolved despite continuous suction of intrathoracic air for 3 days, a complete lobectomy of the left cranial lung lobe was performed. The excised lobe was not grossly divided into cranial and caudal parts, but a tissue mass less than 1 cm in size was present at the hilum and cranial to the excised lobe. Postoperatively, the dog recovered rapidly without air retention in the thoracic cavity. Histopathologically, the mass was identified as a hypoplastic lung tissue with collapsed alveoli, bronchial dysplasia, and pulmonary arterial hypertrophy. Additionally, the excised lung lobe presented CLE with marked ectasia of alveoli, various blebs and bullae, and general bronchial cartilage dysplasia. According to gross and histopathologic findings, the dog was diagnosed with concurrent PH and CLE in the left cranial lung lobe. During 16 months of follow-up, the dog was well and without any respiratory problems. CONCLUSIONS:This case report confirmed the clinical and histologic features of two different types of rare congenital pulmonary anomalies, PH and CLE, which occurred concurrently in a single lung lobe of a young dog. The condition was successfully managed with lobectomy.	0
Cataracts are the principal cause of treatable blindness worldwide. Inherited congenital cataract (CC) shows all types of inheritance patterns in a syndromic and nonsyndromic form. There are more than 100 genes associated with cataract with a predominance of autosomal dominant inheritance. A cataract is defined as an opacity of the lens producing a variation of the refractive index of the lens. This variation derives from modifications in the lens structure resulting in light scattering, frequently a consequence of a significant concentration of high-molecular-weight protein aggregates. The aim of this review is to introduce a guide to identify the gene involved in inherited CC. Due to the manifold clinical and genetic heterogeneity, we discarded the cataract phenotype as a cardinal sign; a 4-group classification with the genes implicated in inherited CC is proposed. We consider that this classification will assist in identifying the probable gene involved in inherited CC.	0
Piezo type mechanosensitive ion channel component 2 (PIEZO2) is a mechanically activated ion channel. Mutations in PIEZO2 may cause distal arthrogryposis 3 (DA3)/Gordon syndrome (GS), DA5, Marden-Walker syndrome (MWS) and associated diseases. To date, no systematic study has analyzed and compared the influence of different gene mutations of PIEZO2 on its transcription, as well as translation and protein function. Therefore, the objective of the present study was to systematically assess the effect of different pathological mutations of PIEZO2 on transcription, translation, as well as protein structure and function that contribute to GS/DA3, DA5, MWS and associated diseases based on a bioinformatics analysis using the Pubmed, ClinVar, RaptorX and Phyre2 online databases. The results indicated the presence of 27 pathological mutations in PIEZO2, including dominant and recessive mutations. Dominant mutations were mainly located in the C-terminal region, whereas recessive mutations were mainly localized in the N-terminal region, and most reported mutation sites exhibited high evolutionary conservation among different species. Loss-of-function mutations result in nonsense-mediated transcript decay or premature termination codons, consequently leading to a lack of PIEZO2 protein, whereas gain-of-function mutations may lead to increased PIEZO2-associated channel activity. The bioinformatics analysis results also indicated that the p.Ala1486Pro, p.Thr2221Ile and p.Glu2727del mutations modify the secondary structure of the PIEZO2 protein, while p.Thr2221Ile, p.Arg2718Leu and p.Arg2718Pro mutations reduce the solvent accessibility of PIEZO2 protein. Furthermore, the p.Ala1486Pro, p.Thr2221Ile, p.Ser2223Leu, p.Thr2356Met, p.Arg2686His, p.Arg2718Leu, p.Arg2718Pro and p.Glu2727del mutations affect the transmembrane region. These changes of PIEZO2 may contribute to a gain-of-function of PIEZO2. Variable clinical phenotypes were present between and among the gain- and loss-of-function mutations linked with PIEZO2-associated disease, which implied that different mutations in PIEZO2 have different pathophysiological effects. Of course, further functional studies to explore the precise structure and function of PIEZO2 are necessary and may offer useful clues for the prevention and treatment of associated diseases.	0
Lichen planus (LP) is a violent, paranormal inflammatory disease that can affect the skin or any lining of the mucous membrane. LPs are a branch of immune-mediated inflammatory disease (IMID) that collaborates with the function and structure of the immune system that are precipitated through various etiological infectious agents. Oral lichen planus (OLP) is one of the most common kinds of IMID. These traumas might limit the normal life of patients and, in some cases, can be treated spontaneously. In patients who are affected by OLP, the dental clinicians must be capable of the proper diagnosis of the disorder. Dental implants are progressively applied for the treatment of partial or complete edentulism. Implant rehabilitation in OLP patients is one of the main challenges for patients and dental clinicians. There is not enough knowledge about this condition, and also medical documents are limited. In this study, by conducting a comprehensive review of literature, we tried to collect related data around the safety and success rate of implant rehabilitation in patients who suffer from OLP disorder. There proved to be no relation between implant survival rate and OLP diseases, but it is proven that some factors such as bone quality and fracture resistance, parafunctional habits, and resection of the marginal mandible could powerfully affect it. For evaluation of the advantages and disadvantages of applying implants in patients with OLP disorders, implementation of controlled studies is required.	0
INTRODUCTION:Persistent genital arousal disorder (PGAD) is a condition that is still poorly understood. Etiologies reported for PGAD are vascular, neurological, pharmacological, and psychological. Determining the neurophysiological etiology of PGAD began with developing an understanding of the underlying biomechanics of the pudendal nerve and the female sexual response. AIM:To summarize the anatomy, physiology, etiologies, diagnostics, and treatments of the pertinent peripheral nerves involved in the pathology of PGAD. METHODS:We performed a PubMed, Cochrane, Embase, Web of Science, and Google Scholar search for English-language articles in peer-reviewed journals with no predefined time period for inclusion. Terms included "humans"[All Fields] AND "persistent"[All Fields] AND/OR ("genitalia"[All Fields] OR "genital"[All Fields]) AND/OR "arousal"[All Fields] AND/OR ("disease"[All Fields] OR "disorder"[All Fields]) AND/OR "nerve"[All Fields]. The main outcomes of the papers were reviewed. MAIN OUTCOME MEASURE:The main outcome measures were the anatomy and physiology, etiologies, history and physical examination, diagnostic imaging, and current evidence for the treatment of PGAD related to the peripheral nervous system. RESULTS:Most of the literature for PGAD originates from case studies. The diagnosis of PGAD itself is still a debated topic of discussion. More recent data published indicate that this disease affects males, as well. CONCLUSION:Nerve entrapment may be a source of continuous arousal. Associated PGAD symptoms would depend on the segment of the nerve involved. Unwelcomed or unwanted arousal has been observed as the most common detrimental symptom. Pelvic 3-tesla magnetic resonance imaging is recommended in all patients with suspected nerve entrapment. Lumbosacral 3-tesla magnetic resonance imaging is recommended if a Tarlov cyst or a herniated intervertebral disc is suspected. If the peripheral nerve is the source of the pathology, surgical intervention may be curative. A multidisciplinary team approach consisting of a medical provider, pelvic floor physical therapist, and sex therapist has demonstrated benefits. There are currently no Food and Drug Administration-approved evidenced-based treatments for PGAD. Klifto KM, Dellon AL. Persistent Genital Arousal Disorder: Review of Pertinent Peripheral Nerves. Sex Med Rev 2020;8:265-273.	0
BACKGROUND:Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous group of hereditary diabetes, generally caused by one abnormal gene. MODY5 is caused by mutations of the hepatocyte nuclear factor 1 homeobox β gene (HNF1β), always as a part of Chr17q12 deletion, whereas heterozygous mutation in B lymphocyte kinase (BLK) gene is responsible for MODY11. CASE PRESENTATION:We report a patient who developed diabetes with a 1.58-Mb Chr17q12 microdeletion and BLK gene c.211G > A mutation using the cytoscan high-density array and whole-exome sequencing analysis. The patient received the surgery at five days after birth for the duodenal atresia and had normal growth postoperatively. Mild elevated liver enzymes were found along with the normal renal function. Quantitative analysis of β-cell function markers, including fasting insulin (< 0.2 mIU/L), fasting C-peptide (0.02 μg/L), postprandial-2 h insulin (< 0.2 mIU/L), and postprandial-2 h C-peptide (0.03 μg/L) suggested a severe loss of insulin secreting capacity. Meanwhile, islet autoantibodies (GADA, IA-2, ICA, and IAA) in the patient's blood appeared negative. Neither dysplasia in other tissues nor abnormality in development and behavior was found. CONCLUSION:To date, gastrointestinal malformations were extremely rarely reported in patients with MODY. Our clinical report further expands the clinical presentation and variability of MODY5.	0
[Purpose] This study examined characteristics of dynamic standing balance, with an without an insole, in patients with spastic diplegia cerebral palsy (CP). [Participants and Methods] This cross-sectional study used a crossover design. Eleven patients with spastic diplegia CP and gross motor levels between I and III with spastic diplegia CP (according to the Gross Motor Function Classification System expanded and revised version) were randomly allocated to either the barefoot or insole groups. The Index of postural stability (IPS) was evaluated while each patient was barefoot and while wearing insoles. The Pediatric Evaluation of Disability Inventory (PEDI) was used to measure functional self-care and mobility domains. [Results] While wearing the insoles, the center movement distance between right and left positions was significantly higher. While barefoot, IPS and area of postural sway correlated with the PEDI subscales for mobility and self-care. [Conclusion] Insoles promote standing balance and dynamic balance to move the center of pressure within the base of support. Such improvements may enhance activities of daily living in patients with spastic diplegia CP.	0
In X-linked myopathy with excessive autophagy (XMEA) progressive sarcoplasmic accumulation of autolysosomes filled with undegraded debris leads to atrophy and weakness of skeletal muscles. XMEA is caused by compromised acidification of lysosomes resulting from hypofunction of the proton pump vacuolar ATPase (V-ATPase), due to hypomorphic mutations in VMA21, whose protein product assembles V-ATPase. To what extent the cardiac muscle is affected is unknown. Therefore we performed a comprehensive cardiac evaluation in four male XMEA patients, and also examined pathology of one deceased patient's cardiac and skeletal muscle. None of the symptomatic men (aged 25-48 years) had history or symptoms of cardiomyopathy. Resting electrocardiograms and echocardiographies were normal. MRI showed normal left ventricle ejection fraction and myocardial mass. Myocardial late-gadolinium enhancement was not detected. The deceased patient's skeletal but not cardiac muscle showed characteristic accumulation of autophagic vacuoles. In conclusion, in classic XMEA the myocardium is structurally, electrically and clinically spared.	0
OBJECTIVE:This study assessed the percentage and type of congenital anomalies diagnosed at first-trimester ultrasound (US) scan in a primary care setting without following a standardized protocol for fetal anatomical assessment. MATERIALS AND METHODS:US scans performed between 11+0 and 13+6 weeks of gestation in pregnancies with estimated date of delivery between January 1, 2012 and January 1, 2016 were searched. Data were supplemented with results of 20-week scans and pregnancy outcome. RESULTS:Of all scans, 38.6% were dating scans and 61.4% were part of first-trimester screening. Anomalies were diagnosed prenatally in 200 (1.8%) fetuses; 81 (0.7%) were chromosomal and 119 (1.1%) were structural. Of all prenatally detected anomalies, 27% (n = 32) were detected at first-trimester scan, with a false-positive rate of 0.04%. All cases of anencephaly (n = 4), encephalocele (n = 2), exomphalos (n = 9), megacystis (n = 4), and limb reduction (n = 1) were diagnosed. First-trimester detection of gastroschisis and congenital heart defects was 67 and 19%, respectively. CONCLUSION:In a primary care setting, global fetal anatomical assessment at first-trimester scan without following a standardized protocol detects about 30% of all structural anomalies and most of the severe anomalies, with an extremely low false-positive rate. We hypothesize that additional training and use of a systematic protocol would improve early detection of structural anomalies.	0
Aagenaes syndrome, also called lymphoedema cholestasis syndrome 1 (LSC1), is characterized by neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age and severe chronic lymphoedema, mainly affecting the lower extremities. The condition is autosomal recessively inherited, and the gene is located on chromosome 15q. The locus, LCS1, was mapped to a 6.6 cM region on chromosome 15. Angioid streaks are visible irregular crack-like dehiscences in bruch's membrane that are associated with atrophic degeneration of the overlying retinal pigment epithelium. Angioid streaks have been described to be associated with pseudoxanthoma elasticum, paget's disease, sickle-cell anaemia, acromegaly, Ehlers-Danlos syndrome, and diabetes mellitus, but also appear in patients without any systemic diseases. Patients with angioid streaks are generally asymptomatic, unless the lesions extend towards the foveola or develop complications such as traumatic bruch's membrane rupture or macular choroidal neovascularization.	0
BACKGROUND:Dystroglycanopathies, which are caused by reduced glycosylation of alpha-dystroglycan, are a heterogeneous group of neurodegenerative disorders characterized by variable brain and skeletal muscle involvement. Muscle-eye-brain disease (or muscular dystrophy-dystroglycanopathy type 3 A) is an autosomal recessive disorder characterized by congenital muscular dystrophy, ocular abnormalities, and lissencephaly. CASE PRESENTATION:We report clinical and genetic characteristics of a 6-year-old boy affected by muscular dystrophy-dystroglycanopathy. He has severe a delay in psychomotor and speech development, muscle hypotony, congenital myopia, partial atrophy of the optic nerve disc, increased level of creatine kinase, primary-muscle lesion, polymicrogyria, ventriculomegaly, hypoplasia of the corpus callosum, cysts of the cerebellum. Exome sequencing revealed compound heterozygous mutations in POMGNT1 gene (transcript NM_001243766.1): c.1539 + 1G > A and c.385C > T. CONCLUSIONS:The present case report shows diagnostic algorithm step by step and helps better understand the clinical and genetic features of congenital muscular dystrophy.	0
BACKGROUND:Familial adenomatous polyposis (FAP) is characterized by colorectal polyposis and adenocarcinoma that is frequently accompanied by extracolonic neoplasm. The risk of gastric carcinoma is increasing in Western FAP patients as well as Asian patients. METHODS:We report the case of an FAP patient with fundic gland polyposis who developed gastric adenocarcinoma and metachronous pyloric gland adenomas. These tumors were endoscopically resected, and immunohistochemistry with gastric mucin (i.e., MUC6, MUC5AC) showed that the tumors belonged to the gastric subtype. Somatic mutation profiles were determined by target amplicon sequencing using a next-generation sequencer. RESULTS:Germline APC variant c.5782delC was found by direct sequencing and somatic KRAS mutations in these tumors were identified by next-generation sequencing. Different KRAS mutation alleles (KRAS p.Gly12Ala, p.Gly12Arg, and p.Gly12Asp) indicated these dysplastic lesions developed from a distinct origin in fundic gland polyposis. Sequential mutations of the APC and KRAS were judged-based on a database search-to be characteristic of the adenoma-carcinoma sequence in colorectal carcinogenesis. CONCLUSION:The colonic adenoma-carcinoma sequence among gastric adenocarcinoma and dysplastic lesions was indicated in FAP-associated gastric carcinogenesis.	0
Deficiency of arginase is associated with hyperargininemia, and prominent features include spastic diplegia/tetraplegia, clonus, and hyperreflexia; loss of ambulation, intellectual disability and progressive neurological decline are other signs. To gain greater insight into the unique neuromotor features, we performed gene expression profiling of the motor cortex of a murine model of the disorder. Coexpression network analysis suggested an abnormality with myelination, which was supported by limited existing human data. Utilizing electron microscopy, marked dysmyelination was detected in 2-week-old homozygous Arg1-KO mice. The corticospinal tract was found to be adversely affected, supporting dysmyelination as the cause of the unique neuromotor features and implicating oligodendrocyte impairment in a deficiency of hepatic Arg1. Following neonatal hepatic gene therapy to express Arg1, the subcortical white matter, pyramidal tract, and corticospinal tract all showed a remarkable recovery in terms of myelinated axon density and ultrastructural integrity with active wrapping of axons by nearby oligodendrocyte processes. These findings support the following conclusions: arginase deficiency is a leukodystrophy affecting the brain and spinal cord while sparing the peripheral nervous system, and neonatal AAV hepatic gene therapy can rescue the defects associated with myelinated axons, strongly implicating the functional recovery of oligodendrocytes after restoration of hepatic arginase activity.	0
Pelvic lipomatosis is an uncommon disease with no clear etiology and it occurs secondary to deposition of a large amount of fatty tissue in the pelvis. This deposition causes compression to the rectum, bladder, and venous structures. Because of this compression, various symptoms, such as recurrent urinary infections, dysuria, tenesmus, and constipation, have mostly been reported. However, iliac or superior vena cava thrombosis secondary to vascular compression of pelvic lipomatosis is rare. This report describes a case of pelvic lipomatosis, which was associated with right-sided mild hydronephrosis and portal vein thrombosis.	0
Osteopetrosis is a rare congenital bone disorder, characterized by systemic osteosclerosis due to a deficiency of or functional defect in osteoclasts. Autosomal dominant osteopetrosis (ADOP) is the most common form with a late onset, a stable condition, relatively few symptoms and a good prognosis. Few studies to date have reported successful total hip arthroplasty (THA) in patients with ADOP and its operative difficulties. We herein describe a case of left hip osteoarthritis in a patient with OP via THA in order to share our experience during the treatment process. The patient was a 52-years-old female with osteopetrosis who was referred to our department due to a history of left hip pain with activity limitation for 20 years. The patient reported no history of fracture or family history. The patient underwent THA in the left hip. At the 6-month, 1- and 2-year follow-up, the components were in a good position and the patient remained asymptomatic and pain-free. Therefore, THA may be a feasible treatment option when patients with ADOP suffer from painful hip osteoarthritis.	0
OBJECTIVE:To study the types and characteristics of TUBB1 mutation in children with congenital hypothyroidism (CH) and thyroid dysgenesis (TD) in Shandong, China. METHODS:Mutations of the whole coding region of the TUBB1 gene were analyzed for 289 children with CH and TD in Shandong. Whole-genome DNA was extracted from peripheral blood leukocytes. PCR multiplication was performed for the whole coding region of the TUBB1 gene. Sanger sequencing was performed for the PCR products, and a biological information analysis was performed. RESULTS:Among the 289 children with CH and TD, 4 (1.4%) were found to have a c.952C>T(p.R318W) heterozygous mutation in the TUBB1 gene, resulting in the change of tryptophan into arginine at codon 318 of TUBB1 protein. This mutation was evaluated as "potentially pathogenic" based on the classification criteria and guidelines for genetic variation by American College of Medical Genetics and Genomics. CONCLUSIONS:A novel mutation is detected in the exon of the TUBB1 gene in children with CH and TD in Shandong, suggesting that the TUBB1 gene may be a candidate pathogenic gene for CH children with TD.	0
Introduction:Spondylo-epi-metaphyseal dysplasia (SEMD) represents a group of osteo-chondrodysplasias characterized by vertebral, epiphyseal as well as metaphyseal abnormalities. Several genes have been identified underlying the different forms. Methodology and results:Two relatives (cousins) in a family were found to have disproportionate short stature with clinical and radiological features suggestive of SEMD. Metabolic bone profile was normal including parathyroid hormone and 25(OH)vitamin D3. Exome sequencing revealed a missense mutation (p. T120M) in the von-Willebrand factor A-domain of the Matrilin 3 (MATN3) gene that segregates with the disease in the family. Conclusion:We identified a homozygous missense mutation in MATN3, an important structural component of the extracellular matrix of cartilage, as the genetic cause of SEMD in this pedigree. MATN3 mutations have been more commonly associated with multiple epiphyseal dysplasia than SEMD. Recognition of this mutation will aid in enhancing the understanding and expanding the spectrum of this particular skeletal dysplasia.	0
Encephalocraniocutaneous lipomatosis (ECCL) is a rare sporadic congenital neurocutaneous disorder with quite specific clinical features and neuroimaging pattern that is well seen on MR imaging.	0
Piebaldism is a genetic pigmentation disorder, which is caused by absence of melanocytes in parts of the skin and/or hair follicles, with eyes and claws normally pigmented. The occurrence of piebaldism in natural populations is rare and the effects on fitness are still unknown. This article reports the first case of pigmentation disorders in the Fringe-lipped Bat Trachops cirrhosus (Spix, 1823) (Chiroptera: Phyllostomidae) caught in Barra do Triunfo, city of João Neiva, northeastern state of Espírito Santo, southeast Brazil.	0
CONTEXT:Congenital hypopituitarism (CH) is characterized by the presence of deficiencies in one or more of the 6 anterior pituitary (AP) hormones secreted from the 5 different specialized cell types of the AP. During human embryogenesis, hypothalamo-pituitary (HP) development is controlled by a complex spatio-temporal genetic cascade of transcription factors and signaling molecules within the hypothalamus and Rathke's pouch, the primordium of the AP. EVIDENCE ACQUISITION:This mini-review discusses the genes and pathways involved in HP development and how mutations of these give rise to CH. This may present in the neonatal period or later on in childhood and may be associated with craniofacial midline structural abnormalities such as cleft lip/palate, visual impairment due to eye abnormalities such as optic nerve hypoplasia (ONH) and microphthalmia or anophthalmia, or midline forebrain neuroradiological defects including agenesis of the septum pellucidum or corpus callosum or the more severe holoprosencephaly. EVIDENCE SYNTHESIS:Mutations give rise to an array of highly variable disorders ranging in severity. There are many known causative genes in HP developmental pathways that are routinely screened in CH patients; however, over the last 5 years this list has rapidly increased due to the identification of variants in new genes and pathways of interest by next-generation sequencing. CONCLUSION:The majority of patients with these disorders do not have an identified molecular basis, often making management challenging. This mini-review aims to guide clinicians in making a genetic diagnosis based on patient phenotype, which in turn may impact on clinical management.	0
BACKGROUND:Recommendations regarding head and neck paragangliomas (HNPGL) have undergone a fundamental reorientation in the last decade as a result of increased understanding of the genetic and pathophysiologic basis of these disorders. OBJECTIVE:We aim to provide an overview of HNPGL and recent discoveries regarding their molecular genetics, along with updated recommendations on workup, treatment, and surveillance, and their implications for otolaryngologists treating patients with these disorders. RESULTS:SDHx susceptibility gene mutations, encoding subunits of the enzyme succinate dehydrogenase (SDH), give rise to the Hereditary Pheochromocytoma/Paraganglioma Syndromes. SDHA, SDHB, SDHC, SDHD, and SDHAF2 mutations each result in unique phenotypes with distinct penetrance and risk for variable tumor development as well as metastasis. Genetic and biochemical testing is recommended for every patient with HNPGL. Multifocal disease should be managed in multi-disciplinary fashion. Patients with SDHx mutations require frequent biochemical screening and whole-body imaging, as well as lifelong follow-up with an expert in hereditary pheochromocytoma and paraganglioma syndromes. CONCLUSION:Otolaryngologists are likely to encounter patients with HNPGL. Keeping abreast of the latest recommendations, especially regarding genetic testing, workup for additional tumors, multi-disciplinary approach to care, and need for lifelong surveillance, will help otolaryngologists appropriately care for these patients.	0
BACKGROUND:Cutis laxa (CL) is a rare connective tissue disorder characterized by loose, redundant, inelastic and wrinkled skin. Patients develop a prematurely aged appearance. Inheritance can be autosomal dominant or autosomal recessive. The X-linked form is now classified in the group of copper transport diseases. Autosomal dominant CL is characterized by wrinkled, redundant and sagging, inelastic skin and in some cases is associated with internal organ involvement. CASE PRESENTATION:We report a familial case of autosomal dominant CL, which includes a 33-year-old woman and her 11-year-old son with dry, thin and wrinkled skin that appeared prematurely aged. No serious involvement of internal organs was found. In both patients, we identified novel heterozygous mutation c.2323delG (p.Ala775fs) in exon 34 of elastin transcript NM_001278939.1. Similar frameshift mutations in the last exons of elastin gene were previously reported in patients with autosomal dominant CL. CONCLUSIONS:Our results show a novel frameshift mutation that was found in patients with cutis laxa. Exome sequencing is effective and useful technology for properly diagnosis of diseases with similar phenotype to ensure proper treatment is provided.	0
Erdheim-Chester disease (ECD) is a rare but increasingly recognized multi-system disorder. Its diagnosis and treatment require integration of clinical information, imaging studies, and pathology studies. Of note, ECD can now be defined as a clonal myeloid disorder due to mutations which activate mitogen-activated protein kinase (MAPK) pathways and where an inflammatory milieu is important in the pathogenesis and clinical manifestations of the disease. Biopsy demonstrating characteristic histopathologic features in addition to clinical and radiographic features, most often sclerosing long bone involvement, is required to establish a diagnosis. Detection of somatic MAPK pathway mutations can also assist in the differential diagnosis of ECD and related histiocytic neoplasms. Also, genetic analysis establishing BRAF and RAS mutational status is critical in all ECD patients, as these features will impact therapy with MAPK inhibition. Therapy is recommended at diagnosis in all patients, except for those patients with minimally symptomatic disease. Prospective therapeutic trials are essential to furthering therapeutic progress in ECD.	0
The role of X-inactivation is often ignored as a prime cause of sex differences in disease. Yet, the way males and females express their X-linked genes has a major role in the dissimilar phenotypes that underlie many rare and common disorders, such as intellectual deficiency, epilepsy, congenital abnormalities, and diseases of the heart, blood, skin, muscle, and bones. Summarized here are many examples of the different presentations in males and females. Other data include reasons why women are often protected from the deleterious variants carried on their X chromosome, and the factors that render women susceptible in some instances.	0
A family presented to our dermatology clinic with a complaint of white nails. Physical examination revealed clinical feature of leukonychia totalis and the presence of sensorineural hearing loss, palmo plantar keratoderma and knuckle pads (four essential criteria for the diagnosis of Bart Pumphrey syndrome).Three consecutive generations of this family were affected with variable presentations of Bart Pumphrey syndrome in male and female; and autosomal dominant pattern of inheritance.	0
Spinal intradural arachnoid cysts are rare with only a few patients reported so far. Idiopathic, traumatic, posthemorrhagic, and postinflammatory causes have been reported in the literature. Especially, idiopathic lesions, in which other possible etiological factors have been ruled out, seem to be rare.We systematically reviewed the literature in regards to localization within the spinal canal, treatment options, complications, and outcome. Additionally, we present management strategies in two progressively symptomatic children less than 3 years of age with idiopathic intradural arachnoid cysts.In total, 21 pediatric cases including the presented cases have been analyzed. Anterior idiopathic spinal arachnoid cysts are predominantly located in the cervical spine in 87.5 % of all cases, whereas posterior cysts can be found at thoracic and thoracolumbar segments in 84.6 % of the patients. Most children presented with motor deficits (76.2 %). Twenty-five percent of anterior spinal arachnoid cysts caused back pain as the only presenting symptom. Open fenestration by a dorsal approach has been used in the vast majority of cases. No major surgical complications have been reported. Ninety-four percent of all patients did improve or showed no neurological deficits. Recurrence rate after successful surgical treatment was low (9.5 %).Idiopathic spinal intradural arachnoid cysts can present with neurological deficits in children. Pathologies are predominantly located in the cervical spine anteriorly and in thoracic and thoracolumbar segments posteriorly to the spinal cord. In symptomatic cases, microsurgical excision and cyst wall fenestration via laminotomy are recommended. Our radiological, intraoperative, and pathological findings support the cerebrospinal fluid obstruction and vent mechanism theory of arachnoid cysts.	0
A family with familial cerebellar ataxia and hypogonadotropic hypogonadism is described. The condition was inherited as an autosomal recessive defect. CT scan in one case revealed cerebellar and brain stem atrophy. Endocrinological tests showed abnormalities only in two patients who were clinically affected. In both cases raised gonadotropic levels were found after repetitive stimulation with luteining hormone-releasing hormone which suggests that the hypogonadism was due to a primary hypothalamic disturbance.	0
Occipital horn syndrome (OHS) is a rare connective tissue disorder caused by pathogenic variants in ATP7A, encoding a copper transporter. The main clinical features, including cutis laxa, bony exostoses, and bladder diverticula are attributed to a decreased activity of lysyl oxidase (LOX), a cupro-enzyme involved in collagen crosslinking. The absence of large case series and natural history studies precludes efficient diagnosis and management of OHS patients. This study describes the clinical and molecular characteristics of two new patients and 32 patients previously reported in the literature. We report on the need for long-term specialized care and follow-up, in which MR angiography, echocardiography and spirometry should be incorporated into standard follow-up guidelines for OHS patients, next to neurodevelopmental, orthopedic and urological follow-up. Furthermore, we report on ultrastructural abnormalities including increased collagen diameter, mild elastic fiber abnormalities and multiple autophagolysosomes reflecting the role of lysyl oxidase and defective ATP7A trafficking as pathomechanisms of OHS.	0
Buschke-Ollendorff syndrome (BOS; OMIM 166700) is a rare autosomal dominant disorder characterized by the existence of connective tissue nevus and/or osteopoikilosis. The skin lesions usually present as firm, yellow, or flesh-colored papules and nodules, which may coalesce into plaques and increase in size and number over time. We present a case of a 26-year-old male with multiple subcutaneous nodules on the waist and thigh for more than 20 years. Being deeply seated, his skin lesions were not visible and could only be appreciated by palpation. Accordingly, pathology showed an increase in thick, crossed, or paralleled, elastic fibers arranged between the collagen bundles in the lower part of the reticular dermis and the subcutaneous fat with mucin deposition. Heterozygous point mutation in exon 8 of the LEMD3 gene was detected, which confirmed the diagnosis of BOS. The deeply situated nature of skin lesions noted in our case has not been reported in the literature of BOS. Our case thus expands the clinical and pathological features of the disease.	0
INTRODUCTION:Iodine deficiency is a leading cause of preventable physical and mental retardation. Potassium iodate is used for iodine supplementation to prevent iodine deficiency. We herein report a case of toxic retinopathy following intentional ingestion of potassium iodine. CASE PRESENTATION:A 41-year-old male presented with a 5-day history of blurred vision in both eyes. His visual acuity (VA) was hand motion and his pupillary reactions were sluggish bilaterally. The fundus examination revealed bilaterally diffuse retinal pigment epithelium atrophy and secondary pigmentary changes at the posterior pole, but his peripheral fundus was relatively spared. Choroidal thinning, punctate hyperreflective dots along the retinal pigment epithelium layer, and outer retinal atrophy were the optical coherence tomography findings, which were consistent with widespread areas of retinal pigment epithelium window defects observed on fundus fluorescein angiography. The visual evoked potential test showed no response in the right eye and revealed a delay in the latency and a decrease in the amplitude of the P100 wave in the left eye. Wave b responses of the photoreceptors could not be observed in the patient's electroretinogram. After a vitamin supplementation protocol consistent with the literature, at the 4-month follow-up visit his visual acuity had improved to 0.3 in the right eye and counting fingers in the left eye. CONCLUSION:Potassium iodate toxicity is a cause of serious retinal and choroidal damage and results in severe vision loss. Hydration, hemodialysis, and antioxidants can be helpful to minimize the complications.	0
Mutations in SNX14 cause the autosomal recessive cerebellar ataxia 20 (SCAR20). Mutations generally result in loss of protein although several coding region deletions have also been reported. Patient-derived fibroblasts show disrupted autophagy, but the precise function of SNX14 is unknown. The yeast homolog, Mdm1, functions in endoplasmic reticulum (ER)-lysosome/vacuole inter-organelle tethering, but functional conservation in mammals is still required. Here, we show that loss of SNX14 alters but does not block autophagic flux. In addition, we find that SNX14 is an ER-associated protein that functions in neutral lipid homeostasis and inter-organelle crosstalk. SNX14 requires its N-terminal transmembrane helices for ER localization, while the Phox homology (PX) domain is dispensable for subcellular localization. Both SNX14-mutant fibroblasts and SNX14KO HEK293 cells accumulate aberrant cytoplasmic vacuoles, suggesting defects in endolysosomal homeostasis. However, ER-late endosome/lysosome contact sites are maintained in SNX14KO cells, indicating that it is not a prerequisite for ER-endolysosomal tethering. Further investigation of SNX14- deficiency indicates general defects in neutral lipid metabolism. SNX14KO cells display distinct perinuclear accumulation of filipin in LAMP1-positive lysosomal structures indicating cholesterol accumulation. Consistent with this, SNX14KO cells display a slight but detectable decrease in cholesterol ester levels, which is exacerbated with U18666A. Finally, SNX14 associates with ER-derived lipid droplets (LD) following oleate treatment, indicating a role in ER-LD crosstalk. We therefore identify an important role for SNX14 in neutral lipid homeostasis between the ER, lysosomes and LDs that may provide an early intervention target to alleviate the clinical symptoms of SCAR20.	0
BACKGROUND AND PURPOSE:Nephrogenic systemic fibrosis following administration of intravenous gadobenate during MR imaging is rare. This study aimed to analyze any nephrogenic systemic fibrosis-related risks and quantify skin gadolinium levels in patients with impaired renal function but without nephrogenic systemic fibrosis who had received gadobenate. MATERIALS AND METHODS:In this retrospective study with a prospective skin biopsy phase, patients with estimated glomerular filtration rates of <60 mL/min/1.73 m2 undergoing contrast-enhanced MR imaging from July 2007 through June 2014 were screened for nephrogenic systemic fibrosis using a questionnaire. This was highly sensitive but not specific and reliably excluded nephrogenic systemic fibrosis if responses to at least 6 of the 8 questions were negative. If no nephrogenic systemic fibrosis was detected, a skin biopsy was requested. RESULTS:Of 2914 patients who met these criteria, 1988 were excluded for various reasons. Of the remaining 926 patients, 860 were screened negative for nephrogenic systemic fibrosis. Of these, 17 (2%) had estimated glomerular filtration rates of <15 mL/min/1.73 m2, 51 (6%) had levels of 15 < 30 mL/min/1.73 m2, 234 (27%) had levels of 30 < 45 mL/min/1.73 m2, and 534 (62%) had levels of 45 < 60 mL/min/1.73 m2. Of the 66 who were not cleared of nephrogenic systemic fibrosis by the questionnaire, 6 patients were evaluated by a dermatologist and confirmed not to have nephrogenic systemic fibrosis (no biopsy required). CONCLUSIONS:A diagnosis of nephrogenic systemic fibrosis was excluded in 860 patients with impaired renal function who were followed up and received gadobenate during MR imaging. In 14 such patients who underwent at least 1 gadobenate-enhanced MR imaging examination and did not have nephrogenic systemic fibrosis, gadolinium levels in the skin were exceedingly low.	0
The UDP-glucose 4-epimerase (GALE) is a glycosyltransferase, which acts on protein and lipid glycosylation in normal and neoplastic cells. This study is aimed at investigating the differential tissue expression of GALE and its possible association with clinical-pathological parameters and the outcome of gastric adenocarcinoma patients. Seventy-one patients were evaluated in relation to GALE expression by immunohistochemistry. Our results showed that 48 (67.6%) patients were GALE positive and 23 (32.4%) negative. Positive staining was present on well-differentiated and moderate-differentiated histological grade of gastric adenocarcinomas (p < 0.0001). There was no significant association with outcome parameters (p > 0.05). Besides that, our results corroborated with the validation cohort analysis, where the expression of GALE mRNA was also associated with the histological grade (p < 0.001). These results suggest a possible use of this enzyme as a biomarker for well and moderately differentiated tumors.	0
Previous research has demonstrated the mutation, c.712T>A (p.L238Q) of the gene for α-L- iduronidase (IDUA) in patients with Hurler-Scheie syndrome is relatively severe when paired with a nonsense or deletion or splice-site mutation. This mutation was also found to be associated with psychiatric symptoms. This research presents longitudinal data and protein analysis to further investigate the severity and natural history of these unique patients. Methods:Six patients heterozygous for L238Q were compared to six patients with Hurler-Scheie without the L238Q mutations. Somatic burden of disease, IQ, memory, attention, adaptive functioning and behavioral measures were given yearly over 2 to 4 years from 2009 to 2014. The impact of L238Q on the IDUA enzyme was examined using 7 bioinformatics tools and a 3D structural analysis. Results:Similar to the cross sectional study, the L238Q patients had more severe abnormalities in IQ, attention, adaptive functioning, and behavioral functioning than the comparison group. There were no major differences between the two groups in change over time; IQ for both groups was stable with some behavioral areas showing improvement. Over time, both groups declined in visual spatial memory and, attention/visual processing. They also showed increased anxiety. Structural and bioinformatics analysis of the L238Q suggest that this mutation causes a significant reduction in the IDUA enzyme's potential catalytic activity, and this mutation may be more severe than other mutations contributing to the Hurler-Scheie syndrome phenotype, presumably causing the psychiatric disease. Conclusion:L238Q patients demonstrate severe neurocognitive and neurobehavioral deficits but are relatively stable. Like the comparison group, decreasing visual spatial memory and attention and increasing anxiety suggest more intervention in life skills and emotional social supports are needed.	0
BACKGROUND:Neurodevelopmental disorders (NDDs) such as autism spectrum disorder, intellectual disability, developmental disability, and epilepsy are characterized by abnormal brain development that may affect cognition, learning, behavior, and motor skills. High co-occurrence (comorbidity) of NDDs indicates a shared, underlying biological mechanism. The genetic heterogeneity and overlap observed in NDDs make it difficult to identify the genetic causes of specific clinical symptoms, such as seizures. METHODS:We present a computational method, MAGI-S, to discover modules or groups of highly connected genes that together potentially perform a similar biological function. MAGI-S integrates protein-protein interaction and co-expression networks to form modules centered around the selection of a single "seed" gene, yielding modules consisting of genes that are highly co-expressed with the seed gene. We aim to dissect the epilepsy phenotype from a general NDD phenotype by providing MAGI-S with high confidence NDD seed genes with varying degrees of association with epilepsy, and we assess the enrichment of de novo mutation, NDD-associated genes, and relevant biological function of constructed modules. RESULTS:The newly identified modules account for the increased rate of de novo non-synonymous mutations in autism, intellectual disability, developmental disability, and epilepsy, and enrichment of copy number variations (CNVs) in developmental disability. We also observed that modules seeded with genes strongly associated with epilepsy tend to have a higher association with epilepsy phenotypes than modules seeded at other neurodevelopmental disorder genes. Modules seeded with genes strongly associated with epilepsy (e.g., SCN1A, GABRA1, and KCNB1) are significantly associated with synaptic transmission, long-term potentiation, and calcium signaling pathways. On the other hand, modules found with seed genes that are not associated or weakly associated with epilepsy are mostly involved with RNA regulation and chromatin remodeling. CONCLUSIONS:In summary, our method identifies modules enriched with de novo non-synonymous mutations and can capture specific networks that underlie the epilepsy phenotype and display distinct enrichment in relevant biological processes. MAGI-S is available at https://github.com/jchow32/magi-s .	0
Little is known about the risk of progression of lentigo maligna to lentigo maligna melanoma. We determine the annual risk of progression of lentigo maligna to lentigo maligna melanoma by analysing a prospective population-based survey of recently diagnosed anterior (visible in a mirror) head and neck lentigo malignas and lentigo maligna melanomas. Six hundred eighty-two consecutive patients aged 18-80 years with non-recurrent lentigo maligna or lentigo maligna melanoma, diagnosed between 1 July 2015 and 20 April 2016, were identified from pathology notifications to the New South Wales Cancer Registry (Australia) and sent survey questionnaires soon after diagnosis (median 4.6 months interquartile range: 3.8-5.7). Details of the time the lesion was present and when changes to it were noticed before diagnostic biopsy were ascertained by surveying the patients, of whom 53.5% agreed to participate. There was little difference between the proportions of lentigo maligna melanoma and lentigo maligna in the consenting and non-consenting patients (P = 0.56). Two hundred twenty-eight lentigo maligna (median age 67 years, range: 38-80) and 33 lentigo maligna melanoma (70 years, 43-80) were surveyed. There was no difference between the time lentigo maligna melanoma was present on the skin (median 18 months, range: 0-690) and the time lentigo maligna was (18 months, 0-665) (P = 0.972). The estimated risk of progression of lentigo maligna to lentigo maligna melanoma was 3.5% per year (95% confidence interval: 2.5-5.0). This equates to an average time for lentigo maligna to progress to lentigo maligna melanoma of 28.3 years (95% confidence interval: 20.0-40.5) in this population. Although our data suggests that the annual progression rate of lentigo maligna is more than 25 times greater than previously suggested, the rate is still low.	0
BACKGROUND: To carefully assess the phenotype and genotype of a patient with partial mosaic trisomy 8 with particular attention to ophthalmologic features. METHODS: Ophthalmologic and neuro-ophthalmologic examination; neuroimaging; conventional karyotyping; and array comparative genomic hybridization (CGH). RESULTS: The proband was the only affected child of a non-consanguineous family. At birth she was noted to have facial dysmorphism including telecanthus, low set ears, prominent nares, and an everted lower lip. She had an accommodative esotropia with otherwise normal globes, optic nerves, retinae, and orbits. She also had delayed motor milestones and mild mental retardation associated with agenesis of the corpus callosum. Both karyotyping and array CGH documented mosaic partial trisomy of chromosome 8 that included all of the "q" arm and part of the proximal "p" arm. CONCLUSIONS: This girl had a number of the classic features of mosaic trisomy 8, including an accommodative esotropia with none of the other ocular and orbital anomalies described in patients with mosaic trisomy 8. This report constitutes an initial effort to create a virtual database of patients with mosaic chromosome 8 in which careful phenotype-genotype correlation employing high resolution array CGH may help identify clues regarding the genetic etiology of ophthalmologic features of this syndrome.	0
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene, characterized by the clinical triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency. CMC can be complicated by systemic candidiasis or oral squamous cell carcinoma (SCC), and may lead to death. The role of chronic Candida infection in the etiopathogenesis of oral SCC is unclear. Long-term use of fluconazole has led to the emergence of Candida albicans strains with decreased susceptibility to azoles. CMC is associated with an impaired Th17 cell response; however, it remains unclear whether decreased serum IL-17 and IL-22 levels are related to a defect in cytokine production or to neutralizing autoantibodies resulting from mutations in the AIRE gene.	0
OBJECTIVE:This study characterizes the expression of tau (p-tau) and α-synuclein (α-syn) by immunohistochemistry in the skin of three different populations: healthy control (HC), Parkinson disease (PD), and progressive supranuclear paralysis (PSP) subjects, with the purpose of finding a biomarker that could differentiate between subjects with PD and PSP. MATERIAL AND METHODS:We evaluated the presence of p-tau and α-syn in a pilot study in the skin of three distinct groups of patients: 17 healthy subjects, 17 patients with PD, and 10 patients with PSP. Four millimeters punch biopsies were obtained from the occipital area and analyzed by immunohistochemistry using antibodies against α-syn and phosphorylated species of tau. PHF (paired helical filaments) antibody identifies p-tau in both normal and pathological conditions and AT8 recognizes p-tau characteristic of pathological conditions. Differences between the three groups were assessed by quantification of immunopositive areas in the epidermis. RESULTS:The immunopositivity pattern of p-tau and α-syn was significantly different among the three groups. Healthy subjects showed minimal staining using AT8 and α-syn. The PD group showed significantly higher α-syn and AT8 immunopositivity, while the PSP group only expressed higher AT8 immunopositivity than HCs. CONCLUSION:These data suggest that the skin reflects brain pathology. Therefore, immunohistochemical analysis of p-tau and α-syn in the skin can be useful for further characterization of PD and PSP.	0
Spondylocostal dysostosis (SCDO) is a heterogeneous group of skeletal disorders characterized by multiple segmentation defects involving vertebrae and ribs. Seven disease genes have been reported as causal genes for SCDO: DLL3, MESP2, TBX6, HES7, RIPPLY2, DMRT2, and LFNG. Here we report a Japanese SCDO case with multiple severe vertebral anomalies from cervical to sacral spine. The patient was a compound heterozygote for c.372delG (p.K124Nfs*) and c.601G>A (p.D201N) variants of LFNG, which encodes a glycosyltransferase (O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase). The missense variant was in the DxD motif, an active-site motif of the glycosyltransferase, and its loss of the enzyme function was confirmed by an in vitro enzyme assay. This is the second report of LFNG mutations in SCDO.	0
Skeletal dysplasias are a diverse group of heritable diseases affecting bone and cartilage growth. Throughout the years, the molecular defect underlying many of the diseases has been identified. These identifications led to novel insights in the mechanisms regulating bone and cartilage growth and homeostasis. One of the pathways that is clearly important during skeletal development and bone homeostasis is the Wingless and int-1 (WNT) signaling pathway. So far, three different WNT signaling pathways have been described, which are all activated by binding of the WNT ligands to the Frizzled (FZD) receptors. In this review, we discuss the skeletal disorders that are included in the latest nosology of skeletal disorders and that are caused by genetic defects involving the WNT signaling pathway. The number of skeletal disorders caused by defects in WNT signaling genes and the clinical phenotype associated with these disorders illustrate the importance of the WNT signaling pathway during skeletal development as well as later on in life to maintain bone mass. The knowledge gained through the identification of the genes underlying these monogenic conditions is used for the identification of novel therapeutic targets. For example, the genes underlying disorders with altered bone mass are all involved in the canonical WNT signaling pathway. Consequently, targeting this pathway is one of the major strategies to increase bone mass in patients with osteoporosis. In addition to increasing the insights in the pathways regulating skeletal development and bone homeostasis, knowledge of rare skeletal dysplasias can also be used to predict possible adverse effects of these novel drug targets. Therefore, this review gives an overview of the skeletal and extra-skeletal phenotype of the different skeletal disorders linked to the WNT signaling pathway.	0
BACKGROUND:Vascular anomalies currently are classified according to their clinical and histological characteristics. Recent advances in molecular genetics have enabled the identification of somatic mutations in most types of vascular anomalies. The purpose of this study was to collate information regarding the genetic basis of vascular anomalies. METHODS:The PubMed literature was reviewed for all citations that identified a mutation in a vascular anomaly between 1994 and 2017. Search terms included "vascular anomaly," "mutation," "gene," "hemangioma," "pyogenic granuloma," "kaposiform hemangioendothelioma," "capillary malformation," "venous malformation," lymphatic malformation," "arteriovenous malformation," and "syndrome." Articles that identified both germline and somatic mutations in vascular anomalies were analyzed. Mutations were categorized by type (germline or somatic), gene, signaling pathway, and cell(s) enriched for the mutation. RESULTS:The majority of vascular anomalies had associated mutations that commonly affected tyrosine kinase receptor signaling through the RAS or PIK3CA pathways. Mutations in PIK3CA and G-protein-coupled receptors were most frequently identified. Specific types of vascular anomalies usually were associated with a single gene. However, mutations in the same gene occasionally were found in different vascular lesions, and some anomalies had a mutation in more than one gene. Mutations were most commonly enriched in endothelial cells. CONCLUSIONS:Identification of somatic mutations in vascular anomalies is changing the paradigm by which lesions are diagnosed and understood. Mutations and their pathways are providing potential targets for the development of novel pharmacotherapy. In the future, vascular anomalies will be managed based on clinical characteristics and molecular pathophysiology.	0
We herein report a 32-year-old woman with adult-onset reducing body myopathy (RBM) who had a mutation in the four-and-a-half LIM domain 1 gene (FHL1) and showed a marked asymmetrical involvement of sternocleidomastoid and trapezius muscles. At 30 years of age she noticed bilateral foot drop, and over the next two years developed difficulty raising her right arm. At 32 years of age she was admitted to our hospital for a diagnostic evaluation. Neurological examination showed moderate weakness and atrophy of her right sternocleidomastoid muscle, right trapezius muscle, and bilateral upper proximal muscles. There were severe weakness and atrophy of her bilateral tibialis anterior muscles. Her deep tendon reflexes were hypoactive in her upper extremities. Her serum creatine kinase level was mildly increased. Muscle biopsy specimens from the left tibialis anterior muscle revealed marked variation in fiber size, some necrotic or regenerating fibers, and reducing bodies. Gene analysis of FHL1 demonstrated a mutation: a heterozygous missense mutation of c.377G>A (p. C126T) in FHL1. Compared with previous adult-onset RBM cases harboring mutations in FHL1, our case was characterized by asymmetrical atrophy of the sternocleidomastoid and trapezius muscles.	0
OBJECTIVE:Determining the genetic basis of speech disorders provides insight into the neurobiology of human communication. Despite intensive investigation over the past 2 decades, the etiology of most speech disorders in children remains unexplained. To test the hypothesis that speech disorders have a genetic etiology, we performed genetic analysis of children with severe speech disorder, specifically childhood apraxia of speech (CAS). METHODS:Precise phenotyping together with research genome or exome analysis were performed on children referred with a primary diagnosis of CAS. Gene coexpression and gene set enrichment analyses were conducted on high-confidence gene candidates. RESULTS:Thirty-four probands ascertained for CAS were studied. In 11/34 (32%) probands, we identified highly plausible pathogenic single nucleotide (n = 10; CDK13, EBF3, GNAO1, GNB1, DDX3X, MEIS2, POGZ, SETBP1, UPF2, ZNF142) or copy number (n = 1; 5q14.3q21.1 locus) variants in novel genes or loci for CAS. Testing of parental DNA was available for 9 probands and confirmed that the variants had arisen de novo. Eight genes encode proteins critical for regulation of gene transcription, and analyses of transcriptomic data found CAS-implicated genes were highly coexpressed in the developing human brain. CONCLUSION:We identify the likely genetic etiology in 11 patients with CAS and implicate 9 genes for the first time. We find that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous. Highly penetrant variants implicate shared pathways in broad transcriptional regulation, highlighting the key role of transcriptional regulation in normal speech development. CAS is a distinctive, socially debilitating clinical disorder, and understanding its molecular basis is the first step towards identifying precision medicine approaches.	0
Maturity-onset diabetes of the young (MODY) classically describes dominantly inherited forms of monogenic diabetes diagnosed before 25 years of age due to pancreatic β-cell dysfunction. In contrast, mutations in certain MODY genes can also present with transient or persistent hyperinsulinemic hypoglycemia in newborn infants, reflecting instead β-cell dysregulation. Of the MODY genes described to date, only hepatocyte nuclear factor-4-alpha (HNF4A; MODY1) and hepatocyte nuclear factor-1-alpha (HNF1A; MODY3) mutations may result in a biphasic phenotype of hypoglycemia in early life and hyperglycemia in later life. We report a family with a novel HNF4A mutation with diverse phenotypic presentations of glucose dysregulation. The proband was a term, appropriate-for-gestational age male infant with symptomatic hypoglycemia on day 3 of life needing high glucose infusion rate to maintain normoglycemia. He was born to a non-obese and non-diabetic mother. Glucose regulation was optimized using diazoxide upon confirmation of hyperinsulinism. Cascade genetic screening identified the same mutation in his father and elder sister, but mother was negative. Father was diagnosed with Type 1 diabetes at 15 years of age that required insulin therapy. Proband's elder sister, born at term appropriate for gestational age, presented with transient neonatal hypoglycemia needing parenteral glucose infusion for a week followed by spontaneous resolution. The paternal grandparents were negative for this mutation, confirming a paternal de novo mutation and autosomal dominant inheritance in this family. This pedigree suggests that the presence of early-onset paternal diabetes should prompt molecular testing in infants presenting in the newborn period with diazoxide-responsive hyperinsulinemic hypoglycemia, even in the absence of maternal diabetes and macrosomia.	0
OBJECTIVES:Malformations of cortical Development (MCDs) are associated with refractory epilepsy. We evaluated scalp inter-ictal EEG patterns in various types of MCD, and its association with clinical features and seizure control. PATIENTS AND METHODS:Retrospective analysis of demographic, clinical, inter-ictal EEG and seizure outcome data of 665 patients with epilepsy and MCD with at least two years follow up was performed. RESULTS:Average age of study population was 15.95 ± 10.79 years with 291(43.8 %) women. Multiregional spikes were more common in children (22.7 % vs 8.5; p < 0.001), if age of onset of epilepsy was <2 years (21.8 % vs 11.4 %; p = 0.001) and polymicrogyria (12.1 % vs 37.3 %; p < 0.001). Generalized epileptiform discharges were more frequent in patients with developmental delay (24.7 % vs 12.6 %; p < 0.001); and were associated with lissencephaly(14.0 % vs 59.3 %; p < 0.001) and heterotopias(14.5 % vs 34.9 %;p = 0.002). Regional spikes were more common if age of onset of epilepsy is >2 years (26.2 % vs 38.4 %; p = 0.003), and also in FCD (17.1 % vs 42.6 %; p < 0.001). At latest follow-up, 151(22.7 %) patients were seizure free; 401(60.7 %) had refractory epilepsy and the rest had remissions with relapse. No association was found between inter-ictal EEG patterns and seizure control. CONCLUSION:In patients with MCD, generalized epileptiform discharges were associated with developmental delay, lissencephaly and heterotopias. Regional spikes were frequent in FCD while multiregional spikes in children and polymicrogyria. Inter-ictal EEG patterns did not influence seizure outcome.	0
Bartter syndrome and Gitelman syndrome (GS) are autosomal recessive disorders usually caused by homozygous or compound heterozygous mutations in causative genes. In some patients, these two syndromes cannot be discriminated based on clinical features or mutation type; thus, a single disease concept, salt-losing tubulopathies (SLTs), has been used instead. Despite the existence of several SLT causative genes, cases of digenic heterozygous mutations in two different genes are extremely rare. Here, we report the case of a 36-year-old woman with renal insufficiency and hypokalemia caused by an SLT. To evaluate the SLT phenotype, we performed next-generation sequencing (NGS) with a gene panel including SLC12A3, SLC12A1, CLCNKB, and CLCNKA as well as laboratory examinations and diuretic loading tests. The results of the diuretic loading tests were consistent with a GS phenotype, while the NGS results showed that the patient had heterozygous mutations in SLC12A1 and CLCNKB. Both genes have been associated with BS, suggesting that the SLT was caused by digenic heterozygous mutations in two different genes. To date, only a few SLT cases caused by digenic heterozygous mutations in two different genes have been reported. The digenic SLT phenotype in the patient was presumably accelerated by moderate renal insufficiency.	0
BACKGROUND:Studies of individuals with autism spectrum disorder (ASD) have revealed a strong multigenic basis with the identification of hundreds of ASD susceptibility genes. ASD is characterized by social deficits and a range of other phenotypes, implicating complex genetics and involvement of a variety of brain regions. However, how mutations and mis-expression of select gene sets are associated with the behavioral components of ASD remains unknown. We reasoned that for genes to be associated with ASD core behaviors they must be: (1) expressed in brain regions relevant to ASD social behaviors and (2) expressed during the ASD susceptible window of brain development. METHODS:Focusing on the amygdala, a brain region whose dysfunction has been highly implicated in the social component of ASD, we mined publicly available gene expression databases to identify ASD-susceptibility genes expressed during human and mouse amygdala development. We found that a large cohort of known ASD susceptibility genes is expressed in the developing human and mouse amygdala. We further performed analysis of single-nucleus RNA-seq (snRNA-seq) data from microdissected amygdala tissue from five ASD and five control human postmortem brains ranging in age from 4 to 20 years to elucidate cell type specificity of amygdala-expressed genes and their dysregulation in ASD. RESULTS:Our analyses revealed that of the high-ranking ASD susceptibility genes, 80 are expressed in both human and mouse amygdala during fetal to early postnatal stages of development. Our human snRNA-seq analyses revealed cohorts of genes with altered expression in the ASD amygdala postnatally, especially within excitatory neurons, with dysregulated expression of seven genes predicted from our datamining pipeline. LIMITATIONS:We were limited by the ages for which we were able to obtain human tissue; therefore, the results from our datamining pipeline approach will require validation, to the extent possible, in human tissue from earlier developmental stages. CONCLUSIONS:Our pipeline narrows down the number of amygdala-expressed genes possibly involved in the social pathophysiology of ASD. Our human single-nucleus gene expression analyses revealed that ASD is characterized by changes in gene expression in specific cell types in the early postnatal amygdala.	0
Musculocontractural Ehlers-Danlos syndrome caused by mutations in CHST14 (mcEDS-CHST14) is a recently delineated disorder, characterized by craniofacial, skeletal, visceral, and ocular malformations; and progressive cutaneous, skeletal, vascular, and visceral fragility-related manifestations. Spinal lesions, though one of the most serious complications, have not been investigated systematically. In this study, we report detailed and comprehensive information about spinal lesions of 12 patients with a mean age at the first visit of 13.4 years. Eight patients (66.7%) had scoliosis with a Cobb angle ≥10°, including one with severe scoliosis with a Cobb angle ≥45°. Five patients (41.7%) had kyphosis at the thoracolumbar junction with a kyphotic angle ≥20°. Three patients (25%) developed severe thoracolumbar kyphosis with a kyphotic angle ≥50° accompanied by thoracic lordosis with a wedge-like vertebral deformity and anterior vertebral osteophyte at the thoracolumbar junction, and two of them underwent surgical correction: complicated by fistula formation in one and performed safely and effectively through two-staged operation in the other. Six patients (50.0%) had cervical kyphosis, all of whom except one had kyphosis ≥20° at the thoracolumbar level. Two patients (16.7%) had atlantoaxial subluxation, and 10 patients (83.3%) had cervical vertebral malformations. Patients with mcEDS-CHST14 are susceptible to develop scoliosis, thoracolumbar kyphosis, and cervical kyphosis; and are recommended to have regular surveillance including total spine radiology. The present findings also suggest the critical role of dermatan sulfate in the development and maintenance of the spine.	0
Autosomal recessive spinocerebellar ataxia type 18 (SCAR18) is caused by pathogenic variants in the Glutamate Receptor, Ionotropic, Delta-2 (GRID2) gene. We describe the long-term follow-up from 1 to 31 years of an Italian patient with congenital SCAR18 who is compound heterozygous for a maternally-inherited nonsense variant and a de novo microdeletion. To date, this is the longest follow-up in congenital SCAR18.	0
Dyschromatosis universalis hereditaria (DUH) is a rare autosomal dominant inherited dermatosis which usually appears during childhood and is characterized by dyspigmentation, with both hypopigmented and hyperpigmented macules. We report a case of DUH with unexplained childhood-onset renal failure. The association between DUH and renal failure is yet to be proven by further studies.	0
Therapy-related myeloid neoplasm (t-MN) is a rare but devastating consequence of chemotherapy and/or radiotherapy used for the treatment of solid cancers and various hematologic malignancies. Our current understanding of the etiology is that hematopoietic clones that are contemporaneous with the primary cancer and resistant to the cytotoxic exposure have the potential to undergo selective expansion and transformation to t-MN. Consequently, a large proportion of cases are associated with adverse risk factors, resulting in limited effective treatment options. Despite the emergence of some therapies with promising activity in t-MN, most effects are short-lived and allogeneic stem cell transplantation remains the only curative option for eligible patients. This review summarizes the current literature on t-AML and t-MDS, with the aim of providing practical recommendations on the clinical evaluation and management of these conditions.	0
The association of Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase (EC 3.2.1.45), and congenital ichthyosis was first noted a decade ago. Subsequently, a null allele type 2 Gaucher mouse was generated that also exhibited ichthyotic skin, confirming that the skin disorder and enzyme deficiency were directly related. This paper details the clinical and molecular characterisation of 6 cases of type 2 Gaucher disease presenting with the collodion baby phenotype. The identified mutant glucocerebrosidase alleles include two novel mutations (S196P and R131L) and two rare point mutations (R120W and R257Q), as well as alleles resulting from recombination with the nearby glucocerebrosidase pseudogene. There is significant genotypic heterogeneity in this rare subset of patients with type 2 Gaucher disease. Gaucher disease should be considered in the differential diagnosis of congenital ichthyosis in the newborn period.	0
Leukemoid reaction and myeloproliferative syndrome are close mimickers and frequently pose a diagnostic dilemma, particularly when the leukocyte count is very high. Leukocyte alkaline phosphatase score frequently aids in diagnosis but may or may not be contributory, especially in differentiating chronic neutrophilic leukemia. Herein, we document a case of leukemoid reaction with extensive hyperleukocytosis in a 46-year-old female with poorly differentiated carcinoma. The tumor itself as well as the associated leukocytosis portends a poor prognosis.	0
Dyggve-Melchior-Clausen (DMC) syndrome is a rare autosomal recessive disorder characterized by the association of a progressive spondyloepimetaphyseal dysplasia and mental retardation ranging from mild to severe. The disorder results from mutations in the dymeclin (DYM) gene in the 18q12-12.1 chromosomal region. We report two siblings with classical clinical and radiological features of DMC and asymptomatic atlanto-axial dislocation. A novel homozygous splice-site mutation (IVS15+3G>T) was detected. Reverse transcriptase polymerase chain reaction (RT-PCR) confirmed that this mutation affects normal splicing. To the best of our knowledge, this is the first report of DMC from Saudi Arabia. The splice mutation noted in our patients was compared to the previously reported cases and supports the hypothesis that loss of DYM function is the likely mechanism of disease pathogenesis. In conclusion, distinction between this type of skeletal dysplasia and Morquio disease (MPS IV) is important for paediatricians and clinical geneticist in providing standard patient care and genetic counselling.	0
We report on 2 brothers with lethal multiple pterygium syndrome (LMPS) born to non-consanguineous parents as late spontaneous abortions. Both fetuses presented with massive nuchal edema, and facial anomalies including cleft palate and broad ribs. Apparently, several subgroups of LMPS exist. Differentiation is difficult, as there is no consistent agreement on a workup protocol for autopsies. We compared the findings in the literature on cases with LMPS, and we suggest a standardized workup as an initial step for more efficient differentiation between various subgroups.	0
BACKGROUND:The risk for nephrogenic systemic fibrosis (NSF) after exposure to newer versus older gadolinium-based contrast agents (GBCAs) remains unclear. PURPOSE:To synthesize evidence about NSF risk with newer versus older GBCAs across the spectrum of kidney function. DATA SOURCES:MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science for English-language references from inception to 5 March 2020. STUDY SELECTION:Randomized controlled trials, cohort studies, and case-control studies that assessed NSF occurrence after GBCA exposure. DATA EXTRACTION:Data were abstracted by 1 investigator and verified by a second. Investigator pairs assessed risk of bias by using validated tools. DATA SYNTHESIS:Of 32 included studies, 20 allowed for assessment of NSF risk after exposure to newer GBCAs and 12 (11 cohort studies and 1 case-control study) allowed for comparison of NSF risk between newer and older GBCAs. Among 83 291 patients exposed to newer GBCAs, no NSF cases developed (exact 95% CI, 0.0001 to 0.0258 case). Among the 12 studies (n = 118 844) that allowed risk comparison between newer and older GBCAs, 37 NSF cases developed after exposure to older GBCAs (exact CI, 0.0001 to 0.0523 case) and 4 occurred (3 confounded) after exposure to newer GBCAs (exact CI, 0.0018 to 0.0204 case). Data were scant for patients with acute kidney injury or those at risk for chronic kidney disease. LIMITATIONS:Study heterogeneity prevented meta-analysis. Risk of bias was high in most studies because of inadequate exposure and outcome ascertainment. CONCLUSION:Although NSF occurrence after exposure to newer GBCAs is very rare, the relatively scarce data among patients with acute kidney injury and those with risk factors for chronic kidney disease limit conclusions about safety in these populations. PRIMARY FUNDING SOURCE:U.S. Department of Veterans Affairs. (PROSPERO: CRD42019135783).	0
Infantile spasms (IS) and Lennox-Gastaut syndrome (LGS) are epileptic encephalopathies characterized by early onset, intractable seizures, and poor developmental outcomes. De novo sequence mutations and copy number variants (CNVs) are causative in a subset of cases. We used exome sequence data in 349 trios with IS or LGS to identify putative de novo CNVs. We confirm 18 de novo CNVs in 17 patients (4.8%), 10 of which are likely pathogenic, giving a firm genetic diagnosis for 2.9% of patients. Confirmation of exome-predicted CNVs by array-based methods is still required due to false-positive rates of prediction algorithms. Our exome-based results are consistent with recent array-based studies in similar cohorts and highlight novel candidate genes for IS and LGS.	0
OBJECTIVES:To study the epidemiological characteristics of myasthenia gravis in Greece. METHODS:A population based study was carried out of seropositive myasthenia gravis in Greece for the period from 1 January 1983 to 30 June 1997; 843 patients were studied. RESULTS:The average annual incidence for the period 1992-7, for which the database is complete, was 7.40/million population/year (women 7.14; men 7.66). On 1 July 1997, there were 740 prevalent cases. The point prevalence rate was 70.63/million (women 81.58; men 59.39). The average overall annual mortality rate in the patients was 0.67/million population (women 0.53; men 0.82), and the mortality rate attributed to myasthenia gravis was 0.43/million population (women 0.41; men 0.45). The average age at onset was 46.50 years (women 40.16; men 54.46), and the mean age of the prevalent patients was 52.58 (women 47.65; men 59.48). The women:men incidence ratio was 1:1.04, and the prevalence ratio was 1.41:1. It is predicted that the prevalence and women: men prevalence ratio would increase if the patient list included all patients with a date of onset before 1983. CONCLUSIONS:The largest epidemiological study ever performed on myasthenia gravis is presented. The most important epidemiological indexes are provided.	1
Human disorganization syndrome (HDS) is an extremely rare congenital syndrome characterized by a seemingly random distribution of multiple developmental anomalies involving all three germinal layers. Case Report:We report a rare case of a female child whose congenital anomalies are consistent with HDS. The orthopaedic features of this patient include a popliteus pterygium with an associated flexion contracture secondary to an elongated biceps femoris tendon that attached to the gastrocnemius-soleus muscle complex, two finger-like appendages, a tethered cord, a lipomeningomyelocele at the level of L5, and a leglength discrepancy. The patient was treated with a splinting program, release of the biceps femoris tendon at its erroneous insertion from the gastrocs-soleus, and surgical excision of the finger-like appendages. She underwent three subsequent soft-tissue releases to address recurrence of the knee flexion contracture and an anteromedial and lateral distal femoral eight plate procedure for guided growth and slow correction of the remaining flexion deformity. Conclusion:The treatment of HDS can be quite complex and can present with a variety of anomalies with distinctive orthopaedic features correctable with surgical management, including soft-tissue releases, excision of appendages, and growth modulation.	0
The fungus Stachybotrys (S.) chartarum was isolated from culinary herbs, damp building materials, and improperly stored animal forage. Two distinct chemotypes of the fungus were described that produced either high-cytotoxic macrocyclic trichothecenes (S type) or low-cytotoxic atranones (A type). Recently, two distinct gene clusters were described that were found to be necessary for the biosynthesis of either macrocyclic trichothecenes (21 SAT (Satratoxin) genes) or atranones (14 ATR (Atranone) genes). In the current study, PCR primers were designed to detect SAT and ATR genes in 19 S. chartarum chemotype S and eight S. chartarum chemotype A strains. Our analysis revealed the existence of three different genotypes: satratoxin-producing strains that harbored all SAT genes but lacked the ATR gene cluster (genotype S), non-satratoxin-producing strains that possessed the ATR genes but lacked SAT genes (genotype A), and a hitherto undescribed hybrid genotype among non-satratoxin-producing strains that harbored all ATR genes and an incomplete set of SAT genes (genotype H). In order to improve the discrimination of genotypes, a triplex PCR assay was developed and applied for the analysis of S. chartarum and S. chlorohalonata cultures. The results show that genes for macrocyclic trichothecenes and atranones are not mutually exclusive in S. chartarum. Correlation of the new genotype-based concept with mycotoxin production data shows also that macrocyclic trichothecenes are exclusively produced by S. chartarum genotype S strains.	0
Human adenovirus (HAdV) is the most common cause of infectious conjunctivitis, accounting for up to 75% of all conjunctivitis cases and affecting people of all ages and demographics. In addition to ocular complications, it can cause systemic infections in the form of gastroenteritis, respiratory disease, and dissemination in immunocompromised individuals. HAdV causes lytic infection of the mucoepithelial cells of the conjunctiva and cornea, as well as latent infection of lymphoid and adenoid cells. Epidemic keratoconjunctivitis (EKC) is the most severe ocular manifestation of HAdV infection, in which the presence of subepithelial infiltrates (SEIs) in the cornea is a hallmark feature of corneal involvement. SEIs have the tendency to recur and may lead to long-term visual disability. HAdV persistence and dissemination are linked to sporadic outbreaks of adenoviral keratoconjunctivitis. There is no FDA-approved antiviral for treating adenoviral keratoconjunctivitis, and as such, solutions should be proffered to handle the challenges associated with viral persistence and dissemination. Several treatment modalities have been investigated, both systemically and locally, to not only mitigate symptoms but reduce the course of the infection and prevent the risk of long-term complications. These options include systemic and topical antivirals, in-office povidone-iodine irrigation (PVI), immunoglobulin-based therapy, anti-inflammatory therapy, and immunotherapy. More recently, combination PVI/dexamethasone ophthalmic formulations have shown favorable outcomes and were well tolerated in clinical trials for the treatment of EKC. Possible, future treatment considerations include sialic acid analogs, cold atmospheric plasma, N-chlorotaurine, and benzalkonium chloride. Continued investigation and evaluation of treatment are warranted to reduce the economic burden and potential long-term visual debilitation in affected patients. This review will focus on how persistence and dissemination of HAdV pose a significant challenge to the management of adenoviral keratoconjunctivitis. Furthermore, current and future trends in prophylactic and therapeutic modalities for adenoviral keratoconjunctivitis will be discussed.	0
PURPOSE:We observed four individuals in two unrelated but consanguineous families from Portugal and Brazil affected by early-onset retinal degeneration, sensorineural hearing loss, microcephaly, intellectual disability, and skeletal dysplasia with scoliosis and short stature. The phenotype precisely matched that of an individual of Azorean descent published in 1986 by Liberfarb and coworkers. METHODS:Patients underwent specialized clinical examinations (including ophthalmological, audiological, orthopedic, radiological, and developmental assessment). Exome and targeted sequencing was performed on selected individuals. Minigene constructs were assessed by quantitative polymerase chain reaction (qPCR) and Sanger sequencing. RESULTS:Affected individuals shared a 3.36-Mb region of autozygosity on chromosome 22q12.2, including a 10-bp deletion (NM_014338.3:c.904-12_904-3delCTATCACCAC), immediately upstream of the last exon of the PISD (phosphatidylserine decarboxylase) gene. Sequencing of PISD from paraffin-embedded tissue from the 1986 case revealed the identical homozygous variant. In HEK293T cells, this variant led to aberrant splicing of PISD transcripts. CONCLUSION:We have identified the genetic etiology of the Liberfarb syndrome, affecting brain, eye, ear, bone, and connective tissue. Our work documents the migration of a rare Portuguese founder variant to two continents and highlights the link between phospholipid metabolism and bone formation, sensory defects, and cerebral development, while raising the possibility of therapeutic phospholipid replacement.	0
The aim of this review is to summarize and discuss recent findings and new insights in the etiology and phenotype of metabolic myopathies. The review relies on a systematic literature review of recent publications. Metabolic myopathies are a heterogeneous group of disorders characterized by mostly inherited defects of enzymatic pathways involved in muscle cell metabolism. Metabolic myopathies present with either permanent (fixed) or episodic abnormalities, such as weakness, wasting, exercise-intolerance, myalgia, or an increase of muscle breakdown products (creatine-kinase, myoglobin) during exercise. Though limb and respiratory muscles are most frequently affected, facial, extra-ocular, and axial muscles may be occasionally also involved. Age at onset and prognosis vary considerably. There are multiple disease mechanisms and the pathophysiology is complex. Genes most recently related to metabolic myopathy include PGM1, GYG1, RBCK1, VMA21, MTO1, KARS, and ISCA2. The number of metabolic myopathies is steadily increasing. There is limited evidence from the literature that could guide diagnosis and treatment of metabolic myopathies. Treatment is limited to mainly non-invasive or invasive symptomatic measures. In conclusion, the field of metabolic myopathies is evolving with the more widespread availability and application of next generation sequencing technologies worldwide. This will broaden the knowledge about pathophysiology and putative therapeutic strategies for this group of neuromuscular disorders.	0
Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system, neurocutaneous disorder that predisposes to the development of benign and malignant tumors. Classical skeletal abnormalities encompass sphenoid wing dysplasia, congenital bowing of the long bones and vertebral osteopathy associated with non-dystrophic or dystrophic scoliosis found in about 10% of NF1 patients. We report a 17-year-old boy affected by NF1 with extreme severe spinal and thoracic malformations affecting bone and lung tissues, including hypoplasia of the right lung, unilateral costal agenesis and severe dystrophic scoliosis characterized by association of hemivertebra, fusion of adjacent vertebral bodies and defective pedicles. At birth, he presented an acute respiratory distress requiring invasive ventilator support. The diagnosis of NF1 was confirmed at age 5 by the identification of a de novo heterozygous mutation c.4537C > T, p.Arg1513* in NF1. Trio-based Whole Exome Sequencing (WES) was performed to exclude coexistence of a second hit but no clearly other pathogenic variant has been identified. Until now, only one similar NF1 patient suffering from the same association of severe scoliosis and chest deformity leading to respiratory insufficiency was described. The severe prenatal NF1-related scoliosis could explain the lung abnormal development by absence of mechanical constraints. Severe Thoracic and Spinal Bone Abnormalities may be part of the NF1 bone phenotype and should be taken into account to allow adequate genetic counseling.	0
OBJECTIVES:The primary aim of this study was to identify the ease and safety of office-based lower airway endoscopy (OLAE) in patients with and without comorbidities. In addition, we identified the most common indications for OLAE and the associated diagnosis. METHODS:A retrospective review on 567 patients and 706 in-office flexible fiberoptic procedures was performed. Using a previously established grading system, the ease of visualization of the subglottis, trachea, and carina was assessed, in addition to the overall ease of the exam. RESULTS:Four hundred and eighty-eight videos were available for review. Of those, 105 videos included an OLAE, accounting for 21.5% of all procedures. Laryngomalacia was the most common diagnosis in 35 of 105 (36%) OLAE. For all laryngomalacia cases, the overall ease was found to be on average 2.15 (standard error 0.12). Fisher exact testing showed a statistical significance in the ability to visualize the trachea between the types of Laryngomalacia (LM) (P = .035). Fisher exact testing was performed comparing LM types I, II, or III, and combined types of LM; no statistical difference was found between groups. In 4.76% of OLAE procedures, a subglottic pathology was diagnosed. Comorbidities were found in OLAE 26 of 105 patients. There were no complications identified. CONCLUSION:We found OLAE more challenging than previously reported. OLAE of combined types of laryngomalacia was subjectively more difficult, but this difference did not reach statistical significance. OLAE continues to be a safe alternative to operative laryngoscopy in pediatric patients and appears safe in those with comorbidities when precautions are taken. LEVEL OF EVIDENCE:4. Laryngoscope, 2020.	0
Twenty-five years ago, RET was identified as the primary driver of multiple endocrine neoplasia type 2 (MEN2) syndrome. MEN2 is characterized by several transformation events including pheochromocytoma, parathyroid adenoma and, especially penetrant, medullary thyroid carcinoma (MTC). Overall, MTC is a rare but aggressive type of thyroid cancer for which no effective treatment currently exists. Surgery, radiation, radioisotope treatment and chemotherapeutics have all shown limited success, and none of these approaches have proven durable in advanced disease. Non-mammalian models that incorporate the oncogenic RET isoforms associated with MEN2 and other RET-associated diseases have been useful in delineating mechanisms underlying disease progression. These models have also identified novel targeted therapies as single agents and as combinations. These studies highlight the importance of modeling disease in the context of the whole animal, accounting for the complex interplay between tumor and normal cells in controlling disease progression as well as response to therapy. With convenient access to whole genome sequencing data from expanded thyroid cancer patient cohorts, non-mammalian models will become more complex, sophisticated and continue to complement future mammalian studies. In this review, we explore the contributions of non-mammalian models to our understanding of thyroid cancer including MTC, with a focus on Danio rerio and Drosophila melanogaster (fish and fly) models.	0
Objective:To investigate the clinical chacteration and molecular pathology of Waardenburg syndrome type 2 in seven families, and provide genetic diagnosis and hereditary counseling for family members. Method:Clinical data of seven families with WS2（14 patients）were collected. Peripheral blood samples of the probands and related family members were collected and genomic DNA was extracted. The coding sequences of microphthalmia associated transcription factor (MITF), sex-determining region Y-box 10(SOX10), snail family zinc finger 2 (SNAI2) and endothelin receptor type B（EDNRB）were analyzed by polymerase chain reaction and DNA sequencing. Then the raw data was analyzed. Result:The most common manifestations of WS2 are sensorineural hearing loss(10/14,71.4%), freckle(7/14, 50.0%)，heterochromia iridis(6/14, 42.9%) and premature greying(5/14,35.7%). All the deafness phenotype is congenital, bilateral profound sensorineural hearing loss. Freckles phenotype is different from cutaneous pigment abnormalities of WS in Westerners. The heterozygous mutation, c.328C>T in exon 3 of the MITF gene was detected in the proband and all patients of pedigree 2. However, no pathological mutation of the relevant genes (SOX10,SNAI2 and EDNRB) was detected in other pedigrees. Conclusion:There are obvious variations in clinical features of WS, while freckles may be a special subtype of cutaneous pigment disturbances. The MITF gene mutation, R110X,is therefore considered the disease causing mutation in pedigree WS02.However, there are novel disease causing genes or copy number variations in Waardenburg syndrome type 2, which require further research.	0
PURPOSE OF REVIEW:Atypical chronic myeloid leukemia (aCML), BCR-ABL1-negative, is a rare myelodysplastic/myeloproliferative neoplasm (MDS/MPN) characterized by leukocytosis, granulocytic dysplasia, and typically poor patient outcomes. Since its first description as a variant CML lacking the Philadelphia chromosome (Ph), the diagnostic criteria for aCML have evolved significantly. Nevertheless, distinguishing it from other Ph-negative myeloid neoplasms can still be very challenging, and given its generally worse prognosis, this is a clinically important distinction. The purpose of this review is to conceptualize our understanding of aCML molecular genetics based on recent advances, and describe how genetic features can be used in conjunction with clinical and morphologic features to better diagnose this elusive entity. RECENT FINDINGS:The classification criteria for aCML have evolved and changed multiple times over the past decades, and is now based on strict application of morphologic, clinical and laboratory criteria. Recent work has elucidated the mutational landscape of aCML, especially with respect to potentially differentiating profiles compared with other Ph-negative myeloid neoplasms. SUMMARY:Atypical CML is a rare MDS/MPN overlap syndrome that can be diagnostically challenging; however, its emerging molecular genetic understanding and clinicomorphologic phenotype can help in distinguishing it from other Ph-negative myeloid neoplasms.	0
Tyrosinemia type 1 (TT1) is a rare metabolic disease caused by a defect in tyrosine catabolism. TT1 is clinically characterized by acute liver failure, development of hepatocellular carcinoma, renal and neurological problems, and consequently an extremely poor outcome. This review showed that the introduction of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) in 1992 has revolutionized the outcome of TT1 patients, especially when started pre-clinically. If started early, NTBC can prevent liver failure, renal problems, and neurological attacks and decrease the risk for hepatocellular carcinoma. NTBC has been shown to be safe and well tolerated, although the long-term effectiveness of treatment with NTBC needs to be awaited. The high tyrosine concentrations caused by treatment with NTBC could result in ophthalmological and skin problems and requires life-long dietary restriction of tyrosine and its precursor phenylalanine, which could be strenuous to adhere to. In addition, neurocognitive problems have been reported since the introduction of NTBC, with hypothesized but as yet unproven pathophysiological mechanisms. Further research should be done to investigate the possible relationship between important clinical outcomes and blood concentrations of biochemical parameters such as phenylalanine, tyrosine, succinylacetone, and NTBC, and to develop clear guidelines for treatment and follow-up with reliable measurements. This all in order to ultimately improve the combined NTBC and dietary treatment and limit possible complications such as hepatocellular carcinoma development, neurocognitive problems, and impaired quality of life.	0
The E3 subunit of the pyruvate dehydrogenase complex (dihydrolipoamide dehydrogenase/dihydrolipoyl dehydrogenase/DLD/lipoamide dehydrogenase/LAD), is a mitochondrial matrix enzyme and also a part of the branched-chain ketoacid dehydrogenase and alpha-ketoglutarate dehydrogenase complexes. DLD deficiency (MIM #246900), is relatively frequent in the Ashkenazi Jewish population but occurs in other populations as well. Early diagnosis is important to prevent episodes of metabolic decompensation, liver failure, and encephalopathy. The clinical presentations are varied and may include Reye-like syndrome, hepatic failure, myopathy, and myoglobinuria. Laboratory markers, such as elevated urinary alpha-ketoglutarate, blood pyruvate, lactate, and ammonia, are mostly nonspecific and not always present, making the diagnosis difficult. Since we observed elevated plasma citrulline levels in a number of confirmed cases, we retrospectively examined the value of citrulline as a biochemical marker for DLD deficiency. Data was gathered from the files of 17 pediatric patients with DLD deficiency, confirmed by enzymatic and genetic analysis. The control group included 19 patients in whom urea cycle defects were ruled out but DLD deficiency was suspected. Seven of the DLD-deficient patients presented with elevated plasma citrulline levels (median value 205 μM, range 59-282 μM) (normal range 1-45 μM) while none in the control patient group. In five patients, elevated citrulline was associated with elevated plasma glutamine and metabolic acidosis. Interestingly, elevated plasma citrulline was associated with the common G229C mutation. In conclusion, we suggest that elevated plasma citrulline in the absence of urea cycle defects warrants an investigation for DLD deficiency.	0
BACKGROUND:Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant genodermatosis characterized by benign growth of the hair follicles, the presence of pulmonary cysts, spontaneous pneumothorax, and bilateral renal tumors that are usually hybrid oncocytic or multifocal chromophobe renal cell carcinoma. The diagnosis is confirmed by the presence of a pathogenic variant in the tumor suppressor folliculin (FLCN) gene mapped at 17p11.2. Although the dermatological lesions typical of BHDS are benign and only cause aesthetic concerns, and the pulmonary manifestations are controllable, the greater tendency of patients with this syndrome to present benign or malignant renal tumors, often bilateral and multifocal, makes the diagnosis of this syndrome important for the prognosis of the patients. The objective was to report the case of a patient with BHDS, without pulmonary manifestations and with hyperplastic polyposis of the gastrointestinal tract, and to perform a literature review. CASE PRESENTATION:A 60-year-old man complained of abdominal pain and diarrhoea for 2 months. Physical examination was normal except for the presence of normochromic papules in the frontal region of the face associated with hyperkeratotic and hyperchromic papules in the dorsal region. The excisional biopsies of the skin lesions indicated trichodiscomas. Esophagogastroduodenoscopy, enteroscopy, and colonoscopy showed the presence of hyperplastic polyps in the stomach, duodenum, jejunum, colon, and rectum. Computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen revealed multiple expansive solid lesions in both kidneys, with necrotic and calcified areas. Renal magnetic resonance angiography also showed a solid lesion in the right kidney measuring 5 cm in diameter and another solid lesion in the left kidney measuring 8 cm in diameter, both suggestive of renal angiomyolipoma. CT scans of the skull, chest, and temporal bones were normal. The genetic study revealed the presence of a variant of FLCN in the intron 13. CONCLUSIONS:To the best of our knowledge, this is the first reported case of BHDS with the simultaneous finding of gastrointestinal hyperplastic polyposis, which may represent a possible phenotypic expression of this syndrome that has not yet been described.	0
Quantification of mitochondrial DNA (mtDNA) content is an essential tool for the diagnosis of mtDNA depletion syndrome (MDS). Samples collected and processed for anatomopathology studies represent a unique source of archived biological material. Thus, the possibility to study mtDNA copy number in these specimens would be a useful way to screen for MDS. In this study, we designed and validated the methodology to determine mtDNA content by quantitative real-time polymerase chain reaction (qRT-PCR) in formalin-fixed paraffin-embedded (FFPE) muscle tissue. We studied 14 frozen muscle biopsies and compared the results with a portion of the same biopsy embedded in paraffin. Our results showed a similar variability among frozen and FFPE muscle biopsies. Patients with MDS detected in frozen muscle were also confirmed in their corresponding FFPE samples, which validate the usefulness of this approach. We conclude that the analysis of mtDNA copy number in FFPE muscle tissue by qRT-PCR is a useful method for the molecular screening of patients suspected to have MDS when frozen biopsies are not available. Analysis of these samples would facilitate retrospective studies and diagnostic procedures.	0
Diffuse alveolar hemorrhage (DAH) is a life-threatening and medical emergency that can be caused by numerous disorders and presents with hemoptysis, anemia, and diffuse alveolar infiltrates. Early bronchoscopy with bronchoalveolar lavage is usually required to confirm the diagnosis and rule out infection. Most cases of DAH are caused by capillaritis associated with systemic autoimmune diseases such as anti-neutrophil cytoplasmic antibody-associated vasculitis, anti-glomerular basement membrane disease, and systemic lupus erythematosus, but DAH may also result from coagulation disorders, drugs, inhaled toxins, or transplantation. The diagnosis of DAH relies on clinical suspicion combined with laboratory, radiologic, and pathologic findings. Early recognition is crucial, because prompt diagnosis and treatment is necessary for survival. Corticosteroids and immunosuppressive agents remain the gold standard. In patients with DAH, biopsy of involved sites can help to identify the cause and to direct therapy. This article aims to provide a general review of the causes and clinical presentation of DAH and to recommend a diagnostic approach and a management plan for the most common causes.	0
Myopathies due to mutations in the skeletal muscle ryanodine receptor (RYR1) gene are amongst the most common non-dystrophic neuromuscular disorders and have been associated with both dominant and recessive inheritance. Several cases with apparently de novo dominant inheritance have been reported. Here we report two siblings with features of Central Core Disease (CCD) born to unaffected parents. Genetic testing revealed a heterozygous dominant RYR1 c.14582G>A (p. Arg4861His) mutation previously identified in other CCD pedigrees. The variant was absent in blood from the asymptomatic mother but detected at low but variable levels in blood- and saliva-derived DNA from the unaffected father, suggesting that this mutation has arisen as a paternal post-zygotic de novo event. These findings suggest that parental mosaicism should be considered in RYR1-related myopathies, and may provide one possible explanation for the marked intergenerational variability seen in some RYR1 pedigrees.	0
BACKGROUND:Trigeminal neuralgia (TN) is a severe, disabling form of painful cranial neuropathy. Even though TN has a typical clinical picture, diagnosis it is often missed or delayed in clinical practice. In order to investigate the occurrence of diagnostic and therapeutic errors in TN, we studied 102 patients suffering from TN recruited through a multicentric survey. METHODS:We performed a Pubmed database search on errors and pittfalls in TN diagnosis and management. Then, patients with TN were consecutively enrolled in the period from February 2017 to October 2019, by several European Headache Centers participating in the study, following a call of the Headache and Pain Scientific Panels of the European Academy of Neurology (EAN). Diagnosis of Classical Trigeminal Neuralgia (CTN) was made according to the International Headache Society (IHS) criteria (Tölle et al., Pain Pract 6:153-160, 2006). All the patients were evaluated using telephone/frontal interviews conducted by headache/pain specialists using an ad hoc questionnaire. RESULTS:A number of 102 patients were recruited, mostly females (F:M ratio 2.64:1). Eighty-six percent of the patients consulted a physician at the time they experienced the first pain attacks. Specialists consulted before TN diagnosis were: primary care physicians (PCP) (43.1%), dentists (in 30.4%), otorhinolaryngologists (3.9%), neurosurgeons (3.9%), neurologists or headache specialists (14.7%), others (8%). The final diagnosis was made mainly by a neurologist or headache specialist (85.3%), and the mean interval between the disease onset and the diagnosis made by a specialist was 10.8 ± 21.2 months. The "diagnostic delay" was 7.2 ± 12.5 months, and misdiagnoses at first consultation were found in 42.1% of cases. Instrumental and laboratory investigations were carried out in 93.1% of the patients before the final diagnosis of TN. CONCLUSION:While TN has typical features and it is well defined by the available international diagnostic criteria, it is still frequently misdiagnosed and mistreated. There is a need to improve the neurological knowledge in order to promptly recognize the clinical picture of TN and properly adhere to the specific guidelines. This may result in a favorable outcome for patients, whose quality of life is usually severely impaired.	0
The basic helix-loop-helix (bHLH) transcription factor, neuronal differentiation 1 (NEUROD1) (also known as BETA2) is involved in the development of neural elements and endocrine pancreas. Less than 10 reports of adult-onset non-insulin-dependent diabetes mellitus (NIDDM) due to heterozygous NEUROD1 mutations and 2 cases with permanent neonatal diabetes mellitus (PNDM) and neurological abnormalities due to homozygous NEUROD1 mutations have been published. A 13 year-old female was referred to endocrine department due to hyperglycemia. She was on insulin therapy following a diagnosis of neonatal diabetes mellitus (NDM) at the age of 9-weeks but missed regular follow-up. Parents are second cousin. There was a significant family history of adult onset NIDDM including patient's father. Auxological measurements were within normal ranges. On laboratory examination blood glucose was 33.2 mmol/L with undetectable c-peptide and glycosylated hemoglobin level of 8.9% (73.8 mmol/mol). She had developed difficulty in walking at the age of 4 years which had worsened over time. On further evaluation, a diagnosis of visual impairment, mental retardation, ataxic gait, retinitis pigmentosa and sensory-neural deafness were considered. Cranial magnetic resonance imaging revealed cerebellar hypoplasia. Molecular genetic analysis using targeted next generation sequencing detected a novel homozygous missense mutation, p.Ile150Asn(c.449T>A), in NEUROD1. Both parents and 2 unaffected siblings were heterozygous for the mutation. We report the third case of PNDM with neurological abnormalities caused by homozygous NEUROD1 mutation, the first caused by a missense mutation. Heterozygous carriers of the p.Ile150Asn mutation were either unaffected or diagnosed with diabetes in adulthood. It is currently unclear whether the NEUROD1 heterozygous mutation has contributed to diabetes development in these individuals.	0
We report the case of an adolescent with hypohidrotic ectodermal dysplasia, who had obsessive-compulsive disorder and was later diagnosed with body dysmorphic disorder (BDD). BDD is a highly distressing, adolescent-onset disorder that may lead to social isolation, the development of comorbid mental health disorders and suicidality. Patients typically lack insight into their BDD and frequently present to dermatologists for medical treatment. In this paper, we address the challenges faced when working with patients with BDD.	0
This study explored the taxonomy of cognitive impairment within temporal lobe epilepsy and characterized the sociodemographic, clinical and neurobiological correlates of identified cognitive phenotypes. 111 temporal lobe epilepsy patients and 83 controls (mean ages 33 and 39, 57% and 61% female, respectively) from the Epilepsy Connectome Project underwent neuropsychological assessment, clinical interview, and high resolution 3T structural and resting-state functional MRI. A comprehensive neuropsychological test battery was reduced to core cognitive domains (language, memory, executive, visuospatial, motor speed) which were then subjected to cluster analysis. The resulting cognitive subgroups were compared in regard to sociodemographic and clinical epilepsy characteristics as well as variations in brain structure and functional connectivity. Three cognitive subgroups were identified (intact, language/memory/executive function impairment, generalized impairment) which differed significantly, in a systematic fashion, across multiple features. The generalized impairment group was characterized by an earlier age at medication initiation (P < 0.05), fewer patient (P < 0.001) and parental years of education (P < 0.05), greater racial diversity (P < 0.05), and greater number of lifetime generalized seizures (P < 0.001). The three groups also differed in an orderly manner across total intracranial (P < 0.001) and bilateral cerebellar cortex volumes (P < 0.01), and rate of bilateral hippocampal atrophy (P < 0.014), but minimally in regional measures of cortical volume or thickness. In contrast, large-scale patterns of cortical-subcortical covariance networks revealed significant differences across groups in global and local measures of community structure and distribution of hubs. Resting-state fMRI revealed stepwise anomalies as a function of cluster membership, with the most abnormal patterns of connectivity evident in the generalized impairment group and no significant differences from controls in the cognitively intact group. Overall, the distinct underlying cognitive phenotypes of temporal lobe epilepsy harbor systematic relationships with clinical, sociodemographic and neuroimaging correlates. Cognitive phenotype variations in patient and familial education and ethnicity, with linked variations in total intracranial volume, raise the question of an early and persisting socioeconomic-status related neurodevelopmental impact, with additional contributions of clinical epilepsy factors (e.g., lifetime generalized seizures). The neuroimaging features of cognitive phenotype membership are most notable for disrupted large scale cortical-subcortical networks and patterns of functional connectivity with bilateral hippocampal and cerebellar atrophy. The cognitive taxonomy of temporal lobe epilepsy appears influenced by features that reflect the combined influence of socioeconomic, neurodevelopmental and neurobiological risk factors.	0
Scleromyxedema or generalized lichen myxedematosus is a rare depositional disorder. Diagnostic criteria encompass a generalized papular and sclerodermoid eruption, monoclonal gammopathy (paraproteinemia), most often with G-lambda type immunoglobulin, a characteristic microscopic triad (mucin deposition, fibroblast proliferation, fibrosis), and absence of thyroid disease. Many internal manifestations of scleromyxedema have been described to date, leading to high mortality and morbidity. Because the disease is rare, the etiology is not fully understood and there is a lack of well-designed studies, so no optimal treatment exists so far. This paper reports the follow-up on a patient in 5.5-year remission after successful intravenous immunoglobulin therapy 10.5 years since initial diagnosis.	0
Once-a-week cotrimoxazole is an effective prophylaxis for pneumocystosis during antineoplastic chemotherapy or autologous stem cell transplant. Following allogeneic stem cell transplant, this schedule is at risk of pneumocystosis or neurotoxoplasmosis, as demonstrated by these case reports. Therefore, a 3-times-a-week schedule must be adopted in these patients.	0
Fournier gangrene is an emergency condition that is associated with a high mortality rate. It is defined as a rapidly progressing infective necrotizing fasciitis of the perineal, perianal, and genital regions. Early diagnosis, broad-spectrum antibiotic coverage, and adequate surgical debridement are crucial and lead to better prognosis and patient survival. There is increasing utilization of computed tomography (CT) in the initial evaluation of Fournier gangrene. CT can confirm the diagnosis in equivocal cases, determine the source of infection, and evaluate the disease extent. In this pictorial review, we discuss the pathogenesis of Fournier gangrene and display the imaging spectrum with an emphasis on CT findings, including asymmetrical fascial thickening, soft tissue stranding, soft tissue gas, collection, and abscess formation. The infection originating from colorectal pathology, the affected anatomy, and the involvement of the abdominal wall are important predictors of mortality. The familiarity of the varied imaging appearance of Fournier gangrene is necessary to provide an accurate diagnosis, and evaluation of disease extent is crucial for optimal surgical debridement.	0
OBJECTIVE:To determine if findings of "cartilage icing" and chondrocalcinosis on knee radiography can differentiate between gout and calcium pyrophosphate deposition (CPPD). METHODS:IRB-approval was obtained and informed consent was waived for this retrospective study. Electronic medical records from over 2.3 million patients were searched for keywords to identify subjects with knee aspiration-proven cases of gout or CPPD. Radiographs were reviewed by two fellowship-trained musculoskeletal radiologists in randomized order, blinded to the patients' diagnoses. Images were evaluated regarding the presence or absence of cartilage icing, chondrocalcinosis, tophi, gastrocnemius tendon calcification, and joint effusion. Descriptive statistics, sensitivity, specificity, positive and negative predictive values, and accuracy were calculated. RESULTS:From 49 knee radiographic studies in 46 subjects (31 males and 15 females; mean age 66±13 years), 39% (19/49) showed gout and 61% (30/49) CPPD on aspiration. On knee radiographs, cartilage icing showed a higher sensitivity for CPPD than gout (53-67% and 26%, respectively). Chondrocalcinosis also showed a higher sensitivity for CPPD than gout (50-57% versus 5%), with 95% specificity and 94% positive predictive value for diagnosis of CPPD versus gout. Soft tissue tophus-like opacities were present in gout at the patellar tendon (5%, 1/19) and at the popliteus groove in CPPD (15%, 4/27). Gastrocnemius tendon calcification was present in 30% (8/27) of subjects with CPPD, and 5% (1/19) of gout. CONCLUSION:In subjects with joint aspiration-proven crystal disease of the knee, the radiographic finding of cartilage icing was seen in both gout and CPPD. Chondrocalcinosis (overall and hyaline cartilage) as well as gastrocnemius tendon calcification positively correlated with the diagnosis of CPPD over gout.	0
Our objective was to estimate the contemporary incidence and prevalence of sarcoidosis using Swedish population-based register data.Adults with any sarcoidosis-coded visit were identified from the National Patient Register (hospitalisations 1964-2013 and outpatient care 2001-2013). Demographic and medication dispensing data were retrieved from national registers. We estimated the prevalence of sarcoidosis in 2013 overall and by county of residence. The incidence of sarcoidosis during 2003-2012 was estimated by sex, age, education level and year of diagnosis. Case definitions were varied to test their robustness.More than 16 000 individuals had a history of sarcoidosis in 2013. When defined as two or more sarcoidosis-coded visits, the prevalence was 160 per 100 000. Using different definitions, the prevalence ranged from 152 (requiring a specialist visit) to 215 per 100 000 (only one visit required). The highest prevalence was observed in northern less densely populated counties. The incidence was 11.5 per 100 000 per year and varied by -10% to +30% depending on case definition. The incidence peaked in males aged 30-50 years and in females aged 50-60 years, but did not differ by education level and was stable over time.This study represents the largest epidemiological investigation of sarcoidosis using population-based individual-level data. Age at diagnosis in men was 10 years younger than in women and geographical variation was observed.	1
Generalized pigmentation in a child may be seen in a variety of disorders which can be clinically differentiated. Accuracy of diagnosis can be increased by classifications based on both clinical and histological findings. The authors report a case of siblings in whom hyperpigmentation started at age of about 6 mo and was progressing. Histology of skin revealed shortening and blunting of rete ridges with presence of melanocytes in stratum basal layer. This is a rare type of hypermelanosis and termed as universal acquired melanosis or carbon baby syndrome. This is a rare presentation and first case report in siblings.	0
SAPHO (synovitis-acne-pustulosis-hyperostosis-osteitis) syndrome is a chronic inflammatory disease involving multiple organs such as skin and bones. At present, its etiology and pathogenesis are still unclear. Due to the variety of clinical manifestations and the small number of SAPHO syndrome involving the mandible, accurate diagnosis is difficult for oral and maxillofacial surgeons. Here, the authors report that a male patient with SAPHO syndrome involving the maxillofacial skin and mandible, followed for 3 years. We used Tc-MDP (technetium-99 conjugated with methylene disphosphonate) (commercially known as Yunke) to treat this disease and achieved significant clinical treatment. This suggests that Tc-MDP can be used as a bisphosphonate to treat SAPHO syndrome.	0
BACKGROUND:Fraser syndrome or "cryptophthalmos syndrome" is a rare autosomal recessive disease. It is characterized by a group of congenital malformations such as: crytophthalmos, syndactyly, abnormal genitalia, and malformations of the nose, ears, and larynx. Although cryptophthalmos is considered as a main feature of Fraser syndrome, its absence does not exclude the diagnosis. Clinical diagnosis can be made by Thomas Criteria. Here we present the first documented case of Fraser Syndrome in Aleppo, Syria that is characterized by bilateral anophthalmia and intrahepatic biliary atresia. CASE PRESENTATION:During pregnancy, several ultrasound scans revealed hyperechoic lungs, ascites, and unremarkable right kidney at the 19th-week visit; bilateral syndactyly on both hands and feet at the 32nd-week visit. On the 39th week of gestation, the stillborn was delivered by cesarean section due to cephalopelvic disproportion. Gross examination showed bilateral anophthalmia, bilateral syndactyly on hands and feet, low set ears, and ambiguous genitalia. Microscopic examination of the lung, spleen, liver, ovary, and kidneys revealed abnormalities in these organs. CONCLUSION:The diagnosis of Fraser syndrome can be made prenatally and postnatally; prenatally by ultrasound at 18 weeks of gestation and postnatally by clinical examination using Thomas criteria. Moreover, intrahepatic biliary atresia was not described previously with Fraser syndrome; this recommends a more detailed pathologic study for Fraser syndrome cases.	0
Fibrolamellar carcinoma (FLC) is a rare liver cancer that affects adolescents and young adults. Genomic analysis of FLC has revealed a 400 kb deletion in chromosome 19 that leads to the chimeric transcript DNAJB1-PRKACA (DnaJ-PKAc), comprised of the first exon of heat shock protein 40 (DNAJB1) and exons 2-10 of the catalytic subunit of protein kinase A (PRKACA). Here, we report a new zebrafish model of FLC induced by ectopic expression of zebrafish Dnaja-Pkaca (zfDnaJa-Pkaca) in hepatocytes that is amenable to live imaging of early innate immune inflammation. Expression of zfDnaJa-Pkaca in hepatocytes induces hepatomegaly and increased hepatocyte size. In addition, FLC larvae exhibit early innate immune inflammation characterized by early infiltration of neutrophils and macrophages into the liver microenvironment. Increased Caspase-a (the zebrafish homolog for human caspase-1) activity was also found in the liver of FLC larvae, and pharmacological inhibition of Tnfα and caspase-a decreased liver size and inflammation. Overall, these findings show that innate immune inflammation is an early feature in a zebrafish model of FLC and that pharmacological inhibition of TNFα or caspase-1 activity might be targets to treat inflammation and progression in FLC patients.This article has an associated First Person interview with the first author of the paper.	0
OBJECTIVE:To perform prenatal diagosis for two fetuses carrying partial deletion of Y chromosome. METHODS:Routine G- and C-banding were carried out to analyze the chromosomal karyotypes of the fetuses and their fathers. Fetal DNA was also subjected to low-coverage massively parallel copy number variation sequencing (CNV-seq), fluorescence in situ hybridization (FISH), SRY gene and AZF factor testing. RESULTS:Both fetuses showed a 46, XN, del(Y) (q11.2) karyotype at 320-400 band level by the analysis of amniotic fluid chromosomes. FISH with Y chromosome centromere probe indicated that in both cases the number of Y chromosome was normal. Both fathers had an apparently normal karyotype at 320-400 band level. For fetus 1, CNV-seq test revealed a 12.88 Mb deletion at Yq11.221-q12, which encompassed the whole of AZFb+AZFc regions and may lead to male infertility, sperm deficiency and/or severe oligospermia. In fetus 2, CNV-seq also detected a 14.84 Mb deletion at Yq11.21-q12, which encompassed the whole of the AZF region and may lead to severe spermatogenesis disorder resulting in severe oligoasthenospermia and azoospermia. In both cases, testing of SRY gene was positive. No point mutation of the SRY gene was identified. Analysis of amniotic fluid DNA confirmed partial or total absence of AZF in the two fetuses, respectively. CONCLUSION:Combined use of various technologies can enable accurate detection of structural abnormalities of the Y chromosome and facilitate genetic counseling. CNV-seq can help with rapid screening of Y chromosome microdeletions and may be used as a complementary test for chromosomal karyotyping.	0
BACKGROUND:Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disorder of the central nervous system that predominantly targets optic nerves and spinal cord. Studies of NMOSD are scarce in the Middle East. OBJECTIVE:To evaluate the MRI characteristics of NMOSD patients in Kuwait. PATIENT AND METHODS:This is an observational, retrospective study on NMOSD patients who attended the MS clinic. Patients who fulfilled the 2015 diagnostic criteria of NMOSD were included. Patients` clinical, radiological and serological data were extracted from the medical records. The radiological variables were compared according to gender and AQP4 serostatus. RESULTS:Forty-two patients fulfilling the NMOSD diagnostic criteria. The mean age and mean age of onset were 32.6 ± 11.4 and 28.9 ± 9.8 years respectively. Females represented 83.3 % of the cohort with female-to-male ratio of 5:1. Thirty-one patients (73.8 %) tested positive for AQP4 antibody. Nineteen patients (45.2 %) had bilateral optic nerve involvement, while chiasmal involvement was seen in 8 (19.0 %) patients. Spinal cord was involved in 36 (85.7 %) patients; of whom 27 (64.3 %) had LETM. The most common spinal segment involved was the cervical (72.2 %) followed by the dorsal (25.0 %) regions. The brain was involved in 39 (92.8 %) patients and the periventricular region around fourth and lateral ventricles was the most commonly involved site (n = 35; 83.3 %), along with periaqueductal (n = 25; 61.9 %) and corpus callosal (n = 24; 57.1 %) regions. Isolated area postrema involvement was observed in 9 (21.4 %) patients. CONCLUSION:This is the first study describing the radiological characteristics of NMOSD in Kuwait. Although our data is comparable with the previous international studies, a higher percentage of bilateral optic nerve, brain, and callosal involvement was observed. Further multicenter studies with a larger cohort are needed to confirm our results.	0
Background:In vitro fertilization with preimplantation genetic testing is a growing reproductive option for people who want to avoid passing a single-gene condition on to their offspring. The spinocerebellar ataxias are a group of rare, autosomal-dominant neurodegenerative disorders which are strong candidates for the use of this technology. Objectives:This study aimed to assess knowledge of genetic risk and perceptions of reproductive options in individuals with a diagnosis of spinocerebellar ataxia. Methods:We administered an online survey to U.S. residents of reproductive age who have been clinically or genetically diagnosed with spinocerebellar ataxia. We assessed their understanding of inheritance and their reproductive opinions. Results:Of 94 participants, 70.2% answered all four inheritance questions correctly. The majority felt they could describe each reproductive option except prenatal diagnosis. Individuals were most interested in in vitro fertilization with preimplantation genetic testing: 48.4% (45 of 93) said they would consider it. They were least interested in prenatal diagnosis and donated embryos or gametes. Having spinocerebellar ataxia with anticipation and choosing inheritance risk as an important factor were both significantly associated with interest in preimplantation genetic testing. Choosing religion/morality as an important factor was associated with less interest in preimplantation genetic testing and prenatal diagnosis. Conclusions:Our population displayed basic knowledge of inheritance risk, and the majority wanted to avoid having affected children. Consistent with literature for other autosomal-dominant adult-onset conditions, individuals showed a preference for preimplantation genetic testing. Health care providers should continue to educate patients about reproductive options and their risks and limitations.	0
Magic syndrome is a very uncommon disease, and vascular involvement is exceptional; only one case has been reported in the literature associated to a true aortic aneurysm. The treatment of aneurysms recommended in these patients is based on isolated cases and includes corticosteroids, other immunosuppressant drugs, and surgery. We report a case of a patient with Magic syndrome who developed aneurysm at the end of the aorta during treatment with infliximab, corticosteroids, and cyclosporine and who needed endovascular prosthesis implantation. After 12 months, she suffered an aneurysm of the ascending aorta, dilatation of the sinotubular junction, and severe aortic insufficiency, which forced surgery. During this time, the patient finally died.	0
Familial leucine-sensitive hypoglycemia of infancy was described in 1956 as a condition in which symptomatic hypoglycemia was provoked by protein meals or the amino acid, leucine. The purpose of this study was to determine the genetic basis for hypoglycemia in a family diagnosed with leucine-sensitive hypoglycemia in 1960. Recently diagnosed family members showed a dominantly transmitted pattern of diazoxide-responsive hyperinsulinism (HI). However, they did not fit the characteristics of HI caused by glutamate dehydrogenase gene mutations, previously felt to explain leucine-sensitive hypoglycemia. Islet function was examined using acute insulin response (AIR) tests to calcium, leucine, glucose, and tolbutamide as well as oral protein tolerance tests. Five of five affected family members showed an abnormal positive calcium AIR, and two of five showed a positive leucine AIR. Protein-induced hypoglycemia was demonstrated in five of six affected subjects. Mutation analysis of four known HI genes (sulfonylurea receptor 1, Kir6.2, glutamate dehydrogenase, and glucokinase) in family members identified an R1353H missense mutation in exon 33 of SUR1. (86)Rb(+) efflux and electrophysiological studies of R1353H SUR1 coexpressed with wild-type Kir6.2 in COSm6 cells demonstrated partially impaired ATP-dependent potassium channel function. Leucine-sensitive hypoglycemia in this family was found to result from a dominantly expressed SUR1 mutation.	0
DISEASE OVERVIEW:Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS), now classified under myelodysplastic syndromes with RS (MDS-RS) and RARS with thrombocytosis (RARS-T); now called myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T). DIAGNOSIS:MDS-RS is a lower-risk MDS, with single or multilineage dysplasia (SLD/MLD), <5% bone marrow (BM) blasts and ≥ 15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥450 × 10(9)/L and large atypical megakaryocytes. MUTATIONS AND KARYOTYPE:Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F, ASXL1, DNMT3A, SETBP1, and TET2 mutations. Cytogenetic abnormalities are uncommon in both. RISK STRATIFICATION:Most patients with MDS-RS-SLD are stratified into lower-risk groups by the revised-IPSS. Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia. Both diseases have a low risk of leukemic transformation. TREATMENT:Anemia and iron overload are complications seen in both and are managed similar to lower-risk MDS and MPN. The advent of luspatercept, a first-in-class erythroid maturation agent will tremendously boost the ability to manage anemia. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs remains uncertain.	0
Spondylospinal thoracic dysostosis can be considered a type of spondylocostal dysostosis because of the occurrence of vertebral defects (hemivertebrae and vertebral body fusion) and thoracic anomalies (short thorax and pulmonary hypoplasia). This syndrome was described by Johnson et al. (1997) in two siblings with dwarfism, short thorax, curved spine, fusion of the vertebrae and spinal process, multiple pterygium, and arthrogryposis. We describe the case of a 16-year-old Mexican girl with the longest survival recorded (the previous oldest patient was 7 years old) and analyze the natural history and describe some new features of this rare entity.	0
Joubert syndrome is a rare autosomal recessive neurodevelopmental disease characterized by abnormal breathing patterns composed of episodic tachypnea/apnea, hypotonia, ataxia, developmental delay, intellectual impairment, ocular impairment, renal cysts, and hepatic fibrosis. We report the case of a 4-year-old boy who presented with global developmental delay, bilateral nystagmus, and gaze instability with difficulty walking and maintaining an upright posture. A detailed examination revealed facial dysmorphic features with a depressed nasal bridge and deepened orbital sockets. Neurological examination yielded positive results for hypotonia, gait ataxia, bilateral horizontal pendular nystagmus, and a grade 1 ptosis more prominent in the right eye. However, no abnormal breathing patterns were observed in our case. Magnetic resonance imaging revealed the characteristic molar tooth sign and a batwing appearance of the fourth ventricle.	0
Olmsted syndrome (OS) is a rare disorder characterized by the combination of periorificial, keratotic plaques, and bilateral palmoplantar keratoderma. Synonyms are mutilating palmoplantar keratoderma with periorificial keratotic plaques (ORPHA659, MIM #614594 and #300918). A number sign (#) is used with this entry because of evidence that mutilating palmoplantar keratoderma with periorificial keratotic plaques (OS) is caused by heterozygous mutation in the TRPV3 gene on chromosome 17p13.2. We report three cases of OS, two females and one male in the same family, who presented with palmoplantar keratoderma, sparse scalp hair, cheilitis, and periorificial fissures. We are reporting the cases due to the rarity of occurrence and to highlight the trichoscopy findings.	0
BACKGROUND:When tested in a controlled clinic environment, individuals with neuromuscular-related symptoms may complete motor tasks within normal predicted ranges. However, measuring activity at home may better reflect typical motor performance. The accuracy of accelerometry measurements in individuals with congenital muscular dystrophy (CMD) is unknown. We aimed to compare accelerometry and manual step counts and assess free-living physical activity intensity in individuals with CMD using accelerometry. METHODS:Ambulatory pediatric CMD participants (n = 9) performed the 6-minute walk test in clinic while wearing ActiGraph GT3X accelerometer devices. During the test, manual step counting was conducted to assess concurrent validity of the ActiGraph step count in this population using Bland-Altman analysis. In addition, activity intensity of 6 pediatric CMD participants was monitored at home with accelerometer devices for an average of 7 days. Cut-point values previously validated for neuromuscular disorders were used for data analysis. RESULTS:Bland-Altman and intraclass correlation analyses showed no concurrent validity between manual and ActiGraph-recorded step counts. Fewer steps were recorded by ActiGraph step counts compared with manual step counts (411 ± 74 vs 699 ± 43, respectively; P = .004). Although improved, results were in the same direction with the application of low-frequency extension filters (587 ± 40 vs 699 ± 43, P = .03). ActiGraph step-count data did not correlate with manual step count (Spearman ρ = 0.32, P = .41; with low-frequency extension: Spearman ρ = 0.45, P = .22). Seven-day physical activity monitoring showed that participants spent more than 80% of their time in the sedentary activity level. CONCLUSIONS:In a controlled clinic setting, step count was significantly lower by ActiGraph GT3X than by manual step counting, possibly because of the abnormal gait in this population. Additional studies using triaxial assessment are needed to validate accelerometry measurement of activity intensity in individuals with CMD. Accelerometry outcomes may provide valuable measures and complement the 6-minute walk test in the assessment of treatment efficacy in CMD.	0
The association of immunodeficiency-related vaccine-derived rubella virus (iVDRV) with cutaneous and visceral granulomatous disease has been reported in patients with primary immunodeficiency disorders (PIDs). The majority of these PID patients with rubella-positive granulomas had DNA repair disorders. To support this line of inquiry, we provide additional descriptive data on seven previously reported patients with Nijmegen breakage syndrome (NBS) (n = 3) and ataxia telangiectasia (AT) (n = 4) as well as eight previously unreported patients with iVDRV-induced cutaneous granulomas and DNA repair disorders including NBS (n = 1), AT (n = 5), DNA ligase 4 deficiency (n = 1), and Artemis deficiency (n = 1). We also provide descriptive data on several previously unreported PID patients with iVDRV-induced cutaneous granulomas including cartilage hair hypoplasia (n = 1), warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome (n = 1), MHC class II deficiency (n = 1), Coronin-1A deficiency (n = 1), X-linked severe combined immunodeficiency (X-SCID) (n = 1), and combined immunodeficiency without a molecular diagnosis (n = 1). At the time of this report, the median age of the patients with skin granulomas and DNA repair disorders was 9 years (range 3-18). Cutaneous granulomas have been documented in all, while visceral granulomas were observed in six cases (40%). All patients had received rubella virus vaccine. The median duration of time elapsed from vaccination to the development of cutaneous granulomas was 48 months (range 2-152). Hematopoietic cell transplantation was reported to result in scarring resolution of cutaneous granulomas in two patients with NBS, one patient with AT, one patient with Artemis deficiency, one patient with DNA Ligase 4 deficiency, one patient with MHC class II deficiency, and one patient with combined immunodeficiency without a known molecular etiology. Of the previously reported and unreported cases, the majority share the diagnosis of a DNA repair disorder. Analysis of additional patients with this complication may clarify determinants of rubella pathogenesis, identify specific immune defects resulting in chronic infection, and may lead to defect-specific therapies.	0
BACKGROUND:Glomerulopathy with fibronectin deposits is an autosomal dominant disease associated with proteinuria, hematuria, hypertension and renal function decline. Forty percent of the cases are caused by mutations in FN1, the gene that encodes fibronectin. CASE PRESENTATION:This report describes two cases of Glomerulopathy with fibronectin deposits, involving a 47-year-old father and a 14-year-old son. The renal biopsies showed glomeruli with endocapillary hypercellularity and large amounts of mesangial and subendothelial eosinophilic deposits. Immunohistochemistry for fibronectin was markedly positive. Whole exome sequencing identified a novel FN1 mutation that leads to an amino-acid deletion in both patients (Ile1988del), a variant that required primary amino-acid sequence analysis for assessment of pathogenicity. Our primary sequence analyses revealed that Ile1988 is very highly conserved among relative sequences and is positioned in a C-terminal FN3 domain containing heparin- and fibulin-1-binding sites. This mutation was predicted as deleterious and molecular mechanics simulations support that it can change the tertiary structure and affect the complex folding and its molecular functionality. CONCLUSION:The current report not only documents the occurrence of two GFND cases in an affected family and deeply characterizes its anatomopathological features but also identifies a novel pathogenic mutation in FN1, analyzes its structural and functional implications, and supports its pathogenicity.	0
We report a 65 year-old man with a large cystic phyllodes tumor of the prostate. The patient complained of abdominal discomfort and had a soft palpable mass. Computer tomography showed a solid and cystic mass in the pelvic fossa; the mass was adjacent only to the prostate. We excised the mass. Microscopic findings of the mass showed hyperplastic epithelium lined cysts with leaf-like intraluminal epithelia lined stromal projections, less than 2 mitotic counts/10 HPF, low-to-moderated cellularity, and mild-to-moderate cytoplasm atypia. The pathological findings were consistent with a phyllodes tumor of the prostate, a low-grade tumor. Twenty-eight months after the operation, the patient was well with no recurrence or metastases.	0
AIMS: Our purpose was to identify the genetic defect in a Chinese cerulean cataract family. METHODS: After obtaining informed consent, genomic DNA was extracted from leukocytes. Genotyping and 2-point linkage analysis were carried out using the MLINK component of the LINKAGE program package version 5.10. Mutational analysis of the candidate gene was performed by bidirectional sequencing. The structure homology modeling of the mutant protein was based on Swiss-Model Serve, and its structure was displayed and compared with native beta-B2-crystallin using the RasMol software. RESULTS: The disease locus was mapped within a 4.05-cM interval on 22q11.22-22q12.1. By sequencing, a cytosine to thymine transition (NM_000496.2:c.463C>T) was detected in exon 6 of CRYBB2, which resulted in the insertion of a premature stop codon (p.Q155X). In addition, there existed another transition (NM_000496.2:c.471C>T) in the same exon, which does not change the amino acid sequence. Neither NM_000496.2:c.463C>T nor NM_000496.2:c.471C>T were found in 171 normal Chinese controls. The homology modeling showed that the second structure of the mutant protein was different from that of native human beta-B2-crystallin. CONCLUSIONS: This is the first report of congenital cerulean cataract associated with a mutation in CRYBB2 in a Chinese family. This finding further strengthens the association between CRYBB2 and cerulean cataracts. Two transitions, NM_000496.2:c.463C>T and NM_000496.2:c.471C>T, in CRYBB2 are identical to the sequence of CRYBB2P1, which has over 97% homology to CRYBB2. This supports the possibility of gene conversion between CRYBB2 and CRYBB2P1 as a mechanism responsible for congenital cataract.	0
McKusick Kaufman Syndrome (MKS), a rare genetic condition, presents in the neonatal period with a classic triad of postaxial polydactyly, congenital heart disease, and hydrometrocolpos. The diagnosis is typically clinical, based on the presence of polydactyly and hydrometrocolpos.We report the case of a 13-year-old female, who was diagnosed with MKS in infancy and underwent vaginal reconstructive surgery for a urogenital sinus. She was lost to follow-up thereafter. She presented to our institution at age 13 with pyometra, pyosalpinx, and tubo-ovarian abscess due to a stenotic cervix obstructing menstrual outflow.Gynecologic follow-up is imperative in patients with history of vaginal reconstruction to monitor for hematometra from outflow obstruction to prevent life threatening secondary bacterial infections.	0
BACKGROUND:X-linked hydrocephalus (XLH), characterized by mental retardation and bilateral adducted thumbs, often come out to be a genetic disorder of L1CAM. It codes the protein L1 cell adhesion molecule (L1CAM), playing a crucial role in the development of the nervous system. The objective of the study was to report a new disease-causing mutation site of L1CAM, and gain further insight into the pathophysiology of hydrocephalus. METHODS:We collect the samples of a couple and their second hydrocephalic fetus. Then, the whole-exome sequencing and in-depth mutation analysis were performed. RESULTS:The variant c.2491delG (p.V831fs), located in the exon 19 of L1CAM (chrX:153131214), could damage the L1CAM function by producing a frameshift in the translation of fibronectin type-III of L1CAM. CONCLUSION:We identified a novel disease-causing mutation in L1CAM for the first time, which further confirmed L1CAM as a gene underlying XLH cases.	0
The surgical management of patients with congenital diaphragmatic hernia (CDH) is challenging and ever changing. It requires the highest expertise not only on the surgical level but also of neonatologists and anesthesiologists. In selected patients traditional open surgery is increasingly replaced by thoracoscopic CDH repair in many centers worldwide. Despite obvious and well-described advantages of the minimally invasive approach like a shorter ventilatory time, less pain, a shorter hospital length of stay, and a better cosmesis, important controversies remain. This review discusses hot topics of minimally invasive CDH repair, such as extracorporeal membrane oxygenation, hypercapnia/acidosis, patch repair, surgical training, and recurrence.	0
Calcium (Ca2+ ) acts as a ubiquitous second messenger, and normal cell and tissue physiology strictly depends on the precise regulation of Ca2+ entry, storage, and release. Store-operated Ca2+ entry (SOCE) is a major mechanism controlling extracellular Ca2+ entry, and mainly relies on the accurate interplay between the Ca2+ sensor STIM1 and the Ca2+ channel ORAI1. Mutations in STIM1 or ORAI1 result in abnormal Ca2+ homeostasis and are associated with severe human disorders. Recessive loss-of-function mutations impair SOCE and cause combined immunodeficiency, while dominant gain-of-function mutations induce excessive extracellular Ca2+ entry and cause tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK). TAM and STRMK are spectra of the same multisystemic disease characterized by muscle weakness, miosis, thrombocytopenia, hyposplenism, ichthyosis, dyslexia, and short stature. To date, 42 TAM/STRMK families have been described, and here we report five additional families for which we provide clinical, histological, ultrastructural, and genetic data. In this study, we list and review all new and previously reported STIM1 and ORAI1 cases, discuss the pathomechanisms of the mutations based on the known functions and the protein structure of STIM1 and ORAI1, draw a genotype/phenotype correlation, and delineate an efficient screening strategy for the molecular diagnosis of TAM/STRMK.	0
PURPOSE:Carotid body tumors (CBTs) are rare tumors of the head and neck area. We evaluated outcomes after carotid body tumor resection (CBR) requiring vascular reconstruction. METHODS:We retrospectively reviewed the patients, who underwent CBR in our clinic. Medical records were retrospectively reviewed for clinical data, operative details, Shamblin's classification, complications. Comparisons were performed between those undergoing CBR alone and CBR requiring vascular reconstruction (CBR-VASC). RESULTS:Of the 60 patients, who underwent CBR, 29 (48.3%) underwent vascular reconstruction after the tumor resection. In patients; who underwent carotid endarterectomy and reconstruction of a kinked carotid artery, the blood flow measurements obtained before and after the vascular reconstruction were significantly different. The blood flow measurement parameters obtained before and after the vascular reconstruction were not significantly different in patients undergoing primary repair surgery, patch graft angioplasty, and the use of reversed saphenous vein graft procedures. The overall complication rate was 25% (n = 60) for at least one perioperative problem (CBR 6.4% vs. CBR-VASC 44.8%, p > 0.05). While most patients with Shamblin's class I and II tumors underwent CBR, CBR-VASC was performed more frequently in patients with Shamblin's class III tumors (p = 0.016). The tumor size ( p = 0.016), the volume of intraoperative blood loss (p = 0.002), and the length of hospital stay (p = 0.006) were significantly different between the two groups. The length of the operation time (p = 0.154) and the volume of the postoperative blood drainage (p = 0.122) were not different between the two groups. CONCLUSION:The decision for surgical reconstruction should be made by evaluating the carotid artery blood flow before and after CBR. The type of the reconstruction method does not cause differences in the duration of the surgery and does not elevate the complication rates.	0
The scalp-ear-nipple (SEN) syndrome is an infrequent congenital disease. Its main features are scalp defects, malformed ears, and absence of nipples. Most of the reported cases are autosomal dominant. We report on a patient suffering SEN syndrome with possible autosomal recessive inheritance. It is concluded that SEN syndrome should be recognized as an entity with genetic heterogeneity once there is evidence of different genetic manner of inheritance described in this disease.	0
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a focal epilepsy with attacks typically arising in the frontal lobe during non-rapid eye movement (NREM) sleep. It is characterized by clusters of complex and stereotyped hypermotor seizures, frequently accompanied by sudden arousals. Cognitive and psychiatric symptoms may be also observed. Approximately 12% of the ADNFLE families carry mutations on genes coding for subunits of the heteromeric neuronal nicotinic receptors (nAChRs). This is consistent with the widespread expression of these receptors, particularly the α4β2(*) subtype, in the neocortex and thalamus. However, understanding how mutant nAChRs lead to partial frontal epilepsy is far from being straightforward because of the complexity of the cholinergic regulation in both developing and mature brains. The relation with the sleep-waking cycle must be also explained. We discuss some possible pathogenetic mechanisms in the light of recent advances about the nAChR role in prefrontal regions as well as the studies carried out in murine models of ADNFLE. Functional evidence points to alterations in prefrontal GABA release, and the synaptic unbalance probably arises during the cortical circuit maturation. Although most of the available functional evidence concerns mutations on nAChR subunit genes, other genes have been recently implicated in the disease, such as KCNT1 (coding for a Na(+)-dependent K(+) channel), DEPD5 (Disheveled, Egl-10 and Pleckstrin Domain-containing protein 5), and CRH (Corticotropin-Releasing Hormone). Overall, the uncertainties about both the etiology and the pathogenesis of ADNFLE point to the current gaps in our knowledge the regulation of neuronal networks in the cerebral cortex.	0
Erectile dysfunction and penile shrinkage are the common complications after radical prostatectomy. Penile rehabilitation is widely applied after the surgery. Vacuum therapy is one of the three penile rehabilitation methods used in the clinical setting, but its mechanism is not well known. This study was designed to investigate whether vacuum erectile device (VED) can prevent corporeal veno-occlusive dysfunction and penile shrinkage in the bilateral cavernous nerve crush (BCNC) rat model. Adult male Sprague-Dawley rats were randomly assigned into three groups: sham group, BCNC group, and BCNC + VED group. After 4 weeks, penile length and intracavernosal pressure (ICP) were measured, and then the middle part of the penis was harvested after dynamic infusion cavernosometry to complete the following items: smooth muscle/collagen ratios and collagen I/III ratios; ultramicrostructure of the tunica albuginea, endothelial cell, and smooth muscle cell; and the expression of calponin-1 and osteopontin. The penile shortening, peak ICP and ICP drop rate after alprostadil injection were significantly improved with vacuum therapy after 4-week treatment. Compared with BCNC group, VED significantly increased smooth muscle/collagen ratios, decreased collagen I/III ratios, and preserved the ultramicrostructure of the tunica albuginea, endothelial cell, and smooth muscle cell. The data also showed that animals exposed to VED could partially reverse the expression of calponin-1 and osteopontin induced by BCNC. In conclusion, vacuum therapy is effective to prevent penile shrinkage and veno-occlusive dysfunction in penile rehabilitation, which may be associated with well-preserved structure and function of the tunica albuginea, endothelial cell, and smooth muscle cell.	0
Intralesional triamcinolone acetonide is an effective treatment for acanthoma fissuratum, and recognition of this condition can negate the need for unnecessary surgical intervention.	0
To determine the cortical mechanism that underlies the cognitive impairment and motor disability in hereditary spastic paraplegia (HSP), nine HSP patients from a Chinese family were examined using clinical evaluation, cognitive screening, and genetic testing. Controls were matched healthy subjects. White-matter fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD; tract-based spatial statistics), cortical thickness (FreeSurfer), and subcortical gray matter (FIRST) based on T1-weighted MRI and diffusion tensor imaging were analyzed. A novel mutation in the SPAST gene (NM_014946.3, c.1321+2T>C) was detected. Patients had motor disability and low Montreal Cognitive Assessment (MoCA) scores. Patients showed significantly decreased total gray- and white-matter volumes, corpus callosum volume, cortical thickness, and subcortical gray-matter volume as well as significantly lower FA and AD values and significantly higher MD and RD values in the corpus callosum and corticospinal tract. Cortical thickness, subcortical gray-matter volume, and MoCA score were negatively correlated with disease duration. Cortical thickness in the right inferior frontal cortex was negatively correlated with Spastic Paraplegia Rating Scale score. Cortical thickness and right hippocampus volume were positively correlated with the MoCA score and subscores. In conclusion, brain damage is not restricted to the white matter in SPG4-HSP patients, and widespread gray-matter damage may account for the disease progression, cognitive impairment, and disease severity in SPG4-HSP.	0
An 80-year-old man was admitted to our hospital because of pancytopenia. Bone marrow examination revealed an increase in the number of dysplastic cells indicating trilineage dysplasia. A 5q13q31 deletion was the only genetic abnormality found, and consequently, 5q deletion syndrome was diagnosed. Although lenalidomide therapy was initiated, it had to be discontinued because of Stevens-Johnson syndrome, which occurred during the second course of treatment. There was no discernible hematological improvement, and bone marrow aspiration showed transformation to refractory anemia with excess blasts-2(RAEB-2)after lenalidomide therapy. However, by changing the therapy to azacitidine, cytogenetic remission was achieved.	0
A case of accessory scrotum with duplicated penis (diphallia) in a male fetus is reported because of its rarity. This case is presented with proved negative androgen receptors in the accessory genitalia. The results of excisional surgery as well as immunostaining for androgen receptors in the resected specimens are presented as well. The outcomes of prenatal ultrasonography, clinical examination of the infant, and pathologic findings of the resected accessory genitalia are also discussed.	0
Endochondral ossification at the level of the growth plate, an essential process involved in longitudinal growth, is regulated by hormonal and local factors including C-type natriuretic peptide and its receptor, natriuretic peptide receptor B. Biallelic loss-of-function mutations in the NPR2 gene, which encodes this receptor, cause acromesomelic dysplasia, Maroteaux type (AMDM), a skeletal dysplasia characterized by severe short stature and disproportionate shortening of limbs. Heterozygous NPR2 mutations have been reported in patients previously classified with idiopathic short stature (ISS). We report the presentation of a 7-year-old girl and her mother with short stature, both of whom were identified with the same NPR2 mutation, and who demonstrated clinical and radiological features consistent with a skeletal dysplasia. We also report the patient's response to recombinant human growth hormone (rhGH) over a 2-year period. We encourage clinicians who evaluate children with ISS to consider genetic testing, particularly when the presentation is associated with features suggestive of a skeletal dysplasia.	0
BACKGROUND:Charcot-Marie-Tooth (CMT) disease is a group of hereditary neuropathies with high phenotypic and genetic heterogeneity. In this study, we report a large family with X-linked CMT (CMTX) caused by a novel GJB1 mutation. METHODS:A family with the clinical diagnosis of CMTX was investigated. For mutation analysis, the coding region of GJB1 was sequenced using DNA from 15 family members. The identified GJB1 mutation was investigated by DHPLC in 120 normal controls. Mutation reanalysis was performed based on whole-exome sequencing (WES). Cell transfection studies were performed to characterize the function of the novel mutation. RESULTS:A missense mutation (c.605T>A) in GJB1 was detected in five patients and eight female carriers but not in two unaffected members of the family. The mutation was not found in 120 healthy controls and has not been previously reported. WES excluded other pathogenic mutations in the family. The pathogenicity of the mutation was confirmed by disrupting the membrane localization of the encoded proteins. CONCLUSION:Our findings demonstrate that a novel mutation (c.605T>A) in GJB1 is associated with CMTX and adds to the repertoire of GJB1 mutations related to CMTX.	0
BACKGROUND AND AIMS:We describe the pathophysiology, treatment, and outcome of Crigler-Najjar type 1 syndrome (CN1) in 28 UGT1A1 c.222C>A homozygotes followed for 520 aggregate patient-years. APPROACH AND RESULTS:Unbound ("free") bilirubin (Bf ) was measured in patient sera to characterize the binding of unconjugated bilirubin (BT ) to albumin (A) and validate their molar concentration ratio (BT /A) as an index of neurological risk. Two custom phototherapy systems were constructed from affordable materials to provide high irradiance in the outpatient setting; light dose was titrated to keep BT /A at least 30% below intravascular BT binding capacity (i.e., BT /A = 1.0). Categorical clinical outcomes were ascertained by chart review, and a measure (Lf ) was used to quantify liver fibrosis. Unbound bilirubin had a nonlinear relationship to BT (R2  = 0.71) and BT /A (R2  = 0.76), and Bf as a percentage of BT correlated inversely to the bilirubin-albumin equilibrium association binding constant (R2  = 0.69), which varied 10-fold among individuals. In newborns with CN1, unconjugated bilirubin increased 4.3 ± 1.1 mg/dL per day. Four (14%) neonates developed kernicterus between days 14 and 45 postnatal days of life; peak BT  ≥ 30 mg/dL and BT /A ≥ 1.0 mol:mol were equally predictive of perinatal brain injury (sensitivity 100%, specificity 93.3%, positive predictive value 88.0%), and starting phototherapy after age 13 days increased this risk 3.5-fold. Consistent phototherapy with 33-103 µW/cm2 •nm for 9.2 ± 1.1 hours/day kept BT and BT /A within safe limits throughout childhood, but BT increased 0.46 mg/dL per year to reach dangerous concentrations by 18 years of age. Liver transplantation (n = 17) normalized BT and eliminated phototherapy dependence. Liver explants showed fibrosis ranging from mild to severe. CONCLUSION:Seven decades after its discovery, CN1 remains a morbid and potentially fatal disorder.	0
INTRODUCTION:The glossopharyngeal nerve lies posterior to the internal carotid artery at the submandibular region. The primary objective of this study was to compare ultrasound-guided glossopharyngeal nerve block (UGPNB) and landmark glossopharyngeal nerve block (GPNB). MATERIALS & METHODS:Inclusion criteria were patients with unilateral Eagle syndrome and ear pain. Group UGPNB (N = 25) received three UGPNBs at weekly intervals with 1.5 mL of 0.5% ropivacaine and 20 mg of methylprednisolone. Group GPNB (N = 26) received landmark GPNB. Pain intensity was evaluated with the numerical rating scale (NRS) before every block, 30 minutes after every block, and at one, three, and five weeks after the third block. Quality of life, assessed using the Brief Pain Inventory (BPI), and satisfaction scores were noted. RESULTS:NRS scores before the second and third blocks and a week after were significantly lower in group UGPNB and comparable at weeks 3 and 5. NRS scores 30 minutes after every block were significantly decreased from the preblock values but were comparable between groups. In 68% of patients, a curvilinear probe delineated the internal carotid artery (ICA). Out-of-plane needle trajectory was required in 64% of patients. BPI and satisfaction scores were significantly better in the UGPNB group in the "block" weeks. CONCLUSIONS:UGPNB with 1.5 mL of 0.5% ropivacaine and 20 mg of methylprednisolone injected posterior to the ICA in the submandibular region provides better pain relief for at least a week compared with an extraoral landmark technique when three weekly consecutive blocks are given. In most patients, a curvilinear probe and out-of-plane needle trajectory are most suitable for ultrasound block.	0
BACKGROUND:Takotsubo syndrome is an uncommon, acute, and reversible cardiomyopathy that occurs primarily in postmenopausal females. The clinical presentation of the syndrome resembles acute coronary syndrome, but coronary angiography reveals no obstructive coronary artery disease. Rarely, a catecholamine surge due to pheochromocytoma may induce Takotsubo syndrome. The clinical features of pheochromocytoma include paroxysmal hypertension, headache, palpitations, and profuse sweating. However, owing to the episodic, rather than continued, symptoms and signs of pheochromocytoma, its timely diagnosis poses a challenge for clinicians. Here, we report a rare case of long-term undetected pheochromocytoma leading to Takotsubo syndrome in an older male patient. CASE PRESENTATION:A 70-year-old man presented with paroxysmal chest distress and chest pain. Examinations revealed acute coronary syndrome with normal coronary arteries, heart failure, reversible left ventricular regional wall motion abnormalities, labile blood pressure, a giant left adrenal mass, and extremely high levels of metanephrine and normetanephrine. Clinical manifestations, laboratory reports, and imaging findings suggested a diagnosis of Takotsubo syndrome caused by pheochromocytoma. Supportive therapy, administration of alpha- adrenergic receptor blockers, and left adrenal mass resection resolved the patient's symptoms. A histological examination confirmed the presence of pheochromocytoma. We reviewed his history of midbrain hemorrhage 6 years prior and found a mass in the left adrenal region by reviewing the computed tomography images of the lung that were also taken 6 years prior, on which the pheochromocytoma was evident. CONCLUSIONS:Our case illustrates the importance of understanding the link between pheochromocytoma and Takotsubo syndrome. A diagnosis of pheochromocytoma-induced Takotsubo syndrome should be considered during the differential diagnosis of acute coronary syndrome, especially in patients with labile blood pressure and normal coronary angiography findings; meanwhile, assessments of catecholamines and its metabolites and abdominal computed tomography scan should be performed at the right time. Clinicians should also be alert to potential pheochromocytoma in patients with unexplained cerebral hemorrhage, even in the absence of symptoms of catecholamine excess.	0
The diagnosis of autoimmune gastrointestinal dysmotility requires a high level of clinical suspicion when standard work-up is unrevealing. We report the case of a 56-year-old male patient with history of tobacco use and a subacute presentation of weight loss, vomiting and cerebellar ataxia. The discovery of paraneoplastic type 1 antineuronal nuclear antibodies and neuronal acetylcholine receptor antibodies led to further directed imaging and diagnostic studies in spite of prior negative chest imaging. Bronchoscopy with endobronchial ultrasound was used to confirm a diagnosis of small cell lung cancer and paraneoplastic syndrome as the cause of the presenting upper gastrointestinal symptoms.	0
OBJECTIVE To analyze a neonate with multiple malformations and to correlate its genotype with phenotype. METHODS The karotypes of the child and her parents were subjected to G-banding chromosome analysis, and array comparative genomic hybridization (array-CGH) was used for fine mapping of the aberrant region. RESULTS The karyotype of the child was ascertained as 46,XX,del(18)(p11.2). Array CGH has identified a 9.8 Mb deletion at 18p11.32-p11.22. The patient has presented features such as holoprosencephaly, choanal atresia, heart defect, and craniofacial dysmorphisms. CONCLUSION The de novo 18p deletion probably underlies the main clinical manifestations of the child.	0
Despite progress over the past 30 years, pulmonary arterial hypertension remains a condition with high morbidity and mortality. Pharmacological and technological advances have shifted the approach to treating pulmonary arterial hypertension. Recent developments revolve heavily around novel routes of drug administration and delivery. In 2009, inhaled treprostinil was approved followed by oral treprostinil in 2013 providing patients with more convenient routes of administration compared with the parenteral alternatives. We are on the cusp of having the first fully implantable infusion pump for continuous intravenous treprostinil delivery. In 2019, generic treprostinil was approved, making the medication much more affordable for patients. In this review, we discuss in detail the recent developments surrounding both traditional and novel treprostinil products.	0
Infantile-onset Pompe disease (IOPD) is a life-threatening multi-organ disease caused by an inborn defect of lysosomal acid α-glucosidase (GAA), which can degrade glycogen into glucose. Lack of GAA causes abnormal accumulation of glycogen in the lysosomes, particularly in the skeletal muscle, liver, and heart. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) is the only available treatment; however, its effect varies by organ. Thus, to fully understand the pathomechanism of IOPD, organ-specific disease models are necessary. We previously generated induced pluripotent stem cells (iPSCs) from three unrelated patients with IOPD and establish a skeletal muscle model of IOPD. Here, we used the same iPSC lines as the previous study and differentiated them into hepatocytes. As a result, hepatocytes differentiated from iPSC of IOPD patients showed abnormal accumulation of lysosomal glycogen, the hallmark of Pompe disease. Using this model, we also demonstrated that glycogen accumulation was dose-dependently restored by rhGAA treatment. In conclusion, we have successfully established an in vitro liver model of IOPD using patient-specific iPSCs. This model can be a platform to elucidate the underlying disease mechanism or to be applied to drug-screening. Moreover, our study also suggest that an iPSC-based approach is suitable for modeling of diseases that affect multiple organs like Pompe disease.	0
Idiopathic pulmonary hemosiderosis is characterized by the triad of hemoptysis, iron deficiency anemia and pulmonary infiltrates. Though idiopathic pulmonary hemosiderosis has classically been described as a childhood disease, survival into adulthood is possible. Treatment options for advanced and/or refractory disease is limited, and in our unique case of idiopathic pulmonary hemosiderosis with precapillary pulmonary hypertension, lung transplantation has had a favorable short-term outcome. We also demonstrate that disease recurrence of idiopathic pulmonary hemosiderosis following lung transplantation is possible.	0
Embryonal tumor with multilayered rosettes (ETMR) is a new entity in the group of primitive neuroectodermal tumors of the central nervous system (CNS). It combines histopathological features of neuroblastoma and ependymoblastoma. This tumor occurs mostly in the first five years of life. A hallmark cytogenetic abnormality at the chromosome locus 19q13.42 has been identified. The authors report a case of ETMR in the parietooccipital region in a 3-year-old girl who presented with features of raised intracranial tension. The exact diagnosis could be made by the finding of true rosettes in a single low power field. ETMR is a newly described rare pediatric CNS tumor and large case studies regarding its differentiation from usual PNETs are lacking. Reporting each case with the morphological features of this tumor would add to the existing data on these tumors as regards pathology, diagnosis and management.	0
Biallelic mutations in the AP4B1 gene, encoding adaptor-related protein complex 4 beta-1 subunit, have been recognized as an important cause of a group of conditions leading to adaptor-related protein complex 4 (AP4)-associated hereditary spastic paraplegia (SPG47). We describe a homozygous, known variant c.1160_1161delCA (p.Thr387fs) that was found in the largest ever group of patients coming from four families. The patients exhibited early hypotonia progressing to spastic paraplegia, microcephaly, epilepsy, and central nervous system (CNS) defects and global developmental delay that are consistent with the nature of SPG47. Our findings expand phenotypic spectrum of SPG47 to include polymorphic seizures, mild/moderate intellectual disability, and intracerebral cysts as well as point to founder mutation in AP4 deficiency disorders in apparently non-consanguineous Polish families without shared ancestry.	0
Bronchogenic cysts are generally detected in the mediastinum, along the tracheobronchial tree, or in the lung parenchyma. Subcutaneous presternal bronchogenic cysts have been rarely described, and they are usually of small size (<3 cm) and reported in children. We report a case of giant presternal subcutaneous bronchogenic cyst in a 20-year-old man. Presternal subcutaneous bronchogenic cysts, despite their rarity, should be considered in the differential diagnosis of all subcutaneous cystic masses, independent of their size and the patient's age.	0
Congenital myasthenic syndromes are a group of rare disorders that are clinically and genetically heterogeneous and caused by mutations in the genes encoding proteins of the neuromuscular junction. Here, we described a Chinese family that presented with phenotypes of classic slow-channel congenital myasthenic syndrome (SCCMS).Clinical characteristics and electrophysiological features of three patients from a Chinese family were examined, and next-generation sequencing followed by direct sequencing was carried out.The patients revealed variability in clinical and electrophysiological features. However, weakness, scoliosis, and repetitive-compound muscle action potential were found in all affected members in the family. A heterozygous C>T missense mutation at nucleotide 865 in acetylcholine receptor epsilon-subunit (CHRNE) gene that causes a leucine-to-phenylalanine substitution at position 289 (L289F) was found.We reported a SCCMS family of Chinese origin. In the family, classical clinical phenotype with phenotypic variability among different members was found. Genetic testing could help diagnose this rare disease.	0
Objective  This paper aims to compare clinical and radiographic features of symptomatic and asymptomatic hips in patients with unilateral femoroacetabular impingement syndrome (FAIS) and to establish a correlation between these findings. Methods  This is a retrospective study, based on medical records of patients diagnosed with FAIS between January 2014 and April 2017. The patients were assessed clinically as per the International Hip Outcome Tool 33 (iHOT33) questionnaire, visual analogue pain scale, hip rotation, and hip and knee muscular strength. The radiographic evaluation consisted of measurements of the alpha angle, crossover signal, acetabular retroversion index, ischial spine signal, and posterior wall sign. Results  A total of 45 patients were included in the study, with mean time from symptom onset to diagnosis of 28.6 months and mean iHOT33 score was 39.9. The mean medial rotation was 20.5° in symptomatic hip and 27.2° in asymptomatic hip ( p  < 0.001). The crossover signal was positive on 68.9% of the symptomatic hips and 55.6% of the asymptomatic hips ( p  = 0.03). The mean retroversion index was 0.15 in symptomatic hips and 0.11 in asymptomatic hips ( p  = 0.02). There was a positive correlation between the total time of symptoms and medial hip rotation reduction ( p  = 0.04) and between body mass index (BMI) and medial hip rotation reduction ( p  = 0.02). Conclusion  When comparing clinical and radiographic features, we observed reduction of medial rotation and increase of acetabular retroversion index in the symptomatic hip, as well as association between the long symptom time and the high BMI with loss of medial rotation of the hips.	0
Erythromelalgia is a rare clinical syndrome characterized by a triad of redness, warmth, and burning pain, most notably affecting the extremities. It usually affects the lower extremities (most commonly feet) or may involve upper extremities (hands) in few cases. The episodes are typically precipitated by exercise and relieved by cooling the affected parts. Although erythromelalgia is typically bilateral, it can present unilaterally, especially in secondary cases. Atypical cases presenting with lesions and symptoms solely involving the face have been observed; however, they are extremely rare and are often misdiagnosed. Other terms used to describe the erythromelalgia are burning feet syndrome, erythermalgia, Gerhardt disease, and Mitchell disease.[1][2][3][4]  The term erythromelalgia is derived from the Greek words erythros, meaning "red," melos meaning "limb," and algos meaning "pain." It was first described in 1878 by Silas Weir Mitchell and was initially termed "Mitchell Disease." Smith and Allen proposed another term erythermalgia in 1938 to emphasize the characteristic warmth of this syndrome. Two gentlemen from the Netherland by the names of Drenth and Michiels proposed the name erythromelalgia in 1990.[5]   Classification The term erythromelalgia and erythermalgia were differentiated on the basis of responsiveness to aspirin by Drenth and Michiels and following three categories were established:[6] (a) Erythromelalgia in thrombocythemia: It is platelet mediated and aspirin responsive. This occurs in association with essential thrombocytosis and polycythemia vera. (b) Primary erythermalgia: Refers to an idiopathic or inherited disorder. Also called aspirin resistant erythermalgia of unknown origin. (c) Secondary erythermalgia: Aspirin resistant and associated with different medical conditions.	0
PURPOSE OF REVIEW:We would like to inform clinicians that the systematic administration of oral and intravenous L-arginine is therapeutically beneficial and clinically useful for patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), when they maintain plasma arginine concentration at least 168 μmol/l. RECENT FINDINGS:MELAS is associated with endothelial dysfunction by decreased plasma L-arginine, nitric oxide (NO), and cyclic guanosine monophosphate. Endothelial dysfunction is also evident using flow-mediated vasodilation measurement by high-resolution Doppler echocardiography in the forearm artery in patients with MELAS. L-arginine is known to be an important precursor of NO to normalize the endothelial function in MELAS. In our clinical trial followed by 7 years follow-up study, the systematic administration of L-arginine to patients with MELAS significantly improved the survival curve of patients compared with natural history. Maintaining plasma arginine concentration at least 168 μmol/l may prevent the ictuses through the putative pathophysiologic mechanism and optimal normalization of endothelial dysfunction. SUMMARY:Neither death nor bedriddenness occurred during the 2-year clinical trials, and the latter did not develop during the 7-year follow-up despite the progressively neurodegenerative and eventually life-threatening nature of MELAS. Therapeutic regimen of L-arginine on MELAS may be beneficial and clinically useful for patient care with MELAS.	0
Cerebral folate deficiency (CFD) results in neurological alterations and a massive degeneration of the choroid/retina if left untreated, which limit the visual field and visual acuity. This article reports the case of a female patient with CFD, who developed autistic personal characteristics prior to reaching school age and first started to speak at the age of 3 years. At the age of 6 years she was presented because of unclear reduced visual acuity in the right eye. At that time mild bilateral peripheral chorioretinal atrophy was present, which subsequently became more pronounced. Additionally, a centrally emphasized chorioretinal atrophy further developed. Visual acuity of both eyes progressively deteriorated until stagnating at 0.1 at the age of 14 years. The causal assignment of the findings of the patient was not possible for many years. Choroideremia was excluded by molecular genetic testing (CHM gene with no mutations) and gyrate atrophy was ruled out by a normal ornithine level. The existence of a mitochondrial disease was almost completely excluded by exome sequencing. After the onset of further nonocular symptoms, e.g. neuromuscular disorders, electroencephalograph (EEG) alterations and autistic disorder, intensified laboratory diagnostics were performed in the treating pediatric hospital. Finally, an extremely low level of the folic acid metabolite 5‑methyltetrahydrofolate was detected in the cerebrospinal fluid (CSF) leading to the diagnosis of CFD. High-dose substitution treatment with folic acid was subsequently initiated. After excluding the presence of a pathogenic mutation of the FOLR1 gene for the cerebral folate receptor 1, a high titer blocking autoantibody against cerebral folate receptor 1 was detected as the cause.	0
Salivary gland tumors are uncommon in children. They consist of variable histopathological subtypes of benign and malignant tumors. EMC is a discrete entity among the WHO classification of salivary gland tumors since 1991. EMC is considered a low-grade malignant salivary gland tumor arising from intercalated ducts. Typically, it affects an adult female individual. Surgical resection with a negative margin is the mainstay treatment option. EMC has a potential for metastasis with a high rate of recurrence. Based on the available English literature, two cases of EMC diagnosed in a pediatric age group have been reported. Therefore, we describe the third EMC that developed in the left parotid gland of a young child. The diagnosis of EMC was established through histopathological examination of the total parotidectomy specimen and neck lymph node dissection, together with ancillary studies. Later, the patient suffered from cervical lymph node enlargement due to metastasis in which FNAB was taken. Metastasis from the known EMC was suspected with cytomorphological features in smears and cell block. Immunohistochemistry markers for the biphasic components were supportive of EMC. Due to advanced disease, the patient necessitated a concomitant treatment of radiochemotherapy. Besides, there was radiological evidence of bilateral multiple lung metastatic nodules. However, a biopsy was not sent for pathological confirmation.	0
Intracranial calcifications in the pediatric population can have many etiologies including neoplastic, infectious, neurodegenerative, metabolic, or cerebrovascular abnormalities. We present the case of a 2-year-old boy with vein of Galen malformation, a rare cause of intracranial calcifications with a review of literature.	0
Actin, an ATPase superfamily protein, regulates some vital biological functions like cell locomotion, cytokinesis, synaptic plasticity and cell signaling in higher eukaryotes, and is dependent on the dynamics of actin polymerization process. Impaired regulation of actin polymerization has been implicated in the formation and deposition of rod-like paracrystalline structures called as Hirano bodies in neuronal cells of patients suffering from Alzheimer's disease, Pick's disease, Guam amyotrophic lateral sclerosis and parkinsonism-dementia complex. Aggregation of actin forming amorphous deposition in the brain cells is also associated with chronic alcoholism and aging of the neurons. In the current article, we propose the breaking of the highly amorphous and dysregulated actin aggregates using generic compounds like tetracycline, oxytetracycline, doxycycline and minocycline which are used as antibiotics against tuberculosis and infection caused due to various Gram-negative bacteria. We have investigated the effect and affinity of binding of these four compounds to that of actin aggregates using 90° light scattering, size exclusion chromatography, dynamic light scattering, circular dichroism, scanning electron microscopy, transmission electron microscopy imaging and kinetic analysis. The isothermal calorimetric measurements showed that the binding constant for the cycline family molecules used in this study range from 9.8 E4 M-1 to 1.3 E4 M-1. To understand the in vivo effect, we also studied the effect of these drugs on Saccharomyces cerevisiae Δend3 mutant cells. Our data suggest that these generic compounds can plausibly be used for the treatment of various neurodegenerative diseases occurring due to Hirano body formation in brain cells.Communicated by Ramaswamy H. Sarma.	0
To review the efficacy and safety of pharmacological and nonpharmacological strategies used to treat primary orthostatic hypotension (OH).A literature review using PubMed and MEDLINE databases searching hypotension, non-pharmacological therapy, midodrine, droxidopa, pyridostigmine, fludrocortisone, atomoxetine, pseudoephedrine, and octreotide was performed.Randomized or observational studies, cohorts, case series, or case reports written in English between January 1970 and November 2016 that assessed primary OH treatment in adult patients were evaluated.Based on the chosen criteria, it was found that OH patients make up approximately 15% of all syncope patients, predominantly as a result of cardiovascular or neurological insults, or offending medication. Nonpharmacological strategies are the primary treatment, such as discontinuing offending medications, switching medication administration to bedtime, avoiding large carbohydrate-rich meals, limiting alcohol, maintaining adequate hydration, adding salt to diet, and so on. If these fail, pharmacotherapy can help ameliorate symptoms, including midodrine, droxidopa, fludrocortisone, pyridostigmine, atomoxetine, sympathomimetic agents, and octreotide.Midodrine and droxidopa possess the most evidence with respect to increasing blood pressure and alleviating symptoms. Pyridostigmine and fludrocortisone can be used in patients who fail to respond to these agents. Emerging evidence with low-dose atomoxetine is promising, especially in those with central autonomic failure, and may prove to be a viable alternative treatment option. Data surrounding other therapies such as sympathomimetic agents or octreotide are minimal. Medication management of primary OH should be guided by patient-specific factors, such as tolerability, adverse effects, and drug-drug and drug-disease interactions.	0
OBJECTIVE:To evaluate the effect of definitive radiotherapy dose on survival in patients with human papillomavirus positive oropharyngeal carcinoma. METHODS:Human papillomavirus positive oropharyngeal carcinoma patients staged T1-3 and N0-2c, who received definitive radiotherapy (fraction sizes of 180 cGy to less than 220 cGy), were identified from the National Cancer Database 2010-2014 and stratified by radiation dose (50 Gy to less than 66 Gy, or 66 Gy or more). RESULTS:A total of 2173 patients were included, of whom 124 (6 per cent) received a radiation dose of 50 Gy to less than 66 Gy. With a median follow up of 33.8 months, patients had a 3-year overall survival rate of 88.6 per cent (95 per cent confidence interval = 87.1-90.1 per cent). On multivariate Cox analysis, a radiotherapy dose of 50 Gy to less than 66 Gy (hazard ratio = 0.95, 95 per cent confidence interval = 0.52-1.74, p = 0.86) was not a predictor of increased mortality risk. CONCLUSION:Human papillomavirus positive oropharyngeal carcinoma patients had excellent outcomes with definitive radiotherapy doses of 50 Gy to less than 66 Gy. These results further support patients enrolling into clinical trials for radiation dose de-escalation.	0
OBJECTIVE:Propriospinal myoclonus (PSM) is a rare disorder with repetitive, usually flexor arrhythmic brief jerks of the trunk, hips, and knees in a fixed pattern. It has a presumed generation in the spinal cord and diagnosis depends on characteristic features at polymyography. Recently, a historical paradigm shift took place as PSM has been reported to be a functional (or psychogenic) movement disorder (FMD) in most patients. This review aims to characterize the clinical features, etiology, electrophysiologic features, and treatment outcomes of PSM. METHODS:Re-evaluation of all published PSM cases and systematic scoring of clinical and electrophysiologic characteristics in all published cases since 1991. RESULTS:Of the 179 identified patients with PSM (55% male), the mean age at onset was 43 years (range 6-88 years). FMD was diagnosed in 104 (58%) cases. In 12 cases (26% of reported secondary cases, 7% of total cases), a structural spinal cord lesion was found. Clonazepam and botulinum toxin may be effective in reducing jerks. CONCLUSIONS:FMD is more frequent than previously assumed. Structural lesions reported to underlie PSM are scarce. Based on our clinical experience and the reviewed literature, we recommend polymyography to assess recruitment variability combined with a Bereitschaftspotential recording in all cases.	0
Maintaining mitochondrial health is emerging as a keystone in aging and associated diseases. The selective degradation of mitochondria by mitophagy is of particular importance in keeping a pristine mitochondrial pool. Indeed, inherited monogenic diseases with defects in mitophagy display complex multisystem pathologies but particularly progressive neurodegeneration. Fortunately, therapies are being developed that target mitophagy allowing new hope for treatments for previously incurable diseases. Herein, we describe mitophagy and associated diseases, coin the term mitophaging and describe new small molecule interventions that target different steps in the mitophagic pathway. Consequently, several age-associated diseases may be treated by targeting mitophagy.	0
Laurence-Moon-Bardet-Biedl syndrome (LMBBS), a rare autosomal recessive defect, mostly occurs in children born from consanguineous marriages. The major features of this syndrome are cone-rod dystrophy, polydactyly, obesity, learning disabilities, hypogonadism in males, renal anomalies, nystagmus, speech disorders, developmental delay, polyuria/polydipsia, ataxia, and poor coordination/clumsiness. In this report, we present a case of a 19-year-old man with pain and swelling of the left ankle and knee joints because of which he could not walk, with an onset of loose stools since a week. He presented with multiple non-itchy hyperpigmented macules on his face and back, polydactyly in his left foot, central obesity, proteinuria, macrocytic anemia, low intelligence quotient, reduced power in the left lower limb, reduced plantar reflexes, nystagmus, pigmented black lesions in the temporal retina on fundoscopy, a micropenis, absent pubic and axillary hair, and a small scrotum containing testes. The patient was diagnosed with LMBBS.	0
Infectious bursal disease (IBD) is an acute, highly contagious and immunosuppressive avian disease caused by infectious bursal disease virus (IBDV). In recent years, remarkable progress has been made in the understanding of the pathogenesis of IBDV infection and the host response, including apoptosis, autophagy and the inhibition of innate immunity. Not only a number of host proteins interacting with or targeted by viral proteins participate in these processes, but microRNAs (miRNAs) are also involved in the host response to IBDV infection. If an IBDV-host interaction at the protein level is taken imaginatively as the front line of the battle between invaders (pathogens) and defenders (host cells), their fight at the RNA level resembles the hidden front line. miRNAs are a class of non-coding single-stranded endogenous RNA molecules with a length of approximately 22 nucleotides (nt) that play important roles in regulating gene expression at the post-transcriptional level. Insights into the roles of viral proteins and miRNAs in host response will add to the understanding of the pathogenesis of IBDV infection. The interaction of viral proteins with cellular targets during IBDV infection were previously well-reviewed. This review focuses mainly on the current knowledge of the host response to IBDV infection at the RNA level, in particular, of the nine well-characterized miRNAs that affect cell apoptosis, the innate immune response and viral replication.	0
Hypoglycaemia in infants and children is caused by a number of endocrine and metabolic defects, some of which are unique to this age group. Growth hormone deficiency (GHD) has been rarely reported as a cause of recurrent fasting hypoglycaemia in children. An 18-month-old male child presented to us for evaluation of neuroglycopenic symptoms caused by recurrent episodes of fasting hypoglycaemia. Laboratory evaluation revealed ketotic hypoinsulinaemic hypoglycaemia. The child was diagnosed to have GHD on the basis of two failed stimulation tests. A detailed work-up for metabolic and other hormonal causes of hypoglycaemia was negative. We present the case for its rarity and to highlight the importance of a detailed metabolic and hormonal assessment in evaluation of childhood hypoglycaemia.	0
The prevention of relapse is the major therapeutic challenge in older patients with acute myeloid leukemia (AML) who have obtained a complete remission (CR) on intensive chemotherapy. In this randomized phase 3 study (HOVON97) in older patients (≥60 years) with AML or myelodysplastic syndrome with refractory anemia with excess of blasts, in CR/CR with incomplete hematologic recovery (CRi) after at least 2 cycles of intensive chemotherapy, we assessed the value of azacitidine as postremission therapy with respect to disease-free survival (DFS; primary end point) and overall survival (OS; secondary end point). In total, 116 eligible patients were randomly (1:1) assigned to either observation (N = 60) or azacitidine maintenance (N = 56; 50 mg/m2, subcutaneously, days 1-5, every 4 weeks) until relapse, for a maximum of 12 cycles. Fifty-five patients received at least 1 cycle of azacitidine, 46 at least 4 cycles, and 35 at least 12 cycles. The maintenance treatment with azacitidine was feasible. DFS was significantly better for the azacitidine treatment group (logrank; P = .04), as well as after adjustment for poor-risk cytogenetic abnormalities at diagnosis and platelet count at randomization (as surrogate for CR vs CRi; Cox regression; hazard ratio, 0.62; 95% confidence interval, 0.41-0.95; P = .026). The 12-month DFS was estimated at 64% for the azacitidine group and 42% for the control group. OS did not differ between treatment groups, with and without censoring for allogeneic hematopoietic cell transplantation. Rescue treatment was used more often in the observation group (n = 32) than in the azacitidine maintenance group (n = 9). We conclude that azacitidine maintenance after CR/CRi after intensive chemotherapy is feasible and significantly improves DFS. The study is registered with The Netherlands Trial Registry (NTR1810) and EudraCT (2008-001290-15).	0
OBJECTIVE:To explore the genetic etiology of three pedigrees with a gestational history of fetal renal anomalies. METHODS:Peripheral venous blood or skin samples were derived from the probands of the three pedigrees. Copy number variation sequencing (CNV-seq) was applied to detect alterations of genome CNVs. RESULTS:The patient from pedigree 1 and the fetuses from pedigrees 2 and 3 all carried a heterozygous 17q12 deletion, with the size ranging from 1.4 Mb to 1.48 Mb encompassing the HNF1B gene. CONCLUSION:The diagnosis of 17q12 microdeletion may be difficult during fetal period for its variable phenotypes. Alterations of chromosomal copy numbers need to be excluded in such patients.	0
The Romualdo Formation (Araripe Basin) is worldwide known for the large number of well-preserved fossils but the dinosaur record is rather scarce. Here we describe a new coelurosaur, which is the first tetrapod recovered from the basal layers of this stratigraphic unit that consist of dark shales. Aratasaurus museunacionali gen. et sp. nov. is known by an incomplete but articulated right hind limb with the distal portion of the femur, proximal half of tibia and incomplete pes. The new species differs from other coelurosaurs by a medial fossa in the tibia and digits II, III and IV being symmetric. The phylogenetic analysis recovered Aratasaurus museunacionali closely related to Zuolong salleei, forming a basal coelurosaur lineage. The paleohistology indicate that the specimen is a juvenile, with an estimated body length around 3.12 m. The new taxon represents the first occurrence of basal coelurosaurians in the Araripe Basin and suggests a widespread distribution of this group during the Lower Cretaceous.	0
The RNA exosome is an evolutionarily-conserved ribonuclease complex critically important for precise processing and/or complete degradation of a variety of cellular RNAs. The recent discovery that mutations in genes encoding structural RNA exosome subunits cause tissue-specific diseases makes defining the role of this complex within specific tissues critically important. Mutations in the RNA exosome component 3 (EXOSC3) gene cause Pontocerebellar Hypoplasia Type 1b (PCH1b), an autosomal recessive neurologic disorder. The majority of disease-linked mutations are missense mutations that alter evolutionarily-conserved regions of EXOSC3. The tissue-specific defects caused by these amino acid changes in EXOSC3 are challenging to understand based on current models of RNA exosome function with only limited analysis of the complex in any multicellular model in vivo. The goal of this study is to provide insight into how mutations in EXOSC3 impact the function of the RNA exosome. To assess the tissue-specific roles and requirements for the Drosophila ortholog of EXOSC3 termed Rrp40, we utilized tissue-specific RNAi drivers. Depletion of Rrp40 in different tissues reveals a general requirement for Rrp40 in the development of many tissues including the brain, but also highlight an age-dependent requirement for Rrp40 in neurons. To assess the functional consequences of the specific amino acid substitutions in EXOSC3 that cause PCH1b, we used CRISPR/Cas9 gene editing technology to generate flies that model this RNA exosome-linked disease. These flies show reduced viability; however, the surviving animals exhibit a spectrum of behavioral and morphological phenotypes. RNA-seq analysis of these Drosophila Rrp40 mutants reveals increases in the steady-state levels of specific mRNAs and ncRNAs, some of which are central to neuronal function. In particular, Arc1 mRNA, which encodes a key regulator of synaptic plasticity, is increased in the Drosophila Rrp40 mutants. Taken together, this study defines a requirement for the RNA exosome in specific tissues/cell types and provides insight into how defects in RNA exosome function caused by specific amino acid substitutions that occur in PCH1b can contribute to neuronal dysfunction.	0
OBJECTIVES:To analyze cases of therapy-related acute myeloid leukemia and myelodysplastic syndrome diagnosed after chemotherapy for refractory testicular and extragonadal germ cell tumor in our experience. METHODS:A total of 171 consecutive patients who were diagnosed and treated as refractory germ cell tumor and had records of detailed chemotherapy doses between April 1998 and December 2015 were retrospectively reviewed. RESULTS:Four testicular tumor patients (4/171, 2.3%) developed therapy-related acute myeloid leukemia and myelodysplastic syndrome. Three of them were affected after complete remission of the primary testicular tumor. A median time interval from a start of chemotherapy to a secondary tumor development was 6.8 years (range 3.7-11.5 years). The median total dose of etoposide, ifosfamide, cisplatin and nedaplatin were 3640 mg/m2 (range 2906-4000 mg/m2 ), 42.7 g (range 19.5-54.0 g), 1100 mg/m2 (range 600-1500 mg/m2 ) and 500 mg/m2 (range 300-1600 mg/m2 ), respectively. Etoposide had the only significant relationship between a cumulative dose and leukemogenesis in univariate analysis (P < 0.05). One patient had complete remission, but the other three patients died. CONCLUSIONS:The present findings show that refractory germ cell tumor patients have an increased risk of therapy-related acute myeloid leukemia and myelodysplastic syndrome. A cumulative dose of etoposide is a significant risk of leukemogenesis. As therapy-related acute myeloid leukemia and myelodysplastic syndrome has a poor prognosis, close follow up is required for refractory germ cell tumor patients.	0
Autosomal recessive primary microcephaly (MCPH) is a rare hereditary neurodevelopmental disorder characterized by a marked reduction in brain size and intellectual disability. MCPH is genetically heterogeneous and can exhibit additional clinical features that overlap with related disorders including Seckel syndrome, Meier-Gorlin syndrome, and microcephalic osteodysplastic dwarfism. In this review, we discuss the key proteins mutated in MCPH. To date, MCPH-causing mutations have been identified in twelve different genes, many of which encode proteins that are involved in cell cycle regulation or are present at the centrosome, an organelle crucial for mitotic spindle assembly and cell division. We highlight recent findings on MCPH proteins with regard to their role in cell cycle progression, centrosome function, and early brain development.	0
New neuroprotective treatments of natural origin are being investigated. Both, plant extracts and isolated compounds have shown bioactive effects. Hempseed is known for its composition of fatty acids, proteins, fibre, vitamins, as well as a large number of phytochemical compounds. After a defatting process of the seeds, hydroxycinnamic acids and its amine derivatives are the majoritarian compounds in an ethyl acetate fraction (EAF). In the present study, we investigated in vitro effect on neuronal enzymes: MAO-A, MAO-B, tyrosinase and acetylcholinesterase. Besides, the effect of EAF on striatal biogenic amines in mice was evaluated. Both, EAF and isolated compounds (N-trans-caffeoyltyramine and N-trans-coumaroyltyramine), showed inhibitory action on MAO-A, MAO-B and tyrosinase. Furthermore, an increasing of biogenic amines was observed in the corpus striatum of the mice, after administration of EAF. These findings show that EAF and the hydroxycinnamic acid derivatives may represent a potential treatment in degenerative neuronal diseases.	0
BACKGROUND:De novo malignancy is a severe complication after liver transplantation (LT), but de novo leiomyosarcoma is extremely rare. METHODS:We reported de novo leiomyosarcoma occurring after LT. The patient's status for Epstein-Barr virus was negative. The donor was a 21-year-old man with a central nervous system malignancy who underwent surgery. Three months later brain death occurred and his organs were donated. RESULTS:Leiomyosarcoma in the recipient was detected shortly after LT. It progressed after minimization of immunosuppression and apatinib therapy, and the patient died of cachexia 17 months after LT. CONCLUSIONS:De novo leiomyosarcoma is a rare but serious event after LT, needing comprehensive management.	0
Rheumatoid vasculitis (RV) usually occurs in patients with refractory rheumatoid arthritis (RA). An 80-year-old woman was transferred to our hospital because of muscle weakness and paresthesia in all 4 limbs. She had been diagnosed with RA 30 years ago and achieved sustained clinical remission. At presentation, polyarthritis and drop foot were observed, and rheumatoid factor was prominently elevated. A peripheral nerve conduction test revealed mononeuritis multiplex in her limbs. We suspected that RV had developed rapidly despite RA having been stable for many years and started immunosuppression therapy with steroids combined with azathioprine. The treatment prevented worsening of muscle weakness and paresthesia.	0
Osteosclerotic metaphyseal dysplasia (OSMD) is a rare autosomal recessive sclerosing skeletal dysplasia. We report on a 34-year-old patient with sandwich vertebrae, platyspondyly, osteosclerosis of the tubular bones, pathologic fractures, and anemia. In the third decade, he developed osteonecrosis of the jaws, which was progressive in spite of repeated surgical treatment over a period of 11 years. An iliac crest bone biopsy revealed the presence of hypermineralized cartilage remnants, large multinucleated osteoclasts with abnormal morphology, and inadequate bone resorption typical for osteoclast-rich osteopetrosis. After exclusion of mutations in TCIRG1 and CLCN7 we performed trio-based exome sequencing. The novel homozygous splice-site mutation c.261G>A in the gene LRRK1 was found and co-segregated with the phenotype in the family. cDNA sequencing showed nearly complete skipping of exon 3 leading to a frameshift (p.Ala34Profs*33). Osteoclasts differentiated from the patient's peripheral blood monocytes were extremely large. Instead of resorption pits these cells were only capable of superficial erosion. Phosphorylation of L-plastin at position Ser5 was strongly reduced in patient-derived osteoclasts showing a loss of function of the mutated LRRK1 kinase protein. Our analysis indicates a strong overlap of LRRK1-related OSMD with other forms of intermediate osteopetrosis, but an exceptional abnormality of osteoclast resorption. Like in other osteoclast pathologies an increased risk for progressive osteonecrosis of the jaws should be considered in OSMD, an intermediate form of osteopetrosis. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.	0
Perforating necrobiosis lipoidica (PNL) is a granulomatous inflammatory skin disease that usually occurs in patients with diabetic. We present a case of a female patient affected by a disseminated form of necrobiosis lipoidica.	0
Phosphatidylinositol 3 kinases (PI3K) are a family of lipid kinases that are activated by a variety of cell-surface receptors, and regulate a wide range of downstream readouts affecting cellular metabolism, growth, survival, differentiation, adhesion, and migration. The importance of these lipid kinases in lymphocyte signaling has recently been highlighted by genetic analyses, including the recognition that both activating and inactivating mutations of the catalytic subunit of PI3Kδ, p110δ, lead to human primary immunodeficiencies. In this article, we discuss how studies on the human genetic disorder "Activated PI3K-delta syndrome" and mouse models of this disease (Pik3cdE1020K/+ mice) have provided fundamental insight into pathways regulated by PI3Kδ in T and B cells and their contribution to lymphocyte function and disease, including responses to commensal bacteria and the development of autoimmunity and tumors. We highlight critical roles of PI3Kδ in T follicular helper cells and the orchestration of the germinal center reaction, as well as in CD8+ T-cell function. We further  present data demonstrating the ability of the AKT-resistant FOXO1AAA mutant to rescue IgG1 class switching defects in Pik3cdE1020K/+ B cells, as well as data supporting a role for PI3Kδ in promoting multiple T-helper effector cell lineages.	0
PURPOSE OF REVIEW:Idiopathic pulmonary hemosiderosis (IPH) is one of the rarest and least understood causes of pulmonary hemorrhage in children. Illustrated by a complex case presentation, we discuss the clinical manifestations, diagnosis, pathology, proposed etiologies, and treatment of this rare disease. We also compare IPH with anti-glomerular basement membrane antibody syndrome (anti-GBM disease), another rare causes of pediatric pulmonary hemorrhage. RECENT FINDINGS:Recent retrospective studies regarding IPH along with advanced immunotherapy have led to an improved understanding of how to best treat this condition, potential associations, and improved prognosis. Pathogenesis remains unknown, but several reports have suggested involvement of the alveolar capillary basement membrane. IPH is a poorly understood disease of unknown etiology that is a diagnosis of exclusion. Our patient was diagnosed with IPH after an exhaustive workup, including lung biopsy, into other immune-mediated causes of disease. While the pathogenesis of this rare disease remains elusive, our patient's immunofluorescent staining along the alveolar basement membrane without evidence of circulating antibody to type IV collagen raises the question of an immune-mediated pathogenesis of the disease with involvement of the alveolar basement membrane.	0
In plants, Δ1-pyrroline- 5-carboxylate synthase (P5CS) is the rate-limiting enzyme in proline biosynthesis. In this study, we introduced the LpP5CS (Lolium perenne L.) gene into switchgrass by Agrobacterium-mediated transformation. The transgenic lines (TG) were classified into two groups based on their phenotypes and proline levels. The group I lines (TG4 and TG6) had relatively high proline levels and improved biomass yield. The group II lines (TG1 and TG2) showed low proline levels, severely delayed flowering, stunted growth and reduced biomass yield. Additionally, we used RNA-seq analysis to detect the most significant molecular changes, and we analyzed differentially expressed genes, such as flowering-related and CYP450 family genes. Moreover, the biomass yield, physiological parameters, and expression levels of reactive oxygen species scavenger-related genes under salt stress all indicated that the group I plants exhibited significantly increased salt tolerance compared with that of the control plants, in contrast to the group II plants. Thus, genetic improvement of switchgrass by overexpressing LpP5CS to increase proline levels is feasible for increasing plant stress tolerance.	0
INTRODUCTION:Ciguatera fish poisoning (CFP) is a common Poisoning in the tropical countries. France is directly concerned with French tourists in endemic area and with French citizens living in the French overseas territories. METHOD:Retrospective, descriptive study of CFP cases handled by the French Poison Control Centre Network from 2012 through 2019. RESULTS:Fifty-two events were studied concerning 130 patients. The fish species was identified for 41 events, mainly belonging to five fish families: 14 groupers, 11 snappers, 5 jacks, 4 parrotfishes, 4 barracudas. The origin of the fish was the Atlantic Ocean (23 events), the Indian Ocean (17 events) and the Pacific Ocean (12 events). 91% of the poisonings occurring in the Atlantic Ocean began with gastrointestinal effects while in 44% of events occurring in the Pacific Ocean, the patients had no gastrointestinal effects (onset with neurological symptoms: paraesthesia and dysesthesia). The evolution of the 130 patients has been classic for CFP with persistent symptoms during 1 to 45 weeks. Numerous patients reported exacerbation of neurological signs several months after poisoning following consumption of alcoholic beverages (23 patients) or seafood (19 patients). DISCUSSION:Medical practitioners in Europe must be trained to manage CFP as cases are reported with tourists returning from endemic areas but also with poisoned patients far from tropical areas after consumption of imported fish.	0
We report characteristics of three cases of cavernous haemangioma of the retina, bringing to 37 the number now reported in the available literature. This rare, benign, congenital malformation is non-progressive, usually unilateral, somewhat more frequent in women, and rarely a source of intraocular haemorrhage. The fluorescein angiographic features include a normal arterial and venous supply, extraordinarily slowed venous drainage, no arterio-venous shunting, no disturbances of vascular permeability, and no secondary retinal exudation. Almost always, isolated clusters of vascular globules with plasma/erythrocyte sedimentation surround the main body of the malformation. These findings differentiate the anomaly from other retinal vascular diseases. Therapeutic intervention is seldom necessary.	0
The objective of this study was to investigate the fat and carbohydrate metabolism in a patient with propionic acidemia (PA) during exercise by means of indirect calorimetry and stable isotope technique. A 34-year-old patient with PA performed a 30-minute submaximal cycle ergometer test. Data were compared to results from six gender- and age-matched healthy controls. Main findings are that the patient with PA had impaired lipolysis, blunted fatty acid oxidation, compensatory increase in carbohydrate utilization, and low work capacity. Our findings indicate that PA should be added to the list of metabolic myopathies.	0
Primary malignant melanoma (MM) of the uterine cervix is a rare neoplasm and the overall prognosis of patients with this disease is poor. Immunohistochemical methods and exclusion of other primary melanoma sites are used to confirm the diagnosis. In the present study, the case of a 65-year-old female patient with an MM of the uterine cervix is reported. Diagnosis was confirmed by immunohistochemical methods using human melanoma black 45 antibody and S-100 protein. The tumor was identified as stage IB1 using the International Federation of Gynecology and Obstetrics classification. Chest X-ray and abdominopelvic computed tomography results were normal. The patient subsequently underwent a radical hysterectomy with bilateral salpingo-oophorectomy and pelvic lymphadenectomy. Following combined radical surgery and chemotherapy, complete remission of the tumor was achieved. The patient has since been well for 30 months without recurrence subsequent to the surgery.	0
Human gnathostomiasis is mainly caused by third-stage larvae of Gnathostoma spinigerum (G. spinigerum L3). Excretory-secretory products (ES) released from infective helminthic larvae are associated with larval migration and host immunity modulation. Natural killer (NK) cells have important immune functions against helminth infection. Currently, the effects of ES from G. spinigerum L3 (G. spinigerum ES) on NK cell activity are unclear. This study investigated whether G. spinigerum ES affected human NK cells. Human normal peripheral blood mononuclear cell (PBMC) cultures were used to mimic immune cells within the circulation. PBMC were co-cultured with G. spinigerum ES (0.01-0.05 μg/ml) for 5 or 7 days. Levels of IFN-γ in cultured supernatants were measured by enzyme-linked immunosorbent assay. The expressions of mRNA encoding NK cell receptors, especially the C type killer cell lectin-like family (KLR; NKG2A, NKG2C, and NKG2D) and IFN-γ in ES induced PBMC were determined by quantitative reverse transcription-polymerase chain reaction (RT-qPCR). ES induced PBMC markedly decreased the levels of IFN-γ and increased the expressions of NKG2A and NKG2D on NK cells. In conclusion, low amounts of G. spinigerum ES modulated NK cells by downregulating the transcription of IFN-γ and upregulating the expressions of KLR (NKG2A and NKG2D receptors) during the 7-day observation period. These findings indicate more in-depth studies of NK cell function are required to better understand the mechanism involved in immune evasive strategies of human gnathostomiasis.	0
Sneddon syndrome (SS) is a rare progressive non-inflammatory thrombotic vasculopathy affecting small/medium-sized blood vessels of unknown origin. It is strongly associated with the presence of antiphospholipid antibodies (AA). The presence of livedo reticularis and cerebrovascular disease are hallmark features. The condition is far more common in young women. We report a case of SS in a 43 year-old male with a two-year history of progressive cognitive impairment consistent with dementia syndrome, and major personality changes, besides livedo reticularis and cerebral angiographic pattern of vasculitis. AA were borderline. The recognition of skin blemishes that precede strokes should raise the hypothesis of SS. AA are elevated in more than half of cases, but their role in the pathogenesis or association of positive antibodies and SS remains unclear. Dementia syndrome in young patients should be extensively investigated to rule out reversible situations. Typical skin findings, MRI and angiography may aid diagnosis.	0
Our aim is to report the periodontal findings of a 10-year-old boy who visited the outpatient department of periodontology, with the chief complaint of swelling in the right cheek region for the last 2 months, increasing mobility of the teeth, and frequent bleeding from the gums. Since the age of 4 years, he suffered from recurrent febrile episodes, with boils and furuncles on the face. After several hematological and immunological investigations, he was diagnosed with chronic idiopathic neutropenia. He was prescribed a 150 μg subcutaneous injection of recombinant granulocyte colony-stimulating factor, once daily for 8 days. For reducing oral inflammation, he was advised an oral rinse of 15 ml of chlorhexidine gluconate (0.12%) twice daily and advised for a routine periodontal checkup, every 3-4 weeks for evaluation, maintenance, and avoiding any acute inflammatory flare-ups.	0
Human T-cell leukemia virus type 1 (HTLV-1) establishes persistent infection in vivo in two distinct ways: de novo infection and clonal proliferation of infected cells. Two viral genes, Tax and HTLV-1 bZIP factor (HBZ) play critical roles in viral transcription and promotion of T-cell proliferation, respectively. Tax is a potent transactivator not only for viral transcription but also for many cellular oncogenic pathways, such as the NF-κB pathway. HBZ is a suppressor of viral transcription and has the potential to change the immunophenotype of infected cells, conferring an effector regulatory T cell (eTreg)-like signature (CD4+ CD25+ CCR4+ TIGIT+ Foxp3+) and enhancing the proliferation of this subset. Reports that mice transgenic for either gene develop malignant tumors suggest that both Tax and HBZ are involved in leukemogenesis by HTLV-1. However, the immunogenicity of Tax is very high, and its expression is generally suppressed in vivo. Recently, it was found that Tax can be expressed transiently in a small subpopulation of adult T-cell leukemia-lymphoma (ATL) cells and plays a critical role in maintenance of the overall population. HBZ is expressed in almost all infected cells except for the rare Tax-expressing cells, and activates the pathways associated with cell proliferation. These findings indicate that HTLV-1 fine-tunes the expression of viral genes to control the mode of viral propagation. The interplay between Tax and HBZ is the basis of a sophisticated strategy to evade host immune surveillance and increase transmission - and can lead to ATL as a byproduct.	0
This is the first case of concurrent Mycobacterium genavense lymphadenitis and Epstein-Barr virus (EBV)-positive lymphoproliferative disorder (LPD) in the same lymph node with no immunocompromised history. M. genavense infection is a rare opportunistic infection mainly for human immunodeficiency virus (HIV)-infected patients. Although no immunodeficiency was detected in our patient, our case indicates that the immunodeficiency in the background of EBV latency type III and the immunosuppression by malignant lymphoma itself might induce the M. genavense lymphadenitis. This case highly alerts clinicians to the immunosuppressive state of EBV-positive LPD with latency type III even if any immunodeficient serological factors are not detected.	0
Purpose:To report best vitelliform macular dystrophy (BVMD) with an intriguing pattern of vascular flow on optical coherence tomography angiography (OCTA). Methods:Four eyes of two patients with BVMD were evaluated. Complete ophthalmic examination including best corrected visual acuity (BCVA), spectral domain optical coherence tomography (SD-OCT), and OCTA were performed. Diagnosis was confirmed by electroretinography (ERG) and electrooculography (EOG) testing. Results:All eyes had the electrophysiologic confirmation of the BVMD. The first patient was 35 years old with BCVA of 20/20 and pseudohypopyon stage macular lesion in right eye (RE) and BCVA of 20/32 and vitelliruptive stage macular lesion in the left eye (LE). The second patient was 18 years old with BCVA of 20/25 and macular lesion in vitelliform stage in the RE and BCVA of 20/60 and choroidal neovascularization (CNV) in the LE. In all eyes, a distinct foveal avascular zone (FAZ) was not detectable in OCTA, with a bridging vessel in the FAZ. A dense subretinal capillary network compatible with CNV in the LE of second patient was observed. Conclusion:In our cases, we found bridging vessel in the FAZ, and it may be due to the effects of bestrophin on the calcium content and vascular endothelial growth factor (VEGF) secretion of the retinal pigment epithelium (RPE) cells.	0
Obtaining reliable and high fidelity next-generation sequencing (NGS) data requires to choose a suitable sequencing platform and a library preparation approach, which both have their inherent assay-specific limitations. Here, we present the results of successful adaptation of SureSelect hybridisation-based target enrichment protocol for the sequencing on the Ion Torrent S5 platform, which is designed to work preferably with amplicon-based panels. In our study, we applied a custom NGS panel to screen a cohort of 16 unrelated patients affected by premature fusion of the cranial sutures, i.e. craniosynostosis (CS). CS occurs either as an isolated malformation or in a syndromic form, representing a genetically heterogeneous and clinically variable group of disorders. The approach presented here allowed us to achieve high quality NGS data and confirmed molecular diagnosis in 19% of cases, reaching the diagnostic yield similar to some of the published research reports. In conclusion, we demonstrated that an alternative enrichment strategy for library preparations can be successfully applied prior to sequencing on the Ion Torrent S5 platform. Also, we proved that the custom NGS panel designed by us represents a useful and effective tool in the molecular diagnostics of patients with CS.	0
We describe the natural history of 'Amish' nemaline myopathy (ANM), an infantile-onset, lethal disease linked to a pathogenic c.505G>T nonsense mutation of TNNT1, which encodes the slow fiber isoform of troponin T (TNNT1; a.k.a. TnT). The TNNT1 c.505G>T allele has a carrier frequency of 6.5% within Old Order Amish settlements of North America. We collected natural history data for 106 ANM patients born between 1923 and 2017. Over the last two decades, mean age of molecular diagnosis was 16 ± 27 days. TNNT1 c.505G>T homozygotes were normal weight at birth but failed to thrive by age 9 months. Presenting neonatal signs were axial hypotonia, hip and shoulder stiffness, and tremors, followed by progressive muscle weakness, atrophy and contractures. Affected children developed thoracic rigidity, pectus carinatum and restrictive lung disease during infancy, and all succumbed to respiratory failure by 6 years of age (median survival 18 months, range 0.2-66 months). Muscle histology from two affected children showed marked fiber size variation owing to both Type 1 myofiber smallness (hypotrophy) and Type 2 fiber hypertrophy, with evidence of nemaline rods, myofibrillar disarray and vacuolar pathology in both fiber types. The truncated slow TNNT1 (TnT) fragment (p.Glu180Ter) was undetectable in ANM muscle, reflecting its rapid proteolysis and clearance from sarcoplasm. Similar functional and histological phenotypes were observed in other human cohorts and two transgenic murine models (Tnnt1-/- and Tnnt1 c.505G>T). These findings have implications for emerging molecular therapies, including the suitably of TNNT1 gene replacement for newborns with ANM or other TNNT1-associated myopathies.	0
Ocular cicatricial pemphigoid (OCP) is an autoimmune ocular disease that causes severe dry eye syndrome, conjunctival scarring with inferior fornix shortening and entropion along with trichiasis. Corneal keratinization and corneal ulcers may lead to permanent vision loss. The therapeutic approach of OCP is a challenging one. Thus, the treatment consists of a systemic therapy that includes immunosuppressive as well as corticosteroid medication. Also, surgical procedures for modifications of eyelid position, symblepharon and cataract may aggravate the evolution of the disease. Dry eye syndrome, which is known to be a multifactorial disorder of the ocular surface secondary to qualitative or quantitative alteration of the tear film, is a severe and frequent complication of OCP. In this article, we presented 3 patients diagnosed with OCP, who developed severe dry eye syndrome, entropion, corneal erosions and ultimately, permanent vision loss.	0
Trichorhinophalangeal syndrome (TRPS), a type of skeletal dysplasia, is characterized by a triad of dysmorphic (bulbous nose and large ears); ectodermal (thin and sparse hair); and skeletal (short stature and cone-shaped epiphyses) findings, and this combination is helpful for early diagnosis and appropriate follow-up. A 14-year-old boy presented with short stature and distinctive facial features, and following the first clinical and biological evaluation, no precise diagnosis was reached. Progressive bilateral development of noninflammatory and painless deformity of his second finger required a radiological exam that highlighted the key elements (cone-shaped epiphyses) for final diagnosis. This case illustrates the difficulties to early recognition of TRPS when the clinical presentation is not complete and radiological findings are missing.	0
Introduction:Florid cemento-osseous dysplasia is a non-neoplastic fibro-osseous lesion which often has an asymptomatic slow growth. Unfortunately, these lesions are usually diagnosed through routine radiographic examination. The aim of this study was to describe the main clinical, radiological and histological characteristics of two case reports diagnosed with florid cemento-osseous dysplasia. Case reports:Two cases of florid cemento-osseous dysplasia with different clinical and radiological features were presented. Panoramic radiographs showed multiple radiopacities compatible with fibro-osseous lesions in distinct areas of the maxillary bones. The histological study revealed a sclerotic mass which continued imperceptibly with root cement with scarce fibrous lax tissue. Conclusions:The replacement of healthy bone by metaplastic bone and fibrous tissue is the main histological feature. Therapeutic abstention with active clinical and radiographic control visits is recommended in asymptomatic cases. Key words:Fibro-osseous lesions, cemento-osseous dysplasia, florid cemento-osseous dysplasia, gigantiform cementoma, osseous dysplasia.	0
Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare skeletal disorder characterized by aggressive osteolysis associated with progressive nephropathy. The early clinical presentation can mimic polyarticular juvenile idiopathic arthritis. Since 2012, MAFB mutations have been discovered in all MCTO patients. Therefore, the early diagnosis can be made based on genetic confirmation. We report the clinical manifestation of mineral bone disease and the molecular genetic study of a Thai female adolescent with MCTO. She presented with end-stage renal disease, bilateral wrist and ankle joint deformities, and subtle facial dysmorphic features. We identified a heterozygous missense MAFB mutation at nucleotide 197 from C to G (NM_005461.4; c.197C>G), predicting the change of amino acid at codon 66 from serine to cysteine (p.Ser66Cys), and the mutation was absent in the parents, indicating a de novo mutation. This report confirms the previous link between MAFB mutation and MCTO. Her unexplained hypercalcemia after a regular dose of calcium and active vitamin D supported an important role of MafB in the negative regulation of RANKL-mediated osteoclast differentiation. Therefore, we would encourage the physicians who take care of MCTO patients to closely monitor serum calcium level and perform a genetic study as a part of the management and investigation.	0
Limb girdle muscular dystrophy type 2I (LGMD2I) is an autosomal recessive muscular dystrophy that is rare in Asia and is caused by mutations in the fukutin-related protein gene (FKRP). The aim of this study was to determine if there are any characteristic features of muscle on magnetic resonance imaging (MRI) in patients with LGMD2I harboring the founder mutation c.545A>G in FKRP. Using MRI, we delineated changes in the thigh muscles of ten patients with genetically confirmed LGMD2I. The majority of muscle biopsy specimens showed reduced glycosylation of α-dystroglycan, decreased expression of laminin α2, and a dystrophic pattern. In our cohort, the muscles with the most severe fatty infiltration were adductor magnus and vastus intermedius, whereas the rectus femoris, sartorius, and gracilis muscles were relatively spared. In seven patients, we identified a concentric fatty infiltration pattern that was most pronounced in the vastus intermedius and vastus medialis muscles around the distal femoral diaphysis. In this disease, the initial fatty infiltration of the posterior thigh muscles gradually progresses anteriorly regardless of the founder mutation in FKRP. Muscle tissue in patients with LGMD2I who have the founder mutation c.545A>G in FKRP shows a distinctive concentric pattern of fatty infiltration and edema on MRI.	0
Aplasia cutis congenita is a rare malformation characterized by localized congenital absence of the skin. It rarely occurs on the trunk and limbs, and can occur in isolation or as part of a heterogeneous group of syndromes. We report a case of a 4-day-old boy with a 5.6-cm- diameter tumor, with a central crust, non-indurate and no inflammatory rim; localized on the scalp and a small, atrophic hairless scar appeared 6 months later (approximately 5 cm in length) at the site of the previous tumor.	0
Objective: To describe a case of surgically induced scleral necrosis in Treacher Collins syndrome after strabismus surgery. Methods: A 19-year-old girl underwent bilateral squint surgery. Two weeks postoperatively, she presented with subconjunctival abscess in the left eye. The surrounding conjunctiva was markedly inflamed with raised edges. Surgical debridement, microbiological evaluation and medical management were started immediately. Screening for autoimmune and vasculitic conditions did not provide any positive results. Results: On subsequent follow-up, conjunctival retraction and an area of scleral necrosis with thinning was noted. Significant healing with antibiotics and steroids was noted within one week. The integrity of the globe was well maintained and no further procedure for tectonic support was performed. Conclusion: Surgically induced scleral necrosis can be immune-mediated or following surgical site infection. Pre-existing scleral thinning due to neuroectodermal apoptosis in Treacher Collins syndrome remains a possible explanation for the accelerated necrotising scleritis in our case.	0
Genetic factors play an important role in the development of psychotic disorders. With increasing evidence, several rare copy number variants (cnvs) have been identified as risk factors. We describe a patient who had two psychotic episodes during his adolescence. In this patient, a 16p11.2 duplication was detected. This duplication is a recurrent cnv associated with various somatic and psychiatric phenotypes including psychosis and schizophrenia. The potential clinical relevance of this finding is discussed.	0
OBJECTIVE:Early-onset schizophrenia is a severe and rare form of schizophrenia that is clinically and neurobiologically continuous with the adult form of schizophrenia. Neuregulin1 (NRG1)-mediated signaling is crucial for early neurodevelopment, which exerts its function by limited β-secretase 1 (BACE1) proteolysis processing. However, circulating neuregulin1-β1 (NRG1-β1), an isoform of NRG1, and its cleavage enzyme BACE1 have not been studied in early-onset patients with schizophrenia. METHODS:In this study, we collected plasma and clinical information from 71 young patients (7 ≤ age years ≤20) with schizophrenia and 53 age- and sex-matched healthy controls. Immunoassay was used to test levels of circulating NRG1-β1 and BACE1 expression. We further analyzed the relationship of disease-onset age and gender with NRG1-β1 and BACE1 levels. RESULTS:We found that circulating plasma levels of NRG1-β1 were significantly decreased in young patients with early-onset schizophrenia. In males with childhood onset schizophrenia (COS), NRG1-β1 was reduced and was inversely correlated with positive symptom of PANSS; moreover, these male patients with higher plasma BACE1 levels showed more severe general symptoms of PANSS and defective social functioning; whereas, no aforementioned results were found in adolescent-onset schizophrenia (AOS). Notably, young female patients with COS and AOS had no significant change in NRG1-β1 and BACE1, which demonstrated a sex-dependent effect in early-onset schizophrenia. CONCLUSION:Our results suggest that decreased levels of NRG1-β1 and its cleavage enzyme BACE1 contribute to increased risk of etiology of schizophrenia. Synthetic biomarkers may have clinical applications for the early diagnosis of male COS.	0
Keratosis follicularis spinulosa decalvans (KFSD) is an X-linked xenodermatosis characterized by scarring alopecia and follicular hyperkeratosis. This condition mainly affects males with females being carriers and will have milder symptoms. We present two sisters with severe form of KFSD, progressing to scarring alopecia.	0
Trichoepithelioma is a benign hair follicle tumor that can undergo malignant transformation into basal cell carcinoma in rare cases. Due to the similar clinical and histological features of trichoepithelioma and basal cell carcinoma, distinguishing between these types of tumors can be a diagnostic challenge. Punch biopsy obtains only a small sample of the entire lesion, and thus inherently involves a risk of misdiagnosis between histologically similar diseases. Therefore, if the possibility of misdiagnosis can reasonably be suspected, clinicians should conduct an excisional biopsy or immunohistochemical staining (e.g., CD10 and Bcl-2) to ensure an exact diagnosis. Although trichoepithelioma is benign, the surgical excision of solitary trichoepithelioma should be considered in order to avoid the possibility of malignant transformation, which has occasionally been documented for multiple familial trichoepitheliomas. Herein, we report a case that was initially misdiagnosed as trichoepithelioma before ultimately being diagnosed as basal cell carcinoma through excision and immunohistochemical staining.	0
INTRODUCTION:Mutations in the BICD2 gene are causative for an autosomal dominant form of spinal muscular atrophy (SMALED2). Further, BICD2 mutations have been implicated in hereditary spastic paraplegia (HSP), but only very few such patients have been described. In this report we aimed to investigate the frequency of BICD2 mutations in patients with HSP and hereditary motor and sensory neuropathy (HMSN) who were negative for the most common known genetic causes. METHODS:The cohorts comprised 171 HSP and 189 HMSN patients. Mutational analysis was performed with high-resolution melting analysis followed by Sanger sequencing. RESULTS:In both cohorts, we found no known or likely pathogenic mutations in the BICD2 gene. DISCUSSION:BICD2 mutations appear rather unlikely to cause a phenotype of HMSN and are a very rare cause of the HSP phenotype. Muscle Nerve 59:484-486, 2019.	0
Gastrointestinal angiodysplasia (GIA) is the most common cause of occult gastrointestinal bleeding (GIB) requiring often hospitalization and transfusions, especially in patients with hemorrhagic disorders. Thalidomide, impairing neo-angiogenesis, has been successfully used in the management of bleeding in patients with GIA and in particular in patients with inherited bleeding disorders. Only one case of short-term treatment with thalidomide in a patient with Glanzmann thrombasthenia (GT) and recurrent GIB due to GIA has been reported so far.We report the case of a woman with GT developing high frequency recurrent GIB due to GIA requiring repeated blood and platelet transfusions, who was treated with thalidomide obtaining a striking and stable reduction of GIB and of the requirement of platelet and blood transfusions for over 5 years. Moreover, we raise the suspicion that the association between GT and GIA may not be fortuitous.	0
Myxoid adrenal cortical adenoma with a pseudoglandular structure is a special histological variant and is extremely rare. We report about a 32-year-old Chinese woman with a right adrenal mass during a routine physical examination. The cut surface of the mass had a vague nodular, which gross appearance was pale, yellowish, and semitransparent. Histologically, the region is mostly characterised by pseudoglandular pattern with myxoid stroma. They are filled with clear cells or eosinophilic cells, as well as semitransparent regions, in which anastomosing small eosinophilic cells arranged in pseudoglandular, cord-like, or wreath-shaped structure float in the mucous pool. Immunohistochemical staining shows Melan-A, vimentin, and CD56 were positive and CK (AE1/AE3) were nucleus-side staining. A small number of tumor cells were positive for alpha-inhibin and synaptophysin, ki-67 labeling index was 3%. EMA, chromogranin A, WT-1, and P63 were negative. This report aimed to emphasize pseudoglandular patterns with mucus secretion which could occur in adenomas of the adrenal cortex, nucleus-side positive for CK is remarkable. However, this type may have malignant potential, so regular follow-up is needed.	0
INTRODUCTION:We encountered a patient with Klinefelter syndrome (KS) who experienced poor outcomes after vitrectomy for proliferative diabetic retinopathy (PDR). CASE:A 44-year-old male with poorly controlled diabetes was diagnosed with KS by chromosome analysis. Ocular findings revealed severe PDR complicated with extensive preretinal hemorrhages and traction retinal detachment in his left eye, and pars plana vitrectomy was subsequently performed for treatment. RESULTS:A clotting hemorrhage developed during surgery and proved difficult to control. Due to postoperative bleeding and redetachment, the vitrectomy was repeated. At the second operation, we performed a silicone oil tamponade; however, the retina was redetached under the silicone oil, and the light perception vision ultimately disappeared. CONCLUSION:The patient, despite showing increased blood coagulability due to diabetes, presented severe coagulopathy, likely related to KS. In patients with KS and severe PDR, the potential difficulty of vitrectomy should always be kept in mind.	0
OBJECTIVE:The aim of this study was to determine the relationship between the thickness of masticatory and cervical muscles (temporalis, masseter and sternocleidomastoid) and facial asymmetries in young patients. METHODS:21 subjects were selected, through a detailed anamnesis and clinical examination, in order to assess the normality of oral tissues, the presence of normal occlusion, the absence of alteration in tooth dimensions and of congenital or developmental anomalies of lips, mouth or face. RESULTS:The present investigation showed that temporalis, masseter and sternocleidomastoid muscles in untreated and growing individuals with facial asymmetries are thinner on the omolateral side when compared with controlateral normal side, but in the untreated one this value is more statistically significantly. CONCLUSIONS:In conclusion, the cervical muscle's thickness resulted increased in young patients Ultrasound is beginning to be recognized to have potential use in dentistry as a safe, noninvasive, comfortable and cost-effective adjunct to diagnosis by producing high-resolution images more easily than magnetic resonance (MRI) and computed tomography (CT) (27-kubo).	0
Pulmonary sarcoidosis and chronic beryllium disease (CBD) are inflammatory granulomatous lung diseases defined by the presence of non-caseating granulomas in the lung. CBD results from beryllium exposure in the workplace, while the cause of sarcoidosis remains unknown. CBD and sarcoidosis are both immune-mediated diseases that involve Th1-polarized inflammation in the lung. Beryllium exposure induces trafficking of dendritic cells to the lung in a mechanism dependent on MyD88 and IL-1α. B cells are also recruited to the lung in a MyD88 dependent manner after beryllium exposure in order to protect the lung from beryllium-induced injury. Similar to most immune-mediated diseases, disease susceptibility in CBD and sarcoidosis is driven by the expression of certain MHCII molecules, primarily HLA-DPB1 in CBD and several HLA-DRB1 alleles in sarcoidosis. One of the defining features of both CBD and sarcoidosis is an infiltration of activated CD4+ T cells in the lung. CD4+ T cells in the bronchoalveolar lavage (BAL) of CBD and sarcoidosis patients are highly Th1 polarized, and there is a significant increase in inflammatory Th1 cytokines present in the BAL fluid. In sarcoidosis, there is also a significant population of Th17 cells in the lungs that is not present in CBD. Due to persistent antigen exposure and chronic inflammation in the lung, these activated CD4+ T cells often display either an exhausted or anergic phenotype. Evidence suggests that these T cells are responding to common antigens in the lung. In CBD there is an expansion of beryllium-responsive TRBV5.1+ TCRs expressed on pathogenic CD4+ T cells derived from the BAL of CBD patients that react with endogenous human peptides derived from the plexin A protein. In an acute form of sarcoidosis, there are expansions of specific TRAV12-1/TRBV2 T cell receptors expressed on BAL CD4+ T cells, indicating that these T cells are trafficking to and expanding in the lung in response to common antigens. The specificity of these pathogenic CD4+T cells in sarcoidosis are currently unknown.	0
BACKGROUND:Pierson syndrome (PS) is a rare autosomal recessive disorder, characterized by congenital nephrotic syndrome and microcoria. Advances in renal replacement therapies have extended the lifespan of patients, whereas the full clinical spectrum of PS in infancy and beyond remains elusive. CASE PRESENTATION:We present the case of a 12-month-old boy with PS, manifesting as the bilateral microcoria and congenital nephrotic syndrome. He was born without asphyxia, and was neurologically intact from birth through the neonatal period. Generalized muscle weakness and hypotonia were recognized from 3 months of age. The infant showed recurrent vomiting at age 5 months of age, and was diagnosed with gastroesophageal reflux and intestinal malrotation. Despite the successful surgical treatment, vomiting persisted and led to severely impaired growth. Tulobuterol treatment was effective in reducing the frequency of vomiting. Targeted sequencing confirmed that he had a compound heterozygous mutation in LAMB2 (NM_002292.3: p.Arg550X and p.Glu1507X). A search of the relevant literature identified 19 patients with severe neuro-muscular phenotypes. Among these, only 8 survived the first 12 months of life, and one had feeding difficulty with similar gastrointestinal problems. CONCLUSIONS:This report demonstrated that severe neurological deficits and gastrointestinal dysfunction may emerge in PS patients after the first few months of life.	0
INTRODUCTION:'Vanishing Bone Disease' or Gorham's disease is a very rare form of primary idiopathic osteolysis with only around 200 cases being reported till date. We present in this case report a ten year follow-up of a patient who had progressive osteolysis of the right shoulder girdle and eventually involved the spine inspite of supplementary calcium and bisphosphonate therapy. We also report the utility of using an intra-medullary device is to attain acceptable union in case of pathological long bone fracture in Gorham's disease. CASE:A four year old child presented to us with a spontaneous osteolysis of the right scapula ten years ago in 2003. Within two years, the osteolysis progressed to the entire scapula, clavicle and he had a clavicular fracture. The patient was treated conservatively, oral calcium and bisphosphonate therapy was initiated after ruling out any metabolic bone disease. The patient again sustained a pathological fracture humerus five years later, which was treated with open reduction and internal fixation with an intra-medullary K wire. The fracture united without any other supplementary treatment but osteolysis continued to progressively involve the entire scapula, proximal humerus, clavicle, upper two ribs and the cervical spine. CONCLUSION:Gorham's disease is a rare disease with an unpredictable course without any satisfactory treatment. There is still a role for surgical intervention to treat long bone pathological fractures secondary to Gorham's disease with an intra-medullary device. The fractures unite without any other supplementary radio or chemotherapy.	0
BACKGROUND:Juvenile Sjögren's Syndrome (jSS) is a rare phenomenon that may appear as primary jSS or associated with mixed connective tissue disease (MCTD) and other autoimmune diseases as secondary jSS. With currently no standard diagnostic procedures available, jSS in MCTD seems to be underdiagnosed. We intended to describe and identify similar distinct salivary gland ultrasound (SGUS) findings in a cohort of primary and secondary jSS patients, focusing on sicca like symptoms and glandular pain/swelling in the patients'history. METHODS:We present a single-center study with chart data collection. B-mode examinations of salivary glands were obtained with a linear high-frequency transducer and evaluated using the scoring-system of Hocevar. Inclusion criteria were: (i) primary or secondary jSS and/or (ii) diagnosis of MCTD and additionally (iii) any presence of sicca like symptoms or glandular pain/swelling. RESULTS:Twenty five patients with primary (pjSS) and secondary jSS (sjSS) were included in the study (n = 25, 21 female, 4 male), with a median age of 15.3 years at the time of first visit and a mean disease duration of 4.9 years. Pathologic SGUS findings were observed in 24 of 25 patients, with inhomogeneous parenchymal appearances with hypoechoic lesions present in 96% of patients. At least one submandibular gland was affected in 88.5% of the whole group, and all patients in the MCTD-group. Twenty of twenty five patients were scanned and scored on a second visit. Pre-malignancies or mucosa-associated lymphoid tissue (MALT) were detected in biopsies of three patients (Hocevar scoring of 40, 33, and 28). CONCLUSION:SGUS in patients with pjSS and sjSS is a helpful first-line tool to detect and score salivary gland involvement, in particular when keratoconjunctivitis sicca, xerostomia, or glandular swelling occurs. Juvenile MCTD patients have a significant risk of developing secondary jSS. We propose SGUS as a method in the diagnostic workup and screening for inflammatory changes. Further studies have to determine the predictive value of SGUS for follow up.	0
Drug-induced immune thrombocytopenia (DITP) is a life-threatening clinical syndrome that is under-recognized and difficult to diagnose. Many drugs can cause immune-mediated thrombocytopenia, but the most commonly implicated are abciximab, carbamazepine, ceftriaxone, eptifibatide, heparin, ibuprofen, mirtazapine, oxaliplatin, penicillin, quinine, quinidine, rifampicin, suramin, tirofiban, trimethoprim-sulfamethoxazole, and vancomycin. Several different mechanisms have been identified in typical DITP, which is most commonly characterized by severe thrombocytopenia due to clearance and/or destruction of platelets sensitized by a drug-dependent antibody. Patients with typical DITP usually bleed when symptomatic, and biological confirmation of the diagnosis is often difficult because detection of drug-dependent antibodies (DDabs) in the patient's serum or plasma is frequently not possible. This is in contrast to heparin-induced thrombocytopenia (HIT), which is a particular DITP caused in most cases by heparin-dependent antibodies specific for platelet factor 4, which can strongly activate platelets in vitro and in vivo, explaining why affected patients usually have thrombotic complications but do not bleed. In addition, laboratory tests are readily available to diagnose HIT, unlike the methods used to detect DDabs associated with other DITP that are mostly reserved for laboratories specialized in platelet immunology.	0
BACKGROUND:Prader-Willi syndrome (PWS) is a multisystem genetic disorder, which has a typical eating behavior and growth pattern. In the infancy period, children with PWS have low body weight followed by hyperphagia in later childhood. Disease-specific growth charts have been recommended for monitoring PWS patients. Previous literature demonstrated growth differences among individuals with PWS of different ethnicity. METHODS:A retrospective multicenter study was performed in PWS patients from different areas of Thailand included collaboration with the Thai PWS support group during 2000-2017. Baseline characteristics and anthropometric data were reviewed. Both growth hormone and non-growth hormone received patients were included, but the data after receiving GH were excluded before curve construction. Growth charts for Thai PWS compared to the 50th normative centile were constructed using Generalized Least Squares (GLS) methods. Curve smoothing was performed by Fractional Polynomials and Exponential Transformation. RESULT:One hundred and thirteen patients with genetically confirmed PWS (55 males and 58 females) were enrolled. Fifty percent of patients were diagnosed less than 6 months of age. We developed growth charts for non-growth hormone treated Thai children with PWS aged between 0 and 18 years. A growth pattern was similar to other ethnicities while there were some differences. Mean birth weight of PWS patients was less than that of typical newborns. Mean adult height at 18 years of age in Thai children with PWS was lower than that in American children, but taller than Japanese. Mean weight of Thai PWS males at 18 years of age was more than those from other countries. CONCLUSION:This study is the first to document PWS-specific growth charts in Southeast Asian population. These growth charts will be useful in improving the quality of patient care and in evaluating the impact of growth hormone treatment in the future.	0
Clinical variability is commonly seen in Li-Fraumeni syndrome. Phenotypic heterogeneity is present among different families affected by the same pathogenic variant in TP53 gene and among members of the same family. However, causes of this huge clinical spectrum have not been studied in depth. TP53 type mutation, polymorphic variants in TP53 gene or in TP53-related genes, copy number variations in particular regions, and/or epigenetic deregulation of TP53 expression might be responsible for clinical heterogeneity. In this review, recent advances in the understanding of genetic and epigenetic aspects influencing Li-Fraumeni phenotype are discussed.	0
A 76-year-old postmenopausal woman presented with a bloody attachment on the left nipple. She had a 3 cm-sized tumor in her left breast. Mammography showed a spiculated irregular mass. Ultrasonography showed a 38 mm, low echoic mass with an irregular border. Core needle biopsy examination indicated apocrine carcinoma of the breast, ER(-), PgR(-), and HER2(-). An overall examination showed no distant metastasis. We diagnosed her with apocrine carcinoma of the breast(T2N0M0, cStageⅡA). We performed total mastectomy with sentinel lymph node biopsy. The postoperative histopathological examination revealed apocrine carcinoma without lymph node metastasis. The patient recovered uneventfully and was discharged 8 days after the surgery. She has not experienced any recurrence for 1 year and 7 months after the surgery.	0
Splice-site defects account for about 10% of pathogenic mutations that cause Mendelian diseases. Prevalence is higher in neuromuscular disorders (NMDs), owing to the unusually large size and multi-exonic nature of genes encoding muscle structural proteins. Therapeutic genome editing to correct disease-causing splice-site mutations has been accomplished only through the homology-directed repair pathway, which is extremely inefficient in postmitotic tissues such as skeletal muscle. Here we describe a strategy using nonhomologous end-joining (NHEJ) to correct a pathogenic splice-site mutation. As a proof of principle, we focus on congenital muscular dystrophy type 1A (MDC1A), which is characterized by severe muscle wasting and paralysis. Specifically, we correct a splice-site mutation that causes the exclusion of exon 2 from Lama2 mRNA and the truncation of Lama2 protein in the dy2J/dy2J mouse model of MDC1A. Through systemic delivery of adeno-associated virus (AAV) carrying clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 genome-editing components, we simultaneously excise an intronic region containing the mutation and create a functional donor splice site through NHEJ. This strategy leads to the inclusion of exon 2 in the Lama2 transcript and restoration of full-length Lama2 protein. Treated dy2J/dy2J mice display substantial improvement in muscle histopathology and function without signs of paralysis.	0
An amendment to this paper has been published and can be accessed via a link at the top of the paper.	0
Congenital disorders of glycosylation (CDGs) comprise a large number of inherited metabolic defects that affect the biosynthesis and attachment of glycans. CDGs manifest as a broad spectrum of disease, most often including neurodevelopmental and skeletal abnormalities and skin laxity. Two patients with biallelic CSGALNACT1 variants and a mild skeletal dysplasia have been described previously. We investigated two unrelated patients presenting with short stature with advanced bone age, facial dysmorphism, and mild language delay, in whom trio-exome sequencing identified novel biallelic CSGALNACT1 variants: compound heterozygosity for c.1294G>T (p.Asp432Tyr) and the deletion of exon 4 that includes the start codon in one patient, and homozygosity for c.791A>G (p.Asn264Ser) in the other patient. CSGALNACT1 encodes CSGalNAcT-1, a key enzyme in the biosynthesis of sulfated glycosaminoglycans chondroitin and dermatan sulfate. Biochemical studies demonstrated significantly reduced CSGalNAcT-1 activity of the novel missense variants, as reported previously for the p.Pro384Arg variant. Altered levels of chondroitin, dermatan, and heparan sulfate moieties were observed in patients' fibroblasts compared to controls. Our data indicate that biallelic loss-of-function mutations in CSGALNACT1 disturb glycosaminoglycan synthesis and cause a mild skeletal dysplasia with advanced bone age, CSGALNACT1-CDG.	0
Leber congenital amaurosis (LCA) is a group of severe congenital retinal diseases. Variants in the guanylate cyclase 2D gene (GUCY2D), which encodes guanylate cyclase 1 (ROS-GC1), are associated with LCA1 and account for 6%-21% of all LCA cases. In this study, one family with LCA1 was recruited from China. A combination of next generation sequencing and Sanger sequencing was used to screen for disease-causing mutations. We found three novel mutations (c.139delC, p.Ala49Profs*36; c.835G>A, p.Asp279Asn and c.2783G>A, p.Gly928Glu) in the GUCY2D gene. Proband III-2 carries mutations c.139delC and c.2783G>A, which are inherited from the heterozygous mutation carriers, II-2 (c.139delC) and II-3 (c.2783G>A) that possess c.139delC and c.2783G>A. Additionally, II-8 carries heterozygous mutation c.835G>A. Sanger sequencing was used to confirm the presence of the three novel mutations in other family members. Mutation c.139delC results in a truncated protein. Mutations c.835G>A and c.2783G>A significantly reduce the catalytic activity of ROS-GC1. Our findings highlight the gene variants range of LCA. Moreover, HPLC-coupled tandem mass spectrometry (HPLC-MS/MS) was used to analyze the concentration of 3',5'-cyclic guanosine monophosphate (cGMP), suggesting that HPLC-MS/MS is an effective alternative method to evaluate the catalytic activity of wild-type and mutant ROS-GC1.	0
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an orphan hematologic malignancy with poor outcomes. Tagraxofusp (SL-401) was the first drug approved specifically for patients with BPDCN, in 2018. Additional therapeutic strategies are still needed to improve survival and minimize treatment-related toxicity. This article outlines novel targeted approaches that are in preclinical or clinical development for BPDCN. Although there is no known targetable genetic abnormality that defines BPDCN, data from functional testing of primary tumors, gene expression analyses, and adaptation of targeted drug approaches from other cancers to BPDCNs harboring specific mutations have nominated several promising strategies.	0
Lycium shawii Roem. & Schult and resin of Aloe vera (L.) BURM. F. are commonly used in Omani traditional medication against various ailments. Herein, their antiproliferative and antioxidant potential was explored. Bioassay-guided fractionation of the methanol extract of both plants led to the isolation of 14 known compounds, viz., 1-9 from L. shawii and 10-20 from A. vera. Their structures were confirmed by combined spectroscopic techniques including 1D (1H and 13C) and 2D (HMBC, HSQC, COSY) nuclear magnetic resonance (NMR), and electrospray ionization-mass spectrometry (ESI-MS). The cytotoxic potential of isolates was tested against the triple-negative breast cancer cell line (MDA-MB-231). Compound 5 exhibited excellent antiproliferative activity in a range of 31 μM, followed by compounds 1-3, 7, and 12, which depicted IC50 values in the range of 35-60 μM, while 8, 6, and 9 also demonstrated IC50 values >72 μM. Subsequently, in silico target fishing was applied to predict the most potential cellular drug targets of the active compounds, using pharmacophore modeling and inverse molecular docking approach. The extensive in silico analysis suggests that our compounds may target carbonic anhydrase II (CA-II) to exert their anticancer activities. When tested on CA-II, compounds 5 (IC50 = 14.4 µM), 12 (IC50 = 23.3), and 2 (IC50 = 24.4 µM) showed excellent biological activities in vitro. Additionally, the ethyl acetate fraction of both plants showed promising antioxidant activity. Among the isolated compounds, 4 possesses the highest antioxidant (55 μM) activity followed by 14 (241 μM). The results indicated that compound 4 can be a promising candidate for antioxidant drugs, while compound 5 is a potential candidate for anticancer drugs.	0
Linear porokeratosis is a rare variant of porokeratosis that most often presents in newborns and children; development of this porokeratosis variant in adulthood is far less common. We report the case of a 25-year-old female who presented with a progressive eruption on the proximal upper extremity of 6-year duration, which was ultimately diagnosed as adult-onset linear porokeratosis and safely treated with oral isotretinoin. We propose that a sporadic mutation resulting in mosaicism after birth may explain the development of linear porokeratosis in adulthood, although the exact trigger of such a somatic mutation is not known. This case also describes a unique clinical presentation, with linear porokeratosis lesions originating on the proximal extremity rather than on the more common distal extremity. This demonstrates a distinctive clinical presentation not seen in the pediatric forms of disease.	0
Carbohydrate-deficient glycoprotein syndromes (CDGS) type I are a group of genetic diseases characterized by a deficiency of N-linked protein glycosylation in the endoplasmic reticulum. The majority of these CDGS patients have phosphomannomutase (PMM) deficiency (type A). This enzyme is required for the synthesis of GDP-mannose, one of the substrates in the biosynthesis of the dolichol-linked oligosaccharide Glc3Man9GlcNAc2. This oligosaccharide serves as the donor substrate in the N-linked glycosylation process. We report on the biochemical characterization of a novel CDGS type I in fibroblasts of four related patients with normal PMM activity but a strongly reduced ability to synthesize glucosylated dolichol-linked oligosaccharide leading to accumulation of dolichol-linked Man9GlcNAc2. This deficiency in the synthesis of dolichol-linked Glc3Man9GlcNAc2 oligosaccharide explains the hypoglycosylation of serum proteins in these patients, because nonglucosylated oligosaccharides are suboptimal substrates in the protein glycosylation process, catalyzed by the oligosaccharyltransferase complex. Accordingly, the efficiency of N-linked protein glycosylation was found to be reduced in fibroblasts from these patients.	0
Background 5.2% of people are carriers for at least two recessive diseases; it can be concluded that a much smaller proportion develop these conditions as two mutated copies of a gene must be present for the disease to manifest clinically. Case presentation We present a 38-year-old Caucasian female affected by two autosomal recessive disorders which can affect the eyes, pseudoxanthoma elasticum (PXE) and retinitis pigmentosa (RP). PXE is an autosomal recessive disorder caused by mutations in ABCC6, affecting 1:25 000 to 1:100 000 people; its classical features involve the dermatological, ophthalmological and cardiovascular systems. Our patient presented with dermatological features of PXE and ophthalmological features of RP. RP presents with significant locus heterogeneity; our patient had biallelic mutations in USH2A. Conclusions This report highlights an interesting case of two unrelated autosomal recessive diseases presenting in one person, both of which have the potential to manifest with ophthalmological symptoms and signs. Though it is likely that only one condition has caused the ophthalmological findings in this case, it raises the question of how we can distinguish the causative disease when two conditions are present that have a shared target organ.	0
Runt-related transcription factor 2 (RUNX2) is well-known for its role in bone development and tooth morphogenesis. Most RUNX2 mutations described in the literature result in loss-of-function mutations of RUNX2 responsible for cleidocranial dysplasia, an autosomal dominant disorder. We describe here the oro-dental phenotype of four patients of a unique family with a 285 kb duplication including the entire sequence of RUNX2, likely responsible for three functional copies of the gene, leading to an increased RUNX2 dosage. Several dental anomalies of number (hypodontia or oligodontia), morphology (microdontia, radiculomegaly, taurodontism or dens invaginatus) and tooth position (rotation) were found in these patients.	0
The Renpenning syndrome spectrum is a rare X-linked mental retardation syndrome characterized by intellectual disability, microcephaly, low stature, lean body and hypogonadism. Mutations in the polyglutamine tract binding protein 1 (PQBP1) locus are causative for disease. Here, we describe the generation of an iPSC line from a patient mutated in the polar amino acid-rich domain of PQBP1 resulting in a C-terminal truncated protein (c.459_462 delAGAG, type p.R153fs193X).	0
Gianotti-Crosti syndrome is a rare disease characterized by acral papular eruption with symmetrical distribution. It is a benign and self-limited disease; the symptoms disappear after two to eight weeks, without recurrences or scars. Skin lesions are usually asymptomatic. Prodrome might occur, suggesting upper respiratory infection, or constitutional symptoms. Diagnosis is eminently clinical, and this disease is associated with viral infections. Due to its rarity and low occurrence in adolescents and adults, we report a case of Gianotti-Crosti syndrome of a teenager.	0
This report describes a case of proliferative verrucous leukoplakia (PVL) of the gingiva with no discernible aetiology, which presented in a 36-year-old female. The initial nonscrapable gingival lesion was treated with CO2 laser ablation, and the histopathological evaluation was carried out. The presence of koilocytic cells in the superficial epithelium led to immunohistochemical investigations with p16 antibody, which showed strong nuclear positivity and slight cytoplasmic positivity in >50% of the cells with >25% confluency. However, it was not possible to confirm the presence of HPV infection with further investigations due to logistic reasons. The lesion recurred twice within a short time despite the surgical resection following the first recurrence. Thus, this paper presents a case of proliferative verrucous leukoplakia, which demonstrated a significant resistance to routine treatment protocols recommended in the management of such lesions.	0
Recurrent hydatidiform mole is defined as episodes of two molar pregnancies in a female. Often, complete moles only derive androgenic nuclear genome. We described two cases with repeated molar pregnancies attempted to prevent future episodes by performing intracytoplasmic sperm injection (ICSI) and preimplantation genetic diagnosis (PGD) to assess genetic disorders. The first patient had previously six complete molar pregnancies and advised to carry out ICSI with ovum donation to achieve a normal pregnancy. The second case had previously five molar pregnancies and no XY embryos from the ICSI/PGD process. We had to (at the insistence of the patient) transfer XX embryos in this patient which resulted in a complete hydatidiform mole (CHM). Hence, available data based on our patients and previous studies demonstrated that oocyte might play a critical role in the pathophysiology of recurrent hydatidiform mole, while it has not been often considered.	0
Purpose: In this study, the aim was to evaluate the safety of transcorneal electrical stimulation (TES) treatment in retinitis pigmentosa (RP) patients and to investigate the effect of TES to the visual acuity (VA), visual field (VF), and multifocal electroretinogram (mfERG) findings. Methods: Two hundred two eyes of 101 RP patients with different stages were studied. TES was applied for 30 min once a week for 8 consecutive weeks. Two hundred eyes of 100 RP patients were enrolled as control. After the 2-month TES therapy sessions, patients were followed for 4 months without treatment. Examinations were done at the baseline before TES treatment and 1 and 6 months after the treatment. Best-corrected VA (BCVA), color fundus photography, VF test, optical coherence tomography, and mfERG tests were done at each visit. Results: The mean BCVA and VF tests improved 1 month after the beginning of TES treatment and the improvements were statistically significant (P < 0.05). There was an improvement in p1 wave amplitude in rings 1, 2, and 3 at the first month. The latency of the p1 wave showed a statistically significant shortening in rings 1 and 2. These improvements partially disappeared at 6-month follow-up. There were no serious ocular side effects related to the therapy. Mild dry eye symptoms were observed, which were revealed by artificial tears. Conclusions: TES is a safe therapy without any serious advers effects. Although it can improve VA and VF of RP patients, the beneficial effects could be transient and repeated sessions can be necessary for maintaining the efficiency.	0
Granulomatous pigmented purpuric dermatosis clinically manifests as hyperpigmented maculae and petechiae, predominantly on the lower extremities. Histopathologically, it is characterized by a lymphocytic infiltrate in the upper dermis, extravasated erythrocytes, and hemosiderin deposits. There is an infrequent variant called granulomatous pigmented purpuric dermatosis, which histologically is characterized by the presence of non-necrotizing granulomas associated with the classic findings of other pigmented purpuric dermatoses. It more frequently affects middle-aged women of Asian origin, and predominantly on the lower extremities. The authors present the case of a female patient with granulomatous pigmented purpuric dermatosis on the lower extremities with blaschkoid distribution.	0
We report on a rare case of thumb polydactyly with metacarpophalangeal joint synostosis in a 14-year old otherwise healthy boy. Our case can only be classified in the Rotterdam classification, was treated with resection of the hypoplastic radial component and yielded a very satisfactory outcome with a stable thumb.	0
Repetitive involuntary head nodding was first reported in the 1960s in the Wapogoro tribe of Tanzania.We describe the natural history of head nodding in the Wapogoro tribe, with special reference to the earliest reported dates of onset.We analyzed clinical data from 150 historical patients seen between 1960 and 1971.Head nodding with or without grand mal convulsions was present in 33/150 (∼20%) cases, was mostly familial and equally distributed by gender. Age at onset of head nodding ranged from 2-22 years (mean: ∼10 years) in the period 1934-1962. Head nodding preceded onset of grand mal convulsions by up to 12 months, and motor and psychomotor deficits indicative of brain damage developed with time. Fourteen of the 33 cases died at 13-39 years of age (mean: ∼20 years) while nineteen aged 16-28 years (mean: ∼16 years) were still alive.Historical accounts of head nodding (amesinzia kichwa, Swahili) among the Wapogoro tribe fit the August 2012 World Health Organization (WHO) case definition of probable Nodding Syndrome. Reported to have existed in this population for at least 80 years, Nodding Syndrome is a progressive seizure disorder that leads to generalized convulsions (kifafa), brain damage and death.	0
Healthy muscle relies on a complex and interdependent network that includes, but is not limited to, proteins, ion channels, and the production and utilization of ATP. Disruptions to the system can occur for a number of reasons (genetic mutations, toxins, systemic disease, inflammation), yet they clinically present with symptoms that are nonspecific and common to myopathies: weakness, muscle pain, cramping, hypotonia. This article uses a case-based format to review the clinical reasoning and diagnostic tools that guide the accurate diagnosis of myopathies. We specifically focus on toxic, metabolic, mitochondrial, and late-onset congenital myopathies.	0
We describe a treatment strategy for an aberrant arterial aneurysm associated with pulmonary sequestration. A 58-year-old man with impending aberrant arterial aneurysm rupture underwent a 2-stage surgery that included an emergency thoracic endovascular aortic repair (TEVAR) of the descending aorta to occlude the origin of the aberrant artery, followed by lobectomy. TEVAR can lead to faster occlusion of the aneurysm and can avoid operative risk of aneurysm rupture during lobectomy. The aberrant artery was broad where it branched off the aorta and had a short neck, rendering primary ligation or stump-forming unsuitable. Pathological findings revealed the fragility of the aberrant artery; thus, its root was prone to breakdown of the stump after simple aneurysmectomy. Furthermore, TEVAR may reduce graft infection during lobectomy in the second surgery. The 2-stage surgery may be useful for aberrant aneurysms complicated by pulmonary sequestration.	0
The Coronavirus (COVID-19) Pandemic represents a once in a century challenge to human healthcare with over 4.5 million cases and over 300,000 deaths thus far. Surgical practice has been significantly impacted with all specialties writing guidelines for how to manage during this crisis. All specialties have had to triage the urgency of their daily surgical procedures and consider non-surgical management options where possible. The Pandemic has had ramifications for ways of working, surgical techniques, open vs minimally invasive, theatre workflow, patient and staff safety, training and education. With guidelines specific to each specialty being implemented and followed, surgeons should be able to continue to provide safe and effective care to their patients during the COVID-19 pandemic. In this comprehensive and up to date review we assess changes to working practices through the lens of each surgical specialty.	0
Polydactyly, hypopigmentation, and squamous cell carcinoma are common in cats. However, a cat exhibiting all of these conditions has not yet been reported. This study presents the case of a 14- year-old male Mexican cat, hypopigmented, with supernumerary fingers, two preaxial and one on each posterior limb, admitted to the clinic with a lesion in the left periocular region. The cat was subjected to a general physical examination, blood, and urine chemistry, as well as a biopsy and genomic instability assessment with an analysis of the red blood cells (RBC) micronucleated erythrocytes (RBC-MNE) in the peripheral blood. The biopsy was positive for squamous cell carcinoma, and the RBC-MNE count (8.6 MNE/1000 erythrocytes) was high compared to that previously described in other domestic cats or wild cats. Thus, the genomic instability of the RBC-MNE could be used as an indicator to identify clinical conditions of felines, particularly those with one of the characteristics exhibited by this Mexican cat. The RBC-MNE test is the most widely used in the world for the evaluation of DNA damage, but to our knowledge, it has not been used to identify vulnerable non-human specimens.	0
Leukodystrophies (LD) and genetic leukoencephalopathies (gLE) are disorders that result in white matter abnormalities in the central nervous system (CNS). Magnetic resonance (MR) imaging (MRI) has dramatically improved and systematized the diagnosis of LDs and gLEs, and in combination with specific clinical features, such as Addison's disease in Adrenoleukodystrophy or hypodontia in Pol-III related or 4H leukodystrophy, can often resolve a case with a minimum of testing. The diagnostic odyssey for the majority LD and gLE patients, however, remains extensive--many patients will wait nearly a decade for a definitive diagnosis and at least half will remain unresolved. The combination of MRI, careful clinical evaluation and next generation genetic sequencing holds promise for both expediting the diagnostic process and dramatically reducing the number of unresolved cases. Here we present a workflow detailing the Global Leukodystrophy Initiative (GLIA) consensus recommendations for an approach to clinical diagnosis, including salient clinical features suggesting a specific diagnosis, neuroimaging features and molecular genetic testing. We also discuss recommendations on the use of broad-spectrum next-generation sequencing in instances of ambiguous MRI or clinical findings. We conclude with a proposal for systematic trials of genome-wide agnostic testing as a first line diagnostic in LDs and gLEs given the increasing number of genes associated with these disorders.	0
CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, M-protein agglutination, disialosyl antibodies) syndrome is a rare polyneuropathy. IgM paraproteins react with ganglioside-containing disialylated epitopes resulting in dorsal root ganglionopathy and B-lymphocyte infiltration of cranial and peripheral nerves. Clinical features include ataxia, slight muscle weakness, areflexia, sensory- and cranial nerve symptoms. Case studies have reported the efficacy of rituximab and intravenous immunoglobulin (IVIg) treatments. We present the case of a 57-year-old man, who had difficulty walking, with numbness and clumsiness in all limbs. He had areflexia, vibratory sensation loss and ataxia. Laboratory tests showed IgM monoclonal components and disialosyl antibodies in the serum. Nerve conduction studies indicated severe sensorimotor demyelinating polyneuroradiculopathy. Despite IVIg and rituximab treatments, the patient's disease course gradually worsened and he died of respiratory failure. Neuropathological examination revealed dorsal column- and dorsal root atrophy with mixed mononuclear cell infiltration. This article aims to draw attention to this syndrome, and the use of early potent immunosuppressive treatment to improve patients' quality of life.	0
Aortopulmonary window with interrupted aortic arch is rarely reported beyond infancy. Pre-operative assessment and surgical repair are challenging. We report successful surgical repair of aortopulmonary window with interrupted aortic arch in a 6-year-old girl with near-normal pulmonary artery pressure immediately following surgery.	0
We report a newly recognized bone disorder consisting of polyostotic expansile osteolysis affecting long bones and iliac bones; hyperostosis of the skull, thoracic cage, and medial portion of both clavicles; pectus carinatum; gigantiform synovial masses of the elbows and knees; atrial septal defect; cardiomegaly; unilateral cryptorchidism; and mental deficiency. Affected bones can be grouped into four general types of skeletal pathology: (1) expansile osteolysis, (2) osteolysis without expansion, (3) expansion without osteolysis, and (4) hyperostosis. Some bones remained unaffected. We have named the condition "polyosteolysis/hyperostosis syndrome." It is clearly at variance with any previously reported bone disorder, including familial expansile osteolysis, juvenile Paget disease, and McCune-Albright syndrome (and polyostotic fibrous dysplasia). Because our patient shared some features in common with juvenile Paget disease, we thought that mutational analysis of TNFRSF11B was indicated, even though our patient had some manifestations not found in juvenile Paget disease. Direct sequencing failed to identify a TNFRSF11B mutation. Because the parents of our propositus were first cousins suggests that polyosteolysis/hyperostosis syndrome may possibly have autosomal recessive inheritance.	0
Hindbrain energy state shapes hypothalamic control of glucostasis. Dorsal vagal complex (DVC) L-lactate deficiency is a potent glucose-stimulatory signal that triggers neuronal transcriptional activation in key hypothalamic metabolic loci. The energy gauge AMPK is activated in DVC metabolic-sensory A2 noradrenergic neurons by hypoglycemia-associated lactoprivation, but sensor reactivity is diminished by antecedent hypoglycemia (AH). Current research addressed the premise that AH alters hindbrain lactoprivic regulation of hypothalamic metabolic transmitter function. AH did not modify reductions in A2 dopamine-beta-hydroxylase and monocarboxylate-2 (MCT2) protein expression elicited by caudal fourth ventricular delivery of the MCT inhibitor alpha-cyano-4-hydroxycinnamic acid (4CIN), but attenuated 4CIN activation of A2 AMPK. 4CIN constraint of hypothalamic norepinephrine (NE) activity was averted by AH in a site-specific manner. 4CIN induction of Fos immunolabeling in hypothalamic arcuate (ARH), ventromedial (VMN), dorsomedial (DMN) and paraventricular (PVN) nuclei and lateral hypothalamic area (LHA) was avoided by AH. AH affected reactivity of select hypothalamic metabolic neurotransmitter/enzyme marker proteins, e.g. ARH neuropeptide Y, VMN glutamate decarboxylase, DMN RFamide-related peptide-1 and -3, and LHA orexin-A profiles to 4CIN, but did not alleviate drug inhibition of ARH proopiomelanocortin. AH prevented 4CIN augmentation of circulating glucagon, but did not alter hyperglycemic or hypocorticosteronemic responses to that treatment. Results identify hindbrain lactate deficiency as a stimulus for glucagon secretion, and imply that habituation of this critical counter-regulatory hormone to recurring hypoglycemia may involve one or more hypothalamic neurotransmitters characterized here by acclimation to this critical sensory stimulus.	0
To discuss the imaging appearances of various pathologies affecting adult male urethra and to review the role of imaging in the assessment of artificial urinary sphincters and penile prostheses. Diagnosis of common male urethral diseases heavily depends on two conventional fluoroscopic techniques namely retrograde urethrography and voiding cystourethrography. These are useful in evaluating common urethral diseases like traumatic injury, infections, and strictures. Cross-sectional imaging can be useful in evaluating periurethral pathologies. Artificial urinary sphincters, slings, and periurethral bulking agents are used in the management of urinary incontinence and imaging can be utilized to detect complications in these devices. Cross-sectional imaging especially MRI plays a significant role in evaluating the different types of penile prostheses and their malfunctioning.	0
Skeletal dysplasia (SD) is a complex group of bone and cartilage disorders often detectable by fetal ultrasound, but the definitive diagnosis remains challenging because the phenotypes are highly variable and often overlap among different disorders. The molecular mechanisms underlying this condition are also diverse. Hundreds of genes are involved in the pathogenesis of SD, but most of them are yet to be elucidated, rendering genotyping almost infeasible except those most common such as fibroblast growth factor receptor 3 (FGFR3), collagen type I alpha 1 chain (COL1A1), collagen type I alpha 2 chain (COL1A2), diastrophic dysplasia sulfate transporter (DTDST), and SRY-box 9 (SOX9). Here, we report the use of trio-based whole exome sequencing (trio-WES) with comprehensive gene set analysis in two Taiwanese non-consanguineous families with fetal SD at autopsy. A biparental-origin homozygous c.509G>A(p.G170D) mutation in peptidylprolyl isomerase B (PPIB) gene was identified. The results support a diagnosis of a rare form of autosomal recessive SD, osteogenesis imperfecta type IX (OI IX), and confirm that the use of a trio-WES study is helpful to uncover a genetic explanation for observed fetal anomalies (e.g., SD), especially in cases suggesting autosomal recessive inheritance. Moreover, the finding of an identical PPIB mutation in two non-consanguineous families highlights the possibility of the founder effect, which deserves future investigations in the Taiwanese population.	0
Familial tumoral calcinosis (FTC) is a rare autosomal recessive disorder characterized by the progressive deposition of calcified masses in cutaneous and subcutaneous tissues, which results in painful ulcerative lesions and severe skin and bone infections. Two major types of FTC have been recognized: hyperphosphatemic FTC (HFTC) and normophosphatemic FTC (NFTC). HFTC was recently shown to result from mutations in two different genes: GALNT3, which codes for a glycosyltransferase, and FGF23, which codes for a potent phosphaturic protein. To determine the molecular cause of NFTC, we performed homozygosity mapping in five affected families of Jewish Yemenite origin and mapped NFTC to 7q21-7q21.3. Mutation analysis revealed a homozygous mutation in the SAMD9 gene (K1495E), which was found to segregate with the disease in all families and to interfere with the protein expression. Our data suggest that SAMD9 is involved in the regulation of extraosseous calcification, a process of considerable importance in a wide range of diseases as common as atherosclerosis and autoimmune disorders.	0
To study the phenotypes and proline-rich transmembrane protein 2 (PRRT2) mutations in families with benign familial infantile epilepsy (BFIE).Data of all BFIE probands and their family members were collected from Peking University First Hospital between September 2006 and August 2013. Clinical phenotypes of affected members were analyzed. Genomic DNA was extracted from peripheral blood samples with standard protocol. Mutations in PRRT2 were screened using PCR amplification and Sanger sequencing.Twenty-nine BFIE families were recruited in this study. In total, 110 family members were affected. The age of seizure onset of these affected members was between 2 and 12 months (median: 4.5 months). All probands presented with clusters of seizures. Two probands had one seizure induced by diarrhea respectively at 25 months and 31 months. In four BFIE families, four family members had a history of febrile seizures. PRRT2 mutations were found in 17 of the 29 (58.6%) BFIE families. Mutation c.649_650insC was detected in 12 of the 17 families with PRRT2 mutations. Mutation c.649delC (p.R217EfsX12) was identified in three families. Mutation c.323_324delCA (p. T108SfsX25) and c.904_ 905insG (p. D302GfsX39) were detected in one family, respectively.The minimum seizure onset age of affected members in BFIE families was 2 months of age. The seizures often occur in clusters. PRRT2 is the major causative gene of BFIE in Chinese families. Mutation c.649_650insC is the hotspot mutation of PRRT2. A novel mutation c.323_324delCA was first reported in BFIE family. Few affected members with PRRT2 mutation presented with febrile seizures phenotype.	0
Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are lymphocytic, cicatricial alopecias. Clinically, LPP presents with multifocal patchy alopecia, while FFA, considered a variant of LPP, results in hairline recession. Frontal recession in FFA may progress as far as the mid-scalp and infrequently beyond. Treatment to arrest the inflammatory process can be challenging and response variable. We report a case of recalcitrant lichen planopilaris and frontal fibrosing alopecia demonstrating significant clinical improvement after four doses of the interleukin-23 monoclonal antibody tildrakizumab.	0
Computational biomechanics via finite element analysis (FEA) has long promised a means of assessing patient-specific abdominal aortic aneurysm (AAA) rupture risk with greater efficacy than current clinically used size-based criteria. The pursuit stems from the notion that AAA rupture occurs when wall stress exceeds wall strength. Quantification of peak (maximum) wall stress (PWS) has been at the cornerstone of this research, with numerous studies having demonstrated that PWS better differentiates ruptured AAAs from non-ruptured AAAs. In contrast to wall stress models, which have become progressively more sophisticated, there has been relatively little progress in estimating patient-specific wall strength. This is because wall strength cannot be inferred non-invasively, and measurements from excised patient tissues show a large spectrum of wall strength values. In this review, we highlight studies that investigated the relationship between biomechanics and AAA rupture risk. We conclude that combining wall stress and wall strength approximations should provide better estimations of AAA rupture risk. However, before personalized biomechanical AAA risk assessment can become a reality, better methods for estimating patient-specific wall properties or surrogate markers of aortic wall degradation are needed. Artificial intelligence methods can be key in stratifying patients, leading to personalized AAA risk assessment.	0
Cystathionine β-synthase (CBS)-deficient patients are prone to vascular thrombosis. In contrast, Cbs-/- mice show no abnormalities in blood coagulation. To identify molecular basis underlying these disparately different thrombotic phenotypes, we analyzed plasma proteomes of Cbs-/- vs. Cbs+/+ mice (8-month-old, 12/group, sex-matched) and CBS-/- vs. CBS+/+ humans (37 ± 7-year-old, 10-14/group, sex-matched) using label-free mass spectrometry. We identified 117 and 41 differentiating plasma proteins in Cbs-/- mice and CBS-/- humans, respectively. Twenty-one proteins were shared between CBS-/- humans and Cbs-/- mice, with sixteen changed in the opposite direction. Proteins involved in blood coagulation and complement/coagulation cascades represented a greater fraction of the differentiating proteins in CBS-/- patients (51%) than in Cbs-/- mice (21%). Top canonical pathways, identified by Ingenuity Pathways Analysis, such as LXR/RXR, FXR/RXR activation (- log[P-value] = 30-31) and atherosclerosis signaling (- log[P-value] = 10-11) were similarly affected in Cbs-/- mice and CBS-/- humans. The Coagulation System was affected stronger in CBS-/- humans than in Cbs-/- mice (- log[P-value] = 15 vs. 10, respectively) while acute phase response and complement system were affected stronger in Cbs-/- mice (- log[P-value] = 33 and 22, respectively) than in humans (- log[P-value] = 22 and 6, respectively). Other pathways, including IL-7 signaling and B cell development were affected only in Cbs-/- mice. Taken together, our findings suggest that differences in these processes, in particular in the Coagulation System, could account for the thrombotic phenotype in CBS-/- patients and the absence of thrombosis in Cbs-/- mice. Overall, our findings suggest that Cbs-/- mice have a better adaptive response to protect from prothrombotic effects of hyperhomocysteinemia than CBS-/- humans.	0
Even high-quality collection and reporting of study metadata in microbiome studies can lead to various forms of inadvertently missing or mischaracterized information that can alter the interpretation or outcome of the studies, especially with nonmodel organisms. Metabolomic profiling of fecal microbiome samples can provide empirical insight into unanticipated confounding factors that are not possible to obtain even from detailed care records. We illustrate this point using data from cheetahs from the San Diego Zoo Safari Park. The metabolomic characterization indicated that one cheetah had to be moved from the non-antibiotic-exposed group to the antibiotic-exposed group. The detection of the antibiotic in this second cheetah was likely due to grooming interactions with the cheetah that was administered antibiotics. Similarly, because transit time for stool is variable, fecal samples within the first few days of antibiotic prescription do not all contain detected antibiotics, and the microbiome is not yet affected. These insights significantly altered the way the samples were grouped for analysis (antibiotic versus no antibiotic) and the subsequent understanding of the effect of the antibiotics on the cheetah microbiome. Metabolomics also revealed information about numerous other medications and provided unexpected dietary insights that in turn improved our understanding of the molecular patterns on the impact on the community microbial structure. These results suggest that untargeted metabolomic data provide empirical evidence to correct records and aid in the monitoring of the health of nonmodel organisms in captivity, although we also expect that these methods may be appropriate for other social animals, such as cats.IMPORTANCE Metabolome-informed analyses can enhance omics studies by enabling the correct partitioning of samples by identifying hidden confounders inadvertently misrepresented or omitted from carefully curated metadata. We demonstrate here the utility of metabolomics in a study characterizing the microbiome associated with liver disease in cheetahs. Metabolome-informed reinterpretation of metagenome and metabolome profiles factored in an unexpected transfer of antibiotics, preventing misinterpretation of the data. Our work suggests that untargeted metabolomics can be used to verify, augment, and correct sample metadata to support improved grouping of sample data for microbiome analyses, here for nonmodel organisms in captivity. However, the techniques also suggest a path forward for correcting clinical information in microbiome studies more broadly to enable higher-precision analyses.	0
Rheumatoid nodulosis is considered a benign variant of rheumatoid arthritis. Several therapies have been used with variable results. We report a 63-year-old man who presented with nodular lesions on the metacarpophalangeal joints and knees which were diagnosed of rheumatoid nodulosis. Topical tacrolimus was started with good response on the following months.	0
To assess EDI-OCT (enhanced depth imaging optical coherence tomography) of choroid for inflammatory signs in children with polyarteritis nodosa (PAN) and adenosine deaminase-2 deficiency (DADA-2). In this cross-sectional study conducted between June 2017 and September 2018, we evaluated children diagnosed with PAN (n = 11) and DADA-2 (n = 4) and an age- and sex-matched control group (n = 15). Demographic and laboratory data were retrospectively analyzed from patient charts. Disease activity was assessed using the pediatric vasculitis activity score (PVAS). Choroidal images were obtained with spectral domain-OCT to measure choroidal thickness (ChT) at 5 points (750 and 1500 μm from the foveal center in the temporal and nasal quadrants and beneath the fovea), and to calculate the total subfoveal choroidal area (TCA), luminal area (LA), stromal area (SA), and the choroidal vascularity index (CVI). The median (min-max) age was 8 (4-16) years in PAN patients, 6 (5-16) years in DADA-2 patients and 8 (8-10) years in control group at the OCT visit (p = 0.214). The ChT at 3 points and the TCA, LA, and SA were higher in children with both PAN and DADA-2 patients compared to those of the control group (p < 0.0001, p = 0.049, p = 0.007, p = 0.007, p = 0.006, p = 0.033, respectively). The CVI was similar in both groups. No association was observed between the OCT findings, PVAS, and the erythrocyte sedimentation rate, and serum leukocyte and C-reactive protein levels. Similar CVI scores were obtained from PAN and DADA2 patients under treatment and from healthy controls. Increased subfoveal ChT without any other signs of ocular involvement may suggest choroidal thickening as a sign of mild subclinical inflammation.	0
There are 16.5 million newborns in China annually. However, the incidence of congenital heart disease (CHD) has not been evaluated. In 2004, we launched an active province-wide hospital-based CHD registry in the Guangdong Province of southern China. In this study, we examined the incidence of CHD and its subtypes from 2004 to 2012 and compared our findings to the literature. Our results indicate there is an increasing trend of CHD incidence. The increase in incidence occurred mainly for single lesion and the most common subtypes (e.g., ventricular or atrial septal defect, patent ductus arteriosus). There were no increases found for multiple lesions or more complex subtypes. The proportion of CHD cases that were detected early (e.g., 1 week) increased over time. The incidence of CHD stabilized in 2010-2012 with the average cumulative incidences of 9.7, 9.9, and 11.1 per 1,000 live births at 1 week, 1 month, and 1 year, respectively. The incidences of CHD subtypes were comparable with recent international results. The data did not support previous reports that Asian children have a higher incidence of pulmonary outflow obstructions and lower incidence of transposition of the great arteries. However, there was a lower incidence of left ventricular outflow tract obstructions observed in our series. The increase in CHD incidence observed over time was due to improved detection and diagnosis. The true incidence of CHD in China was approximately 11.1 per 1,000 live births, which is higher than previously reported.	1
Hailey-Hailey disease is an autosomal dominant genodermatosis leading to chronic hyperkeratotic and fissured lesions in the intertriginous areas. We present a 53-year-old woman with a case of vulvar and inguinal Hailey-Hailey disease resistant to usual treatments. She was efficiently treated with alitretinoin 10 mg daily combined with injections of onabotulinumtoxinA every 9 months. The combination led to an almost complete resolution of the lesions and symptoms at follow-ups.	0
BACKGROUND: Merkel cell carcinoma (MCC) is a rare skin cancer that was recently found to be associated with a polyomavirus and with immunosuppression, provoking new interest in its epidemiology. We conducted a nationwide study in Denmark to describe MCC incidence and mortality and the association between MCC and other cancers. METHODS: We used data from Danish national health and population registers on MCC diagnoses, deaths, and population counts during the study period (1978-2006) to calculate MCC incidence rates, cumulative risks of MCC at age 100 years, and MCC mortality rates by tumor stage. We used Poisson regression to estimate the excess mortality rate ratio attributable to MCC and examined associations between MCC and other cancers diagnosed before and after the MCC diagnosis using standardized incidence rate ratios (SIRs). All statistical tests were two-sided. RESULTS: Between January 1, 1978, and December 31, 2006, 185 persons were diagnosed with MCC in Denmark. MCC incidence between 1995 and 2006 was 2.2 cases per million person-years. In the first year after MCC diagnosis, 22% of persons with localized disease died compared with 54% of patients with nonlocalized disease; by 5 years after diagnosis, the proportions of MCC patients who had died increased to 55% and 84%, respectively. MCC incidence was statistically significantly increased more than 1 year after a diagnosis of squamous cell carcinoma of the skin (SIR = 14.6, 95% confidence interval [CI] = 8.4 to 25.6), basal cell carcinoma (SIR = 4.3, 95% CI = 2.7 to 6.6), malignant melanoma (SIR = 3.3, 95% CI = 1.1 to 10.3), chronic lymphocytic leukemia (SIR = 12.0, 95% CI = 3.8 to 37.8), Hodgkin lymphoma (SIR = 17.6, 95% CI = 2.5 to 126), and non-Hodgkin lymphoma (SIR = 5.6, 95% CI = 1.4 to 22.4). Squamous cell carcinoma (SIR = 12.1, 95% CI = 5.1 to 29.1) and chronic lymphocytic leukemia (SIR = 14.7, 95% CI = 3.7 to 58.8) occurred in statistically significant excess more than 1 year after MCC diagnosis. CONCLUSIONS: These results support the existence of shared risk factors for MCC and other cancers. Heightened awareness of the association between MCC and other cancers, particularly squamous cell carcinoma and chronic lymphocytic leukemia, may facilitate earlier clinical detection and treatment of MCC, thereby improving patient survival.	1
A case is described of diffuse idiopathic phlebectasia and its clinical symptoms; dilatation of veins were located in superficial and deep systems. The arteries had no changes. Genuine diffuse phlebectasia must be differentiated from phlebarteriectasia and cirsoid angioma. Angiography shows the absence of the ulnar artery and of some of the digital arteries. It shows excessive dilatation of veins and some phleboliths. The X-rays show cortical changes of the bones of the hand skeleton.	0
Lysinuric protein intolerance (LPI) is a rare autosomal disease caused by defective cationic amino acid (CAA) transport due to mutations in SLC7A7, which encodes for the y+LAT1 transporter. LPI patients suffer from a wide variety of symptoms, which range from failure to thrive, hyperammonemia, and nephropathy to pulmonar alveolar proteinosis (PAP), a potentially life-threatening complication. Hyperammonemia is currently prevented by citrulline supplementation. However, the full impact of this treatment is not completely understood. In contrast, there is no defined therapy for the multiple reported complications of LPI, including PAP, for which bronchoalveolar lavages do not prevent progression of the disease. The lack of a viable LPI model prompted us to generate a tamoxifen-inducible Slc7a7 knockout mouse (Slc7a7-/-). The Slc7a7-/- model resembles the human LPI phenotype, including malabsorption and impaired reabsorption of CAA, hypoargininemia and hyperammonemia. Interestingly, the Slc7a7-/- mice also develops PAP and neurological impairment. We observed that citrulline treatment improves the metabolic derangement and survival. On the basis of our findings, the Slc7a7-/- model emerges as a promising tool to further study the complexity of LPI, including its immune-like complications, and to design evidence-based therapies to halt its progression.	0
Congenital diseases that could result in hyperphosphatemia at an early age include hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) and congenital hypoparathyroidism/pseudohypoparathyroidism due to the insufficient activity of fibroblast growth factor (FGF) 23 and parathyroid hormone. HFTC/HHS is a rare autosomal recessive disease caused by inactivating mutations in the FGF23, UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), or Klotho (KL) genes, resulting in the excessive cleavage of active intact FGF23 (FGF23, GALNT3) or increased resistance to the action of FGF23 (KL). Massive ectopic calcification, known as tumoral calcinosis (TC), is seen in periarticular soft tissues, typically in the hip, elbow, and shoulder in HFTC/HHS, reducing the range of motion. However, other regions, such as the eye, intestine, vasculature, and testis, are also targets of ectopic calcification. The other symptoms of HFTC/HHS are painful hyperostosis of the lower legs, dental abnormalities, and systemic inflammation. Low phosphate diets, phosphate binders, and phosphaturic reagents such as acetazolamide are the treatment options for HFTC/HHS and have various consequences, which warrant the development of novel therapeutics involving recombinant FGF23.	0
Muehrcke's lines are a type of apparent leukonychia that are common in patients receiving chemotherapeutic agents. They are self-limited, and there is no need to more workup.	0
BACKGROUND:The mitochondrial aminoacyl-tRNA synthetase proteins (mt-aaRSs) are a group of nuclear-encoded enzymes that facilitate conjugation of each of the 20 amino acids to its cognate tRNA molecule. Mitochondrial diseases are a large, clinically heterogeneous group of disorders with diverse etiologies, ages of onset, and involved organ systems. Diseases related to mt-aaRS mutations are associated with specific syndromes that affect the central nervous system and produce highly characteristic MRI patterns, prototypically the DARS2, EARS, and AARS2 leukodystrophies, which are caused by mutations in mitochondrial aspartyl-tRNA synthetase, mitochondria glutamate tRNA synthetase, and mitochondrial alanyl-tRNA synthetase, respectively. BODY: The disease patterns emerging for these leukodystrophies are distinct in terms of the age of onset, nature of disease progression, and predominance of involved white matter tracts. In DARS2 and EARS2 disorders, earlier disease onset is typically correlated with more significant brain abnormalities, rapid neurological decline, and greater disability. In AARS2 leukodystrophy cases reported thus far, there is nearly invariable progression to severe disability and atrophy of involved brain regions, often within a decade. Although most mutations are compound heterozygous inherited in an autosomal recessive fashion, homozygous variants are found in each disorder and demonstrate high phenotypic variability. Affected siblings manifest disease on a wide spectrum. CONCLUSION:The syndromic nature and selective vulnerability of white matter tracts in these disorders suggests there may be a shared mechanism of mitochondrial dysfunction to target for study. There is evidence that the clinical variability and white matter tract specificity of each mt-aaRS leukodystrophy depend on both canonical and non-canonical effects of the mutations on the process of mitochondrial translation. Furthermore, different sensitivities to the mt-aaRS mutations have been observed based on cell type. Most mutations result in at least partial retention of mt-aaRS enzyme function with varied effects on the mitochondrial respiratory chain complexes. In EARS2 and AARS2 cells, this appears to result in cumulative impairment of respiration. Mt-aaRS mutations may also affect alternative biochemical pathways such as the integrated stress response, a homeostatic program in eukaryotic cells that typically confers cytoprotection, but can lead to cell death when abnormally activated in response to pathologic states. Systematic review of this group of disorders and further exploration of disease mechanisms in disease models and neural cells are warranted.	0
True thymic hyperplasia is a very rare entity. We present an instance of idiopathic true massive thymic hyperplasia in a 9-month-old girl with a very large left-sided mediastinal mass noted on diagnostic imaging. Percutaneous biopsy revealed normal thymic tissue. Steroids were administered with no response. Surgery may be required in patients with respiratory distress unresponsive to steroids.	0
Background:Aggressive natural killer cell leukemia (ANKL) is extremely rare and habitually manifests as a systemic disease with multiorgan failure that rapidly evolves to death. The neoplastic natural killer (NK) cells usually harbor the Epstein-Barr virus (EBV) with a latent viral infection pattern type II; they often have a cytoplasmic CD3ε+ and surface CD3-, CD2+, and CD56+ immunophenotype, and they show complex genetic abnormalities affecting multiple tumor suppressor genes and oncogenes. We present a rare case of CD56-negative ANKL and review the clinical and laboratorial criteria for the diagnosis, as well as the available therapies. Case Presentation:A European 36-year-old male presented with acute onset fever, pallor, weakness, and jaundice. He had hepatosplenomegaly, severe pancytopenia, hepatic cytolysis, and very high serum lactic dehydrogenase levels. The bone marrow studies resulted in the diagnosis of an EBV-positive, CD56-negative ANKL. The patient failed to respond to gemcitabine and cisplatin-based polychemotherapy, dying three months later with leukemic meningitis and multiple cranial nerves palsies. Conclusions:The diagnosis of ANKL is difficult and requires both clinical suspicion and an extensive laboratorial approach. Absence of CD56 expression on the neoplastic NK cells may impose difficulties in the diagnosis, which requires morphological, immunophenotypic, histopathological, immunohistochemical, cytogenetic, and molecular studies.	0
Human piebald trait is an autosomal dominant defect in melanocyte development characterized by patches of hypopigmented skin and hair. Although the molecular basis of piebaldism has been unclear, a phenotypically similar "dominant spotting" of mice is caused by mutations in the murine c-kit protooncogene. In this regard, one piebald case with a point mutation and another with a deletion of c-kit have been reported, although a polymorphism or the involvement of a closely linked gene could not be excluded. To confirm the hypothesis that piebaldism results from mutations in the human gene, c-kit exons were amplified by polymerase chain reaction from the DNA of 10 affected subjects and screened for nucleotide changes by single-stranded conformation polymorphism analysis. In one subject with a variant single-stranded conformation polymorphism pattern for the first exon encoding the kinase domain, DNA sequencing demonstrated a missense mutation (Glu583----Lys). This mutation is identical to the mouse W37 mutation which abolishes autophosphorylation of the protein product and causes more extensive depigmentation than "null" mutations. In accord with this "dominant negative" effect, the identical mutation in this human kindred is associated with unusually extensive depigmentation. Thus, the finding of a piebald subject with a mutation that impairs receptor activity strongly implicates the c-kit gene in the molecular pathogenesis of this human developmental defect.	0
Dyssegmental dysplasia, Silverman-Handmaker type (DDSH), is a lethal autosomal recessive form of dwarfism with characteristic anisospondylic micromelia. The remarkable similarities in the radiographic, clinical, and chondroosseous morphology of DDSH patients to those of perlecan-null mice led to the identification of mutations in the perlecan gene (HSPG2) of DDSH. Perlecan, a large heparan sulfate proteoglycan, is expressed in various tissues and is a component of all basement membrane extracellular matrices. A chondrodysplasia phenotype caused by the loss of perlecan was unexpected, because cartilage does not have basement membranes. Insertion and splicing mutations in HSPG2 of DDSH were found that were predicted to create a premature termination codon. Immunostaining and biochemical analysis revealed that the mutant perlecan molecules were unstable and not secreted into the extracellular matrix. These results indicate that DDSH is caused by functional null mutations of HSPG2 and that perlecan is essential for cartilage development. Published 2002 Wiley-Liss, Inc.	0
Physiological development requires precise spatiotemporal regulation of cellular and molecular processes. Disruption of these key events can generate developmental toxicity in the form of teratogenesis or mortality. The mechanism behind many developmental toxicants remains unknown. While recent work has focused on the unfolded protein response (UPR), oxidative stress, and apoptosis in the pathogenesis of disease, few studies have addressed their relationship in developmental toxicity. Redox regulation, UPR, and apoptosis are essential for physiological development and can be disturbed by a variety of endogenous and exogenous toxicants to generate lethality and diverse malformations. This review examines the current knowledge of the role of oxidative stress, UPR, and apoptosis in physiological development as well as in developmental toxicity, focusing on studies and advances in vertebrates model systems.	0
Patent ductus venosus is caused by a defect in obliteration of ductus venosus after birth. Ductus venosus connects umbilical vein and inferior vena cava during fetal period. Patent ductus venosus is a very rare cause of cholestatic jaundice.	0
Scoliosis and limb length discrepancy are the major orthopaedic abnormalities in patients with Silver-Russel syndrome (SRS). In this paper, we describe a series of orthopaedic interventions in an attempt to overcome the progressive pathologic mechanism in a 7-year-old girl who manifested the full phenotypic features of SRS.Unilateral hip dislocation, progressive scoliosis and limb length discrepancy have been dealt with through Pemberton osteotomy, spinal fusion and Taylor-Spatial-Frame respectively.In order to correct the axial and the appendicular deformities a sum of seven operations were performed (between the age of 7 years and 13 years). Pemberton osteotomy was performed to treat dislocation of her right hip because of developmental dysplasia of the hip. Spinal fusion (spondylodesis) of segments Th3-L5 was done to correct her scoliosis. And, to overcome the limb length discrepancy of 15-cm we used Taylor-Spatial-Frame with percutaneous distal corticotomy of the femur, and the proximal tibia, as well as the foot, were performed. We were able to minimize the limb length discrepancy to 5 cm. The girl became able to walk with the aid of a below knee orthosis and through lifting the left limb with 5-cm height shoe.Limb lengthening surgery in patients with multiple malformation complex as in SRS is associated with high recurrence risk because of; muscular hypotonia, overtubulation of the long bones, and the poor bone regenerative quality. Our interventions were principally directed towards improving the cosmetic outlook, functions and the biomechanics.	0
Macular involvement is a common finding in patients with Eales disease. The purpose of this communication is to describe the diagnosis of Eales disease from the finding of a macular epiretinal membrane in a young patient. The case is presented of a 38-year-old man referred to this medical service unit with blurred vision developed over the past 3 months, and was associated with vitreoretinal traction and a macular epiretinal membrane. After an ophthalmological examination including the retinal periphery, optical coherence tomography, tuberculin test, interferon gamma release assay (IGRA), and a systemic study, the patient was diagnosed with Eales disease. Macular oedema or epiretinal membranes due to Eales disease are relatively common. Sd-OCT is recommended in all patients with Eales disease. On the other hand, the presence of epiretinal membranes in young patients usually suggests a non-idiopathic aetiology.	0
PURPOSE:Idiopathic hypogonadotropic hypogonadism (IHH) and CHARGE (C, coloboma; H, heart abnormalities; A, choanal atresia, R, retardation of growth and/or development; G, gonadal defects; E, ear deformities and deafness) syndrome are 2 distinct developmental disorders sharing features of hypogonadism and/or impaired olfaction. CHD7 variants contribute to >60% CHARGE syndrome and ~10% IHH patients. A variety of extended CHARGE-like features are frequently reported in CHARGE patients harboring CHD7 variants. In this study, we aimed to systematically analyze the diagnostic CHARGE features and the extended CHARGE-like features in patients with IHH with CHD7 variants. METHODS:Rare sequencing variants (RSVs) in CHD7 were identified through exome sequencing in 177 IHH probands. Detailed phenotyping was performed in the IHH patients harboring CHD7 variants and their available family members. RESULTS:CHD7 RSVs were identified in 10.2% (18/177) of the IHH probands. Two diagnostic CHARGE features, hearing loss and ear deformities, were significantly enriched in patients with CHD7 variants. Furthermore, CHD7 variants were significantly associated with a panel of extended CHARGE-like phenotypes, including mild ocular defects, dyspepsia/gastroesophageal reflux disease and skeletal defects. We also developed a predictive model for prioritizing CHD7 genetic testing in IHH patients. CONCLUSION:CHD7 variants rarely cause isolated IHH. Surveillance of symptoms in CHARGE syndrome-affected organs will facilitate the proper treatment for these patients. Certain clinical features can be useful for prioritizing CHD7 genetic screening.	0
Pediatric cataract is clinically and genetically heterogeneous and is the most common cause of childhood blindness worldwide. In this study, we aimed to identify disease-causing variants in three large British families and one isolated case with autosomal dominant congenital cataract, using whole exome sequencing. We identified four different heterozygous variants, three in the large families and one in the isolated case. Family A, with a novel missense variant (c.178G>C, p.Gly60Arg) in GJA8 with lamellar cataract; family B, with a recurrent variant in GJA8 (c.262C>T, p.Pro88Ser) associated with nuclear cataract; and family C, with a novel variant in GJA3 (c.771dupC, p.Ser258GlnfsTer68) causing a lamellar phenotype. Individual D had a novel variant in GJA3 (c.82G>T, p.Val28Leu) associated with congenital cataract. Each sequence variant was found to co-segregate with disease. Here, we report three novel and one recurrent disease-causing sequence variant in the gap junctional protein encoding genes causing autosomal dominant congenital cataract. Our study further extends the mutation spectrum of these genes and further facilitates clinical diagnosis. A recurrent p.P88S variant in GJA8 causing isolated nuclear cataract provides evidence of further phenotypic heterogeneity associated with this variant.	0
A 7-year-old castrated male French Bulldog was examined for chronic large intestinal enteropathy. A colonic mass and thickened rectal mucosa were identified, and histopathologic examination of endoscopic biopsy specimens disclosed eosinophilic proctitis with large (5-20 μm), irregularly shaped, pauciseptate hyphae that were Gomori methenamine silver and periodic acid-Schiff positive. Amplification and sequencing of ribosomal DNA extracted from paraffin-embedded tissues yielded a sequence with 97% identity to GenBank sequences for Basidiobolus ranarum. After itraconazole, terbinafine, and prednisone administration, clinical signs resolved rapidly, and sonographic lesions were largely absent after 6 weeks. Treatment was discontinued by the owner 15 weeks after diagnosis. Three weeks later, the dog collapsed acutely and was euthanized. Necropsy identified metastatic islet cell carcinoma and grossly unremarkable colorectal tissues. However, histopathology of the rectum disclosed multifocal submucosal granulomas with intralesional hyphae morphologically similar to those previously observed. This report is the first to describe medical treatment of gastrointestinal basidiobolomycosis in a dog.	0
BACKGROUND:Lateral meningocele syndrome (LMS) is an exceedingly rare connective tissue disease with phenotypic anomalies similar to those seen in Marfan syndrome, Ehler-Danlos syndrome, and Loeys-Dietz syndrome. However, this syndrome is invariably associated with the presence of multiple lateral thoracolumbar spinal meningoceles: a distinct point of phenotypic divergence from other connective tissue disorders. The etiopathogenesis of this syndrome has recently been linked to truncating mutations within exon 33 of NOTCH3. Despite numerous reports, neurosurgical management of multiple spinal meningoceles remains poorly defined in the literature. We conducted a literature review to provide insight into the nosology, clinical significance, and neurosurgical management strategies of this distinct connective tissue disorder. SUMMARY:Our literature search revealed 11 articles (16 cases) of LMS, which included 9 males and 7 females, belonging to 14 different families. Half of these cases underwent genetic screening: all of which were discovered to exhibit a truncating mutation within exon 33 of NOTCH3. All patients exhibited multiple lateral thoracolumbar spinal meningoceles with craniofacial dysmorphisms. Other clinical characteristics included pathologic changes in spine morphology, Chiari I malformation, syringomyelia, hydrocephalus, and tethered cord. Operative management of multiple spinal meningoceles in LMS is complicated by the presence of such coexisting structural neurologic pathologies, which may alter cerebrospinal fluid flow dynamics and, ultimately, impact operative intervention. Key Messages: LMS is an exceedingly rare connective tissue disorder with severe spinal dural involvement. Neurosurgical management of multiple spinal meningoceles is complex, which is further complicated by the presence of coexisting neuropathology, such as pathologic transformation of spine morphology and Chiari I malformation. Patients with a connective tissue disorder phenotype found to have multiple spinal meningoceles on imaging studies may benefit from evaluation by a medical geneticist and a pediatric neurosurgeon.	0
Tourniquet syndrome is a rare condition where a tourniquet applied to an appendage leads to an obstructed blood flow and subsequent ischemic injury. Meningomyelocele and meningocele are common birth defects, and involvement of meningocele in tourniquet syndrome is never mentioned in the literature. We managed a 10-day-old male child presenting with infected lumber meningocele with a tourniquet tied at its base. It is being presented with review of relevant literature.	0
Mollaret meningitis, a benign recurrent aseptic disease, is known to be associated with intracranial epidermoid cysts. In this report, we describe a case of Mollaret meningitis caused by an intraspinal epidermoid cyst located at thoracic level 12. The patient's clinical manifestations and cerebrospinal fluid features were similar to those with bacterial meningitis characterized by predominant polymorphonuclear leukocytes. However, Mollaret cells, not bacteria, were identified in the patient's cerebrospinal fluid. The illness ceased after surgical resection of the cyst, and the cyst tissue was pathologically diagnosed as epidermoid. Therefore, an intraspinal epidermoid cyst can be etiologically associated with Mollaret meningitis and should be included in the differential diagnosis of recurrent aseptic meningitis.	0
Roberts syndrome and SC phocomelia syndrome are rare autosomal recessive genetic disorders representing the extremes of the spectrum of severity of the same condition, caused by mutations in ESCO2 gene. We report three new patients with Roberts syndrome from three unrelated consanguineous Egyptian families. All patients presented with growth retardation, mesomelic shortening of the limbs more in the upper than in the lower limbs and microcephaly. Patients were subjected to clinical, cytogenetic and radiologic examinations. Cytogenetic analysis showed the characteristic premature separation of centromeres and puffing of heterochromatic regions. Further, sequencing of the ESCO2 gene identified a novel mutation c.244_245dupCT (p.T83Pfs*20) in one family besides two previously reported mutations c.760_761insA (p.T254Nfs*27) and c.764_765delTT (p.F255Cfs*25). All mutations were in homozygous state, in exon 3. The severity of the mesomelic shortening of the limbs and craniofacial anomalies showed variability among patients. Interestingly, patient 1 had abnormal skin hypopigmentation. Serial fetal ultrasound examinations and measurements of long bones diagnosed two affected fetuses in two of the studied families. A literature review and case comparison was performed. In conclusion, we report a novel ESCO2 mutation and expand the clinical spectrum of Roberts syndrome.	0
To determine the cortical mechanism that underlies the cognitive impairment and motor disability in hereditary spastic paraplegia (HSP), nine HSP patients from a Chinese family were examined using clinical evaluation, cognitive screening, and genetic testing. Controls were matched healthy subjects. White-matter fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD; tract-based spatial statistics), cortical thickness (FreeSurfer), and subcortical gray matter (FIRST) based on T1-weighted MRI and diffusion tensor imaging were analyzed. A novel mutation in the SPAST gene (NM_014946.3, c.1321+2T>C) was detected. Patients had motor disability and low Montreal Cognitive Assessment (MoCA) scores. Patients showed significantly decreased total gray- and white-matter volumes, corpus callosum volume, cortical thickness, and subcortical gray-matter volume as well as significantly lower FA and AD values and significantly higher MD and RD values in the corpus callosum and corticospinal tract. Cortical thickness, subcortical gray-matter volume, and MoCA score were negatively correlated with disease duration. Cortical thickness in the right inferior frontal cortex was negatively correlated with Spastic Paraplegia Rating Scale score. Cortical thickness and right hippocampus volume were positively correlated with the MoCA score and subscores. In conclusion, brain damage is not restricted to the white matter in SPG4-HSP patients, and widespread gray-matter damage may account for the disease progression, cognitive impairment, and disease severity in SPG4-HSP.	0
We report the case of a Caucasian Spanish origin female who showed severe psychomotor developmental delay, hypotonia, strabismus, epilepsy, short stature, and poor verbal language development. Brain magnetic resonance imaging scans showed thickened corpus callosum, cortical malformations, and dilated and abnormal configuration of the lateral ventricles without hydrocephalus. Whole-exome sequence uncovered a de novo variant in the microtubule associated serine/threonine kinase 1 gene (MAST1; NM_014975.3:c.1565G>A:p.(Gly522Glu)) that encodes for the MAST1. Only 12 patients have been identified worldwide with 10 different variants in this gene: six patients with mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations; two patients with microcephaly and cerebellar hypoplasia; two patients with autism, one patient with diplegia, and one patient with microcephaly and dysmorphism. Our patient shows a new phenotypic subtype defined by mega-corpus-callosum syndrome with cortical malformations without cerebellar hypoplasia. In conclusion, our data expand the phenotypic spectrum associated to MAST1 gene variants.	0
Cases of epidermolysis bullosa (EB) diagnosed in Northern Ireland during a 23-year period (1962-84) were identified from dermatology clinic files, paediatric hospital notes and cases known by general practitioners. A total of 48 confirmed new cases of EB were diagnosed during the screening period. This involved 31 families, with identification of 36 further cases. The distribution of incident EB subtypes was: simplex 31 (65%), junctional 1 (2%), dystrophic 12 (25%) and acquisita 4 (8%). The incidence rate of new cases of EB diagnosed per year is 1.4/million and prevalence of all forms estimated at 32/million. The prevalence of simplex, junctional and dystrophic forms is 28, 0.7 and 3/million, respectively.	1
BACKGROUND Persistent cloacal malformations are rare anomalies that are anorectal malformations occurring in females. In cases of persistent cloaca, prenatal ultrasonography shows fetal ascites, cystic tumor in the abdomen, oligohydramnios, and hydronephrosis. There are various types of persistent cloaca, and symptoms vary. CASE REPORT A 38-year-old pregnant woman was referred to our hospital because of suspected fetal expansion of the intestinal tract. Prenatal ultrasonography revealed a fetal growth restriction, oligohydramnios, fetal abdominal cyst, and bilateral hydronephrosis, and persistent cloaca was suspected. Also, magnetic resonance imaging (MRI) revealed a double uterus and bilateral hydronephrosis, hydrocolpos; as such, persistent cloaca was diagnosed. Cesarean section was performed at 36 weeks+3 days gestation and delivered a female infant weighing 1957 g, with Apgar scores of 9 (1 min)/9 (5 min). CONCLUSIONS We report a case of persistent cloaca detected in the prenatal ultrasonography and MRI examination. Prenatal diagnosis is important because it can lead to a better outcome for infants with persistent cloaca. In the image inspection in persistent cloaca, there are characteristic findings such as ascites, cystic tumor in the abdomen, difficulty in visualizing the bladder, oligohydramnios, and hydronephrosis. So, if persistent cloaca is suspected, use of ultrasonography and MRI will allow its diagnosis.	0
Muscle disorders are characterized by differential involvement of various muscle groups. Among these, weakness predominantly affecting finger flexors is an uncommon pattern, most frequently found in sporadic inclusion-body myositis. This finding is particularly significant when the full range of histopathological findings of inclusion-body myositis is not found on muscle biopsy. Prominent finger flexor weakness, however, is also observed in other myopathies. It occurs commonly in myotonic dystrophy types 1 and 2. In addition, individual reports and small case series have documented finger flexor weakness in sarcoid and amyloid myopathy, and in inherited myopathies caused by ACTA1, CRYAB, DMD, DYSF, FLNC, GAA, GNE, HNRNPDL, LAMA2, MYH7, and VCP mutations. Therefore, the finding of finger flexor weakness requires consideration of clinical, myopathological, genetic, electrodiagnostic, and sometimes muscle imaging findings to establish a diagnosis.	0
Pemphigus foliaceus is an autoimmune bullous disease with autoantibodies against desmoglein 1. Case reports of pemphigus after surgery have also been described, which may simulate an infection of the surgical wound, a contact dermatitis, or even a tumor recurrence. Cytoimmunofluorescence can help to establish a rapid diagnosis.	0
There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers.	0
Aneuploidy mosaicism involving two complementary different autosomal trisomy cell lines is extremely rare. Although a mosaic double trisomy 8/trisomy 21 has been described in literature, this is the first report of Warkany (+8)-Down (+21) syndrome due to two complementary mosaic trisomy cell lines. The phenotype of the male patient with Warkany-Down syndrome includes upslanting palpebral fissures, hypertelorism, small low-set ears with unilateral aural stenosis, large and broad hands and feet with deep palmar and plantar creases, bilateral cryptorchidism, generalized mild hypotonia and transient neonatal thrombocytopenia. At the age of two years, his developmental quotient is around 50. His height, weight and head circumference are below the third centile. We speculate on the mechanism of origin of the complementary trisomy cell lines based on molecular cytogenetic studies that showed no evidence for a chimera.	0
The striking and complex phenotype of Cockayne syndrome (CS) patients combines progeria-like features with developmental deficits. Since the establishment of the in vitro culture of skin fibroblasts derived from patients with CS in the 1970s, significant progress has been made in the understanding of the genetic alterations associated with the disease and their impact on molecular, cellular, and organismal functions. In this review, we provide a historic perspective on the research into CS by revisiting seminal papers in this field. We highlighted the great contributions of several researchers in the last decades, ranging from the cloning and characterization of CS genes to the molecular dissection of their roles in DNA repair, transcription, redox processes and metabolism control. We also provide a detailed description of all pathological mutations in genes ERCC6 and ERCC8 reported to date and their impact on CS-related proteins. Finally, we review the contributions (and limitations) of many genetic animal models to the study of CS and how cutting-edge technologies, such as cell reprogramming and state-of-the-art genome editing, are helping us to address unanswered questions.	0
Cephalic parapagia, a rare congenital anomaly caused by the fusion of two monozygotic embryos, is characterized by a single body and a spectrum of duplication of craniofacial structures. The authors describe the clinical and pathological aspects of the parapagus conjoined twin defect in nine calves referred to the Department of Animal Pathology, Turin, between 1999 and 2009. The majority of the calves (eight cases) presented two snouts that shared three or four eyes (diprosopia); one calf presented two separate skulls fused at the foramen magnum (dicephalia). Bilateral inferior brachygnathia was observed in four calves. Post-mortem examination of the skull revealed complete brain duplication with fusion at the caudal portion of the brainstem in all calves. Histological features of the cerebral hemispheres and brainstem were normal; moderate disorganization of the cerebellar cortex was noted in two cases. Cardiac malformations were observed in three calves. No aetiologic cause was determined. This article underscores the importance of diprosopia in cattle species and suggests the need for more detailed investigations to better understand its pathogenesis.	0
To evaluate corticomotoneuronal integrity in monomelic amyotrophy using threshold tracking transcranial magnetic stimulation (TT-TMS).Cortical excitability studies were prospectively performed in 8 monomelic amyotrophy patients and compared to 21 early-onset amyotrophic lateral sclerosis (ALS) patients and 40 healthy controls. Motor evoked potentials responses were recorded over abductor pollicis brevis.Maximal motor evoked potential (MEP/CMAP ratio) was significantly increased in monomelic amyotrophy compared with controls (monomelic amyotrophy 51.2±12.4%; control 22.7±2.1%, p=0.04). Averaged short-interval intracortical inhibition (SICI, ISI 1-7ms) in monomelic amyotrophy patients was similar to controls (monomelic amyotrophy 9.6±2.1%; control 10.0±0.9%, p=0.98). However, it was significantly reduced in early-onset ALS in comparison with monomelic amyotrophy patients (monomelic amyotrophy 9.6±2.1%; ALS 2.3±1.7%, p<0.001). Averaged SICI is a good parameter (area under the curve 0.79, p=0.02) to discriminate between monomelic amyotrophy and early-onset ALS patients.TT-TMS technique has identified normal cortical function in monomelic amyotrophy, a feature that distinguishes it from early-onset ALS. The greater corticomotoneuronal projections to spinal motoneurons may represent central nervous system adaptive change in monomelic amyotrophy.Corticomotoneuronal dysfunction does not drive the lower motor neurone loss presented in monomelic amyotrophy.	0
Introduction: Krabbe disease (KD) is an autosomal recessive lysosomal disorder caused by mutations in the galactocerebrosidase (GALC) gene. This results in defective myelination in the peripheral and central nervous systems due to low GALC activity. Treatment at this time is limited to hematopoietic stem cell transplantation (HSCT) in pre-symptomatic individuals. While this treatment extends the lives of treated individuals, most have difficulty walking by the end of the first decade due to peripheral neuropathy. Studies in the murine model of KD, twitcher (twi) combining bone marrow transplantation (BMT) with AAVrh10-mGALC showed a great extension of life from 40 days to about 400 days, with some living a full life time. Methods: In order to find the optimum conditions for dosing and timing of this combined treatment, twi mice were injected with five doses of AAVrh10-mGALC at different times after BMT. Survival, as well as GALC expression were monitored along with studies of sciatic nerve myelination and possible liver pathology. Results: Dosing had a pronounced effect on survival and measured GALC activity. There was window of time after BMT to inject the viral vector and see similar results, however delaying both the BMT and the viral injection shortened the lifespans of the treated mice. Lowering the viral dose too much decreased the correction of the sciatic nerve myelination. There was no evidence for hepatic neoplasia. Conclusion: These studies provide the conditions optimum for successfully treating the murine model of KD. There is some flexibility in dosing and timing to obtain a satisfactory outcome. These studies are critical to the planning of a human trial combining the "standard of care", HSCT, with a single iv injection of AAVrh10-GALC.	0
Hepatitis C virus (HCV) infection is a systemic disorder that frequently associates with extrahepatic manifestations, including nephropathies. Cryoglobulinemia is a typical extrahepatic manifestation of HCV infection that often involves kidneys with a histological pattern of membranoproliferative glomerulonephritis. Other, less common renal diseases related to HCV infection include membranous nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, fibrillary and immunotactoid glomerulopathy. Over the last decades, the advent of direct-acting antiviral therapies has revolutionized treatment of HCV infection, dramatically increasing the rates of viral clearance. In patients where antiviral therapy alone fails to induce renal disease remission add-on B-cell depleting agents represent an alternative to counteract the synthesis of pathogenic antibodies. Immunosuppressive therapies, such as steroids, alkylating agents, and plasma exchanges, may still represent an effective option to inhibit immune-complex driven inflammatory response, but the potentially associated increase of HCV replication and worsening of liver disease represent a serious limitation to their use.	0
OBJECTIVE:Early onset epileptic encephalopathy with suppression-burst is one of the most severe epilepsy phenotypes in human patients. A significant proportion of cases have a genetic origin, and the most frequently mutated gene is KCNQ2, encoding Kv7.2, a voltage-dependent potassium channel subunit, leading to so-called KCNQ2-related epileptic encephalopathy (KCNQ2-REE). To study the pathophysiology of KCNQ2-REE in detail and to provide a relevant preclinical model, we generated and described a knock-in mouse model carrying the recurrent p.(Thr274Met) variant. METHODS:We introduced the p.(Thr274Met) variant by homologous recombination in embryonic stem cells, injected into C57Bl/6N blastocysts and implanted in pseudopregnant mice. Mice were then bred with 129Sv Cre-deleter to generate heterozygous mice carrying the p.(Thr274Met), and animals were maintained on the 129Sv genetic background. We studied the development of this new model and performed in vivo electroencephalographic (EEG) recordings, neuroanatomical studies at different time points, and multiple behavioral tests. RESULTS:The Kcnq2Thr274Met/+ mice are viable and display generalized spontaneous seizures first observed between postnatal day 20 (P20) and P30. In vivo EEG recordings show that the paroxysmal events observed macroscopically are epileptic seizures. The brain of the Kcnq2Thr274Met/+ animals does not display major structural defects, similar to humans, and their body weight is normal. Kcnq2Thr274Met/+ mice have a reduced life span, with a peak of unexpected death occurring for 25% of the animals by 3 months of age. Epileptic seizures were generally not observed when animals grew older. Behavioral characterization reveals important deficits in spatial learning and memory in adults but no gross abnormality during early neurosensory development. SIGNIFICANCE:Taken together, our results indicate that we have generated a relevant model to study the pathophysiology of KCNQ2-related epileptic encephalopathy and perform preclinical research for that devastating and currently intractable disease.	0
In Ecuador, a developing South American country, subjects affected with genetic syndromes of severe short stature are commonly referred to as dwarfs or midgets. Furthermore, and because in earlier studies some patients had evidenced mental retardation, such abnormality is assumed to exist in all affected subjects. Herein, we present two discrete instances in which this type of branding occurs. The first is that of individuals with Laron syndrome who are still called 'dwarfs' and considered as having a degree of mental retardation despite evidence showing otherwise. A similar problem, that of a girl affected with a genetic syndrome of short stature, which might include mental retardation, is also discussed. Considering that stigmatising is a form of discrimination, it concerns us all. Hence, the use of derogatory terms such as midget, dwarf or cretin, that might unintentionally occur even when delivering the best and most devoted medical care, must be eliminated.	0
Congenital lipoid adrenal hyperplasia (lipoid CAH) results in impairment of adrenal and gonadal steroidogenesis caused by STAR mutations. Our previous study revealed upregulation of genes associated with inflammatory or immune response and macrophage infiltration in the adrenal cortex of Star-knockout mice. This study aimed at investigating macrophage infiltration in the gonads from human patients with lipoid CAH.This study includes seven patients with lipoid CAH who underwent gonadectomy: two XX women (age, 22 and 40 years) and five XY boys (1 year). Two women with ovarian cysts (32 and 40 years) and six boys with autopsy or tumor (1 year) were examined as controls. Immunohistochemical analysis of their gonads was performed to determine steroidogenic cells by NR5A1 or CYP17A1 and macrophages by IBA1 or CD68.An increased number of macrophages infiltrated into the ovaries of lipoid CAH and consisted of two subpopulations: one scattered within and around a layer of theca cells of maturing follicles and the other massively aggregated in the stroma. Abundant cytoplasmic lipid droplets were observed not only in the theca cells but also in the stromal macrophages. There was no significant difference in the number of macrophages in the testicular interstitium between lipoid CAH (95% confidence interval (95% CI: 19.3-47.7 per 0.2mm(2)) and controls (95% CI: 13.3-25.8 per 0.2mm(2)) (P=0.10).These results demonstrate that macrophages infiltrate the ovaries of lipoid CAH, where the theca cells and the stromal macrophages have abundant cytoplasmic lipid droplets.	0
OBJECTIVES: To investigate the prevalence of Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) in a rural Japanese district. METHOD: Collaboration with the medical institutions, the long-term care insurance system facilities, and the public health office. RESULTS: The crude prevalence rates were 175 per 100,000 (95% CI: 143-206) for PD, 18 (8-28) for progressive supranuclear palsy, 17 (7-26) for multiple system atrophy (MSA), and 9 (2-16) for corticobasal degeneration. The age-adjusted prevalence rates were 109 per 100,000 (88-134), 10 (2-17), 13 (4-21), and 6 (0-12), for each condition. There was a preponderance of women with PD and of men with APS. Nine of the 116 PD patients and 7 of the 29 APS patients were newly diagnosed in this study. CONCLUSIONS: There are high prevalence rates for PD and APS and suboptimal recognition of APS. This is the first epidemiological prevalence study of MSA from Japan.	1
We describe a case of bilateral inhalation of barium in an infant following a barium swallow for investigation of dusky spells associated with feeds. A bronchoscopy subsequently revealed the presence of a mid-tracheal tracheo-esophageal cleft. To date, little has been reported on barium aspiration in children and there is no consensus for management. We review the literature on barium aspiration, its consequences, and make recommendations for management.	0
BACKGROUND: Define the pattern and birth prevalence of the different types of osteochondrodysplasias in newborn infants in the United Arab Emirates (UAE) population, which is highly inbred and where termination of pregnancy is not accepted. METHODS: All infants with a birth weight of 500 gm and above in the three hospitals in Al Ain Medical District of the UAE were studied prospectively over a period of 5 years. For each live birth or stillbirth with suspected skeletal dysplasia, a detailed clinical and radiological examination was carried out. Pregnancy history and information regarding parental age, ethnic origin, family history, and level of consanguinity were obtained and a pedigree was constructed. RESULTS: Among the 38,048 births during the study period, 36 (9.46/10,000 births) had some type of skeletal dysplasia. Eighteen cases were attributed to autosomal recessive genes (4.7/10,000 births), 10 were due to apparent new dominant mutations (2.62/10,000), five were autosomal dominant type (1.3/10,000) and one was X-linked dominant type (0.26/10,000). In three cases, inheritance was unknown. The most common recessive type of skeletal dysplasia in our series was fibrochondrogenesis (1.05/10,000), followed by chondrodysplasia punctata (0.78/10,000). The birth prevalence rate of skeletal dysplasia doubled in the last 2 years of the 5-year observation period (6.74/10,000 in 1996 vs. 12.86/10,000 in 1999, and 13.45/10,000 in 2000). This increase involved cases caused by new dominant mutations, and occurred mainly in the first half of 1999. CONCLUSION: This prospective study has identified a high birth prevalence of skeletal dysplasia, and risk factors are postulated. These findings represent an accurate birthprevalence figure and a useful baseline for this group of birth defects in the UAE.	1
Increased photosensitivity is a common cutaneous adverse effect associated with the BRAF inhibitor vemurafenib. Clinically, it presents as an immediate sensation of heat and edematous erythema during sun exposure, as well as a sunburn reaction in terms of a late reaction. Phototesting has shown that the UVA range (320 nm to 400 nm), for both the immediate and the late reaction. In terms of pathogenesis, photochemical studies have suggested that exposure of vemurafenib to UVA radiation produces an UVA-absorbing photoproduct. In vitro studies on various cell models have also demonstrated that the phototoxic effects of vemurafenib are exclusively caused by UVA irradiation. This latter mechanism is mainly responsible for the photosensitivity clinically observed in patients receiving vemurafenib. In addition, vemurafenib is able to inhibit ferrochelatase. The resulting increase in protoporphyrin IX has also been observed in some human studies involving the drug. However, it is yet unproven whether porphyrins actually contribute to the immediate skin reactions seen in individuals on vemurafenib, even though the clinical presentation is similar to that found in erythropoietic protoporphyria with a comparable pathomechanism. Other BRAF inhibitors, such as dabrafenib and encorafenib, are associated with significantly lower photosensitivity. It is essential that patients treated with vemurafenib are informed about the immediate and delayed reactions potentially caused even by low doses of UVA. This includes counseling on photoprotective measures.	0
Abnormal findings on routine skin exams are common and can be a source of unnecessary medical workup if a clinician is unfamiliar with the finding. Sebaceous nevi are rare skin lesions that are most often benign but may be associated with a multiorgan syndrome or local skin cancer. Dermatologists and primary care physicians may encounter these on routine exams and thus must be comfortable with diagnosis and management. We present the clinical characteristics of a benign sebaceous nevus to help aid in diagnosis of these lesions and outline suggestions for appropriate management options.	0
OBJECTIVE:To review the mosaic autosomal trisomies in chorionic villi sample (CVS) trophoblasts, mesenchyme, and both cell lineages and to compare them with trisomies in spontaneous abortions. METHODS:Mosaic autosomal trisomies from 76 102 diagnostic CVS tests were classified as involving trophoblasts, involving mesenchyme, or present in both. Autosomal trisomies in products of conception were based on 18 published studies. We evaluated correlates between trisomy frequency with chromosome size or number of protein coding genes in the imbalance. RESULTS:Distinctly different patterns of trisomy were found in trophoblasts, mesenchyme, or both. In trisomic spontaneous abortions, there was a weak, borderline significant, inverse association between frequency and trisomic chromosome size and also with the number of protein coding genes involved (r = 0.43, P = 0.04 and r = 0.39, P = 0.07, respectively). These associations became stronger after excluding trisomy 16 (r = 0.52, P = 0.01 and r = 0.64, P = 0.001, respectively). Only CVS trisomies in both trophoblasts and mesenchyme resembled the trisomies found in spontaneous abortions and these were also associated with chromosome size and protein coding genes (r = 0.42, P = 0.05 and r = 0.57, P = 0.006, respectively). CONCLUSION:The abnormalities seen in CVS differ from those reported in early embryos. From conception through birth, there are lineage-specific, evolving spectrums of aneuploidy in trophoblasts, mesenchyme, and fetus. This article is protected by copyright. All rights reserved.	0
INTRODUCTION:X-linked hyper-IgM syndrome is a type of primary combined immunodeficiency disorder caused by mutations in CD40 ligand. Opportunistic infections caused by P jirovecii, cytomegalovirus (CMV), or fungi are frequently the first presenting symptom of the patients with X-linked hyper-IgM syndrome. PATIENT CONCERNS:Here, we report a 10-month-old infant who presented with cyanosis and shortness of breath. The infant exhibited no medical or birth history indicating a primary immune deficiency and was first diagnosed with interstitial pneumonia and acute respiratory failure on admission. DIAGNOSES:The infant was diagnosed with Pneumocystis jirovecii pneumonia combined with CMV and fungal infection through gene sequencing by nasopharyngeal swab and G-test. Whole-exome sequencing from a blood sample was performed and identified a functional mutation across the CD40 ligand gene (NM_000074;exon1;C.86_87del) resulting in an amino acid change (P.T29Sfl*18) attributed to X-linked hyper IgM syndrome. INTERVENTIONS:The infant received continuous positive airway pressure ventilation treatment combined with trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia, ganciclovir for CMV, voriconazole for fungal infection and substitution of high-dose immunoglobulin. OUTCOMES:Six months after discharge from our hospital, the infant remained well. CONCLUSION:Opportunistic infections should be suspected in infants presenting with severe interstitial pneumonia. Primary immune deficiency diseases should also be considered in infants diagnosed with opportunistic infections.	0
BACKGROUND:Renal multiparametric magnetic resonance imaging (MRI) is a promising tool for diagnosis, prognosis, and treatment monitoring in kidney disease. PURPOSE:To determine intrasubject test-retest repeatability of renal MRI measurements. STUDY TYPE:Prospective. POPULATION:Nineteen healthy subjects aged over 40 years. FIELD STRENGTH/SEQUENCES:T1 and T2 mapping, R2 * mapping or blood oxygenation level-dependent (BOLD) MRI, diffusion tensor imaging (DTI), and intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI), 2D phase contrast, arterial spin labelling (ASL), dynamic contrast enhanced (DCE) MRI, and quantitative Dixon for fat quantification at 3T. ASSESSMENT:Subjects were scanned twice with ~1 week between visits. Total scan time was ~1 hour. Postprocessing included motion correction, semiautomated segmentation of cortex and medulla, and fitting of the appropriate signal model. STATISTICAL TEST:To assess the repeatability, a Bland-Altman analysis was performed and coefficients of variation (CoVs), repeatability coefficients, and intraclass correlation coefficients were calculated. RESULTS:CoVs for relaxometry (T1 , T2 , R2 */BOLD) were below 6.1%, with the lowest CoVs for T2 maps and highest for R2 */BOLD. CoVs for all diffusion analyses were below 7.2%, except for perfusion fraction (FP ), with CoVs ranging from 18-24%. The CoV for renal sinus fat volume and percentage were both around 9%. Perfusion measurements were most repeatable with ASL (cortical perfusion only) and 2D phase contrast with CoVs of 10% and 13%, respectively. DCE perfusion had a CoV of 16%, while single kidney glomerular filtration rate (GFR) had a CoV of 13%. Repeatability coefficients (RCs) ranged from 7.7-87% (lowest/highest values for medullary mean diffusivity and cortical FP , respectively) and intraclass correlation coefficients (ICCs) ranged from -0.01 to 0.98 (lowest/highest values for cortical FP and renal sinus fat volume, respectively). DATA CONCLUSION:CoVs of most MRI measures of renal function and structure (with the exception of FP and perfusion as measured by DCE) were below 13%, which is comparable to standard clinical tests in nephrology. LEVEL OF EVIDENCE:2 TECHNICAL EFFICACY: Stage 1.	0
BACKGROUND:Chondrodysplasia punctata is a skeletal dysplasia caused by a diverse spectrum of etiologies, with outcomes ranging from antenatal demise to a normal life span. Prenatal detection can be challenging. OBJECTIVE:To review a series of cases of chondrodysplasia punctata associated with nasomaxillary hypoplasia, known as the Binder phenotype, and to highlight prenatal ultrasound and MRI findings, as well as postnatal MRI and radiographic findings. MATERIALS AND METHODS:We retrospectively reviewed ultrasound, MRI and radiographic imaging findings in postnatally confirmed cases of chondrodysplasia punctata from 2001 to 2017. We analyzed prenatal findings and correlated them with maternal history, postnatal imaging, phenotype, genetics and outcome. RESULTS:We identified eight cases, all with prenatal US and six of eight with prenatal MRI between 18 weeks and 32 weeks of gestational age. Reasons for referral included midface hypoplasia in four cases; family history in one case; intrauterine growth restriction in one case; short long-bones, intrauterine growth restriction and multicystic kidney in one case; and multiple anomalies in one case. In six cases, postnatal radiographs were performed. In four cases, postnatal spine MRI imaging was performed. The diagnosis of chondrodysplasia punctata was suggested in prenatal reports in six of eight fetuses. Seven of eight fetuses had Binder phenotype with severe nasomaxillary hypoplasia. Limb length was mildly symmetrically short in four of eight cases and normal in four of eight fetuses. Two of eight fetuses had epiphyseal stippling identified prenatally by US; this was present postnatally in six neonates on radiographs. Hand and foot abnormalities of brachytelephalangy were not detected on the prenatal US or MRI but were present in six of eigth fetuses on postnatal radiographs or physical exam. Four of eight fetuses had prenatal spine irregularity on US from subtle stippling. Six of eight had spine stippling on postnatal radiographs. One fetus had cervicothoracic kyphosis on prenatal US and MRI, and this was postnatally present in one additional neonate. One case had prenatally suspected C1 spinal stenosis with possible cord compression, and this was confirmed postnatally by MRI. There was a maternal history of systemic lupus erythematosus in two and hyperemesis gravidarum in one. Outcomes included one termination and seven survivors. CONCLUSION:Chondrodysplasia punctata can be identified prenatally but findings are often subtle. The diagnosis should be considered when a fetus presents with a hypoplastic midface known as the Binder phenotype. Maternal history of lupus, or other autoimmune diseases or hyperemesis gravidarum can help support the diagnosis.	0
BACKGROUND:Epidermolysis bullosa (EB) is a rare genetic disorder that manifests as blistering and/or skin erosion. There is no approved treatment for EB; current standard of care consists of wound and pain management. SD-101 6% is a topical cream containing 6% allantoin that was developed for treating skin lesions in patients with EB. The aim of this phase 3, multicenter, randomized, double-blind, vehicle-controlled study was to assess the efficacy and safety of SD-101 6% cream versus vehicle (0% allantoin) on lesions in patients with EB. METHODS:Eligible patients were ≥1 month old, had a diagnosis of EB (simplex, recessive dystrophic, or intermediate junctional) and a target wound 10-50 cm2 in size that was present for ≥21 days. Patients were randomly assigned to SD-101 6% cream or vehicle, which was applied topically once a day to the entire body for 3 months. Primary efficacy endpoints were time to complete target wound closure within 3 months and the proportion of patients who experienced complete target wound closure within 3 months. Post hoc subgroup analyses were conducted by patient age and in those with body surface area index of total body wound burden ≥5% at baseline. RESULTS:In total, 169 patients were enrolled and randomly assigned to SD-101 6% (n = 82) or vehicle (n = 87). Baseline demographics and disease characteristics were similar between treatment groups. There were no statistically significant differences between treatment groups in time to target wound closure (hazard ratio, 1.004; 95% confidence interval [CI] 0.651, 1.549; P = 0.985) or proportion of patients with complete target wound closure within 3 months (odds ratio [95% CI], 0.733 [0.365, 1.474]; nominal P = 0.390). A positive trend toward faster wound closure with SD-101 6% versus vehicle was observed in patients aged 2 to <12 years and those with total body wound burden ≥5% at baseline. SD-101 6% cream was well tolerated. CONCLUSIONS:SD-101 6% cream for treatment of EB-associated lesions was not more effective than vehicle in shortening the time to complete target wound closure or achieving complete target wound closure within 3 months. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02384460; Date of trial registration, February 13, 2015; First participant enrolled, March 11, 2015.	0
X-linked Charcot-Marie-Tooth disease-5 (CMTX5) is a rare hereditary disorder caused by mutations in the gene for phosphoribosyl pyrophosphate synthetase-1 (PRPS1). We investigated a boy with a novel PRPS1 mutation (c.334G>C, p.V112L) via genetic, neuropathological and enzymatic tests. The proband was a 13-year-old boy with congenital non-syndromic sensorineural deafness. At 3 year old, he developed progressive distal weakness of all limbs with muscle atrophy of both hands and shanks. Nerve conduction study revealed the loss of sensory nerve action potentials, and slowing down of motor nerve conduction velocities with a decrease of amplitudes of compound motor action potentials. Visual evoked potentials and brainstem auditory evoked potentials were not bilaterally evocable. Sural biopsy proved the loss of myelinated nerve fibers, with axonal degeneration, regenerating clusters and onion bulbs. Enzymatically, PRPS1 activity was close to zero in the proband and mildly reduced in his mother, compared with controls. To our knowledge, this is the first report of CMTX5 in a Chinese population. The genetic finding has expanded the genotypic spectrum of PRPS1 mutations.	0
BACKGROUND:Zimmermann-Laband-1 syndrome (ZLS-1; OMIM# 135500) is a rare genetic disorder whose oral pathognomonic sign is the development of progressive, diffuse, and severe gingival hypertrophy. Most children with abnormally gingival hyperplasia may also present multiple unerupted teeth and skeletal deformities of maxillary arches (i.e., skeletal anterior open bite). Despite phenotypic variability of the clinical spectrum, gingival fibromatosis is the hallmark of ZLS-1. METHOD:In this study, we report a 3-year-old male patient with a ZLS-1-related gingival overgrowth and failure of eruption of the deciduous teeth in the molar area. Surgical excision was performed under general anesthesia. RESULTS:At three weeks follow-up, esthetics was significantly improved in terms of gingival appearance, and teeth eruption allowed an adequate masticatory function. CONCLUSION:In severe cases, surgical removal of the hyperplasic fibrous tissue may be required to expose unerupted teeth and establish a proper gingival contour. Surgical excision under general anesthesia is an elective procedure for patients with special needs, mental disability, as well as young and adult patients with dental anxiety type II and IV associated with poor oral health.	0
PURPOSE:To evaluate whether silicone foam implants have a different evolution pattern compared to conventional texture implants. METHODS:Fifty-eight female patients underwent surgery. They were divided into two groups (silicone foam - Lifesil® - and microtexturized silicone - Lifesil®). The evolution was analyzed in postoperative consultations, with physical examination, photographic documentation and filling in a satisfaction questionnaire, in the postoperative period of one month, four months, one year and then annually, up to a maximum of 3 years of follow-up. RESULTS:There were no statistically significant differences in presence of rippling, stretch marks, breast ptosis, capsular contracture and quality of scars. There was a higher rate of patients who were very satisfied with the outcome 360 days after surgery in the group receiving silicone foam implants (p = 0.036). CONCLUSION:In short time, silicone foam envelope implants proved to be as reliable as textured silicone envelope implants, making them an option for augmentation mammoplasty.	0
Neonatal free air on X-ray images is generally due to intestinal perforation, and requires surgical intervention. However, some cases without intestinal perforation show free air on X-ray images. Pneumoperitoneum without perforation is caused by an air leak syndrome. We present here the case of a low-birth-weight infant with free air on X-ray images, who had no evidence of intestinal perforation intraoperatively.	0
A 70-year-old woman was admitted to our hospital complaining of shortness of breath. She was diagnosed with acute decompensated heart failure due to left ventricular dysfunction. Her symptoms began to improve with standard therapy for heart failure with diuretics, noninvasive pressure ventilation, and inotropes, but paroxysmal atrial fibrillation and premature ventricular contractions (PVCs) occurred. After treatment with amiodarone, the number of PVCs decreased, and the left ventricular wall motion gradually improved. However, on day 28, ventricular fibrillation and cardiopulmonary arrest occurred suddenly, and she could not be resuscitated. She was diagnosed with giant cell myocarditis via an autopsy. The autopsy revealed diffuse inflammatory cells that comprised giant cells and eosinophils as well as cellular degeneration and necrosis. <Learning objective: We herein report a case of sudden cardiac death due to giant cell myocarditis diagnosed at an autopsy.>.	0
The structures of the bovine and human BBSome reveal that a conformational change is required to recruit the complex to the ciliary membrane.	0
Osteoarthritis (OA) is a degenerative joint disease associated with chronic pain and disability in humans and companion animals. The canine species can be subdivided into non-chondrodystrophic (NCD) and chondrodystrophic (CD) dogs, the latter having disproportionally short limbs due to disturbance in endochondral ossification of long bones. This phenotype is associated with retrogene insertions of the fibroblast growth factor 4 (FGF4) gene, resulting in enhanced fibroblast growth factor receptor 3 (FGFR3) signaling. The effect on cartilage is unknown and in experimental studies with dogs, breeds are seemingly employed randomly. The aim of this study was to determine whether CD- and NCD-derived cartilage differs on a structural and biochemical level, and to explore the relationship between FGF4 associated chondrodystrophy and OA. Cartilage explants from CD and NCD dogs were cultured for 21 days. Activation of canonical Wnt signaling was assessed in primary canine chondrocytes. OA and synovitis severity from an experimental OA model were compared between healthy and OA samples from CD and NCD dogs. Release of glycosaminoglycans, DNA content, and cyclooxygenase 2 (COX-2) expression were higher in NCD cartilage explants. Healthy cartilage from NCD dogs displayed higher cartilage degeneration and synovitis scores, which was aggravated by the induction of OA. Dikkopf-3 gene expression was higher in NCD cartilage. No differences in other Wnt pathway read outs were found. To conclude, chondrodystrophy associated with the FGF4 retrogene seems to render CD dogs less susceptible to the development of OA when compared with NCD dogs. These differences should be considered when choosing a canine model to study the pathobiology and new treatment strategies of OA. © 2019 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. J Orthop Res 37:2550-2560, 2019.	0
AIM:To describe the complex, overlapping phenotype of four Chinese patients with inherited retinal dystrophies (IRDs) who harbored two pathogenic genes simultaneously. METHODS:This retrospective study included 4 patients affected with IRDs. Medical and ophthalmic histories were obtained, and clinical examinations were performed. A specific Hereditary Eye Disease Enrichment Panel (HEDEP) based on exome capture technology was used for genetic screening. RESULTS:Four patients were identified to harbor disease-causing variants in two different genes. Patient retinitis pigmentosa (RP) 01-II:1 exhibited both classical ABCA4-induced Stargardt disease (STGD) 1 and USH2A-associated RP, patient RP02-III:2 exhibited both classical ABCA4-induced STGD1 and CDH23-associated RP, patient RP03-II:1 exhibited both USH2A-induced autosomal recessive retinitis pigmentosa (arRP) syndrome and SNRNP200-induced autosomal dominant retinitis pigmentosa (adRP), and patient RP04-II:2 exhibited USH2A-induced arRP syndrome and EYS-induced arRP at the same time. CONCLUSION:Our study demonstrates that genotype-phenotype correlations and comprehensive genetic screening is crucial for diagnosing IRDs and helping family planning for patients suffering from the disease.	0
BACKGROUND:The present study aimed to determine functional outcomes in patients undergoing deltoid muscle resection for soft tissue sarcoma. METHODS:Between 2002 and 2014, 18 patients with soft tissue sarcoma of the shoulder who underwent wide resection including the deltoid muscle, and were followed up for more than 12 months, were retrospectively included in the study. In all, 11 patients were male and 7 were female. The median age was 59 years, median follow-up duration was 37 months. The extent of resection of deltoid muscle, with or without rotator cuff damage, reconstruction methods, adjuvant therapy, oncological outcomes, and the International Society of Limb Salvage (ISOLS) score as functional outcomes were analyzed. RESULTS:Six patients underwent total resection, and twelve underwent partial resections of deltoid muscle. The rotator cuff was resected in four patients. Soft tissue reconstruction was performed in 17 patients using a pedicled latissimus dorsi muscle flap. Two local recurrences and three distant metastases occurred during follow-up. Median overall survival was 72 months. The mean ISOLS score was 25.0 points (±4.6points). Univariate analysis revealed that there was no significant difference in ISOLS score regarding the extent of deltoid muscle resection. Multivariate analysis identified only combined resection of the rotator cuff as a significant prognostic factor for poor functional outcomes (P < 0.001). CONCLUSIONS:The extent of resection of the deltoid muscle might not affect the functional outcomes determined by ISOLS score. If the rotator cuff is resected concurrently, satisfactory functional outcomes might not be obtained.	0
Nicotinic acid and nicotinamide are called niacin. They are the antipellagra vitamin essential to many animals for growth and health. In human being, niacin is believed necessary together with other vitamins for the prevention and cure of pellagra. Niacin is widely distributed in nature; appreciable amounts are found in liver, fish, yeast and cereal grains. Nicotinamide is a precursor of the coenzyme NAD and NADP. Some of the most understood metabolic processes that involve niacin are glycolysis, fatty acid synthesis and respiration. Niacin is also related to the following diseases: Hartnup disease; blue diaper syndrome; tryptophanuria; hydroxykynureninuria; xanthurenic aciduria; Huntington's disease.	0
Lysosomal disorders are diseases that involve mutations in genes responsible for the coding of lysosomal enzymes, transport proteins, activator proteins and protein processing enzymes. These defects lead to the storage of specific metabolites within lysosomes resulting in a great variety of clinical features depending on the tissues with the storage, the storage products and the extent of the storage. The methods for rapidly diagnosing patients started in the late 1960's when the enzyme defects were identified eliminating the need for tissue biopsies. The first requests for diagnostic help in this laboratory came in 1973. In that year, patients with Krabbe disease and Niemann-Pick type A were diagnosed. Since that time samples from about 62 000 individuals have been received for diagnostic studies, and 4900 diagnoses have been made. The largest number of diagnosed individuals had metachromatic leukodystrophy and Krabbe disease because of our research interest in leukodystrophies. A number of new disorders were identified and the primary defects in other disorders were clarified. With new methods for diagnosis, including newborn screening, molecular analysis, microarrays, there is still a need for biochemical confirmation before treatment is considered. With new treatments, including gene therapy, stem cell transplantation, enzyme replacement used alone or in combination becoming more available, the need for rapid, accurate diagnosis is critical.	0
OBJECTIVE:Electromyography (EMG) Guided botulinum toxin (BTX) injection is considered first-line treatment for adductor spasmodic dysphonia (SD). Failure rate can range between 6% and 29%. Study objective was to determine which factors were associated with failure. METHODS:This was a retrospective review conducted at a tertiary, academic center. Adductor SD patients presenting for BTX injections from August 2017 to October 2018 were eligible. Age, gender, Voice Handicap Index (VHI-10), Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V), number of injections, disease duration, unilateral/bilateral injection, right/left injection, dose quantity, body mass index (BMI), professional voice user, employment, psychiatric comorbidity, breathiness, and dysphagia were investigated. Outcomes included failure as defined by the patient and dosage change. Univariate and multivariate statistical analysis was conducted. RESULTS:Sixty seven out of 564 injections (12%) were categorized as failure by 131 patients. In multivariate analysis, dosage change was associated with shorter duration of good effect (P < .001), BTX dose (P = .016), breathiness (P < .001), bilateral injection (P = .024), dysphagia (P = .012) and professional voice user (P = .021). Failure was associated with first injection with a new physician (P < .001), professional voice user P < .001) and lack of breathiness (P = .003). Failure rate was not associated with age, gender, VHI-10, CAPE-V, disease duration, left/right injection, dose quantity, BMI, psychiatric comorbidity, and dysphagia. CONCLUSION:Failure rate was 12% and associated with patients' first injection with a physician, professional voice user, and lack of breathiness. Dosage change occurred in 29% of injections and was associated with injection side effects, bilateral injections, BTX dose, professional voice user, and shorter duration of good effect. Level of evidence: 3.	0
A pathogenic GGGCCC hexanucleotide expansion in the first intron/promoter region of the C9orf72 gene is the most common mutation associated with amyotrophic lateral sclerosis (ALS). The C9orf72 gene product forms a complex with SMCR8 (Smith-Magenis Syndrome Chromosome Region, Candidate 8) and WDR41 (WD Repeat domain 41) proteins. Recent studies have indicated roles for the complex in autophagy regulation, vesicle trafficking, and immune response in transgenic mice, however a direct connection with ALS etiology remains unclear. With the aim of increasing understanding of the multi-functional C9orf72-SMCR8-WDR41 complex, we determined by mass spectrometry analysis the proteins that directly associate with SMCR8. SMCR8 protein binds many components of the ubiquitin-proteasome system, and we demonstrate its poly-ubiquitination without obvious degradation. Evidence is also presented for localization of endogenous SMCR8 protein to cytoplasmic stress granules. However, in several cell lines we failed to reproduce previous observations that C9orf72 protein enters these granules. SMCR8 protein associates with many products of genes associated with various Mendelian neurological disorders in addition to ALS, implicating SMCR8-containing complexes in a range of neuropathologies. We reinforce previous observations that SMCR8 and C9orf72 protein levels are positively linked, and now show in vivo that SMCR8 protein levels are greatly reduced in brain tissues of C9orf72 gene expansion carrier individuals. While further study is required, these data suggest that SMCR8 protein level might prove a useful biomarker for the C9orf72 expansion in ALS.	0
BACKGROUND: Pancytopenia is not a disease entity but a triad of findings that may result from various disease processes, primarily or secondarily involving the bone marrow. Bone marrow aspiration and biopsy evaluation along with good clinical correlation is of utmost importance to evaluate the causes of pancytopenia and planning further investigations. AIMS: The present study was a prospective clinicohaematological study undertaken to analyse the various causes of pancytopenia by evaluating bone marrow aspiration and biopsy and correlating with clinical findings, complete blood counts and peripheral blood picture. MATERIALS AND METHODS: Fifty patients of pancytopenia were included in the study in which relevant history and physical examination findings were recorded. Bone marrow aspiration and biopsy were performed simultaneously in all cases. Perl's stain was done in all cases and special stains like MPO, PAS and reticulin were also done wherever necessary. RESULTS AND CONCLUSION: The maximum cases of pancytopenia were in the age group of 10 to 30 y with male preponderance. Aplastic anaemia was found to be the most common aetiology of pancytopenia followed by normoblastic erythroid hyperplasia, megaloblastic anaemia, acute leukemias, myelofibrosis, lymphoid neoplasia and iron deficiency anaemia. It was concluded from the study that although the advantages of bone marrow aspiration and biopsy differ, both are complimentary to each other and should be performed simultaneously for a complete bone marrow work up and evaluation. It is only through the correlation of clinical, hematological and bone marrow examination findings that proper evaluation and management of patients of pancytopenia can be made.	0
Prevalence of Rett syndrome (RS) was studied in Tokyo. Based on the experience of our pilot study, we chose schools to identify the cases. We visited forty-four schools for mentally/physically handicapped children. The population of girls aged 6-14 years in the area was 598,000 and the number of girls examined at the schools was 1,311. We identified 24 cases with "classical" RS and 6 cases with "variant" RS. About one-third of the cases had not been diagnosed properly. The prevalence of RS was 0.50/10,000 girls age 6-14 years in metropolitan Tokyo, 1 April, 1988, including variants. The rate showed no statistical difference compared to those reported from European countries.	1
Tick-borne encephalitis virus (TBEV) accounts for approximately 10,000 annual cases of severe encephalitis in Europe and Asia and causes encephalitis in humans. In this study, we demonstrate TBEV appears to activate the interferon (IFN)-β dependent on RIG-I/MDA5. Both the IFN-β accumulation and the IFN stimulated genes (ISGs) transcription greatly delay. Further studies reveal that TBEV NS4A could block the phosphorylation and dimerization of STAT1/STAT2 to affect type I and II IFN-mediated STAT signalling. Additional data indicate that the residue at K132 of TBEV NS4A could be modified by ubiquitination and this modification is necessary for the interaction of NS4A with STAT1. Dynamic ubiquitination of the NS4 protein during TBEV infection might account for delayed activation of the ISGs. These results define the TBEV NS4A as an antagonist of the IFN response, by demonstrating a correlation between the association and STAT interference. Our findings provide a foundation for further understanding how TBEV evade innate immunity and a potential viral target for intervention.	0
Recurrence of severe microbial infections results from a primary immunodeficiency disorder known as major histocompatibility complex class II deficiency or bare lymphocyte syndrome type II. Immunologic function is severely impaired due to the absence of MHC class II molecules on the surface of immune cells. Here, we report a 5-year-old boy with a novel homozygous mutation in RFXANK gene that negatively affects the proper expression of MHC class II molecules by antigen presenting cells. The frame shift mutations in RFXANK gene and negative HLA-DR proteins expression on peripheral blood mononuclear cells were identified and confirmed by whole exome sequencing, Sanger sequencing, and flow cytometry. The patient was referred with long-term severe prolonged diarrhea, fever, coughing, and vomiting. Also, antibiotic resistance, normal T cell, and NK cell counts with low B cell count and reduced serum immunoglobulin level were observed. The patient did not give a dramatic response to intravenous immunoglobulin infusion. The significancy of this report is the novelty of mutation and low B cell count which is not commonly expected in such patients. The final diagnosis of BLS type II is based on WES, Sanger sequencing, and flow cytometric evaluation. Moreover, it seems that the only therapeutic choice is hematopoietic stem cell transplantation.	0
Urethral duplication is an extremely rare condition discovered in adults where most of them are diagnosed in childhood. Overall, it has 3 types according to Effman et al. The authors presented a case of an adult male complaining of dysuria, who was diagnosed with urethral duplication type IIB after performing retrograde urethrography and micturating cystourethrography. This is an extremely rare type of duplication of the urethra (type IIB) with late presentation. Further study may be required regarding the surgical management.	0
A deterministic model of onchocerciasis disease dynamics is considered in a community partitioned into compartments based on the disease status. Public health education is offered in the community during the implementation of mass treatment using ivermectin drugs. Also, larviciding and trapping strategies are implemented in the vector population with the aim of controlling population growth of black flies. We fit the model to the data to check the suitability of the model. Expressions are derived for the influence on the reproduction numbers of these strategies. Numerical results show that the dynamics of onchocerciasis and the growth of black flies are best controlled when the four strategies are implemented simultaneously. Also, the results suggest that for the elimination of the disease in the society there is a need for finding another drug which will be implemented to ineligible human as well as killing the adult worms instead of ivermectin.	0
Monogenic disorders offer unique opportunities for researchers to shed light upon fundamental physiological processes in humans. We investigated a large family affected with autosomal-dominant adermatoglyphia (absence of fingerprints) also known as the "immigration delay disease." Using linkage and haplotype analyses, we mapped the disease phenotype to 4q22. One of the genes located in this interval is SMARCAD1, a member of the SNF subfamily of the helicase protein superfamily. We demonstrated the existence of a short isoform of SMARCAD1 exclusively expressed in the skin. Sequencing of all SMARCAD1 coding and noncoding exons revealed a heterozygous transversion predicted to disrupt a conserved donor splice site adjacent to the 3' end of a noncoding exon uniquely present in the skin-specific short isoform of the gene. This mutation segregated with the disease phenotype throughout the entire family. Using a minigene system, we found that this mutation causes aberrant splicing, resulting in decreased stability of the short RNA isoform as predicted by computational analysis and shown by RT-PCR. Taken together, the present findings implicate a skin-specific isoform of SMARCAD1 in the regulation of dermatoglyph development.	0
AIM:To report an analysis of ~1 year of setmelanotide treatment for obesity and hunger, as well as metabolic and cardiac outcomes, in individuals with Bardet-Biedl syndrome (BBS). MATERIALS AND METHODS:Individuals aged 12 years and older with BBS received once-daily setmelanotide. The dose was titrated every 2 weeks to establish the individual therapeutic dose (≤3 mg); treatment continued for an additional 10 weeks. Participants who lost 5 kg or more (or ≥5% of body weight if <100 kg at baseline) continued into the 52-week extension phase. The primary outcome was mean percent change from baseline in body weight at 3 months. Hunger scores and safety were secondary outcomes. RESULTS:From February 2017 and February 2018, 10 individuals were screened; eight completed the 3-month treatment phase and seven completed the extension phase. Mean percent change in body weight from baseline to 3 months was -5.5% (90% CI, -9.3% to -1.6%; n = 8); change from baseline was -11.3% (90% CI, -15.5% to -7.0%; n = 8) at 6 months and -16.3% (90% CI, -19.9% to -12.8%; n = 7) at 12 months. All participants reported at least one treatment-emergent adverse event (AE), most commonly injection-site reaction. No AEs led to study withdrawal or death. Most, morning, and average hunger scores were reduced across time points. CONCLUSIONS:Setmelanotide reduced body weight and hunger in individuals with BBS and had a safety profile consistent with previous reports. Setmelanotide may be a treatment option in individuals with BBS-associated obesity and hyperphagia.	0
Nephronophthisis-related ciliopathies (NPHP-RC) are a group of inherited diseases that affect genes encoding proteins that localize to primary cilia or centrosomes. With few exceptions, ciliopathies are inherited in an autosomal recessive manner, and affected individuals manifest early during childhood or adolescence. NPHP-RC are genetically very heterogeneous, and, currently, mutations in more than 90 genes have been described as single-gene causes. The phenotypes of NPHP-RC are very diverse, and include cystic-fibrotic kidney disease, brain developmental defects, retinal degeneration, skeletal deformities, facial dimorphism, and, in some cases, laterality defects, and congenital heart disease. Mutations in the same gene can give rise to diverse phenotypes depending on the mutated allele. At the same time, there is broad phenotypic overlap between different monogenic genes. The identification of monogenic causes of ciliopathies has furthered the understanding of molecular mechanism and cellular pathways involved in the pathogenesis.	0
Heme and Fe-S clusters regulate a plethora of essential biological processes ranging from cellular respiration and cell metabolism to the maintenance of genome integrity. Mutations in genes involved in heme metabolism and Fe-S cluster biogenesis cause different forms of ataxia, like posterior column ataxia and retinitis pigmentosa (PCARP), Friedreich's ataxia (FRDA) and X-linked sideroblastic anemia with ataxia (XLSA/A). Despite great efforts in the elucidation of the molecular pathogenesis of these disorders several important questions still remain to be addressed. Starting with an overview of the biology of heme metabolism and Fe-S cluster biogenesis, the review discusses recent progress in the understanding of the molecular pathogenesis of PCARP, FRDA and XLSA/A, and highlights future line of research in the field. A better comprehension of the mechanisms leading to the degeneration of neural circuity responsible for balance and coordinated movement will be crucial for the therapeutic management of these patients.	0
BACKGROUND:Malignant peripheral nerve sheath tumors (MPNSTs) are rare nervous system tumors that rarely appear on the scalp. About half of the scalp MPNSTs described in the literature have reached giant dimensions at the time of diagnosis. The surgical treatment is the gold standard for this type of tumor. Some authors suggest adjuvant radiotherapy for local tumor control, although there is uncertainty about its advantages and its use is not without risks. CASE DESCRIPTION:We present the case of a 31-year-old man who presented with a large necrotic scalp tumor of the left frontoparietal convexity. magnetic resonance imaging showed a large extra-axial tumor, measuring 17 x 17 x 8 cm, centered on the soft tissues, with skull erosion and signs of dural invasion, although with no intradural component. The tumor was surgically removed and the osteocutaneous defect was reconstructed with a latissimus dorsi muscle free flap. The anatomopathologic diagnosis was MPNST. The patient then underwent adjuvant radiotherapy. After 7 months he developed a progressive right hemiparesis and magnetic resonance imaging showed results compatible with cerebral radiation necrosis. This motor deficit improved with corticotherapy. After 9 months the patient went back to his home country and was subsequently lost to follow-up. CONCLUSIONS:Giant MPNSTs of the scalp are highly aggressive lesions that should primarily be treated in a surgical fashion. Although adjuvant radiotherapy has been used routinely for local tumor control, there is uncertainty about its advantages.	0
RNU4ATAC pathogenic variants to date have been associated with microcephalic osteodysplastic primordial dwarfism, type 1 and Roifman syndrome. Both conditions are clinically distinct skeletal dysplasias with microcephalic osteodysplastic primordial dwarfism, type 1 having a more severe phenotype than Roifman syndrome. Some of the overlapping features of the two conditions include developmental delay, microcephaly, and immune deficiency. The features also overlap with Lowry Wood syndrome, another rare but well-defined skeletal dysplasia for which the genetic etiology has not been identified. Characteristic features include multiple epiphyseal dysplasia and microcephaly. Here, we describe three patients with Lowry Wood syndrome with biallelic RNU4ATAC pathogenic variants. This report expands the phenotypic spectrum for biallelic RNU4ATAC disorder causing variants and is the first to establish the genetic cause for Lowry Wood syndrome.	0
Extragonadal teratomas are rare, and localization in the endometrium and cervix is exceptional, with fewer than 10 case reports documented so far in the English literature. We report here the case of a 46-year-old patient who presented with simultaneous immature teratoma in the endometrium and mature teratomas in the ovary in association with gliomatosis peritonei but with no evidence of gestational origin; she subsequently developed multiple solid mature teratomas in the cervix and parauterine tissue. No other similar cases have been previously reported to our knowledge. There are many similarities between the patient's pattern of recurrence and "growing teratoma syndrome (GTS)". Although the patient was not treated with chemotherapy after her first presentation and this case does not meet formal criteria for GTS, we believe that the pattern and histology of recurrences in this case represent a variant of GTS. Considering that the initial presentation in this case was endometrial and ovarian makes the occurrence of GTS-like syndrome even more unique.	0
In patients with asymptomatic papules of hands and feet, a clinical differential of acral persistent papular mucinosis should be thought of.	0
INTRODUCTION:The occurrence of sporadic colonic neurofibroma particularly in a patient without neurofibromatosis type 1 has been rarely reported. Therefore, the clinical significance of this disease has not been fully elucidated. PRESENTATION OF CASE:An 81-year-old woman with a positive fecal occult blood test result was referred to our institution for the evaluation of anemia. On colonoscopy, a 50-mm submucosal tumor-like mass was found in the hepatic flexure of the colon. Superficial biopsy and boring biopsy showed unspecific granulation tissues, and immunostaining revealed that the mesenchymal tumor was negative for CD34, c-kit, desmin, and S100 protein. The patient underwent laparoscopic right colectomy with complete mesocolic excision (CME). Pathologically, the tumor was diagnosed as neurofibroma. DISCUSSION:Gastrointestinal neurofibromas are known to cause clinical symptoms. No colonic neurofibroma has been diagnosed before resection. Moreover, neurofibromas, particularly large lesions, reportedly undergo malignant transformation. Surgical extirpation with clear margins is the primary treatment, and laparoscopic surgery is considered acceptable for colonic neurofibroma and colon cancer. CONCLUSION:Based on our experience, a preoperative diagnosis was impossible for colonic neurofibroma. Laparoscopic surgery with CME is considered feasible for sporadic colonic neurofibroma.	0
BACKGROUND:Wolcott-Rallison syndrome (WRS) is caused by a biallelic mutation in the gene encoding eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3) on chromosome 2p11.2. This condition is characterized by permanent early-onset diabetes mellitus, epiphyseal dysplasia, and hepatic dysfunction. We report a patient with WRS born to a consanguineous marriage due to a novel biallelic frameshift mutation in the EIF2AK3 gene. CASE PRESENTATION:Our patient was a 2-year-and-6-month-old Yemeni girl born to consanguineous parents who was diagnosed with neonatal diabetes at 20 days of age. She presented with chronic diarrhea and liver dysfunction. The child was normocephalic and exhibited failure to thrive and hepatomegaly with no skeletal deformities. Further investigations revealed microcytic anemia, liver impairment and primary hypothyroidism. Genetic testing confirmed the diagnosis of WRS via identification of a novel biallelic frameshift mutation in the EIF2AK3 gene. During her hospital stay, she went into septic shock and developed multi-organ failure, including fulminant hepatic failure. She unfortunately died within 2 weeks of her hospital stay. CONCLUSIONS:Wolcott-Rallison syndrome is recognized as the most common cause of early-onset diabetes in infants born to consanguineous marriages. Screening for genetic mutations in EIF2AK3 is recommended for establishing early diagnosis, providing genetic counselling, and predicting the development of additional clinical features, most importantly hepatic failure. Hence, this screening is important for guiding optimal management and improving patient outcome.	0
Camurati-Engelmann disease is an extremely rare disease characterized by hyperostosis of multiple long bones. This condition is caused by heterozygous mutations in the TGFB1 gene.We describe the clinical and genetic characteristics of 4 Korean patients with this rare disease diagnosed at Asan Medical Center in Korea between June 2012 and May 2016, to increase awareness about this condition among general physicians and orthopedists. The presenting features, biochemical findings, radiographic and nuclear imaging findings, molecular analysis, and treatment outcomes of 4 patients were reviewed retrospectively.Two patients had sporadic disease, whereas the other 2 were familial cases. The average age at symptom onset was 8.8 ± 5.5 (4-14) years. Symptoms included waddling gait or leg pain. Bone pain and easy fatigability were documented in all patients. Skeletal deformities such as osteoporosis, genu valgum, and severe scoliosis were observed. Visual and otologic manifestations presenting as exophthalmos, retinal detachment, and vestibulopathy were found in 3 patients. Skeletal survey showed diaphyseal expansion with diffuse cortical thickening of long bones in all patients. Bone scintigraphy images showed increased uptake of radioactive material in the calvarium and diaphysis of long bones. The mean erythrocyte sedimentation rate was 46.5 ± 22.2 (20-72) mm/h. Sequence analysis of TGFB1 revealed the previously reported mutations p.Arg218His, p.Arg218Cys, and p.Glu169Lys. Corticosteroid was effective in relieving pain, and losartan was used as maintenance therapy.Our experience suggests that this rare condition can be suspected in patients with characteristic symptoms and skeletal findings. Considering the presence of effective medical treatment, efforts are needed to identify more cases.	0
Fanconi anemia (FA) is a rare genetic disorder, involving all three blood cell lines. It is the most common cause of inherited bone marrow failure characterized by the pancytopenia. Additionally, it affects almost all organs of the body.[1] Fanconi anemia is mainly based upon the molecular mechanism involving a defective homologous recombination DNA repair pathway, defects in proteins as well as other enzymes involved in the repair of damaged DNA following various alkylating agents, irradiation, and cytotoxic drugs. It is also referred to as the inherited form of aplastic anemia. The discovery of Fanconi anemia had implications far beyond the disease itself. An extensive study of other bone marrow failure syndromes and chromosome fragility diseases has enhanced the scientific understanding of the bone marrow failure in Fanconi anemia. It is mostly associated with other congenital deformities and is susceptible to hematological and solid tumors. It usually is more common during childhood, with an average age of diagnosis being 7 yrs. Advancement of molecular genetic studies have helped in the comprehensive study of Fanconi anemia.	0
Cerebral, ocular, dental, auricular, skeletal (CODAS) syndrome is a rare autosomal recessive multisystem disorder caused by mutations in LONP1. It is characterized by intellectual disability, cataracts, delayed tooth eruption, malformed auricles and skeletal abnormalities. We performed whole-exome sequencing on a 12-year-old Japanese male with severe intellectual disability, congenital bilateral cataracts, spasticity, hypotonia with motor regression and progressive cerebellar atrophy with hyperintensity of the cerebellar cortex on T2-weighted images. We detected compound heterozygous mutation in LONP1. One allele contained a paternally inherited frameshift mutation (p.Ser100Glnfs*46). The other allele contained a maternally inherited missense mutation (p.Arg786Trp), which was predicted to be pathogenic by web-based prediction tools. The two mutations were not found in Exome Variant Server or our 575 in-house control exomes. Some features were not consistent with CODAS syndrome but overlapped with Marinesco-Sjögren syndrome, a multisystem disorder caused by a mutation in SIL1. An atypical mutation site may result in atypical presentation of the LONP1 mutation.	0
A ring chromosome replacing a normal chromosome could involve variable structural rearrangements and mitotic instability. However, most previously reported cases lacked further genomic characterization. High-resolution oligonucleotide array comparative genomic hybridization with single-nucleotide polymorphism typing (aCGH+SNP) was used to study 2 unrelated cases with a ring chromosome 21. Case 1 had severe myopia, hypotonia, joint hypermobility, speech delay, and dysmorphic features. aCGH detected a 1.275-Mb duplication of 21q22.12-q22.13 and a 6.731-Mb distal deletion at 21q22.2. Case 2 showed severe growth and developmental retardations, intractable seizures, and dysmorphic features. aCGH revealed a contiguous pattern of a 3.612- Mb deletion of 21q22.12-q22.2, a 4.568-Mb duplication of 21q22.2-q22.3, and a 2.243-Mb distal deletion at 21q22.3. Mitotic instability was noted in 13, 30, and 76% of in vitro cultured metaphase cells, interphase cells, and leukocyte DNA, respectively. The different phenotypes of these 2 cases are likely associated with the unique genomic structure and distinct mitotic behavior of their ring chromosome 21. These 2 cases represent a subtype of ring chromosome 21 probably involving somatic dicentric ring breakage and reunion. A cytogenomic approach is proposed for characterizing the genomic structure and mitotic instability of ring chromosome abnormalities.	0
CONTEXT:Paget disease of bone (PDB) is a metabolic bone disease whose genetic cause remains unknown in up to 50% of familial patients. OBJECTIVE:Our aim was to investigate the underlying genetic defect in a large pedigree with a severe, early onset, autosomal dominant form of PDB across 3 generations. METHODS:Whole exome sequencing was performed in affected and unaffected family members, and then mutation screening was replicated in a sample of PDB patients with early-onset, polyostotic PDB. RESULTS:We identified a frameshift D107Rfs*3 mutation in PFN1 (encoding for profilin 1, a highly conserved regulator of actin-polymerization and cell motility) causing the truncation of the C-terminal part of the protein. The mutation was also detected in a 17-year-old asymptomatic family member who upon biochemical and radiological analyses was indeed found to be affected. Sequencing of the entire PFN1 coding region in unrelated PDB patients identified the same mutation in 1 patient. All mutation carriers had a reduced response to bisphosphonates, requiring multiple zoledronate infusions to control bone pain and achieve biochemical remission over a long term. In vitro osteoclastogenesis in peripheral blood mononuclear cells (PBMCs) from mutation carriers showed a higher number of osteoclasts with PDB-like features. A similar phenotype was observed upon PFN1 silencing in murine bone marrow-derived monocytes, suggesting that the frameshift PFN1 mutation confers a loss of function in profilin 1 activity that induces PDB-like features in the osteoclasts, likely due to enhanced cell motility and actin ring formation. CONCLUSIONS:Our findings indicate that PFN1 mutation causes an early onset, polyostotic PDB-like disorder.	0
Coccidioidomycosis is an endemic fungal infection of the desert southwestern United States. Intact cellular immunity is critical to the control of this infection. A recently released reformulated spherulin antigen (Spherusol; Nielsen BioSciences, Inc.) was approved to detect delayed-type hypersensitivity, which implies the presence of cellular immunity, to Coccidioides species. We aimed to summarize our experience with this test in patients with primary pulmonary coccidioidomycosis. We retrospectively reviewed clinical data for all patients with primary pulmonary coccidioidomycosis who had a Coccidioides (spherulin) skin test (CST) placed at our institution between January 1, 2015, and August 31, 2017. During the study period, 172 patients had a CST placed, and 122 met our inclusion criteria for proven or probable pulmonary coccidioidomycosis. Of these 122, 88 (72.1%) had a positive CST result and 34 (27.9%) had a negative result. In the positive CST group, 74 of the 79 treated patients (93.7%) had antifungal treatment stopped, 1 of whom (1.4%) had relapsed infection. In contrast, 27 of the 33 treated patients in the negative CST group (81.8%) had their antifungal treatment stopped, and none had a relapse. Seven patients overall (5.7%), all of whom had a positive CST, experienced mild local adverse reactions to the CST. Although previous controlled studies of CST showed sensitivity and specificity greater than 98%, our real-world experience with the CST showed lower rates of positivity. Negative CST results did not predict relapse with antifungal agent withdrawal.	0
Purpose:To evaluate the phenotypic spectrum of autosomal recessive RP1-associated retinal dystrophies and assess genotypic associations. Methods:A retrospective multicenter study was performed of patients with biallelic RP1-associated retinal dystrophies. Data including presenting symptoms and age, visual acuity, kinetic perimetry, full field electroretinogram, fundus examination, multimodal retinal imaging, and RP1 genotype were evaluated. Results:Nineteen eligible patients from 17 families were identified and ranged in age from 10 to 56 years at the most recent evaluation. Ten of the 21 unique RP1 variants identified were novel, and mutations within exon 2 accounted for nearly half of alleles across the cohort. Patients had clinical diagnoses of retinitis pigmentosa (13), cone-rod dystrophy (3), Leber congenital amaurosis (1), early-onset severe retinal dystrophy (1), and macular dystrophy (1). Macular atrophy was a common feature across the cohort. Symptom onset occurred between 4 and 30 years of age (mean 14.9 years, median 13 years), but there were clusters of onset age that correlated with the effects of RP1 mutations at a protein level. Patients with later-onset disease, including retinitis pigmentosa, had at least one missense variant in an exon 2 DCX domain. Conclusions:Biallelic RP1 mutations cause a broad spectrum of retinal disease. Exon 2 missense mutations are a significant contributor to disease and can be associated with a considerably later onset of retinitis pigmentosa than that typically associated with biallelic RP1 mutations.	0
INTRODUCTION:Primary hyperoxaluria type 1 (PH1) is a genetic autosomal recessively inherited disorder due to mutation in the alanine-glyoxylate aminotransferase (AGXT) gene. It usually presents in children with nephrolithiasis and/or nephrocalcinosis and progressive renal function impairment and end stage renal disease (ESRD). PATIENT CONCERNS:A 13 years old Saudi boy with history of recurrent urolithiasis since the age of 2 years presented to us with picture of ESRD. He has strong family history of urolithiasis. DIAGNOSIS:Working up the patient suggested the diagnosis of PH1 based on the typical clinical, laboratory, and imaging findings which was genetically proved by positive AXGT gene mutation. The mutation detected was not previously reported in literature. The mutation detected was not previously reported in literature. The novel mutation c. 799A>T p. (IIe267Phe) detected in our patient extend the spectrum of the known AGXT gene mutations. INTERVENTIONS AND OUTCOMES:Hemodialysis as a temporary step followed by renal transplantation which is the only cure. CONCLUSION:High index of suspicion of PH1 before ESRD should be considered in any patient who has recurrent urolithiasis since early life especially in presence of strong family history.	0
OBJECTIVE:To assess whether published scales for measuring upper motor neuron burden (UMNB) show longitudinal change in patients with primary lateral sclerosis (PLS). Design: Retrospective calculation of three UMNB scales on a prospectively collected dataset from 53 patients with PLS enrolled in a longitudinal natural history study with at least 2 evaluation visits. UMNB scales were calculated according to their published descriptions. Non-linear trends over time of UMNB scale scores and slopes were calculated for each patient and correlations between UMNB scores and clinical measures were assessed. Results: All three UMNB scales exhibited increasing scores over the first 7.8 years of symptoms, with a flattening in slope after approximately 8 years. A scale used in imaging studies and the UPENN UMNS scale provided a better fit to the dataset than the MGH UMNB scale. All three UMNB scales exhibited moderate correlations with some clinical measures of movement, such as finger-tapping rate and timed gait. Correlations were strongest for the UPENN UMNS, which was also moderately correlated with the revised ALS functional rating scale. Conclusion: In a cohort of PLS patients enrolled in a natural history study, the three UMNB scales exhibited modest linear increases over the first 8 years of symptoms, followed by a plateau. Future clinical trials in PLS should consider stratification of patients by disease duration. UMNB scales may be useful secondary outcomes, but more sensitive primary outcome measures are needed for clinical trials for PLS.	0
OBJECTIVE:To describe and explore sleep problems in a population-based cohort of young children with cerebral palsy (CP) in Stockholm, Sweden. METHODS:All children with CP, aged 5-10 years, and living in the Northern Karolinska University Hospital's catchment area were invited to participate in a cross-sectional study. Medical records obtained in the previous two-year period were reviewed, and a pre-planned parental telephone interview that included five structured questions and the Insomnia Severity Index (ISI) was conducted. RESULTS:In total, 118 children, with a mean age of 7.4 years (SD 1.5), were included. Bilateral CP was present in 45%, unilateral in 37%, dyskinetic in 15%, and ataxic CP in 3%. Parents of 81% of the children participated in the interview. They reported sleep problems in 41% of their children, and in 80% of these children, night-time sleep was negatively affected by pain. Differences between the ISI total score in relation to CP subtypes (p < 0.025) and levels in GMFCS-E&R (p < 0.001) were detected, with increasing sleep problems for children with dyskinetic CP and children in GMFCS-E&R V. Sleep problems affected by pain were associated to the total score at ISI (rs = 0.83, p < 0.001, n = 95). CONCLUSION:The results identified that sleep problems were present in more than 40% of children with CP. Sleep problems were more frequently and extensively present in children with dyskinetic CP and children in GMFCS-E&R level V. Sleep problems were associated with the presence of pain and, in particular, in the most severely affected children.	0
Pulmonary hypertension (PH), a serious disorder with a high morbidity and mortality rate, is known to occur in a number of unrelated systemic diseases. Several hematological disorders such as sickle cell disease, thalassemia and myeloproliferative diseases develop PH which worsens the prognosis. Associated oxidant injury and vascular inflammation cause endothelial damage and dysfunction. Pulmonary vascular endothelial damage/dysfunction is an early event in PH resulting in the loss of vascular reactivity, activation of proliferative and antiapoptotic pathways leading to vascular remodeling, elevated pulmonary artery pressure, right ventricular hypertrophy and premature death. Hemolysis observed in hematological disorders leads to free hemoglobin which rapidly scavenges nitric oxide (NO), limiting its bioavailability, and leading to endothelial dysfunction. In addition, hemolysis releases arginase into the circulation which converts L-arginine to ornithine, thus bypassing NO production. Furthermore, treatments for hematological disorders such as immunosuppressive therapy, splenectomy, bone marrow transplantation, and radiation have been shown to contribute to the development of PH. Recent studies have shown deregulated iron homeostasis in patients with cardiopulmonary diseases including pulmonary arterial hypertension (PAH). Several studies have reported low iron levels in patients with idiopathic PAH, and iron deficiency is an important risk factor. This article reviews PH associated with hematological disorders and its mechanism; and iron homeostasis and its relevance to PH.	0
Plasmablastic lymphoma (PBL) is an aggressive lymphoma often seen in immunodeficient patients. It can be a diagnostic challenge given its high-grade appearance and lack of staining for traditional B-cell markers. We present an interesting case of a 65-year-old African-American female who presented to the emergency department (ED) with complaints of progressively worsening weakness, fatigue, and dizziness for one month, and dark-colored urine for three days. The patient's medical history was remarkable for a renal and pancreatic transplant in 2008.	0
The head and neck region is one of the most important locations predisposed for tobacco-associated cancer. Chemoprevention might offer a chance to decrease the risk for this type of disease.Mini-organ cultures (MOC) of macroscopically-healthy pharyngeal tissues from 20 patients with oropharyngeal squamous cell carcinoma (SCC) and from 20 controls were employed in the study. MOC were firstly incubated with Celecoxib, and DNA damage was induced by incubation with Benz[a]pyren-7,8-diol-9,10-epoxid (BPDE), a major representative of tobacco-associated carcinogens. DNA damage was evaluated with the alkaline single-cell microgel electrophoresis (Comet assay). Furthermore, fragmentation of the cyclin D1 gene, a gene of special importance in head and neck carcinogenesis was examined by the Comet-FISH assay. Finally, the chemoprotective potential of Celecoxib was analyzed after incubation with MOC.As expected, BPDE caused significant DNA fragmentation in tumor compared to negative control tissues. No enhanced damage was observed in the cyclin D1 gene. DNA fragmentation was significantly reduced when MOC were incubated with Celecoxib in the tumor group. Surprisingly, these effects were also observed in the group without cancer of the oropharynx, although COX-2 is not expressed in macroscopically-healthy mucosa.Celecoxib showed considerable chemoprotective effeciency against BPDE in both groups and this effect seems to be independent of COX-2 expression. No evidence for higher mutagen sensitivity in the Cyclin D1 gene was observed.	0
OBJECTIVE: Kleine-Levin syndrome is a rare disease characterized by recurrent episodes of hypersomnia with behavioral and cognitive disturbances. We aimed at describing the diagnosis procedure, risk factors, and severe forms. METHODS: In consecutive patients referred for suspected Kleine-Levin syndrome, we detailed differential diagnoses, and atypical and secondary cases, compared typical patients with healthy subjects, and examined the characteristics of patients with prolonged (>30 days) episodes. RESULTS: Among 166 referred patients, 120 had typical primary Kleine-Levin syndrome (syndrome secondary to brain diseases; n = 4, atypical syndrome, n = 7; differential diagnoses that were mostly psychiatric, n = 29; incomplete information, n = 6). The prevalence in France was 1.8 per million. The patients were often male (64%) and had more frequent birth and developmental abnormalities (45%) than controls (despite normal karyotypes), and most (80%) had teenage onset, with no difference between patients with prolonged (n = 34) and short (n = 85) episodes. In patients with prolonged episodes, the durations of the first episode (32 ± 33 vs 11 ± 6 days) and subsequent episodes were longer (mean episode duration = 23 ± 19 vs 10 ± 3 days) and the disease course tended to be longer (9 ± 6 vs 6 ± 4 years). During episodes, patients with prolonged episodes had shorter sleep time, higher levels of anxiety, increased agitation, and more feelings of disembodiment and amnesia. Between episodes, they were more tired, needed more naps, fell asleep more rapidly, and had higher anxiety/depression scores. INTERPRETATION: Mental disorders are frequent differential diagnoses of Kleine-Levin syndrome. One-third of patients have prolonged (>1 month) episodes with more frequent immediate and long-term consequences of the disease, prompting therapeutic trials.	1
We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.	0
Fetal central nervous system (CNS) abnormalities are second only to cardiac malformations in their frequency of occurrence. Early and accurate diagnosis at prenatal US is therefore essential, allowing improved prenatal counseling and facilitating appropriate referral. Thorough knowledge of normal intracranial anatomy and adoption of a logical sonographic approach can improve depiction of abnormal findings, leading to a more accurate differential diagnosis earlier in pregnancy. Four standard recommended views-transventricular, falx, cavum, and posterior fossa or transcerebellar views-provide an overview of fetal intracranial anatomy during the second trimester anatomy scan. Essential elements surveyed in the head and neck include the lateral cerebral ventricles, choroid plexus, midline falx, cavum septi pellucidi, cerebellum, cisterna magna, upper lip, and nuchal fold. CNS abnormalities can be organized into six main categories at prenatal US. Developmental anomalies include neural tube defects and neuronal migration disorders. Posterior fossa disorders include Dandy-Walker malformation variants and Chiari II malformation. Ventricular anomalies include aqueductal stenosis. Midline disorders include those on the spectrum of holoprosencephaly, agenesis of the corpus callosum, and septo-optic dysplasia. Vascular anomalies include vein of Galen malformations. Miscellaneous disorders include hydranencephaly, porencephaly, tumors, and intracranial hemorrhage. Correlation with postnatal MRI is helpful for confirmation and clarification of suspected diagnoses after birth. The authors discuss a standard US imaging approach to the fetal CNS and review cases in all categories of CNS malformations, providing postnatal MRI correlation when available.©RSNA, 2020.	0
Myotonic Dystrophy Type 1 (DM1) is the most frequent hereditary, adult-onset muscular dystrophy. Nevertheless, DM1-associated cognitive-motor impairments have not been fully characterized so far. This study aimed at profiling cognitive and locomotor dysfunctions in these patients. In addition, cognitive-motor interactions were assessed using a dual-task paradigm. Comprehensive cognitive-motor impairment profiles were generated for 19 patients with DM1 and 19 healthy subjects by thorough clinical, biomechanical and neuropsychological examinations. Detailed gait analysis was performed using a 3D motion capture system, whereas cognitive function was assessed using a standardized neuropsychological test battery. Patients with DM1 showed impaired functional mobility, gait velocity and endurance. DM1-related gait pathology was mainly characterized by enhanced dynamic instability, gait variability, and restricted ankle dorsiflexion. Patients' cognitive impairments particularly concerned attentional functions. Dual-task conditions induced gait deviations that slightly differed between patients and controls. DM1-associated cognitive impairments correlated with reduced functional mobility and impaired ankle dorsiflexion. Patients with DM1 revealed significant impairments of walking function, balance and cognitive performance. Differential cognitive-motor interference and significant interactions between cognitive and motor dysfunctions point towards a prominent role of cognition in gait performance of patients with DM1.	0
Human T-cell leukemia virus type 1 (HTLV-1) causes incurable adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have increased levels of HTLV-1-infected cells compared with asymptomatic HTLV-1 carriers. However, the roles of cellular genes in HTLV-1-infected CD4+ T cells await discovery. We performed microarray analysis of CD4+ T cells from HAM/TSP patients and found that the ABL1 is an important gene in HAM/TSP. ABL1 is a known survival factor for T- and B-lymphocytes and is part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML). ABL1 tyrosine kinase inhibitors (TKIs), including imatinib, nilotinib, and dasatinib, are used clinically for treating CML. To evaluate whether ABL1 is indeed important for HAM/TSP, we investigated the effect of TKIs on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and dead cells. Using this method, we were able to measure the HTLV-1 proviral load (PVL) in live cells alone when peripheral blood mononuclear cells (PBMCs) from HAM/TSP cases were treated with TKIs. Treating the PBMCs with nilotinib or dasatinib induced significant reductions in PVL (21.0% and 17.5%, respectively) in live cells. Furthermore, ABL1 siRNA transfection reduced cell viability in HTLV-1-infected cell lines, but not in uninfected cell lines. A retrospective survey based on our clinical records found a rare case of HAM/TSP who also suffered from CML. The patient showed an 84.2% PVL reduction after CML treatment with imatinib. We conclude that inhibiting the ABL1 tyrosine kinase specifically reduced the PVL in PBMCs from patients with HAM/TSP, suggesting that ABL1 is an important gene for the survival of HTLV-1-infected cells and that TKIs may be potential therapeutic agents for HAM/TSP.	0
Ketamine is used widely in emergency departments for a variety of purposes, including procedural sedation and pain management. A major benefit of using ketamine is the rapid onset and lack of respiratory depression. The known side effects include emergence reactions, hallucinations, hypertension, dizziness, nausea, and vomiting. Recent studies have shown the benefit of ketamine for refractory status epilepticus; however, this application of the drug is still being studied. We present a case where ketamine likely induced a seizure in a patient on whom it was used as a single agent in procedural sedation. Seizure is not a known side effect of ketamine in patients without a seizure history. Given the eagerness over additional uses for ketamine, this novel case of a seizure following procedural sedation with ketamine should be of interest to emergency providers.	0
Infantile haemangiomas (IHs) are the most common benign tumours of childhood; despite the benign histology, prognosis depends on severity of visceral involvement, with a mortality rate ranging from 50 to 90%. In this paper, we describe two infants with multifocal infantile haemangiomatosis and hepatic involvement. This condition should receive appropriate management as it can be potentially lethal due to the high risk of systemic complications such as cardiac or fulminant hepatic failure and abdominal compartment syndrome. Both cases presented with liver involvement, but only the infant who had an excellent response to propranolol is still alive. A review of current therapeutic approaches is also presented even though there are, at present, no uniform guidelines for treatment, despite the relative frequency of infantile haemangiomatosis and the potential severe complications.	0
Pancreas-sparing duodenectomy (PSD) is a known surgical technique used in patients with duodenal pathologies in the adult age group. We present a 3-year-old female patient with intestinal lymphangiectasia who underwent PSD. This is the first case in which this surgical technique was used in childhood. We believe that PSD can be used in the pediatric age group for benign pathologies. Introducing a stent to the common bile duct and the main pancreatic duct is not a requirement, especially if the ampulla is preserved as a "button" duodenal patch.	0
Eastern equine encephalitis virus (EEEV), a mosquito-borne RNA virus, is one of the most acutely virulent viruses endemic to the Americas, causing between 30% and 70% mortality in symptomatic human cases. A major factor in the virulence of EEEV is the presence of four binding sites for the hematopoietic cell-specific microRNA, miR-142-3p, in the 3' untranslated region (3' UTR) of the virus. Three of the sites are "canonical" with all 7 seed sequence residues complimentary to miR-142-3p while one is "non-canonical" and has a seed sequence mismatch. Interaction of the EEEV genome with miR-142-3p limits virus replication in myeloid cells and suppresses the systemic innate immune response, greatly exacerbating EEEV neurovirulence. The presence of the miRNA binding sequences is also required for efficient EEEV replication in mosquitoes and, therefore, essential for transmission of the virus. In the current studies, we have examined the role of each binding site by point mutagenesis of the seed sequences in all combinations of sites followed by infection of mammalian myeloid cells, mosquito cells and mice. The resulting data indicate that both canonical and non-canonical sites contribute to cell infection and animal virulence, however, surprisingly, all sites are rapidly deleted from EEEV genomes shortly after infection of myeloid cells or mice. Finally, we show that the virulence of a related encephalitis virus, western equine encephalitis virus, is also dependent upon miR-142-3p binding sites.	0
Aptamers are short, single-stranded oligonucleotides which are capable of specifically binding to single molecules and cellular structures. Aptamers are also known as "chemical antibodies". Compared to monoclonal antibodies, they are characterized by higher reaction specificity, lower molecular weight, lower production costs, and lower variability in the production stage. Aptamer research has been extended during the past twenty years, but only Macugen® has been accepted by the Food and Drug Administration (FDA) to date, and few aptamers have been examined in clinical trials. In vitro studies with aptamers have shown that they may take part in the regulation of cancer progression, angiogenesis, and metastasis processes. In this article, we focus on the potential use of aptamers in non-small cell lung cancer treatment.	0
We report a rare case of a solitary synovial osteochondroma (SSO) in the cervical canal. A 37-year-old man presented with neck pain and the forearm dysesthesia developed immediately after a trivial motor accident. Because of aggravation he visited our hospital though he was treated conservatively for 3 months. A computed tomography (CT) scan showed an oval shaped small mass with high density rim in the cervical canal at the level of the C6/7 facet joint. This mass compressing the dural sac was visualized with a high intensity signal in T2-weighted magnetic resonance imaging (MRI) and, interestingly, with high intensity in T1-weighted images. A surgical removal was carried out. Macroscopically, it consists of a solitary, firm, juxta-articular mass associated with synobia but lacking connection with the adjacent bone. Microscopically, it is similar to conventional osteochondromas. It differs from this entity by not arising from a bone surface and by a whole coverage of synobial tissue. The final diagnosis was a SSO. There have been anecdotal case reports of a SSO in various site including knee, fingers, buttocks, wrist, and so on. To the best of our knowledge, this is the first case report of SSO arising in the spinal canal.	0
BACKGROUND Cutaneous larva migrans (CLM) is caused by nematode parasites of the hookworm family of Ancylostomatidae. Ancylostomiasis is a zoonosis found in cats and dogs, and humans are an accidental host. This report presents a case of CLM in an 8-year-old boy, which was due to the zoonotic transmission of Ancylostoma caninum from domestic dogs in an urban area of Vinces, Ecuador, and demonstrates how awareness and early diagnosis contributed to the timely treatment of CLM. CASE REPORT An 8-year-old boy from the urban area of Vinces city in the Los Ríos province of Ecuador presented with a serpiginous palpable lesion on the sole of the right foot, consistent with a diagnosis of cutaneous larva migrans (CLM). He was infected through contact with the soil where canine Ancylostoma larvae were found. Twenty samples of feces were analyzed from the soil, and Ancylostoma larvae were found in 100% of these samples. Also, 120 dog stool samples were examined, and 75 (62.5%) contained Ancylostoma larvae, which were identified using the modified Willis and Baermann method. CONCLUSIONS CLM is a zoonotic disease that can affect the population in endemic areas. In this case, CLM was identified in the sole of the foot of a child. The presence of Ancylostoma larvae were identified in the soil and in the feces of dogs, indicating that the community was exposed to a significant environmental risk from this zoonotic disease.	0
Peters' anomaly is a rare congenital eye condition characterized by anterior segment dysgenesis and commonly presents as unilateral or bilateral corneal opacity in the early neonatal period. Peters' anomaly is often associated with congenital brain and skull abnormalities, which are frequently overlooked. In this paper, we present a case of a 5-day-old female neonate with Peters' anomaly, and review the literature for similar reports that describe associated brain imaging findings. In our case, imaging studies show abnormalities involving the anterior segments of both globes with absent intracranial manifestations. Although Peters' anomaly is a condition of interest for ophthalmologists, radiological studies should be performed, and neuroradiologists should be aware of the imaging findings associated with this rare entity.	0
Antibodies play a critical protective role in the host response to blood-stage malaria infection. The role of cytokines in shaping the antibody response to blood-stage malaria is unclear. Interferon lambda (IFNλ), a type III interferon, is a cytokine produced early during blood-stage malaria infection that has an unknown physiological role during malaria infection. We demonstrate that B cell-intrinsic IFNλ signals suppress the acute antibody response, acute plasmablast response, and impede acute parasite clearance during a primary blood-stage malaria infection. Our findings demonstrate a previously unappreciated role for B cell intrinsic IFNλ-signaling in the initiation of the humoral immune response in the host response to experimental malaria.	0
To evaluate surgical results in adults with aortic arch interruption.Seven patients with aortic arch interruption were operated. Two of them (28.6%) underwent aortic arch repair using allograft, 4 (57.21%) - distal arch and proximal descending aortic replacement, 1 (14.3%) - supra-coronary ascending aortic, aortic arch and proximal descending aortic replacement. All operations were performed under moderate hypothermia (25 °С), circulatory arrest with unilateral cerabral perfusion 8-10 ml/kg/min via innominate artery and pressure 69.6±14.7 mm Hg in arterial.Cardiopulmonary bypass (CPB) time was 242±36.1 min, aortic cross-clamping - 110.7±40.4 min, circulatory arrest - 58.6±17.9 min. There were no cases of renal insufficiency, vascular lesion of brain and spinal cord, cardiac events. Resternotomy for bleeding was performed in 1 (14.3%) case. Sufficient descending aortic lumen was achieved in 100% according to CT postoperatively. Peak descending aortic pressure gradient after repair with allograft was 29±1.4 mm Hg, after aortic replaement - 10±4.2 mm Hg. Postoperative and in-hospital 30-day mortality was absent.Reconstructive surgery for aortic arch interruption in adults is effective approach with good clinical and hemodynamic results.	0
In the context of the current global COVID-19 pandemic, this Consensus Statement provides current recommendations for patients with, or at risk of developing, genetic heart disease, and for their health care management and service provision in Australia and New Zealand. Apart from general recommendations, there are specific recommendations for the following conditions: cardiomyopathy, Brugada syndrome (including in children), long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Other recommendations are relevant to patient self-care and primary health care.	0
Camurati-Engelmann disease is an extremely rare disease characterized by hyperostosis of multiple long bones. This condition is caused by heterozygous mutations in the TGFB1 gene.We describe the clinical and genetic characteristics of 4 Korean patients with this rare disease diagnosed at Asan Medical Center in Korea between June 2012 and May 2016, to increase awareness about this condition among general physicians and orthopedists. The presenting features, biochemical findings, radiographic and nuclear imaging findings, molecular analysis, and treatment outcomes of 4 patients were reviewed retrospectively.Two patients had sporadic disease, whereas the other 2 were familial cases. The average age at symptom onset was 8.8 ± 5.5 (4-14) years. Symptoms included waddling gait or leg pain. Bone pain and easy fatigability were documented in all patients. Skeletal deformities such as osteoporosis, genu valgum, and severe scoliosis were observed. Visual and otologic manifestations presenting as exophthalmos, retinal detachment, and vestibulopathy were found in 3 patients. Skeletal survey showed diaphyseal expansion with diffuse cortical thickening of long bones in all patients. Bone scintigraphy images showed increased uptake of radioactive material in the calvarium and diaphysis of long bones. The mean erythrocyte sedimentation rate was 46.5 ± 22.2 (20-72) mm/h. Sequence analysis of TGFB1 revealed the previously reported mutations p.Arg218His, p.Arg218Cys, and p.Glu169Lys. Corticosteroid was effective in relieving pain, and losartan was used as maintenance therapy.Our experience suggests that this rare condition can be suspected in patients with characteristic symptoms and skeletal findings. Considering the presence of effective medical treatment, efforts are needed to identify more cases.	0
Abnormalities in the protocadherin 19 (PCDH19) gene cause early-onset epilepsy exclusively in females. We aimed to explore the genetic and clinical characteristics of PCDH19-related epilepsy by focusing on its early features and treatment efficacy. PCDH19 was analyzed in 159 Japanese female patients with early-onset epilepsy via direct sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis. We identified 17 patients with PCDH19 abnormalities: point mutations were observed in 14 patients and whole PCDH19 deletions were detected in 3 patients. One affected sister of a proband with a mild phenotype was also analyzed. The frequency of PCDH19 deletion among all probands identified in Japan was 12.5% (3/24, including 7 probands reported previously by us). Clinical features included early onset (mean age at onset, 8.6 months), recurrent clusters of brief seizures (17/18), fever sensitivity (18/18), tonic seizures (13/18, probably including focal tonic seizures), tonic-clonic seizures (8/18), focal seizures often with subsequent generalization (17/18), intellectual disabilities (15/18), and autistic traits (13/18). Three patients exhibited delay in motor milestones before seizure onset. In 16 patients, seizures appeared in clusters from the onset of the disease. Among 6 patients for whom detailed information at onset was available, 2 onset patterns were identified: a biphasic course of short seizure clusters (each within days) in 2 patients and a prolonged course of clusters (from weeks to a month) in 4 patients. In both cases, initial seizures started during fever and transiently disappeared with the decline of fever; however, afebrile clusters recurred. In the former patients, motor development was delayed before onset, and seizures appeared in strong clusters from the onset of the disease. In the latter patients, initial development was normal and initial seizures were mild, but were followed by strong clusters lasting several weeks, even without fever. Treatment using phenytoin, potassium bromide, and clobazam showed high efficacy. Although focal seizures were the main feature in PCDH19-epilepsy, the efficacy of carbamazepine was poor. This study highlighted the significance of PCDH19 deletion, a unique pattern of initial seizure clusters, and the efficacy of antiepileptic drugs. Our data will facilitate early diagnosis and development of a treatment strategy for better clinical management of patients with PCDH19-related epilepsy.	0
TP53 aberrations reportedly predict favorable responses to decitabine (DAC) in acute myeloid leukemia (AML). We evaluated clinical features and outcomes associated with chromosome 17p loss or TP53 gene mutations in older, unfit DAC-treated AML patients in a phase II trial. Of 178 patients, 25 had loss of 17p in metaphase cytogenetics; 24 of these had a complex (CK+) and 21 a monosomal karyotype (MK+). In analyses in all patients and restricted to CK+ and MK+ patients, 17p loss tended to associate with higher rates of complete remission (CR), partial remission (PR), or antileukemic effect (ALE). Despite favorable response rates, there was no significant OS difference between patients with or without loss of 17p in the entire cohort or in the CK+ and MK+ cohort. TP53 mutations were identified in eight of 45 patients with material available. Five of the eight TP53-mutated patients had 17p loss. TP53-mutated patients had similar rates of CR/PR/ALE but shorter OS than those with TP53 wild type (P = 0.036). Moreover, patients with a subclone based on mutation data had shorter OS than those without (P = 0.05); only one patient with TP53-mutated AML had a subclone. In conclusion, 17p loss conferred a favorable impact on response rates, even among CK+ and MK+ patients that however could not be maintained. The effect of TP53 mutations appeared to be different; however, patient numbers were low. Future research needs to further dissect the impact of the various TP53 aberrations in HMA-based combination therapies. The limited duration of favorable responses to HMA treatment in adverse-risk genetics AML should prompt physicians to advance allografting for eligible patients in a timely fashion.	0
Muscular dystrophies are a heterogeneous group of disorders that commonly involve cardiac and skeletal muscle. Comprehensive guidelines for the management of cardiac failure and arrhythmias are available. However, the studies from which their recommendations are derived did not include any patients with muscular dystrophy. Some medications (eg, betablockers) may have significant side effects in this cohort. In some situations the use of agents with unique mechanisms of action such as ivabradine (a 'funny' channel inhibitor) may be more appropriate. Use of ivabradine has not previously been reported in limb girdle muscular dystrophy (LGMD). We describe the course of a patient with LGMD type 2I, cardiomyopathy and inappropriate sinus tachycardia treated with ivabradine. As advances in respiratory support have improved the outcomes of patients with muscular dystrophy; the prognostic significance of cardiac disease has increased. Ivabradine is tolerated and may reduce symptoms, morbidity and mortality in this cohort.	0
We describe a father and his daughter who had a unique pattern of preaxial brachydactyly, and unusual facial appearance. Both had short broad abducted thumbs and halluces. The second digits of both hands were also short and broad and those of feet were medially angulated. The radiographic findings were short first metacarpals and first metatarsals and hypoplastic phalanges of first two digits of hands and feet. A similar pattern of brachydactyly was described by Christian et al. [1972: Am J Hum Genet 24:694-701] and Mononen et al. [1992: Am J Med Genet 42: 706-713]. Our patients differ from those described by Christian et al. in that they did not have any mental retardation and from those of Mononen et al. by the absence of short stature and epiphyseal and metaphyseal changes. The heterogeneity of this new type of brachydactyly remains to be resolved.	0
This review provides an updated summary of the state of our knowledge of the genetic contributions to the pathogenesis of congenital heart disease. Since 2007, when the initial American Heart Association scientific statement on the genetic basis of congenital heart disease was published, new genomic techniques have become widely available that have dramatically changed our understanding of the causes of congenital heart disease and, clinically, have allowed more accurate definition of the pathogeneses of congenital heart disease in patients of all ages and even prenatally. Information is presented on new molecular testing techniques and their application to congenital heart disease, both isolated and associated with other congenital anomalies or syndromes. Recent advances in the understanding of copy number variants, syndromes, RASopathies, and heterotaxy/ciliopathies are provided. Insights into new research with congenital heart disease models, including genetically manipulated animals such as mice, chicks, and zebrafish, as well as human induced pluripotent stem cell-based approaches are provided to allow an understanding of how future research breakthroughs for congenital heart disease are likely to happen. It is anticipated that this review will provide a large range of health care-related personnel, including pediatric cardiologists, pediatricians, adult cardiologists, thoracic surgeons, obstetricians, geneticists, genetic counselors, and other related clinicians, timely information on the genetic aspects of congenital heart disease. The objective is to provide a comprehensive basis for interdisciplinary care for those with congenital heart disease.	0
The COL2A1 gene consists of 54 exons spanning over 31.5 kb and encodes for type II collagen. Type II collagen is the main component of hyaline cartilage extracellular matrix, nucleus pulposus of intervertebral discus, vitreous humor of the eye and inner ear structure. Molecular defects in COL2A1 gene cause a wide variety of rare autosomal-dominant conditions known as type II collagenopathies. A clear genotype-phenotype relationship is not yet known. However, some correlations are described. Spondyloephyseal dysplasia congenita was suggested for a short-trunk dwarfing condition affecting primarily the vertebrae and the proximal epiphyses of the long bones.	0
Camptodactyly refers to permanent flexion contracture at the proximal interphalangeal joint. Most cases are limited to fifth-finger involvement. Although common, the treatment of camptodactyly is controversial. Many published studies have emphasized conservative treatment, while others have described surgical procedures. The problem with this deformity is that it presents in several forms, which means that there is no single model for effective treatment. The aim of this paper is to present the difficulties encountered with this condition and the management thereof on an individual basis.This is a case series of 14 patients (nine males, five females) who underwent surgical treatment. The results were classified using the method from Mayo Clinic as excellent, good, fair, and poor.Fourteen patients with 15 fingers underwent surgery, and the results achieved were as follows: excellent, 0; good, 1; fair, 6; poor, 8. The treatment of camptodactyly still remains controversial, and hence proper planning individualized to each patient is needed to achieve the maximal improvement with realistic goals.Although we performed individualised surgery, our careful follow-up was not able to identify any method as superior over another with respect to gain in extension and loss of flexion. We therefore propose that the extensor mechanism should not be disturbed during surgery to treat camptodactyly cases.	0
Purpose:To report a carefully studied case of high voltage electrical injury of the retina and optic nerve with anatomically reversible retinoschisis. Methods:Observational case report. Results:A 22 year old power company worker was electrocuted with 12,000 V, with his left forehead being the exit point of the current. After regaining consciousness he reported decreased vision with both eyes. He was extensively tested with optical coherence tomography (OCT) and angiography (OCT-A), fundus photography, fluorescein angiography (FA), multifocal electroretinography (mfERG), full field electroretinography (ffERG), visual evoked potentials (VEP), and Goldmann-type Octopus automated perimetry in addition to careful clinical examinations. Our investigations revealed severe visual field constriction in both eyes, severe coagulative damage leading to inner and outer retinal atrophy, subretinal fluid collection, retinoschisis cavities, and papillitis. Initially he was treated with 100 mg prednisone per day for one week and 250 mg acetazolamide per day which was continued for 3 months. Over time the OCT signs of retinoschisis resolved but visual acuity and visual field improvement did not occur. Conclusion:Resolution of retinoschisis cavities following electrical damage does not necessarily lead to improvement in visual function due to the many accompanying structural injuries.	0
AIM: Cardiac arrhythmias are an important cause of morbidity in infants. Although the spectrum of types of arrhythmia has been reported, there has been no previous population-based study of the incidence of arrhythmias in infancy. Our aim was to define the population incidence of arrhythmia in infants. METHODS: We based this study on the Northern Region of England with a resident population of 3.1 million and an annual live birth rate of 33,000. We identified all clinically significant arrhythmias in infants in 1991-2010 from the regional cardiac database. All diagnoses were based on analysis of the electrocardiogram. Infants with only the substrate for arrhythmia (such as QT prolongation or ventricular pre-excitation) were excluded. RESULTS: In 20 years, there were 662,698 live births. We identified 162 cases of newly diagnosed arrhythmia of which 22 had associated structural cardiovascular malformations. The incidence of arrhythmia was 24.4 per 100,000 live births. The most common arrhythmia was atrioventricular re-entry tachycardia with an incidence of 16.3 per 100,000. Complete atrioventricular block and atrial flutter both occurred at 2.1 cases per 100,000 live births, and other arrhythmias were rare. CONCLUSIONS: This study is the first to report a population incidence of arrhythmia in infants.	1
We retrospectively analysed 71 cases of Unicentric Castleman disease, a rare, usually asymptomatic, benign lymphoproliferative disorder presenting as a unique nodal mass. Although surgery is considered as the gold standard therapy, only 38 patients (54%) underwent initial surgical resection and 95% were cured. An additional 9 patients had surgery after an attempt at medical reduction. Reduction therapy was used in 21 patients with a 55% response rate, but without evidence for an optimal regimen. Radiotherapy was limited to 8 patients because of associated toxicity. Watch and wait was considered in 13 asymptomatic patients and 11 of these remained stable for up to 17 years.	0
Congenital fusion of jaw and its association with ankyloblepharon filiforme adnatum is reported but is a quite rare congenital benign anomaly. It may be unilateral or bilateral and can present with a single system or multiple systems involvement. This report concentrates on describing the clinical features of above disease, likely aetiological causes, and embryogenesis with classification, diagnostic, and, treatment modality, anesthesia problems and review of literature.	0
The roles of ceramide and its catabolites, i.e., sphingosine and sphingosine 1-phosphate, in the development of malignancies and the response to anticancer regimens have been extensively described. Moreover, an abundant literature points to the effects of glucosylceramide synthase, the mammalian enzyme that converts ceramide to β-glucosylceramide, in protecting tumor cells from chemotherapy. Much less is known about the contribution of β-glucosylceramide and its breakdown products in cancer progression. In this chapter, we first review published and personal clinical observations that report on the increased risk of developing cancers in patients affected with Gaucher disease, an inborn disorder characterized by defective lysosomal degradation of β-glucosylceramide. The previously described mechanistic links between lysosomal β-glucosylceramidase, β-glucosylceramide and/or β-glucosylphingosine, and various hallmarks of cancer are reviewed. We further show that melanoma tumor growth is facilitated in a Gaucher disease mouse model. Finally, the potential roles of the β-glucosylceramidase protein and its lipidic substrates and/or downstream products are discussed.	0
Polymyositis is a diagnosis of exclusion. In patients with odd features, it can be of infective etiology. A high index of suspicion is required for diagnosis. A 55-year-old gentleman presented with gradual-onset proximal muscle weakness. Examination revealed mild distal weakness but no rash. Muscle enzymes were raised and tests for autoantibodies were negative. Biopsy revealed microsporidiosis. In view of this unusual infection, immunodeficiency was considered and he was found to have lymphopenia which antedated his illness. Later, he developed cranial nerve palsies due to multiple lesions in the pons. In addition, he had Cytomegalovirus viremia. Literature was reviewed to identify 20 cases of microsporidial myositis, its presentation, underlying immunodeficient state, and clinical course. Infective polymyositis should be considered in a patient with paucity of clinical and serological autoimmune features. Lymphopenia can point to underlying immunodeficiency. CMV infection could be the contributor to or bystander-effect of idiopathic lymphopenia.	0
Stromal‑epithelial interaction serves a pivotal role in normal prostate growth, as well as the onset of benign prostatic hyperplasia (BPH). The present study aimed to explore the role of cyclopamine in the proliferation and apoptosis of epithelial and stromal cells in rats with BPH by blocking the Hedgehog signaling pathway. Cyclopamine (an inhibitor of the Hedgehog signaling pathway) was administered in a rat model of BPH, and the expression of Ki67 (proliferation factor) was determined by immunohistochemistry. In addition, epithelial and stromal cells were separated and cultured in order to investigate the role of cyclopamine in the progression of BPH. The expression of Hedgehog signaling pathway‑ and apoptosis‑related genes, including basic fibroblastic growth factor (b‑FGF) and transforming growth factor β (TGF‑β), was evaluated using reverse transcription‑quantitative polymerase chain reaction and western blot analysis. Cell proliferation, cell cycle and apoptosis were analyzed using an MTT assay and flow cytometry. We identified upregulated Ki67 expression and activated Hedgehog signaling pathway in rats with BPH. Cyclopamine inhibited the activation of the Hedgehog signaling pathway. In response to cyclopamine treatment, epithelial and stromal cell proliferation was inhibited; this was concomitant with decreased Ki67, TGF‑β, and b‑FGF expression. On the other hand, epithelial cell apoptosis was enhanced, which was associated with increased Bax and reduced Bcl‑2 expression. Based on these findings, we proposed that cyclopamine may serve as a potential therapeutic agent in the treatment of BPH. Cyclopamine could inhibit epithelial and stromal cell proliferation, and induce epithelial cell apoptosis by suppressing the Hedgehog signaling pathway.	0
Femoral neck stress fractures are rare and when treating are difficult to achieve favorable outcomes. This study characterizes outcomes associated with the use of cephalomedullary nails for fixation of Pauwels type-3 vertical femoral neck undisplaced-incomplete insufficiency fractures. Four consecutive patients with a Pauwels type-3 vertical femoral neck tensile insufficiency fracture from 2016 to 2018 were reviewed. Magnetic resonance imaging data revealed tensile visible fracture lines and hip-joint effusions with a high shear angle. For all patients, bone mineral density and vitamin D levels were low; vitamin D therapy was initiated immediately. Surgical procedures were conducted with cephalomedullary nails (Gamma 3 locking nail system; Stryker) under general anesthesia. A cephalomedullary nail appears to be a safe and effective alternative to the use of multiple parallel screws or a sliding hip screw for fixation of vertical femoral neck stress fractures (level of evidence: Level V).	0
Temple-Baraitser syndrome, previously described in two unrelated patients, is the association of severe mental retardation and abnormal thumbs and great toes. We report two additional unrelated patients with Temple-Baraitser syndrome, review clinical and radiological features of previously reported cases and discuss mode of inheritance. Patients share a consistent pattern of anomalies: hypo or aplasia of the thumb and great toe nails and broadening and/or elongation of the thumbs and halluces, which have a tubular aspect. All patients were born to unrelated parents and occurred as a single occurrence in multiple sibships, suggesting sporadic inheritance from a de novo mutation mechanism. Comparative genomic hybridization in Patients 1, 2 and 3 did not reveal any copy number variations. We confirm that Temple-Baraitser syndrome represents a distinct syndrome, probably unrecognized, possibly caused by a de novo mutation in a not yet identified gene.	0
Introduction:Zika virus (ZIKV) is a little-known emerging mosquito-borne flavivirus. The perinatal ZIKV infection was associated with birth defects during the Brazilian outbreak. There was an increased risk of intrauterine transmission of the virus and a marked increase in the number of newborns with microcephaly. We report on two such cases. Case Report:The first case was a 25-year-old pregnant woman from Colombia who became acutely ill with general symptoms during the tenth week of gestation, followed by severe generalized itching and maculopapular rash for approximately five days. This case was reported during the epidemic stage of the ZIKV infection in Colombia. At 23.3 gestational weeks, ultrasonography showed abnormal intracranial anatomy with cerebral ventriculomegaly, microcephaly, and parenchymal calcification. Given the grave prognosis, the patient elected to terminate the pregnancy at 25 gestational weeks. The second case was a 24-year-old pregnant woman who became acutely ill during the 17th week of gestation, which corresponded with the ZIKV epidemic in Colombia. At 30.5 gestational weeks, ultrasonography showed isolated fetal cerebral ventriculomegaly. We detected ZIKV in the amniotic fluid; however, the virus was not detected in the urine or serum of the mother or fetus. Tests for dengue virus, chikungunya virus, Toxoplasma gondii, rubella virus, cytomegalovirus, herpes simplex virus, HIV, hepatitis B and C, and parvovirus B19 were all negative. Different samples obtained from the placenta, amniotic liquid, and cerebrospinal fluid were positive for viral isolation of ZIKV RNA using TaqMan RT-PCR. Additionally, the parents and fetuses were tested for genetic diseases using whole exome sequencing and array CGH to rule out possible genetic syndromes that produce these congenital abnormalities. Conclusion:These were the first cases in Colombia to show early vertical transmission of ZIKV and the first cases associated with congenital cerebral abnormalities in which molecular, infectious, and genomic tests were performed.	0
Background:Corticotomy is a technique presumed as useful to decrease the time for orthodontic treatment, however, it is necessary to do a systematic review in order to determine if there is enough scientific evidence to back up the use of Corticotomy to accelerate the treatment. Material and Methods:Data was stockpiled from the electronic database such as PubMed, Cochrane, Scopus y Science Direct, according to the PRISMA linings for systematic reviews, using the following keywords: accelerated movement of the teeth AND osteotomy AND piezocision AND corticotomy AND orthodontics. Only English, Spanish and French language articles that met the criteria needed were included. Results:In the different accelerated orthodontics techniques, a significant reduction in the total time of orthodontic treatment was obtained. There were no major complications reported in any study. The less invasive procedures had better acceptance. Discussion:The surgical approaches are not only limited to usual orthodontic treatments, but they have also been used as an alternative for the approach of a palatal fistula in a patient with bilateral cleft lip and palatine orofaciodigital syndrome Type I. Conclusions:There has been a growing interest in the use of alveolar corticotomies as an adjunct to orthodontic treatment, due to a deeper understanding of its effects and a more robust investigation based on the evidence. All published results indicate a decrease in the total treatment time. Key words:Accelerated movement of the teeth, piezocision, corticotomy AND orthodontics.	0
Glioblastoma is the most common adult primary brain tumor that occurs in the central nervous system and is characterized by rapid growth and diffuse invasiveness with respect to the adjacent brain parenchyma, which renders surgical resection inefficient. Although it is a highly infiltrative tumor, it is rarely disseminated beyond the central nervous system, wherein extracranial metastasis is a unique but rare manifestation of this kind of tumor. It is very common for acquired immunodeficiency syndrome (AIDS) patients to be infected with the human immunodeficiency virus (HIV), which suggests that a possible association between HIV infection and tumor development exists. In this paper, we present a new case of a young patient's HIV-associated glioblastoma, with glioblastoma metastasis within the T9 vertebral body and lymph nodes in the anterior neck tissue. Initially, the patient was diagnosed with a grade III plastic astrocytoma. The patient lived a normal life for a year while being treated with temozolomide, radiotherapy, and highly active antiretroviral therapy. However, the tumor quickly evolved into a glioblastoma. We believe that the drastic progression of the tumor from a grade III anaplastic astrocytoma to a metastatic glioblastoma is due to the HIV infection that the patient had acquired, which contributed to a weakened immune system, thus accelerating progression of the cancer.	0
Background:We performed robotic parotidectomy with or without robotic neck dissection via a retroauricular approach in patients with parotid benign and malignant tumors and analyzed treatment outcomes of the patients to evaluate the safety and feasibility of robotic parotidectomy. Methods:Between January 2017 and July 2018, 53 patients received robotic parotidectomy with/without robotic neck dissection through a remote access retroauricular incision without a preauricular incision. Results:All operations were successfully performed in all patients without significant perioperative complications or tumor spillage. Tumors were located in the superficial lobe of the parotid gland in 40 patients, and the remaining 13 tumors were located in the deep lobe of the parotid gland. Postoperative pathologic examination revealed benign tumor in 32 patients and malignant tumors in 18 patients. The mean operation time was 226 minutes in patients who underwent only parotidectomy and 375 minutes in patients who underwent parotidectomy with robotic neck dissection. The average amount of bleeding was 23 mL, and the amount of drainage after operation averaged 171 mL. The average length of hospital stay was 6 days. Postoperative complications were limited to transient facial paralysis in three patients, all of which resolved within 1 month. All patients were satisfied with their cosmetic results at 6 months after operation. Conclusions:Robotic parotidectomy with/without robotic neck dissection through a retroauricular approach was a feasible and safe technique in patients with parotid benign and malignant tumor. Specifically, we found it to be helpful in young patients with malignant parotid tumors who should receive cervical lymphadenectomy and parotidectomy, because it does not leave a visible scar on the face or neck. In the future, long-term follow-up will be necessary to validate its oncologic safety and functional outcomes.	0
To determine the prevalence and mortality of retinitis pigmentosa (RP) patients in Korea.Population-based retrospective cohort study.We used data covering the 2011-2014 period from the Rare Intractable Disease (RID) registry and Health Insurance Review and Assessment (HIRA) service, which include information on all patients diagnosed with RP based on predefined diagnostic criteria. Using the HIRA-RID database, we evaluated the prevalence and age at diagnosis of RP patients across the entire Korean population. We further linked the data from Statistics Korea to the HIRA-RID database to confirm mortality and causes of death.The prevalence in the total population across all ages was 11.09 per 105 people, and the prevalence in those over the age of 40 was 16.16 per 105 people. The age at diagnosis ranged from 0 to 95 and, on average, was 44.8. The standardized mortality ratio (SMR) was 1.56 for all ages, peaking at 2.61 in men aged 40-59, which was attributed to 6.6-fold higher suicide rates than the same age group in the general male population.This is the first nationwide epidemiologic study of RP patients covering the entire population of all ages. The results suggest that the prevalence of RP in Korea is about 1 in 9000 for all ages and 1 in 6000 for those over 40 years of age. The higher mortality of RP patients than that of the general population is attributable to a high suicide rate in male RP patients of working ages, which necessitates a careful attention to their mental health.	1
A 24-year-old black woman from Uganda was seen for treatment of multiple papules on her hands and feet. The lesions corresponded microscopically to foci of hyperkeratosis and acanthosis. Acid orcein stain revealed marked elastic fiber fragmentation. Acrokeratoelastoidosis of Costa (AKE) was diagnosed. The same damage to the elastic fibers was also present in an additional specimen from grossly uninvolved skin. On electron microscopy there were pronounced changes of the elastic fibers with elastolysis in both specimens. This case with generalized damage of the dermal elastic tissue supports the view that elastorrhexis is the key feature of AKE. Accordingly, the disease could be regarded as a primary elastic tissue disorder. The marginal acral keratoderma that is seen in AKE patients could represent epidermal changes secondary to chronic trauma.	0
Cowden syndrome is an autosomal dominant disorder characterized by hamartomas, as well as benign and malignant neoplasms that may present in organ systems throughout the body. It also poses an increased lifetime cancer risk in those with the disorder. Its clinical presentation is often variable, and diagnosis can be challenging. In the head and neck region, it can present as thyroid enlargement or mass formation, cutaneous and mucocutaneous lesions of the skin and the oral cavity. The most typical oral manifestations of Cowden syndrome are oral papillomatosis and a cobblestone appearance of the mucosa. We present a case of vascular malformation of the tongue in a patient with Cowden syndrome. This lesion was similar in appearance to a cutaneous hamartoma on the patient's upper extremity. He had received prior surgical intervention for this tongue mass, and complete resection was recommended subsequently. However, in search of a less invasive treatment to minimize impact on speech and oral function, sclerotherapy was performed, resulting in resolution of the lesion. Sclerotherapy is a well-documented treatment for head and neck vascular malformations, but it is not universally employed. In our patient with atypical oral manifestation of Cowden syndrome, bleomycin sclerotherapy was employed, resulting in resolution of the lesion, as well as preservation of speech articulation and oral function.	0
Spinocerebellar ataxia type 2 (SCA2) is a rare autosomal dominant progressive degenerative disease of the nervous system, which is characterized by a progressive cerebellar syndrome associated with saccadic eye scan, peripheral neuropathy, cognitive disorders, and other multisystem features. The gene predisposing to SCA2 has been mapped, which encodes the ataxin 2 protein. A CAG repeat expansion in the coding region of ATXN2 gene can cause extension of polyglutamine chain in the protein. This paper reviews recent progress made in the research on SCA2 in regard to its clinical features, pathology, etiology, pathogenesis and treatment.	0
We present a case of hereditary multiple exostoses in a male child, who presented to us with bony outgrowths on the chest and recurrent respiratory infections. On questioning, it was revealed that the child had a family history of bony outgrowths, though those affected in his family were not symptomatic. Other causes of recurrent respiratory infections were systematically ruled out, which led us to our conclusion. The treatment of this condition can be either conservative or surgical, but owing to the seriousness of our patient's condition, the preferred option was surgery in this case.	0
Parkes Weber syndrome is a rare congenital condition of the vascular system with severe symptoms and life-threatening complications. The challenge is to manage the arteriovenous malformations, and there is no consensus on optimal treatment. We report the case of an 18-year-old woman with Parkes Weber syndrome who was treated with ethanol combined with coil embolisation at an early stage. After two sessions of embolisation, a significant devascularisation was achieved. No sign of recurrence was observed two years after the initial procedure. The patient's symptoms and signs were greatly relieved during the follow-up period. This case raises awareness of Parkes Weber syndrome and highlights the importance of timely intervention, as well as offering a promising therapeutic option for this condition.	0
Glycosylation is the most ubiquitous post-translational modification in eukaryotes. N-glycan is attached to nascent glycoproteins and is processed and matured by various glycosidases and glycosyltransferases during protein transport. Genetic and biochemical studies have demonstrated that alternations of the N-glycan structure play crucial roles in various physiological and pathological events including progression of cancer, diabetes, and Alzheimer's disease. In particular, the formation of N-glycan branches regulates the functions of target glycoprotein, which are catalyzed by specific N-acetylglucosaminyltransferases (GnTs) such as GnT-III, GnT-IVs, GnT-V, and GnT-IX, and a fucosyltransferase, FUT8s. Although the 3D structures of all enzymes have not been solved to date, recent progress in structural analysis of these glycosyltransferases has provided insights into substrate recognition and catalytic reaction mechanisms. In this review, we discuss the biological significance and structure-function relationships of these enzymes.	0
Vascular occlusive events can complicate recovery following trauma. We examined risk factors for venous and arterial vascular occlusive events in trauma patients and the extent to which the risk of vascular occlusive events varies with the severity of bleeding.We conducted a cohort analysis using data from a large international, double-blind, randomised, placebo-controlled trial (The CRASH-2 trial) [1]. We studied the association between patient demographic and physiological parameters at hospital admission and the risk of vascular occlusive events. To assess the extent to which risk of vascular occlusive events varies with severity of bleeding, we constructed a prognostic model for the risk of death due to bleeding and assessed the relationship between risk of death due to bleeding and risk of vascular occlusive events. There were 20,127 trauma patients with outcome data including 204 (1.01%) patients with a venous event (pulmonary embolism or deep vein thrombosis) and 200 (0.99%) with an arterial event (myocardial infarction or stroke). There were 81 deaths due to vascular occlusive events. Increasing age, decreasing systolic blood pressure, increased respiratory rates, longer central capillary refill times, higher heart rates and lower Glasgow Coma Scores (all p<0.02) were strong risk factors for venous and arterial vascular occlusive events. Patients with more severe bleeding as assessed by predicted risk of haemorrhage death had a greatly increased risk for all types of vascular occlusive event (all p<0.001).Patients with severe traumatic bleeding are at greatly increased risk of venous and arterial vascular occlusive events. Older age and blunt trauma are also risk factors for vascular occlusive events. Effective treatment of bleeding may reduce venous and arterial vascular occlusive complications in trauma patients.	0
Congenital disorders of glycosylation (CDG) are metabolic disorders that affect the glycosylation of proteins and lipids. Since glycosylation affects all organs, CDG show a wide spectrum of phenotypes. We present a patient with microcephaly, dysmorphic facies, congenital heart defect, focal epilepsy, infantile spasms, skeletal dysplasia, and a type 1 serum transferrin isoelectrofocusing due to a novel CDG caused by a homozygous variant in the oligosaccharyltransferase complex noncatalytic subunit (OSTC) gene involved in glycosylation and confirmed by serum transferrin electrophoresis.	0
Congenital mesoblastic nephroma (CMN) also called leimyomatous harmartoma is a mesenchymal renal tumor. CMN is the most common solid tumor in newborns and young infants which is basically benign. Pathologically there are three variants of CMN - classic (conventional), cellular (which is more aggressive) and mixed. In a complete surgical removal of the tumor (nephrectomy), the literature results are excellent.	0
Resistance to thyroid hormone β (RTHβ) due to homozygous THRB defects is exceptionally rare, with only five kindreds reported worldwide. Cardiac dysfunction, which can be life-threatening, is recognized in the disorder. Here we describe the clinical, metabolic, ophthalmic, and cardiac findings in a 9-year-old boy harboring a biallelic THRB mutation (R243Q), along with biochemical, physiologic, and cardiac responses to carbimazole and triiodothyroacetic acid (TRIAC) therapy. The patient exhibits recognized features (goiter, nonsuppressed thyroid-stimulating hormone levels, upper respiratory tract infections, hyperactivity, low body mass index) of heterozygous RTHβ, with additional characteristics (dysmorphic facies, winging of scapulae) and more markedly elevated thyroid hormone levels, associated with the homozygous form of the disorder. Notably, an older sibling with similar clinical features and probable homozygous RTHβ had died of cardiac failure at age 13 years. Features of early dilated cardiomyopathy in our patient prompted combination treatment with carbimazole and TRIAC. Careful titration of therapy limited elevation in TSH levels and associated increase in thyroid volume. Subsequently, sustained reduction in thyroid hormones with normal TSH levels was reflected in lower basal metabolic rate, gain of lean body mass, and improved growth and cardiac function. A combination of antithyroid drug and TRIAC therapy may prevent thyrotoxic cardiomyopathy and its decompensation in homozygous or even heterozygous RTHβ in which life-threatening hyperthyroid features predominate.	0
We report on an infant with tetrasomy of 5q35.2-5q35.3, an interstitial triplication on one chromosome and normal complement on the other. The patient has some features of Hunter-McAlpine syndrome including intrauterine growth retardation (IUGR), almond-shaped eyes, epicanthal folds, and downturned mouth with thin vermillion of the upper lip. In addition, left ventricular noncompaction and absent thumbs were identified, which have never been described in Hunter-McAlpine syndrome. This chromosome abnormality is distinct from those previously reported. Within this region of tetrasomy is MSX2, a highly conserved homeobox containing gene. Increased copies of MSX2 have been previously associated with craniosynostosis. Our patient's only skeletal defect is absent thumbs, also potentially related to increased dosage of MSX2 which is important for limb formation. In addition, MSX2 is expressed in the developing heart and overexpression of this gene may disrupt the co-regulation of other cardiac genes in this region, namely CSX1.	0
Childhood disintegrative disorder (CDD) is a rare autistic-like clinical condition with unknown etiology, in that previously acquired age-appropriate language, social and adaptive abilities deteriorate significantly in 2-10-year-old healthy children, although physical and neurological evaluations display no observable abnormality. Our case is a 22-year-old female born of a consanguineous marriage, with the appearance of CDD symptoms in her fifth year of age following normal mental and physical development during her initial four years of life. Without any precipitating factor, she gradually lost her language abilities, social relational skills, affectionate behavior, adaptive capacities, peer play and meaningful interest in her surrounding, friends and family members over a period of 4 years, reaching a plateau in her ninth year of age. The unique special clinical symptom in this case is a seasonal total mutism, which after the beginning of her CDD symptoms is revealing every year covering the spring. As no additional physical or psychological change accompanies her total seasonal speech loss, it cannot be attributed to any mental condition known as having a seasonal pattern. Because in the literature CDD is presented mostly as case reports with lacking of advanced research data, describing any new case is recommended to improve the knowledge about this rare condition, especially if it displays some new unusual signs, not reported till now.	0
Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is a rare autosomal recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic plaques, ichthyosiform scaling, circular constrictions around the fingers, and numerous papules distributed linearly in the arm folds and on the wrists. Histologically, the affected skin shows hypertrophy and hyperplasia of the spinous, granular, and horny epidermal layers with mild infiltration of inflammatory cells in the upper dermis. There are 14 patients with KLICK syndrome described in the literature, and they all carry the same nucleotide deletion. Proteasome maturation protein (POMP), encoded by POMP, is an ubiquitously expressed protein that functions as a chaperone for proteasome maturation. KLICK syndrome is caused by a reduction in POMP levels that leads to proteasome insufficiency in differentiating keratinocytes. It is noteworthy that POMP is also known to be the causative gene for proteasome-associated autoinflammatory syndrome-2 (PRAAS2). It is considered that the disrupted proteasome assembly caused by the POMP mutation might lead to both skin inflammation and then hyperkeratosis in KLICK syndrome. Inflammation caused by the hyperactivation of innate immunity occasionally leads to inflammatory diseases of the skin, recently denoted as autoinflammatory keratinization diseases (AiKDs). We propose that KLICK syndrome caused by the specific 1-bp nucleotide deletion mutation in the regulatory region of POMP might be in a spectrum of proteasome-associated phenotypes.	0
BACKGROUND:Prurigo nodularis (PN) is a chronic disease characterized by intensely pruritic, raised, nodular lesions. As there are currently no US Food and Drug Administration-approved therapies specifically for PN, management is highly variable and no consensus exists on treatment regimens. OBJECTIVE:To provide practical guidance to help US dermatologists diagnose and effectively treat patients with PN. METHODS:The authors participated in a roundtable discussion to develop consensus recommendations on diagnosis and treatment of PN from a US perspective. RESULTS:The core findings in PN are the presence of firm, nodular lesions; pruritus lasting at least 6 weeks; and history and/or signs of repeated scratching, picking, or rubbing. The diagnostic workup involves a complete review of systems, considering potential systemic diseases, and assessment of disease severity, including disease burden and pruritus intensity. Treatment should be selected based on a patient's clinical presentation, comorbidities, and response to prior treatments and should address both neural and immunologic components of pruritus. LIMITATIONS:Data on PN are from anecdotal or small clinical trials, and all treatments are currently used off-label. CONCLUSION:An effective treatment approach for patients with PN should be based on clinical judgment and tailored to the individual needs of the patient.	0
Cytokines play an important role in the pathogenesis of lymphomas via autocrine or paracrine mechanisms, or both. Here we determined the proportion of CD3-positive T lymphocytes containing various types of cytokines in enlarged lymph nodes. Lymph nodes were obtained from 16 patients with various lymphoproliferative disorders, including 3 cases with angioimmunoblastic lymphadenopathy with dysproteinemia (AILD), 3 cases with adult T cell leukemia/lymphoma (ATLL), 2 cases with T-cell nonspecific malignant lymphoma (T-ML), 3 cases with B-cell diffuse large malignant lymphoma (BDL), 3 cases with histiocytic necrotizing lymphadenitis (HNL), and 2 cases with non-specific lymphadenitis (NSL). The percentages of T lymphocytes positive for cytoplasmic cytokines IL-2, IL-4, IL-5, IL-6, IL-13, TNF-alpha, and INF-gamma were determined. The percentage of INF-gamma positive T lymphocytes was high in reactive lymphadenopathy of NSL and HNL. AILD showed a high proportion of TNF-alpha positive T-lymphocytes, and in addition, the percentages of IL-2, IL-4, IL-5, IL-6, IL-13 and INF-gamma positive T-lymphocytes were relatively higher than in other diseases. Our results supported the state of multiple hypercytokinemia typically seen in AILD and suggested that the source of the cytokines is the lymph nodes. Our results also suggested that multiple cytokine networks play an important role in the clinical and histopathological features of AILD. Modulation of the cytokine network may be the logical objective in future therapeutic strategies designed for AILD.	0
May-Thurner syndrome is characterized by unilateral lower extremity venous hypertension and stasis due to compression of an iliac vein between an iliac artery and the lumbar spine. In almost all cases, the left common iliac vein is compressed by the right common iliac artery; however, other patterns have been described. Rarely, May-Thurner syndrome may be created iatrogenically as a result of iliac artery stenting. We present an unusual case of new left common iliac vein thrombosis caused by ipsilateral left iliac artery compression after aortobi-iliac endovascular aneurysm repair.	0
D-2-hydroxyglutaric aciduria Type I (D-2-HGA Type I), a neurometabolic disorder with a broad clinical spectrum, is caused by recessive variants in the D2HGDH gene encoding D-2-hydroxyglutarate dehydrogenase (D-2-HGDH). We and others detected 42 potentially pathogenic variants in D2HGDH of which 31 were missense. We developed functional studies to investigate the effect of missense variants on D-2-HGDH catalytic activity. Site-directed mutagenesis was used to introduce 31 missense variants in the pCMV5-D2HGDH expression vector. The wild type and missense variants were overexpressed in HEK293 cells. D-2-HGDH enzyme activity was evaluated based on the conversion of [2 H4 ]D-2-HG to [2 H4 ]2-ketoglutarate, which was subsequently converted into [2 H4 ]L-glutamate and the latter quantified by LC-MS/MS. Eighteen variants resulted in almost complete ablation of D-2-HGDH activity and thus, should be considered pathogenic. The remaining 13 variants manifested residual activities ranging between 17% and 94% of control enzymatic activity. Our functional assay evaluating the effect of novel D2HGDH variants will be beneficial for the classification of missense variants and determination of pathogenicity.	0
Plasmodium falciparum malaria is classified as either uncomplicated or severe, determining clinical management and providing a framework for understanding pathogenesis. Severe malaria in children is defined by the presence of one or more features associated with adverse outcome, but there is wide variation in the predictive value of these features. Here we review the evidence for the usefulness of these features, alone and in combination, to predict death and other adverse outcomes, and we consider the role that molecular biomarkers may play in augmenting this prediction. We also examine whether a more personalized approach to predicting outcome for specific presenting syndromes of severe malaria, particularly cerebral malaria, has the potential to be more accurate. We note a general need for better external validation in studies of outcome predictors and for the demonstration that predictors can be used to guide clinical management in a way that improves survival and long-term health.	0
OBJECTIVE: Autoimmune hepatitis (AIH) is a chronic liver disease, which if untreated can lead to cirrhosis and hepatic failure. The aim of the study was to investigate the incidence, prevalence, diagnostic tradition and clinical initial presentation of AIH. MATERIAL AND METHODS: Analyses were performed in 473 patients identified as having probable or definite AIH. RESULTS: The incidence of AIH was 0.85/100,000 (95% CI 0.69-1.01) inhabitants, which is somewhat lower than reported previously. The point prevalence amounted to 10.7/100,000 (95% CI 8.8-13.1), and 76% of the cases were females. The age-related incidence curve was bimodal but men were found to have only one incidence peak in the late teens, whereas women had a peak after menopause. AIH was presented as a spectrum of clinical settings from detected "en passant" to acute liver failure. Almost 30% of patients already had liver cirrhosis at diagnosis. Autoantibodies indicative of AIH type 1 were found in 79% of cases. Other concomitant autoimmune diseases were frequently found (49%). CONCLUSIONS: The incidence and prevalence figures confirm that AIH is a fairly uncommon disease in the Swedish population. Symptoms at presentation were unspecific, but almost half of the patients were jaundiced, with around 30% having liver cirrhosis. The majority of Swedish AIH patients had AIH type 1.	1
Mouse models may provide an important tool for basic and applied research on human diseases. An ideal tumour model should replicate the phenotypic and molecular characteristics of human malignancy as well as the typical physiological effects and dissemination patterns. The histopathological and molecular genetic characterization of anaplastic plasmacytoma (APCT) in strain NSF.V(+) mice provides an example to achieve this goal for a specific lymphoma subtype. Firstly, it demonstrates that, like plasma-cell neoplasms in humans, those in mice occur as distinct subtypes. Secondly, it shows that mouse APCT exhibits striking parallels to possible human tumour counterparts for which good mouse models of de novo tumour development are sorely needed: IgM(+) multiple myeloma and Waldenström's macroglobulinaemia. Thirdly, it strongly suggests that insertional somatic mutagenesis, by either a murine leukaemia virus or an oncogenic transposon, would be an effective experimental approach to accelerating malignant transformation of mature B cells and plasma cells in mice and, thereby, tagging and uncovering cancer driver genes that may be of great relevance for the tumour initiation and progression in lymphoma.	0
Centronuclear myopathies (CNM) describe a group of rare muscle diseases typically presenting an abnormal positioning of nuclei in muscle fibers. To date, three genes are known to be associated to a classical CNM phenotype. The X-linked neonatal form (XLCNM) is due to mutations in MTM1 and involves a severe and generalized muscle weakness at birth. The autosomal dominant form results from DNM2 mutations and has been described with early childhood and adult onset (ADCNM). Autosomal recessive centronuclear myopathy (ARCNM) is less characterized and has recently been associated to mutations in BIN1, encoding amphiphysin 2. Here we present the first clinical description of intrafamilal variability in two first-degree cousins with a novel BIN1 stop mutation. In addition to skeletal muscle defects, both patients have mild mental retardation and the more severely affected male also displays abnormal ventilation and cardiac arrhythmia, thus expanding the phenotypic spectrum of BIN1-related CNM to non skeletal muscle defects. We provide an up-to-date review of all previous cases with ARCNM and BIN1 mutations.	0
Febrile ulceronecrotic Mucha-Habermann disease is a very rare and severe variant of pityriasis lichenoides et varioliformis acuta. Adult cases are difficult to diagnose as in the early course they can mimic erythema multiforme or lymphomatoid papulosis. We report a case of a 38-year-old woman who presented with 90% body surface area involvement, fever, diarrhea, malaise and associated comorbidities. She was treated with systemic steroids and methotrexate but suffered a fatal outcome. So far, a total of 65 cases are reported in the literature.	0
Non-small-cell lung cancer (NSCLC) is the main pathological type of lung cancer and has a low overall five-year survival rate. miR-187 has been reported to play major roles in various tumor types. In this study, we explored the impact of miR-187 on NSCLC. qRT-PCR results demonstrated that miR-187 expression is lower in NSCLC and cancer cells than normal tissues and normal lung cells. miR-187 expression levels are associated with tumor size, TNM stage and overall survival rate. MTS and colony formation assays showed that high miR-187 expression inhibits NSCLC cell proliferation and colony formation ability, and flow cytometry showed that miR-187 overexpression induces cell cycle arrest at the G0/G1 phase. A luciferase reporter assay showed that FGF9 is a target of miR-187. miR-187 overexpression reduces the expression of FGF9, cyclin D1 CDK4 and CDK6. Therefore, miR-187 may present a new NSCLC treatment target by regulates cyclins-related protein expression.	0
INTRODUCTION:X-linked adrenoleukodystrophy (X-ALD) encompasses several clinical and neuroimaging phenotypes, including cerebral X-ALD, the most common phenotype in children, and adrenomyeloneuropathy, the most common phenotype in adults. A spinocerebellar variant of X-ALD has been described in individuals from the Far East, but the criteria for its diagnosis are unclear. CASE REPORT:A 35-year-old man from Albania was assessed because of a familial, slowly progressive spastic-ataxic gait associated with neurogenic bladder, sexual dysfunctions, and manic-like behavior. There was no definite clinical feature that suggested cerebellar involvement (eg, cerebellar limb ataxia, nystagmus, and dysarthria). A few months earlier, he had received a diagnosis of Addison disease. Brain magnetic resonance imaging showed a leukoencephalopathy with predominant cerebellum and brainstem involvement, and FDG-PET revealed marked cerebellar hypometabolism. The diagnosis of X-ALD was made because we found an increase of very long chain fatty acids, and a new ABCD1 mutation (c.1627C>T, p.Pro543Ser). CONCLUSIONS:X-ALD should be included in the differential diagnosis of adult leukoencephalopathies with predominant involvement of infratentorial structures, that is, the cerebellum and brainstem. From a classification perspective, our patient (of white origin), like others (all of Asian origin), should be considered as suffering from a variant of adrenomyeloneuropathy rather than from spinocerebellar X-ALD. Actually, the term "spinocerebellar" or similar ones, such as "cerebello-brainstem dominant form," should be limited to those exceptional cases, in which both the clinical and neuroimaging findings point exclusively (or at least predominantly) to the involvement of infratentorial structures.	0
Trisomy 8 mosaicism is a relatively rare chromosomal abnormality and has extremely variable phenotype with a wide range of clinical manifestations. Although no well-defined criteria for cardiac surgical indications are available for patients with mosaic trisomy 8, we present a case of hypoplastic left heart syndrome with total anomalous pulmonary venous connection (TAPVC) in a neonate with mosaic trisomy 8. Although primary sutureless repair of TAPVC with concomitant bilateral pulmonary artery banding was performed successfully in this case, the indications for cardiac surgery in patients with mosaic trisomy 8 should be carefully individualized. The entire dialog with parents and family, including the process of informed consent, is of great importance.	0
The Senataxin (SETX) protein exhibits strong sequence conservation with the helicase domain of the yeast protein Sen1p, and recessive SETX mutations cause a severe ataxia, known as Ataxia with Oculomotor Apraxia type 2, while dominant SETX mutations cause Amyotrophic Lateral Sclerosis type 4. SETX is a very low abundance protein, and its expression is tightly regulated, such that large increases in mRNA levels fail to significantly increase protein levels. Despite this, transient transfection in cell culture can boost SETX protein levels on an individual cell basis. Here we found that over-expression of normal SETX, but not enzymatically-dead SETX, is associated with S-phase cell-cycle arrest in HEK293A cells. As SETX interacts with the nuclear exosome to ensure degradation of incomplete RNA transcripts, and SETX localizes to sites of collision between the DNA replication machinery and the RNAP II complex, altered dosage or aberrant function of SETX may impede this process to promote S-phase cell-cycle arrest. Because neurons are enriched for long transcripts with additional antisense regulatory transcription, collisions of RNAP II complexes may occur in such post-mitotic cells, underscoring a role for SETX in maintaining neuron homeostasis.	0
Absence of part or all of the iris, aniridia, is a feature of several genetically distinct conditions. This review focuses on iris development and then the clinical features and molecular genetics of these iris malformations. Classical aniridia, a panocular eye malformation including foveal hypoplasia, is the archetypal phenotype associated with heterozygous PAX6 loss-of-function mutations. Since this was identified in 1991, many genetic mechanisms of PAX6 inactivation have been elucidated, the commonest alleles being intragenic mutations causing premature stop codons, followed by those causing C-terminal extensions. Rarely, aniridia cases are associated with FOXC1, PITX2 and/or their regulatory regions. Aniridia can also occur as a component of many severe global eye malformations. Gillespie syndrome-a triad of partial aniridia, non-progressive cerebellar ataxia and intellectual disability-is phenotypically and genotypically distinct from classical aniridia. The causative gene has recently been identified as ITPR1. The same characteristic Gillespie syndrome-like iris, with aplasia of the pupillary sphincter and a scalloped margin, is seen in ACTA2-related multisystemic smooth muscle dysfunction syndrome. WAGR syndrome (Wilms tumour, aniridia, genitourinary anomalies and mental retardation/intellectual disability), is caused by contiguous deletion of PAX6 and WT1 on chromosome 11p. Deletions encompassing BDNF have been causally implicated in the obesity and intellectual disability associated with the condition. Lastly, we outline a genetic investigation strategy for aniridia in light of recent developments, suggesting an approach based principally on chromosomal array and gene panel testing. This strategy aims to test all known aniridia loci-including the rarer, life-limiting causes-whilst remaining simple and practical.	0
Few spatial ecological studies on selenoprotein P (SePP) and Keshan disease (KD) have been reported. The main objective of this study is to investigate the relationships of SePP with KD, economic indicators and soil selenium and to visualize the evidence for KD precise prevention and control. An ecological study design was employed. The serum SePP of 2351 subjects living in rural areas, general cities and developed cities in 15 KD endemic provinces and 13 KD non-endemic provinces in China were measured. Spatial description and spatial analysis of SePP were conducted. The subjects were adults aged. The mean serum SePP level of KD endemic area residents was 14.20 mg/L, significantly lower than that in non-endemic areas, 15.30 mg/L (t = - 3.19, P = 0.0010). Serum SePP levels were low among the people in the KD endemic provinces of Shandong, Inner Mongolia, Heilongjiang, etc. The mean serum SePP level of the 2351 people was 15.04 (95% CI: 14.76 and 15.31) mg/L. The mean serum SePP levels of residents in developed cities, general cities and rural areas were 16.54 mg/L, 14.98 mg/L and 14.44 mg/L, respectively, and were significantly different (F = 17.00, P < 0.0010). Spatial regression analysis showed that the spatial distribution of SePP was positively correlated with per capita consumption expenditure and soil selenium. Selenium deficiency may still exist among residents living in the KD endemic provinces. Shandong, Inner Mongolia, and Heilongjiang should be the target provinces, visualized by spatial analysis, for KD precise prevention and control.	0
Cowden syndrome is extremely rare and is characterized by multiple hamartomas in various tissues, including the skin, mucous membranes, gastrointestinal tract, breast, thyroid, and brain, and has an increased risk of breast, thyroid, and uterine cancers. Here, we report a case of Cowden syndrome diagnosed following presentation with bilateral breast cancer and provide a discussion of the relevant literature. A 47-year-old woman with a tumor in her right breast was referred to our hospital. She was diagnosed with bilateral breast cancer upon imaging and underwent a bilateral mastectomy and sentinel lymph node biopsy. Previously, she had undergone total thyroidectomy to treat a thyroid tumor. Approximately 3 years later, she was diagnosed with Lhermitte-Duclos disease affecting her left cerebellar hemisphere. As her sister and mother had also been diagnosed with breast cancer, we suspected that she might have an inherited disease. Since 80% of individuals with Cowden syndrome have a mutation in the phosphatase and tension homolog (PTEN) gene, we did not perform any genetic testing. Instead, we used the syndrome's pathognomonic criteria and major criteria (breast cancer, thyroid tumor, and Lhermitte-Duclos disease) to diagnose our patient with Cowden syndrome. While treatment of Cowden syndrome is currently limited to strategies that can manage the symptoms, patients are at an increased risk of certain cancers and require regular screening to allow for early detection of disease.	0
Collagen type IV, alpha-1 (COL4A1) variants can cause cerebrovascular diseases, such as porencephaly and cerebral hemorrhage, in addition to other autosomal dominant hereditary diseases. Patients with COL4A1 variants can present with epilepsy, most commonly focal epilepsy. In this paper, we present five patients, three of whom were examined by the authors, and two who were previously reported. Clinically, these five patients were characterized by the presence of West syndrome (WS), periventricular leukomalacia (PVL), and microcephaly, but none had a history of premature birth or hypoxic ischemic encephalopathy (HIE). Genetic testing results indicated that all patients had heterozygous variants of COL4A1. Genetic testing for the COL4A1 variants should be considered when a patient without a history of prematurity or HIE develops WS with PVL and microcephaly.	0
Lactose is the main source of calories in milk, an essential nutriedigestion, patients with visceral hypersensitivity nt in infancy and a key part of the diet in populations that maintain the ability to digest this disaccharide in adulthood. Lactase deficiency (LD) is the failure to express the enzyme that hydrolyses lactose into galactose and glucose in the small intestine. The genetic mechanism of lactase persistence in adult Caucasians is mediated by a single C→T nucleotide polymorphism at the LCTbo -13'910 locus on chromosome-2. Lactose malabsorption (LM) refers to any cause of failure to digest and/or absorb lactose in the small intestine. This includes primary genetic and also secondary LD due to infection or other conditions that affect the mucosal integrity of the small bowel. Lactose intolerance (LI) is defined as the onset of abdominal symptoms such as abdominal pain, bloating and diarrhoea after lactose ingestion by an individual with LM. The likelihood of LI depends on the lactose dose, lactase expression and the intestinal microbiome. Independent of lactose digestion, patients with visceral hypersensitivity associated with anxiety or the Irritable Bowel Syndrome (IBS) are at increased risk of the condition. Diagnostic investigations available to diagnose LM and LI include genetic, endoscopic and physiological tests. The association between self-reported LI, objective findings and clinical outcome of dietary intervention is variable. Treatment of LI can include low-lactose diet, lactase supplementation and, potentially, colonic adaptation by prebiotics. The clinical outcome of these treatments is modest, because lactose is just one of a number of poorly absorbed carbohydrates which can cause symptoms by similar mechanisms.	0
CASE:Two firefighters developed Parsonage-Turner syndrome (PTS) shortly after sustaining episodes of heat stroke. Patient 1 was a 40-year-old man who presented with shoulder pain and supraspinatus and infraspinatus weakness. Patient 2 was a 35-year-old man who presented with shoulder pain and absent external rotation strength. Both had electrodiagnostic testing and magnetic resonance imaging findings consistent with PTS. Both demonstrated partial but incomplete recovery at 1- and 2.5-year follow-ups, respectively. CONCLUSIONS:PTS should remain on the differential diagnosis for any patient presenting with sudden onset shoulder pain and neurological deficits after an episode of heat-related illness.	0
Poorly controlled diabetes mellitus leads to several comorbidities, including susceptibility to infections. Hyperglycemia increases phagocyte responsiveness, however immune cells from people with diabetes show inadequate antimicrobial functions. We and others have shown that aberrant production of leukotriene B4 (LTB4) is detrimental to host defense in models of bacterial infection. Here, we will unveil the consequences of high glucose in the outcome of Leishmania braziliensis skin infection in people with diabetes and determine the role of LTB4 in human phagocytes. We show that diabetes leads to higher systemic levels of LTB4, IL-6 and TNF-α in cutaneous leishmaniasis. Only LTB4 correlated with blood glucose levels and healing time in diabetes comorbidity. Skin lesions of people with leishmaniasis and diabetes exhibit increased neutrophil and amastigote numbers. Monocyte-derived macrophages from these individuals showed higher L. braziliensis loads, reduced production of Reactive Oxygen Species and unbalanced LTB4/PGE2 ratio. Our data reveal a systemic inflammation driven by diabetes comorbidity in opposition to a local reduced capacity to resolve L. braziliensis infection and a worse disease outcome.	0
Next-generation sequencing has enabled patient selection for targeted drugs, some of which have shown remarkable efficacy in cancers that have the cognate molecular signatures. Intriguingly, rapidly emerging data indicate that altered genes representing oncogenic drivers can also be found in sporadic non-malignant conditions, some of which have negligible and/or low potential for transformation to cancer. For instance, activating KRAS mutations are discerned in endometriosis and in brain arteriovenous malformations, inactivating TP53 tumor suppressor mutations in rheumatoid arthritis synovium, and AKT, MAPK, and AMPK pathway gene alterations in the brains of Alzheimer's disease patients. Furthermore, these types of alterations may also characterize hereditary conditions that result in diverse disabilities and that are associated with a range of lifetime susceptibility to the development of cancer, varying from near universal to no elevated risk. Very recently, the repurposing of targeted cancer drugs for non-malignant conditions that are associated with these genomic alterations has yielded therapeutic successes. For instance, the phenotypic manifestations of CLOVES syndrome, which is characterized by tissue overgrowth and complex vascular anomalies that result from the activation of PIK3CA mutations, can be ameliorated by the PIK3CA inhibitor alpelisib, which was developed and approved for breast cancer. In this review, we discuss the profound implications of finding molecular alterations in non-malignant conditions that are indistinguishable from those driving cancers, with respect to our understanding of the genomic basis of medicine, the potential confounding effects in early cancer detection that relies on sensitive blood tests for oncogenic mutations, and the possibility of reverse repurposing drugs that are used in oncology in order to ameliorate non-malignant illnesses and/or to prevent the emergence of cancer.	0
BACKGROUND:Cold-induced urticaria is a kind of physical urticaria characterized by the appearance of wheals after exposure to cold. The atypical form is a rare sub-type characterized by appearance of hives even in areas not directly exposed to the cold and by a negative cold stimulation test. Its diagnosis is often challenging because of the lack of specific tests and it is usually based on the patient's clinical history. Hypotension due to generalized exposure to the cold is described both in the typical and the atypical forms. CASE PRESENTATION:We describe a 9-year-old boy who, at the beginning of the summer after the first swim in the sea, developed generalized urticaria, dyspnea, conjunctival hyperemia, blurred vision and loss of strength. The child was treated with intramuscular steroid and intravenous antihistamine, and the symptoms quickly resolved. Insect bite, contact with fish and drug ingestion were denied, and no unusual food had been eaten before the swim. A tentative diagnosis was made of either aquagenic urticaria or cold urticaria, but the specific tests were negative. Although the cause was unknown, prophylactic treatment with antihistamines was prescribed but in spite of this, wheals developed all over the body, after every swim in the sea. The child then came to our attention and relying on clinical history a diagnosis of atypical cold urticaria was made: development of hives even in areas not directly exposed to cold and a negative response to the cold stimulation test, are the characteristic features of this rare form of cold urticaria. CONCLUSION:Atypical cold urticaria should be suspected in all cases of anaphylaxis related to cold exposure (i.e. contact with water) with a negative cold stimulation test.	0
Oculocutaneous albinism type 1 (OCA1) is an autosomal recessive disorder caused by mutations in the tyrosinase gene. Two subtypes of OCA1 have been described: severe OCA1A with complete absence of tyrosinase activity and less severe OCA1B with residual tyrosinase activity. Here, we characterize the recombinant human tyrosinase intramelanosomal domain and mutant variants, which mimic genetic changes in both subtypes of OCA1 patients. Proteins were prepared using site-directed mutagenesis, expressed in insect larvae, purified by chromatography, and characterized by enzymatic activities, tryptophan fluorescence, and Gibbs free energy changes. The OCA1A mutants showed very low protein expression and protein yield and are enzymatically inactive. Mutants mimicking OCA1B were biochemically similar to the wild type, but exhibited lower specific activities and protein stabilities. The results are consistent with clinical data, which indicates that OCA1A mutations inactivate tyrosinase and result in severe phenotype, while OCA1B mutations partially inactivate tyrosinase and result in OCA1B albinism.	0
Reconstituted high density lipoprotein (rHDL) has been regarded as a promising brain-targeting vehicle for anti-glioma drugs under the mediation of apolipoprotein A-I (apoA-I). However, some stability issues relating to drug leakage and consequent reduced targeting efficiency in the course of discoidal rHDL (d-rHDL) circulating in blood hinder its broad application. The objective of the study was to develop a novel stabilized d-rHDL by replacing cholesterol and apoA-I with mono-cholesterol glutarate (MCG) modified apoA-I (termed as mA) and to evaluate its allosteric behavior and glioma targeting. MCG was synthesized through esterifying the hydroxyl of cholesterol with glutaric anhydride and characterized by FI-IR and 1H NMR. d-rHDL assembled with mA (termed as m-d-rHDL) presented similar properties such as minute particle size and disk-like appearance resembling nascent HDL. Morphological transformation observation and in vitro release plots convinced that the modification of cholesterol could effectively inhibit the remolding of d-rHDL. The uptake of m-d-rHDL by LCAT-pretreated bEND.3 cells was significantly higher than that of d-rHDL, thereby serving as another proof for the capability of m-d-rHDL in enhancing targeting property. Besides, apoA-I anchoring into m-d-rHDL played a critical role in the endocytosis process into bEND.3 cells and C6 cells, which implied the possibility of traversing blood brain barrier and accumulating in the brain and glioma. These results suggested that the modification toward cholesterol to improve the stability of d-rHDL is advantageous, and that this obtained m-d-rHDL revealed great potential for realization of suppressing the remolding of d-rHDL in the brain-targeted treatment of glioma for drug delivery.	0
Bi-allelic variants in the subunits of the adaptor protein complex 4 lead to childhood-onset, complex hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1), and SPG52 (AP4S1). Here, we describe the generation of induced pluripotent stem cells (iPSCs) from three AP-4-HSP patients with compound-heterozygous, loss-of-function variants in AP4B1 and sex-matched parents. Fibroblasts were reprogrammed using non-integrating Sendai virus. iPSCs were characterized according to standard protocols including karyotyping, embryoid body formation, pluripotency marker expression and STR profiling. These first iPSC lines for SPG47 provide a valuable resource for studying this rare disease and related forms of hereditary spastic paraplegia.	0
Subependymal nodular heterotopia (SNH) is a cortical development malformation that is commonly associated with medically resistant epilepsy. Cases of SNH are challenging to treat surgically because there are typically multiple nodules, which may be involved in epileptogenesis. Moreover, dual pathology may exist in these patients. Here, we present a case with unilateral subependymal heterotopic nodules associated with ipsilateral hippocampal atrophy. Invasive and non-invasive work-ups revealed that the hippocampus was the actual ictal onset zone and that the SNH was not involved. An anterior temporal lobectomy was carried out, and postoperative seizure outcome was class Ia at the end of 2 years. The case demonstrates that SNH may not play a major role in patients with dual pathology. However, direct electroencephalography (EEG) recording from areas of SNH and other possible epileptogenic regions is indispensable in defining the ictal onset zone and avoiding poor surgical outcomes.	0
Propionic acidemia [MIM 606054] is a form of organic acidemia caused by genetic deficiency of propionyl-CoA carboxylase (PCC) and characterized by attacks of severe metabolic acidemia and hyperammonemia beginning in the neonatal period or in early infancy. There are, however, patients who have higher PCC activities and present later with unusual symptoms, such as mild mental retardation or extrapyramidal symptoms, sometimes even without metabolic acidosis. Through the neonatal screening of more than 130,000 Japanese newborns we detected a frequency of patients with propionic acidemia more than ten times higher than previously reported, most of them with milder phenotypes. The mutational spectrum was quite different from that of patients with the severe form and there was a common mutation (Y435C) in the beta subunit of the PCC gene (PCCB). Since patients with the mild form could present with unusual symptoms and therefore could easily remain unrecognized, it is important to identify those patients and clarify their natural history. Molecularly, one of the mutations (A1288C) caused an unusual pattern of multiple exon skipping and another unidentified mutation lead to the absence of mRNA. Taking into consideration previous findings regarding PCCB mutations, it appears that this gene is particularly prone to posttranscriptional modifications such as missense mediated exon skipping, mRNA decay, or rapid product degradation.	1
Background:The maxillofacial and dental manifestations of Osteogenesis imperfecta (OI) have significant implications in terms of management. Although the occurrence of abnormal dentine in some forms of OI is well documented, there is scant information on the association of abnormal dentine in the Black African persons with phenotypic OI III and genotypic OI XI in South Africa. Methods:This was a cross-sectional analytic study. A series of 64 Black South African individuals with a confirmed phenotypic diagnosis of OI III, ages ranging from 3 months to 29 years, were assessed clinically, radiographically, and at a molecular level. Results:A total number of 64 saliva samples were analyzed and 3 DNA variations were identified in exon 5 of the FKBP10 gene. The homozygous mutation, c.[831dupC]; [831dupC], was identified in 23 affected persons who had no clinically obvious features of DI in their primary and secondary teeth. Radiologically, mild features of DI were evident in 10 persons in whom radiographic images were obtained and were given a Clinical-radiological score of 2. A compound heterozygous mutation, c. [831delC]; [831dupC], was identified in three siblings. An intraoral examination of these affected persons revealed no clinically apparent features of DI in their primary and secondary teeth. Due to the lack of radiological facilities, the presence or absence of DI could not be confirmed or negated. A second compound heterozygous mutation, c.[831dupC]; [1400-4C>G], was identified in a female of 29 years belonging to the Xhosa linguistic group. Her teeth appeared clinically normal but it was not possible to obtain radiographs. In 37 affected individuals, no disease-causing mutations were identified. Conclusion:Black African individuals in SA with the homozygous mutation in the FKBP10 gene have clinically unaffected teeth yet exhibited radiographic features of DI to varying degrees. This characterization is suggestive of a relationship between the genetic abnormality and the clinical manifestations of DI. The authors suggest that this diagnosis must include teeth that are clinically and/or radiologically aberrant, and should not exclude the presence of other, milder, dentinal aberrations associated with OI. There was no correlation between severity of OI and DI in this cohort of individuals.	0
Retinitis pigmentosa is the most common blinding inherited retinal dystrophy. Gene therapy is a burgeoning revolutionary approach that paves the way to treatment of previously incurable diseases. At the end of 2017 and 2018, a gene therapy, Luxturna®, obtained a marketing authorization by respectively the FDA (Food and Drug Administration) and the EMA (European Medicines Agency). This treatment, with proven efficacy, is available to patients with Leber congenital amaurosis and retinitis pigmentosa associated with bi-allelic mutations of the RPE 65 gene. In this paper, we present the current advances in gene therapy for retinitis pigmentosa and discuss the technological, economic and ethical challenges to overcome for gene therapy to improve medical practices.	0
Waardenburg syndrome (WS) is an auditory-pigmentary disease characterized by a clinical and genetic variability. WS is classified into four types depending on the presence or absence of additional symptoms: WS1, WS2, WS3 and WS4. Type 1 and 3 are mostly caused by PAX3 mutations, while type 2 and type 4 are genetically heterogeneous. The aims of this study are to confirm the diagnostic of WS1 by the sequencing of PAX3 gene and to evaluate the genotype phenotype correlation. A clinical classification was established for 14 patients WS, as proposed by the Waardenburg Consortium, and noted a predominance of type 1 and type 2 with 6 patients WS1, 7 patients WS2 and 1 patient WS3. A significant inter and intra-familial clinical heterogeneity was also observed. A sequencing of PAX3 gene in the 6 patients WS1 confirmed the diagnosis in 4 of them by revealing three novel mutations that modify two functional domains of the protein: the c.942delC; the c.933_936dupTTAC and the c.164delTCCGCCACA. These three variations are most likely responsible for the phenotype, however their pathogenic effects need to be confirmed by functional studies. The MLPA analysis of the 2 patients who were sequence negative for PAX3 gene revealed, in one of them, a heterozygous deletion of exons 5 to 9 confirming the WS1 diagnosis. Both clinical and molecular approaches led to the conclusion that there is a lack of genotype-phenotype correlation in WS1, an element that must be taken into account in genetic counseling. The absence of PAX3 mutation in one patient WS1 highlights the fact that the clinical classification is sometimes insufficient to distinguish WS1 from other types WS hence the interest of sequencing the other WS genes in this patient.	0
Chromosome 10p terminal deletions have been associated with a DiGeorge like phenotype. Haploinsufficiency of the region 10p14-pter, results in hypoparathyroidism, sensorineural deafness, renal anomaly, that is the triad that features the HDR syndrome. Van Esch (2000) identified in a HDR patient, within a 200 kb critical region, the GATA3 gene, a transcription factor involved in the embryonic development of the parathyroids, auditory system and kidneys. We describe a new male patient, 33-year-old, with 10p partial deletion affected by hypocalcemia, basal ganglia calcifications and a severe autistic syndrome associated with mental retardation. Neurologically he presented severe impairment of language, hypotonia, clumsiness and a postural dystonic attitude. A peripheral involvement of auditory pathways was documented by auditory evoked potentials alterations. CT scan documented basal ganglia calcifications. Hyperintensity of the lentiform nuclei was evident at the MRI examination. Renal ultrasound scan was normal. Haploinsufficiency for GATA3 gene was documented with FISH analysis using cosmid clone 1.2. Phenotypic spectrum observed in del (10p) is more severe than the classical DGS spectrum. GATA3 has been found to regulate the development of serotoninergic neurons. A serotoninergic dysfunction may be linked with autism in this patient.	0
The epidemiology of immune thrombocytopenia (ITP) is not well known. The purpose of this study was to assess ITP incidence at a nationwide level (France) with recent data (mid-2009 to mid-2011; 129 248 543 person-years). The data source is the French health insurance database. We selected cases with diagnosis codes for in-hospital stays and long-term disease attributions, thus restricting our search to ITPs necessitating health care. We studied incidence by age, gender, calendar month, regions, and proportion of secondary ITPs, of ITPs becoming persistent or chronic, and of severe bleeding at disease onset. We identified 3771 incident ITP patients. Incidence was 2.9/100,000 person-years, with peaks among children and in those >60 years of age. ITP was more frequent among males in these subgroups. The incidence was lower in overseas Caribbean French departments, suggesting a lower incidence among Afro-American people. There was a north-south gradient in mainland France and seasonal variations (peak in winter and nadir in summer). Persistence or chronicity occurred in 36% of children compared with 67% of adults. Among adults, 18% of ITPs were secondary. Malignancy was the main cause (10.9%). Myelodysplastic syndromes were not rare (2.3%). Severe gastrointestinal or central nervous system bleeding at ITP onset was rare (<1%).	1
BACKGROUND:Abnormally increased immune activation is one of the main pathological features of acquired immunodeficiency syndrome (AIDS). This study aimed to determine whether long-term nonprogression (LTNP) suppresses the upregulation of immune activation and to elucidate the mechanisms whereby the LTNP state is maintained. METHODS:For this study we selected 4 rhesus macaques(RMs) infected with simian immunodeficiency virus (SIV) that were long-term nonprogressors (LTNP); for comparison we chose 4 healthy RMs that were seronegative for SIV (hereafter referred to as the Control group), and 4 progressing infection (Progressive group) SIV RMs. We observed these animals for 6 months without intervention and explored the immunological and pathological differences among the 3 groups. A series of immune activation and inflammation markers-such as C- C chemokine receptor type 5 (CCR5), beta 2- microglobulin (β2-MG), Human Leukocyte Antigen - antigen D Related (HLA-DR), CD38, the levels of microbial translocation (LPS -binding protein), and MAVS-and histological features were monitored during this period. RESULTS:Both SIV RNA and SIV DNA in the plasma and lymph nodes (LNs) of the LTNP group were at significantly lower levels than those of the Progressive group (P < 0.05). The CD4/CD8 ratio and CD4 cell count and proportion in the LTNP group were between those of the Progressive and Control groups (P < 0.05): that is, they were higher than in the Progressive group and lower than in the Control group. The LTNP macaques manifested slow progression and decreased immune activation and inflammation; they also had lower levels of CCR5, LPS-binding protein, and β2-MG than the Progressive RMs (P < 0.05). Activation of LTNP in both CD4+ and CD8+ T cells was significantly lower than in the Progressive group and closer to that in the Control group. The histological features of the LTNP macaques were also closer to those of the Control group, even though they had been infected with SIV 4 years earlier. These data point to low viral replication in the LTNP macaques but it is not static. The expression of MAVS in peripheral blood and LNs was lower in the LTNP group than that in the Progressive group (P < 0.01), and MAVS was positively correlated with SIV DNA in LNs (P < 0.05). This may reflect the low activation of T lymphocytes. It was speculated that MAVS may be the link between innate and acquired antiviral immunity in SIV infection. CONCLUSIONS:The LTNP RMs in our study were in a relatively stable state of low activation and inflammation, some biological progression with no disease events. This may have been associated with their low levels of the mitochondrial antiviral signaling protein (MAVS).	0
Spondylocarpotarsal synostosis syndrome (SCTS) is characterized by intervertebral fusions and fusion of the carpal and tarsal bones. Biallelic mutations in FLNB cause this condition in some families, whereas monoallelic variants in MYH3, encoding embryonic heavy chain myosin 3, have been implicated in dominantly inherited forms of the disorder. Here, five individuals without FLNB mutations from three families were hypothesized to be affected by recessive SCTS on account of sibling recurrence of the phenotype. Initial whole-exome sequencing (WES) showed that all five were heterozygous for one of two independent splice-site variants in MYH3. Despite evidence indicating that three of the five individuals shared two allelic haplotypes encompassing MYH3, no second variant could be located in the WES datasets. Subsequent genome sequencing of these three individuals demonstrated a variant altering a 5' UTR splice donor site (rs557849165 in MYH3) not represented by exome-capture platforms. When the cohort was expanded to 16 SCTS-affected individuals without FLNB mutations, nine had truncating mutations transmitted by unaffected parents, and six inherited the rs557849165 variant in trans, an observation at odds with the population allele frequency for this variant. The rs557849165 variant disrupts splicing in the 5' UTR but is still permissive of MYH3 translational initiation, albeit with reduced efficiency. Although some MYH3 variants cause dominant SCTS, these data indicate that others (notably truncating variants) do not, except in the context of compound heterozygosity for a second hypomorphic allele. These observations make genetic diagnosis challenging in the context of simplex presentations of the disorder.	0
Complete androgen insensitivity syndrome is a rare condition, wherein a genetic male is phenotypically female and is raised as a female. Treatement requires timely gonadectomy, need for long term hormonal replaceent therapy, psycological and genetic counseling. The type, dose, duration of hrt is not well studied. Reproductive issues also need to be addressed in these young woman. We report here a case of complete androgen insensitivity which posed a quandary for management of long term bone health. Review of literature for management is discussed. These cases are best managed by a multi-disciplenary team comprising of gynecologist, geneticist, endocrinologist and clinical psycologist or psychiatrist.	0
Erythema nodosum (EN) is the most frequent panniculitis, and although it can be idiopathic, it presents multiple causal processes. We made a retrospective, observational and descriptive study about causes of EN in patients admitted to a third-level Spanish hospital over a period of 11 years, and we compared the results obtained with those published in other studies. We compared the analytical markers of inflammation between inflammatory and non-inflammatory causes of EN. The final cohort was composed by 52 patients, with 20% of idiopathic cases, 34% of cases secondary to infections and another 34% of cases secondary to autoimmune diseases. There were no cases secondary to drugs or lymphomas. We did not observe significant differences in the analytical parameters of inflammation between inflammatory or non-inflammatory cause of EN.	0
BACKGROUND:Tetrasomy 18p is a rare disorder. It is known to affect about 250 families worldwide. Tetrasomy 18p is also the most common type of isochromosome. Here we report a de novo tetrasomy 18p. METHODS:The copy number variation of the patient was detected by microarray. Whether the abnormal gene was inherited from the parents was detected by karyotype analysis. Then the source of the chromosome was located by fluorescence in situ hybridization. Finally, we used MLPA technology to validate the results of patient testing. RESULTS:Microarray detection found that patients with 18p11.32p11.21 had duplication, with a copy number of four, which was tetrasomy 18 syndrome. The karyotype results showed 48,XY,+2mar?. Chromosome 18 telomere probe FISH experimental results: 48,XY,+i(18)(p10),+mar.ish. MLPA results showed that the number of chromosome 18 short arm copies is increased. Karyotype analysis results of his mother were 47,XX,+mar. Microarray results showed normal. Karyotype results of his father were normal. CONCLUSIONS:This case is de novo case, the patient's marker chromosome may be inherited from his mother, which does not rule out the influence of his mother's marker chromosome on his isochromosome 18.	0
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disease. First respiratory symptoms already occur within the first hours after birth. Major symptoms are an unexplained neonatal respiratory distress syndrome, situs inversus, persistant cough, and chronic nasal congestion, recurrent paranasal sinus disorders with or without polyps, bronchiectasis as well as male infertility. Diagnostics is complex and includes transmission electron microscopy, nasal NO assessment, high-speed video microscopy and genetic evaluations. This review gives an overview over the current diagnostic procedures and therapeutic options. The management of PCD is a multidisciplinary approach, which should be reserved to in highly specialized centers.	0
The prevalence of myotonic dystrophy (MyD) in the Saguenay-Lac-Saint-Jean (SLSJ) region (Quebec, Canada) is 30 to 60 times the world's prevalence. We identified 746 patients (673 still alive) distributed in 88 families. Using a population-based register of the SLSJ area and several marriage repositories from northeastern Quebec, we could trace back all patients to a couple who settled in "Nouvelle-France" in 1657. The MyD gene was then passed on over 10 to 14 generations. This genealogical reconstruction is a strong argument in favor of the genetic homogeneity of MyD in the SLSJ region.	1
Primary cilia are microtubule-based cellular structures located on the surfaces of most mammalian cells and play important roles in detecting external stimuli, signal transduction, and cell cycle regulation. Primary cilia are also present in several structures of the eye, and their abnormal development or dysfunction can cause various ocular diseases. The rapid development of proteomics and metabolomics technologies have helped in the identification of many ocular disease-related proteins, some of which are dysregulated in primary cilia. This review focuses on ciliary dysregulation in a number of ocular diseases and discusses the potential of targeting primary cilia in gene and stem cell therapy for these diseases.	0
OBJECTIVES: Mixed connective tissue disease (MCTD) is an immune-mediated, systemic disorder of unknown aetiology. As the epidemiology of the disease is largely unknown, the authors performed a nationwide cross-sectional retrospective study to assess the prevalence and incidence of MCTD in Norway. METHODS: Every adult patient (≥ 18 years) with MCTD seen at one of the departments of rheumatology was reviewed for inclusion. Only patients who satisfied the following four criteria were included: clinical diagnosis of MCTD verified by a rheumatologist; positive serum anti-ribonucleoprotein antibody test; fulfilment of at least one of three of following criteria sets: the modified Sharp's criteria, the criteria of Alarcón-Segovia and Villareal and those of Kasukawa; and exclusion of other connective tissue diseases. RESULTS: The four inclusion criteria were fulfilled by 147 adult Caucasian patients. The female to male ratio was 3.3 and the mean age at diagnosis of adult-onset MCTD was 37.9 years (95% CI 35.3 to 40.4 years). At the end of 2008, the point prevalence of living adult MCTD patients in Norway was 3.8 (95% CI 3.2 to 4.4) per 100,000 adults. The incidence of adult-onset MCTD in Norway during the period from 1996 to 2005 was 2.1 (95% CI 1.7 to 2.5) per million per year. CONCLUSIONS: MCTD has a female predominance and the incidence and prevalence of MCTD is low, and lower than reported figures for polymyositis, dermatomyositis, systemic sclerosis and systemic lupus erythematosus. The prevalence estimates were similar across the three criteria sets of MCTD.	1
We describe a unique case of skeletal and extraskeletal angiomatosis complicated by Kasabach-Merritt syndrome. The patient was a 3-year-old boy, who presented with involvement of both femurs and left tibia, as well as with soft tissue lesions of the left thigh. At birth, multiple hemangiomas of the soft tissues of the frontal and parietal scalp had been identified, together with a space-occupying lesion of the lung. Histologically, the skeletal and soft tissue lesions consisted of a proliferation of thin-walled, dilated blood vessels, with an endothelial lining devoid of atypia and exhibiting immunoreactivity for CD31 and CD34, while podoplanin and GLUT1 were negative. Whole exome sequencing performed on samples from the lesion of the femur, the tibia and the skin of the thigh, showed a GNAQ (c.286A>T:p.T96S) variant in all specimens, that was confirmed with digital droplet PCR. This case expands the clinical and pathologic spectrum of vascular proliferations showing similar molecular biology, characterized by GNAQ, GNA11 or GNA14 mutations.	0
This review concentrates on the definition and classification of degenerative movement disorders in which Parkinsonian symptoms are often prominent. The pathological spectrum and clinical manifestations of Lewy body disease are described, and associations with Alzheimer's disease and motor neuron disease are explored. A classification of pallidonigral degenerations is based on clinical features, distribution of pathology, and morphological abnormalities; some of these patients have mild nigral degeneration and no Parkinsonian features. Many other juvenile and familial Parkinsonian cases are not included among the pallidonigral degenerations. Most of these latter syndromes have been organised into preliminary groups, in particular, autosomal dominant dystonia-Parkinson syndrome, juvenile Parkinsonian disorder and autosomal dominant Lewy body disease.	0
BACKGROUND:Interstitial deletions of 2q are rare. Those that have been reported show varying clinical manifestations according to the size of the deletion and the genomic region involved. METHOD AND RESULTS:We describe a preterm male harboring a novel interstitial deletion encompassing the 2q21.2-q23.3 region of 2q, a deletion that has not been described previously. The patient had multiple congenital anomalies including agenesis of the corpus callosum, congenital cardiac defects, bilateral hydronephrosis, spontaneous intestinal perforation, hypospadias and cryptorchidism, sacral dimple and rocker-bottom feet. Array comparative genomic hybridization (aCGH) analysis revealed a de novo >18 Mb deletion at 2q21.1-q23.3, a region that included (605802, 611472 and 604593) OMIM genes. CONCLUSION:To the best of our knowledge this is the first report of a de novo interstitial deletion at 2q21.1-q23.3 in which haploinsufficiency of dose-sensitive genes is shown to contribute to the patient's phenotype.	0
INTRODUCTION: We present the study of the clinical and epidemiological characteristics of Brachmann-de Lange syndrome in our population. PATIENTS AND METHODS: In this study we present the analysis of 13 cases of Brachmann-de Lange syndrome identified among 24,696 infants with congenital defects registered by the Spanish Collaborative Study of Congenital Malformations (ECEMC) between April 1976 and June 1996. RESULTS: The minimum estimation of the prevalence in our population is 0.97 per 100,000 live births. We have epidemiologically confirmed the presence of intrauterine growth retardation and have observed that parental ages tend to be relatively young. We have observed a wide range of clinical expression of this syndrome. One hundred percent of our cases have limb reduction defects, followed in frequency by craniofacial alterations (84.62%), abnormal hair distribution (76.92%) and genital defects (69.23%). Upper limbs are predominantly affected and one case of diaphragmatic hernia is worth mentioning. We underline the importance of the differential diagnosis with Fryns'syndrome. CONCLUSIONS: The cases studied correspond to the most severe form of the syndrome, reason for which the prevalence is a minimal estimate. However, the mild forms of the syndrome are more frequent and it is important to consider that the face, especially the form of the eyebrow, could be a good guide for the diagnosis of mild forms of the syndrome.	1
A 39 year old male with multiple dysmorphic features was found to have an unstable ring chromosome 7. Clinical findings are presented and compared with the other five reported cases of ring chromosome 7. The main characteristics found in patients with this chromosome constitution are prenatal onset growth deficiency, bone anomalies, pigmentary or vascular skin changes, and ocular and genital anomalies.	0
Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) may cause whole-brain functional changes due to mitochondrial dysfunction. Our purpose is to comprehensively evaluate the alterations of spontaneous brain activity in MELAS patients at stroke-like episodes (SLE) attack and remission stages using resting-state functional magnetic resonance imaging. Forty MELAS patients at attack stage (n = 20) and remission stage (n = 20) and 22 healthy controls were enrolled in this study. We suggested that MELAS patients presented decreased spontaneous brain activities beyond the areas of stroke-like lesions (SLLs), with a downward trend from SLE attack stage to remission stage. In addition, the regional spontaneous activity of SLL, an inherent change in MELAS, was less than that in unaffected areas. Furthermore, the fractional amplitude of low frequency fluctuations value in left precuneus may be used as a promising neuroimaging biomarker for monitoring the disease status of MELAS.	0
Parkinson disease (PD) is a chronic neurodegenerative condition that leads to progressive disability. PD-related reductions in muscle strength have been reported to be associated with lower functional performance and balance confidence with an increased risk of falls. Progressive resistance training (PRT) improves strength, balance, and functional abilities. This umbrella review examines the efficacy of PRT regarding muscular strength in PD patients. The PubMed, PEDro, Scopus, and Cochrane Library databases were searched from January 2009 to August 2019 for systematic reviews and meta-analyses conducted in English. The populations included had diagnoses of PD and consisted of males and females aged >18 years old. Outcomes measured were muscle strength and enhanced physical function. Eight papers (six systematic reviews and meta-analyses and two systematic reviews) were considered relevant for qualitative analysis. In six of the eight studies, the reported severity of PD was mild to moderate. Each study analyzed how PRT elicited positive effects on muscle strength in PD patients, suggesting 10 weeks on average of progressive resistance exercises for the upper and lower limbs two to three times per week. However, none of the studies considered the postworkout follow-up, and there was no detailed evidence about the value of PRT in preventing falls. The possibility of PRT exercises being effective for increasing muscle strength in patients with PD, but without comorbidities or severe disability, is discussed. Overall, this review suggests that PRT should be included in rehabilitation programs for PD patients, in combination with balance training for postural control and other types of exercise, in order to preserve cardiorespiratory fitness and improve endurance in daily life activities.	0
Stüve-Wiedemann syndrome is a rare autosomal recessive disorder characterized by bowed long bones, joint restrictions, dysautonomia, and respiratory and feeding difficulties, leading to death in the neonatal period and infancy in several occasions. Since the first cases in 1971, much has been learned about this condition, including its molecular basis - mutations in the leukemia inhibitory factor receptor gene (LIFR) -, natural history and management possibilities. This review aims to highlight the clinical aspects, radiological features, molecular findings, and management strategies in Stüve-Wiedemann syndrome.	0
Objective:We detailed the electrophysiological patterns of peripheral nerve temporal dispersion across spectrum of POEMS syndrome and Castleman disease (CD). Methods:Compound muscle action potentials (CMAP) duration of 3 patients with POEMS syndrome and 2 with hyaline vascular type CD without clonal plasma cell dyscrasia were retrospectively analysed. Results:Median and ulnar nerves distal CMAP duration were prolonged in all patients irrespective of plasma cell dyscrasia or M protein. All lower limbs distal CMAP responses were absent. Greatest distal CMAP duration prolongation was observed in median nerves for POEMS syndrome (17.0 ms, 158% upper limit normal) and in ulnar nerves for CD (9.8 ms, 47% upper limit normal). Distal/proximal CMAP duration ratio of <0.7 were seen in 33% of median and ulnar nerves studied among POEMS syndrome. Among nerves with ratio >0.7, all had distal CMAP duration prolongation (Range 7%-158% of upper limit normal). Conclusions:Abnormal distal CMAP dispersion is not uncommon in POEMS syndrome and CD without clonal plasma cell dyscrasia or M protein. POEMS syndrome has greater distal CMAP duration in median and ulnar nerves, particularly in median nerve that can reach up to 150% of upper limit normal, compared to <50% in CD. Significance:Detailed electrophysiological analysis of distal CMAP duration may help in distinguishing POEMS syndrome and CD.	0
Multiple system atrophy cerebellar type (MSA-C) and spinocerebellar ataxia type 3 (SCA3) demonstrate similar manifestations, including ataxia, pyramidal and extrapyramidal signs, as well as atrophy and signal intensity changes in the cerebellum and brainstem. MSA-C and SCA3 cannot be clinically differentiated through T1-weighted magnetic resonance imaging (MRI) alone; therefore, clinical consensus criteria and genetic testing are also required. Here, we used diffusion tensor imaging (DTI) to measure water molecular diffusion of white matter and investigate the difference between MSA-C and SCA3. Four measurements were calculated from DTI images, including fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD). Fifteen patients with MSA-C, 15 patients with SCA3, and 30 healthy individuals participated in this study. Both patient groups demonstrated a significantly decreased FA but a significantly increased AD, RD, and MD in the cerebello-ponto-cerebral tracts. Moreover, patients with SCA3 demonstrated a significant decrease in FA but more significant increases in AD, RD, and MD in the cerebello-cerebral tracts than patients with MSAC. Our results may suggest that FA and MD can be effectively used for differentiating SCA3 and MSA-C, both of which are cerebellar ataxias and have many common atrophied regions in the cerebral and cerebellar cortex.	0
Hypocomplementemic urticarial vasculitis syndrome (HUVS), or McDuffie syndrome, is a rare small vessel vasculitis associated with urticaria, hypocomplementemia and positivity of anti-C1q antibodies. In rare cases, HUVS can manifest as an immune-complex mediated glomerulonephritis with a membranoproliferative pattern of injury. Due to the rarity of this disorder, little is known about the clinical manifestation, pathogenesis, treatment response and outcome of such patients. We describe here three cases of HUVS with severe renal involvement. These patients had a rapidly progressive form of glomerulonephritis with severe nephrotic syndrome against a background of a membranoproliferative pattern of glomerular injury with extensive crescent formation. Therefore, these patients required aggressive induction and maintenance immunosuppressive therapy, with a clinical and renal response in two patients, while the third patient progressed to end-stage renal disease. Because of the rarity of this condition, there are few data regarding the clinical presentation, pathology and outcome of such patients. Accordingly, we provide an extensive literature review of cases reported from 1976 until 2020 and place them in the context of the current knowledge of HUVS pathogenesis. We identified 60 patients with HUVS and renal involvement that had adequate clinical data reported, out of which 52 patients underwent a percutaneous kidney biopsy. The most frequent renal manifestation was hematuria associated with proteinuria (70% of patients), while one third had abnormal kidney function on presentation (estimated glomerular filtration (GFR) below 60 mL/min/1.73 m2). The most frequent glomerular pattern of injury was membranoproliferative (35%), followed by mesangioproliferative (21%) and membranous (19%). Similar to other systemic vasculitis, renal involvement carries a poorer prognosis, but the outcome can be improved by aggressive immunosuppressive treatment.	0
Maturity onset diabetes of the young (MODY) is an autosomal dominant form of non-insulin-dependent diabetes mellitus caused by mutations in at least 13 different genes. The hepatocyte nuclear factor (HNF)-1α gene is affected in the most common form (HNF1A-MODY [MODY3]).We describe the co-inheritance of a novel heterozygous missense mutation c.1761C > G (p.Pro588Ala) with a novel complex deletion insertion mutation (c.1765_1766delinsGCCCGfs86*) in the HNF-1α gene among affected members of one family. Both mutations were present in the affected patients and neither was present in unaffected family members. The family had not only inheritance of MODY but also increased susceptibility to type 2 diabetes. Therefore one family member had classical type 2 diabetes including metabolic syndrome aggravated by a genetic predisposition in the form of HNF1A-MODY.The presence of common type 2 diabetes features should not detract from the possibility of MODY in patients with a striking autosomal-dominant family history.	0
BACKGROUND:Intracranial hypotension (IH) has a widely variable clinical and radiologic presentation. Secondary IH may be caused by degenerative spine disorders and in particular by thoracic disk herniations (TDHs). METHODS:We present 2 patients with a transdural TDH, a secondary IH, and superficial siderosis in 1. RESULTS:Case 1 presented with headache, cognitive decline, staggering gait, bilateral subdural effusions, cerebral sagging, an extradural spinal cerebrospinal fluid (CSF) collection suggesting secondary IH, and a calcified TDH at T9-T10. Case 2 presented with intermittent pain at the craniocervical junction provoked exclusively by specific physical activities, superficial siderosis mainly in the posterior fossa, an extradural spinal CSF collection, and a calcified TDH at T7-T8 yet no intracranial signs of IH. In both cases, using strict thoracoscopic technique, we removed a transdural TDH and reconstructed an underlying longitudinal slitlike dural defect with smooth lining. Follow-up magnetic resonance imaging scans confirmed a dramatically improved situation without residual extradural intraspinal CSF collection or signs of IH. CONCLUSIONS:This paper adds to the evidence that some cases of IH and even superficial siderosis are caused by transdural erosion of a TDH that may be otherwise asymptomatic. The dura may degenerate due to chronic compression, and a longitudinal slitlike dural defect with smooth lining may develop, causing continuous (Case 1) or intermittent (Case 2) intraspinal CSF leakage. To the best of our knowledge, such dural defects closely resembling the ones observed in idiopathic spinal cord herniation have never been demonstrated on intraoperative endoscopic video in IH patients.	0
Pulmonary alveolar proteinosis is a rare lung disease in which lipoproteinaceous material accumulates within the alveoli, interfering with gas exchange. The disease is classified into congenital, secondary, and acquired. The congenital form includes inborn errors of surfactant metabolism, lysinuric protein intolerance and mutations in the components of granulocyte-macrophage colony-stimulating factor receptor. The main symptoms are non-specific. The radiologic appearance of pulmonary alveolar proteinosis is bilateral, symmetric and perihilar airspace consolidation. Bronchoalveolar lavage is crucial for diagnosis of the disease. There is only one ten-year-old patient with diagnosed congenital form in Croatia. What makes him different from other children in the world is that since the ninth month of his life he has been mechanically ventilated. Diagnosis of postnatal alveolar proteinosis should be considered in every infant with respiratory distress with diffuse alveolar and interstitial infiltrate.	0
Centronuclear myopathies are congenital muscle disorders characterized by type I myofibre predominance and an increased number of muscle fibres with nuclear centralization. The severe neonatal X-linked form is due to mutations in MTM1, autosomal recessive centronuclear myopathy with neonatal or childhood onset results from mutations in BIN1 (amphiphysin 2), and dominant cases were previously associated to mutations in DNM2 (dynamin 2). Our aim was to determine the genetic basis and physiopathology of patients with mild dominant centronuclear myopathy without mutations in DNM2. We hence established and characterized a homogeneous cohort of nine patients from five families with a progressive adult-onset centronuclear myopathy without facial weakness, including three sporadic cases and two families with dominant disease inheritance. All patients had similar histological and ultrastructural features involving type I fibre predominance and hypotrophy, as well as prominent nuclear centralization and clustering. We identified heterozygous BIN1 mutations in all patients and the molecular diagnosis was complemented by functional analyses. Two mutations in the N-terminal amphipathic helix strongly decreased the membrane-deforming properties of amphiphysin 2 and three stop-loss mutations resulted in a stable protein containing 52 supernumerary amino acids. Immunolabelling experiments revealed abnormal central accumulation of dynamin 2, caveolin-3, and the autophagic marker p62, and general membrane alterations of the triad, the sarcolemma, and the basal lamina as potential pathological mechanisms. In conclusion, we identified BIN1 as the second gene for dominant centronuclear myopathy. Our data provide the evidence that specific BIN1 mutations can cause either recessive or dominant centronuclear myopathy and that both disorders involve different pathomechanisms.	0
Pediatric brain tumors are the leading cause of cancer-related death in children. Patient-derived orthotopic xenografts (PDOX) of childhood brain tumors have recently emerged as a biologically faithful vehicle for testing novel and more effective therapies. Herein, we provide the histopathological and molecular analysis of 37 novel PDOX models generated from pediatric brain tumor patients treated at St. Jude Children's Research Hospital. Using a combination of histopathology, whole-genome and whole-exome sequencing, RNA-sequencing, and DNA methylation arrays, we demonstrate the overall fidelity and inter-tumoral molecular heterogeneity of pediatric brain tumor PDOX models. These models represent frequent as well as rare childhood brain tumor entities, including medulloblastoma, ependymoma, atypical teratoid rhabdoid tumor, and embryonal tumor with multi-layer rosettes. PDOX models will be valuable platforms for evaluating novel therapies and conducting pre-clinical trials to accelerate progress in the treatment of brain tumors in children. All described PDOX models and associated datasets can be explored using an interactive web-based portal and will be made freely available to the research community upon request.	0
Omphalocele can be associated with single gene disorders, neural tube defects, diaphragmatic defects, fetal valproate syndrome, and syndromes of unknown etiology. This article provides a comprehensive review of omphalocele-related disorders: otopalatodigital syndrome type II; Melnick-Needles syndrome; Rieger syndrome; neural tube defects; Meckel syndrome; Shprintzen-Goldberg omphalocele syndrome; lethal omphalocele-cleft palate syndrome; cerebro-costo-mandibular syndrome; fetal valproate syndrome; Marshall-Smith syndrome; fibrochondrogenesis; hydrolethalus syndrome; Fryns syndrome; omphalocele, diaphragmatic defects, radial anomalies and various internal malformations; diaphragmatic defects, limb deficiencies and ossification defects of skull; Donnai-Barrow syndrome; CHARGE syndrome; Goltz syndrome; Carpenter syndrome; Toriello-Carey syndrome; familial omphalocele; Cornelia de Lange syndrome; C syndrome; Elejalde syndrome; Malpuech syndrome; cervical ribs, Sprengel anomaly, anal atresia and urethral obstruction; hydrocephalus with associated malformations; Kennerknecht syndrome; lymphedema, atrial septal defect and facial changes; and craniosynostosismental retardation syndrome of Lin and Gettig. Perinatal identification of omphalocele should alert one to the possibility of omphalocele-related disorders and familial inheritance and prompt a thorough genetic counseling for these disorders.	0
Oculoectodermal syndrome (OES) and encephalocraniocutaneous lipomatosis (ECCL) are rare disorders that share many common features, such as epibulbar dermoids, aplasia cutis congenita, pigmentary changes following Blaschko lines, bony tumor-like lesions, and others. About 20 cases with OES and more than 50 patients with ECCL have been reported. Both diseases were proposed to represent mosaic disorders, but only very recently whole-genome sequencing has led to the identification of somatic KRAS mutations, p.Leu19Phe and p.Gly13Asp, in affected tissue from two individuals with OES. Here we report the results of molecular genetic studies in three patients with OES and one with ECCL. In all four cases, Sanger sequencing of the KRAS gene in DNA from lesional tissue detected mutations affecting codon 146 (p.Ala146Val, p.Ala146Thr) at variable levels of mosaicism. Our findings thus corroborate the evidence of OES being a mosaic RASopathy and confirm the common etiology of OES and ECCL. KRAS codon 146 mutations, as well as the previously reported OES-associated alterations, are known oncogenic KRAS mutations with distinct functional consequences. Considering the phenotype and genotype spectrum of mosaic RASopathies, these findings suggest that the wide phenotypic variability does not only depend on the tissue distribution but also on the specific genotype.	0
Surgical treatment of deep or difficult to access lesions represents a unique and significant challenge for pediatric neurosurgeons. The introduction of stereotactic magnetic resonance-guided laser interstitial thermal therapy (LITT) over the last decade has had a dramatic impact on the landscape of pediatric neurosurgery. LITT provides a safe and effective option for children with epilepsy from hypothalamic hamartoma that represents a ground-breaking new therapy for a condition which was historically very difficult to treat with previous neurosurgical techniques. LITT has also been used as an alternative surgical technique for mesial temporal sclerosis, focal cortical dysplasia, MR-negative epilepsy, cavernoma-related epilepsy, insular epilepsy, and corpus callosotomy among other epilepsy etiologies. In some cases, LITT has been associated with improved cognitive outcomes compared to standard techniques, as in mesial temporal lobe epilepsy. Initial experiences with LITT for neuro-oncologic processes are also promising. LITT is often attractive to patients and providers as a minimally invasive approach, but the differences in safety and clinical outcome between LITT and traditional approaches are still being studied. In this review, we examine the emerging indications and clinical evidence for LITT in pediatric neurosurgery.	0
Dynamin 2 (DNM2) is a ubiquitously expressed GTPase implicated in many cellular functions such as membrane trafficking and cytoskeleton regulation. Dominant mutations in DNM2 result in tissue-specific diseases affecting peripheral nerves (Charcot-Marie-Tooth neuropathy, CMT) or skeletal muscles (centronuclear myopathy, CNM). However, the reason for this tissue specificity is unknown, and it remains unclear if these diseases share a common pathomechanism. To compare the disease pathophysiological mechanisms in skeletal muscle, we exogenously expressed wild-type DNM2 (WT-DNM2), the DNM2-CMT mutation K562E or DNM2-CNM mutations R465W and S619L causing adult and neonatal forms, respectively, by intramuscular adeno-associated virus (AAV) injections. All muscles expressing exogenous WT-DNM2 and CNM or CMT mutations exhibited reduced muscle force. However, only expression of CNM mutations and WT-DNM2 correlated with CNM-like histopathological hallmarks of nuclei centralization and reduced fiber size. The extent of alterations correlated with clinical severity in patients. Ultrastructural and immunofluorescence analyses highlighted defects of the triads, mitochondria and costameres as major causes of the CNM phenotype. Despite the reduction in force upon expression of the DNM2-CMT mutation, muscle histology and ultrastructure were almost normal. However, the neuromuscular junction was affected in all DNM2-injected muscles, with the DNM2-CMT mutation inducing the most severe alterations, potentially explaining the reduction in force observed with this mutant. In conclusion, expression of WT and CNM mutants recreate a CNM-like phenotype, suggesting CNM mutations are gain-of-function. Histological, ultrastructural and molecular analyses pointed to key pathways uncovering the different pathomechanisms involved in centronuclear myopathy or Charcot-Marie-Tooth neuropathy linked to DNM2 mutations.	0
Hennekam syndrome is a rare autosomal recessive disorder resulting from malformation of the lymphatic system. The characteristic signs of Hennekam syndrome are lymphangiectasia, lymph edema, facial anomalies, and mental retardation. This is a case in which a patient presented with left-arm lymphedema, facial-feature anomalies, and multiple organ lymphangiectasia consistent with symptoms of Hennekam syndrome. There is no curative therapy at this time, but rehabilitative treatments including complete decongestive therapy for edema control appeared to be beneficial.	0
Purpose:To evaluate the phenotypic spectrum of autosomal recessive RP1-associated retinal dystrophies and assess genotypic associations. Methods:A retrospective multicenter study was performed of patients with biallelic RP1-associated retinal dystrophies. Data including presenting symptoms and age, visual acuity, kinetic perimetry, full field electroretinogram, fundus examination, multimodal retinal imaging, and RP1 genotype were evaluated. Results:Nineteen eligible patients from 17 families were identified and ranged in age from 10 to 56 years at the most recent evaluation. Ten of the 21 unique RP1 variants identified were novel, and mutations within exon 2 accounted for nearly half of alleles across the cohort. Patients had clinical diagnoses of retinitis pigmentosa (13), cone-rod dystrophy (3), Leber congenital amaurosis (1), early-onset severe retinal dystrophy (1), and macular dystrophy (1). Macular atrophy was a common feature across the cohort. Symptom onset occurred between 4 and 30 years of age (mean 14.9 years, median 13 years), but there were clusters of onset age that correlated with the effects of RP1 mutations at a protein level. Patients with later-onset disease, including retinitis pigmentosa, had at least one missense variant in an exon 2 DCX domain. Conclusions:Biallelic RP1 mutations cause a broad spectrum of retinal disease. Exon 2 missense mutations are a significant contributor to disease and can be associated with a considerably later onset of retinitis pigmentosa than that typically associated with biallelic RP1 mutations.	0
BACKGROUND:The treatment of congenital pseudoarthrosis of the tibia (CPT) remains challenging in pediatric orthopedics due to the difficulties in bone union, continuous angulation, joint stiffness, and severe limb length discrepancy. Mesenchymal stem cells (MSCs) therapy offers a complementary approach to improve the conventional surgical treatments. Although the autologous MSC treatment shows a promising strategy to promote bone healing in CPT patients, the quality of MSCs from CPT patients has not been well studied. The purpose of this study is to investigate the quality of MSCs isolated from patients with CPT. METHODS:The bone marrow-derived MSCs from the fracture site and iliac crest of six CPT patients were isolated and compared. The cumulative population doubling level (cPDL), phenotype characteristics, and trilineage differentiation potency were observed to assess the quality of both MSCs. RESULTS:There were no significant differences of the MSCs derived from the fracture site and the MSCs from the iliac crest of the subjects, in terms of cPDL, phenotype characteristics, and trilineage differentiation potency (all p > 0.05). However, MSCs from the fracture site had a higher senescence tendency than those from the iliac crest. CONCLUSION:MSC quality is not the main reason for delayed bone regeneration in those with CPT. Thus, autologous MSC is a promising source for treating CPT patients.	0
BACKGROUND:Greenberg dysplasia is a rare, autosomal recessive, prenatal lethal bone dysplasia caused by biallelic pathogenic variants in the lamin B receptor (LBR) gene. Pathogenic variants in LBR are also associated with Pelger-Huët anomaly, an autosomal dominant benign abnormality of the nuclear shape and chromatin organization of blood granulocytes, and Pelger-Huët anomaly with variable skeletal anomalies, a mild, regressing to moderate-severe autosomal recessive condition. Conditions with abnormal sterol metabolism and different genetic basis have clinical and radiographic features similar to Greenberg dysplasia, for example X-linked dominant chondrodysplasia punctata, Conradi-Hünermann type, and CHILD syndrome, and other conditions with unknown genetic etiology display very similar features, for example, dappled diaphyseal dysplasia and Astley-Kendall dysplasia. METHODS:We present a fetus with typical clinical and radiographic features of Greenberg dysplasia, and review the literature. RESULTS:Genetic testing confirmed the diagnosis Greenberg dysplasia: homozygosity for a pathogenic variant in LBR. CONCLUSION:Comparing the clinical and radiographic phenotypes of Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia, we suggest that these are allelic disorders.	0
Pulmonary arteriovenous malformation (PAVM) is a potential cause of hemothorax. The risk of PAVM rupture is reported to be higher during pregnancy for several reasons, including increased body fluid and a change in hormonal conditions. A 34-year-old pregnant woman suddenly felt right chest pain and dyspnea in the 28th week of gestation. Chest X-ray and computed tomography showed massive right pleural effusion. Her vital signs gradually deteriorated with hemorrhagic shock, necessitating emergency surgery. During exploratory thoracoscopy, active bleeding from the middle lobe was noticed and gauze packing was required to maintain her blood pressure. Following conversion to major thoracotomy, wedge resection of the middle lobe was performed with a linear stapler, and finally, her general condition became stable. Her postoperative course was uneventful. A histological examination of the resected specimen confirmed the diagnosis of ruptured PAVM. Her baby was successfully delivered at the 38th week of gestation.	0
There are three human enzymes with HMG-CoA lyase activity that are able to synthesize ketone bodies in different subcellular compartments. The mitochondrial HMG-CoA lyase was the first to be described, and catalyzes the cleavage of 3-hydroxy-3-methylglutaryl CoA to acetoacetate and acetyl-CoA, the common final step in ketogenesis and leucine catabolism. This protein is mainly expressed in the liver and its function is metabolic, since it produces ketone bodies as energetic fuels when glucose levels are low. Another isoform is encoded by the same gene for the mitochondrial HMG-CoA lyase (HMGCL), but it is located in peroxisomes. The last HMG-CoA lyase to be described is encoded by a different gene, HMGCLL1, and is located in the cytosolic side of the endoplasmic reticulum membrane. Some activity assays and tissue distribution of this enzyme have shown the brain and lung as key tissues for studying its function. Although the roles of the peroxisomal and cytosolic HMG-CoA lyases remain unknown, recent studies highlight the role of ketone bodies in metabolic remodeling, homeostasis, and signaling, providing new insights into the molecular and cellular function of these enzymes.	0
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 and TSC2 genes on chromosomes 9 and 16 respectively. Diagnosis is based on clinical features but can be difficult as a result of variable phenotypic expression. With the advantage of mutation analysis in making a diagnosis of TSC, and improved identification of the associated clinical features, there have been few new data on its prevalence and on the proportion of cases due to new mutations. We have performed a retrospective epidemiological study on the prevalence of TSC, the clinical features attributed to it, and the availability of mutational analysis. We identified 73 known patients with TSC (5 deceased): 39 were female and 34 male. Ages ranged from 10 months to 69 years, with a mean age of 27 years 11 months (SD 16y 10mo). The point prevalence of TSC in our study was estimated at 1 out of 24 956 on the prevalence day (30 April 2004). The majority of patients (42.5%) were diagnosed at less than 15 months of age; 25% were not given a diagnosis on first developing symptoms. In all, 93.2% had epilepsy and 71.2% had a learning disability. A mutation was identified in 95.8% of those tested (26% TSC1 and 74% TSC2). TSC2 mutations were correlated with a more severe phenotype. The new mutation rate was calculated at 64%. We conclude that the prevalence of TSC is higher than previously calculated. We recommend that all children with epilepsy be assessed for features of TSC. Larger studies will be required to assess the prevalence of mutations in each gene, and genotype-phenotype correlation.	1
Background:Cor triatriatum sinister (CTS) is a rare congenital cardiac anomaly defined by a fibromuscular membrane which bisects the left atrium. Cor triatriatum sinister has been associated with cardioembolic stroke through mechanisms including stagnation of blood flow within the left atrium, an association with atrial fibrillation (AF), and/or an accompanying atrial septal defect (ASD) or patent foramen ovale. We describe a case highlighting the role that CTS may play in cardioembolic stroke, provide high-quality computed tomography angiography and two- and three-dimensional echocardiography of the CTS membrane, and outline management strategies for this uncommon clinical scenario. Case summary:A 35-year-old man with no prior medical history presented with acute onset weakness and aphasia. He was found to have an embolic stroke with left M1 and A1 occlusions and received tissue plasminogen activator followed by mechanical thrombectomy with successful recanalization. A thorough stroke workup revealed CTS with an associated ASD as well as potential protein C deficiency. He was managed with indefinite anticoagulation with apixaban. Discussion:This is the 13th reported case of CTS associated with stroke. In most previous cases evidence of blood stasis or frank thrombus was associated with the CTS membrane, and/or existing AF was noted. In this case, none of these were identified, particularly highlighting the surreptitious risk of CTS. In addition, the presence of potential protein C deficiency in this case compounded the risk for thromboembolism and factored into multidisciplinary management decisions.	0
BACKGROUND: The role of gastro-protecting agents on symptomatic chronic gastritis is unclear. This multicenter, open, randomized trial was designed to compare the comprehensive effects of gefarnate with sucralfate on erosive gastritis with dyspeptic symptoms. METHODS: Totally 253 dyspepsia patients confirmed with erosive gastritis were enrolled from six centers in China. They randomly received either daily 300 mg gefarnate or 3 g sucralfate for six weeks. The primary endpoint was the effective rate of both treatments on endoscopic erosion at week six. RESULTS: Gefarnate showed an effective rate of 72% and 67% on endoscopic score and dyspeptic symptom release, which is statistically higher than sucralfate (40.1% and 39.3%, P < 0.001, intension-to-treat). For histological improvement, gefarnate showed both effective in decreasing mucosal chronic inflammation (57.7% vs. 24.8%, P < 0.001, intension-to-treat) and active inflammation (36.4% vs. 23.1%, P < 0.05, intension-to-treat) than the control. A significant increase of prostaglandins and decrease of myeloperoxidase in mucosa were observed in gefarnate group. Severity of erosion is non-relevant to symptoms but Helicobacter pylori (H. pylori) status does affect the outcome of therapy. CONCLUSIONS: Gefarnate demonstrates an effective outcome on the mucosal inflammation in patients with chronic erosive gastritis. Endoscopic and inflammation score should be the major indexes used in gastritis-related trials.	0
BACKGROUND:Hereditary spastic paraplegia is a heterogeneous group of clinically and genetically neurodegenerative diseases characterized by progressive gait disorder. Hereditary spastic paraplegia can be inherited in various ways, and all modes of inheritance are associated with multiple genes or loci. At present, more than 76 disease-causing loci have been identified in hereditary spastic paraplegia patients. Here, we report a novel mutation in SPAST gene associated with hereditary spastic paraplegia in a Chinese family, further enriching the hereditary spastic paraplegia spectrum. METHODS:Whole genomic DNA was extracted from peripheral blood of the 15 subjects from a Chinese family using DNA Isolation Kit. The Whole Exome Sequencing of the proband was analyzed and the result was identified in the rest individuals. RaptorX prediction tool and Protein Variation Effect Analyzer were used to predict the effects of the mutation on protein tertiary structure and function. RESULTS:Spastic paraplegia has been inherited across at least four generations in this family, during which only four HSP patients were alive. The results obtained by analyzing the Whole Exome Sequencing of the proband exhibited a novel disease-associated in-frame deletion in the SPAST gene, and this mutation also existed in the rest three HSP patients in this family. This in-frame deletion consists of three nucleotides deletion (c.1710_1712delGAA) within the exon 16, resulting in lysine deficiency at the position 570 of the protein (p.K570del). This novel mutation was also predicted to result in the synthesis of misfolded SPAST protein and have the deleterious effect on the function of SPAST protein. CONCLUSION:In this case, we reported a novel mutation in the known SPAST gene that segregated with HSP disease, which can be inherited in each generation. Simultaneously, this novel discovery significantly enriches the mutation spectrum, which provides an opportunity for further investigation of genetic pathogenesis of HSP.	0
Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1), or Taybi-Linder syndrome is characterized by distinctive skeletal dysplasia, severe intrauterine and postnatal growth retardation, microcephaly, dysmorphic features, and neurological malformations. It is an autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the RNU4ATAC gene resulting in impaired function of the minor spliceosome. Here, we present the first report on bone morphology, bone density and bone microstructure in two adult MOPD1 patients and applied radiographs, dual energy X-ray absorptiometry, high-resolution peripheral quantitative computed tomography and biochemical evaluation. The MOPD1 patients presented with short stature, low BMI but normal macroscopic bone configuration. Bone mineral density was low. Compared to Danish reference data, total bone area, cortical bone area, cortical thickness, total bone density, cortical bone density, trabecular bone density and trabecular bone volume per tissue volume (BV/TV) were all low. These findings may correlate to the short stature and low body weight of the MOPD1 patients. Our findings suggest that minor spliceosome malfunction may be associated with altered bone modelling.	0
Photoreceptor neuronal degenerations are common and incurable causes of human blindness with one in 2000 affected. Approximately, half of all patients are associated with known mutations in more than 200 disease genes. Most retinal degenerations are restricted to the retina (primary retinal degeneration) but photoreceptor degeneration can also be found in a wide variety of systemic and syndromic diseases. These are called secondary retinal degenerations. We review several well-known systemic diseases with retinal degenerations (RD). We discuss RD with hearing loss, RD with brain disease, and RD with musculoskeletal disease. We then postulate which retinal degenerations may also have previously undetected systemic features. Emerging new and exciting evidence is showing that ubiquitously expressed genes associated with multitissue syndromic disorders may also harbor mutations that cause isolated primary retinal degeneration. Examples are RPGR, CEP290, CLN3, MFSD5, and HK1 mutations that cause a wide variety of primary retinal degenerations with intact systems.	0
Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-Kučinskas syndrome (MIM 617822). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Severe loss-of-function cases were incompatible with life, whereas those individuals with milder missense variants presented with severe global developmental delay, syndactyly of 2nd and 3rd toes, and severe muscle hypotonia resulting in incapacity to stand without support. Consistent with a causative role for KIAA1109 loss-of-function/hypomorphic variants in this syndrome, knockdowns of the zebrafish orthologous gene resulted in embryos with hydrocephaly and abnormally curved notochords and overall body shape, whereas published knockouts of the fruit fly and mouse orthologous genes resulted in lethality or severe neurological defects reminiscent of the probands' features.	0
Sensenbrenner syndrome (cranioectodermal dysplasia, CED) is a very rare autosomal recessive ciliopathy first described by Judith Sensenbrenner in 1975. CED is a complex disorder characterized by craniofacial, skeletal, and ectodermal abnormalities. The clinical symptoms are variable and the CED phenotype may present intrafamilial and interfamilial differences. Sensenbrenner syndrome belongs to a group of ciliary chondrodysplasias and is a genetically heterogeneous disease. Mutations in six genes: IFT122, WDR35, IFT43, WDR19, IFT52, and IFT140 have been associated with this disorder. All known CED genes encode proteins that are part of the intraflagellar transport complex, which plays an important role in the assembly and maintenance of cilia.We report a on 2-year-old male patient affected by Sensenbrenner syndrome. Dysmorphic features included short stature with rhizomelic shortening of limbs, short fingers, narrow chest, high forehead, epicanthal folds, telecanthus, broad nasal bridge, low-set ears, sparse hair, and widely space teeth. Craniosynostosis was surgically corrected at the age of 4 months. The patient presented chronic renal disease. Nephrologic picture showed early stages of nephronophthisis. Psychomotor development was apparently normal. Molecular analysis of the affected individual revealed compound heterozygosity for a novel nonsense p.(Arg113*) and a missense p.(Asp841Val) variant in the WDR35 gene.The observations of the CED patient in this study provide additional clinical data and expand the molecular spectrum of Sensenbrenner syndrome. Moreover, the two variants identified in the proband provide further evidence for the WDR35 mutations as the most common cause of this rare syndrome.	0
BACKGROUND:The association between Hashimoto's thyroiditis (HT) and papillary thyroid carcinoma (PTC) is a controversial question that is still under debate, its pathological significance and the eventual clinical implications of this association remaining unclear. METHODS:The data regarding 305 patients were retrospectively analyzed. The patients were divided in two different groups. A first group made up of 142 patients undergoing surgery for differentiated thyroid carcinoma was compared to a control group of 142 analogous subjects operated for normofunctioning goiter. A second group was made up of 163 patients who had undergone total thyroidectomy (TT) with pre-operative diagnosis of HT. RESULTS:In the first group of patients an association with HT was found in 28,6% of the patients with final histopathological diagnosis of PTC versus 7,7% of the patients with histopathological diagnosis of multinodular goiter, which was a significant difference (p <  0.001). In the second group, the association with PTC was found in 43 (40,2%) cases of HT nodular variant and in 3 cases (8,1%) of HT diffuse variant (p <  0.001). CONCLUSIONS:The relationship between HT and PTC is still far from clear and represents an unresolved issue. Our own study has underlined the frequent coexistence of these two pathologies, an aspect not to be neglected in clinical practice. Patients receiving HT diagnosis should undergo careful follow-up and, especially those with the nodular variant, should undergo a frequent both clinical and cytological evaluation of the nodular lesions, taking always into great consideration the surgical approach of total thyroidectomy.	0
Introduction:Ledderhose's disease, also known asplantar fibromatosis, is a rare benign nodular hyperplasia of the plantar aponeurosis. The disease is locally aggressive and can be managed very well conservatively. In patients who present with severe pain on weight-bearing might require surgical excision. Case Report:We would like to report about a case of 40-year-old female with bilateral Ledderhose's disease. She was treated conservatively to no avail. On surgical excision of the fibrosis tissue, the patient gives complete relief of symptoms. In this paper, we would to discuss both the conservative and surgical methods adopted to prevent post-operative complications. Conclusion:Ledderhose disease is a rare benign aggressive disease which presents as nodules over the sole of the foot. The disease is usually manageable conservatively. Wide margin surgical excision of the nodule in severe cases will provide pain-free mobilization and prevent recurrence.	0
Proteinuria is a well-known risk factor, not only for renal disorders, but also for several other problems such as cardiovascular diseases and overall mortality. In the kidney, the chloride channel Cl-/H+ exchanger ClC-5 encoded by the CLCN5 gene is actively involved in preventing protein loss. This action becomes evident in patients suffering from the rare proximal tubulopathy Dent disease because they carry a defective ClC-5 due to CLCN5 mutations. In fact, proteinuria is the distinctive clinical sign of Dent disease, and mainly involves the loss of low-molecular-weight proteins. The identification of CLCN5 disease-causing mutations has greatly improved our understanding of ClC-5 function and of the ClC-5-related physiological processes in the kidney. This review outlines current knowledge regarding the CLCN5 gene and its protein product, providing an update on ClC-5 function in tubular and glomerular cells, and focusing on its relationship with proteinuria and Dent disease.	0
Dowling-Degos disease (DDD) is a rare autosomal dominant genodermatosis characterized by reticulate brown-to-black pigmentation of the flexures, pitted perioral acneiform scars, and comedo-like follicular papules on the flexures. The diagnosis is based on characteristic clinical and histopathological features. DDD has been found to occur in association with hidradenitis suppurativa (HS), arthritis, epidermoid cysts, keratoacanthomas, and squamous cell carcinoma. To date, there is only one report of DDD associated with HS and polyarticular arthritis.	0
With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross-species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in ataxic and preataxic subjects of two independent multicentric SCA3 cohorts and in a SCA3 knock-in mouse model. Ataxic SCA3 subjects showed increased levels of both NfL and pNfH. In preataxic subjects, NfL levels increased with proximity to the individual expected onset of ataxia, with significant NfL elevations already 7.5 years before onset. Cross-sectional NfL levels correlated with both disease severity and longitudinal disease progression. Blood NfL and pNfH increases in human SCA3 were each paralleled by similar changes in SCA3 knock-in mice, here also starting already at the presymptomatic stage, closely following ataxin-3 aggregation and preceding Purkinje cell loss in the brain. Blood neurofilaments, particularly NfL, might thus provide easily accessible, cross-species validated biomarkers in both ataxic and preataxic SCA3, associated with earliest neuropathological changes, and serve as progression, proximity-to-onset and, potentially, treatment-response markers in both human and preclinical SCA3 trials.	0
The ectodermal dysplasias (EDs) are a large and complex nosological group of diseases, first described by Thurnam in 1848. In the last 10 years more than 170 different pathological clinical conditions have been recognised and defined as EDs, all sharing in common anomalies of the hair, teeth, nails, and sweat glands. Many are associated with anomalies in other organs and systems and, in some conditions, with mental retardation.The anomalies affecting the epidermis and epidermal appendages are extremely variable and clinical overlap is present among the majority of EDs. Most EDs are defined by particular clinical signs (for example, eyelid adhesion in AEC syndrome, ectrodactyly in EEC). To date, few causative genes have been identified for these diseases. We recently reviewed genes known to be responsible for EDs in light of their molecular and biological function and proposed a new approach to EDs, integrating both molecular-genetic data and corresponding clinical findings. Based on our previous report, we now propose a clinical-genetic classification of EDs, expand it to other entities in which no causative genes have been identified based on the phenotype, and speculate on possible candidate genes suggested by associated "non-ectodermal" features.	0
We report the case of a child with congenital nonbullous ichthyosiform erythroderma on long-term isotretinoin who developed progressively worsening ichthyosis along with recurrent bouts of sinusitis. Endoscopic sinus surgery revealed osteophytes, most likely an isotretinoin-related adverse event, and post operatively the patient's sinus disease and skin disease both dramatically improved. This case represents the first report, to our knowledge, of ichthyosis improving after endoscopic sinus surgery.	0
Intellectual disability (ID) is a clinically and genetically heterogeneous developmental brain disorder. The present study describes two male siblings, aged 7 and 1 yr old, with severe ID, spastic quadriplegia, nystagmus, and brain atrophy with acquired microcephaly. We used the exome sequencing to identify the causative gene in the patients and identified a hemizygous missense variant, c.1282T>A (p.W428R), in the p21-activated serine/threonine kinase 3 gene (PAK3), which is associated with X-linked ID. p.W428R is located within the highly conserved kinase domain and was predicted to induce loss of enzymatic function by three mutation prediction tools (SIFT, PolyPhen-2, and MutationTaster). In addition, this variant has not been reported in public databases (as of the middle of December 2018) or in the data from 3275 individuals of the Japanese general population analyzed using high-depth whole-genome sequencing. To date, only 13 point mutations and deletions in PAK3 in ID have been reported. The literature review illustrated a phenotypic spectrum of PAK3 pathogenic variant, and our cases represented the most severe form of the PAK3-associated phenotypes. This is the first report of a PAK3 pathogenic variant in Japanese patients with X-linked ID.	0
OBJECTIVE:The present report aimed to document the clinical features of a case of Marshall-Smith syndrome (MSS), an extremely rare embryonic developmental disorder with associated craniosynostosis. PATIENT AND METHOD:We presented herein a case of a 2-year-old female patient with MSS who underwent fronto-orbital advancement for multisuture craniosynostosis. RESULTS:The patient's proptosis improved after surgery, and no further surgical intervention was required for corneal exposure. A second FOA followed by revision tarsorrhaphy further improved eye closure. CONCLUSION:Surgical procedures to correct dysplastic features and limit neurological impairment are a worthwhile supportive treatment for improving the quality of life and general condition of patients with MSS.	0
Congenital erythropoietic porphyria (CEP) is an inborn error of heme synthesis resulting from uroporphyrinogen III synthase (UROS) deficiency and the accumulation of non-physiological porphyrin isomer I metabolites. Clinical features are heterogeneous among CEP patients but usually combine skin photosensitivity and chronic hemolytic anemia, whose severity is related to porphyrin overload. Therapeutic options are essentially symptomatic and unsatisfactory. One promising strategy to treat CEP is to reduce the erythroid production of porphyrins through substrate reduction therapy by inhibiting 5-aminolevulinate synthase 2 (ALAS2), the first and rate-limiting enzyme in the heme biosynthetic pathway. We efficiently reduced porphyrin accumulation after RNAi-mediated downregulation of ALAS2 in human erythroid cellular models of CEP disease. Taking advantage of the physiological iron-dependent post-transcriptional regulation of ALAS2, we evaluated whether iron chelation with deferiprone could decrease ALAS2 expression and subsequent porphyrin production in vitro and in vivo in a CEP murine model. Treatment of UROS-deficient erythroid cell lines and peripheral blood CD34+-derived erythroid cultures from a CEP patient with deferiprone inhibited iron-dependent protein ALAS2 and IRP2 expression and reduced porphyrin production. Furthermore, porphyrin accumulation progressively decreased in red blood cells and urine, and skin photosensitivity in CEP mice treated with deferiprone (1 or 3 mg/ml in drinking water) for 26 weeks was reversed. Hemolysis and iron overload improved upon iron chelation with a full correction of anemia in CEP mice treated at the highest dose of deferiprone. Our findings highlight in both mouse and human models, the therapeutic potential of iron restriction to modulate the phenotype in CEP.	0
Dysplastic gangliocytoma or Lhermitte-Duclos disease is a rare disorder characterized by a slowly progressive unilateral tumour mass of the cerebellar cortex. It is probably hamartomatous, although the exact pathogenesis remains unknown. Lhermitte-Duclos disease was recently encountered to be part of a multiple hamartoma-neoplasia complex (Cowden's syndrome). It typically presents in young adults, although it has been encountered at all ages. We present the case of bilateral cerebellar location of this pathology in a 50-year-old man presented with a progressive onset and worsening of headaches accompanied by nuchal rigidity, photophobia and nausea awakening each morning. Upon physical examination, the patient was awake with a discrete right vestibular syndrome made of positive Romberg without nystagmus. Magnetic Resonance Imaging (MRI) was performed and revealed salient "tiger stripe" appearance of the bilateral cerebellar cortex relevant to a Lhermitte-Duclos disease.	0
Mutations in FBN1 cause a range of overlapping but distinct conditions including Marfan syndrome (MFS), Weill-Marchesani syndrome (WMS), familial thoracic aortic aneurysms/dissections (FTAAD), acromicric dysplasia (AD), and geleophysic dysplasia (GD). Two forms of acromelic dysplasia, AD and GD, characterized by short stature, brachydactyly, reduced joint mobility, and characteristic facies, result from heterozygous missense mutations occurring in exons 41 and 42 of FBN1; missense mutations in these exons have not been reported to cause MFS or other syndromes. Here we report on probands with MFS and WMS who have heterozygous FBN1 missense mutations in exons 41 and 42, respectively. The proband with WMS has ectopia lentis, short stature, thickened pinnae, tight skin, striae atrophicae, reduced extension of the elbows, contractures of the fingers and toes, and brachydactyly and has a missense mutation in exon 42 of FBN1 (c.5242T>C; p.C1748R). He also experienced a previously unreported complication of WMS, an acute thoracic aortic dissection. The second proband displays classic characteristics of MFS, including ectopia lentis, skeletal features, and aortic root dilatation, and has a missense mutation in exon 41 of FBN1 (c.5084G>A; p.C1695Y). These phenotypes provide evidence that missense mutations in exons 41 and 42 of FBN1 lead to MFS and WMS in addition to AD and GD and also suggest that all individuals with pathogenic FBN1 mutations in these exons should be assessed for thoracic aortic disease and ectopia lentis. Further studies are necessary to elucidate the factors responsible for the different phenotypes associated with missense mutations in these exons of FBN1.	0
BACKGROUND:Thrombotic microangiopathies (TMAs) occurring in the postpartum period may be difficult to manage. They present as the combination of mechanical hemolytic anemia and consumption thrombocytopenia due to endothelial dysfunction. The cause of this endothelial aggression can be multiple: thrombocytopenic thrombotic purpura (TTP), HELLP syndrome, antiphospholipid syndrome, atypical hemolytic and uremic syndrome or acute fatty liver of pregnancy. TTP results from a severe deficiency of ADAMTS13, which is a protease cleaving specifically von Willebrand factor chiefly produced by liver cells. There are two main causes, the production of anti-ADAMTS13 auto-antibodies and, more rarely, a genetic deficiency in ADAMTS13. First-line treatment is based on plasma exchange. HELLP syndrome occurs in the third trimester of pregnancy usually in association with preeclampsia and represents a form of TMA characterized by damage to the sinusoidal capillaries of the liver. Prompt delivery is the main treatment. We present a case illustrating the challenges in discriminating between different postpartum TMAs, with a focus on the distinction between TTP and HELLP syndrome. Specifically, we highlight how acute liver failure (ALF) stemming from HELLP may lead to TTP with a spectacular response to plasma exchanges. CASE:A 28-year-old, 33 + 4 weeks pregnant woman presented with severe preeclampsia complicated by ALF in the setting of partial liver necrosis, disseminated intravascular coagulation, microangiopathic hemolytic anemia and acute kidney injury. Greatly diminished levels of ADAMTS13 (< 5%) activity and neurological impairment suggested an initial diagnosis of thrombotic thrombocytopenic purpura (TTP). Therapeutic plasma exchange (TPE) was initiated and complete renal, neurological, hematological and hepatic recovery was observed. Secondary TTP induced by ALF due to HELLP syndrome was the final diagnosis. CONCLUSION:Our case addresses the overlapping nature of postpartum TMAs and raises the possibility that HELLP-induced ALF may constitute an additional mechanism resulting in TTP, thereby opening a possible indication for TPE.	0
It is controversial whether a functional androgen receptor (AR) on germ cells, including spermatogonia, is essential for their development into sperm and, thus, initiation and maintenance of spermatogenesis. It was recently shown that many spermatocytes underwent apoptosis in the testes of Hsp90α KO mice. We had generated Hsp90α KO mice independently and confirmed this phenotype. However, the important question of whether Hsp90α is required to maintain spermatogenesis in adult mice in which testicular maturation is already completed could not be addressed using these conventional KO mice. To answer this question, we generated a tamoxifen-inducible deletion mutant of Hsp90α and found that conditional deletion of Hsp90α in adult mice caused even more severe apoptosis in germ cells beyond the pachytene stage, leading to complete arrest of spermatogenesis and testicular atrophy. Importantly, immunohistochemical analysis revealed that AR expression in WT testis was more evident in spermatogonia than in spermatocytes, whereas its expression was aberrant and ectopic in Hsp90α KO testis, raising the possibility that an AR abnormality in primordial germ cells is involved in spermatogenesis arrest in the Hsp90α KO mice. Our results suggest that the AR, specifically chaperoned by Hsp90α in spermatogonia, is critical for maintenance of established spermatogenesis and for survival of spermatocytes in adult testis, in addition to setting the first wave of spermatogenesis before puberty.	0
A 4-yr-old female with congenital knee dislocations and joint laxity was noted to have a strong maternal family history comprising multiple individuals with knee problems and clubfeet. As the knee issues were the predominant clinical features, clinical testing included sequencing of LMX1B, TBX2, and TBX4, which identified no significant variants. Research genome sequencing was performed in the proband, parents, and maternal grandfather. A heterozygous in-frame deletion in FLNB c. 5468_5470delAGG, which predicts p.(Glu1823del), segregated with the disease. The variant is rare in the gnomAD database, removes a residue that is evolutionarily conserved, and is predicted to alter protein length. Larsen syndrome may present with pathology that primarily involves one joint and thus may be difficult to differentiate clinically from other skeletal dysplasias or arthrogryposis syndromes. The p.(Glu1823del) variant maps to a filamin repeat domain where other disease-causing variants are clustered, consistent with a probable gain-of-function mechanism. It has reportedly been observed in two individuals in the gnomAD database, suggesting that mild presentations of Larsen syndrome, like the individual reported here, may be underdiagnosed in the general population.	0
Frontonasal dysplasia is a rare congenital anomaly affecting the eyes, nose and forehead, and occurs sporadically in most of the cases. A 24-year-old woman was referred to our unit at 27 weeks gestation due to the preliminary diagnosis of encephalocele. The sagittal and axial sonography of the fetal face depicted a midline mass measuring 3.8 × 4.2 cm, projecting anteriorly between the fetal orbits and extending from the the upper aspects of the forehead to the nasal bridge, which was consistent with the frontal (anterior) encephalocele. There were prominent hypertelorism and two facial clefts, and the nostrils were extremely separated. Following genetic counseling, the couple requested termination of pregnancy. Fetal pathologic examination confirmed the diagnosis of frontonasal dysplasia and anterior encephalocele with no additional major malformation. The fetal karyotype was normal and no mutation in the ALX1 gene was found, excluding ALX1-related frontonasal dysplasia in the differential diagnosis. Fetuses with neural tube defect may suffer from associated syndromes and disorders, as with our case. The presence of frontonasal dyplasia should be considered when an anterior encephalocele is detected by ultrasonography.	0
BACKGROUND:Cockayne Syndrome (CS) is a rare autosomal recessive disorder characterized by neurological and sensorial impairment, dwarfism, microcephaly and photosensitivity. CS is caused by mutations in ERCC6 (CSB) or ERCC8 (CSA) genes. METHODS:Three patients with CS were referred to the Medical Genetics Unit of Saint Joseph University. Sanger sequencing of both ERCC8 and ERCC6 genes was performed: ERCC8 was tested in all patients while ERCC6 in one of them. RESULTS:Sequencing led to the identification of three homozygous mutations, two in ERCC8 (p.Y322* and c.843 + 1G > C) and one in ERCC6 (p.R670W). All mutations were previously reported as pathogenic except for the c.843 + 1G > C splice site mutation in ERCC8 which is novel. CONCLUSIONS:Molecular diagnosis was established in all patients included in our study. A genotype-phenotype correlation is discussed and a link, between mutations and some specific religious communities in Lebanon, is suggested.	0
Atypical pigmentation, which is rarely observed in the wild, may influence social interactions between animals and can be detrimental for survival. Hypopigmentation, which is the lack of pigment in a part or on the entire body, is a type of atypical pigmentation pattern that can be either acquired (e.g. vitiligo) or congenital resulting from the inheritance of mutations in pigment-related genes (e.g. albinism, leucism and piebaldism). This study documents atypical pigmentation in a fin whale Balaenoptera physalus off the northwestern coast of the Iberian Peninsula (Atlantic Ocean). Photographic and video data collected between 2016 and 2017 on 30 individual fin whales were examined. One fully-grown fin whale exhibited hypopigmentation. Several white patches of different shapes and sizes were present across the body of the fin whale including on the head, body, dorsal fin, flippers, and flukes. The position, shape, and lack of inflammation of the white patches on the whale observed, along with its body length and condition, might indicate that the depigmentation pattern is due to vitiligo. To our knowledge, this is the first case of atypical pigmentation pattern in fin whales described with photographs and video records. As these observations are rare, especially in highly migratory, long-lived, marine mammal species, this study provides valuable information to better understand the occurrence of this phenomenon. Further studies are needed to determine the ecological and physiological implications of atypical colourations, which might have a significant influence on the animal's survival.	0
We report on a family with occipital horn syndrome (OHS) diagnosed in the proband's late fifties. A novel ATP7A pathogenic variant (c.4222A > T, p.(Lys1408*)), representing the first nonsense variant and the second late truncation causing OHS rather than classic Menkes disease, was found to segregate in the family. The predicted maintenance of transmembrane domains is consistent with a residual protein activity, which may explain the mild clinical presentation.	0
For more than two decades, papillary renal cell carcinoma has been recognized as a possible distinct clinicopathologic subtype of renal cell carcinoma (RCC). However, the histologic criteria for its diagnosis and the clinical outcome are still debated. In an attempt to clarify the diagnostic criteria and resolve issues pertaining to biologic potential, we have evaluated the histologic spectrum of 62 papillary RCCs and assessed significance of conventional pathologic prognostic parameters (Fuhrrman's nuclear grade [NG], pathologic stage [Robson and TNM], tumor size, multifocality, necrosis, and foam cells) and correlated these with outcome. The mean age of patients was 61.8 years (range 22-83), and males were more commonly affected (1.8:1). Grossly, most tumors were well circumscribed, averaged 6.7 cm in size (range 1.8-18), and were predominantly localized to the renal poles (polar vs. mid-renal, 3:1). Multifocality was a prominent feature (24 cases), and in three cases tumors were bilateral. Microscopically, papillary RCCs were predominantly papillary or tubulopapillary, often with a thick fibrous capsule, foam cells, necrosis, hemorrhage, and multifocality. Thirty-five percent of these tumors were low grade (NG I and II) and 65% high grade (NG III and IV). Sixteen of these tumors presented in a higher stage (stages III and IV), and the overall stage correlated with NG (chi 2, p = 0.009). Tumors were further distinguished by cytoplasmic features: eosinophilic (42%), basophilic (34%) and mixed (24%). Eosinophilic tumors were predominantly high grade, and basophilic tumors low grade (chi 2, p = 0.000). A mean follow-up of 57 months showed progression (metastasis, recurrence, or death due to disease) in 21%, whereas 63% were free of disease. Eleven percent died of unrelated causes, and 5% were lost to follow-up. Kaplan-Meier survival analysis showed that both high NG and stage were strongly associated with decreased survival (p = 0.0000 each), as were decreased foam cell (p = 0.0025) and vascular invasion (p = 0.0002). Comparison of 196 reported cases of papillary RCC, including the current series, with reported large series of conventional RCC indicates that papillary RCC usually presents at an early stage, and stage I (Robson) papillary RCC has better 5 year survival rates (87%-100%) than does RCC of the same stage (65-75%). The overall 5 years survival rate for papillary carcinoma (82-90%) was also higher than that of conventional RCC (44-54%). In a Cox proportional hazard regression model, TNM stage appeared to be the only significant variable (p = 0.0000, hazard ratio 10.1) in predicting outcome among papillary RCC. Based on this experience, we conclude that (a) papillary RCC is a malignant tumor, with a tendency to present at a lower stage, but with a distinct potential for progression and aggressive behavior; (b) stratification of these tumors according to cell type, amount of foam cells, presence or absence of vascular invasion, nuclear grade, and pathologic stage provides useful prognostic information; (c) the better 5-year survival rate of papillary RCC (overall and for stage I tumors) compared with that of conventional RCC suggests that it is a tumor with lower malignant potential. Thus, histologic subcategorization of a renal carcinoma as papillary RCC appears to have prognostic implications.	0
The tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare disorder that is probably underdiagnosed in clinical practice. Ocular involvement in TINU syndrome not only presents with the nongranulomatous anterior uveitis in 80% of patients but also manifests as intermediate, posterior, or panuveitis. This case report mentions an adult male patient who presented with granulomatous iridocyclitis with panuveitis and mild renal insufficiency. Workup for connective tissue and infectious diseases was negative for the patient. He was diagnosed with TINU syndrome based on the findings of renal biopsy. Both the uveitis and nephritis promptly responded well to steroid treatment, and there was no recurrence during the follow-up of 24 months.	0
Lissencephaly ('smooth brain') is a severe brain disease associated with numerous symptoms, including cognitive impairment, and shortened lifespan. The main causative gene of this disease - lissencephaly-1 (LIS1) - has been a focus of intense scrutiny since its first identification almost 30 years ago. LIS1 is a critical regulator of the microtubule motor cytoplasmic dynein, which transports numerous cargoes throughout the cell, and is a key effector of nuclear and neuronal transport during brain development. Here, we review the role of LIS1 in cellular dynein function and discuss recent key findings that have revealed a new mechanism by which this molecule influences dynein-mediated transport. In addition to reconciling prior observations with this new model for LIS1 function, we also discuss phylogenetic data that suggest that LIS1 may have coevolved with an autoinhibitory mode of cytoplasmic dynein regulation.	0
BACKGROUND:Chromothripsis is an event of genomic instability leading to complex chromosomal alterations in cancer. Frequent long-range chromatin interactions between transcription factors (TFs) and targets may promote extensive translocations and copy-number alterations in proximal contact regions through inappropriate DNA stitching. Although studies have proposed models to explain the initiation of chromothripsis, few discussed how TFs influence this process for tumor progression. METHODS:This study focused on genomic alterations in amplification associated regions within chromosome 17. Inter-/intra-chromosomal rearrangements were analyzed using whole genome sequencing data of breast tumors in the Cancer Genome Atlas (TCGA) cohort. Common ERα binding sites were defined based on MCF-7, T47D, and MDA-MB-134 breast cancer cell lines using univariate K-means clustering methods. Nanopore sequencing technology was applied to validate frequent rearrangements detected between ATC loci on 17q23 and an ERα hub on 20q13. The efficacy of pharmacological inhibition of a potentially druggable target gene on 17q23 was evaluated using breast cancer cell lines and patient-derived circulating breast tumor cells. RESULTS:There are five adjoining regions from 17q11.1 to 17q24.1 being hotspots of chromothripsis. Inter-/intra-chromosomal rearrangements of these regions occurred more frequently in ERα-positive tumors than in ERα-negative tumors. In addition, the locations of the rearrangements were often mapped within or close to dense ERα binding sites localized on these five 17q regions or other chromosomes. This chromothriptic event was linked to concordant upregulation of 96 loci that predominantly regulate cell-cycle machineries in advanced luminal tumors. Genome-editing analysis confirmed that an ERα hub localized on 20q13 coordinately regulates a subset of these loci localized on 17q23 through long-range chromosome interactions. One of these loci, Tousled Like Kinase 2 (TLK2) known to participate in DNA damage checkpoint control, is an actionable target using phenothiazine antipsychotics (PTZs). The antiproliferative effect of PTZs was prominent in high TLK2-expressing cells, compared to low expressing cells. CONCLUSION:This study demonstrates a new approach for identifying tumorigenic drivers from genomic regions highly susceptible to ERα-related chromothripsis. We found a group of luminal breast tumors displaying 17q-related chromothripsis for which antipsychotics can be repurposed as treatment adjuncts.	0
RecQ helicases belong to a ubiquitous family of DNA unwinding enzymes that are essential to maintain genome stability by acting at the interface between DNA replication, recombination, and repair. Humans have five different paralogues of RecQ helicases namely RecQ1, BLM, WRN, RecQ4, and RecQ5. Germ-line mutations in these helicases give rise to distinct human genetic disorders, Bloom Syndrome, Werner Syndrome, Rothmund-Thomson, RAPADILINO, and Baller-Gerold syndromes. Other than distinct clinical symptoms, all these genetic disorders show a predisposition to cancer. While the three paralogues BLM, WRN, and RecQ4 are directly associated with syndromes, loss of function of RecQ1 and RecQ5 are also emerging to be causative of various types of cancer. This review summarizes the domain architecture of RecQ helicases and the mutations that are associated with various diseases. Here we observe the occurrence of disease-causing mutations mainly in the catalytic regions of the proteins, and that some of these mutations are common between the respective disorders and cancer. Furthermore, this review discusses the results of several reports that study the role of residues with disease-causing mutations. It also overviews the research focusing on RecQ helicases as potential targets for cancer therapy.	0
OBJECTIVES:There are several types of metaphyseal chondrodysplasia and various clinical types have been differentiated. The Schmid type of metaphyseal chondrodysplasia is the most common. Diffuse metaphyseal flaring, irregularity, and growth plate widening, which are most severe in the knees, are the most striking radiological features of this disease. The Schmid type of metaphyseal dysostosis is characterized by failure of normal mineralization of the zone of provisional calcification, leading to widened physes and enlarged knobby metaphyses, effectively causing shortening of the tubular bones, splaying of the metaphyses, coxa vara, and bow legs. Orthopaedic interventions were primarily performed on the lower extremities. METHODS:Twelve children (seven girls and five boys) aged 7-10 years were enrolled in this study. Moderate short stature was a uniform feature associated with predominant involvement of the proximal femora and bow legs resulted in the development of angular deformities. A waddling gait was a consequence of coxa vara in eight children. Valgus osteotomy of the proximal femur was planned after physeal closure for the group of children with coxa vara. Hemiepiphysiodesis was performed to re-align the genu varum in three children. RESULTS:Other forms of metaphyseal dysostosis were ruled based on full clinical and radiographic phenotypes, with confirmation through molecular pathology. Mutations in the COL10A1 gene located on chromosome 6q21-q22.3 were confirmed. Re-alignment was accomplished in our group of patients. CONCLUSION:The most striking clinical features of Schmid metaphyseal chondrodysplasia which appear within the first 2-3 years of life are: moderate short limbs and short stature, a waddling gait, and increasing shortness of stature with age. The Schmid type of metaphyseal chondrodysplasia is a disorder that arises from defective type X collagen, which is typically found in the hypertrophic zone of the physes. Moderate short stature and a waddling gait associated with pain are the most common clinical presentations. Osteotomies to correct bow legs are sometimes combined with lengthening procedures. Recurrence of the deformities with growth is not uncommon; therefore, hemiepiphysiodesis or stapling might be indicated in some cases.	0
Imatinib, which inhibits tyrosine kinase activity of Bcr-Abl protein, is a standard form of treatment for chronic myeloid leukemia (CML). Through its immunomodulatory effect it affects T cell function in a number of ways. It inhibits antigen-induced T cell activation and proliferation. Antigen-specific T-cells and macrophages are vital for protection against Mycobacterium tuberculosis. Here we present a case of renal tuberculosis associated with imatinib therapy in the maintenance phase of CML. With granulomatous interstitial nephritis and positive tubercular DNA on renal biopsy, the condition was successfully treated with anti-tubercular therapy. This case provides support to the hypothesis that imatinib therapy in CML increases the susceptibility to tuberculosis and strict vigilance is required to enable its early detection and treatment.	0
Introduction:White matter signal changes are common in wide spectrum of disorders other than primary demyelinating diseases. Knowledge into their characteristics is of great relevance as treatment options are available in most cases, if diagnosed early. Patient and methods:Patients both children and adults who showed radiological evidences of leukoencephalopathy which was not due to primary demyelinating disorders were evaluated in detail. Results:There were a total of 55 patients in the last 2 years. 58% patients were <10 years, 16% were <20years, 9% were <30 years and the rest of the patients were 40 and above. Commonest condition was ALD, followed by SSPE and Unclassified group. There were 3 cases each of MLD, Krabbe's, Vanishing White Matter Disease and Hypomyelination. Discussion and Conclusion:White matter disorders belong to a wide spectrum of illnesses which varies from degeneration to a spectrum of other disorders. Correlating the clinical, radiological and other laboratory data are mandatory for proper diagnosis. Those who belong to older age with shorter duration and uncharacterized radiological features suffered from acquired treatable causes.	0
Ameloblastoma is a benign odontogenic tumor which undergoes malignant transformation to ameloblastic carcinoma. However, rarely it metastasizes without undergoing cytological malignant changes, an entity referred to as Metastasizing Ameloblastoma (MA). Through this study we aimed to review cases of MA reported since 2000 to explore the impact of clinico-demographic variables on its prognosis. Based on PRISMA guidelines, a review of relevant literature from PubMed/Medline, Science Direct and Cochrane database was performed from January 2000 to March 2019. A total of 65 cases were considered for further evaluation as per predefined inclusion and exclusion criteria. Results showed that lungs followed by lymph nodes were the most common sites for benign metastatic deposits. Multiple recurrences and inadequate surgical removal increase the probability of distant metastatic spread. Despite having benign cytological features, tumor recurrence and metastasis were associated with an unfavorable clinical outcome in MA.	0
Isodicentric chromosome 15, also called idic(15), is a rare chromosomal abnormality resulting from inverted duplication of proximal 15q. It is associated with specific clinical findings such as early central hypotonia, developmental delay, cognitive dysfunction, autism spectrum disorders, and seizure. Herein we describe a case of a girl with idic(15) syndrome who developed acute lymphoblastic leukemia (ALL) at the age of 9 years. Our case suggests a possible correlation between idic(15) and ALL, and possible functional links between these two conditions.	0
We investigated a four-generation family of German ancestry with distal myopathy. Four individuals in two generations were affected. Foot and toe extensor paresis progressing very slowly over decades was the core neurological sign, reflected by fatty infiltration of the lower leg extensor muscles on muscle MRI. Additionally, finger extensor paresis was present in two patients and quadriceps muscle paresis in one. Distal sensory signs had initially given rise to the diagnosis of axonal Charcot-Marie-Tooth (CMT) disease. Two patients had extended verrucae of their foot sole, which may or may not be part of the disease spectrum. All four patients had a novel c.4645G > C mutation in exon 34 of the MYH7 gene that was not present in three clinically unaffected family members. Muscle biopsy of one patient revealed a myopathic pattern associated with type 1 muscle fibre atrophy and core-like lesions in many muscle fibres consistent with a myosin-related myopathy. We conclude that some of the typical clinical signs such as extensor weakness of the big toe and the little finger may only develop in the further course of the disease.	0
RATIONALE:Neonatal cholestasis is one of the most serious diseases in infancy. Progressive familial intrahepatic cholestasis (PFIC) is a disease that leads to intrahepatic cholestasis. It is one of the common causes of neonatal cholestasis in addition to biliary atresia (BA). The differential diagnosis of neonatal cholestasis is clinically challenging for pediatricians. PATIENT CONCERNS:A 4-month-old female presented with severe jaundice, pruritus, and pale stool for 20 days. Abnormally strong echoes near the portal area, an abnormally small gallbladder with an irregularly stiff wall, and splenomegaly were identified on abdominal ultrasound. Blood tests showed elevated alanine aminotransferase, total bilirubin, conjugated bilirubin, gamma-glutamyltranspeptidase, and total bile acid levels. DIAGNOSIS:Intraoperative cholangiography showed BA. ABCB4 gene mutation IVS13+6G>A/G was confirmed by genetic testing. The patient was diagnosed with BA combined with PFIC3. INTERVENTIONS:Kasai portoenterostomy and ursodeoxycholic acid were used for treatment. OUTCOMES:Her clinical symptoms and blood tests improved gradually. No recurrence was noted during 1 year of follow-up. LESSONS:Additional examinations, such as genetic testing, should be considered in patients with BA who had refractory jaundice after Kasai portoenterostomy in order to exclude intrahepatic cholestasis.	0
ALG11-Congenital Disorder of Glycosylation (ALG11-CDG, also known as congenital disorder of glycosylation type Ip) is an inherited inborn error of metabolism due to abnormal protein and lipid glycosylation. We describe two unrelated patients with ALG11-CDG due to novel mutations, review the literature of previously described affected individuals, and further expand the clinical phenotype. Both affected individuals reported here had severe psychomotor disabilities and epilepsy. Their fibroblasts synthesized truncated precursor glycan structures, consistent with ALG11-CDG, while also showing hypoglycosylation of a novel biomarker, GP130. Surprisingly, one patient presented with normal transferrin glycosylation profile, a feature that has not been reported previously in patients with ALG11-CDG. Together, our data expand the clinical and mutational spectrum of ALG11-CDG.	0
Ataxia with oculomotor apraxia (AOA) is a clinical syndrome featuring a group of genetic diseases including at least four separate autosomal-recessive cerebellar ataxias. All these disorders are due to altered genes involved in DNA repair. AOA type 4 (AOA4) is caused by mutations in DNA repair factor polynucleotide kinase phosphatase (PNKP), which encodes for a DNA processing enzyme also involved in other syndromes featured by microcephaly or neurodegeneration. To date, only a few AOA4 patients have been reported worldwide. All these patients are homozygous or compound heterozygous carriers for mutations in the kinase domain of PNKP. In this report, we describe a 56 years old patient affected by AOA4 characterized by ataxia, polyneuropathy, oculomotor apraxia, and cognitive impairment with the absence of dystonia. The disease is characterized by a very late onset (50 years) when compared with other AOA4 patients described so far (median age of onset at 4 years). In this proband, Clinical Exome Analysis through Next Generation Sequencing (NGS) consisting of 4,800 genes, identified the PNKP homozygous mutation p.Gln50Glu. This variant, classified as a likely pathogenic variant according to American College of Medical Genetics (ACMG) guidelines, does not involve the kinase domain but falls in the fork-head-associated (FHA) domain. So far, mutations in such a domain were reported to associate only with a pure seizure syndrome without the classic AOA4 features. Therefore, this is the first report of patients carrying a mutation of the FHA domain within the PNKP gene which expresses the clinical phenotype known as the AOA4 syndrome and the lack of any seizure activity. Further studies are required to investigate specifically the significance of various mutations within the FHA domain, and it would be worth to correlate these variants with the age of onset of the AOA4 syndrome.	0
The clinical evaluation of a patient with dystonia is a stepwise process, beginning with classification of the phenomenology of the movement disorder(s), then formulation of the dystonia syndrome, which, in turn, leads to a targeted etiological differential diagnosis. In recent years, there have been significant advances in our understanding of the etiological basis of dystonia, aided especially by discoveries in imaging and genetics. In this review, we provide an update on the assessment of a patient with dystonia, including the phenomenology of dystonia and highlighting how to integrate clinical, imaging, blood, and neurophysiological investigations in order to formulate a dystonia syndrome. Evolving or emerging dystonia syndromes are reviewed, and potential etiologies of these as well as established dystonia syndromes listed to guide diagnostic testing. © 2013 Movement Disorder Society.	0
In this report, we describe a 2.5-year-old severely mentally retarded boy with peculiar appearance and generalized ichthyosis, born to consanguineous Turkish parents. The histological finding in the skin biopsy of unusually large oval keratohyalin granules in the granular cells is unique, and hitherto has not been reported in other ichthyosis-mental retardation syndromes.	0
Background: REEP1 is a common cause of autosomal dominant hereditary spastic paraplegia (HSP) but is rare in China. The pathological mechanism of REEP1 is not fully understood. Methods: We screened for REEP1 mutations in 31 unrelated probands from Chinese HSP families using next-generation sequencing targeting pathogenic genes for HSP and other related diseases. All variants were validated by Sanger sequencing. The proband family members were also screened for variants for the segregation analysis. All previously reported REEP1 mutations and cases were reviewed to clarify the genetic and clinical features of REEP1-related HSP. Results: A pathogenic mutation, REEP1c. 125G>A (p.Trp42*), was detected in a pure HSP family from North China out of 31 HSP families (1/31). This locus, which is located in the second hydrophobic domain of REEP1, is detected in both Caucasian patients with complicated HSP phenotypes and Chinese pure HSP families. Conclusion: REEP1-related HSP can be found in the Chinese population. The 42nd residue is a novel transethnic mutation hotspot. Mutations in this spot can lead to both complicated and pure form of HSP. Identification of transethnic hotspot will contribute to clarify the underlying pathological mechanisms.	0
Limb girdle muscular dystrophy type 2I (LGMD2I) is a progressive disorder caused by mutations in the FuKutin-Related Protein gene (FKRP). LGMD2I displays clinical heterogeneity with onset of severe symptoms in early childhood to mild calf and thigh hypertrophy in the second or third decade. Patients homozygous for the common FKRP mutation c.826C>A (p.Leu276Ile) show phenotypes within the milder end of the clinical spectrum. However, this group also manifests substantial clinical variability. FKRP deficiency causes hypoglycosylation of α-dystroglycan; a component of the dystrophin associated glycoprotein complex. α-Dystroglycan hypoglycosylation is associated with loss of interaction with laminin α2, which in turn results in laminin α2 depletion. Here, we have attempted to clarify if the clinical variability seen in patients homozygous for c.826C>A is related to alterations in muscle fibre pathology, α-DG glycosylation levels, levels of laminin α2 as well as the capacity of α-DG to bind to laminin. We have assessed vastus lateralis muscle biopsies from 25 LGMD2I patients harbouring the c.826C>A/c.826C>A genotype by histological examination, immunohistochemistry and immunoblotting. No clear correlation was found between clinical severity, as determined by self-reported walking function, and the above features, suggesting that more complex molecular processes are contributing to the progression of disease.	0
Cases of jaw masses abound in our environment which is a tropical one, with Burkitt lymphoma being the commonest aetiology. However rarer causes like juvenile aggressive ossifying fibroma should also be considered. It is a locally aggressive tumor with high recurrent potentials occurring in children and adolescent. Here we present the clinical features, physical findings and challenges in diagnosing and management of a 7-year-old boy who presented to the Paediatric unit of our institute with a right jaw mass.	0
Background:To describe the presence of epiretinal proliferation in eyes with various retinal and vitreoretinal interface conditions. Methods:Consecutive patients seen at the Stein Eye Institute, by one retina specialist, from December 2018 to March 2019, and demonstrating epiretinal proliferation on optical coherence tomography (OCT) were enrolled in this cross-sectional study. Included patients were divided into two groups: vitreoretinal interface pathologies group or retinal diseases group. Presence of epiretinal proliferation and its localization within the 9 macular sectors, as defined by the Early Treatment Diabetic Retinopathy Study (ETDRS), were assessed on OCT. Results:77 eyes from 69 patients demonstrated epiretinal proliferation on OCT. The most frequently involved ETDRS sector was the 1-mm central subfield, followed by inner temporal and inner nasal sectors. Localization of epiretinal proliferation correlated with the presence of any retinal abnormalities in the same quadrant (r = 0.962; P < 0.0001). 31 eyes (40.3%) demonstrated symptomatic vitreoretinal interface pathologies including lamellar macular hole, full-thickness macular hole, epiretinal membrane and history of macular peeling. 46 eyes (59.7%) manifested various retinal diseases, including age-related macular degeneration, diabetic retinopathy, refractory macular edema, vein occlusion and high myopia. Conclusions:Epiretinal proliferation was noted in several retinal conditions and not limited only to full-thickness and lamellar macular holes. Different mechanisms affecting retinal homeostasis might trigger Müller cells dysregulation, potentially leading to abnormal retinal remodeling.	0
INTRODUCTION:CNV is a vital pathogenic factor of congenital heart disease (CHD). However, few CNVs have been reported for total anomalous pulmonary venous connection (TAPVC), which is a rare form of CHD. Using case-control study, we identified 15q11.2 deletion associated with TAPVC. We then used a TAPVC trio as model to reveal possible molecular basis of 15q11.2 microdeletion. METHODS:CNVplex and Chromosomal Microarray were used to identify and validate CNVs in samples from 231 TAPVC cases and 200 healthy controls from Shanghai Children's Medical Center. In vitro cardiomyocyte differentiation of induced pluripotent stem cells from peripheral blood mononuclear cells for a TAPVC trio with paternal inherited 15q11.2 deletion was performed to characterise the effect of the deletion on cardiomyocyte differentiation and gene expression. RESULTS:The 15q11.2 microdeletion was significantly enriched in patients with TAPVC compared with healthy control (13/231 in patients vs 0/200 in controls, p=5.872×10-2, Bonferroni adjusted) using Fisher's exact test. Induced pluripotent stem cells from the proband could not differentiate into normal cardiomyocyte. Transcriptomic analysis identified a number of differentially expressed genes in the 15q11.2 deletion carriers of the family. TAPVC disease-causing genes such as PITX2, NKX2-5 and ANKRD1 showed significantly higher expression in the proband compared with her healthy mother. Knockdown of TUBGCP5 could lead to abnormal cardiomyocyte differentiation. CONCLUSION:We discovered that the 15q11.2 deletion is significantly associated with TAPVC. Gene expression profile that might arise from 15q11.2 deletion for a TAPVC family was characterised using cell experiments.	0
OBJECTIVE:The diagnosis of fetal akinesia deformation sequence (FADS) is a challenge. Motor assessment is of additional value to advanced ultrasound examinations (AUE) for in utero FADS diagnosis before 24 weeks of gestation. METHODS:All consecutive fetuses with greater than or equal to two contractures on the 20 week structural anomaly scan (2007-2016) were included. Findings at AUE, including motor assessment were analysed and related to outcome. RESULTS:Sixty-six fetuses fulfilled the inclusion criteria. On the basis of the first AUE, FADS was suspected in 13 of 66, arthrogryposis multiplex congenita (AMC) in 12 of 66, bilateral pes equinovares (BPEV) in 40 of 66, and Holt-Oram syndrome in one of 66. On the basis of the first motor assessment, the suspected diagnosis changed in 19 of 66, in 13 of 66 worsening to FADS, six of 66 amelioration from FADS, and confirmed FADS in seven of 13. The result was 20 FADS, seven AMC, and 38 BPEV. Second AUE in 44 fetuses showed additional contractures in two of eight FADS, and one intrauterine fetal death (IUFD). The second motor assessment changed the diagnosis in three of 43, one worsening from BPEV into FADS, two ameliorations from FADS, and confirmed FADS in seven by deterioration of motility. The result was nine FADS, six AMC, and 29 BPEV. CONCLUSION:The results suggest that motor assessment has additional value to distinguish between FADS, AMC, and BPEV.	0
BACKGROUND:The purpose of this study was to compare the impact of the extent of excision and the patent bile duct flow on treatment outcomes of bile duct cysts (BDCs). METHODS:We retrospectively analyzed the records of 382 patients who received surgery for BDCs from January 2005 to December 2014. RESULTS:For Type Ia cysts, proper bile flow was associated with good long-term treatment outcomes with a greater level of significance (p < 0.001) than complete excision (p = 0.012). For Type IVa cysts, proper bile flow, but not complete excision, was associated with good long-term outcomes (p < 0.00001). In addition, 96.3% (104/108) of Type IVa patients with proper bile flow had no late complications and good biliary function, while no patient without patent bile flow had a good clinical outcome. For Type Ic cysts, 92 patients who received partial excisions had good outcomes when proper bile flow was restored. Regression analysis revealed that the absence of proper bile flow, in comparison to incomplete excision, is a greater risk factor for poor long-term treatment effects for Type Ia and Type IVa cysts. CONCLUSIONS:Compared to complete excision, the establishment of proper bile flow exerted a greater impact on improving long-term clinical outcomes after BDC surgery.	0
BACKGROUND:Idiopathic hypertrophic pachymeningitis is a rare inflammatory condition with diffuse thickening of the dura mater, which may cause a compressive effect or vascular compromise. CASE DESCRIPTION:A 40-year-old Chinese man presented with persistent headache for 6 months and a sudden epileptic seizure 2 days ago. Magnetic resonance imaging demonstrated a large (71 × 34 × 27 mm) extra-axial mass at the right frontal convexity with severe edema mimicking meningioma. The lesion and peripheral dura mater showed contrast enhancement. Additionally, the skull near the lesion was eroded. Meningioma was diagnosed, and the patient underwent surgery. During the operation, we found the lesion texture was very tough, and the superior sagittal sinus was occluded. Histopathologic findings revealed a large number of infiltrated lymphocytes with fibrosis and microabscess formation; intracranial idiopathic hypertrophic pachymeningitis was diagnosed. Follow-up magnetic resonance imaging performed 3 months after surgery demonstrated the enhancement was notably alleviated. CONCLUSIONS:Idiopathic hypertrophic pachymeningitis should be part of the differential diagnosis of some cases of meningioma.	0
A large solitary intrathoracic mass was identified in a patient with concurrent immunodeficiency. The patient was found to have a type AB thymoma and was diagnosed with Good's syndrome. A case report demonstrates the importance of timely surgical intervention for this rare syndrome.	0
Individuals affected with autosomal recessive cutis laxa type 2B and 3 usually show translucent skin with visible veins and abnormal elastic fibers, intrauterine and/or postnatal growth restriction and a typical triangular facial gestalt. Here we describe three unrelated individuals in whom such a cutis laxa syndrome was suspected, especially after electron microscopy revealed immature and less dense dermal elastic fibers in one of them. However, one of these children also displayed optic atrophy and two hypogammaglobulinemia. All had elevated liver enzymes and acute liver failure during febrile episodes leading to early demise in two of them. The only surviving patient had been treated with immunoglobulins. Through exome sequencing we identified mutations in NBAS, coding for a protein involved in Golgi-to-ER transport. NBAS deficiency causes several rare conditions ranging from isolated recurrent acute liver failure to a multisystem disorder mainly characterized by short stature, optic nerve atrophy and Pelger-Huët anomaly (SOPH). Since we subsequently verified Pelger-Huët anomaly in two of the patients the diagnosis SOPH syndrome was unequivocally proven. Our data show that SOPH syndrome can be regarded as a differential diagnosis for the progeroid forms of cutis laxa in early infancy and that possibly treatment of the hypogammaglobulinemia can be of high relevance for the prognosis.	0
Neocentromeres are fully functional centromeres that have arisen in previously noncentromeric chromosomal locations on rearranged chromosomes. The formation of neocentromeres results in the mitotic stability of chromosomal fragments that do not contain endogenous centromeres and that would normally be lost. Here we describe a unique collection of eight independent patient-derived cell lines, each of which contains a neocentromere on a supernumerary inversion duplication of a portion of human chromosome 13q. Findings in these patients reveal insight into the clinical manifestations associated with polysomy for portions of chromosome 13q. The results of FISH and immunofluorescent analysis of the neocentromeres in these chromosomes confirm the lack of alpha-satellite DNA and the presence of CENtromere proteins (CENP)-C, -E, and hMAD2. The positions of the inversion breakpoints in these chromosomes have been placed onto the physical map of chromosome 13, by means of FISH mapping with cosmid probes. These cell lines define, within chromosome 13q, at least three distinct locations where neocentromeres have formed, with five independent neocentromeres in band 13q32, two in band 13q21, and one in band 13q31. The results of examination of the set of 40 neocentromere-containing chromosomes that have thus far been described, including the 8 neocentromere-containing chromosomes from chromosome 13q that are described in the present study, suggest that chromosome 13q has an increased propensity for neocentromere formation, relative to some other human chromosomes. These neocentromeres will provide the means for testing hypotheses about sequence requirements for human centromere formation.	0
Aristaless-like homeobox 4 (ALX4) gene is an important transcription regulator in skull and limb development. In humans and mice ALX4 mutations or loss of function result in a number of skeletal and organ malformations, including polydactyly, tibial hemimelia, omphalocele, biparietal foramina, impaired mammary epithelial morphogenesis, alopecia, coronal craniosynostosis, hypertelorism, depressed nasal bridge and ridge, bifid nasal tip, hypogonadism, and body agenesis. Here we show that a complex skeletal malformation of the hind limb in Galloway cattle together with other developmental anomalies is a recessive autosomal disorder most likely caused by a duplication of 20 bp in exon 2 of the bovine ALX4 gene. A second duplication of 34 bp in exon 4 of the same gene has no known effect, although both duplications result in a frameshift and premature stop codon leading to a truncated protein. Genotyping of 1,688 Black/Red/Belted/Riggit Galloway (GA) and 289 White Galloway (WGA) cattle showed that the duplication in exon 2 has allele frequencies of 1% in GA and 6% in WGA and the duplication in exon 4 has frequencies of 23% in GA and 38% in WGA. Both duplications were not detected in 876 randomly selected German Holstein Friesian and 86 cattle of 21 other breeds. Hence, we have identified a candidate causative mutation for tibial hemimelia syndrome in Galloway cattle and selection against this mutation can be used to eliminate the mutant allele from the breed.	0
Treatment during pregnancy is problematic. The Food and Drug Administration established drug categories to help in the treatment process. First-generation antihistamines are considered safe but they have sedative properties. Second-generation antihistamines cause less adverse reactions but besides cetirizine and loratadine they belong to category C. All retinoids should be avoided during pregnancy due to the risk of fetal malformations. Antimalarial drugs should be considered based on the clinical data. Sulfones can be considered as safe for use during pregnancy only with proper monitoring. Prednisone is administered in pregnancy. Other glucocorticosteroids have a different safety profile. Cyclosporine A treatment should be reserved as rescue therapy in severe stages of the disease. Treatment during pregnancy should be precise when it comes to pregnant woman and safe for the fetus.	0
Headache is one of the commonest complaints reported to physicians worldwide. Yet, arriving at the proper diagnosis can be a challenge in many patients. Although most headaches belong to common categories of migraine and tension-type headache, which are diagnosed and managed relatively easily, several uncommon headache disorders can lead to delays in diagnosis. Certain medications are more efficacious than others in managing these headache disorders, hence establishing the correct diagnosis is of paramount importance.An 86-year-old female presented with chronic daily headache of 1 year duration. Her headaches were exclusively nocturnal and woke her up daily around midnight. Clinical examination was unremarkable. All basic investigations were normal. Subsequent gadolinium enhanced Magnetic Resonance Imaging (MRI) brain did not show any significant pathology. There was no satisfactory response to paracetamol, diclofenac sodium, mefenamic acid, tramadol, flunarizine and sodium valproate. Indomethacin was started with the provisional diagnosis of hypnic headache. There was absolute response by day 3 of indomethacin. She remains headache free on low dose indomethacin maintenance at 1 year after the diagnosis.Better understanding of uncommon headache syndromes can help in early diagnosis and appropriate treatment. Hypnic headache should be considered in the differential diagnosis of chronic daily headaches, especially when nocturnal and occurs during sleep.	0
Amino acid transporters play very important roles in nutrient uptake, neurotransmitter recycling, protein synthesis, gene expression, cell redox balance, cell signaling, and regulation of cell volume. With regard to transporters that are closely connected to metabolism, amino acid transporter-associated diseases are linked to metabolic disorders, particularly when they involve different organs, cell types, or cell compartments. To date, 65 different human solute carrier (SLC) families and more than 400 transporter genes have been identified, including 11 that are known to include amino acid transporters. This review intends to summarize and update all the conditions in which a strong association has been found between an amino acid transporter and an inherited metabolic disorder. Many of these inherited disorders have been identified in recent years. In this work, the physiological functions of amino acid transporters will be described by the inherited diseases that arise from transporter impairment. The pathogenesis, clinical phenotype, laboratory findings, diagnosis, genetics, and treatment of these disorders are also briefly described. Appropriate clinical and diagnostic characterization of the underlying molecular defect may give patients the opportunity to avail themselves of appropriate therapeutic options in the future.	0
49,XXXXY was previously associated with profound to severe intellectual deficits. However, prior research papers on the cognitive profiles of this population were confounded by small samples sizes, wide age spreads, and incomplete histories of testosterone replacement therapy. This study is the first comprehensive, international investigation of the neurocognitive aspects of 49,XXXXY, and the potential effects of biological treatment on this profile. Sixty-seven boys from infancy to 11 years of age were enrolled in this longitudinal study, with the majority of boys postnatally diagnosed though chromosomal analysis. These boys received a comprehensive neurocognitive evaluation tailored to specific language-based deficits and cognitive challenges. Results revealed higher neurocognitive capacities, both verbally and nonverbally, than previously reported in this disorder. Infant boys with 49,XXXXY who received early hormonal therapy (EHT) had significantly higher scores on the cognitive domain of the Bayley Scales of Infant Development than untreated infants (p = .013). In addition, treated school-aged participants had significantly better scaled scores than untreated boys in form completion (p = .042), a task that requires deductive reasoning, on nonverbal testing on the Leiter International Performance Scales. This study indicates greater cognitive capacities with a wide range of abilities in the child with 49,XXXXY, thus warranting further investigation to identify and understand the critical influences on the etiology and the variability of those capacities.	0
INTRODUCTION:Bilateral giant parathyroid adenoma in the absence of multiple endocrine neoplasia (MEN) type 1 is extremely rare and literature on this subject is limited. CASE HISTORY:A 79-year-old man presented with acute kidney injury secondary to hypercalcaemia. Blood test results indicated primary hyperparathyroidism. Ultrasonography revealed bilateral parathyroid adenomas measuring 19.4mm x 19.5mm x 18.8mm (left) and 15.2mm x 18.3mm x 19.6mm (left) whereas on computed tomography, the measurements were 31mm x 20mm (left) and 30mm x 14mm (right). Intraoperatively, giant adenomas measuring 50mm x 25mm x 12mm (left, weighing 8.101g) and 48mm x 22mm x 10mm (right, weighing 7.339g) were identified and excised. Parathyroid hormone level dropped from 44.6pmol/l preoperatively to 8.9pmol/l postoperatively (normal range 1.3-7.6pmol/l). The patient was discharged with no complications. CONCLUSIONS:We report a rare phenomenon where bilateral giant parathyroid adenoma occurred in the absence of MEN type 1. It highlights the importance of cross-sectional imaging in delineating the anatomy of adenomas as their size can be grossly underestimated by ultrasonography alone.	0
A 53-year-old man was admitted to a peripheral hospital with the diagnosis of acute myocardial infarction without ST elevation. Due to the concomitant presence of first-diagnosed thrombocytopenia (platelet count 50.000/μL), it was decided to be treated conservatively with clopidogrel. Five days later, he developed an acute myocardial infarction with ST elevation (STEMI) and was transferred to our department for primary percutaneous coronary intervention (PCI). Coronary angiography revealed three-vessel disease. The left anterior descending lesion was considered culprit, and PCI was successfully performed using a drug-eluting balloon. This approach was considered safer due to the risk of intolerance of prolonged dual antiplatelet therapy in case of stent implantation. Indeed, four days later, aspirin was discontinued, and the patient remained only on clopidogrel due to a platelet fall. Meanwhile, idiopathic thrombocytopenic purpura (ITP) was diagnosed by hematology consultation, and specific ITP treatment was initiated. Seven days following the procedure, the patient was transferred to the Hematology clinic, where a continuous rise of platelet count up to 115.000/μL while on clopidogrel was observed, and he was discharged from the hospital asymptomatic. Unfortunately, twenty days later, the patient died of a lung infection. In ITP patients with STEMI, primary PCI with drug-eluting balloon angioplasty may be a reasonable approach.	0
Richter syndrome (RS) is an uncommon evolution of chronic lymphocytic leukaemia (CLL) with a dismal prognosis. Clinical-biological features predicting outcome and best therapeutic approach for these patients remain to be established. In this study, 128 patients with RS, including 112 diffuse large B-cell lymphoma (DLBCL)-type RS, 15 Hodgkin lymphoma (HL)-type RS, and one plasmablastic lymphoma, were identified in 11 centres of the Spanish CLL Study Group (GELLC). The median overall survival (OS) was 5·9 months for DLBCL-type RS and 30·8 months for HL-type RS. Eastern Cooperative Oncology Group Performance Status, haemoglobin level, platelet count, serum lactate dehydrogenase and β2-microglobulin levels, tumour protein p53 (TP53) abnormalities in the CLL clone concomitant to RS, number of prior therapies, and clonal relationship between CLL and RS, were associated with OS in patients with DLBCL-type RS. A platelet count of <100 × 109 /l, prior CLL therapy (0 vs. ≥1), and presence of TP53 alterations maintained an independent prognostic impact in the multivariate analysis. Patients without any of these factors had a better clinical outcome, with a median OS of 75·3 months, while patients with one or two or more of these factors presented a median OS of 25·5 and 3 months, respectively. Although OS of patients with RS is generally poor, a proportion of patients achieved prolonged survival. Treatment of RS remains a medical need, and further therapeutic approaches with novel therapies are warranted.	0
Urinary dysfunctions are not considered symptoms of spinocerebellar ataxias (SCAs). However, given that a patient with SCAs without a family history might be misdiagnosed as MSA-C when having urinary dysfunctions, characterization of urinary dysfunctions in SCAs is needed not only to understand SCAs but also to correctly diagnosis patients with ataxia. We retrospectively reviewed medical records of 143 patients with genetically confirmed SCA1, 2, 3, 6, 7, 17, and DRPLA. Twenty-two patients (men n = 9; age 62.1 ± 10.9; disease duration 8.2 ± 2.9 years) who had lower urinary track symptoms (LUTS) were included in this study. Six patients underwent urodynamic study (UDS), and 2 underwent uroflowmetry. LUTS was present in 1 of 11 patients with SCA1, in 4 of 51 with SCA2, in 2 of 26 with SCA3, in 3 of 20 with SCA6, in 2 of 4 with SCA7, in 8 of 26 with SCA17, and in 2 of 5 with DRPLA. Overall, urinary frequency was the most common symptom (16 patients, 72.7%) followed by voiding difficulty. In three of the 6 patients with UDS, post-micturition residuals were > 100 ml. Detrusor overactivity was noted in three patients. Detrusor areflexia was observed in one. Four patients were diagnosed with a neurogenic bladder, 3 with a storage problem, and 1 with both storage and voiding problems. Fifteen percent of the patients with SCAs had LUTS, and LUTS occurred in various types of SCAs. Our results indicate that SCAs should be considered in patients with progressive cerebellar ataxia and urinary dysfunctions.	0
WAGR syndrome (OMIM #194072) is a rare genetic disorder that consists of development of Wilms' tumor (nephroblastoma), aniridia, genitourinary anomalies and intellectual disability (mental retardation). It is associated with WAGR-region deletions in the 11p13 chromosome region. Our previous study of congenital aniridia patients revealed a noticeable number of aniridia patients with WAGR-region deletions but without Wilms' tumor in their medical history. We assessed the involvement of other neighboring genes from affected chromosome regions in the patients with and without Wilms' tumor. Reliable confidence was obtained for the LMO2 gene, which is significantly more often deleted in patients with nephroblastoma. Thus, our study presents genetic evidence that the development of Wilms tumors in WAGR syndrome patients should be attributed to the deletion of WT1 and LMO2 rather than WT1 only.	0
BACKGROUND:Manganese is a critical trace element that not only has antioxidant properties, but also is essential for various metabolic pathways and neurotransmitters production. However, it can be toxic at high levels, particularly in the central nervous system. Manganese intoxication can be acquired, but an inherited form due to autosomal-recessive mutations in the SLC30A10 gene encoding a Mn transporter protein has also been reported recently. These mutations are associated with significant failure of manganese excretion and its storage in the liver, brain (especially basal ganglia), and other peripheral tissues, resulting in toxicity. CASE PRESENTATION:A 10-year-old boy from consanguineous parents presented with a history of progressive truncal instability, gait difficulty, and frequent falls for 2 months. He had dystonia, rigidity, ataxia, dysarthria, bradykinesia and a plethoric skin. Investigations showed polycythemia, low serum iron and ferritin levels, and increased total iron binding capacity. A brain MRI revealed symmetric hyperintensities in the basal ganglia and dentate nucleuses on TI images that were suggestive of brain metal deposition together with clinical manifestations. Serum calcium and copper levels were normal, while the manganese level was significantly higher than normal values. There was no history of environmental overexposure to manganese. Genetic testing showed a homozygous missense mutation in SLC30A10 (c.C1006T, p.His336Tyr) and Sanger sequencing confirmed a homozygous state in the proband and a heterozygous state in the parents. Regular treatment with monthly infusions of disodium calcium edetate and oral iron compounds resulted in decreased serum manganese and hemoglobin levels to normal values, significant resolution of MRI lesions, and partial improvement of neurological symptoms during 6 months of follow-up. CONCLUSION:The syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by SLC30A10 mutation is a treatable inherited metal deposition syndrome. The patient may only have pure neurological without hepatic manifestations. Although this is a rare and potentially fatal inborn error of metabolism, early diagnosis and continuous chelation therapy might improve the symptoms and prevent disease progression.	0
Objective: To analyze the detection of CYP21A2 gene mutations in 21-hydroxylase deficiency (21-OHD) patients, so as to determine the accuracy of clinical diagnosis. Methods: Totally, 514 patients with 21-OHD who visited Peking Union Medical College Hospital from January 2015 to January 2018 were enrolled and their clinical and biochemical data were collected. DNAs were extracted from peripheral blood leukocytes and CYP21A2 mutations were detected by Sanger sequencing and multiple ligation probe amplification (MLPA) technique. We divided 514 patients into three groups: two mutations of CYP21A2 alleles (group A), one mutation of CYP21A2 (group B), and no mutation of CYP21A2 (group C). Results: Mutation was detected in each allele of CYP21A2 gene in 401 (78.0%) patients, ninety (17.5%) had only one mutant allele and 23 (4.5%) had no mutation. There was no significant difference between the patients with different clinical phenotypes and the number of CYP21A2 gene mutations detected. In male, the cortisol of the patients with simple virilizing 21-OHD in group A [0.04 (0.02, 0.20) nmol/L] was lower than that of group B [0.24 (0.17, 0.28) nmol/L] and the difference was statistically significant (P=0.014). In female, 17-hydroxyprogesterone (17-OHP) of patients with salt wasting 21-OHD in group A [153.7 (90.1, 204.5) nmol/L] was higher than that of group B [38.2 (31.0, 183.3) nmol/L] and C [42.6 (27.8, 48.1) nmol/L] and the differences were statistically significant (both P<0.05). The progesterone of patients with simple virilizing 21-OHD in group C [23.0 (8.6, 33.2) nmol/L] was lower than that of gourp A [57.8 (34.4, 110.2) nmol/L] and B [63.6 (31.4, 110.8) nmol/L] and the difference were statistically significant (both P<0.05). The 17-OHP of patients with non-classical 21-OHD in group C [24.5 (20.4, 54.2) nmol/L] was lower than that of group A [158.7 (59.1, 187.6) nmol/L] and B [147.8 (131.9, 179.3) nmol/L]. The difference were statistically significant (both P<0.05). Conclusions: Mutations of two alleles have not been found in all patients with clinically diagnosed 21-OHD. Other congenital adrenal hyperplasia (CAH) types which can cause similar changes in 17-OHP and other hormones may be misdiagnosed as 21-OHD. Therefore, 21-OHD cannot be diagnosed with help of 17-OHP level only, and gene detection plays a vital role in the differential diagnosis of different CAH types.	0
BACKGROUND:Response evaluation of neoadjuvant chemotherapy (NACT) in patients with osteosarcoma is significant for the termination of ineffective treatment, the development of postoperative chemotherapy regimens, and the prediction of prognosis. However, histological response and tumour necrosis rate can currently be evaluated only in resected specimens after NACT. A preoperatively accurate, noninvasive, and reproducible method of response assessment to NACT is required. In this study, the value of multi-parametric magnetic resonance imaging (MRI) combined with machine learning for assessment of tumour necrosis after NACT for osteosarcoma was investigated. METHODS:Twelve patients with primary osteosarcoma of limbs underwent NACT and received MRI examination before surgery. Postoperative tumour specimens were made corresponding to the transverse image of MRI. One hundred and two tissue samples were obtained and pathologically divided into tumour survival areas (non-cartilaginous and cartilaginous tumour viable areas) and tumour-nonviable areas (non-cartilaginous tumour necrosis areas, post-necrotic tumour collagen areas, and tumour necrotic cystic/haemorrhagic and secondary aneurismal bone cyst areas). The MRI parameters, including standardised apparent diffusion coefficient (ADC) values, signal intensity values of T2-weighted imaging (T2WI) and subtract-enhanced T1-weighted imaging (ST1WI) were used to train machine learning models based on the random forest algorithm. Three classification tasks of distinguishing tumour survival, non-cartilaginous tumour survival, and cartilaginous tumour survival from tumour nonviable were evaluated by five-fold cross-validation. RESULTS:For distinguishing non-cartilaginous tumour survival from tumour nonviable, the classifier constructed with ADC achieved an AUC of 0.93, while the classifier with multi-parametric MRI improved to 0.97 (P = 0.0933). For distinguishing tumour survival from tumour nonviable, the classifier with ADC achieved an AUC of 0.83, while the classifier with multi-parametric MRI improved to 0.90 (P < 0.05). For distinguishing cartilaginous tumour survival from tumour nonviable, the classifier with ADC achieved an AUC of 0.61, while the classifier with multi-parametric MRI parameters improved to 0.81(P < 0.05). CONCLUSIONS:The combination of multi-parametric MRI and machine learning significantly improved the discriminating ability of viable cartilaginous tumour components. Our study suggests that this method may provide an objective and accurate basis for NACT response evaluation in osteosarcoma.	0
Here, we report brain white matter alterations in individuals clinically and genetically diagnosed with periodontal Ehlers-Danlos syndrome, a rare disease characterized by premature loss of teeth and connective tissue abnormalities. Eight individuals of two families clinically diagnosed with periodontal Ehlers-Danlos syndrome were included in the present study and underwent general physical, dental, and neurological examination. Whole exome sequencing was performed, and all patients included in the study underwent MRI of the brain. Whole exome sequencing revealed heterozygous C1R mutations c.926G>T (p.Cys309Phe, Family A) and c.149_150TC>AT (p.Val50Asp, Family B). All adult individuals (n = 7; age range 31 to 68 years) investigated by MRI had brain white matter abnormalities. The MRI of one investigated child aged 8 years was normal. The MRI pattern was suggestive of an underlying small vessel disease that is progressive with age. As observed in other leukoencephalopathies related to microangiopathies, the extent of the white matter changes was disproportionate to the neurologic features. Medical history revealed recurrent headaches or depression in some cases. Neurological examination was unremarkable in all individuals but one had mild cognitive decline and ataxia and experienced a seizure. The observation that periodontal Ehlers-Danlos syndrome caused by missense mutations in C1R is consistently associated with a leukoencephalopathy opens a new pathogenic link between the classical complement pathway, connective tissue, brain small vessels, and brain white matter abnormalities.	0
OBJECTIVE:To describe the incidence and prevalence of primary biliary cirrhosis in an urban population between 1987 and 1994, using stringent inclusion criteria and a well-defined study area and population. DESIGN:Descriptive study based on a case register compiled by a retrospective and prospective case-finding exercise and examination of case notes. SETTING:The city of Newcastle upon Tyne. MAIN INCLUSION CRITERIA: (1) Definite cases: fulfilling all three of the following diagnostic criteria: positive antimitochondrial antibody (AMA) > or = 1:40; cholestatic liver function tests (LFT); diagnostic or compatible liver histology. (2) Probable cases: fulfilling two of these criteria. SUBJECTS:All cases of primary biliary cirrhosis identified by multiple case-finding methods, alive from 1 January 1987 to 31 December 1994, in the defined area. MAIN OUTCOME MEASUREMENTS:Incidence and point prevalence rates by age and sex. RESULTS:In all, 202 potential cases were identified, of whom 160 met at least two inclusion criteria. In definite cases annual incidence varied from 14 to 32 (mean 22) per million whole population (with no clear trend) and point prevalence rose from 180 per million in 1987 to 240 in 1994. Mean age at diagnosis in cases incident during the study period was 63.2 years (S.D. 11.1 years, range 39.8-85.7 years). CONCLUSIONS:Primary biliary cirrhosis is much more common in Newcastle than has previously been reported anywhere in the world, and prevalence appears to be rising.	1
Clinical glycomics comprises a spectrum of different analytical methodologies to analyze glycan structures, which provides insights into the mechanisms of glycosylation. Within clinical diagnostics, glycomics serves as a functional readout of genetic variants, and can form a basis for therapy development, as was described for PGM1-CDG. Integration of glycomics with genomics has resulted in the elucidation of previously unknown disorders of glycosylation, namely CCDC115-CDG, TMEM199-CDG, ATP6AP1-CDG, MAN1B1-CDG, and PGM1-CDG. This review provides an introduction into protein glycosylation and presents the different glycomics methodologies ranging from gel electrophoresis to mass spectrometry (MS) and from free glycans to intact glycoproteins. The role of glycomics in the diagnosis of congenital disorders of glycosylation (CDG) is presented, including a diagnostic flow chart and an overview of glycomics data of known CDG subtypes. The review ends with some future perspectives, showing upcoming technologies as system wide mapping of the N- and O-glycoproteome, intact glycoprotein profiling and analysis of sugar metabolism. These new advances will provide additional insights and opportunities to develop personalized therapy. This is especially true for inborn errors of metabolism, which are amenable to causal therapy, because interventions through supplementation therapy can directly target the pathogenesis at the molecular level.	0
Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC) syndrome is an autosomal dominant genetic disease caused by COL4A1 gene mutation, with major clinical manifestations of white matter lesion, aneurysm, retinal artery tortuosity, polycystic kidney, microscopic hematuria and muscle cramps. This article reports the clinical features and genotype of one toddler with HANAC syndrome caused by COL4A1 gene mutation. The boy, aged 1 year and 8 months, had an insidious onset, with the clinical manifestations of pyrexia and convulsion, white matter lesions in the periventricular region and the centrum semiovale on both sides, softening lesions beside the left basal ganglia, retinal arteriosclerosis, microscopic hematuria and muscle cramps. Whole exome sequencing revealed a pathogenic de novo heterozygous mutation in the COL4A1 gene, (NM_001845) c.4150+1(IVS46)G>T, and therefore, the boy was diagnosed with HANAC syndrome. COL4A1 gene mutation detection should be performed for children with unexplained white matter lesion, stroke, hematuria, polycystic kidney, cataract and retinal artery tortuosity or families with related history.	0
Although Bell's palsy is a common etiology for isolated facial paralysis, it is important clinicians perform a complete neurologic examination to avoid misdiagnosis. Multiple cranial neuropathy is often caused by tumor or infection.	0
Cysteine is one of the two key sulfur-containing amino acids with important functions in redox homeostasis, protein functionality and metabolism. Cysteine is taken up by mammals via their diet and can also be derived from methionine via the transsulfuration pathway. The cellular concentration of cysteine is kept within a narrow range by controlling its synthesis and degradation. There are two pathways for the catabolism of cysteine leading to sulfate, taurine and thiosulfate as terminal products. The oxidative pathway produces taurine and sulfate, while the H2 S pathway involves different enzymatic reactions leading to the formation and clearance of H2 S, an important signalling molecule in mammals, resulting in thiosulfate and sulfate. Sulfite is a common intermediate in both catabolic pathways. Sulfite is considered as cytotoxic and produces neurotoxic S-sulfonates. As a result, a deficiency in the terminal steps of cysteine or H2 S catabolism leads to severe forms of encephalopathy with the accumulation of sulfite and H2 S in the body. This review links the homeostatic regulation of both cysteine catabolic pathways to sulfite and H2 S. LINKED ARTICLES: This article is part of a themed section on Chemical Biology of Reactive Sulfur Species. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.4/issuetoc.	0
The currently recognized two forms of "anabolic" protein aggregate myopathies, that is, defects in development, maturation and final formation of respective actin and myosin filaments encompass actinopathies and myosinopathies. The former are marked by mutations in the ACTA1 gene, largely of the de novo type. Aggregates of actin filaments are deposited within muscle fibers. Early clinical onset is often congenital; most patients run a rapidly progressive course and die during their first 2 years of life. Myosinopathies or myosin storage myopathies also commence in childhood, but show a much more protracted course owing to mutations in the myosin heavy chain gene MYH7. Protein aggregation consists of granular material in muscle fibers and few, if any, filaments.	0
Context: Post-traumatic syringomyelia treatment usually focuses on restoring normal cerebrospinal fluid (CSF) flow. Herein, the first-reported case of delayed post-traumatic syringomyelia associated with an L2 compression fracture 30 years prior to syringomyelia symptoms that rapidly progressed to the brainstem within 5 months, leading to respiratory and circulatory impairments, is summarized. The improvement in symptoms and significant decrease in size of the syringomyelia/syringobulbia achieved in this patient suggest that the initial treatment of choice in such acute cases should be posterior fossa decompression (PFD). Intradural exploration in order to restore the normal CSF flow at the level of trauma can then be planned in a later time.Findings: A retrospective analysis of clinical manifestations and findings obtained from magnetic resonance (MR) imaging, including pre-operative and post-operative follow-up data acquired 6 months later, provided adequate comparisons of the neurological deficits and syrinx size. Interestingly, serial MR images showed that a cervical syrinx acutely progressed to the brainstem within 5 months. PFD and sectioning of the thick veil completely obstructing the foramen of Magendie resulted in partial resolution of the neurological deficits and syringomyelia regression after surgery.Conclusions: To our knowledge, this is the first case report to summarize the delayed complications of a spinal cord injury and acute syringomyelia progression to the brainstem in a short period. The symptoms were relieved by an emergency PFD, chosen due to the rapid progression of symptoms. An atypical treatment strategy is described for extremely rare cases, but with a good short-term prognosis.	0
We report two cases of gastric metastases from primary breast cancers. In case 1, a 31-year-old woman with right-sided ductal breast carcinoma presented with nausea, vomiting and frank haematemesis, 8 months after mastectomy and adjuvant chemotherapy. An esophagogastroduodenoscopy (EGD) revealed multiple ulcerated gastric lesions secondary to metastatic adenocarcinoma from primary breast tumour. In case 2, an 84-year-old woman with a history of left lobular carcinoma presented with early satiety, 17 years after initial mastectomy and adjuvant endocrine therapy. An EGD revealed unspecific gastric mucosa with thickened and erythematous folds and biopsies revealed adenocarcinoma from primary breast carcinoma. Our cases demonstrate how gastric metastases have variable, non-specific clinical and endoscopic presentations. Symptoms may include nausea, vomiting, early satiety and gastrointestinal (GI) bleeding. Endoscopic appearance may range from thickened gastric folds to ulcerating lesions. Our cases demonstrate that gastric metastases should be considered in patients with breast cancer history presenting with GI symptoms.	0
OBJECTIVE:Contralateral elective neck dissection (cEND) in oral and oropharyngeal squamous cell cancer (OC/OPC) is still a matter of debate. The current study analyzed the outcome in OC/OPC patients with/without cEND. METHODS:OC/OPC patients (n = 471) were diagnosed with contralateral N0 after CT/MRI-scan combined with neck ultrasound. Clinico-pathological features were analyzed using Chi-square/Fisher exact/Student's t test. Survival rates were calculated using Kaplan-Meier and log-rank test. Prognostic variables were evaluated by Cox regression. Primary/secondary endpoints were overall/recurrence-free survival (OS/RFS). RESULTS:Pre-therapeutic imaging revealed a significantly over-staged N-status (p = 0.01), while occult contra-lateral N + was diagnosed in one patient only (0.4%). OC patients did not show differences in OS/RFS between the groups (ipsi- vs. bi-lateral). There was a strong tendency towards a better OS in OPC patients who underwent ipsi-lateral ND (p = 0.07). Cox-regression demonstrated that only tumor recurrence was associated with a fivefold increased risk of recurrence-associated death (p < 0.0001) that referred to a significant higher recurrence rate at primary tumor site (rT +) and increased distant metastatic outgrowth in OPC who underwent bi-lateral neck dissection (p = 0.03). While RFS of any cause (rT + /rN + /rM +) was significantly better in OPC with ipsi-lateral ND (p < 0.05), RFS of contralateral lymph node recurrence (rN2c) was comparable in both groups. CONCLUSION:END of the contralateral cN0 neck is not correlated by an increased RFS or OS. Standard imaging techniques including CT/MRI scan and neck ultrasound warrant watchful waiting for neck dissection of the contralateral cN0 neck.	0
In Hungary the national newborn screening programme for the detection of biotinidase deficiency was launched in 1989. In this study, we determined the genotypes of all patients identified at the Budapest Screening Centre that covers half of the country. The incidence of the disorder in Western Hungary is about three times the worldwide incidence. Overall, 21 different mutations were identified in 49 patients, including four novel mutations. Ten mutations proved to be unique to the Hungarian population.	1
OBJECTIVE:To explore phenotypic and mutational characteristics of a pedigree affected with autosomal dominant Charcot-Marie-Tooth disease (CMT) and nephropathy. METHODS:Clinical data of the proband and his family members was collected. Electrophysiology, renal biopsy and next-generation sequencing were carried out for the proband. RESULTS:The proband presented with distal lower limb weakness and proteinuria in childhood. His mother and brother had similar symptoms. Electrophysiological test of the proband revealed demyelination and axonal changes in both motor and sensory nerves. Renal biopsy suggested focal segmental glomerulosclerosis. Genetic testing revealed a heterozygous c.341G>A (p.G114D) mutation in exon 2 of the INF2 gene. CONCLUSION:The phenotypic feature of the pedigree is autosomal dominant intermediate CMT and focal segmental glomerulosclerosis, which may be attributed to the c.341G>A mutation of the INF2 gene.	0
Atrial septal defects are common congenital heart defects, characterized by insufficient/absent tissue at the interatrial septum. An unrepaired defect may be associated with right heart volume overload, atrial arrhythmia or pulmonary arterial hypertension. The 3 major types of atrial septal defect are: ostium secundum defect, ostium primum defect, and sinus venosus. Characteristic physical findings include a midsystolic pulmonary flow or ejection murmur, accompanied by a fixed split-second heart sound. Small defects may spontaneously close; larger defects may persist and result in hemodynamic and clinical sequelae requiring percutaneous or surgical intervention. Severe pulmonary arterial hypertension is a contraindication to closure.	0
•Sentinel lymph node mapping is feasible in patients with vaginal cancer.•Here we report a positive sentinel lymph node in a patient with clinically early-stage vaginal cancer.•Sentinel lymph node mapping and dissection may guide primary treatment decisions.	0
Purpose:To report unusual and rare clinical changes of retinal vessel pattern in a series of patients affected by Juvenile Idiopathic Arthritis (JIA) uveitis with a follow-up longer than 16 years. Methods:A series of three patients with JIA-uveitis followed at the University of Rome "Sapienza" from 1998 to 2014 were reported. The retinal vessels were analyzed with fluorescein angiography using Heidelberg Retinal Angiogram-2 (HRA-2; Heidelberg Engineering GmBH, Dossenheim, Germany) and the Topcon TRC-50LX retinal camera (Topcon Europe, The Netherlands). A Spectralis Domain OCT (SD-OCT) (Spectralis Family Heidelberg, Germany) was performed to evaluate vessel anatomy. Results:Fundus photography showed sheathed vessels localized around the optic disc in every case. Angiography revealed a normal physiology of vessel walls and flow; no sheathing or leakage of dye was observed. SD-OCT demonstrated reflective vessel walls. Vessel lumen appeared patent, and the normal "hourglass configuration" was blurred, but identifiable. Conclusions:Vessel modifications observed in long-standing JIA-uveitis are not signs of vascular inflammation and are not associated to hypoperfusion. In these cases, ophthalmologists should avoid further invasive investigation and should consider introducing SD-OCT as a routine method to evaluate the vessel changes during the follow-up.	0
Chromosome 15q24 microdeletion syndrome is characterized by developmental delay, facial dysmorphism, hearing loss, hypotonia, recurrent infection, and other congenital malformations including microcephaly, scoliosis, joint laxity, digital anomalies, as well as sometimes having autism spectrum disorder (ASD) and attention deficit hyperactivity disorder. Here, we report a boy with a 2.58-Mb de novo deletion at chromosome 15q24. He is diagnosed with ASD and having multiple phenotypes similar to those reported in cases having 15q24 microdeletion syndrome. To delineate the critical genes and region that might be responsible for these phenotypes, we reviewed all previously published cases. We observe a potential minimum critical region of 650 kb (LCR15q24A-B) affecting NEO1 among other genes that might pertinent to individuals with ASD carrying this deletion. In contrast, a previously defined minimum critical region downstream of the 650-kb interval (LCR15q24B-D) is more likely associated with the developmental delay, facial dysmorphism, recurrent infection, and other congenital malformations. As a result, the ASD phenotype in this individual is potentially attributed by genes particularly NEO1 within the newly proposed critical region.	0
Brittle cornea syndrome (BCS) is a rare autosomal recessive connective tissue disorder characterised by severe corneal thinning, with the major ocular risk being spontaneous ocular perforation due to progressive stromal thinning and ectasia. It is a complex condition with limited treatment options. The purpose of this review is to highlight the difficulties associated with the condition and examine the available published evidence with regards to management.	0
Keratosis follicularis spinulosa decalvans is a disorder affecting the hair follicles characterized by scarring alopecia of the scalp, eyebrows, and axillae, sometimes associated with photophobia and keratoderma. Being X-linked, it is more commonly seen in males but can be rarely seen in females also. We report three cases of this rare disorder including one in a female.	0
RATIONALE:Hereditary elliptocytosis is an inherited disorder characterized by the elliptical red blood cells (RBCs) on the peripheral blood smear and related hemolysis, mainly results from a heterozygous mutation in the genes that encode protein 4.1, α-spectrin, β-spectrin. Mutations of SPTA1 are the most common. PATIENT CONCERNS:A 21-year-old female presented with left epigastric pain and jaundice with numerous elliptical RBCs on blood film. The family history review discovered jaundice in her sibling. DIAGNOSIS:A novel heterozygous mutation of SPTA1 was detected in the proband, her brother and father, c.7220_7221del:p.Tyr2407* in exon 52. Bioinformatics analysis indicated that this mutation was likely pathogenic and results in early termination of transcription and production of defective protein. INTERVENTIONS:The proband underwent splenectomy and cholecystectomy due to symptomatic splenomegaly and gallstone. OUTCOMES:After surgery, the bilirubin levels decreased to normal (i.e., total bilirubin 16.4 μmol/L; indirect bilirubin 12.3 μmol/L), and the pain and uncomfortableness in the upper abdomen relieved completely. LESSONS:We suggest that simultaneous whole exome sequencing of causative genes of all family members is a useful strategy to identify pathogenetic mutations for hereditary RBC membrane disorders, mainly in cases with an ambiguous phenotype.	0
Here, we report about reducing body myopathy, associated with a mutation in the four and a half LIM domain 1 gene (FHL1), identified in a 40-year-old woman who was suffering from subtle muscle weakness since the age of six and a limping gait since the age of 22 years. In addition to her elevated muscle enzyme level and magnetic resonance imaging, myopathy was highly suspected considering progression of symptoms. Nerve conduction studies and electromyogram suggested myopathy. The muscle biopsy revealed severe dystrophic features with many reducing bodies on hematoxylin and eosin, nicotinomide adenine dinucleotide dehydrogenase-tetrazolium reductase (NADH-TR), and modified Gomori stains and ubiquitin immunohistochemistry. Whole-exome sequencing revealed Xq26.3 encoding FHL1 missense mutations (NM_001159704) in exon 4: p.C150R, c.T448C. FHL1-mutated "reducing body myopathy" is worth reporting based on its rarity and unique clinicopathologic features including ultrastructure. The confirmative diagnosis is still very difficult before gene analysis because clinical and pathological features of this disease overlap with other myofibrillar myopathies. We stress the importance of genotype-phenotype correlation to obtain a precise diagnosis.	0
Parathyroid glands secrete the parathyroid hormone that plays an essential role in bone remodeling. Excessive production of parathyroid hormone causes a common metabolic bone disorder known as hyperparathyroidism that is classified into primary, secondary, or tertiary. In hyperparathyroidism, the late bony complication is manifested as a giant cell osteolytic lesion called "brown tumor." Primary hyperparathyroidism is usually a sporadic disorder, but in minority of cases it occurs in inherited forms, and one of these forms is the hyperparathyroidism-jaw tumor syndrome, which is characterized by primary hyperparathyroidism and ossifying fibroma in the mandible and/or maxilla.	0
We describe an extremely rare case of Phyllodes tumor of the prostate in a 35-year-old man. The patient was referred to our hospital for the recurrent episodes of urinary retention. He complained of severe obstructive lower urinary tract symptoms and dysuria. Serum prostate-specific antigen (PSA) was within the normal range. Transabdominal ultrasonography showed a few heterogenous echoic areas in a 110-gm prostate and some cystic areas with invasion to the urinary bladder. In the past, transurethral resections of the prostate (TURP) had been performed for him twice and microscopic examination of the specimens had shown cystically dilated glands consisting of bizarre cells with nuclear atypia. Finally, radical retropubic prostatectomy was performed against the recurrences of the tumor. Here we describe the morphological features and immuno-histochemical presentations of Phyllodes tumor of the prostate and its long-term follow-up in the patient.	0
Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is an inborn error of ketone body metabolism and causes episodic ketoacidosis. We report clinical and molecular analyses of 5 patients with SCOT deficiency. Patients GS07, GS13, and GS14 are homozygotes of S405P, L327P, and R468C, respectively. GS17 and GS18 are compound heterozygotes for S226N and A215V, and V404F and E273X, respectively. These mutations have not been reported previously. Missense mutations were further characterized by transient expression analysis of mutant cDNAs. Among 6 missense mutations, mutants L327P, R468C, and A215V retained some residual activities and their mutant proteins were detected in immunoblot analysis following expression at 37°C. They were more stable at 30°C than 37°C, indicating their temperature sensitive character. The R468C mutant is a distinct temperature sensitive mutant which retained 12% and 51% of wild-type residual activities at 37 and 30°C, respectively. The S226N mutant protein was detected but retained no residual activity. Effects of missense mutations were predicted from the tertiary structure of the SCOT molecule. Main effects of these mutations were destabilization of SCOT molecules, and some of them also affected catalytic activity. Among 5 patients, GS07 and GS18 had null mutations in both alleles and the other three patients retained some residual SCOT activities. All 5 developed a first severe ketoacidotic crisis with blood gas pH <7.1, and experienced multiple ketoacidotic decompensations (two of them had seven such episodes). In general, the outcome was good even following multiple ketoacidotic events. Permanent ketosis or ketonuria is considered a pathognomonic feature of SCOT deficiency. However, this condition depends not only on residual activity but also on environmental factors.	0
BACKGROUND:Pseudodiastrophic dysplasia (PDD) is a severe skeletal dysplasia associated with prenatal manifestation and early lethality. Clinically, PDD is classified as a 'dysplasia with multiple joint dislocations'; however, the molecular aetiology of the disorder is currently unknown. METHODS:Whole exome sequencing (WES) was performed on three patients from two unrelated families, clinically diagnosed with PDD, in order to identify the underlying genetic cause. The functional effects of the identified variants were characterised using primary cells and human cell-based overexpression assays. RESULTS:WES resulted in the identification of biallelic variants in the established skeletal dysplasia genes, B3GAT3 (family 1) and CANT1 (family 2). Mutations in these genes have previously been reported to cause 'multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects' ('JDSCD'; B3GAT3) and Desbuquois dysplasia 1 (CANT1), disorders in the same nosological group as PDD. Follow-up of the B3GAT3 variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstream in vitro functional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of the CANT1 variant showed impaired nucleotidase activity, which results in inhibition of glycosaminoglycan synthesis through accumulation of uridine diphosphate. CONCLUSION:For the families described in this study, the PDD phenotype was caused by mutations in the known skeletal dysplasia genes B3GAT3 and CANT1, demonstrating the advantage of genomic analyses in delineating the molecular diagnosis of skeletal dysplasias. This finding expands the phenotypic spectrum of B3GAT3-related and CANT1-related skeletal dysplasias to include PDD and highlights the significant phenotypic overlap of conditions within the proteoglycan biosynthesis pathway.	0
Melkerrson-Rosenthal syndrome is a rare disorder of unknown aetiology and characterized by the triad of oro-facial edema, facial nerve palsy, and furrowing of the tongue. Two or more of the above are essential for making a clinical diagnosis. The mainstay of treatment is corticosteroids. Intralesional triamcinolone acetonide may be used for the treatment of oro-facial edema. Another treatment option for oro-facial edema includes intralesional betamethasone, along with oral doxycycline. The review discusses the management strategies in Melkersson-Rosenthal syndrome.	0
OBJECTIVES:Nearly one third of children with cryptogenic epileptic encephalopathies have been reported to have focal cortical defects on 18fluorodeoxyglucose (FDG) PET. As diffuse cortical dysfunction and involvement of subcortical structures, particularly the thalami, is postulated to underlie the propensity to seizures in these conditions, the aim was to determine the frequency of bilateral and diffuse cortical metabolic defects and of subcortical metabolic abnormalities in the same patients. METHODS:The interictal uptake of FDG was studied in 32 children with epileptic encephalopathies. Using a semiquantitative technique, the ratio of uptake in cortical regions and subcortical structures to that in the cerebellum was compared with that of age matched historical controls. Uptake more than 2 SD above ("hypermetabolic") or below ("hypometabolic") that of age matched controls was considered abnormal. RESULTS:Diffusely abnormal cortical up-take (nearly always hypometabolic) occurred in almost two thirds of patients; in all but two of the remaining patients at least one cortical region showed significantly decreased uptake bilaterally. When analysed as age cohorts, the mean cortical:cerebellar FDG uptake was significantly lower than that of controls in all cortical regions (P<0.005). Ninety per cent of patients had evidence of relative thalamic hypometabolism and in each age group there was a significant reduction in relative thalamic FDG uptake compared with that of controls (P<0.005). In nine out of 11 patients with unilateral cortical hypometabolic defects thalamic FDG up-take was lower ipsilateral to the cortical abnormality. CONCLUSIONS:Diffuse cortical dysfunction is common in the epileptic encephalopathies and may reflect the underlying cause of the condition or arise as a consequence of uncontrolled seizures. Altered thalamic glucose metabolism is further evidence of subcortical involvement in these conditions.	0
Hypophosphatasia (HPP) is a rare inherited bone disorder identified by impaired bone mineralization. There are seven subtypes of HPP mainly characterized by their age of onset. These subtypes consist of perinatal (prenatal) benign, perinatal lethal, infantile, childhood, adult, odontohypophosphatasia, and pseudohypophosphatasia. Due to limited awareness of the condition, either misdiagnosis or delayed diagnosis is common. Furthermore, the condition is frequently treated with contraindicated drugs. This literature illustrates the most recent findings on the etiology, pathophysiology, clinical manifestations, diagnosing, and treatment for HPP and its subtypes. The etiology of the disease consists of loss-of-function mutations of the ALPL gene on chromosome one, which encodes for tissue nonspecific isoenzyme of alkaline phosphatase (TNAP). A decrease of TNAP reduces inorganic phosphate (Pi) for bone mineralization and allows for an increase in inorganic pyrophosphate (PPi) and phosphorylated osteopontin (p-OPN), which further reduces bone mineralization. The combination of these processes softens bone and mediates a clinical presentation similar to rickets/osteomalacia. HPP has an additional wide range of clinical features depending on its subtype. Although a concrete diagnostic guideline has not yet been established, many studies have supported a similar method of identifying HPP. Clinical features, radiological findings, and/or biomarker levels of the disorder should raise suspicion and encourage the inclusion of HPP as a differential diagnosis. Biomarkers, especially alkaline phosphatase (ALP), are major contributors to diagnosis. However, genetic testing is done for definitive diagnosis. The primary treatment for HPP is the reintroduction of TNAP as a recombinant enzyme called asfotase alfa. There are additional pharmaceutical treatments and in some cases, surgical intervention may be indicated. Pharmaceutical therapies such as bisphosphonates, denosumab, potent antiresorptive agents, and vitamin D are contraindicated in adults with HPP. We hope to raise awareness for HPP in order to prevent delayed diagnosis or misdiagnosis. We plan to encourage appropriate care and avoid treatments that may be contraindicating. We also encourage the development of a diagnostic guideline that will promote a consistently favorable patient prognosis.	0
We describe a case of hantavirus pulmonary syndrome in a patient exposed to Sin Nombre virus in a coastal county in California, USA, that had no previous record of human cases. Environmental evaluation coupled with genotypic analysis of virus isolates from the case-patient and locally trapped rodents identified the likely exposure location.	0
Dihydrolipoamide dehydrogenase deficiency, also known as maple syrup urine disease (MSUD) type III, is caused by the deficiency of the E3 subunit of branched chain alpha-ketoacid dehydrogenase (BCKDH), α-ketoglutarate dehydrogenase (αKGDH), and pyruvate dehydrogenase (PDH). DLD deficiency variably presents with either a severe neonatal encephalopathic phenotype or a primarily hepatic phenotype. As a variant form of MSUD, it is considered a core condition recommended for newborn screening. The detection of variant MSUD forms has proven difficult in the past with no asymptomatic DLD deficiency patients identified by current newborn screening strategies. Citrulline has recently been identified as an elevated dried blood spot (DBS) metabolite in symptomatic patients affected with DLD deficiency. Here we report the retrospective DBS analysis and second-tier allo-isoleucine testing of 2 DLD deficiency patients. We show that an elevated citrulline and an elevated allo-isoleucine on second-tier testing can be used to successfully detect DLD deficiency. We additionally recommend that DLD deficiency be included in the "citrullinemia/elevated citrulline" ACMG Act Sheet and Algorithm.	0
BACKGROUND:Ring chromosome 2 is a rare constitutional abnormality that generally occurs de novo. About 14 cases have been described to date, but the vast majority of papers report exclusively conventional cytogenetic investigations and only two have been characterized by array-CGH. RESULTS:Here we describe the clinical, neuroradiological, and molecular features of a 5-year-old boy harbouring a ring chromosome 2 presenting with severe growth failure, facial and bone dysmorphisms, microcephaly, and renal malformation. Brain MR with diffusion tensor imaging revealed simplified cortical gyration, pontine hypoplasia, and abnormally thick posterior corpus callosum, suggesting an underlying axonal guidance defect. Cytogenetic investigations showed a karyotype with a ring chromosome 2 and FISH analysis with subtelomeric probes revealed the absence of signals on both arms. These results were confirmed by array-CGH showing terminal deletions on 2p25.3 (~439 kb) and 2q37.3 (~3.4 Mb). CONCLUSIONS:Our report describes a new patient with a ring chromosome 2 completely characterised by array-CGH providing additional information useful not only to study genotype-phenotype correlation but also to validate the role of already reported candidate genes and to suggest novel ones which could improve our understanding of the clinical features associated with ring chromosome 2.	0
Propionyl CoA carboxylase (PCC) is a mitochondrial, biotin-dependent enzyme involved in the catabolism of amino acids, odd-chain fatty acids, and other metabolites. PCC consists of two subunits, alpha and beta, encoded by the PCCA and PCCB genes, respectively. Inherited PCC deficiency due to mutations in either gene results in propionic acidemia (PA), an autosomal recessive disease. Surprisingly, PA is highly prevalent among Inuits in Greenland. We have analyzed reverse transcriptase-PCR products of the beta-subunit mRNA, to characterize the responsible mutation(s). A 3-bp insertion, 1540insCCC, was found in homozygous form in three patients and in compound heterozygous form in one patient. The resulting PCC has no measurable activity, and the mutant beta-subunit appears to be very unstable. To test the hypothesis that a common mutation is responsible for PA in the Greenlandic Inuit population, 310 anonymous DNA samples of Inuit origin were screened for 1540insCCC. We found a carrier frequency of 5%, which is very high compared with those of most other autosomal recessive diseases. Analysis of alleles of a very closely linked marker, D3S2453, revealed a high degree of linkage disequilibrium between one specific allele and 1540insCCC, suggesting that this mutation may be a founder mutation.	1
Orofaciodigital syndrome 1 (OFD-1) is a rare, X-linked, dominantly inherited disorder caused by an OFD1 mutation that can cause polycystic kidneys. A 37-year-old woman on hemodialysis therapy was admitted to our hospital for trans-catheter arterial embolization therapy for enlarged polycystic kidneys. Lobulated tongue and brachydactyly were noticed, prompting an OFD1 sequencing analysis. Sequencing revealed a causal four-base-pair deletion in exon 13, both in the patient and in her mother, whose renal function had been retained. The peripheral leukocyte X chromosome inactivation pattern was skewed in the patient but not in her mother, suggesting some role in their phenotypic difference.	0
A 72-year-old Tongan female was admitted to our facility with dyspnea and refractory hypoxia. She became febrile and blood cultures were positive for Enterococcus faecalis. Transesophageal echocardiography was performed showing two large vegetations on the tricuspid valve causing severe regurgitation. The tricuspid regurgitant jet with the assistance of a large Chiari network was being directed across an ostium secundum atrial septal defect. This clinical scenario represented an unusual cause of acute right to left shunt explaining the patient's refractory hypoxia. <Learning objective: Acute right to left intra-cardiac shunts occur rarely however should be considered in any patient with acute onset refractory hypoxia.>.	0
Posterior polymorphous corneal dystrophy (PPCD) is a rare autosomal dominant genetically heterogeneous disorder. Nineteen Czech PPCD pedigrees with 113 affected family members were identified, and 17 of these kindreds were genotyped for markers on chromosome 20p12.1- 20q12. Comparison of haplotypes in 81 affected members, 20 unaffected first degree relatives and 13 spouses, as well as 55 unrelated controls, supported the hypothesis of a shared ancestor in 12 families originating from one geographic location. In 38 affected individuals from nine of these pedigrees, a common haplotype was observed between D20S48 and D20S107 spanning approximately 23 Mb, demonstrating segregation of disease with the PPCD1 locus. This haplotype was not detected in 110 ethnically matched control chromosomes. Within the common founder haplotype, a core mini-haplotype was detected for D20S605, D20S182 and M189K2 in all 67 affected members from families 1-12, however alleles representing the core mini-haplotype were also detected in population matched controls. The most likely location of the responsible gene within the disease interval, and estimated mutational age, were inferred by linkage disequilibrium mapping (DMLE+2.3). The appearance of a disease-causing mutation was dated between 64-133 generations. The inferred ancestral locus carrying a PPCD1 disease-causing variant within the disease interval spans 60 Kb on 20p11.23, which contains a single known protein coding gene, ZNF133. However, direct sequence analysis of coding and untranslated exons did not reveal a potential pathogenic mutation. Microdeletion or duplication was also excluded by comparative genomic hybridization using a dense chromosome 20 specific array. Geographical origin, haplotype and statistical analysis suggest that in 14 unrelated families an as yet undiscovered mutation on 20p11.23 was inherited from a common ancestor. Prevalence of PPCD in the Czech Republic appears to be the highest worldwide and our data suggests that at least one other novel locus for PPCD also exists.	1
BACKGROUND: Anencephaly is a neural tube defect incompatible with life. The aim of this prospective study was to determine the prevalence of anencephaly in Gorgan, northern Iran. METHODS: During 1998 - 2005, 49,534 newborns at Dezyani hospital in Gorgan were screened for neural tube defects. Clinical and demographic data of the diagnosed cases were recorded in a pre-designed questionnaire for analysis. These data included sex, ethnicity, parental consanguinity, and residential area. RESULTS: The overall prevalence of neural tube defects and anencephaly were 28 and 12 per 10000 births, respectively. The prevalence of anencephaly was 11 and 12 per 10000 births in male and female newborns, respectively. Considering the parental ethnicity, the prevalence of anencephaly was 12, 16, and 7 per 10000 in Fars, Turkman, and Sistani ethnicity, respectively. The prevalence of anencephaly was 13.1/10000 in newborns with mothers aged >35 years. Consanguinity was seen in 36% of the parents. The highest rate of anencephaly occurred in 1999 (23/10000) and the least was in 2003 (2/10000). The most prevalent season for the occurrence of anencephaly was winter (16/10000). CONCLUSION: The present study indicated that the prevalence of anencephaly among Iranian newborns in northern Iran was higher than in the European population.	1
The presentation and treatment of a patient with a type B interrupted aortic arch with an isolated left subclavian artery is described.	0
Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy. A distinctive characteristic of KS is oligozoospermia. Despite multiple studies that have described the natural history of the degenerative process of germ cells in patients with KS, the molecular mechanisms that initiate this process are not well characterized. MicroRNA (miRNA)-mediated post-transcriptional control mechanisms have been increasingly recognized as important regulators of spermatogenesis; however, only a few studies have evaluated the role of miRNAs in the gonadal failure of these patients. Here, we describe a differential expression profile for the miRNAs in testicular tissue samples taken from KS patients. We analysed testicular tissue samples from 4 KS patients and 5 control patients (obstructive azoospermia) through next-generation sequencing, which can provide information about the mechanisms involved in the degeneration of germ cells. A distinctive differential expression profile was identified for 166 miRNAs in the KS patients: 66 were upregulated, and 100 were downregulated. An interactome analysis was performed for 7 of the upregulated and the 20 downregulated miRNAs. The results showed that the target genes are involved in the development, proliferation, and differentiation processes of spermatogenesis, which may explain their role in the development of infertility. This is the first report of a miRNA expression profile generated from testicular tissue samples of KS patients.	0
Double-orifice mitral valve (DOMV) is an uncommon congenital anomaly account for 1% of congenital heart disease. However, accurate diagnosis and evaluation of valve stenosis or regurgitation and other concomitant congenital anomalies due to DOMV are required to obtain suitable treatment. Two- and three-dimensional echocardiography can contribute valuable functional and anatomic information that can support to reach this goal. Here, we present a case of complete bridge-type DOMV that causes mitral stenosis after surgical repair of the partial atrioventricular septal defect in childhood.	0
Intense exercise-induced right ventricular remodeling is a potential adaptation of cardiac function and structure. The features of the remodeling may overlap with those of a very early form of arrhythmogenic right ventricular cardiomyopathy (ARVC): at this early stage, it could be difficult to discriminate ARVC, from exercise-induced cardiac adaptation that may develop in normal individuals. The purpose of this paper is to discuss which exercise-induced remodeling may be a pathological or a physiological finding. A complete evaluation may be required to identify the pathological features of ARVC that would include potential risk of sudden cardiac death during sport or, to avoid the false diagnosis of ARVC. The most recent expert assessment of arrhythmogenic cardiomyopathy focuses on endurance athletes presenting with clinical features indistinguishable from ARVC.	0
Thanatophoric dysplasia (TD) is a lethal form of skeletal dysplasia with short-limb dwarfism. Two types distinguished with their radiological characteristics have been defined clinically. The femur is curved in type 1, while it is straight in type 2. TD is known to be due to a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. We report a male patient who showed clinical findings congruent with TD type 2 and a new mutation in the FGFR3 gene, a finding which has not been reported previously.	0
BACKGROUND:Mucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT. METHODS:This 2-year open-label pilot study of laronidase included ten patients (age 5-13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls. RESULTS:The two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients. CONCLUSIONS:Laronidase seemed to improve growth in participants <8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made.	0
Grape berries are susceptible to Aspergillus niger (A. niger) infection during storage, leading to a significant reduction in its nutritional quality. However, most alternations in nutrient contents and related gene expression during fungal infection or treated with antimycotics remain unexplored. This work aimed to monitor and verify the metabolic changes in berries caused by A. niger or Melaleuca alternifolia oil (MAO) by using UHPLC-ESI-MS2 and Quantitative Real-time PCR (RT-qPCR). Results showed that sucrose, glucose, fructose, trans-resveratrol and pterostilbene levels were down and pentose phosphate pathway, glycolysis pathway and phenylpropanoid pathway were significantly down-regulated compared with healthy berries due to A. niger infection, all of which were alleviated by MAO treated. A. niger also induced down-regulation of key genes expression associated with metabolic pathways and magnitude of down-regulation was reduced by MAO. These results provide a theoretical basis for MAO used to control the risk of A. niger-mediated diseases.	0
BACKGROUND:Pathogenic variants in the FKRP gene cause impaired glycosylation of α-dystroglycan in muscle, producing a limb-girdle muscular dystrophy with cardiomyopathy. Despite advances in understanding the pathophysiology of FKRP-associated myopathies, clinical research in the limb-girdle muscular dystrophies has been limited by the lack of normative biomarker data to gauge disease progression. METHODS:Participants in a phase 2 clinical trial were evaluated over a 4-month, untreated lead-in period to evaluate repeatability and to obtain normative data for timed function tests, strength tests, pulmonary function, and body composition using DEXA and whole-body MRI. Novel deep learning algorithms were used to analyze MRI scans and quantify muscle, fat, and intramuscular fat infiltration in the thighs. T-tests and signed rank tests were used to assess changes in these outcome measures. RESULTS:Nineteen participants were observed during the lead-in period for this trial. No significant changes were noted in the strength, pulmonary function, or body composition outcome measures over the 4-month observation period. One timed function measure, the 4-stair climb, showed a statistically significant difference over the observation period. Quantitative estimates of muscle, fat, and intramuscular fat infiltration from whole-body MRI corresponded significantly with DEXA estimates of body composition, strength, and timed function measures. CONCLUSIONS:We describe normative data and repeatability performance for multiple physical function measures in an adult FKRP muscular dystrophy population. Our analysis indicates that deep learning algorithms can be used to quantify healthy and dystrophic muscle seen on whole-body imaging. TRIAL REGISTRATION:This study was retrospectively registered in clinicaltrials.gov (NCT02841267) on July 22, 2016 and data supporting this study has been submitted to this registry.	0
This case report aimed to describe various psychiatric manifestation and treatment course in a patient with DiGeorge syndrome. Psychiatric symptoms and treatment course in a female patient with DiGeorge syndrome were described. This patient showed psychotic symptoms, mood symptoms, and intellectual disability. As well as various psychiatric symptoms, treatment response and sensitivity of side effect by antipsychotics were different from typical characteristics in psychiatric disorders. This case suggests that the genetic defect in DiGeorge syndrome might have a great association with psychiatric problems and response of antipsychotics.	0
A 65-year-old healthy woman presented with a 15-year history of binocular horizontal diplopia worse when looking left. She had previously been thoroughly investigated multiple times for a left sixth nerve palsy (6NP) 15 years ago and had three normal magnetic resonance imaging (MRI) scans of the brain/orbits with contrast, normal acetylcholine receptor antibodies, normal thyroid function tests, normal cerebrospinal fluid, and normal nerve conduction studies and single-fibre electromyography. She was treated with prism glasses, which resulted in resolution of her symptoms in primary position.	0
This 10-year (1991 to 2000) prospective study of MG in the county of Osona (Barcelona, Spain) reveals an annual incidence rate of 21.27 cases per million inhabitants (95% CI 13.89 to 31.16). Incidence increased from 5.03 x 10(6) in the age group of 0 to 14 years to 14.68 x 10(6) in the age group of 15 to 64 years and to 63.38 x 10(6) in the older population. These results, the highest reported to date, may be explained by the population aging.	1
Ataxia with oculomotor apraxia type 2 (AOA2) is a rare autosomal recessive neurodegenerative disorder characterized by cerebellar atrophy, peripheral neuropathy and oculomotor apraxia. It is caused by mutations in the SETX gene that encodes senataxin, a ubiquitously expressed protein that mediates processes, including transcription, transcription termination, DNA repair, RNA processing, DNA-RNA hybrid (R-loop) elimination and telomere stability. In mice, senataxin is essential for male germ cell development and fertility through its role in meiotic recombination and sex chromosome inactivation. AOA2 is associated with hypogonadism in women, but there are no reports of hypogonadism or infertility in men. We describe the first case of human male infertility caused by germ cell arrest in a man with AOA2. Our patient has a homozygous mutation in the SETX gene (NC_000009.11:g.135158775dup), which results in a frameshift and premature protein termination (NM_015046.6:c.6422dup, p.[Ser2142Glufs*23]). In accordance with the murine phenotype, testis histology revealed disrupted seminiferous tubules with spermatogonia and primary spermatocytes, but absent spermatids. Collectively, these data support an essential role of senataxin in human spermatogenesis, and provide a compelling case that men with AOA2 should be counselled at diagnosis about the possibility of infertility.	0
A hard palate mass was surgically removed from an Australian green tree frog (Litoria caerulea) and examined pathologically. The tumor consisted of sheets of small cells arranged in a tubular structure and cords or rosettes with fibrovascular stroma. Immunohistochemically, neoplastic cells were diffusely positive for cytokeratin and neuron-specific enolase and partially positive for S-100 and doublecortin. These findings indicate that the tumor originated from the neuroectodermal tissue. Based on these findings, the tumor was classified as a neuromastoma (neuroepithelioma). Sensory cells located in the hard palate of the frog were considered to be the origin of the tumor. The frog died after going through 3 surgeries and experiencing difficulties closing its mouth.	0
The adult congenital heart diseases (ACHD) population is exceeding the pediatric congenital heart diseases (CHD) population and is progressively expanding each year, representing more than 90% of patients with CHD. Of these, about 75% have undergone surgical and/or percutaneous intervention for palliation or correction. Autopsy can be a very challenging procedure in ACHD patients. The approach and protocol to be used may vary depending on whether the pathologists are facing native disease without surgical or percutaneous interventions, but with various degrees of cardiac remodeling, or previously palliated or corrected CHD. Moreover, interventions for the same condition have evolved over the last decades, as has perioperative myocardial preservations and postoperative care, with different long-term sequelae depending on the era in which patients were operated on. Careful clinicopathological correlation is, thus, required to assist the pathologist in performing the autopsy and reaching a diagnosis regarding the cause of death. Due to the heterogeneity of the structural abnormalities, and the wide variety of surgical and interventional procedures, there are no standard methods for dissecting the heart at autopsy. In this paper, we describe the most common types of CHDs that a pathologist could encounter at autopsy, including the various types of surgical and percutaneous procedures and major pathological manifestations. We also propose a practical systematic approach to the autopsy of ACHD patients.	0
BACKGROUND: ECLAMC is a registry, aimed to assess the incidence of congenital malformations, that started in 1967 and Chile incorporated to it in 1969. AIM: To report the incidence of cleft lip/palate, updated to 1999 in the University of Chile Maternity Hospital and other Chilean hospitals participating in the ECLAMC. PATIENTS AND METHODS: A review of the ECLAMC database that registers all births or stillbirths of more than 500 g. RESULTS: The incidence of orofacial cleft, at the University of Chile Maternity Hospital, in the period 1991-1999 was 17.8 per 10,000 (12.6 for cleft lip and 5.2 for cleft palate). The incidence in the rest of participating hospitals was 12.04 and 4.6 respectively. Males had a higher incidence of cleft lip and 80% of children with cleft palate, had other malformations, most of them as part of a syndrome (13 and 18 trisomy, holoproscencephalia, Pierre Robin, Apert en EE syndromes, anencephaly etc). In three of 12 children with cleft lip but without cleft palate, there was a relative with the same malformation. CONCLUSIONS: It is proposed that both entities, cleft lip with or without cleft palate and cleft palate without cleft lip, are two etiopathogenically different conditions.	1
The role of X-inactivation is often ignored as a prime cause of sex differences in disease. Yet, the way males and females express their X-linked genes has a major role in the dissimilar phenotypes that underlie many rare and common disorders, such as intellectual deficiency, epilepsy, congenital abnormalities, and diseases of the heart, blood, skin, muscle, and bones. Summarized here are many examples of the different presentations in males and females. Other data include reasons why women are often protected from the deleterious variants carried on their X chromosome, and the factors that render women susceptible in some instances.	0
Cytoplasmic p27 plays an important role in regulating the cell cycle. Recent studies have revealed p27 protein translocation from the nucleus to the cytoplasm in many tumour cells. The aim of this study was to investigate the role and molecular mechanisms of cytoplasmic p27 in the progression of nasopharyngeal carcinoma (NPC) and to explore its prognostic value. We found increased cytoplasmic p27 expression by immunohistochemistry in NPC tissues, and its expression level was significantly correlated with the T classification and TNM clinical stage of NPC. The survival rate was significantly lower for NPC patients with cytoplasmic p27 immunopositivity than for NPC patients with cytoplasmic p27 immunonegativity, and cytoplasmic p27 was an independent risk factor that affected the prognosis of patients with NPC. Cytoplasmic p27 promoted the proliferation, cell cycle progression, migration, and invasion of NPC cells, increased Bim-1 and Twist1 protein levels, and decreased RhoA-GTP level. Collectively, these findings suggest that cytoplasmic relocalization of p27 is involved in the pathogenesis of NPC and is closely related to the unfavourable prognosis of patients with NPC. Therefore, cytoplasmic p27 might be a useful prognostic factor and potential therapeutic target for patients with NPC.	0
BACKGROUND:Studies on the relationship between antiepileptic drug (AED) administration and clinical outcomes in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) remain scarce. Levetiracetam (LEV) is an AED that is neuroprotective in various neurologic disorders. This study aimed to determine the impact of LEV on the outcome of MELAS. METHODS:A retrospective, single-center study was performed based on a large cohort of patients with MELAS with a history of seizures (n = 102). Decisions on antiepileptic therapies were made empirically. Patients were followed up for 1 to 8 years (median, 4 years) and divided into 2 groups based on whether LEV was administered (LEV or non-LEV). The modified Rankin scale (mRS) scores and mortality risks were analyzed in all patients. RESULTS:LEV, carbamazepine, benzodiazepines, topiramate, oxcarbazepine, valproate, and lamotrigine were administered in 48, 37, 18, 13, 11, 9, and 9 patients, singly or in combination, respectively. The mean mRS score of the LEV group (n = 48) was lower than that of the non-LEV group (n = 54; mean ± standard deviation, 2.79 ± 1.47 vs. 3.83 ± 1.93, P = 0.006) up to the end of the study. Nevertheless, there was no difference in the proportion of subjects without disability (mRS ranging 0-1) between the groups (P = 0.37). The multivariate regressions revealed that LEV treatment was associated with lower mRS scores (odds ratio 0.32, 95% confidence interval [CI] 0.15-0.68, P = 0.003) and mortality rates (hazard ratio 0.24, 95% CI 0.08-0.74, P = 0.013). There was a significant difference in the Kaplan-Meier survival curves between the groups (χ = 4.29, P = 0.04). CONCLUSIONS:The LEV administration is associated with lower mortality in patients with MELAS in this retrospective study. Further laboratory research and prospective cohort studies are needed to confirm whether LEV has neuroprotective effects on patients with mitochondrial diseases.	0
BACKGROUND:Alpha-dystroglycan (αDG) is an extracellular peripheral glycoprotein that acts as a receptor for both extracellular matrix proteins containing laminin globular domains and certain arenaviruses. An important enzyme, known as Like-acetylglucosaminyltransferase (LARGE), has been shown to transfer repeating units of -glucuronic acid-β1,3-xylose-α1,3- (matriglycan) to αDG that is required for functional receptor as an extracellular matrix protein scaffold. The reduction in the amount of LARGE-dependent matriglycan result in heterogeneous forms of dystroglycanopathy that is associated with hypoglycosylation of αDG and a consequent lack of ligand-binding activity. Our aim was to investigate whether LARGE expression showed correlation with glycosylation of αDG and histopathological parameters in different types of muscular dystrophies, except for dystroglycanopathies. METHODS:The expression level of LARGE and glycosylation status of αDG were examined in skeletal muscle biopsies from 26 patients with various forms of muscular dystrophy [Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), sarcoglycanopathy, dysferlinopathy, calpainopathy, and merosin and collagen VI deficient congenital muscular dystrophies (CMDs)] and correlation of results with different histopathological features was investigated. RESULTS:Despite the fact that these diseases are not caused by defects of glycosyltransferases, decreased expression of LARGE was detected in many patient samples, partly correlating with the type of muscular dystrophy. Although immunolabelling of fully glycosylated αDG with VIA4-1 was reduced in dystrophinopathy patients, no significant relationship between reduction of LARGE expression and αDG hypoglycosylation was detected. Also, Merosin deficient CMD patients showed normal immunostaining with αDG despite severe reduction of LARGE expression. CONCLUSIONS:Our data shows that it is not always possible to correlate LARGE expression and αDG glycosylation in different types of muscular dystrophies and suggests that there might be differences in αDG processing by LARGE which could be regulated under different pathological conditions.	0
This is a case of a 31-year-old male patient who presented with signs and symptoms of an incarcerated inguinal hernia. The patient's preoperative imaging showed a tubular structure in the inguinal canal and given the patient's history at presentation, there was a concern for herniation of the appendix, known as an Amyand hernia. On laparoscopy, there was no evidence of appendiceal involvement and a standard open inguinal hernia was completed. On the final pathology of the hernia sac, roundworms were identified with Y-shaped lateral cords suggesting infection by Anisakis spp. On a further interview with the patient, he revealed that he had recently travelled to Alaska and had consumed raw salmon on a fishing trip. This case demonstrates the importance of a thorough social and travel history. One should also have a low threshold to broaden the differential diagnosis when medical work-up deviates from the standard course.	0
There are more than 7000 described rare diseases, most lacking specific treatment. Autosomal-dominant hyper-IgE syndrome (AD-HIES, also known as Job's syndrome) is caused by mutations in STAT3. These patients present with immunodeficiency accompanied by severe nonimmunological features, including skeletal, connective tissue, and vascular abnormalities, poor postinfection lung healing, and subsequent pulmonary failure. No specific therapies are available for these abnormalities. Here, we investigated underlying mechanisms in order to identify therapeutic targets. Histological analysis of skin wounds demonstrated delayed granulation tissue formation and vascularization during skin-wound healing in AD-HIES patients. Global gene expression analysis in AD-HIES patient skin fibroblasts identified deficiencies in a STAT3-controlled transcriptional network regulating extracellular matrix (ECM) remodeling and angiogenesis, with hypoxia-inducible factor 1α (HIF-1α) being a major contributor. Consistent with this, histological analysis of skin wounds and coronary arteries from AD-HIES patients showed decreased HIF-1α expression and revealed abnormal organization of the ECM and altered formation of the coronary vasa vasorum. Disease modeling using cell culture and mouse models of angiogenesis and wound healing confirmed these predicted deficiencies and demonstrated therapeutic benefit of HIF-1α-stabilizing drugs. The study provides mechanistic insights into AD-HIES pathophysiology and suggests potential treatment options for this rare disease.	0
Type 2 Diabetes Mellitus (T2DM) is a chronic disease which corresponds to 90% of the worldwide cases of diabetes, mainly due to epigenetic factors such as unhealthy lifestyles. First line therapeutic approaches are based on lifestyle changes, most of the time complemented with medication mostly associated with several side effects and high costs. As a result, the scientific community is constantly working for the discovery and development of natural therapeutic strategies that provide lower financial impact and minimize side effects. This review focus on these nature-based therapeutic strategies for prevention and control of T2DM, with a special emphasis on natural compounds that present pharmacological activity as dipeptidyl peptidase-4 (DPP4), alpha-amylase, alpha-glucosidase, lipase, and protein tyrosine phosphatase 1B (PTP1B) inhibitors.	0
BACKGROUND:Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive disease with characteristic neuro-endocrine manifestations. WSS encompasses heterogeneous phenotypes and disease course. OBJECTIVE:We aimed to characterize neurological involvement of the disease through subgrouping of core neurological manifestations. METHODS:A single-institution retrospective analysis of patients with clinically and genetically confirmed diagnosis of WSS. RESULTS:A total of 38 individuals belonging to 17 families were identified to have WSS. The mean age at enrollment was 30.1 years (range 16-53 years). Neurological involvement was noted in 31 patients (81.5%). Dystonia was the most common neurological manifestation (67%), followed by intellectual disability (45%) and sensorineural hearing loss (30%). Based on the Neurological Impairment Scale (NIS), the disease was recognized to have two distinct patterns. A disabling, rapidly progressive pattern (NIS of 3-4; Type 1) was noted in eighteen patients (12 males, 6 females; 47.4%) with severe disability that occurs within a mean duration of 7.4 ± 3.6 years. Type 2 WSS was identified in twenty patients (8 males, 12 females; 52.6%), and showed either absent or mild neurological involvement with preserved activities of daily living (NIS of 0-1). The mean age of onset for neurological manifestations was earlier in type 1 (12.6 ± 4.5 years) compared to type 2 (18.1 ± 4.3 years). Type 1 WSS has a significantly higher rate of intellectual disability (p= <0.001). CONCLUSIONS:In this pleiotropic syndrome, we identified two distinct phenotypes with variable prognosis. A high Interfamilial and intrafamilial phenotypic variability despite having a similar gene mutation suggests a possible role of genetic or environmental modifying factor.	0
Cutaneous mucinosis of infancy (CMI) is a rare dermatologic condition, first reported in 1980 and currently classified within the complex group of papular mucinoses. We report a case of CMI and review the prior 13 cases in the literature. The patient was a 5-year-old girl who presented with asymptomatic dermal papules and plaques on her leg and back with no overlying color change. These lesions were first noticed during infancy and had become slightly more evident over time. The patient had a history of birthmarks and eczema. Her family history included eczema, allergies, photosensitivity, and Graves disease. Pre-biopsy clinical differential diagnosis included connective tissue nevus, granuloma annulare, myofibroma, lipofibroma, and lymphangioma. Biopsies revealed significant increase in interstitial mucin within the reticular and mid dermis, without significant sclerosis or fibroblastic proliferation. The relatively quiescent pattern of interstitial mucinosis with slight fibrocyte hyperplasia presenting as dermal papules-plaques on the trunk and extremities was most consistent with a diagnosis of CMI. We report another case of CMI in an otherwise healthy patient. Our patient is unique as she is the first CMI patient with a family history of Graves disease, although our patient appeared euthyroid. We will also review the literature on this rare entity.	0
Central nervous system (CNS) cryptococcosis in non-HIV infected patients affects solid organ transplant (SOT) recipients, patients with malignancy, rheumatic disorders, other immunosuppressive conditions and immunocompetent hosts. More recently described risks include the use of newer biologicals and recreational intravenous drug use. Disease is caused by Cryptococcus neoformans and Cryptococcus gattii species complex; C. gattii is endemic in several geographic regions and has caused outbreaks in North America. Major virulence determinants are the polysaccharide capsule, melanin and several 'invasins'. Cryptococcal plb1, laccase and urease are essential for dissemination from lung to CNS and crossing the blood-brain barrier. Meningo-encephalitis is common but intracerebral infection or hydrocephalus also occur, and are relatively frequent in C. gattii infection. Complications include neurologic deficits, raised intracranial pressure (ICP) and disseminated disease. Diagnosis relies on culture, phenotypic identification methods, and cryptococcal antigen detection. Molecular methods can assist. Preferred induction antifungal therapy is a lipid amphotericin B formulation (amphotericin B deoxycholate may be used in non-transplant patients) plus 5-flucytosine for 2-6 weeks depending on host type followed by consolidation/maintenance therapy with fluconazole for 12 months or longer. Control of raised ICP is essential. Clinicians should be vigilant for immune reconstitution inflammatory syndrome.	0
Propriospinal myoclonus (PSM) is a rare type of spinal myoclonus characterized by muscle jerks that usually start in the midthoracic segments and then slowly propagate up and down into the spinal cord, resulting in repetitive and irregular jerky flexion, or extension of the trunk, neck, knees and hips. PSM can be symptomatic, but up to 80% of reported cases appear idiopathic. PSM tends to occur especially while the subject is lying down. PSM at sleep onset was first described by experts in sleep medicine. The original electrophysiological features included fixed pattern of muscle activations, slow spinal cord conduction (5-15 m/s), electromyographic burst duration less than 1000 ms, synchronous activation of agonist and antagonist muscles and no involvement of facial muscles. PSM has been reported to be a functional (psychogenic) movement disorder in a number of cohorts. The differential diagnosis between idiopathic PSM and the functional forms is not always straightforward. A consistent polymyographically documented muscle activation pattern may be supportive but by no means sufficient and additional neurophysiological investigations are required. PSM should be differentiated from other movement disorders involving the abdomen and trunk, or occurring at sleep-wake transition. This article offers a comprehensive overview of the spectrum of PSM phenotypes.	0
Background: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease. The clinical manifestations of NIID are complex and easily misdiagnosed. Based on the current knowledge of this disease, it is usually chronic, with almost no acute cases. Stroke-like disease is an extremely rare type of NIID. Case Presentation: A 61-year-old woman was admitted to our hospital with sudden left limb weakness. Diffusion magnetic resonance imaging (MRI) demonstrated high signal intensity in the skin-medullary junction area. Tissue pathology showed eosinophilic inclusions in the nuclei of the sweat gland cells and fat cells of the skin. Subsequent genetic analysis of the fragile X chromosome mental retardation gene 1 (FMR1) gene showed that the CGG repeat number was in the normal range, excluding fragile X-related tremor/ataxia syndrome (FXTAS). After 3 weeks of hospitalization, the patient's condition improved, and the left limb muscle strength recovered. Her symptoms were almost completely diminished after 3 months. Conclusion: This case demonstrates the strong clinical heterogeneity of NIID. NIID can manifest as acute hemiplegia and a stroke-like attack. This case study provides new information for the diagnosis of NIID and the classification of the clinical characteristics.	0
BACKGROUND AND AIM:Atrial septal defects with anomalous venous connections are commonly repaired via sternotomy, requiring careful baffle reconstruction to redirect pulmonary venous return and ensure a durable result. The cosmetically appealing periareolar incision may provide an esthetically superior alternative to the anterolateral minithoracotomy incision used in minimally invasive cardiac surgery. METHODS:We describe a patient with a sinus venosus atrial septal defect and partial anomalous pulmonary venous connection who underwent successful minimally invasive, endoscopic repair with apical vein translocation and autologous pericardial baffle reconstruction through a periareolar approach. RESULTS:Post-operative echocardiography demonstrated excellent results with no residual shunt and a widely patent baffle and preserved biventricular function. At 1-year post-op, our patient has had a greatly improved quality of life and an excellent cosmetic result with normal nipple-areolar sensation. CONCLUSIONS:We believe that periareolar approaches should be considered for all adult patients with simple and complex atrial septal defects.	0
Uniparental disomy (UPD) gives a description of the inheritance of both homologues of a chromosome pair from the same parent. The consequences of UPD depend on the specific chromosome/segment involved and its parental origin.We report prenatal phenotypes of 2 rare cases of UPD.The prenatal phenotype of case 1 included sonographic markers such as enlarged nuchal translucency (NT), absent nasal bone, short femur and humerus length, and several structural malformations involving Dandy-Walker malformation and congenital heart defects. The prenatal phenotype of Case 2 are sonographic markers, including enlarged NT, thickened nuchal fold, ascites, and polyhydramnios without apparent structural malformations.Conventional G-band karyotype appears normal in case 1, while it shows normal chromosomes with a small supernumerary marker chromosome (sSMC) in case 2. Genetic etiology was left unknown until single-nucleotide polymorphism-based array (SNP-array) was performed, and segmental paternal UPD 22 was identified in case 1 and segmental paternal UPD 14 was found in case 2.The parents of case 1 chose termination of pregnancy. The neonate of case 2 was born prematurely with a bellshaped small thorax and died within a day.UPD cases are rare and the phenotypes are different, which depend on the origin and affected chromosomal part. If a fetus shows multiple anomalies that cannot be attributed to a common aneuploidy or a genetic syndrome, or manifests some features possibly related to an UPD syndrome, such as detection of sSMC, SNP-array should be considered.	0
We delivered plasmid DNA encoding therapeutic genes to the muscles of mouse models of limb girdle muscular dystrophy (LGMD) 2A, 2B, and 2D, deficient in calpain3, dysferlin, and alpha-sarcoglycan, respectively. We also delivered the human follistatin gene, which has the potential to increase therapeutic benefit. After intramuscular injection of DNA, electroporation was applied to enhance delivery to muscle fibers. When plasmids encoding the human calpain3 or dysferlin cDNA sequences were injected into quadriceps muscles of LGMD2A and LGMD2B mouse models, respectively, in 3-month studies, robust levels of calpain3 and dysferlin proteins were detected. We observed a statistically significant decrease in Evans blue dye penetration in LGMD2B mouse muscles after delivery of the dysferlin gene, consistent with repair of the muscle membrane defect in these mice. The therapeutic value of delivery of the genes for alpha-sarcoglycan and follistatin was documented by significant drops in Evans blue dye penetration in gastrocnemius muscles of LGMD2D mice. These results indicated for the first time that a combined gene therapy involving both alpha-sarcoglycan and follistatin would be valuable for LGMD2D patients. We suggest that this non-viral gene delivery method should be explored for its translational potential in patients.	0
After 3 cows of a dairy herd had died from severe hemorrhagic diarrhea, a 4th sick cow was transported to the clinic. Blood analyses revealed the complete absence of white blood cells, the presence of a type 1b strain of bovine viral diarrhea virus (BVDV), and seroconversion to BVDV.	0
The α-tocopherol transfer protein (α-TTP) is a liver protein that transfers α-tocopherol (vitamin E) to very-low-density lipoproteins (VLDLs). These VLDLs are then circulated throughout the body to maintain blood α-tocopherol levels. Mutations to the α-TTP gene are associated with ataxia with vitamin E deficiency, a disease characterized by peripheral nerve degeneration. In this study, molecular dynamics simulations of the E141K and R59W disease-associated mutants were performed. The mutants displayed disruptions in and around the ligand-binding pocket. Structural analysis and ligand docking to the mutant structures predicted a decreased affinity for α-tocopherol. To determine the detailed mechanism of the mutation-related changes, we developed a new tool called ContactWalker that analyzes contact differences between mutant and wild-type proteins and highlights pathways of altered contacts within the mutant proteins. Taken together, our findings are in agreement with experiment and suggest structural explanations for the weakened ability of the mutants to bind and carry α-tocopherol.	0
Porokeratosis of Mibelli (PM) is a rare condition with the potential for malignant transformation that presents a clinical and pathologic diagnostic challenge. An improperly oriented biopsy may lead to the wrong histopathologic diagnosis. We report a case of PM that was previously misdiagnosed and describe a biopsy technique for suspected PM that maximizes the potential for histopathologic confirmation of the diagnosis.	0
Sertoli cell-only syndrome (SCOS) is a severe phenotype of male infertility; autosomal gene defects are thought to be the causes for this disease. The iPSC line generated from a SCOS patient carrying a mutation in PIWIL2 gene expresses pluripotent markers, has a normal karyotype and the mutation c.731_732delAT in PIWIL2 gene and is able to differentiate into three germ layers. This cell line will help to study the pathogenesis of SCOS, and the roles of PIWIL2 in human germ cells development and spermatogenesis.	0
OBJECTIVE: To determine the type and incidence of hyperthyroxinemic disorders detected by follow-up of infants with elevated screening total T4 (TT4) values. STUDY DESIGN: Infants born in Oregon with a screening TT4 measurement >3 SD above the mean were offered enrollment. Serum TT4, free T4, total T3, free T3, and thyroid-stimulating hormone concentrations were measured in study infants and their mothers. RESULTS: Over a 20-month period, 101 infants (51 boys) and their mothers enrolled in the study (of 241 eligible infants), from a total screening population of 80,884; 17 infants were identified with persistent hyperthyroxinemia (TT4 >16 microg/dL). Ten had thyroxine-binding globulin excess (1:8088), 5 had evidence for increased T4 binding but not thyroxine-binding globulin excess (1:16,177), and 2 had findings compatible with thyroid hormone resistance (1:40,442); the other 84 infants had transient hyperthyroxinemia. Sequence analysis revealed a point mutation in the thyroid hormone receptor-beta gene in one infant with thyroid hormone resistance; no mutation was identified in the other infant. CONCLUSIONS: Although neonatal Graves' disease occurs in approximately 1 in 25,000 newborn infants, we did not detect any case among 80,884 infants, most likely because their mothers were receiving antithyroid drugs. Although the other hyperthyroxinemic disorders in the aggregate occur frequently (1:4758) and may benefit from detection, in general they do not require treatment.	1
BACKGROUND:Hereditary spastic paraplegia is a heterogeneous group of clinically and genetically neurodegenerative diseases characterized by progressive gait disorder. Hereditary spastic paraplegia can be inherited in various ways, and all modes of inheritance are associated with multiple genes or loci. At present, more than 76 disease-causing loci have been identified in hereditary spastic paraplegia patients. Here, we report a novel mutation in SPAST gene associated with hereditary spastic paraplegia in a Chinese family, further enriching the hereditary spastic paraplegia spectrum. METHODS:Whole genomic DNA was extracted from peripheral blood of the 15 subjects from a Chinese family using DNA Isolation Kit. The Whole Exome Sequencing of the proband was analyzed and the result was identified in the rest individuals. RaptorX prediction tool and Protein Variation Effect Analyzer were used to predict the effects of the mutation on protein tertiary structure and function. RESULTS:Spastic paraplegia has been inherited across at least four generations in this family, during which only four HSP patients were alive. The results obtained by analyzing the Whole Exome Sequencing of the proband exhibited a novel disease-associated in-frame deletion in the SPAST gene, and this mutation also existed in the rest three HSP patients in this family. This in-frame deletion consists of three nucleotides deletion (c.1710_1712delGAA) within the exon 16, resulting in lysine deficiency at the position 570 of the protein (p.K570del). This novel mutation was also predicted to result in the synthesis of misfolded SPAST protein and have the deleterious effect on the function of SPAST protein. CONCLUSION:In this case, we reported a novel mutation in the known SPAST gene that segregated with HSP disease, which can be inherited in each generation. Simultaneously, this novel discovery significantly enriches the mutation spectrum, which provides an opportunity for further investigation of genetic pathogenesis of HSP.	0
BACKGROUND:GATA2 is a transcription factor that is a critical regulator of gene expression in hematopoietic cells. GATA2 deficiency presents with multi-lineage cytopenia, mycobacterial, fungal and viral infections. Patients with GATA2 mutation have a high risk of developing myelodysplastic syndrome or acute myeloid leukemia. CASE PRESENTATION:We described a 43 years-old white male with 20-year follow-up of autoimmune and thrombotic phenomena, hypothyroidism, disseminated refractory Mycobacterium kansasii infection and MonoMAC syndrome. GATA2 c.1061 C > T; p.T354 M mutation was identified after he progressed from myelodysplastic pancytopenia to refractory anemia with excess blasts type II. His relatives were also investigated and he underwent unsuccessful haematopoietic stem cell transplantation. We discuss the clinical features, genetic diagnosis and treatment of this immunodeficiency disorder. CONCLUSIONS:This case illustrates the challenge how a multidisciplinary disease should be handle. Once usual causes of immunodeficiency were excluded, clinicians should considerGATA2 deficiency in patients with myelodysplasia and long-standing Mycobacterium kansasii infection.	0
OBJECTIVE:Since the time of inception of autoimmune pancreatitis (AIP), our knowledge of autoimmune pancreatitis has expanded significantly. The aim of this review is to provide an update on clinical manifestations, diagnosis, imaging features, and treatment of AIP. BACKGROUND AND CLINICAL SIGNIFICANCE:Type 1 AIP is the pancreatic manifestation of IgG4-related systemic disease, which can be diagnosed using a combination of clinical, histopathological, pancreatic imaging findings in conjunction with manifestation in other organs, as well of responsiveness to steroid treatment. It is vital to differentiate AIP from pancreatic cancer since both can mimic each other clinically and radiologically. Type 2 AIP is a rare but distinct subtype of AIP which occurs mostly in the younger patient. CONCLUSION:AIP is steroid-responsive chronic pancreatitis with distinct manifestations on imaging.	0
This paper proposes a malaria transmission model to describe the dynamics of malaria transmission in the human and mosquito populations. This model emphasizes the impact of limited resource on malaria transmission. We derive a formula for the basic reproductive number of infection and investigate the existence of endemic equilibria. It is shown that this model may undergo backward bifurcation, where the locally stable disease-free equilibrium co-exists with an endemic equilibrium. Furthermore, we determine conditions under which the disease-free equilibrium of the model is globally asymptotically stable. The global stability of the endemic equilibrium is also studied when the basic reproductive number is greater than one. Finally, numerical simulations to illustrate our findings and brief discussions are provided.	0
Benign multicystic peritoneal mesothelioma is a rare benign tumor originating from the peritoneum, affecting mostly young, fertile women. Its presentation is non-specific, thus the final diagnosis is made after the histological examination. A young female patient presented with incarcerated inguinal hernia of which an emergency surgery was performed. During the operation a cystic mass neighboring the round ligament in the canal of Nuck was removed. No inguinal hernia was found. The histological examination confirmed the diagnosis of benign multicystic mesothelioma. The patient was referred to a center performing hyperthermic intraperitoneal chemotherapy, where laparoscopic exploration was performed. The second surgery revealed no residual tumor or any other pathology. A 41-year-old male patient, 4 years before presenting at our ward, had an elective umbilical hernia repair surgery. During the operation 2 cm big cystic mass was removed from the peritoneum, and the histological examination revealed benign multicystic mesothelioma. In 2018, acute surgery was performed due to a periappendicular abscess, while during the surgery a multicystic mass situated on the distal end of the appendix was also removed. The pathological finding confirmed the recurrence of the first tumor. The radiological examination did not find any signs of residual tumor mass anywhere else. The chances of malignant transformation in cases of benign multicystic peritoneal mesothelioma are low. The suggested treatment is en bloc surgical removal of the mass, however, in these cases recurrence is still 50%. If during follow-ups the recurrence of the tumor is found, a total peritonectomy or hyperthermic intraperitoneal chemotherapy is advisable. Orv Hetil. 2019; 160(21): 839-843.	0
BACKGROUND: Determining the prevalence of neuromuscular disorders for the general population is important to identify the scope of burden on society and enable comparisons with other health conditions. This systematic review aims to identify and collate the findings of studies published between 1960 and 2013 on the prevalence of all types of muscular dystrophies. SUMMARY: Relevant articles were identified through electronic database searches and manual searches of reference lists. There were 38 articles from across 19 countries that met the inclusion criteria. The total combined prevalence for all muscular dystrophies for studies classified as having a low risk of bias ranged between 19.8 and 25.1 per 100,000 person-years. Myotonic dystrophy (0.5-18.1 per 100,000), Duchenne muscular dystrophy (1.7-4.2) and facioscapulohumeral muscular dystrophy (3.2-4.6 per 100,000) were found to be the most common types of disorder. There was wide variation in study methodology, case ascertainment, and verification procedures and populations studied, all of which may contribute to the wide prevalence range, in addition to the likely variation in prevalence by country. Key Messages: Greater consistency in the conduct and reporting of neuroepidemiological studies is urgently needed to enable comparisons to be made between studies, countries, and over time.	1
Allergic bronchopulmonary aspergillosis (ABPA) is a specific complex immunological response to the spores of Aspergillus fumigatus (Af) colonizing the bronchi of asthmatic or cystic fibrosis patients. Recurrent episodes of bronchial obstruction and inflammation, as well as mucoid impaction cause bronchiectasis, pulmonary infiltrates and fibrotic alterations of the lung parenchyma, resulting in significant morbidity and mortality. The pathogenesis of ABPA remains incompletely understood, so it is not clear why certain colonized subjects develop hypersensitivity to Af, and why some sensitized patients develop ABPA and others do not. There is no simple and specific test for diagnosing ABPA. The diagnosis is based on the combination of clinical, radiological and immunological criteria. Systemic steroids are the cornerstone of treatment.	0
Here, we discussed a 55 y/o African man who recently immigrated from Nigeria to the United States and who presented to Parkland Memorial Hospital with a productive, intermittent cough of one year duration. The cough was associated with shortness of breath and chest pain. Cough was not associated with voice hoarseness, hemoptysis, melanoptysis, and wheezing. He had a computed tomography (CT) scan of the chest that showed a 1.9 cm mass in the right main stem bronchus with ipsilateral right lower lobe consolidation and bronchiectasis. The patient was seen by pulmonology who recommended bronchoscopy for diagnosis and possible intervention. Bronchoscopy showed a 90% obstructing mass in the proximal right mainstem bronchus and bronchus intermedius. The mass was large and endobronchial, circumferential, exophytic, and polypoid. The decision was made to undergo bronchoscopic tumor ablation using electrocautery snare, argon plasma coagulation (APC), suction, and forceps. The tumor was successful ablated. Microscopic examination revealed eosinophilic ducts tightly coupled with a surrounding layer of clear cell myoepithelial cells and the diagnosis of epithelial-myoepithelial carcinoma (EMC) of the lung was made. The patient was discharged from the hospital with scheduled outpatient visits for monitoring of the carcinoma by pulmonology and thoracic surgery. Unfortunately, he was lost to follow up.	0
PURPOSE:To report a case of acute posterior multifocal placoid pigment epitheliopathy occurring in temporal association with multiple immunizations in a previously healthy 25-year-old woman. METHODS:Acute posterior multifocal placoid pigment epitheliopathy was diagnosed based on ophthalmological findings of bilateral placoid subretinal lesions complicated by a serous retinal detachment in the left eye. RESULTS:Through HLA typing, the patient was found to possess the HLA-B*40 and HLA-DB1*15 alleles. She was treated with topical prednisolone acetate 1% and monitored for several months. The serous retinal detachment resolved, and visual acuity returned to normal. CONCLUSION:This case report adds to the body of knowledge regarding possible atypical interplay between vaccines and specific T-cell receptors of the host immune system and adds Polio and Tetanus to the growing list of vaccines potentially triggering acute posterior multifocal placoid pigment epitheliopathy. Increased awareness of the presentation of acute posterior multifocal placoid pigment epitheliopathy and that it may arise after immunization may also improve evaluation of acute changes in visual acuity.	0
Normophosphataemic familial tumoral calcinosis, charac-terized by ectopic mineralization of skin, is caused by mutations in the SAMD9 gene located in human chromosome 7q21, next to a paralogous gene, SAMD9-like (SAMD9L). The mouse does not have a SAMD9 orthologue, Samd9, because it has been deleted during evolution owing to genomic rearrangements. It has been suggested that the mouse Samd9l gene serves as a functional paralogue of human SAMD9. In this study, we examined Samd9l knockout mice with respect to ectopic mineralization. We also crossed these mice with Abcc6(tm1JfK) mice, a model system to study pseudoxanthoma elasticum, to see whether the absence of the Samd9l gene modifies the mineralization process. Necropsy analysis of Samd9l(tm1Homy) mice revealed no evidence of ectopic mineralization, and deletion of the Samd9l gene in mice failed to modify the mineralization process on the Abcc6(tm1JfK) background. Collectively, the results suggest that mouse Samd9l is not a functional paralogue of human SAMD9.	0
Relapsing polychondritis is a rare disease characterized by cartilage inflammation. Our aim was to estimate the incidence, prevalence and mortality of relapsing polychondritis and describe the clinical features of relapsing polychondritis in a large population.All participants diagnosed with relapsing polychondritis were sampled from the Clinical Practice Research Datalink. Prevalence and incidence rates for 1990-2012 were estimated. Relative mortality rates were estimated in a time-to-event framework using reference UK life tables. A questionnaire validation study assessed diagnostic accuracy.There were 117 participants with relapsing polychondritis ever recorded. Fifty (82%) of 61 cases were validated by a physician and unconfirmed cases were excluded. The analysis included 106 participants (42 men, 64 women) diagnosed with relapsing polychondritis. The mean age (range) at diagnosis in men was 55 (range 17-81) years and in women 51 (range 11-79) years. The median interval from first symptom to diagnosis was 1.9 years. The incidence of relapsing polychondritis between 1990 and 2012 was 0.71 (95% CI 0.55, 0.91) per million population per year. There were 19 deaths from any cause. There were 16 observed deaths eligible for survival analysis and 7.4 deaths expected for the UK population of the same age, sex and period. The standardized mortality ratio was 2.16 (95% CI 1.24, 3.51), P < 0.01. Respiratory disease, cardiac conditions and cancer were the most frequent causes of death.The incidence of relapsing polychondritis may be lower than previously estimated, and diagnostic misclassification and delay are common. Mortality in relapsing polychondritis is more than twice that of the general population.	1
Lichen planus is a common chronic inflammatory condition that affects skin and mucous membranes. Management is often delayed because of patient embarrassment or misdiagnosis by the clinician. Early recognition and treatment is essential to reduce the morbidity of this condition. We present a 58-year-old woman diagnosed with generalized hypertrophic lichen planus, a rare event, reported to occur usually on lower extremities, but found to be generalized in our patient, requiring excision of symptomatic lesions. We suggest a multidisciplinary approach to allay the anxiety and symptoms of these patients and to improve the quality of life and clinical outcomes.	0
BACKGROUND: Cryohydrocytosis is an inherited dominant hemolytic anemia characterized by mutations in a transmembrane segment of the anion exchanger (band 3 protein). Transfection experiments performed in Xenopus oocytes suggested that these mutations may convert the anion exchanger into a non-selective cation channel. The present study was performed to characterize so far unexplored ion transport pathways that may render erythrocytes of a single cryohydrocytosis patient cation-leaky. DESIGN AND METHODS: Cold-induced changes in cell volume were monitored using ektacytometry and density gradient centrifugation. Kinetics, temperature and inhibitor-dependence of the cation and water movements in the cryohydrocytosis patient's erythrocytes were studied using radioactive tracers and flame photometry. Response of the membrane potential of the patient's erythrocyte membrane to the presence of ionophores and blockers of anion and cation channels was assessed. RESULTS: In the cold, the cryohydrocytosis patient's erythrocytes swelled in KCl-containing, but not in NaCl-containing or KNO(3)-containing media indicating that volume changes were mediated by an anion-coupled cation transporter. In NaCl-containing medium the net HOE-642-sensitive Na(+)/K(+) exchange prevailed, whereas in KCl-containing medium swelling was mediated by a chloride-dependent K(+) uptake. Unidirectional K(+) influx measurements showed that the patient's cells have abnormally high activities of the cation-proton exchanger and the K(+),Cl(-) co-transporter, which can account for the observed net movements of cations. Finally, neither chloride nor cation conductance in the patient's erythrocytes differed from that of healthy donors. Conclusions These results suggest that cross-talk between the mutated band 3 and other transporters might increase the cation permeability in cryohydrocytosis.	0
Developmental and epileptic encephalopathies (DEEs) are a group of severe, early onset epilepsies characterized by refractory seizures, developmental delay or regression associated with ongoing epileptic activity, and generally poor prognosis. DEE is genetically and phenotypically heterogeneous, and there is a plethora of genetic testing options to investigate the rapidly growing list of epilepsy genes. However, more than 50% of patients with DEE remain without a genetic diagnosis despite state-of-the-art genetic testing. In this review, we discuss the major advances in epilepsy genomics that have surfaced in recent years. The goal of this review is to reach a larger audience and build a better understanding of pathogenesis and genetic testing options in DEE.	0
PURPOSE OF REVIEW:The goal of this review is to describe the presenting features of fulminant idiopathic intracranial hypertension (IIH) and outline the multimodal approach to its treatment. RECENT FINDINGS:Venous sinus stenting may be an appropriate alternative to optic nerve sheath fenestration or cerebrospinal fluid shunting in select patients with fulminant IIH. Prompt surgical intervention maximizes the chance of visual recovery in patients with fulminant IIH. "Fulminant IIH" is defined as intracranial hypertension with no secondary cause, severe vision loss within 4 weeks of symptom onset, and progressive vision loss over days. Rapid recognition of the fulminant phenotype of IIH by emergency department physicians, neurologists, and ophthalmologists is critical. Without appropriate triage and rapid medical and surgical intervention, patients with fulminant IIH are at high risk for profound, permanent vision loss. Prompt surgical intervention with optic nerve sheath fenestration, cerebrospinal fluid shunting, or venous sinus stenting minimizes the chance of poor visual outcome. If a delay is anticipated, serial lumbar punctures or temporary cerebrospinal fluid drainage and medical therapy may forestall irreversible vision loss.	0
We previously reported that mice transgenic (Tg) for thrombopoietin (TPO) developed progressive fibrosis and osteosclerosis of the bone marrow. Here, we show that TPO-overexpressing mice also exhibited notable histological changes in the kidneys, including an increased number of mesangial cells, expansion of the mesangial matrix in the glomerulus, and atrophy of the renal tubuli. Plasma transforming growth factor (TGF)-beta1 and platelet-derived growth factor (PDGF)-BB, which could induce mesangioproliferative responses in glomeruli, were both elevated in TPO Tg mice, even though TPO itself has no effect on mesangial cells due to their lack of c-Mpl. The mesangial proliferative change in TPO Tg mice was thought to be induced by the elevation of these cytokines. In conclusion, our finding that TPO-overexpressing mice developed mesangioproliferative glomerulopathy might represent an undesirable effect of chronically elevated TPO in vivo, which should be taken into consideration before new TPO-like growth factors become available in clinical practice.	0
Idiopathic juvenile osteoporosis (IJO) is a term used to describe a primary osteoporosis of unknown etiology in prepubertal children. It is rarely described in the literature and treatment modalities vary with spontaneous remission also being reported at the time of puberty. We report a 5-year-old girl with IJO who had spinal deformities and was successfully treated with oral alendronate.	0
Osteopetrosis is a rare congenital bone disorder, characterized by systemic osteosclerosis due to a deficiency of or functional defect in osteoclasts. Autosomal dominant osteopetrosis (ADOP) is the most common form with a late onset, a stable condition, relatively few symptoms and a good prognosis. Few studies to date have reported successful total hip arthroplasty (THA) in patients with ADOP and its operative difficulties. We herein describe a case of left hip osteoarthritis in a patient with OP via THA in order to share our experience during the treatment process. The patient was a 52-years-old female with osteopetrosis who was referred to our department due to a history of left hip pain with activity limitation for 20 years. The patient reported no history of fracture or family history. The patient underwent THA in the left hip. At the 6-month, 1- and 2-year follow-up, the components were in a good position and the patient remained asymptomatic and pain-free. Therefore, THA may be a feasible treatment option when patients with ADOP suffer from painful hip osteoarthritis.	0
Isolated brachydactyly is an umbrella term describing disproportionally shortened fingers and toes, often following an autosomal dominant mode of inheritance. Various forms of brachydactyly have been characterized and several causative genes have been found, but many types remain genetically undefined. We describe an Ontario family with mild brachydactyly in which whole-exome sequencing identified a novel variant for brachydactyly type A1 (exon 1, c.285_287dupGAA, p.Glu95_Asn96insLys) in the Indian hedgehog (IHH) gene. This rare variant co-segregated with affected status in the pedigree and was associated with (1) shortened middle phalange length by 21.1% (p < 0.001); (2) shortened palm length by 13.8% (p < 0.01); (3) reduced digit-palm ratio by 6.8% (p < 0.03); and (4) reduced stature by 9.5% (p < 0.001). We report the first IHH in-frame insertion causing brachydactyly type A1.	0
Calcifying fibrous pseudotumour (CFPT) is a rare lesion that has only recently been reported in the literature. Usually, the lesion develops in subcutaneous tissue, deep soft tissues or viscera. It appears as a uniform, hypocellular and well-circumscribed mass without a capsule. Only nine cases of gastric CFPT have been reported in the literature so far. Here, we report a new case of gastric CFPT, which was, surprisingly, associated with an ulcer. To our knowledge, a gastric CFPT with an ulcer has not been previously reported in the literature. The patient (a healthy 49-year-old man) had vomited approximately 300 g brown liquid and developed syncope once. CT scan and gastroscopy revealed a polypoid mass at the great curvature of the gastric body with a larger ulcer on its top. The mass was removed by surgery. During a follow-up of 5 months, the patient was asymptomatic with no recurrence. We discuss the imaging findings, as well as the clinicopathological features of this unusual case and review the related literature.	0
Neisseria meningitidis-induced acute systemic meningococcal disease is an emergency and a fatal condition that has a high mortality rate. In patients with a fulminant infection, a maculopapular petechial eruption, purpura fulminans, or an ecchymotic lesion are worrisome signs reflecting disseminated intravascular coagulation (DIC) and hint at Waterhouse-Friderichsen syndrome (WFS). Here, we describe a rare case of a patient with a fulminant Neisseria meningitidis-induced acute systemic meningococcal disease presenting with high-grade fever without meningitis symptoms. Fatal septicemia with DIC and multiple organ failure was noted. WFS was chiefly suspected. We highlight the clinical features and pathogenesis of Neisseria meningitidis-induced meningococcemia and WFS. We propose that they should be kept in mind, especially in patients presenting with a petechial eruption and purpura fulminans.	0
Alport syndrome is experiencing a remarkable increase in preclinical investigations. To proactively address the needs of the Alport syndrome community, as well as offer clarity for future clinical research sponsors, the Alport Syndrome Foundation hosted a workshop to generate consensus recommendations for prospective trials for conventional drugs. Opinions of key stakeholders were carefully considered, including those of the biopharmaceutical industry representatives, academic researchers, clinicians, regulatory agency representatives, and-most critically-patients with Alport syndrome. Recommendations were established for preclinical researchers, the use and selection of biomarkers, standards of care, clinical trial designs, trial eligibility criteria and outcomes, pediatric trial considerations, and considerations for patient engagement, recruitment, and treatment. This paper outlines their recommendations.	0
BACKGROUND:There is a growing base of literature describing BK nephropathy (BKVN) in patients outside of the setting of kidney transplant. Previous systematic reviews of the literature have been limited by methodology or by the scope of patients included. STUDY DESIGN AND METHODS:Systematic Review (Prospero # CRD42018088524). SETTING & POPULATION:Patients without kidney transplant who had biopsy-proven BKVN. SELECTION CRITERIA FOR STUDIES:Full-text articles that describe native BKVN patient cases. ANALYTICAL APPROACH:Descriptive synthesis. RESULTS:The search identified 630 unique articles of which 51 were included in the final review. Sixty-five cases (including two new cases presented in this review) were identified, all but one occurred in the setting of known immunosuppression. LIMITATIONS:The primary limitation was the exclusion of studies that did not fulfill the stringent review criteria. We excluded reports with only a clinical diagnosis of BKVN, such as those with viruria and/or viremia without biopsy. CONCLUSIONS:As of May 2018, there are 65 reported cases of BKVN in native kidneys. This represents the most comprehensive description of biopsy-proven BKVN in native kidneys to date. Evaluation for BK nephropathy should be considered in immunocompromised patients who exhibit unexplained renal failure.	0
Lafora disease is a rare, genetic, glycogen metabolism disorder inherited as autosomal recessive characterized by the presence of inclusion bodies, known as Lafora bodies, within the cytoplasm of the cells in the heart, liver, muscle, and skin. Lafora disease presents as a neurodegenerative disorder that causes impairment in the development of cerebral cortical neurons. We present here a case of Lafora disease that presented with progressive myoclonus epilepsy (PME) and investigated at our center. She was diagnosed to have Lafora disease with typical histological findings on skin biopsy and was found to be positive for the pathogenic mutation on genetic testing.	0
Hereditary hemorrhagic telangiectasia (HHT) can be clinically diagnosed, but children often lack characteristic features. We report a family with homozygous growth differentiation factor 2 (GDF2)-related HHT diagnosed by genetic testing. A boy aged 5 years and 2 months presented with isolated hypoxemia. He was the product of a consanguineous marriage; his parents were second cousins. Physical examination revealed cyanosis of nail beds and clubbed fingers. Pulse oxygen saturation was 84% to 89%. Lung function, contrast-enhanced lung computed tomography, and noncontrast echocardiography were normal. A pulmonary perfusion scan revealed radioactivity in the brain and bilateral kidney, suggesting the existence of a intrapulmonary shunt. Whole-exome sequencing revealed a homozygous variant [c.1060_1062delinsAG (p.Tyr354ArgfsTer15)] in GDF2, which was found to be inherited from his heterozygous parents. At the age of 8 years, he developed epistaxis, and an angiogram revealed diffuse pulmonary arteriovenous malformations. At the age of 9 years, he was treated with sirolimus, and his condition improved significantly. However, his now 7-year-old sister with the same homozygous variant currently has no symptoms. Physical examinations revealed 1 pinpoint-sized telangiectasia on the chest of his mother and a vascular lesion on the forehead of his sister. Additionally, the patient's father and great-uncle had a history of mild to moderate epistaxis. Mutation in GDF2 is a rare cause of HHT. Ours is the first report of homozygous GDF2-related HHT; in addition, this variant has not been reported previously. In our report, we also confirm variable expressivity, even with the same pathogenic variant in GDF2-related HHT.	0
Benign recurrent intrahepatic cholestasis represents a rare class of autosomal recessive chronic cholestasis disorders, usually presenting with recurrent episodes of intense pruritus and jaundice. We report a 27-year-old woman presenting with benign recurrent intrahepatic cholestasis type 2 due to heterozygosity in ABCB11. Interestingly, she was also found to be heterozygous in cystic fibrosis transmembrane conductance regulator, NPHP4, and A1ATD (SERPINA1), which may explain the severe nature of her disease expression because heterozygosity in each of these genes has been associated with cholestasis. Finally, she exhibited a response to steroids that may have implications for future treatment of bile salt export pump-related diseases.	0
Hereditary spastic paraplegias (HSP) constitute a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower extremities. We performed the first clinical, epidemiological and genetic study of HSP in Southern Tunisia. We investigated 88 patients belonging to 38 unrelated Tunisian HSP families. We could establish the minimal prevalence of HSP in the district of Sfax at 5.75/100,000. Thirty-one percent of the families had a pure HSP, whereas 69% had a complicated form. The mode of inheritance was almost exclusively compatible with an autosomal recessive trait (97%, 37/38). Taking into account previously published results and new data generated in this work, genetic studies revealed significant or putative linkage to known HSP loci in 13 families (34.2%) to either SPG11 (7/38, 18.4%), SPG15 (4/38, 10.5%) or to SPG4 and SPG5 in one family each. The linkage results could be validated through the identification of two recurrent truncating mutations (R2034X and M245VfsX246) in the SPG11 gene, three different mutations (Q493X, F683LfsX685 and the novel S2004T/r.?) in the SPG15 gene, the recurrent R499C mutation in the SPG4 gene as well as the new R112X mutation in the SPG5 gene. SPG11 and SPG15 are the major responsible HSP genes in Tunisia.	1
OBJECTIVE:To determine the key sonographic features for the diagnosis of sirenomelia in the first trimester of pregnancy. METHODS:Cases of sirenomelia from several prenatal diagnosis centers were retrospectively identified and reviewed. The diagnosis was established through the detection of fused lower limbs. Additional sonographic findings were also noted. RESULTS:A total of 12 cases were collected. The most striking sonographic finding was the detection of malformed lower limbs, which appeared to be fused and in an atypical position. Nuchal translucency thickness was mildly increased in three cases (25%). An abdominal cyst, representing the dilated blind-ending bowel, was noted in seven cases (58%). Color flow imaging detected a single umbilical artery in six cases (50%) and the associated intra-abdominal vascular anomalies in three cases (25%). No cases of aneuploidy were detected. The pregnancy was terminated in nine cases (75%) and intrauterine demise occurred in the remaining three cases (25%). CONCLUSIONS:The sonographic detection of abnormal lower limbs or an intra-abdominal cyst located laterally during the first-trimester scan may be warning signs of sirenomelia. This should prompt a detailed examination of the fetal lower body and intra-abdominal anatomy, including the main abdominal vessels, in order to look for additional confirmatory findings.	0
BACKGROUND:Although Mitochondrial DNA depletion syndrome (MDS) can be classified into three forms: myopathic, encephalomyopathic and hepatocerebral form, it is difficult to identify its form due to its clinical heterogeneity. Therefore, it is very important to conduct molecular genetic analysis on suspected patients. This study presented a male 38 weeks and 5 days infant with liver cytolysis and leukodystrophy. CASE PRESENTATION:A male infant proband was admitted to the department of NICU for feeding intolerance, irregular rhythm of respiration, hypoglycemia, lactic acidosis, liver cytolysis and neurological abnormalities. He was onset of mild jaundice with leukodystrophy and high lactate and phenylderivatives for urine organic acids on the 7th day. Whole exome sequencing (WES) and Sanger sequencing were performed to screen and confirm the suspicious pathogenic mutations. The results revealed this proband carried two compound heterozygous mutations in TWNK: c.1186 C > T / p.Pro396Ser and c.1844 G > C / p.Gly615Ala inherited by an autosomal recessive form from his parents, of which protein conservative analysis and structural modeling supported the pathogenicity of the two mutations. Unfortunately, the conditions described above were not improved until he was discharged from the hospital on the 23rd day and died at 4 months of age. CONCLUSIONS:In this study, we investigated a Chinese family with the hepatocerebral form of MDS and conducted WES and Sanger sequencing to explore the causative mutations for this proband born from non-consanguineous and healthy parents. We identified two novel TWNK c.1186 C > T/ c.1844 G > C compound heterozygous mutations which were probably the disease-causing mutations of hepatocerebral form of MDS and described the clinical manifestations of the proband, which expanded the phenotypic spectrum of MDS caused by variants in TWNK. This study also emphasized WES technology can provide the genetic diagnosis of Mendelian genetic disease.	0
Hereditary congenital facial paresis is a rare syndrome of isolated facial nerve palsy causing facial asymmetry and ptosis. Most described cases follow an autosomal dominant pattern of inheritance. It differs from Moebius syndrome, which is usually sporadic and associated with the involvement of other cranial nerves, commonly the abducens nerve in addition to orofacial and limb malformations and defects of the musculoskeletal system. We present three patients from the same family with features of congenital hereditary facial paresis. Facial asymmetry and facial weakness were the most remarkable findings. High-resolution imaging showed both facial nerves to be present but symmetrically and markedly hypoplastic with no other structural abnormality in the brainstem. This syndrome has been previously mapped to chromosome 3q21-22 but no gene has been identified as yet.	0
BACKGROUND:Infant leukemia most commonly present with pallor and hepatosplenomegaly. The possibility of other differential diagnosis also has to be kept in mind during evaluation, as identifying the precise etiology for this clinical presentation is crucial for management. OBSERVATION:An infant, was referred to us with suspected infant leukemia and was subsequently diagnosed to have lysosomal acid lipase deficiency/Wolman disease with a novel 5 bp deletion "c.1180_1184del" in the last exon (exon 10) of the lipase A (LIPA) gene. CONCLUSIONS:Hepatosplenomegaly and pallor resulting from nutritional deficiency or bone marrow involvement in Wolman disease can mimic infant leukemia.	0
Liposarcomas are considered to be the most common soft tissue sarcomas and have five histological subtypes. The myxoid subtype often occurs in the lower limbs and the retroperitoneum; however, the abdominal wall location is extremely rare. The clinical presentation and radiological findings are non-specific. Wide local excision with a minimum margin of 3 cm remains the mainstay of treatment to prevent local recurrences. We herein report a rare location of myxoid liposarcoma in the abdominal wall.	0
WAGR 11p13 deletion syndrome is associated with abnormalities including (W) ilms tumor, (A) niridia, (G) enitourinary abnormalities, and growth and mental (R) etardation (WAGR). Potocki-Schaffer syndrome is a contiguous gene syndrome associated with deletions in 11p11.2, principal features of which are multiple exostoses, parietal foramina development delay, mental retardation, and facial dysmorphism. In some cases, males may have enlarged anterior fontanels and genital abnormalities. Each of these syndromes is very rare. Here we report a patient with both WAGR and Potocki-Shaffer syndromes who presented with aniridia, nystagmus, macular dysplasia, enlarged anterior fontanel, mental retardation, ptosis, low-set ears, micrognathia, and atrial septal defect at 6 months old. SNP array revealed a large (26.25 Mb)deletion: arr[hg19]11p15.1p11.2(18742043-44991839)× 1. Genetic testing allowed for diagnosis of this patient at a very young age. In addition to the postnatal phenotype of the patient, we found one prenatal symptom of these syndromes is oligohydramnios, which when present might indicate advanced prenatal diagnosis. This made the possibility of prenatal diagnosis for these syndromes.	0
Prolyl endopeptidase-like (PREPL) deficiency (MIM 616224) is a very rare congenital disorder characterized by neonatal hypotonia and feeding difficulties, ptosis, neuromuscular symptoms, cognitive impairments, growth hormone deficiency, short stature, and hypergonadotropic hypogonadism. This syndrome is an autosomal recessive disease resulting from mutations in the PREPL gene. Previous reports have associated PREPL deficiency with only one nucleotide substitution, the deletion of four nucleotides, and eight small microdeletions in the PREPL gene In this study, we used whole exome sequencing (WES) to identify a novel homozygous splicing mutation (c.616 + 1G > T) in a 14-year-old Chinese girl with PREPL deficiency. Sequencing of the RT-PCR products from the patient's blood sample revealed that the c.616 + 1G > T variant disrupted normal splicing in intron 4 leading to an aberrant inclusion of 43 nucleotides in intron, a frameshift, and premature termination codon. Our patient exhibited several of the common phenotypes, including severe neonatal hypotonia, growth impairment and cognitive problems. However, we also observed several unusual phenotypic characteristics: absence of the ovaries, hypoplasia of the uterus, microcephaly and a short neck in patient is alsoobserved. These results provide further evidence for the involvement of PREPL development of the ovaries and uterus. Our findings may provide further insight into the relationship between the genotype and phenotype in collagen-associated diseases and improve the clinical diagnosis of Prolyl endopeptidase-like deficiency.	0
Objective:To update the congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency clinical practice guideline published by the Endocrine Society in 2010. Conclusions:The writing committee presents updated best practice guidelines for the clinical management of congenital adrenal hyperplasia based on published evidence and expert opinion with added considerations for patient safety, quality of life, cost, and utilization.	0
OBJECTIVE:To investigate trends in the incidence of epithelial ovarian cancer (EOC), according to histologic subtypes, in Korean women between 1999 and 2012. METHODS:Data from the Korea Central Cancer Registry recorded between 1999 and 2012 were evaluated. The incidences of EOC histologic subtypes were counted. Age-standardized incidence rates (ASRs) and annual percentage changes (APCs) in incidence rates were calculated. Patient data were divided into three groups based on age (<40, 40 to 59, and >59 years), and age-specific incidence rates were compared. RESULTS:Overall, the incidence of EOC has increased. Annual EOC cases increased from 922 in 1999 to 1,775 in 2012. In 1999, the ASR was 3.52 per 100,000 and increased to 4.79 per 100,000 in 2012 (APC, 2.53%; p<0.001). The ASRs in 2012 and APCs between 1999 and 2012 for the four major histologic subtypes were as follows (in order of incidence): serous carcinoma (ASR, 2.32 per 100,000; APC, 4.34%; p<0.001), mucinous carcinoma (ASR, 0.73 per 100,000; APC, -1.05%; p=0.131), endometrioid carcinoma (ASR, 0.51 per 100,000; APC, 1.48%; p=0.032), and clear cell carcinoma (ASR, 0.50 per 100,000; APC, 8.13%; p<0.001). In the sub-analyses based on age, clear cell carcinoma was confirmed as the histologic subtype whose incidence had increased the most since 1999. CONCLUSION:The incidence of EOC is increasing in Korea. Among the histologic subtypes, the incidence of clear cell carcinoma has increased markedly across all age groups since 1999.	1
Antiphospholipid syndrome (APS) is an autoimmune disease characterised by vascular thrombosis and/or pregnancy morbidity in the presence of persistently positive serum tests for antiphospholipid antibodies. Management of APS centres on preventing these clinical events and in preventing chronic damage caused by these events. In patients with thrombotic APS, long-term anticoagulation is recommended in the majority of cases. Although there were hopes that direct-acting oral anticoagulants could replace warfarin for prevention of thrombosis in patients with APS, this now seems less likely due to recent trial results. There is no evidence for use of anticoagulation in people who are aPL-positive but have never had a thrombosis but low-dose aspirin may be beneficial in those who have a higher-risk aPL profile. Management of obstetric APS is with daily subcutaneous heparin and low-dose aspirin. This gives a live birth rate of 70% or more. Catastrophic APS is rare, occurring in 1% of patients with APS. It is characterised by thrombosis in multiple organs simultaneously, with a high mortality rate. The management is with corticosteroids, anticoagulation, and immunoglobulins or plasma exchange.	0
Background:Pemphigus vulgaris (PV) is a potentially life-threatening mucocutaneous autoimmune blistering disease characterized by suprabasal acantholysis, causing painful mucocutaneous blisters and erosions. Current mainstay therapy for pemphigus is systemic corticosteroids in combination with or without immunosuppressive adjuvants, which may cause severe adverse effects and seriously impact on the quality of life in pemphigus patients. The objective of this study was to evaluate the efficacy and safety of thalidomide therapy in patients with PV. Methods:This study examined six PV patients from June 5, 2017, to November 11, 2018, in the dermatology department of Peking Union Medical College Hospital. Treatment with thalidomide was applied at a dose of 50-100 mg/day for disease control. Results:The mean age of the six patients (two male and four female patients) at the time of thalidomide therapy initiation was 50.2 years (range: 38-67 years), and the total duration of follow-up after thalidomide therapy was 13.2 months (range: 5-25 months). All patients responded favorably to thalidomide treatment, and three patients showed a dramatic reduction in anti-Dsg3 autoantibodies in the serologic examinations within 1 year. Five patients were found to have mucosal involvement. Mild adverse effects were noted in three patients, which could be managed after the application of symptomatic treatment and did not interfere with the pemphigus therapy. Conclusion:These results demonstrate that thalidomide could be an effective and safe option for PV patients, especially those who are concerned about steroid-induced severe complications, and have mucosal diseases.	0
INTRODUCTION:Immune checkpoint inhibitors and angiogenesis inhibitors are novel treatment options for renal cell carcinoma and widely used in clinical practice. They are related with adverse events that occur as a consequence of immune system activation and inhibition of angiogenesis. Herein, we report a rare case of inflammatory arthritis seen in a patient treated with an anti Programmed cell death-1 pembrolizumab and an anti-vascular endothelial growth factor pazopanib. CASE REPORT:A 60-year-old Caucasian male presented to our clinic with inflammatory arthritis with pitting edema. He had been started on pembrolizumab therapy for metastatic renal cell carcinoma after enrolling in the KEYNOTE-679 study. After six cycles of treatment with pembrolizumab, metastasis had been determined in the lung. Then, the patient's therapy was changed to pazopanib. While the patient was on pazopanib treatment, he noticed a gradual swelling of both hands. Rheumatoid factor, anti-nuclear antibody and anti-cyclic citrullinated peptide were negative. Joint ultrasonography revealed acute tenosynovitis and soft tissue swelling with pitting edema, and a diagnosis of remitting seronegative symmetrical synovitis with pitting edema was made. Management and outcome: He was started on 10 mg prednisolone daily. His symptoms dramatically responded to corticosteroid. He continued to take pazopanib. Then, the patient was discharged with 10 mg prednisolone daily. DISCUSSION:Pembrolizumab- and/or pazopanib-induced remitting seronegative symmetrical synovitis with pitting edema can be among the rare rheumatic immune-related adverse events that clinicians may encounter as the immune check point inhibitors and anti-VEGF use increases. Corticosteroid therapy can relieve symptoms and cessation of therapy may not be necessary.	0
Background:Anterior sacral meningocele (ASM) is a rare congenital anomaly. It is characterized by herniation of the dura through a defect in the anterior sacrum. Rarely, however, it may extend to the rectal area through a rectothecal fistula with or without rectorrhea. Case Description:Here, we present a case of ASM associated with a rectothecal fistula and rectorrhea. Surgical closure of the ostium of the cyst through a posterior approach resulted in long-term improvement. Conclusion:An ASM with both rectothecal fistula and rectorrhea is extremely rare.	0
In order to make a correct diagnosis of idiopathic Parkinson's disease (PD), it is essential to exclude atypical parkinsonian features, such as early dementia, fall, and autonomic dysfunction. Rheumatoid arthritis (RA), which is a systemic inflammatory disorder, although most patients present in a polyarticular manner. Still some may also present with extra-articular involvement including skin, lung, heart, and the central or peripheral nervous systems. A possible pathogenetic link between RA and PD are proposed. However, the coexistence of RA and progressive supranuclear palsy (PSP) is rarely reported. Here, we report a parkinsonian patient with a newly diagnosed flare-up RA presenting with early falls, postural instability and supra-nuclear gaze palsy, which suggestive of clinically probable PSP. Furthermore, the parkinsonian features respond to anti-rheumatic agents, but not levodopa. Finally, the patient looks like a clinical possible PD. In summary, Parkinsonian patient with newly diagnosed flare-up RA can present with clinically probable PSP. Unbearably painful limb contracture is a clue of the coexistence of RA. Both typical and atypical parkinsonian features respond dramatically to anti-rheumatic medication, but not levodopa.	0
Background: Tracheal agenesis/atresia (TA) presents with respiratory distress at birth and subsequent difficulty in endotracheal intubation. The antenatal course is complicated by polyhydramnios and premature labor. Case report: We present a newborn baby boy with respiratory distress and unsuccessful intubation. Postmortem neck dissection revealed tracheal atresia with esophageal atresia and high tracheoesophageal fistula. Conclusion: In this variant of tracheal atresia, the coexistent esophageal atresia precluded the establishment of a functional air passage. This variant that does not fall into the any of the described categories in accepted classification systems. The lack of any distal communication makes this case inoperable and fatal.	0
Huntington Disease Like-2 (HDL2) is a rare autosomal dominant genetic disease caused by a mutation in the JPH3 gene. HDL2 is the Huntington Disease (HD) phenocopy that has the greatest clinical resemblance to HD. Both are characterized by movement, psychiatric and cognitive dysfunction, which progress to dementia. The present study compared the neuropsychological profile of HDL2 with that of HD. Using a Single Case-Control Methodology in Neuropsychology, three HDL2 and seven matched HD patients were assessed with a comprehensive neuropsychological battery and compared to matched control samples, considering age, years of education, type of school (public/government) and language (all bi/multilingual). Potential double dissociations were explored by using Crawford, Garthwaite, and Wood's Inferential Methods for Comparing the Scores of Two Single-Cases in Case-Control Designs. Double dissociation between HDL2 and HD were identified in three tests, namely Letter Number Sequencing, Rey Auditory Learning Test Delayed and Recognition Trials. These dissociations possible are due to methodological limitations.	0
Objective: To document the clinical, radiographic, and histological characteristics of mandibular first molar teeth with developmental abnormalities previously attributed to dens invaginatus and enamel pearls in dogs. Materials and Methods: Affected mandibular first molar teeth from dogs were evaluated grossly and via intraoral radiography. Endodontically and/or periodontally compromised teeth were extracted and subjected to some combination of micro-computed tomography, histopathology, and immunohistochemistry with anti-amelogenin antibody. Results: Six dogs with developmental abnormalities of mandibular first molar teeth were identified, representing 11 affected teeth. The condition was bilateral in 5 dogs, while in 1 dog, only one mandibular first molar tooth was present. Patient weight ranged from 1.7 to 6 kg (median = 4.09 kg). On intraoral radiographs, root convergence or parallelism was noted in 6 of 11 teeth, and root dilaceration was noted in 3 of 11 teeth. Eight teeth required extraction due to periapical lucencies or periodontitis. On micro-CT, the abnormal teeth were characterized by the presence of abnormal, heterogenous hard tissue with beam attenuation characteristics midway between that of enamel and dentin. Enamel fissures were identified in 4 of 8 teeth, while ectopic radicular enamel was identified in 2 of 8 teeth. The abnormal tissue was traversed by channels measuring 20-40 μm in diameter. Channels communicated with the enamel fissures in 2/8 teeth, the furcation in 2/8 teeth and the pulp in 4/8 teeth. The abnormal tissue was frequently surrounded by disorganized dentin. Histologic features of enamel and dentin were absent from the abnormal tissue and immunohistochemistry to detect amelogenin in the abnormal tissue was negative in all samples. Conclusion: The dental abnormalities described here correspond to a previously unrecognized developmental abnormality involving the mandibular first molar teeth in dogs. The developmental origin of the abnormal tissue could not be ascertained, and further investigations are required to determine the mode of formation, origin of the abnormal tissue, and factors associated with development. These developmental abnormalities more closely resemble molar-incisor malformation, rather than dens invaginatus or enamel pearls as described in humans. The authors propose that affected mandibular first molar teeth simply be referred to as having carnassial tooth malformations.	0
Interferon-γ receptor 1 (IFNγR1) deficiency is one of the inborn errors of IFN-γ immunity underlying Mendelian Susceptibility to Mycobacterial Disease (MSMD). This molecular circuit plays a crucial role in regulating the interaction between dendritic cells (DCs) and T lymphocytes, thus affecting DCs activation, maturation, and priming of T cells involved in the immune response against intracellular pathogens. We studied a girl who developed at the age of 2.5 years a Mycobacterium avium infection characterized by disseminated necrotizing granulomatous lymphadenitis, and we compared her findings with other patients with the same genetic condition. The patient carried a heterozygous 818del4 mutation in the IFNGR1 gene responsible of autosomal dominant (AD) partial IFNγR1 deficiency. During the acute infection blood cells immunophenotyping showed a marked reduction in DCs counts, including both myeloid (mDCs) and plasmacytoid (pDCs) subsets, that reversed after successful prolonged antimicrobial therapy. Histology of her abdomen lymph node revealed a profound depletion of tissue pDCs, as compared to other age-matched granulomatous lymphadenitis of mycobacterial origin. Circulating DCs depletion was also observed in another patient with AD partial IFNγR1 deficiency during mycobacterial infection. To conclude, AD partial IFNγR1 deficiency can be associated with a transient decrease in both circulating and tissular DCs during acute mycobacterial infection, suggesting that DCs counts monitoring might constitute a useful marker of treatment response.	0
Brown-black pigment network is the hallmark dermoscopic feature of melanocytic lesions. Several non-melanocytic disorders also exhibit a pigment network as one of their main or useful dermoscopic diagnostic features. This article presents a compilation of such disorders to the readers describing their essential dermoscopic features with an emphasis on the characteristics of the pigment network exhibited by them.	0
Background:Hirschsprung-associated enterocolitis (HAEC) is the most common complication of Hirschsprung disease (HSCR) that may happen pre-operatively. Several methods have been reported to determine HAEC. Because the diagnosis of pre-operative HAEC might change the surgical plan, we aimed to determine the accuracy of the classical criteria for diagnosis of pre-operative HAEC and using the Delphi method as a gold standard. Methods:Medical records of HSCR children who were admitted to our hospital from January 2009 to December 2015 were retrospectively analyzed. Results:Ninety-six subjects were involved in this study, consisting of 74 males and 22 females. The most common findings of the Delphi score were abdominal distension (100%) and dilated loops of bowel (100%), followed by leucocytosis (78.6%), lethargy (71.4%), cutoff sign in rectosigmoid with absence of distal air (71.4%), and shift to left (71.4%). The frequency of pre-operative HAEC was 4.2% and 14.6% using the classical criteria and Delphi method, respectively (p = 0.016). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rates of the classical criteria for diagnosis of pre-operative HAEC were 14.3% (95% CI: 1.8-42.8%), 97.6% (95% CI: 91.5-99.7%), 50% (95% CI: 13.3-86.7%), 87% (95% CI: 84.3-89.2), and 85.4% (95% CI: 76.7-91.8%), respectively. Conclusions:The frequency of pre-operative HAEC is low in our hospital. The accuracy of the classical criteria is considered relatively moderate for diagnosis of pre-operative HAEC.	0
The Irish national registry for inherited retinal degenerations (Target 5000) is a clinical and scientific program to identify individuals in Ireland with inherited retinal disorders and to attempt to ascertain the genetic cause underlying the disease pathology. Potential participants first undergo a clinical assessment, which includes clinical history and analysis with multimodal retinal imaging, electrophysiology, and visual field testing. If suitable for recruitment, a sample is taken and used for genetic analysis. Genetic analysis is conducted by use of a retinal gene panel target capture sequencing approach. With over 1000 participants from 710 pedigrees now screened, there is a positive candidate variant detection rate of approximately 70% (495/710). Where an autosomal recessive inheritance pattern is observed, an additional 9% (64/710) of probands have tested positive for a single candidate variant. Many novel variants have also been detected as part of this endeavor. The target capture approach is an economic and effective means of screening patients with inherited retinal disorders. Despite the advances in sequencing technology and the ever-decreasing associated processing costs, target capture remains an attractive option as the data produced is easily processed, analyzed, and stored compared to more comprehensive methods. However, with decreasing costs of whole genome and whole exome sequencing, the focus will likely move towards these methods for more comprehensive data generation.	0
Acute promyelocytic leukemia (APL) is characterized by a unique chromosome translocation t(15;17)(q24;q21), which leads to the PML/RARA gene fusion formation. However, it is acknowledged that this rearrangement alone is not able to induce the whole leukemic phenotype. In addition, epigenetic processes, such as DNA methylation, may play a crucial role in leukemia pathogenesis. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), involves the covalent transfer of a methyl group (-CH3) to the fifth carbon of the cytosine ring in the CpG dinucleotide and results in the formation of 5-methylcytosine (5-mC). The aberrant gene promoter methylation can be an alternative mechanism of tumor suppressor gene inactivation. Understanding cancer epigenetics and its pivotal role in oncogenesis, can offer us not only attractive targets for epigenetic treatment but can also provide powerful tools in monitoring the disease and estimating the prognosis. Several genes of interest, such as RARA, RARB, p15, p16, have been studied in APL and their methylation status was correlated with potential diagnostic and prognostic significance. In the present manuscript we comprehensively examine the current knowledge regarding DNA methylation in APL pathogenesis. We also discuss the perspectives of using the DNA methylation patterns as reliable biomarkers for measurable residual disease (MRD) monitoring and as a predictor of relapse. This work also highlights the possibility of detecting aberrant methylation profiles of circulating tumor DNA (ctDNA) through liquid biopsies, using the conventional methods, such as methylation-specific polymerase chain reaction (MS-PCR), sequencing methods, but also revolutionary methods, such as surface-enhanced Raman spectroscopy (SERS).	0
Isodicentric Y chromosomes are considered one of the most common structural abnormalities of the Y chromosome. Neocentric marker chromosomes, with neocentromeres, have drawn increasing attention in recent years. The present study reported an azoospermic male with a neocentric isochromosome Yp, neo(Yp), and an isodicentric Yq, idic(Yq). The karyotype was analyzed using G‑banding, chromosome microarray analysis (CMA), and fluorescence in situ hybridization (FISH) with various detection probes, including sex‑determining region on the Y chromosome (SRY) and Y centromeric, applied at the same time. G‑banding initially revealed the karyotype 47,X,i(Y)(q10),+mar. CMA indicated the presence of an extra Y chromosome, seemingly equivalent to 47,XYY males. FISH delineated the existence of two centromeres on the idic(Yq). For the marker chromosome, two SRY signals were detected instead of the Y‑specific centromere signal, and a visual centromere was observed. This indicated the possible existence of a neocentromere in the marker chromosome, located in the connected region in Yp11.2 band. Finally, the patient's karyotype was established as 47,X,idic(Y)(p11.2), neo(Y)(pter→Yp11.2::Yp11.2→pter). The findings suggested that both idic(Yq) and neo(Yp) could be the main causes of the patient's azoospermia, despite the fact that the partial disomy of Ypter to Yp11.2 did not lead to any major malformations. The present study not only improves the understanding of karyotype/phenotype relationships between neocentric marker Y chromosomes and male infertility, but also supports the hypothesis that the combined application of molecular cytogenetic analysis could aid in reliably confirming breakpoints, origins, and the constitution of the marker chromosomes.	0
BACKGROUND:Bainbridge-Ropers syndrome is a rare autosomal dominant genetic disorder. CASE CHARACTERISTICS:A 26-day-old neonate presented with feeding difficulties, excessive sleeping, and hirsutism over forehead and lumbosacral skin. OUTCOME:Whole-exome sequencing identified a novel nonsense mutation. MESSAGE:We report a novel mutation in a Chinese neonate with Bainbridge-Ropers syndrome.	0
Background/Aims:Per-oral endoscopic myotomy (POEM) is an established treatment for achalasia. The technique of POEM is still evolving and the impact of length of esophageal myotomy on the outcomes of POEM is not known. In this study, we aim to compare the outcomes of short (3 cm) versus long (6 cm and above) esophageal myotomy in patients undergoing POEM for achalasia cardia. Methods:Consecutive patients with idiopathic achalasia (type I and II) were randomized to receive short (3 cm) or long esophageal myotomy (≥ 6 cm). Both groups were compared for clinical success, operative time, adverse events, and gastroesophageal reflux disease (GERD). Results:Seventy-one consecutive patients with type I and II achalasia underwent POEM with short (n = 34) or long (n = 37) esophageal myotomy techniques. Mean length of esophageal myotomy in short and long groups was 2.76 ± 0.41 and 7.97 ± 2.40, respectively (P < 0.001). Mean operative time was significantly shorter in short myotomy group (44.03 ± 13.78 minutes and 72.43 ± 27.28 minutes, P < 0.001). Clinical success was comparable in both arms at 1-year (Eckardt score 0.935 ± 0.929 vs 0.818 ± 0.983, P = 0.627). Improvement in objective parameters including integrated relaxation pressure and barium column height at 5 minutes was similar in both groups. GERD was detected in 50.88% patients with no significant difference in short and long myotomy groups (44.44% vs 56.67%, P = 0.431). Conclusions:A short esophageal myotomy is non-inferior to long myotomy with regards to clinical success, adverse events, and GERD in cases with type I and II achalasia. Reduced operating duration favors short esophageal myotomy in these patients.	0
Mutations in transforming growth factor-beta-induced (TGFBI) gene cause clinically distinct types of corneal dystrophies. To delineate the mechanisms driving these dystrophies, we focused on the R124C mutation in TGFBI that causes lattice corneal dystrophy type1 (LCD1) and generated novel transgenic mice harbouring a single amino acid substitution of arginine 124 with cysteine in TGFBI via ssODN-mediated base-pair substitution using CRISPR/Cas9 technology. Eighty percent of homozygous and 9.1% of heterozygous TGFBI-R124C mice developed a corneal opacity at 40 weeks of age. Hematoxylin and eosin and Masson trichrome staining showed eosinophilic deposits in subepithelial corneal stroma that stained negative for Congo-red. Although amyloid deposition was not observed in TGFBI-R124C mice, irregular amorphous deposits were clearly observed via transmission electron microscopy near the basement membrane. Interestingly, we found that the corneal deposition of TGFBI protein (TGFBIp) was significantly increased in homozygous TGFBI-R124C mice, suggesting a pathogenic role for the mutant protein accumulation. Furthermore, as observed in the LCD1 patients, corneal epithelial wound healing was significantly delayed in TGFBI-R124C mice. In conclusion, our novel mouse model of TGFBI-R124C corneal dystrophy reproduces features of the human disease. This mouse model will help delineate the pathogenic mechanisms of human corneal dystrophy.	0
OBJECTIVE:We present prenatal diagnosis low-level mosaic trisomy 17 with maternal uniparental disomy (UPD) 17 at amniocentesis in a pregnancy with a favorable outcome. MATERIALS AND METHODS:A 40-year-old, primigravid woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. This pregnancy was conceived by in vitro fertilization and embryo transfer. Amniocentesis revealed a karyotype of 47,XX,+17 [13]/ 46, XX [23]. Repeat amniocentesis was performed at 21 weeks of gestation. Conventional cytogenetic analysis was applied on cultured amniocytes, parental bloods and cord blood. Simultaneous molecular genetic analysis such as interphase fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH) and quantitative fluorescent polymerase chain reaction (QF-PCR) assays were applied on uncultured amniocytes. Interphase FISH was applied on postnatal buccal cells. RESULTS:Repeat amniocentesis revealed a karyotype of 47,XX,+17[6]/46,XX[28]. Genetic analyses on uncultured amniocytes showed the results of mosaic trisomy 17 (12/101 cells = 11.9%) in FISH analysis, no genomic imbalance in aCGH analysis and maternal UPD 17 in QF-PCR assays. The parental karyotypes were normal. Prenatal ultrasound findings were unremarkable. The parents decided to continue the pregnancy, and a 1449-g, phenotypically normal female baby was delivered prematurely at 31 weeks of gestation. The cord blood had a karyotype of 46,XX. She had a normal psychomotor development at age 22 months at follow-up. Interphase FISH analysis on buccal cells showed trisomy 17 signals in 1/66 cells (1.5%). CONCLUSIONS:Low-level mosaicism for trisomy 17 associated with maternal UPD 17 detected by amniocentesis without ultrasound abnormality can be associated with a favorable outcome. Molecular genetic analysis of uncultured amniocytes at repeat amniocentesis is useful for confirmation and genetic counseling under such as circumstance.	0
In this report, we review the relationship between succinate dehydrogenase (SDH) deficiency and the epigenome, especially with regards to two clinical conditions. Carney triad (CT) is a very rare disease with synchronous or metachronous occurrence of at least three different tumor entities; gastric gastrointestinal stromal tumor (GIST), paraganglioma (PGL), and pulmonary chondroma. This condition affects mostly females and it is never inherited. Another disease that shares two of the tumor components of CT, namely GIST and PGL is the Carney-Stratakis syndrome (CSS) or dyad. CSS affects both genders during childhood and adolescence. We review herein the main clinical features and molecular mechanisms behind those two syndromes that share quite a bit of similarities, but one is non-hereditary (CT) whereas the other shows an autosomal-dominant, with incomplete penetrance, inheritance pattern (CSS). Both CT and CSS are caused by the deficiency of the succinate dehydrogenase (SDH) enzyme. The key difference between the two syndromes is the molecular mechanism that causes the SDH deficiency. Most cases of CT show down-regulation of SDH through site-specific hyper-methylation of the SDHC gene, whereas CSS cases carry inactivating germline mutations within one of the genes coding for the SDH subunits A, B, C, or D (SDHA, SDHB, SDHC, and SDHD). There is only partial overlap between the two conditions (there are a few patients with CT that have SDH subunit mutations) but both lead to increased methylation of the entire genome in the tumors associated with them. Other tumors (outside CT and CSS) that have SDH deficiency are associated with increased methylation of the entire genome, but only in CT there is site-specific methylation of the SDHC gene. These findings have implications for diagnostics and the treatment of patients with these, often metastatic tumors.	0
BACKGROUND: Metachromatic leukodystrophy (MLD) is a severe neurometabolic disease caused mainly by deficiency of arylsulfatase A encoded by the ARSA gene. Based on epidemiological surveys the incidence of MLD per 100,000 live births varied from 0.6 to 2.5. Our purpose was to estimate the birth prevalence of MLD in Poland by determining population frequency of the common pathogenic ARSA gene mutations and to compare this estimate with epidemiological data. METHODOLOGY: We studied two independently ascertained cohorts from the Polish background population (N∼3000 each) and determined carrier rates of common ARSA gene mutations: c.459+1G>A, p.P426L, p.I179S (cohort 1) and c.459+1G>A, p.I179S (cohort 2). PRINCIPAL FINDINGS: Taking into account ARSA gene mutation distribution among 60 Polish patients, the expected MLD birth prevalence in the general population (assuming no selection against homozygous fetuses) was estimated as 4.0/100,000 and 4.1/100,000, respectively for the 1(st) and the 2(nd) cohort with a pooled estimate of 4.1/100,000 (CI: 1.8-9.4) which was higher than the estimate of 0.38 per 100,000 live births based on diagnosed cases. The p.I179S mutation was relatively more prevalent among controls than patients (OR = 3.6, P = 0.0082, for a comparison of p.I179S frequency relative to c.459+1G>A between controls vs. patients). CONCLUSIONS/SIGNIFICANCE: The observed discrepancy between the measured incidence of metachromatic leukodystrophy and the predicted carriage rates suggests that MLD is substantially underdiagnosed in the Polish population. The underdiagnosis rate may be particularly high among patients with p.I179S mutation whose disease is characterized mainly by psychotic symptoms.	1
As the field of neurogenetics is expanding rapidly and variant classification criteria evolve, genetic variants in databases are re-evaluated overtime allowing updated classifications of pathogenicity predication. When caring for patients with genetic disorders, it is important to obtain the original genetic report and also consider an updated reanalysis.	0
X-linked adrenoleukodystrophy (X-ALD) occurs due to mutations in the ABCD1 gene that encodes the peroxisomal membrane protein peroxisomal transporter ATP-binding cassette sub-family D member 1 (ABCD1). Degradation of very long-chain fatty acids in peroxisomes is impaired owing to ABCD dysfunction, subsequently leading to adrenomyeloneuropathy, cerebral adrenoleukodystrophy, and adrenal insufficiency. X-ALD frequently induces idiopathic Addison's disease in young male patients. Here, we confirmed the diagnosis of X-ALD in a young male patient with primary adrenal insufficiency, and identified a novel ABCD1 gene mutation (p.Trp664*, c.1991 G>A).	0
The Ochoa syndrome is the association of a non-neurogenic neurogenic bladder with abnormal facial muscle expression. Patients are at risk for renal failure due to obstructive uropathy. We report a family of three siblings, with an emphasis on the abnormalities in facial expression. Careful examination shows an unusual co-contraction of the orbicularis oculi and orbicularis oris muscles only when full facial expressions are exhibited, across a range of emotional or voluntary situations. This suggests a peripheral disorder in facial muscle control. Two thirds of patients have anal sphincter abnormalities. Aberrant organisation of the facial motor and urinary-anal sphincter nuclei may explain these symptoms.	0
GNAS is one of the most complex gene loci in the human genome and encodes multiple gene products including Gsα, XLαs, NESP55, A/B, and AS transcripts. XLαs, the extra-large G protein ɑ-subunit, is paternally expressed. XLɑs and Gsɑ share the common 2-13 exons with different promoters and first exons. Therefore, XLɑs contains most of the functional domains of Gsα including receptor and effector binding sites. In vitro studies suggest a "Gsɑ"-like function of XLɑs regarding the stimulation of cAMP generation in response to receptor activation with different cellular actions. However, it is unclear whether XLαs has an important physiological function in humans. Pseudopseudohypoparathyroidism (PPHP) and progressive osseous heteroplasia (POH) are caused by paternally inherited mutations of GNAS. Maternal uniparental disomy of chromosome 20 [UPD(20)mat] lacks paternal chromosome 20. Therefore, the phenotypes of these diseases may be secondary to the abnormal functions of XLɑs, at least partly. From the phenotypes of human diseases like PPHP, POH, and UPD(20)mat, as well as some animal models with deficient XLɑs functions, it could be seen that XLɑs is involved in the growth and development of the mammalian fetus, plays a different role in glucose, lipid, and energy metabolism when compared with Gsɑ, and could prevent heterotopic ossification in humans and mice. More in vivo and in vitro studies, especially the development of conditional XLɑs knockout mice, are needed to clarify the physiopathologic roles and related signal pathways of XLɑs.	0
OBJECTIVE:The main objective of the study was to identify the determinants that contribute to the malignant transformation of oral leukoplakia in a group of patients managed in secondary care. A secondary objective was to compare two dysplasia grading systems to determine their utility in assessing the prognosis. MATERIAL AND METHODS:The cohort consisted of 93 patients diagnosed during the period 2009-2013. The variables recorded and analysed included age and sex, clinical presentation (colour) and severity of oral epithelial dysplasia (OED) scored by the WHO (2005) and the binary grading systems. The planned management included excision of high-grade dysplasia and observation of low-grade dysplasia lesions based on the WHO grading system. Patient factors were transcribed from the pathology records and updated using a questionnaire sent out to the whole group of patients. Data were analysed using χ2 test and Kaplan-Meier analysis (P < 0.05). RESULTS:Complete follow-up data were available for 93 patients. Malignant transformation occurred in 7 patients (7.5%) during a mean follow-up period of 30 months. Among the surgically excised group (n = 51), a recurrence of oral leukoplakia was noted in 16 patients (31%). WHO OED grading (P = 0.02) and the presence of red areas (P = 0.012) were useful in predicting malignant transformation with severe epithelial dysplastic lesions and red and white mixed lesions showing higher rates. CONCLUSION:Leukoplakias (7.5%) transformed over a mean follow-up period of 30 months. Dysplasia grading and the clinical appearance by colour (mixed white and red) were significant predictors of malignant transformation CLINICAL SIGNIFICANCE: Patients with erythroleukoplakia and those diagnosed with moderate or severe epithelial dysplasia require more intensive interventions as such lesions have a higher risk of developing a malignancy.	0
BACKGROUND:Congenital analbuminemia (CAA) is a very rare disorder. Our data describes the clinical features and laboratory results of a new case established by mutation analysis of the albumin gene in a 39-year-old woman presenting with hypercholesterolemia. Our findings contribute to shed light on the molecular genetics of the disorder and confirm that safe and well tolerated hypocholesterolemic treatment with atorvastatin may be administered in dislipidemic patient with CAA in order to reduce their cardiovascular risk. CASE SUMMARY:Our patient presented with a history of hypercholesterolemia and referred asthenia and heaviness in both legs. She was born from healthy and non-consanguineous parents and her development was normal. She had not familiarity for early cardiovascular disease, and did not report personal history of hypertension, chronic kidney or liver diseases. Clinical laboratories results showed critically reduced value of albumin whereas other serum proteins were elevated. Main causes of hypoalbuminemia (proteinuria, inflammatory state and insufficient hepatic synthesis) were ruled out by normal procedures and laboratory tests. So the hypothesis of a CAA was tested through mutation analysis of the albumin gene that revealed a homozygous CA deletion in exon 12, at nucleotide positions c1614-1615. This finding brought to the diagnosis of CAA. Currently the patient receives Atorvastatin 20 mg od and undergoes clinical and laboratory follow-up every six months. She never needed albumin infusions. CONCLUSION:Our experience shows how treatment with atorvastatin may be safely administered and well tolerated in patients affected by CAA.	0
Purpose:We comprehensively evaluated the mutational spectrum of Leber congenital amaurosis (LCA) and investigated the molecular diagnostic rate and genotype-phenotype correlation in a Korean cohort. Methods:This single-center retrospective case series included 50 Korean patients with LCA between June 2015 and March 2019. Molecular analysis was conducted using targeted panel-based next-generation sequencing, including deep intronic and regulatory variants or whole exome sequencing. The molecular diagnosis was made based on the inheritance pattern, zygosity, and pathogenicity. Results:Among the 50 patients, 27 patients (54%) were male, and 11 (22%) showed systemic features. Genetic variants highly likely to be causative were identified in 78% (39/50) of cases and segregated into families. We detected two pathogenic or likely pathogenic variants in a gene linked to a recessive trait without segregation analysis in three cases (6.0%). GUCY2D (20%), NMNAT1 (18%), and CEP290 (16%) were the most frequently mutated genes in Korean LCA. Copy number variations were found in three patients, which accounted for 6% of LCA cases. A possible dual molecular diagnosis (Senior-Løken syndrome along with Leigh syndrome, and Joubert syndrome with transposition of the great arteries) was made in two patients (4%). Three of 50 patients were medically or surgically actionable: one patient for RPE65 gene therapy and two patients with WDR19 Senior-Løken syndrome for early preparation for kidney and liver transplantations. Conclusions:This study demonstrated that approximately 4% of patients may have dual molecular diagnoses, and 6% were surgically or medically actionable in LCA. Therefore, accurate molecular diagnosis and careful interpretation of next-generation sequencing results can be of great help in patients with LCA.	0
The primary bone tumor is usually observed in adolescence age group which has been shown to be part of nearly 20% of the sarcomas known today. Giant cell tumor of bone (GCTB) can be benign as well as malignant tumor which exhibits localized dynamism and is usually associated with the end point of a long bone. Giant cell tumor (GCT) involves mononuclear stromal cells which proliferate at a high rate, multinucleated giant cells and stromal cells are equally present in this type of tumor. Cancer stem cells (CSCs) have been confirmed to play a potential role in the development of GCT. Cancer stem cell-based microRNAs have been shown to contribute to a greater extent in giant cell tumor of bone. CSCs and microRNAs present in the tumors specifically are a great concern today which need in-depth knowledge as well as advanced techniques to treat the bone cancer effectively. In this review, we attempted to summarize the role played by cancer stem cells involving certain important molecules/factors such as; Mesenchymal Stem Cells (MSCs), miRNAs and signaling mechanism such as; mTOR/PI3K-AKT, towards the formation of giant cell tumor of bone, in order to get an insight regarding various effective strategies and research advancements to obtain adequate knowledge related to CSCs which may help to focus on highly effective treatment procedures for bone tumors.	0
Programmed axonal degeneration, also known as Wallerian degeneration, occurs in immune-mediated central nervous system (CNS) inflammatory disorders such as multiple sclerosis and the animal model experimental allergic encephalomyelitis (EAE). Sterile alpha and TIR domain containing protein 1 (SARM1) functions to promote programmed axonal degeneration. To test the hypothesis that loss of SARM1 will reduce axonal degeneration in immune-mediated CNS inflammatory disorders, the course and pathology of EAE was compared in Sarm1 knockout mice and wild type littermates. The clinical course of EAE was similar in Sarm1 knockout and wild type. Analysis of EAE in mice expressing neuronal yellow fluorescent protein (YFP) showed significantly less axonal degeneration in Sarm1 knockout mice compared to wild type littermates at 14 days post-induction of EAE. At 21 days post-induction, however, difference in axonal degeneration was not significant. At 42 days post-induction, Sarm1 knockout mice were indistinguishable from wild type with respect to markers of axonal injury, and were similar with respect to axonal density in the lumbar cords. There was no significant change in peripheral immune activation or CNS inflammatory cell infiltration associated with EAE in Sarm1 knockout mice. In conclusion, Sarm1 deletion delayed axonal degeneration early in the course of CNS inflammation, but did not confer long-term protection from axonal degeneration in an animal model of immune-mediated CNS inflammation.	0
OBJECTIVE: To investigate the clinicopathological characteristics, diagnosis and treatment of primary testicular yolk sac tumor (YST). METHODS: We studied 8 cases of primary testicular YST by microscopy and immunohistochemistry. RESULTS: The 8 cases of primary testicular YST, including 2 consultation cases, were confirmed from 1998 to 2013, accounting for 10.7% (8/75) of all the testicular germ cell tumors diagnosed in our hospital. The patients ranged in age from 7 to 43 years, 23.9 years on average. The main clinical manifestation of the patients was painless unilateral testis swelling. Microscopically, reticular tissues, schiller-duvaI (S-D) bodies, and eosin-stain transparent bodies were seen in the tumors. One of the cases was confirmed to be simple YST, while the other 7 mixed YST. AFP was a characteristic immunophenotype marker of the tumors. CONCLUSION: Primary testicular YST is a rare malignancyr with poor prognosis. Its diagnosis depends on preoperative AFP test and postoperative pathology. Comprehensive treatment, including orchiectomy, chemotherapy, and radiotherapy, can prolong the survival of the patients.	0
We have calculated the incidence of Menkes disease for Denmark, France, The Netherlands, the United Kingdom and West Germany, based on known Menkes patients born during the time period 1976-87. Considering live-born Menkes patients, the combined incidence for these five countries is 1 Menkes patient per 298,000 live-born babies. If the number of affected aborted fetuses are taken into account, the incidence is 1 Menkes per 254,000 live-born babies. This incidence, which is 2-4 times lower than earlier published incidence figures, places Menkes disease as an extremely rare disease. The mutation rate for Menkes disease is estimated to be 1.96 x 10(-6), based on the number of isolated Menkes cases born during the time period 1976-87 and the total number of newborn males during this time.	1
PURPOSE:To assess the effect of type of insurance coverage on the ability of a pediatric patient to obtain an outpatient orthopedic appointment for trigger thumb. METHODS:A list of 200 orthopedic practices in 4 states were contacted and presented with a fictitious 3-year-old patient with trigger thumb. The patient was presented as having Blue Cross Blue Shield Insurance during the first call and Medicaid during the second call. Data regarding whether an appointment was offered or denied were recorded. RESULTS:Of the 200 practices, 81 were excluded, 22 because they did not answer the calls, 25 needed the patient's social security number, 19 needed medical records, 5 had no hand surgeon in the practice, and 10 would not see any children at all. Of the 119 practices included in the analysis, the private insurance patient was able to get an appointment 51.3% of the time whereas the Medicaid patient was able to get an appointment in 26.9% of instances. CONCLUSIONS:There is a significant effect of insurance status on the ability of pediatric patients with trigger thumb to obtain outpatient orthopedic appointments. CLINICAL RELEVANCE:Pediatric patients with Medicaid face greater barriers to accessing proper care for trigger thumb than patients with private insurance.	0
Introduction. Angiofollicular lymph node hyperplasia (Castleman's disease) is a nonmalignant lymphoproliferative disorder that generally involves the lymph nodes of young adults, most commonly in the mediastinum. Rarely, Castleman's disease may present in the parotid gland. The disease can be further classified into unicentric or multicentric forms, with considerable differences in presentation, treatment, and prognosis. Case(s). We present cases of two pediatric patients, aged 7 and 11, who both presented with a slow-growing, painless parotid mass. In each case, the mass was excised via a superficial parotidectomy and the diagnosis made postoperatively upon further pathologic examination. At 6 months of follow-up, both had fully intact facial nerve function and no evidence of recurrence. Discussion. Castleman's disease presents a diagnostic challenge in the head and neck region, as radiographic characteristics and fine needle aspiration results are often inconclusive. Definitive diagnosis requires surgical excision for pathologic examination. The unicentric form generally presents as a painless mass and can be successfully treated with complete excision. The multicentric form is associated with constitutional symptoms and its treatment remains controversial. Conclusion. Although rare, clinicians should be aware of both forms of Castleman's disease when creating a differential diagnosis for parotid masses.	0
Background: Radiation exposure is a known risk factor for meningioma but there are no data regarding hemangiopericytoma and radiation exposure.Case Description: We report a 29-year-old pineoblastoma patient diagnosed with a hemangiopericytoma at a different location, after a successful surgical excision and adjuvant radiotherapy for the original tumor 4-year prior.Conclusion: Hemangiopericytoma emergence can be seen after radiotherapy.	0
BACKGROUND:Intrathecal fluorescein is commonly used to localize cerebrospinal fluid leaks. This technique is invasive and associated with several potential adverse effects. The purpose of this video presentation is to demonstrate an alternative technique, the intranasal use of dilute topical fluorescein, to localize a cerebrospinal fluid leak intraoperatively. METHODS:A 45-year-old male with a history of benign intracranial hypertension and 2 months of right-sided rhinorrhea underwent surgical repair of a cerebrospinal fluid leak. Topical fluorescein was applied intraoperatively to localize the defect. RESULTS:At 1- and 3-month follow-ups the patient was without cerebrospinal fluid rhinorrhea and the middle turbinate flap was intact. CONCLUSION:Topical application of dilute intranasal fluorescein is a feasible and efficient tool for localizing cerebrospinal fluid leaks.	0
Investigators for the FAiRE DS Study Group assessed the efficacy and safety of Fenfluramine for treating seizures in patients less than 18 y.o. with Dravet Syndrome in an international double-blind, placebo-controlled clinical trial. A total of 119 patients (mean age 9.0 y, 54% male) were enrolled in the study.	0
CD4+ T lymphocytes are crucial for controlling a range of innate and adaptive immune effectors. For CD8+ cytotoxic T lymphocyte (CTL) responses, CD4+ T cells can function as helpers (TH) to amplify magnitude and functionality or as regulatory cells (Treg) capable of profound inhibition. It is unclear what determines differentiation to these phenotypes and whether pathogens provoke alternate programs. We find that, depending on the size of initial dose, Listeria infection drives CD4+ T cells to act as TH or induces rapid polyclonal conversion to immunosuppressive Treg. Conversion to Treg depends on the TLR9 and IL-12 pathways elicited by CD8α+ dendritic cell (DC) sensing of danger-associated neutrophil self-DNA. These findings resolve long-standing questions regarding the conditional requirement for TH amongst pathogens and reveal a remarkable degree of plasticity in the function of CD4+ T cells, which can be quickly converted to Tregin vivo by infection-mediated immune modulation.	0
The diagnosis of inborn errors of metabolism (IEM) takes many forms. Due to the implementation and advances in newborn screening (NBS), the diagnosis of many IEM has become relatively easy utilizing laboratory biomarkers. For the majority of IEM, early diagnosis prevents the onset of severe clinical symptoms, thus reducing morbidity and mortality. However, due to molecular, biochemical, and clinical variability of IEM, not all disorders included in NBS programs will be detected and diagnosed by screening alone. This article provides a general overview and simplified guidelines for the diagnosis of IEM in patients with and without an acute metabolic decompensation, with early or late onset of clinical symptoms. The proper use of routine laboratory results in the initial patient assessment is also discussed, which can help guide efficient ordering of specialized laboratory tests to confirm a potential diagnosis and initiate treatment as soon as possible.	0
BACKGROUND:Post-thrombotic syndrome (PTS) is a significant complication of pediatric deep venous thrombosis (DVT). There is a gap in the understanding of the risk factors associated with the development of pediatric PTS preventing the early identification of those patients at greatest risk, and the development of risk-stratified interventions. OBJECTIVES:To conduct a systematic review and meta-analysis of the literature on prognostic factors for PTS development in pediatric patients. METHODS:A systematic search of MEDLINE, EMBASE, and the Cochrane Library from 1960 to December 2018 was performed. Eligible studies reported at least one prognostic factor for PTS development in patients <21 years of age with a radiographically confirmed DVT. To be included in the meta-analysis, prognostic factors had to be reported in at least three published studies. RESULTS AND CONCLUSIONS:Twelve studies (n= 1,160 patients) met criteria for inclusion. Ninety-three percent of patients with an extremity DVT(n=1076) were assessed for PTS. PTS developed in 40% (n=434) of these patients. Central venous catheter-associated DVT (odds ratio [OR] 1.8, 95% CI 1.08-2.98), complete veno-occlusion (OR 1.89, 95% CI 1.04-3.46), and incomplete DVT resolution (OR 2.07, 95% CI 1.4-3.07) were identified as candidate prognostic factors for pediatric PTS. These findings should be interpreted in the context of the heterogeneity of the included studies and the limitations of current pediatric PTS assessment tools. Further, the predictive value of these prognostic factors will need to be validated in future collaborative prospective multicenter studies that maximize the homogeneity of pediatric DVT patients.	0
One hundred eighteen cases of nevoid basal cell carcinoma syndrome (NBCCS, Gorlin's syndrome or basal cell nevus syndrome) are presented in this study. In aiming to ascertain all the affected families in Australia, we have examined the largest series to date. Relative frequencies of associated complications are presented and compared with those of the recent English survey by Evans et al. [J Med Genet 30:460-464, 1993]. The frequencies of most manifestations are similar. However, one major difference is that the multiple basal cell carcinomas are manifest from an earlier age in the Australian population, which probably reflects greater exposure to ultraviolet radiation. Of the 64 families ascertained, 37 represented simplex cases, and, accordingly, the apparent new mutation rate is surprisingly high (14-81%) given the lack of impact of NBCCS on reproductive capabilities. There is some evidence to suggest that this may be attributable to anticipation.	1
To describe a patient with unilateral hypotonic maculopathy and optic disc edema after spontaneous bulbar perforation of a full-thickness scleral defect.An 11-year-old girl underwent scleral buckling surgery. Preoperative and postoperative evaluation included optical coherence tomography and high-resolution 3T magnetic resonance imaging.The scleral defect was covered with Tenon capsule sheaths and a meridional silicone buckle. One year postoperatively, visual acuity and macular and optic disc morphology were completely restored.Ocular hypotony related to a defect of the sclera forming the roof of a retinochoroidal coloboma is a rare event. Hypotony was a consequence of a defect at the level of an atypical retinochoroidal coloboma where the scleral wall was found to be absent.	0
Based on attachment theory and a social-cognitive model of posttraumatic stress disorder (PTSD), this study examined the roles of parent-child communication, perceived parental depression, and intrusive rumination in the association between insecure attachment to parents and PTSD among adolescents following the Jiuzhaigou earthquake. In this study, 620 adolescents were recruited to complete self-report questionnaires. The results showed that the direct association between anxious attachment and PTSD was significant, but that between avoidant attachment and PTSD was non-significant. In addition, both anxious and avoidant attachment had indirect associations with PTSD via the mediating effects of parent-child communication openness and problems, perceived parental depression, and intrusive rumination. However, the specific paths between anxious and avoidant attachment and PTSD were different. The findings indicated that insecure attachment among adolescents following the earthquake was predictive for their PTSD, and the mechanisms underlying the association between anxious attachment and PTSD and the association between avoidant attachment and PTSD were distinct. To alleviate PTSD, more attention should be paid to improving the quality of parent-child communication for adolescents with avoidant attachment to parents, and to reducing negative cognition in adolescents with anxious attachment.	0
We describe 27 individuals of 7 families related to each other with high probability who showed manifestations of ectodermal dysplasia and other anomalies affecting females as severely as males with variable expressivity. All parents were normal. These families were detected in a relatively isolated and inbred population with very small neighbouring communities from a Caribbean Sea island, Margarita Island, in Northeastern Venezuela (Nueva Esparta State). The clinical picture common to all patients could not be classified within the heterogeneous group of known ectodermal dysplasias and the published cases do not resemble our patients. We believe that this condition constitutes a newly recognized autosomal recessive dysplasia/malformation syndrome of ectodermal dysplasia.	0
The A8344G mitochondrial DNA (mtDNA) mutation is best known for the MERRF phenotype (myoclonic epilepsy, myopathy, and ragged red fibers). We describe a sporadic case of an infant with the A8344G mtDNA mutation who presented with failure to thrive and sudden unexpected death at 11 months of age. The autopsy revealed a histiocytoid cardiomyopathy, diffuse steatosis of the liver, and bilateral retinal hypoplasia. Electron micrographs of cardiac myocytes showed striking mitochondrial hyperplasia, dispersing the sarcomeres. Special stains of frozen heart muscle showed an absence of complex IV (cytochrome c oxidase) in many of the myocytes. Both complexes I and IV of the respiratory chain were reduced in cardiac muscle. The A8344G mtDNA mutation was detected in both liver and cardiac muscle tissue. To our knowledge, this is the first description of the A8344G mtDNA mutation presenting as a sporadic case of fatal infantile cardiomyopathy and the first occurrence of this mutation associated with histiocytoid cardiomyopathy.	0
Galen aneurysmal malformation is a rare complex congenital vascular malformation of the brain, (less than 1% of intracranial arteriovenous malformations) characterized by pseudoaneurismal dilation of Galen's ampulla associated with one or several arteriovenous fistulas. In most cases, diagnosis is made in the neonatal or postnatal period, exceptionally in adulthood. We report the case of an 18-year male patient hospitalized for psychomotor retardation. Brain computed tomography (CT) scan using spontaneous contrast (A,B,C) showed voluminous isodense mass in the pineal region behind the third ventricle with peripheral calcifications, compatible with large vein of galen aneurysm. Its anteroposterior diameter was 8.5cm, its transverse diameter was 3cm in the axial plane (C) and its height was 3cm in the sagittal plane (G). Imaging objectified homogeneous contrast enhancement (D,E,F,G,H,I). The mass was associated with dilation of the superior sagittal sinus measured at 2.7cm (A,D), of transverse sinuses measured at 1.5cm to the right and at 1,1cm to the left (B,E). Multiple venous perianeurysmal derivations (I), hydrocephaly and small parenchymal cortical-subcortical calcifications were detected. Embolization can't be performed in Bamako, so the patient is waiting for transfer.	0
Chronic wasting disease (CWD) is a fatal, progressive disease that affects cervid species, including Rocky mountain elk (Cervus elaphus nelsoni). There are 2 allelic variants in the elk prion protein gene: L132 (leucine) and M132 (methionine). Following experimental oral challenge with the CWD agent incubation periods are longest in LL132 elk, intermediate in ML132 elk, and shortest in MM132 elk. In order to ascertain whether such CWD-infected elk carry distinct prion strains, groups of Tg12 mice that express M132 elk prion protein were inoculated intracranially with brain homogenate from individual CWD-infected elk of various genotypes (LL132, LM132, or MM132). Brain samples were examined for microscopic changes and assessment of the biochemical properties of disease-associated prion protein (PrPSc). On first passage, mice challenged with LL132 elk inoculum had prolonged incubation periods and greater PrPSc fibril stability compared to mice challenged with MM132 or LM132 inoculum. On second passage, relative incubation periods, western blot profiles, and neuropathology were maintained. These results suggest that the CWD prion isolated from LL132 elk is a novel CWD strain and that M132 PrPC is able to propagate some biophysical properties of the L132 PrPSc conformation.	0
Epidemiological data on chronic polyneuropathies, especially inflammatory types, is limited. The purpose of this study was to examine the spectrum of causes and estimated prevalence of various polyneuropathy types in Vest-Agder, and to examine the clinical features of the Vest-Agder population of chronic inflammatory demyelinating polyneuropathy (CIDP). In Vest-Agder county (population of 155 464), polyneuropathy patients are registered in a database and followed prospectively. We did a measure of the database on October 31 1999. A total of 192 patients were registered. The prevalence for chronic inflammatory demyelinating polyneuropathy (CIDP) was 7.7 per 100 000 population. The course was relapsing in five of fifteen patients, progressive in four patients and slowly progressive in six of fifteen patients. Two of the fifteen patients had pure sensory symptoms. The mean Rankin disability score was 3.4 at maximal deficit and 2.1 at last follow-up. The prevalence of paraproteinemic polyneuropathy was 5.1 per 100 000 population. None of the patients with paraproteinemic polyneuropathy were worse than slightly disabled (disability score < or = 2). The prevalences for other polyneuropathies were as follows: polyneuropathy and RA, 1.3; polyneuropathy and Sjögren's syndrome or sicca complex, 4.5 (polyneuropathy was the presenting symptom in five of seven patients); sarcoidosis 1.9; polyneuropathy and chronic Lyme, 0.6; paraneoplastic polyneuropathy, 1.9; diabetic polyneuropathy 23.2; vitamin deficiency, 5.1; alcoholic and toxic polyneuropathy, 19.9; hereditary polyneuropathy, 14.8. Cryptogenic polyneuropathies made up 26% of all polyneuropathies. The mean disability score was 2.0 (SD 1.1). In conclusion, prevalence of CIDP was significantly higher than previously reported, and the prognosis was good in the majority of patients. Patients with paraproteinemic polyneuropathy were not severely disabled. Polyneuropathy was the presenting symptom in the majority of patients with Sjögren's syndrome or sicca complex.	1
A 25-year-old man presented with a 2-month history of dysphagia and past history of pulmonary and intestinal tuberculosis. A barium swallow showed a point of constriction 42 mm above the gastroesophageal junction. Computed tomography revealed large opacities in bilateral lung fields, encroaching more on the esophagus. The lesion progressively compressed the esophagus as it moved inferiorly. A right posterolateral thoracotomy was performed for sub-anatomical resection of the mass. A biopsy revealed homogenous whirling hyalinized collagen fibers, highly suggestive of pulmonary hyalinizing granuloma, with no evidence of malignancy. Pulmonary hyalinizing granuloma should be considered in the differential diagnosis of longstanding dysphagia.	0
BACKGROUND:Fabry disease is the second most common lysosomal storage disorder, carrying a large morbidity and mortality. It has been recently reported that lysosomal storage disorders could cause inflammation and, subsequently, AA amyloidosis. Our aim was to describe AA amyloidosis cases occurring in the course of Fabry disease. PATIENTS AND METHODS:We described 2 patients displaying both AA amyloidosis and Fabry disease and an additional case from the literature. RESULTS:Three female patients originating from Europe (n=2) and Algeria (n=1) harboured heterozygous GLA mutations. The median age at AA amyloidosis diagnosis was 61years old. The diagnosis of Fabry was made before the diagnosis of AA amyloidosis (n=1) or concomitantly (n=2). At AA amyloidosis diagnosis, two patients displayed a nephrotic syndrome; all had inflammation. CONCLUSION:Fabry disease can be associated with AA amyloidosis, suggesting that an inflammatory component could exist in this genetic disease.	0
RATIONALE:Jacobsen syndrome (JBS) is a rare chromosomal disorder with variable phenotypic expressivity, which is usually diagnosed in infancy and childhood based on clinical examination and hematological and cytogenetic findings. Prenatal diagnosis and fetal ultrasonographic findings of JBS are rare. PATIENT CONCERNS:A 38-year-old, gravida 3, para 1, pregnant woman underwent clinical ultrasound examination at 22 weeks of gestation. DIAGNOSES:Ultrasonographic findings indicated an interventricular septal defect, the presence of septal blood flow, dilation of the left renal pelvis, and a single umbilical artery. Amniocentesis was performed to evaluate possible genetic causes of this diagnosis by cytogenetic and single nucleotide polymorphism (SNP) array analysis. INTERVENTIONS:After genetic counseling and informed consent, the couple elected to terminate the pregnancy. OUTCOMES:Karyotype analysis showed that the fetal karyotype was 46,XX,del(11)(q23). The SNP array revealed a 6.118 Mb duplication of 11q23.2q23.3 and a 15.03 Mb deletion of 11q23.3q25. LESSONS:Ultrasonographic findings of fetal JBS, including an interventricular septal defect, dilation of the left renal pelvis, and a single umbilical artery, may be associated with a 15.03 Mb deletion of 11q23.3q25. Further cases correlating phenotype and genotype are required to predict the postnatal phenotype.	0
Oculofaciocardiodental (OFCD) syndrome is a rare X-linked dominant condition. Mutations in BCOR have been described as causal in OFCD syndrome. Almost all BCOR mutations result in premature termination codons (PTCs); therefore, nonsense-mediated mRNA decay (NMD) might have an important role in pathogenesis. The purpose of this study was to identify BCOR mutations in two OFCD patients, if it present, and to clarify the pathogenesis of radiculomegaly using one OFCD patient's pulp and periodontal ligament (PDL) cells. In our genetic analysis, two novel BCOR mutations were found. We also examined the transcript levels and the effects of NMD using cultured pulp and PDL cells from one affected patient. BCOR expression was normal in pulp but reduced in PDL cells, which is consistent with the higher rates of NMD in PDL cells. The mutant PDL cells had unstable mutant transcripts and proliferated faster than did wild-type cells, but mutant pulp cells appeared normal by these measures. In summary, the nonsense and frameshift mutations, which introduce PTCs, were found to contribute to OFCD syndrome in our two patients. Furthermore, in PDL cells, the mutation resulting in a PTC corresponded to greater NMD, unstable mutant transcripts and increased cell proliferation, which may contribute to hyperactive root formation.	0
BACKGROUND:Spinal cord infarction (SCI) is rarely caused by vertebral artery dissection (VAD), which is an important cause of posterior circulation stroke in young and middle-aged patients. We report the case of a middle-aged patient without obvious risk factors for atherosclerosis who had SCI from right VAD. CASE PRESENTATION:An otherwise healthy 40-year-old man presented with acute right-sided body weakness. Six days earlier, he had experienced posterior neck pain without obvious inducement. Neurologic examination revealed a right Brown-Séquard syndrome. Magnetic resonance imaging (MRI) of the head was normal. Further, cervical spine MRI showed spinal cord infarction (SCI) on the right at the C1-C3 level. Three-dimensional high-resolution MRI (3D HR-MRI) volumetric isotropic turbo spin echo acquisition (VISTA) scan showed evidence of vertebral artery dissection (VAD). The patient was significantly relieved of symptoms and demonstrated negative imaging findings after therapy with anticoagulation (AC) and antiplatelets (AP) for 3 months. CONCLUSIONS:The possibility of vertebral artery dissection (VAD) should be considered in the case of young and middle-aged patients without obvious risk factors for atherosclerosis. Furthermore the VISTA black blood sequence plays an important role in the pathological diagnosis of vertebral artery stenosis. Early correct diagnosis and active therapy are crucial to the prognosis.	0
Satoyoshi syndrome is a rare condition of presumed autoimmune etiology that is characterized by intermittent painful spasms, diarrhea, hair loss, and bone abnormalities. We report the first case of adult onset Satoyoshi syndrome in South America. A 32-year-old Caucasian male presented with sudden involuntary muscle contractions and painful cramps that had started at the age of 21. He also presented with trismus and complete loss of body hair. Electroneuromyography showed abnormal spontaneous activity. Diagnosis of Satoyoshi syndrome was made after extensive investigation; improvement was achieved with corticosteroids and azathioprine. It is a rare disease; few cases have been described worldwide, most of them in Asian children and almost all sporadic. There are several atypical presentations described in the literature. Immunosuppression is the basis of treatment. Professionals dealing with neuromuscular diseases should be aware of this condition and its atypical presentations, given the possible response to immunosuppressive treatment.	0
INTRODUCTION:Bethlem myopathy is caused by dysfunctional collagen VI assembly, leading to varying degrees of hyperlaxity, contractures and muscle weakness. Previous studies demonstrate that cardiovascular training is safe and beneficial in patients with myopathies. However, exercise exacerbates the dystrophic phenotype in collagen VI-knockout mice. METHODS:Six men with Bethlem myopathy were included (4 training; 2 controls). After training, 2 patients detrained. Patients performed 10 weeks of home-based, moderate-intensity exercise monitored by a pulse-watch. The primary outcome was change in peak oxygen uptake (VO2peak ). Secondary outcomes were performances in functional tests. RESULTS:VO2peak improved in the training group (16%, P = 0.017). Detraining led to regression of VO2peak toward baseline values (-8%; P = 0.03). No change was seen in the control group (-7%; P = 0.47). Performance in functional tests did not change significantly. Creatine kinase values were stable during the study. CONCLUSIONS:Moderate-intensity exercise seems to safely improve oxidative function in patients with Bethlem myopathy. Muscle Nerve 60: 183-188, 2019.	0
Greenish staining of human skin may result from a gamut of causes, such as chlorosis, exogenous copper, resolving ecchymosis, drugs, green textile dyes, green tattoos, apocrine and eccrine chromhidrosis, hyper biliverdinemia, chloromas, use of green dyes during tube feeding in patient with multiorgan failure, Pseudomonas infections, and Wells' syndrome in its second stage. Physicians may rarely encounter patients with green skin, hair, nails, or mucosae.	0
The goal of screening programs for inborn errors of metabolism (IEM) is early detection and timely intervention to significantly reduce morbidity, mortality and associated disabilities. Phenylketonuria exemplifies their success as neonates are identified at birth and then promptly treated allowing normal neurological development. Lysosomal diseases comprise about 50 IEM arising from a deficiency in a protein required for proper lysosomal function. Typically, these defects are in lysosomal enzymes with the concomitant accumulation of the enzyme's substrate as the cardinal feature. None of the lysosomal diseases are screened at birth in Australia and in the absence of a family history, traditional laboratory diagnosis of the majority, involves demonstrating a deficiency of the requisite enzyme. Diagnostic confusion can arise from interpretation of the degree of residual enzyme activity causative of disease and is impractical when the disorder is not due to an enzyme deficiency per se. Advances in mass spectrometry technologies has enabled simultaneous measurement of the enzymes' substrates and their metabolites which facilitates the efficiency of diagnosis. Employing urine chemistry as a reflection of multisystemic disease, individual lysosomal diseases can be identified by a characteristic substrate pattern complicit with the enzyme deficiency. Determination of lipids in plasma allows the diagnosis of a further class of lysosomal disorders, the sphingolipids. The ideal goal would be to measure biomarkers for each specific lysosomal disorder in the one mass spectrometry-based platform to achieve a diagnosis. Confirmation of the diagnosis is usually by identifying pathogenic variants in the underlying gene, and although molecular genetic technologies can provide the initial diagnosis, the biochemistry will remain important for interpreting molecular variants of uncertain significance.	0
BACKGROUND:Colorectal cancer liver metastasis (CRCLM) concomitant with infiltration of lymph nodes (LNs) in the hepatic pedicle is difficult to manage, and is regarded as an extrahepatic metastasis; undertaking hepatectomy is controversial in such a scenario. CASE PRESENTATION:Case 1, A 55-year-old woman was diagnosed with multiple liver metastases arising from rectal cancer along with enlargement of a retropancreatic LN. A characteristic image prior to hepatectomy demonstrated evident tumor progression from a metastatic lesion in segment 5 of the liver (S5) to the hepatic hilum along with Glisson 5. Post-operative histopathological examination revealed viable adenocarcinoma cancer cells originating from rectal cancer in all the liver metastatic lesions and retropancreatic LN. Case 2, A 89-year-old woman was diagnosed with transverse colon cancer with multiple liver metastases. Radiological examination before hepatectomy revealed tumor progression from a metastatic lesion in the segment 6 of the liver (S6) to the hepatic hilum along with Glisson 6 and LN involvement in the hepatoduodenal ligament. Post-operative histopathological examination demonstrated adenocarcinoma cancer cells in the liver metastatic lesions and in a hepatoduodenal LN. CONCLUSION:When encountering tumor progression from liver metastatic lesions to hepatic hilum along with its Glisson branch, the possibility of hepatic hilar LN involvement should be considered. Indeed, the surgical management of CRCLM with hepatic hilar LN involvement is controversial, but could be acceptable if the positive LNs are limited to the hepatic pedicle and retropancreatic area.	0
Optic nerve hypoplasia (ONH) is a congenital malformation with a reduced number of retinal ganglion cell axons in a thin optic nerve. It is a common cause of visual impairment in children and ONH is associated with neurodevelopmental disorders, pituitary hormone deficiencies, and brain malformations. In most cases, the aetiology is unknown, but both environmental factors and genetic causes have been described. This study aimed to identify genetic variants underlying ONH in a well-characterised cohort of individuals with ONH. We performed array comparative genomic hybridization and whole genome sequencing in 29 individuals with ONH. Rare variants were verified by Sanger sequencing and inheritance was assessed in parental samples. We identified 11 rare single nucleotide variants (SNVs) in ten individuals, including a homozygous variant in KIF7 (previously associated with Joubert syndrome), a heterozygous de novo variant in COL4A1 (previously described in an individual with porencephaly), and a homozygous variant in COL4A2. In addition, one individual harboured a heterozygous variant in OPA1 and a heterozygous variant in COL4A1, both were inherited and assessed as variants of unknown clinical significance. Finally, a heterozygous deletion of 341 kb involving exons 7-18 of SOX5 (associated with Lamb-Schaffer syndrome) was identified in one individual. The overall diagnostic yield of pathogenic or likely pathogenic variants in individuals with ONH using whole genome sequencing was 4/29 (14%). Our results show that there is a genetic heterogeneity in ONH and indicate that genetic causes of ONH are not rare. We conclude that genetic testing is valuable in a substantial proportion of the individuals with ONH, especially in cases with non-isolated ONH.	0
Complete congenital cleft sternum associated with pectus excavatum is a rare abnormality. Case reports and case series currently provide the technical standards for comparison in surgical repair. We present a case report of surgical repair of cleft sternum and anterior pericardial defect associated with pectus excavatum in a 13-year-old girl. The surgical repair of the cleft sternum and pectus excavatum was performed with a modified Ravitch procedure, closure of the defect with stainless steel wires, and insertion of a pectus bar. Preoperative imaging is important in better defining the defect.	0
Marshall-Smith syndrome (MSS) is a distinctive entity of unknown etiology with fewer than 50 patients described in the medical literature to date. Through an International collaboration and use of an online wiki to facilitate data collection and sharing, we further delineate the phenotype and natural history of this syndrome. We present 15 new patients, the oldest being 30 years, provide an update on four previously published cases, and compare all patients with other patients reported in literature. Main clinical features are moderate to severe developmental delay with absent or limited speech, unusual behavior, dysharmonic bone maturation, respiratory compromise secondary to upper airway obstruction, short stature, and kyphoscoliosis. Facial features are characteristic with high forehead, underdeveloped midface, proptosis, anteverted nares, and everted lips. Minor abnormalities of brain morphology such as hypoplasia of the corpus callosum are common. Mortality from respiratory complications is high, but airway support increasingly allows survival into adulthood. Array-CGH was performed on 12 of the cohort and no copy number variants of clear clinical relevance were identified. The present study is the first reported use of an online wiki to aid delineation of a genetic syndrome, and illustrates its value in collecting detailed data in rare conditions.	0
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome immunodeficiency is caused by autosomal dominant gain-of-function mutations in chemokine receptor CXCR4. Patient WHIM-09 was spontaneously cured by chromothriptic deletion of 1 copy of 164 genes, including the CXCR4WHIM allele, presumably in a single hematopoietic stem cell (HSC) that repopulated HSCs and the myeloid lineage. Testing the specific contribution of CXCR4 hemizygosity to her cure, we previously demonstrated enhanced engraftment of Cxcr4+/o HSCs after transplantation in WHIM (Cxcr4+/w) model mice, but the potency was not quantitated. We now report graded-dose competitive transplantation experiments using lethally irradiated Cxcr4+/+ recipients in which mixed BM cells containing approximately 5 Cxcr4+/o HSCs and a 100-fold excess of Cxcr4+/w HSCs achieved durable 50% Cxcr4+/o myeloid and B cell chimerism in blood and approximately 20% Cxcr4+/o HSC chimerism in BM. In Cxcr4+/o/Cxcr4+/w parabiotic mice, we observed 80%-100% Cxcr4+/o myeloid and lymphoid chimerism in the blood and 15% Cxcr4+/o HSC chimerism in BM from the Cxcr4+/w parabiont, which was durable after separation from the Cxcr4+/o parabiont. Thus, CXCR4 haploinsufficiency likely significantly contributed to the selective repopulation of HSCs and the myeloid lineage from a single chromothriptic HSC in WHIM-09. Moreover, the results suggest that WHIM allele silencing of patient HSCs is a viable gene therapy strategy.	0
We have reviewed all known UK cases of Smith-Lemli-Opitz syndrome. Among 49 cases with proven 7-dehydrocholesterol reductase deficiency, half had been terminated or had died in infancy. The minimum incidence is 1 in 60,000. The frequent occurrence of hypospadias may account for 71% of recognised cases being male. Important common features which emerged include short thumbs, severe photosensitivity, aggressive behaviour, and atrioventricular septal defect. The typical facial appearance becomes less obvious with age and 20% of cases did not have 2/3 toe syndactyly. Biochemical measurements of serum 7-dehydrocholesterol did not correlate with clinical severity.	1
INTRODUCTION:Pheochromocytoma are neuroendocrine tumors that arise from sympathetic chromaffin cells within the adrenal medulla. They principally secrete catecholamines, potentially causing life-threatening cardiovascular complications. A myriad of symptomatology and clinical findings are associated with pheochromocytoma, including a catecholamine-induced dilated cardiomyopathy. PRESENTATION OF CASE:A 50-year-old woman presented with retrosternal chest pain and underwent diagnostic evaluation for acute coronary syndrome. Cardiac catheterization demonstrated patent coronary arteries and a pattern of ventricular hypokinesis consistent with takotsubo cardiomyopathy, also known as broken heart syndrome. Further imaging with abdominal CT revealed an adrenal mass. Laboratory markers supported the clinical picture of pheochromocytoma. Right adrenalectomy was performed and our patient was symptom-free at discharge on post-operative day three. DISCUSSION:Alpha and beta adrenergic blockade are used in a critical care setting to prevent perioperative hemodynamic instability as well as catecholamine-induced heart failure in the setting of pheochromocytoma. Patients commonly require vasopressors in the postoperative period due to the rapid reduction in circulating catecholamines following resection. Discharge planning should include recommendations for genetic counseling to screen for syndromic causes of pheochromocytoma that increase the risk for other neoplasms. CONCLUSION:We present a case report of a rare adrenal tumor in a middle-aged woman that manifested as acute coronary syndrome. A presumptive diagnosis of takotsubo cardiomyopathy on cardiac catheterization led to further investigation. Abdominal imaging located an adrenal mass that correlated with laboratory studies positive for high levels of catecholamines and their metabolites. The tumor was excised and the patient recovered without complications.	0
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social communication and restricted and repetitive behaviors and interests. Identifying the genetic background may be one of the key features for the future diagnosis and treatment of ASD. With the tremendous development in genetic diagnosis techniques, next-generation sequencing (NGS) can be used to analyze multiple genes simultaneously with a single test in laboratory and clinical settings and is well suited for investigating autism genetics. According to previous studies, there are two types of genetic variants in ASD, rare variants and common variants, and both are important in explaining pathogenesis. In this study, NGS data from 137 participants with ASD were reviewed retrospectively with consideration for comorbid epilepsy. Diagnostic yield was 17.51% (24/137), and pathogenic/likely pathogenic variants were seen more frequently in female participants. Fourteen participants were diagnosed with comorbid epilepsy, six of them had pathogenic/likely pathogenic variants (43%). Genes with variants of unknown significance (VOUS) which have one or more evidence of pathogenicity following the American College of Medical Genetics (ACMG) criteria were also reviewed in both ASD and ASD with comorbid epilepsy groups. We found that most frequently found VOUS genes have previously been reported as genes related to ASD or other developmental disorders. These results suggest that when interpreting the NGS results in the clinical setting, careful observation of VOUS with some pathological evidence might contribute to the discovery of genetic pathogenesis of neurodevelopmental disorders such as ASD and epilepsy.	0
A homozygous mutation in the complex III chaperone BCS1L causes GRACILE syndrome (intrauterine growth restriction, aminoaciduria, cholestasis, hepatic iron overload, lactacidosis). In control and patient fibroblasts we localized BCS1L in inner mitochondrial membranes. In patient liver, kidney, and heart BCS1L and Rieske protein levels, as well as the amount and activity of complex III, were decreased. Major histopathology was found in kidney and liver with cirrhosis and iron deposition, but of iron-related proteins only ferritin levels were high. In placenta from a GRACILE fetus, the ferrooxidases ceruloplasmin and hephaestin were upregulated suggesting association between iron overload and placental dysfunction.	0
BACKGROUND:Computed tomography (CT) enables quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, helping in outcome prediction. METHODS:From 1 to 22 March 2020, patients with pneumonia symptoms, positive lung CT scan, and confirmed SARS-CoV-2 on reverse transcription-polymerase chain reaction (RT-PCR) were consecutively enrolled. Clinical data was collected. Outcome was defined as favourable or adverse (i.e., need for mechanical ventilation or death) and registered over a period of 10 days following CT. Volume of disease (VoD) on CT was calculated semi-automatically. Multiple linear regression was used to predict VoD by clinical/laboratory data. To predict outcome, important features were selected using a priori analysis and subsequently used to train 4 different models. RESULTS:A total of 106 consecutive patients were enrolled (median age 63.5 years, range 26-95 years; 41/106 women, 38.7%). Median duration of symptoms and C-reactive protein (CRP) was 5 days (range 1-30) and 4.94 mg/L (range 0.1-28.3), respectively. Median VoD was 249.5 cm3 (range 9.9-1505) and was predicted by lymphocyte percentage (p = 0.008) and CRP (p < 0.001). Important variables for outcome prediction included CRP (area under the curve [AUC] 0.77), VoD (AUC 0.75), age (AUC 0.72), lymphocyte percentage (AUC 0.70), coronary calcification (AUC 0.68), and presence of comorbidities (AUC 0.66). Support vector machine had the best performance in outcome prediction, yielding an AUC of 0.92. CONCLUSIONS:Measuring the VoD using a simple CT post-processing tool estimates SARS-CoV-2 burden. CT and clinical data together enable accurate prediction of short-term clinical outcome.	0
The Crumbs complex has prominent roles in the control of apical cell polarity, in the coupling of cell density sensing to downstream cell signaling pathways, and in regulating junctional structures and cell adhesion. The Crumbs complex acts as a conductor orchestrating multiple downstream signaling pathways in epithelial and neuronal tissue development. These pathways lead to the regulation of cell size, cell fate, cell self-renewal, proliferation, differentiation, migration, mitosis, and apoptosis. In retinogenesis, these are all pivotal processes with important roles for the Crumbs complex to maintain proper spatiotemporal cell processes. Loss of Crumbs function in the retina results in loss of the stratified appearance resulting in retinal degeneration and loss of visual function. In this review, we begin by discussing the physiology of vision. We continue by outlining the processes of retinogenesis and how well this is recapitulated between the human fetal retina and human embryonic stem cell (ESC) or induced pluripotent stem cell (iPSC)-derived retinal organoids. Additionally, we discuss the functionality of in utero and preterm human fetal retina and the current level of functionality as detected in human stem cell-derived organoids. We discuss the roles of apical-basal cell polarity in retinogenesis with a focus on Leber congenital amaurosis which leads to blindness shortly after birth. Finally, we discuss Crumbs homolog (CRB)-based gene augmentation.	0
Loeys-Dietz syndrome (LDS) is a rare connective tissue genetic disorder that is caused by a pathogenic variant in genes of transforming growth factor (TGF) beta receptor 1 (TGFBR1), TGFBR2, mothers against decapentaplegic homolog 2 (SMAD2), SMAD3, TGFB2, or TGFB3. It is characterized by aggressive vascular pathology, aneurysms, arterial tortuosity, bifid uvula, hypertelorism, and cleft palate. Here we present a 42-year-old female patient with LDS. The patient underwent rapidly progressing artery aneurysms and life-threatening aortic dissection. Spontaneous fracture of the first metatarsal bone was noted in her medical record. Physical examination revealed a delayed wound healing on her left abdomen. Considering these clinical manifestations, we speculated that there was a genetic defect in the connective tissue, which provides strength and flexibility to structures such as bones, skins, ligaments, and blood vessels. Thus, whole exome sequencing (WES) was performed on the proband and revealed a heterozygous missense pathogenic variant (c.1613T > C/p.Val538Ala) in TGFBR2, which was a de novo variant in the proband as confirmed by the segregation analysis in parental samples. Although this variant was discovered and associated with the phenotype of LDS previously, the pathogenicity of the variant had not been confirmed by cellular functional assay yet. To further validate the effects of the variant in vitro, we assessed the canonical TGF-β signaling pathway in mutant cells. Our results showed that the p.Val538Ala variant significantly decreased TGF-β-induced gene transcription and the phosphorylation of Smad2, which were consistent with other pathogenic variants of TGFBR2. In conclusion, this study demonstrates that the p.Val538Ala pathogenic variant in TGFBR2 leads to aberrant TGF-β signaling and LDS in this patient.	0
Hereditary anemias are a group of heterogeneous disorders including hemolytic anemias and hyporegenerative anemias, as congenital dyserythropoietic anemia (CDA). Causative mutations occur in a wide range of genes leading to deficiencies in red cell production, structure, or function. The genetic screening of the main genes is important for timely diagnosis, since routine laboratory tests fail in a percentage of the cases, appropriate treatment decisions, and genetic counseling purposes. A conventional gene-by-gene sequencing approach is expensive and highly time-consuming, due to the genetic complexity of these diseases. To overcome this problem, we customized a targeted sequencing panel covering 35 genes previously associated to red cell disorders. We analyzed 36 patients, and potentially pathogenic variants were identified in 26 cases (72%). Twenty variants were novel. Remarkably, mutations in the SPTB gene (β-spectrin) were found in 34.6% of the patients with hereditary spherocytosis (HS), suggesting that SPTB is a major HS gene in the Southeast of Brazil. We also identified two cases with dominant HS presenting null mutations in trans with α-LELY in SPTA1 gene. This is the first comprehensive genetic analysis for hereditary anemias in the Brazilian population, contributing to a better understanding of the genetic basis and phenotypic consequences of these rare conditions in our population.	0
Downbeat nystagmus (DBN) is a frequent form of acquired persisting central fixation nystagmus, often associated with other cerebellar ocular signs, such as saccadic smooth pursuit or gaze-holding deficits. Despite its distinct clinical features, the underlying etiology of DBN often remains unclear. Therefore, a genome-wide association study (GWAS) was conducted in 106 patients and 2609 healthy controls of European ancestry to identify genetic variants associated with DBN. A genome-wide significant association (p < 5 × 10-8) with DBN was found for a variation on chromosome 13 located within the fibroblast growth factor 14 gene (FGF14). FGF14 is expressed in Purkinje cells (PCs) and a reduction leads to a decreased spontaneous firing rate and excitability of PCs, compatible with the pathophysiology of DBN. In addition, mutations in the FGF14 gene cause spinocerebellar ataxia type 27. Suggestive associations (p < 1 × 10-05) could be detected for 15 additional LD-independent loci, one of which is also located in the FGF14 gene. An association of a region containing the dihydrofolate reductase (DHFR) and MutS Homolog 3 (MSH3) genes on chromosome 5 was slightly below the genome-wide significance threshold. DHFR is relevant for neuronal regulation, and a dysfunction is known to induce cerebellar damage. Among the remaining twelve suggestive associations, four genes (MAST4, TPPP, FTMT, and IDS) seem to be involved in cerebral pathological processes. Thus, this GWAS analysis has identified a potential genetic contribution to idiopathic DBN, including suggestive associations to several genes involved in postulated pathological mechanisms of DBN (i.e., impaired function of cerebellar PCs).	0
CONTEXT.—:Paget disease of the breast, in most cases, represents intraepidermal spread of ductal carcinoma in situ. Molecular subtypes of invasive carcinoma of the breast have prognostic and therapeutic significance and show characteristic distribution. Little is known about the distribution of molecular subtypes in Paget disease of the breast. OBJECTIVES.—:To examine the distribution of molecular subtypes in Paget disease of the breast and to compare them to concurrent invasive carcinoma of the breast, if present. DESIGN.—:We examined 48 cases of Paget disease of the breast with immunohistochemistry and antibodies against estrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2), and Ki-67, as well as HER2 chromogenic in situ hybridization, to classify the cases into molecular subtypes. Then, we compared the results to the molecular subtypes of associated invasive carcinoma of the breast, if present. RESULTS.—:The HER2 subtype was the most common found in Paget disease of the breast, followed by the luminal B subtype and 2 cases of the triple-negative subtype. The associated invasive carcinoma cases were most often of the luminal B subtype, followed by the HER2 subtype and the triple-negative subtype. The molecular subtype of Paget disease and invasive carcinoma was congruent in most of the cases. CONCLUSIONS.—:Molecular subtypes of invasive carcinoma of the breast can already be detected in Paget disease. The distribution of molecular subtypes of Paget disease and of Paget disease-associated invasive carcinoma differs from invasive carcinoma without associated Paget disease, with the HER2 subtype overrepresented in Paget disease and associated invasive carcinoma and the luminal and triple-negative subtypes underrepresented.	0
Patients with the 15q11.2 BP1-BP2 microdeletion can present with developmental and language delay, neurobehavioral disturbances and psychiatric problems. Autism, seizures, schizophrenia and mild dysmorphic features are less commonly seen. The 15q11.2 BP1-BP2 microdeletion involving four genes (i.e., TUBGCP5, CYFIP1, NIPA1, NIPA2) is emerging as a recognized syndrome with a prevalence ranging from 0.57%-1.27% of patients presenting for microarray analysis which is a two to four fold increase compared with controls. Review of clinical features from about 200 individuals were grouped into five categories and included developmental (73%) and speech (67%) delays; dysmorphic ears (46%) and palatal anomalies (46%); writing (60%) and reading (57%) difficulties, memory problems (60%) and verbal IQ scores ≤75 (50%); general behavioral problems, unspecified (55%) and abnormal brain imaging (43%). Other clinical features noted but not considered as common were seizures/epilepsy (26%), autism spectrum disorder (27%), attention deficit disorder (ADD)/attention deficit hyperactivity disorder (ADHD) (35%), schizophrenia/paranoid psychosis (20%) and motor delay (42%). Not all individuals with the deletion are clinically affected, yet the collection of findings appear to share biological pathways and presumed genetic mechanisms. Neuropsychiatric and behavior disturbances and mild dysmorphic features are associated with genomic imbalances of the 15q11.2 BP1-BP2 region, including microdeletions, but with an apparent incomplete penetrance and variable expressivity.	1
Objectives Leigh syndrome (LS) is one of the most common mitochondrial diseases and has variable clinical symptoms. However, the genetic variant spectrum of this disease is incomplete. Methods Next-generation sequencing (NGS) was used to identify the m.14430A > G (p.W82R) variant in a patient with LS. The pathogenesis of this novel complex I (CI) variant was verified by determining the mitochondrial respiration, assembly of CI, ATP, MMP and lactate production, and cell growth rate in cybrids with and without this variant. Results A novel m.14430A > G (p.W82R) variant in the NADH dehydrogenase 6 (ND6) gene was identified in the patient; the mutant loads of m.14430A > G (p.W82R) in the patient were much higher than those in his mother. Although the transmitochondrial cybrid-based study showed that mitochondrial CI assembly remains unaffected in cells with the m.14430G variant, control cells had significantly higher endogenous and CI-dependent mitochondrial respiration than mutant cells. Accordingly, mutant cells had a lower ATP, MMP and higher extracellular lactate production than control cells. Notably, mutant cells had impaired growth in a galactose-containing medium when compared to wild-type cells. Conclusions A novel m.14430A > G (p.W82R) variant in the ND6 gene was identified from a patient suspected to have LS, and this variant impaired mitochondrial respiration by decreasing the activity of mitochondrial CI.	0
Distal arthrogryposis (DA) type 2B (DA2B) is an autosomal dominant congenital disorder, characterized by camptodactyly, thumb adduction, ulnar deviation and facial features, including small mouth, down‑slanting palpebral fissure and slight nasolabial fold. It has been reported that four genes are associated with DA2B, including troponin I, fast‑twitch skeletal muscle isoform, troponin T3, fast skeletal, myosin heavy chain 3 (MYH3) and tropomyosin 2, which are all associated with embryonic limb morphogenesis and skeletal muscle contraction. In the present study, three affected family members and five unaffected individuals were identified through clinical and radiological assessment. Genomic DNA was obtained from the three patients, which then underwent whole‑exome sequencing, and candidate mutations were verified by Sanger sequencing in all available family members and 100 healthy volunteers. Then, the spatial models of embryonic MYH were further constructed. In the clinic, the three patients recruited to the present study were diagnosed with DA2B. Mutation analysis indicated that there was a novel heterogeneous missense mutation c.2506 A>G (p.K836E) in the MYH3 gene among the affected individuals, which was highly conserved and was not identified in the unaffected family members and healthy controls. Furthermore, protein modeling revealed that the altered position interacted with regulatory light chain. Thus, the present study identified a novel pathogenic mutation of the MYH3 gene in a Chinese family with DA2B, which expanded the mutational spectrum of MYH3 and provided additional information regarding the association between mutation locations and different types of DA.	0
OBJECTIVE:MATR3-associated distal myopathy is a rare distal myopathy predominantly affecting lower legs as well as wrist- and finger extensors. Whilst most distal myopathies are clinically and genetically well characterized, diagnosis often remains challenging. Pattern-based magnetic resonance imaging (MRI) approaches offer valuable additional information. However, a consistent pattern of muscular affection is missing for most distal myopathies. Thus, the aim of the present study was to establish a disease-specific pattern of muscular involvement in MATR3-associated distal myopathy using whole-body MRI. METHODS:15 patients (25-79 years of age, 7 female) with MATR3-associated distal myopathy were subjected to whole-body MRI. The grade of fatty involution for individual muscles was determined using Fischer-Grading. Results were compared to established MRI-patterns of other distal myopathies. RESULTS:There was a predominant affection of the distal lower extremities. Lower legs showed a severe fatty infiltration, prominently affecting gastrocnemius and soleus muscle. In thighs, a preferential involvement of semimembranous and biceps femoris muscle was observed. Severe affection of gluteus minimus muscle as well as axial musculature, mainly affecting the thoracic segments, was seen. A sufficient discrimination to other forms of distal myopathy based solely on MRI-findings of the lower extremities was not possible. However, the inclusion of additional body parts seemed to yield specificity. INTERPRETATION:Muscle MRI of patients with MATR3-associated distal myopathy revealed a distinct pattern of muscular involvement. The usage of whole-body muscle MRI provided valuable additional findings as compared to regular MRI of the lower extremities to improve distinction from other disease entities.	0
PURPOSE OF REVIEW:The most serious DNA damage, DNA double strand breaks (DNA-dsb), leads to mutagenesis, carcinogenesis or apoptosis if left unrepaired. Non-homologous end joining (NHEJ) is the principle repair pathway employed by mammalian cells to repair DNA-dsb. Several proteins are involved in this pathway, defects in which can lead to human disease. This review updates on the most recent information available for the specific diseases associated with the pathway. RECENT FINDINGS:A new member of the NHEJ pathway, PAXX, has been identified, although no human disease has been associated with it. The clinical phenotypes of Artemis, DNA ligase 4, Cernunnos-XLF and DNA-PKcs deficiency have been extended. The role of haematopoietic stem cell transplantation, following reduced intensity conditioning chemotherapy, for many of these diseases is being advanced. In the era of newborn screening, urgent genetic diagnosis is necessary to correctly target appropriate treatment for patients with DNA-dsb repair disorders.	0
LAMA2-related congenital muscular dystrophy, also known as MDC1A, is caused by loss-of-function mutations in the alpha2 chain of Laminin-211. Loss of this protein interrupts the connection between the muscle cell and its extracellular environment and results in an aggressive, congenital-onset muscular dystrophy characterized by severe hypotonia, lack of independent ambulation, and early mortality driven by respiratory complications and/or failure to thrive. Of the pathomechanisms of MDC1A, the earliest and most prominent is widespread and rampant fibrosis. Here, we will discuss some of the key drivers of fibrosis including TGF-beta and renin-angiotensin system signaling and consequences of these pathways including myofibroblast transdifferentiation and matrix remodeling. We will also highlight some of the differences in fibrogenesis in congenital muscular dystrophy (CMD) with that seen in Duchenne muscular dystrophy (DMD). Finally, we will connect the key signaling pathways in the pathogenesis of MDC1A to the current status of the therapeutic approaches that have been tested in the preclinical models of MDC1A to treat fibrosis.	0
Weyers ulnar ray/oligodactyly syndrome is characterized by variable ulnar, radial, or fibular ray limb reductions, single central incisor, and renal, splenic or cardiac anomalies. Split hand/split foot malformation is a central reduction defect of the hands and feet, and may occur either as an isolated malformation or as a part of syndrome. We describe a patient with Weyers-like ulnar ray/oligodactyly reduction limb defects and split hand malformation.	0
Kuwait has a cosmopolitan population of 1.7 million, mostly Arabs. This population is a mosaic of large and small minorities representing most Arab communities. In general, Kuwait's population is characterized by a rapid rate of growth, large family size, high rates of consanguineous marriages within the Arab communities with low frequency of intermarriage between them, and the presence of genetic isolates and semi-isolates in some extended families and Bedouin tribes. Genetic services have been available in Kuwait for over a decade. During this time it has become clear that Arabs have a high frequency of genetic disorders, and in particular autosomal recessive traits. Their pattern is unique and some disorders are relatively common. Examples are Bardet-Biedl and Meckel syndromes, phenylketonuria, and familial Mediterranean fever. A relatively large number of new syndromes and variants have been delineated in Kuwait's population, many being the result of homozygosity for autosomal recessive genes that occurred because of inbreeding. Some of these syndromes have subsequently been found in other parts of the world, negating the concept of the private syndrome. This paper provides an overview of autosomal recessive disorders among the Arabs in Kuwait from a personal perspective and published studies, and highlights the need for genetic services in Arab countries with the goal of prevention and treatment of genetic disorders.	0
Limb development is clinically and biologically important. Polydactyly is common and caused by aberrant anterior-posterior patterning. Human disorders that include polydactyly are diverse. To facilitate an understanding of the biology of limb development, cataloging the genes that are mutated in patients with polydactyly would be useful. In 2002, I characterized human phenotypes that included polydactyly. Subsequently, many advances have occurred with refinement of clinical entities and identification of numerous genes. Here, I update human polydactyly entities by phenotype and mutated gene. This survey demonstrates phenotypes with overlapping manifestations, genetic heterogeneity, and distinct phenotypes generated from mutations in single genes. Among 310 clinical entities, 80 are associated with mutations in 99 genes. These results show that knowledge of limb patterning genetics is improving rapidly. Soon, we will have a comprehensive toolkit of genes important for limb development, which will lead to regenerative therapies for limb anomalies.	0
PSEN1 gene is considered to be the most common gene, which is responsible for the development of an autosomal dominant Alzheimer disease with early onset and sometimes broad phenotype. We present a patient with a spinocerebellar ataxia (SCA)-like phenotype who was found to carry an M233V mutation. General and neurological exam was carried out. Brain MRI as well as genetic testing for SCAs 1, 2, 3, 6, and 17 were performed. The patient was then referred for a next-generation sequencing-based gene panel test with 723 genes included. A 26-year-old man of an Azerbaijani origin presented with a progressive impairment of coordination followed by memory impairment. Family history was positive for a similar disorder suggesting autosomal dominant inheritance. Brain MRI showed bilateral hippocampal atrophy (more pronounced in the left), as well as mild atrophy of the left temporoparietal cortex. Tests for SCAs 1, 2, 3, 6, and 17 came negative. Gene panel test showed c.697A > G heterozygous variant in the PSEN1 gene leading to a M233V amino acid change, which was validated by a Sanger sequencing. So far, M233V mutation has not been associated with a combination of cerebellar and cognitive features at onset. Our case contributes to a better characterization of the PSEN1 mutations and expands the phenotype of the M233V carriers. We propose to consider PSEN1 mutations in patients presenting with an SCA-like phenotype but negative for common types of SCA.	0
3M syndrome is characterized by severe pre- and postnatal growth retardation, typical facial features, and normal intelligence. Homozygous or compound heterozygous mutations in either CUL7, OBSL1, or CCDC8 have been identified in the etiology so far. Clinical and molecular features of 24 patients (23 patients and a fetus) from 19 unrelated families with a clinical diagnosis of 3M syndrome were evaluated and genotype-phenotype correlations were investigated with the use of DNA sequencing, chromosomal microarray, and whole exome sequencing accordingly. A genetic etiology could be established in 20 patients (n = 20/24, 83%). Eleven distinct CUL7 or OBSL1 mutations, among which eight was novel, were identified in 18 patients (n = 18/24, 75%). Ten patients had CUL7 (n = 10/18, 56%) while eight had OBSL1 (n = 8/18, 44%) mutations. Birth weight and height standard deviation scores at admission were significantly (p < 0.05) lower in patients with CUL7 mutation compared to that of patients with OBSL1 mutation. Two patients with a similar phenotype had a de novo 20p13p deletion involving BMP2. No genetic etiology could be established in four patients (n = 4/28, 17%). This study yet represents the largest cohort of 3M syndrome patients from a single center in Turkey. Microdeletions involving BMP2 may cause a phenotype similar to 3M syndrome with some distinctive features. Larger cohort of patients are required to establish genotype-phenotype correlations in 3M syndrome.	0
Background:Rat-bite fever is a rare disease associated with rat bites or direct/indirect rodent contact. Methods:We examined rat-bite fever and rat-bite injury diagnoses in the United States during 2001-2015. We analyzed national, state, and Indian Health Service healthcare encounter datasets for rat-bite fever and rat-bite injury diagnoses. We calculated average-annual encounter rates per 1 000 000 persons. Results:Nationally, the rat-bite fever Emergency Department visit rate was 0.33 (95% confidence interval [CI], 0.19-0.47) and the hospitalization rate was 0.20 (95% CI, 0.17-0.24). The rat-bite injury Emergency Department visit rate was 10.51 (95% CI, 10.13-10.88) and the hospitalization rate was 0.27 (95% CI, 0.23-0.30). The Indian Health Service Emergency Department/outpatient visit rate was 3.00 for rat-bite fever and 18.89 for rat-bite injury. The majority of rat-bite fever encounters were among individuals 0-19 years of age. Conclusions:Our results support the literature that rat-bite fever is rare and affects children and young adults. Targeted education could benefit specific risk groups.	0
Indolent B cell lymphomas are a group of lymphoid malignancies characterized by their potential to undergo histologic transformation to aggressive lymphomas. While different subtypes of indolent B cell lymphomas demonstrate specific clinical and imaging features, histologic transformation can be suspected on cross-sectional imaging when disproportionate lymph node enlargement or new focal lesions in extranodal organs are seen. On PET/CT, transformed indolent lymphoma may show new or increased nodal FDG avidity or new FDG-avid lesions in different organs. In this article, we will (1) review the imaging features of different subtypes of indolent B cell lymphomas, (2) discuss the imaging features of histologic transformation, and (3) propose a diagnostic algorithm for transformed indolent lymphoma. The purpose of this review is to familiarize radiologists with the spectrum of clinical and imaging features of indolent B cell lymphomas and to define the role of imaging in raising concern for transformation and in guiding biopsy for confirmation.	0
OBJECTIVES:To determine the characteristics of juvenile idiopathic arthritis (JIA) patients seen during the transition period in order to compare paediatric classification criteria with those for adults. METHODS:Patients with JIA according to the ILAR classification and who had a consultation at transition between 2010 and 2017 were included in a retrospective bi-centre (Lyon, Lausanne) study. JIA classification criteria were compared to ACR/EULAR 2010 criteria for rheumatoid arthritis (RA), Yamaguchi criteria for adult-onset Still's disease (AOSD), ASAS criteria for spondyloarthritis and CASPAR criteria for psoriatic arthritis. RESULTS:130 patients were included: 13.9% with systemic JIA, 22.3% with polyarticular JIA, 22.3% with oligoarticular JIA, 34.6% with enthesitis-related arthritis (ERA) and 6.9% with psoriatic arthritis. 13.1% had suffered from uveitis. 14.5% of patients had erosions or carpitis, mainly those with psoriatic arthritis, polyarticular or systemic JIA. 37.5% of patients with ERA displayed radiological sacroiliitis. When comparing paediatric JIA criteria with adult classifications, we found that: 66.6% of patients with systemic JIA fulfilled the criteria for AOSD, 87.5% of rheumatoid factor-positive polyarticular JIA and 9.5% of rheumatoid factor-negative polyarticular JIA met the criteria for RA, and 34.5% of oligoarticular JIA fulfilled the criteria for spondyloarthritis. Finally, 77.7% of patients with ERA met the criteria for spondyloarthritis, and 100% of patients with psoriatic arthritis JIA met the criteria for psoriatic arthritis. CONCLUSION:Oligoarticular JIA and rheumatoid factor-negative polyarticular JIA seem to be paediatric entities, whereas the other types of JIA tended to meet the respective adult classification criteria.	0
Treatment for ulcerative colitis often requires the administration of immunosuppressive therapy. Shortly after rescue therapy with infliximab for acute severe colitis, a patient who was also taking corticosteroids, azathioprine and adalimumab became rapidly unwell with atypical pneumonia, which did not respond to conventional antimicrobials. Re-examining the travel history revealed a prior caving trip to Costa Rica. Dimorphic fungal serology was thus tested and a diagnosis of paracoccidioidomycosis was made. After a lengthy intensive care unit admission, the patient made a recovery after the administration of appropriate antifungal therapy and was discharged home on long-term oral antifungals.	0
Excitation-contraction coupling, the process that regulates contractions by skeletal muscles, transduces changes in membrane voltage by activating release of Ca(2+) from internal stores to initiate muscle contraction. Defects in excitation-contraction coupling are associated with muscle diseases. Here we identify Stac3 as a novel component of the excitation-contraction coupling machinery. Using a zebrafish genetic screen, we generate a locomotor mutation that is mapped to stac3. We provide electrophysiological, Ca(2+) imaging, immunocytochemical and biochemical evidence that Stac3 participates in excitation-contraction coupling in muscles. Furthermore, we reveal that a mutation in human STAC3 is the genetic basis of the debilitating Native American myopathy (NAM). Analysis of NAM stac3 in zebrafish shows that the NAM mutation decreases excitation-contraction coupling. These findings enhance our understanding of both excitation-contraction coupling and the pathology of myopathies.	0
Excessive tumor necrosis factor (TNF) is known to cause significant pathology. Paradoxically, deficiency in TNF (TNF-/-) also caused substantial pathology during respiratory ectromelia virus (ECTV) infection, a surrogate model for smallpox. TNF-/- mice succumbed to fulminant disease whereas wild-type mice, and those engineered to express only transmembrane TNF (mTNF), fully recovered. TNF deficiency did not affect viral load or leukocyte recruitment but caused severe lung pathology and excessive production of the cytokines interleukin (IL)-6, IL-10, transforming growth factor beta (TGF-β), and interferon gamma (IFN-γ). Short-term blockade of these cytokines significantly reduced lung pathology in TNF-/- mice concomitant with induction of protein inhibitor of activated STAT3 (PIAS3) and/or suppressor of cytokine signaling 3 (SOCS3), factors that inhibit STAT3 activation. Consequently, inhibition of STAT3 activation with an inhibitor reduced lung pathology. Long-term neutralization of IL-6 or TGF-β protected TNF-/- mice from an otherwise lethal infection. Thus, mTNF alone is necessary and sufficient to regulate lung inflammation but it has no direct antiviral activity against ECTV. The data indicate that targeting specific cytokines or cytokine-signaling pathways to reduce or ameliorate lung inflammation during respiratory viral infections is possible but that the timing and duration of the interventive measure are critical.	0
BACKGROUND:Rare bone diseases account for 5% of all birth defects yet very few have personalised treatments. Developments in genetic diagnosis, molecular techniques and treatment technologies however, are leading to unparalleled therapeutic advance. This review explores the evolving therapeutic landscape of genetic skeletal disorders (GSDs); the key conditions and there key differentials. METHODS:A retrospective literature based review was conducted in December 2018 using a systematic search strategy for relevant articles and trials in Pubmed and clinicaltrials.gov respectively. Over 140 articles and 80 trials were generated for review. RESULTS:Over 20 personalised therapies are discussed in addition to several novel disease modifying treatments in over 25 GSDs. Treatments discussed are at different stages from preclinical studies to clinical trials and approved drugs, including; Burosumab for X-linked hypophosphatemia, Palovarotene for Hereditary Multiple Exostoses, Carbamazepine for Metaphyseal Chondrodysplasia (Schmid type), Lithium carbonate and anti-sclerostin therapy for Osteoporosis Pseudoglioma syndrome and novel therapies for Osteopetrosis. We also discuss therapeutic advances in Achondroplasia, Osteogenesis Imperfecta (OI), Hypophosphotasia (HPP), Fibrodysplasia Ossificans Progressiva, and RNA silencing therapies in preclinical studies for OI and HPP. DISCUSSION:It is an exciting time for GSD therapies despite the challenges of drug development in rare diseases. In discussing emerging therapies, we explore novel approaches to drug development from drug repurposing to in-utero stem cell transplants. We highlight the improved understanding of bone pathophysiology, genetic pathways and challenges of developing gene therapies for GSDs.	0
Bardet-Biedl syndrome (BBS) is a recessive disorder characterized by heterogeneous clinical manifestations, including truncal obesity, rod-cone dystrophy, renal anomalies, postaxial polydactyly, and variable developmental delays. At least 20 genes have been implicated in BBS, and all are involved in primary cilia function. We report a 1-year-old male child from Guyana with obesity, postaxial polydactyly on his right foot, hypotonia, ophthalmologic abnormalities, and developmental delay, which together indicated a clinical diagnosis of BBS. Clinical chromosomal microarray (CMA) testing and high-throughput BBS gene panel sequencing detected a homozygous 7p14.3 deletion of exons 1-4 of BBS9 that was encompassed by a 17.5 Mb region of homozygosity at chromosome 7p14.2-p21.1. The precise breakpoints of the deletion were delineated to a 72.8 kb region in the proband and carrier parents by third-generation long-read single molecule real-time (SMRT) sequencing (Pacific Biosciences), which suggested non-homologous end joining as a likely mechanism of formation. Long-read SMRT sequencing of the deletion breakpoints also determined that the aberration included the neighboring RP9 gene implicated in retinitis pigmentosa; however, the clinical significance of this was considered uncertain given the paucity of reported cases with unambiguous RP9 mutations. Taken together, our study characterized a BBS9 deletion, and the identification of this shared haplotype in the parents suggests that this pathogenic aberration may be a BBS founder mutation in the Guyanese population. Importantly, this informative case also highlights the utility of long-read SMRT sequencing to map nucleotide breakpoints of clinically relevant structural variants.	0
Purpose:To report a case of peripheral elevated lesions mimicking retinal detachment which were ultimately ascertained to be giant pars plana cysts through ophthalmoscopy with scleral depression. Methods:This was a case report documented with ophthalmoscopy and Optos imaging. Results:Patient initially referred for assessment of bilateral retinal detachment was found by careful ophthalmoscopy with scleral depression to have bilateral giant pars plana cysts with no frank retinal breaks. Conclusion:Large pars plana cysts may mimic retinal detachment or other peripheral retinal pathology. The lesions in question were found to originate from the pars plana and overhang the retina. No frank retinal breaks or associated rhegmatogenous retinal detachments were noted in either eye. Ophthalmoscopy with a complete scleral depressed exam allowed for the differentiation.	0
Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide. Most cases are multifactorial in etiology, but some are associated with variants in the myocilin gene, MYOC Here, we report the identification of a novel MYOC variant, c.1153G>A, in a 24-yr-old female patient with a personal and family history of juvenile/early-onset POAG. Further genetic testing within her family demonstrated that this variant segregates with the POAG phenotype in an autosomal dominant pattern. Identification of this MYOC variant in multiple affected relatives provides evidence for its pathogenicity, supporting previous findings linking MYOC mutations, in particular in the third exon's olfactomedin domain, to juvenile-onset POAG. This case also emphasizes the potential value of genetic testing in families with histories of eye disorders.	0
Palatoglossal bands are one of the very rare congenital anomaly with very few documented cases worldwide. They can present with respiratory distress which requires immediate surgical intervention, or with feeding difficulties. The management of such a patient is a challenge to any anaesthesiologist because of inability to perform conventional laryngoscopy and associated cardiac or digital anomalies. We discuss here the management of such an infant who presented at 18 months with feeding difficulties.	0
BACKGROUND: Observational studies showed that the profile of infective endocarditis (IE) significantly changed over the past decades. However, most studies involved referral centers. We conducted a population-based study to control for this referral bias. The objective was to update the description of characteristics of IE in France and to compare the profile of community-acquired versus healthcare-associated IE. METHODS: A prospective population-based observational study conducted in all medical facilities from 7 French regions (32% of French individuals aged ≥18 years) identified 497 adults with Duke-Li-definite IE who were first admitted to the hospital in 2008. Main measures included age-standardized and sex-standardized incidence of IE and multivariate Cox regression analysis for risk factors of in-hospital death. RESULTS: The age-standardized and sex-standardized annual incidence of IE was 33.8 (95% confidence interval [CI], 30.8-36.9) cases per million inhabitants. The incidence was highest in men aged 75-79 years. A majority of patients had no previously known heart disease. Staphylococci were the most common causal agents, accounting for 36.2% of cases (Staphylococcus aureus, 26.6%; coagulase-negative staphylococci, 9.7%). Healthcare-associated IE represented 26.7% of all cases and exhibited a clinical pattern significantly different from that of community-acquired IE. S. aureus as the causal agent of IE was the most important factor associated with in-hospital death in community-acquired IE (hazard ratio [HR], 2.82 [95% CI, 1.72-4.61]) and the single factor in healthcare-associated IE (HR, 2.54 [95% CI, 1.33-4.85]). CONCLUSIONS: S. aureus became both the leading cause and the most important prognostic factor of IE, and healthcare-associated IE appeared as a major subgroup of the disease.	1
OBJECTIVE:The objective of this phase 2a study was to assess the activity of PF-06372865, a positive allosteric modulator (PAM) of α2/3/5 subunit-containing GABAA receptors with minimal activity at α1-containing receptors, which are believed to mediate many of the adverse events associated with benzodiazepines, in the epilepsy photosensitivity model as a proof-of-principle of efficacy. METHODS:Seven participants with a photoparoxysmal response to intermittent photic stimulation (IPS) at baseline were randomized in a double-blind, 4-period cross-over study examining single doses of 17.5 and 52.5 mg PF-06372865, 2 mg lorazepam (active control), and placebo. Standardized photosensitivity ranges (SPRs) to IPS were recorded at screening, predose, and 1, 2, 4, and 6 hours postdose. The primary endpoint was the average least squares mean change in the SPR in the participant's most sensitive eye condition, across all time points. RESULTS:Both doses of PF-06372865 produced a marked and statistically significant mean reduction in SPR compared to placebo, which was similar in degree to lorazepam. There was complete suppression of SPR in 6/7 participants following PF-06372865 or lorazepam administration. PF-06372865 was safe and well-tolerated. CONCLUSION:PF-06372865 demonstrated highly robust efficacy. This demonstrates anticonvulsant activity of a novel α2/3/5-subtype selective GABAA PAM in humans. Further study of the antiepileptic properties of PF-06372865 is warranted. CLINICALTRIALSGOV IDENTIFIER:NCT02564029. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that for people with a stable photoparoxysmal response to intermittent photic stimulation, PF-06372865 reduces the SPR.	0
Introduction: The present status of amifampridine (AFP) for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) is reviewed. Areas covered: All relevant literature identified through a PubMed search under treatment of LEMS, aminopyridine, and amifampridine are reviewed. An expert opinion on AFP was formulated. Expert opinion: AFPs, 3,4-DAP and 3,4-DAPP, are the most studied drugs in neuromuscular diseases. Randomized and non-randomized studies showed the most effective drug as symptomatic medication for LEMS. AFPs are safe and tolerable. Thus, AFPs should be the drug of choice for the symptomatic treatment in LEMS. As long as the daily dose is less than 80 mg a day, there is no concern for the serious side-reaction, seizure. Because of short-acting drug effects, it should be given three or four times a day. Peri-oral and finger paresthesia, the most common side-reaction, is accepted as a sign of drug-intake by many patients. Gastro-intestinal side reactions, the next common side-reaction of AFPs, are tolerable. AFPs are also the drug of choice and life-saving for LEMS crisis. For the long-term usage, it is proven to be safe and AFPs can be supplemented with liberal amount of pyridostigmine to sustain a symptomatic improvement without any undue side-reaction.	0
PURPOSE:Uniparental disomy (UPD) is a way cancer cells duplicate a mutated gene, causing loss of heterozygosity (LOH). Patients with cytogenetically normal acute myeloid leukemia (CN-AML) do not have microscopically detectable chromosome abnormalities, but can harbor UPDs. We examined the prognostic significance of UPDs and frequency of LOH in patients with CN-AML.Experimental Design: We examined the frequency and prognostic significance of UPDs in a set of 425 adult patients with de novo CN-AML who were previously sequenced for 81 genes typically mutated in cancer. Associations of UPDs with outcome were analyzed in the 315 patients with CN-AML younger than 60 years. RESULTS:We detected 127 UPDs in 109 patients. Most UPDs were large and typically encompassed all or most of the affected chromosome arm. The most common UPDs occurred on chromosome arms 13q (7.5% of patients), 6p (2.8%), and 11p (2.8%). Many UPDs significantly cooccurred with mutations in genes they encompassed, including 13q UPD with FLT3-internal tandem duplication (FLT3-ITD; P < 0.001), and 11p UPD with WT1 mutations (P = 0.02). Among patients younger than 60 years, UPD of 11p was associated with longer overall survival (OS) and 13q UPD with shorter disease-free survival (DFS) and OS. In multivariable models that accounted for known prognostic markers, including FLT3-ITD and WT1 mutations, UPD of 13q maintained association with shorter DFS, and UPD of 11p maintained association with longer OS. CONCLUSIONS:LOH mediated by UPD is a recurrent feature of CN-AML. Detection of UPDs of 13q and 11p might be useful for genetic risk stratification of patients with CN-AML.	0
Turcot syndrome is a rare hereditary syndrome characterized by a combination of brain tumors and colorectal cancer. According to the literature, about 150 such cases have been reported. This article presents a rare clinical case and a literature review.	0
Biliary atresia (BA) is a fatal condition resulting in the lack of effective biliary drainage leading invariably to liver failure and cirrhosis within a year, and it is often lethal within a few months in the absence of corrective surgery or liver transplantation. In fact, BA is the most common indication for pediatric liver transplantation.Herein, we present a rare case of unexpected infant death due to BA diagnosed only postmortem in a context of child neglect and carelessness on the part of the parents. It emerged from the clinical history that after a few months, the parents no longer took their daughter to any medical checkups despite the indications and express recommendations for follow-up. The autopsy revealed agenesis of the gallbladder with BA and complete disruption of the hepatic architecture and parenchyma from biliary cirrhosis. Histological examinations documented severe biliary cirrhosis from hypoplasia of the biliary ducts.The child neglect in this case proved fatal inasmuch as an early diagnosis by a pediatrician would have likely allowed appropriate surgical treatment, thus avoiding the untimely death of the child. We highlight the importance of educating and informing parents (especially the disadvantaged) in matters of health. At the same time, primary care physicians should closely monitor the conditions and development of infants so as to recognize the early warning signs and symptoms of BA, bearing in mind that a timely diagnosis and proper surgical treatment can save the lives of most of these children.	0
BACKGROUND:Tamsulosin is the most potent adrenergic alpha-1 antagonist used for treatment of benign prostatic hyperplasia (BPH). Priapism has been reported as a rare side effect through direct inhibition of the sympathetic input necessary for detumesence. PRESENTATION OF CASE:We describe an otherwise healthy man with recurrent and then persistent unresolved priapism after the use of tamsulosin and concomitant use of ace inhibitor and beta blocker for hypertension. We then performed aspiration and intracavernosal irrigation of saline and vasoconstrictive agent. DISCUSSION:Health-care professionals should inform all patients taking such medications about this rare but possible serious adverse effect. Tamsulosin is a useful medication for the management of Lower Urinary Tract Symptoms (LUTS) related to BPH and medical expulsion of distal ureteric calculi. However, its use may be associated on rare occasions with priapism, hence Health-care professionals should be aware in order to advice all patients taking such medications about this rare but serious adverse effect and to seek help as soon as possible. CONCLUSION:With caution against the use of tamsulosin in hypertension treated patient, the possibility of the adverse effect can be more noticed and encourage practitioners to look for other alternatives that are safer and better for dealing with LUTS in the future and develop better treatment strategies.	0
Excluding human papillomavirus (HPV)-driven conditions, oral papillary lesions consist of a variety of reactive and neoplastic conditions and, on occasion, can herald internal malignancy or be part of a syndrome. The objectives of this paper are to review the clinical and histopathological features of the most commonly encountered non-HPV papillary conditions of the oral mucosa. These include normal anatomic structures (retrocuspid papillae, lingual tonsils), reactive lesions (hairy tongue, inflammatory papillary hyperplasia), neoplastic lesions (giant cell fibroma), lesions of unknown pathogenesis (verruciform xanthoma, spongiotic gingival hyperplasia) and others associated with syndromes (for instance Cowden syndrome) or representing paraneoplastic conditions (malignant acanthosis nigricans). Common questions regarding differential diagnosis, management, and diagnostic pitfalls are addressed, stressing the importance of clinico-pathologic correlation and collaboration.	0
We report two male sibs and two female sibs from separate families, both with normal parents, who had a lethal condition with features of the Yunis-Varon syndrome and radiological signs of severe osteodysplasty. Autosomal recessive inheritance is likely in both families. The additional features described represent further delineation of the phenotype of the Yunis-Varon syndrome.	0
Spinal muscular atrophy with respiratory distress (SMARD1) presents within the first 13months of age with low birth weight, progressive length dependent motor neuropathy, and respiratory failure from diaphragmatic paralysis. SMARD1 is caused by mutations in IGHMBP2, encoding the immunoglobulin μ-binding protein 2. Because of the severity of the disorder, many infantile-onset SMARD1 patients do not live past the first decade of life. This report documents the clinical course of a 20-year-old man diagnosed with SMARD1.	0
COVID-19 disease is a highly contagious and particularly popular problem in all countries. A variety of repurposed drugs and investigational drugs such as remdesivir, chloroquine, hydroxychloroquine, ritonavir, lopinavir, interferon-beta, and other potential drugs have been studied for COVID19 treatment. We reviewed the potential dermatological side-effects of these drugs.	0
BACKGROUND:A single variant in NAA10 (c.471+2T>A), the gene encoding N-acetyltransferase 10, has been associated with Lenz microphthalmia syndrome. In this study, we aimed to identify causative variants in families with syndromic X-linked microphthalmia. METHODS:Three families, including 15 affected individuals with syndromic X-linked microphthalmia, underwent analyses including linkage analysis, exome sequencing and targeted gene sequencing. The consequences of two identified variants in NAA10 were evaluated using quantitative PCR and RNAseq. RESULTS:Genetic linkage analysis in family 1 supported a candidate region on Xq27-q28, which included NAA10. Exome sequencing identified a hemizygous NAA10 polyadenylation signal (PAS) variant, chrX:153,195,397T>C, c.*43A>G, which segregated with the disease. Targeted sequencing of affected males from families 2 and 3 identified distinct NAA10 PAS variants, chrX:g.153,195,401T>C, c.*39A>G and chrX:g.153,195,400T>C, c.*40A>G. All three variants were absent from gnomAD. Quantitative PCR and RNAseq showed reduced NAA10 mRNA levels and abnormal 3' UTRs in affected individuals. Targeted sequencing of NAA10 in 376 additional affected individuals failed to identify variants in the PAS. CONCLUSION:These data show that PAS variants are the most common variant type in NAA10-associated syndromic microphthalmia, suggesting reduced RNA is the molecular mechanism by which these alterations cause microphthalmia/anophthalmia. We reviewed recognised variants in PAS associated with Mendelian disorders and identified only 23 others, indicating that NAA10 harbours more than 10% of all known PAS variants. We hypothesise that PAS in other genes harbour unrecognised pathogenic variants associated with Mendelian disorders. The systematic interrogation of PAS could improve genetic testing yields.	0
BACKGROUND:A genetic disorder should be considered when an infant presents with multiple congenital anomalies. Because of the acute presentation of an infant with multiple life-threatening defects, a genetic diagnosis of a rare disorder took weeks to delineate. CLINICAL FINDINGS:This case describes a late preterm infant who presented at birth with congenital diaphragmatic hernia, tetralogy of Fallot, cleft lip, low-set ears, and hypertelorism. PRIMARY DIAGNOSIS:Donnai-Barrow syndrome was the final diagnosis confirmed by a defect observed on the LRP2 (2q31.1) gene using sequence analysis. This is a rare disorder that presents with a variety of phenotypic features in infants. INTERVENTIONS:Initial neonatal resuscitation in the delivery room included intubation, positive pressure ventilation, and oxygen supplementation. Extracorporeal membrane oxygenation therapy was initiated from day of life 3 to 15. Initial surgery included correction of the congenital diaphragmatic hernia, and further surgical procedures included tracheostomy, gastrostomy tube, circumcision, ventricular septal defect repair, and cleft lip repair. Physical, occupational, and speech therapies were also initiated. OUTCOMES:The infant was transported to a pediatric rehabilitation facility at 6 months of life for further management of his chronic lung disease requiring tracheostomy with ventilator dependence. PRACTICE RECOMMENDATIONS:Early recognition and diagnosis of genetic syndromes can improve family education and guide treatment interventions. An underlying syndrome should be suspected when an infant presents with multiple congenital defects. Infants with Donnai-Barrow syndrome should have thorough cardiac, neurologic, ophthalmologic, audiologic, and renal examinations due to the gene mutation effects on those systems.	0
Coach Syndrome is a rare cause of Congenital Hepatic Fibrosis associated with neurological features. COACH is a mnemonic comprising of Cerebellar vermis hypo/aplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma and Hepatic fibrosis. Here we describe a 12 years boy who presented with hepatic encephalopathy. He was subsequently found to have marked developmental delay, bilateral ptosis and ataxia. CT scan revealed brain stem molar tooth sign, ophthalmoscopy showed optic disc coloboma and elastography showed hepatic fibrosis to confirm him as a case of COACH Syndrome.	0
Disruption of the minor spliceosome due to mutations in RNU4ATAC is linked to primordial dwarfism in microcephalic osteodysplastic primordial dwarfism type 1, Roifman syndrome, and Lowry-Wood syndrome. Similarly, primordial dwarfism in domesticated animals is linked to positive selection in minor spliceosome components. Despite being vital for limb development and size regulation, its role remains unexplored. Here we disrupt minor spliceosome function in the developing mouse limb by ablating one of its essential components, U11 small nuclear RNA, which resulted in micromelia. Notably, earlier loss of U11 corresponded to increased severity. We find that limb size is reduced due to elevated minor intron retention in minor intron-containing genes that regulate cell cycle. As a result, limb progenitor cells experience delayed prometaphase to metaphase transition and prolonged S-phase. Moreover, we observed death of rapidly dividing, distally located progenitors. Despite cell cycle defects and cell death, the spatial expression of key limb patterning genes was maintained. Overall, we show that the minor spliceosome is required for limb development via size control potentially shared in disease and domestication.	0
Ornithine transcarbamylase (OTC) deficiency is an X-linked recessive disorder that leads to hyperammonemia and liver damage. Hepatocellular adenoma in OTC deficiency patients has not been previously described. Here we report the first such case to be described in the English language scientific literature.	0
Mucolipidosis III alpha/beta (ML III alpha/beta) is an autosomal recessive lysosomal storage disorder caused by N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) deficiency. It is characterized by coarse facial features, developmental delay, short stature, and skeletal deformities. Its cardiovascular symptoms include valvular thickening or hypertrophic cardiomyopathy. A 32-year-old female patient received heart transplantation due to end-stage heart failure caused by dilated cardiomyopathy (DCM). We performed whole exome sequencing to determine the etiology of DCM and/or skeletal deformities. The test revealed c.2715+1G>A and c.3173C>G mutations in the GNPTAB gene encoding the alpha and beta subunits of GlcNAc-phosphotransferase. Finally, she was diagnosed with ML III alpha/beta. This report describes a rare case of ML III alpha/beta associated with DCM. Our findings expand the clinical spectrum of ML III alpha/beta.	0
BACKGROUND:IL-10 has been implicated as the major cytokine responsible for the modulation of parasite-specific responses in filarial infections; however, the role of other IL-10 superfamily members in filarial infection is less well studied. METHODS:Peripheral blood mononuclear cells from loiasis patients were stimulated with or without filarial antigen. Cytokine production was quantified using a Luminex platform, and T cell expression patterns were assessed by flow cytometry. RESULTS:All patients produced significant levels of IL-10, IL-13, IL-5, IL-4, and IL-9 in response to filarial antigen indicating a common infection-driven response. When comparing mf positive (mf+) and mf negative (mf-) patients, there were no significant differences in spontaneous cytokine nor in parasite-driven IL-10, IL-22, or IL-28a production. In marked contrast, mf+ individuals had significantly increased filarial antigen-driven IL-24, and IL-19 compared to mf- subjects. Mf+ patients also demonstrated significantly higher frequencies of T cells producing IL-19 in comparison to mf- patients. T cell expression of IL-19 and IL-24 by was positively regulated by IL-10 and IL-1β. IL-24 production was also regulated by IL-37. CONCLUSION:These data provide an important link between IL-10 and its related family members IL-19 and IL-24 in the modulation of the immune response in human filarial infections.	0
Invasive group A streptococcal (GAS) infections cause significant morbidity and mortality. A national survey was initiated to assess the burden of invasive GAS infections in France, describe their clinical characteristics, and assess the molecular characteristics of GAS strains responsible for these infections. The survey was conducted in 194 hospitals, accounting for 51% of acute care hospital admissions in France. Clinical data, predisposing factors, and demographic data were obtained, and all GAS isolates were emm sequence typed. We identified 664 cases of invasive GAS infections, with an annual incidence of 3.1 per 100,000 population. The case-fatality ratio was 14% and rose to 43% in the case of streptococcal toxic shock syndrome. Bacteremia without identified focus (22%) and skin/soft tissue infections (30%) were the most frequent clinical presentations. Necrotizing fasciitis was frequent in adults (18%) and uncommon in children (3%). The 3 predominant emm types were emm1, emm89, and emm28, accounting for 33%, 16%, and 10% of GAS isolates, respectively. The emm1 type was associated with fatal outcomes and was more frequent in children than in adults. Six clusters of cases were identified, with each cluster involving 2 invasive cases due to GAS strains which shared identical GAS emm sequence types. Four clusters of cases involved eight postpartum infections, one family cluster involved a mother and child, and one cluster involved two patients in a nursing home. Invasive GAS infection is one of the most severe bacterial diseases in France, particularly in persons aged ≥ 50 years or when associated with toxic shock syndrome.	1
Treacher Collins syndrome (TCS: OMIM 154500) is an autosomal dominant craniofacial disorder belonging to the heterogeneous group of mandibulofacial dysostoses. OBJECTIVE:To investigate four Treacher Collins syndrome patients of the Sgaw Karen family living in Thailand. METHOD:Clinical examination, hearing tests, lateral cephalometric analyses, Computed tomography, whole exome sequencing and Sanger direct sequencing were performed. RESULTS:All of the patients affected with Treacher Collins syndrome carried a novel TCOF1 mutation (c.4138_4142del; p.Lys1380GlufsTer12), but clinically they did not have the typical facial gestalt of Treacher Collins syndrome, which includes downward-slanting palpebral fissures, colobomas of the lower eyelids, absence of eyelashes medial to the colobomas, malformed pinnae, hypoplastic zygomatic bones and mandibular hypoplasia. Lateral cephalometric analyses identified short anterior and posterior cranial bases, and hypoplastic maxilla and mandible. Computed tomography showed fusion of malleus and incus, sclerotic mastoid, hypoplastic middle ear space with a soft tissue remnant, dehiscence of facial nerve and monopodial stapes. CONCLUSION:Treacher Collins syndrome in Sgaw Karen patients has not been previously documented. This is the first report of monopodial stapes in a TCS patient who had a TCOF1 mutation. The absence of a common facial phenotype and/or the presence of monopodial stapes may be the effects of this novel TCOF1 mutation.	0
BACKGROUND:The unique anatomy and biomechanical features of the cervical spine and sacrum may impact treatment outcomes following spine stereotactic body radiotherapy (SBRT). Current data for spine metastases are not specific for these locations. OBJECTIVE:To report imaging-based SBRT outcomes to cervical and sacral metastases. METHODS:We retrospectively reviewed our prospective spine SBRT database for cervical and sacral metastases. Patients were followed at 2- to 3-mo intervals with a clinical visit and full spine magnetic resonance imaging (MRI) and we report overall survival (OS), vertebral compression fracture (VCF), and MR imaging-based local control (LC) rates. RESULTS:Fifty-two patients and 93 treated spinal segments were identified. Fifty-six segments were within the cervical spine and 37 within the sacrum, the median follow-up was 14.4 and 19.5 mo, and the median total dose/number of fractions was 24 Gy/2, respectively. Cumulative LC at 1 and 2 yr were 94.5% and 92.7% for the cervical cohort, and 86.5% and 78.7% in the sacral cohort, respectively. Lack of posterior spinal element involvement in the cervical spine (P < .0001) and absence of epidural disease (hazard ratio 0.275, 95% confidence interval 0.076-0.989, P = .048) in the sacral cohort predicted LC. Median OS was 16.3 and 28.5 mo in the cervical spine and sacrum cohorts, respectively. Two cases of sacral VCF, 1 brachial plexopathy, and 1 lumbar-sacral plexopathy were observed. CONCLUSION:Although high rates of LC were observed, strategies specific to the sacrum may require further optimization.	0
Peutz-Jeghers syndrome is a rare autosomal dominant disorder. Approximately 1:25,000 to 1:280,000 cases are registered annually. The pathogenesis of the disease is based on the mutation of the STK 11 gene on chromosome 19. Peutz-Jeghers syndrome is characterized by several symptoms: the formation of multiple hamartomatous polyps primarily in the gastrointestinal tract and hyperpigmentation of the mucous membranes and skin. Patients with Peutz-Jeghers syndrome often develop various malignant neoplasms, mainly localized in the pancreas and colon. We describe Peutz-Jeghers syndrome in a girl 4 years 7 months old. Initially, the child was diagnosed with vitiligo due to complaints of depigmentation of the skin of the face and hands. During re-examination after half a year, foci of hyperpigmentation on the lip and mucous membranes of the oral cavity were noted. Esophagogastroduodenoscopy showed the presence of a polypous lump in the stomach. Genetic consultation confirmed the diagnosis of Peutz-Jeghers syndrome. The absence of family history indicates a sporadic case characterized by diseases with an autosomal-dominant mode of inheritance. This clinical case demonstrates the need for gastroenterological and genetic examinations in the presence of lesions on the oral mucosa and the vermillion border of the lips to confirm or exclude Peutz-Jeghers syndrome.	0
BACKGROUND:Juvenile polyposis syndrome (JPS) is a rare disorder characterized by the presence of multiple juvenile polyps in the gastrointestinal tract, and germline mutations in SMAD4 or BMPR1A. Due to its rarity and complex clinical manifestation, misdiagnosis often occurs in clinical practice. CASE PRESENTATION:A 42-year-old man with multiple pedunculated colorectal polyps and concomitant rectal adenocarcinoma was admitted to our hospital. His mother had died of colon cancer. He was diagnosed with familial adenomatous polyposis (FAP) and underwent total proctocolectomy and ileal pouch anal anastomosis. Two polyps were selected for pathological examination. One polyp had cystically dilated glands with slight dysplasia. The other polyp displayed severe dysplasia and was diagnosed as adenoma. Three years later, his 21-year-old son underwent a colonoscopy that revealed more than 50 pedunculated colorectal juvenile polyps. Both patients harbored a germline pathogenic mutation in BMPR1A. Endoscopic resection of all polyps was attempted but failed. Finally, the son received endoscopic resection of polyps in the rectum and sigmoid colon, and laparoscopic subtotal colectomy. Ten polyps were selected for pathological examination. All were revealed to be typical juvenile polyps, with cystically dilated glands filled with mucus. Thus, the diagnosis of JPS was confirmed in the son. A review of the literatures revealed that patients with JPS can sometimes have adenomatous change. Most polyps in patients with JPS are benign hamartomatous polyps with no dysplasia. A review of 767 colorectal JPS polyps demonstrated that 8.5% of the polyps contained mild to moderate dysplasia, and only 0.3% had severe dysplasia or cancer. It is difficult to differentiate juvenile polyps with dysplasia from adenoma, which could explain why juvenile polyps have been reported to have adenomatous changes in patients with JPS. Therefore, patients with JPS, especially those with concomitant dysplasia and adenocarcinoma, might be easily diagnosed as FAP in clinical practice. CONCLUSIONS:Juvenile polyp with dysplasia is often diagnosed as adenoma, which might lead to the misdiagnosis of JPS as FAP. The differential diagnosis of JPS versus FAP, should be based on comprehensive evaluation of clinical presentation, endoscopic appearance and genetic investigations; not on the presence or absence of adenoma.	0
Abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) are extremely rare recessive forms of hypobetalipoproteinemia characterized by intestinal lipid malabsorption and severe vitamin E deficiency. Vitamin E is often supplemented in the form of fat-soluble vitamin E acetate, but fat malabsorption considerably limits correction of the deficiency. In this crossover study, we administered two different forms of vitamin E, tocofersolan (a water-soluble derivative of RRR-α-tocopherol) and α-tocopherol acetate, to three patients with ABL and four patients with CMRD. The aims of this study were to evaluate the intestinal absorption characteristics of tocofersolan versus α-tocopherol acetate by measuring the plasma concentrations of α-tocopherol over time after a single oral load and to compare efficacy by evaluating the ability of each formulation to restore vitamin E storage after 4 months of treatment. In patients with ABL, tocofersolan and α-tocopherol acetate bioavailabilities were extremely low (2.8% and 3.1%, respectively). In contrast, bioavailabilities were higher in patients with CMRD (tocofersolan, 24.7%; α-tocopherol acetate, 11.4%). Plasma concentrations of α-tocopherol at 4 months were not significantly different by formulation type in ABL or CMRD. This study provides new insights about vitamin E status in ABL and CMRD and suggests the potential of different formulations as treatment options.	0
Epithelial-myoepithelial carcinoma (EMC) is a rare subtype of salivary gland neoplasms. Since the initial description of the cancer, just over 300 cases have been reported. EMCs occupy a biphasic cellular differentiation-state defined by the constitution of two cell types representing epithelial and myoepithelial lineages, yet the functional consequence of the differentiation-state heterogeneity with respect to therapy resistance of the tumors remains unclear. The reported local recurrence rate of the cases is approximately 30%, and while distant metastases are rare, a significant fraction of these cases are reported to receive no survival benefit from radio- or chemotherapy given in addition to surgery. Moreover, no targeted therapies have been reported for these neoplasms. We report here the first use and application of ex vivo drug screening together with next generation sequencing to assess targeted treatment strategies for a rare metastatic epithelial-myoepithelial carcinoma. Results of the ex vivo drug screen demonstrate significant differential therapeutic sensitivity between the epithelial and myoepithelial intra-tumor cell lineages suggesting that differentiation-state heterogeneity within epithelial-myoepithelial carcinomas may present an outlet to partial therapeutic responses to targeted therapies including MEK and mTOR inhibitors. These results suggest that the intra-tumor lineage composition of EMC could be an important factor to be assessed when novel treatments are being evaluated for management of metastatic EMC.	0
BACKGROUND:There is an ongoing debate about the concept of restricted phenotypes of amyotrophic lateral sclerosis (ALS), including progressive bulbar palsy (PBP). OBJECTIVE:The study was designed to investigate specific white matter alterations in diffusion tensor imaging (DTI) data from PBP patients using a hypothesis-guided tract-of-interest-based approach (compared with 'classical' ALS patients and controls) to identify in vivo microstructural changes according to the neuropathologically defined ALS-related corticoefferent tract pathology. METHODS:DTI-based white matter mapping was performed both by an unbiased voxel-wise statistical comparison and by a hypothesis-guided tract-wise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern for 23 PBP and 23 ALS patients vs 23 matched controls. RESULTS:The analysis of white matter integrity demonstrated regional FA reductions along the CST and also in frontal and prefrontal brain areas both in PBP patients and ALS patients with additional regional FA reduction in the pons of the PBP group. In the tract-specific analysis according to the neuropathological ALS-staging pattern, PBP and ALS patients showed identical significant alterations of ALS-related tract systems when compared with controls. CONCLUSIONS:The DTI study including the tract-of-interest-based analysis showed the same microstructural corticoefferent involvement patterns in PBP patients as in ALS, which supports the hypothesis that PBP is a phenotypical variant of ALS.	0
This study was conducted to identify the genetic basis of retinal dystrophies in consanguineous Pakistani families. We recruited two families with retinitis pigmentosa (RP) displaying visual difficulties, including nyctalopia and constricted visual fields. Linkage analysis and Sanger sequencing resulted in the identification of a previously reported nonsense mutation, c.847C > T, in exon 5 of CERKL in one family and a novel four-base pair deletion in exon 4 of RP1, c.delAGAA4218_4221, leading to premature protein termination in the second family. Here, we report two RP-causing mutations extending the genetic heterogeneity of the disease.	0
We report a family affected with Witkop tooth and nail syndrome. This is a rare syndrome among the ectodermal dysplasias in which there are abnormalities of teeth, nails, and hair with normal sweat gland function.	0
Gain of function variants in SAMD9 cause MIRAGE syndrome, a rare Mendelian disorder that results in myeloid dysplastic syndrome (MDS), poor immune response, restricted growth, adrenal insufficiency, ambiguous genitalia, feeding difficulties and most often significantly reduced lifespan. In this study, we describe histomorphologic and genetic changes occurring in serial bone marrow measurements in a patient with MIRAGE syndrome and untreated MDS of 9 years. Histomorphological analysis during childhood showed progressive hypocellularity with erythroid and megakaryocytic dysplasia and cytogenetic testing demonstrated monosomy 7. Serial leukemia gene panel testing performed over a seven year period revealed multiple pre-leukemic clones arising at age 7 years followed by sequential mutational events in ETV6 and RUNX1 driving acute myeloid leukemia (AML) at age 9. Comprehensive genotype-phenotype analysis with 28 previously reported patients found the presence of MDS did not impact overall survival, but in silico variant pathogenicity prediction scores for SAMD9 distinguished patients with poor prognosis. Overall, our analysis shows progression of MDS to AML can be monitored by following mutation evolution in leukemia related genes in patients with MIRAGE syndrome, and specific SAMD9 mutations likely influence disease severity and overall survival.	0
An infant with congenital bilateral ophthalmoplegia with levator and pupillary sparing is presented. The eyes are fixed in a divergent position with no apparent motility. The baby is otherwise clinically normal and is developing in a normal fashion except for delayed growth pattern. Visual attention is present and he fixates with either eye. Computed tomography demonstrates an associated dysplasia of the corpus callosum and an abnormal ventricular system. Neuroendocrine studies performed at one year of age demonstrate subnormal levels of growth hormone. It is postulated that this represents an embryodysgenesis involving the developing mesencephalic tegmentum (oculomotor nuclei) and the diencephalic lamina reuniens (corpus callosum). It is the first reported case of congenital ophthalmoplegia with corpus callosum dysplasia. The "embryodysgenic" relationship with other forebrain-ocular anomalies has been alluded to and remains speculative.	0
A 43-year-old man was referred by his general practitioner to the hepatology clinic with deranged serum aminotransferases, discovered as part of routine blood tests. The objective was to identify the cause of elevated serum aminotransferases in this patient in a systematic manner. Thorough history and physical examination revealed a background history of rippling muscle disease secondary to caveolin-3 protein deficiency, with typical clinical signs. There was a positive family history of musculoskeletal disease in the patient's father and brother. Previous diagnostic tests performed to investigate the patient's musculoskeletal symptoms, including muscle biopsies, were revisited. Subsequent systematic investigations such as blood tests, liver ultrasound scan and Fibroscan(®) were performed to exclude potential causes of the deranged serum aminotransferases. Liver biopsy was not performed. A consistent pattern of chronic low-grade elevations of serum aminotransferases, less than three times the upper limit of the normal range, was found. This was associated with a consistently elevated serum creatine kinase and normal renal function tests. Previous muscle biopsies had revealed chronic degenerative and regenerative changes suggestive of a focal necrotizing myopathy. Liver ultrasound scan and Fibroscan(®) were normal. With exclusion of other liver diseases and identification of profoundly elevated serum creatine kinase concentration, the deranged aminotransferases were attributed to rippling muscle disease.	0
Rosacea, a frequent chronic inflammatory disease of the adnexal structures, is associated with an increased number of demodex mites. In patients with immunosuppression, it can present in fulminant progressions like granulomatous rosacea. In this specific subgroup of patients, treatment is not only complicated by aggressive occurrences, but is also limited by possible drug interactions with immunosuppressive drugs. We present a case of a 66-year-old lung transplant recipient, who was successfully treated with oral metronidazole and ivermectin cream.	0
This chapter offers a perspective on the origin, operational definition, historic vicissitudes, and current status of Gerstmann syndrome. The main issues and controversy accompanying Gerstmann syndrome throughout the years are reviewed. The clinical picture of Gerstmann syndrome as it emerges from a series of modern-day pure cases is described. In current clinical practice, a diagnosis of Gerstmann syndrome indicates the concomitant presence of four acquired symptoms: finger agnosia, acalculia, left-right disorientation, and agraphia. Finally, based on empiric work conducted in recent years, the chapter concludes with a new interpretation of Gerstmann syndrome. If seen as an instance of intraparietal disconnection, this classic parietal syndrome will acquire fresh clinical and theoretic significance.	0
BACKGROUND:Classic galactosemia (OMIM# 230400) is an autosomal recessive disorder due to galactose-1-phosphate uridyltransferase deficiency. Newborn screening and prompt treatment with a galactose-free diet prevent the severe consequences of galactosemia, but clinical outcomes remain suboptimal. METHODS:Five men and 5 women with classic galactosemia (mean age = 27.2 ± 5.47 years) received comprehensive neurological and neuropsychological evaluations, electroencephalogram (EEG) and magnetic resonance imaging (MRI). MRI data from nine healthy controls (mean age = 30.22 ± 3.52 years) were used for comparison measures. RESULTS:Galactosemia subjects experienced impaired memory, language processing, visual-motor skills, and increased anxiety. Neurological examinations revealed tremor and dysarthria in 6 subjects. In addition, there was ataxia in 3 subjects and 6 subjects had abnormal gait. Mean full scale IQ was 80.4 ± 17.3. EEG evaluations revealed right- sided abnormalities in 5 subjects and bilateral abnormalities in 1 subject. Compared to age- and gender-matched controls, subjects with galactosemia had reduced volume in left cerebellum white matter, bilateral putamen, and left superior temporal sulcus. Galactosemia patients also had lower Fractional Anisotropy (FA) and higher radial diffusivity (RD) values in the dorsal and ventral language networks compared to the controls. Furthermore, there were significant correlations between neuropsychological test results and the T1 volume and diffusivity scalars. CONCLUSIONS:Our findings help to identify anatomic correlates to motor control, learning and memory, and language in subjects with galactosemia. The results from this preliminary assessment may provide insights into the pathophysiology of this inborn error of metabolism. TAKE-HOME MESSAGE:Subjects with galactosemia, even treated within the first week of life, may exhibit neurologic problems in adulthood with structural changes in the brain that we have identified by MRI imaging and tractography. This article is protected by copyright. All rights reserved.	0
BACKGROUND:Scalp metastases from anaplastic oligodendroglioma (AO) are extremely rare and mostly involve intracranial recurrence or widely metastatic disease. Here we describe an exceptional case of histopathologically proven scalp metastasis of AO 6 years after surgical resection and postoperative adjuvant radiation. CASE DESCRIPTION:A 42-year-old woman presented with several months of progressive headache and dizziness. Preoperative magnetic resonance imaging (MRI) showed an irregular enhancing lesion in the left frontal lobe extending to the ependymal surface. Left frontal craniotomy was performed through a coronal approach, and gross total resection was achieved. Pathologic examination confirmed a World Health Organization grade III AO. The patient subsequently received 60 Gy of external beam radiotherapy in 30 fractions over 6 weeks. During 8 years of follow-up, the patient remained symptom free, and no evidence of intracranial recurrence was found. However, 6 years after intracranial tumor resection, the patient noticed a subcutaneous mass in her right frontal scalp, which was the site contralateral to her craniotomy. MRI revealed a homogeneously marked enhancing nodular lesion in the subcutaneous tissue of the right frontal scalp without intracranial recurrence. Gross total resection was performed, and the pathologic findings, which identified the mass as an AO, were consistent with those of the primary left frontal tumor. CONCLUSIONS:This study presents a rare case of long-term AO scalp metastasis without intracranial recurrence. Intraoperative seeding and longer survival for oligodendroglial tumors may cause this rare entity. Optimal surgical strategies and standard operative procedures can promote the prevention of iatrogenic seeding.	0
Pelizaeus-Merzbacher disease (PMD) is an X-linked leukodystrophy caused by mutations in Proteolipid Protein 1 (PLP1), encoding a major myelin protein, resulting in profound developmental delay and early lethality. Previous work showed involvement of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways, but poor PLP1 genotype-phenotype associations suggest additional pathogenetic mechanisms. Using induced pluripotent stem cell (iPSC) and gene-correction, we show that patient-derived oligodendrocytes can develop to the pre-myelinating stage, but subsequently undergo cell death. Mutant oligodendrocytes demonstrated key hallmarks of ferroptosis including lipid peroxidation, abnormal iron metabolism, and hypersensitivity to free iron. Iron chelation rescued mutant oligodendrocyte apoptosis, survival, and differentiationin vitro, and post-transplantation in vivo. Finally, systemic treatment of Plp1 mutant Jimpy mice with deferiprone, a small molecule iron chelator, reduced oligodendrocyte apoptosis and enabled myelin formation. Thus, oligodendrocyte iron-induced cell death and myelination is rescued by iron chelation in PMD pre-clinical models.	0
OBJECTIVE:Analyze a large sample with detailed clinical data of misophonia subjects in order to determine the psychiatric, somatic and psychological nature of the condition. METHODS:This observational study of 779 subjects with suspected misophonia was conducted from January 2013 to May 2017 at the outpatient-clinic of the Amsterdam University Medical Centers, location AMC, the Netherlands. We examined DSM-IV diagnoses, results of somatic examination (general screening and hearing tests), and 17 psychological questionnaires (e.g., SCL-90-R, WHOQoL). RESULTS:The diagnosis of misophonia was confirmed in 575 of 779 referred subjects (74%). In the sample of misophonia subjects (mean age, 34.17 [SD = 12.22] years; 399 women [69%]), 148 (26%) subjects had comorbid traits of obsessive-compulsive personality disorder, 58 (10%) mood disorders, 31 (5%) attention-deficit (hyperactivity) disorder, and 14 (3%) autism spectrum conditions. Two percent reported tinnitus and 1% hyperacusis. In a random subgroup of 109 subjects we performed audiometry, and found unilateral hearing loss in 3 of them (3%). Clinical neurological examination and additional blood test showed no abnormalities. Psychological tests revealed perfectionism (97% CPQ>25) and neuroticism (stanine 7 NEO-PI-R). Quality of life was heavily impaired and associated with misophonia severity (rs (184) = -.34 p = < .001, p = < .001). LIMITATIONS:This was a single site study, leading to possible selection-and confirmation bias, since AMC-criteria were used. CONCLUSIONS:This study with 575 subjects is the largest misophonia sample ever described. Based on these results we propose a set of revised criteria useful to diagnose misophonia as a psychiatric disorder.	0
Wilson disease (WD) is a rare, recessively inherited disorder of copper metabolism mainly affecting liver and brain. In childhood, it is known to have a predominant hepatic phenotype. It is likely that the low awareness for WD-associated neuropsychiatric signs and symptoms in this age group means that neurological Wilson's disease is underdiagnosed in children and young people. Practitioners should be alert for this complication in children with or without liver disease. Management of children with WD requires a dedicated multidisciplinary approach involving hepatologists, geneticists, neurologists and psychiatrists to ensure subtle neuropsychiatric symptoms are identified early and addressed appropriately. This review highlights recent advances in hepatic and neuropsychiatric symptoms of WD in childhood, specific diagnostic tools and pitfalls and summarises existing and potential future treatment options.	0
We present the case of a patient who was operated for cerulean cataract one year ago and who developed light-blue posterior capsule opacifications similar to that of the initial cataract. This case suggests that the mechanism of the light-blue color formation in the cerulean cataract was also present in the lens epithelial cells, forming the posterior capsule opacity.	0
Disorders of mitochondrial oxidative phosphorylation (OXPHOS) are renowned for their variability in clinical features and genetic causes. This makes it difficult to determine their true prevalence, but recent studies have documented a minimum birth prevalence of 13.1/100000 or 1/7634 for oxidative phosphorylation disorders with onset at any age. This clearly remains an underestimate but it indicates that oxidative phosphorylation disorders can be regarded as the most common group of inborn errors of metabolism. Pathogenic mutations causing human oxidative phosphorylation disorders have now been identified in more than 30 of the 37 mitochondrial DNA genes and in more than 30 nuclear genes. Most of the nuclear gene defects cause autosomal recessive diseases, but autosomal dominant and X-linked disorders also occur. It is likely that at least another 30, and perhaps over 100, nuclear-encoded oxidative phosphorylation disorders await identification. Oxidative phosphorylation genetics are complex and there appear to be a number of common misconceptions about mitochondrial DNA mutations that may impede optimal investigation and management of patients. In our experience, mitochondrial DNA mutations are not a negligible cause of OXPHOS disorders in children but account for 20-25% of cases. Similarly, a family history suggesting maternal inheritance is the exception rather than the norm for children with mitochondrial DNA mutations, many of whom have de novo mutations. Only some mitochondrial DNA mutations disappear from cultured cells, so deficient enzyme activity in fibroblasts does not imply the presence of a nuclear defect. Finally, it is still widely thought that there are very few reproductive options that can be offered to women at risk of transmitting a mitochondrial DNA mutation. While a cautious approach is needed, there is now a consensus that prenatal diagnosis should be offered to some women, particularly those at lower recurrence risk. Preimplantation genetic diagnosis can also be an option.	1
We report on 3 members of a Spanish family with partial aphalangia, syndactyly with duplication of metatarsal IV, microcephaly, dull intelligence, and short stature. The MCA pattern observed in this family appears to constitute a previously undescribed syndrome.	0
BACKGROUND:Rare bone diseases account for 5% of all birth defects yet very few have personalised treatments. Developments in genetic diagnosis, molecular techniques and treatment technologies however, are leading to unparalleled therapeutic advance. This review explores the evolving therapeutic landscape of genetic skeletal disorders (GSDs); the key conditions and there key differentials. METHODS:A retrospective literature based review was conducted in December 2018 using a systematic search strategy for relevant articles and trials in Pubmed and clinicaltrials.gov respectively. Over 140 articles and 80 trials were generated for review. RESULTS:Over 20 personalised therapies are discussed in addition to several novel disease modifying treatments in over 25 GSDs. Treatments discussed are at different stages from preclinical studies to clinical trials and approved drugs, including; Burosumab for X-linked hypophosphatemia, Palovarotene for Hereditary Multiple Exostoses, Carbamazepine for Metaphyseal Chondrodysplasia (Schmid type), Lithium carbonate and anti-sclerostin therapy for Osteoporosis Pseudoglioma syndrome and novel therapies for Osteopetrosis. We also discuss therapeutic advances in Achondroplasia, Osteogenesis Imperfecta (OI), Hypophosphotasia (HPP), Fibrodysplasia Ossificans Progressiva, and RNA silencing therapies in preclinical studies for OI and HPP. DISCUSSION:It is an exciting time for GSD therapies despite the challenges of drug development in rare diseases. In discussing emerging therapies, we explore novel approaches to drug development from drug repurposing to in-utero stem cell transplants. We highlight the improved understanding of bone pathophysiology, genetic pathways and challenges of developing gene therapies for GSDs.	0
BACKGROUND:Mycobacterial species other than Mycobacterium tuberculosis and Mycobacterium leprae are generally free-living organisms and Mycobacterium simiae is one of the slowest growing Non-tuberculous mycobacteria. This is the first case report of Mycobacterium simiae infection in Sri Lanka and only very few cases with extrapulmonary manifestation reported in the literature. CASE PRESENTATION:A 24-year-old, previously healthy Sri Lankan male presented with generalized lymphadenopathy with discharging sinuses, evening pyrexia, weight loss, poor appetite and splenomegaly. Lymph node biopsies showed sheets of macrophages packed with organisms in the absence of granulomata. Ziehl Neelsen, Wade Fite and Giemsa stains revealed numerous red coloured acid-fast bacilli within foamy histiocytes. Slit skin smear for leprosy was negative and tuberculosis, fungal and bacterial cultures of the lymph node and bone marrow did not reveal any growth. Later he developed watery diarrhea and colonoscopy revealed multiple small polyps and ulcers throughout the colon extending up to the ileum, Which was confirmed to be due to cytomegalovirus confirmed by PCR and successfully treated with ganciclovir. Positron emission tomography scan guided biopsies of the gut and lymph nodes confirmed presence of mycobacterial spindle cell pseudo-tumours and PCR assays revealed positive HSP65. The culture grew Mycobacterium Simiae. Flow cytometry analysis on patient's blood showed extremely low T and B cell counts and immunofixation revealed low immunoglobulin levels. His condition was later diagnosed as adult onset immunodeficiency due to anti- interferon - gamma autoantibodies. He was initially commenced on empirical anti-TB treatment with atypical mycobacterial coverage. He is currently on a combination of daily clarithromycin, ciprofloxacin, linezolid with monthly 2 g/kg/intravenous immunoglobulin to which, he had a remarkable clinical response with complete resolution of lymphadenopathy and healing of sinuses. CONCLUSIONS:This infection is considered to be restricted to certain geographic areas such as mainly Iran, Cuba, Israel and Arizona and this is the first case report from Sri lanka. Even though the infection is mostly seen in the elderly patients, our patient was only 24 years old. In the literature pulmonary involvement was common presentation, but in this case the patient had generalized lymphadenopathy and colonic involvement without pulmonary involvement.	0
The nose is central in the determination of facial esthetics. The variations in its structural characteristics greatly influence the ultimate dentoskeletal positioning at the end of an orthodontic therapy. A careful insight into its developmental etiology will greatly aid the health care professional in identifying patient's real concern about the facial appearance. This in turn will aid in the fabrication of a better treatment plan regarding the end placement goals for the teeth and jaws in all the three dimensions of space. However, this important structure is often missed as a part of the diagnostic and treatment planning regime owing to the lack of meticulous understanding of its developmental etiology by the orthodontists. The development of the nose in the embryo occurs in pre skeletal and skeletal phases by a well-coordinated and regulated interaction of multiple signaling cascades with the crucial importance of each factor in the entire mechanism. The five key factors, which control frontonasal development are sonic hedgehog (SHH), fibroblast growth factors (FGF), transforming growth factor β (TGFβ), wingless (WNT) proteins, and bone morphogenetic protein (BMP). The recent evidence suggests the association of various nasal dimensions and their related syndromes with multiple genes. The revelation of nasal genetic makeup in totality will aid in ascertaining the direction of growth, which will govern our orthodontic treatment results and will also act as a harbinger for potential genetic editing and tissue engineering. This article describes at length the morphological and genetic aspect of nasal growth and development in light of the gender and racial variability along with the emphasis on the importance of knowing these nasal features with regard to diagnosis and treatment planning in orthodontics.	0
Osteoporosis represent one of main characteristics of Turner syndrome (TS), a rare diseases caused by aberrant deletion of X chromosomes, however, the underlying pathological mechanism remains unknown yet. In this study, we used pluripotent stem cells (iPSCs) derived from a Turner syndrome patient and a health control to induce functional osteoblasts and osteoclasts, in order to compare their difference in these two differentiation. We successfully produced functional osteoblasts and osteoclasts from iPSCs through embryoid bodies (EBs) and mesoderm stages, as demonstrated obvious mineralized nodules and multi-nuclear giant cells with positive tartrate-resistant acid phosphatase (TRAP) staining, and significant up-regulated differentiation marker genes. Interestingly, we found that there was no significant difference in phenotype and marker genes expression between osteoblasts from Turner syndrome and healthy control iPSCs. In contrast, Turner syndrome showed increased osteoclastogenesis compared to the healthy control indicating higher frequency of multi-nuclear TRAP staining cells and elevated osteoclast marker genes TRAP, MMP9, CA2, OSCAR. Therefore, our results suggest that the low bone density of Turner syndrome patients may be caused by aberrant osteoclast differentiation, and further investigation towards osteoclast function under Turner syndrome is deserved.	0
The 2016 revised 4th edition of the World Health Organization classification of hematopoietic neoplasms updated the diagnostic criteria for chronic myelomonocytic leukemia (CMML). Persistent peripheral blood monocytosis of at least 1 × 109 /L and a percentage of monocytes ≥10% of the circulating white blood cell count (WBC) are both prerequisite criteria for this diagnosis. CMML represents the prototype of "overlapping" myeloid neoplasms with concurrent myeloproliferative and myelodysplastic features. However, clinical presentation is heterogeneous, with cases showing prevailing "dysplastic" features and others a predominant "proliferative" phenotype. Accounting for this diversity, two variants of CMML are recognized: "dysplastic" CMML defined by WBC < 13 × 109 /L and "proliferative" CMML with WBC ≥ 13 × 109 /L often showing features mimicking a myeloproliferative neoplasm. Although not an official WHO category, the "oligomonocytic" variant of CMML is defined by relative monocytosis with an absolute monocyte count of 0.5-0.9 × 109 /L. It can be considered a "pre-phase," as it frequently anticipates the development of an overt, classic CMML. In an attempt at improving disease prognostication, the blast count based grading system for CMML of the WHO 2008 Classification has been expanded in 2016 to include a new "CMML-0" category. Lastly, the large body of knowledge on the molecular events occurring in CMML has been used to assist diagnosis and assess prognosis. Despite the step forwards, diagnosis of CMML still remains one of exclusion as no clinical, pathologic or molecular findings are specific for this disease. The current review brings insight into the spectrum of CMML and provides practical advice to approach suspected cases of CMML.	0
Congenital bifid tongue is a rare malformation, which is usually present in association with other oral findings such as cleft palate and tongue mass. The authors present a rare case of congenital bifid tongue together with cleft palate, labial-buccal frenulum deformity, absence of lingual frenulum, and 3 hamartomas in the oral cavity. The authors excised oral hamartomas and repaired the palate and tongue with satisfactory results.	0
BACKGROUND:Renal hypouricemia (RHUC) is a genetic disorder caused by mutations in the SLC22A12 gene, which encodes the major uric acid (UA) transporter, URAT1. The clinical course of related, living donor-derived RHUC in patients undergoing kidney transplantation is poorly understood. Here, we report a case of kidney transplantation from a living relative who had an SLC22A12 mutation. After the transplantation, the recipient's fractional excretion of UA (FEUA) decreased, and chimeric tubular epithelium was observed. CASE PRESENTATION:A 40-year-old man underwent kidney transplantation. His sister was the kidney donor. Three weeks after the transplantation, he had low serum-UA, 148.7 μmol/L, and elevated FEUA, 20.8% (normal: < 10%). The patient's sister had low serum-UA (101.1 μmol/L) and high FEUA (15.8%) before transplant. Suspecting RHUC, we performed next-generation sequencing on a gene panel containing RHUC-associated genes. A heterozygous missense mutation in the SLC22A12 gene was detected in the donor, but not in the recipient. The recipient's serum-UA level increased from 148.7 μmol/L to 231.9 μmol/L 3 months after transplantation and was 226.0 μmol/L 1 year after transplantation. His FEUA decreased from 20.8 to 11.7% 3 months after transplantation and was 12.4% 1 year after transplantation. Fluorescence in situ hybridization of allograft biopsies performed 3 months and 1 year after transplantation showed the presence of Y chromosomes in the tubular epithelial cells, suggesting the recipient's elevated serum-UA levels were owing to a chimeric tubular epithelium. CONCLUSIONS:We reported on a kidney transplant recipient that developed RHUC owing to his donor possessing a heterozygous mutation in the SLC22A12 (URAT1) gene. Despite this mutation, the clinical course was not problematic. Thus, the presence of donor-recipient chimerism in the tubular epithelium might positively affect the clinical course, at least in the short-term.	0
Gestational diabetes insipidus (GDI) is a rare, self-limited complication of pregnancy. As it is related to excess placental vasopressinase enzyme activity, which is metabolized in the liver, GDI is more common in pregnancies complicated by conditions associated with liver dysfunction. We present a case of a 41-year-old woman at 38 weeks' gestation who presented with pre-eclampsia with severe features, including impaired liver function and renal insufficiency. Following cesarean section she was diagnosed with GDI, which was further complicated by cerebral vasoconstriction as demonstrated by magnetic resonance angiography. This case raises the possibility that cerebral vasoconstriction may be related to the cause of GDI. A high index of suspicion of GDI should be maintained in patients who present with typical signs and symptoms, especially in the setting of pregnancy complications associated with liver dysfunction.	0
The antisynthetase syndrome (ASS) is clinically characterized by fever, myositis, interstitial lung disease, joint involvement, mechanic's hands, or Raynaud's phenomenon, and the presence of antisynthetase autoantibodies. These clinical manifestations may not occur simultaneously. Therefore, the aim of this study was to analyze the sequence in which these clinical manifestations can develop at the onset of ASS. This retrospective, single-center cohort study enrolled 55 ASS patients. Their mean age at the onset of ASS symptoms was 42.3±11.8 years. There was a predominance of female patients (75.9%) and white patients (72.7%). At initial presentation, 41.8% of the patients had fever, 43.6% had joint symptoms, 38.2% had myositis, 36.4% had interstitial lung disease, 18.2% had Raynaud's phenomenon, and 16.4% had mechanic's hands. Subsequent clinical symptoms emerged at varying time points. In two out of 55 cases, joint, muscle, and lung manifestations developed simultaneously. The median time between the onset of symptoms and the complete ASS clinical manifestation was 19.9 (4.0-60.2) months; whereas, the timeframe between the onset of symptoms and the ASS diagnosis was 29.0 (11.0-63.0) months. The confounding misdiagnoses interfering with the initial diagnosis were polymyositis (52.7%), dermatomyositis (29.1%), nonspecific interstitial pneumopathy (23.6%), rheumatoid arthritis (18.2%), and others (10.9%). Clinical features at the onset of ASS are highly variable. Consequently, confounding factors can lead to significant delays for the final and definitive diagnosis of ASS. Therefore, ASS should be considered a differential diagnosis in patients with initial symptoms of joint, lung, and/or muscle involvements, as well as fever, mechanic's hands, and/or Raynaud's phenomenon manifestations.	0
Splenectomy for the treatment of hypersplenism in patients with cirrhosis (HIC) is related with complications. Laparoscopic splenic artery ligation (LSAL) may be an alternative treatment option.To evaluate safety and feasibility of LSAL in the treatment of HIC.Retrospective analysis of prospectively collected data of ten patients with HIC who were treated with LSAL from October 2012 to February 2015.The median (range) age was 33.2 (13-56) years and sex distribution was equal. The median (range) leukocyte counts (×10(9)/L) before, and at 3, 6 and 12 months after LSAL were 2.2 (0.8-8.2) and 5.65 (2.78-10.7), 4.7 (2.8-7.8) and 4.95 (3.4-7.7) respectively. The median (range) platelet counts (×10(9)/L) before and at 3, 6 and 12 months after LSAL were 25.5 (11-65) and 75 (39-289), 74 (32-184) and 76 (56-251) respectively. Following LSAL, there was a significant improvement in total leucocyte count, platelet count and Model for End-Stage Liver Disease (MELD) score (P < 0.05). Two patients (20%) developed intraoperative bleeding and required conversion; one of these two patients developed splenic cyst that required radiological intervention. Four patients (40%) had post ligation syndrome (PLS) that was managed conservatively. During a median (range) follow-up of 19.5 (5-29) months, one patient (10%) required splenectomy due to inadequate response.LSAL is a safe and feasible treatment option for the palliation of symptomatic HIC, however, further prospective trials are necessary for confirmation.	0
F syndrome (acropectorovertebral syndrome) is a dominantly inherited skeletal dysplasia affecting the hands, feet, sternum, and lumbosacral spine, which has previously been described in only two families. Here we report a six generation Turkish family with a related but distinct dominantly inherited acropectoral syndrome. All 22 affected subjects have soft tissue syndactyly of all fingers and all toes and 14 also have preaxial polydactyly of the hands and/or feet. In addition, 14 have a prominent upper sternum and/or a blind ending, inverted U shaped sinus in the anterior chest wall. Linkage studies and haplotype analysis carried out in 16 affected and nine unaffected members of this family showed that the underlying locus maps to a 6.4 cM interval on chromosome 7q36, between EN2 and D7S2423, a region to which a locus for preaxial polydactyly and triphalangeal thumb-polysyndactyly has previously been mapped. Our findings expand the range of phenotypes associated with this locus to include total soft tissue syndactyly and sternal deformity, and suggest that F syndrome may be another manifestation of the same genetic entity. In mice, ectopic expression of the gene Sonic hedgehog (Shh) in limb buds and lateral plate mesoderm during development causes preaxial polydactyly and sternal defects respectively, suggesting that misregulation of SHH may underlie the unusual combination of abnormalities in this family. A recently proposed candidate gene for 7q36 linked preaxial polydactyly is LMBR1, encoding a novel transmembrane receptor which may be an upstream regulator of SHH.	0
Cerebral tumor embolism is a rare cause of acute ischemic stroke, and extracardiac carcinoma is an extremely rare cause. A 34-year-old man who had been diagnosed with lung cancer developed right hemiparesis and aphasia, with the National Institutes of Health Stroke Scale (NIHSS) score of 17. Magnetic resonance imaging (MRI) showed early ischemic change in the insular cortex and frontotemporal lobe and left internal carotid artery (ICA) terminal occlusion was confirmed by magnetic resonance angiogram (MRA). Mechanical thrombectomy (MT) with contact aspiration by a Penumbra ACE 68, followed by combined technique with a stent retriever was performed, and a soft, fragile embolus was retrieved. Finally, good recanalization was achieved (Thrombolysis in Cerebral Infarction [TICI] scale 2b), and on the next day, the right hemiparesis and aphasia were improved. However, the patient's general condition gradually worsened, and 43 days after thrombectomy, he died from respiratory failure. The retrieved embolus was examined pathologically and diagnosed as mucoepidermoid carcinoma of the same type as his lung cancer. Chest computed tomography (CT) showed that tumor invaded the right pulmonary vein and left atrium; these findings suggested that a piece of the tumor in the left atrium flowed into the left ICA and caused the acute ischemic stroke.	0
BACKGROUND:The metabolic behavior of plasmacytoma at 18F-FDG PET/CT is not yet clear. OBJECTIVE:The aim of this systematic review was to analyze published data about the role of 18F-FDG PET or PET/CT in patients affected by plasmacytoma. METHODS:Acomprehensive computer literature search of the Scopus, PubMed/MEDLINE, Embase and Cochrane Library databases was conducted including articles up to July 2019 to find relevant published papers about the performance of 18F-FDG PET and PET/CT in plasmacytoma. RESULTS:The comprehensive computer literature search revealed 371 articles. On reviewing the titles and abstracts, 363 articles were excluded because the reported data were not within the field of interest of this review. Eight articles were selected and retrieved in full-text version. From the analyses of the selected studies, the following main findings have been founded: 1) plasmacytoma generally is a 18F-FDG-avid tumor and PET/CT had good diagnostic performance with high sensitivity; 2) 18F-FDG PET/CT influenced patient management in most cases avoiding useless therapies and choosing the best therapeutic approach; 3) prognostic value of PET/CT qualitative and semiquantitative parameters is only suggested with controversial reports. CONCLUSION:Despite several limitations affect this analysis, especially related to the low number of articles and patients studied, plasmacytoma looks to be an 18F-FDG-avid tumor in most of the cases; 18F-FDG PET or PET/CT had good diagnostic performance and had a significant clinical impact in change of therapeutic approach. Moreover, a possible prognostic role of PET/CT features is described.	0
Autosomal recessive epidermolytic ichthyosis is a rare skin condition associated with KRT10 loss-of-function mutations. It presents with severe life-threatening clinical manifestations. Here we describe a case of autosomal recessive epidermolytic ichthyosis with an unusually mild, spontaneously improving phenotype. Erythroderma and superficial blistering were present at birth, but the skin recovered and remained almost intact at the age of 1 year. Mild scaling on the neck and skin fragility manifesting as superficial erosions after scratching were the only clinical features as the child grew. As a cause, previously unreported compound heterozygous KRT10 pathogenic variants were found: a nonsense mutation leads to mRNA decay, while the other synonymous variant induces a leaky splice site, explaining the residual keratin 10 expression and mild clinical phenotype. What's already known about this topic? Autosomal recessive epidermolytic ichthyosis is a rare skin condition caused by loss-of-function KRT10 mutations. The clinical phenotype is severe with superficial skin blistering, scaling and hyperkeratosis. What does this study add? Here we extend the mutational and phenotypic spectrum of autosomal recessive epidermolytic ichthyosis. Our case presented with erythroderma and superficial blistering at birth, but the skin recovered and was almost intact at the age of 1 year. The only disease manifestations were mild scaling on the neck and skin fragility appearing as superficial erosions after scratching. The causative factors were found to be one nonsense mutation in KRT10 that leads to mRNA decay, and one synonymous variant that affects the donor splice site of exon 3. We hypothesize that this leaky splice site explains the residual keratin 10 expression and self-improving clinical phenotype.	0
Leprosy is a chronic infectious disease with a wide range of clinical manifestations. The early diagnosis of leprosy is a worldwide challenge. We present a case of leprosy with unusual severe pruritus and generalized excoriated papules and nodules.	0
Caudal duplication syndrome is an exceedingly rare condition that manifests as duplicative anomalies of the gastrointestinal and genitourinary systems. We present a case of an adult patient born with multiple congenital anomalies including duplicated reproductive and urinary systems. She presented to our center for initial evaluation 11 years ago largely experiencing right-sided pelvic organ prolapse and bilateral urinary tract voiding dysfunction. She underwent successful surgical management and presented several years later for recurrent symptoms. We describe her presentation and our surgical experience, including complications and outcomes, for this case. We also review caudal duplication syndrome-its etiology, clinical presentation, diagnostic workup, surgical intervention (if any), and recommendations.	0
Neurophysiological and radiological studies provide accumulating evidence for the involvement of the brainstem in the pathogenesis of restless legs syndrome (RLS). The analysis of the various subregions of the brainstem may help us better understand the pathophysiological mechanisms underlying the disorder. In this study, we investigated the structural and functional changes in the various subregions of the brainstem in RLS patients. The subregional changes in gray matter density and functional connectivity in the brainstem were analyzed in 20 drug-naive idiopathic RLS patients, as well as 18 normal control (NC) subjects for comparison. Correlation analyses and multivariate pattern analyses using linear support vector machine (SVM) were conducted. We found significantly increased gray matter density in two clusters in the pons (designated pons_1 and pons_2) and in one cluster in the midbrain in RLS patients compared with NC subjects. Further functional connectivity analyses revealed significantly decreased functional connectivity between the midbrain and the right middle occipital gyrus, between pons_1 and the right orbital part of the superior frontal gyrus, and between pons_2 and the right parahippocampus in RLS compared with NC. Moreover, the functional connectivity between pons_2 and the right supplementary motor area (SMA) was significantly increased in RLS compared with NC. This change in RLS was marginally correlated with RS_RLS scores in the RLS patients. SVM-based classification showed an AUC of 0.955 using gray matter density of pons_2, and functional connectivity between pons_2 and SMA as features. Collectively, our findings suggest that changes in gray matter density and functional connectivity in the pons may play a pathologic role in RLS. Furthermore, these abnormal changes in the pons might help to discriminate RLS from healthy subjects.	0
AIM:To examine the usefulness of the neutrophil : lymphocyte (N/L) ratio as a cost-effective and simple diagnostic marker of mature cystic teratoma (MCT) with malignant transformation (MT). METHODS:A retrospective chart review was performed between 1998 and 2013 of 12 MCT patients with MT and between 2009 and 2013 of 130 patients with benign MCT. Data were collected on age, tumor size, white blood cell count with differential counts, tumor marker levels, and presenting features. RESULTS:Older age, greater tumor size, higher CA19-9 or CA125, higher neutrophil count, and higher N/L ratio were associated with MT on univariate analysis. White blood cell count; lymphocyte count; and the tumor marker squamous cell carcinoma antigen were not associated with MT. Older age (≥median), larger tumor size (≥10 cm), and high N/L ratio (≥5.0) were predictors of MT (hazard ratio, 11.51, 5.87, and 11.11, respectively). Six of 12 patients were diagnosed with MT on preoperative magnetic resonance imaging and five of 12 had an N/L ratio ≥5.0. CONCLUSIONS:Neutrophil : lymphocyte ratio is a potential preoperative diagnostic marker of MT. The optimal cut-off should be determined in future large-scale studies.	0
Glassy cell carcinoma of the cervix (GCCC) is a very rare and aggressive form of cervical cancer. An adolescent female with advanced metastatic disease was enrolled in our genomic profiling research protocol. We identified high-level amplification of epidermal growth factor receptor (EGFR) and Yes-associated protein-1 (YAP1), which led to the addition of EGFR inhibitors to the chemotherapy regimen. Here, we report the first genetically profiled case of GCCC with potential therapeutic implications.	0
Late-onset Brown-Séquard syndrome (BSS) is a rare condition resulting from a spinal cord injury that develops weeks to years after a blunt trauma. Acute-onset BSS after a blunt injury has been rarely reported. Here, we report on a case of BSS, in a 58-year-old man, that developed immediately after a motor vehicle accident. Upon admission, loss of right thoracic motion, complete right paresis, and loss of pain and temperature sensations below the C3 level on the left side were observed. Magnetic resonance imaging showed hyperintensities within the cervical spinal cord at the C2-C3 level, confirming the diagnosis of BSS. Thoracic motion rapidly recovered, but other neurological sequelae persisted. BSS related to cervical cord injury should be suspected when patients develop hemiparesis and contralateral sensory loss immediately after a blunt trauma. Likewise, clinicians should be aware that unilateral loss of thoracic motion could be an important sign of BSS.	0
Mutations in the myotubularin 1 (MTM1) gene can cause the fatal disease X-linked centronuclear myopathy (XLCNM), but the underlying mechanism is incompletely understood. In this report, using an Mtm1 -/y disease model, we found that expression of the intragenic microRNA miR-199a-1 is up-regulated along with that of its host gene, dynamin 2 (Dnm2), in XLCNM skeletal muscle. To assess the role of miR-199a-1 in XLCNM, we crossed miR-199a-1 -/- with Mtm1 -/y mice and found that the resultant miR-199a-1-Mtm1 double-knockout mice display markers of improved health, as evidenced by lifespans prolonged by 30% and improved muscle strength and histology. Mechanistic analyses showed that miR-199a-1 directly targets nonmuscle myosin IIA (NM IIA) expression and, hence, inhibits muscle postnatal development as well as muscle maturation. Further analysis revealed that increased expression and phosphorylation of signal transducer and activator of transcription 3 (STAT3) up-regulates Dnm2/miR-199a-1 expression in XLCNM muscle. Our results suggest that miR-199a-1 has a critical role in XLCNM pathology and imply that this microRNA could be targeted in therapies to manage XLCNM.	0
BACKGROUND:Fetal magnetic resonance imaging (MRI) is obtained for prenatal diagnosis and prognostication of skeletal dysplasias; however, related literature is limited. OBJECTIVE:The purpose of this study was to define the utility of fetal MRI for skeletal dysplasias and to report MRI findings associated with specific diagnoses. MATERIALS AND METHODS:This retrospective study was approved by the institutional review board; informed consent was waived. Women referred for suspected fetal skeletal dysplasia who underwent MRI between January 2003 and December 2018 were included. Definitive diagnoses were determined by genetic testing, autopsy, physical examination and/or postnatal/postmortem imaging. Fetal MRI examinations and reports were reviewed. Descriptive statistics were used to summarize imaging findings. RESULTS:Eighty-nine women were referred for fetal MRI for possible skeletal dysplasia. Forty-three (48%) were determined to have a diagnosis other than skeletal dysplasia and nine were excluded for lack of specific skeletal dysplasia diagnosis. Thirty-seven cases of skeletal dysplasia with available fetal MRI and specific diagnosis were included for analysis. Diagnoses included achondrogenesis (n=2), achondroplasia (n=5), Boomerang dysplasia (n=1), campomelic dysplasia (n=2), Jeune syndrome (n=1), Kniest dysplasia (n=1), osteogenesis imperfecta (n=15) and thanatophoric dysplasia (n=10). A specific skeletal dysplasia diagnosis was mentioned in 17/37 (46%) of MRI imaging reports and correct for 14/17 (82%). MRI findings were reported for each specific skeletal dysplasia diagnosis. CONCLUSION:Fetal MRI is a useful diagnostic tool for skeletal dyplasias and excluded the diagnosis in nearly half of referred pregnancies. In addition to providing fetal lung volumes, fetal MRI demonstrates findings of the brain in achondroplasia and thanatophoric dysplasia, of the spine in achondroplasia and achondrogenesis, of the calvarium in osteogenesis imperfecta and thanatophoric dysplasia, and of the cartilage in Kniest dysplasia.	0
The potential etiologies of third-degree complete heart block include idiopathic, pathologic, and iatrogenic causes. We present a rare case of complete heart block in an elderly woman with microscopic polyangiitis (MPA), who presented with dyspnea on exertion and dizziness.	0
BACKGROUND:Tuberculosis (TB) and AIDS are the leading causes of infectious disease death worldwide. In some TB-HIV co-infected individuals treated for both diseases simultaneously, a pathological inflammatory reaction termed immune reconstitution inflammatory syndrome (IRIS) may occur. The risk factors for IRIS are not fully defined. We investigated the association of HLA-B, HLA-C, and KIR genotypes with TB, HIV-1 infection, and IRIS onset. METHODS:Patients were divided into four groups: Group 1- TB+/HIV+ (n = 88; 11 of them with IRIS), Group 2- HIV+ (n = 24), Group 3- TB+ (n = 24) and Group 4- healthy volunteers (n = 26). Patients were followed up at INI/FIOCRUZ and HGNI (Rio de Janeiro/Brazil) from 2006 to 2016. The HLA-B and HLA-C loci were typed using SBT, NGS, and KIR genes by PCR-SSP. Unconditional logistic regression models were performed for Protection/risk estimation. RESULTS:Among the individuals with TB as the outcome, KIR2DS2 was associated with increased risk for TB onset (aOR = 2.39, P = 0.04), whereas HLA-B*08 and female gender were associated with protection against TB onset (aOR = 0.23, P = 0.03, and aOR = 0.33, P = 0.01, respectively). Not carrying KIR2DL3 (aOR = 0.18, P = 0.03) and carrying HLA-C*07 (aOR = 0.32, P = 0.04) were associated with protection against TB onset among HIV-infected patients. An increased risk for IRIS onset was associated with having a CD8 count ≤500 cells/mm3 (aOR = 18.23, P = 0.016); carrying the KIR2DS2 gene (aOR = 27.22, P = 0.032), the HLA-B*41 allele (aOR = 68.84, P = 0.033), the KIR2DS1 + HLA-C2 pair (aOR = 28.58, P = 0.024); and not carrying the KIR2DL3 + HLA-C1/C2 pair (aOR = 43.04, P = 0.034), and the KIR2DL1 + HLA-C1/C2 pair (aOR = 43.04, P = 0.034), CONCLUSIONS: These results suggest the participation of these genes in the immunopathogenic mechanisms related to the conditions studied. This is the first study demonstrating an association of HLA-B*41, KIR2DS2, and KIR + HLA-C pairs with IRIS onset among TB-HIV co-infected individuals.	0
Cri-du-chat syndrome (CdCS) is caused by the deletion of the short arm of chromosome 5. Most patients with CdCS develop intellectual disabilities. Therefore, they have poor oral hygiene and a high caries index. However, treating such patients is not an easy task, because of the difficulty in communication. General anesthesia may be a useful option in adult patients with CdCS and intellectual disability. General anesthesia should be administered very carefully, owing to the presence of comorbid diseases, which may need airway management. Infants with CdCS need general anesthesia if they have a concomitant cardiac anomaly. Intubation is reportedly difficult for such patients was, owing to the structural and functional abnormalities in the larynx and vocal cords. The purpose of this study was to report a case of difficult intubation while inducing general anesthesia in a patient with CdCS during dental treatment, due to a narrow larynx and trachea.	0
Pulmonary arterial hypertension (PAH), associated with congenital heart disease (CHD), usually results from a systemic-to-pulmonary shunt. Eisenmenger syndrome (ES) is characterised by severe irreversible PAH and reversal of a previous systemic-to-pulmonary shunt. A national registry of ES patients was initiated to optimise patient care and to provide epidemiological information regarding PAH and CHD in Belgium.All ES patients, older than 18 years, were selected through the local databases of ten centres in Belgium. After written informed consent, demographic, clinical, biochemical, technical, and treatment data were entered into the web-based registry.Ninety-one patients were included in the registry. Mean age was 36 +/- 11 years (range 18-59 years). Complete atrioventricular septal defect (N=26, 28.6%), followed by ventricular septal defect (N=25, 27.5%) were the commonest defects. Forty-five percent were patients with Down syndrome. Down patients were younger (32 +/- 9 versus 40 +/- 12 years; P = 0.039), had worse functional capacity (class II/III ratio: 15/16 versus 21/8; P = 0.035) and received significantly less specific PAH treatment (7% versus 38%; P = 0.002).Through the national Eisenmenger registry, 91 adult patients with ES were identified (estimated prevalence II per million inhabitants). Almost half of them were Down patients. Although having worse functional capacity, significantly less Down patients were receiving specific PAH treatment.	1
The formation of human enamel is highly regulated at the molecular level and involves thousands of genes. Requisites for development of this highly mineralized tissue include cell differentiation; production of a unique extracellular matrix; processing of the extracellular matrix; altering of cell function during different stages of enamel formation; cell movement and attachment; regulation of ion and protein movement; and regulation of hydration, pH, and other conditions of the microenvironment, to name just a few. Not surprising, there is a plethora of hereditary conditions with an enamel phenotype. The objective of this review was to identify the hereditary conditions listed on Online Mendelian Inheritance in Man (OMIM) that have an associated enamel phenotype and whether a causative gene has been identified. The OMIM database was searched with the terms amelogenesis, enamel, dental, and tooth, and all results were screened by 2 individuals to determine if an enamel phenotype was identified. Gene and gene product function was reviewed on OMIM and from publications identified in PubMed. The search strategy revealed 91 conditions listed in OMIM as having an enamel phenotype, and of those, 71 have a known molecular etiology or linked genetic loci. The purported protein function of those conditions with a known genetic basis included enzymes, regulatory proteins, extracellular matrix proteins, transcription factors, and transmembrane proteins. The most common enamel phenotype was a deficient amount of enamel, or enamel hypoplasia, with hypomineralization defects being reported less frequently. Knowing these molecular defects allows an initial cataloging of molecular pathways that lead to hereditary enamel defects in humans. This knowledge provides insight into the diverse molecular pathways involved in enamel formation and can be useful when searching for the genetic etiology of hereditary conditions that involve enamel.	0
The Landau-Kleffner syndrome (LKS), formerly known as acquired epileptic aphasia, is a rare syndrome that typically presents in early childhood with language regression and seizures. We report a case of LKS in an 7-year-old boy who presented with aggressive behavior, difficulty in maintaining posture, and language regression. Systemic examination, including neurological evaluation, was normal. Cerebrospinal fluid (CSF) analysis and magnetic resonance imaging (MRI) were normal. Electroencephalogram (EEG) showed abnormal findings associated with generalized seizure discharge during sleep with more spikes being noted in bilateral frontal and temporal regions. LKS was diagnosed and was treated with anticonvulsants and steroids. On follow-up, the child showed improvement in maintaining posture, was able to walk independently and had improved linguistic functions. This case adds another variant of LKS to the existing literature.	0
As genomic characterization becomes increasingly necessary for accurate diagnosis of tumors of the central nervous system, identification of rapidly assessible biomarkers is equally important to avoid excessive cost and delay in initiation of therapy. This article reviews novel immunohistochemical markers that may be used to determine mutation status, activation of signaling pathways, druggable targets, and cell lineage in many diverse tumor types. In particular, recently added entities to the 2016 WHO classification of central nervous system tumors will be addressed, including IDH-mutant gliomas, diffuse midline glioma, epithelioid glioblastoma, angiocentric glioma, RELA-rearranged ependymoma, embryonal tumors (medulloblastoma, atypical teratoid/rhabdoid tumor, pineoblastoma, embryonal tumor with multilayered rosettes, and other genetically defined high-grade neuroepithelial tumors), and meningiomas associated with germline alterations.	0
We describe a family with an autosomal dominant familial dyskinesia resembling myoclonus-dystonia associated with a novel missense mutation in ADCY5, found through whole-exome sequencing. A tiered analytical approach was used to analyse whole-exome sequencing data from an affected grandmother-granddaughter pair. Whole-exome sequencing identified 18,000 shared variants, of which 46 were non-synonymous changes not present in a local cohort of control exomes (n = 422). Further filtering based on predicted splicing effect, minor allele frequency in the 1000 Genomes Project and on phylogenetic conservation yielded 13 candidate variants, of which the heterozygous missense mutation c.3086T>G, p. M1029R in ADCY5 most closely matched the observed phenotype. This report illustrates the utility of whole-exome sequencing in cases of undiagnosed movement disorders with clear autosomal dominant inheritance. Moreover, ADCY5 mutations should be considered in cases with apparent myoclonus-dystonia, particularly where SCGE mutations have been excluded. ADCY5-related dyskinesia may manifest variable expressivity within a single family, and affected individuals may be initially diagnosed with differing neurological phenotypes.	0
A subset of acute myeloid leukemia (AML) arises either from an antecedent myeloid malignancy (secondary AML, sAML) or as a complication of DNA-damaging therapy for other cancers (therapy-related myeloid neoplasm, t-MN). These secondary leukemias have unique biological and clinical features that distinguish them from de novo AML. Over the last decade, molecular techniques have unraveled the complex subclonal architecture of sAML and t-MN. In this review, we compare and contrast biological and clinical features of de novo AML with sAML and t-MN. We discuss the role of genetic mutations, including those involved in RNA splicing, epigenetic modification, tumor suppression, transcription regulation, and cell signaling, in the pathogenesis of secondary leukemia. We also discuss clonal hematopoiesis in otherwise healthy individuals, as well as in the context of another malignancy, and how it challenges the conventional notion of sAML/t-MN. We conclude by summarizing the current and emerging treatment strategies, including allogenic transplant, in these complex scenarios.	0
BACKGROUND:Fibrolamellar carcinoma (FLC) is a very rare liver tumor. We aimed to retrospectively analyze the clinicopathological factors and treatment modalities affecting overall survival (OS) in FLC. The objective of the study was to identify predictors of survival in FLC. PATIENTS AND METHODS:Using the National Cancer Database, we identified 496 patients diagnosed with FLC between 2004 and 2015. Clinicopathological, treatment, and survival data were collected. RESULTS:Hepatic resection was performed on 254 (51.2%) patients, liver-directed therapy on 13 (2.6%) patients, and liver transplantation on 15 (3.0%) patients. Median OS by stage were 142.1, 87.2, 32.3, and 14.1 months for stages 1, 2, 3, and 4, respectively. Metastatectomy was not associated with superior median OS (23.4 vs. 10.5 months, p=0.163). Age ≤40, low Charlson-Deyo comorbidity score, early stage and hepatic resection were independently associated with longer OS. CONCLUSION:Our study reports current trends in FLC management, and identifies independent predictors of OS.	0
OBJECTIVES:We sought to characterise the outcomes of patients with haematological malignancy and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hospital in our regional network of 7 hospitals. METHODS:Consecutive hospitalised patients with haematological malignancy and SARS-CoV-2 infection were identified from 01/03/2020 to 06/05/2020. Outcomes were categorised as death, resolved or ongoing. The primary outcome was preliminary case fatality rate (pCFR), defined as the number of cases resulting in death as a proportion of all diagnosed cases. Analysis was primarily descriptive. RESULTS:66 Patients were included, overall pCFR was 51.5%. Patients ≥ 70 years accounted for the majority of hospitalised cases (42, 63%) and fatalities (25, 74%). Mortality was similar between females (52%) and males (51%). Immunosuppressive or cytotoxic treatment within 3 months of the diagnosis of SARS-CoV-2 infection was associated with a significantly higher pCFR of 70%, compared with 28% in those not on active treatment (P = .0013, 2 proportions z test). CONCLUSIONS:Mortality rates in patients with haematological malignancy and SARS-CoV-2 infection in hospital are high supporting measures to minimise the risk of infection in this population.	0
Teratomas of the umbilical cord are very rare lesions. We found only five cases in the literature from 1887 to 1993, the latest reported in 1985. We report a case of a 10 x 7 x 5-cm mass located just at the end of an omphalocele in the umbilical cord of a full-term baby. The mass exhibited something like a cranial and a caudal pole, and tissues of all three germinal layers could be found, but there were no skeletal structures. Therefore, this lesion was diagnosed as a teratoma of the umbilical cord. We review the literature and discuss the relationship between the teratoma of the umbilical cord and the holoacardius amorphus.	0
We describe a case of an 81-year-old male presenting with bitemporal visual field defects and blurry vision in the right eye. The patient was found to have a recurrent primary paraganglioma in the sellar and suprasellar region requiring a repeat transsphenoidal endoscopic resection. Immunohistochemical examination confirmed paraganglioma with the classic zellballen appearance which stained positive for chromogranin, synaptophysin, and S-100 in the periphery. Paragangliomas (PGLs) in the sella turcica are a rare entity; only 19 cases have ever been reported in the literature. PGLs in the sellar region are often misdiagnosed or diagnosed in a delayed fashion. Earlier diagnosis of this locally aggressive tumor and meticulous debulking can prevent morbidity secondary to the tumor's compressive effects. This report highlights the effectiveness of surgical interventions in treatment of paragangliomas. More research is still needed to determine the need for adjuvant therapies such as radiation.	0
BACKGROUND:Conotruncal heart defects (CTDs) are a group of congenital heart malformations that cause anomalies of cardiac outflow tracts. In the past few decades, many genes related to CTDs have been reported. Serum response factor (SRF) is a ubiquitous nuclear protein that acts as transcription factor, and SRF was found to be a critical factor in heart development and to be strongly expressed in the myocardium of the developing mouse and chicken hearts. The targeted inactivation of SRF during heart development leads to embryonic lethality and myocardial defects in mice. METHODS:To illustrate the relationship between SRF and human heart defects, we screened SRF mutations in 527 CTD patients, a cross sectional study. DNA was extracted from peripheral leukocyte cells for target sequencing. The mutations of SRF were detected and validated by Sanger sequencing. The affection of the mutations on wild-type protein was analyzed by in silico softwares. Western blot and real time PCR were used to analyze the changes of the expression of the mutant mRNA and protein. In addition, we carried out dual luciferase reporter assay to explore the transcriptional activity of the mutant SRF. RESULTS:Among the target sequencing results of 527 patients, two novel mutations (Mut1: c.821A > G p.G274D, the adenine(A) was mutated to guanine(G) at position 821 of the SRF gene coding sequences (CDS), lead to the Glycine(G) mutated to Asparticacid(D) at position 274 of the SRF protein amino acid sequences; Mut2: c.880G > T p.G294C, the guanine(G) was mutated to thymine (T) at position 880 of the SRF CDS, lead to the Glycine(G) mutated to Cysteine (C) at position 294 of the SRF protein amino acid sequences.) of SRF (NM_003131.4) were identified. Western blotting and real-time PCR showed that there were no obvious differences between the protein expression and mRNA transcription of mutants and wild-type SRF. A dual luciferase reporter assay showed that both SRF mutants (G274D and G294C) impaired SRF transcriptional activity at the SRF promoter and atrial natriuretic factor (ANF) promoter (p < 0.05), additionally, the mutants displayed reduced synergism with GATA4. CONCLUSION:These results suggest that SRF-p.G274D and SRF-p.G294C may have potential pathogenic effects.	0
PAGOD syndrome is an extremely rare congenital malformation complex involving multiple organs. These include pulmonary artery and lung hypoplasia, diaphragm defects, omphalocele, sex reversal or ambiguous genitalia, and complex cardiac defects. Eight cases have been reported to date. We report a case of PAGOD syndrome that is manifested by right diaphragm eventration, horseshoe lung with right lung hypoplasia, hypoplastic left heart syndrome (mitral atresia, aortic atresia), scimitar syndrome, agonadism with ambiguous genitalia. A karyotype revealed normal 46-XY. This patient received a modified Norwood procedure for hypoplastic left heart syndrome as an initial palliation and bidirectional cavopulmonary anastomosis as a second stage of operation. The postoperative courses were uneventful. This patient is waiting for Fontan operation.	0
Chronic lymphocytic leukemia (CLL) is a malignancy of B cells with a variable clinical course. Prognostication is important to place patients into different risk categories for guiding decisions on clinical management, to treat or not to treat. Although several clinical, cytogenetic, and molecular parameters have been established, in the past decade, a tremendous understanding of molecular lesions has been obtained with the advent of high-throughput sequencing. Meanwhile, rapid advances in the understanding of the CLL oncogenic pathways have led to the development of small-molecule targeting signal transducers, tyrosine-protein kinase BTK and phosphatidylinositol 3-kinase, as well as anti-apoptotic protein apoptosis regulator Bcl-2. After an initial response to these targeted therapies, some patients develop resistance and experience disease progression. Novel gene mutations have been identified that account for some of the drug resistance mechanisms. This article focuses on the prognostic and predictive molecular biomarkers in CLL relevant to the molecular pathology practice, beginning with a review of well-established prognostic markers that have already been incorporated into major clinical guidelines, which will be followed by a discussion of emerging biomarkers that are expected to impact clinical practice soon in the future. Special emphasis will be put on predictive biomarkers related to newer targeted therapies in hopes that this review will serve as a useful reference for molecular diagnostic professionals, clinicians, as well as laboratory investigators and trainees.	0
Kleefstra syndrome (KS) is an autosomal dominant disorder caused by a chromosomal deletion at 9q34.3 resulting in pathogenic variants of the gene that codes for the enzyme, euchromatin histone methyltransferase 1 (EHMT1). KS is a rare, yet clinically relevant congenital disorder for anesthesiologists because of its potential for cardiac and craniofacial involvement. We present a 3-month-old patient with KS who required anesthetic care for diagnostic laryngoscopy and rigid bronchoscopy. The end-organ effects of KS are reviewed and our anesthetic care presented.	0
Spinal adhesive arachnoiditis (SAA) is a rare, but often devastating, cause of compressive myelopathy. We report a patient with SAA resulting in a longitudinally extensive T2-hyperintense spinal cord lesion with initial nodular pial and dural enhancement mimicking neurosarcoidosis. Neurologists should be aware of this entity, especially in patients who have pertinent risk factors, such as prior meningitis, spinal cord trauma, or surgery.	0
Hyperammonemia is a typical symptom of urea cycle disorders. While early-onset argininosuccinic aciduria (ASA) can often be detected by hyperammonemia, patients with late-onset ASA predominantly present with psychomotor retardation and mental disorders. However, in late-onset ASA that develops during early childhood, hyperammonemia can sometimes be caused by acute infections, stress, and reduced dietary intake. Here, we report the case of a 14-year-old boy with late-onset ASA associated with hyperammonemia that was triggered by an influenza A infection. Due to the infection, he presented with a fever and was unable to eat food or take oral medication. He then experienced restlessness, a disturbance in his level of consciousness, and seizures. Hyperammonemia (3286 μg/dL, reference value ≤100 μg/dL) was detected. He was biochemically diagnosed with ASA based on increased serum and urinary argininosuccinic acid levels. Additionally, genetic testing revealed compound heterozygous mutations in the ASL gene: c.91G > A(p.Asp31Asn) and c.1251-1G > C. This case revealed that in late-onset ASA, hyperammonemia can occur not only in early childhood but also during adolescence. Late-onset ASA may have a very broad clinical spectrum that includes hyperammonemia. We suggest that urea cycle disorders such as ASA must be considered when patients present with hyperammonemic decompensation during adolescence.	0
Mechanical ventilation of patients with Duchenne muscular dystrophy continues to be a subject of study. The purpose was to estimate prevalence, incidence, mortality and use of mechanical ventilation in the total Duchenne muscular dystrophy population in Denmark between 1977 and 2001 and further, to reconstruct the introduction of mechanical ventilation to assess the role of the patient organization. Study objects were collected from five sources and verifiable cases identified. Negotiations between health authorities and the patient organization constituted main empirical data for the reconstruction. While overall incidence remained stable at 2.0 per 10(5), prevalence rose from 3.1 to 5.5 per 10(5), mortality fell from 4.7 to 2.6 per 100 years at risk and prevalence of Duchenne muscular dystrophy ventilator users rose from 0.9 to 43.4 per 100. We conclude that survival of Duchenne muscular dystrophy patients has increased and ventilator use is probably a main reason. The patient organization exercised a key role but acted upon preconditions created by other players.	1
Parry-Romberg syndrome is a rare degenerative disorder causing progressive atrophy of skin and soft tissues of the face and neck, which is usually unilateral. The mean age of onset is usually in the second decade of life and the disease causes functional, aesthetic and psychological disabilities in the affected individual. We present a 14-year-old boy with this disorder. The diagnosis was based on clinical characteristics. A multidisciplinary team approach involving rheumatologists, dermatologists, maxillofacial surgeons, dentists and psychologists is required for the management of this problem, which is mainly targeted at controlling active inflammation with the use of immunosuppressive agents in addition to possible surgical correction of repositioning of adipose tissue that is lost due to atrophy.	0
In prior research, intrathecal tigecycline was successfully used to treat central nervous system infection by extensively drug-resistant Acinetobacter baumannii. However, little is known about its safe dose and adverse reactions. This study reports the case of a 28-year-old male patient who was diagnosed with central nervous system infection by extensively drug-resistant A. baumannii after the removal of a ventriculoperitoneal shunt. Intravenous and intrathecal tigecycline were administrated simultaneously. Spinal arachnoiditis was discovered after nine doses of intrathecal tigecycline. Spinal arachnoiditis was resolved after discontinuation of the antibiotic. This is the first report of an adverse reaction to intrathecal tigecycline. The case was complicated by spinal arachnoiditis, which obstructed the assessment of cerebrospinal fluid. The appropriate dose and administration schedule of intrathecal tigecycline remain to be determined.	0
In 1937, Siemens described a Dutch family with superficial blistering, flexural hyperkeratosis, and characteristic mauserung appearance. Since then, less than 20 kindreds with this condition have been described in the English dermatologic literature. A 14-year-old boy presented with history of recurrent blistering and peeling of skin since the age of 1 month, predominantly seen over limbs and trunk, often associated with secondary infection. His mother also had similar symptoms from childhood. On examination, the child had typical mauserung peeling of the skin and dirty gray hyperkeratosis in a rippled pattern over flexures. Skin biopsy from the boy showed intracorneal blistering with epidermolytic hyperkeratosis in the upper spinous layers. The typical history and clinical features along with characteristic histological findings confirmed our diagnosis of ichthyosis bullosa of Siemens. It must be differentiated from other conditions with epidermolytic hyperkeratosis and skin peeling, such as bullous ichthyosiform erythroderma of Brocq and peeling skin syndrome. Our patient responded well to 0.05% topical tazarotene gel over four weeks.	0
Hereditary channelopathies, that is, mutations in channel genes that alter channel function and are causal for the pathogenesis of the disease, have been described for several members of the transient receptor potential channel family. Mutations in the TRPV4 gene, encoding a polymodal Ca(2+) permeable channel, are causative for several human diseases, which affect the skeletal system and the peripheral nervous system, with highly variable phenotypes. In this review, we describe the phenotypes of TRPV4 channelopathies and overlapping symptoms. Putative mechanisms to explain the puzzle, and how mutations in the same region of the channel cause different diseases, are discussed and experimental approaches to tackle this surprising problem are suggested.	0
Channelopathies are disorders caused by abnormal ion channel function in differentiated excitable tissues. We discovered a unique neurodevelopmental channelopathy resulting from pathogenic variants in SCN3A, a gene encoding the voltage-gated sodium channel NaV1.3. Pathogenic NaV1.3 channels showed altered biophysical properties including increased persistent current. Remarkably, affected individuals showed disrupted folding (polymicrogyria) of the perisylvian cortex of the brain but did not typically exhibit epilepsy; they presented with prominent speech and oral motor dysfunction, implicating SCN3A in prenatal development of human cortical language areas. The development of this disorder parallels SCN3A expression, which we observed to be highest early in fetal cortical development in progenitor cells of the outer subventricular zone and cortical plate neurons and decreased postnatally, when SCN1A (NaV1.1) expression increased. Disrupted cerebral cortical folding and neuronal migration were recapitulated in ferrets expressing the mutant channel, underscoring the unexpected role of SCN3A in progenitor cells and migrating neurons.	0
Here, we report on a 28-year old male patient presenting with neck and shoulder pain, dysesthesia of all four limbs and hypesthesia of both hands, without motor deficits. Magnetic resonance imaging showed an intradural, intramedullary mass of the cervical spinal cord of 6.4 cm length and 1.7 cm diameter. The patient underwent surgical resection. Histological and immunohistochemical evaluation showed pleomorphic glial tumor cells, mitoses, calcifications, and atypical ganglioid cells compatible with the morphology of anaplastic ganglioglioma (WHO Grade III). Extensive molecular workup revealed H3F3A K27M, TERT C228T and PDGFRα Y849C mutations indicating poor prognosis. The H3F3A K27M mutation assigned the tumor to the molecular group of diffuse midline glioma (WHO Grade IV). Epigenome-wide methylation profiling confirmed the methylation class of diffuse midline glioma. Thus, this is a very rare case of malignant glioma with H3 K27M genotype phenotypically mimicking anaplastic ganglioglioma. This case emphasizes the importance of comprehensive morphological and molecular workup including methylome profiling for advanced patient care.	0
Mollaret's meningitis is characterized by recurrent episodes of aseptic meningitis that last two to seven days and resolve spontaneously without any residual neurological deficit or complication. Viruses are the most common cause of aseptic meningitis and herpes simplex virus (HSV) type 2 has been noted as the most commonly associated virus in Mollaret's meningitis. We describe a rare case of a female who had four episodes of meningitis in a five-year period associated with chronic intractable migraine and papilledema attributed to Mollaret's meningitis.	0
Acquired generalized lipodystrophy (AGL) is a rare condition characterized by an altered distribution of adipose tissue and predisposition to develop hepatic steatosis and fibrosis, diabetes, and hypertriglyceridemia. Diagnosis of AGL is based on the observation of generalized fat loss, autoimmunity and lack of family history of lipodystrophy. The pathogenic mechanism of fat destruction remains unknown but evidences suggest an autoimmune origin. Anti-adipocyte antibodies have been previously reported in patients with AGL, although their involvement in the pathogenesis has been poorly studied and the autoantibody target/s remain/s to be identified. Using a combination of immunochemical and cellular studies, we investigated the presence of anti-adipocyte autoantibodies in patients with AGL, acquired partial lipodystrophy, localized lipoatrophy due to intradermic insulin injections or systemic lupus erythematosus. Moreover, the impact of anti-adipocyte autoantibodies from AGL patients was assessed in cultured mouse preadipocytes. Following this approach, we identified anti-perilipin 1 IgG autoantibodies in the serum of patients with autoimmune variety-AGL, but in no other lipodystrophies tested. These autoantibodies altered the ability of perilipin 1 to regulate lipolysis in cultured preadipocytes causing abnormal, significantly elevated basal lipolysis. Our data provide strong support for the conclusion that perilipin 1 autoantibodies are a cause of generalized lipodystrophy in these patients.	0
OBJECTIVES:Skin improvement in diffuse cutaneous SSc (dcSSc), measured with modified Rodnan skin score (mRSS), is frequently used as a primary outcome in clinical trials, but it is uncertain whether mRSS changes reflect changes in other organ systems. This aim of this study was to explore if skin changes in early dcSSc over 1 and 2 years are associated with changes in severity of other organ involvement. METHODS:Canadian Scleroderma Research Group database patients with dcSSc, disease duration of ≤5 years, no evidence of initial end-stage organ damage and/or significant comorbidity who had 1 year (n = 154) and 2 years (n = 128) of follow-up data were included. mRSS changes of 25% and/or ≥5 points were considered significant. Organ involvement was assessed by Medsger Disease Severity Score and Canadian Scleroderma Research Group definitions using bivariate, chi-square, ANOVA, adjusted regression and longitudinal mixed effect model analyses. RESULTS:Improvement in mRSS was found in 41% of patients at 1 year and in 50% at 2 years. Improved patients showed less forced vital capacity decline (P = 0.012) and less frequent new cardiac involvement (P = 0.02) over 1 year, as well as better lung (by both Disease Severity Score, P = 0.006, and Δforced vital capacity%, P = 0.026), peripheral vascular (P = 0.006) and joint/tendon (P = 0.002) involvement over 2 years. mRSS worsening was consistently linked to less favourable lung outcomes at both 1- and 2-year follow-up visits, and more severe gastrointestinal disease at 2 years. CONCLUSION:Changes in lung function in early dcSSc closely parallel skin changes. mRSS improvement reflects better prognosis for visceral disease and may be a reliable outcome measure in clinical trials.	0
The technological advances in diagnostics and therapy of primary immunodeficiency are progressing at a fast pace. This review examines recent developments in the field of inborn errors of immunity, from their definition to their treatment. We will summarize the challenges posed by the growth of next-generation sequencing in the clinical setting, touch briefly on the expansion of the concept of inborn errors of immunity beyond the classic immune system realm, and finally review current developments in targeted therapies, stem cell transplantation, and gene therapy.	0
Cancer immunotherapy has been used in several malignancies with clinical benefit. Despite the clinical success, immune-related adverse events are frequent and endocrinopathies can be particularly severe. We report a 55-year-old male patient with stage IV pulmonary carcinoma treated with nivolumab who presented with thyroid dysfunction after the sixth administration of the drug. One year after thyroid dysfunction, the patient complained of severe fatigue, asthenia and weight loss. Laboratory testing showed low morning cortisol with undetected adrenocorticotropic hormone; other pituitary hormones were normal and MRI showed homogeneous enhancement of the pituitary gland and no space-occupying lesions. The diagnosis of nivolumab-induced hypophysitis was made and replacement treatment with hydrocortisone was started with clinical improvement. This case demonstrates that patients under immunotherapy are at risk for a large spectrum of endocrine dysfunctions that may worsen their prognosis. Close monitoring of these patients is warranted.	0
BACKGROUND:Elevated blood C24:0- and C26:0-carnitines and lysophosphatidylcholines (LPCs) were reported as diagnostic biomarkers for X-linked adrenoleukodystrophy (X-ALD). Our aim was to establish the reference intervals of very long-chain (VLC) acylcarnitines (C20-C26) and LPCs in Chinese population, and evaluate valuable biomarkers and develop panel for screening X-ALD in China. METHODS:The method of FIA-MS/MS-based quantification of VLC acylcarnitines and LPCs was validated in order to determine their concentrations in dried blood spots from 7 X-ALD boys, 396 age-matched healthy controls, and 3078 putative normal newborns. Screening performance of these metabolites for X-ALD was clinically evaluated. RESULTS:The reference intervals of VLC acylcarnitines, LPCs and their ratios were established in Chinese population, and for some metabolites like C26 and C26:0-LPC, the reference intervals were found to be significantly different between children and newborns. C24 and C26, C26:0-LPC, C24/C22 and C26/C22 ratios were found to have better performance than other analytes to identify X-ALD boys from normal children. CONCLUSION:C26:0-LPC, C24 and C26 are three most valuable biomarkers for screening of X-ALD in children group. The information of age-related variations in concentration of some biomarkers is helpful for accurate screening of X-ALD.	0
Congenital hyperinsulinism is a rare but significant cause of severe and persistent hypoglycaemia in infancy. Although a biphasic phenotype of congenital hyperinsulinism in infancy followed by Maturity-Onset Diabetes of the Young (MODY) in later life has been established for HNF4A, the existence of a similar phenotype for a related MODY gene, HNF1A, is less clear. We describe two cases of congenital hyperinsulinism in association with dominantly inherited variants in HNF1A. They presented in the early neonatal period with unequivocal biochemical evidence of congenital hyperinsulinism and persistence into childhood with ongoing need for medical therapy. Both cases inherited HNF1A variants from a parent with a diabetes phenotype consistent with MODY, without obesity, insulin resistance or other metabolic syndrome features. In the first case, a paternally inherited novel c.-230_-101del variant was found that deletes the minimal promoter region presumably required for HNF1A expression. In the second case, a maternally inherited missense variant (c.713G>T, p.(Arg238Met)) was identified. This variant is predicted to cause haploinsufficiency via aberrant splicing and has previously been associated with MODY but not congenital hyperinsulinism. Our cases further strengthen the evidence for HNF1A as a CHI-causing gene requiring long-term follow-up.	0
The myelin regulatory factor gene (MYRF) encodes a transcription factor that is widely expressed. There is increasing evidence that heterozygous loss-of-function variants in MYRF can lead to abnormal development of the heart, genitourinary tract, diaphragm, and lungs. Here, we searched a clinical database containing the results of 12,000 exome sequencing studies. We identified three previously unreported males with putatively deleterious variants in MYRF: one with a point mutation predicted to affect splicing and two with frameshift variants. In all cases where parental DNA was available, these variants were found to have arisen de novo. The phenotypes identified in these subjects included a variety of congenital heart defects (CHD) (hypoplastic left heart syndrome, scimitar syndrome, septal defects, and valvular anomalies), genitourinary anomalies (ambiguous genitalia, hypospadias, and cryptorchidism), congenital diaphragmatic hernia, and pulmonary hypoplasia. The phenotypes seen in our subjects overlap those described in individuals diagnosed with PAGOD syndrome [MIM# 202660], a clinically defined syndrome characterized by pulmonary artery and lung hypoplasia, agonadism, omphalocele, and diaphragmatic defects that can also be associated with hypoplastic left heart and scimitar syndrome. These cases provide additional evidence that haploinsufficiency of MYRF causes a genetic syndrome whose cardinal features include CHD, urogenital anomalies, congenital diaphragmatic hernia, and pulmonary hypoplasia. We also conclude that consideration should be given to screening individuals with PAGOD for pathogenic variants in MYRF, and that individuals with MYRF deficiency who survive the neonatal period should be monitored closely for developmental delay and intellectual disability.	0
Elongation factor Tu guanosine-5'-triphosphate (GTP) binding domain containing 2 (EFTUD2) encodes a major component of the spliceosomal GTPase and, if mutated, causes mandibulofacial dysostosis with microcephaly (MFDM; MIM#610536). Despite the increasing number of potentially pathogenic variants reported in the literature, most previous studies have relied solely on in silico prediction of the pathogenic potential of EFTUD2 variants, which may result in misclassification of the variant's pathogenicity. Given the importance of the functional verification of EFTUD2 variants, we identified a novel splice donor site variant, c.271+1G>A of EFTUD2, whose pathogenicity was clearly verified at the RNA level using a minigene assay. A child with MFDM, mixed hearing loss, microcephaly, and a congenital cardiac defect was identified with this variant, which arose in a de novo fashion. The minigene assay showed erroneous integration of the 118 bp IVS3 of EFTUD2 exclusively among the c.271+1G>A variant clone. We first applied the minigene assay to identify the splice function of a splice site variant of EFTUD2, thereby allowing for in vitro functional verification of splice site variants in EFTUD2.	0
Cardiolipin (CL) is a unique tetra-acyl phospholipid localized to the inner mitochondrial membrane and essential for normal respiratory function. It has been previously reported that the failing human heart and several rodent models of cardiac pathology have a selective loss of CL. A rare genetic disease, Barth syndrome (BTHS), is similarly characterized by a cardiomyopathy due to reduced levels of cardiolipin. A mouse model of cardiolipin deficiency was recently developed by knocking-down the cardiolipin biosynthetic enzyme tafazzin (TAZ KD). These mice develop an age-dependent cardiomyopathy due to mitochondrial dysfunction. Since reduced mitochondrial capacity in the heart may promote the accumulation of lipids, we examined whether cardiolipin deficiency in the TAZ KD mice promotes the development of a lipotoxic cardiomyopathy. In addition, we investigated whether treatment with resveratrol, a small cardioprotective nutraceutical, attenuated the aberrant lipid accumulation and associated cardiomyopathy. Mice deficient in tafazzin and the wildtype littermate controls were fed a low-fat diet, or a high-fat diet with or without resveratrol for 16 weeks. In the absence of obesity, TAZ KD mice developed a hypertrophic cardiomyopathy characterized by reduced left-ventricle (LV) volume (~36%) and 30-50% increases in isovolumetric contraction (IVCT) and relaxation times (IVRT). The progression of cardiac hypertrophy with tafazzin-deficiency was associated with several underlying pathological processes including altered mitochondrial complex I mediated respiration, elevated oxidative damage (~50% increase in reactive oxygen species, ROS), the accumulation of triglyceride (~250%) as well as lipids associated with lipotoxicity (diacylglyceride ~70%, free-cholesterol ~44%, ceramide N:16-35%) compared to the low-fat fed controls. Treatment of TAZ KD mice with resveratrol maintained normal LV volumes and preserved systolic function of the heart. The beneficial effect of resveratrol on cardiac function was accompanied by a significant improvement in mitochondrial respiration, ROS production and oxidative damage to the myocardium. Resveratrol treatment also attenuated the development of cardiac steatosis in tafazzin-deficient mice through reduced de novo fatty acid synthesis. These results indicate for the first time that cardiolipin deficiency promotes the development of a hypertrophic lipotoxic cardiomyopathy. Furthermore, we determined that dietary resveratrol attenuates the cardiomyopathy by reducing ROS, cardiac steatosis and maintaining mitochondrial function.	0
Background: REEP1 is a common cause of autosomal dominant hereditary spastic paraplegia (HSP) but is rare in China. The pathological mechanism of REEP1 is not fully understood. Methods: We screened for REEP1 mutations in 31 unrelated probands from Chinese HSP families using next-generation sequencing targeting pathogenic genes for HSP and other related diseases. All variants were validated by Sanger sequencing. The proband family members were also screened for variants for the segregation analysis. All previously reported REEP1 mutations and cases were reviewed to clarify the genetic and clinical features of REEP1-related HSP. Results: A pathogenic mutation, REEP1c. 125G>A (p.Trp42*), was detected in a pure HSP family from North China out of 31 HSP families (1/31). This locus, which is located in the second hydrophobic domain of REEP1, is detected in both Caucasian patients with complicated HSP phenotypes and Chinese pure HSP families. Conclusion: REEP1-related HSP can be found in the Chinese population. The 42nd residue is a novel transethnic mutation hotspot. Mutations in this spot can lead to both complicated and pure form of HSP. Identification of transethnic hotspot will contribute to clarify the underlying pathological mechanisms.	0
Despite the well documented increased risk of thrombosis in patients with cancer and during chemotherapy, cerebral venous sinus thrombosis (CVT) remains a rare entity. We present a rare case of cerebrospinal fluid (CSF) rhinorrhoea secondary to a left transverse sinus thrombus which occurred 2 years previously during chemotherapy for breast cancer. The patient underwent a three-layer repair using Neuro-Patch, septal cartilage and middle turbinate pedicle flap and was started on acetazolamide. There was no recurrence at 1-year follow-up. Raised intracranial pressure secondary to cerebral venous occlusion can erode the base of skull and predispose to CSF leaks. Despite the theoretical risk, there have been no cases reported where CSF leaks have occurred following chemotherapy induced CVT. We describe the first case and discuss pathophysiology and management.	0
Eosinophilic cystitis is an inflammatory disease of the bladder wall. It is rare, so there are no standard treatment guidelines. We conducted a retrospective study of 10 patients with eosinophilic cystitis diagnosed and treated in our Department between 2006 and 2017. The average age of patients was 46 years; there was a male predominance. Three patients were atopic. The most common symptoms were irritative urinary symptoms in 9 cases, macroscopic haematuria in 8 cases and pelvic pain in 6 cases. Four patients had high levels of eosinophils in their blood. Cystoscopy showed petechiae in 5 cases, pseudotumor in 4 cases. It was normal in one case. Patients with pseudotumor underwent endoscopic resection. Four patients were treated with nonsteroidal anti-inflammatory drugs, with improvement in symptoms. Six patients were monitored. After a mean follow-up interval of 50 months, no recidivism was reported. Eosinophilic cystitis is rare with non-specific clinical manifestations. Patients with little symptomatic eosinophilic cystitis undergo non-invasive medical treatments.	0
Odontogenic myxoma (OM) is an uncommon benign odontogenic tumor arising in the jaw. Though it has slight histologic overlap with other entities, definitive diagnosis is imperative considering the tumor's aggressive nature, high recurrence rate, and necessity of radical surgical intervention in large-sized lesions. With IRB approval, a retrospective search of the University of Florida College of Dentistry Oral Pathology Biopsy Service archives from 1994 to 2017 for diagnosis of OM of the jaw was performed. Biopsy reports and original slides for each case were assessed and reviewed along with any accompanying radiographs to confirm the diagnosis. Immunohistochemical staining was utilized to exclude entities with histologic overlaps, such as intraosseous myxoid neurofibroma. A total of 38 cases were included. The patients' age ranged from 6 to 84 years, with a mean age of 37.47 years. Females comprised two-thirds of the cases (n = 25) versus males (n = 13). The mandible was the most affected at 60.5% (n = 23), followed by maxilla 39.4% (n = 15). Posterior jaw involvement was higher than anterior in both the mandible (n = 20 versus n = 3) and the maxilla (n = 11 versus n = 4). Most lesions presented clinically as expansile masses with variable radiographic appearance. The clinical impression from submitting providers included "gelatinous masses", abscesses, odontogenic lesions, fibro-osseous lesions, soft tissue or bone neoplasms, and reactive gingival lesions. A consensus of odontogenic myxoma as a diagnosis was rendered for 30 cases (79%), while in 8 cases (21%) that exhibited a more fibrous stroma was identified as fibromyxoma. OM may exhibit a varied demographic and clinical profile with a wide spectrum of histologic presentations. Pathologists should be sentient of this variability in order to arrive at an accurate diagnosis and correctly manage these patients.	0
Evolutionary studies are often limited by missing data that are critical to understanding the history of selection. Selection experiments, which reproduce rapid evolution under controlled conditions, are excellent tools to study how genomes evolve under selection. Here we present a genomic dissection of the Longshanks selection experiment, in which mice were selectively bred over 20 generations for longer tibiae relative to body mass, resulting in 13% longer tibiae in two replicates. We synthesized evolutionary theory, genome sequences and molecular genetics to understand the selection response and found that it involved both polygenic adaptation and discrete loci of major effect, with the strongest loci tending to be selected in parallel between replicates. We show that selection may favor de-repression of bone growth through inactivating two limb enhancers of an inhibitor, Nkx3-2. Our integrative genomic analyses thus show that it is possible to connect individual base-pair changes to the overall selection response.	0
BACKGROUND/AIMS: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 and TSC2 genes. Previous studies have estimated the prevalence of TSC to be 1:8,000 to 1:30,000. The numbers of patients and the populations accessed in these studies are relatively small. The aim of this study is to evaluate the prevalence of TSC in Taiwan with a population of 23 million people. METHODS: 95% of Taiwanese are enrolled in a single national health insurance database. This study uses this database to estimate the prevalence of TSC in a large Chinese population. RESULTS: The prevalence of TSC in Taiwan is estimated at 1:95,136. There is no prevalence difference in rural or urban areas. The ages of the patients ranges from 3 months to 75 years, with a mean of 14 +/- 11 years. Prevalence by age is 1:14,608, 1:18,851, and 1:24,617 for ages <6, 12, and 18 years, respectively. Only 15% of patients disclose a family history of TSC. The majority of cases (71.2%) are diagnosed in an outpatient visit by a pediatrician. CONCLUSION: The low prevalence of TSC in Taiwan might result from differences in penetrance, family planning, ethnic groups, and disease-modifying genes.	1
The study of early T-cell development in humans is challenging because of limited availability of thymic samples and the limitations of in vitro T-cell differentiation assays. We used an artificial thymic organoid (ATO) platform generated by aggregating a DLL4-expressing stromal cell line (MS5-hDLL4) with CD34+ cells isolated from bone marrow or mobilized peripheral blood to study T-cell development from CD34+ cells of patients carrying hematopoietic intrinsic or thymic defects that cause T-cell lymphopenia. We found that AK2 deficiency is associated with decreased cell viability and an early block in T-cell development. We observed a similar defect in a patient carrying a null IL2RG mutation. In contrast, CD34+ cells from a patient carrying a missense IL2RG mutation reached full T-cell maturation, although cell numbers were significantly lower than in controls. CD34+ cells from patients carrying RAG mutations were able to differentiate to CD4+CD8+ cells, but not to CD3+TCRαβ+ cells. Finally, normal T-cell differentiation was observed in a patient with complete DiGeorge syndrome, consistent with the extra-hematopoietic nature of the defect. The ATO system may help determine whether T-cell deficiency reflects hematopoietic or thymic intrinsic abnormalities and define the exact stage at which T-cell differentiation is blocked.	0
BACKGROUND:Point and copy number variant mutations in the PRRT2 gene have been identified in a variety of paroxysmal disorders and different types of epilepsy. In this study, we analyzed the phenotypes and PRRT2-related mutations in Chinese epilepsy children. METHODS:A total of 492 children with epilepsy were analyzed by whole exome sequencing (WES) and low-coverage massively parallel CNV sequencing (CNV-seq) to find the single nucleotide variants and copy number variations (CNVs). And quantitative polymerase chain reaction was utilized to verify the CNVs. Their clinical information was followed up. RESULTS:We found PRRT2-related mutations in 19 patients (10 males and nine females, six sporadic cases and 13 family cases). Twelve point mutations, four whole gene deletion, and three 16p11.2 deletions were detected. The clinical features of 39 patients in 19 families included one early childhood myoclonic epilepsy (ECME), one febrile seizure (FS), two infantile convulsions with paroxysmal choreoathetosis (ICCA), six paroxysmal kinesigenic dyskinesias (PKD), 12 benign infantile epilepsy (BIE), and 17 benign familial infantile epilepsy (BFIE). All patients had normal brain MRI. Interictal EEG showed only one patient had generalized polyspike wave and five patients had focal transient discharges. Focal seizures originating in the frontal region were recorded in one patient, two from the temporal region, and two from the occipital region. Most patients were treated effectively with VPA or OXC, and the child with myoclonic seizures was not sensitive to antiepileptic drugs. CONCLUSION:PRRT2 mutations can be inherited or de novo, mainly inherited. The clinical spectrum of PRRT2 mutation includes BIE, BFIE, ICCA, PKD, FS, and ECME. The PRRT2-related mutations contained point mutation, whole gene deletion and 16p11.2 deletions, and large microdeletion mutations mostly de novo. It is the first report of PRRT2 mutation found in ECME. Our report expands the mutation and clinical spectrum of PRRT2-related epilepsy.	0
The importance of the complete absence of a hemidiaphragm or unilateral diaphragmatic agenesis in adulthood in relation to performing laparoscopic procedures has not been well documented. This article reports for the first time in literature a case of successful laparoscopic cholecystectomy in an adult with previously undiagnosed unilateral diaphragmatic agenesis. A 36-year-old female complaining of stubborn right upper abdominal pain radiating to her upper back was diagnosed as having cholelithiasis and was scheduled for laparoscopic cholecystectomy. There were also bilateral upper extremity malformations to a certain level. Routine diagnostic tests demonstrated that her entire liver and some bowel loops were in the right hemithorax, suggesting right-sided diaphragmatic hernia. Laparoscopic procedure was performed with the insertion of four trocars. Exploration of abdomen revealed total absence of the right hemidiaphragm. Cholecystectomy was completed laparoscopically in about 45 minutes without need for additional trocars. Patient had an uneventful recovery and was discharged on the second postoperative day without any complaint. Laparoscopic cholecystectomy in adults with diaphragmatic agenesis and intrathoracic abdominal viscera can be performed successfully. Nevertheless, any bile duct aberrations must be documented prior to surgery, and the surgeon should be able to convert to open procedure if necessary.	0
Craniopharyngiomas are rare benign epithelial tumors, arising from the pituitary stalk or gland and developing in the sellar and suprasellar region, affecting both adults and children. Incidence is 0.5 to 2 new cases per million inhabitants. Clinical features essentially include visual disturbances, endocrine deficiencies, and neurological signs. Initial signs are often visual loss and increased intracranial pressure in children, growth and pubertal delay in teenagers, visual disturbances or cognitive impairment in adults. Diagnosis is made on MRI and CT scan, demonstrating a sellar or suprasellar tumor, heterogeneous, with frequent calcifications. Craniopharyngiomas can be classified depending on their locations from the sella, the diaphragma sellae, and upon their origins from the pituitary stalk or the infundibulum. They can also be classified depending on the location from the optic chiasm and the third ventricle. This classification allows surgical series comparison, which is of importance since developments and extensions of the tumor can explain surgical difficulties. The management of this lesion is still controversial. Because it is an extra-cerebral benign lesion, the ideal goal of treatment should be complete tumor removal with improvement of altered visual functions, minimal deterioration of endocrine function, and no neuropsychological impairment. But the situation of the tumor, its relationship with third ventricle, hypothalamus, optic tract, vascular structures make its removal often difficult. However, great progresses have been realized in surgical treatment, resulting in a dramatic improvement of the prognosis of craniopharyngiomas. Nowadays, one can expect total removal in 60 to 70% of patients, subtotal removal in 20 to 30%, and partial removal in 10%. When total removal is impossible, radiotherapy may reduce the risk of a poor evolution. Recurrences are a problem in 15% of patients with total removal, 35% in subtotal removal, 70% in partial removal. If radiotherapy has not been performed as first treatment, it is efficient in 80% of recurrences. Long term follow up is necessary in these patients, due to medical management of endocrine, visual and psychological problems, and risk of late recurrence. With close involvement in this management, most of patients may enjoy a good outcome, 80% being able to return to normal active life.	1
Ganglioneuroma is a rare tumor. Such tumor arising from cranial nerve is further rare. So far our knowledge, in the literature there is no report of ganglioneuroma involving glossopharyngeal nerve. Here, we report a case of very small glossopharyngeal nerve ganglioneuroma and the patient also had longstanding glossopharyngeal neuralgia (GPN). Case Report: A 40-year-old male diagnosed case of left GPN for last 7 years presented with gradual unresponsiveness of drug for last 5 years. Due to severity of pain sometime, he wished to do suicide. Magnetic resonance imaging (MRI) of head revealed only suspected loop of vessel in root entry zones of 9th and 10 cranial nerves on left side. The patient underwent explorative posterior fossa craniotomy. Careful dissection of arachnoid over 9th cranial nerve near jugular foramen (JF) revealed thick and red color nerve with nodularity (tumor like). Dissection of arachnoid at nerve root entry zones of 9th and 10th nerves also revealed an aberrant loop of posterior inferior cerebellar artery (PICA). The 9th nerve was transected and suspected "tumorous portion" of nerve was sent for histopathological examination. The PICA loop was dissected away from root entry zones by placing muscle and surgical between 10th nerve roots and PICA loop. He made an uneventful recovery. Histopathological examination revealed ganglioneuroma. Immunohistochemistry confirmed ganglioneuroma. Six months after the operation, he was free of symptoms. In this case, probably previously existing GPN was worsen by the growth of ganglioneuroma and surgical treatment brought gratifying result.	0
Obtaining reliable and high fidelity next-generation sequencing (NGS) data requires to choose a suitable sequencing platform and a library preparation approach, which both have their inherent assay-specific limitations. Here, we present the results of successful adaptation of SureSelect hybridisation-based target enrichment protocol for the sequencing on the Ion Torrent S5 platform, which is designed to work preferably with amplicon-based panels. In our study, we applied a custom NGS panel to screen a cohort of 16 unrelated patients affected by premature fusion of the cranial sutures, i.e. craniosynostosis (CS). CS occurs either as an isolated malformation or in a syndromic form, representing a genetically heterogeneous and clinically variable group of disorders. The approach presented here allowed us to achieve high quality NGS data and confirmed molecular diagnosis in 19% of cases, reaching the diagnostic yield similar to some of the published research reports. In conclusion, we demonstrated that an alternative enrichment strategy for library preparations can be successfully applied prior to sequencing on the Ion Torrent S5 platform. Also, we proved that the custom NGS panel designed by us represents a useful and effective tool in the molecular diagnostics of patients with CS.	0
Androgen receptor (AR) is essential for maintaining normal spermatogenesis and male fertility, and its mutation can cause complete or partial androgen insensitivity syndrome (CAIS or PAIS) in patients. We established an induced pluripotent stem cell line (SKLRMi001-A) from a PAIS patient with AR mutation (c.2710G > A; p. V904M). The iPSC line expressed pluripotency markers, retained normal karyotype, carried the mutation, showed capability of differentiating into three germ layers and was absence of mycoplasma infection. The iPSC line will help to further elucidate the pathogenic mechanisms of AR mutation, and benefit treatment for PAIS in the future.	0
BACKGROUND:Thin nodular melanoma (NM) often lacks conspicuous melanoma-specific dermatoscopic criteria, and escapes clinical detection until it progresses to a thicker and more advanced tumor. OBJECTIVE:To investigate the dermatoscopic morphology of thin (≤2mm Breslow thickness) versus thick (>2mm) NM and to identify dermatoscopic predictors of its differential diagnosis from other nodular tumors. METHODS:Retrospective, morphological case-control study, conducted on behalf of the International Dermoscopy Society. Dermatoscopic images of NM and other nodular tumors from 19 skin cancer centers worldwide were collected and analyzed. RESULTS:Overall, 254 tumors were collected (69 NM of Breslow thickness ≤ 2 mm, 96 NM >2mm and 89 non-melanoma nodular lesions). Light brown coloration (50.7%) and irregular brown dots/globules (42.0%) were most frequently observed in ≤2mm NMs. Multivariate analysis revealed that dotted vessels (3.4-fold), white shiny streaks (2.9-fold) and irregular blue structureless area (2.4-fold) were predictors for thinner NM compared to non-melanoma nodular tumors. Overall, irregular blue structureless area (3.4-fold), dotted vessels (4.6-fold) and serpentine vessels (1.9-fold) were predictors of all NM compared to non-melanoma nodular lesions. LIMITATIONS:Absence of a centralized, consensus pathology review and cases selected form tertiary centers maybe not reflecting the broader community. CONCLUSIONS:Our study sheds light into the dermatoscopic morphology of thin NM in comparison to thicker NM and could provide useful clues for its differential diagnosis from other non-melanoma nodular tumors.	0
In inherited retinal diseases such retinitis pigmentosa, characterized by progressive loss of light sensitive neurons (photoreceptors), cell therapy is now considered as an attractive strategy. Photoreceptor cell replacement would be valuable for restoring function to retinas in a way that is independent from the cause of the disease. With advances in stem cell biology, considerable strides have been made towards the generation of retinal cells, in particular with the development of 3D culture systems allowing the generation of retinal organoids from pluripotent stem cells. In this review, we present a state-of-the art of preclinical strategies conducted in animal models for photoreceptor replacement from stem cell-derived photoreceptors and we discuss the important obstacles to overcome in the future.	0
AIMS:Amiodarone (AMIO) is currently used in medical practice to reverse ventricular tachycardia. Here we determine the effects of AMIO in the electromechanical properties of isolated left ventricle myocyte (LVM) from mice and guinea pig and in a cellular model of Long QT Syndrome Type 3 (LQTS-3) using anemone neurotoxin 2 (ATX II), which induces increase of late sodium current in LVM. MAIN METHODS AND KEY FINDINGS:Using patch-clamp technique, fluorescence imaging to detect cellular Ca2+ transient and sarcomere detection systems we evaluate the effect of AMIO in healthy LVM. AMIO produced a significant reduction in the percentage of sarcomere shortening (0.1, 1 and 10 μM) in a range of pacing frequencies, however, without significant attenuation of Ca2+ transient. Also, 10 μM of AMIO caused the opposite effect on action potential repolarization of mouse and guinea pig LVM. When LVM from mouse and guinea pig were paced in a range of pacing frequencies and exposed to ATX (10 nM), AMIO (10 μM) was only able to abrogate electromechanical arrhythmias in LVM from guinea pig at lower pacing frequency. SIGNIFICANCE:AMIO has negative inotropic effect with opposite effect on action potential waveform in mouse and guinea pig LVM. Furthermore, the antiarrhythmic action of AMIO in LQTS-3 is species and frequency-dependent, which indicates that AMIO may be beneficial for some types of arrhythmias related to late sodium current.	0
Hypertrophic cardiomyopathy (HCM) is a group of myocardial diseases defined by cardiac hypertrophy which cannot be explained by secondary causes with a non-dilated left ventricle and preserved or increased ejection fraction. Sometimes it can be combined with restrictive cardiomyopathy. Here we describe a very rare case of a 12-year-old girl with non-obstructive hypertrophic cardiomyopathy accompanied by restrictive phenotype, complete left bundle branch block and intermittent third-degree atrioventricular block, who presented with recurrent syncope. Her father was also found to have hypertrophic cardiomyopathy and treated with implantable cardioverter defibrillator for ventricular tachycardia. Her younger brother is currently asymptomatic but echocardiogram showed hypertrophic cardiomyopathy. Genetic analysis identified a heterozygous missense mutation (c.2155C>T, p.R719W) of MYH7 in the proband girl, her father and her brother. The girl was treated with left bundle pacing and recovered well. The case we present further demonstrates the feasibility of left bundle pacing in children.	0
Cockayne syndrome (CS) is a rare genetic disorder caused by mutations (dysfunction) in CSA and CSB. CS patients exhibit mild photosensitivity and severe neurological problems. Currently, CS diagnosis is based on the inefficiency of CS cells to recover RNA synthesis upon genotoxic (UV) stress. Indeed, upon genotoxic stress, ATF3, an immediate early gene is activated to repress up to 5000 genes encompassing its responsive element for a short period of time. On the contrary in CS cells, CSA and CSB dysfunction impairs the degradation of the chromatin-bound ATF3, leading to a permanent transcriptional arrest as observed by immunofluorescence and ChIP followed by RT-PCR. We analysed ChIP-seq of Pol II and ATF3 promoter occupation analysis and RNA sequencing-based gene expression profiling in CS cells, as well as performed immunofluorescence study of ATF3 protein stability and quantitative RT-PCR screening in 64 patient cell lines. We show that the analysis of few amount (as for example CDK5RAP2, NIPBL and NRG1) of ATF3 dependent genes, could serve as prominent molecular markers to discriminate between CS and non-CS patient's cells. Such assay can significantly simplify the timing and the complexity of the CS diagnostic procedure in comparison to the currently available methods.	0
Fowler syndrome is a rare autosomal recessive brain vascular disorder caused by mutation in FLVCR2 in humans. The disease occurs during a critical period of brain vascular development, is characterized by glomeruloid vasculopathy and hydrocephalus, and is almost invariably prenatally fatal. Here, we sought to gain insights into the process of brain vascularization and the pathogenesis of Fowler syndrome by inactivating Flvcr2 in mice. We showed that Flvcr2 was necessary for angiogenic sprouting in the brain, but surprisingly dispensable for maintaining the blood-brain barrier. Endothelial cells lacking Flvcr2 had altered expression of angiogenic factors, failed to adopt tip cell properties, and displayed reduced sprouting, leading to vascular malformations similar to those seen in humans with Fowler syndrome. Brain hypovascularization was associated with hypoxia and tissue infarction, ultimately causing hydrocephalus and death of mutant animals. Strikingly, despite severe vascular anomalies and brain tissue infarction, the blood-brain barrier was maintained in Flvcr2 mutant mice. Our Fowler syndrome model therefore defined the pathobiology of this disease and provided new insights into brain angiogenesis by showing uncoupling of vessel morphogenesis and blood-brain barrier formation.	0
BACKGROUND:VACTERL association is a sporadic, nonrandom series of congenital malformations diagnosed by the presence of three or more of the following: vertebral malformations, anal atresia, cardiac defects, tracheoesophageal fistula, renal malformations, and limb malformations. Situs inversus totalis (SIT) and esophageal malformations are rarely associated. This is the first reported case in North America of VACTERL association with SIT. IMPLICATIONS FOR PRACTICE:Respiratory distress in the term infant requires full exploration of all possible causes because the etiology may be far more complex than routinely diagnosed respiratory distress syndrome. This particular case demonstrates physical exam findings and supportive imaging that would be observed in infants with VACTERL association and with SIT, highlighting considerations when, rarely, both occur simultaneously.	0
PURPOSE:To investigate whether the natural progression rate of retinitis pigmentosa can be decreased by subtenon autologous platelet-rich plasma application alone or combination with retinal electromagnetic stimulation. METHODS:The study includes retrospective analysis of 60 patients with retinitis pigmentosa. Patients constitute three groups with similar demographic characteristics: the combined management group (group 1) consists of 20 patients with retinitis pigmentosa (40 eyes) who received combined retinal electromagnetic stimulation and subtenon platelet-rich plasma; the subtenon platelet-rich plasma-only group (group 2) consisted of 20 patients with retinitis pigmentosa (40 eyes); the natural course (control) group (group 3) consists of 20 patients with retinitis pigmentosa (40 eyes) who did not receive any treatment. Horizontal and vertical ellipsoid zone width, fundus perimetry deviation index, and best corrected visual acuity changes were compared within and between groups after a 1-year follow-up period. RESULTS:Detected horizontal ellipsoid zone percentage changes were + 1% in group 1, - 2.85% in group 2, and - 9.36% in group 3 (Δp 1 > 2 > 3). Detected vertical ellipsoid zone percentage changes were + 0.34% in group 1, - 3.05% in group 2, and - 9.09% in group 3 (Δp 1 > 2 > 3). Detected fundus perimetry deviation index percentage changes were + 0.05% in group 1, - 2.68% in group 2, and - 8.78% in group 3 (Δp 1 > 2 > 3). CONCLUSION:Platelet-rich plasma is a good source of growth factors, but its half-life is 4-6 months. Subtenon autologous platelet-rich plasma might more effectively slow down photoreceptor loss when repeated as booster injections and combined with retinal electromagnetic stimulation. TRIAL REGISTRATION:ClinicalTrials.gov identifier, NCT04252534.	0
This study reports on the use of whole exome sequencing (WES) to diagnose children with inborn errors of metabolism and other disorders in United Arab Emirates.From January 2012 to December 2014, 85 patients (46 % females) were seen in the metabolic center at Tawam Hospital (Abu Dhabi) and WES testing was requested because definitive diagnoses were not reached by conventional methods.Eighty (93 %) patients were <18 years old and 44 (52 %) were <5 years. Sixty-eight (80 %) patients had neurologic abnormalities. WES facilitated rapid diagnosis in 50 % of the patients, especially those with mitochondrial disorders. Yet, in most cases extensive investigation was required after the results were available. Most patients with confirmed molecular diagnoses had autosomal recessive disorders and were homozygous for the rare alleles. Most patients with autosomal dominant disorders and all patients with X-linked disorders had de novo mutations. WES results were negative (no pathogenic variants related to patient phenotype were identified) in six patients and incorrect in two patients. One patient had a reported "deleterious" hemizygous mutation in SLC35A2, c.617_620del (p.Q206fs), suggesting 'congenital disorder of glycosylation, TYPE IIm', but glycosylation studies were normal and healthy brothers had the same mutation. Another patient had "pathogenic" mutation in MCCC2, c.1015G > A (p.V339M), but urine organic acids was normal. WES confirmed inborn errors of metabolism (five mitochondrial diseases, three lysosomal storage diseases, and six other disorders) in 14 patients and genetic disorders (14 neurological diseases and three non-neurological diseases) in 17 patients. Variants of unknown significance were identified in 48 patients; 12 had "confirmed pathologic variants"and 12 had "likely pathologic variants", based on consistent phenotypes, biochemical/ segregation studies, or reported pathogenicity. In 24 patients, the variants were inconsistent with phenotypes or biochemical/ familial studies.Although WES provided molecular diagnoses, the results required careful interpretations and many patients required additional investigations. This tool is useful when conventional diagnostic methods fail. Staff competence in obtaining consent/ permission, interpreting the findings, and providing the proper counseling are essential before incorporating this technology into routine clinical practices.	0
A 22-year-old Hispanic man with sickle cell trait presented with blurred vision, double vision, and pain with OD movement. MRI demonstrated an extra-axial mass centered around the temporal bone with extension into the middle cranial fossa and lateral aspect of the extra-conal right orbit, and mass effect on the lateral rectus muscle. Biopsy of the lesion was consistent with renal medullary carcinoma. CT chest/abdomen/pelvis confirmed a primary tumor in the right kidney. No additional metastases were found. Renal medullary carcinoma is a rare, highly aggressive malignancy, which almost exclusively affects young men of African descent with sickle cell trait or sickle cell disease. The authors present the second confirmed case of renal medullary carcinoma metastatic to the orbit, with ocular symptoms prior the typical presenting symptoms of flank pain and hematuria.Renal medullary carcinoma is a highly aggressive malignancy, most commonly seen in African American patients with sickle cell disease. Involvement of the orbit is rare and visual symptoms may precede systemic diagnosis.	0
This study was the first to evaluate the influence of the combination strategies of flavor addition and microwave-assisted thermal sterilization (MATS) processing for salt reduction implications. In freshly prepared mashed potatoes, a 30% and 50% salt reduction (w/w) in comparison to a 100% salt sample with three flavor variations (no additional flavor, garlic, and pepper) were investigated. Also, using the ideal profile method (IPM), the influence of MATS versus retort processing, in comparison to a freshly prepared sample, and flavor addition on mashed potato sensory properties and acceptance was investigated. Chemical characterization using the electronic tongue for nonvolatile compounds and headspace solid-phase microextraction (HS-SPME)/gas chromatography-mass spectrometry (GC-MS) for volatile analysis was completed. IPM revealed the ideal data were consistent at both the panel and consumer levels from a sensory and hedonic perspective. Results demonstrated the ideal mashed potato product would remain low in bitterness but have more intense pepper and potato aromas and flavors than the current samples evaluated. The salt level could be reduced by 50% while still maintaining flavor and overall acceptance in freshly prepared samples, but this was accompanied by a loss in saltiness intensity perception. The saltiness intensity was not different from the freshly prepared samples when processed via MATS but was different when processed by the retort. For chemical characterization, the electronic tongue showed a high discrimination index (>89%) and correlated highly (>0.8) with many sensory attributes. As salt concentration in the mashed potatoes decreased, the recovery of volatile compounds decreased. The present work contributes to the understanding of product reformulation for the purpose of salt reduction. PRACTICAL APPLICATION: Product developers need strategies to bring salt down to target levels while maintaining consumer acceptance. The combination strategies of flavor addition and MATS processing may allow for a new strategy to assist product developers in reaching salt reduction targets. Furthermore, developers should bear in mind that noticeable intensity differences may not alter the preference for the product. Thus, intensity differences that result in changes in acceptance should be the focus of quality insurance rather than utilizing just noticeable differences.	0
Diffuse panbronchiolitis (DPB) is a rare progressive and eventually fatal pulmonary disease first identified in Japan and initially seen predominantly in Southeast Asia. Macrolide antibiotics rapidly reverse symptoms and pathology, and their use increased the 5 and 10-year survival from 50 and 30 percent, respectively, to over 90%. Review of 181 case reports from previous publications found patients with DPB commonly had their pulmonary symptoms preceded by rhinosinusitis, frequently by many years. Long delays in diagnosis for many years were common. The review further identified DPB in all ethnic groups and multiple areas outside of Southeast Asia. Although diagnosis was most commonly made in adults, 13% of the diagnoses were made in children and nine of the adult cases described onset in childhood. Few cases of relapse were reported, but extended periods of monitoring after treatment were not generally present.	0
Endocardial fibroelastosis (EFE) is primarily a disease of infants and children, but can rarely present in adulthood as well.[1] In 1943, endocardial fibroelastosis term was coined by Weinberg et al. in children who presented with unexplained heart failure previously known as 'fetal endocarditis.'[2] It is broadly defined as the thickening of endocardium due to the excessive proliferation of fibrous and elastic tissue.[3]  The endocardium is normally a thin layer of endothelial cells lining the inner side of heart chambers. The presentation is versatile and is often overlapping with other cardiac anomalies. It is frequently noticed with other congenital heart conditions like hypoplastic left heart syndrome.[4] Cases have been reported where the anomalous left coronary artery from the pulmonary artery (ALCAPA) was initially labeled as EFE due to similar echocardiographic findings.[5] Hence, it is pertinent to know conditions that can present similar to EFE as well. The detail is mentioned in the differential diagnosis section.	0
Palmoplantar keratoderma (PPK) is a defect in cornification that is characterized by progressive hyperkeratosis of palms and soles. Many phenotypes are linked with PPK, making exome-based diagnosis increasingly efficient. In this report, we identified tyrosinemia type II on whole-exome sequencing in a 7-year-old Syrian refugee that presented with PPK. Dietary therapy helped improve her overall symptoms.	0
INTRODUCTION:Anorectal malformations (ARM) in newborns classically present with the absence of a normal anus or an abnormally located anus. In a male infant with a high ARM, an initial diverting colostomy is later followed by a definitive posterior sagittal anorectoplasty (PSARP). Prior to definitive surgery an augmented-pressure colostogram is performed to identify the location of the fistula between the rectum and urogenital tract. However, on occasion, the augmented-pressure colostogram fails to identify the location of the fistula tract. We present a case of ARM where augmented-pressure colostogram failed to identify a fistula tract, thus requiring an alternative diagnostic approach. PRESENTATION OF CASE:A newborn male presented with a high anorectal malformation and suspected rectourinary fistula on initial augmented-pressure colostogram. The patient ultimately underwent a laparoscopic assisted PSARP after cystoscopy with air colostogram identified the exact location of the fistulous connection in the prostatic urethra. DISCUSSION:Augmented-pressure colostogram remains the gold standard in diagnosing rectourinary fistulae in cases of ARM. However, a number of alternative and adjunctive techniques have been proposed in recent years. We provide a brief review of the literature in addition to a case presentation highlighting the potential benefits of pre-operative cystoscopy-assisted air colostogram in male patients with ARM. CONCLUSION:Cystoscopy-assisted air colostogram via a distal mucous fistula can be utilized as an alternative diagnostic modality, especially when the augmented-pressure distal colostogram fails to identify rectourinary fistulae in high anorectal malformations.	0
Acrocallosal syndrome (ACLS) is an autosomal recessive neurodevelopmental disorder caused by KIF7 defects and belongs to the heterogeneous group of ciliopathies related to Joubert syndrome (JBTS). While ACLS is characterized by macrocephaly, prominent forehead, depressed nasal bridge, and hypertelorism, facial dysmorphism has not been emphasized in JBTS cohorts with molecular diagnosis. To evaluate the specificity and etiology of ACLS craniofacial features, we performed whole exome or targeted Sanger sequencing in patients with the aforementioned overlapping craniofacial appearance but variable additional ciliopathy features followed by functional studies. We found (likely) pathogenic variants of KIF7 in 5 out of 9 families, including the original ACLS patients, and delineated 1000 to 4000-year-old Swiss founder alleles. Three of the remaining families had (likely) pathogenic variants in the JBTS gene C5orf42, and one patient had a novel de novo frameshift variant in SHH known to cause autosomal dominant holoprosencephaly. In accordance with the patients' craniofacial anomalies, we showed facial midline widening after silencing of C5orf42 in chicken embryos. We further supported the link between KIF7, SHH, and C5orf42 by demonstrating abnormal primary cilia and diminished response to a SHH agonist in fibroblasts of C5orf42-mutated patients, as well as axonal pathfinding errors in C5orf42-silenced chicken embryos similar to those observed after perturbation of Shh signaling. Our findings, therefore, suggest that beside the neurodevelopmental features, macrocephaly and facial widening are likely more general signs of disturbed SHH signaling. Nevertheless, long-term follow-up revealed that C5orf42-mutated patients showed catch-up development and fainting of facial features contrary to KIF7-mutated patients.	0
We describe two brothers with congenital lymphedema of lower limbs, atrial septal defect (ASD), and similar facial appearance. A sister had severe hydrops fetalis, ASD, omphalocele, and other anomalies. This combination of congenital lymphedema and ASD differs from other reported cases of congenital lymphedema and most likely constitutes a previously unrecognized autosomal recessive syndrome.	0
PCNT encodes a large coiled- protein localizing to pericentriolar material and is associated with microcephalic osteodysplastic primordial dwarfism type II syndrome (MOPD II). We report our experience of nine new patients from seven unrelated consanguineous Egyptian families with the distinctive clinical features of MOPD II in whom a customized NGS panel showed homozygous truncating variants of PCNT. The NGS panel results were validated thereafter using Sanger sequencing revealing three previously reported and three novel PCNT pathogenic variants. The core phenotype appeared homogeneous to what had been reported before although patients differed in the severity showing inter and intra familial variability. The orodental pattern showed atrophic alveolar ridge (five patients), rootless tooth (four patients), tooth agenesis (three patients), and malformed tooth (three patients). In addition, mesiodens was a novel finding found in one patient. The novel c.9394-1G>T variant was found in two sibs who had tooth agenesis. CNS anomalies with possible vascular sequelae were documented in two male patients (22.2%). Simplified gyral pattern with poor development of the frontal horns of lateral ventricles was seen in four patients and mild thinning of the corpus callosum in two patients. Unilateral coronal craniosynstosis was noted in one patient and thick but short corpus callosum was an unusual finding noted in another. The later has not been reported before. Our results refine the clinical, neuroradiological, and orodental features and expand the molecular spectrum of MOPD II.	0
Purpose:To assess the corneal endothelium in patients with Fuchs heterochromic iridocyclitis (FHI) and compare it with the normal fellow eye. Methods:Retrospective, observational, cross-sectional study of 31 patients seen between Jan 2016 to Dec 2018, with clinical diagnosis of Fuchs heterochromic iridocyclitis, was performed. Specular microscopic examination was documented in both eyes. The affected eyes formed the study group and the fellow healthy eyes served as controls. Results:The mean age of the patients was 29.9 ± 8.2 years. The endothelial cell density (P = 0.0001) was significantly lower, whereas average cell size (P = 0.0001), coefficient of variation (P = 0.004), and maximum cell area (P = 0.01) were significantly higher in the affected eye compared to the control eye. In three patients, the affected eye showed guttae, while the healthy fellow eye revealed a normal specular mosaic. Conclusion:Specular microscopic analysis shows endothelial alterations in the affected eyes in FHI.	0
The inner ear is a morphologically complex sensory structure with auditory and vestibular functions. The developing otic epithelium gives rise to neurosensory and non-sensory elements of the adult membranous labyrinth. Extrinsic and intrinsic signals manage the patterning and cell specification of the developing otic epithelium by establishing lineage-restricted compartments defined in turn by differential expression of regulatory genes. FGF3 and FGF16 are excellent candidates to govern these developmental events. Using the chick inner ear, we show that Fgf3 expression is present in the borders of all developing cristae. Strong Fgf16 expression was detected in a portion of the developing vertical and horizontal pouches, whereas the cristae show weaker or undetected Fgf16 expression at different developmental stages. Concerning the rest of the vestibular sensory elements, both the utricular and saccular maculae were Fgf3 positive. Interestingly, strong Fgf16 expression delimited these Fgf16-negative sensory patches. The Fgf3-negative macula neglecta and the Fgf3-positive macula lagena were included within weakly Fgf16-expressing areas. Therefore, different FGF-mediated mechanisms might regulate the specification of the anterior (utricular and saccular) and posterior (neglecta and lagena) maculae. In the developing cochlear duct, dynamic Fgf3 and Fgf16 expression suggests their cooperation in the early specification and later cell differentiation in the hearing system. The requirement of Fgf3 and Fgf16 genes in endolymphatic apparatus development and neurogenesis are discussed. Based on these observations, FGF3 and FGF16 seem to be key signaling pathways that control the inner ear plan by defining epithelial identities within the developing otic epithelium.	0
Melnick-Needles syndrome (MNS; MIM 309350) is an X-linked skeletal dysplasia caused by mutations in FLNA. Females with the condition present with characteristic facial features, short stature, skeletal anomalies, including poorly modeled and sclerotic bones, and structural abnormalities such as cardiac and urological defects. Previously males were thought to present with either a mild phenotype compatible with life or a severe lethal presentation depending on the maternal phenotype. The discovery of a limited number of mutations in FLNA as the cause of the condition has clarified the molecular basis of the disorder, but only a very small number of severely affected males have been reported with MNS. Furthermore, no mildly affected males have been described with a molecular confirmation of the condition. In this report, we describe the clinical and molecular findings of a mildly affected mother with MNS and her severely affected son. They shared a well-documented disease-causing variant in FLNA, p.(Ala1188Thr), one of two highly recurrent mutations leading to the disorder. This is only the fourth report of a male with perinatal lethal MNS and a molecular confirmation; it is the first description of this specific mutation in a male.	0
The case of a neonate with cutaneous lesions consistent with epidermal naevi is presented. In addition to typical epidermal naevi, this baby had an unusual, bullous form of aplasia cutis congenita. Although aplasia cutis has been described as bullous and has been found in association with the epidermal naevus syndrome, both of these occurrences are rare in medical publications. This case illustrates an unusual presentation of epidermal naevi with bullous aplasia cutis congenita and raises difficult diagnostic and counselling issues.	0
Transposition of the great arteries (TGA) and interruption of the aortic arch (IAA) are uncommon congenital heart diseases. The association between TGA and IAA is rare. The aim of this study is to present a case with combined TGA and IAA, who underwent the primary repair and review the literature with similar cases. The one-month-old patient was admitted with tachypnea and cyanosis. Delayed diagnosis was caused due to the absence of prenatal examination. Echocardiography and computed tomography angiography confirmed TGA with anterior-posterior-oriented great arteries, wide patent ductus arteriosus, type B IAA, ventricular septal defect (VSD) and pulmonary arterial hypertension. The patient underwent a single-stage primary surgical repair process leading to VSD closure, reconstruction of the aortic arch and arterial switch operation in October 2019. The patient is doing well at a 3-month follow-up post-surgery. The echocardiogram suggests a normal systolic function of the ventricles and trivial regurgitation for both aortic and pulmonary valves. CONCLUSIONS: The single-stage repair with VSD closure, reconstruction of aortic arch and arterial switch operation might be an applicable approach for most of the patients with combined TGA and IAA. Long term follow-up is required as a high re-intervention rate for recurrent coarctation, supravalvular aortic stenosis, neoaortic valve regurgitation, obstruction of the right heart system and coronary stenosis has been reported.	0
BACKGROUND:Benign recurrent intrahepatic cholestasis is a genetic disorder with recurrent cholestatic jaundice due to ATP8B1 and ABCB11 gene mutations encoding for hepato-canalicular transporters. Herein, we firstly provide the evidence that a nonsense variant of ATP8B1 gene (c.1558A>T) in heterozygous form is involved in BRIC pathogenesis. CASE SUMMARY:A 29-year-old male showed severe jaundice and laboratory tests consistent with intrahepatic cholestasis despite normal gamma-glutamyltranspeptidase. Acute and chronic liver diseases with viral, metabolic and autoimmune etiology were excluded. Normal intra/extra-hepatic bile ducts were demonstrated by magnetic resonance. Liver biopsy showed: Cholestasis in the centrilobular and intermediate zones with bile plugs and intra-hepatocyte pigment, Kupffer's cell activation/hyperplasia and preserved biliary ducts. Being satisfied benign recurrent intrahepatic cholestasis diagnostic criteria, ATP8B1 and ABCB11 gene analysis was performed. Surprisingly, we found a novel nonsense variant of ATP8B1 gene (c.1558A>T) in heterozygosis. The variant was confirmed by Sanger sequencing following a standard protocol and tested for familial segregation, showing a maternal inheritance. Immunohistochemistry confirmed a significant reduction of mutated gene related protein (familial intrahepatic cholestasis 1). The patient was treated with ursodeoxycholic acid 15 mg/kg per day and colestyramine 8 g daily with total bilirubin decrease and normalization at the 6th and 12th mo. CONCLUSION:A genetic abnormality, different from those already known, could be involved in familial intrahepatic cholestatic disorders and/or pro-cholestatic genetic predisposition, thus encouraging further mutation detection in this field.	0
Cystathionine β-synthase (CBS)-deficient patients are prone to vascular thrombosis. In contrast, Cbs-/- mice show no abnormalities in blood coagulation. To identify molecular basis underlying these disparately different thrombotic phenotypes, we analyzed plasma proteomes of Cbs-/- vs. Cbs+/+ mice (8-month-old, 12/group, sex-matched) and CBS-/- vs. CBS+/+ humans (37 ± 7-year-old, 10-14/group, sex-matched) using label-free mass spectrometry. We identified 117 and 41 differentiating plasma proteins in Cbs-/- mice and CBS-/- humans, respectively. Twenty-one proteins were shared between CBS-/- humans and Cbs-/- mice, with sixteen changed in the opposite direction. Proteins involved in blood coagulation and complement/coagulation cascades represented a greater fraction of the differentiating proteins in CBS-/- patients (51%) than in Cbs-/- mice (21%). Top canonical pathways, identified by Ingenuity Pathways Analysis, such as LXR/RXR, FXR/RXR activation (- log[P-value] = 30-31) and atherosclerosis signaling (- log[P-value] = 10-11) were similarly affected in Cbs-/- mice and CBS-/- humans. The Coagulation System was affected stronger in CBS-/- humans than in Cbs-/- mice (- log[P-value] = 15 vs. 10, respectively) while acute phase response and complement system were affected stronger in Cbs-/- mice (- log[P-value] = 33 and 22, respectively) than in humans (- log[P-value] = 22 and 6, respectively). Other pathways, including IL-7 signaling and B cell development were affected only in Cbs-/- mice. Taken together, our findings suggest that differences in these processes, in particular in the Coagulation System, could account for the thrombotic phenotype in CBS-/- patients and the absence of thrombosis in Cbs-/- mice. Overall, our findings suggest that Cbs-/- mice have a better adaptive response to protect from prothrombotic effects of hyperhomocysteinemia than CBS-/- humans.	0
Pili annulati is a rare hair shaft abnormality and, as far as we know, there are no published data on pili annulati's racial distribution. To our knowledge, this is the first case reported in an African-American patient.	0
Biliary atresia (BA) is a devastating fibro-inflammatory disease characterized by the obstruction of extrahepatic and intrahepatic bile ducts in infants that can have fatal consequences, when not treated in a timely manner. It is the most common indication of pediatric liver transplantation worldwide and the development of new therapies, to alleviate the need of surgical intervention, has been hindered due to its complexity and lack of understanding of the disease pathogenesis. For that reason, significant efforts have been made toward the development of experimental models and strategies to understand the etiology and disease mechanisms and to identify novel therapeutic targets. The only characterized model of BA, using a Rhesus Rotavirus Type A infection of newborn BALB/c mice, has enabled the identification of key cellular and molecular targets involved in epithelial injury and duct obstruction. However, the establishment of an unleashed chronic inflammation followed by a progressive pathological wound healing process remains poorly understood. Like T cells, macrophages can adopt different functional programs [pro-inflammatory (M1) and resolutive (M2) macrophages] and influence the surrounding cytokine environment and the cell response to injury. In this review, we provide an overview of the immunopathogenesis of BA, discuss the implication of innate immunity in the disease pathogenesis and highlight their suitability as therapeutic targets.	0
BACKGROUND:Ectodermal dysplasias (ED) are a group of diseases that affects the development or function of the teeth, hair, nails and exocrine and sebaceous glands. One type of ED, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC or Hay-Wells syndrome), is an autosomal dominant disease characterized by the presence of skin erosions affecting the palms, soles and scalp. Other clinical manifestations include ankyloblepharon filiforme adnatum, cleft lip, cleft palate, craniofacial abnormalities and ectodermal defects such as sparse wiry hair, nail changes, dental changes, and subjective hypohydrosis. CASE PRESENTATION:We describe a patient presenting clinical features reminiscent of AEC syndrome in addition to recurrent infections suggestive of immune deficiency. Genetic testing for TP63, IRF6 and RIPK4 was negative. Microarray analysis revealed a 2 MB deletion on chromosome 1 (1q21.1q21.2). Clinical exome sequencing uncovered compound heterozygous variants in CHUK; a maternally-inherited frameshift variant (c.1365del, p.Arg457Aspfs*6) and a de novo missense variant (c.1388C > A, p.Thr463Lys) on the paternal allele. CONCLUSIONS:To our knowledge, this is the fourth family reported with CHUK-deficiency and the second patient with immune abnormalities. This is the first case of CHUK-deficiency with compound heterozygous pathogenic variants, including one variant that arose de novo. In comparison to cases found in the literature, this patient demonstrates a less severe phenotype than previously described.	0
Alpers syndrome is a rare autosomal recessive hepatocerebral degenerative disorder. Seventeen patients with Alpers syndrome or polymerase-γ gene mutations were identified. Case records of 12 patients with Alpers syndrome and polymerase-γ mutations in both alleles were reviewed. All patients manifested developmental delay or regression, refractory epilepsy, and biochemical liver dysfunction. Liver failure occurred in three patients previously treated with valproate. Other signs included ataxia, visual disturbance, motor paresis, and tremor. Myoclonic and focal motor seizures were common, often manifesting as status epilepticus. Electroencephalograms demonstrated absent/slow posterior dominant rhythms. Interictal discharges were common, usually involving the occipital lobes. Rhythmic high-amplitude delta with (poly)spikes was evident in four patients. Magnetic resonance imaging showed migratory, cortical, and subcortical T(2) hyperintensities in four children most often affected the parietal and occipital lobes. Developmental regression and refractory focal motor or myoclonic seizures are consistent clinical features of Alpers syndrome with polymerase-γ mutations. Liver dysfunction constitutes a late manifestation. Migratory T(2)/fluid attenuated inversion recovery signal abnormalities involving metabolically active occipital and sensorimotor cortical regions comprise characteristic imaging findings. Interictal and ictal electroencephalogram patterns are more variable than previously reported. Three common polymerase-γ mutations, in patients of European descent, can assist with rapid diagnosis, circumventing the need for liver biopsy.	0
A 32-year-old man initially received a diagnosis of Duchenne muscular dystrophy (DMD). Genetic analysis revealed two novel heterozygous FKRP variants: c.169G>A (p.Glu57Lys) and c.692G>A (p.Trp231*). These results indicated that the patient had limb-girdle muscular dystrophy type 2I (LGMD2I) caused by recessive FKRP variants. Patients with LGMD2I and DMD have many overlapping phenotypes. LGMD2I should be considered in patients who have a DMD phenotype but not a DMD pathogenic variant.	0
BACKGROUND: Sex chromosomal abnormalities are relatively common, yet many aspects of these syndromes remain unexplored. For instance epidemiological data in 47,XYY persons are still limited. METHODS: Using a national Danish registry, we identified 208 persons with 47,XYY or a compatible karyotype, whereof 36 were deceased; all were diagnosed from 1968 to 2008. For further analyses, we identified age matched controls from the male background population (n = 20,078) in Statistics Denmark. We report nationwide prevalence data, data regarding age at diagnosis, as well as total and cause specific mortality data in these persons. RESULTS: The average prevalence was 14.2 47,XYY persons per 100,000, which is reduced compared to the expected 98 per 100,000. Their median age at diagnosis was 17.1 years. We found a significantly decreased lifespan from 77.9 years (controls) to 67.5 years (47,XYY persons). Total mortality was significantly increased compared to controls, with a hazard ratio of 3.6 (2.6-5.1). Dividing the causes of deaths according to the International Classification of Diseases, we identified an increased hazard ratio in all informative chapters, with a significantly increased ratio in cancer, pulmonary, neurological and unspecified diseases, and trauma. CONCLUSION: We here present national epidemiological data regarding 47,XYY syndrome, including prevalence and mortality data, showing a significantly delay to diagnosis, reduced life expectancy and an increased total and cause specific mortality.	1
Wnt, a secreted glycoprotein, has an approximate molecular weight of 40 kDa, and it is a cytokine involved in various biological phenomena including ontogeny, morphogenesis, carcinogenesis, and maintenance of stem cells. The Wnt signaling pathway can be classified into two main pathways: canonical and non-canonical. Of these, the canonical Wnt signaling pathway promotes osteogenesis. Sclerostin produced by osteocytes is an inhibitor of this pathway, thereby inhibiting osteogenesis. Recently, osteoporosis treatment using an anti-sclerostin therapy has been introduced. In this review, the basics of Wnt signaling, its role in bone metabolism and its involvement in skeletal disorders have been covered. Furthermore, the clinical significance and future scopes of Wnt signaling in osteoporosis, osteoarthritis, rheumatoid arthritis and neoplasia are discussed.	0
STUDY DESIGN: Retrospective observational study utilizing prospectively collected population-based data. OBJECTIVE: To describe the epidemiology and demographics of all patients with traumatic spinal cord injury (TSCI) treated at a single institution, which represents the sole referral center and specialized SCI unit for a population of 4 million people. SUMMARY OF BACKGROUND DATA: Although many studies report on the epidemiology of TSCI, studies in which patients are prospectively characterized in the acute setting with precise recording of their baseline neurological impairment are uncommon. METHODS: Data on all patients admitted to a level 1 trauma center with TSCI between 1995 and 2004 were prospectively collected using a customized, fully relational, locally designed, spine database. RESULTS: The incidence of TSCI averaged 35.7 per million and did not change substantially during 10 years of data collection. However, the median age of TSCI patients increased from 34.5 to 45.5 years during this period. The men-to-women ratio was 4.4:1. In those older than 55 years, cervical-level injuries with incomplete American Spinal Injury Association (ASIA) Impairment Scale (AIS) scores C and D were most common, with men demonstrating predominantly lower cervical injuries and women more likely to exhibit upper cervical injuries. Increasing rates of surgical treatment during 10 years of this study (61.8%-86.4%) were not associated with improvements in mortality rate or length of hospital stay. Patients older than 75 years who presented with an acute TSCI had a mortality rate of 20% while in hospital. CONCLUSION: The incidence of TSCI in our population has remained remarkably stable, and age-related changes mirror those in the population across 10 years. An increased tendency to surgical treatment during the 10 years of this study has not resulted in concomitant changes in patients' in-hospital mortality or length of stay.	1
4H leukodystrophy, also known as Pol III-related leukodystrophy, is a rare autosomal recessive neurodegenerative disorder characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. It is caused by biallelic mutations in POLR3A, POL3RB, or POLR1C. So far, only two patients have been described with homozygosity for the common c.1568T>A (p.Val523Glu) POLR3B mutation, both of them showing a remarkably mild clinical course. Here, we report another patient with homozygosity for the same mutation, but with a more severe phenotype including ataxia, developmental delay, and intellectual disability. This information is of importance for clinicians to provide comprehensive counseling to patients with 4H leukodystrophy and their families.	0
Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506∗ and p.Glu496∗ were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.	0
To establish the incidence of giant cell arteritis (GCA), cumulative use of prednisolone, and comorbidities most associated with GCA.The data source was the UK Clinical Practice Research Datalink. Selection criteria included ≥1 record of a diagnostic term for GCA between January 1, 2000 and December 31, 2011, age ≥50 years, and ≥1 prescription of oral or systemic corticosteroid. Controls were selected randomly (2:1), with year of birth, practice, and followup duration (<2 or ≥2 years) as matching variables. Analysis was data driven; all comorbidities were identified in a 2-year window, with relative risk (RR) calculated and rank ordered.A total of 4,671 patients fulfilled the definition of GCA (incidence, 1.0 per 10,000 person-years), with highest incidence (7.4 per 10,000 person-years) in women ages 70-79 years. Of the 4,671 patients, 4,655 (99.7%) were prescribed prednisolone. In the group with ≥2 years' followup (n = 3,074), the mean number of prednisolone prescriptions was 32.1, and the mean cumulative dose was 8,640 mg; 1,034 patients (33.4%) received a cumulative dose of ≥10,000 mg. Comorbidities strongly associated with GCA were polymyalgia rheumatica (RR 14.9, 95% confidence interval [95% CI] 11.9-18.7), visual disturbances (RR 4.6, 95% CI 2.7-7.8), facial pain (RR 3.3, 95% CI 2.1-5.3), osteoporosis (RR 2.9, 95% 2.3-3.7), hypokalemia (RR 2.5, 95% CI 1.6-3.9), and various infections such as oral/esophageal thrush (RR 3.7, 95% CI 2.2-6.0) and herpes zoster (RR 2.6, 95% CI 1.6-4.1).GCA is relatively uncommon; its incidence peaks at age 70-79 years in women. Overall, GCA patients in the UK are treated with high cumulative prednisolone doses. Many conditions are associated with GCA, including several related to corticosteroid use.	1
A 22-year-old woman with rapidly progressing metastatic paraganglioma due to hereditary paraganglioma-pheochromocytoma syndrome from an SDHB mutation, who recurred after neoadjuvant chemotherapy, was found to be MIBG avid. She was treated with 2 I-MIBG treatments and concurrent sunitinib, achieving a complete response. She was in full remission for 9 months before developing bone metastases.	0
Cutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability. Cutis laxa, autosomal recessive, type IIIA and autosomal dominant 3 syndromes are caused by autosomal recessive or de novo pathogenic variants in ALDH18A1. Autosomal recessive variants are known to lead to the most severe neurological phenotype, and very few patients have been described.We describe a 13-month-old patient with cutis laxa, autosomal recessive, type IIIA, with an extremely severe phenotype, including novel neurological findings. This description enlarges the neurological spectrum associated to cutis laxa, autosomal recessive, type IIIA, and provides an additional description of this syndrome.	0
Progressive multifocal leukoencephalopathy (PML) is a viral disease of the brain associated with immunodeficiency, immune suppressing medications, and malignancy. In the absence of effective anti-viral therapy for the causative JC virus, immune restoration has emerged as the critical therapeutic alternative. The evolving treatment of PML (and other rare JC virus-associated neurologic syndromes) requires consideration of baseline immune functioning and comorbid diseases while selecting from a number of therapeutic options to restore an effective immune response. This review focuses on the current options for management of PML in typical situations where this disease presents, including several where immune restoration is a standard therapeutic approach such as in PML associated with HIV/AIDS and in multiple sclerosis associated with natalizumab. Other circumstances in which PML occurs including associated with primary immunodeficiencies, malignancies, and transplants present greater challenges to immune reconstitution, but emerging concepts may enhance therapeutic options for these situations. Particular attention is focused on recent experience with checkpoint inhibitors, guidance for MS drug discontinuation, and strategies to monitor and facilitate immune restoration.	0
Purpose:To describe foveal sparing (FS) in central retinal dystrophies (RD). Methods:Participants for this retrospective study were identified from the retinal dystrophy database of the Department of Ophthalmology at Radboud University Medical Center. FS was defined as an intact foveal structure surrounded by at least 180° of chorioretinal atrophy, and a best-corrected visual acuity (BCVA) of <1.0 logMAR (>20/200 Snellen). Eligible eyes were identified using fundus autofluorescence (FAF) images, and FS was confirmed using near-infrared reflectance (NIR) imaging and spectral-domain optical coherence tomography when available. Clinical and demographic data were extracted from medical records. We performed quantification of FS and chorioretinal atrophic areas using semiautomated software on fundus autofluorescence and NIR images. We calculated the chronologic change using eye-wise linear regression. Results:We identified 36 patients (56 eyes) with FS. RDs included: Stargardt disease (STGD1;20 patients), central areolar choroidal dystrophy (CACD; 7 patients), mitochondrial retinal dystrophy (MRD; 6 patients), pseudo-Stargardt pattern dystrophy (PSPD; 3 patients). Median age at first presentation was 60 (interquartile range [IQR] 54-63) years. Median BCVA at first presentation ranged from 20/25 Snellen in STGD1, to 20/38 Snellen in MRD. Progression of the chorioretinal atrophic area ranged from 0.26 (0.25-0.28) mm/year in PSPD, to 0.14 (0.11-0.22) in CACD. Change in FS area over time was similar between the different dystrophies. Conclusions:The presence of FS in different RDs suggests a disease-independent mechanism that prolongs the survival of the fovea. The associated preservation of BCVA is important for the individual prognosis and has implications for the design of therapeutic trials for RDs.	0
Purpose Communication interactions between parents and children during shared book reading impact a child's development of both language and literacy skills. This study examined maternal language input and child expressive communication during a shared book reading activity in children with Down syndrome (DS) and children with typical development (TD). Additionally, children's receptive language was examined to understand the relationship between maternal language input and child receptive language ability. Method Participants included 22 children with DS and 22 children with TD between 22 and 63 months of age and their mothers. Each mother-child dyad participated in a 7-min naturalistic shared book reading activity. Results Compared to mothers of children with TD, mothers of children with DS used significantly more utterances with less grammatical complexity, but a similar range of vocabulary diversity. Mothers of children with DS used more questions, descriptions, gestures, and labels, whereas mothers of children with TD used nearly half of their utterances to read directly from books. Children with DS communicated at a similar frequency compared to their peers with TD; however, they produced significantly fewer spoken words. Conclusions This study reveals important differences between early shared book reading interactions and provides implications for future research targeting parent-coached intervention strategies that may enhance children's learning during shared book reading by providing access to expressive language and print instruction.	0
Infective endocarditis (IE) is a life-threatening disease associated with serious complications. The GBD 2010 (Global Burden of Disease, Injuries, and Risk Factors) study IE expert group conducted a systematic review of IE epidemiology literature to inform estimates of the burden on IE in 21 world regions in 1990 and 2010. The disease model of IE for the GBD 2010 study included IE death and 2 sequelae: stroke and valve surgery. Several medical and science databases were searched for IE epidemiology studies in GBD high-, low-, and middle-income regions published between 1980 and 2008. The epidemiologic parameters of interest were IE incidence, proportions of IE patients who developed stroke or underwent valve surgery, and case fatality. Literature searches yielded 1,975 unique papers, of which 115 published in 10 languages were included in the systematic review. Eligible studies were population-based (17%), multicenter hospital-based (11%), and single-center hospital-based studies (71%). Population-based studies were reported from only 6 world regions. Data were missing or sparse in many low- and middle-income regions. The crude incidence of IE ranged between 1.5 and 11.6 cases per 100,000 people and was reported from 10 countries. The overall mean proportion of IE patients that developed stroke was 0.158 ± 0.091, and the mean proportion of patients that underwent valve surgery was 0.324 ± 0.188. The mean case fatality risk was 0.211 ± 0.104. A systematic review for the GBD 2010 study provided IE epidemiology estimates for many world regions, but highlighted the lack of information about IE in low- and middle-income regions. More complete knowledge of the global burden of IE will require improved IE surveillance in all world regions.	1
The acrofacial dysostoses (AFD) are a clinically and causally heterogeneous group of conditions characterized by mandibulofacial dysostosis and a variety of limb anomalies. Several abnormalities affecting different internal organs and the central nervous system (CNS) have been described. Depending on the type of limb defects, two major groups have been delineated: (1) with predominantly pre-axial anomalies, Nager type AFD, and (2) with predominantly post-axial involvement, Genee-Wiedemann form of AFD, also known as POADS, respectively. Other forms of "true AFD" have been described as Kelly, Reynolds, Arens (also Tel Aviv form), Rodríguez (or Madrid form), Richieri-Costa, and Patterson-Stevenson-Fontaine types. However, whether they are distinct entities or represent variants of the same condition remains unclear. Rodríguez AFD was described as a new lethal form of AFD in three affected sibs with severe mandibular hypoplasia, severe predominantly pre-axial limb deficiencies, absent fibulae and ribs, and internal organ anomalies, the most remarkable of which are arrhinencephaly and abnormal lung lobulation. We present a newborn girl with Rodríguez type of AFD, who died a few days after the birth due to respiratory failure. The phenotype and the cause of this condition are discussed.	0
In obesity, high levels of saturated fatty acids (SFAs) contribute to adipose tissue inflammation and dysfunction. Obesity-induced macrophage infiltration leads to insulin resistance, but the adipocyte itself may play a role in generating the inflammatory milieu. Given our recent findings of the role of TLR4 in myeloid biasing in obesity, we next investigated the role of TLR4 in adipocyte generated inflammatory responses to SFAs and lipopolysaccharides. We used WT and Tlr4-/- ear mesenchymal stem cell derived adipocytes (EMSC Ad) and bone marrow dendritic cells (BMDCs) to evaluate cell specific responses. Our work demonstrates a role for TLR4 in adipocyte- immune cell crosstalk and that SFA derived metabolites from adipocytes may induce proinflammatory stimulation of immune cells in a TLR4 independent manner.	0
Aims:Neonatal tumors (NTs) include a group of diverse neoplasms. In this study, we reviewed our data for clinical presentations, management options, and outcome. Materials and Methods:All patients from 0- to 1-month age presenting with solid tumors, from 2006 to 2018 were studied. The gender, presentation, location, type of tumor, and management were analyzed. The final diagnosis was made with histopathology in all cases. Hemangiomas and lymphangiomas were excluded from the study. Results:A total of 32 neonates were studied. The most common tumor was sacrococcygeal teratoma (SCT,16) followed by teratoma at other sites including two cases of fetus-in-fetu, soft-tissue sarcoma (STS, 4), mesenchymal hamartoma (2), hemangioendothelioma (2), and other rare tumors. Three tumors were diagnosed antenatally; of whom, two were neither visible externally nor palpable. Complete surgical excision was done for all except in a case of ovarian cyst where near-total cystectomy was done. No patient received chemotherapy or radiotherapy. Six patients had postoperative complications, including two who had local recurrence requiring excision. There was one mortality. All the other patients are doing well during follow-up. Conclusion:NTs have varied presentations. SCT and STS were the most common benign and malignant tumor, respectively. Early diagnosis and complete surgical excision are often curative for all, regardless of the pathology with the minimal role of chemotherapy or radiotherapy.	0
We report an infant with pre- and postnatal microcephaly and growth retardation, a distinctive face, and developmental delay. The initial diagnosis was of Seckel syndrome. He became pancytopenic at 16 months and died soon after. His bone marrow was of normal cellularity but had a small lymphocyte infiltration. Increased spontaneous chromosome breakage was seen in blood and fibroblasts. Mitomycin C induced chromosome damage was increased and comparable to that seen in Fanconi anaemia. Reports of similar patients are reviewed. This entity of severe intrauterine growth retardation and increased mitomycin C sensitivity is hypothesised to be a distinct chromosome breakage syndrome.	0
Reticulated pigmentation is a unique pigmentary change caused by a heterogeneous group of hereditary and acquired disorders. This pigmentation is characterized by a mottled appearance, with lesions that vary in size and pigmentary content. This review discusses the hereditary group of the reticulated pigmentation disorders, such as dyschromatosis symmetrica hereditaria, dyschromatosis universalis hereditaria, and reticulate acropigmentation of Kitamura. The clinical presentation and histopathological features often overlap, making diagnosis difficult. However, each of these hereditary conditions possesses a unique genetic mutation, and genetic analysis is thus more useful in the diagnosis of these conditions. This article delivers an update regarding the clinical features, detailed histopathological description, and genetic information concerning hereditary reticulate pigmentary disorders and aims to provide useful background for use by clinical dermatologists and histopathologists when approaching this group of hereditary disorders.	0
OBJECTIVES:To describe the demographics, clinical features and outcomes among people with cystic fibrosis (CF) in Australia and to estimate incidence of the disease. DESIGN AND SETTING:Cross-sectional analysis using data from the Australian Cystic Fibrosis Data Registry for 2009. MAIN OUTCOME MEASURES:Numbers of diagnoses, pulmonary and anthropometric measurements, microbiological culture results, rates of hospitalisation and transplantation, and numbers of medical complications and deaths. RESULTS:In 2009, data were submitted on 2986 people (48% female). Median age was 17.6 years and 49% of people were aged 18 years or over. Seventy-eight people were newly diagnosed. Fourteen people died and 14 people underwent lung transplantation in the year. Lung function and nutrition were relatively normal among children but deteriorated (more rapidly) among adolescents. With increasing age, progressive respiratory disease was apparent, and the frequency of CF-related complications and use of health care resources increased. In all age groups, there was a wide range in severity of lung disease and nutritional status. CONCLUSIONS:CF remains a progressive respiratory disease and is associated with multisystem complications. The acceleration in disease severity in adolescence and early adulthood suggests that better treatment at these stages is required to further improve survival.	1
The slowly and rapidly activating delayed rectifier K+ channels (IKs and IKr, respectively) contribute to the repolarization of ventricular action potential in human heart and thereby determine QT interval on an electrocardiogram. Loss-of-function mutations in genes encoding IKs and IKr cause type 1 and type 2 long QT syndrome (LQT1 and LQT2, respectively), accompanied by a high risk of malignant ventricular arrhythmias and sudden cardiac death. This study was designed to investigate which cardiac electrophysiological conditions exaggerate QT-prolonging and arrhythmogenic effects of sevoflurane. We used the O'Hara-Rudy dynamic model to reconstruct human ventricular action potential and a pseudo-electrocardiogram, and simulated LQT1 and LQT2 phenotypes by decreasing conductances of IKs and IKr, respectively. Sevoflurane, but not propofol, prolonged ventricular action potential duration and QT interval in wild-type, LQT1 and LQT2 models. The QT-prolonging effect of sevoflurane was more profound in LQT2 than in wild-type and LQT1 models. The potent inhibitory effect of sevoflurane on IKs was primarily responsible for its QT-prolonging effect. In LQT2 model, IKs was considerably enhanced during excessive prolongation of ventricular action potential duration by reduction of IKr and relative contribution of IKs to ventricular repolarization was markedly elevated, which appears to underlie more pronounced QT-prolonging effect of sevoflurane in LQT2 model, compared with wild-type and LQT1 models. This simulation study clearly elucidates the electrophysiological basis underlying the difference in QT-prolonging effect of sevoflurane among wild-type, LQT1 and LQT2 models, and may provide important information for developing anesthetic strategies for patients with long QT syndrome in clinical settings.	0
Identification of a monogenic etiology is possible in a proportion of patients with childhood-onset nephrolithiasis or nephrocalcinosis. Bartter syndrome (BS), a hereditary tubulopathy characterized by polyuria, hypokalemic alkalosis and growth retardation that rarely presents with isolated nephrocalcinosis. Patients with defect in renal outer medullary potassium channel, encoded by the KCNJ1 gene causing BS type 2, typically present during the neonatal period. We describe a 14-year-old girl with mild late-onset BS type 2 with reported pathogenic compound heterozygous variations in exon 2 of KCNJ1 (c.146G > A and c.657C > G). This patient presented with isolated medullary nephrocalcinosis due to hypercalciuria; absence of hypokalemia and metabolic alkalosis was unique. This case highlights the importance of screening the KCNJ1 gene in patients with hypercalciuria and nephrocalcinosis, even in older children.	0
Context: Pseudohypoparathyroidism type Ia (PHP1A) is caused by inactivating mutations involving GNAS exons 1-13, encoding the alpha-subunit of the stimulatory G protein (Gsα). Particularly PHP1A, but also other disorders involving the Gsα-cAMP-signaling pathway, have been associated with early-onset obesity. Thus, patients with mutations in the genes encoding PDE4D and PRKAR1A can also be obese. Furthermore, epigenetic GNAS changes, as in pseudohypoparathyroidism type Ib (PHP1B), can lead to excessive weight. Objective: Search for genetic variants in GNAS, PDE4D, and PRKAR1A and for methylation alterations at the GNAS locus in Finnish subjects with isolated severe obesity before age 10 years. Methods: Next generation sequencing to identify pathogenic variants in the coding exons of GNAS, PDE4D, and PRKAR1A; Multiplex Ligation-dependent Probe Amplification (MLPA) and methylation-sensitive MLPA (MS-MLPA) to search for deletions in GNAS and STX16, and for epigenetic changes at the four differentially methylated regions (DMR) within GNAS. Results: Among the 88 subjects (median age 13.8 years, median body mass index Z-score +3.9), we identified one rare heterozygous missense variant of uncertain significance in the XL exon of GNAS in a single patient. We did not identify clearly pathogenic variants in PDE4D and PRKAR1A, and no GNAS methylation changes were detected by MS-MLPA. Conclusions: Our results suggest that coding GNAS mutations or methylation changes at the GNAS DMRs, or coding mutations in PDE4D and PRKAR1A are not common causes of isolated childhood obesity in Finland.	0
A 9-yr 8-mo-old right-handed female presented with a history of gait difficulties, which first became apparent at age 9 mo of age, along with slurred speech and hand tremors while holding a tray. Her past medical history was significant for global developmental delay, and she was attending fourth grade special education classes. On examination, she had an ataxic gait, dysarthria, absent deep tendon reflexes, and flexor plantar responses. There were no signs of optic atrophy or hearing loss. Nerve conduction studies were consistent with an axonal neuropathy. A fascicular sural nerve biopsy showed a marked decrease of myelinated fibers larger than 6 µm in diameter as compared with an age-matched control. By electron microscopy, clusters of degenerating axonal mitochondria in both myelinated and unmyelinated fibers were frequently found. Whole-exome sequencing revealed a heterozygous c.314C > T (p.Thr105Met) missense variant in MFN2 in the patient but not in her mother. The father was unavailable for testing. The phenotypes with MFN2 variants can be quite variable, including intellectual disability, optic atrophy, auditory impairment, spinal atrophy with or without hydromyelia, and hydrocephalus. We report here that early onset ataxia with intellectual disability can also be associated with MFN2-related Charcot-Marie-Tooth, Type 2A2A diagnosis, the most common type of autosomal dominant axonal neuropathy.	0
CYP4V2, a relatively new member of human cytochrome P450 (P450) enzymes, is termed an "orphan" P450 because its substrate specificity and physiological roles are unknown. Mutations in the CYP4V2 gene is associated with an autosomal recessive inherited ocular disease named Bietti's crystalline dystrophy (BCD). The strong gene-disease associations provide unique opportunities for elucidating the substrate specificity of this orphan P450s and unraveling the biochemical pathways that may be impacted in patients with CYP4V2 functional deficits.	0
INTRODUCTION: Rippling muscle disease (RMD) is a rare disorder of muscle hyperexcitability clinically characterized by painful muscle stiffness, rippling phenomenon, percussion-induced muscle mounding, and rapid contraction. RMD is typically considered to be electrically silent, but electrical activity during the muscle rippling has been occasionally described. RMD could be genetically determined or immune-mediated (iRMD). The association between cancer and iRMD is extremely rare. CASE REPORT: We present here a patient with electrically active iRMD preceding the diagnosis of breast cancer. The patient had acetylcholine receptor binding antibodies but no clinical or electrophysiological signs of myasthenia. Muscle biopsy revealed inflammatory changes and a mosaic distribution of sarcolemmal caveolin-3 deficiency. Sequencing of caveolin-3 gene detected no mutation. Immunotherapy led to the resolution of the RMD and disappearance of the serum acetylcholine receptor antibodies. CONCLUSIONS: The abnormal electrical activity in this patient suggests that an acquired neuromuscular hyperexcitability syndrome represents a continuum of disorders. The close temporal relationship between the onset of iRMD and the diagnosis of breast cancer raises the possibility that iRMD might be paraneoplastic.	0
We report the case of a 46-year-old man with hemicrania continua presenting as exacerbations mimicking trigeminal neuralgia. The patient was tentatively diagnosed with trigeminal neuralgia, and treatment with various combinations of drugs was performed after the onset of pain. However, when the condition of the patient did not improve, we suspected hemicrania continua, and treatment with indomethacin was initiated. There was a marked alleviation of his pain within 24 hours. Thus, clinicians should be aware that the duration and frequency of exacerbations of hemicrania continua are variable.	0
A variety of Magnetic Resonance (MR) and nuclear medicine (NM) techniques have been used in symptomatic and presymptomatic SCA2 gene carriers to explore,in vivo, the physiopathological biomarkers of the neurological dysfunctions characterizing the associated progressive disease that presents with a cerebellar syndrome, or less frequently, with a levodopa-responsive parkinsonian syndrome. Morphometry performed on T1-weighted images and diffusion MR imaging enable structural and microstructural evaluation of the brain in presymptomatic and symptomatic SCA2 gene carriers, in whom they show the typical pattern of olivopontocerebellar atrophy observed at neuropathological examination. Proton MR spectroscopy reveals, in the pons and cerebellum of SCA2 gene carriers,a more pronounced degree of abnormal neurochemical profile compared to other spinocerebellar ataxias with decreased NAA/Cr and Cho/Cr, increased mi/Cr ratios, and decreased NAA and increased mI concentrations. These neurochemical abnormalities are detectable also in presymtomatic gene carriers. Resting state functional MRI (rsfMRI) demonstrates decreased functional connectivity within the cerebellum and of the cerebellum with fronto-parietal cortices and basal ganglia in symptomatic SCA2 subjects. 18F-fluorodeoxyglucose Positron Emission Tomography (PET) shows a symmetric decrease of the glucose uptake in the cerebellar cortex, the dentate nucleus, the brainstem and the parahippocampal cortex. Single photon emission tomography and PET using several radiotracers have revealed almost symmetric nigrostriatal dopaminergic dysfunction irrespective of clinical signs of parkinsonism which are already present in presymtomatic gene carriers. Longitudinal small size studies have proven that morphometry and diffusion MR imaging can track neurodegeneration in SCA2, and hence serve as progression biomarkers. So far, such a capability has not been reported for proton MR spectroscopy, rsfMRI and NM techniques. A search for the best surrogate marker for future clinical trials represents the current challenge for the neuroimaging community.	0
Introduction: Progressive myoclonus epilepsies (PMEs) are a group of neurodegenerative diseases, invariably leading to severe disability or fatal outcome in a few years or decades. Nowadays, PMEs treatment remains challenging with a significant burden of disability for patients. Pharmacotherapy is primarily used to treat seizures, which impact patients' quality of life. However, new approaches have emerged in the last few years, which try to curb the neurological deterioration of PMEs through a better knowledge of the pathogenetic process. This is a review on the newest therapeutic options for the treatment of PMEs.Areas covered: Experimental and clinical results on novel therapeutic approaches for the different forms of PME are reviewed and discussed. Special attention is primarily focused on the efficacy and tolerability outcomes, trying to infer the role novel approaches may have in the future.Expert opinion: The large heterogeneity of disease-causing mechanisms prevents researchers from identifying a single approach to treat PMEs. Understanding of pathophysiologic processes is leading the way to targeted therapies, which, through enzyme replacement or underlying gene defect correction have already proved to potentially strike on neurodegeneration.	0
A case of recalcitrant dissecting cellulitis of the scalp (DCS) in a 23-year-old male patient was treated with 4 times of topical ALA-PDT at intervals of 10-15 days. The patient responded well without any unbearable adverse effects and presented satisfactory effects. Before applying this therapy, the patient and his doctors had tried other methods, specifically glucocorticoids, intradermal injection, and even surgical treatment, but none of them had presented satisfactory effects. This suggests that topical ALA-PDT could be an effective and safe alternative for DCS patients who are refractory to other standard therapies.	0
Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) is an uncommon cause of microcephaly and intrauterine growth retardation in a newborn. Early identifying features include but are not limited to sloping forehead, micrognathia, sparse hair, including of eyebrows and short limbs. Immediate radiological findings may include partial or complete agenesis of the corpus callosum, interhemispheric cyst and shallow acetabula leading to dislocation. Genetic testing displaying a mutation in RNU4ATAC gene is necessary for definitive diagnosis. Early identification is important as MOPD1 is an autosomal recessive condition and could present in subsequent pregnancies. The purpose of this case is to both identify and describe some common physical findings related to MOPD1. We present a case of MOPD1 in a girl born to non-consanguineous parents that was distinct for subglottic stenosis and laryngeal cleft.	0
Skeletal dysplasias are a diverse group of heritable diseases affecting bone and cartilage growth. Throughout the years, the molecular defect underlying many of the diseases has been identified. These identifications led to novel insights in the mechanisms regulating bone and cartilage growth and homeostasis. One of the pathways that is clearly important during skeletal development and bone homeostasis is the Wingless and int-1 (WNT) signaling pathway. So far, three different WNT signaling pathways have been described, which are all activated by binding of the WNT ligands to the Frizzled (FZD) receptors. In this review, we discuss the skeletal disorders that are included in the latest nosology of skeletal disorders and that are caused by genetic defects involving the WNT signaling pathway. The number of skeletal disorders caused by defects in WNT signaling genes and the clinical phenotype associated with these disorders illustrate the importance of the WNT signaling pathway during skeletal development as well as later on in life to maintain bone mass. The knowledge gained through the identification of the genes underlying these monogenic conditions is used for the identification of novel therapeutic targets. For example, the genes underlying disorders with altered bone mass are all involved in the canonical WNT signaling pathway. Consequently, targeting this pathway is one of the major strategies to increase bone mass in patients with osteoporosis. In addition to increasing the insights in the pathways regulating skeletal development and bone homeostasis, knowledge of rare skeletal dysplasias can also be used to predict possible adverse effects of these novel drug targets. Therefore, this review gives an overview of the skeletal and extra-skeletal phenotype of the different skeletal disorders linked to the WNT signaling pathway.	0
Since organic acid analysis in urine with gaschromatography-mass spectrometry (GC-MS) is a time-consuming technique, we developed a new liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) method to replace the classical analysis for diagnosis of inborn errors of metabolism (IEM). Sample preparation is simple and experimental time short. Targeted mass extraction and automatic calculation of z-scores generated profiles characteristic for the IEMs in our panel consisting of 71 biomarkers for defects in amino acids, neurotransmitters, fatty acids, purine, and pyrimidine metabolism as well as other disorders. In addition, four medication-related metabolites were included in the panel. The method was validated to meet Dutch NEN-EN-ISO 15189 standards. Cross validation of 24 organic acids from 28 urine samples of the ERNDIM scheme showed superiority of the UPLC-QTOF/MS method over the GC-MS method. We applied our method to 99 patient urine samples with 32 different IEMs, and 88 control samples. All IEMs were unambiguously established/diagnosed using this new QTOF method by evaluation of the panel of 71 biomarkers. In conclusion, we present a LC-QTOF/MS method for fast and accurate quantitative organic acid analysis which facilitates screening of patients for IEMs. Extension of the panel of metabolites is easy which makes this application a promising technique in metabolic diagnostics/laboratories.	0
Muenke syndrome (MIM #602849), the most common syndromic craniosynostosis, results from the recurrent pathogenic p.P250R variant in FGFR3. Affected patients exhibit wide phenotypic variability. Common features include coronal craniosynostosis, hearing loss, carpal and tarsal anomalies, and developmental/behavioral issues. Our study examined the phenotypic findings, medical management, and surgical outcomes in a cohort of 26 probands with Muenke syndrome identified at the Children's Hospital of Philadelphia. All probands had craniosynostosis; 69.7% had bicoronal synostosis only, or bicoronal and additional suture synostosis. Three male patients had autism spectrum disorder. Recurrent ear infections were the most common comorbidity, and myringotomy tube placement the most common extracranial surgical procedure. Most patients (76%) required only one fronto-orbital advancement. de novo mutations were confirmed in 33% of the families in which proband and both parents were genetically tested, while in the remaining 66% one of the parents was a mutation carrier. In affected parents, 40% had craniosynostosis, including 71% of mothers and 13% of fathers. We additionally analyzed the medical resource utilization of probands with Muenke syndrome. To our knowledge, these data represent the first comprehensive examination of long-term management in a large cohort of patients with Muenke syndrome. Our study adds valuable information regarding neuropsychiatric and medical comorbidities, and highlights findings in affected relatives.	0
Chronic exposure to n-hexane, a widely used solvent in industry, causes sensorimotor neuropathy, which is mainly mediated by its toxic metabolite, 2,5-hexanedione (HD). However, the mechanisms remain unclear. This study is designed to investigate whether nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is involved in HD-induced neurotoxicity. Results showed that HD intoxication significantly elevated NLRP3 expression, caspase-1 activation and interleukin-1β (IL-1β) maturation in the spinal cord of rats, indicating NLRP3 inflammasome activation. Glibenclamide, a sulfonylurea inhibitor of NLRP3 inflammasome, reduced HD-induced NLRP3 inflammasome activation, which was associated with mitigated gasdermin D (GSDMD) cleavage, neurofilament protein L (NF-L) reduction and demyelination as well as axon degeneration in the spinal cord of rats. Subsequently, we found that inhibition of NLRP3 inflammasome by glibenclamide suppressed microglial activation and M1 polarization and simultaneously recovered M2 polarization in HD-intoxicated rats. Furthermore, glibenclamide treatment reduced the contents of malondialdehyde (MDA) as well as elevated glutathione (GSH) levels and total-antioxidative capacity in the spinal cord of HD-intoxicated rats, indicating attenuated oxidative stress. Collectively, our findings suggested that NLRP3 inflammasome activation contributed to HD-induced neurotoxicity by enhancing microglial M1 polarization and oxidative damage. Inhibition of NLRP3 inflammasome by glibenclamide might a potential avenue to combat n-hexane-induced neuropathy.	0
AIM:To analyze the current literature on neurocutaneous melanosis (NCM), as well as, our cases, in order to better define the prognosis and the presence of risk factors affecting it, thus, offering better information to the parents. MATERIAL AND METHODS:Two cases observed at the Pediatric Neurosurgery Unit of the Catholic University Medical School in Rome are described. Both of them had cutaneous stigmata and cerebral MR evidence of intracranial melanin deposits. These two children showed a very different clinical course. RESULTS:The present study enlighten the differences among the two cases and review the literature on the subject, with the attempt to understand which are clinical and disease related factors that might influence the prognosis. CONCLUSION:Beside malignant features of cutaneous melanotic lesions, the presence of hydrocephalus at diagnosis and the early appearance of clinical symptoms, when appearing contemporarily, are predicting the rapid progression of the disease and a worse prognosis.	0
BACKGROUND:Extra-pelvic intravenous leiomyomatosis (IVL) extending into inferior vena cava (IVC) or heart (i.e. intracardiac leiomyomatosis, ICL) is an extremely rare benign disease. No consensus has been reached on the optimal surgical strategy. The aim of this study is to introduce four types of one-stage surgical strategies including less invasive options and a guideline to select patient-specific strategy for this disease. METHODS:Twenty-four patients of extra-pelvic IVLs receiving one-stage resections at the Zhongshan Hospital from July 2011 to November 2019 were reviewed retrospectively. Base on the initial experiences of the indiscriminate choices of tumor thrombectomies through sterno-laparotomy under cardiopulmonary bypass (CPB) in 6 ICLs, an anatomy-based guideline for four types of surgical strategies was developed and applied for the next 18 patients. RESULTS:Under the direction of guideline, tumor thrombectomies through single laparotomy were applied without CPB in 2 ICLs and 4 IVLs confined in IVC, or with CPB in 7 ICLs. Guideline-directed double-incisions with CPB were applied in only 5 ICLs, including 1 receiving mini-thoracotomy and 4 receiving sternotomy because of tumor adherences with right atriums in 2 and with pulmonary arteries in 2. All 24 patients accomplished one-stage panhysterectomy, bilateral adnexectomy and complete resections of intracaval and intracardiac tumors. For residual pelvic intravenous tumors in 19 patients, 17 received macroscopically complete resections while the other 2 failed because of high risk of hemorrhage. Intraoperative blood losses, operation time and hospitalization expense in the single-laparotomy non-CPB group were significantly lesser than the other groups. In CPB groups, inpatient stay and hospitalization expense in the single-incision group were significantly lesser than the double-incisions group. All patients were alive and free of recurrences during a mean follow-up of 35.4 ± 27.2 months (range, 1-100 months). The pelvic tumor residues in 2 patients remained unchanged for 51 and 52 months since operation, respectively. CONCLUSIONS:For various extra-pelvic IVLs, the 4 types of surgical strategies including less invasive options are feasible, providing these are selected by a guideline base on the tumor extension and morphology. The proposed guideline is believed to accommodate more patients receiving less invasive surgery without compromising the curative effect.	0
C1q nephropathy is a rare glomerular disease defined by the presence of characteristic mesangial dominant or codominant C1q deposition on immunofluorescence microscopy. Neurofibromatosis type 1 (NF-1) is an autosomal dominant syndrome caused by a mutation of a gene located on chromosomal segment 17q11.2. Nephrotic syndrome has rarely been reported in patients of NF-1, and the relation of NF-1 with nephrotic syndrome is unclear. Here, we present a rare case of C1q nephropathy in a patient of NF-1.	0
The bladder exstrophy-epispadia complex (BEEC) includes malformations with midline closing defects of the lower abdomen and external genitalia. Long-term consequences with urinary incontinence and sexual dysfunction, in spite of multiple surgical interventions, are common and expected to affect the patient's health-related quality of life (HRQOL). The extent and the predictive factors are, however, not known. New patient-reported outcome research is emerging, but valid and reliable condition-specific HRQOL are still missing. The aim of this review is to summarize and discuss the latest published reports (2015-2019) on HRQOL in patients with the BEEC and its relationship to incontinence and sexual factors.	0
CGL type 2 is a rare autosomal recessive syndrome characterized by an almost complete lack of body fat. CGL is caused by loss-of-function mutations in both alleles of the BSCL2 gene that codifies to seipin. Subjects often show hyperglycemia, decreased HDL-c, and hypoadiponectinemia. These laboratory findings are important triggers for changes in redox and ER homeostasis. Therefore, our aim was to investigate whether these intracellular mechanisms are associated with this syndrome. We collected blood from people from Northeastern Brazil with 0, 1, and 2 mutant alleles for the rs786205071 in the BSCL2 gene. Through the qPCR technique, we evaluated the expression of genes responsible for triggering the antioxidant response, DNA repair, and ER stress in leukocytes. Colorimetric tests were applied to quantify lipid peroxidation and to evaluate the redox status of glutathione, as well as to access the panorama of energy metabolism. Long extension PCR was performed to observe leukocyte mitochondrial DNA lesions, and the immunoblot technique to investigate plasma adiponectin concentrations. Subjects with the rs786205071 in both BSCL2 alleles showed increased transcription of NFE2L2, APEX1, and OGG1 in leukocytes, as well as high concentrations of malondialdehyde and the GSSG:GSH ratio in plasma. We also observed increase of mitochondrial DNA lesions and XBP1 splicing, as well as a decrease in adiponectin and HDL-c. Our data suggest the presence of lipid lesions due to changes in redox homeostasis in that group, associated with increased levels of mitochondrial DNA damage and transcriptional activation of genes involved with antioxidant response and DNA repair.	0
We report a case of a 78-year-old woman with a urachal tumor of the bladder wall. We performed a biopsy and revealed the tumor as a villous adenoma. We excised the tumor by partial cystectomy together with the umbilical ligament, because it was possible there was a co-existing malignancy. The tumor turned out to be villous adenoma and a urachal adenocarcinoma. Because the superficial section of the tumor consisted only of adenoma, a biopsy could not identify the malignant component. Villous adenoma of the urinary tract or the urachus is very rare, and it is considered as an intestinal premalignancy.	0
Age-related cognitive decline and many dementias involve complex interactions of both genetic and environmental risk factors. Recent evidence has demonstrated a strong association of obesity with the development of dementia. Furthermore, white matter damage is found in obese subjects and mouse models of obesity. Here, we found that components of the complement cascade, including complement component 1qa (C1QA) and C3 are increased in the brain of Western diet (WD)-fed obese mice, particularly in white matter regions. To functionally test the role of the complement cascade in obesity-induced brain pathology, female and male mice deficient in C1QA, an essential molecule in the activation of the classical pathway of the complement cascade, were fed a WD and compared with WD-fed wild type (WT) mice, and to C1qa knock-out (KO) and WT mice fed a control diet (CD). C1qa KO mice fed a WD became obese but did not show pericyte loss or a decrease in laminin density in the cortex and hippocampus that was observed in obese WT controls. Furthermore, obesity-induced microglia phagocytosis and breakdown of myelin in the corpus callosum were also prevented by deficiency of C1QA. Collectively, these data show that C1QA is necessary for damage to the cerebrovasculature and white matter damage in diet-induced obesity.	0
CONTEXT:Congenital hypopituitarism (CH) is rarely observed in combination with severe joint contractures (arthrogryposis). Schaaf-Yang syndrome (SHFYNG) phenotypically overlaps with Prader-Willi syndrome, with patients also manifesting arthrogryposis. L1 syndrome, a group of X-linked disorders that include hydrocephalus and lower limb spasticity, also rarely presents with arthrogryposis. OBJECTIVE:We investigated the molecular basis underlying the combination of CH and arthrogryposis in five patients. PATIENTS:The heterozygous p.Q666fs*47 mutation in the maternally imprinted MAGEL2 gene, previously described in multiple patients with SHFYNG, was identified in patients 1 to 4, all of whom manifested growth hormone deficiency and variable SHFYNG features, including dysmorphism, developmental delay, sleep apnea, and visual problems. Nonidentical twins (patients 2 and 3) had diabetes insipidus and macrocephaly, and patient 4 presented with ACTH insufficiency. The hemizygous L1CAM variant p.G452R, previously implicated in patients with L1 syndrome, was identified in patient 5, who presented with antenatal hydrocephalus. RESULTS:Human embryonic expression analysis revealed MAGEL2 transcripts in the developing hypothalamus and ventral diencephalon at Carnegie stages (CSs) 19, 20, and 23 and in the Rathke pouch at CS20 and CS23. L1CAM was expressed in the developing hypothalamus, ventral diencephalon, and hindbrain (CS19, CS20, CS23), but not in the Rathke pouch. CONCLUSION:We report MAGEL2 and L1CAM mutations in four pedigrees with variable CH and arthrogryposis. Patients presenting early in life with this combined phenotype should be examined for features of SHFYNG and/or L1 syndrome. This study highlights the association of hypothalamo-pituitary disease with MAGEL2 and L1CAM mutations.	0
Familial keloids have been reported, having either autosomal dominant or autosomal recessive inheritance. We wished to determine the inheritance pattern and phenotype of keloids among multigenerational families, as a prelude to a positional mapping strategy to identify candidate genes.We studied three African American families, one Afro-Caribbean family and one Asian-American family. Phenotyping including assessing all patients for the presence, distribution, and appearance of keloids, together with the timing of keloid onset and provocative factors. The clinical trial was registered at clinicaltrials.gov (NCT 00005802).Age of keloid onset varied considerably within families, but commonly occurred by the second decade. The fraction of affected individuals was 38%, 45%, 62%, 67% and 73% among the five families respectively. Keloid severity and morphology differed within and between families. A novel finding is that certain families manifest keloids in distinct locations, with one family showing an excess of extremity keloids and two families showing an excess of axilla-groin keloids.Familial keloids appear to most commonly manifest autosomal dominant or semidominant inheritance, and there may be familial patterns of keloid distribution.	0
T-cell large granular lymphocytic leukemia (T-cell LGLL) is the most common presentation of chronic lymphocytic leukemia (CLL) in dogs. Aleukemic or subleukemic leukemia is a particularly rare variation in both humans and dogs, where bone marrow proliferation is either not or only sparsely translated in the peripheral blood. Neutropenia is a prominent feature in cases of human T-cell LGLL but is normally absent in canine CLL. This report describes a case of a dog presented with an almost 3-year history of asymptomatic neutropenia, lymphopenia, and thrombocytopenia (without anemia). A bone marrow examination, the exclusion of infectious diseases, and clonality testing led to the diagnosis of subleukemic LGLL that responded well to therapy (death occurred 2.5 years later due to an unrelated cause).	0
Background/Aims:Corneal dystrophies (CDs) belong to a group of hereditary heterogeneous corneal diseases which result in visual impairment due to the progressive accumulation of deposits in different corneal layers. So far, mutations in several genes have been responsible for various CDs. The purpose of this study is to identify gene mutations in a three-generation Hui-Chinese family associated with granular corneal dystrophy type I (GCD1). Methods:A three-generation Hui-Chinese pedigree with GCD1 was recruited for this study. Slit-lamp biomicroscopy, optical coherence tomography, and confocal microscopy were performed to determine the clinical features of available members. Whole exome sequencing was performed on two patients to screen for potential disease-causing variants in the family. Sanger sequencing was used to test the variant in the family members. Results:Clinical examinations demonstrated bilaterally abundant multiple grayish-white opacities in the basal epithelial and superficial stroma layers of corneas of the two patients. Whole exome sequencing revealed that a heterozygous missense mutation (c.1663C > T, p.Arg555Trp) in the transforming growth factor beta-induced gene (TGFBI) was shared by the two patients, and it cosegregated with this disease in the family confirmed by Sanger sequencing. Conclusions:The results suggested that the heterozygous TGFBI c.1663C > T (p.Arg555Trp) mutation was responsible for GCD1 in the Hui-Chinese family, which should be of great help in genetic counseling for this family.	0
Bordetella pertussis can cause serious and potentially fatal complications, especially in very young infants. Early diagnosis and treatment of pertussis with a macrolide antibiotic, such as azithromycin, before the paroxysmal stage of disease can help mitigate complications and reduce the spread of this highly contagious disease.	0
OBJECTIVE:The aim of this study was to perform a systematic analysis of the nicotinamide adenine dinucleotide phosphate (NAD[P])-dependent steroid dehydrogenase-like (NSDHL) gene in cases of oral verruciform xanthoma (VX) and to test for the presence of mutations associated with congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome. STUDY DESIGN:DNA was extracted from archived paraffin-embedded tissue of oral VX and control cases. Polymerase chain reaction (PCR) was then used to screen exons 4 and 6 of the NSDHL gene for the presence of 4 known germline mutations associated with CHILD syndrome and 1 somatic mutation previously identified in VX lesions with no known association with CHILD syndrome. RESULTS:Of the 16 oral VX tissue samples, 8 (50%) had known missense mutations associated with CHILD syndrome. Furthermore, 2 of these 8 tissue samples also had an additional missense mutation previously identified in cutaneous VX lesions. No mutations of exons 4 and 6 were found in the 5 negative control tissue samples. CONCLUSIONS:NSDHL gene mutations associated with CHILD syndrome are common in sporadic oral VX cases, suggesting that these mutations confer a greater risk for the development of epithelial barrier defects that promote recurrent oral VX lesions and the potential for direct germline transmission of oral VX susceptibility.	0
Fogo selvagem (FS) is a blistering skin disease caused by pathogenic IgG4 autoantibodies to desmoglein 1 (DSG1). Preclinical FS and leishmaniasis are endemic to certain regions of Brazil and exhibit nonpathogenic anti-DSG1 antibodies. Recurring bites from Lutzomyia longipalpis, the sand fly vector of leishmaniasis, immunize individuals with L. longipalpis salivary antigens LJM17 and LJM11. We measured the antibody responses to LJM17, LJM11, and DSG1 in normal settlers and patients with FS from an endemic focus of FS and nonendemic control populations. We also immunized mice with these antigens and assessed the IgG response. Healthy individuals and patients with FS from endemic areas had significantly higher values of IgG4 anti-LJM17 antibodies than nonendemic controls (P < 0.001 for both). The levels of IgG anti-DSG1 and IgG4 anti-LJM17 and anti-LJM11 antibodies correlated positively in normal settlers and patients with FS. Mice immunized with recombinant LJM17 produced IgG1 antibodies (human IgG4 homolog) that strongly cross-reacted with recombinant DSG1; these IgG1 antibodies were inhibited by LJM17, LJM11, and DSG1 in a dose-dependent manner. However, they did not bind human or mouse epidermis by indirect immunofluorescence. Lastly, we identified short-sequence homologies of surface-exposed residues within the human DSG1 ectodomain and LJM17. Inoculation by LJM17 from L. longipalpis-elicited DSG1-cross-reactive IgG4 antibodies may lead to FS in genetically predisposed individuals.	0
Objective:Retinitis pigmentosa-related retinal detachment (RPRD) is rare, and the full spectrum of retinal complications is not well defined. To describe the types of retinal detachment in patients with retinitis pigmentosa and the surgical outcomes of RPRD. Methods:This is a non-comparative, retrospective case series. An electronic database search was performed using Moorfields OpenEyes electronic health records. We identified 90 patients with RPRD between January 2000 and August 2017. Main outcome and measures are visual acuity (VA), surgical outcomes and classification of RPRD. Results:Of the 90 patients/detachments, 61 (67.8%) were rhegmatogenous retinal detachment (RRD), 19 (21.1%) were exudative, 3 (3.3%) were tractional retinal detachment (TRD) and 7 (7.8%) had combined. 37.5% (9/24) of patients with exudative retinal detachment were treated with either cryotherapy or laser, and one patient underwent vitrectomy for vitreous haemorrhage. 56/90 patients underwent surgical intervention. Nine patients presented late and were deemed inoperable (two exudative and seven RRD). Of the RRD patients with full operative record, the primary attachment rate was 76.2% (16/21) and final reattachment rate was 85.7% (18/21) over a mean 15.4-year follow-up period. Mean VA for RRD surgery improved from 6/190 (1.51 logMAR) to 6/120 (1.31 logMAR) (p=0.194). In the TRD group, the mean VA was 6/300 (1.66 logMAR) at baseline and improved after surgery to 6/48 (0.90 logMAR) (p=0.421). Conclusions:We demonstrated a final reattachment rate of 85.7% with a trend toward better vision following intervention for patients with RPRD. However, the final long-term vision may be poor due to the natural progression of retinitis pigmentosa-associated macular degeneration.	0
Gene therapy approaches are being deployed to treat recessive genetic disorders by restoring the expression of mutated genes. However, the feasibility of these approaches for dominantly inherited diseases - where treatment may require reduction in the expression of a toxic mutant protein resulting from a gain-of-function allele - is unclear. Here we show the efficacy of allele-specific RNAi as a potential therapy for Charcot-Marie-Tooth disease type 2D (CMT2D), caused by dominant mutations in glycyl-tRNA synthetase (GARS). A de novo mutation in GARS was identified in a patient with a severe peripheral neuropathy, and a mouse model precisely recreating the mutation was produced. These mice developed a neuropathy by 3-4 weeks of age, validating the pathogenicity of the mutation. RNAi sequences targeting mutant GARS mRNA, but not wild-type, were optimized and then packaged into AAV9 for in vivo delivery. This almost completely prevented the neuropathy in mice treated at birth. Delaying treatment until after disease onset showed modest benefit, though this effect decreased the longer treatment was delayed. These outcomes were reproduced in a second mouse model of CMT2D using a vector specifically targeting that allele. The effects were dose dependent, and persisted for at least 1 year. Our findings demonstrate the feasibility of AAV9-mediated allele-specific knockdown and provide proof of concept for gene therapy approaches for dominant neuromuscular diseases.	0
PURPOSE OF REVIEW:To provide a current review of the embryology, classification, evaluation, surgical management, and clinical outcomes related to preaxial polydactyly. RECENT FINDINGS:Recent studies include a proposed embryologic link between preaxial polydactyly and other congenital abnormalities, an evaluation of long-term postsurgical outcomes, and an examination of important predictors for postsurgical outcomes. Preaxial polydactyly, while relatively uncommon, is a complex congenital hand abnormality that requires careful preoperative classification and proper surgical intervention timing to yield optimal outcomes.	0
Very high IgM levels represent the hallmark of hyper IgM (HIGM) syndromes, a group of primary immunodeficiencies (PIDs) characterized by susceptibility to infections and malignancies. Other PIDs not fulfilling the diagnostic criteria for HIGM syndromes can also be characterized by high IgM levels and susceptibility to malignancies. The aim of this study is to characterize clinical phenotype, immune impairment, and pathogenic mechanism in six patients with very high IgM levels in whom classical HIGM syndromes were ruled out. The immunological analysis included extended B-cell immunophenotyping, evaluation of class switch recombination and somatic hypermutation, and next generation sequencing (NGS). Recurrent or severe infections and chronic lung changes at the diagnosis were reported in five out of six and two out of six patients, respectively. Five out of six patients showed signs of lymphoproliferation and four patients developed malignancies. Four patients showed impaired B-cell homeostasis. Class switch recombination was functional in vivo in all patients. NGS revealed, in one case, a pathogenic mutation in PIK3R1. In a second case, the ITPKB gene, implicated in B- and T-cell development, survival, and activity was identified as a potential candidate gene. Independent of the genetic basis, very high IgM levels represent a risk factor for the development of recurrent infections leading to chronic lung changes, lymphoproliferation, and high risk of malignancies.	0
PURPOSE:We investigated the diagnostic and clinical performance of trio exome sequencing (ES) in parent-fetus trios where the fetus had sonographic abnormalities but normal karyotype, microarray and, in some cases, normal gene-specific sequencing. METHODS:ES was performed from DNA of 102 anomalous fetuses and from peripheral blood from their parents. Parents provided consent for the return of diagnostic results in the fetus, medically actionable findings in the parents, and identification as carrier couple for significant autosomal recessive conditions. RESULTS:In 21/102 (20.6%) fetuses, ES provided a positive-definitive or positive-probable diagnosis. In 10/102 (9.8%), ES provided an inconclusive-possible result. At least 2/102 (2.0%) had a repeat pregnancy during the study period and used the information from the study for prenatal diagnosis in the next pregnancy. Six of 204 (2.9%) parents received medically actionable results that affected their own health and 3/102 (2.9%) of couples received results that they were carriers for the same autosomal recessive condition. CONCLUSION:ES has diagnostic utility in a select population of fetuses where a genetic diagnosis was highly suspected. Challenges related to genetics literacy, variant interpretation, and various types of diagnostic results affecting both fetal and parental health must be addressed by highly tailored pre- and post-test genetic counseling.	0
Myeloperoxidase (MPO) is an enzyme expressed mostly by neutrophils and is a primary mediator of neutrophils oxidative stress response. While a profound body of evidence associates neutrophil-derived MPO in the pathogenesis of Alzheimer's disease (AD), this role has not been assessed in an animal model of AD. Here, we produced hematologic chimerism in the 5XFAD mouse model of AD, with MPO deficient mice, resulting in 5XFAD with hematologic MPO deficiency (5XFAD-MPO KO). Behavioral examinations of 5XFAD-MPO KO showed significant superior performance in spatial learning and memory, associative learning, and anxiety/risk assessment behavior, as compared to 5XFAD mice transplanted with WT cells (5XFAD-WT). Hippocampal immunohistochemical and mRNA expression analyses showed significantly reduced levels of inflammatory mediators in 5XFAD-MPO KO mice with no apparent differences in the numbers of amyloid-β plaques. In addition, immunoblotting and mRNA analyses showed significantly reduced levels of APOE in 5XFAD-MPO KO. Together, these results indicate a substantial involvement of neutrophil-derived MPO in the pathology of 5XFAD model of AD and suggest MPO as a potential therapeutic target in AD.	0
BACKGROUND:Exome/genome sequencing (ES/GS) have been recently used in neonatal and pediatric/cardiac intensive care units (NICU and PICU/CICU) to diagnose and care for acutely ill infants, but the effectiveness of targeted gene panels for these purposes remains unknown. METHODS:RapSeq, a newly developed panel targeting 4,503 disease-causing genes, was employed on selected patients in our NICU/PICU/CICU. Twenty trios were sequenced from October 2015 to March 2017. We assessed diagnostic yield, turnaround times, and clinical consequences. RESULTS:A diagnosis was made in 10/20 neonates (50%); eight had de novo variants (ASXL1, CHD, FBN1, KMT2D, FANCB, FLNA, PAX3), one was a compound heterozygote for CHAT, and one had a maternally inherited GNAS variant. Preliminary reports were generated by 9.6 days (mean); final reports after Sanger sequencing at 16.3 days (mean). In all positive infants, the diagnosis changed management. In a case with congenital myasthenia, diagnosis and treatment occurred at 17 days versus 7 months in a historical control. CONCLUSIONS:This study shows that a gene panel that includes the majority of known disease-causing genes can rapidly identify a diagnosis in a large number of tested infants. Due to simpler deployment and interpretation and lower costs, this approach might represent an alternative to ES/GS in the NICU/PICU/CICU.	0
Osteopetrosis is a rare congenital bone disorder, characterized by systemic osteosclerosis due to a deficiency of or functional defect in osteoclasts. Autosomal dominant osteopetrosis (ADOP) is the most common form with a late onset, a stable condition, relatively few symptoms and a good prognosis. Few studies to date have reported successful total hip arthroplasty (THA) in patients with ADOP and its operative difficulties. We herein describe a case of left hip osteoarthritis in a patient with OP via THA in order to share our experience during the treatment process. The patient was a 52-years-old female with osteopetrosis who was referred to our department due to a history of left hip pain with activity limitation for 20 years. The patient reported no history of fracture or family history. The patient underwent THA in the left hip. At the 6-month, 1- and 2-year follow-up, the components were in a good position and the patient remained asymptomatic and pain-free. Therefore, THA may be a feasible treatment option when patients with ADOP suffer from painful hip osteoarthritis.	0
Split-hand/foot malformation (SHFM) is a genetic limb anomaly disturbing the central rays of the autopod. SHFM is a genetically heterogeneous disorder with variable expressivity inherited as syndromic and nonsyndromic forms. We provide an update of the clinical and molecular aspects of nonsyndromic SHFM. This rare condition is highly complex due to the clinical variability and irregular genetic inheritance observed in the affected individuals. Nonsyndromic SHFM types have been reviewed in terms of major molecular genetic alterations reported to date. This updated overview will assist researchers, scientists, and clinicians in making an appropriate molecular diagnosis, providing an accurate recurrence risk assessment, and developing a management plan.	0
Aplasia cutis congenita (ACC) is a skin disorder in which localized or widespread areas of skin are absent at birth. It has been associated with numerous anomalies and recognizable syndromes. We report a newborn infant with ACC of the scalp, multiple facial abnormalities including cleft palate but not cleft lip, hypoplasia of the distal phalanges of the hands, ectrodactyly of the feet, and epidermolysis bullosa of the extremities and lower trunk. Although this patient had some features that overlapped with ectrodactyly-ectodermal dysplasia-clefting syndrome, the absence of cleft lip and presence of additional skin abnormalities made that diagnosis unlikely. This could represent a newly recognized syndrome of numerous malformations in which ACC is associated with a constellation of previously undescribed structural anomalies.	0
Ataxia with vitamin E deficiency is an autosomal recessive cerebellar ataxia caused by mutations in the α-tocopherol transfer protein coding gene localized on chromosome 8q, leading to lower levels of serum vitamin E. More than 91 patients diagnosed with ataxia with vitamin E deficiency have been reported worldwide. The majority of cases originated in the Mediterranean region, and the 744delA was the most common mutation among the 22 mutants previously described. We examined the clinical and molecular features of a large cohort of 132 Tunisian patients affected with ataxia with vitamin E deficiency. Of these patients, nerve conduction studies were performed on 45, and nerve biopsy was performed on 13. Serum vitamin E was dramatically reduced for 105 of the patients analysed. Molecular analysis revealed that 91.7% of the patients (n = 121) were homozygous for the 744delA mutation. Three other mutations were detected among the remaining patients (8.3%, n = 11) in the homozygous state. Two were previously reported (400C>T and 205-1G>T), and one was novel (553+1T>A). Age of onset was 13.2 ± 5.9 years, with extremes of 2 and 37 years. All described patients exhibited persistent progressive cerebellar ataxia with generally absent tendon reflexes. Deep sensory disturbances, pyramidal syndrome and skeletal deformities were frequent. Head tremor was present in 40% of the patients. Absence of neuropathy or mild peripheral neuropathy was noted in more than half of the cohort. This is the largest study of the genetic, clinical and peripheral neuropathic characteristics in patients with ataxia and vitamin E deficiency. The 744delA mutation represents the most common pathological mutation in Tunisia and worldwide, likely because of a Mediterranean founder effect. Our study led us to suggest that any patient displaying an autosomal recessive cerebellar ataxia phenotype with absent tendon reflexes and minor nerve abnormalities should first be screened for the 744delA mutation, even in the absence of a serum vitamin E measurement.	0
Birk Barel syndrome also known as KCNK9 imprinting syndrome is a rare developmental disorder associated with a loss-of-function variant in KCNK9, an imprinted gene with maternal expression on the 8th chromosome encoding the TASK3 (TWIK-related acidity inhibited K + -channel 3). Only two variants of KCNK9 have been associated with this condition before, both of them leading to the same amino-acid exchange p.Gly236Arg (Barel, 2008, Graham, 2016). We describe a case of a 17-year-old girl presenting with very similar phenotype and pure motor neuropathy with a novel variant c.710C > A: p.Ala237Asp (NM_001282534.1) in KCNK9 found by whole exome sequencing. Our case suggests that Birk Barel syndrome may not be caused only by variants leading to amino-acid exchange p.Gly236Arg but also by other missense variant in this gene and that peripheral motor neuropathy might be a feature of this syndrome.	0
While the associations between pulmonary sequestration (PS) and congenital diaphragmatic hernia (CDH) are known, CDH may be obscured by PS and thus, overlooked on prenatal ultrasonography when coexisting with PS. We present 2 cases of postnatally diagnosed CDH combined with PS. In both cases, PS was prenatally diagnosed as an isolated lung mass, while CDH was confirmed only after birth. Both newborns were sufficiently stable that management was not required immediately after birth. PS may function as an "anatomical barrier" to prevent herniation of the abdominal contents into the chest, thus acting as a "protector" providing normal lung maturation throughout pregnancy. If PS is suspected prenatally, coexisting CDH may be obscured; thus, close prenatal care and counseling of the parents regarding the possibility of CDH are essential. These infants should be delivered at a tertiary center, and imaging should be performed to exclude coexisting CDH.	0
Evans syndrome is a rare haematological disease that may cause several complications during heart surgery. Herein we documented heart valve surgery in a patient with Evans syndrome who was receiving monoclonal antibody therapy, and valve replacement was successfully performed via prophylactic measures against haemolysis.	0
OBJECTIVES:To develop and evaluate the feasibility of an objective method using artificial intelligence (AI) and image processing in a semi-automated fashion for tumour-to-cortex peak early-phase enhancement ratio (PEER) in order to differentiate CD117(+) oncocytoma from the chromophobe subtype of renal cell carcinoma (ChRCC) using convolutional neural networks (CNNs) on computed tomography imaging. METHODS:The CNN was trained and validated to identify the kidney + tumour areas in images from 192 patients. The tumour type was differentiated through automated measurement of PEER after manual segmentation of tumours. The performance of this diagnostic model was compared with that of manual expert identification and tumour pathology with regard to accuracy, sensitivity and specificity, along with the root-mean-square error (RMSE), for the remaining 20 patients with CD117(+) oncocytoma or ChRCC. RESULTS:The mean ± sd Dice similarity score for segmentation was 0.66 ± 0.14 for the CNN model to identify the kidney + tumour areas. PEER evaluation achieved accuracy of 95% in tumour type classification (100% sensitivity and 89% specificity) compared with the final pathology results (RMSE of 0.15 for PEER ratio). CONCLUSIONS:We have shown that deep learning could help to produce reliable discrimination of CD117(+) benign oncocytoma and malignant ChRCC through PEER measurements obtained by computer vision.	0
PURPOSE:The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion in humans, with highly variable phenotypic expression. Whereas congenital heart defects, palatal anomalies, immunodeficiency, hypoparathyroidism, and neuropsychiatric conditions are observed in over 50% of patients with 22q11DS, a subset of patients present with additional "atypical" findings such as craniosynostosis and anorectal malformations. Recently, pathogenic variants in the CDC45 (Cell Division Cycle protein 45) gene, located within the LCR22A-LCR22B region of chromosome 22q11.2, were noted to be involved in the pathogenesis of craniosynostosis. METHODS:We performed next-generation sequencing on DNA from 15 patients with 22q11.2DS and atypical phenotypic features such as craniosynostosis, short stature, skeletal differences, and anorectal malformations. RESULTS:We identified four novel rare nonsynonymous variants in CDC45 in 5/15 patients with 22q11.2DS and craniosynostosis and/or other atypical findings. CONCLUSION:This study supports CDC45 as a causative gene in craniosynostosis, as well as a number of other anomalies. We suggest that this association results in a condition independent of Meier-Gorlin syndrome, perhaps representing a novel condition and/or a cause of features associated with Baller-Gerold syndrome. In addition, this work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to pathogenic variants on the nondeleted chromosome.	0
Plague is a re-emerging disease caused by the bacteria Yersinia pestis. Humans usually get the disease through the bite of an infected flea. Plague is a fulminant systemic disease, with pneumonic plague being the most lethal form. Late diagnosis is one of the main causes of mortality and spread of the disease, as it limits the effectiveness of control measures. We present the case of a 42-year-old male, who had previously traveled to an endemic plague area and then presented hyperpyrexia, hypotension, and inflammatory inguinal adenopathy. Despite the very characteristic clinical picture, nobody (before admission to our hospital) suspected plague. An effective combination of antibiotics and intensive treatment was initiated only on the fifth day of illness. The patient went into septic shock, respiratory failure, and death. Plague was confirmed by polymerase chain reaction (PCR). This case emphasizes the importance of having a high suspicion rate for plague.	0
Premature thelarche is a self-limited condition characterized by Tanner stage II-III breast development in girls younger than 8 years of age with no evidence of advancing puberty. Evaluation concentrates on excluding central or peripheral causes of precocious puberty.A girl aged 2 years 4 months with profound hypotonia and delayed developmental milestones presented with Tanner II breast development, elevated follicle-stimulating hormone levels, suppressed luteinizing hormone level, normal growth and skeletal development, and prepubertal uterine length and ovarian volume. Monitoring until 8 years of age revealed no pubertal progression. Whole exome sequencing at 8 years revealed an autosomal-dominant mutation in the purine-rich element-binding protein A (PURA) gene. Previous patients with PURA syndrome have had pituitary dysfunction and precocious puberty.Purine-rich element-binding protein A syndrome can be associated with premature thelarche.	0
BACKGROUND:Hajdu-Cheney syndrome (HCS) is a rare inherited skeletal disorder caused by pathogenic mutations in exon 34 of NOTCH2. Its highly variable phenotypes make early diagnosis challenging. In this paper, we report a case of early-onset HCS with severe phenotypic manifestations but delayed diagnosis. CASE PRESENTATION:The patient was born to non-consanguineous, healthy parents of Chinese origin. She presented facial anomalies, micrognathia and skull malformations at birth, and was found hearing impairment, congenital heart disease and developmental delay during her first year of life. Her first visit to our center was at 1 year of age due to cardiovascular repair surgery for patent ductus arteriosus (PDA) and ventricular septal defect (VSD). Skull X-ray showed wormian bones. She returned at 7 years old after she developed progressive skeletal anomalies with fractures. She presented with multiple wormian bones, acro-osteolysis, severe osteoporosis, bowed fibulae and a renal cyst. Positive genetic test of a de novo heterozygous frameshift mutation in exon 34 of NOTCH2 (c.6426dupT) supported the clinical diagnosis of HCS. CONCLUSION:This is the second reported HCS case caused by the mutation c.6426dupT in NOTCH2, but presenting much earlier and severer clinical expression. Physicians should be aware of variable phenotypes so that early diagnosis and management may be achieved.	0
INTRODUCTION:Fetal valproate syndrome was first described in 1984. Valproic acid crosses the placenta and can potentially lead to major congenital malformation, dysmorphism and neurodevelopmental disorder. METHODS:A retrospective study of 29 cases of FVS diagnosed by geneticists from 1995 to 2016. The cases were diagnosed based on criteria of fetal anticonvulsant syndrome. RESULTS:A total of 29 cases reported in the last 21 years. Features commonly described are prominent metopic ridge, midface hypoplasia, epicanthic folds, micrognathia and broad and flat nasal bridge. Four (13.7%) had cleft palate, three (10%) had neural tube defect, four (13.7%) with cardiac malformation, 15 (52%) experienced developmental delay including six (40%) with speech delay, 11 (38%) with limb defects, four (13.7%) reported with neurodevelopmental disorder and two (7%) had hypospadias. CONCLUSION:FVS is still seen in the Irish population even though the teratogenicity of the VPA has been known for over 32 years. It is very important to create public and professional awareness to prevent FVS whenever possible.	0
Epidermolysis bullosa is a debilitating dermatologic disorder affecting the adhesive capability between the epidermis and dermis. The severe recessive dystrophic variant is caused by mutations in COL7A1, the gene encoding type VII collagen which is the major structural protein of the anchoring fibrils linking these 2 skin layers.1 The management of recessive dystrophic epidermolysis bullosa (RDEB) remains complex with no curative therapy. We present herein the novel use of a porcinederived extracellular matrix dressing to effectively treat extensive erosions in a newborn.	0
In this study, we investigated the immune responses against Mycobacterium gordonae in ginbuna crucian carp. Cumulative mortality of ginbuna injected with 2.0 × 107 CFU of M. gordonae was 50% at 170 days post-infection. CD4-1, CD8α, T-bet and IFNγ2 gene expression levels were significantly upregulated in ginbuna injected with 1.9 × 108 CFU of M. gordonae at 21 and 28 days post-infection. The CD4-2 level did not change during the experiment. Granulomatous responses consisted of central macrophage accumulation and surrounding lymphocytes, and Ziehl-Neelsen-positive bacteria were observed in the trunk kidney of the challenged fish. Immunohistochemistry using anti-ginbuna IFNγs and anti-ginbuna CD4-1 polyclonal antibody revealed that the marginal lymphocytes were positive for CD4-1, and the IFNγ-producing cells surrounded the mycobacterial cell-laden phagocytes. These results suggest that CD4-1+ cells and IFNγ2 play important roles in the granulomatous inflammation against Mycobacterial infections in teleosts.	0
INTRODUCTION:Congenital fibrinogen disorders (CFDs) comprise the quantitative and qualitative fibrinogen molecule abnormalities that are caused by fibrinogen gene mutations. The objective of this cohort research was to study the molecular and clinical profiles of patients with CFDs. MATERIALS AND METHODS:Genomic DNA Sanger sequencing of 14 Iranian patients was performed to determine CFDs-causing mutations. The disorders were diagnosed by routine and specific (fibrinogen antigen and functional assay) coagulation tests, and clinical data were obtained from medical records. Molecular dynamics (MD) simulations were performed to investigate the effect of missense mutation on the protein structure. RESULTS:Thirteen out of 14 patients had afibrinogenemia while the remaining patient had dysfibrinogenemia. Umbilical cord bleeding was the most common clinical presentation (n: 9, ~70%) which led to the diagnosis of afibrinogenemia, while menorrhagia led to the diagnosis of dysfibrinogenemia. Six homozygous mutations were identified in afibrinogenemia: three previously described variants in FGA (p.Trp52Ter, p.Ser312AlafsTer109 and p.Gly316GlufsTer105), one in FBG (p.Gly430Asp), and two novel mutations in FGB (p.Gly430Arg) and FGG (p.His366ThrfsTer40), while the FGA (p.Arg38Thr) heterozygous mutation was identified in dysfibrinogenemia. MD simulation indicated that the FGA p. Arg38Thr mutation probably interferes with polymerization of fibrin monomers. CONCLUSIONS:In Iran, with its high rate of consanguinity, autosomal recessive afibrinogenemia with severe clinical presentations is relatively common due to heterogeneous molecular defects.	0
BACKGROUND:The surgical management of glaucoma associated with Axenfeld-Rieger Syndrome (ARS) is poorly described in the literature. The goal of this study is to compare the effectiveness of various glaucoma surgeries on intraocular pressure (IOP) management in ARS. METHODS:Retrospective cohort study at a university hospital-based practice of patients diagnosed with ARS between 1973 and 2018. Exclusion criterion was follow-up less than 1 year. The number of eyes with glaucoma (IOP ≥ 21 mmHg with corneal edema, Haabs striae, optic nerve cupping or buphthalmos) requiring surgery was determined. The success and survival rates of goniotomy, trabeculotomy±trabeculectomy (no antifibrotics), cycloablation, trabeculectomy with anti-fibrotics, and glaucoma drainage device placement were assessed. Success was defined as IOP of 5-20 mmHg and no additional IOP-lowering surgery or visually devastating complications. Kaplan-Meier survival curves and the Wilcoxon test were used for statistical analysis. RESULTS:In 32 patients identified with ARS (median age at presentation 6.9 years, 0-58.7 years; median follow-up 5.4 years, 1.1-43.7 years), 23 (71.9%) patients were diagnosed with glaucoma at median age 6.3 years (0-57.9 years). In glaucomatous eyes (46 eyes), mean IOP at presentation was 21.8 ± 9.3 mmHg (median 20 mmHg, 4-45 mmHg) on 1.0 ± 1.6 glaucoma medications. Thirty-one eyes of 18 patients required glaucoma surgery with 2.2 ± 1.2 IOP-lowering surgeries per eye. Goniotomy (6 eyes) showed 43% success with 4.3 ± 3.9 years of IOP control. Trabeculotomy±trabeculectomy (6 eyes) had 17% success rate with 14.8 ± 12.7 years of IOP control. Trabeculectomy with anti-fibrotics (14 eyes) showed 57% success with 16.5 ± 13.5 years of IOP control. Ahmed© (FP7 or FP8) valve placement (8 eyes) had 25% success rate with 1.7 ± 1.9 years of IOP control. Baerveldt© (250 or 350) device placement (8 eyes) showed 70% success with 1.9 ± 2.3 years of IOP control. Cycloablation (4 eyes) had 33% success rate with 2.7 ± 3.5 years of IOP control. At final follow-up, mean IOP (12.6 ± 3.8 mmHg, median 11.8 mmHg, 7-19 mmHg) in glaucomatous eyes was significantly decreased (p < 0.0001), but there was no difference in number of glaucoma medications (1.6 ± 1.5, p = 0.1). CONCLUSIONS:In our series, greater than 70% of patients with ARS have secondary glaucoma that often requires multiple surgeries. Trabeculectomy with anti-fibrotics and Baerveldt glaucoma drainage devices showed the greatest success in obtaining IOP control.	0
Cutis laxa is a heterogeneous group of disorders with variable phenotypes and inheritance patterns. Type II cutis laxa has features overlapping with wrinkly skin syndrome, as a result of which they are regarded as one disorder with a variable spectrum of severity by some authors. To overcome this existing confusion, we present three patients with cutis laxa type II and review the literature to highlight the important differentiating features between cutis laxa type II and wrinkly skin syndrome.	0
OBJECTIVE To detect potential mutations of GCDH gene in five patients with glutaric acidemia type I (GA-I). METHODS Genomic DNA was extracted from peripheral blood samples from the patients. The 11 exons and their flanking sequences of the GCDH gene were amplified with PCR and subjected to direct sequencing. RESULTS Four mutations of the GCDH gene were identified among the patients, which included c.532G>A (p.G178R), c.533G>A (p.G178E), c.106_107delAC (p.Q37fs*5) and c.1244-2A>C. Among these, c.1244-2A>C was the most common, while c.106_107delAC was a novel mutation, which was predicted to be pathogenic by MutationTaster software. CONCLUSION The diagnosis of GA-I has been confirmed in all of the five patients. Identification of the novel GCDH mutations has enriched the mutational spectrum of the GCDH gene.	0
Background: Drooling related to bulbar weakness and dysfunction is a common concern in patients with neuromuscular disease. While there are numerous medications to manage sialorrhea, they are often limited by side effects and lack of efficacy. Botulinum toxin has shown to benefit ALS patients in a few studies, but there is scant data on the benefit in other neuromuscular conditions. Objective: To assess the effectiveness of Botulinum toxin in reducing sialorrhea in patients with various neuromuscular disease. Design/Methods: 25 patients (19M, 6F; 54.36 ± 17.09 yr) with documented neuromuscular illness and concern for drooling was followed for 6 weeks after Botulinum toxin injection. These patients had one of the following diagnoses: Duchenne muscular dystrophy (3), myotonic dystrophy (3), oculopharyngeal muscular dystrophy (1), inclusion body myositis (2), primary lateral sclerosis (1), amyotrophic lateral sclerosis (9), spinal muscular atrophy type 2 and 3 (2), spinal-bulbar muscular atrophy (2), and Becker's muscular dystrophy (2). A subjective drooling scale (1: markedly worse, 5: markedly better) and drooling thickness score (0=normal, 100=thick) was calculated on these patients prior to the injection and 4 and 6 weeks after the injection. Botulinum toxin 20-30 units were injected into bilateral parotid gland (70% of the dose) and submandibular gland (30% of the dose). Results: The drooling thickness score at before the injection was 75.2 ± 10.46. At 4 and 6 weeks, average scores reduced to 47.2 ± 6.14 and 18.8 ± 5.26, respectively (p < 0.05). The average pre injection perception about drooling was 3.0 (p < 0.05). The average change in perception was +0.84 and +1.28 at 4 and 6 weeks, respectively, (p < 0.05) implying significant improvement. There were no reported adverse effects. Conclusion: This study provides preliminary evidence for the use of botulinum toxin for refractory sialorrhea for a variety of neuromuscular conditions.	0
BACKGROUND:Linear scleroderma "en coups de sabre" is a disease that causes scar-like lesions in the forehead and the scalp, and atrophy of the underlying structures. The result is an acute facial asymmetry that can be distressing to affected young adults. Several surgical treatments are available such as free tissue transfer and synthetic fillers. AIMS:In this report, we present a rare case of linear scleroderma "en coups de sabre," which was successfully managed with single-stage autologous fat grafting. PATIENTS/METHODS:The patient was a 17-year-old male who presented with a soft-tissue defect in the left forehead region. Treatment consisted of transferring autologous fat into the defect in a retrograde fashion, as described by Coleman, and overcorrecting the defect to account for fat resorption. RESULTS:At 6 mo postoperatively, the patient had maintained a satisfactory correction of his left forehead and scalp regions with minimal resorption of fat. CONCLUSION:Autologous fat grafting provides a safe and easy approach for the treatment of linear scleroderma "en coups de sabre". With minimal manipulation of the aspirated fat, combined with overcorrection of the defect, long-term clinically satisfactory results can be obtained.	0
The nuclear lamina is a fibrous meshwork of proteins found adjacent to the inner nuclear membrane that plays a critical role in the maintenance of nuclear architecture. Made up of A and B type lamins, the nuclear lamina has recently been shown to contribute to numerous cellular functions such as chromatin organization, DNA replication, cellular proliferation, senescence, and aging. While at least a dozen disorders are associated with LMNA, the focus of this review is Autosomal Dominant Leukodystrophy (ADLD), the only disease associated with the lamin B1 gene (LMNB1). ADLD is a fatal, adult onset CNS demyelinating disorder that is caused by either genomic duplications involving LMNB1 or deletions upstream of the gene. Both mutation types result in increased LMNB1 gene expression. How the increased levels of this widely expressed nuclear structural component results a phenotype as specific as demyelination is a great mystery. This review summarizes what is currently known about the disease and describes recent work using animal and cell culture models that have provided critical insights into ADLD pathological mechanisms. The delineation of these pathways provides a fascinating glimpse into entirely novel roles for the nuclear lamina and will be critical for the identification of therapies for this fatal disease.	0
ALG13-CDG has been recently discovered as a disorder of severe developmental, intellectual and speech disability, microcephaly, visual abnormalities, seizures, hepatomegaly, coagulation abnormalities, and abnormal serumtransferrin isoelectric focusing in serum. A male with seizures, delayed motor, and speech development, but normal cognition carried a hemizygous, predicted pathogenic ALG13 variant (p.E463G). N-glycosylation studies in plasma were normal. ICAM-1 expression was decreased in patient fibroblasts, supporting the variant's pathogenicity. Adding D-galactose to the patient's fibroblast culture increased ICAM-1 expression in vitro, offering a potential treatment option in ALG13-CDG. The present report is a new example for an N-glycosylation disorder, that may present with normal transferrin isoform analysis, and also demonstrates, that CDG type I patients can have normal cognitive development.	0
Pompe disease is an autosomal recessive lysosomal storage disorder characterized by progressive muscle weakness. The disease is caused by mutations in the acid α-glucosidase (GAA) gene. Despite the currently available enzyme replacement therapy (ERT), roughly half of the infants with Pompe disease die before the age of 3 years. Limitations of ERT are immune responses to the recombinant enzyme, incomplete correction of the disease phenotype, lifelong administration, and inability of the enzyme to cross the blood-brain barrier. We previously reported normalization of glycogen in heart tissue and partial correction of the skeletal muscle phenotype by ex vivo hematopoietic stem cell gene therapy. In the present study, using a codon-optimized GAA (GAAco), the enzyme levels resulted in close to normalization of glycogen in heart, muscles, and brain, and in complete normalization of motor function. A large proportion of microglia in the brain was shown to be GAA positive. All astrocytes contained the enzyme, which is in line with mannose-6-phosphate receptor expression and the key role in glycogen storage and glucose metabolism. The lentiviral vector insertion site analysis confirmed no preference for integration near proto-oncogenes. This correction of murine Pompe disease warrants further development toward a cure of the human condition.	0
Nodding syndrome (NS) is a progressive encephalopathy of children and adolescents characterized by seizures, including periodic vertical head nodding. Epidemic NS, which has affected parts of East Africa, appears to have clinical overlap with sub-Saharan Nakalanga syndrome (NLS), a brain disorder associated with pituitary dwarfism that appears to have a patchy distribution across sub-Sahara. Clinical stages of NS include inattention and blank stares, vertical head nodding, convulsive seizures, multiple impairments, and severe cognitive and motorsystem disability, including features suggesting parkinsonism. Head nodding episodes occur in clusters with an electrographic correlate of diffuse high-amplitude slow waves followed by an electrodecremental pattern with superimposed diffuse fast activity. Brain imaging reveals differing degrees of cerebral cortical and cerebellar atrophy. Brains of NS-affected children with mild frontotemporal cortical atrophy display neurofibrillary pathology and dystrophic neurites immunopositive for tau, consistent with a progressive neurodegenerative disorder. The etiology of NS and NLS appears to be dominated by environmental factors, including malnutrition, displacement, and nematode infection, but the specific cause is unknown.	0
BACKGROUND:The FYB gene encodes adhesion and degranulation-promoting adaptor protein (ADAP), a hematopoietic-specific protein involved in platelet activation, cell motility and proliferation, and integrin-mediated cell adhesion. No ADAP-related diseases have been described in humans, but ADAP-deficient mice have mild thrombocytopenia and increased rebleeding from tail wounds. PATIENTS AND METHODS:We studied a previously reported family of five children from two consanguineous sibships of Arab Christian descent affected with a novel autosomal recessive bleeding disorder with small-platelet thrombocytopenia. Homozygosity mapping and exome sequencing were used to identify the genetic lesion causing the disease phenotype on chromosome 5. Bone-marrow morphology and platelet function were analyzed. Platelets were characterized by scanning electron microscopy. RESULTS:We identified a homozygous deleterious nonsense mutation, c.393G>A, in FYB. A reduced percentage of mature megakaryocytes was found in the bone marrow. Patients' platelets showed increased basal expression of P-selectin and PAC-1, and reduced increments of activation markers after stimulation with ADP, as detected by flow cytometry; they also showed reduced pseudopodium formation and the presence of trapped platelets between the fibrin fibers after thrombin addition, as observed on scanning electron microscopy. CONCLUSIONS:This is the first report of a disease caused by an FYB defect in humans, manifested by remarkable small-platelet thrombocytopenia and a significant bleeding tendency. The described phenotype shows ADAP to be important for normal platelet production, morphologic changes, and function. It is suggested that mutation analysis of this gene be included in the diagnosis of inherited thrombocytopenia.	1
Purpose:To investigate the association between aqueous flare and progression of visual field loss using the Humphrey Field Analyzer in patients with retinitis pigmentosa (RP). Methods:We examined a total of 101 eyes of 101 patients who were diagnosed with typical RP. Sixty-one percent of the patients were female, and the mean age of the total group was 47.4 years. Aqueous flare, visual field (by an Humphrey Field Analyzer, the central 10-2 SITA-Standard program), and optical coherence tomography measurements were obtained for all patients. The slope, which was derived from serial values of mean deviation, macular sensitivity, or foveal sensitivity for each eye with univariate linear regression, was used for analysis. Results:Aqueous flare values were significantly correlated with the mean deviation slope (r = -0.20, P = 0.046), macular sensitivity slope (r = -0.28, P = 0.005) and foveal sensitivity slope (r = -0.20, P = 0.047). The values of the retinal sensitivity slope significantly decreased as the aqueous flare level increased (all P < 0.05). These associations remained unchanged after adjustment for age, sex, and posterior subcapsular cataract, and epiretinal membrane. Conclusions:Elevation of aqueous flare is a risk factor for the decline of central visual function in RP. Aqueous flare may be a useful marker for disease progression in RP.	0
RATIONALE:Familial hemophagocytic lymphohistiocytosis (FHL) is a rare fatal autosomal recessively inherited disease and can be divided into five types. The mortality of untreated patients is up to 95% and it can be healed only after immunochemotherapy for disease control and hematopoietic stem cell transplantation. Clinical data of a girl with late-onset and recurrent hemophagocytic lymphohistiocytosis (HLH) was retrospectively analyzed to determine the etiology and potential pathogenic gene. PATIENT CONCERNS AND CLINICAL FINDINGS:The proband was a female child patient from a consanguineous marriage family who was 11 years old, and clinically manifested delayed (onset at the age of 4 years and 6 months) and recrudescent HLH. Both of her elder brothers died at the ages of 4 and 5 years, respectively. The patient had a degranulation function defect of CD107a in natural killer (NK) cells, and the degranulation function of cytotoxic T lymphocytes (CTL) obviously declined (ΔMFI: 1.4%, normal ≧2.8%); the degranulation function of NK cells and CTL of her father was also obviously reduced. To identify possible underlying genetic causes, gene mutation analysis was undertaken. A novel homozygous nonsense mutation in STX11 (c.49C>T, p.Q17X) was documented, arising from both her parents. DIAGNOSIS:According to the clinical manifestations and detection results of STX11, the diagnosis of FHL-type 4 was confirmed and her parents were heterozygotic carriers. INTERVENTIONS AND OUTCOMES:Good responses to HLH-2004 chemotherapy had been achieved for each onset, and the maximum remission duration (without taking any drug) was 23 months. The patient has been alive for 82 months since the onset, and has stopped taking dexamethasone and etoposide, but is still on oral cyclosporine to maintain the treatment. She has performed HLA matching and now is actively looking for a donor to prepare hematopoietic stem cell transplantation. CONCLUSIONS:Relevant gene detections should be implemented at the earliest for young patients from consanguineous marriages and with a family history of HLH so as to provide a basis for etiological diagnosis and radical treatment by hematopoietic stem cell transplantation and provide accurate genetic counseling for family members.	0
BACKGROUND:Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia and is characterized by the presence of insulin autoantibodies. Patients with IAS usually complain of hypoglycemia without any previous insulin received. Glucocorticoids and immunosuppressants are used to treat IAS. CASE PRESENTATION:We report four patients with diabetes who were diagnosed with non-classical IAS and describe the treatment of these patients. Moreover, the differential diagnosis with hyperinsulinism is discussed. CONCLUSION:High levels of insulin autoantibodies, as well as hyperinsulinemic hypoglycemia, are found in patients with diabetes mellitus and prior exogenous insulin exposure. This situation that we classified as non-classical IAS should be attached importance to.	0
NEDD4L encodes an ubiquitin ligase which is expressed in the cortex and ventricular zone of the fetal brain. Missense variants in NEDD4L have been reported in nine patients with periventricular nodular heterotopia (PNH), polymicrogyria, cleft palate, and syndactyly. All reported variants are located in the HECT domain, causing deregulation of signaling pathways, including the AKT/mTOR pathway. Here we describe a first familial case with four affected members with a high degree of intra-familial phenotypic variability. Phenotypic features in the proband consisted of severe neurodevelopmental delay, refractory seizures, bilateral PNH, and perisylvian polymicrogyria. The other family members were less severely affected with mild developmental delay and isolated bilateral PNH. All family members had syndactyly. An unrelated patient presented with severe neurodevelopmental delay, seizures, and hypospadias, expanding the phenotypic spectrum. MRI revealed bilateral PNH and perisylvian polymicrogyria. All tested patients carry the recurrent variant c.623G > A, p.(Arg208Gln) in the WW domain of NEDD4L. The variant in the unrelated patient occurred de novo. This is the first report of a NEDD4L variant located in the WW domain which is probably involved in the recognition of substrates for ligation suggesting a loss of function variant.	0
We report the first case of mandibuloacral dysplasia with type B lipodystrophy (MADB) in Chile, South America. MADB is a very rare illness, characterized by short stature, mandibular hypoplasia, acro-osteolysis in hands, feet and clavicles, lipodystrophy, changes in skin pigments and skin calcinosis at knees and hands. Diagnosis was confirmed by molecular study that showed two compound heterozygous variants in ZMPSTE24 gene, c.1085dup p.(Leu362Phefs*19) and c.794A>G p.(Asn265Ser). This article could help in establishing the correlation between genotype and phenotype of this disorder, comparing with other cases previously described.	0
Background:Proximal symphalangism (SYM1) is a rare genetic bone disorder characterized by the fusion of proximal interphalangeal joints in the hands and feet. Genetic studies have identified two genes underlying SYM1 as the noggin (NOG) and the growth differentiation factor 5 (GDF5). Case Report:In the present report, a 43-year-old gravida at 11 weeks of gestation was referred for evaluation of abnormal fusions of the joints. In the initial diagnosis, physical examination was undertaken. However, traditional radiological examination was not applied due to the need to protect the fetus, making diagnosis results inefficient to determine the exact disease affecting the proband. To acquire alternative clinical evidences, we conducted radiological examinations on two other affected family members. The radiological examination revealed that they carried the symphalangism accompanied with tarsal coalition, a very rare manifestation of SYM1. A combination of whole exome sequencing (WES) and Sanger sequencing revealed a novel heterozygous missense mutation (c.163G > T; p.Asp55Tyr) in the NOG gene, which could be associated with the observed pathogenic SYM1 in the studied family. The p.Asp55Tyr mutation co-segregated with SYM1 through the affected and unaffected family members. In silico structural modeling of the p.Asp55Tyr mutation showed that it abolishes the interaction with the Arg167 residue and causes a change in the electrostatic potential profile of the type II binding site of the noggin protein. Conclusion:Our findings indicate that the genetic test based on WES can be useful in diagnosing SYM1 patients, with particular advantages in preventing the fetus from contacting harmful X-ray through the traditional radiography. The novel pathogenic mutation identified would further expand our understanding of the mutation spectrum of NOG in association with SYM1 disease and provide a guidance on how to determine whether the fetus is affected by SYM1 through the prenatal diagnosis.	0
Multifocal atrial tachycardia has certain electrocardiographic similarities to atrial fibrillation. The mechanism of atrial fibrillation is heterogenous but in some cases may arise from a single ectopic driver with fibrillatory conduction to the rest of the atria. This has led to the speculation that multifocal atrial tachycardia may have a similar mechanistic unifocal site that disperses through the atrium in a fibrillatory pattern. Ivabradine has been reported to be efficacious in an adult with paroxysmal atrial fibrillation as well as in children with junctional or ectopic atrial tachycardias. This is the first report of successfully using ivabradine, a novel anti-arrhythmic If blocking agent, to convert multifocal atrial tachycardia in a 5-month-old critically ill infant to a pattern indicating a single ectopic atrial focus. This allowed the patient's single atrial focus to be ablated with return to sinus rhythm and decannulation from ventriculoarterial extracorporeal membrane oxygenation. This case suggests that multifocal atrial tachycardia may arise from a single automatic focus with downstream fibrillatory conduction to the atria.	0
BACKGROUND:Central Neurocytomas (CNs) are rare brain tumors, making up less than 1% of all primary tumors within the CNS. They are commonly located in the lateral ventricles, and often present with visual changes and symptoms of obstructive hydrocephalus. Histopathology shows characteristics similar to ependymomas and oligodendrogliomas, however tumor cells display neuronal differentiation, and immunohistochemical stains typically for synaptophysin. Gross total resection is the most important prognostic indicator of survival. CASE DESCRIPTION:We describe the case of a 48-year-old male with a CN originating in the third ventricle with expansion through the cerebral aqueduct into the fourth ventricle. He presented with bi-frontal headaches, imaging revealed an avidly enhancing tumor occupying the inferior third ventricle, cerebral aqueduct, with expansion into the fourth ventricle. An interhemispheric craniotomy with a transcallosal transchoroidal approach to the third ventricle was performed, this provided a trajectory that paralleled the long axis of the tumor. Postoperative imaging confirmed a near total resection with linear residual enhancement on the anterior wall of the fourth ventricle. Intensity modulated radiotherapy was performed, 7-month follow-up imaging was clean. CONCLUSION:CNs are rare brain tumors, most commonly located within the lateral ventricles. We describe a rare case of a CN spanning from the third ventricle into the cerebral aqueduct and fourth ventricle. To our knowledge, this is only the fourth reported case of such a tumor. Surgical approach must be carefully selected, as gross total resection is the most important prognostic indicator.	0
Introduction: Lambert-Eaton myasthenic syndrome is an autoimmune disease of the neuromuscular junction characterized by a presynaptic defect of neuromuscular transmission resulting in muscle weakness and fatigability. Diagnostic features are specific neurophysiological alterations and autoantibody detection. The present review is focused on the use of Amifampridine Phosphate to treat LEMS patients.Areas covered: Medline search from 1990 to 2019 was examined using the free subject terms: Lambert-Eaton myasthenic syndrome, LEMS, Amifampridine, 3,4-diaminopyridine, which were then combined with Treatment, Therapy, Clinical Trial, Controlled Clinical Trial, Randomized Clinical Trial and Cochrane Review. The author has done a supervised analysis of the retrieved articles and focused on those subjectively evaluated as most relevant.Expert commentary: Data from randomized clinical trials and case series have demonstrated that Lambert-Eaton myasthenic syndrome symptoms were successfully treated by Amifampridine Phosphate. Hence, the drug represents a substantial step forward in the symptomatic treatment of the disease due to its efficacy, safety and reliable GMP formulation. As Amifampridine Phosphate works by enhancing the release of acetylcholine at the neuromuscular junction by blocking K+ efflux at the pre-synaptic membrane, it is also conceivable to use it for other diseases of the neuromuscular junction in which such an effect is searched for.	0
Felty's syndrome (FS) is a deforming disease, characterized by the triad of rheumatoid arthritis (RA), neutropenia, and splenomegaly. Currently, FS patients are treated mainly with immunosuppressants, such as methotrexate and glucocorticoids, which however are not suitable to some patients and may cause severe side effects. Here we report a clinical FS case that was treated with Tocilizumab (TCZ) successfully. The patient had symmetrical swelling and pain of multiple joints, deformity of elbow joints with obvious morning stiffness. Joint color Doppler ultrasound showed synovial hyperplasia and bone erosion of wrist and proximal interphalangeal joints and CT scan suggested splenomegaly. Further examination showed neutropenia and anemia, a high titer of anti-cyclic citrullinated peptide antibody, rheumatoid factor and anti-nuclear antibodies, positive p-ANCA, and elevated IgA and IgG. After treating with TCZ, the patient has been relieved of clinical symptoms. His spleen has recovered to normal size. The absolute neutrophil count (ANC) tended to be stable, and joint erosion did not deteriorate. We have reviewed the literatures on FS treatment with biological agents and found only a few reports using TNF-α antagonist and rituximab treating FS, but none with TCZ. So, it is the first time to report a successful FS case treated with TCZ. This case suggests that the TCZ may be a new choice for FS treatment, under the condition of closely monitoring the ANC.	0
We report a case of epidermolysis bullosa simplex, Dowling-Meara type (EBS-DM), which was associated with congenital pyloric atresia (PA) and various urologic abnormalities, a diagnosis confirmed by immunofluorescence mapping and electron microscopic findings. Immunofluorescent mapping showed the serum from a patient with bullous pemphigoid faintly binding to the floor of the blister, and monoclonal antibodies against type IV and VII collagens were also stained on the floor of the blister. Electron microscopy showed epidermolytic cleavage and prominent clumping of tonofilaments in the basal and suprabasal keratinocytes. An abdominal radiograph and barium swallow showed a complete obstruction at the pyloric channel level. The widespread bullae healed without any scar formation and the bullae formation was localized on the extremities after 3 months of age without any specific treatment. Multiple urologic abnormalities such as bilateral hydronephrosis, hydroureter and a distended bladder with trabeculation were observed at 12 months of age. Currently, with the patient at 4 years of age, bullae still appear on the hands and feet and nail shedding can be observed. The patient's father, a paternal uncle and a paternal aunt had had similar bullous eruptions in infancy, all of which had improved spontaneously by the age of one.	0
BACKGROUND:Inflammation of the pituitary gland can occur in a variety of primary or secondary disorders. Idiopathic granulomatous hypophysitis is a rare inflammatory disease of the pituitary gland that can closely mimic a pituitary adenoma clinicoradiologically. Most authorities agree on minimally invasive transsphenoidal surgery as the mainstay in diagnosis and treatment of this disorder. There is still some controversy regarding pure medical management of idiopathic granulomatous hypophysitis in the literature. CASE PRESENTATION:A 47-year-old Iranian woman of Azeri ethnicity with a history of benign breast cysts with a chief complaint of galactorrhea presented to our endocrinology clinic. Her past medical history was negative for any menstrual irregularities, hirsutism, visual complaints, diplopia, polyuria and polydipsia or seizures. She was taking 100 mcg of levothyroxine daily. Her familial history and physical examination were unremarkable. Her initial laboratory work-up revealed hyperprolactinemia (82.4 ng/mL) with otherwise normal pituitary axes. Brain magnetic resonance imaging showed a pituitary macroadenoma for which she was treated with 0.5 mg of cabergoline weekly. Although her serum prolactin level dropped to 1.7 ng/mL and her galactorrhea was resolved, she continued to complain of headaches and nausea. Repeated imaging showed no decrease in size of the macroadenoma. Therefore, she underwent transsphenoidal surgery of the macroadenoma which was reported as chronic granulomatous hypophysitis by expert pathologists. Tuberculosis, sarcoidosis, Wegener's granulomatosis, Langerhans cell histiocytosis, and syphilis were ruled out by appropriate tests and she was diagnosed as having idiopathic granulomatous hypophysitis. Fortunately, her condition was not complicated by hypopituitarism and she was symptom free 9 months after transsphenoidal surgery. CONCLUSIONS:Idiopathic granulomatous hypophysitis, a rare inflammatory disease of the pituitary gland, is a diagnosis of exclusion for which both medical and surgical management are reported in the literature. We present a case of idiopathic granulomatous hypophysitis who was symptom free with no complications of hypopituitarism following its transsphenoidal resection after 9 months of follow-up.	0
Background:Factors determining the prognosis of diffuse panbronchiolitis (DPB) remain unclear at present. The objective of this study was to identify the prognostic value of concomitant bronchiectasis in the macrolide treatment efficacy and exacerbation risk in DPB patients. Methods:Data of patients initially diagnosed with DPB at the Shanghai Pulmonary Hospital between January 2007 and December 2017 were retrospectively collected and analyzed. The patients were divided into two groups according to the existence of bronchiectasis. Clinical manifestations, laboratory findings, microbiological culture results, as well as exacerbation risks and treatment outcomes, were compared between these two groups. The survival curve and Cox regression analysis models were additionally constructed to further demonstrate the predicting role of bronchiectasis in DPB exacerbation. Results:Baseline data revealed more respiratory symptoms, lower body mass index (BMI), and forced expiratory volume in one second (FEV1) as well as increased isolates of Pseudomonas aeruginosa (P. aeruginosa) in DPB subjects with bronchiectasis than those without. Furthermore, bronchiectasis was associated with a lower rate of responsiveness to macrolides and increased exacerbation frequency during follow-up. The survival curve and Cox regression analysis showed that comorbid bronchiectasis was linked to increased time to episode relapse, which remained significant even after controlling for BMI, FEV1, and P. aeruginosa culture results. Conclusion:The coexistence of bronchiectasis predicted a poor outcome of maintenance macrolide therapy and an increased exacerbation risk in DPB subjects, possibly through its impacts on nutritional status, pulmonary function, and P. aeruginosa infections.	0
BACKGROUND:The purpose of this study is to review 10 years of surgical experience in the management of Apert syndrome, focusing on an updated algorithm which includes hand reconstruction and posterior vault distraction osteogenesis (PVDO). Additionally, the authors compare PVDO, which is currently used, with fronto-orbital advancement (FOA), which was utilized in a previous algorithm. METHODS:An observational retrospective study was performed on consecutive patients with Apert syndrome who underwent upper and lower limb reconstruction and craniofacial surgery between 2007 and 2017. A modified Clavien-Dindo surgical complication scale was used to stratify complications between PVDO and FOA. Demographic, surgical, and outcome data was also recorded. The blood transfusion rate between PVDO and FOA was also assessed and compared utilizing the Student t test. RESULTS:The present study included 69 patients with Apert syndrome (34 males and 35 females). Craniofacial surgeries were performed on a total of 38 patients. A total of 210 operations were performed on the respective upper and lower limbs of patients included in this study. A total of 18 patients underwent PVDO (n = 9) and FOA (n = 9). Posterior vault distraction osteogenesis required significantly less transfused blood volume than FOA (P < 0.05). Complication rate and length of hospital stay were similar for each procedure. CONCLUSION:An updated algorithm to treat Apert patients was implemented. Posterior vault distraction osteogenesis incorporated into an updated algorithm results in a lower blood transfusion rate.	0
Neuronal ceroid lipofuscinosis (NCL) is a lysosomal storage disorder that causes progressive neurodegenerative disease as a result of storage in neurons and other cells. Late infantile type (NCL Type 2) of NCL, which is the most common neurodegenerative disease in childhood, is characterised by a homozygous mutation in the tripeptidyl peptidase-1 (TPP-1) gene. A male infant was referred to our neonatal intensive care unit (NICU) on 26th day of life with a diagnosis of metabolic disease. He was intubated. He was hypotonic and newborn reflexes were not present. Cranial magnetic resonance (MR) imaging revealed severe atrophy and delayed myelination of cerebellum and cerebral hemispheres. A novel homozygous pathological mutation was detected in exon 9 of the TPP-1 gene. With this case, it should be kept in mind that NCL may rarely start early in neonatal period and should be suspected in newborns with cerebral and cerebellar atrophy for early diagnosis. Key Words: Hypotonia, Lysosomal storage diseases, Metabolic disease, Neuronal ceroid lipofuscinosis, Newborn.	0
PURPOSE:To evaluate the clinical characteristics and evolution of lamellar macular hole (LMH) in high myopia and the parameters associated with structural worsening, defined as the development of foveal detachment or full-thickness macular hole. METHODS:Patients with high myopia and LMH were retrospectively recruited. The clinical characteristics and various parameters of optical coherence tomography were identified at baseline and during follow-up visits. Cox regression analysis was used to evaluate the hazard ratios for foveal detachment and full-thickness macular hole. RESULTS:Among 112 eyes (98 patients), 64.3% were female; the mean axial length of all eyes was 29.6 ± 1.9 mm. The 'LMH without retinoschisis' group accounted for 39.3% of the eyes. Forty-two percent developed structural worsening within a median follow-up of 67 months. Multivariable regression on all cases showed elevated tissue inside the LMH (P = 0.003) protected against structural worsening while V-shaped LMH (P = 0.006) predicted it. In the "LMH with retinoschisis group", ellipsoid zone disruption (P = 0.035), and V-shaped LMH (P = 0.014) predicted structural worsening, while elevated tissue inside the LMH (P = 0.028) protected against it. In the "LMH without retinoschisis group", no associated factor was identified. CONCLUSIONS:LMHs in high myopia are unstable, especially those with V-shaped LMH. Elevated tissue inside LMHs have a protective effect against further structural worsening.	0
BACKGROUND:Childhood epilepsies are a heterogeneous group of conditions differing in diagnostic criteria, management, and outcome. Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is a neurodegenerative condition caused by biallelic TPP1 variants. This disorder presents with subtle and relatively non-specific symptoms, mimicking those observed in more common paediatric epilepsies and followed by rapid psychomotor deterioration and drug-resistant epilepsy. A prompt diagnosis is essential to adopt appropriate treatment and disease management strategies. METHODS:This is a prospective, multicentre study on the efficiency of targeted re-sequencing in the early identification of the genetic causes of childhood epilepsy, with particular regard to CLN2. After phenotypic characterization, a 283-gene Next Generation Sequencing panel was performed in 21 Italian children with neurodevelopmental abnormalities, aged between 24 and 60 months, experiencing first unprovoked seizure after 2 years of age. RESULTS:The average age at enrolment was 39.9 months, with a mean age at seizure onset of 30.9 months and a mean time interval between seizure onset and targeted resequencing of 9 months. Genetic confirmation was achieved in 4 out of 21 patients, with a diagnostic yield of 19%. In one case, the homozygous splice acceptor variant c.509-1G > C in TPP1 was identified, leading to a CLN2 diagnosis. Three pathogenic variants in MECP2 were also detected in three patients, including the frameshift variant c.1157_1186delinsA (p.Leu386Hisfs*9) in a girl with negative single gene sequencing. Variants of unknown significance (VUS) were found in 11 out of 21 (52.4%) individuals, whereas no clinically significant variants were observed in the remaining 6 subjects. CONCLUSIONS:Our findings support the efficacy of target re-sequencing in the identification of the genetic causes of childhood epilepsy and suggest that this technique might prove successful in the early detection of CLN2 as well as other neurodevelopmental conditions.	0
Recent progress in Omics technologies has started to empower personalized healthcare development at a thorough biomolecular level. Omics have subsidized medical breakthroughs that have started to enter clinical proceedings. The use of this scientific know-how has surfaced as a way to provide a more far-reaching view of the biological mechanisms behind diseases. This review will focus on the discoveries made using Omics and the utility of these approaches for Emery-Dreifuss muscular dystrophy.	0
The Xp11.22-p11.23 duplication syndrome was described in 2009 by Giorda et al and is characterized by intellectual disability, speech delay, and electroencephalography anomalies. We report a case of a 23-month-old girl who presented with epilepsy and global developmental delay and who had a small duplication at Xp11.23. The case we present here is the first case showing the clinical features of Xp11.22-p11.23 duplication syndrome only involving synovial sarcoma, X breakpoint ( SSX ) genes: SSX1 , SSX3 , SSX4 , and SSX9 . This case report contributes to an expanding clinical spectrum of Xp11.22-p11.23 duplication syndrome.	0
In acute erythroleukemia, erythroid/myeloid subtype, blasts usually comprise 5-19% of total bone marrow cells, similar to the myelodysplastic syndrome subtype refractory anemia with excess blasts; recent studies have raised the question if acute erythroleukemia should be considered as a myelodysplastic syndrome subtype. We reviewed 77 de novo acute erythroleukemia and 279 de novo refractory anemia with excess blasts from three large medical centers. Compared to refractory anemia with excess blasts, acute erythroleukemia patients had higher total bone marrow blasts, lower platelets, hemoglobin, and absolute neutrophil counts, with more patients being assigned a very-poor-karyotype risk and very-high Revised International Prognostic Scoring System score. Induction chemotherapy was administered to 55% of acute erythroleukemia patients, but was not associated with longer overall survival compared to acute erythroleukemia patients treated with lower-intensity therapies or supportive care (P=0.44). In multivariable analysis of all patients, Revised International Prognostic Scoring System very high (P<0.0001) or high (P=0.005) risk, but not a diagnosis of acute erythroleukemia (P=0.30), were independent risk factors for shorter overall survival. Our data show that acute erythroleukemia patients have similar risk-adjusted outcome to refractory anemia with excess blasts patients and do not appear to gain survival advantage with acute myeloid leukemia-type induction chemotherapy. These data suggest that acute erythroleukemia, erythroid/myeloid subtype with <20% blasts may be more appropriately classified as refractory anemia with excess blasts rather than as an acute myeloid leukemia subtype.	0
Arthrogryposis multiplex congenita (AMC) describes disorders with multiple joint contractures that arise from neurological, neuromuscular, or mechanical origin. Although impaired fetal movement is the typical clinical presentation, the etiology underlying this phenotype for a number of conditions remains unknown. In an effort to better characterize and define the etiologies underlying these disorders, we recommend a standardized autopsy protocol that will allow for appropriate diagnosis and a methodical approach for examination that will facilitate subsequent study by investigators across disciplines. To further support investigation, we have also established an AMC autopsy registry to bank tissue obtained at autopsy for subsequent study.	0
OBJECTIVE:To assess the value of combined cytogenetic and molecular techniques for the prenatal diagnosis of a pregnant woman with intellectual disability (ID). METHODS:The fetus and its parents were subjected to G-banding karyotyping analysis, single nucleotide polymorphism array (SNP-array) and fluorescence in situ hybridization (FISH) analysis. RESULTS:G-banding karyotype analysis revealed that the woman has carried a chromosomal microdeletion 46,XX,del(11)(q24), and the fetus was a carrier of 46,XN,del(11)(q24)mat. Subsequent SNP-array and FISH analysis of the pregnant woman indicated that the microdeletion has mapped to 11q24.1-q25. Both the pregnant woman and her fetus were diagnosed with Jacobsen syndrome. CONCLUSION:Combined use of cytogenetic and molecular genetic techniques can facilitate diagnosis of patients with intellectual disability.	0
Differentiating between trichoepithelioma and basal cell carcinoma (BCC) is sometimes diagnostically challenging. We present a case of a 61-year-old male with a BCC arising within a trichoepithelioma, which is rarely reported in the literature. Clinical and histological diagnosis of trichoepithelioma is sometimes complicated by its many similarities to BCC. Therefore, immunohistochemical analysis and adequate tissue sampling are essential in suspicious lesions. In addition, as represented by our patient's presentation, it is important for clinicians to remember that the presence of a concurrent malignant neoplasm may be masked by the benign nature of a trichoepithelioma and that a superficial shave biopsy may not be sufficient for accurately diagnosing such suspicious lesions.	0
A 9-month-old boy presented with the complaints of loose motion, vomiting and difficulty in breathing. His scalp hairs were thin, brittle, and sparse and were of differing lengths with twisted appearance. Hair shaft microscopy revealed alternate light and dark segments and twisting of the hair shafts by 180 degrees along the axis. Serum copper levels were normal. The audiological testing revealed bilateral sensorineural hearing loss. Child was diagnosed as a case of Bjornstad Syndrome.	0
Despite intensive multimodal therapy, the survival rate for high risk neuroblastoma (HR-NB) remains <50%. Most cases initially respond to treatment but almost half will subsequently relapse with aggressive treatment resistant disease. Novel treatments exploiting the molecular pathology of NB and/or overcoming resistance to current genotoxic therapies are needed before survival rates can significantly improve. DNA damage response (DDR) defects are frequently observed in HR-NB including allelic deletion and loss of function mutations in key DDR genes, oncogene induced replication stress and cell cycle checkpoint dysfunction. Exploiting defects in the DDR has been a successful treatment strategy in some adult cancers. Here we review the genetic features of HR-NB which lead to DDR defects and the emerging molecular targeting agents to exploit them.	0
The role of X-inactivation is often ignored as a prime cause of sex differences in disease. Yet, the way males and females express their X-linked genes has a major role in the dissimilar phenotypes that underlie many rare and common disorders, such as intellectual deficiency, epilepsy, congenital abnormalities, and diseases of the heart, blood, skin, muscle, and bones. Summarized here are many examples of the different presentations in males and females. Other data include reasons why women are often protected from the deleterious variants carried on their X chromosome, and the factors that render women susceptible in some instances.	0
Tay-Sachs disease (TSD), a deficiency of b-hexosaminidase A (Hex A), is a rare but debilitating hereditary metabolic disorder. Symptoms include extensive neurodegeneration and often result in death in infancy. We report an in silico study of 42 Hex A variants associated with the disease. Variants were separated into three groups according to the age of onset: infantile (n=28), juvenile (n=9) and adult (n=5). Protein stability, aggregation potential and the degree of conservation of residues were predicted using a range of in silico tools. We explored the relationship between these properties and the age of onset of TSD. There was no significant relationship between proteinstability and disease severity or between protein aggregation and disease severity. Infantile TSD had a significantly higher mean conservation score than nondisease associated variants. This was not seen in either juvenile or adult TSD. This study has established that the degree of residue conservation may be predictive of infantile TSD. It is possible that these more highly conserved residues are involved in trafficking of the protein to the lysosome. In addition, we developed and validated software tools to automate the process of in silico analysis of proteins involved in inherited metabolic diseases. Further work is required to identify the function of well-conserved residues to establish an in silico predictive model of TSD severity.	0
Marjolin's ulcer is an atypical malignancy that develops from deep scars of chronically traumatised skin. Laron syndrome (LS) is a rare autosomal recessive growth retardation from a mutation in the growth hormone receptor (GHR) gene leading to defective GHR, growth hormone insensitivity and eventual low levels of insulin-like growth factor type 1 (IGF-1). Affected individuals present with proportionate dwarfism and other characteristic physical defects, but at the same time are conferred protection against cancer due to low serum levels of IGF-1. We report an exceptional case of Marjolin's ulcer in the foot of a female LS patient 30 years after she sustained flame burns as a 6-month-old baby. Three months before coming to us, she had a 2x3cm ulcer that turned into a rapidly enlarging fungating mass involving the leg, ankle, and foot. Histopathologic analysis of an incision biopsy showed well-differentiated squamous cell carcinoma. The extent of her lesion precluded wide excision. Below knee amputation was done. A second biopsy confirmed the histopathologic diagnosis. This is the first reported case in the literature of Marjolin's ulcer in LS which raises the possibility that IGF-1 deficiency does not completely protect against squamous cell cancer.	0
Acrocapitofemoral dysplasia is a recently delineated autosomal recessive skeletal dysplasia, characterized clinically by short stature with short limbs and radiographically by cone-shaped epiphyses, mainly in hands and hips. Genomewide homozygosity mapping in two consanguineous families linked the locus to 2q35-q36 with a maximum two-point LOD score of 8.02 at marker D2S2248. Two recombination events defined the minimal critical region between markers D2S2248 and D2S2151 (3.74 cM). Using a candidate-gene approach, we identified two missense mutations in the amino-terminal signaling domain of the gene encoding Indian hedgehog (IHH). Both affected individuals of family 1 are homozygous for a 137C-->T transition (P46L), and the three patients in family 2 are homozygous for a 569T-->C transition (V190A). The two mutant amino acids are strongly conserved and predicted to be located outside the region where brachydactyly type A-1 mutations are clustered.	0
Kartagener syndrome (KS), a subtype of primary ciliary dyskinesia (PCD), is characterized by bronchiectasis, chronic sinusitis, male infertility and situs inversus. KS is a genetically heterogeneous disease that is inherited in an autosomal recessive form; however, X-linked inheritance has also been reported. As of this writing [late 2020], at least 34 loci, most of which have known genes, have been reported in the literature as associating with KS. In the present study, we identified a frame shift mutation, c.167delG (p.G56Dfs*26), in the coiled-coil domain containing 151 gene (CCDC151) responsible for KS in a Han-Chinese family. To our knowledge, this is the first report of a CCDC151 c.167delG mutation in the KS patient. These findings may expand the CCDC151 mutation spectrum of KS, and contribute to future genetic counseling and gene-targeted therapy for this disease.	0
BACKGROUND:Serum protein glycosylation is an area of investigation in inflammatory arthritic disorders such as rheumatoid arthritis (RA). Indeed, some studies highlighted abnormalities of protein glycosylation in RA. Considering the numerous types of enzymes, monosaccharides and glycosidic linkages, glycosylation is one of the most complex post translational modifications. By this work, we started with a preliminary screening of glycoproteins in serum from RA patients and controls. METHODS:In order to isolate glycoproteins from serum, lectin wheat germ agglutinin was used and quantitative differences between patients and controls were investigated by LC-MS/MS. Consequently, we focused our attention on two glycoproteins found in this explorative phase: corticosteroid-binding globulin (CBG) and lipopolysaccharide-binding protein (LBP). The subsequent validation with immunoassays was widened to a larger number of early RA (ERA) patients (n = 90) and well-matched healthy controls (n = 90). RESULTS:We observed a significant reduction of CBG and LBP glycosylation in ERA patients compared with healthy controls. Further, after 12 months of treatment, glycosylated CBG and LBP levels increased both to values comparable to those of controls. In addition, these changes were correlated with clinical parameters. CONCLUSIONS:This study enables to observe that glycosylation changes of CBG and LBP are related to RA disease activity and its response to treatment.	0
Background:Teratocarcinosarcoma (TCS) is a rare malignant neoplasm with epithelial and mesenchymal components such as fibroblasts, cartilage, bone and smooth muscle. With less than 100 total reported cases, this malignant neoplasm is rarely encountered by neurosurgeons because it primarily involves the nasal cavity and paranasal sinuses. Case Description:A 55-year-old male with chronic frontal headaches was found to have a frontal mass with involvement of nasal sinus and right ethmoid sinus. The patient underwent preoperative embolization of tumor followed by bilateral frontal craniotomy for near total resection of the tumor. Patient did well postoperatively without new neurological deficits. Conclusion:Although cases with intracranial involvement are scarce, treatment with surgical resection with or without adjuvant treatments of chemotherapy and radiation therapy is the most widely accepted with goal for gross total resection. In our case, we achieved near total resection and the patient continues to do well without any gross neurological deficits.	0
'Locked-in syndrome (LIS)' is a neurological disorder, often missed initially and can have grave consequences. A rare case of LIS caused due to folic acid deficiency-induced hyperhomocysteinemia is being described here. A 16-year-old boy presented with complaints of sudden onset weakness of all the four limbs with loss of voice for one day. All the tendon reflexes were increased, bilateral planters were extensor and sensory system was intact. Patient was conscious and responded to verbal commands by ocular movements in vertical direction. Hence, a diagnosis of LIS was made. Magnetic resonance imaging of the head revealed an acute infarct in ventral pons. Serum homocysteine level was elevated (20.65 μmol/l) and folic acid level was severely low (1.7 nmol/ml). Cause of LIS was found to be hyperhomocysteinemia induced stroke in the pons, related to folic acid deficiency. The patient was managed with antiplatelet agents and folic acid supplementation and was discharged subsequently. Recognition of LIS is important as casual remarks at bedside can severely traumatize an already paralyzed but conscious and awake patient. Folic acid deficiency can lead to hyperhomocysteinemia, which can cause strokes and even LIS. Prevention of hyperhomocysteinemia may possibly prevent such neurological disasters.	0
Hypoglycaemic due to congenital hyperinsulinism in Beckwith-Wiedemann syndrome is commonly seen. It is usually transient and is managed by enteral feeds, high glucose-containing intravenous fluids and medications like diazoxide. We describe a case of an infant with genetically proven Beckwith-Wiedemann syndrome with prolonged hyperinsulinemic hypoglycaemia. Despite treatment with high glucose-containing intravenous fluids, diazoxide and octreotide, her hypoglycaemia persisted. In addition to this, she also developed features of intestinal obstruction, which further complicated the management of hypoglycaemia. She underwent a rectal biopsy for this, which was highly suggestive of Hirschprung's disease. Following surgery, her abdominal distension and feed intolerance were settled and sugar control was improved. We present a rare association of Hirschsprung's disease with Beckwith-Wiedemann syndrome. To the best of our knowledge, this association has not been previously reported and this added to the difficulty in managing hyperinsulinemic hypoglycaemia in our patient.	0
BACKGROUND:Giant presacral Tarlov cysts (TCs) with pelvic extension are extremely rare and have many special features that differ from normal TCs in examination, diagnosis, symptoms, and treatment. We report 3 rare cases of giant presacral TCs with pelvic extension and review the pertinent literature. CASE DESCRIPTION:We report 3 cases of giant presacral TCs with rare pelvic extension and analyzed the symptoms, diagnoses, and surgical procedures. Operations with the key point of blocking the inlet of the fistula from inside the dural sac were performed in all 3 cases. All 3 patients revealed alleviation of previous symptoms with no serious complications. Postoperative magnetic resonance imaging showed all the cysts were well blocked with no cyst recurrence. CONCLUSIONS:Giant TC with pelvic extension is extremely rare and often is discovered on gynecological ultrasound, where it might be misdiagnosed as adnexal mass. Different from patients with normal TCs, these patients also may present with abdominal symptoms like hydronephrosis, abdominal, or pelvic pain due to the cyst's ventral mass effect. Thus, patients with abdominal and back symptoms at the same time should be paid particular attention for lumbosacral magnetic resonance imaging examination to avoid misdiagnosis. Surgical procedures are recommended for symptomatic cases. However, cyst resection by laparotomy is doomed to postoperative recurrence because the fistula still exists. We describe a simple procedure with the key point of blocking the inlet of cyst fistula, which is more applicable and minimizes the probability of cyst recurrence.	0
Intracranial abnormalities are commonly suspected findings on antenatal ultrasound that require evaluation by magnetic resonance imaging. This review depicts multiple abnormalities imaged as a means to guide clinicians in proper diagnosis.	0
BACKGROUND:Chromosome 14q11-q22 deletion syndrome (OMIM 613457) is a rare contiguous gene syndrome. Two regions of overlap (RO) of the 14q12q21.1 deletion have been identified: a proximal region (RO1), including FOXG1(*164874), NKX2-1(*600635), and PAX9(*167416) and a distal region (RO2), including NKX2-1 and PAX9. We report a 6-year-old boy with mild dysmorphic facial features, global developmental delay, and hypoplasia of the corpus callosum. METHODS AND RESULTS:Array-CGH analysis revealed a 14q12q13.2 microdeletion. We compared the phenotype of our patient with previously published cases in order to establish a genotype-phenotype correlation. CONCLUSION:The study hypothesizes the presence of a new RO, not including the previously reported candidate genes, and attempt to define the associated molecular and psychomotor/neurobehavioral phenotype. This region encompasses the distal breakpoint of RO1 and the proximal breakpoint of RO2, and seems to be associated with intellectual disability (ID), hypotonia, epilepsy, and corpus callosum abnormalities. Although more cases are needed, we speculated on SNX6(*606098) and BAZ1A(*605680) as potential candidate genes associated with the corpus callosum abnormalities.	0
Objective:Heterozygous variants in KCNQ2 or, more rarely, KCNQ3 genes are responsible for early-onset developmental/epileptic disorders characterized by heterogeneous clinical presentation and course, genetic transmission, and prognosis. While familial forms mostly include benign epilepsies with seizures starting in the neonatal or early-infantile period, de novo variants in KCNQ2 or KCNQ3 have been described in sporadic cases of early-onset encephalopathy (EOEE) with pharmacoresistant seizures, various age-related pathological EEG patterns, and moderate/severe developmental impairment. All pathogenic variants in KCNQ2 or KCNQ3 occur in heterozygosity. The aim of this work was to report the clinical, molecular, and functional properties of a new KCNQ3 variant found in homozygous configuration in a 9-year-old girl with pharmacodependent neonatal-onset epilepsy and non-syndromic intellectual disability. Methods:Exome sequencing was used for genetic investigation. KCNQ3 transcript and subunit expression in fibroblasts was analyzed with quantitative real-time PCR and Western blotting or immunofluorescence, respectively. Whole-cell patch-clamp electrophysiology was used for functional characterization of mutant subunits. Results:A novel single-base duplication in exon 12 of KCNQ3 (NM_004519.3:c.1599dup) was found in homozygous configuration in the proband born to consanguineous healthy parents; this frameshift variant introduced a premature termination codon (PTC), thus deleting a large part of the C-terminal region. Mutant KCNQ3 transcript and protein abundance was markedly reduced in primary fibroblasts from the proband, consistent with nonsense-mediated mRNA decay. The variant fully abolished the ability of KCNQ3 subunits to assemble into functional homomeric or heteromeric channels with KCNQ2 subunits. Significance:The present results indicate that a homozygous KCNQ3 loss-of-function variant is responsible for a severe phenotype characterized by neonatal-onset pharmacodependent seizures, with developmental delay and intellectual disability. They also reveal difference in genetic and pathogenetic mechanisms between KCNQ2- and KCNQ3-related epilepsies, a crucial observation for patients affected with EOEE and/or developmental disabilities.	0
Three relatives carrying a t(4;8)(p15.2;p23.2) translocation had juvenile myoclonic epilepsy, self-limited photosensitive occipital epilepsy and migraine with aura. The t(4;8) translocation interrupted the coding sequence of CSMD1 gene and occurred immediately to the 3'UTR of STIM2 gene. STIM2 was overexpressed in the patient carrying the unbalanced translocation, and all three individuals had a single functional copy of CSMD1. Array CGH study disclosed that these three individuals also carried a deletion at 5q12.3 that involves the RGS7BP gene. The overall results favor the view that CSMD1, STIM2, and RGS7BP genes could contribute to epilepsy and migraine phenotypes in our family.	0
An 89-year-old woman with small papules on her face presented to our hospital complaining of progressive dyspnoea. Chest computed tomography (CT) showed bilateral multiple lung cysts, a nodular opacity in the right lower lobe, and bilateral pleural effusion. She was diagnosed with adenocarcinoma. Her son, a 65-year-old man, also had bilateral basally located lung cysts and a past medical history of spontaneous pneumothorax. He had multiple papules on the face and neck, which were pathologically diagnosed as fibrofolliculomas. We considered these cases to be Birt-Hogg-Dubé syndrome (BHDS). Folliculin (FLCN) gene mutations that may be tumour suppressive are suspected to be causative of this syndrome. FLCN dysfunction might lead to the development of various types of tumours other than renal tumours.	0
Eastern equine encephalitis virus (EEEV) is the most pathogenic member of the Alphavirus genus in the Togaviridae family. This virus continues to circulate in the New World and has a potential for deliberate use as a bioweapon. Despite the public health threat, to date, no attenuated EEEV variants have been applied as live EEEV vaccines. Our previous studies demonstrated the critical function of the hypervariable domain (HVD) in EEEV nsP3 in the assembly of viral replication complexes (vRCs). EEEV HVD contains short linear motifs that recruit host proteins required for vRC formation and function. In this study, we developed a set of EEEV mutants, which contained combinations of deletions in nsP3 HVD and clustered mutations in capsid protein, and tested the effects of these modifications on EEEV infection in vivo These mutations had cumulative negative effects on viral ability to induce meningoencephalitis. The deletions of two critical motifs, which interact with the members of cellular FXR and G3BP protein families, made EEEV no longer neurovirulent. The additional clustered mutations in capsid protein, which affect its ability to induce transcriptional shutoff, diminished EEEV's ability to develop viremia. Most notably, despite the inability to induce detectable disease, the designed EEEV mutants remained highly immunogenic and after a single dose, protected mice against subsequent infection with wt EEEV. Thus, alterations of interactions of EEEV HVD and likely HVDs of other alphaviruses with host factors represent an important direction of development of highly attenuated viruses that can be applied as live vaccines.IMPORTANCE Hypervariable domains (HVDs) of alphavirus nsP3 proteins recruit host proteins into viral replication complexes. The sets of HVD-binding host factors are specific for each alphavirus, and we have previously identified those specific for EEEV. The results of this study demonstrate that the deletions of the binding sites of G3BP and FXR protein families in nsP3 HVD of EEEV make virus avirulent for mice. Mutations in the nuclear localization signal in EEEV capsid protein have an additional negative effect on viral replication in vivo Despite the inability to cause a detectable disease, the double HVD and triple HVD/capsid mutants induce high levels of neutralizing antibodies. Single immunization protects mice against the following infection with the highly pathogenic North American strain of EEEV. High safety, the inability to revert to wild type phenotype and high immunogenicity make the designed mutants attractive vaccine candidates for EEEV infection.	0
We present a case of the transcanal endoscopic resection of a glomus tympanicum tumor. A 51-year-old woman presented with pulsatile tinnitus of the right ear persisting for 6 months. A reddish mass was observed through her tympanic membrane. A computed tomography scan revealed a small mass in the mesotympanum. She was diagnosed with a right-sided glomus tympanicum tumor. The glomus tympanicum tumor was classified as type 1 using the Glasscock-Jackson classification, class A using the Fisch classification, and class A1 using the modified Fisch and Mattox classification. The tumor was transcanally and completely resected by endoscopy without any complication. Before and after the surgery, pure-tone audiometry showed a normal hearing level. Preoperative right-sided pulsatile tinnitus resolved after the surgery. Transcanal endoscopic ear surgery is a favorable surgical method for small localized glomus tympanicum tumors.	0
BACKGROUND:The lymph node (Ln) status of patients with resectable pancreatic ductal adenocarcinoma is an important predictor of survival. The survival benefit of extended lymphadenectomy during pancreatectomy is, however, disputed, and there is no true definition of the optimal extent of the lymphadenectomy. The aim of this study was to formulate a definition for standard lymphadenectomy during pancreatectomy. METHODS:During a consensus meeting of the International Study Group on Pancreatic Surgery, pancreatic surgeons formulated a consensus statement based on available literature and their experience. RESULTS:The nomenclature of the Japanese Pancreas Society was accepted by all participants. Extended lymphadenectomy during pancreatoduodenectomy with resection of Ln's along the left side of the superior mesenteric artery (SMA) and around the celiac trunk, splenic artery, or left gastric artery showed no survival benefit compared with a standard lymphadenectomy. No level I evidence was available on prognostic impact of positive para-aortic Ln's. Consensus was reached on selectively removing suspected Ln's outside the resection area for frozen section. No consensus was reached on continuing or terminating resection in cases where these nodes were positive. CONCLUSION:Extended lymphadenectomy cannot be recommended. Standard lymphadenectomy for pancreatoduodenectomy should strive to resect Ln stations no. 5, 6, 8a, 12b1, 12b2, 12c, 13a, 13b, 14a, 14b, 17a, and 17b. For cancers of the body and tail of the pancreas, removal of stations 10, 11, and 18 is standard. Furthermore, lymphadenectomy is important for adequate nodal staging. Both pancreatic resection in relatively fit patients or nonresectional palliative treatment were accepted as acceptable treatment in cases of positive Ln's outside the resection plane. This consensus statement could serve as a guide for surgeons and researchers in future directives and new clinical studies.	0
To date, the research on dendritic cells (DCs) and their correlated neoplasms has not been clear. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) and mature plasmacytoid dendritic cell proliferation (MPDCP) are two types of malignancies originating from plasmacytoid dendritic cells (pDCs). Some evidence has indicated the existence of other pDC neoplasms. In addition, cases of myeloid neoplasms (MNs), acute myeloblastic leukemia (AML), and myelodysplastic syndrome (MDS) with increased pDCs (AML/MDS-pDCs) seem to have immature DCs according to the vaguely consistent expression of markers among MNs and pDCs, which appear to fit the developmental pattern of normal DCs. We analyzed 14 AML/MDS-pDC cases mainly for their immunophenotype by flow cytometry and inferred their CD expression pattern. The patients' clinical information and other laboratory data were collected and reviewed. AML/MDS-pDCs show a different pattern of markers from BPDCN and MPDCP. Three maturation-involved stages were found in these AML/MDS-pDCs patients. Stage I was the most immature stage and displayed an expression profile of CD34+/st+ CD117+/st+ BDCA2- BDCA4- CD123+ HLA-DR+/st+ CD4- CD45dim+ ; Stage II was the more immature stage displayed a phenotype of CD34dim+ CD117dim+ BDCA2-/dim+ BDCA4-/dim+ CD123st+ HLA-DR+/st+ CD4- CD45+ ; and Stage III was the mature stage showed CD34- CD117- BDCA2+ /BDCA4+ CD123st+ HLA-DR+/st+ CD4+ CD45+/st+ . Three maturation-involved stages overlapped well with the phenotypes of normal DC progenitors in a continuously developmental process: granulocyte, monocyte, and DC progenitors (GMDPs) and/or monocyte and DC progenitors (MDPs), common DC progenitors (CDPs), pDCs, and/or pre-DCs. In this study, we considered AML/MDS-pDCs as entities that were distinct from BPDCN and MPDCP and correlated the components of this tumor with the normal DC differentiation pathway, which provides new evidence for understanding DC neoplasms. © 2019 International Society for Advancement of Cytometry.	0
Burning mouth syndrome/glossodynia and trigeminal neuropathic conditions can have serious negative impact on a patient's overall quality of life. These conditions are often hard to diagnose and even harder to fully treat and manage, but it is important for dentists/oral and maxillofacial surgeons to be aware of these conditions and modalities of their treatment. Often the only method for arriving at the proper diagnosis is for patients to undergo traditional approaches for treatment of presenting signs and symptoms, and it is the unexpected failure of interventional therapies that leads ultimately to a proper diagnosis.	0
PURPOSE:Bardet-Biedl syndrome is a complex ciliopathy that usually manifests with some form of retinal degeneration, amongst other ciliary-related deficiencies. One of the genetic causes of this syndrome results from a defect in Bardet-Biedl Syndrome 5 (BBS5) protein. BBS5 is one component of the BBSome, a complex of proteins that regulates the protein composition in cilia. In this study, we identify a smaller molecular mass form of BBS5 as a variant formed by alternative splicing and show that expression of this splice variant is restricted to the retina. METHODS:Reverse transcription PCR from RNA was used to isolate and identify potential alternative transcripts of Bbs5. A peptide unique to the C-terminus of the BBS5 splice variant was synthesized and used to prepare antibodies that selectively recognized the BBS5 splice variant. These antibodies were used on immunoblots of tissue extracts to determine the extent of expression of the alternative transcript and on tissue slices to determine the localization of expressed protein. Pull-down of fluorescently labeled arrestin1 by immunoprecipitation of the BBS5 splice variant was performed to assess functional interaction between the two proteins. RESULTS:PCR from mouse retinal cDNA using Bbs5-specific primers amplified a unique cDNA that was shown to be a splice variant of BBS5 resulting from the use of cryptic splicing sites in Intron 7. The resulting transcript codes for a truncated form of the BBS5 protein with a unique 24 amino acid C-terminus, and predicted 26.5 kD molecular mass. PCR screening of RNA isolated from various ciliated tissues and immunoblots of protein extracts from these same tissues showed that this splice variant was expressed in retina, but not brain, heart, kidney, or testes. Quantitative PCR showed that the splice variant transcript is 8.9-fold (+/- 1.1-fold) less abundant than the full-length transcript. In the retina, the splice variant of BBS5 appears to be most abundant in the connecting cilium of photoreceptors, where BBS5 is also localized. Like BBS5, the binding of BBS5L to arrestin1 can be modulated by phosphorylation through protein kinase C. CONCLUSIONS:In this study we have identified a novel splice variant of BBS5 that appears to be expressed only in the retina. The BBS5 splice variant is expressed at approximately 10% of full-length BBS5 level. No unique functional or localization properties could be identified for the splice variant compared to BBS5.	0
Objective: Previous studies have shown that patients with hereditary fructose intolerance (HFI) are characterized by a greater intrahepatic triglyceride content, despite a fructose-restricted diet. The present study aimed to examine the long-term consequences of HFI on other aldolase-B-expressing organs, i.e. the kidney and vascular endothelium. Methods: Fifteen adult HFI patients were compared to healthy control individuals matched for age, sex and body mass index. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (cf-PWV) and endothelial function by peripheral arterial tonometry, skin laser doppler flowmetry and the endothelial function biomarkers soluble E-selectin [sE-selectin] and von Willebrand factor. Serum creatinine and cystatin C were measured to estimate the glomerular filtration rate (eGFR). Urinary glucose and amino acid excretion and the ratio of tubular maximum reabsorption of phosphate to GFR (TmP/GFR) were determined as measures of proximal tubular function. Results: Median systolic blood pressure was significantly higher in HFI patients (127 versus 122 mmHg, p = .045). Pulse pressure and cf-PWV did not differ between the groups (p = .37 and p = .49, respectively). Of all endothelial function markers, only sE-selectin was significantly higher in HFI patients (p = .004). eGFR was significantly higher in HFI patients than healthy controls (119 versus 104 ml/min/1.73m2, p = .001, respectively). All measurements of proximal tubular function did not differ significantly between the groups. Conclusions: Adult HFI patients treated with a fructose-restricted diet are characterized by a higher sE-selectin level and slightly higher systolic blood pressure, which in time could contribute to a greater cardiovascular risk. The exact cause and, hence, clinical consequences of the higher eGFR in HFI patients, deserves further study.	0
Ankylosis of the temporomandibular joint (TMJ) is defined as the emergence of a bony or fibrous compound between the condyle and the cranial base. It can result in divergent craniofacial characteristics. The aim of this study was to present an orthodontic-surgical approach in a case series of 4 patients with a diagnosis of TMJ ankylosis as a complication of otomastoiditis. The patient characteristics of 4 patients in whom TMJ ankylosis was diagnosed as a complication of otomastoiditis were described. All patients were treated with gap arthroplasty with costochondral graft, physiotherapy, and orthodontic therapy to achieve acceptable mouth opening and function. All reacted differently to this therapy, and additional interventions were required during childhood. In early-onset ankylosis, however, guiding the mandibular growth orthodontically can prevent increasing facial asymmetry and canting of the occlusal plane. After the pubertal growth spurt is finished, orthodontic treatment combined with surgical intervention may be considered to correct facial asymmetry and provide good dental occlusion. Orthodontic and surgical treatments showed themselves to be fundamental for patients with TMJ ankylosis as a complication of otomastoiditis, although continual monitoring until the end of growth is necessary to achieve the most functional recovery possible.	0
Desmoplastic infantile astrocytomas (DIAs), are rare supratentorial tumors, usually observed in the first 24 months of life. Despite their aggressive appearance, they tend to follow a favorable clinical course. Total or near total resection of tumor is usually the treatment option. Desmoplastic Infantile Ganglioglioma (DIG) and DIA are WHO grade I tumors that have similar clinical and morphological findings. The only criterion in differential diagnosis is the neural component of DIG. These tumors both have dense fibroblastic stroma and positive staining with glial fibrillar acidic protein (GFAP) and CD34. A rare case of desmoplastic infantile astrocytoma presenting with right side partial seizures presented in a 1-year-old child. A rare case of desmoplastic infantile astrocytoma presenting with focal onset generalized seizures presented in a 1-year-old child. Despite their radiological and histological properties, these tumors have a benign course. After 3-year follow-up for the first case and 1-year follow-up for the second case, there was no recurrence.	0
Gastrointestinal stromal tumor (GIST) is defined as mesenchymal tumors of the gastrointestinal tract expressing proto-oncogene protein CD117. They are the most common sarcomatous tumors of the gastrointestinal tract. GISTs are presumed to arise from interstitial cells of Cajal or gastrointestinal pacemaker cells which control gut motility. They have unpredictable biological behavior. Prognosis is dependent on tumor size as well as mitotic count. Radical surgical excision is the treatment of choice. They rarely metastasize to lymph nodes. Imatinib therapy is used as an adjuvant therapy. The follow-up of patients postsurgery is not standardized.	0
Brachydactyly type A2 (BDA2, MIM 112600) is characterized by the deviation and shortening of the middle phalange of the index finger and the second toe. Using genome-wide linkage analysis in a Chinese BDA2 family, we mapped the maximum candidate interval of BDA2 to a ∼1.5 Mb region between D20S194 and D20S115 within chromosome 20p12.3 and found that the pairwise logarithm of the odds score was highest for marker D20S156 (Zmax = 6.09 at θ = 0). Based on functional and positional perspectives, the bone morphogenetic protein 2 (BMP2) gene was identified as the causal gene for BDA2 in this region, even though no point mutation was detected in BMP2. Through further investigation, we identified a 4,671 bp (Chr20: 6,809,218-6,813,888) genomic duplication downstream of BMP2. This duplication was located within the linked region, co-segregated with the BDA2 phenotype in this family, and was not found in the unaffected family members and the unrelated control individuals. Compared with the previously reported duplications, the duplication in this family has a different breakpoint flanked by the microhomologous sequence GATCA and a slightly different length. Some other microhomologous nucleotides were also found in the duplicated region. In summary, our findings support the conclusions that BMP2 is the causing gene for BDA2, that the genomic location corresponding to the duplication region is prone to structural changes associated with malformation of the digits, and that this tendency is probably caused by the abundance of microhomologous sequences in the region.	0
Rhabdomyosarcoma is a malignant tumor composed of neoplastic mesenchymal cells, with varying degrees of striated muscle cell differentiation. With most cases occurring in children younger than 10 years, it is remarkably rare in adults. Further in adults, the typical pediatric rhabdomyosarcoma variants (embryonal and alveolar sub-types) occur less frequently and exhibit predilection for viscera followed by the head and neck region. A rare case of embryonal rhabdomyosarcoma arising from the buccal mucosa in a 36-year old male patient is herewith reported. Recognition of the correct diagnosis and histological sub-type is of critical importance in the therapy of this disease, since the treatment is not uniform in the literature because of the rarity of this neoplasm in the adult population.	0
We conducted this study to explore the extent of occult helminth infection identified by fecal parasitological examinations or organ-specific examinations such as colonoscopy and abdominal ultrasonography (US) during health checkups. We analyzed 197,422 fecal samples from 99,451 subjects who received health checkups at a single center over 10 years. We found that 3,472 (1.8%) samples from 3,342 (3.4%) subjects tested positive for parasitic ova, including clonorchiasis, metagonimiasis, trichuriasis, ascariasis, trichostrongylosis, taeniasis, and enterobiasis. The detection rate for clonorchiasis was higher in those who were taking their first examination than in those who had been examined previously. The detection rate for clonorchiasis decreased gradually over the 10 years. Only 2.5% of the patients with clonorchiasis showed US or computed tomography (CT) images that were compatible with the disease. Clonorchiasis patients who had abdominal US or CT images that suggested clonorchiasis were older and had lower body mass indices and higher eosinophil counts than did those whose US or CT images did not suggest the disease. We observed worms in 9% of the patients with trichuriasis who had received a colonoscopy. Colonoscopy also uncovered adult worms in 0.03% of subjects who were not identified as having Trichuris trichiura ova in their fecal helminth examinations. In summary, our study shows that occult helminth infection is fairly frequently identified by a variety of methods during health checkups, which suggests that doctors need to make greater effort to identify and treat occult helminth infections in Korea.	0
Aims: The aim was to determine whether anti-neutrophil cytoplasmic antibody (ANCA)-positive serology in patients with lupus nephritis (LN) is associated with different clinicopathologic features and outcomes.Methods: In our retrospective analysis, 283 patients were enrolled between 2013 and 2018. Thirty-six patients were ANCA-positive, and this group was compared with the remaining 247 patients who were confirmed as ANCA-negative at the time of biopsy.Results: ANCA-positive LN patients exhibited higher anti-dsDNA antibody titers and serum creatinine levels and lower serum hemoglobin concentrations than ANCA-negative LN patients. On pathological evaluation, segmental endocapillary hypercellularity observed by light microscopy was significantly more common in the ANCA-positive group. This feature was not significantly different in the treatment group, but the response to treatment was significantly different, as was remission (76.1% vs 69.4%, p < 0.001), between the ANCA-negative and ANCA-positive groups. During follow-up, the times to renal replacement therapy (RRT) and death were significantly different between the two unmatched groups (chi-square test, p = 0.041). Multivariate Cox analysis revealed that neurological disorders, ANCA positivity, and the chronicity index (CI) remained independent risk factors for patient survival. Pulmonary infection was the main cause of death and was most often due to fungal infection.Conclusion: ANCA-positive LN patients typically exhibited higher anti-dsDNA antibody titers, lower serum hemoglobin concentrations and worse renal function than ANCA-negative LN patients. Fungal infection was the main cause of death. We observed that ANCA positivity was an independent risk factor for patient survival.	0
The 5q- syndrome is the most distinct of the myelodysplastic syndromes (MDS) and patients with this disorder have a deletion of chromosome 5q [del(5q)] as the sole karyotypic abnormality. Several genes mapping to the commonly deleted region of the 5q- syndrome have been implicated in disease pathogenesis in recent years. Haploinsufficiency of the ribosomal gene RPS14 has been shown to cause the erythroid defect in the 5q- syndrome. Loss of the microRNA genes miR-145 and miR-146a has been associated with the thrombocytosis observed in 5q- syndrome patients. Haploinsufficiency of CSNK1A1 leads to hematopoietic stem cell expansion in mice and may play a role in the initial clonal expansion in patients with 5q- syndrome. Moreover, a subset of patients harbor mutation of the remaining CSNK1A1 allele. Mouse models of the 5q- syndrome, which recapitulate the key features of the human disease, indicate that a p53-dependent mechanism underlies the pathophysiology of this disorder. Importantly, activation of p53 has been demonstrated in the human 5q- syndrome. Recurrent TP53 mutations have been associated with an increased risk of disease evolution and with decreased response to the drug lenalidomide in del(5q) MDS patients. Potential new therapeutic agents for del(5q) MDS include the translation enhancer L-leucine.	0
Background: Muckle-Wells syndrome (MWS) represents a moderate phenotype of cryopyrinopathies. Sensorineural hearing loss and AA amyloidosis belong to the most severe manifestations of uncontrolled disease. Simultaneous discovery of MWS in four generations of one large kindred has enabled us to document natural evolution of untreated disease and their response to targeted therapy. Methods: A retrospective case study, clinical assessment at the time of diagnosis and 2-year prospective follow-up using standardized disease assessments were combined. Results: Collaborative effort of primary care physicians and pediatric and adult specialists led to identification of 11 individuals with MWS within one family. Presence of p.Ala441Val mutation was confirmed. The mildest phenotype of young children suffering with recurrent rash surprised by normal blood tests and absence of fevers. Young adults all presented with fevers, rash, conjunctivitis, and arthralgia/arthritis with raised inflammatory markers. Two patients aged over 50 years suffered with hearing loss and AA amyloidosis. IL-1 blockade induced disease remission in all individuals while hearing mildly improved or remained stable in affected patients as did renal function in one surviving individual with amyloidosis. Conclusions: We have shown that severity of MWS symptoms gradually increased with age toward distinct generation-specific phenotypes. A uniform trajectory of disease evolution has encouraged us to postpone institution of IL-1 blockade in affected oligosymptomatic children. This report illustrates importance of close interdisciplinary collaboration.	0
Developmental and epileptic encephalopathies (DEEs) are a group of severe, early onset epilepsies characterized by refractory seizures, developmental delay or regression associated with ongoing epileptic activity, and generally poor prognosis. DEE is genetically and phenotypically heterogeneous, and there is a plethora of genetic testing options to investigate the rapidly growing list of epilepsy genes. However, more than 50% of patients with DEE remain without a genetic diagnosis despite state-of-the-art genetic testing. In this review, we discuss the major advances in epilepsy genomics that have surfaced in recent years. The goal of this review is to reach a larger audience and build a better understanding of pathogenesis and genetic testing options in DEE.	0
Background: The VATER/VACTERL association (VACTERL) is defined as the non-random occurrence of the following congenital anomalies: Vertebral, Anal, Cardiac, Tracheal-Esophageal, Renal, and Limb anomalies. As no unequivocal candidate gene has been identified yet, patients are diagnosed phenotypically. The aims of this study were to identify patients with monogenic disorders using a genetics-first approach, and to study whether variants in candidate genes are involved in the etiology of VACTERL or the individual features of VACTERL: Anorectal malformation (ARM) or esophageal atresia with or without trachea-esophageal fistula (EA/TEF). Methods: Using molecular inversion probes, a candidate gene panel of 56 genes was sequenced in three patient groups: VACTERL (n = 211), ARM (n = 204), and EA/TEF (n = 95). Loss-of-function (LoF) and additional likely pathogenic missense variants, were prioritized and validated using Sanger sequencing. Validated variants were tested for segregation and patients were clinically re-evaluated. Results: In 7 out of the 510 patients (1.4%), pathogenic or likely pathogenic variants were identified in SALL1, SALL4, and MID1, genes that are associated with Townes-Brocks, Duane-radial-ray, and Opitz-G/BBB syndrome. These syndromes always include ARM or EA/TEF, in combination with at least two other VACTERL features. We did not identify LoF variants in the remaining candidate genes. Conclusions: None of the other candidate genes were identified as novel unequivocal disease genes for VACTERL. However, a genetics-first approach allowed refinement of the clinical diagnosis in seven patients, in whom an alternative molecular-based diagnosis was found with important implications for the counseling of the families.	0
Rheumatoid vasculitis (RV) is an infrequent complication of longstanding severe rheumatoid arthritis (RA). The active vasculitis associated with rheumatoid disease occurs in about 1%-5% of the patient population. RV is a manifestation of "extra-articular" rheumatoid arthritis and involves the small- and medium-sized arteries in the body. Newer RA treatments, including biologic therapies, offer a broader array of potential therapeutic options, although no controlled trials exist to guide treatment. In general, following tissue confirmation of the diagnosis, the severity of organ involvement and disease manifestations can guide treatment decisions. We want to alert clinicians of this unique yet severe complication of RA which has high morbidity and mortality. We describe a thought-provoking case of a 44-year-old male with past medical history (PMH) of hypertension who presented with over three-month history of lower extremity (LE) swelling, discoloration, and ulceration. Arthralgias with constitutional symptoms (fatigue, weight loss), large pericardial effusion, was found to have leukocytoclastic vasculitis along with rheumatoid factor (RF) >650, and anti-cyclic citrullinated peptide (anti-CCP) antibodies >300, low C4 and normal C3. Pericardial fluid appeared serous, exudative, showed histiocytes, multinucleated giant cells and necrotic debris consistent with rheumatoid effusion. Skin, right shin, punch biopsy showed epidermal necrosis from underlying occlusive vasculopathy. Skin, left lower back, punch biopsy showed focal leukocytoclastic vasculitis. The patient was started on high dose steroids with marked improvement in the symptoms, Rituximab was planned awaiting QuantiFERON to be negative. Pan-CT angiography of the whole body was negative for any vascular changes ruling out polyarteritis nodosa (PAN).	0
Candida species are the most commonly isolated invasive human fungal pathogens. A role for phosphate acquisition in their growth, resistance against host immune cells, and tolerance of important antifungal medications is becoming apparent. Phosphorus is an essential element in vital components of the cell, including chromosomes and ribosomes. Producing the energy currency of the cell, ATP, requires abundant inorganic phosphate. A comparison of the network of regulators and effectors that controls phosphate acquisition and intracellular distribution, the PHO regulon, between the model yeast Saccharomyces cerevisiae, a plant saprobe, its evolutionarily close relative C. glabrata, and the more distantly related C. albicans, highlights the need to coordinate phosphate homeostasis with adenylate biosynthesis for ATP production. It also suggests that fungi that cope with phosphate starvation as they invade host tissues, may link phosphate acquisition to stress responses as an efficient mechanism of anticipatory regulation. Recent work indicates that connections among the PHO regulon, Target of Rapamycin Complex 1 signaling, oxidative stress management, and cell wall construction are based both in direct signaling links, and in the provision of phosphate for sufficient metabolic intermediates that are substrates in these processes. Fundamental differences in fungal and human phosphate homeostasis may offer novel drug targets.	0
Few studies have explored issues of sensitivity and specificity for using the fatigue construct to identify patients meeting chronic fatigue syndrome (CFS) criteria. In this article, we examine the sensitivity and specificity of several fatigue scales that have attempted to define severe fatigue within CFS. Using Receiver Operating Characteristic (ROC) curve analysis, we found most scales and sub-scales had either significant specificity and/or sensitivity problems. However, the post-exertional subscale of the ME/CFS Fatigue Types Questionnaire (Jason, Jessen, et al., 2009) was the most promising in terms of specificity and sensitivity. Among the more traditional fatigue scales, Krupp, LaRocca, Muir-Nash, and Steinberg's (1989) Fatigue Severity Scale had the best ability to differentiate CFS from healthy controls. Selecting questions, scales and cut off points to measure fatigue must be done with extreme care in order to successfully identify CFS cases.	0
Carotid artery agenesis is a rare congenital anomaly, and there are controversies in the leading cause for it. We present a 6-year-old girl with resolved focal neurological ischemic stroke that showed bilateral internal carotid artery (ICA) agenesis. Through this paper, we highlight the carotid canal congenital obliteration hypothesis as it may be a risk for such finding.	0
To identify new and existing cases of dermatomyositis and its subtypes in Olmsted County, Minnesota, from 1976 through 2007, and to establish a population-based estimate of the incidence and prevalence of dermatomyositis and amyopathic dermatomyositis.Retrospective population-based study.Community-based epidemiology project. Patients Patients with a diagnosis of dermatomyositis were identified from the Rochester Epidemiology Project.Incidence of dermatomyositis and clinically amyopathic dermatomyositis and risk of malignancy in clinically amyopathic dermatomyositis.Of the 29 patients identified, 6 (21%) had the clinically amyopathic subtype of dermatomyositis and 22 (76%) were female. Overall age- and sex-adjusted incidence of dermatomyositis including all subtypes was 9.63 (95% confidence interval [CI], 6.09-13.17) per 1 million persons and 2.08 (95% CI, 0.39-3.77) per 1 million persons for clinically amyopathic dermatomyositis. Age- and sex-adjusted prevalence for all subtypes of dermatomyositis was 21.42 (95% CI, 13.07-29.77) per 100,000 persons. Eight patients (28%) had a malignant condition during the study period; the risk of malignancy (odds ratio) for classic dermatomyositis compared with clinically amyopathic dermatomyositis was 4.61 but was not statistically significant (95% CI, 0.22-96.09) (P=.44).Dermatomyositis is a rare disease, and clinically amyopathic dermatomyositis represents an estimated 20% of all dermatomyositis cases. Larger population-based studies are needed to estimate the risk of malignancy associated with subtypes of dermatomyositis, particularly clinically amyopathic dermatomyositis.	1
Pathogenic variants in the X-chromosome Aristaless-related homeobox (ARX) gene contribute to intellectual disability, epilepsy, and associated comorbidities in affected males. Here, we report a novel splice variant in ARX in a family with three affected individuals. The proband had early onset developmental and epileptic encephalopathy, his brother and mother had severe and mild intellectual disability, respectively. Massively parallel sequencing identified a novel c.1449-1G>C in intron 4 of the ARX gene, predicted to abolish the splice acceptor site, retaining intron 4 and leading to a premature termination codon immediately after exon 4. As exon 5 is the last exon of the ARX gene, the premature termination codon at position p.L484* would be predicted to escape nonsense-mediated mRNA decay, potentially producing at least some C-terminally truncated protein. Analysis of cDNA from patient lymphoblastoid cells confirmed retention of intron 4 and loss of detectable expression of ARX mRNA across exon 4 to exon 5. We review published cases of variants that lead to altered or early termination of the ARX protein, but not complete loss of function, and are associated with phenotypes of intellectual disability and infantile onset developmental and epileptic encephalopathies, including Ohtahara and West syndromes. Taken together, this novel splice variant retaining intron 4 is likely to be the cause of the early onset developmental and epileptic encephalopathy in the proband.	0
OBJECTIVE:We characterised the clinical and neuro-otological characteristics of patients with Susac syndrome. METHODS:The medical records of 30 patients with Susac syndrome were reviewed for details of their clinical presentation and course, neuro-otological symptoms, investigation results including audiology and vestibular function tests, treatment and outcomes. RESULTS:Our findings demonstrate that 29 of our 30 patients with Susac syndrome developed neuro-otological symptoms such as hearing loss, disequilibrium, tinnitus or vertigo during their disease course. Hearing loss was the most common neuro-otological symptom occurring in 93% of patients. A rising configuration of low-frequency greater than the high-frequency sensorineural hearing loss was the most characteristic finding on audiological testing (37% of reviewed audiograms). Disproportionately poor speech discrimination was identified in 20% of cases, and one case demonstrated a retrocochlear pattern on electrophysiological testing. Four patients required hearing aids and a further two patients required a cochlear implant due to severe hearing loss. Two out of two treated patients had improvements in hearing after the prompt administration of corticosteroids, indicating the potential for recoverable hearing loss if relapses are treated early. Effects on vestibular function were variable in ten patients who were tested, with most showing preservation of function despite significant hearing loss. CONCLUSIONS:Neuro-otological symptoms in Susac syndrome are almost universal. In the correct clinical context, a rising configuration of low to high-frequency sensorineural hearing loss should prompt consideration of Susac syndrome. Treatment of inner ear symptoms in Susac syndrome requires further research as early immunotherapy may be beneficial.	0
We describe a family with autosomal dominant inheritance of anal anomalies, renal tract abnormalities, genital malformations, and syndactyly. These clinical manifestations do not clearly fall into any previously described syndrome. A mother and daughter had almost identical congenital malformations, short stature, and unusual facies. The proband was born with anal stenosis, a rectovaginal fistula, clitoral hypertrophy, a pelvic right kidney, and syndactyly of both feet. Her daughter had the same anal, clitoral, and foot anomalies, a solitary pelvic kidney, and no fistula. This family is likely to represent autosomal dominant inheritance of a new combination of malformations, which may overlap with the Townes-Brocks syndrome, but does not fall into a current diagnostic category.	0
Cilia are microtubule-based organelles, protruding from the apical cell surface and anchoring to the cytoskeleton. Primary (nonmotile) cilia of the kidney act as mechanosensors of nephron cells, responding to fluid movements by triggering signal transduction. The impaired functioning of primary cilia leads to formation of cysts which in turn contribute to development of diverse renal diseases, including kidney ciliopathies and renal cancer. Here, we review current knowledge on the role of ciliary genes in kidney ciliopathies and renal cell carcinoma (RCC). Special focus is given on the impact of mutations and altered expression of ciliary genes (e.g., encoding polycystins, nephrocystins, Bardet-Biedl syndrome (BBS) proteins, ALS1, Oral-facial-digital syndrome 1 (OFD1) and others) in polycystic kidney disease and nephronophthisis, as well as rare genetic disorders, including syndromes of Joubert, Meckel-Gruber, Bardet-Biedl, Senior-Loken, Alström, Orofaciodigital syndrome type I and cranioectodermal dysplasia. We also show that RCC and classic kidney ciliopathies share commonly disturbed genes affecting cilia function, including VHL (von Hippel-Lindau tumor suppressor), PKD1 (polycystin 1, transient receptor potential channel interacting) and PKD2 (polycystin 2, transient receptor potential cation channel). Finally, we discuss the significance of ciliary genes as diagnostic and prognostic markers, as well as therapeutic targets in ciliopathies and cancer.	0
BACKGROUND: There is very little published information about the prevalence, patterns, and predictors of peripheral neuropathies. The current study is a community-based survey was conducted in the Assiut Governorate to estimate their prevalence and clinical profile. MATERIAL AND METHODS: A door-to-door study was carried out on 42,223 persons from rural and urban communities in the Assiut Governorate, Egypt. There were 13,288 (31.5%) subjects from the urban and 28,935 (68·5%) from the rural area. All subjects filled in a questionnaire designed specifically for diagnosis of peripheral neuropathy. Positive cases were then given a complete medical and neurological examination, routine laboratory tests, neurophysiology, and neuroimaging (magnetic resonance). RESULTS: The crude prevalence rate (CPR) of peripheral neuropathy was 3181/100,000 inhabitants. There was a significantly higher prevalence in the rural compared with the urban population (3795 versus 1844/100,000) and in females than males (4473 versus 1943/100,000; P<0.001 for both). The most common type reported was entrapment neuropathy (736 cases with CPR of 1743/100,000), particularly carpal tunnel syndrome (1686/100,000). Diabetic neuropathy was the most common non-compressive neuropathy with a CPR of 649/100,000. Type II diabetes was recorded in 241 patients with a CPR of 571/100,000. Compressive radiculopathy had a crude prevalence of 358/100,000; traumatic and iatrogenic radiculopathy had a prevalence rate of 149/100,000. Less common conditions were: uremic neuropathy (21/100,000) hepatic neuropathy (14/100,000), Bell's palsy (28/100,000), Guillian-Barre' syndrome (12/100,000), chronic inflammatory demyelinating polyneuropathy (12/100,000), hereditary sensory motor neuropathy (12/100,000), and idiopathic neuropathy (92/100,000). CONCLUSION: The overall prevalence of peripheral neuropathies was high in comparison to other studies. Entrapment neuropathy, diabetic neuropathy, and spondylotic radiculopathy were the most common. Overall, the prevalence of peripheral neuropathy was higher in the rural than in the urban population.	1
Here, we report a rare case of anaplastic pleomorphic xanthoastrocytoma (PXA) associated with an H3G34 mutation. A 12-year-old male presented with loss of appetite, vomiting, headache, and a generalized seizure, and CT revealed a 9.0 cm left frontal lobe mass with some septal walls and a localized high-density area suggestive of hemorrhage or calcification, causing severe midline shift. He emergently underwent subtotal resection and the tumor was morphologically diagnosed as anaplastic PXA. DNA sequencing identified an H3F3A G34R mutation and a TP53 R273H mutation, and immunohistochemically, ATRX nuclear expression was lost. In CNS tumors, H3G34 mutations are essentially detected in glioblastoma (GBM) or central nervous system primitive neuroectodermal tumors. Those tumors most likely comprise a single biological entity (high-grade glioma with H3G34 mutation) because of no significant difference in molecular profiling and prognosis between GBM and PNET morphologies. To our knowledge, our present case is the first one of anaplastic PXA associated with an H3G34 mutation, and whether it biologically corresponds to "high-grade glioma with H3G34 mutation" needs further studies.	0
AIM:Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare endocrine disorder caused by autosomal recessive variants in GALNT3, FGF23, and KL leading to progressive calcification of soft tissues and subsequent clinical effects. The aim of this was to study the cause of HFTC in an Iranian family. PATIENTS AND METHODS:Four generations of a family with HFTC were studied for understanding the genetic pattern of the disease. Whole exome sequencing was applied on genomic DNA of the proband. Based on its result, genetically altered sequences were checked in his family through sanger sequencing. Then bioinformatics approaches as well as co-segregation analysis were applied to validate the genetic alteration. RESULTS:A novel homozygous variant in exon four of GALNT3, namely p.R261Q was found. The parents and sister were carriers. CONCLUSION:To our knowledge, it is the first-reported Iranian family with GALNT3-CDG novel variant.	0
We present two half siblings with significant short stature who proved a diagnostic challenge for several years. Radiological findings included subtle epiphyseal changes. The diagnosis was made through whole genome sequencing via the 100,000 genome project. A maternally inherited pathogenic heterozygous CDKN1C variant was found in the PCNA (proliferating cell nuclear antigen) domain. Mutations of the PCNA domain of the CDKN1C gene are known to be associated with IMAGe syndrome thus with adrenal disease, although neither affected patient in our case had evidence of adrenal dysfunction. This report supports the previously reported findings of Russell-Silver syndrome (RSS) like phenotype caused by this unusual mechanism (CDKN1C mutations in the PCNA domain), highlights subtle radiological features not described previously and the phenotypic variability between two affected siblings. Additionally it reminds clinicians of the importance of considering associated adrenal disease/diabetes mellitus for variants within the PCNA domain. Finally it confirms RSS-like disorders should be considered in patients who have epiphyseal or metaphyseal changes and short stature, since CDKN1C PCNA domain mutations can result in this phenotype.	0
To report the phenomenology of movement disorder (MD) in neurological Wilson disease (NWD), and correlate these with MRI, and biomarkers of oxidative stress, excitotoxicity, and inflammation. Eighty-two patients were included, and their phenomenology of MD was categorized. The severity of dystonia was assessed using the Burke-Fahn-Marsden score, and chorea, athetosis, myoclonus, and tremor on a 0-4 scale. The MRI changes were noted. Serum glutamate, cytokines, and oxidative stress markers were measured. Movement disorders were noted in 78/82 (95.1%) patients and included dystonia in 69 (84.1%), chorea in 31 (37.8%), tremor in 24 (29.3%), parkinsonism in 19 (23.2%), athetosis in 13 (15.9%), and myoclonus in 9 (11.0%) patients. Dystonia was more frequently observed in the patients with thalamic (76.8 vs 23.2%), globus pallidus (72.0 vs 28.0%), putamen (69.5 vs 30.5%), caudate (68.3 vs 31.7%) and brainstem (61.0 vs 39.0%) involvement, and tremor with cerebellar involvement (37.5 vs 5.2%). The median age of onset of neurological symptoms was 12 (5-50) years. WD patients had higher levels of malondialdehyde (MDA), glutamate, and cytokines (IL-6, IL-8, IL-10, and TNFα) and lower levels of glutathione and total antioxidant capacity (TAC) compared with the controls. Serum glutamate, IL-6, IL-8, and plasma MDA levels were increased with increasing neurological severity, while glutathione and TAC levels decreased. The severity of dystonia related to the number of MRI lesions. MD is the commonest neurological symptoms in WD. Oxidative stress, glutamate, and cytokine levels are increased in WD and correlate with neurological severity.	0
Pityriasis lichenoides is a scarce cutaneous disorder with unknown etiology. It contains a range of clinical manifestations including acute papular lesions that quickly grow into pseudo vesicles and central necrosis to small, scaling, benign-appearing papules.1,2.	0
A case of a 17-month-old boy with dissegmental dysplasia of the Rolland-Desbuquois type, who was scheduled for bilateral inguinal herniotomy, is presented. Preoperative assessment showed limited mouth opening, head extension, and kyphosis. Intubation with a size 4 mm endotracheal tube (ETT) was achieved with fiberoptic bronchoscopy, after which surgery proceeded uneventfully and the ETT was carefully removed. Copious airway secretions required frequent suctioning. On the second postoperative day, respiratory status stabilized, and the patient was discharged home.	0
Simpson-Golabi-Behmel Syndrome (SGBS) is an X-linked overgrowth syndrome characterized by pre- and post-natal overgrowth, typical facial appearance and multiple visceral, skeletal, and neurological anomalies. There is only few information in the current literature, on clinical and particularly dentofacial findings due to recent identification of the syndrome and its clinical overlap with other overgrowth syndromes. The aim of this case report is to present dentofacial findings in a 16-year-old boy who had been diagnosed with SGBS. Following comprehensive clinical, radiographic and histopathological examinations, six pathologically distinct lesions including odontogenic keratocyst, ameloblastoma, lateral periodontal cyst, dentigerous cyst and mucous retention cyst in both mandible and maxilla were identified. The clinical report is followed by a discussion aimed to clarify unique features of this condition and how practitioners should consider similar cases.	0
BACKGROUND:Tarsal tunnel syndrome is an entrapment neuropathy that can be provoked by either intrinsic or extrinsic factors that compresses the posterior tibial nerve beneath the flexor retinaculum. Osteochondroma, the most common benign bone tumor, seldom occur in foot or ankle. This is a rare case of tarsal tunnel syndrome secondary to osteochondroma of the sustentaculum tali successfully treated with open surgical excision. CASE PRESENTATION:A 15-year-old male presented with the main complaint of burning pain and paresthesia on the medial plantar aspect of the forefoot to the middle foot region. Hard mass-like lesion was palpated on the posteroinferior aspect of the medial malleolus. On the radiological examination, 2.5 × 1 cm sized bony protuberance was found below the sustentaculum tali. Surgical decompression of the posterior tibial nerve was performed by complete excision of the bony mass connected to the sustentaculum tali. The excised mass was diagnosed to be osteochondroma on the histologic examination. After surgery, the pain was relieved immediately and hypoesthesia disappeared 3 months postoperatively. Physical examination and radiographic examination at 2-year follow up revealed that tarsal tunnel was completely decompressed without any evidence of complication or recurrence. CONCLUSIONS:As for tarsal tunnel syndrome secondary to the identifiable space occupying structure with a distinct neurologic symptom, we suggest complete surgical excision of the causative structure in an effort to effectively relieve symptoms and prevent recurrence.	0
Eosinophilic pustular folliculitis (EPF) is a recurrent inflammatory dermatosis primarily involving hair follicles. Several subtypes of EPF have been described: Classic EPF, infantile EPF, and immunosuppression-associated EPF. Although classic EPF has a predilection for face, involvement of hairless areas such as palms and soles has been reported frequently. There are rare case reports of mucosal EPF. Herein, we report a woman who presented with classic EPF involving the lip and oral mucosa.	0
Nestin, an intermediate filament protein widely used as a marker of neural progenitors, was recently found to be expressed transiently in developing cortical neurons in culture and in developing mouse cortex. In young cortical cultures, nestin regulates axonal growth cone morphology. In addition, nestin, which is known to bind the neuronal cdk5/p35 kinase, affects responses to axon guidance cues upstream of cdk5, specifically, to Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, and changes in microtubules and actin filaments are well studied. In contrast, the roles of intermediate filament proteins in this process are poorly understood, even in cultured neurons. Here, we investigate the molecular mechanism by which nestin affects growth cone morphology and Sema3a sensitivity. We find that nestin selectively facilitates the phosphorylation of the lissencephaly-linked protein doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected by nestin. We uncover that this substrate selectivity is based on the ability of nestin to interact with DCX, but not with other cdk5 substrates. Nestin thus creates a selective scaffold for DCX with activated cdk5/p35. Last, we use cortical cultures derived from Dcx KO mice to show that the effects of nestin on growth cone morphology and on Sema3a sensitivity are DCX-dependent, thus suggesting a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating the intracellular kinase signaling environment in developing neurons. The sex of animal subjects is unknown.SIGNIFICANCE STATEMENT Nestin, an intermediate filament protein highly expressed in neural progenitors, was recently identified in developing neurons where it regulates growth cone morphology and responsiveness to the guidance cue Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, but the roles of intermediate filaments in this process are poorly understood. We now report that nestin selectively facilitates phosphorylation of the lissencephaly-linked doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected. This substrate selectivity is based on preferential scaffolding of DCX, cdk5, and p35 by nestin. Additionally, we demonstrate a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating intracellular kinase signaling in developing neurons.	0
Purpose:To describe an infant with Adams Oliver syndrome (AOS) with ocular signs similar to familial exudative vitreoretinopathy. Observations:A full-term female infant presented with a congenital scalp defect, hypoplasia of the fingers and toes along with a radial retinal fold in the right eye and tractional retinal detachment in the left eye. Fluorescein angiography findings included peripheral retinal nonperfusion, irregular vascular sprouting beyond the vascular-avascular junction, pinpoint areas of hyperfluorescence as well as late peripheral and posterior vascular leakage. The patient was clinically diagnosed with Adams Oliver syndrome based on the collective findings. Laser photocoagulation to the avascular retina was performed in both eyes which resulted in stabilization of the condition after 2 years of follow up. Conclusion and importance:The ocular phenotype in AOS may be similar to familial exudative vitreoretinopathy. Therefore, suspicion of the diagnosis should prompt ophthalmic evaluation including fluorescein angiography to detect and possibly treat the ischemic retinopathy.	0
Waardenburg syndrome type 4 (WS4) is a rare neural crest disorder defined by the combination of Waardenburg syndrome (sensorineural hearing loss and pigmentation defects) and Hirschsprung disease (intestinal aganglionosis). Three genes are known to be involved in this syndrome, that is, EDN3 (endothelin-3), EDNRB (endothelin receptor type B), and SOX10. However, 15-35% of WS4 remains unexplained at the molecular level, suggesting that other genes could be involved and/or that mutations within known genes may have escaped previous screenings. Here, we searched for deletions within recently identified SOX10 regulatory sequences and describe the first characterization of a WS4 patient presenting with a large deletion encompassing three of these enhancers. Analysis of the breakpoint region suggests a complex rearrangement involving three Alu sequences that could be mediated by a FosTes/MMBIR replication mechanism. Taken together with recent reports, our results demonstrate that the disruption of highly conserved non-coding elements located within or at a long distance from the coding sequences of key genes can result in several neurocristopathies. This opens up new routes to the molecular dissection of neural crest disorders.	0
RATIONALE:Tarsal tunnel syndrome (TTS) is a compressive neuropathy of the posterior tibial nerve and its branches. Tarsal coalition is defined as a fibrous, cartilaginous, or osseous bridging of 2 or more tarsal bones. TTS with tarsal coalition is uncommon. Here, we present a rare example of successful surgical management of TTS with posterior facet talocalcaneal coalition. PATIENT CONCERNS:A 74-year-old woman presented with hypoesthesia, numbness, and an intermittent tingling sensation on the plantar area over the right forefoot to the middle foot area. The hypoesthesia and paresthesia of the right foot began 6 years previously and were severe along the lateral plantar aspect. The symptoms were mild at rest and increased during daily activities. Tinel sign was positive along the posteroinferior aspect of the medial malleolus. DIAGNOSIS:Lateral ankle radiography showed joint-space narrowing and sclerotic bony changes with a deformed C-sign and humpback sign. Oblique coronal and sagittal computed tomography revealed an irregular medial posterior facet, partial coalition, narrowing, and subcortical cyst formation of the posterior subtalar joint. Magnetic resonance imaging showed an abnormal posterior talocalcaneal coalition compressing the posterior tibia nerve. Electromyography and nerve conduction velocity studies were performed, and the findings indicated that there was an incomplete lesion of the right plantar nerve, especially of the lateral plantar nerve, around the ankle level. INTERVENTIONS:Surgical decompression was performed. Intraoperatively, the lateral plantar nerve exhibited fibrotic changes and tightening below the posterior facet talocalcaneal coalition. The coalition was excised, and the lateral plantar nerve was released with soft-tissue dissection. OUTCOMES:The patient's symptoms of tingling sensation and hypoesthesia were almost relieved at 4 months postoperatively, but she complained of paresthesia with an itching sensation when the skin of the plantar area was touched. The paresthesia had disappeared almost completely at 8 months after surgery. She had no recurrence of symptoms at the 1-year follow-up. LESSONS:The TTS with tarsal coalition is rare. Supportive history and physical examination are essential for diagnosis. Plain radiographs and computed tomography or magnetic resonance imaging are helpful to determine the cause of TTS and verify the tarsal coalition. After diagnosis, surgical excision of the coalition may be appropriate for management with a good outcome.	0
Papillary cystadenocarcinoma is a rare malignant neoplasm of the salivary gland, characterized by noticeable cystic and solid areas with papillary endophytic projections. These tumours lack features that characterize cystic variants of several more common salivary gland carcinomas. It was first described in 1991 by World Health Organization as a separate entity and cystadenocarcinoma with or without papillary component in the AFIP classification. Most of these tumours occurred in the major salivary glands followed by minor salivary glands. Cystadenocarcinoma is the malignant counterpart of cystadenoma. We report a case of papillary cystadenocarcinoma of parotid. A 40-year-old lady presented with gradually progressive swelling below the right ear associated with occasional pain. Clinical and radiological features suggested benign neoplasm. Right lobe superficial parotidectomy was performed. The histopathologic diagnosis showed papillary cystadenocarinoma of the parotid gland. Histologic confirmation of stromal invasion is required to differentiate it from the benign lesion. Conservative wide local surgical excision is the treatment of choice.	0
Aims: The aim was to determine whether anti-neutrophil cytoplasmic antibody (ANCA)-positive serology in patients with lupus nephritis (LN) is associated with different clinicopathologic features and outcomes.Methods: In our retrospective analysis, 283 patients were enrolled between 2013 and 2018. Thirty-six patients were ANCA-positive, and this group was compared with the remaining 247 patients who were confirmed as ANCA-negative at the time of biopsy.Results: ANCA-positive LN patients exhibited higher anti-dsDNA antibody titers and serum creatinine levels and lower serum hemoglobin concentrations than ANCA-negative LN patients. On pathological evaluation, segmental endocapillary hypercellularity observed by light microscopy was significantly more common in the ANCA-positive group. This feature was not significantly different in the treatment group, but the response to treatment was significantly different, as was remission (76.1% vs 69.4%, p < 0.001), between the ANCA-negative and ANCA-positive groups. During follow-up, the times to renal replacement therapy (RRT) and death were significantly different between the two unmatched groups (chi-square test, p = 0.041). Multivariate Cox analysis revealed that neurological disorders, ANCA positivity, and the chronicity index (CI) remained independent risk factors for patient survival. Pulmonary infection was the main cause of death and was most often due to fungal infection.Conclusion: ANCA-positive LN patients typically exhibited higher anti-dsDNA antibody titers, lower serum hemoglobin concentrations and worse renal function than ANCA-negative LN patients. Fungal infection was the main cause of death. We observed that ANCA positivity was an independent risk factor for patient survival.	0
Very high IgM levels represent the hallmark of hyper IgM (HIGM) syndromes, a group of primary immunodeficiencies (PIDs) characterized by susceptibility to infections and malignancies. Other PIDs not fulfilling the diagnostic criteria for HIGM syndromes can also be characterized by high IgM levels and susceptibility to malignancies. The aim of this study is to characterize clinical phenotype, immune impairment, and pathogenic mechanism in six patients with very high IgM levels in whom classical HIGM syndromes were ruled out. The immunological analysis included extended B-cell immunophenotyping, evaluation of class switch recombination and somatic hypermutation, and next generation sequencing (NGS). Recurrent or severe infections and chronic lung changes at the diagnosis were reported in five out of six and two out of six patients, respectively. Five out of six patients showed signs of lymphoproliferation and four patients developed malignancies. Four patients showed impaired B-cell homeostasis. Class switch recombination was functional in vivo in all patients. NGS revealed, in one case, a pathogenic mutation in PIK3R1. In a second case, the ITPKB gene, implicated in B- and T-cell development, survival, and activity was identified as a potential candidate gene. Independent of the genetic basis, very high IgM levels represent a risk factor for the development of recurrent infections leading to chronic lung changes, lymphoproliferation, and high risk of malignancies.	0
Butterfly vertebrae are rare developmental anomalies representing failure of formation of the vertebral body. There have only been 8 previous reports of a butterfly vertebra occurring at S1. This is the first described case of a butterfly vertebra presenting with a sacral fracture and pelvic ring injury.	0
PURPOSE:We investigated whether men with biopsy verified, low grade cancer and a family history of lethal or advanced prostate cancer are at particularly high risk for harboring undetected high grade disease. MATERIALS AND METHODS:Upgrading and up staging of prostate cancer are common after prostatectomy. In a nationwide population based cohort we identified 6,854 men with low risk prostate cancer who underwent radical prostatectomy. Among these men 1,739 (25%) had a history of prostate cancer in a first-degree relative and 289 (4%) had a first-degree relative with lethal or advanced prostate cancer. RESULTS:Compared to men with no familial occurrence of prostate cancer, the odds ratio for the risk of up staging among men with a familial occurrence of high risk or lethal prostate cancer was 1.06 (95% CI 0.76-1.47). The corresponding odds ratio for upgrading was 1.17 (0.91-1.50). CONCLUSIONS:We found no association between family history of prostate cancer and up staging or upgrading after radical prostatectomy.	0
Distal arthrogryposis (DA) is a skeletal muscle disorder which can be classified under a broader term as Arthrogryposis multiplex contractures. DA is characterized by the presence of joint contractures at various parts of the body, particularly in distal extremities. It is identified as an autosomal dominant and a rare X-linked recessive disorder associated with increased connective tissue formation around joints in such way that immobilizes muscle movement causing deformities. DA is again classified into various types since it manifests as a range of conditions representing different etiologies. Myopathy is one of the most commonly listed etiologies of DA. The mutations in sarcomeric protein-encoding genes lead to decreased sarcomere integrity, which is often associated with this disorder. Also, skeletal disorders are often associated with cardiac disorders. Some studies mention the presence of cardiomyopathy in patients with skeletal dysfunction. Therefore, it is hypothesized that the congenitally mutated protein that causes DA can also lead to cardiomyopathy. In this review, we will summarize the different forms of DA and their clinical features, along with gene mutations responsible for causing DA in its different forms. We will also examine reports that list mutations also known to cause heart disorders in the presence of DA.	0
Described are previously unreported features presenting in a case of Freeman-Sheldon syndrome (FSS); these apparently unreported features may substantively inform current therapy and further research. While considered to be primarily a craniofacial syndrome, FSS is officially described as a myopathic distal arthrogryposis. Clinical diagnosis requires microstomia, whistling-face appearance (pursed lips), H-shaped chin dimpling, nasolabial folds, and two or more contractures of hands and feet. Spinal deformities, metabolic and gastroenterological problems, other dysmorphic craniofacial characteristics, and visual and auditory impairments are frequent findings. Differential diagnoses include: distal arthrogryposis type 1, 2B (Sheldon-Hall syndrome) and 3; arthrogryposis multiplex congenita and isolated non-syndromic deformities. Expression is frequently from new allelic variation. Important implications exist for geneticists, neonatologists, paediatricians, plastic surgeons and others to facilitate patients' legitimate opportunity to meaningfully overcome functional limitations and become well. Despite complexities and complications, early craniofacial surgery and aggressive physiotherapy for limb contractures can achieve excellent outcomes for patients.	0
A serosurvey for Tahyna virus (TAHV), a mosquito-borne California encephalitis orthobunyavirus (Peribunyaviridae) endemic to Europe, was performed to estimate the activity of TAHV on a broad geographic scale. Sera from wild boar (Sus scrofa), roe deer (Capreolus capreolus) and red deer (Cervus elaphus) were collected from Austria, Hungary and Romania. Samples were tested for neutralizing antibodies against TAHV using a virus microneutralization assay. The results demonstrate that TAHV transmission to mammals is widespread in Europe, particularly in the wild boar population where the mean rate of seroconversion is 15.2%.	0
Ileosigmoid knotting, also known as compound volvulus or double volvulus, is a rare surgical emergency causing intestinal obstruction. Principally, it is a closed-loop intestinal obstruction that involves the sigmoid and ileum. It is considered a rare cause of intestinal obstruction. Differentiation of ileosigmoid knot from simple sigmoid volvulus is important because endoscopic decompression in ileosigmoid knot might be hazardous and even fatal. Endoscopic decompression of ileosigmoid knot may lead to perforation or injury. The mortality rate of ileosigmoid knot in general may reach 48%. We present a case of a 30-year-old male patient who presented with ileosigmoid knot at our emergency room. The aim of reporting this case is to increase understanding of the condition to promote earlier diagnosis.	0
Proteoglycans (PGs) are macromolecules present on the cell surface and in the extracellular matrix that confer specific mechanical, biochemical, and physical properties to tissues. Sulfate groups present on glycosaminoglycans, linear polysaccharide chains attached to PG core proteins, are fundamental for correct PG functions. Indeed, through the negative charge of sulfate groups, PGs interact with extracellular matrix molecules and bind growth factors regulating tissue structure and cell behavior. The maintenance of correct sulfate metabolism is important in tissue development and function, particularly in cartilage where PGs are fundamental and abundant components of the extracellular matrix. In chondrocytes, the main sulfate source is the extracellular space, then sulfate is taken up and activated in the cytosol to the universal sulfate donor to be used in sulfotransferase reactions. Alteration in each step of sulfate metabolism can affect macromolecular sulfation, leading to the onset of diseases that affect mainly cartilage and bone. This review presents a panoramic view of skeletal dysplasias caused by mutations in genes encoding for transporters or enzymes involved in macromolecular sulfation. Future research in this field will contribute to the understanding of the disease pathogenesis, allowing the development of targeted therapies aimed at alleviating, preventing, or modifying the disease progression.	0
This is the first population based study to estimate the birth prevalence of DNA proven Prader-Willi syndrome. Thirty infants were reported to the Australian Paediatric Surveillance Unit between 1998 and 2000, a prevalence of 4 per 100,000 live births or approximately 1/25,000 live births per annum.	1
To establish a diagnosis and provide counseling and treatment for 3 adult patients from one family presenting with peripheral osteolysis.Following clinical and radiographic assessment, exome sequencing, targeted gene resequencing, and determination of enzyme activity in cultured fibroblasts were performed.The proband (age 40 years) had a history of episodic fever and pain in childhood that subsided around puberty. He and 2 of his older sisters (ages 58 and 60 years, respectively) showed adult-onset progressive shortening of fingers and toes with redundancy of the overlying skin. Radiographs showed severe osteolysis of the distal radius and ulna, carpal bones, metacarpal bones, and phalanges. Sequencing of the known genes for recessively inherited osteolysis, MMP2 and MMP14, failed to show pathogenic mutations. Exome sequencing revealed compound heterozygosity for mutations c.505T>C (p.Trp169Arg) and c.760A>G (p.Arg254Gly) in ASAH1, the gene coding for acid ceramidase. Sanger sequencing confirmed correct segregation in the family, and enzyme activity in fibroblast cultures from the patients was reduced to ∼8% of that in controls, confirming a diagnosis of Farber's disease.Our findings indicate that hypomorphic mutations in ASAH1 may result in an osteoarticular phenotype with a juvenile phase resembling rheumatoid arthritis that evolves to osteolysis as the final stage in the absence of neurologic signs. This observation delineates a novel type of recessively inherited peripheral osteolysis and illustrates the long-term skeletal manifestations of acid ceramidase deficiency (Farber's disease) in what appear to be the oldest affected individuals known so far.	0
BACKGROUND:Pathogenic variants of the ARID1B gene are recognized as the most common cause of Coffin-Siris syndrome (CSS) and also one of the most common causes for intellectual disability (ID). Reported ARID1B variants in association with CSS are mostly from patients of European ancestry. METHODS:We performed next-generation sequencing to identify pathogenic variants in patients with congenital disorders from the Genetics clinics. The identified variants were validated by Sanger sequencing. Parental samples were tested by Sanger sequencing to determine inheritance status. RESULTS:Truncating variants in ARID1B were identified in five unrelated Asian patients (one Malay, two Chinese and two Indian) with features of CSS. One was a nonsense mutation which had been documented in three other reports while the other four were novel variants, including two nonsense substitutions and two small deletions resulting in premature termination of translation. Similar to previous reports, all patients have developmental and speech delay, with additional presentations such as ectodermal/facial abnormalities commonly observed in CSS patients. CONCLUSIONS:Our results unveil ARID1B variants in association with CSS in multiple Southeast Asian ethnic groups, and confirm that variants associated with this disorder tend to be of the truncating type. This finding may provide additional insight into the function of the protein and the disease mechanism.	0
Increased expression and activity of cardiac and circulating cathepsin D and soluble fms-like tyrosine kinase-1 (sFlt-1) have been demonstrated to induce and promote peripartum cardiomyopathy (PPCM) via promoting cleavage of 23-kD prolactin (PRL) to 16-kD PRL and neutralizing vascular endothelial growth factor (VEGF), respectively. We hypothesized that activation of Hes1 is proposed to suppress cathepsin D via activating Stat3, leading to alleviated development of PPCM. In the present study, we aimed to investigate the role of Notch1/Hes1 pathway in PPCM. Pregnant mice between prenatal 3 days and postpartum 3 weeks were fed with LY-411575 (a notch inhibitor, 10 mg/kg/d). Ventricular function and pathology were evaluated by echocardiography and histological analysis. Western blotting analysis was used to examine the expression at the protein level. The results found that inhibition of Notch1 significantly promoted postpartum ventricular dilatation, myocardial hypertrophy and myocardial interstitial fibrosis and suppressed myocardial angiogenesis. Western blotting analysis showed that inhibition of Notch1 markedly increased cathepsin D and sFlt-1, reduced Hes1, phosphorylated Stat3 (p-Stat3), VEGFA and PDGFB, and promoted cleavage of 23k-D PRL to 16-kD PRL. Collectively, inhibition of Notch1/Hes1 pathway induced and promoted PPCM via increasing the expressions of cathepsin D and sFlt-1. Notch1/Hes1 was a promising target for prevention and therapeutic regimen of PPCM.	0
Background:Myoclonic epilepsy with ragged red fibers (MERRF) syndrome is characterized by myoclonus, generalized epilepsy, cerebellar ataxia, and ragged red fibers (RRFs) in the muscle. T-to-C transition at nucleotide position 14709 in the mitochondrial tRNA glutamic acid (tRNAGlu) gene has previously been associated with maternally inherited diabetes and deafness. However, the association between MERRF and mitochondrial T14709C mutation (m.T14709C) has never been reported before. Methods:Clinical information of a 17-year-old patient was collected; muscle biopsy and next-generation sequencing (NGS) of whole mitochondrial and neuromuscular disease panel were then conducted. Finally, sanger sequencing was carried out to confirm the mutations. Results:The patient presented a typical MERRF phenotype with muscle weakness, epileptic seizure, clonic episodes, cerebellar ataxia, and spinal scoliosis. Muscle biopsy showed RRFs which indicated abnormal mitochondrial functions. NGS of whole mitochondrial gene revealed m.T14709C mutation, confirmed by Sanger sequencing. Conclusion:We present a sporadic patient with typical MERRF presentation carrying the mutation of m.T14709C, which expanded the spectrum of m.T14709C.	0
OBJECTIVES:To evaluate computed tomography findings and assess the clinical course of patients with pulmonary epithelioid hemangioendothelioma. METHODS:Patients diagnosed with pulmonary epithelioid hemangioendothelioma at our institution between 2000 and 2019 were retrospectively analyzed. Patients with pleural involvement were excluded. Computed tomography findings of the lung at diagnosis were classified into three patterns: multiple small nodules pattern (˂15 mm), multiple nodules with large lesions pattern (≥15 mm) and single lesion pattern. Additionally, the clinical course of patients was evaluated. RESULTS:Thirty-five patients (15 men and 20 women; median age, 44 years) with pulmonary epithelioid hemangioendothelioma were identified. The multiple small nodules pattern, multiple nodules with large lesions pattern and single lesion pattern were observed in 25 (71.4%), 8 (22.9%) and 2 (5.7%) patients, respectively. In 22 (62.9%) patients, extra-pulmonary epithelioid hemangioendothelioma lesions were found. Most patients were followed without initial treatment, while two patients with single lesion pattern underwent surgical resection. The median follow-up period was 63 months. Five-year overall survival rate of all patients was 96.3%. Latest clinical information revealed that 20 (20/25, 80%) patients with multiple small nodules pattern were alive without symptoms. In patients with multiple nodules with large lesion pattern, four (4/8, 50%) patients were alive without symptoms, three (3/8, 37.5%) patients were alive with symptoms and one (1/8, 12.5%) died. No recurrence was observed in patients with single lesion pattern. CONCLUSIONS:Multiple small nodules pattern was the most common findings of pulmonary epithelioid hemangioendothelioma. Patients with pulmonary epithelioid hemangioendothelioma have good prognosis.	0
Infantile myofibromatosis (IM) is an aggressive neoplasm composed of myofibroblast-like cells in children. Although typically localized, it can also present as multifocal disease, which represents a challenge for effective treatment. IM has previously been linked to activating somatic and germline point mutations in the PDGFRβ tyrosine kinase encoded by the PDGFRB gene. Clinical panel-based targeted tumor sequencing of a tumor from a newborn with multifocal IM revealed a novel PDGFRB rearrangement, which was reported as being of unclear significance. Additional sequencing of cDNA from tumor and germline DNA confirmed a complex somatic/mosaic PDGFRB rearrangement with an apparent partial tandem duplication disrupting the juxtamembrane domain. Ectopic expression of cDNA encoding the mutant form of PDGFRB markedly enhanced cell proliferation of mouse embryo fibroblasts (MEFs) compared to wild-type PDGFRB and conferred tumor-forming capacity on nontumorigenic 10T1/2 fibroblasts. The mutated protein enhanced MAPK activation and retained sensitivity to the PDGFRβ inhibitor imatinib. Our findings reveal a new mechanism by which PDGFRB can be activated in IM, suggest that therapy with tyrosine kinase inhibitors including imatinib may be beneficial, and raise the possibility that this receptor tyrosine kinase might be altered in a similar fashion in additional cases that would similarly present annotation challenges in clinical DNA sequencing analysis pipelines.	0
The PROM1 (prominin 1) gene encodes an 865-amino acid glycoprotein that is expressed in retinoblastoma cell lines and in the adult retina. The protein is localized to photoreceptor outer segment disc membranes, where it plays a structural role, and in the retinal pigment epithelium (RPE), where it acts as a cytosolic protein that mediates autophagy. Mutations in PROM1 are typically associated with cone-rod dystrophy 12 (OMIM#3612657), autosomal dominant retinal macular dystrophy 2 (OMIM#608051), autosomal recessive retinitis pigmentosa 41 (OMIM#612095), and Stargardt disease 4 (OMIM#603786). Here we describe the first case of PROM1-associated Leber congenital amaurosis (LCA) in a 12-yr-old Asian male, caused by two not previously described deleterious frameshift variants in the compound heterozygous state. Clinical features include the presence of bull's eye maculopathy, pendular horizontal nystagmus, and photodysphoria consistent with the clinical diagnosis of LCA. The patient was evaluated using ophthalmic imaging, electroretinography, and whole-exome sequencing. Electroretinography revealed extinguished retinal activity.	0
Idiopathic noncirrhotic portal hypertension is a rare clinical entity. Even rarer is the littoral cell angioma of the spleen. The almost simultaneous appearance of the two disorders in a 64-year-old Greek woman was a tempting stimulus for us to attempt to identify a common denominator between these two, apparently distinct, entities.	0
BACKGROUND:Rare disease information sources are incompletely and inconsistently cross-referenced to one another, making it difficult for information seekers to navigate across them. The development of such cross-references established manually by experts is generally labor intensive and costly. OBJECTIVES:To develop an automatic mapping between two of the major rare diseases information sources, GARD and Orphanet, by leveraging terminological resources, especially the UMLS. METHODS:We map the rare disease terms from Orphanet and ORDR to the UMLS. We use the UMLS as a pivot to bridge between the rare disease terminologies. We compare our results to a mapping obtained through manually established cross-references to OMIM. RESULTS:Our mapping has a precision of 94%, a recall of 63% and an F1-score of 76%. Our automatic mapping should help facilitate the development of more complete and consistent cross-references between GARD and Orphanet, and is applicable to other rare disease information sources as well.	0
PURPOSE OF REVIEW:New daily persistent headache (NDPH) is a rare primary headache disorder, which often has a refractory clinical course. This narrative review seeks to highlight what is known about the development of NDPH, to outline a diagnostic approach to a patient with new daily headache, and to explore management considerations and potential future therapies for patients diagnosed with NDPH. RECENT FINDINGS:Interval work at the level of case series and cohort studies has identified novel triggering factors (e.g., Valsalva), subgroups with unique temporal profiles (e.g., thunderclap onset), psychophysical profiles (e.g., increased pain catastrophizing), and potential treatment options. The approach to the diagnosis and treatment of NDPH remains individualized, driven by clinical features and challenging in most cases. Earlier identification of patients (e.g., prediction of patients with status migrainosus destined to develop NDPH) may allow for more effective treatment.	0
Calcific aortic valve stenosis (CAVS) is a common age-related disease characterized by active calcification of the leaflets of the aortic valve. How innate immune cells are involved in disease pathogenesis is not clear. In this study we investigate the role of the pattern recognition receptor Toll-like receptor 7 (TLR7) in CAVS, especially in relation to macrophage subtype. Human aortic valves were used for mRNA expression analysis, immunofluorescence staining, or ex vivo tissue assays. Response to TLR7 agonist in primary macrophages and valvular interstitial cells (VICs) were investigated in vitro. In the aortic valve, TLR7 correlated with M2 macrophage markers on mRNA levels. Expression was higher in the calcified part compared with the intermediate and healthy parts. TLR7+ cells were co-stained with M2-type macrophage receptors CD163 and CD206. Ex vivo stimulation of valve tissue with the TLR7 ligand imiquimod significantly increased secretion of IL-10, TNF-α, and GM-CSF. Primary macrophages responded to imiquimod with increased secretion of IL-10 while isolated VICs did not respond. In summary, in human aortic valves TLR7 expression is associated with M2 macrophages markers. Ex vivo tissue challenge with TLR7 ligand led to secretion of immunomodulatory cytokine IL-10. These results connect TLR7 activation in CAVS to reduced inflammation and improved clearance.	0
There has been an ever-expanding list of the Limb-Girdle Muscular Dystrophies (LGMD). There are currently 8 subtypes of autosomal dominant (AD) and 26 subtypes of autosomal recessive (AR) LGMD. Despite continued research efforts to conquer this group of genetic neuromuscular disease, patients continue to be treated symptomatically with the aim of prevention or addressing complications. Mouse models have been helpful in clarifying disease pathogenesis as well as strategizing pathways for treatment. Discoveries in translational research as well as molecular therapeutic approaches have kept clinicians optimistic that more promising clinical trials will lead the way to finding the cure for these devastating disorders. It is well known that the challenge for these rare diseases is the ability to assemble adequate numbers of patients for a clinically meaningful trial, but current efforts in developing patient registries have been encouraging. Natural history studies will be essential in establishing and interpreting the appropriate outcome measures for clinical trials. Nevertheless, animal studies continue to be key in providing proof of concept that will be necessary in moving research along. This review will briefly discuss each type of LGMD, highlighting their distinguishing features, then focus on research efforts that have been published in the literature for the past few years, many of which are still in the preclinical trial stage.	0
Disorders (or differences) of sex development (DSD) are a heterogeneous group of congenital conditions with variations in chromosomal, gonadal, or anatomical sex. Impaired gonadal development is central to the pathogenesis of the majority of DSDs and therefore a clear understanding of gonadal development is essential to comprehend the impacts of these disorders on the individual, including impacts on future fertility. Gonadal development was traditionally considered to involve a primary 'male' pathway leading to testicular development as a result of expression of a small number of key testis-determining genes. However, it is increasingly recognized that there are several gene networks involved in the development of the bipotential gonad towards either a testicular or ovarian fate. This includes genes that act antagonistically to regulate gonadal development. This review will highlight some of the novel regulators of gonadal development and how the identification of these has enhanced understanding of gonadal development and the pathogenesis of DSD. We will also describe the impact of DSDs on fertility and options for fertility preservation in this context.	0
Neurodevelopmental disorders (NDDs) are multifaceted pathologic conditions manifested with intellectual disability, autistic features, psychiatric problems, motor dysfunction, and/or genetic/chromosomal abnormalities. They are associated with skewed neurogenesis and brain development, in part through dysfunction of the neural stem cells (NSCs) where abnormal transcriptional regulation on key genes play significant roles. Recent accumulated evidence highlights C2H2-type zinc finger proteins (C2H2-ZNFs), the largest transcription factor family in humans, as important targets for the pathologic processes associated with NDDs. In this review, we identified their significant accumulation (74 C2H2-ZNFs: ~10% of all human member proteins) in brain physiology and pathology. Specifically, we discuss their physiologic contribution to brain development, particularly focusing on their actions in NSCs. We then explain their pathologic implications in various forms of NDDs, such as morphological brain abnormalities, intellectual disabilities, and psychiatric disorders. We found an important tendency that poly-ZNFs and KRAB-ZNFs tend to be involved in the diseases that compromise gross brain structure and human-specific higher-order functions, respectively. This may be consistent with their characteristic appearance in the course of species evolution and corresponding contribution to these brain activities.	0
Palatoglossal bands are one of the very rare congenital anomaly with very few documented cases worldwide. They can present with respiratory distress which requires immediate surgical intervention, or with feeding difficulties. The management of such a patient is a challenge to any anaesthesiologist because of inability to perform conventional laryngoscopy and associated cardiac or digital anomalies. We discuss here the management of such an infant who presented at 18 months with feeding difficulties.	0
Leigh syndrome (LS), or subacute necrotizing encephalomyelopathy, is a genetically heterogeneous, relentlessly progressive, devastating neurodegenerative disorder that usually presents in infancy or early childhood. A diagnosis of Leigh-like syndrome may be considered in individuals who do not fulfil the stringent diagnostic criteria but have features resembling Leigh syndrome.We describe a unique presentation of Leigh-like syndrome in a 3-year-old boy with elevated 3-hydroxyisovalerylcarnitine (C5-OH) on newborn screening (NBS). Subsequent persistent plasma elevations of C5-OH and propionylcarnitine (C3) as well as fluctuating urinary markers were suggestive of multiple carboxylase deficiency (MCD). Normal enzymology and mutational analysis of genes encoding holocarboxylase synthetase (HLCS) and biotinidase (BTD) excluded MCD. Biotin uptake studies were normal excluding biotin transporter deficiency. His clinical features at 13 months of age comprised psychomotor delay, central hypotonia, myopathy, failure to thrive, hypocitrullinemia, recurrent episodes of decompensation with metabolic keto-lactic acidosis and an episode of hyperammonemia. Biotin treatment from 13 months of age was associated with increased patient activity, alertness, and attainment of new developmental milestones, despite lack of biochemical improvements. Whole exome sequencing (WES) analysis failed to identify any other variants which could likely contribute to the observed phenotype, apart from the homoplasmic (100%) m.8993T>G variant initially detected by mitochondrial DNA (mtDNA) sequencing.Hypocitrullinemia has been reported in patients with the m.8993T>G variant and other mitochondrial disorders. However, persistent plasma elevations of C3 and C5-OH have previously only been reported in one other patient with this homoplasmic mutation. We suggest considering the m.8993T>G variant early in the diagnostic evaluation of MCD-like biochemical disturbances, particularly when associated with hypocitrullinemia on NBS and subsequent confirmatory tests. An oral biotin trial is also warranted.	0
Objective:Clinical, radiologic, and molecular analysis of patients with genomic deletions upstream of the LMNB1 gene. Methods:Detailed neurologic, MRI examinations, custom array comparative genomic hybridization (aCGH) analysis, and expression analysis were performed in patients at different clinical centers. All procedures were approved by institutional review boards of the respective institutions. Results:Five patients from 3 independent families presented at ages ranging from 32 to 52 years with neurologic symptoms that included progressive hypophonia, upper and lower limb weakness and spasticity, and cerebellar dysfunction and MRIs characterized by widespread white matter alterations. Patients had unique nonrecurrent deletions upstream of the LMNB1, varying in size from 250 kb to 670 kb. Deletion junctions were embedded in repetitive elements. Expression analysis revealed increased LMNB1 expression in patient cells. Conclusions:Our findings confirmed the association between LMNB1 upstream deletions and leukodystrophy previously reported in a single family, expanding the phenotypic and molecular description of this condition. Although clinical and radiologic features overlapped with those of autosomal dominant leukodystrophy because of LMNB1 duplications, patients with deletions upstream of LMNB1 had an earlier age at symptom onset, lacked early dysautonomia, and appeared to have lesser involvement of the cerebellum and sparing of the spinal cord diameter on MRI. aCGH analysis defined a smaller minimal critical region required for disease causation and revealed that deletions occur at repetitive DNA genomic elements. Search for LMNB1 structural variants (duplications and upstream deletions) should be an integral part of the investigation of patients with autosomal dominant adult-onset leukodystrophy.	0
In May 2019, we investigated monkeypox in a traveler from Nigeria to Singapore. The public health response included rapid identification of contacts, use of quarantine, and postexposure smallpox vaccination. No secondary cases were identified. Countries should develop surveillance systems to detect emerging infectious diseases globally.	0
Leukonychia totalis and leukonychia partialis are rare nail findings characterized by complete or partial whitening of the nail plate. Leukonychia totalis and leukonychia partialis are usually inherited or associated with systemic disease. Here, we report the case of a 25-year-old man with idiopathic acquired leukonychia totalis and leukonychia partialis and review the literature on this topic.	0
BACKGROUND:Axenfeld-Rieger syndrome (ARS) is an autosomal dominant genetic disease characterized by ocular developmental disorders and its association with torsion of wandering spleen (WS) has not been reported to date to the best of our knowledge. This study aimed to describe a rare case of ARS observed at our emergency department. CASE SUMMARY:A 25-year-old female presented with a constant lower abdominal pain of increasing severity. Diagnostic computed tomography with intravenous contrast material showed a non-homogenously enhanced splenic parenchyma with a twisted vascular pedicle. Further, an emergent laparoscopic exploration was performed, and an ischemic spleen without its normal ligamentous attachments was noted. Notably, the spleen did not regain its normal vascularity after detorsion; thus, we performed the laparoscopic total splenectomy. The postoperative course was uneventful, and the patient was discharged on the 5th postoperative day. This case demonstrates a rare association of WS and ARS. CONCLUSION:Early diagnosis of WS in the emergency department is important to prevent pedicle torsion or splenic necrosis and to avoid splenectomy.	0
A 37-year-old woman developed deep venous thrombosis (DVT) of the left lower extremity at 8 weeks of gestation during her second pregnancy. There was no personal or family history of thrombosis. She received intravenous heparin, but heparin resistance was noted. The plasma antithrombin activity decreased to 45% in the acute phase, and it remained low postpartum. Her mother also had low plasma antithrombin activity (46%), and genetic testing revealed a heterozygous SERPINC1 mutation. Even without a family history of thrombosis, we should suspect hereditary antithrombin deficiency in patients with initial DVT and perform thorough investigation.	0
PURPOSE OF REVIEW:The current article highlights recent developments in the field of pediatric cutaneous mastocytosis. Mastocytosis is a spectrum of conditions that range from fleetingly benign to aggressively malignant. Through recognizing the natural progression of disease, the role of biomarkers and mutational analysis, treatment and risk of triggers, physicians can confidently stage, counsel and manage patients with pediatric cutaneous mastocytosis. RECENT FINDINGS:Many lesions of cutaneous mastocytosis are chronic with some resolving around the mid-teenage years. KIT mutations are found in the majority of pediatric cutaneous mastocytosis but are not correlated with prognosis. Serum tryptase levels may be elevated in pediatric cutaneous mastocytosis patients without systemic mastocytosis. Pimecrolimus, omalizumab and tyrosine kinase inhibitors are effective treatment options. The low risk of NSAIDs and vaccinations has been characterized and epinephrine autoinjectors are rarely utilized in the pediatric cutaneous mastocytosis patient. SUMMARY:Pediatric cutaneous mastocytosis is a heterogeneous disease with good outcome overall. Organomegaly, elevated tryptase levels and the presence of KIT mutation in peripheral blood may aid in the decision to pursue bone marrow biopsy. The armamentarium of treatments has expanded and better understanding of the significance of triggers and vaccination safety allows the clinician to thoughtfully counsel and allay anxiety around pediatric cutaneous mastocytosis.	0
Smartphones and other personal electronic devices present novel cortical processing tasks with potential for identification of novel EEG waveforms. A 17-year-old patient with epilepsy manifested as recurrent myoclonic seizures, absence seizures, and a single generalized tonic-clonic seizure was hospitalized to undergo video-EEG monitoring for seizure quantification and classification of the epilepsy syndrome. During the monitoring session, a frontocentral predominant 5 to 6 Hz theta rhythm was identified only when the patient was actively texting or playing a video game on his smartphone. Previously, patients with focal epilepsy have been found to have a frontocentral theta rhythm on EEG while texting on mobile devices. We report similar EEG findings in a patient with genetic generalized epilepsy during smartphone gaming to expand the population and triggers for this theta waveform. Given the young age and type of epilepsy, we suggest that the waveform represents the EEG manifestation of the attention-visuomotor pathway that is stimulus independent.	0
BACKGROUND/OBJECTIVES:Lichen sclerosus is a rare, pruritic, mucocutaneous disease affecting mostly the anogenital area. Reports have occasionally associated lichen sclerosus with overlapping vascular lesions. This study explores this association in children. METHODS:A retrospective study was conducted in the dermatology unit of a pediatric tertiary care medical center. Electronic medical records were searched for patients diagnosed with lichen sclerosus from 2006 to 2019. Review of the cases was performed to identify overlapping vascular lesions and review the clinical course of overlap cases. RESULTS:Of 74 children diagnosed with lichen sclerosus during the study period, five (6.75%) had overlapping vascular lesions and genital lichen sclerosus. Four patients presented with reticular telangiectatic macules and patches (n = 4, 5.4%) that appeared at or shortly after disease onset; resolution occurred a few months after treatment initiation. The fifth patient presented with telangiectases that appeared more than 2 years after the onset of the first symptoms of lichen sclerosus (n = 1, 1.3%). CONCLUSION:Vascular lesions in children with genital lichen sclerosus are common and have variable clinical manifestations. Early appearance of reticular macules, patches, and papules is a variant of the disease and is followed by prompt resolution of these lesions. Pathogenesis is attributed to structural changes and repositioning of the papillary vascular plexus. These changes may be alarming to parents and therefore must be recognized by physicians to prevent unnecessary concern and investigations.	0
Nav1.4 channelopathies due to SCN4A mutations can present with episodic attacks of myotonia triggered by fluctuation in the potassium level (potassium-aggravated myotonia). We report a case of potassium-aggravated myotonia due to Nav1.4-M1592V channelopathy with severe and long-lasting focal attacks of myotonia resembling dystonic posturing with diffuse muscle edema in the affected muscles in magnetic resonance imaging and almost constant presence of myotonic discharges in electromyography that can best be described as focal "status myotonicus".	0
Case presentation:We report for the first time a synchronous papillary and follicular thyroid carcinoma in a 12-year-old girl presenting with a large (5 cm diameter) left thyroid nodule, an increased left and right upper pole technetium tracer uptake at scintigraphy and hyperthyroidism. The uptake at the right lobe was explained by the crossing of the left nodule to the right site of the neck at Computed Tomography (CT) scanning. Background:Although thyroid nodules are less common in children than in adults, there is more vigilance required in children because of the higher risk of malignancy. According to literature, about 5% of the thyroid nodules in adults are malignant versus 20-26% in children. The characteristics of 9 other pediatric cases with a differentiated thyroid carcinoma presenting with a toxic nodule, which have been reported during the last 20 years, are summarized. A nodular size of more than 3.5 cm and female predominance was a common finding. Conclusions:The presence of hyperthyroidism in association with a hyperfunctioning thyroid nodule does not rule out thyroid cancer and warrants careful evaluation, even in the absence of cervical lymph node invasion.	0
Desmoplastic infantile ganglioglioma (DIG) is a rare, distinctive, supratentorial neoplasm with a generally favorable prognosis. Clinical, radiographic, and pathologic features can sometimes mimic those of a malignant tumor and other serious intracranial disorders. The author describes his experience with 3 cases of DIG, each of which initially masqueraded as another neurological disease with a very different prognosis. Case 1 was an infant boy referred for evaluation of a hemorrhagic infarction at birth. Case 2 was an infant girl referred for evaluation of a holohemispheric malignant neoplasm. Case 3 was an infant girl referred for evaluation of an intracranial mass believed to be a subdural empyema or possible sarcoma. In each case the lesion was resected and found to be a WHO grade I DIG. Each child has had a benign postoperative course. DIG can be mistaken for other serious neurological conditions including malignant neoplasm, cerebral infarction, and infection. It is prudent to consider this rare, low-grade resectable tumor in the differential diagnosis of atypical intracranial masses of childhood, as the impact on prognosis can be profound. The author discusses management strategies for DIG, including a role for molecular sequencing.	0
Context:Defining the underlying etiology of idiopathic short stature (ISS) improves the overall management of an individual. Objective:To assess the frequency of pathogenic ACAN variants in selected individuals. Design:The single-center cohort study was conducted at a tertiary university children's hospital. From 51 unrelated patients with ISS, the 16 probands aged between 3 and 18 years (12 females) with advanced bone age and/or autosomal dominant inheritance pattern of short stature were selected for the study. Fifteen family members of ACAN-positive probands were included. Exome sequencing was performed in all probands, and additional copy number variation (CNV) detection was applied in selected probands with a distinct ACAN-associated phenotype. Results:Systematic phenotyping of the study cohort yielded 37.5% (6/16) ACAN-positive probands, with all novel pathogenic variants, including a 6.082 kb large intragenic deletion, detected by array comparative genomic hybridization (array CGH) and exome data analysis. All variants were co-segregated with short stature phenotype, except in one family member with the intragenic deletion who had an unexpected growth pattern within the normal range (-0.5 SDS). One patient presented with otosclerosis, a sign not previously associated with aggrecanopathy. Conclusions:ACAN pathogenic variants presented a common cause of familial ISS. The selection criteria used in our study were suggested for a personalized approach to genetic testing of the ACAN gene in clinical practice. Our results expanded the number of pathogenic ACAN variants, including the first intragenic deletion, and suggested CNV evaluation in patients with typical clinical features of aggrecanopathy as reasonable. Intra-familial phenotypic variability in growth patterns should be considered.	0
Fetal central nervous system (CNS) abnormalities are second only to cardiac malformations in their frequency of occurrence. Early and accurate diagnosis at prenatal US is therefore essential, allowing improved prenatal counseling and facilitating appropriate referral. Thorough knowledge of normal intracranial anatomy and adoption of a logical sonographic approach can improve depiction of abnormal findings, leading to a more accurate differential diagnosis earlier in pregnancy. Four standard recommended views-transventricular, falx, cavum, and posterior fossa or transcerebellar views-provide an overview of fetal intracranial anatomy during the second trimester anatomy scan. Essential elements surveyed in the head and neck include the lateral cerebral ventricles, choroid plexus, midline falx, cavum septi pellucidi, cerebellum, cisterna magna, upper lip, and nuchal fold. CNS abnormalities can be organized into six main categories at prenatal US. Developmental anomalies include neural tube defects and neuronal migration disorders. Posterior fossa disorders include Dandy-Walker malformation variants and Chiari II malformation. Ventricular anomalies include aqueductal stenosis. Midline disorders include those on the spectrum of holoprosencephaly, agenesis of the corpus callosum, and septo-optic dysplasia. Vascular anomalies include vein of Galen malformations. Miscellaneous disorders include hydranencephaly, porencephaly, tumors, and intracranial hemorrhage. Correlation with postnatal MRI is helpful for confirmation and clarification of suspected diagnoses after birth. The authors discuss a standard US imaging approach to the fetal CNS and review cases in all categories of CNS malformations, providing postnatal MRI correlation when available.©RSNA, 2020.	0
BACKGROUND:The neuronal ceroid lipofuscinosis 2 (NCL2) or classic late-infantile neuronal ceroid lipofuscinosis (LINCL) is a neurogenetic disorder caused by mutations in the TPPI gene, which codes for the lysosomal tripeptidyl peptidase 1 (TPPI) EC 3.4.14.9. Loss of functional TPPI activity results in progressive visual and neurological symptoms starting at around 1-2 years of age causing early death. METHODS:We report a DBS-based TPPI assay that cleaves a synthetic tetrapeptide substrate generating a product that is detected by HPLC. Probands and carriers were identified with 100% accuracy (7 probands, 30 carriers, 13 controls). RESULTS:The assay detected a single TPPI activity at a lower pH towards the substrate tested. TPPI activity measurable when extracted at lower pH while inactive at neutral pH showed steady increase for at least 8 h incubation. No loss in TPPI activity was observed when DBS were stored for at least 2 weeks either in freezer, refrigerator, room temperature or 42 °C. CONCLUSION:A sequence variant causing Arg339Gln substitution in a proband had 12% TPPI. TPPI activity can be reliably measured in DBS, giving an opportunity to diagnose NCL2 at birth and refer patients for enzyme replacement or other therapies for earliest intervention, or alternatively offers a second-tier confirmatory test.	0
Background:The clinical phenotyping of patients with achromatopsia harboring variants in phosphordiesterase 6C (PDE6C) has poorly been described in the literature. PDE6C encodes the catalytic subunit of the cone phosphodiesterase, which hydrolyzes the cyclic guanosine monophosphate that proceeds with the hyperpolarization of photoreceptor cell membranes, as the final step of the phototransduction cascade. Methods:In the current study, two patients from a consanguineous family underwent full ophthalmologic examination and molecular investigations including WES. The impact of the variant on the functionality of the protein has been analyzed using in silico molecular modeling. Results:The patients identified with achromatopsia segregated a homozygous missense variant (c.C1775A:p.A592D) in PDE6C gene located on chromosome 10q23. Molecular modeling demonstrated that the variant would cause a protein conformational change and result in reduced phosphodiesterase activity. Conclusion:Our data extended the phenotypic spectrum of retinal disorders caused by PDE6C variants and provided new clinical and genetic information on achromatopsia.	0
Horstick et al. (2013) previously reported a homozygous p.Trp284Ser variant in STAC3 as the cause of Native American myopathy (NAM) in 5 Lumbee Native American families with congenital hypotonia and weakness, cleft palate, short stature, ptosis, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH). Here we present two non-Native American families, who were found to have STAC3 pathogenic variants. The first proband and her affected older sister are from a consanguineous Qatari family with a suspected clinical diagnosis of Carey-Fineman-Ziter syndrome (CFZS) based on features of hypotonia, myopathic facies with generalized weakness, ptosis, normal extraocular movements, cleft palate, growth delay, and kyphoscoliosis. We identified the homozygous c.851G>C;p.Trp284Ser variant in STAC3 in both sisters. The second proband and his affected sister are from a non-consanguineous, Puerto Rican family who was evaluated for a possible diagnosis of Moebius syndrome (MBS). His features included facial and generalized weakness, minimal limitation of horizontal gaze, cleft palate, and hypotonia, and he has a history of MH. The siblings were identified to be compound heterozygous for STAC3 variants c.851G>C;p.Trp284Ser and c.763_766delCTCT;p.Leu255IlefsX58. Given the phenotypic overlap of individuals with CFZS, MBS, and NAM, we screened STAC3 in 12 individuals diagnosed with CFZS and in 50 individuals diagnosed with MBS or a congenital facial weakness disorder. We did not identify any rare coding variants in STAC3. NAM should be considered in patients presenting with facial and generalized weakness, normal or mildly abnormal extraocular movement, hypotonia, cleft palate, and scoliosis, particularly if there is a history of MH.	0
OBJECTIVE:Dystonia is a complex movement disorder. Research progress has been difficult, particularly in developing widely effective therapies. This is a review of the current state of knowledge, research gaps, and proposed research priorities. METHODS:The NIH convened leaders in the field for a 2-day workshop. The participants addressed the natural history of the disease, the underlying etiology, the pathophysiology, relevant research technologies, research resources, and therapeutic approaches and attempted to prioritize dystonia research recommendations. RESULTS:The heterogeneity of dystonia poses challenges to research and therapy development. Much can be learned from specific genetic subtypes, and the disorder can be conceptualized along clinical, etiology, and pathophysiology axes. Advances in research technology and pooled resources can accelerate progress. Although etiologically based therapies would be optimal, a focus on circuit abnormalities can provide a convergent common target for symptomatic therapies across dystonia subtypes. The discussions have been integrated into a comprehensive review of all aspects of dystonia. CONCLUSION:Overall research priorities include the generation and integration of high-quality phenotypic and genotypic data, reproducing key features in cellular and animal models, both of basic cellular mechanisms and phenotypes, leveraging new research technologies, and targeting circuit-level dysfunction with therapeutic interventions. Collaboration is necessary both for collection of large data sets and integration of different research methods.	0
PRRT2 mutations are the major causative agent of paroxysmal kinesigenic dyskinesia with infantile convulsion (PKD/IC). The study is aimed at screening PRRT2 gene mutations in patients who suffered from PKD/IC in Chinese population. Thirteen Chinese patients with PKD/IC were screened randomly for coding exons of the PRRT2 gene mutation along with 50 ethnically coordinated control people. Nine (2 unaffected) and 4 of the patients showed familial PKD/IC and apparently sporadic cases, respectively. We identified 5 different PRRT2 mutations in 10 individuals, including 8 familial and 2 apparently sporadic cases. However, no mutations were found in the 50 ethnically matched controls. Unknown (novel) NM_145239.2:c.686G>A and previously reported NM_145239.2:c.743G>C variants were identified in two familial and sporadic patients. All affected members of family A showed mutation NM_145239.2:c.650_670delinsCAATGGTGCCACCACTGGGTTA. The previously identified NM_145239.2:c.412 C>G and NM_145239.2:c.709G>A variants are seen in two individuals assessed in family B. Other than the previously identified variants, some of the patients with PRRT2-PKD/IC showed a new PRRT2 substitution variant. Thus, the spectrum of PRRT2 variants is expanded. The possible role and probability of PRRT2 variants involved in PKD/IC are highlighted.	0
Substantial acute and chronic intakes of alcohol or ethanol (EtOH) severely influence oral sensations, such as thirst and oral dryness (dry mouth, xerostomia). Thirst sensation and oral dryness are primarily caused by the activation of neurons in brain regions, including the circumventricular organs and hypothalamus, which are referred to as the dipsogenic center, and by a decrease in salivary secretion, respectively. The sensation of thirst experienced after heavy-alcohol drinking is widely regarded as a consequence of EtOH-induced diuresis; however, EtOH in high doses induces anti-diuresis. Recently, it has been proposed that the ethanol metabolite acetaldehyde induces thirst via two distinct processes in the central nervous system from EtOH-induced diuresis, based on the results of animal experiments. The present review describes new insights regarding the induction mechanism of thirst sensation and oral dryness after drinking alcohol.	0
PURPOSE:Voriconazole was shown to inhibit ergosterol synthesis in various acanthamoeba species. The purpose of this study was to evaluate the clinical outcome of treatment with supplemental topical voriconazole in patients with acanthamoeba keratitis (AK). METHODS:All patients who had been treated for AK with voriconazole 1% drops in conjunction with topical first-line antiacanthamoeba therapy composed of polyhexamethylene biguanide (PHMB) 0.02% and propamidine isethionate 0.1% (Brolene) between November 2014 and August 2017 at the Department of Ophthalmology, University Medical Center Mainz, were included. The main outcomes were treatment failure and recurrence rate. Secondary outcomes were visual acuity, need for keratoplasty, and presence of adverse reactions. RESULTS:Twenty-eight eyes of 28 patients with AK, whose treatment had included topical voriconazole, were identified (12 men, 16 women, mean age: 41.7 ± 16.3 years), and 26 of them could be tracked for at least 3 months after cessation of therapy. Resolution of infection under therapy was seen in all eyes, and only one of 26 (3.85%) had a relapse after the therapy had been stopped. Best-corrected visual acuity improved during therapy. Keratoplasty because of central corneal scarring was scheduled in 5 of 26 patients (19.2%) after the pharmacological therapy had been stopped. Five of 26 patients (19.2%) reported on stinging or burning sensation after application of voriconazole 1% drops. CONCLUSIONS:Topical voriconazole 1% combined with first-line therapy composed of polyhexamethylene biguanide 0.02% and propamidine isethionate 0.1% appears to be an effective option with minor side effects for the treatment of AK.	0
The advent of the direct mutation test for Huntington disease (HD) has made it possible to identify a previously unrecognized symptomatic population of HD, including those with an atypical presentation or patients without a family history of HD. The present study investigated the uptake of this test in the province of British Columbia (BC), Canada and assessed the incidence rate and rate of identification of new mutations for HD. All symptomatic individuals residing in BC who were referred for the genetic test for HD between 1993 and 2000 (n=205) were analyzed for CAG expansion, baseline demographics and clinical data, and a family history of HD. A total of 141 (or 68.8%) had a CAG expansion > or =36. Of these, almost one-quarter (24.1%) did not have a family history of HD. An extensive chart review revealed that 11 patients (or 7.8%) had reliable information on both parents (who lived well into old age) and therefore possibly could represent new mutations for HD. This indicates a three to four times higher new mutation rate than previously reported. Our findings also show that the yearly incidence rate for HD was 6.9 per million, which is two times higher than previous incidence studies performed prior to the identification of the HD mutation. We also identified five persons with a clinical presentation of HD but without CAG expansion (genocopies) (2.4%).	1
Disorders and abnormalities of pupil reactions comprise important part in the clinical practice of both ophthalmologists and neurologists. The present article presents a historical perspective on one of such pathologies - Adie syndrome, and discusses its etiology, pathogenesis and clinical symptomatology. The article also describes a clinical case of one patient with comorbidity.	0
Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare autosomal recessive multisystemic disease that is associated with the liver, kidney, skin, and central nervous and musculoskeletal systems. ARC occurs as a result of mutations in the VPS33B (Vacuolar protein sorting 33 homolog B) or VIPAR (VPS33B interacting protein, apical-basolateral polarity regulator) genes. A female infant presented with neonatal cholestasis with a severe clinical outcome. She was diagnosed with ARC syndrome using targeted exome sequencing (TES). Exome sequencing revealed compound heterozygous mutations, c.707A>T and c.239+5G>A, in VPS33B, where c.707A>T was a novel variant; the resultant functional protein defects were predicted via in silico analysis. c.239+5G>A, a pathogenic mutation that affects splicing, is found in less than 0.1% of the general population. Invasive techniques, such as liver biopsies, did not contribute to a differential diagnosis of ARC syndrome; thus, early TES together with clinical presentations constituted an apparently accurate diagnostic procedure.	0
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNEC) is an abnormal proliferation of pulmonary neuroendocrine cells that occur without underlying etiology. Here, we report a unique case of 55-year-old female with unusual presentation of DIPNECH and thymoma and on the background history of Crohn's disease that might point toward an autoimmune phenomenon. To the best of our knowledge, there were no previous reports of DIPNECH with either thymoma or Crohn's disease. DIPNECH has premalignant potential and reported in association with carcinoid and non-small cell lung cancer; however, its autoimmune association never reported. The presence of multiple lung nodules along with evidence of small airway disease should alert the physician to include DIPNECH as part of the differential diagnosis given its malignant potential. The prognosis is variable and depends on the presence or absence of underlying malignancy as well as the severity of airflow obstruction.	0
INTRODUCTION:Autoantibodies (autoAbs) against desmoglein-1 (DSG1) and desmoglein-3 (DSG3) have conventionally been studied and well accepted in the pathogenesis of pemphigus vulgaris (PV) and foliaceus (PF). Recent studies have suggested that non-DSG autoAbs may contribute to the pathogenesis of pemphigus, including autoAbs directed at acetylcholine receptors (AChR) and thyroid peroxidase (TPO). The purpose of this study is to retrospectively analyze PV and PF patient sera to better understand the relationship between anti-AChR and -TPO Abs to disease activity and DSG reactivity between patients treated with prednisone and steroid sparing agents (SSA; n = 22) or prednisone and rituximab (n = 21). METHODS:Patients were evaluated at 2 time points, T1 and T2, for disease activity using the Pemphigus Disease Area Index (PDAI), and sera were tested for the presence of TPO, DSG1, DSG3, muscarinic (M3) and nicotinic (n) AChR IgG autoAbs, as well as antibodies against Varicella Zoster Virus (VZV) by ELISA. RESULTS:Disease activity significantly decreased in patients from T1 to T2 (p < .0001). A significant difference was seen in IgG anti-DSG1 (p < .0001) and anti-DSG3 (p = .0049) levels when T1 was compared to T2 in both treatment groups. A significant increase was found between pemphigus patients and normal subjects with nAChR (p < .0001) at T1 but not with m3AChR, TPO or VZV Abs. No significant difference was seen between T1 and T2 values in patients with pemphigus for the non-desmoglein Abs TPO (p = .7559), M3AChR (p = .9003), nAChR (p = .5143) or VZV (p = .2454). These findings demonstrate that although an increase in IgG anti-nAChR autoAbs was found in PV and PF subjects, these Abs did not decrease with treatment. No other non-DSG Abs were increased or significantly changed over time in patients with pemphigus. This suggests that anti -AChR and -TPO Abs may not play a direct role in the pathogenesis of most patients with pemphigus, but does not rule out a role for non-DSG auto antibodies in distinct subsets of pemphigus patient.	0
Background: Lesch-Nyhan disease (LND) is a rare X-linked recessive inborn error of purine metabolism. Late diagnosis of LND may cause significant morbidity. LND cases have never been reported in Indonesia.Case report: A 15-year-old male who had been diagnosed with cerebral palsy was referred to our hospital due to renal failure requiring emergency dialysis. The patient presented with three classic manifestations of LND: increased uric acid levels, neurological disorders, and self-injurious behaviors. LND was suspected because of an abscess-like lump on the left ankle that was confirmed to be a tophus, which had burst and discharged thick masses containing blood, debris, and white crystal materials. The diagnosis of LND was confirmed by the presence of a deletion to exon 1 of the HPRT1 gene. The patient received oral allopurinol daily and treatment for end-stage renal disease (ESRD), which included regular dialysis and subcutaneous administration of erythropoietin. At a 2-month follow-up, he improved clinically with a 71% decrease in uric acid levels after regular dialysis and allopurinol treatment.Conclusion: In developed countries, LND can be diagnosed as early as 3 days after birth. However, diagnosis in the present case was delayed due to the rarity of the disease and the limited number of facilities in Indonesia that offer genetic counseling. Late diagnosis of LND leads to ESRD and irreversible abnormalities. This is the first case of LND presenting with a unique clinical presentation of tophus burst reported in Indonesia.	0
Complement component 3 (C3), a pivotal molecule in the complement system, is an essential immune mediator in various diseases, including psoriasis. However, the mechanistic role of C3 in psoriasis pathology and development remains elusive. Here, we showed that C3 deficiency dramatically augmented imiquimod-induced psoriasis-like skin inflammation, characterized by greater epidermal hyperplasia, inflammatory cell infiltration, and inflammatory gene expression than those in wild-type counterparts. In addition, C3 deficiency promoted imiquimod-induced skin cell apoptosis and supported greater proportions of IFN-γ+ T cells in the inflamed tissues. Accordingly, C3 supplement in the C3 deficient mice reduced skin inflammation and cells apoptosis. Moreover, blocking apoptosis with Z-VAD-FMK, a broad caspase inhibitor, markedly attenuated imiquimod-induced psoriasis-like skin inflammation and IFN-γ+ T cell responses in C3-deficient mice. Collectively, our results suggest that C3 prevents imiquimod-induced psoriasis-like skin inflammation by inhibiting apoptosis.	0
Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disease caused by CAG (encoding glutamine) repeat expansion in the Ataxin-3 (ATXN3) gene. We have shown previously that ATXN3-depleted or pathogenic ATXN3-expressing cells abrogate polynucleotide kinase 3'-phosphatase (PNKP) activity. Here, we report that ATXN3 associates with RNA polymerase II (RNAP II) and the classical nonhomologous end-joining (C-NHEJ) proteins, including PNKP, along with nascent RNAs under physiological conditions. Notably, ATXN3 depletion significantly decreased global transcription, repair of transcribed genes, and error-free double-strand break repair of a 3'-phosphate-containing terminally gapped, linearized reporter plasmid. The missing sequence at the terminal break site was restored in the recircularized plasmid in control cells by using the endogenous homologous transcript as a template, indicating ATXN3's role in PNKP-mediated error-free C-NHEJ. Furthermore, brain extracts from SCA3 patients and mice show significantly lower PNKP activity, elevated p53BP1 level, more abundant strand-breaks in the transcribed genes, and degradation of RNAP II relative to controls. A similar RNAP II degradation is also evident in mutant ATXN3-expressing Drosophila larval brains and eyes. Importantly, SCA3 phenotype in Drosophila was completely amenable to PNKP complementation. Hence, salvaging PNKP's activity can be a promising therapeutic strategy for SCA3.	0
Triphalangeal thumb (TPT), a rare malformation of uncertain pathogenesis, may occur as an isolated defect, in association with other malformations of the hands, or as a feature of a syndrome or sequence. Isolated TPT occurs in two functional types: opposable and non-opposable. The latter appears to be inherited as a simple autosomal dominant trait, while the former is generally sporadic. TPT is associated with a number of specific malformations of the hand or foot, several of which have a well documented autosomal dominant pattern of inheritance. TPT is a feature of a number of specific syndromes. In this setting it may be associated with radial hypoplasia, bone marrow dysfunction, congenital heart disease, lung hypoplasia or agenesis, anorectal malformations, sensorineural hearing loss, onychodystrophy, mental retardation, and other disorders. TPT serves as a useful marker in such patients; in conjunction with the clinical and radiological findings, it can help to establish the correct diagnosis, leading to appropriate management and genetic counselling.	0
Paroxysmal cold hemoglobinuria is a rare cause of autoimmune hemolytic anemia predominantly seen as an acute form in young children after viral illnesses and in a chronic form in some hematological malignancies and tertiary syphilis. It is a complement mediated intravascular hemolytic anemia associated with a biphasic antibody against the P antigen on red cells. The antibody attaches to red cells at colder temperatures and causes red cell lysis when blood recirculates to warmer parts of the body. Treatment is mainly supportive and with red cell transfusion, but immunosuppressive therapy may be effective in severe cases.	0
Situs inversus totalis is a congenital syndrome characterized by a total left-right transposition of all abdominal and thoracic organs. It may be associated with chronic respiratory conditions such as sinusitis and bronchiectasis, composing the Kartagener syndrome. If not detected, this condition may compromise the early diagnosis of surgical emergencies such as cholecystitis and appendicitis. A rare case of appendicitis in a patient with Kartagener syndrome is here reported.	0
Kidney diseases are becoming a major cause of global burden with high mortality and morbidity. The origins of most kidney diseases are known, but for some the exact aetiology is not yet understood. Dermatoglyphics is the scientific study of epidermal ridge patterns and it has been used as a non-invasive diagnostic tool to detect or predict different medical conditions that have foetal origin. However, there have been a limited number of studies that have evaluated a dermatoglyphic relationship in different kidney diseases. The aim of this review was to systematically identify, review and appraise available literature that evaluated an association of different dermatoglyphic variables with kidney diseases. This review is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. The PubMed(®) (Medline), POPLINE, Cochrane Library and Trip Database and grey literature sources such as OpenGrey, Google Scholar, and Google were searched to earliest date to 17 April 2014. Of the 36 relevant publications, 15 were included in the review. Of these studies, there are five case reports, seven case series and three comparative studies. Possible association of dermatoglyphics with Wilms tumor (WT) had been evaluated in two comparative studies and one case series that found fewer whorls and a lower mean total ridge count (TRC). Another study evaluated adult polycystic kidney disease (APCD) type III that revealed lower TRC means in all cases. All other case series and case reports describe dermatoglyphics in various kidney disease such as acro-renal-ocular syndrome, potter syndrome, kabuki makeup syndrome, neurofaciodigitorenal syndrome, syndactyly type V, ring chromosome 13 syndrome, trisomy 13 syndrome and sirenomelia. It is evident that whorl pattern frequency and TRC have been used widely to investigate the uncertainty related to the origin of several kidney diseases such as WT and APCD type III. However, small sample sizes, possibly methodological issues, and discrepancy in the make up between cases and control groups limits interpretation of any significant findings. Future studies with proper protocol, adequate cases, and control groups may provide stronger evidence to resolve uncertainty related to the aetiology of kidney diseases.	0
OBJECTIVE: We aimed to report the clinical picture of two asymptomatic daughters of a patient with autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) due to a mutation in the DNA (cytosine-5-)-methyltransferase gene, DNMT1. METHODS: Clinical assessment based on history, neurologic examination, sleep recordings, neurophysiologic neuroimaging, and genetic tests was performed. RESULTS: History and neurologic examination in both subjects were unremarkable. Genetic analysis disclosed in both the paternally-inherited heterozygous point mutation in the DNMT1 gene. Sleep recordings found sleep-onset rapid eye movement periods (SOREMPs) and proton magnetic resonance spectroscopy (MRS) revealed increased cerebellar myoinositol (mI) in both subjects. Auditory and ophthalmologic investigations as well as structural brain magnetic resonance imaging (MRI) scans revealed no abnormalities. CONCLUSIONS: The two asymptomatic carriers of the heterozygous DNMT1 mutation for ADCA-DN, a late-onset neurodegenerative disease, presented with SOREMPs associated with an increase of mI in the brain, a marker of glial cell activity and density characteristic of early stages of neurodegenerative diseases. Therefore, SOREMPs may precede the clinical picture of ADCA-DN as an early polysomnographic marker of central nervous system involvement detected by MRS.	0
Dentatorubral-pallidoluysian atrophy (DRPLA) is an incurable autosomal dominant disease caused by an expansion of a CAG repeats in ATN1 gene encoding atrophin 1 protein. Here we report the generation of IBCHi001-A, an induced pluripotent stem cell (iPSC) line derived from DRPLA patient fibroblasts using non-integrative reprogramming technology with OCT4, SOX2, cMYC and KLF4 reprogramming factors. The pluripotency of iPSC was confirmed by immunocytochemistry and PCR for pluripotency markers and by the ability to form three germ layers in vitro. The established iPSC line offers a useful resource to study the pathogenesis of DPRLA.	0
Tyrosinemia type III is the rarest type of tyrosinemia, because of a mutation in 4-OH-phenylpyruvate dioxygenase (HPD). This causes two different types of diseases with different modes of inheritance: tyrosinemia type III and hawkinsinuria. Hawkinsinuria is an autosomal dominant disease, which presents a failure to thrive and metabolic acidosis; however, the liver is not affected. P.A33T heterozygous mutation was reported by Tomoeda et al. to cause hawkinsinuria. This case report will present the first case of an Egyptian-Lebanese male who developed direct hyperbilirubinemia and was found to have tyrosinemia type III, due to elevated tyrosine levels in the blood and tyrosine derivatives in the urine, but genetic testing revealed a P.A33T heterozygous mutation, a cause of hawkinsinuria.	0
MATERIAL:Linked-read whole genome sequencing (WGS) presents a new opportunity for cost-efficient singleton sequencing in place of traditional trio-based designs while generating informative-phased variants, effective for recessive disorders when parental DNA is unavailable. METHODS:We have applied linked-read WGS to identify novel causes of Meier-Gorlin syndrome (MGORS), a condition recognised by short stature, microtia and patella hypo/aplasia. There are eight genes associated with MGORS to date, all encoding essential components involved in establishing and initiating DNA replication. RESULTS:Our successful phasing of linked-read data led to the identification of biallelic rare variants in four individuals (24% of our cohort) in DONSON, a recently established DNA replication fork surveillance factor. The variants include five novel missense and one deep intronic variant. All were demonstrated to be deleterious to function; the missense variants all disrupted the nuclear localisation of DONSON, while the intronic variant created a novel splice site that generated an out-of-frame transcript with no residual canonical transcript produced. CONCLUSION:Variants in DONSON have previously been associated with extreme microcephaly, short stature and limb anomalies and perinatal lethal microcephaly-micromelia syndrome. Our novel genetic findings extend the complicated spectrum of phenotypes associated with DONSON variants and promote novel hypotheses for the role of DONSON in DNA replication. While our findings reiterate that MGORS is a disorder of DNA replication, the pathophysiology is obviously complex. This successful identification of a novel disease gene for MGORS highlights the utility of linked-read WGS as a successful technology to be considered in the genetic studies of recessive conditions.	0
Information on the outcome of pregnancy was collected on 92 fetuses with cystic hygroma or nuchal pad, identified prenatally. Forty three (47% of the total) were associated with abnormal karyotype. Twenty five (27%) had normal karyotype but an additional abnormality was identified on ultrasound scan. There were 10 liveborn babies in this group of whom seven had significant problems postnatally. In twenty four (26%) cases the cystic hygroma or nuchal pad was an isolated finding. Seventeen (89% of those in which the pregnancy was electively continued) were liveborn and reported to be normal. Those with a normal karyotype, no other anomaly identified on antenatal scan, and smaller non-septate lesions have a good prognosis.	0
Reconstruction of the aortic arch in type B interruption requires extensive mobilization of the descending aorta and the proximal branches of the arch to perform a tension-free anastomosis. The association of a coexistent type II aortopulmonary window and an aberrant subclavian artery reduces the degree of mobility that can be achieved by dissection alone, and it usually entails sacrifice of the aberrant artery to achieve satisfactory mobilization. We report a novel technique to use the aberrant subclavian artery as autologous tissue in the reconstruction of the aortic arch for repair of type B interruption associated with type II aortopulmonary window.	0
Peter plus syndrome (PPS) is a rare, hereditary (autosomal recessive) disorder characterized by a mutation in the beta-1,3-galactosyltransferase-like gene (chromosome 13q12), which causes impaired glycosylation of several structural and functional proteins throughout the body. Clinical signs and symptoms of PPS are highly variable and include structural malformations affecting multiple organ systems including central nervous system. We aim to discuss a neurosurgeon's perspective to PPS in this report. A 2-year-old boy presented with congenital dysmorphic facies, bilateral central corneal opacities, delayed developmental milestones, short-stature (75cm), rhizomelia with brachydactyly, and history of surgery for anal atresia on the second day of life. Screening craniospinal magnetic resonance imaging revealed mild ventriculomegaly, cavum septum pellucidum, cavum velum interpositum, vermian hypoplasia, and normal spine. Cytogenetic analysis showed a mutation in the beta-1,3-galactosyltransferase-like gene on chromosome 13. Clinical picture in our patient suggested the diagnosis of PPS. Parents often seek ophthalmological consultation due to visual impairment predominantly, and this syndrome largely remains unknown among neurosurgeons. Nonetheless, babies with PPS may present with neurological symptoms such as seizures, spastic diplegia, tinnitus, or hearing loss as well as a life-threatening neurosurgical emergency arising due to raised intracranial pressure. Therefore, the role of neurosurgeon becomes crucial in managing these cases.	0
Sperm motility is the most important parameter involved in the fertilization process and it is strictly required for reproductive success. Although sperm movements are essential for the physiologic fertilization process, the data, deriving from studies focused on the research of altered cell pathways involved in asthenozoospermia, offer only limited information about the molecular mechanism underlying sperm motility. The aim of this study was to identify proteins involved in human sperm motility deficiency by using label-free mass-spectrometry liquid chromatography (LC-MS/MS). For this purpose, we selected sperm samples with three different classes of progressive motility: low, medium (asthenozoospermic samples) and high (normozoospermic samples). We found that several differential expressed proteins in asthenozoospermic samples were related to energetic metabolism, suggesting an interesting link between bioenergetics pathways and the regulation of sperm motility, necessary for the flagellum movement. Therefore, our results provide strong evidence that mass spectrometry-based proteomics represents an integrated approach to detect novel biochemical markers of sperm motility and quality with diagnostic relevance for male infertility and unravel the molecular etiology of idiopathic cases.	0
There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers.	0
Phenotypic manifestations of the autosomal recessive form of VACTERL-hydrocephaly syndrome (David-O'Callaghan syndrome) and the X-linked recessive form (Hunter-MacMurray) syndrome are almost identical. The absence of cardiovascular malformations in cases with undoubtedly X-linked inheritance may be the only exception. The comparison of patients with David-O'Callaghan syndrome and nonclassified sporadic cases of VACTERL-hydrocephaly showed two marked differences. First, radial involvement (usually bilateral) occurred in all familial but only in 22 of 36 sporadic cases. Therefore, radial noninvolvement may be evidence against a genetic origin of the complex in a sporadic case. Second, predominantly severe forms of cardiovascular malformations were found in cases of David-O'Callaghan syndrome, whereas in sporadic cases almost all cardiovascular malformations were simple defects with minimal, if any, hemodynamic disturbances. The similarity of the spectrum and frequency of main manifestations of David-O'Callaghan and von Voss-Cherstvoy syndromes allows us to think that both of these syndromes actually might be 2 forms of one genetic entity. There are some syndromes with abnormalities of the brain (different for each syndrome) sharing the same limb defects (mainly preaxial), congenital heart defects, abnormalities of kidneys, and anal atresia/ectopia. Baller-Gerold syndrome, Steinfeld syndrome, XK-aprosencephaly, and DK-phocomelia (von Voss-Cherstvoy) syndrome as well as Mendelian forms of VACTERL-hydrocephaly syndromes fit into this "cerebro-cardio-radio-reno-rectal community."	0
Oculo-auriculo-vertebral spectrum (OAVS) is an uncommon congenital disorder of abnormal development of the first and second pharyngeal arches. This spectrum is characterized by craniofacial microsomia, epibulbar dermoids, ear abnormalities, renal and cardiac defects, and a wide range of vertebral segmentation and formation disorders. Frequently, the cervicothoracic spine is involved. Only recently, the morbidity attributed to the spinal abnormalities has gained attention. Strategy and timing of spine surgery has become increasingly important in patients with OAVS. Here, we report a case of OAVS with characteristic vertebral cervical and thoracic involvement and its sequelae requiring multiple spinal procedures, further complexed by an unprecedented occult tethered cord syndrome, which was successfully treated by surgical detethering. In this context, the recent literature on spinal anomalies is reviewed.	0
Mesomelic dysplasias are a group of skeletal disorders characterised by shortness of the middle limb segments (mesomelia). They are divided into 11 different categories. Among those without known molecular basis is mesomelic dysplasia Savarirayan type, characterised by severe shortness of the middle segment of the lower limb.To identify the molecular cause of mesomelic dysplasia Savarirayan type.We performed array comparative genomic hybridisation in three unrelated patients with mesomelic dysplasia Savarirayan type and identified 2 Mb overlapping de novo microdeletions on chromosome 6p22.3. The deletions encompass four known genes: MBOAT1, E2F3, CDKAL1 and SOX4. All patients showed mesomelia of the lower limbs with hypoplastic tibiae and fibulae. We identified a fourth patient with intellectual disability and an overlapping slightly larger do novo deletion also encompassing the flanking gene ID4. Given the fact that the fourth patient had no skeletal abnormalities and none of the genes in the deleted interval are known to be associated with abnormalities in skeletal development, other mutational mechanisms than loss of function of the deleted genes have to be considered. Analysis of the genomic region showed that the deletion removes two regulatory boundaries and brings several potential limb enhancers into close proximity of ID4. Thus, the deletion could result in the aberrant activation and misexpression of ID4 in the limb bud, thereby causing the mesomelic dysplasia.Our data indicate that the distinct deletion 6p22.3 is associated with mesomelic dysplasia Savarirayan type featuring hypoplastic, triangular-shaped tibiae and abnormally shaped or hypoplastic fibulae.	0
BACKGROUND:The Waterhouse-Friderichsen syndrome (WFS) is a serious illness associated with a high mortality rate and characterized by septic shock and signs of adrenocortical insufficiency. CASE DESCRIPTION:A 33-year-old male was seen in the emergency department with severe abdominal and back pain with diffuse mottled skin and rapidly progressive petechiae all over his body. Laboratory results showed severe lactate acidosis with renal dysfunction and indications of diffuse intravascular coagulation. Because he had signs of progressive septic shock, the patient was admitted to the ICU. There he subsequently developed hypoglycaemia (glucose < 0.1 mmol/l) and CPR had to be performed twice - the patient died shortly afterwards. Autopsy showed bilateral necrosis and haemorrhage of the adrenal glands, indicative of the diagnosis of WFS. Streptococcus pneumoniae was identified. CONCLUSION:In case of sepsis, with fever, rapidly expanding petechiae and purpura the Waterhouse-Friderichsen syndrome should be considered. Intensive therapy with antibiotics, fluids, vasopressors, and corticosteroids should be initiated immediately.	0
Mucopolysaccharidosis Type II (MPS II; Hunter syndrome) is an X- linked lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS). IDS deficiency leads to primary accumulation of dermatan sulfate (DS) and heparan sulfate (HS). MPS II is both multi-systemic and progressive. Phenotypes are classified as either attenuated or severe (based on absence or presence of central nervous system impairment, respectively).Current treatments available are intravenous enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), anti-inflammatory treatment, and palliative care with symptomatic surgeries. Clinical trials are being conducted for intrathecal ERT and gene therapy is under pre-clinical investigation. Treatment approaches differ based on age, clinical severity, prognosis, availability and feasibility of therapy, and health insurance.This review provides a historical account of MPS II treatment as well as treatment development with insights into benefits and/or limitations of each specific treatment.Conventional ERT and HSCT coupled with surgical intervention and palliative therapy are currently the treatment options available to MPS II patients. Intrathecal ERT and gene therapy are currently under investigation as future therapies. These investigative treatments are critical to address the limitations in treatment of the central nervous system (CNS).	0
INTRODUCTION:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy that previously lacked standardized therapeutic approaches. CD123 (interleukin-3 receptor alpha unit) is highly expressed in many hematologic malignancies, including BPDCN. Tagraxofusp-ezrs (tagraxofusp from herein) is an agent that consists of interleukin-3 fused to a truncated diphtheria toxin, targeting CD123. The Food and Drug Administration recently approved tagraxofusp as therapy for BPDCN for adults and children aged 2 years and older. AREAS COVERED:We discuss the history and clinical background of BPDCN along with tagraxofusp as its first-line therapy. We review the clinical efficacy and safety profile of tagraxofusp in adults including proposed sensitivity and resistance. Finally, we summarize tagraxofusp use in the pediatric population. EXPERT OPINION:Tagraxofusp is a newly approved therapy for BPDCN, a hematologic malignancy that has overall historically poor outcomes. With its significant efficacy, many patients were successfully bridged to stem cell transplantation in the clinical trial leading to its ultimate approval. Clinical awareness for major toxicities, including capillary leak syndrome will be a critical aspect of using this novel agent. In the future, investigation of its use in other hematologic malignancies and expansion of clinical trials in pediatric populations with BPDCN are warranted.	0
Introduction:Idiopathic hypereosinophilic syndrome is defined as persistently elevated peripheral blood absolute eosinophil count of more than 1.5 × 109/L for at least six months with no obvious secondary cause. Case Presentation:We report the case of a 26-year-old gentleman of Malay ethnicity who presented to the medical department with a three-week history of abdominal distension associated with dyspepsia and epigastric pain. Physical examination revealed ascites. The complete blood count portrayed peripheral leucocytosis with eosinophilia of 8.84 × 109/L. Parasitic serology was negative. Paracentesis analysis showed exudative ascites with an absolute eosinophil count of 8 × 109/L. He was referred to the haematology department. He was noticed to have bilateral tonsillitis and pruritic skin rash at the legs. There were no palpable lymph nodes or organomegaly. A peripheral blood film showed 44% eosinophils with no excess blasts. Clonal eosinophilic fusion studies did not detect FIP1L1-PDGFRA mutation. JAK2 V617F and BCR-ABL1 mutations were undetected. Serum B12 and tryptase levels were normal. A whole-body computed tomography imaging showed bowel wall thickening at the duodenum, jejunum, ileum, rectosigmoid and splenic flexure. Sections of fragments taken from the endoscopy showed features of eosinophilic gastritis and colitis on histology. Bone marrow biopsy depicted marked eosinophilia. He was started on oral imatinib mesylate 200 mg daily and oral prednisolone 0.5 mg/kg daily which was tapered based on response. He achieved complete remission and is now asymptomatic. Conclusion:The diagnosis of hypereosinophilic syndrome should be considered in a patient with unexplained ascites. Secondary sinister causes such as malignancy should always be excluded.	0
As an essential vitamin, the role of riboflavin in human diet and health is increasingly being highlighted. Insufficient dietary intake of riboflavin is often reported in nutritional surveys and population studies, even in non-developing countries with abundant sources of riboflavin-rich dietary products. A latent subclinical riboflavin deficiency can result in a significant clinical phenotype when combined with inborn genetic disturbances or environmental and physiological factors like infections, exercise, diet, aging and pregnancy. Riboflavin, and more importantly its derivatives, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), play a crucial role in essential cellular processes including mitochondrial energy metabolism, stress responses, vitamin and cofactor biogenesis, where they function as cofactors to ensure the catalytic activity and folding/stability of flavoenzymes. Numerous inborn errors of flavin metabolism and flavoenzyme function have been described, and supplementation with riboflavin has in many cases been shown to be lifesaving or to mitigate symptoms. This review discusses the environmental, physiological and genetic factors that affect cellular riboflavin status. We describe the crucial role of riboflavin for general human health, and the clear benefits of riboflavin treatment in patients with inborn errors of metabolism.	0
To evaluate the effect of amyloid imaging on clinical decision making.We conducted a retrospective analysis of 140 cognitively impaired patients (mean age 65.0 years, 46% primary β-amyloid (Aβ) diagnosis, mean Mini-Mental State Examination 22.3) who underwent amyloid (Pittsburgh compound B [PiB]) PET as part of observational research studies and were evaluated clinically before and after the scan. One hundred thirty-four concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed for changes between the pre- and post-PET clinical diagnosis (from Aβ to non-Aβ diagnosis or vice versa) and Alzheimer disease treatment plan. The association between PiB/FDG results and changes in management was evaluated using χ(2) and multivariate logistic regression. Postmortem diagnosis was available for 24 patients (17%).Concordance between scan results and baseline diagnosis was high (PiB 84%, FDG 82%). The primary diagnosis changed after PET in 13/140 patients (9%) overall but in 5/13 (38%) patients considered pre-PET diagnostic dilemmas. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (unadjusted p < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (adjusted p = 0.00013). Changes in treatment were associated with discordant PiB in patients with non-Aβ diagnoses (adjusted p = 0.028), while FDG had no effect on therapy. Both PiB (96%) and FDG (91%) showed high agreement with autopsy diagnosis.PET had a moderate effect on clinical outcomes. Discordant PiB had a greater effect than discordant FDG, and influence on diagnosis was greater than on treatment. Prospective studies are needed to better characterize the clinical role of amyloid PET.	0
Angiomatoid fibrous histiocytoma is a rare soft tissue tumor usually discovered in young individuals. This tumor is often mistaken for a hematoma and typically misdiagnosed. It is commonly found in the extremities and may be associated with a site of recent or previous trauma. Characteristic histology includes nodules of histiocytoid spindle cells with pseudoangiomatoid spaces, fibrous pseudocapsules, and lymphoid cuffing. We describe the case of an 8-year-old girl who presented after incision and drainage of a superficial thigh lesion and experienced subsequent chronic bleeding of her wound. Her initial presentation was concerning for an underlying bleeding disorder, and laboratory analysis uncovered a paraneoplastic platelet function disorder that resolved with therapy of the primary tumor.	0
In children, differentiated thyroid carcinoma is a rare condition. Early diagnosis is not always easy, because of the lack of clinical symptoms, but it has a pivotal role in performing a correct therapeutic process. The study describes three cases of papillary thyroid carcinoma. None of the three patients had a positive familiarity or exposure to risk factors. In two cases, the tumor occurred as a non-injurious swelling in the anterior cervical region, in the other case it occurred with a latero-cervical lymphadenopathy that had been persistent for a year. In the first two patients we made a certain diagnosis by the needle aspiration of the thyroid nodule; in the other case the diagnosis was made by surgical exeresis and histological analysis of the lymph nodes. We also performed blood chemistry and hormonal tests, neck ultrasound, chest x-ray. The three children underwent total thyroidectomy and two of them also underwent right-sided cervical lymph node exeresis because there was the presence of metastasis. In our experience, the best therapeutic strategy for children with differentiated thyroid carcinoma is the total thyroidectomy, followed or not by latero-cervical lymph node exeresis and radioiodiotherapy. The removal of the whole gland reduces the risk of relapse.	0
Lipodystrophies are a heterogeneous group of congenital or acquired disorders, characterized by partial or generalized loss of adipose tissue. Familial partial lipodystrophy (FPLD) presents with genetic and phenotypic variability with insulin resistance, hypertriglyceridemia and hepatic steatosis being the cardinal metabolic features. The severity of the metabolic derangements is in proportion with the degree of lipoatrophy. The underpinning pathogenetic mechanism is the limited capacity of adipose tissue to store lipids leading to lipotoxicity, low-grade inflammation, altered adipokine secretion and ectopic fat tissue accumulation. Advances in molecular genetics have led to the discovery of new genes and improved our knowledge of the regulation of adipose tissue biology. Diagnosis relies predominantly on clinical findings, such as abnormal fat tissue topography and signs of insulin resistance and is confirmed by genetic analysis. In addition to anthropometry and conventional imaging, new techniques such as color-coded imaging of fat depots allow more accurate assessment of the regional fat distribution and differentiation of lipodystrophic syndromes from common metabolic syndrome phenotype. The treatment of patients with lipodystrophy has proven to be challenging. The use of a human leptin analogue, metreleptin, has recently been approved in the management of FPLD with evidence suggesting improved metabolic profile, satiety, reproductive function and self-perception. Preliminary data on the use of glucagon-like peptide 1 receptor agonists (GLP1 Ras) and sodium-glucose co-transporter 2 (SGLT2) inhibitors in cases of FPLD have shown promising results with reduction in total insulin requirements and improvement in glycemic control. Finally, investigational trials for new therapeutic agents in the management of FPLD are underway.	0
Progressive deterioration of neuroimaging and electroencephalography (EEG) had been described in rhizomelic chondrodysplasia punctata (RCDP); however, serial EEG data showing sequential EEG changes(before and after seizure onset) is lacking. We report a child with a diagnosis of type 1 RCDP, who had a progressive decline in EEG and radiologic findings over a 5 year period. Her first EEG was normal at the age of 8 months. Follow-up EEG at the age of 2 years showed a mild background slowing as well as frequent 1-2 Hz central-parietal spike wave with midline involvement. Just before 3 years of age, she started to seizures, when the EEG showed further worsening with frequent multifocal spikes and bursts of generalized high amplitude spike and spike-wave discharges. The transition of EEG from normal background to the appearance of focal epileptiform abnormality before the seizure onset followed by further deterioration at the seizure onset had not been reported as per our knowledge. This study emphasizes that serial EEGs may provide valuable information about impending seizure activity. Further studies are needed to calculate the lag time between the detection of epileptiform activities and the onset of clinical seizure activities. In addition, research studies are warranted to determine if early (before or at the onset of epileptogenesis rather than after seizure onset) use of replacement therapy or antiepileptic therapy (antiepileptic drugs or diet) can modify epilepsy severity and neurologic prognosis in this devastating disease.	0
Background:Congenital generalized lipodystrophy (CGL) is a rare disorder characterized by the lack of adipose tissue and metabolic complications with predominantly autosomal recessive inheritance. There are 6 different genes known to cause CGL with 4 main types recognized to date, which differ by the degree of fat loss, association with mental retardation and metabolic disorders, with CGL type 1 and 2 being the most common. Twenty seven cases of СGL type 4 from Japan, Oman, UK, Turkey, Mexico, Saudi Arabia, USA were reported previously. This report details our clinical experience with the first patient from Russia with CGL type 4. Case presentation:A 36-year-old patient, who has been suffering from generalized lipoatrophy since the first months of life and myopathy and gastrointestinal dysmotility since early childhood, developed dysmenorrhea and diabetes mellitus at the age of 19, bilateral cataracts when she was only 22 y.o., osteoporosis with vitamin D deficiency and hypocalcemia at the age of 28, diabetic foot syndrome and hyperuricemia when she was 35 y.o. Sequencing of lipodystrophy candidate genes detected a novel pathogenic homozygous variant p.631G < T: p.E211X in the CAVIN1 gene, confirming the diagnosis of CGL type 4. Conclusions:In comparison with previously reported patients with CGL type 4, our patient has diabetes mellitus, vitamin D deficiency, hypocalcemia, bilateral cataracts and hyperuricemia. All these manifestations are known to be associated with other lipodystrophy syndromes, but to our knowledge it is the first time they have been reported to be associated with CGL type 4.	0
The effectiveness of chemotherapy or chemoradiotherapy for diffuse astrocytoma (DA) has been largely unknown until recently. However, a randomized controlled study (RTOG 9802) showed that adding of procarbazine, CCNU, and vincristine (PCV) chemotherapy to fractionated radiotherapy (FRT) in patients with "high-risk" WHO grade II gliomas, including DA, has significant positive impact on both progression-free survival and overall survival. Effectiveness of temozolomide (TMZ) in cases of low-grade gliomas was also reported, and a randomized phase III trial comparing FRT alone or in combination with TMZ in cases of unresectable DA (JCOG 1303) is currently ongoing.	0
Osteogenesis imperfecta (OI) is a heterogeneous connective tissue disorder characterized by repeated fractures and skeletal disorders. At present, bisphosphonate (BP) therapy is the gold standard for OI treatment. The present retrospective study evaluated the effect of BP therapy on tooth development and eruption of permanent teeth in a cohort of children receiving pamidronate. Three groups were studied: patients with OI who were treated with BPs (n = 45), patients with OI who were not treated with BPs (n = 117), and age- and gender-matched healthy controls (n = 121). Dental age, dental maturity, and tooth eruption were assessed on panoramic radiographs using the methods of Demirjian et al. (Hum Biol 45(2):211-227, 1973) and Haavikko (Suom Hammaslaak Toim 66(3):103-170, 1970) and were evaluated using the t-test, Chi-square test, and the Mann-Whitney U test. Dental age in the study group was significantly (p < 0.05) lower than chronological age compared with both control groups. Dental maturity and the eruption of permanent teeth were also significantly (p < 0.05) delayed in the study group in relation to the two control groups. The dental age was significantly lower (p < 0.001) in patients with OI type III treated with BPs compared with healthy controls and the dental maturation was significantly delayed in patients with OI type IV treated with BPs compared with those not treated. In conclusion, BP therapy in OI patients seems to lower the dental age, delay the dental maturity, and tooth eruption. BP administration before 2 years of age might be a contributing factor.	0
We describe a rare case of newborn with aortic atresia and transposition of the great arteries who underwent successful surgical repair. To the best of our knowledge, no such case has been previously reported. We demonstrated that, even with a complex diagnosis, the patient could survive after rapid two-stage Norwood procedure.	0
AIM:To compare whether aphakic contact lenses or secondary iris-claw intraocular lenses are superior in the refractive management post-pars plana vitreolensectomy in a pedigree with an FBN1 mutation causing non-syndromic ectopia lentis (NSEL) with retinal detachment (RD). METHODS:Eight affected individuals had pars plana vitreolensectomy for bilateral ectopia lentis (EL). Twelve eyes of 6 patients had secondary iris-claw intraocular lenses inserted and 4 eyes of 2 patients were managed with contact lenses. Rhegmatogenous retinal detachment (RRD) was treated when necessary. Pre- and post-operative assessment included visual acuity, endothelial cell count and dilated fundal examination. RESULTS:Macula-on RRD was present in all individuals >18y, 64% (7/11 eyes) presenting post-vitreolensectomy with 57% having bilateral non-synchronous RRD. Surgical aphakia was managed with iris-fixated intraocular lenses (IOL group, n=6), or contact lenses (CL group, n=2). Visual acuity ≥0.3 logMAR (driving standard) was achieved in 75% of IOL group eyes and 25% of the CL group eyes. Mean loss of corneal endothelial cell count in the IOL group was 4% at 2y post-operative. CONCLUSION:In this cohort, refractive management with iris-claw IOLs provided superior outcomes to contact lenses and the authors recommend this as the optimal refractive correction in EL patients.	0
In 1974, Lenz and Majewski gave a short description of a 2-year-old girl with generalized hyperostosis, proximal symphalangism, syndactyly, brachydactyly, cutis laxa, mental retardation, marked hypertelorism, and enamel hypoplasia. This disorder was later named Lenz-Majewski hyperostotic dwarfism. We describe the reexamination of the original patient at the age of 30 years.	0
X-linked inhibitor of apoptosis (XIAP) deficiency, also known as X-linked lymphoproliferative syndrome type 2 (XLP2), is a rare inherited primary immunodeficiency resulting from the XIAP (also known as BIRC4) mutation. XIAP deficiency is mainly associated with familial hemophagocytic lymphohistiocytosis (HLH) phenotypes, and genetic testing is crucial in diagnosing this syndrome. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only successful strategy for the treatment of this disease; however, a limited number of studies has been published concerning the outcomes of allogeneic HSCT in patients with XIAP deficiency. The present study reported a successful allogeneic HSCT performed to treat XIAP deficiency in a Chinese boy presenting with HLH. Polymerase chain reaction and DNA sequencing were performed to confirm the diagnosis of XIAP deficiency, and allogeneic HSCT was performed. Genetic tests revealed a two-nucleotide deletion (c.1021_1022delAA) in the patient, which was inherited from his mother, and resulted in frameshift mutation and premature stop codon (p.N341fsX348); this is considered to be a disease-causing mutation. The XIAP deficiency patient underwent allogeneic HSCT, receiving busulfan-containing reduced intensity myeloablative conditioning regimen, with a good intermediate follow-up result obtained. Therefore, genetic testing is essential to confirm the diagnosis of XIAP deficiency and detect the carrier of mutation. The present case study may promote the investigation of allogeneic HSCT in patients with XIAP deficiency.	0
OBJECTIVES: To evaluate the natural history of cystic hygroma (CH) in fetal and neonatal periods to enrich parental counselling. Ultrasonographic characteristics, associated syndromes, chromosomal anomalies, fetal cardiac pathology and life after birth were considered. STUDY DESIGN: From May 1985 to September 2010, 207 pregnancies were seen the authors' centre with suspected vascular-lymphatic fetal malformation: 156 of them had CH. Cases were followed up by telephone interview to determine fetal and neonatal outcomes. Chi-squared test was used for statistical analysis. RESULTS: Among the 156 cases of CH, the condition was septated in 75% of cases, associated with other pathologies in 74%, and retronuchal in 88%. Intrauterine regression was seen in 36% of cases, with complete disappearance in 77%. The karyotype was normal in 55% of cases. Follow-up was completed in 85 cases and revealed 54 spontaneous abortions (63%) and 31 live births (37%). Amongst these, 21 out of 31 children had a favourable outcome (68%). A negative embryo-fetal outcome was significantly associated with CH being associated with other pathologies, such as hydrops, retronuchal position and altered karyotype. Spontaneous regression or resolution of CH was associated with live births. CONCLUSIONS: The management of pregnancies with a diagnosis of fetal CH requires knowledge of natural history of the malformation for appropriate parental counselling.	0
BACKGROUND:Chromosomal microarray analysis (CMA) is nowadays widely used in the diagnostic path of patients with clinical phenotypes. However, there is no ascertained evidence to date on how to assemble single/combined clinical categories of developmental phenotypic findings to improve the array-based detection rate. METHODS:The Italian Society of Human Genetics coordinated a retrospective study which included CMA results of 5,110 Italian patients referred to 17 genetics laboratories for variable combined clinical phenotypes. RESULTS:Non-polymorphic copy number variants (CNVs) were identified in 1512 patients (30%) and 615 (32%) present in 552 patients (11%) were classified as pathogenic. CNVs were analysed according to type, size, inheritance pattern, distribution among chromosomes, and association to known syndromes. In addition, the evaluation of the detection rate of clinical subgroups of patients allowed to associate dysmorphisms and/or congenital malformations combined with any other single clinical sign to an increased detection rate, whereas non-syndromic neurodevelopmental signs and non-syndromic congenital malformations to a decreased detection rate. CONCLUSIONS:Our retrospective study resulted in confirming the high detection rate of CMA and indicated new clinical markers useful to optimize their inclusion in the diagnostic and rehabilitative path of patients with developmental phenotypes.	0
Pigmentation, defined as the placement of pigment in skin, hair, and eyes for coloration, is distinctive because the location, amount, and type of pigmentation provides a visual manifestation of genetic heterogeneity in pathways regulating the pigment-producing cells, melanocytes. The scope of this genetic heterogeneity in humans ranges from normal to pathological pigmentation phenotypes. Clinically, normal human pigmentation encompasses a variety of skin and hair color as well as punctate pigmentation such as melanocytic nevi (moles) or ephelides (freckles), while abnormal human pigmentation exhibits markedly reduced or increased pigment levels, known as hypopigmentation and hyperpigmentation, respectively. Elucidation of the molecular genetics underlying pigmentation has revealed genes important for melanocyte development and function. Furthermore, many pigmentation disorders show additional defects in cells other than melanocytes, and identification of the genetic insults in these disorders has revealed pleiotropic genes, where a single gene is required for various functions in different cell types. Thus, unravelling the genetics of easily visualized pigmentation disorders has identified molecular similarities between melanocytes and less visible cell types/tissues, arising from a common developmental origin and/or shared genetic regulatory pathways. Herein we discuss notable human pigmentation disorders and their associated genetic alterations, focusing on the fact that the developmental genetics of pigmentation abnormalities are instructive for understanding normal pathways governing development and function of melanocytes.	0
We report the clinical and molecular characteristics of 12 Spanish families with multiple members affected with Léri-Weill dyschondrosteosis (LWD) or Langer mesomelic dysplasia (LMD), who present the SHOX (short stature homeobox gene) mutation p.A170P (c.508G>C) in heterozygosity or homozygosity, respectively. In all studied families, the A170P mutation co-segregated with the fully penetrant phenotype of mesomelic limb shortening and Madelung deformity. A shared haplotype around SHOX was observed by microsatellite analysis, confirming the presence of a common ancestor, probably of Gypsy origin, as 11 of the families were of this ethnic group. Mutation screening in 359 Eastern-European Gypsies failed to identify any carriers. For the first time, we have shown SHOX expression in the human growth plate of a 22-week LMD fetus, homozygous for the A170P mutation. Although the mutant SHOX protein was expressed in all zones of the growth plate, the chondrocyte columns in the proliferative zone were disorganized with the chondrocytes occurring in smaller columnal clusters. We have also identified a novel mutation at the same residue, c. 509C>A (p.A170D), in two unrelated Spanish LWD families, which similar to A170P mutation impedes nuclear localization of SHOX. In conclusion, we have identified A170P as the first frequent SHOX mutation in Gypsy LWD and LMD individuals.	0
Autoimmune autonomic ganglionopathy (AAG) is a rare acquired immune-mediated disorder that leads to autonomic failure. It is sometimes complicated by mental and behavioral symptoms. We report a case of 72-year-old male with AAG who was admitted to the psychiatric department for prolonged severe delirium. Repeated loss of consciousness attributed to severe orthostatic hypotension disturbed recovery from delirium. In addition, intracerebral hemorrhage occurred during hospitalization, and this cerebrovascular event may have been substantially affected by unstable blood pressure due to AAG. This case suggests importance of differential diagnosis of AAG in patients with mental and behavioral symptoms accompanying severe autonomic failure.	0
Measles continues to be a threat in most European countries due to suboptimum vaccination coverage. Although measles leads to several complications, measles-related hemophagocytic lymphohistiocytosis (HLH) has been rarely reported. Herein, we present a case of a four-month-old male infant, the first child of unrelated, healthy parents, with no significant medical history or unexplained infant death in the family, otherwise healthy, who was diagnosed with measles-associated HLH and was successfully treated with IV dexamethasone and IV immunoglobulin (IVIG). Additionally, we review previously reported cases of HLH secondary to measles and highlight the diagnostic and therapeutic challenges associated with its early recognition and treatment. High suspicion, early recognition, and appropriate treatment are essential for a favorable outcome of measles-associated HLH.	0
Dyggve-Melchior-Clausen syndrome is a rare spondylo-epiphyseal disease, which almost constantly leads to both bilateral hip degeneration and dislocation. Few authors have reported to date the surgical management of this orthopaedic disorder. We present two new cases affecting siblings. One brother was treated by unilateral triple pelvic osteotomy combined with varus osteotomy of the proximal femur; the other was treated by bilateral Pemberton osteotomies with varus osteotomy of the proximal femur. At a respective 5-year and 3-year follow-up delay, both cases had evolved towards progressive subluxation recurrence along with severe hip degeneration. Based on both our experience and literature review, it seems that one should avoid operating these hips unless pain renders surgery mandatory. Total hip arthroplasty seems the only reliable surgical solution at the adult age and paediatric surgeons should keep in mind that previous femoral osteotomies will make it more challenging for adult orthopaedic surgeons to implant on a remodeled anatomy.	0
This case highlights an important lesson for laboratory genetic testing. Geneticists and Genetic Counselors should be aware that although rare, mosaic variegated aneuploidy should be considered if mosaic aneuploidies are observed on karyotype, particularly in the context of short stature.	0
BACKGROUND:Dyskeratosis congenita (DC) is a syndrome resulting from defective telomere maintenance. Immunodeficiency associated with DC can cause significant morbidity and lead to premature mortality, but the immunological characteristics and molecular hallmark of DC patients, especially young patients, have not been described in detail. METHODS:We summarize the clinical data of two juvenile patients with DC. Gene mutations were identified by whole-exome and direct sequencing. Swiss-PdbViewer was used to predict the pathogenicity of identified mutations. The relative telomere length was determined by QPCR, and a comprehensive analysis of lymphocyte subsets and CD57 expression was performed by flow cytometry. RESULTS:Both patients showed typical features of DC without severe infection. In addition, patient 1 (P1) was diagnosed with Hoyeraal-Hreidarsson syndrome due to cerebellar hypoplasia. Gene sequencing showed P1 had a compound heterozygous mutation (c.204G > T and c.178-245del) in PARN and P2 had a novel hemizygous mutation in DKC1 (c.1051A > G). Lymphocyte subset analysis showed B and NK cytopenia, an inverted CD4:CD8 ratio, and decreased naïve CD4 and CD8 cells. A significant increase in CD21low B cells and skewed numbers of helper T cells (Th), regulatory T cells (Treg), follicular regulatory T cells (Tfr), and follicular helper T cells (Tfh) were also detected. Short telomere lengths, increased CD57 expression, and an expansion of CD8 effector memory T cells re-expressing CD45RA (TEMRA) were also found in both patients. CONCLUSION:Unique immunologic abnormalities, CD8 T-cell senescence, and shortened telomere together as a hallmark occur in young DC patients before progression to severe disease.	0
Chromosome 6p duplication is very rare and clinically characterized by short stature, mental retardation, and congenital heart diseases. Patients with mental retardation may present with poor oral health conditions. Dental treatment may need to be performed under general anesthesia in such patients. Our case report deals with induction of general anesthesia to a patient with chromosome 6p duplication, for dental treatment. The selection of a nasotracheal tube of an appropriate size, because of the patient's short stature, was especially important for airway management. In the present case, the patient with chromosome 6p duplication was intubated with a nasotracheal tube, which was not age-matched but adapted to the height and physique of the patient.	0
BACKGROUND:To report the case of a patient with two distinct genetic systemic diseases - pseudoxanthoma elasticum (PXE) and Usher syndrome - confirmed by genetic testing. MATERIALS AND METHODS:Single Retrospective Case Report. RESULTS:A 36-year-old woman presented with acute central vision loss of the left eye (OS). Fundus exam revealed choroidal neovascularization OS in the setting of angioid streaks secondary to an underlying diagnosis of PXE. Unexpectedly, she also exhibited peripheral bony spicules with significant visual field constriction. Physical exam revealed skin papules on her neck and hearing loss. The presence of angioid streaks and skin findings was compatible with PXE; the etiology of her pigmentary retinopathy and hearing loss was elucidated using genetic testing. The patient was found to be compound heterozygous for pathogenic variants in both the ABCC6 and USH2A genes, confirming the diagnosis of two rare disorders in a single patient. CONCLUSIONS:PXE and Usher syndrome are rare systemic disorders that cause distinctive retinal abnormalities. This report highlights the importance of genetic testing in diagnosing uncommon hereditary retinal disorders and outlines the progression of disease over 6 years.	0
Previous studies have mainly examined emotion recognition through face processing in individuals with Williams syndrome (WS). Contextual integration is an automatic and basic comprehension ability emerged from distinct modalities. This ability requires sensation to global configuration and local elements. However, neurodevelopmental disorders are characterized by local-focusing and global-ignoring in visuospatial perception. This causes cognitive atypicality as compared to typical development, including atypical face processing and emotion recognition. These impairments might result in deficits in theory of mind and social cognition. People with WS demonstrate impaired false-belief attribution, which was reported to be improved with emotional cues. Yet, no previous study has examined knowledge of emotional language in people with WS, which might be one of the factors affecting the development of the theory of mind in people with WS. In the present study, we examined knowledge of emotional language in people with WS by testing three emotions: positive, negative, and neutral. Participants were asked to press buttons indexing emotions in reaction to auditory targets. In the emotional event study, people with WS demonstrated responses to positive events in the normal range, delayed responses to negative events, and deviant responses to neutral events. In the emotion word study, people with WS showed the lowest accuracy and longest reaction times for neutral words. These findings indicated asymmetrical and atypical knowledge of emotional language in people with WS, confirming that knowledge of emotional expressions influences the development of the theory of mind and social cognition.	0
Lacrimo-auriculo-dento-digital syndrome (LADD) is a rare autosomal dominant disorder arising from heterozygous mutations in the genes encoding fibroblast growth factor receptors two and three and the gene encoding the fibroblast growth factor 10. The characteristics associated with LADD are mainly related with hypoplasia or aplasia of lacrimal and salivary ducts, low cup-shaped ears, sensorineural or conductive hearing loss, abnormalities of teeth, and anomalies of the hands and feet. The purpose of this paper is to describe a 13-year-old female patient with a history of a blocked tear duct, mild hearing loss, congenitally missing teeth, tauro- dontism, and malformation of the fingers who was referred for a dental evaluation. She was diagnosed with LADD syndrome based on her clinical picture. (J Dent Child 2019;86(1):53-60)<br/> Received August 16, 2018; Last Revision November 8, 2018; Accepted November 9, 2018.	0
Increasing evidence points to the respiratory Complex II (CII) as a source and modulator of reactive oxygen species (ROS). Both functional loss of CII as well as its pharmacological inhibition can lead to ROS generation in cells, with a relevant impact on the development of pathophysiological conditions, i.e. cancer and neurodegenerative diseases. While the basic framework of CII involvement in ROS production has been defined, the fine details still await clarification. It is important to resolve these aspects to fully understand the role of CII in pathology and to explore its therapeutic potential in cancer and other diseases.	0
Meromelia is a rare skeletal abnormality characterized by the partial absence of at least one limb. Several mechanisms have been postulated to explain the etiopathogenesis of the disorder. Most of the cases of meromelia are reported to be sporadic. It can occur either in isolation or with other congenital malformations. VACTERL association, gastroschisis, atrial septal defect, proximal femoral focal deficiency, and fibular hemimelia are the congenital abnormalities reported to be in association with meromelia. However, no other congenital abnormalities in association with meromelia have been recorded to date. We herein present an unusual case of bilateral upper limb meromelia accompanied by unilateral oligodactyly and brachymesophalangy of the foot.	0
BACKGROUND AND AIMS:Phenylketonuria (PKU)-affected women may become pregnant, and dietary phenylalanine (Phe) intake must be adjusted according to Phe tolerance. We report our experience with maternal PKU in relation to genotype PKU heterogeneity. METHODS AND RESULTS:A total of 10 pregnancies in 7 PKU women (7 different genotypes) were followed up as part of personalized care. Phe tolerance during preconception and pregnancy was assessed by strict dietary control and weekly Phe measurement (blood spots) in relation to genotype. Most women had stopped PKU diet during childhood or adolescence and six pregnancies were unplanned; a phenylalanine-restricted diet was reinstituted soon after conception. Women were classified according to their Phe levels at birth screening and genotype. Phe tolerance increased systematically in the course of pregnancy in all cases, but the increase was different in subjects with classic PKU (cPKU) when compared with cases with mild hyperphenylalaninemia (mHPA), both on average (+297 mg/day in cPKU vs. 597 in mHPA; P = 0.017) and as percentage (+107% in cPKU vs. +17% in mHPA). Notably, Phe tolerance also varied in the same women in the course of different pregnancies, when body weight gain was also different. Two newborns from the same cPKU mother (unplanned pregnancies on free diet) were affected by congenital alterations. CONCLUSIONS:Several factors influence metabolic phenotype in maternal PKU, to an unpredictable extent even in the same woman. The number of maternal PKU cases is growing in dedicated Nutrition Units, and the burden associated with careful management of this condition for the health care system should be adequately considered.	0
OBJECTIVE:Elastin gene deletion or mutation leads to arterial stenoses due to vascular smooth muscle cell (SMC) proliferation. Human induced pluripotent stem cells-derived SMCs can model the elastin insufficiency phenotype in vitro but show only partial rescue with rapamycin. Our objective was to identify drug candidates with superior efficacy in rescuing the SMC phenotype in elastin insufficiency patients. Approach and Results: SMCs generated from induced pluripotent stem cells from 5 elastin insufficiency patients with severe recurrent vascular stenoses (3 Williams syndrome and 2 elastin mutations) were phenotypically immature, hyperproliferative, poorly responsive to endothelin, and exerted reduced tension in 3-dimensional smooth muscle biowires. Elastin mRNA and protein were reduced in SMCs from patients compared to healthy control SMCs. Fourteen drug candidates were tested on patient SMCs. Of the mammalian target of rapamycin inhibitors studied, everolimus restored differentiation, rescued proliferation, and improved endothelin-induced calcium flux in all patient SMCs except one Williams syndrome. Of the calcium channel blockers, verapamil increased SMC differentiation and reduced proliferation in Williams syndrome patient cells but not in elastin mutation patients and had no effect on endothelin response. Combination treatment with everolimus and verapamil was not superior to everolimus alone. Other drug candidates had limited efficacy. CONCLUSIONS:Everolimus caused the most consistent improvement in SMC differentiation, proliferation and in SMC function in patients with both syndromic and nonsyndromic elastin insufficiency, and offers the best candidate for drug repurposing for treatment of elastin insufficiency associated vasculopathy.	0
BACKGROUND:Some patients experience long-term declines in quality of life following meningioma resection, but associated factors are not well understood. OBJECTIVE:To investigate whether long-term declines in quality of life (specifically impaired adaptive functioning) after meningioma resection are associated with specific personality disturbances that often develop with lesions in ventromedial prefrontal cortex (vmPFC). METHODS: We studied 38 patients who underwent resection of meningioma, 18 of whom had vmPFC lesions and 20 with lesions elsewhere (non-vmPFC). A total of 30 personality characteristics were rated by spouse or family, and a neuropsychologist blindly rated adaptive functioning an average of 3.8 yr postresection. Relevant personality disturbance was defined by a priori process: the presence of "conjoint personality disturbance" required specific disturbances in at least 2 of 4 types of disturbance: executive disorders, disturbed social behavior, emotional dysregulation, and hypoemotionality. RESULTS:Fourteen patients had impaired adaptive functioning: 12 had vmPFC lesions and 2 had non-vmPFC lesions. Fourteen patients had conjoint personality disturbance, and 12 of them had impaired adaptive functioning. By contrast, among the 24 patients who did not have conjoint personality disturbance, only 2 had impaired adaptive functioning. Mediation analysis showed that the association between vmPFC lesions and impaired adaptive functioning was mediated by the negative impact of acquired personality disturbance on adaptive functioning. CONCLUSION:Anterior skull base meningiomas plus resection surgery may result in specific personality disturbances that are highly associated with impaired adaptive functioning at long-term follow-up. These patients may benefit from early counseling regarding potential personality changes and their implications for adaptive functioning.	0
Having reported spheroid body myopathy from Indiana (IN) inherited in an autosomal-dominant fashion several years ago, we now describe additional findings from the Oregon branch--briefly recorded earlier--and confirm earlier studies in another clinically affected IN member of this kinship demonstrating identical spheroid bodies within the myopathic muscle specimens. The spheroid bodies also contained increased amounts of desmin, alpha-B crystallin, and ubiquitin within muscle fibers. Our studies now have established that spheroid body myopathy is a member of the growing family of desminopathic neuromuscular conditions.	0
Patients diagnosed with pseudohypoparathyroidism type Ia (PHP Ia) suffer from hormonal resistance and abnormal postural features, in a condition classified as Albright hereditary osteodystrophy (AHO) syndrome. This syndrome is linked to a maternally inherited mutation in the GNAS complex locus, encoding for the GTPase subunit Gsα. Here, we investigated how platelet phenotype and omics analysis can assist in the often difficult diagnosis. By coupling to the IP receptor, Gsα induces platelet inhibition via adenylyl cyclase and cAMP-dependent protein kinase A (PKA). In platelets from seven patients with suspected AHO, one of the largest cohorts examined, we studied the PKA-induced phenotypic changes. Five patients with a confirmed GNAS mutation, displayed impairments in Gsα-dependent VASP phosphorylation, aggregation, and microfluidic thrombus formation. Analysis of the platelet phosphoproteome revealed 2,516 phosphorylation sites, of which 453 were regulated by Gsα-PKA. Common changes in the patients were: (1) a joint panel of upregulated and downregulated phosphopeptides; (2) overall PKA dependency of the upregulated phosphopeptides; (3) links to key platelet function pathways. In one patient with GNAS mutation, diagnosed as non-AHO, the changes in platelet phosphoproteome were reversed. This combined approach thus revealed multiple phenotypic and molecular biomarkers to assist in the diagnosis of suspected PHP Ia.	0
Split-hand/foot malformation (SHFM) is a genetic limb anomaly disturbing the central rays of the autopod. SHFM is a genetically heterogeneous disorder with variable expressivity inherited as syndromic and nonsyndromic forms. We provide an update of the clinical and molecular aspects of nonsyndromic SHFM. This rare condition is highly complex due to the clinical variability and irregular genetic inheritance observed in the affected individuals. Nonsyndromic SHFM types have been reviewed in terms of major molecular genetic alterations reported to date. This updated overview will assist researchers, scientists, and clinicians in making an appropriate molecular diagnosis, providing an accurate recurrence risk assessment, and developing a management plan.	0
Warsaw breakage syndrome (WABS) is a very rare recessive hereditary disease caused by mutations in the gene coding for the DNA helicase DDX11, involved in genome stability maintenance and sister cohesion establishment. Typical clinical features observed in WABS patients include growth retardation, facial dysmorphia, microcephaly, hearing loss due to cochlear malformations and, at cytological level, sister chromatid cohesion defects. Molecular bases of WABS have not yet been elucidated, due to lack of disease animal model systems and limited knowledge of the DDX11 physiological functions. However, WABS is considered to belong to the group of cohesinopathies, genetic disorders due to mutations of subunits or regulators of cohesin, the protein complex responsible for tethering sister chromatids from the time of their synthesis till they separate in mitosis. Recent evidences suggest that cohesin and its regulators have additional key roles in chromatin organization by promoting the formation of chromatin loops. This "non-canonical" function of cohesin is expected to impact gene transcription during cell differentiation and embryonic development and its dis-regulation, caused by mutation/loss of genes encoding cohesin subunits or regulators, could originate the developmental defects observed in cohesinopathies. Ethiopathogenesis of WABS is discussed in line with these recent findings and evidence of a possible role of DDX11 as a cohesin regulator.	0
OBJECTIVE:Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with diverse neuropsychiatric expression. Five genes were reported as PFBC causative when carrying pathogenic variants. Haploinsufficiency of SLC20A2, which encodes an inorganic phosphate importer, is a major cause of autosomal-dominant PFBC. However, PFBC remains genetically unexplained in a proportion of patients, suggesting the existence of additional genes or cryptic mutations. We analyzed exome sequencing data of 71 unrelated, genetically unexplained PFBC patients with the aim to detect copy number variations that may disrupt the expression of core PFBC-causing genes. METHODS:After the identification of a deletion upstream of SLC20A2, we assessed its consequences on gene function by reverse transcriptase droplet digital polymerase chain reaction (RT-ddPCR), an ex vivo inorganic phosphate uptake assay, and introduced the deletion of a putative SLC20A2 enhancer mapping to this region in human embryonic kidney 293 (HEK293) cells by clustered regularly interspaced short palindromic repeats (CRISPR) - CRISPR-associated protein 9 (Cas9). RESULTS:The 8p11.21 deletion, segregating with PFBC in a family, mapped 35 kb upstream of SLC20A2. The deletion carriers/normal controls ratio of relative SLC20A2 mRNA levels was 60.2% (P < 0.001). This was comparable with that of patients carrying an SLC20A2 premature stop codon (63.4%; P < 0.001). The proband exhibited a 39.3% decrease of inorganic phosphate uptake in blood (P = 0.015). In HEK293 cells, we observed a 39.8% decrease in relative SLC20A2 mRNA levels after normalization on DNA copy number (P < 0.001). DISCUSSION:We identified a deletion of an enhancer of SLC20A2 expression, with carriers showing haploinsufficiency in similar ranges to loss-of-function alleles, and we observed reduced mRNA levels after deleting this element in a cellular model. We propose a 3-step strategy to identify and easily assess the effect of such events. © 2020 International Parkinson and Movement Disorder Society.	0
Our aim was to add to the list of pseudodystonia published by Berlot et al. a relatively rare, but possible form, describing fibrodysplasia ossificans progressiva (FOP) as an entity that can mimic dystonia (accompanied with video). We also provide the first report on the botulinum toxin type A (BoNT/A) therapy in FOP. We describe potential mechanisms that can be responsible for the good outcome of BoNT/A therapy observed in our patient.	0
RATIONALE:Oculofaciocardiodental syndrome (OFCD) patients who show radiculomegaly are very rare. We treated a new OFCD patient orthodontically, and performed longitudinal observation for 30 years. New findings, termed calcified-dental-papillae (CDPs) beneath open-apices (OAs) of developing radiculomegalies, pulp-stone-like-calcifications (PSLCs) and the process of radiculomegaly development were observed. A novel mutation of BCL-6 interacting corepressor (BCOR) was identified. Cone-beam-computed-tomography (CBCT) images of the radiculomegalies clarified their morphology. PATIENT CONCERNS:A female patient and her parents were referred to orthodontic clinic for alignment of the teeth. DIAGNOSIS:A CDP that harbored bulbous-round-calcified-tissue in the dental papilla beneath the OA of a developing radiculomegaly was found radiographically. PSLCs were observed in the dental pulp. Genetic analysis revealed a novel mutation c.265G>A on Exon 4 and diagnosed as OFCD. CBCT images confirmed round-calcified-tissue and PSLC and that the length of an affected canine was 38.0 mm and calculated as +14.8SD. These novel findings were not observed in lateral incisors and molars. INTERVENTIONS:Observation was performed for 29 years and 3 months including orthodontic treatment for 2 years and 9 months. OUTCOME:Longitudinal follow-up for 26 years and 7 months after the treatment revealed that the development of radiculomegaly every few months or years, CDPs beneath OAs and PSLCs were observed. CDPs, PSLCs, and OAs were associated with radiculomegaly. The patient and the affected teeth including aligned teeth showed no particular change after the completion of the radiculomegaly. CBCT images showed bulbous-calcified-tissue and PSLCs in the mature dental pulp associated with radiculomegaly. LESSONS:The radiographical findings of CDP, OA and PSLC help early diagnose of OFCD and have importance for initiating orthodontic treatment until radiculomegaly completion.	0
McCune-Albright syndrome (MAS) is caused by postzygotic somatic activating mutations of GNAS and is classically characterized by the clinical triad of peripheral precocious puberty, café-au-lait pigmentation, and polyostotic fibrous dysplasia. It can also present with other hyperfunctioning endocrinopathies, including growth hormone excess, hyperprolactinemia, hypercortisolemia, hyperthyroidism, and renal phosphate wasting due to excess fibroblast growth factor 23. We review the clinical, biochemical, radiological, and genetic findings in a 7-year-old girl diagnosed with MAS at age 4 and then with autoimmune type 1 diabetes mellitus at age 7. While MAS is associated with hyperglycemia secondary to growth hormone excess and hypercortisolemia, an association with diabetes mellitus has not been demonstrated. We review the unique presentation of a patient with these two rare conditions.	0
BACKGROUND:Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease with autosomal dominant inheritance. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in more than 90% of cases submitted to molecular diagnosis. METHODS:We used data from the RiHHTa (Computerized Registry of Hereditary Hemorrhagic Telangiectasia) registry to describe genetic variants and to assess their genotype-phenotype correlation among HHT patients in Spain. RESULTS:By May 2019, 215 patients were included in the RiHHTa registry with a mean age of 52.5 ± 16.5 years and 136 (63.3%) were women. Definitive HHT diagnosis defined by the Curaçao criteria were met by 172 (80%) patients. Among 113 patients with genetic test, 77 (68.1%) showed a genetic variant in ACVRL1 and 36 (31.8%) in ENG gene. The identified genetic variants in ACVRL1 and ENG genes and their clinical significance are provided. ACVRL1 mutations were more frequently nonsense (50%) while ENG mutations were more frequently, frameshift (39.1%). ENG patients were significantly younger at diagnosis (36.9 vs 45.7 years) and had pulmonary arteriovenous malformations (AVMs) (71.4% vs 24.4%) and cerebral AVMs (17.6% vs 2%) more often than patients with ACVRL1 variants. Patients with ACVRL1 variants had a higher cardiac index (2.62 vs 3.46), higher levels of hepatic functional blood tests, and anemia (28.5% vs 56.7%) more often than ENG patients. CONCLUSIONS:ACVRL1 variants are more frequent than ENG in Spain. ACVRL1 patients developed symptomatic liver disease and anemia more often than ENG patients. Compared to ACVRL1, those with ENG variants are younger at diagnosis and show pulmonary and cerebral AVMs more frequently.	0
Enterohemorrhagic Escherichia coli (EHEC) is a highly pathogenic strain leading to hemorrhagic colitis and to the hemolytic-uremic syndrome (HUS) in humans. The mechanisms by which pathogenic E. coli infect and colonize humans leading to the typical disease pattern are in focus of many investigations. The adhesion of EHEC to epithelial cells by the coordinated translocation of receptor Tir and surface expression of corresponding adhesin intimin is a key event in host-pathogen-interaction. However, less is known about other adhesins encoded by EHEC, especially about the complex set of fimbrial adhesins varying among various serotypes. Here, we investigate EHEC serotype O157:H7 strain Sakai possessing at least 16 putative fimbrial gene clusters. Using a synthetic heterologous expression system in a non-pathogenic E. coli strain, a subset of 6 gene clusters for fimbrial adhesins was analyzed. We were able to visualize surface expression of two γ1 class fimbriae (Fim and Ycb), two γ4 class fimbriae (Yad and Yeh), and two fimbrial adhesins which are assembled by the nucleation/precipitation pathway (Curli fimbriae), and by a type 2 secretion system (type 4 pili). Further, we elucidated the impact of these fimbrial adhesins in adhesion to various epithelial cells lines (HeLa, MDCK, and CaCo2), and the contribution on biofilm formation. We demonstrate the ultrastructure of Fim fimbriae and Yad fimbriae of EHEC Sakai, and Yeh fimbriae of E. coli in general. The involvement of Fim fimbriae of EHEC Sakai to adhesion to various epithelial cell lines, and contribution to biofilm formation is reported here. Our approach provides first ultrastructural and functional data for novel EHEC adhesins, and enables further understanding of the involvement of fimbrial adhesins in pathogenesis of EHEC Sakai.	0
Neurodegenerative diseases (Alzheimer's, Parkinson's etc.) causes brain cell damage leading to dementia. The major restriction remains in delivering drug to the central nervous system is blood brain barrier (BBB). The aim of this study was to develop a liposomal drug delivery system of Aphanamixis polystachya leaf extract for the treatment of neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In this study GC-MS analysis is used to determine major constituents of Aphanamixis polystachya leaf extract. Liposomal batches of Aphanamixis polystachya leaf extract was prepared using design of experiment (DoE) and characterized using Malvern zetasizer, transmission electron microscopy (TEM), and FT-IR. Stability study of blank and leaf extract loaded liposome were performed in gastric media. In-vivo neurobehavioral and anti-inflammatory studies were performed on mice and rat model respectively. GC-MS data showed that major constituents of Aphanamixis polystachya leaf extract are 2-Pentanone, different acids (Octadec-9-enoic acid, 5-Hydroxypipeloic acid etc.), and Beta-Elemene etc. Malvern Zetasizer and TEM data showed that liposome batches of Aphanamixis polystachya leaf extract were in the range of 120 - 180 nm. Interactions between process parameters and material attributes found to have more impact on the average particle size and polydispersity of liposome batches compared to the impact of each parameter in isolation. Stability studies data suggest that blank and leaf extract loaded liposomes were stable at gastric conditions after 4 hours. In-vivo neurobehavioural study data indicated that significant improvement in the memory function, locomotor activity and ambulatory performance of dementia induced mice was observed for the liposomal batches compared to merely A. polystachya leaf extract.	0
This study aimed to investigate early life of Coreoperca herzi living in Han River and compare morphological differences between different groups during the development in order to provide basic data for relevant taxonomic research. On average, one female individual spawned 541 to 861 eggs (average 701) at once. After 259 hours, the tail broke out of the egg membrane and hatching began. Immediately after hatching, the larvae were average 7.81±0.10 mm (n=5) in total length. 60 days the juvenile was average 35.9±1.30 mm (n=5) in total length. The white spots spread to the rest of the body, rending the same pattern as that on the body of their broodstock fish.	0
Fibulin-3 (F3) is a secreted, disulfide-rich glycoprotein which is expressed in a variety of tissues within the body, including the retina. An Arg345Trp (R345W) mutation in F3 was identified as the cause of a rare retinal dystrophy, Malattia Leventinese/Doyne Honeycomb Retinal Dystrophy (ML/DHRD). ML/DHRD shares many phenotypic similarities with age-related macular degeneration (AMD). The most prominent feature of ML/DHRD is the development of radial or honeycomb patterns of drusen which can develop as early as adolescence. Two independent mouse models of ML/DHRD show evidence of complement activation as well as retinal pigment epithelium (RPE) atrophy, strengthening the phenotypic connection with AMD. Because of its similarities with AMD, ML/DHRD is receiving increasing interest as a potential surrogate disease to study the underpinnings of AMD. This mini-review summarizes the current knowledge of F3 and points toward potential therapeutic strategies which directly or indirectly target cellular dysfunction associated with R345W F3.	0
Anonychia refers to the absence of nail plates owing to an autosomal dominant or recessive inheritance. Congenital anonychia is a rare condition that may be associated with other ectodermal or mesodermal malformations like epidermolysis bullosa, (deafness, onychodystrophy, osteodystrophy, and mental retardation) syndrome and Iso-Kikuchi syndrome. Here, we report 3 cases with anonychia congenita appearing in different generations of a single family in Kingdom of Saudi Arabia.	0
Familial glucocorticoid deficiency type 1 (FGD1) is an autosomal recessive disorder caused by mutations in the melanocortin 2 receptor (MC2R) gene, characterized by a low or undetectable serum cortisol level and a high adrenocorticotropic hormone (ACTH) level. Clinical manifestations include hypoglycemia, seizure, skin hyperpigmentation, hyperbilirubinemia, cholestasis, and a tall stature. Some dysmorphic features such as, a prominent forehead, hypertelorism, a broad nasal bridge, and small tapering fingers, have been reported. Children with FGD1 may have other isolated endocrine abnormalities. To date, no patient with FGD1 has been reported in mainland China. Here we report on a Chinese patient with FGD1 having a novel MC2R gene variant, a mild transverse palm crease, hypertelorism, and subtle/transient endocrine abnormalities relating to all three zones of the adrenal cortex and thyroid gland. We also reviewed cases with dysmorphic features or additional endocrine abnormalities.	0
Hereditary mucoepithelial dysplasia (HMD) is a rare autosomal dominant disorder characterized by mucoepithelial disruption of the skin, hair and mucous membranes. It results from defective gap junction formation and leads to non-scarring alopecia, mucosal erythema, perineal erythematous intertrigo, involvement of the conjunctival mucosa, and pulmonary disease. We present a case of severe respiratory distress in an initially healthy full term infant born to a mother with HMD. This infant later developed signs and symptoms of HMD. A high index of suspicion for pulmonary infection with atypical organism is essential in infants with a family history of HMD who present with respiratory distress.	0
INTRODUCTION:Pathogenic DNA variants in the GLI-Kruppel family member 3 (GLI3) gene are known to cause multiple syndromes: for example, Greig syndrome, preaxial polydactyly-type 4 (PPD4) and Pallister-Hall syndrome. Out of these, Pallister-Hall is a different entity, but the distinction between Greig syndrome and PPD4 is less evident. Using latent class analysis (LCA), our study aimed to investigate the correlation between reported limb anomalies and the reported GLI3 variants in these GLI3-mediated polydactyly syndromes. We identified two subclasses of limb anomalies that relate to the underlying variant. METHODS:Both local and published cases were included for analysis. The presence of individual limb phenotypes was dichotomised and an exploratory LCA was performed. Distribution of phenotypes and genotypes over the classes were explored and subsequently the key predictors of latent class membership were correlated to the different clustered genotypes. RESULTS:297 cases were identified with 127 different variants in the GLI3 gene. A two-class model was fitted revealing two subgroups of patients with anterior versus posterior anomalies. Posterior anomalies were observed in cases with truncating variants in the activator domain (postaxial polydactyly; hand, OR: 12.7; foot, OR: 33.9). Multivariate analysis supports these results (Beta: 1.467, p=0.013 and Beta: 2.548, p<0.001, respectively). Corpus callosum agenesis was significantly correlated to these variants (OR: 8.8, p<0.001). CONCLUSION:There are two distinct phenotypes within the GLI3-mediated polydactyly population: anteriorly and posteriorly orientated. Variants that likely produce haploinsufficiency are associated with anterior phenotypes. Posterior phenotypes are associated with truncating variants in the activator domain. Patients with these truncating variants have a greater risk for corpus callosum anomalies.	0
Objective:Major birth defects are inborn structural or functional anomalies with long-term disability and adverse impacts on individuals, families, health-care systems, and societies. Approximately 20% of birth defects are due to chromosomal and genetic conditions. Inspired by the fact that neonatal deaths are caused by birth defects in about 20 and 10% of cases in Iran and worldwide respectively, we conducted the present study to unravel the role of chromosome abnormalities, including microdeletion/microduplication(s), in multiple congenital abnormalities in a number of Iranian patients. Materials and Methods:In this descriptive cross-sectional study, 50 sporadic patients with Multiple Congenital Anomalies (MCA) were selected. The techniques employed included conventional karyotyping, fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and array comparative genomic hybridisation (array-CGH), according to the clinical diagnosis for each patient. Results:Chromosomal abnormalities and microdeletion/microduplication(s) were observed in eight out of fifty patients (16%). The abnormalities proved to result from the imbalances in chromosomes 1, 3, 12, and 18 in four of the patients. However, the other four patients were diagnosed to suffer from the known microdeletions of 22q11.21, 16p13.3, 5q35.3, and 7q11.23. Conclusion:In the present study, we report a patient with 46,XY, der(18)[12]/46,XY, der(18), +mar[8] dn presented with MCA associated with hypogammaglobulinemia. Given the patient's seemingly rare and highly complex chromosomal abnormality and the lack of any concise mechanism presented in the literature to justify the case, we hereby propose a novel mechanism for the formation of both derivative and ring chromosome 18. In addition, we introduce a new 12q abnormality and a novel association of an Xp22.33 duplication with 1q43q44 deletion syndrome. The phenotype analysis of the patients with chromosome abnormality would be beneficial for further phenotype-genotype correlation studies.	0
BACKGROUND AND PURPOSE:Whether the Lewis-Sumner syndrome (L-SS) is a distinct entity from other types of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP-ot) remains controversial. METHOD:The clinical/electrophysiological characteristics and long-term outcomes of 45 L-SS and 35 CIDP-ot patients were retrospectively compared. RESULTS:The CIDP-ot group was composed of 11 patients with a typical CIDP, 17 with a pure sensory form, four with a distal form and three with a pure motor form. In the L-SS group, asymmetric (P < 0.001) and monomelic involvement (P = 0.04) of the upper limbs (P < 0.001) was significantly more frequent; paucisymptomatic forms (Overall Neuropathy Limitations Scale ≤ 1) were less frequent (P < 0.001); electroneuromyography showed that conduction block in intermediate nerve segments was the main demyelinating feature, with frequent F-wave abnormalities on nerves without conduction block (44%). Long-term prognosis was globally poorer in the L-SS group with more frequent aggravation during treatment (P = 0.02), less frequent treatment withdrawal (P = 0.03) and longer time to achieve successful withdrawal (39 vs. 15 months). CONCLUSIONS:Our study suggests that L-SS patients have a less favourable therapeutic response rate and long-term outcomes. Rapid differentiation of L-SS from other forms of CIDP is important in order to anticipate a more complicated disease course management, with from one side the inefficacy or even harmfulness of corticosteroids and from the other side a difficult weaning procedure. A prospective study is necessary to confirm these results.	0
Waardenburg Syndrome (WS) is a condition characterized by sensorineural deafness and pigment disturbances of the skin, hair and iris. By using the latest genomics technology, the WS-related gene mutations and corresponding mechanisms have been widely studied and reported. and the high genetic heterogeneity of the disease has also been explained. However, the SOX10 gene transcription and expression has still be unclear. In this study, we determined the phenotypic gene expression of WS patients in two Chinese WS families. More importantly, we identified two novel SOX10 mutations, c.482-487del (p.R161-M162del)and c.52G > T (p.E18X) in WSII for the first time in the Chinese population.	0
BACKGROUND:Likely pathogenic variants in SLC17A5 results in allelic disorders of free sialic acid metabolism including (1) infantile free sialic acid storage disease with severe global developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; (2) intermediate severe Salla disease with moderate to severe global developmental delay, hypotonia, and hypomyelination with or without coarse facial features, and (3) Salla disease with normal appearance, mild cognitive dysfunction, and spasticity. PATIENT DESCRIPTION:This five-year-old girl presented with infantile-onset severe global developmental delay, truncal hypotonia, and generalized dystonia following normal development during her first six months of life. Brain magnetic resonance imaging showed marked hypomyelination and a thin corpus callosum at age 19 months, both unchanged on follow-up at age 28 months. Urine free sialic acid was moderately elevated. Cerebrospinal fluid free sialic acid was marginally elevated. Sequencing of SLC17A5 revealed compound heterozygous likely pathogenic variants, namely, a known missense (c.291G>A) variant and a novel truncating (c.819+1G>A) variant, confirming the diagnosis of Salla disease at age 3.5 years. CONCLUSION:We report a new patient with intermediate severe Salla disease. Normal or marginally elevated urine or cerebrospinal fluid free sialic acid levels cannot exclude Salla disease. In patients with progressive global developmental delay and hypomyelination on brain magnetic resonance imaging, Salla disease should be included into the differential diagnosis.	0
Potter sequence is a rare congenital malformation that primarily affects male fetuses and is characterized by pulmonary hypoplasia, skeletal malformation, and kidney abnormalities. The pressure of the uterine wall due to oligohydramnios leads to an unusual facial appearance, abnormal limbsor limbs in abnormal positions or contractures. The fetus generally dies soon after birth due to respiratory insufficiency. We presented a male baby of 35 wks gestation with birth weight 1200gms delivered by primi mother. She had severe oligohydramnios and virtually there was no liquor during birth. The baby had severe perinatal depression at birth requiring resuscitation. Multiple congenital anomalies like absence of left eye, congenital cataract on the right eye, right-sided choanal atresia, micrognathia, low set ears, beaked nose, bilateral clubbed foot with hip deformity were noted. After 2 hours of life,baby developed fast breathing and cyanosis and died due to respiratory failure.	0
Secondary hypertension is a common condition with a broad differential diagnosis. Identification of the true cause of hypertension can be critical for guiding appropriate management. Here, we review hereditary conditions underlying the most common cause of secondary hypertension, primary aldosteronism, as well as other disorders impacting various levels of mineralocorticoid action. Recently, several pathogenic variants of ion channels have been described as etiologies of familial aldosteronism. Defects in steroid hormone synthesis cause hypertension in 11β-hydroxylase deficiency and 17α-hydroxylase deficiency, two types of congenital adrenal hyperplasia. Inappropriate activation of mineralocorticoid receptors underlies the syndrome of apparent mineralocorticoid excess and constitutive activation of the mineralocorticoid receptor. Finally, Liddle syndrome and pseudohypoaldosteronism type 2 are disorders impacting the function of renal sodium channels, the endpoint of mineralocorticoid action. We discuss the pathophysiology, clinical presentation, diagnosis and management of these low renin hypertension states that ultimately result in apparent excess mineralocorticoid activity.	0
The ridged skin of the palms and soles has several unique features: (i) presence of dermatoglyphics created by alternating ridges and grooves forming a unique pattern, (ii) presence of the highest density of eccrine sweat glands and absence of pilosebaceous units, and (iii) differential expression of keratins compared to the glabrous skin. These features explain the preferential localization of palmoplantar keratoderma (PPK) and several of its characteristic clinical features. PPK develops as a compensatory hyperproliferation of the epidermis and excessive production of stratum corneum in response to altered cornification of the palmoplantar skin due to mutations in the genes encoding several of the proteins involved in it. PPK can manifest as diffuse, focal, striate, or punctate forms per se or as a feature of several dermatological or systemic diseases. There is a wide genetic and phenotypic heterogeneity in hereditary PPK, due to which reaching an accurate diagnosis only on the basis of clinical features may be sometimes challenging for the clinicians in the absence of molecular studies. Nevertheless, recognizing the clinical patterns of keratoderma, extent of involvement, degree of mutilation, and associated appendageal and systemic involvement may help in delineating different forms. Molecular studies, despite high cost, are imperative for accurate classification, recognizing clinical patterns in resource poor settings is important for appropriate diagnosis, genetic counseling, and management. This review intends to develop a practical approach for clinical diagnosis of different types of hereditary PPK with reasonable accuracy.	0
Fetal alcohol spectrum disorders comprise the spectrum of cognitive, behavioral, and neurological impairments caused by prenatal alcohol exposure (PAE). Diffusion tensor imaging (DTI) was performed on 54 children (age 10.1 ± 1.0 years) from the Cape Town Longitudinal Cohort, for whom detailed drinking histories obtained during pregnancy are available: 26 with full fetal alcohol syndrome (FAS) or partial FAS (PFAS), 15 nonsyndromal heavily exposed (HE), and 13 controls. Using voxelwise analyses, children with FAS/PFAS showed significantly lower fractional anisotropy (FA) in four white matter (WM) regions and higher mean diffusivity (MD) in seven; three regions of FA and MD differences (left inferior longitudinal fasciculus (ILF), splenium, and isthmus) overlapped, and the fourth FA cluster was located in the same WM bundle (right ILF) as an MD cluster. HE children showed lower FA and higher MD in a subset of these regions. Significant correlations were observed between three continuous alcohol measures and DTI values at cluster peaks, indicating that WM damage in several regions is dose dependent. Lower FA in the regions of interest was attributable primarily to increased radial diffusivity rather than decreased axonal diffusivity, suggesting poorer axon packing density and/or myelination. Multiple regression models indicated that this cortical WM impairment partially mediated adverse effects of PAE on information processing speed and eyeblink conditioning. Hum Brain Mapp 37:2943-2958, 2016. © 2016 Wiley Periodicals, Inc.	0
Retinal venous occlusive events are a rare complication of arteriovenous malformations of the retina found in Wyburn-Mason syndrome. The authors present a case of a 28-year-old man diagnosed with Wyburn-Mason syndrome and cutaneous reactive angiomatosis, a reactive angioproliferative disorder induced by vascular occlusion. He developed a central retinal vein occlusion complicated by macular edema and received treatment with intravitreal bevacizumab, which led to resolution of the edema. To the best of the authors' knowledge, this is the first report of an anti- vascular endothelial growth factor agent employed as an effective treatment for macular edema in the setting of Wyburn-Mason syndrome. The association between Wyburn-Mason syndrome and cutaneous reactive angiomatosis is also a novel finding.	0
BACKGROUND:Massive gastrointestinal bleeding in children is uncommon. Dieulafoy lesion is an uncommon disease which may lead to massive and repeated upper gastrointestinal hemorrhage. We report two cases of gastric Dieulafoy lesion successfully treated with either band ligation or endoscopic hemoclipping. CASE PRESENTATION:First case report: A previously healthy 18-month-old female infant with E. coli sepsis, pneumonia and respiratory failure with bilateral pneumothorax requiring chest drainage. Over a few days, the patient presented hematemesis and melena with progressively worsening anemia. The esophagogastroduodenoscopy revealed an arterial vessel with eroded apex located between the body and the fundus of the stomach. Two elastic bands were applied which resulted in resolution of hematemesis and melena and improvement of the anemia. Second case report: A 8-year-old male was admitted to our department with sudden massive hematemesis and melena. Clinical examination revealed anemia (hemoglobin, 6.8 g/dl). Esophagogastroduodenoscopy revealed a mucosal erosion with visible vessel located along the small curvature, close to the antrum. Three hemostatic clips were placed on the Dieulafoy lesion and hemostasis was obtained. CONCLUSIONS:we showed that, similar to gastric DL in adult patients,, gastric DL in pediatric patients can be successfully treated with endoscopic therapy, and both hemoclipping and band ligation are suitable techniques.	0
Newborn screening for cystathionine beta-synthase deficiency (homocystinuria; HCU) was started in the late 1960s using a bacterial inhibition assay (BIA). At least seven countries have either national or regional screening programmes; 12 programmes are known to have discontinued. The worldwide incidence of HCU is approximately 1 in 335,000 but varies from 1:65,000 (Ireland) to 1:900,000 (Japan). Methodologies include the BIA, one-dimensional or thin-layer amino acid chromatography and, more recently, tandem mass spectrometry. The BIA diagnostic cut off concentration of blood methionine varies from 67 to 270 micromol/ (10-40 mg/l) with a median of 135 micromol/l (20 mg/l). In Ireland, 25 cases of HCU from 19 families have been identified from 1.58 million newborn infants since 1971; 21 cases were detected through the screening programme. Of the four missed cases, three were breast-fed at the time of blood collection and one was pyridoxine responsive. These findings were in broad agreement with the results from five other programmes, in which approximately one in every five cases was missed by the screening programme. Early hospital discharge, low protein intake, high blood methionine cut-off concentration and pyridoxine responsiveness were all identified as contributing to missed cases.	1
Mal de Meleda (OMIM# 248300; keratosis palmoplantaris transgrediens) is an autosomal recessive form of palmoplantar keratoderma, clinically characterized by sharp demarcated erythema and hyperkeratosis of the palms and soles that progress with age and extend to the dorsal aspects of the hands and feet. The mal de Meleda is caused by mutations in the SLURP1 gene that encodes secreted lymphocyte antigen 6/urokinase-type plasminogen receptor-related protein 1 (SLURP1). To date no reported cases from Indonesia. The aims of the study were to describe the typical features of mal de Meleda cases in a Javanese family in Indonesia and identify the mutation in the ARS B gene which encodes SLURP1.In this study, three Javanese patients, siblings from nonconsanguineous nonaffected parents, presented with classical symptoms of mal de Meleda. Genetic analysis screening SLURP1 gene was conducted for the specimens from the patients and other family members.A novel homozygous three-nucleotide deletion in exon 3, i.e. c.271-273TCTdel, was identified in the patients. Subcloning and sequencing revealed both parents (I.2 and I.3) and one of the father's siblings (I.1) carry heterozygous c.271-273TCTdel, while the other father's sibling (I.2), the mother's sister (I.4), and a healthy control matched the ethnicity of the family, showing normal sequence of the entire SLURP1.This is the first mal de Meleda case of Javanese ethnicity to be documented, and the unique mutation has not previously been reported. The finding supports the notion that despite the rarity, SLURP1 mutation causing mal de Meleda is ubiquitous.	0
STUDY OBJECTIVES:To report the diagnostic and treatment challenges of sighted non-24-hour sleep-wake disorder (N24SWD). METHODS:We report a series of seven sighted patients with N24SWD clinically evaluated by history and sleep diaries, and when available wrist actigraphy and salivary melatonin levels, and treated with timed melatonin and bright light therapy. RESULTS:Most patients had a history of a delayed sleep-wake pattern prior to developing N24SWD. The typical sleep-wake pattern of N24SWD was seen in the sleep diaries (and in actigraphy when available) in all patients with a daily delay in midpoint of sleep ranging 0.8 to 1.8 hours. Salivary dim light melatonin onset (DLMO) was evaluated in four patients but was missed in one. The estimated phase angle from DLMO to sleep onset ranged from 5.25 to 9 hours. All six patients who attempted timed melatonin and bright light therapy were able to entrain their sleep-wake schedules. Entrainment occurred at a late circadian phase, possibly related to the late timing of melatonin administration, though the patients often preferred late sleep times. Most did not continue treatment and continued to have a non-24-hour sleep-wake pattern. CONCLUSIONS:N24SWD is a chronic debilitating disorder that is often overlooked in sighted people and can be challenging to diagnose and treat. Tools to assess circadian pattern and timing can be effectively applied to aid the diagnosis. The progressive delay of the circadian rhythm poses a challenge for determining the most effective timing for melatonin and bright light therapies. Furthermore, once the circadian sleep-wake rhythm is entrained, long-term effectiveness is limited because of the behavioral and environmental structure that is required to maintain stable entrainment.	0
Polycystic liver disease (PLD) is a rare hereditary disease that independently exists in isolated PLD, or as an accompanying symptom of autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease with complicated mechanisms. PLD currently lacks a unified diagnostic standard. The diagnosis of PLD is usually made when the number of hepatic cysts is more than 20. Gigot classification and Schnelldorfer classification are now commonly used to define severity in PLD. Most PLD patients have no clinical symptoms, and minority with severe complications need treatments. Somatostatin analogues, mammalian target of rapamycin inhibitor, ursodeoxycholic acid and vasopressin-2 receptor antagonist are the potentially effective medical therapies, while cyst aspiration and sclerosis, transcatheter arterial embolization, fenestration, hepatic resection and liver transplantation are the options of invasion therapies. However, the effectiveness of these therapies except liver transplantation are still uncertain. Furthermore, there is no unified strategy to treat PLD between medical centers at present. In order to better understand recent study progresses on PLD for clinical practice and obtain potential directions for future researches, this review mainly focuses on the recent progress in PLD classification, clinical manifestation, diagnosis and treatment. For information, we also provided medical treatment processes of PLD in our medical center.	0
Osteopetrosis is a rare congenital bone disorder, characterized by systemic osteosclerosis due to a deficiency of or functional defect in osteoclasts. Autosomal dominant osteopetrosis (ADOP) is the most common form with a late onset, a stable condition, relatively few symptoms and a good prognosis. Few studies to date have reported successful total hip arthroplasty (THA) in patients with ADOP and its operative difficulties. We herein describe a case of left hip osteoarthritis in a patient with OP via THA in order to share our experience during the treatment process. The patient was a 52-years-old female with osteopetrosis who was referred to our department due to a history of left hip pain with activity limitation for 20 years. The patient reported no history of fracture or family history. The patient underwent THA in the left hip. At the 6-month, 1- and 2-year follow-up, the components were in a good position and the patient remained asymptomatic and pain-free. Therefore, THA may be a feasible treatment option when patients with ADOP suffer from painful hip osteoarthritis.	0
Joubert syndrome is a very rare disorder characterized by respiratory irregularities, nystagmus, hypotonia, and global developmental delay with abnormalities of cerebellum. We present two cases of this syndrome with different phenotypes. The first case was an 8-month-old girl with hypotonia, apnea, and mild developmental delay as well as retinal degeneration and unilateral renal cystic dysplasia. The second case was a 27-month-old boy who presented with episodes of hyperpnea, apnea, retinal dystrophy, and severe global developmental delay. Both patients had normal metabolic profile and prototype imaging of joubert syndrome including vermis agenesis and molar tooth sign.	0
OBJECTIVE:To explore clinical and genetic features of a pedigree affected with autosomal recessive neuromyotonia and axonal neuropathy (NMAN). METHODS:For the proband and her parents, clinical data was collected, genomic DNA was extracted from peripheral blood samples. Triplet primed-PCR was carried out to detect dynamic mutation of DMPK and ZNF9 genes, which are responsible for myotonic dystrophy, by capillary electrophoresis. High-throughput sequencing was used to screen variants of candidate genes for Mendelian disorders involving the nervous system. Candidate variants were confirmed by Sanger sequencing. The genotype of the variant was determined in the parents and 100 healthy controls. Pathogenicity of the variant was assessed by ACMG criterion. RESULTS:Mutation of DMPK and ZNF9 genes was excluded. DNA sequencing has identified a homozygous missense variant (c.335C>T, p.R119W) in the HINT1 gene. Both parents were found to carry the variant. The same variant was not found among the healthy controls. According to the ACMG criterion, the missense variant was classified as a pathogenic variant. CONCLUSION:The c.335C>T (p.R119W) of the HINT1 gene probably underlie the disease in this pedigree. Above finding provided further evidence for the connection between HINT1 and NMAN and enriched the mutation spectrum of HINT1 gene.	0
Hemolytic-uremic syndrome (HUS) is a clinical triad of microangiopathic hemolytic anemia, impaired renal function and thrombocytopenia, primarily affecting pre-school-aged children. HUS can be classified into diarrhea-associated HUS (D(+)HUS), usually caused by Shiga toxin-producing Escherichia coli (STEC), and non-diarrhea-associated HUS (D(-)HUS), both with potentially serious acute and long-term complications. Few data exists on the clinical features and long-term outcome of HUS in Norway. The aim of this paper was to describe these aspects of HUS in children over a 10-year period.We retrospectively collected data on clinical features, therapeutic interventions and long-term aspects directly from medical records of all identified HUS cases <16 years of age admitted to Norwegian pediatric departments from 1999 to 2008. Cases of D(+)HUS and D(-)HUS are described separately, but no comparative analyses were possible due to small numbers. Descriptive statistics are presented in proportions and median values with ranges, and/or summarized in text.Forty seven HUS cases were identified; 38 D(+)HUS and nine D(-)HUS. Renal complications were common; in the D(+)HUS and D(-)HUS group, 29/38 and 5/9 developed oligoanuria, 22/38 and 3/9 needed dialysis, with hemodialysis used most often in both groups, and plasma infusion(s) were utilized in 6/38 and 4/9 patients, respectively. Of extra-renal complications, neurological complications occurred in 9/38 and 2/9, serious gastrointestinal complications in 6/38 and 1/9, respiratory complications in 10/38 and 2/9, and sepsis in 11/38 and 3/9 cases, respectively. Cardiac complications were seen in two D(+)HUS cases. In patients where data on follow up ≥1 year after admittance were available, 8/21 and 4/7 had persistent proteinuria and 5/19 and 4/5 had persistent hypertension in the D(+)HUS and D(-)HUS group, respectively. Two D(+)HUS and one D(-)HUS patient were diagnosed with chronic kidney disease and one D(+)HUS patient required a renal transplantation. Two D(+)HUS patients died in the acute phase (death rate; 5 %).The HUS cases had a high rate of complications and sequelae, including renal, CNS-related, cardiac, respiratory, serious gastrointestinal complications and sepsis, consistent with other studies. This underlines the importance of attention to extra-renal manifestations in the acute phase and in renal long-term follow-up of HUS patients.	0
BACKGROUND:Urea cycle disorders are congenital metabolism errors that affect ammonia elimination. Clinical signs and prognosis are strongly influenced by peak ammonia levels. Numerous triggers associated with metabolic decompensation have been described with many of them, including fasting or stress, being related to the perioperative period. AIMS:We aimed to assess perioperative complications in pediatric patients with urea cycle disorders requiring general anesthesia in our center. METHODS:We reviewed the clinical history of all the pediatric patients with a confirmed urea cycle disorders diagnosis requiring surgery or a diagnostic procedure with anesthesia between January 2002 and June 2018. RESULTS:We included 33 operations (major surgery, minor surgery, and diagnostic procedures) carried out on 10 patients via different anesthetic techniques. We observed the following complications: intraoperative hyperglycemia in one case, postoperative vomiting in eight cases, and slightly increased postoperative ammonia levels (54, 59, and 69 µmol/L) with normal preoperative levels in three cases without associated metabolic decompensation. There were two cases of perioperative hyperammonemia (72 and 69 µmol/L) secondary to preoperative metabolic decompensation (137 and 92 µmol/L) with the levels progressively dropping and normalizing in the first 24-48 hours, respectively. CONCLUSIONS:Procedures under anesthesia on pediatric patients with urea cycle diseases should be performed by experienced multidisciplinary teams at specialized centers. Perioperative management focused on avoiding catabolism (especially during fasting) and monitoring signs associated with metabolic decompensation to allow for its early treatment should be included in routine anesthetic techniques for children with urea cycle disorders.	0
There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers.	0
A 71-year-old man was admitted with confusion having been discovered on the floor of his unkempt home. Social services would later confirm that the home was infested by rats. An infection of unclear origin was suspected, and he was immediately started on broad spectrum antibiotics. He subsequently developed a swollen left knee. Two knee aspirates showed a raised white cell count but no microbiological or cytological diagnosis. Finally, samples sent for 16S rDNA PCR identified Streptobacillus monilliformis Fastidious organisms and early treatment with antibiotics can limit microbiological diagnosis through standard laboratory analysis. Newer techniques such as sequence-based testing can overcome these limitations; however, they are not widely available and require the clinician to have a high index of suspicion. Crucially, the patient continued to be treated for his clinical sepsis despite initial laboratory results being negative and conflicting specialist opinions.	0
The ginkgo tree is a well-known, highly adaptable urban plant. Ginkgo nuts are the product of the ginkgo tree. Interior ginkgo nuts are cooked and served in Asian countries; however, the potential toxicity of the gingko nuts is not commonly known. Herein, we report a 48-year-old male patient experiencing acute convulsions presumably due to overconsumption of gingko nuts. The patient was transferred to our department after several episodes of acute generalized tonicclonic seizures lasting approximately 30 seconds each and starting one hour before the visit. The patient also complained of vomiting, vertigo, diarrhea, and tremors in both upper limbs following the seizures. Elevated 4-O-methylpyridoxine (312 ng/mL), low blood pyridoxal phosphate (2.4 μg/L), and low vitamin B1 (20 ng/mL) levels were found in the blood analysis. No other remarkable abnormalities were detected. We diagnosed the patient with ginkgo nut intoxication, and he was orally administered 400 mg of pyridoxal phosphate. His symptoms resolved after treatment, and no seizures recurred thereafter. Our report may help raise awareness of the clinical presentation and management of this intoxication among emergency physicians.	0
<label>BACKGROUND</label>To report a patient who presented with bluish scleral discoloration, keratoconus, and progressive high myopia.<label>CASE PRESENTATION</label>A 6-year-old Chinese female patient presented with a significant bluish discoloration of the sclera in both eyes and extreme corneal thinning with anterior corneal protrusion. General pediatric physical examination was normal for all systems and no genetic disorders known were observed.<label>CONCLUSIONS</label>We aim to highlight the importance of diagnosis and treatment of patients suffering from Brittle cornea syndrome. Timely diagnosis and early provision of protective glasses seem to be the most important step in treating BCS. To our knowledge, this is the first case of BCS being reported in the Asia area.	0
Amebiasis caused by protozoa Entamoeba histolytica (EH) is the third leading parasitic cause of human mortality. Although amebiasis is endemic in India, only about 10% of the infected individuals manifest disease. Clinical spectrum of amebiasis ranges from asymptomatic colonization to amebic colitis to hemorrhagic and fulminant colitis. Factors causing an invasive infection are not completely understood. Pathogen virulence, host immunity, and ability of the pathogen to evade host immune response play vital role in determining the disease course. Host factors such as immunocompromised states may make an individual susceptible to develop symptomatic infection. Malignancies usually result in chronic debilitation which may make the individual prone to develop invasive amebiasis with rapid progression. We report two cases of invasive amebiasis which developed a fulminant course in the immediate postoperative period after abdominal surgeries for visceral malignancies.	0
BACKGROUND:Tumors invading the trachea are rare, and although literature often suggests five tracheal rings as the maximum limit of tracheal resection with primary closure, longer tracheal resections and primary closure are possible in many patients. One such locally invasive tumor with propensity for tracheal invasion is carcinoma showing thymic-like differentiation (CASTLE) of the thyroid. METHODS:A 53-year-old woman presents with a 2-year history of hoarseness, newly diagnosed right vocal cord paralysis, and a thyroid mass with significant tracheal and esophageal muscularis invasion. Pathology suggests CASTLE. Segmental nine-ring tracheal resection with primary closure is illustrated, demonstrating important tracheal reconstructive techniques. RESULTS:At the completion of total thyroidectomy and central compartment dissection (not illustrated), the area of tracheoesophageal tumor involvement is isolated. First, the disease is sharply dissected from the tracheal wall and esophagus, excising 4 cm of esophageal muscularis. Next, a plane is established between the membranous trachea and esophagus. The intact left recurrent laryngeal nerve is released from the left tracheoesophageal groove. Substernal thoracic tracheal attachments are released, and a suprahyoid muscle release is performed. Tracheal rings 1 through 9 are resected en bloc, and circumferential tracheal closure is illustrated, with careful attention to technique of tracheal closure and management of the endotracheal tube. Finally, given the degree of tracheoesophageal resection and indication for postoperative radiation therapy, a pectoralis muscle flap is rotated over the trachea and esophagus. CONCLUSION:To our knowledge, this is the first video demonstration of a segmental resection and reconstruction of a CASTLE of the thyroid in the peer-reviewed literature. Unique to this case is the significant length of tracheal resection with primary closure, as well as demonstration of concurrent esophageal muscularis resection. Resection and reconstruction of longer segments of cervical trachea require stepwise surgical technique to safely preserve recurrent laryngeal nerve (s), while releasing the larynx and thoracic trachea to minimize tension on the tracheal closure.	0
Idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome typically affects young, healthy individuals. Despite the dramatic fundus appearance seen in this syndrome, these patients are usually asymptomatic. The syndrome includes peculiar vascular abnormalities in the form of multiple aneurysmal dilatations seen along retinal arterioles and optic nerve-head arterioles, which are best appreciated on fluorescein angiography. Neuroretinitis and retinal vasculitis are seen in all patients, and manifested by staining of the optic nerve head and diffuse leakage from vessels, mainly arterioles, on fluorescein angiography. The devastating vision-threatening outcomes of this syndrome include exudative retinopathy and extensive peripheral retinal nonperfusion areas, which can eventually lead to neovascularization. This review summarizes current knowledge on the variable clinical aspects of this disease, highlighting diagnostic and treatment strategies.	0
Alkaptonuria (AKU) is a rare metabolic disease correlated with the deficiency of homogentisate 1,2-dioxygenase and leading to an accumulation of the metabolite homogentisic acid (HGA) which can be subjected to oxidation and polymerization reactions. These events are considered a trigger for the induction of oxidative stress in AKU but, despite the large description of an altered redox status, the underlying pathogenetic processes are still unstudied. In the present study, we investigated the molecular mechanisms responsible for the oxidative damage present in an osteoblast-based cellular model of AKU. Bone, in fact, is largely affected in AKU patients: severe osteoclastic resorption, osteoporosis, even for pediatric cases, and an altered rate of remodeling biomarkers have been reported. In our AKU osteoblast cell model, we found a clear altered redox homeostasis, determined by elevated hydrogen peroxide (H2O2) levels and 4HNE protein adducts formation. These findings were correlated with increased NADPH oxidase (NOX) activity and altered mitochondrial respiration. In addition, we observed a decreased activity of superoxide dismutase (SOD) and reduced levels of thioredoxin (TRX) that parallel the decreased Nrf2-DNA binding. Overall, our results reveal that HGA is able to alter the cellular redox homeostasis by modulating the endogenous ROS production via NOX activation and mitochondrial dysfunctions and impair the cellular response mechanism. These findings can be useful for understanding the pathophysiology of AKU, not yet well studied in bones, but which is an important source of comorbidities that affect the life quality of the patients.	0
Background: Bruck syndrome is a rare autosomal recessive condition that presents with many of the symptoms of osteogenesis imperfecta. In addition to defective type I collagen, manifesting as bone fragility, osteoporosis, and blue sclera, Bruck syndrome is additionally characterized by arthrogryposis with pterygia. Joint contractures are frequently bilateral and severe. Case Report: We report the medical record and radiographic data for 2 siblings with Bruck syndrome type 2-a male (age 6 years) and a female (age 5 years)-born to nonaffected parents. The male has experienced more than 45 fractures, developed severe scoliosis, and has debilitating flexion contractures. The female has minimal flexion contractures, a history of 15 fractures, and severe scoliosis. Conclusion: The dramatic difference between the phenotypes of these 2 cases is significant because it is the largest known variability of phenotypic presentation in siblings. Previous cases of siblings with differing presentations at birth have been reported, but the extent of these differences is not as extreme as in our cases. Because Bruck syndrome presents similarly to osteogenesis imperfecta and could be clinically mistaken for a form of osteogenesis imperfecta if contractures are minimal, a reasonable focus for research efforts is the development of genetic diagnostic protocols for osteogenesis imperfecta with the goal of ruling out Bruck syndrome.	0
An estimation of the prevalence of epidermolysis bullosa was carried out in Japan. A questionnaire was sent by mail to the departments of dermatology and pediatrics in 644 main hospitals throughout Japan requesting confirmation of the number of epidermolysis bullosa cases experienced. The response rate was 63.0% or 406 hospitals. Based on the secondary questionnaire survey, we confirmed 393 cases of epidermolysis bullosa, and then divided them into the five following groups: "simplex" type 182 (48.2%), "junctional" type 23 (6.0%), "dominant dystrophic" type 72 (18.7%), "recessive dystrophic" type 109 (28.2%), unclassified 7 (1.8%). Using the respondent rate by geographic region and clinical department, the estimated prevalence of each type of epidermolysis bullosa was calculated as follows: "simplex" type 340-470 (0.29-0.40 per 100,000 population), "junctional" type 18-24 (0.015-0.020), "dominant dystrophic" type 130-180 (0.11-0.15) and "recessive dystrophic" type 180-250 (0.15-0.21). The total number of epidermolysis bullosa patients in Japan was estimated as being more than 670 in 1983.	1
OBJECTIVE:To study the molecular basis of hereditary antithrombin (AT) deficiency in a Chinese family. It will help us understand the pathogenesis of this type of disease. METHOD:AT activity (AT:A) and the AT antigen (AT:Ag) level were tested by chromogenic substrate and immunoturbidimetry, respectively. To identify the novel mutations, SERPINC1 gene sequencing was carried out. The possible impact of the mutations was analyzed by model and bioinformatic analyses. RESULTS:AT:A and the AT:Ag level of the proband were 43% and 113 mg/L (normal range: 98-119% and 250-360 mg/L), respectively. Sequencing analysis revealed compound heterozygous mutations, including a frameshift mutation (c.318_319insT) resulting in Asn75stop and a missense mutation (c.922G>T) resulting in Gly276Cys. The bioinformatic and model analyses indicated that these mutations may disrupt the function and structure of the AT protein. CONCLUSION:We detected 2 novel heterozygous mutations (c.318_319insT and c.922G>T) in the proband, and these were associated with decreased AT:A.	0
Congenital disorders of glycosylation (CDG) are rare genetic defects mainly in the post-translational modification of proteins via attachment of carbohydrate chains. We describe an infant with the phenotype of a congenital muscular dystrophy, with borderline microcephaly, hypotonia, camptodactyly, severe motor delay, and elevated creatine kinase. Muscle biopsy showed muscular dystrophy and reduced α-dystroglycan immunostaining with glycoepitope-specific antibodies in a pattern diagnostic of dystroglycanopathy. Carbohydrate deficient transferrin testing showed a pattern pointing to a CDG type I. Sanger sequencing of DPM1 (dolichol-P-mannose synthase subunit 1) revealed a novel Gly > Val change c.455G > T missense mutation resulting in p.Gly152Val) of unknown pathogenicity and deletion/duplication analysis revealed an intragenic deletion from exons 3 to 7 on the other allele. DPM1 activity in fibroblasts was reduced by 80%, while affinity for the substrate was not depressed, suggesting a decrease in the amount of active enzyme. Transfected cells expressing tagged versions of wild type and the p.Gly152Val mutant displayed reduced binding to DPM3, an essential, non-catalytic subunit of the DPM complex, suggesting a mechanism for pathogenicity. The present case is the first individual described with DPM1-CDG (CDG-Ie) to also have clinical and muscle biopsy findings consistent with dystroglycanopathy.	0
Accumulating evidence demonstrates that long noncoding RNAs (lncRNAs) may be involved in the regulation of cancer biology. PVT1, which is overexpressed in tumor samples, acts as an oncogenic promoter in several kinds of cancers, including ovarian cancer. However, the mechanisms of its regulation of malignant behaviors in ovarian cancer remain largely unknown. In this study, the expression of PVT1 in several ovarian cancer cell lines was analyzed by qRT-PCR. The effect of PVT1 on malignant behaviors, including cell proliferation, migration and invasion, was analyzed. The posttranscriptional regulation of FOXM1 by PVT1 was analyzed by western blotting. The results illustrated that PVT1 acted as a sponge and bound miR-370 on two binding sites. The expression of PVT1 positively regulated malignant behaviors in ovarian cancer cells, including cell proliferation, migration and invasion, which could be reversed by the introduction of miR-370 mimics. Sponged miR-370 failed to posttranscriptionally regulate FOXM1, which resulted in the promotion of malignant behavior. PVT1 was also found to bind to FOXM1 directly and stabilize the FOXM1 protein. The promoting effect of PVT1 on malignant behaviors and chemoresistance to cisplatin could be reversed by knockdown of FOXM1 and introduction of miR-370 mimics. Together, these results suggest that lncRNA PVT1 promotes malignant behavior and induces chemoresistance in ovarian cancer by epigenetic and posttranscriptional regulation of FOXM1.	0
Ring chromosome 18 has a highly variable phenotype, depending on the extent of distal arm deletions. It is most commonly presented as a combination of 18p- and distal 18q- syndrome. IgA deficiency and autoimmune diseases have been previously described in these patients. Seven cases of juvenile rheumatoid arthritis (JRA) have been reported. Here we report the first case of late onset rheumatoid arthritis (RA) in a 32 year old Dominican woman with hypothyroidism, vitiligo, IgA deficiency, interstitial lung disease (ILD), cystic bronchiectasis, and features consistent with 18p- and distal 18q syndrome. Comparative genome hybridization analysis showed a del(18p11.21p11.32), dup(18q11.21-q22.1), and del(18q22.1-q23). Chromosomal analysis and fluorescence in situ hybridization showed three cell lines. One cell line was detected with a dicentric ring chromosome, another with duplication of the long arm and no short arm, and lastly a long arm terminal deletion of 18. The multiple autoimmune findings in our patient lends further support to the idea of loci on chromosome 18 playing a role in autoimmune disease expression. Late onset RA and ILD in a patient with chromosome 18 abnormalities are novel findings and are additional conditions to be aware of in this population.	0
The nuclear factor κB (NF-κB) signaling cascade has been implicating in a broad range of biological processes, including inflammation, cell proliferation, differentiation, and apoptosis. The past three decades have witnessed a great progress in understanding the impact of aberrant NF-κB regulation on human autoimmune and inflammatory disorders. In this review, we discuss how aberrant NF-κB activation contributes to multiple sclerosis, a typical inflammatory demyelinating disease of the central nervous system, and its involvement in developing potential therapeutic targets.	0
Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism caused by mutations in EFTA, EFTB, or ETFDH. Many MADD patients are responsive to treatment with riboflavin, termed riboflavin-responsive MADD (RR-MADD). Here, we report three novel mutations and one previously reported mutation in ETFDH in four RR-MADD patients who presented at various ages, and characterize the corresponding changes in ETF-QO protein structure. Clinicians should consider MADD in the differential diagnosis when patients present with muscle weakness and biochemical abnormalities. Gene testing plays a critical role in confirming the diagnosis of MADD, and may not only prevent patients from invasive testing, but also allow timely initiation of riboflavin treatment. The novel variants in ETFDH and the corresponding clinical features reported here enrich the allelic heterogeneity of RR-MADD and provide insight into genotype-phenotype relationships.	0
Isolated unilateral absence of the pulmonary artery (UAPA) is a congenital anomaly where involution of the extrapulmonary PA is insufficient and the intrapulmonary PA is only fed by the ductus arteriosus. Affected lung disorder causes complications years after ductus closure; thus, early diagnosis is of importance to avoid these complications. Here, we present the case of a male infant who was admitted to the neonatal intensive care unit because of transient tachypnea of the newborn and absence of the left PA (LPA) was indicated. Intensive echocardiography could detect neither the LPA nor the aortopulmonary collateral arteries to the left lung. Although the ductus was orthotopic with the right aortic arch, use of prostaglandin (PG) E1 unmasked the diagnosis of UAPA with bilateral ductus arteriosus. After ductal closure, delineation of the anatomy is not necessarily easy even with catheterization, whereas early use of PGE1 facilitates anatomical understanding by echocardiography, particularly early after birth. <Learning Objectives: While identification of disrupted pulmonary artery is often unsuccessful after ductal closure in the patients with unilateral absence of pulmonary artery, use of prostaglandin in the neonate with right aortic arch and large orthotropic right ductus arteriosus allowed successful recirculation of the disrupted pulmonary artery by reopening closed contralateral ductus arteriosus. Prostaglandin infusion early after birth delineated anatomical diagnosis of unilateral absence of pulmonary artery due to bilateral ductus, and it also made it possible to perform single stage uni-focalization.>.	0
A 2-year-old domestic shorthair cat was presented to us with decreased activity and anorexia. Hematologic findings revealed a mild non-regenerative anemia, thrombocytopenia, and leukocytosis with an increase in blast cells. Bone marrow aspirates also revealed a marked increase of blasts. The blastic cells were shown to be positive for peroxidase. Acute myeloblastic leukemia without maturation (M1) was diagnosed according to the FAB classification. Chemotherapy was initiated with cyclophosphamide, vincristine, prednisolone, and cytosine arabinoside. The cat responded partially. In total, the cats were given 7 blood transfusions. The cat died 14 weeks after first being presented to us.	0
Thalidomide remains notorious as a result of the damage it caused to children born to mothers who used it to treat morning sickness between 1957 and 1961. The re-emergence of the drug to treat a range of conditions including erythema nodosum leprosum (a complication of leprosy) has led to a new generation of thalidomide damaged children being born in Brazil. Although thalidomide affects most of the developing tissues and organs of the body, the damage to the limbs is striking. Indeed phocomelia, the severe reduction or loss of the proximal long bones with retention of the distal hand/foot plate remains the stereotypical image of thalidomide. This review focuses on the type and range of damage thalidomide caused to the limbs, reviews current understanding of the mechanisms underlying thalidomide-induced limb malformations and outlines some of the challenges remaining in elucidating its teratogenicity.	0
Background: Juvenile amyotrophic lateral sclerosis (jALS) is a rare form of ALS with an onset age of less than 25 years and is frequently thought to be genetic in origin. DDHD1 gene mutations have been reported to be associated with the SPG28 subtype of autosomal recessive HSP but have never been reported in jALS patients. Methods: Gene screens for the causative genes of ALS, HSP and CMT using next-generation sequencing (NGS) technologies were performed on a jALS patient. Sanger sequencing was used to validate identified variants and perform segregation analysis. Results: We identified a novel c.1483A>G (p.Met495Val) homozygous missense mutation of the DDHD1 gene in the jALS patient. All of his parents and young bother were heterozygous for this mutation. The mutation was not found in 800 Chinese control subjects or the database of dbSNP, ExAC and 1000G. Conclusion: The novel c.1483A>G (p.Met495Val) missense mutation of the DDHD1 gene could be a causative mutation of autosomal recessive jALS.	0
We report on a 4-year-old boy with mental retardation, facial and skeletal anomalies, cerebral angiomas, femoral nucleus necrosis, mild biochemical abnormalities. This complex of features resembles the Hall-Riggs syndrome but could represent a novel syndrome.	0
Juberg-Hayward syndrome is a rare autosomal recessive syndrome characterised by the association of growth retardation, microcephaly, cleft lip and palate, and thumb and radial ray abnormalities. To date, no prenatal cases have been reported. Here, we report on the first prenatal case of Juberg-Hayward syndrome. The diagnosis was established following fetopathological study. Besides the cardinal features of the syndrome, this prenatal case was remarkable for the severity of the short arm malformation and by the finding of big toe agenesis and cerebral abnormalities including hydrocephalus, agenesis of corpus callosum, and cerebellar hypoplasia. We conclude that the diagnosis of Juberg-Hayward syndrome can be discussed prenatally following ultrasound diagnosis of the association of intrauterine growth restriction, microcephaly, thumb/radial anomalies, and cleft lip/palate.	0
Dermatomyositis (DM) is a rare idiopathic inflammatory myopathy characterized by muscle weakness and cutaneous manifestations in adults and children. Calcinosis, a complication of DM, is the abnormal deposition of insoluble calcium salts in tissues, including skin, subcutaneous tissue, tendons, fascia, and muscle. Calcinosis is more commonly seen in juvenile DM (JDM), but also develops in adult DM. Although the mechanism of calcinosis remains unclear, several pathogenic hypotheses have been proposed, including intracellular accumulation of calcium secondary to an alteration of the cellular membrane by trauma and inflammation, local vascular ischemia, dysregulation of mechanisms controlling the deposition and solubility of calcium and phosphate, and mitochondrial damage of muscle cells. Identifying calcinosis biomarkers is important for early disease detection and risk assessment, and may lead to novel therapeutic targets for the prevention and treatment of DM-associated calcinosis. In this review, we summarize myositis autoantibodies associated with calcinosis in DM, histopathology and chemical composition of calcinosis, genetic and inflammatory markers that have been studied in adult DM and JDM-associated calcinosis, as well as potential novel biomarkers.	0
Eye development in vertebrates is a highly coordinated multistep process while defects in key factors might lead to severe congenital ocular disorders. SMO encodes a G protein-coupled receptor that functions in Hedgehog signal transduction, an essential step during eye development. Here we reported the first identification of compound heterozygous mutations (c.G338A; p.R113Q and c.C1619T; p.A540V) in the SMO gene in a patient with both anterior segment dysgenesis (congenital corneal opacity, cataract) and morning glory syndrome, using trio-based whole exome sequencing. The clinical manifestations of this patient were quite consistent with the phenotypes observed in murine SMO null mutants. In silico bioinformatics analyses showed that the newly identified mutations revealed extremely low allele frequencies in the general populations, and were predicted to affect SMO protein stability and residues physiochemical properties. Further investigations revealed a significant decrease of SMO expression in the patient compared with healthy controls (0.71 ± 0.04 vs. 1.49 ± 0.29, P = 0.0265). Therefore, this study pinpoints, for the first time, the potential key sites in SMO that contribute to the maintenance of healthy ocular development, highlighting potential targets for upcoming gene therapy.	0
Cornelia de Lange syndrome (CdLS) is a rare syndromic genetic disorder characterized by multiple congenital anomalies with upper limb reduction defects, along with cardiac, gastrointestinal, and genitourinary defects. It is caused by genetic variations in the chromatin regulator genes, most commonly, the cohesin complex. Even though molecular genetic testing is highly recommended to confirm the diagnosis, high costs and unavailability in some settings are significant setbacks, and clinical criteria could be used. The typical craniofacial features include generalized hirsutism, synophrys, microbrachycephaly, highly arched eyebrows, and long eyelashes, along with height and weight below the 5th percentile. In this paper, we present a case of a 16-day-old male infant in whom a clinical diagnosis of classical CdLS was made.	0
A-Type lamins, arising from the LMNA gene, are intermediate filaments proteins that belong to the lamina, a ubiquitous nuclear network. Naturally occurring mutations in these proteins have been shown to be responsible for several distinct diseases that display skeletal and/or cardiac muscle or peripheral nerve involvement. These include familial partial lipodystrophy of the Dunnigan type and the mandibuloacral dysplasia syndrome. The pathophysiology of this group of diseases, often referred to as laminopathies, remains elusive. We report a new condition in a 30-yr-old man exhibiting a previously undescribed heterozygous R133L LMNA mutation. His phenotype associated generalized acquired lipoatrophy with insulin-resistant diabetes, hypertriglyceridemia, hepatic steatosis, hypertrophic cardiomyopathy with valvular involvement, and disseminated whitish papules. Immunofluorescence microscopic analysis of the patient's cultured skin fibroblasts revealed nuclear disorganization and abnormal distribution of A-type lamins, similar to that observed in patients harboring other LMNA mutations. This observation broadens the clinical spectrum of laminopathies, pointing out the clinical variability of lipodystrophy and the unreported possibility of hypertrophic cardiomyopathy and skin involvement. It emphasizes the fact that the diagnosis of genetic alterations in A-type lamins requires careful and complete clinical and morphological investigations in patients regardless of the presenting signs.	0
Background:Dual-energy computed tomography (DECT) is being considered as a non-invasive diagnostic and characterization tool in calcium crystal-associated arthropathies. Our objective was to assess the potential of DECT in distinguishing between basic calcium phosphate (BCP) and calcium pyrophosphate (CPP) crystal deposition in and around joints in vivo. Methods:A total of 13 patients with calcific periarthritis and 11 patients with crystal-proven CPPD were recruited prospectively to undergo DECT scans. Samples harvested from BCP and CPP calcification types were analyzed using Raman spectroscopy and validated against synthetic crystals. Regions of interest were placed in BCP and CPP calcifications, and the following DECT attenuation parameters were obtained: CT numbers (HU) at 80 and 140 kV, dual-energy index (DEI), electron density (Rho), and effective atomic number (Z eff). These DECT attenuation parameters were compared and validated against crystal calibration phantoms at two known equal concentrations. Receiver operating characteristic (ROC) curves were plotted to determine the highest accuracy thresholds for DEI and Z eff. Results:Raman spectroscopy enabled chemical fingerprinting of BCP and CPP crystals both in vitro and in vivo. DECT was able to distinguish between HA and CPP in crystal calibration phantoms at two known equal concentrations, most notably by DEI (200 mg/cm3: 0.037 ± 0 versus 0.034 ± 0, p = 0.008) and Z eff (200 mg /cm3: 9.4 ± 0 versus 9.3 ± 0, p = 0.01) analysis. Likewise, BCP calcifications had significantly higher DEI (0.041 ± 0.005 versus 0.034 ± 0.005, p = 0.008) and Z eff (9.5 ± 0.2 versus 9.3 ± 0.2, p = 0.03) than CPP crystal deposits with comparable CT numbers in patients. With an area under the ROC curve of 0.83 [best threshold value = 0.0 39, sensitivity = 90. 9% (81.8, 97. 7%), specificity = 64.6% (50.0, 64. 6%)], DEI was the best parameter in distinguishing between BCP and CPP crystal depositions. Conclusion:DECT can help distinguish between crystal-proven BCP and CPP calcification types in vivo and, thus, aid in the diagnosis of challenging clinical cases, and in the characterization of CPP and BCP crystal deposition occurring in osteoarthritis.	0
OBJECTIVE:To differentiate juvenile polymyositis (PM) and muscular dystrophy, both of which may present with chronic muscle weakness and inflammation. METHODS:We studied 39 patients with probable or definite juvenile PM and 9 patients with muscular dystrophies who were initially misdiagnosed as having juvenile PM. Differences in demographic, clinical, and laboratory results; outcomes; and treatment responses were evaluated by Fisher's exact and rank sum tests. Random forests classification analysis and logistic regression were performed to examine significant differences in multivariable models. RESULTS:Clinical features and serum muscle enzyme levels were similar between juvenile PM and dystrophy patients, except 89% of dystrophy patients had muscle atrophy compared with 46% of juvenile PM patients. Dystrophy patients had a longer delay to diagnosis (median 12 versus 4 months) and were less frequently hospitalized than juvenile PM patients (22% versus 74%). No dystrophy patients, but 54% of juvenile PM patients, had a myositis autoantibody. Dystrophy patients more frequently had myopathic features on muscle biopsy, including diffuse variation of myofiber size, fiber hypertrophy, and myofiber fibrosis (44-100% versus 8-53%). Juvenile PM patients more frequently had complex repetitive discharges on electromyography and a complete response to treatment with prednisone or other immunosuppressive agents than dystrophy patients (44% versus 0%). Random forests analysis revealed that the most important features in distinguishing juvenile PM from dystrophies were myositis autoantibodies, clinical muscle atrophy, and myofiber size variation on biopsy. Logistic regression confirmed muscle atrophy, myofiber fibrosis, and hospitalization as significant predictors. CONCLUSION:Muscular dystrophy can present similarly to juvenile PM. Selected clinical and laboratory features are helpful in combination in distinguishing these conditions.	0
BACKGROUND:The molecular cause of severe congenital neutropenia (SCN) is unknown in 30% to 50% of patients. SEC61A1 encodes the α-subunit of the Sec61 complex, which governs endoplasmic reticulum protein transport and passive calcium leakage. Recently, mutations in SEC61A1 were reported to be pathogenic in common variable immunodeficiency and glomerulocystic kidney disease. OBJECTIVE:Our aim was to expand the spectrum of SEC61A1-mediated disease to include autosomal dominant SCN. METHODS:Whole exome sequencing findings were validated, and reported mutations were compared by Western blotting, Ca2+ flux assays, differentiation of transduced HL-60 cells, in vitro differentiation of primary CD34 cells, quantitative PCR for unfolded protein response (UPR) genes, and single-cell RNA sequencing on whole bone marrow. RESULTS:We identified a novel de novo missense mutation in SEC61A1 (c.A275G;p.Q92R) in a patient with SCN who was born to nonconsanguineous Belgian parents. The mutation results in diminished protein expression, disturbed protein translocation, and an increase in calcium leakage from the endoplasmic reticulum. In vitro differentiation of CD34+ cells recapitulated the patient's clinical arrest in granulopoiesis. The impact of Q92R-Sec61α1 on neutrophil maturation was validated by using HL-60 cells, in which transduction reduced differentiation into CD11b+CD16+ cells. A potential mechanism for this defect is the uncontrolled initiation of the unfolded protein stress response, with single-cell analysis of primary bone marrow revealing perturbed UPR in myeloid precursors and in vitro differentiation of primary CD34+ cells revealing upregulation of CCAAT/enhancer-binding protein homologous protein and immunoglobulin heavy chain binding protein UPR-response genes. CONCLUSION:Specific mutations in SEC61A1 cause SCN through dysregulation of the UPR.	0
High-molecular-weight kininogen (HMWK) deficiency is a very rare hereditary disorder caused by a defect of Kininogen-1 gene (KGN1). A 67-year-old asymptomatic male with an isolated prolonged activated partial thromboplastin time (aPTT) was recognized to have HMWK deficiency. The propositus had less than 1% HMWK procoagulant activity. The plasma HMWK procoagulant activities of his 2 younger sisters were 1.1% and less than 1%, respectively. Prekallikrein (PK) activity was also reduced in the propositus and two of his younger sisters with severe HMWK deficiency. Genetic testing to identify the KGN1 mutation provides a precise diagnosis for the patient and other family members. This Chinese family has a novel KGN1 nonsense variant, C to T, at nucleotide position 1456 leading to a stop codon in position 486 (p. Gln486*).	0
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disease caused by mutations in the CLDN16 or CLDN19 gene; however, few cases develop classical amelogenesis imperfecta. Herein, we report the case of a boy with early clinical renal manifestations that started at 1 year of age and presenting with dental hypoplasia and growth delay. The patient presented with vomiting, polyuria, and polydipsia. Apart from recurrent sterile leukocyturia, erroneously treated as infectious, he was normal, except for short stature and amelogenesis imperfecta with gradually discolored teeth. Laboratory tests revealed hyperparathyroidism, hypomagnesemia, severe hypercalciuria, and hypermagnesuria on 24-h urine testing. Helical computed tomography confirmed nephrocalcinosis. We performed whole-exome sequencing (WES) to test the hypothesis of FHHNC and oligogenic inheritance of amelogenesis. Analysis of the WES binary sequence alignment/map file revealed the presence of exon 1 of the CLDN16 and absence of the other exons [c.325_c918*? (E2_E5del)]. We confirmed a CLDN16 E2_E5 homozygous deletion by multiplex ligation-dependent probe amplification and polymerase chain reaction assays. Although most mutations causing FHHNC are missense and nonsense mutations in the CLDN16 or CLDN19 gene, large deletions occur and may be misled by WES, which is generally used for genetic screening of oligogenic disorders. The patient received cholecalciferol, magnesium oxide and potassium citrate. Later, the combination with hydrochlorothiazide plus amiloride was prescribed, with a good response during follow-up. Our report broadens the phenotype of FHHNC, including severe early-onset amelogenesis and short stature, and reinforces the phenotype-genotype correlation of the large deletion found in CLDN16.	0
Background: Congenital cataract is the most common cause of blindness in the world. Congenital cataracts are clinically and genetically heterogeneous and are mostly inherited in an autosomal dominant fashion. We identified the genetic cause of isolated autosomal dominant cataract in a four-generation British family and a Czech family.Methods: Whole exome sequencing (WES) was performed on one affected member in the British family and two affected members in the Czech family.Results: A novel missense variant c.388C > T; p.(R130C) was identified in the Lens integral membrane protein (LIM2) and found to co-segregate with disease in both families.Conclusions: Here we report the first autosomal dominant congenital cataract variant p.(R130C) in LIM2, causing a non-syndromic pulverulent and nuclear phenotype in European families.	0
We performed shallow single-cell sequencing of genomic DNA across 1475 cells from a cell-line, COLO829, to resolve overall complexity and clonality. This melanoma tumor-line has been previously characterized by multiple technologies and is a benchmark for evaluating somatic alterations. In some of these studies, COLO829 has shown conflicting and/or indeterminate copy number and, thus, single-cell sequencing provides a tool for gaining insight. Following shallow single-cell sequencing, we first identified at least four major sub-clones by discriminant analysis of principal components of single-cell copy number data. Based on clustering, break-point and loss of heterozygosity analysis of aggregated data from sub-clones, we identified distinct hallmark events that were validated within bulk sequencing and spectral karyotyping. In summary, COLO829 exhibits a classical Dutrillaux's monosomic/trisomic pattern of karyotype evolution with endoreduplication, where consistent sub-clones emerge from the loss/gain of abnormal chromosomes. Overall, our results demonstrate how shallow copy number profiling can uncover hidden biological insights.	0
Weber's syndrome was described first by the German-born English physician Hermann Weber in a 52-year-old gentleman who had developed left-sided third nerve palsy with right-sided hemiplegia caused by an acute bleed in the left cerebral peduncle.[1] Weber syndrome, classically described as a midbrain stroke syndrome and superior alternating hemiplegia, involves oculomotor fascicles in the interpeduncular cisterns and cerebral peduncle, thereby causing ipsilateral third nerve palsy with contralateral hemiparesis. It most commonly results from the occlusion of a branch of the posterior cerebral artery. The oculomotor(third cranial) nerve has two main motor nuclei, the main motor nucleus, and the accessory parasympathetic nucleus. The main motor nucleus is located in the tectum portion of the midbrain at the level of the superior colliculus and supplies all the extraocular muscles except the lateral rectus and the superior oblique muscles[2], and the levator palpebrae superioris. The accessory parasympathetic nucleus, also known as the Edinger Westphal nucleus, is situated posterior to the main motor nucleus and its postganglionic fibers pass through the short ciliary nerves to supply the constrictor pupillae of the iris and the ciliary muscles. The nerve fascicles then travel forward and lateral through the red nucleus and converge at the interpeduncular fossa before exiting the midbrain. As the nucleus and fascicles are spread over a large area of the midbrain, lesions in the midbrain can present with either partial or complete third nerve palsy. The lesions in lower midbrain affect the extraocular muscles but spare the pupils, while lesions affecting both upper and middle parts of the midbrain are associated with pupillary dilatation.[2] 	0
Abnormal neurodevelopment has been widely reported in combined methylmalonic aciduria (MMA) and homocystinuria, cblC type (cblC disease), but neurodevelopmental phenotypes in cblC have not previously been systematically studied. We sought to further characterize developmental neurology in children with molecularly-confirmed cblC. Thirteen children at our center with cblC, born since implementation of expanded newborn screening in New York State, undertook standard-of-care evaluations with a pediatric neurologist and pediatric ophthalmologist. At most recent follow-up (mean age 50 months, range 9-84 months), of twelve children with early-onset cblC, three (25%) had a history of clinical seizures and two (17%) meet criteria for microcephaly. A majority of children had hypotonia and nystagmus. Twelve out of thirteen (92%) underwent neurodevelopmental evaluation (mean age 41 months; range 9-76 months), each child tested with standardized parental interviews and, where possible, age- and disability-appropriate neuropsychological batteries. All patients showed evidence of developmental delay with the exception of one patient with a genotype predictive of attenuated disease and near-normal biochemical parameters. Neurodevelopmental deficits were noted most prominently in motor skills, with relative preservation of socialization and communication skills. Nine children with early-onset cblC underwent magnetic resonance imaging and spectroscopy (MRI/MRS) at mean age of 47 months (range 6-81 months); common abnormalities included callosal thinning, craniocaudally short pons, and increased T2 FLAIR signal in periventricular and periatrial white matter. Our study further characterizes variable neurodevelopmental phenotypes in treated cblC, and provides insights into the etiopathogenesis of disordered neurodevelopment frequently encountered in cblC. Plasma homocysteine and MMA, routinely measured at clinical follow-up, may be poor predictors for neurodevelopmental outcomes. Additional data from large, prospective, multi-center natural history studies are required to more accurately define the role of these metabolites and others, as well as that of other genetic and environmental factors in the etiopathogenesis of the neurologic components of this disorder.	0
BACKGROUND AND PURPOSE:Guidelines on monogenic cerebral small-vessel disease (cSVD) diagnosis and management are lacking. Endorsed by the Stroke and Neurogenetics Panels of the European Academy of Neurology, a group of experts has provided recommendations on selected monogenic cSVDs, i.e. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), autosomal dominant High Temperature Requirement A Serine Peptidase 1 (HTRA1), cathepsin-A-related arteriopathy with strokes and leukoencephalopathy (CARASAL), pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), Fabry disease, mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and type IV collagen (COL4)A1/2. METHODS:We followed the Delphi methodology to provide recommendations on several unanswered questions related to monogenic cSVD, including genetic testing, clinical and neuroradiological diagnosis, and management. RESULTS:We have proposed 'red-flag' features suggestive of a monogenic disease. General principles applying to the management of all cSVDs and specific recommendations for the individual forms of monogenic cSVD were agreed by consensus. CONCLUSIONS:The results provide a framework for clinicians involved in the diagnosis and management of monogenic cSVD. Further multicentre observational and treatment studies are still needed to increase the level of evidence supporting our recommendations.	0
Anorectal conditions are one of the most common problems evaluated by primary care physicians. Most patients present with rectal pain, rectal bleeding, or purulent drainage per rectum. Colorectal conditions have overlapping symptoms. Thorough history and careful anorectal examination can differentiate common anorectal conditions like hemorrhoids, anorectal abscesses, anal fistula, anal fissure, and anal condyloma. Most of these conditions can be diagnosed and treated without imaging.	0
BACKGROUND:To study the histological structure and immunohistochemical (IHC) parameters of the plasmacytoma tumour substrate in patients with multiple myeloma (MM). METHODS:The study included 21 patients (10 men/11 women) aged 23 to 73 years old with newly diagnosed MM complicated by plasmacytoma. Bone plasmacytoma was diagnosed in 14 patients, and extramedullary plasmacytoma was diagnosed in 7 patients. Plasmacytoma tissue specimens were examined using a LEICA DM4000B microscope. Anti-CD56, anti-CD166, anti-CXCR4, anti-Ki-67, and anti-c-MYC antibodies were used for IHC study of plasmacytoma biopsies. RESULTS:When comparing the morphology of bone and extramedullary plasmacytoma, no significant differences were revealed; however, the substrate of extramedullary plasmacytoma was more often represented by tumour cells with an immature morphology than was the bone plasmacytoma substrate (57.1% vs. 28.6%, respectively). We revealed a significant difference in the expression of CD166 between bone and extramedullary plasmacytoma. The mean values ​​of CD166 expression in bone plasmacytoma cells were significantly higher (36.29 ± 7.61% versus 9.57 ± 8.46%, respectively; p = 0.033) than those in extramedullary plasmacytoma cells. We noticed that in extramedullary plasmacytoma cells, there were higher values for the Ki-67 index than in bone plasmacytoma cells, and this result was independent of cell morphology. CONCLUSION:The mechanisms involved in the dissemination of tumour plasma cells are currently unexplored. Even in such a small sample, some differences in expression could be identified, which may indicate that different mechanisms lead to the formation of bone and extramedullary plasmacytomas. Specifically, the expression of CD166 in extramedullary plasmacytoma cells was almost 4 times lower than that in bone plasmacytoma cells, which may indicate the involvement of CD166 in the mechanisms of bone destruction. The proliferative activity of extramedullary plasmacytoma cells was shown to be higher than that of bone plasmacytoma cells.	0
Naegeli(-Franceschetti-Jadassohn) syndrome and Dermatopathia Pigmentosa Reticularis are allelic disorders, both characterized by a congenital generalized reticulate hyperpigmentation, palmoplantar hyperkeratosis and other ectodermal symptoms. The disorders differ in their primary pigmentation localization and hair and dental manifestations. They resemble Dyskeratosis Congenita and Poikiloderma Clericuzio type in many of the skin changes, but especially the presence of leukoplakia and bone marrow disfunctioning in the first, and of telangiectasias, generalized hyperkeratosis of palms and soles, and nail pachyonychia in the latter are distinguishing features. Here we present two unrelated patients who have prenatal and postnatal growth retardation, microcephaly, developmental delay, generalized reticulate hyperpigmentation, hypohidrosis, absent fingertip prints, and absent palmoplantar hyperkeratosis. The patients differ in nail manifestations and hair colour. No Keratin14 mutation or genomic imbalance at CGHarray could be found in either of them. Although their phenotype overlaps with Naegeli syndrome, dermatopathia pigmentosa reticularis, dyskeratosis congenita and poikiloderma Clericuzio type, the differences in ectodermal manifestations, immunological functioning, growth pattern and cognition may indicate the presence of a separate entity.	0
The molybdenum cofactor deficiency is an autosomal recessive disease, characterized by rapidly progressive and severe neurological damage that mimics a hypoxic-ischemic encephalopathy due to the accumulation of toxic metabolites that cause rapid neurodegeneration after the delivery. It is eventually lethal, in a similar way to the rare isolated sulfite oxidase deficiency. This serious pathology usually causes death in the immediate neonatal period in the more severe variants. We report a case of two consecutive pregnancies with enlarged cisterna magna as the only prenatal pathological finding since 26 weeks of gestation (WG) and the subsequent death of the newborns in the first week after birth. After the second pregnancy, we reached the diagnosis of molybdenum cofactor deficiency due to MOCS1 gene mutation. According to the cases reported in the literature, this is the case with the earliest neuroimage prenatal findings.	0
The prevention of relapse is the major therapeutic challenge in older patients with acute myeloid leukemia (AML) who have obtained a complete remission (CR) on intensive chemotherapy. In this randomized phase 3 study (HOVON97) in older patients (≥60 years) with AML or myelodysplastic syndrome with refractory anemia with excess of blasts, in CR/CR with incomplete hematologic recovery (CRi) after at least 2 cycles of intensive chemotherapy, we assessed the value of azacitidine as postremission therapy with respect to disease-free survival (DFS; primary end point) and overall survival (OS; secondary end point). In total, 116 eligible patients were randomly (1:1) assigned to either observation (N = 60) or azacitidine maintenance (N = 56; 50 mg/m2, subcutaneously, days 1-5, every 4 weeks) until relapse, for a maximum of 12 cycles. Fifty-five patients received at least 1 cycle of azacitidine, 46 at least 4 cycles, and 35 at least 12 cycles. The maintenance treatment with azacitidine was feasible. DFS was significantly better for the azacitidine treatment group (logrank; P = .04), as well as after adjustment for poor-risk cytogenetic abnormalities at diagnosis and platelet count at randomization (as surrogate for CR vs CRi; Cox regression; hazard ratio, 0.62; 95% confidence interval, 0.41-0.95; P = .026). The 12-month DFS was estimated at 64% for the azacitidine group and 42% for the control group. OS did not differ between treatment groups, with and without censoring for allogeneic hematopoietic cell transplantation. Rescue treatment was used more often in the observation group (n = 32) than in the azacitidine maintenance group (n = 9). We conclude that azacitidine maintenance after CR/CRi after intensive chemotherapy is feasible and significantly improves DFS. The study is registered with The Netherlands Trial Registry (NTR1810) and EudraCT (2008-001290-15).	0
Glycogen storage disease type XV (GSD XV) is a recently described muscle glycogenosis due to glycogenin-1 (GYG1) deficiency characterized by the presence of polyglucosan bodies on muscle biopsy (Polyglucosan body myopathy-2, PGBM2). Here we describe a 44 year-old man with limb-girdle muscle weakness mimicking a limb-girdle muscular dystrophy (LGMD), and early onset exertional myalgia. Neurologic examination revealed a waddling gait with hyperlordosis, bilateral asymmetric scapular winging, mild asymmetric deltoid and biceps brachii weakness, and pelvic-girdle weakness involving the gluteal muscles and, to a lesser extent, the quadriceps. Serum creatine kinase levels were slightly elevated. Electrophysiological examination showed a myopathic pattern. There was no cardiac or respiratory involvement. Whole-body muscle MRI revealed atrophy and fat replacement of the tongue, biceps brachii, pelvic girdle and erector spinae. A deltoid muscle biopsy showed the presence of PAS-positive inclusions that remained non-digested with alpha-amylase treatment. Electron microscopy studies confirmed the presence of polyglucosan bodies. A diagnostic gene panel designed by the Genetic Diagnosis Laboratory of Strasbourg University Hospital (France) for 210 muscular disorders genes disclosed two heterozygous, pathogenic GYG1 gene mutations (c.304G>C;p.(Asp102His) + c.164_165del). Considering the clinical heterogeneity found in the previously described 38 GYG-1 deficient patients, we suggest that GYG1 should be systematically included in targeted NGS gene panels for LGMDs, distal myopathies, and metabolic myopathies.	0
BACKGROUND:Verheij syndrome is a rare microdeletion syndrome of chromosome 8q24.3 that harbors PUF60, SCRIB, and NRBP2 genes. Subsequently, loss of function mutations in PUF60 have been found in children with clinical features significantly overlapping with Verheij. CASE PRESENTATION:Here we present the first Chinese Han patient with a de novo nonsense variant (c.1357C > T, p.Gln453*) in PUF60 by clinical whole exome sequencing. The 5-year-old boy presents with dysmorphic facial features, intellectual disability, and growth retardation but without apparent cardiac, renal, ocular, and spinal anomalies. CONCLUSIONS:Our finding contributes to the understanding of the genotype and phenotype in PUF60 related disorder.	0
Kenny-Caffey syndrome (KCS) is a rare dysmorphologic syndrome characterized by proportionate short stature, cortical thickening and medullary stenosis of tubular bones, delayed closure of anterior fontanelle, eye abnormalities, and hypoparathyroidism. The autosomal dominant form of KCS (KCS type 2 [KCS2]) is distinguished from the autosomal recessive form of KCS (KCS type 1 [KCS1]), which is caused by mutations of the tubulin-folding cofactor E (TBCE) gene, by the absence of mental retardation. In this study, we recruited four unrelated Japanese patients with typical sporadic KCS2, and performed exome sequencing in three patients and their parents to elucidate the molecular basis of KCS2. The possible candidate genes were explored by a de novo mutation detection method. A single gene, FAM111A (NM_001142519.1), was shared among three families. An identical missense mutation, R569H, was heterozygously detected in all three patients but not in the unaffected family members. This mutation was also found in an additional unrelated patient. These findings are in accordance with those of a recent independent report by a Swiss group that KCS2 is caused by a de novo mutation of FAM111A, and R569H is a hot spot mutation for KCS2. Although the function of FAM111A is not known, this study would provide evidence that FAM111A is a key molecule for normal bone development, height gain, and parathyroid hormone development and/or regulation.	0
Imerslund-Gräsbeck Syndrome is a rare autosomal recessive disorder characterized by proteinuria and selective malabsorption of cobalamin. Deficiency of cobalamin can lead to megaloblastic anemia, pancytopenia and even "pseudo"-thrombotic microangiopathy (TMA). Signs of mechanical hemolysis on peripheral blood smear, elevated lactate dehydrogenase and thrombocytopenia are common findings of TMA. We report a child presenting with TMA features with cobalamin deficiency. Because of her family history of vitamin B12 deficiency and proteinuria, the performed genetic analysis revealed that an Imerslund-Gräsbeck Syndrome with the detection of a homozygous mutation in AMN gene.	0
Skeletal dysplasias are a diverse group of heritable diseases affecting bone and cartilage growth. Throughout the years, the molecular defect underlying many of the diseases has been identified. These identifications led to novel insights in the mechanisms regulating bone and cartilage growth and homeostasis. One of the pathways that is clearly important during skeletal development and bone homeostasis is the Wingless and int-1 (WNT) signaling pathway. So far, three different WNT signaling pathways have been described, which are all activated by binding of the WNT ligands to the Frizzled (FZD) receptors. In this review, we discuss the skeletal disorders that are included in the latest nosology of skeletal disorders and that are caused by genetic defects involving the WNT signaling pathway. The number of skeletal disorders caused by defects in WNT signaling genes and the clinical phenotype associated with these disorders illustrate the importance of the WNT signaling pathway during skeletal development as well as later on in life to maintain bone mass. The knowledge gained through the identification of the genes underlying these monogenic conditions is used for the identification of novel therapeutic targets. For example, the genes underlying disorders with altered bone mass are all involved in the canonical WNT signaling pathway. Consequently, targeting this pathway is one of the major strategies to increase bone mass in patients with osteoporosis. In addition to increasing the insights in the pathways regulating skeletal development and bone homeostasis, knowledge of rare skeletal dysplasias can also be used to predict possible adverse effects of these novel drug targets. Therefore, this review gives an overview of the skeletal and extra-skeletal phenotype of the different skeletal disorders linked to the WNT signaling pathway.	0
The aim of the present study was to present the diagnosis and treatment course of a patient with cobalamin C deficiency (cblC) hospitalized with renal function abnormality from the onset. A female, 7-year-old patient who presented with a cough and progressive dyspnea for 1 day was admitted to the Children's Hospital of Nanjing Medical University (Nanjing, China). A routine clinical examination was performed, including physical examination, routine blood and urine tests, blood gas analysis, computed tomography scans of the head, chest and abdomen, electrocardiogram, echocardiography and abdominal ultrasonography. In addition, laboratory tests were performed, including tests for viral infection and markers of autoimmunity, humoral immunity, myocardial enzymes and tumors. Tandem mass analysis and renal biopsy were conducted. Next generation sequencing (NGS) was performed to identify mutated genes, and structural investigation was conducted to identify the key residue mutations in the patient. Routine clinical examination revealed that the patient had multiple organ failure, indicating the presence of metabolic disease. Tandem mass analysis and renal biopsy also indicated that the patient had methylmalonic acidemia (MMA) and thrombotic microangiopathy combined with focal renal cortical necrosis. Furthermore, next-generation sequencing identified the presence of two heterozygous mutations in the MMA cblC type with homocystinuria (MMACHC) gene. Structural analysis demonstrated that the two mutations were in key components of the MMACHC protein. The patient was finally diagnosed with cblC according to the results obtained. In conclusion, NGS may aid in the diagnosis and therapeutic management of cblC with renal abnormality from the onset in children.	0
BACKGROUND:Heavy proteinuria at diagnostic renal biopsy has been reported as an independent risk factor for deteriorating renal function in benign nephrosclerosis (BNS). However, studies investigating the relationship between the amount of proteinuria during follow-up and long-term renal prognosis in BNS are limited. This study aimed to assess the relationship between time-averaged proteinuria (TAP) and renal prognosis in BNS. METHODS:The study participants included 98 patients with biopsy-proven BNS (average age 52 ± 13 years, estimated glomerular filtration rate (eGFR) 53 ± 25 ml/min/1.73 m2, urine protein excretion at baseline 1.34 ± 1.30 g/gCr) from the Jikei University Hospital. Multivariate analysis was used to investigate the effects of TAP and other clinicopathological findings on the risk for renal outcome in biopsy-proven BNS (a 30% decline in eGFR from baseline or end-stage renal disease). Proteinuria was measured every 6 months and the mean value was used as an indicator of TAP. RESULTS:The average observation period was 56 ± 43 months. In the unadjusted model, higher levels of TAP and urinary protein at baseline, glomerulosclerosis, and tubulointerstitial damage were associated with renal prognosis. The adjusted model demonstrated a significant association between TAP and renal outcomes (hazard ratio 5.45, 95% confidence interval 3.02-10.7), which was independent of higher baseline proteinuria, glomerulosclerosis, and tubulointerstitial damage. CONCLUSIONS:TAP is an independent risk factor for renal prognosis in patients with BNS, indicating the significance of urinary protein excretion during follow-up for the progression of BNS. Clinicians should understand the importance of follow-up evaluation for proteinuria in patients with BNS.	0
Pontocerebellar hypoplasias are a group of autosomal recessive neurodevelopmetal disorders with varied phenotypic presentations and extensive genetic mutational landscape that are currently classified into ten subtypes. This classification is based predominantly on the genetic iterations as the phenotypic presentations are often broad and overlapping. Pontocerebellar hypoplasia type-3 (PCH3) is an autosomal recessive disorder characterized by a small cerebellar vermis, hyperreflexia, and seizures, described in Middle Eastern families in association with a homozygous truncating mutation of the PCLO gene in locus 7q11-21. This is a case of PCH, with previously unreported novel genetic alterations. The patient is a 1-week-old girl, born at term to a 26-year-old G4P0A3 woman in a nonconsanguinous relation. At birth, the baby was depressed and hypertonic with abnormal tonic-clonic movements of extremities. MRI revealed cerebellar and brainstem hypoplasia. Postmortem examination revealed a palmar simian crease. The cerebellum measured 2.5 cm from side to side and 1 cm from rostral to caudal. The vermis was rudimentary. Sectioning revealed a flattened linear fourth ventricle, scant abortive cerebellar foliae, and a markedly small cerebellum when compared with the cerebrum and with age-matched size. H&E-stained sections of cerebellum revealed scant rudimentary foliae. A rudimentary unilateral embolliform nucleus was identified. The remaining cerebellar nuclei were absent. Chromosomal microarray showed an interstitial duplication of 841 kB on chromosome 7q11.23. Locus 7q11.23 contains FGL2 and GSAP genes and is 5 MB upstream of the 7q11-21 region, suggesting a possible linkage. This novel genomic finding possibly represents a new familial variant of PCH closely associated with PCH-3 and further strengthens its association with the 7q11 locus.	0
The authors present the case of a 27-year-old patient who suffered from spontaneous bleeding during infancy and from a severe and central venous thrombosis in adult years. The patient underwent a thorough laboratory work-up on both occasions and was diagnosed with hypofibrinogenaemia as well as protein S deficiency, 2 diseases that contrast in their intrinsic bleeding/thrombotic risk. The patient's high-risk pregnancy was carried out up to a successful full-term eutocic delivery which required fibrinogen concentrate to reduce life-threatening bleeding. The patient's child was also diagnosed with hypofibrinogenaemia, later on confirmed with the pathogenic mutation Fibrinogen Marseilles II. This case was used to conduct a literature review of congenital fibrinogen disorders, rare entities that require more awareness for early diagnosis and accurate management. LEARNING POINTS:Fibrinogen disorders are uncommon causes of either bleeding or thrombotic events and may be acquired or inherited in a recessive or dominant autosomal manner.Congenital fibrinogen deficiencies are rare but should be investigated when undergoing diagnostic work-up for thrombotic or haemorrhagic events in adult years.Determination of molecular defects is important for confirmation and to elaborate a treatment strategy according to the inherent risk for either thrombotic or haemorrhagic events.	0
The novel coronavirus disease 2019, a pandemic of global concern, caused by the novel severe acute respiratory syndrome coronavirus 2 has severely revealed the need for public monitoring and efficient screening techniques. Despite the various advancements made in the medical and research field, containment of this virus has proven to be difficult on several levels. As such, it is a necessary requirement to identify possible hotspots in the early stages of any disease. Based on previous studies carried out on coronaviruses, there is a high likelihood that severe acute respiratory syndrome coronavirus 2 may also survive in wastewater. Hence, we propose the use of nanofiber filters as a wastewater pretreatment routine and upgradation of existing wastewater evaluation and treatment systems to serve as a beneficial surveillance tool.	0
Greig cephalopolysyndactyly syndrome (GCPS) is one of the autosomal dominant-inherited syndromes, caused by haploinsufficiency of the GLI3 gene. It is a rare, multiple congenital syndrome with an estimated rate of 0.009%. With the classic clinical triad of preaxial polydactyly with cutaneous syndactyly of at least one limb, hypertelorism, and macrocephaly, presumptive diagnosis of GCPS is made. The purpose of this article is to report a case of GCPS with emphasis on craniofacial and oral features.	0
The use of antineoplastic drugs has a central role in treatment of patients affected by cancer but is often associated with numerous electrolyte derangements which, in many cases, could represent life-threatening conditions. In fact, while several anti-cancer agents can interfere with kidney function leading to acute kidney injury, proteinuria, and hypertension, in many cases alterations of electrolyte tubular handling and water balance occur. This review summarizes the mechanisms underlying the disturbances of sodium, potassium, magnesium, calcium, and phosphate metabolism during anti-cancer treatment. Platinum compounds are associated with sodium, potassium, and magnesium derangements while alkylating agents and Vinca alkaloids with hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH). Novel anti-neoplastic agents, such as targeted therapies (monoclonal antibodies, tyrosine kinase inhibitors, immunomodulators, mammalian target of rapamycin), can induce SIADH-related hyponatremia and, less frequently, urinary sodium loss. The blockade of epidermal growth factor receptor (EGFR) by anti-EGFR antibodies can result in clinically significant magnesium and potassium losses. Finally, the tumor lysis syndrome is associated with hyperphosphatemia, hypocalcemia and hyperkalemia, all of which represent serious complications of chemotherapy. Thus, clinicians should be aware of these side effects of antineoplastic drugs, in order to set out preventive measures and start appropriate treatments.	0
A 43-year-old woman underwent radiofrequency pulmonary vein ablation for symptomatic paroxysmal atrial fibrillation. At 3 months, she developed worsening dyspnea and exercise intolerance; tests revealed severe stenosis in her right pulmonary veins at the venoatrial junction and an abnormally small left atrium.	0
PURPOSE:We aim to propose a new protocol for olfaction rehabilitation after total laryngectomy based on training of sensory perception levels using the Nasal Airflow-Inducing Maneuver. METHODS:This is a randomized clinical trial including patients undergoing total laryngectomy between March 2010 and March 2019. Patients with nasal or oral abnormalities, prior olfaction impairment, a muco-ciliary transport time higher than 30 min, positive history for feeding, and neurological disorders were excluded. Thirty-three patients were enrolled and were randomized into two groups: an Experimental group, submitted to the new protocol (olfactory perception rehabilitation after total laryngectomy-OPRAT) and a Control group that did not receive any treatment. Subjective Olfactometry, Chemosensory Complaints Score, and University of Washington Quality of Life version 4 questionnaires were used to assess the outcomes before and after treatment, and at 3-month, 6-month, and 10-month follow-up. RESULTS:Among the 33 patients included (32 men and 1 woman; mean age, 67.94 ± 5.64 years), 17 were subjected to olfaction rehabilitation and 16 did not receive any treatment. At baseline evaluation, there were not significant differences between the two groups. At the end of treatment, the rehabilitated group improved their olfaction capability significantly. Such improvement remained stable over time, and after 10 months, only the Experimental group had significant improvements in all outcome measures. CONCLUSIONS:The OPRAT may guarantee excellent results in the short- and long-term time with positive effects on the Quality of Life.	0
Alveolar rhabdomyosarcoma (ARMS) is a rare mesenchymal tumor with differentiation toward the skeletal muscle. Although several cases of canine ARMS have been reported in veterinary medicine, only one case of abdominal ARMS has been reported in a cow. A 13-month-old, Japanese black heifer was referred for pus-like nasal discharge. On autopsy, an 11 × 7 × 4.5-cm pedunculated mass closed to the left palatine tonsillar sinus that occupied the laryngopharynx. Histopathological and immunohistochemical analyses indicated that the tumor was a typical ARMS. To the best of our knowledge, this has been the first case of primary pharyngeal ARMS in a Japanese black heifer, which is rare among cows. Nonetheless, its characteristics, including site, age and subtype, are identical to those among humans and dogs.	0
Null mutations in CRTAP or P3H1, encoding cartilage-associated protein and prolyl 3-hydroxylase 1, cause the severe bone dysplasias, types VII and VIII osteogenesis imperfecta. Lack of either protein prevents formation of the ER prolyl 3-hydroxylation complex, which catalyzes 3Hyp modification of types I and II collagen and also acts as a collagen chaperone. To clarify the role of the A1 3Hyp substrate site in recessive bone dysplasia, we generated knock-in mice with an α1(I)P986A substitution that cannot be 3-hydroxylated. Mutant mice have normal survival, growth, femoral breaking strength and mean bone mineralization. However, the bone collagen HP/LP crosslink ratio is nearly doubled in mutant mice, while collagen fibril diameter and bone yield energy are decreased. Thus, 3-hydroxylation of the A1 site α1(I)P986 affects collagen crosslinking and structural organization, but its absence does not directly cause recessive bone dysplasia. Our study suggests that the functions of the modification complex as a collagen chaperone are thus distinct from its role as prolyl 3-hydroxylase.	0
Paediatric skull lesions are commonly identified on imaging. They can be challenging to image, given their location and size, and often require several imaging modalities to narrow down the differential diagnosis. Accurate diagnosis of these lesions is paramount because the clinical therapy can vary tremendously. In this review, we provide a simple and systematic approach to clinical-radiological features of primary skull lesions. We highlight the imaging characteristics and differentiate pathologies based on imaging appearances. We also accentuate the role of cross-sectional imaging in lesion identification and management implications.	0
BACKGROUND:Mucopolysaccharidosis type II (MPS II) or Hunter syndrome is an X-linked recessive lysosomal storage disorder resulting from deficient activity of iduronate 2-sulfatase (IDS) and the progressive lysosomal accumulation of sulfated glycosaminoglycans (GAGs). METHODS:A diagnosis of MPS II or Hunter syndrome was performed based on the following approach after a clinical and paraclinical suspicion. Two biochemical and molecular tests were carried out separately and according to the availability of the biological material. RESULTS:All patients in this cohort presented the most common MPS II clinical features. Electrophoresis of GAGs on a cellulose acetate plate in the presence of a high concentration of heparane sulfate showed an abnormal dermatan sulfate band in the patients compared with that in a control case. Furthermore, leukocyte IDS activity ranged from 0.00 to 0.75 nmol/h/mg of leukocyte protein in patients. Five previously reported mutations were identified in this study patients: one splice site mutation, c.240 + 1G > A; two missense mutations, p.R88P and p.G94D; a large deletion of exon 1 to exon 7; and one nonsense mutation, p.Q396*. In addition, two novel alterations were identified in the MPS II patients: one frame shift mutation, p.D450Nfs*95 and one nonsense mutation, p.Q204*. Additionally, five known IDS polymorphisms were identified in the patients: c.419-16 delT, c.641C > T (p.T214M), c.438 C > T (p.T146T), c.709-87G > A, and c.1006 + 38 T > C. CONCLUSIONS:The high level of urine GAGs and the deficiency of iduronate 2-sulfatase activity was associated with the phenotype expression of Hunter syndrome. Molecular testing was useful for the patients' phenotypic classification and the detection of carriers.	0
Congenital chloride diarrhea is a rare cause of severe infantile diarrhea with excessive chloride excretion. Mutations in the SLC26A3 gene cause congenital chloride diarrhea. It generally becomes apparent in the neonatal period and is characterized by electrolyte imbalances, metabolic alkalosis, and failure to thrive. The diagnosis of congenital chloride diarrhea is based on detecting excessive chloride in the stool (90 mmol/L). We report a Turkish neonate with congenital chloride diarrhea whose sibling had the same disease. The newborn was born by cesarean delivery. Diarrhea, vomiting, and weight loss started soon after birth. She was diagnosed as having congenital chloride diarrhea based on its typical clinical signs and a high concentration of stool chloride and was confirmed by genetic analysis. She was treated by means of salt supplementations and lansoprazole. Family history may play an important role in the early diagnosis because the disease is inherited autosomal recessively.	0
Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor, affecting the liver, the lungs and the bones most frequently. It has a heterogenous clinical presentation and there is no consensus on optimal treatment. This report aims to present a rare case of a retroperitoneal EHE and to discuss on proper management.	0
AIMS:To evaluate the diagnosis and imaging of patients with suspected endocarditis and the management in routine clinical practice across Europe, the EACVI Scientific Initiatives Committee performed a survey across European centres. In particular, the routine use of echocardiography, advanced imaging modalities and multidisciplinary team was explored. METHODS AND RESULTS:A total of 100 European Echocardiography Laboratories from 29 different countries responded to the survey, which consisted of 20 questions. For most of the use of echocardiography and advanced imaging, answers from the centres were relatively homogeneous and demonstrated good adherence to current recommendations. In particular, two-thirds of centres report the use of a specific endocarditis team for decision-making. Echocardiography plays a key role in the diagnosis and management of endocarditis. Nuclear imaging modalities are broadly available among the centres and are mainly used in prosthetic valve endocarditis and cardiac device-related infective endocarditis. Computed tomography (CT) is widely available and used to assess for structural valve abnormalities, neurological complications, and to preoperative assessment of the coronary arteries. Most institutions provide structured patients follow-up following hospital discharge. CONCLUSION:In Europe, a relatively homogenous adherence to current recommendation was observed for most diagnostic and management including the follow-up of patients with endocarditis. Decision-making is most commonly performed by a multidisciplinary team. Echocardiography remains the first line and central imaging modality for patient diagnosis and assessment, but 60% of centres also commonly use CT, whilst positron emission tomography imaging is used in patients with prosthetic valve endocarditis or device infection.	0
The urachus is an embryologic remnant which degenerates after the birth. An infected urachal cyst is one of a spectrum of presentations of urachal pathology, all of which are rare in adulthood. Infected urachal cyst is a rare pathology in adult women and it should be considered in the differential diagnosis of acute abdomen. We report here a case of a 50-year-old women with an infected urachal cyst reveled by an acute abdomen.	0
A family with five members who have variable findings of leuconychia, knuckle pads, hearing loss, and palmoplantar hyperkeratosis is described. The findings in these subjects are compared with those noted in previously reported patients with Bart-Pumphrey syndrome. The range of disorders which include knuckle pads as part of the phenotype is reviewed.	0
Acquired pure red cell aplasia (PRCA) following use of recombinant erythropoietin (rEPO) is distinctly rare and sporadically reported in the literature. We discuss a case of PRCA following the usage of rEPO (darbepoetin-α) during the management of anemia of chronic kidney disease in an elderly male subject with review of literature and a brief insight into proposed pathophysiologic mechanism, diagnosis, and management.	0
Background:To describe the clinical and multimodal imaging findings of a Brazilian family with Best vitelliform macular dystrophy. Methods:A retrospective chart review of a Brazilian family was conducted and complementary fundus images (color photography, autofluorescence, fluorescein angiography and optical coherence tomography) were analyzed. Results:Seven patients had typical macular lesions at different stages of Best vitelliform macular dystrophy. Electrooculography was performed in two of them and showed abnormal Arden ratio. The pedigree strongly suggests an autosomal dominant inheritance. Low visual acuity was mainly associated with advanced age, retinal pigment epithelium atrophy, and photoreceptors damage. However, yellow subretinal deposits were evidenced in patients with better visual acuity. Conclusion:We present the largest case series of a Brazilian family with Best vitelliform macular dystrophy. Multimodal imaging analysis is important to determine retinal abnormalities. Retinal pigment epithelium atrophy and loss of photoreceptors outer segments seem to be a late but important finding related to severe visual acuity impairment.	0
Brain tumors constitute the largest source of oncologic mortality in children and low-grade gliomas are among most common pediatric central nervous system tumors. Pediatric low-grade gliomas differ from their counterparts in the adult population in their histopathology, genetics, and standard of care. Over the past decade, an increasingly detailed understanding of the molecular and genetic characteristics of pediatric brain tumors led to tailored therapy directed by integrated phenotypic and genotypic parameters and the availability of an increasing array of molecular-directed therapies. Advances in neuroimaging, conformal radiation therapy, and conventional chemotherapy further improved treatment outcomes. This article reviews the current classification of pediatric low-grade gliomas, their histopathologic and radiographic features, state-of-the-art surgical and adjuvant therapies, and emerging therapies currently under study in clinical trials.	0
BACKGROUND AND METHODS:Apocrine adenocarcinoma is a rare subtype of breast cancer. We sought to compare the characteristics and survival of patients diagnosed with triple-negative apocrine adenocarcinoma to those of patients diagnosed with triple-negative invasive ductal carcinoma. Utilizing data from the National Cancer Database between 2004 and 2013, 70 524 eligible female patients with triple-negative breast cancer were identified including 566 patients with apocrine adenocarcinomas and 69 958 patients with invasive ductal carcinoma. Descriptive statistics for each variable were reported. A comparison of each covariate between the study cohorts was assessed in univariate and multivariate analysis. Cox proportional models were used to calculate hazard ratios. Additionally, the propensity score matching method was implemented to reduce treatment selection bias. RESULTS:Patients with triple-negative apocrine tumors were more likely to be older, Caucasian, and have smaller, moderately to well-differentiated tumors. Multivariable analysis noted a significantly improved survival for patients with triple-negative apocrine carcinoma (TNAC) vs triple-negative invasive ductal carcinoma (TNBC) (hazard ratio [HR] 0.65 [95% confidence interval [CI] [0.53-0.81], P = 0 < .001). Propensity score matching analysis confirmed a significant difference in overall survival for patients with TNAC in comparison to TNBC (HR 0.79 [95% CI [0.63-1.00], P = .05). DISCUSSION:Triple-negative apocrine adenocarcinomas have a modestly improved long-term survival when compared with triple-negative invasive ductal cancers.	0
BACKGROUND:SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. This study aimed to broaden the phenotypic-spectrum of disease related with SCN8A mutations. METHODS:To identify the pathogenic gene of a Chinese family, in which six members suffered from epilepsy, whole-exome sequencing was performed. In addition, target next-generation sequencing (NGS) was performed on 178 sporadic patients, who had epilepsy of unknown etiology within 6 months after birth. A detailed clinical history was obtained. RESULTS:A heterozygous missense mutation of SCN8A was identified in the Chinese family. Six de novo mutations of SCN8A were detected in 6 sporadic patients with epilepsy. In the family, six members developed seizures within a few years after birth. Five of them had milder clinical performance, that they had normal cognition and developmental milestones, and seizure-free was achieved by mono-therapy. The other one affected member presented with refractory epilepsy and developmental regression. She died from sudden unexpected death in epilepsy (SUDEP) at 17-year-old. Clinical features of six sporadic patients with SCN8A mutations were diverse, ranging from severe epileptic encephalopathy to benign epilepsy with normal cognition. Seizures started at the mean age of 3.9 months (from 2 months to 6 months). Seizure-free was achieved in four of them by mono- or multi-antiepileptic drugs. Five of them demonstrated mild or severe psychomotor retardation, whereas the other one was normal in development and intelligence. CONCLUSIONS:Our findings extend the spectrum of SCN8A mutations and the clinical features of patients with SCN8A mutations. The majority of SCN8A mutations were de novo, inherited mutations from the heterozygous parents can also occur. The phenotypic spectrum of SCN8A mutation varied largely. Most affected patients manifested as refractory epilepsy and severe intellectual disability, only a small number of patients presented with milder clinical patterns. Additionally, our study confirmed that the same mutation can lead to different phenotypes.	0
PURPOSE:Flow cytometry helps to elucidate the cellular immune repertoire's mechanisms in patients with temporal lobe epilepsy (TLE) due to limbic encephalitis (LE) subcategories and carries potential significance for subtype-specific treatment. METHODS:We enrolled 62 patients with TLE due to LE associated with no autoantibodies (n = 40), neural autoantibodies (n = 22), as well as autoantibodies against intracellular antigens (n = 15/22). All patients underwent neuropsychological testing, brain magnetic resonance imaging (MRI), electroencephalography (EEG) recordings, and peripheral blood (PB) and cerebrospinal fluid (CSF) investigations including flow cytometry. RESULTS:CD19+ B-cells were increased in the PB and CSF of patients with antibody-negative LE compared with those associated with antibodies against intracellular antigens (Kruskal-Wallis one way analysis of variance (ANOVA) on ranks with Dunn's test, p < 0.05). There were no differences in CD138+ B-cells, CD4+ T-cells, human leukocyte antigen - DR isotype (HLA-DR+) CD4+ T-cells, CD8+ T-cells, and HLA-DR+ CD8+ T-cells in the CSF between groups with LE. The blood-brain barrier is more often impaired in patients with antibody-negative LE than in LE with antibodies against intracellular antigens (chi-square test, p < 0.05). In addition, we detected no correlations between immune cell subsets and clinical or paraclinical parameters in patients with antibody-negative and intracellular antibody-positive LE. CONCLUSIONS:The increase of CD19+ B-cells in the CSF and frequent signs of dysfunctional blood-brain barrier in patients with antibody-negative rather than intracellular antibody-positive LE suggest that CD19+ B-cells play a role in antibody-negative encephalitis although their pathogenic role in the central nervous system (CNS) immunity because of missing correlations between immune cells and clinical and paraclinical parameters remains unknown. Further studies are required to evaluate the usefulness of these B-cells as a biomarker for the stratification of treatment strategies.	0
The extracellular matrix (ECM) is a highly dynamic and heterogeneous structure that plays multiple roles in living organisms. Its integrity and homeostasis are crucial for normal tissue development and organ physiology. Loss or alteration of ECM components turns towards a disease outcome. In this review, we provide a general overview of ECM components with a special focus on collagens, the most abundant and diverse ECM molecules. We discuss the different functions of the ECM including its impact on cell proliferation, migration and differentiation by highlighting the relevance of the bidirectional cross-talk between the matrix and surrounding cells. By systematically reviewing all the hereditary disorders associated to altered collagen structure or resulting in excessive collagen degradation, we point to the functional relevance of the collagen and therefore of the ECM elements for human health. Moreover, the large overlapping spectrum of clinical features of the collagen-related disorders makes in some cases the patient clinical diagnosis very difficult. A better understanding of ECM complexity and molecular mechanisms regulating the expression and functions of the various ECM elements will be fundamental to fully recognize the different clinical entities.	0
Hay and Wells in 1976 reported seven patients from four families who had an inherited condition of which the main features were ankyloblepharon, ectodermal defects, and cleft lip and palate. The inheritance pattern was determined to be autosomal dominant. This condition is known as AEC syndrome or Hay-Wells syndrome. We report a family with two sibs showing some of these features and congenital adhesions between the upper and lower jaws (alveolar synechiae). There seems to be a recessive pattern of inheritance as neither of the parents has any features of the syndrome. This could be described as a recessive form of Hay-Wells syndrome with additional features or be named as a new syndrome.	0
We report here on a young woman with multiple sclerosis, who developed a condition with eosinophilia and swelling of limbs seven weeks after initiation of ocrelizumab treatment. We consider her drug reaction to be compatible with a drug reaction with eosinophilia and systemic symptoms (DRESS), also called drug-induced hypersensitivity syndrome. She was treated with antihistamine and corticosteroid treatments, and recovered fully within three months of symptom onset. Ocrelizumab was not re-initiated. We are not aware of other DRESS-like cases related to ocrelizumab treatment.	0
Peeling skin syndrome is a rare genodermatosis characterized by variably pruritic superficial generalized peeling of the skin with several genes involved until now little is known about the association between FLG2 and peeling skin syndrome. We describe multiple family members from a consanguineous Saudi family with peeling skin syndrome. Next Generation Sequencing identifies a cosegregating novel variant in FLG2 c.632C>G (p.Ser211*) as a likely etiology in this family. Here, we reported on the clinical manifestation of homozygous loss of function variant in FLG2 as a disease-causing gene for peeling skin syndrome and expand the dermatology findings.	0
Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, also known as Hay-Wells syndrome, is an autosomal genetic disease with the main features of ankyloblepharon filiforme adnatum, ectodermal defects, and cleft lip/palate. The authors report a patient with 17 months old girl with AEC syndrome having ankyloblepharon, cleft and palate, and ectrodactyly with some associated features. Etiology, clinical features, differential diagnosis, and treatment have been elaborated in this clinical report.	0
The condition termed 46,XY complete gonadal dysgenesis is characterized by a completely female phenotype and streak gonads. In contrast, subjects with 46,XY partial gonadal dysgenesis and those with embryonic testicular regression sequence usually present ambiguous genitalia and a mix of Müllerian and Wolffian structures. In 46,XY partial gonadal dysgenesis gonadal histology shows evidence of incomplete testis determination. In 46,XY embryonic testicular regression sequence there is lack of gonadal tissue on both sides. Various lines of evidence suggest that embryonic testicular regression sequence is a variant form of 46,XY gonadal dysgenesis. The sex-determining region Y chromosome gene (SRY) encodes sequences for the testis-determining factor. To date germ-line mutations in SRY have been reported in approximately 20% of subjects with 46,XY complete gonadal dysgenesis. However, no germ-line mutations of SRY have been reported in subjects with the partial forms. We studied 20 subjects who presented either 46,XY partial gonadal dysgenesis or 46,XY embryonic testicular regression sequence. We examined the SRY gene and the minimum region of Y-specific DNA known to confer a male phenotype. The SRY-open reading frame (ORF) was normal in all subjects. However a de novo interstitial deletion 3' to the SRY-ORF was found in one subject. Although it is possible that the deletion was unrelated to the subject's phenotype, we propose that the deletion was responsible for the abnormal gonadal development by diminishing expression of SRY. We suggest that the deletion resulted either in the loss of sequences necessary for normal SRY expression or in a position effect that altered SRY expression. This case provides further evidence that deletions of the Y chromosome outside the SRY-ORF can result in either complete or incomplete sex reversal.	0
A 3-year-old boy presented to us with swelling of the right upper lip and the surrounding perioral area with the multiple clear fluid-filled grouped vesicles on the mucosal surface. The patient's mother had a similar swelling located at the same anatomic location extending to the cheek and the ala of nose on the same side. Magnetic resonance imaging and histopathological examination were suggestive of microcystic lymphatic malformation (LM) in both mother and child. Although an autosomal recessive inheritance pattern has been reported for isolated cystic hygromas, no familial case of microcystic LM has been reported previously.	0
We report the first family with a glycyl-tRNA synthetase (GARS) mutation with autosomal dominant intermediate Charcot-Marie-Tooth disease (DI-CMT). The proband and the proband's father presented with gait disturbance and hand weakness. Both patients displayed moderately decreased conduction velocities (MNCV) (ranging from 29.2 to 37.8 m/s). A sural nerve biopsy of the father revealed evidence of both axonal loss and demyelination. On exome sequencing, in both the proband and his father, we identified a novel missense mutation (c.643G > C, p.Asp215His) in the GARS gene in a heterozygous state, which is considered to be pathogenic for this DI-CMT family. The present study broadens current knowledge about intermediate CMT and the phenotypic spectrum of defects associated with GARS.	0
Frank Ter Haar syndrome (FTHS) is a rare autosomal recessive disorder with characteristic skeletal, cardiac, ocular, and craniofacial abnormalities. We report a sibling pair presenting with clinical features typical of FTHS, born to consanguineous parents, with a novel mutation in the SH3PXD2B gene on chromosome 5q35.1 that results in premature truncation of the protein encoded. The children presented with brachycephaly, multiple joint contractures, cardiac valvular defects, bilateral megalocornea, and congenital glaucoma. Trabeculotomy combined with trabeculectomy was performed in both siblings to control intraocular pressure. The characteristic clinical features with the underlying genetic defects confirmed the diagnosis of FTHS. Early diagnosis and treatment of congenital glaucoma preserved vision in the children.	0
Constitutional translocations, typically involving chromosome 3, have been recognized as a rare cause of inherited predisposition to renal cell carcinoma (RCC) for four decades. However, knowledge of the molecular basis of this association is limited. We have characterized the breakpoints by genome sequencing (GS) of constitutional chromosome abnormalities in five individuals who presented with RCC. In one individual with constitutional t(10;17)(q11.21;p11.2), the translocation breakpoint disrupted two genes: the known renal tumor suppressor gene (TSG) FLCN (and clinical features of Birt-Hogg-Dubé syndrome were detected) and RASGEF1A. In four cases, the rearrangement breakpoints did not disrupt known inherited RCC genes. In the second case without chromosome 3 involvement, the translocation breakpoint in an individual with a constitutional t(2;17)(q21.1;q11.2) mapped 12 Kb upstream of NLK. Interestingly, NLK has been reported to interact indirectly with FBXW7 and a previously reported RCC-associated translocation breakpoint disrupted FBXW7. In two cases of constitutional chromosome 3 translocations, no candidate TSGs were identified in the vicinity of the breakpoints. However, in an individual with a constitutional chromosome 3 inversion, the 3p breakpoint disrupted the FHIT TSG (which has been reported previously to be disrupted in two apparently unrelated families with an RCC-associated t(3;8)(p14.2;q24.1). These findings (a) expand the range of constitutional chromosome rearrangements that may be associated with predisposition to RCC, (b) confirm that chromosome rearrangements not involving chromosome 3 can predispose to RCC, (c) suggest that a variety of molecular mechanisms are involved the pathogenesis of translocation-associated RCC, and (d) demonstrate the utility of GS for investigating such cases.	0
BACKGROUND:Deafness, dystonia, and cerebral hypomyelination (DDCH) is an X-linked disorder due to hemizygous mutations of BCAP31. METHODS:We report an 8-year-old boy with DDCH who possibly accompanied mitochondrial dysfunction. Clinical evaluation, respiratory chain enzyme assay, and whole exome sequencing analysis were performed. RESULTS:Mitochondrial dysfunction was suspected by respiratory chain enzyme assay on his cultured skin fibroblasts which showed significantly decreased complex I enzyme activity. Whole exome sequencing analysis revealed a recurrent BCAP31 mutation (c.97C>T:p.Gln33*) which confirmed the diagnosis of DDCH for the patient. CONCLUSION:We speculate that mitochondrial dysfunction may be a feature in patients with DDCH.	0
Joubert syndrome is a rare autosomal recessive neurodevelopmental disease characterized by abnormal breathing patterns composed of episodic tachypnea/apnea, hypotonia, ataxia, developmental delay, intellectual impairment, ocular impairment, renal cysts, and hepatic fibrosis. We report the case of a 4-year-old boy who presented with global developmental delay, bilateral nystagmus, and gaze instability with difficulty walking and maintaining an upright posture. A detailed examination revealed facial dysmorphic features with a depressed nasal bridge and deepened orbital sockets. Neurological examination yielded positive results for hypotonia, gait ataxia, bilateral horizontal pendular nystagmus, and a grade 1 ptosis more prominent in the right eye. However, no abnormal breathing patterns were observed in our case. Magnetic resonance imaging revealed the characteristic molar tooth sign and a batwing appearance of the fourth ventricle.	0
Mitochondrial dysfunction has been implicated in multiple neurodegenerative diseases but remains largely unexplored in Creutzfeldt-Jakob disease. Here, we characterize the mitochondrial respiratory chain at the individual neuron level in the MM1 and VV2 common molecular subtypes of sporadic Creutzfeldt-Jakob disease. Moreover, we investigate the associations between the mitochondrial respiratory chain and neuropathological markers of the disease.Brain tissue from individuals with sporadic Creutzfeldt-Jakob disease and age-matched controls were obtained from the brain collection of the Austrian Creutzfeldt-Jakob Surveillance. The mitochondrial respiratory chain was studied through a dichotomous approach of immunoreactivities in the temporal cortex and the hippocampal subregions of CA4 and CA3.We show that profound deficiency of all mitochondrial respiratory complexes (I-V) occurs in neurons of the severely affected temporal cortex of patients with Creutzfeldt-Jakob disease. This deficiency correlates strongly with the severity of neuropathological changes, including vacuolation of the neuropil, gliosis and disease associated prion protein load. Respiratory chain deficiency is less pronounced in hippocampal CA4 and CA3 regions compared to the temporal cortex. In both areas respiratory chain deficiency shows a predilection for the MM1 molecular subtype of Creutzfeldt-Jakob disease.Our findings indicate that aberrant mitochondrial respiration could be involved early in the pathogenesis of sporadic Creutzfeldt-Jakob disease and contributes to neuronal death, most likely via ATP depletion. Based on these results, we propose that the restricted MRI diffusion profile seen in the brain of patients with sporadic Creutzfeldt-Jakob disease might reflect cytotoxic changes due to neuronal respiratory chain failure and ATP loss.	0
We have studied 23 patients with Rett syndrome with particular reference to the character and natural history of the clinical disorder. We found a prevalence of 0.8 per 10,000 girls 0-14 years in the region from which cases came. We consider that the disorder of tone, posture and movement is extrapyramidal in nature and suggest that the gradual emergence of its fully developed pattern leads to the familiar regression in skills on presentation. We have not found proof of dementia at this stage but rather of severe mental handicap.	1
BACKGROUND:Lymphopenia, thrombocytopenia, and elevated D-dimer and ferritin levels are frequently reported in patients with severe coronavirus disease 2019 (COVID-19). Here we report a case of cold agglutinin disease (CAD), autoimmune hemolytic anemia (AIHA), and pulmonary embolism as a presentation of COVID-19 infection. CASE REPORT:A 51-year-old African-American woman presented to the emergency room with fever and shortness of breath. She was tachycardic, febrile, and had an oxygen saturation of 88% on room air. Laboratory studies showed hemoglobin (Hb) 5.1 g/dL, D-dimer 4.55 µg/mL, and C-reactive protein 12.3 mg/dL. Computed tomography scan of the chest showed acute pulmonary embolism involving the bilateral lower lobe segmental branches. Her influenza test was negative, but her SARS-CoV-2 test returned positive. Due to severe anemia, she was not started on any anticoagulation. Haptoglobin was low. Direct antiglobulin test returned positive for anticomplement and negative for anti-immunoglobulin G. Cold agglutinin titer was 80. Mycoplasma, Epstein-Barr virus, parvovirus, human immunodeficiency viruses, and acute hepatitis screen were negative. Abdominal and pelvic computed tomography showed a normal liver and spleen without lymphadenopathy. Peripheral blood smear showed red blood cell agglutination. On Day 2, she became hypoxic requiring 6 L oxygen. Since her Hb remained stable, she was started on low-intensity unfractionated heparin. Inflammatory markers subsequently improved and she was weaned off oxygen. Her Hb remained stable at 9 g/dL and she was discharged home. After 2 weeks, her Hb increased to 11 g/dL. CONCLUSION:As exemplified in this case report, COVID-19 infection can lead to thromboembolism, CAD, and AIHA and it should be recognized as a potential etiology to such rare diseases.	0
BACKGROUND:Cdc42 is a member of the Rho GTPase family and functions as a molecular switch in regulating cytoskeleton remodeling and cell polarity establishment. Inactivating Cdc42 in cardiomyocytes resulted in embryonic lethality with heart developmental defects, including ventricular septum defects and thin ventricle wall syndrome. FINDINGS:In this study, we have generated a Cdc42 cardiomyocyte knockout mouse line by crossing Cdc42/flox mice with myosin light chain 2a (MLC2a)-Cre mice. We found that the deletion of Cdc42 in embryonic cardiomyocytes resulted in an underdeveloped right ventricle. Microarray analysis and real-time PCR data analysis displayed that the deletion of Cdc42 decreased dHand expression level. In addition, we found evaginations in the ventricle walls of Cdc42 knockout hearts. CONCLUSION:We concluded that Cdc42 plays an essential role in right ventricle growth.	0
BACKGROUND:Carnitine-acylcarnitine translocase (CACT) deficiency is a rare autosomal recessive disease in the mitochondrial transport of long-chain fatty acids. Despite early diagnosis and treatment, the disease still has a high mortality rate. METHODS:Clinical symptoms, long-term follow-up, and biochemical and molecular results of four cases are described and compared with the reviewed literature data of 55 cases. RESULTS:Two cases with neonatal onset, carrying in homozygosity the novel variant sequences p.Gly20Asp (c.59G>A) and p.Arg179Gly (c.536A>G), died during an intercurrent infectious process in the first year of life despite adequate dietetic treatment (frequent feeding, high-carbohydrate/low-fat diet, MCT, carnitine). The other two cases, one with infantile onset and the other diagnosed in the newborn period after a previous affected sibling, show excellent development at 4 and 16 years of age under treatment. The review shows that the most frequent presenting symptoms of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress. The onset of symptoms is predominantly neonatal in 82% and infantile in 18%. The mortality rate is high (65%), most in the first year of life due to myocardiopathy or sudden death. Outcomes seem to correlate better with the absence of cardiac disease and with a higher long-chain fatty acid oxidation rate in cultured fibroblasts than with residual enzyme activity. CONCLUSION:Diagnosis before the occurrence of clinical symptoms by tandem MS-MS and very early therapeutic intervention together with good dietary compliance could lead to a better prognosis, especially in milder clinical cases.	0
INTRODUCTION:Lipoprotein(a) [Lp(a)] is a genetically determined risk factor of coronary heart disease and its complications. Meanwhile data about the role of Lp(a) in development of ischemic stroke are controversial. AIM:To investigate the association of Lp(a) with atherothrombotic ischemic stroke and stenotic (≥50%) atherosclerosis of carotid arteries. MATERIAL AND METHODS:The study included 490 patients (mean age 60 years, 53% male). The first group comprised 157 patients with ischemic stroke, the second group 68 patients with isolated stenotic atherosclerosis of carotid arteries, but without significant lesion of coronary and low limbs arteries. The control group included 265 patients without stroke, myocardial infarction, stenotic atherosclerosis of coronary, carotid and low limbs arteries according to instrumental examinations. The levels of Lp(a) and lipids were measured in blood serum of all patients. RESULTS:Lp(a) concentration was significantly higher in patients of the first and second groups in comparison with the control group (median [interquartile range]): 24 [9; 48], 20 [8; 55] vs 13 [5; 27] mg/dl, respectively (p<0,05 in both cases). Hyperlipoproteinemia(a) (Lp(a) ≥30 mg/dl) was more frequent in the group with stroke, stenotic atherosclerosis of carotid arteries, than in the control group: 43%, 40% vs 22% (p<0.01 in all cases). In patients with hyperlipoproteinemia(a), odds ratio (OR) for ischemic stroke was 2.7 (95% confidence interval (CI) 1.7-4.1), and OR for stenotic atherosclerosis of carotid arteries was 2.3 (95% CI 1.3-4.0) compared to the patients with Lp(a) level <30 mg/dl (p<0.01 in both cases). In logistic regression analysis adjusted for age, sex, hypertension, type 2 diabetes, smoking and Lp(a) concentration, the hyperlipoproteinemia(a) was associated with ischemic stroke and isolated stenotic carotid atherosclerosis. In the group with severe carotid atherosclerosis, 16 patients (24%) had ischemic stroke. Lp(a) concentration in these patients was higher 36 [20; 59] mg/dl, than in the patients with isolated carotid atherosclerosis without stroke 15 [7; 54] mg/dl (p=0.04). Other risk factors of atherosclerosis did not differ in patients with or without ischemic stroke. CONCLUSION:The study shows the association of elevated level of Lp(a) with ischemic stroke and isolated stenotic atherosclerosis of carotid arteries. In the presence of isolated stenotic carotid atherosclerosis, the median of Lp(a) concentration was significantly higher in patients with ischemic stroke than in patients without stroke.	0
Juvenile X-linked retinoschisis (XLRS, MIM#312700) belongs to a group of the vitreoretinal dystrophies. We aimed to describe the phenotype-genotype correlation of three XLRS cases in juveniles with different novel mutations from the Lithuanian population. The patients demonstrated macular retinoschisis and typical cyst-like cavities on spectral-domain optical coherence tomography (SD-OCT) images. The mean central foveal thickness was 569.7 µm. Two patients presented with peripheral retinoschisis. Flash electroretinogram demonstrated a reduced b/a ratio (<1.0) in all patients. RS1 (NM_000330.3) gene coding exons Sanger sequencing was performed. RS1 c.599G>T (p.R200L) mutation was detected in one case, showing to be pathogenic in silico analysis. c. (92_97) insC (p.W33fs) mutation was identified for another patient, indicating the variant is possibly damaging in silico analysis. The third case was identified with a pathogenic mutation c.422C>G (p.R141H), HGMD CM981753. These are the first cases of XLRS in the Lithuanian population confirmed by molecular genotyping. Presented patients had a different genotype but similar phenotypic traits.	0
Newborn screening (NBS) by tandem mass spectrometry started in Galicia (Spain) in 2000. We analyse the results of screening and clinical follow-up of inborn errors of metabolism (IEM) detected during 10 years. Our programme basically includes the disorders recommended by the American College of Medical Genetics. Since 2002, blood and urine samples have been collected from every newborn on the 3rd day of life; before then, samples were collected between the 5th and 8th days. Newborns who show abnormal results are referred to the clinical unit for diagnosis and treatment. In these 10 years, NBS has led directly to the identification of 137 IEM cases (one per 2060 newborns, if 35 cases of benign hyperphenylalaninemia are excluded). In addition, 33 false positive results and 10 cases of transitory elevation of biomarkers were identified (making the positive predictive rate 76.11%), and 4 false negative results. The use of urine samples contributed significantly to IEM detection in 44% of cases. Clinical symptoms appeared before positive screening results in nine patients (6.6%), four of them screened between days 5 and 8. The death rate was 2.92%; of the survivors, 95.5% were asymptomatic after a mean observation period of 54 months, and only two had an intellectual/psychomotor development score less than 85. Compared to other studies, a high incidence of type I glutaric aciduria was detected, one in 35,027 newborns. This report highlights the benefits of urine sample collection during screening, and it is the first study on expanded newborn screening results in Spain.	1
There are few instances in oncology where reciprocal clinical and laboratory translation studies have accelerated the understanding of disease biology and treatment more so than the decade following the Food and Drug Administration (FDA) approval of lenalidomide (RevlimidTM; Celgene Corporation, Summit, NJ, USA) for the treatment of patients with myelodysplastic syndrome (MDS) and chromosome 5q deletion (del(5q)). Lenalidomide was approved by the FDA in December 2005 on the merits of a multicenter phase 2 study, which demonstrated sustained and prolonged transfusion independence in the majority of participants. Since then, del(5q) MDS has emerged as one of the best characterized bone marrow malignancies and, in particular, has raised our understanding as to how allelic haplodeficiency underlies both its hematological phenotype and the selective sensitivity to lenalidomide by virtue of synthetic lethality. Herein, we review the clinical and biological discoveries that have advanced our understanding of del(5q) MDS and its treatment since its approval by United States and European regulatory agencies.	0
Stroke-like episodes (SLE) occur in phosphomannomutase deficiency (PMM2-CDG), and may complicate the course of channelopathies related to Familial Hemiplegic Migraine (FHM) caused by mutations in CACNA1A (encoding CaV2.1 channel). The underlying pathomechanisms are unknown. We analyze clinical variables to detect risk factors for SLE in a series of 43 PMM2-CDG patients. We explore the hypothesis of abnormal CaV2.1 function due to aberrant N-glycosylation as a potential novel pathomechanism of SLE and ataxia in PMM2-CDG by using whole-cell patch-clamp, N-glycosylation blockade and mutagenesis. Nine SLE were identified. Neuroimages showed no signs of stroke. Comparison of characteristics between SLE positive versus negative patients' group showed no differences. Acute and chronic phenotypes of patients with PMM2-CDG or CACNA1A channelopathies show similarities. Hypoglycosylation of both CaV2.1 subunits (α1A and α2α) induced gain-of-function effects on channel gating that mirrored those reported for pathogenic CACNA1A mutations linked to FHM and ataxia. Unoccupied N-glycosylation site N283 at α1A contributes to a gain-of-function by lessening CaV2.1 inactivation. Hypoglycosylation of the α₂δ subunit also participates in the gain-of-function effect by promoting voltage-dependent opening of the CaV2.1 channel. CaV2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDG patients. Aberrant CaV2.1 N-glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities.	0
Renal cancer is a common neoplasm in the genitourinary tract. It characterized by unpredictable site and duration of metastasis. Distant metastases are common and may involve any region of the body. It spread in a way that is not clear. Late metastasis could occur even after complete resection of the tumor. An extended follow-up is advised to deal with the risk of delayed metastases.	0
Eosinophilic fasciitis (EF) is a rare form of fibrosing disorder associated with peripheral eosinophilia with scleroderma-like skin induration and fasciitis in the extremities resulting in painful swelling, erythema and progressive contracture. We present a case report of EF and a literature review to raise awareness of this unusual condition and also highlight key features in its management.	0
Lysinuric protein intolerance (LPI) is a rare autosomal disease caused by defective cationic amino acid (CAA) transport due to mutations in SLC7A7, which encodes for the y+LAT1 transporter. LPI patients suffer from a wide variety of symptoms, which range from failure to thrive, hyperammonemia, and nephropathy to pulmonar alveolar proteinosis (PAP), a potentially life-threatening complication. Hyperammonemia is currently prevented by citrulline supplementation. However, the full impact of this treatment is not completely understood. In contrast, there is no defined therapy for the multiple reported complications of LPI, including PAP, for which bronchoalveolar lavages do not prevent progression of the disease. The lack of a viable LPI model prompted us to generate a tamoxifen-inducible Slc7a7 knockout mouse (Slc7a7-/-). The Slc7a7-/- model resembles the human LPI phenotype, including malabsorption and impaired reabsorption of CAA, hypoargininemia and hyperammonemia. Interestingly, the Slc7a7-/- mice also develops PAP and neurological impairment. We observed that citrulline treatment improves the metabolic derangement and survival. On the basis of our findings, the Slc7a7-/- model emerges as a promising tool to further study the complexity of LPI, including its immune-like complications, and to design evidence-based therapies to halt its progression.	0
BACKGROUND AND OBJECTIVES:The published tissue adequacy requirement of kidney medulla for BK virus allograft nephropathy diagnosis lacks systematic verification and competes against potential increased procedural risks from deeper sampling. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:We evaluated whether the presence of kidney medulla improved the diagnostic rate of BK nephropathy in 2244 consecutive biopsy samples from 856 kidney transplants with detailed histologic and virologic results. RESULTS:Medulla was present in 821 samples (37%) and correlated with maximal core length (r=0.35; P<0.001). BK virus allograft nephropathy occurred in 74 (3% overall) but increased to 5% (42 of 821) with medulla compared with 2% (32 of 1423) for cortical samples (P<0.001). Biopsy medulla was associated with infection after comprehensive multivariable adjustment of confounders, including core length, glomerular number, and number of cores (adjusted odds ratio, 1.81; 95% confidence interval, 1.02 to 3.21; P=0.04). In viremic cases (n=275), medulla was associated with BK virus nephropathy diagnosis (39% versus 19% for cortex; P<0.001) and tissue polyomavirus load (Banff polyomavirus score 0.64±0.96 versus 0.33±1.00; P=0.006). Biopsy medulla was associated with BK virus allograft nephropathy using generalized estimating equation (odds ratio, 2.04; 95% confidence interval, 1.05 to 3.96; n=275) and propensity matched score comparison (odds ratio, 2.24; 95% confidence interval, 1.11 to 4.54; P=0.03 for 156 balanced pairs). Morphometric evaluation of Simian virus 40 large T immunohistochemistry found maximal infected tubules within the inner cortex and medullary regions (P<0.001 versus outer cortex). CONCLUSIONS:Active BK virus replication concentrated around the corticomedullary junction can explain the higher detection rates for BK virus allograft nephropathy with deep sampling. The current adequacy requirement specifying targeting medulla can be justified to minimize a missed diagnosis from undersampling.	0
Frank-Ter Haar syndrome (FTHS), Winchester syndrome (WS), and multicentric osteolysis, nodulosis, and arthropathy (MONA) are ultra-rare multisystem disorders characterized by craniofacial malformations, reduced bone density, skeletal and cardiac anomalies, and dermal fibrosis. These autosomal recessive syndromes are caused by homozygous mutation or deletion of respectively SH3PXD2B (SH3 and PX Domains 2B), MMP14 (matrix metalloproteinase 14), or MMP2. Here, we give an overview of the clinical features of 63 previously reported patients with an SH3PXD2B, MMP14, or MMP2 mutation, demonstrating considerable clinical overlap between FTHS, WS, and MONA. Interestingly, the protein products of SH3PXD2B, MMP14, and MMP2 directly cooperate in collagen remodeling. We review animal models for these three disorders that accurately reflect the major clinical features and likewise show significant phenotypical similarity with each other. Furthermore, they demonstrate that defective collagen remodeling is central in the underlying pathology. As such, we propose a nosological revision, placing these SH3PXD2B, MMP14, and MMP2 related syndromes in a novel "defective collagen-remodelling spectrum (DECORS)". In our opinion, this revised nosology better reflects the central role for impaired collagen remodeling, a potential target for pharmaceutical intervention.	0
Malignant peripheral nerve sheath tumors (MPNST), also known as malignant schwannoma, are rare soft tissue sarcomas [1]. They commonly invade axial sites and rarely do they occur in the thorax [2]. Herein, we present the case of an enormous metastatic multilobulated intrathoracic MPNST that was first misdiagnosed as desmoid fibromatosis and successfully resected for palliative purpose.	0
Intellectual disability refers to significantly subaverage intellectual function (intelligence quotient < 70) with impairment of adaptive function. The IQSEC2 gene is one of the pathogenic genes located on chromosome Xp11.22. IQSEC2 is an X-linked gene correlated with intellectual disability and epilepsy. In this study, we reported a 2-year-old male patient presented with reacting sluggishly with people and surroungdings. Active electroencephalogram showed the background of epileptic activity. Brain MRI revealed patchy hyperintensity of bilateral parietal lobe white matter on fluid-attenuated inversion recovery image and widened ventricle, cistern and sulci on T2-weighted image. Delayed myelination was considered. The diagnosis of intellectual disability and epilepsy was made. Whole exome-sequencing was conducted and identified a novel frameshift mutation in exon 15 of IQSEC2 (NM_001111125.2: c.4164dupC: p.Ile1389 Hisfs*218). The variant resulted in the deletion of termination codon, and the protein was extended to termination after stretch of 218 amino acids.This study expands the mutation spectrum of IQSEC2. It supports the published data suggesting that IQSEC2 plays a significant part in patients with intellectual disability and epilepsy. IQSEC2 should be detected in patients with intellectual disability and epilepsy.	0
Sclerosteosis, a rare autosomal recessive genetic disorder caused by a mutation of the Sost gene, manifests in the facial skeleton by gigantism, facial distortion, mandibular prognathism, cranial nerve palsy, and, in extreme cases, compression of the medulla oblongata. Mice lacking sclerostin reflect some symptoms of sclerosteosis, but this is the first report of the effect on the facial skeleton. We used geometric morphometrics (GMM) to analyse the deformations of the murine facial skeleton from the wild type to the Sost gene knockout. Landmark coordinates were obtained by surface reconstructions from microcomputed tomography. Centroid Size, principal component (PC) scores in shape space and form space, and asymmetry were computed by the standard GMM formulas, and dental and skeletal jaw lengths were examined as ratios. We show here that, compared to wild type controls, mice lacking Sost have larger Centroid Size (Effect size, p-value: 4.59, < 0.001), higher mean asymmetry (1.14, 0.065), dental and skeletal mandibular prognathism (1.36, 0.010), (5.92, <0.001), a smaller foramen magnum (-1.71, 0.015), and calvaria that are more highly curved (form space p= 4.09, 0.002; shape space p= 12.82, 0.002). These features of mice lacking sclerostin largely correspond to the changes of the facial skeleton observed in sclerosteosis. This alignment further supports claims that the Sost gene plays a fundamental role in bony facial development in rodents and humans alike. This article is protected by copyright. All rights reserved.	0
Aquagenic syringeal acrokeratoderma is a rare, transient, and usually bilaterally symmetric, palmoplantar keratoderma. Patients complain of tingling and pain in the hands starting a few minutes after exposure to water and lasting for 20-30 minutes after removal. Clinically, there is marked wrinkling with edematous white papules on the palms or, less often, the soles. We present the case of a 21-year-old woman who used spironolactone for polycystic ovary syndrome and had similar clinical features 2 weeks later, after withdrawing the drug.	0
Due to the multiethnic patient population with varying skin types in Singapore, clinicians often find the management of acne in their patients to be challenging. The authors developed these guidelines to provide comprehensive advice on individualized acne treatment and to provide a reference guide for all doctors who treat patients of Asian descent. Unique features of acne in Singapore are highlighted. We address concerns such as diet, special population needs, and the benefits, side effects, risks, and cost-effectiveness of currently available acne treatments. These treatment guidelines outline recommendations for the diagnosis, grading, and treatment of children, adolescents, and adults with acne of varying severity, and include advice pertaining to the use of cosmeceuticals and management of scars.	0
We offer further biological characterization of the XK atelen/aprosencephaly syndrome in two infants, one with prolonged survival, the other presenting prenatally with apparent hydranencephaly and an orbital tumor (OS). Familial occurrence in the former born to presumably nonconsanguineous Lybian parents may represent parental germinal mosaicism or autosomal recessive inheritance. Both had apparently normal chromosomes; however, the Lybian infant had slightly increased induced chromosome breakage suggesting that this rare multiple congenital anomalies syndrome may involve a DNA repair defect. Virtual absence of atelen/aprosencephalic structures may lead to an arthrogryposis-like prenatal movement disorder. The orbital tumor in the Utah infant consisted of dystopic neural tissue compressing a rudimentary globe and was connected by a thin bridge of neural tissue to the small mass of disorganized brain tissue usually found in atelen/aprosencephalic infants and fetuses. No evidence of an encephaloclastic process was found in the autopsied Utah infant.	0
Cardiofacio-cutaneous syndrome is a rare genodermatoses with multiple congenital anomalies (MCA) and mental retardation. Although various mutations have been described, the diagnosis can be made clinically based on constellation of symptoms. Herein, we report a classical case with typical craniofacial features and atrial septal defect.	0
BACKGROUND:De novo heterozygous mutations in the GNAO1 gene, encoding the Gα o subunit of G-proteins, are the cause of a severe neurodevelopmental disorder, featuring early infantile seizures, profound cognitive dysfunction and, occasionally, movement disorder (early infantile epileptic encephalopathy-17). METHODS:We report a further case of this association in a 20 month-old Spanish girl with neonatal-onset refractory seizures, progressive microcephaly, oral-lingual dyskinesia and nearly absent psychomotor development. We performed whole-exome sequencing, a computational structural analysis of the novel gene variant identified and reviewed the previously reported cases. RESULTS:Trio whole-exome-sequencing uncovered a de novo p.Leu199Pro GNAO1 mutation. Computational structural analysis indicates this novel variant adversely affects the stability of the G-protein heterotrimeric complex as a whole. Of note, our patient showed a sustained seizure reduction while on a ketogenic diet. CONCLUSIONS:With this observation, a total of twelve patients with GNAO1 encephalopathy have been reported. Oral-lingual dyskinesia and responsiveness of seizures to ketogenic diet are novel features. The distorted sex ratio (12/12 females) of the condition remains unexplained; a differential gender effect of the disruption of G-protein- mediated signal transduction on the developing brain can be hypothesized.	0
Objective:To characterize the genetic background of molecularly undefined childhood-onset ataxias in Finland. Methods:This study examined a cohort of patients from 50 families with onset of an ataxia syndrome before the age of 5 years collected from a single tertiary center, drawing on the advantages offered by next generation sequencing. A genome-wide genotyping array (Illumina Infinium Global Screening Array MD-24 v.2.0) was used to search for copy number variation undetectable by exome sequencing. Results:Exome sequencing led to a molecular diagnosis for 20 probands (40%). In the 23 patients examined with a genome-wide genotyping array, 2 additional diagnoses were made. A considerable proportion of probands with a molecular diagnosis had de novo pathogenic variants (45%). In addition, the study identified a de novo variant in a gene not previously linked to ataxia: MED23. Patients in the cohort had medically actionable findings. Conclusions:There is a high heterogeneity of causative mutations in this cohort despite the defined age at onset, phenotypical overlap between patients, the founder effect, and genetic isolation in the Finnish population. The findings reflect the heterogeneous genetic background of ataxia seen worldwide and the substantial contribution of de novo variants underlying childhood ataxia.	0
INTRODUCTION:RLBP1 RP is an autosomal recessive form of retinitis pigmentosa (RP), characterized by night blindness, prolonged dark adaptation, constricted visual fields and impaired macular function. This study aimed to better understand the patient experience of RLBP1 RP and evaluate the content validity of existing patient reported outcome (PRO) instruments in this condition. METHODS:Semi-structured concept elicitation and cognitive debriefing interviews were conducted with RLBP1 RP patients in Canada and Sweden. Interviews started with open-ended concept elicitation questioning, and then patients were cognitively debriefed on The National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25), the Low Luminance Questionnaire (LLQ) and four light/dark adaptation items of the Visual Activities Questionnaire (VAQ). Qualitative interviews were also conducted with three expert clinicians. Anonymized, verbatim transcripts were analyzed using thematic analysis. RESULTS:Twenty-one patients were interviewed (Canada n = 10; Sweden n = 11). Symptoms reported included night blindness (n = 21), difficulty adapting to changes in lighting (n = 21) and difficulties seeing in bright lighting (n = 18). Patients experienced substantial impacts on daily activities (n = 21) and physical functioning (n = 17). Patients had difficulty interpreting and selecting a response for some items in the NEI VFQ-25 and LLQ. Some items were not relevant to patients' disease experience. There were both gaps and overlaps in the conceptual coverage of the instruments. CONCLUSIONS:Visual impairment due to RLBP1 RP has a substantial impact on physical functioning and daily activities. To adequately assess all important symptoms and associated functional impacts in RLBP1 RP, it is recommended to either modify one or more existing instruments or to develop a new non-syndromic RP specific instrument.	0
Mouse hepatitis virus (MHV) is a murine betacoronavirus (m-CoV) that causes a wide range of diseases in mice and rats, including hepatitis, enteritis, respiratory diseases, and encephalomyelitis in the central nervous system (CNS). MHV infection in mice provides an efficient cause-effect experimental model to understand the mechanisms of direct virus-induced neural-cell damage leading to demyelination and axonal loss, which are pathological features of multiple sclerosis (MS), the most common disabling neurological disease in young adults. Infiltration of T lymphocytes, activation of microglia, and their interplay are the primary pathophysiological events leading to disruption of the myelin sheath in MS. However, there is emerging evidence supporting gray matter involvement and degeneration in MS. The investigation of T cell function in the pathogenesis of deep gray matter damage is necessary. Here, we employed RSA59 (an isogenic recombinant strain of MHV-A59)-induced experimental neuroinflammation model to compare the disease in CD4-/- mice with that in CD4+/+ mice at days 5, 10, 15, and 30 postinfection (p.i.). Viral titer estimation, nucleocapsid gene amplification, and viral antinucleocapsid staining confirmed enhanced replication of the virions in the absence of functional CD4+ T cells in the brain. Histopathological analyses showed elevated susceptibility of CD4-/- mice to axonal degeneration in the CNS, with augmented progression of acute poliomyelitis and dorsal root ganglionic inflammation rarely observed in CD4+/+ mice. Depletion of CD4+ T cells showed unique pathological bulbar vacuolation in the brain parenchyma of infected mice with persistent CD11b+ microglia/macrophages in the inflamed regions on day 30 p.i. In summary, the current study suggests that CD4+ T cells are critical for controlling acute-stage poliomyelitis (gray matter inflammation), chronic axonal degeneration, and inflammatory demyelination due to loss of protective antiviral host immunity.IMPORTANCE The current trend in CNS disease biology is to attempt to understand the neural-cell-immune interaction to investigate the underlying mechanism of neuroinflammation, rather than focusing on peripheral immune activation. Most studies in MS are targeted toward understanding the involvement of CNS white matter. However, the importance of gray matter damage has become critical in understanding the long-term progressive neurological disorder. Our study highlights the importance of CD4+ T cells in safeguarding neurons against axonal blebbing and poliomyelitis from murine betacoronavirus-induced neuroinflammation. Current knowledge of the mechanisms that lead to gray matter damage in MS is limited, because the most widely used animal model, experimental autoimmune encephalomyelitis (EAE), does not present this aspect of the disease. Our results, therefore, add to the existing limited knowledge in the field. We also show that the microglia, though important for the initiation of neuroinflammation, cannot establish a protective host immune response without the help of CD4+ T cells.	0
This study is aimed at exploring the levels of peripheral blood circular RNAs (circRNAs) as biomarker candidates for the diagnosis of new-onset rheumatoid arthritis (RA). The selected twenty-two circRNAs in peripheral blood from new-onset RA patients and healthy controls (HC) were determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The levels of hsa_circ_0002715, hsa_circ_0001947, hsa_circ_0000367, and hsa_circ_0035197 were significantly increased in the peripheral blood of new-onset RA patients than in the peripheral blood of HC. And, there were obvious differences in the above four peripheral blood circRNAs between new-onset RA patients and systemic lupus erythematosus (SLE) patients and ankylosing spondylitis (AS) patients. Moreover, there were obvious differences in hsa_circ_0001947 and hsa_circ_0035197 between new-onset RA patients and patients with undiagnosed arthritis (UA). Receiver operating characteristic (ROC) curve analysis suggested that the levels of hsa_circ_0002715 and hsa_circ_0000367 in peripheral blood could distinguish new-onset RA patients from the HC, AS patients, and SLE patients, and the levels of hsa_circ_0001947 and hsa_circ_0035197 in peripheral blood could distinguish new-onset RA patients from the HC, AS patients, SLE patients, and UA patients. The logistic regression model showed that the combination of hsa_circ_0002715 and hsa_circ_0035197 could provide the best diagnostic accuracy with an area under the curve (AUC) of 0.758 (sensitivity: 72.9%, specificity: 71.4%). Moreover, the levels of peripheral blood hsa_circ_0002715 were correlated with swollen joint count (SJC), tender joint count (TJC), disease duration, rheumatoid factor (RF), anticitrullinated protein antibodies (ACPA), and hematologic disorder. And, the levels of peripheral blood hsa_circ_0035197 were correlated with hematologic disorder. This study suggests that the combination of hsa_circ_0002715 and hsa_circ_0035197 in peripheral blood may be a potential biomarker of patients with new-onset RA and may be associated with disease activity.	0
Gene therapy has been a long-lasting goal of scientists and there are many ideal methods and tools that have been developed to correct disease-causing mutations in human. Recently, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology has been progressively used for the assessment or treatment of human diseases, including Thalassemia, Parkinson disease, Cystic Fibrosis, Glaucoma, Huntington's disease and Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS). CRISPR sequences is a part of the bacterial immune system, which includes nuclease Cas enzyme and a RNA sequence. The RNA sequence is unique and pathogen-specific, which identifies and binds to the DNA of invasive viruses, and allows the nuclease Cas enzyme to cut identified DNA and destroy the invasive viruses. This feature provides a possibility to edit mutations in DNA sequence of live cells through replacement of a specific targeted RNA sequence with the RNA sequence in the CRISPR system. Previous studies showed the improvement steps in confrontation to human diseases caused by single nucleotide mutations using this system. In this review, we first concisely introduce CRISPR and its functions, and next study the use of CRISPR in the treatment of human diseases.	0
The glycosylphosphatidylinositol (GPI) anchor links over 150 proteins to the cell surface and is present on every cell type. Many of these proteins play crucial roles in neuronal development and function. Mutations in 18 of the 29 genes implicated in the biosynthesis of the GPI anchor have been identified as the cause of GPI biosynthesis deficiencies (GPIBDs) in humans. GPIBDs are associated with intellectual disability and seizures as their cardinal features. An essential component of the GPI transamidase complex is PIGU, along with PIGK, PIGS, PIGT, and GPAA1, all of which link GPI-anchored proteins (GPI-APs) onto the GPI anchor in the endoplasmic reticulum (ER). Here, we report two homozygous missense mutations (c.209T>A [p.Ile70Lys] and c.1149C>A [p.Asn383Lys]) in five individuals from three unrelated families. All individuals presented with global developmental delay, severe-to-profound intellectual disability, muscular hypotonia, seizures, brain anomalies, scoliosis, and mild facial dysmorphism. Using multicolor flow cytometry, we determined a characteristic profile for GPI transamidase deficiency. On granulocytes this profile consisted of reduced cell-surface expression of fluorescein-labeled proaerolysin (FLAER), CD16, and CD24, but not of CD55 and CD59; additionally, B cells showed an increased expression of free GPI anchors determined by T5 antibody. Moreover, computer-assisted facial analysis of different GPIBDs revealed a characteristic facial gestalt shared among individuals with mutations in PIGU and GPAA1. Our findings improve our understanding of the role of the GPI transamidase complex in the development of nervous and skeletal systems and expand the clinical spectrum of disorders belonging to the group of inherited GPI-anchor deficiencies.	0
We describe 2 cases of healthcare-associated Legionnaires' disease in patients in France hospitalized 5 months apart in the same room. Whole-genome sequencing analyses showed that clinical isolates from the patients and isolates from the room's toilet clustered together. Toilet contamination by Legionella pneumophila could lead to a risk for exposure through flushing.	0
Acute myeloid leukemia (AML) is characterized by chromosomal abnormalities affecting both prognosis and course of treatment. While most AML patients have well described chromosomal aberrations, around 10% present with rare chromosomal abnormalities. We herein, report a rare balanced translocation t(12;19)(q13;q13) in a 66-year old M5-AML patient identified by Conventional cytogenetic analysis and confirmed by SNP array. We suggest that t(12;19) as a sole chromosomal abnormality could be associated with a poor prognosis. Further studies are needed to understand the molecular basis of this translocation in AML.	0
Syndactyly is one of the most frequent hereditary limb malformations with clinical and genetical complexity. Autosomal dominant syndactyly type IV (SD4) is a rare form of syndactyly, caused by heterozygous mutations in a sonic hedgehog (SHH) regulatory element (ZRS) which resides in intron 5 of the LMBR1 gene on chromosome 7q36.3. SD4 is characterized by complete cutaneous syndactyly of the fingers, accompanied by cup-shaped hands due to flexion of the fingers and polydactyly. Here, for the first time, we reported a large Chinese family from Fujian province, manifesting cup-shaped hands consistent with SD4 and intrafamilial heterogeneity in clinical phenotype of tibial and fibulal shortening, triphalangeal thumb-polysyndactyly syndrome (TPTPS). We identified a novel duplication of ∼222 kb covering exons 2-17 of the LMBR1 gene in this family by sub-exome target sequencing. This case expands our new clinical understanding of SD4 phenotype and again confirms the feasibility to detect copy number variation by sub-exome target sequencing.	0
We report on a child with bilateral anophthalmia, esophageal atresia, and cryptorchidism. This is the first case observed in the Spanish Collaborative Study of Congenital Malformations (ECEMC) with this constellation of congenital anomalies, and it is similar to that described in 1988 by Rogers. We think that it may constitute a new syndrome.	0
Background:Glycogen storage disease type IV (GSD IV; Andersen's disease) is a rare autosomal recessive disease caused by mutation in the GBE1 gene. Presentation of GSD IV varies on a continuum of severity and symptomatology ranging from neonatal death to mild adult-onset disease with variable involvement of hepatic, muscular, neurologic, dermatologic, and cardiac systems. Cardiomyopathy seen in GSD IV is also heterogeneous and its appearance on cardiac magnetic resonance imaging (CMR) is rarely described. Case summary:A 29-year-old man without previous medical history was admitted to our facility multiple times over 2 years for focal sensorimotor deficits, gout arthropathy, chronic hyperlactataemia and hyperuricaemia, and severe decompensated non-ischaemic cardiomyopathy complicated by episodes of thromboembolic organ infarction. Echocardiography and CMR showed severe biventricular failure with the presence of intraventricular thrombi with increased right ventricular trabeculation and absent late gadolinium enhancement. He underwent muscle biopsy which showed prominent glycogen in skeletal muscle followed by genetic testing showing a single heterozygous splicing mutation c.993-1G>T found at the junction of intron 7 and exon 8 of the GBE1 gene which had not previously been reported and was predicted to be pathologic. He was referred to a tertiary care centre with glycogen storage disease specialists but expired prior to establishing care at that facility. Discussion:Discovery of GSD IV in our patient was unexpected due to a highly variant clinical presentation. Our case stresses the clinical heterogeneity of GSD IV and the importance of genetic sequencing studies in the evaluation of potential glycogen storage disease.	0
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. The search for genetic causes of CAKUT has led to genetic diagnosis in approximately 5-20 % of CAKUT patients from Western countries. In this study, genetic causes of CAKUT in Korean children were sought using targeted exome sequencing (TES) of 60 genes reported to cause CAKUT in human or murine models. We identified genetic causes in 13.8% of the 94 recruited patients. Pathogenic single nucleotide variants of five known disease-causing genes, HNF1B, PAX2, EYA1, UPK3A, and FRAS1 were found in 7 cases. Pathogenic copy number variations of 6 patients were found in HNF1B, EYA1, and CHD1L. Genetic abnormality types did not significantly differ according to CAKUT phenotypes. Patients with pathogenic variants of targeted genes had syndromic features more frequently than those without (p < 0.001). This is the first genetic analysis study of Korean patients with CAKUT. Only one-seventh of patients were found to have pathogenic mutations in known CAKUT-related genes, indicating that there are more CAKUT-causing genes or environmental factors to discover.	0
BACKGROUND Shprintzen-Goldberg syndrome (SGS) is an extremely rare collagenopathy, most often caused by autosomal-dominant mutations in the SKI proto-oncogene, which is a component of the transforming growth factor beta (TGF-ß) signaling pathway. Approximately 50-60 cases of SGS have been recorded in the literature worldwide since its discovery in 1982. This collagen disorder affects bone and vascular development throughout the body, resulting in craniosynostosis, scoliosis, chest deformities, and aortic root dilation. Patients may have problems in the central nervous system, including Chiari 1 malformation, hydrocephalus, and dilation of the lateral ventricles. Unfortunately, the symptoms of SGS closely parallel those of related collagenopathies involving mutations in the TGF-ß signaling pathway, which makes accurate diagnosis difficult without genetic testing, especially in cases with complex presentation. CASE REPORT In this report we present the unique and complex disease manifestations in a 9-year-old girl with SGS. The patient had severe cervical spinal instability that resolved after surgical occipital-C4 fusion with an autograft from the rib. Midface distraction surgery was used to treat the patient's craniosynostosis and related facial deformities. This surgery was complicated by loss of 750 mL of blood due to insufficient dura and prominent vasculature. CONCLUSIONS Connective tissue symptoms associated with SGS can involve dural and vascular problems, as seen in this case report. Thus, the risk of extreme blood loss should be anticipated any time midface distraction surgery is performed on an SGS patient. Continued research is needed to define how this case relates to the SGS patient population.	0
BACKGROUND:Fraser syndrome or "cryptophthalmos syndrome" is a rare autosomal recessive disease. It is characterized by a group of congenital malformations such as: crytophthalmos, syndactyly, abnormal genitalia, and malformations of the nose, ears, and larynx. Although cryptophthalmos is considered as a main feature of Fraser syndrome, its absence does not exclude the diagnosis. Clinical diagnosis can be made by Thomas Criteria. Here we present the first documented case of Fraser Syndrome in Aleppo, Syria that is characterized by bilateral anophthalmia and intrahepatic biliary atresia. CASE PRESENTATION:During pregnancy, several ultrasound scans revealed hyperechoic lungs, ascites, and unremarkable right kidney at the 19th-week visit; bilateral syndactyly on both hands and feet at the 32nd-week visit. On the 39th week of gestation, the stillborn was delivered by cesarean section due to cephalopelvic disproportion. Gross examination showed bilateral anophthalmia, bilateral syndactyly on hands and feet, low set ears, and ambiguous genitalia. Microscopic examination of the lung, spleen, liver, ovary, and kidneys revealed abnormalities in these organs. CONCLUSION:The diagnosis of Fraser syndrome can be made prenatally and postnatally; prenatally by ultrasound at 18 weeks of gestation and postnatally by clinical examination using Thomas criteria. Moreover, intrahepatic biliary atresia was not described previously with Fraser syndrome; this recommends a more detailed pathologic study for Fraser syndrome cases.	0
Data on the incidence of Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) in East European countries and Asia are limited. The objective of this prospective population-based study was to determine the incidence of PD and APS in the Russian population. The study area was a large district of Moscow with a population of 1,237,900 inhabitants. Multiple sources of case ascertainment were used to identify incident cases of PD and APS between July 2006 and December 2008. All incident cases were examined by a specialist and followed up prospectively to confirm the diagnosis. The age-standardized incidence rates per 100,000/year were 9.03 [95% confidence interval (CI) 8.01-10.15] for PD, 0.11 (95% CI 0.03-0.23) for multiple system atrophy, 0.14 (95% CI 0.08-0.21) for progressive supranuclear palsy, and 0.02 (95% CI 0.01-0.12) for corticobasal degeneration. The age-standardized male-to-female ratio of PD was 0.87 for all ages and 1.46 for those aged 60 and older. A high proportion of new cases with PD (34%) and APS (50%) had comorbid depressive symptoms. Given the rapid growth of the elderly population in Eastern Europe and Asia, the epidemiology of PD and APS in these regions should be investigated in greater depth. The incidence of PD in our study was slightly lower than in studies of Western populations and the male-to-female ratio was closer to those reported in studies from Asia. The clinical implication of our study is that it highlights the need for better diagnosis and treatment of depression in early stages of PD.	1
We report on a girl with trisomy 12 mosaicism diagnosed postnatally. She has been followed from 4 months of age for developmental delay, unilateral sensorineural hearing loss, intestinal malrotation, hemi-hyperplasia, pigmentary dysplasia, retinopathy, and a vascular ring. To our knowledge, there have been no reports of complete trisomy 12 in the literature. However there have been a few reports describing the phenotype of individuals with trisomy 12 mosaicism. This case report is a description of the eighth liveborn individual diagnosed postnatally with this condition.	0
Serum level of alpha-1-antitrypsin is significantly reduced in newborns with idiopathic respiratory distress when compared to matched controls. This decrease was predominantly due to the group of infants who died from I.R.D., provided that alpha-1-antitrypsin determination was carried out on the first day of life. Alpha-1-antitrypsin was demonstrable by indirect immunofluorescence in hyaline membranes whereas fluorescence was negative in the alveolae of infants who had no hyaline membranes.	0
The windblown hand deformity, also known as congenital ulnar drift of the fingers and congenital contractures of the digits is reported infrequently in the literature. Although the syndrome is well described, authors' use of different terms is confusing. In more than 20 years of practice, we have observed 11 patients with the windblown hand and have operated on 7 hands in 4 patients. The anomaly appears to be inherited as an autosomal dominant trait and may represent a variation of some type of arthrogryposis. Ulnar drift of the digits is often present at birth and becomes more pronounced as the child grows. The one factor common to all case reports is a flexion contracture of the metacarpophalangeal joints, with ulnar deviation of the fingers. Also, the thumb is webbed to the palm by a soft tissue bridge. Most cases of the windblown hand should be treated within the first 2 years of life. Because the windblown hand has many variations, each patient must be treated individually. We report a series on the windblown hand and propose a treatment plan for this rare anomaly.	0
Ligneous conjunctivitis (LC) is a rare form of pseudomembranous conjunctivitis seen in children, perhaps due to plasminogen deficiency, which manifest as a chronic refractory pseudomembranous conjunctivitis. LC cases are incapable in maintaining their fibrinolytic activity due to plasminogen deficiency; consequently, transudates of plasma assume as a thick, gelatinous, woody membranes over the mucosal surfaces. This is a short case report on a child with a LC, who presented with recurrent pseudomembranous conjunctivitis in conjunction with progressive congenital hydrocephalus due to aqueductal stenosis (Dandy-Walker syndrome). This rare association was clinically confirmed and prompt corrective surgical measures were instituted.	0
The Nathalie syndrome (OMIM 255990) comprises a combination of features that do not resemble any other known syndrome and is as such an independent, rare entity. It is characterized by sensorineural hearing impairment, juvenile cataract, spinal muscular atrophy, skeletal abnormalities, retardation of growth, underdeveloped secondary gender characteristics and cardiomyopathy. Worldwide, only one family with this syndrome is known. An update of the clinical follow-up in this family and the results of autopsy are given. Audiometry showed a downsloping configuration that corresponded to the findings at histopathological examination of the cochlea: a diffuse atrophy of the organ of Corti, severe and diffuse atrophy of the stria vascularis and moderate loss of cochlear neurons in all turns. Another new striking feature is that individuals with the Nathalie syndrome have a shortened life expectancy with a risk of sudden death or death from heart failure resulting from (dilated) cardiomyopathy.	0
We report the case of a 35-year-old woman with deep-red asymptomatic macules on the plantar and dorsal skin of the right great toe. Histopathologic findings were compatible with Angioma serpiginosum. Immunohistochemical stains for estrogens and progesterone receptors were negative. Dermoscopy showed an erythematous parallel ridge pattern with double rows of irregular dots and globules. We report an unusual case of angioma serpiginosum with acral volar skin involvement. The dermoscopic features described may aid in the diagnosis of AS in this specific skin area. Acral volar skin involvement must be included in the clinical spectrum of Angioma serpiginosum and in the differential diagnosis of acral vascular lesions.	0
Preservation and development of life depend on the adequate segregation of sister chromatids during mitosis and meiosis. This process is ensured by the cohesin multi-subunit complex. Mutations in this complex have been associated with an increasing number of diseases, termed cohesinopathies. The best characterized cohesinopathy is Cornelia de Lange syndrome (CdLS), in which intellectual and growth retardations are the main phenotypic manifestations. Despite some overlap, the clinical manifestations of cohesinopathies vary considerably. Novel roles of the cohesin complex have emerged during the past decades, suggesting that important cell cycle regulators exert important biological effects through non-cohesion-related functions and broadening the potential pathomechanisms involved in cohesinopathies. This review focuses on non-cohesion-related functions of the cohesin complex, gene dosage effect, epigenetic regulation and TGF-β in cohesinopathy context, especially in comparison to Chronic Atrial and Intestinal Dysrhythmia (CAID) syndrome, a very distinct cohesinopathy caused by a homozygous Shugoshin-1 (SGO1) mutation (K23E) and characterized by pacemaker failure in both heart (sick sinus syndrome followed by atrial flutter) and gut (chronic intestinal pseudo-obstruction) with no intellectual or growth delay. We discuss the possible impact of SGO1 alterations in human pathologies and the potential impact of the SGO1 K23E mutation in the sinus node and gut development and functions. We suggest that the human phenotypes observed in CdLS, CAID syndrome and other cohesinopathies can inform future studies into the less well-known non-cohesion-related functions of cohesin complex genes. Abbreviations: AD: Alzheimer Disease; AFF4: AF4/FMR2 Family Member 4; ANKRD11: Ankyrin Repeat Domain 11; APC: Anaphase Promoter Complex; ASD: Atrial Septal Defect; ATRX: ATRX Chromatin Remodeler; ATRX: Alpha Thalassemia X-linked intellectual disability syndrome; BIRC5: Baculoviral IAP Repeat Containing 5; BMP: Bone Morphogenetic Protein; BRD4: Bromodomain Containing 4; BUB1: BUB1 Mitotic Checkpoint Serine/Threonine Kinase; CAID: Chronic Atrial and Intestinal Dysrhythmia; CDK1: Cyclin Dependent Kinase 1; CdLS: Cornelia de Lange Syndrome; CHD: Congenital Heart Disease; CHOPS: Cognitive impairment, coarse facies, Heart defects, Obesity, Pulmonary involvement, Short stature, and skeletal dysplasia; CIPO: Chronic Intestinal Pseudo-Obstruction; c-kit: KIT Proto-Oncogene Receptor Tyrosine Kinase; CoATs: Cohesin Acetyltransferases; CTCF: CCCTC-Binding Factor; DDX11: DEAD/H-Box Helicase 11; ERG: Transcriptional Regulator ERG; ESCO2: Establishment of Sister Chromatid Cohesion N-Acetyltransferase 2; GJC1: Gap Junction Protein Gamma 1; H2A: Histone H2A; H3K4: Histone H3 Lysine 4; H3K9: Histone H3 Lysine 9; HCN4: Hyperpolarization Activated Cyclic Nucleotide Gated Potassium and Sodium Channel 4;p HDAC8: Histone deacetylases 8; HP1: Heterochromatin Protein 1; ICC: Interstitial Cells of Cajal; ICC-MP: Myenteric Plexus Interstitial cells of Cajal; ICC-DMP: Deep Muscular Plexus Interstitial cells of Cajal; If: Pacemaker Funny Current; IP3: Inositol trisphosphate; JNK: C-Jun N-Terminal Kinase; LDS: Loeys-Dietz Syndrome; LOAD: Late-Onset Alzheimer Disease; MAPK: Mitogen-Activated Protein Kinase; MAU: MAU Sister Chromatid Cohesion Factor; MFS: Marfan Syndrome; NIPBL: NIPBL, Cohesin Loading Factor; OCT4: Octamer-Binding Protein 4; P38: P38 MAP Kinase; PDA: Patent Ductus Arteriosus; PDS5: PDS5 Cohesin Associated Factor; P-H3: Phospho Histone H3; PLK1: Polo Like Kinase 1; POPDC1: Popeye Domain Containing 1; POPDC2: Popeye Domain Containing 2; PP2A: Protein Phosphatase 2; RAD21: RAD21 Cohesin Complex Component; RBS: Roberts Syndrome; REC8: REC8 Meiotic Recombination Protein; RNAP2: RNA polymerase II; SAN: Sinoatrial node; SCN5A: Sodium Voltage-Gated Channel Alpha Subunit 5; SEC: Super Elongation Complex; SGO1: Shogoshin-1; SMAD: SMAD Family Member; SMC1A: Structural Maintenance of Chromosomes 1A; SMC3: Structural Maintenance of Chromosomes 3; SNV: Single Nucleotide Variant; SOX2: SRY-Box 2; SOX17: SRY-Box 17; SSS: Sick Sinus Syndrome; STAG2: Cohesin Subunit SA-2; TADs: Topology Associated Domains; TBX: T-box transcription factors; TGF-β: Transforming Growth Factor β; TGFBR: Transforming Growth Factor β receptor; TOF: Tetralogy of Fallot; TREK1: TREK-1 K(+) Channel Subunit; VSD: Ventricular Septal Defect; WABS: Warsaw Breakage Syndrome; WAPL: WAPL Cohesin Release Factor.	0
INTRODUCTION:We report a local human case of Thelazia callipaeda eye infection in a 49-year-old lady with history of fly contact in Hong Kong. CASE DESCRIPTION:A 49-year-old lady presented with right eye foreign body sensation for one month. She recalled a fly being stuck onto her right upper eyelashes with mascara when she went hiking in a forest trail in Hong Kong. On assessment there were a lot of giant papillae on palpebral conjunctiva. Three living worms crawling on conjunctiva were discovered and removed in total. The worms were identified as Thelazia callipaeda by morphology and molecular sequencing. After removal, her symptoms resolved completely. CONCLUSION:Human thelaziasis is probably under-reported in many countries. The presence of giant papillary conjunctivitis in non-contact lens wearers should alert clinicians to the possibility of thelaziasis in patients with compatible exposure history in endemic regions. Ophthalmologists should increase their awareness towards this uncommon disease and should not wrongly attributed the symptoms to allergic conjunctivitis.	0
A 35-year-old man presented with significant weight loss of 30 kg over the previous 6 months, with newly diagnosed diabetes. Routine laboratory tests were normal, except for markedly elevated blood glucose. Computed tomography (CT) of the abdomen revealed a large severely enhanced mass replacing most of the pancreas and liver metastatic nodules and multiple paraaortic lymph node metastases, 18F-fluorodeoxygluocse positron emission tomography/computed tomography (18F-FDG PET/CT) was performed and revealed mild FDG uptake in the pancreatic mass, as well as mild uptake in the liver and lymph node metastases. A biopsy of the liver metastasis was consistent glucagonoma that was confirmed with markedly elevated serum glucagon level. Subsequently, 68Ga-DOTATATE PET/CT was performed for better tumor characterization and for assessment of the tumors' response to therapy, 68Ga-DOTATATE scan revealed intense uptake in the pancreatic mass, liver metastases, and paraaortic lymph node metastases. The patient responded well to peptide receptor radionuclide therapy. This case highlights the role of both 68Ga-DOTATATE and 18FDG-PET/CT in the diagnosis and management of a glucagonoma. 68Ga-DOTATATE is the tracer of choice for well-differentiated glucagonoma and offers very high diagnostic accuracy as compared with that of cross-sectional and other functional imaging and enables correct patient selection for peptide receptor radionuclide therapy.	0
BACKGROUND:Pathogenic variants of USH1C, encoding a PDZ-domain-containing protein called harmonin, have been known to cause autosomal recessive syndromic or nonsyndromic hearing loss (NSHL). We identified a causative gene in a large Korean family with NSHL showing a typical pattern of autosomal dominant (AD) inheritance. METHODS:Exome sequencing was performed for five affected and three unaffected individuals in this family. Following identification of a candidate gene variant, segregation analysis and functional studies, including circular dichroism and biolayer interferometry experiments, were performed. RESULTS:A novel USH1C heterozygous missense variant (c.667G>T;p.Gly223Cys) was shown to segregate with the NSHL phenotype in this family. This variant affects an amino acid residue located in the highly conserved carboxylate-binding loop of the harmonin PDZ2 domain and is predicted to disturb the interaction with cadherin-related 23 (cdh23). The affinity of the variant PDZ2 domain for a biotinylated synthetic peptide containing the PDZ-binding motif of cdh23 was approximately 16-fold lower than that of the wild-type PDZ2 domain and that this inaccessibility of the binding site was caused by a conformational change in the variant PDZ2 domain. CONCLUSIONS:A heterozygous variant of USH1C that interferes with the interaction between cdh23 and harmonin causes novel AD-NSHL.	0
Embryologically, incomplete conotruncal septation with resultant single aortopulmonary trunk and defective ventricular septation defines the congenital cardiac lesion known as persistent truncus arteriosus (PTA). Torrential pulmonary blood flow is inevitable when this rare lesion is further compounded by patency of the arterial ductus. Such was the case of a patient who presented with fast breathing, reduced suck, darkening of the tongue, and extremities. Urgent echocardiographic diagnosis was PTA (Type A1) with patent ductus arteriosus and pulmonary hypertension and left ventricular systolic dysfunction.	0
To explore genetic mutations and clinical features of osteogenesis imperfecta type V.Clinical record of five patients (including one familial case) with osteogenesis imperfecta type V were retrospectively analyzed. Peripheral blood samples of the patients, one family member, as well as healthy controls were collected. Mutation of IFITM5 gene was identified by PCR amplification and Sanger sequencing.A heterozygous mutation (c.-14C>T) in the 5-UTR of the IFITM5 gene was identified in all of the patients and one mother. The clinical findings included frequent fractures and spine and/or extremities deformities, absence of dentinogenesis imperfecta, absence of hearing impairment, and blue sclera in 1 case. Radiographic findings revealed calcification of the interosseous membrane between the radius-ulna in all cases. Hyperplastic callus formation was found in 3 cases. Four had radial-head dislocation.A single heterozygous mutation c.-14C>T was found in the 5-UTR of the IFITM5 gene in 5 patients with osteogensis imperfecta type V. The patients showed specific radiological features including calcification of interosseous membrane, hyperplastic callus formation, and radial-head dislocation.	0
Cockayne Syndrome (CS) is an autosomal recessive neurodegenerative premature aging disorder associated with defects in nucleotide excision repair (NER). Cells from CS patients, with mutations in CSA or CSB genes, present elevated levels of reactive oxygen species (ROS) and are defective in the repair of a variety of oxidatively generated DNA lesions. In this study, six purine lesions were ascertained in wild type (wt) CSA, defective CSA, wtCSB and defective CSB-transformed fibroblasts under different oxygen tensions (hyperoxic 21%, physioxic 5% and hypoxic 1%). In particular, the four 5',8-cyclopurine (cPu) and the two 8-oxo-purine (8-oxo-Pu) lesions were accurately quantified by LC-MS/MS analysis using isotopomeric internal standards after an enzymatic digestion procedure. cPu levels were found comparable to 8-oxo-Pu in all cases (3-6 lesions/106 nucleotides), slightly increasing on going from hyperoxia to physioxia to hypoxia. Moreover, higher levels of four cPu were observed under hypoxia in both CSA and CSB-defective cells as compared to normal counterparts, along with a significant enhancement of 8-oxo-Pu. These findings revealed that exposure to different oxygen tensions induced oxidative DNA damage in CS cells, repairable by NER or base excision repair (BER) pathways. In NER-defective CS patients, these results support the hypothesis that the clinical neurological features might be connected to the accumulation of cPu. Moreover, the elimination of dysfunctional mitochondria in CS cells is associated with a reduction in the oxidative DNA damage.	0
Background:The goal of this study is to systematically evaluate the magnetic resonance imaging (MRI) signal characteristics and size of cataracts that may be encountered in pediatric and young adult patients. Methods:A retrospective analysis of the MRI features with cataracts in a series of cases, including characterization of signal intensity on T2-weighted and T1-weighted sequences, as well as measuring the thickness of the lens. Results:Among nine cataracts in seven patients, three lenses were thickened and hyperintense on T2-weighted sequences, presumably related to osmotic effects. The rest of the lenses were either normal in size and signal characteristics, such as in the cases of neurofibromatosis type 2 or small in cases of microphthalmos, with signal characteristics related to calcifications. Conclusions:There are several different types of cataracts that can occur in pediatric and young adult patients, which may or may not be conspicuous on MRI. The findings in this study can serve as a guide for what abnormalities of the lens may be encountered on MRI.	0
The skin is a high turnover organ, and its constant renewal depends on the rapid proliferation of its progenitor cells. The energy requirement for these metabolically active cells is met by mitochondrial respiration, an ATP generating process driven by a series of protein complexes collectively known as the electron transport chain (ETC) that is located on the inner membrane of the mitochondria. However, reactive oxygen species (ROS) like superoxide, singlet oxygen, peroxides are inevitably produced during respiration and disrupt macromolecular and cellular structures if not quenched by the antioxidant system. The oxidative damage caused by mitochondrial ROS production has been established as the molecular basis of multiple pathophysiological conditions, including aging and cancer. Not surprisingly, the mitochondria are the primary organelle affected during chronological and UV-induced skin aging, the phenotypic manifestations of which are the direct consequence of mitochondrial dysfunction. Also, deletions and other aberrations in the mitochondrial DNA (mtDNA) are frequent in photo-aged skin and skin cancer lesions. Recent studies have revealed a more innate role of the mitochondria in maintaining skin homeostasis and pigmentation, which are affected when the essential mitochondrial functions are impaired. Some common and rare skin disorders have a mitochondrial involvement and include dermal manifestations of primary mitochondrial diseases as well as congenital skin diseases caused by damaged mitochondria. With studies increasingly supporting the close association between mitochondria and skin health, its therapeutic targeting in the skin-either via an ATP production boost or free radical scavenging-has gained attention from clinicians and aestheticians alike. Numerous bioactive compounds have been identified that improve mitochondrial functions and have proved effective against aged and diseased skin. In this review, we discuss the essential role of mitochondria in regulating normal and abnormal skin physiology and the possibility of targeting this organelle in various skin disorders.	0
CONTEXT:Familial partial lipodystrophy (FPLD) is most commonly caused by pathogenic variants in LMNA and PPARG. Leptin replacement with metreleptin has largely been studied in the LMNA group. OBJECTIVE:To understand the efficacy of metreleptin in PPARG vs LMNA pathogenic variants and investigate predictors of metreleptin responsiveness. DESIGN:Subgroup analysis of a prospective open-label study of metreleptin in lipodystrophy. SETTING:National Institutes of Health, Bethesda, Maryland. PARTICIPANTS:Patients with LMNA (n = 22) or PPARG pathogenic variants (n = 7), leptin <12 ng/mL, and diabetes, insulin resistance, or high triglycerides. INTERVENTION:Metreleptin (0.08 to 0.16 mg/kg) for 12 months. OUTCOME:Hemoglobin A1c (HbA1c), lipids, and medication use at baseline and after 12 months. RESULTS:Baseline characteristics were comparable in patients with PPARG and LMNA: HbA1c, 9.2 ± 2.3 vs 7.8 ± 2.1%; median [25th, 75th percentile] triglycerides, 1377 [278, 5577] vs 332 [198, 562] mg/dL; leptin, 6.3 ± 3.8 vs 5.5 ± 2.5 ng/mL (P > 0.05). After 12 months of metreleptin, HbA1c declined to 7.7 ± 2.4 in PPARG and 7.3 ± 1.7% in LMNA; insulin requirement decreased from 3.8 [2.7, 4.3] to 2.1 [1.6, 3.0] U/kg/d in PPARG and from 1.7 [1.3, 4.4] to 1.2 [1.0, 2.3] U/kg/d in LMNA (P < 0.05). Triglycerides decreased to 293 [148, 406] mg/dL in LMNA (P < 0.05), but changes were not significant in PPARG: 680 [296, 783] mg/dL at 12 months (P = 0.2). Both groups were more likely to experience clinically relevant triglyceride (≥30%) or HbA1c (≥1%) reduction with metreleptin if they had baseline triglycerides ≥500 mg/dL or HbA1c >8%. CONCLUSION:Metreleptin resulted in similar metabolic improvements in patients with LMNA and PPARG pathogenic variants. Our findings support the efficacy of metreleptin in patients with the two most common genetic causes of FPLD.	0
Despite international initiatives like Orphanet, it remains difficult to find up-to-date information about rare diseases. The aim of this study is to propose an exhaustive set of queries for PubMed based on terminological knowledge and to evaluate it versus the queries based on expertise provided by the most frequently used resource in Europe: Orphanet.Four rare disease terminologies (MeSH, OMIM, HPO and HRDO) were manually mapped to each other permitting the automatic creation of expended terminological queries for rare diseases. For 30 rare diseases, 30 citations retrieved by Orphanet expert query and/or query based on terminological knowledge were assessed for relevance by two independent reviewers unaware of the query's origin. An adjudication procedure was used to resolve any discrepancy. Precision, relative recall and F-measure were all computed.For each Orphanet rare disease (n = 8982), there was a corresponding terminological query, in contrast with only 2284 queries provided by Orphanet. Only 553 citations were evaluated due to queries with 0 or only a few hits. There were no significant differences between the Orpha query and terminological query in terms of precision, respectively 0.61 vs 0.52 (p = 0.13). Nevertheless, terminological queries retrieved more citations more often than Orpha queries (0.57 vs. 0.33; p = 0.01). Interestingly, Orpha queries seemed to retrieve older citations than terminological queries (p < 0.0001).The terminological queries proposed in this study are now currently available for all rare diseases. They may be a useful tool for both precision or recall oriented literature search.	0
The patient was a 26-year-old female who had undergone conservative treatment for acute appendicitis at another clinic and was referred to our hospital for interval appendectomy. We performed a single-incision laparoscopic appendectomy, and the patient was diagnosed with goblet cell carcinoid(GCC)based on the postoperative pathological examination. Since GCC is considered a high-grade tumor, we performed a laparoscopic ileocolic resection with D3 lymphadenectomy. There was no residual disease or lymph node metastasis detected in the resected specimen. Patients with advanced GCC typically have poor prognosis, because GCC is characterized by peritoneal dissemination and lymph node metastasis. However, our findings suggested that an additional laparoscopic surgery could be one of the curative and safe treatment options for selected pa- tients with GCC.	0
Neuroblastoma is a cancer of the developing sympathetic nervous system. It is diagnosed in 600-700 children per year in the United States and accounts for 12% of pediatric cancer deaths. Despite recent advances in our understanding of this malignancy's complex genetic architecture, the contribution of rare germline variants remains undefined. Here, we conducted a genome-wide analysis of large (>500 kb), rare (<1%) germline copy number variants (CNVs) in two independent, multi-ethnic cohorts totaling 5,585 children with neuroblastoma and 23,505 cancer-free control children. We identified a 550-kb deletion on chromosome 16p11.2 significantly enriched in neuroblastoma cases (0.39% of cases and 0.03% of controls; p = 3.34 × 10-9). Notably, this CNV corresponds to a known microdeletion syndrome that affects approximately one in 3,000 children and confers risk for diverse developmental phenotypes including autism spectrum disorder and other neurodevelopmental disorders. The CNV had a substantial impact on neuroblastoma risk, with an odds ratio of 13.9 (95% confidence interval = 5.8-33.4). The association remained significant when we restricted our analysis to individuals of European ancestry in order to mitigate potential confounding by population stratification (0.42% of cases and 0.03% of controls; p = 4.10 × 10-8). We used whole-genome sequencing (WGS) to validate the deletion in paired germline and tumor DNA from 12 cases. Finally, WGS of four parent-child trios revealed that the deletion primarily arose de novo without maternal or paternal bias. This finding expands the clinical phenotypes associated with 16p11.2 microdeletion syndrome to include cancer, and it suggests that disruption of the 16p11.2 region may dysregulate neurodevelopmental pathways that influence both neurological phenotypes and neuroblastoma.	0
S-adenosylmethionine (SAMe) is involved in many transmethylation reactions in most living organisms and is also required in the synthesis of several substances such as monoamine neurotransmitters and the N-methyl-D-aspartate (NMDA) receptor. Due to its important role as an epigenetic modulator, we discuss in some length the process of DNA methylation and demethylation and the critical periods of epigenetic modifications in the embryo, fetus, and thereafter. We also discuss the effects of SAMe deficiency and the attempts to use SAMe for therapeutic purposes such as the treatment of major depressive disorder, Alzheimer disease, and other neuropsychiatric disorders. SAMe is an approved food additive and as such is also used during pregnancy. Yet, there seems to scanty data on the possible effects of SAMe on the developing embryo and fetus. Valproic acid (VPA) is a well-tolerated and effective antiepileptic drug that is also used as a mood stabilizer. Due to its high teratogenicity, it is contraindicated in pregnancy. A major mechanism of its action is histone deacetylase inhibition, and therefore, it acts as an epigenetic modulator, mainly on the brain. This prompted clinical trials using VPA for additional indications i.e., treating degenerative brain disease such as Alzheimer disease, dementia, HIV, and even cancer. Therefore, we discuss the possible effects of VPA and SAMe on the conceptus and early postnatally, during periods of susceptibility to epigenetic modifications. VPA is also used as an inducer of autistic-like behavior in rodents and was found by us to modify gene expression when administered during the first postnatal week but not when administered to the pregnant dams on day 12 of gestation. In contrast, SAMe modified gene expression when administered on day 12 of pregnancy but not postnatally. If administered together, VPA prevented the changes in gene expression induced by prenatal SAMe administration, and SAMe prevented the gene expression changes and autistic-like behavior induced by early postnatal VPA. It is concluded that both VPA and SAMe are powerful epigenetic modifiers with antagonistic actions on the brain that will probably be used in the future more extensively for the treatment of a variety of epigenetic diseases of the nervous system.	0
BACKGROUND:Congenital dyserythropoietic anemia type I (CDA I), is an autosomal recessive disease with macrocytic anemia in which erythroid precursors in the bone marrow exhibit pathognomonic abnormalities including spongy heterochromatin and chromatin bridges. We have shown previously that the gene mutated in CDA I encodes Codanin-1, a ubiquitously expressed and evolutionarily conserved large protein. Recently, an additional etiologic factor for CDA I was reported, C15Orf41, a predicted nuclease. Mutations in both CDAN1 and C15Orf41 genes results in very similar erythroid phenotype. However, the possible relationships between these two etiologic factors is not clear. RESULTS:We demonstrate here that Codanin-1 and C15Orf41 bind to each other, and that Codanin-1 stabilizes C15Orf41. C15Orf41 protein is mainly nuclear and Codanin-1 overexpression shifts it to the cytoplasm. Phylogenetic analyses demonstrated that even though Codanin-1 is an essential protein in mammals, it was lost from several diverse and unrelated animal taxa. Interestingly, C15Orf41 was eliminated in the exact same animal taxa. This is an extreme case of the Phylogenetic Profiling phenomenon, which strongly suggests common pathways for these two proteins. Lastly, as the 3D structure is more conserved through evolution than the protein sequence, we have used the Phyre2 alignment program to find structurally homologous proteins. We found that Codanin-1 is highly similar to CNOT1, a conserved protein which serves as a scaffold for proteins involved in mRNA stability and transcriptional control. CONCLUSIONS:The physical interaction and the stabilization of C15Orf41 by Codanin-1, combined with the phylogenetic co-existence and co-loss of these two proteins during evolution, suggest that the major function of the presumptive scaffold protein, Codanin-1, is to regulate C15Orf41 activities. The similarity between Codanin-1 and CNOT1 suggest that Codanin-1 is involved in RNA metabolism and activity, and opens up a new avenue for the study of the molecular pathways affected in CDAI.	0
BACKGROUND:Pseudo-Bartter syndrome (PBS) is a rare complication of cystic fibrosis (CF) and there are limited data in the literature about it. We aimed to compare clinical features and accompanying findings of patients with PBS in a large patient population. METHODS:The data were collected from the Cystic Fibrosis Registry of Turkey where 1170 CF patients were recorded in 2017. Clinical features, diagnostic test results, colonization status, complications, and genetic test results were compared in patients with and without PBS. RESULTS:Totally 1170 patients were recorded into the registry in 2017 and 120 (10%) of them had PBS. The mean age of diagnosis and current age of patients were significantly younger and newborn screening positivity was lower in patients with PBS (P < .001). There were no differences between the groups in terms of colonization status, mean z-scores of weight, height, BMI, and mean FEV1 percentage. Types of genetic mutations did not differ between the two groups. Accompanying complications were more frequent in patients without PBS. CONCLUSION:PBS was detected as the most common complication in the registry. It could be due to warm weather conditions of our country. It is usually seen in younger ages regardless of mutation phenotype and it could be a clue for early diagnosis of CF.	0
BACKGROUND:The Clinica del Lavoro of Milan provided several contributions to industrial hygiene and occupational toxicology during the twentieth century. OBJECTIVES:Describe the first years of the laboratory of industrial hygiene of Milan through three figures who played a leading role: Enrico Carlo Vigliani, Nicola Zurlo and Gianmario Cavagna. METHODS:Scientific literature of the period 1948-1970 was investigated, also interviewing first-hand witnesses of that period. RESULTS:Enrico Vigliani was the first European scholar to understand the importance of a laboratory of industrial hygiene within his institution. Thanks to the support of private (Montecatini) and public (INAIL) institutions he succeeded in creating a laboratory in 1948. Nicola Zurlo, who directed this structure in the first thirty years, conducted innovative studies on chronic mercury intoxication, lead intoxication and silicosis, designing and creating instruments for capturing and analyzing atmospheric dust and protection devices. He conducted analysis of the health effects of organophosphorus insecticides and started to study the air pollution. Zurlo also provided an epistemological and methodological content to the discipline. Gianmario Cavagna, one of the first Italian toxicologists, contributed to the discovery of the origin of fevers caused by the inhalation of metal fumes and to the studies on the pathogenesis of byssinosis, hypothesizing a role of bacterial endotoxins in the genesis of this disease. CONCLUSIONS:The contributions provided by these three protagonists to industrial hygiene and occupational toxicology were relevant and made in those years the Clinica del Lavoro of Milan as a landmark, not only in Italy but also abroad.	0
BACKGROUND:Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant disease characterized by the episodic weakness of skeletal muscles and hypokalemia. More than half patients with HypoPP carry mutations in CACNA1S, encoding alpha-1 subunit of calcium channel. Few reports have documented the non-neuromuscular phenotypes of HypoPP. METHODS:The proband is a Japanese woman who developed HypoPP at 6 years of age. An excessive insulin secretion with the oral glucose tolerance test rationalized that she had experienced frequent attacks of paralysis on high-carbohydrate diets. RESULTS:Voglibose and acetazolamide effectively controlled her paralytic episodes. Her 8-year-old son and 2-year-old daughter started showing the paralytic symptoms from 4 and 2 years of age, respectively. Laboratory tests revealed high concentrations of creatinine kinase in serum and elevated renin activities in plasma of these children. The targeted sequencing confirmed that these three patients had an identical heterozygous mutation (p.V876E) in CACNA1S. CONCLUSION:Our data indicate that the p.V876E mutation in CACNA1S contributes to the early onset of neuromuscular symptoms and unusual clinical phenotypes of HypoPP.	0
BACKGROUND: Bladder exstrophy (BE) and cloacal exstrophy (CE) are rare birth defects that have been reported to occur in 1:30,000-50,000 and 1:200,000-400,000 live births. Disagreement exists as to whether they comprise two distinct disorders or are part of a spectrum. We examined epidemiologic trends and risk factors for BE and CE in a large population-based dataset. METHODS: Potential cases were identified in the New York State (NYS) Congenital Malformations Registry. When nonspecific codes for CE were reported, narrative descriptions were reviewed for classification. Birth certificate data were analyzed with descriptive statistics and Poisson regression was used to calculate crude (PR) and adjusted prevalence ratios (aPR) and 95% confidence intervals (CI). RESULTS: In NYS from 1983 through 1999, 95 BE cases and 29 CE cases were identified for a live-birth prevalence of 2.1 and 0.6 per 100,000 live births. BE showed a statistically significant downward linear trend by year. Factors associated with BE included summer conception (vs. winter, aPR 2.46, CI 1.19-5.10), white, non-Hispanic maternal race/ethnicity (vs. black non-Hispanic, aPR 3.20, CI 1.20-8.52), and male sex (female vs. male, aPR 0.53, CI 0.33-0.87). Factors associated with CE included preterm low birth weight birth (aPR 14.55, CI 5.28-40.07), multiple birth (aPR 6.68, CI 1.19-23.27), non-New York City residence (aPR 3.27, CI 1.04-10.22), and female sex (aPR 2.57, CI 1.00-6.64). Infant mortality was greater in the CE group. CONCLUSIONS: The epidemiology suggests different risk factor patterns for BE and CE. Classification of BE and CE is difficult due to the nonspecific coding.	1
Early identification and adequate treatment of actinic cheilitis (AC), which affects the lower lip vermillion and is considered a precursor of squamous cell carcinoma, is mandatory. Photodynamic therapy (PDT) has been successfully used in AC. PDT with the use of daylight (DLPDT) is equally effective and more convenient than the conventional PDT. Data on short and long-term efficacy of DLPDT in AC are limited. Our primary purpose was to assess efficacy of DLPDT in AC as well as safety and tolerance. Twenty-two individuals with histologically confirmed AC received 2 MAL (5-aminolevulinic acid)-DLPDT sessions 1 week apart. Patients were evaluated clinically 3, 6, and 12 months after treatment. Non-complete responders were biopsied and excluded from the study if histological alterations were indicative of AC. Adverse events were recorded from baseline to the end of the 12-month follow-up period. Twenty patients completed the study. Overall, complete clinical response 12 months after treatment was 80% (16/20), while an association between treatment response and grade of dysplasia was observed (p = 0.016). With respect to response by grade, complete clinical response achieved in grade I AC was 100% (12/12) and 50% (4/8) in grade II AC. Main adverse events included mild erythema, oedema, and scaling, with no pain associated with DLPDT. According to our results, DLPDT seems to be of significant benefit for the treatment of grade I AC. Combination with the other treatment modalities could improve the efficacy in grade II AC. Further studies are needed for the assessment of late recurrences.	0
Recent advances in scanner technology have enabled computed tomography (CT) scan to evolve into a valuable tool in the noninvasive evaluation of coronary artery disease. Due to its high negative predictive value, CT can act as a gatekeeper, determining which patients require cardiac catheterization. Although mainly used for the evaluation of coronary artery disease, cardiac CT is also useful in the evaluation of various non-coronary cardiac conditions involving the pericardium, pulmonary veins, and the coronary veins and valves, as well as in the assessment of cardiomyopathies, masses, and ventricular and valvular function. This review discusses and illustrates the various non-coronary applications of cardiac CT.	0
Ossifying fibroma (OF) is a rare, benign, non-odontogenic tumor of the jaw which comes under the group of fibro-osseous lesions. Ossifying fibromas of the mandible are more common than in the maxillary region. Juvenile ossifying fibroma has been distinguished from conventional ossifying fibroma on the basis of patient's age, site predilection, and clinical behavior. The lesion should be differentiated from other fibro-osseous lesions as its management varies from surgical enucleation to complete resection. Present report describes the case of juvenile ossifying fibroma of anterior maxillary region in a 7 year old male patient, with a detailed description of clinical, radiographic, histopathologic features, and its surgical management.	0
To observe the clinical efficacy of Huazhuo Jiedu formula in treating chronic erosive gastritis (CEG) patients with syndrome of accumulation of turbidity and toxicity, explore its mechanism by observing the changes in expression levels of hypoxia inducible factor (HIF-1α), vascular endothelial growth factor (VEGF) in serum and gastric mucosa tissues after treatment, and provide theoretical basis for the clinical application of Huazhuo Jiedu formula in treating chronic erosive gastritis. All 70 patient of CEG were randomly divided into control group and treatment group, 35 cases in each group. The patients in control group received Alatan Wuwei Wan, bid, 1 bag/time; while the patients in treatment group were given with Huazhuo Jiedu formula, 1 dose/day. The course of the treatment was 6 months in both groups. The changes in clinical symptoms, gastroscopic signs, pathology and the expression levels of HIF-1α, VEGF, and phosphatase and tensin homolog deleted on chromosome ten (PTEN) in serum and gastric mucosa tissues were observed in both groups. The results showed that treatment group was better than control group in clinical efficacy, gastroscopic efficacy and pathological effect after treatment (P<0.05); the levels of HIF-1α and VEGF in serum of treatment group were lower than those in the control group after treatment (P<0.05), while the level of PTEN in serum of treatment group was higher than that in the control group after treatment (P<0.05); the levels of HIF-1α and VEGF in gastric mucosa tissues in the treatment group were lower than those in the control group after treatment, while the level of PTEN in gastric mucosa tissues in treatment group was higher than that in the control group after treatment (P<0.05), with statistically significant differences between these two groups (P<0.05). Huazhuo Jiedu formula can improve the clinical symptoms, gastroscopic signs and pathological conditions in CEG patients with syndrome of accumulation of turbidity and toxicity, and the mechanism may be associated with decreasing the expression level of HIF-1α, VEGF and increasing the expression level of PTEN.	0
Brucellosis caused by Brucella melitensis is considered to be one of the most important zoonotic diseases in China. In this study, Conventional bio-typing, MLVA (multiple locus variable-number tandem repeat analysis), and WGS (whole-genome sequencing)-SNP (single nucleotide polymorphism) were used to study the genetic similarity of B. melitensis in northern and southern China and analyze its relationship with worldwide lineages. Currently, the distribution of species/biovars of B. melitensis has obviously changed, and B. melitensis has become the dominant species in southern regions of China. Strains from the southern had a common geographic origin with strains from the northern. Many MLVA-16 events were shared in the genotypes of the southern and northern strains, suggest that genotypic movement occurred from north to south. Based on WGS-SNP analysis, strains from different provinces were closely related and may have descended from one common ancestor, suggests that the southern strains originated from northern China. These data indicate that B. melitensis is a latent "travel bacterium" that spread and expanded from North China to South China. Moreover, B. melitensis strains from China are also genetically related to strains from other Asian regions (Kazakhstan, Russia, Mongolia, and India). The movement of infected sheep and their products requires control.	0
BACKGROUND:Ascending aortic aneurysms are one of the major causes of mortality. In recent years, there is a growing interest of epicardial adipose tissue (EAT) and related diseases. The aim of this study was to investigate the relationship of EAT, and PAT with ascending aortic dilatation (AAD). METHODS:We included 934 patients with hypertension in this study. The patients were evaluated by a complete transthoracic echocardiographic examination, including measurements of EAT, PAT, and aortic dimensions. Aortic size index (ASI) was used for diagnosing AAD. The patients were divided into two groups: dilated ascending aorta diameter (ASI ≥ 21 mm / m2, n = 102) or normal aortic diameter (ASI < 21 mm / m2, n = 832) according to the ASI. Characteristics of these patients were compared before and after propensity score matching analysis. RESULTS:Patients with AAD were older (72.3 ± 11.6 vs. 61.7 ± 12.7 years, p <  0.001), had more female gender (66% vs. 54%,p = 0.021) than patients with normal ascending aorta (AA). After propensity score matching analysis (77 vs. 77), EAT [OR:1.461, %95CI (1.082-1.974), p = 0.013] was independently associated with AAD in multivariate logistic regression analysis. In ROC curve analysis, EAT > 0.45 cm had 51.9% sensitivity and 62.3% specificity [AUC = 0.617, P = 0.012, 95% CI (0.529-0.707)]. CONCLUSION:Based on our findings, increased EAT may be suggested as an independent risk factor for AAD due to local or systemic effects in hypertensive patients.	0
Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by degeneration of motor neurons and muscles, and death is usually a result of impaired respiratory function due to loss of motor neurons that control upper airway muscles and/or the diaphragm. Currently, no cure for ALS exists and treatments to date do not significantly improve respiratory or swallowing function. One cause of ALS is a mutation in the superoxide dismutase-1 (SOD1) gene; thus, reducing expression of the mutated gene may slow the progression of the disease. Our group has been studying the SOD1G93A transgenic mouse model of ALS that develops progressive respiratory deficits and dysphagia. We hypothesize that solely treating the tongue in SOD1 mice will preserve respiratory and swallowing function, and it will prolong survival. At 6 weeks of age, 11 SOD1G93A mice (both sexes) received a single intralingual injection of gene therapy (AAVrh10-miRSOD1). Another 29 mice (both sexes) were divided into two control groups: (1) 12 SOD1G93A mice that received a single intralingual vehicle injection (saline); and (2) 17 non-transgenic littermates. Starting at 13 weeks of age, plethysmography (respiratory parameters) at baseline and in response to hypoxia (11% O2) + hypercapnia (7% CO2) were recorded and videofluoroscopic swallow study testing were performed twice monthly until end-stage disease. Minute ventilation during hypoxia + hypercapnia and mean inspiratory flow at baseline were significantly reduced (p < 0.05) in vehicle-injected, but not AAVrh10-miRSOD1-injected SOD1G93A mice as compared with wild-type mice. In contrast, swallowing function was unchanged by AAVrh10-miRSOD1 treatment (p > 0.05). AAVrh10-miRSOD1 injections also significantly extended survival in females by ∼1 week. In conclusion, this study indicates that intralingual AAVrh10-miRSOD1 treatment preserved respiratory (but not swallowing) function potentially via increasing upper airway patency, and it is worthy of further exploration as a possible therapy to preserve respiratory capacity in ALS patients.	0
Intellectual disability (ID), megalencephaly, frontal predominant pachygyria, and seizures, previously called "thin" lissencephaly, are reported to be caused by recessive variants in CRADD. Among five families of different ethnicities identified, one homozygous missense variant, c.509G>A p.(Arg170His), was of Finnish ancestry. Here we report on the phenotypic variability associated for this potential CRADD founder variant in 22 Finnish individuals. Exome sequencing was used to identify candidate genes in Finnish patients presenting with ID. Targeted Sanger sequencing and restriction enzyme analysis were applied to screen for the c.509G>A CRADD variant in cohorts from Finland. Detailed phenotyping and genealogical studies were performed. Twenty two patients were identified with the c.509G>A p.(Arg170His) homozygous variant in CRADD. The majority of the ancestors originated from Northeastern Finland indicating a founder effect. The hallmark of the disease is frontotemporal predominant pachygyria with mild cortical thickening. All patients show ID of variable severity. Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients and megalencephaly in three patients. This study provides detailed data about the phenotypic spectrum of patients with lissencephaly due to a CRADD variant that affects function. High inter- and intrafamilial phenotypic heterogeneity was identified in patients with pachygyria caused by the homozygous CRADD founder variant. The phenotype variability suggests that additional genetic and/or environmental factors play a role in the clinical presentation. Since frontotemporal pachygyria is the hallmark of the disease, brain imaging studies are essential to support the molecular diagnosis for individuals with ID and a CRADD variant.	0
Collection of hematopoietic progenitor cells by apheresis (HPC-A) requires separation of cells by density. Previous studies highlighted the challenges of HPC-A collection from patients with abnormal red blood cells (RBCs). TEMPI syndrome is a recently described condition defined by teleangiectasias, elevated erythropoietin and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting. Patients with TEMPI syndrome have responded to therapies used to treat plasma cell dyscrasias and may benefit from autologous HPC transplantation. We report HPC-A collection from a patient with TEMPI syndrome that was complicated by severe iron deficiency.The patient received granulocyte-colony-stimulating factor (G-CSF) and plerixafor for HPC mobilization and underwent 3 days of HPC-A collection.The patient presented for collection with a microcytic erythrocytosis. Over 3 days, approximately 50 L of whole blood was processed, and 2 × 10(8) CD34+ cells were collected (2.8 × 10(6) CD34+ cells/kg). The mean collection efficiency (CE), percentage of mononuclear cells, hematocrit (Hct), and RBC count were 18%, 90%, 14%, and 9 × 10(11) , respectively. Altering collection variables to avoid RBC contamination reduced CE. Ficoll preparations of the products after freeze-thaw showed RBC contamination and hemolysis. Postthaw viability exceeded 95%. The products were not RBC reduced or washed. There were no adverse reactions during or after infusion.HPC-A collection from a patient with TEMPI syndrome was complicated by microcytic erythrocytosis, leading to RBC contamination and hemolysis in the product. Adequate HPCs were collected and the patient tolerated infusion without RBC depletion or washing. Our report highlights difficulties of HPC-A collection from iron-deficient patients.	0
BACKGROUND:Loss-of-function mutations of human cardiac sodium channel gene SCN5A induce a wide range of arrhythmic disorders. Mutation carriers with co-existing conditions such as congenital heart diseases and histories of cardiac surgeries, could develop complex arrhythmic events that are difficult to diagnose. CASE PRESENTATION:A 41-year-old Japanese male with a history of a surgical closure of an ASD presented impairment of consciousness by wide QRS tachycardia. Because the patient's baseline ECG in sinus rhythm showed similar QRS axis with right bundle brunch block morphology, we suspected supraventricular tachycardia (SVT). During hospitalization, the patient developed polymorphic ventricular tachycardia that was induced by bradycardia. In an electrophysiological study, the SVT was identified as right atrial incisional tachycardia circulating around the scar in the right atrium. The genetic analysis revealed a heterozygous SCN5A c.4037-4038 del TC, p. L1346HfsX38 variant. We diagnosed this patient as having progressive cardiac conduction disorder (PCCD) and polymorphic VT caused by the mutation. Incisional tachycardia with wide QRS morphology was a by-standing comorbidity related to the history of cardiac surgery which could miss lead the diagnosis. The patient's SVT was eliminated by radiofrequency catheter ablation. An implantable cardioverter defibrillator (ICD) was implanted for the secondary prevention of polymorphic VT. Cardiac pace-making therapy by the ICD to avoid bradycardia effectively suppressed the patient's arrhythmic events. CONCLUSIONS:We treated a patient with a sodium channel gene variant. Co-existing SVT originated by a scar in the right atrium made the diagnosis extremely difficult. A multilateral diagnostic approach using an ECG analysis, an electrophysiological study, and genetic screening enabled effective combination therapy comprised of catheter ablation and an ICD.	0
Although neonatal vaccination with bacille Calmette-Guérin (BCG) is considered to be safe, complications with disseminated disease are associated with underlying immuno-deficiency disorders. A BCG-vaccinated 4-month-old girl of Sri Lankan parentage developed progressive left axillary lymphadenopathy and severe bronchopneumonia. Lymph node biopsy demonstrated epithelioid granulomata and acid-fast bacilli. An older sibling had had a similar clinical presentation and the outcome had been fatal. Investigation for immuno-deficiency detected complete IL12RB1 deficiency. Full recovery followed a prolonged course of anti-tuberculous chemotherapy. She was put on lifelong isoniazid prophylaxis. In HIV-negative infants with unusual complications related to BCG vaccination, a primary immuno-deficiency disorder should be considered.	0
Aim: To explore what is currently known regarding participation among children and youth with arthrogryposis multiplex congenita (AMC) using empirical studies, gray literature, and YouTube videos. The secondary objectives included identifying activity types, outcome measures used, interventions provided, and barriers and facilitators to participation.Method: Empirical studies and gray literature were searched through electronic databases and videos were searched on YouTube. Articles and videos pertaining to participation and youth with AMC were included by two reviewers. Data regarding activity types, location, outcomes measures, interventions, and barriers and facilitators to participation was extracted. Data was critically appraised using specific evaluation criteria.Result: Eleven empirical studies, six gray literature articles and 71 videos met the inclusion criteria. The most common activity types reported in the empirical studies and YouTube videos were active-physical, social, and skill-based activities. Outcome measures included evaluations and questionnaires, none of which were designed to address participation. Interventions did not target participation although the environments could affect participation.Conclusion: The paucity of research indicates a need for future studies of participation in this population. Interventions should target participation and address environmental barriers. Videos provide insight for clinicians, youth, and families to help promote participation in the natural environment.	0
BACKGROUND:Quantitative analysis of brain positron-emission tomography (PET) depends on structural segmentation, which can be time-consuming and operator-dependent when performed manually. Previous automatic segmentation usually registered subjects' images onto an atlas template (defined as RSIAT here) for group analysis, which changed the individuals' images and probably affected regional PET segmentation. In contrast, we could register atlas template to subjects' images (RATSI), which created an individual atlas template and may be more accurate for PET segmentation. We segmented two representative brain areas in twenty Parkinson disease (PD) and eight multiple system atrophy (MSA) patients performed in hybrid positron-emission tomography/magnetic resonance imaging (PET/MR). The segmentation accuracy was evaluated using the Dice coefficient (DC) and Hausdorff distance (HD), and the standardized uptake value (SUV) measurements of these two automatic segmentation methods were compared, using manual segmentation as a reference. RESULTS:The DC of RATSI increased, and the HD decreased significantly (P < 0.05) compared with the RSIAT in PD, while the results of one-way analysis of variance (ANOVA) found no significant differences in the SUVmean and SUVmax among the two automatic and the manual segmentation methods. Further, RATSI was used to compare regional differences in cerebral metabolism pattern between PD and MSA patients. The SUVmean in the segmented cerebellar gray matter for the MSA group was significantly lower compared with the PD group (P < 0.05), which is consistent with previous reports. CONCLUSION:The RATSI was more accurate for the caudate nucleus and putamen automatic segmentation and can be used for regional PET analysis in hybrid PET/MR.	0
The rare autosomal dominant Charcot-Marie-Tooth type 2B (CMT2B) is associated with mutations in the RAB7A gene, involved in the late endocytic pathway. CMT2B is characterized by predominant sensory loss, ulceromutilating features, with lesser-to-absent motor deficits. We characterized clinically and genetically a family harboring a novel pathogenic RAB7A variant and performed structural and functional analysis of the mutant protein. A 39-year-old woman presented with early-onset walking difficulties, progressive distal muscle wasting and weakness in lower limbs and only mild sensory signs. Electrophysiology demonstrated an axonal sensorimotor neuropathy. Nerve biopsy showed a chronic axonal neuropathy with moderate loss of all caliber myelinated fibers. Next-generation sequencing (NGS) technology revealed in the proband and in her similarly affected father the novel c.377A>G (p.K126R) heterozygous variant predicted to be deleterious. The mutation affects the biochemical properties of RAB7 GTPase, causes altered interaction with peripherin, and inhibition of neurite outgrowth, as for previously reported CMT2B mutants. However, it also shows differences, particularly in the epidermal growth factor receptor degradation process. Altogether, our findings indicate that this RAB7A variant is pathogenic and widens the phenotypic spectrum of CMT2B to include predominantly motor CMT2. Alteration of the receptor degradation process might explain the different clinical presentations in this family.	0
Anomalies of pyramidal tract decussation are rare phenomena that can be caused by ectodermal dysplasia. Herein, we describe a patient with ichthyosis who exhibited ipsilateral hemiparesis after stroke and whose neuroimaging results showed evidence of motor control being provided by the ipsilateral motor cortex. A 24-year-old right-handed man presented with skin abnormalities, sudden-onset left hemiparesis, and dysarthria. He exhibited a mild-to-moderate left-sided weakness (grade 4 on the Medical Research Council scale). Magnetic resonance imaging revealed an acute infarct in the left corona radiata. Diffusion tensor imaging revealed uncrossed corticospinal tracts. Next-generation sequencing identified heterozygous FLG mutations. The patient was diagnosed with cerebral infarction and ichthyosis vulgaris and was treated with aspirin (100 mg/d). His symptoms gradually dissipated. This case suggests that pyramidal decussation anomalies can be associated with ichthyosis. Patients with ichthyosis should therefore be evaluated for nerve involvement.	0
We report a familial case of acrogeria in a mother and son, with characteristic cutaneous involvement and no clinical signs of vascular Ehlers-Danlos syndrome (former EDS type IV) in spite of some tendency to bruising. The biochemical and molecular studies did not disclose any abnormality of collagen type III, which favours the diagnosis of acrogeria. It appears that recognition of acrogeria as an entity is of clinical significance since these cases are not associated with systemic involvement, and specifically with rupture of vessels and internal organs, occasionnally occurring in EDS.	0
Several molecular markers drive diagnostic classification, prognostic stratification, and/or prediction of response to therapy in patients with gliomas. Among them, IDH gene mutations are valuable markers for defining subtypes and are strongly associated with epigenetic silencing of the methylguanine DNA methyltransferase (MGMT) gene. However, little is known about the percentage of MGMT-methylated alleles in IDH-mutated cells or the potential association between MGMT methylation and deletion of chromosome 10q, which encompasses the MGMT locus. Here, we quantitatively assessed MGMT methylation and IDH1 mutation in 208 primary glioma samples to explore possible differences associated with the IDH genotype. We also explored a potential association between MGMT methylation and loss of chromosome 10q. We observed that MGMT methylation was heterogeneously distributed within glioma samples irrespective of IDH status suggesting an incomplete overlap between IDH1-mutated and MGMT-methylated alleles and indicating a partial association between these two events. Moreover, loss of one MGMT allele did not affect the methylation level of the remaining allele. MGMT was methylated in about half of gliomas harboring a 10q deletion; in those cases, loss of heterozygosity might be considered a second hit leading to complete inactivation of MGMT and further contributing to tumor progression.	0
Despite 30 years of research there are still significant unknowns and controversies associated with multifocal motor neuropathy (MMN) including disease pathophysiology, diagnostic criteria and treatment. Foremost relates to the underlying pathophysiology, specifically whether MMN represents an axonal or demyelinating neuropathy and whether the underlying pathophysiology is focused at the node of Ranvier. In turn, this discussion promotes consideration of therapeutic approaches, an issue that becomes more directed in this evolving era of precision medicine. It is generally accepted that MMN represents a chronic progressive immune-mediated motor neuropathy clinically characterised by progressive asymmetric weakness and electrophysiologically by partial motor conduction block. Anti-GM1 IgM antibodies are identified in at least 40% of patients. There have been recent developments in the use of neuromuscular ultrasound and MRI to aid in diagnosing MMN and in further elucidation of its pathophysiological mechanisms. The present Review will critically analyse the knowledge accumulated about MMN over the past 30 years, culminating in a state-of-the-art approach to therapy.	0
A case study of a 38-year-old woman with a diagnosis of placental site trophoblastic tumor is presented. The patient had a 22-month history of amenorrhea since her last pregnancy, and a dilation and curettage procedure was performed after a 3.1×2.4×2.8 cm endometrial echogenic lesion was visualized on a pelvic ultrasound. When the diagnosis of placental site trophoblastic tumor was made by histopathologic and immunohistochemical analysis, complementary examinations including including pelvic magnetic resonance imaging (MRI) and a chest computed tomography (CT) were done. There was no evidence of disease outside the uterus, and a laparoscopic hysterectomy with bilateral salpingectomy was performed. After a surveillance period of 12 months, no disease recurrence was identified. Best imaging studies, treatment options, and proper surveillance for these type of tumors are discussed alongside the case study.	0
Tracheomalacia (TM) is a weakness of the trachea either due to impaired cartilage integrity or atrophy of muscular elastic fibers. We present the first-ever case of chronic vaping induced altered immunological defenses that led to frequent pulmonary infections, ultimately culminating in severe TM which we successfully treated with positive airway pressure (PAP) therapy. A 53-year-old male presented with hypoxia and pneumonia refractory to outpatient antibiotics and steroids. He underwent bronchoscopy which showed severe TM, prompting transfer to our institution. He started vaping seven years ago and noted frequent bronchitis requiring antibiotics and steroids along with 10 life-time surgeries. He underwent repeat bronchoscopy noting TM, worst 3 cm above the carina and extending 4 cm proximally. The lesion was deemed not suitable for stenting, so PAP therapy was initiated. Bronchoalveolar lavage (BAL) confirmed 40% alveolar macrophages positive for lipid in Oil-O-Red stain consistent with EVALI. He tolerated PAP therapy with significant improvement in his ground glass opacities (GGO) and TM on subsequent imaging. TM is generally defined as >50% narrowing in the sagittal diameter. It is often further characterized into primary (congenital) or secondary (acquired) causes. Notable secondary causes include postintubation, chronic infection/bronchitis, chronic inflammation, and frequent steroid exposure -- all present in this case. Furthermore, there is existing literature that chronic inflammation due to irritants like cigarette smoke may be an important contributor to the development of TM. However, such data are lacking for EVALI. Our patient started experiencing repeated bronchitis episodes after he started vaping, leading to chronic inflammation and frequent antibiotics/steroids. Given his additional risk factor of multiple surgeries, this case not only presents a perfect storm for TM, but also a novel manifestation of EVALI. This case, to our knowledge, is the first-ever manifestation of EVALI presenting with TM. Management with PAP therapy helped avoid major surgery.	0
Aortoatrial fistula formation is a rare complication of bacterial endocarditis. Fistulous tracts may form between the aorta and either atrium. Clinical presentation varies from an insignificant murmur to refractory congestive heart failure. Most clinically relevant fistula manifests with acute and severe symptoms. Transesophageal echocardiography (TEE) is more sensitive than transthoracic echocardiography (TTE) in diagnosing intracardiac shunts, and invaluable in guiding intraoperative surgical repair. Definitive therapy involves closure of the fistula either through an open surgical approach or percutaneously with an occluder device.	0
The nails have a functional and esthetic importance for patients. Almost always, the nail disorders are diagnosed on the basis of clinical findings, but imaging methods may be required for a better assessment. These imaging methods, such as ultrasound and magnetic resonance, may help to establish an accurate diagnosis. Magnetic resonance imaging is not widely available and sometimes may be very expensive; that is why, ultrasound is an excellent imaging modality. Our objective is to expose the nail unit anatomy, the nail unit anatomy in ultrasound, and some of the frequent pathologies found in our daily practice.A review of the literature was done to review the anatomy, technical aspects, and different findings in normal and abnormal nail unit ultrasound.Ultrasound offers an appropriate alternative for the evaluation of the nail unit, allows a real-time evaluation of each one of the components of the nail unit with an optimal visualization of these structures, and allows the evaluation of the thickness of the components, the vascularity, and blood flow by Doppler application. In addition, the nail unit disorder, such as infectious diseases, inflammatory and rheumatologic conditions, nail tumors, among others, may be assessed, not only in the diagnosis but also in the follow-up. Pre-surgical evaluation, surgical follow-up, and some procedures, such as biopsies, may be done by this technique.Ultrasound is an excellent technique for evaluation of normal anatomy, diagnosis, and follow-up of patients with nail unit diseases. This is an alternative for other imaging methods and may be used for an accurate diagnosis approach.	0
PURPOSE:To investigate the development and progression of retinal pigment epithelial (RPE) and outer retinal atrophy (RORA) secondary to Maternally Inherited Diabetes and Deafness (MIDD). DESIGN:Retrospective observational case series. METHODS:Thirty-six eyes of 18 patients (age range, 22.4-71.6 years) with genetically proven MIDD and serial optical coherence tomography (OCT) images were included. As proposed reference standard to diagnose and stage atrophy, OCT images were longitudinally evaluated and analyzed for presence and precursors of RORA. RORA was defined as an area of (I) hypertransmission, (II) disruption of the RPE, (III) photoreceptor degeneration, and (IV) absence of other signs of an RPE tear. RESULTS:The majority of patients revealed areas of RORA in a circular area around the fovea between 5- and 15-degrees eccentricity. Over the observation time (range, 0.5-8.5 years), evidence for a consistent sequence of OCT-features from earlier disease stages to the endstage of RORA could be found starting with loss of ellipsoid zone and subretinal deposits, followed by loss of external limiting membrane and loss of RPE with hypertransmission of OCT-signal into the choroid, and leading to loss of the outer nuclear layer bordered by hyporeflective wedges. Outer retinal tabulations seemed to develop in regions of coalescent areas of RORA. CONCLUSIONS:The development and progression of RORA could be tracked in MIDD patients using OCT images, allowing potential utilization as novel surrogate markers. Similarities to OCT-features in age-related macular degeneration, where mitochondrial dysfunction has been implicated in the pathogenesis support wide-ranging benefits from proof-of-concept studies in MIDD.	0
Multiple pterygium syndrome (MPS) disorders are a phenotypically and genetically heterogeneous group of conditions characterized by multiple joint contractures (arthrogryposis), pterygia (joint webbing) and other developmental defects. MPS is most frequently inherited in an autosomal recessive fashion but X-linked and autosomal dominant forms also occur. Advances in genomic technologies have identified many genetic causes of MPS-related disorders and genetic diagnosis requires large targeted next generation sequencing gene panels or genome-wide sequencing approaches. Using the Illumina TruSightOne clinical exome assay, we identified a recurrent heterozygous missense substitution in TPM2 (encoding beta tropomyosin) in three unrelated individuals. This was confirmed to have arisen as a de novo event in the two patients with parental samples. TPM2 mutations have previously been described in association with a variety of dominantly inherited neuromuscular phenotypes including nemaline myopathy, congenital fibre-type disproportion, distal arthrogryposis and trismus pseudocamptodactyly, and in a patient with autosomal recessive Escobar syndrome and a nemaline myopathy. The three cases reported here had overlapping but variable features. Our findings expand the range of TMP2-related phenotypes and indicate that de novo TMP2 mutations should be considered in isolated cases of MPS-related conditions.	0
Calciphylaxis is a cutaneous vasculopathy with high morbidity and mortality characterized by vascular intimal fibrosis, calcification, stenosis, thrombosis, and eventual tissue death due to ischemia. Histopathologic diagnosis is often difficult, frequently necessitating multiple tissues samples due to lack of specific histopathologic features and subtle changes on biopsies of early lesions. In this study, we review the reported clinical and histopathologic features of calciphylaxis, correlating them with relevant imaging, ancillary studies, and pathophysiology. Although many histopathologic changes seen in calciphylaxis are also reported in other conditions (eg, Mönckeberg sclerosis, lupus panniculitis, pancreatic panniculitis, and peripheral artery disease), calcification of subcutaneous small vessels, thrombosis and/or ischemic changes, pseudoxanthoma elasticum-like changes in the subcutis, and perieccrine calcification may serve as helpful clues. von Kossa and Alizarin red stains can assist in the identification of subtle calcification. Netlike calcification of the affected blood vessels on imaging further supports the diagnosis. Studies into the pathophysiology of calciphylaxis are ongoing and will hopefully facilitate the development of additional diagnostic adjuncts to increase sensitivity and specificity for the diagnosis of this disease.	0
Brucellosis is a bacterial zoonotic disease mainly transmitted to humans by ruminants. In France, brucellosis has disappeared from ruminants herds. Human brucellosis surveillance is performed through mandatory notification and the national reference center.We report the results of human brucellosis surveillance from 2004 to 2013 with regards to epidemiological, clinical and microbiological data.A total of 250 cases were notified, making an annual incidence of 0.3 cases per million inhabitants. Brucella melitensis biovar 3 was the most frequently identified bacterium (79% of isolated strains). In total, 213 (85%) cases had been contaminated abroad in endemic countries. In 2012, an episode of re-emergence of brucellosis in cattle occurred in Haute-Savoie, in the French Alps, and was responsible for 2 human cases.Brucellosis has become a disease of travelers in France. However, maintaining a stringent epidemiological surveillance is necessary to be able to early detect any local re-emergence in humans or animals. The multidisciplinary surveillance was implemented in France years ago and is a successful example of the One Health Concept.	1
Mutations in the CHD7 gene, encoding for the chromodomain helicase DNA-binding protein 7, are found in approximately 60% of individuals with CHARGE syndrome (coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear abnormalities and/or hearing loss). Herein, we present a clinical case of a 14-year-old male presenting for evaluation of poor growth and pubertal delay highlighting the diagnostic challenges of CHARGE syndrome. The patient was born full term and underwent surgery at 5 days of life for bilateral choanal atresia. Developmental milestones were normally achieved. At age 14 his height and weight were -2.04 and -1.74 standard deviation score respectively. He had anosmia as well as prepubertal testes and micropenis (4 cm×1 cm). The biological profile showed low basal serum testosterone and gonadotropins (testosterone, 0.2 nmol/L; luteinizing hormone, 0.5 U/L; follicle-stimulating hormone, 1.3 U/L), and otherwise normal pituitary function and normal imaging of the hypothalamic-pituitary area. The constellation of choanal atresia, anosmia, mild dysmorphic features, micropenis and delayed puberty were suggestive of CHARGE syndrome. Targeted genetic testing of CHD7 was performed revealing a de novo heterozygous CHD7 mutation (c.4234T&gt;G [p.Tyr1412Asp]). Further paraclinical investigations confirmed CHARGE syndrome. Despite the presence of suggestive features, CHARGE syndrome remained undiagnosed in this patient until adolescence. Genetic testing helps clarify the phenotypic and genotypic spectrum to facilitate diagnosis, thus promoting optimal follow-up, treatment, and appropriate genetic counselling.	0
Hypokalemic periodic paralysis (HypoKPP) is a rare disorder characterized by the occurrence of episodic severe muscle weakness, usually triggered by strenuous exercise or high carbohydrate diets. HypoKPP episodes are associated with low serum potassium levels. Most cases of the HypoKPP are hereditary or familial. The familial form of HypoKPP is a rare channelopathy caused by the mutation in either of the calcium or sodium ion channels, primarily affecting the skeletal muscle cells. Acquired cases of HypoKPP are also identified and are associated with hyperthyroidism. Hypokalemic periodic paralysis was first described in 1727 by Musgrave, in 1853 by Cavare and in 1857 by Romberg.[1] The disease-causing mutation in HypoKPP, CACNA1S gene, was identified by Jurkat-Rott et al. in 1994.[1]	0
Dermatomyositis is defined by characteristic skin features and proximal muscle weakness. Skin manifestations are crucial for diagnosing dermatomyositis.1,2 Common cutaneous manifestations include heliotrope rash edema, poikiloderma and erythema which is frequently observed in the malar area.3-5 We described two novel facial skin signs in a case series of Hispanic patients with dermatomyositis.	0
Subacute necrotizing encephalomyelopathy (SNE), also known as Leigh syndrome, is a genetically heterogeneous disease that primarily affects the central nervous system. Originally characterized in 1951, the syndrome is characterized by focal and bilaterally symmetrical, necrotic lesions involving the thalamus, brainstem, and posterior columns of the spinal cord.[1]	0
Mucolipidosis type IV (MLIV) is an ultra-rare lysosomal storage disorder caused by biallelic mutations in MCOLN1 gene encoding the transient receptor potential channel mucolipin-1. So far, 35 pathogenic or likely pathogenic MLIV-related variants have been described. Clinical manifestations include severe intellectual disability, speech deficit, progressive visual impairment leading to blindness, and myopathy. The severity of the condition may vary, including less severe psychomotor delay and/or ocular findings. As no striking recognizable facial dysmorphism, skeletal anomalies, organomegaly, or lysosomal enzyme abnormalities in serum are common features of MLIV, the clinical diagnosis may be significantly improved because of characteristic ophthalmological anomalies. This review aims to outline the pathophysiology and genetic defects of this condition with a focus on the genotype-phenotype correlation amongst cases published in the literature. The authors will present their own clinical observations and long-term outcomes in adult MLIV cases.	0
BACKGROUND:A convergent association between polycystic ovary syndrome (PCOS) and periodontal disease, in particular chronic periodontitis (CP), has recently been proposed. The underlying molecular mechanisms of this association are not fully understood, though it is thought that chronic inflammation is responsible. Therefore, the aim of this study was to evaluate the association between periodontal disease-gingivitis and CP-and PCOS. MATERIALS AND METHODS:The PICO (Participants, Intervention, Control, and Outcomes) question was as follows: "Is there an association between PCOS and CP?" A systematic review of three databases-PubMed, Embase and Scopus-was performed following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Original studies in human cohorts carried out in the last 10 years and including a control group were eligible for inclusion. Letters to the editor, case reports, and reviews were not considered. RESULTS:Ten articles met all the selection criteria and provided a positive answer to the PICO question. Our review of these articles revealed an association between CP and PCOS, since periodontal parameters were altered more frequently in patients with these conditions than in healthy young women. This altered periodontal response in PCOS was associated with a proinflammatory status that seemed to increase susceptibility to periodontal disease. CONCLUSION:Patients with PCOS appear to be more susceptible to developing periodontal diseases than women without the pathology.	0
As part of a multidisciplinary study program, an epidemiological descriptive survey was carried out in the province of Ferrara, northern Italy. The temporal trend of Huntington chorea (HC) in the last century (1871-1987) was determined in the study area, and the patients and subjects at risk were identified with the aim of creating genetic advisory councils offering preventive interventions to eliminate the disease. The final study population consisted of 10 unrelated families with HC and 47 HC cases who lived in the province of Ferrara in the survey period. The estimate of the prevalence rate varied over the time period considered between 3.09 and 0.36 cases per 100,000 inhabitants. The temporal trend was characterized by increasing and decreasing phases, reflecting the incidence (varying between 0.20 and 0.00 annual cases per 100,000 inhabitants) and mortality (varying between 0.21 and 0.00 annual deaths per 100,000 inhabitants) rates. This trend shows that the frequency of HC in the study area was not stable. It was characterized by a cyclic course with a period of about 50 years. In the recent decades of the study, the incidence and the prevalence rates showed a relative increase. Thus, HC persists in the Ferrara population despite a greater public awareness and the recent lower birth rate. A new peak of prevalence is likely in the near future.	1
Cockayne syndrome is an autosomal recessive disorder principally characterized by postnatal growth failure and progressive neurological dysfunction, due primarily to mutations in ERCC6 and ERCC8. Here, we report our diagnostic experience for two patients in a Chinese family suspected on clinical grounds to have Cockayne syndrome. Using multiple molecular techniques, including whole exome sequencing, array comparative genomic hybridization and quantitative polymerase chain reaction, we identified compound heterozygosity for a maternal splicing variant (chr5:60195556, NM_000082:c.618-2A > G) and a paternal complex deletion/inversion/deletion rearrangement removing exon 4 of ERCC8, confirming the suspected pathogenesis in these two subjects. Microhomology (TAA and AGCT) at the breakpoints indicated that microhomology-mediated FoSTeS events were involved in this complex ERCC8 rearrangement. This diagnostic experience illustrates the value of high-throughput genomic technologies combined with detailed phenotypic assessment in clinical genetic diagnosis.	0
Objective: Prevalence of aplastic anemia (AA) is high in the Asian population. This study was done to explore the etiology and association of AA with various socio-economic and environmental factors.Study design and setting: Study included 1324 consecutive AA cases registered at Armed Forces Bone Marrow Transplant Centre Rawalpindi, Pakistan, from March 2001 to August 2016. The study questionnaire was completed through an interview. It included patients' socio-demographic details, personal and family medical history, environmental attributes and clinico-hematological features.Results: The median age of patients was 20 years, 997 were male and 327 female. Distribution of non-severe, severe and very severe AA was 230 (17.4%); 598 (45.2%) and 496 (37.4%), respectively. The majority of patients were from low (n = 761, 57.5%) or middle socioeconomic class (n = 543, 41%). Consanguinity among patients (n = 806, 61%) was slightly higher than the national statistics. History of chemical exposures included fertilizers (n = 116, 8.7%), pesticides (n = 56, 4.2%) and industrial chemicals (n = 37, 2.8%). PNH clone was found in 63 of AA patients. After excluding 298 patients undergoing HSCT and 660 deaths/lost to follow-up, disease evolution was observed in 38(10.4%) patients out of 366 evaluable patients. These included PNH = 18, MDS = 11 and AML = 9.Discussion: Due to lack of funding and adequate human resource at the center, age and sex-matched controls could not be included. Other limitations were a lack of molecular testing to exclude the possibility of inherited bone marrow failure syndromes on a genetic basis.Conclusion: Younger age, male predominance and higher consanguinity point toward genetic factors in AA etiology among the South Asian population.	0
Authors report on the genetic epidemiologic investigation of the upper limb--cardiovascular (Holt-Oram) syndrome. The source of cases was the material of the Hungarian Congenital Malformation Registry. Birth prevalence was 0.95/100,000 total births. 85% of all cases proved to be consequences of new mutations, hence the mutation rate was 4.07 x 10(-6) +/- 3.12 x 10(-6).	1
Objective:To specifically report on ataxic-hypotonic cerebral palsy (CP) using registry data and to directly compare its features with other CP subtypes. Methods:Data on prenatal, perinatal, and neonatal characteristics and gross motor function (Gross Motor Function Classification System [GMFCS]) and comorbidities in 35 children with ataxic-hypotonic CP were extracted from the Canadian Cerebral Palsy Registry and compared with 1,804 patients with other subtypes of CP. Results:Perinatal adversity was detected significantly more frequently in other subtypes of CP (odds ratio [OR] 4.3, 95% confidence interval [CI] 1.5-11.7). The gestational age at birth was higher in ataxic-hypotonic CP (median 39.0 weeks vs 37.0 weeks, p = 0.027). Children with ataxic-hypotonic CP displayed more intrauterine growth restriction (OR 2.6, 95% CI 1.0-6.8) and congenital malformation (OR 2.4, 95% CI 1.2-4.8). MRI was more likely to be either normal (OR 3.8, 95% CI 1.4-10.5) or to show a cerebral malformation (OR 4.2, 95% CI 1.5-11.9) in ataxic-hypotonic CP. There was no significant difference in terms of GMFCS or the presence of comorbidities, except for more frequent communication impairment in ataxic-hypotonic CP (OR 4.2, 95% CI 1.5-11.6). Conclusions:Our results suggest a predominantly genetic or prenatal etiology for ataxic-hypotonic CP and imply that a diagnosis of ataxic-hypotonic CP does not impart a worse prognosis with respect to comorbidities or functional impairment. This study contributes toward a better understanding of ataxic-hypotonic CP as a distinct nosologic entity within the spectrum of CP with its own pathogenesis, risk factors, clinical profile, and prognosis compared with other CP subtypes.	0
This review focuses on the role of the Cytochrome p450 subfamily 26 (CYP26) retinoic acid (RA) degrading enzymes during development and regeneration. Cyp26 enzymes, along with retinoic acid synthesising enzymes, are absolutely required for RA homeostasis in these processes by regulating availability of RA for receptor binding and signalling. Cyp26 enzymes are necessary to generate RA gradients and to protect specific tissues from RA signalling. Disruption of RA homeostasis leads to a wide variety of embryonic defects affecting many tissues. Here, the function of CYP26 enzymes is discussed in the context of the RA signalling pathway, enzymatic structure and biochemistry, human genetic disease, and function in development and regeneration as elucidated from animal model studies.	0
Glycosylation is an essential process by which sugars are attached to proteins and lipids. Complete lack of glycosylation is not compatible with life. Because of the widespread function of glycosylation, inherited disorders of glycosylation are multisystemic. Since the identification of the first defect on N-linked glycosylation in the 1980s, there are over 40 different congenital protein hypoglycosylation diseases. This review will include defects of N-linked glycosylation, O-linked glycosylation and disorders of combined N- and O-linked glycosylation.	0
PURPOSE:To report the resolution of anterior corneal fibrosis after Descemet's stripping automated endothelial keratoplasty (DSAEK), in a patient with chronic corneal edema and anterior stromal scarring. METHODS:A 63-year-old woman, with a history of Fuchs endothelial dystrophy, presented with increasing discomfort and gradual visual loss in her right eye. Clinical examination revealed long-standing bullous keratopathy accompanied by marked subepithelial fibrosis (SEF). Based on the low postoperative visual potential due to glaucomatous optic neuropathy, we decided to proceed with DSAEK. RESULTS:During the follow-up period, SEF was found to gradually resolve. Corneal clarity was restored and an improvement in visual acuity was observed up to 12 months after surgery. CONCLUSION:DSAEK alone may represent an effective therapeutic option for the restoration of impaired corneal clarity in patients with long-standing corneal edema and concomitant anterior subepithelial scarring.	0
RATIONALE:Univentricular dextrocardia is a rare congenital heart disease that usually presents cyanotic manifestations from childhood. Due to the sustained dysfunction of blood oxygenation, it is very difficult to keep an asymptomatic survival. Herein, we described an interesting case of univentricular dextrocardia who suffered from initial symptoms in his middle age. PATIENT CONCERNS:A 54-year-old male patient with numbness and tingling of limbs was admitted to hospital due to the secondary manifestations of congenital heart disease. DIAGNOSIS:The patient was diagnosed as univentricular dextrocardia with pulmonary hypertension and secondary erythrocytosis based on computed tomography (CT) scan, echocardiography, and laboratory examinations. INTERVENTIONS:Intravenous hydration therapy with normal saline successfully eliminated his hyperviscosity associated symptoms. In view of socio-economic reasons, this patient refused surgical evaluation and further medical interventions. OUTCOMES:During 18-month follow up, he received no drug except for regular water intake. Fortunately, his life quality was satisfactory, and no other symptoms emerged except for mild numbness of limbs. LESSONS:In univentricular dextrocardia, it is possible to keep a long-term asymptomatic period due to the slow progress of pathophysiology. In this population, regular cardiac function evaluation and avoiding dehydration may help improve the quality of life.	0
INTRODUCTION:Pulmonary vein isolation (PVI) affects the ganglionated plexi (GP) around the atrium leading to a modification of intrinsic cardiac autonomic system (ANS). In animal models, GP ablation has the potential risk of QT prolongation and ventricular arrhythmias. However, the impact of PVI on QT intervals in human remains unclear. METHODS AND RESULTS:We analyzed electrocardiograms of 117 consecutive patients with paroxysmal atrial fibrillation (AF) who underwent their first PVI procedures and maintained sinus rhythm without antiarrhythmic drugs at all evaluation points (4 h, 1 day, 1 month, and 3 months after PVI). Heart rate significantly increased at 4 h, 1 day, and 1 month. Raw QT interval prolonged at 4 h (417.1 ± 41.6 ms, p < .001) but shortened at 1 day (376.4 ± 34.1 ms, p < .001), 1 month (382.2 ± 31.5 ms, p < 0.001), and 3 months (385.1 ± 32.8 ms, p < 0.001) compared with baseline (391.6 ± 31.4 ms). Bazett-corrected QTc intervals were significantly prolonged at 4 h (430.8 ± 27.9 ms, p < .001), 1 day (434.8 ± 22.3 ms, p < .001), 1 month (434.8 ± 22.3 ms, p < .001), and 3 months (420.1 ± 21.8 ms, p < .001) compared with baseline (404.9 ± 25.2 ms). Framingham-corrected QTc intervals significantly prolonged at 4 h (424.1 ± 26.6 ms, p < .001) and 1 day (412.3 ± 29.3 ms, p < .01) compared with baseline (399.2 ± 22.7 ms). Multiple regression analysis revealed that female sex is a significant predictor of raw QT and QTc interval increase at 4 h after PVI. CONCLUSION:Raw QT and QTc were prolonged after PVI, especially in the acute phase. Female sex is a risk factor for QT increase.	0
Tumid lupus erythematosus (TLE) is a rare form of chronic cutaneous lupus that has triggered much debate regarding its clinical and histopathological features. It has been classically defined as annular erythematous, succulent, plaques involving the face and trunk that typically are devoid of any papulosquamous features such as scale and follicular plugging. These lesions are a clinical mimicker of other urticarial lesions such as urticarial vasculitis and lymphocytic infiltrate of Jessner. We report a case of TLE presenting in a 49-year-old Caucasian female whose initial clinical presentation was concerning for urticarial vasculitis due to presence of urticarial-like lesions present for approximately three months. Laboratory studies and histopathological correlations confirmed the diagnosis of TLE and the patient was successfully treated with topical corticosteroids.	0
Midline facial clefts are rare and challenging deformities caused by failure of fusion of the medial nasal prominences. These anomalies vary in severity, and may include microform lines or midline lip notching, incomplete or complete labial clefting, nasal bifidity, or severe craniofacial bony and soft tissue anomalies with orbital hypertelorism and frontoethmoidal encephaloceles. In this study, the authors present 4 cases, classify the spectrum of midline cleft anomalies, and review our technical approaches to the surgical correction of midline cleft lip and bifid nasal deformities. Embryology and associated anomalies are discussed.The authors retrospectively reviewed our experience with 4 cases of midline cleft lip with and without nasal deformities of varied complexity. In addition, a comprehensive literature search was performed, identifying studies published relating to midline cleft lip and/or bifid nose deformities. Our assessment of the anomalies in our series, in conjunction with published reports, was used to establish a 5-tiered classification system. Technical approaches and clinical reports are described.Functional and aesthetic anatomic correction was successfully achieved in each case without complication. A classification and treatment strategy for the treatment of midline cleft lip and bifid nose deformity is presented.The successful treatment of midline cleft lip and bifid nose deformities first requires the identification and classification of the wide variety of anomalies. With exposure of abnormal nasolabial anatomy, the excision of redundant skin and soft tissue, anatomic approximation of cartilaginous elements, orbicularis oris muscle repair, and craniofacial osteotomy and reduction as indicated, a single-stage correction of midline cleft lip and bifid nasal deformity can be safely and effectively achieved.	0
This review summarizes the status of genetic laboratory testing in Prader-Willi syndrome (PWS) with different genetic subtypes, most often a paternally derived 15q11-q13 deletion and discusses benefits and limitations related to prenatal screening. Medical literature was searched for prenatal screening and genetic laboratory testing methods in use or under development and discussed in relationship to PWS. Genetic testing includes six established laboratory diagnostic approaches for PWS with direct application to prenatal screening. Ultrasonographic, obstetric and cytogenetic reports were summarized in relationship to the cause of PWS and identification of specific genetic subtypes including maternal disomy 15. Advances in genetic technology were described for diagnosing PWS specifically DNA methylation and high-resolution chromosomal SNP microarrays as current tools for genetic screening and incorporating next generation DNA sequencing for noninvasive prenatal testing (NIPT) using cell-free fetal DNA. Positive experiences are reported with NIPT for detection of numerical chromosomal problems (aneuploidies) but not for structural problems (microdeletions). These reports will be discussed along with future directions for genetic screening of PWS. In summary, this review describes and discusses the status of established and ongoing genetic testing options for PWS applicable in prenatal screening including NIPT and future directions for early diagnosis in PWS. © 2016 John Wiley & Sons, Ltd.	0
Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.2 with genome-wide significant linkage in a large European Australian family with autosomal dominant inheritance of frontotemporal dementia and amyotrophic lateral sclerosis and no mutation in known amyotrophic lateral sclerosis or dementia genes. Here we demonstrate the segregation of a novel missense variant in CYLD (c.2155A>G, p.M719V) within the linkage region as the genetic cause of disease in this family. Immunohistochemical analysis of brain tissue from two CYLD p.M719V mutation carriers showed widespread glial CYLD immunoreactivity. Primary mouse neurons transfected with CYLDM719V exhibited increased cytoplasmic localization of TDP-43 and shortened axons. CYLD encodes a lysine 63 deubiquitinase and CYLD cutaneous syndrome, a skin tumour disorder, is caused by mutations that lead to reduced deubiquitinase activity. In contrast with CYLD cutaneous syndrome-causative mutations, CYLDM719V exhibited significantly increased lysine 63 deubiquitinase activity relative to the wild-type enzyme (paired Wilcoxon signed-rank test P = 0.005). Overexpression of CYLDM719V in HEK293 cells led to more potent inhibition of the cell signalling molecule NF-κB and impairment of autophagosome fusion to lysosomes, a key process in autophagy. Although CYLD mutations appear to be rare, CYLD's interaction with at least three other proteins encoded by frontotemporal dementia and/or amyotrophic lateral sclerosis genes (TBK1, OPTN and SQSTM1) suggests that it may play a central role in the pathogenesis of these disorders. Mutations in several frontotemporal dementia and amyotrophic lateral sclerosis genes, including TBK1, OPTN and SQSTM1, result in a loss of autophagy function. We show here that increased CYLD activity also reduces autophagy function, highlighting the importance of autophagy regulation in the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.	0
Although hepatitis C virus (HCV) infection is often associated with extrahepatic cutaneous manifestations such as lichen planus, it is unclear whether HCV per se or HCV-specific immune responses play a pathophysiological role in the development of HCV-related cutaneous diseases. We recently treated a patient who developed parapsoriasis en plaque-like lesions after ingestion of various drugs. She showed hypersensitivity to multiple drugs after interferon therapy. Her clinical course was complicated by flares of parapsoriasis-like lesions which returned at precisely the same sites. The flares had begun within hours of ingesting nicardipine hydrochloride, amlodipine besilate, candesartan cilexetil and atenolol for the first time despite showing a low level of HCV RNA. Interestingly, the flares gradually subsided during continued treatment with these drugs while her HCV RNA level paradoxically increased: thus, there was an inverse correlation between flares and HCV RNA level. The eruptions were eventually diagnosed as fixed drug eruption, although the clinical manifestations mimicked parapsoriasis en plaque. Our results suggest that multiple drug hypersensitivity could be induced by antiviral immune responses that are cross-reactive to multiple drugs, but not by HCV per se.	0
Mesomelic dysplasia Kantaputra type (MDK) is characterized by marked mesomelic shortening of the upper and lower limbs originally described in a Thai family. To identify the cause of MDK, we performed array CGH and identified two microduplications on chromosome 2 (2q31.1-q31.2) encompassing ∼481 and 507 kb, separated by a segment of normal copy number. The more centromeric duplication encompasses the entire HOXD cluster, as well as the neighboring genes EVX2 and MTX2. The breakpoints of the duplication localize to the same region as the previously identified inversion of the mouse mutant ulnaless (Ul), which has a similar phenotype as MDK. We propose that MDK is caused by duplications that modify the topography of the locus and as such result in deregulation of HOXD gene expression.	0
Background:Spinocerebellar ataxia type 23 (SCA23) is an autosomal dominant cerebellar ataxia caused by pathogenic variants in the prodynorphin gene (PDYN). The frequency of PDYN variants is reportedly very low (~ 0.1%) in several ataxia cohorts screened to date. Case presentations:We found five cases of SCA23 in two families (mean age at onset: 37.8 ± 5.5 years; mean age at examination: 64.2 ± 12.3 years) with a novel PDYN variant (c.644G > A:p.R215H). We identified marked heterogeneity in the clinical features in Family 1: the proband showed clinical and neuroimaging features suggestive of multiple system atrophy with predominant parkinsonism (MSA-P). Conversely, the proband's mother with the PDYN p.R215H variant had no subjective symptoms; she had not come to medical attention before our survey, although she showed apparent cerebellar atrophy on brain magnetic resonance imaging (MRI). The other two patients in Family 1 and a patient in Family 2 showed slowly progressive cerebellar ataxia. Conclusions:We here report two Japanese families with SCA23, one of which showed considerable phenotypic variation in affected members. Our findings support that SCA23 can phenotypically overlap with MSA.	0
Monogenic forms of vasculitis are rare but increasingly recognized. Furthermore, genetic immunodeficiency is increasingly associated with inflammatory immune dysregulatory features, including vasculitis. This case report describes a child of non-consanguineous parents who presented with chronic digital vasculitis early in life, is of short stature, has facial dysmorphia, immunodeficiency (low serum IgA, high serum IgM), recurrent bacterial infections, lymphoproliferation, absence of detectable serum C1q, and low classical complement pathway activity. We identified a previously reported de novo heterozygous pathogenic splice mutation in PIK3R1 (c.1425 + 1G > A), resulting in the skipping of exon 11 of the p85α subunit of phosphatidylinositol 3-kinase and causing activated PI3Kδ syndrome type II (APDS2). This explained the phenotype, with the exception of digital vasculitis and C1q deficiency, which have never been described in association with APDS2. No mutations were identified in C1QA, B, or C, their promoter regions, or in any other complement component. Functional studies indicated normal monocytic C1q production and release, suggesting that the observed C1q deficiency was caused by peripheral consumption of C1q. Since C1q deficiency has never been associated with APDS2, we assessed C1q levels in two unrelated patients with genetically confirmed APDS2 and confirmed C1q deficiency in those two cases as well. This observation suggests C1q deficiency to be an inherent but previously unrecognized feature of APDS2. We speculate that the consumption of C1q is driven by increased apoptotic bodies derived from immune cellular senescence, combined with elevated IgM production (both inherent features of APDS2). Secondary C1q deficiency in APDS2 may further contribute to immunodeficiency and could also be associated with inflammatory immune dysregulatory phenotypes, such as the digital vasculitis observed in our case.	0
This report is concerned with neurofibromatosis type 1 (NF-1, 17q11.2) in south-western Ontario, an ethnically diverse population derived from multiple immigrations. The population incidence, prevalence, and mutation rates for this disease are similar in most racial groups of this population and are also comparable to earlier reports. NF-1 is one of the most common single gene disorders in this population. The occurrence of the disease is not affected by the birth order or sex of the transmitting parent. The severe manifestation of this disease is statistically related to paternal transmission. Five polymorphic DNA probes (pA1041, pHHH202, pTH1719, NF1, pEW206, pEW207) were evaluated in relation to segregation of NF-1 using appropriate restriction enzymes. The observed heterozygosity was found to be relatively high, ranging from 25% to 55% for all the probes on 17q and flanking the NF-1 gene. We recommend the use of pHHH202/pTH1719 and pEW206 in any linkage analysis for detection of the presence of the NF-1 mutation. For informative families the degree of certainty is as high as 99.5%. Some future modifications may include the use of NF-1 exon specific probes and primers that remain to be evaluated for heterogeneity and heterozygosity among populations.	1
COTI-2 is a third-generation thiosemicarbazone, which is effective against a diverse group of human cancer cell lines at nanomolar concentrations. COTI-2 also showed superior activity against tumor cells, in vitro and in vivo. As a high efficacy and low toxicity agent, it currently candidates in a phase I clinical study of gynecological malignancies and head and neck squamous cell carcinoma (HNSCC). However, its effect in pediatric T-cell acute lymphoblastic leukemia (T-ALL) is not clear. This study investigates the effect of COTI-2 on T-ALL Jurkat cells in vitro and in vivo. Jurkat cells were exposure to COTI-2 at different concentration and time. Cell apoptosis was detected by flow cytometry to examine the sensitivity of Jurkat cell lines treated with either COTI-2 alone or in combination with MiR-203 mimic or inhibitor in vitro. An orthotopic mouse model was used to examine the sensitivity of Jurkat cells treated with COTI-2 in vivo. Western blotting and RT-qPCR were performed to dissect molecular mechanisms. The results showed that COTI-2 promotes apoptosis of Jurkat cells in dose-and time-dependent way. Enforced expression of miR-203 promotes COTI-2-mediated cell apoptosis, whereas miR-203 silencing attenuates COTI-2-mediated cell apoptosis in Jurkat cells in vitro. COTI-2 is also effective against growth of Jurkat cells in vivo. Mechanistically, COTI-2 induced miR-203 upregulation and inhibited caspase-3/9 activaty leading to inhibition of cell apoptosis. Taken together, COTI-2 inhibits tumor growth in vitro and in vivo in Jurkat cells likely through miR-203-dependent mechanisms. COTI-2 may be a potential approach for T-ALL treatment.	0
Most patients affected by Glycogen storage disease type 1a (GSD-1a), an inherited metabolic disorder caused by mutations in the enzyme glucose-6-phosphatase-alpha (G6Pase-α), develop renal and liver complications, including development of hepatocellular adenoma/carcinoma. The purpose of this study was to identify potential biomarkers of the pathophysiology of the GSD1a affected liver. To this end, we utilized the plasma exosomes of a murine model of GSD-1a, LS-G6pc-/- mice, to uncover microRNA expression modulation associated with the disease. Differentially expressed microRNA between LS-G6pc-/- and wild type mice, LS-G6pc-/- mice with hepatocellular adenoma and LS-G6pc-/- mice without adenoma, and LS-G6pc-/- mice with amyloidosis and LS-G6pc-/- mice without amyloidosis were identified. Pathway analysis demonstrated that the target genes of the differentially expressed microRNA were significantly enriched for insulin signaling pathway, glucose and lipid metabolism, Wnt-beta catenin, telomere maintenance and hepatocellular carcinoma, and chemokine and immune regulation signaling pathways. While some microRNA were common to the different pathologic conditions others were unique to cancerous or inflammatory status of the animals. Therefore, the altered expression of several microRNA correlates with various pathologic liver statuses and may help discriminate during the progression of the disease and the development of late GSD1-a associated complications.	0
OBJECTIVES:Autofluorescence is considered a useful technique in the early detection of oral mucosal alterations. However, its efficacy to discriminate tumor margins is still under debate. The purpose of this pilot study was to confirm the existence of molecular divergence from the centre of a lesion compared to white light and autofluorescence (VELscopeTM ) visualized margins in leukoplakia and oral carcinoma. MATERIALS AND METHODS:Molecular divergence from the centre of the lesion to white light and VELscopeTM defined margins was compared in patients with leukoplakia (n=3) and oral carcinoma (n=4). Expression profiling of 45 selected genes was performed through custom-made TaqMan arrays. Gene Ontology was used for biological pathway analysis. RESULTS:Irrespective of pathology, the greatest molecular divergence existed between the centre of the lesion and both white light and VELscopeTM margins. VELscopeTM and white light margins were also molecularly distinct in oral carcinoma samples. Indeed, the white light margin retained molecular abnormalities observed in the centre of the lesion thus suggesting the existence of a "partially transformed" cell population. CONCLUSION:Despite the limited low number of patients, our data confirm the benefit of combining autofluorescence with conventional oral examination in identifying surgical margins during biopsy procedures for leukoplakia and oral carcinoma.	0
Sjögren-Larsson syndrome (SLS) is a rare inborn error of lipid metabolism. The syndrome is caused by mutations in the ALDH3A2 gene, resulting in a deficiency of fatty aldehyde dehydrogenase. Most patients have a clearly recognizable severe phenotype, with congenital ichthyosis, intellectual disability, and spastic diplegia. In this study, we describe two patients with a remarkably mild phenotype. In both patients, males with actual ages of 45 and 61 years, the diagnosis was only established at an adult age. Their skin had been moderately affected from childhood onward, and both men remained ambulant with mild spasticity of their legs. Cognitive development, as reflected by school performance and professional career, had been unremarkable. Magnetic resonance spectroscopy of the first patient was lacking the characteristic lipid peak. We performed a literature search to identify additional SLS patients with a mild phenotype. We compared the clinical, radiologic, and molecular features of the mildly affected patients with the classical phenotype. We found 10 cases in the literature with a molecular proven diagnosis and a mild phenotype. Neither a genotype-phenotype correlation nor an alternative explanation for the strikingly mild phenotypes was found. New biochemical techniques to study the underlying metabolic defect in SLS, like lipidomics, may in the future help to unravel the reasons for the exceptionally mild phenotypes. In the meantime, it is important to recognize these mildly affected patients to provide them with appropriate care and genetic counseling, and to increase our insights in the true disease spectrum of SLS.	0
Various degrees of bone marrow aplasia have been described in association with distinctive congenital anomalies such as the Fanconi Pancytopenia Syndrome (F.P.S.), Thrombocytopenia Absent Radii Syndrome (T.A.R. Syndrome) the Aase Syndrome and Diamond-Blackfan Anemia. This case report describes a child with pancytopenia and several dysmorphic features which have never collectively been described in any of the bone marrow aplasia syndromes listed above. In this paper, we report a constellation of dysmorphic features and pancytopenia which may constitute a new syndrome.	0
Lichen planus (LP) is a chronic inflammatory disorder that most commonly affects middle-aged individuals. LP involves the skin and/or mucous membranes, including oral, vulvovaginal, esophageal, laryngeal, and conjunctival mucosa. Linear LP, a rare distinct variant of LP, is characterised by pruritic eruption of lichenoid and violaceous papules in a linear distribution. We report an unusual presentation of linear LP in a 14-year-old child that extended from the left anterior nares to upper lip and into the oral mucosa up to the upper gum margin.	0
Cryptorchidism or undescended testis is the single most common genitourinary disease in male neonates. In most cases, the testes will descend spontaneously by 3 months of age. If the testes do not descend by 6 months of age, the probability of spontaneous descent thereafter is low. About 1%-2% of boys older than 6 months have undescended testes after their early postnatal descent. In some cases, a testis vanishes in the abdomen or reascends after birth which was present in the scrotum at birth. An inguinal undescended testis is sometimes mistaken for an inguinal hernia. A surgical specialist referral is recommended if descent does not occur by 6 months, undescended testis is newly diagnosed after 6 months of age, or testicular torsion is suspected. International guidelines do not recommend ultrasonography or other diagnostic imaging because they cannot add diagnostic accuracy or change treatment. Routine hormonal therapy is not recommended for undescended testis due to a lack of evidence. Orchiopexy is recommended between 6 and 18 months at the latest to protect the fertility potential and decrease the risk of malignant changes. Patients with unilateral undescended testis have an infertility rate of up to 10%. This rate is even higher in patients with bilateral undescended testes, with intra-abdominal undescended testis, or who underwent delayed orchiopexy. Patients with undescended testis have a threefold increased risk of testicular cancer later in life compared to the general population. Self-examination after puberty is recommended to facilitate early cancer detection. A timely referral to a surgical specialist and timely surgical correction are the most important factors for decreasing infertility and testicular cancer rates.	0
BACKGROUND:Osteosarcoma, which is the most common primary bone tumor, occurs most frequently in adolescents, but there is a second incidence peak among individuals aged > 60 years. Most osteosarcoma epidemiology studies have been embedded in large analyses of all bone tumors or focused on cases occurring in adolescence. Detailed descriptions of osteosarcoma incidence and survival with direct comparisons among patients of all ages and ethnicities are not available. METHODS:Frequency, incidence, and survival rates for 3482 patients with osteosarcoma from the National Cancer Institute's population-based Surveillance, Epidemiology, and End Results (SEER) Program between 1973 and 2004 were investigated by age (ages 0-24 years, 25-59 years, and 60 to > or = 85 years), race, sex, pathology subtype, stage, and anatomic site. RESULTS:There were large differences in incidence and survival rates by age. There was a high percentage of osteosarcoma with Paget disease and osteosarcoma as a second or later cancer among the elderly. There was a high percentage of osteosarcoma among patients with Paget disease and osteosarcoma as a second or later cancer among the elderly. Tumor site differences among age groups were noted. Survival rates varied by anatomic site and disease stage and did not improve significantly from 1984 to 2004. CONCLUSIONS:This comprehensive, population-based description of osteosarcoma, identified important differences in incidence, survival, pathologic subtype, and anatomic site among age groups, and quantified the impact of osteosarcoma in patients with Paget disease or as a second cancer on incidence and mortality rates. These findings may have implications in understanding osteosarcoma biology and epidemiology.	1
BACKGROUND:Data from electronic health records (EHRs) are increasingly used in the field of genetic research to further precision medicine initiatives. However, many of these efforts exclude individuals with intellectual disabilities, which often stem from genetic conditions. To include this important subpopulation in EHR research, important ethical, legal, and social issues should be considered. OBJECTIVE:The goal of this study was to review prior research to better understand what ethical, legal, and social issues may need further investigation when considering the research use of EHRs for individuals with genetic conditions that may result in intellectual disability. This information will be valuable in developing methods and best practices for involving this group in research given they are considered a vulnerable population that may need special research protections. METHODS:We conducted a scoping review to examine issues related to the use of EHRs for research purposes and those more broadly associated with genetic research. The initial search yielded a total of 460 unique citations. We used an evaluative coding process to determine relevancy for inclusion. RESULTS:This approach resulted in 59 articles in the following areas: informed consent, privacy and security, return of results, and vulnerable populations. The review included several models of garnering informed consent in EHR or genetic research, including tiered or categorical, blanket or general, open, and opt-out models. Second, studies reported on patients' concerns regarding the privacy and security of EHR or genetic data, such as who has access, type of data use in research, identifiability, and risks associated with privacy breach. The literature on return of research results using biospecimens examined the dissension in the field, particularly when sharing individualized genetic results. Finally, work involving vulnerable populations highlighted special considerations when conducting EHR or genetic research. CONCLUSIONS:The results frame important questions for researchers to consider when designing EHR studies, which include individuals with intellectual disabilities, including appropriate safeguards and protections.	0
OBJECTIVE:The objective of this study was to highlight anesthetic and perioperative management and the outcomes of infants with complete atrioventricular (AV) canal defects. DESIGN:This retrospective descriptive study included children who underwent staged and primary biventricular repair for complete AV canal defects from 1999 to 2013. SETTING:A single-center study at a university affiliated heart center. PARTICIPANTS:One hundred and fifty-seven patients with a mean age at surgery of 125 ± 56.9 days were included in the study. About 63.6% of them were diagnosed as Down syndrome. Mean body weight at surgery was 5.6 ± 6.3 kg. METHODS:Primary and staged biventricular repair of complete AV canal defects. MEASUREMENTS AND MAIN RESULTS:A predefined protocol including timing of surgery, management of induction and maintenance of anesthesia, cardiopulmonary bypass, and perioperative intensive care treatment was used throughout the study. Demographic data as well as intraoperative and perioperative Intensive Care Unit (ICU) data, such as length of stay in ICU, total duration of ventilation including reintubations, and total length of stay in hospital and in hospital mortality, were collected from the clinical information system. Pulmonary hypertension was noted in 60% of patients from which 30% needed nitric oxide therapy. Nearly 2.5% of patients needed permanent pacemaker implantation. Thorax was closed secondarily in 7% of patients. In 3.8% of patients, reoperations due to residual defects were undertaken. Duration of hospital stay was 14.5 ± 4.7 days. The in-hospital mortality was 0%. CONCLUSION:Protocolized perioperative management leads to excellent outcome in AV canal defect repair surgery.	0
BACKGROUND:Otocephaly is a rare lethal malformation of the first branchial arch. While the knowledge on the causes of otocephaly in animals is limited, different syndromic forms in man are associated with variants of the PRRX1 and OTX2 genes. CASE PRESENTATION:A stillborn male lamb of the Istrian Pramenka sheep breed showed several congenital craniofacial anomalies including microstomia, agnathia, aglossia, and synotia. In addition, the lamb had a cleft palate, a small opening in the ventral neck region, a cystic oesophagus and two hepatic cysts. The brain was normally developed despite the deformed shape of the head. Taken together the findings led to a diagnosis of otocephaly. Whole-genome sequencing was performed from DNA of the affected lamb and both parents revealing a heterozygous single nucleotide variant in the OTX2 gene (Chr7: 71478714G > A). The variant was absent in both parents and therefore due to a de novo mutation event. It was a nonsense variant, XM_015097088.2:c.265C > T; which leads to an early premature stop codon and is predicted to truncate more than 70% of the OTX2 open reading frame (p.Arg89*). CONCLUSIONS:The genetic findings were consistent with the diagnosis of the otocephaly and provide strong evidence that the identified loss-of-function variant is pathogenic due to OTX2 haploinsufficiency. The benefits of trio-based whole-genome sequencing as an emerging tool in veterinary pathology to confirm diagnosis are highlighted.	0
Lethal congenital contracture syndrome type 7 (LCCS7) and congenital hypomyelinating neuropathy type 3 (CHN3) are rare autosomal recessive diseases, characterized by severe neonatal hypotonia, polyhydramnios, arthrogryposis, facial diplegia, and severe motor paralysis, leading to death in early infancy. They are related to mutations in the CNTNAP1 (contactin associated protein 1) gene, playing an important role in myelination. Recent studies have shown that both diseases could present with a wide phenotypic spectrum, with promising survival up to early childhood. We report on a 7-year-old boy from a nonconsanguineous Lebanese family presenting with neonatal hypotonia, respiratory distress, and arthrogryposis. Molecular analysis revealed the presence of a pathogenic variant in the CNTNAP1 gene leading to a premature stop codon: NM_003632.2:c.3361C>T p.(Arg1121 ∗ ). A review of the literature is discussed.	0
Deficiency of adenosine deaminase 2 (ADA2) due to homozygous or compound heterozygous mutations in the cat eye syndrome chromosome region, candidate 1 (CECR1) gene causes an autoimmune phenotype with systemic vasculitis affecting the skin, inner organs, and the central nervous system. Typically, stroke has been reported to follow systemic inflammatory disease and predominantly affects posterior and central brain areas. Here, we describe one of the rare patients in whom acute mesencephalic stroke preceded systemic inflammation and presented as initial clinical symptom. Symptoms typical for ADA2 deficiency such as fever, livedo racemosa, abdominal colics, arthralgias, and Raynaud phenomenon were observed later. Moreover, angiography of cerebral arteries did not reveal typical vasculitic findings supporting the hypothesis that alternative mechanism of vascular occlusion might have caused the stroke. ADA2 deficiency should be considered in patients with childhood stroke despite the absence of systemic inflammation and cerebral vasculitis.	0
Palmoplantarkeratodermas (PPKs) are a heterogeneous group of hereditary and acquired disorders with underlying gene defects, and characterized by hyperkeratosis of palms and soles with or without other ectodermal and systemic abnormalities. Huriez syndrome is a rare autosomal dominant transgradient type of PPK with high frequency of squamous cell carcinoma in the affected skin. We hereby describe a case of a very rare autosomal dominant PPK in a 40-year-old male patient presenting since birth with PPK extending onto the dorsal aspects of hands and feet with peeling of the skin. The complaints were associated with sclerodactyly, hyperhidrosis, and nail abnormalities. Also superadded dermatophyte infection was observed involving abdomen. No history of loss of any digit. No mucosal, dental, or any systemic involvement was present. No sign of malignancy was noted. Baseline investigations, including ultrasonography of abdomen were normal. Histological findings were nonspecific with only orthohyperkeratosis and acanthosis. Diagnosis was mainly done on clinical grounds. The patient is better with oral retinoids and topical emollients and keratolytics along with antifungal treatment for dermatophyte infection. He is under follow up.	0
BACKGROUND:Androgen Insensitivity Syndrome (AIS) is a rare X-linked recessive androgen receptor (AR) disorder with 46XY karyotype. Partial AIS affects 5-7 per 1,000,000 genetically male individuals whereas Complete AIS affects 2-5 per 100,000 genetically male individuals. CAIS CAIS is characterized by complete resistance to the action of androgens. PRESENTATION OF CASE:17-year patient presented with swelling in bilateral inguinal region. Patient also complained of primary amenorrhea with serum FSH and LH levels being raised, serum testosterone level much above normal range. MRI Pelvis revealed agenesis of vagina, uterine body, both ovaries and cervix. Bilateral testes were noted in bilateral superficial inguinal ring. Bilateral orchidectomy was done and the patient was advised estrogen substitution therapy. DISCUSSION:CAIS is usually diagnosed at puberty, when the patient presents with primary amenorrhea. Karyotype has to be mapped in order to differentiate from other genetic disorders. Orchidectomy should be done to avoid risk of malignancy of undescended intra-abdominal testes (3.6 % at 25 years old, and 33 % at 50 years old, reported by various studies). Hormonal substitution therapy should be administered. Comprehensive psychiatric assessment and intervention go a long way in alleviating distress and enhancing quality of life. CONCLUSION:Androgen Insensitivity Syndrome requires expert and sympathetic handling. Close collaboration between surgeon, gynaecologist and psychologist is essential for proper management of complete androgen insensitivity syndrome.	0
PURPOSE:To investigate complex and different phenotypes in seven Chinese patients diagnosed with Bardet-Biedl syndrome (BBS) and carrying pathogenic mutations. METHODS:Seven unrelated BBS patients were enrolled. Their medical and ophthalmic histories were reviewed, and comprehensive clinical examinations, such as fundus photography, optical coherence tomography, and medical imaging, were performed. A specific hereditary eye disease enrichment panel based on exome-capture technology was used to collect and amplify the protein-coding regions of 441 targeted hereditary eye disease genes, followed by high-throughput sequencing using the Illumina HiSeq platform. RESULTS:All patients exhibited the primary clinical phenotype of BBS. Seven BBS mutations were found in five patients (BBS7 in two patients, BBS10 in two patients, BBS12 in one patient), for a detection rate of 71% (5/7). The ratio of novel to known BBS mutations was 5:2. CONCLUSIONS:This study showed the phenotypic and genotypic spectrum of BBS patients from China, and the findings underscore the importance of obtaining comprehensive clinical observations and molecular analyses for ciliopathies.	0
PURPOSE:Autosomal recessive bestrophinopathy (ARB) is a rare inherited retinal dystrophy resulted from mutations in bestrophin-1 (BEST1) which affect functioning of the retinal pigment epithelium (RPE). Descriptions of disease findings in patients with ARB to date have focused only on macular changes. In this case series, we report previously undescribed mid-peripheral retinal changes occurring in 4 patients with ARB. DESIGN:Case series. METHODS:A single-center, retrospective review of medical records from Mayo Clinic patients with ARB was performed. Imaging reviewed include fundus photography, fundus autofluorescence, spectral domain optical coherence tomography (OCT), and fluorescein angiography. Demographic information and disease progression were noted. RESULTS:4 affected patients from 3 families were identified. All 4 patients were female, and mean age was 12.5 years (range 5-19 years). Diffuse mid-peripheral whitening was consistently noted on fundus photography. Concomitant OCT imaging demonstrated areas of hyperreflectivity in the photoreceptor outer segment layer in areas corresponding to whitening seen on fundus photography. In 1 patient who was followed for 12 years, this finding persisted. Subretinal fluid was also consistently present. Other pathologic imaging findings observed in each patient were in agreement with previous reports of ARB. CONCLUSIONS:This is the first descriptive report of pathologic findings occurred beyond the posterior pole in patients with ARB. These mid-peripheral retinal changes potentially imply that the entirety of the RPE is affected by mutations in BEST1, as also suggested by previous electro-oculogram (EOG) findings. Such implications will be important when developing treatment trials, as past trials have focused only on the posterior pole of the RPE.	0
BACKGROUND:Dyssegmental dysplasia Silverman-Handmaker (DDSH; MIM 224410) type is an extremely rare skeletal dysplasia caused by functional null mutations in the perlecan gene. Less than forty cases are reported in the literature, of which only four were prenatally detected. METHODS:We report on a dizygotic twin pregnancy from consanguineous parents for which one of the twins presented prenatally with severe micromelia, limb bowing and scoliosis, and postnatally with clinical and radiological features compatible with a diagnosis of dyssegmental dysplasia. Molecular studies were undertaken to confirm the clinical diagnosis of DDSH. RESULTS:Molecular analysis results revealed a novel homozygous variant in the HSPG2 gene (MIM 142461), NM_005529.6(HSPG2):c.4029 + 1G>A, consistent with a diagnosis of DDSH. CONCLUSION:To the best of our knowledge, the current report is only the seventh molecularly confirmed case of DDSH.	0
We report on a girl with Ullrich-Turner phenotype and 45,X/47,XX,+18 chromosomal mosaicism. Only two other patients with similar mosaicism have been reported, both girls with XY sex chromosome constitution. The face of the patient was highly asymmetric, the right side being almost normal, the left showing a typical Ullrich-Turner syndrome appearance. This clinical impression was strengthened by photographic doubling of both hemifaces. The patient had normal intelligence and did not show any stigmata of trisomy 18.	0
A 60-year-old woman presented to our department with severe tongue pain. On initial examination, the mucosal surface of the tongue was intact but a hard submucosal mass on the dorsum of the tongue was detected on palpation. Magnetic resonance imaging demonstrated an ill-defined tumor in the intrinsic tongue muscles. Sequential whole-body positron emission tomography/computed tomography revealed a tumor of the pancreas apart from the tongue lesion, and upper gastrointestinal endoscopy revealed gastric mucosa ulceration. On biopsy, the tongue lesion was confirmed to be metastatic gastric adenocarcinoma, and the gastric ulcer was simultaneously diagnosed as poorly differentiated gastric adenocarcinoma. The definitive diagnosis was thus gastric adenocarcinoma and synchronous pancreatic cancer, with gastric carcinoma metastases to the tongue. We administered FOLFIRINOX treatment for pancreatic cancer and FLTAX treatment for gastric cancer. Because of difficulty with oral intake due to the growth of the tongue lesion, we administered palliative radiation therapy at a dose of 30 Gy in 10 fractions following which the patient was able to resume oral intake and was satisfied with this outcome. She died 8 months after her first visit to our department.	0
Autosomal dominant distal renal tubular acidosis (dRTA) is a rare disorder caused by a mutation in the AE1 gene encoding the chloride-bicarbonate (Cl-/HCO3-) anion exchanger 1 (AE1). Most patients with this disorder present with clinical symptoms in adulthood and their phenotype is milder than that of those with autosomal recessive dRTA. In this report, we describe a Japanese family with autosomal dominant dRTA in which the mother and her daughter presented with severe symptoms caused by hypokalemia at 2 years of age. The heterozygous AE1 mutation G609R, which is a known causative mutation of dRTA, was identified in both patients. To our knowledge, this is the first report of a Japanese family with autosomal dominant type dRTA caused by an AE1 mutation. We, therefore, propose that alterations of AE1 should be considered causative of autosomal dominant dRTA even if typical symptoms appear during early childhood and the clinical features are severe.	0
A total of 186 cases of motor neuron disease (MND) was identified in two Danish counties during the period 1974-1986. The average annual incidence rate was 1.4/100,000 population, and the male:female ratio of incidence rates was 1.5. Mean age at diagnosis was 64.3 +/- 10.0 years. The incidence rates increased significantly with advancing age and reached a maximum at age 60-79 years, followed by a nonsignificant decrease. The average point prevalence was 3.1/100,000 population. Bulbar symptoms were part of the initial symptoms in 65% of cases, and patients with bulbar onset were older than patients with spinal onset. Age- and sex-specific incidence rates indicated a marked male preponderance amongst the youngest patients, in contrast to a female preponderance in patients above 60 years with bulbar onset of MND. Familial MND accounted for 2.7% of cases.	1
Childhood obesity is a modern worldwide epidemic with significant burden for health. It is a chronic metabolic disorder associated with multiple cardiovascular risk factors such as dyslipidemia, hypertension, stroke, and insulin resistance. Many obese adolescents remain obese into adulthood, with increased morbidity and mortality. As childhood obesity is a risk factor for adult obesity, the childhood obesity-related disorders account for an increased risk of cardiovascular consequences in adults, in addition to the effects already exerted by the fat mass in adulthood. Several papers have already described the cardiovascular implications of idiopathic obesity, while few data are available about syndromic obesity, due to the small sample size, not homogeneous phenotypes, and younger age at death. The aim of this mini-review is to give a comprehensive overview on knowledge about cardiovascular implications of idiopathic and syndromic obesity to allow the reader a quick comparison between them. The similarities and differences will be highlighted.	0
Vascular Ehlers-Danlos syndrome (OMIM 130050, 1/150,000 birth) is caused by mutations in collagen 3A1 gene. It is associated with severe phenotype associating early arterial dissection and rupture, digestive and uterine perforations, and skin and joints fragility. Until recently, no treatment was available. Celiprolol, a beta1 antagonist with beta2 partial antagonist properties betablocker was tested in a randomized, controlled trial. We could show that this compound was associated with a 3-fold decrease in major events related to the disease. This effect was similar in molecular-proven patients. Administration of celiprolol in a cohort of patients followed routinely in France was accompanied to similar benefit. Celiprolol is unavailable in the USA. The ACER Therapeutics company applied for new drug application (NDA) to the Food and Drug Administration.	0
We describe the clinical outcome of asfotase alfa therapy in a 16-year-old boy with severe childhood hypophosphatasia (HPP), who began therapy at age 15 years. The patient was diagnosed with HPP at age 2 years when he presented with genu varum and premature loss of primary teeth. He had a history of multiple fractures requiring 16 orthopedic surgeries with rod and pin placement in his lower extremities. He had chronic skeletal pain and used cane to ambulate with great difficulty. His height Z score at age 15 years was - 5. He had severe scoliosis and deformity of both legs. Bone radiograph showed hypomineralization and characteristic "tongues" of radiolucency in the distal radius and ulna. His serum alkaline phosphatase level was stable, with elevated serum pyridoxal 5'-phosphate and urine phosphoethanolamine, consistent with HPP. He was started on asfotase alfa 2 mg/kg given subcutaneously thrice weekly. He had marked clinical improvement in mobility with no report of pain after 3 months of treatment. At 6 month, he walked without cane and participated in outdoor activities with peers. Bone radiograph at 6 months showed striking improvement in previous radiolucent areas. At 9 months, his annualized growth velocity was 9.5 cm/year, while growth velocity of arm span was 12 cm/year. However, at 12 months, he was noted to have worsening scoliosis from 60 degrees before therapy to 110 degrees, with a slight decrease in height, necessitating a spinal fusion surgery. In conclusion, treatment with asfotase alfa significantly improved physical function, pain, overall quality of life, and skeletal radiographic findings in this patient. Close monitoring for progression of scoliosis in adolescents with HPP treated with asfotase alfa is recommended.	0
We report the biochemical profiling in two siblings with mitochondrial 2-methylacetoacetyl-CoA thiolase deficiency. Organic aciduria typical of this rare inborn error metabolism was found when the elder sibling presented with an episode of severe ketoacidosis at 20 months of age, which consisted of excessive excretion of ketones, tiglylglycine, 2-methyl-3-hydroxybutyrate, and 2-methylacetoacetate. Blood acylcarnitiness profile showed elevation of C5OH-carnitine, which represents 2-methyl-3-hydroxybutyrylcarnitine. A similar biochemical profile was identified in the younger sibling during screening although he had only mild clinical symptoms. Both patients reported a favourable outcome on follow-up.	0
Dextrocardia with situs inversus is a state which is characterized by abnormal positioning of the heart and other internal organs. It is a rare congenital anomaly and the exact cause is not known. More than 60 recognized genes are significant for the proper positioning and patterning of the organs in the body. However, a specific genetic cause of dextrocardia with situs inversus has not been identified and inheritance prototypes have not been established in the majority cases. There are partial available case reports of successful percutaneous coronary intervention (PCI) in these patients who have atherosclerotic coronary artery disease, especially when presenting with myocardial infarction. PCI is technically difficult because of dextrocardia. We hereby describe a 51-year-old male, who had a recent inferior wall myocardial infarction and underwent successful coronary angiography and PCI at a tertiary level hospital in Dhaka, Bangladesh.	0
BACKGROUND:The cost-effectiveness, utility outcomes, and most optimal timing of mandibular distraction osteogenesis (MDO) in craniofacial microsomia (CFM) continue to be a topic of debate, especially in the population of patients with mild or nonsignificant functional issues. The objective of this study was to quantitatively assess the burden of mandibular asymmetry in CFM, and to accurately evaluate the impact of early MDO on patients' perceived quality of life and social acceptance, in addition to examining the cost-effectiveness of early MDO in CFM. METHODS:A validated crowdsourcing platform was utilized to recruit participants. Psychosocial acceptance and utility outcomes were assessed for patients with CFM. Participants were presented with health-state scenarios supplemented with pre- and postoperative images. Quality-adjusted life years (QALYs) were subsequently calculated and costs were estimated based on Medicare fee schedules using the Current Procedural Terminology codes. Incremental cost-effectiveness ratios for early MDO were calculated and plotted against a $100,000/QALY threshold. RESULTS::A total of 463 participants were included in the study. The mean visual analog scale score for untreated mandibular hypoplasia in CFM was 0.48 ± 0.24, which improved significantly (P < 0.0001) to 0.63 ± 0.20 following early MDO. Time trade-off scores for an imaginary surgery leading to perfect health with no complications were not statistically different from undergoing early MDO (P = 0.113). Early mandibular distraction decreased social distance in all 8 social situations assessed. Incremental cost-effectiveness ratios varied by the duration of time between early MDO and a potential second intervention, ranging from $148,142.09 per QALY gained at an interval of 1 year to $9876.14 per QALY gained after 15 years. Using a willingness-to-pay threshold of $100,000/QALY, early MDO in CFM becomes cost-effective when patients enjoy an improved health-state post-MDO for more than 1.48 years before a potential second intervention, if deemed necessary. CONCLUSION:Early mandibular distraction may lead to tangible positive gains in CFM patients based on utility outcome scores, psychosocial acceptance, and social distance. Therefore, although further interventions may be needed at skeletal maturity, early MDO can improve the psychological well-being of CFM patients during their crucial developmental years in a cost-effective manner. The incremental cost per QALY gained post-early MDO correlates negatively with time until a second potential surgical intervention.	0
Glanzmann thrombasthenia is a rare platelet disorder characterized by an abnormal integrin receptor on the surface of platelets that results in the failure of platelets to aggregate. Currently, curative therapy is allogeneic hematopoietic stem cell transplantation (HSCT). The authors report 2 patients with Glanzmann thrombasthenia who successfully underwent allogeneic HSCT from unrelated donors, including one using umbilical cord blood stem cells. Although both patients had evidence of engraftment, hematopoietic recovery, and normalization of platelet aggregation, they also experienced several post-transplant complications. Allogeneic HSCT carries a significant risk of morbidity and mortality that should be considered before proceeding with the transplant.	0
Subareolar abscess of the male breast is a rare condition, which can be complicated by a fistula from the areolar skin into a lactiferous duct. In 1951, Zuska et al first characterised this entity in women. Literature on mammillary fistulas in men is scarce and therefore standardisation of treatment does not exist. We present two cases of recurrent subareolar abscesses with draining fistulas. Both patients were successfully treated by complete excision of the lactiferous duct fistula, and continue to do well with no evidence of disease recurrence. When male patients present with a draining subareolar abscess, one should have a high index of suspicion for a mammillary fistula. Failure to identify and surgically excise the fistula may lead to recurrence of the abscess and prolonged morbidity. The most effective management of this uncommon entity includes complete excision of the lactiferous duct fistula.	0
BACKGROUND:Acromicric dysplasia is a rare heritable short-stature syndrome with joint stiffness and varying degrees of cutaneous hardness. Stiff skin syndrome is a rare connective tissue disorder characterized by diffusely thick and hard skin from the time of birth. Heterozygous point mutations in the FBN1 have been proposed as the predominant cause of both diseases. METHODS:By performing skin biopsy, X-ray imaging, electrocardiography, as well as whole-genome sequencing and Sanger sequencing, we diagnosed an 8-year-old Chinese boy as acromicric dysplasia with severe skin stiffness caused by a heterogeneous mutation in the FBN1. RESULTS:The patient presented with skin tightness, wrist and ankle stiffness, short stature and limbs, several deformed joints in the extremities, cone-shaped epiphyses, and distinct facial features. He also had a patent foramen ovale and frequent respiratory infections. Skin biopsy showed thickened dermis and excessive collagen aggregation. Alcian blue staining indicated dermal mucopolysaccharide deposition. Mutation analysis revealed a heterozygous missense mutation, c.5243G>A (p.Cys1748Tyr), in exon 42 of the FBN1. CONCLUSION:This is a report about acromicric dysplasia with stiff skin syndrome-like severe cutaneous presentation caused by a single hotspot mutation, further revealing the gene pleiotropy of FBN1.	0
Inherited endocrine tumors are neoplasms of endocrine cells, transmitted via autosomal dominant germinal mutations. They present in two different forms: non-syndromic (patient has a single affected endocrine organ during his/her lifetime) or syndromic forms (multiple tumors in endocrine and non-endocrine organs during his/her lifetime).In addition to their common tumoral manifestations, many of these diseases present clinical affection of bone tissues and/or mineral metabolism, both as secondary complications of primary tumors and as primary defects due to genetic mutation. To date, few studies have documented these bone complications, and there are no systematic reviews in this area.We present a revision of medical literature about skeletal and mineral metabolism affections in inherited endocrine tumor syndromes, and studies, in cells and animal models, investigating the direct role of some genes, whose mutations are responsible for the development of endocrine tumors, in the regulation of bone and mineral metabolism.	0
Our patient presented with leukonychia totalis at the age of 15 years. Other malformations such as syndromes or underlying internal diseases did not exist. The patient's family history was unremarkable. In the classification of leukonychias, the real, usually hereditary leukonychia can be distinguished from the acquired form. The white color of the nails can be isolated, depending on its present form, appear as part of a syndrome, or as a result of internal disease. An effective treatment of hereditary leukonychia is not known.	0
The inborn errors of heme biosynthesis, the porphyrias, are 8 genetically distinct metabolic disorders that can be classified as "acute hepatic," "hepatic cutaneous," and "erythropoietic cutaneous" diseases. Recent advances in understanding their pathogenesis and molecular genetic heterogeneity have led to improved diagnosis and treatment. These advances include DNA-based diagnoses for all the porphyrias, new understanding of the pathogenesis of the acute hepatic porphyrias, identification of the iron overload-induced inhibitor of hepatic uroporphyrin decarboxylase activity that causes the most common porphyria, porphyria cutanea tarda, the identification of an X-linked form of erythropoietic protoporphyria due to gain-of-function mutations in erythroid-specific 5-aminolevulinate synthase (ALAS2), and new and experimental treatments for the erythropoietic porphyrias. Knowledge of these advances is relevant for hematologists because they administer the hematin infusions to treat the acute attacks in patients with the acute hepatic porphyrias, perform the chronic phlebotomies to reduce the iron overload and clear the dermatologic lesions in porphyria cutanea tarda, and diagnose and treat the erythropoietic porphyrias, including chronic erythrocyte transfusions, bone marrow or hematopoietic stem cell transplants, and experimental pharmacologic chaperone and stem cell gene therapies for congenital erythropoietic protoporphyria. These developments are reviewed to update hematologists on the latest advances in these diverse disorders.	0
Immunotherapy-induced vitiligo is an immune-related adverse event (irAE) observed in metastatic melanoma patients treated with immune checkpoint inhibitors that target the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1) pathways. To date, the development of leukoderma, poliosis, and halo nevi during immunotherapy has largely been reported in metastatic melanoma patients. We report a case of immunotherapy-induced leukoderma presenting as halo nevi in a patient with non-small cell lung cancer (NSCLC) treated with atezolizumab, a programmed cell death ligand (PD-L1) antibody. Immunotherapy-induced vitiligo in metastatic melanoma patients may be associated with improved survival, but it remains to be determined whether its occurrence in non-melanoma cancers has the same prognostic significance. <p><em>J Drugs Dermatol. 2017;16(10):1047-1049.</em></p>.	0
The acronym FAVA (Fibro-Adipose Vascular Anomaly) has been recently given to a distinct vascular entity that is characterized by fibrofatty infiltration of muscle, unusual phlebectasia with pain, and contracture of the affected extremity. We report a new case of FAVA in a 10-year-old girl with pain in her right lower leg and equinus contracture. As in our case, FAVA typically presents in young females with calf involvement and limited ankle dorsiflexion with local pain. FAVA should be considered as a differential diagnosis when evaluating vascular anomalies in the lower extremities.	0
Background:This study aimed to investigate the genetic causes of hypohidrotic ectodermal dysplasia (HED) in two families and elucidate the molecular pathogenesis of HED in Chinese Han patients. Methods:Whole-exome sequencing (WES) was used to screen HED-related genes in two family members, followed by confirmatory Sanger sequencing. Bioinformatics analysis was performed for the mutations. We reviewed HED-related articles in PubMed. χ 2- and Fisher's tests were used to analyze the genotype-phenotype correlations. Results:(1) WES identified EDA missense mutations [c.1127 C > T (p.T376M; NM_001005609)] in family 1 and an EDA nonframeshift deletion mutation [c.648_683delACCTGGTCCTCCAGGTCCTCCTGGTCCTCAAGGACC (p.216_228delPPGPPGPPGPQGP; NM_001005609)] in family 2. Sanger sequencing validated the results. ANNOVAR (ANNOtate VARiation) annotation indicated that c.1127 c > T was a deleterious mutation. (2) The review of published papers revealed 68 novel mutations related to HED: 57 (83.8%) were EDA mutations, 8 (11.8%) were EDAR mutations, 2 (2.9%) were EDARADD mutations, 1 (1.5%) was a WNT10A mutation, 31 (45.6%) were missense mutations, 23 (33.8%) were deletion mutations, and 1 (1.5%) was an indel. Genotype-phenotype correlation analysis revealed that patients with EDA missense mutations had a higher frequency of hypohidrosis (P = 0.021). Conclusions:This study identified two EDA gene mutations in two Chinese Han HED families and provides a foundation for genetic diagnosis and counseling.	0
A severe mandibular hypoplasia and microstomy with intraoral anomalies including hypoglossia, fused gums, persistence of buccopharyngeal membrane, and laryngeal hypoplasia were noted in a female newborn with the dysgnathia complex (DC). Additionally, our proposita also presented natal teeth as a probably new finding. These clinical manifestations overlapped with those of the fourth report of hypomandibular faciocranial syndrome (HFS) (31), and given that both lack for craniosynostosis (pathognomonic of HFS), we considered that both represent a subtype of DC proposed as DC sine holoprosencephaly nor synotia (DCSHS). Differential characteristics between the DCSHS, the HFS, and the DC with holoprosencephaly sine synotia are reviewed and additionally, we discussed some aspects about the nosology of the DC.	0
AIMS:The aim of this study was to analyze the complications and outcomes of treatment in a series of previously untreated patients with a primary aneurysmal bone cyst (ABC) who had been treated by percutaneous sclerosant therapy using polidocanol. METHODS:Between January 2010 and December 2016, 56 patients were treated primarily with serial intralesional sclerosant injections. Their mean age was 20 years (1 to 54). The sites involved were clavicle (n = 3), humeri (n = 11), radius (n = 1), ulna (n = 3), hand (n = 2), pelvis (n = 12), femur (n = 7), tibia (n = 13), fibula (n = 3), and foot (n = 1). After histopathological confirmation of the diagnosis, 3% polidocanol (hydroxypolyaethoxydodecan) was injected into the lesion under image intensifier guidance. Patients were evaluated clinically and radiologically every six to eight weeks. In the absence of clinical and/or radiological response, a repeat sclerosant injection was given after eight to 12 weeks and repeated at similar intervals if necessary. RESULTS:There were no complications of treatment. One patient was lost to follow-up. Overall, 46/55 (84%) of lesions healed after one or more injections of polidocanol: 24/55 (44%) patients healed with a single injection, and 43/55 (78%) within two injections. Of these 46, four (9%) patients developed local recurrence, two of whom healed with a repeat sclerosant injection. Thus, 44/55 (80%) patients of primary ABC healed with sclerotherapy. The mean follow-up was 62 months (20 to 111). The local recurrence free survival (LRFS) with percutaneous sclerosant therapy with polidocanol was 100%, 98% (95% confidence interval (CI) 85 to 100) and 93% (95% CI 78 to 98) at two, three, and five years, respectively. CONCLUSION:Percutaneous sclerotherapy using polidocanol is a safe, effective, minimally invasive and inexpensive method of treating a primary ABC of the limbs or pelvis. Cite this article: Bone Joint J 2020;102-B(2):186-190.	0
The aim of this review was to analyse the pathophysiology of axonal degeneration in Guillain-Barré syndrome (GBS) with emphasis on early stages (≤ 10 days after onset). An overview of experimental autoimmune neuritis (EAN) models is provided. Originally GBS and acute inflammatory demyelinating polyneuropathy were equated, presence of axonal degeneration being attributed to a "bystander" effect. Afterwards, primary axonal GBS forms were reported, designated as acute motor axonal neuropathy/acute motor-sensory axonal neuropathy. Revision of the first pathological description of axonal GBS indicates the coexistence of active axonal degeneration and demyelination in spinal roots, and pure Wallerian-like degeneration in peripheral nerve trunks. Nerve conduction studies are essential for syndrome subtyping, though their sensitivity is scanty in early GBS. Serum markers of axonal degeneration include increased levels of neurofilament light chain and presence of anti-ganglioside reactivity. According to nerve ultrasonographic features and autopsy studies, ventral rami of spinal nerves are a hotspot in early GBS. In P2-induced EAN models, the initial pathogenic change is inflammatory oedema of spinal roots and sciatic nerve, which is followed by demyelination, and Wallerian-like degeneration in nerve trunks possessing epi-perineurium; a critical elevation of endoneurial fluid pressure is a pre-requisite for inducing ischemic axonal degeneration. Similar lesion topography may occur in GBS. The repairing role of adaxonal Schwann cytoplasm in axonal degeneration is analysed. A novel pathophysiological mechanism for nerve trunk pain in GBS, including pure motor forms, is provided. The potential therapeutic role of intravenous boluses of methylprednisolone for early severe GBS and intractable pain is argued.	0
BACKGROUNDDICER1 is the only miRNA biogenesis component associated with an inherited tumor syndrome, featuring multinodular goiter (MNG) and rare pediatric-onset lesions. Other susceptibility genes for familial forms of MNG likely exist.METHODSWhole-exome sequencing of a kindred with early-onset MNG and schwannomatosis was followed by investigation of germline pathogenic variants that fully segregated with the disease. Genome-wide analyses were performed on 13 tissue samples from familial and nonfamilial DGCR8-E518K-positive tumors, including MNG, schwannomas, papillary thyroid cancers (PTCs), and Wilms tumors. miRNA profiles of 4 tissue types were compared, and sequencing of miRNA, pre-miRNA, and mRNA was performed in a subset of 9 schwannomas, 4 of which harbor DGCR8-E518K.RESULTSWe identified c.1552G>A;p.E518K in DGCR8, a microprocessor component located in 22q, in the kindred. The variant identified is a somatic hotspot in Wilms tumors and has been identified in 2 PTCs. Copy number loss of chromosome 22q, leading to loss of heterozygosity at the DGCR8 locus, was found in all 13 samples harboring c.1552G>A;p.E518K. miRNA profiling of PTCs, MNG, schwannomas, and Wilms tumors revealed a common profile among E518K hemizygous tumors. In vitro cleavage demonstrated improper processing of pre-miRNA by DGCR8-E518K. MicroRNA and RNA profiling show that this variant disrupts precursor microRNA production, impacting populations of canonical microRNAs and mirtrons.CONCLUSIONWe identified DGCR8 as the cause of an unreported autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter with schwannomatosis.FUNDINGCanadian Institutes of Health Research, Compute Canada, Alex's Lemonade Stand Foundation, the Mia Neri Foundation for Childhood Cancer, Cassa di Sovvenzioni e Risparmio fra il Personale della Banca d'Italia, and the KinderKrebsInitiative Buchholz/Holm-Seppensen.	0
Uncombable hair syndrome (UHS), also known as "spun glass hair syndrome," "pili trianguli et canaliculi," or "cheveux incoiffables" is a rare anomaly of the hair shaft that occurs in children and improves with age. UHS is characterized by dry, frizzy, spangly, and often fair hair that is resistant to being combed flat. Until now, both simplex and familial UHS-affected case subjects with autosomal-dominant as well as -recessive inheritance have been reported. However, none of these case subjects were linked to a molecular genetic cause. Here, we report the identification of UHS-causative mutations located in the three genes PADI3 (peptidylarginine deiminase 3), TGM3 (transglutaminase 3), and TCHH (trichohyalin) in a total of 11 children. All of these individuals carry homozygous or compound heterozygous mutations in one of these three genes, indicating an autosomal-recessive inheritance pattern in the majority of UHS case subjects. The two enzymes PADI3 and TGM3, responsible for posttranslational protein modifications, and their target structural protein TCHH are all involved in hair shaft formation. Elucidation of the molecular outcomes of the disease-causing mutations by cell culture experiments and tridimensional protein models demonstrated clear differences in the structural organization and activity of mutant and wild-type proteins. Scanning electron microscopy observations revealed morphological alterations in hair coat of Padi3 knockout mice. All together, these findings elucidate the molecular genetic causes of UHS and shed light on its pathophysiology and hair physiology in general.	0
Germline mutations of runt-related transcription factor-1 (RUNX1) cause familial platelet disorder with predisposition to myeloid malignancy (FPDMM), most commonly associated with thrombocytopenia and propensity to develop myeloid neoplasms. A key clinical question is which patients with a family history of thrombocytopenia should undergo genetic testing for RUNX1 mutations. Typically, molecular diagnosis by genetic sequencing is performed when the clinical phenotype is suggestive of this diagnosis; however, our understanding of the spectrum of associated features suggestive of this diagnosis continues to evolve. Herein, we report a case series of 3 unrelated families with RUNX1-associated FPDMM and clinical phenotypes not typically reported with this condition. These cases expand our understanding of FPDMM and highlight the complexity of transcriptional regulation of hematopoiesis and its potentially diverse phenotypes. We describe our approach to diagnosis and management of these individuals and the importance of long-term surveillance in these cases.	0
Current methods for screening Enterohemorrhagic Escherichia coli (EHEC) O157 and non-O157 in beef enrichments typically rely on the molecular detection of stx, eae, and serogroup-specific wzx or wzy gene fragments. As these genetic markers can also be found in some non-EHEC strains, a number of "false positive" results are obtained. Here, we explore the suitability of five novel molecular markers, espK, espV, ureD, Z2098, and CRISPRO26:H11 as candidates for a more accurate screening of EHEC strains of greater clinical significance in industrialized countries. Of the 1739 beef enrichments tested, 180 were positive for both stx and eae genes. Ninety (50%) of these tested negative for espK, espV, ureD, and Z2098, but 12 out of these negative samples were positive for the CRISPRO26:H11 gene marker specific for a newly emerging virulent EHEC O26:H11 French clone. We show that screening for stx, eae, espK, and espV, in association with the CRISPRO26:H11 marker is a better approach to narrow down the EHEC screening step in beef enrichments. The number of potentially positive samples was reduced by 48.88% by means of this alternative strategy compared to the European and American reference methods, thus substantially improving the discriminatory power of EHEC screening systems. This approach is in line with the EFSA (European Food Safety Authority) opinion on pathogenic STEC published in 2013.	0
The aim of the present case report was to investigate the clinical features, pathological examination and treatment of eosinophilic cystitis (EC) in children. Two cases of EC were reported and reviewed from January 2016 to March 2017. Case 1 (male; 6 years old) had intermittent hematuria, frequent urination, urgent urination, difficulty in urination and abdominal pain. Case 2 (male; 7 years old) had frequent urination, urgent urination, urinary pain, dysuria and suprapubic pain with no hematuria. One patient had a history of allergies and both patients underwent a cystoscope biopsy. Blood eosinophils were clearly increased and a bone marrow biopsy examination revealed that marrow eosinophils were also increased in both cases. The urine culture results were negative. Ultrasonography and computed tomography revealed uneven thickening of the bladder wall and diffusive mucosal lesions. Cystoscopy revealed that the bladder volume became smaller and the mucosa at the bladder floor and neck was red. Lesions were biopsied through the urethra and the following characteristics were observed: Congestion and edema of the bladder mucosa, infiltration of the blood vessels and eosinophils in the muscular layer, accompanied by focal muscle necrosis. Patient 1 was administered anti-inflammatory and cetirizine hydrochloride treatments, followed by 6 weeks of prednisone dose-reduction therapy. Patient 2 was administered antibiotics and cetirizine hydrochloride. Following 6-month follow-ups, abnormal voiding symptoms had disappeared in each case. Ultrasonography and computed tomography revealed no bladder wall thickening or space-occupying lesions. EC in children is rare and easily misdiagnosed as nonspecific bladder inflammation or bladder occupying lesions. Cystoscopy and biopsy are necessary to diagnose EC and conservative treatments with anti-inflammatory, anti-allergic and cortical hormone nonspecific treatments are suggested.	0
This study aimed to identify, clinically and molecularly, the causality of Rabson-Mendenhall syndrome in an Emirati family. It is one of the monogenic syndromes of abnormal glucose homeostasis, which result from insulin receptor defects.A novel nonsynonymous variant in the INSR gene was uncovered by whole exome sequencing and confirmed using Sanger sequencing in the patient and his parents. Various in silico tools were utilized to analyze the functional consequences of the variant.Results revealed a previously unreported INSR variant in the family: c.421C>T (p.Arg141Trp). Homozygosity for the variant was found in the patient, while both parents were heterozygous.The nonsynonymous protein change hit a highly conserved arginine residue in the insulin-binding α-subunit of the receptor and was deemed 'functionally damaging' by a myriad of bioinformatics tools. This report is a step forward along the way of achieving a better molecular and clinical characterization of Rabson-Mendenhall syndrome.	0
Placoid pigment epitheliopathy and serpiginous choroiditis are among the white dot retinal syndromes and possess similarities that can cause confusion between these two diseases. However, they are very different in terms of their progression and prognosis, which requires a diagnosis of certainty in order to better manage the patients with the diseases and identify potentially serious progressive complications. The clinical presentation, results of testing, differential diagnoses and treatment of these two pathologies are discussed in this article.	0
Atresia and stenosis are some of the most common birth defects affecting the small intestine. Few population-based studies have examined the epidemiology of small intestinal atresia/stenosis. Eighty-two cases of small intestinal atresia/stenosis were identified through a population-based birth defects registry in Hawaii during 1986-2000. The relationships of various clinical and demographic factors with small intestinal atresia/stenosis and duodenal atresia/stenosis were examined. The small intestinal atresia/stenosis and duodenal atresia/stenosis rates were 2.9 per 10,000 live births [95% confidence interval (CI) 2.3-3.6] and 1.3 per 10,000 live births (95% CI 1.0-1.9), respectively. No secular trend was observed (P = 0.067 and 0.090, respectively). Maternal age risk for small intestinal atresia/stenosis was U-shaped, while duodenal atresia/stenosis rates were highest with maternal age of 35 years or more. Small intestinal atresia/stenosis was substantially more common among Far East Asians than Caucasians [rate ratio (RR) 1.96, 95% CI 1.24-2.94]. Duodenal atresia/stenosis risk was higher in Hawaii County than in Honolulu County (RR 2.55, 95% CI 1.10-5.02). Small intestinal atresia/stenosis was also associated with low birth weight (RR 11.50, 95% CI 8.05-15.92), low gestational age (RR 8.60, 95% CI 6.34-11.41) and multiple births (RR 3.79, 95% CI 1.39-8.24). In conclusion, this study found associations between small intestinal atresia/stenosis and maternal age, maternal race/ethnicity, county of residence, birth weight, gestational age and plurality, but not delivery period. Many of the associations between small intestinal atresia/stenosis and other factors noted in this investigation were similar to those reported by other studies.	1
The clinical use of array comparative genomic hybridization in the evaluation of patients with multiple congenital anomalies and/or mental retardation has recently led to the discovery of a number of novel microdeletion and microduplication syndromes. We present four male patients with overlapping molecularly defined de novo microdeletions of 16q24.3. The clinical features observed in these patients include facial dysmorphisms comprising prominent forehead, large ears, smooth philtrum, pointed chin and wide mouth, variable cognitive impairment, autism spectrum disorder, structural anomalies of the brain, seizures and neonatal thrombocytopenia. Although deletions vary in size, the common region of overlap is only 90 kb and comprises two known genes, Ankyrin Repeat Domain 11 (ANKRD11) (MIM 611192) and Zinc Finger 778 (ZNF778), and is located approximately 10 kb distally to Cadherin 15 (CDH15) (MIM 114019). This region is not found as a copy number variation in controls. We propose that these patients represent a novel and distinctive microdeletion syndrome, characterized by autism spectrum disorder, variable cognitive impairment, facial dysmorphisms and brain abnormalities. We suggest that haploinsufficiency of ANKRD11 and/or ZNF778 contribute to this phenotype and speculate that further investigation of non-deletion patients who have features suggestive of this 16q24.3 microdeletion syndrome might uncover other mutations in one or both of these genes.	0
Background: Both whole exome sequencing and copy number variants sequencing were applied to identify the genetic cause of rare pediatric disorders. In our study, we aimed to investigate the diagnostic yield of parallel tests of trio whole exome sequencing and copy number variants sequencing and its clinical utility. Methods: After collecting detailed clinical information, a total of 60 patients were referred to parallel tests of whole exome sequencing and copy number variants sequencing, which used shared initial libraries. Results: 26 pathogenic or likely pathogenic single nucleotide variants and 11 copy number variants were identified in 32 patients. 65.4% (17/26) of the SNVs were novel. The overall diagnosis rate was 53.3%. For the patients with positive results, 22 (36.7%) patients were diagnosed by whole exome sequencing and 10 (16.7%) patients were diagnosed by copy number variants sequencing. We also reviewed clinical impact on selected cases. Conclusion: We adopted an approach by performing parallel tests of trio whole exome sequencing and copy number variants sequencing with shared initial libraries. This strategy is relatively efficient and cost-effective for the diagnosis of rare pediatric disorders with high heterogeneity.	0
Background: Neural tube defects can be as mild as spina bifida, to as severe as anencephaly, with only a fraction of these cases presenting as both craniorachischisis and exencephaly. Case report: The G3, P1011 mother was 25-years old, who at an estimated fetal gestational age of 17 weeks had a fetal diagnosis of anencephaly based on a sonogram, resulting in elective pregnancy termination. The female fetus had an open neural tube defect, consisting of craniorachischisis and exencephaly. No abnormalities were noted in any other organs. Conclusion: Although mostly associated with anencephaly, craniorachischisis can also be associated with exencephaly in early pregnancy.	0
Understanding how context (e.g., host species, environmental conditions) drives disease susceptibility is an essential goal of disease ecology. We hypothesized that in bat white-nose syndrome (WNS), species-specific host-pathogen interactions may partly explain varying disease outcomes among host species. We characterized bat and pathogen transcriptomes in paired samples of lesion-positive and lesion-negative wing tissue from bats infected with Pseudogymnoascus destructans in three parallel experiments. The first two experiments analyzed samples collected from the susceptible Nearctic Myotis lucifugus and the less-susceptible Nearctic Eptesicus fuscus, following experimental infection and hibernation in captivity under controlled conditions. The third experiment applied the same analyses to paired samples from infected, free-ranging Myotis myotis, a less susceptible, Palearctic species, following natural infection and hibernation (n = 8 sample pairs/species). Gene expression by P. destructans was similar among the three host species despite varying environmental conditions among the three experiments and was similar within each host species between saprophytic contexts (superficial growth on wings) and pathogenic contexts (growth in lesions on the same wings). In contrast, we observed qualitative variation in host response: M. lucifugus and M. myotis exhibited systemic responses to infection, while E. fuscus up-regulated a remarkably localized response. Our results suggest potential phylogenetic determinants of response to WNS and can inform further studies of context-dependent host-pathogen interactions.	0
We present the case of a 5 year old female with a unilateral conductive hearing loss which had a relapsing and remitting course over a 3 year period. An initial noncontrast CT temporal bone study was unremarkable and a diagnosis of otitis media was made in the first instance. However, a second CT temporal bone study performed 3 years later demonstrated bilateral demineralisation of the ossicles and abnormal lucency affecting both the otic capsules. A diagnosis of otosyphilis was proposed on the basis of the imaging features and a prior medical history of previously treated congenital syphilis. With the benefit of hindsight, early pericochlear lucency was identified on the initial CT temporal bone study. There has been a steady rise of syphilis cases since the millennium with resurgence in many high income countries. Otosyphilis has a highly variable clinical presentation and there is limited data to establish the pattern of hearing loss in pediatric patients with a background of congenital otosyphilis. Temporal bone and otic capsule demineralisation carries a broad differential diagnosis including osteogenesis imperfecta, otosclerosis, Paget's disease and radiation related changes. Otosyphilis is a rare but potentially treatable cause of deafness and a high index of suspicion is required to make the diagnosis. In conjunction with a positive syphilis serology, a noncontrast temporal bone CT can aid the diagnosis and expedite the treatment.	0
Hepatocellular adenoma is a heterogeneous group of benign neoplasms arising from hepatocellular cells and can be subclassified into four major groups based on genotypic and phenotypic characteristics. These four subtypes are hepatocyte nuclear factor (HNF) 1α-inactivated, β-catenin-activated, inflammatory, and unclassified adenomas. Immunohistochemistry studies have demonstrated that since β-catenin-activated adenomas have a higher risk of malignant transformation, the identification of the subtype of adenoma remains crucial in patient management. However, malignant transformation of hepatic adenoma without β-catenin overexpression can be seen in 30-65% cases. We report a case of malignant transformation of hepatic adenoma without overexpression of β-catenin in a 31-year-old man with a known glycogen storage disease (GSD) Type-1a, which was diagnosed on surveillance magnetic resonance imaging (MRI). The MRI showed a mild interval increase in one lesion with relative stability of the other adenomas. The lesion was presumed to be suspicious for a hepatocellular carcinoma (HCC) and was confirmed on pathology.	0
Synpolydactyly type 1 (SPD1, OMIM 186000) is inherited as autosomal dominant and is caused by HOXD13 mutations. The condition is rare and is known for its phenotypic heterogeneity. In the homozygous state, the phenotype is generally more severe and is characterized by three main features: a more severe degree of syndactyly, a more severe degree of brachydactyly, and the frequent loss of the normal tubular shape of the metacarpals/metatarsals. Due to the phenotypic heterogeneity and the phenotypic overlap with other types of syndactyly, no pathognomonic feature has been described for the homozygous phenotype of SPD1. In the current communication, the author reviews the literature on the phenotypes of SPD1 in homozygous patients. The review documents that not all homozygous patients show a severe hand phenotype. The review also defines the "relatively long and medially deviated big toe with/without cupping of the forefoot" as a pathognomonic feature in the phenotype. Illustration of this feature is done through a demonstrative clinical report in a multigeneration family with SPD1 and HOXD13 polyalanine repeat expansion. Finally, the pathogenesis of the clinical features is reviewed.	0
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse reaction characterized by a morbilliform cutaneous eruption, fever, lymphadenopathy, and multiorgan involvement. Alopecia universalis is a variant of alopecia areata characterized by complete loss of hair on the entire body. Herein, we report a case of alopecia universalis that presented after DRESS.	0
Inherited heart disease represent a very heterogenous group of cardiac disorders, characterized by inherited, acquired, and often rare disorders affecting the heart muscle (cardiomyopathies) or the cardiac electrical system (ion channel disease). They are often familial diseases, and are among the leading cause of juvenile sudden death and heart failure. The aim of this paper is to give a perspective on how to run a clinical service during an epidemic or pandemic emergency and to describe the potential COVID-19 associated risks for patients affected by inherited heart diseases.	0
CONTEXT:Congenital hypopituitarism (CH) is rarely observed in combination with severe joint contractures (arthrogryposis). Schaaf-Yang syndrome (SHFYNG) phenotypically overlaps with Prader-Willi syndrome, with patients also manifesting arthrogryposis. L1 syndrome, a group of X-linked disorders that include hydrocephalus and lower limb spasticity, also rarely presents with arthrogryposis. OBJECTIVE:We investigated the molecular basis underlying the combination of CH and arthrogryposis in five patients. PATIENTS:The heterozygous p.Q666fs*47 mutation in the maternally imprinted MAGEL2 gene, previously described in multiple patients with SHFYNG, was identified in patients 1 to 4, all of whom manifested growth hormone deficiency and variable SHFYNG features, including dysmorphism, developmental delay, sleep apnea, and visual problems. Nonidentical twins (patients 2 and 3) had diabetes insipidus and macrocephaly, and patient 4 presented with ACTH insufficiency. The hemizygous L1CAM variant p.G452R, previously implicated in patients with L1 syndrome, was identified in patient 5, who presented with antenatal hydrocephalus. RESULTS:Human embryonic expression analysis revealed MAGEL2 transcripts in the developing hypothalamus and ventral diencephalon at Carnegie stages (CSs) 19, 20, and 23 and in the Rathke pouch at CS20 and CS23. L1CAM was expressed in the developing hypothalamus, ventral diencephalon, and hindbrain (CS19, CS20, CS23), but not in the Rathke pouch. CONCLUSION:We report MAGEL2 and L1CAM mutations in four pedigrees with variable CH and arthrogryposis. Patients presenting early in life with this combined phenotype should be examined for features of SHFYNG and/or L1 syndrome. This study highlights the association of hypothalamo-pituitary disease with MAGEL2 and L1CAM mutations.	0
BACKGROUND:The incidence of congenital hypothyroidism (CH) has been increasing in Western countries, and some populations, including Asians, have a higher incidence. Delayed diagnosis and early treatment influence the outcome of CH. We investigated the incidence and clinical characteristics of CH in Taiwan. METHODS:In this retrospective database study we identified cases of CH diagnosed during 1997-2008 in the Taiwan National Health Insurance Research Database (NHIRD). Patients who had a Serious Accidents and Diseases certificate were included in the incidence calculation. We focused on CH patients who were born during 1997-2003 and determined their age at diagnosis and CH-related clinical features. Mental retardation and physiological delays were evaluated with respect to age at diagnosis. RESULTS:A total of 1482 cases were identified. Incidence during the 12-year period was 5.02 per 10 000 births. Among 1115 patients, the most common clinical features of CH were developmental delay (9.6%), constipation (11.6%), and delayed physiological development (9.1%). Congenital anomalies of the heart (7.7%), epilepsy (2.7%), and infantile cerebral palsy (3.2%) were also noted. Survival analysis showed that the risks of mental retardation (hazard ratio [HR], 3.180) and delayed physiological development (HR, 1.908) were greater when age at diagnosis was greater than 1 year. CONCLUSIONS:CH incidence was higher in Taiwan than in Western countries. Early diagnosis may decrease the risk of mental and physiological delay.	1
Dendritic cells (DCs) play a critical role in the immune system which sense pathogens and present their antigens to prime the adaptive immune responses. As the progression of sepsis occurs, DCs are capable of orchestrating the aberrant innate immune response by sustaining the Th1/Th2 responses that are essential for host survival. Hence, an in-depth understanding of the characteristics of DCs would have a beneficial effect in overcoming the obstacle occurring in sepsis. This paper focuses on the role of DCs in the progression of sepsis and we also discuss the reverse sepsis-induced immunosuppression through manipulating the DC function. In addition, we highlight some potent immunotherapies that could be used as a novel strategy in the early treatment of sepsis.	0
Hypophosphatasia (HPP) is a rare bone disease caused by inactivating mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP). Patients with HPP have varied clinical manifestations and are classified based on the age of onset and severity. Recently, enzyme replacement therapy using bone-targeted recombinant alkaline phosphatase (ALP) has been developed, leading to improvement in the prognosis of patients with life-threatening HPP. Considering these recent advances, clinical practice guidelines have been generated to provide physicians with guides for standard medical care for HPP and to support their clinical decisions. A task force was convened for this purpose, and twenty-one clinical questions (CQs) were formulated, addressing the issues of clinical manifestations and diagnosis (7 CQs) and those of management and treatment (14 CQs). A systematic literature search was conducted using PubMed/MEDLINE, and evidence-based recommendations were developed. The guidelines have been modified according to the evaluations and suggestions from the Clinical Guideline Committee of The Japanese Society for Pediatric Endocrinology (JSPE) and public comments obtained from the members of the JSPE and a Japanese HPP patient group, and then approved by the Board of Councils of the JSPE. We anticipate that the guidelines will be revised regularly and updated.	0
AIMS:To present four examples of clonally related Epstein-Barr virus (EBV)-associated large-cell transformation of marginal zone lymphoma (MZL) (of nodal, extranodal and splenic types), occurring 120, 11 and 5 months after the initial diagnosis in three instances, and concurrently in one case; and to discuss several interesting features of EBV infection. METHODS AND RESULTS:Somatic mutations were detected by use of a customised panel for next-generation sequencing and polymerase chain reaction studies of IgH in both low-grade and high-grade components of each case. In case 1, the initial biopsy of nodal MZL showed scattered EBV-positive cells, which might constitute an indication of EBV-induced progression. Case 2 showed heterogeneous EBV expression, a phenomenon attributable to loss of the EBV episomes during cell division, or to a secondary superinfection or reactivation of the virus. In case 3, p53 overexpression related to gene mutation and EBV-encoded small RNAs were identified in the same neoplastic component. In case 4, the mucosa-associated lymphoid tissue-type MZL and the high-grade component were identified concurrently in a patient previously treated with methotrexate for an autoimmune disorder. CONCLUSION:These data suggest that the presence of EBV should be added to the list of potential markers to be analysed for MZL prognosis.	0
Detailed comprehensive knowledge of the structures of individual long-range telomere-terminal haplotypes are needed to understand their impact on telomere function, and to delineate the population structure and evolution of subtelomere regions. However, the abundance of large evolutionarily recent segmental duplications and high levels of large structural variations have complicated both the mapping and sequence characterization of human subtelomere regions. Here, we use high throughput optical mapping of large single DNA molecules in nanochannel arrays for 154 human genomes from 26 populations to present a comprehensive look at human subtelomere structure and variation. The results catalog many novel long-range subtelomere haplotypes and determine the frequencies and contexts of specific subtelomeric duplicons on each chromosome arm, helping to clarify the currently ambiguous nature of many specific subtelomere structures as represented in the current reference sequence (HG38). The organization and content of some duplicons in subtelomeres appear to show both chromosome arm and population-specific trends. Based upon these trends we estimate a timeline for the spread of these duplication blocks.	0
Tissue-nonspecific alkaline phosphatase (TNAP) is necessary for skeletal mineralization by its ability to hydrolyze the mineralization inhibitor inorganic pyrophosphate (PPi), which is mainly generated from extracellular ATP by ectonucleotide pyrophosphatase phosphodiesterase 1 (NPP1). Since children with TNAP deficiency develop bone metaphyseal auto-inflammations in addition to rickets, we hypothesized that TNAP also exerts anti-inflammatory effects relying on the hydrolysis of pro-inflammatory adenosine nucleotides into the anti-inflammatory adenosine. We explored this hypothesis in bone metaphyses of 7-day-old Alpl+/- mice (encoding TNAP), in mineralizing hypertrophic chondrocytes and osteoblasts, and non-mineralizing mesenchymal stem cells (MSCs) and neutrophils, which express TNAP and are present, or can be recruited in the metaphysis. Bone metaphyses of 7-day-old Alpl+/- mice had significantly increased levels of Il-1β and Il-6 and decreased levels of the anti-inflammatory Il-10 cytokine as compared with Alpl+/+ mice. In bone metaphyses, murine hypertrophic chondrocytes and osteoblasts, Alpl mRNA levels were much higher than those of the adenosine nucleotidases Npp1, Cd39 and Cd73. In hypertrophic chondrocytes, inhibition of TNAP with 25 μM of MLS-0038949 decreased the hydrolysis of AMP and ATP. However, TNAP inhibition did not significantly modulate ATP- and adenosine-associated effects in these cells. We observed that part of TNAP proteins in hypertrophic chondrocytes was sent from the cell membrane to matrix vesicles, which may explain why TNAP participated in the hydrolysis of ATP but did not significantly modulate its autocrine pro-inflammatory effects. In MSCs, TNAP did not participate in ATP hydrolysis nor in secretion of inflammatory mediators. In contrast, in neutrophils, TNAP inhibition with MLS-0038949 significantly exacerbated ATP-associated activation and secretion of IL-1β, and extended cell survival. Collectively, these results demonstrate that TNAP is a nucleotidase in both hypertrophic chondrocytes and neutrophils, and that this nucleotidase function is associated with autocrine effects on inflammation only in neutrophils.	0
Treatment and outcome of systemic lupus erythematosus (SLE) in C1q deficient patients are rarely reported. The aim of this report is to share our experience about the course of management of three cases diagnosed as SLE with C1q deficiency, in light of present literature. Initial and dominant complaints of three cases from two different families were cutaneous manifestations. One patient was also diagnosed with arthritis and thrombocytopenia. Antinuclear antibody was positive in all cases, whereas anti-dsDNA was negative with normal levels of complement C3, C4 and decreased CH50 activity. C1QA gene of two patients had homozygous nonsense mutation (c.622 > T/p.Gln208Ter). Previously, all of them had been treated with steroids, hydroxychloroquine and methotrexate or azathioprine. It was learned that they had responded only to high dosage prednisolone and their symptoms flared up during dosage reduction even under methotrexate or azathioprine. All symptoms of all three cases improved by daily fresh frozen plasma (FFP) infusions, and once cutaneous lesions subsided, the infusions were reduced to a frequency that would prevent the flare up of the symptoms. Literature search revealed seven reports on fresh frozen plasma treatment in SLE with C1q deficient patients. In this report, it is concluded that severe cutaneous lesions, as seen in these C1q deficient SLE patients, cannot be controlled with conventional immunosuppressive treatment. Instead, regular fresh frozen plasma infusions are proposed as a more reasonable method of treatment.	0
Central core disease (CCD) is a dominantly inherited congenital myopathy. CCD is also associated with muscular and skeletal abnormalities such as abnormal curvature of the spine (scoliosis), hip dislocation, and joint deformities. CCD and malignant hyperthermia (MH) are both associated with mutations in the ryanodine receptor on chromosome 19q13.1. An 11-year-old boy with CCD complicated with severe scoliosis was scheduled for spinal fusion surgery under general anesthesia. Furthermore, he had trismus caused by temporomandibular contracture. He was considered as MH susceptible. Anesthesia was managed with remifentanil and propofol without using muscle relaxtants and volatile anesthetics. We could intubate the trachea with Airtraq laryngoscope without any complications. The perioperative course was uneventful.	0
In this case study, we investigate a child presenting with patent ductus arteriosus, short philtrum, duck-bill lips, strabismus, a flat nasal bridge, a broad forehead, low-set ears, hypertelorism, up-slanting palpebral fissures, almond-shaped eyes, and hypodontia, all leading to the clinical diagnosis of Char syndrome. Genetic analysis showed heterozygosity for the novel variant c.851T>C, p. Leu284Ser in the TFAP2B gene. Family analysis suggested that at least 20 members, extending six generations back, were affected. All 10 members available for genetic testing were heterozygous for the novel pathogenic variant. Qualitative analysis of the facial dysmorphology in the proband and three of the affected family members using three-dimensional surface scanning showed that the major deviations were observed in the forehead/eyebrow, nose, upper lip, and chin regions with, for example, a flattened nose and reduced height of the upper lip and the face. Furthermore, it is suggested that Char syndrome is associated with disturbances of tooth formation and eruption.	0
Summary PTPN11 gene encodes tyrosine phosphatase SHP-2 which locates on chromosome 12（12q24.1）, expresses in most embryonic and adult tissues, and plays pivotal roles in cell proliferation, differentiation, survival and cell death. SHP-2 apparently participates in signaling events downstream of RAS-MAPK and JAK/STAT. Diseases related to PTPN11 gene mutations include the Noonan syndrome（NS） and the NS with Multiple Lentigines（NSML）. Both NS and NSML contain the phenotypes of deafness, craniofacial anomalies, short stature, congenital heart defects, skin disorders, ophthalmologic abnormalities and cancer predisposition.	0
: A 64-year-old man, whose medical history was significant only for locally advanced squamocellular carcinoma of the right palatine tonsil treated with extended neck radiotherapy 9 years before, was evaluated for traumatic cerebral haemorrhage secondary to syncope after a postural change. The selective angiographic study of cerebral vessels was negative. No heart arrhythmias were recorded at ECG monitoring. The 24-h ABPM revealed sudden pressor and depressor episodes during day-time and a reverse dipper pattern during night-time. Noninvasive autonomic nervous system function testing showed supine hypertension and orthostatic hypotension caused by afferent baroreflex failure. According to literature, even if only few cases are described, neck irradiation can be assumed to be the major cause of baroreflex failure. No treatment is currently approved. The patient was treated with a selective beta-blocker (bisoprolol) administered at bedtime. Repeated ABPM after 1 month of therapy showed absence of sudden pressor and depressor episodes and no dipper pattern during night-time.	0
Background: REEP1 is a common cause of autosomal dominant hereditary spastic paraplegia (HSP) but is rare in China. The pathological mechanism of REEP1 is not fully understood. Methods: We screened for REEP1 mutations in 31 unrelated probands from Chinese HSP families using next-generation sequencing targeting pathogenic genes for HSP and other related diseases. All variants were validated by Sanger sequencing. The proband family members were also screened for variants for the segregation analysis. All previously reported REEP1 mutations and cases were reviewed to clarify the genetic and clinical features of REEP1-related HSP. Results: A pathogenic mutation, REEP1c. 125G>A (p.Trp42*), was detected in a pure HSP family from North China out of 31 HSP families (1/31). This locus, which is located in the second hydrophobic domain of REEP1, is detected in both Caucasian patients with complicated HSP phenotypes and Chinese pure HSP families. Conclusion: REEP1-related HSP can be found in the Chinese population. The 42nd residue is a novel transethnic mutation hotspot. Mutations in this spot can lead to both complicated and pure form of HSP. Identification of transethnic hotspot will contribute to clarify the underlying pathological mechanisms.	0
Mutations in ATP6V1B2, which encodes the B2 subunit of the vacuolar H + ATPase have previously been associated with Zimmermann-Laband syndrome 2 (ZLS2) and deafness-onychodystrophy (DDOD) syndrome. Recently epilepsy has also been described as a potentially associated phenotype. Here we further uncover the role of ATP61VB2 in epilepsy and report autosomal dominant inheritance of a novel missense variant in ATP6V1B2 in a large Polish family with relatively mild gingival and nail problems, no phalangeal hypoplasia and with generalized epilepsy. In light of our findings and review of the literature, we propose that the ATP6V1B2 gene should be considered in families with autosomal dominant epilepsy both with or without intellectual disability, and that presence of subtle gingival and nail problems may be another characteristic calling card of affected individuals with ATP6V1B2 mutations.	0
In the 1980s, after the mitochondrial DNA (mtDNA) had been sequenced, several diseases resulting from mtDNA mutations emerged. Later, numerous disorders caused by mutations in the nuclear genes encoding mitochondrial proteins were found. A group of these diseases are due to defects of mitochondrial carriers, a family of proteins named solute carrier family 25 (SLC25), that transport a variety of solutes such as the reagents of ATP synthase (ATP, ADP, and phosphate), tricarboxylic acid cycle intermediates, cofactors, amino acids, and carnitine esters of fatty acids. The disease-causing mutations disclosed in mitochondrial carriers range from point mutations, which are often localized in the substrate translocation pore of the carrier, to large deletions and insertions. The biochemical consequences of deficient transport are the compartmentalized accumulation of the substrates and dysfunctional mitochondrial and cellular metabolism, which frequently develop into various forms of myopathy, encephalopathy, or neuropathy. Examples of diseases, due to mitochondrial carrier mutations are: combined D-2- and L-2-hydroxyglutaric aciduria, carnitine-acylcarnitine carrier deficiency, hyperornithinemia-hyperammonemia-homocitrillinuria (HHH) syndrome, early infantile epileptic encephalopathy type 3, Amish microcephaly, aspartate/glutamate isoform 1 deficiency, congenital sideroblastic anemia, Fontaine progeroid syndrome, and citrullinemia type II. Here, we review all the mitochondrial carrier-related diseases known until now, focusing on the connections between the molecular basis, altered metabolism, and phenotypes of these inherited disorders.	0
BACKGROUND:Loss-of-function mutations of human cardiac sodium channel gene SCN5A induce a wide range of arrhythmic disorders. Mutation carriers with co-existing conditions such as congenital heart diseases and histories of cardiac surgeries, could develop complex arrhythmic events that are difficult to diagnose. CASE PRESENTATION:A 41-year-old Japanese male with a history of a surgical closure of an ASD presented impairment of consciousness by wide QRS tachycardia. Because the patient's baseline ECG in sinus rhythm showed similar QRS axis with right bundle brunch block morphology, we suspected supraventricular tachycardia (SVT). During hospitalization, the patient developed polymorphic ventricular tachycardia that was induced by bradycardia. In an electrophysiological study, the SVT was identified as right atrial incisional tachycardia circulating around the scar in the right atrium. The genetic analysis revealed a heterozygous SCN5A c.4037-4038 del TC, p. L1346HfsX38 variant. We diagnosed this patient as having progressive cardiac conduction disorder (PCCD) and polymorphic VT caused by the mutation. Incisional tachycardia with wide QRS morphology was a by-standing comorbidity related to the history of cardiac surgery which could miss lead the diagnosis. The patient's SVT was eliminated by radiofrequency catheter ablation. An implantable cardioverter defibrillator (ICD) was implanted for the secondary prevention of polymorphic VT. Cardiac pace-making therapy by the ICD to avoid bradycardia effectively suppressed the patient's arrhythmic events. CONCLUSIONS:We treated a patient with a sodium channel gene variant. Co-existing SVT originated by a scar in the right atrium made the diagnosis extremely difficult. A multilateral diagnostic approach using an ECG analysis, an electrophysiological study, and genetic screening enabled effective combination therapy comprised of catheter ablation and an ICD.	0
Lipedematous scalp (LS) and lipedematous alopecia (LA) are both rare conditions with an unknown etiology. LS is characterized by boggy swelling under the skin as a result of hyperplasia of subcutaneous layer. LA is basically LS associated with hair growth abnormalities such as alopecia and short broken hair. Herein, we present two patients who were diagnosed with LS and LA where case with LA had a new diagnosis of systemic lupus erythematosus.	0
Thiamine-responsive megaloblastic anemia syndrome is a rare autosomal recessive disorder defined by the occurrence of megaloblastic anemia, diabetes mellitus, and bilateral sensorineural deafness, responding in varying degrees to thiamine treatment. We report a precedence case for the treatment of deafness associated with the typical triad of thiamine-responsive megaloblastic anemia in a 4-year-old boy who showed a poor use of preoperative hearing aids but demonstrated significant improvements in hearing ability 1 year after receiving a cochlear implant.	0
Jeune syndrome (JS) is a rare disease, with systemic manifestations, such as renal and hepatic insufficiency, retinal pigmentation, and respiratory insufficiency. Etiological factors have not been completely elucidated, but the molecular biology has contributed to the diagnosis and understanding of JS with DNA sequencing, showing the association among polymorphisms in different genes DYNC2H1 (MIM 603297) and TCTEX1D2 (MIM617353), which are the main genes associated with JS. There are a few reports on buccal findings in these patients; here, we present dental anomalies and clinical oral findings in a patient with JS, focusing on a multidisciplinary approach for rehabilitation. A 15-year-old boy with JS was referred to our dental clinic. Clinical and radiographic examination revealed the presence of dental agenesis, taurodontism, and geographic tongue with lobulations. The treatment plan consisted of preventive, restorative, surgical, and oral rehabilitation. We observed that the treatment improved the patient's quality of life owing to improved functions, maintenance of oral health, and above all, self-esteem. Clinical findings in this case may contribute to a better characterization of JS and other ciliopathies.	0
A severe and unusual complication found in children with influenza is an acute necrotizing encephalopathy. A 20-month-old female with no significant past medical history was admitted to our facility, presenting with a 4-day history of worsening fever, upper respiratory symptoms, new-onset altered mental status and episodes of extensor posturing. The initial concern was a dystonic reaction secondary to promethazine following a recent diagnosis of influenza A virus. A head computed tomography scan indicated concern for widespread edema, and the video EEG revealed focal slowing in the frontocentral regions with no epileptiform activity during episodes of extensor posturing. The first magnetic resonance imaging results were consistent with acute hemorrhagic encephalitis or severe anoxic brain injury for which there is a broad differential. A second MRI five days later found new areas of restricted diffusion that were consistent with acute necrotizing encephalitis.	0
The historical and clinical basis for classification of Freeman-Sheldon syndrome as a craniofacial syndrome and explanation of the rationale underlying this decision is provided. Correctly classifying the condition will avoid confusion and may help to clarify the vernacular employed and eventually aid in improving diagnosis.	0
Blue diaper syndrome (BDS) (Online Mendelian Inheritance in Man number 211000) is an extremely rare disorder that was first described in 1964. The characteristic finding is a bluish discoloration of urine spots in the diapers of affected infants. Additional clinical features of the first described patients included diarrhea, inadequate weight gain, hypercalcemia, and nephrocalcinosis. An intestinal defect of tryptophan absorption was postulated as the underlying pathology. However, functional evidence for this theory is lacking. No genetic cause has been identified so far. Here, we report on a boy who presented with neonatal-onset diarrhea, metabolic acidosis, transient hepatopathy, recurrent hypoglycemia, and blue-stained urine spots in his diapers. An ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry analysis of urine samples at different time points demonstrated the constant presence of indigo derivatives, thereby confirming the diagnosis of BDS. Of note, the visibility of indigo derivatives in the urine was highly dependent on the urine's pH. To identify the underlying genetic cause of the disease, whole-exome sequencing was performed, leading to the identification of a homozygous frameshift mutation in proprotein convertase subtilisin/kexin type 1 (PCSK1; NM_000439.4: c.679del, p.[Val227Leufs*12]). PCSK1 encodes prohormone convertase 1/3, and mutations within this gene have been reported as a rare cause of early-onset malabsorptive diarrhea and multiple endocrine dysfunction. In our report, we suggest that BDS can be caused by PCSK1 mutations.	0
Hypohidrotic ectodermal dysplasia (HED) is a rare genetic disorder characterized by hypotrichosis, hypohidrosis and hypodontia. The disease shows X-linked recessive, autosomal dominant or autosomal recessive inheritance traits. The X-linked form of HED is caused by mutations in the EDA gene, while autosomal forms result from mutations in either EDAR or EDARADD genes. Regarding recessive mutations in the EDAR gene, the pathomechanisms have been well characterized. However, it has remained largely unknown how dominant mutations in the EDAR cause HED. In this study, we performed in vitro analyses for a dominant EDAR gene mutation, p.F398*, as a representative. We showed that the p.F398* mutant EDAR completely lost its affinity to EDARADD, and suppressed the downstream nuclear factor-κB activation induced by wild-type EDAR in a dominant-negative manner. Furthermore, we demonstrated that the mutant EDAR was capable of binding with the wild-type EDAR, which led to reduced interaction between the wild-type EDAR and EDARADD. Our findings not only underscore an essential role of the interaction between EDAR and EDARADD in ectodermal development, but also disclose, in part, the molecular basis of autosomal dominant HED.	0
This study represents the first epidemiological study based on the national registry of primary immunodeficiencies (PID) in Korea. Patient data were collected from 23 major hospitals. A total of 152 patients with PID (under 19 yr of age), who were observed from 2001 to 2005, have been entered in this registry. The period prevalence of PID in Korea in 2005 is 11.25 per million children. The following frequencies were found: antibody deficiencies, 53.3% (n = 81), phagocytic disorders, 28.9% (n = 44); combined immunodeficiencies, 13.2% (n = 20); and T cell deficiencies, 4.6% (n = 7). Congenital agammaglobulinemia (n = 21) and selective IgA deficiency (n = 21) were the most frequently reported antibody deficiency. Other reported deficiencies were common variable immunodeficiencies (n = 16), X-linked agammaglobulinemia (n = 15), IgG subclass deficiency (n = 4). Phagocytic disorder was mostly chronic granulomatous disease. A small number of patients with Wiskott-Aldrich syndrome, hyper-IgE syndrome, and severe combined immunodeficiency were also registered. Overall, the most common first manifestation was pneumonia. This study provides data that permit a more accurate estimation PID patients in Korea.	1
Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome, caused by alterations in a cluster of imprinted genes located within the chromosome region 11p15.5. Common clinical features are overgrowth, macroglossia, lateralized overgrowth, abdominal wall defects, neonatal hypoglycemia and an increased risk of embryonal tumors, such as hepatoblastomas. Periodic screening for abdominal tumors is recommended. Vascular tumors are uncommon in BWS. Diffuse infantile hepatic hemangiomas (DIHHs) are rare vascular tumors with potentially lethal complications, in particular acquired consumptive hypothyroidism, high-output cardiac failure, liver failure and abdominal compartment syndrome. We describe a 2-month-old patient with hallmark clinical features of BWS and confirmed a genetic diagnosis with mosaic paternal uniparental disomy of chromosome 11p15.5 (UPD[11]pat). The patient developed hepatomegaly and elevated alpha-fetoprotein (AFP) and was therefore suspected of having a hepatoblastoma. Abdominal echo-color Doppler and a CT-scan allowed diagnosis of DIHHs. She was closely monitored and underwent treatment with propranolol. Oral propranolol was effective in reducing hepatic lesions without side effects. This report may suggest that vascular tumors can also be associated with BWS.	0
Wolfram Syndrome 1 (WFS1) protein is an endoplasmic reticulum (ER) factor whose deficiency results in juvenile-onset diabetes secondary to cellular dysfunction and apoptosis. The mechanisms guiding β-cell outcomes secondary to WFS1 function, however, remain unclear. Here, we show that WFS1 preserves normal β-cell physiology by promoting insulin biosynthesis and negatively regulating ER stress. Depletion of Wfs1 in vivo and in vitro causes functional defects in glucose-stimulated insulin secretion and insulin content, triggering Chop-mediated apoptotic pathways. Genetic proof of concept studies coupled with RNA-seq reveal that increasing WFS1 confers a functional and a survival advantage to β-cells under ER stress by increasing insulin gene expression and downregulating the Chop-Trib3 axis, thereby activating Akt pathways. Remarkably, WFS1 and INS levels are reduced in type-2 diabetic (T2DM) islets, suggesting that WFS1 may contribute to T2DM β-cell pathology. Taken together, this work reveals essential pathways regulated by WFS1 to control β-cell survival and function primarily through preservation of ER homeostasis.	0
Purpose: To explore life strategies in people with Usher syndrome type 2a. Background: There are no studies on life strategies in people with Usher syndrome. People with deafblindness are often described in terms of poor health and low quality of life, or as being vulnerable. From a clinical point of view, it is of importance to balance this picture, with an increased knowledge of life strategies. Methods: The study had a qualitative explorative design. Fourteen people aged 20-64 years (4 women, 10 men) with USH2a in Sweden participated in focus group interviews, which were transcribed and analysed by qualitative content analysis. Results: The content analysis resulted in seven categories; remaining active, using devices, using support, sharing knowledge, appreciating the present, maintaining a positive image and alleviating emotional pain. Two sub-themes: resolve or prevent challenges and comforting oneself was abstracted forming a theme "being at the helm". Conclusion: The findings show that people with USH2a have a variety of life strategies that can be interpreted as highlighting different aspects of psychological flexibility in a life adjustment process. The study demonstrates that people with USH2a manage in many ways, and metaphorically, by "taking the helm", they strive to actively navigate towards their own chosen values.	0
Four middle-aged male Chinese with polyneuropathy, skin hyperpigmentation, oedema, hepatosplenomegaly, ascites, gynaecomastia and white nails are described. In Japan and United States this syndrome has been associated with plasma cell dyscrasia. However, neither M-protein nor skeletal lesions were demonstrated in these four patients.	0
PURPOSE:We explored the use of intraventricular 131I-Omburtamab targeting B7-H3 in patients with ETMR. METHODS:Patients were enrolled in an IRB approved, phase 1, 3 + 3 dose escalation trial. Patients with CNS disease expressing the antibody target antigen B7-H3 were eligible. We report on a cohort of three patients with ETMR who were enrolled on the study. Three symptomatic children (ages 14 months, 3 and 3.5 years) had large parietal masses confirmed to be B7-H3-reactive ETMR. Patients received 2 mCi 131I-Omburtamab as a tracer followed by one or two therapeutic 131I-Omburtamab injections. Dosimetry was based on serial CSF, blood samplings and region of interest (ROI) on nuclear scans. Brain and spine MRIs and CSF cytology were done at baseline, 5 weeks after 131I-Omburtamab, and approximately every 3 months thereafter. Acute toxicities and survival were noted. RESULTS:Patients received surgery, focal radiation, and high dose chemotherapy. Patients 1 and 2 received 131I-Omburtamab (80 and 53 mCi, respectively). Patient 3 had a local recurrence prior to 131I-Omburtamab treated with surgery, external beam radiation, chemotherapy, then 131I-Omburtamab (36 mCi). 131I-Omburtamab was well-tolerated. Mean dose delivered by 131I-Omburtamab was 68.4 cGy/mCi to CSF and 1.95 cGy/mCi to blood. Mean ROI doses were 230.4 (ventricular) and 58.2 (spinal) cGy/mCi. Patients 1 and 2 remain in remission 6.8 years and 2.3 years after diagnosis, respectively; patient 3 died of progressive disease 7 months after therapy (2 years after diagnosis). CONCLUSIONS:131I-Omburtamab appears safe with favorable dosimetry therapeutic index. When used as consolidation following surgery and chemoradiation therapy, 131I-Omburtamab may have therapeutic benefit for patients with ETMR.	0
Spinocerebellar ataxia (SCA) is one of the most severe neurodegenerative diseases and is often associated with misfolded protein aggregates derived from the genetic mutation of related genes. Recently, mutations in CD10 such as C143Y have been identified as SCA type 43. CD10, also known as neprilysin or neuroendopeptidase, digests functional neuropeptides, such as amyloid beta, in the extracellular region. In this study, we explored the cellular behavior of CD10 C143Y to gain an insight into the functional relationship of the mutation and SCA pathology. We found that wild-type CD10 is expressed on the plasma membrane and exhibits endopeptidase activity in a cultured cell line. CD10 C143Y, however, forms a disulfide bond-mediated oligomer that does not appear by the wild-type CD10. Furthermore, the CD10 C143Y mutant was retained in the endoplasmic reticulum (ER) by the molecular chaperone BiP and was degraded through the ER-associated degradation (ERAD) process, in which representative ERAD factors including EDEM1, SEL1L, and Hrd1 participate in the degradation. Suppression of CD10 C143Y ERAD recovers intracellular transport but not enzymatic activity. Our results indicate that the C143Y mutation in CD10 negatively affects protein maturation and results in ER retention and following ERAD. These findings provide beneficial insight into SCA type 43 pathology.	0
OBJECTIVES:To examine the association between beta-globin sequence variations and phenotypes of sickle-cell disease (SCD) complications among Palestinian refugees in Lebanon correlating them with chromatographic readings and co-inheritance with β-thalassemia traits.   Methods: This cross-sectional study included 47 Palestinian refugees aged 4 to 54 living in different regions in Lebanon during the year 2015. Participant filled a well-designed questionnaire. Deoxyribonucleic acid (DNA) was purified from the blood collected from all participants, followed by polymerase chain reaction (PCR) amplification of exon 1, exon 2, and IVS 1 of hemoglobin beta. Multiple sequence alignment for comparative analysis was performed against normal hemoglobin sequences. Results: In addition to well-known SCD mutations, rare beta globin variations were identified. Participants with these variations have phenotypic thalassemia despite the absence of known β-thalassemia mutations.  Conclusion: The genetic variation seen among our study population is correlated with reduced beta globin transcription, and phenotypic β-thalassemia complications among SCD patients under study.	0
Human hydrocephalus is a disorder of abnormality in CSF flow or resorption, which has been classified in pertinent literature as congenital and acquired. Congenital hydrocephalus can present as an isolated phenomenon which is common; or with associated anomalies affecting other organs, disturbing physiology or presenting as a syndrome. This report describes a case with congenital foetal hydrocephalus, hypoplastic lungs with super-numery lobations and large left lobe of liver compared to right. Thus far, a review of the literature indicates that this case can be postulated as a subtype of Game-Friedman-Paradice syndrome.	0
Peripheral Nervous System (PNS) involvement occurs in 10 to 40 percent of patients presenting with sarcoidosis. Axonal polyneuropathies and mononeuropathies are the most frequently reported whereas acute or chronic polyradiculoneuritis are rarely described. We report the case of a 54 year-old-woman admitted for a progressive sensorimotor deficit of the lower limbs. Bilateral ocular redness corresponding to an uveitis was also observed. Neurological examination and electrophysiological data were consistent with a chronic polyradiculoneuritis. The neurological status of the patient improved after six months of treatment with oral corticotherapy associated with immunosuppressive treatment. Our case allows a review of the literature concerning PNS involvements and treatments in sarcoidosis.	0
BACKGROUND AND IMPORTANCE:Patients with severe thoracic or lumbar deformities can achieve satisfactory correction through appropriate osteotomies. However, patients with multiple craniocervical malformations commonly undergo conservative or finite surgical therapy mainly because of the involvement of the vertebral artery. Anterior oral meningocele is an extremely rare pathology that has not been previously reported. Here, we provide the first report of complex craniocervical anomalies combined with oral meningocele treated with a 1-stage anteroposterior atlantoaxial osteotomy correction surgery, with outcomes after 16 mo follow-up. CLINICAL PRESENTATION:A 10-yr-old boy presented with recurrent dyspnea, cyanosis, and progressive torticollis. Imaging studies revealed complicated bony abnormalities accompanied by an anterior oral meningocele. A 1-stage extensive atlantoaxial osteotomy through anterior and posterior approaches was performed with an innovatively designed vertebral artery exclusion technique. Lumbar cistern drainage and ceftazidime were used to address the leakage of cerebrospinal fluid and intracranial infection. CONCLUSION:The satisfactory outcome demonstrates the feasibility of extensive atlantoaxial osteotomy via a vertebral artery exclusion technique that might also be applicable to osteotomy in segments of C3-C6.	0
Clostridium septicum is an anaerobic, gram-positive bacillus known to cause myonecrosis, also known as gas gangrene, a life-threatening necrotizing soft tissue infection. Though it accounts for just 1 % of all infections attributable to Clostridia spp., C. septicum is a highly virulent and aggressive pathogen. Classic presentations of infection include bacteremia resulting in shock, myonecrosis, and vascular seeding. C. septicum-associated gas gangrene most commonly occurs in the setting of traumatic injury, but has also been reported in patients with colorectal malignancy, immunosuppression, neutropenia, and exceedingly rare in association with breast cancer. We report the case of a 56-year-old female patient with stage IV mixed lobar and ductal breast carcinoma with metastasis to the bone and liver, who presented with spontaneous C. septicum myonecrosis of the right hand. No prior traumatic injury was noted. Following amputation of the right forearm, antibiotic treatment, and multiorgan support, the patient passed following transition to palliative care. We hope to increase awareness of this relatively uncommon, though potentially deadly pathogen, as well as to discuss treatment options in patients infected with C. septicum.	0
Hairs are complex structures, making a protective layer and serves different biological functions. TRPS1, a transcription factor is one of the candidate genes causing congenital hypertrichosis, an excessive hair growth at inappropriate body parts. SNPs of TRPS1 were retrieved from dbSNP which were screened by SIFT and PolyPhen servers based on their functional impacts. Out of the screened SNPs, rs181507248 and rs146506752 were predicted as intolerant and damaging by both the servers. The predicted tertiary structure of the native TRPS1 after refinement and validation was successfully submitted to the Protein Model Database and was assigned with PMDB ID PM0077843, as it was previously unpredicted. It was observed through the structure based analysis that, the SNPs rs181507248 and rs146506752 caused significant changes in the secondary and tertiary structures as well as the physiochemical properties of TRPS1 protein. It can thus be concluded that the changed properties due to these single nucleotide polymorphisms effect the interactions of TRPS1 which result in congenital hypertrichosis.	0
The main energy substrate of adult cardiomyocytes for their contractility are the fatty acids. Its metabolism generates high ATP levels at the expense of high oxygen consumption in the mitochondria. Under low oxygen supply, they can get energy from other substrates, mainly glucose, lactate, ketone bodies, etc., but the mitochondrial dysfunction, in pathological conditions, reduces the oxidative metabolism. In consequence, fatty acids are stored into epicardial fat and its accumulation provokes inflammation, insulin resistance, and oxidative stress, which enhance the myocardium dysfunction. Some therapies focused on improvement the fatty acids entry into mitochondria have failed to demonstrate benefits on cardiovascular disorders. Oppositely, those therapies with effects on epicardial fat volume and inflammation might improve the oxidative metabolism of myocardium and might reduce the cardiovascular disease progression. This review aims at explain (a) the energy substrate adaptation of myocardium in physiological conditions, (b) the reduction of oxidative metabolism in pathological conditions and consequences on epicardial fat accumulation and insulin resistance, and (c) the reduction of cardiovascular outcomes after regulation by some therapies.	0
Malformations of the human neocortex in development constitute a heterogeneous group of complex disorders, resulting in pathologies such as intellectual disability and abnormal neurological/psychiatric conditions such as epilepsy or autism. Advances in genomic sequencing and genetic techniques have allowed major breakthroughs in the field, revealing the molecular basis of several of these malformations. Here, we focus on those malformations of the human neocortex, notably microcephaly, and macrocephaly, where an underlying basis has been established at the level of the neural stem/progenitor cells (NPCs) from which neurons are directly or indirectly derived. Particular emphasis is placed on NPC cell biology and NPC markers. A second focus of this review is on experimental model systems used to dissect the underlying mechanisms of malformations of the human neocortex in development at the cellular and molecular level. The most commonly used model system have been genetically modified mice. However, although basic features of neocortical development are conserved across the various mammalian species, some important differences between mouse and human exist. These pertain to the abundance of specific NPC types and/or their proliferative capacity, as exemplified in the case of basal radial glia. These differences limit the ability of mouse models to fully recapitulate the phenotypes of malformations of the human neocortex. For this reason, additional experimental model systems, notably the ferret, non-human primates and cerebral organoids, have recently emerged as alternatives and shown to be of increasing relevance. It is therefore important to consider the benefits and limitations of each of these model systems for studying malformations of the human neocortex in development.	0
Introduction: This study aimed to investigate the clinical characteristics, risk factors, and outcomes of infection-related hospitalization (IRH) in patients with lupus nephritis (LN) and ANCA glomerulonephritis after intensive immunosuppressive therapy.Methods: Patients diagnosed with LN or ANCA glomerulonephritis who received intensive immunosuppressive therapy at the First Affiliated Hospital of Sun Yat-sen University from 2005 to 2014 were enrolled. Demographics, laboratory parameters, immunosuppressive agents, and IRH details were collected. Multivariable Cox regression was used, and hazard ratios (HRs) and 95% confidence intervals (CIs) were reported.Results: Totally, 872 patients with 806 LN and 66 ANCA glomerulonephritis were enrolled, and 304 (34.9%) patients with 433 episodes of IRH were recorded. ANCA glomerulonephritis patients were more vulnerable to IRH than LN patients (53.0% vs. 33.4%, p = .001). Multivariable Cox regression analysis showed that ANCA glomerulonephritis (HR = 1.62, 95% CI: 1.06-2.49, p = .027), diabetes (HR = 1.82, 95% CI: 1.03-3.22, p = .039) and a higher initial dose of prednisone (HR = 1.01, 95% CI: 1.00-1.02, p = .013) were associated with a higher likelihood of IRH. Higher albumin (HR = 0.96, 95% CI: 0.94-0.98, p < .001), globulin (HR = 0.98, 95% CI: 0.96-0.99, p = .008), and eGFR (HR = 0.99, 95% CI: 0.99-1.00, p < .001), were associated with a lower likelihood of IRH. The rates of transfer to ICU and mortality for ANCA glomerulonephritis patients were higher than those for LN patients (22.9% vs. 1.9%, p < .001, and 20.0% vs. 0.7%, p < .001, respectively).Conclusions: ANCA glomerulonephritis patients had a higher risk of IRH and poorer outcome once infected after intensive immunosuppressive therapy than LN patients. More strict control for infection risks is required for ANCA glomerulonephritis patients who undergo intensive immunosuppressive therapy.	0
The rare Nievergelt syndrome (NS) is the most severe form of mesomelic dysplasia and is characterized by disproportionate shortness of the limbs. The aim of this case report was to describe the clinical and radiological features of a rare case of NS.Here we describe a female patient originally presenting with bilateral hand, lower leg, and foot deformities at the age of 10 years old. In addition to the characteristic features of NS, this patient presented with finger-like projections on her heels, bilateral hand anomalies, and atypical facial features. She underwent concomitant bilateral tibial lengthening and deformity correction using external fixators due to severe bilateral lower leg deformities with shortness. At 10 years of age, this patient was able to walk independently with significant improvement in her ambulation.There is a clear gap in the literature regarding the orthopedic management of mesomelic limb deformities due to NS. No studies have been designed to illustrate surgical planning in the management of orthopedic deformities in this rare syndrome.Limb lengthening and deformity correction using an external fixator can be considered as a salvage method or alternative to amputation for patients with severe mesomelic limb deformities due to NS.	0
PURPOSE:To establish a single-nucleotide polymorphism-based analysis (SBA) method to identify triploidy in the miscarriage tissue by using low-coverage whole-genome sequencing (LC-WGS). METHODS:The method was established by fitting a quadratic curve model by counting the distribution of three heterozygous mutation content intervals. The triploid test result was mainly determined by the opening direction and the axis of symmetry of the quadratic curve, and Z test between the same batch samples was also used for auxiliary judgment. RESULTS:Two hundred thirteen diploid samples and 8 triploid samples were used for establishment of the analytical method and 203 unknown samples were used for blind testing. In the blind testing, we found 2 cases positive for triploidy. After chromosome microarray analysis (CMA) and mass spectrometry verification, we found that both samples were true positives. We randomly selected 5 samples from the negative samples for mass spectrometry verification, and the results showed that these samples were all true negatives. CONCLUSIONS:Our method achieved accurate detection of triploidy in the miscarriage tissue and has the potential to detect more chromosomal abnormality types such as uniparental disomy (UPD) using a single LC-WGS approach.	0
BACKGROUND:Syndromic congenital heart disease accounts for 30% of cases and can be determined by genetic, environmental or multifactorial causes. In many cases the etiology remains uncertain. Many known genes are responsible for specific morphopathogenetic mechanisms during the development of the heart whose alteration can determine specific phenotypes of cardiac malformations. CASE PRESENTATION:We report on two cases of association of conotruncal heart defect with facial dysmorphisms in sibs. In both cases the malformations' identification occurred by ultrasound in the prenatal period. It was followed by prenatal invasive diagnosis. The genetic analysis revealed no rearrangements in Array-CGH test, while gene panel sequencing identified a new hemizygous variant of uncertain significance (c.887G > A; p.Arg296Gln) in the MED12 gene, located on the X chromosome and inherited from the healthy mother. CONCLUSION:No other reports about the involvement of MED12 gene in syndromic conotruncal heart defects are actually available from the literature and the international genomic databases. This novel variant is a likely pathogenic variant of uncertain significance and it could broaden the spectrum of genes involved in the development of congenital heart diseases and the phenotypic range of MED12-related disorders.	0
We describe a family with Charcot Marie Tooth disease type 4J presenting with features of Charcot Marie Tooth disease plus parkinsonism and aphemia. Genetic testing found two variants in the FIG4 gene: c.122T>C (p.I41T) - the most common Charcot Marie Tooth disease type 4J variant - and c.1949-10T>G (intronic). Proband fibroblasts showed absent FIG4 protein on western blot, and skipping of exon 18 by RT-PCR. As most patients with Charcot Marie Tooth disease type 4J do not have central nervous system deficits, we postulate the intronic variant and I41T mutation together are causing loss of FIG4 protein and subsequently the central nervous system findings in our family.	0
Lateral meningocele syndrome (LMS) is a rare genetic disorder characterized by neurological complications and osteoporosis. LMS is associated with mutations in exon 33 of NOTCH3 leading to a truncated protein lacking sequences for NOTCH3 degradation and presumably causing NOTCH3 gain of function. To create a mouse model reproducing human LMS-associated mutations, we utilized CRISPR/Cas9 to introduce a tandem termination codon at bases 6691-6696 (ACCAAG→TAATGA) and verified this mutation (Notch3tm1.1Ecan ) by DNA sequencing of F1 mice. One-month-old male and female heterozygous Notch3tm1.1Ecan mice had cancellous and cortical bone osteopenia but exhibited no obvious neurological alterations, and histopathology of multiple organs revealed no abnormalities. Microcomputed tomography of these mutants revealed a 35-60% decrease in cancellous bone volume associated with a reduction in trabecular number and decreased connectivity. During maturation, cancellous and cortical bones were restored in female but not in male mice, which exhibited cancellous bone osteopenia at 4 months. Cancellous bone histomorphometry revealed increased osteoblast and osteocyte numbers and a modest increase in osteoclast surface and bone formation rate. Notch3tm1.1Ecan calvarial osteoblasts had increased proliferation and increased bone γ-carboxyglutamate protein (Bglap) and TNF superfamily member 11 (Tnfsf11) mRNA levels and lower Tnfrsf11b levels. Tnfsf11 mRNA was increased in osteocyte-rich femora from Notch3tm1.1Ecan mice. Cultures of bone marrow-derived macrophages from Notch3tm1.1Ecan mice revealed increased osteoclast formation, particularly in cocultures with osteoblasts from Notch3tm1.1Ecan mice. In conclusion, the Notch3tm1.1Ecan mutation causes osteopenia despite an increase in osteoblast proliferation and function and is associated with enhanced Tnfsf11 expression in osteoblasts and osteocytes.	0
INTRODUCTION:Polycythemia vera (PV), a Philadelphia chromosome-negative myeloproliferative neoplasm, is characterized by panmyelosis, pancytosis, and a JAK2 mutation. Patients are at increased risk of thrombohemorrhagic events, and progression to myelofibrosis or acute leukemia. Current treatments include aspirin, phlebotomy, and cytoreductive drugs (most commonly hydroxyurea). Givinostat is a potent, class I/II histone deacetylase (HDAC) inhibitor that is in phase I/II clinical trials in PV. Givinostat was well tolerated and yielded promising clinico-hematological responses. A phase III study of givinostat versus hydroxyurea in high-risk PV patients is planned. AREAS COVERED:We present an overview of PV, current treatment guidelines, and the putative mechanism(s) of action of givinostat. We discuss the preclinical and clinical studies of givinostat in PV and briefly review approved and investigational competitor compounds. EXPERT OPINION:HDAC inhibitors have long been known to be active in PV, but chronic toxicities can be challenging. Givinostat, however, is active and well tolerated, and is entering a pivotal Phase III randomized trial. Givinostat offers the possibility of replacing hydroxyurea as the standard first-line cytoreductive choice for PV patients. This would completely change the current therapeutic paradigm and guidelines for PV management. Although surrogate clinical study endpoints may suffice for regulatory purposes, thrombosis reduction and prevention of disease progression remain most important to patients and clinicians.	0
BACKGROUND:Satoyoshi syndrome (SS) [OMIM 600705; ORFHA 3130] is a multisystemic disease with a probable autoimmune basis, whose main symptoms are muscle spasms, alopecia, diarrhea and skeletal alterations. Chronic diarrhea may be severe and result in malnutrition, anemia, growth retardation, cachexia, disability and even death. However, to date, no review of the digestive symptoms has been carried out. METHODS:A search was performed in MEDLINE, Scopus and Web of Science databases. Cases of SS, without language or date restrictions, were recorded. Sixty-seven cases of SS were found up until December 2019. Thirty-nine cases described gastrointestinal manifestations. RESULTS:Chronic diarrhea was the main digestive symptom (92.3%). Other symptoms such as abdominal pain (15.4%), nausea (7.7%) and vomiting (7.7%), were less frequent. The D-xylose test was positive in 10 out of 12 patients, and 9 out of 13 cases showed a flattened oral glucose tolerance test suggesting carbohydrate malabsorption. Antinuclear antibodies were detected in 8 out of 16 cases. Antibodies to stomach or duodenum tissue lysates were also detected by Western blot. Histological data revealed predominantly lymphoplasmacytic inflammatory infiltrate that can affect any section of the digestive tract. In 6 out of 10 patients, diarrhea improved with a treatment regimen that included corticosteroids. Other treatments, such as methotrexate, carbohydrate restricted diets or otilonium bromide, improved digestive symptoms in isolated patients. Improvement of symptoms up to three years of follow-up has been described. None of the three patients who died had received corticosteroids or immunosuppressants. CONCLUSION:Chronic diarrhea with malabsorption is one of the most disabling symptoms in SS. The early recognition of this disease is essential for immunosuppressive treatment and a better outcome.	0
The Leucine Rich Repeat Kinase 2 (LRRK2) is one of causative genes of familial Parkinson's disease (PD). The M2397T polymorphism in LRRK2 is genetically associated with sporadic Crohn's disease (CD). LRRK2 is expressed in human CD14+ monocytes, induced by interferon-γ (IFN-γ) and suppresses inflammatory activation. We hypothesize that IFN-γ-induced LRRK2 and inflammatory gene expression is altered by LRRK2 genetic polymorphism found in CD and PD cases. A total of 46 CD and 51 control cases, and 16 PD cases and 16 PD-linked LRRK2 mutation cases were recruited. Live human CD14+ monocytes were isolated from donors for ex vivo IFN-γ stimulation and gene expression analysis. IFN-γ potently enhanced TNFA, IL12, HLADRA1 and LRRK2 expression, which was suppressed by FK506, a calcineurin-specific inhibitor, but further enhanced by LRRK2-specific kinase inhibitor (GSK2578215A). The 2397-M/M CD risk allele enhanced IFN-γ responses of CD14+ cells in CD but not in control group. CD14+ monocytes from G2019S and R1441C LRRK2 mutated PD cases and carriers show no changes in IFN-γ responses for TNFA or IL12, reduced response for HLADRA1, and enhanced responses for LRRK2 in FK506-sensitive manner. These data demonstrate that CD-associated LRRK2 mutations are significant modifiers of innate immune response in CD14+ monocytes, and PD-associated LRRK2 mutation may contribute to reduced antigen presentation response. Graphical Abstract.	0
BACKGROUND:Urachal cancer is a rare type of cancer, often following a clinically aggressive course. Due to its rarity, knowledge about its molecular background is still limited. In addition, no sufficiently reliable diagnostic markers are available. OBJECTIVES:The aim of the present study is to give an overview of our recent molecular projects on urachal cancer and to connect it with current literature in the field. MATERIALS AND METHODS:Three projects are introduced. The first project identified and validated diagnostic biomarkers in urachal adenocarcinomas compared to colorectal adenocarcinomas and primary adenocarcinomas of the bladder using various proteomic methods. In the second project, the most relevant differential diagnostic markers between urachal adenocarcinomas and colorectal adenocarcinomas compared to normal tissue (urachal remnants) were determined by analyzing a miRNA panel. Sequence analyses were performed in the third project. The focus was on molecular differences to colorectal adenocarcinomas and urothelial carcinomas. RESULTS AND CONCLUSIONS:We detected potential biomarker candidates for the immunohistochemical differential-diagnosis and generated a miRNA-based diagnostic scoring system with a potentially high differential-diagnostic significance. The sequence analyses data confirm the molecular autonomy of the urachal adenocarcinomas compared to other entities.	0
Idiopathic Inflammatory myopathies (IIM) are rare disorders. The aim of our study was to determine the incidence of IIM in a well-defined Slovenian region. This retrospective study was conducted at the Department of Rheumatology, University Medical Centre Ljubljana, the only secondary/tertiary rheumatology center in a region with a population of 704,342 adults. We identified potential IIM cases by searching the electronic patient records for ICD-10 codes M33, M35.1, M35.8, M60, G72, G73, and J84. We included incipient IIM cases between January 2010 and December 2017, who were at the time of the diagnosis, residents of the inspected region. To avoid under-reporting due to miscoded cases, we obtained a list of the patients who had histological patterns consistent with IIM on muscle biopsy from the Institute of Pathology. The annual incidence rate for IIM was calculated. During the eight-year observation period, we identified 65 IIM cases (72.3% female, median (IQR) patient age 64.8 (54.8-73.2) years). The estimated annual incidence of IIM in the studied population was 11.5 (95% CI 9.0-14.6) per 106 adults, in females 16.2 (95% CI 12.1-21.4), and in males 6.6 (95% CI 4.0-10.2) per 106 adults. The incidence rate of IIM in Slovenia is consistent with data from the literature.	1
Late-onset retinal degeneration (L-ORD) is a rare autosomal dominant retinal dystrophy, characterised by extensive sub-retinal pigment epithelium (RPE) deposits, RPE atrophy, choroidal neovascularisation and photoreceptor cell death associated with severe visual loss. L-ORD shows striking phenotypic similarities to age-related macular degeneration (AMD), a common and genetically complex disorder, which can lead to misdiagnosis in the early stages. To date, a single missense mutation (S163R) in the C1QTNF5 gene, encoding C1q And Tumor Necrosis Factor Related Protein 5 (C1QTNF5) has been shown to cause L-ORD in a subset of affected families. Here, we describe the identification and characterisation of three novel pathogenic mutations in C1QTNF5 in order to elucidate disease mechanisms. In silico and in vitro characterisation show that these mutations perturb protein folding, assembly or polarity of secretion of C1QTNF5 and, importantly, all appear to destabilise the wildtype protein in co-transfection experiments in a human RPE cell line. This suggests that the heterozygous mutations in L-ORD show a dominant negative, rather than a haploinsufficient, disease mechanism. The function of C1QTNF5 remains unclear but this new insight into the pathogenetic basis of L-ORD has implications for future therapeutic strategies such as gene augmentation therapy.	0
BACKGROUND:Semantic dementia (SD) is characterized by progressive semantic anomia extending to a multimodal loss of semantic knowledge. Although often considered an early-onset dementia, SD also occurs in later life, when it may be misdiagnosed as Alzheimer disease (AD). OBJECTIVE:To evaluate late-onset SD in comparison to early-onset SD and to AD. METHODS:We identified 74 individuals with SD and then compared those with late-onset SD (≥65 years of age) to those with early-onset SD (<65) on demographic and clinical features. We also compared a subgroup of 23 of the late-onset SD individuals with an equal number of individuals with clinically probable AD. RESULTS:Twenty-six (35.1%) of the SD individuals were late onset, and 48 (64.9%) were early onset. There were no differences between the two groups on clinical measures, although greater asymmetry of temporal involvement trended to significance in the late-onset SD group. Compared to the 23 AD individuals, the subgroup of 23 late-onset SD individuals had worse performance on confrontational naming, irregular word reading, and face recognition; however, this subgroup displayed better verbal delayed recall and constructions. The late-onset SD individuals also experienced early personality changes at a time when most individuals with AD had not yet developed behavioral changes. CONCLUSIONS:Approximately one-third of SD individuals may be late onset, and the differentiation of late-onset SD from AD can lead to better disease management, education, and prognosis. SD may be distinguished by screening for disproportionate changes in reading, face recognition, and personality.	0
The pentose phosphate pathway (PPP) branches from glucose 6-phosphate (G6P), produces NADPH and ribose 5-phosphate (R5P), and shunts carbons back to the glycolytic or gluconeogenic pathway. The PPP has been demonstrated to be a major regulator for cellular reduction-oxidation (redox) homeostasis and biosynthesis. Enzymes in the PPP are reported to play important roles in many human diseases. In this review, we will discuss the role of the PPP in type 2 diabetes and cancer.	0
Hereditary distal renal tubular acidosis (dRTA) is a rare disease of H+ excretion defect of α-intercalated cells in renal collecting duct, caused by decreased V-ATPase function due to mutations in the ATP6V1B1 or ATP6V0A4 genes. In the present study, a genetic family with 5 members of the complete dRTA phenotype were found with distal tubule H+ secretion disorder, hypokalemia, osteoporosis, and kidney stones. A variant NM_020632.2:c.1631C > T (p.Ser544Leu) in exon 16 on an ATP6V0A4 gene associated with dRTA was detected by next generation sequencing target region capture technique and verified by Sanger sequencing, which suggested that except for one of the patients who did not receive the test, the other four patients all carried the p.S544L heterozygote. In transfected HEK293T cells, cells carrying p.S544L-mut showed early weaker ATPase activity and a slower Phi recovery rate after rapid acidification. By immunofluorescence localization, it was observed that the expression level of p.S544L-mut on the cell membrane increased and the distribution was uneven. Co-immunoprecipitation showed the a4 subunit of ATP6V0A4/p.S544L-mut could not bind to the B1 subunit, which might affect the correct assembly of V-ATPase. The present study of dRTA family suggests that the p.S544L variant may be inherited in a dominant manner.	0
Malonyl-CoA decarboxylase deficiency is an extremely rare autosomal recessive inborn error of fatty acid metabolism. It usually follows a severe disease course and presents poor prognosis without treatment. Here, we report an affected female juvenile with a mild clinical and biochemical phenotype who mainly featured poor schooling without cardiomyopathy and metabolic acidosis. She was suspected of malonyl-CoA decarboxylase deficiency due to a 57-kb deletion in 16q23.3 encompassing the MLCYD gene revealed by chromosome microarray. Malonyl-CoA decarboxylase deficiency was then confirmed by acylcarnitine analysis and organic acid analysis. Real-time PCR analysis of the patient revealed the first three exon deletion of the MLYCD gene, which was maternally inherited. DNA sequencing of the MLYCD gene of the patient identified a novel heterozygous mutation (c.911G>A, p.G304E) in exon 4 that was paternally inherited. The patient urine malonic acid dissolved and had a better school record in 6 month after initiation of fat-limited diet. At 1 year post treatment, the blood malonylcarnitine level decreased remarkably. Our result expands the phenotype of malonyl-CoA decarboxylase deficiency and suggests attentions should be paid to the mild form of disorders, for example, malonyl-CoA decarboxylase deficiency, which usually present a severe disease course.	0
Purposes: To establish a relation between pendular low amplitude high frequency (PLAHF) components and congenital retinal disorders.Methods: Patients who showed PLAHF components in their eye-movement recording between January 2016 to January 2019 were included. Best corrected visual acuity (BCVA), refraction, strabismus assessment, fundus photograph, spectral domain-optical coherence tomography (SD-OCT), full-field electroretinography (f-ERG), clinical ophthalmological examination, and gene tests were used to determine their clinical conditions, especially their retina conditions in all patients.Results: Among 136 patients there were 76 males and 60 females with mean age of 11.4.5 ± 4.5 years. Pure PLAHF waveforms were found in 38 patients (28%), the amplitude of the PLAHF was 2°±1.6° and frequency was 5-10 Hz. Superimposed PLAHF waveforms were found in 98 patients (72%). BCVA was worse than Log MAR1.0 in 94 patients (69%), between LogMar 0.5-1.0 (20/63-20/200) in 30 cases (22%); higher than LogMar 0.5 (20/63) in 12 cases (9%). Fifty-eight patients were diagnosed with exotropia and six patients with esotropia. Abnormal Fundus were found in 71 cases (52%), fovea hypoplasia was identified with OCT in 95 cases (70%) and retinal thinning in 92 cases (68%). Abnormal on-off VEP were found in 116 cases (85%). The f-ERG responses were reduced in all patients. In 46 patients, gene mutations were found to related to retinal disease, including 3 congenital stationary night blindness (CSNB), 14 achromatopsia (ACHM), 5 Aland Island eye disease (AIED), 7 Alstrom syndrome (AS), 11 Leber congenital amaurosis (LCA), 6 cone-rod dystrophy (CRD).Conclusions: Patients presenting with PLAHF usually had retinal disorders.	0
OBJECTIVES:The Harlequin syndrome is a complication observed in patients receiving peripheral venoarterial extracorporeal membrane oxygenation. This condition is defined as a critical variation in the oxygen saturation between the upper and the lower part of the body deriving from a poor lung function. METHODS:Between July 2018 and November 2019, a total of 60 patients (42 men and 18 women; mean age 57.4 ± 10.0 years; range = 28-71 years) underwent peripheral venoarterial extracorporeal membrane oxygenation in our center. Harlequin syndrome was identified in eight cases (six men and two women; 13.3%) of the 60 venoarterial extracorporeal membrane oxygenation-supported patients. As a result of the Harlequin syndrome, all these patients required conversion to veno-arteriovenous extracorporeal membrane oxygenation. Control and monitoring of the blood flows of the return cannulae were performed using two centrifugal pumps, one for each inlet line, according to the patient requirements to achieve optimum hemodynamic and oxygenation. RESULTS:Mean duration of veno-arteriovenous extracorporeal membrane oxygenation support was 5.3 ± 1.4 days. Seven patients (87.5%) were switched to venovenous extracorporeal membrane oxygenation, and after 13.5 ± 2.7 days, those patients were totally weaned from extracorporeal membrane oxygenation support. One patient (12.5%) had an improvement in the pulmonary function, but the cardiac function was poor. This patient was switched to venoarterial extracorporeal membrane oxygenation, and after 10 days, the patient was completely weaned from extracorporeal membrane oxygenation support. CONCLUSION:The use of a secondary centrifugal pump to manage the blood flow directed to the internal jugular vein, in the veno-arteriovenous extracorporeal membrane oxygenation setup, allows the reduction in the risk of blood clot formation, clotting factor consumption, and pulmonary embolism when compared to the use of an external clamp.	0
Glycogen storage disease type IV (GSD IV) is a rare inborn metabolic disorder characterized by the accumulation of amylopectin-like glycogen in the liver or other organs. The hepatic subtype may appear normal at birth but rapidly develops to liver cirrhosis in infancy. Liver pathological findings help diagnose the hepatic form of the disease, supported by analyses of enzyme activity and GBE1 gene variants. Pathology usually shows periodic acid-Schiff (PAS) positive hepatocytes resistant to diastase. We report two cases of hepatic GSD IV with pathology showing PAS positive hepatocytes that were mostly digested by diastase, which differ from past cases. Gene analysis was critical for the diagnosis. Both cases were found to have the same variants c.288delA (p.Gly97GlufsTer46) and c.1825G > A (p.Glu609Lys). These findings suggest that c.1825G > A variant might be a common variant in the non-progressive hepatic form of GSD IV.	0
As the most common subtype of Leber congenital amaurosis (LCA), LCA10 is a severe retinal dystrophy caused by mutations in the CEP290 gene. The most frequent mutation found in patients with LCA10 is a deep intronic mutation in CEP290 that generates a cryptic splice donor site. The large size of the CEP290 gene prevents its use in adeno-associated virus (AAV)-mediated gene augmentation therapy. Here, we show that targeted genomic deletion using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system represents a promising therapeutic approach for the treatment of patients with LCA10 bearing the CEP290 splice mutation. We generated a cellular model of LCA10 by introducing the CEP290 splice mutation into 293FT cells and we showed that guide RNA pairs coupled with SpCas9 were highly efficient at removing the intronic splice mutation and restoring the expression of wild-type CEP290. In addition, we demonstrated that a dual AAV system could effectively delete an intronic fragment of the Cep290 gene in the mouse retina. To minimize the immune response to prolonged expression of SpCas9, we developed a self-limiting CRISPR/Cas9 system that minimizes the duration of SpCas9 expression. These results support further studies to determine the therapeutic potential of CRISPR/Cas9-based strategies for the treatment of patients with LCA10.	0
Inherited defects in adenosine deaminase (ADA) cause a subtype of severe combined immunodeficiency (SCID) known as severe combined immune deficiency caused by adenosine deaminase defects (ADA-SCID). Most affected infants can receive a diagnosis while still asymptomatic by using an SCID newborn screening test, allowing early initiation of therapy. We review the evidence currently available and propose a consensus management strategy. In addition to treatment of the immune deficiency seen in patients with ADA-SCID, patients should be followed for specific noninfectious respiratory, neurological, and biochemical complications associated with ADA deficiency. All patients should initially receive enzyme replacement therapy (ERT), followed by definitive treatment with either of 2 equal first-line options. If an HLA-matched sibling donor or HLA-matched family donor is available, allogeneic hematopoietic stem cell transplantation (HSCT) should be pursued. The excellent safety and efficacy observed in more than 100 patients with ADA-SCID who received gammaretrovirus- or lentivirus-mediated autologous hematopoietic stem cell gene therapy (HSC-GT) since 2000 now positions HSC-GT as an equal alternative. If HLA-matched sibling donor/HLA-matched family donor HSCT or HSC-GT are not available or have failed, ERT can be continued or reinstituted, and HSCT with alternative donors should be considered. The outcomes of novel HSCT, ERT, and HSC-GT strategies should be evaluated prospectively in "real-life" conditions to further inform these management guidelines.	0
INTRODUCTION:Chromosome 18q deletion syndrome (18q-) is a rare chromosomal disorder with phenotypic variability, including mental deficiency, short stature, hypotonia, cleft palate, and hearing impairment. We present a case with features of 18q- syndrome who had combined 18q partial monosomy and 18p partial trisomy. MATERIAL AND METHODS:A 50-year-old female patient was examined during the genetic counseling of her brother. She had a history of congenital cleft palate and developmental deficiency with hypotonia, hearing loss, and epilepsy until adulthood. Her family history was free of related cases. Karyotype analysis and comparative genomic hybridization array (aCGH) were performed in patient's blood samples. RESULTS:Clinical examination showed features of 18q- syndrome including hypotonia and tremor. Neuropsychological deficiency of moderate cognitive disorder was noticed. The patient's karyotype was normal. The aCGH analysis revealed 8 Mb deletion (del18q22.3q23) and 7.2 Mb duplication (dup18p11.32p11.23). CONCLUSION:Almost all patients' clinical features were associated with 18q- syndrome. There are very few reported cases with similar genotype possibly caused by a de novo unequal recombination mechanism.	0
BACKGROUND:Focal cortical dysplasia (FCD) is a neuronal migration disorder and is a major cause of drug-resistant epilepsy. However, many focal abnormalities remain undetected during routine visual inspection, and many patients with histologically confirmed FCD have normal fluid-attenuated inversion recovery (FLAIR-negative) images. The aim of this study was to quantitatively evaluate the changes in cortical thickness with magnetic resonance (MR) imaging of patients to identify FCD lesions from FLAIR-negative images. METHODS:We first used the three-dimensional (3D) Laplace method to calculate the cortical thickness for individuals and obtained the cortical thickness mean image and cortical thickness standard deviation (SD) image based on all 32 healthy controls. Then, a cortical thickness extension map was computed by subtracting the cortical thickness mean image from the cortical thickness image of each patient and dividing the result by the cortical thickness SD image. Finally, clusters of voxels larger than three were defined as the FCD lesion area from the cortical thickness extension map. RESULTS:The results showed that three of the four lesions that occurred in non-temporal areas were detected in three patients, but the detection failed in three patients with lesions that occurred in the temporal area. The quantitative analysis of the detected lesions in voxel-wise on images revealed the following: specificity (99.78%), accuracy (99.76%), recall (67.45%), precision (20.42%), Dice coefficient (30.01%), Youden index (67.23%) and area under the curve (AUC) (83.62%). CONCLUSION:Our studies demonstrate an effective method to localize lesions in non-temporal lobe regions. This novel method automatically detected FCD lesions using only FLAIR-negative images from patients and was based only on cortical thickness feature. The method is noninvasive and more effective than a visual analysis for helping doctors make a diagnosis.	0
Developmental prosopagnosia (DP) is a cognitive condition characterised by a relatively selective deficit in face recognition. Some adults and children with DP experience severe psychosocial consequences related to the condition, yet are reluctant to disclose it to others. The remediation of DP is therefore an urgent issue, but has been met with little success. Given that developmental conditions may only benefit from compensatory rather than remedial training, this study aimed to examine (a) the positive and negative effects of DP disclosure, and (b) compensatory techniques that may circumvent recognition failure. Qualitative questionnaires and interviews were carried out with 79 participants: 50 adults with DP, 26 of their non-affected significant others, and three parents of DP children. Findings indicated positive effects of disclosure, yet most adults choose not to do so in the workplace. Effective compensatory strategies include the use of extra-facial information, identity prompts from others, and preparation for planned encounters. However, changes in appearance, infrequent contact, or encounters in unexpected contexts often cause strategy failure. As strategies are effortful and disrupted by heavily controlled appearance (e.g., the wearing of uniform), disclosure of DP may be necessary for the safety, wellbeing and optimal education of children with the condition.	0
Although a previous study suggested that erythropoietin-producing hepatoma (EPH) receptors play important roles in tumor progression and the overexpression of EPHs in cancer patients is related to poor prognoses, high-throughput gene expression profiling of EPH family members in different types and subtypes of cancers has so far not been conducted. We herein carried out a series of bioinformatic analyses on expressive profiles of every EPH member across 21 different types of clinical cancers versus matched normal tissues gathered from the Oncomine platform. We validated these results by protein expression study of all EPHs family members by The Human Protein Atlas repository. Our results uncovered the overexpression of most EPH subunits in numerous cancer types, especially the dramatic overexpression of six EPHs members, namely EPHA1, EPHA2, EPHA3, EPHA4 and EPHB1, EPHB2, EPHB3, EPHB4 in bladder, colorectal, esophageal, gastric, and prostate cancers. Furthermore, EPHB2 was specifically highly expressed in cervical cancer, EPHA3 in liver cancer, and EPHB1 in uterine cancer. Collectively, expressive profiles of these EPHs were confirmed and correlated with different cancer subtypes as potential biomarkers. This study provides useful information for further studies on cancer development and clinical treatments.	0
PTEN hamartoma tumour syndrome (PHTS) is caused by heterozygous variants in PTEN and is characterised by tumour predisposition, macrocephaly, and cognition impairment. Bi-allelic loss of PTEN activity has not been reported so far and animal models suggest that bi-allelic loss of PTEN activity is embryonically lethal. Here, we report the identification of a novel homozygous variant in PTEN, NM_000314.4; c.545T>C; p.Leu182Ser, in two adolescent siblings with severe macrocephaly and mild intellectual disability. The variant is predicted to be damaging and is associated with significantly increased phospho-S6 downstream of PTEN. The absence of tumours in the two homozygous siblings as well as lack of symptoms of PHTS in the heterozygous carriers of the family suggest that this particular variant is functionally hypomorphic rather than deleterious.	0
OBJECTIVES:To examine the treatment decision-making process of patients with dcSSc in the context of haematopoietic stem cell transplantation (HSCT). METHODS:A qualitative semi-structured interview study was done in patients before or after HSCT, or patients who chose another treatment than HSCT. Thematic analysis was used. Shared decision-making (SDM) was assessed with the 9-item Shared Decision Making Questionnaire (SDM-Q-9). RESULTS:Twenty-five patients [16 male/nine female, median age 47 (range 27-68) years] were interviewed: five pre-HSCT, 16 post-HSCT and four following other treatment. Whereas the SDM-Q-9 showed the decision-making process was perceived as shared [median score 81/100 (range 49-100)], we learned from the interviews that the decision was predominantly made by the rheumatologist, and patients were often steered towards a treatment option. Strong guidance of the rheumatologist was appreciated because of a lack of accessible, reliable and SSc-specific information, due to the approach of the decision-making process of the rheumatologist, the large consequence of the decision and the trust in their doctor. Expectations of outcomes and risks also differed between patients. Furthermore, more than half of patients felt they had no choice but to go for HSCT, due to rapid deterioration of health and the perception of HSCT as 'the holy grail'. CONCLUSION:This is the first study that provides insight into the decision-making process in dcSSc. This process is negatively impacted by a lack of disease-specific education about treatment options. Additionally, we recommend exploring patients' preferences and understanding of the illness to optimally guide decision-making and to provide tailor-made information.	0
OBJECTIVE:Identify, diagnose, and document oral clinical and radiographic evidence associated with the genetic condition known as special AT-rich sequence-binding protein 2 (SATB2)-associated syndrome. Through identifying and publishing these common dental and behavioral findings, we hope to educate oral and medical healthcare providers to identify this condition in an attempt to develop meaningful comprehensive care to this patient population. METHODS:A total of 37 patients (19 female), ranging from ages 2 to 20 were evaluated at Arkansas Children's Hospital in Little Rock, Arkansas. Patient geographic distribution included: the United States, Canada, Portugal, Spain, and the Netherlands. Patients were clinically and radiographically examined for oral findings. Panoramic radiographs were obtained when patient's behavior allowed. Patient's parents or guardians were also interviewed concerning dental, medical, and behavioral histories. RESULTS:Clinical findings included delayed tooth eruption, bruxism, sialorrhea, larger than normal teeth with an increased propensity for maxillary anterior tooth trauma due to unsteady ambulation. Radiographic findings included delayed permanent root formation, significantly delayed or missing second bicuspids, malformed teeth, and taurodontism. Medical and behavioral issues included: insomnia, hyperphagia, cognitive delays, and an extremely high pain threshold. CONCLUSION:Patients with SATB2-associated syndrome have shown to have a consistent and unique set of dental findings both clinically and radiographically. A thorough health and dental history along with the aforementioned results of the study may facilitate a diagnosis of this syndrome. Due to the complexity of the patient's dental needs and behavior, a health practitioner with special needs care experience on a comprehensive craniofacial team would be optimal.	0
This case describes a parturient with Barnes syndrome, a rare disorder characterized by subglottic stenosis, thoracic dystrophy, and small pelvic inlet, who underwent cesarean delivery of a neonate diagnosed with Barnes syndrome. Live simulation training was performed by multidisciplinary team to prepare for the spinal anesthetic, personnel flow between 2 operating rooms, and management of various airway scenarios for the newborn. After delivery, the neonate underwent laryngoscopy-bronchoscopy with successful intubation in the operating room because of labored breathing. Airway evaluation revealed subglottic stenosis, tracheomalacia/bronchomalacia. Collaboration among perinatologists, obstetric/pediatric anesthesiologists, pediatric head and neck surgeons, and neonatologists was integral to perioperative management of both the mother and child.	0
Nutcracker syndrome (NCS) is caused by compression of left renal vein (LRV), usually between the aorta and the superior mesenteric artery (SMA). This can lead to obstruction of flow into the inferior vena cava and secondary left renal venous hypertension. Despite potential serious consequences, diagnosing NCS is often challenging, circuitous and commonly delayed. We report an extremely unique case of NCS. A 34-year-old woman presented with left flank pain and discomfort. On investigation, it was found that high pressure in the LRV, due to compression by the SMA, had led to a large venous aneurysm that had caused pelviureteric junction obstruction and hydronephrosis. Management was with stenting of the LRV and coil embolisation of the venous aneurysm with excellent clinical outcome.	0
BACKGROUND:Large maxillofacial venous malformation (VM) lesions can affect the craniofacial skeleton, causing occlusal and craniofacial deformity. Few studies have discussed the management of these skeletal disorders. It is unclear whether orthodontic treatment and orthognathic surgery are necessary after such a VM lesion has been significantly reduced. METHODS:A 13-year-old boy with a large, extensive maxillofacial VM lesion, severe facial asymmetry, macroglossia, and lower lip hypertrophy visited our department in 2010. He received more than 100 sclerotherapy treatments and 20 laser treatments in the past 8 years. RESULTS:The patient's cosmetic disfigurement greatly improved, and the VM lesion diminished by more than 80%. Changes in the bite and craniofacial skeleton progressed from "normal" to "open bite with skeletal deformity" and finally to "spontaneously close to normal". CONCLUSIONS:During the progression of VM, removal of pathogenic factors can inhibit the aggravation of open bite deformity and promote the spontaneous improvement, thereby circumventing the need for complicated osteotomy, orthodontic intervention and/or orthognathic surgery.	0
PURPOSE:Abnormalities in cerebrospinal fluid (CSF) have been reported in Hurler syndrome, a fatal neurodegenerative lysosomal disorder. While no biomarker has predicted neurocognitive response to treatment, one of these abnormalities, glycosaminoglycan nonreducing ends (NREs), holds promise to monitor therapeutic efficacy. A trial of intrathecal enzyme replacement therapy (ERT) added to standard treatment enabled tracking of CSF abnormalities, including NREs. We evaluated safety, biomarker response, and neurocognitive correlates of change. METHODS:In addition to intravenous ERT and hematopoietic cell transplantation, patients (N = 24) received intrathecal ERT at four peritransplant time points; CSF was evaluated at each point. Neurocognitive functioning was quantified at baseline, 1 year, and 2 years posttransplant. Changes in CSF biomarkers and neurocognitive function were evaluated for an association. RESULTS:Over treatment, there were significant decreases in CSF opening pressure, biomarkers of disease activity, and markers of inflammation. Percent decrease in NRE from pretreatment to final intrathecal dose posttransplant was positively associated with percent change in neurocognitive score from pretreatment to 2 years posttransplant. CONCLUSION:Intrathecal ERT was safe and, in combination with standard treatment, was associated with reductions in CSF abnormalities. Critically, we report evidence of a link between a biomarker treatment response and neurocognitive outcome in Hurler syndrome.	0
Variants in the KIF1A gene can cause autosomal recessive spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or autosomal (de novo) dominant mental retardation type 9. More recently, variants in KIF1A have also been described in a few cases with autosomal dominant spastic paraplegia. Here, we describe 20 KIF1A variants in 24 patients from a clinical exome sequencing cohort of 347 individuals with a mostly 'pure' spastic paraplegia. In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0-57 years). Segregation analyses showed a de novo occurrence in seven cases, and a dominant inheritance pattern in 11 families. The motor domain of KIF1A is a hotspot for disease causing variants in autosomal dominant spastic paraplegia, similar to mental retardation type 9 and recessive spastic paraplegia type 30. However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families. Finally, three missense variants were outside the motor domain and need further characterization. In conclusion, KIF1A variants are a frequent cause of autosomal dominant spastic paraplegia in our cohort (6-7%). The identification of KIF1A loss-of-function variants suggests haploinsufficiency as a possible mechanism in autosomal dominant spastic paraplegia.	0
Penetrating neck injury can have potentially devastating consequences due to the many vital structures contained within the neck. In patients who do not require immediate surgery, computed tomography angiography of the neck is the test of choice to characterize the injury. A systematic approach to assessment will ensure a thorough evaluation and give the reporting radiologist the best chance of identifying the significant findings, which can often be subtle. Clear communication with the trauma team at both the time of request and after the imaging has been evaluated to relay any significant findings is vital to ensure the best outcome for the patient.	0
BACKGROUND:Wolff-Parkinson-White (WPW) syndrome is a relatively common arrhythmia affecting ~1-3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals. Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population. METHODS:We applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, candidate gene approach, and burden testing to explore the genetic contributions to WPW. RESULTS:A heterozygous deleterious variant in PRKAG2 was identified in one subject, accounting for 0.6% (1/151) of the genetic basis of WPW in this study. Another individual with WPW and left ventricular hypertrophy carried a known pathogenic variant in MYH7. We found rare de novo variants in genes associated with arrhythmia and cardiomyopathy (ANK2, NEBL, PITX2, and PRDM16) in this cohort. There was an increased burden of rare deleterious variants (MAF ≤ 0.005) with CADD score ≥ 25 in genes linked to AF in cases compared to controls (P = .0023). CONCLUSIONS:Our findings show an increased burden of rare deleterious variants in genes linked to AF in WPW syndrome, suggesting that genetic factors that determine the development of accessory pathways may be linked to an increased susceptibility of atrial muscle to AF in a subset of patients.	0
Chronic disorders of consciousness cause a total or partial and fluctuating unawareness of the surrounding environment. Virtual reality (VR) can be useful as a diagnostic and/or a neurorehabilitation tool, and its effects can be monitored by means of both clinical and electroencephalography (EEG) data recording of brain activity. We reported on the case of a 17-year-old patient with a disorder of consciousness (DoC) who was provided with VR training to improve her cognitive-behavioral outcomes, which were assessed using clinical scales (the Coma Recovery Scale-Revised, the Disability Rating Scale, and the Rancho Los Amigos Levels of Cognitive Functioning), as well as EEG recording, during VR training sessions. At the end of the training, significant improvements in both clinical and neurophysiological outcomes were achieved. Then, we carried out a systematic review of the literature to investigate the role of EEG and VR in the management of patients with DoC. A search on PubMed, Web of Science, Scopus, and Google Scholar databases was performed, using the keywords: "disorders of consciousness" and "virtual reality", or "EEG". The results of the literature review suggest that neurophysiological data in combination with VR could be useful in evaluating the reactions induced by different paradigms in DoC patients, helping in the differential diagnosis. In conclusion, the EEG plus VR approach used with our patient could be promising to define the most appropriate stimulation protocol, so as to promote a better personalization of the rehabilitation program. However, further clinical trials, as well as meta-analysis of the literature, are needed to be affirmative on the role of VR in patients with DoC.	0
Autosomal dominant optic atrophy (ADOA) is a neuro-ophthalmic condition characterized by bilateral degeneration of the optic nerves. Although heterozygous mutations in OPA1 represent the most common genetic cause of ADOA, a significant number of cases remain undiagnosed.Here, we describe a family with a strong ADOA history with most family members spanning three generation having childhood onset of visual symptoms. The proband, in addition to optic atrophy, had neurological symptoms consistent with relapsing remitting multiple sclerosis. Clinical exome analysis detected a novel mutation in the AFG3L2 gene (NM_006796.2:c.1010G > A; p.G337E), which segregated with optic atrophy in family members. AFG3L2 is a metalloprotease of the AAA subfamily which exerts quality control in the inner mitochondrial membrane. Interestingly, the identified mutation localizes close to the AAA domain of AFG3L2, while those localized in the proteolytic domain cause dominant spinocerebellar ataxia type 28 (SCA28) or recessive spastic ataxia with epilepsy (SPAX5). Functional studies in patient fibroblasts demonstrate that the p.G337E AFG3L2 mutation strongly destabilizes the long isoforms of OPA1 via OMA hyper-activation and leads to mitochondrial fragmentation, thus explaining the family phenotype. This study widens the clinical spectrum of neurodegenerative diseases caused by AFG3L2 mutations, which shall be considered as genetic cause of ADOA.	0
Extracranial metastasis (ECM) of glioma is a rare condition that occurs in the internal nervous axis. A 23-year-old woman presented with anaplastic oligoastrocytoma (WHO III) in a left temporal tumor. The patient received chemoradiotherapy after surgery in our center. Three years after treatment, the patient experienced multiple ECMs in the right lung, left iliac bone, and multiple swollen subcutaneous nodules including the right clavicle, back of the neck, left forearm, right upper arm, and right clavicle. The patient died of cerebral herniation at the age of 27 due to recurrent intracranial glioma. Treatment of ECM of glioma remains very challenging, and further investigations are needed.	0
OBJECTIVE: To give an epidemiological description of the clinical entity given the name Pierre Robin sequence, defined by retro- and micrognathia, cleft palate, and respiratory distress and describe other malformations and possible intrauterine impairment. METHODS: Using the inclusion criteria of micrognathia, cleft palate, and neonatal respiratory distress, a retrospective population-based study of all Danish live births during 1990 through 1999 were carried out. We found 50 children, 25 boys and 25 girls, fulfilling the inclusion criteria, giving an incidence of 1 in 14,000 live births. RESULTS: Two-thirds (n = 33) of the children had the classical U-shaped cleft palate. More than one-third (n = 19) had one or several other malformations, and in five patients the triad of Pierre Robin was a minor feature of a complex syndrome. The most common noncomplex syndrome was the Stickler syndrome found in 6 of the 50 patients. More than one-fourth (n = 17) had some kind of intrauterine impairment, with no specific obstetric diagnosis predominant. Consistent with this, the average birth weight was well below normal. CONCLUSIONS: Several authors have stated that the triad of Pierre Robin is not a nosological entity, in that it has diverse etiology and diverse pathogenesis. We conclude that the triad of Pierre Robin still can be regarded as a clinical entity, readily defined at birth, experiencing the same neonatal problems in varying degrees and hence the possibility of designing treatment protocols for later scientific evaluation.	1
Liver transplantation has been established as a curative therapy for acute and chronic liver failure, as well as liver-based inherited metabolic diseases. Because of the complexity of organ transplantation and the worldwide shortage of donor organs, hepatocyte transplantation is being developed as a bridging therapy until donor organs become available, or for amelioration of inherited liver-based diseases. The Gunn rat is a molecular and metabolic model of Crigler-Najjar syndrome type 1, which is characterized by lifelong unconjugated hyperbilirubinemia due to the lack of uridinediphosphoglucuronate glucuronosyltransferase-1 (UGT1A1)-mediated bilirubin glucuronidation. Gunn rats are convenient for evaluating the effect of hepatocyte transplantation or gene therapy, because the extent of UGT1A1 replacement can be assessed by serial determination of serum bilirubin levels, and excretion of bilirubin glucuronides in bile provide definitive evidence of the function of the transplanted hepatocytes or the effect of gene therapy. The core techniques involved in hepatocyte transplantation in Gunn rats are discussed in this chapter.	0
The skull vault, formed by the flat bones of the skull, has a limited spectrum of disease that lies between the fields of neuro- and musculoskeletal radiology. Its unique abnormalities, as well as other ubiquitous ones, present particular features in this location. Moreover, some benign entities in this region may mimic malignancy if analyzed using classical bone-tumor criteria, and proper patient management requires being familiar with these presentations. This article is structured as a practical review offering a systematic diagnostic approach to focal calvarial lesions, broadly organized into four categories: (1) pseudolesions: arachnoid granulations, meningo-/encephaloceles, vascular canals, frontal hyperostosis, parietal thinning, parietal foramina, and sinus pericrani; (2) lytic: fibrous dysplasia, epidermal inclusion and dermoid cysts, eosinophilic granuloma, hemangioma, aneurysmal bone cyst, giant cell tumor, metastasis, and myeloma; (3) sclerotic: osteomas, osteosarcoma, and metastasis; (4) transdiploic: meningioma, hemangiopericytoma, lymphoma, and metastasis, along with other less common entities. Tips on the potential usefulness of functional imaging techniques such as MR dynamic susceptibility (T2*) perfusion, MR spectroscopy, diffusion-weighted imaging, and PET imaging are provided.	0
In the 2013 updated classification of the American Thoracic Society/European Respiratory Society, airway-centered interstitial fibrosis (ACIF) is included as a bronchiolocentric pattern of interstitial pneumonia (IP) among idiopathic IPs. We encountered a case of severe pulmonary hypertension (PH) with chronic IP. The patient initially presented with shortness of breath and often lost consciousness due to PH, and seven years after his first visit, he ultimately died. An autopsy revealed ACIF and usual IP. In particular, the ACIF comprised non-atypical smooth muscle hyperplasia, and pulmonary hypertensive vascular degeneration was detected. This case may represent a new pathological feature of ACIF.	0
Pleuropulmonary blastomas (PPB) are pediatric, embryonal cancers of the lung parenchyma and pleural surfaces and are among the most common DICER1-related disorders. These tumors undergo evolution through several forms, allowing division into types I, Ir, II, and III, with correlates to the age of diagnosis and prognosis. We sought to provide a comprehensive review of the relevant literature describing the characteristics of these tumors and their multidisciplinary treatment, with an emphasis on surgical management. We describe the complementary roles of chemotherapy and surgery in the successful management of this disease. We discuss the timing of surgery and options for surgical approaches. We address the differentiation of PPB from congenital pulmonary airway malformation and the role of DICER1 testing for children with pulmonary cysts.	0
This report presents a case of an eightyear- old girl affected by a progeroid syndrome of unclear genetic origins. The patient's dental history included oligodontia, premature deciduous exfoliation and roots abnormalities. She was treated with comprehensive oral rehabilitation using dentures. Oral health instructions were given during the whole treatment and follow- up period. The goal of improving the masticatory function and the esthetic was achieved, allowing the patient to increase her social abilities and self-confidence.	0
Opsoclonus myoclonus syndrome (OMS) is a rare neurological syndrome caused by a paraneoplastic autoimmune process that affects children with neuroblastic tumors. Treatment includes corticosteroids, intravenous gamma globulin (IVIG), rituximab, and other immunosuppressive therapies. Here, we describe a patient diagnosed with OMS associated with a localized inflammatory myofibroblastic tumor. The patient has no evidence of tumor recurrence following surgical resection with 8-month follow-up. The neurologic symptoms resolved with corticosteroids and IVIG. This case demonstrates that in children, neoplasms other than neuroblastoma may be associated with this paraneoplastic syndrome, and highlights the importance of evaluating patients with OMS for underlying malignancies.	0
Barber-Say syndrome is a rare autosomal dominant disease characterized by dysmorphic features, mainly of the eyelids and skin. It is caused by heterozygous mutations in gene TWIST2, localized in chromosome 2q37.3. The authors present the case of a pediatric patient with a clinical diagnosis of Barber-Say syndrome with ocular symptoms related to exposure keratitis. Molecular analysis of her DNA revealed a mutation on TWIST2 gene confirming the diagnosis of Barber-Say syndrome. Surgical treatment of the patient's eyelids resolved her signs and symptoms.	0
Myotonic Dystrophy type 1 (DM1) is a neuromuscular disease showing strong genetic anticipation, and is caused by the expansion of a CTG repeat tract in the 3'-UTR of the DMPK gene. Congenital Myotonic Dystrophy (CDM1) represents the most severe form of the disease, with prenatal onset, symptoms distinct from adult onset DM1, and a high rate of perinatal mortality. CDM1 is usually associated with very large CTG expansions, but this correlation is not absolute and cannot explain the distinct clinical features and the strong bias for maternal transmission. This review focuses upon the molecular and epigenetic factors that modulate disease severity and might be responsible for CDM1. Changes in the epigenetic status of the DM1 locus and in gene expression have recently been observed. Increasing evidence supports a role of a CTCF binding motif as a cis-element, upstream of the DMPK CTG tract, whereby CpG methylation of this site regulates the interaction of the insulator protein CTCF as a modulating trans-factor responsible for the inheritance and expression of CDM1.	0
Despite much progress in understanding the genetics of syndromic tooth agenesis (TA), the causes of the most common, isolated TA remain elusive. Recent studies have identified novel genes and variants contributing to the etiology of TA, and revealed new pathways in which tooth development genes belong. Further, the use of new research approaches including next-generation sequencing has provided increased evidence supporting an oligogenic inheritance model for TA, and may explain the phenotypic variability of the condition. In this review, we present current knowledge about the genetic mechanisms underlying syndromic and isolated TA in humans, and highlight the value of incorporating next-generation sequencing approaches to identify causative and/or modifier genes that contribute to the etiology of TA.	0
Malformations of cortical development encompass heterogeneous groups of structural brain anomalies associated with complex neurodevelopmental disorders and diverse genetic and nongenetic etiologies. Recent progress in understanding the genetic basis of brain malformations has been driven by extraordinary advances in DNA sequencing technologies. For example, somatic mosaic mutations that activate mammalian target of rapamycin signaling in cortical progenitor cells during development are now recognized as the cause of hemimegalencephaly and some types of focal cortical dysplasia. In addition, research on brain development has begun to reveal the cellular and molecular bases of cortical gyrification and axon pathway formation, providing better understanding of disorders involving these processes. New neuroimaging techniques with improved resolution have enhanced our ability to characterize subtle malformations, such as those associated with intellectual disability and autism. In this review, we broadly discuss cortical malformations and focus on several for which genetic etiologies have elucidated pathogenesis.	0
Cerebral folate deficiency is typically defined as a deficiency of the major folate species 5-methyltetrahydrofolate in the cerebrospinal fluid (CSF) in the presence of normal peripheral total folate levels. However, it should be noted that cerebral folate deficiency is also often used to describe conditions where CSF 5-MTHF is low, in the presence of low or undefined peripheral folate levels. Known defects of folate transport are deficiency of the proton coupled folate transporter, associated with systemic as well as cerebral folate deficiency, and deficiency of the folate receptor alpha, leading to an isolated cerebral folate deficiency associated with intractable seizures, developmental delay and/or regression, progressive ataxia and choreoathetoid movement disorders. Inborn errors of folate metabolism include deficiencies of the enzymes methylenetetrahydrofolate reductase, dihydrofolate reductase and 5,10-methenyltetrahydrofolate synthetase. Cerebral folate deficiency is potentially a treatable condition and so prompt recognition of these inborn errors and initiation of appropriate therapy is of paramount importance. Secondary cerebral folate deficiency may be observed in other inherited metabolic diseases, including disorders of the mitochondrial oxidative phosphorylation system, serine deficiency, and pyridoxine dependent epilepsy. Other secondary causes of cerebral folate deficiency include the effects of drugs, immune response activation, toxic insults and oxidative stress. This review describes the absorption, transport and metabolism of folate within the body; analytical methods to measure folate species in blood, plasma and CSF; inherited and acquired causes of cerebral folate deficiency; and possible treatment options in those patients found to have cerebral folate deficiency.	0
Human triosephosphate isomerase (TIM) deficiency is a very rare disease, but there are several mutations reported to be causing the illness. In this work, we produced nine recombinant human triosephosphate isomerases which have the mutations reported to produce TIM deficiency. These enzymes were characterized biophysically and biochemically to determine their kinetic and stability parameters, and also to substitute TIM activity in supporting the growth of an Escherichia coli strain lacking the tim gene. Our results allowed us to rate the deleteriousness of the human TIM mutants based on the type and severity of the alterations observed, to classify four "unknown severity mutants" with altered residues in positions 62, 72, 122 and 154 and to explain in structural terms the mutation V231M, the most affected mutant from the kinetic point of view and the only homozygous mutation reported besides E104D.	0
Anorectal disorders encompass structural, neuromuscular, and functional disorders. They are common, often distressing, and in some cases debilitating, and significantly add to the health care burden. They present with multiple, overlapping symptoms that can often obscure the underlying pathology and can pose significant diagnostic and management dilemmas. A meticulous history and comprehensive digital rectal examination can provide clarity on the diagnosis, appropriate testing, and management of these conditions. Today, with the development of sophisticated diagnostic tools such as high-resolution and high-definition (3-D) anorectal manometry, 3-D anal ultrasonography, magnetic resonance defecography and imaging, and neurophysiological tests such as translumbosacral anorectal magnetic stimulation, it is possible to more accurately define and characterize the underlying structural and functional abnormalities. In this review, we present a succinct update on the latest knowledge with regards to the pathophysiology, diagnosis and management of anal fissure, hemorrhoids, rectal prolapse, intussusception, rectocele, solitary rectal ulcer syndrome, levator ani syndrome, dyssynergic defecation and fecal incontinence.	0
BACKGROUND:Antilaminin-332 mucous membrane pemphigoid is a chronic severe pemphigoid disease characterized by autoantibodies to laminin-332. At present no commercial assay is available to demonstrate antilaminin-332 antibodies, and diagnosis relies on in-house techniques with limited sensitivities. OBJECTIVES:In order to move, keratinocytes cultured in vitro secrete laminin-332 to attach to the culture dish. In that way, they leave behind a unique footprint trail of laminin-332. We aimed to develop a sensitive and specific laboratory assay to determine antilaminin-332 autoantibodies in patient serum based on binding of patient IgG to these unique footprints. METHODS:Normal human keratinocytes were grown on glass coverslips and incubated with patient or control serum for 1 h. The binding of IgG was then investigated by immunofluorescence. After validating the test for its ability to identify antilaminin-332 autoantibodies it was converted into a daily available test based on binding of IgG to dried coverslips that can be stored frozen. The staining patterns of sera from patients with antilaminin-332 pemphigoid were then compared with those of sera from patients with other autoimmune bullous diseases and normal human sera. RESULTS:IgG of all antilaminin-332 pemphigoid sera (n = 16) bound to laminin-332 footprints, while all normal human controls (n = 55) were negative. From the sera of patients with other diseases (n = 72) four sera tested positive. The footprint assay was also positive for sera that were negative by salt-split skin analysis, demonstrating that it is a very sensitive technique. CONCLUSIONS:The keratinocyte footprint assay is a fast and specific assay to confirm or rule out the presence of antilaminin-332 autoantibodies. What's already known about this topic? Antilaminin-332 mucous membrane pemphigoid is a severe form of pemphigoid, and patients may have an increased risk of malignancies. The diagnosis of antilaminin-332 mucous membrane pemphigoid is complicated by the lack of specific commercial tests for antilaminin-332 antibodies and can be confirmed only in specialized laboratories. Keratinocytes in culture need laminin-332 for adhesion and migration and therefore deposit it on the bottom of the culture dish. What does this study add? The keratinocyte footprint assay detects antilaminin-332 autoantibodies in patient serum using the native laminin-332 produced by cultured keratinocytes. What is the translational message? The keratinocyte footprint assay is a fast and specific assay to confirm or rule out the presence of antilaminin-332 autoantibodies.	0
We present an adult woman with subcutaneous nodules without any signs or symptoms of rheumatoid arthritis. These nodules are believed to be pseudorheumatoid nodules, which are considered a deep form of granuloma annulare. This case is unique because these are typically found in children and have rarely been reported in adults. These nodules are typically asymptomatic and do not require treatment. However, attempts have been made to treat them with intralesional corticosteroids, cryotherapy, or excision. Owing to the fact that this is considered a deep form of granuloma annulare, they are sometimes treated similarly with a combination of monthly rifampin, ofloxacin, and minocycline.	0
Primary immunodeficiencies (PID) comprise a group of more than 300 mostly monogenetic disorders of the immune system leading to infection susceptibility and a variety of associated clinical and immunological complications. In a majority of these disorders the absence, disproportions or dysfunction of leucocyte subpopulations or of proteins expressed by these cells are observed. These distinctive features are studied by multicolour flow cytometry and the results are used for diagnosis, follow up, classification and therapy monitoring in patients with PIDs. Although a definite diagnosis almost always relies on genetic analysis in PIDs, the results of flow cytometric diagnostics are pivotal in the initial diagnostic assessment of suspected PID patients and often guide the treating physician to a more selective and efficient genetic diagnostic procedure, even in the era of next generation sequencing technology. Furthermore, phenotypic and functional flow cytometry tests allow to validate novel genetic variants and the mapping of complex disturbances of the immune system in individual patients in a personalized manner. In this review we give an overview on phenotypic, functional as well as disease/protein specific flow cytometric assays in the diagnosis of PID and highlight diagnostic strategies and specialties for several selected PIDs by way of example.	0
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an uncommon cardiomyopathy most classically associated with mutations in genes encoding desmosomal proteins. Recent literature has identified mutations in several non-desmosomal proteins including lamins that may result in the ARVC phenotype. We describe a patient who discovered her own pathogenic LMNA mutation that offered a unifying diagnosis explaining her ARVC and Charcot-Marie-Tooth phenotypes as well as musculoskeletal abnormalities. Suspicion for LMNA-mediated cardiomyopathy should arise in patients with extracardiac manifestations of laminopathies and testing for specific gene mutations may be helpful in establishing an unifying diagnosis.	0
Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease due to motor neuron loss variably associated with frontotemporal dementia (FTD). Next generation sequencing technology revealed an increasing number of rare and novel genetic variants and interpretation of their pathogenicity represents a major challange in the diagnosis of ALS. We selected 213 consecutive patients with sporadic or familial (16%) ALS, tested negative for SOD1, FUS, TARDBP, and C9orf72 mutations. To reveal rare forms of genetic ALS, we performed a comprehensive multi-gene panel screening including 46 genes associated with ALS, hereditary motor neuronopathies, spastic paraplegia, and FTD. Our study allowed the identification of pathogenic or likely pathogenic variants in 4.2% of patients. The genes with the highest percentage of pathogenic variants were OPTN (1%), VCP (1%) SQSTM1(1%), SETX (0.4%), FIG4 (0.4%), and GARS1 (0.4%) genes. We also found 49 novel or rare gene variants of unknown significance in 30 patients (14%), 44 unlikely pathogenic variants (39%), and 48 variants in ALS susceptibility genes. The results of our study suggest the screening of OPTN, VCP, and SQSTM1 genes in routine diagnostic investigations for both sporadic and familial cases, and confirm the importance of diagnosis and couselling for patients and their relative family members.	0
Dentin dysplasia type I is a rare hereditary disturbance of dentin formation characterised clinically by nearly normal appearing crowns and hypermobility of teeth that affects one in every 100,000 individuals and manifests in both primary and permanent dentitions. Radiographic analysis shows obliteration of all pulp chambers, short, blunted, and malformed roots, and periapical radiolucencies of non-carious teeth. This paper presents three cases demonstrating classic features of type I dentin dysplasia.	0
Microglossia is a congenital birth defect in humans and adversely impacts quality of life. In vertebrates, tongue muscle derives from the cranial mesoderm, whereas tendons and connective tissues in the craniofacial region originate from cranial neural crest (CNC) cells. Loss of transforming growth factor β (TGFβ) type II receptor in CNC cells in mice (Tgfbr2(fl/fl);Wnt1-Cre) causes microglossia due to a failure of cell-cell communication between cranial mesoderm and CNC cells during tongue development. However, it is still unclear how TGFβ signaling in CNC cells regulates the fate of mesoderm-derived myoblasts during tongue development. Here we show that activation of the cytoplasmic and nuclear tyrosine kinase 1 (ABL1) cascade in Tgfbr2(fl/fl);Wnt1-Cre mice results in a failure of CNC-derived cell differentiation followed by a disruption of TGFβ-mediated induction of growth factors and reduction of myogenic cell proliferation and differentiation activities. Among the affected growth factors, the addition of fibroblast growth factor 4 (FGF4) and neutralizing antibody for follistatin (FST; an antagonist of bone morphogenetic protein (BMP)) could most efficiently restore cell proliferation, differentiation, and organization of muscle cells in the tongue of Tgfbr2(fl/fl);Wnt1-Cre mice. Thus, our data indicate that CNC-derived fibroblasts regulate the fate of mesoderm-derived myoblasts through TGFβ-mediated regulation of FGF and BMP signaling during tongue development.	0
Incontinentia pigmenti (IP; Bloch-Sulzberger syndrome) is a rare, genetic syndrome inherited as an X-linked dominant trait. It primarily affects female infants and is lethal in the majority of males during fetal life. The clinical findings include skin lesions, developmental defects, and defects of the eyes, teeth, skeletal system, and central nervous system. Cardiovascular complications of this disease in general, and pulmonary hypertension in particular, are extremely rare. This report describes the case of a 3-year-old girl with IP complicated by pulmonary arterial hypertension. Extensive cardiology workup done to the patient indicates underlying vasculopathy. This report sheds light on the relationship between IP and pulmonary hypertension, reviews the previously reported cases, and compares them with the reported case.	0
Primary mitochondrial disorders are a group of clinically variable and heterogeneous inborn errors of metabolism (IEMs), resulting from defects in cellular energy, and can affect every organ system of the body. Clinical presentations vary and may include symptoms of fatigue, skeletal muscle weakness, exercise intolerance, short stature, failure to thrive, blindness, ptosis and ophthalmoplegia, nystagmus, hearing loss, hypoglycemia, diabetes mellitus, learning difficulties, intellectual disability, seizures, stroke-like episodes, spasticity, dystonia, hypotonia, pain, neuropsychiatric symptoms, gastrointestinal reflux, dysmotility, gastrointestinal pseudo-obstruction, cardiomyopathy, cardiac conduction defects, and other endocrine, renal, cardiac, and liver problems. Most phenotypic manifestations are multi-systemic, with presentations varying at different age of onset and may show great variability within members of the same family; making these truly complex IEMs. Most primary mitochondrial diseases are autosomal recessive (AR); but maternally-inherited [from mitochondrial (mt) DNA], autosomal dominant and X-linked inheritance are also known. Mitochondria are unique energy-generating cellular organelles, geared for survival and contain their own unique genetic coding material, a circular piece of mtDNA about 16,000 base pairs in size. Additional nuclear (n)DNA encoded genes maintain mitochondrial biogenesis by supervising mtDNA replication, repair and synthesis, which is modified during increased energy demands or physiological stress. Despite our growing knowledge of the hundreds of genetic etiologies for this group of disorders, diagnosis can also remain elusive due to unique aspects of mitochondrial genetics. Though cure and FDA-approved therapies currently elude these IEMs, and current suggested therapies which include nutritional supplements and vitamins are of questionable efficacy; multi-center, international clinical trials are in progress for primary mitochondrial disorders.	0
Topical use of immune response modifiers, such as imiquimod, has increased in dermatology. Although its topical use is well tolerated, it may be associated with exacerbations of generalized cutaneous inflammatory diseases, possibly through the systemic circulation of pro-inflammatory cytokines. This report describes a case of development of pityriasis rubra pilaris, a rare erythematous-papulosquamous dermatosis, in a woman aged 60 years during treatment with imiquimod 5% cream for actinic keratosis. It evolved with erythrodermic conditions and palmoplantar keratoderma, presenting progressive clinical resolution after the introduction of methotrexate. The authors emphasize the importance of recognizing possible systemic reactions associated with the topical use of imiquimod.	0
PURPOSE:Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. METHODS:Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. RESULTS:One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the β-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH). CONCLUSION:We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.	0
Background: Leri-Weill dyschondrosteosis (LWD) is a pseudoautosomal form of skeletal dysplasia, characterized by abnormal craniofacial phenotype, short stature, and mesomelia of the upper and lower limbs. Methods: We describe two female patients with LWD. Their prime clinical complaints were severe bouts of migraine and antalgic gait. Results: Interestingly, via a 3D reconstruction CT scan we encountered several major anomalies. Notable features of craniosynostosis through premature fusion of the squamosal sutures and partial closure of the coronal sutures were the reason behind the development of abnormal craniofacial contour. A 3D reconstruction CT scan showed apparent bulging of the clavarium through the partially synostosed coronal and totally synostosed squamosal sutures. Additional deformities include deficient number of ribs (10 ribs on both sides), defective ossification of the ischium and dysplasia of the iliac-ischial junction, and coxa valga have been noted. Conclusions: The constellation of observed deformities can be considered as a novel features associated with LWD.	0
Opitz and Kaveggia [Opitz and Kaveggia (1974); Z Kinderheilkd 117:1-18] reported on a family of five affected males with distinctive facial appearance, mental retardation, macrocephaly, imperforate anus, and hypotonia. Risheg et al. [Risheg et al. (2007); Nature Genetics 39:451-453] identified an identical mutation (p.R961W) in MED12 in six families with Opitz-Kaveggia syndrome, including a surviving affected man from the original family reported in 1974. The previously described behavior phenotype of hyperactivity, affability, and excessive talkativeness is very frequent in young boys with FG syndrome, along with socially oriented, attention-seeking behaviors. We present case studies of five adult males who were previously published with the clinical diagnosis of FG syndrome and then subsequently proven by Risheg et al. [Risheg et al. (2007); Nature Genetics 39:451-453] to have the recurrent p.R961W mutation. These individuals had episodic and longstanding behavior patterns, sometimes aggressive or self-abusing, that occurred more frequently in puberty and early adulthood. We try to describe the triggers for these behaviors, indicate how these behaviors change with advancing age, and suggest specific recommendations and interventional strategies based on the clinical histories of affected adolescent males with FG syndrome [Graham et al., 2008; Clark et al., 2009]. Young men who exhibit these behaviors may benefit from a careful examination to detect medical problems, use of mood stabilizers if needed, and/or behavioral intervention. The transition to a community living situation can be challenging without careful planning and timely behavioral intervention. They remain impulsive and can have aggressive outbursts when making the transition to adult life, but these challenges can be managed, as demonstrated by these clinical histories.	0
Background:Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome with variable clinical phenotype and complex molecular aetiology. It is mainly caused by dysregulation of the chromosome 11p15 imprinted region, which results in overgrowth in multiple tissues, often in a mosaic manner. Case presentation:A large-for-gestational-age infant without any other somatic features of BWS presented with medically refractory hyperinsulinism (HI) requiring 80% pancreatectomy. Next generation sequencing with congenital HI sequencing panel identified a pathogenic ABCC8:c.1792C > T (p.Arg598Ter) variant of paternal origin, suggestive of focal HI. However, pancreatic histology revealed atypical findings of coalescing nests and trabeculae of adenomatosis scattered with islets with isolated enlarged, hyperchromatic nuclei scattered throughout the pancreas. Methylation analysis, SNP-based chromosomal microarray and short tandem repeat markers analysis revealed mosaic segmental paternal uniparental disomy (UPD) 11p15.5-p15.1 in the pancreatic tissue, but not the peripheral blood, suggestive of BWS/BW-spectrum HI. Conclusions:This case highlights the importance of integrating the clinical presentation and subsequent clinical course, together with radiological, genetic and histological findings in the definitive diagnosis of this rare yet clinically important entity. In addition, this is the first report that demonstrated the level of paternal inherited c.1792 T pathogenic variant in the pancreatic tissue being directly correlated to the mosaic level of pUPD.	0
Background:Pulmonary Alveolar Microlithiasis (PAM) is an uncommon, gradually progressive and eventually fatal hereditary disease that affects young population. Familial cases account for up to 50% of reported cases. There are few described cases of extrapulmonary manifestations of PAM and rare reports of cardiac involvement. Case report:A 45-year-old male patient presented to our center with progressive shortness of breath and dry cough. On physical examination, he was tachypneic and chest examination revealed diminished breath sounds with bilateral early inspiratory crackles. Further workup revealed the diagnosis of PAM. Echocardiography revealed calcifications covering the tricuspid valve with elevated right ventricular systolic pressure. He reported having two sisters with similar illnesses and chest radiographic abnormalities, one died at the age of 38 years from respiratory failure and the other is 42-year-old and still alive and was diagnosed with PAM. Another 35 member of his family were diagnosed with PAM. Unfortunately, few days after discharge, he arrested at home. Conclusions:Recently, type-II sodium/phosphate co-transporter has been identified in a human aortic valve. Studies have suggested penetrance of mutations of SLC34A2 gene might explain such variability of pulmonary and extrapulmonary involvement. Our case reports a familial cluster of PAM, and the first case of concomitant tricuspid calcification. This finding might be a useful in the investigation for a future genetic targeted therapy.	0
Since December 2019, a series of highly infectious cases of unexplained pneumonia have been discovered in Wuhan, Hubei Province, which have been confirmed as '2019 corona virus disease' caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 virus can invade many human systems including the lungs. Patients with central nervous system involvement may show a series of neurological symptoms, which is easy to be misdiagnosed and neglected, thereby increasing the risk of SARS-CoV-2 transmission. Hereditary ataxia is a large group of neurodegenerative diseases with great clinical and genetic heterogeneity and high mortality and disability. In view of the seriousness of the COVID-19 epidemic, a series of prevention and control measures adopted by the government have restricted the follow-up, diagnosis and treatment of patients by the hospitals, which has a great impact on their mental and physical health. In order to standardize the management of patients during the prevention and control of COVID-19 epidemic, the Specialized Committee of Neurogenetics of the Neurophysician Branch of Chinese Medical Doctor Association has formulated this consensus, with an aim to help patients to overcome the difficulties and pass the epidemic prevention period safely.	0
To assess whether antithrombotic prophylaxis with low-molecular-weight heparin effectively prevents recurrence of late pregnancy complications, 135 women with previous history of preeclampsia, hemolytic anemia, elevated liver enzymes and low platelet count syndrome, intrauterine fetal death, fetal growth restriction, or placental abruption who had been referred within the 12th gestational week were randomized to medical surveillance alone (n = 68) or combined to open-label nadroparin (3800 IU daily subcutaneous injections) treatment (n = 67) in the setting of a randomized, parallel-group, superiority trial, run in Italy from April 2007 to April 2010. Primary outcome was a composite end point of late-pregnancy complications. Analysis was by intention to treat. The study was stopped for futility at the time of the first planned interim analysis. Among the 128 women eventually available for final analyses, 13 of the 63 (21%) randomized to nadroparin compared with 12 of the 65 (18%) on medical surveillance alone progressed to the primary end point. The absolute event risk difference between treatment arms (2.2; -1.6 to 16.0) was not statistically significant (P = .76). Thus, nadroparin did not prevent late-pregnancy complications in women at risk of recurrence. This finding challenges the role of antithrombotic prophylaxis with low-molecular-weight heparin in the prevention of recurrent late pregnancy complications The trial was registered at http://ricerca-clinica.agenziafarmaco.it as EudraCT 2006-004205-26.	0
Background:Primary orbital lymphomas are a rare subset of tumors constituting 1-2% of non-Hodgkin's lymphoma. They are mostly indolent B-cell lymphomas presenting with gradual progressive proptosis, decreased visual acuity, restricted ocular mobility, and diplopia. The role of surgery is mainly for obtaining a biopsy. Most of these tumors require multimodality treatment including chemotherapy, radiation, or both, which have major role. Case Description:We report one such case of marginal zone lymphoma of the orbit in a female with significant proptosis who was treated with multimodality treatment, including surgical excision as a major treatment modality. Decompression of symptomatic proptosis was followed by chemotherapy and radiation. Conclusion:Primary orbital lymphoma is a rare clinical entity with diverse clinical outcomes. It can be successfully managed with surgical excision for decompression of mechanical proptosis followed by chemotherapy, radiation, or both.	0
A 7 1/2-year-old girl had the clinical features of the rigid spine syndrome of Dubowitz. Muscle biopsy showed a predominance of type 2 fibres with neither myopathic features nor an increase in connective tissue. In addition, she had a hypertrophic cardiomyopathy with which she presented in heart failure and from which she died suddenly one month later. The association of rigid spine syndrome with cardiomyopathy has not been reported previously.	0
We report a novel ALAS2 gene mutation c.1315A>G (p.Lys439Glu) identified in a family, which caused evidently different hematologic phenotypes. The proband was a 17-year-old man with severe microcytic hypochromic anemia, excessive ring sideroblasts in the bone marrow, and iron overload. A hemizygous ALAS2 mutation in exon 9, c.1315A>G (p.Lys439Glu), was identified through sequence analysis. We assume that this amino acid substitution affects the enzymatic activity of ALAS2 by affecting its interaction with the cofactor pyridoxal 5'-phosphate, since the patient was responsive to pyridoxine treatment. This novel mutation likely accounts for variable hematologic phenotypes in the family of this patient: his 15-year-old hemizygous brother was asymptomatic, while his heterozygous mother was mildly anemic.	0
Mitochondrial diseases are a diverse group of inherited and acquired disorders that result in inadequate energy production. They can be caused by inheritable genetic mutations, acquired somatic mutations, and exposure to toxins (including some prescription medications). Normal mitochondrial physiology is responsible, in part, for the aging process itself, as free radical production within the mitochondria results in a lifetime burden of oxidative damage to DNA, especially the mitochondrial DNA that, in turn, replicate the mutational burden in future copies of itself, and lipid membranes. Primary mitochondrial diseases are those caused by mutations in genes that encode for mitochondrial structural and enzymatic proteins, and those proteins required for mitochondrial assembly and maintenance. A number of common adult maladies are associated with defective mitochondrial energy production and function, including diabetes, obesity, hyperthyroidism, hypothyroidism, and hyperlipidemia. Mitochondrial dysfunction has been demonstrated in many neurodegenerative disorders, including Alzheimer's disease, Parkinson disease, amyotrophic lateral sclerosis, and some cancers. Polymorphisms in mitochondrial DNA have been linked to disease susceptibility, including death from sepsis and survival after head injury. There is considerable overlap in symptoms caused by primary mitochondrial diseases and those illnesses that affect mitochondrial function, but are not caused by primary mutations, as well as disorders that mimic mitochondrial diseases, but are caused by other identified mutations. Evaluation of these disorders is complex, expensive, and not without false-negative and false-positive results that can mislead the physician. Most of the common heritable mitochondrial disorders have been well-described in the literature, but can be overlooked by many clinicians if they are uneducated about these disorders. In general, the evaluation of the classic mitochondrial disorders has become straightforward if the clinician recognized the phenotype and orders appropriate confirmatory testing. However, the majority of patients referred for a mitochondrial evaluation do not have a clear presentation that allows for rapid identification and testing. This article provides introductory comments on mitochondrial structure, physiology, and genetics, but will focus on the presentation and evaluation of adults with mitochondrial symptoms, but who may not have a primary mitochondrial disease.	0
A 30-year-old man was admitted to Osaka University Hospital for the treatment of gastric varices and assessment of indication for liver transplant. When he was 6 years old, liver dysfunction was pointed out and diagnosed as chronic inactive hepatitis by liver biopsy. At 13 years of age, the second liver biopsy proved congenital hepatic fibrosis (CHF). The third liver biopsy was performed when he was 30 years old, and the progression of hepatic fibrosis was confirmed. Besides CHF, we recognized oligophrenia, cerebellar ataxia, hypoplasia of cerebellar vermis and coloboma, leading to the diagnosis of COACH syndrome. COACH syndrome is quite rare, and our case is especially valuable because he was diagnosed as an adult case and the progression of hepatic fibrosis could be followed through several liver biopsies. We should be aware of COACH syndrome in mind when we encounter CHF patients.	0
To adjust cell growth and metabolism according to environmental conditions, the conserved TORC1 signaling network controls autophagy, protein synthesis, and turnover. Here, we dissected the signals controlling phosphorylation and activity of the TORC1-effector kinase Npr1, involved in tuning the plasma membrane permeability to nitrogen sources. By evaluating a role of pH as a signal, we show that, although a transient cytosolic acidification accompanies nitrogen source entry and is correlated to a rapid TORC1-dependent phosphorylation of Npr1, a pH drop is not a prerequisite for TORC1 activation. We show that the Gtr1/Gtr2 and Pib2 regulators of TORC1 both independently and differently contribute to regulate Npr1 phosphorylation and activity. Finally, our data reveal that Npr1 mediates nitrogen-dependent phosphorylation of Pib2, as well as a Pib2-dependent inhibition of TORC1. This work highlights a feedback control loop likely enabling efficient downregulation and faster re-activation of TORC1 in response to a novel stimulating signal.	0
Filippi syndrome is an autosomal recessive condition characterized by variable soft tissue syndactyly of the fingers and toes, microcephaly, pre- and postnatal growth retardation, mildly abnormal craniofacial appearance, and mental retardation. We report on a child with Filippi syndrome who shows syndactyly of fingers, severe postnatal growth retardation, postnatal microcephaly, and moderate to severe mental retardation. In addition, there is a mildly dysmorphic face along with ocular and a number of dental abnormalities. Radiologically, hands demonstrate bony syndactyly, without any hypoplasia of bones. This phenotype can easily be classified in the group of craniodigital syndromes, but it is difficult to make a more clearly defined diagnosis, based on other minor anomalies, because of the presence of overlapping features. On the basis of various pathognomic features, we conclude that our patient could be an additional case of Filippi syndrome. Moreover, newly recognised features in this patient may be due to variability in phenotypic expression.	0
Hemorrhagic shock and encephalopathy syndrome (HSES) is characterized by abrupt onset of hyperpyrexia, encephalopathy(seizure and coma), shock, diarrhea, disseminated intravascular coagulation, and renal and hepatic failure. HSES occurs in infants and prognosis is quite poor; early death in 35-82%, severe neurological squeal in 20-30%, and normal in only 10-20%. The underlying pathogenesis is still unknown. Although previous reports revealed that lowered plasma alpha1-antitrypsin level or elevated cytokine levels including IL-6 and TNF-alpha, the results are controversial.	0
Chromosomal microarray (CMA) is now recommended as first tier for the evaluation in individuals with unexplained neurodevelopmental disorders (ND). However, in developing countries such as Brazil, classical cytogenetic tests are still the most used in clinical practice, as reflected by the scarcity of publications of microarray investigation in larger cohorts. This is a retrospective study which analyses the reading files of CMA and available clinical data from 420 patients from the south of Brazil, mostly children, with neurodevelopmental disorders requested by medical geneticists and neurologists for diagnostic purpose. Previous karyotyping was reported for 138 and includes 17 with abnormal results. The platforms used for CMA were CYTOSCAN 750K (75%) and CYTOSCAN HD (25%). The sex ratio of the patients was 1.625 males :1 female and the mean age was 9.5 years. A total of 96 pathogenic copy number variations (CNVs), 58 deletions and 38 duplications, were found in 18% of the patients and in all chromosomes, except chromosome 11. For 12% of the patients only variants of uncertain clinical significance were found. No clinically relevant CNV was found in 70%. The main referrals for chromosomal microarrays (CMA) were developmental delay (DD), intellectual disability (ID), facial dysmorphism and autism spectrum disorder (ASD). DD/ID were present in 80%, facial dysmorphism in 52% and ASD in 32%. Some phenotypes in this population could be predictive of a higher probability to carry a pathogenic CNV, as follows: dysmorphic facial features (p-value = < 0.0001, OR = 0.32), obesity (p-value = 0.006, OR = 0.20), short stature (p-value = 0.032, OR = 0.44), genitourinary anomalies (p-value = 0.032, OR = 0.63) and ASD (p-value = 0.039, OR = 1.94). The diagnostic rate for CMA in this study was 18%. We present the largest report of CMA data in a cohort with ND in Brazil. We characterize the rare CNVs found together with the main phenotypes presented by each patient, list phenotypes which could predict a higher diagnostic probability by CMA in patients with a neurodevelopmental disorder and show how CMA and classical karyotyping results are complementary.	0
Trichoepitheliomas are benign skin tumors with follicular differentiation that present most commonly as solitary lesions. They can also present as multiple centrofacial papules due to several mutations in the CYLD gene. Multiple unilateral trichoepitheliomas in a linear or dermatomal distribution may rarely be seen. Herein, we report a case of multiple unilateral trichoepitheliomas on the face of a healthy 34-year-old woman of Caucasian origin.	0
The purpose of this study was to investigate recent epidemiological trends of myasthenia gravis (MG) in Austria.We used the national hospital discharge register, which records the discharge diagnoses of all inpatient stays in Austria to calculate the yearly inpatient prevalence of MG from 1992 to 2009 (main or secondary diagnosis of MG). The population prevalence was indirectly estimated. The temporal and geographical variability of the inpatient prevalence was correlated with the number of practicing neurologists.The inpatient prevalence of 2009 was calculated as 8.0 and the population prevalence as 15.69 (95 % CI 13.16-19.42) per 100,000. We observed a 2.2 fold increase in the inpatient prevalence between 1992 and 2009, which was mainly due to a rise in the number of older patients (³ 50 years). Partly this could be accounted for by an ageing of the population as a whole and a rise in the age of hospitalised patients. However, after adjusting for demographic factors an unexplained average yearly rise of 3.7-3.9 % remained. We found a significant spatial and temporal correlation of MG inpatient prevalence rates with the number of practicing neurologists, which increased over the same period.The results from this study support the notion that the prevalence rate of MG in Austria is rising and near the higher end of the wide range discussed in the literature. Our data argue for the importance of specialist neurological care for the diagnosis of this disease.	1
A 41-year-old woman presented with short-stepped gait from 20 years old and with repeated loss of consciousness from 21 years old. She had a deep cerebral white matter lesion on brain MRI at 34 years of age, but she did not reach a definitive diagnosis. At the age of 41, the gait disorder rapidly worsened after fall and fall-related head trauma. She had fixation nystagmus, dysphonia, speech disorder and exaggerated tendon reflexes. Her bilateral plantar reflex was positive, and she was not able to walk by herself. The brain and cervical MRI showed atrophy of the medulla and upper spinal cord and a deep cerebral white matter lesion. As these imaging features were suggestive of Alexander disease (AxD), we sequenced the GFAP gene. As a result, we identified a heterozygous p.R79H (c.250 G>A) missense mutation of the GFAP gene in the patient. This case suggests that loss of consciousness may be caused by autonomic disorder due to orthostatic hypotension and reflex syncope (vasovagal syncope), psychogenic non-epileptic seizures (PNES) by mental and physical stress. It is important to consider the pathophysiology and management of Alexander disease, in which the progression of gait disorder caused by pyramidal tract disorder is rapidly exacerbated by fall and head injury.	0
BACKGROUND:The development of the face occurs during the early days of intrauterine life by the formation of facial processes from the first Pharyngeal arch. Derangement in these well-organized fusion events results in Orofacial clefts (OFC). Van der Woude syndrome (VWS) is one of the most common causes of syndromic cleft lip and/or palate accounting for 2% of all cases. Mutations in the IRF6 gene account for 70% of cases with the majority of these mutations located in the DNA-binding (exon 3, 4) or protein-binding domains (exon 7-9). The current study was designed to update the list of IRF6 variants reported for VWS by compiling all the published mutations from 2013 to date as well as including the previously unreported VWS cases from Africa and Puerto Rico. METHODS:We used PubMed with the search terms; "Van der Woude syndrome," "Popliteal pterygium syndrome," "IRF6," and "Orofacial cleft" to identify eligible studies. We compiled the CADD score for all the mutations to determine the percentage of deleterious variants. RESULTS:Twenty-one new mutations were identified from nine papers. The majority of these mutations were in exon 4. Mutations in exon 3 and 4 had CADD scores between 20 and 30 and mutations in exon 7-9 had CADD scores between 30 and 40. The presence of higher CADD scores in the protein-binding domain (exon 7-9) further confirms the crucial role played by this domain in the function of IRF6. In the new cases, we identified five IRF6 mutations, three novel missense mutations (p.Phe36Tyr, p.Lys109Thr, and p.Gln438Leu), and two previously reported nonsense mutations (p.Ser424*and p.Arg250*). CONCLUSION:Mutations in the protein and DNA-binding domains of IRF6 ranked among the top 0.1% and 1% most deleterious genetic mutations, respectively. Overall, these findings expand the range of VWS mutations and are important for diagnostic and counseling purposes.	0
We report a fetus with heterogeneous colonic content, an isolated sonographic prenatal sign of lysinuric protein intolerance, a very rare metabolic disease. Familial genetic enquiries confirmed heterozygote mutation in the implicated gene in parents. The prenatal diagnosis led to neonatal dietary adaptation and avoided acute complications.	0
Objectives:To observe and analyze the parameters of the sacral reflex and pudendal nerve somatosensory evoked potential (SSEP) in patients with multiple system atrophy (MSA) with respect to factors such as age, disease course, and subtype and provide evidence for the clinical diagnosis of MSA. Materials and Methods:A total of 51 MSA patients and 30 healthy controls were selected from the First Affiliated Hospital of Wenzhou Medical University from May 2013 to November 2015. Electrophysiological sacral reflex detection and SSEP detection were performed using the Keypoint EMG/EP system. The extraction rate, latency, and amplitude of the sacral reflex and SSEP in the MSA group and control group were compared. Results:The sacral reflex latency and amplitude in patients with MSA were statistically different from those of the healthy controls. The latency of sacral reflex increases with the prolongation of the disease course, and the amplitude and initiation rate decrease with the prolongation of the disease course. There was no significant difference in sacral reflex latency and amplitude between MSA patients of different ages and subtypes. There was no significant difference in the latency or amplitude of SSEP between the MSA group and healthy control group. Conclusions:The latency of sacral reflex increases with the prolongation of the disease course, and the amplitude and extraction rate decrease with the prolongation of the disease course. There was no significant difference in the parameters of sacral reflex between young MSA patients and elderly patients. And there was no statistically significant difference between MSA-P subtypes and MSA-C subtypes. This trial is registered with ISRCTNCR2009041.	0
BACKGROUND:Methanol is highly toxic to human beings and naturally exists in some beverages. Having access to an easy and cheap method for its determination is of great importance to increase the safety of use of these beverages. Our main aim is to evaluate methanol concentration of some alcoholic beverages in Iran black market and compare it with the European and US standards. Also, we evaluated the efficacy of a newly designed and produced chemical kit in determining the risk of methanol toxicity by drinking of such samples compared to gas chromatography method. METHODS:Methanol content of suspected alcoholic beverages referred to forensic toxicology laboratory, Guilan province, Iran was measured using gas chromatography and a recently designed kit based on modified colorimetric chromotropic acid method. RESULTS:Of 1221 samples, 145 (11.9%) had no ethanol content, while in three samples (0.25%), methanol was high enough (700,000; 870,000; 920,000 mg/L) to cause severe methanol toxicity. Median [IQR] ethanol content of the suspected samples was 9% [3.7, 32.75]. Methanol was detected in 128 (10.48%) samples using gas chromatography method and 160 samples (13.1%) with designed kit with 100% sensitivity, 97.07% specificity, and 100% negative-predictive-value. CONCLUSIONS:Alcoholic beverages produced in local black market in Iran are not safe at all. The application of the new method is practical, rapid, easy, and accurate to evaluate the risk of methanol toxicity in suspected alcoholic drinks.	0
Background:No clear guidelines exist for the management of phlegmasia cerulea dolens. This case report shows how a hybrid approach might be successful. It also shows how rare pathologies can combine to create a life- and limb-threatening condition. Case Presentation. A 75-year-old man, known for nephrotic syndrome currently under investigation, presented to the emergency department with a 24-hour history of left leg swelling followed by intense pain. The left lower limb showed a phlegmasia cerulean dolens. Renal function, coagulation profile, and inflammatory parameters were normal; D-Dimers 5,6 mg/L. The CT scan showed juxtarenal thrombosis of the hypoplastic IVC, involving both renal veins, reaching the left iliac-femoral-popliteal axis, with collateralization to the pelvic and mesenteric veins, associated with bilateral segmental pulmonary embolisms. A suspected left breast nodule was also found. Intravenous heparin was immediately administered, and urgent hybrid procedure with surgical thrombectomy and venous angiography and thromboaspiration, liberating the iliolumbar collaterals, was performed. A lateral leg fasciotomy was mandatory due to the phlegmasia cerulea. Postoperative Doppler US showed a good venous compressibility of the left leg. Thrombophilia screening was negative. The breast nodule was biopsied showing an invasive ductal carcinoma. The patient was discharged with oral rivaroxaban and indication for left mastectomy and oncological therapy with aromatase inhibitors. Conclusion:This case highlights the dramatic consequence of different risk factors for venous thromboembolism as cancer and nephrotic syndrome in a patient with hypoplasia of the inferior cava vein. Venous thromboaspiration has been used in order to timely recanalize important collaterals. Phlegmasia cerulea dolens was resolved after the procedure and lateral calf fasciotomy. Further evidence is needed to clearly define the role of venous thromboaspiration in the treatment of complex proximal deep venous thrombosis of the lower extremity.	0
BACKGROUND:Segmental progeroid syndromes are a heterogeneous group of rare and often severe genetic disorders that have been studied since the twentieth century. These progeroid syndromes are defined as segmental because only some of the features observed during natural aging are accelerated. METHODS:Since 2015, the Molecular Genetics Laboratory in Marseille La Timone Hospital proposes molecular diagnosis of premature aging syndromes including laminopathies and related disorders upon NGS sequencing of a panel of 82 genes involved in these syndromes. We analyzed the results obtained in 4 years on 66 patients issued from France and abroad. RESULTS:Globally, pathogenic or likely pathogenic variants (ACMG class 5 or 4) were identified in about 1/4 of the cases; among these, 9 pathogenic variants were novel. On the other hand, the diagnostic yield of our panel was over 60% when the patients were addressed upon a nosologically specific clinical suspicion, excepted for connective tissue disorders, for which clinical diagnosis may be more challenging. Prenatal testing was proposed to 3 families. We additionally detected 16 variants of uncertain significance and reclassified 3 of them as benign upon segregation analysis in first degree relatives. CONCLUSIONS:High throughput sequencing using the Laminopathies/ Premature Aging disorders panel allowed molecular diagnosis of rare disorders associated with premature aging features and genetic counseling for families, representing an interesting first-level analysis before whole genome sequencing may be proposed, as a future second step, by the National high throughput sequencing platforms ("Medicine France Genomics 2025" Plan), in families without molecular diagnosis.	0
We herein illustrate a case of an adult male presenting with silvery hair and generalized guttate hypopigmented macules on a background of diffuse cutaneous hyperpigmentation, since birth. Histopathology showed enlarged melanocytes with abundant melanin. Based on these clinicopathological features, differential diagnoses considered were Griscelli syndrome 3 (GS3) and familial giagantic melanocytosis. GS3 belongs to a group of inherited autosomal recessive (AR) disorders of partial albinism, known as silvery hair syndromes, while familial gigantic melanocytosis (FGM) is a putative disorder of dyschromia with silvery hairs. A pertinent literature search revealed hyperpigmentation or dyschromatosis as a rare manifestation of silvery hair syndromes, especially in dark-skin populations. A comparative analysis of previously reported cases depicted close morphological similarities between GS3 and FGM. We discuss the uncertainty pertaining to cases described in literature as FGM, to be truly representative of a distinctive entity, or merely a morphological variation of GS3.	0
We present an analysis of two first historically documented limb body wall complex (LBWC) cases and our own contemporary perinatal autopsy series of this rare complex. So far it was supposed that the first case of this complex was reported in 1685 by Paul Portal. Studying the Joachim Oelhaf's autopsy report from 1613 with attached engraving showing the neonate with multiple birth defects led our research team to a conclusion that it was genuinely the first description of LBWC in the medical literature so far. We compared the Oelhaf's case from 1613 and the Portal's autopsy report from 1685 with our series of LBWC cases dissected in the Medical University of Gdansk between 1999 and 2011. Reviewing 1100 autopsy reports performed we encountered 9 cases of this unique complex. The analysis was supported by the literature review.	0
Hereditary spastic paraplegias are heterogeneous disorders with diversified clinical manifestations, and genetic testing is important for the diagnosis and typing of hereditary spastic paraplegias.Gene panel sequencing containing 55 hereditary spastic paraplegias-related genes was performed to screen the pathogenic genes for hereditary spastic paraplegias. Sanger sequencing was adopted to validate if the family member carried the same pathogenic gene as the proband.Fifteen out of 53 patients carried mutation(s) in the screened hereditary spastic paraplegias-related genes. Among the 23 identified mutations, only one mutation had been previously reported as a pathogenic mutation. In the pedigree of case 6, the proband, his mother and uncle all carried the same novel deletion mutation (c.1459delA) at SPAST gene. Based on the pedigree, the disease was inherited in an AD pattern. In the pedigree of case 53, the family disease may be in an X-linked recessive inheritance pattern. The proband (case 53) carried two novel mutations in ALT1 gene and L1CAM gene (c.2511C>A), respectively. The L1CAM gene is the causative gene for the SPG1 X-linked recessive-hereditary spastic paraplegias.Our data confirm the genetic heterogeneity of hereditary spastic paraplegias, and SPG4/SPAST were the most frequent forms. The pathogenicity of the novel mutations is worth to be further investigated.	0
Homozygous and compound heterozygous mutations in GNB5 gene have been associated with a wide spectrum of clinical presentations, ranging from neurodevelopmental issues with or without cardiac arrhythmia (LADCI) to severe developmental delay with epileptic encephalopathy, retinal dystrophy, and heart rhythm abnormalities (IDDCA). While missense or missense/non-sense mutations usually lead to milder form, the biallelic loss of function of GNB5 gene causes the severe multisystemic IDDCA phenotype. So far, only 27 patients have been described with GNB5-associated disease. We report the first case of a patient carrying a homozygous 15q21.2 microdeletion, encompassing GNB5 and the two contiguous genes BCL2L10 and MYO5C. The clinical features of the child are consistent with the severe IDDCA phenotype, thus confirming the GNB5 loss-of-function mechanism in determining such presentation of the disease.	0
Pulmonary alveolar microlithiasis (PAM) is a rare disease caused by a mutation in the SLC34A2 gene encoding the type IIb sodium phosphate cotransporter in alveolar type II cells. This results in the formation and accumulation of calcium phosphates crystals in the alveoli. Early in the disease, most patients are asymptomatic or might experience mild symptoms. However, in some patients, PAM can progress resulting in pulmonary fibrosis, cor pulmonale, and respiratory failure. We report the case of a 33-year-old Omani male who was referred to our institute with a history of fever and shortness of breath. A chest radiograph revealed bilateral dense consolidation. Chest computed tomography showed bilateral dense interlobular thickening and extensive consolidations with a lower lung predominance. Our findings were highly suggestive of PAM. The diagnosis was confirmed by bronchoalveolar lavage.	0
Smith-Lemli-Opitz syndrome (SLOS) is a congenital multiple anomaly/intellectual disability syndrome caused by a deficiency of cholesterol synthesis resulting from a deficiency of 7-dehydrocholesterol (7DHC) reductase encoded by DHCR7. SLOS is inherited in an autosomal recessive pattern. It is characterized by prenatal and postnatal growth retardation, microcephaly, a variable degree of intellectual disability that encompasses normal intelligence to severe intellectual deficiency, and multiple major and minor malformations. External malformations include distinctive facial features, cleft palate, postaxial polydactyly, 2-3 syndactyly of the toes, and underdeveloped external genitalia in males, while internal anomalies may affect every organ system. The clinical spectrum is wide, and rare individuals have been described with normal development and only minor malformations. The clinical diagnosis of SLOS is confirmed by demonstrating an abnormally elevated concentration of the cholesterol precursor, 7DHC, in serum or other tissues, or by the presence of two DHCR7 mutations. The enzymatic deficiency results in decreased cholesterol and increased 7DHC levels, both during embryonic development and after birth. The malformations found in SLOS may result from decreased cholesterol, increased 7DHC or a combination of these two factors. This review discusses the physical and behavioral phenotype of SLOS, the diagnostic approaches, the natural history from the prenatal period to adulthood, and current understanding of the pathophysiology of SLOS.	1
Considerable progress has been made in the delineation of the genetic skeletal dysplasias, a heterogeneous group of disorders, that consist of over 80 distinct conditions. Morphologic studies have added a further dimension to the delineation of these conditions, their diagnosis, and the investigation of their pathogenetic mechanisms. In certain diseases, the morphologic alterations are characteristic and pathognomonic. In others only nonspecific alterations are observed, whereas in still other disorders growth-plate structure is essentially normal. Histologic, histochemical, and electronmicroscopic studies of growth-plate cartilage have provided new insights into the complexity of morphogenetic events in normal growth through the demonstration of morphologic defects in the genetic disorders of skeletal growth. As yet, very little is known of the biochemical abnormalities underlying the morphologic abnormalities. However, the great variety of morphologic findings points to a number of different pathogenetic defects in the synthesis, release, and assembly of connective tissue macromolecules and in the cells involved in growth-plate metabolism.	0
Type X collagen is a homotrimer of alpha 1 (X) chains encoded by the COL10A1 gene. It is synthesised specifically and transiently by hypertrophic chondrocytes at sites of endochondral ossification. Point mutations and deletions in the region of the COL10A1 gene encoding the alpha 1 (X) carboxyl-terminal (NC1) domain have previously been identified in subjects with metaphyseal chondrodysplasia type Schmid (MCDS). To determine whether mutations in other regions of the gene caused MCDS or comparable phenotypes, we used PCR followed by SSCP to analyse the coding and promoter regions of the COL10A1 gene, as well as the intron/exon boundaries of five further subjects with MCDS, one subject with atypical MCDS, and nine subjects with other forms of metaphyseal chondrodysplasia. Using this approach, three of the subjects with MCDS were found to be heterozygous for the deletions 1864delACTT, 1956delT, and 2029delAC in the region of COL10A1 encoding the NC1 domain. These deletions would lead to alterations in the reading frame, premature stop codons, and the translation of truncated protein products. A fourth subject with MCDS was found to be heterozygous for a single base pair transition, T1894C, that would lead to the substitution of the amino acid residue serine at position 600 by proline within the NC1 domain. We did not, however, detect mutations in the coding and non-coding regions of COL10A1 in one subject with MCDS, the subject with atypical MCDS, and in the nine subjects with other forms of metaphyseal chondrodysplasia. We propose that the nature and distribution of mutations within the NC1 domain of COL10A1 causing MCDS argues against the hypothesis that the phenotype arises simply through haploinsufficiency but that an, as yet, unexplained mutation mechanism underlies this phenotype.	0
As a highly aggressive pediatric brainstem tumor, diffuse intrinsic pontine glioma (DIPG) accounts for 10% to 20% of childhood brain tumors. The survival rate for DIPG remains very low, with a median survival time as less than one year even under radiotherapy, the current standard treatment. Moreover, over than 250 clinical trials have failed when trying to improve the survival compared to radiotherapy. The sphingolipid metabolism and related signaling pathways have been found closely related to cancer cell survival; however, the sphingolipid metabolism targeted therapies have never been investigated in DIPG. In the current study, the anti-DIPG activity of ABC294640, the only first-in-class orally available Sphingosine kinase (SphK) inhibitor was explored. Treatment with ABC294640 significantly repressed DIPG cell growth by inducing intracellular pro-apoptotic ceramides production and cell apoptosis. We also profiled ABC294640-induced changes in gene expression within DIPG cells and identified many new genes tightly controlled by sphingolipid metabolism, such as IFITM1 and KAL1. These genes are required for DIPG cell survival and display clinical relevance in DIPG patients' samples. Together, our findings in this study indicate that targeting sphingolipid metabolism may represent a promising strategy to improve DIPG treatment.	0
We report a rare case of osteoglophonic dysplasia affecting father and daughter. Osteoglophonic dysplasia is a very rare skeletal dysplasia with craniosynostosis, multiple radiolucencies of bone and clinical anodontia. It is an autosomal dominant disorder characterised by short stature. The affected children have normal intelligence. Close association with missense mutation of fibroblast growth factor receptor-1 has been reported. Life expectancy depends on the degree of cranial malformation. In previous reports, bone defects usually resolved by adulthood, but multiple tooth impaction may cause aesthetic and masticatory problems. Cytogenetic studies and routine laboratory tests were all within normal limits.	0
The term adrenocorticotropin (ACTH) resistance syndrome is used for a group of rare inherited disorders, which present with primary adrenal insufficiency during childhood. The syndrome includes two disorders inherited in an autosomal recessive fashion - familial glucocorticoid deficiency and triple A syndrome. Herein, we report our experience of three cases with ACTH resistance syndrome, highlighting the approach to diagnosis and management in such patients.	0
Haemophilus influenzae typically causes illness and infection in the paediatric population. We report a case of a 53-year-old man who developed invasive non-typeable H. influenzae infection associated with purpura fulminans and multiorgan failure. On review of the literature, this is the first reported case of non-typeable H. influenzae causing purpura fulminans. The patient was treated with intravenous ceftriaxone 2 g/day and was eventually discharged from the hospital almost 2 months after admission. We discuss the role that infection/sepsis plays in disturbances to the coagulation cascade leading to purpura fulminans and the virulence factors that make non-typeable H. influenzae unique. Finally, we review other cases of H. influenzae associated with purpura fulminans and discuss the similarities with our case.	0
Objectives: Barth syndrome is an ultra-rare, infantile-onset, X-linked recessive mitochondrial disorder, primarily affecting males, due to variants in TAZ encoding for the cardiolipin transacylase tafazzin. This review aimed to summarize and discuss recent and earlier findings concerning the etiology, pathogenesis, clinical presentation, diagnosis, treatment, and outcome of Barth syndrome. Method: A literature review was undertaken through a MEDLINE search. Results: The phenotype of Barth syndrome is highly variable but most frequently patients present with hypertrophic/dilated/non-compaction cardiomyopathy, fibroelastosis, arrhythmias, neutropenia, mitochondrial myopathy, growth retardation, dysmorphism, cognitive impairment, and other, rarer features. Lactic acid and creatine kinase, and blood and urine organic acids, particularly 3-methylglutaconic acid and monolysocardiolipin, are often elevated. Cardiolipin is decreased. Biochemical investigations may show decreased activity of various respiratory chain complexes. The diagnosis is confirmed by documentation of a causative TAZ variant. Treatment is symptomatic and directed toward treating heart failure, arrhythmias, neutropenia, and mitochondrial myopathy. Conclusions: Although Barth syndrome is still an orphan disease, with fewer than 200 cases described so far, there is extensive ongoing research with regard to its pathomechanism and new therapeutic approaches. Although most of these approaches are still experimental, it can be expected that causative strategies will be developed in the near future.	0
INTRODUCTION:Skeletal dysplasias are a heterogeneous group of disorders comprising of more than 300 entities, many of which manifest in the prenatal period, emphasizing the importance of accurate prenatal diagnosis. Detection of a lethal skeletal dysplasia via prenatal ultrasound is often straightforward. However, establishing the specific diagnosis and detailed evaluation of intracranial anomalies are often challenging. Fetal magnetic resonance imaging (MRI) is superior to ultrasound in the detection of abnormal sulcation pattern, corpus callosal agenesis, and posterior fossa anomalies. Hence, it has the potential of delineating neuroimaging features that may not be fully elucidated by ultrasound. The objective of this article is to describe an unusual case of thanatophoric dysplasia (TD) with dysplastic tectal plate and resultant aqueductal stenosis diagnosed on fetal MRI. To the best of our knowledge, this has never been reported before in the literature. A comprehensive review of literature pertaining to TD-associated CNS abnormalities will also be included. CONCLUSIONS:Our reported case adds to the current limited knowledge of this rare entity and emphasizes the crucial role of fetal MRI in expanding the neuroimaging phenotypes of TD.	0
BACKGROUND:Classic "do not touch" and benign osseous lesions are sometimes detected on 18-F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) studies. These lesions are often referred for biopsy because the physician interpreting the PET/CT may not be familiar with the spectrum of 18F-FDG uptake patterns that these lesions display. AIM:To show that "do not touch" and benign osseous lesions can have increased 18F-FDG uptake above blood-pool on PET/CT; therefore, the CT appearance of these lesions should dictate management rather than the standardized uptake values (SUV). METHODS:This retrospective study evaluated 287 independent patients with 287 classic "do not touch" (benign cystic lesions, insufficiency fractures, bone islands, bone infarcts) or benign osseous lesions (hemangiomas, enchondromas, osteochondromas, fibrous dysplasia, Paget's disease, osteomyelitis) who underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) at a tertiary academic healthcare institution between 01/01/2006 and 12/1/2018. The maximum and mean SUV, and the ratio of the maximum SUV to mean blood pool were calculated. Pearson's correlations between lesion size and maximum SUV were calculated. RESULTS:The ranges of the maximum SUV were as follows: For hemangiomas (0.95-2.99), bone infarcts (0.37-3.44), bone islands (0.26-3.29), enchondromas (0.46-2.69), fibrous dysplasia (0.78-18.63), osteochondromas (1.11-2.56), Paget's disease of bone (0.93-5.65), insufficiency fractures (1.06-12.97) and for osteomyelitis (2.57-12.64). The range of the maximum SUV was lowest for osteochondromas (maximum SUV 2.56) and was highest for fibrous dysplasia (maximum SUV of 18.63). There was at least one lesion that demonstrated greater 18F-FDG avidity than the blood pool amongst each lesion type, with the highest maximum SUV ranging from 9.34 times blood pool mean (osteomyelitis) to 1.42 times blood pool mean (hemangiomas). There was no correlation between the maximum SUV and the lesion size except for enchondromas. Larger enchondromas had higher maximum SUV (r = 0.36, P = 0.02). CONCLUSION:The classic "do not touch" lesions and classic benign lesions can be 18F-FDG avid. The CT appearance of these lesions should dictate clinical management rather than the maximum SUV.	0
Progressive familial intrahepatic cholestasis refers to a collection of rare genetic disorders due to defective mechanisms of bile secretion. Typically divided into three subtypes, PFIC type 1, PFIC type 2, PFIC type 3, the condition is usually diagnosed in the early years of life and often presents with signs and symptoms of intrahepatic cholestasis such as pruritis, dark urine, pale stool, loss of appetite, and fatigue.[1]	0
Background:Spinocerebellar ataxia type 23 (SCA23) is an autosomal dominant cerebellar ataxia caused by pathogenic variants in the prodynorphin gene (PDYN). The frequency of PDYN variants is reportedly very low (~ 0.1%) in several ataxia cohorts screened to date. Case presentations:We found five cases of SCA23 in two families (mean age at onset: 37.8 ± 5.5 years; mean age at examination: 64.2 ± 12.3 years) with a novel PDYN variant (c.644G > A:p.R215H). We identified marked heterogeneity in the clinical features in Family 1: the proband showed clinical and neuroimaging features suggestive of multiple system atrophy with predominant parkinsonism (MSA-P). Conversely, the proband's mother with the PDYN p.R215H variant had no subjective symptoms; she had not come to medical attention before our survey, although she showed apparent cerebellar atrophy on brain magnetic resonance imaging (MRI). The other two patients in Family 1 and a patient in Family 2 showed slowly progressive cerebellar ataxia. Conclusions:We here report two Japanese families with SCA23, one of which showed considerable phenotypic variation in affected members. Our findings support that SCA23 can phenotypically overlap with MSA.	0
Spinal muscular atrophy (SMA) with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease that is characterized by distal and proximal muscle weakness and diaphragmatic palsy that leads to respiratory distress. Without intervention, infants with the severe form of the disease die before 2 years of age. SMARD1 is caused by mutations in the IGHMBP2 gene that determine a deficiency in the encoded IGHMBP2 protein, which plays a critical role in motor neuron survival because of its functions in mRNA processing and maturation. Although it is rare, SMARD1 is the second most common motor neuron disease of infancy, and currently, treatment is primarily supportive. No effective therapy is available for this devastating disease, although multidisciplinary care has been an essential element of the improved quality of life and life span extension in these patients in recent years. The objectives of this review are to discuss the current understanding of SMARD1 through a summary of the presently known information regarding its clinical presentation and pathogenesis and to discuss emerging therapeutic approaches. Advances in clinical care management have significantly extended the lives of individuals affected by SMARD1 and research into the molecular mechanisms that lead to the disease has identified potential strategies for intervention that target the underlying causes of SMARD1. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to halt or possibly prevent neurodegenerative disease in SMARD1 patients. The recent approval of the first gene therapy approach for SMA associated with mutations in the SMN1 gene may be a turning point for the application of this strategy for SMARD1 and other genetic neurological diseases.	0
Central hypoventilation (CH) is a quite rare disorder caused by some congenital or acquired conditions. It is featured by increased arterial concentration of serum carbon dioxide related to an impairment of respiratory drive. Patients affected by CH need to be treated by mechanical ventilation in order to achieve appropriate ventilation and oxygenation both in sleep and wakefulness. In fact, in severe form of Congenital Central Hypoventilation Syndrome (CCHS) hypercarbia can be present even during the day. Positive pressure ventilation via tracheostomy is the first therapeutic option in this clinical condition, especially in congenital forms. Non-Invasive ventilation is a an option that must be reserved for more stable clinical situations and that requires careful monitoring over time.	0
We present a rare case of acute febrile neutrophilic dermatosis, also known as Sweet syndrome, associated with recurrence of metastatic cervical cancer. This report highlights similar reports and serves as an important reminder of the relationship between Sweet syndrome and cervical cancer. Increasing awareness of Sweet syndrome assists clinicians in recognizing characteristic findings and encourages evaluation of patients for new-onset or recurrent neoplastic disease. Additionally, we discuss the typical presentation of the syndrome, the proper workup and treatment, and a common pitfall encountered in the diagnosis of Sweet syndrome.	0
Large, atypical peripheral ossifying fibromas are known as giant peripheral ossifying fibromas. These lesions have often been associated with heterogeneous clinical and radiographic characteristics subsequently leading to their misdiagnosis. Biopsies have been the gold standard for the diagnosis of such lesions. This study reports on an acute presentation of giant peripheral ossifying fibroma, clinically mimicking a malignant lesion due to its atypical presentation along with its characteristic histological features, which led to the establishment of the diagnosis.	0
BACKGROUND:Nonsyndromic hearing loss is clinically and genetically heterogeneous. In this study, we characterized the clinical features of 12 Chinese Han deaf families in which mutations in common deafness genes GJB2, SLC26A4, and MT-RNR1 were excluded. METHODS:Targeted next-generation sequencing of 147 known deafness genes was performed in probands of 10 families, while whole-exome sequencing was applied in those of the rest two. RESULTS:Pathogenic mutations in a total of 11 rare deafness genes, OTOF, CDH23, PCDH15, PDZD7, ADGRV1, KARS, OTOG, GRXCR2, MYO6, GRHL2, and POU3F4, were identified in all 12 probands, with 16 mutations being novel. Intrafamilial cosegregation of the mutations and the deafness phenotype were confirmed by Sanger sequencing. CONCLUSION:Our results expanded the mutation spectrum and genotype-phenotype correlation of nonsyndromic hearing loss in Chinese Hans and also emphasized the importance of combining both next-generation sequencing and detailed auditory evaluation to achieve a more accurate diagnosis for nonsyndromic hearing loss.	0
Increasing evidence points to the respiratory Complex II (CII) as a source and modulator of reactive oxygen species (ROS). Both functional loss of CII as well as its pharmacological inhibition can lead to ROS generation in cells, with a relevant impact on the development of pathophysiological conditions, i.e. cancer and neurodegenerative diseases. While the basic framework of CII involvement in ROS production has been defined, the fine details still await clarification. It is important to resolve these aspects to fully understand the role of CII in pathology and to explore its therapeutic potential in cancer and other diseases.	0
Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling. Here, we show that CJS is caused by recurrent somatic mosaicism for a nonsynonymous variant in SMO (c.1234C>T [p.Leu412Phe]), encoding smoothened (SMO), a G-protein-coupled receptor that transduces Hh signaling. We identified eight mutation-positive individuals (two of whom had not been reported previously) with highly similar phenotypes and demonstrated varying amounts of the mutant allele in different tissues. We present detailed findings from brain MRI in three mutation-positive individuals. Somatic SMO mutations that result in constitutive activation have been described in several tumors, including medulloblastoma, ameloblastoma, and basal cell carcinoma. Strikingly, the most common of these mutations is the identical nonsynonymous variant encoding p.Leu412Phe. Furthermore, this substitution has been shown to activate SMO in the absence of Hh signaling, providing an explanation for tumor development in CJS. This raises therapeutic possibilities for using recently generated Hh-pathway inhibitors. In summary, our work uncovers the major genetic cause of CJS and illustrates strategies for gene discovery in the context of low-level tissue-specific somatic mosaicism.	0
Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder characterized by pyramidal weakness and spasticity of the lower limbs. SPG46, one of autosomal recessive HSP, is clinically characterized by spasticity and pyramidal weakness of the lower limbs, mental retardation, congenital bilateral cataract, thin corpus callosum, and hypogonadism in males. Mutations in the nonlysosomal glucosylceramidase β2 (GBA2) gene have been identified in patients with SPG46. A Japanese woman was identified with bilateral cataracts when she was in an elementary school. She felt falling easily, speaking unclearness, and difficulty in walking and raising her left leg in her 30s. Her neurological examination at the age of 44 revealed dysarthria, spasticity in the upper and lower extremities, increased jaw jerk and tendon reflexes in the extremities, bilateral extensor plantar reflexes, ataxia, and pollakiuria. Magnetic resonance imaging showed thinning of the corpus callosum body as well as atrophy in the pons and cerebellum. A novel homozygous c.1838A > G (p.D613G) missense mutation was detected at exon 12 in GBA2. We diagnosed her illness as an autosomal-recessive form of hereditary SPG46. The clinical features matched previously reported phenotype of SPG46. This is the first report of a Japanese patient with SPG46 with a novel mutation in GBA2. We presume that the novel GBA2 missense mutation found in our patient would cause loss of GBA2 activity, resulting in the neurological manifestations of SPG46.	0
Case summary:A 6-year-old neutered female European Shorthair cat was referred for chronic, moderately pruritic, alopecic and exfoliative dermatosis that was unresponsive to antiparasitic, antibiotic or steroidal anti-inflammatory drugs. The cat presented with truncular alopecia and numerous whitish adherent scales covering the whole body. Differential diagnoses included sebaceous adenitis, dermatophytosis, demodicosis, exfoliative dermatitis associated or not with thymoma, drug reaction, feline immunodeficiency virus- or feline leukaemia virus-associated dermatoses, epitheliotropic T-cell lymphoma, and Malassezia yeasts and/or bacterial overgrowth. Blood tests were within normal limits and the retrovirus tests were negative. Skin scrapings, fungal culture, coat brushing and skin cytology were negative for parasitic or microbial elements. Radiographs showed no signs of a thymic mass. Histological examination of skin biopsies revealed marked orthokeratotic hyperkeratosis, lymphocytic (CD3+) interface dermatitis and mural folliculitis with absence of sebaceous glands and occasional apoptotic cells in different epidermal layers. Clinical and histological findings were consistent with non-thymoma-associated exfoliative dermatitis syndrome. Ciclosporin A (7 mg/kg) was administered once daily. A dramatic improvement was observed after 3 weeks. Ciclosporin A intake was then progressively spaced out as the clinical signs diminished. Skin biopsies revealed resolution of hyperkeratosis, disappearance of the inflammatory infiltrate and recovery of the sebaceous glands. Relevance and novel information:T-cell infiltration with signs of epidermal cytotoxicity, in the absence of infectious agents or neoplastic process, suggests an immune-mediated process, and ciclosporin A, a calcineurin inhibitor, would be the drug of choice. This is the first report showing resolution of both the clinical and histological signs of non-thymoma-associated exfoliative dermatitis.	0
Primary systemic vasculitides are rare diseases that may manifest similarly to more commonly encountered conditions. Depending on the size of the vessel affected (large vessel, medium vessel, or small vessel), different vasculitis mimics must be considered. Establishing the right diagnosis of a vasculitis mimic will prevent unnecessary immunosuppressive therapy.	0
Split-hand-split-foot malformation (SHFM) is a rare condition that occurs in 1 in 8500-25,000 newborns and accounts for 15% of all limb reduction defects. SHFM is heterogeneous and can be isolated, associated with other malformations, or syndromic. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but can be X-linked or autosomal recessive. Seven loci are currently known: SHFM1 at 7q21.2q22.1 (DLX5 gene), SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27 (TP63 gene), SHFM5 at 2q31 and SHFM6 as a result of variants in WNT10B (chromosome 12q13). Duplications at 17p13.3 are seen in SHFM when isolated or associated with long bone deficiency. Tandem genomic duplications at chromosome 10q24 involving at least the DACTYLIN gene are associated with SHFM3. No point variant in any of the genes residing within the region has been identified so far, but duplication of exon 1 of the BTRC gene may explain the phenotype, with likely complex alterations of gene regulation mechanisms that would impair limb morphogenesis. We report on 32 new index cases identified by array-CGH and/or by qPCR, including some prenatal ones, leading to termination for the most severe. Twenty-two cases were presenting with SHFM and 7 with monodactyly only. Three had an overlapping phenotype. Additional findings were identified in 5 (renal dysplasia, cutis aplasia, hypogonadism and agenesis of corpus callosum with hydrocephalus). We present their clinical and radiological findings and review the literature on this rearrangement that seems to be one of the most frequent cause of SHFM.	0
Inflammatory breast cancer (IBC), a rare form of breast cancer associated with increased angiogenesis and metastasis, is largely driven by tumor-stromal interactions with the vasculature and the extracellular matrix (ECM). However, there is currently a lack of understanding of the role these interactions play in initiation and progression of the disease. In this study, we developed the first three-dimensional, in vitro, vascularized, microfluidic IBC platform to quantify the spatial and temporal dynamics of tumor-vasculature and tumor-ECM interactions specific to IBC. Platforms consisting of collagen type 1 ECM with an endothelialized blood vessel were cultured with IBC cells, MDA-IBC3 (HER2+) or SUM149 (triple negative), and for comparison to non-IBC cells, MDA-MB-231 (triple negative). Acellular collagen platforms with endothelialized blood vessels served as controls. SUM149 and MDA-MB-231 platforms exhibited a significantly (p < .05) higher vessel permeability and decreased endothelial coverage of the vessel lumen compared to the control. Both IBC platforms, MDA-IBC3 and SUM149, expressed higher levels of vascular endothelial growth factor (p < .05) and increased collagen ECM porosity compared to non-IBCMDA-MB-231 (p < .05) and control (p < .01) platforms. Additionally, unique to the MDA-IBC3 platform, we observed progressive sprouting of the endothelium over time resulting in viable vessels with lumen. The newly sprouted vessels encircled clusters of MDA-IBC3 cells replicating a key feature of in vivo IBC. The IBC in vitro vascularized platforms introduced in this study model well-described in vivo and clinical IBC phenotypes and provide an adaptable, high throughput tool for systematically and quantitatively investigating tumor-stromal mechanisms and dynamics of tumor progression.	0
Histiocytosis-lymphadenopathy plus syndrome (H syndrome) is caused by mutations in the SLC29A3 gene that result in histiocytic infiltration of numerous organs. Patients suffering from this disorder can be easily mistaken for similar conditions such as Muckle-Wells syndrome. We present a 9.5-year-old boy, who is the offspring of a consanguineous marriage. He suffered from sensorineural hearing loss, dark hyperpigmented indurated dry areas on the medial thighs sparing the knees with hypertrichosis on the affected areas, and areas of hypopigmentation on the abdomen. The patient displayed mild dysmorphism including frontal bossing, synophrys, bilateral proptosis (with normal thyroid function), thick eyebrows, flat nose, long philtrum, and pectus excavatum. Formal intelligence testing showed that he was a slow learner. Laboratory findings included elevated serum amyloid-A, erythrocyte sedimentation rate, and total proteins in urine tests. Complete blood count showed mild microcytic hypochromic anemia. The molecular analysis was crucial to confirm the provisional clinical diagnosis. H syndrome is a rare autoinflammatory syndrome with pleiotropic manifestations that affect many organs and can be mistaken for other conditions. Our patient's description may expand the phenotype of H syndrome, as areas of hypopigmentation were observed on the abdomen. Molecular analysis of SLC29A3 -related diseases is essential to highlight the variability and increase the awareness of H syndrome aiming for early diagnosis and proper treatment.	0
We describe an extremely rare case of Phyllodes tumor of the prostate in a 35-year-old man. The patient was referred to our hospital for the recurrent episodes of urinary retention. He complained of severe obstructive lower urinary tract symptoms and dysuria. Serum prostate-specific antigen (PSA) was within the normal range. Transabdominal ultrasonography showed a few heterogenous echoic areas in a 110-gm prostate and some cystic areas with invasion to the urinary bladder. In the past, transurethral resections of the prostate (TURP) had been performed for him twice and microscopic examination of the specimens had shown cystically dilated glands consisting of bizarre cells with nuclear atypia. Finally, radical retropubic prostatectomy was performed against the recurrences of the tumor. Here we describe the morphological features and immuno-histochemical presentations of Phyllodes tumor of the prostate and its long-term follow-up in the patient.	0
Inherited ichthyoses, defined as the generalized form of Mendelian disorders of cornification, are characterized by visible scaling and/or hyperkeratosis of most or all of the skin. This etiologically and phenotypically heterogenous group of conditions is caused by mutations in various different genes important for keratinocyte differentiation and epidermal barrier function. Diagnosing a specific entity is a particular challenge for the nonspecialist presented with the common clinical scaling. For the clinician, this review outlines an algorithmic approach for utilizing diagnostic clues to narrow down the differential diagnosis and to guide further testing and treatment options.	0
An extended family is described in which four sisters and half sisters presented with ectrodactyly. Two of the sisters had associated agenesis of the tibiae. The paper describes the malformations and discusses the management and possible genetic inheritance involved. An autosomal recessive gene seems likely to be the mode of inheritance.	0
INTRODUCTION:Preeclampsia is a medical condition complicated with hypertension and proteinuria during pregnancy. While preeclampsia affects approximately 5% of pregnancies, it remains without a cure. In addition, women who had preeclampsia during pregnancy have been reported to have an increased risk for cardiovascular disease later in life. However, the disease etiology and molecular mechanisms remain poorly understood. The paucity in the literature on preeclampsia associated maternal cardiovascular risk in different ethnic populations also present a need for more research. Therefore, the objective of this study was to identify cardiovascular/metabolic single nucleotide polymorphisms (SNPs), genes, and regulatory pathways associated with early-onset preeclampsia. MATERIALS AND METHODS:We compared maternal DNAs from 31 women with early-onset preeclampsia with those from a control group of 29 women without preeclampsia who delivered full-term normal birthweight infants. Women with multiple gestations and/or known medical disorders associated with preeclampsia (pregestational diabetes, chronic hypertension, renal disease, hyperthyroidism, and lupus) were excluded. The MetaboChip genotyping array with approximately 197,000 SNPs associated with metabolic and cardiovascular traits was used. Single nucleotide polymorphism analysis was performed using the SNPAssoc program in R. The Truncated Product Method was used to identify significantly associated genes. Ingenuity Pathway Analysis and Ingenuity Causal Network Analysis were used to identify significantly associated disease processes and regulatory gene networks respectively. RESULTS:The early-onset preeclampsia group included 45% Filipino, 26% White, 16% other Asian, and 13% Native Hawaiian and other Pacific Islanders, which did not differ from the control group. There were no SNPs associated with early-onset preeclampsia after correction for multiple comparisons. However, through gene-based tests, 68 genes and 23 cardiovascular disease-related processes were found to be significantly associated. Associated gene regulatory networks involved cellular movement, cardiovascular disease, and inflammatory disease. CONCLUSIONS:Multiple cardiovascular genes and diseases demonstrate associations with early-onset preeclampsia. This unfolds new areas of research regarding the genetic determinants of early-onset preeclampsia and their relation to future cardiovascular disease.	0
Patients with Poland syndrome were ascertained through the British Columbia Health Surveillance Registry, through hospital records, and through practicing plastic and orthopedic surgeons. Of 44 patients who were ascertained, 28 had family histories taken and were examined. Physical findings were: absence of the sternal head of the pectoralis major in all patients, symbrachydactyly in most patients, and infrequent other associations such as ipsilateral undescended testis, Möbius syndrome, clubfoot, and submucous cleft palate. Family histories were "negative" in all cases. The 8 affected adults had 24 reportedly normal children. Mean paternal age was significantly higher than the paternal age in the population. The incidence was 1/32,000 livebirths in British Columbia. It was concluded that in the British Columbia population the syndrome is usually a sporadic event.	1
Context and Aim:The aim of this study is to highlight the rarity of this disorder and its associated anomalies and our objective was to review our experience in the management of colonic atresia (CA) with respect to staged surgery versus one-step procedure for a better outcome of the disease. Settings and Design:A randomized, controlled, single-center study conducted over a period of 4 years from October 2013 to 2017. Subjects and Methods:Nine cases were operated for CA of which three underwent primary anastomosis and six underwent initial colostomy followed by definitive surgery. Age, sex, body weight, clinical presentation, type of atresia, site, time interval of operation, associated anomalies, initial procedure, postoperative complications, final procedure, biopsy, hospital stay, and outcome were noted. Statistical Analysis Used:Microsoft Excel was used for statistical analysis. Results:Out of 9 patients, 6 were males and 3 were females, 7 patients survived and 2 patients died (mortality 22.2%), of which one patient with primary anastomosis had leak and sepsis and one patient with primary anastomosis had associated Hirschsprung's disease (HD). Mean time gap for operation was 12.8 h and mean hospital stay was 3.5 days for initial colostomy and 21 days for primary anastomosis. Wound dehiscence occurred in 4 patients. Malrotation was found in 3 patients, HD in 2 patients, cardiac anomaly in 2, Meckel's diverticulum in 1, and cleft lip in 1 patient. Type IIIa atresia was found in in 6 patients, Type I in 2, and Type II in 1 patient. The most common site was transverse colon (n = 5). Conclusion:Diagnosis and management of CA is a challenge. Early presentation and diagnosis should be prompt. Staged procedure with initial colostomy followed by definitive procedure is the preferred choice. Associated anomaly HD must be ruled out.	0
Enterovirus 71 (EV71) infection causes hand, foot, and mouth disease (HFMD), and even fatal neurological complications. However, the mechanisms underlying EV71 neurological pathogeneses are largely unknown. This study reveals a distinct mechanism by which EV71 induces apoptosis and autophagy in neural cells. EV71 non-structure protein 3D (also known as RNA-dependent RNA polymerase, RdRp) interacts with the peroxisomal protein acyl-CoA oxidase 1 (ACOX1), and contributes to ACOX1 downregulation. Further studies demonstrate that EV71 reduces peroxisome numbers. Additionally, knockdown of ACOX1 or peroxin 19 (PEX19) induces apoptosis and autophagy in neural cells including human neuroblastoma (SK-N-SH) cells and human astrocytoma (U251) cells, and EV71 infection induces neural cell death through attenuating ACOX1 production. Moreover, EV71 infection and ACOX1 knockdown facilitate reactive oxygen species (ROS) production and attenuate the cytoprotective protein deglycase (DJ-1)/Nuclear factor erythroid 2-related factor 2 (NRF2)/Heme oxygenase 1 (HO-1) pathway (DJ-1/NRF2/HO-1), which collectively result in ROS accumulation in neural cells. In conclusion, EV71 downregulates ACOX1 protein expression, reduces peroxisome numbers, enhances ROS generation, and attenuates the DJ-1/NRF2/HO-1 pathway, thereby inducing apoptosis and autophagy in neural cells. These findings provide new insights into the mechanism underlying EV71-induced neural pathogenesis, and suggest potential treatments for EV71-associated diseases.	0
Neuroserpin (NS) is a member of the serine protease inhibitors superfamily. Specific point mutations are responsible for its accumulation in the endoplasmic reticulum of neurons that leads to a pathological condition named familial encephalopathy with neuroserpin inclusion bodies (FENIB). Wild-type NS presents two N-glycosylation chains and does not form polymers in vivo, while non-glycosylated NS causes aberrant polymer accumulation in cell models. To date, all in vitro studies have been conducted on bacterially expressed NS, de facto neglecting the role of glycosylation in the biochemical properties of NS. Here, we report the expression and purification of human glycosylated NS (gNS) using a novel eukaryotic expression system, LEXSY. Our results confirm the correct N-glycosylation of wild-type gNS. The fold and stability of gNS are not altered compared to bacterially expressed NS, as demonstrated by the circular dichroism and intrinsic tryptophan fluorescence assays. Intriguingly, gNS displays a remarkably reduced polymerisation propensity compared to non-glycosylated NS, in keeping with what was previously observed for wild-type NS in vivo and in cell models. Thus, our results support the relevance of gNS as a new in vitro tool to study the molecular bases of FENIB.	0
Porokeratosis is an uncommon cutaneous condition with multiple clinical variants that is defined by round patches with a raised, fine scaling border. Punctate porokeratosis is a rare variant of porokeratosis that is characterized by elevated, seed-like lesions of the palms and soles. While variants of porokeratosis may be associated with an increased risk of squamous cell carcinoma within the lesion, punctate porokeratosis does not increase the risk of squamous cell carcinoma. However, punctate porokeratosis may mimic other dermatoses affecting the palms and soles including spiny keratoderma, arsenical keratosis, and nevus comedonicus. Distinguishing punctate porokeratosis and spiny keratoderma is important, as spiny keratoderma may be associated with underlying solid organ malignancy or chronic medical conditions, including chronic kidney disease. Here, we present a case of punctate porokeratosis mimicking spiny keratoderma in order to distinguish the two conditions and aid in their differentiation from other dermatologic conditions involving the palms and soles.	0
BACKGROUND:Cholesteryl ester storage disease (CESD) is a rare genetic disease. Its symptoms and severity are highly variable. CESD is a systemic disease that can lead to the accumulation of fat and inflammation in the liver, as well as gastrointestinal and cardiovascular disease. The majority of patients require liver transplantation due to decompensated cirrhosis. Enzyme replacement therapy has been approved based on a randomized trial. Our study aims to clinically and genetically evaluate two siblings with CESD who underwent liver transplantation, as well as their first-degree family members. CASE SUMMARY:The siblings were compound heterozygous for the missense variant in LIPA exon 8, c.894G>A, (p.Gln298Gln) and a single base pair deletion, c.482del (p.Asn161Ilefs*19). Analyses of single nucleotide polymorphisms showed variants with an increased risk of fatty liver disease and fibrosis for both patients. Clinically, both patients show signs of recurrence of CESD in the liver after transplantation and additional gastrointestinal and cardiovascular signs of CESD. Three family members who were LIPA heterozygous had a lysosomal acid lipase activity below the reference value. One of these carriers, a seven-year-old boy, was found to have severe dyslipidemia and was subsequently treated with statins. CONCLUSION:Our study underlines that CESD is a multi-organ disease, the progression of which may occur post-liver transplantation. Our findings underline the need for monitoring of complications and assessment of possible further treatment.	0
Nontuberculous mycobacteria have emerged as an important group of pathogens worldwide; however, infections of the hand are rare. Infections caused by nontuberculous mycobacteria are often opportunistic in humans, and notoriously difficult to treat due to intrinsic resistance to many antibiotics. Here we reported a case of Mycobacterium marinum infection of the hand in a patient who presented with a nodular skin lesion.	0
Dowling-Degos Disease is a rare, pigmentary disorder with variable presentations. The most common among them are hyperpigmented macules and reticulate pigmentary anomaly of flexures. Many other phenotypic variations of Dowling-Degos disease have been reported in literature. We present here a case of Dowling-Degos disease with comedo-like lesions and pits without typical flexural hyperpigmented macules.	0
Thyroid dyshormonogenesis is characterized by impairment in one of the several stages of thyroid hormone synthesis and accounts for 10%-15% of congenital hypothyroidism (CH). Seven genes are known to be associated with thyroid dyshormonogenesis: SLC5A5 (NIS), SCL26A4 (PDS), TG, TPO, DUOX2, DUOXA2, and IYD (DHEAL1). Depending on the underlying mechanism, CH can be permanent or transient. Inheritance is usually autosomal recessive, but there are also cases of autosomal dominant inheritance. In this review, we describe the molecular basis, clinical presentation, and genetic diagnosis of CH due to thyroid dyshormonogenesis, with an emphasis on the benefits of targeted exome sequencing as an updated diagnostic approach.	0
PURPOSE OF REVIEW:The purpose of this review is to provide an update on advances in the understanding of pediatric demyelinating optic neuritis. RECENT FINDINGS:In the past decade, the disease phenotypes for demyelinating syndromes in children have been more clearly defined. Pediatric optic neuritis may present as a clinically isolated syndrome or in the setting of underlying neurologic disease. In addition to optic neuritis associated with multiple sclerosis or neuromyelitis optica, recent work has identified antibodies to the myelin oligodendrocyte glycoprotein (MOG IgG) as a unique demyelinating cause with distinct features regarding treatment and prognosis. The disease phenotypes for demyelinating pediatric optic neuritis have expanded. Treatment strategies vary and are not universally effective for each cause of demyelinating disease. Accurately distinguishing among these unique clinical syndromes is therefore critical for initiation of appropriate treatment to prevent disability, to maximize visual outcomes, and to provide insight into long-term prognosis.	0
Thiamine (vitamin B1) is an essential nutrient that serves as a cofactor for a number of enzymes, mostly with mitochondrial localization. Some thiamine-dependent enzymes are involved in energy metabolism and biosynthesis of nucleic acids whereas others are part of the antioxidant machinery. The brain is highly vulnerable to thiamine deficiency due to its heavy reliance on mitochondrial ATP production. This is more evident during rapid growth (i.e., perinatal periods and children) in which thiamine deficiency is commonly associated with either malnutrition or genetic defects. Thiamine deficiency contributes to a number of conditions spanning from mild neurological and psychiatric symptoms (confusion, reduced memory, and sleep disturbances) to severe encephalopathy, ataxia, congestive heart failure, muscle atrophy, and even death. This review discusses the current knowledge on thiamine deficiency and associated morbidity of neurological and psychiatric disorders, with special emphasis on the pediatric population, as well as the putative beneficial effect of thiamine supplementation in autism spectrum disorder (ASD) and other neurological conditions.	0
Kuwait has a cosmopolitan population of 1.7 million, mostly Arabs. This population is a mosaic of large and small minorities representing most Arab communities. In general, Kuwait's population is characterized by a rapid rate of growth, large family size, high rates of consanguineous marriages within the Arab communities with low frequency of intermarriage between them, and the presence of genetic isolates and semi-isolates in some extended families and Bedouin tribes. Genetic services have been available in Kuwait for over a decade. During this time it has become clear that Arabs have a high frequency of genetic disorders, and in particular autosomal recessive traits. Their pattern is unique and some disorders are relatively common. Examples are Bardet-Biedl and Meckel syndromes, phenylketonuria, and familial Mediterranean fever. A relatively large number of new syndromes and variants have been delineated in Kuwait's population, many being the result of homozygosity for autosomal recessive genes that occurred because of inbreeding. Some of these syndromes have subsequently been found in other parts of the world, negating the concept of the private syndrome. This paper provides an overview of autosomal recessive disorders among the Arabs in Kuwait from a personal perspective and published studies, and highlights the need for genetic services in Arab countries with the goal of prevention and treatment of genetic disorders.	0
PURPOSE:To characterize rheumatological manifestations of GATA2 deficiency. METHODS:Single-center, retrospective review of 157 patients with GATA2 deficiency. Disease course, laboratory results, and imaging findings were extracted. In-person rheumatological assessments were performed on selected, available patients. A literature search of four databases was conducted to identify additional cases. RESULTS:Rheumatological findings were identified in 28 patients, out of 157 cases reviewed (17.8%). Twenty-two of those patients (78.6%) reported symptom onset prior to or in conjunction with the molecular diagnosis of GATA2 deficiency. Notable rheumatological manifestations included: piezogenic pedal papules (PPP), joint hyperextensibility, early onset osteoarthritis, ankylosing spondylitis, and seronegative erosive rheumatoid arthritis. In peripheral blood of patients with rheumatological manifestations and GATA2 deficiency, CD4+ CD3+ helper T cells and naïve CD3+ CD4+ CD62L+ CD45RA+ helper T cell subpopulation fractions were significantly lower, while CD8+ cytotoxic T cell fractions were significantly higher, compared to those without rheumatological manifestations and with GATA2 deficiency. No changes in CD19, CD3, or NK populations were observed. CONCLUSION:GATA2 deficiency is associated with a broad spectrum of rheumatological disease manifestations. Low total helper T lymphocyte proportions and low naïve helper T cell proportions are associated with those most at risk of overt rheumatological manifestations. Further, PPP and joint hyperextensibility may explain some of the nonimmunologically-mediated joint problems encountered in patients with GATA2 deficiency. This catalogue suggests that rheumatological manifestations and immune dysregulation are relatively common in GATA2 deficiency.	0
Autistic children with selective diets have an elevated risk for vitamin A deficiency. The authors present the case of a 7-year-old boy with keratomalacia resulting from dietary vitamin A deficiency. Optical coherence tomography and ultrasound biomicroscopy can provide useful details of the cornea and underlying structures. Vitamin A supplementation can result in significant resolution, obviating the need for surgical intervention. [J Pediatr Ophthalmol Strabismus. 2020;57:e1-e3.].	0
Background 5.2% of people are carriers for at least two recessive diseases; it can be concluded that a much smaller proportion develop these conditions as two mutated copies of a gene must be present for the disease to manifest clinically. Case presentation We present a 38-year-old Caucasian female affected by two autosomal recessive disorders which can affect the eyes, pseudoxanthoma elasticum (PXE) and retinitis pigmentosa (RP). PXE is an autosomal recessive disorder caused by mutations in ABCC6, affecting 1:25 000 to 1:100 000 people; its classical features involve the dermatological, ophthalmological and cardiovascular systems. Our patient presented with dermatological features of PXE and ophthalmological features of RP. RP presents with significant locus heterogeneity; our patient had biallelic mutations in USH2A. Conclusions This report highlights an interesting case of two unrelated autosomal recessive diseases presenting in one person, both of which have the potential to manifest with ophthalmological symptoms and signs. Though it is likely that only one condition has caused the ophthalmological findings in this case, it raises the question of how we can distinguish the causative disease when two conditions are present that have a shared target organ.	0
The RNA polymerase II transcription subunit 12 homolog (MED12) is a member of the mediator complex, which plays a critical role in RNA transcription. Mutations in MED12 cause X-linked intellectual disability and other anomalies collectively grouped as MED12-related disorders. While MED12 mutations have been most commonly reported in male patients, we present the case of a 1-year-old girl with clinical characteristics similar to MED12-related disorders. To explore the clinical characteristics of the condition and its possible pathogenesis, we analyzed the patient's clinical data; genetic testing by whole-exome sequencing revealed a de novo heterozygous mutation (c.1249-1G > C) in MED12. Further cDNA experiments revealed that the patient had an abnormal splicing at the skipping of exon9, which may have produced a truncated protein. qPCR showed decreased MED12 gene expression level in the patient, and an X-chromosome inactivation test confirmed a skewed inactivation of the X-chromosome. The lymphoblast transcription levels of the genes involved in the Gli3-dependent sonic hedgehog (SHH) signaling pathway, namely, CREB5, BMP4, and NEUROG2, were found to be significantly elevated compared with those of her parents and sex- and age-matched controls. Our results support the view that MED12 mutations may dysregulate the SHH signaling pathway, which may have accounted for the aberrant craniofacial morphology of our patient.	0
The differential diagnosis for hoarseness is extensive and includes a multitude of etiologies that span a large geographic area from the brainstem to the mediastinum. Therefore, localizing a causative lesion can be extremely difficult for clinicians and radiologists alike. In this review, we will first discuss the normal anatomy of the larynx and its innervation via the vagus and recurrent laryngeal nerves. We will then proceed with a guided tour of the various infectious/inflammatory, neoplastic, congenital, and traumatic/iatrogenic causes of hoarseness subdivided by anatomic location (brainstem, skull base, carotid sheath, thyroid, larynx, and superior mediastinum). Along the way, we will discuss the various cross-sectional imaging modalities best suited to detect the often subtle signs of recurrent laryngeal nerve injury. With thorough knowledge of these entities, radiologists can impact patient care by suggesting the appropriate imaging test and tailoring their search patterns to detect the subtle findings of laryngeal dysfunction.	0
Usher syndrome includes a group of genetically and clinically heterogeneous autosomal recessive diseases, such as retinitis pigmentosa (RP) and sensorineural hearing loss. Usher syndrome type I (USHI) is characterized by profound hearing impairment beginning at birth, vestibular dysfunction, and unintelligible speech in addition to RP. The relationships between the Usher syndrome causing genes and the resultant phenotypes of Usher syndrome have not yet been fully elucidated. In the present study, we recruited a Chinese family with Usher syndrome and conducted paneled next-generation sequencing, Sanger sequencing, segregation analysis, and expression profile analysis. The functional effects of the identified cadherin-related 23 (CDH23) pathogenic variants were analyzed. The M101 pedigree consisted of a proband and seven family members, and the proband was a 39-year-old Chinese male who claimed that he first began to experience night blindness 11 years ago. We revealed novel, missense compound heterozygous variants c. 2572G > A (p.V858I) and c. 2891G > A (p.R964Q) in the CDH23 gene, which co-segregated with the disease phenotype causing Usher syndrome type ID (USH1D) in this Chinese pedigree. CDH23 mRNA was highly expressed in the retina, and this protein was highly conserved as revealed by the comparison of Homo sapiens CDH23 with those from nine other species. This is the first study to identify the novel, missense compound heterozygous variants c. 2572G > A (p.V858I) and c.2891G > A (p.R964Q) of CDH23, which might cause USH1D in the studied Chinese family, thereby extending CDH23 mutation spectra. Identifying CDH23 pathogenic variants should help in the detailed phenotypic characterization of USH1D.	0
Defects in serine biosynthesis resulting from loss of function mutations in PHGDH, PSAT1, and PSPH cause a set of rare, autosomal recessive diseases known as Neu-Laxova syndrome (NLS) or serine-deficiency disorders. The diseases present with a broad range of phenotypes including lethality, severe neurological manifestations, seizures, and intellectual disability. However, because L-serine supplementation, especially if started prenatally, can ameliorate and in some cases even prevent symptoms, knowledge of pathogenic variants is medically actionable. Here, we describe a functional assay that leverages the evolutionary conservation of an enzyme in the serine biosynthesis pathway, phosphoserine aminotransferase, and the ability of the human protein-coding sequence (PSAT1) to functionally replace its yeast ortholog (SER1). Results from our quantitative, yeast-based assay agree well with clinical annotations and expectations based on the disease literature. Using this assay, we have measured the functional impact of the 199 PSAT1 variants currently listed in ClinVar, gnomAD, and the literature. We anticipate that the assay could be used to comprehensively assess the functional impact of all SNP-accessible amino acid substitution mutations in PSAT1, a resource that could aid variant interpretation and identify potential NLS carriers.	0
A 2-year-old girl with a diagnosis of loose anagen hair syndrome was treated with a tapering regime of minoxidil 5% solution over 28 months, resulting in quick, significant clinical improvement with no adverse effects.	0
Hereditary ataxias (HA) are a group of inherited neurological disorders caused by changes in genes. At least 115 different mutations in the senataxin (SETX) gene causing ataxia have been identified. There are no reports of any SETX gene mutation among the Iranian population. Here we report on two cases with homozygous and heterozygous mutations in which one patient was affected by HA with oculomotor apraxia type 2, and the other was a carrier of the disorder. In 2016, the affected patient was referred to the Biogene Medical and Genetic Laboratory (Tehran, Iran) suffering from imbalance and tremor of both head and body. The coding regions of 18 genes, including the SETX gene, were screened. The target regions were captured using the NimbleGen chip followed by next-generation sequencing (NGS) technology on the Illumina Hiseq2500 platform. NGS, a DNA sequencing technology, has greatly increased the ability to identify new causes of ataxia; a useful tool for the prevention of primary manifestations and treatment of affected patients. In the present study, a novel mutation in the SETX gene has been identified.	0
We describe a girl presented with facial asymmetry and oral mucosal cleft and with further investigations other anomalies were found including hearing loss, Duane syndrome, Klippel-Feil anomaly, Chiari malformation and accessory bone mass in mandibular ramus leading to the clinical diagnosis of cervico-oculo-acoustic (Wildervanck) syndrome (COAS). The patient underwent surgical occipital decompression by preforming suboccipital craniectomy and C1 posterior laminectomy to relieve the cerebellar tonsillar herniation. Surgical removal of mandibular bony mass was done and the patient is now under orthodontic treatment to correct facial asymmetry and malocclusion.	0
Rhabdomyomatous mesenchymal hamartoma is a rare dermal lesion which was first described in 1986 as "striated muscle hamartoma". It usually develops in the head and neck region of newborns. We report a 38-day-old girl with a congenital skin tag in the perianal region. Physical examination did not reveal any congenital abnormalities or other dermal lesions. Histopathological examination showed a hamartoma with disorganized skeletal muscle fibers. The differential diagnosis includes skin tag, accessory tragus and soft fibroma. Rhabdomyomatous mesenchymal hamartoma differs from the listed lesions with its striated muscle component. Since it does not carry the risk of recurrence and malignant transformation, it is not very important to distinguish it from these lesions. However, a correct diagnosis is important because approximately one third of the cases are associated with congenital anomalies. Also, histopathological diagnosis should be made in children with perianal localization due to similar clinical manifestation of rhabdomyosarcoma.	0
Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant skeletal dysplasia characterised by metaphyseal flaring of the long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, brachydactyly, dental anomalies and mild osteoporosis. To date, only one large French Canadian family and a Finnish woman have been reported with the condition. In both, intragenic duplication encompassing exons 3-5 of the RUNX2 gene was identified. We describe a new, three-generation family with clinical features of MDMHB and an intragenic tandem duplication of RUNX2 exons 3-6. Dental problems were the primary presenting feature in all four affected individuals. We compare the features in our family to those previously reported in MDMHB, review the natural history of this condition and highlight the importance of considering an underlying skeletal dysplasia in patients presenting with significant dental problems and other suggestive features, including disproportionate short stature and/or digital anomalies.	0
OBJECTIVE:Small-fiber sensory and autonomic symptoms are early presentations of familial amyloid polyneuropathy (FAP) with transthyretin (TTR) mutations. This study aimed to explore the potential of skin nerve pathologies as early and disease-progression biomarkers and their relationship with skin amyloid deposits. METHODS:Skin biopsies were performed in patients and carriers to measure intraepidermal nerve fiber (IENF) density, sweat gland innervation index of structural protein gene product 9.5 (SGII[PGP9.5]) and peptidergic vasoactive intestinal peptide (SGII[VIP]), and cutaneous amyloid index. These skin pathologies were analyzed with clinical disability assessed by FAP stage score (stage 0-4) and compared to neurophysiological and psychophysical tests. RESULTS:There were 70 TTR-mutant subjects (22 carriers and 48 patients), and 66 cases were TTR-A97S. Skin nerve pathologies were distinct according to stage. In carriers, both skin denervation and peptidergic sudomotor denervation were evident: (1) IENF density was gradually reduced from stage 0 through 4, and (2) SGII(VIP) was markedly reduced from stage 1 to 2. In contrast, SGII(PGP9.5) was similar between carriers and controls, but it declined in patients from stage 2. Skin amyloids were absent in carriers and became detectable from stage 1. Cutaneous amyloid index was correlated with SGII(PGP9.5) and stage in a multivariate mixed-effect model. When all tests were compared, only IENF density, SGII(PGP9.5), and cutaneous amyloid index were correlated with stage, and IENF density had the highest abnormal rate in carriers. INTERPRETATION:Biomarkers of sensory and sudomotor innervation exhibited a stage-dependent progression pattern, with sensory nerve degeneration as the early skin nerve pathology. Ann Neurol 2019;85:560-573.	0
Pain is one of the most significant causes of suffering and disability world-wide, and arguably the most burdensome global health challenge. The growing number of patients suffering from chronic pain conditions such as fibromyalgia, complex regional pain syndrome, migraine and irritable bowel syndrome, not only reflect the complexity and heterogeneity of pain types, but also our lack of understanding of the underlying mechanisms. Sensory neurons within the dorsal root ganglia (DRG) have emerged as viable targets for effective chronic pain therapy. However, DRG's contain different classes of primary sensory neurons including pain-associated nociceptive neurons, non-nociceptive temperature sensing, mechanosensory and chemoreceptive neurons, as well as multiple types of immune and endothelial cells. This cell-population heterogeneity makes investigations of individual subgroups of DRG neurons, such as nociceptors, difficult. In attempts to overcome some of these difficulties, a limited number of immortalized DRG-derived cell lines have been generated over the past few decades. In vitro experiments using DRG-derived cell lines have been useful in understanding sensory neuron function. In addition to retaining phenotypic similarities to primary cultured DRG neurons, these cells offer greater suitability for high throughput assays due to ease of culture, maintenance, growth efficiency and cost-effectiveness. For accurate interpretation and translation of results it is critical, however, that phenotypic similarities and differences of DRG-derived cells lines are methodically compared to native neurons. Published reports to date show notable variability in how these DRG-derived cells are maintained and differentiated. Understanding the cellular and molecular differences stemming from different culture methods, is essential to validate past and future experiments, and enable these cells to be used to their full potential. This review describes currently available DRG-derived cell lines, their known sensory and nociceptor specific molecular profiles, and summarize their morphological features related to differentiation and neurite outgrowth.	0
Doxorubicin is widely used against cancer but carries the risk of a progressive cardiomyopathy associated with mitochondrial loss. Using genetic models, our recent study demonstrates that mitochondrial genomic DNA regulation by tumor protein p53 (TP53, best known as p53) prevents the cardiotoxicity of low dose doxorubicin which does not activate the p53-dependent cell death pathway.	0
Palmoplantar tylosis is a focal non epidermolytic palmoplantar hyperkeratosis and is associated with a very high lifetime risk of developing squamous cell carcinoma of the esophagus (OSCC). It is generally inherited as an autosomal dominant trait with complete penetrance involving the RHBDF2 gene located on 17q25.1. The data regarding endoscopic appearance of the mucosa in patients with tylosis before development of cancer is limited. Surveillance endoscopy is recommended in family members which include annual esophagogastroscopy with biopsy of suspicious lesion with quadratic biopsies from upper, middle and lower esophagus. We describe characteristic endoscopy findings in a tylosis with no evidence of cancer. Prospective documentation of endoscopic findings of similar mucosal changes and disease process to establish a better screening protocol and supplemental intervention with agents like carotenoids (beta-carotene, alpha-carotene, lycopene, beta-cryptoxanthin, lutein, and zeaxanthin) may delay the progression and possibly revert to normal.	0
BACKGROUND:Thromboses and phenotypic evolutions (leukemia, myelofibrosis) are the most frequent complications in polycythemia vera (PV) and essential thrombocythemia (ET). Aquagenic pruritus (AP) is not only PV symptom, but is also present in ET. The presence of pruritus in PV is associated with a lower risk of arterial thrombosis. AIMS:To date, no equivalent study has been done to analyse the impact of AP for ET patients. MATERIALS & METHODS:We used the data from our cohort of patients with myeloproliferative neoplasms seen in our institution (OBENE database, NCT02897297). We collect information at diagnosis, presence or not of AP and all types of complications during their follow-up. To avoid masked PV, all JAK2 positive cases were tested isotopic red mass cell if appropriate. RESULTS:Among 396 ET patients, presence of AP was found in 42 (10.6%). ET patients with AP were more proliferative, more symptomatic at diagnosis and more difficult to treat. Furthermore, they presented increased risk of thromboses (30.9 versus 17%, P = .03; OR = 2.2 [1.01;4.66]) and phenotypic evolutions (33.3 versus 13.3%, P = .0007; OR = 3.2 [1.44;6.77]), during follow-up. DISCUSSION:Aquagenic pruritus is classically associated to PV. But we confirmed here that AP is also present in ET and characterizes patients with higher risk of morbidity (thrombotic events and phenotypic evolutions). CONCLUSIONS:The systematic determination of the presence of AP in ET patients should permit us to better identify these high-risk patients for better management and follow-up.	0
BACKGROUND:Congenitally corrected transposition of great arteries (CCTGA) is caused by atrioventricular and ventriculoarterial discordance. Cases of CCTGA with spontaneous chordae rupture of tricuspid valve have not been reported before. CASE PRESENTATION:Here we diagnosed a 38-year-old man, who was found CCTGA 14 years ago, as spontaneous chordae rupture by real-time three dimentional transesophageal echocardiography (RT-3D-TEE). The present case is the first report to describe a CCTGA patient combine with spontaneous chordae rupture in tricuspid valve. After tricuspid valve replacement, the patient was uneventful after 6 years' follow-up. CONCLUSION:We reported a rare case with spontaneous chordae rupture of tricuspid valve in a CCTGA patient and explored its etiology here. RT-3D-TEE is an important supplement to 2-dimentional transthoracic echocardiography and can provide more accurate detections in tricuspid valve diseases in CCTGA.	0
The Richards-Rundle syndrome (RRS) is characterized by hearing loss, mental deterioration, ataxia, primary hypogonadism and autosomal recessive transmission. In a sibship of six members we found two sisters with RRS together with baldness, impaired GH and PRL secretion after stimulation and different degrees of impaired insulin secretion. Cochleovestibular investigation of the sibship revealed in each subject more or less severe forms of bulbo-pontine cochleovestibular dysfunction. Three members of the same sibship had cutaneous signs of abortive forms of neurofibromatosis: the son of one of these subjects had a severe form of fully developed neurofibromatosis. Whether there is a pathogenetic linkage between the hereditary multisystemic degeneration (RRS), the dysembryopathy (neurofibromatosis) and the cochleovestibular dysfunction in this family is still not clear.	0
Ménétrier disease is a very rare chronic gastric disorder characterized by gastric mucosal hypertrophy. We present a case of Ménétrier disease with CT, MRI, and FDG PET/CT findings. Enhanced CT and MRI showed diffuse thickened mucosa of the greater curvature and elongated mucosa of the antrum with remarkable enhancement. The early and delayed FDG PET/CT showed increased FDG uptake of these thickened mucosa. The increased FDG uptake may be due to the mucosal inflammation. This case indicates Ménétrier disease should be included in the differential diagnosis of abnormal gastric FDG accumulation along with tumor and nontumor processes.	0
Polyarteritis nodosa is a systemic necrotizing vasculitis that typically affects medium-sized muscular arteries, with occasional involvement of small muscular arteries. Most cases of polyarteritis nodosa are idiopathic but multiple infectious agents have been associated with this disease. We present a clinical case of a 72-year-old male with fever, diarrhoea and haemodynamic instability, diagnosed with a bacterial infection caused by Salmonella Typhi. One week after clinical resolution of the infection, the patient developed purpuric lesions with ulcers, pustules and necrotic areas accompanied by testicular pain and weight loss of 5 kg over the previous 15 days. A skin biopsy was performed and it revealed typical histologic signs of polyarteritis nodosa. The aetiologic association between bacteria of the genus Salmonella and polyarteritis nodosa has been previously described in the scientific literature but seldom meeting classification criteria and with histologic confirmation. LEARNING POINTS:Polyarteritis nodosa is a systemic necrotizing vasculitis associated with a multitude of aetiologic agents.Salmonella infection might be a possible trigger for the development of polyarteritis nodosa.A high index of suspicion and awareness is essential for a swift diagnosis and treatment of this disease.	0
VACTERL/VATER association is a condition defined by the presence of at least three of the following congenital malformations: vertebral defects (V), anal atresia (A), cardiac defects (C), tracheo-oesophageal fistula (TE), renal anomalies (R) and limb abnormalities (L). We describe a stillborn female piglet with cardiac anomalies, renal defects, vertebral anomalies, anal atresia and a single umbilical artery (SUA), which are the main features of VACTERL association. In addition, the piglet had a unilateral abdominal wall defect. This was the only affected animal in a litter of 16 piglets. The molecular inductive mechanisms of this disorder are discussed, as well as the comparative and embryological implications.	0
PURPOSE:To describe the demographics, characteristics, management pitfalls, and outcomes of pseudoptosis associated with congenital fibrosis of the extraocular muscles (CFEOM). METHODS:A retrospective review was performed of eight patients presenting with ptosis and hypotropia to oculoplastic service. All patients underwent full ocular evaluation and magnetic resonance imaging of brain and orbit. Five of these patients underwent stepwise correction of hypotropia by single-stage adjustable strabismus surgery (SSASS), followed by a frontalis sling if needed. RESULTS:Eight patients had congenital strabismus with severe ptosis and a positive forced duction test. There was a highly significant improvement from preoperative mean hypotropia angle of 30 prism diopters (PD) to 9 PD mean postoperative angle (P = 0.006). Surgery for ptosis was not needed in 80% of eyes. CONCLUSION:CFEOM involving both ptosis and hypotropia could be properly managed with the correct sequence of surgical steps. Proper vertical alignment by correction of hypotropia utilizing SSASS may alleviate the need for ptosis surgery.	0
Mucopolysaccharidosis type II (MPS II) is a rare lysosomal storage disease (LSD) involving a genetic error in iduronic acid-2-sulfatase (IDS) metabolism that leads to accumulation of glycosaminoglycans within intracellular lysosomes. The primary treatment for MPS II, enzyme replacement therapy, is not effective for central nervous system (CNS) symptoms, such as intellectual disability, because the drugs do not cross the blood-brain barrier. Recently, autophagy has been associated with LSDs. In this study, we examined the morphologic relationship between neuronal damage and autophagy in IDS knockout mice using antibodies against subunit c of mitochondrial adenosine triphosphate (ATP) synthetase and p62. Immunohistological changes suggesting autophagy, such as vacuolation, were observed in neurons, microglia, and pericytes throughout the CNS, and the numbers increased over postnatal development. Oral administration of chloroquine, which inhibits autophagy, did not suppress damage to microglia and pericytes, but greatly reduced neuronal vacuolation and eliminated neuronal cells with abnormal inclusions. Thus, decreasing autophagy appears to prevent neuronal degeneration. These results suggest that an autophagy modulator could be used in addition to conventional enzyme replacement therapy to preserve the CNS in patients with MPS II.	0
A diagnosis of congenital adrenal hyperplasia (CAH) in a '46, XX' newborn with ambiguous genitalia is like a 'knee jerk reaction' of the paediatrician because of its higher frequency and life-threatening consequences if remain undiagnosed and hence untreated. Aromatase deficiency (AD), a rare cause of '46, XX' disorder of sex development, mimics virilising CAH in many aspects; thus, the disease is often overlooked. Diagnosis of AD in women is much easier around puberty due to the presence of primary amenorrhoea, undeveloped breasts, androgen excess and tall stature with eunuchoid proportions. Diagnosing AD with confidence immediately after birth or during early childhood is a challenging task without genetic analysis. In resource-restricted settings, AD remains a diagnosis of exclusion particularly in this age group and history of maternal virilisation, non-progressive genital ambiguity, elevated gonadotrophins (follicle-stimulating hormone >>luteinising hormone), mildly delayed bone age with/without enlarged polycystic ovaries serve as important clues to the underlying AD.	0
Tyrosine hydroxylase deficiency is a rare autosomal recessive, treatable disorder of neurotransmission. Fewer than 100 cases have been reported so far. We present a case of a 10-month-old infant who was symptomatic since 5 months of age and who received an initial diagnosis of infantile tremor syndrome. She presented with rest tremor, decreased facial expression, global hypokinesia, and later on with oculogyric crisis and dystonia. This diagnosis was revised after confirmation of tyrosine hydroxylase deficiency by CSF neurotransmitter analysis. Genetic studies revealed one previously reported missense variant, p.Thr399Met, and another large deletion starting upstream of exon 1 and encompassing exon 1. She was started on treatment with escalating doses of L-Dopa/Carbidopa, with folinic acid supplementation. At 3.5 years of age, her cognitive functioning and development is appropriate for age. There is complete subsidence of dystonia and oculogyric episodes. She has occasional chorieform movements which appear to be drug related.	0
Human arylamine N-acetyltransferase 1 (NAT1), present in all tissues, is classically described as a phase-II xenobiotic metabolizing enzyme but can also catalyze the hydrolysis of acetyl-Coenzyme A (acetyl-CoA) in the absence of an arylamine substrate using folate as a cofactor. NAT1 activity varies inter-individually and has been shown to be overexpressed in estrogen receptor-positive (ER+) breast cancers. NAT1 has also been implicated in breast cancer progression however the exact role of NAT1 remains unknown. The objective of this study was to evaluate the effect of varying levels of NAT1 N-acetylation activity in MDA-MB-231 breast cancer cells on global cellular metabolism and to probe for unknown endogenous NAT1 substrates. Global, untargeted metabolomics was conducted via ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) on MDA-MB-231 breast cancer cell lines constructed with siRNA and CRISPR/Cas9 technologies to vary only in NAT1 N-acetylation activity. Many metabolites were differentially abundant in NAT1-modified cell lines compared to the Scrambled parental cell line. N-acetylasparagine and N-acetylputrescine abundances were strongly positively correlated (r = 0.986 and r = 0.944, respectively) with NAT1 N-acetylation activity whereas saccharopine abundance was strongly inversely correlated (r = -0.876). Two of the most striking observations were a reduction in de novo pyrimidine biosynthesis and defective β-oxidation of fatty acids in the absence of NAT1. We have shown that NAT1 expression differentially affects cellular metabolism dependent on the level of expression. Our results support the hypothesis that NAT1 is not just a xenobiotic metabolizing enzyme and may have a role in endogenous cellular metabolism.	0
WAGR 11p13 deletion syndrome is associated with abnormalities including (W) ilms tumor, (A) niridia, (G) enitourinary abnormalities, and growth and mental (R) etardation (WAGR). Potocki-Schaffer syndrome is a contiguous gene syndrome associated with deletions in 11p11.2, principal features of which are multiple exostoses, parietal foramina development delay, mental retardation, and facial dysmorphism. In some cases, males may have enlarged anterior fontanels and genital abnormalities. Each of these syndromes is very rare. Here we report a patient with both WAGR and Potocki-Shaffer syndromes who presented with aniridia, nystagmus, macular dysplasia, enlarged anterior fontanel, mental retardation, ptosis, low-set ears, micrognathia, and atrial septal defect at 6 months old. SNP array revealed a large (26.25 Mb)deletion: arr[hg19]11p15.1p11.2(18742043-44991839)× 1. Genetic testing allowed for diagnosis of this patient at a very young age. In addition to the postnatal phenotype of the patient, we found one prenatal symptom of these syndromes is oligohydramnios, which when present might indicate advanced prenatal diagnosis. This made the possibility of prenatal diagnosis for these syndromes.	0
Objective:Retinitis pigmentosa-related retinal detachment (RPRD) is rare, and the full spectrum of retinal complications is not well defined. To describe the types of retinal detachment in patients with retinitis pigmentosa and the surgical outcomes of RPRD. Methods:This is a non-comparative, retrospective case series. An electronic database search was performed using Moorfields OpenEyes electronic health records. We identified 90 patients with RPRD between January 2000 and August 2017. Main outcome and measures are visual acuity (VA), surgical outcomes and classification of RPRD. Results:Of the 90 patients/detachments, 61 (67.8%) were rhegmatogenous retinal detachment (RRD), 19 (21.1%) were exudative, 3 (3.3%) were tractional retinal detachment (TRD) and 7 (7.8%) had combined. 37.5% (9/24) of patients with exudative retinal detachment were treated with either cryotherapy or laser, and one patient underwent vitrectomy for vitreous haemorrhage. 56/90 patients underwent surgical intervention. Nine patients presented late and were deemed inoperable (two exudative and seven RRD). Of the RRD patients with full operative record, the primary attachment rate was 76.2% (16/21) and final reattachment rate was 85.7% (18/21) over a mean 15.4-year follow-up period. Mean VA for RRD surgery improved from 6/190 (1.51 logMAR) to 6/120 (1.31 logMAR) (p=0.194). In the TRD group, the mean VA was 6/300 (1.66 logMAR) at baseline and improved after surgery to 6/48 (0.90 logMAR) (p=0.421). Conclusions:We demonstrated a final reattachment rate of 85.7% with a trend toward better vision following intervention for patients with RPRD. However, the final long-term vision may be poor due to the natural progression of retinitis pigmentosa-associated macular degeneration.	0
INTRODUCTION:Noonan syndrome is the second most common syndromic cause of congenital heart disease. Most patients have an autosomal dominant inheritance, but some cases may be sporadic. Pulmonary stenosis is the most common cardiac manifestation in Noonan syndrome, associated with the atrial septal defect and hypertrophic cardiomyopathy. A combination of these three is present only in 5% of patients. PRESENTATION OF CASE:We report a case of a 21-year-old female who presented to our hospital concomitant cardiac lesions associated with pulmonary stenosis, atrial septal defect, and hypertrophic cardiomyopathy. This combination of cardiac defects is an infrequent manifestation of Noonan syndrome. The patient presented with complaints of exertion syncope over the past two years. 2D-Echocardiography showed biventricular hypertrophy, dysplastic pulmonary valve, severe pulmonary stenosis, asymmetric septal hypertrophy and large atrial septal defect. The genetic analysis report showed autosomal dominant inheritance with Ras/MAPK (mitogen-activated protein kinase) Positive. DISCUSSION:Due to the wide spectrum of symptoms and presentations in Noonan cases, accurate clinical and genetic diagnosis, and comprehensive management of the disorder are strongly recommended. CONCLUSION:We have described a case of rare combination of cardiovascular defects in Noonan Syndrome with a view to achieve better insight into the disease course and advantages of timely treatment and follow up. Our patient is currently in follow-up after treatment with percutaneous balloon pulmonary valvuloplasty, has improved symptoms, and is awaiting heart transplant.	0
Since 2013, the International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) has published an updated phenotypic classification of IEI, which accompanies and complements their genotypic classification into ten tables. This phenotypic classification is user-friendly and serves as a resource for clinicians at the bedside. There are now 430 single-gene IEI underlying phenotypes as diverse as infection, malignancy, allergy, autoimmunity, and autoinflammation. We herein report the 2019 phenotypic classification, including the 65 new conditions. The diagnostic algorithms are based on clinical and laboratory phenotypes for each of the ten broad categories of IEI.	0
A four-generation kindred (14 affected and 10 unaffected members) from Missouri, U.S.A. in which spondyloepimetaphyseal dysplasia (SEMD) had been inherited as an autosomal dominant disorder was investigated for linkage to 13 candidate loci: COL2AI, COL9AI, COL9A2, COL9A3, COL10A1, COL11A1, COL11A2, PSACH, FGFR3, decorin, CRTL1, COMP, and PTHRP. Mutations of COL2A1, COL9A2, COL10, and FGFR3 have been reported previously in the Strudwick type of SEMD, multiple epiphyseal dysplasia type 2 (EDM2), the Schmid type of metaphyseal dysplasia, and in achondroplasia, respectively, and the pseudoachondroplasia (PSACH) locus has been mapped to chromosome 19p12. In addition, mutations in COL9 and COL11A are associated with murine forms of degenerative joint disease and chondroplasia, respectively. The family proved informative for 12 of the 13 loci and was uninformative at the decorin locus. Linkage between this form of SEMD, designated the Missouri variant, SEMDMO, and the 12 informative candidate loci was excluded (LOD scores < -2.00 at theta = 0.005 to 0.15), thereby indicating further genetic heterogeneity in these inherited disorders of bone and cartilage development.	1
Lenz microphthalmia is inherited in an X-linked recessive pattern and comprises microphthalmia, mental retardation, and skeletal and other anomalies. Two loci associated with this syndrome, MAA (microphthalmia with associated anomalies) and MAA2, are situated respectively at Xq27-q28 (refs. 1,2) and Xp11.4-p21.2 (ref. 3). We identified a substitution, nt 254C-->T; P85L, in BCOR (encoding BCL-6-interacting corepressor, BCOR) in affected males from the family with Lenz syndrome previously used to identify the MAA2 locus. Oculofaciocardiodental syndrome (OFCD; OMIM 300166) is inherited in an X-linked dominant pattern with presumed male lethality and comprises microphthalmia, congenital cataracts, radiculomegaly, and cardiac and digital abnormalities. Given their phenotypic overlap, we proposed that OFCD and MAA2-associated Lenz microphthalmia were allelic, and we found different frameshift, deletion and nonsense mutations in BCOR in seven families affected with OFCD. Like wild-type BCOR, BCOR P85L and an OFCD-mutant form of BCOR can interact with BCL-6 and efficiently repress transcription. This indicates that these syndromes are likely to result from defects in alternative functions of BCOR, such as interactions with transcriptional partners other than BCL-6. We cloned the zebrafish (Danio rerio) ortholog of BCOR and found that knock-down of this ortholog caused developmental perturbations of the eye, skeleton and central nervous system consistent with the human syndromes, confirming that BCOR is a key transcriptional regulator during early embryogenesis.	0
BACKGROUND:McLeod syndrome is a rare X-linked recessive acanthocytosis associated with neurological manifestations including progressive chorea, cognitive impairment, psychiatric disturbances, seizures, and sensorimotor axonal polyneuropathy. However, no studies have investigated the functioning of central sensorimotor tracts in patients with McLeod syndrome. CASE PRESENTATION:A 66-year-old man had experienced slowly progressive chorea and gait disturbance due to lower limb muscle weakness since his early fifties. Blood examinations showed erythrocyte acanthocytosis and the reduction of Kell antigens in red blood cells. Brain magnetic resonance imaging showed atrophy of the bilateral caudate nuclei and putamen. The diagnosis of McLeod syndrome was confirmed by the presence of a mutation of the XK gene on the X chromosome. Somatosensory-evoked potential and transcranial magnetic stimulation studies demonstrated that the central sensory and motor conduction times were abnormally prolonged for the lower extremity but normal for the upper extremity. CONCLUSIONS:This is the first report of the involvement of the central sensorimotor tracts for the legs in a patient with McLeod syndrome. The clinical neurophysiological technique revealed the central sensorimotor tracts involvements clinically masked by neuropathy.	0
Importance:As genetic and genomic screening is becoming more widely accessed, correctly distinguishing pathogenic from nonpathogenic variants is of increasing relevance. Objective:To reevaluate a previously reported family in whom the p.(Pro50Leu) variant in the gene GUCA1A was associated with a dominant retinal dystrophy, in light of new examination findings in the proband's daughter. Design, Setting, and Participants:A genetic study relating to a family with an inherited retinal dystrophy was performed at the retinal genetics service of Moorfields Eye Hospital from October 27, 2009, to May 23, 2019, after the proband's daughter underwent fundus examination. Main Outcomes and Measures:Results of sequencing of X chromosome-linked retinitis pigmentosa genes in the proband and specific analysis of the repetitive ORF15 region of the RPGR gene. Results:A frame-shifting single-nucleotide deletion was found in the ORF15 exon of RPGR (GRCh37 [hg19] x:38145160delT; NM_001034853.1: c.3092delA p.[Glu1031Glyfs*58]), which may be associated with the loss of 121 amino acid residues at the carboxyl terminus of the protein. The p.(Pro50Leu) variant in GUCA1A was also found to be too common in a publicly available genome database to be a fully penetrant cause of a dominant retinal dystrophy. Conclusions and Relevance:The phenotype in the family is now associated with the variant in RPGR. The findings suggest that the p.(Pro50Leu) variant in GUCA1A should not be regarded as pathogenic. This report also highlights the relevance of examining relatives, of reevaluating diagnoses in light of new data, and of considering X chromosome-linked inheritance in apparently autosomal dominant pedigrees unless there is clear male-to-male transmission.	0
BACKGROUND:Loss-of-function mutations of human cardiac sodium channel gene SCN5A induce a wide range of arrhythmic disorders. Mutation carriers with co-existing conditions such as congenital heart diseases and histories of cardiac surgeries, could develop complex arrhythmic events that are difficult to diagnose. CASE PRESENTATION:A 41-year-old Japanese male with a history of a surgical closure of an ASD presented impairment of consciousness by wide QRS tachycardia. Because the patient's baseline ECG in sinus rhythm showed similar QRS axis with right bundle brunch block morphology, we suspected supraventricular tachycardia (SVT). During hospitalization, the patient developed polymorphic ventricular tachycardia that was induced by bradycardia. In an electrophysiological study, the SVT was identified as right atrial incisional tachycardia circulating around the scar in the right atrium. The genetic analysis revealed a heterozygous SCN5A c.4037-4038 del TC, p. L1346HfsX38 variant. We diagnosed this patient as having progressive cardiac conduction disorder (PCCD) and polymorphic VT caused by the mutation. Incisional tachycardia with wide QRS morphology was a by-standing comorbidity related to the history of cardiac surgery which could miss lead the diagnosis. The patient's SVT was eliminated by radiofrequency catheter ablation. An implantable cardioverter defibrillator (ICD) was implanted for the secondary prevention of polymorphic VT. Cardiac pace-making therapy by the ICD to avoid bradycardia effectively suppressed the patient's arrhythmic events. CONCLUSIONS:We treated a patient with a sodium channel gene variant. Co-existing SVT originated by a scar in the right atrium made the diagnosis extremely difficult. A multilateral diagnostic approach using an ECG analysis, an electrophysiological study, and genetic screening enabled effective combination therapy comprised of catheter ablation and an ICD.	0
INTRODUCTION:The coexistence of progressive familial intrahepatic cholestasis type 2, failure to thrive due to an LPIN3 mutation, and stigmata of neonatal neurofibromatosis represents a complex diagnostic challenge. CASE REPORT:We present a child with cholestasis requiring hepatic transplantation, explained by the progressive familial intrahepatic cholestasis type 2, failure to thrive could be contributed to by the LPIN3 mutation, and skin findings along with the family history of the patient was due to neurofibromatosis type 1. CONCLUSION:Our case illustrates the complexities of multiple genetic mutations in a child.	0
PURPOSE OF REVIEW:The discovery of new disease-causing genes and availability of next-generation sequencing platforms have both progressed rapidly over the last few years. For the practicing neurologist, this presents an increasingly bewildering array both of potential diagnoses and of means to investigate them. We review the latest newly described genetic conditions associated with dystonia, and also address how the changing landscape of gene discovery and genetic testing can best be approached, from both a research and a clinical perspective. RECENT FINDINGS:Several new genetic causes for disorders in which dystonia is a feature have been described in the last 2 years, including ZNF142, GSX2, IRF2BPL, DEGS1, PI4K2A, CAMK4, VPS13D and VAMP2. Dystonia has also been a newly described feature or alternative phenotype of several other genetic conditions, notably for genes classically associated with several forms of epilepsy. The DYT system for classifying genetic dystonias, however, last recognized a new gene discovery (KMT2B) in 2016. SUMMARY:Gene discovery for dystonic disorders proceeds rapidly, but a high proportion of cases remain undiagnosed. The proliferation of rare disorders means that it is no longer realistic for clinicians to aim for diagnosis to the level of predicting genotype from phenotype in all cases, but rational and adaptive use of available genetic tests can certainly expedite diagnosis.	0
A 34-year-old man presents with recurrent episodes of acute reversible muscle weakness, soreness, pain, cramps and myoglobinuria with elevated creatine kinase. Symptoms were triggered by fasting, sustained long duration exercise and viral infection. A metabolic myopathy was suspected. Genetic testing showed a homozygous pathogenic variant in CPT2 gene resulting in deficiency of Carnitine Pamitoyl transferase II, an enzyme in the carnitine cycle. The cycle plays a vital role in transport of long chain hydrophobic fatty acids from the cytosol into the mitochondrial matrix for the production of energy via β-oxidation. Carnitine Pamitoyl transferase II deficiency is the most common inherited disorder of lipid metabolism affecting the skeletal muscle of adults. It is also the most frequent cause of hereditary myoglobinuria across all ages. Our case presents an analysis of important clinical features of carbohydrate and lipid metabolism disorders. It highlights how thermolability of the mutant enzyme, rather than its actual deficiency, explains triggering of muscle symptoms by prolonged exercise, infections, febrile episodes, or exposure to cold.	0
The recombination activating genes, including RAG1 and RAG2, are essential for V(D)J somatic recombination in lymphocytes. Leaky severe combined immunodeficiency disorder (SCID) is characterized by normal or intermediate T cells and normal to absent B cells associated with partial T cell and B cell dysfunction. We present a newly found RAG1 deficiency in a 21-year-old boy with leaky SCID. Immunoglobulin levels, flow cytometry, and whole exome sequencing (WES) were evaluated. Flow cytometric analysis revealed a decreased number of CD3+, CD4+, and CD8+ T cells, and B cells whereas NK cell counts were normal. Immunoglobulin levels were also decreased. The WES revealed a newly found homozygous mutation of RAG1 gene (NM_000448: exon 2: c.C2275T). Atypical features, including leukopenia, candidiasis, and low lymphocyte counts in patients with late-onset combined immunodeficiency disorders (CID) such as leaky SCID due to RAG1 deficiency may result in misdiagnosis and inadequate therapy instead of adopting the curative hematopoietic stem cell transplantation in these patients.	0
PURPOSE:Hirschsprung disease (HSCR) has previously been associated with increased risk of medullary thyroid cancer. The aim of this study was to assess the overall risk of malignancies in patients with Hirschsprung disease in a population-based cohort. METHODS:This was a nationwide, population-based cohort study. The study exposure was HSCR and the study outcome was malignancy. The cohort included all individuals with HSCR registered in the Swedish National Patient Register between 1964 and 2013 and ten age- and sex-matched controls per patient, randomly selected from the Population Register. Data were linked with the Swedish National Cancer Register to identify individuals with malignancy diagnosis. RESULTS:The cohort comprised 739 individuals with HSCR (565 male) and 7390 controls (5650 male). Median age of the cohort was 19 years (range 2-49). In total nine (1.2%) individuals in the exposed cohort were diagnosed with malignancies compared to 57 (0.8%) in the non-exposed cohort (p = 0.195). Median age at malignancy diagnosis was 3 years (range 0-46) in the exposed group, compared to 23 (range 0-42), p = 0.132. No cases with medullary carcinoma of the thyroid were found in this cohort. CONCLUSIONS:There was no significant difference in risk of malignancies in the exposed group compared to the unexposed group.	0
BACKGROUND:In mammals, hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that is characterized by sparse hair, tooth abnormalities, and defects in cutaneous glands. Only four genes, EDA, EDAR, EDARADD and WNT10A account for more than 90% of HED cases, and EDA, on chromosome X, is involved in 50% of the cases. In this study, we explored an isolated case of a female Holstein calf with symptoms similar to HED. RESULTS:Clinical examination confirmed the diagnosis. The affected female showed homogeneous hypotrichosis and oligodontia as previously observed in bovine EDAR homozygous and EDA hemizygous mutants. Under light microscopy, the hair follicles were thinner and located higher in the dermis of the frontal skin in the affected animal than in the control. Moreover, the affected animal showed a five-fold increase in the number of hair follicles and a four-fold decrease in the diameter of the pilary canals. Pedigree analysis revealed that the coefficient of inbreeding of the affected calf (4.58%) was not higher than the average population inbreeding coefficient (4.59%). This animal had ten ancestors in its paternal and maternal lineages. By estimating the number of affected cases that would be expected if any of these common ancestors carried a recessive mutation, we concluded that, if they existed, other cases of HED should have been reported in France, which is not the case. Therefore, we assumed that the causal mutation was dominant and de novo. By analyzing whole-genome sequencing data, we identified a large chromosomal inversion with breakpoints located in the first introns of the EDA and XIST genes. Genotyping by PCR-electrophoresis the case and its parents allowed us to demonstrate the de novo origin of this inversion. Finally, using various sources of information we present a body of evidence that supports the hypothesis that this mutation is responsible for a skewed inactivation of X, and that only the normal X can be inactivated. CONCLUSIONS:In this article, we report a unique case of X-linked HED affected Holstein female calf with an assumed full inactivation of the normal X-chromosome, thus leading to a severe phenotype similar to that of hemizygous males.	0
Krüppel-like factor 1 (KLF1/EKLF) is a transcription factor that globally activates genes involved in erythroid cell development. Various mutations are identified in the human KLF1 gene. The E325K mutation causes congenital dyserythropoietic anemia (CDA) type IV, characterized by severe anemia and non-erythroid-cell-related symptoms. The CDA mutation is in the second zinc finger of KLF1 at a position functionally involved in its interactions with DNA. The molecular parameters of how CDA-KLF1 exerts its biological effects have not been addressed. Here, using an in vitro selection strategy, we determined the preferred DNA-binding site for CDA-KLF1. Binding to the deduced consensus sequence is supported by in vitro gel shifts and by in vivo functional reporter gene studies. Two significant changes compared to wild-type (WT) binding are observed: G is selected as the middle nucleotide, and the 3' portion of the consensus sequence is more degenerate. As a consequence, CDA-KLF1 did not bind the WT consensus sequence. However, activation of ectopic sites is promoted. Continuous activation of WT target genes occurs if they fortuitously contain the novel CDA site nearby. Our findings provide a molecular understanding of how a single mutation in the KLF1 zinc finger exerts effects on erythroid physiology in CDA type IV.	0
The linker of nucleoskeleton and cytoskeleton (LINC) complex is an essential multi-protein structure spanning the eukaryotic nuclear envelope. The LINC complex functions to maintain nuclear architecture, positioning, and mobility, along with specialized functions in meiotic prophase and chromosome segregation. Members of the LINC complex were recently identified in maize, an important scientific and agricultural grass species. Here we characterized Maize LINC KASH AtSINE-like2, MLKS2, which encodes a highly conserved SINE-group plant KASH protein with characteristic N-terminal armadillo repeats (ARM). Using a heterologous expression system, we showed that actively expressed GFP-MLKS2 is targeted to the nuclear periphery and colocalizes with F-actin and the endoplasmic reticulum, but not microtubules in the cell cortex. Expression of GFP-MLKS2, but not GFP-MLKS2ΔARM, resulted in nuclear anchoring. Genetic analysis of transposon-insertion mutations, mlks2-1 and mlks2-2, showed that the mutant phenotypes were pleiotropic, affecting root hair nuclear morphology, stomatal complex development, multiple aspects of meiosis, and pollen viability. In male meiosis, the mutants showed defects for bouquet-stage telomere clustering, nuclear repositioning, perinuclear actin accumulation, dispersal of late prophase bivalents, and meiotic chromosome segregation. These findings support a model in which the nucleus is connected to cytoskeletal F-actin through the ARM-domain, predicted alpha solenoid structure of MLKS2. Functional conservation of MLKS2 was demonstrated through genetic rescue of the misshapen nuclear phenotype of an Arabidopsis (triple-WIP) KASH mutant. This study establishes a role for the SINE-type KASH proteins in affecting the dynamic nuclear phenomena required for normal plant growth and fertility. Abbreviations: FRAP: Fluorescence recovery after photobleaching; DPI: Days post infiltration; OD: Optical density; MLKS2: Maize LINC KASH AtSINE-like2; LINC: Linker of nucleoskeleton and cytoskeleton; NE: Nuclear envelope; INM: Inner nuclear membrane; ONM: Outer nuclear membrane.	0
OBJECTIVE: To examine the performance of the 11-13 weeks scan in detecting non-chromosomal abnormalities. METHODS: Prospective first-trimester screening study for aneuploidies, including basic examination of the fetal anatomy, in 45 191 pregnancies. Findings were compared to those at 20-23 weeks and postnatal examination. RESULTS: Aneuploidies (n = 332) were excluded from the analysis. Fetal abnormalities were observed in 488 (1.1%) of the remaining 44 859 cases; 213 (43.6%) of these were detected at 11-13 weeks. The early scan detected all cases of acrania, alobar holoprosencephaly, exomphalos, gastroschisis, megacystis and body stalk anomaly, 77% of absent hand or foot, 50% of diaphragmatic hernia, 50% of lethal skeletal dysplasias, 60% of polydactyly, 34% of major cardiac defects, 5% of facial clefts and 14% of open spina bifida, but none of agenesis of the corpus callosum, cerebellar or vermian hypoplasia, echogenic lung lesions, bowel obstruction, most renal defects or talipes. Nuchal translucency (NT) was above the 95th percentile in 34% of fetuses with major cardiac defects. CONCLUSION: At 11-13 weeks some abnormalities are always detectable, some can never be and others are potentially detectable depending on their association with increased NT, the phenotypic expression of the abnormality with gestation and the objectives set for such a scan.	0
Acquired hypoganglionosis (HG) is a rare enteric gastrointestinal neuromuscular disorder previously associated with chronic inflammation that can lead to constipation, ileus, and even death. There is little known about the pathophysiology of acquired hypoganglionosis, and it is unclear if medications are related to the development of the disease. Clozapine is an atypical antipsychotic used to treat refractory schizophrenia that is well known for its side effects including agranulocytosis and gastrointestinal dysmotility. This is an unusual case of acquired hypoganglionosis in a patient with anticholinergic toxicity on clozapine therapy.	0
INTRODUCTION: Few data are available on the epidemiology of interstitial lung diseases (ILDs), especially after the current classification of idiopathic interstitial pneumonias. The aim of this study is to provide data on the epidemiology of ILDs in Greece, under the ATS/ERS international consensus. METHODS: Departments of Pneumonology were contacted and asked to complete a questionnaire for every case of ILD that was alive on 2004 as well as for every new case from 1st January 2004 to 31st December 2004. Questions on the patients' demographic data, the exact diagnosis and the procedures used to establish the diagnosis were included. Centers covering about 60% of the Greek population have been analyzed. RESULTS: A total of 967 cases have been registered. The estimated prevalence of ILDs is 17.3 cases per 100,000 inhabitants. The estimated annual incidence of ILDs is 4.63 new cases per 100,000 inhabitants. The most frequent disease is sarcoidosis (34.1%), followed in decreasing order by idiopathic pulmonary fibrosis (19.5%), ILD associated with collagen vascular diseases (12.4%), cryptogenic organizing pneumonia (5.3%), histiocytosis (3.8%), and hypersensitivity pneumonitis (2.6%). Unclassified ILD or not otherwise specified accounted for the 8.5% of prevalent cases. CONCLUSIONS: These data suggest that sarcoidosis and idiopathic pulmonary fibrosis are the most frequent ILDs in our population. In comparison with the few previous reports, interesting dissimilarities have been observed.	1
AIMS:Nodal staging in colorectal cancer (CRC) informs prognosis and guides adjuvant treatment decisions. A standard minimum of 12 lymph nodes is widely used, with additional sampling performed as required. However, there is little data on how lymph node resampling in this context has an impact on nodal stage. The aim of this study was to evaluate the effectiveness of resampling in detecting metastases and tumour deposits, and the impact on stage. METHODS AND RESULTS:A retrospective cohort analysis was performed on CRC resections that underwent resampling due to an initial yield of <12, from 2008-2018. Data relating to the patient demographics, specimen, malignancy, and prosection were collected. Slides were reviewed to quantify nodal metastases and tumour deposits before and after resampling. Among ≥pN1 cases, logistic regression analysis was performed to evaluate factors that predicted finding additional metastases and tumour deposits. The cohort comprised 395 cases, of which resampling identified nodal metastases and/or tumour deposits in 30 (7.6%) cases; nodal upstaging occurred in 20 (5.1%) cases; 8 (2.0%) changed from pN0 to ≥pN1. No factors predicted resampling positive lymph nodes or tumour deposits, and pN upstaging occurred across a variety of cases. A subgroup analysis was performed to assess the impact of resampling on high-risk features in stage II cases (n=117). There were 33 (8.5%) patients who no longer had any high-risk features after resampling. CONCLUSIONS:Lymph node resampling has an impact on nodal staging and possible treatment decisions in a considerable proportion of patients and is recommended in all cases with <12 lymph nodes.	0
Background:Corticotomy is a technique presumed as useful to decrease the time for orthodontic treatment, however, it is necessary to do a systematic review in order to determine if there is enough scientific evidence to back up the use of Corticotomy to accelerate the treatment. Material and Methods:Data was stockpiled from the electronic database such as PubMed, Cochrane, Scopus y Science Direct, according to the PRISMA linings for systematic reviews, using the following keywords: accelerated movement of the teeth AND osteotomy AND piezocision AND corticotomy AND orthodontics. Only English, Spanish and French language articles that met the criteria needed were included. Results:In the different accelerated orthodontics techniques, a significant reduction in the total time of orthodontic treatment was obtained. There were no major complications reported in any study. The less invasive procedures had better acceptance. Discussion:The surgical approaches are not only limited to usual orthodontic treatments, but they have also been used as an alternative for the approach of a palatal fistula in a patient with bilateral cleft lip and palatine orofaciodigital syndrome Type I. Conclusions:There has been a growing interest in the use of alveolar corticotomies as an adjunct to orthodontic treatment, due to a deeper understanding of its effects and a more robust investigation based on the evidence. All published results indicate a decrease in the total treatment time. Key words:Accelerated movement of the teeth, piezocision, corticotomy AND orthodontics.	0
Autoimmune and autoinflammatory diseases are associated with severe morbidity, and represent an impactful health and economic burden worldwide. The treatment of these diseases can include a course with detrimental side effects. Immunosuppression increases the risk of opportunistic infections, but in some cases, the abrupt discontinuation of these medications can result in immune reconstitution inflammatory syndrome. Special attention must be directed to endemic tropical infections, such as leishmaniasis, Chagas disease, malaria, arbovirosis, yellow fever, leprosy, paracoccidioidomycosis, disseminated strongyloidiasis, and ectoparasitosis. These endemic diseases of developing countries can be considered as possible emerging diseases in developed regions partially because of environmental factors and migration. In the present article, we aim to review the evidence-based aspects of the most important opportunistic tropical infections in immunosuppressed patients. We also aim to review the important aspects of vaccination, chemical prophylaxis, and treatment for these infections in people with medication-induced immunosuppression.	0
BACKGROUND:Dubowitz syndrome is a rare, autosomal recessive disorder characterized by intrauterine and postnatal growth retardation, severe microcephaly, psychomotor retardation, hyperactivity, eczema, and characteristic dysmorphic facial features. Although many cases have been reported, the cause of this disease is still unknown. CASE:We present here the case of a Lebanese girl with Dubowitz syndrome in whom an unpleasant urine odor was persistently reported since birth. CONCLUSION:Although Dubowitz syndrome has been largely described in the medical literature, this is the first time that a peculiar urine odor was reported. This case report adds a new and unusual feature to the numerous findings related to this rare polymorphous syndrome.	0
We report the case of a 69-year-old man five-month post double lung transplant for idiopathic pulmonary fibrosis (IPF) who presented with progressive breathlessness, loss of lung function, and diffuse ground glass shadowing on the chest computed tomography. Transbronchial lung biopsy revealed foamy macrophages, hyperplasia of type II pneumocytes, and eosinophilic material in the alveolar space. Video thoracic lung biopsy was performed, and histology confirmed pulmonary alveolar proteinosis. Anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies were negative. Bilateral sequential whole lung lavage (WLL) was performed. Lavage fluid recovered during WLL was notably dark brown in colour and upon analysis was shown to contain heavily oxidized protein (lipofuscin), giant lipofuscin-engorged macrophages, and a highly pro-inflammatory gene expression profile. Following WLL, the patient's symptoms, lung function, and radiology appearance improved. His repeat bronchoalveolar lavage (BAL) fluid analysis showed reduced lipofuscin and normalized macrophage size and gene expression.	0
A well-known typical feature of ectopic pregnancy is an evident gestational sac structure outside of the uterus. However, some cases show atypical appearance that is described as a heterogeneous hypervascular mass. We report two cases of ectopic pregnancy that presented heterogeneous findings mimicking gestational trophoblastic diseases but were correctly diagnosed as ectopic pregnancies on MRI. The first case was an interstitial pregnancy in which the patient underwent surgical treatment. The second case was a cesarean scar pregnancy that was treated conservatively but showed spurious enlargement of pregnancy-related lesions after the treatment. Both cases lacked myometrial invasion on MRI, and the patients were diagnosed with ectopic pregnancies. Invasive findings on MRI may discriminate ectopic pregnancy from trophoblastic tumors and avoid unnecessary hysterectomy.	0
Progressive deterioration of neuroimaging and electroencephalography (EEG) had been described in rhizomelic chondrodysplasia punctata (RCDP); however, serial EEG data showing sequential EEG changes(before and after seizure onset) is lacking. We report a child with a diagnosis of type 1 RCDP, who had a progressive decline in EEG and radiologic findings over a 5 year period. Her first EEG was normal at the age of 8 months. Follow-up EEG at the age of 2 years showed a mild background slowing as well as frequent 1-2 Hz central-parietal spike wave with midline involvement. Just before 3 years of age, she started to seizures, when the EEG showed further worsening with frequent multifocal spikes and bursts of generalized high amplitude spike and spike-wave discharges. The transition of EEG from normal background to the appearance of focal epileptiform abnormality before the seizure onset followed by further deterioration at the seizure onset had not been reported as per our knowledge. This study emphasizes that serial EEGs may provide valuable information about impending seizure activity. Further studies are needed to calculate the lag time between the detection of epileptiform activities and the onset of clinical seizure activities. In addition, research studies are warranted to determine if early (before or at the onset of epileptogenesis rather than after seizure onset) use of replacement therapy or antiepileptic therapy (antiepileptic drugs or diet) can modify epilepsy severity and neurologic prognosis in this devastating disease.	0
Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, also known as Hay-Wells syndrome, is an autosomal genetic disease with the main features of ankyloblepharon filiforme adnatum, ectodermal defects, and cleft lip/palate. The authors report a patient with 17 months old girl with AEC syndrome having ankyloblepharon, cleft and palate, and ectrodactyly with some associated features. Etiology, clinical features, differential diagnosis, and treatment have been elaborated in this clinical report.	0
Several cases have recently been reported concerning the development of a syndrome of acute lung injury associated with the use of electronic cigarettes, leading to respiratory failure and several deaths. We present a case of a young veteran who presented with e-cigarette vaping associated lung injury (EVALI) to a primary care clinic and who required subsequent inpatient admission and home oxygen therapy after discharge. The patient afterwards improved after a three-month course of steroids and cessation of THC-containing electronic cigarettes, consistent with previously reported cases. Furthermore, evidence on bronchoscopy and biopsy demonstrated intracellular lipid droplets in the patient's macrophages. This outpatient case of EVALI prompts primary care providers to raise suspicion of this condition, and enquire about the use of e-cigarettes, particularly THC-containing vaping products. Furthermore, in the setting of the COVID-19 pandemic, similar clinical and radiographic presentations between COVID-19 and EVALI can be seen.	0
PURPOSE:Stargardt disease (On-Line Mendelian Inheritance In Man 242000, STGD1) is the most common inherited macular dystrophy. STGD1 is typically a young-adult-onset disease that is recurrently associated with the ABCA4 mutant allele G1961E in homozygosity or compound heterozygosity. The genetics of ABCA4-related retinopathy in the Arabian Gulf region have not been well-studied. This report reviews the experience of the Ocular Genetics Service at Cleveland Clinic Abu Dhabi with clinically diagnosed ABCA4-related retinopathy in Emirati patients who underwent genetic testing. METHODS:Retrospective case series (2016-2018, inclusive). RESULTS:All 22 identified patients (19 families; 11 males, 11 females; first visual symptoms 5-33 years old) were found to harbor biallelic ABCA4 pathologic variants. There were 14 childhood-onset cases (onset before 18 years of age; 12 families; 7 males, 7 females; first visual symptoms from 5 to 12 years old, median 8)-all were homozygous, 11 for the same novel double mutant allele G1961E/L857P. Those who underwent electroretinography (8) had cone-rod rather than isolated macular dystrophy. There were 8 adult-onset cases (onset at or after 18 years of age; 7 families; 4 males, 4 females; first visual symptoms from 18 to 33 years old, median 22)-all were compound heterozygous, seven harboring the common G1961E mutant allele. CONCLUSION:The molecular yield for biallelic ABCA4 pathogenic variants is high for clinically diagnosed ABCA4-related retinopathy in Emiratis (100% in this case series). Homozygosity for a novel complex allele G1961E/L857P causes a childhood-onset cone-rod dystrophy rather than the young-adult-onset macular dystrophy that is associated with G1961E alone. This G1961/L857P complex allele likely represents a founder effect for the region.	0
Congenital lactic acidosis due to pyruvate dehydrogenase phosphatase (PDP) deficiency is very rare. PDP regulates pyruvate dehydrogenase complex (PDC) and defective PDP leads to PDC deficiency. We report a case with functional PDC deficiency with low activated (+dichloroacetate) and inactivated (+fluoride) PDC activities in lymphocytes and fibroblasts, normal activity of other mitochondrial enzymes in fibroblasts, and novel biallelic frameshift mutation in the PDP1 gene, c.575dupT (p.L192FfsX5), with absent PDP1 product in fibroblasts. Unexpectedly, the patient also had low branched-chain 2-ketoacid dehydrogenase (BCKDH) activity in fibroblasts with slight elevation of branched-chain amino acids in plasma and ketoacids in urine but with no pathogenic mutations in the enzymes of BCKDH, which could suggest shared regulatory function of PDC and BCKDH in fibroblasts, potentially in other tissues or cell types as well, but this remains to be determined. The clinical presentation of this patient overlaps that of other patients with primary-specific PDC deficiency, with neonatal/infantile and childhood lactic acidosis, normal lactate to pyruvate ratio, elevated plasma alanine, delayed psychomotor development, epileptic encephalopathy, feeding difficulties, and hypotonia. This patient exhibited marked improvement of overall development following initiation of ketogenic diet at 31 months of age. To the best of our knowledge, this is the fourth case of functional PDC deficiency with a defined mutation in PDP1. Synopsis:Pyruvate dehydrogenase phosphatase (PDP) regulates pyruvate dehydrogenase complex (PDC) and defective PDP due to PDP1 mutations leads to PDC deficiency and congenital lactic acidosis.	0
Although the clinical presentations of patients with pityriasis lichenoides et varioliformis acuta (PLEVA) may vary, bullae are not usually part of the clinical spectrum. To date, only two other cases of a bullous variant of PLEVA with evidence of autoantibodies against hemidesmosomal antigens have been reported. The term PLEVA pemphigoides was suggested for this unique clinical, pathological and serological combination of both PLEVA and bullous pemphigoid.	0
Patients with multiple myeloma (MM) accumulate adverse copy number aberrations (CNAs), gains of 1q21, and 17p deletions during disease progression. A subset of these patients develops heightened 1q12 pericentromeric instability and jumping translocations of 1q12 (JT1q12), evidenced by increased copy CNAs of 1q21 and losses in receptor chromosomes (RC). To understand the progression of these aberrations we analyzed metaphase cells of 50 patients with ≥4 CNAs of 1q21 by G-banding, locus specific FISH, and spectral karyotyping. In eight patients with ≥5 CNAs of 1q21 we identified a chromosome instability phenotype similar to that found in ICF syndrome (immunodeficiency, centromeric instability, and facial anomalies). Strikingly, the acquired instability phenotype identified in these patients demonstrates the same transient structural aberrations of 1q12 as those found in ICF syndrome, suggesting similar underlying pathological mechanisms. Four types of clonal aberrations characterize this phenotype including JT1q12s, RC deletions, 1q12-21 breakage-fusion-bridge cycle amplifications, and RC insertions. In addition, recurring transient aberrations include 1q12 decondensation and breakage, triradials, and 1q micronuclei. The acquired self-propagating mobile property of 1q12 satellite DNA drives the continuous regeneration of 1q12 duplication/deletion events. For patients demonstrating this instability phenotype, we propose the term "Jumping 1q Syndrome."	0
To date, only one study assessed quality of life (QoL) in patients with hereditary neuropathy with liability to pressure palsies (HNPP). We aimed to fill in this gap by investigating QoL in a cohort of patients with HNPP compared to Charcot-Marie-Tooth type 1A (CMT1A) patients, as well as to analyze sociodemographic and clinical features associated with QoL in HNPP. Eighteen genetically confirmed HNPP patients were age-and gender-matched with 18 CMT1A patients. SF-36 questionnaire was used to assess QoL. Medical Research Council (MRC) Sum Score, CMT Neuropathy Score (CMTNS), Overall Neuropathy Limitation Scale Score (ONLS), Falls Efficacy Score (FES), Visual Analog Pain Scale, Beck Depression Inventory (BDI) and Fatigue Severity Scale (FSS) were also used in our study. Although HNPP patients were less clinically impaired, no difference was observed in these two cohorts regarding SF-36 scores. Worse QoL in HNPP patients was associated with lower education (p < 0.01), physical work (p < 0.05), higher number of clinically affected nerves during the disease course (p < 0.01), worse MRC-SS score (p < 0.01), worse ONLS score (p < 0.01), and with more severe pain (p < 0.01), depression (p < 0.01), and fatigue (p < 0.01). Worse pain at the moment of testing appeared as a significant independent predictor of worse QoL in HNPP patients (β = - 0.93, p < 0.001). QoL was similarly impaired in patients with HNPP and patients with CMT1A. We identified different factors associated with QoL in HNPP, and many of these factors are amenable to treatment which is of special interest in these still incurable disease.	0
BACKGROUND:Hyperthyroidism in pregnancy may pose a great threat to maternal and fetal health. The risk of hyperthyroid heart disease (HHD), even heart failure, is significantly elevated in pregnant women. AIM:To investigate the clinical characteristics, prognosis, and therapy of HHD in pregnant women. METHODS:We searched the patient registry data at West China Second University Hospital of Sichuan University in Chengdu, China, following the approval by the Ethics Committee. We retrospectively analyzed the clinical characteristics of pregnant women diagnosed with HHD. The medical records of women with HHD during pregnancy from January 2012 to December 2017 were obtained from the electronic medical records system. All the included patients were followed in outpatient clinics and by telephone interviews until October 2018. RESULTS:A total of 155 patients were diagnosed with thyrotoxicosis, of whom six were diagnosed with HHD. Three of them had regular antenatal care. Two patients were complicated with acute heart failure attacks, and one of them had a stillbirth. Both of these patients had a long history of Graves' disease with poor treatment compliance. Treatments of precipitating factors such as the control of infection could relieve the symptoms and prolong gestation for a better prognosis. Hyperthyroid heart failure could be controlled with aggressive diuretics and management of the coexisting complications. Intense monitoring and timely anti-heart failure treatment were crucial in patients with severe cardiac damage. Our findings indicated the importance of regular antenatal care and treatment adherence in patients with hyperthyroidism. CONCLUSION:The timely and accurate diagnosis of HHD and the implementation of effective management are important for a better prognosis in pregnant women with HHD. Improvement in patients' awareness of thyrotoxicosis is needed.	0
OBJECTIVE:We performed a systematic literature review to identify all reports of immune checkpoint inhibitor-associated inflammatory arthritis to describe it phenotypically and serologically. METHODS:PubMed, Embase, and Cochrane databases were searched for reports of musculoskeletal immune-related adverse events secondary to ICI treatment. Publications were included if they provided individual patient level data regarding the pattern of joint involvement. Descriptive statistics were used to summarize results. RESULTS:A total of 4339 articles were screened, of which 67 were included, encompassing 372 patients. The majority of patients had metastatic melanoma (57%), and they were treated with anti-PD1 or anti-PDL1 therapy (78%). Median time to onset of arthritis was 4 months (range, 1 day to 53 months). Forty-nine percent had polyarthritis, 17% oligoarthritis, 3% monoarthritis, 10% arthralgia, and 21% polymyalgia rheumatica. More than half of patients were described as having a "rheumatoid arthritis-like" presentation. Nine percent tested positive for rheumatoid factor or anti-cyclic citrullinated peptide antibodies. Seventy-four percent required corticosteroids, and 45% required additional medications. Sixty-three percent achieved arthritis control, and 32% were ultimately able to discontinue antirheumatic treatments. Immune checkpoint inhibitors were continued in 49%, transiently withheld in 11%, and permanently discontinued due to musculoskeletal immune-related adverse events in 13%. CONCLUSIONS:Half of reported immune checkpoint inhibitor-associated arthritis cases present with polyarthritis (often RA-like), but only 9% are seropositive. Polymyalgia rheumatica is also common. Most patients respond to steroids alone, but about half require additional medications. Further studies are needed to determine long-term musculoskeletal outcomes in these patients, and the impact of arthritis treatment on cancer survival.	0
OBJECTIVE:To explore the genetic basis for three patients with development delay and to correlate their clinical phenotypes with genetic findings. METHODS:The karyotypes of the probands and their parents were analyzed by conventional G-banding. Chromosomal microarray analysis (CMA) was used to detect microdeletion and microduplication. RESULTS:No kartotypic abnormality was detected in the patients and their parents. CMA analysis identified a de novo 3.10 Mb deletion on chromosome 15q24.1q24.2 in case 1, a de novo 3.14 Mb deletion at 15q24.1q24.2 in case 2, and a 3.13 Mb deletion at 15q24.1q24.2 in case 3. All deletions have encompassed the CPLX3,SEMA7A and SIN3A genes. CONCLUSION:The three patients were diagnosed with 15q24 microdeletion syndrome. CPLX3,SEMA7A and SIN3A may be the key genes responsible for this syndrome.	0
The corpus callosum is the largest fibre tract in the brain, connecting the two cerebral hemispheres, and thereby facilitating the integration of motor and sensory information from the two sides of the body as well as influencing higher cognition associated with executive function, social interaction and language. Agenesis of the corpus callosum is a common brain malformation that can occur either in isolation or in association with congenital syndromes. Understanding the causes of this condition will help improve our knowledge of the critical brain developmental mechanisms required for wiring the brain and provide potential avenues for therapies for callosal agenesis or related neurodevelopmental disorders. Improved genetic studies combined with mouse models and neuroimaging have rapidly expanded the diverse collection of copy number variations and single gene mutations associated with callosal agenesis. At the same time, advances in our understanding of the developmental mechanisms involved in corpus callosum formation have provided insights into the possible causes of these disorders. This review provides the first comprehensive classification of the clinical and genetic features of syndromes associated with callosal agenesis, and provides a genetic and developmental framework for the interpretation of future research that will guide the next advances in the field.	0
INTRODUCTION:Chronic beryllium disease (CBD) is characterized by accumulation of macrophages and beryllium-specific CD4+ T cells that proliferate and produce Th1 cytokines. 5-Amino salicylic acid (5-ASA) is currently used to treat inflammatory bowel disease and has both antioxidant and anti-inflammatory actions. We hypothesized that 5-ASA may be a beneficial therapeutic in CBD. METHODS:Seventeen CBD patients were randomized 3:1 to receive 5-ASA 500-mg capsules or placebo four times daily for 6 weeks orally. Primary study endpoints included changes in beryllium lymphocyte proliferation (BeLPT). Secondary endpoints included changes in bronchoalveolar lavage (BAL) fluid, cells, serum, and blood cell glutathione (GSH) levels, BAL cell TNF-α levels, lung function, and quality of life measures. RESULTS:5-ASA decreased BAL cell BeLPT by 20% within the 5-ASA treatment group. No significant changes were observed in serum, PBMCs, BALF, or BAL cell GSH levels in either the 5-ASA or placebo treatment group. 5-ASA treatment decreased ex vivo Be-stimulated BAL cell TNF-α levels within the 5-ASA group and when compared to placebo. Significant improvements were noted in quality of life measurements with 5-ASA treatment. CONCLUSIONS:5-ASA's ability to decrease BAL cell BeLPT and Be-stimulated BAL cell TNF-α levels suggests that 5-ASA may impact the beryllium-specific immune response in CBD. 5-ASA use in other non-infectious granulomatous lung diseases, such as sarcoidosis, may prove to be a useful alternative treatment to corticosteroids for those with mild to moderate disease.	0
OBJECTIVE:Using data from the German Biologics JIA Registry (BIKER), long-term safety of biologics for systemic-onset JIA with regard to adverse events of special interest was assessed. METHODS:Safety assessments were based on adverse event reports after first dose through 90 days after last dose. Rates of adverse event, serious adverse event and 25 predefined adverse events of special interest were analysed. Incidence rates were compared for each biologic against all other biologics combined applying a mixed-effect Poisson model. RESULTS:Of 260 systemic-onset JIA patients in this analysis, 151 patients received etanercept, 109 tocilizumab, 71 anakinra and 51 canakinumab. Patients with etanercept had higher clinical Juvenile Arthritis Disease Activity Score 10 scores, active joint counts and steroid use at therapy start. Serious adverse events were reported with higher frequency in patients receiving canakinumab [20/100 patient years (PY)] and tocilizumab (21/100 PY). Cytopenia and hepatic events occurred with a higher frequency with tocilizumab and canakinumab. Medically important infections were seen more often in patients with IL-6 or IL-1 inhibition. Macrophage activation syndrome occurred in all cohorts with a higher frequency in patients with canakinumab (3.2/100 PY) and tocilizumab (2.5/100 PY) vs anakinra (0.83/100 PY) and etanercept (0.5/100 PY). After adjustment only an elevated risk for infections in anakinra-treated patients remained significant. Three definite malignancies were reported in patients ever exposed to biologics. Two deaths occurred in patients treated with etanercept. CONCLUSION:Surveillance of pharmacotherapy as provided by BIKER is an import approach especially for patients on long-term treatment. Overall, tolerance was acceptable. Differences between several biologics were noted and should be considered in daily patient care.	0
The coordinate growth of the brain and skull is achieved through a series of interactions between the developing brain, the growing bones of the skull, and the fibrous joints, or sutures, that unite the bones. These interactions couple the expansion of the brain to the growth of the bony plates at the sutures. Craniosynostosis, the premature fusion of the bones of the skull, is a common birth defect (1 in 3000 live births) that disrupts coordinate growth and often results in profoundly abnormal skull shape. Individuals affected with Boston-type craniosynostosis, an autosomal dominant disorder, bear a mutated copy of MSX2, a homeobox gene thought to function in tissue interactions. Here we show that expression of the mouse counterpart of this mutant gene in the developing skulls of transgenic mice causes craniosynostosis and ectopic cranial bone. These mice provide a transgenic model of craniosynostosis as well as a point of entry into the molecular mechanisms that coordinate the growth of the brain and skull.	0
INTRODUCTION:Bilateral renal agenesis (BRA) is a lethal diagnosis, specifically meaning that natural survival beyond birth is not expected secondary to pulmonary hypoplasia. Limited contemporary data are available about intervention and the impact of restoring amniotic fluid volume in relation to the risk for lethal pulmonary hypoplasia and other factors that might influence survival in cases of fetal BRA. OBJECTIVE:We report the largest series of patients undergoing fetal intervention and postnatal care for BRA at a single comprehensive fetal center. METHODS:All patients with fetal BRA were reviewed from January 2004 to November 2017. Maternal and neonatal data were collected in an institutional review board-approved retrospective review. RESULTS:From 2014 to 2017, 20 singleton pregnancies with isolated fetal BRA were evaluated and 14 had amnioinfusion. Eight had serial infusions. Of those, there were 6 neonatal deaths. There were 2 neonatal survivors beyond 30 days; however, both died of sepsis on dialysis. One of these survivors received amnioinfusions by percutaneous approach and one via amnioport. There were no survivors to transplantation. CONCLUSION:Fetal intervention via amnioinfusion may promote pulmonary survivorship after birth, but postnatal survival remains poor. Future studies must place an emphasis on standardizing the postnatal approach to this patient population.	0
BACKGROUND:Congenital pseudoarthrosis of the clavicle (CPC) is rare and may require treatment, usually because of an unacceptable appearance or occasionally because of pain in an adolescent patient. Spontaneous union is unknown, and consequently any desired union requires open reduction and bone grafting. Many authors recommend performing the operation at the age of 3-5 years and using different fixation methods. We present our experience with three cases and literature review in an attempt to further elucidate the appropriate timing of the procedure and the fixation method. METHODS:This was a retrospective review of three cases presenting with pseudoarthrosis of the clavicle. All cases were treated by curettage of the pseudoarthrosis, with the void filled using full-thickness ileac crest autologous bone graft and bridging plate-one compression and two anatomical, at different ages. We performed a literature review with emphasis on timing of the procedure, fixation method and complications. RESULTS:All patients healed with good callus formation. One patient (5-year-old female treated using a compression plate) experienced overlying skin irritation and underwent removal of the plate. There were no restriction of movement, pain or any other complaint on the final follow-up. We did not find any difference in the operating complexity at different ages, but when a compression plate was used, it had to be removed later due to bulging of the plate. DISCUSSION:No clinical difference was observed between earlier and late operation. Therefore, we suggest performing a curettage of the pseudoarthrosis, gapping the void using autologous bone graft, and using an anatomical bridging plate.	0
Mutations in SLC4A1, encoding the chloride-bicarbonate exchanger known as anion exchanger 1, have been reported as the sole genetic cause of autosomal dominant distal renal tubular acidosis (dRTA). This disorder is extremely rare and most patients show no clinical symptoms during childhood. Here, we report a case of an infant with early-onset autosomal dominant dRTA caused by SLC4A1 mutation p.Gly609Arg that is detected as a hot spot world widely. Despite the fact that the patient's mother and sister had the same SLC4A1 mutation, all family members presented different clinical courses. A 9-month-old boy was referred to our hospital because of insufficient body weight gain. At the initial visit, his height and weight were 68.2 cm (-1.0 SD) and 6.4 kg (-2.2SD) respectively. Metabolic acidosis with a normal serum anion gap and inappropriate alkaline urine were detected. Abdominal ultrasound indicated bilateral renal medullary high-echoic lesions which suspected nephrocalcinosis. The genetic test revealed a heterozygous mutation c.1825G > A (p.Gly609Arg) in SLC4A1 that directed his diagnosis of autosomal dominant dRTA. The genetic test was performed on the patient's family members, indicating that the same SLC4A1 mutation was detected in his mother and sister. His mother had nephrocalcinosis and metabolic acidosis at the age of 35 years. However, his sister had no clinical symptoms at the age of 6 years without any laboratory abnormalities. This familial case demonstrated that the significant heterogeneity in clinical manifestations may develop even among familial members sharing the same variant.	0
Thyroid hormone replacement for hypothyroidism can be achieved via several approaches utilizing different preparations of thyroid hormones, T3, and/or T4. "Combination therapy" involves administration of both T3 and T4, and was technically the first treatment for hypothyroidism. It was lauded as a cure for the morbidity and mortality associated with myxedema, the most severe presentation of overt hypothyroidism. In the late nineteenth and the early Twentieth centuries, combination therapy per se could consist of thyroid gland transplant, or more commonly, consumption of desiccated animal thyroid, thyroid extract, or thyroglobulin. Combination therapy remained the mainstay of therapy for decades despite development of synthetic formulations of T4 and T3, because it was efficacious and cost effective. However, concerns emerged about the consistency and potency of desiccated thyroid hormone after cases were reported detailing either continued hypothyroidism or iatrogenic thyrotoxicosis. Development of the TSH radioimmunoassay and discovery of conversion of T4-to-T3 in humans led to a major transition in clinical practices away from combination therapy, to adoption of levothyroxine "monotherapy" as the standard of care. Levothyroxine monotherapy has a favorable safety profile and can effectively normalize the serum TSH, the most sensitive marker of hypothyroidism. Whether levothyroxine monotherapy restores thyroid hormone signaling within all tissues remains controversial. Evidence of persistent signs and symptoms of hypothyroidism during levothyroxine monotherapy at doses that normalize serum TSH is mounting. Hence, in the last decade there has been acknowledgment by all thyroid professional societies that there may be a role for the use of combination therapy; this represents a significant shift in the clinical practice guidelines. Further bolstering this trend are the recent findings that the Thr92AlaD2 polymorphism may reduce thyroid hormone signaling, resulting in localized and systemic hypothyroidism. This strengthens the hypothesis that treatment options could be personalized, taking into consideration genotypes and comorbidities. The development of long-acting formulations of liothyronine and continued advancements in development of thyroid regenerative therapy, may propel the field closer to adoption of a physiologic thyroid hormone replacement regimen with combination therapy.	0
BACKGROUND:Erythema elevatum diutinum (EED) belongs to the spectrum of cutaneous leukocytoclastic vasculitides. EED is a very rare dermatosis presenting with reddish to browning papules and plaques. EED may be associated with infections, hematologic and autoimmune disorders. CASE REPORTS:We present two patients with EED, a 50-year-old woman and a 42-year-old man. While the woman shows an association with colitis ulcerosa, the man had an anti-thrombin deficiency. Treatment was started with oral corticosteroid and dapsone, respectively. In both cases, there was a partial and temporary response. CONCLUSIONS:EED is a rare vasculitis with an unusual clinical presentation and a chronic course. Response to treatment is unsatisfactory and in the long-term run sometimes frustrating.	0
Lysosomal storage disorders (LSDs) are a group of genetic disorders caused by mutations in genes encoding enzymes involved in lysosomal function. Schindler disease is an autosomal recessive, inherited LSD caused by defective or non-existent activity of the enzyme α-N-acetylgalactosaminidase (α-NAGA). To date, three main phenotypes of Schindler disease have been described. We report the case of a 68-year-old man presenting with axonal and demyelinating polyneuropathy, sensorineural hearing loss, chronic lymphoedema, angiokeratoma corporis diffusum and bilateral carpal tunnel syndrome. Genetic testing (PCR) for α-galactosidase revealed the c.577G>T (p.Glu193*) mutation in the NAGA gene, confirming Schindler disease, which is clinically compatible with Kanzaki disease and Schindler disease type II. LEARNING POINTS:Schindler disease is a very rare lysosomal storage disorder.To our knowledge, fewer than 20 cases have been described to date.Consequently, each new case should be reported to enhance understanding of the wide range of presentations.	0
Focal facial dermal dysplasias (FFDD) are characterized by congenital bitemporal or preauricular atrophic skin lesions, and either autosomal dominant or autosomal recessive inheritance. Setleis syndrome (SS), FFDD type III, is a severe form of FFDD with the ectodermal lesions plus other striking facial features. Autosomal recessive nonsense and frameshift mutations in TWIST2 have been found to cause SS in some but not all individuals. Here, we report on four unrelated individuals, one with an unclassified FFDD and the other three with classic SS. Chromosomal microarray analyses revealed unique copy number variants of 1p36 in two individuals with duplications at 1p36.22p36.21 and one with a triplication at 1p36.22p36.21. The fourth patient had normal chromosomes by microarray analysis. All four patients had normal TWIST2 exonic sequences. We propose that a dosage effect of one or more of the 30 genes in the 1.3 Mb 1p36.22p36.21 region of overlap is responsible for FFDD/SS manifestations in some individuals, and this mechanism would be inherited as an autosomal dominant trait. In patients with no duplication/triplication of the 1p36.22p36.21 region and no mutations in TWIST2, there are mutation(s) in one of the 30 genes in this region or mutations in other as yet unidentified genes at different locations that may affect the expressions of genes in this region or act independently to cause this developmental disease phenotype.	0
We report on a sibling pair with the EPG5 c.1007A > G mutation who developed a severe form of Vici syndrome and died in infancy. The c.1007A > G (p.Gln336Arg) mutation, affecting the penultimate nucleotide and the splicing of exon 2 is the most common mutation of EPG5 and is typically associated with a less devastating prognosis: cardiomyopathy and cataract are less frequent consequences and the median survival time is 78 months compared to an overall median survival of 42 months. The less severe course related to c.1007A > G was formerly explained by the preserved canonical splicing in 25% of the transcripts. In contrast, we found the messenger RNA encoded by the c.1007A > G allele to be absent, explaining the severe course of the disease. This family provides another example of phenotypic variability related to a differential splicing.	0
We describe a patient with acute leukemia of ambiguous lineage who had trisomy 4 as the sole cytogenetic abnormality. Clinical, pathological, immunophenotypic and molecular features are presented and compared with the previous 4 published cases. Over expression of c-kit, which is localized to chromosome 4, was documented on the leukemic blasts. Prognosis seems to be poor. Treatment with acute lymphoblastic leukemia like regimens seems to be superior compared to acute myeloid leukemia like regimens and allogeneic stem cell transplant is recommended after achieving remission.	0
Thyroid metastasis revealing a primary lung cancer is an extremely rare condition. Only few cases have been reported in the literature. A multidisciplinary approach is essential for the diagnosis. The prognosis is generally poor. We report a case of a 50-year-old man presented with cervical nodules corresponding to a thyroid nodule and lymph nodes. The ultrasonography-guided fine-needle aspiration cytology of the thyroid nodule and a cervical lymphadenopathy concluded to a poorly differentiated adenocarcinoma. Cervical lymphadenopathy biopsy with immunohistochemistry and additional imaging explorations contributed to the diagnosis of a lung adenocarcinoma stage IVB. He died few days after the diagnosis.	0
Progressive osseous heteroplasia (POH) (OMIM 166350) is a rare autosomal dominant condition, characterized by heterotopic ossification of the skin, subcutaneous fat, and deep connective tissue. This condition is distinct from Albright's hereditary osteodystrophy or McCune Albright syndrome (OMIM 103580) and fibrodysplasia ossificans progressiva (OMIM 135100). We present an unusual presentation of POH in a 7-year-old female child. The clinical features included a painful swelling on the left foot, with mechanical complaints. There was no congenital hallux valgus. Family anamnesis was positive in the father. There were subcutaneous ossifications of his left upper arm, right-sided thorax, and lateral side of the right ankle. The father did not allow any radiographs or further examinations. Radiographic examination of the patient revealed ossified subcutaneous plaques on the left foot, lumbar spine, and left scapulae. Additional blood samples were analyzed, revealing no pseudohypoparathyroidism. Sequence analysis of the gene associated with POH, the GNAS1 gene, revealed the heterozygote mutation c.565_568del, previously found in Albright's hereditary osteodystrophy. Histopathological examination of the subcutaneous ossification showed presence of chondrocyte clusters, a feature usually found in fibrodysplasia ossificans progressiva. The combination of the clinical features, the absence of pseudohypoparathyroidism, histology revealing chondrocyte clusters, and the specific GNAS mutation in this patient makes this a truly unusual presentation of POH. The findings in the described case might denote subdivisions of POH. The condition is associated with progressive superficial to deep ossification, progressive restriction of range of motion, and recurrence if excised. We hope to inform pediatricians and orthopedic surgeons to create more awareness of this disorder so that unnecessary treatments can be avoided and proper counseling offered.	0
Infection is an important factor leading to the exacerbation of heart failure (HF), resulting in hospitalization. Demodex species are obligatory parasites in human skin, and increased density was reported in immunocompromised patients. In this study, we aimed to investigate the Demodex density in hospitalized HF patients compared to that of healthy controls. METHODS:This study included 36 HF patients and 36 age and sex-matched healthy controls. Five standardized biopsies were taken from the face of participants and assessed for Demodex by a light microscope. RESULTS:At least one Demodex mite was detected in 20 HF patients and nine of the control group. The number of Demodex mites was significantly higher in the HF group (median 1; min. 0 and max. 10) compared to the control group (median 0; minimum. 0 and maximum. 3). Demodicidosis was positive in 14 of the HF patients. Demodicidosis was not detected in the control group. CONCLUSIONS:This study showed that Demodex positivity is more common in HF patients hospitalized for HF exacerbation. Demodicidosis should be considered in hospitalized HF patients.	0
KEY POINTS:The pathogenic mechanism and the neuromuscular reflex-related phenotype (e.g. tremors accompanied by clonus) of Amish nemaline myopathy, as well as of other recessively inherited TNNT1 myopathies, remain to be clarified. The truncated slow skeletal muscle isoform of troponin T (ssTnT) encoded by the mutant TNNT1 gene is unable to incorporate into myofilaments and is degraded in muscle cells. By contrast to extrafusal muscle fibres, spindle intrafusal fibres of normal mice contain a significant level of cardiac TnT and a low molecular weight splice form of ssTnT. Intrafusal fibres of ssTnT-knockout mice have significantly increased cardiac TnT. Rotarod and balance beam tests have revealed abnormal neuromuscular co-ordination in ssTnT-knockout mice and a blunted response to a spindle sensitizer, succinylcholine. The loss of ssTnT and a compensatory increase of cardiac TnT in intrafusal nuclear bag fibres may increase myofilament Ca2+ -sensitivity and tension, impairing spindle function, thus identifying a novel mechanism for the development of targeted treatment. ABSTRACT:A nonsense mutation at codon Glu180 of TNNT1 gene causes Amish nemaline myopathy (ANM), a recessively inherited disease with infantile lethality. TNNT1 encodes the slow skeletal muscle isoform of troponin T (ssTnT). The truncated ssTnT is unable to incorporate into myofilament and is degraded in muscle cells. The symptoms of ANM include muscle weakness, atrophy, contracture and tremors accompanied by clonus. An ssTnT-knockout (KO) mouse model recapitulates key features of ANM such as atrophy of extrafusal slow muscle fibres and increased fatigability. However, the neuromuscular reflex-related symptoms of ANM have not been explained. By isolating muscle spindles from ssTnT-KO and control mice aiming to examine the composition of myofilament proteins, we found that, in contrast to extrafusal fibres, intrafusal fibres contain a significant level of cardiac TnT and the low molecular weight splice form of ssTnT. Intrafusal fibres from ssTnT-KO mice have significantly increased cardiac TnT. Rotarod and balance beam tests revealed impaired neuromuscular co-ordination in ssTnT-KO mice, indicating abnormality in spindle functions. Unlike the wild-type control, the beam running ability of ssTnT-KO mice had a blunted response to a spindle sensitizer, succinylcholine. Immunohistochemistry detected ssTnT and cardiac TnT in nuclear bag fibres, whereas fast skeletal muscle TnT was detected in nuclear chain fibres, and cardiac α-myosin was present in one of the two nuclear bag fibres. The loss of ssTnT and a compensatory increase of cardiac TnT in nuclear bag fibres would increase myofilament Ca2+ -sensitivity and tension, thus affecting spindle activities. This mechanism provides an explanation for the pathophysiology of ANM, as well as a novel target for treatment.	0
Hemorrhagic shock and encephalopathy syndrome is a devastating disease, but the pathogenesis remains unclear. The aim of this study was to examine the usefulness of neuroimaging in establishing a diagnosis and elucidating the pathogenesis. We analyzed the neuroradiologic features of 22 patients who fulfilled the Levin criteria. All patients underwent brain computed tomography (CT), and 14 patients underwent brain magnetic resonance imaging (MRI) including diffusion-weighted imaging in 10 patients. Initial CT showed normal findings in 14 of 18 (78%) patients, but subsequently hypodensities appeared in bilateral watershed zones and progressed to whole brain edema. MRI revealed cytotoxic edema, showing hyperintensities in bilateral watershed zones on diffusion-weighted imaging with a low apparent diffusion coefficient. Serial neuroimaging showed characteristic features of a widespread brain ischemic event mainly in watershed zones in hemorrhagic shock and encephalopathy syndrome.	0
Two sisters with a rare inborn error of histidine metabolism resulting from urocanase deficiency are being presented. The more common form of familial histidinemia due to histidase deficiency is excluded. The urocanase deficiency is proven by demonstrating increased excretion of metabolites of the product of the urocanase enzyme action. Further, the strongest evidence for the urocanase defect rests on the demonstration of urocanase deficiency and normal histidase activity in liver.	0
BACKGROUND: Recent studies reported no reduction in the frequency of lipomeningomyelocele (LMMC) in Hawaii and Nova Scotia after the implementation of a folic acid food fortification policy in 1998, while a marked reduction in the prevalence of other NTDs was observed. This study was performed to assess the prevalence of LMMC in Canada in relation to the timing of food fortification. METHODS: The study population included livebirths, stillbirths, and terminations of pregnancies because of fetal anomaly to women residing in seven Canadian provinces, from 1993 to 2002. In each province, the ascertainment of NTD cases relied on multiple sources, and in addition all medical charts were reviewed. The study period was divided into pre-, partial, and full fortification periods, based on results of red cell folate tests published in the literature. RESULTS: A total of 86 LMMC cases were recorded among approximately 1.9 million live births. The average birth prevalence rate was 0.05/1,000, ranging from a minimum of 0.01/1,000 in 2002 to a maximum of 0.08/1,000 in 1999. There was statistical heterogeneity between years (p = .01), but no pattern compatible with a decrease following fortification. Comparing the full fortification period with the prefortification period, there was a slight but not statistically significant decrease in LMMC birth prevalence. CONCLUSIONS: LMMC seems to be pathogenically distinct from myelomeningocele and more studies are needed to understand the embryologic mechanisms leading to this condition, and the environmental and genetic factors involved in its etiology.	1
A case of a 16-year-old male with xeroderma pigmentosum (XP) who presented with multiple pigmented and nonpigmented conjunctival lesions in both eyes is reported. He had a keratinized lesion at the limbus and a pigmented lesion in bulbar conjunctiva in the left eye and multiple pigmented bulbar conjunctival lesions and a keratinized limbal nodule in the right eye. Excision biopsy confirmed the diagnosis of ocular surface squamous neoplasia (OSSN) and conjunctival intraepithelial melanocytic neoplasia-2 (CIMN-2) in the right eye and OSSN and conjunctival melanoma in situ (CIMN-5) in the left eye. Two malignant conjunctival lesions occurring simultaneously in the same eye of a patient with XP have not been reported earlier.	0
BACKGROUND:The only hereditary neurologic disorder described so far in American Staffordshire Terriers is adult-onset cerebellar degeneration secondary to ceroid lipofuscinosis. We have seen several dogs with a newly recognized neurological disease characterized by locomotor weakness with or without respiratory signs and juvenile onset consistent with degenerative polyneuropathy of genetic origin. OBJECTIVES:To characterize a novel polyneuropathy in juvenile American Staffordshire Terriers. ANIMALS:Fourteen American Staffordshire Terriers presented with clinical signs consistent with juvenile-onset polyneuropathy at 5 veterinary hospitals between May 2005 and July 2017. METHODS:Case series. Dogs were included retrospectively after a diagnosis of degenerative polyneuropathy had been confirmed by nerve biopsy. Clinical, pathological, electrophysiological, histological data, and outcome were reviewed and a pedigree analysis performed. RESULTS:All dogs displayed clinical signs of neuromuscular disease with generalized motor and sensory involvement, associated with focal signs of laryngeal paralysis (10/14 dogs) and megaesophagus (1/14 dogs). Histopathological findings were consistent with degenerative polyneuropathy. Follow-up was available for 11 dogs, and 3 dogs were euthanized shortly after diagnosis. In these 11 dogs, the disease was slowly progressive and the animals maintained good quality of life with ability to walk. Pedigree analysis was mostly consistent with an autosomal recessive mode of inheritance. CONCLUSIONS AND CLINICAL IMPORTANCE:Juvenile polyneuropathy, associated with laryngeal paralysis, is a newly described entity in American Staffordshire Terriers, and results from degenerative neuropathy. When surgery for laryngeal paralysis is performed, lifespan may be similar to that of normal dogs even though affected dogs have locomotor disturbance.	0
The large majority of cases with intellectual disability are syndromic (i.e. occur with other well-defined clinical phenotypes) and have been studied extensively. Autosomal recessive nonsyndromic intellectual disability is a group of genetically heterogeneous disorders for which a number of potentially causative genes have been identified although the molecular basis of most of them remains unexplored. Here, we report the clinical characteristics and genetic findings of a family with two male siblings affected with autosomal recessive nonsyndromic intellectual disability. Whole exome sequencing was carried out on two affected male siblings and unaffected parents. A potentially pathogenic variant identified in this study was confirmed by Sanger sequencing to be inherited in an autosomal recessive fashion. We identified a novel nonsense mutation (p.Gln368Ter) in the LINS1 gene which leads to loss of 389 amino acids in the C-terminus of the encoded protein. The truncation mutation causes a complete loss of LINES_C domain along with loss of three known phosphorylation sites and a known ubiquitylation site in addition to other evolutionarily conserved regions of LINS1. LINS1 has been reported to cause MRT27 (mental retardation, autosomal recessive 27), a rare autosomal recessive nonsyndromic intellectual disability, with limited characterization of the phenotype. Identification of a potentially pathogenic truncating mutation in LINS1 in two profoundly intellectually impaired patients also confirms its role in cognition.	0
Neurofibromatosis type 1 (NF1) is the most common disorder characterized by multiple café-au-lait macules. Most individuals with this autosomal dominant disorder also have other features, such as skinfold freckling, iris Lisch nodules and benign or malignant peripheral nerve sheath tumours. Legius syndrome is a less frequent autosomal dominant disorder with similar multiple café-au-lait macules and skinfold freckling. Legius syndrome is not characterized by an increased risk of tumours, and a correct diagnosis is important. In young children with a sporadic form of multiple café-au-lait macules with or without freckling and no other manifestations of NF1 these 2 conditions cannot be differentiated based on clinical examination. Molecular analysis of the NF1 and SPRED1 genes is usually needed to differentiate the 2 conditions. Other less frequent conditions with café-au-lait macules are Noonan syndrome with multiple lentigines, constitutional mismatch repair deficiency and McCune-Albright syndrome.	0
Peters' anomaly is a rare congenital eye condition characterized by anterior segment dysgenesis and commonly presents as unilateral or bilateral corneal opacity in the early neonatal period. Peters' anomaly is often associated with congenital brain and skull abnormalities, which are frequently overlooked. In this paper, we present a case of a 5-day-old female neonate with Peters' anomaly, and review the literature for similar reports that describe associated brain imaging findings. In our case, imaging studies show abnormalities involving the anterior segments of both globes with absent intracranial manifestations. Although Peters' anomaly is a condition of interest for ophthalmologists, radiological studies should be performed, and neuroradiologists should be aware of the imaging findings associated with this rare entity.	0
BACKGROUND/METHODS: A door-to-door ('every door') study was carried out to assess the incidence and prevalence rates of epilepsy, stroke, Bell's palsy and cerebral palsy, as well as the prevalence of dementia, extrapyramidal syndromes, muscle and neuromuscular disorders, cerebellar ataxia and primary nocturnal enuresis among the urban and rural populations of Al Kharga district, New Valley, Egypt. The study was carried out in 3 stages from June 1, 2005 to May 31, 2009. A door-to-door screening including every door was carried out using a standardized questionnaire, which was administered by 3 neurologists to all inhabitants (62,583) of Al Kharga district. The study was designed to assess the prevalence, incidence and risk factors of major neurological disorders in Al Kharga district and aimed to reduce the burden of these neurological disorders in the entire region. RESULTS/CONCLUSIONS: This study clarified that dementia, primary nocturnal enuresis, epilepsy, stroke and cerebral palsy are the most common neurological disorders. On the other hand, Bell's palsy, extrapyramidal syndromes, cerebellar ataxia, muscle dystrophies and myasthenia gravis are less common neurological disorders in Al Kharga district.	1
Poikiloderma is a hereditary pathologic situation in which the appearance of skin rash is associated with epidermal atrophy, telangiectasia, and reticular dyspigmentation skin symptoms of poikiloderma are usually caused by sun damage. The main reason forpoikiloderma is unknown. We introduce a 14- month-old boy who referred to our center with a complaint of fever and cough. Furthermore, hepatosplenomegaly symptoms had been presented at the time of birth and were continuously observed at age one. He had transient thrombocytopenia when he was born due to his prematurity condition, which was resolved during Intravenous Immunoglobin (IVIG) treatment. Therefore, the presence of various mutation scan lead to distinct clinical symptoms. Immunohematologic abnormalities such as increased level of IgM and IgE antibodies, as well as increased C-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR), have been reported. However, mutation of the C16orf57 gene was identified in this patient. We also introduced a new genetic mutation in a particular part of DNA sequence (NM_001195302: exon6: c.T703C) that leads to new clinical finding in PN.	0
Thalassemia syndrome has diverse clinical presentations and a global spread that has far exceeded the classical Mediterranean basin where the mutations arose. The mutations that give rise to either alpha or beta thalassemia are numerous, resulting in a wide spectrum of clinical severity ranging from carrier state to life-threatening, inherited hemolytic anemia that requires regular blood transfusion. Beta thalassemia major constitutes a remarkable challenge to health care providers. The complications arising due to the anemia, transfusional iron overload, as well as other therapy-related complications add to the complexity of this condition. To produce this consensus opinion manuscript, a PubMed search was performed to gather evidence-based original articles, review articles, as well as published work reflecting the experience of physicians and scientists in the Arabian Gulf region in an effort to standardize the management protocol.	1
Mutations in the ATP1A3 gene, which encodes the alpha3-subunit of sodium-potassium ATPase, are related to a spectrum of neurological diseases including Rapid onset Dystonia-Parkinsonism (RDP), Alternating Hemiplegia of Childhood (AHC) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss (CAPOS) syndrome. Moreover, an increasing number of patients with intermediate and non classical phenotypes have been reported. Herein we describe 7 patients with 6 different de novo ATP1A3 mutations, and we focus on paroxysmal and chronic movement disorders with the help of video documentation. Our cases confirm that ATP1A3-related neurological disorders make up a phenotypic continuum rather than overlapping syndromes, in which early onset dystonia, ataxia and paroxysmal episodes with triggering or worsening factors are key diagnostic clues. Moreover, our experience suggests that ATP1A3 gene analysis should be extended both to children with channelopathy-like spells and to patients with early onset, fever-related encephalopathy.	0
BACKGROUND:Postinfectious Moyamoya syndrome (MMS) is a rare vasculopathy that can follow meningitis. Only 9 cases of MMS after meningitis have been reported in the literature. We present a unique case of MMS after meningitis caused by Aspergillus fumigatus and Escherichia coli and review all cases of MMS postmeningitis in the literature. CASE DESCRIPTION:A 41-year-old man was admitted to our emergency department for sudden hypoesthesia in the left arm and an intense headache not responsive to drugs. Computed tomography scan and magnetic resonance imaging showed acute ischemic lesions in the right centrum semiovale associated with bilateral chronic watershed cerebral ischemic lesions. The cerebral digital subtraction angiography documented a typical Moyamoya pattern. In anamnesis, the patient suffered from meningitis caused by A. fumigatus and E. coli infection after neurosurgery for subependymoma of the fourth ventricle 2 years before. Laboratory tests, clinical investigation, and imaging ruled out any other cause of vasculopathy and led to the final diagnosis of postinfectious MMS. The patient started medical therapy with oral acetyl salicylic acid, verapamil, and prednisone while surgical approach was excluded in the first instance. CONCLUSIONS:Physicians should be aware of an uncommon but severe complication of meningitis such as MMS, even several years after the infection. Neuroimaging is essential for the diagnosis and to exclude other causes of neurologic symptoms in these patients.	0
INTRODUCTION:Zoonotic enteric parasites are ubiquitous and remain a public health threat to humans due to our close relationship with domestic animals and wildlife, inadequate water, sanitation, and hygiene practices and diet. While most communities are now sedentary, nomadic and pastoral populations still exist and experience unique exposure risks for acquiring zoonotic enteric parasites. Through this systematic review we sought to summarize published research regarding pathogens present in nomadic populations and to identify the risk factors for their infection. METHODS:Using systematic review guidelines set forth by PRISMA, research articles were identified, screened and summarized based on exclusion criteria for the documented presence of zoonotic enteric parasites within nomadic or pastoral human populations. A total of 54 articles published between 1956 and 2016 were reviewed to determine the pathogens and exposure risks associated with the global transhumance lifestyle. RESULTS:The included articles reported more than twenty different zoonotic enteric parasite species and illustrated several risk factors for nomadic and pastoralist populations to acquire infection including; a) animal contact, b) food preparation and diet, and c) household characteristics. The most common parasite studied was Echinococcosis spp. and contact with dogs was recognized as a leading risk factor for zoonotic enteric parasites followed by contact with livestock and/or wildlife, water, sanitation, and hygiene barriers, home slaughter of animals, environmental water exposures, household member age and sex, and consumption of unwashed produce or raw, unprocessed, or undercooked milk or meat. CONCLUSION:Nomadic and pastoral communities are at risk of infection with a variety of zoonotic enteric parasites due to their living environment, cultural and dietary traditions, and close relationship to animals. Global health efforts aimed at reducing the transmission of these animal-to-human pathogens must incorporate a One Health approach to support water, sanitation, and hygiene development, provide education on safe food handling and preparation, and improve the health of domestic animals associated with these groups, particularly dogs.	0
A recurrent proximal microdeletion at 15q25.2 with an approximate 1.5 megabase smallest region of overlap has recently been reported in seven patients and is proposed to be associated with congenital diaphragmatic hernia (CDH), mild to moderate cognitive deficit, and/or features consistent with Diamond-Blackfan anemia. We report on four further patients and define the core phenotypic features of individuals with this microdeletion to include mild to moderate developmental delay or intellectual disability, postnatal short stature, anemia, and cryptorchidism in males. CDH and structural organ malformations appear to be less frequent associations, as is venous thrombosis. There is no consistent facial dysmorphism. Features novel to our patient group include dextrocardia, obstructive sleep apnea, and cleft lip.	0
Fibrillin is an evolutionarily ancient protein that lends elasticity and resiliency to a variety of tissues. In humans, mutations in fibrillin-1 cause Marfan and related syndromes, conditions in which the eye is often severely affected. To gain insights into the ocular sequelae of Marfan syndrome, we targeted Fbn1 in mouse lens or non-pigmented ciliary epithelium (NPCE). Conditional knockout of Fbn1 in NPCE, but not lens, profoundly affected the ciliary zonule, the system of fibrillin-rich fibers that centers the lens in the eye. The tensile strength of the fibrillin-depleted zonule was reduced substantially, due to a shift toward production of smaller caliber fibers. By 3 months, zonular fibers invariably ruptured and mice developed ectopia lentis, a hallmark of Marfan syndrome. At later stages, untethered lenses lost their polarity and developed cataracts, and the length and volume of mutant eyes increased. This model thus captures key aspects of Marfan-related syndromes, providing insights into the role of fibrillin-1 in eye development and disease.	0
There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers.	0
Cystoisospora belli (previously known as Isospora belli) is a tropical coccidian parasite sometimes leading to severe diarrhea in immunocompromised patients. Here we describe a fatal case of cystoisosporiasis in a non HIV-immunocompromised 71-year-old female with no recent travel history. Infection was either latent or potentially caused by the consumption of contaminated imported food from Asia. Diagnosis was made by microscopical detection of numerous C. belli oocysts in stools without specific staining. Treatment with TMP-SMZ slightly improved diarrhea within 3days, but dehydration subsequently led to acute decompensated heart failure and a fatal evolution. This report illustrates the possibility of severe cystoisosporiasis in non HIV-immunocompromised patients in a non-endemic country and highlights the risk of transmission through imported contaminated food consumption.	0
Staphylococcal food poisoning (SFP) is caused by staphylococcal enterotoxins (SEs) preformed in food materials. SE genes are encoded on mobile genetic elements and are widely found across Staphylococcus species including S. argenteus, although most SFP cases are caused by S. aureus. S. argenteus, recently discriminated from S. aureus as a novel species, are non-pigmented staphylococci phenotypically related to S. aureus. In 2014 and 2015, two independent food poisoning cases occurred in Osaka, Japan, in which non-pigmented staphylococci were predominantly isolated. Several enterotoxin genes (seb, seg, sei, sem, sen, seo, and selu2) were found in their genome and the production of SEB was confirmed by reverse passive agglutination tests. The non-pigmented isolates from patients, food handlers, food, and cooking utensils all produced the same pulsed-field gel electrophoresis pattern. These non-pigmented isolates were coagulase-positive and biochemically identical to S. aureus. We performed further genetic analysis using nucA sequencing and multi-locus sequence typing, and identified these isolates as S. argenteus. We also found that seb was encoded on the Staphylococcus aureus pathogenicity island, while seg, sei, sem, sen, seo, and selu2 were encoded on the enterotoxin gene cluster. From these results, we concluded that the two food poisoning outbreaks were SFP cases caused by S. argenteus harboring SE genes.	0
The thymus is involved in autoimmune Myasthenia gravis (MG) associated with anti-acetylcholine (AChR) antibodies. In MG, thymic regulatory T cells (Treg) are not efficiently suppressive, and conventional T cells (Tconv) are resistant to suppression. To better understand the specific role of the thymus in MG, we compared the phenotype and function of peripheral and thymic Treg and Tconv from controls and MG patients. Suppression assays with thymic or peripheral CD4 + T cells showed that the functional impairment in MG was more pronounced in the thymus than in the periphery. Phenotypic analysis of Treg showed a significant reduction of resting and effector Treg in the thymus but not in the periphery of MG patients. CD31, a marker lost with excessive immunoreactivity, was significantly reduced in thymic but not blood resting Treg. These results suggest that an altered thymic environment may explain Treg differences between MG patients and controls. Since thymic epithelial cells (TECs) play a major role in the generation of Treg, we co-cultured healthy thymic CD4 + T cells with control or MG TECs and tested their suppressive function. Co-culture with MG TECs consistently hampers regulatory activity, as compared with control TECs, suggesting that MG TECs contribute to the immune regulation defects of MG CD4 + T cells. MG TECs produced significantly higher thymic stromal lymphopoietin (TSLP) than control TECs, and a neutralizing anti-TSLP antibody partially restored the suppressive capacity of Treg derived from co-cultures with MG TECs, suggesting that TSLP contributed to the defect of thymic Treg in MG patients. Finally, a co-culture of MG CD4 + T cells with control TECs restored numbers and function of MG Treg, demonstrating that a favorable environment could correct the immune regulation defects of T cells in MG. Altogether, our data suggest that the severe defect of thymic Treg is at least partially due to MG TECs that overproduce TSLP. The Treg defects could be corrected by replacing dysfunctional TECs by healthy TECs. These findings highlight the role of the tissue environment on the immune regulation.	0
OBJECTIVE:De novo mutations of SCN8A, encoding the voltage-gated sodium channel NaV 1.6, have been associated with a severe infant onset epileptic encephalopathy. Individuals with SCN8A encephalopathy have a mean age of seizure onset of 4-5 months, with multiple seizure types that are often refractory to treatment with available drugs. Anecdotal reports suggest that high-dose phenytoin is effective for some patients, but there are associated adverse effects and potential for toxicity. Functional characterization of several SCN8A encephalopathy variants has shown that elevated persistent sodium current is one of several common biophysical defects. Therefore, specifically targeting elevated persistent current may be a useful therapeutic strategy in some cases. METHODS:The novel sodium channel modulator GS967 has greater preference for persistent as opposed to peak current and nearly 10-fold greater potency than phenytoin. We evaluated the therapeutic effect of GS967 in the Scn8aN1768D/+ mouse model carrying an SCN8A patient mutation that results in elevated persistent sodium current. We also performed patch clamp recordings to assess the effect of GS967 on peak and persistent sodium current and excitability in hippocampal neurons from Scn8aN1768D/+ mice. RESULTS:GS967 potently blocked persistent sodium current without affecting peak current, normalized action potential morphology, and attenuated excitability in neurons from heterozygous Scn8aN1768D/+ mice. Acute treatment with GS967 provided dose-dependent protection against maximal electroshock-induced seizures in Scn8aN1768D/+ and wild-type mice. Chronic treatment of Scn8aN1768D/+ mice with GS967 resulted in lower seizure burden and complete protection from seizure-associated lethality observed in untreated Scn8aN1768D/+ mice. Protection was achieved at a chronic dose that did not cause overt behavioral toxicity or sedation. SIGNIFICANCE:Persistent sodium current modulators like GS967 may be an effective precision targeting strategy for SCN8A encephalopathy and other functionally similar channelopathies when elevated persistent sodium current is the primary dysfunction.	0
DISEASE OVERVIEW:Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS), now classified under myelodysplastic syndromes with RS (MDS-RS) and RARS with thrombocytosis (RARS-T); now called myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T). DIAGNOSIS:MDS-RS is a lower-risk MDS, with single or multilineage dysplasia (SLD/MLD), <5% bone marrow (BM) blasts and ≥ 15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥450 × 10(9)/L and large atypical megakaryocytes. MUTATIONS AND KARYOTYPE:Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F, ASXL1, DNMT3A, SETBP1, and TET2 mutations. Cytogenetic abnormalities are uncommon in both. RISK STRATIFICATION:Most patients with MDS-RS-SLD are stratified into lower-risk groups by the revised-IPSS. Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia. Both diseases have a low risk of leukemic transformation. TREATMENT:Anemia and iron overload are complications seen in both and are managed similar to lower-risk MDS and MPN. The advent of luspatercept, a first-in-class erythroid maturation agent will tremendously boost the ability to manage anemia. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs remains uncertain.	0
Familial idiopathic nonarteriosclerotic cerebral calcification (FINCC) constitutes a rare but pathologically well defined disorder. Thus far, central nervous system symptoms and signs have been the only recorded expression of this disease. Autosomal dominant and autosomal recessive inheritance have both been postulated as cause. We describe three sibs who had symmetrical cerebral calcifications, but three also had cirrhosis and pulmonary emphysema; two had congenital cerebral aneurysms. All were male and of short stature; they also had delayed development and seizures, and two had other neurologic deficits. One sib died at age 3 years of hepatic failure and portal hypertension. Ruptured cerebral aneurysms led to the death of the other two boys at ages 8 and 13 years. The cerebral calcifications symmetrically involved the basal ganglia and thalami, the dentate nucleus, and the cortical and subcortical areas of the cerebrum. The liver was studied by sequential biopsies in two of the children and in all three by autopsy. Fatty degeneration and portal fibrosis preceded a periportal and micronodular cirrhosis. Severe bilateral pulmonary emphysema was present in one sib at age 12 years, whereas all three had bullae and cysts at autopsy. Ruptured left middle cerebral artery aneurysms were demonstrated in two sibs, and one also had aneurysms of the anterior and posterior communicating arteries. We conclude that in this family FINCC is a complex pleiotropic mendelian mutation, either of autosomal or X-linked recessive nature, whose basic pathogenesis remains unknown but may involve a metabolic defect. This form of FINCC may be a previously undescribed syndrome or a form of FINCC in which extraneural manifestations were previously overlooked.	0
Warm antibody autoimmune hemolytic anemia usually is associated with extravascular hemolysis. We report a case of a 42-year-old man with sustained and moderately severe warm antibody autoimmune hemolytic anemia, hemoglobinuria, hemosiderinuria, and acute kidney injury. We show marked induction of heme oxygenase-1 and increased ferritin expression in renal tubules, along with increased iron deposition in renal proximal tubules. These findings in this clinical case thus recapitulate those observed in experimental models of heme protein-induced kidney injury in which a coupled induction of heme oxygenase-1 and ferritin occurs in the kidney. We discuss the pathobiological significance of these findings and suggest that this linked response confers cytoprotection to the kidney exposed to hemoglobin and mitigates the severity of acute kidney injury that may otherwise occur. Finally, this case report documents that nephrotic-range proteinuria can occur in patients with autoimmune hemolytic anemia complicated by hemoglobinuria.	0
BACKGROUND:Wandering spleen is defined as the localization of the spleen in the lower parts of the abdomen or the pelvic region, rather than the left upper quadrant. The torsion of wandering spleen is a rare clinical condition. CASE REPORT:We evaluate a case diagnosed with torsion of wandering spleen and underwent splenectomy in our hospital and discuss it in light of the literature. A 26-year-old man presented to the emergency department with abdominal pain and abdominal distention. The patient was diagnosed with the torsion of wandering spleen based on computed tomography scan results. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The torsion of wandering spleen is rare in patients presenting with acute abdominal pain, but it is an important condition that should be considered in the differential diagnosis. The diagnosis of wandering spleen should be made before the development of potentially life-threatening complications. Emergency surgery should be undertaken in patients with splenic infarction.	0
OBJECTIVE:Deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) is an alternative therapy in ameliorating the clinical symptoms of primary Meige syndrome. Nevertheless, proof of its efficacy and safety is insufficient due to several case reports and small-sample clinical studies. This study aims to investigate postoperative long-term efficacy in patients undergoing DBS of the GPi for primary Meige syndrome. METHODS:We performed a retrospective study to assess the efficacy and safety of bilateral GPi stimulation in 40 patients with primary Meige syndrome who responded poorly to medical treatments or botulinum toxin injections. All participants were postoperatively followed up at the outpatient clinic, and their motor functions were assessed using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). The severity of patients' dystonia was evaluated before surgery and at follow-up neurostimu-lation. RESULTS:The implanted stimulator was turned on 1 month after surgery. All 40 patients received monopolar stimulation using the following parameters: voltage 2.5-3.5 V (average: 2.6 ± 0.8 V), frequency 60-160 Hz (average: 88.0 ± 21.3 Hz), and pulse width 60-185 μS (average: 90.0 ± 21.1 μS). In 28 of 40 patients, the symptoms had signifi-cantly improved within 1 week of stimulation. Most of the patients had been followed up for 6-24 months (average: 15.0 ± 7.8 months). The clinical symptoms of all patients had significantly improved. At 6, 12, and 24 months after surgery, the BFMDRS subscores of eyes, mouth, speech, and swallowing were significantly lower, and subscores of mouth movement showed progressively decreased with prolonged stimulation time. The overall improvement rate was 83%. Five adverse events occurred in the 40 patients; all of these events resolved without permanent sequelae. CONCLUSIONS:Bilateral GPi-DBS demonstrated satisfactory long-term efficacy in the treatment of primary Meige syndrome and could serve as an effective and safe option.	0
Congenitally missing teeth is a common feature for the third molars. However, missing teeth, macrodontia and radiculomegaly occurring in a single patient is very rare. This article describes a case of agenesis of mandibular second premolars, radiculomegaly with dilacerations of a canine tooth together with elongated roots of other canines. All these features had been discerned through diagnostic radiographs taken during a routine treatment planning.	0
Rhombencephalosynapsis (RES) is a unique cerebellar malformation characterized by fusion of the cerebellar hemispheres with partial or complete absence of a recognizable cerebellar vermis. Subsets of patients also have other brain malformations such as midbrain fusion with aqueductal stenosis, characteristic craniofacial features (prominent forehead, flat midface, hypertelorism, ear abnormalities), and somatic malformations (heart, kidney, spine, and limb defects). Similar to known genetic brain malformations, the RES cerebellar malformation is highly stereotyped, yet no genetic causes have been identified. Here, we outline our current understanding of the genetic basis for RES, discuss limitations, and outline future approaches to identifying the causes of this fascinating brain malformation.	0
We studied an unusual combination of severe short stature, mesomelia (Leri-Weill dyschondrosteosis syndrome), and multiple exostosis in several family subjects over three generations. The pattern of inheritance was compatible with autosomal dominant.Of 21 affected members over three generations, shortness of stature, associated with mesomelia resembling Leri-Weill dyschondrosteosis syndrome with no exostoses was evident in three family subjects. The rest of the family subjects manifested with normal height, and yet multiple exostoses. In this family, the skeletal manifestations were sufficiently variable for the presentation to be with either short stature or scoliosis, a Madelung' deformity, or with severe hallux valgus associated with exostosis and with Leri-Weill dyschondrosteosis syndrome.Subjects with structural chromosomal aberrations of the proband IV-7, who manifested with normal height but with multiple exostoses were excluded via 20 CAG-banded mitoses (there were no microdeletions or microduplication after performing Array-CGH-analysis). In addition, DNA examination for subject IV-8 (male cousin of the proband showed short stature and Leri-Weill dyschondrosteosis syndrome) revealed no evidence of SHOX deletions.We described a multigenerational non-consanguineous North African family , in which mesomelic dysplasia, whose clinical and radiological phenotypes resembled dyschondrosteosis, was a prominent feature in three family subjects. Multiple exostoses were evident in several other family subjects (most were with normal height). We would like to emphasize the variability in the phenotypic expression of multiple exostosis, especially the confusion that might arise when the condition appears both clinically and radiologically to be more complicated, and the overall picture might then be overlapped with one of the other bone dysplasias such as Leri-Weill dyschondrosteosis syndrome.	0
Deregulation of GSK-3β is strongly implicated in a variety of serious brain conditions, such as Alzheimer disease, bipolar disorder and schizophrenia. To understand how GSK-3β becomes dysregulated in these conditions, it is important to understand its physiological functions in the central nervous system. In this context, GSK-3β plays a role in the induction of NMDA receptor-dependent long-term depression (LTD) and several substrates for GSK-3β have been identified in this form of synaptic plasticity, including KLC-2, PSD-95 and tau. Stabilization of NMDA receptors at synapses has also been shown to involve GSK-3β, but the substrates involved are currently unknown. Recent work has identified phosphatidylinositol 4 kinase type IIα (PI4KIIα) as a neuronal GSK-3β substrate that can potentially regulate the surface expression of AMPA receptors. In the present study, we investigated the synaptic role of PI4KIIα in organotypic rat hippocampal slices. We found that knockdown of PI4KIIα has no effect on synaptic AMPA receptor-mediated synaptic transmission but substantially reduces NMDA receptor-mediated synaptic transmission. Furthermore, the ability of the selective GSK-3 inhibitor, CT99021, to reduce the amplitude of NMDA receptor-mediated currents was occluded in shRNA-PI4KIIα transfected neurons. The effects of knocking down PI4KIIα were fully rescued by a shRNA-resistant wild-type construct, but not by a mutant construct that cannot be phosphorylated by GSK-3β. These data suggest that GSK-3β phosphorylates PI4KIIα to stabilize NMDA receptors at the synapse.	0
Trichofolliculoma is a rare benign tumor of the skin, with distinct pilar differentiation and a predilection for the head and neck. To the best of the authors' knowledge, only 10 cases of eyelid trichofolliculoma has been described in the English literature. Moreover, these benign hair follicle lesions have been reported to clinically mimic eyelid malignancy. The authors report a case of a 58-year-old woman with a nodule on the eyelid margin, with typical clinical features and characteristic histopathological findings aiding the diagnosis of trichofolliculoma. Complete resection was performed to prevent recurrence. The authors also reviewed all the cases of eyelid trichofolliculoma reported in literature to highlight the demography, clinical features, and management of this rare eyelid tumor.	0
The deficiency of Vitamin D (VD) is a common symptom of systemic scleroderma (SSc), but the correlation of VD deficiency and SSc is not completely clear. Therefore, a strategy based on network pharmacology was designed to explore the correlation of VD deficiency and SSc. After a series of network construction and analysis, 5 integrins were predicated as the kernel targets in the correlation of VD deficiency and SSc, including ITGA5, ITGA4, ITGB3, ITGB1 and ITGAV. The crucial pathways in which the kernel targets participated were mainly involved in the function of immune, vascular and internal organ. The regulation modules of crucial pathways were closely related to the biological processes in the pathological of SSc. Taken together, the analysis predicted that the deficiency of VD might affect the pathological of SSc through the mediation of these integrins. Therefore, targeted regulation of these integrins might be an effective therapy against SSc.	0
Giant papillary conjunctivitis (GPC), which is characterized by the development of "giant" papillae on the superior tarsal conjunctiva, is a common complication in contact lens wearers. This condition can be associated with excessive mucus production, itching, blurry vision, and diminished contact lens tolerance. Risk factors for GPC include non-disposable lenses, infrequent lens replacement, long wearing time, inadequate lens hygiene, and atopy. Although the exact pathophysiology of GPC remains incompletely understood, it likely develops from the combination of mechanical trauma to the superior tarsal conjunctiva and an immunologic response by the conjunctiva to deposits on the anterior surface of the contact lens. With proper management, GPC has an excellent prognosis. In mild cases, prompt contact lens cessation is sufficient for the resolution of signs and symptoms. For more severe cases, the use of topical anti-histaminic agents is indicated. Uncommonly, topical steroids, non-steroidal anti-inflammatory agents, immunomodulatory medications, or very rarely surgery may be needed. In this review article, we provide a comprehensive review of the available literature on GPC, with an emphasis on recent findings and treatment advances for this common condition.	0
BACKGROUNDRecessive dystrophic epidermolysis bullosa (RDEB) patients have mutations in the COL7A1 gene and thus lack functional type VII collagen (C7) protein; they have marked skin fragility and blistering. This single-center phase 1/2a open-label study evaluated the long-term efficacy, safety, and patient-reported outcomes in RDEB patients treated with gene-corrected autologous cell therapy.METHODSAutologous keratinocytes were isolated from participant skin biopsies. Epidermal sheets were prepared from cells transduced with a retrovirus carrying the full-length human COL7A1 gene. These gene-corrected autologous epidermal sheets measured 5 × 7 cm (35 cm2) and were transplanted onto 6 wound sites in each of 7 adult participants (n = 42 sites total) from 2013 to 2017. Participants were followed for 2 to 5 years.RESULTSNo participants experienced any serious related adverse events. Wound healing of 50% or greater by Investigator Global Assessment was present in 95% (36 of 38) of treated wounds versus 0% (0 of 6) of untreated control wounds at 6 months (P < 0.0001). At year 1, 68% (26 of 38) of treated wounds had 50% or greater healing compared with 17% (1 of 6) of control wounds (P = 0.025). At year 2, 71% (27 of 38) of treated wounds had 50% or greater healing compared with 17% (1 of 6) of control wounds (P = 0.019).CONCLUSIONC7 expression persisted up to 2 years after treatment in 2 participants. Treated wounds with 50% or greater healing demonstrated improvement in patient-reported pain, itch, and wound durability. This study provides additional data to support the clinically meaningful benefit of treating chronic RDEB wounds with ex vivo, C7 gene-corrected autologous cell therapy. This approach was safe and promoted wound healing that was associated with improved patient-reported outcomes.TRIAL REGISTRATIONClinicaltrials.gov identifier: NCT01263379.FUNDINGEpidermolysis Bullosa Research Partnership, Epidermolysis Bullosa Medical Research Foundation, NIH R01 AR055914, Office of Research and Development at the Palo Alto Veteran's Affairs Medical Center, and the Dermatology Foundation.	0
Early intervention for psychotic disorders, a growing international priority, typically targets help-seeking populations with emerging psychotic ("positive") symptoms. We assessed the nature of and degree to which treatment of individuals at high risk for psychosis preceded or followed the onset of positive symptoms. The North American Prodrome Longitudinal Study-2 collected psychosocial treatment histories for 745 (98%) of 764 high-risk participants (M age = 18.9, 57% male, 57.5% Caucasian, 19.1% Hispanic) recruited from 8 North American communities. Similar to prior findings, 82% of participants reported psychosocial treatment prior to baseline assessment, albeit with significant variability across sites (71%-96%). Participants first received treatment a median of 1.7 years prior to the onset of a recognizable psychosis-risk syndrome. Only one fourth sought initial treatment in the year following syndrome onset. Although mean sample age differed significantly by site, age at initial treatment (M = 14.1, SD = 5.0) did not. High rates of early treatment prior to syndrome onset make sense in light of known developmental precursors to psychotic disorders but are inconsistent with the low rates of treatment retrospectively reported by first-episode psychosis samples. Findings suggest that psychosis risk studies and clinics may need to more actively recruit and engage symptomatic but non-help-seeking individuals and that community clinicians be better trained to recognize both positive and nonspecific indicators of emerging psychosis. Improved treatments for nonspecific symptoms, as well as the characteristic attenuated positive symptoms, are needed.	0
Importance:Olmsted syndrome is a rare and disabling genodermatosis for which no successful treatment is currently available. Objective:To evaluate the clinical response to the mammalian target of rapamycin (mTOR) inhibitor sirolimus and/or the epidermal growth factor receptor (EGFR) inhibitor erlotinib among patients with Olmsted syndrome. Design, Setting, and Participants:This case series focused on 4 children with treatment-refractory Olmsted syndrome. These children received treatments (initiated in 2017 and 2018) at the outpatient dermatology clinic at the Children's Hospital of Wisconsin in Milwaukee, Wisconsin; Children's National Hospital in Washington, DC; and Hospital Infantil Pequeno Príncipe, Curitiba in Paraná, Brazil. Exposures:Immunohistochemical analyses for mTOR and EGFR activation were performed on skin biopsy specimens from 2 patients. Oral sirolimus was administered to these 2 patients at a dosage of 0.8 mg/m2 twice daily, titrated to a goal trough whole-blood concentration of 10 to 15 ng/mL. Erlotinib was administered to all 4 patients at a dosage of 2 mg/kg/d. Main Outcomes and Measures:Clinical responses were assessed with visual analog scales for pruritus and pain and/or the Children's Dermatology Life Quality Index. Adverse effects were monitored throughout treatment. Results:Four patients (mean [SD] age, 7 [6] years; 2 boys and 2 girls) were analyzed. Lesional skin immunostaining showed increased phosphorylated ribosomal protein S6 (RPS6) and phosphorylated EGFR staining in the epidermis, indicating enhanced mTOR and EGFR signaling activation. Patients 1 and 2 were initially treated with sirolimus, displaying substantial clinical improvement in erythema and periorificial hyperkeratosis afterward. When switched to erlotinib, these patients showed substantial palmoplantar keratoderma (PPK) improvement. Patients 3 and 4 were treated with erlotinib only and later showed rapid and near complete resolution of PPK and substantial improvement in Children's Dermatology Life Quality Index scores. All 4 patients had sustained improvements in pruritus and pain. No severe adverse effects were reported. Conclusions and Relevance:This study's findings suggest that the EGFR-mTOR cascade may play a substantial role in the pathophysiological process of Olmsted syndrome and may serve as a major therapeutic target. Oral sirolimus and erlotinib may be a promising, life-altering treatment for pediatric patients with Olmsted syndrome.	0
Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease across all age groups. Obesity, diabetes, and metabolic syndrome, are the primary causes that are closely linked with the development of NAFLD. However, in young children, rare inborn errors of metabolism are predominant secondary causes of NAFLD. Furthermore, inborn errors of metabolism causing hepatosteatosis are often misdiagnosed as NAFLD in adolescents and adults. Many inborn errors of metabolism are treatable disorders and therefore require special consideration. This review aims to summarize the basic characteristics and diagnostic clues of inborn errors of metabolism associated with fatty liver disease. A suggested clinical and laboratory diagnostic approach is also discussed.	0
Hearing loss affects 380 million people worldwide due to environmental or genetic causes. Determining the cause of deafness in individuals without previous family history of hearing loss is challenging and has been relatively unexplored in Pakistan. We investigated the spectrum of genetic variants in hearing loss in a cohort of singleton affected individuals born to consanguineous parents. Twenty-one individuals with moderate to severe hearing loss were recruited. We performed whole-exome sequencing on DNA samples from the participants, which identified seventeen variants in ten known deafness genes and one novel candidate gene. All identified variants were homozygous except for two. Eleven of the variants were novel, including one multi-exonic homozygous deletion in OTOA. A missense variant in ESRRB was implicated for recessively inherited moderate to severe hearing loss. Two individuals were heterozygous for variants in MYO7A and CHD7, respectively, consistent with de novo variants or dominant inheritance with incomplete penetrance as the reason for their hearing loss. Our results indicate that similar to familial cases of deafness, variants in a large number of genes are responsible for moderate to severe hearing loss in sporadic individuals born to consanguineous couples.	0
Immunoglobulin light-chain (AL) amyloidosis is a systemic disease characterized by the production and deposition of light chain-derived amyloid fibrils in different organs. Prompt treatment directed to the underlying plasma cell clone is crucial in order to achieve a rapid, deep and durable hematologic response. The decrease in the production of the amyloidogenic light chains is a required condition to obtain the organ response, which is commonly delayed. Meanwhile, supportive treatment is aimed to maintain quality of life of these patients and preserve their involved organs' function. From simple measures, such as salt restriction or compressive stockings, to very complex interventions, such as heart transplantation in very selected patients with isolated severe cardiac involvement, this supportive care is essential and has to be necessarily included in the multidisciplinary management of this disease.	0
The primary hypertrophic osteoarthropathy (PHOA) (pachydermoperiostosis) is a rare genetic/hereditary disease characterized by skin changes (pachydermia), clubbing of fingers and periosteal thickening (periostitis) with sub-periosteal new bone formation. Here we describe a case of an adolescent male who presented with clubbing and polyarthralgia. On evaluation with scintigraphy and SPECT-CT, he was diagnosed to have incomplete form of PHOA(skeletal manifestations without skin changes). The identification of incomplete form of primary hypertrophic osteoarthropathy which can be easily misdiagnosed as rheumatoid arthritis is discussed here.	0
Muscular dystrophies are a group of genetic disorders characterized by muscle degeneration and consequent substitution by fat and fibrous tissue. Cardiac involvement is an almost constant feature in a great part of these diseases, as both primary myocardial involvement and secondary involvement due to respiratory insufficiency, pulmonary hypertension or reduced mobility. Primary myocardial involvement usually begins more precociously compared to the secondary involvement. In fact the first signs of cardiomyopathy can be observed in the first decade of life in muscular dystrophies with childhood onset and later in adult form of muscular dystrophies as myotonic dystrophy type 1. At least an annual cardiac follow-up is recommended in these patients including clinical and instrumental examination (ECG, 24h Holter monitoring, ECHO), to detect cardiac involvement. A more frequent monitoring may be required according to the type of cardiomyopathy and the patient's needs. In this short review practical guide-lines are shown for physicians routinely involved in the management of these patients.	0
BACKGROUND.: Prognostic factors and outcomes in patients with marginal zone lymphoma (MZL) have been studied in small cohort studies, which may not reflect the population at large. METHODS.: Clinical characteristics and survival outcomes of adult patients with MZL who were diagnosed between 1995 and 2009 were evaluated using the Surveillance, Epidemiology, and End Results (SEER) database. The authors generated clinical prognostic models for subtypes of MZL and compared survival during the periods of 1995 through 2000, 2001 through 2004, and 2005 through 2009. RESULTS.: The prognosis was significantly better for patients with mucosa-associated lymphoid tissue (MALT) lymphoma (5-year relative survival rate of 88.7%; P < .0001) compared with those with the splenic MZL (SMLZ)or nodal MZL (NMZL) subtypes (5-year relative survival rates of 79.7% and 76.5%, respectively). There was evidence of improved outcomes in patients with NMZL and MALT lymphomas between 1995 and 2009 (P < .0001), with no difference noted in patients with SMZL (P = .56). Advancing age and the presence of B symptoms had prognostic significance in all MZL subtypes. Male sex and stage of disease were significant only for the NMZL and MALT categories. Survival in patients with MALT lymphomas varied depending on the site of origin, with a worse prognosis noted in those with gastrointestinal and pulmonary locations of origin (5-year incidence rate of lymphoma-related death, 9.5%-14.3%) compared with ocular, cutaneous, and endocrine sites (4.5%-7.8%; P < .0001). CONCLUSIONS.: The survival for patients with SMZL is similar to that for those with NMZL, and unlike the NMZL and MALT subtypes, it has not improved over the past decade. The prognosis of patients with MALT lymphoma varies according to the anatomical site of origin.	1
BACKGROUND:A wide range of Nipah virus (NiV) encephalitis case fatality rates (CFR) have been reported. Data on the involvement of several potential risk factors in Nipah virus transmission remain controversial. We performed a systematic review and meta-analysis to estimate the pooled CFR of NiV encephalitis and to assess the risk factors for NiV infection. METHODS:Articles published up to the 27thof November 2018 in MedLine, Embase and Web of knowledge databases were considered for this study. We included cross-sectional, cohort, and case-control studies that have reported NiV CFR and/or risk factors. Data were pooled with random-effects model. This review was registered in the PROSPERO, CRD42018116242. FINDINGS:This global review included 22 citations (25 studies) including 2156, 1682, and 474 suspected, probable, and confirmed cases of NiV encephalitis, respectively. We determined a pooled CFR for NiV encephalitis at 61.0% (95% CI, 45.7-75.4; I² = 96.8%). Climbing trees (OR = 1.4; 95% CI; 1.0-1.9), male gender (OR = 1.5; 95% CI; 1.1-2.0), travel outside their own sub-district (OR = 2.0; 95% CI; 1.4-2.9), and exposure to date palm sap (DPS) (OR = 5.7; 95% CI; 3.8-8.6) or pigs (OR = 7.6; 95% CI; 1.2-45.4) were significantly associated with NiV infection. CONCLUSION:Findings from this study suggest that NiV Encephalitis is associated with a high CFR and that male gender, travel outside their sub-district, climbing trees, and exposure to pigs and DPS are associated with an increased risk of NiV encephalitis.	0
Patients with CTCL are at increased risk for bacteremia which is a leading cause of morbidity and mortality. We assessed risk factors for and the impact of bacteremia on survival in a retrospective cohort of 188 CTCL patients at a single US academic institution treated between 1990 and 2018. With a median follow up of 6.2 years, 20% of patients (n = 36) developed 79 bacteremia events. Risk factors for bacteremia included advanced stage, female gender, African American (AA) race, invasive lines, and chemotherapy. Bacteremia was associated with an increased risk of death on univariate and multivariable models. Bacteremia is associated with an increased risk of death in patients with CTCL. The greatest avoidable risk factors included chemotherapy treatment and presence of an invasive line.Key points20% of patients developed bacteremia at any point in time in this analysis.Bacteremia is associated with an increased risk of death in patients with CTCLRisk factors for bacteremia include advanced stage, female gender, AA race, invasive line, and chemotherapy.	0
Chromosomes occupy distinct interphase territories in the three-dimensional nucleus. However, how these chromosome territories are arranged relative to one another is poorly understood. Here, we investigated the inter-chromosomal interactions between chromosomes 2q, 12, and 17 in human mesenchymal stem cells (MSCs) and MSC-derived cell types by DNA-FISH We compared our findings in normal karyotypes with a three-generation family harboring a 2q37-deletion syndrome, featuring a heterozygous partial deletion of histone deacetylase 4 (HDAC4) on chr2q37. In normal karyotypes, we detected stable, recurring arrangements and interactions between the three chromosomal territories with a tissue-specific interaction bias at certain loci. These inter-chromosomal interactions were confirmed by Hi-C. Interestingly, the disease-related HDAC4 deletion resulted in displaced inter-chromosomal arrangements and altered interactions between the deletion-affected chromosome 2 and chromosome 12 and/or 17 in 2q37-deletion syndrome patients. Our findings provide evidence for a direct link between a structural chromosomal aberration and altered interphase architecture that results in a nuclear configuration, supporting a possible molecular pathogenesis.	0
Homozygous mutations of ALDH5A1 have been reportedly associated with Succinic semialdehyde dehydrogenase deficiency (SSADHD) that affects gamma-aminobutyric acid (GABA) catabolism and evinces a wide range of clinical phenotype from mild intellectual disability to severe neurodegenerative disorders. We report clinical and molecular data of a Lor family with 2 affected members presenting with severe intellectual disability, developmental delay, and generalized tonic-clonic seizures. A comprehensive genetic study that included whole-exome sequencing identified a homozygous missense substitution (NM_001080:c.G1321A:p.G441R) in ALDH5A1 (Aldehyde Dehydrogenase 5 Family Member A1) gene, consistent with clinical phenotype in the patients and co-segregating with the disease in the family. The non-synonymous mutation, p.G441R, affects a highly conserved amino acid residue, which is expected to cause a severe destabilization of the enzyme. Protein modeling demonstrated an impairment of the succinic semialdehyde (SSA) binding tunnel accessibility, and the anticipation of the protein folding stability and dynamics was a decrease in the free energy by 4.02 kcal/mol. Consistent with these in silico findings, excessive γ -hydroxybutyrate (GHB) could be detected in patients' urine as the byproduct of the GABA pathway. SSADHD, Succinic semialdehyde dehydrogenase deficiency; GABA, gamma-aminobutyric acid; ALDH5A1, Aldehyde Dehydrogenase 5 Family Member A1; GHB, γ -hydroxybutyrate; SSA, succinic semi aldehyde; WISC, Wechsler Intelligence Scale for Children; CNS, central nervous system ; EEG, electroencephalography; EEEF, empirical effective energy functions; ASD, autism spectrum disorder; ADHD, attention deficit hyperactivity disorder; IQ, intelligence quotient; EMG, electromyography; NCV, nerve conduction velocity; CP, cerebral palsy.	0
Introduction:Methylmalonic Aciduria (MMA) is a heterogeneous group of rare diseases leading to accumulation of methylmalonic acid in body fluids. One of the causes of the disease is the methylmalonic aciduria, cblA type (cblA - type MMA), conditioned by a mutation in the MMAA gene, which is essential for the proper functioning of a cofactor of the methylmalonyl-CoA mutase. The symptoms of the disease, depending on the cause, may manifest themselves at different ages. Most patients are sensitive to high doses of hydroxycobalamin, which is associated with better prognosis. Material and method:The purpose of the study was to retrospectively analyze the clinical picture and effects of treatment of patients with methylmalonic aciduria related to mutation in the MMAA gene. Results:Five patients with diagnosed cblA - type MMA were presented. At the time of diagnosis the median of age was 18.8 months, but the symptoms had already appeared since infancy, as recurrent vomiting and delayed psychomotor development. Significant excretion of methylmalonic acid in urine and metabolic acidosis traits with significantly increased anionic gap were observed in all patients. All of them were sensitive to the treatment with vitamin B12. The median of therapy duration and observation is 12.2 years. During the treatment, good metabolic control was achieved in all patients, but their cognitive development is delayed. Three patients have renal failure and pharmacologically treated arterial hypertension. Conclusions:Patients with a mutation in the MMAA gene are sensitive to treatment with hydroxocobalamine, but the inclusion of appropriate treatment does not protect against neurodevelopmental disorders and chronic kidney disease.	0
BACKGROUND:Greenberg dysplasia is a rare, autosomal recessive, prenatal lethal bone dysplasia caused by biallelic pathogenic variants in the lamin B receptor (LBR) gene. Pathogenic variants in LBR are also associated with Pelger-Huët anomaly, an autosomal dominant benign abnormality of the nuclear shape and chromatin organization of blood granulocytes, and Pelger-Huët anomaly with variable skeletal anomalies, a mild, regressing to moderate-severe autosomal recessive condition. Conditions with abnormal sterol metabolism and different genetic basis have clinical and radiographic features similar to Greenberg dysplasia, for example X-linked dominant chondrodysplasia punctata, Conradi-Hünermann type, and CHILD syndrome, and other conditions with unknown genetic etiology display very similar features, for example, dappled diaphyseal dysplasia and Astley-Kendall dysplasia. METHODS:We present a fetus with typical clinical and radiographic features of Greenberg dysplasia, and review the literature. RESULTS:Genetic testing confirmed the diagnosis Greenberg dysplasia: homozygosity for a pathogenic variant in LBR. CONCLUSION:Comparing the clinical and radiographic phenotypes of Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia, we suggest that these are allelic disorders.	0
A number of neuromuscular and muscular diseases, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and several myopathies, are associated to mutations in related RNA-binding proteins (RBPs), including TDP-43, FUS, MATR3 or hnRNPA1/B2. These proteins harbor similar modular primary sequence with RNA binding motifs and low complexity domains, that enables them to phase separate and create liquid microdomains. These RBPs have been shown to critically regulate multiple events of RNA lifecycle, including transcriptional events, splicing and RNA trafficking and sequestration. Here, we review the roles of these disease-related RBPs in muscle and motor neurons, and how their dysfunction in these cell types might contribute to disease.	0
BACKGROUND:Surgical site infections are more frequent among patients with rheumatic disease. To what extent this is related to immunosuppressive antirheumatic drugs is unclear, as is the value of discontinuing medication perioperatively. The aim of study was to assess the rate of surgical site infections after knee and hip replacement in patients with inflammatory joint disease, with an emphasis on periprosthetic joint infection, and to investigate the influence of treatment with disease-modifying antirheumatic drugs (DMARDs) in this regard. METHODS:Data were collected from 494 primary elective hip (51.4%) and knee arthroplasties, along with demographic and medication data. The primary outcome was surgical site infection during the first year after surgery. RESULTS:In 78% (n = 385) of the cases the patient used 1 to 3 disease-modifying antirheumatic drugs perioperatively. Thirty-two percent (n = 157) of patients used a TNF-alpha inhibitor. The rate of surgical site infection was 3.8% (n = 19). The rate of periprosthetic joint infection was 1.4% (n = 7), all of which occurred after knee arthroplasty. Periprosthetic joint infection occurred in only 1 patient medicating perioperatively with a TNF-alpha inhibitor. CONCLUSION:Surgical site infections were not associated with ongoing medication with disease-modifying antirheumatic drugs. Due to the low event rate this should be interpreted with caution, but our center will maintain its routine of continuing treatment with TNF-alpha inhibitors perioperatively.	0
BACKGROUND: The prevalence of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) in the US is largely unknown. Prior research has estimated PAH prevalence in Europe at ∼15-52 per million. METHODS: Using a privately insured claims database (1999-2007) for the under age 65 population and a Medicare claims database for the 65+ population, and following the current clinical classification of PH, CTEPH patients were identified as having: ≥2 claims for pulmonary hypertension (PH) [ICD-9-CM: 416.0, 416.8]; ≥1 claim for pulmonary embolism (PE) ≤12 months prior or 1 month after the initial PH claim (index date). PAH patients were identified: ≥2 claims for primary PH [416.0]; no left heart disease, lung diseases, CTEPH, or miscellaneous PH diagnoses ≤12 months prior or 1 month after the index date. Both cohorts were required to have ≥1 claim for right heart catheterization ≤6 months prior to any PH claim, or ≥1 claim for echocardiogram ≤6 months prior to a specialist-diagnosed PH claim. Age- and gender-standardized prevalence rates per million individuals (PMI) were calculated using appropriate population weights. RESULTS: Prevalence rates (95% CI) of CTEPH were estimated at 63 (34-91) PMI among the privately insured (<65), and 1007 (904-1111) PMI among the Medicare population (≥65). The corresponding estimates for PAH were 109 (71-146) PMI among the <65 population, and 451 (384-519) PMI for Medicare. LIMITATIONS: Identification of PAH and CTEPH patients in administrative claims data is challenging, due to lack of specific ICD-9-CM codes for the conditions and risk of misdiagnosis. CONCLUSIONS: Prevalence rates of CTEPH and PAH increase with age, and are higher among women. The increased risk of PE may explain the sharp age gradient for CTEPH prevalence. The estimated US prevalence of PAH is higher than existing estimates.	1
The technological advances in diagnostics and therapy of primary immunodeficiency are progressing at a fast pace. This review examines recent developments in the field of inborn errors of immunity, from their definition to their treatment. We will summarize the challenges posed by the growth of next-generation sequencing in the clinical setting, touch briefly on the expansion of the concept of inborn errors of immunity beyond the classic immune system realm, and finally review current developments in targeted therapies, stem cell transplantation, and gene therapy.	0
Hemispherotomy is a surgical treatment indicated in patients with drug-resistant epilepsy due to unilateral hemispheric pathology. Hemispherotomy is less invasive compared with hemispherectomy. We reviewed our experience performing 24 hemispherotomy and report the results of 16 patients with prolonged follow-up of this relatively uncommon procedure in two centers in Indonesia. This is a retrospective observational study conducted from 1999 to July 2019 in two epilepsy neurosurgical centers in Semarang, Indonesia. Surgical techniques included vertical parasagittal hemispherotomy (VPH), peri-insular hemispherotomy (PIH), and modified PIH called the Shimizu approach (SA). The postoperative assessment was carried out using the Engel classification system of seizure outcome. Seizure freedom (Engel class I) outcome was achieved in 10 patients (62.5%), class II in 3 patients (18.7%), class III in 2 patients (12.5%), and class IV in 1 patient (6.3%) with follow-up duration spanning from 24 to 160 months. To the best of our knowledge, this series is the most extensive documentation of hemispherotomy in an Indonesian population.	0
Megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth syndrome that is diagnosed by clinical criteria. Recently, somatic and germline variants in genes that are involved in the PI3K-AKT pathway (AKT3, PIK3R2 and PIK3CA) have been described to be associated with MCAP and/or other related megalencephaly syndromes. We performed trio-exome sequencing in a 6-year-old boy and his healthy parents. Clinical features were macrocephaly, cutis marmorata, angiomata, asymmetric overgrowth, developmental delay, discrete midline facial nevus flammeus, toe syndactyly and postaxial polydactyly--thus, clearly an MCAP phenotype. Exome sequencing revealed a pathogenic de novo germline variant in the PTPN11 gene (c.1529A>G; p.(Gln510Arg)), which has so far been associated with Noonan, as well as LEOPARD syndrome. Whole-exome sequencing (>100 × coverage) did not reveal any alteration in the known megalencephaly genes. However, ultra-deep sequencing results from saliva (>1000 × coverage) revealed a 22% mosaic variant in PIK3CA (c.2740G>A; p.(Gly914Arg)). To our knowledge, this report is the first description of a PTPN11 germline variant in an MCAP patient. Data from experimental studies show a complex interaction of SHP2 (gene product of PTPN11) and the PI3K-AKT pathway. We hypothesize that certain PTPN11 germline variants might drive toward additional second-hit alterations.	0
Brachial plexus neuropathy (BPN) is a clinical entity of unknown cause characterized by the acute or subacute onset of pain and weakness, with occasional atrophy of the arm muscles. Information on the incidence of the disease in a delineated population is lacking, as the data available on BPN have come essentially from case reports or selected series. Using the Mayo Clinic records-linkage system as the source of data, 579 clinical records were reviewed of Rochester, Minnesota, residents in which a diagnosis suggestive of BPN was reported for the period 1970 through 1981. Eleven cases fulfilled all criteria, providing an overall annual incidence rate of 1.64 cases per 100,000 population. An infectious disease and/or tetanus toxoid immunization preceded the onset of BPN in 4 cases. The upper brachial plexus was involved in 6 cases, the lower brachial plexus in 2, and the whole plexus in 3; in 1 case there was bilateral BPN. The neuropathy ran a mild to moderate course in 10 cases, and complete recovery was recorded in 6, with slight residua in the others. The occurrence of antecedent events and the features of the disease are supportive of the concept of an immune-mediated process.	1
Leigh Syndrome (OMIM 256000) is a heterogeneous neurologic disorder due to damage in mitochondrial energy production that usually starts in early childhood. The first description given by Leigh pointed out neurological symptoms in children under 2 years and premature death. Following cases brought some hypothesis to explain the cause due to similarity to other neurological diseases and led to further investigation for metabolic diseases. Biochemical evaluation and specific metabolic profile suggested impairment in energy production (OXPHOS) in mitochondria. As direct approach to involved tissues is not always possible or safe, molecular analysis is a great cost-effective option and, besides biochemical results, is required to confirm the underlying cause of this syndrome face to clinical suspicion. The Next Generation Sequencing (NGS) advance represented a breakthrough in molecular biology allowing simultaneous gene analysis giving short-time results and increasing the variants underlying this syndrome, counting over 75 monogenic causes related so far. NGS provided confirmation of emerging cases and brought up diagnosis in atypical presentations as late-onset cases, which turned Leigh into a heterogeneous syndrome with variable outcomes. This review highlights clinical presentation in both classic and atypical phenotypes, the investigation pathway throughout confirmation emphasizing the underlying genetic heterogeneity and increasing number of genes assigned to this syndrome as well as available treatment.	0
Successful completion of daily activities relies on the ability to select the relevant features of the environment for memory and recall. Disruption to these processes can lead to various disorders, such as attention-deficit hyperactivity disorder (ADHD). Dopamine is a neurotransmitter implicated in the regulation of several processes, including attention. In addition to the higher-order brain function, dopamine is implicated in the regulation of adult neurogenesis. Previously, we generated mice lacking Shati, an N-acetyltransferase-8-like protein on a C57BL/6J genetic background (Shati/Nat8l-/- ). These mice showed a series of changes in the dopamine system and ADHD-like behavioral phenotypes. Therefore, we hypothesized that deficiency of Shati/Nat8l would affect neurogenesis and attentional behavior in mice. We found aberrant morphology of neurons and impaired neurogenesis in the dentate gyrus of Shati/Nat8l-/- mice. Additionally, research has suggested that impaired neurogenesis might be because of the reduction of dopamine in the hippocampus. Galantamine (GAL) attenuated the attentional impairment observed in the object-based attention test via increasing the dopamine release in the hippocampus of Shati/Nat8l-/- mice. The α7 nicotinic acetylcholine receptor antagonist, methyllycaconitine, and dopamine D1 receptor antagonist, SCH23390, blocked the ameliorating effect of GAL on attentional impairment in Shati/Nat8l-/- mice. These results suggest that the ameliorating effect of GAL on Shati/Nat8l-/- attentional impairment is associated with activation of D1 receptors following increased dopamine release in the hippocampus via α7 nicotinic acetylcholine receptor. In summary, Shati/Nat8l is important in both morphogenesis and neurogenesis in the dentate gyrus and attention, possible via modulation of dopaminergic transmission.	0
Cutaneous T cell lymphomas (CTCL) comprise of a heterogeneous group of non-Hodgkin lymphomas derived from skin-homing T cells. Variation in clinical presentation and lack of definitive molecular markers make diagnosis especially challenging. The biology of CTCL remains elusive and clear links between genetic aberrations and epigenetic modifications that would result in clonal T cell expansion have not yet been identified. Nevertheless, in recent years, next generation sequencing (NGS) has enabled a much deeper understanding of the genomic landscape of CTCL by uncovering aberrant genetic pathways and epigenetic dysregulations. Additionally, single cell profiling is rapidly advancing our understanding of patients-specific tumor landscape and its interaction with the surrounding microenvironment. These studies have paved the road for future investigations that will explore the functional relevance of genetic alterations in the progression of disease. The ultimate goal of elucidating the pathogenesis of CTCL is to establish effective therapeutic targets with more durable clinical response and treat relapsing and refractory CTCL.	0
We present a patient with preauricular tags, preauricular and branchial pits, stenosis of the external auditory canals, mild hearing loss, and mild developmental delay who had a de novo 19p13.12 submicroscopic deletion. The size of the deletion was 760-kb, extending from 15,300,338 to 16,064,271 (hg18; NCBI Build 36.1). Our finding supports the notion that 19p13.12 represents a unique microdeletion syndrome characterized by branchial arch defects and the concept of exclusion mapping indicates that the putative locus for the branchial arch development is included in the 0.8-Mb interval defined by the deletion in the presently reported patient.	0
Nemaline myopathies are a heterogenous group of congenital myopathies caused by de novo, dominantly or recessively inherited mutations in at least twelve genes. The genes encoding skeletal α-actin (ACTA1) and nebulin (NEB) are the commonest genetic cause. Most patients have congenital onset characterized by muscle weakness and hypotonia, but the spectrum of clinical phenotypes is broad, ranging from severe neonatal presentations to onset of a milder disorder in childhood. Most patients with adult onset have an autoimmune-related myopathy with a progressive course. The wide application of massively parallel sequencing methods is increasing the number of known causative genes and broadening the range of clinical phenotypes. Nemaline myopathies are identified by the presence of structures that are rod-like or ovoid in shape with electron microscopy, and with light microscopy stain red with the modified Gömöri trichrome technique. These rods or nemaline bodies are derived from Z lines (also known as Z discs or Z disks) and have a similar lattice structure and protein content. Their shape in patients with mutations in KLHL40 and LMOD3 is distinctive and can be useful for diagnosis. The number and distribution of nemaline bodies varies between fibres and different muscles but does not correlate with severity or prognosis. Additional pathological features such as caps, cores and fibre type disproportion are associated with the same genes as those known to cause the presence of rods. Animal models are advancing the understanding of the effects of various mutations in different genes and paving the way for the development of therapies, which at present only manage symptoms and are aimed at maintaining muscle strength, joint mobility, ambulation, respiration and independence in the activities of daily living.	0
Hairy Elbows Syndrome (Hypertrichosis Cubiti; OMIM# 139600) is a rare syndrome, and characterized by the presence of long vellus hair localized on the extensor surfaces of the distal third of the arms and proximal third of the forearm bilaterally. Occasionally hypertrichosis of other body regions may accompany hairy elbows. About half of the reported patients have short stature. Aside from short stature other relatively rare abnormalities related with this syndrome were also described. Most of the reported cases were sporadic, but autosomal dominant as well as autosomal recessive inheritance patterns have also been postulated. In this report, we present a girl with Hairy Elbows syndrome who has both characteristic and uncommon findings of the syndrome. She has excessive hair on her elbows, along with short stature, microcephaly, joint hyperlaxity, thin-long-webbed neck, dysmorphic facial features and mental retardation.	0
Baraitser-Winter cerebrofrontofacial syndrome (BWCS) is a rare, autosomal dominant condition that is characterized by intellectual disability, distinctive craniofacial features, structural brain abnormalities, seizures, microcephaly, hearing loss, and ocular colobomas. The first three cases were described in 1988 by Baraitser and Winter and included two siblings and an unrelated third patient. Subsequently, causative missense variants in the ACTB and ACTG1 genes were identified, with de novo occurrence in patients with the condition. Herein, we describe two adult siblings who were born to unaffected parents and who were diagnosed with BWCS in their fourth and sixth decade of life following exome sequencing performed for intellectual disability. We review the literature reports of adult patients with BWCS to document the clinical features and phenotypic variability that can occur later in life. This is the first molecularly confirmed report of germline mosaicism in BWCS and one of only a few reports to describe two BWCS patients belonging to the same family.	0
Rhinocerebral mucormycosis, also called zygomycosis, is a rare disease caused by filamentous fungi involving the nose, paranasal sinuses, and brain. It is an opportunistic pathogen commonly found in immunocompromised individuals. Because of its involvement with already immunocompromised patients, the fungus grows rapidly and aggressively, causing a well-defined fulminant and life-threatening disease. Early intervention is a must to save lives and prevent permanent neurological complications. It is an acute fungal infection in most cases, but chronic presentations have also been described, which is indolent and slowly progressive, occurring over several weeks.[1] Commonly associated diseases include diabetic ketoacidosis, severe burns, steroid therapy, solid organ transplantation, prolonged corticosteroid therapy, hemochromatosis, patients with HIV, neutropenia, malnutrition, hematologic malignancies, etc.[2] But the absence of predisposing factors does not exclude the presence of mucormycosis. Some research demonstrated that about 9% of Rhinocerebral mucormycosis was found in patients without any predisposing factors.[3] 	0
PURPOSE:A key property to consider in all genetic tests is clinical utility, the ability of the test to influence patient management and health outcomes. Here we assess the current clinical utility of genetic testing in diverse pediatric inherited eye disorders (IEDs). METHODS:Two hundred one unrelated children (0-5 years old) with IEDs were ascertained through the database of the North West Genomic Laboratory Hub, Manchester, UK. The cohort was collected over a 7-year period (2011-2018) and included 74 children with bilateral cataracts, 8 with bilateral ectopia lentis, 28 with bilateral anterior segment dysgenesis, 32 with albinism, and 59 with inherited retinal disorders. All participants underwent panel-based genetic testing. RESULTS:The diagnostic yield of genetic testing for the cohort was 64% (ranging from 39% to 91% depending on the condition). The test result led to altered management (including preventing additional investigations or resulting in the introduction of personalized surveillance measures) in 33% of probands (75% for ectopia lentis, 50% for cataracts, 33% for inherited retinal disorders, 7% for anterior segment dysgenesis, 3% for albinism). CONCLUSION:Genetic testing helped identify an etiological diagnosis in the majority of preschool children with IEDs. This prevented additional unnecessary testing and provided the opportunity for anticipatory guidance in significant subsets of patients.	0
Atrophoderma of Pasini and Pierini is a skin disorder affecting dermal collagen and is clinically characterized by well-defined plaques of depressed skin. Histopathological changes are subtle, and in most cases, the diagnosis requires a comparative study with healthy skin from the same anatomical site. High frequency ultrasound is a useful imaging method for diagnosis of atrophic skin changes. A case is presented in which ultrasound can support the clinical and the histopathological diagnosis of atrophoderma of Pasini and Pierini.	0
Severe combined immunodeficiency is an inherited disease with profoundly defective T cells, B cells, and natural killer cells. X-linked severe combined immunodeficiency is the most common form. In this report, we describe a 4-month-old male infant who was admitted to our hospital with progressive breathlessness and abdominal mass. He was diagnosed with hepatoblastoma and presented a pneumocystis jirovecii pneumonia at the beginning of chemotherapy. Definitive diagnosis of X-linked severe combined immunodeficiency was established by DNA analysis of the interleukin 2 receptor gamma chain gene. This case is the first report which describes an X-linked severe combined immunodeficiency patient with hepatoblastoma.	0
Weill-Marchesani syndrome (WMS) is a rare disorder displaying short stature, brachydactyly and joint stiffness, and ocular features including microspherophakia and ectopia lentis. Brachydactyly and joint stiffness appear less commonly in patients with WMS4 caused by pathogenic ADAMTS17 variants. Here, we investigated a large family with WMS from Newfoundland, Canada. These patients displayed core WMS features, but with proportionate hands that were clinically equivocal for brachydactyly. Whole exome sequencing and autozygosity mapping unveiled a novel pathogenic missense ADAMTS17 variant (c.3068 G > A, p.C1023Y). Sanger sequencing demonstrated variant co-segregation with WMS, and absence in 150 population matched controls. Given ADAMTS17 involvement, we performed deep phenotyping of the patients' hands. Anthropometrics applied to hand roentgenograms showed that metacarpophalangeal measurements of affected patients were smaller than expected for their age and sex, and when compared to their unaffected sibling. Furthermore, we found a possible sub-clinical phenotype involving markedly shortened metacarpophalangeal bones with intrafamilial variability. Transfection of the variant ADAMTS17 into HEK293T cells revealed significantly reduced secretion into the extracellular medium compared to wild-type. This work expands understanding of the molecular pathogenesis of ADAMTS17, clarifies the variable hand phenotype, and underscores a role for anthropometrics in characterizing sub-clinical brachydactyly in these patients.	0
Schimmelpenning-Feuerstein-Mims syndrome is a congenital neurocutaneous disorder, comprising of organoid epidermal nevus with a broad spectrum of multiorgan dysfunction (neurologic, skeletal, cardiovascular, ophthalmic, and urologic) secondary to postzygotic mutation in the early embryonic period. Predominant neurological manifestations include epilepsy, intellectual impairment, and focal deficits. Here, we report a 3-year-old girl who presented with epileptic spasms and had a characteristic linear sebaceous nevus. This report not only highlights the importance of early diagnosis of this condition but also emphasizes the need for multiorgan screening in children with seizures and nevi.	0
Overt aseptic meningitis rarely complicates varicella-zoster virus (VZV) reactivation in young and immunocompetent adults. Many of the cases of VZV meningitis are associated with an exanthem. We describe an otherwise healthy 36-year-old adult who had aseptic meningitis without skin rash, caused by reactivation of varicella-zoster virus. Cerebrospinal fluid (CSF) analysis revealed lymphocytosis, increased total protein, and low glucose. Diagnosis was made by polymerase chain reaction in CSF. The present case highlights the fact that VZV should be considered as a cause of aseptic meningitis with hypoglycorrhachia in healthy and young individuals, even in the absence of an exanthem.	0
Acute hemorrhagic leukoencephalitis (AHL) is a rare and mostly fatal fulminant demyelinating disease. This case describes a 63-year old male in status epilepticus associated with an intracerebral hemorrhage following a one week viral prodrome with rapid decline to coma. He exhibited peripheral leukocytosis, neutrophilic pleocytosis with normal glucose and high protein in cerebrospinal fluid (CSF). Additionally, CSF was positive for herpes simplex virus (HSV) polymerase chain reaction (PCR). Medical decompression, low-dose dexamethasone, antibiotics and acyclovir were initially given. Magnetic resonance imaging (MRI) was suggestive of AHL, thus he was treated with methylprednisolone 1 g/day for 5 days. The patient improved and was discharged with significant neurologic morbidity. This is the first reported case of AHL in the Philippines presenting as a diagnostic dilemma with a protracted clinical course who responded to high dose intravenous steroids.	0
Astrocytes, the most numerous cells of the central nervous system, exert critical functions for brain homeostasis. To this purpose, astrocytes generate a highly interconnected intercellular network allowing rapid exchange of ions and metabolites through gap junctions, adjoined channels composed of hexamers of connexin (Cx) proteins, mainly Cx43. Functional alterations of Cxs and gap junctions have been observed in several neuroinflammatory/neurodegenerative diseases. In the rare leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts (MLC), astrocytes show defective control of ion/fluid exchanges causing brain edema, fluid cysts, and astrocyte/myelin vacuolation. MLC is caused by mutations in MLC1, an astrocyte-specific protein of elusive function, and in GlialCAM, a MLC1 chaperon. Both proteins are highly expressed at perivascular astrocyte end-feet and astrocyte-astrocyte contacts where they interact with zonula occludens-1 (ZO-1) and Cx43 junctional proteins. To investigate the possible role of Cx43 in MLC pathogenesis, we studied Cx43 properties in astrocytoma cells overexpressing wild type (WT) MLC1 or MLC1 carrying pathological mutations. Using biochemical and electrophysiological techniques, we found that WT, but not mutated, MLC1 expression favors intercellular communication by inhibiting extracellular-signal-regulated kinase 1/2 (ERK1/2)-mediated Cx43 phosphorylation and increasing Cx43 gap-junction stability. These data indicate MLC1 regulation of Cx43 in astrocytes and Cx43 involvement in MLC pathogenesis, suggesting potential target pathways for therapeutic interventions.	0
Congenital analbuminemia is a rare autosomic recessive inherited disorder characterized by low plasma albumin and hypercholesterolemia, which may increase cardiovascular risk. Patients are essentially asymptomatic, apart from ease of fatigue, minimal ankle oedema and hypotension. There is no accepted strategy for safely treating both hypercholesterolemia and analbuminemia in order to eventually decrease the atherosclerotic risk. We report a case of congenital analbuminemia (1.0 g/dL) in a 38-year-old male with hypercholesterolemia (range: 406-475 mg/dL) and severe arterial dysfunction [no brachial artery flow-mediated dilation (FMD)]. Long-term, cholesterol-lowering treatment with atorvastatin was associated with the appearance of peripheral edema. Two-months of infusion with albumin improved FMD (7%) and reduced serum cholesterol (273 mg/dL), supporting the hypothesis of a compensatory role of hypercholesterolemia. Statin treatment, together with periodical albumin infusions, may contribute to the safe reduction of cardiovascular risk.	0
Spontaneous regression of cystic adventitial disease (CAD) of the popliteal artery is rare. In this report, we describe a 53-year-old woman who presented with left calf pain and was diagnosed with CAD with popliteal artery stenosis, which regressed without therapy. The disease was diagnosed via computed tomography, and a surgical intervention was planned at the time of diagnosis. However, her symptoms disappeared 2 months after the initial presentation. Ultrasonography and computed tomography revealed spontaneous regression of the cystic lesions and resolution of the popliteal artery stenosis. During the 29-month follow-up period, her symptoms did not recur. Although CAD often requires surgical intervention, it may be acceptable to carefully observe patients with spontaneous regression for some time to check for recurrence.	0
BACKGROUND:Yaws is a chronic relapsing disease caused by Treponema pallidum subspecies pertunue, which can result in severe disability and deformities. Children below the age of 15 years in resource-poor communities are the most affected. Several non-specific factors facilitate the continuous transmission and resurgence of the disease. Endemic communities in rural Ghana continue to report cases despite the roll out of several intervention strategies in the past years. The objective of this study was to determine the factors associated with cutaneous ulcers among children in two yaws-endemic districts in Ghana. METHODS:A community-based unmatched 1:2 case-control study was conducted among children between 1 and 15 years. Data on socio-demographic, environmental and behavioral factors were collected using a structured questionnaire. Active case search and confirmation was done using the Dual Path Platform (DPP) Syphilis Screen and Confirm test kit. Data were analyzed using STATA 15. Logistic regression was done to determine the exposures that were associated with yaws infection at 0.05 significant level. RESULTS:Sixty-two cases and 124 controls were recruited for the study. The adjusted multivariable logistic regression model showed that yaws infection was more likely among individuals who reside in overcrowded compound houses (aOR = 25.42, 95% CI: 6.15-105.09) and with poor handwashing habits (aOR = 6.46, 95% CI: 1.89-22.04). Male (aOR = 4.15, 95% CI: 1.29-13.36) and increasing age (aOR = 5.90, 95% CI: 1.97-17.67) were also associated with yaws infection. CONCLUSIONS:Poor personal hygiene, overcrowding and lack of access to improved sanitary facilities are the factors that facilitate the transmission of yaws in the Awutu Senya West and Upper West Akyem districts. Yaws was also more common among males and school-aged children. Improving living conditions, access to good sanitary facilities and encouraging good personal hygiene practices should be core features of eradication programs in endemic communities.	0
Background:Tuberculous meningitis (TBM) is a highly devastating manifestation of tuberculosis. So far, the major role of the neuroradiology in the management of TBM has been restricted to diagnosis and follow-up of the complications. This study aimed to establish the use of advanced magnetic resonance imaging (MRI) techniques in the early detection of sequelae of TBM like vasculitis and hydrocephalous. Materials and Methods:In this prospective observational study, 30 patients of TBM were recruited during 1 year at a tertiary care health center of northern India and their serial MRI brain was done. Patients were between 18 and 45 years of age. Results:Basal/Sylvian exudates were seen in 90% of patients, hydrocephalus was found in 30% of patients and infarcts were found in 27% of patients. No significant difference was found between the mean, mean diffusivity (MD), and mean fractional anisotropy (FA) in frontal white matter, basal ganglia, thalamus, pons of cases and controls. A significant difference was seen between mean cerebral blood flow (CBF) in the region of basal ganglia of cases and controls (P < 0.05). No significant difference was seen between mean CBF in frontal white matter, thalamus of cases and controls. Diffusion tensor imaging parameters, MD, and FA were abnormal in the region of infarcts (basal ganglia) in three patients in the first scan, the parameters normalized in one patient (late subacute to chronic infarct in the first scan), and they remained abnormal in two patients. Conclusion:Advanced MRI techniques (magnetization transfer imaging) is helpful in visualizing hyperintense thickened meninges in basal cisterns and Sylvian fissures on pre-contrast imaging, and in identifying reduced CBF in the region of basal ganglia.	0
Cancer-associated retinopathy (CAR) is a rare cause of vision loss that was first reported in 1976. It is reported that the retinopathy associated with cancer occurs due to antibodies against the tumor antigens that cross-react with retinal cell layers. We present the case of a young male who came to the emergency department with sudden onset of bilateral vision loss. He had a large-sized testicular seminoma with metastatic retroperitoneal lymphadenopathy. Several primary ophthalmological and systemic conditions were considered. He had multiple, positive anti-retinal antibodies. The cancer was felt to be the cause of the vision loss based on the clinical presentation and the presence of anti-retinal antibodies. He was treated with intravenous steroids, plasmapheresis, and curative chemotherapy, but there was no improvement in vision. Unfortunately, he died due to multiorgan failure. Our case is the second on seminoma-associated retinopathy in the literature.	0
Perturbations in carbohydrate, lipid, and protein metabolism contribute to obesity-induced type 2 diabetes (T2D), though whether alterations in ketone body metabolism influence T2D pathology is unknown. We report here that activity of the rate-limiting enzyme for ketone body oxidation, succinyl-CoA:3-ketoacid-CoA transferase (SCOT/Oxct1), is increased in muscles of obese mice. We also found that the diphenylbutylpiperidine pimozide, which is approved to suppress tics in individuals with Tourette syndrome, is a SCOT antagonist. Pimozide treatment reversed obesity-induced hyperglycemia in mice, which was phenocopied in mice with muscle-specific Oxct1/SCOT deficiency. These actions were dependent on pyruvate dehydrogenase (PDH/Pdha1) activity, the rate-limiting enzyme of glucose oxidation, as pimozide failed to alleviate hyperglycemia in obese mice with a muscle-specific Pdha1/PDH deficiency. This work defines a fundamental contribution of enhanced ketone body oxidation to the pathology of obesity-induced T2D, while suggesting pharmacological SCOT inhibition as a new class of anti-diabetes therapy.	0
A syndrome of ocular and cutaneous hypopigmentation, severe mental retardation with spastic tetraplegia and athetosis was first observed by Cross in three siblings of an inbred Amish family. Since then, seven other patients, three sporadic and four with familial recurrence, have been reported in the literature, confirming the autosomal recessive inheritance. The clinical spectrum of the syndrome has been expanded to include true developmental defects of the CNS such as cystic malformation of the posterior fossa of the Dandy-Walker type. We report a new case of Cross syndrome.	0
OBJECTIVES:To collect clinical information and NOD2 mutation data on patients with Blau syndrome and to evaluate their prognosis. METHODS:Fifty patients with NOD2 mutations were analysed. The activity of each NOD2 mutant was evaluated in HEK293 cells by reporter assay. Clinical information was collected from medical records through the attending physicians. RESULTS:The study population comprised 26 males and 24 females aged 0-61 years. Thirty-two cases were sporadic, and 18 were familial from 9 unrelated families. Fifteen different mutations in NOD2 were identified, including 2 novel mutations (p.W490S and D512V); all showed spontaneous nuclear factor kappa B activation, and the most common mutation was p.R334W. Twenty-six patients had fever at relatively early timepoints in the disease course. Forty-three of 47 patients had a skin rash. The onset of disease in 9 patients was recognised after BCG vaccination. Forty-five of 49 patients had joint lesions. Thirty-eight of 50 patients had ocular symptoms, 7 of which resulted in blindness. After the diagnosis of Blau syndrome, 26 patients were treated with biologics; all were antitumour necrosis factor agents. Only 3 patients were treated with biologics alone; the others received a biologic in combination with methotrexate and/or prednisolone. None of the patients who became blind received biologic treatment. CONCLUSIONS:In patients with Blau syndrome, severe joint contractures and blindness may occur if diagnosis and appropriate treatment are delayed. Early treatment with a biologic agent may improve the prognosis.	0
Leukodystrophies are genetic white matter disorders. In the young, they represent an important cause of progressive neurological disability. Impairment of the bladder function may be part of the clinical picture of leukodystrophies. A neurogenic bladder is a dysfunctional urinary bladder caused by a disease of the central or peripheral nervous system involved in the control of micturition. In our patient, leukodystrophy-induced neurogenic bladder and acute kidney injury were revealed. If untreated, a neurogenic bladder can cause renal failure and urinary incontinence. Patients with a neurogenic bladder should be monitored, and management should aim to preserve renal function and achieve social continence.	0
Objective: Investigate the clinicopathological features for secretory carcinoma of breast (SCB). Methods: The clinical data of 3 SCB cases were collected, immunohistochemical staining was performed by the streptavidin-peroxidase (SP) method to test the expression of the antibodies: ER, PR, HER-2, Ki-67, S100, CK5/6, p63, SMA, calponin, GCDFP-15, and EGFR. Fluorescence in situ hybridization (FISH) was used to detect the ETV6-NTRK3 gene fusion. Results: ER was focal weakly positive in case 1 and case 2 (about 5%) , and negative in case 3. PR was focal weakly positive in case 1 (about 5%) and completely negative in case 2 and case 3. Three cases showed that HER-2, SMA, calponin, GCDFP-15 were negative, while S100, CK5/6, EGFR were diffuse strongly positive. The proliferation index was nearly 15% in case 1 and case 2, and 10% in case 3. p63 was negative in mostly tumor cells of case 1, and focal positive expression in the nucleus and cytoplasm. In case 2, p63 was completely negative. However, p63 was observed positive in the cytoplasm as well as some secretory material in case 3. ETV6-NTRK3 gene fusion detection by FISH was positive in all cases. Conclusions: SCB is a rare low grade triple-negative breast cancer with the unique pathomorphologic features, while its recurrent t (12; 15) (p13; q25) translocation resulting in ETV6 -NTRK3 gene fusion. It has the indolent clinical behavior and good prognosis.	0
Agenesis of the internal carotid artery (ICA) is a rare congenital vascular disorder of the cerebral circulation. CT scan of the skull base disclosing complete absence of the bony carotid canal helps to differentiate an agenesis from aplasia or hypoplasia. Although most of the patients remain asymptomatic (thanks to the sufficient collateral circulation provided by the circle of Willis) cerebral infarcts, transient ischemic attacks or intracranial aneurysms have been rarely described in association with agenesis of the ICA. Most often, the vascular territory of the involved ICA is supplied by the contralateral carotid artery and from the vertebrobasilar circulation through the anterior and posterior communicating arteries, respectively. However, collateral supply can also be provided thanks to a transcavernous anastomosis, an aberrant vascular communication between the cavernous portions of the ICAs coursing through the sella turcica. We report here the case of a 55-year-old man with right carotid agenesis and associated transcavernous anastomosis revealed by transient ischemic attack. Embryogenesis, imaging findings, possibilities of collateral circulation and potential complications have also been discussed.	0
UNLABELLED:We reviewed of a number of genetic diseases known or at risk for sedation or anesthesia complications. Some of these conditions are relatively common (e.g., Down's syndrome) whereas others are rare or present with multiple congenital anomalies that have an impact on health care delivery. We listed complications, recommended presedation evaluations, and included checklist items to assist the health care provider administering sedation and anesthesia. A better recognition and awareness of risk factors associated with specific genetic diseases should lessen the likelihood of complications during these procedures. IMPLICATIONS:This article provides a brief description of potential problematic genetic disorders and associated complications that may manifest during sedation or anesthesia. Recommendations for presedation evaluation and checklist items are given that may impact on the delivery of care for these patients.	0
Thiamine is an essential cofactor in several enzymatic reactions for all living organisms. Animals cannot synthesize thiamine and depend on their diet. Enhancing the content of thiamine is one of the most important goals of plant breeding to solve the thiamine deficiency associated with the low-thiamin staple crops. In this study, a Glycine max pale green leaf 1 (Gmpgl1) mutant was isolated from the EMS mutagenized population of soybean cultivar, Williams 82. Map-based cloning of the GmPGL1 locus revealed a single nucleotide deletion at the 292th nucleotide residue of the first exon of Glyma.10g251500 gene in Gmpgl1 mutant plant, encoding a thiamine thiazole synthase. Total thiamine contents decreased in both seedlings and seeds of the Gmpgl1 mutant. Exogenous application of thiazole restored the pale green leaf phenotype of the mutant. The deficiency of thiamine in Gmpgl1 mutant led to reduced activities of the pyruvate dehydrogenase (PDH) and pyruvate decarboxylase (PDC), and decreased contents of six amino acids as compared to that in the wild type plants. These results revealed that GmPGL1 played an essential role in thiamine thiazole biosynthesis.	0
Some autism spectrum disorders (ASD) likely arise as a result of abnormalities during early embryonic development of the brain. Studying human embryonic brain development directly is challenging, mainly due to ethical and practical constraints. However, the recent development of cerebral organoids provides a powerful tool for studying both normal human embryonic brain development and, potentially, the origins of neurodevelopmental disorders including ASD. Substantial evidence now indicates that cerebral organoids can mimic normal embryonic brain development and neural cells found in organoids closely resemble their in vivo counterparts. However, with prolonged culture, significant differences begin to arise. We suggest that cerebral organoids, in their current form, are most suitable to model earlier neurodevelopmental events and processes such as neurogenesis and cortical lamination. Processes implicated in ASDs which occur at later stages of development, such as synaptogenesis and neural circuit formation, may also be modeled using organoids. The accuracy of such models will benefit from continuous improvements to protocols for organoid differentiation.	0
BACKGROUND:Extensive evidence shows that well over 50% of people prefer to be cared for and to die at home provided circumstances allow choice. Despite best efforts and policies, one-third or less of all deaths take place at home in many countries of the world. OBJECTIVES:1. To quantify the effect of home palliative care services for adult patients with advanced illness and their family caregivers on patients' odds of dying at home; 2. to examine the clinical effectiveness of home palliative care services on other outcomes for patients and their caregivers such as symptom control, quality of life, caregiver distress and satisfaction with care; 3. to compare the resource use and costs associated with these services; 4. to critically appraise and summarise the current evidence on cost-effectiveness. SEARCH METHODS:We searched 12 electronic databases up to November 2012. We checked the reference lists of all included studies, 49 relevant systematic reviews, four key textbooks and recent conference abstracts. We contacted 17 experts and researchers for unpublished data. SELECTION CRITERIA:We included randomised controlled trials (RCTs), controlled clinical trials (CCTs), controlled before and after studies (CBAs) and interrupted time series (ITSs) evaluating the impact of home palliative care services on outcomes for adults with advanced illness or their family caregivers, or both. DATA COLLECTION AND ANALYSIS:One review author assessed the identified titles and abstracts. Two independent reviewers performed assessment of all potentially relevant studies, data extraction and assessment of methodological quality. We carried out meta-analysis where appropriate and calculated numbers needed to treat to benefit (NNTBs) for the primary outcome (death at home). MAIN RESULTS:We identified 23 studies (16 RCTs, 6 of high quality), including 37,561 participants and 4042 family caregivers, largely with advanced cancer but also congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), HIV/AIDS and multiple sclerosis (MS), among other conditions. Meta-analysis showed increased odds of dying at home (odds ratio (OR) 2.21, 95% CI 1.31 to 3.71; Z = 2.98, P value = 0.003; Chi(2) = 20.57, degrees of freedom (df) = 6, P value = 0.002; I(2) = 71%; NNTB 5, 95% CI 3 to 14 (seven trials with 1222 participants, three of high quality)). In addition, narrative synthesis showed evidence of small but statistically significant beneficial effects of home palliative care services compared to usual care on reducing symptom burden for patients (three trials, two of high quality, and one CBA with 2107 participants) and of no effect on caregiver grief (three RCTs, two of high quality, and one CBA with 2113 caregivers). Evidence on cost-effectiveness (six studies) is inconclusive. AUTHORS' CONCLUSIONS:The results provide clear and reliable evidence that home palliative care increases the chance of dying at home and reduces symptom burden in particular for patients with cancer, without impacting on caregiver grief. This justifies providing home palliative care for patients who wish to die at home. More work is needed to study cost-effectiveness especially for people with non-malignant conditions, assessing place of death and appropriate outcomes that are sensitive to change and valid in these populations, and to compare different models of home palliative care, in powered studies.	0
We report a preterm male neonate presenting with a lumbosacral meningomyelocele, type II Arnold Chiari malformation, hypoplasia of the aortic arch, bicuspid aortic valve, ventricular septal defect, secundum atrial septal defect, multicystic dysplastic kidney, and hydronephrosis. Analysis with whole genome SNP microarray revealed an interstitial deletion of about 237 kb in chromosome 6q26. Long contiguous stretches of homozygosity (>3 Mb) were seen in 18 chromosomes with a total genomic size of 219 Mb. The phenotype seen in our patient has not been reported in association with the genes in the homozygous regions. However, our patient shares many phenotypic features with other reported cases that have shown a deletion in the same region of chromosome 6.	0
Intraneural perineuriomas are rare benign neoplasms. The gene associated with neurofibromatosis 2 (NF2) is located on chromosome 22q12, and mutations in NF2 are commonly seen in soft tissue perineuriomas. However, an association between NF2 mutations and intraneural perineuriomas (INPs) has not been well established. We present a 20-year-old male with NF2, multiple schwannomas and an intraneural perineurioma in the radial nerve at the spiral groove. Sequencing of NF2, SMARCB1, and LZTR1 was performed and demonstrated loss of the long arm of chromosome 22 including NF2, SMARCB1, and LZTR1, and a constitutional NF2:c.(-4577_-854)_(45-185)del alteration. We review the literature supporting two mutually exclusive pathways involving NF2 and TRAF7 mutations that lead to the development of INPs.	0
This study was performed to investigate the feasibility of using a three-dimensional (3D) finite element model for laryngomalacia severity assessment. We analyzed laryngeal computed tomography images of seven children with laryngomalacia using Mimics software. The gray threshold of different tissues was distinguishable, and a 3D visualization model and finite element model were constructed. The laryngeal structure parameters were defined. The peak von Mises stress (PVMS) value was obtained through laryngeal mechanical analysis. The PVMS values of the laryngeal soft tissue and cartilage scaffolds were independently correlated with disease severity. After stress loading the model, the relationship between laryngomalacia severity and the PVMS value was apparent. However, the PVMS value of laryngeal soft tissue was not correlated with laryngomalacia severity. This study established the efficacy of a finite element model to illustrate the morphological features of the laryngeal cavity in infants with laryngomalacia. However, further study is required before widespread application of 3D finite element modeling of laryngomalacia. PVMS values of the laryngeal cartilage scaffold might be useful for assessment of laryngomalacia severity. These findings support the notion that structural abnormalities of the laryngeal cartilage may manifest as quantifiable changes in stress variants of the supraglottic larynx.	0
Although inborn errors of metabolism do not represent the most common cause of seizures, their early identification is of utmost importance, since many will require therapeutic measures beyond that of common anti-epileptic drugs, either in order to control seizures, or to decrease the risk of neurodegeneration. We translate the currently-known literature on metabolic etiologies of epilepsy (268 inborn errors of metabolism belonging to 21 categories, with 74 treatable errors), into a 2-tiered diagnostic algorithm, with the first-tier comprising accessible, affordable, and less invasive screening tests in urine and blood, with the potential to identify the majority of treatable conditions, while the second-tier tests are ordered based on individual clinical signs and symptoms. This resource aims to support the pediatrician, neurologist, biochemical, and clinical geneticists in early identification of treatable inborn errors of metabolism in a child with seizures, allowing for timely initiation of targeted therapy with the potential to improve outcomes.	0
Lamellar ichthyosis (LI) is a rare inherited disease where affected infants present a extensive skin scaling characterized by hyperkeratosis. Inherited mutations in the Transglutaminase 1 (TGM1) protein is one of the known causative genetic factor for the LI. The main objective of this study is to explore the impact of LI causative missense mutations on the structural and stability aspects of TGM1 protein using structural modeling, molecular docking and molecular dynamics approaches. By testing all LI causative TMG1 mutations against multiple stability prediction methods, we found that L362R and L388P mutations positioned in the Transglut_core domain were most destabilizing to the stability of TGM1 protein. These 2 mutations were 3D protein modeled and further analyzed by molecular docking and dynamic simulation methods. Molecular docking of these TGM1 mutant structures with chitosan, a natural polyphenolic compound and known inducer for transglutaminase enzyme, has shown stable molecular interactions between the native TGM1-chitosan and TGM1(L388P)-chitosan complex, when compared to the TGM1(L362R)-chitosan complex. Interestingly, molecular dynamics analysis have also yielded similar findings, where L388P-chitosan complex is shown to develop B-sheets and attain better stability, whereas TGM1-L362R complex possessed coils over the simulation period, pointing its highly destabilizing behavior on the protein structure. This study concludes that missense mutations in Transglut_core domain of the TGM1 are deleterious to the stability and structural changes of TGM1 protein and also suggest that chitosan molecule could act as a natural activator against few pathogenic TGM1 mutations. Communicated by Ramaswamy H. Sarma.	0
The human X and Y chromosomes evolved from a pair of autosomes approximately 180 million years ago. Despite their shared evolutionary origin, extensive genetic decay has resulted in the human Y chromosome losing 97% of its ancestral genes while gene content and order remain highly conserved on the X chromosome. Five 'stratification' events, most likely inversions, reduced the Y chromosome's ability to recombine with the X chromosome across the majority of its length and subjected its genes to the erosive forces associated with reduced recombination. The remaining functional genes are ubiquitously expressed, functionally coherent, dosage-sensitive genes, or have evolved male-specific functionality. It is unknown, however, whether functional specialization is a degenerative phenomenon unique to sex chromosomes, or if it conveys a potential selective advantage aside from sexual antagonism. We examined the evolution of mammalian orthologs to determine if the selective forces that led to the degeneration of the Y chromosome are unique in the genome. The results of our study suggest these forces are not exclusive to the Y chromosome, and chromosomal degeneration may have occurred throughout our evolutionary history. The reduction of recombination could additionally result in rapid fixation through isolation of specialized functions resulting in a cost-benefit relationship during times of intense selective pressure.	0
Pancreatic cancer (PC) is a highly lethal disease, mostly incurable when detected. Thus, despite advances in PC treatments, only around 7% of patients survive 5-years after diagnosis. This morbid outcome is secondary to multifactorial reasons, such as late-stage diagnosis, rapid progression and minimal response to chemotherapy. Based on these factors, it is of special relevance to identify PC high-risk individuals in order to establish preventive and early detection measures. Although most PC are sporadic, approximately 10% cases have a familial basis. No main causative gene of PC has been identified but several known germline pathogenic mutations are related with an increased risk of this tumor. These inherited cancer syndromes represent 3% of all PC. On the other hand, in 7% of cases of PC, there is a strong family history without a causative germline mutation, a situation known as familial pancreatic cancer (FPC). In recent years, there is increasing evidence supporting the benefit of genetic germline analysis in PC patients, and periodic pancreatic screening in PC high-risk patients (mainly those with a lifetime risk greater than 5%), although there is no general agreement in the group of patients and individuals to study and screen. In the present review, we expose an update in the field of hereditary and FPC, with the aim of describing the current strategies and implications in genetic counseling, surveillance and therapeutic interventions.	0
Various neurologic syndromes have been described in patients with COVID-19 and other coronavirus infections. In this paper, we systematically reviewed the available imaging findings of patients diagnosed with neurological symptoms associated with coronavirus infections. Diverse radiologic results in the context of different neurologic presentations have been demonstrated using CT and MRI. While many patients have normal imaging evaluations, some patients present with intra-axial and extra-axial abnormalities. Stroke (both ischemic and hemorrhagic), encephalomyelitis, meningitis, demyelinating disorders such as acute disseminated encephalomyelitis (ADEM), and encephalopathy have been reported. Familiarity with these radiologic patterns will guide radiologists and referring clinicians to consider coronavirus infections in patients with worsening or progressive neurologic findings, particularly during the current COVID-19 pandemic. As data on this topic is very limited, further research and investigation are required.	0
As gestation proceeds the human placenta is in a constant state of renewal and placental debris is released into the maternal circulation where it can trigger adverse physiological and immunological responses. Trophoblast cells of the placenta differentiate from mononuclear cytotrophoblast cells to fuse and form the syncytiotrophoblast, a multinuclear layer that covers the entire surface of the placenta. As part of this process there are significant changes to cellular cytoskeletal organization and organelle morphology. In this study we have examined the molecular changes that occur in mitochondria from these two cellular compartments and identified differential expression of key proteins that underpin changes in mitochondrial morphology, metabolism and function. Mitochondria were isolated for term placental tissue and separated according to size and density by sequential differential centrifugation. Isolated mitochondrial populations were then subjected to proteomics using HPLC separation of peptides and MS identification. Differential expression of proteins of interest was confirmed by western blots. Using a bioinformatics approach we also examined published protein databases to confirm our observations. In total 651 proteins were differentially regulated in mitochondria from cytotrophoblast versus syncytiotrophoblast. Of these 29 were statistically significant and chosen for subsequent analysis. These included subunits of ATP synthase that would affect ATP production and cristae structure, carbohydrate metabolizing enzymes phospoenolpyruvate carboxykinase-2, pyruvate carboxylase (PC) and pyruvate dehydrogenase (PDH), fatty acid metabolizing enzyme acyl-CoA dehydrogenase, stress responses such a glucose regulated protein-78 and protein disulfide isomerase, and mitochondrial dynamics proteins mitofusin 1 and 2. Placental cell biology and mitochondrial function is central to the pathogenesis of many gestational disorders such as preeclampsia, pre-term birth, fetal growth restriction and gestational diabetes. These studies show important shifts in mitochondrial metabolism and dynamics post trophoblast differentiation and provide key molecular targets for study in pathological pregnancies.	0
Giant condyloma acuminatum is a rare variant of genital warts also known as Buschke-Löwenstein tumor. It is characterized by a slow progression of exophytic, ulcerative, and cauliflower-shaped tumor with benign histological features. Verrucous carcinoma however is a rare variant of well-differentiated squamous cell carcinoma with limited metastatic potential.	0
Introduction:Persistent genital arousal (PGAD) is a syndrome of unprovoked sexual arousal/orgasm of uncertain cause primarily reported in female patients. Most patients are referred for mental-health treatment, but as research suggests associations with neurological symptoms and conditions, there is need to analyze cases comprehensively evaluated by neurologists. Methods:The IRB waived consent requirements for this retrospective university-hospital study. We extracted and analyzed neurological symptoms, test, and treatment results from all qualifying participants' records and recontacted some for details. Results:All 10 participants were female; their PGAD symptoms began between ages 11 to 70 years. Two patterns emerged: 80% reported daily out-of-context sexual arousal episodes (≤30/day) that usually included orgasm and 40% reported lesser, often longer-lasting, nonorgasmic arousals. Most also had symptoms consistent with sacral neuropathy-70% had urologic complaints and 60% had neuropathic perineal or buttock pain. In 90% of patients, diagnostic testing identified anatomically appropriate and plausibly causal neurological lesions. Sacral dorsal-root Tarlov cysts were most common (in 4), then sensory polyneuropathy (2). One had spina bifida occulta and another drug-withdrawal effect as apparently causal; lumbosacral disc herniation was suspected in another. Neurological treatments cured or significantly improved PGAD symptoms in 4/5 patients, including 2 cures. Conclusions:Although limited by small size and referral bias to neurologists, this series strengthens associations with Tarlov cysts and sensory polyneuropathy and suggests new ones. We hypothesize that many cases of PGAD are caused by unprovoked firing of C-fibers in the regional special sensory neurons that subserve sexual arousal. Some PGAD symptoms may share pathophysiologic mechanisms with neuropathic pain and itch.	0
PURPOSE OF REVIEW:The aim of this study was to evaluate the potential role of genetic testing, particularly next-generation DNA sequencing, in diagnosing and managing dyslipidaemias, particularly monogenic dyslipidaemias. RECENT FINDINGS:Targeted DNA sequencing of the genes causing monogenic dyslipidaemias is becoming more accessible. Some societies' position statements advise selective utilization of DNA testing in combination with clinical and biochemical assessment. However, high-quality peer-reviewed evidence showing that a DNA-based diagnosis impacts upon long-term patient outcomes is currently lacking. Nonetheless, we show anecdotal examples of tangible clinical actions following from a genetic diagnosis. In any event, care must be taken when interpreting genetic reports. We strongly feel that expertise in both genetics and dyslipidaemias is required to adequately interpret and report results to patients, as well as to make informed treatment decisions that can have a potential lifelong impact. SUMMARY:There are some examples of monogenic dyslipidaemias for which having a molecular diagnosis might beneficially affect patient outcomes, for example certain cases of suspected familial hypercholesterolemia, familial chylomicronemia syndrome, sitosterolemia or lysosomal acid lipase deficiency. In general, we recommend limiting genetic testing to selected cases of monogenic dyslipidaemias. Finally, we advise that there is currently no proven clinical benefit in testing for polygenic dyslipidaemias.	0
OBJECTIVE:Autosomal dominant optic atrophy (ADOA) starts in early childhood with loss of visual acuity and color vision deficits. OPA1 mutations are responsible for the majority of cases, but in a portion of patients with a clinical diagnosis of ADOA, the cause remains unknown. This study aimed to identify novel ADOA-associated genes and explore their causality. METHODS:Linkage analysis and sequencing were performed in multigeneration families and unrelated patients to identify disease-causing variants. Functional consequences were investigated in silico and confirmed experimentally using the zebrafish model. RESULTS:We defined a new ADOA locus on 7q33-q35 and identified 3 different missense variants in SSBP1 (NM_001256510.1; c.113G>A [p.(Arg38Gln)], c.320G>A [p.(Arg107Gln)] and c.422G>A [p.(Ser141Asn)]) in affected individuals from 2 families and 2 singletons with ADOA and variable retinal degeneration. The mutated arginine residues are part of a basic patch that is essential for single-strand DNA binding. The loss of a positive charge at these positions is very likely to lower the affinity of SSBP1 for single-strand DNA. Antisense-mediated knockdown of endogenous ssbp1 messenger RNA (mRNA) in zebrafish resulted in compromised differentiation of retinal ganglion cells. A similar effect was achieved when mutated mRNAs were administered. These findings point toward an essential role of ssbp1 in retinal development and the dominant-negative nature of the identified human variants, which is consistent with the segregation pattern observed in 2 multigeneration families studied. INTERPRETATION:SSBP1 is an essential protein for mitochondrial DNA replication and maintenance. Our data have established pathogenic variants in SSBP1 as a cause of ADOA and variable retinal degeneration. ANN NEUROL 2019;86:368-383.	0
Background:Congenital generalized lipodystrophy (CGL) is a rare disorder characterized by the lack of adipose tissue and metabolic complications with predominantly autosomal recessive inheritance. There are 6 different genes known to cause CGL with 4 main types recognized to date, which differ by the degree of fat loss, association with mental retardation and metabolic disorders, with CGL type 1 and 2 being the most common. Twenty seven cases of СGL type 4 from Japan, Oman, UK, Turkey, Mexico, Saudi Arabia, USA were reported previously. This report details our clinical experience with the first patient from Russia with CGL type 4. Case presentation:A 36-year-old patient, who has been suffering from generalized lipoatrophy since the first months of life and myopathy and gastrointestinal dysmotility since early childhood, developed dysmenorrhea and diabetes mellitus at the age of 19, bilateral cataracts when she was only 22 y.o., osteoporosis with vitamin D deficiency and hypocalcemia at the age of 28, diabetic foot syndrome and hyperuricemia when she was 35 y.o. Sequencing of lipodystrophy candidate genes detected a novel pathogenic homozygous variant p.631G < T: p.E211X in the CAVIN1 gene, confirming the diagnosis of CGL type 4. Conclusions:In comparison with previously reported patients with CGL type 4, our patient has diabetes mellitus, vitamin D deficiency, hypocalcemia, bilateral cataracts and hyperuricemia. All these manifestations are known to be associated with other lipodystrophy syndromes, but to our knowledge it is the first time they have been reported to be associated with CGL type 4.	0
OBJECTIVE:The goal of this study was to characterize a Swedish family with members affected by spinocerebellar ataxia 27 (SCA27), a rare autosomal dominant disease caused by mutations in fibroblast growth factor 14 (FGF14). Despite normal structural neuroimaging, psychiatric manifestations and intellectual disability are part of the SCA27 phenotype raising the need for functional neuroimaging. Here, we used clinical assessments, structural and functional neuroimaging to characterize these new SCA27 patients. Since one patient presents with a psychotic disorder, an exploratory study of markers of schizophrenia associated with GABAergic neurotransmission was performed in fgf14-/- mice, a preclinical model that replicates motor and learning deficits of SCA27. METHODS:A comprehensive characterization that included clinical assessments, cognitive tests, structural neuroimaging studies, brain metabolism with 18 F-fluorodeoxyglucose PET ([18F] FDG PET) and genetic analyses was performed. Brains of fgf14-/- mice were studied with immunohistochemistry. RESULTS:Nine patients had ataxia, and all affected patients harboured an interstitial deletion of chromosome 13q33.1 encompassing the entire FGF14 and integrin subunit beta like 1 (ITGBL1) genes. New features for SCA27 were identified: congenital onset, psychosis, attention deficit hyperactivity disorder and widespread hypometabolism that affected the medial prefrontal cortex (mPFC) in all patients. Hypometabolism in the PFC was far more pronounced in a SCA27 patient with psychosis. Reduced expression of VGAT was found in the mPFC of fgf14-/- mice. CONCLUSIONS:This is the second largest SCA27 family identified to date. We provide new clinical and preclinical evidence for a significant psychiatric component in SCA27, strengthening the hypothesis of FGF14 as an important modulator of psychiatric disease.	0
INTRODUCTION:Type 1 GM1 gangliosidosis is an ultra-rare, rapidly fatal lysosomal storage disorder, with life expectancy of <3 years of age. To date, only one prospective natural history study of limited size has been reported. Thus, there is a need for additional research to provide a better understanding of the progression of this disease. We have leveraged the past two decades of medical literature to conduct the first comprehensive retrospective study characterizing the natural history of Type 1 GM1 gangliosidosis. OBJECTIVES:The objectives of this study were to establish a large sample of patients from the literature in order to identify: 1) clinically distinguishing factors between Type 1 and Type 2 GM1 gangliosidosis, 2) age at first symptom onset, first hospital admission, diagnosis, and death, 3) time to onset of common clinical findings, and 4) timing of developmental milestone loss. METHODS:PubMed was searched with the keyword "GM1 Gangliosidosis" and for articles from the year 2000 onwards. A preliminary review of these results was conducted to establish subtype classification criteria for inclusion of only Type 1 patients, resulting in 44 articles being selected to generate the literature dataset of 154 Type 1 GM1 gangliosidosis patients. Key clinical events of these patient cases were recorded from the articles. RESULTS:Comprehensive subtyping criteria for Type 1 GM1 gangliosidosis were created, and clinical events, including onset, diagnosis, death, and symptomology, were mapped over time. In this dataset, average age of diagnosis was 8.7 months, and average age of death was 18.9 months. DISCUSSION:This analysis demonstrates the predictable clinical course of this disease, as almost all patients experienced significant multi-organ system dysfunction and neurodevelopmental regression, particularly in the 6- to 18-month age range. Patients were diagnosed at a late age relative to disease progression, indicating the need for improved public awareness and screening. CONCLUSION:This study highlights the significant burden of illness in this disease and provides critical natural history data to drive earlier diagnosis, inform clinical trial design, and facilitate family counseling.	0
The objective of this study is to undertake a population based study on the incidence, prevalence, natural history, and response to treatment of complex regional pain syndrome (CRPS). All Mayo Clinic and Olmsted Medical Group medical records with codes for reflex sympathetic dystrophy (RSD), CRPS, and compatible diagnoses in the period 1989-1999 were reviewed as part of the Rochester Epidemiology Project. We used IASP criteria for CRPS. The study population was in the Olmsted County, Minnesota (1990 population, 106,470). The main outcome measures were CRPS I incidence, prevalence, and outcome. Seventy-four cases of CRPS I were identified, resulting in an incidence rate of 5.46 per 100,000 person years at risk, and a period prevalence of 20.57 per 100,000. Female:male ratio was 4:1, with a median age of 46 years at onset. Upper limb was affected twice as commonly as lower limb. All cases reported an antecedent event and fracture was the most common trigger (46%). Excellent concordance was found between symptoms and signs and vasomotor symptoms were the most commonly present. Three phase bone scan and autonomic testing diagnosed the condition in >80% of cases. Seventy-four percent of patients underwent resolution, often spontaneously. CRPS I is of low prevalence, more commonly affects women than men, the upper more than the lower extremity, and three out of four cases undergo resolution. These results suggest that invasive treatment of CRPS may not be warranted in the majority of cases.	1
Importance:The hypothesis that disrupted immune function is implicated in the pathophysiology of psychiatric disorders and suicide is gaining traction, but the underlying mechanisms are largely unknown. Primary humoral immunodeficiencies (PIDs) are rare deficiencies of the immune system-mainly dysfunction of antibody production-and are associated with adverse health problems, such as recurrent infections and autoimmune diseases. Objective:To establish whether PIDs that affect antibody function and level are associated with lifetime psychiatric disorders and suicidal behavior and whether this association is explained by the co-occurrence of autoimmune diseases. Design, Setting, and Participants:This population- and sibling-based cohort study included more than 14 million individuals living in Sweden from January 1, 1973, through December 31, 2013. Register-based data on exposure, outcomes, and covariates were collected through December 31, 2013. Individuals with a record of PID were linked to their full siblings, and a family identification number was created. Data were analyzed from May 17, 2019, to February 21, 2020. Exposures:Lifetime records of PID and autoimmune disease. Main Outcomes and Measures:Lifetime records of 12 major psychiatric disorders and suicidal behavior, including suicide attempts and death by suicide. Results:A lifetime diagnosis of PID affecting immunoglobulin levels was identified in 8378 patients (4947 women [59.0%]; median age at first diagnosis, 47.8 [interquartile range, 23.8-63.4] years). A total of 4776 clusters of full siblings discordant for PID was identified. After adjusting for comorbid autoimmune diseases, PIDs were associated with greater odds of any psychiatric disorder (adjusted odds ratio [AOR], 1.91; 95% CI, 1.81-2.01) and any suicidal behavior (AOR, 1.84; 95% CI, 1.66-2.04). The associations were also significant for all individual psychiatric disorders (range of AORs, 1.34 [95% CI, 1.17-1.54] for schizophrenia and other psychotic disorders to 2.99 [95% CI, 2.42-3.70] for autism spectrum disorders), death by suicide (AOR, 1.84; 95% CI, 1.25-2.71), and suicide attempts (AOR, 1.84; 95% CI, 1.66-2.04). In the sibling comparisons, the associations were attenuated but remained significant for aggregated outcomes (AOR for any psychiatric disorder, 1.64 [95% CI, 1.48-1.83]; AOR for any suicidal behavior, 1.37 [95% CI, 1.14-1.66]), most individual disorders (range of AORs, 1.46 [95% CI, 1.23-1.73] for substance use disorders to 2.29 [95% CI, 1.43-3.66] for autism spectrum disorders), and suicide attempts (AOR, 1.41; 95% CI, 1.17-1.71). Joint exposure for PID and autoimmune disease resulted in the highest odds for any psychiatric disorder (AOR, 2.77; 95% CI, 2.52-3.05) and any suicidal behavior (AOR, 2.75; 95% CI, 2.32-3.27). The associations with psychiatric outcomes (AORs, 2.42 [95% CI, 2.24-2.63] vs 1.65 [95% CI, 1.48-1.84]) and suicidal behavior (AORs, 2.43 [95% CI, 2.09-2.82] vs 1.40 [95% CI, 1.12-1.76]) were significantly stronger for women than for men with PID. Conclusions and Relevance:Primary humoral immunodeficiencies were robustly associated with psychopathology and suicidal behavior, particularly in women. The associations could not be fully explained by co-occurring autoimmune diseases, suggesting that antibody dysfunction may play a role, although other mechanisms are possible. Individuals with both PID and autoimmune disease had the highest risk of psychiatric disorders and suicide, suggesting an additive effect. Future studies should explore the underlying mechanisms of these associations.	0
TRPV4, a nonselective calcium permeable ion channel, is expressed broadly in many organs including bone and neurons. Pathogenic variants in TRPV4 are known to cause both a spectrum of skeletal dysplasias and neuropathies. Recent publications have documented a few patients who have a combined phenotype of skeletal dysplasia and neuropathy secondary to TRPV4 pathogenic variants. We present an additional patient who has an overlapping neuromuscular and skeletal phenotype secondary to a TRPV4 pathogenic variant. The patient has spondylometaphyseal dysplasia-Kozlowski type and Charcot-Marie-Tooth disease type 2C. This and prior reports illustrate that TRPV4-related skeletal dysplasias and TRPV4-related neuropathies are not fully distinct disorders secondary to unique sets of pathogenic variants as originally postulated, but rather are 2 phenotypes on the same spectrum that may or may not overlap. We suggest that evaluation for patients presenting with any TRPV4-related disorder include assessment for both skeletal and neurological findings.	0
OBJECTIVES:Caregiver burden in neurologic Wilson disease (NWD) has received little attention. We investigated predictors of caregiver burden in Chinese NWD patients. METHODS:Participants in this retrospective study were NWD patients admitted to The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine from 1 August to 31 December 2019. Sociodemographic information was recorded for caregivers and NWD patients. Caregiver burden was evaluated using the Caregiver Burden Inventory (CBI). Cognitive impairment, functional problems, depression and anxiety were evaluated by professional interviewers. Path analysis was used to evaluate predictors of CBI scores. RESULTS:Sixty NWD patients were enrolled (mean age: 21.35 ± 4.89 years; mean NWD duration: 7.85 ± 3.11 years). The mean CBI score was 52.00 ± 17.16. Care duration had a significant direct effect on CBI score after controlling for confounders (r = 0.493). Cognitive impairment (r = -0.426), functional problems (r = 0.581), depression (r = 0.349) and anxiety (r = 0.317) had significant indirect effects on CBI score. CONCLUSION:Caregivers of NWD patients may experience a medium level of caregiver burden. NWD duration, cognitive impairment, functional problems, depression and anxiety in NWD patients may be useful predictors of caregiver burden.	0
OBJECTIVE:To study the effect of pranlukast (Pran) on neonatal rats with periventricular leukomalacia (PVL). METHODS:The rats, aged 3 days, were randomly divided into a sham-operation group, a PVL group, and a Pran group. A rat model of PVL was prepared by right common carotid artery ligation and postoperative hypoxia. The rats in the sham-operation group were given isolation of the right common carotid artery without ligation or hypoxic treatment. The rats in the Pran group were given intraperitoneal injection of Pran (0.1 mg/kg) once every 12 hours, for 3 consecutive days, and those in the sham-operation group and the PVL group were given intraperitoneal injection of an equal volume of normal saline. On day 14 after modeling, hematoxylin-eosin (HE) staining was used to observe the pathological changes of brain tissue; immunofluorescent staining was used to measure the expression of myelin basic protein (MBP) in brain tissue (n=8); Western blot was used to measure the expression of cyclic nucleotide phosphodiesterase (CNPase), MBP, and G protein-coupled receptor 17 (GPR17) (n=8). On day 21 after modeling, Morris water maze test was used to evaluate the learning and memory abilities of rats in each group (n=8). RESULTS:The results of HE staining showed that the PVL group had greater pathological changes of white matter than the sham-operation group, and compared with the PVL group, the Pran group had a significant improvement in such pathological changes. The results of immunofluorescence assay showed that the PVL group had a lower mean fluorescence intensity of MBP than the sham-operation group (P<0.05), and the Pran group had a higher mean fluorescence intensity of MBP than the PVL group (P<0.05). Western blot showed that compared with the sham-operation group, the PVL group had significantly lower relative expression of MBP and CNPase (P<0.05) and significantly higher relative expression of GPR17 (P<0.05), and compared with the PVL group, the Pran group had significantly higher relative expression of MBP and CNPase (P<0.05) and significantly lower relative expression of GPR17 (P<0.05). Morris water maze test showed that compared with the sham-operation group, the PVL group had a significant increase in escape latency and a significant reduction in the number of platform crossings, and compared with the PVL group, the Pran group had a significant reduction in escape latency and a significant increase in the number of platform crossings (P<0.05). CONCLUSIONS:Pran can alleviate brain damage, promote myelination, and improve long-term learning and memory abilities in neonatal rats with PVL, possibly by reducing the expression of GPR17.	0
BACKGROUND:Dubin-Johnson syndrome (DJS) is a rare autosomal recessive disorder characterized by predominantly conjugated hyperbilirubinemia that is caused by pathogenic mutations in the adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2) gene, which encodes multidrug resistance-associated protein 2 (MRP2). However, little is known about the causative mutation of DJS in China. Recently, we have reported ABCC2 p.G693R mutation in two unrelated cases. In the present study, we investigated the pathogenicity of the ABCC2 p.G693R mutation in DJS in China. METHODS:Clinical and genetic analysis was conducted for the two patients with the ABCC2 p.G693R mutation. Whole exome sequencing for mutations in other known hyperbilirubinemia-related genes was conducted for the cases with ABCC2 p.G693R. Expression and cellular localization of the mutant MRP2 p.G693R were analyzed by Western blotting and immunofluorescence assay, respectively. Organic anion transport activity was evaluated by the analysis of glutathione-conjugated-monochlorobimane. RESULTS:The two DJS patients with ABCC2 p.G693R mutation, which was conserved among different species, showed typical hyperbilirubinemia phenotype. No pathogenic mutation was identified in the other known hyperbilirubinemia related genes. Functional studies in three cell lines showed that the expression, localization and the organic anion transport activity were significantly compromised by MRP2 p.G693R mutation compared with wild-type MRP2. CONCLUSIONS:The recurrent ABCC2 p.G693R mutation is associated with loss of function of the MRP2 protein and may result in hyperbilirubinemia in DJS in China.	0
Peroxisomal biogenesis disorders (PBDs) are autosomal recessive diseases caused by mutations in one of the 14 PEX genes described in the scientific literature. All of these syndromes may be associated with different mutations in the PEX genes, the most frequent being PEX1 for patients with Zellweger syndrome (ZS). In this paper, we present the case of a patient with a peculiar clinical history: evisceration of the left eye (LE) at 4 years of age because of a benign ocular teratoid medulloepithelioma and a progressive loss of visual acuity (VA) in the right eye (RE) beginning at 9 years of age, leading to the diagnosis of ZS. In addition, the patient presented a mutation in the PEX14 gene that has not been previously described in the literature. This case broadens the spectrum of clinical expression in ZS patients because of not only the presence of a benign ocular teratoid medulloepithelioma at 4 years of age but also the late clinical expression of ZS (at 9 years of age).	0
Alzheimer's disease (AD) and mixed dementia (MxD) comprise the majority of dementia cases in the growing global aging population. MxD describes the coexistence of AD pathology with vascular pathology, including cerebral small vessel disease (SVD). Cardiovascular disease increases risk for AD and MxD, but mechanistic synergisms between the coexisting pathologies affecting dementia risk, progression and the ultimate clinical manifestations remain elusive. To explore the additive or synergistic interactions between AD and chronic hypertension, we developed a rat model of MxD, produced by breeding APPswe/PS1ΔE9 transgenes into the stroke-prone spontaneously hypertensive rat (SHRSP) background, resulting in the SHRSP/FAD model and three control groups (FAD, SHRSP and non-hypertensive WKY rats, n = 8-11, both sexes, 16-18 months of age). After behavioral testing, rats were euthanized, and tissue assessed for vascular, neuroinflammatory and AD pathology. Hypertension was preserved in the SHRSP/FAD cross. Results showed that SHRSP increased FAD-dependent neuroinflammation (microglia and astrocytes) and tau pathology, but plaque pathology changes were subtle, including fewer plaques with compact cores and slightly reduced plaque burden. Evidence for vascular pathology included a change in the distribution of astrocytic end-foot protein aquaporin-4, normally distributed in microvessels, but in SHRSP/FAD rats largely dissociated from vessels, appearing disorganized or redistributed into neuropil. Other evidence of SVD-like pathology included increased collagen IV staining in cerebral vessels and PECAM1 levels. We identified a plasma biomarker in SHRSP/FAD rats that was the only group to show increased Aqp-4 in plasma exosomes. Evidence of neuron damage in SHRSP/FAD rats included increased caspase-cleaved actin, loss of myelin and reduced calbindin staining in neurons. Further, there were mitochondrial deficits specific to SHRSP/FAD, notably the loss of complex II, accompanying FAD-dependent loss of mitochondrial complex I. Cognitive deficits exhibited by FAD rats were not exacerbated by the introduction of the SHRSP phenotype, nor was the hyperactivity phenotype associated with SHRSP altered by the FAD transgene. This novel rat model of MxD, encompassing an amyloidogenic transgene with a hypertensive phenotype, exhibits several features associated with human vascular or "mixed" dementia and may be a useful tool in delineating the pathophysiology of MxD and development of therapeutics.	0
Neural tube defects (NTDs) are debilitating human congenital abnormalities due to failure of neural tube closure. Sonic Hedgehog (SHH) signaling is required for dorsal-ventral patterning of the neural tube. The loss of activation in SHH signaling normally causes holoprosencephaly while the loss of inhibition causes exencephaly due to failure in neural tube closure. WDR34 is a dynein intermedia chain component which is required for SHH activation. However, Wdr34 knockout mouse exhibit exencephaly. Here we screened mutations in WDR34 gene in 100 anencephaly patients of Chinese Han population. Compared to 1000 Genome Project data, two potentially disease causing missense mutations of WDR34 gene (c.1177G>A; p.G393S and c.1310A>G; p.Y437C) were identified in anencephaly patients. These two mutations did not affect the protein expression level of WDR34. Luciferase reporter and endogenous target gene expression level showed that both mutations are lose-of-function mutations in SHH signaling. Surprisingly, WDR34 could promote planar cell polarity (PCP) signaling and the G393S lost this promoting effect on PCP signaling. Morpholino knockdown of wdr34 in zebrafish caused severe convergent extension defects and pericardial abnormalities. The G393S mutant has less rescuing effects than both WT and Y437C WDR34 in zebrafish. Our results suggested that mutation in WDR34 could contribute to human NTDs by affecting both SHH and PCP signaling.	0
Isolated hypogonadotropic hypogonadism (IHH), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) constitute a disease spectrum whose etiology remains largely unknown. This study aimed to clarify whether mutations in SMCHD1, an epigenetic regulator gene, might underlie this disease spectrum. SMCHD1 is a causative gene for Bosma arhinia microphthalmia syndrome characterized by arhinia, microphthalmia and IHH. We performed mutation screening of SMCHD1 in patients with etiology-unknown IHH (n = 31) or CPHD (n = 43, 19 of whom also satisfied the SOD diagnostic criteria). Rare variants were subjected to in silico analyses and classified according to the American College of Medical Genetics and Genomics guidelines. Consequently, a rare likely pathogenic variant, p.Asp398Asn, was identified in one patient. The patient with p.Asp398Asn exhibited CPHD, optic nerve hypoplasia, and a thin retinal nerve fiber layer, and therefore satisfied the criteria of SOD. This patient showed a relatively low DNA methylation level of the 52 SMCHD1-target CpG sites at the D4Z4 locus. Exome sequencing for the patient excluded additional variants in other IHH/CPHD-causative genes. In vitro assays suggested functional impairment of the p.Asp398Asn variant. These results provide the first indication that SMCHD1 mutations represent a rare genetic cause of the HH-related disease spectrum.	0
We report on 2 brothers with chorea and monocular horizontal nystagmus beginning in early infancy, both of which remit during the first decade of life, and peripheral cataracts. While this condition shares manifestations with benign hereditary chorea and several other familial movement disorders, the slowly remitting course of the chorea combined with the visual abnormalities appears to be unique.	0
CASE:Fractures in patients with osteopetrosis pose unique technical challenges to the orthopaedic surgeon. We present a case of a 43-year-old man with osteopetrosis who underwent tension band wiring of a patella fracture. The intraoperative appearance of osteopetrotic bone, technical difficulties in passing wires through dense bone, and how this was overcome are presented. CONCLUSIONS:A simple transverse fracture of the patella in a patient with osteopetrosis can be fixed successfully using a standard tension band construct.	0
Combined pituitary hormone deficiency (CPHD) is a genetically heterogeneous disorder caused by mutations in over 30 genes. The loss-of-function mutations in many of these genes, including orthodenticle homeobox 2 (OTX2), can present with a broad range of clinical symptoms, which provides a challenge for predicting phenotype from genotype. Another challenge in human genetics is functional evaluation of rare genetic variants that are predicted to be deleterious. Zebrafish are an excellent vertebrate model for evaluating gene function and disease pathogenesis, especially because large numbers of progeny can be obtained, overcoming the challenge of individual variation. To clarify the utility of zebrafish for the analysis of CPHD-related genes, we analyzed the effect of OTX2 loss of function in zebrafish. The otx2b gene is expressed in the developing hypothalamus, and otx2bhu3625/hu3625 fish exhibit multiple defects in the development of head structures and are not viable past 10 days post fertilization (dpf). Otx2bhu3625/hu3625 fish have a small hypothalamus and low expression of pituitary growth hormone and prolactin (prl). The gills of otx2bhu3625/hu3625 fish have weak sodium influx, consistent with the role of prolactin in osmoregulation. The otx2bhu3625/hu3625 eyes are microphthalmic with colobomas, which may underlie the inability of the mutant fish to find food. The small pituitary and eyes are associated with reduced cell proliferation and increased apoptosis evident at 3 and 5 dpf, respectively. These observations establish the zebrafish as a useful tool for the analysis of CPHD genes with variable and complex phenotypes.	0
PLO-SL (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy) is a recessively inherited disorder characterized by systemic bone cysts and progressive presenile frontal-lobe dementia, resulting in death at <50 years of age. Since the 1960s, approximately 160 cases have been reported, mainly in Japan and Finland. The pathogenesis of the disease is unknown. In this article, we report the assignment of the locus for PLO-SL, by random genome screening using a modification of the haplotype-sharing method, in patients from a genetically isolated population. By screening five patient samples from 2 Finnish families, followed by linkage analysis of 12 Finnish families, 3 Swedish families, and 1 Norwegian family, we were able to assign the PLO-SL locus to a 9-cM interval between markers D19S191 and D19S420 on chromosome 19q13. The critical region was further restricted, to approximately 1.8 Mb, by linkage-disequilibrium analysis of the Finnish families. According to the haplotype analysis, one Swedish and one Norwegian PLO-SL family are not linked to the chromosome 19 locus, suggesting that PLO-SL is a heterogeneous disease. In this chromosomal region, one potential candidate gene for PLO-SL, the gene encoding amyloid precursor-like protein 1, was analyzed, but no mutations were detected in the coding region.	1
We herein report a rare case presenting with severe hypercholesterolemia, massive Achilles tendon xanthomas, and multi-vessel coronary artery disease. Initially, the patient was misdiagnosed with familial hypercholesterolemia. However, a genetic analysis using our custom sequencing panel covering genes associated with Mendelian lipid disorders revealed him to have a genetic basis of sitosterolemia with compound heterozygous mutations in the adenosine triphosphate binding cassette subfamily G5 (ABCG5) gene. A comprehensive genetic analysis can be particularly useful for diagnosing cases with severe phenotypes, leading to appropriate and medical therapies. Our patient was refractory to statins, whereas ezetimibe and PCSK9 inhibitor with a low-plant-sterol diet successfully reduced his serum levels of low-density lipoprotein cholesterol.	0
Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling. Here, we show that CJS is caused by recurrent somatic mosaicism for a nonsynonymous variant in SMO (c.1234C>T [p.Leu412Phe]), encoding smoothened (SMO), a G-protein-coupled receptor that transduces Hh signaling. We identified eight mutation-positive individuals (two of whom had not been reported previously) with highly similar phenotypes and demonstrated varying amounts of the mutant allele in different tissues. We present detailed findings from brain MRI in three mutation-positive individuals. Somatic SMO mutations that result in constitutive activation have been described in several tumors, including medulloblastoma, ameloblastoma, and basal cell carcinoma. Strikingly, the most common of these mutations is the identical nonsynonymous variant encoding p.Leu412Phe. Furthermore, this substitution has been shown to activate SMO in the absence of Hh signaling, providing an explanation for tumor development in CJS. This raises therapeutic possibilities for using recently generated Hh-pathway inhibitors. In summary, our work uncovers the major genetic cause of CJS and illustrates strategies for gene discovery in the context of low-level tissue-specific somatic mosaicism.	0
Surgical resection remains the preferred approach for some patients with glioblastoma (GBM), and eradication of the residual tumour niche after surgical resection is very helpful for prolonging patient survival. However, complete surgical resection of invasive GBM is difficult because of its ambiguous boundary. Herein, a novel targeting material, c(RGDyk)-poloxamer-188, was synthesized by modifying carboxyl-terminated poloxamer-188 with a glioma-targeting cyclopeptide, c(RGDyk). Quantum dots (QDs) as fluorescent probe were encapsulated into the self-assembled c(RGDyk)-poloxamer-188 polymer nanoparticles (NPs) to construct glioma-targeted QDs-c(RGDyk)NP for imaging-guided surgical resection of GBM. QDs-c(RGDyk)NP exhibited a moderate hydrodynamic diameter of 212.4 nm, a negative zeta potential of -10.1 mV and good stability. QDs-c(RGDyk)NP exhibited significantly lower toxicity against PC12 and C6 cells and HUVECs than free QDs. Moreover, in vitro cellular uptake experiments demonstrated that QDs-c(RGDyk)NP specifically targeted C6 cells, making them display strong fluorescence. Combined with ultrasound-targeted microbubble destruction (UTMD), QDs-c(RGDyk)NP specifically accumulated in glioma tissue in orthotropic tumour rats after intravenous administration, evidenced by ex vivo NIR fluorescence imaging of bulk brain and glioma tissue sections. Furthermore, fluorescence imaging with QDs-c(RGDyk)NP guided accurate surgical resection of glioma. Finally, the safety of QDs-c(RGDyk)NP was verified using pathological HE staining. In conclusion, QDs-c(RGDyk)NP may be a potential imaging probe for imaging-guided surgery.	0
We report two sibs with features overlapping those of orofaciodigital syndrome type VI (Varadi syndrome). Both presented at birth with oculomotor abnormalities, dysmorphic facial features, and dysgenesis of the cerebellar vermis. There were minimal oral manifestations (high arched palate) in both of them and one had postaxial polydactyly of both hands and one foot. In addition, there was evidence of aplasia of the pituitary gland on MRI scan in both of them with evidence of hypopituitarism. Both responded well to hormone replacement therapy with improvement in their linear growth and mental ability. These cases may represent a new autosomal recessive midline defect syndrome with features overlapping OFDS VI. Alternatively the features in these children could represent variability within OFDS VI.	0
Rud's syndrome is a rare autosomal recessive hereditary disorder characterized by congenital ichthyosis, epilepsy, dwarfism, sexual infantilism, polyneuritis, and macrocytic anemia. We report here an interesting case of this disorder in an 18-year-old girl for its rarity and academic interest.	0
Collagen VI-related congenital muscular dystrophies (COL6-CMDs) are the second most common form of congenital muscular dystrophy. Currently, there is no effective treatment available. COL6-CMDs are caused by recessive or dominant mutations in one of the three genes encoding for the α chains of collagen type VI (COL6A1, COL6A2, and COL6A3). One of the most common mutations in COL6-CMD patients is a de novo deep intronic c.930+189C > T mutation in COL6A1 gene. This mutation creates a cryptic donor splice site and induces incorporation of a novel in-frame pseudo-exon in the mature transcripts. In this study, we systematically evaluated the splice switching approach using antisense oligonucleotides (ASOs) to correct this mutation. Fifteen ASOs were designed using the RNA-tiling approach to target the misspliced pseudo-exon and its flanking sequences. The efficiency of ASOs was evaluated at RNA, protein, and structural levels in skin fibroblasts established from four patients carrying the c.930+189C > T mutation. We identified two additional lead ASO candidates that efficiently induce pseudo-exon exclusion from the mature transcripts, thus allowing for the restoration of a functional collagen VI microfibrillar matrix. Our findings provide further evidence for ASO exon skipping as a therapeutic approach for COL6-CMD patients carrying this common intronic mutation.	0
BACKGROUND:Treacher Collins syndrome (TCS), the most common type of mandibulofacial dysostosis (MFD), is genetically homogeneous. Other types of MFD are less common and, of these, only the Bauru type of MFD has an autosomal dominant (AD) mode of inheritance established. Here we report clinical features of a kindred with a unique AD MFD with the exclusion of linkage to the TCS locus (TCOF1) on chromosome 5q31-q32. METHODS:Six affected family members underwent a complete medical genetics physical examination and two affected subjects had skeletal survey. All available medical records were reviewed. Linkage analysis using the markers spanning the TCOF1 locus was performed. One typically affected family member had a high resolution karyotype. RESULTS:Affected subjects had significant craniofacial abnormalities without any significant acral changes and thus had a phenotype consistent with a MFD variant. Distinctive features included hypoplasia of the zygomatic complex, micrognathia with malocclusion, auricular abnormalities with conductive hearing loss, and ptosis. Significantly negative two point lod scores were obtained for markers spanning the TCOF1 locus, excluding the possibility that the disease in our kindred is allelic with TCS. High resolution karyotype was normal. CONCLUSIONS:We report a kindred with a novel type of MFD that is not linked to the TCOF1 locus and is also clinically distinct from other types of AD MFD. Identification of additional families will facilitate identification of the gene causing this type of AD MFD and further characterisation of the clinical phenotype.	0
Sneddon syndrome(SS) is a rare clinical syndrome characterized by ischemic cerebrovascular disease and livedo reticularis, which involves the heart, kidney, fundus and other organs. We reported a case of a 45-year old male patient with recurrent ischemic cerebrovascular accidents as the first manifestation, accompanied by significant declines in cognitive function and livedo reticularis in trunk and limbs. The final diagnosis was SS. This article summarized the possible etiology, clinical characteristics, diagnosis and treatment for SS. Clinicians should improve the understanding of the disease to make the correct diagnosis and treatment and to prevent the occurrence of severe neurologic impairment and vascular dementia.	0
Gliomatosis cerebri (GC) has classically been considered a rare malignancy with a poor prognosis and is developmentally unique from solid tumors. More recently, GC has become better understood as a phenotype along the spectrum of gliomas and, most importantly, not mutually exclusive from the more common presentation of a tumor mass. The following case report illustrates not only the implications of the ontogeny of gliomas in clinical practice but also the successes that can accompany the early recognition of such a disease. Here, we report the presentation of a solid temporal lobe glioma, which, on presentation, was disseminating along well-defined mesolimbic white matter tracts. Once properly diagnosed and managed, the patient remarkably proceeded to achieve an impressive outcome given the extent of her pathology.	0
CLINICAL CHARACTERISTICS:PNPLA6-related disorders span a phenotypic continuum characterized by variable combinations of cerebellar ataxia, upper motor neuron involvement manifesting as spasticity and/or brisk reflexes, chorioretinal dystrophy associated with variable degrees of reduced visual function, and hypogonadotropic hypogonadism (delayed puberty and lack of secondary sex characteristics), either in isolation or as part of anterior hypopituitarism (growth hormone, thyroid hormone, or gonadotropin deficiencies). Common but less frequent features are peripheral neuropathy (usually of axonal type manifesting as reduced distal reflexes, diminished vibratory sensation, and/or distal muscle wasting), hair anomalies (long eyelashes, bushy eyebrows, or scalp alopecia), short stature, and impaired cognitive functioning (learning disabilities in children and deficits in attention, visuospatial abilities, and recall in adults). Some of these features can occur in distinct clusters on the phenotypic continuum: Boucher-Neuhäuser syndrome (cerebellar ataxia, chorioretinal dystrophy, and hypogonadotropic hypogonadism); Gordon Holmes syndrome (cerebellar ataxia, hypogonadotropic hypogonadism, and – to a variable degree – brisk reflexes); Oliver-McFarlane syndrome (trichomegaly, chorioretinal dystrophy, short stature, intellectual disability, and hypopituitarism); Laurence-Moon syndrome; and spastic paraplegia type 39 (SPG39) (upper motor neuron involvement, peripheral neuropathy, and sometimes reduced cognitive functioning and/or cerebellar ataxia). DIAGNOSIS/TESTING:The diagnosis of a PNPLA6-related disorder is suspected on clinical and neuroimaging findings and confirmed by identification of biallelic pathogenic variants in PNPLA6. MANAGEMENT:Treatment of manifestations: Management is symptomatic and individually tailored. Ataxia: continuous training of speech and swallowing, fine-motor skills, gait, and balance. Spasticity: interventions to improving strength and agility such as exercises, assistive walking devices and/or ankle-foot orthotics, drugs to reduce muscle spasticity. Chorioretinal dystrophy: low vision aids when central acuity is reduced; involvement with agencies for the visually impaired re vocational training, mobility training, and skills for independent living. Hypothyroidism: hormone replacement therapy as soon as identified. Growth hormone deficiency: hormone replacement therapy during childhood and/or adolescence as indicated. Hypogonadotropic hypogonadism: hormone replacement therapy at the expected time of puberty. Prevention of secondary complications: A daily regimen of physical therapy to maintain and improve coordination, muscle strength, and gait; to reduce spasticity; and to prevent contractures. Surveillance: Periodic evaluations (annually or as needed) by a neurologist, ophthalmologist and (if necessary) an endocrinologist to assess progression and develop treatment strategies. Agents/circumstances to avoid: Alcohol; obesity; inactive, sedentary lifestyle; exposure to medications or chemicals that exacerbate neuropathy. GENETIC COUNSELING:PNPLA6-related disorders are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the PNPLA6 pathogenic variants in the family have been identified.	0
Objective Ethylmalonic encephalopathy (EE) is a severe mitochondrial disease of early infancy clinically characterized by a combination of developmental delay, progressive pyramidal signs, and vascular lesions including petechial purpura, orthostatic acrocyanosis, and chronic hemorrhagic diarrhea. Biochemical hallmarks of the disease are persistently high level of lactate, and C4-C5-acylcarnitines in blood, markedly elevated urinary excretion of methylsuccinic and ethylmalonic (EMA) acids. Here we report two patients with EE as a 16-months-old male infant and a 2-yr-old boy referred to Pediatric Neurology Clinic in Children's Medical Center, Tehran-Iran that in one patient genetic analysis revealed a homozygous mutation of the ETHE1 gene in favor of ethylmalonic acidemia.	0
OBJECTIVES:This study aimed to determine the sensitivity of a first-trimester routine scan in detecting spina bifida (SB) and evaluating the first-trimester intracranial signs. METHODS:This retrospective study was a review of a prospectively collected database. All cases of SB diagnosed in a tertiary center from 2008 to 2015 were identified. The ultrasound images and medical records were reviewed. All cases of SB diagnosed prenatally were confirmed at birth or autopsy. RESULTS:A total of 24 cases of SB were diagnosed from 53,349 pregnancy cases. Except for 10 cases with a body stalk anomaly, craniorachischisis, or iniencephaly, 7 cases with open spina bifida (OSB) and 7 cases with closed spina bifida (CSB) were analyzed. The first-trimester detection rates were 100% (7 of 7) for OSB and 28.5% (2 of 7) for CSB. Eight cases were highly suspected of SB in the first trimester because of an abnormal appearance of the posterior brain; 3 were false-positive cases. Two isolated cases of OSB had first-trimester intracranial signs. An obliterated cisterna magna (CM) showed the highest sensitivity for OSB but low specificity. Two cases of OSB had no discernible landmark of intracranial translucency and the CM, and 4 showed normal intracranial translucency with an obliterated CM. All CSB cases were coupled with a normal hind brain except for 2 cases. CONCLUSIONS:A first-trimester routine scan has high sensitivity in screening for OSB. The CM may be the most sensitive intracranial sign.	0
Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive soft-tissue malignancy with a poor overall survival and no effective therapeutic options. The tumor is believed to be dependent on the continued activity of the oncogenic EWS-WT1 transcription factor. However, the dependence of the tumor on EWS-WT1 has not been well established. In addition, there are no studies exploring the downstream transcriptional program across multiple cell lines. In this study, we have developed a novel approach to selectively silence EWS-WT1 without impacting either wild-type EWSR1 or WT1. We show a clear dependence of the tumor on EWS-WT1 in two different cell lines, BER and JN-DSCRT-1. In addition, we identify and validate important downstream target pathways commonly dysregulated in other translocation-positive sarcomas, including PRC2, mTOR, and TGFB. Surprisingly, there is striking overlap between the EWS-WT1 and EWS-FLI1 gene signatures, despite the fact that the DNA-binding domain of the fusion proteins, WT1 and FLI1, is structurally unique and classified as different types of transcription factors. This study provides important insight into the biology of this disease relative to other translocation-positive sarcomas, and the basis for the therapeutic targeting of EWS-WT1 for this disease that has limited therapeutic options.	0
BACKGROUND:Variants in the SLC25A1 gene are associated with a severe neurometabolic disease, D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). A report in 2014 presented the first account of congenital myasthenic syndrome (CMS) with mild intellectual disability (ID) caused by SLC25A1. To date, only two missense variants in SLC25A1 have been linked to CMS. CASE PRESENTATIONS:A Chinese boy presented fatigable muscular weakness, myasthenic crisis, epilepsy and developmental delay along with mild elevation of urinary 2-ketoglutarate (2-KG) and lactic acid levels. He showed a partial response to pyridostigmine. Genetic analysis using trio whole-exome sequencing (WES), Sanger sequencing, and cosegregation analyses revealed two novel pathogenic variants of SLC25A1 (c.628C > T, p.R210X; c.145G > A, p.V49M). CONCLUSIONS:We report a boy who carries novel compound heterozygous variants of SLC25A1 and presents a phenotype intermediate between CMS and D/L-2-HGA. This case expands the range of known phenotypes and genotypes associated with SLC25A1.	0
Blastomyces dermatitidis is the causal agent of blastomycosis, an invasive and often serious fungal infection. Blastomycosis typically presents as a pulmonary infection, but common extrapulmonary manifestations of blastomycosis include the skin, bones, and reticuloendothelial systems. Disseminated blastomycosis occurs more prominently in immunocompromised individuals, such as organ transplant recipients, HIV patients, and pregnant women. We report here a rare case of disseminated blastomycosis to the thyroid in a pregnant patient. This case emphasizes the unique challenges of diagnosing and treating disseminated fungal infections in pregnancy.	0
Purpose:To describe quantitative characteristics of macular neovascularization (MNV) in vitelliform macular dystrophy (VMD) patients by means of optical coherence tomography angiography (OCTA). Methods:The study design was a prospective case series. All patients underwent complete ophthalmologic assessment, optical coherence tomography, and OCTA. The quantitative OCTA parameters examined included vessel tortuosity and vessel dispersion of the MNV. The primary outcome was OCTA characterization of MNV in VMD. Secondary outcomes included the evolution of MNV over the follow-up. Results:A total of 78 eyes were recruited for the study. MNV was identified in 50 eyes (64%) at baseline and in 51 eyes (65%) at the end of the follow-up (mean follow-up, 24.7 ± 9.7 months). MNV was detected in four out of the 30 eyes classified as stages 2 and 3 (13%), showing exudative manifestations and undergoing ranibizumab treatment, leading to clinical stabilization. OCTA detected MNV in 46 out of 48 eyes (96%) classified as stages 4 and 5, showing no evidence of exudative manifestation. All of the non-exudative MNVs were merely observed over the follow-up and received no treatment. At the end of the follow-up, 47 out of 48 eyes displayed MNV (98%). Non-exudative MNVs remained stable over the follow-up. Statistically significant differences were found when comparing vessel tortuosity and vessel dispersion in the two MNV subforms. Conclusions:VMD is characterized by two MNV subforms. Exudative MNV is rare and may develop in the early stages of the disease, in association with bleeding and fluid formation. Non-exudative MNV develops very commonly in the advanced stage of VMD, without any exudative manifestation.	0
Clinicoepidemiological manifestations of the vasculitides differ geographically. According to a nationwide, hospital-based survey in Japan, the prevalence of microscopic polyangiitis (MPA) and/or renal-limited vasculitis (RLV) is much higher than that of Wegener's granulomatosis (WG). However, little is known about the incidence of antineutrophil cytoplasmic autoantibodies (ANCA)-associated primary renal vasculitis (PRV) in Japan. The incidence of PRV was retrospectively determined by a population-based method in Miyazaki Prefecture in Japan between 2000 and 2004. PRV was defined according to the following criteria from the European Systemic Vasculitis Study Group: (1) new patients with WG, MPA, Churg-Strauss syndrome (CSS), or RLV, (2) renal involvement attributable to active vasculitis, and (3) ANCA considered positive if the disease was not histologically confirmed. The numbers of patients with PRV in the years 2000, 2001, 2002, 2003, and 2004 were 9, 9, 9, 16, and 13, respectively. The male to female ratio was 24:32 and the average age was 70.4 +/- 10.9 (mean +/- SD) yr. The estimated annual incidence of PRV was 14.8 (95% confidence interval [CI] 10.8 to 18.9) and 44.8 (95% CI 33.2 to 56.3) per million adults (>15 yr old) and seniors (>65 yr old), respectively. Ninety-one percent of the patients were myeloperoxidase (MPO)-ANCA positive, but none were positive for proteinase 3 (PR3)-ANCA. There were no WG or CSS patients. The incidence of PRV did not differ between Japan and Europe, but WG was not widespread in Japan. Furthermore, the ratio of serum MPO to PR3-ANCA among Japanese with PRV was much higher than that found among European and US patients.	1
Clubfoot is the most frequent congenital malformation of the foot, affecting more than 1-2 subjects per 1.000 newborns. Without appropriate treatment, a child with congenital clubfoot will never be able to walk physiologically with a dramatic impact on the quality of life. In the last decades, different corrective solutions have been proposed, and there is rising scientific evidence that the Ponseti non-invasive method is safe and effective in the treatment of the clubfoot. So, what should a general paediatrician know about this condition and what should he concretely do in the suspect of a congenital clubfoot?	0
BACKGROUND:Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). OBJECTIVE:To identify pathogenic mutation in the Korean patients with CMT and distal hereditary motor neuronopathy (dHMN). METHODS:We screened AARS1 mutations in 373 unrelated CMT families including 318 axonal CMT, 36 dHMN, and 19 intermediate CMT (Int-CMT) who were negative for 17p12 (PMP22) duplication or deletion using whole exome sequencing and targeted sequencing of CMT-related genes. RESULTS:This study identified an early onset Int-CMT family harboring an AARS1 p.Arg329His mutation which was previously reported as pathogenic in French and Australian families. The mutation was located in the highly conserved tRNA binding domain and several in silico analyses suggested pathogenic prediction of the mutations. The patients harboring p.Arg329His showed clinically similar phenotypes of the early onset and electrophysiological intermediate type as those in Australian patients with same mutation. We also found a novel c.2564A>G (p.Gln855Arg) in a CMT2 patient, but its' pathogenic role was uncertain (variant of uncertain significance). CONCLUSION:This study suggests that the frequency of the AARS1 mutations appears to be quite low in Korean CMT. This is the first report of the AARS1 mutation in Korean CMT patients and will be helpful for the exact molecular diagnosis and treatment of Int-CMT patients.	0
Acrodermatitis enteropathica is a rare autosomal recessive disorder of zinc deficiency. The genetic defect has been mapped to 8q24 and the defective gene identified as SLC39A4, which encodes the zinc transporter Zip4. The diagnosis is made by way of clinical presentation together with histopathology and laboratory tests. Here we provide an overview of zinc metabolism and a description of inherited and acquired zinc deficiency.	1
BACKGROUND:Maple syrup urine disease is a rare autosomal-recessive aminoacidopathy, caused by deficient branched-chain 2-keto acid dehydrogenase (BCKD), with subsequent accumulation of branched-chain amino acids (BCAAs): leucine, isoleucine and valine. While most cases of MSUD are classic, some 20% of cases are non-classic variants, designated as intermediate- or intermittent-types. Patients with the latter form usually develop normally and are cognitively intact, with normal BCAA levels when asymptomatic. However, intercurrent febrile illness and catabolism may cause metabolic derailment with life-threatening neurological sequelae. Thus, early detection and dietary intervention are warranted in intermittent MSUD. PATIENTS AND METHODS:We describe eight patients from four unrelated families, diagnosed with intermittent MSUD. Their presenting symptoms during metabolic crises varied from confusion and decreased consciousness, to ataxia, and acute psychosis. Molecular confirmation of MSUD was pursued via sequencing of the BCKDHA, BCKDHB and DBT genes. RESULTS:All affected individuals were found to harbor bi-allelic pathogenic variants in either BCKDHB or DBT. Of the seven variants, four variants in BCKDHB (p.G101D, p. V103A, p. A221D, p. Y195C) and one variant in DBT (p.K427E) were not previously described. CONCLUSIONS:While newborn screening programs allow for early detection of classic MSUD, cases of the intermittent form might go undetected, and present later in childhood following metabolic derailment, with an array of non-specific symptoms. Our experience with the families reported herein adds to the current knowledge regarding the phenotype and mutational spectrum of this unique inborn error of branched-chain amino acid metabolism, and underscore the high index of suspicion required for its diagnosis.	0
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Prognosis is highly variable, ranging from few months to more than 30 years. 25OH vitamin D (25OH VD) blood levels have been associated with worse prognosis of ALS, but these results remain in dispute. We addressed this controversy with a prospective study and multivariate analysis to study the influence of known clinical prognostic factors of the disease and 25OH VD levels on Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) severity score (ALS-SS), as defined by the monthly rate of decline of ALSFRS-R score, to identify the factors most closely linked to the risk of worsening of the disease. Results:This prospective cohort of ALS patients recruited 127 individuals, and 105 of them met inclusion criteria. Mean age of onset was 62.2 ± 12.1 years, 32% of subjects had bulbar onset, and gender ratio was 1.44 (male/female). Mean 25OH VD level was 26.8 ± 10.8 ng/ml and was similar between males and females. Patients with 25OH VD levels <15 ng/ml had significantly higher ALS-SS at inclusion (ALS-SSi) than those with normal levels (>30 ng/ml), p = 0.011. The study of ALS-SS as calculated at the end of follow-up (ALS-SSe) was not found correlated to initial 25OH VD levels (r = -0.19; p = 0.084). Univariate analysis showed that ALS-SSe correlated with 25OH VD levels, ALS duration at inclusion, slow vital capacity (SVC) at inclusion, and SVC loss. Multivariate model showed that 25OH VD levels were independently associated with ALS-SSe: r = -0.0125, p = 0.033. Log rank test with Kaplan-Meier curves did not show significant differences of survival between the groups defined by 25OH VD levels: <15, >15 and <30, and > 30 ng/ml, p = 0.88. Conclusions: This prospective study in ALS patients confirmed previous retrospective results: ALS-SSi is significantly higher in patients with severe VD deficiency. For the first time, multivariate analysis showed that 25OH VD level was an independent prognostic factor correlated to ALS-SSe, suggesting that discrepancies between previous works could be due to confounders. It would be important that the present work be replicated in larger samples to confirm the present findings.	0
BACKGROUND: Severe anomalies of the forebrain together with radial limb anomalies have been reported in Steinfeld syndrome, XK aprosencephaly, and partial monosomy 13q. Steinfeld syndrome is an extremely variable autosomal dominant condition that, in severe cases, is characterized by holoprosencephaly, radial limb defects, and renal and/or cardiac defects. In mild cases there may be only thumb hypoplasia, ocular coloboma, or oral clefts. XK aprosencephaly, also called Garcia-Lurie syndrome (GLS), is a usually sporadic disorder with radial limb defects and aprosencephaly/atelencephaly. Based on two atypical sibships, autosomal recessive inheritance has been suggested. Two patients with variations of monosomy 13q have been described with atelencephaly but, generally, Steinfeld and XK aprosencephaly patients are chromosomally normal. Holoprosencephaly in 13q deletion patients appears to be due to ZIC2 mutations, but ZIC2 has not been previously tested in Steinfeld syndrome or GLS patients. CASES: We report three sporadic cases with clinical features intermediate between Steinfeld and GLS, including severe forebrain malformations and radial limb defects. All had normal karyotypes, and mutations in ZIC2 were absent in the two cases tested. CONCLUSIONS: In our cases and in the literature there is significant clinical overlap between Steinfeld syndrome and GLS. We propose these conditions may not be nosologically or etiologically distinct. The spectrum of severe forebrain anomalies in these conditions is broader than previously thought and may include some neural tube defects. Mild cases are difficult to identify and the full range of expression remains unknown. Autosomal dominant inheritance with incomplete penetrance and frequent new mutations is postulated. Thorough clinical evaluation is recommended for children with severe forebrain and radial limb defects.	0
Anonychia refers to the absence of nail plates owing to an autosomal dominant or recessive inheritance. Congenital anonychia is a rare condition that may be associated with other ectodermal or mesodermal malformations like epidermolysis bullosa, (deafness, onychodystrophy, osteodystrophy, and mental retardation) syndrome and Iso-Kikuchi syndrome. Here, we report 3 cases with anonychia congenita appearing in different generations of a single family in Kingdom of Saudi Arabia.	0
Nucleotide excision repair (NER) is a versatile DNA repair pathway which can be activated in response to a broad spectrum of UV-induced DNA damage, such as bulky adducts, including cyclobutane-pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs). Based on the genomic position of the lesion, two sub-pathways can be defined: (I) global genomic NER (GG-NER), involved in the ablation of damage throughout the whole genome regardless of the transcription activity of the damaged DNA locus, and (II) transcription-coupled NER (TC-NER), activated at DNA regions where RNAPII-mediated transcription takes place. These processes are tightly regulated by coordinated mechanisms, including post-translational modifications (PTMs). The fine-tuning modulation of the balance between the proteins, responsible for PTMs, is essential to maintain genome integrity and to prevent tumorigenesis. In this review, apart from the other substantial PTMs (SUMOylation, PARylation) related to NER, we principally focus on reversible ubiquitylation, which involves E3 ubiquitin ligase and deubiquitylase (DUB) enzymes responsible for the spatiotemporally precise regulation of NER.	0
Background Epidermolysis bullosa simplex (EBS) is a rare genodermatosis resulting from multiple gene mutations, including KRT5 and KRT14. The clinical expression of the mechanobullous skin fragility disease has not been fully explained by the genotype. Case Description An 11-day-old Japanese newborn infant was hospitalized because of herpetiform skin blistering on the feet, which expanded systemically after birth. There was no evidence of virus infection. The biopsied skin lesion showed a blister on the lamina densa without keratin clumps, indicating a diagnosis of EBS-generalized intermediate. We punctured the blisters to remove the contents daily, which led to no exacerbation or infection. The genetic study determined that the patient carried double substitutions of KRT5 c.1424A > G (p.E475G) and KRT14 c.1237G > A (p.A413T). The asymptomatic mother and sister carried the KRT14 substitution, but the healthy father had no substitution of the KRT gene. Conclusion This is the first report of EBS-generalized intermediate in a newborn with de novo KRT5 gene mutation and KRT14 gene polymorphism, and no familial history of epidermolysis. Neonatal blistering due to EBS requires optimal skin management after excluding infectious and immunobullous diseases.	0
Sclerodermalike syndromes (SLSs) comprise diseases with mucin deposition (eg, scleromyxedema, scleredema), with eosinophilia (eg, eosinophilic fasciitis), metabolic or biochemical abnormalities (eg, nephrogenic systemic fibrosis), or endocrine disorders (eg, POEMS syndrome, or polyneuropathy, organomegaly, endocrinopathy, monoclonal lymphoproliferative disorder, and hypothyroidism). Chronic graft-versus-host disease may also show sclerodermalike skin changes. Inherited progeria syndromes with early aging (eg, Werner syndrome) and a heterogeneous group of hereditary disorders with either skin thickening (eg, stiff skin syndrome) or atrophy and tightening (eg, acrogeria) can also imitate classic systemic sclerosis (SSc). In addition, SLSs can be provoked by several drugs, chemicals, or even physical injury (eg, trauma, vibration stress, radiation). In SLSs, the distribution of skin involvement seems to be atypical compared with SSc. The acral skin involvement is usually missing, and lack of Raynaud phenomenon, scleroderma-specific antinuclear antibodies, the absence of scleroderma capillary pattern, and internal organ manifestations indicate the presence of an SLS. Skin involvement is sometimes nodular, and the underlying tissues can also be affected. For the differential diagnosis, a skin biopsy of the deeper layers including fascia and muscle is required. Histology does not always allow differentiation between SSc and SLSs; therefore, the diagnosis is often based on the distribution, quality of cutaneous involvement, and other accompanying clinical features.	0
OBJECTIVES:Familial Mediterranean fever (FMF) is a monogenic auto-inflammatory disease which might rarely cause glomerulopathy in patients. The aim of this study was to determine the clinical, demographic, and genetic characteristics and type of glomerular lesions in pediatric FMF patients who underwent kidney biopsy. METHODS:The data of 30 pediatric FMF patients with biopsy-proven glomerulopathy were retrospectively reviewed. Patients were grouped into 2 categories as amyloid nephropathy (AN, n = 16) and non-amyloid nephropathy (N-AN, n = 14). RESULTS:The mean age at FMF diagnosis was 7.2 ± 3.0 years. The AN group showed higher rates of hypertension, higher levels of 24-h protein excretion and serum creatinine, and lower estimated glomerular filtration rate at the time of kidney biopsy. The rate of ESRD was found to be higher in the AN group (p = 0.011). Mesangioproliferative glomerulonephritis was the most common pathology in the N-AN group (21.4%). The frequency of amyloidosis was significantly higher in patients with homozygous p.M694V mutations than non-homozygous p.M694V mutations (p = 0.039). CONCLUSIONS:In children with FMF, nephropathy is rare. To our knowledge, this is the first study performed in pediatric FMF patients exploring amyloid and non-amyloid glomerulopathies. Patients with AN had higher rates of proteinuria, lower estimated glomerular filtration rate levels, and higher blood pressure than N-AN patients at the time of biopsy.	0
BACKGROUND:Ectrodactyly-Ectodermal dysplasia-Cleft lip/palate (EEC) syndrome and Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndrome belong to p63 syndromes, a group of rare disorders exhibiting a wide variety of clinical manifestations. TP63 mutations have been reported to be associated with both EEC and AEC. METHODS:Analysis of whole exome sequencing (WES) from patients with EEC or AEC syndrome and Sanger sequencing from family members. RESULTS:We confirmed that three Chinese pedigrees affected with EEC or AEC harboring a distinct TP63 mutation, and described novel clinical phenotypes of EEC and AEC, including the presence of cubitus valgus deformity and taurodontism, which were discordant to their classical disease features. We also analyzed the genotype-phenotype correlation based on our findings. CONCLUSION:We reported that the cubitus valgus deformity in patients with EEC and severe taurodontism in a patient with AEC had not been mentioned previously. Our study expands the phenotypic spectrum of EEC and AEC syndrome.	0
Hereditary spastic paraplegias are heterogeneous disorders with diversified clinical manifestations, and genetic testing is important for the diagnosis and typing of hereditary spastic paraplegias.Gene panel sequencing containing 55 hereditary spastic paraplegias-related genes was performed to screen the pathogenic genes for hereditary spastic paraplegias. Sanger sequencing was adopted to validate if the family member carried the same pathogenic gene as the proband.Fifteen out of 53 patients carried mutation(s) in the screened hereditary spastic paraplegias-related genes. Among the 23 identified mutations, only one mutation had been previously reported as a pathogenic mutation. In the pedigree of case 6, the proband, his mother and uncle all carried the same novel deletion mutation (c.1459delA) at SPAST gene. Based on the pedigree, the disease was inherited in an AD pattern. In the pedigree of case 53, the family disease may be in an X-linked recessive inheritance pattern. The proband (case 53) carried two novel mutations in ALT1 gene and L1CAM gene (c.2511C>A), respectively. The L1CAM gene is the causative gene for the SPG1 X-linked recessive-hereditary spastic paraplegias.Our data confirm the genetic heterogeneity of hereditary spastic paraplegias, and SPG4/SPAST were the most frequent forms. The pathogenicity of the novel mutations is worth to be further investigated.	0
A comprehensive study of inherited neuromuscular disease was carried out in Northern Ireland between 1 February 1993 and 30 June 1994. Cases were ascertained from eight different sources and investigations and diagnoses were reviewed. Five hundred and forty three individuals were identified giving an overall prevalence of inherited neuromuscular disease of 1 in 2900 of the population. The prevalence of myotonic dystrophy was higher than that in most previously reported studies and accounted for 25% of all cases. Congenital myopathies were also found more frequently than expected. The overall prevalence compares well with that estimated by Emery from the reported prevalence rates of individual diseases.	1
Background Hypothalamic damage may alter glucagon-like peptide-1 (GLP-1) secretion and be involved in the pathogenesis of obesity. We aim to evaluate the metabolic features and the dynamic changes of GLP-1 levels during an oral glucose tolerance test (OGTT) in children with hypothalamic obesity (HO) compared with simple obesity controls. Methods Subjects included eight patients (six females, aged 9-16 years) with hypothalamo-pituitary tumors who later developed obesity and eight controls with simple obesity matched for age, body mass index (BMI), gender and puberty. We assessed the metabolic syndrome features, fat mass, severity of hyperphagia using a standardized questionnaire, and measured glucose, insulin and GLP-1 levels during a standard 75 g OGTT. Results Age, gender distribution, pubertal status and BMI-Z scores were not significantly different. Subjects with HO had higher fasting triglycerides (TG) than controls (128 vs. 94 mg/dL; p=0.05). Four HO subjects and three controls met the criteria for the metabolic syndrome. Fasting and 120 min post-glucose load GLP-1 levels were significantly higher in HO patients than in controls (21.9 vs. 19.7 pg/mL; p=0.025, 22.1 vs. 17.7 pg/mL; p=0.012). Patients with HO had significantly higher hyperphagia scores than in simple obese controls (13 vs. 2.5; p=0.012). Conclusions Patients with HO appear to have more metabolic complications and hyperphagia than controls with simple obesity. Impaired satiety may play an important role in HO. Fasting and glucose-induced serum GLP-1 concentrations seem to be altered in HO patients and could be a part of the pathogenesis of HO.	0
The surfaces of oral mucosa are protected from infections by antimicrobial proteins and natural immunoglobulins that are constantly secreted in saliva, serving as principal innate immune defense in the oral cavity. MyD88 is an important adaptor protein for signal transduction downstream of Toll-like receptors and TACI, receptors for regulation of innate immunity and B cell responses, respectively. Although MyD88-mediated signaling has a regulatory role in the intestinal mucosal immunity, its specific role in the oral cavity has remained elusive. In the present study, we assessed the influence of MyD88 deficiency on the oral innate defense, particularly the expression of antimicrobial proteins in salivary glands and production of salivary basal immunoglobulins, in mice. Microarray analysis of the whole tissues of submandibular glands revealed that the expression of several genes encoding salivary antimicrobial proteins, such as secretory leukocyte peptidase inhibitor (SLPI), S100A8, and lactotransferrin, was reduced due to MyD88 deficiency. Histologically, SLPI-expressing acinar cells were evidently decreased in the glands from MyD88 deficient mice compared to wild-type mice. Flow cytometric analysis revealed that B cell populations, including B-1 cells and IgA+ plasma cells, residing in submandibular glands were increased by MyD88 deficiency. The level of salivary anti-phosphorylcholine IgA was elevated in MyD88 deficient mice compared to wild-type mice. Thus, this study provides a detailed description of the effect of MyD88 deficiency on expression of several salivary antimicrobial factors in mice, illustrating the role for MyD88-mediated signaling in the innate immune defense in the oral cavity.	0
A 27-year old female presented with a 3 day history of fever, itchy maculopapular rash progressing cephalocaudally and facial swelling. She was a known case of multiple sclerosis (MS) taking oral teriflunomide 14 mg for past 27 days. She was not taking any other drug. Symptom appeared 3 weeks after initiation of drug. Clinical examination revealed dusky maculopapular rash involving trunk (Figure 1a) and extremities (Figure 1b) and diffuse facial swelling with erythema and scaling.	0
BACKGROUND:OFD1 has long been recognized as the gene implicated in the classic dysmorphology syndrome, oral-facial-digital syndrome type I (OFDSI). Over time, pathogenic variants in OFD1 were found to be associated with X-linked intellectual disability, Joubert syndrome type 10 (JBTS10), Simpson-Golabi-Behmel syndrome type 2 (SGBS2), and retinitis pigmentosa. Recently, OFD1 pathogenic variants have been implicated in primary ciliary dyskinesia (PCD), a disorder of the motile cilia with a phenotype that includes recurrent oto-sino-pulmonary infections, situs abnormalities, and decreased fertility. METHODS:We describe three male patients with PCD who were found to have hemizygous pathogenic variants in OFD1, further supporting that PCD is part of a clinical spectrum of OFD1-related disorders. In addition, we provide a review of the available clinical literature describing patients with OFD1 variants and highlight the phenotypic variability of OFD1-related disease. RESULTS:Some individuals with hemizygous OFD1 variants have PCD, either apparently isolated or in combination with other features of OFD1-related disorders. CONCLUSION:As clinicians consider the presence or absence of conditions allelic at OFD1, PCD should be considered part of the spectrum of OFD1-related disorders. Understanding the OFD1-related disease spectrum may allow for more focused genetic testing and more timely management of treatable sequelae.	0
Kaposi's sarcoma (KS) is the most common cancer in HIV-positive individuals and is caused by KS-associated herpesvirus (KSHV). It is believed that a small number of latently infected KS tumor cells undergo spontaneous lytic reactivation to produce viral progeny for infection of new cells. Here we use matched donor-derived human dermal blood and lymphatic endothelial cells (BEC and LEC, respectively) to show that KSHV-infected BEC progressively lose viral genome as they proliferate. In sharp contrast, KSHV-infected LEC predominantly entered lytic replication, underwent cell lysis, and released new virus. Continuous lytic cell lysis and de novo infection allowed LEC culture to remain infected for a prolonged time. Due to the strong propensity of LEC toward lytic replication, LEC maintained virus as a population, despite the death of individual host cells from lytic lysis. The master regulator of lymphatic development Prox1 bound the promoter of the RTA gene to upregulate its expression and physically interacted with RTA protein to coregulate lytic genes. Thus, LEC may serve as a proficient viral reservoir that provides viral progeny for continuous de novo infection of tumor origin cells, and potentially BEC and mesenchymal stem cells, which give rise to KS tumors. Our study reveals drastically different host cell behaviors between BEC and LEC and defines the underlying mechanisms of the lymphatic cell environment supporting persistent infection in KS tumors.	0
OBJECTIVE:To determine the frequency of fetal urinary tract anomalies and to characterize the types of such abnormalities detected on ultrasonography and the outcome of affected patients during a 15-year period at our institution. DESIGN:We retrospectively reviewed the findings on maternal prenatal ultrasound examinations and the postnatal medical records of 56 children with urinary tract abnormalities detected by prenatal ultrasound examination at Mayo Clinic Rochester from November 1979 to June 1994. RESULTS:Of the 56 children, 18 (32%) had severe urinary tract anomalies in conjunction with oligohydramnios, pulmonary hypoplasia, and perinatal death (Potter's syndrome). The other 38 infants had various urinary tract abnormalities--most commonly, isolated hydronephrosis and multicystic dysplasia of the kidney. Six of the 38 children had more than one renal abnormality detected prenatally. Reflux was noted in association with prenatally detected urinary tract abnormalities in 4 of 32 newborns (12%) who underwent voiding cystourethrography. In fetuses with normal amniotic fluid volume, the perinatal outcome was good. Children with lower urinary tract obstruction had evidence of more severe renal dysfunction than did those with involvement at more proximal levels. The presence or absence of urinary tract obstruction postnatally could not be determined reliably on the basis of prenatal ultrasound appearance. CONCLUSION:In this study, more than half of all prenatally detected urinary tract abnormalities were isolated hydronephrosis or multicystic dysplasia of the kidney. Postnatal renal function could not be reliably predicted on the basis of prenatal ultrasound findings.	1
Usher syndrome encompasses a group of genetically and clinically heterogeneous autosomal recessive disorders with hearing deficiencies and retinitis pigmentosa. The mechanisms underlying the Usher syndrome are highly variable. In the present study, a Chinese family with Usher syndrome was recruited. Whole exome sequencing (WES), Sanger sequencing, homozygosity mapping, short tandem repeat (STR) analysis and segregation analysis were performed. Functional domains of the pathogenic variant for USH2A were analysed. We identified a homozygous frameshift variant c.99_100insT (p.Arg34Serfs*41) in the USH2A gene in the proband that showed discordant segregation in the father. Further homozygosity mapping and STR analysis identified an unusual homozygous variant of proband that originated from maternal uniparental disomy (UPD). The p.Arg34Serfs*41 variant produced a predicted truncated protein that removes all functional domains of USH2A. The variant was not included in the 1000 Human Genomes Project database, ExAC database, HGMD or gnomAD database, but was included in the ClinVar databases as pathogenic. Although USH2A is an autosomal recessive disease, the effects of UPD should be informed in genetic counselling since the recurrence risk of an affected child is greatly reduced when the disease is due to the UPD mechanism. To test potential patients, WES, combined with STR analysis and homozygosity mapping, provides an accurate and useful strategy for genetic diagnosis. In summary, our discoveries can help further the understanding of the molecular pathogenesis of Usher syndrome type IIA to advance the prevention, diagnosis and therapy for this disorder.	0
The supralittoral amphipod Traskorchestia ditmari (Derzhavin, 1923) was identified as the intermediate host for Antechiniella septentrionalis Ivanova, Dokuchaev & Spiridonov, 2019, a parasite of the tundra vole Microtus oeconomus and Skrjabinocerca sp. (both Spirurida: Acuariidae) in Magadan Oblast in north-eastern Russia. Joint infection by both larval spirurids was not observed. The infective stage of A. septentrionalis was the encysted larvae, while larvae of Skrjabinocerca sp. were free in the amphipod's coelom. The identity of A. septentrionalis was confirmed using cox1 mtDNA gene analysis, performed on adult stages from a tundra vole and on larvae from amphipods. Possible transmission routes of A. septentrionalis are discussed.	0
Boerhaave syndrome is the spontaneous rupture of the oesophagus, usually due to vomiting. The condition is rare but can be fatal. A 30-year-old male presented with vomiting and pain in his left flank and chest. Computed tomography scanning of the chest, abdomen and pelvic revealed a 4 mm left proximal ureteric stone and pneumo-mediastinum due to oesophageal rupture, consistent with Boerhaave syndrome. The patient underwent insertion of left ureteric stent, with staged left ureteroscopy and laser lithotripsy. The patient's oesophageal rupture was managed conservatively, and he made a full recovery. This is only the second report of renal colic causing Boerhaave syndrome.	0
The present authors report the first case of Beare-Stevenson syndrome in Taiwan. The patient shares several clinical characteristics of Beare-Stevenson syndrome such as cutis gyrata, cloverleaf skull, prominent eyes, cleft palate, ear defects and a protruding umbilical stump. Molecular genetic analysis of the FGFR2 gene in this patient's DNA revealed a missense A --> G mutation on nucleotide 1303 of the FGFR2 cDNA. This mutation leads to a Tyr --> Cys substitution at residue 375 located at the N-terminal end of the transmembrane domain of FGFR2. The present results are in accordance with other previously published reports and strengthen the importance of the FGFR2 gene in the pathogenesis of Beare-Stevenson syndrome.	0
There has been an increasing demand and interest in post-mortem imaging techniques, either as an adjunct or replacement for the conventional invasive autopsy. Post-mortem ultrasound (PMUS) is easily accessible and more affordable than other cross-sectional imaging modalities and allows visualisation of normal anatomical structures of the brain, thorax and abdomen in perinatal cases. The lack of aeration of post-mortem foetal lungs provides a good sonographic window for assessment of the heart and normal pulmonary lobulation, in contrast to live neonates.In a previous article within this journal, we published a practical approach to conducting a comprehensive PMUS examination. This covered the basic principles behind why post-mortem imaging is performed, helpful techniques for obtaining optimal PMUS images, and the expected normal post-mortem changes seen in perinatal deaths. In this article, we build upon this by focusing on commonly encountered pathologies on PMUS and compare these to autopsy and other post-mortem imaging modalities.	0
The objective of the current study is to explore the association of thyroid-stimulating hormone receptor (TSHR) rs1991517 polymorphism (c.2337 C > G, p.D727E) with congenital hypothyroidism (CH) through a case-control study followed by a meta-analysis. The case-control study was based on 45 CH subjects and 700 healthy controls. Meta-analysis comprised of seven published studies and our current findings (1044 CH cases and 1649 healthy controls). The allele contrast model showed that the presence of G- allele increased CH risk by 45% (OR: 1.45, 95% CI 1.20-1.76) and 41% (OR: 1.41, 95% CI 1.03-1.93) in fixed effect and random effect models, respectively. The GG- genotype is associated with 2.3-fold (95% CI 1.32-3.99) increased risk for CH in the fixed-effect model. I 2 (0.58) and Cochran's Q test (Q: 16.72, p = 0.02) revealed evidence of heterogeneity in the association. No publication bias was observed by Egger's test (p = 0.70). Sensitivity analysis revealed that even after excluding any study this polymorphism is associated with risk for CH. The rs1991517 mutation alters the binding affinity to cAMP (ΔG of 727D vs.727E: - 7.27 vs. - 7.34 kcal/mol). In conclusion, rs1991517 is a genetic risk factor for CH and exerts its impact by altering cAMP-mediated signal transduction.	0
Dyskeratosis congenita (DC) is a very rare inherited disorder. It is caused by dysfunction of telomere maintenance. It involves RNA telomerase components relevant to various mutations leading to a classic triad of physical findings consisting of nail dystrophy of the hands and feet, mucosal leukoplakia, and reticular pigmentation of the skin, most commonly on the head, neck, and trunk. Bone marrow failure along with pulmonary complications and malignancies are all common causes of premature death in patients with DC as well as other abnormalities. We report a new case of DC with impure nephrotic syndrome relevant to histopathologic signs of a diffuse mesangial sclerosis, leading to an early end-stage renal disease. Challenges remain to understand the diverse spectrum of DC especially in children. To the best of our knowledge this is the first case of DC associated to diffuse mesangial sclerosis.	0
OBJECTIVE:To determine whether amyloid imaging with the positron emission tomography (PET) agent Pittsburgh compound B (PiB) can detect vascular β-amyloid (Aβ) in the essentially pure form of cerebral amyloid angiopathy associated with the Dutch-type hereditary cerebral amyloid angiopathy (D-CAA) mutation. METHODS:PiB retention in a cortical composite of frontal, lateral, and retrosplenial regions (FLR) was measured by PiB-PET in 19 D-CAA mutation carriers (M+ ; 13 without neurologic symptoms, 6 with prior lobar intracerebral hemorrhage) and 17 mutation noncarriers (M- ). Progression of PiB retention was analyzed in a subset of 18 serially imaged individuals (10 asymptomatic M+ , 8 M- ). We also analyzed associations between PiB retention and cerebrospinal fluid (CSF) Aβ concentrations in 17 M+ and 11 M- participants who underwent lumbar puncture and compared the findings to PiB-PET and CSF Aβ in 37 autosomal dominant Alzheimer disease (ADAD) mutation carriers. RESULTS:D-CAA M+ showed greater age-dependent FLR PiB retention (p < 0.001) than M- , and serially imaged asymptomatic M+ demonstrated greater longitudinal increases (p = 0.004). Among M+ , greater FLR PiB retention associated with reduced CSF concentrations of Aβ40 (r = -0.55, p = 0.021) but not Aβ42 (r = 0.01, p = 0.991). Despite comparably low CSF Aβ40 and Aβ42, PiB retention was substantially less in D-CAA than ADAD (p < 0.001). INTERPRETATION:Increased PiB retention in D-CAA and correlation with reduced CSF Aβ40 suggest this compound labels vascular amyloid, although to a lesser degree than amyloid deposits in ADAD. Progression in PiB signal over time suggests amyloid PET as a potential biomarker in trials of candidate agents for this untreatable cause of hemorrhagic stroke. ANN NEUROL 2019;86:616-625.	0
Charcot-Marie-Tooth disease is one of the most common inherited neurological disorders affecting the peripheral nervous system. The common clinical manifestations of the disease are distal muscle weakness and atrophy, often associated with a characteristic steppage gait and foot deformities. Transient acute and recurrent or chronic central nervous system manifestations, predominantly, dysarthria, dysphagia, motor weakness, and ataxia, have been recognized as a feature of the X-linked type 1 of CMT (CMTX1). The CNS symptoms occur typically in young age and often precede the clinical manifestation of the polyneuropathy. Several predisposing factors such as exercise, fever, and returning from areas of high altitude have been described as triggers of the CNS symptoms; however, in many cases, a substantial cause remains undetermined. In this report, we describe a patient with three attacks of transient CNS deficits at the ages of 11, 21, and 38 years, respectively, which were also accompanied by transient white matter abnormalities on MRI. Two of the attacks occurred after prolonged exposure to sunlight. In our knowledge, this is the first documented case with such long latency periods between CNS attacks as well as the only report describing intense sun exposure as a possible provoking factor.	0
An eight-week old Doberman Pinscher was diagnosed with Ehlers Danlos syndrome based on the dog's hyper-mobile carpal, tarsal and stifle joints and abnormal skin. The skin was loose and hyper-elastic with several wounds and large atrophic scars. The dog was euthanized after a severe degloving injury from minimal trauma. A whole-genome sequence, generated with DNA from the dog's blood, contained a rare, homozygous C-to-T transition at position 2408978 on chromosome 11. This transition is predicted to alter the ADAMTS2 transcript (ADAMTS2:c.769C>T) and encode a nonsense mutation (p.Arg257Ter). Biallelic ADAMTS2 mutations have caused a type of Ehlers Danlos syndrome known as dermatosparaxis in other species.	0
Lenalidomide is an immunomodulatory drug approved in the United States for use with rituximab in patients with relapsed/refractory follicular lymphoma. We reviewed data from trials addressing the safety and efficacy of lenalidomide alone and in combination with rituximab as a first-line therapy and as a treatment of patients with relapsed/refractory follicular lymphoma. Lenalidomide-rituximab has been demonstrated to be an effective chemotherapy-free therapy that improves upon single-agent rituximab and may become an alternative to chemoimmunotherapy.	0
Purpose:To describe the outcome of microscope integrated optical coherence tomography (MiOCT) guided removal of lenticulo-corneal adhesion and intralenticular lens aspiration (ILLA) in cases with anterior dislocation of the crystalline lens and corneal edema. Methods:MiOCT-guided ILLA was performed in three eyes of two cases of homocystinuria with spontaneous anterior dislocation of lens and corneal edema. Lenticulo-corneal adhesion was noted intraoperatively, which was not apparent pre-operatively. The lenticulo-corneal adhesion could be successfully peeled using intravitreal forceps and viscodissection with visco-dispersive viscoelastic under the guidance of MiOCT. Results:In all cases, the lenticulo-corneal adhesion could be successfully removed without any complication such as Descemet tear or worsening in corneal edema. Improvement in visual acuity was noted in all cases with resolution in corneal edema by 1 week. Conclusion:MiOCT-guided ILLA can be extremely useful in cases of lenticulo-corneal adhesion especially in cases with corneal edema.	0
Nemaline myopathy (NEM) is a congenital myopathy that typically presents with proximal muscle weakness and hypotonia. To date, 13 genes have been associated with NEM. The Kelch repeat and BTB domain-containing protein 13 (KBTBD13) gene (KBTBD13)-related NEM is a rarely reported condition, and not a single case has been reported in Asia. Here, we report the case of a mother and daughter in China with NEM caused by a mutation (c.1222C>T) in KBTBD13. Their shared clinical phenotype is symmetrical muscle weakness in the arms and legs with childhood onset. Muscle magnetic resonance imaging showed the unique replacement mode of muscle with fibro-fatty tissue. Histopathological examination revealed the presence of fibers containing rod-shaped structures in the cytoplasm or under the sarcolemma. DNA sequencing analysis detected a heterozygous mutation (c.1222C>T) in KBTBD13 in this family. A founder effect for the variant may exist in the Low Countries of Belgium and the Netherlands, and the mutation may be a hotspot mutation in Europe, as it has not been reported in Asia. Our case study expands the spectrum of KBTBD13-related NEM.	0
According to Rome criteria, chronic constipation (CC) includes functional constipation (FC) and irritable bowel syndrome with constipation (IBS-C). Some patients do not meet these criteria (No Rome Constipation, NRC). The aim of the study was is to evaluate the various clinical presentation and management of FC, IBS-C and NRC in Italy.During a 2-month period, 52 Italian gastroenterologists recorded clinical data of FC, IBS-C and NRC patients, using Bristol scale, PAC-SYM and PAC-QoL questionnaires. In addition, gastroenterologists were also asked to record whether the patients were clinically assessed for CC for the first time or were in follow up. Diagnostic tests and prescribed therapies were also recorded.Eight hundred seventy-eight consecutive CC patients (706 F) were enrolled (FC 62.5%, IBS-C 31.3%, NRC 6.2%). PAC-SYM and PAC-QoL scores were higher in IBS-C than in FC and NRC. 49.5% were at their first gastroenterological evaluation for CC. In 48.5% CC duration was longer than 10 years. A specialist consultation was requested in 31.6%, more frequently in IBS-C than in NRC. Digital rectal examination was performed in only 56.4%. Diagnostic tests were prescribed to 80.0%. Faecal calprotectin, thyroid tests, celiac serology, breath tests were more frequently suggested in IBS-C and anorectal manometry in FC. More than 90% had at least one treatment suggested on chronic constipation, most frequently dietary changes, macrogol and fibers. Antispasmodics and psychotherapy were more frequently prescribed in IBS-C, prucalopride and pelvic floor rehabilitation in FC.Patients with IBS-C reported more severe symptoms and worse quality of life than FC and NRC. Digital rectal examination was often not performed but at least one diagnostic test was prescribed to most patients. Colonoscopy and blood tests were the "first line" diagnostic tools. Macrogol was the most prescribed laxative, and prucalopride and pelvic floor rehabilitation represented a "second line" approach. Diagnostic tests and prescribed therapies increased by increasing CC severity.	0
Despite remarkable progress in understanding and treating gastrointestinal stromal tumors (GISTs) during the past two decades, the pathological characteristics of GISTs have not been made clear yet. Furthermore, concrete diagnostic criteria of malignant GISTs are still uncertain. We collected pathology reports of 1,227 GISTs from 38 hospitals in Korea between 2003 and 2004 and evaluated the efficacy of the NIH and AFIP classification schemes as well as the prognostic factors among pathologic findings. The incidence of GISTs in Korea is about 1.6 to 2.2 patients per 100,000. Extra-gastrointestinal GISTs (10.1%) are more common in Korea than in Western countries. In univariate analysis, gender, age, tumor location, size, mitosis, tumor necrosis, vascular and mucosal invasions, histologic type, CD34 and s-100 protein expression, and classifications by the NIH and AFIP criteria were found to be significantly correlated with patient's survival. However, the primary tumor location, stage and classification of the AFIP criteria were prognostically significant in predicting patient's survival in multivariate analysis. The GIST classification based on original tumor location, size, and mitosis is more efficient than the NIH criteria in predicting patient's survival, but the mechanism still needs to be clarified through future studies.	1
Secretory carcinoma (SC) of the salivary gland is a relatively newly described disease, separate from acinic cell carcinoma (ACC), which frequently displays ETV6-NTRK3 gene fusion. However, the differences between SC and ACC remain unclear. Here, histological reevaluation of 12 formerly diagnosed ACC cases was performed, which yielded a new diagnosis of SC in four cases due to a lack of obvious acinar-like cells. Immunohistochemically, phosphorylated signal transducer and activator of transcription 5 (p-STAT5) was expressed in SC but not in ACC, whereas discovered on GIST-1 (DOG1) was expressed in ACC but not in SC. Molecular analysis was possible in three SC cases, of which two showed the ETV6-NTRK3 fusion transcript on reverse-transcription polymerase chain reaction, as well as breaks in the ETV6 gene on fluorescence in situ hybridization. However, the remaining SC cases did not show this fusion transcript. Recently, several reports have suggested that SC might not be adequately diagnosed if the focus is placed solely on the ETV6-NTRK3 fusion gene due to genetic diversity. In this regard, immunohistochemistry of p-STAT5 and DOG1 is expected to be a useful alternative diagnostic tool to discriminate SC from ACC.	0
Risankizumab, an interleukin (IL)-23 antagonist, is a highly effective treatment for moderate to severe psoriasis. Crusted scabies (CS) is a rare and severe form of scabies, occurring mainly in immunosuppressed patients and/or neurologically or mentally ill patients. A young girl with Down syndrome was diagnosed with a hyperkeratotic form of psoriasis. As treatment with topical dermocorticosteroids, UVB-phototherapy and acitretin for 6 weeks did not improve the lesions, two injections of risankizumab were administered. Following these injections, the lesions became rapidly even more severely crusted, and new lesions appeared on the extremities and the face of the patient. There was histological evidence of a high charge of scabies, leading to a diagnosis of CS. The patient was hospitalized and successfully treated by local permethrine and systemic ivermectine. This case suggests that even though anti-IL23 antagonists display an excellent overall safety profile, a particular caution for infections should still be respected in patients with underlying risk factors.	0
BACKGROUND:Urinary dysfunction is one of the main features of human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, a comprehensive assessment of the severity is difficult because a standardized assessment measure is unavailable. Therefore, this study aimed to develop a novel symptom score for the assessment of urinary dysfunction in HAM/TSP. We interviewed 449 patients with HAM/TSP using four internationally validated questionnaires for assessment of urinary symptoms (27 question items in total): the International Prostate Symptom Score; the International Consultation on Incontinence Questionnaire-Short Form; the Overactive Bladder Symptom Score; and the Nocturia Quality-of-Life questionnaire. We developed a symptom score based on the data of 322 patients who did not use urinary catheters by selecting question items from questionnaires focused on descriptive statistics, correlation analysis, and exploratory factor analysis. The score distribution, reliability, and validity of the developed score were evaluated. RESULTS:First, 16 questions related to quality of life, situations, or subjective assessment were omitted from the 27 questions. Exploratory factor analysis revealed that the remaining 11 questions pertained to three factors: frequent urination, urinary incontinence, and voiding symptoms. Three questions, which had similar questions with larger factor loading, were deleted. Finally, we selected eight question items for inclusion in the novel score. The score distribution exhibited no ceiling or floor effect. The Cronbach's alpha (0.737) demonstrated reliable internal consistency. The new score comprised two subscales with acceptable factorial validity (inter-factor correlation coefficient, 0.322): storage symptoms (frequent urination plus urinary incontinence) and voiding symptoms. The correlation between each item and the subscales suggested acceptable construct validity. CONCLUSIONS:We developed a novel score, the HAM/TSP-Bladder Dysfunction Symptom Score, and demonstrated its reliability and validity. The applicability of this score to patients using catheters should be examined in future research.	0
Our objective was to investigate the potential of three microRNAs, miR-181a-5p, miR-30c-5p, and miR-206 as prognostic biomarkers for long-term follow up of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients. We analyzed the expression of three microRNAs in serum of 18 patients (DMD 13, BMD 5) and 13 controls using droplet digital PCR. Over 4 years a minimum of two and a maximum of three measurements were performed at different time points in the same patient. Correlations between microRNA serum levels, age, and functional outcome measures were analyzed. We show the individual evolution of the levels of the three microRNAs in 12 patients and also the effect of corticosteroid treatment on microRNAs expression. We measure the expression of three microRNAs in the muscle of six DMD patients and also the expression of target genes for miR-30c. We found that levels of miR-30c and miR-206 remained significantly elevated in DMD patients relative to controls over the entire study length. The introduction of the corticosteroid treatment did not significantly influence the levels of these microRNAs. We report a trend for microRNA levels to decrease with age. Moreover, miR-206 expression levels are capable to distinguish DMD from BMD patients according to ROC analysis. We found miR-30c expression decreased in the muscle of DMD patients and marked upregulation of the target genes for this microRNA. MiR-30c and miR-206 represent sensitive biomarkers for DMD, while miR-206 may have an additional value to distinguish the DMD and BMD phenotype. This may be particularly relevant to assess the effectiveness of treatments aimed at converting the DMD to the less-severe BMD like phenotype.	0
De novo balanced chromosomal aberrations (BCAs), such as reciprocal translocations and inversions, are genomic aberrations that, in approximately 25% of cases, affect the human phenotype. Delineation of the exact structure of BCAs may provide a precise diagnosis and/or point to new disease loci. We report on six patients with de novo balanced chromosomal translocations (BCTs) and one patient with a de novo inversion, in whom we mapped breakpoints to a resolution of 1 bp, using shallow whole-genome mate pair sequencing. In all seven cases, a disruption of at least one gene was found. In two patients, the phenotypic impact of the disrupted genes is well known (NFIA, ATP7A). In five patients, the aberration damaged genes: PARD3, EPHA6, KLF13, STK24, UBR3, MLLT10 and TLE3, whose influence on the human phenotype is poorly understood. In particular, our results suggest novel candidate genes for retinal degeneration with anophthalmia (EPHA6), developmental delay with speech impairment (KLF13), and developmental delay with brain dysembryoplastic neuroepithelial tumor (UBR3). In conclusion, identification of the exact structure of symptomatic BCTs using next generation sequencing is a viable method for both diagnosis and finding novel disease candidate genes in humans.	0
Inherited retinal disorder (IRD) is a leading cause of blindness, and CRX is one of a number of genes reported to harbour autosomal dominant (AD) and recessive (AR) causative variants. Eighteen patients from 13 families with CRX-associated retinal disorder (CRX-RD) were identified from 730 Japanese families with IRD. Ophthalmological examinations and phenotype subgroup classification were performed. The median age of onset/latest examination was 45.0/62.5 years (range, 15-77/25-94). The median visual acuity in the right/left eye was 0.52/0.40 (range, -0.08-2.00/-0.18-1.70) logarithm of the minimum angle of resolution (LogMAR) units. There was one family with macular dystrophy, nine with cone-rod dystrophy (CORD), and three with retinitis pigmentosa. In silico analysis of CRX variants was conducted for genotype subgroup classification based on inheritance and the presence of truncating variants. Eight pathogenic CRX variants were identified, including three novel heterozygous variants (p.R43H, p.P145Lfs*42, and p.P197Afs*22). A trend of a genotype-phenotype association was revealed between the phenotype and genotype subgroups. A considerably high proportion of CRX-RD in ADCORD was determined in the Japanese cohort (39.1%), often showing the mild phenotype (CORD) with late-onset disease (sixth decade). Frequently found heterozygous missense variants located within the homeodomain underlie this mild phenotype. This large cohort study delineates the disease spectrum of CRX-RD in the Japanese population.	0
OBJECTIVES: The aim of this study was to determine the prevalence of primary Sjogren's syndrome (pSS) in a general Turkish population according to the latest proposed American-European Consensus Group (AECG) criteria and European-1 (EU-1) criteria. METHODS: The study was conducted in two districts of Izmir and involved 2835 subjects 20 years of age and older. In the first stage, face-to-face interviews were performed at the registered households. In the second stage, subjects reporting symptoms of both dry eye and dry mouth were invited to the hospital for a full examination, which included Schirmer-1, sialometry and serologic tests. In the third stage, a minor salivary gland biopsy was performed as required. RESULTS: A total of 2887 subjects were contacted and a complete interview was obtained for 2835 (1551 female, 1284 male) subjects. A total of 159 subjects (126 female, 33 male) confirmed oral and ocular dryness, and 86 of these patients (54.1%) underwent a detailed clinical examination in the hospital. pSS was diagnosed in 10 patients (nine females) according to the EU-1 criteria, and in six patients (six females) according to the AECG criteria. We found a minimum crude prevalence of 0.21% [95% confidence interval (CI): 0.03-0.29] in the sample population and an age-sex adjusted prevalence of 0.16% (95% CI: 0.06-0.35), according to AECG criteria. According to EU-1 criteria, these prevalence rates were found to be 0.35% (95% CI: 0.10-0.45) and 0.28% (95% CI: 0.13-0.51) respectively. CONCLUSION: The pSS prevalence rates found in the Turkish population in this study were lower than the estimated prevalence rate in a general population.	1
Progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is an early childhood onset, severe autosomal recessive encephalopathy characterized by extreme cerebellar atrophy due to almost total granule neuron loss. By combining homozygosity mapping in Finnish families with Sanger sequencing of positional candidate genes and with exome sequencing a homozygous missense substitution of leucine for serine at codon 31 in ZNHIT3 was identified as the primary cause of PEHO syndrome. ZNHIT3 encodes a nuclear zinc finger protein previously implicated in transcriptional regulation and in small nucleolar ribonucleoprotein particle assembly and thus possibly to pre-ribosomal RNA processing. The identified mutation affects a highly conserved amino acid residue in the zinc finger domain of ZNHIT3. Both knockdown and genome editing of znhit3 in zebrafish embryos recapitulate the patients' cerebellar defects, microcephaly and oedema. These phenotypes are rescued by wild-type, but not mutant human ZNHIT3 mRNA, suggesting that the patient missense substitution causes disease through a loss-of-function mechanism. Transfection of cell lines with ZNHIT3 expression vectors showed that the PEHO syndrome mutant protein is unstable. Immunohistochemical analysis of mouse cerebellar tissue demonstrated ZNHIT3 to be expressed in proliferating granule cell precursors, in proliferating and post-mitotic granule cells, and in Purkinje cells. Knockdown of Znhit3 in cultured mouse granule neurons and ex vivo cerebellar slices indicate that ZNHIT3 is indispensable for granule neuron survival and migration, consistent with the zebrafish findings and patient neuropathology. These results suggest that loss-of-function of a nuclear regulator protein underlies PEHO syndrome and imply that establishment of its spatiotemporal interaction targets will be the basis for developing therapeutic approaches and for improved understanding of cerebellar development.	0
Idiopathic pulmonary hemosiderosis is characterized by the triad of hemoptysis, iron deficiency anemia and pulmonary infiltrates. Though idiopathic pulmonary hemosiderosis has classically been described as a childhood disease, survival into adulthood is possible. Treatment options for advanced and/or refractory disease is limited, and in our unique case of idiopathic pulmonary hemosiderosis with precapillary pulmonary hypertension, lung transplantation has had a favorable short-term outcome. We also demonstrate that disease recurrence of idiopathic pulmonary hemosiderosis following lung transplantation is possible.	0
Pathogenic variants in the SCN2A gene are associated with a variety of neurodevelopmental phenotypes, defined in recent years through multicenter collaboration. Phenotypes include benign (self-limited) neonatal and infantile epilepsy and more severe developmental and epileptic encephalopathies also presenting in early infancy. There is increasing evidence that an important phenotype linked to the gene is autism and intellectual disability without epilepsy or with rare seizures in later childhood. Other associations of SCN2A include the movement disorders chorea and episodic ataxia. It is likely that as genetic testing enters mainstream practice that new phenotypic associations will be identified. Some missense, gain of function variants tend to present in early infancy with epilepsy, whereas other missense or truncating, loss of function variants present with later-onset epilepsies or intellectual disability only. Knowledge of both mutation type and functional consequences can guide precision therapy. Sodium channel blockers may be effective antiepileptic medications in gain of function, neonatal and infantile presentations.	0
OBJECTIVE:Hemi-laryngopharyngeal spasm (HeLPS) has recently been described in the neurosurgical literature as a cause of intermittent laryngopharyngeal spasm and cough due to vascular compression of the vagus nerve at the cerebellopontine angle. We present the diagnostic criteria for this syndrome. METHODS:A retrospective chart review of six patients with HeLPS and three patients misdiagnosed with this condition are presented. All patients were diagnosed and treated at a tertiary care academic centre from July 2013 to July 2017. RESULTS:Patients with HeLPS had five defining characteristics: 1) All patients had symptoms of episodic laryngopharyngeal spasm and coughing. Patients were asymptomatic between episodes and were refractory to speech therapy and reflux management. 2) Laryngoscopy showed hyperactive twitching of the ipsilateral vocal fold in two of the six patients. No other inter-episodic abnormalities were seen. 3) Botulinum toxin A injections into the thyroarytenoid muscle on the affected ipsilateral side reduced laryngopharyngeal spasms. Botulinum toxin injection in the contralateral thyroarytenoid muscle did not improve laryngopharyngeal spasm. 4) Magnetic resonance imaging revealed ipsilateral neurovascular compression of the vagus nerve rootlets by the posterior inferior cerebellar artery. 5) Microvascular decompression (MVD) surgery of the ipsilateral vagus nerve resolved all symptoms (follow-up 2-4 years). CONCLUSION:The diagnostic criteria for hemi-laryngopharyngeal spasm (HeLPS) are proposed. Otolaryngology recognition of this new clinical entity may lead to a surgical cure and avoid the unnecessary therapies associated with misdiagnosis. LEVEL OF EVIDENCE:4.	0
The DNA damage response network guards the stability of the genome from a plethora of exogenous and endogenous insults. An essential feature of the DNA damage response network is its capacity to tolerate DNA damage and structural impediments during DNA synthesis. This capacity, referred to as DNA damage tolerance (DDT), contributes to replication fork progression and stability in the presence of blocking structures or DNA lesions. Defective DDT can lead to a prolonged fork arrest and eventually cumulate in a fork collapse that involves the formation of DNA double strand breaks. Four principal modes of DDT have been distinguished: translesion synthesis, fork reversal, template switching and repriming. All DDT modes warrant continuation of replication through bypassing the fork stalling impediment or repriming downstream of the impediment in combination with filling of the single-stranded DNA gaps. In this way, DDT prevents secondary DNA damage and critically contributes to genome stability and cellular fitness. DDT plays a key role in mutagenesis, stem cell maintenance, ageing and the prevention of cancer. This review provides an overview of the role of DDT in these aspects.	0
FGF23 is a hormone produced by osteocytes in response to an elevation in the concentration of extracellular phosphate. Excess production of FGF23 by bone cells, or rarely by tumors, is the hormonal basis for several musculoskeletal syndromes characterized by hypophosphatemia due to renal phosphate wasting. FGF23-dependent chronic hypophosphatemia causes rickets and osteomalacia, as well as other skeletal complications. Genetic disorders of FGF23-mediated hypophosphatemia include X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), fibrous dysplasia of bone, McCune-Albright syndrome, and epidermal nevus syndrome (ENS), also known as cutaneous skeletal hypophosphatemia syndrome (CSHS). The principle acquired form of FGF23-mediated hypophosphatemia is tumor-induced osteomalacia (TIO). This review summarizes current knowledge about the pathophysiology and clinical presentation of the most common FGF23-mediated conditions, with a focus on new treatment modalities. For many decades, calcitriol and phosphate supplements were the mainstay of therapy. Recently, burosumab, a monoclonal blocking antibody to FGF23, has been approved for treatment of XLH in children and adults, and an active comparator trial in children has shown good efficacy and safety for this drug. The remainder of FGF23-mediated hypophosphatemic disorders continue to be treated with phosphate and calcitriol, although ongoing trials with burosumab for treatment of tumor-induced osteomalacia show early promise. Burosumab may be an effective treatment for the remainder of FGF23-mediated disorders, but clinical trials to support that possibility are at present not available.	0
Mal de debarquement syndrome (MdDS) is a disorder of persistent vertigo characterized by a feeling of oscillation such as rocking, bobbing, or swaying. It is triggered by passive motion, typically by exposure to water, air, or land transportation. This syndrome affects middle-aged individuals who are predominantly women. MdDS presents as a balance disorder that carries significant risk of morbidity due to both the direct effects of balance impairment and associated symptoms of fatigue, cognitive slowing, and visual motion intolerance. The Barany Society will be publishing criteria for diagnosing persistent MdDS. In addition, more insight has been gained into the pathophysiology of MdDS, with current hypotheses pointing to a cerebral and cerebellar basis. Treatments have expanded beyond medication trials, and now include the use of noninvasive brain stimulation and readaptation of the vestibulo-ocular reflex.	0
Background and study aims:Collagenous gastritis is a rare entity divided in two subgroups (paediatric and adult). In the paediatric population, it often causes anaemia and abdominal pain. Therapy remains the most challenging part as no randomized clinical trial exists and long-term outcome is not well established. Patients and methods:We reviewed the 43 paediatric patients with diagnosis of collagenous gastritis reported in Pubmed from 1989 to mid 2019 to analyse clinical and histological response depending on the treatment choice. Results:In 43 patients (M/F ratio 1:2), a clinical response was observed in 85.7% of patients and a histological response in 20.8% of patients. PPI treatment associated with oral iron supplement was the most frequent choice with clinical improvement in 78.5% of patients. Other treatments such as gluten-free diet or corticoids showed relatively good rates of clinical improvement. Histological remission seems difficult to achieve and recurrence of symptoms after treatment interruption was often reported. Conclusions:Collagenous gastritis in children is mainly characterized by symptoms of anaemia, abdominal pain or diarrhea. Gastroscopy with fundic biopsies helps to confirm diagnosis and treatment with PPI's (associated with oral iron supplement in case of anaemia) seems to be the most efficient choice to achieve clinical and sometimes histological remission. Long-term outcome of these young patients is unknown. A better understanding of the pathogenesis could lead to new medications focusing on this histological remission.	0
Trim32 belongs to the tripartite motif (TRIM) protein family, which is characterized by a common domain structure composed of a RING-finger, a B-box, and a coiled-coil motif. In addition to these motifs, Trim32 possesses six C-terminal NHL-domains. A point mutation in one NHL domain (D487N) has been linked to two forms of muscular dystrophy called limb girdle muscular dystrophy type 2H and sarcotubular myopathy. In the present study we demonstrate that Trim32 is an E3 ubiquitin ligase that acts in conjunction with ubiquitin-conjugating enzymes UbcH5a, UbcH5c, and UbcH6. Western blot analysis showed that Trim32 is expressed primarily in skeletal muscle, and revealed its differential expression from one muscle to another. The level of Trim32 expression was elevated significantly in muscle undergoing remodeling due to changes in weight bearing. Furthermore, expression of Trim32 was induced in myogenic differentiation. Thus, variability in Trim32 expression in different skeletal muscles could be due to induction of Trim32 expression upon changes in physiological conditions. We show that Trim32 associates with skeletal muscle thick filaments, interacting directly with the head and neck region of myosin. Our data indicate that myosin is not a substrate of Trim32; however, Trim32 was found to ubiquitinate actin in vitro and to cause a decrease in the level of endogenous actin when transfected into HEK293 cells. In conclusion, our results demonstrate that Trim32 is a ubiquitin ligase that is expressed in skeletal muscle, can be induced upon muscle unloading and reloading, associates with myofibrils and is able to ubiquitinate actin, suggesting its likely participation in myofibrillar protein turnover, especially during muscle adaptation.	0
Properdin enhances complement-mediated opsonization of targeted cells and particles for immune clearance. Properdin occurs as dimers, trimers and tetramers in human plasma, which recognize C3b-deposited surfaces, promote formation, and prolong the lifetime of C3bBb-enzyme complexes that convert C3 into C3b, thereby enhancing the complement-amplification loop. Here, we report crystal structures of monomerized properdin, which was produced by co-expression of separate N- and C-terminal constructs that yielded monomer-sized properdin complexes that stabilized C3bBb. Consistent with previous low-resolution X-ray and EM data, the crystal structures revealed ring-shaped arrangements that are formed by interactions between thrombospondin type-I repeat (TSR) domains 4 and 6 of one protomer interacting with the N-terminal domain (which adopts a short transforming-growth factor B binding protein-like fold) and domain TSR1 of a second protomer, respectively. Next, a structure of monomerized properdin in complex with the C-terminal domain of C3b showed that properdin-domain TSR5 binds along the C-terminal α-helix of C3b, while two loops, one from domain TSR5 and one from TSR6, extend and fold around the C3b C-terminus like stirrups. This suggests a mechanistic model in which these TSR5 and TSR6 "stirrups" bridge interactions between C3b and factor B or its fragment Bb, and thereby enhance formation of C3bB pro-convertases and stabilize C3bBb convertases. In addition, properdin TSR6 would sterically block binding of the protease factor I to C3b, thus limiting C3b proteolytic degradation. The presence of a valine instead of a third tryptophan in the canonical Trp-ladder of TSR domains in TSR4 allows a remarkable ca. 60°-domain bending motion of TSR4. Together with variable positioning of TSR2 and, putatively, TSR3, this explains the conformational flexibility required for properdin to form dimers, trimers, and tetramers. In conclusion, the results indicate that binding avidity of oligomeric properdin is needed to distinguish surface-deposited C3b molecules from soluble C3b or C3 and suggest that properdin-mediated interactions bridging C3b-B and C3b-Bb enhance affinity, thus promoting convertase formation and stabilization. These mechanisms explain the enhancement of complement-mediated opsonization of targeted cells and particle for immune clearance.	0
Onychotrichodysplasia, a rare autosomal recessive disorder, presents with hypoplastic fingernails, trichorrhexis, chronic neutropenia, and psychomotor retardation. Here, we describe a rare presentation of a child with onycotrichodysplasia associated with intellectual disability, but without neutropenia. He had sparse, short, dry, curly hair, dysplastic nails and intellectual disability. In contrast to cases described earlier, our patient had normal neutrophil count.	0
Reversible cerebral vasoconstriction syndrome (RCVS) is an under-diagnosed condition that results from reversible segmental and multifocal vasoconstriction of cerebral arteries. It can present with a variety of symptoms including sudden "thunder clap" headaches, neurologic deficits, photophobia, phonophobia, nausea, vomiting, and can mimic life-threatening conditions such as a ruptured intracranial aneurysm, primary angiitis of the central nervous system, and cervical artery dissection. The pathology of this condition is still not fully understood and the etiologies vary, making treatment difficult. Our objective is to draw attention to an under-diagnosed condition with common presenting symptoms. We present a 60-year-old male with sudden onset of severe headache, left-sided numbness and weakness, blurred vision, ataxia, nausea, and dyspnea. CT and MRI brain showed no evidence of infarct or hemorrhage. CT angiography (CTA) of the head and neck showed a narrow caliber basilar artery. With the patient's clinical presentation and imaging findings, RCVS was suspected and the patient was started on a calcium channel blocker and glucocorticoids. A repeat CTA of the head and neck was performed after initiation of therapy and showed dilation of the basilar artery. Treatment with verapamil and prednisone was continued and the patient's symptoms gradually improved. He was discharged to skilled nursing for continued physical therapy. RCVS is a little-understood, under-diagnosed condition that needs to be considered in patients presenting with headaches and neurologic deficits. Additionally, more research needs to be done to truly understand the etiology of this condition.	0
Background: REEP1 is a common cause of autosomal dominant hereditary spastic paraplegia (HSP) but is rare in China. The pathological mechanism of REEP1 is not fully understood. Methods: We screened for REEP1 mutations in 31 unrelated probands from Chinese HSP families using next-generation sequencing targeting pathogenic genes for HSP and other related diseases. All variants were validated by Sanger sequencing. The proband family members were also screened for variants for the segregation analysis. All previously reported REEP1 mutations and cases were reviewed to clarify the genetic and clinical features of REEP1-related HSP. Results: A pathogenic mutation, REEP1c. 125G>A (p.Trp42*), was detected in a pure HSP family from North China out of 31 HSP families (1/31). This locus, which is located in the second hydrophobic domain of REEP1, is detected in both Caucasian patients with complicated HSP phenotypes and Chinese pure HSP families. Conclusion: REEP1-related HSP can be found in the Chinese population. The 42nd residue is a novel transethnic mutation hotspot. Mutations in this spot can lead to both complicated and pure form of HSP. Identification of transethnic hotspot will contribute to clarify the underlying pathological mechanisms.	0
PURPOSE OF REVIEW:In this article, we review the current state of artificial intelligence applications in retinopathy of prematurity (ROP) and provide insight on challenges as well as strategies for bringing these algorithms to the bedside. RECENT FINDINGS:In the past few years, there has been a dramatic shift from machine learning approaches based on feature extraction to 'deep' convolutional neural networks for artificial intelligence applications. Several artificial intelligence for ROP approaches have demonstrated adequate proof-of-concept performance in research studies. The next steps are to determine whether these algorithms are robust to variable clinical and technical parameters in practice. Integration of artificial intelligence into ROP screening and treatment is limited by generalizability of the algorithms to maintain performance on unseen data and integration of artificial intelligence technology into new or existing clinical workflows. SUMMARY:Real-world implementation of artificial intelligence for ROP diagnosis will require massive efforts targeted at developing standards for data acquisition, true external validation, and demonstration of feasibility. We must now focus on ethical, technical, clinical, regulatory, and financial considerations to bring this technology to the infant bedside to realize the promise offered by this technology to reduce preventable blindness from ROP.	0
GM1-gangliosidosis is a rare autosomal recessive lysosomal storage disease caused by deficiency of β-galactosidase (GLB1). Newborn screening (NBS) may be warranted in the near future given the initiation of a number of gene therapy clinical trials. Here we report a tandem mass spectrometry (MS/MS) enzymatic assay of GLB1 using dried blood spots (DBS), and the demonstration that GLB1 activities in newborn DBS from seven GM1-gangliosidosis patients are well below those measured in random newborn DBS. MS/MS analysis of two glycan biomarkers, dp5 and A2G2, shows high elevation in newborn DBS from GM1-gangliosidosis compared to the levels in the non-affected reference range. This article is protected by copyright. All rights reserved.	0
Charcot-Marie-Tooth disease type 4H (CMT4H) is a rare variant of autosomal recessive hereditary neuropathy. It is caused by FGD4 mutations and characterized by early infantile onset, slowly progressive distal muscle weakness, scoliosis, and myelin outfoldings visible in nerve biopsy samples. Here, we report a 65-year-old male born to consanguineous parents, who carries a novel homozygous FGD4 c.724C>T nonsense mutation. He developed lower limb weakness in his teens, which progressed slowly and was accompanied by diplopia, bilateral hearing loss, and erectile dysfunction from his twenties. At the age of 65, he was wheelchair-bound and had mild scoliosis, bilateral ophthalmoplegia, facial muscle weakness, inner ear hearing loss, distal-dominant weakness, and sensory disturbance, but no cognitive deterioration. Magnetic resonance imaging revealed enlarged bilateral trigeminal and facial nerves. Accordingly, we believe that this mutation causes slowly progressive sensorimotor neuropathy with apparent cranial nerve involvement, thereby further expanding the clinical spectrum of CMT4H.	0
PURPOSE:Leber's hereditary optic neuropathy (LHON) is a genetic disease of the mitochondrial genome that mainly affects the retinal ganglion cells (RGC) of the inner retina resulting in central vision loss. New understandings in mitochondrial genetics are helping to elucidate the nuances of conversion and allow for new therapeutic options. RECENT FINDINGS:Appreciation of the mitochondrial fission-fusion balance has allowed for increased understanding of the cascade of events that leads to clinical conversion in LOHN. Mathematical and computational models have helped to interpret the role of ROS in conversion, both as oxidative agents and as signaling molecules for cell death. The conversion from the LHON carrier to the affected patient has been clinically characterized, but the pathophysiology is just beginning to be understood. External stressors alter the mitochondrial dynamics of RGCs, leading to ROS buildup, energy shortages, decreased biogenesis and increased mitophagy, and ultimately axon degeneration and ganglion cell death. New therapeutic alternatives targeting these newly understood pathophysiological changes in the mitochondria and directly addressing the genetic mutations involved in LHON are being developed.	0
Well-differentiated thyroid cancer accounts for 95% of thyroid malignancies. In contrast to medullary thyroid carcinoma, in which about 25% are familial, only 5% of follicular cell-derived thyroid carcinomas are a component of a familial cancer syndrome. The familial follicular cell-derived tumors or nonmedullary thyroid carcinoma encompass a heterogeneous group of diseases, and are classified into 2 distinct groups: syndromic-associated tumors, occurring in syndromes in which nonmedullary thyroid carcinomas are the predominant tumor encountered, and nonsyndromic tumors, those occurring in tumor syndromes in which thyroid involvement is a minor component. The first group, syndromic-associated tumors, includes phosphase and tensin (PTEN)-hamartoma tumor syndrome/Cowden syndrome, familial adenomatous polyposis/Gardner syndrome, Carney complex type 1, Werner syndrome, and Pendred syndrome. Other syndromes, as McCune Albright syndrome, Peutz-Jeghers syndrome, and Ataxia-teleangiectasia syndrome may be associated with the development of follicular cell-derived tumors, but the link is less established than the above syndromes. The syndromic-associated tumors are the focus of this review. The second group of familial follicular cell-derived tumors syndromes or nonsyndromic tumors, in which nonmedullary thyroid carcinomas are the major findings, include pure familial papillary thyroid carcinoma, with or without oxyphilia, familial papillary thyroid carcinoma with papillary renal cell carcinoma, and familial papillary thyroid carcinoma with multinodular goiter. This review will discuss the clinical and pathological findings of the patients with familial syndrome-associated tumors: PTEN-hamartoma tumor syndrome/Cowden syndrome, familial adenomatous polyposis syndrome, Carney complex type 1, Werner syndrome, and Pendred syndrome.	0
Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes occurring within 6 months from birth. NDM can be permanent or transient (TNDM). We report the case of a preterm infant with TNDM due to an ABCC8 mutation identified by next-generation sequencing. The pancreatic adenosine triphosphate (ATP)-sensitive K+ (K-ATP) channel is a key regulator of insulin secretion. Gain-of-function mutations in the genes encoding the Kir6.2 (KCNJ11) and SUR1 (ABCC8) subunits of the channel cause neonatal diabetes. The patient was successfully managed with insulin lispro at a 1:100 dilution, drawn up in an insulin pen injector with a 4-mm needle. The insulin lispro dilution allowed administration of the exact insulin doses, obtaining a good glycemic control and minimizing the burden of injections. At 2 months, corrected age insulin doses were progressively decreased until discontinuation.	0
Sjögren's syndrome (SS) is a chronic autoimmune inflammatory disease that affects primarily older women and is characterized by irreversible damage of the exocrine glands, including tear (xerophthalmia) and salivary glands (xerostomia). Secretory glands lose their functionality due to the infiltration of immune cells, which produce cytokines and cause inflammation. Primary SS is characterized by dry syndrome with or without systemic commitment in the absence of other pathologies. Secondary SS is accompanied by other autoimmune diseases with high activation of B lymphocytes and the production of autoantibodies, including the rheumatoid factor. Other cells, such as CD4+ T cells and mast cells (MCs), participate in SS inflammation. MCs are ubiquitous, but are primarily located close to blood vessels and nerves and can be activated early in autoimmune diseases to express a wide variety of cytokines and chemokines. In the SS acute phase, MCs react by generating chemical mediators of inflammation, tumor necrosis factor (TNF), and other pro-inflammatory cytokines such as interleukin (IL)-1 and IL-33. IL-33 is the specific ligand for ST2 capable of inducing some adaptive immunity TH2 cytokines but also has pro-inflammatory properties. IL-33 causes impressive pathological changes and inflammatory cell infiltration. IL-1 family members can have paracrine and autocrine effects by exacerbating autoimmune inflammation. IL-37 is an IL-1 family cytokine that binds IL-18Rα receptor and/or Toll-like Receptor (TLR)4, exerting an anti-inflammatory action. IL-37 is a natural inhibitor of innate and acquired immunity, and the level is abnormal in patients with autoimmune disorders. After TLR ligand activation, IL-37 mRNA is generated in the cytoplasm, with the production of pro-IL-37 and later mature IL-37 caspase-1 mediated; both precursor and mature IL-37 are biologically active. Here, we discuss, for the first time, the current knowledge of IL-37 in autoimmune disease SS and propose a new therapeutic role.	0
Epidermolysis bullosa acquisita (EBA) is a rare acquired subepidermal bullous autoimmune dermatosis, associated with autoantibodies against collagen type VII, the most important component of dermal anchoring fibrils. Blister induction occurs after binding of autoantibodies to collagen type VII, leading to complement activation, recruitment of neutrophils and secretion of proteases. Clinically, the disease is mostly characterized by tense blisters on trauma-exposed body areas which heal with scarring (mechanobullous form of EBA). The second most frequent subtype of EBA is inflammatory EBA, a bullous pemphigoid-like disease associated with pruritus. Involvement of mucous membranes and/or lesions in the head and neck area additionally point to the diagnosis of EBA. The mechanobullous type of EBA and EBA with intensive mucous membrane lesions display a chronic course and are often extremely resistant to therapy. Topical and systemic glucocorticoids, dapsone, colchicine, classical immunosuppressants, anti-CD20 antibodies, immunoadsorption or intravenous immunoglobulins have been reported as treatments.	0
BACKGROUND: Keratolytic winter erythema (KWE) or Oudtshoorn skin disease is a rare autosomal dominant monogenic disorder of epidermal keratinisation characterized clinically by cyclical peeling of the palms and soles. Due to a founder effect many KWE families have been identified in South Africa and the gene has been localized to 8p23.1-22, but the causal gene has yet to be identified. OBJECTIVE: To examine two compelling positional and functional candidate genes within the critical region on 8p: cathepsin B (CTSB), a lysosomal cysteine protease localized to pericellular spaces between keratinocytes, possibly playing a role in cell-cell adhesion; and farnesyl-diphosphate farnesyltransferase (FDFT1), a membrane-associated enzyme in cholesterol biosynthesis which, among its many functions, plays a role in barrier permeability and integrity. METHOD: Mutation screening of the coding regions, 5'UTRs and intron/exon boundaries of CTSB and FDFT1 in genomic DNA and cDNA of patients affected with KWE. Relative gene expression profiles of CTSB and FDFT1 in palmoplantar skin biopsies were assessed by real-time RT-PCR. RESULTS: No DNA variants that segregate exclusively with KWE were identified. There was no significant difference in the CTSB expression profiles but a trend towards increased expression of FDFT1 was observed in the skin of affected individuals (p=0.063). This observation prompted analysis of the FDFT1 promoter region; however, no genetic variants segregating with the KWE phenotype were observed and it is likely that the increased expression was triggered in response to skin inflammation and peeling. CONCLUSION: CTSB and FDFT1 are excluded as candidates for KWE.	0
Coronavirus 2 (CoV) Severe Acute Respiratory Syndrome (SARS-CoV2) is causing a highly infectious pandemic pneumonia. Coronaviruses are positive sense single-stranded RNA viruses that infect several animal species, causing symptoms that range from those similar to the common cold to severe respiratory syndrome. The Angiotensin Converting Enzyme 2 (ACE2) is the SARS-CoV2 functional receptor. Measures are currently undertaken worldwide to control the infection to avoid disruption of the social and economic equilibrium, especially in countries with poor healthcare resources. In a guarded optimistic view, we hope that the undertaken preventive and treatment measures will at least contribute to contain viral diffusion, attenuate activity, or even eliminate SARS-CoV2. In this review, we discuss emerging perspectives for prevention/treatment of COVID-19 infection. In addition to vaccines under development, passive immunization is an open opportunity since patients develop neutralizing antibodies. A full spectrum of potential drugs for COVID-19 infections could in turn affect virus binding or enzymatic activities involved in viral replication and transcription. Furthermore, clinical trials are currently evaluating the safety and efficacy of anti-inflammatory drugs, such as tocilizumab. Bioinformatics may allow characterization of specific CD8+ and CD4+ T cell responses; thus, CoV2 T cells' frequency can be correlated with the disease severity and outcome. Combinatorial antibody phage display may be empowered to identify the immune repertoire of CoV2-specific neutralizing antibodies.	0
BACKGROUND: The elimination of rubella and prevention of congenital rubella syndrome (CRS) by 2015 are established goals for Europe. Our aim was to review the epidemiology of rubella in relation to this goal. MATERIAL AND METHODS: National surveillance institutions from 32 European countries provided information on rubella and CRS surveillance systems and data for 2000-08. We reported the number of notified rubella cases by year for countries with a national mandatory notification system for rubella covering total country population consistently throughout 2000-08 and analysed rubella surveillance data for 2008. RESULTS: Throughout 2000-08, 24 countries conducted passive routine surveillance based on mandatory reporting rubella covering total country population. Altogether these countries reported 526,751 rubella cases. The median incidence per million inhabitants declined from 7.2 in 2000 to 0.3 in 2008. By 2008, the number of countries with mandatory notification systems for rubella increased to 28. These countries reported 21,475 rubella cases of which 1.5% (n=317) were laboratory-confirmed. Most cases (n=21,075; 98%) were reported from Poland, Italy and Romania. Ten countries reported zero rubella cases and five others reported an incidence of <1 per million inhabitants. In 2008, 20 CRS cases were reported from five countries. CONCLUSION: The overall decline in rubella incidence and increase in the number of countries conducting rubella surveillance through a mandatory notification system are notable achievements toward the goal of rubella elimination in Europe. However, in a few countries with high rubella incidence the risk for CRS still exists. Achievement and maintenance of the required high vaccination coverage and high-quality surveillance of rubella and CRS including laboratory testing of all suspected cases are fundamental to eliminate rubella and prevent CRS in Europe.	1
The c.907delGAG mutation in the TOR1A gene (also named DYT1) is the most common cause of early-onset primary dystonia. The mutation frequency and prevalence have so far been only estimated from rare clinical epidemiological reports in some populations. The purpose of this study was to investigate the incidence at birth of the c.907delGAG mutation in a French-representative mixed population of newborn from South-Eastern France. We applied an automated high-throughput genotyping method to dried blood spot samples from 12,000 newborns registered in Hérault between 2004 and 2005. Only one allele was found to carry the mutation, which allows to determine its incidence at birth as 1/12,000 per year in this area.	1
BACKGROUND:numerous researches on the pathological mechanism of Enlarged Vestibular Aqueduct (EVA) syndrome mainly focuses on the genetic characteristics of SLC26A4 gene and the function of its encoding protein, Pendrin. One of the limitations with these explanations is that it does not explain why cerebrospinal fluid pressure can affect clinical manifestations. OBJECTIVES:To establish a new approach to explain the clinical manifestations of EVA syndrome with biomechanical method. MATERIAL AND METHODS:108 cases of EVA syndrome who received cochlear implantation were analyzed retrospectively. A cochlear model was built to reflect the differences of the structure in EVA syndrome with or without Mondini malformation. The CFD software was used to simulate and display the differences in mechanical pathogenic factors to which the model was subjected. RESULTS:EVA syndrome patients with Mondini malformation suffer more mechanical damage from the cerebrospinal fluid pressure due to their structural reason and their symptoms appear earlier and progress faster. CONCLUSIONS:Biomechanics is an important aspect of pathological mechanism of EVA syndrome, and it provides a new angle for clinical decision-making.	0
Waardenburg-Shah syndrome is a rare autosomal recessive [AR] inherited disorder characterized by the presence of Hirschsprung's disease with a high likelihood of aganglionic megacolon, due to which the mortality is high. The management of the condition involves surgical intervention for the removal of the aganglionic segment of the colon. Here, we report a neonate that presented with a white forelock, white eyelashes, iris hypopigmentation, and sensorineural deafness associated with bilious vomiting, refusal to feed, and failure to pass meconium indicating intestinal obstruction.	0
Intellectual disability (ID) is a common neurodevelopmental disorder exhibiting extreme genetic heterogeneity, and more than 500 genes have been implicated in Mendelian forms of ID. We performed exome sequencing in a large family affected by an autosomal-dominant form of mild syndromic ID with ptosis, growth retardation, and hypotonia, and we identified an inherited 2 bp deletion causing a frameshift in BRPF1 (c.1052_1053del) in five affected family members. BRPF1 encodes a protein modifier of two histone acetyltransferases associated with ID: KAT6A (also known as MOZ or MYST3) and KAT6B (MORF or MYST4). The mRNA transcript was not significantly reduced in affected fibroblasts and most likely produces a truncated protein (p.Val351Glyfs∗8). The protein variant shows an aberrant cellular location, loss of certain protein interactions, and decreased histone H3K23 acetylation. We identified BRPF1 deletions or point mutations in six additional individuals with a similar phenotype. Deletions of the 3p25 region, containing BRPF1 and SETD5, cause a defined ID syndrome where most of the clinical features are attributed to SETD5 deficiency. We compared the clinical symptoms of individuals carrying mutations or small deletions of BRPF1 alone or SETD5 alone with those of individuals with deletions encompassing both BRPF1 and SETD5. We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome but that some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency.	0
Intractable epilepsy remains a significant medical challenge, resulting in recurrent and prolonged intensive care unit (ICU) admissions. Autoimmune encephalitis is emerging as a treatable cause of intractable epilepsy. It is characterized by antibodies against cerebral antigens, such as potassium channels such as leucine-rich, glioma inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2), calcium channels such as the voltage-gated calcium channel (VGCC), or neurotransmitter receptors such as the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), gamma aminobutyric acid receptor (GABAR), and N-methyl-D-aspartate receptor (NMDAR). Diagnosis requires a syndrome consistent with an antibody identified in serum or cerebrospinal fluid (CSF) using methods that minimize risk of false-positives. Although there is no officially approved therapy for these disorders, typical approaches involve chronic high-dose steroids, intravenous immunoglobulin (IVIG), or plasma exchange. Rituximab is effective for antibody-associated disorders such as lupus, myasthenia gravis, and neuromyelitis optica. Here, we present three patients who were admitted with recalcitrant status epilepticus and demonstrated serum antibodies against NMDAR, LGI1, or VGCC using a cell-based assay. All patients demonstrated complete, long-term epilepsy control and improvement in symptoms with rituximab.	0
Actinic lichen planus (ALP) is a distinct variant of lichen planus mainly involving teenagers with an Asian racial profile. Three clinical types of ALP have been described: annular, pigmented, and dyschromic. We report an ALP with unusual presentation in a 56-year-old woman with no relevant medical history, which was clinically suggestive of actinic keratosis. Histological findings refined the diagnosis by showing typical aspects of lichen planus. This dermatosis, which is frequent in Tunisia because of sun exposure, may cause mainly aesthetic damage and requires adequate photoprotection.	0
Lissencephaly is one of the central nervous system anomalies of Miller-Dieker Syndrome (MDS). Fetuses with lissencephaly have an abnormal smooth brain with fewer folds and grooves that will be detected by ultrasounds or fetal magnetic resonance imaging (MRI) after 30 weeks of gestation. We report a fetus with lissencephaly diagnosed as Miller-Dieker Syndrome postnatally. G banded chromosome analysis revealed 45,X,psu dic(17;Y)(p13;p11.32).ish dic (17;Y)(LIS1-,RARA+, SRY+, DYZ3+) by G-banding analysis using high resolution banding technique. Fetal delayed cortical development will be the findings to perform further investigations including fluorescence in situ hybridization analysis for MDS, a 17p13.3 microdeletion syndrome, pre/postnatally. This will be the first case of MDS with unbalanced translocation between deleted short arm of chromosome 17 and Y chromosome.	0
Mutations in myotubularin-related protein 2 (MTMR2) were shown to underlie Charcot-Marie-Tooth type 4B1 (CMT4B1) disease, a rare autosomal recessive demyelinating neuropathy, characterized by severe early-onset motor and sensory neuropathy. We describe three siblings of consanguineous kindred presenting with hypotonia, reduced muscle tone, action tremor, dysmetria, areflexia, and skeletal deformities, consistent with a diagnosis of CMT. Whole-exome sequencing identified a novel homozygous c.336_337 insertion mutation in MTMR2, resulting in a frameshift and putative truncated protein. In this concise report, we discuss the clinical presentation of this rare disease and support the limited number of observations regarding the pathogenesis of MTMR2-related neuropathies.	0
Results of previous studies suggest that children and adolescents with osteogenesis imperfecta (OI) type IV have muscle force deficits. However, muscle function remains to be objectively quantified in this population. This study aimed to assess upper and lower extremity muscle function in patients with OI type IV. It was carried out in the outpatient department of a pediatric orthopedic hospital; 27 individuals with OI type IV (7-21 years; 13 males), 27 age- and sex-matched individuals with OI type I, and 27 age- and sex-matched controls. Upper extremity muscle force was assessed with hydraulic hand dynamometry, and lower extremity muscle function (peak force per body weight and peak power per body mass) was measured by mechanography through five tests: multiple two-legged hopping, multiple one-legged hopping, single two-legged jump, chair-rise test, and heel-rise test. Upper-limb grip force was normal for patients with OI type IV when compared to height and sex reference data (average z-score = 0.17 ± 1.30; P = 0.88). Compared to age- and sex-matched controls, patients with OI type IV had approximately 30% lower-limb peak force and 50% peak power deficits (P values <0.05). At the lower-limb level, they had a 50% lower peak power than age- and sex-matched patients with OI type I (P < 0.05). Patients with OI type IV have normal upper-limb muscle force but a muscle function deficit at the lower-limb level. These results suggest that lower-limb muscle weakness may contribute to functional deficits in these individuals.	0
Ocular albinism type 1 is a genetic eye disease caused by mutations in the GPR143 gene. Little is known about the molecular pathways involved in this disease and no therapeutic candidate has been identified as yet. Here we report the generation of an iPSC line from the skin fibroblasts of a patient with a mutation in the GPR143 gene using Sendai Virus vectors. This new iPSC line will allow a better understanding of the Ocular Albinism type 1 disease and to screen for potential therapeutic candidates.	0
Wyburn-Mason syndrome is associated with unilateral retinal racemose hemangioma. Rarely, it presents with bilateral and symmetrical grade of malformation. We describe a 37-year old male, who presented with Wyburn-Mason syndrome presenting with bilateral but asymmetrical retinal hemangioma. The eye with advanced grade of hemangioma was complicated with exudation, intraretinal fluid, neurosensory detachment, and reduced vision. He was treated with one intravitreal injection of bevacizumab, after which both the intraretinal fluid and neurosensory detachment resolved. His vision improved and was maintained till 1 year of follow-up.	0
Primary hepatic angiosarcoma (PHA) is a rare mesenchymal liver tumor, accounting for 0.1-2% of primary liver malignancies. The clinical presentations of PHA are variable, from asymptomatic to liver failure or complicated with tumor rupture. The diagnosis of PHA is difficult due to the lack of specific clinical manifestation and investigation results, which can be confused with other liver tumors resulting in late diagnosis. However, there is currently a paucity of effective therapeutic approaches. We advocate early diagnosis with radiological imaging and histopathology because most of them are diagnosed in late-stage and carry a grave prognosis. Surgical resection remains the mainstay of treatment, which can significantly prolong survival. Chemotherapy, including transarterial chemoembolization, is an option for palliative treatment. Unfortunately, molecular treatment has limited efficacy and liver transplantation is also not recommended due to high rate of recurrence. We present a case series of four patients with biopsy-proven PHA which had distinct presentations and clinical courses.	0
This is a case report of a woman in her sixth decade of life diagnosed with primary angiosarcoma of the breast using mammography and ultrasound, confirmed with imaging-guided biopsy, and finally treated with surgery and radiation. Imaging studies obtained and discussed include mammography, ultrasonography, and MRI. Further discussion on the presenting symptoms, useful imaging modalities, and treatment options takes place. It is important to consider primary angiosarcoma of the breast, though rare, in any woman presenting with a palpable breast mass and, if feasible, an MRI will be most helpful in the diagnosis of this rare tumor.	0
Porphyrias are rare genetic disorders which cause a deficiency in the enzymes involved in the biosynthesis of heme. The treatment of epilepsy in patients with acute intermittent porphyria can be difficult since many anticonvulsants can increase heme synthesis and trigger porphyric attacks. We report a patient with focal epilepsy successfully treated with eslicarbazepine without exacerbation of porphyria.	0
Progressive pseudorheumatoid dysplasia (PPRD) is a genetic bone disorder characterised by the progressive degeneration of articular cartilage that leads to pain, stiffness and joint enlargement. As PPRD is a rare disease, available literature is mainly represented by single case reports and only a few larger case series. Our aim is to review the literature concerning clinical, laboratory and radiological features of PPRD. PPRD is due to a mutation in Wnt1-inducible signalling protein 3 (WISP3) gene, which encodes a signalling factor involved in cartilage homeostasis. The disease onset in childhood and skeletal changes progresses over time leading to significant disability. PPRD is a rare condition that should be suspected if a child develops symmetrical polyarticular involvement without systemic inflammation, knobbly interphalangeal joints of the hands, and gait abnormalities. A full skeletal survey, or at least a lateral radiograph of the spine, can direct towards a correct diagnosis that can be confirmed molecularly. More than 70 WISP3 mutations have so far been reported. Genetic testing should start with the study of genomic DNA extracted from blood leucocytes, but intronic mutations in WISP3 causing splicing aberrations can only be detected by analysing WISP3 mRNA, which can be extracted from cultured skin fibroblasts. A skin biopsy is, therefore, indicated in patients with typical PPRD findings and negative mutation screening of genomic DNA.	0
Red cell pyruvate kinase deficiency is the most common glycolytic defect associated with congenital non-spherocytic hemolytic anemia. The disease, transmitted as an autosomal recessive trait, is caused by mutations in the PKLR gene and is characterized by molecular and clinical heterogeneity; anemia ranges from mild or fully compensated hemolysis to life-threatening forms necessitating neonatal exchange transfusions and/or subsequent regular transfusion support; complications include gallstones, pulmonary hypertension, extramedullary hematopoiesis and iron overload. Since identification of the first pathogenic variants responsible for PK deficiency in 1991, more than 300 different variants have been reported, and the study of molecular mechanisms and the existence of genotype-phenotype correlations have been investigated in-depth. In recent years, where progress in genetic analysis, next-generation sequencing technologies and personalized medicine have opened up important landscapes for diagnosis and study of molecular mechanisms of congenital hemolytic anemias, genotyping has become a prerequisite for accessing new treatments and for evaluating the disease state and progression. This review examines the extensive molecular heterogeneity of PK deficiency, focusing on the diagnostic impact of genotypes and new acquisition on pathogenic non-canonical variants. The recent progress and the weakness in understanding the genotype-phenotype correlation, and its practical usefulness in light of new therapeutic opportunities for PK deficiency is also discussed.	0
Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) is an early onset hereditary form of cerebral amyloid angiopathy (CAA) caused by a point mutation resulting in an amino acid change (NP_000475.1:p.Glu693Gln) in the amyloid precursor protein (APP). Post-mortem frontal and occipital cortical brain tissue from nine patients and nine age-related controls was used for RNA sequencing to identify biological pathways affected in HCHWA-D. Although previous studies indicated that pathology is more severe in the occipital lobe in HCHWA-D compared to the frontal lobe, the current study showed similar changes in gene expression in frontal and occipital cortex and the two brain regions were pooled for further analysis. Significantly altered pathways were analyzed using gene set enrichment analysis (GSEA) on 2036 significantly differentially expressed genes. Main pathways over-represented by down-regulated genes were related to cellular aerobic respiration (including ATP synthesis and carbon metabolism) indicating a mitochondrial dysfunction. Principal up-regulated pathways were extracellular matrix (ECM)-receptor interaction and ECM proteoglycans in relation with an increase in the transforming growth factor beta (TGFβ) signaling pathway. Comparison with the publicly available dataset from pre-symptomatic APP-E693Q transgenic mice identified overlap for the ECM-receptor interaction pathway, indicating that ECM modification is an early disease specific pathomechanism.	0
Orofaciodigital syndrome 1 (OFD-1) is a rare, X-linked, dominantly inherited disorder caused by an OFD1 mutation that can cause polycystic kidneys. A 37-year-old woman on hemodialysis therapy was admitted to our hospital for trans-catheter arterial embolization therapy for enlarged polycystic kidneys. Lobulated tongue and brachydactyly were noticed, prompting an OFD1 sequencing analysis. Sequencing revealed a causal four-base-pair deletion in exon 13, both in the patient and in her mother, whose renal function had been retained. The peripheral leukocyte X chromosome inactivation pattern was skewed in the patient but not in her mother, suggesting some role in their phenotypic difference.	0
Background: Dissecting cellulitis is a chronic inflammatory dermatosis that results in disfiguring and painful, purulent lesions. Treatment of patients with disease resistant to standard therapies, including intralesional or topical steroids or antibiotics, can be a dilemma for clinicians. Methods: We performed a systematic review of the literature in November 2018 to find articles which presented treatment options and outcomes of patients who failed prior treatment with standard therapies. Results: We identified 57 articles of interest, with 53 being case studies or series. Isotretinoin was the most often reported, but the response was limited. Biologics and laser therapy were used less often but demonstrated a better chance of remission. X-ray epilation and surgical excision demonstrated the best remission rates but can be complicated by serious morbidity. Conclusion: We propose a regimen for the treatment of recalcitrant cases of dissecting cellulitis. In the future, more robust studies including randomized control trials are needed to identify the preferred treatment options for refractory dissecting cellulitis.	0
Filamin C (encoded by the FLNC gene) is a large actin-cross-linking protein involved in shaping the actin cytoskeleton in response to signaling events both at the sarcolemma and at myofibrillar Z-discs of cross-striated muscle cells. Multiple mutations in FLNC are associated with myofibrillar myopathies of autosomal-dominant inheritance. Here, we describe for the first time a boy with congenital onset of generalized muscular hypotonia and muscular weakness, delayed motor development but no cardiac involvement associated with a homozygous FLNC mutation c.1325C>G (p.Pro442Arg). We performed ultramorphological, proteomic, and functional investigations as well as immunological studies of known marker proteins for dominant filaminopathies. We show that the mutant protein is expressed in similar quantities as the wild-type variant in control skeletal muscle fibers. The proteomic signature of quadriceps muscle is altered and ultrastructural perturbations are evident. Moreover, filaminopathy marker proteins are comparable both in our homozygous and a dominant control case (c.5161delG). Biochemical investigations demonstrate that the recombinant mutant protein is less stable and more prone to degradation by proteolytic enzymes than the wild-type variant. The unusual congenital presentation of the disease clearly demonstrates that homozygosity for mutations in FLNC severely aggravates the phenotype.	0
Autophagy involves engulfment of cytoplasmic contents by double-membraned autophagosomes, which ultimately fuse with lysosomes to enable degradation of their substrates. We recently proposed that the tubular-vesicular recycling endosome membranes were a core platform on which the critical early events of autophagosome formation occurred, including LC3-membrane conjugation to autophagic precursors. Here, we report that the release of autophagosome precursors from recycling endosomes is mediated by DNM2-dependent scission of these tubules. This process is regulated by DNM2 binding to LC3 and is increased by autophagy-inducing stimuli. This scission is defective in cells expressing a centronuclear-myopathy-causing DNM2 mutant. This mutant has an unusual mechanism as it depletes normal-functioning DNM2 from autophagosome formation sites on recycling endosomes by causing increased binding to an alternative plasma membrane partner, ITSN1. This "scission" step is, thus, critical for autophagosome formation, is defective in a human disease, and influences the way we consider how autophagosomes are formed.	0
A 19-year-old male presented with complaints of fluid-filled lesions on the body of 2 weeks duration. On examination, he was found to have multiple tense bullae distributed on the flexures, face, and genitalia with associated oral ulcers and "cluster of jewels" sign. The diagnosis was confirmed by histopathology and direct immunofluorescence. There are very few reports of linear IgA earlier from India according to the literature available so far, that too from the Southern part of the country. The patient had bullous pemphigoid-like lesions typically seen in adults, but the distribution of lesions was akin to that of the "chronic bullous disease of childhood variant" found in children. This case has been reported for rarity in this region and also because the patient had atypical morphology and distribution of lesions.	0
Background:Cognitive dysfunctions being core features of schizophrenia (SZ), cause disability, increase burden and are refractory to treatment. Viral infections are not risk factors for SZ, but growing evidence indicates infection with some neurotropic viruses, particularly Herpes simplex virus type 1 (HSV -1) as a risk factor for cognitive dysfunction. Studies in India:Three research studies in India are described. In the first, participants were evaluated for HSV-1 infection and cognitive functions (cases 198 and controls 100). In the second, patients and normal nonpsychotic control individuals were examined at baseline and followed up over 1-3 years (cases 138 and controls 88). In the third, a randomized, double-blind placebo-controlled antipsychotic adjunctive trial was conducted to examine the effect of anti-viral drug valacyclovir over 16 weeks on cognitive functioning (valacyclovir 30; placebo 32, treatment for 16 weeks). Results of Indian Studies:Cross-sectional study: HSV-1 infection was associated with modest dysfunction, especially on attention (accuracy) and spatial processing (speed). Longitudinal Study:HSV-1 seropositive participants had lower scores at baseline on 6/16 measures, regardless of SZ diagnoses. At follow-up, there was a significant decline in HSV-1-positive participants for abstraction and mental flexibility and emotion discrimination. Randomized Controlled Trial:Significantly, greater improvement in accuracy index of emotion discrimination in the valacyclovir-treated versus placebo sample was found. Conclusions:Indian studies are consistent with a causative role for HSV-1 in cognitive dysfunction regardless of SZ diagnosis; more rigorous studies of the causal hypothesis are needed, particularly larger randomized controlled trials.	0
Objectives: To summarize the clinical and genetic characteristics of the patients with isolated methylmalonic acidemia and investigate the strategies for the diagnosis, treatment and prevention. Methods: Three hundred and fourteen patients (180 males, 134 females) with isolated methylmalonic acidemia were ascertained from 26 provinces or cities across the mainland of China during January 1998 to March 2020. Genetic analysis was performed by Sanger sequencing, gene panel sequencing, whole exome sequencing, multiplex ligation-dependent probe amplification or quantitative PCR. According to the age of onset, the patients were divided to early-onset group (≤12 months of age) and the late-onset group (>12 months of age). They were treated by cobalamin, L-carnitine and (or) special diet and symptomatic treatment. Statistical analysis was done using Chi-square test. Results: Fifty-eight of 314 (18.5%) patients were detected by Newborn screening using liquid chromatography tandem mass spectrometry. Five cases (1.6%) had a postmortem diagnosis. Two hundred and fifty-one patients (79.9%) were clinically diagnosed with an age of onset ranged from 3 hours after birth to 18 years. One hundred and fifty-nine patients (71.0%) belonged to early-onset groups, 65 patients (29.0%) belonged to the late-onset group. The most common symptoms were metabolic crises, psychomotor retardation, epilepsy, anemia and multiple organ damage. Metabolic acidosis and anemia were more common in early-onset patients than that in late-onset patients (20.8%(33/159) vs. 9.2% (6/65), 34.6% (55/159) vs. 16.9% (11/165), χ(2)=4.261, 6.930, P=0.039, 0.008). Genetic tests were performed for 236 patients (75.2%), 96.2%(227/236) had molecular confirmation. One hundred and twenty-seven variants were identified in seven genes (MMUT, MMAA, MMAB, MMADHC, SUCLG1, SUCLA2, and MCEE), of which 49 were novel. The mut type, caused by the deficiency of methylmalonyl-CoA mutase, was the most common (n=211, 93%) cause of this condition. c.729_730insTT, c.1106G>A and c.914T>C were the three most frequent mutations in MMUT gene. The frequency of c.914T>C in early-onset patients was significantly higher than that in late-onset patients (8.3% (18/216) vs. 1.6% (1/64), χ(2)=3.859, P=0.037). Metabolic crisis was more frequent in mut type than the other types (72.6% (114/157) vs. 3/13, χ(2)=13.729, P=0.001),developmental delay and hypotonia were less frequent in mut type (38.2% (60/157) vs. 9/13, 25.5% (40/157) vs. 8/13, χ(2)=4.789, 7.705, P=0.030, 0.006). Of the 58 patients identified by newborn screening, 44 patients (75.9%) who were treated from asymptomatic phase developed normally whereas 14 patients (24.1%) who received treatment after developing symptoms exhibited varying degrees of psychomotor retardation. Conclusions: The characteristics of phenotypes and genotypes among Chinese patients with isolated methylmalonic acidemia were analyzed. Expanded the mutation spectrum of the associated genes. Because of the complex clinical manifestations and severe early onset of isolated methylmalonic acidemia, Newborn screening is crucial for early diagnosis and improvement of prognosis. MMUT gene is recommended for carrier screening as an effort to move the test earlier as a part of the primary prevention of birth defects.	0
The heritable disorder osteogenesis imperfecta (OI) is characterized by bone fragility and low bone mass. OI type VI is an autosomal recessive form of the disorder with moderate to severe bone fragility. OI type VI is caused by mutations in the serpin peptidase inhibitor, clade F, member 1 (SERPINF1), the gene coding for pigment epithelium-derived factor (PEDF). Here, we report a patient with OI type VI caused by a novel homozygous intronic variant in SERPINF1 identified by whole-exome sequencing (WES). The mutation was not identified using a low bone mass gene panel based on next-generation sequencing. This variant creates a novel consensus splice donor site (AGGC to AGGT) in intron 4. Analysis of cDNA generated from fibroblasts revealed retention of a 32-bp intronic fragment between exons 4 and 5 in the cDNA, a result of alternative splicing from the novel splice-donor site. As a result, the aberrant insertion of this intronic fragment generated a frameshift pathogenic variant and induced nonsense-mediated decay. Furthermore, gene expression by quantitative PCR showed SERPINF1 expression was dramatically reduced in patient fibroblasts, and PEDF level was also significantly reduced in the patient's plasma. In conclusion, we report a novel homozygous variant that generates an alternative splice-donor in intron 4 of SERPINF1 which gives rise to severe bone fragility. The work also demonstrates clinical utility of WES analysis, and consideration of noncoding variants, in the diagnostic setting of rare bone diseases. © 2018 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.	0
Congenital tracheal stenosis can lead to symptomatic airway obstruction in children and often mandates surgical correction. Over the past half-century, numerous tracheal reconstruction techniques have been developed, including tracheal resection with end-to-end anastomosis (for short-segment complete tracheal stenosis), patch tracheoplasty, slide tracheoplasty, and homograft and autograft augmentation repairs. However, operative management of congenital tracheal stenosis is often complicated by the presence of congenital heart disease, the most common of which is pulmonary artery sling. When present concomitantly, combined repair of both defects is feasible and is currently the preferred approach. Questions have been raised about the optimal timing and sequence of surgery, and some have advocated staged repair for patients with complex associated cardiac lesions. However, evidence from the past two decades suggests that concomitant repair can be performed with excellent results. The current standard of care involves the use of cardiopulmonary bypass to simultaneously repair the tracheal defect using slide tracheoplasty and all associated cardiac anomalies. Advances in operative techniques and extracorporeal circulation, progressive understanding of the pathological basis of combined congenital tracheal and cardiac disease, and a multidisciplinary approach to patient care have all contributed to the successful outcomes seen in the modern era. This article describes the combined surgical correction of tracheal stenosis and double-outlet right ventricle-tetralogy of Fallot type in an infant, provides a detailed step-by-step description for performing a slide tracheoplasty along with various other less favored tracheoplasty techniques, and reviews the current literature discussing such combined repairs.	0
Becker's nevus (BN) classically presents as a single, sharply demarcated, unilateral, hyperpigmented, tan colored macule over the shoulder or pectoral area and is more frequent in adolescent males than females. In this study, we present an acquired, non-syndromic atypical BN in a Saudi female.	0
Immune checkpoint inhibitors (ICI) have been approved by the Food and Drug Administration (FDA) for use in many solid tumors and hematological malignancies. Immune-related adverse events (irAEs) are potential side effects that can arise during or after treatment with ICI therapy. We describe a case of ICI-induced Fanconi syndrome in a 58-year-old man with extensive-stage small-cell lung cancer (ES-SCLC), who had disease progression after initial chemotherapy and radiation. He was started on nivolumab and ipilimumab as second-line treatment. Three weeks into the therapy, he developed abdominal pain with grade 3 transaminitis and required steroids and mycophenolate for presumed autoimmune hepatitis. Subsequently, he presented with worsening abdominal pain and was found to have an enlarging right adrenal mass. Laboratory work-up revealed a white blood cell (WBC) count of 17 K/µL, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) 99/210 U/L, direct bilirubin 2.8 mg/dL, blood urea nitrogen (BUN) 43 mg/dL, Cr 2.31 mg/dL (baseline: 1.1 mg/dL), phosphorus 2.3 mg/dL, and glucose 303 mg/dL with metabolic acidosis. There was no evidence of urinary tract obstruction. Urinary findings were notable for glucosuria (>500 mg/dL), fractional excretion of phosphorus and uric acid of 56% (normal range 10%-20%) and 75% (normal range 7%-10%), respectively. He was started on intravenous (IV) bicarbonate and methylprednisolone. Fanconi syndrome with proximal tubular damage secondary to ICI therapy was diagnosed. He was discharged on oral bicarbonate and steroid taper. On follow-up after four weeks, his renal function recovered to baseline.	0
Mucinous metaplasia in Warthin tumor (WT) is a recognized phenomenon. Nevertheless, its presence can create a diagnostic challenge in the distinction from the newly proposed variant of mucoepidermoid carcinoma (MEC), Warthin-like MEC. In this study, we evaluated the significance and diagnostic relevance of mucinous metaplasia in WTs. A total of 30 WTs diagnosed based on resection specimens formed the basis of this retrospective study. Mucicarmine staining was performed to identify mucinous metaplasia, and fluorescence in situ hybridization (FISH) analysis was used to detect MAML2 gene rearrangement. After review, one MAML2 rearranged case was reclassified as Warthin-like MEC as the classic bilayered epithelium in WT was not identified. The diagnosis of WT was confirmed in the remaining 29 cases. Mucinous metaplasia was encountered in 24 WTs (83%), with 14% (4/29) having an abundant amount. We found that mucinous metaplasia correlated with tumor size (p < 0.05). Age and sex distribution were similar in WT cases with or without mucinous metaplasia. In addition, neither the presence of squamous metaplasia nor the time interval between fine-needle aspiration and surgery was related to mucinous metaplasia (p > 0.05). The MAML2 FISH analyses performed in 18 WTs with variable amounts of mucinous metaplasia were negative for rearrangement. In conclusion, mucinous metaplasia is fairly common in WTs and shows a significant correlation with tumor size. Therefore, caution should be taken to avoid overinterpretation of WT with mucinous metaplasia as MEC in cases showing the classic bilayered oncocytic lining epithelium.	0
Benign familial neonatal epilepsy (BFNE) is caused, in about 5% of families, by mutations in the KCNQ3 gene encoding voltage-gated potassium channel subunits. Usually, newborns with BFNE show a normal neurological outcome, but recently, refractory seizures and/or developmental disability have been reported suggesting phenotype variability associated with KCNQ3-related BFNE. Here, we describe a proband from a BFNE family carrying a novel variant in the KCNQ3 gene. Regarding the paucity of data in the literature, we describe the presented case with a view to further establishing: (1) a genotype/phenotype correlation in order to define a BFNE phenotype associated with favourable outcome; (2) an electroclinical pattern associated with BFNE based on video-EEG recording; (3) appropriate first-line AEDs; and (4) the duration of AED treatment. The presented case from Day 3 exhibited a cluster of ictal events, identified as epileptic seizures on Day 10 based on continuous video-EEG polygraphy. The seizures were characterized by asymmetric tonic posturing, associated with a generalized decrease in EEG amplitude, and followed by bilateral asynchronous clonic movements associated with bicentral sharp-wave discharges. The seizures were refractory to intravenous pyridoxine, whereas levetiracetam resulted in rapid total seizure control which has remained to date. This study demonstrates that the novel heterozygous KCNQ3 (c.<strike> </strike>914A>T; p.Asp305Val) variant, affecting residues in the pore region, is associated with a specific electroclinical pattern and favourable neurodevelopmental outcome. [Published with video sequence on www.epilepticdisorders.com].	0
BACKGROUND:Vici syndrome is a neurodevelopmental disorder of the autophagy pathway. Almost all cases reported have the cardinal features of agenesis of corpus callosum, cataract, cardiomyopathy, immunodeficiency and hypopigmentation. CASE CHARACTERISTICS:8-month-old boy with developmental delay, myoclonic jerks, repeated respiratory infections, coarse facial features, cataract and hypopigmented hair. Echocardiography revealed dilated cardiomyopathy and magnetic resonance imaging of brain suggested agenesis of corpus callosum. Exome sequencing detected a novel homozygous nonsense mutation in the EPG5 gene. OUTCOME:Establishing a definite diagnosis helped in proper prognostication, providing genetic counseling and prenatal diagnosis to the family. MESSAGE:Though uncommon, presence of the characteristic features makes Vici syndrome a clinically recognizable cause of developmental delay.	0
Mutations in TUBB4A have been identified to cause a wide phenotypic spectrum of diseases ranging from hereditary generalized dystonia with whispering dysphonia (DYT-TUBB4A) and hereditary spastic paraplegia (HSP) to leukodystrophy hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). TUBB4A encodes the brain-specific β-tubulin isotype, β-tubulin 4A. To elucidate the pathogenic mechanisms conferred by TUBB4A mutations leading to the different phenotypes, we functionally characterized three pathogenic TUBB4A variants (c.4C>G,p.R2G; c.745G>A,p.D249N; c.811G>A, p.A271T) as representatives of the mutational and disease spectrum) in human neuroblastoma cells and human induced pluripotent stem cell (iPSC)-derived neurons. We showed that mRNA stability was not affected by any of the TUBB4A variants. Although two mutations (p.R2G and p.D249N) are located at the α/β-tubulin interdimer interface, we confirmed incorporation of all TUBB4A mutants into the microtubule network. However, we showed that the mutations p.D249N and p.A271T interfered with motor protein binding to microtubules and impaired neurite outgrowth and microtubule dynamics. Finally, TUBB4A mutations, as well as heterozygous knockout of TUBB4A, disrupted mitochondrial transport in iPSC-derived neurons. Taken together, our findings suggest that functional impairment of microtubule-associated transport is a shared pathogenic mechanism by which the TUBB4A mutations studied here cause a spectrum of diseases.	0
This article describes the clinical and electromyographic findings of neuromyotonia in a 19-month-old male crossbred Quarter Horse that presented with stiffness and muscle asymmetry in the hind limbs as well as sacrococcygeal, paravertebral, and gluteal myokymia. An electromyographic study showed spontaneous continuous muscle fiber activity with high-frequency discharges, fibrillations, positive sharp waves, fasciculation potentials, and complex repetitive discharges. Histological examination of the gluteal muscle showed a mixed neurogenic and myopathic pattern. The findings are consistent with neuromyotonia.	0
EPM2A has been certified as a causative gene in patients with Lafora disease (LD), which is a rare autosomal recessive and severe form of progressive myoclonus epilepsy. LD classically starts in adolescence, characterized by various types of seizure with myoclonic seizure as the main type. Typically within 10 years, intractable seizure attack, rapidly progressing dementia, and a vegetative state were present. LD is particularly frequently found in Mediterranean countries. Here, we report a Chinese family with a novel compound heterozygous mutation in the EPM2A gene, characterized by recurrent vomiting, intractable epilepsy, and progressive cognitive decline.	0
CEDNIK (CErebral Dysgenesis, Neuropathy, Ichthyosis, and Keratoderma) syndrome is a neuroichthyotic syndrome characterized by a constellation of clinical features including severe developmental retardation, microcephaly, and facial dysmorphism. Here, we report the first case of CEDNIK syndrome from India presenting with characteristic clinical features and harboring a novel mutation of SNAP29 gene.	0
Primary fallopian tube carcinoma (PFTC) is rare but may be under-diagnosed. We have analysed the incidence, clinical findings and outcome in patients with PFTC at the RUH Gynaecological Cancer Centre in Bath between 1999 and 2004, and compared the incidence with that of advanced ovarian carcinoma (OC). Eight patients had PFTC, seven of whom were diagnosed after 2001, and 55 patients had advanced OC. Our data suggest a relative increase in the number of patients with PFTC over the study period. PFTC patients had a mean age of 69.6 years, most presented with postmenopausal bleeding, two had a second carcinoma, three were nulliparous and none were diagnosed pre-operatively. All were treated surgically and received platinum-based chemotherapy. Although PFTC patients had better outcomes than those with advanced OC, the difference was not statistically significant (p = 0.088). Accurate diagnosis and differentiation of PFTC from advanced OC are important for monitoring trends in incidence, for better characterisation of prognostic features and improved management.	1
2-Oxoglutarate dehydrogenase (OGDH) is a rate-limiting enzyme in the mitochondrial TCA cycle, encoded by the OGDH gene. α-Ketoglutarate dehydrogenase (OGDH) deficiency was previously reported in association with developmental delay, hypotonia, and movement disorders and metabolic decompensation, with no genetic data provided. Using whole exome sequencing, we identified two individuals carrying a homozygous missense variant c.959A>G (p.N320S) in the OGDH gene. These individuals presented with global developmental delay, elevated lactate, ataxia and seizure. Fibroblast analysis and modeling of the mutation in Drosophila were used to evaluate pathogenicity of the variant. Skin fibroblasts from subject # 2 showed a decrease in both OGDH protein and enzyme activity. Transfection of human OGDH cDNA in HEK293 cells carrying p.N320S also produced significantly lower protein levels compared to those with wild-type cDNA. Loss of Drosophila Ogdh (dOgdh) caused early developmental lethality, rescued by expressing wild-type dOgdh (dOgdhWT ) or human OGDH (OGDHWT ) cDNA. In contrast, expression to the mutant OGDH (OGDHN320S ) or dOgdh carrying homologous mutations to human OGDH p.N320S variant (dOgdhN324S ) failed to rescue lethality of dOgdh null mutants. Knockdown of dOgdh in the nervous system resulted in locomotion defects which were rescued by dOgdhWT expression but not by dOgdhN324S expression. Collectively, the results indicate that c.959A>G variant in OGDH leads to an amino acid change (p.N320S) causing a severe loss of OGDH protein function. Our study establishes in the first time a genetic link between an OGDH gene mutation and OGDH deficiency.	0
OBJECTIVES:Low-intensity ultrasound (LIU)/low-intensity pulsed ultrasound (LIPUS) may influence nerve tissue regeneration and axonal changes in the context of carpal tunnel syndrome (CTS) and in the animal model. The purpose of this pragmatic review is to understand the current knowledge for the effects of low-intensity therapeutic ultrasound in the animal and human model and determine the future directions of this novel field. DESIGN:Pragmatic review. METHODS:We performed a literature search of available material using OVID, EmBase, and PubMed for LIU/LIPUS, all of which were preclinical trials, case reports, and case series using animal models. For CTS, a literature search was performed on PubMed (1954 to 2019), CENTRAL (the Cochrane Library, 1970 to 2018), Web of Science (1954 to 2019), and SCOPUS (1954 to 2019) to retrieve randomized controlled trials. RESULTS:Eight articles were discussed showing the potential effects of LIU on nerve regeneration in the animal model. Each of these trials demonstrated evidence of nerve regeneration in the animal model using LIPUS or LIU. Seven randomized controlled trials were reviewed for ultrasound effects for the treatment of carpal tunnel syndrome, each showing clinical efficacy comparable to other treatment modalities. CONCLUSIONS:LIU/LIPUS is a promising and noninvasive means of facilitating nerve regeneration in the animal model and in the treatment of carpal tunnel syndrome. Although many of the trials included in this review are preclinical, each demonstrates promising outcomes that could eventually be extrapolated into human studies.	0
Objective: To investigate the mutation characteristics and clinical relevance of Gilbert syndrome (GS) and Crigler-Najjar syndrome (CNS) in relation to uridine diphosphate glucuronosyltransferase A1 (UGT1A1) gene. Methods: The characteristics of UGT1A1 gene mutation and their clinical relevance were analyzed by searching PubMed and Human Gene Mutation Databases. Results: A total of 163 mutation sites were found in the UGT1A1 gene since November 16, 2018. The following patterns existed at the above sites: (1) the numbers of gene mutations occurring between different exons of UGT1A1 was related to GS or CNS phenotypes, and were positively correlated with the length of the exon; (2) nonsense point mutations was mainly occurred in type I of CNS; (3) GS, Crigler-Najjar syndrome type II compound heterozygous mutation sites had a certain combination and distribution, among which - 3279t > G mutation was found in all four GS complex heterozygous compositions; (4) UGT1A1 gene mutation sites reported in Asia had marked aggregation in c.211-c.558. Conclusion: UGT1A1 gene mutation characteristics and clinical relevance varies with different mutation sites, reporting areas and populations. This study has reference value for basic research and clinical diagnosis and treatment of GS and CNS.	0
Neutrophil disorders are an uncommon yet important cause of morbidity and mortality in infants and children. This article is an overview of these conditions, with emphasis on clinical recognition, rational investigation, and treatment. A comprehensive list of references is provided for further reading.	0
Background:Angle closure glaucoma (ACG) whether primary or secondary lens induced has rare occurrence in cases with retinitis pigmentosa (RP). Method:Five patients with history of diminished vision, ocular pain, and nyctalopia were clinically evaluated. Four patients had unilateral presentations of circumciliary congestion, corneal edema, and high intraocular pressure (IOP), while one had bilateral presentation, respectively. Anterior chambers were shallow; fundoscopy revealed the features of RP and gonioscopy affirmed closed angles in all the cases. The management strategies were individualized based on the specific ocular condition. Result:The raised IOP were not well controlled with conventional medical treatment. Neodymium yttrium aluminium garnet laser peripheral iridotomy (LPI) was performed in two patients and in the fellow eye in other two patients as a prophylactic measure. Phacoemulsification surgery with implantation of intraocular lens (IOL) was performed in three patients, whereas phacoemulsification only without IOL and trabeculectomy performed in one patient. Among them, two patients had subluxated lens, where one was managed with capsular tension ring and the other was left aphakic, respectively. However, the vision was not improved significantly in these patients. Conclusion:RP may be associated with ACG in rare instances. In these patients, angle closure-related high IOP can have a detrimental effect on the pre-existing visual impairment. However, this can be prevented by thorough clinical examination and timely intervention in those susceptible eyes.	0
Electroconvulsive therapy (ECT) is an increasingly popular treatment for drug-resistant depression that may have utility for some patients with neuroleptic malignant syndrome (NMS) who are unresponsive to pharmacotherapy. Using a case study as an example, this article discusses the diagnosis of a patient with NMS, the use of ECT as a treatment for NMS, and the importance of nursing care for these patients.	0
Obesity is a metabolic disorder that results from complex interactions between genetic predisposition and dietary factors. Interleukin-4 (IL-4), besides its role in immunity, has metabolic effects on insulin efficacy. We studied the effects of IL-4 on metabolic abnormalities in a mice model of obesity involving leptin deficiency and leptin resistance. Leptin-deficient 145E and leptin-resistant high-fat diet (HFD) mice showed lower levels of circulating IL-4. 145E and HFD mice showed a number of abnormalities: Obesity, hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, liver injury, and adiposity with concurrent inflammation, decreases in Akt, signal transducer and activator of transcription 3 (STAT3), and STAT6 phosphorylation in the hypothalamus, liver, and epididymal fat. Independent of leptin-deficient obesity and dietary obesity, a course of 8-week IL-4 supplementation improved obesity and impairment in Akt, STAT3, and STAT6 signaling. Amelioration of cytokine expression, despite variable extents, was closely linked with the actions of IL-4. Additionally, the browning of white adipocytes by IL-4 was found in epididymal white adipose tissues and 3T3-L1 preadipocytes. Chronic exercise, weight management, and probiotics are recommended to overweight patients and IL-4 signaling is associated with clinical improvement. Thus, IL-4 could be a metabolic regulator and antiobesity candidate for the treatment of obesity and its complications.	0
Bowenoid papulosis (BP) is a premalignant condition usually caused by oncogenic types of human papillomavirus (HPV) presenting clinically as warty genital papules. Adult T-cell leukaemia-lymphoma (ATLL) is a peripheral T-cell leukaemia-lymphoma caused by the retrovirus, human T-cell lymphotropic virus 1 (HTLV-1). We report a case of BP initially mistaken as genital warts; on detailed evaluation the patient had features of chronic immunosuppression. The presence of leukaemic cells in the peripheral blood, bone marrow and skin along with a positive HTLV-1 serology confirmed the diagnosis of ATLL.	0
INTRODUCTION:The aim of this study is to compare immediate and long-term obstetrical outcomes of patients who underwent cesarean delivery with and without uterine artery embolization (UAE) for the management of placenta accreta spectrum disorder. MATERIAL AND METHODS:A retrospective case control study including all pregnant women admitted to a single tertiary medical center between December 2001 and May 2018 with a diagnosis of placenta accreta spectrum disorder, who underwent cesarean delivery with and without UAE. Groups were compared for maternal characteristics, operative management, postoperative complication rate and long-term outcomes. Follow up on future obstetrical outcomes was conducted via telephone questionnaire. Non-parametric statistics were used. RESULTS:During the study period, 272 women met the inclusion criteria: 64 (23.53%) and 208 (76.47%) underwent preservative cesarean section with and without UAE, respectively. UAE procedure was associated with a longer operative time (82.5 [68-110] vs 50.5 [39-77] minutes; P = .001), and higher blood loss (2000 (1500-3000) vs 1000 (600-2000) mL; P = .001). Hysterectomy rate was comparable between the groups (9 [14%] vs 35 [16.82%]; P = .88); however, multivariate logistic regression analysis found UAE to be an independent factor associated with lower hysterectomy rate (P = .02). Postoperative complications were more frequent in the UAE group. Follow up was achieved in 29 (59.18%) and 72 (51.79%) of the women with and without UAE, respectively (P = .36). No differences were found in rate of abortions, pregnancy and deliveries between the groups. CONCLUSIONS:Cesarean delivery using UAE in placenta accreta spectrum disorder is associated with a higher rate of operative and postoperative complications. Nevertheless, in cases of severe adherence of the placenta, embolization reduces the need for hysterectomy, allowing future fertility.	0
The mongolian spot, nevus of Ota, and nevus of Ito are the most common morphologic forms of the dermal melanocytoses, a group of benign pigmented lesions histologically characterized by the presence of melanocytes within the dermis. Nevus of Ito is clinically distinct, presenting with unilateral, bluish gray, patchy discolorations in the skin within the distributions of the posterior supraclavicular and lateral cutaneous brachial nerves. Although all dermal melanocytoses are generally considered benign, rare cases of malignant transformation associated with nevus of Ota have been described. Only one case of malignant melanoma transformation in association with nevus of Ito has previously been reported. We present the second description of malignant melanoma transformation within a nevus of Ito and provide comment on the malignant potential of the dermal melanocytoses.	0
OBJECTIVES:The present study was carried out to evaluate the effectiveness of medical therapy with potassium citrate in preventing calculosis complicating Medullary Sponge Kidney (MSK) without renal acidification defects. MATERIALS AND METHODS:In a open, uncontrolled, retrospective analysis, 49 MSK patients with nephrolithiasis without renal tubular acidosis, underwent a complete metabolic evaluation and received potassium citrate therapy 4-6 g/day. The course of stone disease before and after citrate therapy was determined in each patient from a combination of clinical history, past records, radiographs and kidney ultrasound. The rate of new stone formation/pt/yr, of endourological and extracorporeal procedures, of urinary tract infection (UTI) and number of hospitalization before and after medical treatment were calculated. RESULTS:Metabolic anomalies (hypercalciuria, hypocitraturia, hyperuricuria and hyperoxaluria) were present in 83% of the patients. Follow-up before and after alkali citrate therapy was comparable (4.7+/-1.4 and 4.9+/-1.7 years respectively). Medical treatment significantly reduced rates of stone formation from 2.0+/-1.0 to 0.2+/-0.5 pt/yr, ureteroscopy (URS) from 0.9+/0.8 to 0.4+/-0.5 pt/yr, extratracoporeal lithotripsy (ESWL) from 1.1+/-0.8 to 0.4+/-0.6 pt/yr, urinary tract infections (UTIs) from 0.8+/-1.2 to 0.3+/-0.5 pt/yr and hospitalization from 1.1+/-0.6 to 0.2+/-0.3 pt/yr, p < 0.001. This effect was observed also in MSK patients without metabolic anomalies. In 35 patients the asymptomatic disappearance of calcium stones was also observed. CONCLUSIONS:Our study documents the effectiveness of potassium citrate therapy in preventing neprolithiasis in MSK patients also in the absence of distal tubular acidosis. It suggests that in MSK patients alkali citrate may promote calcium stone dissolution by oral administration.	0
Purpose:To investigate the association between PAX6 genotype and macular morphology in congenital aniridia. Methods:The study included 37 participants (15 males) with congenital aniridia (aged 10-72 years) and 58 age-matched normal controls (18 males). DNA was isolated from saliva samples. PAX6 exons, intron/exon junctions, and known regulatory regions were amplified in PCR and sequenced. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect larger deletions or duplications in PAX6 or known cis-regulatory regions. Spectral-domain optical coherence tomography images were acquired and segmented semiautomatically. Mean thicknesses were calculated for inner and outer retinal layers within the macula along nasal and temporal meridians. Results:Mutations in PAX6 or regulatory regions were found in 97% of the participants with aniridia. Foveal hypoplasia was observed in all who had a mutation within the PAX6 gene. Aniridic eyes had thinner outer retinal layers than controls, but with large between-individual variation (mean ± SD, 156.3 ± 32.3 µm vs 210.8 ± 12.3 µm, P < 0.001). Parafoveal and perifoveal inner and outer retinal layers were thinner in aniridia. Participants with mutations in noncoding PAX6 regions had thicker foveal outer retinal layers than those with mutations in the PAX6 coding regions (P = 0.04) and showed signs of postnatal development and maturation. Mutations outside the PAX6 gene were associated with the mildest retinal phenotypes. Conclusions:PAX6 mutations are associated with significant thinning of macular inner and outer retinal layers, consistent with misdirected retinal development resulting in abnormal foveal formation and reduced number of neurons in the macula, with mutations in PAX6 coding regions giving the worst outcome.	0
Acute necrotizing encephalopathy of childhood (ANEC) is a disease, characterized by a respiratory or gastrointestinal infection, accompanied with fever, rapid alteration of consciousness, and seizures. The clinical characteristics of ANEC include acute encephalopathy following a viral infection, seizure, altered consciousness, and absence of cerebrospinal fluid (CSF) pleocytosis, with an occasional increase in the level of proteins. This disease is almost exclusively seen in previously healthy infants and children from East Asia. Serial magnetic resonance imaging (MRI) examinations have demonstrated symmetric lesions involving the thalami, brainstem, cerebellum, and white matter. ANEC has a poor prognosis with high morbidity and mortality rates. Herein, we present three cases of ANEC, who were referred to Bu-Ali Hospital of Ardabil, Iran during two weeks. Report of these three cases promoted the idea of an epidemic. The purpose of this case series was to raise the issue that ANEC may occur as an epidemic.	0
1q44 deletion is a rare syndrome associated with facial dysmorphism and developmental delay, in particular related with expressive speech, seizures, and hypotonia (ORPHA:238769). Until today, the distinct genetic causes for the different symptoms remain not entirely clear. We present a patient with a 2.3-Mb 1q44 deletion, including AKT3, ZBTB18, and HNRNPU, who shows microcephaly, developmental delay, abnormal corpus callosum, and seizures. The genetic findings in this case and a review of the literature spotlight a region between 243 Mb and 245 Mb on chromosome 1q related to the genesis of the typical symptoms of 1q44 deletion.	0
Background:Coxa vara is a hip deformity in which the femoral neck-shaft angle decreases below its normal value. Standard surgical treatment for this condition is corrective valgus osteotomy. Appropriate correction of the Hilgenreiner-epiphyseal angle is important to prevent recurrence. The purpose of this study is to: 1) evaluate the recurrence of the deformity at the latest follow up; and 2) find the appropriate angle of correction associated with the lowest recurrence. Methods:34 hips in 31 patients who underwent surgery for treatment of coxa vara from 2005 to 2014 were included. Patient-reported outcomes, Hilgenreiner-epiphyseal angle, and neck-shaft angle were assessed preoperatively, postoperatively, and at latest follow-up. Results:The mean age at surgery was 10.99, with a range of 5-30, years. Preoperative neck-shaft angle ranged from 60 to 100 degrees, and Hilgenreiner-epiphyseal angle ranged from 60 to 90 degrees. At the latest follow up, the neck-shaft angle ranged from 120 to 135 degrees and the Hilgenreiner-epiphyseal angle ranged from 22 to 35 degrees (p < 0.001). The Harris hip score improved from 47.20 (34-66) to 79.68 (60-100) (p < 0.001). There was no recurrence of deformities at the mean follow up of 37.87 months. Conclusion:Surgical correction of coxa vara in various pathologies can be done successfully with the Hilgenreiner-epiphyseal angle corrected to ≤ 35 degrees or the neck shaft angle corrected to > 120 degrees in order to prevent recurrence of the deformity. Majority of the patients were reported improvement of hip function. However, a longer-term follow up is required to determine further outcomes regarding to recurrence of the deformity.	0
Purpose: In this study, the aim was to evaluate the safety of transcorneal electrical stimulation (TES) treatment in retinitis pigmentosa (RP) patients and to investigate the effect of TES to the visual acuity (VA), visual field (VF), and multifocal electroretinogram (mfERG) findings. Methods: Two hundred two eyes of 101 RP patients with different stages were studied. TES was applied for 30 min once a week for 8 consecutive weeks. Two hundred eyes of 100 RP patients were enrolled as control. After the 2-month TES therapy sessions, patients were followed for 4 months without treatment. Examinations were done at the baseline before TES treatment and 1 and 6 months after the treatment. Best-corrected VA (BCVA), color fundus photography, VF test, optical coherence tomography, and mfERG tests were done at each visit. Results: The mean BCVA and VF tests improved 1 month after the beginning of TES treatment and the improvements were statistically significant (P < 0.05). There was an improvement in p1 wave amplitude in rings 1, 2, and 3 at the first month. The latency of the p1 wave showed a statistically significant shortening in rings 1 and 2. These improvements partially disappeared at 6-month follow-up. There were no serious ocular side effects related to the therapy. Mild dry eye symptoms were observed, which were revealed by artificial tears. Conclusions: TES is a safe therapy without any serious advers effects. Although it can improve VA and VF of RP patients, the beneficial effects could be transient and repeated sessions can be necessary for maintaining the efficiency.	0
OBJECTIVE: To examine trends in the incidence of primary, malignant penile cancer in the United States. METHODS AND MATERIALS: A total of 1,817 men with primary, malignant penile cancer diagnosed between 1973 and 2002 from the Surveillance, Epidemiology and End Results Program Public-use data were used for analysis. Incidence rates were calculated by clinical and demographic variables of interest and decade of diagnosis (1973-1982, 1983-1992, and 1993-2002) using Surveillance, Epidemiology and End Results-Stat 6.1, and trends were examined using the annual percent change statistic. Additional incidence calculations were performed to examine further racial/ethnic differences. RESULTS: The overall incidence of primary, malignant penile cancer from 1973 to 2002 was 0.69 per 100,000. Incidence decreased significantly over time: 0.84 per 100,000 in 1973-1982 to 0.69 per 100,000 in 1982-1992 to 0.58 per 100,000 in 1993-2002. Incidence increased with increasing age at diagnosis. The majority of cases had squamous cell carcinomas, graded as I or II, and originated at the glans penis. Incidence of unknown grade primary, malignant penile cancer decreased significantly over the last 30 years, as did incidence of primary site penis, not otherwise specified primary, malignant penile cancer. The incidence of regional stage disease also increased over time. From 1993 to 2002, White Hispanics had the highest incidence rates (1.01 per 100,000) followed by Alaska Native/American Indians (0.77 per 100,000) and Blacks (0.62 per 100,000). CONCLUSIONS: The overall incidence of primary, malignant penile cancer in the United States has decreased, and these rates varied by race/ethnicity. Incidence rates increased with increasing age at diagnosis, and the incidence of regional stage disease increased over time, while incidence of unknown grade primary, malignant penile cancer decreased over the last 30 years.	1
The 21st century is an exciting time to be in the field of metabolic medicine. As with many fields, one of the keys to anticipating the future is to understand the past. The term "inborn error of metabolism" was first coined in 1908 by Sir Archibald Garrod, in reference to four disorders (alkaptonuria, pentosuria, cystinuria and albinism). The first (and still most definitive) textbook on the subject, "The Metabolic Basis of Inherited Disease" was initially published in 1960 and covered 80 disorders in 1,477 pages. After the eighth edition of this text became unwieldy at 6,338 pages in 4 volumes covering more than 1,000 disorders, the book was changed to an online reference text with 259 chapters and is still growing. Current newborn screening on a few dried blood spots on filter paper identifies more than 1 in 2,000 newborns as having a metabolic disorder. The availability of metabolomic and genomic analyses is resulting in the diagnosis of many new disorders. Enzyme replacement therapy (ERT) has provided treatments for previously untreatable metabolic disorders, and the promise of gene therapy on the near horizon will certainly revolutionize the field.	0
OBJECTIVE:To explore the genetic basis for a patient featuring multiple carboxylase deficiency (MCD). METHODS:PCR and Sanger sequencing were used to detect variant in the coding region of BT and HLCS genes in the patient. Suspected variants were verified in her parents and 80 unrelated healthy controls by a PCR-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS:The patient was found to carry compound heterozygous variants of the HLCS gene, namely c.286delG (p.Val96Leufs*162) and c.1648G>A (p.Val550Met). The c.286delG (p.Val96Leufs*162) was verified to be novel variant based on the result of PCR-RFLP analysis. No variant was found in the coding regions of BT gene in the patient. CONCLUSION:The compound c.286delG (p.Val96Leufs*162) and c.1648G>A (p.Val550Met) variants probably underlie the MCD disorder in this patient. Above results have enriched the variant spectrum of MCA.	0
An 18-year-old female tertiary student was referred to a lipid clinic with hypertriglyceridaemia discovered after presentation with acute pancreatitis. The patient's only medication was l-thyroxine for treatment of hypothyroidism. She was overweight, normotensive, with unremarkable facies. However, she had hypermobile hand joints and brachydactyly resulting in loss of left 3-5 and right 4 and 5 knuckle definitions. Radiography revealed shortening of metacarpals 3-5 on the left and 4 and 5 on the right. Her mother had similar skeletal changes, consistent with a dominant mode of inheritance. Abnormally short digits involving the metacarpals, classified as brachydactyly type E, can be isolated or occur as part of a syndrome. Turner syndrome, Albright hereditary osteodystrophy, hypertension with brachydactyly, chromosome 2q37 microdeletion and PTHLH mutations were excluded following clinical, biochemical and genetic testing. No specific treatment was required. Genetic testing for isolated and syndromic forms of brachydactyly facilitates family screening and prepregnancy counselling.	0
BACKGROUND:Perrault syndrome is a genetically heterogenous, very rare disease, characterized clinically by sensorineural hearing loss, ovarian dysfunction and neurological symptoms. We present the case of a 33 years old female patient with TWNK-associated Perrault syndrome. The TWNK gene is coding the mitochondrial protein Twinkle and currently there are only two reports characterizing the phenotype of TWNK-associated Perrault syndrome. None of these publications reported about special brain MRI alterations and neuropathological changes in the muscle and peripheral nerves. CASE PRESENTATION:Our patients with TWNK-dependent Perrault syndrome had severe bilateral hypoacusis, severe ataxia, polyneuropathy, lower limb spastic paraparesis with pyramidal signs, and gonadal dysgenesis. Psychiatric symptoms such as depression and paranoia were present as well. Brain MRI observed progressive cerebellar hyperintensive signs associated with cerebellar, medulla oblongata and cervical spinal cord atrophy. Light microscopy of the muscle biopsy detected severe neurogenic lesions. COX staining was centrally reduced in many muscle fibers. Both muscle and sural nerve electron microscopy detected slightly enlarged mitochondria with abnormal cristae surrounded by lipid vacuoles. In the sural nerve, dystrophic axons had focally uncompacted myelin lamellae present. Genetic investigation revealed multiple mtDNA deletion and compound heterozygous mutations of the TWNK gene (c.1196 A > G, c.1358 G > A). CONCLUSION:This study demonstrates that TWNK associated Perrault syndrome has a much broader phenotype as originally published. The coexistence of severe hypoacusis, spastic limb weakness, ataxia, polyneuropathy, gonadal dysgensia, hyperintense signals in the cerebellum and the presence of the mtDNA multiple deletion could indicate the impairment of the TWNK gene. This is the first report about pyramidal tract involvement and cerebellar MRI alteration associated with TWNK-related Perrault syndrome.	0
BACKGROUND:Predicting drug-disease interactions (DDIs) is time-consuming and expensive. Improving the accuracy of prediction results is necessary, and it is crucial to develop a novel computing technology to predict new DDIs. The existing methods mostly use the construction of heterogeneous networks to predict new DDIs. However, the number of known interacting drug-disease pairs is small, so there will be many errors in this heterogeneous network that will interfere with the final results. RESULTS:A novel method, known as the dual-network L2,1-collaborative matrix factorization, is proposed to predict novel DDIs. The Gaussian interaction profile kernels and L2,1-norm are introduced in our method to achieve better results than other advanced methods. The network similarities of drugs and diseases with their chemical and semantic similarities are combined in this method. CONCLUSIONS:Cross validation is used to evaluate our method, and simulation experiments are used to predict new interactions using two different datasets. Finally, our prediction accuracy is better than other existing methods. This proves that our method is feasible and effective.	0
Unlike disorders of primary cilium, primary ciliary dyskinesia (PCD) has a much narrower clinical spectrum consistent with the limited tissue distribution of motile cilia. Nonetheless, PCD diagnosis can be challenging due to the overlapping features with other disorders and the requirement for sophisticated tests that are only available in specialized centers. We performed exome sequencing on all patients with a clinical suspicion of PCD but for whom no nasal nitric oxide test or ciliary functional assessment could be ordered. Among 81 patients (56 families), in whom PCD was suspected, 68% had pathogenic or likely pathogenic variants in established PCD-related genes that fully explain the phenotype (20 variants in 11 genes). The major clinical presentations were sinopulmonary infections (SPI) (n = 58), neonatal respiratory distress (NRD) (n = 2), laterality defect (LD) (n = 6), and combined LD/SPI (n = 15). Biallelic likely deleterious variants were also encountered in AKNA and GOLGA3, which we propose as novel candidates in a lung phenotype that overlaps clinically with PCD. We also encountered a PCD phenocopy caused by a pathogenic variant in ITCH, and a pathogenic variant in CEP164 causing Bardet-Biedl syndrome and PCD presentation as a very rare example of the dual presentation of these two disorders of the primary and motile cilia. Exome sequencing is a powerful tool that can help "democratize" the diagnosis of PCD, which is currently limited to highly specialized centers.	0
PURPOSE:Chyloperitoneum is an extremely rare finding following myelomeningocele (MMC) repair in neonates. We aimed to describe the characteristics of such a case and explore its clinical significance. CASE REPORT:A male baby born at term with open MMC and hydrocephalus underwent MMC repair surgery with rotational flaps on the first postnatal day. The procedure was uneventful. Three days later, he underwent a right ventriculoperitoneal shunt (VPS) insertion. On opening the peritoneum, a remarkable amount of yellowish opaque fluid was observed. Chyloperitoneum was suspected, but the VPS procedure was completed as planned. Biochemical analysis was consistent with that of chyle. DISCUSSION:Neonatal chylous ascites is a rare condition; hence, available data on pathophysiology and therapy in the literature are scarce. It is postulated that the MMC repair in neonates causes abdominal tautness, which leads to rupture of small lymphatics and raised intraportal pressure. The combination of these two processes results in extravasation of chyle from the gastrointestinal tract. Presence of chyloperitoneum is not a contraindication for VPS insertion. CONCLUSION:Chyloperitoneum is an extremely rare sequela of MMC repair in neonates. Pediatric neurosurgeons should be aware of it, especially when a VPS procedure is to follow a repair, in order to know how to deal with it and avoid unnecessary abandonment of the shunt.	0
Larsen syndrome is chronic debilitating disease that presents with multiple joint dislocations and severely affects the cervical spine in the form of cervical kyphosis and atlantoaxial dislocation. Children usually present in early with a myriad of deficits, compressive myelopathy being the most common. In addition to a bony compression, there is sometimes a soft tissue component, which is seldom addressed. We present here a case of atlantoaxial dislocation with cervical kyphosis due to Larsen syndrome, and along with our previous experience on syndromic atlantoaxial dislocations, we try to define an algorithm for the treatment approach of these onerous challenges. The importance of early intervention is also emphasized with a literature review of similar cases. In addition to the obvious physical damage, early intervention can also avoid the more sinister socioeconomic face of this debilitating disease.	0
Klippel-Trenaunay Syndrome (KTS) is a rare genetic vascular disorder characterized by a limb affected by varicose veins, port wine stains, and hypertrophy of bone and soft tissue. It can also present with vascular malformations in the gastrointestinal tract, liver, spleen, genitourinary tract, and heart. We present a 27-year-old case of KTS diagnosed in adulthood associated with recurrent venous thromboembolism and gastrointestinal bleeding.	0
BACKGROUND:Ring chromosome 20 (R20) syndrome is a chromosomal disorder characterized mainly by drug-resistant frontal lobe seizures, recurrent nonconvulsive status epilepticus (NCSE), and typical EEG features. The aim of this study was to investigate if this triad is common and specific to all patients with R20. METHODS:In this cross-sectional study (from 2000 to 2011), we selected patients who fulfilled at least two out of three criteria: drug-resistant frontal lobe seizures, recurrent NCSE, and characteristic electroencephalography (EEG) features. In all patients, diagnosis was based on karyotype analysis of at least 100 metaphases. RESULTS:We identified 36 patients who met at least two of the selected criteria: six patients (16.7%) with R20 and 30 (83.3%) without R20 (non-R20). All patients with R20 met all three criteria. Eleven (36.7%) patients without R20, however, also displayed the full triad. In 19 patients without R20 (63.3%), one of the three clinical features was missing: frontal lobe seizures were not resistant to antiepileptic drugs (AED) in four (13.3%), recurrent NCSE was missing in six (20%), and nine (30%) patients did not have typical EEG features. Based on this data, specificity was 63.3%, positive predictive value was 35.3%, and sensitivity and negative predictive values were 100%. Additionally, a review of all publications describing the R20 phenotype revealed that 81.98% of patients with R20 display the full electroclinical triad. CONCLUSIONS:In our study, all patients with R20 displayed the three electroclinical characteristics. This is in line with previous reports (presenting high sensitivity and negative predictive value). However, these features can also be observed in other epilepsies and are not specific to R20. Our findings suggest that in the presence of the full triad of symptoms, karyotype analysis focused on chromosome 20 should be conducted.	0
Short stature is a common and heterogeneous condition that is often genetic in etiology. For most children with genetic short stature, the specific molecular causes remain unknown; but with advances in exome/genome sequencing and bioinformatics approaches, new genetic causes of growth disorders have been identified, contributing to the understanding of the underlying molecular mechanisms of longitudinal bone growth and growth failure. Identifying new genetic causes of growth disorders has the potential to improve diagnosis, prognostic accuracy, and individualized management, and help avoid unnecessary testing for endocrine and other disorders.	0
In Denmark, the Faroe Islands, and Greenland, comprehensive screening of newborns for phenylketonuria and congenital hypothyroidism has been carried out for 20 years. The screening programme has detected 98 and 356 patients, respectively, corresponding to incidences of 1:12,000 and 1:3,400. The future savings on health care expenditures resulting from one year of neonatal screening are estimated to be 196 million DKK in present day value, which is 28 times higher than the cost of screening. The screening samples are stored in a biobank, which is used in diagnosis of congenital diseases and infant deaths and for development of future screening methods. It is desirable to expand the existing screening programme to include a range of rare inherited metabolic diseases, which collectively are frequent. This is realistic with the advent of tandem mass spectrometry, which allows cost-effective simultaneous screening for a group of inborn errors of metabolism.	1
Importance:Impairment of dopaminergic transmission may contribute to cognitive dysfunction in Alzheimer disease (AD). Objective:To investigate whether therapy with dopaminergic agonists may affect cognitive functions in patients with AD. Design, Setting, and Participants:This phase 2, monocentric, randomized, double-blind, placebo-controlled trial was conducted in Italy. Patients with mild to moderate AD were enrolled between September 1, 2017, and December 31, 2018. Data were analyzed from July 1 to September 1, 2019. Interventions:A rotigotine 2 mg transdermal patch for 1 week followed by a 4 mg patch for 23 weeks (n = 47) or a placebo transdermal patch for 24 weeks (n = 47). Main Outcomes and Measures:The primary end point was change from baseline on the Alzheimer Disease Assessment Scale-Cognitive Subscale. Secondary end points were changes in Frontal Assessment Battery, Alzheimer Disease Cooperative Study-Activities of Daily Living, and Neuropsychiatric Inventory scores. Prefrontal cortex activity was evaluated by transcranial magnetic stimulation combined with electroencephalography. Results:Among 94 patients randomized (mean [SD] age, 73.9 [5.6] years; 58 [62%] women), 78 (83%) completed the study. Rotigotine, as compared with placebo, had no significant effect on the primary end point: estimated mean change in Alzheimer Disease Assessment Scale-Cognitive Subscale score was 2.92 (95% CI, 2.51-3.33) for the rotigotine group and 2.66 (95% CI, 2.31-3.01) for the placebo group. For the secondary outcomes, there were significant estimated mean changes between groups for Alzheimer Disease Cooperative Study-Activities of Daily Living score (-3.32 [95% CI, -4.02 to -2.62] for rotigotine and -7.24 [95% CI, -7.84 to -6.64] for placebo) and Frontal Assessment Battery score (0.48 [95% CI, 0.31 to 0.65] for rotigotine and -0.66 [95% CI, -0.80 to -0.52] for placebo). There was no longitudinal change in Neuropsychiatric Inventory scores (1.64 [95% CI, 1.06-2.22] for rotigotine and 1.26 [95% CI, 0.77-1.75] for placebo group). Neurophysiological analysis of electroencephalography results indicated that prefrontal cortical activity increased in rotigotine but not in the placebo group. Adverse events were more common in the rotigotine group, with 11 patients dropping out compared with 5 in the placebo group. Conclusions and Relevance:In this randomized clinical trial, rotigotine treatment did not significantly affect global cognition in patients with mild to moderate AD; however, improvement was observed in cognitive functions highly associated with the frontal lobe and in activities of daily living. These findings suggest that treatment with the dopaminergic agonist rotigotine may reduce symptoms associated with frontal lobe cognitive dysfunction and thus may delay the impairment of activities of daily living. Trial Registration:ClinicalTrials.gov Identifier: NCT03250741.	0
OBJECTIVE:Immunotherapy revolutionized melanoma treatment; however, immune-related adverse events, especially neurotoxicity, may be severe and require early and correct diagnosis as well as early treatment commencement. METHODS:We report an unusual severe multiorgan manifestation of neurotoxicity after treatment with the anti-PDL1 immune checkpoint inhibitor, nivolumab, and the anticytotoxic T-lymphocyte-associated antigen 4 immune checkpoint inhibitor, ipilimumab, in a 47-year-old male patient with metastatic melanoma. RESULTS:The patient developed immune-mediated synovitis and cranial neuritis, followed by longitudinal transverse myelitis, encephalitis, and optic neuritis. Early treatment with high-dose steroids and maintenance therapy with rituximab resulted in a favorable neurologic outcome. CONCLUSIONS:The frequency of spinal cord involvement and neuronal toxicity after cancer immunotherapy is very low and requires an extensive diagnostic workup to differentiate between disease progression and side effects. Immune checkpoint inhibitors should be discontinued and treatment with corticosteroids should be initiated early as the drug of first choice. Therapy may be escalated by other immune-modulating treatments, such as rituximab.	0
A boy is presented with frontofacionasal dysplasia. The severity of his malformations exceeds that encountered in the cases described previously. The range of clinical abnormality seen in this disorder is reviewed and the delineation of the condition as a separate entity is explored.	0
Melnick-Needles syndrome (M-NS) is a rare genetic disorder which primarily affects skeletal developments. M-NS may also affect the cardiorespiratory and renal systems. A 35 kg patient presented complaining of abdominal pain. Following a positive pregnancy test and ultrasound examination, she was diagnosed with a ruptured ectopic pregnancy. She had a significant background history of M-NS, obstructive sleep apnoea (with narrow gauge tracheostomy in situ), obstructive lung disease and scoliosis. She received fluid resuscitation, and the case was managed using an open salpingectomy and clot evacuation under combined spinal/epidural anaesthesia. Anticipated difficulty in securing a definitive airway was pivotal to choosing a regional anaesthetic technique. The operation was successful and the patient recovered well. This was a unique surgical and anaesthetic challenge due to abnormal facial, spinal and abdominal morphology compounded by the time-critical emergency nature of the case. Individually tailored perioperative management is frequently required for patients with rare syndromes.	0
Pneumocephalus is usually induced by trauma, infections, tumors of the skull base, and surgical interventions. Spontaneous pneumocephalus occurs due to a defect in the temporal bone with no obvious cause. Few cases have been reported with spontaneous otogenic pneumocephalus. However, delayed postoperative pneumocephalus is rarely reported in the literature. Here, we present a case of otogenic pneumocephalus through Eustachian tube (ET) preceded by nose blowing 10 days after surgical treatment of meningoencephalocele of the right middle ear (ME) cleft and reconstruction of tegmen and dural defects. Pneumocephalus was provoked by decreased intracranial pressure (ICP) secondary to placement of lumbar drain, which caused direct communication between unsutured dural defect and the defective posterior wall of external auditory canal skin. A revision surgery of combined transmastoid/middle cranial fossa approach was performed for intracranial decompression followed by appropriate closure by suturing the dura, obliterating the ET and ME.	0
A 61-year-old Japanese man with the pure spinal form of cerebrotendinous xanthomatosis developed dysesthesia of the lower limbs and gait disturbance at 57 years of age. At 61 years old, he was unable to walk without support. A neurological examination showed spasticity and sensory disturbance in the lower limbs. Spinal MRI showed long hyperintense lesions involving the lateral and posterior funiculus in the cervical and thoracic cord on T2-weighted images. His serum cholestanol level was markedly elevated. A CYP27A1 gene analysis identified two missense variants, p.R474W, and a novel p.R262C variant. Combination therapy with chenodeoxycholic acid and HMG-CoA reductase decreased his serum cholestanol level.	0
Importance:The effectiveness of afamelanotide treatment in patients with erythropoietic protoporphyria (EPP) in clinical practice who experience pain after light exposure that substantially impairs quality of life is unknown. Objective:To evaluate the association of afamelanotide treatment with outcomes in patients with EPP in regular practice during longer-term follow-up. Design, Setting, and Participants:This single-center, prospective postauthorization safety and efficacy cohort study was directed and approved by the European Medicines Agency. Data were collected from patients with EPP treated with afamelanotide at Erasmus MC between June 2016 and September 2018. Analysis began October 2018. Main Outcomes and Measures:Time spent outside during treatment, number of phototoxic reactions, disease-specific quality of life, usage of protective clothing, and adverse events. Results:A total of 117 patients with EPP (59 women [50.4%]; mean [SD] age, 43.0 [15.5] years) were treated with afamelanotide. Nearly all patients continued treatment (115 [98%]) with a median (interquartile range) follow-up of 2.0 (1.3-2.1) years. Compared with baseline, mean time spent outside during treatment increased significantly by an added 6.1 hours per week (95% CI, 3.62-8.67; P < .001). Mean quality of life score improved significantly by 14.01% (95% CI, 4.53%-23.50%; P < .001). Phototoxic reactions were less painful (β, -0.85; 95% CI, -1.43 to -0.26; P < .001), but there was no significant difference in number or duration of reactions. Minor self-limiting adverse events occurred, such as nausea, fatigue, and headache. Conclusions and Relevance:This cohort study found that afamelanotide treatment was associated with improved clinical outcomes and a good safety profile for patients with EPP. The treatment has clinically significant, sustained positive associations with quality of life, is associated with increased duration of sun exposure, and is associated with less severe phototoxic reactions.	0
Ichthyosis – also called fish scale disease – is a group of skin diseases, which are characterised by xerosis and scaling. Most commonly, the diseases are genetically inherited, but an acquired type also exists. Ichthyosis vulgaris (IV), is the most common type, affecting 1:250 individuals. Diagnosing IV can be challenging, because its clinical features are subject to great variation, ranging from mild cases with slight xerosis to severe cases with marked scaling and formation of fissures. In this review, IV and its most relevant differential diagnoses, X-linked ichthyosis, autosomal recessive congenital ichthyosis and acquired ichthyosis are reviewed.	0
Singleton Merten syndrome (SMS) is a rare autosomal dominant genetic disorder with variable expression. Its characteristic features include abnormal aortic calcification, abnormal ossification of extremities, and dental anomalies. We present a young man with dyspnea who was noted to have aortic stenosis in the background of glaucoma, psoriasis, dental anomalies, hand and foot deformities, Achilles tendinitis, osteopenia, and nephrolithiasis. The conglomeration of features led to the diagnosis of SMS. His mother had a very similar phenotype.	0
Gaucher disease (GD) is caused by insufficient activity of acid β-glucosidase (GCase) resulting from mutations in GBA1. To understand the pathogenesis of the neuronopathic GD, induced pluripotent stem cells (iPSCs) were generated from fibroblasts isolated from three GD type 2 (GD2) and 2 unaffected (normal and GD carrier) individuals. The iPSCs were converted to neural precursor cells (NPCs) which were further differentiated into neurons. Parental GD2 fibroblasts as well as iPSCs, NPCs, and neurons had similar degrees of GCase deficiency. Lipid analyses showed increases of glucosylsphingosine and glucosylceramide in the GD2 cells. In addition, GD2 neurons showed increased α-synuclein protein compared to control neurons. Whole cell patch-clamping of the GD2 and control iPSCs-derived neurons demonstrated excitation characteristics of neurons, but intriguingly, those from GD2 exhibited consistently less negative resting membrane potentials with various degree of reduction in action potential amplitudes, sodium and potassium currents. Culture of control neurons in the presence of the GCase inhibitor (conduritol B epoxide) recapitulated these findings, providing a functional link between decreased GCase activity in GD and abnormal neuronal electrophysiological properties. To our knowledge, this study is first to report abnormal electrophysiological properties in GD2 iPSC-derived neurons that may underlie the neuropathic phenotype in Gaucher disease.	0
INTRODUCTION:Congenital hypoplasia of the depressor anguli oris muscle is a rare mimic disorder depicted by a lower lip asymmetry apparent when laughing or crying. PRESENTATION OF CASE:A 10-year-old boy consulted our department for an asymmetry when opening his mouth. According to the family, this asymmetry was present since birth. Perinatal characteristics and childhood medical history were investigated with no abnormalities. Physical exam revealed an inability to draw down the right lower lip unilaterally. At rest position, facial asymmetry was not noticeable. Several investigations were done: A CT scan of the petrous part of the temporal bone, an MRI of soft tissues, an electromyography and a heart ultrasound. No anomalies were found. DISCUSSION:This condition has stimulated great interest because of its potential association with congenital anomalies but also in order to reassure families often worried by the situation. A large therapeutic armamentarium is described in literature. CONCLUSION:Among the large armamentarium of therapeutic options, we opted for a wait and see strategy through photographic smile tracking leading to an evidence of Asymmetric crying faces over time improvement.	0
Although there is increasing importance placed on the use of mathematical models for the effective design and management of long-term parasite elimination, it is becoming clear that transmission models are most useful when they reflect the processes pertaining to local infection dynamics as opposed to generalized dynamics. Such localized models must also be developed even when the data required for characterizing local transmission processes are limited or incomplete, as is often the case for neglected tropical diseases, including the disease system studied in this work, viz. lymphatic filariasis (LF). Here, we draw on progress made in the field of computational knowledge discovery to present a reconstructive simulation framework that addresses these challenges by facilitating the discovery of both data and models concurrently in areas where we have insufficient observational data. Using available data from eight sites from Nigeria and elsewhere, we demonstrate that our data-model discovery system is able to estimate local transmission models and missing pre-control infection information using generalized knowledge of filarial transmission dynamics, monitoring survey data, and details of historical interventions. Forecasts of the impacts of interventions carried out in each site made by the models estimated using the reconstructed baseline data matched temporal infection observations and provided useful information regarding when transmission interruption is likely to have occurred. Assessments of elimination and resurgence probabilities based on the models also suggest a protective effect of vector control against the reemergence of LF transmission after stopping drug treatments. The reconstructive computational framework for model and data discovery developed here highlights how coupling models with available data can generate new knowledge about complex, data-limited systems, and ultimately support the effective management of disease programs in the face of critical data gaps.	0
PURPOSE:This study aimed to examine pathogenic mutation within one Chinese family of five-generations suffering from autosomal dominant cataract. METHODS:Next-generation sequencing and Sanger sequencing were used to find the pathogenic variants. RESULTS:A rare mutation, c.563G > A, in CRYBB2 gene was found in the proband that showed symptom of non-syndromic congenital autosomal dominant cataract. This mutation had been found in all affected individuals and in one healthy infant, but it did not exist between two individuals who did not develop such disease in that family, as well as in 100 healthy subjects who showed no relation with that family. Cataracts in this family varied with different severity of lens opacities and elongation of axial length. CONCLUSION:One missense mutation c.563G > A is reported in the CRYBB2 gene among one Chinese family suffering from early-onset cataract, and associated novel phenotypes are the elongation of axial length and the types of cataract. Our results expand the spectrum of associated phenotypes of CRYBB2 mutation.	0
Ischemic colitis and proctitis is a rare manifestation of systemic lupus erythematosus (SLE) and results from mesenteric vasculitis. Owing to diverse blood supply and presence of multiple collaterals, rectum is the least effected site in SLE enteritis. Ischemic proctocolitis as the presenting feature of SLE is exceedingly rare, with only three cases reported in the published scientific literature. We present the first case of SLE presenting as ischemic proctitis, leading to intraperitoneal hemorrhage and abdominal compartment syndrome. A young lady presented with ischemic proctitis and a hematoma masquerading as a pelvic mass, with subsequent development of massive intraperitoneal hemorrhage, shock, and rectal perforation. The patient required urgent surgery and was initiated on high-dose steroids.	0
Background: REEP1 is a common cause of autosomal dominant hereditary spastic paraplegia (HSP) but is rare in China. The pathological mechanism of REEP1 is not fully understood. Methods: We screened for REEP1 mutations in 31 unrelated probands from Chinese HSP families using next-generation sequencing targeting pathogenic genes for HSP and other related diseases. All variants were validated by Sanger sequencing. The proband family members were also screened for variants for the segregation analysis. All previously reported REEP1 mutations and cases were reviewed to clarify the genetic and clinical features of REEP1-related HSP. Results: A pathogenic mutation, REEP1c. 125G>A (p.Trp42*), was detected in a pure HSP family from North China out of 31 HSP families (1/31). This locus, which is located in the second hydrophobic domain of REEP1, is detected in both Caucasian patients with complicated HSP phenotypes and Chinese pure HSP families. Conclusion: REEP1-related HSP can be found in the Chinese population. The 42nd residue is a novel transethnic mutation hotspot. Mutations in this spot can lead to both complicated and pure form of HSP. Identification of transethnic hotspot will contribute to clarify the underlying pathological mechanisms.	0
Background and Purpose:Behavioral variant frontotemporal dementia (bvFTD) is a subtype of frontotemporal dementia, which has clinical symptoms of progressive personality and behavioral changes with deterioration of social cognition and executive functions. The pathology of bvFTD is known to be tauopathy or TDP-43 equally. We analyzed the 18F-THK5351 positron emission tomography (PET) scans, which were recently developed tau PET, in patients with clinically-diagnosed bvFTD. Methods:Forty-eight participants, including participants with behavioral variant frontotemporal dementia (bvFTD, n=3), Alzheimer's disease (AD, n=21) and normal cognition (NC, n=24) who completed 3T magnetic resonance images, 18F-THK5351 PET scans, and detailed neuropsychological tests were included in the study. Voxel-wise statistical analysis and region of interest (ROI)-based analyses were performed to evaluate the retention of THK in bvFTD patients. Results:In the voxel-based and ROI-based analyses, patients with bvFTD showed greater THK retention in the prefrontal, medial frontal, orbitofrontal, anterior cingulate, insula, anterior inferior temporal and striatum regions compared to NC participants. Left-right asymmetry was noted in the bvFTD patients. A patient with extrapyramidal symptoms showed much greater THK retention in the brainstem. Conclusions:The distribution of THK retention in the bvFTD patients was mainly in the frontal, insula, anterior temporal, and striatum regions which are known to be the brain regions corresponding to the clinical symptoms of bvFTD. Our study suggests that 18F-THK5351 PET imaging could be a supportive tool for diagnosis of bvFTD.	0
Downbeat nystagmus (DBN) is a frequent form of acquired persisting central fixation nystagmus, often associated with other cerebellar ocular signs, such as saccadic smooth pursuit or gaze-holding deficits. Despite its distinct clinical features, the underlying etiology of DBN often remains unclear. Therefore, a genome-wide association study (GWAS) was conducted in 106 patients and 2609 healthy controls of European ancestry to identify genetic variants associated with DBN. A genome-wide significant association (p < 5 × 10-8) with DBN was found for a variation on chromosome 13 located within the fibroblast growth factor 14 gene (FGF14). FGF14 is expressed in Purkinje cells (PCs) and a reduction leads to a decreased spontaneous firing rate and excitability of PCs, compatible with the pathophysiology of DBN. In addition, mutations in the FGF14 gene cause spinocerebellar ataxia type 27. Suggestive associations (p < 1 × 10-05) could be detected for 15 additional LD-independent loci, one of which is also located in the FGF14 gene. An association of a region containing the dihydrofolate reductase (DHFR) and MutS Homolog 3 (MSH3) genes on chromosome 5 was slightly below the genome-wide significance threshold. DHFR is relevant for neuronal regulation, and a dysfunction is known to induce cerebellar damage. Among the remaining twelve suggestive associations, four genes (MAST4, TPPP, FTMT, and IDS) seem to be involved in cerebral pathological processes. Thus, this GWAS analysis has identified a potential genetic contribution to idiopathic DBN, including suggestive associations to several genes involved in postulated pathological mechanisms of DBN (i.e., impaired function of cerebellar PCs).	0
This is a first case report of a patient with hypohidrotic ectodermal dysplasia from Oman, who was found to carry a mutation in the EDAR gene after candidate gene selection based on regions of homozygosity in his genome.	0
Split-hand/foot malformation (SHFM) is a genetic limb anomaly disturbing the central rays of the autopod. SHFM is a genetically heterogeneous disorder with variable expressivity inherited as syndromic and nonsyndromic forms. We provide an update of the clinical and molecular aspects of nonsyndromic SHFM. This rare condition is highly complex due to the clinical variability and irregular genetic inheritance observed in the affected individuals. Nonsyndromic SHFM types have been reviewed in terms of major molecular genetic alterations reported to date. This updated overview will assist researchers, scientists, and clinicians in making an appropriate molecular diagnosis, providing an accurate recurrence risk assessment, and developing a management plan.	0
A frameshift (fs) mutation in the natriuretic peptide precursor A (NPPA) gene, encoding a mutant atrial natriuretic peptide (Mut-ANP), has been linked with familial atrial fibrillation (AF) but the underlying mechanisms by which the mutation causes AF remain unclear. We engineered 2 transgenic (TG) mouse lines expressing the wild-type (WT)-NPPA gene (H-WT-NPPA) and the human fs-Mut-NPPA gene (H-fsMut-NPPA) to test the hypothesis that mice overexpressing the human NPPA mutation are more susceptible to AF and elucidate the underlying electrophysiologic and molecular mechanisms. Transthoracic echocardiography and surface electrocardiography (ECG) were performed in H-fsMut-NPPA, H-WT-NPPA, and Non-TG mice. Invasive electrophysiology, immunohistochemistry, Western blotting and patch clamping of membrane potentials were performed. To examine the role of the Mut-ANP in ion channel remodeling, we measured plasma cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity in the 3 groups of mice. In H-fsMut-NPPA mice mean arterial pressure (MAP) was reduced when compared to H-WT-NPPA and Non-TG mice. Furthermore, injection of synthetic fs-Mut-ANP lowered the MAP in H-WT-NPPA and Non-TG mice while synthetic WT-ANP had no effect on MAP in the 3 groups of mice. ECG characterization revealed significantly prolonged QRS duration in H-fsMut-NPPA mice when compared to the other two groups. Trans-Esophageal (TE) atrial pacing of H-fsMut-NPPA mice showed increased AF burden and AF episodes when compared with H-WT-NPPA or Non-TG mice. The cardiac Na+ (NaV1.5) and Ca2+ (CaV1.2/CaV1.3) channel expression and currents (INa, ICaL) and action potential durations (APD90/APD50/APD20) were significantly reduced in H-fsMut-NPPA mice while the rectifier K+ channel current (IKs) was markedly increased when compared to the other 2 groups of mice. In addition, plasma cGMP levels were only increased in H-fsMut-NPPA mice with a corresponding reduction in plasma cAMP levels and PKA activity. In summary, we showed that mice overexpressing an AF-linked NPPA mutation are more prone to develop AF and this risk is mediated in part by remodeling of the cardiac Na+, Ca2+ and K+ channels creating an electrophysiologic substrate for reentrant AF.	0
PURPOSE OF REVIEW:Duchenne muscular dystrophy is one of many neuromuscular disorders, but it frequently causes severe disability early in life and early death. Cardiac involvement is an important cause of morbidity and mortality. RECENT FINDINGS:Heart disease in Duchenne muscular dystrophy can include a cardiomyopathy leading to end-stage heart failure along with associated supraventricular and ventricular arrhythmias. This article reviews the diagnosis and treatment of heart disease in Duchenne muscular dystrophy as well as emerging therapies.	0
Human T-lymphotropic virus type 1 (HTLV-1) is associated with adult T cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is an inflammatory disease of the spinal cord and clinically characterized by progressive spastic paraparesis, urinary incontinence, and mild sensory disturbance. The interaction between the host immune response and HTLV-1-infected cells regulates the development of HAM/TSP. HTLV-1 preferentially infects CD4+ T cells and is maintained by proliferation of the infected T cells. HTLV-1-infected cells rarely express viral antigens in vivo; however, they easily express the antigens after short-term culture. Therefore, such virus-expressing cells may lead to activation and expansion of antigen-specific T cell responses. Infected T cells with HTLV-1 and HTLV-1-specific CD8+ cytotoxic T lymphocytes invade the central nervous system and produce various proinflammatory cytokines and chemokines, leading to neuronal damage and degeneration. Therefore, cellular immune responses to HTLV-1 have been considered to play important roles in disease development of HAM/TSP. Recent studies have clarified the viral strategy for persistence in the host through genetic and epigenetic changes by HTLV-1 and host immune responses including T cell function and differentiation. Newly developed animal models could provide the opportunity to uncover the precise pathogenesis and development of clinically effective treatment. Several molecular target drugs are undergoing clinical trials with promising efficacy. In this review, we summarize recent advances in the immunopathogenesis of HAM/TSP and discuss the perspectives of the research on this disease.	0
The nonenveloped polyomavirus simian virus 40 (SV40) must penetrate the host endoplasmic reticulum (ER) membrane to enter the cytosol in order to promote infection. How this is accomplished is not entirely clear. Here, we demonstrate that the cytosolic chaperone Ubiquilin4 (Ubqln4) binds directly to the ER membrane J proteins B12 and B14. Strategically localized at the ER-cytosol interface, Ubqln4 captures SV40 emerging from the ER, thereby facilitating escape of the virus from the ER into the cytosol, which leads to infection. Strikingly, Ubqln4 engages the J proteins in a J-domain-independent manner, in contrast to the previously reported Hsc70-Hsp105-SGTA-Bag2 cytosolic complex that also mediates SV40 ER-to-cytosol transport. Our results also reveal that the H domain and STI1 motif (1-2) of Ubqln4 support J protein binding, essential for SV40 infection. Together, these data further clarify the molecular basis by which a nonenveloped virus escapes a host membrane during infectious entry.IMPORTANCE How a nonenveloped virus escapes from a host membrane to promote infection remains enigmatic. In the case of the nonenveloped polyomavirus SV40, penetration of the ER membrane to reach the cytosol is a decisive virus infection step. In this study, we found a new host factor called Ubqln4 that facilitates escape of SV40 from the ER into the cytosol, thereby providing a path for the virus to enter the nucleus to cause infection.	0
Recurrent hydatidiform mole is defined as episodes of two molar pregnancies in a female. Often, complete moles only derive androgenic nuclear genome. We described two cases with repeated molar pregnancies attempted to prevent future episodes by performing intracytoplasmic sperm injection (ICSI) and preimplantation genetic diagnosis (PGD) to assess genetic disorders. The first patient had previously six complete molar pregnancies and advised to carry out ICSI with ovum donation to achieve a normal pregnancy. The second case had previously five molar pregnancies and no XY embryos from the ICSI/PGD process. We had to (at the insistence of the patient) transfer XX embryos in this patient which resulted in a complete hydatidiform mole (CHM). Hence, available data based on our patients and previous studies demonstrated that oocyte might play a critical role in the pathophysiology of recurrent hydatidiform mole, while it has not been often considered.	0
The most commonly identified pathogens related to bacterial meningitis are group B streptococcus and gram-negative enteric flora; anaerobic sepsis and meningitis are very rare. We report a case on a preterm and extremely low-birth weight infant who developed meningitis caused by Bacteroides fragilis and his mother who had postpartum sepsis also caused by the same agent.	0
OBJECTIVE: The aim of this study is to examine factors associated with early neonatal (death within first 7 days of birth) and infant (death during the first year of life) mortality among infants born with myelomeningocele. STUDY DESIGN: We examined linked data from the California Perinatal Quality Care Collaborative, vital records, and hospital discharge records for infants born with myelomeningocele from 2006 to 2011. Survival probability was calculated using Kaplan-Meier Product Limit method and 95% confidence intervals (CI) using Greenwood's method; Cox proportional hazard models were used to estimate unadjusted and adjusted hazard ratios (HR) and 95% CI. RESULTS: Early neonatal and first-year survival probabilities among infants born with myelomeningocele were 96.0% (95% CI: 94.1-97.3%) and 94.5% (95% CI: 92.4-96.1%), respectively. Low birthweight and having multiple co-occurring birth defects were associated with increased HRs ranging between 5 and 20, while having congenital hydrocephalus and receiving hospital transfer from the birth hospital to another hospital for myelomeningocele surgery were associated with HRs indicating a protective association with early neonatal and infant mortality. CONCLUSION: Maternal race/ethnicity and social disadvantage did not predict early neonatal and infant mortality among infants with myelomeningocele; presence of congenital hydrocephalus and the role of hospital transfer for myelomeningocele repair should be further examined. KEY POINTS:· Mortality in myelomeningocele is a concern. · Social disadvantage was not associated with death. · Hospital-based factors should be further examined.	0
In Susac syndrome, occlusions of microvessels--presumed to be mediated by an autoimmune response to an as yet unknown antigen--lead to a characteristic clinical triad of CNS dysfunction, branch retinal artery occlusions, and sensorineural hearing impairment. Susac syndrome is considered a rare but important differential diagnosis in numerous neurological, psychiatric, ophthalmological, and ear, nose and throat disorders. Improved understanding of this disorder is crucial, therefore, to ensure that patients receive appropriate treatment and care. Current knowledge on Susac syndrome is largely based on reports of single patients, small case series, and nonsystematic reviews. The aim of this Review is to extend these previous, primarily anecdotal findings by compiling data from all 304 cases of Susac syndrome that have been published worldwide, which were identified following a literature search with predefined search, inclusion and exclusion criteria. From this data, we present an overview of demographic, clinical and diagnostic data on Susac syndrome, providing a reliable basis for our current understanding of this rare disease. Where possible, we make recommendations for clinical diagnosis, differential diagnosis, and management of patients with suspected Susac syndrome.	1
Weill-Marchesani syndrome (WMS) is a rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, eye anomalies, including microspherophakia, ectopia of the lenses, severe myopia, glaucoma and occasionally heart defects. Given these complex clinical manifestations and genetic heterogeneity, WMS patients presented misdiagnosed as high myopia or angle closure glaucoma. Here, we report ADAMTS17 mutations, a member of the extracellular matrix protease family, from a Chinese family. Patients have features that fall within the WMS spectrum. The exome (protein-coding regions of the genome) makes up ~1 % of the genome, it contains about 85% of known disease-related variants. Whole exome sequencing (WES) has been performed to identify the disease-associated genes, including one patient, his healthy sister, and his asymptomatic wife. Genome-wide homozygosity map was used to identify the disease caused locus. SNVs and INDELs were further predicted with MutationTaster, LRT, SIFT and SiPhy and compared to dbSNP150 and 1000 Genomes project. Filtered mutation was confirmed with Sanger sequencing in whole family members. The Genome-wide homozygosity map based on WES identified a total of 20 locus which were possible pathogenic. Further, a novel nonsense mutation c.1051A >T result in p.(lys351Ter) in ADAMTS17 had been identified in a candidate loci. The Sanger sequencing data has verified two consanguineous WMS patients in the family pedigree and revealed autosomal recessive (AR) inheritance pattern. The nonsense mutation in ADAMTS17 was analyzed in silico to explore its effects on protein function. We predicted the mutation produced non-function protein sequence. A novel nonsense mutation c.1051 A > T in ADAMTS17 had been identified caused autosomal recessive WMS in the Chinese family.	0
None:Mutations in exons 21 and 20 of the DMNT1 gene have been associated with two multisystem neurodegenerative diseases that involve central and peripheral nervous system ADCADN (Autosomal Dominant Cerebellar Ataxia with Deafness and Narcolepsy) and HSAN 1E (Hereditary Sensory and Autonomic Neuropathy IE). We describe a new case of ADCADN that was referred to us in the suspicion of secondary narcolepsy. A 44-year-old female with personal and familiar longstanding history of progressive bilateral sensorineural deafness, and sensitive cerebellar ataxia, presenting with brief episodes of falls while laughing and excessive diurnal somnolence. Clinical and neurophysiological evaluations reveled signs of cerebellar, pyramidal, peripheral, cognitive involvement, and optical atrophy. A 48-hour continuous polysomnography (PSG) and Multiple Sleep Latency Test at first evaluation revealed a normal sleep structure with frequent diurnal sleep episodes and a pathological sleep latency without sleep onset REM periods (SOREMPs). Normal level of cerebrospinal fluid (CSF) hypocretine 1 was detected. Given the reminiscence with DNMT 1 spectrum a direct sequencing of exons 20 and 21 of the DNMT1 gene was performed revealing the p.Glu575Lys mutation in exon 21 in the proband and her mother. During the 4 years of follow-up her walking ability declined, she became more somnolent and repeated PSG documented REM sleep latency shortening, and finally the evidence of de novo spontaneous SOREMPs, although normal CSF hrct-1 at second revaluation. This case highlights the progressive course of disease although a full-blown picture of classical narcolepsy type 1 was never reached.	0
BACKGROUND:Follow-up cytogenetic analysis has been recommended for cases with positive noninvasive prenatal screening (NIPS) results. This study of five cases with numerical and structural sex chromosomal abnormalities (SCA) and a review of large case series of NIPS provided guidance to improve prenatal diagnosis for SCA. METHODS:Following positive NIPS results for SCA, karyotype analysis, chromosomal microarray analysis (CMA), fluorescence in situ hybridization (FISH), and locus-specific quantitative PCR were performed on cultured amniocytes, chorionic villi cells, and stimulated lymphocytes. Review of large case series was performed to evaluate the NIPS positive rate, follow-up rate of cytogenetic analysis, positive predictive value (PPV) for major types of SCA, and relative frequencies of subtypes of major SCA. RESULTS:Of the five cases with positive NIPS for SCA, case 1 showed a mosaic pattern of monosomy X and isodicentric Y; case 2 showed a mosaic pattern of monosomy X confined to the placenta; cases 3 and 4 had an isochromosome of Xq, and case 5 showed a derivative chromosome 14 from a Yq/14p translocation of maternal origin. Review of literature showed that mean positive rate of NIPS for SCA was 0.61%, follow-up rate of cytogenetics analysis was 76%, and mean PPV for SCA was 48%. Mosaic patterns and structural rearrangements involving sex chromosomes were estimated in 3%-20% and 3% of SCA cases, respectively. CONCLUSION:These five cases further demonstrated the necessity to pursue follow-up cytogenetic analysis to characterize mosaic patterns and structural abnormalities involving sex chromosomes and their value for prenatal genetic counseling. A workflow showing the performance of current NIPS and cytogenetic analysis for SCA was summarized. These results could facilitate an evidence-based approach to guide prenatal diagnosis of SCA.	0
Hürthle cell thyroid carcinoma (HTC) accounts for 3-5% of all thyroid malignancies. Widely invasive HTC is characterized by poor prognosis and limited responsiveness to standard therapy with radioiodine. The molecular landscape of HTC is significantly different from the genetic signature seen in other forms of thyroid cancer. We performed a comprehensive literature review on the association between the molecular features of HTC and cancer metabolism. We searched the Pubmed, Embase, and Medline databases for clinical and translational studies published between 1980 and 2020 in English, coupling "HTC" with the following keywords: "genomic analysis", "mutations", "exome sequencing", "molecular", "mitochondria", "metabolism", "oxidative phosphorylation", "glycolysis", "oxidative stress", "reactive oxygen species", and "oncogenes". HTC is characterized by frequent complex I mitochondrial DNA mutations as early clonal events. This genetic signature is associated with the abundance of malfunctioning mitochondria in cancer cells. HTC relies predominantly on aerobic glycolysis as a source of energy production, as oxidative phosphorylation-related genes are downregulated. The enhanced glucose utilization by HTC is used for diagnostic purposes in the clinical setting for the detection of metastases by fluorodeoxyglucose positron emission tomography (FGD-PET/CT) imaging. A comprehensive metabolomic profiling of HTC in association with its molecular landscape might be necessary for the implementation of tumor-specific therapeutic approaches.	0
BACKGROUND:Cryoglobulins and hyperviscosity syndrome (HS) sometimes occur in multiple myeloma (MM), which are considered clinical emergencies. In laboratory practice, aspiration failure in routine blood tests sometimes occurs when the sample is inadequate. Here, a case of cryoglobulinemia and HS associated with advanced multiple myeloma was reported, which unusually is initially confirmed by aspiration failure in a routine blood test with sufficient sample. METHODS:A case of a 48-year-old female whose diagnosis of cryoglobulinemia and hyperviscosity syndrome secondary to MM-IgA kappa was confirmed from routine blood test. RESULTS:The sufficient sample for routine blood test could not be analyzed in a hematology analyzer due to aspiration failure, which was found to be caused by high viscosity and poor liquidity. A peripheral blood smear showed numerous non-cellular clouds, erythrocyte rouleaux formation, and plasma cell infiltration. After a water bath, the non-cellular clouds evidently disappeared, and the routine blood test was successfully conducted. Centrifugation of the sample for biochemical test, which had previously failed, was also possible. The case was confirmed as complications of cryoglobulinemia and HS associated with advanced MM, and the non-cellular clouds were identified as cryoglobulins. CONCLUSIONS:This case report provides an effective way for clinicians to deal with this kind of abnormal sample and limited but important laboratory evidence to establish early diagnosis of cryoglobulinemia and HS secondary to MM.	0
Odaman-Al I, Gezdirici A, Yıldız M, Ersoy G, Aydoğan G, Şalcıoğlu Z, Tahtakesen TN, Önal H, Küçükemre-Aydın B. A novel mutation in the SLC19A2 gene in a Turkish male with thiamine-responsive megaloblastic anemia syndrome. Turk J Pediatr 2019; 61: 257-260. Thiamine-responsive megaloblastic anemia (TRMA) is a very rare syndrome characterized by the triad of early onset megaloblastic anemia, sensorineural deafness and diabetes mellitus. Here we report, a 5-year-old boy who presented with transfusion dependent anemia and diabetes mellitus and was diagnosed with TRMA. Besides reporting a novel mutation of the causative gene SLC19A2, we wanted to emphasize this syndrome in the aspect of coexistence of insulin dependent diabetes, transfusion dependent anemia and thrombocytopenia.	0
Copper coordinated with amino acid residues is essential for the function of many proteins. In addition, copper complexed to free l-Histidine, as [Cu(His)2], is used in the treatment of the neurodegenerative Menkes disease and of cardioencephalomyopathy. This study was aimed to coordinate copper(II) with four small ligands (l-Serine, l-Histidine, Urea and Biuret) and to evaluate structural features, stability, antioxidant activity and neuronal compatibility of the resulting complexes. All complexes were synthesized with CuCl2 and purified by precipitation in alcohol. Elemental composition, X-rays diffraction and FTIR indicated that the complexes were in form of [Cu(ligand)2] and exhibited tridentate (l-Histidine), bidentate (l-Serine and Biuret) or monodentate (Urea) coordination with copper. UV-Vis absorbance profiles in physiologically relevant solutions and cyclic voltammetry revealed that, contrarily to [Cu(Urea)2Cl2] and [Cu(Biuret)2Cl2], the [Cu(Ser)2] and [Cu(His)2Cl2] complexes were stable in different media including water, physiological saline and intestinal-like solutions. All complexes and their ligands had antioxidant capacity as evaluated by DPPH (1,1-diphenyl-2,2-picrylhydrazyl) and DPD (N,N-diethyl-p-phenylenediamine) methods, and the [Cu(His)2Cl2] complex was the most potent. Neuronal compatibility was assessed through cell viability measurements using cultured neurons derived from mouse P19 stem cells. Although only [Cu(His)2Cl2] showed a good neurocompatibility (about 90% at concentrations up to 200 μM), the cytotoxicity of the other copper complexes was lower compared to equivalent concentrations of CuCl2. These findings open new perspectives for the use of these copper complexes as antioxidants and possibly as therapeutic agents for neurodegenerative diseases. Furthermore, study of these complexes may help to improve chelation therapy for copper dysfunctions.	0
A 55-year-old male presented with severe mitral valve stenosis that was caused by a rare condition called caseous calcification of mitral valve annulus (CCMA). The condition was provisionally diagnosed by multi-imaging modalities, and the diagnosis was further established by histopathology. The patient required surgical excision of CCMA and mitral valve replacement. In addition, this patient exhibited a classical picture of another rare condition called familial multiple lipomatosis (FML). No such associations have been reported between the two rare conditions of CCMA and FML. Rare pathologies such as CCMA should be considered in the deferential diagnosis of calcified mass involving mitral valve annulus with or without valvular dysfunction.	0
BACKGROUND Patients with end-stage renal disease undergoing long-term maintenance hemodialysis are more likely than the general population to exhibit primary hypothyroidism. Only a few cases of isolated adrenocorticotropic hormone deficiency (IAD) among hemodialysis patients have been reported. We herein report an unusual case of a patient undergoing long-term hemodialysis who exhibited both IAD and primary hypothyroidism. CASE REPORT A 82-year-old male with end-stage renal disease secondary to immunoglobulin A nephropathy, undergoing hemodialysis for 20 years, was found to have primary hypothyroidism without obvious symptoms and consequently began thyroid hormone replacement therapy with oral levothyroxine. At 84 years of age, he developed anorexia, fatigue, and lethargy. A systemic workup using computed tomography and gastrointestinal endoscopy detected no abnormalities. He did not exhibit electrolyte imbalances, such as hyponatremia or hyperkalemia, and had normal morning blood levels of cortisol and adrenocorticotropic hormone. However, he exhibited hypoglycemic coma 4 months later. Detailed endocrinological examinations using dynamic function tests indicated IAD. After commencement of corticosteroid replacement therapy, his symptoms resolved without complications. CONCLUSIONS To our knowledge, this is the first report of a hemodialysis patient with both IAD and primary hypothyroidism. This case highlights the importance of regular assessments of thyroid function for primary hypothyroidism in hemodialysis patients, even when they are asymptomatic. Furthermore, timely dynamic endocrine testing of hypothalamic-pituitary-adrenal function is needed to diagnose possible IAD in hemodialysis patients with symptoms suggestive of adrenal insufficiency, even in the absence of abnormal laboratory findings such as electrolyte imbalances or low morning blood levels of cortisol or adrenocorticotropic hormone.	0
Amino acid transporters play very important roles in nutrient uptake, neurotransmitter recycling, protein synthesis, gene expression, cell redox balance, cell signaling, and regulation of cell volume. With regard to transporters that are closely connected to metabolism, amino acid transporter-associated diseases are linked to metabolic disorders, particularly when they involve different organs, cell types, or cell compartments. To date, 65 different human solute carrier (SLC) families and more than 400 transporter genes have been identified, including 11 that are known to include amino acid transporters. This review intends to summarize and update all the conditions in which a strong association has been found between an amino acid transporter and an inherited metabolic disorder. Many of these inherited disorders have been identified in recent years. In this work, the physiological functions of amino acid transporters will be described by the inherited diseases that arise from transporter impairment. The pathogenesis, clinical phenotype, laboratory findings, diagnosis, genetics, and treatment of these disorders are also briefly described. Appropriate clinical and diagnostic characterization of the underlying molecular defect may give patients the opportunity to avail themselves of appropriate therapeutic options in the future.	0
Dandy-Walker complex (DWC) is a malformative association of the central nervous system. DWC includes four different types: Dandy-Walker malformation (vermis agenesis or hypoplasia, cystic dilatation of the fourth ventricle and a large posterior fossa); Dandy-Walker variant (vermis hypoplasia, cystic dilatation of the fourth ventricle, normal posterior fossa); mega cysterna magna (large posterior fossa, normal vermis and fourth ventricle) and posterior fossa arachnoid cyst. We present and discuss four cases with different morphological and clinical forms of the Dandy-Walker complex. In all four cases, diagnosis was reached by incorporation of clinical (macrocephaly, seizures) and imaging [X-ray, computed tomography (CT), magnetic resonance imaging (MRI)] data. Two patients were diagnosed with Dandy-Walker complex, one patient was diagnosed with Dandy-Walker variant in a rare association with neurofibromatosis and one patient was diagnosed with a posterior fossa arachnoid cyst associated with left-sided Claude Bernard-Horner syndrome, congenital heart disease (coarctation of the aorta, mitral stenosis) and gastroesophageal reflux. In all forms of DWC, the clinical, radiological and functional manifestations are variable and require adequate diagnostic and therapeutic measures.	0
Dysosteosclerosis (DOS) is a form of sclerosing bone disease characterized by irregular osteosclerosis and platyspondyly. Its mode of inheritance is autosomal recessive. SLC29A3 mutations have been reported as the causal gene in two DOS families, however, genetic heterogeneity has been suggested. By whole-exome sequencing in a Turkish patient with DOS, we found a novel splice-site mutation in TNFRSF11A. TNFRSF11A mutations have previously been reported in two autosomal dominant diseases (osteolysis, familial expansile and Paget disease of bone 2, early-onset) and an autosomal recessive disease (osteopetrosis, autosomal recessive 7). The biallelic mutation, c.616+3A>G, identified in our study was located in the splice donor site of intron 6 of TNFRSF11A. Exon trapping assay indicated the mutation caused skipping of exon 6, which was predicted to induce a frame-shift and an early termination codon in all known alternative transcript variants of TNFRSF11A. The predicted effect of the mutation for the isoforms was different from those of the previously reported mutations, which could explain the difference of their phenotypes. Thus, our study identified the second disease gene for DOS. TNFRSF11A isoforms may have the different roles in skeletal development and metabolism.	0
When patients with cancer develop neurologic symptoms, common causes include metastasis, infections, coagulopathy, metabolic or nutritional disturbances, and neurotoxicity from treatments. A thorough clinical history, temporal association with cancer therapies, and results of ancillary tests usually reveal one of these mechanisms as the etiology. When no etiology is identified, the diagnosis considered is often that of a paraneoplastic neurologic disorder (PND). With the recognition that PNDs are more frequent than previously thought, the availability of diagnostic tests, and the fact that, for some PNDs, treatment helps, PNDs should no longer be considered diagnostic zebras, and when appropriate should be included in the differential diagnosis early in the evaluation.	0
Vasculitis is a group of several clinical conditions in which the main histopathological finding is fibrinoid necrosis in the walls of blood vessels. This article assesses the main dermatological aspects relevant to the clinical and laboratory diagnosis of small- and medium-vessel cutaneous and systemic vasculitis syndromes. The most important aspects of treatment are also discussed.	0
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: 1. To evaluate the efficacy of statin therapy in reducing the frequency or severity of the neurobehavioral abnormalities seen in people with SLOS (e.g. aggression, anxiety, irritability, self-mutilation, autistic behaviors, sleep disturbances, etc.) (Wassif 2017). 2. To evaluate the potential effects of statin therapy on survival.	0
Quebec platelet disorder (QPD) is a condition that causes delayed-onset bleeding after hemostatic challenges. While there are interventional spine procedure (ISP) guidelines for managing patients on blood thinners or with common bleeding disorders, there are none for approaching patients with unique coagulopathies. We report a patient with QPD and extensive history of postprocedural bleeding complications (PPBCs) who presented with chronic cervical facet pain. After consulting a hematologist and administering antifibrinolytic agent with platelet transfusions, the patient underwent medial branch nerve blocks (MBNBs) followed by radiofrequency ablation (RFA) without experiencing PPBCs. A comprehensive team approach is critical to maximize patient safety when performing an ISP in such a population.	0
By searching a clinical database of over 60,000 individuals referred for array-based CNV analyses and online resources, we identified four males from three families with intellectual disability, developmental delay, hypotonia, joint hypermobility and relative macrocephaly who carried small, overlapping deletions of Xp11.22. The maximum region of overlap between their deletions spanned ~430 kb and included two pseudogenes, CENPVL1 and CENPVL2, whose functions are not known, and two protein coding genes-the G1 to S phase transition 2 gene (GSPT2) and the MAGE family member D1 gene (MAGED1). Deletions of this ~430 kb region have not been previously implicated in human disease. Duplications of GSPT2 have been documented in individuals with intellectual disability, but the phenotypic consequences of a loss of GSPT2 function have not been elucidated in humans or mouse models. Changes in MAGED1 have not been associated with intellectual disability in humans, but loss of MAGED1 function is associated with neurocognitive and neurobehavioral phenotypes in mice. In all cases, the Xp11.22 deletion was inherited from an unaffected mother. Studies performed on DNA from one of these mothers did not show evidence of skewed X-inactivation. These results suggest that deletions of an ~430 kb region on chromosome Xp11.22 that encompass CENPVL1, CENPVL2, GSPT2 and MAGED1 cause a distinct X-linked syndrome characterized by intellectual disability, developmental delay, hypotonia, joint hypermobility and relative macrocephaly. Loss of GSPT2 and/or MAGED1 function may contribute to the intellectual disability and developmental delay seen in males with these deletions.	0
PURPOSE:To investigate the outcome of mitomycin C (MMC)-augmented trabeculectomy with subconjunctival bevacizumab in the management of Fuchs heterochromic iridocyclitis (FHI)-related glaucoma in 1-year follow-up period. METHODS:This retrospective study included 50 eyes with FHI-related glaucoma those had underwent initial trabeculectomy with MMC (0.2 mg/ml-3 min). Thirty-one of them had single-dose bevacizumab injection (1.25 mg/0.05 ml) into the bleb area just at the end of the surgery, while 19 eyes did not have. The intraocular pressure (IOP) and the mean number of anti-glaucomatous medications were evaluated. The IOP value ≤ 21 mmHg was defined as complete or qualified surgical success in terms of using medical anti-glaucomatous treatment. Bleb height and vascularity were evaluated with Indiana bleb grading system. Paired sample t test, t test, Chi-square and Kolmogorov-Smirnov tests were used for statistical analysis. RESULTS:The preoperative IOP values of bevacizumab and without bevacizumab groups were 32.8 ± 4.5 mmHg and 32.8 ± 4.5 mmHg, respectively, and they decreased to 17.5 ± 4.6 mmHg and 17 ± 5.2 mmHg at the final visit (p < 0.001 for all values). There were no significant differences in postoperative IOP and the number of medications between the groups at the final visit. In bevacizumab group, complete success was achieved in 100% within the third month but decreased to 22.5% (complete) and 74.1% (qualified) at the first year. In the other group (without bevacizumab group), complete success was achieved in 94.7% within the third month but decreased to 15.8% (complete) and 84.2% (qualified) at the first year. CONCLUSION:Initial trabeculectomy with MMC and subconjunctival bevacizumab injection was found to have lower rates of complete success with relatively acceptable qualified success rates in the management of FHI-related glaucoma. Subconjunctival bevacizumab was not found to have additional effect to improve the surgical success.	0
Hartsfield syndrome (HS) is an ultrarare developmental disorder mainly featuring holoprosencephaly and ectrodactyly. It is caused by heterozygous or biallelic variants in FGFR1. Recently, a dominant-negative effect was suggested for FGFR1 variants associated with HS. Here, exome sequencing analysis in a 12-year-old boy with HS disclosed a novel de novo heterozygous variant c.1934C>T in FGFR1 predicted to cause the p.(Ala645Val) amino-acid substitution. In order to evaluate whether the variant, changing a highly conserved residue of the kinase domain, affects FGFR1 function, biochemical studies were employed. We measured the FGFR1 receptor activity in FGF2-treated cell lines exogenously expressing wild-type or Ala645Val FGFR1 by monitoring the activation status of FGF2/FGFR1 downstream pathways. Our analysis highlighted that RAS/ERK1/2 signaling was significantly perturbed in cells expressing mutated FGFR1, in comparison with control cells. We also provided preliminary evidence showing a modulation of the autophagic process in cells expressing mutated FGFR1. This study expands the FGFR1 mutational spectrum associated with HS, provides functional evidence further supporting a dominant-negative effect of this category of FGFR1 variants and offers initial insights on dysregulation of autophagy in HS.	0
BACKGROUND:There are few reports describing the proximal deletions of the short arm of chromosome 20, making it difficult to predict the likely consequences of these deletions. Most previously reported cases have described the association of 20p11.2 deletions with Alagille syndrome, while there are others that include phenotypes such as panhypopituitarism, craniofacial dysmorphism, polysplenia, autism, and Hirschsprung disease. METHODS:Molecular karyotyping, cytogenetics, and DNA sequencing were undertaken in a child to study the genetic basis of a complex phenotype consisting of craniofacial dysmorphism, ocular abnormalities, ectopic inguinal testes, polysplenia, growth hormone deficiency, central hypothyroidism, and gastrointestinal system anomalies. RESULTS:We report the smallest described de novo proximal 20p11.2 deletion, which deletes only the FOXA2 leading to the above complex phenotype. CONCLUSIONS:Haploinsufficiency of the FOXA2 only gene is associated with a multisystem disorder.	0
We describe the presentation and follow-up of a three-year-old girl with nemaline myopathy due to a de-novo variant in ACTA1 (encoding skeletal alpha actin) and moderately low enzyme level of Complex I of the mitochondrial respiratory chain. She presented in the neonatal period with hypotonia, followed by weakness in the facial, bulbar, respiratory and neck flexors muscles. A biopsy of her quadriceps muscle at the age of one year showed nemaline rods. Based on her clinical presentation of a congenital myopathy and histopathological features on a muscle biopsy, ACTA1 was sequenced, and this revealed a novel sequence variant, c.760 A>C p. (Asn254His). In addition, mitochondrial respiratory chain enzymatic activity of skeletal muscle biopsy showed a moderately low activity of complex I (nicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase). Disturbances of Complex I of the respiratory chain have been reported in patients with nemaline myopathy, although the mechanism remains unclear.	0
To achieve proper synaptic development and function, coordinated signals must pass between the pre- and postsynaptic membranes. Such transsynaptic signals can be comprised of receptors and secreted ligands, membrane associated receptors, and also pairs of synaptic cell adhesion molecules. A critical open question bridging neuroscience, developmental biology, and cell biology involves identifying those signals and elucidating how they function. Recent work in Drosophila and vertebrate systems has implicated a family of proteins, the Teneurins, as a new transsynaptic signal in both the peripheral and central nervous systems. The Teneurins have established roles in neuronal wiring, but studies now show their involvement in regulating synaptic connections between neurons and bridging the synaptic membrane and the cytoskeleton. This review will examine the Teneurins as synaptic cell adhesion molecules, explore how they regulate synaptic organization, and consider how some consequences of human Teneurin mutations may have synaptopathic origins.	0
Acute myeloid leukemia (AML) is a heterogeneous group of diseases, whose classification is based on lineage-commitment and genetics. Although rare in childhood, it is the most common type of acute leukemia in adults, accounting for 80% of all cases in this age group. The prognosis of this disease remains poor (especially in childhood, as compared to acute lymphoblastic leukemia); however, overall survival has significantly improved over the past 30 years. The health of the oral cavity is a remarkable reflection of the systemic status of an individual. Identification of the signs and symptoms of oral lesions can act as a warning sign of hidden and serious systemic involvement. Moreover, they may be the presenting feature of acute leukemia and provide important diagnostic indicators. Primary oral alterations are identified in up to 90% of cases of acute myeloid leukemia and consist of petechiae, spontaneous bleeding, mucosal ulceration, gingival enlargement with or without necrosis, infections, hemorrhagic bullae on the tongue, and cracked lips. Poor oral hygiene is a well-known risk factor for local and systemic infectious complications. Oro-dental complications due to AML treatment can affect the teeth, oral mucosa, soft and bone tissue, and contribute to opportunistic infections, dental decay, and enamel discoloration. The treatment of acute myeloid leukemia is still associated with high mortality and morbidity. The management is multimodal, involving aggressive multidrug chemotherapy and, in most cases, allogenic bone marrow transplantation. Periodontal and dental treatment for patients with leukemia should always be planned and concerted with hematologists.	0
INTRODUCTION:The two available therapies for idiopathic pulmonary fibrosis (IPF), pirfenidone and nintedanib, slow down but do not halt IPF progression. As such, in the last few years several agents with specific molecular targets have been investigated to find a cure forIPF. Pamrevlumab, a recombinant human antibody that binds to connective tissue growth factor (CTGF) has emerged as a potential therapy for IPF and has advanced to phase 3 clinical trials. AREAS COVERED:The authors offer a backdrop to the current IPF treatment market and describe the chemistry, pharmacokinetics and pharmacodynamics of pamrevlumab. They summarize the preclinical and early clinical evidence on pamrevlumab and propose ways of progressing this agent further as a potential IPF treatment. EXPERT OPINION:Pamrevlumab was effective and safe in patients in a placebo-controlled phase 2 trial, demonstrating its potential to become an alternative therapeutic option for IPF; however, the feasibility of intravenous administration in clinical practice may be a hurdle to its use as a first-line treatment. Further studies are necessary to assess its effects when administered with pirfenidone or nintedanib and this could open up a new era of combined therapeutic approaches for IPF.	0
Treacher Collins syndrome (TCS) is a type of mandibulofacial dysostosis with incomplete penetrance and high intra- and interfamilial clinical heterogeneity, and it is associated with mutations of treacle ribosome biogenesis factor 1 (TCOF1), and RNA polymerase I and III subunit (POLR1)C and POLR1D genes. In the present case report, a patient with TCS with auricle dysplasia and hearing loss accompanied with intellectual disability is described. Sequence analysis was performed on blood samples from the patient and his father via oligonucleotide-based target capture, followed by next-generation sequencing. Alignment and variant calls were generated using the Burrows-Wheeler Aligner and Genome Analysis Toolkit, followed by bioinformatics analysis of the detected variants. A novel heterozygous mutation, c.911C>T (p.Ser304Leu), was detected in the TCOF1 gene, which was inherited from the father. The father of the patient only suffered from hearing loss. The present report is the first to identify an association between phenotypic variability and TCOF1 gene mutations and thus contributes to our understanding of the association between the genotype and phenotype in patients with TCS and offers clinically relevant information for diagnosis of the syndrome.	0
OBJECTIVE:Trigeminal neuralgia (TN) is a common cranial nerve disease. Inflammation is suggested in many recent studies to be involved in neuropathic pain, but its role in TN remains unclear so far. Therefore, the current study aimed to explore the relationship of inflammation with TN. METHODS:The levels of inflammatory markers, such as white blood cell (WBC), neutrophil (NE), lymphocyte (LY), monocyte (MO), platelet (PLT), and albumin (ALB), as well as the neutrophil/lymphocyte ratio (NLR), derived NLR (dNLR), platelet/lymphocyte ratio (PLR), monocyte/lymphocyte ratio (MLR), and prognostic nutritional index (PNI) had been compared between TN patients and healthy controls using nonparametric tests. Moreover, multiple logistic regression models had been employed to assess the associations of inflammatory markers with TN. Besides, the receiver operating characteristic (ROC) curve was plotted to analyze the values of these inflammatory makers, as well as their matched combinations in diagnosing TN. RESULTS:The levels of WBC, NE, MO, NLR, dNLR, and MLR in TN patients were evidently increased combined with those in normal subjects. In addition, multivariate logistic regression models illustrated that inflammation had close correlation with TN. Meanwhile, the area under the curve (AUC) values for NE, NLR, and dNLR, as well as those for the matched combinations of NLR+PLR, NLR+PNI, dNLR+NLR, and dNLR+PLR in TN were >0.7, which might have predictive value for TN compared with those for normal subjects. CONCLUSIONS:Findings of this study reveal that inflammation could have played a close and important role in the progression and etiology of TN.	0
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that exert important functions in mediating the pleiotropic effects of diverse exogenous factors such as physical exercise and food components. Particularly, PPARs act as transcription factors that control the expression of genes implicated in lipid and glucose metabolism, and cellular proliferation and differentiation. In this review, we aim to summarize the recent advancements reported on the effects of lifestyle and food habits on PPAR transcriptional activity in chronic disease.	0
Osseous manifestations of neurofibromatosis 1 (NF-1) occur in a minority of the affected subjects but may be because of significant clinical impairment. Typically, they involve the long bones, commonly the tibia and the fibula, the vertebrae, and the sphenoid wing. The pathogenesis of NF-1 focal osseous lesions and its possible relationships with other osseous NF-1 anomalies leading to short stature are still unknown, though it is likely that they depend on a common mechanism acting in a specific subgroup of NF-1 patients. Indeed, NF-1 gene product, neurofibromin, is expressed in all the cells that participate to bone growth: osteoblasts, osteoclasts, chondrocytes, fibroblasts, and vascular endothelial cells. Absent or low content of neurofibromin may be responsible for the osseous manifestations associated to NF-1. Among the focal NF-1 osseous anomalies, the agenesis of the sphenoid wing is of a particular interest to the neurosurgeon because of its progressive course that can be counteracted only by a surgical intervention. The sphenoid wing agenesis is regarded as a dysplasia, which is a primary bone pathology. However, its clinical progression is related to a variety of causes, commonly the development of an intraorbital plexiform neurofibroma or the extracranial protrusion of temporal lobe parenchyma and its coverings. Thus, the cranial bone defect resulting by the primary bone dysplasia is progressively accentuated by the orbit remodeling caused by the necessity of accommodating the mass effect exerted by the growing tumor or the progression of the herniated intracranial content. The aim of this paper is to review the neurosurgical and craniofacial surgical modalities to prevent the further progression of the disease by "reconstructing" the normal relationship of the orbit and the skull.	0
A 4-year-old girl, the child of nonconsanguineous parents was referred for clinical assessment because of postaxial limb defects associated with mild facial dysmorphism. The overall phenotypic features were compatible with the Miller syndrome. The proband manifested distinctive bone defects, consisting of triangular-shaped terminal phalanges and cone-shaped epiphyses of the middle phalanges of the feet. Using the sequence analysis of the DHODH gene we identified compound heterozygous mutations in the proband. Furthermore, both the parents were found to be heterozygous carriers of one of the two mutations found in the proband. Interestingly, the father had a history of postaxial polydactyly. We speculated that the postaxial polydactyly in the father was either a heterozygote manifestation or is unrelated.	0
Dysequilibrium syndrome (DES) is a non-progressive congenital ataxia characterized by severe intellectual deficit, truncal ataxia and markedly delayed, quadrupedal or absent ambulation. Recessive loss-of-function mutations in the very low density lipoprotein receptor (VLDLR) gene represent the most common cause of DES. Only two families have been reported harbouring homozygous missense mutations, both with a similarly severe phenotype. We report an Italian girl with very mild DES caused by the novel homozygous VLDLR missense mutation p.(C419Y). This unusually benign phenotype possibly relates to a less disruptive effect of the mutation, falling within a domain (EGF-B) not predicted as crucial for the protein function.	0
Testicular neuroendocrine tumors, commonly called carcinoid, are extremely rare and account for less than 1% of all testicular neoplasms. The most common type is primary carcinoid followed by testicular metastasis from another primary and rarely carcinoid within a testicular teratoma. To date, less than 25 cases of carcinoid associated teratomas have been reported in the literature. Herein, we present a unique case of testicular carcinoid tumor arising in association with mature teratoma in a patient with contralateral classic seminoma.	0
BACKGROUND: It is well known that familial sick sinus syndrome (SSS) is caused by functional alterations of ion channels and gap junction. Limited information is available on the mechanism of age-related non-familial SSS. Although evidence shows a close link between arrhythmia and the renin-angiotensin system (RAS), it remains to be determined whether the RAS is involved in the pathogenesis of non-familial SSS. METHODS: In this study, 113 patients with documented non-familial SSS and 125 controls were screened for angiotensinogen (AGT) and gap junction protein-connexin 40 (Cx40) promoter polymorphisms by gene sequencing, followed by an association study. A luciferase assay was used to determine the transcriptional activity of the promoter polymorphism. The interaction between nuclear factors and the promoter polymorphism was characterized by an electrophoretic mobility shift assay (EMSA). RESULTS: Association study showed the Cx40 -44/+71 polymorphisms are not associated with non-familial SSS; however, it indicated that four polymorphic sites at positions -6, -20, -152, and -217 in the AGT promoter are linked to non-familial SSS. Compared to controls, SSS patients had a lower frequency of the G-6A AA genotype (OR 2.88, 95% CI 1.58-5.22, P = 0.001) and a higher frequency of the G allele at -6 position (OR 2.65, 95% CI 1.54-4.57, P = 0.0003). EMSA and luciferase assays confirmed that nucleotide G at position -6 modulates the binding affinity with nuclear factors and yields a lower transcriptional activity than nucleotide A (P<0.01). CONCLUSION: G-6A polymorphism, which modulates the transcriptional activity of the AGT promoter, may contribute to non-familial SSS susceptibility.	0
Healthy brain function is mediated by several complementary signalling pathways, many of which are driven by extracellular vesicles (EVs). EVs are heterogeneous in both size and cargo and are constitutively released from cells into the extracellular milieu. They are subsequently trafficked to recipient cells, whereupon their entry can modify the cellular phenotype. Here, in order to further analyse the mRNA and protein cargo of neuronal EVs, we isolated EVs by size exclusion chromatography from human induced pluripotent stem cell (iPSC)-derived neurons. Electron microscopy and dynamic light scattering revealed that the isolated EVs had a diameter of 30-100 nm. Transcriptomic and proteomics analyses of the EVs and neurons identified key molecules enriched in the EVs involved in cell surface interaction (integrins and collagens), internalisation pathways (clathrin- and caveolin-dependent), downstream signalling pathways (phospholipases, integrin-linked kinase and MAPKs), and long-term impacts on cellular development and maintenance. Overall, we show that key signalling networks and mechanisms are enriched in EVs isolated from human iPSC-derived neurons.	0
Dystonias are a clinically and etiologically diverse group of disorders. Numerous genes have now been associated with different dystonia syndromes, and multiple strategies have been proposed for how these genes should be lumped and split into meaningful categories. The traditional approach has been based on the Human Genome Organization's plan for naming genetic loci for all disorders. For dystonia this involves a DYT prefix followed by a number (e.g., DYT1, DYT2, DYT3, etc.). A more recently proposed approach involves assigning multiple prefixes according to the main elements of the phenotype (e.g., DYT, PARK, CHOR, TREM, etc.) followed by the name of the responsible gene. This article describes these nomenclature systems and summarizes some of their limitations. We focus on dystonia as an example, although the concepts may be applied to all movement disorders.	0
Human C1q deficiency is associated with systemic lupus erythematosus (SLE) and increased susceptibility to severe bacterial infections. These patients require extensive medical therapy and some develop treatment-resistant disease. Because C1q is produced by monocytes, it has been speculated that allogeneic hematopoietic stem cell transplantation (allo-HSCT) may cure this disorder.We have so far treated 5 patients with C1q deficiency. In 3 cases, SLE symptoms remained relatively mild after the start of medical therapy, but 2 patients developed treatment-resistant SLE, and we decided to pursue treatment with allo-HSCT. For this purpose, we chose a conditioning regimen composed of treosulfan (14 g/m) and fludarabine (30 mg/m) started on day -6 and given for 3 and 5 consecutive days, respectively. Thymoglobulin was given at a cumulative dose of 8 mg/kg, and graft-versus-host disease prophylaxis was composed of cyclosporine and methotrexate.A 9-year-old boy and a 12-year-old girl with refractory SLE restored C1q production after allo-HSCT. This resulted in normal functional properties of the classical complement pathway followed by reduced severity of SLE symptoms. The boy developed posttransplant lymphoproliferative disease, which resolved after treatment with rituximab and donor lymphocyte infusion. Unfortunately, donor lymphocyte infusion induced severe cortisone-resistant gastrointestinal graft-versus-host disease, and the patient died from multiple organ failure 4 months after transplantation. The girl is doing well 33 months after transplantation, and clinically, all signs of SLE have resolved.Allo-HSCT can cure SLE in human C1q deficiency and should be considered early in subjects resistant to medical therapy.	0
Purpose:Acquired vitelliform lesions (AVLs) are associated with age-related macular degeneration and other variable macular disorders. AVLs often lead to outer retinal atrophy, sometimes accompanying a macular hole and choroidal neovascularization. The purpose of this study was to report a rare case with bilateral AVLs, in which one eye had accompanied a macular hole and the second eye a serous pigment epithelial detachment (sPED). Observations:A 66-year-old woman complained of bilateral metamorphopsia. AVLs were observed in the right eye and a flat sPED in the left eye. The best-corrected visual acuity (BCVA) was 20/17 in both eyes. Fluorescein angiography revealed local leakage in the right eye and pattern dystrophy-like hypofluorescence in both eyes. The sPED progressed with AVLs in the left eye and was treated with a combination therapy of intravitreal aflibercept, a sub-Tenon's injection of triamcinolone acetonide, and photodynamic therapy (IVA/STTA/PDT), which successfully flattened the sPED and sustained good vision for 4 years. The right eye was treated with intravitreal ranibizumab and tissue plasminogen activator, which enhanced absorption of the vitelliform material. However, 14 months later, a macular hole with typical metamorphopsia formed above a subretinal fibrotic scar at the vitelliruptive stage. Although pars plana vitrectomy closed the macular hole, enlargement of the outer retinal atrophy worsened the BCVA to 20/100. Conclusions and importance:We successfully treated one eye with a sPED with AVLs using the combination therapy of IVA/STTA/PDT, while the second eye with a macular hole secondary to AVLs ultimately developed outer retinal atrophy with visual loss.	0
Immune checkpoint inhibitors can induce immune-related adverse events (irAEs) in different organs. Dermatomyositis is a rare form of systemic irAE. Although dermatomyositis-specific antibodies, especially anti-transcriptional intermediary factor 1-γ (anti-TIF1-γ) antibodies, have been detected in a few cases of immune checkpoint inhibitor-associated dermatomyositis, their titers before immunotherapy have not been examined. We hereby report the first irAE case of dermatomyositis accompanied by seroconversion of anti-TIF1-γ antibody following nivolumab treatment for advanced lung adenocarcinoma. A 64-year-old Japanese male with an advanced lung adenocarcinoma (cT4N2M1a stage IVA) received nivolumab as third-line therapy. Skin rashes appeared two days later, and were treated with a topical steroid as just drug eruptions. 7 weeks later, he was emergently admitted because of high serum creatine kinase level. Clinical examination showed deteriorated rashes along with slightly weakened proximal muscles. Muscle biopsy revealed myopathic changes consistent with dermatomyositis. Anti-TIF1-γ antibody was positive, which was found to be within normal range before nivolumab administration. He was diagnosed with dermatomyositis and treated with systemic corticosteroids, tacrolimus, and intravenous immunoglobulin. However, these drugs showed limited effectiveness against the progression of muscle weakness. He died of respiratory failure due to lung cancer and muscle weakness progression 6 months after the admission. In conclusion, our case demonstrates that the development of dermatomyositis was causally related to immune activation by nivolumab. Given the potential exacerbation of autoimmune paraneoplastic disorders in cancer patients receiving immunotherapy, clinicians should be aware of early manifestations of systemic irAEs that require prompt diagnosis and intervention.	0
Diffuse cutaneous mastocytosis is a rare variant of mastocytosis in the neonatal period. We describe a case of c-KIT (DV) mutation-positive fatal diffuse cutaneous mastocytosis with systemic involvement of the gastrointestinal tract and associated malabsorption and hepatosplenomegaly associated with mast cell mediator release symptoms.	0
BACKGROUND:Development of nonmelanoma skin cancers (NMSCs) has been associated with certain risk factors, but studies of the association between ABO blood group and NMSCs have been rare and inconclusive. The aim of this study was to assess the association of the previously known risk factors and blood group as a new potential risk factor in NMSCs. METHODS:The study included 401 patients, 202 men, and 199 women, which included 367 diagnosed cases of basal cell carcinoma and 148 diagnosed cases of squamous cell carcinoma. The control group consisted of 438 subjects, 198 men, and 240 women. A standardized questionnaire adapted for this targeted study was used. The relation between the dependent variable (NMSCs) and independent variables was investigated by logistic regression. RESULTS:Compared to the non AB blood group, the risk of developing NMSCs was significantly higher in the AB blood group (MOR = 2.28; 95% CI = 1.41-3.69). We established a logistic model that could best describe the probability of NMSCs development. CONCLUSION:Study results are expected to instigate basic research into the role of A and B antigens in normal skin epithelium, NMSCs etiopathogenesis, possible effect on metastatic potential and disease prognosis, potential tumor immunotherapy, and targeted detection and prevention in subjects at an increased risk of NMSCs development.	0
Purpose:To determine the rate of posterior capsular rupture (PCR) and assess the postoperative outcomes in patients of posterior polar cataract (PPC) undergoing phacoemulsification using a combination of "V" or "λ" nucleofractis and viscodissection. Methods:It was a retrospective study of 80 eyes of 64 patients undergoing surgery for PPC. All surgeries were performed by a single surgeon. After completion of the continuous curvilinear capsulorrhexis (CCC), controlled hydrodelineation was used to separate the endonucleus from the epinuclear shell with limited viscodissection. Phacoemulsification was then carried out by making a "V" or lambda-shaped nucleofractis with the phaco tip followed by multiple chopping of the nucleus, ensuring the integrity of the epinuclear part of the lens. The epinuclear plate was removed after viscodissection. Results:The overall rate of PCR was 7.5% (6 out of 80 eyes). Of the 6 eyes, 4 eyes had been documented to have a pre-existing posterior capsular defect on slit-lamp examination. The rate of "on table" PCR, that is, PCR occurring intraoperatively was only 2.6% (2 of 76 eyes). Nucleus drop was not encountered in any case. Overall 87.5% eyes achieved a final visual acuity of 20/40 or better with 68.75% being 20/20 or better. Of the eyes developing PCR, two-third achieved a visual acuity of 20/30 or better. Conclusion:Using a combination of surgical techniques of V groove or lambda technique for nucleofractis and removal of epinucleus by viscodissection can result in a low rate of PCR and extremely good postoperative outcomes in cases of PPC.	0
BACKGROUND:The term pseudohypoparathyroidism (PHP) describes disorders derived from resistance to the parathyroid hormone. Albright hereditary osteodystrophy (AHO) is a disorder with several physical features that can occur alone or in association with PHP. The subtype 1B, classically associated with resistance to PTH and TSH, derives from the epigenetic dysregulation of the GNAS locus. Patients showing features of AHO were described, but no explanation for such phenotypic heterogeneity is available. An AHO-like phenotype was associated with the loss of genetic information stored in chromosome 2q37, making this genomic region an interesting object of study as it could contain modifier genes involved in the development of AHO features in patients with GNAS imprinting defects. The present study aimed to screen a series of 65 patients affected with GNAS imprinting defects, with or without signs of AHO, for the presence of 2q37 deletions in order to find genes involved in the clinical variability. RESULTS:The molecular investigations performed on our cohort of patients with GNAS imprinting defects identified two overlapping terminal deletions of the long arm of chromosome 2. The smaller deletion was of approximately 3 Mb and contained 38 genes, one or more of which is potentially involved in the clinical presentation. Patients with the deletions were both affected by a combination of the most pathognomic AHO-like features, brachydactyly, cognitive impairment and/or behavioural defects. Our results support the hypothesis that additional genetic factors besides GNAS methylation defects are involved in the development of a complex phenotype in the subgroup of patients showing signs of AHO. CONCLUSIONS:For the first time, the present work describes PHP patients with hormone resistance and AHO signs simultaneously affected by GNAS imprinting defects and 2q37 deletions. Although further studies are needed to confirm the cause of these two rare molecular alterations and to identify candidate genes, this finding provides novel interesting clues for the identification of factors involved in the still unexplained clinical variability observed in PHP1B.	0
Variations in genes encoding for the enzymes responsible for synthesizing the linker region of proteoglycans may result in recessive conditions known as "linkeropathies". The two phenotypes related to mutations in genes B4GALT7 and B3GALT6 (encoding for galactosyltransferase I and II respectively) are similar, characterized by short stature, hypotonia, joint hypermobility, skeletal features and a suggestive face with prominent forehead, thin soft tissue and prominent eyes. The most outstanding feature of these disorders is the combination of severe connective tissue involvement, often manifesting in newborns and infants, and skeletal dysplasia that becomes apparent during childhood. Here, we intend to more accurately define some of the clinical features of B4GALT7 and B3GALT6-related conditions and underline the extreme hypermobility of distal joints and the soft, doughy skin on the hands and feet as features that may be useful as the first clues for a correct diagnosis.	0
Folliculitis decalvans is an inflammatory presentation of cicatrizing alopecia characterized by inflammatory perifollicular papules and pustules. It generally occurs in adult males, predominantly involving the vertex and occipital areas of the scalp. The use of dermatoscopy in hair and scalp diseases improves diagnostic accuracy. Some trichoscopic findings, such as follicular tufts, perifollicular erythema, crusts and pustules, can be observed in folliculitis decalvans. More research on the pathogenesis and treatment options of this disfiguring disease is required for improving patient management.	0
OBJECTIVE:This study was designed for the characterization and establishment of antibiotic susceptibility profiles of non-fermentative gram negative bacteria isolated from hospitalized patients in a tertiary care hospital of Nepal. RESULTS:A total of 402 non-fermentative gram negative bacteria was isolated in 1486 culture-positive cases from 6216 different clinical samples obtained from hospitalized patients. Among total non-fermentative gram negative bacterial isolates, the highest number was recovered from specimens collected from lower respiratory tract infections (n = 173, 43.0%) of hospitalized patients followed by pus/swab samples (n = 99, 24.6%) and urinary tract infections (n = 49, 12.2%). The most common non-fermentative gram negative bacteria identified were Acinetobacter baumannii (n = 177, 44.0%), Pseudomonas aeruginosa (n = 161, 40.1%) and Burkholderia cepacia complex (n = 33, 8.2%). These bacterial isolates exhibited a higher rate of insusceptibility to beta-lactam antibiotics, fluoroquinolones, and aminoglycosides. On the other hand, all the isolates of P. aeruginosa and A. baumannii were completely susceptible to colistin sulfate and polymyxin B. Among total isolates, 78.1% (n = 314) were multidrug-resistant with a high rate of multidrug-resistant among A. baumannii (91.0%).	0
BACKGROUND:Gastric cancer is rare during pregnancy and often diagnosed at a later stage due to overlapping symptoms of pregnancy. Breast metastasis of gastric cancer is another uncommon entity. We present a rare case of breast metastasis of gastric cancer during pregnancy. CASE REPORT:A 26-year-old female was diagnosed with gastric cancer at 14 weeks of gestation and underwent total gastrectomy. She rejected adjuvant chemotherapy and continued pregnancy without any follow-up. Cancer recurred in bilateral breasts at 34th week of gestation mimicking primary inflammatory breast cancer. MANAGEMENT AND OUTCOME:It was difficult to diagnose breast metastasis during pregnancy because of overlapping pregnancy symptoms. Following an unresponsive period to antibiotherapy, a fine needle biopsy on breast was performed and signet cell adenocarcinoma metastasis was determined. We started chemotherapy after delivery. There was a near complete response after first line of chemotherapy. Unfortunately, cancer was relapsed within three months and we started second-line chemotherapy. DISCUSSION:To our knowledge, this is the fourth case reported in medical literature of gastric cancer presented with breast metastasis during pregnancy. We will try to draw attention to diagnosis, treatment and different presentation of gastric cancer during pregnancy with review of the literature.	0
PURPOSE:Gallbladder cancer (GBC) is the most common malignancy of the biliary tract. The median survival of the disease is around 6 months. In this study, we explore clinical trials related to non-resectable GBC, determine the shortcomings leading to the lack of development of new treatment, and shed light on possible areas of improvement. METHODS:On April 20, 2019 the authors completed a search on ClinicalTrials.gov for all therapeutic and interventional clinical trials involving non-resectable GBC, without any limits on date or location. Trial characteristics such as duration, phase, sample size, and whether a publication was produced were collected and analyzed. RESULTS:Sixty-two trials met our selection criteria. The average duration of trials was 5 years. Trials were conducted in 8 different countries: most of them in North America (USA and Canada). About 88% of trials were in early phases (I, I/II, and II) and 85% of trials were completed. Only 4 relevant publications were produced from all the trials in our study. Gemcitabine was the most common drug used. Use of gemcitabine alone or in combination with either capecitabine or cisplatin showed significant increase mean progression-free survival. CONCLUSION:This study revealed a low number of trials, lack of geographic diversity, and scarcity of publications concerning non-resectable GBC. Adequate management of is of great importance to reach effective therapies for this disease.	0
Vascular injuries are an extremely rare complication of clavicle osteosynthesis, though several cases are reported in the literature. Cadaver studies have established recommended safe lengths for clavicle screws based on precise measurements of bone thickness and distance from subjacent neurovascular structures. We present the case of a 27-year-old female who underwent orthopedic plate and screw fixation of a clavicle fracture and subsequently sustained iatrogenic vascular injury from one of the screws. This necessitated endovascular repair and orthopedic revision. This case underscores the importance of selecting appropriate screws based on available imaging.	0
OBJECTIVE:To explore phenotypic and mutational characteristics of a pedigree affected with autosomal dominant Charcot-Marie-Tooth disease (CMT) and nephropathy. METHODS:Clinical data of the proband and his family members was collected. Electrophysiology, renal biopsy and next-generation sequencing were carried out for the proband. RESULTS:The proband presented with distal lower limb weakness and proteinuria in childhood. His mother and brother had similar symptoms. Electrophysiological test of the proband revealed demyelination and axonal changes in both motor and sensory nerves. Renal biopsy suggested focal segmental glomerulosclerosis. Genetic testing revealed a heterozygous c.341G>A (p.G114D) mutation in exon 2 of the INF2 gene. CONCLUSION:The phenotypic feature of the pedigree is autosomal dominant intermediate CMT and focal segmental glomerulosclerosis, which may be attributed to the c.341G>A mutation of the INF2 gene.	0
Distal arthrogryposis (DA) is a skeletal muscle disorder which can be classified under a broader term as Arthrogryposis multiplex contractures. DA is characterized by the presence of joint contractures at various parts of the body, particularly in distal extremities. It is identified as an autosomal dominant and a rare X-linked recessive disorder associated with increased connective tissue formation around joints in such way that immobilizes muscle movement causing deformities. DA is again classified into various types since it manifests as a range of conditions representing different etiologies. Myopathy is one of the most commonly listed etiologies of DA. The mutations in sarcomeric protein-encoding genes lead to decreased sarcomere integrity, which is often associated with this disorder. Also, skeletal disorders are often associated with cardiac disorders. Some studies mention the presence of cardiomyopathy in patients with skeletal dysfunction. Therefore, it is hypothesized that the congenitally mutated protein that causes DA can also lead to cardiomyopathy. In this review, we will summarize the different forms of DA and their clinical features, along with gene mutations responsible for causing DA in its different forms. We will also examine reports that list mutations also known to cause heart disorders in the presence of DA.	0
Background: Generalized pustular psoriasis (GPP) is an uncommon variant of psoriasis that is characterized clinically by sterile pustule formation superimposed over inflamed, erythematous skin.Methods: In June 2019, we conducted a systematic search of the PubMed Medline database using the keywords 'pustular psoriasis' and 'treatment'.Results: First-line treatment for the condition consists of established therapies, such as acitretin, cyclosporine, methotrexate, and infliximab. Several medications targeting IL-17 or IL-23 have also emerged recently with drugs such as ixekizumab, secukinumab, brodalumab, guselkumab, and ustekinumab having shown some efficacy.Conclusions: This review highlights the research in support of common treatments of GPP, including classically used medications and newer monoclonal antibodies, and addresses the continued need for high quality studies regarding treatments for this condition.	0
Leigh syndrome, or infantile necrotizing subacute encephalopathy (OMIM #256000), is one of the most common manifestations of mitochondrial dysfunction, due to mutations in more than 75 genes, with mutations in respiratory complex I subunits being the most common cause. In the present study, we used the recently described PHP.B serotype, characterized by efficient capacity to cross the blood-brain barrier, to express the hNDUFS4 gene in the Ndufs4 -/- mouse model of Leigh disease. A single intravenous injection of PHP.B-hNDUFS4 in adult Ndufs4 -/- mice led to a normalization of the body weight, marked amelioration of the rotarod performance, delayed onset of neurodegeneration, and prolongation of the lifespan up to 1 year of age. hNDUFS4 protein was expressed in virtually all brain regions, leading to a partial recovery of complex I activity. Our findings strongly support the feasibility and effectiveness of adeno-associated viral vector (AAV)-mediated gene therapy for mitochondrial disease, particularly with new serotypes showing increased permeability to the blood-brain barrier in order to achieve widespread expression in the central nervous system.	0
STUDY OBJECTIVE: To determine anesthetic considerations for patients with de Barsy syndrome, a rare complex whose hallmark findings include cutis laxa, progeria, and multiple orthopedic and ophthalmologic abnormalities. DESIGN: Retrospective chart review. SETTING: Medical center. MEASUREMENTS: A search of Mayo Clinic medical records from 1968 to 2007 identified two patients with de Barsy syndrome who underwent a combined total of 35 anesthetics for diagnostic and surgical procedures. Data collected included: age, gender, ASA physical status, relevant comorbidities, surgical procedures, airway management, vascular access, monitoring, anesthetic induction, maintenance, and other observations. MAIN RESULTS: A wide range of anesthetics and techniques were used. Apart from 4 episodes of intraoperative hyperthermia and postoperative tachycardia, no complications were noted. These episodes may be similar to the nonmalignant hyperthermia reported in osteogenesis imperfecta and Costello syndrome patients. CONCLUSIONS: While the safety of any anesthetic technique cannot be established or extrapolated from a small series, given the extreme rarity of the syndrome, these cases suggest the relative safety of anesthesia in de Barsy syndrome patients.	0
Müllerian and vaginal anomalies are congenital malformations of the female reproductive tract resulting from alterations in the normal developmental pathway of the uterus, cervix, fallopian tubes, and vagina. The most common of the Müllerian anomalies affect the uterus and may adversely impact reproductive outcomes highlighting the importance of gaining understanding of the genetic mechanisms that govern normal and abnormal development of the female reproductive tract. Modern molecular genetics with study of knock out animal models as well as several genetic syndromes featuring abnormalities of the female reproductive tract have identified candidate genes significant to this developmental pathway. Further emphasizing the importance of understanding female reproductive tract development, recent evidence has demonstrated expression of embryologically significant genes in the endometrium of adult mice and humans. This recent work suggests that these genes not only play a role in the proper structural development of the female reproductive tract but also may persist in adults to regulate proper function of the endometrium of the uterus. As endometrial function is critical for successful implantation and pregnancy maintenance, these recent data suggest a target for gene therapy. Future research will be needed to determine if gene therapy may improve reproductive outcomes for patients with demonstrated deficient endometrial expression related to abnormal gene expression.	0
Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.	0
BACKGROUND:Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that is characterized by motor symptoms such as tremor, rigidity, slowness of movement and problems with gait. Large-scale meta-analyses of genome-wide association studies (GWAS) have identified few susceptibility loci in patients with sporadic PD. The aim of this study was to investigate the association between NMD3 single nucleotide polymorphism (SNP) and symptoms in PD patients in South China. METHODS:A total of 217 PD patients were recruited in this study and genotyped by using the SNaPshot technique and the polymerase chain reaction. All subjects were evaluated by the Mini-Mental State Examination (MMSE), Beijing version Montreal Cognitive Assessment (MoCA), Sniffin' Sticks 16 (SS-16), Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, 39-item Parkinson's Disease Questionnaire (PDQ-39) and MDS Unified PD Rating Scale (MDS-UPDRS). RESULTS:NMD3 rs34016896 (C > T) carriers have worse cognitive function than wild types (MMSE: p = 0.042, NMD3 wild type: 27.44 ± 2.89, NMD3 carriers: 26.31 ± 3.79; MoCA: p = 0.005, NMD3 wild type: 23.15 ± 4.20, NMD3 carriers: 20.75 ± 6.68). CONCLUSIONS:The recessive and overdominant model of NMD3 rs34016896 was associated with cognitive impairment in PD patients.	0
Dermoscopy is a noninvasive diagnostic technique that permits the visualization of morphologic features that are not visible to the naked eye. It is currently widely used for examination of pigmented skin lesions and early detection of cutaneous melanoma. Dermoscopy of mucous membranes is significantly less investigated and less popular among clinicians.This article reviews current knowledge about characteristic dermoscopy features of pigmented lesions of the oral mucous membranes and lips. It has to emphasized that a major advantage of dermoscopy is the capability to exclude melanoma and avoid unnecessary excisional biopsies and extensive surgery, often resulting in significant disfigurement of face and oral cavity.It has to be pointed out that there is a necessity to intensify research, which would result in clear-cut dermoscopy criteria for mucosal melanoma and the need for constructing thin, flexible dermoscopes suitable for investigation of oral mucous membranes.	0
A 28-year-old man came to us with a solitary skin colored, mildly tender nodule of 6 months duration on the dorsum of the right hand. On histological examination, multiple dilated ducts without apparent continuity with the surface were found in the dermis. These dilated ducts had branching tubules with eosinophilic amorphous material filling most of the lumina. The peripheral cells of the tubules resembled myoepithelial cells, whereas the luminal border cells were cuboidal or low columnar. Papillary projections arising from the inner cells were seen extending into the lumen. These features were diagnostic of a rare tumor, papillary eccrine adenoma.	0
The following is a case of an 81-year-old male adult who presented to our emergency department with signs of urosepsis. The patient came with an indwelling urinary catheter due to benign prostatic hyperplasia. Extended diagnostic investigation demonstrated an infected urachal cyst as the cause of infection, which was surgically treated.	0
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized by obesity, mental impairment, rod-cone dystrophy, polydactyly, male hypogonadism, and renal abnormalities. This disorder is caused by mutations in BBS1-21. Alström syndrome (AS), caused solely by mutations in ALMS1, is another genetic obesity syndrome clinically similar to BBS. We previously conducted the first nationwide survey of BBS in Japan and found four patients with genetically definite BBS. In this study, exome analyses were performed on new patients whose symptoms fulfilled the diagnostic criteria for BBS. We identified one reported heterozygous mutation in BBS1 (p.R429*) in one patient, two novel mutations (p.L493R and p.H719Y) in BBS20 in a second patient, and one novel mutation (p.Q920*) and one reported mutation (p.R2928*) in ALMS1 in a third patient, who was subsequently diagnosed with AS. The first patient with BBS was previously considered to have digenic heterozygous mutations in BBS1 and BBS4. RT-PCR and long-range genomic PCR analyses identified a new heterozygous mutation in BBS1, the deletion of exons 10 and 11. Thus, this patient was compound heterozygous for mutations in BBS1. Many studies have described digenic heterozygous mutations in BBS. However, undetected mutations might have existed in either one of the mutated genes.	0
OBJECTIVE:To explore the genetic basis for a child with supravalvular aortic stenosis. METHODS:The child and his parents were subjected to conventional G-banding karyotyping, array comparative genomic hybridization (aCGH) and multiplex ligation-dependent probe amplification (MLPA) analysis. RESULTS:No karyotypic abnormality was detected in the child and his parents. aCGH has identified a de novo 278 kb deletion encompassing the ELN gene in 7q11.23, which overlapped with the critical region of Williams-Beuren syndrome (WBS). MLPA has confirmed above findings. CONCLUSION:The proband was diagnosed with atypical WBS. Deletion of the ELN gene may predispose to supravalvular aortic stenosis in the proband.	0
Narcolepsy is a sleep disorder characterised by loss of hypothalamic hypocretin (orexin) neurons. The prevalence of narcolepsy is about 30 per 100 000 people, and typical age at onset is 12-16 years. Narcolepsy is strongly associated with the HLA-DQB1*06:02 genotype, and has been thought of as an immune-mediated disease. Other risk genes, such as T-cell-receptor α chain and purinergic receptor subtype 2Y11, are also implicated. Interest in narcolepsy has increased since the epidemiological observations that H1N1 infection and vaccination are potential triggering factors, and an increase in the incidence of narcolepsy after the pandemic AS03 adjuvanted H1N1 vaccination in 2010 from Sweden and Finland supports the immune-mediated pathogenesis. Epidemiological observations from studies in China also suggest a role for H1N1 virus infections as a trigger for narcolepsy. Although the pathological mechanisms are unknown, an H1N1 virus-derived antigen might be the trigger.	1
BACKGROUND:Congenital pulmonary airway malformation is a rare congenital lung lesion. Infants with large Congenital pulmonary airway malformation can present with a series of serious symptoms. Surgery is still the main treatment. Thoracoscopic lobectomy for neonates is rarely reported. CASE PRESENTATION:The authors report a case of a congenital pulmonary airway malformation located in the left lower lung of a 4-day-old female infant. Prenatally, the cystic adenomatoid malformation volume ratio was 2.99 according to ultrasound scan. After birth, thoracoscopic lobectomy was performed to alleviate respiratory failure and mediastinal hernia. The patient's clinical symptoms and the X-ray re-examination showed good postoperative recovery. CONCLUSIONS:The purpose of this study is to indicate that a safe and effective minimally invasive surgery for the giant congenital pulmonary airway malformation is feasible, even for infants only 4 days old.	0
Carcinoid syndrome (CS) is a paraneoplastic syndrome caused by the release of serotonin and other substances from well-differentiated neuroendocrine tumors (NETs). The hallmark symptoms of carcinoid syndrome are flushing and diarrhea; atypical signs and symptoms can include wheezing, abdominal pain, valvular heart disease, telangiectasias, pellagra, and the complications of mesenteric fibrosis, including ureteral obstruction, bowel obstruction, and bowel ischemia. These symptoms are mediated by the release of serotonin (5-HT), histamine, kallikrein, prostaglandins, and tachykinins. The diagnosis of CS requires these symptoms and corresponding elevations in lab tests. Treatment options include surgery and medical management with somatostatin analogs.	0
OBJECTIVE:The liver is a central target organ of growth hormone (GH), which stimulates the synthesis of insulin-like growth factor 1 (IGF1) and affects multiple biochemical pathways. A systematic multi-omics analysis of GH effects in the liver has not been performed. GH receptor (GHR) deficiency is a unique model for studying the consequences of lacking GH action. In this study, we used molecular profiling techniques to capture a broad spectrum of these effects in the liver of a clinically relevant large animal model for Laron syndrome. METHODS:We performed holistic proteome and targeted metabolome analyses of liver samples from 6-month-old GHR-deficient (GHR-KO) pigs and GHR-expressing controls (four males, four females per group). RESULTS:GHR deficiency resulted in an increased abundance of enzymes involved in amino acid degradation, in the urea cycle, and in the tricarboxylic acid cycle. A decreased ratio of long-chain acylcarnitines to free carnitine suggested reduced activity of carnitine palmitoyltransferase 1A and thus reduced mitochondrial import of fatty acids for beta-oxidation. Increased levels of short-chain acylcarnitines in the liver and in the circulation of GHR-KO pigs may result from impaired beta-oxidation of short-chain fatty acids or from increased degradation of specific amino acids. The concentration of mono-unsaturated glycerophosphocholines was significantly increased in the liver of GHR-KO pigs without morphological signs of steatosis, although the abundances of several proteins functionally linked to non-alcoholic fatty liver disease (fetuin B, retinol binding protein 4, several mitochondrial proteins) were increased. Moreover, GHR-deficient liver samples revealed distinct changes in the methionine and glutathione metabolic pathways, in particular, a significantly increased level of glycine N-methyltransferase and increased levels of total and free glutathione. Several proteins revealed a sex-related abundance difference in the control group but not in the GHR-KO group. CONCLUSIONS:Our integrated proteomics/targeted metabolomics study of GHR-deficient and control liver samples from a clinically relevant large animal model identified a spectrum of biological pathways that are significantly altered in the absence of GH action. Moreover, new insights into the role of GH in the sex-related specification of liver functions were provided.	0
OBJECTIVES:In this study we describe several cases of ocular dirofilariasis in Bulgaria. MATERIALS AND METHODS:In the period 2010-2019, we studied 7 patients with subconjunctival or periorbital form of Dirofilaria repens infection. Morphological, serological and paraclinical diagnostic methods were used. RESULTS:The patients were aged between 23 and 72, 6 females and 1 male. In 3 patients, subcutaneous nodules were detected in the area of the upper eyelid, in one patient the location was suborbital. In 3 other patients, subconjunctival location was found. All patients were cured definitively by removal of the larva, without etiologic treatment. CONCLUSION:The most reliable and easily accessible diagnostic method is morphological analysis by microscopy of histological preparations of the parasite. In dirofilariasis, ocular location is one of the most common cases in humans, and it deserves special attention of clinicians.	0
The complement system is the primary innate immune determinant protecting against invasive diseases caused by the Gram-negative bacterium Neisseria meningitidis (Nme, meningococcus), as evidenced by the extreme susceptibility of individuals with complement deficiencies. In contrast, the role of phagocytes such as neutrophils is much less well understood, although they are recruited in great numbers to the cerebrospinal fluid during meningococcal meningitis. Here, we consider the interaction of Nme with primary human neutrophils using either purified cells or a whole blood model of infection. We found that neutrophils are capable of non-opsonic uptake and killing of different Nme strains. However, in the presence of immune serum featuring active complement, Nme association is strongly increased, whereas this is not the case in heat-inactivated immune serum. Blockade of complement at the level of C3 using the inhibitor compstatin Cp20 reduces the uptake dramatically. In addition, purified neutrophils did not mount an oxidative burst towards Nme unless complement was added and, vice versa, the oxidative burst was strongly reduced in whole blood upon complement inhibition. In contrast, there was no significant impact of complement on neutrophil degranulation or IL-8 secretion. Taken together, neutrophils require complement activation in order to mount a full response towards Nme.	0
Purpose:To describe the diagnosis and management of a patient with rupture of the posterior capsule (PC) following blunt trauma to the left eye. Observation:68 year-old man presented with complaints of left eye pain, blurry vision and photophobia after getting hit in the left eye with a baseball. He was found to have a posterior capsule rupture, as well as mydriasis and zonular dialysis without formation of intumescent traumatic cataract. Femtosecond laser associated cataract surgery (FLACS) was performed to facilitate creation of an anterior capsulotomy and segmentation of the nucleus without additional strain on the posterior capsule, facilitating placement of a capsular tension ring segment and a 3-piece IOL in the sulcus. At three-month post-operative visit, his BCVA was 20/30 in the left eye with a well-centered IOL. Conclusions and Importance:Isolated PC tear following high-speed blunt trauma is relatively rare and prior reports have managed these cases using standard phacoemulsification and IOL insertion. Our case highlights the advantages of using FLACS in management of traumatic PC tears and outlines modifications to this technique for such cases.	0
The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.	0
Introduction:The risk of developing ketoacidosis in patients with type 1 diabetes at high altitude is high. Anorexia associated with acute mountain sickness, dehydration and additional exercise associated with climbing exacerbates the generation of ketones and the development of ketoacidosis. Case presentation:A 33-year-old gentleman with known history of uncontrolled type 1 diabetes mellitus trekked to Everest Base Camp at an altitude of 3440 m and became unwell. He developed altered sensorium and shortness of breath. He ingested eight tablets of acetazolamide (250 mg each) to address these symptoms. Upon presentation to emergency, he was diagnosed with severe diabetes ketoacidosis (DKA) with shock. Resuscitation was started with fluid, insulin, vasopressors and mechanical ventilation. Despite adequate fluid resuscitation, insulin, bicarbonates and other supportive measures, his acidosis and shock persisted and then managed with hemodialysis. After the first session of hemodialysis, improvement in acidosis and shock was noted. He was successfully extubated and later discharged. Discussion:In this case report, DKA due to acute mountain sickness was complicated by acetazolamide use and noncompliance to his regular insulin intake. There is no proper guideline regarding the role of renal replacement therapy in management of DKA. However, evidence of hemodialysis in DKA is limited to few case reports. Improvement seen in our patient after dialysis is related to dialyzable nature of acetazolamide. Conclusion:We present a case of a severe DKA potentially precipitated by acute mountain sickness, use of acetazolamide, noncompliance to his regular insulin intake and managed with hemodialysis in addition to conventional treatment for DKA.	0
Hypertension (HTN) affects about 1 billion people worldwide and the lack of a single identifiable cause complicates its treatment. Blood pressure (BP) levels are influenced by environmental factors, but there is a strong genetic component. Linkage analysis has identified several genes involved in Mendelian forms of HTN and the associated pathophysiological mechanisms have been unravelled, leading to targeted therapies. The majority of these syndromes are due to gain-of-function or loss-of-functions mutations, resulting in an alteration of mineralocorticoid, glucocorticoid, or sympathetic pathways. The diagnosis of monogenic forms of HTN has limited practical implications on the population and a systematic genetic screening is not justifiable. Genome-wide linkage and association studies (GWAS) have identified single nucleotide polymorphisms (SNPs), which influence BP. Forty-three variants have been described with each SNP affecting systolic and diastolic BP by 1.0 and 0.5 mmHg, respectively. Taken together Mendelian inheritance and all GWAS-identified HTN-associated variants explain 2-3% of BP variance. Epigenetic modifications, such as DNA methylation, histone modification and non-coding RNAs, have become increasingly recognized as important players in BP regulation and may justify a further part of missing heritability. In this review, we will discuss how genetics and genomics may assist clinicians in managing patients with HTN.	0
Cerebellar malformations are a rare group of disorders with clinical heterogeneity. The usual posterior fossa malformations comprise of the cystic lesions like Dandy-walker complex, enlarged cisterna magna or arachnoid cysts. The vermis is a commonly associated structure in both cystic and non-cystic posterior fossa malformations. The congenital malformations affecting the cerebellar parenchyma are however very rare. Magnetic resonance imaging (MRI) is an excellent modality to detect and accurately classify these malformations. We describe a case of 14 years old boy with unilateral cerebellar hypoplasia and recurrent seizures with emphasis on the MRI features of this rare entity.	0
The Cre-mediated genetic switch combines the ability of Cre recombinase to stably invert or excise a DNA fragment depending upon the orientation of flanking mutant loxP sites. In this work, we have tested this strategy in vivo with the aim to generate two conditional knock-in mice for missense mutations in the Impad1 and Clcn7 genes causing two different skeletal dysplasias. Targeting constructs were generated in which the Impad1 exon 2 and an inverted exon 2* and the Clcn7 exon 7 and an inverted exon 7* containing the point mutations were flanked by mutant loxP sites in a head-to-head orientation. When the Cre recombinase is present, the DNA flanked by the mutant loxP sites is expected to be stably inverted leading to the activation of the mutated exon. The targeting vectors were used to generate heterozygous floxed mice in which inversion of the wild-type with the mutant exon has not occurred yet. To generate knock-in mice, floxed animals were mated to a global Cre-deleter mouse strain for stable inversion and activation of the mutation. Unexpectedly the phenotype of homozygous Impad1 knock-in animals overlaps with the lethal phenotype described previously in Impad1 knock-out mice. Similarly, the phenotype of homozygous Clcn7 floxed mice overlaps with Clcn7 knock-out mice. Expression studies by qPCR and RT-PCR demonstrated that mutant mRNA underwent abnormal splicing leading to the synthesis of non-functional proteins. Thus, the skeletal phenotypes in both murine strains were not caused by the missense mutations, but by aberrant splicing. Our data demonstrate that the Cre mediated genetic switch strategy should be considered cautiously for the generation of conditional knock-in mice.	0
RATIONALE:Wiedemann-Steiner syndrome (WDSTS, online mendelian inheritance in man 605130) is a rare autosomal dominant disorder characterized by hypertrichosis cubiti. Here, we report a Chinese boy who do not show the characteristic of hypertrichosis cubiti, and was misdiagnosed as blepharophimosis-ptosis-epicanthus inversus syndrome at first. We found a de novo frameshift mutation (p.Glu390Lysfs*10) in the KMT2A gene, which was not reported before. Our study increases the cohort of Chinese WDSTS patients, and expand the WDSTS phenotypic and variation spectrum. PATIENT CONCERNS:The patient demonstrated typical craniofacial features of blepharophimosis-ptosis-epicanthus inversus syndrome, including small palpebral fissures, ptosis, telecanthus, and epicanthus inversus, besides he had congenital heart disease (ventricular septal defects), strabismus, hypotonia, amblyopia, delayed speech and language development, delayed psychomotor development, and amblyopia (HP:0000646) which was not reported before. DIAGNOSIS:FOXL2 gene was cloned and sequenced, however, there was no mutation detected in this patient. The result of Chromosomal microarray analysis was normal. The patient was diagnosed as WDSTS by whole exome sequencing. INTERVENTIONS:The patient received cardiac surgery, frontalis suspension and regular speech and occupational therapy. He also treated with growth hormone (GH). OUTCOMES:The patient's symptoms are improved after cardiac surgery and frontalis suspension, he can express himself well now and had a 10 cm gain in height. LESSONS:As the relationship between genotype and phenotype becomes more and more clear, WES is incredibly powerful tool to diagnose the disease of WDSTS.	0
OBJECTIVE: To determine the prevalence of cleft lip and palate in births taking place in hospitals in the Yazd province, Iran. METHOD: The records of 65,236 live births delivered at 12 hospitals in Yazd province, including Yazd city and four cities of the states, over a four year period from 2003 to 2006 were examined. RESULTS: Fifty six cases of cleft lip and palate were found, a prevalence of 0.86 per 1,000. Among the fifty six cases, there were seventeen cases (30.4%) of isolated cleft palate; thirteen cases (23.2%) of cleft lip and twenty six cases (46.4%) of cleft lip and palate. No statistically significant difference in the occurrence of cleft lip and palate were observed by the season of the birth, gender of newborn or maternal age. In regard to type of cleft, the prevalence of isolated cleft palate was higher in females than in males (p = 0.04). The prevalence of cleft lip was higher in summer than other seasons (p = 0.01). CONCLUSION: The prevalence of cleft lip and palate among live births in Yazd is 0.86 per 1,000 births, that is 1 per 1,163 births.	1
BACKGROUND:Usher syndrome, the most common form of inherited deaf-blindness, is unlike many other forms of syndromic hereditary hearing loss in that the extra aural clinical manifestations are also detrimental to communication. Usher syndrome patients with early onset deafness also experience vision loss due to progressive retinitis pigmentosa that can lead to legal blindness in their third or fourth decade. METHODS:Using a multi-omic approach, we identified three novel pathogenic variants in two Usher syndrome genes (USH2A and ADGRV1) in cases initially referred for isolated vision or hearing loss. RESULTS:In a multiplex hearing loss family, two affected sisters, the product of a second cousin union, are homozygous for a novel nonsense pathogenic variant in ADGRV1 (c.17062C > T, p.Arg5688*), predicted to create a premature stop codon near the N-terminus of ADGRV1. Ophthalmological examination of the sisters confirmed typical retinitis pigmentosa and prompted a corrected Usher syndrome diagnosis. In an unrelated clinical case, a child with hearing loss tested positive for two novel USH2A splicing variants (c.5777-1G > A, p. Glu1926_Ala1952del and c.10388-2A > G, p.Asp3463Alafs*6) and RNA studies confirmed that both pathogenic variants cause splicing errors. Interestingly, these same USH2A variants are also identified in another family with vision loss where subsequent clinical follow-up confirmed pre-existing hearing loss since early childhood, eventually resulting in a reassigned diagnosis of Usher syndrome. CONCLUSION:These findings provide empirical evidence to increase Usher syndrome surveillance of at-risk children. Given that novel antisense oligonucleotide therapies have been shown to rescue retinal degeneration caused by USH2A splicing pathogenic variants, these solved USH2A patients may now be eligible to be enrolled in therapeutic trials.	0
Angioimmunoblastic T-cell lymphoma (AITL) is an unusual subtype of mature peripheral T-cell lymphoma originating from the follicular T-helper cells and is often associated with autoimmune disorders. AITL is an aggressive lymphoma, presenting with constitutional symptoms, generalized lymphadenopathy, and hepatosplenomegaly. Immunohistochemistry and biopsy are diagnostic methods. The treatment modalities range from steroids, immunomodulators, and cytotoxic chemotherapy. An 87-year-old female presented to the emergency department with cough, dyspnea, dizziness, night sweats, and unintentional weight loss with multiple discrete swellings over her body for a duration of three days. Her physical exam was significant for tachycardia with dry mucous membranes and generalized lymphadenopathy. However, no hepatosplenomegaly was noted. Laboratory investigations revealed neutrophilic leukocytosis (12.8 K/uL), with elevated inflammatory markers (C-reactive protein of 1.39 mg/dL, sedimentation rate of 86 mm/hour). The biopsy of the cervical lymph node revealed atypical lymphoid infiltrates. Flow cytometry showed CD10+ and CD4+/CD8+ T-cells with a minority of CD23+ B-cells, and fluorescence in situ hybridization (FISH) reported gains of the BCL2 gene region on chromosome 18, all of which were suggestive of AITL. She was transferred to an advanced hematology center for staging and targeted therapy. A careful review of the patient with the prompt clinical and histological examination is essential for the correct diagnosis as the differentials are vast due to its non-specific clinical presentation and accurate treatment is a must for complete remission.	0
Purpose: To assess the frequency of clinical signs in patients with viral acute anterior uveitis (AAU), and their ability to differentiate viral versus non-viral AAU.Methods: 168 patients with AAU, including 84 with presumed viral etiology, were evaluated. Sensitivity, specificity, area under the curve (AUC), positive and negative predictive value were calculated for each clinical sign. The model built with these parameters was tested on a validation group comprising 66 patients with AAU.Results: The most useful clinical signs were unilaterality (sensitivity: 98.8%, specificity: 57.1%), intraocular pressure (IOP) ≥24 mmHg (sensitivity: 68.7%, specificity: 91.7%), and the association between the two (sensitivity: 68.7%, specificity: 95.2%). In the validation group, the model built with these parameters presented AUC of 0.939. Adding iris atrophy AUC increased to 0.97. Considering these signs, it was possible to diagnose viral uveitis in 93.9% of the patients.Conclusion: Unilaterality, IOP≥24 mmHg and iris atrophy are significant predictors of possible viral etiology in AAU.	0
BACKGROUND:The effects of intravenous immunoglobulin G replacement on perceived health and infection susceptibility of patients suffering from immunoglobulin G (IgG) deficiencies should be evaluated in a prospective analysis. METHODS:Patients with symptomatic primary or secondary IgG deficiencies were interviewed prior to the first IgG infusion (t0) and over the course of their treatment (t1 - t6). The respondents rated their current health using a 100 point scale (EQ-5D-5L), ranging from 0 ('worst imaginable health') to 100 ('best imaginable health'). The patients also provided information on the frequency of infections and of infections requiring antibiotics in the past 8 weeks. A healthy control group (CG) without oncologic diseases answered the questions once. RESULTS:One hundred six patients with a median age of 65 years (21-85 years) were investigated. The median serum IgG concentration changed from 500 mg/dl (t0) to 772 mg/dl (t6). The mean number of infections and of infections requiring antibiotics decreased during IgG replacement significantly. Current health according to EQ-5D-5L improved from 57 (t0) to 68 (t6), compared to 73 in the CG. CONCLUSION:During the course of IgG replacement patients reported fewer and less severe infections. Their health assessment improved but still was inferior to the healthy CG.	0
The striking and complex phenotype of Cockayne syndrome (CS) patients combines progeria-like features with developmental deficits. Since the establishment of the in vitro culture of skin fibroblasts derived from patients with CS in the 1970s, significant progress has been made in the understanding of the genetic alterations associated with the disease and their impact on molecular, cellular, and organismal functions. In this review, we provide a historic perspective on the research into CS by revisiting seminal papers in this field. We highlighted the great contributions of several researchers in the last decades, ranging from the cloning and characterization of CS genes to the molecular dissection of their roles in DNA repair, transcription, redox processes and metabolism control. We also provide a detailed description of all pathological mutations in genes ERCC6 and ERCC8 reported to date and their impact on CS-related proteins. Finally, we review the contributions (and limitations) of many genetic animal models to the study of CS and how cutting-edge technologies, such as cell reprogramming and state-of-the-art genome editing, are helping us to address unanswered questions.	0
The role of X-inactivation is often ignored as a prime cause of sex differences in disease. Yet, the way males and females express their X-linked genes has a major role in the dissimilar phenotypes that underlie many rare and common disorders, such as intellectual deficiency, epilepsy, congenital abnormalities, and diseases of the heart, blood, skin, muscle, and bones. Summarized here are many examples of the different presentations in males and females. Other data include reasons why women are often protected from the deleterious variants carried on their X chromosome, and the factors that render women susceptible in some instances.	0
Background:Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by the near-total loss of subcutaneous adipose tissue soon after birth, resulting in ectopic fat deposition and severe metabolic disturbances. Most cases are caused by AGPAT2 or BSCL2 gene mutations. We aimed to report two unrelated CGL patients with a novel frameshift mutation in AGPAT2 (p.Leu124Serfs*26). Methods:Clinical features and laboratory were obtained by medical interview and medical records review. DNA was extracted, amplified and sequenced. Mutation Taster was used to estimate the potential biological impact of the AGPAT2 mutations on the protein function. Results:Patient 1: a 30-year-old woman with lipodystrophy phenotype at birth and diagnosis of diabetes at age 13 presented with severe hypertriglyceridemia and pancreatitis at age 17, hypertension and albuminuria at age 18, proliferative diabetic retinopathy with visual loss at age 25, and an acute myocardial infarction due to multivessel coronary disease during a hospitalization for forefoot amputation at age 29. At this time, she required hemodialysis due to end-stage renal disease. Patient 2: a 12-year-old girl with lipodystrophy phenotype and hypertriglyceridemia detected in the first year of life and abnormalities in the global longitudinal strain, evaluated by speckle-tracking echocardiography last year. Molecular analysis identified a c.369_372delGCTC (p.Leu124Serfs*26) AGPAT2 mutation in both unrelated patients, a compound heterozygous mutation in Patient 1, and homozygous mutation in Patient 2. Conclusion:We describe two unrelated patients with type 1 CGL due to Leu124Serfs*26, a novel AGPAT2 frameshift mutation, presenting as early cardiovascular disease. These findings suggest an association between Leu124Serfs*26 and a more aggressive phenotype.	0
Pallidal deep brain stimulation is an established treatment in dystonia. Available data on the effect in DYT-THAP1 dystonia (also known as DYT6 dystonia) are scarce and long-term follow-up studies are lacking. In this retrospective, multicenter follow-up case series of medical records of such patients, the clinical outcome of pallidal deep brain stimulation in DYT-THAP1 dystonia, was evaluated. The Burke Fahn Marsden Dystonia Rating Scale served as an outcome measure. Nine females and 5 males were enrolled, with a median follow-up of 4 years and 10 months after implant. All benefited from surgery: dystonia severity was reduced by a median of 58% (IQR 31-62, p = 0.001) at last follow-up, as assessed by the Burke Fahn Marsden movement subscale. In the majority of individuals, there was no improvement of speech or swallowing, and overall, the effect was greater in the trunk and limbs as compared to the cranio-cervical and orolaryngeal regions. No correlation was found between disease duration before surgery, age at surgery, or preoperative disease burden and the outcome of deep brain stimulation. Device- and therapy-related side-effects were few. Accordingly, pallidal deep brain stimulation should be considered in clinically impairing and pharmaco-resistant DYT-THAP1 dystonia. The method is safe and effective, both short- and long-term.	0
BACKGROUND/OBJECTIVES:Bart syndrome was initially described as association of congenital absence of skin (CAS), nail abnormalities, and epidermolysis bullosa (EB). Further reports of patients with CAS and EB have been made with wide clinical heterogeneity among them. Current guidelines recommend the elimination of eponyms and use of the descriptive term EB with CAS. METHODS:We performed a PubMed and Medline database search of patients with Bart syndrome or EB with CAS. We included case reports or case series that contained clinical and demographic information. RESULTS:After review, 55 articles were included, reporting 96 patients. CAS involved the lower extremities in all patients, with additional upper limb, trunk, or head involvement in 17%. In all patients, the time to healing ranged from 2 weeks to 6 months; most received only conservative treatment. The subtype and frequency of associated EB most frequently reported were recessive dystrophic EB (41.4%) and dominant dystrophic EB (22.8%). Extracutaneous features were present in 29 patients; with pyloric atresia and ear malformations being the most common. The prognosis varied based on the subtype of EB and the presence of additional comorbidities; 50% of the patients with junctional EB with pyloric atresia and CAS died during the first months of life, while mortality among those with recessive dystrophic EB was 6.8%. CONCLUSION:Epidermolysis bullosa with CAS is a clinically heterogeneous disorder, most often associated with recessive dystrophic EB, but other EB subtypes may occur. Further investigations are necessary to better establish a pathological mechanism for CAS, and its association with EB.	0
Classic Ehlers-Danlos syndrome is a heritable connective tissue disorder characterized by skin hyperextensibility, fragile and soft skin, delayed wound healing with formation of atrophic scars, easy bruising, and generalized joint hypermobility. It comprises Ehlers-Danlos syndrome type I and Ehlers-Danlos syndrome type II, but it is now apparent that these form a continuum of clinical findings and differ only in phenotypic severity. It is currently estimated that approximately 50% of patients with a clinical diagnosis of classic Ehlers-Danlos syndrome harbor mutations in the COL5A1 and the COL5A2 gene, encoding the α1 and the α2-chain of type V collagen, respectively. However, because no prospective molecular studies of COL5A1 and COL5A2 have been performed in a clinically well-defined patient group, this number may underestimate the real proportion of patients with classic Ehlers-Danlos syndrome harboring a mutation in one of these genes. In the majority of patients with molecularly characterized classic Ehlers-Danlos syndrome, the disease is caused by a mutation leading to a nonfunctional COL5A1 allele and resulting in haploinsufficiency of type V collagen. A smaller proportion of patients harbor a structural mutation in COL5A1 or COL5A2, causing the production of a functionally defective type V collagen protein. Most mutations identified so far result in a reduced amount of type V collagen in the connective tissues available for collagen fibrillogenesis. Inter- and intrafamilial phenotypic variability is observed, but no genotype-phenotype correlations have been observed. No treatment for the underlying defect is presently available for Ehlers-Danlos syndrome. However, a series of preventive guidelines are applicable.	1
Tel Hashomer camptodactyly syndrome (THCS) was diagnosed in a 4-month-old boy whom we have followed for 12 years. In addition to the characteristic clinical findings, he had preductal coarctation of the aorta, persistent ductus arteriosus, and multiple ventricular septal defects. The electron-microscopic evaluation of his muscle biopsy showed anomalies of the sarcoplasmic reticulum and mitochondria; the organization of the myofibrils was normal. The morphological findings suggested primary or secondary involvement of neuromuscular signal transduction and involvement of mitochondria in the development of the myopathy in this child.	0
Balanced de novo non-robertsonian translocations (non-RTs), which involve acrocentric chromosomes, are rare findings in clinical cytogenetics and may be associated with an abnormal phenotype. These translocations, detected by conventional karyotyping, are found in approximately 1:1,000 neonates. In most of these cases, one of the parents carries the same translocation. In this study, we report a rare non-RT involving chromosomes 15 and 22 defined as 45, XX, -22,der(15;22)t(15;22)/46, XX, der(15)t(15;22),der(22). To our knowledge, this is the first report of a non-RT t(15;22) with these breakpoints.	0
A case of Morgagni Stewart Morel syndrome with progressive depression in frontal bone, headache, transient monoparesis, obesity; imbalance, neuropsychiatric symptoms and recurrent disc prolapse with absent right radial pulse is discussed. This syndrome was first mentioned 235 years back, but till now exact pathology is not known. Balance assessment using dynamic posturography was done, which revealed abnormal vestibular function. To our knowledge this is the first case examined for Dynamic Posturography.	0
Background:The expression of the parathyroid transcription factors, encoded by the genes GATA3, GCM2, and MAFB, persists after parathyroid morphogenesis. This suggests a role of these genes in the regulatory program that governs parathyroid function in the adult. Indeed, these 3 genes form a transcriptional cascade able to activate PTH gene expression. Materials and Methods:Adult adenoma parathyroid tissues were put in primary cell culture to evaluate the messenger ribonucleic acid (mRNA) expression of the PTH gene, of the genes involved in the calcium regulatory signaling pathway (CaSR, GNA11, and AP2S1), and of the 3 genes (GATA3, GCM2, and MAFB) involved in the parathyroid morphogenesis in the presence of different extracellular calcium concentrations from 0.1 mM to 3.0 mM. Aim:The aim of the study was to investigate whether different extracellular calcium conditions could control the expression of transcription factors critical for parathyroid embryogenesis. Results:The results of the experiments showed that the mRNA expression of GATA3, GCM2, and MAFB genes follows the same response as the PTH gene to extracellular calcium concentrations, with the highest expression at low calcium (0.1 mM) and the lowest at high calcium (3.0 mM). Conversely, the genes involved in the calcium signaling in the parathyroid cells showed a variable response to the extracellular calcium concentrations, with the CaSR and GNA11 genes exhibiting a sensitivity to low calcium concentrations. Conclusions:These findings indicate that transcription factors recognized for their role in parathyroid embryogenesis show a response to extracellular calcium later in adulthood that parallels the behavior of the PTH gene.	0
Plaque brachytherapy is a well-accepted modality to manage selected cases of ocular melanoma. Although this modality provides validated oncologic and quality of life benefits, severe complications and adverse events can occur. This article reviews complications and adverse events of plaque brachytherapy, including scleral necrosis, strabismus, cataract, glaucoma, and retinopathies as well as management of these conditions. For practicing oncologists and ophthalmologists, these complications are important to understand, identify, and treat. Additionally, an understanding of common complications of brachytherapy should influence the decision of pursuing it as a treatment option.	0
Introduction:Corpus callosotomy (CCT) is a palliative procedure to treat injurious drop attacks or multifocal/generalized seizures in which resection of the epileptogenic focus is not feasible. We are presenting our experience in treating intractable epilepsy patients by CCT procedures. Methods:We observed 16 patients who underwent callosotomy (male to female ratio 7:9; adult to pediatric ratio 3:13). Initial seizure frequency was reported ranged from 1 to 2 attacks daily to very often (more than 20 episodes daily). Results:Our observation showed that among patients with drop attacks, complete and >90% seizure freedom was reported by 4 and 6 of 13 patients, respectively (76.9% combined). Conclusion:Our observation showed that corpus callosotomy yielded good outcome in patients with intractable epilepsy in Indonesia. Our observation showed total callosotomy achieved complete seizure freedom better compared to partial callosotomy patients.	0
In the presence of megacystis in the second half of pregnancy, with increased amniotic fluid, especially in a female fetus, the most likely diagnostic result is megacystis, microcolon, intestinal hypoperistalsis syndrome, MMIHS. In these cases, the diagnosis of MMIHS should be strongly considered instead of lower urinary tract obstruction.	0
Microtia is a congenital malformation of the external ear caused by genetic and/or environmental factors. However, no causal genetic mutations have been identified in isolated microtia patients. In this study, we utilized targeted genomic capturing combined with next-generation sequencing to screen for mutations in 307 deafness genes in 32 microtia patients. Forty-two rare heterozygous mutations in 25 genes, including 22 novel mutations in 24 isolated unilateral microtia cases were identified. Pathway analysis found five pathways especially focal adhesion pathway and ECM-receptor interaction pathway were significantly associated with microtia. The low-frequency variants association study was used and highlighted several strong candidate genes MUC4, MUC6, COL4A4, MYO7A, AKAP12, COL11A1, DSPP, ESPN, GPR98, PCDH15, BSN, CACNA1D, TPRN, and USH1C for microtia (P = 2.51 × 10-4). Among these genes, COL4A4 and COL11A1 may lead to microtia through focal adhesion pathway and ECM-receptor interaction pathway which are connected to the downstream Wnt signaling pathway. The present results indicate that certain genes may affect both external/middle and inner ear development, and demonstrate the benefits of using a capture array in microtia patients.	0
OBJECTIVES:There is controversy regarding surgical margins in the management of early oral squamous cell carcinoma (OSCC). The main objectives of this study were to assess the: relevance of the margin independent of tumour variables; threshold for a safe margin; relevance of dysplasia at the margin. MATERIALS & METHODS:UK based retrospective multicenter cohort study of patients with previously untreated and clinically early OSCC between 1998 and 2016. All patients had surgery as the primary modality and had surgical staging of the neck. Minimum follow-up was 2 years. Margins were classified as: clear ≥5.0 mm; close 1.0-4.9 mm; involved not cut-through (INC-T) 0.1-0.9 mm; cut-through (C-T) 0 mm. RESULTS:669 patients were included. After adjusting for tumour variables Cox multivariate regression analysis demonstrated that close margins had similar survival outcomes to clear margins (Hazard Ratio(HR) 0.99 (95%CI 0.50-1.95) for Local Recurrence Free Survival (LRFS); HR 1.08 (95%CI 0.7-1.66) for Disease Free Survival (DFS); HR 0.74 (95%CI 0.44-1.25) for Disease Specific Survival (DSS); HR 0.80 (95%CI 0.58-1.11) for Overall Survival (OS)). C-T margins had significantly worse LRFS (HR 5.01 (95%CI 2.02-12.39)) and DFS (HR 2.58 (95%CI 1.28-5.20)). INC-T margins had significantly worse DFS (HR 1.98 (95% CI 1.01-3.87)). Time dependent receiver operating characteristic curve analysis did not demonstrate a clear margin threshold for LRFS within 24 months (AUC = 0.53 (95%CI 0.41-0.64)). Dysplasia at the margin did not influence LRFS or DFS. CONCLUSION:Only resection margins <1 mm independently affected survival outcomes. This should be considered when making decisions regarding adjuvant treatment.	0
Variants in TGFBR1 have been reported to induce two completely distinct diseases, namely Loeys-Dietz syndrome (LDS) and multiple self-healing squamous epithelioma (MSSE). However, detailed mechanisms underlying this effect remain unknown. We report a Japanese familial case of LDS with a novel splice donor site variant in TGFBR1 gene (c.973 + 1 G > A; NG_007461.1). The intronic variant was predicted to mediate in-frame exon 5 skipping within the serine/threonine kinase (STK) domain, which may also be mediated by a similar TGFBR1 variant of a splice acceptor site in intron 4 (c.806-2 A > C), identified in a British familial case of MSSE. Therefore, ex vivo splicing and functional assays were performed in mammalian cells to evaluate the effect of these sequence variants. The MSSE variant activated a cryptic acceptor site at 76 bp downstream of the 3' natural splice acceptor site, which produced an out-of-frame transcript (r.807_882del, p.Asn270Thrfs*8). In contrast, the LDS variant generated two types of in-frame transcription products, r.[806_973del, 965_973 del], and produced two functionally inactivated proteins, p.[Asp269_Gln324del, Thr323_Gly325del], as a result of exon 5 skipping and the activation of a cryptic donor splice site at 9 bp upstream of the 5' natural splice donor site, respectively. Our results support the previously proposed but not yet approved mechanism that dominant-negative and truncating variants in STK domain induce LDS and MSSE, respectively.	0
Fatty acid oxidation (FAO)-driven H2O2 has been shown to be a major source of oxidative stress in several tissues and disease states. Here, we established that the mitochondrial flavoprotein long-chain acyl-CoA dehydrogenase (LCAD), which catalyzes a key step in mitochondrial FAO, directly produces H2O2in vitro by leaking electrons to oxygen. Kinetic analysis of recombinant human LCAD showed that it produces H2O2 15-fold faster than the related mitochondrial enzyme very long-chain acyl-CoA dehydrogenase (VLCAD), but 50-fold slower than a bona fide peroxisomal acyl-CoA oxidase. The rate of H2O2 formation by human LCAD is slow compared to its activity as a dehydrogenase (about 1%). However, expression of hLCAD in HepG2 cells is sufficient to significantly increase H2O2 in the presence of fatty acids. Liver mitochondria from LCAD-/- mice, but not VLCAD-/- mice, produce significantly less H2O2 during incubation with fatty acids. Finally, we observe highest LCAD expression in human liver, followed by kidney, lung, and pancreas. Based on our data, we propose that the presence of LCAD drives H2O2 formation in response to fatty acids in these tissues.	0
BACKGROUND:Benign recurrent intrahepatic cholestasis is a genetic disorder with recurrent cholestatic jaundice due to ATP8B1 and ABCB11 gene mutations encoding for hepato-canalicular transporters. Herein, we firstly provide the evidence that a nonsense variant of ATP8B1 gene (c.1558A>T) in heterozygous form is involved in BRIC pathogenesis. CASE SUMMARY:A 29-year-old male showed severe jaundice and laboratory tests consistent with intrahepatic cholestasis despite normal gamma-glutamyltranspeptidase. Acute and chronic liver diseases with viral, metabolic and autoimmune etiology were excluded. Normal intra/extra-hepatic bile ducts were demonstrated by magnetic resonance. Liver biopsy showed: Cholestasis in the centrilobular and intermediate zones with bile plugs and intra-hepatocyte pigment, Kupffer's cell activation/hyperplasia and preserved biliary ducts. Being satisfied benign recurrent intrahepatic cholestasis diagnostic criteria, ATP8B1 and ABCB11 gene analysis was performed. Surprisingly, we found a novel nonsense variant of ATP8B1 gene (c.1558A>T) in heterozygosis. The variant was confirmed by Sanger sequencing following a standard protocol and tested for familial segregation, showing a maternal inheritance. Immunohistochemistry confirmed a significant reduction of mutated gene related protein (familial intrahepatic cholestasis 1). The patient was treated with ursodeoxycholic acid 15 mg/kg per day and colestyramine 8 g daily with total bilirubin decrease and normalization at the 6th and 12th mo. CONCLUSION:A genetic abnormality, different from those already known, could be involved in familial intrahepatic cholestatic disorders and/or pro-cholestatic genetic predisposition, thus encouraging further mutation detection in this field.	0
Scleromyxedema (SME) is characterized by widespread waxy papules on the skin, with mucin deposits in the upper dermis. Twenty-one SME cases of myopathy have been reported; of the cases, six showed vacuolar formation, and two showed mucin deposition. We report the first case of SME with mucin-containing vacuolated fibers. A 45-year-old woman with SME developed progressive proximal muscle weakness. Muscle biopsy revealed myopathic changes with numerous vacuoles linked to mucin in the affected muscle fibers, which were heavily immunostained for fibroblast growth factor 2 (FGF2). Despite repeated high dose oral prednisolone and intravenous immunoglobulin administrations, muscle weakness recurred continuingly, culminating in death due to congestive heart failure. Immunotherapy was partly effective in our case, although it was refractory. Treatment responsiveness in patients with SME myopathy varied; however, due to its rarity, the mechanism remains to be elucidated. To address this issue, we investigated muscle specimens immunohistochemically and detected marked upregulation of FGF2 in the affected muscle fibers of our patient. FGF2, a strong myogenesis inhibitor, may exert a suppressive effect on muscle fiber regeneration, which may have conferred refractoriness to our patient's SME myopathy.	0
To demonstrate the clinical application of the Korean version of the Modified Barthel Index (K-MBI) using Rasch analysis.A total of 276 patients with neurological disorders were assessed with the K-MBI in outpatient clinics. The Rasch partial-credit model was used to generate a keyform based on investigating the psychometric properties of the K-MBI, including dimensionality, precision (person strata and reliability), and hierarchical item difficulty. The Minimal Detectable Change (MDC) in item difficulty was used to establish right-challenging treatment goals and long-term treatment plans.The findings demonstrated that the Korean version of the MBI satisfied the assumption of unidimensionality. It also showed a hierarchical structure in terms of item difficulty, good reliability (Cronbach alpha, 0.92), and approximately five distinct person strata (4.6). The MDC (raw score, 20.1) of the item difficulty of the test items demonstrated equivalent cutoff scores for targeted short-term treatment goals on the keyform, a Rasch-derived display of patient responses. Long-term treatment goals were identified based on the test items of the keyform.The findings suggest that a Rasch keyform can be applied to clinical practice in Korean settings by identifying clinically and statistically meaningful test items and their step thresholds as short- and long-term goals.	0
RATIONALE:Holocarboxylase synthetase (HCLS) deficiency, especially the late-onset type, is a rare disease. Affected patients can present with irreversible metabolic acidosis and may be misdiagnosed with a glucose metabolic disorder. Prompt and correct diagnosis and treatment can reduce mortality to a great extent. PATIENT CONCERNS:We report 2 Chinese patients who were diagnosed with late-onset HCLS deficiency. The age of onset of the 2 patients was approximately 8 months. The 2 patients had skin lesions, severe profound metabolic acidosis, dyspnea, and hyperglycemia. DIAGNOSES:The results of urinary and blood organic acid analysis with gas chromatography/mass spectrometry revealed multiple carboxylase deficiency. Maple syrup urine disease and diabetic ketoacidosis could not be excluded. This finding is different from those of hypoglycemic complications reported in previous reports. Human genetic analysis eventually provided a definite diagnosis. INTERVENTIONS:Prompt oral treatment with biotin dramatically corrected the metabolic imbalances of the 2 patients, and continued oral biotin therapy was essential to the improvement of their prognoses. OUTCOMES:Their metabolic disorders were corrected within 48 hours. During long-term follow-up, the patients achieved developmental milestones. LESSONS:Late-onset HCLS deficiency may present with obvious hyperglycemia. Human genetic analysis eventually provided a definite diagnosis. Prompt treatment with biotin is vital to correct metabolic imbalances, and continued therapy is essential to the improving long-term prognoses. Their mutations were p.R508W and c.1088T > A, and these mutations might represent hot-spot genes in Chinese populations with HCLS deficiency. The variants c.1484T > G(p.L495*) and c.835G > T(p.E279x) are likely pathogenic, and more studies are needed to confirm these results.	0
A 65-year-old man was diagnosed with agammaglobulinemia at the age of 53 years. To investigate the cause of the increased CRP value, CT was performed and revealed thickening of the walls of the ascending colon and rectum. Colonoscopy revealed tumors and stenoses in the ascending colon and rectum. Both tumors were found to be adenocarcinomas in histological examinations. The preoperative diagnosis of the ascending colon and rectal cancers was cT4aN0M0, cStageⅡb. Preoperatively, we administered 10.0 g of immunoglobulin intravenously. We performed laparoscopic right hemicolectomy and high anterior resection with D3 dissection of the lymph node. On postoperative day 1, we again administered 10.0 g of immunoglobulin intravenously. The patient recovered uneventfully and was discharged on postoperative day 13. Laparoscopic colectomy for patients with agammaglobulinemia can be performed safely by administering immunoglobulin during the perioperative period.	0
Waardenburg syndrome (WS) is a rare autosomally inherited and genetically heterogeneous disorder of neural crest cell development. Literature regarding the anesthetic management of these cases is limited. We present 2 cases of Shah-Waardenburg syndrome and discuss them in the context of review of previously published cases.	0
Carney triad is a rare syndrome that involves gastrointestinal stromal tumor (GIST), pulmonary chondroma and extra-adrenal paraganglioma. Patients presenting GIST and pulmonary chondroma account for 72.7% of all incomplete Carney triad cases. Clinically, it is mainly diagnosed by radiological images and pathological results. Some studies have elucidated the pathogenesis of Carney triad. Surgical resection is the preferred treatment for Carney triad. Generally speaking, the prognosis of patients with Carney triad has been satisfied. According to current reports, the rate of 40-year survival is up to 73%. The case reports an 18-year-old girl suffering from pulmonary chondroma and posterior mediastinal paraganglioma, simultaneously with pulmonary hamartoma, breast fibroma and lower limb chondroma.	0
BACKGROUND:Neu-Laxova syndrome (NLS) is a rare hereditary disorder featuring intrauterine growth retardation, remarkable oedema with skin restriction, limb contracture, ichthyosis, and craniofacial anomaly. NLS shares multiple overlapping characteristics with several other inheritable refractory diseases: for example, harlequin foetus and restrictive dermopathy. To date, many NLS patients have been described, although the number of NLS cases with clear genetic aetiology remains limited. OBJECTIVES:To characterize the clinical and genetic features of NLS in two Chinese families. MATERIALS AND METHODS:Relevant skin tissue samples, blood specimens, and follow-up data from two unrelated Chinese families with perinatal fatal disorders were collected. To obtain a definitive diagnosis, six genes (ABCA12, LMNA, ZMPSTE24, PHGDH, PSAT1 and PSPH), previously implicated in the pathogenesis of inheritable refractory diseases with similar phenotypic expression to that of the affected members in the two pedigrees, were sequenced. We also performed tandem mass spectrometry, structural protein modelling, and immunohistochemical analysis to further support the genetic findings. RESULTS:New and recurrent missense mutations were identified in two genes (PHGDH and PSAT1) associated with NLS, which further supports the recent findings that NLS is genetically heterogeneous and could result from mutations in genes encoding enzymes of the L-serine biosynthesis pathway. Structural changes in PHGDH and PSAT1 proteins were revealed by molecular modelling. Finally, a tandem mass spectrometry assay and immunohistochemical analysis further corroborated the diagnosis of NLS. CONCLUSION:This study is the first description of PHGDH and PSAT1 mutations in Chinese NLS patients, which strongly implicates them in the pathogenesis of NLS.	0
Constitutional GATA2 deficiency caused by heterozygous germline GATA2 mutations has a broad spectrum of clinical phenotypes, including systemic infections, lymphedema, cytopenias, and myeloid neoplasms. Genotype-phenotype correlation is not well understood mechanistically in GATA2 deficiency. We performed whole transcriptome sequencing of single hematopoietic stem and progenitor cells from 8 patients, who had pathogenic GATA2 mutations and myelodysplasia. Mapping patients' cells onto normal hematopoiesis, we observed deficiency in lymphoid/myeloid progenitors, also evident from highly constrained gene correlations. HSPCs of patients exhibited distinct patterns of gene expression and coexpression compared with counterparts from healthy donors. Distinct lineages showed differently altered transcriptional profiles. Stem cells in patients had dysregulated gene expression related to apoptosis, cell cycle, and quiescence; increased expression of erythroid/megakaryocytic priming genes; and decreased lymphoid priming genes. The prominent deficiency in lympho-myeloid lineages in GATA2 deficiency appeared at least partly due to the expression of aberrant gene programs in stem cells prior to lineage commitment. We computationally imputed cells with chromosomal abnormalities and determined their gene expression; DNA repair genes were downregulated in trisomy 8 cells, potentially rendering these cells vulnerable to second-hit somatic mutations and additional chromosomal abnormalities. Cells with complex cytogenetic abnormalities showed defects in genes related to multilineage differentiation and cell cycle. Single-cell RNA sequencing is powerful in resolving transcriptomes of cell subpopulations despite a paucity of cells in marrow failure. Our study discloses previously uncharacterized transcriptome signatures of stem cells and progenitors in GATA2 deficiency, providing a broad perspective of potential mechanisms by which germline mutations modulate early hematopoiesis in a human disease. This trial was registered at www.clinicaltrials.gov as NCT01905826, NCT01861106, and NCT00001620.	0
The PI3K/AKT/mTOR signaling pathway is significantly activated in rheumatoid arthritis. In addition, somatic activating mutations of the PI3K/AKT/mTOR pathway may result in PIK3CA-related overgrowth spectrum diseases, including CLOVES (Congenital Lipomatous Overgrowth, Vascular malformation, Epidermal nevi, Skeletal abnormalities/Scoliosis) syndrome. We describe the case of a young female patient, with anti-citrullinated peptide antibodies-positive rheumatoid arthritis, referred for persistent finger pain and stiffness. Examination revealed discrete macrodactyly involving two fingers, scoliosis, asymmetrical calves, venectasias, a shoulder nevus and triangular feet with a "sandal gap" between two toes. These mild dysmorphic features with early-onset and the history of surgeries for thoracic lipoma and venous malformation were strongly suggestive of CLOVES syndrome. Confirmatory mutation analysis was not performed, as blood or saliva testing is not contributive for tissue-specific localized effects in the PIK3CA-related overgrowth spectrum. Nevertheless, lack of detection of a PIK3CA mutation does not exclude the diagnosis in patients fulfilling clinical criteria. Due to the patient's wish to plan a pregnancy, therapy consisted in sulfasalazine and hydroxychloroquine, along with orthotic correction of leg length discrepancy. Overgrowth syndromes and arthritis may share common pathways. Mild macrodactyly should be differentiated from dactylitis. Diagnosing patients with minimal dysmorphic features within the PI3K-related overgrowth spectrum may help design better care strategies, in the quest for personalized medicine.	0
 Tietze syndrome (TS) is an inflammatory condition characterized by chest pain and swelling of costochondral junction. Primary chest wall tumors may mimic TS. In this article, we report our experience of approximately 121 patients initially diagnosed as TS and determined chest wall tumor in some cases at the follow-up. This is a retrospective review of patients diagnosed as TS by clinical examination, chest X-ray, electrocardiogram, routine laboratory tests, and computed tomography (CT) of chest: all treated and followed up between March 2001 and July 2012. There were 121 cases (41 males and 80 females; mean age, 39.6 ± 3.2 years) of TS.In 27 patients with initial normal radiological findings, the size of swellings had doubled during the follow-up period (mean, 8.51 ± 2.15 months). These patients were reevaluated with chest CT and bone scintigraphy and then early diagnostic biopsy was performed. Pathologic examination revealed primary chest wall tumor in 13 patients (5 malignant, 8 benign). CT had a sensitivity of 92.3% and a specificity of 64.2% in detection of tumors (kappa: 0.56, p = 0.002), whereas the sensitivity and the specificity of bone scan were 84.6 and 35.7%, respectively (kappa: 0.199, p = 0.385). Primary chest wall tumors could mimic TS. Bone scintigraphy or CT is not specific enough to determine malignant and other benign disorders of costochondral junction. Therefore, clinicians should follow TS patients more closely, and in case of increasing size of swelling, early diagnostic biopsy should be considered.	0
Cryopyrin-associated periodic syndrome (CAPS) is a hereditary autoinflammatory syndrome caused by mutations in NLRP3 (encoding cryopyrin), which presents with fever, fatigue and arthralgia. Thus far, however there have been no reports of CAPS in Korea. Herein, we report 3 cases of CAPS for the first time in Korea. The first case, a 28-year-old man with recurrent urticaria, arthralgia and fever induced by cold, all of which were observed in his father, showed elevated erythrocyte sedimentation rate and C-reactive protein. He exhibited a p.Gly303Asp variant of the NLPR3 gene. The second case, a 2-year-old girl who had recurrent urticaria, arthritis and oral and genital ulcers, was positive for HLA B51 and a p.Glu569Lys mutation in exon 3 of the NLRP3 gene. Administration of anakinra greatly improved her symptoms. The third case, a 4-year-old boy who presented with recurrent urticaria, arthralgia, and fever, exhibited a p.Val72Met mutation in exon 1 of the NLRP3 gene. Administration of tocilizumab improved all of his symptoms. This small case series suggests that clinicians consider CAPS and conduct genetic studies when arthralgia and fever are accompanied by urticaria in Korea.	0
BACKGROUND:Neutrophils are essential innate cells to fight bacterial and fungal pathogens. Jagunal homolog 1 (JAGN1) mutations were recently defined as rare genetic defects causing severe congenital neutropenia. JAGN1 participates in the secretory pathway and is required for granulocyte colony-stimulating factor receptormediated signalling. This gene is required for normal ultrastructure and granulation of endoplasmic reticulum of myeloid progenitor cells. Its defect is related to increased predisposition to apoptosis. In the literature, a few cases have been reported with congenital anomalies such as cardiac and renal anomalies. CASE:Here we report a patient in which JAGN1 deficiency was found after several years. Apart from syndromic facial appearance we were unable to detect any other systemic malformations. CONCLUSION:The causes of multisystemic features of mutations in JAGN1 gene remain unknown. JAGN1 mutations must be considered in patients with severe congenital neutropenia especially with facial dismorphism even in the absence of systemic manifestations.	0
The catabolism of ganglioside GM2 is dependent on three gene products. Mutations in any of these genes result in a different type of GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease, and the B1 and AB variants of GM2 gangliosidosis), with GM2 as the major lysosomal storage compound. GM2 is also a secondary storage compound in lysosomal storage diseases such as Niemann-Pick disease types A-C, with primary storage of SM in type A and cholesterol in types B and C, respectively. The reconstitution of GM2 catabolism at liposomal surfaces carrying GM2 revealed that incorporating lipids into the GM2-carrying membrane such as cholesterol, SM, sphingosine, and sphinganine inhibits GM2 hydrolysis by β-hexosaminidase A assisted by GM2 activator protein, while anionic lipids, ceramide, fatty acids, lysophosphatidylcholine, and diacylglycerol stimulate GM2 catabolism. In contrast, the hydrolysis of the synthetic, water-soluble substrate 4-methylumbelliferyl-6-sulfo-2-acetamido-2-deoxy-β-d-glucopyranoside was neither significantly affected by membrane lipids such as ceramide or SM nor stimulated by anionic lipids such as bis(monoacylglycero)phosphate added as liposomes, detergent micelles, or lipid aggregates. Moreover, hydrolysis-inhibiting lipids also had an inhibiting effect on the solubilization and mobilization of membrane-bound lipids by the GM2 activator protein, while the stimulating lipids enhanced lipid mobilization.	0
RESULTS:Abnormalities: Disheveled: Cacosmious. Personal hygiene poor. Facial expression odd and inappropriate. Loud but low quantity of speech. Unable to interpret similarities or proverbs. Calculation: poor. CONCLUSION:In those who present with BMS, query as to the delusional nature of their symptoms is warranted and may suggest a treatment strategy.	0
Circumportal annular pancreas (CAP) also known as portal annular pancreas (PAP) is an uncommon pancreatic anatomic variant in which normal pancreatic tissue completely surrounds the portal vein and can be mistaken for mass of pancreatic head. We present here a case of a 65 years old woman who was a diagnosed case of endometrial carcinoma, underwent CT scan for further metastatic workup which revealed this rare pancreatic variant.	0
BACKGROUND:Achondroplasia is characterised by a shorter appendicular limb to torso ratio, compared to age matched individuals of average stature (controls). Despite the well documented shorter leg length of individuals with compared to controls, there are few complete descriptions of gait kinematics reported for the population. AIM:The aim of this study was to report the spatio-temporal and kinematic characteristics of self-selected walking (SSW) in a group with Achondroplasia (N = 10) and age matched group without Achondroplasia (controls, N = 17). METHOD:Whole body 3D analysis of both groups was conducted using a 14 camera VICON system. Spatio-temporal and kinematic variables were determined through a Plug-in-Gait model. SSW was obtained from an average of three trials equating to a total of ∼120 m walking. RESULTS:The group with Achondroplasia were 23 % slower (P < 0.001), had a 29 % shorter stride length (P < 0.001) and a 13 % higher stride frequency (P < 0.001) compared to controls. There were no differences in time normalised temporal measures of left toe off (P = 0.365), right heel contact (P = 0.442) or the duration of double support (P = 0.588) between groups. A number of discrete joint kinematic differences existed between groups, resulting in the group with Achondroplasia having more 'flexed' lower limbs than controls throughout the gait cycle. CONCLUSION:Differences in absolute spatio-temporal variables between groups is likely due to the shorter leg length of the group with Achondroplasia, while their more flexed position of the lower limbs may facilitate toe-clearance during the swing phase.	0
Recent advances in clinical as well as basic research on large and small vessel vasculitis in Japan were described based upon the investigations performed by the members of the Research Committee of Intractable vasculitis, sponsored by the Japanese Ministry of Health and Welfare.	1
Background. Melnick-Needles Syndrome is rare congenital hereditary skeletal dysplasia caused by mutations in the FLNA gene, which codifies the protein filamin A. This condition leads to serious skeletal abnormalities, including the stomatognathic region. Case Presentation. This paper describes the case of a 13-year-old girl diagnosed with Melnick-Needles Syndrome presenting with different forms of skeletal dysplasia, such as cranial hyperostosis, short upper limbs, bowed long bones, metaphyseal thickening, genu valgum (knock-knee), shortened distal phalanges, narrow pelvis and shoulders, rib tapering and irregularities, elongation of the vertebrae, kyphoscoliosis, micrognathia, hypoplastic coronoid processes of the mandible, left stylohyoid ligament suggesting ossification, and dental development anomalies. Conclusion. Knowledge of this rare syndrome on the part of dentists is important due to the fact that this condition involves severe abnormalities of the stomatognathic system that cause an impact on the development of the entire face as well as functional and esthetic impairments.	0
PURPOSE:Aspirin has been the cornerstone of antiplatelet therapy in patients with acute coronary syndromes and is well accepted and recommended by several major healthcare organizations. A combination of aspirin and a P2Y12 inhibitor, commonly known as dual antiplatelet therapy, is recommended in patients with coronary stent implantation to reduce the risk of stent thrombosis and ischemic events. SUMMARY:We recently cared for an adult male who presented with an acute coronary syndrome who had a history of Reye syndrome during childhood. During this admission, he was rechallenged with low-dose aspirin for the first time since his diagnosis of Reye syndrome as a child after aspirin therapy. There have been various case reports in children and adults who have been rechallenged with aspirin within days to weeks after the initial diagnosis of Reye syndrome. These reports show mixed results in children and adults regarding the return of Reye syndrome upon aspirin rechallenge shortly after initial aspirin exposure. CONCLUSION:This, to our knowledge, appears to be the first report of a low-dose aspirin rechallenge 30 years later in life in an adult patient with a history of Reye syndrome while receiving aspirin therapy during childhood.	0
PURPOSE OF REVIEW:The present review summarizes recent advances in the diagnosis and management of patients with congenital hypothyroidism. RECENT FINDINGS:Although most newborn screening strategies are designed to detect severe primary hypothyroidism that presents shortly after birth, some infants display a pattern of delayed TSH rise despite normal initial newborn screening. Recent studies suggest that delayed TSH rise may be more common and more severe than previously recognized. Although much less common than primary hypothyroidism, central congenital hypothyroidism is as likely to be of moderate or severe degree, which has implications for its detection and treatment. The discovery of new genetic causes of central congenital hypothyroidism, including the X-linked genes IGSF1, TBL1X, and IRS4, has begun to expand our understanding of thyroid axis regulation. Recent long-term data indicate that current treatment recommendations for congenital hypothyroidism result in grossly normal neurocognitive outcomes even in severely affected patients, and that overtreatment may not be as harmful as previously suspected. Liquid levothyroxine is now commercially available in the United States, but more studies are needed to determine optimal dosing using this formulation. SUMMARY:Prompt identification and adequate treatment of patients with congenital hypothyroidism is critical to optimize outcomes. New information continues to accumulate about how to improve detection of congenital hypothyroidism in specific subgroups of infants (particularly those with delayed TSH rise and central hypothyroidism) and about treatment of patients with this disorder.	0
Malignant mesothelioma is an uncommon tumor that may be difficult to diagnose. The International Mesothelioma Interest Group has been writing guidelines for pathological diagnosis that are periodically updated. The guidelines are being updated based on published literature in the last 3 years, and experience of more than 20 leading international pathologists in the field who will be co-authors. Updates were discussed by attendees of the Pulmonary Pathology Society Biennial Meeting (Dubrovnik, Croatia, June 2019). Areas with significant advancements/changes include utilization of immunohistochemistry (establishing mesothelial lineage and benign versus malignant), prognosis and nuclear grading, biphasic malignant mesothelioma, transitional pattern, malignant mesothelioma in situ, and therapeutic/molecular targets.	0
The aim of the present study is to present the results of the surgical management of late presenting cases of congenital muscular torticollis. Between 1990 and 2010, 31 cases of late presenting congenital muscular torticollis were managed surgically in our department. Postoperatively, head halter traction was applied for 10 days; a cervical brace was applied for 5 weeks, followed by a soft one collar for 3 months. The final result was assessed on the basis of the criteria of Cheng and Tang. In total, 84% of patients achieved an excellent final result and 16% of the patients achieved a good result. Our results indicated that in children older than 7 years, surgical release combined with appropriate orthosis and a structured physiotherapy regime can lead to satisfactory results.	0
BACKGROUND:Progressive familial intrahepatic cholestasis (PFIC) is a rare group of autosomal recessive hereditary hepatic diseases. There are three types of PFIC, classified according to the mutated gene. For example, PFIC type 3 (PFIC3) is due to mutations in the ABCB4 gene (encoding multidrug-resistant protein 3 [MDR3]). CASE PRESENTATION:We present a 19-year-old Chinese female patient who had a 2-year history of recurrent liver dysfunction, with mainly elevated alkaline phosphatase and γ-glutamyl transpeptidase(γ-GT) levels. After excluding other causes of abnormal liver function and cholestasis, the final diagnosis of PFIC3 was confirmed by histopathological examination and gene detection. The immunohistochemical results showed no MDR3 protein expression in the bile duct membrane. Genetic sequencing analysis revealed a novel heterozygous 2137G > A; p. V713M mutation (Exon 17) and a synonymous 504C > T; p. N168N mutation (Exon 6) in ABCB4. CONCLUSIONS:Our patient with long-term liver dysfunction demonstrated that elevated alkaline phosphatase and γ-GT levels should be associated with the diagnosis of PFIC3, and gene detection is the key to diagnosis. From our in silico analysis, the novel mutation p. V713M in Exon 17 was predicted to affect protein function, with a SIFT (Sorting Intolerant from Tolerant) score of 0.02, indicating a deleterious effect. Further studies are necessary to investigate the impact of the novel heterozygous 2137G > A; p. V713M mutation (Exon 17) on functional defects of MDR3 and PFIC3.	0
Focal cortical dysplasia (FCD) type II and hemimegalencephaly (HME) are currently considered as a continuum of pathology, the most important distinction being the extent or the size/volume of the lesion. While partial HME involving the posterior cortex has been well described, we present an unusual case with a dysplastic lesion of the whole frontal lobe. A 17-year-old boy had focal seizures from the age of nine years. Apart from diminished right-hand dexterity, his neurological and cognitive status were unremarkable. The course of his epilepsy exhibited a relapsing-remitting pattern, with prolonged periods of remission. Imaging showed dysplastic left frontal lobe (including paracentral lobule) thickened cortex with an abnormal gyration pattern resembling polymicrogyria, as well as dystrophic calcifications and hypodensity scattered throughout the white matter. This patient represents an intermediate case within the FCD type II/HME spectrum. Localization of the lesion in the frontal lobe as well as clinical characteristics (childhood onset, relapsing-remitting epilepsy, without hemiparesis and overt cognitive impairment) are more consistent with FCD type II, while a range of MRI features is shared between HME and FCD type II.	0
Chromosome 2p15p16.1 microdeletion is an emerging syndrome recently described in patients with dysmorphic facial features, congenital microcephaly, mild to moderate developmental delay and neurodevelopmental abnormalities. Using clinical ultra-high resolution Affymetrix SNP 6.0 array we identified a de novo interstitial deletion on the short arm of chromosome 2, spanning approximately 2.5 Mb in the cytogenetic band position 2p15p16.1, in a female infant with characteristic features of 2p15p16.1 deletion syndrome including severe developmental delay, congenital microcephaly, intractable epilepsy, and renal anomalies, as well as a congenital choledochal cyst which has not been previously reported in other patients with this cytogenetic defect. We further redefined the previously reported critical region, supporting the presence of a newly recognized microdeletion syndrome involving haploinsufficiency of one or more genes deleted within at least a 1.1 Mb segment of the 2p15p16.1 region.	0
Pontocerebellar hypoplasia (PCH) type 2 is a very rare autosomal recessive neurodegenerative disorder with prenatal onset that disrupts brain development. We present three patients (two siblings and one unrelated child) with PCH 2 linked to the most common mutation c.919G > T (p.Ala307Ser) in TSEN54 gene. The disease started soon after birth with feeding difficulties, extrapyramidal symptoms, psychomotor retardation, progressive microcephaly. Two of the patients were diagnosed with dyskinetic cerebral palsy (CP) at first. Despite the neurodegenerative character of PCH 2, the absence of regression and even some developmental progress in few patients, might erroneously lead to the incorrect diagnosis of dyskinetic CP. Megacisterna magna on brain ultrasound makes the diagnosis of PCH 2 highly probable and should prompt further imaging with MRI. MRI findings of PCH are pivotal for the diagnosis. Genetic testing for the most common mutation in TSEN54 gene should also be performed. Correct diagnosis of PCH 2 is essential not only for the prognosis of the patient, but also for prenatal diagnosis in future pregnancies. Knowledge of the clinical picture of PCH 2 will lead to correct and timely diagnosis. Advanced neuroimaging procedures and molecular genetic techniques provide valuable tools for prompt diagnosis of rare, but clinically important, neurogenetic imitators of CP.	0
Syndromic obesity is an umbrella term used to describe cases where obesity occurs with additional phenotypes. It often arises as part of a distinct genetic syndrome with Prader-Willi syndrome being a classical example. These rare forms of obesity provide a unique source for identifying obesity-related genetic changes. Chromosomal microarray analysis (CMA) has allowed the characterization of new genetic forms of syndromic obesity, which are due to copy number variants (CNVs); however, CMA in large cohorts requires more study. The aim of this study was to characterize the CNVs detected by CMA in 279 patients with a syndromic obesity phenotype.Pathogenic CNVs were detected in 61 patients (22%) and, among them, 35 had overlapping/recurrent CNVs. Genomic imbalance disorders known to cause syndromic obesity were found in 8.2% of cases, most commonly deletions of 1p36, 2q37 and 17p11.2 (5.4%), and we also detected deletions at 1p21.3, 2p25.3, 6q16, 9q34, 16p11.2 distal and proximal, as well as an unbalanced translocation resulting in duplication of the GNB3 gene responsible for a syndromic for of childhood obesity. Deletions of 9p terminal and 22q11.2 proximal/distal were found in 1% and 3% of cases, respectively. They thus emerge as being new putative obesity-susceptibility loci. We found additional CNVs in our study that overlapped with CNVs previously reported in cases of syndromic obesity, including a new case of 13q34 deletion (CHAMP1), bringing to 7 the number of patients in whom such defects have been described in association with obesity. Our findings implicate many genes previously associated with obesity (e.g. PTBP2, TMEM18, MYT1L, POU3F2, SIM1, SH2B1), and also identified other potentially relevant candidates including TAS1R3, ALOX5AP, and GAS6.Understanding the genetics of obesity has proven difficult, and considerable insight has been obtained from the study of genomic disorders with obesity associated as part of the phenotype. In our study, CNVs known to be causal for syndromic obesity were detected in 8.2% of patients, but we provide evidence for a genetic basis of obesity in as many as 14% of cases. Overall, our results underscore the genetic heterogeneity in syndromic forms of obesity, which imposes a substantial challenge for diagnosis.	0
Obesity is a complex, heritable trait influenced by the interplay of genetics, epigenetics, metagenomics and the environment. With the increasing access to high precision diagnostic tools for genetic investigations, numerous genes influencing the phenotype have been identified, especially in early onset severe obesity. This review summarizes the current knowledge on the known genetic causes of obesity and the available therapeutic options. Furthermore, we discuss the role and potential mechanism of epigenetic changes that may be involved as mediators of the environmental influences and that may provide future opportunities for intervention.	0
We aimed to understand the etiology behind the abnormal craniofacial contour and other clinical presentations in a number of children with Robinow syndrome. Seven children with Robinow syndrome were enrolled in this study (autosomal recessive caused by homozygous mutations in the ROR2 gene on chromosome 9q22, and the autosomal dominant caused by heterozygous mutation in the WNT5A gene on chromosome 3p14). In the autosomal recessive (AR) group, the main clinical presentations were intellectual, disability, poor schooling achievement, episodes of headache/migraine, and poor fine motor coordinative skills, in addition to massive restrictions of the spine biomechanics causing effectively the development of kyposcoliosis and frequent bouts of respiratory infections. Three-dimensional reconstruction computed tomography scan revealed early closure of the metopic and the squamosal sutures of skull bones. Massive spinal malsegmentation and unsegmented spinal bar were noted in the AR group. In addition to severe mesomelia and camptodactyly, in the autosomal dominant (AD) group, no craniosynostosis but few Wormian bones and the spine showed limited malsegemetation, and no mesomelia or camptodactyly have been noted. We wish to stress that little information is available in the literature regarding the exact pathology of the cranial bones, axial, and appendicular malformations in correlation with the variable clinical presentations in patients with the 2 types of Robinow syndrome.	0
Idiopathic granulomatous mastitis (IGM) is an unusual benign inflammatory disease of breast. Breast cancer mimics IGM both radiologically and clinically. However, IGM is a benign disease and awareness of such an entity prevents unnecessary surgical procedures. Although its etiology is unknown, it may be an autoimmune disease. There are few patients reported in the literature presenting with reactive arthritis and/or erythema nodosum accompanying IGM of breast. Granulomatous mastitis should be considered as a possible underlying cause of arthritis and erythema nodosum. In this article, we report this interesting association of IGM as an underlying cause of arthritis and generalized erythema nodosum in a 32-year-old female patient. Comprehensive examination for granulomatous mastitis showed no apparent underlying cause. Indomethacin was beneficial in treatment of arthritis and erythema nodosum. Resistant IGM was responsive to colchicine treatment. Clinical management and therapeutic approach have been discussed in detail.	0
Cramp-fasciculation syndrome (CFS) is a rare peripheral nerve hyperexcitability syndrome. There are only a few reports on clinical and serological profile of a CFS cohort that was followed up by a single outpatient clinic.Clinical, electrophysiological, and serological features of 6 CFS patients (5 men, 1 woman; 27-65 years old) were investigated.All patients presented with cramps, fasciculations, muscle pain, and autonomic symptoms, and 2 also reported numbness and burning sensation in limbs, suggestive of neuropathic pain. Antibodies to uncharacterized voltage-gated potassium channel (VGKC)-complex proteins were found in 2 patients and to contactin-associated protein-like 2 (CASPR2) in 1 patient. None of the patients had a tumor. Most of the patients revealed prolonged after-discharges following tibial nerve stimulation. Nerve conduction studies and R-R interval variability tests were normal, whereas sympathetic skin responses were increased in amplitude in 3 seronegative patients. Five patients showed favorable response to carbamazepine or pregabalin treatment, whereas 1 VGKC-antibody-positive patient was resistant to carbamazepine and immunosuppressant treatment.Neuropathic pain and VGKC-complex antibodies may be encountered in CFS patients. Although autonomic symptoms are commonly found in CFS, routine autonomic system tests which are done in electrophysiology laboratories might yield normal results.	0
PURPOSE:Newborns who test positive for very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) in newborn screening may have a severe phenotype with early onset of life-threatening symptoms but may also have an attenuated phenotype and never become symptomatic. The objective of this study is to investigate whether metabolomic profiles in dried bloodspots (DBS) of newborns allow early phenotypic prediction, permitting tailored treatment and follow-up. METHODS:A metabolic fingerprint was generated by direct infusion high resolution mass spectrometry in DBS of VLCADD patients (n = 15) and matched controls. Multivariate analysis of the metabolomic profiles was applied to differentiate subgroups. RESULTS:Concentration of six acylcarnitine species differed significantly between patients and controls. The concentration of C18:2- and C20:0-carnitine, 13,14-dihydroretinol and deoxycytidine monophosphate allowed separation between mild and severe patients. Two patients who could not be prognosticated on early clinical symptoms, were correctly fitted for severity in the score plot based on the untargeted metabolomics. CONCLUSION:Distinctive metabolomic profiles in DBS of newborns with VLCADD may allow phenotypic prognostication. The full potential of this approach as well as the underlying biochemical mechanisms need further investigation.	0
We report a very rare case of granular cell tumor with a center ulcer of the rectum, which was detected in a 47-year-old man during screening colonoscopy. It is difficult to distinguish granular cell tumor from other subepithelial tumors. However, our case had a center ulcer unlike previous cases. We confirmed the diagnosis using histological and immunohistochemical examinations. In addition to our case report, we discuss the morphology, size, layer of invasion, and treatment of rectal granular cell tumors based on a literature review.	0
Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases, with a variable probability of transformation into acute leukemia, which is, in the vast majority of cases, of myeloid lineage. Nevertheless, rare cases of acute lymphoblastic leukemia in patients with previously diagnosed MDS have been reported. We describe a series of 3 cases of MDS/CMML marked with evolution to acute lymphoblastic leukemia (ALL) and provide a comprehensive review of the 49 cases documented in the literature so far. These sporadic events have only been published as single-case reports or small series to date. Such atypical cases emphasize the possibility of major phenotypic switches arising at the leukemic stem cell (LSC) and/or early progenitor levels, as a consequence of epigenetic and genomic events driving these changes in the bone marrow niche.	0
Background:NPHP is a progressive tubulointestinal kidney condition that demonstrates an AR inheritance pattern. Up to now, more than 20 various genes have been detected for NPHP, with NPHP1 as the first one detected. XPNPEP3 mutation is related to NPHP-like 1 nephropathy and late onset NPHP. Methods:The proband (index patient) had polyuria, polydipsia and chronic kidney disease who was clinical suspected of NPHP. After collection of blood sample from proband and her parents, WES was performed to identify the possible variants in a proband from a consanguineous marriage. The functional importance of variants was estimated by bioinformatic analysis. In the affected proband and her parents, Sanger sequencing was conducted for variants' confirmation and segregation analysis. Results:Clinical and paraclinical investigations of the patient was not informative. By using WES, we, herein, a novel homozygous frameshift mutation in XPNPEP3 was detected (NM_022098.2: c.719_720insA; p. Q241Tfs*13) and Sanger sequencing demonstrated an insertion in XPNPEP3. Conclusion:The homozygous genotype of the novel p.Q241Tfs*31 variant in XPNPEP3 may cause NPHP in the early childhood age.	0
Prominent dermal infiltration by Langerhans cells (LC) is a rare finding in patients with Omenn syndrome (OS). Here, we report the case study of a 7-month-old boy with OS and with prominent dermal infiltration by LC, which is a rare histological manifestation of the skin. Striking erythroderma appeared in the patient 2 weeks after birth. We also noted alopecia, lymphadenopathy, hepatosplenomegaly, eosinophilia and an elevated serum immunoglobulin E level with hypogammaglobulinemia. Peripheral blood flow cytometry showed the Tlow NK+ B+ immunophenotype and genetic analysis, a novel mutation in the IL2RG gene (c.337_339delTCT, p.Ser113del). The final diagnosis was that of OS. He responded well to an allograft umbilical cord blood transplantation that was performed when the patient was 8 months of age. We speculate that the LC accumulated in the dermis will eventually migrate to the regional lymph node, then stimulate autoreactive T cells by overpresenting antigens, thus causing OS-specific skin symptoms.	0
Chromosome 15 imprinting disorders include Prader-Willi (PWS) and Angelman (AS) syndromes, which are caused by absent expression from the paternal and maternal alleles in the chromosome 15q11. 2-q13 region, respectively. In addition, chromosome 15q duplication caused by the presence of at least one additional maternally derived copy of the 15q11.2-q13 region can lead to seizures, cognitive and behavioral problems. We focus on PWS and AS in the report, and expand the discussion of clinical care and description with genetic testing to include high-resolution studies to more specifically characterize the molecular mechanisms of disease. The importance of early diagnosis with the necessity for accurate molecular characterization through a step-wise algorithm is emphasized in an era of targeted therapeutic interventions. We present a flowchart to aid in ordering specialized genetic testing as several methods are available for patients presenting with features of PWS and/or AS.	0
BACKGROUND:Sanfilippo syndrome (mucopolysaccharidosis type IIIA; MPS IIIA) is an inherited paediatric-onset neurodegenerative disorder caused by the lysosomal deficiency of sulphamidase with subsequent accumulation of heparan sulphate. The pathological mechanisms responsible for clinical disease are unknown; however, intraneuronal accumulation of aggregation-prone proteins such as α-synuclein, phosphorylated tau and amyloid precursor protein suggests inefficient intracellular trafficking and lysosomal degradation. AIM:To investigate the contribution the accumulating α-synuclein plays in early symptom emergence that is, impaired cognition, reduced anxiety and motor deficits, first detectable between 3-5 months of age. METHODS:We have crossed congenic MPS IIIA mice with α-synuclein-deficient (Sncatm1Rosl /J) mice and evaluated phenotype and brain disease lesions. RESULTS:In a battery of behavioural tests performed on mice aged 12-22 weeks, we were unable to differentiate α-synuclein-deficient MPS IIIA mice from those with one or both copies of the α-synuclein gene; all three affected genotypes were significantly impaired in test performance when compared to wild-type littermates. Histological studies revealed that the rate, location and nature of deposition of other proteinaceous lesions, the disruption to endolysosomal protein expression and the inflammatory response seen in the brain of α-synuclein-deficient MPS IIIA mice reflected that seen in MPS IIIA mice homo- or heterozygous for α-synuclein. CONCLUSION:Deletion and/or deficiency of α-synuclein does not influence clinical and neuropathological disease progression in murine MPS IIIA, demonstrating that in and of itself, this protein does not initiate the cognitive and motor symptoms that occur in the first 5 months of life in MPS IIIA mice.	0
This report describes a case of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome in a 1-year-old boy, born to healthy nonconsanguineous parents. Megalencephaly and bilateral postaxial polydactyly of upper and lower limbs were noted at birth. He had profound developmental delay and moderate hypotonia. Magnetic resonance imaging (MRI) of the brain revealed hydrocephalus, polymicrogyria in both frontal lobes and perisylvian regions, and thin corpus callosum. Array-comparative genomic hybridization was normal. The patient's clinical and radiologic findings fit the classic description of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. The possible overlap between megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome and other similar conditions is discussed.	0
Objective:To describe the clinical and molecular genetic findings in a family segregating a novel mutation in the AIFM1 gene on the X chromosome. Methods:We studied the clinical features and performed brain MRI scans, nerve conduction studies, audiometry, cognitive testing, and clinical exome sequencing (CES) in the proband, his mother, and maternal uncle. We used in silico tools, X chromosome inactivation assessment, and Western blot analysis to predict the consequences of an AIFM1 variant identified by CES and demonstrate its pathogenicity. Results:The proband and his maternal uncle presented with childhood-onset nonprogressive cerebellar ataxia, hearing loss, intellectual disability (ID), peripheral neuropathy, and mood and behavioral disorder. The proband's mother had mild cerebellar ataxia, ID, and mood and behavior disorder, but no neuropathy or hearing loss. The 3 subjects shared a variant (c.1195G>A; p.Gly399Ser) in exon 12 of the AIFM1 gene, which is not reported in the exome/genome sequence databases, affecting a critical amino acid for protein function involved in NAD(H) binding and predicted to be pathogenic with very high probability by variant analysis programs. X chromosome inactivation was highly skewed in the proband's mother. The mutation did not cause quantitative changes in protein abundance. Conclusions:Our report extends the molecular and phenotypic spectrum of AIFM1 mutations. Specific findings include limited progression of neurologic abnormalities after the first decade and the coexistence of mood and behavior disorder. This family also shows the confounding effect on the phenotype of nongenetic factors, such as alcohol and drug use and side effects of medication.	0
Proliferating onychomatricoma is a new challenging variant of onychomatricoma that can clinically and histologically mimic squamous cell carcinoma/onycholemmal carcinoma. This is a retrospective case series study of the clinicopathologic and dermoscopic features of 6 patients with a pathologic diagnosis of proliferating onychomatricoma, which was conducted in the dermatology and dermatopathology departments of 2 university hospitals and a private nail's dermatology consultation. The clinical, histological, and immunohistochemical features and follow-up of 6 patients with proliferating onychomatricoma were analyzed; we compare our finding with 6 cases of conventional onychomatricoma. The female-to-male ratio was 1:1 with involvement of fingers in 4 and toe in 2. Among the symptoms were verrucous lesion simulating squamous cell carcinoma, nail thickening, periungual erythema, and pain; symptom duration ranged from 5 to 8 years. Clinical, dermoscopical en face free-margin view, and nail-clipping histologic findings reveal a nail wall-like pattern with pitting. Intraoperative, noncontact, polarizing, light dermoscopy was available in 1 case and showed the typical signs of onychomatricoma (OM). Histologically, all cases showed a well-differentiated, infiltrative, squamous, proliferative lesion exhibiting a lobulated and cystic pattern of growth in the dermis. Abrupt keratinization reminiscent of trichilemmal keratinization, but corresponding in fact to keratogenous spheres, was noted as well as a dysmaturative epithelial pattern. No atypical cytomorphological changes were found. Proliferating onychomatricoma is a new variant of onychomatricoma, which can be misdiagnosed as squamous cell carcinoma/onycholemmal carcinoma; its proper recognition may minimize morbidity associated with inappropriate treatment. Proliferating OM can be differentiated from conventional OM clinically by a free-edge wall-like pattern and on histology of nail clipping by the relatively small size of the cavities. Dermoscopic and nail clipping attributes as free-edge honeycomb-like cavities associated with conventional OM are well established and permit a diagnosis of OM without an invasive nail biopsy. The free-edge wall-like pattern is a distinct new dermoscopic and nail-clipping pattern that should raise for the others onychogenic neoplasms and prompt the clinician to obtain a biopsy specimen. In addition to proliferating OM, the differential diagnosis includes a micropapilliferum variant of OM, onychocytic matricoma, and onychocytic carcinoma.	0
Skeletal dysplasias are a diverse group of heritable diseases affecting bone and cartilage growth. Throughout the years, the molecular defect underlying many of the diseases has been identified. These identifications led to novel insights in the mechanisms regulating bone and cartilage growth and homeostasis. One of the pathways that is clearly important during skeletal development and bone homeostasis is the Wingless and int-1 (WNT) signaling pathway. So far, three different WNT signaling pathways have been described, which are all activated by binding of the WNT ligands to the Frizzled (FZD) receptors. In this review, we discuss the skeletal disorders that are included in the latest nosology of skeletal disorders and that are caused by genetic defects involving the WNT signaling pathway. The number of skeletal disorders caused by defects in WNT signaling genes and the clinical phenotype associated with these disorders illustrate the importance of the WNT signaling pathway during skeletal development as well as later on in life to maintain bone mass. The knowledge gained through the identification of the genes underlying these monogenic conditions is used for the identification of novel therapeutic targets. For example, the genes underlying disorders with altered bone mass are all involved in the canonical WNT signaling pathway. Consequently, targeting this pathway is one of the major strategies to increase bone mass in patients with osteoporosis. In addition to increasing the insights in the pathways regulating skeletal development and bone homeostasis, knowledge of rare skeletal dysplasias can also be used to predict possible adverse effects of these novel drug targets. Therefore, this review gives an overview of the skeletal and extra-skeletal phenotype of the different skeletal disorders linked to the WNT signaling pathway.	0
Acute encephalopathic crisis in glutaryl-CoA dehydrogenase deficiency results in an unfavourable disease course and poor outcome, dominated by dystonia, feeding problems, seizures and secondary complications, and quite often leading to early death. The prerequisite for the prevention of irreversible brain damage in this disease is the detection of affected patients and initiation of treatment before the manifestation of such crisis. Apart from macrocephaly there are no signs or symptoms characteristic for this disease in presymptomatic children and, thus, they are usually missed. In some countries, implementation of extended neonatal screening programmes using electrospray ionization tandem mass spectrometry (ESI-MS/MS) allows detection of affected newborns and start of therapy before onset of neurological complications. This article summarizes recent strategies, pitfalls and shortcomings of a mass screening for glutaryl-CoA dehydrogenase deficiency using ESI-MS/MS. Furthermore, an alternative strategy, namely DNA-based neonatal screening for the Oji-Cree variant of this disease, is demonstrated. An optimization of diagnostic as well as therapeutic procedures must be achieved before GCDH deficiency unequivocally fulfills the criteria of a reliable and successful newborn screening programme.	1
OBJECTIVE: To evaluate the potency of vecuronium and duration of vecuronium-induced neuromuscular blockade in dogs with centronuclear myopathy (CNM). ANIMALS: 6 Labrador Retrievers with autosomal-recessive CNM and 5 age- and weight-matched control dogs. PROCEDURES: Dogs were anesthetized on 2 occasions (1-week interval) with propofol, dexmedetomidine, and isoflurane. Neuromuscular function was monitored with acceleromyography and train-of-four (TOF) stimulation. In an initial experiment, potency of vecuronium was evaluated by a cumulative-dose method, where 2 submaximal doses of vecuronium (10 μg/kg each) were administered IV sequentially. For the TOF's first twitch (T1), baseline twitch amplitude and maximal posttreatment depression of twitch amplitude were measured. In the second experiment, dogs received vecuronium (50 μg/kg, IV) and the time of spontaneous recovery to a TOF ratio (ie, amplitude of TOF's fourth twitch divided by amplitude of T1) ≥ 0.9 and recovery index (interval between return of T1 amplitude to 25% and 75% of baseline) were measured. RESULTS: Depression of T1 after each submaximal dose of vecuronium was not different between groups. Median time to a TOF ratio ≥ 0.9 was 76.7 minutes (interquartile range [IQR; 25th to 75th percentile], 66.7 to 99.4 minutes) for dogs with CNM and 75.0 minutes (IQR, 47.8 to 96.5 minutes) for controls. Median recovery index was 18.0 minutes (IQR, 9.7 to 23.5 minutes) for dogs with CNM and 20.2 minutes (IQR, 8 to 25.1 minutes) for controls. CONCLUSIONS AND CLINICAL RELEVANCE: For the study dogs, neither potency nor duration of vecuronium-induced neuromuscular blockade was altered by CNM. Vecuronium can be used to induce neuromuscular blockade in dogs with autosomal-recessive CNM.	0
BACKGROUND:Pulmonary Cryptococcosis is a common fungal infection mainly caused by Cryptococcus neoformans/C.gattii species in immunocompromised patients. Cases of pulmonary cryptococcosis in patients with normal immune function are increasingly common in China. Clinical and radiographic features of pulmonary cryptococcosis are various and without obvious characteristics, so it is often misdiagnosed as pulmonary metastatic tumor or tuberculosis. When coexisting with malignant lung tumors, it was more difficult to differentiate from metastatic lung cancer, although the coexistence of pulmonary cryptococcosis and central type lung cancer is rare. Reviewing the imaging manifestations and diagnosis of the case and the relevant literature will contribute to recognition of the disease and a decrease in misdiagnoses. CASE PRESENTATION:A 72-year-old immunocompetent Han Chinese man had repeated dry cough for more than half a year. CT examination of chest showed an irregular mass at the left hilum of the lung, and two small nodules in the right lung, which were considered as the left central lung cancer with right lung metastasis. However, the patient was diagnosed with pulmonary cryptococcosis coexisting with central type lung cancer based on the results of laboratory examination, percutaneous lung biopsy, fiberoptic bronchoscopy, and surgical pathology. The patient underwent surgical resection of the left central type lung cancer and was placed on fluconazole treatment after a positive diagnosis was made. Five years after the lung cancer surgery, the patient had a recurrence, but the pulmonary cryptococcus nodule disappeared. CONCLUSION:Our case shows that CT findings of central type lung cancer with multiple pulmonary nodules are not necessarily metastases, but may be coexisting pulmonary cryptococcosis. CT images of cryptococcosis of the lung were diverse and have no obvious characteristics, so it was very difficult to distinguish from metastatic tumors. CT-guided percutaneous lung biopsy was a simple and efficient method for identification.	0
The second case of Shokeir syndrome (congenital total permanent alopecia, psychomotor epilepsy, mental retardation and pyorrhea) is described in a Hungarian boy. This syndrome was associated with a giant pigmented nevus in this case.	0
Neonatal-onset multisystem inflammatory disease (NOMID) is not widely recognized in China. This study aimed to investigate the diagnosis and treatment of NOMID.To analyze the clinical characteristics and laboratory results including skin biopsy, gene analysis and serum interleukin 1β of a boy admitted to Peking University First Hospital in November of 2013. Reports on NOMID were searched and the clinical and laboratory characteristics of reported cases were summarized.The patient was a 1-year-old boy. He had urticaria since 2 days after birth, and presented with episodes of fever, aseptic meningitis, symptoms of joints, short statue, hearing loss, abnormal fundus findings, and leucocytosis, high level of c-reactive protein (CRP) and abnormal findings of head MRI including ventriculomegaly and white matter dysplasia. Urticaria was confirmed by skin biopsy. Gene analysis showed T1702T/A in exon 4 of NLRP3 gene, which causes Phe568lle. Serum interleukin 1β increased dramatically. The boy was diagnosed as NOMID. He did not respond to antibiotic therapy and anti-allergy therapy. Corticosteroid therapy induced normalization of body temperature, and alleviation of rash, but not improvement in cerebrospinal fluid cell numbers. After searching reports of NOMID at PubMed, and Chinese literature published before November 2013, we summarized cases from 8 reports and reviewed 148 cases. The results showed that fever, urticaria, meningitis and arthropathy are the most common manifestations of NOMID, only 57% (69/122) of patients had mutation of NLRP3.This is a rare report of NOMID in children in China. Fever, urticaria, aseptic meningitis and persistently high level of CRP are characteristics of NOMID. Gene analysis and serum interleukin-1β detection can aid in diagnosis.	0
Congenital bilateral absence of the vas deferens (CBAVD) is a rare obstructive anomaly contributing to male factor infertility. Various congenital anomalies associated with CBAVD involve the seminal vesicles and epididymis. Physical examinations are often not reliable. However, transrectal ultrasonography (TRUS) can distinguish seminal vesicle and epididymal anomalies. In this clinical report, a rare case of CBAVD without seminal vesical anomalies is presented. PE and TRUS revealed no remarkable findings. The patient underwent vaso-epididymal anastomosis for the seminal tract obstruction and was accidentally diagnosed with CBAVD. Although ultrasonography is a reliable approach, surgical methods are critical for the diagnosis of CBAVD.	0
Reticulohistiocytomas represent a group of benign histiocytic dermal proliferations, which occur either sporadically as solitary cutaneous nodules or, when multiple, in association with systemic disease. Due to its nonspecific clinical presentation, reticulohistiocytoma may mimic other benign or malignant skin neoplasms; therefore, in most cases, a biopsy is needed in order to establish the correct diagnosis. The histology is typically characterized by the presence of large histiocytes with abundant eosinophilic cytoplasm with immunohistochemical profile positive for CD68, CD163, and vimentin. The authors report the case of a patient with solitary reticulohistiocytoma with illustrative clinical, dermoscopic, and histologic features.	0
Background:Spinocerebellar ataxia type 23 (SCA23) is an autosomal dominant cerebellar ataxia caused by pathogenic variants in the prodynorphin gene (PDYN). The frequency of PDYN variants is reportedly very low (~ 0.1%) in several ataxia cohorts screened to date. Case presentations:We found five cases of SCA23 in two families (mean age at onset: 37.8 ± 5.5 years; mean age at examination: 64.2 ± 12.3 years) with a novel PDYN variant (c.644G > A:p.R215H). We identified marked heterogeneity in the clinical features in Family 1: the proband showed clinical and neuroimaging features suggestive of multiple system atrophy with predominant parkinsonism (MSA-P). Conversely, the proband's mother with the PDYN p.R215H variant had no subjective symptoms; she had not come to medical attention before our survey, although she showed apparent cerebellar atrophy on brain magnetic resonance imaging (MRI). The other two patients in Family 1 and a patient in Family 2 showed slowly progressive cerebellar ataxia. Conclusions:We here report two Japanese families with SCA23, one of which showed considerable phenotypic variation in affected members. Our findings support that SCA23 can phenotypically overlap with MSA.	0
The DAX1 protein is an orphan nuclear hormone receptor based on sequence similarity in the putative ligand-binding domain (LBD). DAX1 mutations result in X-linked adrenal hypoplasia congenita (AHC). Our objective was to identify DAX1 mutations in a series of families, to determine the types of mutations resulting in AHC and to locate single-amino-acid changes in a DAX1 structural model. The 14 new mutations identified among our 17 families with AHC brought the total number of families with AHC to 48 and the number of reported mutations to 42; 1 family showed gonadal mosaicism. These mutations included 23 frameshift, 12 nonsense, and six missense mutations and one single-codon deletion. We mapped the seven single-amino-acid changes to a homology model constructed by use of the three-dimensional crystal structures of the thyroid-hormone receptor and retinoid X receptor alpha. All single-amino-acid changes mapped to the C-terminal half of the DAX1 protein, in the conserved hydrophobic core of the putative LBD, and none affected residues expected to interact directly with a ligand. We conclude that most genetic alterations in DAX1 are frameshift or nonsense mutations and speculate that the codon deletion and missense mutations give insight into the structure and function of DAX1.	0
Paediatric chylous ascites in tropics is commonly caused by infections and trauma. We describe the clinical characteristics of an uncommon inherited cause of chylous ascites, Hennekam syndrome, treated by nutritional modification.	0
After standard treatment of glioblastoma, pseudoprogression versus true progression is a clinical challenge. Indeed, to differentiate these 2 on contrast MRI (cMRI) is problematic. In recent time, Ga-prostate-specific membrane antigen-11 (Ga-PSMA) PET/CT has been suggested to have high accuracy in glioblastoma recurrence. We present a case of a 40-year-old man with right frontotemporal glioblastoma underwent surgery and radiotherapy. One month posttreatment cMRI showed a new enhancing lesion in the right hippocampal region, which was also positive on Ga-PSMA-11 PET/CT. On follow-up with conservative management, both cMRI and Ga-PSMA-11 PET/CT showed regression in new lesion, hence suggest pseudoprogression.	0
We report on 2 related children, a boy and a girl, from a large Turkish clan. Their parents are both first cousins and have several common ancestors. Both children have tyrosinase-positive oculocutaneous albinism, recurrent bacterial infections, granulocytopenia, intermittent thrombopenia, and microcephaly, a protruding midface, rough and projecting hair, and mild mental retardation. Chromosomes are normal. Metabolic disorders were excluded. None of 14 well-known types of albinism, including Hermansky-Pudlak syndrome and Chediak-Higashi syndrome, nor any other genetic syndrome, characterizes our patients sufficiently. Thus, this combination of symptoms is considered a new autosomal recessive syndrome.	0
Bobble-head doll syndrome (BHDS) is a rare entity, characterized by antero-posterior head bobbing, which is of the type "yes-yes." Less frequently, having a head movement of the type "no-no" is described. We report an unusual case of an 80-year-old man with a cystic mass of the lamina quadrigemina, extending to the posterior fossa. We conclude that ventriculocystocisternotomy associated with a cystoperitoneal shunt is an effective treatment for a symptomatic giant arachnoid cyst in the lamina quadrigemina.	0
Of 41 patients with craniofrontonasal syndrome, 35 were female and 6 were male. Although most cases were sporadic, 7 familial instances were found. Craniofrontonasal syndrome represents a unique, incompletely understood X-linked disorder. Unusual manifestations in females included thick, wiry, and curly hair (49%), anterior cranium bifidum (6%), axillary pterygia (9%), unilateral breast hypoplasia (postpubertal; 11%), and asymmetric lower limb shortness (14%).	0
Synovial metastasis is a rare presentation with only a few reported cases in the published literature. A majority of cases of malignant synovitis have a primary lung or colorectal origin. It carries a poor prognosis with an average survival of approximately 5 months from diagnosis. The treatment options are limited to palliative approaches, which highlight the aggressive nature of the presentation as well as the necessity for early recognition. We report an index case of synovial metastasis of the knee joint in a patient with progressive transitional cell carcinoma of the bladder and review the literature with respect to synovial metastasis.	0
Spinocerebellar ataxia 17 (SCA17) belongs to the family of 9 genetically inherited, late-onset neurodegenerative diseases, which are caused by polyglutamine (polyQ) expansion in different proteins. In SCA17, the polyQ expansion occurs in the TATA box binding protein (TBP), which functions as a general transcription factor. Patients with SCA17 suffer from a broad array of motor and non-motor defects, and their life expectancy is normally within 20 y after the initial appearance of symptoms. Currently there is no effective treatment, but remarkable efforts have been devoted to tackle this devastating disorder. In this review, we will summarize our current knowledge about the molecular mechanisms underlying the pathogenesis of SCA17, with a primary focus on transcriptional dysregulations. We believe that impaired transcriptional activities caused by mutant TBP with polyQ expansion is a major form of toxicity contributing to SCA17 pathogenesis, and rectifying the altered level of downstream transcripts represents a promising therapeutic approach for the treatment of SCA17.	0
N6-threonyl-carbamoylation of adenosine 37 of ANN-type tRNAs (t6A) is a universal modification essential for translational accuracy and efficiency. The t6A pathway uses two sequentially acting enzymes, YRDC and OSGEP, the latter being a subunit of the multiprotein KEOPS complex. We recently identified mutations in genes encoding four out of the five KEOPS subunits in children with Galloway-Mowat syndrome (GAMOS), a clinically heterogeneous autosomal recessive disease characterized by early-onset steroid-resistant nephrotic syndrome and microcephaly. Here we show that mutations in YRDC cause an extremely severe form of GAMOS whereas mutations in GON7, encoding the fifth KEOPS subunit, lead to a milder form of the disease. The crystal structure of the GON7/LAGE3/OSGEP subcomplex shows that the intrinsically disordered GON7 protein becomes partially structured upon binding to LAGE3. The structure and cellular characterization of GON7 suggest its involvement in the cellular stability and quaternary arrangement of the KEOPS complex.	0
Optic atrophy is a pathological term referring to optic nerve shrinkage caused by the degeneration of retinal ganglion cell (RGC) axons. The term “optic atrophy” is regarded as a misnomer since atrophy implies disuse. Therefore, a better term for optic atrophy would be “optic neuropathy.” However, that term is also controversial since, in certain situations, such as primary optic atrophy or traumatic brain injury, optic neuropathy may not occur.[1] Optic atrophy is the end stage of a disease process affecting the retinogeniculate portion of the visual pathway, characterized by a non-specific sign of optic disc pallor. While the peripheral nervous system has an intrinsic ability for repair and regeneration, the central nervous system, for the most part, is incapable of such processes. The axons of the optic nerve are heavily myelinated by oligodendrocytes and reactive astrocytes, which express many inhibitory factors for axonal regeneration.[2] Thus, the optic nerve, with its 1.2 million fibers, behaves more like a white matter tract rather than a true peripheral nerve. The optic nerve head is supplied by pial capillaries that undergo degeneration contributing to the pallor of the optic disc seen in optic atrophy. It is this neuro-vascular degeneration which forms the foundation for the development of optic atrophy. When light is thrown on the fundus from a light source, it undergoes total internal reflection through the axonal fibers. Subsequently, reflection from the capillaries on the disc surface gives rise to the characteristic yellow-pink color of a healthy optic disc. In eyes with cataract, red color is exaggerated, giving rise to a hyperemic appearance of the disc. Conversely, in pseudophakic individuals, the disc may appear to have some degree of pallor. Usually, 4-6 weeks are required following axonal damage for the optic disc pallor to start developing. In severe cases, the disc ultimately becomes chalky white. The overlying axons and capillaries degenerate so that the white lamina cribrosa becomes visible. This contrasts sharply with the surrounding red-colored retina. The exact mechanisms responsible for the optic disc pallor seen in optic atrophy are not clearly elucidated. It is assumed that the loss of axonal fibers along with the rearrangement of astrocytes contributes to the disc pallor. Cogan and Walsh, as well as Hoyt, have mentioned optic disc pallor as a consequence of loss of smaller blood vessels and the variable amount of reactive gliosis and fibrosis, as the optic nerve shrinks due to various factors. The degenerated axons also lose the optical property of total internal reflection, leading to the pale optic disc seen in this condition.[3] Recognition of optic atrophy might prove to be life-saving for the patient. Therefore, it is imperative to have adequate knowledge regarding this fairly common condition. This review presents the basic concepts of optic atrophy.	0
Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.	0
Epidemiologic information on rare cancers is scarce. The project Surveillance of Rare Cancers in Europe (RARECARE) provides estimates of the incidence, prevalence and survival of rare cancers in Europe based on a new and comprehensive list of these diseases.RARECARE analysed population-based cancer registry (CR) data on European patients diagnosed from 1988 to 2002, with vital status information available up to 31st December 2003 (latest date for which most CRs had verified data). The mean population covered was about 162,000,000. Cancer incidence and survival rates for 1995-2002 and prevalence at 1st January 2003 were estimated.Based on the RARECARE definition (incidence <6/100,000/year), the estimated annual incidence rate of all rare cancers in Europe was about 108 per 100,000, corresponding to 541,000 new diagnoses annually or 22% of all cancer diagnoses. Five-year relative survival was on average worse for rare cancers (47%) than common cancers (65%). About 4,300,000 patients are living today in the European Union with a diagnosis of a rare cancer, 24% of the total cancer prevalence.Our estimates of the rare cancer burden in Europe provide the first indication of the size of the public health problem due to these diseases and constitute a useful base for further research. Centres of excellence for rare cancers or groups of rare cancers could provide the necessary organisational structure and critical mass for carrying out clinical trials and developing alternative approaches to clinical experimentation for these cancers.	1
PURPOSE:Proteus syndrome arises as a result of a post-zygotic mosaic activating mutation in the AKT1 oncogene, causing a disproportionate overgrowth of affected tissues. A small number of ocular complications have been reported. We present the unique findings in a patient who had molecular confirmation of AKT1 mosaicism alongside fulfilling the clinical criteria for Proteus syndrome. METHODS:Pattern electroretinography, visual evoked potentials and multifocal electroretinography testing were performed alongside detailed retinal imaging and clinical examination to detail the ophthalmic characteristics. RESULTS:Electrophysiological findings characterised unilateral macular dysfunction alongside sector retinal dysfunction of the right eye. This was demonstrated through optical coherence tomography and ultra-wide-field imaging to be associated with a misaligned foveal morphology and sector retinal dysfunction extending into the temporal retina. CONCLUSION:We propose this patient has asymmetric foveal development and concomitant sector retinal dysfunction as the result of the mosaic AKT1 mutation, either through disruption in the retinal PI3K-AKT1 signalling pathway or through mechanical distortion of ocular growth, resulting in disproportionate inner retinal development. The findings expand the ocular phenotype of Proteus syndrome and encourage early assessment to identify any incipient ocular abnormalities.	0
OBJECTIVE:To provide the first description of hypofractionated stereotactic radiosurgery (SRS) and evaluate tumor control and safety for vagal paragangliomas (VPs), which begin at the skull base but often have significant extracranial extension. STUDY DESIGN:Retrospective chart review. SETTING:Tertiary-referral neurotology and neurosurgery practice. SUBJECTS AND METHODS:Five VPs in 4 patients (all male, ages 15-56 years) underwent SRS between 2010 and 2018. Outcome measures included tumor dimensions on serial imaging, cranial nerve function, and radiation side effects. RESULTS:CyberKnife hypofractionated SRS was performed. The prescription dose was 24 or 27 Gy (maximum dose 33.4 Gy; range, 29.3-35.5 Gy) delivered in 3 equal fractions. The mean isodose line was 79% (range, 76%-82%). Four VPs were treated primarily, and 1 tumor underwent SRS to treat regrowth 2 years after microsurgical subtotal resection via the modified infratemporal fossa approach. The treatment volume ranged from 8.81 to 86.3 cm3 (mean, 35.7 cm3). All demonstrated stable size (n = 3) or regression (n = 2) at last follow-up, 63 to 85 months after SRS (mean, 76 months). One patient had stable premorbid vocal fold paralysis from a prior ipsilateral glomus jugulare tumor resection. All others demonstrated normal vagal function following SRS. Treatment-related side effects, including dysgeusia (n = 1), mucositis (n = 1), and neck soft-tissue edema (n = 2), were self-limited. CONCLUSIONS:Hypofractionated SRS appears to be both safe and effective for treating VPs, including large-volume and predominantly extracranial tumors, while preserving vagal function. SRS should be considered as a cranial nerve preservation option, especially in settings of contralateral lower cranial nerve deficits or in those with multiple paragangliomas risking both vagal nerves.	0
BACKGROUND: The aim of this study was to analyze the prevalence and incidence of adult-onset myasthenia gravis (MG) in the Belgrade population from 1979 to 2008. METHODS: Data on the number of MG patients and their basic demographic and clinical characteristics were collected from hospital records (1979-1992) and the Belgrade MG Registry (1993-2008). Incidence and prevalence were standardized by the direct method (using the world standard population). A time-trend analysis of MG incidence was performed using a linear regression model. RESULTS: During the study period 562 cases (316 women, 246 men) were registered. On December 31st, 2008, the standardized prevalence (according to the world standard population) was 188.3/1,000,000 (women: 237.8/1,000,000; men: 139.4/1,000,000). The average annual standardized incidence rate was 13.3/1,000,000 (women: 14.1/1,000,000; men: 12.2/1,000,000). The incidence rates tended to increase significantly in both sexes during the study period (y = 3.299 + 14.363x, p = 0.002). Age-specific incidence rates for women demonstrated a bimodal pattern, with the first peak in the 20- to 29-year age group and the second one in the ≥70-year group. For both genders, an increase in age-specific incidence rates was registered for all age groups, although this was significant (p = 0.001) only for an MG onset of ≥60 years of age. CONCLUSIONS: The study confirms an increase in the incidence of MG in the area of Belgrade during the study period, especially for those with MG onset after 60 years of age.	1
Renal-coloboma syndrome is an autosomal dominant disease characterized by renal hypodysplasia and coloboma. A case of a 12-year-old girl with chronic kidney disease, bilateral optic nerve colobomas and an exceptional PAX-2 gene mutation is presented. Diagnosed in prenatal scans with bilateral renal hypoplasia, she presented clinical and laboratory findings of chronic kidney disease at 5 days of life. Following tests showed grade II bilateral vesicoureteral reflux spontaneously solved, maintained non nephrotic proteinuria controlled with enalapril and bilateral colobomas with left macular atrophy. Renal function remained stable. Genetic study showed de novo and non sense mutation p.R104X in heterocygosis. Currently there are 80 published cases of renal-coloboma syndrome associated with this gene mutations. Ophthalmologic and genetic evaluations are crucial in cases affected by renal hypodysplasia. Renal function will establish prognosis. We review the etiopathogenesis of this disease.	0
INTRODUCTION:Noonan syndrome is the second most common syndromic cause of congenital heart disease. Most patients have an autosomal dominant inheritance, but some cases may be sporadic. Pulmonary stenosis is the most common cardiac manifestation in Noonan syndrome, associated with the atrial septal defect and hypertrophic cardiomyopathy. A combination of these three is present only in 5% of patients. PRESENTATION OF CASE:We report a case of a 21-year-old female who presented to our hospital concomitant cardiac lesions associated with pulmonary stenosis, atrial septal defect, and hypertrophic cardiomyopathy. This combination of cardiac defects is an infrequent manifestation of Noonan syndrome. The patient presented with complaints of exertion syncope over the past two years. 2D-Echocardiography showed biventricular hypertrophy, dysplastic pulmonary valve, severe pulmonary stenosis, asymmetric septal hypertrophy and large atrial septal defect. The genetic analysis report showed autosomal dominant inheritance with Ras/MAPK (mitogen-activated protein kinase) Positive. DISCUSSION:Due to the wide spectrum of symptoms and presentations in Noonan cases, accurate clinical and genetic diagnosis, and comprehensive management of the disorder are strongly recommended. CONCLUSION:We have described a case of rare combination of cardiovascular defects in Noonan Syndrome with a view to achieve better insight into the disease course and advantages of timely treatment and follow up. Our patient is currently in follow-up after treatment with percutaneous balloon pulmonary valvuloplasty, has improved symptoms, and is awaiting heart transplant.	0
Cri-du-chat syndrome is characterized by facial dysmorphism, intellectual disability, and multiple congenital anomalies. Most cases occur de novo. Here, we report 3 siblings with cri-du-chat syndrome born to healthy parents. The proband was admitted to our clinic at the age of 6.5 years due to severe intellectual disability, facial dysmorphism, and heart defect. His karyotype showed a deletion of chromosome 5p. Microarray analysis revealed a 29-Mb deletion in chromosome 5p and a 4.7-Mb duplication in chromosome 19q. FISH analysis indicated an unbalanced translocation between 5p13.3 and 19q13.4. During follow-up, the second and the third child of the family were born with the same chromosome abnormality. Parental peripheral blood and skin fibroblast karyotypes as well as the FISH results using chromosome 5p- and 19q-specific subtelomeric probes were normal. FISH analysis of the father's sperm detected a 5p deletion in 12.8% of 200 cells, and microarray analysis confirmed the same unbalanced chromosome abnormality in a mosaic pattern. Uncultured peripheral blood and buccal smear of the father were also studied by FISH to exclude low-level mosaicism and in vitro culture effect. This is the first study that provides molecular evidence of paternal gonadal mosaicism of an unbalanced translocation detected in 3 siblings with cri-du-chat syndrome.	0
Ecuador is one of the Latin American countries where cystic fibrosis has not been thoroughly studied. The goal of this study was to establish the incidence of this specific pathology and the incidence of the 29 most common European CF mutations in Ecuador's population. We performed a prospective-descriptive study with the intention of including patients registered at the Ecuadorian Cystic Fibrosis Foundation as well as the main pediatric hospitals in Ecuador. The inclusion criteria were clinical manifestations of cystic fibrosis plus two positive pilocarpine iontophoresis sweat tests (CI >60 mEq/L). We tested F508del mutation by heteroduplex method and then, we confirmed these results and searched for other 28 frequent European-mutations aside from F508del by a reverse dot blot technique (INNO-LiPA CFTR 29 + Tn). Sixty two unrelated patients were included. Both heteroduplex and reverse dot blot methods identified 53.22% of all mutations. The estimated Ecuadorian cystic fibrosis incidence was 1:11,252. The mutations found and their incidence were F508del (37.1%), G85E (8.9%), G542X (2.4%), N1303K (2.4%), G551D (1.6%) and R334W (0.8%). The incidence of cystic fibrosis in Ecuador is closely similar to other Latin American countries where there is a large "mestizo" population. We are reporting one of the highest incidences of G85E in the world.	1
Amelogenesis imperfecta (AI) is a diverse collection of inherited diseases that exhibit quantitative or qualitative tooth enamel defects in the absence of systemic manifestations. Also known by varied names such as Hereditary enamel dysplasia, Hereditary brown enamel, Hereditary brown opalescent teeth, this defect is entirely ectodermal, since mesodermal components of the teeth are basically normal. The AI trait can be transmitted by either autosomal dominant, autosomal recessive, or X-linked modes of inheritance. Genes implicated in autosomal forms are genes encoding enamel matrix proteins, namely: enamelin and ameloblastin, tuftelin, MMP-20 and kallikrein - 4. This article presents a case reported to Dr. D. Y. Patil, Dental College and Hospital, Pune, India, along with a review of this often seen clinical entity.	0
Russell-Silver syndrome (RSS) is a congenital anomaly characterized by intrauterine and postnatal growth retardation, typical facial features, fifth-finger clinodactyly, and skeletal asymmetry. Although data on intrauterine and postnatal growth retardation have been reported, there are few reports concerning the typical maxillofacial morphology in individuals with RSS. The aim of this study was to describe the details of this systemic condition and to characterize maxillofacial morphology based on cephalograms in 11 Japanese patients (age range, 3.9-12.0 years) with RSS. All 11 individuals had intrauterine and postnatal growth retardation. In addition, most showed mandibular retrognathia and relative macrocephaly. Lateral cephalogram measurements showed that mandibular retrognathia resulted from short mandibular body length, whereas the depth of the cranial base was close to normal. Although asymmetry of hand, foot, and limb length were present in most individuals, obvious facial asymmetry was not common. Differences between left and right skeletal and dental age were not observed, indicating that children with RSS might show asymmetry because of quantitative differences in skeletal growth rather than delayed growth rate. Our findings not only provide important information about the maxillofacial characteristics of RSS, but also help to clarify the association between these characteristics and genetics, which will add to the body of information on clinical symptoms.	0
Prenatal growth is a complex dynamic process controlled by various genetic and environmental factors. Among genetic syndromes characterized by growth restriction, MULIBREY nanism represents a rare autosomal recessive condition presenting with severe pre- and post-natal growth failure, characteristic dysmorphic features but normal neurological development. The phenotype of MULIBREY nanism is variable and overlaps with others such as the Silver-Russell syndrome. We report here three patients in two distinct non-Finnish families from North France who were first suspected to have Silver-Russell syndrome which failed to be confirmed on molecular analyses. Clinical features in the three patients led us to also consider the diagnosis of MULIBREY nanism. Sequencing of the TRIM37 gene showed the three patients shared a novel nonsense mutation (c.181 C>T p.Arg61*) in a heterozygous state. Quantitative fluorescent multiplex PCR identified a new deletion of exons 15 and 16 in TRIM37 in one isolated patient and another deletion of exon 9 in two siblings. Breakpoints of both the deletions were localized in Alu sequences. Given the high number of Alu repeats, which predispose to gene rearrangements, one should always consider such genetic rearrangements in the molecular diagnosis of non-Finnish MULIBREY nanism patients. Early diagnosis of the disease would prompt careful cardiac follow up of such patients as cardiological complication is a characteristic feature of the MULIBREY nanism as described in this report.	0
COL2A1-related disorders represent a heterogeneous group of skeletal dysplasias with a wide phenotypic spectrum. Our aim is to characterize the clinical and molecular phenotypes of Chinese patients with COL2A1-related dysplasia and to explore their phenotype-genotype relations. Clinical data were collected, physical examinations were conducted, and X-ray radiography and genetic analyses were performed in ten families involving 29 patients with COL2A1-related dysplasia. Nine mutations were identified in COL2A1, including five novel (c.816+6C>T, p.Gly246Arg, p.Gly678Glu, p.Gly1014Val and p.Ter1488Gln) and four reported previously (p.Gly204Val, p.Arg275Cys, p.Gly504Ser and p.Arg719Cys). Based on clinical features and molecular mutations, the ten families were classified into five definite COL2A1-related disorders: four families with spondyloepiphyseal dysplasia congenita (SEDC), three with osteoarthritis with mild chondrodysplasia (OSCPD), one with Czech dysplasia, one with Kniest dysplasia, and one with epiphyseal dysplasia, multiple, with myopia and deafness (EDMMD). Based on genetic testing results, prenatal diagnosis and genetic counseling were accomplished for one female proband with OSCDP. Chinese patients with OSCDP, Czech dysplasia and EDMMD caused by COL2A1 mutations were first reported, expanding the spectrum of COL2A1 mutations and the phenotype of COL2A1-related disorders and providing further evidence for the phenotype-genotype relations, which may help improve procreative management of COL2A1-related disorders.	0
Abnormal deposition of misprocessed and aggregated proteins is a common final pathway of most neurodegenerative diseases, including Alzheimer's disease (AD). AD is characterized by the extraneuronal deposition of the amyloid β (Aβ) protein in the form of plaques and the intraneuronal aggregation of the microtubule-associated protein tau in the form of filaments. Based on the biochemically diverse range of pathological tau proteins, a number of approaches have been proposed to develop new potential therapeutics. Here we discuss some of the most promising ones: inhibition of tau phosphorylation, proteolysis and aggregation, promotion of intra- and extracellular tau clearance, and stabilization of microtubules. We also emphasize the need to achieve a full understanding of the biological roles and post-translational modifications of normal tau, as well as the molecular events responsible for selective neuronal vulnerability to tau pathology and its propagation. It is concluded that answering key questions on the relationship between Aβ and tau pathology should lead to a better understanding of the nature of secondary tauopathies, especially AD, and open new therapeutic targets and strategies.	0
Distal arthrogryposis (DA) is a skeletal muscle disorder which can be classified under a broader term as Arthrogryposis multiplex contractures. DA is characterized by the presence of joint contractures at various parts of the body, particularly in distal extremities. It is identified as an autosomal dominant and a rare X-linked recessive disorder associated with increased connective tissue formation around joints in such way that immobilizes muscle movement causing deformities. DA is again classified into various types since it manifests as a range of conditions representing different etiologies. Myopathy is one of the most commonly listed etiologies of DA. The mutations in sarcomeric protein-encoding genes lead to decreased sarcomere integrity, which is often associated with this disorder. Also, skeletal disorders are often associated with cardiac disorders. Some studies mention the presence of cardiomyopathy in patients with skeletal dysfunction. Therefore, it is hypothesized that the congenitally mutated protein that causes DA can also lead to cardiomyopathy. In this review, we will summarize the different forms of DA and their clinical features, along with gene mutations responsible for causing DA in its different forms. We will also examine reports that list mutations also known to cause heart disorders in the presence of DA.	0
X linked intellectual disability (XLID) syndromes account for a substantial number of males with ID. Much progress has been made in identifying the genetic cause in many of the syndromes described 20-40 years ago. Next generation sequencing (NGS) has contributed to the rapid discovery of XLID genes and identifying novel mutations in known XLID genes for many of these syndromes.2 NGS approaches were employed to identify mutations in X linked genes in families with XLID disorders. 1 involved exome sequencing of genes on the X chromosome using the Agilent SureSelect Human X Chromosome Kit. The second approach was to conduct targeted NGS sequencing of 90 known XLID genes.We identified the same mutation, a c.12928 G>C transversion in the HUWE1 gene, which gives rise to a p.G4310R missense mutation in 2 XLID disorders: Juberg-Marsidi syndrome (JMS) and Brooks syndrome. Although the original families with these disorders were considered separate entities, they indeed overlap clinically. A third family was also found to have a novel HUWE1 mutation.As we identified a HUWE1 mutation in an affected male from the original family reported by Juberg and Marsidi, it is evident the syndrome does not result from a mutation in ATRX as reported in the literature. Additionally, our data indicate that JMS and Brooks syndromes are allelic having the same HUWE1 mutation.	0
Anecdotal oculomotor disturbances have been described in spastic paraplegia type 7 (SPG7). We investigated oculomotor and vestibular dysfunction in five patients with genetically verified SPG7. All five patients exhibited significantly slower velocities of vertical saccades compared to controls, but significantly faster than in progressive supranuclear palsy, with upward saccades being particularly affected. Horizontal saccades, cerebellar oculomotor markers, and vestibuloocular reflex seem to be variably affected. Thus, albeit subclinical in some cases, slowing of the vertical saccades may belong to the phenotype of SPG7 and may serve as a valuable biomarker for differentiation from spastic ataxias and atypical parkinsonism.	0
OBJECTIVE:To explore the strategy of surgical treatment of low-grade brain tumors associated with epilepsy. METHODS:Clinical data of 158 patients with low-grade brain tumors were collected from January 2011 to December 2017 in Guangdong Sanjiu brain hospital. All patients received Preoperative evaluation. Lesion site: 18 cases were located in multiple cerebral lobes, 10 cases were in the functional zones, 130 cases were in the non-functional zones (including 74 cases were in the medial of temporal lobe). The surgical strategy included subtotal resection, gross-total resection and enlarged resection. Postoperative effects were evaluated by Engel classification. RESULTS:A total of 158 patients underwent surgical treatment, among these patients, only 1 patient underwent intracranial electrode implantation. Surgical methods: 34 cases of subtotal resection, 3 cases of gross-total resection, 119 cases of enlarged resection (including Anterior temporal lobectomy in 74 cases) and 2 case of Selective hippocampal amygdalectomy. The final pathology suggested that there are 74 cases of ganglionglioma, 25 cases of dysembryoplastic neuroepithelial tumors, 9 cases of pilocytic astrocytoma, 16 cases of oligodendroglioma, 10 cases of pleomorphic xanthoastrocytoma, 4 case of diffuse astrocytoma, 9 cases of unclassified astrocytoma, 11 case of oligoastrocytoma. The follow-up time was between 1 and 7 years, with an average of 3.44±1.77 years. Postoperative recovery: 147 patients had an Engel Class I outcome, 10 patients were in Engel Class II, 1 patient was in Class IV. CONCLUSION:The strategy of surgical treatment of low-grade brain tumors associated with epilepsy should pay more attention to the preoperative assessment of the epileptogenic zone. The tumor is not exactly the same as the epileptogenic zone, and the strategy of surgical treatment depends on the tumor feature as well as whether it was located in temporal lobe or involved in functional areas.	0
Velopharyngeal insufficiency (VPI) can occur in the setting of an unrepaired or repaired cleft lip and palate. The rate of VPI has been documented as high as 33% in some studies with higher rates of recurrences following surgery associated with genetic syndromes such as 22q11.2 deletions. The primary cause of VPI in these groups is still identified as the anatomic abnormalities of the velum. In this review, the anatomy and physiology of the velum are discussed along with genetic mutations associated with VPI.	0
Bardet-Biedl syndrome (BBS) is characterized by six major features: postaxial polydactyly, obesity, learning disabilities, renal anomalies, retinitis pigmentosa and hypogonadism and is inherited in an autosomal recessive manner. BBS is caused by disease causing sequence variants in the 22 BBS genes identified to date. In the present study, a single consanguineous Pakistani Family with BBS was clinically and genetically characterized. After establishing linkage to a BBS gene on chromosome 4q27, Sanger sequencing was performed in all available affected and unaffected members. Sequence analysis of the BBS7 gene revealed novel substitution mutation (c.719G>T; p. Gly240Val). Our findings further extend the body of evidence implicating BBS7 in causing BBS and expand the mutation spectrum.	0
A Japanese boy with a hearing deficit, cataracts, mental retardation, and brachycephaly without craniosynostosis is described. We believe that this patient represents a variant of the Fine-Lubinsky syndrome, and is the first report from a racial group other than Caucasian.	0
Updated, robust estimates of the incidence and prevalence of rare long-term neurological conditions in the UK are not available. Global estimates may be misrepresentative as disease aetiology may vary by location.To systematically review the incidence and prevalence of long-term neurological conditions in the UK since 1988.Medline (January 1988 to January 2009), Embase (January 1988 to January 2009), CINAHL (January 1988 to January 2009) and Cochrane CENTRAL databases.UK population-based incidence/prevalence studies of long-term neurological conditions since 1988. Exclusion criteria included inappropriate diagnoses and incomprehensive case ascertainment.Articles were included based on the selection criteria. Data were extracted from articles with ranges of incidence and prevalence reported.Eight studies met the criteria (3 on motor neurone disease; 4 on Huntington's disease; 1 on progressive supranuclear palsy). The incidence of motor neurone disease ranged from 1.06 to 2.4/100,000 person-years. The prevalence ranged from 4.02 to 4.91/100,000. The prevalence of Huntington's disease ranged from 4.0 to 9.94/100,000. The prevalence of progressive supranuclear palsy ranged from 3.1 to 6.5/100,000.The review updates the incidence/prevalence of long-term neurological conditions. Future epidemiological studies must incorporate comprehensive case ascertainment methods and strict diagnostic criteria.	1
We describe a two generation family with variable ulnar and radial ray reduction and midline craniofacial abnormalities. The features suggest a diagnosis of Weyers' ulnar ray/oligodactyly syndrome originally described in two isolated cases. Syndromes of ulnar ray reduction are briefly reviewed and the relationship between limb bud and midline development discussed.	0
Background:The goal of this study is to systematically evaluate the magnetic resonance imaging (MRI) signal characteristics and size of cataracts that may be encountered in pediatric and young adult patients. Methods:A retrospective analysis of the MRI features with cataracts in a series of cases, including characterization of signal intensity on T2-weighted and T1-weighted sequences, as well as measuring the thickness of the lens. Results:Among nine cataracts in seven patients, three lenses were thickened and hyperintense on T2-weighted sequences, presumably related to osmotic effects. The rest of the lenses were either normal in size and signal characteristics, such as in the cases of neurofibromatosis type 2 or small in cases of microphthalmos, with signal characteristics related to calcifications. Conclusions:There are several different types of cataracts that can occur in pediatric and young adult patients, which may or may not be conspicuous on MRI. The findings in this study can serve as a guide for what abnormalities of the lens may be encountered on MRI.	0
Objective: While osteoporotic fractures are reported in up to 40% of adults with post-poliomyelitis syndrome (PPS), clinical guidelines regarding bone mineral density (BMD) and indications for treatment are scarce. We investigated the characteristics of PPS patients, focusing on fractures and osteoporosis as the primary outcomes. Methods: A cross-sectional retrospective data analysis from medical records of 204 PPS patients regarding their clinical characteristics and long-term outcome, with emphasis on bone metabolism status. Results: Our cohort included 53% women, mean age was 65 years at study entry, and 1.7 years at the diagnosis of acute poliomyelitis. The lower limb was involved in 97.5% of patients, and the BMD in the affected limb tended to be lower than the unaffected, with a T score (Tsc) of -1.64 vs. -1.19, respectively (p=0.06). Recurrent falls were documented in 39.2% of patients, and osteoporosis in 20.6%, being more frequent in women (p=0.003) and patients with fractures (p=0.002). At least one fracture occurred in 52.2% of patients, and more than one in 40.3%. The median age for the first fracture was 57.5 years (range 30-83), and most fractures occurred in the affected limb (73.2%). Conclusion: Underdiagnosis and delayed treatment of osteoporosis in late-adulthood post-poliomyelitis patients underlie the need for comprehensive clinical guidelines to manage these patients, including recommendations on bone health assessment, medical treatment, and their inclusion as a high-risk group for bone fractures.	0
BACKGROUND: Mutations in the SCN9A gene cause chronic pain and pain insensitivity syndromes. We aimed to study clinical, genetic, and electrophysiological features of paroxysmal extreme pain disorder (PEPD) caused by a novel SCN9A mutation. METHODS: Description of a 4-generation family suffering from PEPD with clinical, genetic and electrophysiological studies including patch clamp experiments assessing response to drug and temperature. RESULTS: The family was clinically comparable to those reported previously with the exception of a favorable effect of cold exposure and a lack of drug efficacy including with carbamazepine, a proposed treatment for PEPD. A novel p.L1612P mutation in the Nav1.7 voltage-gated sodium channel was found in the four affected family members tested. Electrophysiologically the mutation substantially depolarized the steady-state inactivation curve (V1/2 from -61.8 ± 4.5 mV to -30.9 ± 2.2 mV, n = 4 and 7, P < 0.001), significantly increased ramp current (from 1.8% to 3.4%, n = 10 and 12) and shortened recovery from inactivation (from 7.2 ± 5.6 ms to 2.2 ± 1.5 ms, n = 11 and 10). However, there was no persistent current. Cold exposure reduced peak current and prolonged recovery from inactivation in wild-type and mutated channels. Amitriptyline only slightly corrected the steady-state inactivation shift of the mutated channel, which is consistent with the lack of clinical benefit. CONCLUSIONS: The novel p.L1612P Nav1.7 mutation expands the PEPD spectrum with a unique combination of clinical symptoms and electrophysiological properties. Symptoms are partially responsive to temperature but not to drug therapy. In vitro trials of sodium channel blockers or temperature dependence might help predict treatment efficacy in PEPD.	0
Plummer-Vinson syndrome is a rare condition associated with dysphagia, iron deficiency, and esophageal webs. Data regarding this condition is limited to mostly case reports and a few small cohort studies. Although most cases have a benign and indolent course, the risk of malignancy warrants long-term surveillance. A multidisciplinary approach among healthcare providers is of the utmost importance in the management of this condition.	0
Recombinase-activating gene-1 (RAG1)-deficient severe combined immunodeficiency (SCID) patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. Gene therapy is an alternative for those RAG1-SCID patients who lack a suitable bone marrow donor. We designed lentiviral vectors with different internal promoters driving codon-optimized RAG1 to ensure optimal expression. We used Rag1 -/- mice as a preclinical model for RAG1-SCID to assess the efficacy of the various vectors. We observed that B and T cell reconstitution directly correlated with RAG1 expression. Mice with low RAG1 expression showed poor immune reconstitution; however, higher expression resulted in phenotypic and functional lymphocyte reconstitution comparable to mice receiving wild-type stem cells. No signs of genotoxicity were found. Additionally, RAG1-SCID patient CD34+ cells transduced with our clinical RAG1 vector and transplanted into NSG mice led to improved human B and T cell development. Considering this efficacy outcome, together with favorable safety data, these results substantiate the need for a clinical trial for RAG1-SCID.	0
Birth defects are structural and/or functional malformations present at birth that cause physical or mental disability and are important public health problems. Our study was aimed at genetic analysis and prenatal diagnosis of congenital anomalies to understand the cause of certain birth defects. Karyotypes and array-comparative genomic hybridization (aCGH) were performed on a pregnant woman, surrounding amniotic fluid, and her husband. A short-stature panel genetic test was conducted in accordance with the phenotype of the fetus. Following examination, it was determined that the karyotype and aCGH results were normal. The RECQL4 gene in the fetus showed compound heterozygous mutations, and each parent was found to be a carrier of one of the mutations. The two heterozygous mutations (c.2059-1G>C and c.2141_2142delAG) were detected in the RECQL4 (NM_004260) gene in the fetus; therefore, the fetus was predicted to have Baller-Gerold syndrome. These two mutations have not previously been reported. In addition, these results identified a 25% risk of the parents having a sec-ond conceptus with this congenital disease. Therefore, prenatal genetic diagnosis was highly recommended for future pregnancies.	0
Objective:To identify novel genetic mechanisms causing Charcot-Marie-Tooth (CMT) disease. Methods:We performed a next-generation sequencing study of 34 genes associated with CMT in a patient with peripheral neuropathy. Results:We found a non-previously described mutation in EGR2 (p.P397H). P397H mutation is located within the loop that connects zinc fingers 2 and 3, a pivotal domain for the activity of this transcription factor. Using promoter activity luciferase assays, we found that this mutation promotes decreased transcriptional activity of EGR2. In this patient, we also found a previously described nonpathogenic polymorphism in lipopolysaccharide-induced TNF-α factor (LITAF) (p.T49M). We show that the p.T49M mutation decreases the steady-state levels of the LITAF protein in Schwann cells. Loss of function of LITAF has been shown to produce deregulation in the NRG1-erbB signaling, a pivotal pathway for EGR2 expression by Schwann cells. Surprisingly, our segregation study demonstrates that p.P397H mutation in EGR2 is not sufficient to produce CMT disease. Most notably, only those patients expressing simultaneously the LITAF T49M polymorphism develop peripheral neuropathy. Conclusions:Our data support that the LITAF loss-of-function interferes with the expression of the transcriptional-deficient EGR2 P397H mutant hampering Schwann cell differentiation and suggest that in vivo both genes act in tandem to allow the proper development of myelin.	0
BACKGROUND:We investigated the proportion of pediatric patients with cerebral paragonimiasis and intracranial hemorrhage who have intracranial pseudoaneurysms. METHODS:Images of 17 pediatric patients with cerebral paragonimiasis that first manifested as secondary intracranial hemorrhage were evaluated. All patients underwent computed tomographic angiography before surgery. A diagnosis of cerebral paragonimiasis was confirmed based on a positive Paragonimus-specific antibody test in serum samples from all 17 patients. Cerebral paragonimiasis in five of the 17 patients was further confirmed by histopathological examination of surgical specimens. RESULTS:Computed tomographic angiographic images for six of the 17 patients (35.3%) showed the presence of intracranial pseudoaneurysms. Follow-up computed tomographic angiographic scans two years later showed that two of the six patients had persistent pseudoaneurysms and underwent aneurysmectomy. The diagnosis of pseudoaneurysm was confirmed by histopathological examination postsurgery. In another two of the six patients, the pseudoaneurysm lesions were absorbed and could no longer be seen on three- to six-month follow-up scans. The final two patients with pseudoaneurysms are still under follow-up. Intracranial pseudoaneurysms with various degrees of surrounding hemorrhage were frequently observed at first manifestation. CONCLUSIONS:The rupture of intracranial pseudoaneurysms is a common characteristic feature of secondary intracranial hemorrhage caused by cerebral paragonimiasis in pediatric patients.	0
Solar urticaria is a chronic inducible urticaria also classified as an idiopathic dermatosis. The objective of this paper is to define the phenotypic characteristics of solar urticaria and to evaluate its incidence.This was a retrospective multicenter study in which data were gathered on the epidemiology and clinical, photobiologic, laboratory, and therapeutic characteristics of solar urticaria.A total of 224 patients (141 women and 83 men) were included from 9 photobiology units. The mean age of the patients was 37.9 years (range, 3-73 years). A history of atopy was detected in 26.7%, and the most common presentation was allergic rhinitis (16.5%). Clinical signs were limited to sun-exposed areas in 75.9% of patients. The light spectrum most commonly implicated was visible light only (31.7%), and in 21% of cases it was only possible to trigger solar urticaria with natural light. The treatments most widely used by photobiology experts were oral antihistamines (65.46%), followed by different forms of phototherapy (34%). Complete resolution was observed most often in patients with solar urticaria triggered exclusively by visible or natural light, with statistically significant differences with respect to other wavelengths (P<.05). No increase in the annual incidence of solar urticaria was observed.We have presented the largest series of solar urticaria published to date. The epidemiological, clinical, and photobiologic findings confirm previously reported data, although there was a particularly high rate of negative phototests in our series. Reactivity exclusively to visible or natural light was associated with a higher probability of resolution. No increasing trend was observed in the annual incidence.	1
PURPOSE:Orbital myositis occurs in typical and atypical forms. This review summarizes and updates the current state of knowledge of all forms of inflammation affecting extraocular muscle, excluding thyroid-associated orbitopathy. METHODS:A comprehensive literature review of orbital myositis was performed. RESULTS:Orbital myositis typically occurs in an idiopathic acute form, with painful diplopia due to inflammation in 1 or more extraocular muscles of young adult females, which usually responds to a course of oral corticosteroids. Atypical forms include idiopathic chronic or recurrent orbital myositis, and myositis related to systemic autoimmune, inflammatory, and infective conditions. The commonest associated autoimmune condition is inflammatory bowel disease. Immunoglobulin G4-related ophthalmic disease often affects extraocular muscle. Drug reactions and rarely paraneoplastic disease may also cause extraocular muscle inflammation. CONCLUSIONS:Orbital myositis occurs in a typical acute steroid responsive form, but atypical forms related to specific autoimmune and inflammatory conditions are increasingly recognized. Orbital myositis has many similarities to uveitis and would benefit from a systematic approach to nomenclature, diagnosis, and treatment.	0
Pontocerebellar hypoplasias represent a group of neurodegenerative autosomal recessive disorders characterized by hypoplasia/atrophy of the cerebellum, hypoplastic ventral pons, and microcephaly and associated with various clinical features. Pontocerebellar hypolasia type 2 is the most common form, and different mutations in genes encoding subunits of the transfer ribonucleic acid (RNA)-splicing endonuclease (TSEN) complex were identified in patients. The authors report clinical, imaging, and molecular studies in 2 unrelated patients with different clinical pictures of the pontocerebellar hypoplasia type 2 spectrum and novel mutations in TSEN54, aiming to further define the clinical spectrum of the disease and possible indicators of more favorable progression. They identified a novel missense mutation c.355T>G/p.Y119D in compound heterozygosity with the "common" c.919G>T/p.A307S (patient 1) and a novel homozygous c.7ins6(CCGGAG)/p.E2-P3insPE variant (patient 2). An expanded array of mutations might contribute in defining possible differences in severity and phenotype-genotype correlations.	0
We describe, the clinical presentation of a rare case of Tracheal Agenesis in a preterm infant and we highlight magnetic imaging resonance (MRI) and autopsy findings to better characterize this anomaly. A 30-year-old female presented for acute polyhydramnios at 30 weeks gestation of a male foetus. Prenatal MRI was performed and excluded this diagnosis. After delivery, the neonate presented a respiratory distress. The laryngoscopy control of tube position concluded to an esophageal intubation. A second reading of antenatal MRI was made. An autopsy was performed. The internal examination of the organs revealed broncho-oesophageal fistula. The upper airways were obstructed at the larynx. Fetal MRI should be interpreted with caution when Tracheal Agenesis is highly suspected.	0
A 62-year-old man was referred to our department with suspected intussusception due to an ileal tumor. Tumor markers including soluble interleukin-2 receptor were not elevated. Contrast-enhanced computed tomography and color Doppler ultrasonography showed a distinct ileal tumor without intratumoral blood flow or surrounding lymphadenopathies. Retrograde single-balloon enteroscopy revealed a submucosal tumor in the ileum that was hard and ulcerated. Partial intestinal resection was performed, and the lesion was diagnosed as an inflammatory myofibroblastic tumor. The patient had no recurrence over 2 years without additional treatment after surgery. This rare tumor should be kept in mind as a cause of ileal intussusception in adult and a multidisciplinary approach is vital to characterize it.	0
BACKGROUND:Recently, several studies have focused on the relationship between blood-brain barrier (BBB) impairment and the etiology of Moyamoya disease (MMD). However, in vivo studies investigating about BBB impairment and cortical perfusion in MMD patients were really rare. METHODS:This study included 16 patients diagnosed with MMD and 9 patients with atherosclerotic cerebrovascular disease (ACVD); all of who were treated with superficial temporal artery-middle cerebral artery (STA-MCA) bypass. Cortical perfusion was assessed using intraoperative indocyanine green (ICG) videoangiography by calculating the blood flow index (BFI). In addition, we used sodium fluorescein (NaFl) to evaluate the permeability of BBB in vivo during operation. RESULTS:The results showed that BBB impairment in MMD patients was more significant than that in ACVD patients, whereas, the cortical perfusion was comparable between two groups. BFI was significantly improved after STA-MCA bypass both in the MMD group (post-operation vs pre-operation: 109.2 ± 67.7 vs 64.3 ± 35.0, p = 0.004) and the ACVD group (post-operation vs pre-operation: 137.6 ± 89.6 vs 90.8 ± 58.3, p = 0.015). Moreover, BFI was significantly decreased in the cortex with BBB impairment as compared with that in the cortex with intact BBB (impaired BBB vs intact BBB: 55.7 ± 26.5 vs 87.6 ± 55.1, p = 0.025). Following bypass, the cortical perfusion significantly improved in the area of BBB impairment (post-operation vs pre-operation: 93.8 ± 75.2 vs 55.7 ± 26.5, p = 0.004), which was not observed in the BBB intact area (post-operation vs pre-operation: 92.4 ± 50.4 vs 87.6 ± 55.1, p = 0.58). CONCLUSION:In summary, we observed that BBB impairment in MMD patients was more significant than that in ACVD patients. This study also demonstrated for the first time that cortical perfusion was significantly decreased in the cortex with BBB impairment as compared with that in the cortex with intact BBB in MMD patients. We also observed that After STA-MCA bypass, the cortical perfusion was significantly improved in the cortex with BBB impairment. These results may provide a new insight for BBB impairment and cortical perfusion in the etiology of MMD.	0
BACKGROUND:Mutations of human androgen receptor (AR) gene are responsible for androgen insensitivity syndrome (AIS). Variable phenotypes and androgen receptor binding activity have permitted the classification of AIS into complete (CAIS), partial (PAIS), and minimal or mild (MAIS) forms. Somatic mosaicism in AIS is a rare condition which happened when de novo mutations occur after the zygotic stage. METHODS:Clinical evaluation, hormone measurements, and molecular analysis were performed to diagnose the patient in the study. RESULTS:A 46, XY girl who conceived through in vitro fertilization (IVF), presented with partial virilization of external genitalia, was found to have the p.C620R in heterozygosity. The variant p.C620R of AR has been previously reported in a patient with completely feminized external genitalia, which was inherited from the heterozygote carrier mother. Mutation analysis of the mother of our patient revealed that the variant was de novo and presented as a somatic mosaicism which indicated an insufficient amount of wild-type AR in our patient. CONCLUSION:This is the first case that AIS was caused by de novo mutation of AR in a 46, XY Disorder of Sexual Development (DSD) patient by the assisted reproduction technique (ART). The phenotype of partial virilization could be explained by AR mutation in somatic mosaicism.	0
Background:The management of T-lymphoblastic lymphoma (T-LBL) in adults poses uncertainties, including optimal chemotherapy regimen, need for radiotherapy, and the benefit of stem cell transplant. This retrospective case series investigated the efficacy of the pediatric BFM-90 regimen in adult patients and evaluated the role of early response assessment by positron emission tomography with computed tomography (PET-CT) in predicting outcomes. Methods:Patients aged 15 years or older with T-LBL diagnosed at Tata Memorial Hospital, Mumbai, India were given chemotherapy according to the European BFM-90 protocol (n = 38). The patients were evaluated for early response by interim PET-CT, post-induction and monitored for toxicity and long-term outcomes. Results:Thirty-eight consecutive patients (median age 23.5 years) were analyzed. After a median follow-up of 33.5 (1-77) months, following induction, 35 out of 38 patients (92.1%) had achieved complete response (CR) on PET-CT. Thirty (78.9%) patients treated according to BFM-90 were alive in first remission. Three-year event-free survival for those with CR on PET-CT was 78%, against no survivors for those who remained PET-positive. Conclusion:This study demonstrates the feasibility and efficacy of BFM-90 approach in adults with T-LBL. We found an early PET response to be highly predictive of outcome.	0
Holt-Oram syndrome (HOS) is a rare, autosomal dominant disorder caused by heterozygous pathogenic variants in cardiac T-box transcription factor, TBX5. Classically, it is associated with upper limb malformations and variable cardiac abnormalities. Limb manifestations are considered to be invariably present, ranging in severity from limitation in movement, to triphalangeal thumbs, absent thumbs, shortened forearms, or phocomelia. Cardiac involvement is characterized by congenital heart defects, most commonly septal structural malformations, and conduction system disease. Recently, novel TBX5 variants have also been reported in association with dilated cardiomyopathy (DCM). In this context, we report eight individuals from four unrelated families, in whom pathogenic variants in TBX5 segregated with an atypical HOS phenotype. Affected individuals exhibit relatively mild skeletal features of HOS, with a predominant cardiac phenotype, which includes several individuals affected by non-ischaemic DCM. To our knowledge, these represent the first reported cases of DCM in families with skeletal features of HOS, some of whom also harbored variants previously linked to a classical HOS phenotype (p. Arg279* and p.Arg237Gln). This finding supports diverse roles of TBX5 in cardiovascular development and function, and confirms the importance of long-term cardiac surveillance for individuals affected by HOS. Furthermore, these families highlight the wide phenotypic variability of HOS, which may include comparatively mild upper limb findings in respect to cardiac manifestations.	0
Background 5.2% of people are carriers for at least two recessive diseases; it can be concluded that a much smaller proportion develop these conditions as two mutated copies of a gene must be present for the disease to manifest clinically. Case presentation We present a 38-year-old Caucasian female affected by two autosomal recessive disorders which can affect the eyes, pseudoxanthoma elasticum (PXE) and retinitis pigmentosa (RP). PXE is an autosomal recessive disorder caused by mutations in ABCC6, affecting 1:25 000 to 1:100 000 people; its classical features involve the dermatological, ophthalmological and cardiovascular systems. Our patient presented with dermatological features of PXE and ophthalmological features of RP. RP presents with significant locus heterogeneity; our patient had biallelic mutations in USH2A. Conclusions This report highlights an interesting case of two unrelated autosomal recessive diseases presenting in one person, both of which have the potential to manifest with ophthalmological symptoms and signs. Though it is likely that only one condition has caused the ophthalmological findings in this case, it raises the question of how we can distinguish the causative disease when two conditions are present that have a shared target organ.	0
Bier spots are a distinct pattern of vascular mottling. Most reported cases are in young adults, with the youngest case in the literature at age 15 years. We report two children, ages 11 and 12 years, with Bier spots. Patient 1 was an 11-year-old boy who presented with white spots on the dorsal aspect of his hands. Patient 2 was a 12-year-old girl who presented with similar spots on the dorsal aspect of her left forearm and left hand. In both patients, the spots were visible when extremities were placed in a dependent position and disappeared with elevation of the extremity. Both patients were otherwise healthy.	0
PURPOSE:To identify symptoms and health care interactions with patients with riboflavin transporter deficiency (RTD) type 2 prior to diagnosis. METHODS:Parents of children with riboflavin transporter deficiency type 2 (n = 10) were interviewed to collect data on the patient's clinical journey. RESULTS:The average diagnostic delay was 27.6 months. Neurologists were the most commonly visited clinician (90%). Common symptoms during the first year of the patient's clinical journey included abnormal gait and/or ataxia (70%), nystagmus (50%), and upper body muscle weakness (40%). Prior to diagnosis, optic atrophy, sleep apnea, breath-holding spells, and dysphagia were commonly observed. Hearing loss was only reported in 40% of subjects prior to diagnosis. Riboflavin responsive megaloblastic anemia is reported for the first time. Mitochondrial disease was the most common suspected diagnosis (30%). CONCLUSION:Despite clinical variability, common early symptoms of riboflavin transporter deficiency type 2 exist that can better allow clinicians to more rapidly identify riboflavin transporter deficiency type 2.	0
Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by a fibroblast growth-factor-23 (FGF-23)-secreting phosphaturic mesenchymal tumour (PMT) and is characterised by hypophosphataemic osteomalacia. We present a 36-year-old man initially presenting with diffuse bone and joint pain who was inappropriately treated for presumed ankylosing spondylitis for 2 years. Whole-body bone scan suggested metabolic bone disease, prompting referral to our endocrine institution. He was subsequently diagnosed with persistent hypophosphataemia, inappropriately high renal tubular phosphate excretion, 1,25-dihydroxyvitamin D3 suppression, severe osteoporosis and severe osteomalacia. FGF-23 concentrations (140 ng/L) were raised 3-fold above the upper limit of normal. Initial Gallium-68 (68Ga) DOTATATE positron emission tomography (PET)/CT scan missed an active lesion in the left fibular head as the field only included the mid-brain to the proximal femora. Histopathology results from tumour resection confirmed a PMT over-expressing FGF-23. Serum phosphate and FGF-23 normalised immediately post-operatively. He developed severe hypocalcaemia 3-weeks post-operatively (1.77 mmol/L) which normalised after 1 month of high-dose caltrate and calcitriol therapy. Osteomalacia, osteoporosis and associated symptoms resolved during medium-term follow-up with >100% improvement in his bone mineral density. This case report and discussion highlights the pitfalls contributing to delayed diagnosis of TIO and alerts clinicians to the potential complication of hungry bone syndrome post-tumour resection.	0
Introduction:Presence of two primary malignancies is rare and occurs in 3-5% of the cancer patients. As per our extensive internet research, this is the only reported case of a synchronous sino-nasal embryonal rhabdomyosarcoma with squamous cell carcinoma-tongue. The case report is important because of the rare diagnosis and the challenge we faced in the diagnosis and treatment of the patient because of the paucity of literature available on management adult rhabdomyosarcoma. Case Report:We present a very rare case of an adult male with a sino-nasal mass diagnosed to be an embryonal type rhabdomyosarcoma. The patient also had a moderately differentiated squamous cell carcinoma-tongue for the past 8 months. Radiological investigations were done to see the extent of the sino-nasal mass and the extent of tongue lesion, which was seen to be involving the base of the tongue. The patient was referred for chemoradiotherapy but succumbed to the disease after 2 weeks of treatment. Conclusion:Occurrence of rhabdomyosarcoma in synchronous malignancies is extremely rare as the most common first as well as second primary malignancy in a diagnosed case of head and neck cancer is squamous cell carcinoma. A multidisciplinary approach to the treatment of adult rhabdomyosarcoma has been recommended. The combined use of chemoradiotherapy and surgery has improved treatment in the recent past but RMS in adults is still a rare head and neck tumour that carries a poor prognosis despite aggressive therapy.	0
The Yemenite deaf-blind hypopigmentation syndrome was first observed in a Yemenite sister and brother showing cutaneous hypopigmented and hyperpigmented spots and patches, microcornea, coloboma and severe hearing loss. A second case, observed in a girl with similar skin symptoms and hearing loss but without microcornea or coloboma, was reported as a mild form of this syndrome. Here we show that a SOX10 missense mutation is responsible for the mild form, resulting in a loss of DNA binding of this transcription factor. In contrast, no SOX10 alteration could be found in the other, severe case of the Yemenite deaf-blind hypopigmentation syndrome. Based on genetic, clinical, molecular and functional data, we suggest that these two cases represent two different syndromes. Moreover, as mutations of the SOX10 transcription factor were previously described in Waardenburg-Hirschsprung disease, these results show that SOX10 mutations cause various types of neurocristopathy.	0
Wandering spleen is a rare clinical entity characterized by splenic hypermobility resulting from laxity or maldevelopment of supporting splenic ligaments. Its major complication is splenic torsion, which is a potentially fatal surgical emergency. We present a rare case of wandering spleen with torsion and splenic infarction in a patient with marfanoid hypermobility syndrome and vertebral abnormalities.	0
We report a novel application of targeted sclerotherapy to eradicate high-output chylothorax. The patient underwent thoracic duct embolization; however, cannulation of the thoracic duct failed, and thoracic duct disruption was performed. Leakage continued; therefore, the leakage site in the mediastinum was punctured directly under fluoroscopic guidance and a drainage catheter was inserted, followed by sclerotherapy using OK-432. Finally, leakage stopped and chylothorax improved. This technique may be useful for refractory chylothorax in patients where thoracic duct embolization fails.	0
We report here two cases of Herpes simplex virus encephalitis (HSE) in adult patients with very rare, previously uncharacterized, non synonymous heterozygous G634R and R203W substitution in mannan-binding lectin serine protease 2 (MASP2), a gene encoding a key protease of the lectin pathway of the complement system. None of the 2 patients had variants in genes involved in the TLR3-interferon signaling pathway. Both MASP2 variants induced functional defects in vitro, including a reduced (R203W) or abolished (G634R) protein secretion, a lost capability to cleave MASP-2 precursor into its active form (G634R) and an in vivo reduced antiviral activity (G634R). In a murine model of HSE, animals deficient in mannose binding lectins (MBL, the main pattern recognition molecule associated with MASP-2) had a decreased survival rate and an increased brain burden of HSV-1 compared to WT C57BL/6J mice. Altogether, these data suggest that MASP-2 deficiency can increase susceptibility to adult HSE.	0
BACKGROUND:Congenital cataract is a clinically and genetically heterogeneous visual impairment. The aim of this study was to identify causative mutations in five unrelated Chinese families diagnosed with congenital cataracts. METHODS:Detailed family history and clinical data were collected, and ophthalmological examinations were performed using slit-lamp photography. Genomic DNA was extracted from peripheral blood of all available members. Thirty-eight genes associated with cataract were captured and sequenced in 5 typical nonsyndromic congenital cataract probands by targeted next-generation sequencing (NGS), and the results were confirmed by Sanger sequencing. Bioinformatics analysis was performed to predict the functional effect of mutant genes. RESULTS:Results from the DNA sequencing revealed five potential causative mutations: c.154 T > C(p.F52 L) in GJA8 of Family 1, c.1152_1153insG(p.S385Efs*83) in GJA3 of Family 2, c.1804 G > C(p.G602R) in BFSP1 of Family 3, c.1532C > T(p.T511 M) in EPHA2 of Family 4 and c.356G > A(p.R119H) in HSF4 of Family 5. These mutations co-segregated with all affected individuals in the families and were not found in unaffected family members nor in 50 controls. Bioinformatics analysis from several prediction tools supported the possible pathogenicity of these mutations. CONCLUSIONS:In this study, we identified five novel mutations (c.154 T > C in GJA8, c.1152_1153insG in GJA3, c.1804G > C in BFSP1, c.1532C > T in EPHA2, c.356G > A in HSF4) in five Chinese families with hereditary cataracts, respectively. NGS can be used as an effective tool for molecular diagnosis of genetically heterogeneous disorders such as congenital cataract, and the results can provide more effective clinical diagnosis and genetic counseling for the five families.	0
BACKGROUND:Primary hyperoxaluria type 3 (PH3) is a recently described cause of childhood renal calculi. It results from mutations in the HOGA1 gene and most cases have been diagnosed after clinical ascertainment, exclusion of other genetic hyperoxalurias and mutation testing. Metabolite testing has not been widely applied but holds promise for the rapid screening and diagnosis of patients who are not specifically suspected to have PH3. CASE-DIAGNOSIS/TREATMENT:Two cases presented with renal calculi. Urine metabolite testing by tandem mass spectrometry was performed as part of the routine diagnostic work-up for this condition. Both had significantly increased levels of the PH3 urine marker 4-hydroxyglutamate and related metabolites. The diagnosis of PH3 was confirmed by the finding of bi-allelic damaging HOGA1 mutations. CONCLUSIONS:Urine screening by tandem mass spectrometry is a rapid, high-throughput test that can detect PH3 cases that may otherwise not be diagnosed.	0
BACKGROUND:Hepatic adrenal ectopia is a common clinical diagnosis, whereas adrenal tumors developed from hepatic adrenal ectopia are rare. Hepatic adrenal tumors are easily misdiagnosed as hepatic carcinoma and frequently treated by unnecessary operations. CASE PRESENTATION:A 50-year-old female patient was hospitalized due to B-ultrasonic detection of "right focal liver lesions." After hospitalization, enhanced CT examination was performed. A 2.2 cm × 1.8 cm tumor was found in the seventh section of the right liver, as indicated by obvious enhancement of the arterial phase and low density during the portal vein and delay stages. Enhanced MRI examination detected a 2.0 cm × 1.8 cm tumor on the right liver, which was considered a "primary hepatic carcinoma". The patient was treated by open hepatectomy and recovered well after the operation. The postoperative pathological diagnosis was hepatic adrenal adenoma. No relapse was observed through the 1-year follow-up visit. CONCLUSIONS:According to imaging manifestations, pathological immunohistochemical treatment, alpha fetoprotein (AFP) and clinical features, hepatic adrenal tumors should be considered in the diagnosis of hepatic carcinoma to prevent misdiagnosis. Hepatic adrenal tumors should be ruled out during the diagnosis to avoid unnecessary operation.	0
BACKGROUND: Waldenstrom macroglobulinemia (WM) is a non-Hodgkin lymphoma (NHL) subtype. Little is known about the incidence and trends for this disease in the United States. METHODS: Twenty-year data from the Surveillance, Epidemiology, and End Results (SEER) program were used for this study. SEER*Stat was used for data analysis. RESULTS: Of the 95,797 cases of NHL diagnosed between 1988 and 2007 in 9 SEER registries, 1835 (1.9%) were new cases of WM. Median age at diagnosis of WM was 73 years. The overall annual age-adjusted incidence was 0.38 per 100,000 persons per year, which increased with age, ranging from 0.03 in patients aged <50 years to 2.85 in patients aged ≥80 years. The incidence of WM was higher in men (0.54) than in women (0.27; P < .001) and was higher in whites (0.41) than in African Americans (0.18) or other races (0.21; P < .05). The annual percentage change for the whole population was 1.01% (P > .05). The annual percentage change was 1.21% for whites (P < .05) and 0.80% (P > .05) for nonwhites. Significant annual percentage change increases were seen in the group aged 70 to 79 years (1.24%; P < .05) and in 3 geographic registries (P < .001). CONCLUSIONS: Although the overall incidence of WM remained steady over time, significant increases in incidence were seen over the past 20 years in whites, in those aged 70 to 79 years, and in 3 geographic registry areas.	1
Following an insult by both intrinsic and extrinsic pathways, complex cellular, and molecular interactions determine a successful recovery or inadequate repair of damaged tissue. The efficiency of this process is particularly important in the heart, an organ characterized by very limited regenerative and repair capacity in higher adult vertebrates. Cardiac insult is characteristically associated with fibrosis and heart failure, as a result of cardiomyocyte death, myocardial degeneration, and adverse remodeling. Recent evidence implies that resident non-cardiomyocytes, fibroblasts but also macrophages -pillars of the innate immunity- form part of the inflammatory response and decisively affect the repair process following a cardiac insult. Multiple studies in model organisms (mouse, zebrafish) of various developmental stages (adult and neonatal) combined with genetically engineered cell plasticity and differentiation intervention protocols -mainly targeting cardiac fibroblasts or progenitor cells-reveal particular roles of resident and recruited innate immune cells and their secretome in the coordination of cardiac repair. The interplay of innate immune cells with cardiac fibroblasts and cardiomyocytes is emerging as a crucial platform to help our understanding and, importantly, to allow the development of effective interventions sufficient to minimize cardiac damage and dysfunction after injury.	0
Understanding of molecular mechanisms of tumor growth has an increasing impact on the development of diagnostics and targeted therapy of human neoplasia. In this review, we summarize the current knowledge on molecular mechanisms and their clinical implications in von Hippel-Lindau (VHL) disease. This autosomal dominant tumor syndrome usually manifests in young adulthood and predisposes affected patients to the development of benign and malignant tumors of different organ systems mainly including the nervous system and internal organs. A consequent screening and timely preventive treatment of lesions are crucial for patients affected by VHL disease. Surgical indications and treatment have been evaluated and optimized over many years. In the last decade, pharmacological therapies have been evolving, but are largely still at an experimental stage. Effective pharmacological therapy as well as detection of biomarkers is based on the understanding of the molecular basis of disease. The molecular basis of von Hippel-Lindau disease is the loss of function of the VHL protein and subsequent accumulation of hypoxia-inducible factor with downstream effects on cellular metabolism and differentiation. Organs affected by VHL disease may develop frank tumors. More characteristically, however, they reveal multiple separate microscopic foci of neoplastic cell proliferation. The exact mechanisms of tumorigenesis in VHL disease are, however, still not entirely understood and knowledge on biomarkers and targeted therapy is scarce.	0
We show the value of genetic screening in 3 adults with limited phenotypes of three bone sclerosing genetic disease (GD): osteopetrosis (OPT), Camurati-Engelmann disease (CED) and pycnodysostosis. INTRODUCTION:OPT, CED and pycnodysostosis are three rare bone diseases often diagnosed in childhood. However, some atypical phenotypes raise the problem of delayed diagnosis in adults. Genetic tests may then be useful to establish a formal diagnosis. METHODS:We report 3 cases of adult patients with symptomatic or asymptomatic bone sclerosing lesions for whom the clinical, radiological and biological explorations were atypical and did not allow a formal diagnosis. These unusual descriptions led to the search for genetic mutations. RESULTS:These 3 cases of limited phenotypes were associated with unknown or poorly described variants of 3 rare bone genetic diseases. CONCLUSIONS:Genetic tests proved useful to establish the diagnosis and manage the condition of adults with rare bone sclerosing GD.	0
Flavaglines are cyclopenta[b]benzofurans found in plants of the genus Aglaia, several species of which are used in traditional Chinese medicine. These compounds target the initiation factor of translation eIF4A and the scaffold proteins prohibitins-1 and 2 (PHB1/2) to exert various pharmacological activities, including antiviral effects against several types of viruses, including coronaviruses. This review is focused on the antiviral effects of flavaglines and their therapeutic potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).	0
Overt Cushing's syndrome is a rare disorder with an annual incidence of 2-3/million of which benign adrenal adenomas account for 0.6/million. The female:male ratio is 3:1. Preliminary data indicate a high proportion of subclinical Cushing's syndrome in certain risk populations such as patients with type 2 diabetes or osteoporosis. The clinical implications of these observations are presently unclear. Surgery remains first line treatment for overt disease and initial cure or remission is obtained in 65-85% of patients with Cushing's disease. Late recurrences, however, occur in up to 20% and the risk does not seem to plateau even after 20 years of follow-up. A 2- to 3-fold increase in mortality is observed in most studies, and this excess mortality seems confined to patients in whom initial cure was not obtained. Cushing's syndrome continues to pose diagnostic and therapeutic challenges and life-long follow-up is mandatory.	1
To identify the genetic mutation in ASS1 gene in a Chinese family with citrullinemia typeI, which may provide a basis for the diagnosis and genetic counseling.Genomic DNA was isolated from peripheral blood samples of the family members. Mutation analysis of ASS1 gene was carried out by PCR and Sanger sequencing. Biostructural analysis of the mutated ASS1 was completed by Phyre server.Double heterozygous mutations in the proband were identified: c.951delT (F317LfsX375) and c.1087C>T (R363W), which were confirmed in the proband's father and mother, respectively. It was found that the c.951delT mutation might change the formation of a dimer or a tetramer and the function of ASS1 protein.Double heterozygous mutations for c.951delT and c.1087C>T have been found in a proband with citrullinemia typeI. The c.951delT is a novel mutation in citrullinemia typeI, which may change the configuration of ASS1 protein and result in ASS1 dysfunction.	0
A pair of sisters was ascertained for multiple congenital defects, including marked craniofacial dysmorphisms with blepharophimosis, and severe psychomotor delay. Two novel compound heterozygous mutations in UBE3B were identified in both the sisters by exome sequencing. These mutations include c.1A>G, which predicts p.Met1?, and a c.1773delC variant, predicted to cause a frameshift at p.Phe591fs. UBE3B encodes a widely expressed protein ubiquitin ligase E3B, which, when mutated in both alleles, causes Kaufman oculocerebrofacial syndrome. We report on the thorough clinical examination of the patients and review the state of art knowledge of this disorder.	0
AIM:To describe the complex, overlapping phenotype of four Chinese patients with inherited retinal dystrophies (IRDs) who harbored two pathogenic genes simultaneously. METHODS:This retrospective study included 4 patients affected with IRDs. Medical and ophthalmic histories were obtained, and clinical examinations were performed. A specific Hereditary Eye Disease Enrichment Panel (HEDEP) based on exome capture technology was used for genetic screening. RESULTS:Four patients were identified to harbor disease-causing variants in two different genes. Patient retinitis pigmentosa (RP) 01-II:1 exhibited both classical ABCA4-induced Stargardt disease (STGD) 1 and USH2A-associated RP, patient RP02-III:2 exhibited both classical ABCA4-induced STGD1 and CDH23-associated RP, patient RP03-II:1 exhibited both USH2A-induced autosomal recessive retinitis pigmentosa (arRP) syndrome and SNRNP200-induced autosomal dominant retinitis pigmentosa (adRP), and patient RP04-II:2 exhibited USH2A-induced arRP syndrome and EYS-induced arRP at the same time. CONCLUSION:Our study demonstrates that genotype-phenotype correlations and comprehensive genetic screening is crucial for diagnosing IRDs and helping family planning for patients suffering from the disease.	0
There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers.	0
Chronic eosinophilic pneumonia (CEP) is a rare disorder characterized by the massive accumulation of eosinophils in the lungs and may be associated with blood eosinophilia. The response to steroids is common as well as a relapse after tapering or suspension; frequently long-term oral corticosteroid administration is needed. We described a clinical case successfully treated with mepolizumab alone during a relapse of CEP, instead of chronic systemic steroids or concomitant steroids therapy as it usually occurs. We observed an improvement of clinical symptoms, radiological thoracic CT scan and biological markers. This case confirms that mepolizumab might be an excellent treatment for CEP when relapses or serious complications occur. It is yet to be known if anti-interleukin 5 therapy could reduce the risk to develop systemic disorders as vasculitis in these patients.	0
Deletion and truncation mutations in the X-linked gene CASK are associated with severe intellectual disability (ID), microcephaly and pontine and cerebellar hypoplasia in girls (MICPCH). The molecular origin of CASK-linked MICPCH is presumed to be due to disruption of the CASK-Tbr-1 interaction. This hypothesis, however, has not been directly tested. Missense variants in CASK are typically asymptomatic in girls. We report three severely affected girls with heterozygous CASK missense mutations (M519T (2), G659D (1)) who exhibit ID, microcephaly, and hindbrain hypoplasia. The mutation M519T results in the replacement of an evolutionarily invariant methionine located in the PDZ signaling domain known to be critical for the CASK-neurexin interaction. CASKM519T is incapable of binding to neurexin, suggesting a critically important role for the CASK-neurexin interaction. The mutation G659D is in the SH3 (Src homology 3) domain of CASK, replacing a semi-conserved glycine with aspartate. We demonstrate that the CASKG659D mutation affects the CASK protein in two independent ways: (1) it increases the protein's propensity to aggregate; and (2) it disrupts the interface between CASK's PDZ (PSD95, Dlg, ZO-1) and SH3 domains, inhibiting the CASK-neurexin interaction despite residing outside of the domain deemed critical for neurexin interaction. Since heterozygosity of other aggregation-inducing mutations (e.g., CASKW919R) does not produce MICPCH, we suggest that the G659D mutation produces microcephaly by disrupting the CASK-neurexin interaction. Our results suggest that disruption of the CASK-neurexin interaction, not the CASK-Tbr-1 interaction, produces microcephaly and cerebellar hypoplasia. These findings underscore the importance of functional validation for variant classification.	0
Iron is an essential nutrient for all living organisms with critical roles in many biological processes. The mammalian host maintains the iron requirements by dietary intake, while the invading pathogenic bacteria compete with the host to obtain those absorbed irons. In order to limit the iron uptake by the bacteria, the human host employs numerous iron binding proteins and withholding defense mechanisms that capture iron from the microbial invaders. To counteract, the bacteria cope with the iron limitation imposed by the host by expressing various iron acquisition systems, allowing them to achieve effective iron homeostasis. The armamentarium used by the human host and invading bacteria, leads to the dilemma of who wins the ultimate war for iron.	0
Hereditary β-mannosidosis causing progressive lysosomal neuropathy and other clinical signs, has been previously described in humans, Nubian goats, and Salers cattle. Here we report the clinicopathological, metabolic, and molecular genetic features of canine beta-mannosidase (MANBA, EC 3.2.1.25) deficiency. A 1-year-old male mix-breed dog from St. Kitts was presented with progressive stumbling, weakness, and regurgitation. Vacuolated lymphocytes were observed on the blood film. Postmortem findings included marked enlargement of nerves, megaesophagus, and internal hydrocephalus. Vacuolated macrophages, neurons, and secretory epithelial cells suggested an oligosaccharide storage disease. Plasma concentration of the β-mannosidosis specific oligosaccharide was approximately 75 fold that of controls. The plasma beta-mannosidase activity was severely reduced to ~5% of controls; five other lysosomal acid hydrolase activities were increased or within their normal reference interval. Genomic sequencing of this dog's MANBA gene identified a homozygous exonic five bp tandem duplication in the penultimate exon of the MANBA gene (c.2377_2381dupTATCA) which results in a reading frame shift, altering the subsequent amino acid sequence and creating a premature stop codon. The truncated beta-mannosidase enzyme is expected to be dysfunctional. This enzyme deficiency causes the accumulation of un-degraded oligosaccharides in cells, which affect the myelination of the peripheral and central nervous systems. This insertion was not encountered in 121 and 80-screened samples from dogs on St. Kitts (all were homozygous for wild-type) and Philadelphia region (wild-type), respectively. In conclusion, canine β-mannosidosis has similar clinicopathological features with some human patients, but milder signs than in ruminants and more severe than in knockout mice. Hence, dogs with β-mannosidosis could become a valuable disease model for the human disease.	0
A 43-year-old woman presented with cognitive decline, focal seizures, brain MRI showing non-enhancing, bilateral hippocampal lesions, but normal cerebrospinal fluid findings, which fulfilled the Graus et al., 2016 criteria for autoimmune limbic encephalitis (ALE). Subjective improvements were observed after immunotherapy. A repeat brain MRI showed new contrast enhancement and positron emission tomography revealed left hippocampal uptake. Biopsy of the right parahippocampus yielded high-grade glioma. Five similar cases, among the 14 with unilateral hippocampal lesions on MRI, were identified in the literature whereby suspected ALE preceded the high-grade glioma diagnosis. Gliomas confined to hippocampi can have clinical features overlapping with ALE.	0
Charcot-Marie-Tooth disease (CMT) is a group of inherited neurological disorders of the peripheral nervous system. CMT is subdivided into two main types: a demyelinating form, known as CMT1, and an axonal form, known as CMT2. Nearly 30 genes have been identified as a cause of CMT2. One of these is the 'dehydrogenase E1 and transketolase domain containing 1' (DHTKD1) gene. We previously demonstrated that a nonsense mutation [c.1455 T > G (p.Y485*)] in exon 8 of DHTKD1 is one of the disease-causing mutations in CMT2Q (MIM 615025). The aim of the current study was to investigate whether human disease-causing mutations in the Dhtkd1 gene cause CMT2Q phenotypes in a mouse model in order to investigate the physiological function and pathogenic mechanisms associated with mutations in the Dhtkd1 gene in vivo. Therefore, we generated a knock-in mouse model with the Dhtkd1Y486* point mutation. We observed that the Dhtkd1 expression level in sciatic nerve of knock-in mice was significantly lower than in wild-type mice. Moreover, a histopathological phenotype was observed, reminiscent of a peripheral neuropathy, including reduced large axon diameter and abnormal myelination in peripheral nerves. The knock-in mice also displayed clear sensory defects, while no abnormalities in the motor performance were observed. In addition, accumulation of mitochondria and an elevated energy metabolic state was observed in the knock-in mice. Taken together, our study indicates that the Dhtkd1Y486* knock-in mice partially recapitulate the clinical phenotypes of CMT2Q patients and we hypothesize that there might be a compensatory effect from the elevated metabolic state in the knock-in mice that enables them to maintain their normal locomotor function.	0
We present the case of an 8-month-old boy with the repeated recurrence of vesicles from the time of birth and who subsequently manifested psychomotor developmental delay. We retrospectively diagnosed the patient with congenital herpes simplex virus (HSV) infection. Computed tomography showed multiple calcifications in the periventricular white matter and thalami. The bilateral deep white matter showed an abnormally high signal intensity on T2-weighted magnetic resonance imaging. The patient required consecutive, suppressive therapy with valacyclovir to prevent the repeated recurrence of vesicles. This case presented a milder phenotype of congenital HSV infection in comparison to previous reports, and highlights the importance of the careful examination for this disease when neonates present with skin lesions.	0
BACKGROUND:The Mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome (OMIM 253200) is an autosomal recessive lysosomal disorder, caused by the deficiency of the enzyme N-acetylgalactosamine 4-sulfatase (also known as arylsulfatase B) due to mutations of the ARSB gene. Cardiologic features are well recognized, and are always present in MPS VI patients. Generally, the onset and the progression of the cardiologic symptoms are insidious, and just a few patients have developed a rapidly progressive disease. Cardiac involvement in MPS VI is a common and progressive feature. For MPS patients, cardiac evaluations are recommended every 1 to 2 years, including blood pressure measurement, electrocardiography and echocardiography. However, congestive heart failure and valvular surgical repair are not frequently seen, and if so, they are performed in adults. Here we report on an atypical MPS VI case with ascites fetalis and a rapidly progressive cardiac disease. CASE PRESENTATION:A 6-month-old Brazilian male, only child of a Brazilian healthy non-consanguineous couple. During pregnancy, second trimester ultrasonography observed fetal ascites and bilateral hydrocele. Physical exam at 6 months-old revealed a typical gibbus deformity and MPS was suspected. Biochemical investigation revealed a diagnosis of MPS type VI, confirmed by molecular test. Baseline echocardiogram revealed discrete tricuspid regurgitation and a thickened mitral valve with posterior leaflet prolapse, causing moderate to severe regurgitation. The patient evolved with mitral insufficiency and congestive heart failure, eventually requiring surgical repair by the first year of age. CONCLUSIONS:We report the first case of MPS VI whose manifestations started in the prenatal period with fetal ascites, with severe cardiac valvular disease that eventually required early surgical repair. Moreover, in MPS with neonatal presentation, including fetal hydrops, besides MPS I, IVA and VII, clinicians should include MPS VI in the differential diagnosis.	0
Background:A large deletion in Xp22.3 can result in contiguous gene syndromes, including X-linked ichthyosis (XLI) and Kallmann syndrome (KS), presenting with short stature, chondrodysplasia punctata, intellectual disability, and strabismus. XLI and KS are caused by the deletion of STS and ANOS1, respectively. Method:Two KS patients with XLI were screened to identify possible pathogenic mutations using whole exome sequencing. The clinical characteristics, molecular genetics, treatment outcomes, and genotype-phenotype association for each patient were analyzed. Results:We identified a novel 3,923 kb deletion within the Xp22.31 region (chrX: 5810838-9733877) containing STS, ANOS1, GPR143, NLGN4X, VCX-A, PUDP, and PNPLA4 in patient 1, who presented with KS, XLI, obesity, hyperlipidemia, and strabismus. We identified a novel 5,807 kb deletion within the Xp22.31-p22.33 regions (chrX: 2700083-8507807) containing STS, ANOS1, and other 24 genes in patient 2, who presented with KS, XLI, obesity, and strabismus. No developmental delay, abnormal speech development, or autistic behavior were noticed in either patient. Conclusion:We identified two novel microdeletions in the X chromosome leading to KS and XLI. These findings contribute to the understanding of the molecular mechanisms that drive contiguous gene syndromes. Our research confirmed that the Kallmann-Ichthyosis phenotype is caused by microdeletions at the chromosome level.	0
We describe a case of acute leukemia of ambiguous lineage with a novel cytogenetic abnormality. A 1-year-old boy presented with abnormal complete blood count findings, and was found to have blasts and mild dysgranulopoiesis. The blasts showed immunophenotypic evidence of myeloid and T-lineage differentiation. Subsequent cytogenetic analysis showed r(2)(p25q31) as the sole stem line cytogenetic defect with clonal evolution. While cytogenetic abnormalities can have a critical role in the classification and prognostication of acute lymphoblastic and acute myeloid leukemia, the significance of cytogenetic abnormalities in acute leukemia of ambiguous lineage remains unclear. This finding has not been reported previously to the best of our knowledge.	0
PURPOSE:To analyze clinical, therapeutic and prognostic features of pediatric Vogt-Koyanagi-Harada (VKH) disease. MATERIAL AND METHODS:This retrospective study included 16 eyes of 8 children diagnosed with VKH disease followed at a teaching hospital over a 10 year period. Diagnosis was based on the revised criteria of VKH disease. All data were analyzed using SPSS® software. RESULTS:There were 62.5% girls and 37.5% boys. The mean age (years) was 14.6±4.4. The mean follow-up (months) was 38.7±28.7. The mean initial visual acuity (VA) (LogMAR) was 1.4 with 68.8% of eyes presenting with severe visual loss at admission. The median time (days) required for resorption of the serous retinal detachment was 10 [8.25-25]. Extraocular signs were present in 62.5% of cases. The mean time until initiation of treatment was 25.6 days. 62.5% of patients received corticosteroids alone, and 37.5% of patients received a combination of corticosteroids and immunosuppressive therapy. Final VA was 0.4 [0.1-2.3]. In our study, the time until consultation, low initial VA and recurrences were statistically associated with severe visual loss (P≤0.05). CONCLUSION:Life expectancy in pediatric cases of VKH disease justifies the early initiation of immunosuppressive treatment or even biological therapy to achieve better steroid sparing and preserve visual function.	0
Inclusion body myositis is a rare sporadic inflammatory-degenerative myopathy of the elderly. Despite being the commonest type of acquired myopathy after the age of 50, misdiagnosis is extremely common. The most frequent hurdle in identifying new cases is the wrong diagnosis of polymyositis or motor neuron disease. Novel insights into pathogenic mechanisms have heralded the quest for newer therapeutics as well as drug repurposing in this otherwise progressive disorder.	0
Corticobasal degeneration (CBD) is a disorder affecting cognition and movement due to a progressive neurodegeneration associated with distinctive neuropathologic features, including abnormal phosphorylated tau protein in neurons and glia in cortex, basal ganglia, diencephalon, and brainstem, as well as ballooned neurons and astrocytic plaques. We identified three cases of CBD with olivopontocerebellar atrophy (CBD-OPCA) that did not have α-synuclein-positive glial cytoplasmic inclusions of multiple system atrophy (MSA). Two patients had clinical features suggestive of progressive supranuclear palsy (PSP), and the third case had cerebellar ataxia thought to be due to idiopathic OPCA. Neuropathologic features of CBD-OPCA are compared to typical CBD, as well as MSA and PSP. CBD-OPCA and MSA had marked neuronal loss in pontine nuclei, inferior olivary nucleus, and Purkinje cell layer. Neuronal loss and grumose degeneration in the cerebellar dentate nucleus were comparable in CBD-OPCA and PSP. Image analysis of tau pathology showed greater infratentorial tau burden, especially in pontine base, in CBD-OPCA compared with typical CBD. In addition, CBD-OPCA had TDP-43 immunoreactive neuronal and glial cytoplasmic inclusions and threads throughout the basal ganglia and in olivopontocerebellar system. CBD-OPCA met neuropathologic research diagnostic criteria for CBD and shared tau biochemical characteristics with typical CBD. These results suggest that CBD-OPCA is a distinct clinicopathologic variant of CBD with olivopontocerebellar TDP-43 pathology.	0
BACKGROUND:Complications involving internal organs are usually present in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, pancreatic complications are rarely reported and studied. OBJECTIVE:To summarize clinical characteristics of SJS/TEN-associated acute pancreatic injuries (API) and to investigate underlying inflammatory mechanisms. METHODS:Clinical records of 124 inpatients with SJS/TEN were reviewed. Serum levels of tumor necrosis factor-α, interleukin (IL)-6, IL-18, IL-15, IL-12p70, and soluble CD56 were determined in 18 healthy donors and 17 patients with SJS/TEN, including three patients with API. RESULTS:API was diagnosed in 7.3% (9/124) of patients in the SJS/TEN cohort. Serum transaminase elevation and hypoalbuminemia occurred more frequently in patients with API compared to those without pancreatic symptoms (P = 0.004, P = 0.0002, respectively). Although API did not alter mortality rate of SJS/TEN, it was associated with longer hospitalization stays (P = 0.008). Within the serum cytokines that were elevated in SJS/TEN, only IL-18 was found to be selectively increased in patients with API compared to those without pancreatic injuries (P = 0.032). LIMITATIONS:Cohort size is small. CONCLUSION:API is a gastrointestinal complication of SJS/TEN in which hepatotoxicity is more likely to occur. Overexpression of IL-18 might be involved in this unique entity.	0
OBJECTIVE:To identify transcriptomic changes, neuropathologic correlates, and cellular subpopulations in the motor cortex of sporadic amyotrophic lateral sclerosis (ALS). METHODS:We performed massive RNA sequencing of the motor cortex of patients with ALS (n = 11) and healthy controls (HCs; n = 8) and analyzed gene expression alterations, differential isoform usage, and gene coexpression networks. Furthermore, we used cell type deconvolution algorithms with human single-nucleus RNA sequencing data as reference to identify perturbations in cell type composition associated with ALS. We performed immunohistochemical techniques to evaluate neuropathologic changes in this brain region. RESULTS:We report extensive RNA expression alterations at gene and isoform levels, characterized by the enrichment of neuroinflammatory and synaptic-related pathways. The assembly of gene coexpression modules confirmed the involvement of these 2 major transcriptomic changes, which also showed opposite directions related to the disease. Cell type deconvolution revealed an overrepresentation of microglial cells in ALS compared with HC. Notably, microgliosis was driven by a subcellular population presenting a gene expression signature overlapping with the recently described disease-associated microglia (DAM). Using immunohistochemistry, we further evidenced that this microglial subpopulation is overrepresented in ALS and that the density of pTDP43 aggregates negatively correlates with the proportion of microglial cells. CONCLUSIONS:DAM has a central role in microglia-related neuroinflammatory changes in the motor cortex of patients with ALS, and these alterations are coupled with a reduced expression of postsynaptic transcripts.	0
Studies on the occurrence of segmental aneuploidoidy in fetuses with isolated echogenic intracardiac focus (EIF) are scarce. The aim of this study was to analyze whether there is an association between abnormal segmental aneuploidies and isolated EIF. This was a prospective case-control study. The study participants in the case group were fetuses that were diagnosed with isolated EIF. Samples without fetal ultrasound abnormalities but received prenatal diagnosis for other reasons (serological screening high-risk, voluntary request) were set as controls. All pregnant women were younger than 35 years old at the expected date of childbirth. Copy number variation sequencing (CNV-seq) was performed for all samples. The case group and control group successfully underwent CNV-seq analysis and exhibited 1,099 and 5,616 amniotic fluid samples, respectively. The detection rates of abnormal segmental aneuploidies in the case group and control group were 0.6% (7/1,099) and 1.1% (64/5,616), respectively; no statistically significant difference was found between the two groups (x2 = 2.220, P = 0.136). Isolated EIF did not increase the risk of fetal segmental aneuploidies.	0
Raine Syndrome (RS) is caused by biallelic loss-of-function mutations in FAM20C gene and characterized by hypophosphatemia, typical facial and skeletal features. Subperiosteal bone formation and generalized osteosclerosis are the most common radiological findings. Here we present a new case with RS. A 9-month-old male patient on a home-type ventilator was referred for hypophosphatemia. He was born with a weight of 3800 g to non-consanguineous parents. Prenatal ultrasound had demonstrated nasal bone agenesis. A large anterior fontanel, frontal bossing, exophthalmos, hypoplastic nose, high arched palate, low set ears, triangular mouth, and corneal opacification were detected on physical examination. Serial skeletal X-rays revealed diffuse osteosclerosis at birth which was gradually decreased by the age of 5 months with subperiosteal undermineralized bone formation and medullary space of long bone could be distinguishable with bone-within-a-bone appearance. At 9 months of age, hand X-ray revealed cupping of the ulna with loose radial bone margin with minimal fraying and osteopenia. Cranial computed tomography scan showed bilateral periventricular calcification and hydrocephalus in progress. The clinical, laboratory, and radiological examinations were consistent with RS. Molecular analyses revealed a compound heterozygous mutation in FAM20C gene (a known pathogenic mutation, c.1645C > T, p.Arg549Trp; and a novel c.863 + 5 G > C variant). The patient died due to respiratory failure at 17 months of age. This case allowed us to demonstrate natural progression of skeletal features in RS. Furthermore, we have described a novel FAM20C variant causing RS. Previous literature on RS is also reviewed.	0
Cystathionine β-synthase (CBS)-deficient patients are prone to vascular thrombosis. In contrast, Cbs-/- mice show no abnormalities in blood coagulation. To identify molecular basis underlying these disparately different thrombotic phenotypes, we analyzed plasma proteomes of Cbs-/- vs. Cbs+/+ mice (8-month-old, 12/group, sex-matched) and CBS-/- vs. CBS+/+ humans (37 ± 7-year-old, 10-14/group, sex-matched) using label-free mass spectrometry. We identified 117 and 41 differentiating plasma proteins in Cbs-/- mice and CBS-/- humans, respectively. Twenty-one proteins were shared between CBS-/- humans and Cbs-/- mice, with sixteen changed in the opposite direction. Proteins involved in blood coagulation and complement/coagulation cascades represented a greater fraction of the differentiating proteins in CBS-/- patients (51%) than in Cbs-/- mice (21%). Top canonical pathways, identified by Ingenuity Pathways Analysis, such as LXR/RXR, FXR/RXR activation (- log[P-value] = 30-31) and atherosclerosis signaling (- log[P-value] = 10-11) were similarly affected in Cbs-/- mice and CBS-/- humans. The Coagulation System was affected stronger in CBS-/- humans than in Cbs-/- mice (- log[P-value] = 15 vs. 10, respectively) while acute phase response and complement system were affected stronger in Cbs-/- mice (- log[P-value] = 33 and 22, respectively) than in humans (- log[P-value] = 22 and 6, respectively). Other pathways, including IL-7 signaling and B cell development were affected only in Cbs-/- mice. Taken together, our findings suggest that differences in these processes, in particular in the Coagulation System, could account for the thrombotic phenotype in CBS-/- patients and the absence of thrombosis in Cbs-/- mice. Overall, our findings suggest that Cbs-/- mice have a better adaptive response to protect from prothrombotic effects of hyperhomocysteinemia than CBS-/- humans.	0
Congenital disorders of glycosylation are a genetically and clinically heterogeneous group of >130 diseases caused by defects in various steps along glycan modification pathways. The vast majority of these monogenic diseases are autosomal recessive and have multi-systemic manifestations, mainly growth failure, developmental delay, facial dysmorphisms, and variable coagulation and endocrine abnormalities. Carbohydrate deficient transferrin (CDT) and protein-linked glycan analysis with mass spectrometry can diagnose some subtypes of congenital disorders of glycosylation (CDG), while many currently rely on massively parallel genomic sequencing for diagnosis. Early detection is important, as a few of these disorders are treatable. Molecular and biochemical techniques continue to further our understanding of this rapidly expanding group of clinically and genetically diverse disorders.	0
MIRAGE syndrome is a multisystem disorder characterized by myelodysplasia, infections, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. Mutations in the sterile alpha motif domain containing 9 (SAMD9) gene which encodes a protein involved in growth factor signal transduction are thought to cause MIRAGE syndrome. SAMD9 mutations lead to an antiproliferative effect resulting in a multisystem growth restriction disorder. Though rare, a few patients with SAMD9 mutations were reported to have hydrocephalus and/or cerebellar hypoplasia on imaging. The neuropathologic features of MIRAGE syndrome have not been previously described. Here, we describe the postmortem neuropathologic examinations of 2 patients with a clinical diagnosis of MIRAGE syndrome and confirmed SAMD9 mutations. Common features included microcephaly, hydrocephalus, white matter abnormalities, and perivascular calcifications. One of the 2 cases showed marked cerebellar hypoplasia with loss of Purkinje and granule neurons as well as multifocal polymicrogyria and severe white matter volume loss; similar findings were not observed in the second patient. These cases demonstrate the variation in neuropathologic findings in patients with MIRAGE syndrome. Interestingly, the findings are similar to those reported in ataxia-pancytopenia syndrome caused by mutations in SAMD9L, a paralogue of SAMD9.	0
The Bardet-Biedl syndrome protein complex (BBSome) is an octameric complex that transports membrane proteins into the primary cilium signaling organelle in eukaryotes and is implicated in human disease. Here we have analyzed the 99-kDa human BBS9 protein, one of the eight BBSome components. The protein is composed of four structured domains, including a β-stranded N-terminal domain. The 1.8 Å crystal structure of the 46-kDa N-terminal domain reveals a seven-bladed β-propeller. A structure-based homology search suggests that it functions in protein-protein interactions. We show that the Bardet-Biedl syndrome-causing G141R mutation in BBS9 likely results in misfolding of the β-propeller. Although the C-terminal half of BBS9 dimerizes in solution, the N-terminal domain only does so in the crystal lattice. This C-terminal dimerization interface might be important for the assembly of the BBSome.	0
Tetraploidy, or whole-genome duplication, is a common phenomenon in cancer and preludes chromosome instability, which strongly correlates with disease progression, metastasis, and treatment failure. Therefore, it is reasonable to hypothesize that tetraploidization confers multidrug resistance. Nevertheless, the contribution of whole-genome duplication to chemo-radiotherapy resistance remains unclear. Here, using isogenic diploid and near-tetraploid clones from three colorectal cancer cell lines and one non-transformed human epithelial cell line, we show a consistent growth impairment but a divergent tumorigenic potential of near-tetraploid cells. Next, we assessed the effects of first-line chemotherapeutic drugs, other commonly used agents and ionizing radiation, and found that whole-genome duplication promoted increased chemotherapy resistance and also conferred protection against irradiation. When testing the activation of apoptosis, we observed that tetraploid cells were less prone to caspase 3 activation after treatment with first-line chemotherapeutic agents. Furthermore, we found that pre-treatment with ataxia telangiectasia and Rad3 related (ATR) inhibitors, which targets response to replication stress, significantly enhanced the sensitivity of tetraploid cells to first-line chemotherapeutic agents as well as to ionizing radiation. Our findings provide further insight into how tetraploidy results in greater levels of tolerance to chemo-radiotherapeutic agents and, moreover, we show that ATR inhibitors can sensitize near-tetraploid cells to commonly used chemo-radiotherapy regimens.	0
Early-onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD) is a myopathic disorder associated with mutations in MEGF10. By novel analysis of SNP array hybridization and exome sequence coverage, we diagnosed a 10-years old girl with EMARDD following identification of a novel homozygous deletion of exon 7 in MEGF10. In contrast to previously reported EMARDD patients, her weakness was more prominent proximally than distally, and involved her legs more than her arms. MRI of her pelvis and thighs showed muscle atrophy and fatty replacement. Ultrasound of several muscle groups revealed dense homogenous increases in echogenicity. Cloning and sequencing of the deletion breakpoint identified features suggesting the mutation arose by fork stalling and template switching. These findings constitute the first genomic deletion causing EMARDD, expand the clinical phenotype, and provide new insight into the pattern and histology of its muscular pathology.	0
FtsK protein contains a fast DNA motor that is involved in bacterial chromosome dimer resolution. During cell division, FtsK translocates double-stranded DNA until both dif recombination sites are placed at mid cell for subsequent dimer resolution. Here, we solved the 3.6-Å resolution electron cryo-microscopy structure of the motor domain of FtsK while translocating on its DNA substrate. Each subunit of the homo-hexameric ring adopts a unique conformation and one of three nucleotide states. Two DNA-binding loops within four subunits form a pair of spiral staircases within the ring, interacting with the two DNA strands. This suggests that simultaneous conformational changes in all ATPase domains at each catalytic step generate movement through a mechanism related to filament treadmilling. While the ring is only rotating around the DNA slowly, it is instead the conformational states that rotate around the ring as the DNA substrate is pushed through.	0
INTRODUCTION:Ectopia is the most common sporadically occurring thyroid heterotopy. We present three cases of ectopic thyroid tissue with compression of the upper aerodigestive tract. The first case involved ectopic thyroid tissue in the lingual area of a 60-year-old male with dysphagia, swelling at the base of the tongue, and stomatolalia. The second case was a 66-year-old female with papillary thyroid carcinoma (PTC) in a thyroglossal duct cyst. The third patient was a 50-year-old female with aberrant thyroid tissue in the right submandibular region, with a cribriform-morular variant of PTC (CMV-PTC). METHODS:After resecting the heterotopic tissue and verifying the presence of PTC, the second and third cases underwent total thyroidectomy, and the third patient also underwent radioactive iodine ablation (RAI). Postoperative athyreosis was compensated by permanent levothyroxine substitution. RESULTS:The diagnosis of ectopic thyroid tissue is challenging. Clinical examination together with imaging methods play a key role, especially postoperative histological examination along with scintigraphy and single photon emission computed tomography (SPECT). Ultrasonography should be used to exclude normally localized thyroid tissue and to distinguish other tumorous diseases. In the pre-operative examination, ultrasound-guided fine-needle aspiration biopsy (US-FNAB) often results in technically-difficult sampling and non-diagnostic cytology. CONCLUSION:Resection is the most suitable therapy for clinical symptoms of a foreign body in the upper aerodigestive tract and inflammatory complications; total thyroidectomy follows in case of malignant transformation. Thyroid heterotopy is a rare pathological condition, yet it should be taken into consideration during differential diagnosis of tumorous oropharyngeal and neck lesions.	0
Alpha-mannosidosis is a rare inherited metabolic disorder (OMIM #248500) caused by mutations in the enzyme α-mannosidase encoded by the gene MAN2B1. Patients have distinct physical and developmental features, but only limited information regarding standardized cognitive functioning of patients has been published. Here we contribute intellectual ability scores (IQ) on 12 patients with alpha-mannosidosis (ages 8-59 years, 10 males, 2 females). In addition, a pooled analysis was performed with data collected from this investigation and 31 cases obtained from the literature, allowing a comprehensive analysis of intellectual functioning in this rare disease. The initial and pooled analyses show that patients with alpha-mannosidosis have variable degrees of intellectual disability but show decline in IQ with age, particularly during the first decade of life. Patients treated with hematopoietic stem cell transplantation tend to show stabilized cognitive abilities.	0
INTRODUCTION:Intrahepatic cholestasis of pregnancy (ICP) is a heterogeneous group of liver disorders with a high recurrence rate. Patients with a history of ICP are at risk of developing contraceptive-induced cholestasis, especially if they harbour a biliary transporter mutation. We report the first case of drug-induced cholestasis associated with a contraceptive vaginal ring (CVR) in a patient with a prior history of ICP. PRESENTATION:Our patient was a women with a history of multiple pregnancies and spontaneous abortions and early and severe ICP. Two to four weeks after initiation of CVR, she developed signs and symptoms of cholestasis, which resolved after discontinuation of the CVR. A thorough investigation to exclude other plausible causes of cholestasis was performed, including a liver biopsy. Genetic testing revealed pathogenic mutations in both the ABCB11 and ABCB4 genes. DISCUSSION:Although a history of ICP used to be an absolute contraindication for oral contraceptive pills (OCP), recent studies suggest a lower risk of cholestasis associated with low-dose oestrogen pills (20-35 mcg compared to the original 50 mcg). No previous case report could confirm the theoretical risk associated with the use of a CVR, which delivers a very low estrogen dose (15 mcg). The two biliary transporter mutations identified in our case could potentially explain the patient's susceptibility to the cholestatic effect of oestrogen. CONCLUSION:This case illustrates that CVR can trigger drug-induced cholestasis in a susceptible patient. While such cases should not discourage the trial of low-dose hormonal contraception in women with prior ICP, an appropriate follow-up is necessary to ensure early detection and treatment of drug-induced cholestasis.	0
Nipah virus (NiV; family Paramyxoviridae, genus Henipavirus) infection can cause severe respiratory and neurological disease in humans. The pathophysiology of disease is not fully understood, and it may vary by presentation and clinical course. In this study, we investigate changes in blood chemistry in NiV-infected Syrian hamsters that survived or succumbed to disease. Increased sodium and magnesium and decreased albumin and lactate levels were detected in animals euthanized with severe clinical disease compared with mock-infected controls. When subjects were grouped by clinical syndrome, additional trends were discernable, highlighting changes associated with either respiratory or neurological disease.	0
An important function of aromatase in the brain is conversion of testosterone secreted from the testis into estradiol. Estradiol produced in the brain is thought to be deeply involved in the formation of sexually dimorphic nuclei and sexual behavior as a neurosteroid. We analyzed the brain-specific promoter to elucidate the control mechanisms of brain aromatase expression that may be highly involved in sexual differentiation of the brain. The 202-bp upstream region of the brain-specific exon 1 has three types of cis-acting elements, aro-AI, AII, and B. We isolated ARP-1 as an aro-AII-binding protein by yeast one-hybrid screening from a cDNA library of mouse fetal brains. ARP-1 is a member of the nuclear receptor superfamily and functions as an orphan-type transcription factor. ARP-1 protein synthesized in vitro showed the same binding property to the aro-AII site as nuclear extract from fetal brains. To determine how the promoter is involved in brain-specific transcription of the aromatase gene, we first detected the in vivo occupancy of the aro-AII site by ARP-1 using chromatin immunoprecipitation assays. Diencephalic regions of fetal brains at embryonic day 16 were analyzed, which revealed ARP-1 recruitment to the aro-AII site. To analyze the effects of ARP-1 on transcriptional regulation of the brain-specific aromatase promoter, a luciferase reporter plasmid driven by the brain-specific promoter was transfected into CV-1 cells together with a plasmid expressing ARP-1 protein. These analyses revealed that ARP-1 induced promoter activity in a dose-dependent manner. Furthermore, to determine whether ARP-1 is required for aromatase expression in neurons, ARP-1 knockdown was conducted in neuronal cell primary culture. Knockdown of ARP-1 significantly suppressed the increase in aromatase mRNA observed in cultured neurons. These results indicate that ARP-1 is involved in the transcriptional regulation of the brain-specific promoter of the aromatase gene.	0
Copy number variants (CNVs) are the genetic bases for microdeletion/ microduplication syndromes (MMSs). Couples with an affected child and desire to have further children are routinely tested for a potential parental origin of a specific CNV either by molecular karyotyping or by two color fluorescence in situ hybridization (FISH), yet. In the latter case a critical region probe (CRP) is combined with a control probe for identification of the chromosome in question. However, CNVs can arise also due to other reasons, like a recombination-event based on a submicroscopic, cryptic inversion in one of the parents.Seventy-four patients with different MMSs and overall 81 CNVs were studied here by a novel three color FISH approach. The way how three locus-specific probes are selected (one is the CRP and two are flanking it in a distance of 5-10 Mb) enables to detect or exclude two possible parental conditions as origins of the CNV seen in the index: (i) direct parental origin of the CNV (deletion or duplication) or (ii) a parental cryptic inversion. Thus, for overall 51/81 CNVs (63%) a parental origin could be determined. 36/51 (70.5%) inherited the CNV directly from one of the parents, but 15/51 (29.5%) were due to an exclusively by three color FISH detectable parental inversion. A 2:1 ratio of maternal versus paternal inheritance was found. Also almost two times more male than female were among the index patients.The new, here suggested three color FISH approach is suited for more comprehensive parental studies of patients with MMS. The detection rate for parental origin was increased by 140% in this study. Still, for 30/81 cases (37%) no reason for the 'de novo' MMS in the affected index patient could be found by the here suggested FISH-probe set.	0
Neuromuscular diseases (NMDs) are inherited or acquired conditions affecting skeletal muscles, motor nerves, or neuromuscular junctions. Most of them are characterized by a progressive damage of muscle fibers with reduced muscle strength, disability, and poor health-related quality of life of affected patients. In this scenario, skeletal health is usually compromised as a consequence of modified bone-muscle cross-talk including biomechanical and bio-humoral issues, resulting in increased risk of bone fragility and fractures. In addition, NMD patients frequently face nutritional issues, including malnutrition due to feeding disorders and swallowing problems that might affect bone health. Moreover, in these patients, low levels of physical activity or immobility are common and might lead to overweight or obesity that can also interfere with bone strength features. Also, vitamin D deficiency could play a critical role both in the pathogenesis and in the clinical scenario of many NMDs, suggesting that its correction could be useful in maintaining or enhancing bone health, especially in the early phases of NMDs. Last but not least, specific disease-modifying drugs, available for some NMDs, are frequently burdened with adverse effects on bone tissue. For example, glucocorticoid therapy, standard of care for many muscular dystrophies, prolongs long-term survival in treated patients; nevertheless, high dose and/or chronic use of these drugs are a common cause of secondary osteoporosis. This review addresses the current state of knowledge about the factors that play a role in determining bone alterations reported in NMDs, how these factors can modify the biological pathways underlying bone health, and which are the available interventions to manage bone involvement in patients affected by NMDs. Considering the complexity of care of these patients, an interdisciplinary and multimodal management strategy based on both pharmacological and non-pharmacological interventions is recommended, particularly targeting musculoskeletal issues that are closely related to functional independence as well as social implications.	0
BACKGROUND:Eccrine poroma is a benign tumour of eccrine duct epithelium. The usual clinical presentation is nodular. CASE REPORT:We present a 78-year-old man with a painful pendulating flesh-coloured malodorous plantar tumour. Differential diagnoses included telangiectatic granuloma, acrochordon, basal cell or squamous cell carcinoma, cylindroma, amelanotic melanoma, and verruca. Microbiological investigations identified numerous bacteria including Corynebacterium striatum, Streptococcus dysgalactiae, Staphylococcus aureus, Citrobacter koseri. We performed surgery since the tumour hampered his mobility. Histopathology revealed a well-circumscribed tumour composed of cuboidal cells with eosinophilic cytoplasm. Healing was unremarkable. CONCLUSIONS:Pendulating plantar eccrine poroma is a rare clinical presentation of this benign adnexal tumour. Often asymptomatic, in some cases the tumour may become painful. Because of the bacterial colonisation, it could lead to deep soft tissue infections. Malignant transformation is possible. Surgical removal is the treatment of choice.	0
Epidermoid cyst of the brain is a rare benign embryonal tumor. It has an excellent prognosis because of its slow-growing nature. Clinically, symptoms are variable and depend on the location of the cyst. Sudden death may occur as a result of lethal complications because of the tumor growth, but it is still rare. In this article, we present a rare case of sudden unexpected death of a 58-year-old man, with no neurologic history, due to an epidermoid cyst of the brain diagnosed at autopsy.	0
The increasing use of three-dimensional (3D) imaging techniques in dental medicine has boosted the development and use of artificial intelligence (AI) systems for various clinical problems. Cone beam computed tomography (CBCT) and intraoral/facial scans are potential sources of image data to develop 3D image-based AI systems for automated diagnosis, treatment planning, and prediction of treatment outcome. This review focuses on current developments and performance of AI for 3D imaging in dentomaxillofacial radiology (DMFR) as well as intraoral and facial scanning. In DMFR, machine learning-based algorithms proposed in the literature focus on three main applications, including automated diagnosis of dental and maxillofacial diseases, localization of anatomical landmarks for orthodontic and orthognathic treatment planning, and general improvement of image quality. Automatic recognition of teeth and diagnosis of facial deformations using AI systems based on intraoral and facial scanning will very likely be a field of increased interest in the future. The review is aimed at providing dental practitioners and interested colleagues in healthcare with a comprehensive understanding of the current trend of AI developments in the field of 3D imaging in dental medicine.	0
PURPOSE:There has not been any valid method for the clinical diagnosis of Childhood Apraxia of Speech (CAS) up to now, and the golden standard for diagnosis is the expert's opinion. The current research was conducted to obtain criteria used by the Iranian Speech-Language Pathologists (SLPs) to establish speech characteristics and co-occurring problems of CAS based on their knowledge and clinical experience. METHODS:This research used a questionnaire-based survey design for data collection. The questionnaire was filled out by 260 anonymous participants, both physically and online. RESULTS:The nine top speech characteristics reported with 75.6% agreement as the core symptoms of CAS included: inconsistency (86.9%), consonant sequencing problems (75%), low intelligibility (75%), groping (72.7%), slow diadochokinetic (DDK) (72.3%), articulatory configuration problems (66.2%), difficulty with multisyllabic words (62.7%), suprasegmental disturbances (56.2%) and metathesis (53.5%). The consent of the Iranian practicing SLPs was consistent with the American Speech-Language-Hearing Association (ASHA) diagnostic criteria, Strand's 10-point checklist, and Ozanne's cluster model. More than half of the respondents have been identified with fine motor deficit and language impairment as the most common co-occurring problems of CAS. CONCLUSIONS:The results of this study are in accordance with the findings of previous practicing SLPs' surveys in different languages. Carrying out researches on the speech characteristics of Persian-speaking children suspected of CAS and compare with the results of clinicians' surveys will help us to find a reliable standard for differential diagnosis of Persian-speaking children in Iran.	0
OBJECTIVES:Developmental dysplasia of the hip (DDH) is a common skeletal disorder. This study was conducted to demonstrate the association between DDH and a polymorphism rs9277935 of COL11A2 gene. RESULTS:A significant difference in genotype distribution in a recessive model (TT+GT vs. GG) between two groups (P=0.017) was demonstrated. Analysis in female patients showed significantly greater frequency of minor allele G(0.49 vs. 0.43, p=0.024) and significantly higher distribution of GG genotype (p=0.006). DDH patients were found to have significantly lower COL11A2 expression than controls. Moreover, DDH patients with rs9277935 genotype TT have a significantly increased expression of COL11A2 than those with genotype GG. COL11A2 demonstrated chondrogenic properties in vitro. CONCLUSION:Polymorphism rs9277935 of gene COL11A2 is a functional variant regulating the expression and the chondrogenic properties of COL11A2 in DDH in Chinese Han population. METHODS:A case-control candidate gene association study was conducted in 945 patients (350 radiologically confirmed DDH patients and 595 healthy controls). Difference of COL11A2 expression in hip joint tissue was compared between the patients and the controls. Allelic difference in Col11a2 expression by rs9277935 was assessed with luciferase activity. Chondrogenic effects of Col11a2 signaling on BMSCs were also determined in vitro.	0
The number of deaths due to systemic fungal infections is increasing alarmingly, which is aggravated by the limitations of traditional treatments and multidrug resistance. Therefore, the research and development of new therapeutic options against pathogenic fungi is an urgent need. To evaluate the fungicidal activity of a synthetic compound, 1,3-bis-(3,4-dichlorophenoxy)propan-2-aminium chloride (2j), through time-kill studies and pharmacokinetics/pharmacodynamics (PK/PD) modeling. The protective effect of the compound was also evaluated using the Drosophila melanogaster minihost model of candidiasis. Mathematical modeling of time-kill data of compound 2j was performed to obtain PD characteristics. Additionally, Toll-deficient D. melanogaster flies were infected with a Candida albicans strain and treated with 2j. We observed that compound 2j demonstrated a time- and dose-dependent fungicidal effect against Candida spp. and dermatophytes, even at low concentrations, and rapidly achieved kill rates reaching the maximum effect in less than one hour. The efficacy of the compound against systemic candidiasis in D. melanogaster flies was comparable to that achieved by fluconazole. These results support the potential of compound 2j as a systemic antifungal agent candidate and serve as a starting point for further studies involving mammalian animal models.	0
Botulism is an acute toxin-mediated neuroparalytic syndrome caused by some Clostridium species. It typically presents itself as an acute symmetric descending paralysis of cranial and peripheral nerves, which can potentially evolve to respiratory failure and death. We report a case of botulism diagnosed in a patient presenting with a parotitis probably due to xerostomia, even though he had already sought medical assistance for blurred vision and dysphagia. The neurological symptoms resolved without administration of antitoxin and botulism diagnosis was confirmed with identification of both toxins B and F in patient's serum. We aim to illustrate the need for a high clinical suspicion for the diagnosis of botulism and to report an atypical case of botulism with the production of toxins B and F, the latter being of rare occurrence.	0
Purpose:To investigate macular structural and microvascular changes in retinitis pigmentosa (RP) eyes compared to age-matched controls using spectral domain optical coherence tomography (SD-OCT) and OCT angiography (OCTA). Methods:This was a cross-sectional study. The foveal and parafoveal thickness and extent of ellipsoid zone (EZ) disruption were measured on OCT. The foveal avascular zone (FAZ) area and retinal vessel density (VD) were automatically calculated for superficial (SCP) and deep capillary plexuses (DCP) and choriocapillaris using OCTA-integrated software. VD was assessed for the whole 6 × 6 mm image, foveal and parafoveal regions. Quantitative measures were compared between healthy and diseased eyes. Results:The study included 30 eyes of 30 RP patients and 24 eyes of 24 controls. Mean age was 26.9±6.4 years for RP patients and 27.4±4.9 years for controls (p=0.76). Mean LogMAR visual acuity (VA) was 0.9±0.5 for RP patients and 0.05±0.05 for controls (p <0.001). Foveal and parafoveal thicknesses were significantly lower in RP cases as compared to the control group. EZ disruption was observed in RP cases only (869±211 µm). Mean FAZ area was significantly larger in RP eyes in both SCP and DCP. VD was significantly reduced in RP eyes at the level of SCP, DCP and choriocapillaris. VA, deep parafoveal VD, foveal, parafoveal and whole image choriocapillaris VD were negatively correlated with the extent of EZ disruption. Conclusion:We report OCTA findings in a relatively young cohort of RP patients. We demonstrated a reduction of retinal microvascular density in all studied layers on OCTA. We believe studying retinal vasculature in these patients is important, as a healthy blood supply is a prerequisite for the success of new cell-based therapies under trial for RP.	0
BACKGROUND:Dilated cardiomyopathy with ataxia syndrome (DCMA) is an understudied autosomal recessive disease caused by loss-of-function mutations in the poorly characterized gene DNAJC19. Clinically, DCMA is commonly associated with heart failure and early death in affected children through an unknown mechanism. DCMA has been linked to Barth syndrome, a rare but well-studied disorder caused by deficient maturation of cardiolipin (CL), a key mitochondrial membrane phospholipid. METHODS:Peripheral blood mononuclear cells from 2 children with DCMA and severe cardiac dysfunction were reprogrammed into induced pluripotent stem cells (iPSCs). Patient and control iPSCs were differentiated into beating cardiomyocytes (iPSC-CMs) using a metabolic selection strategy. Mitochondrial structure and CL content before and after incubation with the mitochondrially targeted peptide SS-31 were quantified. RESULTS:Patient iPSCs carry the causative DNAJC19 mutation (rs137854888) found in the Hutterite population, and the iPSC-CMs demonstrated highly fragmented and abnormally shaped mitochondria associated with an imbalanced isoform ratio of the mitochondrial protein OPA1, an important regulator of mitochondrial fusion. These abnormalities were reversible by incubation with SS-31 for 24 hours. Differentiation of iPSCs into iPSC-CMs increased the number of CL species observed, but consistent, significant differences in CL content were not seen between patients and control. CONCLUSIONS:We describe a unique and novel cellular model that provides insight into the mitochondrial abnormalities present in DCMA and identifies SS-31 as a potential therapeutic for this devastating disease.	0
Copy-number variations (CNVs) are strong risk factors for neurodevelopmental and psychiatric disorders. The 15q13.3 microdeletion syndrome region contains up to ten genes and is associated with numerous conditions, including autism spectrum disorder (ASD), epilepsy, schizophrenia, and intellectual disability; however, the mechanisms underlying the pathogenesis of 15q13.3 microdeletion syndrome remain unknown. We combined whole-genome sequencing, human brain gene expression (proteome and transcriptome), and a mouse model with a syntenic heterozygous deletion (Df(h15q13)/+ mice) and determined that the microdeletion results in abnormal development of cortical dendritic spines and dendrite outgrowth. Analysis of large-scale genomic, transcriptomic, and proteomic data identified OTUD7A as a critical gene for brain function. OTUD7A was found to localize to dendritic and spine compartments in cortical neurons, and its reduced levels in Df(h15q13)/+ cortical neurons contributed to the dendritic spine and dendrite outgrowth deficits. Our results reveal OTUD7A as a major regulatory gene for 15q13.3 microdeletion syndrome phenotypes that contribute to the disease mechanism through abnormal cortical neuron morphological development.	0
Despite tremendous progress through next generation sequencing technologies, familial focal epilepsies are insufficiently understood. We sought to identify the genetic basis in multiplex Palestinian families with familial focal epilepsy with variable foci (FFEVF). Family I with 10 affected individuals and Family II with five affected individuals underwent detailed phenotyping over three generations. The phenotypic spectrum of the two families varied from nonlesional focal epilepsy including nocturnal frontal lobe epilepsy to severe structural epilepsy due to hemimegalencephaly. Whole-exome sequencing and single nucleotide polymorphism array analysis revealed pathogenic variants in NPRL3 in each family, a partial ~38-kb deletion encompassing eight exons (exons 8-15) and the 3'-untranslated region of the NPRL3 gene in Family I, and a de novo nonsense variant c.1063C>T, p.Gln355* in Family II. Furthermore, we identified a truncating variant in the PDCD10 gene in addition to the NPRL3 variant in a patient with focal epilepsy from Family I. The individual also had developmental delay and multiple cerebral cavernomas, possibly demonstrating a digenic contribution to the individual's phenotype. Our results implicate the association of NPRL3 with hemimegalencephaly, expanding the phenotypic spectrum of NPRL3 in FFEVF and underlining that partial deletions are part of the genotypic spectrum of NPRL3 variants.	0
Autoinflammatory diseases include disorders with a monogenic cause and also complex conditions associated to polygenic or multifactorial factors. An increased number of both monogenic and polygenic autoinflammatory conditions have been identified during the last years. Although skin manifestations are often predominant in monogenic autoinflammatory diseases, clinical and histopathological information regarding their dermatological involvement is still scarce. Monogenic autoinflammatory diseases with cutaneous expression can be classified based on the predominant lesion: (1) maculopapular rashes or inflammatory plaques; (2) urticarial rashes; (3) pustular, pyogenic or neutrophilic dermatosis-like rashes; (4) panniculitis or subcutaneous nodules; (5) vasculitis or vasculopathy; (6) hyperkeratotic lesions; (7) hyperpigmented lesions; (8) bullous lesions; and (9) aphthous lesions. By using this classification, this review intends to provide clinical and histopathological knowledge about cutaneous involvement in monogenic autoinflammatory diseases.	0
To describe outcomes in patients with cor triatriatum sinister (CTS).Retrospective review of patients with CTS followed at Mayo Clinic Rochester from 1990 to 2016. Clinical notes, operative reports, and baseline imaging studies were reviewed including echocardiogram, magnetic resonance imaging, computed tomography, and cardiac catheterization.Fifty-seven patients (median age 34 years; men 32 (56%)) were enrolled. Definitive or suspected CTS diagnosis was made by transthoracic echocardiogram in 41 (72%) patients, and additional multimodality imaging was required in 39 (68%) patients. Of these 57 patients, initial diagnosis was made in adulthood in 35 (61%) patients, and 33 of 57 (58%) patients had additional congenital heart disease (CHD) diagnosis. A total of 27 (47%) patients required surgical resection of CTS membrane during median follow-up of 76 months, and these patients were younger at the time of CTS diagnosis (26 vs 41, P = 0.01) and more likely to have associated CHD (55% vs 45%, P = 0.02). There was one perioperative mortality and no late mortality. There was no recurrence of CTS membrane obstruction in the patients that underwent surgery. Similarly there was no significant increase in CTS membrane gradient in the patients that were managed conservatively.The natural history of CTS is stability without progressive left atrial obstruction, especially in patients with isolated CTS and in those with initial CTS diagnosis made in adulthood. In patients requiring surgical membrane resection due to flow obstruction, surgery is safe and effective with very low risk of recurrence.	0
Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is a rare disorder. Patients with this syndrome experience early symptomatic arthropathy of the hips. We report a case of adolescent siblings with bilateral arthropathy associated with CACP syndrome in which total hip arthroplasty was performed as treatment of severe associated disability. Postoperative Harris Hip Scores for patient 1 were 86 for the right at 18 months and 96 for the left at 12 months. Postoperative Harris Hip Score at 6 months for patient 2 was 53; however, he had good range of motion and lacked deformity. Based on our limited experience and the limited available clinical data, we feel that total hip arthroplasty is a reasonable treatment option for adolescents with debilitating hip arthropathy associated with CACP syndrome.	0
The BBSome, a complex of 8 BBS (Bardet-Biedl syndrome) proteins known for its role in the control of cilia function and other cellular processes, has been implicated in blood pressure control, but the underlying mechanisms are not fully understood. Here, we show that neuronal BBSome plays an important role in blood pressure regulation. Targeted inactivation of the BBSome in the nervous system through Bbs1 gene deletion causes sympathetically mediated increase in blood pressure in mice. This phenotype is reproduced by selective ablation of the Bbs1 gene from the LRb (leptin receptor)-expressing neurons. Strikingly, the well-known role of the BBSome in the regulation of cilia formation and function is unlikely to account for the prohypertensive effect of BBSome inactivation as disruption of the IFT (intraflagellar transport) machinery required for ciliogenesis by deleting the Ift88 gene in LRb neurons had no effect on arterial pressure and sympathetic nerve activity. Furthermore, we found that Bbs1 gene deletion from AgRP (agouti-related protein) neurons or POMC (proopiomelanocortin) neurons increased renal and splanchnic sympathetic nerve activity without altering blood pressure. This lack of blood pressure increase despite the sympathetic overdrive may be explained by vascular adrenergic desensitization as indicated by the reduced vascular contractile response evoked by phenylephrine and the decreased expression of adrenergic receptors. Our results identify the neuronal BBSome as a new player in hemodynamic, sympathetic, and vascular regulation, in a manner independent of cilia.	0
Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare and disabling disorder of fibroblast growth factor 23 (FGF23) deficiency or resistance. The disorder is manifest by hyperphosphatemia, inappropriately increased tubular reabsorption of phosphate and 1,25-dihydroxy-Vitamin D, and ectopic calcifications. HFTC has been associated with autosomal recessive pathogenic variants in: (1) the gene encoding FGF23; (2) GALNT3, which encodes a protein responsible for FGF23 glycosylation; and (3) KL, the gene encoding KLOTHO, a critical co-receptor for FGF23 signaling. An acquired autoimmune form of hyperphosphatemic tumoral calcinosis has also been reported. Periarticular tumoral calcinosis is the primary cause of disability in HFTC, leading to pain, reduced range-of-motion, and impaired physical function. Inflammatory disease is also prominent, including diaphysitis with cortical hyperostosis. Multiple treatment strategies have attempted to manage blood phosphate, reduce pain and inflammation, and address calcifications and their complications. Unfortunately, efficacy data are limited to case reports and small cohorts, and no clearly effective therapies have been identified. The purpose of this review is to provide a background on pathogenesis and clinical presentation in HFTC, discuss current approaches to clinical management, and outline critical areas of need for future research.	0
Hereditary sensory and autonomic neuropathy (HSAN) 2B is a rare disease and has been reported mostly in offspring of consanguineous parents. Here we report the case of a patient born to non-consanguineous parents who was diagnosed with HSAN 2B caused due to a novel frameshift mutation (NM_001034850.2: c.765dupT/p.Gly256TrpfsTer7) in the RETREG1 gene and paternal uniparental isodisomy of chromosome 5. Uniparental isodisomy of chromosome 5 is also a rare condition, and these two rare events lead to homozygous expression of a recessive mutation, as in the present case. Clinicians should be aware that autosomal recessive disorders due to homozygous variants can occur because of uniparental disomy in offspring of non-consanguineous parents.	0
Novel derivatives of quinolizidine alkaloid (-)-cytisine were synthesised. ADME properties, cytotoxicity against HEK293 cells and activity against viruses of influenza A/California/07/09(H1N1)pdm09 virus (IAV) and human parainfluenza virus type 3 (HPIV3) were evaluated. It was shown, that 9-carboxamides of methylcytisine (with phenyl and allyl urea's fragments) are most active compounds against IAV probably due to predicted in silico peculiarity of their interactions with the 4R7B active site of IAV neuraminidase. Indexes of selectivity (SI) calculated as ratio of CC50/IC50 of these ureas are 47 and 59 correspondingly. It was also found, that derivatives obtained from allyl isocyanate and (-)-cytisine or 9,11-dibromocytisine are able to inhibit a reproduction of HPIV3 with SI = 58 and 95. Moreover, last compound - (1 R,5R)-N-allyl-9,11-dibromo-8-oxo-1,5,6,8-tetrahydro-2H-1,5-methanopyrido[1,2-a][1,5]diazocine-3(4H)-carboxamide with two bromine atom in 2-pyridone core of starting (-)-cytisine molecule, demonstrated high activity against HPIV3 (SI = 95) and moderate activity against IAV (SI = 16).	0
The aim of this review was to identify the imaging methods at our disposal to optimally manage posterior uveitis at the present time. The focus was put on methods that have become available since the 1990s, some 30 years after fluorescein angiography had revolutionized imaging of posterior uveitis in particular imaging of the retinal vascular structures in the 1960s. We have focussed our review on precise imaging methods that have been standardized and validated and can be used universally thanks to commercially produced and available instruments for the diagnosis and follow-up of posterior uveitis. The first part of this imaging review will deal with noninvasive imaging methods, focusing on fundus autofluorescence and optical coherence tomography as well as recent developments in imaging of the posterior segment.	0
Optimal control mechanisms require prediction capabilities. If one cannot predict the consequences of a motor act or behavior, one will continually collide with walls or become a social pariah. "Looking into the future" is thus one of the most important prerequisites for smooth movements and social interactions. To achieve this goal, the brain must constantly predict future events. This principle applies to all domains of information processing, including motor and cognitive control, as well as the development of decision-making skills, theory of mind, and virtually all cognitive processes. Sequencing is suggested to support the predictive capacity of the brain. To recognize that events are related, the brain must discover links among them in the spatiotemporal domain. To achieve this, the brain must often hold one event in working memory and compare it to a second one, and the characteristics of the two must be compared and correctly placed in space and time. Among the different brain structures involved in sequencing, the cerebellum has been proposed to have a central function. We have suggested that the operational mode of the cerebellum is based on "sequence detection" and that this process is crucial for prediction. Patterns of temporally or spatially structured events are conveyed to the cerebellum via the pontine nuclei and compared with actual ones conveyed through the climbing fibers olivary inputs. Through this interaction, data on previously encountered sequences can be obtained and used to generate internal models from which predictions can be made. This mechanism would allow the cerebellum not only to recognize sequences but also to detect sequence violations. Cerebellar pattern detection and prediction would thus be a means to allow feedforward control based on anticipation. We will argue that cerebellar sequencing allows implementation of prediction by setting the correct excitatory levels in defined brain areas to implement the adaptive response for a given pattern of stimuli that embeds sufficient information to be recognized as a previously encountered template. Here, we will discuss results from human and animal studies and correlate them with the present understanding of cerebellar function in cognition and behavior.	0
BACKGROUND:Neuronal ceroid lipofuscinosis type 5 (CLN5) is a rare form of neuronal ceroid lipofuscinoses (NCLs) which are a group of inherited neurodegenerative diseases characterized by progressive intellectual and motor deterioration, visual failure, seizures, behavioral changes and premature death. CLN5 was initially named Finnish variant late infantile NCL, it is now known to be present in other ethnic populations and with variable age of onset. Few CLN5 patients had been reported in Chinese population. CASE PRESENTATION:In this paper, we report the symptoms of a Chinese patient who suffer from developmental regression and grand mal epilepsy for several years. The DNA was extracted from peripheral blood of proband and both parents, and then whole exome sequencing was performed using genomic DNA. Both sequence variants and copy number variants (CNVs) were analyzed and classified according to guidelines. As the result, a novel frameshift mutation c.718_719delAT/p.Met240fs in CLN5 and a de novo large deletion at 13q21.33-q31.1 which unmasked the frameshift mutation were identified in the proband. Despite the large de novo deletion, which can be classified as a pathogenic copy number variant (CNV), the patient's clinical presentation is mostly consistent with that of CLN5, except for early developmental delay which is believed due to the large deletion. Both variants were detected simultaneously by exome sequencing. CONCLUSIONS:This is the first report of whole gene deletion in combination with a novel pathogenic sequence variant in a CLN5 patient. The two mutations detected with whole exome sequencing simultaneously proved the advantage of the sequencing technology for genetic diagnostics.	0
Pilomatrixoma, an uncommon, usually benign cutaneous appendageal tumor, shows differentiation toward the hair follicle matrix cell. It undergoes various histopathologic stages, early on displaying epithelial and shadow cells along with granulomatous inflammation. In later stages, illustrated by this unusual case, epithelial cells disappear and are replaced by calcification and ossification. Immunohistochemistry in the current case showed transitional cell reactivity for β-catenin, probably linking the tumor to a mutation in the β-catenin gene CTNNB1. There was also transitional cell positivity for cyclin D1, a marker found in matrical cells of the human hair follicle. While pilomatrixoma occurs occasionally in the eyelid, the ossified eyelid variant in the current case is very rare, with only one preceding description in the literature.	0
Autosomal-recessive spinocerebellar ataxia type 18 (SCAR18) is a rare neurologic disorder. It is caused by bi-allelic aberrations in the GRID2 gene, encoding an ionotropic glutamate receptor. In total, 20 affected individuals with mainly homozygous/compound heterozygous intragenic deletions/duplications, two different missense variants and one nonsense variant in GRID2 have been reported, so far. SCAR18 is characterized by delayed psychomotor development, intellectual disability, severely impaired gait due to cerebellar ataxia, ocular movement abnormalities, and cerebellar atrophy in brain imaging. By trio exome sequencing, we now identified a novel homozygous nonsense variant (c.568C > T; p.Gln190*) in GRID2 in a four year old female from a consanguineous family who presented with a particularly severe manifestation of SCAR18. The girl was born after an uneventful pregnancy and showed early-onset, profoundly delayed psychomotor development with no achieved psychomotor milestones at age 4 years. Additionally, she presented with severe muscular hypotonia, progressive truncal and appendicular ataxia, binocular vertical nystagmus, central hearing loss and incomplete loss of sight. She was dystrophic, interacted only very little and had behavioral anomalies such as eating hair and bruxism. Brain imaging showed cerebellar hypoplasia, extended cerebrospinal fluid spaces and beginning reduction of cerebral volume. Our findings further delineate the mutational and clinical spectrum of GRID2-associated spinocerebellar ataxia type 18 and indicate that homozygous nonsense variants are possibly associated with the severe end of the SCAR18 phenotypic spectrum.	0
Sialuria is a rare autosomal dominant inborn error of metabolism characterized by cytoplasmic accumulation and urinary excretion of gram quantities of free sialic acid due to failure of feedback inhibition of the rate-limiting enzyme in the sialic acid synthesis pathway, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK). To date, eight cases had been published worldwide, all with heterozygous missense variants at the allosteric site, specifically at Arginine 294 (formerly 263) and Arginine 297 (formerly 266) of GNE. The described cases so far have rather homogeneous clinical features which include developmental delay, mildly coarse features, hepatomegaly and prolonged neonatal jaundice. The apparent rarity of this disorder is hypothesized to be due to the variable and sometimes transient nature of the clinical features and to the absence of routine testing for urinary sialic acids. Here we present the ninth case of sialuria diagnosed in a child investigated because of clinical signs and symptoms and furthermore describe a novel pathogenic variant in the associated gene, GNE.	0
Aim:To review the published literature on the treatment of aneurysmal bone cysts (ABCs). Method:A systematic review of the English literature to April 2019 for all articles, with a minimum of three patients and 2-year follow-up, reporting on the treatment of spinal ABCs. The various treatment options were compared for the rates of recurrence, complications and mortality. Results:Twenty-one articles and 272 patients (mean age 16.9 years, range 3-67) were included in this review. The overall recurrence rate for ABCs following all treatments is 12.8%. This is highest in those lesions described as being treated with isolated surgiflo injection into the lesion (100%), decompression/laminectomy (42.3%), partial excision/resection (35.7%) and curettage alone (25.0%). Radiotherapy alone or in conjunction with operative intervention offers excellent cure rates. Adjuncts to operative intervention, including cryotherapy or phenol reduce the recurrence rates, whereas embolization does not. The most common complications are persistent neurological deficits, spinal deformity, and continued pain. The overall mortality rates are low (1.5%). The reoperation rates are higher in surgical than non-surgical treatments and most are performed for progressive deformity. Discussion:ABCs are highly radiosensitive. However, with the unknown longer-term risk of radiotherapy, surgical treatments, ideally with complete resection, and the use of adjunctive therapies such as cryotherapy or phenol, offer the best chance of cure. SAE is a useful adjunct to reduce intraoperative bleeding, but this study suggests that it only modestly improves recurrence rates. Newer techniques including bisphosphonate and doxycycline administration offer potential benefits, but their efficacy requires further investigation.	0
BACKGROUND AND PURPOSE:Gliomatosis cerebri (GC) is a rare growth pattern of glioblastoma whose diffuse nature is reflected by unspecific, relatively uniform findings on conventional MRI. In the present study we sought to evaluate the additional value of diffusion (DWI) and perfusion weighted (PWI) MRI for a more detailed characterization. METHODS:We analyzed the MRI findings in patients with histologically proven glioblastoma with GC growth pattern with a specific emphasis on T2 lesion pattern, volume, relative apparent diffusion coefficient (rACD), and relative cerebral blood volume (rCBV) and compared these to age-/gender-matched patients with localized glioblastoma. RESULTS:Overall, 16 patients (median age 59.5 years, 4 male) were included in the study. Of these, 8 patients had a glioblastoma with GC growth pattern, and 8 a classical localized growth pattern. While the median rADC (1.27 [IQR 1.12-1.41]) within the T2 lesion was significant lower in glioblastoma with GC growth pattern compared to localized glioblastoma (1.74 [IQR 1.45-1.96]; p = 0.003), the median T2 lesion volume and rCBV within the T2 lesion did not differ significantly. Furthermore, six patients with glioblastoma with GC growth pattern showed focal areas with significantly reduced rADC (p = 0.043), and/or increased rCBV (p = 0.028). CONCLUSIONS:Lower rADC in glioblastoma with GC growth pattern might reflect the diffuse tumor cell infiltration whereas focal areas with decreased rADC and/or increased rCBV probably indicate high tumor cell density and/or abnormal tumor vessels which may be useful for biopsy guidance.	0
In vascular tissue engineering strategies, the addition of vascular-specific extracellular matrix (ECM) components may better mimic the in vivo microenvironment and potentially enhance cell-matrix interactions and subsequent tissue growth. For this purpose, the exact composition of the human vascular ECM first needs to be fully characterized. Most research has focused on characterizing ECM components in mature vascular tissue; however, the developing fetal ECM matches the active environment required in vascular tissue engineering more closely. Consequently, we characterized the ECM protein composition of active (fetal) and quiescent (mature) renal arteries using a proteome analysis of decellularized tissue. The obtained human fetal renal artery ECM proteome dataset contains higher levels of 15 ECM proteins versus the mature renal artery ECM proteome, whereas 16 ECM proteins showed higher levels in the mature tissue compared to fetal. Elastic ECM proteins EMILIN1 and FBN1 are significantly enriched in fetal renal arteries and are mainly produced by cells of mesenchymal origin. We functionally tested the role of EMILIN1 and FBN1 by anchoring the ECM secreted by vascular smooth muscle cells (SMCs) to glass coverslips. This ECM layer was depleted from either EMILIN1 or FBN1 by using siRNA targeting of the SMCs. Cultured endothelial cells (ECs) on this modified ECM layer showed alterations on the transcriptome level of multiple pathways, especially the Rho GTPase controlled pathways. However, no significant alterations in adhesion, migration or proliferation were observed when ECs were cultured on EMILIN1- or FNB1-deficient ECM. To conclude, the proteome analysis identified unique ECM proteins involved in the embryonic development of renal arteries. Alterations in transcriptome levels of ECs cultured on EMILIN1- or FBN1-deficient ECM showed that these candidate proteins could affect the endothelial (regenerative) response.	0
Large granular lymphocyte leukemia (LGL) is a clonal, lymphoproliferative disorder with an indolent disease course. T-cell LGL (T-LGL) is the most common type of LGL driven from T-cell lineage (85%). The coexistence of T-LGL with several types of autoimmune disorders, mostly rheumatoid arthritis (RA), has been reported. Felty's syndrome (FS) is defined by splenomegaly, low neutrophil count, and destructive arthritis and is usually seen in <1% of patients with RA. About 30% to 40% of patients with FS have been reported to have an expansion of large granulated lymphocytes in the circulation. FS and T-LGL are similar in terms of clinical manifestations, response to immunosuppressive therapy, their smoldering course, and immunogenetic findings, proposing FS and T-LGL with RA might be different aspects of a single disease spectrum. In this article, we present a case with long-standing RA who had never been on DMARD (Disease Modifying Anti-Rheumatic Drugs) treatment found to have constitutional symptoms, neutropenia, and splenomegaly, and the patient was diagnosed with T-LGL.	0
Three relatives carrying a t(4;8)(p15.2;p23.2) translocation had juvenile myoclonic epilepsy, self-limited photosensitive occipital epilepsy and migraine with aura. The t(4;8) translocation interrupted the coding sequence of CSMD1 gene and occurred immediately to the 3'UTR of STIM2 gene. STIM2 was overexpressed in the patient carrying the unbalanced translocation, and all three individuals had a single functional copy of CSMD1. Array CGH study disclosed that these three individuals also carried a deletion at 5q12.3 that involves the RGS7BP gene. The overall results favor the view that CSMD1, STIM2, and RGS7BP genes could contribute to epilepsy and migraine phenotypes in our family.	0
BACKGROUND:Proximal symphalangism is a rare disease with multiple phenotypes including reduced proximal interphalangeal joint space, symphalangism of the 4th and/or 5th finger, as well as hearing loss. At present, at least two types of proximal symphalangism have been identified in the clinic. One is proximal symphalangism-1A (SYM1A), which is caused by genetic variants in Noggin (NOG), another is proximal symphalangism-1B (SYM1B), which is resulted from Growth Differentiation Factor 5 (GDF5) mutations. CASE PRESENTATION:Here, we reported a Chinese family with symphalangism of the 4th and/or 5th finger and moderate deafness. The proband was a 13-year-old girl with normal intelligence but symphalangism of the 4th finger in the left hand and moderate deafness. Hearing testing and inner ear CT scan suggested that the proband suffered from structural deafness. Family history investigation found that her father (II-3) and grandmother (I-2) also suffered from hearing loss and symphalangism. Target sequencing identified a novel heterozygous NOG mutation, c.690C > G/p.C230W, which was the genetic lesion of the affected family. Bioinformatics analysis and public databases filtering further confirmed the pathogenicity of the novel mutation. Furthermore, we assisted the family to deliver a baby girl who did not carry the mutation by genetic counseling and prenatal diagnosis using amniotic fluid DNA sequencing. CONCLUSION:In this study, we identified a novel NOG mutation (c.690C > G/p.C230W) by target sequencing and helped the family to deliver a baby who did not carry the mutation. Our study expanded the spectrum of NOG mutations and contributed to genetic diagnosis and counseling of families with SYM1A.	0
BACKGROUND:Autoimmune hemolytic anemia (AIHA) might be associated with underlying hematological malignancies such as chronic lymphocytic leukemia. However, the association between AIHA and chronic myelogenous leukemia is extremely unusual. SUMMARY:We reviewed case reports and series of 54 patients with chronic myeloid leukemia (CML) who developed autoimmune hemolysis between 1952 and 2018. Almost all the patients were in the chronic phase and were classified into transplant and non-transplant groups. The onset of autoimmune hemolysis was earlier in the transplant group and required second- and third-line therapy to control it. The etiology of hemolysis is poorly understood but attributed in the transplant group to immune reconstitution, viral infections, or CML relapse. On the other hand, it is thought to be related in the non-transplant group to CML medications, especially interferon. Key Messages: Although AIHA is uncommon in chronic myelogenous leukemia patients, it should be in the differential diagnosis list for those who develop a sudden drop in hemoglobin without a bleeding source.	0
BACKGROUND: Hereditary paraganglioma-pheochromocytoma syndromes (PGL/PCC) are rare tumors arising from neuroendocrine cells. METHODS AND RESULTS: The proband, a 59-year-old white man and his 42-year-old elder son had a medical history of bilateral carotid body PGL and both presented for treatment of abdominal PGLs. His 36-year-old daughter had excision of recurrent malignant carotid body PGL and vertebral metastasis. His 33-year-old youngest son presented for excision of a unilateral carotid body PGL. All 4 members had succinate dehydrogenase subunit D (SDHD) mutations, whereas the proband and youngest son also had concurrent rearranged during transfection (RET) mutation. CONCLUSION: This is the first report of PGL/PCC with SDHD and RET mutations. The role of the RET gene as a modifier remains speculative. Additionally, the family pedigree suggests maternal inheritance of disease from the probands' paternal grandmother. Clinicians should refer PGL/PCC families for mutation analysis as well as being alert to changes in the classification of mutations.	0
Phelan-McDermid syndrome (PMS) or 22q13.3 deletion syndrome is characterized by global developmental delay, cognitive deficits, and behaviour in the autism spectrum. Knowledge about developmental and behavioural characteristics of this rare chromosomal disorder is still limited despite a rapid growing number of diagnoses. Our aim was to study a new and relatively large cohort to further characterize the developmental phenotype of children with PMS.We performed a descriptive study of children with a 22q13.3 deletion including SHANK3, aged 8 to 178 months, who were systematically (n = 34) and longitudinally (n = 29) assessed with standardized instruments: Bayley Scales of Infant and Toddler Development, third edition; Wechsler Preschool and Primary Scale of Intelligence, third edition; and Vineland Screener for Social and Adaptive Behavior.Maximal developmental functioning ranged from 34 to 52 months depending on the developmental domain. In general, children performed poorest in the domain of language and best on the domain of motor (young children) or cognitive development (older children). At the individual level, 25 % scored better for receptive and 18 % for expressive language, whereas 22 % scored better for fine and 33 % for gross motor function. Developmental quotients were higher in younger children and decreased with age for all developmental domains, with 38 % of the children showing no improvement of cognitive developmental functioning. Almost all children (33/34) had significant deficits in adaptive behaviour. Children with very small deletions, covering only the SHANK3, ACR, and RABL2B genes, had a more favourable developmental phenotype.Cognitive, motor, and especially language development were significantly impaired in all children with PMS but also highly variable and unpredictable. In addition, deficits in adaptive behaviour further hampered their cognitive development. Therefore, cognitive and behavioural characteristics should be evaluated and followed in each child with PMS to adapt supportive and therapeutic strategies to individual needs. Further research evaluating the relationship between deletion characteristics and the developmental phenotype is warranted to improve counselling of parents.	0
BACKGROUND:In response to energy abundant or deprived conditions, nutrients and hormones activate hypothalamic pathways to maintain energy and glucose homeostasis. The underlying CNS mechanisms, however, remain elusive in rodents and humans. SCOPE OF REVIEW:Here, we first discuss brain glucose sensing mechanisms in the presence of a rise or fall of plasma glucose levels, and highlight defects in hypothalamic glucose sensing disrupt in vivo glucose homeostasis in high-fat fed, obese, and/or diabetic conditions. Second, we discuss brain leptin signalling pathways that impact glucose homeostasis in glucose-deprived and excessed conditions, and propose that leptin enhances hypothalamic glucose sensing and restores glucose homeostasis in short-term high-fat fed and/or uncontrolled diabetic conditions. MAJOR CONCLUSIONS:In conclusion, we believe basic studies that investigate the interaction of glucose sensing and leptin action in the brain will address the translational impact of hypothalamic glucose sensing in diabetes and obesity.	0
We report on a female fetus noted to have severe malformative type of skeletal dysplasia on ultrasonography done at 35 weeks gestation. The girl died shortly after birth. Clinical examination showed a fetus with severe dwarfism, extensive long and short bones, and bone deficiencies associated with multiple dislocations. Computed tomography (CT) scan-based phenotype showed a complex constellation of malformations consistent with the diagnosis of Grebe syndrome. Parents being first cousins (consanguineous marriage) strongly suggests autosomal recessive pattern of inheritance. To our knowledge, this is the first report of neonatal death dwarfism of Grebe syndrome analyzed by CT scan-based phenotype.	0
BACKGROUND:Hereditary spastic paraplegias (HSP) are neurodegenerative disorders characterized by lower limb spasticity and weakness, with or without additional symptoms. Mutations in ATP13A2, known to cause Kufor-Rakeb syndrome (KRS), have been recently implicated in HSP. METHODS:Whole-exome sequencing was done in a Canada-wide HSP cohort. RESULTS:Three additional patients with homozygous ATP13A2 mutations were identified, representing 0.7% of all HSP families. Spastic paraplegia was the predominant feature, all patients suffered from psychiatric symptoms, and one patient had developed seizures. Of the identified mutations, c.2126G>C;(p.[Arg709Thr]) is novel, c.2158G>T;(p.[Gly720Trp]) has not been reported in ATP13A2-related diseases, and c.2473_2474insAAdelC;p.[Leu825Asnfs*32]) has been previously reported in KRS but not in HSP. Structural analysis of the mutations suggested a disruptive effect, and enrichment analysis suggested the potential involvement of specific pathways. CONCLUSION:Our study suggests that in HSP patients with psychiatric symptoms, ATP13A2 mutations should be suspected, especially if they also have extrapyramidal symptoms.	0
Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS, OMIM#603736) and genitopatellar syndrome (GTPTS, OMIM#606170), characterized by global developmental delay/intellectual disability and special clinical manifestations, are two distinct clinically overlapping syndromes caused by truncating sequence variants in the KAT6B (10q22.2) gene. We detected a de novo heterozygous variant within exon 16 of KAT6B (Chr10p: 76781966-76781967) in a 7-months-old female infant who showed symptoms of short stature, global developmental delay, blepharophimosis, and lacrimal duct anomalies highly consistent with SBBYSS. Following the clinical features, we analyzed the KAT6B gene using Next Generation Sequencing (NGS) techniques. Her parents didn't present the same genetic variant. The patient we reported here is mainly characterized by syndromic forms of short stature and developmental delay, which may contribute to the understanding of clinical genetics for KAT6B-associated disorders.	0
Few medications are available and well tested to treat infants who already have developed or inevitably will develop severe bronchopulmonary dysplasia (sBPD). Infants who develop sBPD clearly have not benefited from decades of research efforts to identify clinically meaningful preventive therapies for very preterm infants in the first days and weeks of their postnatal lives. This review addresses challenges to individualized approaches to medication use for sBPD. Specific challenges include understanding the combination of an individual infant's postmenstrual and postnatal age and the developmental status of drug-metabolizing enzymes and receptor expression. This review will also explore the reasons for the variable responsiveness of infants to specific therapies, based on current understanding of developmental pharmacology and pharmacogenetics. Data demonstrating the remarkable variability in the use of commonly prescribed drugs for sBPD are presented, and a discussion about the current use of some of these medications is provided. Finally, the potential use of antifibrotic medications in late-stage sBPD, which is characterized by a profibrotic state, is addressed.	0
OBJECTIVE:To obtain pilot data about the incidence, need for surgical intervention, and demographics of recurrent respiratory papillomas in the United States. DESIGN:Otolaryngologists were surveyed using a questionnaire with structured and open-ended questions. PARTICIPANTS:One thousand board-certified otolaryngologists practicing in the United States as of January 1, 1993, through a random mailing list provided by the American Academy of Otolaryngology-Head and Neck Surgery and all active US members of the American Society of Pediatric Otolaryngology and the American Bronchoesophagological Association. A total of 1346 questionnaires were distributed. MAIN OUTCOME MEASURES:Physician's responses to questions about their current patient load of children and adults with recurrent respiratory papillomas, their surgical and anesthetic management of the disease, and their clinical experiences with risk factors for developing recurrent respiratory papillomas. RESULTS:Projected totals for recurrent respiratory papillomas among children were 2354 new cases (95% confidence interval [CI], 1448 to 3260) and 5970 active cases (95% CI, 3465 to 8474), requiring 16,597 surgical procedures (95% CI, 6938 to 26,255) at a cost of $109 million (95% CI, $45 to 172 million) for March 1, 1993 to March 31, 1994. Projected totals for adult recurrent respiratory papillomas were 3623 new cases (95% CI, 2359 to 4887) and 9015 active cases (95% CI, 6435 to 11,591) requiring 9284 surgical procedures (95% CI, 6003 to 12,565) at a cost of $42 million (95% CI, $27 to $59 million) for March 1, 1993 to March 31, 1994. The incidence of recurrent respiratory papillomas among children is estimated at 4.3 per 100,000; among adults, 1.8 per 100,000. The carbon dioxide laser was favored by 92% of respondents. No consensus was reached on the role for cesarean section. Forty-six percent of respondents favored the use of a laser-safe endotracheal tube for anesthetic management. CONCLUSION:A registry of patients with recurrent respiratory papillomas would benefit future research protocols and provide long-term follow-up of patients.	1
Background:Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome that presents with hypophosphatemia, bone pain, muscle weakness and fractures. We report a case series of four patients with TIO that resulted in significant muscle weakness and multiple atraumatic fractures. Case presentation:Four patients were referred to an endocrinology clinic for the evaluation of multiple atraumatic fractures, muscle weakness, generalized muscle and joint pain. Laboratory evaluation was notable for persistent hypophosphatemia due to urinary phosphate wasting, low to low-normal 1,25-dihydroxyvitamin D, elevated alkaline phosphatase and elevated fibroblast growth factor 23 (FGF23). Tumor localization was successful, and all four patients underwent resection of phosphaturic mesenchymal tumors. Post-operatively, patients exhibited normalization of serum phosphorus, in addition to significant improvement in their ambulatory function. Conclusion:Hypophosphatemia with elevated FGF23 and low 1,25-dihydroxyvitamin D level in the setting of multiple atraumatic fractures necessitates careful evaluation for biochemical evidence of tumor-induced osteomalacia.	0
Biliary colic is a pain in the right upper quadrant or epigastrium thought to be caused by functional gallbladder spasm from a temporary obstructing stone in the gallbladder neck, cystic duct or common bile duct. A 56-year-old man presented with frequent episodes of typical biliary colic. At initial laparoscopy, the gallbladder was absent from its anatomic location. Further inspection revealed a left-sided gallbladder (LSGB), suspended from liver segment 3. Preoperative ultrasound, the most common imaging modality for symptomatic gallstones, has a low positive predictive value for detecting LSGB (2.7%). Laparoscopic cholecystectomy (LC) was delayed to attain additional imaging. A magnetic resonance cholangiopancreatography demonstrated the gallbladder left of the falciform ligament with the cystic duct entering the common hepatic duct from the left. The patient underwent an elective LC 8 weeks later. The critical view of safety is paramount to safe surgical dissection and could be safely achieved for LSGB.	0
Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive condition, characterized by marked atrophy of zona fasiculata and reticalaris with preservation of zona glomerulosa. Out of more than 50 published cases, 18 patients died as a result of glucocorticoid insufficiency. The main objective of this report is to emphasize the early diagnosis and treatment in our 17 month-old patient. Her presenting features following an upper respiratory tract infection were hypoglycemia, seizures as well as deep hyperpigmentation of the limbs and lips. A low cortisol concentration, elevated ACTH level and normal electrolytes and aldosterone level all supported the diagnosis of primary glucocorticoid deficiency. Parents were counseled about the diagnosis, management and the lifelong requirement of steroids. FGD is an easily treatable disease when recognized but frequently missed due to a non-specific presentation. FGD is a treatable disease, delayed diagnosis and treatment can lead to significant morbidity.	0
Hepatic myelopathy or spastic paraparesis of liver disease is an insidious onset condition with pure motor spastic paraparesis without sensory, bladder or bowel involvement in patients with chronic liver disease, in which the neurological dysfunction cannot be explained by other causes. It is a rare, relentlessly progressive and mostly irreversible neurological complication resulting from portosystemic shunts occurring spontaneously, created surgically or due to 'functional shunting'. In some cases, no evidence of shunting is elicitable due to difficulty in locating the hidden collaterals. We report this rare case of a 33-year-old man with chronic liver disease presenting with spastic paraparesis after 11 months of resolution of an episode of hepatic encephalopathy.	0
Massive ovarian edema is a benign tumor like lesion of the ovary. The widely accepted mechanism is disruption of vascular drainage resulting in accumulation of fluid within the stroma and enlargement of the ovary. We report a case of massive ovarian edema in a teenage girl with hemoglobin SC disease. A 16-year-old female with hemoglobin SC disease was admitted with right lower quadrant pain. An ultrasound and CT scan showed a large, heterogeneous solid, and cystic pelvic mass. Due to the size and the possibility of malignancy, the patient underwent a salpingo-oophorectomy. The mass was an 8.3 cm hemorrhagic cyst with some solid areas. Histologic exam showed diffuse edema with scattered entrapped follicles and a narrow rim of normal appearing ovarian stroma. Dilated and occluded capillaries were seen along with hemorrhage and sickled red blood cells but no necrosis was identified. These histologic features were consistent with massive ovarian edema. Massive ovarian edema is thought to be caused by disturbance of the vascular outflow resulting in fluid buildup in the stroma. It is most often attributed to intermittent ovarian torsion that disrupts capillary and venous flow, but arterial flow is maintained. Rare cases of massive ovarian edema caused by tumor emboli or external compression by tumors have been reported, but this is the first case of a patient with hemoglobin SC disease developing vasoocclusions resulting in this lesion.	0
Differences in Sex Development (DSD) encompasses many diagnoses, where the development of chromosomal make-up, gonadal development or anatomical development is atypical. XY, DSD is a classification under the recent international consensus statement, and XY females commonly encapsulate disorders of androgen synthesis and androgen action. Complete Androgen Insensitivity Syndrome (CAIS) is the most common XY, DSD diagnosis, which results in an individual having XY chromosomes, but the person is phenotypically female. This article explores the care and management of children and young people with a DSD and focuses on the diagnosis of CAIS in adolescence. Medical and surgical management is discussed, alongside sexual function, gender identity and the psychological impact of the diagnosis. The involvement of the multidisciplinary team is stressed, together with an emphasis on the investment that is needed in psychological and nursing support for girls with CAIS, and their families.	0
Hand-Foot-Genital syndrome is a rare condition caused by mutations in the HOXA13 gene and characterized by limb malformations and urogenital defects. While the role of Hoxa13 in limb development has been extensively studied, its function during the development of the urogenital system remains elusive mostly due to the embryonic lethality of Hoxa13 homozygous mutant mice. Using a conditional inactivation strategy, we show that mouse fetuses lacking Hoxa13 function develop megaureters, hydronephrosis and malformations of the uterus, reminiscent of the defects characterizing patients with Hand-Foot-Genital syndrome. Our analysis reveals that Hoxa13 plays a critical role in Müllerian ducts fusion and in ureter remodeling by regulating the elimination of the caudal common nephric duct, eventually preventing the separation from the nephric duct. Our data also reveal a specific role for Hoxa13 in the urogenital sinus, which is in part mediated by Gata3, as well as Hoxa13 requirement for the proper organization of the ureter. Finally, we provide evidence that Hoxa13 provides positional and temporal cues during the development of the lower urogenital system, a sine qua non condition for the proper function of the urinary system.	0
Congenital disorders of glycosylation (CDG) are heterogeneous group of genetic protein and lipid glycosylation abnormalities. With some 33 reported patients, MAN1B1-CDG belongs to the more frequent causes of CDG-II. MAN1B1 encodes an α1,2-mannosidase that removes the terminal mannose residue from the middle branch. Several methods have been proposed to characterize the glycosylation changes. In MAN1B1-CDG, the abnormal accumulating N-glycan structures are mostly absent or found in trace amounts in total human serum. To overcome this issue, in this study, we present a straightforward procedure based on the use of Endo-β-N-acetylglucosaminidase H to easily diagnose MAN1B1-CDG patients and mannosidase defects.	0
Methylmalonic acidemia (MMA) is usually caused by a deficiency of the enzyme methylmalonyl-CoA mutase (MCM), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, cblC, cblF, cblD, and cblX), or deficiency of the enzyme methylmalonyl-CoA epimerase. A comprehensive diagnostic approach involves investigations of metabolites with tandem mass spectrometry, organic acid analysis with gas chromatography, enzymatic studies with fibroblast cell culture, and finally, mutation analysis. With biochemical techniques and enzymatic assay the reliable characterization of patients with isolated MMA for mutation analysis can be achieved. Reliable classification of these patients is essential for ongoing and prospective studies on treatments, outcomes, and prenatal diagnoses. This article reviews the diagnostic techniques used to characterize patients with MMA.	0
Mal de Meleda, also known as keratoderma palmoplantaris transgrediens, is a rare type of autosomal recessive palmoplantar keratoderma. A 19-year-old male presented with a congenital yellowish discoloration and thickening of both palms and soles of the feet. His family history revealed that there was no consanguinity between the mother and the father and that the patient had three healthy brothers. The second- and third-degree relatives, five females and one male, also exhibited similar skin findings. From the isolated DNA samples, the extrinsic regions of the SLURP1 gene were screened using the sequence analysis and the Sanger sequencing was performed with the 3130 Sequence Analyzer. Results of this analysis show that a p.Arg 96 Pro (R96P) (c.287 CGA>CCA) homozygous missense point mutation was detected on the SLURP 1 (a secreted toxin-like mammalian lymphocyte antigen 6/urokinase-type plasminogen activator receptor-related protein 1) gene of the patients, while heterozygous p.Arg 96 Pro (R96P) (c.287 CGA>CCA) mutation was detected in the mother, father, and brothers. Our search of the Human Genome Mutation Database and previous literature revealed no reports of this mutation in mal de Meleda. We report this case due to the identification of a novel gene mutation in a patient with mal de Meleda, a palmoplantar keratoderma.	0
Beyond its functions in locomotion, support and protection of vital organs, bone also interacts with other organs to adjust mineral balance in response to physiological requirements. Bone remodelling is a continuous process of bone resorption and formation for the purpose of maintaining healthy bone mass and growth. Any derangement in this process can cause bone disorders with important clinical consequences. The most prominent features of bone diseases in children include early bone fractures, deformities and pain, which can persist and worsen later in life if an accurate and timely diagnosis is not achieved. Biochemical and genetic testing usually help to discriminate the aetiology of the disease, which determines the subsequent management and follow-up. This review focuses on major genetic metabolic bone diseases in children, their pathophysiological mechanisms, the potential therapeutic interventions and the possible consequences in adulthood of the disease and its treatments.	0
Perlecan is a large heparan sulfate (HS) proteoglycan present in all basement membranes and in some other tissues such as cartilage, and is implicated in cell growth and differentiation. Mice lacking the perlecan gene (Hspg2) have a severe chondrodysplasia with dyssegmental ossification of the spine and show radiographic, clinical and chondro-osseous morphology similar to a lethal autosomal recessive disorder in humans termed dyssegmental dysplasia, Silverman-Handmaker type (DDSH; MIM 224410). Here we report a homozygous, 89-bp duplication in exon 34 of HSPG2 in a pair of siblings with DDSH born to consanguineous parents, and heterozygous point mutations in the 5' donor site of intron 52 and in the middle of exon 73 in a third, unrelated patient, causing skipping of the entire exons 52 and 73 of the HSPG2 transcript, respectively. These mutations are predicted to cause a frameshift, resulting in a truncated protein core. The cartilage matrix from these patients stained poorly with antibody specific for perlecan, but there was staining of intracellular inclusion bodies. Biochemically, truncated perlecan was not secreted by the patient fibroblasts, but was degraded to smaller fragments within the cells. Thus, DDSH is caused by a functional null mutation of HSPG2. Our findings demonstrate the critical role of perlecan in cartilage development.	0
OBJECTIVES: To investigate the prevalence at live birth of congenital heart disease (CHD) in Taiwan. STUDY DESIGN: Patients with CHD born from 2000 to 2006 were identified from National Health Insurance databases. RESULTS: CHD prevalence was 13.08 per 1000 live births: 12.05 (simple, 10.53; severe, 1.51) in male infants and 14.21 (simple, 12.90; severe, 1.32) in female infants. Ventricular septal defect (VSD; 4.0) was the most common defect, followed by secundum atrial septal defect (ASDII; 3.2), patent ductus arteriosus (PDA; 2.0), pulmonary stenosis (PS; 1.2), tetralogy of Fallot (TOF; 0.63), coarctation of aorta (CoA; 0.25), transposition of great arteries (TGA; 0.21), endocardial cushion defect (ECD; 0.20), double outlet of right ventricle (DORV; 0.15), total anomalous pulmonary venous return (TAPVR; 0.11), aortic stenosis (0.09), hypoplastic left heart syndrome (HLHS; 0.062), Ebstein anomaly (0.047), and tricuspid atresia (0.046). Female predominance was observed in VSD, ASDII, PDA, and ECD; and male predominance was observed in TGA and TOF. Ratios of western prevalence to our Asian prevalence were high for HLHS (3.68-4.5), CoA (1.13-1.96), TGA (1.09-1.83), and tricuspid atresia (1.09-2.57), but low for PS (0.15-0.99), TOF (0.41-0.92), and possibly ASDII. CONCLUSIONS: In this Asian population, the prevalence of CHD was at the high end of the reported range, with more PS and TOF, but fewer left-sided obstructions, TGA, and tricuspid atresia.	1
WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies and mental retardation) is an uncommon genetic disorder due to the deletion of the 11p13 region that contains the WT1 and PAX6 genes. It involves a distinctive combination of clinical conditions, with aniridia and Wilms tumor being the most notable. We present a 17-month-old infant with microcephaly, ocular alterations (buphthalmos, leukocoria, bilateral aniridia), scrotal hypoplasia, undescended testes and neurodevelopmental delay who underwent multiplex ligation-dependent probe amplification study for WT1, showing haploinsufficiency in the probes that hybridize to the 11p13 region, compatible with an heterozygous deletion of the gene. Wilms tumor was later diagnosed. WAGR syndrome is infrequent; its report in Latin America is low. It is important to disseminate its clinical characteristics, emphasizing an interdisciplinary management focused on the early identification of both the syndrome and its possible complications.	0
To determine occupational risk factors for coccidioidomycosis among adult Hispanic outdoor agricultural workers in California, USA, we conducted a case-control study of workers seen at the Kern County medical facility and referred to the public health laboratory for coccidioidomycosis serologic testing. Participants completed an interviewer-administered health and work questionnaire. Among 203 participants (110 case-patients with positive and 93 controls with negative serologic results), approximately half were women, and more than three quarters were born in Mexico. Associated with coccidioidomycosis were self-reported dust exposure and work with root and bulb vegetable crops. A protective factor was leaf removal, an activity associated with grape cultivation. We conclude that subjective dust exposure and work with root and bulb vegetable crops are associated with increased risk for coccidioidomycosis among Hispanic farm workers. The agricultural industry should evaluate and promote dust-reduction measures, including wetting soil and freshly harvested products.	0
Excessive fructose consumption is closely linked to the pathogenesis of metabolic disease. Carbohydrate response element-binding protein (ChREBP) is a transcription factor essential for fructose tolerance in mice. However, the functional significance of liver ChREBP in fructose metabolism remains unclear. Here, we show that liver ChREBP protects mice against fructose-induced hepatotoxicity by regulating liver glycogen metabolism and ATP homeostasis. Liver-specific ablation of ChREBP did not compromise fructose tolerance, but rather caused severe transaminitis and hepatomegaly with massive glycogen overload in mice fed a high-fructose diet, while no obvious inflammation, cell death, or fibrosis was detected in the liver. In addition, liver ATP contents were significantly decreased by ChREBP deficiency in the fed state, which was rendered more pronounced by fructose feeding. Mechanistically, liver contents of glucose-6-phosphate (G6P), an allosteric activator of glycogen synthase, were markedly increased in the absence of liver ChREBP, while fasting-induced glycogen breakdown was not compromised. Furthermore, hepatic overexpression of LPK, a ChREBP target gene in glycolysis, could effectively rescue glycogen overload and ATP reduction, as well as mitigate fructose-induced hepatotoxicity in ChREBP-deficient mice. Taken together, our findings establish a critical role of liver ChREBP in coping with hepatic fructose stress and protecting from hepatotoxicity by regulating LPK.	0
The TEMPI syndrome is a rare and acquired disorder characterized by 5 salient features, which compose its name: (1) telangiectasias; (2) elevated erythropoietin and erythrocytosis; (3) monoclonal gammopathy; (4) perinephric fluid collections; and (5) intrapulmonary shunting. Complete resolution of symptoms following treatment with plasma cell-directed therapy supports the hypothesis that the monoclonal antibody is causal and pathogenic. Understanding the basis of the TEMPI syndrome will depend on the identification of additional patients and a coordinated international effort.	0
The epidemiology of neuronal ceroid lipofuscinoses (NCL) in Scandinavia was studied. For juvenile NCL 40 Swedish living patients were identified. The corresponding number for Finland was 61, for Norway 28, for Denmark 16 and for Iceland three. The prevalence of juvenile NCL was thus 4.6, 12.2, 6.5, 3.1 and 11 per million inhabitants in Sweden, Finland, Norway, Denmark, and Iceland, respectively. For calculating incidence the years 1976-85 were used. The incidence was 2.2 per 100,000 live births in Sweden, 4.8 in Finland, 3.7 in Norway, 2.0 in Denmark, and 7.0 in Iceland. Late infantile NCL was found in five Swedish children, including one variant form, CLN5. This gives a prevalence of about 0.6 per million. In Finland 13 cases gave a prevalence of 2.6 per million with the variant form in 80% of cases. In Norway, three children corresponded to a prevalence of 0.7 per million and one case in Iceland to 3.8 per million. No Danish cases were reported. As for infantile NCL, sixteen Swedish cases have been diagnosed during the 27-year period 1968-95, six are presently alive. This gives an estimated prevalence of 0.7 per million and an incidence of 0.6 per 100,000. The prevalence and incidence of infantile NCL in Finland were 5.4 per million and 5 per 100,000, respectively. The prevalence in Norway was 0.2 per million inhabitants. The variability of onset, clinical course and symptoms in the Swedish cases of juvenile and infantile NCL were analysed.	1
Pulmonary arterial hypertension (PAH) is a rare disease caused by pulmonary vascular remodeling. Current vasodilator treatments have substantially improved patients' survival. This improved survival has led to the appearance of complications related to conditions previously underdiagnosed or even ignored, such as pulmonary artery aneurysm (PAA). The presence of a dilated pulmonary artery has been shown to be related to an increased risk of sudden cardiac death among PAH patients. This increased risk could be associated to the development of left main coronary artery compression or pulmonary artery dissection. Nevertheless, very little is currently known about the molecular mechanisms related to PAA. Thoracic aortic aneurysm (TAA) is a well-known condition with an increased risk of sudden death caused by acute aortic dissection. TAA may be secondary to chronic exposure to classic cardiovascular risk factors. In addition, a number of genetic variants have been shown to be related to a marked risk of TAA and dissection as part of multisystemic syndromes or isolated familial TAA. The molecular pathways implied in the development of TAA have been widely studied and described. Many of these molecular pathways are involved in the pathogenesis of PAH and could be involved in PAA. This review aims to describe all these common pathways to open new research lines that could help lead to a better understanding of the pathophysiology of PAH and PAA and their clinical implications.	0
We describe a 24-year-old man with a cystic hygroma of the left side of the lower neck that led to sudden death. Cystic hygroma (cystic lymphangioma) is a congenital malformation of the lymphatic system. The patient, who had a tracheostomy because of airway obstruction from the cystic hygroma, was found dead with his tracheostomy tube on the floor next to him. Complications of cystic hygroma include infiltration of the neck causing airway obstruction, dysphagia, pain, and obstructive sleep apnea.	0
BACKGROUND This study used network pharmacology method and cell model to assess the effects of Radix Astragali (RA) on cholangiocarcinoma (CCA) and to predict core targets and molecular mechanisms. MATERIAL AND METHODS We performed an in vitro study to assess the effect of RA on CCA using CCK8 assay, the Live-Cell Analysis System, and trypan blue staining. The components and targets of RA were analyzed using the Traditional Chinese Medicine Systems Pharmacology database, and genes associated with CCA were retrieved from the GeneCards and OMIM platforms. Protein-protein interactions were analyzed with the STRING platform. The components-targets-disease network was built by Cytoscape. The TIMER database revealed the expression of core targets with diverse immune infiltration levels. GO and KEGG analyses were performed to identify molecular-biology processes and signaling pathways. The predictions were verified by Western blotting. RESULTS Concentration-dependent antitumor activity was confirmed in the cholangiocarcinoma QBC939 cell line treated with RA. RA contained 16 active compounds, with quercetin and kaempferol as the core compounds. The most important biotargets for RA in CCA were caspase 3, MAPK8, MYC, EGFR, and PARP. The TIMER database revealed that the expression of caspase3 and MYC was related with diverse immune infiltration levels of CCA. The results of Western blotting showed RA significantly influenced the expression of the 5 targets that network pharmacology predicted. CONCLUSIONS RA is an active medicinal material that can be developed into a safe and effective multi-targeted anticancer treatment for CCA.	0
Stimulating bone formation is an important challenge for bone anabolism in osteoporotic patients or to repair bone defects. The osteogenic properties of matrix glycosaminoglycans (GAGs) have been explored; however, the functions of GAGs at the surface of bone-forming cells are less documented. Syndecan-2 is a membrane heparan sulfate proteoglycan that is associated with osteoblastic differentiation. We used a transgenic mouse model with high syndecan-2 expression in osteoblasts to enrich the bone surface with cellular GAGs. Bone mass was increased in these transgenic mice. Syndecan-2 overexpression reduced the expression of receptor activator of NF-kB ligand (RANKL) in bone marrow cells and strongly inhibited bone resorption. Osteoblast activity was not modified in the transgenic mice, but bone formation was decreased in 4-month-old transgenic mice because of reduced osteoblast number. Increased proteoglycan expression at the bone surface resulted in decreased osteoblastic and osteoclastic precursors in bone marrow. Indeed, syndecan-2 overexpression increased apoptosis of mesenchymal precursors within the bone marrow. However, syndecan-2 specifically promoted the vasculature characterized by high expression of CD31 and Endomucin in 6-week-old transgenic mice, but this was reduced in 12-week-old transgenic mice. Finally, syndecan-2 functions as an inhibitor of Wnt-β-catenin-T-cell factor signaling pathway, activating glycogen synthase kinase 3 and then decreasing the Wnt-dependent production of Wnt ligands and R-spondin. In conclusion, our results show that GAG supply may improve osteogenesis, but also interfere with the crosstalk between the bone surface and marrow cells, altering the supporting function of osteoblasts.	0
Fraser syndrome (cryptophthalmos-syndactyly syndrome) is a rare autosomal recessive malformation disorder. The first description of the syndrome was reported by George Fraser in 1962. Diagnosis is based on the major and minor criteria established by van Haelst et al. in 2007. Unilateral or bilateral cryptophthalmos, syndactyly, unilateral renal agenesis, and genital anomalies are the most frequent anomalies. Several maxillofacial, oro-dental, ear-nose-throat, hormonal, and anorectal disorders are reported. Cardiac malformations and musculoskeletal anomalies are uncommon. The syndrome is related to mutations in three different genes (FRAS1, FREM2, and GRIP1) resulting in failure of the apoptosis program and disruption of the epithelial-mesenchymal interactions during embryonic development. Prenatal diagnosis is based on the detection of renal agenesis and laryngeal atresia, together with a family history. Most foetuses with severe anomalies are terminated or are stillborn. All patients or pregnancies with a diagnosis of Fraser syndrome should be referred to expert centres. A collaborative approach including anaesthetists, ENT specialists, maxillofacial surgeons, and geneticists is necessary for the management of this syndrome. In vivo and in vitro research models are available to better understand the underlying aetiology.	0
Chromosomal abnormalities are responsible for several congenital malformations in the world, some of these are associated to telomeric/subtelomeric deletions. The abnormalities involving the telomere of chromosome 12 are rare, with few reports of deletions involving 12q24.31 region in the literature, and, to our knowledge, only four of them in the 12q24.31-q24.33 region. We report a further case of interstitial deletion of bands 12q24.31-q24.33 associated with autism spectrum disorder. A 2-year-old boy with global developmental delay associated with multiple congenital anomalies. The Human Genome CGH Microarray 60K confirmed the diagnosis of 12q deletion syndrome. This study made a review of the current literature comparing our patient with previously reported cases. These detailed analyses contribute to the development of genotype/phenotype correlations for 12q deletions that will aid in better diagnosis and prognosis of this deletion.	0
Wiedemann-Steiner syndrome is a genetic condition associated with dysmorphic facies, hypertrichosis, short stature, developmental delay, and intellectual disability. Congenital malformations of the cerebral, cardiac, renal, and optic structures have also been reported. Because the majority of reported individuals with this condition have been under age 20, the long-term prognosis is not well defined. Here we report on two further unrelated individuals diagnosed with Wiedemann-Steiner syndrome, one of whom is in her third decade of life. In addition, both individuals have novel KMT2A mutations. The information provided below about the outcome in Wiedemann-Steiner syndrome is important for families of affected individuals.	0
Study Design:Systematic review (Level 4). Objective:To summarize the demographics, clinical presentations, and conditions associated with butterfly vertebrae. Methods:A systematic search was performed of multiple databases. A total of 279 articles were identified for screening. Case series or case reports of butterfly vertebrae with adequate clinical detail were complied. Results:Eighty-two total articles (109 patients) were selected for final inclusion. Sixty-one percent of patients presented with a single butterfly vertebra, while 39% were multiple. The most common location for butterfly vertebrae was T1. Fifty-six percent of cases were associated with a syndrome, the most common being spondylocostal dysostosis. The presence of multiple butterfly vertebra was strongly associated with a syndrome or additional anomalies (P < .001). Overall, the most common presenting complaint was low back pain. Seventy percent of patients had associated spinal disease. Other organ systems affected included musculoskeletal (43%), craniofacial (30%), neurologic (27%), cardiovascular (24%), genitourinary (23%), gastrointestinal (22%), laboratory abnormality (16%), and endocrine (9%). Conclusions:This study is the largest collection of butterfly vertebrae cases to date. Butterfly vertebrae are associated with spinal deformity and multiple butterfly vertebrae may indicate a syndromic illness. Low back pain or disc herniation may occur with lumbar butterfly vertebrae however the etiology of this phenomena has not been rigorously explained. Many diseases and syndromes are associated with butterfly vertebrae.	0
The effects of long-term use of opioid analgesics on the hypothalamic-pituitary-adrenal axis are not well recognized. We report a 41-year-old woman on chronic opioid therapy hospitalized for cardiovascular collapse following a right stellate ganglion nerve block. She developed severe hypotension after the procedure. Morning cortisol was low. The results from the cosyntropin test were consistent with secondary adrenal insufficiency. Her secondary adrenal insufficiency was likely due to long-term use of opioid analgesics for pain in the absence of other etiologies.	0
BACKGROUND:Choroideremia is an X-linked retinal disease characterized by progressive atrophy of the choroid and retinal pigment epithelium caused by mutations in the CHM gene. SVA (SINE-R/VNTR/Alu) elements are a type of non-autonomous retrotransposon that occasionally self-replicate, reinsert randomly into a gene, and cause disease. Intragenic SVA insertions have been reported as the mechanism underlying a number of diseases including a syndromic form of retinal dystrophy, but have never been found in CHM. MATERIALS AND METHODS:Here we identified and characterized a novel hemizygous SVA insertion, c.97_98inSVA (p.Arg33insSVA), in exon 2 of CHM in a male choroideremia patient. The SVA insertion's impact was evaluated by establishing a patient-derived lymphoblastoid cell line as a source of RNA for mRNA analysis of the CHM transcript, and protein for immunoblot analysis of Rab Escort Protein 1 (REP-1). RESULTS:Immunoblot analysis revealed the absence of REP-1 protein, while a smaller than expected PCR product was amplified from cDNA. Sequencing of this PCR product showed skipping of exon 2, denoted r.50_116del. Ophthalmic examination including psychophysical tests, visual electrophysiology, and fundus imaging showed the patient's phenotype was consistent with severe early manifestations of choroideremia. CONCLUSIONS:This case is the first report of a SVA insertion in the CHM gene causing choroideremia.	0
We describe a family severely affected by colorectal cancer (CRC) where whole-exome sequencing identified the coinheritance of the germline variants encoding MSH6 p.Thr1100Met and MUTYH p.Tyr179Cys in, at least, three CRC patients diagnosed before 60 years of age. Digenic inheritance of monoallelic MSH6 variants of uncertain significance and MUTYH variants has been suggested to predispose to Lynch syndrome-associated cancers, however cosegregation with disease in the familial setting has not yet been established. The identification of individuals carrying multiple potential cancer risk variants is expected to rise with the increased application of whole-genome sequencing and large multigene panel testing in clinical genetic counseling of familial cancer patients. Here we demonstrate the coinheritance of monoallelic variants in MSH6 and MUTYH consistent with cosegregation with CRC, further supporting a role for digenic inheritance in cancer predisposition. This article is protected by copyright. All rights reserved.	0
BACKGROUND:Neuroblastoma (NB) is a heterogeneous disease with respect to genomic abnormalities and clinical behaviors. Despite recent advances in our understanding of the association between the genetic aberrations and clinical features, it remains one of the major challenges to predict prognosis and stratify patients for determining personalized therapy in this disease. The aim of this study was to develop an effective prognosis prediction model for NB patients. METHODS:We integrated diverse computational analyses to define gene signatures that reflect MYCN activity and chromosomal aberrations including deletion of chromosome 1p (Chr1p_del) and chromosome 11q (Chr11q_del) as well as chromosome 11q whole loss (Chr11q_wls). We evaluated the prognostic and predictive values of these signatures in seven NB gene expression datasets (the number of samples ranges from 94 to 498, with a total of 2120) generated from both RNA sequencing and microarray platforms. RESULTS:MYCN signature was a more effective prognostic marker than MYCN amplification status and MYCN expression. Similarly, the Chr1p_del score was more prognostic than Chr1p status. The activity scores of MYCN, Chr1p_del and Chr11q_del were associated with poor prognosis, while the Chr11q_wls score was linked to good outcome. We integrated the activity scores of MYCN, Chr1p_del, Chr11q_del, and Chr11q_wls and clinical variables into an integrative prognostic model, which displayed significant performance over the clinical variables or each genomic aberration alone. CONCLUSIONS:Our integrative gene signature model shows a significantly improved forecast performance with prognostic and predictive information, and thereby can be served as a biomarker to stratify NB patients for prognosis evaluation and surveillance programs.	0
PURPOSE:There are controversial debates if patients with Hürthle cell carcinoma, also known as oxyphilic or oncocytic cell follicular thyroid carcinoma, have a poorer outcome. In this study, we systematically evaluated the clinical outcome in a large patient cohort following thyroidectomy and initial I-131 radioactive iodine therapy (RIT). METHODS:We retrospectively evaluated a total of 378 patients with diagnosed oncocytic follicular Hürthle cell carcinoma (OFTC) (N = 126) or with classical follicular thyroid carcinoma (FTC) (N = 252). Patients received thyroidectomy and complementary I-131 RIT. Clinical data regarding basic demographic characteristics, tumor grade, persistent disease and recurrence during follow-up, and disease-free, disease-specific, and overall survival were collected during follow-up of 6.9 years (interquartile range 3.7; 11.7 years). Univariate and multivariate analyses were used to identify factors associated with disease-related and overall survival. RESULTS:Before and after matching for risk factors, recurrence was significantly more frequently diagnosed in OFTC patients during follow-up (17% vs. 8%; p value 0.037). Likewise, OFTC patients presented with a reduced mean disease-free survival of 17.9 years (95% CI 16.0-19.8) vs. 20.1 years (95% CI 19.0-21.1) in FTC patients (p value 0.027). Multivariate analysis revealed OFTC (HR 0.502; 95% CI 0.309-0.816) as the only independent prognostic factor for disease-free survival. Distant metastases of OFTC patients were significantly less iodine-avid (p value 0.014). Mean disease-specific and overall survival did not differ significantly (p value 0.671 and 0.687) during follow-up of median 6.9 years (3.7; 11.7 years). CONCLUSIONS:Our study suggests that recurrence is more often seen in OFTC patients. OFTC patients have a poorer prognosis for disease-free survival. Thus, OFTC and FTC behave differently and should be categorized separately. However, patients suffering from OFTC present with the same overall and disease-specific survival at the end of follow-up indifferent to FTC patients after initial RIT.	0
An 82-year-old woman presented with persistent left leg swelling despite 3 months anticoagulation for deep vein thrombosis. Ultrasound showed venous blood flowing back into the toe. Enhanced computed tomography scans and angiography showed occlusion of the left common iliac vein and a large number of arteriovenous fistulas. We made a diagnosis of May-Thurner syndrome coexisting with arteriovenous fistulas and we performed endovascular therapy only for the common iliac vein. We considered embolization for arteriovenous fistulas, but it seemed to be difficult to perform because of the possibility of development of collateral circulation and a large number of arteriovenous fistulas. After percutaneous balloon angioplasty, antegrade venous blood flow was restored, and stent implantation was not performed. After the procedure, swelling of the leg gradually reduced. She had no symptoms for the following 1 year.	0
Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1-/- mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele.	0
Pathogenic mutations in DPAGT1 cause a rare type of a congenital disorder of glycosylation termed DPAGT1-CDG or, alternatively, a milder version with only myasthenia known as DPAGT1-CMS. Fourteen disease-causing mutations in 28 patients from 10 families have previously been reported to cause the systemic form, DPAGT1-CDG. We here report on another 11 patients from 8 families and add 10 new mutations. Most patients have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. We also present data on three affected females that are young adults and have a somewhat milder, stable disease. Our findings expand both the molecular and clinical knowledge of previously published data but also widen the phenotypic spectrum of DPAGT1-CDG.	0
Wilms tumor is the most frequently occurring pediatric renal malignancy. Wilms tumor suppressor-1-associated protein (WTAP) is a vital component of N6-methyltransferase complex involved in tumorigenesis. However, the roles of WTAP gene single nucleotide polymorphisms (SNPs) in Wilms tumor risk have not been clarified to date. We successfully genotyped three WTAP gene SNPs using TaqMan assay in 405 Wilms tumor patients and 1197 cancer-free controls of Chinese children. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to determine the effects of WTAP gene SNPs on Wilms tumor risk. Carriers of the rs1853259 G variant are less susceptible to developing Wilms tumor, with an adjusted OR of 0.78 (AG vs. AA: 95% CI = 0.61-0.995, P = 0.046). Single locus analysis of rs9457712 G > A and rs7766006 G > T, as well as the combined analysis of risk genotypes, failed to unveil an association with Wilms tumor risk, respectively. Stratified analysis of the three SNPs and their combined risk effects showed more significant relationships with Wilms tumor risk under certain subgroups. In all, we found weak evidence of the association between WTAP gene SNPs and the risk of Wilms tumor. Further replication studies with greater sample size and different ethnicities are necessary to verify our findings.	0
Variants in interphotoreceptor matrix proteoglycans (IMPG2) have been reported in retinitis pigmentosa (RP) and vitelliform macular dystrophy (VMD) patients. However, the underlying molecular mechanisms remain elusive due to a lack of suitable disease models. We developed two independent Impg2 knockout (KO) mouse models using the CRISPR/Cas9 technique to assess the in vivo functions of Impg2 in the retina. Impg2 ablation in mice recapitulated the RP phenotypes of patients, including an attenuated electroretinogram (ERG) response and the progressive degeneration of photoreceptors. The histopathological examination of Impg2-KO mice revealed irregularly arranged rod cells and mislocalized rhodopsin protein in the inner segment at 6 months of age. In addition to the pathological changes in rod cells, cone cells were also affected in KO retinas. KO retinas exhibited progressive cone cell death and impaired cone cell elongation. Further immunoblotting analysis revealed increased levels of endoplasmic reticulum (ER) stress-related proteins, including C/EBP homologous protein (CHOP), immunoglobulin heavy-chain-binding protein (BIP) and protein disulfide isomerase (PDI), in Impg2-KO mouse retinas. Increased gliosis and apoptotic cell death were also observed in the KO retinas. As autophagy is closely associated with ER stress, we then checked whether autophagy was disturbed in Impg2-KO mouse retinas. The results showed that autophagy was impaired in KO retinas, as revealed by the increased accumulation of SQSTM1 and other proteins involved in autophagy. Our results demonstrate the essential roles of Impg2 in the retina, and this study provides novel models for mechanistic investigations and development of therapies for RP caused by IMPG2 mutations.	0
Individuals with fragile X mental retardation 1 (FMR1) premutation (55 to 200 CGG repeats) are typically unaffected by fragile X syndrome. However, a subgroup of older males with the premutation have developed a neurological syndrome, which usually begins between 50 and 70 years and is associated with a progressive intention tremor and/or ataxia manifested by balance problems, frequent falling, and Parkinsonian symptoms, such as masked facies, intermittent resting tremor, and mild rigidity. This finding has been termed the fragile X-associated tremor/ataxia syndrome (FXTAS) and has brought focus to the aging process in individuals with the FMR1 mutation. The premutation is associated with elevated messenger RNA levels leading to the formation of intranuclear inclusions in neurons and astrocytes associated with FXTAS. This review is a summary of our experience with FXTAS in male carriers of the premutation.	1
The detoxification of ammonia to urea requires a functional hepatic urea cycle, which consists of six enzymes and two mitochondrial membrane transporters. The initial step of the urea cycle is catalyzed by carbamyl phosphate synthetase 1 (CPS1). CPS1 deficiency (CPS1D) is a rare autosomal recessive disorder. N-Carbamylglutamate (NCG), a deacylase-resistant analogue of N-acetylglutamate, can activate CPS1. We describe the therapeutic course of a patient suffering from neonatal onset CPS1D with compound heterozygosity for the c.2359C > T (p.Arg787*) and c.3559G > T (p.Val1187Phe) variants in CPS1, treated with NCG. She presented with hyperammonemia, which reached 944 μmol/L at the age of 2 days. The ammonia concentration decreased after treatment with continuous hemodiafiltration, NCG, sodium benzoate, sodium phenylbutyrate, L-arginine, vitamin cocktail (vitamin B1, vitamin B12, vitamin C, vitamin E, biotin), l-carnitine, coenzyme Q10, and parenteral nutrition. Her ammonia and glutamine levels remained low; thus, protein intake was increased to 1.2 g/kg/day. Furthermore, the amount of sodium benzoate and sodium phenylbutyrate were reduced. She remained metabolically stable and experienced no metabolic crisis following treatment with oral NCG, sodium benzoate, sodium phenylbutyrate, citrulline, vitamin cocktail, l-carnitine, and coenzyme Q10 until she underwent liver transplantation at 207 days of age. She had no neurological complications at the age of 15 months. Ammonia and glutamine levels of the patient were successfully maintained at a low level via NCG treatment with increased protein intake, which led to normal neurological development. Thus, undiagnosed urea cycle disorders should be treated rapidly with acute therapy including NCG, which should be maintained until a genetic diagnosis is reached. It is essential to prevent metabolic crises in patients with CPS1D until liver transplantation to improve their prognoses.	0
BACKGROUND:Trichothiodystrophy (TTD) describes a group of rare genetic disorders of DNA repair, characterized by sulphur-deficient hair, skin anomalies and systemic complications like preterm delivery, neurological impairment, haematological and ophthalmological abnormalities and life-threatening infections. OBJECTIVES:The aim of this case report was to investigate the contribution of the gene mutation to the phenotype. METHODS:We describe the clinical and molecular characteristics of a family with two TTD-affected siblings who died before the age of 2 years. RESULTS:The causal mutated gene is the ERCC2 gene, and one of the identified mutations is the c.2164C>T (p.Arg722Trp) variant. The association of this mutation with a severe TTD phenotype was suggested earlier in literature, and the present family adds further evidence to this hypothesis. CONCLUSION:Accurate identification of the underlying genetic defect can guide the clinical follow-up and counselling of patients and their families.	0
Cerebro-facio-thoracic dysplasia (CFTD) is a rare, autosomal recessive disorder characterized by facial dysmorphism, cognitive impairment and distinct skeletal anomalies and has been linked to the TMCO1 defect syndrome.To describe two siblings with features consistent with CFTD with a novel homozygous p.Arg114* pathogenic variant in the TMCO1 gene.We conducted a literature review and summarized the clinical features and laboratory results of two siblings with a novel pathogenic variant in the TMCO1 gene. Facial recognition analysis was utilized to assess the specificity of facial traits.The novel homozygous p.Arg114* pathogenic variant in the TMCO1 gene is responsible for the clinical features of CFTD in two siblings. Facial recognition analysis allows unambiguous distinction of this syndrome against controls.	0
Neurophysiological and radiological studies provide accumulating evidence for the involvement of the brainstem in the pathogenesis of restless legs syndrome (RLS). The analysis of the various subregions of the brainstem may help us better understand the pathophysiological mechanisms underlying the disorder. In this study, we investigated the structural and functional changes in the various subregions of the brainstem in RLS patients. The subregional changes in gray matter density and functional connectivity in the brainstem were analyzed in 20 drug-naive idiopathic RLS patients, as well as 18 normal control (NC) subjects for comparison. Correlation analyses and multivariate pattern analyses using linear support vector machine (SVM) were conducted. We found significantly increased gray matter density in two clusters in the pons (designated pons_1 and pons_2) and in one cluster in the midbrain in RLS patients compared with NC subjects. Further functional connectivity analyses revealed significantly decreased functional connectivity between the midbrain and the right middle occipital gyrus, between pons_1 and the right orbital part of the superior frontal gyrus, and between pons_2 and the right parahippocampus in RLS compared with NC. Moreover, the functional connectivity between pons_2 and the right supplementary motor area (SMA) was significantly increased in RLS compared with NC. This change in RLS was marginally correlated with RS_RLS scores in the RLS patients. SVM-based classification showed an AUC of 0.955 using gray matter density of pons_2, and functional connectivity between pons_2 and SMA as features. Collectively, our findings suggest that changes in gray matter density and functional connectivity in the pons may play a pathologic role in RLS. Furthermore, these abnormal changes in the pons might help to discriminate RLS from healthy subjects.	0
Genetic conditions affecting the skin and kidney are clinically and genetically heterogeneous, and target molecular components present in both organs. The molecular pathology involves defects of cell-matrix adhesion, metabolic or signaling pathways, as well as tumor suppressor genes. This article gives a clinically oriented overview of this group of disorders, highlighting entities which have been recently described, as well as the progress made in understanding well-known entities. The genetic bases as well as molecular cell biological mechanisms are described, with therapeutic applications.	0
Hyperostosis frontalis interna is a common phenomenon, which may have been overrated in its significance in the past, and may, currently be underrated in its significance. We present three cases of hyperostosis frontalis interna found during medicolegal autopsies and discuss their forensic considerations. The patients were all middle-aged women with metabolic and endocrine manifestations and psychiatric ailments; thickening of the inner table of the frontal bone of the skull was found during each autopsy. We describe the relationship between hyperostosis frontalis interna, metabolic manifestations, and neuropsychiatric symptoms as part of Morgagni-Stewart-Morel syndrome. There is still considerable disagreement in the scientific community as to whether this syndrome is a clinical entity. Nonetheless, awareness of Morgagni-Stewart-Morel syndrome can be of help in understanding the circumstances surrounding death. In some other cases, hyperostosis frontalis interna could be used by forensic pathologists as criteria for sexing and aging a skeleton.	0
Sex differences in the manifestations of Alzheimer's disease are under intense investigation. Despite the emerging importance of polygenic predictions for Alzheimer's disease, sex-dependent polygenic effects have not been demonstrated. Here, using a sex crossover analysis, we show that sex-dependent autosomal genetic effects on Alzheimer's disease can be revealed by characterizing disease progress via the hazard function. We first performed sex-stratified genome-wide associations, and then applied derived sex-dependent weights to two independent cohorts. Relative to sex-mismatched scores, sex-matched polygenic hazard scores showed significantly stronger associations with age-at-disease-onset, clinical progression, amyloid deposition, neurofibrillary tangles, and composite neuropathological scores, independent of apolipoprotein E. Models without using hazard weights, i.e. polygenic risk scores, showed lower predictive power than polygenic hazard scores with no evidence for sex differences. Our results indicate that revealing sex-dependent genetic architecture requires the consideration of temporal processes of Alzheimer's disease. This has strong implications not only for the genetic underpinning of Alzheimer's disease but also for how we estimate sex-dependent polygenic effects for clinical use.	0
Primary peritoneal tumors are rarely encountered and their management is usually challenging for the clinicians. Especially when the patients with advanced peritoneal malignancy present as surgical emergencies, usually with symptoms of obstruction, perforation or gross space-occupying lesions, the on-call surgical team has to weigh the pros and cons of urgent versus delayed treatment and plans a safe and simultaneously oncologically beneficial therapeutic approach. Herein, we present a case of a Caucasian man who was referred as suspected complicated appendicitis by his primary care physician, with the final diagnosis being benign multicystic mesothelioma. We describe the challenges of the clinical decision making for the emergency general surgeon and relevant diagnostic and therapeutic pitfalls, which can be potentially minimized by early liaison with tertiary units specializing in the treatment of disseminated peritoneal malignancy.	0
BACKGROUND:Primary microcephaly is defined as reduced occipital-frontal circumference noticeable before 36 weeks of gestation. Large amount of insults might lead to microcephaly including infections, hypoxia and genetic mutations. More than 16 genes are described in autosomal recessive primary microcephaly. However, the cause of microcephaly remains unclear in many cases after extensive investigations and genetic screening. CASE PRESENTATION:Here, we described the case of a boy with primary microcephaly who presented to a neurology clinic with short stature, global development delay, dyskinetic movement, strabismus and dysmorphic features. We performed microcephaly investigations and genetic panels. Then, we performed whole-exome sequencing to identify any genetic cause. Microcephaly investigations and genetic panels were negative, but we found a new D317V homozygous mutation in TELOE-2 interacting protein 2 (TTI2) gene by whole-exome sequencing. TTI2 is implicated in DNA damage response and mutation in that gene was previously described in mental retardation, autosomal recessive 39. CONCLUSIONS:We described the first French Canadian case with primary microcephaly and global developmental delay secondary to a new D317V homozygous mutation in TTI2 gene. Our report also highlights the importance of TTI2 protein in brain development.	0
Childhood-onset systemic lupus erythematosus (cSLE) is a chronic inflammatory multisystem autoimmune disease that requires multiple differential diagnoses. Munchausen by proxy syndrome (MBPS) is a form of child abuse, where a caregiver intentionally creates a medical history and induces or fabricates signs or disease in a patient. To our knowledge, there is no case report of MBPS mimicking cSLE diagnosis. We reported herein a 9-year-old male patient, with a history of multiple hospitalizations due to seizures with altered levels of consciousness. The mother reported malar rash, photosensitivity, alopecia, arthralgia, arterial hypertension, macroscopic hematuria, seizure and positive antinuclear antibodies. In the other service, he was treated with intravenous methylprednisolone, prednisone and mycophenolate mofetil. At 8 years and 8 months, he was admitted to our tertiary center with history of fever and macroscopic hematuria. Laboratory examinations were normal, including negative for antinuclear antibodies, anti-double stranded DNA, anticardiolipin, anti-Ro/SSA, anti-La/SSB, anti-RNP and anti-Sm antibodies. Multiple urine cultures revealed the presence of Enterococcus faecium, Acinetobacter sp., Stenotrophomonas maltophilia and Serratia marcescens, without any association with pyuria. At 8 years and 9 months, he was readmitted at emergency room with history of severe fever, headache, vomiting, photophobia, phonophobia and dizziness. The physical examination showed agitation, confusion, ataxic gait, slurred speech, horizontal nystagmus, painful facial expressions, tachycardia and weight loss. Brain magnetic resonance angiography and cerebrospinal fluid analysis were normal. During hospitalization, he had an acute episode of epistaxis and otalgia with excoriation in the auditory canal. At that moment, the suspicion of MBPS mimicking cSLE was raised and phenytoin intoxication was confirmed (peak phenytoin concentration was 45.4 mcg/mL, therapeutic range 10-20 mcg/mL). The mother and the patient were immediately separated, and she was replaced by another legal guardian. One week later, the neurological and other signs and symptoms were completely resolved. The child was placed under paternal custody with a court order and moved to another state. After that, the mother reported phenytoin use for her child and was referred to psychiatric follow-up. In conclusion, the first case of MBPS mimicking cSLE, resulting in multiple unnecessary examinations and treatments with delayed diagnosis was reported.	0
Background:Glycogen storage disease type IV (GSD IV; Andersen's disease) is a rare autosomal recessive disease caused by mutation in the GBE1 gene. Presentation of GSD IV varies on a continuum of severity and symptomatology ranging from neonatal death to mild adult-onset disease with variable involvement of hepatic, muscular, neurologic, dermatologic, and cardiac systems. Cardiomyopathy seen in GSD IV is also heterogeneous and its appearance on cardiac magnetic resonance imaging (CMR) is rarely described. Case summary:A 29-year-old man without previous medical history was admitted to our facility multiple times over 2 years for focal sensorimotor deficits, gout arthropathy, chronic hyperlactataemia and hyperuricaemia, and severe decompensated non-ischaemic cardiomyopathy complicated by episodes of thromboembolic organ infarction. Echocardiography and CMR showed severe biventricular failure with the presence of intraventricular thrombi with increased right ventricular trabeculation and absent late gadolinium enhancement. He underwent muscle biopsy which showed prominent glycogen in skeletal muscle followed by genetic testing showing a single heterozygous splicing mutation c.993-1G>T found at the junction of intron 7 and exon 8 of the GBE1 gene which had not previously been reported and was predicted to be pathologic. He was referred to a tertiary care centre with glycogen storage disease specialists but expired prior to establishing care at that facility. Discussion:Discovery of GSD IV in our patient was unexpected due to a highly variant clinical presentation. Our case stresses the clinical heterogeneity of GSD IV and the importance of genetic sequencing studies in the evaluation of potential glycogen storage disease.	0
Objectives: Pediatric acute-onset neuropsychiatric syndrome (PANS) is a descriptive clinical entity defined by the abrupt onset of psychiatric and somatic symptoms leading to significant loss of function. Data on well-characterized PANS patients are limited, biomarkers have yet to be identified, and a solid evidence base to guide treatment is lacking. In this study, we present our experience of a systematic evaluation of the first 45 patients included in a Swedish cohort. Methods: During the period 2014-2018, our clinic received 100 referrals regarding suspected PANS. All patients underwent a standardized psychiatric/medical evaluation by a child/adolescent psychiatrist and a clinical psychologist or a nurse. Those with severe symptoms were also assessed by a pediatric neurologist and a pediatric rheumatologist. Laboratory tests were obtained at different time points in an attempt to capture an active disease state. Results: Of the 100 referrals, 45 met strict PANS criteria and consented to participate in a long-term follow-up study. The median age at intake was 7.2 years (range 3.0-13.1) and 56% were male. Ninety-three percent fulfilled both criteria for acute/atypical onset of PANS symptoms and having had an infection in relation to onset. Sixteen percent had an onset of an autoimmune or inflammatory disorder in temporal relation to the onset of PANS-related symptoms. The most common onset symptoms were obsessive-compulsive disorder (89%), anxiety (78%), and emotional lability (71%). Twenty-four percent had a preexisting autoimmune disease (AD) and 18% a preexisting psychiatric/neuropsychiatric diagnosis. Sixty-four percent of biological relatives had at least one psychiatric disorder and 76% at least one AD or inflammatory disorder. Complement activation (37%), leukopenia (20%), positive antinuclear antibodies (17%), and elevated thyroid antibodies (11%) were the most common laboratory findings. Conclusions: In our PANS cohort, there was a strong indication of an association with AD. Further work is needed to establish whether any of the potential biomarkers identified will be clinically useful. Long-term follow-up of these patients using the Swedish national registers will enable a deeper understanding of the course of this patient group.	0
Uniform conduction slowing has been considered a characteristic of inherited demyelinating neuropathies. We present an 18-year-old girl, born from first cousins, that presented a late motor and psychological development, cerebellar ataxia, facial diplegia, abnormal eye movement, scoliosis, and corpus callosum agenesis, whose compound muscle action potentials were slowed and dispersed. A mutation was found on KCC3 gene, confirming Andermann syndrome, a disease that must be included in the differential diagnosis of inherited neuropathies with non-uniform conduction slowing.	0
Diabetes risk increases significantly with age and correlates with lower oxidative capacity in muscle. Decreased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc-1α) and target gene pathways involved in mitochondrial oxidative phosphorylation are associated with muscle insulin resistance, but a causative role has not been established. We sought to determine whether a decline in Pgc-1α and oxidative gene expression occurs during aging and potentiates the development of age-associated insulin resistance. Muscle-specific Pgc-1α knockout (MKO) mice and wild-type littermate controls were aged for 2 yr. Genetic signatures of skeletal muscle (microarray and mRNA expression) and metabolic profiles (glucose homeostasis, mitochondrial metabolism, body composition, lipids, and indirect calorimetry) of mice were compared at 3, 12, and 24 mo of age. Microarray and gene set enrichment analysis highlighted decreased function of the electron transport chain as characteristic of both aging muscle and loss of Pgc-1α expression. Despite significant reductions in oxidative gene expression and succinate dehydrogenase activity, young mice lacking Pgc-1α in muscle had lower fasting glucose and insulin. Consistent with loss of oxidative capacity during aging, Pgc-1α and Pgc-1β expression were reduced in aged wild-type mouse muscle. Interestingly, the combination of age and loss of muscle Pgc-1α expression impaired glucose tolerance and led to increased fat mass, insulin resistance, and inflammatory markers in white adipose and liver tissues. Therefore, loss of Pgc-1α expression and decreased mitochondrial oxidative capacity contribute to worsening glucose tolerance and chronic systemic inflammation associated with aging.	0
Alagille syndrome (ALGS), also known as arteriohepatic dysplasia, is a multisystem disorder due to defects in components of the Notch signalling pathway, most commonly due to mutation in JAG1 (ALGS type 1), but in a small proportion of cases mutation in NOTCH2 (ALGS type 2). The main clinical and pathological features are chronic cholestasis due to paucity of intrahepatic bile ducts, peripheral pulmonary artery stenosis, minor vertebral segmentation anomalies, characteristic facies, posterior embryotoxon/anterior segment abnormalities, pigmentary retinopathy, and dysplastic kidneys. It follows autosomal dominant inheritance, but reduced penetrance and variable expression are common in this disorder, and somatic/germline mosaicism may also be relatively frequent. This review discusses the clinical features of ALGS, including long-term complications, the clinical and molecular diagnosis, and management.	0
Three overlapping conditions, namely Rothmund-Thomson (RTS), Baller-Gerold (BGS) and RAPADILINO syndromes, have been attributed to RECQL4 mutations. Differential diagnoses depend on the clinical presentation, but the numbers of known genes remain low, leading to the widespread prescription of RECQL4 sequencing. The aim of our study was therefore to determine the best clinical indicators for the presence of RECQL4 mutations in a series of 39 patients referred for RECQL4 molecular analysis and belonging to the RTS (27 cases) and BGS (12 cases) spectrum. One or two deleterious RECQL4 mutations were found in 10/27 patients referred for RTS diagnosis. Clinical and molecular reevaluation led to a different diagnosis in 7/17 negative cases, including Clericuzio-type poikiloderma with neutropenia, hereditary sclerosing poikiloderma, and craniosynostosis/anal anomalies/porokeratosis. No RECQL4 mutations were found in the BGS group without poikiloderma, confirming that RECQL4 sequencing was not indicated in this phenotype. One chromosomal abnormality and one TWIST mutation was found in this cohort. This study highlights the search for differential diagnoses before the prescription of RECQL4 sequencing in this clinically heterogeneous group. The combination of clinically defined subgroups and next-generation sequencing will hopefully bring to light new molecular bases of syndromes with poikiloderma, as well as BGS without poikiloderma.	0
BACKGROUND:Deep brain stimulation (DBS) is an effective intervention for Meige syndrome, a type of dystonia characterized by blepharospasm, facial, and oromandibular dystonia. This individual patient-level data meta-analysis was to identify the potential outcome predictors, compare the stimulation targets and summarize the efficacy of DBS for Meige syndrome. METHODS:Three electronic databases (PubMed, Web of Science and Embase) were searched with no publication data restriction to identify studies regarding DBS for Meige syndrome. The primary outcome was the improvement in BFMDRS-M score. Pearson's correlation coefficients and a stepwise multivariate regression analysis were used to identify the potential prognostic factors. RESULTS:Twenty-three studies (115 patients, 94 with pallidal stimulation and 21 with subthalamic stimulation) were eligible. Patients showed significant improvement in Burke-Fahn-Marsden Dystonia Rating Scale movement (BFMDRS-M) (21.5 ± 11.0 vs 8.6 ± 6.9, P < 0.001) and disability (BFMDRS-D) (6.4 ± 5.1 vs 2.9 ± 2.4, P < 0.001) scores at the last follow-up visit (31.9 ± 30.7 months), compared with scores at baseline. Preoperative BFMDRS-M and BFMDRS-D scores were positively correlated with the relative changes in BFMDRS-M score at the last follow-up visit. On the stepwise multivariate regression, only the preoperative BFMDRS remained significant in the best predictive model. CONCLUSIONS:Based on the existing evidence, pallidal/subthalamic stimulation is an effective therapy for even the refractory Meige syndrome. Higher preoperative scores probably indicate larger improvement. Stimulation targets or other clinical factors do not constitute the outcome predictive factors.	0
Objective:Lipodystrophy represents a group of rare diseases characterized by loss of body fat. While patients with generalized lipodystrophy exhibit near-total lack of fat, partial lipodystrophy is associated with selective fat loss affecting certain parts of the body. Although classical familial partial lipodystrophy (FPLD) is a well-described entity, recent reports indicate phenotypic heterogeneity among carriers of LMNA pathogenic variants. Methods:We have encountered 2 unique cases with complex phenotypes, generalized fat loss, and very low leptin levels that made the distinction between generalized versus partial lipodystrophy quite challenging. Results:We present a 61-year-old female with generalized fat loss, harboring the heterozygous pathogenic variant p.R541P (c.1622G>C) on the LMNA gene. The discovery of the pathogenic variant led to correct clinical diagnosis of her muscle disease, identification of significant heart disease, and a recommendation for the implantation of a defibrillator. She was able to start metreleptin based on her generalized fat loss pattern and demonstration of the genetic variant. Secondly, we report a 40-year-old Turkish female with generalized fat loss associated with a novel heterozygous LMNA pathogenic variant p.K486E (c.1456A>G), who developed systemic B cell follicular lymphoma. Conclusion:Clinicians need to recognize that the presence of an LMNA variant does not universally lead to FPLD type 2, but may lead to a phenotype that is more complex and may resemble more closely generalized lipo-dystrophy. Additionally, providers should recognize the multisystem features of laminopathies and should screen for these features in affected patients, especially if the variant is not at the known hotspot for FPLD type 2.	0
Patients with chronic kidney disease (CKD) display significant mineral and bone disorders (CKD-MBD) that induce significant cardiovascular, growth and bone comorbidities. Nephropathic cystinosis is an inherited metabolic disorder caused by the lysosomal accumulation of cystine due to mutations in the CTNS gene encoding cystinosin, and leads to end-stage renal disease within the second decade. The cornerstone of management relies on cysteamine therapy to decrease lysosomal cystine accumulation in target organs. However, despite cysteamine therapy, patients display severe bone symptoms, and the concept of "cystinosis metabolic bone disease" is currently emerging. Even though its exact pathophysiology remains unclear, at least five distinct but complementary entities can explain bone impairment in addition to CKD-MBD: long-term consequences of renal Fanconi syndrome, malnutrition and copper deficiency, hormonal disturbances, myopathy, and intrinsic/iatrogenic bone defects. Direct effects of both CTNS mutation and cysteamine on osteoblasts and osteoclasts are described. Thus, the main objective of this manuscript is not only to provide a clinical update on bone disease in cystinosis, but also to summarize the current experimental evidence demonstrating a functional impairment of bone cells in this disease and to discuss new working hypotheses that deserve future research in the field.	0
We treated a 65-year-old woman with familial cylindromatosis, with cylindromas covering the entire scalp. Subgaleal tumor excision and split skin grafting was performed. The graft take was deemed to be excellent, with almost 100% coverage 2.5 weeks after operation, no complications and a satisfying esthetic result.	0
Fibrillary glomerulonephritis (FGN) is a rare disorder accounting for up to 1% of all glomerulonephritis (GN). FGN usually manifests as nephrotic or subnephrotic proteinuria, hematuria, and hypertension in patients after the sixth decade. The overall prognosis of FGN is very poor. Crescentic presentation of FGN is uncommon which may be diagnosed as rapidly progressive glomerulonephritis (RPGN) unless electron microscopy and/or special stains are done. We report a case of a young female who presented as RPGN but diagnosis was revised to crescentic FGN after electron microscopy and immunohistochemical staining with DNAJB9 stain. Patient remained dialysis-dependent after treatment with steroid and cyclophosphamide for 2 months and progressed to end-stage renal disease (ESRD). Crescentic FGN usually does not respond to treatment and invariably progresses to ESRD over few months. This case emphasizes the defining role of electron microscopy and special stains in diagnosing uncommon glomerular diseases.	0
Spina Bifida is a congenital anomaly that arises from incomplete development of the neural tube. It is commonly used as a nonspecific term referring to any degree of neural tube closure. It can be further subdivided into spina bifida occulta and spina bifida aperta. Spina bifida occulta, or closed spinal dysraphism, is the mildest form of the neural tube defects (NTD) which involves a hidden vertebral defect and minimal neural involvement. Spina bifida aperta, or open spinal dysraphism, refers to a defect in which neural tissues communicate with the external environment such as meningocele and myelomeningocele. These conditions result in a varied spectrum of neurological effects due to the degree of neuralization. Spina bifida is commonly associated with several other developmental abnormalities which makes a multidisciplinary medical plan paramount to survival and positive outcomes.	0
Estimates of the incidence of the Meckel syndrome (MS) from different parts of the world vary from 1:140,000 to 1:13,250 births. In this nationwide study performed in Finland, the incidence of 1:14,400 births was found by retrospective ascertainment during the period 1970-1979, while the incidence was 1:8,500 births when prospective monitoring was performed in 1980-1981. The most probable incidence in Finland is about 1:9,000 births. Autosomal recessive inheritance of MS is confirmed in this study. The ratio of affected sibs, corrected for truncate complete ascertainment, was 0.261. No consanguinity between parents was found, as marriages between close relatives are rare in Finland and the ancestors were not traced back far enough to find remote consanguinities.	1
INTRODUCTION:Type 1 GM1 gangliosidosis is an ultra-rare, rapidly fatal lysosomal storage disorder, with life expectancy of <3 years of age. To date, only one prospective natural history study of limited size has been reported. Thus, there is a need for additional research to provide a better understanding of the progression of this disease. We have leveraged the past two decades of medical literature to conduct the first comprehensive retrospective study characterizing the natural history of Type 1 GM1 gangliosidosis. OBJECTIVES:The objectives of this study were to establish a large sample of patients from the literature in order to identify: 1) clinically distinguishing factors between Type 1 and Type 2 GM1 gangliosidosis, 2) age at first symptom onset, first hospital admission, diagnosis, and death, 3) time to onset of common clinical findings, and 4) timing of developmental milestone loss. METHODS:PubMed was searched with the keyword "GM1 Gangliosidosis" and for articles from the year 2000 onwards. A preliminary review of these results was conducted to establish subtype classification criteria for inclusion of only Type 1 patients, resulting in 44 articles being selected to generate the literature dataset of 154 Type 1 GM1 gangliosidosis patients. Key clinical events of these patient cases were recorded from the articles. RESULTS:Comprehensive subtyping criteria for Type 1 GM1 gangliosidosis were created, and clinical events, including onset, diagnosis, death, and symptomology, were mapped over time. In this dataset, average age of diagnosis was 8.7 months, and average age of death was 18.9 months. DISCUSSION:This analysis demonstrates the predictable clinical course of this disease, as almost all patients experienced significant multi-organ system dysfunction and neurodevelopmental regression, particularly in the 6- to 18-month age range. Patients were diagnosed at a late age relative to disease progression, indicating the need for improved public awareness and screening. CONCLUSION:This study highlights the significant burden of illness in this disease and provides critical natural history data to drive earlier diagnosis, inform clinical trial design, and facilitate family counseling.	0
BACKGROUND:Multiple Mitochondrial Dysfunctions Syndrome 4 (MMDS4) is manifested as a result of ISCA2 mutations. ISCA2 is a vital component of 4Fe-4S clusters assembly machine. Therefore, in MMDS4 patients, deficient mitochondrial respiratory chain complexes I and II, Aconitase and Succinate dehydrogenase of Kerbs cycle and Lipoic Acid Synthetase in the biosynthesis of lipoic acid are expected. CASE PRESENTATIONS:A 7 months boy in an Iranian consanguineous family with progressive neurodegenerative problems was referred to us. Primarily, general laboratory tests, Abdomen ultrasonography and brain magnetic resonance imaging were performed. In order to find out the genetic problem in this case Whole Exome Sequencing (WES) following by Sanger sequencing was carried out. A novel variant (c.355G > A, p.Ala119Thr) in ISCA2 gene was identified by WES in the proband. Confirmation and segregation in the family for this variant was performed by Sanger sequencing. In-Silico prediction of the ISCA2 secondary structure showed that a helix motif in the Fe-S biosynthesis domain of ISCA2 protein will be eliminated as a result of this variant. CONCLUSIONS:We reported the first patient with ISCA2 variant in Iranian population and the third one in the world reported for ISCA2 gene, so far associated with early-onset mitochondrial neurodegeneration. However further functional studies on this variant or finding it in other patients with similar clinical problems are needed to confirm the pathogenicity of this variant.	0
Plasminogen deficiency is an ultra-rare multisystem disorder characterized by the development of fibrin-rich pseudomembranes on mucous membranes. Ligneous conjunctivitis, which can result in vision impairment or loss, is the most frequent symptom reported. Affected systems may also include the respiratory tract, oropharynx, female reproductive tract, gingiva, middle ear, renal collecting system, skin and central nervous system. Untreated, plasminogen deficiency may result in significant reduction in quality of life and morbidity with potential life-threatening complications. Non-specific therapies are inadequate and plasminogen concentrates are not commercially available. The current understanding of plasminogen deficiency and management of disease symptoms and its progression are based on case reports/series and two small clinical trials. To date there has never been a comprehensive, international study to examine the natural history or optimal therapeutic intervention; knowledge gaps include identification of contributing factors and triggers of disease manifestations, inability to predict disease course, and insufficient real-world data for use of therapeutics. We have created an international, observational study (HISTORY) in a large cohort of persons with plasminogen deficiency and first-degree family members to address these gaps and to advance knowledge and care. HISTORY will build upon the established relationship between the Indiana Hemophilia and Thrombosis Center and the Fondazione Angelo Bianchi Bonomi, IRCCS Ca' Granda Ospedale Maggiore Policlinico - University of Milan and will utilize a modified version of the Prospective Rare Bleeding Disorders Database (PRO-RBDD). A biorepository containing samples from subjects with plasminogen deficiency will be established. This article describes the rationale behind the study and efforts towards its goals.	0
BACKGROUND:We propose two new concepts, the Filum Disease (FD) and the Neuro-cranio-vertebral syndrome (NCVS), that group together conditions thus far considered idiopathic, such as Arnold-Chiari Syndrome Type I (ACSI), Idiopathic Syringomyelia (ISM), Idiopathic Scoliosis (IS), Basilar Impression (BI), Platybasia (PTB) Retroflexed Odontoid (RO) and Brainstem Kinking (BSK). METHOD:We describe the symptomatology, the clinical course and the neurological signs of the new nosological entities as well as the changes visible on imaging studies in a series of 373 patients. RESULTS:Our series included 72% women with a mean age of 33.66 years; 48% of the patients had an interval from onset to diagnosis longer than 10 years and 64% had a progressive clinical course. The commonest symptoms were: headache 84%, lumbosacral pain 72%, cervical pain 72%, balance alteration 72% and paresthesias 70%. The commonest neurological signs were: altered deep tendon reflexes in upper extremities 86%, altered deep tendon reflexes in lower extremities 82%, altered plantar reflexes 73%, decreased grip strength 70%, altered sensibility to temperature 69%, altered abdominal reflexes 68%, positive Mingazzini's test 66%, altered sensibility to touch 65% and deviation of the uvula and/or tongue 64%. The imaging features most often seen were: altered position of cerebellar tonsils 93%, low-lying Conus medullaris below the T12L1 disc 88%, idiopathic scoliosis 76%, multiple disc disease 72% and syringomyelic cavities 52%. CONCLUSIONS:This is a paradigm shift that opens up new paths for research and broadens the range of therapeutics available to these patients.	0
The present authors have previously described a consanguineous Pakistani family with fibular hypoplasia and complex brachydactyly (DuPan syndrome) inherited as an autosomal recessive trait. All affected individuals showed either reductions or absence of bones in the limbs, and appendicular bone dysmorphogenesis with unaffected axial bones. Obligate heterozygote parents were phenotypically normal. Mutations in the cartilage-derived morphogenetic protein 1 (CDMP1) gene have been reported in two acromesomelic chondrodysplasias (i.e. Hunter-Thompson type and Grebe type) which are phenotypically related to DuPan syndrome. CDMP1, a member of the transforming growth factor beta super-family of secreted signalling molecules, has been reported to regulate limb patterning and distal bone growth. Therefore, the present authors examined genomic DNA from the family with DuPan syndrome for mutations in the CDMP1 gene. Affected individuals were homozygous for a missense mutation, T1322C, in the coding region of the CDMP1 gene. This mutation was not found in 44 control subjects of Pakistani origin. The T1322C change predicts a leu441pro substitution in the mature domain of the CDMP1 protein. This is likely to cause a conformational change in the CDMP1 protein that influences the expression of genes which are required for normal bone development. This finding extends the spectrum of phenotypes produced by defects in the CDMP1 gene.	0
We report a case of a newborn with severe respiratory distress since birth with two giant intrathoracic and separate eneteric duplication cysts in right hemithorax. On day 19, the intrathoracic cysts were removed, and the baby was discharged on his 22nd day of life. Histologic findings confirmed the diagnosis of a gastric duplication cyst. This report is the first case of two isolated, separated and giant right intrathoracic gastric duplication cysts in literature. The diagnostic values of radiological evaluation and surgical and pathological management for precise diagnosis are discussed.	0
We report a father and son affected by a hitherto unpublished bone dysplasia with moderately severe dwarfism. On initial radiographs, thickening of the diaphyses of the long bones was striking. The small bones of the extremities were almost unaffected. With age, the metaphyseal deformation became more prominent. The epiphyses became irregular and their growth was delayed (particularly the femoral heads). The femoral neck showed an unusual 'lip' on the inner edge. Later, the stubby appearance of the long bones faded and, in adulthood, only enlarged metaphyses and deformed femoral necks persisted. The vertebrae showed moderate deformation with irregular flattening, and narrowing of the spinal canal with a shortened interpedicular distance. The eye defects consisted of high grade myopia, microspherophakia, lens coloboma, lens luxation, and retinal detachment. The name 'microspherophakia-metaphyseal dysplasia' is suggested for this probably autosomal dominant bone dysplasia.	0
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a disease in pregnancy characterized by maternal alloantibodies directed against the human platelet antigen (HPA). These antibodies can cause intracranial hemorrhage (ICH) or other major bleeding resulting in lifelong handicaps or death. Optimal fetal care can be provided by timely identification of pregnancies at risk. However, this can only be done by routinely antenatal screening. Whether nationwide screening is cost-effective is still being debated. HPA-1a alloantibodies are estimated to be found in 1 in 400 pregnancies resulting in severe burden and fetal ICH in 1 in 10.000 pregnancies. Antenatal treatment is focused on the prevention of fetal ICH and consists of weekly maternal IVIg administration. In high-risk FNAIT treatment should be initiated at 12-18 weeks gestational age using high dosage and in standard-risk FNAIT at 20-28 weeks gestational age using a lower dosage. Postnatal prophylactic platelet transfusions are often given in case of severe thrombocytopenia to prevent bleedings. The optimal threshold and product for postnatal transfusion is not known and international consensus is lacking. In this review practical guidelines for antenatal and postnatal management are offered to clinicians that face the challenge of reducing the risk of bleeding in fetuses and infants affected by FNAIT.	0
OBJECTIVE:To determine the prevalence of physician-diagnosed systemic lupus erythematosus (SLE) in a national population-based sample in the United States. METHODS:Data from the Third National Health and Nutrition Examination Survey (NHANES III) were used to estimate the prevalence of self-reported physician-diagnosed SLE. Adult participants (age > or = 17; sample n = 20,050) were asked if they had been diagnosed with SLE by a physician. All medications currently being taken by survey participants were recorded. Two definitions were used to classify participants with SLE: self-reported physician diagnosis and self-reported physician diagnosis and a current prescription for antimalarials, corticosteroids, or other immunosuppressive medications. RESULTS:The prevalence of SLE in adults age > or = 17 based on self-reported physician diagnosis was 241 per 100,000 (95% confidence interval [CI] 130-352). The prevalence of SLE in adults age > or = 17 based on self-reported physician diagnosis and current prescription for antimalarials, corticosteroids, or immunosuppressive medications was 53.6 per 100,000 (95% CI 12.2-95.0). Among adult women, the prevalence of treated SLE was 100 per 100,000 (95% CI 19.8-179.3). CONCLUSIONS:Projecting a prevalence of 100 per 100,000 to the population of the United States, approximately 108,300 adult women had a self-reported physician diagnosis of SLE and were receiving specific treatment in 2000. This estimate is a reasonable lower boundary, as it does not include undiagnosed persons or those not being treated with antimalarials, corticosteroids, or immunosuppressive medications.	1
AIMS:Emotional stress plays a role in the exacerbation and development of interstitial cystitis/bladder pain syndrome (IC/BPS). Given the significant overlap of brain circuits involved in stress, anxiety, and micturition, and the documented role of glutamate in their regulation, we examined the effects of an increase in glutamate transport on central amplification of stress-induced bladder hyperalgesia, a core feature of IC/BPS. METHODS:Wistar-Kyoto rats were exposed to water avoidance stress (WAS, 1 hour/day x 10 days) or sham stress, with subgroups receiving daily administration of ceftriaxone (CTX), an activator of glutamate transport. Thereafter, cystometrograms were obtained during bladder infusion with visceromotor responses (VMR) recorded simultaneously. Cerebral blood flow (CBF) mapping was performed by intravenous injection of [14 C]-iodoantipyrine during passive bladder distension. Regional CBF was quantified in autoradiographs of brain slices and analyzed in three dimensional reconstructed brains with statistical parametric mapping. RESULTS:WAS elicited visceral hypersensitivity during bladder filling as demonstrated by a decreased pressure threshold and VMR threshold triggering the voiding phase. Brain maps revealed stress effects in regions noted to be responsive to bladder filling. CTX diminished visceral hypersensitivity and attenuated many stress-related cerebral activations within the supraspinal micturition circuit and in overlapping limbic and nociceptive regions, including the posterior midline cortex (posterior cingulate/anterior retrosplenium), somatosensory cortex, and anterior thalamus. CONCLUSIONS:CTX diminished bladder hyspersensitivity and attenuated regions of the brain that contribute to nociceptive and micturition circuits, show stress effects, and have been reported to demonstrated altered functionality in patients with IC/BPS. Glutamatergic pharmacologic strategies modulating stress-related bladder dysfunction may be a novel approach to the treatment of IC/BPS.	0
INTRODUCTION:Pilocytic astrocytoma (PA) is the most common primary brain neoplasm in children and treated in curative intent with gross total resection (GTR). However, PA is rare in adults, resulting in limited knowledge on the natural clinical course. This study aimed to describe the clinical course and identify prognostic factors of adult patients with PA. METHODS:46 patients ≥ 18 years at diagnosis of PA and neurosurgical resection or biopsy between 2000 and 2018 were identified from the Neuro-Biobank of the Medical University of Vienna. In two cases with differing histopathological diagnosis at recurrence, DNA methylation analysis was performed using Illumina Infinium HumanMethylation850 BeadChip (850 k) arrays and the Molecular Neuropathology classifier. Clinico-pathological features were correlated with patient outcomes. RESULTS:Median age at diagnosis was 32.5 years (range: 19-75) and median Ki67 proliferation index was 2.8% (0.5-13.4%). Tumor location significantly correlated with resectability (p < 0.001). Tumor progression or recurrence was observed in 9/46 (19.6%) patients after a median follow up time of 53.0 months (range 0.5-300). 5-year overall and progression-free survival rates were 85.3% and 70.0%, respectively. 2/9 (22.2%) patients presented with histological changes in the recurrent tumor specimen. In detail, methylation classification redefined the histological diagnosis to anaplastic astrocytoma with piloid features and glioma in one patient, each. Age > 40 and higher body mass index (BMI) were associated with impaired progression-free and overall survival (p < 0.05). CONCLUSIONS:Tumor recurrence or progression in adult PA patients was higher than the one reported in pediatric patients. Higher age and BMI were associated with impaired prognosis.	0
Most cases of the primary brainstem injuries(PBSI)are fatal, and disturbance of consciousness is often prolonged even if lifesaving is obtained. The mechanisms of PBSI are as follows: diffuse axonal injury from acceleration/deceleration, shear strain at the midbrain, direct injury of neurovascular structures by tentorial margin, and lower brainstem injury by hyperextension of the cervical vertebrae. Though we can use both CT and MRI to diagnose, MRI is more helpful than CT in detecting, localizing, and characterizing PBSI. When the location of PBSI is limited in the ventral side of pons, it may occasionally result in locked in syndrome(LIS). Generally it is difficult to diagnose LIS with severe trauma due to the rarity of this syndrome caused by head injury. Here, we report a case of an elderly man with traumatic brainstem hemorrhage, who transiently presented LIS and finally improved.	0
Congenital mitral stenosis (MS) is a spectrum of anomalies that result in functional and anatomic obstruction of inflow into the left ventricle. Mitral arcade is one of the varieties of congenital MS where there is an abnormal development of chordae tendineae, resulting in stenosis, regurgitation, or both. Here, we describe the case of a mitral arcade in a child, which was diagnosed on echocardiography and confirmed with other imaging modalities.	0
There has been an ever-expanding list of the Limb-Girdle Muscular Dystrophies (LGMD). There are currently 8 subtypes of autosomal dominant (AD) and 26 subtypes of autosomal recessive (AR) LGMD. Despite continued research efforts to conquer this group of genetic neuromuscular disease, patients continue to be treated symptomatically with the aim of prevention or addressing complications. Mouse models have been helpful in clarifying disease pathogenesis as well as strategizing pathways for treatment. Discoveries in translational research as well as molecular therapeutic approaches have kept clinicians optimistic that more promising clinical trials will lead the way to finding the cure for these devastating disorders. It is well known that the challenge for these rare diseases is the ability to assemble adequate numbers of patients for a clinically meaningful trial, but current efforts in developing patient registries have been encouraging. Natural history studies will be essential in establishing and interpreting the appropriate outcome measures for clinical trials. Nevertheless, animal studies continue to be key in providing proof of concept that will be necessary in moving research along. This review will briefly discuss each type of LGMD, highlighting their distinguishing features, then focus on research efforts that have been published in the literature for the past few years, many of which are still in the preclinical trial stage.	0
BACKGROUND:Nonimmune hydrops fetalis (NIHF) is still a challenging diagnosis. The differential diagnosis is extensive and the success of identifying a cause depends on the thoroughness of efforts to establish a diagnosis. For the early diagnosis of NIHF, a virtual gene panel diagnostic tool was developed. The female premature baby in question was delivered via emergency cesarean at 30 + 1 weeks of gestational age (GA) due to rapidly developing NIHF to a healthy mother. The family history was noncontributory. METHODS:DNA of the family was extracted and sequenced by the virtual hydrops panel with whole-exome sequencing. RESULTS:The hydrops panel revealed Noonan syndrome (NS) with a germline mutation in PTPN11 c.218C>T (p.Thr73Ile). CONCLUSION:The diagnosis of our patient was rapidly confirmed by the hydrops panel. The variant of c.218C>T (p.Thr73Ile) has not yet been described in literature relating to NIHF. Only a few case reports of this variant are known. This particular mutation is associated with Noonan syndrome, congenital heart defect and persistent thrombocytopenia. Few reveal juvenile myelomonocytic leukemia.	0
Pulmonary arterial hypertension (PAH) is a rare disease caused by pulmonary vascular remodeling. Current vasodilator treatments have substantially improved patients' survival. This improved survival has led to the appearance of complications related to conditions previously underdiagnosed or even ignored, such as pulmonary artery aneurysm (PAA). The presence of a dilated pulmonary artery has been shown to be related to an increased risk of sudden cardiac death among PAH patients. This increased risk could be associated to the development of left main coronary artery compression or pulmonary artery dissection. Nevertheless, very little is currently known about the molecular mechanisms related to PAA. Thoracic aortic aneurysm (TAA) is a well-known condition with an increased risk of sudden death caused by acute aortic dissection. TAA may be secondary to chronic exposure to classic cardiovascular risk factors. In addition, a number of genetic variants have been shown to be related to a marked risk of TAA and dissection as part of multisystemic syndromes or isolated familial TAA. The molecular pathways implied in the development of TAA have been widely studied and described. Many of these molecular pathways are involved in the pathogenesis of PAH and could be involved in PAA. This review aims to describe all these common pathways to open new research lines that could help lead to a better understanding of the pathophysiology of PAH and PAA and their clinical implications.	0
X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is a dominantly inherited peripheral neuropathy and is caused by mutations in gap junction beta 1 gene (GJB1). Here, a novel variant of c.-170T>G in GJB1 was identified in a large Chinese CMTX1 pedigree. The proband presented transient "stroke-like" episodes in addition to the peripheral neuropathy. At the time of episode, he had transient hyperthyroidism. To our knowledge, this is the first variant found in non-coding region associated with transient central nervous system (CNS) symptoms and in this case, thyroid dysfunction might contribute to the episode. The mechanism of CMTX1 as well as the transient CNS symptoms waits to be elucidated.	0
BACKGROUND AND OBJECTIVES: The aim of this study is to better understand the epidemiological and clinical features of patients with sarcoidosis in Singapore and to ascertain if ethnic differences exist. METHODS: A review of hospital medical records from June 1998 to May 2004 to identify patients with sarcoidosis. RESULTS: There were 59 patients with sarcoidosis identified (19 Chinese, 29 Asian Indian and 11 Malay). The estimated annual incidence of sarcoidosis in Singapore was 0.56 per 100,000. There was a significant difference between the observed and expected disease frequency in Chinese (32.2% vs 78.7%) and Indians (49.2% vs 6.0%, P < 0.005). A bimodal distribution of age at diagnosis was seen with peaks in the 30-39 years and 50-59 years age groups; 38.9% of cases were over the age of 50. Chinese patients were more likely to be asymptomatic (57.9%, P = 0.015) and less likely to have impaired spirometry (P = 0.013). Pulmonary sarcoid presented largely as stage 0 or stage 1 disease (74.4%). Overall mean spirometry was unimpaired and prognosis was good with 79.2% showing no radiological deterioration. There were no significant differences in organ involvement or treatment between ethnic groups. CONCLUSION: Sarcoidosis in Singapore is rare and the incidence differs between ethnic groups. Chinese appear to have a lower incidence and a less symptomatic presentation; Indians have a higher incidence and poorer clinical course.	1
PURPOSE:To investigate the characteristics of tear abnormalities with benign essential blepharospasm (BEB) and the effect of botulinum toxin type A (BTX-A) treatment. STUDY DESIGN:Prospective and clinical study. METHODS:Forty eyes of 40 patients (12 men and 28 women, ages 63.5 ±12.9) with BEB and tear abnormalities were enrolled. RESULTS:The average scores for subjective symptoms as evaluated by the visual analog scale (VAS) were 46.3 and Dry Eye-Related Quality-of-Life Score (DEQS) were 63.7. The fluorescein breakup time (FBUT) was 2.7 ± 1.6 sec. Among fluorescein breakup patterns (FBUPs), dimple break, with the corresponding mechanism of decreased wettability was the most frequent, observed in 29 eyes (73%). The NEI score was 0.4 ± 0.7 and the van Bijesterveld score was 0.6 ± 0.8; the Schirmer 1 test value was 13.1 ± 9.4 mm. Eighteen patients received BTX-A treatment, and significant improvement was found in severity of subjective symptoms both on VAS and DEQS as well as for FBUT. The main FBUPs changed from dimple break to random break. CONCLUSION:Tear abnormalities seen in BEB correspond to short BUT-type dry eye (DE), subclassified into decreased wettability DE in view of FBUPs.	0
BACKGROUND:Benign recurrent intrahepatic cholestasis is a genetic disorder with recurrent cholestatic jaundice due to ATP8B1 and ABCB11 gene mutations encoding for hepato-canalicular transporters. Herein, we firstly provide the evidence that a nonsense variant of ATP8B1 gene (c.1558A>T) in heterozygous form is involved in BRIC pathogenesis. CASE SUMMARY:A 29-year-old male showed severe jaundice and laboratory tests consistent with intrahepatic cholestasis despite normal gamma-glutamyltranspeptidase. Acute and chronic liver diseases with viral, metabolic and autoimmune etiology were excluded. Normal intra/extra-hepatic bile ducts were demonstrated by magnetic resonance. Liver biopsy showed: Cholestasis in the centrilobular and intermediate zones with bile plugs and intra-hepatocyte pigment, Kupffer's cell activation/hyperplasia and preserved biliary ducts. Being satisfied benign recurrent intrahepatic cholestasis diagnostic criteria, ATP8B1 and ABCB11 gene analysis was performed. Surprisingly, we found a novel nonsense variant of ATP8B1 gene (c.1558A>T) in heterozygosis. The variant was confirmed by Sanger sequencing following a standard protocol and tested for familial segregation, showing a maternal inheritance. Immunohistochemistry confirmed a significant reduction of mutated gene related protein (familial intrahepatic cholestasis 1). The patient was treated with ursodeoxycholic acid 15 mg/kg per day and colestyramine 8 g daily with total bilirubin decrease and normalization at the 6th and 12th mo. CONCLUSION:A genetic abnormality, different from those already known, could be involved in familial intrahepatic cholestatic disorders and/or pro-cholestatic genetic predisposition, thus encouraging further mutation detection in this field.	0
It is presented the phenotype of a new compound heterozygous mutation of the genes R384X and Q356X encoding the enzyme of 11-beta-hydroxylase.Severe virilization, peripheral hypertension, and early puberty.Managed with hormone replacement therapy (corticosteroid) and antihypertensive therapy (beta-blocker), resulting in the control of physical changes and levels of arterial tension.According to the phenotypic characteristics of the patient, it is inferred that the R384X mutation carries an additional burden on the Q356X mutation, with the latter previously described as a cause of 11-beta-hydroxylase deficiency. The description of a new genotype, as in this case, expands the understanding of the hereditary burden and deciphers the various factors that lead to this pathology as well as the other forms of congenital adrenal hyperplasia (CAH), presenting with a broad spectrum of clinical presentations. This study highlights the importance of a complete description of the patient's CAH genetic profile as well as their parents' genetic profile.	0
INTRODUCTION:The calcifying epithelial odontogenic tumor (CEOT), also known as Pindborg tumor, is a locally invasive benign neoplasm. Histogenesis is controversial. PRESENTATION OF CASE:A 26-year-old male presented asymptomatic swelling on the right side of the face, with approximately six months of evolution. At intraoral examination, a hard nodule localized in the right posterior region of the maxilla, measuring approximately 5.0 x 3.0 cm was observed. The computed tomography images showed hypodense lesion with points of calcification associated with two non-erupted teeth. We suspect of odontogenic lesions. The final diagnosis of CEOT was established based on the histopathological aspects. DISCUSSION:This tumor is more frequent in adult men, usually develops in the posterior region of the mandible and may present clinical-pathological similarities with others odontogenic lesions. The radiological aspects observed in the CEOT are variable and depend on the time of evolution of the tumor. The histopathological examination is mandatory to establish the final diagnosis. CONCLUSION:Our case was treated with simple enucleation without signs of recurrence in five years of follow-up. Further studies are needed to understand the aetiology and the biological behaviour of this tumor.	0
TPK deficiency, also known as thiamine metabolism dysfunction syndrome 5, is a rare autosomal recessive disorder of inborn error of metabolism caused by TPK1 gene mutation. Its clinical manifestation is highly variable, ranging from spontaneous remission to fatal metabolic crisis. Here, we describe two affected siblings in a Chinese family presenting with recurrent episodes of acute ataxia. Whole exome sequencing identified a homozygous missense variant c.382C > T (p.Leu128Phe) in the TPK gene, which is located in the thiamine binding domain and affects a highly conserved amino acid. Besides, a review of the 18 previously reported patients provides a better understanding of the clinical and genetic features of this disorder. TPK deficiency may be an under-diagnosed cause of acute encephalopathy and ataxia. Given the potential benefit of early intervention, TPK deficiency should be considered in patients with episodic encephalopathy or ataxia, especially those associated with lactic acidosis and α-ketoglutaric aciduria. Significant decreased TPP in the blood is a strong hint of the disease. WES (whole exome sequencing) can help to further identify the molecular diagnosis.	0
INTRODUCTION:Pseudohypoparathyroidism (PHP) indicates a group of rare disorders characterized by end-organ resistance to various hormones, primarily parathyroid hormone (PTH). One of its most common type is PHP-Ia, which is caused by maternally inherited inactivating mutations in GNAS. In this report, we present a Chinese girl with typical features of PHP-Ia and a novel mutation of the GNAS gene. PATIENT CONCERNS:A 9-year-old Chinese girl presented with recurrent epileptic seizure. DIAGNOSIS:Biochemical and imaging findings were consistent with PHP-Ia, including typical Albright hereditary osteodystrophy phenotype (short stature, round face, brachydactyly, and mild mental retardation), PTH resistance (hypocalcemia, hyperphosphatemia, elevated serum PTH, and multiple intracranial calcification) and thyroid stimulating hormone resistance (elevated serum thyroid stimulating hormone). INTERVENTIONS:The patient was given 1α-hydroxylated vitamin D (calcitriol, 0.5 ug/d), calcium carbonate and vitamin D3 tablets (1.5 g/d, including 600 mg calcium and 125 IU vitamin D3). DNA analysis of the GNAS gene was performed for the whole family. OUTCOMES:Investigation of the GNAS gene revealed a novel mutation c.313delG (p.Glu105Lysfs*7) in the patient, as well as her mother. So the diagnosis of PHP-Ia was confirmed. CONCLUSION:The study further expands the spectrum of known GNAS mutations associated with PHP and lay emphasis on the genetic analysis of GNAS gene for identifying genetic abnormalities as well as making diagnosis and differentiation of various subtypes of PHP.	0
The thumb is frequently impaired in rheumatoid arthritis. This leads to major disability in affected patients. Through a clinical case, we describe a reconstructive strategy for a three-joint adduction thumb deformity that caused instability of the interphalangeal and metacarpophalangeal joints, without cartilaginous lesion. Ulnar collateral ligament destruction was treated by a bone-ligament-bone graft at the interphalangeal joint and by a Littler ligamentoplasty at the metacarpophalangeal joint. The trapeziometacarpal lesion was treated by trapeziectomy in combination with suspension ligamentoplasty. Clinical and radiological assessments at 22 months of follow-up revealed good outcomes. This technique is a new option to include in the reconstructive treatment for thumb instability, particularly when caused by rheumatoid arthritis.	0
Mutational inactivation of p53 is a key player in the development of human cancer. Thus, retrieving the tumor suppressor activity of p53 gene is considered a novel strategy in cancer therapy. Current study aimed to investigate the anti-cancer potentials of botulinum toxin type-A (BTX-A) and captopril as a trial to shed light on effective anti-cancer therapy with lower side effects. Cytotoxic effect of captopril and BTX-A was determined using MTT assay against colon (HCT116) and prostate cancer (DU145) cells compared to their effect on normal vero cells. Anti-proliferation assay and anti-metastatic effect were carried out using trypan blue exclusion method and wound scratch migration test, respectively. The ability of test drugs to induce apoptosis in cancer cells was examined using real time PCR. Recorded data revealed that captopril exhibited a statistically significant cytotoxicity (P < 0.05) to cancer cells (IC50 values of 1.5 and 1.2 mg/mL) with much lower toxicity to normal cells. At the same time, IC50 values post BTX-A treatment were 7.2 and 6.4 U/mL for HCT116 and DU145 cells, respectively without any toxicity to vero cells. Both drugs showed inhibitory potentials on cellular proliferation and the ability of cancer cells to migrate in scratched monolayers was obviously inhibited along with increasing their concentrations. P53 expression levels in captopril and BTX-A treated DU145 cells were elevated by 4 and 2.5 folds, respectively, while lower level of apoptosis induction in HCT116 cells was observed. Accordingly, BTX-A and captopril could present potential anti-cancer candidates through triggering cancer cells towards self-destruction.	0
Acromicric dysplasia (AD) is an autosomal dominant disorder characterized by short stature, short extremities, stiff joint and skeleton features including brachymetacarpia, cone-shaped epiphyses, internal notch of the femoral head, and delayed bone age. Recently, we identified fibrillin 1 (FBN1) as the disease gene of AD. The aim of our study was to further describe the long-term follow up of AD patients with an emphasis on orthopedic management. Nine patients with FBN1 mutations were included in the study ranging in age from 5.5 to 64 years. For all, detailed clinical and radiological data were available.Birth parameters were always normal and patients progressively developed short stature <-3 SD. Carpal tunnel syndrome was observed in four patients. We found discrepancy between the carpal bone age and the radius and ulna epiphysis bone ages, a variable severity of hip dysplasia with acetabular dysplasia, epiphyseal and metaphyseal femoral dysplasia resembling Legg-Perthes-Calvé disease and variable pelvic anteversion and hyperlordosis. Orthopedic surgery was required in two patients for hip dysplasia, in one for limb lengthening and in three for carpal tunnel syndrome. Our observations expand the AD phenotype and emphasize the importance of regular orthopedic survey.	0
Tricho-dento-osseous (TDO) syndrome is a rare, autosomal dominant disorder principally characterised by curly hair at infancy, severe enamel hypomineralization and hypoplasia and taurodontism of teeth, sclerotic bone, and other defects. Diagnostic criteria are based on the generalized enamel defects, severe taurodontism especially of the mandibular first permanent molars, an autosomal dominant mode of inheritance, and at least one of the other features (i.e., nail defects, bone sclerosis, and curly, kinky or wavy hair present at a young age that may straighten out later). Confusion with amelogenesis imperfecta is common; however, taurodontism is not a constant feature of any of the types of amelogenesis imperfecta. Management of TDO requires a team approach, proper documentation, and a long-term treatment and follow-up plan. The aim of treatment is to prevent problems such as sensitivity, caries, dental abscesses, and loss of occlusal vertical dimension through attrition of hypoplastic tooth structure. Another aim is to restore function of the dentition and enhance the esthetics and self-esteem of the patient. This paper proposes treatment approaches that include preventive, restorative, endodontic, prosthetic, and surgical options to management. In addition, it sheds light on the difficulties faced during dental treatment of such cases.	0
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. The search for genetic causes of CAKUT has led to genetic diagnosis in approximately 5-20 % of CAKUT patients from Western countries. In this study, genetic causes of CAKUT in Korean children were sought using targeted exome sequencing (TES) of 60 genes reported to cause CAKUT in human or murine models. We identified genetic causes in 13.8% of the 94 recruited patients. Pathogenic single nucleotide variants of five known disease-causing genes, HNF1B, PAX2, EYA1, UPK3A, and FRAS1 were found in 7 cases. Pathogenic copy number variations of 6 patients were found in HNF1B, EYA1, and CHD1L. Genetic abnormality types did not significantly differ according to CAKUT phenotypes. Patients with pathogenic variants of targeted genes had syndromic features more frequently than those without (p < 0.001). This is the first genetic analysis study of Korean patients with CAKUT. Only one-seventh of patients were found to have pathogenic mutations in known CAKUT-related genes, indicating that there are more CAKUT-causing genes or environmental factors to discover.	0
Trichoepitheliomas are uncommon benign adnexal neoplasms that originate from the hair follicles. Multiple familial trichoepithelioma constitute an autosomal dominant disease characterized by the appearance of multiple flesh-colored, symmetrical papules, tumors and/or nodules in the central face and occasionally on the scalp. Although clinical diagnosis is usually straightforward in light of the family history and naked-eye examination, dermoscopy may aid in its confirmation. Dermoscopy of each papule revealed in-focus arborizing vessels, multiple milia-like cysts and rosettes amidst a whitish background. In a patient with multiple facial papules revealing a dermoscopic appearance described above, the diagnosis of sporadic or familial multiple trichoepithelioma should be considered.	0
Objectives:Granular corneal dystrophies (GCD) are characterized by small, discrete, sharp-edged, grayish-white opacities in the corneal stroma. Among the genes responsible for the development of GCD, the most strongly related gene is transforming growth factor beta-induced (TGFBI), located in the 5q31.1 locus. Studies show that R124H in exon 4 and R555W in exon 12 are hot-spot mutations in the TGFBI gene that lead to GCD development. In this study, we aimed to investigate these two hot-spot mutations in exons 4 and 12 of the TGFBI gene and other possible mutations in the same regions, which code important functional regions of the protein, in Turkish families with GCD and to determine the relationship between the mutations and disease and related phenotypes. Materials and Methods:The study included 16 individuals diagnosed with GCD type 1 (GCD1), 11 of these patients' healthy relatives, and 28 unrelated healthy individuals. DNA was obtained from peripheral blood samples taken from each individual and polymerase chain reaction was used to amplify target gene regions. Genotyping studies were done by sequence analysis. Results:The R124S mutation in exon 4 of TGFBI was not detected in the patients or healthy individuals in our study. However, all individuals diagnosed as having GCD1 were found to be heterozygous carriers of the R555W mutation in exon 12 of TGFBI. This mutation was not detected in healthy family members or control individuals unrelated to these families. In addition, we detected the silent mutation F540F in exon 12 and c.32924 G>A substitution in an intronic region of the gene in a few patients and healthy individuals. Conclusion:Our study strongly supports the association of GCD1 with R555W mutation in exon 12 region of the TGFBI gene, as reported in the literature.	0
UNLABELLED:We reviewed of a number of genetic diseases known or at risk for sedation or anesthesia complications. Some of these conditions are relatively common (e.g., Down's syndrome) whereas others are rare or present with multiple congenital anomalies that have an impact on health care delivery. We listed complications, recommended presedation evaluations, and included checklist items to assist the health care provider administering sedation and anesthesia. A better recognition and awareness of risk factors associated with specific genetic diseases should lessen the likelihood of complications during these procedures. IMPLICATIONS:This article provides a brief description of potential problematic genetic disorders and associated complications that may manifest during sedation or anesthesia. Recommendations for presedation evaluation and checklist items are given that may impact on the delivery of care for these patients.	0
Pustules with facial and/or neck edema is one characteristic feature of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) at the early stage. Although several retrospective histopathologic studies on DIHS/DRESS have been reported, the detailed histopathologic findings of facial pustules for DIHS/DRESS are unavailable. We herein report a case of DIHS/DRESS with facial pustules that was histopathologically similar to eosinophilic pustular folliculitis (EPF). Eosinophilic infiltration into expanded follicles and sebaceous glands, which is highly characteristic of EPF, was detected in pustules due to DIHS/DRESS in this case. There are numerous pathophysiological similarities between DIHS/DRESS and EPF, which may cause their histopathologic similarity. Our findings suggest that facial pustules of DIHS/DRESS may histopathologically mimic EPF.	0
The phenotypic similarities have been demonstrated between non-lethal campomelic dysplasia (CD) and small patella syndrome (SPS), in which different genetic defects have been identified. We report on a familial case of skeletal dysplasia with overlapping phenotype of mild CD and SPS, including defective ischio-pubic ossification, elongated femoral neck, hypoplastic patellae, and increased space between the first and the second toes (sandal gap). Direct sequencing analysis demonstrated a novel missense mutation (p.H169Q) within the coding region of the SOX9 gene and negative for TBX4 mutations. Functional analysis of the p.H169Q mutant revealed reduced but not fully abolished transactivation capacity of the mutated protein. Retained residual SOX9 function might contribute to an extremely mild CD phenotype in the present cases. © 2013 Wiley Periodicals, Inc.	0
BACKGROUND:Neuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative disorders characterized by an accumulation of lipofuscin in the body's tissues. NCLs are associated with variable age of onset and progressive symptoms including seizures, psychomotor decline, and loss of vision. METHODS:We describe the clinical and molecular characteristics of four Russian patients with NCL (one female and three males, with ages ranging from 4 to 5 years). The clinical features of these patients include cognitive and motor deterioration, seizures, stereotypies, and magnetic resonance imaging signs of brain atrophy. Exome sequencing was performed to identify the genetic variants of patients with NCL. Additionally, we tested 6,396 healthy Russians for NCL alleles. RESULTS:We identified five distinct mutations in four NCL-associated genes of which two mutations are novel. These include a novel homozygous frameshift mutation in the CLN6 gene, a compound heterozygous missense mutation in the KCTD7 gene, and previously known mutations in KCTD7, TPP1, and MFSD8 genes. Furthermore, we estimated the Russian population carrier frequency of pathogenic and likely pathogenic variants in 13 genes associated with different types of NCL. CONCLUSION:Our study expands the spectrum of mutations in lipofuscinosis. This is the first study to describe the molecular basis of NCLs in Russia and has profound and numerous clinical implications for diagnosis, genetic counseling, genotype-phenotype correlations, and prognosis.	0
In autoimmune/lymphoproliferative syndrome (ALPS), defective Fas death receptor function causes lymphadenomegaly/splenomegaly, the expansion of T-cell receptor αβ(+) CD4/CD8 double-negative T cells, and frequent development of hematologic autoimmunity. Dianzani autoimmune lymphoproliferative disease (DALD) has a similar phenotype but lacks the expansion of double-negative T cells. This work shows that patients with ALPS and DALD have high serum levels of interleukin 17A (IL-17A), IL-17F, and IL-17AF, which are involved in several autoimmune diseases, and that their T cells show increased secretion of these cytokines upon activation in vitro. The following data indicate that these cytokines may contribute to ALPS and DALD: (1) recombinant IL-17A and IL-17F significantly inhibit Fas-induced cell death in Fas-sensitive T cells from healthy donors; (2) this inhibitory effect is also induced by the patients' serum and is reversed by anti-IL-17A antibodies; (3) IL-17A neutralization substantially increases Fas-induced cell death in T cells from ALPS and DALD patients in vitro; and (4) treatment with anti-IL-17A antibodies ameliorates the autoimmune manifestations and, at a lesser extent, the lymphoproliferative phenotype and prolongs survival in MRLlpr/lpr mice, which are an animal model of ALPS. These data suggest that IL-17A and IL-17F could be targeted therapeutically to improve Fas function in ALPS and DALD.	0
Mesomelia-synostoses syndrome (MSS) or mesomelic dysplasia with acral synostoses Verloes-David-Pfeiffer type is a rare autosomal-dominant disorder characterized by mesomelic limb shortening, acral synostoses, and multiple congenital malformations. So far, five patients in four unrelated families have been reported worldwide with MMS. By using whole-genome oligonucleotide array CGH, we have identified an interstitial deletion at 8q13 in all patients. The deletions vary from 582 Kb to 738 Kb in size, but invariably encompass only two genes: SULF1, encoding the heparan sulfate 6-O-endosulfatase 1, and SLCO5A1, encoding the solute carrier organic anion transporter family member 5A1. SULF1 acts as a regulator of numerous growth factors in skeletal embryonic development whereas the function of SLCO5A1 is yet unknown. Breakpoint sequence analyses performed in two families showed nonrecurrent deletions. Real-time quantitative RT-PCR analysis showed the highest levels of SULF1 transcripts in human osteoblasts and cartilage whereas SLCO5A1 was highly expressed in human fetal and adult brain and heart. Our results strongly suggest that haploinsufficiency of SULF1 contributes to this mesomelic chondrodysplasia, highlighting the critical role of endosulfatase in human skeletal development. Codeletion of SULF1 and SLCO5A1--which does not result from a low-copy repeats (LCRs)-mediated recombination event in at least two families--was found in all patients, so we suggest that haploinsufficiency of SULF1 combined with haploinsufficiency of SLCO5A1 (or the altered expression of a neighboring gene through position effect) could be necessary in the pathogenesis of MSS.	0
Extant and extinct reptiles exhibit numerous combinations of tooth implantation and attachment. Tooth implantation ranges from those possessing roots and lying within a socket (thecodonty), to teeth lying against the lingual wall of the jawbone (pleurodonty), to teeth without roots or sockets that are attached to the apex of the marginal jawbones (acrodonty). Attachment may be ligamentous (gomphosis) or via fusion (ankylosis). Generally speaking, adaptative reasonings are proposed as an underlying driver for evolutionary changes in some forms of tooth implantation and attachment. However, a substantiated adaptive hypothesis is lacking for the state of acrodont ankylosis that is seen in several lineages of Lepidosauria, a clade that is plesiomorphically pleurodont. The convergent evolution of acrodont ankylosis in several clades of lepidosaurs suggests a selective pressure shaped the evolution of the trait. We hypothesize that acrodont ankylosis as seen in Acrodonta and Sphenodon punctatus, is an adaptation either resulting from or allowing for a stronger bite force. We analyzed bite force data gathered from the literature to show that those taxa possessing acrodont dentition possess a stronger bite force on average than those taxa with pleurodont dentition. Dietary specialists with pleurodont dentition may also possess relatively high bite forces, though body size may also play a role in their ability to bite hard. Furthermore, our results have implications for the evolution of acrodont ankylosis and potential behaviors related to strong bite force that influenced the evolution of acrodonty within Acrodonta and Rhynchocephalia.	0
Since the update of the 4th edition of the WHO Classification of Central Nervous System (CNS) Tumors published in 2016, particular molecular characteristics are part of the definition of a subset of these neoplasms. This combined 'histo-molecular' approach allows for a much more precise diagnosis of especially diffuse gliomas and embryonal CNS tumors. This review provides an update of the most important diagnostic and prognostic markers for state-of-the-art diagnosis of primary CNS tumors. Defining molecular markers for diffuse gliomas are IDH1/IDH2 mutations, 1p/19q codeletion and mutations in histone H3 genes. Medulloblastomas, the most frequent embryonal CNS tumors, are divided into four molecularly defined groups according to the WHO 2016 Classification: wingless/integrated (WNT) signaling pathway activated, sonic hedgehog (SHH) signaling pathway activated and tumor protein p53 gene (TP53)-mutant, SHH-activated and TP53-wildtype, and non-WNT/non-SHH-activated. Molecular characteristics are also important for the diagnosis of several other CNS tumors, such as RELA fusion-positive subtype of ependymoma, atypical teratoid rhabdoid tumor (AT/RT), embryonal tumor with multilayered rosettes, and solitary fibrous tumor/hemangiopericytoma. Immunohistochemistry is a helpful alternative for further molecular characterization of several of these tumors. Additionally, genome-wide methylation profiling is a very promising new tool in CNS tumor diagnostics. Much progress has thus been made by translating the most relevant molecular knowledge into a more precise clinical diagnosis of CNS tumors. Hopefully, this will enable more specific and more effective therapeutic approaches for the patients suffering from these tumors.	0
Polymorphonuclear neutrophils (PMN) play a key role in innate immunity. Their activation and survival are tightly regulated by microbial products via pattern recognition receptors such as TLRs, which mediate recruitment of the IL-1R-associated kinase (IRAK) complex. We describe a new inherited IRAK-4 deficiency in a child with recurrent pyogenic bacterial infections. Analysis of the IRAK4 gene showed compound heterozygosity with two mutations: a missense mutation in the death domain of the protein (pArg12Cys) associated in cis-with a predicted benign variant (pArg391His); and a splice site mutation in intron 7 that led to the skipping of exon 7. A nontruncated IRAK-4 protein was detected by Western blotting. The patient's functional deficiency of IRAK-4 protein was confirmed by the absence of IRAK-1 phosphorylation after stimulation with all TLR agonists tested. The patient's PMNs showed strongly impaired responses (L-selectin and CD11b expression, oxidative burst, cytokine production, cell survival) to TLR agonists which engage TLR1/2, TLR2/6, TLR4, and TLR7/8; in contrast, the patient's PMN responses to CpG-DNA (TLR9) were normal, except for cytokine production. The surprisingly normal effect of CpG-DNA on PMN functions and apoptosis disappeared after pretreatment with PI3K inhibitors. Together, these results suggest the existence of an IRAK-4-independent TLR9-induced transduction pathway leading to PI3K activation. This alternative pathway may play a key role in PMN control of infections by microorganisms other than pyogenic bacteria in inherited IRAK-4 deficiency.	0
BACKGROUND:DICER1 syndrome is an inherited tumor predisposition syndrome. A germline mutation in DICER1 increases the risk for a spectrum of rare tumors. We describe a case of somatic DICER1 mutation in a pubertal girl, who is affected by different tumors of the DICER1 syndrome, including embryonal rhabdomyosarcoma of the cervix (ERMS) and thyroid adenoma. CASE:A sixteen-year old girl with history of papillary thyroid adenoma presented with abnormal vaginal bleeding and an exophytic cervical mass on examination. Histopathologic examination confirmed cervical ERMS. By using Sanger sequencing of the tumor, we identified one DICER1 mutation (c.3937delG).	0
Rickets is a common bone disease worldwide that is associated with disturbances in calcium and phosphate homeostasis and can lead to short stature and joint deformities. Rickets can be diagnosed based on history and physical examination, radiological features, and biochemical tests. It can be classified into 2 major groups based on phosphate or calcium levels: phosphopenic and calcipenic. Knowledge of categorization of the type of rickets is essential for prompt diagnosis and proper management. Nutritional rickets is a preventable disease through adequate intake of vitamin D through both dietary and sunlight exposure. There are other subtypes of rickets, such as vitamin D-dependent type 1 rickets and vitamin D-dependent type 2 rickets (due to defects in vitamin D metabolism), renal rickets (due to poor kidney function), and hypophosphatemic rickets (vitamin D-resistant rickets secondary to renal phosphate wasting wherein fibroblast growth factor-23 (FGF-23) often plays a major role), which requires closer monitoring and supplementation with activated vitamin D with or without phosphate supplements. An important development has been the introduction of burosumab, a human monoclonal antibody to FGF-23, which is approved for the treatment of X-linked hypophosphatemia among children 1 year and older.	0
Gestational diabetes insipidus (GDI) is a rare endocrine complication during pregnancy that is associated with vasopressinase overproduction from the placenta. Although increased vasopressinase is associated with placental volume, the regulation of placental growth in the later stage of pregnancy is not well known.A 16-year-old pregnant woman was urgently transferred to our hospital because of threatened premature labor when the Kumamoto earthquakes hit the area where she lived. During her hospitalization, she complained of gradually increasing symptoms of polyuria and polydipsia. The serum level of arginine vasopressin (AVP) was 1.7 pg/mL, which is inconsistent with central DI. The challenge of diagnostic treatment using oral 1-deamino-8-D-AVP (DDAVP) successfully controlled her urine and allowed for normal delivery. DDAVP tablets were not necessary to control her polyuria thereafter. Based on these observations, clinical diagnosis of GDI was confirmed. Pathophysiological analyses revealed that vasopressinase expression was more abundant in the GDI patient's syncytiotrophoblast in placenta compared with that in a control subject. Serum vasopressinase was also observed during gestation and disappeared soon after delivery. Vasopressinase is reportedly identical to oxytocinase or insulin regulated aminopeptidase (IRAP), which is an abundant cargo protein associated with the glucose transporter 4 (GLUT4) storage vesicle. Interestingly, the expression and subcellular localization of GLUT4 appeared to occur in a vasopressinase (IRAP)-dependent manner.Because placental volume may be associated with vasopressinase overproduction in GDI, vasopressinase (IRAP)/GLUT4 association appears to contribute to the growth of placenta in this case.	0
Prostatic malacoplakia associated with prostatic abscess is an extremely rare disease. We present a case of prostatic malacoplakia presenting as a prostatic and seminal vesicle abscess in a patient with diabetes. The diagnosis and management are discussed, and the literature is reviewed.	0
N-methyl-d-aspartate receptors (NMDARs) mediate a slow component of excitatory synaptic transmission that plays important roles in normal brain function and development. A large number of disease-associated variants in the GRIN gene family encoding NMDAR GluN subunits have been identified in patients with various neurological and neuropsychiatric disorders. Many of these variants reduce the function of NMDARs by a range of different mechanisms, including reduced glutamate potency, reduced glycine potency, accelerated deactivation time course, decreased surface expression, and/or reduced open probability. We have evaluated whether three positive allosteric modulators of NMDAR receptor function (24(S)-hydroxycholesterol, pregnenolone sulfate, tobramycin) and three co-agonists (d-serine, l-serine, and d-cycloserine) can mitigate the diminished function of NMDARs harboring GRIN variants. We examined the effects of these modulators on NMDARs that contained 21 different loss-of-function variants in GRIN1, GRIN2A, or GRIN2B, identified in patients with epilepsy, intellectual disability, autism, and/or movement disorders. For all variants, some aspect of the reduced function was partially restored. Moreover, some variants showed enhanced sensitivity to positive allosteric modulators compared to wild type receptors. These results raise the possibility that enhancement of NMDAR function by positive allosteric modulators may be a useful therapeutic strategy.	0
To evaluate the presence of atopy in patients with ocular cicatricial pemphigoid (OCP).Patient encounters between August 2005 and November 2016 at the Massachusetts Eye Research and Surgery Institute (MERSI) were searched to identify those with biopsy-proven OCP who had concurrent evidence of atopy.There were 230 patients with biopsy-proven OCP. Thirty-three of them were found to have clinical symptoms of atopy (asthma, hay fever, and eczema) and of these, 23 had evidence of atopy in their conjunctival biopsy specimens. All patients were administered immunomodulatory therapy for treatment of their OCP with 20 patients requiring additional antiallergy treatment to control residual atopic ocular symptoms. Among patients who used antiallergy medications, 80% showed improvement in residual symptoms. Rituximab and/or intravenous immunoglobulin is a preferred OCP medication for patients with OCP with some evidence of atopy.Clinicians should consider the coexistence of atopy in patients with OCP, especially in those with persistent symptoms after initiation of immunomodulatory therapy.	0
Cooks syndrome is characterized by familial congenital anonychia or onychodystrophy, hypoplasia or absence of distal phalanges of the hands and feet with brachydactyly of the fifth finger and digitalization of the thumb (triphalangism). It is listed as a "rare disease" by the Office of Rare Diseases of the National Institutes of Health. Here, we report a case of congenital anonychia and brachydactyly of the left foot, which possibly is a variant of Cooks syndrome with a positive family history of similar deformity.	0
Background:SPANX family members are thought to play an important role in cancer progression. The SPANXN2 is a gene expressed mainly in normal testis, but its role in testicular germ cell tumors (TGCTs) has yet to be investigated. TGCT is one of the most common solid tumors in young men and is associated with poor prognosis; however, effective prognostic indicators remain elusive. Therefore, we investigated the role of SPANXN2 in TGCT development. Methods:SPANXN2 expression levels were validated by quantitative real-time polymerase chain reaction (qRT-PCR) analyses of 14 TGCT samples and five adjacent normal tissue samples. SPANXN2 was transiently overexpressed in TGCT cells to study the consequences for cell function. The effects of SPANXN2 on cell migration were evaluated in transwell and wound healing assays. The effects on cloning ability were evaluated in colony formation assays. MTT assays and cell cycle analysis were used to detect the effects of SPANXN2 on cell proliferation. The expression levels of EMT- and AKT-related proteins in cells overexpressing SPANXN2 were analyzed by Western blotting. Results:Compared with adjacent normal tissues, the Gene Expression Profiling Interactive Analysis database showed SPANXN2 expression was downregulated in TGCTs which was consistent with the qRT-PCR analysis. SPANXN2 overexpression reduced cell migration and colony formation capability and downregulated expression of EMT- and AKT-related proteins, Vimentin, Snail, AKT, and p-AKT. Conclusion:Our results suggest that SPANXN2 regulates TGCT cell migration via EMT- and AKT-related proteins although its role in the occurrence and development of TGCT remains to be fully elucidated.	0
Study Design:Systematic review (Level 4). Objective:To summarize the demographics, clinical presentations, and conditions associated with butterfly vertebrae. Methods:A systematic search was performed of multiple databases. A total of 279 articles were identified for screening. Case series or case reports of butterfly vertebrae with adequate clinical detail were complied. Results:Eighty-two total articles (109 patients) were selected for final inclusion. Sixty-one percent of patients presented with a single butterfly vertebra, while 39% were multiple. The most common location for butterfly vertebrae was T1. Fifty-six percent of cases were associated with a syndrome, the most common being spondylocostal dysostosis. The presence of multiple butterfly vertebra was strongly associated with a syndrome or additional anomalies (P < .001). Overall, the most common presenting complaint was low back pain. Seventy percent of patients had associated spinal disease. Other organ systems affected included musculoskeletal (43%), craniofacial (30%), neurologic (27%), cardiovascular (24%), genitourinary (23%), gastrointestinal (22%), laboratory abnormality (16%), and endocrine (9%). Conclusions:This study is the largest collection of butterfly vertebrae cases to date. Butterfly vertebrae are associated with spinal deformity and multiple butterfly vertebrae may indicate a syndromic illness. Low back pain or disc herniation may occur with lumbar butterfly vertebrae however the etiology of this phenomena has not been rigorously explained. Many diseases and syndromes are associated with butterfly vertebrae.	0
To explore the possible mechanism and protective effect of BMSCs (bone mesenchymal stem cells) carrying superoxide dismutase (SOD) gene on mice with paraquat-induced acute lung injury.To establish the cell line of BMSCs bringing SOD gene, lentiviral vector bringing SOD gene was built and co-cultured with BMSCs. A total of 100 BALB/c mice were randomly divided into five groups, namely Control group, poisoning group (PQ group) , BMSCs therapy group (BMSC group) , BMSCs-Cherry therapy group (BMSC-Cherry group) , BMSCs-SOD therapy group (BMSC-SOD group) . PQ poisoning model was produced by stomach lavaged once with 1 ml of 25 mg/kg PQ solution, and the equal volume of normal saline (NS) was given to Control group mice instead of PQ. The corresponding BMSCs therapy cell lines were delivered to mice through the tail vein of mice 4h after PQ treatment.Five mice of each group were sacrificed 3 d, 7 d, 14 d and 21 days after corresponding BMSCs therapy cell lines administration, and lung tissues of mice were taken to make sections for histological analysis. The serum levels of glutathione (GSH) , malondialdehyde (MDA) , SOD, and the levels of transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α) in lung tissue were determined. The level of SOD was assayed by Westen-blot.Compared with Control group, the early (3 days) levels of SOD protein in lung tissue of PQ group obviously decreased, and the late (21 days) levels of SOD obviously increased, while in therapy groups, that was higher than that in PQ group, and the BMSCs-SOD group showed most obvious (all P<0.05) . Compared with Control group, the levels of plasma GSH and SOD of PQ group and each therapy group wae significantly lower than those in Control group, while in therapy groups, those were higher than those of PQ group, and the BMSCs-SOD group showed most obvious (all P<0.05) .Compared with Control group, the level of plasma MDA, TNF-α and TGF-β in PQ group and therapy groups were significantly higher, while in therapy groups, that was lower than that in PQ group, and the BMSCs-SOD group showed most obvious (all P<0.05) . Lung biopsy showed that, the degree of lung tissue damage in each therapy group obviously reduced.SOD is the key factor of the removal of reactive oxygen species (ROS) in cells, that can obviously inhibit the oxidative stress damage and the apoptosis induced by PQ, thus significantly increasing alveolar epithelial cell ability to fight outside harmful environment.	0
Germline missense mutations in GJB2 encoding connexin (Cx) 26 have been found in keratitis, ichthyosis and deafness (KID) syndrome. We explored the effects of three mouse Cx26 mutants (Cx26-G12R, -G45E and -D50N) corresponding to KID syndrome-causative human mutants on hemichannel activities leading to cell death and the expression of immune response-associated genes. We analyzed the 3D images of cells expressing wild-type (WT) or mutant Cx26 molecules to demonstrate clearly the intracellular localization of Cx26 mutants and hemichannel formation. High extracellular Ca2+ conditions lead to the closure of gap junction hemichannels in Cx26-G12R or Cx26-G45E expressing cells, resulting in prohibition of the Cx26 mutant-induced cell death. Fluorescent dye uptake assays revealed that cells with Cx26-D50N had aberrantly high hemichannel activities, which were abolished by a hemichannel blocker, carbenoxolone and 18α-Glycyrrhetinic acid. These results further support the idea that abnormal hemichannel activities play important roles in the pathogenesis of KID syndrome. Furthermore, we revealed that the expressions of IL15, CCL5, IL1A, IL23R and TLR5 are down-regulated in keratinocytes expressing Cx26-D50N, suggesting that immune deficiency in KID syndrome expressing Cx26-D50N might be associated not only with skin barrier defects, but also with the down-regulated expression of immune response-related genes.	0
The presence of Mallory-Weiss syndrome (MWS) in patients with small-cell lung cancer (SCLC) is uncommon. MWS is characterized by longitudinal superficial mucosal laceration at the esophagogastric junction and can be caused by a variety of causes, with upper digestive tract hemorrhage as the primary manifestation. SCLC is the most invasive histological subtype of lung cancer, and approximately a quarter of all SCLC patients undergo paraneoplastic syndrome of inappropriate antidiuretic hormone secretion, such as hyponatremia. In this study, we report a case of MWS in a middle-aged patient who was diagnosed with SCLC associated with hyponatremia. Clinicians should be alerted of the presence of MWS in upper gastrointestinal bleeding, such as epigastric pain, hematemesis, or melena, and keep SCLC in mind as a potential cause for underlying disease identification.	0
DYT-THAP1 dystonia is known to present a variety of clinical symptoms. To the best of our knowledge, this is the first case with DYT-THAP 1 dystonia and clinical signs of cerebellar involvement studied with transcranial magnetic stimulation in vivo. We report a case of a 51-year-old male DYT-THAP1 mutation carrier with dystonia, who additionally developed ataxia 1.5 years ago. To study cerebellar involvement in our patient, we used a TMS protocol called cerebellar inhibition (CBI). The lack of CBI in our patient strongly suggests cerebellar involvement. According to our findings, cerebellar syndrome may be part of the phenotypical spectrum of DYT-THAP1 mutations.	0
Human herpes virus 6 (HHV-6) infections are frequently detected in patients with immunosuppressed transplant; however, reactivation in an immunocompetent patient is rarely reported. The author reports the case of a 65-year-old woman presenting with status epilepticus with foci in the temporal and occipital lobe and MRI suggestive of encephalitis in the parietal, occipital and temporal regions. The cerebrospinal fluid (CSF) analysis showed normal cell counts, protein and glucose levels and hence viral aetiologies were considered. The patient's workup returned positive for HHV-6 in serum as well as CSF. The patient responded well to a 21-day course of antivirals with complete resolution of her symptoms. This case highlights the importance of considering HHV-6 encephalitis even among immunocompetent patients presenting with encephalitis and having signs of temporal lobe involvement.	0
Talimogene laherparepvec (T-VEC) is an oncolytic virus, approved for the treatment of stage IIIb-IVM1a melanoma with injectable disease (cutaneous, subcutaneous or lymphatic). It is a modified herpes simplex virus type 1 that induces tumor-specific T-cell responses via reduction of virally mediated suppression of antigen presentation, stimulation of viral pathogenicity and enhancement of tumor-selective replication. Response rates up to 82.6% have been reported for stage III disease. Acral lentiginous melanoma (ALM) is a rare subtype of melanoma with a poor prognosis. Here, we present a case of an elderly and frail patient with primary ALM who refused surgical treatment and consented to receive T-VEC as first-line drug therapy. After 10 courses of treatment, a histopathologically confirmed complete response was achieved. To our knowledge, this is the first case ever reported in which a primary ALM is (successfully) treated with T-VEC.	0
Venous cystic adventitial disease (CAD) is an uncommon vascular anomaly that most frequently affects the common femoral vein. Transluminal or transadventitial evacuation followed by cyst excision is considered an effective treatment for this condition, although the recurrence rate is relatively high. Herein, we report a case of a 59-year-old man with venous CAD that was successfully treated with saphenous vein patch angioplasty after mucoid evacuation and cyst excision, and we discuss the options for treating venous CAD.	0
The ridged skin of the palms and soles has several unique features: (i) presence of dermatoglyphics created by alternating ridges and grooves forming a unique pattern, (ii) presence of the highest density of eccrine sweat glands and absence of pilosebaceous units, and (iii) differential expression of keratins compared to the glabrous skin. These features explain the preferential localization of palmoplantar keratoderma (PPK) and several of its characteristic clinical features. PPK develops as a compensatory hyperproliferation of the epidermis and excessive production of stratum corneum in response to altered cornification of the palmoplantar skin due to mutations in the genes encoding several of the proteins involved in it. PPK can manifest as diffuse, focal, striate, or punctate forms per se or as a feature of several dermatological or systemic diseases. There is a wide genetic and phenotypic heterogeneity in hereditary PPK, due to which reaching an accurate diagnosis only on the basis of clinical features may be sometimes challenging for the clinicians in the absence of molecular studies. Nevertheless, recognizing the clinical patterns of keratoderma, extent of involvement, degree of mutilation, and associated appendageal and systemic involvement may help in delineating different forms. Molecular studies, despite high cost, are imperative for accurate classification, recognizing clinical patterns in resource poor settings is important for appropriate diagnosis, genetic counseling, and management. This review intends to develop a practical approach for clinical diagnosis of different types of hereditary PPK with reasonable accuracy.	0
Chromosomal microarray (CMA) is now recommended as first tier for the evaluation in individuals with unexplained neurodevelopmental disorders (ND). However, in developing countries such as Brazil, classical cytogenetic tests are still the most used in clinical practice, as reflected by the scarcity of publications of microarray investigation in larger cohorts. This is a retrospective study which analyses the reading files of CMA and available clinical data from 420 patients from the south of Brazil, mostly children, with neurodevelopmental disorders requested by medical geneticists and neurologists for diagnostic purpose. Previous karyotyping was reported for 138 and includes 17 with abnormal results. The platforms used for CMA were CYTOSCAN 750K (75%) and CYTOSCAN HD (25%). The sex ratio of the patients was 1.625 males :1 female and the mean age was 9.5 years. A total of 96 pathogenic copy number variations (CNVs), 58 deletions and 38 duplications, were found in 18% of the patients and in all chromosomes, except chromosome 11. For 12% of the patients only variants of uncertain clinical significance were found. No clinically relevant CNV was found in 70%. The main referrals for chromosomal microarrays (CMA) were developmental delay (DD), intellectual disability (ID), facial dysmorphism and autism spectrum disorder (ASD). DD/ID were present in 80%, facial dysmorphism in 52% and ASD in 32%. Some phenotypes in this population could be predictive of a higher probability to carry a pathogenic CNV, as follows: dysmorphic facial features (p-value = < 0.0001, OR = 0.32), obesity (p-value = 0.006, OR = 0.20), short stature (p-value = 0.032, OR = 0.44), genitourinary anomalies (p-value = 0.032, OR = 0.63) and ASD (p-value = 0.039, OR = 1.94). The diagnostic rate for CMA in this study was 18%. We present the largest report of CMA data in a cohort with ND in Brazil. We characterize the rare CNVs found together with the main phenotypes presented by each patient, list phenotypes which could predict a higher diagnostic probability by CMA in patients with a neurodevelopmental disorder and show how CMA and classical karyotyping results are complementary.	0
BACKGROUND:Teratoma is a germ cell tumor that develops gonadal or extragonadal. Benign or malign somatic tumors can develop in teratoma. Choroid plexus papilloma is a benign, grade I intraventricular neoplasm that occur mostly in children. Choroid plexus papilloma in a teratoma is not often seen. CASE:We present the fifth case of a choroid plexus papilloma in a teratoma in the English literature. It was extragonadal and localized on the right side of the neck. It included only neuroglial tissue. CONCLUSION:It is important to separate a teratoma with normal choroid plexus from a teratoma with choroid plexus tumor. Pathologists need to be aware of this entity in the distinction from other papillary neoplasms that may be primary or metastatic.	0
FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.	0
A family is reported with nail dysplasia and/or absent nails, long and broad finger-like thumbs, camptodactyly and absent fingers. Radiological studies revealed hypoplasia of metacarpals, metatarsals and distal phalanges. Two affected individuals have absent metacarpals and phalanges. The clinical and radiological features may constitute a distinct syndrome of autosomal dominant onychodystrophy and anonychia with Julia Bell brachydactyly type B.	0
Ovarian remnant syndrome (ORS), in which a portion of the ovary is retained following bilateral salpingo-oophorectomy (BSO), is uncommon but can negatively impact patient management. Evaluation should be performed in a patient who has clinical signs or symptoms suggestive of ORS, especially in a premenopausal woman with breast cancer who is treated with an aromatase inhibitor following bilateral salpingo-oophorectomy (BSO), or a woman with a pathogenic variant in BRCA1 or BRCA2 who undergoes BSO for ovarian cancer risk reduction.	0
Two unrelated children were born with severe congenital malformations: a girl now seven years old and a boy who died in the newborn period. Both had severe cervical hyperextension, severe flexion deformities of the limbs, and bilateral popliteal pterygia. Postmortem examination of the second case showed small, well-formed thoracic vertebrae with mild epidural fibrosis and hemorrhage. These births defects are rare and usually occur separately. We postulate that they are related in these two cases; that the arthrogryposis and popliteal pterygia were probably the result of the spondylohypoplasia and associated changes; and that together, these related defects may constitute a new malformation complex.	0
Centronuclear myopathy (CNM) is an inherited neuromuscular disorder characterised by clinical features of a congenital myopathy and centrally placed nuclei on muscle biopsy.The incidence of X-linked myotubular myopathy is estimated at 2/100000 male births but epidemiological data for other forms are not currently available.The clinical picture is highly variable. The X-linked form usually gives rise to a severe phenotype in males presenting at birth with marked weakness and hypotonia, external ophthalmoplegia and respiratory failure. Signs of antenatal onset comprise reduced foetal movements, polyhydramnios and thinning of the ribs on chest radiographs; birth asphyxia may be the present. Affected infants are often macrosomic, with length above the 90th centile and large head circumference. Testes are frequently undescended. Both autosomal-recessive (AR) and autosomal-dominant (AD) forms differ from the X-linked form regarding age at onset, severity, clinical characteristics and prognosis. In general, AD forms have a later onset and milder course than the X-linked form, and the AR form is intermediate in both respects.Mutations in the myotubularin (MTM1) gene on chromosome Xq28 have been identified in the majority of patients with the X-linked recessive form, whilst AD and AR forms have been associated with mutations in the dynamin 2 (DNM2) gene on chromosome 19p13.2 and the amphiphysin 2 (BIN1) gene on chromosome 2q14, respectively. Single cases with features of CNM have been associated with mutations in the skeletal muscle ryanodine receptor (RYR1) and the hJUMPY (MTMR14) genes.Diagnosis is based on typical histopathological findings on muscle biopsy in combination with suggestive clinical features; muscle magnetic resonance imaging may complement clinical assessment and inform genetic testing in cases with equivocal features. Genetic counselling should be offered to all patients and families in whom a diagnosis of CNM has been made.The main differential diagnoses include congenital myotonic dystrophy and other conditions with severe neonatal hypotonia.Management of CNM is mainly supportive, based on a multidisciplinary approach. Whereas the X-linked form due to MTM1 mutations is often fatal in infancy, dominant forms due to DNM2 mutations and some cases of the recessive BIN1-related form appear to be associated with an overall more favourable prognosis.	1
A 32-year-old patient presented with presenile dementia syndrome and complex-partial seizures. The dementia was preceded by recurrent bone pain which led to surgical intervention for ossear cysts. Computed tomography revealed intracerebral calcification and marked brain atrophy. Clinical, radiological, genetic, and histopathological features of PLOSL disease are discussed in the differential diagnosis of presenile dementia and basal ganglia calcification.	0
X-linked myopathy with excessive autophagy (XMEA), caused by mutations of the VMA21 gene, is a strictly skeletal muscle disease. Extensive studies in yeast established VMA21 as the master assembly chaperone of V-ATPase, the complex multisubunit proton pump that acidifies organelles and that is vital to all mammalian tissues. As such, skeletal muscle disease exclusivity in XMEA is highly surprising. We now show that the severest VMA21 mutation, c.164-6t>g, does result in XMEA-typical pathology with autophagic vacuolar changes outside skeletal muscle, namely in the heart. However, even patients with this mutation do not exhibit clinical extramuscular disease, including cardiac disease, despite extreme skeletal muscle wasting to the extent of ventilation dependence. Uncovering the unique skeletal muscle vulnerability to defective organellar acidification, and resultant tissue-destructive excessive autophagy, will be informative to the understanding of muscle physiology. Alternatively, understanding extramuscular resistance to VMA21 mutation might disclose heretofore unknown mammalian V-ATPase assembly chaperones other than VMA21.	0
Measurement of the optic nerve diameter by echographic technique has been performed in 40 patients with intracranial hypertension syndromes of various origin. In all the cases examined the diameter was always increased. Postoperative checks revealed a decrease of the nerve thickness until it reached the normal values. The changes in the optic nerve diameter reflect the variations of the intracranial pressure and they appear earlier than any changes in the fundus oculi. This simple and non-invasive echographic technique is very useful in following patients with an intracranial hypertension syndrome.	0
Human African trypanosomiasis, or sleeping sickness, is caused by infection with parasites of the genus Trypanosoma, transmitted by the tsetse fly. The disease has two forms, Trypanosoma brucei (T b) rhodesiense and T b gambiense; and is almost always fatal if untreated. Despite a recent reduction in the number of reported cases, patients with African trypanosomiasis continue to present major challenges to clinicians. Because treatment for CNS-stage disease can be very toxic, diagnostic staging to distinguish early-stage from late-stage disease when the CNS in invaded is crucial but remains problematic. Melarsoprol is the only available treatment for late-stage T b rhodesiense infection, but can be lethal to 5% of patients owing to post-treatment reactive encephalopathy. Eflornithine combined with nifurtimox is the first-line treatment for late-stage T b gambiense. New drugs are in the pipeline for treatment of CNS human African trypanosomiasis, giving rise to cautious optimism.	1
BACKGROUND:Isolated sulfite oxidase deficiency (ISOD) is a rare autosomal recessively inherited inborn error of metabolism, caused by mutation in SUOX gene. ISOD has two kind of presentation; early and late-onset. The late-onset form is extremely rare and only 10 cases have been reported. METHODS:We report two new cases of late-onset ISOD with biochemical and genetic confirmation. We did a review of the previously published cases of late-onset ISOD. RESULTS:Together with the presented two cases, 12 cases were available for analysis. The median age at symptom onset and at diagnosis was 8.5 and 23 months respectively. Almost all children had acute regression of milestones followed by slow recovery. The common presenting signs and symptoms were movement disorders, seizures, ectopia lentis and hypertonia. Five children had antecedent events. Trivial trauma precipitating the metabolic crisis was unique to the two cases we report. The most common MRI feature was globus pallidi changes followed by cerebellar white matter changes, vermian hypoplasia and thinned out corpus callosum. Diffusion weighted sequence was performed in 3 children and all had diffusion restriction in the affected area. CONCLUSION:Trivial trauma can precipitate metabolic crisis in late-onset ISOD. Low plasma homocysteine and involvement of globus pallidi with diffusion restriction on the MRI are important diagnostic clues. Early diagnosis and intervention with special diet may be effective in preventing long term neurodisability.	0
Esophagitis dissecans superficialis (EDS), also known as sloughing esophagitis, is a very rare condition and may affect the whole esophagus, resulting in complete sloughing of the mucous membrane. EDS has been associated with various medications and dermatological conditions. In our case, EDS was suspected secondary to methotrexate treatment in a patient with Crohn's disease, although the definitive etiology remains unknown. It is very important for physicians to recognize the endoscopic appearance of EDS to provide appropriate clinical management and differentiate it from other esophageal disorders.	0
Forty five patients (23 boys and 22 girls) with elective mutism (8.7 +/- 3.6 years old), who were referred to a university department and a child guidance clinic within a 15-year-period, were followed up on average 12 years later. For 41 of them, sufficient information could be obtained at follow-up, and 31 patients could be investigated personally. At follow-up, an interview and a standardized psychopathological examination were carried out as well as two standardized biographic inventories. The main results were: 1) a high load of individual and family psychopathology was characteristic of the patients. The disorder started already at age 3 to 4 and referral age was 8 years on average. 2) In 16 out of 41 patients (39%), a complete remission could be observed. All other patients still revealed some communication problems. 3) The formerly mute patients described themselves as less independent, less motivated with regard to school achievement, less self-confident and less mature and healthy in comparison to a normal reference group. 4) A poor outcome could be best predicted by the variable "mutism within the core family"at the time of referral.	0
BACKGROUND:Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy (TMA) with significant morbidity and mortality. Guidelines recommend initiating plasma exchange within 4-8 h of suspected diagnosis. It is unclear what are real-world practice patterns and whether delays >8 h increases mortality. OBJECTIVES:To determine if delayed initiation of plasma exchange is associated with increased risk of death and complications. METHODS:In this retrospective cohort study, we evaluated the time from suspected diagnosis to plasma exchange in all adults presenting with suspected TTP to apheresis centres in Alberta, Canada (2008-2018). Among patients with acquired TTP, the association between delayed plasma exchange and risk of death was evaluated using Cox regression. RESULTS:Overall 190 episodes of suspected TTP were included among 163 individuals. Acquired TTP was confirmed in 61 patients. Inappropriate Emergency Department triage occurred in 59%. The median time from suspected diagnosis to first plasma exchange was 10.7 h; 59% had delayed plasma exchange >8 h, among whom plasma infusion was administered in only 45%. 36% of suspected TTP and 13% of confirmed TTP patients died. Delayed plasma exchange between 8 and 24 h was not associated with a significantly higher risk of death (adjusted hazards ratio; aHR 0.63, 95% CI 0.08-4.83) in confirmed TTP. On the other hand, the risks of death (aHR 1.40, 95% CI 0.20-9.79) and major thrombotic events (aHR 2.9, 95% CI 0.6-12.8) were markedly increased with >24 h delay. CONCLUSIONS:Our study demonstrated that TTP care in a real-world setting is discordant with expert guidelines due to multiple barriers. There is a gradient of increased mortality risk and thrombotic complications with longer treatment delays, although the study is likely underpowered.	0
PURPOSE:To review and discuss current innovations and future implications of promising biotechnology and biomedical offerings in the field of retina. We focus on therapies that have already emerged as clinical offerings or are poised to do so. METHODS:Literature review and commentary focusing on stem cell therapies, gene-based therapies, optogenetic therapies, and retinal prosthetic devices. RESULTS:The technologies discussed herein are some of the more recent promising biotechnology and biomedical developments within the field of retina. Retinal prosthetic devices and gene-based therapies both have an FDA-approved product for ophthalmology, and many other offerings (including optogenetics) are in the pipeline. Stem cell therapies offer personalized medicine through novel regenerative mechanisms but entail complex ethical and reimbursement challenges. CONCLUSION:Stem cell therapies, gene-based therapies, optogenetics, and retinal prosthetic devices represent a new era of biotechnological and biomedical progress. These bring new ethical, regulatory, care delivery, and reimbursement challenges. By addressing these issues proactively, we may accelerate delivery of care to patients in a safe, efficient, and value-based manner.	0
STUDY DESIGN:Retrospective analysis. OBJECTIVE:To evaluate conditional survival after surgical resection for spinal chondrosarcoma patients. SUMMARY OF BACKGROUND DATA:Survival estimates are usually reported as survival from the time of surgery, but survival probabilities can change over time. Conditional survival, which is a measure of prognosis for patients who have survived a defined period of time, may be more clinically precise and relevant. However, data on conditional survival for spinal chondrosarcoma patients after surgical resection are still lacking. METHODS:We used the Surveillance, Epidemiology, and End Results (SEER) database to identify 436 spinal chondrosarcoma patients who underwent surgical resection from 1994 and 2013. Kaplan-Meier analyses and Cox regression modeling were performed to evaluate prognostic factors associated with overall survival. Five-year conditional survival (i.e., probability of surviving an additional 5 years, given that a patient has already survived x years) was calculated as 5-CS(x) = OS(x+5)/OS(x). The effect of prognostic factors on conditional survival was also explored. RESULTS:Four hundred thirty six patients were included in the study cohort. Overall, 1-, 3-, and 5-year overall survival were 92.8%, 79.1%, and 70.3%, respectively. Five-year conditional survival at 1, 3, and 5 years after surgery were 72.9%, 79.0%, and 87.5%. The overall survival rates were lower in cases of age more than or equal to 60 years, male patient, dedifferentiated subtype, Grade III tumor, tumor size more than or equal to 10 cm, distant metastasis, and radiotherapy. Conditional survival improved over time in each subgroup divided by age, sex, race, year of diagnosis, grade, tumor size, extent of disease (EOD), and radiotherapy. In addition, patients with the least favorable prognosis at baseline experienced the greatest increase in 5-year conditional survival over time (e.g., Grade I/II: 78.0%-89.7%, Δ11.7% vs. Grade III: 36.5%-66.6%, Δ30.1%; Localized/Regional: 72.9%-88.1%, Δ15.2% vs. Distant: 43.5%-74.1%, Δ30.6%). CONCLUSION:Conditional survival for spinal chondrosarcoma patients after surgical resection improves over time, especially for patients with initial high-risk characteristics. Information derived from conditional survival analysis may provide individualized approaches to surveillance and treatment of spinal chondrosarcoma. LEVEL OF EVIDENCE:4.	0
Inborn errors of metabolism in adults are still largely unexplored. Despite the fact that adult-onset phenotypes have been known for many years, little attention is given to these disorders in neurological practice. The adult-onset presentation differs from childhood-onset phenotypes, often leading to considerable diagnostic delay. The identification of these patients at the earliest stage of disease is important, given that early treatment may prevent or lessen further brain damage. Neurological and psychiatric symptoms occur more frequently in adult forms. Abnormalities of eye movements are also common and can be the presenting sign. Eye movement disorders can be classified as central or peripheral. Central forms are frequently observed in lysosomal storage disorders, whereas peripheral forms are a key feature of mitochondrial disease. Furthermore, oculogyric crisis is an important feature in disorders affecting dopamine syntheses or transport. Ocular motor disorders are often not reported by the patient, and abnormalities can be easily overlooked in a general examination. In adults with unexplained psychiatric and neurological symptoms, a special focus on examination of eye movements can serve as a relatively simple clinical tool to detect a metabolic disorder. Eye movements can be easily quantified and analyzed with video-oculography, making them a valuable biomarker for following the natural course of disease or the response to therapies. Here, we review, for the first time, eye movement disorders that can occur in inborn errors of metabolism, with a focus on late-onset forms. We provide a step-by-step overview that will help clinicians to examine and interpret eye movement disorders. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.	0
Hyperammonemia is a typical symptom of urea cycle disorders. While early-onset argininosuccinic aciduria (ASA) can often be detected by hyperammonemia, patients with late-onset ASA predominantly present with psychomotor retardation and mental disorders. However, in late-onset ASA that develops during early childhood, hyperammonemia can sometimes be caused by acute infections, stress, and reduced dietary intake. Here, we report the case of a 14-year-old boy with late-onset ASA associated with hyperammonemia that was triggered by an influenza A infection. Due to the infection, he presented with a fever and was unable to eat food or take oral medication. He then experienced restlessness, a disturbance in his level of consciousness, and seizures. Hyperammonemia (3286 μg/dL, reference value ≤100 μg/dL) was detected. He was biochemically diagnosed with ASA based on increased serum and urinary argininosuccinic acid levels. Additionally, genetic testing revealed compound heterozygous mutations in the ASL gene: c.91G > A(p.Asp31Asn) and c.1251-1G > C. This case revealed that in late-onset ASA, hyperammonemia can occur not only in early childhood but also during adolescence. Late-onset ASA may have a very broad clinical spectrum that includes hyperammonemia. We suggest that urea cycle disorders such as ASA must be considered when patients present with hyperammonemic decompensation during adolescence.	0
BACKGROUND:Acute flaccid myelitis has emerged as the leading cause of acute flaccid paralysis in children. Acute flaccid myelitis leads to significant physical disability; hence, objective outcome measures to study disease severity and progression are desirable. In addition, nerve transfer to improve motor function in affected children needs further study. METHODS:Retrospective study of acute flaccid myelitis subjects managed at Children's Healthcare of Atlanta from August 2014 to December 2019. Clinical, electromyography and nerve conduction study, neuropsychological functional independence (WeeFIM), and nerve transfer data were reviewed. RESULTS:Fifteen children (11 boys and 4 girls) mean age 5.1±3.2 years (range 14 months to 12 years) were included. All subjects (n = 15) presented with severe asymmetric motor weakness and absent tendon reflexes. Motor nerve conduction study of the affected limbs in 93% (n = 14) showed absent or markedly reduced amplitude. Ten patients received comprehensive inpatient rehabilitation and neuropsychological evaluation. Admission and discharge WeeFIM scores showed deficits most consistent and pronounced in the domains of self-care and mobility. Multiple nerve transfer surgery was performed on 13 limbs (9 upper and 4 lower extremities) in 6 children. Postsurgery (mean duration of 10.4 ± 5.7 months) follow-up demonstrated improvement on active movement scale (AMS) in 4 subjects. CONCLUSION:Acute flaccid myelitis affects school-age children with asymmetric motor weakness, absent tendon reflexes, and reduced or absent motor amplitude on nerve conduction study. Comprehensive rehabilitation and nerve transfer led to improvement in motor function on neuropsychology WeeFIM and AMS scores.	0
Apert syndrome was studied to determine birth prevalence, mutation rate, sex ratio, parents' age, and ethnicity among 2,493,331 live births registered in the California Birth Defects Monitoring Program (CBDMP) from 1983 through 1993; 31 affected infants were identified. The sample was completed with an additional 22 cases from the Center for Craniofacial Anomalies (CCA), University of California, San Francisco, for a total of 53 affected children. Birth prevalence, calculated from the CBDMP subsample, was 12.4 cases per million live births (confidence interval [CI] 8.6,17.9). The calculated mutation rate was 6.2 x 10(-6) per gene per generation. Asians had the highest prevalence (22.3 per million live births; CI 7.1,61.3) and Hispanics the lowest (7.6 per million, CI 3.3-16.4). In the large population-based CBDMP subsample, there was an almost equal number of affected males and females, (sex ratio 0.94) but in the clinical CCA subsample, there were more affected females (sex ratio 0.79). For all cases, the mean age of mothers was 28.9+/-6.0 years, and of fathers was 34.1+/-6.2 years. Almost half of fathers were older than 35 years when the child was born; for more than 20% of cases, both parents were older than 35 years. These findings may support the view that point mutations appear to be more commonly associated with paternal than with maternal alleles. Representing the largest systematically ascertained population-based study of Apert syndrome to date, they provide a reliable basis for genetic counseling and decision-making, and for focused research to define the cause of this syndrome.	1
BACKGROUND:Congenital symmetric circumferential skin creases (CSCSC) was initially described five decades ago. Exome sequencing has recently revealed the genetic etiology of CSCSC. Pathogenic variants in TUBB (OMIM# 191130) and MAPRE2 (OMIM# 605789) have been linked to CSCSC1 (OMIM# 156610) and CSCSC2 (OMIM# 616734), respectively, in an autosomal dominant manner. Four pathogenic variants in MAPRE2 have been previously reported to be associated with CSCSC2. METHODS:Whole-exome sequencing (WES) has been performed and an in-house pipeline was used to conduct a phenotype-driven data analysis. All candidate variants were confirmed by Sanger sequencing. RESULTS:Here we report a 2-year-old boy characterized by absent expressive speech, normal to mild over growth, facial dysmorphic features, remarkable circumferential skin creases on both forearms and ankles. WES disclosed a de novo missense MAPRE2 variant, c.518G>A (p.Arg173Gln), as the molecular cause of this complex phenotype. We described detailed clinical characterization of this patient and compared the available clinical data of individuals with MAPRE2 variants to demonstrate the phenotypic spectrum. CONCLUSION:Our study reports the first patient of Asian origin with CSCSC2 due to a pathogenic mutation of MAPRE2 and expands the clinical and genetic spectrum of CSCSC2.	0
Posterior cranial vault distraction osteogenesis (PVDO) is evolving as one of the first-line treatments in managing craniosynostosis. Intraoperative decision for sites of osteotomies requires precise planning and accurate placement of distractors. OBJECTIVE:This technique helps in determining and confirming the pre-surgical planned osteotomy sites along with the distraction vectors. TECHNIQUE:intraoperative plain skull radiography is used to determine the osteotomy site guiding placement of distractors using radio-opaque instrument. RESULT AND DISCUSSION:we believe this technique helps translate the planned osteotomy sites and distraction vectors accurately to the skull and minimizes intra-operative error which will subsequently improve outcomes. CONCLUSION:This technique is a quick and safe tool for proper placement of posterior cranial vault distractor. However, further comparative studies are needed in addition to measuring cost, time added to the procedure, and radiation exposure.	0
Background:Musculoskeletal symptoms are a presenting manifestation in a number of lymphoproliferative disorders including leukemia, especially in children. Among these primary symptoms, midfoot arthritis seems to be an important alarm for malignancy in children. The aim of this study is evaluation association of midfoot arthritis with malignancy in children. Method:In this cross-sectional study, all medical records of patients with arthritis were identified and reviewed. All clinical and laboratory data were recorded in the information form and data were analyzed by SPSS 25 software. Results:A total of 557 cases of arthritis were evaluated, of which 18 (3.2%) cases have primary symptoms of midfoot arthritis. Four of 18 patients (22.2%) had B-cell precursor acute lymphoblastic leukemia, that midfoot arthritis was their first manifestation. Also, their laboratory findings confirmed that platelet, lactic acid dehydrogenesis, and uric acid values were significantly higher in these children. Based on statistical evaluation, there was no significant difference between age and sex in these patients. Conclusion:According to the findings of the present study, it can be concluded that "midfoot arthritis" may be the first manifestation of leukemia in children even with a near-normal hematologic values.	0
Ataxia is the absence of voluntary muscle coordination and loss of control of movement that affects gait stability, eye movement, and speech. Spinocerebellar ataxia (SCA) is an inherited (autosomal dominant), progressive, neurodegenerative, and heterogeneous disease that mainly affects the cerebellum. SCA is a subset of hereditary cerebellar ataxia and is a rare disease. To date, more than 40 distinct genetic SCAs have been identified which are classified according to the genetic loci in order of identification. SCA1 was the first SCA described and then further subtypes are identified sequentially. SCA doesn't compulsorily mean that it is restricted to the cerebellum and spinal cord. It may involve the other parts of the central nervous system as well, such as pontine nuclei, spinal cord, peripheral nerves, cortex, basal ganglia, etc. SCA6 is restricted to the cerebellum whereas SCA2 spares cerebellum.[1] Well defined and common types are SCA1, SCA2, SCA3, and SCA6 which accounts for more than half of cases and other rare variants constitute the remaining cases.[1][2] SCA is very complex to understand both genotypically and phenotypically and very difficult to describe all variants at one time. 	0
Pilomatrixoma is a uncommon benign neoplasm of hair matrix origin, with usual occurrence in the head and neck region. It has bimodal age of occurrence, first peek is seen in children and the second in elderly in sixth decade. In this case, we report a case of a young boy presenting with midline neck swelling with differential diagnosis of sebaceous cyst, thyroglossal cyst or dermoid cyst. Definitive diagnosis was not made until the final histopathology report was available after complete excision. Accurate diagnosis and appropriate treatment is essential to obviate the minimal risk of recurrence or very rare malignant transformation. A high index of suspicion is required to diagnose this tumor, especially in unusual locations as in this case.	0
Aicardi-Goutières syndrome (Mendelian inheritance in man Catalog No *225750) is an autosomal recessive encephalopathy which causes developmental arrest, intracerebral calcification, and white matter disease in the presence of chronic cerebrospinal fluid lymphocytosis, and a raised level of cerebrospinal fluid interferon-alpha (IFN-alpha). Diagnosis requires the presence of progressive encephalopathy with onset shortly after birth, and characteristic clinical neurological and neuroimaging signs together with chronic CSF lymphocytosis. The syndrome has superficial resemblance to the neurological sequelae of congenital infection, thus a rigorous search for microbiological and serological evidence of embryopathic infections should be carried out in each case.	0
WAC (WW Domain Containing Adaptor With Coiled-Coil) mutations have been reported in only 20 individuals presenting a neurodevelopmental disorder characterized by intellectual disability, neonatal hypotonia, behavioral problems, and mildly dysmorphic features. Using targeted deep sequencing, we screened a cohort of 630 individuals with variable degrees of intellectual disability and identified five WAC rare variants: two variants were inherited from healthy parents; two previously reported de novo mutations, c.1661_1664del (p.Ser554*) and c.374C>A (p.Ser125*); and a novel c.381+2T>C variant causing the skipping of exon 4 of the gene, inherited from a reportedly asymptomatic father with somatic mosaicism. A phenotypic evaluation of this individual evidenced areas of cognitive and behavioral deficits. The patient carrying the novel splicing mutation had a clinical history of encephalopathy related to status epilepticus during slow sleep (ESES), recently reported in another WAC individual. This first report of a WAC somatic mosaic remarks the contribution of mosaicism in the etiology of neurodevelopmental and neuropsychiatric disorders. We summarized the clinical data of reported individuals with WAC pathogenic mutations, which together with our findings, allowed for the expansion of the phenotypic spectrum of WAC-related disorders.	0
Noonan and LEOPARD syndromes (NS and LS) belong to a group of related disorders called RASopathies characterized by abnormalities of multiple organs and systems including hypertrophic cardiomyopathy and dysmorphic facial features. There are no approved drugs for these two rare diseases, but it is known that a missense mutation in PTPN11 genes is associated with approximately 50% and 70% of NS and LS cases, respectively. In this study, we implemented a hybrid computational drug repositioning framework by integrating transcriptomic and structure-based approaches to explore potential treatment options for NS and LS. Specifically, disease signatures were derived from the transcriptomic profiles of human induced pluripotent stem cells (iPSCs) from NS and LS patients and reverse correlated to drug transcriptomic signatures from CMap and L1000 projects on the basis that if disease and drug transcriptomic signatures are reversely correlated, the drug has the potential to treat that disease. The compounds that were ranked top based on their transcriptomic profiles were docked to mutated and wild-type 3D structures of PTPN11 by an adjusted Induced Fit Docking (IFD) protocol. In addition, we prioritized repositioned candidates for NS and LS by a consensus ranking strategy. Network analysis and phenotypic anchoring of the transcriptomic data could discriminate the two diseases at the molecular level. Furthermore, the adjusted IFD protocol was able to recapitulate the binding specificity of potential drug candidates to mutated 3D structures, revealing the relevant amino acids. Importantly, a list of potential drug candidates for repositioning was identified including 61 for NS and 43 for LS and was further verified from literature reports and on-going clinical trials. Altogether, this hybrid computational drug repositioning approach has highlighted a number of drug candidates for NS and LS and could be applied to identifying drug candidates for other diseases as well.	0
BACKGROUND: Recently, array-comparative genomic hybridization (aCGH) platforms have significantly improved the resolution of chromosomal analysis allowing the identification of genomic copy number gains and losses smaller than 5 Mb. Here we report on a young man with unexplained severe mental retardation, autism spectrum disorder, congenital malformations comprising hypospadia and omphalocele, and episodes of high blood pressure. An ~ 6 Mb interstitial deletion that includes the causative genes is identified by oligonucleotide-based aCGH. RESULTS: Our index case exhibited a de novo chromosomal abnormality at 2q22 [del(2)(q22.1q22.3)dn] which was not visible at the 550 haploid band level. The deleted region includes eight genes: HNMT, SPOPL, NXPH2, LOC64702, LRP1B, KYNU, ARHGAP15 and GTDC1. DISCUSSION: aCGH revealed an ~ 6 Mb deletion in 2q22.1 to 2q22.3 in an as-yet unique clinical case associated with intellectual disability, congenital malformations and autism spectrum disorder. Interestingly, the deletion is co-localized with a fragile site (FRA2K), which could be involved in the formation of this chromosomal aberration. Further studies are needed to determine if deletions of 2q22.1 to 2q22.3 define a new microdeletion syndrome.	0
Localized hypertrophic neuropathy (LHN) of the sciatic nerve in children is a rare condition characterized by a painless neurological deficit in the sciatic nerve territory.To demonstrate the role of MRI using a specific protocol and describe the primary findings in LHN.Imaging in four children (age 2 years to 12 years) is presented. All children presented with lower limb asymmetry. Three had a steppage gait. LHN was confirmed by electrophysiological studies and by MRI of the whole sciatic nerve with a dedicated protocol covering the lumbar spine and the lower limb.There were four direct MRI findings: (1) linear and focal hypertrophy with progressive enlargement of a peripheral nerve or plexus diameter, (2) abnormal hyperintensity of the nerve on T2-weighted images, (3) preserved fascicular configuration, and (4) variable enhancement after intravenous gadolinium administration. In addition there were atrophy and fatty infiltration of innervated muscles. MRI was helpful for determining the extent of lesions and in excluding peripheral nerve compression or tumour.MRI of the whole sciatic nerve is the method of choice for diagnosing LHN of the sciatic nerve.	0
OBJECTIVES:Mothers of school age and older children with developmental disabilities experience poorer health than mothers of typically developing children. This review assesses the evidence for the effect on mothers' health of caring for young children with developmental disabilities, and the influence of different disability diagnoses and socioeconomic status. METHODS:Medline, EMBASE, PsycINFO and CINAHL were searched. Studies measuring at least one symptom, using a quantitative scale, in mothers of preschool children (0-5 years) with and without a diagnosed developmental disability were selected. Random effects meta-analysis was performed, and predictive intervals reported due to high expected heterogeneity. RESULTS:The meta-analysis included 23 estimates of association from 14 retrospective studies for the outcomes of stress (n = 11), depressive symptoms (n = 9), general health (n = 2) and fatigue (n = 1). Caring for a child with a developmental disability was associated with greater ill health (standardised mean difference 0.87; 95% predictive interval - 0.47, 2.22). The largest association was for mixed developmental disabilities (1.36; - 0.64, 3.36) and smallest for Down syndrome (0.38; - 2.17, 2.92). There was insufficient socioeconomic information to perform subgroup analysis. The small number of studies and data heterogeneity limited the precision of the estimates of association and generalizability of the findings. CONCLUSIONS FOR PRACTICE:Mothers of young children with developmental disabilities may have poorer health than those with typically developing children. Research is needed to identify whether the relationship is causal and, if so, interventions that could reduce the negative effect of caregiving.	0
Mevalonate kinase deficiency or hyper-IgD syndrome is a hereditary autoinflammatory syndrome caused by mutations in the mevalonate kinase gene. In this review, we will discuss new findings in this disorder that have been published in the last 2 years. This includes new insights into pathophysiology, treatment, and the clinical phenotype linked to the genetic defect.	0
Charcot-Marie-Tooth disease (CMT) is the most common peripheral neuromuscular disorder worldwide. The axonal degeneration in CMT causes distal muscle weakness and atrophy, resulting in gait problems and difficulties with basic motor coordination skills. A mutation in the cytoplasmic dynein heavy chain (DHC) gene was discovered to cause an autosomal dominant form of the disease designated Charcot-Marie-Tooth type 2O disease (CMT2O) in 2011. The mutation is a single amino acid change of histidine into arginine at amino acid 306 (H306R) in DHC. We previously generated a knock-in mouse carrying the corresponding CMT2O mutation (H304R) and examined the heterozygous H304R/+offspring in a variety of motor skills and histological assays. Here we report the initial characterization of the homozygous H304R/R mouse, which is the first homozygous mutant DHC mouse to survive past the neonatal stage. We show that H304R/R mice have significantly more severe disease symptoms than the heterozygous H304R/+mice. The H304R/R mice have significant defects in motor skills, including grip strength, motor coordination, and gait and also related defects in neuromuscular junction architecture. Furthermore, the mice have defects in sensation, another aspect of CMT disease. Our results show that the H304R/+ and H304R/R mice will be important models for studying the onset and progression of both heterozygous and homozygous CMT disease alleles.	0
Raine Syndrome (RS) is caused by biallelic loss-of-function mutations in FAM20C gene and characterized by hypophosphatemia, typical facial and skeletal features. Subperiosteal bone formation and generalized osteosclerosis are the most common radiological findings. Here we present a new case with RS. A 9-month-old male patient on a home-type ventilator was referred for hypophosphatemia. He was born with a weight of 3800 g to non-consanguineous parents. Prenatal ultrasound had demonstrated nasal bone agenesis. A large anterior fontanel, frontal bossing, exophthalmos, hypoplastic nose, high arched palate, low set ears, triangular mouth, and corneal opacification were detected on physical examination. Serial skeletal X-rays revealed diffuse osteosclerosis at birth which was gradually decreased by the age of 5 months with subperiosteal undermineralized bone formation and medullary space of long bone could be distinguishable with bone-within-a-bone appearance. At 9 months of age, hand X-ray revealed cupping of the ulna with loose radial bone margin with minimal fraying and osteopenia. Cranial computed tomography scan showed bilateral periventricular calcification and hydrocephalus in progress. The clinical, laboratory, and radiological examinations were consistent with RS. Molecular analyses revealed a compound heterozygous mutation in FAM20C gene (a known pathogenic mutation, c.1645C > T, p.Arg549Trp; and a novel c.863 + 5 G > C variant). The patient died due to respiratory failure at 17 months of age. This case allowed us to demonstrate natural progression of skeletal features in RS. Furthermore, we have described a novel FAM20C variant causing RS. Previous literature on RS is also reviewed.	0
Cantú syndrome (CS) is a rare developmental disorder characterized by a coarse facial appearance, macrocephaly, hypertrichosis, skeletal and cardiovascular anomalies and caused by heterozygous gain-of-function variants in ABCC9 and KCNJ8, encoding heterooctameric ATP-sensitive potassium (KATP) channels. CS shows considerable clinical overlap with Zimmermann-Laband syndrome (ZLS), a rare condition with coarse facial features, hypertrichosis, gingival overgrowth, intellectual disability of variable degree, and hypoplasia or aplasia of terminal phalanges and/or nails. ZLS is caused by heterozygous gain-of-function variants in KCNH1 or KCNN3, and gain-of-function KCNK4 variants underlie the clinically similar FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth) syndrome; KCNH1, KCNN3 and KCNK4 encode potassium channels. Within our research project on ZLS, we performed targeted Sanger sequencing of ABCC9 in 15 individuals tested negative for a mutation in the ZLS-associated genes and found two individuals harboring a heterozygous pathogenic ABCC9 missense variant. Through a collaborative effort, we identified a total of nine individuals carrying a monoallelic ABCC9 variant: five sporadic patients and four members of two unrelated families. Among the six detected ABCC9 missense variants, four [p.(Pro252Leu), p.(Thr259Lys), p.(Ala1064Pro), and p.(Arg1197His)] were novel. Systematic assessment of the clinical features in the nine cases with an ABCC9 variant highlights the significant clinical overlap between ZLS and CS that includes early developmental delay, hypertrichosis, gingival overgrowth, joint laxity, and hypoplasia of terminal phalanges and nails. Gain of K+ channel activity possibly accounts for significant clinical similarities of CS, ZLS and FHEIG syndrome and defines a new subgroup of potassium channelopathies.	0
BACKGROUND:Persistent hyperplastic primary vitreous (PHPV) is a congenital form of vitreous dysplasia that can be categorized into anterior, posterior, and mixed types according to the affected location within the eye. Definitive diagnoses of PHPV are usually made based on B-mode ultrasound, optical coherence tomography (OCT), and Doppler ultrasound findings. In this report, we discuss the case of a 7-year-old boy in whom a definitive diagnosis of atypical anterior PHPV was possible based on intraoperative observations, pathological findings, and the results of ophthalmic examination. CASE PRESENTATION:A 7-year-old boy presented with leukocoria and acute glaucoma in his right eye. Imaging suggested characteristics of mixed PHPV. Surgical treatment and pathological examination were performed due to the presence of acute glaucoma and abnormal lens morphology. Typical signs of posterior PHPV (e.g., eyeball shrinkage, the presence of vascular membranes connected to the optic disc, etc.) were not observed. However, there were abundant fibrous vascular membranes around the lens. Pathological examination revealed fibrocyte proliferation in the lens and capsular tissue. Intraoperative findings were used in conjunction with the results of pathological and ophthalmological examinations to make the final diagnosis of anterior PHPV. CONCLUSION:The course and characteristics of PHPV can be unpredictable, and it is often the case that a clear diagnosis cannot be obtained based on clinical characteristics and typical imaging examinations alone. Further surgical treatment and pathological examination may aid in establishing a final diagnosis. In addition to treating the complications of PHPV (e.g., glaucoma), surgery may improve eye appearance and restore visual function to some degree.	0
The aim of our study is to explore the relationship between genotype and phenotype in Chinese PH1 patients and determine the putative mutation hotspot regions. This was a retrospective study regarding 13 Chinese PH1 patients. And all sporadic published researches of Chinese PH1 populations were searched and enrolled based on the inclusive standard. All patients presented with multiple urolithiasis or nephrolithiasis. Urinary oxalate values demonstrated an obvious and extensive variability, ranging from 1.01 to 3.85 mmol/1.73 m2. Molecular diagnosis showed that 13 mutant types were detected. Infantile form patient (pt.) 10 and five patients (pts. 5, 7, 8, 9, 12) carrying c.815_816insGA or c.33_34insC demonstrated a worse prognosis, of whom pt. 5 progressed into ESRD 4 years later and died of chronic kidney failure. Based on the integrated Chinese mutation data, two variants (c.815_816insGA and c.33_34insC) were determined as the most common mutations. Besides, c.1049G>A was initially identified in a Chinese patient. Conclusions: heterogeneity between genotype and phenotype was observed and described in Chinese PH1 patients. c.815_816insGA and c.33_34insC which were recognized as AGXT mutation hotspot regions in China implied a poor prognosis. And c.1049G>A was not determined as the race-specific mutation of Pakistani.	0
Background:The precision of adult height prediction by bone age determination in children with idiopathic growth hormone deficiency (IGHD) is unknown. Methods:The near adult height (NAH) of patients with IGHD in the KIGS database was compared retrospectively to adult height prediction calculated by the Bayley-Pinneau (BP) prediction based on bone age by Greulich-Pyle (GP) in 315 children and based on the Tanner-Whitehouse 2 (TW2) method in 121 children. Multiple linear regression analyses adjusted for age at GH start, age at puberty, mean dose and years of of GH treatment, and maximum GH peak in stimulation test were calculated. Results:The mean underestimation of adult height based on the BP method was at baseline 4.1 ± 0.7 cm in girls and 6.1 ± 0.6 cm in boys, at 1 year of GH treatment 2.5 ± 0.5 cm in girls and 0.9 ± 0.4 cm in boys, while at last bone age determination adult height was overestimated in mean by 0.4 ± 0.6 cm in girls and 3.8 ± 0.5 cm in boys. The mean underestimation of adult height based on the TW2 method was at baseline 5.3 ± 2.0 cm in girls and 7.9 ± 0.8 cm in boys, at 1 year of GH treatment adult height was overestimated in girls 0.1 ± 0.6 cm in girls and underestimated 4.1 ± 0.4 cm in boys, while at last bone age determination adult height was overestimated in mean by 3.1 ± 1.5 cm in girls and 3.6 ± 0.8 cm in boys. Conclusions:Height prediction by BP and TW2 at onset of GH treatment underestimates adult height in prepubertal IGHD children, while in mean 6 years after onset of GH treatment these prediction methods overestimated adult height.	0
COVID-19 is the clinical expression of the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection. Most patients have mild symptoms, but a significant proportion have severe or critical disease, which can include cardiac injury, sepsis, acute kidney failure and respiratory failure. It is also worth highlighting the increasing number of reported COVID-19 cases with dermatological disease/manifestations. The cutaneous clinical spectrum is wide and includes maculopapular, urticarial, varicelliform and petechial rashes, pseudo perniosis, livedo reticularis, and pityriasis rosea-like, violaceous and pustular lesions. Until the physiological mechanism is fully understood, it is important to describe these manifestations, which could help identify a typical pattern. This report describes a cutaneous manifestation in a COVID-19 patient. LEARNING POINTS:SARS-CoV-2 presents with multiple symptoms with the dermatological manifestations currently under-recognized.Clinicians should be aware of patients presenting only with cutaneous symptoms, which in some cases are the initial clinical feature of COVID-19.	0
Epidemiology is the study of the natural history of disease, which includes its frequency, severity, and course and the identification of "risk factors" that influence these aspects. Neuroepidemiology is that branch of epidemiology dealing with disorders that affect the nervous system. Frequency of disease is best measured by population-based rates, which are ratios of the number of cases to the population at risk, expressed as cases per unit of population. Incidence and mortality rates refer, respectively, to new cases of, and deaths caused by, a disease per unit of time and population. Prevalence rate is the cross-sectional count of cases of a disease present at a given time per unit of population. Comparison of rates often requires consideration of age-specific or age-adjusted rates rather than crude rates, all ages. Course of illness (survival, complications, recurrence) can be measured by life-table methods. The annual incidence for disease and injury of the nervous system is about 2.5% (2,500 per 100,000 population) and the prevalence is about 9.5%. Excluding all traumatic, pain, headache, alcohol, psychiatric, and special-sense disorders, neurological diseases have an annual incidence and prevalence rate, respectively, of 1.1 and 3.6% of the population.	1
Thrombotic thrombocytopenic purpura (TTP) can often be life threatening and requires timely diagnosis and prompt initiation of plasmapharesis. Cobalamin deficiency can closely mimic TTP and distinguishing between the two diseases can prove to be a diagnostic challenge. Previously, cobalamin-related pseudo-TTP has been associated with pernicious anemia, dietary insufficiency and hereditary disorders of cobalamin activation. Here in, we discuss the first case of suspected metformin-induced cobalamin deficiency causing pseudo-TTP. Our patient was a 36-year-old female with type 2 diabetes mellitus on metformin for eight years who presented with hemolytic anemia, thrombocytopenia, schistocytes and mild acute renal failure. The initial impression was TTP; however, further workup revealed very low serum cobalamin levels and elevated methylmalonic acid levels. Apart from metformin use, no other cause of cobalamin deficiency was identified. We recommended upper gastrointestinal endoscopy to definitively rule out pernicious anemia.	0
Chromosomal microarray (CMA) is now recommended as first tier for the evaluation in individuals with unexplained neurodevelopmental disorders (ND). However, in developing countries such as Brazil, classical cytogenetic tests are still the most used in clinical practice, as reflected by the scarcity of publications of microarray investigation in larger cohorts. This is a retrospective study which analyses the reading files of CMA and available clinical data from 420 patients from the south of Brazil, mostly children, with neurodevelopmental disorders requested by medical geneticists and neurologists for diagnostic purpose. Previous karyotyping was reported for 138 and includes 17 with abnormal results. The platforms used for CMA were CYTOSCAN 750K (75%) and CYTOSCAN HD (25%). The sex ratio of the patients was 1.625 males :1 female and the mean age was 9.5 years. A total of 96 pathogenic copy number variations (CNVs), 58 deletions and 38 duplications, were found in 18% of the patients and in all chromosomes, except chromosome 11. For 12% of the patients only variants of uncertain clinical significance were found. No clinically relevant CNV was found in 70%. The main referrals for chromosomal microarrays (CMA) were developmental delay (DD), intellectual disability (ID), facial dysmorphism and autism spectrum disorder (ASD). DD/ID were present in 80%, facial dysmorphism in 52% and ASD in 32%. Some phenotypes in this population could be predictive of a higher probability to carry a pathogenic CNV, as follows: dysmorphic facial features (p-value = < 0.0001, OR = 0.32), obesity (p-value = 0.006, OR = 0.20), short stature (p-value = 0.032, OR = 0.44), genitourinary anomalies (p-value = 0.032, OR = 0.63) and ASD (p-value = 0.039, OR = 1.94). The diagnostic rate for CMA in this study was 18%. We present the largest report of CMA data in a cohort with ND in Brazil. We characterize the rare CNVs found together with the main phenotypes presented by each patient, list phenotypes which could predict a higher diagnostic probability by CMA in patients with a neurodevelopmental disorder and show how CMA and classical karyotyping results are complementary.	0
Whole exome sequencing (WES) is utilized in diagnostic odyssey cases to identify the underlying genetic cause associated with complex phenotypes. Recent publications suggest that WES reveals the genetic cause in ~25% of these cases and is most successful when applied to children with neurological disease. The residual 75% of cases remain genetically elusive until more information becomes available in the literature or functional studies are pursued. WES performed on three families with presumed ciliopathy diagnoses, including orofaciodigital (OFD) syndrome, fetal encephalocele, or Joubert-related disorder, identified compound heterozygous variants in C2CD3. Biallelic variants in C2CD3 have previously been associated with ciliopathies, including OFD syndrome type 14 (OFD14; MIM: 615948). As three of the six identified variants were predicted to affect splicing, exon-skipping analysis using either RNA sequencing or PCR-based methods were completed to determine the pathogenicity of these variants, and showed that each of the splicing variants led to a frameshifted protein product. Using these studies in combination with the 2015 ACMG guidelines, each of the six identified variants were classified as either pathogenic or likely pathogenic, and are therefore likely responsible for our patients' phenotypes. Each of the families had a distinct clinical phenotype and severity of disease, extending from lethal to viable. These findings highlight that there is a broad phenotypic spectrum associated with C2CD3-mediated disease and not all patients present with the typical features of OFD14.	0
It is sometimes clinically believed that major depression with melancholic features is more responsive to antidepressants than non-melancholic depression. Proper analysis and, therefore, valid evidence to support or refute this common clinical lore is lacking. The sample was taken from three placebo-controlled randomized trials of duloxetine, escitalopram and paroxetine (n = 1219). We conducted a two-step individual participant data meta-analysis to combine linear mixed-effects regressions modeling melancholic features as prognostic factor (variable that predicts overall response regardless of the treatments) and as effect modifier (variable that predict differential response to drug over placebo). Melancholic features represented a statistically significant prognostic factor for greater reduction in depression severity both on antidepressants and on placebo, especially after 4 weeks of treatment. However, they were not an effect modifier of the antidepressant treatment through the acute phase treatment: in other words. The superiority of antidepressants over placebo was not influenced by the melancholic features. The treatment decision-making as to the benefits of antidepressant treatment for patients with major depression should not be influenced by the presence or absence of melancholic features.	0
Phenothiazines inhibit major antioxidant defense mechanisms in trypanosomatids and exhibit potent cytotoxic effects in vitro. However, the relevance of these drugs in the treatment of Trypanosoma cruzi-induced acute myocarditis is poorly explored, especially in combination with reference trypanocidal drugs. Thus, we compared the antiparasitic and cardioprotective potential of thioridazine (TDZ) and benznidazole (Bz) administered in monotherapy and combined in a murine model of T. cruzi-induced acute myocarditis. Female mice were randomized into six groups: (i) uninfected untreated, (ii) infected untreated, or infected treated with (iii) Bz (100 mg/kg), (iv) TDZ (80 mg/kg), (v) Bz (100 mg/kg) + TDZ (80 mg/kg), or (vi) Bz (50 mg/kg) + TDZ (80 mg/kg). Infected animals were inoculated with 2000 T. cruzi trypomastigotes and treated by gavage for 20 days. Animals that received TDZ alone presented the highest levels of parasitemia, parasitic load and anti-T. cruzi immunoglobulin G titers; cardiac upregulation of N-acetyl-β-D-glucosaminidase activity, nitric oxide, malondialdehyde and cytokines (IFN-γ, TNF-α, IL-10 and IL-17); as well as microstructural damage compared to the other groups (p < 0.05). These parameters were reduced in groups receiving Bz monotherapy compared to the other groups (p < 0.05). The combination of TDZ and Bz attenuated the response to treatment, worsening parasitological control, oxidative heart damage and myocarditis compared to the group treated with Bz alone (p < 0.05). Our results indicate that when administered alone, TDZ potentiated the pathological outcomes in animals infected with T. cruzi. Moreover, TDZ attenuated the antiparasitic effect of Bz when administered together, impairing parasitological control, potentiating inflammation, molecular oxidation and pathological microstructural remodeling of the heart. Thus, our findings indicate that TDZ acts as a pharmacological risk factor and Bz-based monotherapy remains a better cardioprotective drug against Trypanosoma cruzi-induced acute myocarditis.	0
Background: The object of this paper was to provide an overview of rare diseases (RDs) with periodontal manifestations and allocate them to relevant categories. Methods: In ROMSE, a database for "Rare Diseases with Orofacial Involvement", all 541 entities were analyzed with respect to manifestations of periodontal relevance. Inclusion criteria were periodontally relevant changes to the oral cavity, in accordance with the 2018 version of the Classification of Periodontal and Peri-Implant Diseases and Conditions. Rare diseases were recorded, using the methodology described, and subsequently compared with the Orphanet Classification of Rare Diseases. Results: A total of 76 RDs with periodontal involvement were recorded and allocated in accordance with the Classification of Periodontal and Peri-Implant Diseases and Conditions. Of the 541 RDs analyzed as having known orofacial manifestations, almost 14 percent indicated a periodontally compromised dentition. Conclusions: Around 14 percent of RDs with an orofacial involvement showed periodontally relevant manifestations, which present not only as a result of gingivitis and periodontitis, but also gingival hyperplasia in connection with an underlying disease. Thus, dentists play an important role in therapy and early diagnoses of underlying diseases based on periodontally relevant manifestations.	0
Early identification and intervention with conservative measures is important to help manage hip dysplasia in children with a high adductor and iliopsoas tone and delay in weight bearing. The effect of a daily standing program with hip abduction on hip acetabular development in ambulatory children with cerebral palsy was studied.The participants were 26 children with spastic diplegia cerebral palsy (CP), classified at Level III according to the Gross Motor Function Classification System (GMFCS). Thirteen children stood with hip abduction at least 1 h daily from 12 to 14 months of age to 5 years with an individually fabricated standing frame with hip abduction.At the age of 5 years, radiologic results of the study group were compared with a comparison group of 13 children with spastic diplegia CP who had not taken part in a standing program. The migration percentage in all children who stood with abduction remained within stable limits (13-23%) at 5 years of age, in comparison to children who did not stand in abduction (12-47%) (p < 0.01).The results indicate that a daily standing program with hip abduction in the first 5 years may enhance acetabular development in ambulatory children with spastic diplegia CP.Abnormal acetabular development is a problem related to mobility problems and spasticity muscles around the hip. The literature suggests that postural management and standing programs could reduce levels of hip subluxation and increase function in children with cerebral palsy. A standing program with hip abduction can be a beneficial to develop more stable hips in children with spastic diplegic GMFCS level III.	0
The abnormal deposition of calcium within renal parenchyma, termed nephrocalcinosis, frequently occurs as a result of impaired renal calcium handling. It is closely associated with renal stone formation (nephrolithiasis) as elevated urinary calcium levels (hypercalciuria) are a key common pathological feature underlying these clinical presentations. Although monogenic causes of nephrocalcinosis and nephrolithiasis are rare, they account for a significant disease burden with many patients developing chronic or end-stage renal disease. Identifying underlying genetic mutations in hereditary cases of nephrocalcinosis has provided valuable insights into renal tubulopathies that include hypercalciuria within their varied phenotypes. Genotypes affecting other enzyme pathways, including vitamin D metabolism and hepatic glyoxylate metabolism, are also associated with nephrocalcinosis. As the availability of genetic testing becomes widespread, we cannot be imprecise in our approach to nephrocalcinosis. Monogenic causes of nephrocalcinosis account for a broad range of phenotypes. In cases such as Dent disease, supportive therapies are limited, and early renal replacement therapies are necessitated. In cases such as renal tubular acidosis, a good renal prognosis can be expected providing effective treatment is implemented. It is imperative we adopt a precision-medicine approach to ensure patients and their families receive prompt diagnosis, effective, tailored treatment and accurate prognostic information.	0
Sirenomelia is a rare severe malformation sequence of unknown cause characterized by fused legs and severe visceral abnormalities. We present a series of nine families including two rare familial aggregations of sirenomelia investigated by a trio-based exome sequencing strategy. This approach identified CDX2 variants in the two familial aggregations, both fitting an autosomal dominant pattern of inheritance with variable expressivity. CDX2 is a major regulator of caudal development in vertebrate and mouse heterozygotes are a previously described model of sirenomelia. Remarkably, the p.(Arg237His) variant has already been reported in a patient with persistent cloaca. Analysis of the sporadic cases revealed six additional candidate variants including a de novo frameshift variant in the genetically constrained NKD1 gene, encoding a known interactor of CDX2. We provide the first insights for a genetic contribution in human sirenomelia and highlight the role of Cdx and Wnt signaling pathways in the development of this disorder.	0
Mutations in the X-linked gene IQSEC2 are associated with multiple cases of epilepsy, epileptic encephalopathy, intellectual disability and autism spectrum disorder, the mechanistic understanding and successful treatment of which remain a significant challenge in IQSEC2 and related neurodevelopmental genetic diseases. To investigate disease etiology, we studied behaviors and synaptic function in IQSEC2 deficient mice. Hemizygous Iqsec2 null males exhibit growth deficits, hyperambulation and hyperanxiety phenotypes. Adult hemizygotes experience lethal spontaneous seizures, but paradoxically have a significantly increased threshold to electrically induced limbic seizures and relative resistance to chemically induced seizures. Although there are no gross defects in brain morphology, hemizygotes exhibit stark hippocampal reactive astrogliosis. Electrophysiological recordings of hippocampal neurons reveal increased excitatory drive specifically onto interneurons, and significant alterations in intrinsic electrical properties specific to the interneuron population. As they age, hemizygotes also develop an increased abundance of parvalbumin-positive interneurons in the hippocampus, neurons in which IQSEC2 is expressed in addition to the excitatory neurons. These findings point to a novel role of IQSEC2 in hippocampal interneuron synaptic function and development with implications for a class of intractable neurodevelopmental diseases.	0
Acylglycerol kinase (AGK) is a mitochondrial lipid kinase that catalyzes the phosphorylation of monoacylglycerol and diacylglycerol to lysophosphatidic acid and phosphatidic acid, respectively. Mutations in AGK cause Sengers syndrome, which is characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Here we identified AGK as a subunit of the mitochondrial TIM22 protein import complex. We show that AGK functions in a kinase-independent manner to maintain the integrity of the TIM22 complex, where it facilitates the import and assembly of mitochondrial carrier proteins. Mitochondria isolated from Sengers syndrome patient cells and tissues show a destabilized TIM22 complex and defects in the biogenesis of carrier substrates. Consistent with this phenotype, we observe perturbations in the tricarboxylic acid (TCA) cycle in cells lacking AGK. Our identification of AGK as a bona fide subunit of TIM22 provides an exciting and unexpected link between mitochondrial protein import and Sengers syndrome.	0
In the paediatric population, there is some evidence of possible interaction, synergism, and co-toxicity of aspirin and acetaminophen. The toxicity of salicylates such as aspirin in this population is well known and documented, specifically in the form of Reye syndrome. The possible toxic synergism with aspirin and acetaminophen, however, is not previously described; though case reports suggest such co-toxicities with low levels of aspirin and other compounds can exist. In vitro studies into mechanistic processes of salicylate toxicity propose that there is a bi-directional link and potentiation with glutathione (GSH) depletion and salicylate toxicity. Data may suggest a plausible explanation for salicylate and acetaminophen toxic synergism. Further studies investigating this potential toxic synergism are warranted. Given the lack of awareness in the clinical community about potential toxic synergism between these relatively common medications, caution is advised in the co-administration of these drugs, particularly in communities using natural or alternative therapy.	0
Fusarium is a filamentous fungus that is ubiquitous in nature and can cause severe opportunistic infections in immunocompromised hosts. The association between Fusarium and hyper-IgE syndrome is exceedingly rare and has only been documented in a single report previously. A 44-year-old male, working as marijuana grower, with prior diagnosis of hyper-IgE syndrome and recurrent infections presented with enlarging right knee ulcer that did not respond to antimicrobial treatment. The patient was diagnosed with cutaneous fusariosis, confirmed with punch biopsy and positive wound cultures. The patient was managed with extended antifungal therapy (i.e., posaconazole) and surgical debridement resulting in remarkable improvement with wound healing leaving a pale scar. Fusarium should be considered in differential for cutaneous and invasive fungal infections in presence of cutaneous manifestations. Exposure to Cannabis plants is a noticeable risk factor. Multimodal approach involving systemic antifungals and wound debridement is essential for favorable outcome. Posaconazole was demonstrated to be a highly efficacious antifungal choice.	0
BACKGROUND: To investigate the epidemiologic and clinical characteristics (age, sex, tumor location, socioeconomic status) and potential predisposing factors (alcohol, tobacco, mobile phone use, severe head trauma) of cerebral gliomas in a defined area of Northwest Greece. METHODS: The prospective study was conducted in patients with gliomas referred to all 7 hospitals of a study area with a population of 488,435 inhabitants, from June 1, 2005, to May 31, 2007. Incidence rates (IR) were calculated as new cases diagnosed among residents of the study area during the study period per 100,000 inhabitants. A case-control study was carried out in order to study the possible association of the risk of glioma with smoking, alcohol, use of mobile phone, and severe cranial trauma. RESULTS: A total of 56 glioma incident cases were identified with IRs of glioma and glioblastoma (GBM) at 5.73/10(5)/year and 3.69/10(5)/year, respectively. A male to female ratio of 1.25 was obtained in the GBM group. IRs of glioma and GBM for both males and females were higher in the age group 60-79. The most frequent anatomic location was the frontal lobe. 46.5% of the patients originated from the low, 25% from the middle and 28.5% from the high socioeconomic class. There was no significant association between glioma and alcohol consumption, smoking and mobile phone use. A trend for a positive association between the risk of glioma and a history of severe cranial trauma was observed, but this association was not statistically significant. CONCLUSION: The estimated IR of glioma and GBM in this study was higher compared with data from other studies carried out on European, Asian and US populations. Further studies may be needed to assess the possible association of genetic, environmental and lifestyle factors with the high occurrence of gliomas observed in this study.	1
Background and study aims  Nomenclature and descriptions of small bowel (SB) vascular lesions in capsule endoscopy (CE) are scarce in the medical literature. They are mostly based on the reader's opinion and thus differ between experts, with a potential negative impact on clinical care, teaching and research regarding SBCE. Our aim was to better define a nomenclature and to give a description of the most frequent vascular lesions in SBCE. Methods  A panel of 18 European expert SBCE readers was formed during the UEGW 2016 meeting. Three experts constructed an Internet-based four-round Delphi consensus, but did not participate in the voting process. They built questionnaires that included various still frames of vascular lesions obtained with a third-generation SBCE system. The 15 remaining participants were asked to rate different proposals and description of the most common SB vascular lesions. A 6-point rating scale (varying from 'strongly disagree' to 'strongly agree') was used successive rounds. The consensus was reached when at least 80 % voting members scored the statement within the 'agree' or 'strongly agree'. Results  Consensual terms and descriptions were reached for angiectasia/angiodysplasia, erythematous patch, red spot/dot, and phlebectasia. A consensual description was reached for more subtle vascular lesions tentatively named "diminutive angiectasia" but no consensus was reached for this term. Conclusion  An international group has reached a consensus on the nomenclature and descriptions of the most frequent and relevant SB vascular lesions in CE. These terms and descriptions are useful in daily practice, for teaching and for medical research purposes.	0
Within the field of movement disorders, the conceptual understanding of dystonia has continued to evolve. Clinical advances have included improvements in recognition of certain features of dystonia, such as tremor, and understanding of phenotypic spectrums in the genetic dystonias and dystonia terminology and classification. Progress has also been made in the understanding of underlying biological processes which characterize dystonia from discoveries using approaches such as neurophysiology, functional imaging, genetics, and animal models. Important advances include the role of the cerebellum in dystonia, the concept of dystonia as an aberrant brain network disorder, additional evidence supporting the concept of dystonia endophenotypes, and new insights into psychogenic dystonia. These discoveries have begun to shape treatment approaches as, in parallel, important new treatment modalities, including magnetic resonance imaging-guided focused ultrasound, have emerged and existing interventions such as deep brain stimulation have been further refined. In this review, these topics are explored and discussed.	0
We report an index case of a male patient who presented with all clinical manifestations of Pacak-Zhuang syndrome, including early-age polycythemia, multiple pheochromocytomas/paragangliomas, duodenal somatostatinoma, and ocular findings. Sequencing analysis detected an EPAS1 mutation in all tumors tested, but not in the germline.	0
We performed the first population-based clinical and molecular genetic study of Leber hereditary optic neuropathy (LHON) in a population of 2,173,800 individuals in the North East of England. We identified 16 genealogically unrelated families who harbor one of the three primary mitochondrial DNA (mtDNA) mutations that cause LHON. Two of these families were found to be linked genetically to a common maternal founder. A de novo mtDNA mutation (G3460A) was identified in one family. The minimum point prevalence of visual failure due to LHON within this population was 3.22 per 100,000 (95% CI 2.47-3.97 per 100,000), and the minimum point prevalence for mtDNA LHON mutations was 11.82 per 100,000 (95% CI 10.38-13.27 per 100,000). These results indicate that LHON is not rare but has a population prevalence similar to autosomally inherited neurological disorders. The majority of individuals harbored only mutant mtDNA (homoplasmy), but heteroplasmy was detected in approximately 12% of individuals. Overall, however, approximately 33% of families with LHON had at least one heteroplasmic individual. The high incidence of heteroplasmy in pedigrees with LHON raises the possibility that a closely related maternal relative of an index case may not harbor the mtDNA mutation, highlighting the importance of molecular genetic testing for each maternal family member seeking advice about their risks of visual failure.	1
Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a common type of hemophagocytic lymphohistiocytosis (HLH) that exhibits high rates of morbidity and fatalities. Multiorgan failure caused by Epstein-Barr virus (EBV)-induced hypercytokinemia is one of the main reasons for early deaths. Blood purification techniques have been successfully applied in previously treated hypercytokinemia. However, there were insufficient studies to support the combination of plasma exchange (PE) and continuous renal replacement therapy (CRRT) in treating patients with severe EBV-HLH. In this article, we have summarized the effects of early incorporation of PE and CRRT, together with HLH-2004 chemoimmunotherapy, in 8 pediatric patients with severe EBV-HLH. Early use of PE and CRRT appeared to be well tolerated, and no serious side effects and early deaths were observed. After PE and CRRT procedures, cytokine levels were reduced to normal values, except for soluble interleukin 2 receptor, and significant reductions in EBV DNA, serum ferritin, aspartate transaminase, total bilirubin, total bile acid, lactate dehydrogenase, and body temperature values and increases in the neutrophil count in addition to hemoglobin, albumin, and cholinesterase values were observed. Furthermore, through continuous HLH-2004 treatment regimens, lower limits of detection were exhibited for EBV DNA levels, and all other observational indicator levels were restored to normal. Finally, 7 patients achieved and maintained complete remission for 15 to 24 months, culminating in August 2019. Therefore, it is our suggestion that early incorporation of PE and CRRT with chemoimmunotherapy might be a safe and effective treatment for patients with severe EBV-HLH.	0
Myosin storage myopathy is a rare neuromuscular disorder, characterized by subsarcolemmal inclusions exclusively in type I skeletal muscle fibers, known as hyaline bodies. Its clinical spectrum is diverse, as are its modes of inheritance. Myosin storage myopathy, also called hyaline body myopathy, is caused by a pathogenic mutation in the MYH7 gene, encoding for the slow/β-cardiac myosin heavy chain. We describe a patient with this uncommon myopathy, caused by a new p.K1784delK mutation in the MYH7 gene. The patient developed a severe thoracolumbar scoliosis and had scoliosis surgery.	0
Fetuses with prenatal diagnosis of reduced mobility and malformation are at increased risk to sustain neonatal femoral fractures. Labor difficulties even after an elective cesarean section may trigger the fractures of the long bones.	0
BACKGROUND:Multicentric reticulohistiocytosis is a rare form of non-langerhans cell histiocytosis presenting with skin changes and erosive arthritis. Infiltration of histiocytes and multinucleated giant cells are typical histological findings and confirm the diagnosis. CASE PRESENTATION:This case report describes a newly diagnosed case of multicentric reticulohistiocytosis in a healthy 26-year-old female originally from the Philippines. Eruption of papules and nodules on the hands and pain in multiple joints were the main complaints at the initial presentation. Radiographical findings of erosions in the small hand and feet joints were impressive. Initial histological findings did not match the clinical image, although later the clinical diagnosis was supported by histological findings in additional biopsies. CONCLUSIONS:Although initial histological findings did not match the clinical image, additional biopsies were valuable to confirm the diagnosis.	0
BACKGROUND:Disseminated peritoneal leiomyomatosis is a rare condition manifesting as hormone-sensitive soft tissue nodules lining the peritoneal cavity. Given the extensiveness of this disease, surgical management is challenging, making hormonal suppression the primary treatment. CASE:A 23-year-old woman presenting with abdominal pain was found to have innumerable abdominopelvic nodules on imaging. Biopsy of these lesions was consistent with disseminated peritoneal leiomyomatosis. Treatment using leuprolide acetate led to satisfactory results but was discontinued owing to vasomotor symptoms. Treatment was changed to cyclic ulipristal acetate, a selective progesterone receptor modulator. Over the past 2 years, the patient has completed five 3-month courses of ulipristal acetate with excellent symptomatic and radiologic response. CONCLUSION:The use of ulipristal acetate may be an effective, novel therapeutic option for the management of disseminated peritoneal leiomyomatosis.	0
X linked intellectual disability (XLID) syndromes account for a substantial number of males with ID. Much progress has been made in identifying the genetic cause in many of the syndromes described 20-40 years ago. Next generation sequencing (NGS) has contributed to the rapid discovery of XLID genes and identifying novel mutations in known XLID genes for many of these syndromes.2 NGS approaches were employed to identify mutations in X linked genes in families with XLID disorders. 1 involved exome sequencing of genes on the X chromosome using the Agilent SureSelect Human X Chromosome Kit. The second approach was to conduct targeted NGS sequencing of 90 known XLID genes.We identified the same mutation, a c.12928 G>C transversion in the HUWE1 gene, which gives rise to a p.G4310R missense mutation in 2 XLID disorders: Juberg-Marsidi syndrome (JMS) and Brooks syndrome. Although the original families with these disorders were considered separate entities, they indeed overlap clinically. A third family was also found to have a novel HUWE1 mutation.As we identified a HUWE1 mutation in an affected male from the original family reported by Juberg and Marsidi, it is evident the syndrome does not result from a mutation in ATRX as reported in the literature. Additionally, our data indicate that JMS and Brooks syndromes are allelic having the same HUWE1 mutation.	0
Ozurdex® 0.7 mg (dexamethasone 0.7 mg implant, Allergan, Dublin, Ireland), an intravitreal biodegradable implant, is indicated for cystoid macular edema due to various causes. One of its known and uncommon complications is implant migration to the anterior chamber, causing corneal edema that, in some cases, is irreversible. Reported risk factors for device migration are open or defective lens capsule and prior history of vitrectomy. We present a case of dexamethasone implant migration through a congenital iris coloboma in a pseudophakic patient with an intact lens capsule. The patient is a 56-year-old pseudophakic man with a history of congenital iris coloboma, myopia, retinal tears, and a branch retinal vein occlusion with subsequent cystoid macular edema resistant to anti-VEGF medications but responsive to corticosteroids. He presented with sudden painless decreased vision in his left eye, 8 weeks following dexamethasone implant (Ozurdex) injection to the same eye. Upon presentation, he was diagnosed with corneal edema caused by anterior chamber migration of the implant. He was referred for immediate surgical intervention to extract the implant, with a resolution of the corneal edema within 2 weeks postoperatively. To conclude, this is the first case that reports Ozurdex implant migration through an iris coloboma in the setting of an intact posterior capsule. In addition, we describe a novel surgical approach for implant removal from the anterior chamber that is simple and efficient.	0
AIMS:Histology-based tumour microenvironment (TME) scores are useful in predicting the prognosis of gastrointestinal cancer. However, their prognostic roles in distal bile duct cancer (DBDC) have not been previously studied. This study aimed to evaluate the prognostic significance of the TME scores using the Klintrup-Mäkinen (KM) grade, tumour stroma percentage (TSP), and the Glasgow microenvironment score (GMS), in resected DBDC. METHODS AND RESULTS:Eighty-one patients with DBDC who underwent curative resection were enrolled. DBDC was graded according to KM grade, TSP, and GMS. A high KM grade was found in 19 patients (24%), and a high TSP was found in 47 patients (58%). A high TSP was significantly correlated with a low KM grade (P<0.001). The distribution of the GMS, which was developed by combining the KM grade and TSP, was as follows: 0 (n=19, 24%), 1 (n=19, 24%), and 2 (n=43, 52%). A low KM grade, high TSP, and high GMS were significantly associated with short overall survival (OS) (P<0.001) and relapse-free survival (RFS) (P<0.001). Furthermore, multivariate analysis showed that a low KM grade (hazard ratio [HR], 3.826; confidence interval [CI], 1.650-8.869; P=0.014), high TSP (HR, 2.193; CI, 1.173-4.100, P=0.002), and high GMS (HR, 7.148; CI, 2.811-18.173) were independent prognostic factors for short RFS; a low KM grade (HR, 4.324; CI, 1.594-11.733) and high GMS (HR, 6.332; CI, 2.743-14.594) were independent prognostic factors for short OS. CONCLUSION:Histology-based TME scores, including the KM grade, TSP, and GMS, are useful for predicting the survival of patients with resected DBDC.	0
Usher syndrome encompasses a group of genetically and clinically heterogeneous autosomal recessive disorders with hearing deficiencies and retinitis pigmentosa. The mechanisms underlying the Usher syndrome are highly variable. In the present study, a Chinese family with Usher syndrome was recruited. Whole exome sequencing (WES), Sanger sequencing, homozygosity mapping, short tandem repeat (STR) analysis and segregation analysis were performed. Functional domains of the pathogenic variant for USH2A were analysed. We identified a homozygous frameshift variant c.99_100insT (p.Arg34Serfs*41) in the USH2A gene in the proband that showed discordant segregation in the father. Further homozygosity mapping and STR analysis identified an unusual homozygous variant of proband that originated from maternal uniparental disomy (UPD). The p.Arg34Serfs*41 variant produced a predicted truncated protein that removes all functional domains of USH2A. The variant was not included in the 1000 Human Genomes Project database, ExAC database, HGMD or gnomAD database, but was included in the ClinVar databases as pathogenic. Although USH2A is an autosomal recessive disease, the effects of UPD should be informed in genetic counselling since the recurrence risk of an affected child is greatly reduced when the disease is due to the UPD mechanism. To test potential patients, WES, combined with STR analysis and homozygosity mapping, provides an accurate and useful strategy for genetic diagnosis. In summary, our discoveries can help further the understanding of the molecular pathogenesis of Usher syndrome type IIA to advance the prevention, diagnosis and therapy for this disorder.	0
The syndrome was characterized by striking hypoplasia of nails, malformations of hands and feet, curly hair, small lower teeth and seizures. There were no similarly affected relatives. Death occurred at 31 months with the patient apparently in status epilepticus with terminal hepatorenal syndrome.	0
Holoprosencephaly is a congenital defect of the median structures of the brain and face. The epidemiology is poorly known due to the paucity of population-based studies. This study describes the epidemiology of holoprosencephaly in a large population, using cases identified through the New York State Congenital Malformations Registry, and born in 1984-1989. We describe the craniofacial abnormalities present, their frequency, and their cooccurrence, and we examine the correspondence between the severity of craniofacial abnormalities, chromosomal abnormalities, and severity of the brain defect. Liveborn cases totaled 78, yielding a prevalence of 4.8 per 100,000 live births. Prevalence among girls was nearly double that in boys, and was 4.2 times higher among infants of mothers under age 18 compared to infants of older mothers. Only 9.8% of all cases had no craniofacial abnormalities other than the brain defect. Eye malformations were present in 76.8%, nose malformations in 69.5%, ear malformations in 50%, and oral clefts in 41.5%. These malformations arise at different times during gestation. The variability in patterns of cooccurrence suggests variability in the developmental pathways and/or timing of developmental derangements which result in holoprosencephaly. This, in turn, is consistent with a model of multiple causes. Children with alobar holoprosencephaly tended to have the most severe craniofacial anomalies, but the correspondence was not 100%. Craniofacial phenotype does not consistently discriminate between cytogenetically normal and abnormal cases.	1
X-linked hypophosphatemia (XLH) caused by PHEX mutations results in elevated serum FGF23 levels, renal phosphate wasting and low 1,25-dihydroxyvitamin D. The glycophosphoprotein osteopontin, a potent inhibitor of mineralization normally degraded by PHEX, accumulates within the bone matrix. Conventional therapy consisting of supplementation with phosphate and vitamin D analogs is burdensome and the effects on bone material poorly characterized. We analyzed transiliac bone biopsies from four adult patients, two of them severely affected due to no diagnosis and no treatment until adulthood. We used light microscopy, qBEI and FTIRI to study histology, histomorphometry, bone mineralization density distribution, properties of the organic matrix and size of hypomineralized periosteocytic lesions. Non-treatment resulted in severe osteomalacia, twice the amount of mineralized trabecular volume, multiple osteon-like perforations, continuity of lamellae from mineralized to unmineralized areas and distinctive patches of woven bone. Periosteocytic lesions were larger than in treated patients. The latter had nearly normal osteoid thicknesses, although surface was still elevated. The median calcium content of the matrix was always within normal range, although the percentage of lowly mineralized bone areas was highly increased in non-treated patients, resulting in a marked heterogeneity in mineralization. Divalent collagen cross-links were evident independently of the mineral content of the matrix. Broad osteoid seams lacked measurable pyridinoline, a mature trivalent cross-link and exhibited considerable acidic lipid content, typically found in matrix vesicles. Based on our results, we propose a model that possibly integrates the relationship between the observed mineralization disturbances, FGF23 secretion and the known osteopontin accumulation in XLH.	0
Chromosomal rearrangements, such as duplications/deletions, can lead to a variety of genetic disorders. Herein, we reported a prenatal case with right aortic arch and aberrant left subclavian artery, consisting of a complex chromosomal copy number variations. Routine cytogenetic analysis described the chromosomal karyotype as 46,XY, add (2)(q37) for the fetus. However, the chromosomal microarray analysis (CMA) identified a 22.4 Mb duplication in chromosome 4p16.3p15.2, a 3.96 Mb microduplication in 12p11.1q11, and a 1.68 Mb microdeletion in Xp22.31. Fluorescence in situ hybridization (FISH) using a chromosome 4 painting probe was found to hybridize to the terminal of chromosome 2q on the fetus, thus confirming that the extra genetic materials of chromosome 2 was actually trisomy 4p detected through CMA. Meanwhile, the parental karyotypes were normal, which proved that the add (2) was de novo for fetus. The duplication of Wolf-Hirschhorn syndrome critical region (WHSCR) and X-linked recessive ichthyosis associated with Xp22.31 deletion separately were considered potentially pathogenic causes although other abnormalities involving these syndromes were not observed. For prenatal cases, the combined utilization of ultrasonography, traditional cytogenetic, and molecular diagnosis technology will enhance better diagnostic benefits, offer more detailed genetic counselling, and assess the prognosis of the fetuses.	0
Articles about medical diagnostic decision support (MDDS) systems often begin with a disclaimer such as, "despite many years of research and millions of dollars of expenditures on medical diagnostic systems, none is in widespread use at the present time." While this statement remains true in the sense that no single diagnostic system is in widespread use, it is misleading with regard to the state of the art of these systems. Diagnostic systems, many simple and some complex, are now ubiquitous, and research on MDDS systems is growing. The nature of MDDS systems has diversified over time. The prospects for adoption of large-scale diagnostic systems are better now than ever before, due to enthusiasm for implementation of the electronic medical record in academic, commercial, and primary care settings. Diagnostic decision support systems have become an established component of medical technology. This paper provides a review and a threaded bibliography for some of the important work on MDDS systems over the years from 1954 to 1993.	0
Marshall syndrome and type II Stickler syndrome are caused by mutations in COL11A1, which codes for the proα1chain of collagen XI. Collagen XI is a minor fibrillar collagen co-expressed with collagen II in cartilage and the vitreous of the eye. Characteristic features of Marshall syndrome include midfacial hypoplasia, high myopia, and sensorineural-hearing deficit. Deletions, insertions, splice site, and missense mutations in COL11A1 have been identified in Stickler syndrome and Marshall syndrome patients. In this study, we describe the clinical presentations of seven patients with Marshall syndrome from three unrelated Saudi families, inherited as autosomal dominant (two families) and autosomal recessive (one family). Cardinal clinical features of Marshall syndrome are manifested in all patients. One patient had ectodermal abnormalities. Mutations (c.2702G > A in exon 34,IVS50 + 1G > A, and IVS50 + lG > C) were identified in COL11A1 in affected members. Interestingly, the first report of autosomal recessive Marshall syndrome was from Saudi Arabia caused by the same mutation (c.2702G > A, p.Gly901Glu) as in one of our families. This study depicts detailed phenotypic and genetic description of dominant and recessive forms of Marshall syndrome due to COL11A1 mutations.	0
We evaluated the effects of bezafibrate (BEZ) on β-oxidation in fibroblasts obtained from patients with glutaric acidemia type II (GA2) of various clinical severities using an in vitro probe (IVP) assay.Cultured fibroblasts from 12 patients with GA2, including cases of the neonatal-onset type both with and without congenital anomalies (the prenatal- and neonatal-onset forms, respectively), the infantile-onset, and the myopathic forms, were studied. The IVP assay was performed by measuring acylcarnitines (ACs) in the cell culture medium of fibroblasts incubated with palmitic acid for 96h in the presence of 0-800μM BEZ using tandem mass spectrometry.The IVP assay showed that 100μM BEZ markedly reduced the level of palmitoylcarnitine (C16) in the neonatal-onset, infantile-onset, and myopathic forms of GA2, either increasing or maintaining a high level of acetylcarnitine (C2), which serves as an index of energy production via β-oxidation. In the prenatal-onset form, although a small reduction of C16 was also observed in the presence of 100μM BEZ, the level of C2 remained low. At concentrations higher than 100μM, BEZ further decreased the level of ACs including C16, but a concentration over 400μM decreased the level of C2 in most cases.BEZ at 100μM was effective for all GA2 phenotypes except for the prenatal-onset form, as a reduction of C16 without deterioration of C2 is considered to indicate improvement of β-oxidation. The effects of higher doses BEZ could not be estimated by the IVP assay but might be small or nonexistent.	0
The treatment options for systemic light chain amyloidosis (AL) are currently widening in an unprecedented way, brought about by an expanding arsenal of anti-myeloma therapy as well as by novel approaches to target toxic light chains and, most recently, deposited amyloid directly. In this context, accurate estimates of prognosis in AL, which allow for reliable patient advice and for example comparison of different therapies, are particularly important to clinicians. Some biomarkers and especially the genetic background of the underlying clonal disease as evaluated by interphase fluorescence in situ hybridization even have predictive value, enabling an appropriate treatment selection. Derived from the most frequently involved organs in AL, heart and kidney, this review focuses on overall survival and renal survival. A comprehensive overview and summary of reported prognostic factors and biomarkers in AL is given and the most important and validated factors are highlighted. Finally, established staging systems in AL as well as validated and perspective response criteria are presented.	0
Hereditary spastic paraplegias are heterogeneous disorders with diversified clinical manifestations, and genetic testing is important for the diagnosis and typing of hereditary spastic paraplegias.Gene panel sequencing containing 55 hereditary spastic paraplegias-related genes was performed to screen the pathogenic genes for hereditary spastic paraplegias. Sanger sequencing was adopted to validate if the family member carried the same pathogenic gene as the proband.Fifteen out of 53 patients carried mutation(s) in the screened hereditary spastic paraplegias-related genes. Among the 23 identified mutations, only one mutation had been previously reported as a pathogenic mutation. In the pedigree of case 6, the proband, his mother and uncle all carried the same novel deletion mutation (c.1459delA) at SPAST gene. Based on the pedigree, the disease was inherited in an AD pattern. In the pedigree of case 53, the family disease may be in an X-linked recessive inheritance pattern. The proband (case 53) carried two novel mutations in ALT1 gene and L1CAM gene (c.2511C>A), respectively. The L1CAM gene is the causative gene for the SPG1 X-linked recessive-hereditary spastic paraplegias.Our data confirm the genetic heterogeneity of hereditary spastic paraplegias, and SPG4/SPAST were the most frequent forms. The pathogenicity of the novel mutations is worth to be further investigated.	0
PURPOSE:Danon disease (DD) is a rare X-linked disorder caused by pathogenic variants in LAMP2. DD primarily manifests as a severe cardiomyopathy. An early diagnosis is crucial for patient survival. The aim of the study was to determine the usefulness of ocular examination for identification of DD. METHODS:Detailed ocular examination in 10 patients with DD (3 males, 7 females) and a 45-year-old asymptomatic female somatic mosaic carrier of a LAMP2 disease-causing variant. RESULTS:All patients with manifest cardiomyopathy had pigmentary retinopathy with altered autofluorescence and diffuse visual field loss. Best corrected visual acuity (BCVA) was decreased (<0.63) in 8 (40%) out of 20 eyes. The severity of retinal pathology increased with age, resulting in marked cone-rod involvement overtime. Spectral-domain optical coherence tomography in younger patients revealed focal loss of photoreceptors, disruption and deposition at the retinal pigment epithelium/Bruch's membrane layer (corresponding to areas of marked increased autofluorescence), and hyperreflective foci in the outer nuclear layer. Cystoid macular oedema was seen in one eye. In the asymptomatic female with somatic mosaicism, the BCVA was 1.0 bilaterally. An abnormal autofluorescence pattern in the left eye was present; while full-field electroretinography was normal. CONCLUSIONS:Detailed ocular examination may represent a sensitive and quick screening tool for the identification of carriers of LAMP2 pathogenic variants, even in somatic mosaicism. Hence, further investigation should be undertaken in all patients with pigmentary retinal dystrophy as it may be a sign of a life-threatening disease.	0
Expanded newborn screening (NBS) is aimed for early detection and intervention of treatable inborn errors of metabolism and also to establish incidence of these disorders in this part of the globe. The first expanded NBS programme initiated in the capital city of Andhra Pradesh to screen all the newborns born in four major Government Maternity Hospitals in Hyderabad by heel prick capillary blood collected on S&S 903 filter paper. Chromatographic (TLC and HPLC), electrophoretic (cellulose acetate and agarose) and ELISA based assays have been employed for screening of common inborn errors of metabolism. This study has shown a high prevalence of treatable Inborn errors of metabolism. Congenital hypothyroidsm is the most common disorder (1 in 1700) followed by congenital Adrenal Hyperplasia (1 in 2575) and Hyperhomocystenemia (1 in 100). Interestingly, a very high prevalence of inborn errors of metabolism to the extent of 1 in every thousand newborns was observed. The study reveals the importance of screening in India, necessitating nation wide large-scale screening.	1
The identification of the multiple endocrine neoplasia type 1 (MEN1) gene in 1997 has shown that germline heterozygous mutations in the MEN1 gene located on chromosome 11q13 predisposes to the development of tumors in the MEN1 syndrome. Tumor development occurs upon loss of the remaining normal copy of the MEN1 gene in MEN1-target tissues. Therefore, MEN1 is a classic tumor suppressor gene in the context of MEN1. This tumor suppressor role of the protein encoded by the MEN1 gene, menin, holds true in mouse models with germline heterozygous Men1 loss, wherein MEN1-associated tumors develop in adult mice after spontaneous loss of the remaining non-targeted copy of the Men1 gene. The availability of genetic testing for mutations in the MEN1 gene has become an essential part of the diagnosis and management of MEN1. Genetic testing is also helping to exclude mutation-negative cases in MEN1 families from the burden of lifelong clinical screening. In the past 20 years, efforts of various groups world-wide have been directed at mutation analysis, molecular genetic studies, mouse models, gene expression studies, epigenetic regulation analysis, biochemical studies and anti-tumor effects of candidate therapies in mouse models. This review will focus on the findings and advances from these studies to identify MEN1 germline and somatic mutations, the genetics of MEN1-related states, several protein partners of menin, the three-dimensional structure of menin and menin-dependent target genes. The ongoing impact of all these studies on disease prediction, management and outcomes will continue in the years to come.	0
Phosphoglycerate mutase deficiency (PGAM) is a rare metabolic myopathy that results in terminal block in glycogenolysis. Clinically, patients with PGAM deficiency are asymptomatic, except when they engage in brief, strenuous efforts, which may trigger myalgias, cramps, muscle necrosis, and myoglobinuria. An unusual pathologic feature of PGAM deficiency is the association with tubular aggregates.We report an African-American patient from Panama with partial deficiency of PGAM who presented with asymptomatic elevation of creatine kinase levels and tubular aggregates on muscle biopsy.Muscle biopsies showed subsarcolemmal and sarcolemmal tubular aggregates in type 2 fibers. Muscle PGAM enzymatic activity was decreased and gene sequencing revealed a heterozygous mutation in codon 78 of exon 1 of the PGAM2 gene, which is located on the short arm of chromosome 7.PGAM deficiency has been reported in 14 patients, 9 of whom were of African-American ethnicity, and in 5 (36%) tubular aggregates were seen on muscle biopsy. Contrary to previously reported cases, our patient was initially asymptomatic. This further expands the PGAM deficiency phenotype.	0
BACKGROUND:Noonan syndrome is an autosomal dominant disorder secondary to RASopathies, which are caused by germ-line mutations in genes encoding components of the RAS mitogen-activated protein kinase pathway. RIT1 (OMIM *609591) was recently reported as a disease gene for Noonan syndrome. METHODS AND RESULTS:We present a patient with RIT1-associated Noonan syndrome, who in addition to the congenital heart defect, had monocytosis, myeloproliferative disorder, and accelerated idioventricular rhythm that was associated with severe hemodynamic instability. Noonan syndrome was suspected given the severe pulmonary stenosis, persistent monocytosis, and "left-shifted" complete blood counts without any evidence of an infectious process. Genetic testing revealed that the patient had a heterozygous c.221 C>G (pAla74Gly) mutation in the RIT1. CONCLUSION:We report a case of neonatal Noonan syndrome associated with RIT1 mutation. The clinical suspicion for Noonan syndrome was based only on the congenital heart defect, persistent monocytosis, and myeloproliferative process as the child lacked all other hallmarks characteristics of Noonan syndrome. However, the patient had an unusually malignant ventricular dysrhythmia that lead to his demise. The case highlights the fact that despite its heterogeneous presentation, RIT1-associated Noonan syndrome can be extremely severe with poor outcome.	0
Hartsfield syndrome is a rare clinical entity characterized by holoprosencephaly and ectrodactyly with the variable feature of cleft lip/palate. In addition to these symptoms patients with Hartsfield syndrome can show developmental delay of variable severity, isolated hypogonadotropic hypogonadism, central diabetes insipidus, vertebral anomalies, eye anomalies, and cardiac malformations. Pathogenic variants in FGFR1 have been described to cause phenotypically different FGFR1-related disorders such as Hartsfield syndrome, hypogonadotropic hypogonadism with or without anosmia, Jackson-Weiss syndrome, osteoglophonic dysplasia, Pfeiffer syndrome, and trigonocephaly Type 1. Here, we report three patients with Hartsfield syndrome from two unrelated families. Exome sequencing revealed two siblings harboring a novel de novo heterozygous synonymous variant c.1029G>A, p.Ala343Ala causing a cryptic splice donor site in exon 8 of FGFR1 likely due to gonadal mosaicism in one parent. The third case was a sporadic patient with a novel de novo heterozygous missense variant c.1868A>G, p.(Asp623Gly).	0
STUDY DESIGN:Retrospective case series. OBJECTIVE:The aim of this study was to investigate the clinical outcomes >10 years following laminoplasty and pedicle screw fixation for cervical myelopathy associated with athetoid cerebral palsy (CP). SUMMARY OF BACKGROUND DATA:Surgery for cervical myelopathy associated with CP remains a challenge because of perioperative instrumentation failure and adjacent segment problems due to patients' repetitive involuntary neck movements with deformity of the cervical spine. METHODS:A single-center series of 14 patients were reviewed. The patients comprised seven women and seven men with a mean age of 52 years at the time of surgery. The mean follow-up period was 12.5 years. The Barthel index (BI), which shows independence in activities of daily life, and Japanese Orthopaedic Association (JOA) score were assessed. Radiographic evaluation included changes of the C2-C7 angle in the sagittal plane, fusion rate, adjacent segment degeneration, and instrument failure. RESULTS:The 10-year BI and JOA score significantly improved at 36% and 31%, respectively. The preoperative Cobb angle of the sagittal plane from C2-C7 measured 11.9° of kyphosis, which improved to 0.8° of lordosis. In the radiographic analysis, 35% (proximal) and 21% (distal) of the adjacent segment showed progression in degeneration of more than one grade after 10 years. More than 90% of the patients who underwent magnetic resonance imaging showed progressive disc degeneration on either side after 10 years. Autofusion inside the disc or anterior vertebral bony bridging was observed in 86% of intervertebral levels without anterior procedures. CONCLUSION:The procedure showed favorable initial stability and maintained favorable clinical outcomes in patients with CP. More than 90% of the patients showed disc degeneration on either side. The rate of proximal adjacent segment degeneration was higher than that of distal segments with or without symptoms at the >10-year follow-up. LEVEL OF EVIDENCE:4.	0
Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare autoimmune disorder inherited in an autosomal recessive pattern. We present a clinical case of APS-1 in a 10-year-old child. The crux of this case was the lack of awareness to the disease and its complex flow, which resulted in complications during treatment. The progressive nature of the disease promoted further decline in child's condition. Moreover, there was an issue with mother's compliance, resulting in spontaneous and unwarranted drug cancelation.	0
OPINION STATEMENT:Despite its rarity, hairy cell leukemia (HCL) remains a fascinating disease and the physiopathology is becoming more and more understood. The accurate diagnosis of HCL relies on the recognition of hairy cells by morphology and flow cytometry (FCM) in the blood and/or bone marrow (BM). The BRAF V600E mutation, an HCL-defining mutation, represents a novel diagnostic parameter and a potential therapeutic target. The precise cellular origin of HCL is a late-activated postgerminal center memory B cell. BRAF mutations were detected in hematopoietic stem cells (HSCs) of patients with HCL, suggesting that this is an early HCL-defining event. Watch-and-wait strategy is necessary in approximately 10% of asymptomatic HCL patients, sometimes for several years. Purine analogs (PNAs) are the established first-line options for symptomatic HCL patients. In second-line treatment, chemoimmunotherapy combining PNA plus rituximab should be considered in high-risk HCL patients. The three options for relapsed/refractory HCL patients include recombinant immunoconjugates targeting CD22, BRAF inhibitors, and BCR inhibitors. The clinical interest to investigate blood minimal residual disease (MRD) was recently demonstrated, with a high risk of relapse in patients with positive testing for MRD and a low risk in patients with negative testing. However, efforts must be made to standardize MRD analyses in the near future. Patients with HCL are at risk of second malignancies. The increased risk could be related to the disease and/or the treatment, and the respective role of PNAs in the development of secondary malignancies remains a topic of debate.	0
Mutations in the COL4A3 gene are frequently reported to be associated with various types of hereditary nephropathy. COL4A3 encodes the α3 chain of type IV collagen, which is the main structural protein in the basement membrane. Mutations in this gene are always related to kidney performance, and deafness and ocular lesion have also been reported. In this study, using next-generation sequencing, we investigated the DNA of a family visiting a clinic for hearing loss. A new missense mutation was found in COL4A3 of 5 patients, c.3227C>T (p.P1076L). Based on these results, we predict that the mutation is pathogenic and leads to abnormal collagen IV. Here, we report for the first time on this autosomal dominant syndrome, characterized by hearing loss and eye abnormalities, but without renal damage, in all carriers. Since the oldest patient in the trial was less than 50 years old, however, we recommend that renal examination be reviewed regularly. Our results reveal expansion in the mutation spectrum of the COL4A3 gene and phenotypic spectrum of collagen IV disease. Our study suggests that next-generation sequencing is an economical and effective method and may help in the accurate diagnosis and treatment of these patients.	0
Purpose:The aim of the present work is the molecular diagnosis of three patients with deafness and retinal degeneration. Methods:Three patients from two unrelated families were initially analyzed with custom gene panels for Usher genes, non-syndromic hearing loss, or inherited syndromic retinopathies and further investigated by means of clinical or whole exome sequencing. Results:The study allowed us to detect likely pathogenic variants in PEX6, a gene typically involved in peroxisomal biogenesis disorders (PBDs). Beside deaf-blindness, both families showed additional features: Siblings from Family 1 showed enamel alteration and abnormal peroxisome. In addition, the brother had mild neurodevelopmental delay and nephrolithiasis. The case II:1 from Family 2 showed intellectual disability, enamel alteration, and dysmorphism. Conclusions:We have reported three new cases with pathogenic variants in PEX6 presenting with milder forms of the Zellweger spectrum disorders (ZSD). The three cases showed distinct clinical features. Thus, expanding the phenotypic spectrum of PBDs and ascertaining exome sequencing is an effective strategy for an accurate diagnosis of clinically overlapping and genetically heterogeneous disorders such as deafness-blindness association.	0
Glycogen storage disease type XV (GSD XV) is a recently described muscle glycogenosis due to glycogenin-1 (GYG1) deficiency characterized by the presence of polyglucosan bodies on muscle biopsy (Polyglucosan body myopathy-2, PGBM2). Here we describe a 44 year-old man with limb-girdle muscle weakness mimicking a limb-girdle muscular dystrophy (LGMD), and early onset exertional myalgia. Neurologic examination revealed a waddling gait with hyperlordosis, bilateral asymmetric scapular winging, mild asymmetric deltoid and biceps brachii weakness, and pelvic-girdle weakness involving the gluteal muscles and, to a lesser extent, the quadriceps. Serum creatine kinase levels were slightly elevated. Electrophysiological examination showed a myopathic pattern. There was no cardiac or respiratory involvement. Whole-body muscle MRI revealed atrophy and fat replacement of the tongue, biceps brachii, pelvic girdle and erector spinae. A deltoid muscle biopsy showed the presence of PAS-positive inclusions that remained non-digested with alpha-amylase treatment. Electron microscopy studies confirmed the presence of polyglucosan bodies. A diagnostic gene panel designed by the Genetic Diagnosis Laboratory of Strasbourg University Hospital (France) for 210 muscular disorders genes disclosed two heterozygous, pathogenic GYG1 gene mutations (c.304G>C;p.(Asp102His) + c.164_165del). Considering the clinical heterogeneity found in the previously described 38 GYG-1 deficient patients, we suggest that GYG1 should be systematically included in targeted NGS gene panels for LGMDs, distal myopathies, and metabolic myopathies.	0
BACKGROUND:An expanding cohort of patients with spina bifida live well into adulthood and pose complex management challenges due to unique combinations of adult health issues overlying congenital problems. CASE DESCRIPTION:We present a case of a 45-year-old woman with an expanding, disfiguring, painful lumbar meningocele more than 40 years after her only surgery as a 3-year-old child. A team of pediatric and adult neurosurgeons as well as plastic/reconstructive surgeons successfully performed surgery to obliterate the meningocele, with preservation of her baseline functional status, and no evidence of recurrence after more than 1 year of follow-up. CONCLUSIONS:Symptomatic meningocele may present in a long-delayed fashion in adult patients with a history of spina bifida. Surgical treatment may provide symptomatic benefit.	0
Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune liver disease characterized by inflammation and damage of small bile ducts. The NLRP3 inflammasome is a multimeric complex of proteins that after activation with various stimuli initiates an inflammatory process. Increasing data obtained from animal studies implicate the role of NLRP3 inflammasome in the pathogenesis of various diseases. Galectin-3 is a β-galactoside-binding lectin that plays important roles in various biological processes including cell proliferation, differentiation, transformation and apoptosis, pre-mRNA splicing, inflammation, fibrosis and host defense. The multilineage immune response at various stages of PBC development includes the involvement of Gal-3 in the pathogenesis of this disease. The role of Galectin-3 in the specific binding to NLRP3, and inflammasome activation in models of primary biliary cholangitis has been recently described. This review provides a brief pathogenesis of PBC and discusses the current knowledge about the role of Gal-3 in NLRP3 activation and PBC development.	0
OBJECTIVE:Symptomatic long-term hypoparathyroidism following thyroid surgery requires an alternative and permanent therapy that would effectively restore parathyroid function and eliminate the need for substitution drug therapy. The aim of this study was to systematically review the literature on the efficacy and safety of parathyroid allotransplantation to treat post-operative hypoparathyroidism. METHODS:MEDLINE, Embase, BIOSIS and the Cochrane Library were searched for published articles (from inception of each database to September 30, 2018). A total of 9 studies comprising 146 patients (177 allotransplantations) with post thyroidectomy hypoparathyroidism were identified. RESULTS:Parathyroid tissues used for allotransplant were cultured parathyroid cells, cryopreserved parathyroid cells and encapsulated microspheres. Post-transplant immunosuppression was only reported in three studies, mainly with oral prednisolone for 2 weeks to 6 months. Mean graft survival following allotransplantation was 47% (95% CI 24%-71%) when patients were followed-up to 6 months and 41% (95% CI 2.3%-80%) at 12 months. There was significant unexplained heterogeneity observed between studies in both these groups (I2 > 50%). Parathyroid hormone (PTH) levels, and serum calcium levels post intervention was not reported in all studies, but available evidence suggests the levels remains higher (PTH level around 12 pg/ml; Ca level around 8 mg/dl) post-allotransplantation for up to 24 months. CONCLUSIONS:Long-term benefit and harms of allotransplantation is still unclear due to the clinical and statistical heterogeneity observed among the studies. Therefore, conduct of a well-designed controlled clinical trial in the immediate future on allotransplantation is of paramount importance.	0
Weill-Marchesani syndrome (WMS) is a rare disorder displaying short stature, brachydactyly and joint stiffness, and ocular features including microspherophakia and ectopia lentis. Brachydactyly and joint stiffness appear less commonly in patients with WMS4 caused by pathogenic ADAMTS17 variants. Here, we investigated a large family with WMS from Newfoundland, Canada. These patients displayed core WMS features, but with proportionate hands that were clinically equivocal for brachydactyly. Whole exome sequencing and autozygosity mapping unveiled a novel pathogenic missense ADAMTS17 variant (c.3068 G > A, p.C1023Y). Sanger sequencing demonstrated variant co-segregation with WMS, and absence in 150 population matched controls. Given ADAMTS17 involvement, we performed deep phenotyping of the patients' hands. Anthropometrics applied to hand roentgenograms showed that metacarpophalangeal measurements of affected patients were smaller than expected for their age and sex, and when compared to their unaffected sibling. Furthermore, we found a possible sub-clinical phenotype involving markedly shortened metacarpophalangeal bones with intrafamilial variability. Transfection of the variant ADAMTS17 into HEK293T cells revealed significantly reduced secretion into the extracellular medium compared to wild-type. This work expands understanding of the molecular pathogenesis of ADAMTS17, clarifies the variable hand phenotype, and underscores a role for anthropometrics in characterizing sub-clinical brachydactyly in these patients.	0
MOTIVATION:De novo mutations (i.e. newly occurring mutations) are a pre-dominant cause of sporadic dominant monogenic diseases and play a significant role in the genetics of complex disorders. De novo mutation studies also inform population genetics models and shed light on the biology of DNA replication and repair. Despite the broad interest, there is room for improvement with regard to the accuracy of de novo mutation calling. RESULTS:We designed novoCaller, a Bayesian variant calling algorithm that uses information from read-level data both in the pedigree and in unrelated samples. The method was extensively tested using large trio-sequencing studies, and it consistently achieved over 97% sensitivity. We applied the algorithm to 48 trio cases of suspected rare Mendelian disorders as part of the Brigham Genomic Medicine gene discovery initiative. Its application resulted in a significant reduction in the resources required for manual inspection and experimental validation of the calls. Three de novo variants were found in known genes associated with rare disorders, leading to rapid genetic diagnosis of the probands. Another 14 variants were found in genes that are likely to explain the phenotype, and could lead to novel disease-gene discovery. AVAILABILITY AND IMPLEMENTATION:Source code implemented in C++ and Python can be downloaded from https://github.com/bgm-cwg/novoCaller. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.	0
Popliteal pterygium syndrome is a condition characterized by skin webs on the popliteal fossa, which may impair mobility unless surgically repaired. Affected individuals may also have syndactyly on the fingers and/or toes. Most people with this disorder present cleft lip and cleft palate and they can have syngnathia, that is a congenital adhesion between maxilla and mandible by fibrous bands, which affects the opening of the mouth. The case that we report is about a 2-month-old male, who presented skin webs bilaterally on the popliteal fossa, syndactyly between the IV and the V toe of the right foot and between the III and the IV toe of the left foot, and genital malformations. He was born with complete bilateral cleft lip and complete cleft palate on the left side and incomplete cleft palate on the right side and syngnathia with 4 fibrous bands between the mandibular arch and the maxilla arch on the right side, which affected the opening of the mouth. The case of our patient is very interesting because there have been few reported patients affected by popliteal pterygium syndrome with syngnathia.	0
PURPOSE:Posterior column ataxia and retinitis pigmentosa (PCARP) is a rare form of syndromic RP associated with mutations in the FLVCR1 gene. Recent evidence has suggested a spectrum in the phenotype depending on the genotype. METHODS:Six individuals with retinitis pigmentosa (RP) carrying mutations in the FLVCR1 gene underwent detailed ophthalmological examinations at the Center for Ophthalmology and two of these also an extensive neurological examination at the Department of Neurology in Tuebingen, Germany. RESULTS:The mutation spectrum in our cohort comprised one nonsense mutation, one 1-bp deletion, two missense variants, and one splice site variant (c.1092+5G>A). Three patients presented with a typical clinical picture of autosomal recessive RP, two patients presented with atypical RP, and one patient presented with a particularly mild form of RP. The findings of the patients that underwent detailed neurological and neurophysiological testing were not suggestive for the presence of progressive PCA, but one patient showed mild cerebellar signs without worsening over time. Five out of six of our cases carry the splice site variant c.1092+5G>A at least on one allele possibly providing evidence as to that this splice site variant may cause a milder form of non-syndromic autosomal recessive RP. CONCLUSIONS:Mutations in FLVCR1 can present with the clinical picture of a non-syndromic autosomal recessive RP (in this case RP without PCA), RP with mild cerebellar signs, but also PCARP. Additionally, we show evidence for a spectrum of the severity of the retinal involvement likely depending on the genotype.	0
BACKGROUND:Hereditary spastic paraplegia is a heterogeneous group of clinically and genetically neurodegenerative diseases characterized by progressive gait disorder. Hereditary spastic paraplegia can be inherited in various ways, and all modes of inheritance are associated with multiple genes or loci. At present, more than 76 disease-causing loci have been identified in hereditary spastic paraplegia patients. Here, we report a novel mutation in SPAST gene associated with hereditary spastic paraplegia in a Chinese family, further enriching the hereditary spastic paraplegia spectrum. METHODS:Whole genomic DNA was extracted from peripheral blood of the 15 subjects from a Chinese family using DNA Isolation Kit. The Whole Exome Sequencing of the proband was analyzed and the result was identified in the rest individuals. RaptorX prediction tool and Protein Variation Effect Analyzer were used to predict the effects of the mutation on protein tertiary structure and function. RESULTS:Spastic paraplegia has been inherited across at least four generations in this family, during which only four HSP patients were alive. The results obtained by analyzing the Whole Exome Sequencing of the proband exhibited a novel disease-associated in-frame deletion in the SPAST gene, and this mutation also existed in the rest three HSP patients in this family. This in-frame deletion consists of three nucleotides deletion (c.1710_1712delGAA) within the exon 16, resulting in lysine deficiency at the position 570 of the protein (p.K570del). This novel mutation was also predicted to result in the synthesis of misfolded SPAST protein and have the deleterious effect on the function of SPAST protein. CONCLUSION:In this case, we reported a novel mutation in the known SPAST gene that segregated with HSP disease, which can be inherited in each generation. Simultaneously, this novel discovery significantly enriches the mutation spectrum, which provides an opportunity for further investigation of genetic pathogenesis of HSP.	0
The advent of acrylate-based nail treatments-known as gels, dips, or shellac-has resulted in an uptick in nail-related acrylate allergy. Acrylate dermatitis related to nail services can affect both clients and technicians and can present on the hands, fingers, and wrists, as well as on the face and neck. Nail acrylate allergy occurs from sensitization to acrylate monomers; 2-hydroxyethyl methacrylate (HEMA), 2-hydroxypropyl methacrylate, ethyl cyanoacrylate, and others have been identified as relevant allergens. Patch testing with HEMA and ethyl cyanoacrylate can screen for nail acrylate allergy. Avoidance is key, and we recommend less-permanent, acrylate-free nail polishes as alternatives.	0
PURPOSE:Singleton-Merten syndrome manifests as dental dysplasia, glaucoma, psoriasis, aortic calcification, and skeletal abnormalities including tendon rupture and arthropathy. Pathogenic variants in IFIH1 have previously been associated with the classic Singleton-Merten syndrome, while variants in DDX58 has been described in association with a milder phenotype, which is suggested to have a better prognosis. We studied a family with severe, "classic" Singleton-Merten syndrome. METHODS:We undertook clinical phenotyping, next-generation sequencing, and functional studies of type I interferon production in patient whole blood and assessed the type I interferon promoter activity in HEK293 cells transfected with wild-type or mutant DDX58 stimulated with Poly I:C. RESULTS:We demonstrate a DDX58 autosomal dominant gain-of-function mutation, with constitutive upregulation of type I interferon. CONCLUSIONS:DDX58 mutations may be associated with the classic features of Singleton-Merten syndrome including dental dysplasia, tendon rupture, and severe cardiac sequela.	0
Eccrine syringofibroadenoma (ESFA) is a rare benign cutaneous adnexal lesion characterized by a hyperplastic epithelium and eccrine ductal differentiation. In the present case, a 73-year-old Korean male presented with symmetrical numerous widespread, pinkish nodules with a cobblestone appearance over both legs for 2 years. He had a history of generalized erythematous scaly patches over his entire body for 20 years. On histopathologic findings, diagnosis of ESFA was confirmed. Our unusual and interesting case emphasizes the first report described one case in which multiple cobblestone like ESFAs arising from long-standing exfoliative dermatitis.	0
The structures of the bovine and human BBSome reveal that a conformational change is required to recruit the complex to the ciliary membrane.	0
OBJECTIVE:To describe bone densitometry results using lumbar spine dual-energy X-ray absorptiometry and forearm peripheral quantitative computed tomography (pQCT) in children with arthrogryposis multiplex congenita (AMC). STUDY DESIGN:Prospective study. RESULTS:Lumbar spine areal bone mineral density (BMD) was measured in 58 participants (mean age 6.8 years, range 1 month to 19.7 years; 26 males). The diagnostic subgroup was Amyoplasia in 27 participants, distal arthrogryposis (unclassified, n = 13; type 2A, n = 1; type 2B, n = 2; type 8, n = 2) in 18 patients, an unclassified form of arthrogryposis in 6 patients, and a syndromic form of arthrogryposis in 7 patients. The mean lumbar spine areal BMD was -0.4 (SD: 1.5) which was significantly below 0 (p < 0.05, one-sample t-test). The mean lumbar spine bone mineral apparent density z-score (+0.4 [SD: 1.4]), a measure that is largely independent of bone size, was not significantly different from 0 (P > 0.05). A subset of 22 patients aged 6 years or older (mean age 10.9 years, 11 males) had forearm pQCT analysis. Mean z-scores for trabecular and cortical volumetric BMD at the radius were similar to healthy controls. Radius periosteal bone circumference and bone mineral content were appropriate for height. These densitometric results did not differ between patients with Amyoplasia or individuals with other diagnoses. CONCLUSIONS:Low areal BMD in children and adolescents with AMC reflects their smaller bone size rather than a specific bone mass deficit. These data do not suggest that children and adolescents with AMC in general require regular monitoring by bone densitometry unless there are specific clinical concerns.	0
A newborn screening program for congenital hypothyroidism (CH) and phenylketonuria (PKU), a pilot study, was initiated at the Medical Genetics Unit, Department of Pediatrics, Siriraj Hospital Faculty of Medicine, Mahidol University in Bangkok, Thailand from January 1994 to December 1998, using dried blood spots (DBS). A total of 18,739 infants (out of 85,150 livebirths) were screened (22 % coverage). Three cases of congenital hypothyroidism (CH) were identified (incidence of 1: 6,246, livebirths), by enzyme linked immunosorbent (ELISA) and fluoroimmunoassays using a cut-off level of TSH >20 microlU/ml: the recall rate of 0.24%. The screening for PKU was done by fluorometric (Guthrie) and enzyme linked immunosorbent (ELISA) methods; using cut-off levels of phenylalanine > 4 mg/dl and > 3.6 mg/dl respectively, with a recall rate of 0.13%. There was no PKU found. Our study, a voluntary program, emphasizes the importance of parental education and consent; specimen collection and handling; appropriate follow-up and referral to specialists for treatment and counseling. Routine newborn screening for CH and PKU is being established to ascertain the maximum coverage, using recommendations and guidelines from this pilot study.	1
AIM:Patients undergoing resectional surgery for enterovesical fistulas generally have an indwelling urinary catheter postoperatively to prevent a recurrent fistula. The aim of this study was to assess the role of a cystogram as part of the postoperative follow-up of such surgery, when it should be performed and for how long the bladder should be drained after surgery. METHOD:A retrospective single-centre study of all patients undergoing ileocaecal or sigmoid resection for surgery for enterovesical fistula with the primary end-point of recurrent urinary fistula. RESULTS:Between 1994 and 2015, 46 patients (23 male; mean age 55.4 ± 18.3 years) underwent surgery [23 (50%) for diverticular disease, 16 (34.8%) for Crohn's disease, five (10.9%) for malignancy and two (4.3%) for previous radiotherapy]. Closure of the bladder fistula was by simple suture in 21 (46%) patients and with an omental pedicle in 16 (36%). Overall median duration of urinary drainage was 10.5 [interquartile range (IQR): 7.3-14.0] days. A postoperative cystogram was performed in 26 (57%) patients after a median of 10.0 (IQR: 8.0-13.0) days. This demonstrated persistent leakage in three patients, of whom two had undergone surgical closure of the bladder. This group required prolonged drainage (7, 19 and 40 days). One patient who had undergone surgery following radiotherapy for urothelial cancer developed a recurrent malignant fistula at 9 months, even though the postoperative cystogram had been negative. CONCLUSION:This study suggests that a routine postoperative cystogram after surgery for enterovesical fistula may not be necessary for all patients if the bladder is drained for 1-2 weeks after bowel resection.	0
To explore the genetics mechanism for the phenotypic variability in a patient carrying a rare ring chromosome 9.The karyotype of the patient was analyzed with cytogenetics method. Presence of sex chromosome was confirmed with fluorescence in situ hybridization. The SRY gene was subjected to PCR amplification and direct sequencing. Potential deletion and duplication were detected with array-based comparative genomic hybridization (array-CGH).The karyotype of the patient has comprised 6 types of cell lines containing a ring chromosome 9. The SRY gene sequence was normal. By array-CGH, the patient has carried a hemizygous deletion at 9p24.3-p23 (174 201-9 721 761) encompassing 30 genes from Online Mendelian Inheritance in Man.The phenotypic variability of the 9p deletion syndrome in conjunct with ring chromosome 9 may be attributable to multiple factors including loss of chromosomal material, insufficient dosage of genes, instability of ring chromosome, and pattern of inheritance.	0
Baller-Gerold (BGS, MIM#218600) and Roberts (RBS, MIM#268300) syndromes are rare autosomal recessive disorders caused, respectively, by biallelic alterations in RECQL4 (MIM*603780) and ESCO2 (MIM*609353) genes. Common features are severe growth retardation, limbs shortening and craniofacial abnormalities which may include craniosynostosis. We aimed at unveiling the genetic lesions underpinning the phenotype of two unrelated children with a presumptive BGS diagnosis: patient 1 is a Turkish girl with short stature, microcephaly, craniosynostosis, seizures, intellectual disability, midface hemangioma, bilateral radial and thumb aplasia, tibial hypoplasia, and pes equinovarus. Patient 2 is an Iranian girl born to consanguineous parents with craniosynostosis, micrognathism, bilateral radial aplasia, thumbs, and foot deformity in the context of developmental delay. Upon negative RECQL4 test, whole exome sequencing (WES) analysis performed on the two trios led to the identification of two different ESCO2 homozygous inactivating variants: a previously described c.1131+1G>A transition in patient 1 and an unreported deletion, c.417del, in patient 2, thus turning the diagnosis into Roberts syndrome. The occurrence of a Baller-Gerold phenotype in two unrelated patients that were ultimately diagnosed with RBS demonstrates the strength of WES in redefining the nosological landscape of rare congenital malformation syndromes, a premise to yield optimized patients management and family counseling.	0
Spinocerebellar ataxia 8 (SCA8), a triplet repeat expansion disorder, is genetically distinct from the other inherited ataxias, but its unusually variable phenotype can make its diagnosis difficult. In this review we describe 3 new cases of genetically verified SCA8 to highlight the broad clinical spectrum of symptoms observed with this disorder and to draw attention to the features of myoclonus and migraine headaches, which in the context of cerebellar ataxia warrants the clinician to consider SCA8 as a potential diagnosis. We also address the controversy surrounding the genetic testing approach for diagnosing SCA8. Finally, we evaluate the evidence that SCA8 may affect calcium channel function and that the presentation of episodic ataxia and migraines suggests a clinical and pathogenic overlap of SCA8 with the channelopathies.	0
Ehlers-Danlos syndrome (EDS) is an inherited disorder of collagen biosynthesis and structure, characterized by skin hyperextensibility, joint hypermobility, aberrant scars, and tissue friability. Besides the skin, skeleton (joint) and vessels, other organs such as the eyes and the intestine can be affected in this syndrome. Accordingly, interdisciplinary cooperation is necessary for a successful treatment. Three basic surgical problems are arising due to an EDS: decreased the strength of the tissue causes making the wound dehiscence, increased bleeding tendency due to the blood vessel fragility, and delayed wound healing period. Surgery patients with an EDS require an experienced surgeon in treating EDS patients; the treatment process requires careful tissue handling and a long postoperative care. A surgeon should also recognize whether the patient shows a resistance to local anesthetics and a high risk of hematoma formation. This report describes a patient with a wide open wound on the foot dorsum and delayed wound healing after the primary approximation of the wound margins.	0
Altered Bone Morphogenetic Protein (BMP) signaling leads to multiple developmental defects, including brachydactyly and deafness. Here we identify chondroitin synthase 1 (CHSY1) as a potential mediator of BMP effects. We show that loss of human CHSY1 function causes autosomal-recessive Temtamy preaxial brachydactyly syndrome (TPBS), mainly characterized by limb malformations, short stature, and hearing loss. After mapping the TPBS locus to chromosome 15q26-qterm, we identified causative mutations in five consanguineous TPBS families. In zebrafish, antisense-mediated chsy1 knockdown causes defects in multiple developmental processes, some of which are likely to also be causative in the etiology of TPBS. In the inner ears of zebrafish larvae, chsy1 is expressed similarly to the BMP inhibitor dan and in a complementary fashion to bmp2b. Furthermore, unrestricted Bmp2b signaling or loss of Dan activity leads to reduced chsy1 expression and, during epithelial morphogenesis, defects similar to those that occur upon Chsy1 inactivation, indicating that Bmp signaling affects inner-ear development by repressing chsy1. In addition, we obtained strikingly similar zebrafish phenotypes after chsy1 overexpression, which might explain why, in humans, brachydactyly can be caused by mutations leading either to loss or to gain of BMP signaling.	0
Combined liver/kidney transplant is the preferred transplant option for most patients with primary hyperoxaluria type 1 (PH1) since orthotopic liver transplantation replaces the deficient liver-specific AGT enzyme, thus restoring normal metabolic oxalate production. However, primary hyperoxaluria type 2 (PH2) is caused by deficient glyoxylate reductase/hydroxypyruvate reductase (GRHPR), and this enzyme is widely distributed throughout the body. Though the relative abundance and activity of GRHPR in various tissues is not clear, some evidence suggests that the majority of enzyme activity may indeed reside within the liver. Thus the effectiveness of liver transplantation in correcting this metabolic disorder has not been demonstrated. Here we report a case of 44-year-old man with PH2, frequent stone events, and end-stage renal disease; he received a combined liver/kidney transplant. Although requiring confirmation in additional cases, the normalization of plasma oxalate, urine oxalate, and urine glycerate levels observed in this patient within a month of the transplant that remain reduced at the most recent follow-up at 13 months suggests that correction of the GRHPR deficiency in PH2 can be achieved by liver transplantation.	0
Congenital hemolytic anemias (CHAs) are a heterogeneous group of rare hereditary conditions including defects of erythrocyte membrane proteins, red cell enzymes, and disorders due to defective erythropoiesis. They are characterized by variable degree of anemia, chronic extravascular hemolysis, reduced erythrocyte life span, splenomegaly, jaundice, biliary lithiasis, and iron overload. Although few data are reported on the role of the immune system in CHAs, several immune-mediated mechanisms may be involved in the pathogenesis of these rare diseases. We reported in ~60% of patients with hereditary spherocytosis (HS), the presence of naturally-occurring autoantibodies (NAbs) directed against different membrane proteins (α- and β-spectrin, band 3, and dematin). Positive HS subjects showed a more hemolytic pattern and NAbs were more evident in aged erythrocytes. The latter is in line with the function of NAbs in the opsonization of damaged/senescent erythrocytes and their consequent removal in the spleen. Splenectomy, usually performed to reduce erythrocyte catheresis and improve Hb levels, has different efficacy in various CHAs. Median Hb increase is 3 g/dL in HS, 1.6-1.8 g/dL in pyruvate kinase deficiency (PKD), and 1 g/dL in congenital dyserythropoietic anemias (CDA) type II. Consistently with clinical severity, splenectomy is performed in 20% of HS, 45% of CDAII, and in 60% of PKD patients. Importantly, sepsis and thrombotic events have been registered, particularly in PKD with a frequency of ~7% for both. Furthermore, we analyzed the role of pro-inflammatory cytokines and found that interleukin 10 and interferon γ, and to a lesser extent interleukin 6, were increased in all CHAs compared with controls. Moreover, CDAII and enzymatic defects showed increased tumor necrosis factor-α and reduced interleukin 17. Finally, we reported that iron overload occurred in 31% of patients with membrane defects, in ~60% of CDAII cases, and in up to 82% of PKD patients (defined by MRI liver iron concentration >4 mg Fe/gdw). Hepcidin was slightly increased in CHAs compared with controls and positively correlated with ferritin and with the inflammatory cytokines interleukin 6 and interferon γ. Overall the results suggest the existence of a vicious circle between chronic hemolysis, inflammatory response, bone marrow dyserythropoiesis, and iron overload.	0
OBJECTIVE:To determine the event-free survival (EFS), overall survival (OS) and predictors of outcome in pediatric anaplastic large cell lymphoma treated with a uniform protocol. METHOD:This hospital record review was done between June, 2016 to March, 2019 and data was extracted from January, 2003 to May, 2016 for anaplastic large cell lymphoma (ALCL) in patients aged 1 to 18 years (n=27). EFS and OS were calculated by the Kaplan Meier method. Cox proportional model and the Cox regression model were used for univariate analysis and multivariate analysis respectively. RESULTS:EFS and OS at three years was 70.4% (CI: 0.49-0.84) and 77.2% (CI: 0.56 -0.89), respectively. On univariate analysis stage III and IV, hemoglobin less than 10 g/dL and presence of pleural effusion predicted lower survival. On multivariate analysis, pleural effusion was a significant predictor of low EFS and OS. CONCLUSION:Pleural effusion is a potential clinical marker of poor outcome among children with anaplastic large cell lymphoma.	0
OBJECTIVE:To investigate the association between a genetic risk score (GRS) and familial late-onset Alzheimer disease (LOAD) and its predictive value in families multiply affected by the disease. METHODS:Using data from the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease (National Institute on Aging-Late-Onset Alzheimer's Disease Family Study), mixed regression models tested the association of familial LOAD with a GRS based on single nucleotide polymorphisms (SNPs) previously associated with LOAD. We modeled associations using unweighted and weighted scores with estimates derived from the literature. In secondary models, we adjusted subsequent models for presence of the APOE ε4 allele and further tested the interaction between APOE ε4 and the GRS. We constructed a similar GRS in a cohort of Caribbean Hispanic families multiply affected by LOAD by selecting the SNP with the strongest p value within the same regions. RESULTS:In the NIA-LOAD families, the GRS was significantly associated with LOAD (odds ratio [OR] 1.29; 95% confidence interval 1.21-1.37). The results did not change after adjusting for APOE ε4. In Caribbean Hispanic families, the GRS also significantly predicted LOAD (OR 1.73; 1.57-1.93). Higher scores were associated with lower age at onset in both cohorts. CONCLUSIONS:High GRS increases the risk of familial LOAD and lowers the age at onset, regardless of ethnic group.	0
The neuronal type of primary chronic idiopathic intestinal pseudoobstruction (CIIP) results from the developmental failure of enteric neurons to migrate or differentiate correctly. This leads to intestinal motility disorders, which are characterized by symptoms and signs of bowel obstruction in the absence of a mechanical obstacle. Most of these conditions are congenital, and among them some are inherited. One syndromic condition characterized by intestinal pseudoobstruction with morphological abnormalities of the argyrophil neurons in the myenteric plexus, associated with short small bowel, malrotation, and pyloric hypertrophy, has been previously described. We have studied a family affected by this disorder, in which the disease appeared to segregate as an X-linked recessive trait. In order to map the CIIP locus in this family, we performed linkage analysis in 26 family members by use of highly polymorphic microsatellite markers from the X chromosome. One of these markers, DXYS154, located in the distal part of Xq28, shows no recombination with a maximum lod score of 2.32. Multipoint analysis excluded linkage with markers spanning other regions of the X chromosome. Our results, integrated with the current genetic and physical map of Xq28, determine the order of loci as cen-DXS15-(CIIPX)-DXS1108/DXYS154-tel. This study establishes, for the first time, the mapping assignment of a neuropathic form of CIIP other than Hirschsprung disease.	0
Background:Corticotomy is a technique presumed as useful to decrease the time for orthodontic treatment, however, it is necessary to do a systematic review in order to determine if there is enough scientific evidence to back up the use of Corticotomy to accelerate the treatment. Material and Methods:Data was stockpiled from the electronic database such as PubMed, Cochrane, Scopus y Science Direct, according to the PRISMA linings for systematic reviews, using the following keywords: accelerated movement of the teeth AND osteotomy AND piezocision AND corticotomy AND orthodontics. Only English, Spanish and French language articles that met the criteria needed were included. Results:In the different accelerated orthodontics techniques, a significant reduction in the total time of orthodontic treatment was obtained. There were no major complications reported in any study. The less invasive procedures had better acceptance. Discussion:The surgical approaches are not only limited to usual orthodontic treatments, but they have also been used as an alternative for the approach of a palatal fistula in a patient with bilateral cleft lip and palatine orofaciodigital syndrome Type I. Conclusions:There has been a growing interest in the use of alveolar corticotomies as an adjunct to orthodontic treatment, due to a deeper understanding of its effects and a more robust investigation based on the evidence. All published results indicate a decrease in the total treatment time. Key words:Accelerated movement of the teeth, piezocision, corticotomy AND orthodontics.	0
MYH7 gene mutations are associated with wide clinical and genetic heterogeneity. We report a novel founder mutation in MYH7 in Southern Spain (Andalucía). We studied two index patients and 24 family members from two apparently independent families by physical examination, serum creatine-kinase, muscle MRI, sequencing studies and genetic linkage analysis. Sixteen individuals were heterozygous for a (p.R1560P) variant in the MYH7 gene. Haplotype was consistent with a common ancestor for the two families. The patients displayed the classic Laing distal myopathy phenotype, with hanging first toe as the initial presentation, even in mildly affected patients who declared themselves asymptomatic, although neck flexor weakness was revealed as an early sign in some cases. MRI showed that the sartorius was the first muscle involved, even in two out of three asymptomatic carriers. Our findings support the novel variant p.R1560P in MYH7 as a founder mutation in Andalucía. The early involvement of the sartorius muscle in MRI may be useful as an indicator of affection status.	0
Schwartz-Jampel syndrome (SJS) is a rare genetic condition that is characterized by several musculoskeletal abnormalities, such as myotonia, joint contractures, and facial dysmorphisms. Patients with this syndrome can present an anesthetic challenge, due to an increased risk of developing malignant hyperthermia (MH) and the possibility of encountering a difficult airway. Several precautions must be taken when general anesthesia is required, such as the avoidance of potential triggers for MH, continuous core temperature, and end-tidal CO2 monitoring, assuring that dantrolene is readily available. It is also fundamental to prepare for a possible difficult airway, guaranteeing that difficult airway devices are available. We describe the anesthetic management of a 14-year-old boy diagnosed with SJS who was scheduled for multiple dental extractions and was successfully anesthetized with our approach.	0
WRN mutation causes a premature aging disease called Werner syndrome (WS). However, the mechanism by which WRN loss leads to progeroid features evident with impaired tissue repair and regeneration remains unclear. To determine this mechanism, we performed gene editing in reprogrammed induced pluripotent stem cells (iPSCs) derived from WS fibroblasts. Gene correction restored the expression of WRN. WRN+/+ mesenchymal stem cells (MSCs) exhibited improved pro-angiogenesis. An analysis of paracrine factors revealed that hepatocyte growth factor (HGF) was downregulated in WRN-/- MSCs. HGF insufficiency resulted in poor angiogenesis and cutaneous wound healing. Furthermore, HGF was partially regulated by PI3K/AKT signaling, which was desensitized in WRN-/- MSCs. Consistently, the inhibition of the PI3K/AKT pathway in WRN+/+ MSC resulted in reduced angiogenesis and poor wound healing. Our findings indicate that the impairment in the pro-angiogenic function of WS-MSCs is due to HGF insufficiency and PI3K/AKT dysregulation, suggesting trophic disruption between stromal and epithelial cells as a mechanism for WS pathogenesis.	0
Angel-shaped phalango-epiphyseal dysplasia is characterized by the angel shape of the middle phalanx and severe coxarthrosis in adult life. This osteochondrodysplasia shows a further variety of heterogeneous multiple epiphyseal dysplasias. It also shows a late and dysplastic development of the femoral head that leads to osteoarthrotic changes with severe hip pain and gait disturbance. In this report, we show a 35-year-old female with Angel-shaped phalango-epiphyseal dysplasia that was treated by bilateral total hip arthroplasty. She has suffered from her coxalgia since she was 27 and since the age of 30 has been able to walk with the aid of crutches. The radiographs of her bilateral hip showed severe osteochondrotic changes with a progressive disappearance of the joint space. Total hip arthroplasties were performed to treat the osteoarthrosis on the bilateral hip joint due to Angel-shaped phalango-epiphyseal dysplasia. One year after surgery, she is pain-free, and able to walk with a cane. Based on this case, we propose that total hip arthroplasty should be considered one of the treatments for the coxopathy in patients with Angel-shaped phalangoepiphyseal dysplasia.	0
Low circulating high-density lipoproteins (HDL) are not only a defining criteria for metabolic syndrome, but are more generally associated with atherosclerotic cardiovascular disease (ASCVD) and other chronic diseases. Oxidative stress, a hallmark of cardio-metabolic disease, further influences HDL activity by suppressing their function. Especially the leukocyte-derived enzyme myeloperoxidase (MPO) has recently attracted great interest as it catalyzes the formation of oxidizing reactive species that modify the structure and function of HDL, ultimately increasing cardiovascular risk. Contrariwise, paraoxonase-1 (PON1) is an HDL-associated enzyme that protects HDL from lipid oxidation, and then acts as a protective factor against ASCVD. Noteworthy, recent studies have demonstrated how MPO, PON1 and HDL form a functional complex in which PON1 partially inhibits the MPO activity, while MPO in turn partially inactivates PON1.In line with that, high MPO/PON1 ratio characterizes patients with ASCVD and metabolic syndrome and has been suggested as a potential marker of dysfunctional HDL as well as a predictor of ASCVD. In this review, we summarize the evidence on the interactions between MPO and PON1 with regard to their structure, function and interaction with HDL activity. We also provide an overview on in vitro and experimental animal models, finally focusing on clinical evidence from cohort of patients with ASCVD and metabolic syndrome.	0
PURPOSE:The purpose of this study was to compare ventricular vascular coupling ratio (VVCR) between patients with repaired standard tetralogy of Fallot (TOF) and those with repaired TOF-pulmonary atresia (TOF-PA) using cardiovascular magnetic resonance (CMR). MATERIALS AND METHODS:Patients with repaired TOF aged>6 years were prospectively enrolled for same day CMR, echocardiography, and exercise stress test following a standardized protocol. Sanz's method was used to calculate VVCR as right ventricle (RV) end-systolic volume/pulmonary artery stroke volume. Regression analysis was used to examine associations with exercise test parameters, New York Heart Association (NYHA) class, RV size and biventricular systolic function. RESULTS:A total of 248 subjects were included; of these 222 had repaired TOF (group I, 129 males; mean age, 15.9±4.7 [SD] years [range: 8-29 years]) and 26 had repaired TOF-PA (group II, 14 males; mean age, 17.0±6.3 [SD] years [range: 8-29 years]). Mean VVCR for all subjects was 1.54±0.64 [SD] (range: 0.43-3.80). Mean VVCR was significantly greater in the TOF-PA group (1.81±0.75 [SD]; range: 0.78-3.20) than in the standard TOF group (1.51±0.72 [SD]; range: 0.43-3.80) (P=0.03). VVCR was greater in the 68 NYHA class II subjects (1.79±0.66 [SD]; range: 0.75-3.26) compared to the 179 NYHA class I subjects (1.46±0.61 [SD]; range: 0.43-3.80) (P<0.001). CONCLUSION:Non-invasive determination of VVCR using CMR is feasible in children and adolescents. VVCR showed association with NYHA class, and was worse in subjects with repaired TOF-PA compared to those with repaired standard TOF. VVCR shows promise as an indicator of pulmonary artery compliance and cardiovascular performance in this cohort.	0
Objective Pyridoxine responsive seizures (PDRs) are characterized by early-onset seizures and epileptic encephalopathy (neonates and infants) which respond to pyridoxine. Any type of seizures can be the first presentation of PDRs in these children. The aim of this 20-year retrospective study was to report the profile of 35 children with PDRs. Materials and Methods Neonatal and infantile seizures responding to pyridoxine were analyzed retrospectively from 1998 to 2018. Depending on the clinical features, laboratory results, and genetic study, they were divided into following four groups: (A) responders with α-aminoadipic semialdehyde dehydrogenase 7A1 ( ALDH7A1 ) mutation, (B) responders with pyridoxal phosphate homeostasis protein (PLPHP) mutation, (C) responders with none of these two known mutations, (D) and responders in combination with antiepileptic medications. Results Sixteen of 35 children had genetic mutation, 4 with ALDH7A1 mutation, and 12 with PLPHP mutation recently described. Nineteen of 35 children had no genetic positivity. Conclusion A large number of children with pyridoxine response do not have known genetic confirmation. Over time, new genes, responsible for pyridoxine dependency, may be identified or an unknown metabolic disorder may be seen in these children.	0
Polyploidy-or chromosome doubling-plays a significant role in plant speciation and evolution. Much of the existing evidence indicates that fusion of unreduced (or 2n) gametes is the major pathway responsible for polyploid formation. In the early 1900s, a theory was put forward that the mechanism of "hybridization followed by chromosome doubling" would enable the survival and development of the hybrid zygote by providing each chromosome with a homolog with which to pair. However, to date there is only scant empirical evidence supporting this theory. In our previous study, interspecific-interploid crosses between the tetraploid Hylocereus megalanthus, as the female parent, and the diploid H. undatus, as the male parent, yielded only allopentaploids, allohexaploids, and 5x-and 6x-aneuploids instead of the expected allotriploids. No viable hybrids were obtained from the reciprocal cross. Since H. undatus underwent normal meiosis with regular pairing in the pollen mother cells and only reduced pollen grains were observed, the allohexaploids obtained supported the concept of "chromosome doubling." In this work, we report ploidy level, fruit morphology, and pollen viability and diameter in a group of putative hybrids obtained from an embryo rescue procedure following controlled H. megalanthus × H. undatus crosses, with the aim to elucidate, for the first time, the timing and developmental stage of the chromosome doubling. As in our previous report, no triploids were obtained, but tetraploids, pentaploids, hexaploids, and 5x- and 6x-aneuploids were found in the regenerated plants. The tetraploids exhibited the morphological features of the maternal parent and could not be considered true hybrids. Based on our previous studies, we can assume that the pentaploids were a result of a fertilization event between one unreduced (2n) female gamete from the tetraploid H. megalanthus and a normal (n) haploid male gamete from H. undatus. All the allohexaploids obtained from the embryo rescue technique where those that regenerated from fertilized ovules 10 days after pollination (at the pro-embryo stage), showing that the chromosome doubling event occurred at a very early development stage, i.e., at the zygote stage or shortly after zygote formation. These allohexaploids thus constitute empirical evidence of "hybridization followed by chromosome doubling."	0
Caroli disease is a very rare congenital anomaly characterized by non-obstructive saccular or fusiform dilatation of the intrahepatic bile ducts. It is associated with bile stagnation and hepatolithiasis, which explain the recurrent cholangitis and portal hypertension as a consequence of congenital liver fibrosis. Although there are several reports of diagnosis in childhood and adult life, the prenatal diagnosis using conventional 2-D ultrasound is rare, with few reports in the literature.We present a case of a 26-year-old primigravid woman at 24 weeks of gestation which 3-D ultrasound in the rendering mode clearly revealed the enlarged fetal kidneys and the increased abdominal volume, confirming the diagnosis of autosomal recessive polycystic kidney disease. The MRI was essential to the prenatal diagnosis of Caroli disease, identifying the congenital saccular dilations of intrahepatic bile ducts.	0
Lateral meningocele syndrome (LMS) is due to specific pathogenic variants in the last exon of NOTCH3 gene. Besides the lateral meningoceles, this condition presents with dysmorphic features, short stature, congenital heart defects, and feeding difficulties. Here, we report a girl with neurosensorial hearing loss, severe gastroesophageal reflux disease, congenital heart defects, multiple renal cysts, kyphosis and left-convex scoliosis, dysmorphic features, and mild developmental delay. Exome sequencing detected the previously unreported de novo loss-of-function variant in exon 33 of NOTCH3 p.(Lys2137fs). Following the identification of the gene defect, MRI of the brain and spine revealed temporal encephaloceles, inner ears anomalies, multiple spinal lateral meningoceles, and intra- and extra-dural arachnoid spinal cysts. This case illustrates the power of reverse phenotyping to establish clinical diagnosis and expands the spectrum of clinical manifestations related to LMS to include inner ear abnormalities and multi-cystic kidney disease.	0
BACKGROUND Tubular papillary adenoma is a rare eccrine-derivate dermal adnexal tumor, located in the scalp mostly. Earlier, the sebaceous cyst size was larger than 5 cm in diameter and may be confused with subcutaneous tumor. Cases of the tumor on the buttock with rapid growth are rare, therefore magnetic resonance imaging (MRI) may be helpful to determine their precise size, nature, and invasion of nearby organs for further confirmation. CASE REPORT We report on a case of a 35-year-old male with a rapid-growth tumor on the buttock. Initially, he had received drainage by syringe and the amount of drainage was 50 mL. MRI favored diagnosis of sebaceous cyst. As for recurrent tumor, the pathology revealed tubular papillary adenoma. CONCLUSIONS MRI might play an important role on imaging of soft tissue to exclude some uncertain malignant tumors. This case report indicated a rare case of a large rapid-growing tubular papillary adenoma on the buttock that required further management.	0
BACKGROUND:Cholesteryl ester storage disease (CESD) is a rare genetic disease. Its symptoms and severity are highly variable. CESD is a systemic disease that can lead to the accumulation of fat and inflammation in the liver, as well as gastrointestinal and cardiovascular disease. The majority of patients require liver transplantation due to decompensated cirrhosis. Enzyme replacement therapy has been approved based on a randomized trial. Our study aims to clinically and genetically evaluate two siblings with CESD who underwent liver transplantation, as well as their first-degree family members. CASE SUMMARY:The siblings were compound heterozygous for the missense variant in LIPA exon 8, c.894G>A, (p.Gln298Gln) and a single base pair deletion, c.482del (p.Asn161Ilefs*19). Analyses of single nucleotide polymorphisms showed variants with an increased risk of fatty liver disease and fibrosis for both patients. Clinically, both patients show signs of recurrence of CESD in the liver after transplantation and additional gastrointestinal and cardiovascular signs of CESD. Three family members who were LIPA heterozygous had a lysosomal acid lipase activity below the reference value. One of these carriers, a seven-year-old boy, was found to have severe dyslipidemia and was subsequently treated with statins. CONCLUSION:Our study underlines that CESD is a multi-organ disease, the progression of which may occur post-liver transplantation. Our findings underline the need for monitoring of complications and assessment of possible further treatment.	0
The small GTPases of the Rho-family (Rho-family GTPases) have various physiological functions, including cytoskeletal regulation, cell polarity establishment, cell proliferation and motility, transcription, reactive oxygen species (ROS) production, and tumorigenesis. A relatively large number of downstream targets of Rho-family GTPases have been reported for in vitro studies. However, only a small number of signal pathways have been established at the in vivo level. Cumulative evidence for the functions of Rho-family GTPases has been reported for in vivo studies using genetically engineered mouse models. It was based on different cell- and tissue-specific conditional genes targeting mice. In this review, we introduce recent advances in in vivo studies, including human patient trials on Rho-family GTPases, focusing on highly polarized sensory organs, such as the cochlea, which is the primary hearing organ, host defenses involving reactive oxygen species (ROS) production, and tumorigenesis (especially associated with RAC, novel RAC1-GSPT1 signaling, RHOA, and RHOBTB2).	0
José María ("Chema") Cantú (1938-2007), born in Mexico, was a pioneering, loved and respected leader in medical and human genetics and bioethics in Latin America. He graduated as a physician in Mexico and then trained in medical and human genetics in France and the United States. He was instrumental in developing a first-rate research, training and genetic services program in medical and human genetics in Guadalajara, in northwestern Mexico. He acted forcefully at national, regional and international levels to promote scientific development through collaboration and education in science and humanities, while he simultaneously strived for justice, peace, love and human rights. He attained some of the highest honors a scientist and humanist could aspire to as well as the recognition of the communities he served. Hundreds of disciples throughout Latin America and the world have been inspired by his vision of a better world through the conjunction of science, respect for humankind, ethics and love.	0
BACKGROUND:Bardet-Biedl syndrome (BBS) is a rare genetic disorder that severely inhibits primary cilia function. BBS is typified by obesity in adulthood, but pediatric weight patterns, and thus optimal periods of intervention, are poorly understood. OBJECTIVES:To examine body mass differences by age, gender, and genotype in children and adolescents with BBS. METHODS:We utilized the largest international registry of BBS phenotypes. Anthropometric and genetic data were obtained from medical records or participant/family interviews. Participants were stratified by age and sex categories. Genotype and obesity phenotype were investigated in a subset of participants with available data. RESULTS:Height and weight measurements were available for 552 unique individuals with BBS. The majority of birth weights were in the normal range, but rates of overweight or obesity rapidly increased in early childhood, exceeding 90% after age 5. Weight z-scores in groups >2 years were above 2.0, while height z-scores approached 1.0, but were close to 0.0 in adolescents. Relative to those with the BBS10 genotype, the BBS1 cohort had a lower BMI z-score in the 2-5 and 6-11 age groups, with similar BMI z-scores thereafter. Children with biallelic loss of function (LOF) genetic variants had significantly higher BMI z-scores compared to missense variants. CONCLUSION:Despite normal birth weight, most individuals with BBS experience rapid weight gain in early childhood, with high rates of overweight/obesity sustained through adolescence. Children with LOF variants are disproportionally affected. Our findings support the need for earlier recognition and initiation of weight management therapies in BBS.	0
Megalencephalic leukoencephalopathy (MLC) with subcortical cysts, also known as Van der Knaap disease (MIM #604004) is an autosomal recessive neurological disorder characterized by early onset macrocephaly, epilepsy, neurological deterioration with cerebellar ataxia and spasticity. An 8-month-old boy was admitted to our pediatric neurology clinic with macrocephaly. His brain magnetic resonance imaging (MRI) revealed bilateral, diffuse, symmetric structural white matter abnormalities, relatively sparing the cerebellum and bilateral subcortical temporal cysts. The diagnosis of Van der Knaap disease was suspected based on the clinical features and imaging findings and the genetic analysis revealed a novel homozygous c.768+2T>C mutation of the MLC1 gene. For determination of the novel splice-site mutation's effect, cDNA amplification was performed. cDNA analysis showed that the splice-site c.768+2T>C mutation gave rise to exon 9 skipping.	0
The clinical and radiological spectrum of spondylocostal dysostosis syndromes encompasses distinctive costo-vertebral anomalies. RIPPLY2 biallelic pathogenic variants were described in two distinct cervical spine malformation syndromes: Klippel-Feil syndrome and posterior cervical spine malformation. RIPPLY2 is involved in the determination of rostro-caudal polarity and somite patterning during development. To date, only four cases have been reported. The current report aims at further delineating the posterior malformation in three new patients. Three patients from two unrelated families underwent clinical and radiological examination through X-ray, 3D computed tomography and brain magnetic resonance imaging. After informed consent was obtained, family-based whole exome sequencing (WES) was performed. Complex vertebral segmentation defects in the cervico-thoracic spine were observed in all patients. WES led to the identification of the homozygous splicing variant c.240-4T>G in all subjects. This variant is predicted to result in aberrant splicing of Exon 4. The current report highlights a subtype of cervical spine malformation with major atlo-axoidal malformation compromising spinal cord integrity. This distinctive mutation-specific pattern of malformation differs from Klippel-Feil syndrome and broadens the current classification, defining a sub-type of RIPPLY2-related skeletal disorder. Of note, the phenotype of one patient overlaps with oculo-auriculo-vertebral spectrum disorder.	0
Testicular adrenal rest tumors (TART) occur often as asymptomatic nodules in corticotropin-dependent lesions aberrant adrenal tissue in congenital adrenal hyperplasia (CAH) patients. The present manuscript is about an unusual case of a 16-year-old CAH patient due to 11β-hydroxylase deficiency. He underwent testicle biopsy because of testicle tumor suspicion and diagnosed with TART.	0
Primary ciliary dyskinesia (PCD) is a genetic disorder caused by ciliary immotility/dysmotility due to ultrastructural defects of the cilia. Kartagener syndrome (KS), a subtype of PCD, is characterised by situs inversus accompanying the typical PCD symptoms of bronchiectasis and chronic sinusitis. In most cases, PCD is transmitted as an autosomal recessive trait, but its genetic basis is unclear due to extensive genetic heterogeneity.In a genome-wide search for PCD loci performed in 52 KS families and in 18 PCD families with no situs inversus present (CDO, ciliary dysfunction-only), the maximal pairwise LOD score of 3.36 with D15S205 in the KS families indicated linkage of a KS locus to the long arm of chromosome 15. In the follow-up study, 65 additional microsatellite markers encompassing D15S205 were analysed.A maximal pairwise LOD score of 4.34 was observed with D15S154, further supporting linkage of the KS, but not the CDO, families to 15q24-25. Analysis of heterogeneity and haplotypes suggested linkage to this region in 60% of KS families.Reinforced by the results of multipoint linkage, our analyses indicate that a major KS locus is localised within a 3.5 cM region on 15q, between D15S973 and D15S1037.	0
Erythromelalgia is a neurovascular disorder which causes pain, swelling, erythema, and warmth of the distal extremities. Primary disease is due to a genetic mutation in the SCN9A gene, but secondary erythromelalgia can be the consequence of a variety of underlying etiologies, including drug and toxin exposures. The disease is rare, occurring in only 1.3 out of every 100,000 in the United States, and symptoms can vary significantly in severity and presentation. Therefore, it can be difficult to recognize the disorder, identify the source, and promptly treat the condition. We report a reversible cause of erythromelalgia induced by the use of oral cyclosporine. This correlation is poorly documented in literature, with limited accounts identifying an association between erythromelalgia and cyclosporine. As drug-induced erythromelalgia represents a reversible cause of disease, physicians should obtain a detailed medication history during the diagnostic workup, specifically inquiring about the use of cyclosporine.	0
BACKGROUND:Mutations in the IL2RG gene are known to cause X linked severe combined immunodeficiency (XSCID). More than 250 unique variants of the IL2RG gene have been reported to be identified in SCID patients so far, while many of them are of unknown significance which complicate the interpretation of mutation analysis results; furthermore, there are still many novel variants seen in clinical practice. METHODS:In this study we reviewed the testing results in three unrelated SCID families. All three probands had very severe immunodeficiency phenotypes and died in infancy. Next generation sequencing methods based on either SCID gene panel or exome sequencing were applied in causal variant screening for three probands. Sanger sequencing was used for verification of the variants of interest and carrier status study for the family members. STR analysis using the GoldeneyeTM DNA ID system (PeopleSpot Inc., China) was applied to verify the kinship of the family members when a de novo mutation was identified. RESULTS:Causal mutations were identified in all three SCID male probands, among which one was novel (c.557dupT), one was reported to be identified in a common variable immunodeficiency patient in literature (Leu87Pro), and one was a "hot-spot-mutation" (Arg226Cys). The patient with the missense mutation Leu87Pro in this study had much more severe infection phenotypes compared with the reported case in literature. CONCLUSIONS:Combining our findings and the published evidence together, Leu87Pro can be classified as a pathogenic variant following the ACMG guidelines. Correct and undoubted classification of the variants is of great importance for clinical gene testing.	0
Pancreatoblastoma is a malignant exocrine pancreatic tumor that is usually present in childhood. We herein present one case of pediatric living donor liver transplantation (LDLT) combined with spleen-preserving regional total pancreatectomy and portal vein homograft interposition in a 4-year-old boy with advanced pancreatoblastoma invading the portal and superior mesenteric veins. The size of the pancreatoblastoma was gradually reduced along systemic chemotherapy, thus we decided to perform surgery to remove it completely. A cold-stored fresh iliac vein homograft was prepared. Initially, a spleen-preserving distal pancreatectomy was performed. Thereafter, a completion regional total pancreatectomy was performed under superior mesenteric vein-vena cava bypass. A left liver graft from his mother was implanted according to the standardized procedures with portal vein interposition. This patient recovered uneventfully and is currently undergoing scheduled adjuvant chemotherapy. To our knowledge, this is the world-second case of pediatric LDLT for advanced pancreatoblastoma. Availability of fresh vein homografts is helpful to expand the indication of pediatric LDLT.	0
Introduction: Glioblastoma and anaplastic astrocytoma (ANA) are two of the most common primary brain tumors in adults. The differential diagnosis is important for treatment recommendations and prognosis assessment. This study aimed to assess the discriminative ability of texture analysis using machine learning to distinguish glioblastoma from ANA. Methods: A total of 123 patients with glioblastoma (n = 76) or ANA (n = 47) were enrolled in this study. Texture features were extracted from contrast-enhanced Magnetic Resonance (MR) images using LifeX package. Three independent feature-selection methods were performed to select the most discriminating parameters:Distance Correlation, least absolute shrinkage and selection operator (LASSO), and gradient correlation decision tree (GBDT). These selected features (datasets) were then randomly split into the training and the validation group at the ratio of 4:1 and were fed into linear discriminant analysis (LDA), respectively, and independently. The standard sensitivity, specificity, the areas under receiver operating characteristic curve (AUC) and accuracy were calculated for both training and validation group. Results: All three models (Distance Correlation + LDA, LASSO + LDA and GBDT + LDA) showed promising ability to discriminate glioblastoma from ANA, with AUCs ≥0.95 for both the training and the validation group using LDA algorithm and no overfitting was observed. LASSO + LDA showed the best discriminative ability in horizontal comparison among three models. Conclusion: Our study shows that MRI texture analysis using LDA algorithm had promising ability to discriminate glioblastoma from ANA. Multi-center studies with greater number of patients are warranted in future studies to confirm the preliminary result.	0
PURPOSE OF REVIEW:The review provides an update on the diagnosis, pathogenesis, and treatment of cutaneous lupus erythematosus (CLE). RECENT FINDINGS:Diagnostic challenges exist in better defining CLE as an independent disease distinct from systemic lupus erythematosus with cutaneous features and further classifying CLE based on clinical, histological, and laboratory features. Recent mechanistic studies revealed more genetic variations, environmental triggers, and immunologic dysfunctions that are associated with CLE. Drug induction specifically has emerged as one of the most important triggers for CLE. Treatment options include topical agents and systemic therapies, including newer biologics such as belimumab, rituximab, ustekinumab, anifrolumab, and BIIB059 that have shown good clinical efficacy in trials. CLE is a group of complex and heterogenous diseases. Future studies are warranted to better define CLE within the spectrum of lupus erythematosus. Better insight into the pathogenesis of CLE could facilitate the design of more targeted therapies.	0
OBJECTIVE:To assess the value of combined chromosomal karyotyping and chromosomal microarray analysis (CMA) for prenatal diagnosis. METHODS:G-banding karyotyping and CMA were simultaneously performed on 546 women who were subjected to amniocentesis during middle pregnancy. RESULTS:In total 82 cases were detected with chromosomal abnormalities. The two methods were consistent in 43 cases, which included 14 trisomy 21, 6 trisomy 18, 1 trisomy 13, 14 sex chromosomal aneuploidies, 4 chromosomal deletions, 3 chromosomal duplications and 1 sex chromosomal mosaicism. Fifteen fetuses with chromosomal abnormalities detected by CMA were missed by karyotyping analysis, which included 9 microdeletions and 6 microduplications. Sixteen fetuses with chromosomal abnormalities detected by karyotyping analysis were missed by CMA, which included 15 chromosomal translocations and 1 sex chromosomal mosaicism. In 7 cases, the results of karyotyping analysis and CMA were inconsistent. One supernumerary marker chromosome detected by karyotyping analysis was verified by CMA as 9p13.1p21.1 duplication. CONCLUSION:Combined chromosomal karyotyping and CMA can significantly improve the detection rate for chromosomal abnormalities, which has a great value for prenatal diagnosis.	0
Mitochondrial DNA depletion syndromes (MDS) are a group of rare autosomal recessive disorders with early onset and no cure available. MDS are caused by mutations in nuclear genes involved in mitochondrial DNA (mtDNA) maintenance, and characterized by both a strong reduction in mtDNA content and severe mitochondrial defects in affected tissues. Mutations in MPV17, a nuclear gene encoding a mitochondrial inner membrane protein, have been associated with hepatocerebral forms of MDS. The zebrafish mpv17 null mutant lacks the guanine-based reflective skin cells named iridophores and represents a promising model to clarify the role of Mpv17. In this study, we characterized the mitochondrial phenotype of mpv17-/- larvae and found early and severe ultrastructural alterations in liver mitochondria, as well as significant impairment of the respiratory chain, leading to activation of the mitochondrial quality control. Our results provide evidence for zebrafish Mpv17 being essential for maintaining mitochondrial structure and functionality, while its effects on mtDNA copy number seem to be subordinate. Considering that a role in nucleotide availability had already been postulated for MPV17, that embryos blocked in pyrimidine synthesis do phenocopy mpv17-/- knockouts (KOs) and that mpv17-/- KOs have impaired Dihydroorotate dehydrogenase activity, we provided mpv17 mutants with the pyrimidine precursor orotic acid (OA). Treatment with OA, an easily available food supplement, significantly increased both iridophore number and mtDNA content in mpv17 -/- mutants, thus linking the loss of Mpv17 to pyrimidine de novo synthesis and opening a new simple therapeutic approach for MPV17-related MDS.	0
Osteogenesis imperfecta (OI) is a strikingly heterogeneous group of disorders with a broad range of phenotypic variations. It is also one of the differential diagnoses in bent bone dysplasias along with campomelic dysplasia and thanatophoric dysplasia and can usually be distinguished by decreased bone mineralization and bone fractures. Bent bone dysplasias also include syndromes such as kyphomelic dysplasia (MIM:211350) and mesomelic dysplasia Kozlowski-Reardon (MIM249710), both of which have been under debate regarding whether or not they are a real entity or simply a phenotypic manifestation of another dysplasia including OI. Bruck syndrome type 2 (BRKS2; MIM:609220) is a rare form of autosomal recessive OI caused by biallelic PLOD2 variants and is associated with congenital joint contractures with pterygia. In this report, we present six patients from four families with novel PLOD2 variants. All cases had multiple fractures. Other features ranged from prenatal lethal severe angulation of the long bones as in kyphomelic dysplasia and mesomelic dysplasia Kozlowski-Reardon through classical Bruck syndrome to moderate OI with normal joints. Two siblings with a kyphomelic dysplasia-like phenotype who were stillborn had compound heterozygous variants in PLOD2 (p.Asp585Val and p.Ser166*). One infant who succumbed at age 4 months had a bent bone phenotype phenotypically like skeletal dysplasia Kozlowski-Reardon (with mesomelic shortening, camptodactyly, retrognathia, cleft palate, skin dimples, but also with fractures). He was homozygous for the nonsense variant (p.Trp561*). Two siblings had various degrees of Bruck syndrome caused by the homozygous missense variant, p.His687Arg. Furthermore a boy with a clinical presentation of moderate OI had a possibly pathogenic homozygous variant p.Trp588Cys. Our experience of six patients with biallelic pathogenic variants in PLOD2 expands the phenotypic spectrum in the PLOD2-related phenotypes. © 2017 American Society for Bone and Mineral Research.	0
Linear nevus sebaceous syndrome (LNSS) is a multisystem disorder that includes nevus sebaceous and central nervous system, ocular and skeletal anomalies. We report the first case of a KRAS G12D mosaic mutation in a patient diagnosed with LNSS.A 3-month-old female with a clinical diagnosis of LNSS presented with intermittent epilepsy. Her mother carefully collected a skin lesion sample from scratched-off scurf obtained from the patient's nails. DNA was extracted, and long-range PCR was performed to amplify the KRAS gene, which was then analyzed by next-generation sequencing. The results revealed the presence of a low-level heterozygous mutation in the KRAS gene (c.35C>T; p.G12D, 5 %).These findings suggest that the KRAS somatic mosaic mutation in this patient may have caused her skin and eye lesions and epilepsy. With this correct diagnosis, the infant can be effectively treated.	0
The acrofacial dysostoses (AFDs) are a heterogeneous group of disorders combining defects of craniofacial and limb development. The predominantly preaxial form is called Nager AFD, the predominantly postaxial form of AFD (POADS) is also known as the Genée-Wiedemann or Miller syndrome. The former appears to be about twice as common as the latter with well-documented autosomal dominant and recessive occurrences in both conditions. Only 1 AD occurrence of POADS is known, but 5 sets of sibs are suggestive of AR inheritance. Heterogeneity of apparently nonsyndromal AFD of both types is powerful support for the hypothesis that the AFDs are polytopic field defects arising during blastogenesis. Six other previously described forms of AFD include the AFD syndrome of Kelly et al. (AR), the Rodríguez or Madrid form of AFD (AR or XLR), the Reynolds or Idaho form of AFD (AD), the Arens or Tel Aviv type of AFD (AF?), the presumed AR AFD syndrome of Richieri-Costa et al., and the AD Patterson-Stevenson-Fontaine syndrome. Here we review the AFDs and report on a previously apparently undescribed autosomal or X-linked dominant form of AFD with mental retardation in a Sicilian mother and her 4 sons.	0
The surgical approach to hypothalamic hamartomas (HHs) associated with medically refractory epilepsy is challenging because of these lesions' deep midline or paramedian location. Whether the aim is resection or disconnection, the surgical corridor dictates how complete a procedure can be achieved. Here, the authors report a transtemporal approach suitable for Delalande type I, inferior extraventricular component of type III, and type IV lesions. This approach provides optimal visualization of the plane between the hamartoma and the hypothalamus with no manipulation to the pituitary stalk and brainstem, allowing for extensive disconnection while minimizing injury to adjacent neurovascular structures.Through a 1-cm corticectomy in the middle temporal gyrus, a surgical tract is developed under neuronavigational guidance toward the plane of intended disconnection. On reaching the mesial temporal pia-arachnoid margin, it is opened, providing direct visualization of the hamartoma, which is then disconnected or resected as indicated. Critical neurovascular structures are generally not exposed through this approach and are preserved if encountered.Three patients (mean age 4.9 years) with intractable epilepsy were treated using this technique as part of the national Children's Epilepsy Surgery Service. Following resection, the patient in case 1 (Delalande type I) is seizure free off medication at 3 years' follow-up (Engel class IA). The patient in case 2 (Delalande type III) initially underwent partial disconnection through a transcallosal interforniceal approach and at first had significant seizure improvement before the seizures worsened in frequency and type. Complete disconnection of the residual lesion was achieved using the transtemporal approach, rendering this patient seizure free off medication at 14 months postsurgery (Engel class IA). The patient in case 3 (Delalande type IV) underwent incomplete disconnection with a substantial reduction in seizure frequency at 3 years' follow-up (Engel class IIIC). There were no surgical complications in any of the cases.The transtemporal approach is a safe and effective alternative to more conventional surgical approaches in managing HHs with intractable epilepsy.	0
BACKGROUND:Syndromic congenital heart disease accounts for 30% of cases and can be determined by genetic, environmental or multifactorial causes. In many cases the etiology remains uncertain. Many known genes are responsible for specific morphopathogenetic mechanisms during the development of the heart whose alteration can determine specific phenotypes of cardiac malformations. CASE PRESENTATION:We report on two cases of association of conotruncal heart defect with facial dysmorphisms in sibs. In both cases the malformations' identification occurred by ultrasound in the prenatal period. It was followed by prenatal invasive diagnosis. The genetic analysis revealed no rearrangements in Array-CGH test, while gene panel sequencing identified a new hemizygous variant of uncertain significance (c.887G > A; p.Arg296Gln) in the MED12 gene, located on the X chromosome and inherited from the healthy mother. CONCLUSION:No other reports about the involvement of MED12 gene in syndromic conotruncal heart defects are actually available from the literature and the international genomic databases. This novel variant is a likely pathogenic variant of uncertain significance and it could broaden the spectrum of genes involved in the development of congenital heart diseases and the phenotypic range of MED12-related disorders.	0
Dopa-responsive dystonia (DRD) is a complex genetic disorder with either autosomal dominant or autosomal recessive inheritance, with autosomal dominant being more frequent. Autosomal dominant DRD is known to be caused by mutations in the GCH1 gene, with incomplete penetrance frequently reported, particularly in males. Here, we report a male patient with DRD caused by exon 1 deletion in the GCH1 gene inherited from the asymptomatic mother. The patient had an atypical presentation, notably with no dystonia, and underwent extensive workup for a myriad of neuromuscular disorders before a low-dose L-dopa trial and confirmatory genetic testing were performed. Our experience with this family highlights an atypical presentation of DRD and prompts us to consider the genetic complexity of DRD.	0
The pontocerebellar hypoplasias (PCHs) are a heterogeneous group of autosomal recessive disorders characterized by hypoplasia of the ventral pons and cerebellum, with variable cerebral involvement and severe psychomotor retardation. Eight different subtypes (PCH1-8) have been reported up to now. PCH2 is the most common type, generally caused by homozygous mutations in the TSEN54 gene and characterized by cerebellar hypoplasia that affects the hemispheres more severely than the vermis, progressive cerebral atrophy, microcephaly, dyskinesia, seizures and death in early childhood. We present two cousins with PCH2. Both patients presented with exaggerated startle response in the newborn period. Here we discuss the clinical and neuroradiological findings of PCH2, and its differentiation from familial startle disease or hereditary hyperekplexia.	0
Skin disease is an extremely common presenting complaint to the exotic animal practitioner. A systematic diagnostic approach is necessary in these cases to achieve a diagnosis and formulate an effective treatment plan. In all exotic species, husbandry plays a central role in the pathogenesis of cutaneous disease, so a thorough evaluation of the husbandry is critical for successful management. The clinical approach to skin disease in exotic animal patients is reviewed with specific focus on structure and function of the skin, diagnostic testing, and differential diagnoses for commonly encountered cutaneous diseases.	0
Background and objectives: Epithelioid sarcoma (ES) is an aggressive malignancy scarcely reported on due to its rarity. This study is a review of its traits and features of prognosis and survival by analyzing both the literature and a national cancer database.Methods: Data were acquired from both the Survival, Epidemiology, and End Results database and literature. 1, 5, and 10-year Disease Specific Survival rates and hazard ratios (HR) were determined. Data were split into pre-2000 (<2000) and post-2000 (>2000) groups. Overall survival, recurrence, and metastasis rates were obtained.Results: Ninety hundred and ninety eight and 992 cases of ES were identified from the database and literature, respectively. Age, anatomical site, grade, TNM staging, treatment modality and year of diagnosis were demonstrated to be independent predictors of survival. Overall 5- and 10-year survival were 60.4% and 50.2%, respectively. Overall recurrence and metastasis rates were 63.4% and 40.3%. Using cases diagnosed prior to 2000 as reference, those diagnosed after 2000 had a worse prognosis (HR: 1.55).Conclusions: We report using the largest cohort of ES to date. Despite ES's often dismal prognosis, there are factors associated with better outcomes. A worsening survival over the years warrants further investigation into this sarcoma.	0
The homology-independent targeted integration (HITI) strategy enables effective CRISPR/Cas9-mediated knockin of therapeutic genes in nondividing cells in vivo, promising general therapeutic solutions for treating genetic diseases like X-linked juvenile retinoschisis. Herein, supramolecular nanoparticle (SMNP) vectors are used for codelivery of two DNA plasmids-CRISPR-Cas9 genome-editing system and a therapeutic gene, Retinoschisin 1 (RS1)-enabling clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR/Cas9) knockin of the RS1 gene with HITI. Through small-scale combinatorial screenings, two SMNP vectors, with Cas9 and single guide RNA (sgRNA)-plasmid in one and Donor-RS1 and green fluorescent protein (GFP)-plasmid in the other, with optimal delivery performances are identified. These SMNP vectors are then employed for CRISPR/Cas9 knockin of RS1/GFP genes into the mouse Rosa26 safe-harbor site in vitro and in vivo. The in vivo study involves intravitreally injecting the two SMNP vectors into the mouse eyes, followed by repeated ocular imaging by fundus camera and optical coherence tomography, and pathological and molecular analyses of the harvested retina tissues. Mice ocular organs retain their anatomical integrity, a single-copy 3.0-kb RS1/GFP gene is precisely integrated into the Rosa26 site in the retinas, and the integrated RS1/GFP gene is expressed in the retinas, demonstrating CRISPR/Cas9 knockin of RS1/GFP gene.	0
Protocadherin-19 (PCDH19) pathogenic variants cause an early-onset seizure disorder called girls clustering epilepsy (GCE). GCE is an X-chromosome disorder that affects heterozygous females and mosaic males, however hemizygous ("transmitting") males are spared. We aimed to define the neuropsychiatric profile associated with PCDH19 pathogenic variants and determine if a clinical profile exists for transmitting males. We also examined genotype- and phenotype-phenotype associations. We developed an online PCDH19 survey comprising the following standardized assessments: The Behavior Rating Inventory of Executive Function; the Social Responsiveness Scale, 2nd edition; the Strengths and Difficulties Questionnaire; and the Dimensional Obsessive-Compulsive Scale. Genetic, seizure, and developmental information were also collected. The survey was completed by patients or by caregivers on behalf of patients. Of the 112 individuals represented (15 males), there were 70 unique variants. Thirty-five variants were novel and included a newly identified recurrent variant Ile781Asnfs*3. There were no significant differences in phenotypic outcomes between published and unpublished cases. Seizures occurred in clusters in 94% of individuals, with seizures resolving in 28% at an average age of 17.5 years. Developmental delay prior to seizure onset occurred in 18% of our cohort. Executive dysfunction and autism spectrum disorder (ASD) occurred in approximately 60% of individuals. The ASD profile included features of attention-deficit hyperactivity disorder. In addition, 21% of individuals met criteria for obsessive-compulsive disorder that appeared to be distinct from ASD. There were no phenotypic differences between heterozygous females and mosaic males. We describe a mosaic male and two hemizygous males with atypical clinical profiles. Earlier seizure onset age and increased number of seizures within a cluster were associated with more severe ASD symptoms (p = 0.001), with seizure onset also predictive of executive dysfunction (p = 4.69 × 10-4) and prosocial behavior (p = 0.040). No clinical profile was observed for transmitting males. This is the first patient-derived standardized assessment of the neuropsychiatric profile of GCE. These phenotypic insights will inform diagnosis, management, and prognostic and genetic counseling.	0
There is a current paucity of information about the obstetric and perinatal outcomes of pregnant novel coronavirus disease 2019 (COVID-19) patients in North America. Data from China suggest that pregnant women with COVID-19 have favorable maternal and neonatal outcomes, with rare cases of critical illness or respiratory compromise. However, we report two cases of pregnant women diagnosed with COVID-19 in the late preterm period admitted to tertiary care hospitals in New York City for respiratory indications. After presenting with mild symptoms, both quickly developed worsening respiratory distress requiring intubation, and both delivered preterm via caesarean delivery. These cases highlight the potential for rapid respiratory decompensation in pregnant COVID-19 patients and the maternal-fetal considerations in managing these cases.	0
A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was whether treatment with hormones or pleural symphysis is better than operative procedures such as diaphragmatic repair with mesh to surgically manage recurrent pneumothoraces in patients with catamenial pneumothorax. Diaphragmatic repair with synthetic meshes, hormonal treatment and pleural symphysis are all accepted interventions for the treatment of recurrent catamenial pneumothoraces; however, there is uncertainty over the best combination of treatment. Altogether, 396 papers were found using the reported search, of which 13 represented the best evidence to answer the clinical question. However, it should be noted that the studies included were small in terms of sample size, and have demonstrated significant bias and surgical heterogeneity. Our literature review found that the recurrence rates of pneumothorax were greatly reduced in the treatment group where surgery and hormone therapy were combined (pooled average recurrence rate of 0%); however, the recurrence rates were significantly higher when these interventions were used alone: hormone therapy alone (58.5%), diaphragmatic repair alone (33.3%) and surgery alone (63.3%). Our results therefore demonstrate that a multimodality approach is required to reduce pneumothorax recurrence rates in patients with catamenial pneumothorax.	0
Although hepatoblastoma is the most common pediatric liver cancer, its genetic heterogeneity and therapeutic targets are not well elucidated. Therefore, we conducted a multiomics analysis, including mutatome, DNA methylome, and transcriptome analyses, of 59 hepatoblastoma samples. Based on DNA methylation patterns, hepatoblastoma was classified into three clusters exhibiting remarkable correlation with clinical, histological, and genetic features. Cluster F was largely composed of cases with fetal histology and good outcomes, whereas clusters E1 and E2 corresponded primarily to embryonal/combined histology and poor outcomes. E1 and E2, albeit distinguishable by different patient age distributions, were genetically characterized by hypermethylation of the HNF4A/CEBPA-binding regions, fetal liver-like expression patterns, upregulation of the cell cycle pathway, and overexpression of NQO1 and ODC1. Inhibition of NQO1 and ODC1 in hepatoblastoma cells induced chemosensitization and growth suppression, respectively. Our results provide a comprehensive description of the molecular basis of hepatoblastoma and rational therapeutic strategies for high-risk cases.	0
Objective: The expression of glucocorticoid receptors within platelets from newly diagnosed Immune Thrombocytopenia (ITP) patients in the adult was investigated.Methods: GR expression in platelets from newly diagnosed ITP patients and healthy controls was measured using flow cytometry. Subsequently, platelets RNA and proteins were isolated and used for confirming the flow cytometry results by using RT-qPCR and ELISA.Results: Flow cytometry showed that the percentages of platelets expressing GRα and GRβ from ITP patients were significantly higher than those from healthy controls (P < 0.05). qPCR and ELISA confirmed that GRα and GRβ were increased at both RNA transcription and protein expression levels within platelets from ITP patients compared with healthy controls.Conclusion: We speculated that the up-regulation of glucocorticoid receptor within platelets may be an important biological feature of platelets in patients with ITP, and may also play an important role in the treatment of ITP, which is worthy of further study.	0
AIM:To identify disease-causing mutations in four Lebanese families: three families with Bardet-Biedl and one family with Usher syndrome (BBS and USH respectively), using next generation sequencing (NGS). METHODS:We applied targeted NGS in two families and whole exome sequencing (WES) in two other families. Pathogenicity of candidate mutations was evaluated according to frequency, conservation, in silico prediction tools, segregation with disease, and compatibility with inheritance pattern. The presence of pathogenic variants was confirmed via Sanger sequencing followed by segregation analysis. RESULTS:Most likely disease-causing mutations were identified in all included patients. In BBS patients, we found (M1): c.2258A > T, p. (Glu753Val) in BBS9, (M2): c.68T > C; p. (Leu23Pro) in ARL6, (M3): c.265_266delTT; p. (Leu89Valfs*11) and (M4): c.880T > G; p. (Tyr294Asp) in BBS12. A previously known variant (M5): c.551A > G; p. (Asp184Ser) was also detected in BBS5. In the USH patient, we found (M6): c.188A > C, p. (Tyr63Ser) in CLRN1. M2, M3, M4, and M6 were novel. All of the candidate mutations were shown to be likely disease-causing through our bioinformatic analysis. They also segregated with the corresponding phenotype in available family members. CONCLUSION:This study expanded the mutational spectrum and showed the genetic diversity of BBS and USH. It also spotlighted the efficiency of NGS techniques in revealing mutations underlying clinically and genetically heterogeneous disorders.	0
BACKGROUND:Congenital nystagmus is one of the most common neuro-ophthalmological disorders. X chromosome-linked forms are associated with pathogenic variants of the GPR143 and FRMD7 genes. MATERIALS AND METHODS:Patients' DNA was analyzed using a next-generation sequencing (NGS) panel of genes involved in albinism and related pathologies (TYR, OCA2, TYRP1, SLC45A2, SLC24A5, C10ORF11, GPR143, SLC38A8, HPS 1 to 10, LYST, MITF, FRMD7) Results: We report a 4 generation family with 5 affected members initially referred for molecular diagnosis of ocular albinism. A missense variant of FRMD7 was found in 3 affected cases and one female carrier. We show that the disease in the affected girl is due to skewed inactivation of the X chromosome. CONCLUSIONS:By compiling all the published cases we discuss the variable penetrance among females due to different types of mutation and to X-inactivation.	0
Macrodactyly is a disabling congenital disease characterized by overgrowth of soft tissues and bones, which leads to finger enlargement and joint deformity. The mechanism of bone overgrowth in macrodactyly was rarely understood. In our study bone manifestations of three macrodactyly patients were analyzed by micro-CT. PIK3CA mutation was detected by next-generation sequencing (NGS) of a tumor gene-panel. The PI3K/AKT/mTOR pathway activation and target genes were analyzed. The osteogenic potential of macrodactyly-derived bone marrow mesenchymal stem cells (MAC-BMSCs) was compared with polydactyly-derived bone marrow mesenchymal stem cells (PD-BMSCs). PIK3CA inhibitors were tested for proliferation and osteogenesis potential of MAC-BMSCs. Activating PIK3CA mutations and activation of PI3K/AKT/mTOR pathway were detected in all MAC-BMSCs. MAC-BMSCs had enhanced osteogenesis potential compared with PD-BMSCs. PIK3CA knockdown by shRNA or BYL719 treatment significantly reduced osteogenic differentiation capacity of MAC-BMSCs. RNA-Seq and qRT-PCR revealed the upregulation of distal-less homeobox 5 (DLX5) in MAC-BMSCs compared with PD-BMSCs. The osteogenic potential of MAC-BMSCs was inhibited by DLX5 knockdown, indicating that DLX5 is a downstream target of PIK3CA activation-mediated osteogenesis. This study revealed that osteogenic differentiation in MAC-BMSCs is enhanced by PIK3CA activation mutation through PI3K/AKT/mTOR signaling pathway and can be reversed by PIK3CA knockdown or drug inhibition.	0
SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.	0
This study focuses on CT and MR studies of adult patient with giant lesion of the posterior cranial fossa associated with micro- and macroaccumulations with density and signal like "fat" at the level of the cortical and cisternal cerebral spaces. This condition is compatible with previous asymptomatic ruptured dermoid cyst. Histological findings confirm the hypothesis formulated using the imaging. We also integrate elements of differential diagnosis by another giant lesion of the posterior cranial fossa.	0
Glycosylation is a major form of post-translational modification and plays various important roles in organisms by modifying proteins or lipids, which generates functional variability and can increase their stability. Because of the physiological importance of glycosylation, defects in genes encoding proteins involved in glycosylation or glycan degradation are sometimes associated with human diseases. A number of genetic neuromuscular diseases are caused by abnormal glycan modification or degeneration. Heterogeneous and complex modification machinery, and difficulties in structural and functional analysis of glycans have impeded the understanding of how glycosylation contributes to pathology. However, recent rapid advances in glycan and genetic analyses, as well as accumulating genetic and clinical information have greatly contributed to identifying glycan structures and modification enzymes, which has led to breakthroughs in the understanding of the molecular pathogenesis of various diseases and the possible development of therapeutic strategies. For example, studies on the relationship between glycosylation and muscular dystrophy in the last two decades have significantly impacted the fields of glycobiology and neuromyology. In this review, the basis of glycan structure and biosynthesis will be briefly explained, and then molecular pathogenesis and therapeutic concepts related to neuromuscular diseases will be introduced from the point of view of the life cycle of a glycan molecule.	0
RATIONALE:X-linked dominant chondrodysplasia punctata type 2 (CDPX2) is a condition involving facial, skin, and skeletal dysplasia as a result of a mutation in emopamil binding protein (EBP). It usually presents with mild symptoms in female patients but is fatal in male patients. PATIENT CONCERNS:A fetus was diagnosed with asymmetrical short limbs and a narrow and small thorax by prenatal ultrasound examination at 24+5 weeks gestation. The pregnancy was terminated at 27 weeks of gestation; gross examination, postnatal X-ray and, whole exome analysis were performed to clarify the diagnosis. DIAGNOSIS:A provisional diagnosis of fatal skeletal dysplasia was given and the definite diagnosis of CDPX2 was based on postnatal X-ray and genetic testing of the aborted fetus. INTERVENTION:The pregnancy was terminated at 27 weeks' gestation after a fetal ultrasound indicated a severe abnormal phenotype. OUTCOMES:Whole exome analysis of aborted tissue confirmed EBP mutation in this case. Unlike most case reports, this female patient presented a severe phenotype that was considered to be related to X-chromosome inactivation. LESSONS:Chondrodysplasia punctata (CDP) should be considered if prenatal ultrasound shows high punctuate echoes at the metaphysis of long bones and asymmetrical short lower limbs. Postnatal X-ray and measurement of sterol levels in the amniotic fluid may aid in the diagnosis of CDP, but the condition can be confirmed with genetic testing of a blood sample or aborted tissue after delivery.	0
Painful peripheral neuropathy has been correlated with various voltage-gated sodium channel mutations in sensory neurons. Recently Nav1.9, a voltage-gated sodium channel subtype, has been established as a genetic influence for certain peripheral pain syndromes. In this study, we performed a genetic study in six unrelated multigenerational Japanese families with episodic pain syndrome. Affected participants (n = 23) were characterized by infantile recurrent pain episodes with spontaneous mitigation around adolescence. This unique phenotype was inherited in an autosomal-dominant mode. Linkage analysis was performed for two families with 12 affected and nine unaffected members, and a single locus was identified on 3p22 (LOD score 4.32). Exome analysis (n = 14) was performed for affected and unaffected members in these two families and an additional family. Two missense variants were identified: R222H and R222S in SCN11A. Next, we generated a knock-in mouse model harboring one of the mutations (R222S). Behavioral tests (Hargreaves test and cold plate test) using R222S and wild-type C57BL/6 (WT) mice, young (8-9 weeks old; n = 10-12 for each group) and mature (36-38 weeks old; n = 5-6 for each group), showed that R222S mice were significantly (p < 0.05) more hypersensitive to hot and cold stimuli than WT mice. Electrophysiological studies using dorsal root ganglion neurons from 8-9-week-old mice showed no significant difference in resting membrane potential, but input impedance and firing frequency of evoked action potentials were significantly increased in R222S mice compared with WT mice. However, there was no significant difference among Nav1.9 (WT, R222S, and R222H)-overexpressing ND7/23 cell lines. These results suggest that our novel mutation is a gain-of-function mutation that causes infantile familial episodic pain. The mouse model developed here will be useful for drug screening for familial episodic pain syndrome associated with SCN11A mutations.	0
BACKGROUND:We report a large family with four successive generations, presenting with a complex phenotype of severe congenital neutropenia (SCN), partially penetrant monocytosis, and hearing loss of varying severity. METHODS:We performed whole exome sequencing to identify the causative variants. Sanger sequencing was used to perform segregation analyses on remaining family members. RESULTS:We identified and classified a pathogenic GFI1 variant and a likely pathogenic variant in MYO6 which together explain the complex phenotypes seen in this family. CONCLUSIONS:We present a case illustrating the benefits of a broad screening approach that allows identification of oligogenic determinants of complex human phenotypes which may have been missed if the screening was limited to a targeted gene panel with the assumption of a syndromic disorder. This is important for correct genetic diagnosis of families and disentangling the range and severity of phenotypes associated with high impact variants.	0
Several different proteins regulate, directly or indirectly, the production of growth hormone from the pituitary gland, thereby complex genetics is involved. Defects in these genes are related to growth hormone deficiency solely, or deficiency of other hormones, secreted from the pituitary gland including growth hormone. These studies can aid clinicians to trace the pattern of the disease between the families, start early treatment and predict possible future consequences. This paper highlights some of the most common and novel genetic anomalies concerning growth hormone, which are responsible for various genetic defects in isolated growth and combined pituitary hormone deficiency disease.	0
Accumulation of epigenetic alterations causes inactivation of tumor suppressors and contributes to the initiation and progression of hepatocellular carcinoma (HCC). Identification of methylated genes is necessary to improve our understanding of the pathogenesis of HCC and develop novel biomarkers and therapeutic targets. The Kallmann syndrome-1 (KAL1) gene encodes an extracellular matrix-related protein with diverse oncological functions. However, the function of KAL1 in HCC has not been examined. We investigated the methylation status of the KAL1 promoter region in HCC cell lines, and evaluated KAL1 mRNA levels and those of genes encoding potential interacting cell adhesion factors. KAL1 mRNA expression level was heterogeneous in nine HCC cell lines, and reactivation of KAL1 mRNA expression was observed in cells with promoter hypermethylation of KAL1 gene after demethylation. In addition, KAL1 mRNA levels inversely correlated with those of ezrin in all nine HCC cell lines. KAL1 expression levels in 144 pairs of surgically-resected tissues were determined and correlated to clinicopathological parameters. KAL1 mRNA level was independent of the background liver status, whereas HCC tissues showed significantly lower KAL1 mRNA levels than corresponding noncancerous liver tissues. Downregulation of KAL1 mRNA in HCC was significantly associated with malignant phenotype characteristics, including elevated tumor markers, larger tumor size, vascular invasion, and hypermethylation of KAL1. Patients with downregulation of KAL1 were more likely to have a shorter overall survival than other patients, and multivariate analysis identified downregulation of KAL1 as an independent prognostic factor (hazard ratio 2.04, 95% confidence interval 1.11-3.90, P=0.022). Our results indicated that KAL1 may act as a putative tumor suppressor in HCC and is inactivated by promoter hypermethylation. KAL1 may serve as a biomarker of malignant phenotype of HCC.	0
Hypotrichosis simplex (HS) is a rare form of hereditary alopecia characterized by childhood onset of diffuse and progressive scalp and body hair loss. Although research has identified a number of causal genes, genetic etiology in about 50% of HS cases remains unknown. The present report describes the identification via whole-exome sequencing of five different mutations in the gene LSS in three unrelated families with unexplained, potentially autosomal-recessive HS. Affected individuals showed sparse to absent lanugo-like scalp hair, sparse and brittle eyebrows, and sparse eyelashes and body hair. LSS encodes lanosterol synthase (LSS), which is a key enzyme in the cholesterol biosynthetic pathway. This pathway plays an important role in hair follicle biology. After localizing LSS protein expression in the hair shaft and bulb of the hair follicle, the impact of the mutations on keratinocytes was analyzed using immunoblotting and immunofluorescence. Interestingly, wild-type LSS was localized in the endoplasmic reticulum (ER), whereas mutant LSS proteins were localized in part outside of the ER. A plausible hypothesis is that this mislocalization has potential deleterious implications for hair follicle cells. Immunoblotting revealed no differences in the overall level of wild-type and mutant protein. Analyses of blood cholesterol levels revealed no decrease in cholesterol or cholesterol intermediates, thus supporting the previously proposed hypothesis of an alternative cholesterol pathway. The identification of LSS as causal gene for autosomal-recessive HS highlights the importance of the cholesterol pathway in hair follicle biology and may facilitate novel therapeutic approaches for hair loss disorders in general.	0
There are several types of mitochondrial cytopathies, which cause a set of disorders, arise as a result of mitochondria's failure. Mitochondria's functional disruption leads to development of physical, growing and cognitive disabilities and includes multiple organ pathologies, essentially disturbing the nervous and muscular systems. The origins of mitochondrial cytopathies are mutations in genes of nuclear DNA encoding mitochondrial proteins or in mitochondrial DNA. Nowadays, numerous mtDNA mutations significant to the appearance and progress of pathologies in humans are detected. In this mini-review, we accent on the mitochondrial cytopathies related to mutations of mtDNA. As well known, there are definite set of symptoms of mitochondrial cytopathies distinguishing or similar for different syndromes. The present article contains data about mutations linked with cytopathies that facilitate diagnosis of different syndromes by using genetic analysis methods. In addition, for every individual, more effective therapeutic approach could be developed after wide-range mutant background analysis of mitochondrial genome.	0
Background: Cryptorchidism is one of the most frequent congenital birth defects in male children and is present in 2-4% of full-term male births. It has several possible health effects including reduced fertility, increased risk for testicular neoplasia, testicular torsion, and psychological consequences. Cryptorchidism is often diagnosed as comorbid; copresent with other diseases. It is also present in clinical picture of several syndromes. However, this field has not been systematically studied. The aim of the present study was to catalog published cases of syndromes which include cryptorchidism in the clinical picture and associated genomic information. Methods: The literature was extracted from Public/Publisher MEDLINE and Web of Science databases, using the keywords including: syndrome, cryptorchidism, undescended testes, loci, and gene. The obtained data was organized in a table according to the previously proposed standardized data format. The results of the study were visually represented using Gephi and karyotype view. Results: Fifty publications had sufficient data for analysis. Literature analysis resulted in 60 genomic loci, associated with 44 syndromes that have cryptorchidism in clinical picture. Genomic loci included 38 protein-coding genes and 22 structural variations containing microdeletions and microduplications. Loci, associated with syndromic cryptorchidism are located on 16 chromosomes. Visualization of retrieved data is presented in a gene-disease network. Conclusions: The study is ongoing and further studies will be needed to develop a complete catalog with the data from upcoming publications. Additional studies will also be needed for revealing of molecular mechanisms associated with syndromic cryptorchidism and revealing complete diseasome network.	0
PURPOSE Neuroendocrine tumors (NETs) are considered rare tumors and can produce a variety of hormones. In this study, we examined the epidemiology of and prognostic factors for NETs, because a thorough examination of neither had previously been performed. METHODS The Surveillance, Epidemiology, and End Results (SEER) Program registries were searched to identify NET cases from 1973 to 2004. Associated population data were used for incidence and prevalence analyses. Results We identified 35,618 patients with NETs. We observed a significant increase in the reported annual age-adjusted incidence of NETs from 1973 (1.09/100,000) to 2004 (5.25/100,000). Using the SEER 9 registry data, we estimated the 29-year limited-duration prevalence of NETs on January 1, 2004, to be 9,263. Also, the estimated 29-year limited-duration prevalence in the United States on that date was 103,312 cases (35/100,000). The most common primary tumor site varied by race, with the lung being the most common in white patients, and the rectum being the most common in Asian/Pacific Islander, American Indian/Alaskan Native, and African American patients. Additionally, survival duration varied by histologic grade. In multivariate analysis of patients with well-differentiated to moderately differentiated NETs, disease stage, primary tumor site, histologic grade, sex, race, age, and year of diagnosis were predictors of outcome (P < .001). CONCLUSION We observed increased reported incidence of NETs and increased survival durations over time, suggesting that NETs are more prevalent than previously reported. Clinicians need to be become familiar with the natural history and patterns of disease progression, which are characteristic of these tumors.	1
Succinic semialdehyde dehydrogenase deficiency (SSADH-D) is a genetic disorder that results from the aberrant metabolism of the neurotransmitter γ-amino butyric acid (GABA). The disease is caused by impaired activity of the mitochondrial enzyme succinic semialdehyde dehydrogenase. SSADH-D manifests as varying degrees of mental retardation, autism, ataxia, and epileptic seizures, but the clinical picture is highly heterogeneous. So far, there is no approved curative therapy for this disease. In this review, we briefly summarize the molecular genetics of SSADH-D, the past and ongoing clinical trials, and the emerging features of the molecular pathogenesis, including redox imbalance and mitochondrial dysfunction. The main aim of this review is to discuss the potential of further therapy approaches that have so far not been tested in SSADH-D, such as pharmacological chaperones, read-through drugs, and gene therapy. Special attention will also be paid to elucidating the role of patient advocacy organizations in facilitating research and in the communication between researchers and patients.	0
Congenital disorders of glycosylation (CDG) are a group of genetic disorders that affect protein and lipid glycosylation and glycosylphosphatidylinositol synthesis. More than 100 different disorders have been reported and the number is rapidly increasing. Since glycosylation is an essential post-translational process, patients present a large range of symptoms and variable phenotypes, from very mild to extremely severe. Only for few CDG, potentially curative therapies are being used, including dietary supplementation (e.g., galactose for PGM1-CDG, fucose for SLC35C1-CDG, Mn2+ for TMEM165-CDG or mannose for MPI-CDG) and organ transplantation (e.g., liver for MPI-CDG and heart for DOLK-CDG). However, for the majority of patients, only symptomatic and preventive treatments are in use. This constitutes a burden for patients, care-givers and ultimately the healthcare system. Innovative diagnostic approaches, in vitro and in vivo models and novel biomarkers have been developed that can lead to novel therapeutic avenues aiming to ameliorate the patients&rsquo; symptoms and lives. This review summarizes the advances in therapeutic approaches for CDG.	0
X-linked intellectual disability (XLID) is known to contribute up to 10% of intellectual disability (ID) in males and could explain the increased ratio of affected males observed in patients with ID. Over the past decade, next-generation sequencing has clearly stimulated the gene discovery process and has become part of the diagnostic procedure. We have performed targeted next-generation sequencing of 82 XLID genes on 61 non-related male patients with suggestive non-syndromic XLID. These patients were initially referred to the molecular genetics laboratory to exclude Fragile X Syndrome. The cohort includes 47 male patients with suggestive X-linked family history of ID meaning that they had half-brothers or maternal cousins or uncles affected; and 14 male patients with ID and affected brothers whose mothers show skewed X-inactivation. Sequencing data analysis identified 17 candidate variants in 16 patients. Seven families could be re-contacted and variant segregation analysis of the respective eight candidate variants was performed: HUWE1, IQSEC2, MAOA, MED12, PHF8, SLC6A8, SLC9A6, and SYN1. Our results show the utility of targeted next-generation sequencing in unravelling the genetic origin of XLID, especially in retrospective cases. Variant segregation and additional studies like RNA sequencing and biochemical assays also helped in re-evaluating and further classifying the genetic variants found.	0
BACKGROUND AND OBJECTIVES:Microvesicles and exosomes are involved in the pathogenesis of autosomal dominant polycystic kidney disease. However, it is unclear whether they also contribute to medullary sponge kidney, a sporadic kidney malformation featuring cysts, nephrocalcinosis, and recurrent kidney stones. We addressed this knowledge gap by comparative proteomic analysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:The protein content of microvesicles and exosomes isolated from the urine of 15 patients with medullary sponge kidney and 15 patients with autosomal dominant polycystic kidney disease was determined by mass spectrometry followed by weighted gene coexpression network analysis, support vector machine learning, and partial least squares discriminant analysis to compare the profiles and select the most discriminative proteins. The proteomic data were verified by ELISA. RESULTS:A total of 2950 proteins were isolated from microvesicles and exosomes, including 1579 (54%) identified in all samples but only 178 (6%) and 88 (3%) specific for medullary sponge kidney microvesicles and exosomes, and 183 (6%) and 98 (3%) specific for autosomal dominant polycystic kidney disease microvesicles and exosomes, respectively. The weighted gene coexpression network analysis revealed ten modules comprising proteins with similar expression profiles. Support vector machine learning and partial least squares discriminant analysis identified 34 proteins that were highly discriminative between the diseases. Among these, CD133 was upregulated in exosomes from autosomal dominant polycystic kidney disease and validated by ELISA. CONCLUSIONS:Our data indicate a different proteomic profile of urinary microvesicles and exosomes in patients with medullary sponge kidney compared with patients with autosomal dominant polycystic kidney disease. The urine proteomic profile of patients with autosomal dominant polycystic kidney disease was enriched of proteins involved in cell proliferation and matrix remodeling. Instead, proteins identified in patients with medullary sponge kidney were associated with parenchymal calcium deposition/nephrolithiasis and systemic metabolic derangements associated with stones formation and bone mineralization defects. PODCAST:This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_04_24_CJASNPodcast_19_06_.mp3.	0
Neural tube defects (NTD) are among the most common congenital anomalies, affecting about 1:1000 births. In most cases, the etiology of NTD is multifactorial and the genetic variants associated with them remain largely unknown. There is extensive evidence from animal models over the past two decades implicating SHROOM3 in neural tube formation; however, its exact role in human disease has remained elusive. In this report, we present the first case of a human fetus with a homozygous loss of function variant in SHROOM3. The fetus presents with anencephaly and cleft lip and palate, similar to previously described Shroom3 mouse mutants and is suggestive of a novel monogenic cause of NTD. Our case provides clarification on the contribution of SHROOM3 to human development after decades of model organism research.	0
Yellow nail syndrome (YNS) is a rare condition defined by a presence of two of the following: (1) slow-growing, hard, yellow, and dystrophic nails, (2) lymphedema, and (3) respiratory tract disease.[1] The earliest case of YNS was reported by Heller in 1927.[2] However, in 1947, Samman & White published the first case series of YNS in patients with nail discoloration and lymphedema.[3] Pulmonary disease, specifically pleural effusion, was added to the diagnostic criteria by Emerson in 1966.[4] In general, the syndrome is acquired and affects adults over age 50. However, there are case reports of YNS occurring in children and even newborns.[5] Anatomically, YNS affects the fingernails, toenails, the respiratory tract, and gravity-dependent areas that can accumulate fluid (typically lower extremities). These signs and symptoms are believed to be due to dysfunction in lymphatic drainage.[3][4][6][7] Nails As the name suggests, xanthonychia (yellow nail coloration) is a common feature of YNS; however, yellow nails are not required if two of the other clinical signs are present. Discoloration varies from pale yellow to dark green; nails can be opaque or translucent.[8] The manifestations are commonly misdiagnosed as onychomycosis (discoloration due to fungal infection), as the nails may become thickened, hard, and curved.[9] A quick inspection of fingernails and toenails can help expand the differential for a patient with other vague complaints without adding additional expense. Respiratory Tract The respiratory tract is involved in more than half of patients with YNS.[2][7] The most common manifestation is a chronic cough, followed by pleural effusion.[7] In one of the largest reviews of patients with YNS, Valdés et al. found nearly all effusions to be exudative with a lymphocytic predominance. Of the 66 subjects, approximately 70% of effusions were bilateral.[2][10] Other pulmonary manifestations include bronchiectasis, recurrent pneumonia, sinusitis, and pulmonary fibrosis.[11] Pulmonary function testing in YNS is typically unremarkable, and biopsies do not usually contribute to the diagnosis.[10] Lymphedema Lymphedema typically manifests in the bilateral lower extremities and does not differ in appearance from primary lymphedema.[2] Lymphedema occurs in 30% to 80%.[2][7][12] Dynamic lymphatic imaging (lymphoscintigraphy) does differ between patients with edema related to YNS and those with primary lymphedema.[13] Edema can be pitting and can be easily confused with fluid accumulation often seen in patients with decompensated congestive heart failure. This can be especially deceiving if patients present with concurrent pleural effusions. As in primary lymphedema, treatments often involve massage, compression dressing, exercises, and less commonly, surgical interventions.[14] Natural History  The diagnosis of YNS can be difficult because patients rarely present concurrently with all three clinical criteria. Lymphedema is the initial symptom in approximately one-third of YNS diagnoses.[12] Prognosis and disease course depend on the individual's symptoms and timing of diagnosis. In some mild cases, the symptoms of YNS can resolve without intervention. Unfortunately, many symptoms recur despite treatment and require continuous care. YNS has the potential to affect one's quality of life, including both cosmesis and worsening functional status. Recurring soft tissue infections (e.g., cellulitis from severe lymphedema), pulmonary infections (pneumonia/empyema), and pulmonary effusions can lead to complications such as antibiotic resistance, pulmonary scarring, and protein loss.[15] 	0
Diamond-Blackfan anemia (DBA) is a rare congenital erythroid aplasia with a highly heterogeneous genetic background; it usually occurs in infancy. Approximately 30-40% of patients have other associated congenital anomalies; in particular, facial anomalies, such as cleft palate, are part of about 10% of the DBA clinical presentations. Pierre Robin sequence (PRS) is a heterogeneous condition, defined by the presence of the triad of glossoptosis, micrognathia and cleft palate; it occurs in 1/8500 to 1/14,000 births. Klippel Feil (KF) syndrome is a complex of both osseous and visceral anomalies, characterized mainly by congenital development defects of the cervical spine. We describe the case of a 22-years-old woman affected by DBA, carrying a de novo deletion about 500 Kb-long at 12q13.2-q13.3 that included RPS26 and, at least, others 25 flanking genes. The patient showed craniofacial anomalies due to PRS and suffered for KF deformities (type II). Computed Tomography study of cranio-cervical junction (CCJ) drew out severe bone malformations and congenital anomalies as atlanto-occipital assimilation (AOA), arcuate foramen and occipito-condylar hyperplasia. Foramen magnum was severely reduced. Atlanto-axial instability (AAI) was linked to atlanto-occipital assimilation, congenital vertebral fusion and occipito-condyle bone hyperplasia. Basilar invagination and platybasia were ruled out on CT and Magnetic Resonance Imaging (MRI) studies. Furthermore, the temporal Bone CT study showed anomalies of external auditory canals, absent mastoid pneumatization, chronic middle ear otitis and abnormal course of the facial nerve bones canal. The described phenotype might be related to the peculiar deletion affecting the patient, highlighting that genes involved in the in the breakdown of extracellular matrix (MMP19), in cell cycle regulation (CDK2), vesicular trafficking (RAB5B), in ribonucleoprotein complexes formation (ZC3H10) and muscles function (MYL6 and MYL6B) could be potentially related to bone-developmental disorders. Moreover, it points out that multiple associated ribosomal deficits might play a role in DBA-related phenotypes, considering the simultaneous deletion of three of them in the index case (RPS26, PA2G4 and RPL41), and it confirms the association among SLC39A5 functional disruption and severe myopia. This report highlights the need for a careful genetic evaluation and a detailed phenotype-genotype correlation in each complex malformative syndrome.	0
Temozolomide (TMZ) is an alkylating chemotherapy agent used in the clinical treatment of glioblastoma multiforme (GBM) patients. Piperine (PIP) is a naturally occurring pungent nitrogenous substance present in the fruits of peppers. We investigated the anti-cancer efficacies of PIP alone and in combination with TMZ in GBM cellsusingparameters such as cell proliferation, cellular apoptosis,caspase-8/-9/-3 activities, cell cycle kinetics, wound-healing ability, and loss of mitochondrial membrane potential (MMP). Treatment with PIP and alow concentration of PIP-TMZ, inhibited cell growth, similar to TMZ.PIP-TMZ promoted apoptosis by activation of caspase-8/-9/-3, MMP loss, and inhibition of in vitro wound-healing motility. Reverse transcription polymerase chain reaction analysis showed significant inhibition of Cyclin-dependent kinases (CDK)4/6-cyclin D and CDK2-cyclin-E expression upon treatment with a low concentration PIP-TMZ, suggesting an S to G1 arrest. Our findings provide insight into the apoptotic potential of the combination of a low concentration of PIP-TMZ, though further in vivo study will be needed for its validation.	0
We herein report a case of fulminant Legionnaires' disease with autopsy findings in a patient on maintenance hemodialysis (HD). Chronic kidney disease is a strong risk factor for Legionnaires' disease, although there have been only a few reports in HD patients. Because most patients on HD are anuric, the use of rapid assay kits to detect antigens in urine samples for the diagnosis of Legionnaires' disease is not always feasible. We suggest the use of clinical predictive tools or the loop-mediated isothermal amplification (LAMP) method, which can be applied for anuric patients, such as those on HD, with pneumonia.	0
22q11.2 deletion syndrome (DiGeorge), CHARGE syndrome, Nude/SCID and otofaciocervical syndrome type 2 (OTFCS2) are distinct clinical conditions in humans that can result in hypoplasia and occasionally, aplasia of the thymus. Thymic hypoplasia/aplasia is first suggested by absence or significantly reduced numbers of recent thymic emigrants, revealed in standard-of-care newborn screens for T cell receptor excision circles (TRECs). Subsequent clinical assessments will often indicate whether genetic mutations are causal to the low T cell output from the thymus. However, the molecular mechanisms leading to the thymic hypoplasia/aplasia in diverse human syndromes are not fully understood, partly because the problems of the thymus originate during embryogenesis. Rodent and Zebrafish models of these clinical syndromes have been used to better define the underlying basis of the clinical presentations. Results from these animal models are uncovering contributions of different cell types in the specification, differentiation, and expansion of the thymus. Cell populations such as epithelial cells, mesenchymal cells, endothelial cells, and thymocytes are variably affected depending on the human syndrome responsible for the thymic hypoplasia. In the current review, findings from the diverse animal models will be described in relation to the clinical phenotypes. Importantly, these results are suggesting new strategies for regenerating thymic tissue in patients with distinct congenital disorders.	0
Mirror foot is a rare abnormality which presents as a preaxial, postaxial, or central polydactyly of the foot. The latter is encountered infrequently. We describe the case of a central mirror foot. Our patient had eight digits of a central ray pattern type with fully developed metatarsal, proximal, middle, and distal phalanges, as well as a medial toe syndactyly. He had no tarsal bone duplications. He was treated by central ray resection via double V-shaped incisions on the dorsal and plantar aspects of the foot, while preserving the medial and lateral rays. The results were satisfactory. We describe the technique and attempt a review of the literature.	0
BACKGROUND: Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by cerebellar atrophy, peripheral neuropathy, oculomotor apraxia, and elevated serum alpha-fetoprotein (AFP) levels. The disease is caused by a recessive mutation in the senataxin gene. Since it is a very rare cerebellar disorder, no detailed examination of cognitive functions in AOA2 has been published to date. The aim of the present study was to investigate the neuropsychological profile of a 54-year-old patient with AOA2. METHODS: A broad range of neuropsychological examination protocol was administered including the following domains: short-term, working- and episodic-memories, executive functions, implicit sequence learning, and the temporal parameters of speech. RESULTS: The performance on the Listening Span, Letter Fluency, Serial Reaction Time Task, and pause ratio in speech was 2 or more standard deviations (SD) lower compared to controls, and 1 SD lower on Backward Digit Span, Semantic Fluency, articulation rate, and speech tempo. CONCLUSION: These findings indicate that the pathogenesis of the cerebrocerebellar circuit in AOA2 is responsible for the weaker coordination of complex cognitive functions such as working memory, executive functions, speech, and sequence learning.	0
BACKGROUND:Epidermoid tumors, or epidermoid cysts (ECs), are benign, slow-growing, congenital, and rare lesions that represent approximately 0.2%-1.8% of all intracranial tumors. Intraparenchymal ECs are very rare lesions that may account for 1.5% of all intracranial epidermoid tumors; frontal lobe involvement is found in 39.2% of intraparenchymal ECs. We present a case using awake craniotomy to achieve maximal safe gross total resection of a rare intraparenchymal EC close to Broca area in a bilingual patient. CASE DESCRIPTION:A 45-year-old man presented with a generalized seizure episode. He was initially treated with levetiracetam, which led to renal failure. Imaging findings demonstrated an intraparenchymal left frontal EC with peripheral coarse calcifications at Broca area. As the patient was bilingual and had a normal neurologic examination, we performed a left frontal awake craniotomy under local anesthesia so as to map both languages, using the motor task and a test for language monitoring, alternating a naming task in Portuguese and English and a semantic task in Portuguese. A gross total resection was achieved with no neurologic deficits. Histopathologic examination confirmed the diagnosis of an epidermoid cyst. After 1 year, the patient is still seizure-free. CONCLUSIONS:Awake surgery proved to be a useful tool for complete resection of the capsule even in a very eloquent language area. In multilingual patients with benign intra-axial lesions, intraoperative mapping should be performed for all the languages in which the patient is fluent to avoid postoperative neurologic deficits.	0
Sternal cleft (SC) is a rare congenital anomaly, occurring with associated developmental anomalies or in isolation. Surgery to reconstruct the sternum is indicated to protect the visceral organs from trauma, to ensure healthy cardiopulmonary function and growth, and to reconstruct the anterior chest wall. Although infection recognized as a postoperative complication following chest wall reconstruction, spontaneous mediastinal infection is rare. To the authors' knowledge, there is only 1 reported case of spontaneous mediastinal infection with concomitant SC in the literature. Here, the authors present a unique case of a medically complicated infant with a SC who presented with a spontaneous mediastinal abscess.	0
Atrophoderma vermiculata is a rare genodermatosis with usual onset in childhood, characterized by a "honey-combed" reticular atrophy of the cheeks. The course is generally slow, with progressive worsening. We report successful treatment of 2 patients by means of the carbon dioxide and 585 nm pulsed dye lasers.	0
BACKGROUND:Inherited macular dystrophies constitute a group of diseases characterized by bilateral central visual loss with symmetrical macular abnormalities usually presenting in the first two decades of life. The aim of this study were to find out the demographic characteristics and disease pattern of inherited retinal dystrophies in subjects attending retina outpatient department in a tertiary care center. METHODS:An observational study among twenty-six participants diagnosed as macular dystrophy visiting a tertiary care centre in Nepal, during January 2018 to June 2018 were included in the study. Detailed history, slit lamp examination, dilated fundus examination, coloured fundus photography, full field electroretinogram, multifocal electroretinogram, automated visual field and colour vision were done. RESULTS:A total of 52 eyes of 26 subjects were diagnosed with macular dystrophy. The male to female ratio was 1:1. The mean age of presentation was 28.38 years. Most common symptom was blurring of vision seen in 96.15%.The mean visual acuity was 0.67 log mar units in right eye and 0.71 log mar units in the left eye. The most common macular dystrophy was cone dystrophy followed by adult vitelliform macular dystrophy and Stargardts dystrophy. CONCLUSIONS:Cone dystrophy is the most common followed by Stargardt's disease and adult vitelliform macular dystrophy. Most presented in the first two decades of life and the most common presenting symptom was blurring of vision.	0
The purpose of this review is to summarize the pathophysiology of complex regional pain syndrome (CRPS), the underlying molecular mechanisms, and potential treatment options for its management. CRPS is a multifactorial pain condition. CRPS is characterized by prolonged or excessive pain and changes in skin color and temperature, and/or swelling in the affected area, and is generally caused by stimuli that lead to tissue damage. An inflammatory response involving various cytokines and autoantibodies is generated in response to acute trauma/stress. Chronic phase pathophysiology is more complex, involving the central and peripheral nervous systems. Various genetic factors involved in the chronicity of pain have been identified in CRPS patients. As with other diseases of complex pathology, CRPS is difficult to treat and no single treatment regimen is the same for two patients. Stimulation of the vagus nerve is a promising technique being tested for different gastrointestinal and inflammatory diseases. CRPS is more frequent in individuals of 61-70 years of age with a female to male ratio of 3 : 1. Menopause, migraine, osteoporosis, and asthma all represent risk factors for CRPS and in smokers the prognosis appears to be more severe. The pathophysiological mechanisms underlying CRPS involve both inflammatory and neurological pathways. Understanding the molecular basis of CRPS is important for its diagnosis, management, and treatment. For instance, vagal nerve stimulation might have the potential for treating CRPS through the cholinergic anti-inflammatory pathway.	0
OBJECTIVE: A chronic arteriovenous malformation (AVM) model using the swine retia mirabilia (RMB) was developed and compared with the human extracranial AVM (EAVM) both in hemodynamics and pathology, to see if this brain AVM model can be used as an EAVM model. METHODS: We created an arteriovenous fistula between the common carotid artery and the external jugular vein in eight animals by using end-to-end anastomosis. All animals were sacrificed 1 month after surgery, and the bilateral retia were obtained at autopsy and performed hematoxylin and eosin staining and immunohistochemistry. Pre- and postsurgical hemodynamic evaluations also were conducted. Then, the blood flow and histological changes of the animal model were compared with human EAVM. RESULTS: The angiography after operation showed that the blood flow, like human EAVM, flowed from the feeding artery, via the nidus, drained to the draining vein. Microscopic examination showed dilated lumina and disrupted internal elastic lamina in both RMB of model and nidus of human EAVM, but the thickness of vessel wall had significant difference. Immunohistochemical reactivity for smooth muscle actin, angiopoietin 1, and angiopoietin 2 were similar in chronic model nidus microvessels and human EAVM, whereas vascular endothelial growth factor was significant difference between human EAVM and RMB of model. CONCLUSIONS: The AVM model described here is similar to human EAVM in hemodynamics and immunohistochemical features, but there are still some differences in anatomy and pathogenetic mechanism. Further study is needed to evaluate the applicability and efficacy of this model.	0
Genetic disorders involving the skeletal system arise through disturbances in the complex processes of skeletal development, growth and homeostasis and remain a diagnostic challenge because of their variety. The Nosology and Classification of Genetic Skeletal Disorders provides an overview of recognized diagnostic entities and groups them by clinical and radiographic features and molecular pathogenesis. The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists interested in skeletal biology. In the 2010 revision, 456 conditions were included and placed in 40 groups defined by molecular, biochemical, and/or radiographic criteria. Of these conditions, 316 were associated with mutations in one or more of 226 different genes, ranging from common, recurrent mutations to "private" found in single families or individuals. Thus, the Nosology is a hybrid between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum produced by mutations in a given gene. The Nosology should be useful for the diagnosis of patients with genetic skeletal diseases, particularly in view of the information flood expected with the novel sequencing technologies; in the delineation of clinical entities and novel disorders, by providing an overview of established nosologic entities; and for scientists looking for the clinical correlates of genes, proteins and pathways involved in skeletal biology.	0
Spondyloepiphyseal dysplasia (SED) is a descriptive term used for group of inherited disorders of bone growth resulting in short stature, skeletal abnormalities, and problems with hearing and vision. SED have three major forms, SED congenital, pseudoachondroplastic SED, and SED tarda. SED tarda is milder than SED congenita. True generalized microdontia is a rare condition in which all the teeth are abnormally small. This is a report of a rare case having SED with generalized microdontia in a 26-year-old patient.	0
We describe an 11-year-old girl, diagnosed with juvenile polymyositis (JPM), who developed right ureteral obstruction secondary to necrosis. We emphasize the dilemmas regarding optimal timing for surgical intervention and medical treatment. Vascular involvement, which could be a part of juvenile dermatomyositis, may also be a feature of JPM. We discuss the association between vasculopathy and ureteral necrosis and review the literature regarding similar conditions. Whether the ureteral necrosis is a specific feature of vasculopathy, or a result of visceral calcinosis, needs to be further explored.	0
Over three decades, 12 cases of mosaicism for an autosomal rearrangement were recognised in the major cytogenetics laboratories in New Zealand, eight of which were studied between 1990 and 1992. One case inferentially involved the gonad, eight the soma, and three both gonad and soma. This mosaicism could have arisen as a postzygotic event either in a conceptus that was initially normal, with the generation of an abnormal cell line, or in a conceptus having a supernumerary chromosome which was lost at a subsequent mitosis, thereby restoring a normal cell line. Three of the 12 cases involved a presumed direct duplication, an otherwise very uncommon rearrangement. This may indicate a propensity for direct duplications to arise at mitosis rather than at meiosis; unequal sister chromatid exchange is a plausible mechanism. Mosaicism has clinical relevance for genetic counselling, as an intragonadal cell line carrying a rearrangement could generate multiple unbalanced gametes. Mosaicism for an autosomal rearrangement my be very much more common that is, or ever could be, recognised.	0
BACKGROUND:Known as a rare disease, Kimura disease is a chronic, allergic and inflammatory process. It may overlap other allergic conditions, as well. CASE PRESENTATION:This study is going to present a 36-year-old woman, with cough, dyspnea and bone pain. Other differential diagnoses were excluded during the investigations. The definite diagnosis was made by excisional biopsy and pathological investigations. CONCLUSION:This was a rare medical condition with remarkable diagnostic challenge.	0
We describe an otherwise healthy 7-year-old boy who developed confetti-like hypopigmented macules on the dorsal aspects of the hands and feet, spreading to the palms and soles a few months after birth. In 1964 Siemens introduced the term acromelanosis albo-punctata to describe the skin features of a patient who has remained the only reported case in the literature so far and who strongly resembles our patient. By genetic testing we excluded mutations in genes known to be involved in diseases with acral hypo- or hyperpigmentation. We review the differential diagnosis of acral localized spotty dyspigmentation and conclude that acromelanosis albo-punctata may represent a distinct entity.	0
Congenital hemolytic anemias (CHAs) are a heterogeneous group of rare hereditary conditions including defects of erythrocyte membrane proteins, red cell enzymes, and disorders due to defective erythropoiesis. They are characterized by variable degree of anemia, chronic extravascular hemolysis, reduced erythrocyte life span, splenomegaly, jaundice, biliary lithiasis, and iron overload. Although few data are reported on the role of the immune system in CHAs, several immune-mediated mechanisms may be involved in the pathogenesis of these rare diseases. We reported in ~60% of patients with hereditary spherocytosis (HS), the presence of naturally-occurring autoantibodies (NAbs) directed against different membrane proteins (α- and β-spectrin, band 3, and dematin). Positive HS subjects showed a more hemolytic pattern and NAbs were more evident in aged erythrocytes. The latter is in line with the function of NAbs in the opsonization of damaged/senescent erythrocytes and their consequent removal in the spleen. Splenectomy, usually performed to reduce erythrocyte catheresis and improve Hb levels, has different efficacy in various CHAs. Median Hb increase is 3 g/dL in HS, 1.6-1.8 g/dL in pyruvate kinase deficiency (PKD), and 1 g/dL in congenital dyserythropoietic anemias (CDA) type II. Consistently with clinical severity, splenectomy is performed in 20% of HS, 45% of CDAII, and in 60% of PKD patients. Importantly, sepsis and thrombotic events have been registered, particularly in PKD with a frequency of ~7% for both. Furthermore, we analyzed the role of pro-inflammatory cytokines and found that interleukin 10 and interferon γ, and to a lesser extent interleukin 6, were increased in all CHAs compared with controls. Moreover, CDAII and enzymatic defects showed increased tumor necrosis factor-α and reduced interleukin 17. Finally, we reported that iron overload occurred in 31% of patients with membrane defects, in ~60% of CDAII cases, and in up to 82% of PKD patients (defined by MRI liver iron concentration >4 mg Fe/gdw). Hepcidin was slightly increased in CHAs compared with controls and positively correlated with ferritin and with the inflammatory cytokines interleukin 6 and interferon γ. Overall the results suggest the existence of a vicious circle between chronic hemolysis, inflammatory response, bone marrow dyserythropoiesis, and iron overload.	0
Stenosis, atresia, or absence of part of the duodenum, jejunum, or ileum are generally considered small intestinal atresias (SIAs). SIAs occur as isolated defects, in combination with other unrelated congenital anomalies, or as part of syndromes. We performed an epidemiological study of infants with isolated SIAs using data from two large congenital defects registries, one from Latin America (ECLAMC) and the other from Spain (ECEMC). The overall prevalence of SIAs is similar in both programs, being 1.32 per 10,000 livebirths in Spain and 1.29 per 10.000 livebirths in Latin America. Our results suggest that infants with isolated SIAs are characterized epidemiologically on the basis of shorter gestational age and low birthweight, an association with twinning, the parents are more frequently consanguineous, and their pregnancies are more frequently complicated by vaginal bleeding. The results also suggest an association between some maternal infections and ileal atresia. The fact that these characteristics have been observed in children with these types of anomalies occurring in different geographical areas and populations supports the conclusion that these characteristics are causally related to these defects.	1
Paroxysmal movement disorders (PMDs) are rare neurological diseases typically manifesting with intermittent attacks of abnormal involuntary movements. Two main categories of PMDs are recognized based on the phenomenology: Paroxysmal dyskinesias (PxDs) are characterized by transient episodes hyperkinetic movement disorders, while attacks of cerebellar dysfunction are the hallmark of episodic ataxias (EAs). From an etiological point of view, both primary (genetic) and secondary (acquired) causes of PMDs are known. Recognition and diagnosis of PMDs is based on personal and familial medical history, physical examination, detailed reconstruction of ictal phenomenology, neuroimaging, and genetic analysis. Neurophysiological or laboratory tests are reserved for selected cases. Genetic knowledge of PMDs has been largely incremented by the advent of next generation sequencing (NGS) methodologies. The wide number of genes involved in the pathogenesis of PMDs reflects a high complexity of molecular bases of neurotransmission in cerebellar and basal ganglia circuits. In consideration of the broad genetic and phenotypic heterogeneity, a NGS approach by targeted panel for movement disorders, clinical or whole exome sequencing should be preferred, whenever possible, to a single gene approach, in order to increase diagnostic rate. This review is focused on clinical and genetic features of PMDs with the aim to (1) help clinicians to recognize, diagnose and treat patients with PMDs as well as to (2) provide an overview of genes and molecular mechanisms underlying these intriguing neurogenetic disorders.	0
Background:Spinocerebellar ataxia type 23 (SCA23) is an autosomal dominant cerebellar ataxia caused by pathogenic variants in the prodynorphin gene (PDYN). The frequency of PDYN variants is reportedly very low (~ 0.1%) in several ataxia cohorts screened to date. Case presentations:We found five cases of SCA23 in two families (mean age at onset: 37.8 ± 5.5 years; mean age at examination: 64.2 ± 12.3 years) with a novel PDYN variant (c.644G > A:p.R215H). We identified marked heterogeneity in the clinical features in Family 1: the proband showed clinical and neuroimaging features suggestive of multiple system atrophy with predominant parkinsonism (MSA-P). Conversely, the proband's mother with the PDYN p.R215H variant had no subjective symptoms; she had not come to medical attention before our survey, although she showed apparent cerebellar atrophy on brain magnetic resonance imaging (MRI). The other two patients in Family 1 and a patient in Family 2 showed slowly progressive cerebellar ataxia. Conclusions:We here report two Japanese families with SCA23, one of which showed considerable phenotypic variation in affected members. Our findings support that SCA23 can phenotypically overlap with MSA.	0
Cutaneous tuberculosis is a rare extrapulmonary manifestation of tuberculosis which, like disseminated tuberculosis, commonly occurs in immunocompromised patients. Poncet reactive arthritis is a seronegative arthritis affecting patients with extrapulmonary tuberculosis, which is uncommon even in endemic countries. We report a previously healthy 23-year-old male patient with watery diarrhea associated with erythematous ulcers on the lower limbs and oligoarthritis of the hands. Histopathological examination of the skin showed epithelioid granulomatous process with palisade granulomas and central caseous necrosis. AFB screening by Ziehl-Neelsen staining showed intact bacilli, the culture was positive for Mycobacterium tuberculosis, and colonoscopy revealed multiple shallow ulcers. Disseminated tuberculosis associated with reactive Poncet arthritis was diagnosed, with an improvement of the clinical and skin condition after appropriate treatment.	0
Background:Anthracyclines are a mainstay of chemotherapy. However, a relatively frequent adverse outcome of anthracycline treatment is cardiomyopathy. Multiple genetic studies have begun to dissect the complex genetics underlying cardiac sensitivity to the anthracycline drug class. A number of single nucleotide polymorphisms (SNPs) have been identified to be in linkage disequilibrium with anthracycline induced cardiotoxicity in paediatric populations. Methods:Here we screened for the presence of SNPs resulting in a missense coding change in a cohort of children with early onset chemotherapy related cardiomyopathy. The SNP identity was evaluated by Sanger sequencing of PCR amplicons from genomic DNA of patients with anthracycline related cardiac dysfunction. Results:All of the published SNPs were observed within our patient group. There was no correlation between the number of missense variants an individual carried with severity of disease. Furthermore, the time to cardiac disease onset post-treatment was not greater in those individuals carrying a high load of SNPs resulting from missense variants. Conclusions:We conclude that previously identified missense SNPs are present within a paediatric cohort with early onset heart damage induced by anthracyclines. However, these SNPs require further replication cohorts and functional validation before being deployed to assess anthracycline cardiotoxicity risk in the clinic.	0
BACKGROUND/AIM:In the variety of congenital abdominal cystic lesions (CACL) of different origin, ovarian cyst is the most common intra-abdominal pathology in female neonates. The prognosis and timing of treatment varies depending on the nature of CACL. This study aimed to assess the results of diagnostics and treatment of CACL. PATIENTS AND METHODS:A retrospective analysis was performed of 39 cases of CACL, with the spectrum including ovarian, enteric, mesenteric and pancreatic origin. Outcome of minimally invasive surgery, open surgery or conservative approach was analyzed. RESULTS:Twenty-eight neonates underwent surgery, while 11 were treated conservatively. Twenty patients were treated with a laparoscopic technique and eight with laparotomy combined with laparoscopy. Final diagnosis included: Fifteen cases of ovarian pathology (ovarian torsion in 11 cases), 12 treated laparoscopically and three with laparotomy, six enteric duplications (four laparoscopic and two laparotomic), three mesenteric cysts (one laparoscopic and two laparotomic), two pancreatic cysts (both laparoscopic only), two duodenal stenoses, including duodenal septum (both laparotomies with Heineke-Mikulicz plasty). No blood transfusion apart from two cases requiring re-laparotomy and no early complications were observed in any case; no death occurred. CONCLUSION:With the strategy of management based on ultrasound and laboratory data, a laparoscopically assisted minimal access approach resulted in minimal risk of complications and complete recovery in all patients, leading to exclusion of oncological risk.	0
Well-known causes of zinc deficiency, also referred to as acrodermatitis enteropathica (AE), include defects in intestinal zinc transporters and inadequate intake, but a rare cause of acquired zinc deficiency discussed here is an iatrogenic nutritional deficiency caused by parenteral nutrition administered without trace elements. While zinc-depleted parenteral nutrition causing dermatosis of acquired zinc deficiency was first reported in the 1990s, it is now again relevant due to a national vitamin and trace element shortage. A high index of suspicion may be necessary to diagnose zinc deficiency, particularly because early clinical findings are nonspecific. We present this case of acquired zinc deficiency in a patient admitted to a pediatric intensive care unit for respiratory distress and atypical pneumonia, who subsequently developed a severe bullous eruption due to iatrogenic zinc deficiency but was treated effectively with enteral and parenteral zinc supplementation, allowing for rapid re-epithelialization of previously denuded skin.	0
Warsaw breakage syndrome (WBS) is a recently recognized DDX11-related rare cohesinopathy, characterized by severe prenatal and postnatal growth restriction, microcephaly, developmental delay, cochlear anomalies, and sensorineural hearing loss. Only seven cases have been reported in the English literature, and thus the information on the phenotype and genotype of this interesting condition is limited. We provide clinical and molecular information on five additional unrelated patients carrying novel bi-allelic variants in the DDX11 gene, identified via whole exome sequencing. One of the variants was found to be a novel Saudi founder variant. All identified variants were classified as pathogenic or likely pathogenic except for one that was initially classified as a variant of unknown significance (VOUS) (p.Arg378Pro). Functional characterization of this VOUS using heterologous expression of wild type and mutant DDX11 revealed a marked effect on protein stability, thus confirming pathogenicity of this variant. The phenotypic data of the seven WBS reported patients were compared to our patients for further phenotypic delineation. Although all the reported patients had cochlear hypoplasia, one patient also had posterior labyrinthine anomaly. We conclude that while the cardinal clinical features in WBS (microcephaly, growth retardation, and cochlear anomalies) are almost universally present, the breakage phenotype is highly variable and can be absent in some cases. This report further expands the knowledge of the phenotypic and molecular features of WBS.	0
INTRODUCTION:Reconstruction of Wassel IV-D radial polydactyly is challenging and requires a custom strategy dependent on the relative size and shape of the radial and ulnar duplicates. Herein, we describe a technique using a boot-shaped neurovascular island flap and review our outcomes. METHODS:Ninety-one consecutive patients had reconstruction with a boot-shaped neurovascular island flap. The flap was dissected out from the thumb to be removed. Specific flap modifications were inclusion of the lateral nail fold, Bruner incisions dorsally and volarly to reduce scarring at the interphalangeal (IP) joint and also complete mobilization of the island flap on its pedicle to allow easier inset. A flexor pollicis longus and extensor tendon rebalancing technique was used to correct the deviation of the reconstructed thumb IP joint. RESULTS:All boot-shaped neurovascular island flaps survived with good contour, shape, and symmetry. The average follow-up period was 25 months (range 6-60 months). Using the Japanese Society for Surgery of the Hand (JSSH) score for classification of outcomes, seven cases were classified as excellent and 84 cases as good. The median JSSH score was 18. The median Kapandji score for opposition was 9 (range 8-10). CONCLUSION:Using a boot-shaped neurovascular island flap completely mobilized on its pedicle with a custom strategy for each radial duplicate, good outcomes can be achieved in reconstruction of Wassel IV-D radial polydactyly. LEVEL OF EVIDENCE:Therapeutic Level IV.	0
BACKGROUND AND AIMS:Lysosomal acid lipase deficiency is characterized by hepatomegaly and dyslipidemia, which can lead to liver cirrhosis and premature atherosclerosis. Sebelipase alfa is an approved recombinant human lysosomal acid lipase. In an open-label extension study of adults with lysosomal acid lipase deficiency (LAL-CL04), sebelipase alfa treatment for 1 year reduced serum transaminase levels and liver fat content and improved serum lipid levels. METHODS:Final data from LAL-CL04 are reported herein for patients who received sebelipase alfa infusions (1.0 or 3.0 mg/kg every other week) for up to 5 years. RESULTS:Of 8 patients enrolled, 7 received sebelipase alfa for 224-260 weeks; 1 was lost to follow-up. Median baseline levels of alanine aminotransferase and aspartate aminotransferase (81.5 and 50.0 U/L, respectively) were decreased through the end-of-study visit (54.0 and 34.0 U/L). Median low-density lipoprotein cholesterol decreased from 113 to 78 mg/dL, total cholesterol decreased from 171 to 132 mg/dL, and high-density lipoprotein cholesterol increased from 37 to 42 mg/dL. Most treatment-emergent adverse events were nonserious (99%), mild/moderate (98%), and unrelated to sebelipase alfa (87%); no patient discontinued due to treatment-emergent adverse events. One patient had 2 serious treatment-emergent adverse events (cholecystitis and cholelithiasis; assessed as unlikely related to sebelipase alfa). Two patients had 20 nonserious infusion-associated reactions in weeks 6-38; all were manageable. One patient tested positive for anti-drug antibodies (single occurrence). CONCLUSIONS:Sebelipase alfa was well tolerated and improved serum transaminase and lipid levels for up to 5 years in adults with lysosomal acid lipase deficiency.	0
Wolff-Parkinson-White syndrome is the most common form of ventricular preexcitation and affects 1-3 per 1,000 persons worldwide. Many patients remain asymptomatic throughout their lives; however, approximately half of the patients with Wolff-Parkinson-White syndrome experience symptoms secondary to tachyarrhythmias, such as paroxysmal supraventricular tachycardia, atrial fibrillation, atrial flutter, and, rarely, ventricular fibrillation and sudden death. Patients with Wolff-Parkinson-White syndrome may present with a multitude of symptoms such as unexplained anxiety, palpitations, fatigue, light-headedness or dizziness, loss of consciousness, and shortness of breath. We report the case of a patient who presented with a plethora of symptoms related to generalized anxiety along with several confounding factors such as psychosocial stressors, chronic fatigue secondary to high physical and mental demands at work, a strong family history of anxiety, and a history of substance abuse. Keeping cardiac dysrhythmia within his differential diagnosis allowed for accurate diagnosis and treatment.	0
AIM:To describe the clinical manifestations, evolution and treatment of patients with rheumatoid vasculitis. METHODS:Retrospective study (1975-2017) of all patients diagnosed with rheumatoid vasculitis in 2 Rheumatology Services. RESULTS:A total of 41 patients were included, 17 (41.5%) males and 24 (58.5%) females; mean age at diagnosis: 67 ± 9 years; duration of rheumatoid arthritis: 10 ± 8.3 years. Most patients had erosive disease, 33 (80%). Rheumatoid factor and anticitrullinated antibodies were positive in all patients. Constitutional symptoms were present in 30 (73%) patients and extra-articular manifestations in 17 (41%) patients. The clinical manifestations of rheumatoid vasculitis were mainly: cutaneous 28 (68%), and polyneuritis 26 (63%). All patients were treated with glucocorticoids. An immunosuppressant was associated in 24 (58.5%) patients. Five (12%) patients were treated with the association of glucocorticoids and a biologic treatment. The mortality after 2years of follow-up was 33%, the most common causes being infection and progression of the vasculitis. The frequency of rheumatoid vasculitis has decreased over the last decade. CONCLUSION:The clinical manifestations of rheumatoid vasculitis were similar to previous studies. The frequency of rheumatoid vasculitis seems to decrease. However, the clinical picture and severity remains invariable.	0
A 23-year-old woman had presented initially to a podiatrist complaining of poorly fitting shoes during her adolescence. After extensive neurological review, she was diagnosed with ataxia with oculomotor apraxia type 2. This is a progressive autosomal recessive ataxia associated with cerebellar atrophy, peripheral neuropathy and an elevated serum α-fetoprotein. Within Europe, it is the most frequent autosomal recessive ataxia after Friedreich's ataxia and is due to mutations in the senataxin (SETX) gene. The age of onset is approximately 15 years.The diagnosis of oculomotor apraxia type 2 is often challenging. We provide a framework for assessing a young ataxic patient with or without oculomotor apraxia and review clues that will aid diagnosis. The prognosis, level of disability, cancer and immunosuppression risk all markedly differ between the conditions. Patients and their families need the correct diagnosis for genetic counselling, management and long-term surveillance with appropriate subspecialty services.	0
We present a case of a 54-year-old man with primary angiitis of the central nervous system (PACNS) who was initially admitted to a psychiatric clinic with a diagnosis of delirium. We discuss the difficulty in establishing the diagnosis of PACNS and provide the reader with some recommendations on how to promptly and correctly diagnose this disease in order to avoid potentially lethal outcomes.	0
BACKGROUND:Stroke is a severe clinical disorder in sickle cell disease (SCD), and few studies have evaluated transcranial Doppler (TCD) flow velocities in hemoglobin SC disease (HbSC). The guidelines for stroke risk are based on evaluations in sickle cell anemia (SCA) or HbS/β thalassemia. PROCEDURE:In this study, we compare cerebral blood flow in patients with SCD stratified by genotypes. A total of 1,664 pediatric patients with SCD underwent TCD velocity screening, and the time-averaged maximum mean velocity (TAMM) was determined in the middle cerebral artery (MCA), anterior cerebral artery (ACA), and distal intracranial internal carotid artery (ICA). RESULTS:Abnormal velocities were not identified in the ACA; therefore, we only use ICA and MCA velocities. TAMM from the left and right in the ICA and MCA was 134.3 ± 32.0 and 134.4 ± 32.6 cm/s in patients with SCA, and 105.2 ± 20.6 and 104.7 ± 20.0 cm/s in the patients with HbSC, respectively. Mean TAMM between right and left ICA/MCA was 134.5 ± 30.5 cm/s in the SCA group, and 104.9 ± 19.3 cm/s in the HbSC group. Notably, our data show that TCD velocities were significantly lower among the patients with HbSC compared to SCA. TAMM was negatively correlated with hemoglobin and hematocrit in both genotypes. CONCLUSION:These results suggest that a different cut-off value for abnormal TCD velocities could be considered for patients with HbSC. Additional studies are warranted to determine the actual risk of stroke in HbSC genotype associated with this possible TCD risk value.	0
Germline mutations in Fanconi Anemia (FA) genes predispose to chromosomes instability syndromes, such as FA and cancers. FA gene products have traditionally been studied for their role in inter-strand cross link (ICL) repair. A fraction of FA gene products are classical Homologous Recombination (HR) factors that are involved in repairing DNA Double Strand Breaks (DSB's) in an error-free manner. Emerging evidence suggests that, independent of ICL and HR repair, FA genes protect DNA replication forks in the presence of replication stress. Therefore, understanding the precise function of FA genes and their role in promoting genome stability in response to DNA replication stress is crucial for diagnosing FA and FA-associated cancers. Moreover, molecular understanding of the FA pathway will greatly help to establish proper functional assays for Variants of Unknown Significance (VUS), often encountered in clinics. In this short review, we discuss the recently uncovered molecular details of FA genes in replication fork protection pathways. Finally, we examine how novel FA variants predispose to FA and cancer, due to defective replication fork protection activity.	0
Juvenile-onset cataracts are known among the Hutterites of North America. Despite being identified over 30 years ago, this autosomal recessive condition has not been mapped, and the disease gene is unknown.We performed whole exome sequencing of three Hutterite-type cataract trios and follow-up genotyping and mapping in four extended kindreds.Trio exomes enabled genome-wide autozygosity mapping, which localized the disease gene to a 9.5-Mb region on chromosome 6p. This region contained two candidate variants, LEMD2 c.T38G and MUC21 c.665delC. Extended pedigrees recruited for variant genotyping revealed multiple additional relatives with juvenile-onset cataract, as well as six deceased relatives with both cataracts and sudden cardiac death. The candidate variants were genotyped in 84 family members, including 17 with cataracts; only the variant in LEMD2 cosegregated with cataracts (LOD = 9.62). SNP-based fine mapping within the 9.5 Mb linked region supported this finding by refining the cataract locus to a 0.5- to 2.9-Mb subregion (6p21.32-p21.31) containing LEMD2 but not MUC21. LEMD2 is expressed in mouse and human lenses and encodes a LEM domain-containing protein; the c.T38G missense mutation is predicted to mutate a highly conserved residue within this domain (p.Leu13Arg).We performed a genetic and genomic study of Hutterite-type cataract and found evidence for an association of this phenotype with sudden cardiac death. Using combined genetic and genomic approaches, we mapped cataracts to a small portion of chromosome 6 and propose that they result from a homozygous missense mutation in LEMD2.	0
During the mobile clinic activities in Tak Province, Thailand, Paragonimus sp. eggs were found in a fecal sample of a 72-year-old Karen resident. Paragonimus DNA was amplified from the stool sample and identified to P. heterotremus. The patient did not have any symptoms. Apparent pulmonary lesion was not found on the chest X-ray. The patient admitted habitual consumption of semi-cooked or roasted waterfall crabs for several years. The waterfall crabs collected from stream near the village were found negative for Paragonimus metacercariae. In northern Thailand, paragonimiasis remains as one of the public health concerns and should be ruled out for asymptomatic pulmonary patients.	0
Background: Leber congenital amaurosis (LCA) is both genetically and phenotypically heterogeneous group of retinal disorder. Mutations in retinal degeneration 3 (RD3) have been reported as an infrequent cause of LCA which account for less than 1% of all known LCA cases. This case report provides Optical Coherence Tomography (OCT) and Fundus Autofluorescence (FAF) findings of an infant with LCA related to a mutation in RD3.Materials and Methods: Single retrospective case report.Results: TruSight One Expanded Sequencing Panel was applied to the patient on the Illumina NextSeq. Homozygous pathogenic variant (c.112 C > T, p.Arg38Ter) was detected in the RD3 gene. Well-demarcated central foveal atrophy was noted in the infrared imaging. FAF imaging showed perifoveal hyperautofluorescent ring and irregular hyperautofluorescence outside the vascular arcade. An arrest in foveal development and loss of outer retinal structure including outer nuclear layer, external limiting membrane, ellipsoid zone and interdigitation zone at the fovea were detected in the OCT imaging.Conclusion: This study indicates that RD3-related LCA has a very severe phenotype with foveal development arrest and very early loss of all photoreceptor layer and external limiting membrane at the fovea.	0
Omsk hemorrhagic fever (OHF) is a severe disease that emerged in the 1940s in Siberia, Russia. It is caused by the OHF virus (OHFV), belonging to the Flavivirus genus. In wildlife, the principal vector of OHFV is the Dermacentor reticulatus tick. However, humans are mainly infected after contact with an infected muskrat Ondatra zibethicus. The evolutionary history of OHFV is not yet clarified. In an attempt to reconstruct the temporal and spatial phylodynamics of OHFV, a collection of 25 OHFV strains was studied. Maximum likelihood analysis, the Bayesian MCMC approach, and procedures based on continuous-time Markov Chain process, were used for the investigation of OHFV E gene nucleotide sequences. Six statistically supported clusters of OHFV were identified; five of them joined in a main clade A. The first revealed evolutionary event, when OHFV clade A and clade B divided, dated to about 700 years ago. Clusters C, D, and E, within clade A, separated 230 years ago and further evolved during last century. The phylogeographic analysis showed that clade A originated in the Omsk Province, whereas clusters B, C, and E appeared to originate in Kurgan, Novosibirsk, and Omsk Provinces, respectively. In conclusion, OHFV, as a member of the mammalian tick-borne group of flaviviruses, evolved in Western Siberia during the last millennium. When a highly susceptible species, O.zibethicus, was introduced into the region, in the 1930s, OHFV used this species as an amplifying host that lead to numerous fatal epizootics in muskrats and to human OHF outbreaks.	0
Our objective was to investigate the potential of three microRNAs, miR-181a-5p, miR-30c-5p, and miR-206 as prognostic biomarkers for long-term follow up of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients. We analyzed the expression of three microRNAs in serum of 18 patients (DMD 13, BMD 5) and 13 controls using droplet digital PCR. Over 4 years a minimum of two and a maximum of three measurements were performed at different time points in the same patient. Correlations between microRNA serum levels, age, and functional outcome measures were analyzed. We show the individual evolution of the levels of the three microRNAs in 12 patients and also the effect of corticosteroid treatment on microRNAs expression. We measure the expression of three microRNAs in the muscle of six DMD patients and also the expression of target genes for miR-30c. We found that levels of miR-30c and miR-206 remained significantly elevated in DMD patients relative to controls over the entire study length. The introduction of the corticosteroid treatment did not significantly influence the levels of these microRNAs. We report a trend for microRNA levels to decrease with age. Moreover, miR-206 expression levels are capable to distinguish DMD from BMD patients according to ROC analysis. We found miR-30c expression decreased in the muscle of DMD patients and marked upregulation of the target genes for this microRNA. MiR-30c and miR-206 represent sensitive biomarkers for DMD, while miR-206 may have an additional value to distinguish the DMD and BMD phenotype. This may be particularly relevant to assess the effectiveness of treatments aimed at converting the DMD to the less-severe BMD like phenotype.	0
With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross-species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in ataxic and preataxic subjects of two independent multicentric SCA3 cohorts and in a SCA3 knock-in mouse model. Ataxic SCA3 subjects showed increased levels of both NfL and pNfH. In preataxic subjects, NfL levels increased with proximity to the individual expected onset of ataxia, with significant NfL elevations already 7.5 years before onset. Cross-sectional NfL levels correlated with both disease severity and longitudinal disease progression. Blood NfL and pNfH increases in human SCA3 were each paralleled by similar changes in SCA3 knock-in mice, here also starting already at the presymptomatic stage, closely following ataxin-3 aggregation and preceding Purkinje cell loss in the brain. Blood neurofilaments, particularly NfL, might thus provide easily accessible, cross-species validated biomarkers in both ataxic and preataxic SCA3, associated with earliest neuropathological changes, and serve as progression, proximity-to-onset and, potentially, treatment-response markers in both human and preclinical SCA3 trials.	0
BACKGROUND:Ovarian cancer is a spectrum of several histologically distinct tumor types that differ in etiology, response to therapy, and prognosis. In resource-limited settings, the diagnosis of ovarian cancer can be challenging. This study describes the distribution of ovarian cancer tumor types in East Africa as well as assessing the diagnostic accuracy by using contemporary methods. METHODS:Data from 210 women identified from the records with a diagnosis of ovarian cancer in a period of 15 years were included. Two tissue microarrays were constructed and stained with 20 antibodies relevant to ovarian cancer subtyping. An integrated diagnosis was reached by the review of full Haematoxylin and Eosin stained sections, with consideration of immunohistochemical results. The integrated diagnoses were compared with the original diagnoses, and the degree of agreement was evaluated by percentage and Kappa statistics. RESULTS:Though limited by selection bias, the results suggest lower rates of ovarian cancer in East Africa compared to a North American population from Alberta, Canada. There was a higher proportion of sex cord stromal tumors and germ cell tumors in the East African population. Diagnostic accuracy for main ovarian tumor type categories was substantial (Kappa 0.70), but only fair for specific ovarian carcinoma histotypes (Kappa 0.34). Poor Haematoxylin and Eosin stain was the main factor hindering the correct diagnosis, which was not related to tissue processing. CONCLUSIONS:In a resource-limited setting, where immunohistochemistry is not routinely carried out, diagnostic accuracy for the main categories of ovarian carcinoma is substantial and could be further improved by standardization of the basic Haematoxylin and Eosin stain.	0
Total anonychia congenita is a very rare disorder in which all the finger nails and the toenails are absent without significant bone anomalies. This condition is reported to have an autosomal dominant inheritance pattern. There are a variety of syndromes or conditions associated with anonychia congenita. In this study we present a monozygotic twin with isolated anonychia congenita totals. Interestingly there is no family history of anonychia and this condition seems to be caused by a sporadic mutation.	0
We evaluate a knockdown-replacement strategy mediated by mirtrons as an alternative to allele-specific silencing using spinocerebellar ataxia 7 (SCA7) as a model. Mirtrons are introns that form pre-microRNA hairpins after splicing, producing RNAi effectors not processed by Drosha. Mirtron mimics may therefore avoid saturation of the canonical processing pathway. This method combines gene silencing mediated by an artificial mirtron with delivery of a functional copy of the gene such that both elements of the therapy are always expressed concurrently, minimizing the potential for undesirable effects and preserving wild-type function. This mutation- and single nucleotide polymorphism-independent method could be crucial in dominant diseases that feature both gain- and loss-of-function pathologies or have a heterogeneous genetic background. Here we develop mirtrons against ataxin 7 with silencing efficacy comparable to shRNAs, and introduce silent mutations into an ataxin 7 transgene such that it is resistant to their effect. We successfully express the transgene and one mirtron together from a single construct. Hence, we show that this method can be used to silence the endogenous allele of ataxin 7 and replace it with an exogenous copy of the gene, highlighting the efficacy and transferability across patient genotypes of this approach.	0
An 11-year-old girl with dystelephalangy (Kirner deformity) of the right middle, ring, and little, and the left index through little fingers is reported. To the author's best knowledge, such polytopic affection with dystelephalangy has not yet been reported. The parents, one of the siblings and maternal grandfather showed dystelephalangy of the little finger. So, the patient was considered to be a homozygous state of dystelephalangy gene.	0
We describe a 10 year old boy who presented with acute onset rapidly progressing encephalopathy. MRI revealed bilateral insular cortex and basifrontal involvement suggesting Herpes encephalitis.He was treated with acyclovir and his symptoms improved. Six months after the first hospitalization he reported back with two episodes of partial seizures. He was started on Valproate. A week after starting valproate he was readmitted with hyperammonemic encephalpathy, on further investigations Citrullinemia Type 1 was diagnosed. This case highlights a metabolic disorder which radiologically mimics herpes encephalitis. The management of the disorder differs remarkably from herpes encephalitis and hence its recognition and suspicion based on radiology is critical.	0
BACKGROUND:Most studies that examine postoperative outcomes after parotidectomy in patients with benign parotid gland tumors are based on retrospective chart reviews. Data about long-term results in patients with parotid gland surgery with patient contact are still sparsely published. METHODS:During the period of 1960-2005, a total of 127 patients underwent either extracapsular dissection (ECD) or superficial parotidectomy (SP) and were available for interview. Patients were questioned about their postoperative outcome after parotid gland surgery. RESULTS:The mean follow-up was 21.5 years. A total of 42 and 85 patients underwent ECD and SP, respectively. No significant differences were observed in the rates of permanent facial paralysis (SP 1.2% vs. ECD 7.1%; p = 0.1053) or recurrence (SP 4.7% vs. ECD 11.9%; p = 0.1557), and Frey's syndrome was diagnosed only after SP (10.6% vs. 0% after ECD, p = 0.0293). Frey's syndrome was detected more often compared to retrospective chart analysis. CONCLUSION:We conclude that Frey's syndrome is underdiagnosed after SP without standardized follow-up examinations. Long-term follow-up should be applied to detect and treat gustatory sweating.	0
INTRODUCTION: Osteogenesis imperfecta (OI) is a very rare disease compared to other afflictions, running the risk of social isolation for children and their parents, due to the problems specific to the disease. All the social, psychological and physical disadvantages must be removed or at least mitigated, all within the society's limited resources. In Romania, this situation has led in the last couple of years to the selection of a number of extremely severe cases, which could not be solved by orthopedic and classic surgical treatment methods. These patients exhibit gracile long bones, which are distorted, often with cystic degeneration at the level of the extremities, pseudarthroses, limb length discrepancies, most of them being unable to walk, being condemned to sitting in a wheelchair. AIM: This paper deals with the experience of the Orthopedics Department of "Maria Sklodowska Curie" Clinical Emergency Hospital for Children, in Bucharest, in the field of surgical treatment for moderate and severe forms of OI, within the time frame of May 2002-May 2012. For the first time in Romania, on May 20, 2002, the team led by Professor Gh. Burnei, MD, has implanted telescopic rods in the femur and tibia of a patient with OI. One of the most important themes, of great interest in the orthopedic surgery, is the osteoarticular regularization and reconstruction in severe forms of OI, which should allow the patients to stand and walk. These cases are a challenge for the surgeon, who is in the position of applying new, complex procedures, or perfecting, modifying and adapting techniques that have already been established. The aim of the surgical treatment is the increase of the quality of life of these children and adolescents and of their social integration. METHODS AND RESULTS: In the above-mentioned period, from the OI patients who are in the evidence of our clinic, 32 were operated on, totaling 81 surgeries. Out of these, 28 patients, aged 2-27 years, have benefited from reconstructive surgery of the pelvic limbs. Sofield-Millar osteotomies were practiced and 69 Sheffield telescopic rods were implanted in 25 patients and 43 surgeries. The coxa vara / valga correction using the Sheffield rod was applied in 6 patients and 8 hips, respectively. Circular or monoplane external fixators were used in 7 patients for the correction of deformities, lengthening and arthrodiastasis. 9 patients have benefited from various forms of bone transplant: pedicled grafts, auto- and/or allografts. An original bone reconstruction procedure is currently being studied and will be useful in the treatment of large bone defects and the thickening of the gracile diaphyses, which consists in practice of a massive contribution of free bone grafts, auto- and/or allogenic, bone substitutes and, in selected cases, periosteal substitutes, in a composite stratified construction. Postoperatively, 15 patients are able to walk while being supported by crutches or walking frames, 5 patients walk independently and 8 are still wheelchair-bound. It is important to mention that 8 children who were preoperatively dependant on the wheelchair are now walking! DISCUSSION: The surgical treatment in severe forms of OI must be adapted to each case. No matter the surgical technique used, well known or innovative, it is convenient if it restores the ability to walk of a youngster who has been forced to use a wheelchair for almost 20 years and who has suffered dozens of unsuccessful surgeries. The current paper mainly describes the difficulties the surgeon has to deal with while treating the severe, neglected cases of OI, sometimes incorrectly cared for and labeled as inoperable.	0
Methylmalonic aciduria and homocystinuria, cobalamin C (cblC) type, is the most common genetic type of functional cobalamin (vitamin B12) deficiency. This metabolic disease is characterized by marked heterogeneity of neurocognitive disease (microcephaly, seizures, developmental delay, ataxia, hypotonia) and variable extracentral nervous system involvement (failure to thrive, cardiovascular, renal, ocular) manifesting predominantly early in life, sometimes during gestation. To enhance awareness and understanding of renal disease associated with cblC defect, we studied biochemical, genetic, clinical, and histopathological data from 36 patients. Consistent clinical chemistry features of renal disease were intravascular hemolysis, hematuria, and proteinuria in all patients, with nephrotic-range proteinuria observed in three. Renal function ranged from normal to renal failure, with eight patients requiring (intermittent) dialysis. Two thirds were diagnosed with atypical (diarrhea-negative) hemolytic uremic syndrome (HUS). Renal histopathology analyses of biopsy samples from 16 patients revealed glomerular lesions typical of thrombotic microangiopathy (TMA). Treatment with hydroxycobalamin improved renal function in the majority, including three in whom dialysis could be withdrawn. Neurological sequelae were observed in 44 % and cardiopulmonary involvement in 39 % of patients, with half of the latter group demonstrating pulmonary hypertension. Mortality reached 100 % in untreated patients and 79 and 56 % in those with cardiopulmonary or neurological involvement, respectively. In all patients presenting with unclear intravascular hemolysis, hematuria, and proteinuria, cblC defect should be ruled out by determination of blood/plasma homocysteine levels and/or genetic testing, irrespective of actual renal function and neurological status, to ensure timely diagnosis and treatment.	0
INTRODUCTION:The coexistence of progressive familial intrahepatic cholestasis type 2, failure to thrive due to an LPIN3 mutation, and stigmata of neonatal neurofibromatosis represents a complex diagnostic challenge. CASE REPORT:We present a child with cholestasis requiring hepatic transplantation, explained by the progressive familial intrahepatic cholestasis type 2, failure to thrive could be contributed to by the LPIN3 mutation, and skin findings along with the family history of the patient was due to neurofibromatosis type 1. CONCLUSION:Our case illustrates the complexities of multiple genetic mutations in a child.	0
We present the case of a 53-year-old woman with prefibrotic stage primary myelofibrosis who underwent cord blood transplantation. Nine years after transplantation, she relapsed, which was confirmed by a bone marrow examination. We decided to treat her using azacitidine. After three courses of azacitidine, a partial cytogenetic response was confirmed. Azacitidine maintenance therapy successfully maintained a low level of recipient-origin peripheral blood cells with a stable hematological condition. Azacitidine may therefore be a promising therapeutic option for primary myelofibrosis patients who relapse after allogeneic stem cell transplantation.	0
The association of anophthalmia, arrhinia, and hypogonadism constitutes the major clinical features for Bosma arrhinia microphthalmia syndrome. However, there is variability in the presentation of this disease; arrhinia is the most constant clinical feature, which is then combined with a spectrum of anophthalmia/microphthalmia and/or hypogonadism. This rare entity is not associated with any specific genes, but the genes that are related to arrhinia and anophthalmia have been studied in an attempt to explain this phenomenon. We analyzed the PAX6 gene in a Bosma arrhinia microphthalmia syndrome patient but found no variation or mutation that could constitute or establish a causal association in our patient.	0
Microphthalmia is considered to be the most common congenital malformation of the eye after congenital cataract. However, its association with intraorbital cyst is considered to be very rare. Most of the lesions are still misdiagnosed as orbital tumor and teratomas as there is a general paucity of data reported in literature. Herein, we report a rare case of congenital microphthalmia with intraorbital cyst in an eight-month-old male patient.	0
BACKGROUND:Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm characterized by recurrent alterations in the MAPK (mitogen-activating protein kinase) pathway. The existing literature about the neuro-oncological spectrum of ECD is limited. METHODS:We present retrospective clinical, radiographic, pathologic, molecular, and treatment data from 30 patients with ECD neurohistiocytic involvement treated at a tertiary center. RESULTS:Median age was 52 years (range, 7-77), and 20 (67%) patients were male. Presenting symptoms included ataxia in 19 patients (63%), dysarthria in 14 (47%), diabetes insipidus in 12 (40%), cognitive impairment in 10 (33%), and bulbar affect in 9 (30%). Neurosurgical biopsy specimens in 8 patients demonstrated varied morphologic findings often uncharacteristic of typical ECD lesions. Molecular analysis revealed mutations in BRAF (18 patients), MAP2K1 (5), RAS isoforms (2), and 2 fusions involving BRAF and ALK. Conventional therapies (corticosteroids, immunosuppressants, interferon-alpha [IFN-α], cytotoxic chemotherapy) led to partial radiographic response in 8/40 patients (20%) by MRI with no complete responses, partial metabolic response in 4/16 (25%), and complete metabolic response in 1/16 (6%) by 18F-fluorodeoxyglucose (FDG)-PET scan. In comparison, targeted (kinase inhibitor) therapies yielded partial radiographic response in 10/27 (37%) and complete radiographic response in 14/27 (52%) by MRI, and partial metabolic response in 6/25 (24%) and complete metabolic response in 17/25 (68%) by FDG-PET scan. CONCLUSIONS:These data highlight underrecognized symptomatology, heterogeneous neuropathology, and robust responses to targeted therapies across the mutational spectrum in ECD patients with neurological involvement, particularly when conventional therapies have failed.	0
BACKGROUND:Castleman disease (CD) is a lymphoproliferative disorder with an unknown etiology. The disease may be unicentric (UCD) or multicentric (MCD), and three histopathologic variants have been described: hyaline vascular (HV), plasma cell (PC), and mixed type. Extranodal CD is rare. Herein, we report a case of CD presenting as a tonsillar mass, which has not been documented in the literature. CASE PRESENTATION:The patient was a 32-year-old man. Laryngoscopy revealed tonsillar hypertrophy, and the patient underwent a low-temperature plasma tonsillectomy. Microscopic examination of permanent sections showed lymphoid follicular hyperplasia, a portion of which appeared to be a fusion of nodular hyperplasia (composed of lymphoid follicles of variable size and shape). These distinctive follicles with atrophic hyalinized germinal centers and a broad mantle zone of small lymphocytes formed concentric rings (so-called onion-skin arrangement). Medium-sized vessels and a plethora of capillaries were present in the center of the lymphatic follicles, mantle zones, and interfollicular areas. A characteristic lollipop appearance was also observed due to the onion-skin arrangement of the expanded mantle zone lymphocytes with a vessel penetrating the germinal center. No aberrant lymphoid population was present based on CD3, CD5, CD20, CD79α, CD21, CD23, bcl-2, cyclin D1, and ki-67 immunostaining. Tests for human herpesvirus (HHV)-8 and Epstein Barr virus (EBV)-encoded small RNA (EBER) were negative. Therefore, a diagnosis of an HV variant UCD was rendered. The patient was treated by local excision without any other therapy based on the diagnosis. At the 7-month follow up, the patient had no recurrent symptoms or masses. CONCLUSION:We present an unusual case of a tonsil presenting hyaline vascular Castleman disease (HVCD). This study aims to highlight CD as a differential diagnosis that should be considered by otolaryngologists and pathologists for lymphoproliferative disorders of the tonsil.	0
Necrobiotic xanthogranulomatous reaction is a multiorgan, non-Langerhans cell histiocytosis with an unknown etiology. Occurrence in the salivary gland is extremely rare. We recently identified a case of necrobiotic xanthogranulomatous sialadenitis in a 73-year-old Korean woman who presented with a painless palpable lesion in the chin. There was no accompanying cutaneous lesion. Partial resection and subsequent wide excision with neck dissection were performed. Pathological examination showed a severe inflammatory lesion that included foamy macrophages centrally admixed with neutrophils, eosinophils, lymphocytes, plasma cells, and scattered giant cells, as well as necrobiosis. During the 12-month postoperative period, no grossly remarkable change in size was noted. Necrobiotic xanthogranulomatous inflammation may be preceded by or combined with hematologic malignancy. Although rare, clinicians and radiologists should be aware that an adhesive necrobiotic xanthogranuloma in the salivary gland may present with a mass-like lesion. Further evaluation for hematologic disease and close follow-up are needed when a pathologic diagnosis is made.	0
Therapeutic management of pustular psoriasis remains a challenge despite the rapid advance in psoriasis research and the development of drugs, especially biologics. Treatment guidelines have been established for pustular psoriasis, but no controlled studies are present for juvenile pustular psoriasis (JPP). Search of the literature reveals that current evidence of JPP treatment is limited to case reports and case series. Among the conventional drugs for JPP, oral retinoid is the most commonly used, yet concerns for growth disturbance exist. Cyclosporine and methotrexate have also been administered as first-line treatment. Etanercept is the first biological agent approved for juvenile plaque psoriasis, followed by adalimumab. However, infliximab is usually recommended for JPP because of the rapidity of onset, despite not being approved for use in pediatric psoriasis patients. More recently, secukinumab, ixekizumab, brodalumab, guselkumab, and risankizumab have been approved for adult pustular psoriasis in selected countries. Controlled studies are needed to prove the efficacy and long-term safety of the therapeutic treatments currently used for JPP.	0
Laurence-Moon-Bardet-Biedl syndrome (LMBBS), a rare autosomal recessive defect, mostly occurs in children born from consanguineous marriages. The major features of this syndrome are cone-rod dystrophy, polydactyly, obesity, learning disabilities, hypogonadism in males, renal anomalies, nystagmus, speech disorders, developmental delay, polyuria/polydipsia, ataxia, and poor coordination/clumsiness. In this report, we present a case of a 19-year-old man with pain and swelling of the left ankle and knee joints because of which he could not walk, with an onset of loose stools since a week. He presented with multiple non-itchy hyperpigmented macules on his face and back, polydactyly in his left foot, central obesity, proteinuria, macrocytic anemia, low intelligence quotient, reduced power in the left lower limb, reduced plantar reflexes, nystagmus, pigmented black lesions in the temporal retina on fundoscopy, a micropenis, absent pubic and axillary hair, and a small scrotum containing testes. The patient was diagnosed with LMBBS.	0
Renal tubular acidosis (RTA) comprises a group of disorders characterized by low capacity for net acid excretion and persistent hyperchloremic metabolic acidosis, despite preserved glomerular filtration rate. RTA are classified into chiefly three types (1, 2 and 4) based on pathophysiology and clinical and laboratory characteristics. Most patients have primary RTA that presents in infancy with polyuria, growth retardation, rickets and/or hypotonia. Diagnosis requires careful evaluation, including exclusion of other entities that can cause acidosis. A variety of tests, administered stepwise, are useful for the diagnosis and characterization of RTA. A genetic or acquired basis can be determined in majority of patients through focused evaluation. Management involves correction of acidosis and dyselectrolytemia; patients with proximal RTA with Fanconi syndrome and rickets require additional supplements of phosphate and vitamin D.	0
Chromosomal microarray (CMA) is now recommended as first tier for the evaluation in individuals with unexplained neurodevelopmental disorders (ND). However, in developing countries such as Brazil, classical cytogenetic tests are still the most used in clinical practice, as reflected by the scarcity of publications of microarray investigation in larger cohorts. This is a retrospective study which analyses the reading files of CMA and available clinical data from 420 patients from the south of Brazil, mostly children, with neurodevelopmental disorders requested by medical geneticists and neurologists for diagnostic purpose. Previous karyotyping was reported for 138 and includes 17 with abnormal results. The platforms used for CMA were CYTOSCAN 750K (75%) and CYTOSCAN HD (25%). The sex ratio of the patients was 1.625 males :1 female and the mean age was 9.5 years. A total of 96 pathogenic copy number variations (CNVs), 58 deletions and 38 duplications, were found in 18% of the patients and in all chromosomes, except chromosome 11. For 12% of the patients only variants of uncertain clinical significance were found. No clinically relevant CNV was found in 70%. The main referrals for chromosomal microarrays (CMA) were developmental delay (DD), intellectual disability (ID), facial dysmorphism and autism spectrum disorder (ASD). DD/ID were present in 80%, facial dysmorphism in 52% and ASD in 32%. Some phenotypes in this population could be predictive of a higher probability to carry a pathogenic CNV, as follows: dysmorphic facial features (p-value = < 0.0001, OR = 0.32), obesity (p-value = 0.006, OR = 0.20), short stature (p-value = 0.032, OR = 0.44), genitourinary anomalies (p-value = 0.032, OR = 0.63) and ASD (p-value = 0.039, OR = 1.94). The diagnostic rate for CMA in this study was 18%. We present the largest report of CMA data in a cohort with ND in Brazil. We characterize the rare CNVs found together with the main phenotypes presented by each patient, list phenotypes which could predict a higher diagnostic probability by CMA in patients with a neurodevelopmental disorder and show how CMA and classical karyotyping results are complementary.	0
Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare autosomal recessive disorder. The ROBO 3 gene mutation is responsible for the disease. We present a boy aged 12 years who was admitted for scoliosis surgery who had also had horizontal gaze palsy since birth. His brainstem abnormalities were compatible with the syndrome of HGPPS. HGPPS is one of the rare congenital diseases of childhood. Horizontal gaze palsy, ametropia, and progressive scoliosis are the main findings of the disease. This syndrome should be kept in mind for both ophthalmologists and orthopaedic surgeons in patients who present with gaze palsy and scoliosis. Early diagnosis of scoliosis makes it possible to treat the disease at an early stage, and early diagnosis of ametropia is important in the prevention of amblyopia.	0
PURPOSE:The aim of this study was to evaluate the clinical outcomes and postoperative anorectal function in the patients with high/intermediate imperforate anus (HIA/IIA) treated in our institution. In addition, we report our novel procedure, laparoscopically assisted anorectoplasty with anterior perineal incision (LAARP-API), which allows direct approach to the anterior edge of the puborectal sling and muscle complex, and is useful for the creation of a pulling-through route for the rectal pouch. METHODS:From 1976 to 2016, 22 patients with HIA and 43 patients with IIA underwent sacroperineal/sacroabdominoperineal pull-through anorectoplasty (SP/SAP), Potts procedure (Potts), SP with API (SP-API) or LAARP-API. Clinical data and anorectal function of those patients were retrospectively evaluated using the Japanese clinical score. RESULTS:Of the 22 cases of HIA, 15 were treated by SAP, 2 were SP and 5 were LAARP-API. Of the 43 cases of IIA, one was treated by SAP, 31 were SP, two were Potts and nine were SP-API. The mean score of anorectal function of HIA/IIA both increased with age. In IIA, the score after SP-API was significantly higher than the score after SP. CONCLUSION:Long-term outcomes of our anorectoplasty for HIA/IIA are good with excellent anorectal function score.	0
BACKGROUND:Chronic idiopathic intestinal pseudo-obstruction, a syndrome of ineffectual motility due to a primary disorder of enteric nerve or muscle, is rare. AIMS:To determine the clinical spectrum, underlying pathologies, response to treatments, and prognosis in a consecutive unselected group of patients. METHODS:Cross sectional study of all patients with clinical and radiological features of intestinal obstruction in the absence of organic obstruction, associated with dilated small intestine (with or without dilated large intestine), being actively managed in one tertiary referral centre at one time. RESULTS:Twenty patients (11 men and nine women, median age 43 years, range 22-67) fulfilled the diagnostic criteria. Median age at onset of symptoms was 17 years (range two weeks to 59 years). Two patients had an autosomally dominant inherited visceral myopathy. Major presenting symptoms were pain (80%), vomiting (75%), constipation (40%), and diarrhoea (20%). Eighteen patients required abdominal surgery, and a further patient had a full thickness rectal biopsy. The mean time interval from symptom onset to first operation was 5.8 years. Histology showed visceral myopathy in 13, visceral neuropathy in three, and was indeterminate in three. In the one other patient small bowel motility studies were suggestive of neuropathy. Two patients died within two years of symptom onset, one from generalised thrombosis and the other from an inflammatory myopathy. Of the remaining 18 patients, eight were nutritionally independent of supplements, two had gastrostomy or jejunostomy feeds, and eight were receiving home parenteral nutrition. Five patients were opiate dependent, only one patient had benefited from prokinetic drug therapy, and five patients required formal psychological intervention and support. CONCLUSIONS:In a referral setting visceral myopathy is the most common diagnosis in this heterogeneous syndrome, the course of the illness is usually prolonged, and prokinetic drug therapies are not usually helpful. Ongoing management problems include pain relief and nutritional support.	0
Balantidium coli is a common parasite of pig and wild boars (Sus scrofa) which can infect humans and several species of mammals. This study aimed to determine the genotype of Balantidium isolated from Eurasian wild boars in Bushehr province, Southwestern Iran. Twenty-five faecal samples, originating from 25 wild boars captivated in our previous study, were processed. DNA was extracted from the faecal samples and PCR-amplified, targeting an ITS1-5.8s-rRNA-ITS2 region of Balantidium genome. PCR product was purified from the gel, and sequenced. BLAST analysis was performed in order to compare our isolates with other previously reported ones. A phylogenetic tree was constructed, using MegaX software, to find out the phylogenetic diversity of the isolates. With PCR it was possible to detect Balantidium DNA in the faecal samples of 13 out of 25 (52%) of the wild boars. BLAST analysis of seven isolates revealed that the isolates belong to the newly introduced genus Neobalantidium coli. Sequences of three isolates were deposited in the GenBank. Moreover, molecular analysis revealed six areas of nucleotide differences within the isolates and nine areas of difference between the sequences obtained in this study and those available in the GenBank. Phylogenetic analysis revealed that the sequences of isolates of this study have up to 2.2% dissimilarity from those published in the GenBank. The findings of this study, for the first time, revealed that some of the isolates of Balantidium originating from wild boars in Southwestern Iran belonged to the N. coli.	0
Trichothiodystrophy (TTD) is a rare, autosomal recessive disease, characterised by brittle, sulfur deficient hair and multisystem abnormalities. A systematic literature review identified 112 patients ranging from 12 weeks to 47 years of age (median 6 years). In addition to hair abnormalities, common features reported were developmental delay/intellectual impairment (86%), short stature (73%), ichthyosis (65%), abnormal characteristics at birth (55%), ocular abnormalities (51%), infections (46%), photosensitivity (42%), maternal pregnancy complications (28%) and defective DNA repair (37%). There was high mortality, with 19 deaths under the age of 10 years (13 infection related), which is 20-fold higher compared to the US population. The spectrum of clinical features varied from mild disease with only hair involvement to severe disease with profound developmental defects, recurrent infections and a high mortality at a young age. Abnormal characteristics at birth and pregnancy complications, unrecognised but common features of TTD, suggest a role for DNA repair genes in normal fetal development.	1
OBJECTIVES:Analysis of incidence and characteristics of congenital abdominal wall defects, with special reference to the differences between the incidence of gastroschisis and exomphalos (omphalocele). DESIGN:Retrospective analysis using data from the Office of Population Censuses and Surveys (recoded to differentiate exomphalos and gastroschisis) and the National Congenital Malformation Notification Scheme. SETTING:England and Wales, 1987 to 1993. RESULTS:1043 congenital anterior abdominal wall defects were notified within the seven year study period. Of these, 539 were classified as gastroschisis, 448 as exomphalos, 19 as "prune belly syndrome," and 37 as "unclassified." Gastroschisis doubled in incidence from 0.65 in 1987 to 1.35 per 10,000 total births in 1991, with little further change; the incidence of exomphalos decreased from 1.13 to 0.77 per 10000 births. The overall incidence of notified congenital abdominal wall defects was 2.15 per 10000 total births. Gastroschisis was associated with a lower overall maternal age than exomphalos and with a significantly lower proportion of additional reported congenital malformations (5.0%) than in the cohort with exomphalos (27.4%) (odds ratio 0.14, 95% confidence interval 0.09 to 0.22; P < 0.001). The sex ratio of the two cohorts was the same. The incidence of gastroschisis and exomphalos was higher in the northern regions of England than in the south east of the country. CONCLUSIONS:The national congenital malformation notification system showed an increasing trend in the incidence of fetuses born with gastroschisis and a progressive decreasing incidence of exomphalos in England and Wales between 1987 and 1993. Although the reasons for this are likely to be multifactorial, a true differential change seems likely. The observed increase in incidence of gastroschisis relative to exomphalos and the differentiation in maternal age have implications for resource management within the NHS and warrant further epidemiological monitoring. Regional differences may be due to a dietary or environmental factor, which requires further study.	1
Uncombable hair syndrome is a relatively rare anomaly of the hair shaft, with less than 100 cases reported to date, that results in a disorganized, unruly hair pattern that is impossible to comb flat. The characteristic longitudinal grooves along the hair shaft, along with the triangular or kidney-shaped cross section allows this condition to be diagnosed microscopically. The majority of cases are inherited in an autosomal-dominant manner with either complete or incomplete penetrance. There is no definitive treatment, and most cases improve with the onset of puberty.	0
BACKGROUND:Many metabolites serve as important signalling molecules to adjust cellular activities and functions based on nutrient availability. Links between acetyl-CoA metabolism, histone lysine acetylation, and gene expression have been documented and studied over the past decade. In recent years, several additional acyl modifications to histone lysine residues have been identified, which depend on acyl-coenzyme A thioesters (acyl-CoAs) as acyl donors. Acyl-CoAs are intermediates of multiple distinct metabolic pathways, and substantial evidence has emerged that histone acylation is metabolically sensitive. Nevertheless, the metabolic sources of acyl-CoAs used for chromatin modification in most cases remain poorly understood. Elucidating how these diverse chemical modifications are coupled to and regulated by cellular metabolism is important in deciphering their functional significance. SCOPE OF REVIEW:In this article, we review the metabolic pathways that produce acyl-CoAs, as well as emerging evidence for functional roles of diverse acyl-CoAs in chromatin regulation. Because acetyl-CoA has been extensively reviewed elsewhere, we will focus on four other acyl-CoA metabolites integral to major metabolic pathways that are also known to modify histones: succinyl-CoA, propionyl-CoA, crotonoyl-CoA, and butyryl-CoA. We also briefly mention several other acyl-CoA species, which present opportunities for further research; malonyl-CoA, glutaryl-CoA, 3-hydroxybutyryl-CoA, 2-hydroxyisobutyryl-CoA, and lactyl-CoA. Each acyl-CoA species has distinct roles in metabolism, indicating the potential to report shifts in the metabolic status of the cell. For each metabolite, we consider the metabolic pathways in which it participates and the nutrient sources from which it is derived, the compartmentalisation of its metabolism, and the factors reported to influence its abundance and potential nuclear availability. We also highlight reported biological functions of these metabolically-linked acylation marks. Finally, we aim to illuminate key questions in acyl-CoA metabolism as they relate to the control of chromatin modification. MAJOR CONCLUSIONS:A majority of acyl-CoA species are annotated to mitochondrial metabolic processes. Since acyl-CoAs are not known to be directly transported across mitochondrial membranes, they must be synthesized outside of mitochondria and potentially within the nucleus to participate in chromatin regulation. Thus, subcellular metabolic compartmentalisation likely plays a key role in the regulation of histone acylation. Metabolite tracing in combination with targeting of relevant enzymes and transporters will help to map the metabolic pathways that connect acyl-CoA metabolism to chromatin modification. The specific function of each acyl-CoA may be determined in part by biochemical properties that affect its propensity for enzymatic versus non-enzymatic protein modification, as well as the various enzymes that can add, remove and bind each modification. Further, competitive and inhibitory effects of different acyl-CoA species on these enzymes make determining the relative abundance of acyl-CoA species in specific contexts important to understand the regulation of chromatin acylation. An improved and more nuanced understanding of metabolic regulation of chromatin and its roles in physiological and disease-related processes will emerge as these questions are answered.	0
We describe the case of a boy with moderate mental retardation associated with tall stature, obesity, macrocephaly and typical facial features, characterized by a large 'square' forehead, prominent supraorbital ridges, broad nasal tip, prominent lower lip and minor dental anomalies. We think that our proband is affected by Clark-Baraitser syndrome, a rare X-linked mental retardation disorder, to date described only in five male subjects. We present a more complete definition of the clinical phenotype of the syndrome with particular attention to the behavioural aspect that, in combination with the body size and the dysmorphic picture, we think is distinctive for the Clark-Baraitser syndrome. We also summarize the mild features described in female relatives of the patients, as it could disclose a possible carrier condition and be of help with genetic counselling in the families with male patients, until a molecular test is available.	0
OBJECTIVE:The aim of the study was to evaluate efficacy of chemoembolization and radioembolization in treating patients with recurrent hypoglycemia secondary to metastatic insulinoma. METHODS:A retrospective review was performed of all patients with metastatic insulinoma treated with liver-directed therapy (LDT) at a large academic medical center from January 1998 to August 2017. Primary outcomes included blood glucose levels, occurrence of symptomatic hypoglycemic episodes, and tumor imaging response rates. RESULTS:Seven patients were identified (4 male patients). The mean age at the first LDT was 60.9 (standard deviation [SD], 9.2) years. The median follow-up was 1.8 years. Thirty-three sessions of LDT were performed including 30 sessions of chemoembolization and 3 sessions of radioembolization. Technical success rate was 97% (32/33 procedures) with an initial clinical success rate of 100%, defined as absence of recurrent symptomatic hypoglycemia within 1 month after first cycle of LDT and overall clinical success rate of 85%. Random daytime glucose levels increased from 75.0 (SD, 26) mg/dL to 152.8 (SD, 52.4) mg/dL after LDT. The mean time to recurrence of intractable hypoglycemia was 21 (SD, 9) months. No severe complications were reported. CONCLUSIONS:Liver-directed therapy with chemoembolization or radioembolization is effective for treatment of symptomatic hypoglycemia secondary to malignant insulinoma metastatic to liver.	0
Fanconi anemia is a rare chromosome instability disorder with a highly variable phenotype. In the antenatal and neonatal periods, the diagnosis is usually suggested by the presence of typical congenital abnormalities such as intrauterine growth retardation, microcephaly and radial ray defects. We report a newborn female with a prenatal diagnosis of Fanconi anemia, complementation group O (FANCO). Antenatal ultrasounds identified symmetrical intrauterine growth retardation, complex heart defect as well as brain anomalies, overlapping fingers and cleft lip and palate. Imperforate anus was detected after birth. Compound heterozygous RAD51C variants c. [571+5G > A]; [c.935G > A] were detected by prenatal whole exome sequencing and cellular hypersensitivity to DNA interstrand crosslinking agents (DEB, MMC) was confirmed after birth. With only one previously described homozygous RAD51C variant to date, our findings expand the phenotypic spectrum of FANCO and suggest it should be part of the antenatal differential diagnosis for trisomy 13 and 18, due to the presence of atypical findings such as cleft lip and palate, holoprosencephaly, growth restriction and overlapping fingers.	0
Glucose-6-phosphatase deficiency (G6P deficiency), or glycogen storage disease type I (GSDI), is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, between the ages of 3 to 4 months by symptoms of hypoglycemia (tremors, seizures, cyanosis, apnea). Patients have poor tolerance to fasting, marked hepatomegaly, growth retardation (small stature and delayed puberty), generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, full-cheeked round face, enlarged kydneys and platelet dysfunctions leading to frequent epistaxis. In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphtous gingivostomatitis, and inflammatory bowel disease. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma) and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency). GSDI is caused by a dysfunction in the G6P system, a key step in the regulation of glycemia. The deficit concerns the catalytic subunit G6P-alpha (type Ia) which is restricted to expression in the liver, kidney and intestine, or the ubiquitously expressed G6P transporter (type Ib). Mutations in the genes G6PC (17q21) and SLC37A4 (11q23) respectively cause GSDIa and Ib. Many mutations have been identified in both genes,. Transmission is autosomal recessive. Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon. It can be confirmed by demonstrating a deficient activity of a G6P system component in a liver biopsy. To date, the diagnosis is most commonly confirmed by G6PC (GSDIa) or SLC37A4 (GSDIb) gene analysis, and the indications of liver biopsy to measure G6P activity are getting rarer and rarer. Differential diagnoses include the other GSDs, in particular type III (see this term). However, in GSDIII, glycemia and lactacidemia are high after a meal and low after a fast period (often with a later occurrence than that of type I). Primary liver tumors and Pepper syndrome (hepatic metastases of neuroblastoma) may be evoked but are easily ruled out through clinical and ultrasound data. Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villous cells. Pre-implantatory genetic diagnosis may also be discussed. Genetic counseling should be offered to patients and their families. The dietary treatment aims at avoiding hypoglycemia (frequent meals, nocturnal enteral feeding through a nasogastric tube, and later oral addition of uncooked starch) and acidosis (restricted fructose and galactose intake). Liver transplantation, performed on the basis of poor metabolic control and/or hepatocarcinoma, corrects hypoglycemia, but renal involvement may continue to progress and neutropenia is not always corrected in type Ib. Kidney transplantation can be performed in case of severe renal insufficiency. Combined liver-kidney grafts have been performed in a few cases. Prognosis is usually good: late hepatic and renal complications may occur, however, with adapted management, patients have almost normal life span. DISEASE NAME AND SYNONYMS: Glucose-6-phosphatase deficiency or G6P deficiency or glycogen storage disease type I or GSDI or type I glycogenosis or Von Gierke disease or Hepatorenal glycogenosis.	1
Cardiovascular disease (CVD) continues to be the leading cause of global morbidity and mortality. Heart failure remains a major contributor to this mortality. Despite major therapeutic advances over the past decades, a better understanding of molecular and cellular mechanisms of CVD as well as improved therapeutic strategies for the management or treatment of heart failure are increasingly needed. Loss of myocardium is a major driver of heart failure. An attractive approach that appears to provide promising results in reducing cardiac degeneration is stem cell therapy (SCT). In this review, we describe different types of stem cells, including embryonic and adult stem cells, and we provide a detailed discussion of the properties of induced pluripotent stem cells (iPSCs). We also present and critically discuss the key methods used for converting somatic cells to pluripotent cells and iPSCs to cardiomyocytes (CMs), along with their advantages and limitations. Integrating and non-integrating reprogramming methods as well as characterization of iPSCs and iPSC-derived CMs are discussed. Furthermore, we critically present various methods of differentiating iPSCs to CMs. The value of iPSC-CMs in regenerative medicine as well as myocardial disease modeling and cardiac regeneration are emphasized.	0
Biotinidase deficiency is an autosomal recessive inherited neurocutaneous disorder. Clinically untreated patients with BD can present with variable neurological and dermatological signs, such as seizures, hypotonia, feeding problems, developmental delay, hearing loss, optic atrophy ataxia, alopecia, and skin rash. Clinical findings of patients with partial BD reported in the literature show that it can occur from infancy to adulthood. Outcomes of newborn screening programs support the fact that biotin treatment started after birth prevents patients with biotinidase deficiency from developing symptoms. Presence of late-onset cases with different clinical findings indicates that there is still much to learn about BD.	0
Neuroblastoma is the most common type of extracranial solid tumor during childhood. Clinical presentation includes ipsilateral ptosis, myosis, anhydrosis and enophthalmos. The case of a 2.5-year-old boy who had a complaint of constriction of the left pupil for 3 days is presented. In the physical examination, the pupil of the OD was moderately dilated; there was myosis on the OS and ptosis on the left eyelid. Horner syndrome was considered due to these findings. History of the patient revealed that a central venous catheter insertion procedure was tried from the left side.	0
BACKGROUND:Hereditary hemorrhagic telangiectasia (HHT) often involves the liver, and belongs to abnormal blood vessel disease. The etiology of Budd-Chiari syndrome (BCS) is not clear, but congenital vascular dysplasia is considered to be one of the causes. Liver cirrhosis due to hepatic hereditary hemorrhagic telangiectasia concomitant with BCS has not been reported. Here, we report a case of cirrhosis with hepatic hereditary hemorrhagic telangiectasia (HHHT) and BCS. CASE PRESENTATION:A 58-year-old woman with hepatic hereditary hemorrhagic telangiectasia showed decompensated liver cirrhosis, and abdominal imaging revealed Budd-Chiari syndrome. Disease has progressed considerably during 2.5 years after hospital discharge despite subsequent transjugular intrahepatic portosystemic shunting (TIPS). One hypothesis that might explain the coexistence of hepatic hereditary hemorrhagic telangiectasia and Budd-Chiari syndrome in this patient is ischemia and thrombosis of hepatic veins. CONCLUSIONS:Further studies are required to evaluate the relationship between HHHT and BCS. Our observations already challenged the TIPS therapeutic strategy in BCS secondary to HHHT patients.	0
In order to estimate the current coverage rate among all children in Greenland, we conducted an observational cross-sectional study identifying all children in Greenland eligible for a vaccination between 1 March 2018 and 16 June 2019. we found an overall national coverage of 85.4%. The national coverage for the vaccinations given at birth was 97.1%, dropping to 94.3%, 87.7% and 83.6% at ages 3, 5 and 12 months. Among children eligible for the Measles, Mumps and Rubella-vaccinations, the national coverage was 76.9% for children aged 15 months and 64.1% for children aged 4 years, but dropping to 40.9% in the districts. At preschool, the national coverage was 79.9%. Among the 12-year-old, the national coverages of the two vaccinations against Human Papilloma Virus were 88.4% and 71.6%, respectively, and for the three Hepatitis B-vaccinations 89.8%, 84.1% and 69.6%. A subgroup-analysis and test of an SMS-reminder system in Nuuk improved the coverage from 57.8% to 75.5% locally. Overall, we found a high national coverage rate among the newborn in Greenland. The national coverage rates of the remaining vaccinations were below the WHO-recommendations, however with great regional differences.Abbreviations: CVP: Children Vaccination Programme; BCG: Bacille Calmette-Guerin; EMR: Electronic medical Record system; DTPHiB: Diphtheria, Tetanus, Pertussis, Polio, Haemophilus influenza B; HBV: Hepatitis B; HPV: Human Papilloma Virus; MMR: Measles, Mumps, Rubella; SMS: Short Text Message; WHO: World Health Organization; GVAP: Global Vaccine Action Plan; EVAP: The WHO European Vaccine Action Plan.	0
Objective:To characterize a population of patients with radiation-induced angiosarcoma (RIAS) of the breast treated at an oncology center, focusing mainly on the imaging features, although also on the clinical presentation, diagnosis, and management. Materials and Methods:We performed a retrospective review of patients with histologically proven angiosarcoma of the breast or chest wall, all of whom received radiotherapy, after conservative or radical breast surgery, between 2000 and 2015. Results:Eleven patients met the inclusion criteria. The median age at the time of diagnosis of RIAS of the breast was 71.5 years (range, 58-87 years), and the median latency period was 8.9 years (range, 4-27 years). The rate of local recurrence was 54.4%, RIAS recurring after a median period of 10 months (range, 3-18 months), and distant metastases occurred in three patients (27.3%). All of the tumors were accompanied by skin changes, and a palpable mass was seen in four. Most of the imaging findings were nonspecific. Six patients underwent magnetic resonance imaging, which revealed pronounced skin enhancement in all six. Ultrasound-guided core needle biopsies were negative in three of the eight patients. Conclusion:RIAS of the breast is a rare but recognized complication of radiotherapy for breast carcinoma, with a poor prognosis and high recurrence rate, which requires a high index of suspicion for a prompt diagnosis.	0
Movement disorders in childhood comprise a heterogeneous group of conditions that lead to impairment of voluntary movement, abnormal postures, or inserted involuntary movements. Movement disorders in children are frequently caused by metabolic disorders, both inherited and acquired. Many of these respond to vitamin supplementation. Examples include infantile tremor syndrome, biotinidase deficiency, biotin-thiamine-responsive basal ganglia disease, pyruvate dehydrogenase deficiency, aromatic amino acid decarboxylase deficiency, ataxia with vitamin E deficiency, abetalipoproteinemia, cerebral folate deficiency, and cobalamin metabolism defects. Recognition of these disorders by pediatricians and neurologists is imperative as they are easily treated by vitamin supplementation. In this review, we discuss vitamin-responsive movement disorders in children.	0
Congenital neurological disorders are genetically highly heterogeneous. Rare forms of hereditary neurological disorders are still difficult to be adequately diagnosed. Pertinent studies, especially when reporting only single families, need independent confirmation. We present three unrelated families in which whole-exome sequencing identified the homozygous non-sense variants c.430[C>T];[C>T] p.(Arg144*), c.1219[C>T];[C>T] p.(Gln407*) and c.1408[C>T];[C>T] p.(Arg470*) in GTPBP2. Their clinical presentations include early onset and apparently non-progressive motor and cognitive impairment, and thereby overlap with findings in a recently described family harbouring a homozygous GTPBP2 splice site variant. Notable differences include structural brain abnormalities (e.g., agenesis of the corpus callosum, exclusive to our patients), and evidence for brain iron accumulation (exclusive to the previously described family). This report confirms pathogenicity of biallelic GTPBP2 inactivation and broadens the phenotypic spectrum. It also underlines that a potential involvement of brain iron accumulation needs clarification. Further patients will have to be identified and characterised in order to fully define the core features of GTPBP2-associated neurological disorder, but future approaches to molecular diagnosis of neurodevelopmental disorders should implement GTPBP2.	0
BACKGROUND:Dyssegmental dysplasia Silverman-Handmaker (DDSH; MIM 224410) type is an extremely rare skeletal dysplasia caused by functional null mutations in the perlecan gene. Less than forty cases are reported in the literature, of which only four were prenatally detected. METHODS:We report on a dizygotic twin pregnancy from consanguineous parents for which one of the twins presented prenatally with severe micromelia, limb bowing and scoliosis, and postnatally with clinical and radiological features compatible with a diagnosis of dyssegmental dysplasia. Molecular studies were undertaken to confirm the clinical diagnosis of DDSH. RESULTS:Molecular analysis results revealed a novel homozygous variant in the HSPG2 gene (MIM 142461), NM_005529.6(HSPG2):c.4029 + 1G>A, consistent with a diagnosis of DDSH. CONCLUSION:To the best of our knowledge, the current report is only the seventh molecularly confirmed case of DDSH.	0
BACKGROUND: Studies from different countries have reported an increased incidence of primary cutaneous lymphomas over the last decades. OBJECTIVES: To estimate the incidence rates of primary cutaneous T-cell lymphoma (CTCL) and mycosis fungoides (MF)/Sézary syndrome (SS) in Norway, and to compare these rates with those reported from other countries. METHODS: Data from the Cancer Registry of Norway on non-Hodgkin lymphomas during the period 1980-2003 were analysed. RESULTS: In total, 337 cases of CTCL were reported to the Cancer Registry during the study period, of which 262 cases were classified as MF/SS. The incidence rate of CTCL increased significantly (P(trend) < 0.001) from 0.16 (95% confidence interval, CI 0.11-0.20) per 100,000 person-years in 1980-84 to 0.29 (95% CI 0.22-0.36) per 100,000 person-years in 2000-2003. The incidence of MF/SS also increased during the same period (P(trend) = 0.05) from 0.15 (95% CI 0.10-0.19) per 100,000 person-years to 0.18 (95% CI 0.13-0.24) per 100,000 person-years. CONCLUSIONS: The incidence of both CTCL and MF/SS increased in Norway during the period 1980-2003.	1
The purpose of this systematic review was to investigate the scientific evidence to support the use of direct renin inhibitors (DRIs) in diabetic nephropathy (DN). MEDLINE was searched for articles reported until 2018. A standardized dataset was extracted from articles describing the effects of DRIs on plasma renin activity (PRA) in DN. A total of three clinical articles studying PRA as an outcome measure for DRIs use in DN were identified. These clinical studies were randomized controlled trials (RCTs): one double-blind crossover, one post hoc of a double-blind and placebo-controlled study, and one open-label and parallel-controlled study. Two studies reported a significant decrease of albuminuria associated with PRA reduction. One study had a DRI as monotherapy compared with placebo, and two studies had DRI as add-in to an angiotensin II (Ang II) receptor blocker (ARB). Of 10,393 patients with DN enrolled in five studies with DRI, 370 (3.6%) patients had PRA measured. Only one preclinical study was identified that determined PRA when investigating the effects of aliskiren in DN. Moreover, most of observational preclinical and clinical studies identified report on a low PRA or hyporeninemic hypoaldosteronism in DM. Renin inhibition has been suggested for DN, but proof-of-concept studies for this are scant. A small number of clinical and preclinical studies assessed the PRA effects of DRIs in DN. For a more successful translational research for DRIs, specific patient population responsive to the treatment should be identified, and PRA may remain a biomarker of choice for patient stratification.	0
The Arg838Ser mutation in retinal membrane guanylyl cyclase 1 (RetGC1) has been linked to autosomal dominant cone-rod dystrophy type 6 (CORD6). It is believed that photoreceptor degeneration is caused by the altered sensitivity of RetGC1 to calcium regulation via guanylyl cyclase activating proteins (GCAPs). To determine the mechanism by which this mutation leads to degeneration, we investigated the structure and function of rod photoreceptors in two transgenic mouse lines, 362 and 379, expressing R838S RetGC1. In both lines, rod outer segments became shorter than in their nontransgenic siblings by 3-4 weeks of age, before the eventual photoreceptor degeneration. Despite the shortening of their outer segments, the dark current of transgenic rods was 1.5-2.2-fold higher than in nontransgenic controls. Similarly, the dim flash response amplitude in R838S+ rods was larger, time to peak was delayed, and flash sensitivity was increased, all suggesting elevated dark-adapted free cGMP in transgenic rods. In rods expressing R838S RetGC1, dark-current noise increased and the exchange current, detected after a saturating flash, became more pronounced. These results suggest disrupted Ca2+ phototransduction feedback and abnormally high free-Ca2+ concentration in the outer segments. Notably, photoreceptor degeneration, which typically occurred after 3 months of age in R838S RetGC1 transgenic mice in GCAP1,2+/+ or GCAP1,2+/- backgrounds, was prevented in GCAP1,2-/- mice lacking Ca2+ feedback to guanylyl cyclase. In summary, the dysregulation of guanylyl cyclase in RetGC1-linked CORD6 is a "phototransduction disease," which means it is associated with increased free-cGMP and Ca2+ levels in photoreceptors.SIGNIFICANCE STATEMENT In a mouse model expressing human membrane guanylyl cyclase 1 (RetGC1, GUCY2D), a mutation associated with early progressing congenital blindness, cone-rod dystrophy type 6 (CORD6), deregulates calcium-sensitive feedback of phototransduction to the cyclase mediated by guanylyl cyclase activating proteins (GCAPs), which are calcium-sensor proteins. The abnormal calcium sensitivity of the cyclase increases cGMP-gated dark current in the rod outer segments, reshapes rod photoresponses, and triggers photoreceptor death. This work is the first to demonstrate a direct physiological effect of GUCY2D CORD6-linked mutation on photoreceptor physiology in vivo It also identifies the abnormal regulation of the cyclase by calcium-sensor proteins as the main trigger for the photoreceptor death.	0
Chromoanagenesis represents an extreme form of genomic rearrangements involving multiple breaks occurring on a single or multiple chromosomes. It has been recently described in both acquired and rare constitutional genetic disorders. Constitutional chromoanagenesis events could lead to abnormal phenotypes including developmental delay and congenital anomalies, and have also been implicated in some specific syndromic disorders. We report the case of a girl presenting with growth retardation, hypotonia, microcephaly, dysmorphic features, coloboma, and hypoplastic corpus callosum. Karyotype showed a de novo structurally abnormal chromosome 14q31qter region. Molecular characterization using SNP-array revealed a complex unbalanced rearrangement in 14q31.1-q32.2, on the paternal chromosome 14, including thirteen interstitial deletions ranging from 33 kb to 1.56 Mb in size, with a total of 4.1 Mb in size, thus suggesting that a single event like chromoanagenesis occurred. To our knowledge, this is one of the first case of 14q distal deletion due to a germline chromoanagenesis. Genome sequencing allowed the characterization of 50 breakpoints, leading to interruption of 10 genes including YY1 which fit with the patient's phenotype. This precise genotyping of breaking junction allowed better definition of genotype-phenotype correlations.	0
Neurotransmitter diseases are a well-defined group of metabolic conditions caused, in most instances, by genes specifically expressed in the presynaptic button. Better understanding of presynaptic molecular physiology, both in normal and pathological conditions, should help develop therapeutical strategies. The clinical relevance of the presynapse in inherited metabolic disorders is in glaring contrast with that of the postsynaptic component, which so far does not seem to play a relevant role in these disorders. This is somewhat surprising, as postsynaptic proteins are known to be involved in many nervous system diseases, particularly in neurodevelopmental and psychiatric disorders. The goal of this article is to explore if defects in the sophisticated postsynaptic machinery could also have a role in neurometabolic disorders.	0
The Editors have retracted this article [1] as is it is not clear whether parental consent was provided for publication of the images and case. Given the age of the article we have been unable to verify this, therefore the article is no longer available online in order to protect the privacy of the individual. Both authors agree to this retraction.	0
DIRA (deficiency of the IL-1Ra) is a rare condition that usually presents in the neonatal period. Patients with DIRA present with systemic inflammation, respiratory distress, joint swelling, pustular rash, multifocal osteomyelitis, and periostitis. Previously, we reported a patient with a novel mutation in IL1RN with a healthy neonatal period, a late-onset of pustular dermatosis, inflammatory arthritis, and excellent response to canakinumab treatment. Herein, we are presenting a new case of late-onset DIRA syndrome, carrying a different mutation and showing different clinical findings. This patient is the first one in the literature with the inflammatory arthritis, nail psoriasis, and onychomycosis and with her remarkable response to monoclonal antibodies. The case responded well and fully recovered after treatment with adalimumab, but not with canakinumab. The DIRA disease can lead to death from multiple organ failures and if recognized early, the treatment with replacement of the deficient protein with biologic agents induces rapid and complete remission. Therefore, clinical symptoms should be learned exactly by the pediatricians, pediatric rheumatologists, and immunologists; and molecular analysis targeting this defect must be performed as early as possible.	0
RATIONALE:Bartter syndrome is an autosomal-recessive inherited disease in which patients present with hypokalemia and metabolic alkalosis. We present 1 case with Bartter syndrome, due to a novel compound heterozygous mutation in the KCNJ1 gene encoding the ATP-sensitive inward rectifier potassium channel in the thick ascending limb of the loop of Henle. PATIENT CONCERNS:A patient was admitted to our hospital because of weakness, polyuria, and polydipsia. At presentation to our hospital, the female Chinese patient was 34 years old and her physical examination was normal. Laboratory studies revealed hypokalemia, metabolic alkalosis, hypercalciuria, hyperparathyroidemia, and hyper-reninemia. In addition, urinary potassium was obviously higher. Computer tomography scan confirmed the patient had the bilateral medullary nephrocalcinosis. DIAGNOSIS:Blood samples were received from the patient and her parents, and deoxyribonucleic acid was extracted. The genetic analysis of SLC12A1, SLC12A3, KCNJ1, CLCNKB, BSND, and CASR was performed. The compound heterozygous KCNJ1 gene mutation was validated using conventional Sanger sequencing methods. INTERVENTIONS:The patient was treated with potassium supplementation. Her blood and urine chemistries improved over the next week. Serum potassium normalized with improvement in polyuria and polydipsia over the next month. OUTCOMES:Our patient was compound heterozygous for Thr234Ile and Thr71Met in the KCNJ1 gene. The c.701C>T variant predicted a change from a threonine codon to an isoleucine codon (p.Thr234Ile). The c.212C>T variant predicted a change from a threonine codon to a methionine codon (p.Thr71Met). The unaffected mother was heterozygous for the Thr234Ile mutation, whereas unaffected father was heterozygous for the Thr71Met mutation. LESSONS:The phenotypes of the patient were similar to other patients with Bartter syndrome. The phenotypes of the patient could eventually be explained by the presence of the novel compound heterozygous p.Thr234Ile/p.Thr71Met variants in the KCNJ1 gene.	0
Adenosarcoma is a rare tumor which consists of benign glandular epithelium and malignant mesenchymal component. Here we report a case of adenosarcoma of the uterine corpus. Case Presentation. A 59-year-old woman presented with vaginal bleeding and visited a local clinic. She had a uterine tumor pointed out and was referred to our hospital. Ultrasound scans revealed a large heterogeneous mass occupying the whole uterine cavity. Cytological test of endometrium was performed but the result was negative. A fractional endometrial curettage revealed no malignancy. Magnetic resonance imaging (MRI) revealed a heterogeneous solid tumor of 77 × 76 mm. Total abdominal hysterectomy with bilateral salpingo-oophorectomy and pelvic lymphadenectomy was performed. On gross examination, the tumor was arising from the uterine body and occupied the whole uterine cavity. Histopathological examination revealed phyllodes-like architecture on low magnificationandperiglandular cuffing of tumor cells. The lesion was confined to the uterus. Histopathological final diagnosis was adenosarcoma. Her postoperative course was uneventful and she was discharged without postoperative treatment and remains alive without disease 6 months after the surgery.	0
The cellular microenvironment, characterized by an extracellular matrix (ECM), played an essential role in the transition from unicellularity to multicellularity in animals (metazoans), and in the subsequent evolution of diverse animal tissues and organs. A major ECM component are members of the collagen superfamily -comprising 28 types in vertebrates - that exist in diverse supramolecular assemblies ranging from networks to fibrils. Each assembly is characterized by a hallmark feature, a protein structure called a triple helix. A current gap in knowledge is understanding the mechanisms of how the triple helix encodes and utilizes information in building scaffolds on the outside of cells. Type IV collagen, recently revealed as the evolutionarily most ancient member of the collagen superfamily, serves as an archetype for a fresh view of fundamental structural features of a triple helix that underlie the diversity of biological activities of collagens. In this Opinion, we argue that the triple helix is a protein structure of fundamental importance in building the extracellular matrix, which enabled animal multicellularity and tissue evolution.	0
Hermansky-Pudlak syndrome (HPS) is an extremely subtile autosomal recessive disorder characterized by tyrosinase-positive oculocutaneous albinism (Ty-pos OCA), bleeding tendencies, and systemic complications associated to lysosomal dysfunction. The most grave complication of disease is interstitial lung disease (ILD) leading to irrevocable pulmonary fibrosis. Patients with HPS-1, HPS-2, and HPS-4 variants have a penchant to develop pulmonary fibrosis. The pulmonary involvement is characterised by progressive dyspnea hypoxemia respiratory failure and corpulmonale. The disease has an unfortunate prognosis with a high mortality rate and a poor quality of life. The options currently available in the therapeutic armamentarium are dismal with a dire need for opportune research. We hereby narrate an intriguing case scenario of a pair of siblings affected with this rare disorder with its associated ILD.	0
BACKGROUND:Rural Australian populations experience an increased burden of ischaemic heart disease (IHD) compared to their metropolitan counterparts, similar to other developed countries, globally. Policy and other efforts need to address and acknowledge these differences in order to reduce inequalities in health burden. This paper examines rural health policy makers' perceptions and use of evidence in efforts to reduce the burden of IHD in rural areas. METHODS:Policy makers and government advisors (n = 21) who worked with, or advised on, rural health policy at local, state and federal government levels, with specific focus on the state of Victoria (n = 9) were identified from publicly available documents and subsequent snowball sample. Semi-structured qualitative interviews were conducted in regards to the use of evidence in policy to prevent IHD and thematic analysis undertaken applying two theoretical perspectives: context-based evidence-based policy making and the conceptual framework for understanding rural and remote health. RESULTS:The rural context, particularly low resourcing, was seen as limiting potential for evidence based policy at local government (LG) level. Lower levels of political pressure and education were seen as constraints to evidence-based policy in rural communities. Participants described the potential for policy to have a greater impact on reducing heart disease in rural areas though they felt under-resourced and out of touch with the scientific evidence. Scientific studies were less valued than local anecdote to prioritise specific policy. At all levels (local, state and federal) low self-efficacy in interpreting evidence and perceived lack of relevance inhibited development of evidence informed policy. CONCLUSION:The rural context constrains the use of scientific evidence in policy making for the prevention of heart disease in rural areas in Australia with multiple factors influencing the capacity for evidenced based health policy. This is similar to findings at the international scale and is for consideration across other developed countries that experience inequalities in IHD disease burden between rural and urban populations.	0
BACKGROUND:Multiple Sclerosis (MS) has been associated with several immune-mediated diseases but the mechanisms that explain such associations, as well as their implications in clinical practice and treatment are rarely discussed. CASE PRESENTATION:We report the case of a patient with a history of MS since she was 27 years old, followed by a diagnosis of Hypocomplementemic Urticarial Vasculitis (HUV) seven years later. Several disease-modifying treatments for MS and HUV were used but with limited benefit in both diseases and significant MS progression. Activity of both diseases was later stabilized with Rituximab. We discuss the hypotheses of a central nervous system involvement in urticarial vasculitis or an association between MS and HUV, and examine the challenges in their management. CONCLUSIONS:In the presence of concurrent immune-mediated diseases, the diagnosis of MS can be challenging. This clinical presentation posed significant difficulties in disease management, influencing therapeutic options and their effectiveness/adverse effects profile. The best approach in MS patients with concurrent autoimmune diseases remains to be established and more reports are needed to help clarify this subject.	0
Windblown hand is a congenital anomaly characterized by multiple hand deformities. The condition is extremely rare as shown by the paucity of cases reported in the literature. The deformities, which can result in a cosmetically unsatisfactory appearance and, if left untreated, maladaptive behavior, are progressive in nature. Consequently early treatment is necessary.We operated upon 23 hands in 18 patients (age range at surgery 6 months to 16 years) at a tertiary care center over a period of 7 years. The patients were followed for an average period of 7 years. The surgical approach was chosen based on the severity of the condition according to Zancolli and Zancolli's classification [Hand Clin 1:443-456 (1985)].According to the criteria of Wood and Biondi [J Hand Surg 15A:431-438 (1990)], of the 23 hands operated upon, 17 had excellent cosmetic results, and 15 had excellent functional results. The results were better in patients undergoing early surgery-before the age of 2 years. Relapse of the deformity to a lesser extent than the original condition was seen in two hands at the last follow up.Definitive conclusions on this condition cannot be drawn due to limited experience in the surgical management of this rare condition. We believe that early surgical management is probably the best option available for the patient based on the results obtained. Early surgery and good post-operative compliance from patients can facilitate successful management of this rare condition with predictable results.	0
BACKGROUND The pulmonary hypoplasia/agenesis, diaphragmatic hernia/eventration, anophthalmia/microphthalmia, and cardiac defect (PDAC) syndrome is a rare medical condition presumably of autosomal recessive way of inheritance with only a few reported cases. Recessive mutations in the STRA6 and both recessive and dominant mutations in RARB gene have been identified as the cause of anophthalmia/microphthalmia and other abnormalities included in the PDAC spectrum. However, those mutations have not been found in all PDAC syndrome cases reviewed from the literature. CASE REPORT We report a case of a full-term living male infant with pulmonary hypoplasia, left diaphragmatic eventration, bilateral microphthalmia, congenital cardiac defects, and severe pulmonary hypertension. CONCLUSIONS The main feature in the reported cases was anophthalmia/microphthalmia. Therefore, screening for the other associated congenital anomalies is highly suggested. Mutations in STRA6 and RARB genes are commonly encountered in this spectrum. However, whole exome sequencing of suspected cases and their parents is recommended to detect possible de novo mutations. Further reports are needed to identify risk factors and prognosis of this rare syndrome.	0
In the present study whole-exome sequencing using the Complete Genomics platform was employed to scan a proband from a split‑hand/split‑foot malformation (SHFM) 4 family. The missense mutation c.728G>A (p.Arg243Gln) in the TP63 gene was revealed to be associated with SHFM. Sanger sequencing confirmed the sequences of the proband and his father. The father was diagnosed with SHFM and harbored a CGG‑to‑CAG mutation in exon 5, which produced a R243Q substitution in the zinc binding site and dimerization site of TP63. The R243Q mutation was predicted to be pathogenic by PolyPhen‑2. The proband, who was diagnosed with four digit SHFM, exhibited a more severe phenotype. X‑ray analysis returned the following results: Absence of third phalange bilaterally and third metacarpus of the left hand; absence of the second toes bilaterally and partial third toes; and partial fusion of the second, third and metatarsal bones of the right side with deformity of the second metatarsal of the right side. Osteochondroma was present in the fourth proximal radial metacarpal of the left hand and the basal and proximal parts of the second metatarsal of the right side. The proband's father had five digits in both feet. These results indicate that the R243Q mutation produces a novel phenotype named SHFM4. The present study revealed that the R243Q mutation in the TP63 gene produced a novel phenotype named SHFM4, thereby demonstrating the mutational overlap between ectrodactyly‑ectodermal dysplasia‑cleft syndrome and SHFM4.	0
Now 15-year-old girl with glycogen storage disease (GSD) type IIIa (OMIM 232400) developed severe left ventricular obstructive hypertrophy and hepatomegaly while treated with frequent cornstarch meals. Subsequently, she was introduced the ketogenic diet; continuous ketosis has been maintained for over the last 4 years. After the introduction of ketogenic diet, a normalization of the cardiomyopathy and improvement of hepatopathy was achieved, with enhanced overall quality of life.	0
The nucleosome remodeling and deacetylase (NuRD) complex is a major regulator of gene expression involved in pluripotency, lineage commitment, and corticogenesis. This important complex is composed of seven different proteins, with mutations in CHD3, CHD4, and GATAD2B being associated with neurodevelopmental disorders presenting with macrocephaly and intellectual disability similar to other overgrowth and intellectual disability (OGID) syndromes. Pathogenic variants in CHD3 and CHD4 primarily involve disruption of enzymatic function. GATAD2B variants include loss-of-function mutations that alter protein dosage and missense variants that involve either of two conserved domains (CR1 and CR2) known to interact with other NuRD proteins. In addition to macrocephaly and intellectual disability, CHD3 variants are associated with inguinal hernias and apraxia of speech; whereas CHD4 variants are associated with skeletal anomalies, deafness, and cardiac defects. GATAD2B-associated neurodevelopmental disorder (GAND) has phenotypic overlap with both of these disorders. Of note, structural models of NuRD indicate that CHD3 and CHD4 require direct contact with the GATAD2B-CR2 domain to interact with the rest of the complex. Therefore, the phenotypic overlaps of CHD3- and CHD4-related disorders with GAND are consistent with a loss in the ability of GATAD2B to recruit CHD3 or CHD4 to the complex. The shared features of these neurodevelopmental disorders may represent a new class of OGID syndrome: the NuRDopathies.	0
Megacystis microcolon intestinal hypoperistalsis syndrome also known as Berdon syndrome is characterized by enlarged urinary bladder, small colon and reduced or absent intestinal peristalsis. We report a case of 4 days old female suffering from MMIHS presenting with tension pneumoperitoneum. To the best of our knowledge, this is the first reported case of MMIHS, having this unusual presentation.	0
Although historically known as a genetic disorder, epidermodysplasia verruciformis (EV) might be acquired in patients with a noninherited defective cell-mediated immunity. This article reports a case of EV in a patient with systemic lupus erythematosus and a history of 3 years immunosuppressive methylprednisolone treatment. The microscopic features of the skin biopsy showed morphologic changes of the keratinocytes characteristic of human papilloma virus (HPV) infections and immunoreactivity to p16. HPV genotyping demonstrated the presence of HPV 6 which belongs to a low-risk mucosal HPV group and has not been reported in EV previously. The clinical recognition of EV in immunocompromised patients and subsequent HPV typing is important because some patients will develop squamous cell carcinoma.	0
Blunt traumatic cardiac rupture is an uncommon event in trauma and survival is rare. While multiple isolated accounts of repair of blunt cardiac rupture have been reported in the literature, there is not a single report of survival from right ventricular rupture following an emergency department thoracotomy (EDT). We report 2 cases where patients have survived such injuries and have made a full recovery. These patients are from a single institution who lost pulses on arrival to the emergency department; then underwent EDT with relief of cardiac tamponade with hemorrhage control by temporary closure, and subsequent definitive repair of right ventricular rupture in the operating room. Both were multiply injured and survived to discharge without neurologic sequelae and have made a full recovery back to their baseline function. This setting may represent an important use of EDT among blunt trauma patients, where time to survival and recovery may dependent on the speed of hemorrhage control and return of cardiac activity.	0
CONTEXT:21-hydroxylase deficiency is the most common cause of Congenital Adrenal Hyperplasia. It presents as severe or classical forms-salt wasting and simple virilizing-and a mild or nonclassical (NC). Several studies have reported the frequency of pathogenic variants in different populations, although few of them included a large number of NC patients. OBJECTIVE:To analyse the CYP21A2 gene defects in a large cohort of Argentine patients. DESIGN:Molecular characterization of 628 patients (168 classical, 460 nonclassical, representing 1203 nonrelated alleles), 398 relatives, 126 partners. METHODS:Genetic variants were assessed by allele-specific PCR, PCR-RFLP or direct sequencing. Deletions, duplications and large gene conversions (LGC) were studied by Southern blot/MLPA or long-range PCR. Biological implications of novel variants were analysed by structure-based in silico studies. RESULTS:The most frequent pathogenic variants were p.V282L (58%) in NC alleles and c.293-13C>G (31.8%) and p.I173N (21.1%) in classical. Deletions and LGC were found at low frequency (6.2%), 57 alleles had rare pathogenic variants, and 3 had novel variants: p.(S166F); p.(P189R), p.(R436L). Genotype-phenotype correlation was observed in 98.6% of the cases, 11 asymptomatic first-degree relatives had pathogenic variants in both alleles, and 21/126 partners were carriers. CONCLUSIONS:We conducted a comprehensive genetic characterization of the largest cohort of 21-hydroxylase patients from the region. In particular, we add to the molecular characterization of a large number of NC patients and to the estimation of the disease carrier's frequency in our population.	0
PSMA PET imaging was originally used to assess biochemical recurrence of prostate cancer (PCa), but its clinical use was promptly extended to detection, staging and therapy response assessment. The expanding use of PSMA PET worldwide has also revealed PSMA ligand uptake in diverse nonprostatic diseases, which raised questions about the specificity of this imaging modality. Although not very common initially, a growing number of pathologies presenting PSMA uptake on PET have been reported in the last few years, and a proper interpretation of PSMA PET imaging findings suddenly became challenging and, to some extent, confusing. Compared to cytoplasmic PSMA expression in nonprostatic cells, the molecular features of apical PSMA expression in PCa cells can help to distinguish these various conditions. Correlations of imaging findings to patient history, to the expected pattern of disease spread and mainly to computed tomography (CT) and/or magnetic resonance imaging (MRI) characteristics will reinforce the distinction of lesions that are more likely related to PCa from those that could lead to an incorrect diagnosis. The overall benefits of endothelial PSMA expression, which is associated with the neovasculature of malignant neoplasms, will be highlighted, stating the potential use of PSMA ligand uptake as a theranostic tool. This review aims to cover the collection of nonprostatic diseases, including benign and malignant tumors, in a didactic approach according to disease etiology, with discussion of bone-related conditions and inflammatory and infectious processes.	0
Heterozygous mutations in MECOM (MDS1 and EVI1 complex locus) have been reported to be causative of a rare association of congenital amegakaryocytic thrombocytopenia and radioulnar synostosis. Here we report on 12 patients with congenital hypomegakaryocytic thrombocytopenia caused by MECOM mutations (including 10 novel mutations). The mutations affected different functional domains of the EVI1 protein. The spectrum of phenotypes was much broader than initially reported for the first 3 patients; we found familial as well as sporadic cases, and the clinical spectrum ranged from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormality. The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss. No single clinical manifestation was detected in all patients affected by MECOM mutations. Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1. We propose the term MECOM-associated syndrome for this heterogeneous hereditary disease and inclusion of MECOM sequencing in the diagnostic workup of congenital bone marrow failure.	0
The Creeper (Cp) chicken is characterized by chondrodystrophy in Cp/+ heterozygotes and embryonic lethality in Cp/Cp homozygotes. However, the genes underlying the phenotypes have not been fully known. Here, we show that a 25 kb deletion on chromosome 7, which contains the Indian hedgehog (IHH) and non-homologous end-joining factor 1 (NHEJ1) genes, is responsible for the Cp trait in Japanese bantam chickens. IHH is essential for chondrocyte maturation and is downregulated in the Cp/+ embryos and completely lost in the Cp/Cp embryos. This indicates that chondrodystrophy is caused by the loss of IHH and that chondrocyte maturation is delayed in Cp/+ heterozygotes. The Cp/Cp homozygotes exhibit impaired DNA double-strand break (DSB) repair due to the loss of NHEJ1, resulting in DSB accumulation in the vascular and nervous systems, which leads to apoptosis and early embryonic death.	0
Objective:To investigate the value of coagulation indicators D-dimer (DD), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (Fg) in predicting the severity and prognosis of COVID-19. Methods:A total of 115 patients with confirmed COVID-19, who were admitted to Tianyou Hospital of Wuhan University of Science and Technology between January 18, 2020, and March 5, 2020, were included. The dynamic changes of DD, PT, APTT, and Fg were tested, and the correlation with CT imaging, clinical classifications, and prognosis was studied. Results:Coagulation disorder occurred at the early stage of COVID-19 infection, with 50 (43.5%) patients having DD increased and 74 (64.3%) patients having Fg increased. The levels of DD and Fg were correlated with clinical classification. Among 23 patients who deceased, 18 had DD increased at the first lab test, 22 had DD increased at the second and third lab tests, and 18 had prolonged PT at the third test. The results from ROC analyses for mortality risk showed that the AUCs of DD were 0.742, 0.818, and 0.851 in three times of test, respectively; PT was 0.643, 0.824, and 0.937. In addition, with the progression of the disease, the change of CT imaging was closely related to the increase of the DD value (P < 0.01). Conclusions:Coagulation dysfunction is more likely to occur in severe and critically ill patients. DD and PT could be used as the significant indicators in predicting the mortality of COVID-19.	0
Autism spectrum disorder (ASD) consists of a genetically heterogenous group of neurobehavioral disorders characterized by impairment in three behavioral domains including communication, social interaction, and stereotypic repetitive behaviors. ASD affects more than 1% of children in Western societies, with diagnoses on the rise due to improved recognition, screening, clinical assessment, and diagnostic testing. We reviewed the role of genetic and metabolic factors which contribute to the causation of ASD with the use of new genetic technology. Up to 40 percent of individuals with ASD are now diagnosed with genetic syndromes or have chromosomal abnormalities including small DNA deletions or duplications, single gene conditions, or gene variants and metabolic disturbances with mitochondrial dysfunction. Although the heritability estimate for ASD is between 70 and 90%, there is a lower molecular diagnostic yield than anticipated. A likely explanation may relate to multifactorial causation with etiological heterogeneity and hundreds of genes involved with a complex interplay between inheritance and environmental factors influenced by epigenetics and capabilities to identify causative genes and their variants for ASD. Behavioral and psychiatric correlates, diagnosis and genetic evaluation with testing are discussed along with psychiatric treatment approaches and pharmacogenetics for selection of medication to treat challenging behaviors or comorbidities commonly seen in ASD. We emphasize prioritizing treatment based on targeted symptoms for individuals with ASD, as treatment will vary from patient to patient based on diagnosis, comorbidities, causation, and symptom severity.	0
Nablus mask-like facial syndrome (NMLFS) is defined by distinctive craniofacial appearance including tight-appearing glistening facial skin, blepharophimosis, telecanthus, severe arched eyebrows, flat and broad nose, long philtrum, distinctive ears, unusual hair patterns, mild developmental delay and "happy" disposition. We aim to report a 7-year-old boy diagnosed with NMLFS and moderate developmental delay. Literature emphasis that Intellectual Disability is common in this syndrome though it has been diagnosed to only a few people worldwide.	0
Neurofibromatosis type 1 is a monogenetic disorder that predisposes individuals to tumor formation and cognitive and behavioral symptoms. The neuronal circuitry and developmental events underlying these neurological symptoms are unknown. To better understand how mutations of the underlying gene (NF1) drive behavioral alterations, we have examined grooming in the Drosophila neurofibromatosis 1 model. Mutations of the fly NF1 ortholog drive excessive grooming, and increased grooming was observed in adults when Nf1 was knocked down during development. Furthermore, intact Nf1 Ras GAP-related domain signaling was required to maintain normal grooming. The requirement for Nf1 was distributed across neuronal circuits, which were additive when targeted in parallel, rather than mapping to discrete microcircuits. Overall, these data suggest that broadly-distributed alterations in neuronal function during development, requiring intact Ras signaling, drive key Nf1-mediated behavioral alterations. Thus, global developmental alterations in brain circuits/systems function may contribute to behavioral phenotypes in neurofibromatosis type 1.	0
We describe a hitherto under-recognized curious response in some individuals: of sneezing in response either to sexual ideation or in response to orgasm. Our review suggests that it may be much more common than expected. We surmise that an indiscrete stimulation of the parasympathetic nervous system may be an underlying mechanism to explain this and other reported unusual triggers of sneezing.	0
Spinocerebellar ataxia (SCA) is one of the most severe neurodegenerative diseases and is often associated with misfolded protein aggregates derived from the genetic mutation of related genes. Recently, mutations in CD10 such as C143Y have been identified as SCA type 43. CD10, also known as neprilysin or neuroendopeptidase, digests functional neuropeptides, such as amyloid beta, in the extracellular region. In this study, we explored the cellular behavior of CD10 C143Y to gain an insight into the functional relationship of the mutation and SCA pathology. We found that wild-type CD10 is expressed on the plasma membrane and exhibits endopeptidase activity in a cultured cell line. CD10 C143Y, however, forms a disulfide bond-mediated oligomer that does not appear by the wild-type CD10. Furthermore, the CD10 C143Y mutant was retained in the endoplasmic reticulum (ER) by the molecular chaperone BiP and was degraded through the ER-associated degradation (ERAD) process, in which representative ERAD factors including EDEM1, SEL1L, and Hrd1 participate in the degradation. Suppression of CD10 C143Y ERAD recovers intracellular transport but not enzymatic activity. Our results indicate that the C143Y mutation in CD10 negatively affects protein maturation and results in ER retention and following ERAD. These findings provide beneficial insight into SCA type 43 pathology.	0
Purpose:To highlight the striking similarities between the lesions of congenital toxoplasmosis (CT) and North Carolina Macular Dystrophy (NCMD) using multimodal imaging including spectral domain optical coherence tomography (SD-OCT). Observations:We are comparing a case report of CT compared to that of NCMD. The case of a 64-year-old man with a lifelong history of decreased vision OD from toxoplasmosis and new onset of central retinal vein occlusion OS. Color fundus photography, spectral domain optical coherence tomography (SD-OCT), and intravenous fluorescein angiography (IVFA) were used as diagnostic imaging tools to demonstrate the similarities and differences between CT and NCMD. In this case, unilateral CT demonstrated a large, excavated, coloboma-like chorioretinal lesion identical to NCMD grade 3. Serology studies were positive for toxoplasmosis. The similarities of CT and NCMD grade 3 using SD-OCT are especially striking. Conclusion and importance:Lesions of CT and NCMD grade 3 can appear identical on clinical exam and are indistinguishable from one another on SD-OCT. Because CT is a phenocopy of NCMD, many cases of the original NCMD family members had been misdiagnosed as CT. North Carolina Macular Dystrophy may be more common than previously realized and bilateral CT cases should be reexamined along with family members and genetic testing performed. Cases of bilateral CT actually may be NCMD cases. Now that the genetic and molecular mechanisms of NCMD are known, these may provide clues into the pathogenesis of CT.	0
Proteoglycans (PGs) are macromolecules present on the cell surface and in the extracellular matrix that confer specific mechanical, biochemical, and physical properties to tissues. Sulfate groups present on glycosaminoglycans, linear polysaccharide chains attached to PG core proteins, are fundamental for correct PG functions. Indeed, through the negative charge of sulfate groups, PGs interact with extracellular matrix molecules and bind growth factors regulating tissue structure and cell behavior. The maintenance of correct sulfate metabolism is important in tissue development and function, particularly in cartilage where PGs are fundamental and abundant components of the extracellular matrix. In chondrocytes, the main sulfate source is the extracellular space, then sulfate is taken up and activated in the cytosol to the universal sulfate donor to be used in sulfotransferase reactions. Alteration in each step of sulfate metabolism can affect macromolecular sulfation, leading to the onset of diseases that affect mainly cartilage and bone. This review presents a panoramic view of skeletal dysplasias caused by mutations in genes encoding for transporters or enzymes involved in macromolecular sulfation. Future research in this field will contribute to the understanding of the disease pathogenesis, allowing the development of targeted therapies aimed at alleviating, preventing, or modifying the disease progression.	0
AIMS:The coxsackievirus B3 (CVB3) mouse myocarditis model is the standard model for investigation of virus-induced myocarditis but the pancreas, rather than the heart, is the most susceptible organ in mouse. The aim of this study was to develop a CVB3 mouse myocarditis model in which animals develop myocarditis while attenuating viral infection of the pancreas and the development of severe pancreatitis. METHODS AND RESULTS:We developed the recombinant CVB3 variant H3N-375TS by inserting target sites (TS) of miR-375, which is specifically expressed in the pancreas, into the 3'UTR of the genome of the pancreo- and cardiotropic CVB3 variant H3. In vitro evaluation showed that H3N-375TS was suppressed in pancreatic miR-375-expressing EndoC-βH1 cells >5 log10, whereas its replication was not suppressed in isolated primary embryonic mouse cardiomyocytes. In vivo, intraperitoneal (i.p.) administration of H3N-375TS to NMRI mice did not result in pancreatic or cardiac infection. In contrast, intravenous (i.v.) administration of H3N-375TS to NMRI and Balb/C mice resulted in myocardial infection and acute and chronic myocarditis, whereas the virus was not detected in the pancreas and the pancreatic tissue was not damaged. Acute myocarditis was characterized by myocardial injury, inflammation with mononuclear cells, induction of proinflammatory cytokines, and detection of replicating H3N-375TS in the heart. Mice with chronic myocarditis showed myocardial fibrosis and persistence of H3N-375TS genomic RNA but no replicating virus in the heart. Moreover, H3N-375TS infected mice showed distinctly less suffering compared with mice that developed pancreatitis and myocarditis after i.p. or i.v application of control virus. CONCLUSION:In this study, we demonstrate that by use of the miR-375-sensitive CVB3 variant H3N-375TS, CVB3 myocarditis can be established without the animals developing severe systemic infection and pancreatitis. As the H3N-375TS myocarditis model depends on pancreas-attenuated H3N-375TS, it can easily be used in different mouse strains and for various applications.	0
INTRO:Transposition of the great arteries (TGA) is a rare cyanotic congenital heart defect (CHD) typically presenting the first month of life. Late presentations may occur in patients with associated cardiac anomalies allowing for mixing of oxygenated and deoxygenated blood, such as ventral septal defects or large atrial septal defects (ASD). We present a case of a late-presenting TGA with no ventral septal defect, and only small ASD and patent ductus arteriosus (PDA). CASE:A 2-month-old female infant presented to a rural emergency department with respiratory distress for 1 day. On arrival, she was cyanotic with only mild improvement in oxygen saturations on 15-L non-rebreather. Grade IV/VI murmur was noted, and prostaglandin E was started. She required intubation after becoming apneic and was transported to the local pediatric referral hospital. There, echocardiography showed dextro-type TGA, with 8-mm ASD with minimal gradient, small PDA with left to right flow, and ventral septal bowing. She underwent balloon septostomy and then atrial switch, which was well tolerated. DISCUSSION:Our case is unique because of the patient's late presentation and prior lack of symptoms, given minimal levels of blood mixing though small ASD and PDA. Most TGA cases are now identified during prenatal ultrasound or with CHD screening pulse oximetry before discharge from the newborn nursery; however rare cases of late-presenting TGA may exist. CONCLUSION:Practitioners must maintain consideration of TGA, even after the newborn period, despite advances in newborn CHD screening in infants who present with new-onset respiratory distress without infection.	0
Mucopolysaccharidosis type IVA, also known as Morquio A or MPS IV A, is an autosomal recessive disease caused by the deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). The loss of GALNS activity leads to the impaired breakdown of glycosaminoglycans (GAGs) keratan sulfate and chondroitin-6-sulfate. The accumulation of GAGs results in multiple organ damage. The accurate and early diagnosis of this disorder helps enhance the effectiveness of the treatment. The present study uses a pre-designed protocol for testing GALNS activity in the leukocytes of Iranian patients with MPS IV A and their parents and compares it with healthy controls.Patients with MPS IVA previously diagnosed through the measurement of enzyme activity or genetic analysis entered the study. Leukocytes were obtained from the heparinized blood of the participants. The GALNS activity was measured by a fluorometric method using 4-methylumbelliferyl-β-D-galactoside-6-sulfate (4MU-G6S) as the substrate and proper buffer solutions and calibrators.The GALNS activity (nmol/17 h/mg protein) was reported as 0-7.4 in the MPSIV A patients, as 19.85-93.7 in their parents and as 38.4-164 in the healthy controls. Statistically significant differences were observed between the three groups in terms of enzyme activity. There were no significant differences in enzyme activity by age. The female subjects in both the patient and parents groups showed lower enzyme activity compared to the male subjects.The fluorometric method was validated for the measurement of GALNS activity in leukocyte samples and identifying Iranian patients with MPS IV A.	0
PURPOSE:Extrapulmonary infections due to M. xenopi, particularly osteoarticular localizations, are rare. The purpose of this paper is to describe a case of prosthetic hip infection and to review the published literature on cases of M. xenopi osteoarticular infections. METHODS:Literature search was performed in the following databases: MEDLINE (PubMed), Embase, Central (the Cochrane Library 2019, Issue 1), LILACS (BIREME) (Latin American and Caribbean Health Science Information database) and Clinical Trials databases (14th August 2018). We included all case reports and case series on adult patients diagnosed with bone or joint infection by M. xenopi for whom the treatment and outcome were specified. RESULTS:We retrieved 30 cases published between 1982 and 2012, among which 25 (83.3%) were reported from Europe. The two most common infection sites were spine (12/30, 40%) and knee (9/30, 30%). Risk factors for infection were previous invasive procedures (11/30, 36.7%), autoimmune disease (8/30, 26.7%), AIDS (4/30, 13.3%) and other comorbidities (2/30, 6.7%); five patients had no past medical history. All patients were treated with antibiotic combinations, but composition and duration of regimens hugely varied. Surgical intervention was performed in 16 patients (53.3%). Only 11 patients obtained full recovery of articular mobility after treatment. CONCLUSION:This work highlights the difficulties in diagnosing and treating M. xenopi osteoarticular infections. Globally, evidence supporting the best practice for diagnosis and treatment of this infection is scanty.	0
Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a developmental brain disorder characterized by an enlarged brain size with bilateral perisylvian polymicrogyria and a variable degree of ventriculomegaly. MPPH syndrome is associated with oromotor dysfunction, epilepsy, intellectual disability and postaxial hexadactyly. The molecular diagnosis of this disorder is established by the identification of a pathogenic variant in either AKT3, CCND2 or PIK3R2. Previously reported AKT3 variants are associated with various brain abnormalities and may lead to megalencephaly. MPPH syndrome is usually due to germline pathogenic AKT3 variants. Somatic mosaic pathogenic variants associated with hemimegalencephaly, which is similar to MPPH, have also been observed. A Hungarian Roma family with two half-siblings, which present with intellectual disability, dysmorphic features, epilepsy, brain malformations, and megalencephaly was studied. Whole exome sequencing (WES) analysis was performed. WES analysis revealed a heterozygous c.1393C > T p.(Arg465Trp) pathogenic missense AKT3 variant in both affected half-siblings. The variant was verified via Sanger sequencing and was not present in the DNA sample from the healthy mother, which was derived from peripheral blood, suggesting maternal germline mosaicism. In conclusion, this is the first report in which maternal germline mosaicism of a rare pathogenic AKT3 variant leads to autosomal dominantly inherited MPPH syndrome.	0
Inverse Marcus-Gunn phenomenon is very rare. It is usually acquired. We report a young male patient presenting with congenital ptosis and inverse Marcus-Gunn phenomenon.	0
OBJECTIVES:To perform a comprehensive survey of myasthenia gravis in the county of Cambridgeshire, England, establishing contemporary epidemiological data. METHODS:Cases were ascertained from multiple sources. Prevalent patients were visited and assessed by means of a standardised questionnaire and examination complemented by review of medical case notes. RESULTS:One hundred cases were identified in a population of 684000 (prevalence 15 per 100000 population, 95% confidence intervals (95% CIs) 12-18). Thirty eight new diagnoses were made over a five year period providing an incidence of 1.1/100000 population/year. The sex ratio was 2:1 F:M. After a mean follow up of 11.7 years, symptomatic disease was still restricted to ocular muscles in 25 patients. Thirty four of 100 patients underwent thymectomy a mean of 0.8 years after presentation, and a thymoma was present in 12. Highest remission rates were seen in patients presenting with generalised disease who underwent thymectomy but did not have a thymoma (27%). Cosegregation of an additional autoimmune disease occurred in 27 patients and in 24/49 (49%) women with onset<50 years of age. CONCLUSIONS:This, the second highest reported prevalence for myasthenia, is likely to be the result of optimum case ascertainment, increased disease duration, application of complex diagnostic tests, and the impact of an aging population leading to a relative increase in the prevalence of ocular myasthenia.	1
Onychotrichodysplasia, chronic neutropenia and mental retardation syndrome (ONMRS) is a rare autosomal recessive mutation, mostly reported in patients of Mexican ancestry. We describe a second patient with onychotrichodysplasia and chronic neutropenia without mental retardation (ONS). It is unclear if ONS found in the two European patients with normal mental development is due to genetic heterogeneity or variable expressivity of the same syndrome.	0
PURPOSE:This study reports a case of unilateral retinopathy with extinguished full-field ERGs (ffERGs), wherein the visual acuity was 16/16 and the visual field was spared. METHODS:Observational case report. RESULTS:A 39-year-old female had developed nyctalopia in her left eye. Two years later, she visited an ophthalmologist who noted a bilaterally reduced pigmentation of the fundus. Her best-corrected visual acuity was 16/16 in both the eyes. Goldmann perimetry demonstrated that her visual field was bilaterally fully spared. ffERGs measurement was performed in accordance with the ISCEV standard protocol and indicated that her right eye was normal. However, all ERG responses were severely attenuated in her left eye. Multifocal ERG responses were found to be normal in the right eye and extinguished in the left eye except for residual responses that were exclusively located at the center. During the 7 years of the follow-up period, the visual field in the left eye, which was once normal, became shaded, and the development of a ring scotoma was identified. The visual field in the right eye is still full. CONCLUSIONS:The pathogenesis of this patient's condition still remains unknown, while unilateral retinitis pigmentosa, unilateral pigmentary retinopathy, acute zonal occult outer retinopathy, and autoimmune retinopathy can all be considered as possible explanations. The uniqueness of this case study is that the extinguished ERG responses are predictive of the functional alteration in the affected eye, when the initial visual acuity and the visual field were normal.	0
MA is a rare, autosomal recessive disorder characterized by episodes of inflammation and periodic fevers. In its most severe form, it can result in facial dysmorphism, growth inhibition, ataxia, liver dysfunction, intellectual disability, and at times can be fatal. A number of case reports exist stating that SCT is curative in these patients. We present the case of a patient diagnosed with MA at birth, who underwent SCT at the age of 14 months with intent to cure. She achieved complete engraftment and urine mevalonate became undetectable. However, 18 months following transplant, she developed frequent episodes of fevers, rashes, arthritis, and a rising urinary mevalonate. She was subsequently diagnosed with relapse. She now requires treatment with steroids and canakinumab to manage her disease. This case is the first report of disease relapse following transplant for MA. It runs contrary to prior reports that SCT is fully curative of MA and suggests that transplant may instead provide a means of decreasing disease severity without entirely eradicating the condition.	0
Desbuquois dysplasia (DD) is characterized by antenatal and postnatal short stature, multiple dislocations, and advanced carpal ossification. Two forms have been distinguished on the basis of the presence (type 1) or the absence (type 2) of characteristic hand anomalies. We have identified mutations in calcium activated nucleotidase 1 gene (CANT1) in DD type 1. Recently, CANT1 mutations have been reported in the Kim variant of DD, characterized by short metacarpals and elongated phalanges. DD has overlapping features with spondyloepiphyseal dysplasia with congenital joint dislocations (SDCD) due to Carbohydrate (chondroitin 6) Sulfotransferase 3 (CHST3) mutations. We screened CANT1 and CHST3 in 38 DD cases (6 type 1 patients, 1 Kim variant, and 31 type 2 patients) and found CANT1 mutations in all DD type 1 cases, the Kim variant and in one atypical DD type 2 expanding the clinical spectrum of hand anomalies observed with CANT1 mutations. We also identified in one DD type 2 case CHST3 mutation supporting the phenotype overlap with SDCD. To further define function of CANT1, we studied proteoglycan synthesis in CANT1 mutated patient fibroblasts, and found significant reduced GAG synthesis in presence of β-D-xyloside, suggesting that CANT1 plays a role in proteoglycan metabolism.	0
An instance of isolated unilateral temporalis muscle hypertrophy (reactive masticatory muscle hypertrophy with fiber type 1 predominance) confirmed by muscle biopsy with histochemical fiber typing and image analysis in a 62 year-old man is reported. The patient presented with bruxism and a painful swelling of the temple. Absence of asymmetry or other abnormalities of the craniofacial skeleton was confirmed by magnetic resonance imaging and cephalometric analyses. The patient achieved symptomatic improvement only after undergoing botulinum toxin injections. Muscle biopsy is key in the diagnosis of reactive masticatory muscle hypertrophy and its distinction from masticatory muscle myopathy (hypertrophic branchial myopathy) and other non-reactive causes of painful asymmetric temporalis muscle enlargement.	0
PURPOSE OF REVIEW:The purpose of this review is to discuss current knowledge on pediatric intestinal pseudo-obstruction. We will also review new mutations that have been identified through advancement in genetic testing, allowing for a better understanding of the underlying mechanisms of intestinal dysmotility and potential etiologies. RECENT FINDINGS:With the advancements in genetic testing, new mutations have been identified in the diagnosis of megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), a disorder leading to pediatric pseudo-obstruction. MYLK, LMOD1, MYL9, and MYH11 encode for various proteins within smooth muscle cells; abnormalities within these proteins lead to abnormal intestinal smooth muscle contractions. Chronic intestinal pseudo-obstruction (CIPO) is defined by symptoms of bowel obstruction in the absence of a lumen-occluding lesion. CIPO is a heterogeneous group of disorders caused by abnormalities in the enteric neurons, intestinal smooth muscle, and/or the interstitial cells of Cajal (ICC). Symptoms can be non-specific and etiologies include both primary and secondary causes of CIPO that contribute to the delay in recognizing this condition and making the correct diagnosis. Chronic intestinal pseudo-obstruction has been recognized in both adults and children with fundamental differences in the etiology, symptom onset, clinical features and natural history of this disorder. For this reason, it has been considered a separate entity referred to as pediatric intestinal pseudo-obstruction (PIPO).	0
We report a case of chimpanzee trisomy 22 in a captive-born female. Because chromosome 22 in great apes is homologous to human chromosome 21, the present case is analogous to human trisomy 21, also called Down syndrome. The chimpanzee in the present case experienced retarded growth; infantile cataract and vision problems, including nystagmus, strabismus, and keratoconus; congenital atrial septal defect; and hypodontia. All of these symptoms are common in human Down syndrome. This case was the second reported case of trisomy 22 in the chimpanzee. The chimpanzee in our case became blind by 7 years old, making social life with other chimpanzees difficult, but opportunities to interact with other conspecific individuals have been offered routinely. We believe that providing her with the best care over the course of her life will be essential.	0
Germline alterations of the tumor suppressor PTEN have been extensively characterized in patients with PTEN hamartoma tumor syndromes, encompassing subsets of Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus and Proteus-like syndromes, as well as autism spectrum disorder. Studies have shown an increase in the risk of developing specific cancer types in the presence of a germline PTEN mutation. Furthermore, outside of the familial setting, somatic variants of PTEN occur in numerous malignancies. Here we introduce and discuss the prospect of moving toward a systems pathology approach for PTEN diagnostics, incorporating clinical and molecular pathology data with the goal of improving the clinical management of patients with a PTEN mutation. Detection of a germline PTEN mutation can inform cancer surveillance and in the case of somatic mutation, have value in predicting disease course. Given that PTEN functions in the PI3K/AKT/mTOR pathway, identification of a PTEN mutation may highlight new therapeutic opportunities and/or inform therapeutic choices.	0
Alexander disease (AxD) is a rare neurodegenerative disorder characterized by white matter degeneration and formation of cytoplasmic inclusions. Glial fibrillary acidic protein (GFAP) mutations have been reported in various forms of AxD since 2001. However, a definitive diagnosis remains difficult because of uncertain prevalence, and different clinical features seen in infantile AxD and adult AxD may lead to confusion and misdiagnosis. Here we report an epidemiological study conducted in Japan. Two nationwide questionnaire-based surveys were conducted using tentative diagnostic criteria. We gathered information regarding prevalence, neurological findings, magnetic resonance imaging (MRI) findings, electrophysiological findings, genetic information, and the results of therapeutic interventions and home care. Prevalence of various forms of AxD was determined as 27.3% (infantile), 24.2% (juvenile), and 48.5% (adult). Prevalence of AxD in Japan was estimated to be approximately 1 case per 2.7 million individuals. The main characteristics of infantile and juvenile AxD include delayed psychomotor development or mental retardation, convulsions, macrocephaly, and predominant cerebral white matter abnormalities in the frontal lobe on brain MRI. The main characteristics of adult AxD include bulbar signs, muscle weakness with hyperreflexia, and signal abnormalities and/or atrophy of medulla oblongata and cervical spinal cord on MRI. To ensure correct diagnosis of AxD, the physician should understand the importance of the process of GFAP genetic testing, which provides definitive diagnosis. Therefore, we propose new clinical guidelines for diagnosing AxD based on simplified classifications: cerebral AxD (type 1), bulbospinal AxD (type 2), and intermediate form (type 3).	1
In 1937, Heinrich Klüver and Paul Bucy described a dramatic behavioral syndrome in monkeys after bilateral temporal lobectomy. The full Klüver-Bucy syndrome (KBS) - hyperorality, placidity, hypermetamorphosis, dietary changes, altered sexual behavior, and visual agnosia - is evident within 3 weeks following operation. Some KBS features (i.e., hyperorality, placidity, hypermetamorphosis) persist indefinitely, whereas others gradually resolve over several years. Klüver and Bucy were initially unaware of an earlier report of KBS by Sanger Brown and Edward Schäfer in 1888. Human cases were recognized in the 1950s, as surgeons employed bilateral temporal lobectomies to treat seizures. Various attempts were made to localize the component features to specific areas of the temporal lobe, with mixed success. Bilateral ventral temporal ablations and bilateral temporal lobectomies produced marked impairment in visual discrimination, whereas lateral resections or unilateral lesions did not. Discrete bilateral lesions of the lateral amygdaloid nucleus produced a permanent "hypersexed state." By the 1970s, it was clear that the major symptoms of KBS are produced by destroying either the temporal neocortex or the amygdala bilaterally. KBS is now thought to be caused by disturbances of temporal portions of limbic networks that interface with multiple cortical and subcortical circuits to modulate emotional behavior and affect. The clinical features of KBS in man are similar to those in monkeys, but the full syndrome is rarely seen, probably because the anterior temporal lobe dysfunction is usually less severe than that following total temporal lobe ablation in monkeys. Human KBS does not occur in isolation, but is typically part of a complex behavioral syndrome that almost always includes amnesia and aphasia, and that may also include dementia and seizures. The treatment of KBS is difficult and often unsatisfactory.	0
BACKGROUND: Studies reporting the incidence of isolated cutaneous lupus erythematosus (CLE) are rare. OBJECTIVES: To examine in a population-based cohort study the incidence of CLE and its subsets in Sweden. The short-term probability of receiving an additional diagnosis of systemic lupus erythematosus (SLE) is also assessed. METHODS: A population-based open cohort study including all patients with CLE [International Classification of Diseases (ICD) code, ICD-10: L93] in Sweden, 2005-2007. Patients (n=1088) were identified in the Swedish National Patient Register. RESULTS: The incidence of CLE was 4·0/100,000; the female/male ratio was 3:1. Mean age at disease onset was 54 years. The most common subset was discoid lupus erythematosus (DLE) (80%, n = 868). A quarter of the patients (24%, n=260) were already diagnosed with SLE at the time they were diagnosed with CLE. During the whole observation period (2005-2007), an additional 18% (n = 107) were diagnosed with SLE, the probability of receiving an additional SLE diagnosis being highest for the subacute CLE (SCLE) subset. CONCLUSIONS: This is the first nationwide epidemiological study on CLE. We found the incidence of CLE to be about equal to that of SLE, and found a higher short-term probability for receiving an additional diagnosis with SLE than previously described for CLE. Subsets other than DLE and SCLE were rarely reported in our system; an update of the ICD codes for this diagnostic group could increase reporting of these more unusual cases. Our study clarifies that monitoring and follow-up are called for in this patient group due to the risk for SLE, and underscores the need for clear criteria for risk assessment in the large group of patients with CLE who also fulfil criteria for SLE.	1
BACKGROUND:Intradural ependymal cysts are benign, fluid-filled cysts usually situated along the ventral surface of the spinal cord. There are previous reports of 19 intradural cysts in the literature, including one cyst of the filum terminale. Here, we report for the first time the presence of a radiographically occult filum terminale cyst associated with a myxopapillary ependymoma. We propose that mobility of the tumor may provide indirect evidence of the presence of a cyst. CASE DESCRIPTION:A 65-year-old male patient presented with a homogenously enhancing ovoid mass measuring 25 mm × 10 mm within the thecal sac at the L3 through L4 levels. Repeat magnetic resonance imaging demonstrated migration of the tumor 12 mm rostrally. Following the L2 through L4 laminectomy and resection of the intradural tumor, we identified a filum terminale ependymal cyst superior to the tumor, which was also resected. CONCLUSIONS:Ependymal cysts associated with spinal tumors are rare and may be radiographically occult. The change in cyst size may explain tumor mobility. Complete resection of the cyst and histopathologic analysis is recommended to differentiate between ependymal cyst and cystic tumor tissue.	0
Autophagy is an intracellular catabolic process implicated in the recycling and degradation of intracellular components. Few studies have defined its role in corneal pathologies. Animal models are essential for understanding autophagy regulation and identifying new treatments to modulate its effects. A systematic review (SR) was conducted of studies employing animal models for investigations of autophagy in corneal diseases. Studies were identified using a structured search strategy (TS = autophagy AND cornea*) in Web of Science, Scopus, and PubMed from inception to September 2019. In this study, 230 articles were collected, of which 28 were analyzed. Mouse models were used in 82% of the studies, while rat, rabbit, and newt models were used in the other 18%. The most studied corneal layer was the epithelium, followed by the endothelium and stroma. In 13 articles, genetically modified animal models were used to study Fuch endothelial corneal dystrophy (FECD), granular corneal dystrophy type 2 (GCD2), dry eye disease (DED), and corneal infection. In other 13 articles, animal models were experimentally induced to mimic DED, keratitis, inflammation, and surgical scenarios. Furthermore, in 50% of studies, modulators that activated or inhibited autophagy were also investigated. Protective effects of autophagy activators were demonstrated, including rapamycin for DED and keratitis, lithium for FECD, LYN-1604 for DED, cysteamine and miR-34c antagomir for damaged corneal epithelium. Three autophagy suppressors were also found to have therapeutic effects, such as aminoimidazole-4-carboxamide-riboside (AICAR) for corneal allogeneic transplantation, celecoxib and chloroquine for DED.	0
A 28-year-old male patient presented to us with bilateral frontal hyperostosis associated with a small unilateral frontal intracranial meningioma. He underwent successful excision of the involved bone and repair of the large cranial defect using a titanium mesh. Histological examination revealed tumor infiltration of the overlying bone. Surgical challenges in the management of such a case are also discussed.	0
BACKGROUND:Extrauterine leiomyomata is an uncommon lesion that can lead to several problems of differential diagnosis, especially when localized in the external genitalia. There are few reports in the English literature and a novel association with Alport's syndrome has been investigated since the 1980s. CASE PRESENTATION:Here, we describe the case of a premenopausal woman who presented with an indolent swelling of the right interlabial fossa that resulted in a Bartholin cyst. In addition to this cyst, a benign leiomyoma of the right side of the clitoris was also found and removed. Our patient refused any further examination, although she was informed that genetic counselling could be organized to rule out an association with Alport's syndrome. CONCLUSIONS:Extrauterine leiomyomata localized in the external genitalia is an uncommon lesion arising from smooth muscle cells around vascular epithelium or erectile tissue. Since an association between extrauterine leiomyomata and Alport's syndrome has been described, genetic testing can be proposed to these patients. Upper intestinal tract symptoms such as dysphagia should prompt a gastroenterological evaluation as an association with an esophageal leiomyomatosis has been described.	0
Iris malformations are often associated with malformations of the entire eye and systemic diseases. Malformations of the anterior chamber angle can lead to juvenile glaucoma. Axenfeld-Rieger syndromes have autosomal dominant transmission and are associated with juvenile glaucoma in 50-60% of patients. Besides eye anomalies craniofacial malformations are also typical. The etiology of iridocorneal endothelial (ICE) syndrome is unclear but atypical endothelial cells lead to malformations of the entire anterior eye segment of the eye and glaucoma. Aniridia is a bilateral, congenital malformation which manifests sporadically and transmission is usually autosomal dominant. Glaucoma, malformations of the entire eye and systemic malformations are associated with aniridia. Conservative and microsurgical treatment of glaucoma of these syndromes need the cooperation of different medical subspecialties and are often ineffective.	0
Acquired uniparental disomy (aUPD) regions pinpoint homozygousity and monoallelic expressed genes. We analyzed The Cancer Genome Atlas single-nucleotide polymorphism arrays and expression data from oral cavity, oropharynx, and larynx cancers to identify frequency of aUPD in each tumor type and association of aUPD regions and differentially expressed genes in the regions with survival. Cox proportional hazard models were used for survival function; and Student's t test, for differentially expressed genes between groups. The frequency of aUPD was highest in larynx cancers (88.35%) followed by oral cavity (81.11%) and oropharynx cancers (73.85%). In univariate analysis, 11 regions at chromosome 9p were associated with overall survival (OS) in oral cavity cancers. Two regions at chromosome 17p were associated with OS in oropharyngeal cancers, but no aUPD region was associated with survival in patients with larynx cancers. Overexpression of SIGMAR1, C9orf23, and HINT2 was associated with reduced OS in patients with oral cavity cancers, and upregulation of MED27 and YWHAE was associated with shorter OS in patients with oropharynx cancers. In multivariate analysis, four aUPD regions at chromosome 9p and overexpression of HINT2 were associated with shorter OS in oral cavity cancers, and overexpression of MED27 was associated with worse OS in patients with oropharynx cancers. aUPD regions and differentially expressed genes in those regions influence the outcome and may play a role in aggressiveness in oral cavity and oropharynx cancers but not in patients with larynx cancers.	0
Rotor syndrome, a rare autosomal-recessive genetic disorder characterized by conjugated hyperbilirubinemia, is caused by biallelic pathogenic variants in both SLCO1B1 and SLCO1B3 genes. Long interspersed nuclear elements (LINEs) make up about 17% of the human genome and insertion of LINE-1 in genes can result in genetic diseases. In the current study, we examined SLCO1B1 and SLCO1B3 genes in two Chinese patients diagnosed with Rotor syndrome based on laboratory tests. In one patient, a novel exon 4 inversion variant was identified. This variant may have been induced by LINE-1 retrotransposon insertion into SLCO1B3 intron 3, and was identified using genome walking. Splicing assay results indicated that the exon inversion, resulting in SLCO1B3 exon 4 (122 bp) exclusion in the mature mRNA, might generate a premature termination codon. Here, we describe an exon inversion contributing to the molecular etiology of Rotor syndrome. Our results may inform future diagnoses and guide drug prescriptions and genetic counseling.	0
Paraneoplastic cerebellar degeneration (PCD) is a rare disorder that is associated with lung or gynecological malignancies and Hodgkin lymphoma. Neurologic symptoms are commonly the initial presenting sign leading to the diagnosis of an underlying malignancy. We are presenting an Asian male with progressive lower extremity weakness with EBV-positive nasopharyngeal carcinoma (NPC) and anti-Yo antibodies. Peculiarly, transient diffuse leptomeningeal enhancement is seen on MR imaging. This is the first report of PCD associated with NPC and thus illustrates that PCD embodies a boarder set of disease than previously described.	0
Adenylyl cyclases are key points for the integration of stimulatory and inhibitory G protein-coupled receptor (GPCR) signals. Adenylyl cyclase type 5 (AC5) is highly expressed in striatal medium spiny neurons (MSNs), and is known to play an important role in mediating striatal dopaminergic signaling. Dopaminergic signaling from the D1 expressing MSNs of the direct pathway, as well as the D2 expressing MSNs of the indirect pathway both function through the regulation of AC5 activity, controlling the production of the 2nd messenger cAMP, and subsequently the downstream effectors. Here, we used a newly developed cell line that used Crispr-Cas9 to eliminate the predominant adenylyl cyclase isoforms to more accurately characterize a series of AC5 gain-of-function mutations which have been identified in ADCY5-related dyskinesias. Our results demonstrate that these AC5 mutants exhibit enhanced activity to Gαs-mediated stimulation in both cell and membrane-based assays. We further show that the increased cAMP response at the membrane effectively translates into increased downstream gene transcription in a neuronal model. Subsequent analysis of inhibitory pathways show that the AC5 mutants exhibit significantly reduced inhibition following D2 dopamine receptor activation. Finally, we demonstrate that an adenylyl cyclase "P-site" inhibitor, SQ22536 may represent an effective future therapeutic mechanism by preferentially inhibiting the overactive AC5 gain-of-function mutants.	0
Dopamine Transporter Deficiency Syndrome (DTDS) is a rare autosomal recessive disorder caused by loss-of-function mutations in dopamine transporter (DAT) gene, leading to severe neurological disabilities in children and adults. DAT-Knockout (DAT-KO) mouse is currently the best animal model for this syndrome, displaying functional hyperdopaminergia and neurodegenerative phenotype leading to premature death in ~36% of the population. We used DAT-KO mouse as model for DTDS to explore the potential utility of a novel combinatorial adeno-associated viral (AAV) gene therapy by expressing DAT selectively in DA neurons and terminals, resulting in the rescue of aberrant striatal DA dynamics, reversal of characteristic phenotypic and behavioral abnormalities, and prevention of premature death. These data indicate the efficacy of a new combinatorial gene therapy aimed at rescuing DA function and related phenotype in a mouse model that best approximates DAT deficiency found in DTDS.	0
Glyphs representing complex behavior provide a useful and common means of visualizing multivariate data. However, due to their complex shape, overlapping and occlusion of glyphs is a common and prominent limitation. This limits the number of discreet data tuples that can be displayed in a given image. Using a real-world application, glyphs are used to depict agent behavior in a call center. However, many call centers feature thousands of agents. A standard approach representing thousands of agents with glyphs does not scale. To accommodate the visualization incorporating thousands of glyphs we develop clustering of overlapping glyphs into a single parent glyph. This hierarchical glyph represents the mean value of all child agent glyphs, removing overlap and reducing visual clutter. Multi-variate clustering techniques are explored and developed in collaboration with domain experts in the call center industry. We implement dynamic control of glyph clusters according to zoom level and customized distance metrics, to utilize image space with reduced overplotting and cluttering. We demonstrate our technique with examples and a usage scenario using real-world call-center data to visualize thousands of call center agents, revealing insight into their behavior and reporting feedback from expert call-center analysts.	0
The correct formation of the aortic arch arteries depends on a coordinated and regulated gene expression profile within the tissues of the pharyngeal arches. Perturbation of the gene regulatory networks in these tissues results in congenital heart defects affecting the arch arteries and the outflow tract of the heart. Aberrant development of these structures leads to interruption of the aortic arch and double outlet right ventricle, abnormalities that are a leading cause of morbidity in 22q11 Deletion Syndrome (DS) patients. We have recently shown that Pax9 functionally interacts with the 22q11DS gene Tbx1 in the pharyngeal endoderm for 4th pharyngeal arch artery morphogenesis, with double heterozygous mice dying at birth with interrupted aortic arch. Mice lacking Pax9 die perinatally with complex cardiovascular defects and in this study we sought to validate further potential genetic interacting partners of Pax9, focussing on Gbx2 which is down-regulated in the pharyngeal endoderm of Pax9-null embryos. Here, we describe the Gbx2-null cardiovascular phenotype and demonstrate a genetic interaction between Gbx2 and Pax9 in the pharyngeal endoderm during cardiovascular development.	0
Evidence is emerging that IBS, a hitherto enigmatic disorder thought to be predominantly related to psychological factors, has a microorganic basis in a subset of patients with the disease. Post-infectious IBS (PI-IBS), commonly of the diarrhoea-predominant subtype (defined as new development of IBS following acute infectious diarrhoea), is one such condition known to occur in up to 10-30% individuals after acute gastroenteritis. However, following acute infectious gastroenteritis, patients can also develop post-infectious malabsorption syndrome (PI-MAS), popularly known as tropical sprue. As no study on PI-IBS has rigorously excluded tropical sprue by appropriate investigations, including small intestinal biopsy, the frequency of tropical sprue among patients with PI-IBS is not known. Small intestinal bacterial overgrowth (SIBO) has been suggested to be associated with IBS in general, and in particular diarrhoea-predominant IBS, including PI-IBS. SIBO is also known to be associated with tropical sprue. As both IBS, particularly the subset probably associated with SIBO, and tropical sprue improve with antibiotic treatment, we provide evidence and an explanatory model to support a link among these disorders.	0
We report on two sisters with an unusual form of craniosynostosis, protruding nasal spine, micrognathia, short limbs, lung hypoplasia, absent or hypoplastic gallbladder, short intestine with ileal distention, hypoplastic uterus, and intrauterine growth retardation. This combination of defects appears to be a newly recognized and probably autosomal recessive disorder.	0
OBJECTIVES:Precocious puberty seems to be increasing but epidemiological data are scarce. Our objective was to improve the epidemiologic knowledge on this disease. We analyzed the national incidence and spatial trends of idiopathic central precocious puberty in France in 2011-2013 in a cross-sectional descriptive study. DESIGN:We used an indicator based on treatment reimbursements recorded in the national insurance database, in girls under the age of nine years and in boys under the age of 10 years. We considered a time lag of up to one year from the onset of puberty to first drug delivery. We tested four different predictive spatial models at the département scale, selecting the model best fitting the data. We carried out semi-structured interviews with qualified hospital teams in five selected regions to investigate spatial differences in medical practices. RESULTS:The national annual incidence was 2.68 (95% CI: 2.55, 2.81) per 10 000 girls under the age of 9 years and 0.24 (95% CI: 0.21, 0.27) per 10 000 boys under the age of 10 years. Incidence rates conformed to a purely spatial heterogeneity model in girls, consistent between age groups, with a large incidence range. A similar pattern was observed for boys, with peaks in the South West and Center East. Differences in medical practices may have slightly affected incidence locally, but could not entirely explain the marked geographic pattern. CONCLUSIONS:The results suggest that the risk factors are similar for boys and girls and justify further investigations of the role of the environment.	1
The human X and Y chromosomes evolved from a pair of autosomes approximately 180 million years ago. Despite their shared evolutionary origin, extensive genetic decay has resulted in the human Y chromosome losing 97% of its ancestral genes while gene content and order remain highly conserved on the X chromosome. Five 'stratification' events, most likely inversions, reduced the Y chromosome's ability to recombine with the X chromosome across the majority of its length and subjected its genes to the erosive forces associated with reduced recombination. The remaining functional genes are ubiquitously expressed, functionally coherent, dosage-sensitive genes, or have evolved male-specific functionality. It is unknown, however, whether functional specialization is a degenerative phenomenon unique to sex chromosomes, or if it conveys a potential selective advantage aside from sexual antagonism. We examined the evolution of mammalian orthologs to determine if the selective forces that led to the degeneration of the Y chromosome are unique in the genome. The results of our study suggest these forces are not exclusive to the Y chromosome, and chromosomal degeneration may have occurred throughout our evolutionary history. The reduction of recombination could additionally result in rapid fixation through isolation of specialized functions resulting in a cost-benefit relationship during times of intense selective pressure.	0
Loeys-Dietz syndrome is a heritable disorder of the connective tissue leading to multisystem involvement including craniofacial features, skeletal abnormalities, cutaneous findings and early-onset and aggressive disease of the aorta and its branches. There are multiple types of Loeys-Dietz syndrome related to pathogenic variants in TGFBR1, TGFBR2, SMAD3, TGFB2, and TGFB3. Individuals with Loeys-Dietz syndrome may be misdiagnosed as having Marfan syndrome due to shared phenotypic features and aortic root dilation. However, ectopia lentis has been an important discriminating feature, being unique to Marfan syndrome and not reported to be associated with Loeys-Dietz syndrome. We report the case of a 46-year-old woman with Loeys-Dietz syndrome type 4 due to a pathogenic variant in TGFB2 who was diagnosed with ectopia lentis at age 44. The patient underwent whole exome sequencing and no other pathogenic variants were found to explain the ectopia lentis. Our findings indicate that ectopia lentis may be an uncommon finding in Loeys-Dietz syndrome type 4 and emphasize the importance of genetic testing in familial thoracic aortic aneurysm disease.	0
Significance: Cardiovascular disorders are the most important cause of morbidity and mortality in the Western world. Monogenic developmental disorders of the heart and vessels are highly valuable to study the physiological and pathological processes in cardiovascular system homeostasis. The arterial tortuosity syndrome (ATS) is a rare, autosomal recessive connective tissue disorder showing lengthening, tortuosity, and stenosis of the large arteries, with a propensity for aneurysm formation. In histopathology, it associates with fragmentation and disorganization of elastic fibers in several tissues, including the arterial wall. ATS is caused by pathogenic variants in SLC2A10 encoding the facilitative glucose transporter (GLUT)10. Critical Issues: Although several hypotheses have been forwarded, the molecular mechanisms linking disrupted GLUT10 activity with arterial malformations are largely unknown. Recent Advances: The vascular and systemic manifestations and natural history of ATS patients have been largely delineated. GLUT10 was identified as an intracellular transporter of dehydroascorbic acid, which contributes to collagen and elastin cross-linking in the endoplasmic reticulum, redox homeostasis in the mitochondria, and global and gene-specific methylation/hydroxymethylation affecting epigenetic regulation in the nucleus. We revise here the current knowledge on ATS and the role of GLUT10 within the compartmentalization of ascorbate in physiological and diseased states. Future Directions: Centralization of clinical, treatment, and outcome data will enable better management for ATS patients. Establishment of representative animal disease models could facilitate the study of pathomechanisms underlying ATS. This might be relevant for other forms of vascular dysplasia, such as isolated aneurysm formation, hypertensive vasculopathy, and neovascularization. Antioxid. Redox Signal. 00, 000-000.	0
Population-based data on patients with MDS are scarce. Here we report the incidence and prevalence of MDS based on data from the Düsseldorf MDS Registry. Cases in the city of Düsseldorf in the study period were identified from the MDS Registry. We calculated crude, calendar-year, age- and sex-specific and European Standard Population age-standardized incidence rates as well as point prevalences per 100,000 The crude incidence rate was 4.15/100,000/year and the point prevalence per 100,000 persons of 7. We found that the incidence and prevalence of MDS was higher in men than women and increased sharply with increasing age.	1
CASE DESCRIPTION Two 12-week-old Norwegian Buhunds from a litter of 5 were evaluated because of slowly progressive cerebellar ataxia and fine head tremors. Two other females from the same pedigree had been previously evaluated for similar signs. CLINICAL FINDINGS Findings of general physical examination, CBC, and serum biochemical analysis were unremarkable for all affected puppies. Brain MRI and CSF analysis, including PCR assays for detection of Toxoplasma gondii, Neospora caninum, and canine distemper virus, were performed for 3 dogs, yielding unremarkable results. Urinary organic acid screening, enzyme analysis of fibroblasts cultured from skin biopsy specimens, and brainstem auditory-evoked response testing were performed for 2 puppies, and results were also unremarkable. TREATMENT AND OUTCOME The affected puppies were euthanized at the breeder's request, and their brains and spinal cords were submitted for histologic examination. Histopathologic findings included a markedly reduced expression of calbindin D28K and inositol triphosphate receptor 1 by Purkinje cells, with only mild signs of neuronal degeneration. Results of pedigree analysis suggested an autosomal recessive mode of inheritance. Candidate-gene analysis via mRNA sequencing for 2 of the affected puppies revealed no genetic variants that could be causally associated with the observed abnormalities. CLINICAL RELEVANCE Findings for the dogs of this report suggested the existence of a hereditary form of ataxia in Norwegian Buhunds with histologic characteristics suggestive of Purkinje cell dysfunction. The presence of hereditary ataxia in this breed must be considered both in clinical settings and for breeding strategies.	0
The decision to implant a cardiac device in a person with Alzheimer's disease or related dementia requires considering the possible trade-offs of quality of life (QOL) and quantity of life. This study measured the decision-making experience of patients with and without cognitive impairment (CI) who received a cardiac device and their family members who were involved in the decision.Semi-structured interviews and questionnaires were administered with 15 patient-family member dyads. Interviews revealed few conversations between physicians, patients and family members about the patient's cognitive status or about the benefits, risks, and long-term implications of the device for someone with CI. Participants largely stated that the decision to get the device was based on the patient's functional status at the time of the implant, and not on expectations about future functioning. Patients with CI had more regret, measured with the Decision Regret Scale (DRS), (p=0.037) and family members of patients without CI reported more decisional conflict, measured with the Decisional Conflict Scale (p=0.057).Although CI impacts life expectancy and QOL, cognitive status was largely not discussed prior to device implant. Few differences were found between the experiences of dyads that included patients with or without CI.	0
Moebius sequence is one of the rarest congenital cranial nerve abnormalities. Approximately 300 cases have been recorded in medical literature usually from single case report. Frequently characterized by either partial or complete agenesis of the VI and VII cranial nerves, Moebius sequence is also accompanied by vascular abnormalities and other alterations such as an aberrant or hypoplastic posterior fossa. We present 3 patients with Moebius sequence and their clinical and radiological features along with a discussion of their diagnostic approximations. The 3 patients (1 male and 2 females) with ages ranging from 24 days to 7 years in both outpatient and inpatient settings in a high complexity health center. Clinical and radiologic diagnosis with magnetic resonance imaging showed to be consistent with Moebius sequence. Moebius sequence initial diagnosis is based exclusively on nonunified clinical criteria, and there is an apparent genetic pattern of inheritance. Diagnostic clues include the child's inability for proper facial expressions, affectations in eye convergence, or diminished functional hearing. A radiological approach through the use of specific MRI sequences is often warranted in order to not only approximate cranial nerve abnormalities but also accompanying structural malformations.	0
The absence of septum pellucidum (ASP) is a rare disease, which affects the structure of the brain. It is either isolated or associated with various congenital brain malformations. The diagnosis of ASP can be performed by second-trimester ultrasound. When the ASP is isolated, prenatal counseling is optimistic regarding neurological outcome, but there is a 20% risk of septo-optic dysplasia in the neonate.	0
Blepharoptosis (ptosis) is a common but often overlooked sign that may serve as a sign/manifestation of other conditions, ranging from a mild and purely cosmetic presentation to a severe and occasionally progressive disorder. Ptosis may show an acute onset or may manifest as a chronic disorder. Its presentation may vary: unilateral versus bilateral, progressive versus non-progressive, isolated versus complex which occurs in association with other symptoms, and congenital versus acquired (often concomitant with neuromuscular disorders).Congenital ptosis includes the isolated type-the congenital cranial dysinnervation disorders, which are further, distinguished into different subtypes such as Horner syndrome (HS), and ptosis as a sign/manifestation of various congenital malformation syndromes.In this article, we review the primary causes of ptosis occurring in childhood, and its various clinical presentations, including a short report on selected cases observed in our institution: a classical isolated familial ptosis comprising 14 members over 5 generations, 3 sibling with isolated congenital ptosis who in addition suffered by episodes of febrile seizures, a patient with Duane retraction syndrome who presented congenital skin and hair anomalies, and a girl with HS who showed a history of congenital imperforate hymen. A flowchart outlining the congenital and acquired type of ptosis and the clinical approach to the management and treatment of children with this anomaly is reported.	0
Synovial cell sarcomas are malignant tumors originating from pluripotent mesenchymal stem cells, unlike its name. It is a common tumor in the periarticular area, accounting for 8% of all soft tissue sarcomas. Head and neck are among the rarest areas of this tumor. Synovial sarcomas of the head and neck are more aggressive than those seen in other regions and are associated with remarkable mortality and morbidity. Treatment of synovial sarcomas of the head and neck is usually extensive local excision and additional radiation and/or chemotherapy may be performed.	0
Palindromic rheumatism is a distinctive syndrome that has a long-recognized association with rheumatoid arthritis (RA). Palindromic rheumatism is characterized by intermittent flares of pain, erythema and swelling in and around the joints, which are typically severe and unpredictable. The observation that most patients with palindromic rheumatism have RA-related autoantibodies and that many eventually develop RA has led to palindromic rheumatism often being viewed as a relapsing-remitting variant of RA. However, the clinical and imaging phenotypes of palindromic rheumatism suggest important distinctions from RA and imply underlying mechanistic differences between the two conditions. Furthermore, the pattern of inflammation seen in palindromic rheumatism has interesting parallels with that seen in other groups of symptomatic individuals at risk of developing RA. In this Review, we explore the concept of palindromic rheumatism as part of the RA continuum and propose an updated disease paradigm for this unique syndrome.	0
Floating-Harbor syndrome (FHS) is a rare genetic disorder caused by heterozygous mutations in the Snf2-related CREBBP activator protein (SRCAP) gene. The syndrome is characterized by proportional short stature, delayed bone maturation, delayed speech development, and facial dysmorphism. Submucous cleft palate and cleft lip have been reported in FHS, but to our knowledge orofacial clefting in this condition has not been assessed in detail. Here, we report on a case of bilateral cleft lip in a patient with FHS confirmed by exome sequencing.	0
Pontocerebellar hypoplasia (PCH) is a group of autosomal recessive neurodegenerative disorders characterized by prenatal onset of stunted brain growth and progressive atrophy predominantly affecting cerebellum, pons and olivary nuclei, and to a lesser extent also the cerebral cortex. Six subtypes (PCH1-6) were described and genes for four types (PCH1, 2, 4 and 6) were identified. Mutations in the tRNA splicing endonuclease subunit (TSEN) genes 54, 2 and 34 are found in PCH2 and PCH4. One family with severe prenatal onset of PCH has been the only representative of PCH5 published so far, and the molecular genetic status of PCH5 has not been ascertained until now. We screened the previously reported PCH5 family for mutations in the TSEN54 gene. The PCH5 patient was found to be the result of compound heterozygosity for the common TSEN54 mutation (p.A307S) plus a novel splice site mutation. The mutations associated with PCH5 are similar to what has been reported in PCH4. Thus, PCH5, PCH4 and PCH2 represent a spectrum of clinical manifestations caused by different mutations in the TSEN genes. We, therefore, propose to classify PCH2, PCH4 and PCH5 as TSEN mutation spectrum disorders.	0
Scrub typhus is an important arthropod-borne disease causing significant acute febrile illness by infection with Orientia spp.Using a risk-based approach, this review examines current practice, the evidence base and regulatory requirements regarding matters of biosafety and biosecurity, and presents the case for reclassification from Risk Group 3 to Risk Group 2 along with recommendations for safe working practices of risk-based activities during the manipulation of Orientia spp. in the laboratory.We recommend to reclassify Orientia spp. to Risk Group 2 based on the classification for RG2 pathogens as being moderate individual risk, low community risk. We recommend that low risk activities, can be performed within a biological safety cabinet located in a Biosafety Level (BSL) 2 core laboratory using standard personal protective equipment. But when the risk assessment indicates, such as high concentration and volume, or aerosol generation, then a higher biocontainment level is warranted. For, the majority of animal activities involving Orientia spp., Animal BSL 2 (ABSL2) is recommended however where high risk activities are performed including necropsies, Animal BSL (ABSL3) is recommended.	0
Isolated left ventricular noncompaction, where broad trabeculae and deep intertrabecular recesses are observed in the left ventricular myocardium resulting from an arrest in normal embryogenesis, is a rare cardiomyopathy. We present the first report on isolated trabeculectomy and postoperative echocardiographic follow-up showing the recovery of the cardiac function for isolated left ventricular noncompaction.	0
BACKGROUND:Lissencephaly is a brain malformation characterized by smooth and thickened cerebral surface, which may result in structural epilepsy. Lissencephaly is not common in veterinary medicine. Here, we characterize the first cases of lissencephaly in four Shih Tzu dogs, including clinical presentations and findings of magnetic resonance imaging of lissencephaly and several concomitant brain malformations. CASE PRESENTATION:Early-onset acute signs of forebrain abnormalities were observed in all dogs, which were mainly cluster seizures and behavioral alterations. Based on neurological examination, the findings were consistent with symmetrical and bilateral forebrain lesions. Metabolic disorders and inflammatory diseases were excluded. Magnetic resonance imaging for three dogs showed diffuse neocortical agyria and thickened gray matter while one dog had mixed agyria and pachygyria. Other features, such as internal hydrocephalus, supracollicular fluid accumulation, and corpus callosum hypoplasia, were detected concomitantly. Antiepileptic drugs effectively controlled cluster seizures, however, sporadic isolated seizures and signs of forebrain abnormalities, such as behavioral alterations, central blindness, and strabismus persisted. CONCLUSIONS:Lissencephaly should be considered an important differential diagnosis in Shih Tzu dogs presenting with early-onset signs of forebrain abnormalities, including cluster seizures and behavioral alterations. Magnetic resonance imaging was appropriate for ante-mortem diagnosis of lissencephaly and associated cerebral anomalies.	0
BACKGROUND:Fibrolamellar carcinoma (FLC) is a rare primary liver cancer of young adults. A functional chimeric transcript resulting from the in-frame fusion of the DNAJ homolog, subfamily B, member 1 (DNAJB1), and the catalytic subunit of protein kinase A (PRKACA) genes on chromosome 19 is believed to be unique in FLC, with a possible role in pathogenesis, yet with no established therapeutic value. The objective of the current study was to understand the molecular landscape of FLC and to identify potential novel therapeutic targets. METHODS:Archival fresh, formalin-fixed, paraffin-embedded samples from patients with FLC who prospectively consented to an institutional review board-approved protocol were analyzed using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), a next-generation sequencing assay encompassing up to 468 key cancer genes. Custom targeted RNA-Seq was performed in selected patients. Demographics, treatment, and outcome data were collected prospectively. Survival outcomes were estimated and correlated with mutation and/or copy number alterations. RESULTS:A total of 33 tumor samples from 31 patients with FLC were analyzed. The median age of the patients at the time of diagnosis was 18 years and approximately 53% were women. The DNAJB1-PRKACA fusion transcript was detected in 100% of patients. In 10 of 31 patients in which MSK-IMPACT did not detect the fusion, its presence was confirmed by targeted RNA-Seq. TERT promoter mutation was the second most common, and was detected in 7 patients. The median follow up was 30 months (range, 6-153 months). The 3-year overall survival rate was 84% (95% CI, 61%-93%). CONCLUSIONS:The DNAJB1-PRKACA fusion transcript is nonspecific and nonsensitive to FLC. Its potential therapeutic value currently is under evaluation. Opportunities currently are under development for therapy that may be driven or related to the DNAJB1-PRKACA fusion transcript or any therapeutic target identified from next-generation sequencing in patients with FLC.	0
Linear porokeratosis is a rare variant of porokeratosis that most often presents in newborns and children; development of this porokeratosis variant in adulthood is far less common. We report the case of a 25-year-old female who presented with a progressive eruption on the proximal upper extremity of 6-year duration, which was ultimately diagnosed as adult-onset linear porokeratosis and safely treated with oral isotretinoin. We propose that a sporadic mutation resulting in mosaicism after birth may explain the development of linear porokeratosis in adulthood, although the exact trigger of such a somatic mutation is not known. This case also describes a unique clinical presentation, with linear porokeratosis lesions originating on the proximal extremity rather than on the more common distal extremity. This demonstrates a distinctive clinical presentation not seen in the pediatric forms of disease.	0
Consultations have been held to promote the revision of the WHO guidelines for assuring the quality and nonclinical safety evaluation of DNA vaccines adopted by the Expert Committee on Biological Standardization (ECBS) in 2005. The drivers for this revision are described, including the need for regulatory convergence highlighted by the WHO R&D Blueprint. These consultations have driven the revision to its current form, where a new guideline that includes quality, nonclinical, and clinical evaluation of plasmid DNA vaccines is being prepared for public consultation with a view to present to an upcoming ECBS. Major changes to the guidelines include streamlining the existing quality (part A) and nonclinical (part B) sections to reflect the two decades of experience, with manufacturing and control, nonclinical evaluation, and clinical testing of plasmid DNA vaccines, as a platform technology. The urgency for gaining regulatory convergence on this topic is that development of such a platform technology as DNA vaccines for routine use immunizations will prepare manufacturers and regulators across the globe in dealing with rapid development of medical countermeasures against emerging infectious diseases even in the face of an emergency setting. Two examples are described of Zika candidate vaccines that have rapidly advanced in development based on preexisting nonclinical and clinical data that precluded the need to repeat nonclinical toxicology. This report describes the progress stemming from the most recent consultation on the guidelines, including topics discussed and consensus reached.	0
A 14-year-old boy is reported with bilateral hypoplastic patellae and multiple congenital skeletal anomalies. Since this constellation of bony malformations has not been described previously, we believe this represents a new syndrome most probably of genetic etiology.	0
Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1β secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1β at baseline. Finally, both patients displayed elevated levels of inflammasome-induced cytokines in the serum. Six NLRP1 GOF mutations have previously been described to underlie 3 allelic Mendelian diseases with differing phenotypes and modes of inheritance. Our results demonstrate that an autosomal recessive, syndromic form of JRRP can be associated with an NLRP1 GOF mutation.	0
Phosphoglycerate mutase enzyme deficiency in muscle causes a metabolic myopathy (glycogen storage disease X) characterized by exertional muscle contractures, weakness, hyperCKemia, and myoglobinuria. Six different autosomal recessive variants in PGAM-M have been described thus far (Salameh et al., 2013). In this case report, we report a novel disease-causing variant. A 52-year-old African-American woman presented with exertional muscle contractures, myalgias, and weakness since childhood including an episode of rhabdomyolysis. Neurologic examination and EMG were normal. CK was mildly elevated at rest and over 20,000 U/L during her episode of rhabdomyolysis. Muscle biopsy revealed subsarcolemmal collections suggestive of tubular aggregates. Phosphoglycerate mutase activity was 8% of the reference value. PGAM-M sequencing showed compound heterozygous variants: c.233G>A, which has been found only in African-Americans with this disease, and a novel variant, c.278G>A. This case expands the genetic spectrum of phosphoglycerate mutase deficiency.	0
Carney described a disorder characterized by the presence of several uncommon tumors which were pulmonary chondromas, gastric sarcomas and extra-adrenal paragangliomas. We report a 14 year-old girl in whom multiple gastric tumors were discovered during a study of an iron deficiency anemia and was subjected to a partial gastrectomy. At 25 years of age, she developed several pulmonary chondromas and at 33 years, a mediastinal tumor with features of an extra-adrenal paraganglioma was found. At 35 years of age, a total gastrectomy was performed to remove a gastrointestinal stromal tumor with excision of peritoneal and lymph node metastasis. One year later, the patient died due to liver failure secondary to liver metastases.	0
In health, the liver is metabolically flexible over the course of the day, as it undertakes a multitude of physiological processes including the regulation of intrahepatic and systemic glucose and lipid levels. The liver is the first organ to receive insulin and through a cascade of complex metabolic processes, insulin not only plays a key role in the intrahepatic regulation of glucose and lipid metabolism, but also in the regulation of systemic glucose and lipid concentrations. Thus, when intrahepatic insulin signalling becomes aberrant then this may lead to perturbations in intrahepatic metabolic processes that have the potential to impact on metabolic health. For example, obesity is associated with intrahepatic fat accumulation (known as nonalcoholic liver disease (NAFLD)) and hyperinsulinaemia, the latter as a result of insulin hypersecretion or impaired hepatic insulin extraction. Although insulin signalling directly alters intra- and extrahepatic metabolism, the regulation of hepatic glucose and fatty acid metabolism is also indirectly driven by substrate availability. Here we discuss the direct and indirect effects of insulin on intrahepatic processes such as the synthesis of fatty acids and peripherally regulating the flux of fatty acids to the liver; processes that may play a role in the development of insulin resistance and/or intrahepatocellular triacylglycerol (IHTAG) accumulation in humans.	0
Epidermolysis bullosa simplex with mottled pigmentation is a rare subtype of epidermolysis bullosa simplex that is characterized by nonscarring blistering and reticulated hyperpigmentation. We report the first Slovenian case of a newborn with blisters, who later presented with hyperpigmented macules in the first year of life. A missense p.Pro25Leu mutation in the KRT5 gene was confirmed.	0
This case report describes the diagnostic approach to an 18-year-old woman, known with Asperger's syndrome (AS). She presented with abdominal pain, weight loss, nausea and a loss of appetite. Ultrasound and magnetic resonance imaging showed polycystic kidney disease (PKD) and agenesis of the dorsal pancreas (DPA). Genetic testing revealed a 1.5 mega-base deletion at chromosome 17q12, which included the HNF1β. She was diagnosed with 17q12 microdeletion syndrome, which could explain the presence of both DPA, PKD and AS.	0
Elastosis perforans serpiginosa (EPS) is a rare condition within the group of perforating dermatoses. It is characterized by the synthesis of anomalous elastic fibers that are eliminated through perforating channels (transepidermal elimination). It is classified into three subtypes. One of them is drug-induced by prolonged treatment with d-penicillamine. This drug is a heavy metal chelator used to treat diseases such as rheumatoid arthritis, cystinuria, and Wilson's disease. Years of treatment with d-penicillamine at high doses are required for developing EPS, with occasional slow regression after drug withdrawal. There is no established treatment for EPS, with described cases using various treatment options such as corticoids, retinoids, tazarotene, cryotherapy, imiquimod, photodynamic therapy, electrosurgery, and CO2 laser among others with inconsistent results. We present a case of EPS induced by d-penicillamine with favorable response to cyclosporine and allopurinol in a patient with a history of Wilson's disease since childhood. They maybe considered as possible therapeutic options not described so far for an entity with variable response to current treatments. We highlight the extensive involvement of the case with progression, despite the suspension of d-penicillamine and failure to previous treatments with photodynamic therapy and retinoids.	0
Background:Congenital generalized lipodystrophy (CGL) is a rare disorder characterized by the lack of adipose tissue and metabolic complications with predominantly autosomal recessive inheritance. There are 6 different genes known to cause CGL with 4 main types recognized to date, which differ by the degree of fat loss, association with mental retardation and metabolic disorders, with CGL type 1 and 2 being the most common. Twenty seven cases of СGL type 4 from Japan, Oman, UK, Turkey, Mexico, Saudi Arabia, USA were reported previously. This report details our clinical experience with the first patient from Russia with CGL type 4. Case presentation:A 36-year-old patient, who has been suffering from generalized lipoatrophy since the first months of life and myopathy and gastrointestinal dysmotility since early childhood, developed dysmenorrhea and diabetes mellitus at the age of 19, bilateral cataracts when she was only 22 y.o., osteoporosis with vitamin D deficiency and hypocalcemia at the age of 28, diabetic foot syndrome and hyperuricemia when she was 35 y.o. Sequencing of lipodystrophy candidate genes detected a novel pathogenic homozygous variant p.631G < T: p.E211X in the CAVIN1 gene, confirming the diagnosis of CGL type 4. Conclusions:In comparison with previously reported patients with CGL type 4, our patient has diabetes mellitus, vitamin D deficiency, hypocalcemia, bilateral cataracts and hyperuricemia. All these manifestations are known to be associated with other lipodystrophy syndromes, but to our knowledge it is the first time they have been reported to be associated with CGL type 4.	0
Background:Enteropathy-associated T-cell lymphoma (EATL) is a rare and aggressive type of extranodal T-cell lymphoma (TCL) arising in the gastrointestinal (GI) tract and represents 5-8% of all T-cell non-Hodgkin lymphomas (NHL) and 10-25% of primary intestinal lymphomas. Case presentation:We reported a 78-year-old woman presenting with severe hypocalcemia. Investigations confirmed vitamin D and iron deficiency as well as hypoalbuminemia. Celiac disease was suspected and confirmed, but despite intravenous calcium and magnesium supplementation and a gluten-free diet, normal electrolyte levels were never reached. Intestinal perforation was the clue to the diagnosis of enteropathy-associated T-cell lymphoma (EATL). Conclusion:Hypocalcemia can result from multiple conditions. In patients not responding to adequate supplementation, further investigations should be performed to diagnose the underlying condition.	0
Raine syndrome is a rare, autosomal recessive, osteosclerotic bone dysplasia due to pathogenic variants in FAM20C. The clinical phenotype is characterized by generalized osteosclerosis affecting all bones, cerebral calcifications, and craniofacial dysmorphism. Most cases present during the neonatal period with early lethality due to pulmonary hypoplasia and respiratory compromise while only few affected individuals have been reported to survive into adulthood. FAM20C is a ubiquitously expressed protein kinase that contains five functional domains including a catalytic domain, a binding pocket for FAM20A and three distinct N-glycosylation sites. We report a newborn infant with a history of prenatal onset fractures, generalized osteosclerosis, and craniofacial dysmorphism and early lethality. The clinical presentation was highly suggestive of Raine syndrome. A homozygous, novel missense variant in exon 5 of FAM20C (c.1007T>G; p.Met336Arg) was identified by targeted Sanger sequencing. Following in silico analysis and mapping of the variant on a three-dimensional (3D) model of FAM20C it is predicted to be deleterious and to affect N-glycosylation, protein folding, and subsequent secretion of FAM20C. In addition, we reviewed all published FAM20C mutations and observed that most pathogenic variants affect functional regions within the protein establishing evidence for an emerging genotype-phenotype correlation.	0
The mechanistic target of rapamycin (mTOR) pathway coordinates the metabolic activity of eukaryotic cells through environmental signals, including nutrients, energy, growth factors, and oxygen. In the nervous system, the mTOR pathway regulates fundamental biological processes associated with neural development and neurodegeneration. Intriguingly, genes that constitute the mTOR pathway have been found to be germline and somatic mutation from patients with various epileptic disorders. Hyperactivation of the mTOR pathway due to said mutations has garnered increasing attention as culprits of these conditions : somatic mutations, in particular, in epileptic foci have recently been identified as a major genetic cause of intractable focal epilepsy, such as focal cortical dysplasia. Meanwhile, epilepsy models with aberrant activation of the mTOR pathway have helped elucidate the role of the mTOR pathway in epileptogenesis, and evidence from epilepsy models of human mutations recapitulating the features of epileptic patients has indicated that mTOR inhibitors may be of use in treating epilepsy associated with mutations in mTOR pathway genes. Here, we review recent advances in the molecular and genetic understanding of mTOR signaling in epileptic disorders. In particular, we focus on the development of and limitations to therapies targeting the mTOR pathway to treat epileptic seizures. We also discuss future perspectives on mTOR inhibition therapies and special diagnostic methods for intractable epilepsies caused by brain somatic mutations.	0
Ciliopathies are heterogeneous genetic diseases affecting primary cilium structure and function. Meckel-Gruber (MKS) and Bardet-Biedl (BBS) syndromes are severe ciliopathies characterized by skeletal and neurodevelopment anomalies, including polydactyly, cognitive impairment, and retinal degeneration. We describe the generation and molecular characterization of human induced pluripotent stem cell (iPSC)-derived retinal sheets (RSs) from controls, and MKS (TMEM67) and BBS (BBS10) cases. MKS and BBS RSs displayed significant common alterations in the expression of hundreds of developmental genes and members of the WNT and BMP pathways. Induction of crystallin molecular chaperones was prominent in MKS and BBS RSs suggesting a stress response to misfolded proteins. Unique to MKS photoreceptors was the presence of supernumerary centrioles and cilia, and aggregation of ciliary proteins. Unique to BBS photoreceptors was the accumulation of DNA damage and activation of the mitotic spindle checkpoint. This study reveals how combining cell reprogramming, organogenesis, and next-generation sequencing enables the elucidation of mechanisms involved in human ciliopathies.	0
Vascular Ehlers-Danlos Syndrome (VEDS) is a rare autosomal dominant disorder caused by mutations in the COL3A1 or COL1A1 genes. Its mortality is secondary to sudden and spontaneous rupture of arteries or hollow organs. The genotype influences the distribution of arterial pathology with aneurysms of intra-abdominal visceral arteries being relatively uncommon. We describe the case of a young man with probable VEDS who died of a spontaneous rupture and dissection of the cystic artery. The patient initially presented with abdominal pain due to an unrecognized spontaneous perforation of the small intestine complicated by sepsis. We postulate that inflammatory mediators may have triggered the arterial rupture due to remodeling and weakening of vessel walls. The phenotype of the patient's vascular damage included bilateral spontaneous carotid-cavernous sinus fistulae and dissection with pseudoaneurysm formation of large- and medium-sized arteries, predominantly the abdominal aorta and its branches. The autopsy uncovered a long history of vascular events that may have been asymptomatic. These findings along with a positive family history supported the VEDS diagnosis. Loeys-Dietz, Marfan, and familial thoracic aortic aneurysm and dissection syndromes were ruled out based on the absence of arterial tortuosity, eye abnormalities, bone overgrowth, and the distribution of vascular damage among other features. Interestingly, microscopic examination of the hippocampus revealed a focus of neuronal heterotopia, commonly associated with epilepsy; however, the patient had no history of seizures. The natural course of VEDS involves the rupture and dissection of arteries that, if unrecognized, can lead to a rapid death after bleeding into free spaces.	0
Limited studies are available regarding the pathophysiological mechanism of acquired atrioventricular block (AVB). Matrix metalloproteinases (MMPs) and angiotensin-converting enzyme (ACE) have been implicated in the pathogenesis of arrhythmia. However, the relationship between these molecules and acquired AVB is still unclear. One hundred and two patients with documented acquired AVB and 100 controls were studied. Gene polymorphisms of the MMP1 and ACE encoding genes were screened by the gene sequencing method or polymerase chain reaction-fragment length polymorphism assay, followed by an association study. The frequencies of the MMP1 -1607 2G2G genotype and MMP1 -1607 2 G allele were significantly higher in the AVB group than that in the controls (OR = 1.933, P = 0.027 and OR = 1.684, P = 0.012, respectively). Consistently, the level of serum MMP1 was significantly greater in acquired AVB patients than that in controls (6568.9 ± 5748.6 pg/ml vs. 4730.5 ± 3377.1 pg/ml, P = 0.019). In addition, the MMP1 2G2G genotype showed a higher MMP-1 serum level than the other genotypes (1G1G/1G2G) (7048.1 ± 5683.0 pg/ml vs. 5072.4 ± 4267.6 pg/ml, P = 0.042). MMP1 1 G/2 G gene polymorphism may contribute to determining the disease susceptibility of acquired AVB by linking the MMP serum protein level.	0
Background:A large deletion in Xp22.3 can result in contiguous gene syndromes, including X-linked ichthyosis (XLI) and Kallmann syndrome (KS), presenting with short stature, chondrodysplasia punctata, intellectual disability, and strabismus. XLI and KS are caused by the deletion of STS and ANOS1, respectively. Method:Two KS patients with XLI were screened to identify possible pathogenic mutations using whole exome sequencing. The clinical characteristics, molecular genetics, treatment outcomes, and genotype-phenotype association for each patient were analyzed. Results:We identified a novel 3,923 kb deletion within the Xp22.31 region (chrX: 5810838-9733877) containing STS, ANOS1, GPR143, NLGN4X, VCX-A, PUDP, and PNPLA4 in patient 1, who presented with KS, XLI, obesity, hyperlipidemia, and strabismus. We identified a novel 5,807 kb deletion within the Xp22.31-p22.33 regions (chrX: 2700083-8507807) containing STS, ANOS1, and other 24 genes in patient 2, who presented with KS, XLI, obesity, and strabismus. No developmental delay, abnormal speech development, or autistic behavior were noticed in either patient. Conclusion:We identified two novel microdeletions in the X chromosome leading to KS and XLI. These findings contribute to the understanding of the molecular mechanisms that drive contiguous gene syndromes. Our research confirmed that the Kallmann-Ichthyosis phenotype is caused by microdeletions at the chromosome level.	0
Mesomelia-synostoses syndrome (MSS) is a rare, autosomal-dominant, syndromal osteochondrodysplasia characterized by mesomelic limb shortening, acral synostoses, and multiple congenital malformations due to a non-recurrent deletion at 8q13 that always encompasses two coding-genes, SULF1 and SLCO5A1. To date, five unrelated patients have been reported worldwide, and MMS was previously proposed to not be a genomic disorder associated with deletions recurring from non-allelic homologous recombination (NAHR) in at least two analyzed cases. We conducted targeted gene panel sequencing and subsequent array-based copy number analysis in an 11-year-old undiagnosed Japanese female patient with multiple congenital anomalies that included mesomelic limb shortening and detected a novel 590 Kb deletion at 8q13 encompassing the same gene set as reported previously, resulting in the diagnosis of MSS. Breakpoint sequences of the deleted region in our case demonstrated the first LINE-1s (L1s)-mediated unequal NAHR event utilizing two distant L1 elements as homology substrates in this disease, which may represent a novel causative mechanism of the 8q13 deletion, expanding the range of mechanisms involved in the chromosomal rearrangements responsible for MSS.	0
This study aimed to report a rare case of intermittent azoospermia and ring-like small supernumerary marker chromosomes (sSMCs). An infertile man was diagnosed with azoospermia presenting a normal male phenotype with complete masculinization. Karyotyping and polymerase chain reaction (PCR) were used to detect 16 sequence-tagged sites on the AZF subregions of the Y chromosome, and 115 candidate genes were screened for mutations. Mutations included single nucleotide variations, insertions, and deletions. Metaphase chromosomes were studied by standard trypsin-Giemsa banding; fluorescent in situ hybridization and PCR were performed to analyze specific Y chromosome regions; gene mutations were detected. Chromosomal analysis detected 117 metaphase cells; a mosaicism with marker 1 and marker 2 sSMCs in 2 metaphase cells (47, X, +mar1x2 karyotype), a mosaicism with marker 2 sSMCs in 14 metaphase cells (46, X, +mar2 karyotype), and a mosaicism with marker 1 sSMCs in 76 metaphase cells (46, X, +mar1 karyotype), coexisting with a 45,X cell line in the remaining 25 metaphase cells. PCR analysis showed the sY160 heterochromosome on the AZFc subregion was absent. Next-generation sequencing identified an asthenozoospermia-specific mutation in GAPDHS (rs2293681), and Sanger sequencing verified this mutation. This gene encodes a protein belonging to the glyceraldehyde-3-phosphate dehydrogenase family of enzymes that play an important role in carbohydrate metabolism. Like its somatic cell counterpart, this sperm-specific enzyme functions in a nicotinamide adenine dinucleotide-dependent manner to remove hydrogen and add phosphate to glyceraldehyde 3-phosphate to form 1,3-diphosphoglycerate. During spermiogenesis, this enzyme may play an important role in regulating the switch between different energy-producing pathways, and it is required for sperm motility and male fertility. A mosaic 46, X, +mar1[76]/45, X[25]/46, X, +mar2[14]/47, X, +mar1x2[2] karyotype could be the main explanation for the azoospermia/severe oligospermia, while the likely pathogenic GAPDHS intron mutation may contribute to the symptom of immotile sperms detected in the semen analysis.	0
OBJECTIVE:The objective of this study was to determine the incidence and etiology of congenital hypothyroidism (CH) in Uberaba, MG. SUBJECTS AND METHODS:From 2001 to 2010, by reviewing patient files from a public reference outpatient unit. The screening program covered 88% of live-born children. RESULTS:CH was diagnosed in 16 children, representing an incidence of 1:2,017 live-born children screened. The etiological evaluation was done in 15 children and revealed seven cases of thyroid dysgenesis, seven of dyshormonogenesis, and one case of transient hypothyroidism. One child moved away from the state before etiological investigation was carried out. CONCLUSION:We concluded that both the incidence of CH and of dyshormonogenesis as the main causes of CH were increased in the investigated region, but molecular studies are necessary for a better definition of etiology.	1
The complex anatomy of the skull and face arises from the requirement to support multiple sensory and structural functions. During embryonic development, the diverse component elements of the neuro- and viscerocranium must be generated independently and subsequently united in a manner that sustains and promotes the growth of the brain and sensory organs, while achieving a level of structural integrity necessary for the individual to become a free-living organism. While each of these individual craniofacial components is essential, the cranial and facial midline lies at a structural nexus that unites these disparately derived elements, fusing them into a whole. Defects of the craniofacial midline can have a profound impact on both form and function, manifesting in a diverse array of phenotypes and clinical entities that can be broadly defined as frontonasal dysplasias (FNDs). Recent advances in the identification of the genetic basis of FNDs along with the analysis of developmental mechanisms impacted by these mutations have dramatically altered our understanding of this complex group of conditions.	0
We report the case of a young woman who presented at age 10 years with height on the tenth centile, brachydactyly type E and mild developmental delay. Biochemistry and hormonal profiles were normal. Differential diagnoses considered included Albright hereditary osteodystrophy without hormone resistance (a.k.a pseudopseudohypoparathyroidism), 2q37 microdeletion syndrome and acrodysostosis. She had a normal karyotype and normal FISH of 2q37. Whole genome sequencing (WGS) identified a mutation in the ANKRD11 gene associated with KBG syndrome. We review the clinical features of the genetic syndromes considered, and suggest KBG syndrome be considered in patients presenting with syndromic brachydactyly type E, especially if short stature and developmental delay are also present.	0
We recently described X-linked acrogigantism (X-LAG) in sporadic cases of infantile gigantism and a few familial cases of pituitary gigantism in the context of the disorder known as familial isolated pituitary adenomas. X-LAG cases with early onset gigantism (in infants or toddlers) shared copy number gains (CNG) of the distal long arm of chromosome X (Xq26.3). In all patients described to date with Xq26.3 CNG and acro-gigantism, the only coding gene sequence shared by all chromosomal defects was that of GPR101. GPR101 is a class A, rhodopsin-like orphan guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) with no known endogenous ligand. We review what is known about GPR101, specifically its expression profile in human and animal models, the evidence supporting causation of X-LAG and possibly other roles, including its function in growth, puberty and appetite regulation, as well as efforts to identify putative ligands.	0
OBJECTIVE:To determine the relationship of myositis autoantibodies with the diagnosis and severity of idiopathic inflammatory myopathy (IIM) using the 2017 EULAR/ACR idiopathic inflammatory myopathy classification criteria and the myositis disease activity assessment tool (MDAAT). METHODS:Patients who met the new diagnostic criteria were tested for serum myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs), and then classified into different subgroups based on autoantibody positivity. Patients were also diagnosed with possible IIM, probable IIM, and definite IIM. The MDAAT was used to evaluate muscular and extramuscular disease activity. The relationships of diagnostic classification with positivity for different myositis autoantibodies were determined. RESULTS:There were 118 patients, and 81% of them had one or more myositis autoantibody. Anti-Jo-1 was the most common MSA, and anti-Ro-52 was the most common MAA. Sixteen patients (14%) had possible IIM, 36 (31%) had probable IIM, and 66 (56%) had definite IIM. MSA-positive patients were significantly more common in the definite IIM group, but MAA positivity was unrelated to diagnostic classification. Positivity for MSAs or MAAs had no correlations with muscle disease activity. Extramuscular disease activity was greater in MSA-positive than MSA-negative patients, but MAA positivity had no significant association with extramuscular disease activity. CONCLUSIONS:MSA positivity aids in the diagnosis of IIM. MSA positivity was associated with greater extramuscular disease activity. Improving the clinical application of MSAs may enhance the individualized treatment of patients with IMM. Key Points • In this paper, we explore the relationships between the myositis autoantibodies and the diagnosis and the disease activity of inflammatory myopathy. • Positive myositis-specific autoantibodies is associated with the establishment of diagnosis and higher extramuscular disease activity. • Thus, more extensive application of myositis autoantibodies maybe the key for further disease assessment and research.	0
We aimed to review the contributions by Indian researchers to the subspecialty of skeletal dysplasias (SDs). Literature search using specific keywords in PubMed was performed to retrieve all the published literature on SDs as on July 6, 2017. All published literature on SDs wherein at least one author was from an Indian institute was included. Publications were grouped into different categories based on the major emphasis of the research paper. Five hundred and forty publications in English language were retrieved and categorized into five different groups. The publications were categorized as reports based on: (i) phenotypes (n = 437), (ii) mutations (n = 51), (iii) novel genes (n = 9), (iv) therapeutic interventions (n = 31), and (v) reviews (n = 12). Most of the publications were single-patient case reports describing the clinical and radiological features of the patients affected with SDs (n = 352). We enlisted all the significant Indian contributions. We have also highlighted the reports in which Indians have contributed to discovery of new genes and phenotypes. This review highlights the substantial Indian contributions to SD research, which is poised to reach even greater heights given the size and structure of our population, technological advances, and expanding national and international collaborations.	0
This report details prominent neuropsychiatric features in one family with an ADCY5 gene mutation. ADCY5 mutations cause a variable motor phenotype, though most cases have some core involuntary movement features. The psychiatric aspects of the disorder have not been emphasised in previous publications. We discuss possible pathogenesis.	0
According to the recent report, there are 870 million people suffer from ocular diseases worldwide. The present approaches for diagnosis are morphological examination, imaging examination and immunological examination, regrettably, they lack of sensitivity and difficult to make a definite diagnosis in the early stage. Systemic biology as an effective method has been used in clinical diagnosis and treatment for diseases, especially metabolomics which is more attractive with high sensitivity and accuracy. Although previous researches had been confirmed that endogenous metabolites in the ocular matrix play a crucial role in the progress of diseases related diseases, the standard protocols and systematic summary about the biomarker researches based on ocular matrix has not been established. This review article highlights the pretreatment for ocular matrix and the new biomarkers expressed by the eye diseases, expected to promote the application of biomarkers in the diagnosis and treatment of eye diseases.	0
OBJECTIVE:Dystonia is a complex movement disorder. Research progress has been difficult, particularly in developing widely effective therapies. This is a review of the current state of knowledge, research gaps, and proposed research priorities. METHODS:The NIH convened leaders in the field for a 2-day workshop. The participants addressed the natural history of the disease, the underlying etiology, the pathophysiology, relevant research technologies, research resources, and therapeutic approaches and attempted to prioritize dystonia research recommendations. RESULTS:The heterogeneity of dystonia poses challenges to research and therapy development. Much can be learned from specific genetic subtypes, and the disorder can be conceptualized along clinical, etiology, and pathophysiology axes. Advances in research technology and pooled resources can accelerate progress. Although etiologically based therapies would be optimal, a focus on circuit abnormalities can provide a convergent common target for symptomatic therapies across dystonia subtypes. The discussions have been integrated into a comprehensive review of all aspects of dystonia. CONCLUSION:Overall research priorities include the generation and integration of high-quality phenotypic and genotypic data, reproducing key features in cellular and animal models, both of basic cellular mechanisms and phenotypes, leveraging new research technologies, and targeting circuit-level dysfunction with therapeutic interventions. Collaboration is necessary both for collection of large data sets and integration of different research methods.	0
Combining data from epidemiological studies in Friedreich's Ataxia (FRDA) and patient organization membership lists, shows that FRDA prevalence exhibits large regional differences in Europe with a prevalence gradient from west to east. Highest levels are observed in northern Spain, south of France and Ireland, lowest levels in Scandinavia and Russia. The observed distribution of FRDA in Europe co-localizes with the gradient of the chromosomal R1b marker as detected within west Europe. This gradient is either derived from Palaeolithic migrations out of the Franco-Cantabrian Ice age refuge or from Neolithic migrations entering west Europe with the advance of agriculture. FRDA prevalence may have been increased in this population anytime after its separation from the closely related R1a carrying group. East European populations with a high frequency of the R1a marker show 10 fold lower prevalence of FRDA, indicating that the FRDA mutation was present in the common ancestor and was increased in the R1b carrying group. The FRDA carrying population went through a Palaeolithic population bottleneck supporting the view that the observed FRDA distribution and potentially the R1b distribution are derived from Palaeolithic migrations out of the Franco-Cantabrian ice age refuge.	1
A pathogenic GGGCCC hexanucleotide expansion in the first intron/promoter region of the C9orf72 gene is the most common mutation associated with amyotrophic lateral sclerosis (ALS). The C9orf72 gene product forms a complex with SMCR8 (Smith-Magenis Syndrome Chromosome Region, Candidate 8) and WDR41 (WD Repeat domain 41) proteins. Recent studies have indicated roles for the complex in autophagy regulation, vesicle trafficking, and immune response in transgenic mice, however a direct connection with ALS etiology remains unclear. With the aim of increasing understanding of the multi-functional C9orf72-SMCR8-WDR41 complex, we determined by mass spectrometry analysis the proteins that directly associate with SMCR8. SMCR8 protein binds many components of the ubiquitin-proteasome system, and we demonstrate its poly-ubiquitination without obvious degradation. Evidence is also presented for localization of endogenous SMCR8 protein to cytoplasmic stress granules. However, in several cell lines we failed to reproduce previous observations that C9orf72 protein enters these granules. SMCR8 protein associates with many products of genes associated with various Mendelian neurological disorders in addition to ALS, implicating SMCR8-containing complexes in a range of neuropathologies. We reinforce previous observations that SMCR8 and C9orf72 protein levels are positively linked, and now show in vivo that SMCR8 protein levels are greatly reduced in brain tissues of C9orf72 gene expansion carrier individuals. While further study is required, these data suggest that SMCR8 protein level might prove a useful biomarker for the C9orf72 expansion in ALS.	0
Aceruloplasminemia is a rare autosomal recessive genetic disease characterized by mild microcytic anemia, diabetes, retinopathy, liver disease, and progressive neurological symptoms due to iron accumulation in pancreas, retina, liver, and brain. The disease is caused by mutations in the Ceruloplasmin (CP) gene that produce a strong reduction or absence of ceruloplasmin ferroxidase activity, leading to an impairment of iron metabolism. Most patients described so far are from Japan. Prompt diagnosis and therapy are crucial to prevent neurological complications since, once established, they are usually irreversible. Here, we describe the largest series of non-Japanese patients with aceruloplasminemia published so far, including 13 individuals from 11 families carrying 13 mutations in the CP gene (7 missense, 3 frameshifts, and 3 splicing mutations), 10 of which are novel. All missense mutations were studied by computational modeling. Clinical manifestations were heterogeneous, but anemia, often but not necessarily microcytic, was frequently the earliest one. This study confirms the clinical and genetic heterogeneity of aceruloplasminemia, a disease expected to be increasingly diagnosed in the Next-Generation Sequencing (NGS) era. Unexplained anemia with low transferrin saturation and high ferritin levels without inflammation should prompt the suspicion of aceruloplasminemia, which can be easily confirmed by low serum ceruloplasmin levels. Collaborative joint efforts are needed to better understand the pathophysiology of this potentially disabling disease.	0
OBJECTIVE:To develop imaging guidelines for the MR work-up of female genital tract congenital anomalies (FGTCA). METHODS:These guidelines were prepared based on a questionnaire sent to all members of the European Society of Urogenital Radiology (ESUR) Female Pelvic Imaging Working Group (FPI-WG), critical review of the literature and expert consensus decision. RESULTS:The returned questionnaires from 17 different institutions have shown reasonable homogeneity of practice. Recommendations with focus on patient preparation and MR protocol are proposed, as these are key to optimised examinations. Details on MR sequences and planning of uterus-orientated sequences are provided. CONCLUSIONS:The multiplanar capabilities and soft tissue resolution of MRI provide superb characterisation of the wide spectrum of findings in FGTCA. A standardised imaging protocol and method of reporting ensures that the salient features are recognised, contributing to a correct diagnosis and classification of FGTCA, associated anomalies and complications. These imaging guidelines are based on current practice among expert radiologists in the field and incorporate up to date information regarding MR protocols and essentials of recently published classification systems. KEY POINTS:• MRI allows comprehensive evaluation of female genital tract congenital anomalies, in a single examination. • A dedicated MRI protocol comprises uterus-orientated sequences and vaginal and renal evaluation. • Integration of classification systems and structured reporting helps in successful communication of the imaging findings.	0
MOMO syndrome, a condition described in three earlier patients, is a constellation of macrosomia, obesity, macrocephaly, and ocular abnormalities as the main findings. We report a 6-year-old child with these findings as well as significant developmental issues, delayed bone age, clavicular pseudoarthrosis, and straight femurs. We believe that this child should be considered as having MOMO syndrome. Careful consideration of his facial features shows some overlap with Kabuki syndrome. Description of this case may help to better elucidate the clinical features of MOMO syndrome.	0
This consensus-based guideline was developed by all relevant German pediatric medical societies. Ultrasound is the standard imaging modality for pre- and postnatal kidney cysts and should also exclude extrarenal manifestations in the abdomen and internal genital organs. MRI has selected indications. Suspicion of a cystic kidney disease should prompt consultation of a pediatric nephrologist. Prenatal management must be tailored to very different degrees of disease severity. After renal oligohydramnios, we recommend delivery in a perinatal center. Neonates should not be denied renal replacement therapy solely because of their age. Children with unilateral multicystic dysplastic kidney do not require routine further imaging or nephrectomy, but long-term nephrology follow-up (as do children with uni- or bilateral kidney hypo-/dysplasia with cysts). ARPKD (autosomal recessive polycystic kidney disease), nephronophthisis, Bardet-Biedl syndrome and HNF1B mutations cause relevant extrarenal disease and genetic testing is advisable. Children with tuberous sclerosis complex, tumor predisposition (e. g. von Hippel Lindau syndrome) or high risk of acquired kidney cysts should have regular ultrasounds. Even asymptomatic children of parents with ADPKD (autosomal dominant PKD) should be monitored for hypertension and proteinuria. Presymptomatic diagnostic ultrasound or genetic examination for ADPKD in minors should only be done after thorough counselling. Simple cysts are very rare in children and ADPKD in a parent should be excluded. Complex renal cysts require further investigation.	0
Various theories about drugs such as ACE inhibitors or angiotensin II receptor blockers (ARBs) in relation to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clinical outcomes of COVID-19 are circulating in both mainstream media and medical literature. These are based on the fact that ACE2 facilitates SARS-CoV-2 cell invasion via binding of a viral spike protein to ACE2. However, the effect of ACE inhibitors, ARBs and other drugs on ACE2 is unclear and all theories are based on conflicting evidence mainly from animal studies. Therefore, clinical evidence is urgently needed. The aim of this study is to investigate the relationship between use of these drugs on clinical outcome of patients with COVID-19. Patients will be included from several hospitals in Europe. Data will be collected in a user-friendly database (Digitalis) on an external server. Analyses will be adjusted for sex, age and presence of cardiovascular disease, hypertension and diabetes. These results will enable more rational choices for randomised controlled trials for preventive and therapeutic strategies in COVID-19.	0
We report a healthy teenager with involuntary nocturnal tongue biting resulting in recurrent tongue injury. Causes for tongue biting during sleep in children include seizures, bruxism, faciomandibular myoclonia, hypnic myoclonia, and rarely geniospasm, which has been described as a rare inherited movement disorder accompanied with chin quivering. In the absence of family history, we diagnosed our patient with sporadic geniospasm based on polysomnographic findings with good response to clonazepam. Geniospasm should be considered in the differential diagnosis of cases with unexplained tongue injury in sleep.	0
Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide.	0
Bardet-Biedl syndrome (BBS) is a clinically and genetically heterogeneous ciliopathy with several clinical features including retinitis pigmentosa, obesity, kidney dysfunction, postaxial polydactyly, behavioral dysfunction and hypogonadism with wide spectrum of additional features. With multiple phenotypes and heterogeneous distribution, it is unlikely that BBS is caused by single gene defect. We have performed clinical and genetic diagnosis of two individuals from an Indian family with classical BBS symptoms. Whole exome sequencing identified homozygous missense mutation in BBS10 gene, hemizygous missense AR and homozygous missense PDE6B mutations in the proband and affected sibling with BBS. Identification of BBS10 mutation along with AR and PDE6B gene mutation will expand the genetic and phenotypic spectrum in individuals with BBS.	0
We analyzed our two new cases of infantile-onset epilepsy with developmental delay with de novo variant in TUBB2A and review the related literatures. Our two probands were both girls with infantile-onset epilepsy and global developmental delay. Case 1 had a novel de novo heterozygous missense variant: c.728C>T [p.Pro243Leu] (NM_001069.2). Her brain magnetic resonance imaging (MRI) showed nonspecific white matter myelination delay and slightly enlarged anterior horn of lateral ventricle. Her epilepsy had been controlled by TPM monotherapy. Case 2 had a reported de novo variant c.743C>T [p.Ala248Val] (NM_001069.2). Her brain MRI showed bilateral microgyria and corpus callosum dysplasia. A total of seven TUBB2A mutations cases had been published previously in five papers, therefore, until now, there were nine patients with TUBB2A mutations. All patients had developmental delay, among them seven cases also with infantile-onset epilepsy, one case with abnormal EEG but without clinical seizures. There are six cases that have different degree of cortical dysplasia, one case with cerebellar vermis atrophy and brainstem sacsinopathy, the rest two cases have no obvious brain structural abnormalities. There was one case with variant c.1249G>A (p.D417N) that had atypical clinical presentation, including prominent progressive spastic ataxia, sensory motor axonal neuropathy, and bilateral optic macular dystrophy, but relatively mild intellectual disability, his MRI showed cerebellar atrophy, thinning of the corpus callosum and pons sacsinopathy, but no cortical malformation. The p.A248V mutation was the most common mutation occurred in three patients (3/9). The clinical phenotypes of these three patients were similar, all of them had global developmental delay with no language and corpus callosum dysplasia, two cases with epilepsy and the other one only have EEG epileptic discharges without clinical seizure, two cases with cortical dysplasia and the other one without obvious brain malformation. In brief, global developmental delay was the most common phenotype of TUBB2A mutation-related disease, most cases also had infantile-onset epilepsy and cortical dysplasia and corpus callosum dysplasia. The region between seventh and eighth alpha-helix of TUBB2A may be a "hot spot" mutation domain.	0
We report on a boy with hyperphalangism, partial syndactyly, facial anomalies, and diffuse bronchomalacia, born to a nonconsanguineous French-Canadian couple. To our knowledge, this is a hitherto undescribed syndrome.	0
OBJECTIVE:To present our data evaluating the feasibility of simultaneous cochlear implantation with resection of acoustic neuroma. METHODS:This paper describes a case series of eight adult patients with a radiologically suspected acoustic neuroma, treated at a tertiary referral centre in Newcastle, Australia, between 2012 and 2015. Patients underwent cochlear implantation concurrently with removal of an acoustic neuroma. The approach was translabyrinthine, with facial nerve monitoring and electrically evoked auditory brainstem response testing. Standard post-implant rehabilitation was employed, with three and six months' follow-up data collected. The main outcome measures were: hearing, subjective benefit of implant, operative complications and tumour recurrence. RESULTS:Eight patients underwent simultaneous cochlear implantation with resection of acoustic neuroma over a 3-year period, and had 25-63 months' follow up. There were no major complications. All patients except one gained usable hearing and were daily implant users. CONCLUSION:Simultaneous cochlear implantation with resection of acoustic neuroma has been shown to be a safe treatment option, which will be applicable in a wide range of clinical scenarios as the indications for cochlear implantation continue to expand.	0
Ring chromosomes have been described for all human chromosomes and are typically associated with physical and/or mental abnormalities resulting from a deletion of the terminal ends of both chromosome arms. This report describes the presence of a ring chromosome 9 in a 2-year-old male child associated with developmental delay. The proband manifested a severe phenotype comprising facial dysmorphism, congenital heart defects, and seizures. The child also exhibited multiple cell lines with mosaic patterns of double rings, a dicentric ring and loss of the ring associated with mitotic instability and dynamic tissue-specific mosaicism. His karyotype was 46,XY,r(9)(p22q34)[89]/46,XY,dic r(9; 9)(p22q34;p22q34)[6]/45, XY,-9[4]/47,XY,r(9),+r(9)[1]. However, the karyotypes of his parents and elder brother were normal. FISH using mBAND probe and subtelomeric probes specific for p and q arms for chromosome 9 showed no deletion in any of the regions. Chromosomal microarray analysis led to the identification of a heterozygous deletion of 15.7 Mb from 9p22.3 to 9p24.3. The probable role of the deleted genes in the manifestation of the phenotype of the proband is discussed.	0
Tissue expansion reconstruction in clinical practice has existed for over half a century. The technique was initially used for breast reconstruction but later found its use in reconstruction of excisional defects resulting from a variety of causes including surgery for post-burn/post-traumatic deformities, congenital giant naevi, skin cancer, etc. It offers an improved matching of skin colour and texture, and avoids the high infrastructure requirements of microsurgery for free flap transfers. We present a systematic literature review of 35 worldwide English language articles with representative cases of paediatric tissue expansion reconstruction of burn injuries of the head and neck. The review identified 68 children of an average age of 11.3 years. The most common burn aetiology was flame burn injury. The average area to be reconstructed was of 206 cm2 and patients went through expansion processes for an average of 99.7 days. Three articles included cases in which patients had more than one expansion session. Supportive techniques provide examples of developments in the area of tissue expansion reconstruction such as self-inflating expanders and endoscopic approaches. Further studies focussing on particular indications, age groups and anatomical locations of tissues to be expanded are required in order to improve the understanding of this technique's limitations and continue its development.	0
Mutations in the guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) gene are rare. To date, 72 cases with GMPPB gene mutations have been reported. Herein, we reported a case of a 29-year-old Chinese male presenting with limb-girdle muscular dystrophy (LGMD) who was found to have two heterozygous GMPPB mutations. The patient had a progressive limb weakness for 19 years. His parents and elder brother were healthy. On examination he had a waddling gait and absent tendon reflexes in all four limbs. Electromyography showed myogenic damage. Muscle magnetic resonance imaging (MRI) showed fatty degeneration in the bilateral medial thigh muscles. High-throughput gene panel sequencing revealed that the patient carried compound heterozygous mutations in the GMPPB gene, c.553C>T (p.R185C, maternal inheritance) and c.346C>T (p.P116S, paternal inheritance). This case provides additional information regarding the phenotypic spectrum of GMPPB mutations in the Chinese population.	0
Background: The purpose of this study was to evaluate long-term subjective outcomes of barbed reposition pharyngoplasty for obstructive sleep apnea syndrome (OSAS) treatment using a specific questionnaire, the Palate Postoperative Problem Score (PPOPS). Methods: 140 patients who underwent barbed reposition pharyngoplasty (BRP) surgery in the Morgagni Pierantoni Hospital of Forlì, Italy were enrolled in the study. Postoperative outcomes were evaluated in a short- and long-term follow-up using the PPOPS questionnaire. The average period of follow-up was 26 months. All patients received the PPOPS questionnaire by telephone in a period between April and August 2019. Results: 51% of patients complained of swallowing problems after surgery. In 91% of cases, the problem cleared up spontaneously. At the time of the interview, only 9% of patients had a residual swallowing difficult. At the time of PPOPS evaluation, rhinolalia was observed in 8% of patients, whereas nose regurgitation was present in 2% of patients. In 20% of patients, the foreign body sensation was present during follow-up. The value of apnea-hypopnea index (AHI) reduced from the preoperative value of 31.5 to the postoperative value of 11.4. Conclusions: BRP surgery proved to be an effective technique, appreciated by the majority of patients. Use of the PPOPS questionnaire has demonstrated that the BRP technique seems to ensure efficacy and lower morbidity, with few complications after surgery.	0
Lysosomal acid lipase (LAL) deficiency (LAL-D) is a lysosomal lipid storage disorder in which the accumulation of cholesteryl esters and triglycerides predominantly in hepatocytes and cells of the macrophage-monocyte system is observed. The disturbance in the synthesis and trafficking of cholesterol and other lipids (triglycerides as well as phospholipids) as well as the systemic lipoprotein dysregulation, reflects the pathophysiology of LAL-D. The aim of this study was to present the occurrence of macrophage derived structures in LAL-D patient, and to provide an overview on underlying mechanisms, as the literature about the presence of such cluster cells in LAL deficiency is sparse. We describe the case of LAL-D patient diagnosed at 3 years of age, in whom the massive macrophage accumulation resulting in the abdominal lymphadenopathy, subcutaneous papules and hepatosplenomegaly, have been observed within 4 years since diagnosis. Histopathological examination of the excised lymph nodes and subcutaneous papules revealed them to be diffusely infiltrated by lipid-overloaded histiocytes. The immunohistochemistry revealed the macrophages to be CD68-positive. This study comprises one of the first reports of accumulation of lipid-laden macrophages throughout the body in the course of LAL-D.	0
Hepatopulmonary syndrome (HPS) is a common pulmonary complication in patients with liver disease and / or portal hypertension, and is characterized by abnormal arterial oxygenation caused by intrapulmonary vascular dilatation. The pathogenesis of HPS is complex, with a low clinical early diagnosis rate and poor prognosis. HPS currently lacks effective therapeutic drugs; therefore, liver transplantation is the only fundamental treatment. This article summarizes the pathogenesis, clinical manifestations, diagnosis and treatment of HPS in order to further improve the level of clinical screening and diagnosis and treatment of HPS.	0
UBTF (upstream binding transcription factor) exists as two isoforms; UBTF1 regulates rRNA transcription by RNA polymerase 1, whereas UBTF2 regulates mRNA transcription by RNA polymerase 2. Herein, we describe 4 patients with very similar patterns of neuroregression due to recurrent de novo mutations in UBTF (GRCh37/hg19, NC_000017.10: g.42290219C > T, NM_014233.3: c.628G > A) resulting in the same amino acid change in both UBTF1 and UBTF2 (p.Glu210Lys [p.E210K]). Disease onset in our cohort was at 2.5 to 3 years and characterized by slow progression of global motor, cognitive and behavioral dysfunction. Notable early features included hypotonia with a floppy gait, high-pitched dysarthria and hyperactivity. Later features included aphasia, dystonia, and spasticity. Speech and ambulatory ability were lost by the early teens. Magnetic resonance imaging showed progressive generalized cerebral atrophy (supratentorial > infratentorial) with involvement of both gray and white matter. Patient fibroblasts showed normal levels of UBTF transcripts, increased expression of pre-rRNA and 18S rRNA, nucleolar abnormalities, markedly increased numbers of DNA breaks, defective cell-cycle progression, and apoptosis. Expression of mutant human UBTF1 in Drosophila neurons was lethal. Although no loss-of-function variants are reported in the Exome Aggregation Consortium (ExAC) database and Ubtf-/- is early embryonic lethal in mice, Ubtf+/- mice displayed only mild motor and behavioral dysfunction in adulthood. Our data underscore the importance of including UBTF E210K in the differential diagnosis of neuroregression and suggest that mainly gain-of-function mechanisms contribute to the pathogenesis of the UBTF E210K neuroregression syndrome.	0
Skeletal dysplasias are a heterogeneous group of conditions associated with various abnormalities of the skeleton. Some of them are perinatally lethal and can be diagnosed at birth. Lethality is usually due to thoracic underdevelopment and lung hypoplasia. A correct diagnosis and typing of the skeletal disorder is essential for the prognosis as is genetic counseling of the family. A retrospective review of 12 cases of clinico-radiologic diagnosis of skeletal dysplasia, leading to thoracic insufficiency, was conducted.We aimed to make differential diagnosis with special emphasis on radiological findings, and to emphasize the importance of parental counseling.	0
Oculopharyngeal muscular dystrophy (OPMD) is a relatively rare, adult-onset disorder characterised by proximal limb weakness, progressive eyelid drooping and swallowing difficulties. Preliminary research suggests there could be a link between OPMD and dementia; however, the current literature is relatively limited and inconsistent. This case study describes a 75-year-old female with OPMD, presenting to an older adults community mental health team with memory problems and word finding difficulties. A neuropsychological assessment was carried out. The results of her assessment were difficult to interpret; she demonstrated impairments in most cognitive domains tested and her presentation did not appear to reflect any typical dementia profile. It was thought she was most likely presenting with a dementia; however, the exact aetiology remains unclear. The dementia could be a result of OPMD, vascular changes or both. This report emphasises the need for further research into the possible causal link between OPMD and dementia/cognitive decline.	0
Several de novo variants in the KIF1A gene have been reported to cause a complicated form of hereditary spastic paraplegia. Additional symptoms include cognitive impairment and varying degrees of peripheral neuropathy, epilepsy, decreased visual acuity, and ataxia. We describe four patients (ages 10-18 years), focusing on their mobility and gait characteristics. Two patients were not able to walk without assistance and showed a severe abnormal gait pattern, crouch gait. At examination, severe contractures were found.In addition to describing the different phenotypes with specific attention to gait in our cases, we reviewed known KIF1A mutations and summarized their associated phenotypes.We conclude that mobility and cognition are severely affected in children with spastic paraplegia due to de novo KIF1A mutations. Deterioration in mobility is most likely due to progressive spasticity, muscle weakness, and the secondary development of severe contractures, possibly combined with an additional progressive polyneuropathy. Close follow-up and treatment of these patients are warranted.	0
The contribution of immune cells in soft tissue sarcomas (STS) is not completely known and understanding their role is very essential for employing immunotherapy strategies. Here, we show that murine fibrosarcoma-conditioned medium promoted total spleen cell proliferation but inhibited T cell responses to mitogenic and allo-antigen-mediated stimulation. This increased proliferation was found to be in B cells resulting in generation of Breg further leading to Treg population. This was found to be the same in vitro and in vivo. The phenotype of these B cells was CD19+CD81+CD27+CD25+PD-L1hi and they secreted both IL-10 and TGF-β. These tumor evoked Bregs (tBreg), when co-cultured with B depleted T cells, suppressed their proliferation in response to anti-CD3/CD28 stimulation. tBreg-induced suppression of T cell responses was not abrogated by the inhibition or neutralization of IL-10 but by the small molecule inhibitor of TGFβ Receptor type I, SB431542. While SB531542 per se was not cytotoxic to tumor cells, administration of SB431542 in tumor-bearing mice (TBM) significantly reduced the tumor burden. In addition, the treatment significantly reduced Treg cells and rescued proliferation of T cells in response to mitogen and allo-antigen. Collectively, our results identify that tumor evoked Breg cells mediate T cell immune suppression through TGFβ-mediated pathway and that targeting the Breg-Treg axis can be potentially used as an immunotherapy agent.	0
A 10-year-old female llama was presented with a continually growing mass of the left eye. It displayed exophthalmus. The nictitating membrane was hyperemic. The cornea was completely opaque, vascularised, ulcerated and covered with abnormal tissue. Deeper structures of the eye were not visible. The right eye was unaffected. The left eye was removed under general anaesthesia. On histological examination, an amelanotic melanoma was diagnosed. The cornea, sclera, vitreous body and lens could not be differentiated. Fourteen months later, the llama was presented to the clinic because of a mass in the left orbita and right-sided blindness. Because of its poor general condition, the animal was euthanised. Histopathological examination revealed recurrence of the amelanotic melanoma with metastases to the regional lymph nodes and infiltration of the optical nerve, leading to the rightsided blindness.	0
ApreciseKUre is a multi-purpose digital platform facilitating data collection, integration and analysis for patients affected by Alkaptonuria (AKU), an ultra-rare autosomal recessive genetic disease. We present an ApreciseKUre plugin, called AKUImg, dedicated to the storage and analysis of AKU histopathological slides, in order to create a Precision Medicine Ecosystem (PME), where images can be shared among registered researchers and clinicians to extend the AKU knowledge network. AKUImg includes a new set of AKU images taken from cartilage tissues acquired by means of a microscopic technique. The repository, in accordance to ethical policies, is publicly available after a registration request, to give to scientists the opportunity to study, investigate and compare such precious resources. AKUImg is also integrated with a preliminary but accurate predictive system able to discriminate the presence/absence of AKU by comparing histopatological affected/control images. The algorithm is based on a standard image processing approach, namely histogram comparison, resulting to be particularly effective in performing image classification, and constitutes a useful guide for non-AKU researchers and clinicians.	0
Capillary malformation-arteriovenous malformations (CM-AVMs) caused by a RASA-1 or EPHB4 mutation are characterized as hereditary sporadic or multifocal capillary malformations (CMs), associated with potential fast-flow vascular anomalies underlying erythema lesions. Because of the similar phenotype, CM-AVMs should be considered in the differential diagnosis of isolated CMs as well as other disorders with an erythema phenotype, such as hereditary hemorrhagic telangiectasia (HHT).Herein, we report a male patient with facial erythema. Red lesions were located in the V1 region of his left face, the V2 and V3 regions on his right side, and the nasal back. The patient was initially thought to have PWSs because of the unilateral and segmental distribution of his red facial lesions. In contrast to a previous diagnosis, we diagnosed the child with capillary malformation-arteriovenous malformation type 2 (CM-AVM2) based on a family history of erythema, the results of physical examination and ultrasound raising potential fast-flow lesions, and a genetic study revealing a germline EPHB4 mutation. This study emphasizes the importance of differential diagnosis for PWS and CM-AVM. A single clinical diagnosis can be limited, and molecular diagnosis is recommended to provide more information for the evaluation of the potential risk of fast-flow lesions underlying erythema lesions if necessary.	0
Ambras syndrome is a rare and special form of congenital hypertrichosis, characterized by dysmorphic facial features and familial pattern of inheritance. It is rarely associated with gingival hyperplasia. We report such a rare entity in a 38-year-old female patient with a history of consanguinity and positive family history.	0
Mycobacteriosis caused by non-tuberculous mycobacteria (NTM) is a rising concern in human medicine both in immunocompromised and immunocompetent patients. In cats, mycobacteriosis caused by NTM is considered mostly to be a focal or dermal infection, with disseminated disease mostly caused by Mycobacterium avium. We describe three cases of disseminated mycobacteriosis in cats, caused by Mycobacterium malmoense, Mycobacterium branderi/shimoidei and M. avium, with no identified underlying immunosuppression. In all cases, extracellular mycobacteria were seen in the pulmonary epithelium, intestinal lumen and glomerular tufts, which could affect the shedding of the organism. The present study highlights the importance of mycobacteriosis as a differential even in immunocompetent animals. Considering the close relationship of owners and pets and the potential presence of free mycobacteria in secretions, cats should be considered as a possible environmental reservoir for mycobacteria.	0
In the last two decades, an intriguing shift in the understanding of the cerebellum has led to consider the nonmotor functions of this structure. Although various aspects of perceptual and sensory processing have been linked to the cerebellar activity, whether the cerebellum is essential for binding information from different sensory modalities remains uninvestigated. Multisensory integration (MSI) appears very early in the ontogenesis and is critical in several perceptual, cognitive, and social domains. For the first time, we investigated MSI in a rare case of cerebellar agenesis without any other associated brain malformations. To this aim, we measured reaction times (RTs) after the presentation of visual, auditory, and audiovisual stimuli. A group of neurotypical age-matched individuals was used as controls. Although we observed the typical advantage of the auditory modality relative to the visual modality in our patient, a clear impairment in MSI was found. Beyond the obvious prudence necessary for inferring definitive conclusions from this single-case picture, this finding is of interest in the light of reduced MSI abilities reported in several neurodevelopmental and psychiatric disorders-such as autism, dyslexia, and schizophrenia-in which the cerebellum has been implicated.	0
Liver involvement, a common feature in childhood mitochondrial hepatopathies, particularly in the neonatal period, may manifest as neonatal acute liver failure, hepatic steatohepatitis, cholestasis, or cirrhosis with chronic liver failure of insidious onset. There are usually significant neuromuscular symptoms, multisystem involvement, and lactic acidemia. The liver disease is usually progressive and eventually fatal. Current medical therapy of mitochondrial hepatopathies is largely ineffective, and the prognosis is usually poor. The role of liver transplantation in patients with liver failure remains poorly defined because of the systemic nature of the disease that does not respond to transplantation. Several specific molecular defects (mutations in nuclear genes such as SCO1, BCS1L, POLG, DGUOK, and MPV17 and deletion or rearrangement of mitochondrial DNA) have been identified in recent years. Prospective, longitudinal multicenter studies will be needed to address the gaps in our knowledge in these rare liver diseases.	0
Combined malonic and methylmalonic aciduria (CMAMMA) is an inborn error of metabolism which has been proposed being a benign condition. However, older patients may present with neurological manifestations such as seizures, memory problems, psychiatric problems and/ or cognitive decline. In fibroblasts from CMAMMA patients we have recently demonstrated a dysregulation of energy metabolism with increased dependency on β-oxidation for energy production. Because of the inability of the brain to rely efficiently on this pathway to retrieve the required energy to a great extent, we hypothesize an alternative disease-causing mechanism that does not only include the accumulation of the metabolites malonic and methylmalonic acids. Here, we suggest a novel hypothesis on the possible pathophysiological mechanism responsible for the development of neurological symptoms in the long-run.	0
Purpose:To determine the rate of posterior capsular rupture (PCR) and assess the postoperative outcomes in patients of posterior polar cataract (PPC) undergoing phacoemulsification using a combination of "V" or "λ" nucleofractis and viscodissection. Methods:It was a retrospective study of 80 eyes of 64 patients undergoing surgery for PPC. All surgeries were performed by a single surgeon. After completion of the continuous curvilinear capsulorrhexis (CCC), controlled hydrodelineation was used to separate the endonucleus from the epinuclear shell with limited viscodissection. Phacoemulsification was then carried out by making a "V" or lambda-shaped nucleofractis with the phaco tip followed by multiple chopping of the nucleus, ensuring the integrity of the epinuclear part of the lens. The epinuclear plate was removed after viscodissection. Results:The overall rate of PCR was 7.5% (6 out of 80 eyes). Of the 6 eyes, 4 eyes had been documented to have a pre-existing posterior capsular defect on slit-lamp examination. The rate of "on table" PCR, that is, PCR occurring intraoperatively was only 2.6% (2 of 76 eyes). Nucleus drop was not encountered in any case. Overall 87.5% eyes achieved a final visual acuity of 20/40 or better with 68.75% being 20/20 or better. Of the eyes developing PCR, two-third achieved a visual acuity of 20/30 or better. Conclusion:Using a combination of surgical techniques of V groove or lambda technique for nucleofractis and removal of epinucleus by viscodissection can result in a low rate of PCR and extremely good postoperative outcomes in cases of PPC.	0
Children with hemodynamically significant congenital heart disease (CHD) are at elevated risk of morbidity and mortality due to respiratory syncytial virus (RSV) disease compared to their healthy peers. Previous studies have demonstrated lower RSV hospitalization risk among all children with CHD at 12-23 months of age versus 0-11 months of age. However, RSV hospitalization risk at 12-23 months of age by specific CHD diagnosis has not been characterized. Both case-control and cohort studies were conducted using data from the US National Inpatient Sample from 1997 to 2013 to characterize relative risk of RSV hospitalization among children 12-23 months of age with CHD. Related CHD diagnoses were combined for analysis. Hospitalizations for RSV and unspecified bronchiolitis were described by length of stay, mechanical ventilation use, mortality, and total charges. Over the 17-year period, 1,168,886 live birth hospitalizations with CHD were identified. Multiple specific CHD conditions had an elevated odds ratio or relative risk of RSV hospitalization. Mean total RSV hospitalization charges were significantly higher among children with CHD relative to those without CHD ($19,650 vs $7,939 in 2015 dollars) for this period. Compared to children without CHD, children with Ebstein's anomaly, transposition of the great arteries, aortic stenosis, heterotaxia, and aortic arch anomalies had 367-, 344-, 203-, 117- and 47-fold increased risk of inpatient RSV mortality, respectively. Unspecified bronchiolitis hospitalization odds and relative risk across CHD diagnoses were similar to those observed with RSV hospitalization; however, unspecified bronchiolitis hospitalizations were associated with shorter mean days of stay and less frequently associated with mechanical ventilation or mortality. Among children with more severe CHD diagnoses, RSV disease remains an important health risk through the second year of life. These data can help inform decisions regarding interventions to protect children with CHD from severe RSV disease during their second year of life.	0
We report on 2 similarly affected cousins with a compound imbalance resulting from a familial t(5;9)(q34;p23) and entailing both an ∼17-Mb 5q terminal duplication and an ∼12-Mb 9p terminal deletion as determined by G-banding, subtelomere FISH, and aCGH. The proband's karyotype was 46,XX,der(9)t(5;9)(q34;p23)mat.ish der(9)t(5;9)(q34;p23)(9pter-,5qter+).arr 5q34q35(163,328,000-180,629,000)×3, 9p24p23(194,000-12,664,000)×1. Her cousin had the same unbalanced karyotype inherited from his father. The clinical phenotype mainly consists of a distinct craniofacial dysmorphism featuring microcephaly, flat facies, down slanting palpebral fissures, small flat nose, long philtrum, and small mouth with thin upper lip. Additional remarkable findings were craniosynostosis of several sutures, craniolacunia and preaxial polydactyly in the proband and hypothyroidism in both subjects. The observed clinical constellation generally fits the phenotypic spectrum of the 5q distal duplication syndrome (known also as Hunter-McAlpine syndrome), except for the thyroid insufficiency which can likely be ascribed to the concurrent 9p deletion, as at least 4 other 9pter monosomic patients without chromosome 5 involvement had this hormonal disorder. The present observation further confirms the etiology of the HMS phenotype from gain of the 5q35→qter region, expands the clinical pictures of partial trisomy 5q and monosomy 9p, and provides a comprehensive list of 160 patients with 5q distal duplication.	0
OBJECTIVE: To identify the incidence and determine causes and pregnancy outcomes of hydrops fetalis at Srinagarind Hospital. STUDY DESIGN: A retrospective descriptive study. SETTING: Department of Obstetrics and Gynecology, Faculty of Medicine, Srinagarind Hospital, Khon Kaen University. MATERIAL AND METHOD: A retrospective medical record review of all pregnant women and newborns who were diagnosed with hydrops fetalis at all gestational ages and delivered at Srinagarind Hospital between 1996 and 2005. RESULTS: During the period of study, the incidence of hydrops fetalis was 1.80 per 1,000 total births (82 cases of 45,499 total births). Thirty-nine cases (47.56%) were idiopathic, 30 cases (36.58%) were Hb Bart's hydrops fetalis, and three (3.66%) cases were caused by congenital infection. The others 10 cases (12.19%) were achondrogenesis, Turner syndrome, twin-to-twin transfusion syndrome, severe anemia with unknown primary cause, cystic hygroma, multiple congenital anomalies, and Rh isoimmunization. The mortality rate of hydrops fetalis in the present series was 98.78%. One case, caused by Rh isoimmunization, survived. Maternal complications were 30 cases (36.59%) consisting of preeclampsia, preterm labor, disseminated intravascular coagulopathy, placenta previa, and postpartum hemorrhage. CONCLUSION: The incidence of hydrops fetalis was 1.80 per 1,000 total births. The common known cause was Hb Bart's hydrops fetalis. The mortality rate of hydrops fetalis in the present study was very high.	1
Introduction: Primary distal renal tubular acidosis (dRTA) is a rare genetic disorder characterized by an impaired urinary acidification process in distal nephrons that results in the production of alkaline urine. Loss of function variants in any of the three genes, ATP6V0A4, ATP6V1B1, or SLC4A1, which all play a role in normal acidification of urine by kidneys, may lead to dRTA. Objective: This study was designed to identify genetic variants underlying dRTA in Pakistani patients using whole exome sequencing, followed by confirmatory Sanger sequencing. Materials and Methods: Patients were identified following presentation with characteristic clinical features of dRTA including vomiting, dehydration, and highly alkaline urine with metabolic acidosis during the first few days of life. Whole exome sequencing and Sanger sequencing were employed for genetic analyses of the patients. In silico analyses of the identified variants were performed using web-based bioinfomatics programs. Results: Through whole exome sequencing, we identified two splice site variants (c.2257 + 1G>A and c.722 + 5G>A) in the ATP6V0A4 gene that likely underly the disease phenotype in the two families. Multiple in silico tools predicted these variants to affect the respective splice sites supporting their likely role in pathogenesis. Conclusion: The study extends the spectrum of ATP6V0A4 variants associated with dRTA and should benefit the genetic counseling and prenatal diagnosis of the affected families.	0
Localized hypertrophic neuropathy is a rare Schwann cell proliferation that usually affects single nerves from the extremities, and it is of unclear etiology in its pure form. RASopathies are a defined group of genetic diseases with overlapping clinical features, usually secondary to germline mutations in genes encoding either components or regulators of the RAS/MAPK pathway. Herein, we report an 11-year-old boy presenting with café au lait spots and right leg length discrepancy. A fascicular nerve biopsy of the tibial nerve demonstrated a Schwann cell proliferation with prominent onion-bulb formation, satisfying criteria for localized hypertrophic neuropathy. Molecular genetic analysis demonstrated identical KRAS mutations (c38_40dupGCG) in the peripheral nerve lesion and melanocytes from café au lait spots, but not in blood, supporting a diagnosis of a KRAS-mediated rasopathy with mosaicism. Immunohistochemical staining in the peripheral nerve lesion demonstrated strong pERK staining consistent with downstream MAPK pathway activation. This report suggests that at least a subset of localized hypertrophic neuropathies are bonafide, well-differentiated Schwann cell neoplasms developing through oncogenic RAS signaling, which provides new insights into the controversial entity historically known as localized hypertrophic neuropathy.	0
Tumor-associated macrophages (TAMs) constitute the main population of immune cells present in the ovarian tumor microenvironment. These cells are characterized by high plasticity and can be easily polarized by colony-stimulating factor-1, which is released by tumor cells, into an immunosuppressive M2-like phenotype. These cells are strongly implicated in both the progression and chemoresistance of ovarian cancer. The main pro-tumoral function of M2-like TAMs is the secretion of a variety of cytokines, chemokines, enzymes and exosomes that reach microRNAs, directly inducing the invasion potential and chemoresistance of ovarian cancer cells by triggering their pro-survival signaling pathways. The M2-like TAMs are also important players in the metastasis of ovarian cancer cells in the peritoneum through their assistance in spheroid formation and attachment of cancer cells to the metastatic area-the omentum. Moreover, TAMs interplay with other immune cells, such as lymphocytes, natural killer cells, and dendritic cells, to inhibit their responsiveness, resulting in the development of immunosuppression. The detrimental character of the M2-like type of TAMs in ovarian tumors has been confirmed by a number of studies, demonstrating the positive correlation between their high level in tumors and low overall survival of patients.	0
A total of 102 free-range wild boars, 170 hunting dogs, and 49 hunters from 3 Brazilian regions were sampled and tested for antibodies to eastern equine encephalitis virus (EEEV), western equine encephalitis virus, and Venezuelan equine encephalitis virus. Three of the 102 (2.9%) wild boars were positive for antibodies against EEEV by microplate serum neutralization test. Based on our data, free-range wild boars from central-western Brazil may be exposed to EEEV, and further studies are needed to evaluate the potential of incorporating serosurveys in routine arbovirus activity surveillance specifically to identify arbovirus activity foci and to help establish thresholds for epidemic transmission.	0
Miller syndrome (post-axial acrofacial dysostosis) arises from gene mutations for the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). Nonetheless, despite demonstrated loss of enzyme activity dihydroorotate (DHO) has not been shown to accumulate, but paradoxically urine orotate has been reported to be raised, confusing the metabolic diagnosis.We analysed plasma and urine from a 4-year-old male Miller syndrome patient. DHODH mutations were determined by PCR and Sanger sequencing. Analysis of DHO and orotic acid (OA) in urine, plasma and blood-spot cards was performed using liquid chromatography-tandem mass spectrometry. In vitro stability of DHO in distilled water and control urine was assessed for up to 60h. The patient received a 3-month trial of oral uridine for behavioural problems.The patient had early liver complications that are atypical of Miller syndrome. DHODH genotyping demonstrated compound-heterozygosity for frameshift and missense mutations. DHO was grossly raised in urine and plasma, and was detectable in dried spots of blood and plasma. OA was raised in urine but undetectable in plasma. DHO did not spontaneously degrade to OA. Uridine therapy did not appear to resolve behavioural problems during treatment, but it lowered plasma DHO.This case with grossly raised plasma DHO represents the first biochemical confirmation of functional DHODH deficiency. DHO was also easily detectable in dried plasma and blood spots. We concluded that DHO oxidation to OA must occur enzymatically during renal secretion. This case resolved the biochemical conundrum in previous reports of Miller syndrome patients, and opened the possibility of rapid biochemical screening.	0
Copy number increase or decrease of certain dosage-sensitive genes may cause genetic diseases with distinct phenotypes, conceptually termed genomic disorders. The most common cause of Pelizaeus-Merzbacher disease (PMD), an X-linked hypomyelinating leukodystrophy, is genomic duplication encompassing the entire proteolipid protein 1 (PLP1) gene. Although the exact molecular and cellular mechanisms underlying PLP1 duplication, which causes severe hypomyelination in the central nervous system, remain largely elusive, PLP1 overexpression is likely the fundamental cause of this devastating disease. Here, we investigated if adeno-associated virus-mediated (AAV-mediated) gene-specific suppression may serve as a potential cure for PMD by correcting quantitative aberrations in gene products. We developed an oligodendrocyte-specific Plp1 gene suppression therapy using artificial microRNA under the control of human CNP promoter in a self-complementary AAV (scAAV) platform. A single direct brain injection achieved widespread oligodendrocyte-specific Plp1 suppression in the white matter of WT mice. AAV treatment in Plp1-transgenic mice, a PLP1 duplication model, ameliorated cytoplasmic accumulation of Plp1, preserved mature oligodendrocytes from degradation, restored myelin structure and gene expression, and improved survival and neurological phenotypes. Together, our results provide evidence that AAV-mediated gene suppression therapy can serve as a potential cure for PMD resulting from PLP1 duplication and possibly for other genomic disorders.	0
Amelogenesis Imperfecta (AI) represents a group of developmental conditions, genomic in origin, which affect the structure and clinical appearance of enamel of all or nearly all the teeth in a more or less equal manner. AI is a serious problem that reduces oral health-related quality of life and causes some physiological problems. We presented here four case reports of AI (Hypoplastic and Hypomaturation) which we diagnosed on the basis of classical clinical and radiographic features.	0
Neuronal intranuclear inclusion disease (NIID) is a disease that causes leukoencephalopathy (dementia) and peripheral neuropathy (variable manifestation including bladder dysfunction). This is the first urodynamic report to show that bladder dysfunction in NIID is a combination of detrusor overactivity, decreased bladder sensation, large post-void residual, and neurogenic changes in the sphincter electromyogram. This report will help managing bladder dysfunction in NIID.	0
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most frequent inherited defect of fatty acid oxidation, with a significant morbidity and mortality in undiagnosed patients. Adverse outcomes can effectively be prevented by avoiding metabolic stress and following simple dietary measures. Therefore, prospective newborn screening (NBS) is being proposed for this condition. However, technical validation of MCADD population screening and assessment of its overall benefit require broadening of the as-yet-scarce knowledge of the MCADD genetic heterogeneity unraveled by NBS and its phenotypic consequences. Here, we describe the entire spectrum of sequence variations occurring in newborns with MCADD in the population of Bavaria, Germany, in relation to the biochemical phenotype. Among 524,287 newborns, we identified 62 cases of MCADD, indicating a birth incidence of 1 in 8,456. In all of the 57 newborns available for analysis, two alterations within the MCADD gene (ACADM) were identified. The most prevalent alteration c.985A>G (Lys329Glu) occurred in 27 (47%) newborns in the homozygous and in 18 (32%) in the heterozygous state (63% of defective alleles). The mild folding variant c.199T>C (Tyr67His) was identified in nine individuals, six of them being compound heterozygous with c.985A>G (Lys329Glu). Neither of the prevalent alterations were found in the remaining nine newborns. A total of 18 sequence variations were identified; 13 of them were novel: eight missense mutations, one nonsense mutation, two splice variants, and two small deletions. The remaining five were previously reported in MCADD patients. The ACADM heterogeneity uncovered was larger as anticipated from previous c.985A>G (Lys329Glu) carrier screening data. In addition, we show that MCADD appears to occur as frequently in Turkish newborns as in the native German population. Our data validate that biochemical NBS for MCADD is a highly specific procedure for disease detection, with the identification of a significant share of milder biochemical phenotypes, such as c.199T>C (Tyr67His). These show statistically lower acylcarnitine markers, allowing us to distinguish subgroups within the spectrum of ACADM sequence variations that correlate to biochemical MCADD disease expression. Our data might provide technical and medical guidance for decision making in the worldwide efforts to introduce MCADD population screening.	1
Semantic cognition, as described by the controlled semantic cognition (CSC) framework (Rogers et al., , Neuropsychologia, 76, 220), involves two key components: activation of coherent, generalizable concepts within a heteromodal 'hub' in combination with modality-specific features (spokes), and a constraining mechanism that manipulates and gates this knowledge to generate time- and task-appropriate behaviour. Executive-semantic goal representations, largely supported by executive regions such as frontal and parietal cortex, are thought to allow the generation of non-dominant aspects of knowledge when these are appropriate for the task or context. Semantic aphasia (SA) patients have executive-semantic deficits, and these are correlated with general executive impairment. If the CSC proposal is correct, patients with executive impairment should not only exhibit impaired semantic cognition, but should also show characteristics that align with those observed in SA. This possibility remains largely untested, as patients selected on the basis that they show executive impairment (i.e., with 'dysexecutive syndrome') have not been extensively tested on tasks tapping semantic control and have not been previously compared with SA cases. We explored conceptual processing in 12 patients showing symptoms consistent with dysexecutive syndrome (DYS) and 24 SA patients, using a range of multimodal semantic assessments which manipulated control demands. Patients with executive impairments, despite not being selected to show semantic impairments, nevertheless showed parallel patterns to SA cases. They showed strong effects of distractor strength, cues and miscues, and probe-target distance, plus minimal effects of word frequency on comprehension (unlike semantic dementia patients with degradation of conceptual knowledge). This supports a component process account of semantic cognition in which retrieval is shaped by control processes, and confirms that deficits in SA patients reflect difficulty controlling semantic retrieval.	0
Fraser syndrome (MIM#219000) is an autosomal recessive disorder, characterized by the association of cryptophthtalmos, syndactyly of the four extremities, urinary tract abnormalities and laryngo-tracheal anomalies. This condition is due to homozygous or compound heterozygous mutations in the FRAS/FREM complex genes: FRAS1, FREM2 and GRIP1. Here we report two atypical cases of Fraser syndrome due to mutations in the FRAS1 gene without cryptophthalmos. The first proband had syndactyly of three extremities, bilateral nostril coloboma, dysplastic ears with bilateral conductive hearing loss, blepharophimosis and lacrimal duct abnormalities. FRAS1 sequencing identified two pathogenic compound heterozygous variants: a nonsense variant in exon 70 and a missense variant in exon 24. The second proband had membranous syndactyly of the four extremities, left renal agenesis, laryngeal and ano-rectal malformations, dysplastic ears and bilateral conductive hearing loss. FRAS1 sequencing identified a pathogenic homozygous variant in the last exon of the gene. This first description of molecularly confirmed cases with Fraser syndrome without cryptophthalmos could contribute to further delineation of the clinical spectrum of Fraser syndrome, especially for possible phenotypically milder cases. Larger cohorts are required to try to refer the hypothesis of genotype-phenotype correlation.	0
BACKGROUND:Acrodermatitis enteropathica (AE) is a rare autosomal recessive hereditary skin disease caused by mutations in the SLC39A4 gene and is characterized by periorificial dermatitis, alopecia and diarrhoea due to insufficient zinc absorption. Only one of the three known sets of twins with AE has genetic information. This case reports the discovery of new mutation sites in rare twin patients and draws some interesting conclusions by analysing the relationship between genetic information and clinical manifestations. CASE PRESENTATION:Here, we report a pair of 16-month-old twin boys with AE exhibiting periorificial and acral erythema, scales and blisters, while subsequent laboratory examination showed normal plasma zinc and alkaline phosphatase levels. Further Sanger sequencing demonstrated that the patients were compound heterozygous for two unreported SLC39A4 mutations: a missense mutation in exon 5 (c.926G > T), which led to a substitution of the 309th amino acid residue cysteine with phenylalanine, a splice site mutation occurring in the consensus donor site of intron 5 (c.976 + 2 T > A). A family study revealed that the boys' parents were heterozygous carriers of these two mutations. CONCLUSION:We identified a new compound heterozygous mutation in Chinese twins with AE, which consisted of two previous unreported variants in exon 5 and intron 5 of SLC39A4. We propose an up-to-date review that different mutations in SLC39A4 may exhibit different AE manifestations. In conjunction with future research, our work may shed light on genotype-phenotype correlations in AE patients and provide knowledge for genetic counselling and treatment for AE patients.	0
BACKGROUND:Whole-exome sequencing (WES) has emerged as a successful diagnostic tool in molecular genetics laboratories worldwide. In this study, we aimed to find the potential genetic cause of skeletal disease, a heterogeneous disease, revealing the obvious short stature phenotype. In an Iranian family, we used solo-WES in a suspected patient to decipher the potential genetic cause(s). METHODS:A comprehensive clinical and genotyping examination was applied to suspect the disease of the patient. The solo clinical WES was exploited, and the derived data were filtered according to the standard pipelines. In order to validate the WES finding, the region harboring the candidate variant in the CTSK gene was amplified from genomic DNA and sequenced directly by Sanger sequencing. RESULTS:Sequence analysis revealed a rare novel nonsense variant, p.(Trp320*); c.905G>A, in the CTSK gene (NM_000396.3). In silico analysis shed light on the contribution of the variant to the pathogenicity of pycnodysostosis. This variant was confirmed by Sanger sequencing and further clinical examinations of the patient confirmed the disease. CONCLUSION:The present study shows a rare variant of the CTSK gene, which inherited as autosomal recessive, in an Iranian male patient with pycnodysostosis. Taken together, the novel nonsense CTSK variant meets the criteria of being likely pathogenic according to the American College of Medical Genetics and Genomics-the Association for Molecular Pathology (ACMG-AMP) variant interpretation guidelines.	0
Purpose:To report a case of non-paraneoplastic autoimmune retinopathy (npAIR) treated with intravenous immunoglobulin (IVIG). Case report:A 12-year-old boy presented with progressive visual field loss, nyctalopia, and flashing for three months. He had suffered from common cold two weeks before the onset of these symptoms. On the basis of clinical history and paraclinical findings, he was diagnosed with npAIR, and IVIG without immunosuppressive therapy was started. During the one-year follow-up period after the first course of IVIG, flashing disappeared completely. Visual acuity remained 10/10, but nyctalopia did not improve. Multimodal imaging showed no disease progression. Conclusion:Although established retinal degenerative changes seem irreversible in npAIR, IVIG may be a suitable choice to control the disease progression.	0
INTRODUCTION:Nasopharyngeal carcinoma has the highest metastatic potential of all head and neck cancers. The survival time of patients with nasopharyngeal carcinoma has improved significantly in the last decades due to the use of combination of chemotherapy and radiotherapy, as well as advances in radiotherapy techniques. However, appropriately 30% of patients with nasopharyngeal carcinoma suffer a poor prognosis, mainly due to distant metastasis. OBJECTIVE:The study aimed to identify the survival and prognostic factors in metastatic nasopharyngeal carcinoma. METHODS:A retrospective analysis was conducted in patients treated for synchronous metastatic nasopharyngeal carcinoma or metachronous metastatic nasopharyngeal carcinoma for 14 years (2003-2016). Overall survival was analyzed using the Kaplan-Meier method and compared using the log-rank test for the whole population and both groups of patients. Multivariate analysis was performed using the Cox model; p-values < 0.05 were considered to indicate statistical significance. RESULTS:One hundred and twelve patients with metastatic nasopharyngeal carcinoma were included (51 patients with metastatic nasopharyngeal carcinoma, and 61 patients with metachronous metastatic nasopharyngeal carcinoma). In the whole population, the median overall survival was 10 months (1-156 months). In the multivariate analysis, female gender, poor performance status (WHO > 1) and metachronous metastasis were independent prognostic factors. In the metastatic nasopharyngeal carcinoma patients, the median overall survival was 13 months (1-156 months). In multivariate analysis, independent prognostic factors were non-oligometastatic disease, severe (G3‒G4) chemotherapy toxicity and the lack of nasopharyngeal and metastatic site irradiation. In the metachronous metastatic nasopharyngeal carcinoma patients, the median overall survival was 7 months (1-41 months). In multivariate analysis, the poor performance status (WHO > 1) was an independent metastatic nasopharyngeal carcinoma prognostic factor. CONCLUSION:Oligometastatic patients with synchronous metastatic nasopharyngeal carcinoma had better survival. The locoregional treatment of primitive nasopharyngeal carcinoma improved survival in patients with metastatic nasopharyngeal carcinoma who responded to induction chemotherapy. Local irradiation of metastatic sites improved survival of metastatic nasopharyngeal carcinoma patients. Grade 3 or 4 chemotherapy toxicity altered survival among patients with synchronous metastatic nasopharyngeal carcinoma.	0
Nephronophthisis is an autosomal recessive cystic kidney disease and one of the most common genetic disorders causing end-stage renal disease in children. Nephronophthisis is a genetically heterogenous disorder with more than 25 identified genes. In 10%-20% of cases, there are additional features of a ciliopathy syndrome, such as retinal defects, liver fibrosis, skeletal abnormalities, and brain developmental disorders. This review provides an update of the recent advances in the clinical features and related gene mutations of nephronophthisis, and novel approaches for therapy in nephronophthisis patients may be needed.	0
Antenatal Bartter syndrome (BS) is an autosomal recessive hereditary renal tubular disorder caused by mutation in the solute carrier family 12 member 1 (SLC12A1) gene on chromosome 15q21.1. This syndrome is characterized by polyuria, hyponatremia, hypokalemic hypochloremic metabolic alkalosis, and hypercalciuria associated with increased urinary loss of electrolytes. Herein, we report a very low-birth-weight premature newborn with antenatal BS caused by a novel homozygous mutation in the SLC12A1 gene, c.596G>A (p.R199H).	0
Adrenal insufficiency is a rare, potentially life-threatening condition whose diagnosis requires a high index of suspicion. Adrenal insufficiency may be primary, secondary, or tertiary with varied etiologies. Primary insufficiency may be part of a cluster of autoimmune diseases, referred to as autoimmune polyglandular syndrome(s) (APS). We describe a case of a 15-year-old male who presents to a local emergency department complaining of fatigue, fever, abdominal pain, nausea, and vomiting for a few days with a preceding viral illness. The patient was hyponatremic and hyperkalemic with skin hyperpigmentation, raising concern for adrenal insufficiency. Laboratory workup confirmed autoimmune primary adrenal insufficiency, with subsequent laboratory studies revealing autoimmune thyroiditis and celiac disease. Concomitant Addison's and Hashimoto's diseases led to a diagnosis of APS type 2. The patient was started on steroid replacement with rapid clinical improvement.	0
Patients with Joubert syndrome 2 (JBTS2) suffer from a neurological disease manifested by psychomotor retardation, hypotonia, ataxia, nystagmus, and oculomotor apraxia and variably associated with dysmorphism, as well as retinal and renal involvement. Brain MRI results show cerebellar vermis hypoplasia and additional anomalies of the fourth ventricle, corpus callosum, and occipital cortex. The disease has previously been mapped to the centromeric region of chromosome 11. Using homozygosity mapping in 13 patients from eight Ashkenazi Jewish families, we identified a homozygous mutation, R12L, in the TMEM216 gene, in all affected individuals. Thirty individuals heterozygous for the mutation were detected among 2766 anonymous Ashkenazi Jews, indicating a carrier rate of 1:92. Given the small size of the TMEM216 gene relative to other JBTS genes, its sequence analysis is warranted in all JBTS patients, especially those who suffer from associated anomalies.	0
BACKGROUND:No standard treatment has been defined for metastatic uveal melanoma (mUM). Although clinical trials testing Nivolumab/Pembrolizumab for cutaneous melanoma did not include mUM, anti PD-1 agents are commonly used for this disease. PATIENTS AND METHODS:In this prospective observational cohort single arm study, we investigated efficacy and safety of Pembrolizumab as first-line therapy for mUM. The efficacy was evaluated in terms of progression-free survival (PFS), response rate and overall survival (OS). Toxicity was also assessed. RESULTS:Seventeen patients were enrolled. A median of 8 cycles were administered (range 2-28). Two patients achieved partial response (11.7%), 6 a disease stabilization (35.3%), whereas 9 (53%) had a progression. No complete response was observed. PFS of the overall population was 3.8 months. PFS was 9.7 months for patients with an interval higher than 5 years from diagnosis of primary tumor to metastatic disease and 2.6 months for patients with an interval lower than 5 years [p = 0.039, HR 0.2865 (95% CI 0.0869-0.9443)]. Median OS was not reached. The two responding patients were still on treatment with Pembrolizumab at the time of data analysis. Survival was 12.8 months for patients with clinical benefit, while OS for progressive patients was 3.1 months. PD-L1 expression and genomic abnormalities predictive of relapse after diagnosis of primary tumor were not associated with PFS. Toxicity was mild, without grade 3-4 side effects. CONCLUSIONS:The efficacy of Pembrolizumab does not seem particularly different when compared to other agents for mUM, but responding patients had a remarkable disease control.	0
A brother and a sister show very similar clinical features, including sparse hair in the first year of life, prominent nose, small mouth, micrognathia, high arched palate or cleft palate, crumpled upper helices, flexion limitation of the distal interphalangeal joint of the fingers, and mild developmental delay. Their clinical appearance suggests a premature aging phenotype, but is not really compatible with the hitherto known syndromes of that group. The mode of inheritance is likely autosomal recessive.	0
BACKGROUND Paraneoplastic cerebellar degeneration (PCD) is a rare condition that can present as an acute or subacute cerebellar syndrome. PCD is most commonly associated with gynecological and breast cancer, small-cell lung cancer, and classical Hodgkin's lymphoma. The symptoms of PCD can arise several months before tumor diagnosis. This report is of a case of a 44-year-old man with PCD that preceded the diagnosis of classical Hodgkin's lymphoma by 16 months. CASE REPORT A 44-year-old man was admitted to hospital with a cerebellar syndrome that was initially diagnosed as vertebrobasilar insufficiency. Eight months later, cerebral magnetic resonance imaging (MRI) findings and serum anti-Tr antibodies supported the diagnosis of PCD, but no underlying malignancy was initially found. At 16 months after the initial diagnosis of PCD, the patient developed an enlarged inguinal lymph node. Histology of the excisional lymph node biopsy confirmed the diagnosis of classic mixed cellularity Hodgkin's lymphoma, Ann Arbor stage IIA. The patient responded to four cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy. CONCLUSIONS This case illustrates that in patients who present with PCD, an associated malignancy, such as classical Hodgkin's lymphoma, may emerge several months later, which supports long-term follow-up. The presence of anti-Tr antibodies may support a diagnosis of classical Hodgkin's lymphoma in a patient with a history of PCD who develops lymphadenopathy.	0
A solitary patient with symptoms similar to those of shortlasting unilateral neuralgiform conjunctival injection and tearing (SUNCT) was first mentioned in 1978. The term SUNCT was first used in 1991. SUNCT is an acronym; the "S" signifies "Shortlasting"; the "U" symbolizes "Unilateral"; "N" stands for "Neuralgiform"; the "C" for "Conjunctival injection"; and "T" for "Tearing." The term short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms were marketed in 2004. The terminology and new view points are discussed and nosography proposal for SUNCT is presented.	0
BACKGROUND:Crusted scabies (CS) is a rare, severe and highly contagious form of scabies, which has been reported in immunosuppressed patients. A high index of suspicion and awareness of CS is essential to treat this infestation. CASE:A 13-year-old boy presented with pruritic hyperkeratotic squamous plaques located on both inner wrists, the web spaces of both his hands and his feet, and the genital area of 12 months duration. He was diagnosed with focal segmental glomerulosclerosis at the age of 5 and received a kidney transplant at the age of 9. He has been on a maintenance dose of prednisone (5 mg/d) and mycophenolate mofetil (250 mg/d) for the past 2 years. He had a contact history with a school friend with similar lesions. A skin punch biopsy demonstrated the presence of multiple mites in the stratum corneum confirming the diagnosis of CS. Ivermectin, the recommended drug of choice for crusted scabies, is not available in South Africa. The patient was commenced on topical benzoyl benzoate lotion but discontinued its use because of intolerable irritation. We subsequently prescribed the daily application of topical 5% sulfur in petrolatum to which his pruritus subsided significantly after 2 weeks with resolution of all skin lesions at the end of 8 weeks. CONCLUSION:This case is the first documented report of CS in a pediatric renal transplant patient. Our management highlights that classic formularies of magistral drugs are still effective treatment options and can be used especially when standard therapies cannot be tolerated or when optimum treatments are not available.	0
Urethral carcinoma is a rare urological cancer, accounting for only 1% of malignancies in Australia. The most common histology is transitional cell carcinoma (TCC). The majority of these cancers are treated with surgery. The main purpose of this case study is to describe a novel radiation treatment technique for treatment of this uncommon cancer. This report details organ-preserving treatment for a distal penile urethral cancer using definitive radiation therapy (RT). In May 2016 a 69-year-old male presented to Crown Princess Mary Cancer Centre (CPMCC) with a small TCC of the distal urethra. The patient was offered numerous treatment options, both radical and organ-preserving approaches, and came to a final decision of a course of radiation therapy despite the lack of randomised evidence to guide treatment in this setting. A dose of 66 Gy in 33 fractions from parallel opposed lateral beams was prescribed to the distal penile urethra. This case required an unusual approach to patient set up to allow access for accurate treatment delivery and to maintain patient comfort. The patient tolerated the full course of radiation therapy with expected skin side effects. He has maintained adequate penile function and is currently free from disease at 33 months with ongoing clinical follow-up.	0
Five distinct predominant distal myopathies have been identified with discrete clinical and genetic patterns. Miyoshi myopathy (MM; early adult-onset, type 2) is a subtype of dysferlinopathy. Furthermore, MM is the most common form of autosomal recessive distal myopathy. MM is typically characterized by muscular weakness, initially affecting the gastrocnemius or soleus muscle from the late teens or early adulthood. The present study reports a case of MM that was confirmed by pathological and immunohistochemical methods, in addition to a review of the relevant literature. A 37-year-old male patient presented with muscular weakness in the left foot. This clinical manifestation was not typical of MM, and the patient was initially diagnosed with inflammatory myopathy. He was treated with dexamethasone at a dose of 10 mg for 5 days followed by gradual tapering, following which the symptoms were alleviated; however, the pathology, immunohistochemistry and electromyography eventually confirmed the diagnosis of MM. The treatment was then terminated and the patient was discharged. The present study further supports the underlying heterogeneity in atypical MM-like phenotypes. Dysferlin protein deficiency can be identified by pathological examination. The pathology of dysferlinopathy is characterized by changes of muscular dystrophy. Inflammatory cellular infiltration is a relatively common finding in the muscle biopsies from numerous patients with dysferlinopathy. Therefore, the detection of dysferlin deficiency or marked reduction on the sarcolemma using immunohistochemical staining is important for the diagnosis of dysferlinopathy.	0
Warburg micro syndrome (WARBM) is a rare autosomal recessive disorder characterized by microcephaly, cortical dysplasia, intellectual disability, ocular abnormalities, spastic diplegia, and microgenitalia. WARBM has 4 subtypes arising from pathogenic variants in 4 genes (RAB18, RAB3GAP1, RAB3GAP2, and TBC1D20). Here, we report on a patient with a homozygous pathogenic c.665delC (p.Pro222HisfsTer30) variant in the RAB3GAP1 gene identified by whole-exome sequencing (WES) analyses. Only his father was a heterozygous carrier, and homozygosity mapping analysis of the WES data revealed large loss-of-heterozygosity regions in both arms of chromosome 2, interpreted as uniparental isodisomy. This uniparental disomy pattern could be due to paternal meiosis I nondisjunction because of the preserved heterozygosity in the pericentromeric region. This report provides novel insights, including a rare form of UPD, usage of homozygosity mapping analysis for the evaluation of isodisomy, and the first reported case of WARBM1 as a result of uniparental isodisomy.	0
BACKGROUND:Hypertension and brachydactyly syndrome (HTNB), also called Bilginturan syndrome, is a rare autosomal dominant disorder characterized by severe salt-independent hypertension, a short stature, brachydactyly, and death from stroke before the age of 50 years when untreated. The purpose of the present study was to identify a PDE3A mutation leading to HTNB associated with vertebral artery malformation in a Chinese family. METHODS:Peripheral blood samples were collected from all subjects for DNA extraction. Next-generation sequencing and Sanger sequencing were performed to identify the PDE3A mutation. A comparative overview was performed in the probands with HTNB caused by PDE3A mutations. RESULTS:Genetic analysis identified a missense mutation in PDE3A, c.1346G>A, in the proband with HTNB. This mutation, resulting in p.Gly449Asp, was located in a highly conserved domain and predicted to be damaging by different bioinformatics tools. Cosegregation analyses showed that the proband inherited the identified mutation from her father. Antihypertensive therapy was effective for the proband. Comparative overview of HTNB probands with 9 different PDE3A mutations revealed phenotypic heterogeneity. CONCLUSIONS:Genetic screening can significantly improve the diagnosis of HTNB patients at an early age. Our study not only adds to the spectrum of PDE3A mutations in the Chinese population and extends the phenotype of HTNB patients to include vertebral malformation but also improves the awareness of pathogenesis in HTNB patients. We emphasize the importance of antihypertensive treatment and long-term follow-up to prevent stroke and adverse cardiovascular events.	0
This case series describes a novel method for showing the preoperative anatomy of children with anorectal malformations using ultrasound contrast, which we have termed "contrast-enhanced colosonography (ceCS)." Six patients with anorectal malformations without a perineal fistula were studied both by fluoroscopic distal colostography and ceCS, and their results were confirmed surgically. Contrast-enhanced CS precisely showed the complex anatomic relationships in all cases. Compared to traditional fluoroscopic studies, ceCS has the benefit of no associated ionizing radiation and thus is safer for children.	0
The Ki-67 index is an established prognostic factor in gastrointestinal neuroendocrine tumors (GI-NETs) and defines tumor grade. It is currently estimated by microscopically examining tumor tissue single-immunostained (SS) for Ki-67 and counting the number of Ki-67-positive and Ki-67-negative tumor cells within a subjectively picked hot-spot. Intraobserver variability in this procedure as well as difficulty in distinguishing tumor from non-tumor cells can lead to inaccurate Ki-67 indices and possibly incorrect tumor grades. We introduce two computational tools that utilize Ki-67 and synaptophysin double-immunostained (DS) slides to improve the accuracy of Ki-67 index quantitation in GI-NETs: (1) Synaptophysin-KI-Estimator (SKIE), a pipeline automating Ki-67 index quantitation via whole-slide image (WSI) analysis and (2) deep-SKIE, a deep learner-based approach where a Ki-67 index heatmap is generated throughout the tumor. Ki-67 indices for 50 GI-NETs were quantitated using SKIE and compared with DS slide assessments by three pathologists using a microscope and a fourth pathologist via manually ticking off each cell, the latter of which was deemed the gold standard (GS). Compared to the GS, SKIE achieved a grading accuracy of 90% and substantial agreement (linear-weighted Cohen's kappa 0.62). Using DS WSIs, deep-SKIE displayed a training, validation, and testing accuracy of 98.4%, 90.9%, and 91.0%, respectively, significantly higher than using SS WSIs. Since DS slides are not standard clinical practice, we also integrated a cycle generative adversarial network into our pipeline to transform SS into DS WSIs. The proposed methods can improve accuracy and potentially save a significant amount of time if implemented into clinical practice.	0
CLINICAL CHARACTERISTICS:Fibrodysplasia ossificans progressiva (FOP) is characterized by congenital bilateral hallux valgus malformations and early-onset heterotopic ossification, which may be spontaneous or precipitated by trauma including intramuscular vaccinations. Painful, recurrent soft-tissue swellings (flare-ups) may precede localized heterotopic ossification. Heterotopic ossification can occur at any location, but typically affects regions in close proximity to the axial skeleton in the early/mild stages, before progressing to the appendicular skeleton. This can lead to restriction of movement due to ossification impacting joint mobility. Problems with swallowing and speaking can occur with ossification affecting the jaw, head, and neck, and restriction of the airway and breathing may lead to thoracic insufficiency syndrome. DIAGNOSIS/TESTING:The diagnosis of FOP is established in a proband with heterotopic ossification, hallux valgus malformations, and/or a heterozygous pathogenic variant in ACVR1 identified by molecular genetic testing. MANAGEMENT:Treatment of manifestations: Avoid intramuscular injections and arterial punctures. Fall prevention using household safety measures and ambulatory devices; use of protective headgear to reduce sequelae of falls; prompt medical attention after a fall with consideration of prophylactic corticosteroid use; management by a dietician for those with feeding difficulties; preventative dental care with precautions to avoid injury; orthodontic treatment with a practitioner with experience in FOP; consultation with an expert anesthetist with experience in FOP prior to elective anesthesia; use of singing, swimming, incentive spirometry; positive pressure ventilation when indicated for mechanical respiratory difficulties including thoracic insufficiency syndrome; anti-inflammatory medications for flare-ups; consider corticosteroids for flare-ups of the submandibular region or jaw, major joints, after significant soft-tissue trauma, and for prophylaxis prior to dental and surgical procedures. Conservative management for scoliosis. Consider bisphosphonates for corticosteroid-induced osteopenia; fractures should be managed by an expert in FOP; hearing aids and appliances for conductive hearing impairment; encourage hydration and avoidance of high protein and high salt intake to prevent renal stones; occupational therapy; warm water hydrotherapy for mobility difficulties; lower extremity elevation, DVT prophylaxis, and supportive stockings while avoiding traumatic compression for lymphedema. Psychological support. Surveillance: Annual clinical evaluation including evaluation for scoliosis with orthopedist or geneticist familiar with FOP; annual nutrition evaluation and examination for jaw ankylosis; baseline pulmonary function assessment, sleep assessment, and echocardiogram before age ten years followed by annual clinical evaluation of respiratory status; annual evaluation for fracture risk; audiology assessment every 12 to 24 months; annual assessment for signs and symptoms of nephrocalcinosis, gastrointestinal complications, and skin integrity; dental examinations every six months; Doppler ultrasound if DVT is suspected. Agents/circumstances to avoid: Avoid procedures that predispose to soft-tissue injury, including intramuscular injections such as vaccinations, arterial punctures, dental procedures, procedures related to anesthesia, biopsies, removal of heterotopic bone, and all nonemergent surgical procedures. Avoid contact sports, overstretching of soft tissues, muscle fatigue, and passive range of motion. Avoid falls. In individuals with thoracic insufficiency syndrome, avoid supplemental oxygen, which can suppress respiratory drive. GENETIC COUNSELING:FOP is inherited in an autosomal dominant manner. The majority of affected individuals represent simplex cases (i.e., a single occurrence in a family) resulting from a de novoACVR1 pathogenic variant. Rarely, an individual diagnosed with FOP has an affected parent. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to sibs is 50%. Once the ACVR1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.	0
Keutel syndrome (KS) is an autosomal recessive disease characterised by abnormal cartilage calcification, brachytelephalangism, peripheral pulmonary artery stenosis, hearing loss and midface retrusion. KS is caused by homozygous mutations in MGP, a gene encoding Matrix Gla protein which acts as a calcification inhibitor in extracellular matrix. We present two Turkish sisters (22 and 13 years old) who had abnormal cartilage calcification, brachytelephalangism, congenital heart defect and chronic asthmatic bronchitis. The patients were homozygous for c.62-2A>G (IVS1-2 A>G) mutation in MGP gene. Abnormal cartilage calcification, brachytelephalangism and midfacial retrusion are the hallmarks of KS. It was observed that the younger sister had striking cartilaginous calcifications, midfacial retrusion and severe brachytelephalangism while her older sister had mild costal cartilaginous calcifications and brachytelephalangism without any midfacial retrusion. Intrafamiliar clinical variability for KS has not been described previously.	0
A new, precise, and very selective method for increasing the impact and assessment of histidine as a biomarker for early diagnosis of histidinemia disease in new born children was developed. The method depends on the formation of the ion pair associate between histidine and the nano optical samarium tetracycline [Sm-(TC)2]+ complex doped in sol-gel matrix in a borate buffer of pH 9.2. The [Sm-(TC)2]+ complex has +I net charge which is very selective and sensitive for [histidine]- at pH 9.2 in serum and urine samples of histidinemia disease. Histidine enhances the luminescence intensity of the nano optical [Sm-(TC)2]+ complex at 645nm after excitation at 400nm, in borate buffer, pH 9.2. The remarkable enhancement of the luminescence intensity at 645nm of nano [Sm-(TC)2]+ complex doped in sol-gel matrix by various concentrations of the histidine was successfully used as an optical probe for the assessment of histidine in different serum and urine samples of new born children infected by histidinemia. The calibration plot was achieved over the concentration range 1.4×10-5 - 6.5×10-10molL-1 histidine with a correlation coefficient of (0.998) and a detection limit of (3.2×10-10molL-1). The sensitivity (98.88%) and specificity (97.41%) of histidine as a biomarker were calculated.	0
AIM:To analyse the elemental composition of dentine in primary teeth from children diagnosed with Dentinogenesis Imperfecta type II (DI) and from normal sound primary teeth using X-ray microanalysis. MATERIALS AND METHODS:X-ray microanalysis of the elements C, O, Na, Mg, P, Cl, K and Ca were performed in the dentine of five normal primary teeth and in seven primary teeth diagnosed DI. The analysis was made in a low magnification in 10 points from the enamel-dentine junction/root surface toward the pulp. The data was also evaluated with an inductive analysis. RESULTS:Lower values for C were found in DI-dentine compared with normal dentine. Na had significantly higher values in DI-dentine while Mg had significantly lower values. The inductive analysis revealed that Na and Mg were the most important elements for discriminating DI-dentine from normal dentine. CONCLUSIONS:Dentine in primary teeth from patients diagnosed with Dentinogenesis Imperfecta type II analysed with XRMA have lower values of C and Mg and higher values of O and Na compared with normal primary dentine.	0
BACKGROUND: Over activity of the fibrinolytic system (hyperfibrinolysis) occurs in cirrhosis and has been shown to correlate with the risk of variceal hemorrhage. We have developed a model for assessing acute tissue plasminogen activator (t-PA) release in vivo in man. The aims of the study were to assess the contribution of basal and stimulated t-PA release to hyperfibrinolysis in patients with alcoholic cirrhosis. METHODS: Bilateral forearm blood flow and plasma fibrinolytic variables were measured in 8 patients with biopsy proven alcohol induced cirrhosis, ascites and portal hypertension, and 8 age and sex matched healthy controls during infusion of bradykinin (100-900 pmol/min; endothelium-dependent vasodilator that releases t-PA) followed by sodium nitroprusside (SNP 2-8 microg/min; a control endothelium-independent vasodilator). RESULTS: Baseline plasma t-PA antigen concentrations were higher in patients (14+/-2 vs 9+/-1 ng/mL; p<0.05) whereas plasma plasminogen activator inhibitor type-1 (PAI-1) antigen concentrations were similar (59+/-16 vs 55+/-11 ng/mL; p=NS). This resulted in an increased t-PA activity (3+/-1 vs 0+/-0 IU/mL; p<0.05) and reduced PAI-1 activity (9+/-2 vs 21+/-2 AU/mL; p<0.05) indicating a relative deficiency of PAI-1 in patients with cirrhosis. Bradykinin and SNP caused dose-dependent vasodilatation (p<0.001 for both) that did not differ between the two groups. Bradykinin caused a similar release of t-PA antigen (p<0.05 for both) in both patients and controls (24+/-17 vs 23+/-7 ng/100 mL/min; p=ns) without affecting PAI-1 concentrations. Local t-PA activity was increased in patients following acute stimulated t-PA release (5+/-1 vs 3+/-1 IU/mL; p<0.05). SNP caused no significant change in fibrinolytic parameters. CONCLUSION: Patients with alcoholic cirrhosis have a higher basal plasma t-PA activity because of a failure to increase plasma concentrations of its inhibitor, PAI-1. Furthermore, despite releasing normal amounts of t-PA acutely, higher t-PA activity remained due to the relative deficiency of PAI-1. This suggests that the pathogenesis of hyperfibrinolysis in alcoholic cirrhosis is the result of a relative PAI-1 deficiency and enhanced basal t-PA release.	0
AIM OF THE STUDY:To define the effectiveness of ganglion Impar block in improving neuropathic pain. MATERIALS AND METHODS:Patients who had pain around the coccyx for more than three months and did not respond to conservative treatment were included in this study. All the patients underwent fluoroscopy guided transsacrococcygeal ganglion Impar block with injecting 3 mL of 0.5% bupivacaine, 2 mL saline, and 1 mL (40 mg) of methylprednisolone. Patients were evaluated with visual analog scale (VAS) for pain, Leeds assessment of neuropathic symptoms and signs scale (LANSS) for neuropathic pain, Beck depression Inventory (BDI) for mood and Short-form 12 (SF-12) for quality of life before, 1 month 3 months and 6 months after the injection. Patients' painless sitting duration was also recorded. RESULTS:A total of 28 patients were included in the final analyses. VAS and LANSS scores improved significantly throughout the follow-up periods. BDI scores also improved while SF-12 scores did not show significant changes. Painless sitting period of the patients' improved significantly. CONCLUSIONS:Ganglion Impar block is effective in decreasing the neuropathic component of chronic coccygodynia. This improves painless sitting in patients but its reflections on quality of life is not clear.	0
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a malignant primary cutaneous T-cell lymphoma that is challenging to distinguish from other neoplastic and reactive panniculitides. In an attempt to identify somatic variants in SPTCL that may be diagnostically or therapeutically relevant, we performed both exome sequencing on paired tumor-normal samples and targeted sequencing of hematolymphoid-malignancy-associated genes on tumor biopsies. Exome sequencing was performed on skin biopsies from 4 cases of skin-limited SPTCL, 1 case of peripheral T-cell lymphoma, not otherwise specified with secondary involvement of the panniculus, and 2 cases of lupus panniculitis. This approach detected between 1 and 13 high-confidence somatic variants that were predicted to result in a protein alteration per case. Variants of interest identified include 1 missense mutation in ARID1B in 1 case of SPTCL. To detect variants that were present at a lower level, we used a more sensitive targeted panel to sequence 41 hematolymphoid-malignancy-associated genes. The targeted panel was applied to 2 of the biopsies that were evaluated by whole exome sequencing as well as 5 additional biopsies. Potentially pathogenic variants were identified in KMT2D and PLCG1 among others, but no gene was altered in >2 of the 7 cases sequenced. One variant that was notably absent from the cases sequences is RHOA G17V. Further work will be required to further elucidate the genetic abnormalities that lead to this rare lymphoma.	0
The present report presents a case of dens invaginatus (DI) in a patient with 4 maxillary incisors. A 24-year-old female complained of swelling of the maxillary left anterior region and discoloration of the maxillary left anterior tooth. The maxillary left lateral incisor (tooth #22) showed pulp necrosis and a chronic apical abscess, and a periapical X-ray demonstrated DI on bilateral maxillary central and lateral incisors. All teeth responded to a vitality test, except tooth #22. The anatomic form of tooth #22 was similar to that of tooth #12, and both teeth had lingual pits. In addition, panoramic and periapical X-rays demonstrated root canal calcification, such as pulp stones, in the maxillary canines, first and second premolars, and the mandibular incisors, canines, and first premolars bilaterally. The patient underwent root canal treatment of tooth #22 and non-vital tooth bleaching. After a temporary filling material was removed, the invaginated mass was removed using ultrasonic tips under an operating microscope. The working length was established, and the root canal was enlarged up to #50 apical size and obturated with gutta-percha and AH 26 sealer using the continuous wave of condensation technique. Finally, non-vital bleaching was performed, and the access cavity was filled with composite resin.	0
Colon and rectal disorders can be functional and inflammatory. This is the second paper of a three-part series14 and will focus on the diagnosis and treatment of rectal prolapse, fecal incontinence and inflammatory bowel disease.	0
We present a case of Sandifer syndrome in a 3-year-old girl who initially presented with a history of recurrent paroxysmal head drops associated with ataxia-like symptoms and recurrent falls sustaining a clavicular fracture on one occasion. She was referred to and seen by the paediatric neurologist. Physical examination, electroencephalogram, MRI brain, electromyograph single fibre study and blood tests were all normal. With the history of hiccups and choking-like episodes she was referred to the speech and language therapist (SALT). SALT assessment did not reveal indications of swallowing impairment or possible aspiration. A barium swallow later showed small amount of reflux into the distal oesophagus. This prompted a trial of lansoprazole and she was referral to the gastroenterologists. Endoscopy and oesophageal manometry were essentially normal. However, the pH impedance study revealed severe gastro-oesophageal reflux disease. She continued with lansoprazole and dairy-free diet and her symptoms resolved.	0
Familial hepatic veno-occlusive disease with immunodeficiency (VODI, OMIM: 235550) is a rare form of combined immune deficiency (CID) that presents in the first few months of life with failure to thrive, recurrent infections, opportunistic infections along with liver impairment. Herein, we are describing a Pakistani patient with a homozygous novel variant in the SP110 gene, presenting with classical phenotypic manifestations of VODI. He presented at the age of 3 months with opportunistic infections and later developed liver failure. Conclusion. Hepatic veno-occlusive disease with immunodeficiency is a rare cause of immunodeficiency, and this is the first case report from the Middle East in a patient of Pakistani origin. It is important to have a high suspicion for this disease, in patients presenting early life with a picture of CID and deranged liver function, as the earlier the diagnosis and treatment, the better the prognosis.	0
A boy with spastic paraplegia type 2 (SPG2) due to a novel splice site mutation of PLP1 presented with progressive spasticity of lower limbs, which was first observed during late infancy, when he gained the ability to walk with support. His speech was slow and he had dysarthria. The patient showed mildly delayed intellectual development. Subtotal dysmyelination in the central nervous system was revealed, which was especially prominent in structures known to be myelinated during earlier period, whereas structures that are myelinated later were better myelinated. These findings on the brain magnetic resonance imaging were unusual for subjects with PLP1 mutations. Peaks I and II of the auditory brainstem response (ABR) were normally provoked, but peaks III-V were not clearly demarcated, similarly to the findings in Pelizaeus-Merzbacher disease. These findings of brain MRI and ABR may be characteristic for a subtype of SPG2 patients.	0
Neonatal-onset movement disorders, especially in combination with seizures, are rare and often related to mitochondrial disorders. 3-methylglutaconic aciduria (3-MGA-uria) is a marker for mitochondrial dysfunction. In particular, consistently elevated urinary excretion of 3-methylglutaconic acid is the hallmark of a small but growing group of inborn errors of metabolism (IEM) due to defective phospholipid remodeling or mitochondrial membrane-associated disorders (mutations in TAZ, SERAC1, OPA3, CLPB, DNAJC19, TMEM70, TIMM50). Exome/genome sequencing is a powerful tool for the diagnosis of the clinically and genetically heterogeneous mitochondrial disorders. Here, we report 11 individuals, of whom 2 are previously unpublished, with biallelic variants in high temperature requirement protein A2 (HTRA2) encoding a mitochondria-localized serine protease. All individuals presented a recognizable phenotype with neonatal- or infantile-onset neurodegeneration and death within the first month of life. Hallmark features were central hypopnea/apnea leading to respiratory insufficiency, seizures, neutropenia, 3-MGA-uria, tonus dysregulation, and dysphagia. Tremor, jitteriness, dystonia, and/or clonus were also common. HTRA2 defect should be grouped under the IEM with 3-MGA-uria as discriminating feature. Clinical characteristics overlap with other disorders of this group suggesting a common underlying pathomechanism. Urinary organic acid analysis is a noninvasive and inexpensive test that can guide further genetic testing in children with suggestive clinical findings.	0
The phenomenon of histiocytic/dendritic cell sarcomas arising through transformation of a pre-existed lymphoproliferative disease is called transdifferentiation. Langerhans cell sarcoma transdifferentiating from chronic lymphocytic leukemia/small lymphocytic lymphoma is extremely rare and all the reported cases were localized in lymph nodes. We present a case of concurrent cutaneous localization of Langerhans cell sarcoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, in which the chronic lymphocytic leukemia/small lymphocytic lymphoma preceded the development of the Langerhans cell sarcoma. A cutaneous lesion from a 63-year-old patient with a history of chronic lymphocytic leukemia/small lymphocytic lymphoma was biopsied. The histologic examination revealed a mixture of two cell populations infiltrating diffusely the dermis. The first was composed of small lymphoid cells with somewhat monotonous appearance and mild nuclear atypia positive for PAX5, CD79a, CD20, CD23, CD5, and LEF1. The second was composed of large cells with abundant cytoplasm and pleomorphic nuclei. These cells were positive for CD1a, CD207, and S100 protein and exhibited a high mitotic rate and a high MIB-1 immunostaining index. Therefore, two different entities, chronic lymphocytic leukemia/small lymphocytic lymphoma and Langerhans cell sarcoma, were detected in the same skin fragment. The patient died 3 years after initial diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma.	0
Hair shaft abnormalities including woolly hair are traditionally diagnosed by clinical examination and light microscopy which involves plucking of multiple hairs for examination. This is usually an inconvenient procedure especially in children. Trichoscopy may be a useful tool allowing close visualization of multiple hairs without causing discomfort to the patients. Trichoscopic findings of woolly hair have been described only in few reports. We report all of the trichoscopic findings of this rare disorder in one case which have only been reported separately in previous reports.	0
INTRODUCTION & OBJECTIVE:Developmental Dysplasia of the Hip (DDH) is one of the most common congenital skeletal anomalies. Body of evidence suggests that genetic variations in GDF5 are associated with susceptibility to DDH. DDH is a multifactorial disease and its etiology has not been entirely determined. Epigenetic changes such as DNA methylation could be linked to DDH. In this scheme, we hypothesized that changes in GDF5 DNA methylation could predispose a susceptible individual to DDH. METHODS:This study consisted of 45 DDH patients and 45 controls with healthy femoral neck cartilage, who underwent hemi-, or total arthroplasty for the femoral neck fracture. A cartilage sample of 1 cm in diameter and 1 mm in the thickness was obtained for DNA extraction. DNA was extracted and DNA methylation of GDF5 was evaluated by metabisulfite method. RESULTS:Methylation analysis showed that the promoter of GDF5 in cartilage samples from DDH patients was hypermethylated in comparison to healthy controls (p = .001). CONCLUSION:Our study showed that the methylation status of the GDF5 in patients with DDH is dysregulated. This dysregulation indicates that adjustment in the methylation might modify the expression of this gene. Since this gene plays an essential role in cartilage and bone development, thus reducing its expression can contribute to the pathogenesis of DDH. Further studies are needed to elucidate the role of GDF5 in this disease.	0
PURPOSE: To report a new sporadic case of membrane frizzled-related protein gene (MFRP)-related syndrome with a 30-month follow-up, and to review the literature for genotype-phenotype correlation in MFRP mutations. METHODS: A complete ophthalmological evaluation was performed at presentation and 30 months later, including best-corrected visual acuity test, slit lamp examination, fundoscopy, kinetic perimetry, electroretinography, fundus imaging (color, red-free, and autofluorescence), and morphologic-biometric analysis of the eye structures with an optical biometer, anterior-segment optical coherence tomography, retinal optical coherence tomography, and a confocal scanning laser for optic nerve head study. Polymerase chain reaction amplification of DNA obtained from peripheral blood lymphocytes and nucleotide sequencing of the complete MFRP gene were performed. The literature on cases of posterior microphthalmos and retinitis pigmentosa associated with MFRP mutations was reviewed. RESULTS: A 33-year-old female patient presented with posterior microphthalmos, retinitis pigmentosa with patches of retinal pigmented epithelium atrophy and scarce pigment mobilization, foveoschisis, and optic nerve drusen. After 30 months, progression of rod-cone retinal degeneration was detected. One obligate carrier showed a normal eye phenotype. A homozygote mutation in the MFRP gene (c.492delC), predicting a truncated protein (P166fsX190), was identified with genetic analysis. To our knowledge, 17 cases of MFRP-related syndrome have been reported in the literature, including the patient described herein. The phenotype of the syndrome, expressivity, and age of onset varied among and within the affected families. However, all patients sharing homozygous mutation c.492delC (alternatively named c.498delC) showed a complete phenotype (including foveoschisis and optic nerve head drusen), and similar fundus characteristics. CONCLUSIONS: A new sporadic case of MFRP-related syndrome is reported. Review of the literature showed variability in the phenotype, but initial elements of genotype-phenotype correlation have been identified in patients sharing the mutation of the present case.	0
BACKGROUND: The Björnstad syndrome, an autosomal recessive disorder associated with sensorineural hearing loss and pili torti, is caused by mutation of a previously unidentified gene on chromosome 2q34-36. METHODS: Refined genetic mapping and DNA sequencing of 44 genes between D2S2210 and D2S2244 revealed BCS1L mutations. Functional analyses elucidated how BCS1L mutations cause the Björnstad syndrome. RESULTS: BCS1L encodes a member of the AAA family of ATPases that is necessary for the assembly of complex III in the mitochondria. In addition to the Björnstad syndrome, BCS1L mutations cause complex III deficiency and the GRACILE syndrome, which in neonates are lethal conditions that have multisystem and neurologic manifestations typifying severe mitochondrial disorders. Patients with the Björnstad syndrome have mutations that alter residues involved in protein-protein interactions, whereas mutations in patients with complex III deficiency alter ATP-binding residues, as deduced from the crystal structure of a related AAA-family ATPase. Biochemical studies provided evidence to support this model: complex III deficiency mutations prevented ATP-dependent assembly of BCS1L-associated complexes. All mutant BCS1L proteins disrupted the assembly of complex III, reduced the activity of the mitochondrial electron-transport chain, and increased the production of reactive oxygen species. However, only mutations associated with complex III deficiency increased mitochondrial content, which further increased the production of reactive oxygen species. CONCLUSIONS: BCS1L mutations cause disease phenotypes ranging from highly restricted pili torti and sensorineural hearing loss (the Björnstad syndrome) to profound multisystem organ failure (complex III deficiency and the GRACILE syndrome). All BCS1L mutations disrupted the assembly of mitochondrial respirasomes (the basic unit for respiration in human mitochondria), but the clinical expression of the mutations was correlated with the production of reactive oxygen species. Mutations that cause the Björnstad syndrome illustrate the exquisite sensitivity of ear and hair tissues to mitochondrial function, particularly to the production of reactive oxygen species.	0
Extreme hyperhomocysteinemia with low cystathionine and cysteine is virtually diagnostic of cystathionine beta-synthase (CBS) deficiency since remethylation defects and hypermethioninemia due to other inborn errors cause elevated serum cystathionine. However, a pregnant CBS deficient patient was found to have elevated cystathionine in addition to elevated total homocysteine and methionine at 23 weeks of gestation and post-delivery cystathionine decreased to the lower level of normal. A second patient with cystathionine values during gestation also showed a rise from the low pre-pregnant value to massive elevation by delivery. Her infant had severe hyperhomocysteinemia in cord blood with a massive elevation of cystathionine, S-adenosylmethionine, and S-adenosylhomocysteine. The infant corrected her homocysteine value by 2 months and is not affected. This data demonstrates that the fetus when exposed to high homocysteine and methionine has increased synthesis of cystathionine which cannot be cleared because the fetus lacks cystathionine gamma-lyase, and thus cystathionine is returned to the mother's circulation. This situation could lead to a misdiagnosis of the cause of hyperhomocysteinemia in a previously undiagnosed pregnant CBS deficient patient. Assays combining homocysteine with cystathionine measurements are commonly available from commercial laboratories in the USA. The recognition of CBS deficiency vs. remethylation disorders is important in order to maximize treatment. The cord blood values revealed a major disturbance in methionine metabolism including a potential for impaired transmethylation reactions in the fetus due to the buildup of S-adenosylhomocysteine. It is possible that monitoring maternal cystathionine during gestation could provide another measure of fetal exposure to homocysteine.	0
An increased understanding of the factors affecting behavioral and neurological responses to alcohol and alcohol physiology is necessary given the tremendous toll alcohol abuse and alcoholism exert on individuals and society. At the behavioral and molecular levels, the response to alcohol appears remarkably conserved from Drosophila to humans, suggesting that investigations across model species can provide insight into the identification of common modulatory factors. We investigated the interaction between the circadian clock and alcohol sensitivity, alcohol tolerance, and alcohol absorbance in Drosophila melanogaster. Using a loss-of-righting reflex (LoRR) assay, we found that flies exhibit a circadian rhythm in the LoRR, with the greatest sensitivity to alcohol occurring from mid to late night, corresponding to the flies' inactive phase. As predicted, a circadian rhythm in the LoRR was absent in circadian mutant flies and under conditions in which the circadian clock was nonfunctional. Circadian modulation of the response to alcohol was not due to circadian regulation of alcohol absorbance. Similar to other animals, Drosophila develop acute and chronic tolerance to alcohol upon repeat exposures. We found that the circadian clock did not modulate the development of acute alcohol tolerance measured as the difference in sensitivity to alcohol between naïve and pre-exposed flies. Thus, the circadian clock modulates some, but not all, of the behavioral responses to alcohol exposure, suggesting that specific mechanisms underlie the observed circadian modulation of LoRR rather than global cellular circadian regulation. This study provides valuable new insights in our understanding of the circadian modulation of alcohol-induced behaviors that ultimately could facilitate preventative measures in combating alcohol abuse and alcoholism.	0
Australia-wide population-based surveillance for scedosporiosis identified 180 cases, with 118 (65.6%) cases of colonization and 62 (34.4%) cases of infection. Predisposing factors for isolation of Scedosporium spp. included chronic lung disease in 37.8% and malignancy in 21.7% of cases. Predictors of invasive disease (n=62) included haematological stem cell transplantation (n=7), leukaemia (n=16) and diabetes mellitus (n=8). Of 183 phenotypically-speciated isolates, 75 (41%) were Scedosporium prolificans (risk factors: haematologic cancer (n=17), neutropaenia (n=14)) and 108 (59%) had Scedosporium apiospermum/Pseudallescheria boydii phenotype [risk factor: diabetes (n=15)]. Scedosporium prolificans (p 0.01) and leukaemia (p 0.03) independently predicted death. Epidemiological and antifungal susceptibility profiles of Scedosporium aurantiacum (prevalence>or=15.8%) and S. apiospermum were similar. No patient with S. aurantiacum infection (n=6) died. This is the first description of clinical features associated with S. aurantiacum.	1
Recurrent mutations in H3F3A that encodes the histone 3 variant H3.3, lead to amino acid substitutions including K27M and G34R/V-which are observed in high-grade gliomas (HGGs) of children and young adults. Previous studies have focused on gliomas with K27M mutation, whereas gliomas with G34R/V mutation have received little attention. Herein, we report three rare cases of glioblastoma (GBM) with H3.3 G34 mutation arising from a cerebral hemisphere in two children and one young adult. All three cases showed microscopic characteristics of central nervous system primitive neuroectodermal tumor (CNS-PNET, called CNS embryonal tumors in WHO 2016 Revised 4th Edition) and presented H3.3 G34 mutation. H3.3 G34-mutant brain tumors were formerly a group of histopathologically distinct neoplasms, involved in GBM, CNS-PNET, and astroblastoma. However, recent studies have demonstrated that different CNS tumors with H3.3 G34 mutation display coherent epigenetic signatures, implying a single biological origin. Correspondingly, our three cases showed high consistency in tumor location, histological morphology, and molecular phenotype. Their immunophenotypes are similar to astrocytoma, with ATRX loss and TP53 mutation. Therefore it suggests that these H3.3 G34-mutant brain tumors may be a rare entity of HGG.	0
OBJECTIVES:Cystic adventitial disease is an extremely rare vascular disorder and is often misdiagnosed. In order to improve the knowledge and treatment of this disease, a case of venous cystic adventitial disease was reported. METHODS:The whole processes about the diagnosis and treatment of one patient with venous cystic adventitial disease was retrospectively studied. RESULTS:This case of venous cystic adventitial disease was diagnosed accurately by contrast-enhanced computed tomography and treated successfully by surgical resection. No complications were detected after one-year post-operative follow-up. CONCLUSIONS:Surgical resection is a safe and effective method for the treatment of venous CAD.	0
Purpose:The purpose of this study was to report GNAT2-associated achromatopsia (GNAT2-ACHM) natural history, characterize photoreceptor mosaic, and determine a therapeutic window for potential intervention. Methods:Patients with GNAT2-ACHM were recruited from a single tertiary referral eye center (Moorfields Eye Hospital, London, UK). We performed longitudinal clinical evaluation and ophthalmic examination, and multimodal retinal imaging, including adaptive optics scanning light ophthalmoscopy, quantitative analysis of the cone mosaic, and outer nuclear layer (ONL) thickness, including cone densities evaluation in selected regions of interest and comparison with reported healthy controls. Results:All nine subjects (3 women) presented with nystagmus, decreased visual acuity (VA), light sensitivity, and highly variable color vision loss. One patient had normal color vision and better VA. Mean VA was 1.01 (±0.10) logarithms of the minimal angle of resolution (LogMAR) at baseline, and 1.04 (±0.10) LogMAR after a mean follow-up (range) of 7.6 years (1.7-12.8 years). Optical coherence tomography showed preservation of the foveal ellipsoid zone (EZ; n = 8; 88.9%), and EZ disruption (n = 1; 11.1%). Mean ONL thickness (range, ± SD) was 84.72 µm (28.57-113.33, ± 25.46 µm) and 86.47 µm (28.57-113.33, ± 24.65 µm) for right and left eyes, respectively. Mean cone densities (±SD) at 190 µm, 350 µm, and 500 µm from the foveal center, were 48.4 (±24.6), 37.8 (±14.7), and 30.7 (±9.9), ×103 cones/mm2, respectively. Mean cone densities were lower than these of unaffected individuals, but with an overlap. Conclusions:The cone mosaic in GNAT2-ACHM is relatively well preserved, potentially allowing for a wide therapeutic window for cone-directed interventions.	0
Lichen sclerosus et atrophicus (LSA) is a chronic inflammatory dermatosis of the anogenital area, and approximately 15% to 20% of patients with LSA have extragenital lesions. Here, we report the case of an 18-year-old Korean man presenting with multiple asymptomatic punctated hypopigmented atrophic macules on the dorsa of both feet. Dermoscopic examination revealed hypopigmented atrophic macules with several central keratotic plugs. The histopathologic findings indicated LSA but were confined to the acrosyringium. Based on the clinical and histopathological findings, the patient was diagnosed with an acrosyringeal variant of extragenital LSA. The patient in this case showed a unique histopathological finding in which the typical features of LSA were confined to the acrosyringium, as well as an unusual clinical presentation of non-coalescing atrophic punctate macules on the dorsum of the feet.	0
BACKGROUND:Polydactyly is one of the most common congenital hand/foot malformations in humans. Mutations in GLI3 have been reported to cause syndromic and non-syndromic forms of preaxial and postaxial polydactylies. CASE PRESENTATION:The patient was a 2-year-old boy who underwent surgery in our hospital. The right hand and left foot of the patient were labelled as postaxial polydactyly type B, and there was cutaneous webbing between the 3rd and 4th fingers of the left hand. We identified a novel c. 1622C > T variant in GLI3 leading to an isolated postaxial synpolydactyly. CONCLUSIONS:The patient carries a novel autosomal dominant heterozygous missense mutation. This mutation c.1622C > T;p.(Thr541Met) in the GLI3 gene may affect the normal function of the zinc finger domain (ZFD) in a different way. However, it seems that more research is needed to determine the exact effects of this mutation.	0
Sclerosing bone disorders are uncommon diseases and represent a diagnostic challenge. Osteocondensation is a bone alteration, involving both acquired and hereditary conditions. Multiple diaphyseal sclerosis (Ribbing disease) is an inherited condition. It is characterized by excessive proliferation of endosteal and periosteal osseous tissue at the diaphyses of long bones, especially of tibias and femurs. The conventional radiology depicts cortical thickening of diaphyses of long bones while bone scintigraphy shows characteristically an abnormal tracer concentration in the involved diaphyses. The magnetic resonance imaging (MRI) examination confirms the presence of sclerosis and reveals bone marrow edema in the diaphyses of the afflicted bones. Due to the lack of knowledge of the pathophysiology, the treatment is empirical with glucocorticoids or bisphosphonates. Concerning bisphosphonates, the literature reports are conflicting. We report the case of a patient that showed lack of response to intravenous neridronate within 1 year of treatment, both in terms of pain and persistence of bone marrow edema at MRI.	0
Porphyrias are rare diseases caused by altered haem synthesis leading to the accumulation of different haem intermediates. Neurovisceral attacks may occur in acute porphyrias, while photosensitivity is the presenting symptom in cutaneous porphyrias. We present here an overview of symptoms and a flowchart for the diagnosis of cutaneous porphyrias, with recommendations for monitoring and an update of treatment options. From the Danish Porphyria Register, we present the incidences and approximate prevalences of cutaneous porphyrias within the last 25 years. A total of 650 patients with porphyria cutanea tarda were identified, 73 with erythropoietic protoporphyria, 9 with variegate porphyria, 4 with hereditary coproporphyria and one with congenital erythropoietic porphyria. The total incidence of all porphyrias was ~0.52/100,000 per year.	1
Background: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease. The clinical manifestations of NIID are complex and easily misdiagnosed. Based on the current knowledge of this disease, it is usually chronic, with almost no acute cases. Stroke-like disease is an extremely rare type of NIID. Case Presentation: A 61-year-old woman was admitted to our hospital with sudden left limb weakness. Diffusion magnetic resonance imaging (MRI) demonstrated high signal intensity in the skin-medullary junction area. Tissue pathology showed eosinophilic inclusions in the nuclei of the sweat gland cells and fat cells of the skin. Subsequent genetic analysis of the fragile X chromosome mental retardation gene 1 (FMR1) gene showed that the CGG repeat number was in the normal range, excluding fragile X-related tremor/ataxia syndrome (FXTAS). After 3 weeks of hospitalization, the patient's condition improved, and the left limb muscle strength recovered. Her symptoms were almost completely diminished after 3 months. Conclusion: This case demonstrates the strong clinical heterogeneity of NIID. NIID can manifest as acute hemiplegia and a stroke-like attack. This case study provides new information for the diagnosis of NIID and the classification of the clinical characteristics.	0
Despite the contribution of national registries and population-based reports, data concerning the epidemiology of acromegaly is scanty. In addition, the role of the environmental context has not been investigated.Epidemiology of acromegaly was studied in the province of Messina (Sicily, Italy), focusing on the influence of environmental factors.Four zones, characterized by different degrees of exposition to environmental toxins due to industrial pollution, were identified in the province: area A (76,338 inhabitants), area B (287,328 inhabitants), area C (243,381 inhabitants), and area D (47,554 inhabitants) at low, middle-low, middle, and high industrial density respectively. We identified all acromegalics who were born and resided in the province of Messina, among patients either referred to our endocrine unit or referred elsewhere but recorded in the archives of the provincial healthcare agency.In the province of Messina, we found 64 patients (2 in area A, 24 in area B, 28 in area C, and 10 in area D). Macroadenomas were 60%, the male/female ratio was 1, and mean age at diagnosis (±s.e.m.) was 45.4±1.6 years. Overall, prevalence was 97 c.p.m. in the province (26 c.p.m. in area A, 84 c.p.m. in area B, 115 c.p.m. in area C, and 210 c.p.m. in area D). Risk ratio (RR), calculated in every area assuming area A as a reference, showed an increased risk of developing acromegaly in people residing in area D (RR=8.03; P<0.0014).This study confirms the prevalence of acromegaly reported recently. The increased risk of developing this disease in area D suggests that the pathogenetic role of environmental context needs to be better evaluated.	1
Multiple myeloma is a rare malignancy that exhibits a wide range of possible clinical presentations. In recent years, with the advent of stem cell transplantation, the prognosis of patients with multiple myeloma has been increasing. We searched the literature for reports of atypical myeloma presentations to aid clinicians in formulating differential diagnoses and to increase the number of cases diagnosed early. There have been a number of reports of early ocular symptoms, including, but not limited to, proptosis, optic neuropathy, vision loss, retinal hemorrhage, and detachment. Neurological presentations included cranial nerve palsies, vertigo related to cerebellar involvement, and diabetes insipidus related to pituitary involvement. Among gastrointestinal manifestations, there are a number of reports of multiple myeloma presenting as acute and chronic pancreatitis. Mesenteric ischemia due to amyloidosis, acute abdomen, and hepatosplenomegaly were also among reported presentations. When it comes to renal involvement, while acute renal failure and proteinuria are typical, there are reports of patients presenting with both nephritic and nephrotic forms of glomerular disease, as well as end-stage renal disease requiring dialysis. We believe that it is essential for clinicians to keep reporting atypical multiple myeloma presentations and consider it as a possible diagnosis in a patient with serious, atypical symptoms.	0
BACKGROUND:The aim of this study was to investigate the histopathological findings in kidney biopsies in children with atypical hemolytic uremic syndrome (aHUS) and to determine whether specific pathological findings in aHUS have a prognostic value. METHODS:Renal biopsy specimens of 29 patients who were recorded in the national Turkish aHUS registry database were available for review. Histopathological findings were compared with the clinical and laboratory features at the presentation and the final outcome. RESULTS:The mean age at presentation and follow-up period was 4.9 ± 3.9 and 3.9 ± 3.0 years, respectively. The median time interval from the first symptom to biopsy was 10 days. Vascular thrombosis and interstitial fibrosis were significantly related to chronic kidney disease (CKD) requiring dialysis or kidney transplantation during follow-up (5.6-fold, for both). Glomerular necrosis, cortical necrosis, and glomerular sclerosis were markedly associated with CKD without dialysis (6.2-fold, 13.3-fold, and 8.8-fold, respectively). However, presence of endothelial swelling, subendothelial widening, and fragmented erythrocytes was found to be correlated with a favorable final outcome. CONCLUSIONS:Presence of vascular thrombosis, cortical necrosis, and glomerular sclerosis in histopathological evaluation correlated with developing CKD. Chronic changes in the interstitial compartment were also related to poor prognosis, a finding that has been shown for the first time in pediatric aHUS cases.	0
Modifications to diagnostic criteria and introduction of genetic testing have likely affected the pattern and timing of Rett syndrome diagnosis. The trends in incidence and prevalence of Rett syndrome in Australia were examined; the cumulative risk of a female being diagnosed was determined; and the impact of changes to diagnostic criteria and availability of genetic testing on these frequencies was investigated. The population-based Australian Rett Syndrome Database was used to identify a total of 349 verified Rett syndrome females born 1976-2006 and diagnosed 1982-2008. The proportion of female cases born and diagnosed per year and the cumulative risk of a diagnosis were determined. The median age of Rett syndrome diagnosis decreased from 4.5 y if diagnosed before 2000 to 3.5 y if diagnosed after 1999. The cumulative risk of diagnosis had almost doubled by 32 y of age [1/8,905 or 11.23 per 100,000 person-years (95% CI, 10.03-12.45)] in comparison with 5 y of age [1/15,361 or 6.51 per 100,000 person-years (95% CI, 5.65-7.39)]. Earlier age of diagnosis may result in families experiencing less stress and emotional strain compared with those with delayed diagnosis.	1
BACKGROUND:Hypotrichosis simplex of the scalp (HSS) is characterized by progressive loss of scalp hair that results in almost complete baldness at a young age. HSS is often caused by dominant nonsense mutations in CDSN encoding corneodesmosin, leading to the formation of an amyloid-like material, which interferes with normal hair follicle cycle. OBJECTIVES:As gentamicin has been shown to mediate ribosomal read-through, we aimed to ascertain its therapeutic efficacy in a small series of patients carrying a recurrent mutation in CDSN . METHODS:We used a green fluorescence reporter assay system, confocal microscopy and Western blot analysis to ascertain in vitro the ability of gentamicin to induce translational read-through across a causative CDSN mutation. RESULTS:Using a reporter assay, we initially showed that gentamicin induces read-through activity across an HSS-causing nonsense mutation. Gentamicin was further shown to rescue corneodesmosin translation in primary keratinocytes obtained from a patient with HSS. To validate the in vitro data, we conducted a pilot clinical trial where the scalp of four patients was treated topically with gentamicin for 6 months, demonstrating significant improvement as ascertained by the Severity of Alopecia Tool score. CONCLUSIONS:Our findings indicate that topical gentamicin should be considered as a potential therapeutic modality in HSS. What's already known about this topic? Hypotrichosis simplex of the scalp (HSS) is caused by nonsense mutations in CDSN encoding corneodesmosin. The mutant corneodesmosin has been hypothesized to be toxic to the hair follicles, leading to hypotrichosis. Disorders caused by nonsense mutations are amenable to ribosomal read-through using gentamicin. What does this study add? Gentamicin enhanced read-through activity and promoted full-length corneodesmosin synthesis in primary keratinocytes derived from patients carrying a nonsense mutation in CDSN. Topical treatment with gentamicin was found to rescue the hypotrichosis phenotype partially in four patients with HSS. What is the translational message? Topical gentamicin should be considered as a potential treatment for HSS.	0
PURPOSE:Cryofibrinogenemia is a rare cryopathy presenting as acrocyanosis following exposure to cold. Familial presentation has been described but the underlying molecular cause remained undetermined. METHODS:Forty (40) members from a large family with an initial diagnosis of familial cryofibrinogenemia were interviewed and examined to determine affected status and collect DNA. Exome sequencing was performed on three affected individuals from distinct branches of the pedigree. RESULTS:Seventeen (17) family members reported a history of acrocyanosis with cold exposure. None reported symptoms were suggestive of lupus. Exome sequencing of three subjects identified the heterozygous mutation D18N in the TREX1 gene which was then confirmed by Sanger sequencing in all affected as well as 2 unaffected family members. The mutation is already being associated with familial chilblain lupus erythematosus (CHLE), and a systematic review of literature was undertaken to compare reports of familial CHLE and cryofibrinogenemia. Both entities were found to share highly similar clinical presentations suggesting they are part of a same syndrome in which cryofibrinogenemia and lupus manifestations have variable penetrance. CONCLUSIONS:Familial cryofibrinogenemia without lupus should be added to the spectrum of TREX1-related disease.	0
BACKGROUND:Proteus syndrome (PS) is an extremely rare disease characterized by excessive chimeric growth of cells, and progressive and irregular asymmetrical hyperplasia. CASE PRESENTATION:Herein, a PS case with atypical clinical features and syndromes was reported, to improve the understanding of the diagnosis and treatment of the disease. The case was a 3-year-and-11-month-old male child. He was admitted due to a primary diagnosis of McCune-Albright syndrome. After admission, the lesion samples from the milk coffee spots, and nodular thickening skin at hands and feet were subjected to genetic screening. Genetic testing results confirmed the diagnosis of PS. CONCLUSIONS:Based on the clinical manifestations, laboratory tests, imaging data, and literature reviewing, the etiology, diagnosis, treatment and prognosis of PS have been analyzed and discussed.	0
The authors are reporting a case of autoimmune lymphoproliferative syndrome in a newborn who presented with massive hepatosplenomegaly, thrombocytopenia, and anemia at birth. Antenatal ultrasound revealed a fetus with hepatosplenomegaly. The infant was treated with steroids and sirolimus and is doing well at 4 years of age. This is the first case report of autoimmune lymphoproliferative syndrome presenting as hepatosplenomegaly during fetal life.	0
Pharmacologic management of hepatic encephalopathy includes a broad range of therapies. This article covers the specific mainstays of therapies, such as antimicrobials and laxatives, with an established evidence base. This article also covers newer modalities of therapies, such as fecal microbiota transplant, probiotics, bioartificial support systems, small molecular therapies such as l-ornithine l-aspartate, branched chain amino acids, l-carnitine, zinc, and other forms of therapy currently under review.	0
The term NBIA encompasses a heterogeneous group of inherited disorders characterized clinically by progressive extra pyramidal syndrome and pathologically by excessive iron deposition in brain, primarily affecting the basal ganglia (globus pallidus mainly). The hallmark of this syndrome is the age specific phenotypic presentation and intraphenotypic heterogeneity. NBIAs at present include ten subtypes with genes identified in nine subtypes. They form an important differential diagnosis for the phenotype of global developmental delay in infancy/childhood to dystonia-parkinsonism or isolated parkinsonism at all ages and also for the isolated craniocervical dystonia of adult onset. There needs to be a high index of clinical suspicion for this syndrome and the evaluation includes MRI brain T2* weighted imaging which reveal symmetrical iron deposition in bilateral globus pallidi and other basal ganglia. The T2 * imaging pattern of iron deposition varies amongst the different subtypes and the combination of clinical phenotype and MRI signature makes it easier to confidently make a diagnosis of NBIA and to recommend genetic testing. The treatment to date is mostly symptomatic with targeted therapies on the horizon.	0
Oculodentodigital dysplasia is an autosomal dominant disorder due to GJA1 variants characterized by dysmorphic features. Neurologic symptoms have been described in some patients but without a clear neuroimaging pattern. To understand the pathophysiology underlying neurologic deficits in oculodentodigital dysplasia, we studied 8 consecutive patients presenting with hereditary spastic paraplegia due to GJA1 variants. Clinical disease severity was highly variable. Cerebral MR imaging revealed variable white matter abnormalities, consistent with a hypomyelination pattern, and bilateral hypointense signal of the basal ganglia on T2-weighted images and/or magnetic susceptibility sequences, as seen in neurodegeneration with brain iron accumulation diseases. Patients with the more prominent basal ganglia abnormalities were the most disabled ones. This study suggests that GJA1-related hereditary spastic paraplegia is a complex neurodegenerative disease affecting both the myelin and the basal ganglia. GJA1 variants should be considered in patients with hereditary spastic paraplegia presenting with brain hypomyelination, especially if associated with neurodegeneration and a brain iron accumulation pattern.	0
There is a widespread impression that the number of patients with the autoimmune liver disease primary biliary cirrhosis (PBC) is increasing, although its incidence and prevalence vary widely. Using thorough case-finding methods and rigorous definitions to assess changes in incidence and prevalence with time and to explore the symptomatology and mortality of the disease in a large group of unselected patients, we performed a descriptive epidemiological study of PBC in a well defined population over a fixed period of time using established diagnostic criteria and with clinical follow-up of all cases. In a population of 2.05 million in northern England 770 definite or probable PBC cases were identified. Prevalence rose from 201.9 per 10(6) in the adult population and 541. 4 per 10(6) women over 40 in 1987 to 334.6 per 10(6) adults and 939. 8 per 10(6) women over 40 in 1994. Incidence was 23 per 10(6) in 1987 and 32.2 per 10(6) in 1994. Three hundred patients died in median follow-up of 6.27 years (141 liver deaths); the standardized mortality ratio was 2.85. At presumed diagnosis, 60.9% had no symptoms of liver disease. By June 1994 62% of prevalent patients had liver symptoms. PBC is apparently increasing. It is still unclear whether this is because of a true increase, case finding, or increased disease awareness. The study draws attention to (1) high mortality from liver disease and non-liver-related causes even in patients initially with no liver symptoms and (2) apparently poor diagnostic awareness of the disease.	1
This article describes the first reported case of myasthenia gravis (MG) seropositive for both acetylcholine receptor antibody and low-density lipoprotein receptor-related protein 4 antibody, complicated by autoimmune polyglandular syndrome (APS) type 3. The patient exhibited myasthenic weakness restricted to the ocular muscles and ptosis. Severe clinical deterioration ensued with predominant bulbar symptoms. MG rapidly worsened, the patient was intubated, and agranulocytosis due to thiamazole was also present, so it was necessary to perform thyroidectomy with tracheostomy and thymectomy in two phases. Both the double-seropositive MG and the APS were involved in the patient's rapid deterioration.	0
Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by recurrent sensory and motor neuropathy in individual nerves starting in adolescence or young adulthood, focal conduction abnormalities at entrapment sites on nerve conduction studies, and sausage-like swellings (tomacula) of the myelin sheaths by nerve biopsy. It is characterized genetically by the deletion of the chromosome 17p11.2-p12 region including the peripheral myelin protein-22 gene in the overwhelming majority of cases. HNPP may be frequently underdiagnosed or misdiagnosed owing to the heterogeneity of clinical and electrophysiological appearance. The main objective of this review is to describe clinical manifestations, paraclinical features such as electrodiagnostic, pathological, radiological and genetics findings, and possible treatments.	0
It remains largely unclear how stem cells regulate bioenergetics and genome integrity to ensure tissue homeostasis. Here, our integrative gene analyses suggest that metabolic and genotoxic stresses may underlie the common functional defects of both fetal and adult hematopoietic stem and progenitor cells (HSPCs) upon loss of DPY30, an epigenetic modulator that facilitates H3K4 methylation. DPY30 directly regulates expression of several key glycolytic genes, and its loss in HSPCs critically impaired energy metabolism, including both glycolytic and mitochondrial pathways. We also found significant increase in DNA breaks as a result of impaired DNA repair upon DPY30 loss, and inhibition of DNA damage response partially rescued clonogenicity of the DPY30-deficient HSPCs. Moreover, CDK inhibitor p21 was upregulated in DPY30-deficient HSPCs, and p21 deletion alleviated their functional defect. These results demonstrate that epigenetic mechanisms by H3K4 methylation play a crucial role in HSPC function through control of energy metabolism and protecting genome integrity.	0
Carbamoyl phosphate synthetase I (CPS1) deficiency (CPS1D), is a rare autosomal recessive disorder, characterized by life-threatening hyperammonemia. In this study, we presented the detailed clinical features and genetic analysis of two patients with neonatal-onset CPS1D carrying two compound heterozygous variants of c.1631C > T (p.T544M)/c.1981G > T (p.G661C), and c.2896G > T (p.E966X)/c622-3C > G in CPS1 gene, individually. Out of them, three variants are novel, unreported including a missense (c.1981G > T, p.G661C), a nonsense (c.2896G > T, p.E966X), and a splicing change of c.622-3C > G. We reviewed all available publications regarding CPS1 mutations, and in total 264 different variants have been reported, with majority of 157 (59.5%) missense, followed by 35 (13.2%) small deletions. This study expanded the mutational spectrum of CPS1. Moreover, our cases and review further support the idea that most (≥90%) of the mutations were "private" and only ∼10% recurred in unrelated families.	0
OBJECTIVE:To compare sexual function and outcomes of quality of life of patients with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome after vaginal dilation and surgical procedures. STUDY DESIGN:Cross-sectional study from January 2019 to June 2019. SETTING:Tertiary teaching hospital. PATIENT(S):Women with MRKH syndrome treated with vaginal dilation (n = 88) or surgical procedures (n = 45). INTERVENTION:WeChat-based questionnaires were distributed to every group member in our MRKH support group. MAIN OUTCOME MEASURE(S):Sexual functional were assessed by means of the Female Sexual Function Index (FSFI). Outcomes of quality of life were assessed by means of the 12-item World Health Organization Disability Assessment Schedule 2 (WHODAS2). Vaginal length was defined as the maximum depth of the placement of the vaginal mold. RESULT(S):The FSFI scores were similar between the dilation (24.49 ± 4.51) and surgery (23.79 ± 3.57) groups. Except for the higher orgasm score in the dilation group (9.96 ± 3.60 vs. 8.20 ± 2.67), the other dimensions of the FSFI were not significantly different between the groups. No significant differences were found in the WHODAS2 scores between the dilation group (median 8.33 [interquartile range 4.17-15.62]) and the surgery group (6.25 [2.08-14.58]). However, the vaginal length was significantly shorter in the dilation group (6.5 ± 2.04 cm) than in the surgery group (8.1 ± 1.59 cm). CONCLUSION(S):Although the vaginal length was shorter in the dilation therapy group than in the surgical therapy group, sexual function and quality of life were similar between these two groups. Vaginal dilation should be proposed as the first-line therapy for MRKH patients.	0
Aims: To determine the clinical characteristics and genetic cause of Waardenburg syndrome type 1 (WS1) in a Chinese family. Materials and Methods: Evaluations, including history, clinical features, and audiological tests, were performed on the proband and her parents. Genetic analyses were performed targeting 144 known deafness genes using a next-generation sequencing panel. Bioinformatic analyses were used to analyze the candidate mutation. Results: The proband and her parents suffered from congenital bilateral profound hearing loss. Her mother exhibited bilateral blue irides. WS1 was diagnosed in the proband and her mother according to the Waardenburg syndrome consortium criteria: the calculated W index of the proband was 2.39 and that of her mother was 2.31. A novel mutation c.1076_1077del (p.Thr359fs) in exon 7 of the PAX3 gene (paired box 3) was identified in the proband and her mother that was absent in the father and controls. Conclusion: Mutations in exon 7 of the PAX3 gene are rare. We identified a novel frameshift mutation in exon 7 of the PAX3 gene that we determined was responsible for WS1 in this family.	0
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Prognosis is highly variable, ranging from few months to more than 30 years. 25OH vitamin D (25OH VD) blood levels have been associated with worse prognosis of ALS, but these results remain in dispute. We addressed this controversy with a prospective study and multivariate analysis to study the influence of known clinical prognostic factors of the disease and 25OH VD levels on Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) severity score (ALS-SS), as defined by the monthly rate of decline of ALSFRS-R score, to identify the factors most closely linked to the risk of worsening of the disease. Results:This prospective cohort of ALS patients recruited 127 individuals, and 105 of them met inclusion criteria. Mean age of onset was 62.2 ± 12.1 years, 32% of subjects had bulbar onset, and gender ratio was 1.44 (male/female). Mean 25OH VD level was 26.8 ± 10.8 ng/ml and was similar between males and females. Patients with 25OH VD levels <15 ng/ml had significantly higher ALS-SS at inclusion (ALS-SSi) than those with normal levels (>30 ng/ml), p = 0.011. The study of ALS-SS as calculated at the end of follow-up (ALS-SSe) was not found correlated to initial 25OH VD levels (r = -0.19; p = 0.084). Univariate analysis showed that ALS-SSe correlated with 25OH VD levels, ALS duration at inclusion, slow vital capacity (SVC) at inclusion, and SVC loss. Multivariate model showed that 25OH VD levels were independently associated with ALS-SSe: r = -0.0125, p = 0.033. Log rank test with Kaplan-Meier curves did not show significant differences of survival between the groups defined by 25OH VD levels: <15, >15 and <30, and > 30 ng/ml, p = 0.88. Conclusions: This prospective study in ALS patients confirmed previous retrospective results: ALS-SSi is significantly higher in patients with severe VD deficiency. For the first time, multivariate analysis showed that 25OH VD level was an independent prognostic factor correlated to ALS-SSe, suggesting that discrepancies between previous works could be due to confounders. It would be important that the present work be replicated in larger samples to confirm the present findings.	0
The contribution of distinct genes to overlapping phenotypes suggests that such genes share ancestral origins, membership of disease pathways, or molecular functions. A recent study by Liu and colleagues identified mutations in TCF20, a paralog of RAI1, among individuals manifesting a novel syndrome that has phenotypes similar to those of Smith-Magenis syndrome (a disorder caused by disruption of RAI1). This study highlights how structural similarity among genes contributes to shared phenotypes, and shows how this relationship can contribute to our understanding of the genetic basis of complex disorders.	0
Spondylocostal dysostosis is a very rare combination of complex vertebra and rib malformations, accompanied occasionally by other disorders. A 3-year-old girl presented kyphoscoliosis, foot deformities, gate disturbance, and urinary incontinence. The CT and MRI examination revealed kyphosis and scoliosis with a double curve, some absent, broadened, bifurcating and fused ribs, hemivertebrae, butterfly and cleft vertebrae in thoracic and lumbar region, sporadic cleft or absent vertebral arches or pedicles, and hypoplastic sacrum with a cleft of the S2 vertebra. Spina bifida occulta extended from T10 to T11, and from L3 to the end of the sacrum. Two hemicords, separated by a bony septum and surrounded by their own dural tubes (type I), were present from the level of T9 to the conus medullaris. Filum terminale was thick and duplicated. Syringomyelia was present in the thoracic cord from T5 to T8. Finally, a small meningocele was seen at the T10-T11 level, and a subcutaneous lipoma in the thoracolumbar region. To our knowledge, such a combination of vertebra, rib, and cord malformations, including the mentioned additional disorders, has never been reported.	0
Newborn screening for congenital adrenal hyperplasia (CAH) is justified by the sometimes difficult clinical diagnosis and the risks associated with missed diagnosis, particularly the life-threatening salt-wasting crisis. In Switzerland, nationwide screening for CAH by measuring 17-hydroxyprogesterone levels in dried blood spots was introduced in 1992. At the Zurich University Children's Hospital, 50% of the population of Switzerland is screened. The aim of the study was to evaluate the efficiency of the Zurich screening program. Between January 1, 1993, and May 31, 2001, 333,221 newborns were screened for CAH. Thirty-one newborns had CAH (incidence, 1 in 10,749); 30 were detected through screening (sensitivity, 97%). A recall for suspected CAH was performed in only 60 cases, corresponding to a very low recall rate (0.0018%). In 30 recalls CAH was confirmed (positive predictive value, 50%; specificity, 99.99%). Fifteen of 31 patients profited from screening, as CAH had not been recognized clinically. The timely availability of screening results made therapy possible within the first week of life in most cases and helped in preventing salt-wasting crisis in all patients. With a sensitivity of 97%, a specificity of 99.99%, and a positive predictive value of 50%, the Zurich neonatal screening program for CAH can be considered highly reliable.	1
When administered alone, preinfection exercise training and benznidazole-based chemotherapy induce cardioprotection in Chagas disease. However, the effect of concomitant exercise and benznidazole treatment is unknown. We investigated whether exercise and specific chemotherapy could interact to modulate parasitemia, inflammation, redox status and heart damage in a murine model of T. cruzi infection. Wistar rats were randomized into an uninfected control group (CNT) and four groups infected with T. cruzi: sedentary untreated (SUN) and treated (STR), and trained untreated (TUN) and treated (TTR). Running training was administered 5 days/week for 4 weeks. Treated animals concomitantly received 100 mg/kg/day benznidazole. Heart inflammation and reactive damage were not detected in CNT animals. Compared to SUN, TUN animals presented increased levels of parasitemia, myocarditis, nitric oxide, hydrogen peroxide, protein carbonyl, malondialdehyde, cytokines (IFN-γ, TNF-α, IL-4, IL-6, IL-10 and IL-17), catalase, superoxide dismutase and glutathione reductase activity, as well as reduced heart non-protein antioxidant levels (P < 0.05). TTR animals exhibited higher levels of parasitemia, myocarditis, hydrogen peroxide, malondialdehyde, IFN-γ, TNF-α and IL-6 than STR animals (P < 0.05), which showed the lowest levels of all analyzed parameters compared to the other groups (P < 0.05). Our findings indicate that exercise aggravates acute infection. When concomitantly administered with benznidazole, exercise training impaired parasitic control and chemotherapy-induced cardioprotection in T. cruzi-infected rats. Considering that exercise training and T. cruzi infection constitute independent metabolic challenges, the negative effects of concomitant treatment are potentially related to the overlapping oxidative and immunoinflammatory demands of exercise and the infection itself.	0
CONTEXT:Heterozygous frameshift variants in PLIN1 encoding perilipin-1, a key protein for lipid droplet formation and triglyceride metabolism, have been implicated in familial partial lipodystrophy type 4 (FPLD4), a rare entity with only six families reported worldwide. The pathogenicity of other PLIN1 null variants identified in patients with diabetes and/or hyperinsulinemia was recently questioned because of the absence of lipodystrophy in these individuals and the elevated frequency of PLIN1 null variants in the general population. OBJECTIVES:To reevaluate the pathogenicity of PLIN1 frameshift variants owing to new data obtained in the largest series of patients with FPLD4. METHODS:We performed histological and molecular studies for patients referred to our French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity for lipodystrophy and/or insulin resistance and carrying PLIN1 frameshift variants. RESULTS:We identified two heterozygous PLIN1 frameshift variants segregating with the phenotype in nine patients from four unrelated families. The FPLD4 stereotypical signs included postpubertal partial lipoatrophy of variable severity, muscular hypertrophy, acromegaloid features, polycystic ovary syndrome and/or hirsutism, metabolic complications (e.g., hypertriglyceridemia, liver steatosis, insulin resistance, diabetes), and disorganized subcutaneous fat lobules with fibrosis and macrophage infiltration. CONCLUSIONS:These data suggest that some FPLD4-associated PLIN1 variants are deleterious. Thus, the evidence for the pathogenicity of each variant ought to be carefully considered before genetic counseling, especially given the importance of an early diagnosis for optimal disease management. Thus, we recommend detailed familial investigation, adipose tissue-focused examination, and follow-up of metabolic evolution.	0
Vitamin A is a fat-soluble vitamin that plays an important role in the development of the immune system, and a deficiency can cause blindness associated with xerophthalmia and premature mortality. Blindness from vitamin A deficiency is avoidable if supplements such as breast milk and other food fortification are provided to neonates at the time of weaning. The authors describe two infants who presented with keratomalacia and subsequent blindness. [J Pediatr Ophthalmol Strabismus. 2020;57:e12-e14.].	0
Objective:The purpose of this article was to provide a combined pathologic and radiologic review of previous pathologically diagnosed facial nerve "hemangiomas" to confirm that these lesions are most characteristic of venous malformations rather than neoplasms. Study Design:Retrospective radiologic, clinical, and histopathologic review of all patients with a previous pathologically diagnosed facial nerve hemangioma of the temporal bone who underwent computed tomography or magnetic resonance imaging (MRI) were included. A consensus radiologic review for characteristic features and pathologic analysis was performed. Materials and Methods:A panel of 4 neuroradiologists retrospectively analyzed CT and MRI exams for 11 facial nerve hemangiomas and provided a consensus agreement on the characteristic imaging features. Concurrently, two neuropathologists reevaluated archived tissue specimens from these lesions and applied additional immunohistochemical and histochemical stains including D240, CD31, smooth muscle actin (SMA), Verhoeff Van Gieson (VVG) and glucose transporter 1 (GLUT1). Results:Lesions were composed of dilated vascular spaces with a simple, CD31-positive endothelial lining and a smooth muscle component. All lesions were negative for markers found in arterial and lymphatic malformations and infantile hemangiomas. They had characteristic radiologic features previously ascribed to facial nerve hemangiomas. Namely, these lesions are typically T1 isointense or hypointense and T2 hyperintense relative to cerebral cortex and heterogeneously enhance on MRI. Bony canal expansion and erosion, intralesional calcification, and intracranial extension are common. Conclusions:On the basis of this radiologic and pathologic review, these lesions are best characterized as venous malformations. Level of Evidence:4.	0
22q11.2 duplication syndrome is a recently discovered genetic syndrome with unclear neuropsychiatric sequelae. While its connection to 22q11.2 deletion syndrome is actively investigated, case reports on the neuropsychiatric sequelae of affected individuals have been previously described, largely focusing on comorbid autism spectrum disorder. Here, we present the case of an 8-year-old female experiencing episodes of severe behavioural regression following medical illness. We analyze the case and relate it to the available literature and identify potential risk factors.	0
Neonatal diabetes mellitus (NDM) is a rare monogenic form of diabetes which is diagnosed in the first 6 months of life. Several studies in the last few years provide information on genetic causes for NDM.The aim of this study was to identify all patients with diabetes in the first 6 months of life through the Austrian Diabetes Register, which is available since 1989. A retrospective data analyses was performed to calculate the current incidence of NDM.Ten patients were registered with diabetes onset within the first 6 months of life in the Austrian Diabetes Register. Evaluation of detailed clinical data was performed by sending a questionnaire to all diabetes centers.Ten patients from nine different families with NDM were diagnosed in Austria from 1989 until September 2007. Seven patients (one male, six females) had transient NDM (TNDM), three (two males, one female) showed a permanent course [permanent neonatal diabetes mellitus (PNDM)]. One had immunodeficiency, polyendocrinopathy and enteropathy X-linked (IPEX) syndrome and another showed aplasia of the pancreas; no genetic etiology was found in the third case. In three out of seven patients with a transient course of NDM a genetic diagnosis was possible. Two female siblings had activating point mutations in the ABCC8 gene, although one patient had paternal uniparental isodisomy of chromosome 6q24. One patient's family did not consent to genetic testing.The incidence of NDM in Austria is 1/160 949, with an incidence of 1/ 536 499 for PNDM and 1/229 928 for TNDM.	1
The natural history of split spinal cord malformation (SCM) is still unclear. Knowledge of the characteristics of the osseous spur and its relationship with the spinal deformity may allow early identification of patients with a higher risk of a neurological deficit and enhance surgical decision-making.Eighty-five consecutive patients with congenital scoliosis and type-I SCM who had undergone surgical treatment at our hospital from May 2000 to December 2013 were identified retrospectively. There were 22 male and 63 female patients with an average age of 13.9 years at the time of surgery. Preoperative clinical and radiographic data were collected to investigate the characteristics of the scoliosis and the osseous spur. Two groups were identified on the basis of whether the patients had intact neurological function (Group A) or a neurological deficit (Group B).There were 52 patients (61%) in Group A (intact neurological function) and 33 patients (39%) in Group B (neurological deficit). There were no significant differences in the demographic distribution, curve magnitude, or length and thickness of the osseous spur between the 2 groups. In Group A, the location of the osseous spur relative to the apex of the major curve was proximal in 13 patients (25%), distal in 28 (54%), and central in 11 (21%). In Group B, the osseous spur was proximal in 7 (21%), distal in 8 (24%), and central in 18 (55%). The 2 groups differed significantly with respect to the location of the osseous spur (chi square = 10.898, p = 0.004). Group-B patients had a higher proportion of patients with kyphotic deformity (42%) than Group A (10%). The ratio of the diameters of the hemicords (concave side divided by convex side) differed significantly between the 2 groups (0.98 for Group A versus 0.89 for Group B, p = 0.030).The neurological status in patients with congenital scoliosis and type-I SCM appears to be closely related to the location of the osseous spur relative to the congenital scoliosis. An osseous spur at the apex of the scoliosis may be related to a higher risk of developing a neurological deficit, especially in patients with kyphotic deformity. Asymmetric splitting of the spinal cord may contribute to neurological deficits.Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.	0
Background: Gene editing has shown huge potential in correcting aberrant splicing and Cas13 has been identified as being particularly suitable for targeting RNA. It has therefore become increasingly important to highlight new splice site mutations that may be correctable, particularly in genes that are too large to be encoded by AAV vectors. About 20% of Usher Type 1 cases are caused by mutations in CDH23.Purpose: To report a novel splice site mutation of CDH23 associated with Usher Type 1D.Materials and Methods: Case report.Results: A 35-year-old Caucasian female who is congenitally deaf with vestibular dysfunction presented with visual acuity of 6/12 in both eyes. Fundus examination revealed findings typical of retinitis pigmentosa with foveal preservation of photoreceptor layer. Next generation sequencing analysis revealed a novel homozygous variant, c.9319 + 1G>T in CDH23 consistent with the diagnosis of Usher Syndrome Type 1D. The c.9319 + 1G>T variant is predicted to affect splicing at the exon 65/intron 65 boundary, which highly likely leads to complete skipping of exon 65.Conclusions: We describe a case of a typical Usher Syndrome Type 1D caused by a novel splice site variant in CDH23. Currently there are no treatments for CDH23 related retinal degeneration, partly because the cDNA size of 10kb is too large for AAV vector gene augmentation therapy. Alternative strategies include CRISPR-Cas9 adenine base editors and RNA editing with CRISPR-Cas13. Single-nucleotide editing represents a promising approach for targeting this variant in CDH23 to restore the wildtype splice donor site at this position.	0
Objectives:This article reviews the current role of genetics in pediatric hearing loss (HL). Methods:A review of the current literature regarding the genetic basis of HL in children was performed. Results:To date, 119 nonsyndromic genes have been associated with HL. There are also hundreds of syndromic causes that have HL as part of the clinical phenotype. Conclusions:Identifying HL genes coupled with clinical characteristics ("genotype-phenotype") yields a more accurate diagnosis and prognosis. Although the complexity of the auditory apparatus presents challenges, gene therapy is emerging and may be a viable management option in the future.	0
Corticosteroid-binding globulin (CBG) is synthesized by the liver and secreted into the bloodstream where binds to glucocorticoids. Thus CBG has the role of glucocorticoid transport and free hormone control. In addition, CBG has been detected in some extrahepatic tissues without a known role. CBG-deficient mice show decreased total corticosterone levels with missing of classical sexual dimorphism, increased free corticosterone, higher adrenal gland size and altered HPA axis response to stress. Our aim was to ascertain whether CBG deficiency could affect the endocrine synthetic activity of adrenal gland and if the adrenal gland produces CBG. We determined the expression in adrenal gland of proteins involved in the cholesterol uptake and its transport to mitochondria and the main enzymes involved in the corticosterone, aldosterone and catecholamine synthesis. The results showed that CBG is synthesized in the adrenal gland. CBG-deficiency reduced the expression of ACTH receptor, SRB1 and the main genes involved in the adrenal hormones synthesis, stronger in females resulting in the loss of sexual dimorphism in corticosteroid adrenal synthesis, despite corticosterone content in adrenal glands from CBG-deficient females was similar to wildtype ones. In conclusion, these results point to an unexplored and relevant role of CBG in the adrenal gland functionality related to corticosterone production and release.	0
Castleman's disease (CD) is a non-clonal lymph node hyperplasia, mostly seen in the mediastinum. It has various clinical and pathological outcomes. There are different treatments because of its rare occurance and heterogenity. We present 2 cases which were referred to our clinic as retroperitoneal mass and diagnosed as CD after surgical resection.	0
Purpose:To describe an infant with Adams Oliver syndrome (AOS) with ocular signs similar to familial exudative vitreoretinopathy. Observations:A full-term female infant presented with a congenital scalp defect, hypoplasia of the fingers and toes along with a radial retinal fold in the right eye and tractional retinal detachment in the left eye. Fluorescein angiography findings included peripheral retinal nonperfusion, irregular vascular sprouting beyond the vascular-avascular junction, pinpoint areas of hyperfluorescence as well as late peripheral and posterior vascular leakage. The patient was clinically diagnosed with Adams Oliver syndrome based on the collective findings. Laser photocoagulation to the avascular retina was performed in both eyes which resulted in stabilization of the condition after 2 years of follow up. Conclusion and importance:The ocular phenotype in AOS may be similar to familial exudative vitreoretinopathy. Therefore, suspicion of the diagnosis should prompt ophthalmic evaluation including fluorescein angiography to detect and possibly treat the ischemic retinopathy.	0
The clinical diagnosis of Lujan-Fryns syndrome (LFS) comprises X-linked intellectual disability (XLID) with marfanoid habitus, distinct combination of minor facial anomalies and nasal speech. However the definition of syndrome was significantly broadened since the original report and implies ID with marfanoid habitus. Mutations of three genes (MED12, UPF3B, and ZDHHC9) have been reported in "broadly defined" LFS. We examined these genes in 28 individuals with a tentative clinical diagnosis of LFS but we did not identify any causative mutation. By molecular karyotyping we detected other disorders, i.e., Phelan-McDermid syndrome and 16p11.2 microduplication, each in one patient. One affected individual was carrier of a different recurrent duplication on 16p11.2 that has been reported several times to the DECIPHER and ISCA databases in individuals with autism, intellectual disability (ID), and developmental delay. It may represent a new duplication syndrome. We also identified previously unreported de novo duplication on chromosome 12p13.31 which we considered to be disease-causing. X-exome sequencing of four individuals revealed private or non-recurrent mutations in NKAP and LAS1L in one patient each. While LFS is defined as a form of XLID, there seem to be various conditions that have rather similar phenotypes. Therefore, the combination of ID and marfanoid habitus in a male patient is not sufficient for the diagnosis of LFS. We suggest that the diagnosis of LFS in patients with ID and marfanoid habitus should be made only in presence of specific facial features, nasal speech and obvious X-linked segregation of the disorder or an unambiguously pathogenic mutation in the MED12.	0
Mandibuloacral dysplasia with type B lipodystrophy is a rare autosomal recessive disease characterized by atrophic skin, lipodystrophy, and skeletal features. It is caused by mutations in ZMPSTE24, a gene encoding a zinc metalloproteinase involved in the post-translational modification of lamin. Nine distinct pathogenic variants have been identified in 11 patients from nine unrelated families with this disorder. We report a 12-year-old boy with mandibuloacral dysplasia with type B lipodystrophy and a novel homozygous c.1196A>G; p.(Tyr399Cys) mutation in ZMPSTE24. The patient had typical dermatological and skeletal features of mandibuloacral dysplasia with type B lipodystrophy, sparse hair, short stature, mild microcephaly, facial dysmorphism, and a striking failure of ossification of the interparietal region of the occipital bone, up to the position where transverse occipital suture can be observed. Newly recognized signs for mandibuloacral dysplasia with type B lipodystrophy were gaze palsy and ptosis. Delayed closure of cranial sutures and Wormian bones have been described in three patients, but an ossification failure strictly limited to the occipital bone, as seen in the present patient, appears to be unique for mandibuloacral dysplasia with type B lipodystrophy. This observation illustrates that ZMPSTE24 could play a specific role in membranous ossification in the interparietal part of the squama (Inca bone) but not in the intracartilaginous ossification of the supraoccipital. This failure of ossification in the squama appears to be a useful feature for the radiological diagnosis of mandibuloacral dysplasia with type B lipodystrophy. © 2016 Wiley Periodicals, Inc.	0
Abdominal wall mass is not uncommon in clinic, but it is very rare that germ cell tumors (GCTs) arise in the abdominal wall. The authors review the case of a 34-year-old female with abdominal wall mixed malignant GCT composed of embryonal carcinoma and teratoma and combine the relative literature to explain why GCTs originate from anterior abdominal wall.	0
BACKGROUND:The Stewart-Treves syndrome with localisation in the region of the lower extremities is not something unusual as clinical pathology, but the clinical diagnostics is rather difficult, and it can be further complicated maximally because of: the similar locoregional findings in patients with other cutaneous malignancies. CASE REPORT:Presented is a rare form of an epithelioid variant of the Stewart Treves syndrome in a woman, aged 81, localised in the region of the lower leg and significantly advanced only for 2 months. The diagnosis was confirmed histologically and immunohistochemically. Amputation of the affected extremity was planned. Discussed are important etiopathogenetic aspects regarding the approach in patients with lymphedema and possibility for development of the Stewart Treves syndrome. CONCLUSION:Analyzing the evidence from the literature worldwide, we concluded that perhaps the only reliable (to some extent) therapeutic option in patients with Stewart Treves Syndrome is 1) the early diagnostics and 2) the following inevitable radical excision or amputation with the maximal field of surgical security in the proximal direction.	0
Fibro-adipose vascular anomaly (FAVA) is a complex vascular malformation that typically presents with persistent pain, discomfort, contracture and other disabling symptoms. There are no minimally invasive treatment options to effectively control these symptoms. Image-guided percutaneous cryoablation, which has been used to control pain in people with cancer, could be used for similar indications in FAVA.To assess the role of image-guided percutaneous cryoablation for control of symptoms in FAVA lesions.We conducted a retrospective cohort study of 20 children and young adults with FAVA who underwent percutaneous cryoablation at 26 sites, from September 2013 to August 2015. The outcome was based on the brief pain inventory scoring (BPI), concurrent symptoms, clinical response and patient satisfaction.After cryoablation there was significant improvement in pain, which dropped by 3 points (pain now) to 3.7 points (pain in the last 24 h). Most patients indicated that pain interfered less in their everyday social life. Concurrent symptoms like swelling, physical limitations and skin hyperesthesia also improved. Clinical response was greatest at 2-5 months follow-up after cryoablation, with acceptable patient satisfaction thereafter. Technical response was 100%. There were no major complications.Image-guided percutaneous cryoablation is a safe and effective option for treatment of symptomatic FAVA lesions.	0
Pontocerebellar hypoplasia (PCH) is a diverse group of autosomal recessive genetic conditions presenting with hypoplastic changes in the brainstem, cerebellum, and spinal cord. It clinically manifests with neurological symptoms, respiratory failure, and often in a combination with other malformations of the internal organs and musculoskeletal system. In this report, we present an autopsy case report of a two-month-old female patient with blood-relative parents. The patient presented clinically with neonatal-onset respiratory failure, mild neurological symptoms, facial dysmorphism, and developmental delay. On autopsy, the cerebellum and brainstem were severely hypoplastic, and the diagnosis of PCH was established grossly. The central nervous system (CNS) revealed specific hypoplastic changes in the structures, with a decreased neuronal count, stratification disturbances of the cortex of the cerebellum, and cellular misarrangement. The morphological findings in the CNS and their associated parenchymal organ changes, even in the absence of a genetic test, were specific enough to identify PCH type 1B as the main condition.	0
BACKGROUND:Collectin-K1 (CL-K1, or CL-11) is a multifunctional Ca(2+)-dependent lectin with roles in innate immunity, apoptosis and embryogenesis. It binds to carbohydrates on pathogens to activate the lectin pathway of complement and together with its associated serine protease MASP-3 serves as a guidance cue for neural crest development. High serum levels are associated with disseminated intravascular coagulation, where spontaneous clotting can lead to multiple organ failure. Autosomal mutations in the CL-K1 or MASP-3 genes cause a developmental disorder called 3MC (Carnevale, Mingarelli, Malpuech and Michels) syndrome, characterised by facial, genital, renal and limb abnormalities. One of these mutations (Gly(204)Ser in the CL-K1 gene) is associated with undetectable levels of protein in the serum of affected individuals. RESULTS:In this study, we show that CL-K1 primarily targets a subset of high-mannose oligosaccharides present on both self- and non-self structures, and provide the structural basis for its ligand specificity. We also demonstrate that three disease-associated mutations prevent secretion of CL-K1 from mammalian cells, accounting for the protein deficiency observed in patients. Interestingly, none of the mutations prevent folding or oligomerization of recombinant fragments containing the mutations in vitro. Instead, they prevent Ca(2+) binding by the carbohydrate-recognition domains of CL-K1. We propose that failure to bind Ca(2+) during biosynthesis leads to structural defects that prevent secretion of CL-K1, thus providing a molecular explanation of the genetic disorder. CONCLUSIONS:We have established the sugar specificity of CL-K1 and demonstrated that it targets high-mannose oligosaccharides on self- and non-self structures via an extended binding site which recognises the terminal two mannose residues of the carbohydrate ligand. We have also shown that mutations associated with a rare developmental disorder called 3MC syndrome prevent the secretion of CL-K1, probably as a result of structural defects caused by disruption of Ca(2+) binding during biosynthesis.	0
Parenchymal brain metastases from prostate cancer are rare and mostly appear in the terminal phase of the disease. Here, we report a case of cystic cerebral metastases in patient with prostate adenocarcinoma. This patient presented with one large parietal polycystic tumor and three other suspicious-looking nodular lesions as shown on magnetic resonance imaging. This is the twelfth reported case of prostatic brain metastasis occurring as a cystic intraparenchymal tumor in the literature.	0
OBJECTIVE:To study the anatomy of the brachial plexus in fetuses and to evaluate differences in morphology during evolution, or to find anatomical situations that can be identified as the cause of obstetric paralysis. METHODS:Nine fetuses (12 to 30 weeks of gestation) stored in formalin were used. The supraclavicular and infraclavicular parts of the brachial plexus were dissected. RESULTS:In its early course, the brachial plexus had a cord-like shape when it passed through the scalene hiatus. Origin of the phrenic nerve in the brachial plexus was observed in only one fetus. In the deep infraclavicular and retropectoralis minor spaces, the nerve fibers of the brachial plexus were distributed in the axilla and medial bicipital groove, where they formed the nerve endings. CONCLUSION:The brachial plexus of human fetuses presents variations and relations with anatomical structures that must be considered during clinical and surgical procedures for neonatal paralysis of the upper limbs.	0
AIM:To assess whether regular Mediterranean diet and regular intake of vegetables may reduce the risk of blindness, cataract, and glaucoma in these type 2 diabetics. METHODS:A cross-sectional design was carried out among known black diabetics admitted at the diabetic clinics of Kinshasa, between October 2008 and March 2009. The Mediterranean-style dietary score (MSDPS) was used to characterize a Mediterranean-style dietary pattern in the study population using the Harvard semi quantitative FFQ adapted for Africa. RESULTS:Five hundred Type 2 diabetic patients were included in this study (48% of males; 40% aged ≥60 years). There was a significant association between blindness, cataract and aging; between blindness (P<0.05), cataract (P<0.05), glaucoma (P<0.05), and physical inactivity; between blindness (P<0.05), cataract (P<0.0001), glaucoma (P<0.01) and high SES, and a very significant association between blindness (P<0.0001), cataract (P<0.0001), glaucoma (P<0.0001) and exposure to sunlight. There was also a significant association between blindness, glaucoma, and male sex. Regular intake of Mediterranean diet, Brassica Rapa, beans, Abelmoschus, Musa acuminata reduced significantly the risk of blindness, cataract and glaucoma. CONCLUSION:Regular intake of Mediterranean diet, Brassica Rapa, beans, Abelmoschus, and Musa acuminata may significantly reduce the risk of blindness or its major causes among type 2 diabetes mellitus in Africa.	0
BACKGROUND:The neuronal ceroid lipofuscinosis 2 (NCL2) or classic late-infantile neuronal ceroid lipofuscinosis (LINCL) is a neurogenetic disorder caused by mutations in the TPPI gene, which codes for the lysosomal tripeptidyl peptidase 1 (TPPI) EC 3.4.14.9. Loss of functional TPPI activity results in progressive visual and neurological symptoms starting at around 1-2 years of age causing early death. METHODS:We report a DBS-based TPPI assay that cleaves a synthetic tetrapeptide substrate generating a product that is detected by HPLC. Probands and carriers were identified with 100% accuracy (7 probands, 30 carriers, 13 controls). RESULTS:The assay detected a single TPPI activity at a lower pH towards the substrate tested. TPPI activity measurable when extracted at lower pH while inactive at neutral pH showed steady increase for at least 8 h incubation. No loss in TPPI activity was observed when DBS were stored for at least 2 weeks either in freezer, refrigerator, room temperature or 42 °C. CONCLUSION:A sequence variant causing Arg339Gln substitution in a proband had 12% TPPI. TPPI activity can be reliably measured in DBS, giving an opportunity to diagnose NCL2 at birth and refer patients for enzyme replacement or other therapies for earliest intervention, or alternatively offers a second-tier confirmatory test.	0
Post-transplant lymphoproliferative disease (PTLD) is a clinicopathologic entity characterized by an abnormal lymphocytic proliferation that occurs in immunosuppressed patients following organ transplantation. Several sites in the head and neck may be affected by PTLD with rare involvement of the larynx. Affected patients often present with symptoms and signs suggestive of a malignant lesion. Early diagnosis using histopathologic examination is paramount to prevent life-threatening airway compromise. The authors of this manuscript report a 52-year-old women, diagnosed case of renal failure for which she had undergone kidney transplant, who presented with symptoms of laryngeal PTLD. The clinical work-up and management of these cases is reviewed.	0
Neuroblastoma (NB) is responsible for 15% of all childhood cancer deaths. Despite advances in treatment and disease management, the overall 5-year survival rates remain poor in high-risk disease (25-40%). It is well known that miR-145 functions as a tumor suppressor in several types of cancer. However, the impact of miR-145 on NB is still ambiguous. Our aim was to investigate the potential tumor suppressive role and mechanisms of miR-145 in high-risk neuroblastoma. Expression levels of miR-145 in tissues and cells were determined using RT-qPCR. The effect of miR-145 on cell viability was evaluated using MTT assays, apoptosis levels were determined using TUNEL staining, and the MTDH protein expression was determined using western blot and RT-PCR. Luciferase reporter plasmids were constructed to confirm direct targeting for MTDH. The results showed that miR-145 expression was significantly lower in high-risk MYCN amplified (MNA) tumors and low miR-145 expression was associated with worse EFS and OS in our cohort. Over-expression of miR-145 reduced cell viability and increased apoptosis in SH-SY-5Y cells. We identified MTDH as a direct target for miR-145 in SH-SY-5Y cells. Targeting MTDH has the similar results as miR-145 overexpression. Our findings suggest that low miR-145 expression was associated with poor prognosis in patients with NB, and the overexpression of miR-145 inhibited NB cells growth by down-regulating MTDH, thus providing a potential target for the development of microRNA-based approach for NB therapy.	0
We describe the case of an infant with recurrent episodes of staphylococcal skin abscess and subsequent lethal pneumococcal meningitis/septicemia due to interleukin-1 receptor-associated kinase 4 (IRAK-4) deficiency. In this case, systemic signs of inflammatory response were poor and delayed. Among all other reported cases of IRAK-4 deficiency, none involved severe viral or fungal disease, and the range of infecting bacteria was narrow.	0
Cataracts are focal to diffuse opacities of the eye lens causing impaired vision or complete blindness. For bilateral congenital cataracts in Red Holsteins a perfectly cosegregating mutation within the CPAMD8 gene (CPAMD8:g.5995966C>T) has been reported. We genotyped the CPAMD8:g.5995966C>T variant in Holstein calves affected by congenital bilateral congenital cataracts, their unaffected relatives and randomly selected herd mates. Ophthalmological examinations were performed in all affected individuals to confirm a congenital cataract. Whole genome sequencing was employed to screen variants in candidate genes for the Morgagnian cataract phenotype. In the present study, 3/35 cases were confirmed as homozygous mutated and 6/14 obligate carriers. Further 7/46 unaffected animals related with these cases were heterozygous mutated for the CPAMD8:g.5995966C>T variant. However 32 cases with a congenital cataract showed the wild type for the CPAMD8 variant. We did not identify variants in the candidate genes CPAMD8 and NID1 or in their close neighborhood as strongly associated with the congenital cataract phenotype in Holstein calves with the CPAMD8 wild type. In conclusion, the CPAMD8:g.5995966C>T variant is insufficient to explain the majority of Morgagnian congenital cataract phenotypes in Holsteins. It is very likely that congenital bilateral cataracts may be genetically heterogeneous and not yet known variants in genes other than CPAMD8 and NID1 are involved.	0
Abetalipoproteinaemia is an autosomal recessive disorder characterized by very low plasma concentrations of total cholesterol and triglyceride. It results from mutations in the gene encoding microsomal triglyceride transfer protein. Nine-month-old girl was admitted to our hospital because of fever, cough, diarrhea and failure to thrive. She had low cholesterol and triglycerides levels according to her age. The peripheral blood smear revealed acantocytosis. Thyroid function test showed central hypothyroidism. Cranial magnetic resonance imaging revealed the retardation of myelination and the pituitary gland height was 1.7 mm. A homozygous novel mutation [c.506A>T (p. D169V)] was detected in MTTP gene.  Vitamins A, D, E, and K and levothyroxine were started. The coexistence of abetalipoproteinaemia and central hypothyroidism was not previously reported in another case. A homozygous novel mutation [c.506A>T (p. D169V)] was detected in MTTP gene.	0
Urea cycle disorders are rare metabolic disorders that present as encephalopathy with hyperammonemia. Arginase deficiency causing hyperargininemia is one among the urea cycle disorders, which usually presents as spastic diplegia. Hyperammonemic encephalopathy is rare in arginase deficiency. We present a rare case of arginase deficiency presenting as acute encephalopathy in a child.	0
Homozygous mutations in the fibroblast growth factor 3 (FGF3) gene have recently been discovered in an autosomal recessive form of syndromic deafness characterized by complete labyrinthine aplasia (Michel aplasia), microtia, and microdontia (OMIM 610706 - LAMM). In order to better characterize the phenotypic spectrum associated with FGF3 mutations, we sequenced the FGF3 gene in 10 unrelated families in which probands had congenital deafness associated with various inner ear anomalies, including Michel aplasia, with or without tooth or external ear anomalies. FGF3 sequence changes were not found in eight unrelated probands with isolated inner ear anomalies or with a cochlear malformation along with auricle and tooth anomalies. We identified two new homozygous FGF3 mutations, p.Leu6Pro (c.17T>C) and p. Ile85MetfsX15 (c.254delT), in four subjects from two unrelated families with LAMM. The p.Leu6Pro mutation occurred within the signal site of FGF3 and is predicted to impair its secretion. The c.254delT mutation results in truncation of FGF3. Both mutations completely co-segregated with the phenotype, and heterozygotes did not have any of the phenotypic findings of LAMM. Some affected children had large skin tags on the upper side of the auricles, which is a distinctive clinical component of the syndrome. Enlarged collateral emissary veins associated with stenosis of the jugular foramen were noted on computerized tomographies of most affected subjects with FGF3 mutations. However, similar venous anomalies were also detected in persons with non-syndromic Michel aplasia, suggesting that a direct causative role of impaired FGF3 signaling is unlikely.	0
Syndactyly is one of the most frequent hereditary limb malformations with clinical and genetical complexity. Autosomal dominant syndactyly type IV (SD4) is a rare form of syndactyly, caused by heterozygous mutations in a sonic hedgehog (SHH) regulatory element (ZRS) which resides in intron 5 of the LMBR1 gene on chromosome 7q36.3. SD4 is characterized by complete cutaneous syndactyly of the fingers, accompanied by cup-shaped hands due to flexion of the fingers and polydactyly. Here, for the first time, we reported a large Chinese family from Fujian province, manifesting cup-shaped hands consistent with SD4 and intrafamilial heterogeneity in clinical phenotype of tibial and fibulal shortening, triphalangeal thumb-polysyndactyly syndrome (TPTPS). We identified a novel duplication of ∼222 kb covering exons 2-17 of the LMBR1 gene in this family by sub-exome target sequencing. This case expands our new clinical understanding of SD4 phenotype and again confirms the feasibility to detect copy number variation by sub-exome target sequencing.	0
INTRODUCTION:Full-thickness macular hole (FTMH) formation is rarely seen in patients with retinitis pigmentosa (RP) and can have an adverse impact on their residual visual function. The underlying mechanisms are unknown, and clinical experience is limited regarding surgical outcomes. Here, we describe the surgical management of FTMH in a young patient with genetically confirmed Usher syndrome, the most common form of syndromic RP. CASE REPORT:A 28-year-old woman presented with blurred vision in her right eye (RE). She had a history of RP and bilateral hearing impairment since childhood. Fundoscopy and spectral-domain optical coherence tomography revealed a FTMH in the RE along with typical RP features bilaterally. After pars plana vitrectomy (PPV) with internal limiting membrane peel and gas tamponade, the FTMH closed. Six months after PPV the patient underwent cataract surgery in the affected eye, and the visual acuity remained stable compared to baseline. The clinical diagnosis of Usher syndrome was genetically confirmed by whole exome sequencing (WES), which revealed the presence of two pathogenic nucleotide variants in trans (compound heterozygosity) in the gene USH2A. CONCLUSION:We report a rare case of successful closure of a FTMH in a patient with Usher syndrome. Surgical treatment of FTMH can help preserve the central vision in RP patients, whose peripheral vision is severely affected.	0
A case of a 31-day-old infant patient with a Tessier 0-14 deformity related to multiple midline deformities is presented. Although Transnasal endoscopic surgery is the mainstay for the treatment of anterior and middle skull base meningoceles, there are complex cases in which a combined and multidisciplinary approach is necessary. The surgical decisions and techniques are described. To date, this is the first patient reported with Tessier 0-14 deformity treated with a combined endoscopic and external surgical approach.	0
Noonan syndrome with multiple lentigines (NSML) is a rare autosomal dominant disorder that presents with cardio-cutaneous-craniofacial defects. Hypertrophic cardiomyopathy (HCM) represents the major life-threatening presentation in NSML. Mutations in the PTPN11 gene that encodes for the protein tyrosine phosphatase (PTP), SHP2, represents the predominant cause of HCM in NSML. NSML-associated PTPN11 mutations renders SHP2 catalytically inactive with an "open" conformation. NSML-associated PTPN11 mutations cause hypertyrosyl phosphorylation of the transmembrane glycoprotein, protein zero-related (PZR) resulting in increased SHP2 binding. Here we show that NSML mice harboring a tyrosyl phosphorylation-defective mutant of PZR (NSML/PZRY242F) that is defective for SHP2 binding fail to develop HCM. Enhanced AKT/S6K signaling in heart lysates of NSML mice was reversed in NSML/PZRY242F mice demonstrating that PZR/SHP2 interactions promote aberrant AKT/S6K activity in NSML. Enhanced PZR tyrosyl phosphorylation in the hearts of NSML mice was found to drive myocardial fibrosis by engaging a Src/NFkB pathway resulting in increased activation of interleukin-6 (IL6). Increased expression of IL6 in the hearts of NSML mice was reversed in NSML/PZRY242F mice and PZRY242F mutant fibroblasts were defective for IL6 secretion and STAT3-mediated fibrogenesis. These results demonstrate that NSML-associated PTPN11 mutations that induce PZR hypertyrosyl phosphorylation trigger pathophysiological signaling that promotes HCM and cardiac fibrosis.	0
A neonate with unilateral complete duplex system with congenital giant megaureter of the upper moiety presenting as abdominal lump is reported. A left upper moiety nephroureterectomy was performed. Such an anomaly with this presentation has not been reported in neonates.	0
We evaluated a newborn with acrofacial dysostosis in whom a clinical diagnosis of Nager syndrome was entertained. Radiographs revealed hypoplasia of the scapulae and bilateral humeroradial synostosis, with absent ulna on the left and hypoplastic ulna on the right. The finding of bilateral humeroradial synostosis had not been seen in cases of Nager syndrome before and we considered other diagnoses. Humeroradial synostosis has been found in three cases of acrofacial dysostosis Rodriguez type, a syndrome characterized by mandibular hypoplasia, upper and lower extremity phocomelia, and oligodactyly of the upper limbs. More recently, haploinsufficiency of the SF3B4 gene has been identified as the cause of both Nager and Rodriguez syndrome, leading many to believe that Rodriguez syndrome represents a more severe end of a Nager syndrome spectrum. An SF3B4 mutation was found in our patient, prompting a review of the previous known cases of Rodriguez syndrome, which revealed no clustering of SF3B4 mutations, and four cases of Rodriguez syndrome with mutations identical to those in cases of Nager syndrome. Rodriguez syndrome was previously thought of as a lethal acrofacial dysostosis distinct from Nager syndrome. A number of more mild cases, as well as our case, intermediate between the two phenotypes, illustrate that Rodriguez syndrome is a severe manifestation of Nager syndrome, and is not lethal with aggressive medical care.	0
Background: A considerable proportion of pediatric disease burden is mainly caused by inborn errors of metabolism. Succinic semi-aldehyde dehydrogenase (SSADH) deficiency is an unusual disorder of the gamma-aminobutyric acid metabolism. Till date, very few cases have been reported in China.Case presentation: Trio-WES was used to characterize the ALDH5A1 gene in two children of a Chinese family, who presented with seizures, psychomotor delay, development regression, borderline cognition, hypotonia, and harbored the compound heterozygotes NM_001080.3: c.1321G > A (p. Gly441Arg) and c.727_735del (p. Leu243_Ser245del). The former has been reported earlier (rs1041467895), whereas the latter is novel. Amino acid coding at highly conserved amino acid residues was observed to be altered by both mutations. This structural impairment influenced the enzyme structure as indicated by the in silico protein modeling. Cerebral magnetic resonance imaging of the proband and her brother showed excessive gap in the cerebrum and abnormal signals in the bilateral frontal lobe, bilateral basal ganglia, and cerebral foot. Elevated levels of Gamma-hydroxybutyric aciduria were found in their patients on urine organic acid analysis.Conclusion: Our findings contribute to the current knowledge of missense and deletion mutations associated with SSADH deficiency.	0
A 61-year-old elderly male, hypertensive patient presented to the retina clinic with sudden drop in vision in the left eye for 6 days. His best-corrected visual acuity at presentation was counting fingers close to face. Fundus examination of the left eye revealed the presence of subretinal and preretinal haemorrhage at the macula along with hypertensive retinopathy changes in both eyes. Fluorescein angiography was done, which showed a retinal artery macroaneurysm at the optic nerve head. Optical coherence tomogram through the optic nerve head also confirmed the presence of retinal artery macroaneurysm. The patient was treated with injection of 0.4 cc of 100% C3F8 to displace the blood off the macula. At final follow-up visit at 2 months post treatment, his vision improved to 6/12, N8. Fundus examination showed a small residual altered blood nasal to the fovea. No treatment was however done to the retinal artery macroaneurysm due to its atypical location and chance of spontaneous involution. In conclusion, retinal artery macroaneurysm at the optic disc is extremely uncommon. Identification of the retinal artery macroaneurysm lesion is more difficult in glaucoma patients due to the large and deep optic cup. Fluorescein angiography remains the main investigative modality to confirm the diagnosis. Spontaneous involution still remains the mainstay of treatment in optic disc retinal artery macroaneurysm.	0
3MC syndrome is a rare autosomal recessive disorder with characteristic craniofacial dysmorphism and multiple anomalies. It is caused by biallelic mutations in one of three genes, MASP1, COLEC11 and COLEC10, all encoding factors of the lectin complement pathway. In MASP1, either truncating mutations or missense variants in exon 12 encoding the C-terminal serine protease domain specific for isoform MASP-3 are causative. By trio exome sequencing we now identified a novel, homozygous 2kb deletion, partially affecting exon 12 in an adult female with the typical facial gestalt of 3MC syndrome and hearing loss, but without the main feature cleft lip/palate, and without intellectual disability, or short stature. We therefore expand the MASP1 associated mutational and clinical spectrum and describe the development of her clinical presentation over a period of 21 years. As the homozygous deletion in our patient was only found by thorough and visual evaluation of the whole exome sequencing data, such deletions might escape detection in some routine diagnostic workflows and might explain a few of the so far molecularly unconfirmed cases of 3MC syndrome.	0
Although inborn errors of metabolism do not represent the most common cause of seizures, their early identification is of utmost importance, since many will require therapeutic measures beyond that of common anti-epileptic drugs, either in order to control seizures, or to decrease the risk of neurodegeneration. We translate the currently-known literature on metabolic etiologies of epilepsy (268 inborn errors of metabolism belonging to 21 categories, with 74 treatable errors), into a 2-tiered diagnostic algorithm, with the first-tier comprising accessible, affordable, and less invasive screening tests in urine and blood, with the potential to identify the majority of treatable conditions, while the second-tier tests are ordered based on individual clinical signs and symptoms. This resource aims to support the pediatrician, neurologist, biochemical, and clinical geneticists in early identification of treatable inborn errors of metabolism in a child with seizures, allowing for timely initiation of targeted therapy with the potential to improve outcomes.	0
In the era of precision medicine, the identification of several predictive biomarkers and the development of innovative therapies have dramatically increased the request of tests to identify specific targets on cytological or histological samples, revolutionizing the management of the tumoral biomaterials. The Food and Drug Administration (FDA) has recently approved a selective neurotrophic tyrosine receptor kinase (NTRK) inhibitor, larotrectinib. Contemporarily, the development of multi-kinase inhibitors with activity in tumors carrying TRK fusions is ongoing. Chromosomal translocations involving the NTRK1, NTRK2, and NTRK3 genes result in constitutive activation and aberrant expression of TRK kinases in numerous cancer types. In this context, the identification of tumors harboring TRK fusions is crucial. Several methods of detection are currently available. We revise the advantages and disadvantages of different techniques used for identifying TRK alterations, including immunohistochemistry, fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, and next generation sequencing-based approaches. Finally, we propose a diagnostic algorithm based on histology and the relative frequency of TRK fusions in each specific tumor, considering also the economic feasibility in the clinical practice.	0
Gaseous formaldehyde is an organic small molecule formed in the early stages of earth's evolution. Although toxic in high concentrations, formaldehyde plays an important role in cellular metabolism and, unexpectedly, is found even in the healthy brain. However, its pathophysiological functions in the brain are unknown. Here, we report that under physiological conditions, spatial learning activity elicits rapid formaldehyde generation from mitochondrial sarcosine dehydrogenase (SARDH). We find that elevated formaldehyde levels facilitate spatial memory formation by enhancing N-methyl-D-aspartate (NMDA) currents, but that high formaldehyde concentrations gradually inactivate the NMDA receptor by cross-linking NR1 subunits to NR2B via the C232 residue. We also report that in mice with aldehyde dehydrogenase-2 (ALDH2) knockout, formaldehyde accumulation due to hypofunctional ALDH2 impairs memory, consistent with observations of Alzheimer's disease patients. We also find that formaldehyde deficiency caused by mutation of the mitochondrial SARDH gene in children with sarcosinemia or in mice with Sardh deletion leads to cognitive deficits. Hence, we conclude that endogenous formaldehyde regulates learning and memory via the NMDA receptor.	0
Ameloblastic carcinoma (AC) is an exceedingly rare odontogenic cancer about which there is limited information in the literature. We present a case of AC originating in the sinus cavity and extending to the skull base in a patient in the first trimester of pregnancy. Diagnostic work up was complicated by this pregnancy, which delayed radiation exposure with imaging. Once scans were obtained, diagnosis was further complicated by the radiographic similarities between possible lung metastases and previously undiagnosed sarcoid nodules. After thorough work up to rule out metastatic disease, the patient was successfully treated with primary surgical resection followed by adjuvant chemoradiation. The patient remained disease free at one year after therapy. This case demonstrates the importance of thorough work up in the diagnosis of AC, and is an opportunity to review the literature and discuss therapeutic methods to treat this rare, aggressive neoplasm.	0
OBJECTIVES:This study aims to translate and investigate the inter- rater reliability, agreement and validity of the Turkish version of the Cumulated Ambulation Score (CAS-TR) in patients with hip fracture. PATIENTS AND METHODS:This study included patients with a hip fracture of the femoral neck between July 2019 and March 2020 at the Dr. Lütfi Kırdar Kartal Training and Education Hospital, Department of Orthopedics and Traumatology, Istanbul. The CAS manual and score-sheet were translated into Turkish. An orthopedician and a physiotherapist independently administered the CAS-TR to 36 patients (12 males, 24 females; mean age 78.7 years; range, 65 to 90 years) at postoperative days one, two, three and 30. Weighted Cohen's kappa coefficient was used to measure inter-rater reliability. Turkish version of modified Barthel Index was used for analysis of validity. RESULTS:The majority of the patients had type III fracture (72.2%) according to Garden's classification. The kappa value was ≥0.90 for days one-three, the total and 30th day score of CAS-TR. The observed agreement ranged between 91.6% and 100% for all assessments. Validity analysis showed a significantly positive correlation between day two and day 30 CAS-TR and Barthel scores. CONCLUSION:We found almost perfect reliability, high percentage agreement and acceptable convergent validity of the CAS-TR. We recommend the CAS to be used as an easily applicable instrument to assess basic mobility status in Turkish patients with hip fracture. Orthopedic and geriatric patients and patients undergoing any type of surgery can be assessed with CAS for early evaluation of mobility status.	0
Hypotrichosis-lymphedema-telangiectasia syndrome (HLTS) is a rare disorder caused by autosomal recessive and autosomal dominant mutations in SOX18. This gene encodes a transcription factor involved in the regulation and development of the human vasculature, lymphatic, and integumentary systems. Individuals with HLTS develop varying degrees of hypotrichosis, lymphedema, and telangiectasias. Other complications, such as renal failure and aortic dilation, have also been observed. Here, we report a neonate with a novel mutation in SOX18 (c.541C>T; p.Gln181stop) presenting with cardinal features of HLTS in addition to unique findings of severe chylothorax and relentless pulmonary hypertension that culminated in death. The purpose of this report is to summarize what is known about this evolving genetic syndrome and to speculate as to how mutations in SOX18 might produce the phenotype.	0
BACKGROUND:Xeroderma pigmentosum (XP) is a rare autosomal recessive genodermatosis. There are eight complementation groups of XP (XP-A to G and a variant form). XP-E is one of the least common forms, and XP-E patients are generally not diagnosed until they are adults due to a later onset of skin alterations. CASE PRESENTATION:We report a case of a 28-year-old Chinese woman with freckle-like hyperpigmented macules in a sun-exposed area who is prone to develop basal cell carcinomas. A genetic study revealed a novel homozygous c.111_112del deletion in exon 1 of the DDB2 gene. Western blotting analysis revealed that the patient lacked the expression of the wild-type mature DDB2 protein. The proband was first diagnosed with XPE on the basis of clinical findings and genetic testing. Sun protection was recommended, and the patient did not develop any skin cancers during the one-year follow-up. CONCLUSIONS:We identified a novel homozygous deletion in DDB2 gene in Chinese XP-E patients having unique clinical features.	0
BACKGROUND:Nonylphenol (NP) is an environmental endocrine-disrupting chemical (EDC) detected in human cord blood and milk. NP exposure in developmental periods results in hyperadrenalism and increasing 11β-hydroxysteroid dehydrogenase I (11β-HSD1) activity in an adult rat model. Alleviating 11β-HSD1 activity is therefore a logical and common way to treat hyperadrenalism. PF915275 (PF; 4'-cyano-biphenyl-4-sulfonic acid (6-amino-pyridin-2-yl)-amide) is a selective inhibitor for 11β-HSD1. This study aimed to determine whether PF915275 could alleviate the hyperadrenalism induced by NP. In addition to a rat model, the effects of NP and PF915275 were measured in human preadipocytes. METHODS:For the in vivo rat model, female adult rats exposed to NP during the developmental period were divided into two treatment groups, with one receiving oral DMSO solution and the other receiving PF915275 once per day for 4 weeks. After the final treatment, the rats from each group were sacrificed for analysis. For the in vitro human model, human preadipocytes received 2 regimens of NP treatment. One treatment regimen occurred before differentiation (to mimic the sensitive developmental period; P exposure), and the other included continuous exposure from preadipocytes to fully differentiated adipocytes (to mimic the growing and adult periods, respectively; C exposure). Protein and RNA were extracted from rat tissues and the preadipocytes for western blot and real-time PCR analysis. RESULTS:In the rat model, PF915275 alleviated NP-induced effects by interfering with adipogenesis pathways, including enhancing PPARα expression, decreasing PPARγ expression, and reducing both 11β-HSD1 protein and mRNA expression levels. Additionally, PF915275 reduced the effects of the adrenal corticoid synthesis pathway by reducing StAR expression and 11β-hydroxylase and aldosterone synthase activities. With short-term exposure, NP enhanced PPARγ and FASN mRNA expression levels and reduced PPARα expression, whereas PF915275 alleviated these effects. With C exposure, the NP-induced accumulation of intracellular lipids was reduced by PF915275 treatment, which was mediated by decreased PPARγ mRNA and protein expression levels and increased PPARα protein expression. CONCLUSIONS:The effects of NP and PF915275 treatment in both rat and human cell models are similar. Rats may be an appropriate model to study the effects of NP in humans, especially during the developmental period.	0
Mondini dysplasia is a developmental disorder of the inner ear structures and it is a rare cause of recurrent bacterial meningitis in children. A 10-year-old boy presented with acute febrile encephalopathy and right ear pain. In the past, he had suffered from two distinct episodes of pyogenic meningitis. On examination, he had signs of meningeal irritation and right ear sensorineural deafness. Magnetic resonance imaging of the brain and computerized tomography of the temporal bone was suggestive of Mondini dysplasia in the right ear. Our case highlights the need for (a) screening of hearing loss at the bedside by Rinne and Weber test in case of recurrent bacterial meningitis (b) searching for an underlying inner ear malformation if there is a hearing loss.	0
Complement deficiencies are rare and often underdiagnosed primary immunodeficiencies that may be associated with invasive bacterial diseases. Serious infections with encapsulated organisms (mainly Streptococcus pneumoniae, but also Neisseria meningitides and Haemophilus influenzae type B) are frequent in patients with a deficiency of the second component of complement (C2), but no data are available on long-term follow-up. This study aimed to evaluate the long-term clinical outcome and the importance of an early diagnosis and subsequent infection prophylaxis in C2 deficiency. Here, we report the 21-year follow-up of a whole family which was tested for complement parameters, genetic analysis and biochemical measurements, due to recurrent pneumococcal meningitis in the elder brother. The two sons were diagnosed with homozygous type 1 C2 deficiency, while their parents were heterozygous with normal complement parameters. For the two brothers, a recommended vaccination program and antibiotic prophylaxis were prescribed. During the long-term follow-up, no severe/invasive infections were observed in either patient. At the age of 16, the younger brother developed progressive hypogammaglobulinemia of all three classes, IgA, IgM and IgG. A next generation sequencing panel excluded the presence of gene defects related to primary antibody deficiencies. Our data show that early diagnosis, use of vaccinations and antibiotic prophylaxis may allow a normal life in hereditary C2 deficiency, which can be characterized using functional and genetic methods. Moreover, a periodical check of immunoglobulin serum levels could be useful to detect a possible hypogammaglobulinemia.	0
Aneurysms of the sinus of Valsalva are characterized by dilatation of at least one of the three aortic sinuses. We experienced a case with unruptured aneurysm of the right sinus of Valsalva, in which serial imaging studies were useful in assessing a rare complication after surgical repair. An asymptomatic 75-year-old man underwent patch closure of the aneurysm orifice because of progressive enlargement of the aneurysm. The postoperative course was uneventful, and computed tomography (CT), performed a week after the patch repair, showed no leakage of contrast medium into the isolated aneurysm. Three months later, echocardiography showed decreased size of the aneurysm with heterogeneous echogenicity and possible blood flow in the aneurysm, findings suggestive of thrombus formation and a recurrent fistula. CT with contrast medium showed partial recanalization between the patched aneurysm and the right sinus of Valsalva. Follow-up echocardiography, performed 1 year after surgery, revealed neither definite aneurysm nor shunt flow of Valsalva. The present case highlights that non-invasive follow-up can be an alternative option when carried out with caution in selected patients with incomplete closure of Valsalva aneurysm.	0
Adult extracardiac rhabdomyoma (ER) is a rare, slowly growing, benign tumor of skeletal-muscle origin that has a strong predilection for the head and neck. Complete surgical resection has been proposed as the treatment of choice. We describe a case of adult ER that manifested as a nasopharyngeal mass. The diagnosis was made by transnasal endoscopic biopsy, and the patient was managed conservatively. We discuss the current knowledge regarding the clinical presentation, diagnosis, and treatment of adult ER of the parapharyngeal space, and we propose a new concept for treating this tumor nonsurgically in appropriately selected patients.	0
Importance:Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia due to mutations in the aprataxin gene (APTX) that is characterized by early-onset cerebellar ataxia, oculomotor apraxia, axonal motor neuropathy, and eventual decrease of albumin serum levels. Objectives:To improve the clinical, biomarker, and molecular delineation of AOA1 and provide genotype-phenotype correlations. Design, Setting, and Participants:This retrospective analysis included the clinical, biological (especially regarding biomarkers of the disease), electrophysiologic, imaging, and molecular data of all patients consecutively diagnosed with AOA1 in a single genetics laboratory from January 1, 2002, through December 31, 2014. Data were analyzed from January 1, 2015, through January 31, 2016. Main Outcomes and Measures:The clinical, biological, and molecular spectrum of AOA1 and genotype-phenotype correlations. Results:The diagnosis of AOA1 was confirmed in 80 patients (46 men [58%] and 34 women [42%]; mean [SD] age at onset, 7.7 [7.4] years) from 51 families, including 57 new (with 8 new mutations) and 23 previously described patients. Elevated levels of α-fetoprotein (AFP) were found in 33 patients (41%); hypoalbuminemia, in 50 (63%). Median AFP level was higher in patients with AOA1 (6.0 ng/mL; range, 1.1-17.0 ng/mL) than in patients without ataxia (3.4 ng/mL; range, 0.8-17.2 ng/mL; P < .01). Decreased albumin levels (ρ = -0.532) and elevated AFP levels (ρ = 0.637) were correlated with disease duration. The p.Trp279* mutation, initially reported as restricted to the Portuguese founder haplotype, was discovered in 53 patients with AOA1 (66%) with broad white racial origins. Oculomotor apraxia was found in 49 patients (61%); polyneuropathy, in 74 (93%); and cerebellar atrophy, in 78 (98%). Oculomotor apraxia correlated with the severity of ataxia and mutation type, being more frequent with deletion or truncating mutations (83%) than with presence of at least 1 missense variant (17%; P < .01). Mean (SD) age at onset was higher for patients with at least 1 missense mutation (17.7 [11.4] vs 5.2 [2.6] years; P < .001). Conclusions and Relevance:The AFP level, slightly elevated in a substantial fraction of patients, may constitute a new biomarker for AOA1. Oculomotor apraxia may be an optional finding in AOA1 and correlates with more severe disease. The p.Trp279* mutation is the most frequent APTX mutation in the white population. APTX missense mutations may be associated with a milder phenotype.	0
BACKGROUND:Darier's disease has a world-wide distribution, but estimates of prevalence have varied. The discovery that the disease is due to mutations in ATP2A2 provides the opportunity to study the genetic epidemiology of the disease in localized populations. OBJECTIVES:To survey the prevalence of Darier's disease in the west of Scotland and look for founder effects in this population. METHODS:We ascertained cases of Darier's disease in the west of Scotland and used genealogy and mutational analysis to seek common ancestry. RESULTS:Seventy-eight current cases were identified, giving a prevalence of approximately 1 : 30 000. While 63 cases gave a history of Darier's disease in previous generations, conventional genealogy identified only two pairs of two family groups with common ancestry within the last 180 years. Eleven patients (14%; three of whom had in total four affected children) had probable de novo mutations. Causative mutations in ATP2A2 have been identified in 11 of 15 pedigrees screened for mutation, but no two share the same mutation. CONCLUSIONS:High estimates of prevalence are likely to be due to intensive ascertainment, rather than founder effects. Darier's disease is likely to be more common than has been recognized in other populations.	1
Schinzel-Giedion syndrome (SGS) is a rare autosomal dominant disorder that results in facial dysmorphism, multiple congenital anomalies, and an increased risk of malignancy. Recently, using exome sequencing, de novo heterozygous mutations in the SETBP1 gene have been identified in patients with SGS. Most affected individuals do not survive after childhood because of the severity of this disorder. Here, we report SETBP1 mutation confirmed by molecular analysis in a case of SGS with congenital megacalycosis.	0
Mirror foot is a rare abnormality which presents as a preaxial, postaxial, or central polydactyly of the foot. The latter is encountered infrequently. We describe the case of a central mirror foot. Our patient had eight digits of a central ray pattern type with fully developed metatarsal, proximal, middle, and distal phalanges, as well as a medial toe syndactyly. He had no tarsal bone duplications. He was treated by central ray resection via double V-shaped incisions on the dorsal and plantar aspects of the foot, while preserving the medial and lateral rays. The results were satisfactory. We describe the technique and attempt a review of the literature.	0
Limb apraxia is evident in approximately 50% of patients after left hemisphere cerebral vascular accident (LCVA) and increases disability and caregiver dependence. Individuals with apraxia exhibit abnormalities in spatio-temporal aspects of gesture production and/or in knowledge of tool-related actions (action semantics). This preliminary study of three LCVA participants aimed to (i) explore the efficacy of a novel Action Network Treatment (ANT) that focused on improving the semantic association between tool actions and other types of tool knowledge, an intervention inspired by successful semantic network treatments in aphasia (e.g., Edmonds et al., 2009), and (ii) explore whether there are individuals with apraxia who benefit from ANT relative to a version of a comparatively well-studied existing apraxia treatment (Smania et al., 2006; Smania et al., 2000) that shapes gesture via focus on practicing the spatio-temporal aspects of gesture production (Tool Use Treatment or TUT). One participant demonstrated treatment benefits from both ANT and TUT, while another only benefited from TUT. These findings indicate that our novel semantic network strengthening approach to gesture training may be efficacious in at least some individuals with apraxia, and provide a foundation for future study of the characteristics of people with apraxia who benefit from each approach.	0
Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide.	0
Whole exome sequencing detected novel likely pathogenic variants in LRP2 gene in 2 patients presenting with hearing and vision loss, and the Dent disease (DD) classical renal phenotype, that is, low molecular weight proteinuria (LMWP), hypercalciuria and nephrocalcinosis/nephrolithiasis. We propose that a subset of patients presenting as DD may represent unrecognized cases or mild forms of Donnai-Barrow/facio-oculo-acustico-renal (DB/FOAR) syndrome or be on the phenotypic continuum between the 2 conditions.	0
BACKGROUND:Accidentally removed parathyroid glands are still challenging in neck surgery, leading to hypoparathyroidism characterized with abnormally low levels of parathyroid hormone. Parathyroid auto-transplantation is usually applied in compensation. To improve the efficiency of parathyroid transplantation, we introduced a method by co-transplanting with adipose-derived cells, including stromal vascular fractions (SVFs) and adipose-derived stem cells (ADSCs), and investigated the underlying molecular mechanisms involved in parathyroid transplantation survival. METHODS:Rat and human parathyroid tissues were transplanted into nude mice as parathyroid transplantation model to examine the effects of SVFs and ADSCs on grafts angiogenesis and survival rates, including blood vessel assembly and parathyroid hormone levels. Several angiogenic factors, such as vascular endothelial growth factor (VEGF)-A and fibroblast growth factor (FGF) 2, were assessed in parathyroid grafts. The effects of hypoxia were investigated on ADSCs. The modulatory roles of the eyes absent homolog 1 (EYA1), which is vital in parathyroid development, was also investigated on angiogenic factor production and secretion by ADSCs. All experimental data were statistically processed. Student's t test was used to assess significant differences between 2 groups. For multiple comparisons with additional interventions, two-way ANOVA followed by Tukey's post hoc test was performed. P < 0.05 was considered as significant. RESULTS:SVFs improve rat parathyroid transplantation survival and blood vessel assembly, as well as FGF2 and VEGF-A expression levels in parathyroid transplantation mice. Functional human parathyroid grafts have higher microvessel density and increased VEGF-A expression. The supernatant of ADSCs induced tubule formation and migration of human endothelial cells in vitro. Hypoxia had no effect on proliferation and apoptosis of human ADSCs but induced higher angiogenic factor levels of VEGF-A and FGF2, modulated by EYA1, which was confirmed by parathyroid glands transplantation in mice. CONCLUSIONS:Adipose-derived cells, including ADSCs and SVFs, improve parathyroid transplantation survival via promoting angiogenesis through EYA1-regulating angiogenetic factors in vitro and in vivo. Our studies proved an effective method to improve the parathyroid autotransplantation, which is promising for clinical patients with hypoparathyroidism when parathyroid glands were accidentally injured, removed, or devascularized.	0
Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder that manifests as pulmonary emphysema, liver cirrhosis and, rarely, as the skin disease panniculitis, and is characterized by low serum levels of AAT, the main protease inhibitor (PI) in human serum. The prevalence in Western Europe and in the USA is estimated at approximately 1 in 2,500 and 1 : 5,000 newborns, and is highly dependent on the Scandinavian descent within the population. The most common deficiency alleles in North Europe are PI Z and PI S, and the majority of individuals with severe AATD are PI type ZZ. The clinical manifestations may widely vary between patients, ranging from asymptomatic in some to fatal liver or lung disease in others. Type ZZ and SZ AATD are risk factors for the development of respiratory symptoms (dyspnoea, coughing), early onset emphysema, and airflow obstruction early in adult life. Environmental factors such as cigarette smoking, and dust exposure are additional risk factors and have been linked to an accelerated progression of this condition. Type ZZ AATD may also lead to the development of acute or chronic liver disease in childhood or adulthood: prolonged jaundice after birth with conjugated hyperbilirubinemia and abnormal liver enzymes are characteristic clinical signs. Cirrhotic liver failure may occur around age 50. In very rare cases, necrotizing panniculitis and secondary vasculitis may occur. AATD is caused by mutations in the SERPINA1 gene encoding AAT, and is inherited as an autosomal recessive trait. The diagnosis can be established by detection of low serum levels of AAT and isoelectric focusing. Differential diagnoses should exclude bleeding disorders or jaundice, viral infection, hemochromatosis, Wilson's disease and autoimmune hepatitis. For treatment of lung disease, intravenous alpha-1-antitrypsin augmentation therapy, annual flu vaccination and a pneumococcal vaccine every 5 years are recommended. Relief of breathlessness may be obtained with long-acting bronchodilators and inhaled corticosteroids. The end-stage liver and lung disease can be treated by organ transplantation. In AATD patients with cirrhosis, prognosis is generally grave.	1
An autosomal-recessive syndrome of bifid nose and anorectal and renal anomalies (BNAR) was previously reported in a consanguineous Egyptian sibship. Here, we report the results of linkage analysis, on this family and on two other families with a similar phenotype, which identified a shared region of homozygosity on chromosome 9p22.2-p23. Candidate-gene analysis revealed homozygous frameshift and missense mutations in FREM1, which encodes an extracellular matrix component of basement membranes. In situ hybridization experiments demonstrated gene expression of Frem1 in the midline of E11.5 mouse embryos, in agreement with the observed cleft nose phenotype of our patients. FREM1 is part of a ternary complex that includes FRAS1 and FREM2, and mutations of the latter two genes have been reported to cause Fraser syndrome in mice and humans. The phenotypic variability previously reported for different Frem1 mouse mutants suggests that the apparently distinct phenotype of BNAR in humans may represent a previously unrecognized variant of Fraser syndrome.	0
OBJECTIVE:To calculate average annual incidence rates for Huntington's disease (HD) from 1950 through 1989 and to estimate prevalence rates of the disease for January 1, 1960, and January 1, 1990. DESIGN:Health care records from all sources, including hospitals, outpatient clinics, and long-term care institutions, are readily available for all inhabitants of Olmsted County, Minnesota. The diagnoses entered in these records have been coded and indexed. All health care records containing a diagnosis that might suggest HD were reviewed, and those patients for whom the symptoms of HD began between January 1, 1950, and December 31, 1989, were identified. We used specific criteria for diagnosing HD. PARTICIPANTS:Health care records were reviewed; residence in Olmsted County during the year of symptom onset was required. MAIN OUTCOME MEASURES:Average annual incidence rates and prevalence rates for January 1, 1960, and January 1, 1990. RESULTS:Overall incidence rates were 0.4 (95% confidence interval [CI], 0.1 to 0.8) for women and 0.2 (95% CI, 0.04 to 0.6) for men per 100,000 person-years. Estimated prevalence rates for January 1, 1960, per 100,000 person-years were 6 (95% CI, 0.7 to 21.5) for women and 6.6 (95% CI, 0.8 to 23.8) for men. For January 1, 1990, the prevalence rates were 1.8 (95% CI, 0.04 to 10.2) for women and 2 (95% CI, 0.05 to 10.9) for men. CONCLUSIONS:Incidence and prevalence rates of HD in this community are similar to those reported in other communities. The small numbers of affected persons do not allow an estimate of variation over time.	1
Lichen planus pigmentosus (LPP) is an uncommon variant of lichen planus of unclear etiology that predominantly affects patients of skin types III to VI. We report a case of LPP of two years duration in a 67-year-old man involving upper extremities, chest, abdomen, and upper back.	0
Glycosylation is an essential process by which sugars are attached to proteins and lipids. Complete lack of glycosylation is not compatible with life. Because of the widespread function of glycosylation, inherited disorders of glycosylation are multisystemic. Since the identification of the first defect on N-linked glycosylation in the 1980s, there are over 40 different congenital protein hypoglycosylation diseases. This review will include defects of N-linked glycosylation, O-linked glycosylation and disorders of combined N- and O-linked glycosylation.	0
Angiosarcoma is a rare, aggressive malignant vascular neoplasm with poor prognosis that has a predilection for skin and superficial soft tissue. It can arise spontaneously or in association with factors like chronic lymphedema or radiation therapy. Radiotherapy used to treat invasive breast tumors is a known risk factor for the development of the so-called radiation-induced angiosarcoma (RIAS), a condition that has been described in the literature with increasing frequency. Radiation-induced angiosarcoma of the breast usually arises on the previously irradiated skin area several years after radiotherapy and presents as painless multifocal erythematous patches or plaques similar to a hematoma. Cutaneous biopsy is essential for the diagnosis. Histologically, RIAS is characterized by irregular anastomosing vessels lined by endothelial cells showing nuclear atypia. Treatment is mostly surgical, and mastectomy with negative margins is considered the standard procedure. However, recurrences are common, and an approach combining surgery, chemo- and radiotherapy may be more effective. The purpose of this study is to review the most recent medical literature on RIAS of the breast, with emphasis on its pathophysiology, clinical and histological features and current treatment options.	0
Null mutations in CRTAP or P3H1, encoding cartilage-associated protein and prolyl 3-hydroxylase 1, cause the severe bone dysplasias, types VII and VIII osteogenesis imperfecta. Lack of either protein prevents formation of the ER prolyl 3-hydroxylation complex, which catalyzes 3Hyp modification of types I and II collagen and also acts as a collagen chaperone. To clarify the role of the A1 3Hyp substrate site in recessive bone dysplasia, we generated knock-in mice with an α1(I)P986A substitution that cannot be 3-hydroxylated. Mutant mice have normal survival, growth, femoral breaking strength and mean bone mineralization. However, the bone collagen HP/LP crosslink ratio is nearly doubled in mutant mice, while collagen fibril diameter and bone yield energy are decreased. Thus, 3-hydroxylation of the A1 site α1(I)P986 affects collagen crosslinking and structural organization, but its absence does not directly cause recessive bone dysplasia. Our study suggests that the functions of the modification complex as a collagen chaperone are thus distinct from its role as prolyl 3-hydroxylase.	0
A pathogenic GGGCCC hexanucleotide expansion in the first intron/promoter region of the C9orf72 gene is the most common mutation associated with amyotrophic lateral sclerosis (ALS). The C9orf72 gene product forms a complex with SMCR8 (Smith-Magenis Syndrome Chromosome Region, Candidate 8) and WDR41 (WD Repeat domain 41) proteins. Recent studies have indicated roles for the complex in autophagy regulation, vesicle trafficking, and immune response in transgenic mice, however a direct connection with ALS etiology remains unclear. With the aim of increasing understanding of the multi-functional C9orf72-SMCR8-WDR41 complex, we determined by mass spectrometry analysis the proteins that directly associate with SMCR8. SMCR8 protein binds many components of the ubiquitin-proteasome system, and we demonstrate its poly-ubiquitination without obvious degradation. Evidence is also presented for localization of endogenous SMCR8 protein to cytoplasmic stress granules. However, in several cell lines we failed to reproduce previous observations that C9orf72 protein enters these granules. SMCR8 protein associates with many products of genes associated with various Mendelian neurological disorders in addition to ALS, implicating SMCR8-containing complexes in a range of neuropathologies. We reinforce previous observations that SMCR8 and C9orf72 protein levels are positively linked, and now show in vivo that SMCR8 protein levels are greatly reduced in brain tissues of C9orf72 gene expansion carrier individuals. While further study is required, these data suggest that SMCR8 protein level might prove a useful biomarker for the C9orf72 expansion in ALS.	0
Autosomal dominant optic atrophy (ADOA) is a neuro-ophthalmic condition characterized by bilateral degeneration of the optic nerves. Although heterozygous mutations in OPA1 represent the most common genetic cause of ADOA, a significant number of cases remain undiagnosed.Here, we describe a family with a strong ADOA history with most family members spanning three generation having childhood onset of visual symptoms. The proband, in addition to optic atrophy, had neurological symptoms consistent with relapsing remitting multiple sclerosis. Clinical exome analysis detected a novel mutation in the AFG3L2 gene (NM_006796.2:c.1010G > A; p.G337E), which segregated with optic atrophy in family members. AFG3L2 is a metalloprotease of the AAA subfamily which exerts quality control in the inner mitochondrial membrane. Interestingly, the identified mutation localizes close to the AAA domain of AFG3L2, while those localized in the proteolytic domain cause dominant spinocerebellar ataxia type 28 (SCA28) or recessive spastic ataxia with epilepsy (SPAX5). Functional studies in patient fibroblasts demonstrate that the p.G337E AFG3L2 mutation strongly destabilizes the long isoforms of OPA1 via OMA hyper-activation and leads to mitochondrial fragmentation, thus explaining the family phenotype. This study widens the clinical spectrum of neurodegenerative diseases caused by AFG3L2 mutations, which shall be considered as genetic cause of ADOA.	0
Leukocyte adhesion deficiency-III (LAD3) is an extremely rare primary immunodeficiency disorder, transmitted with autosomal-recessive inheritance. It is caused by genetic alteration in the FERMT3 gene, which leads to abnormal expression of kindlin-3. This cytoplasmic protein is highly expressed in leukocytes and platelets, and acts as an important regulator of integrin activation. LAD3 has features like bleeding syndrome of Glanzmann-type and leukocyte adhesion deficiency. FERMT3 mutation(s) have not been well characterized in Pakistani patients with LAD3. In this study, an infant and his family of Pakistani origin, presenting with clinical features of LAD, were investigated to determine the underlying genetic defect. Targeted next generation sequencing (TGS) and Sanger sequencing were performed to identify and confirm the causative mutations, respectively, and their segregation within the family. A novel, homozygous FERMT3 nonsense mutation (c.286C > T, p.Q96∗) was found in the proband, and its co-segregation with LAD3 phenotype within the family was consistent with an autosomal recessive inheritance. Both parents were carriers of the same mutation. This family was offered prenatal diagnosis during first trimester of the subsequent pregnancy; the fetus carried the variant. In conclusion, our study is the first report to identify the novel homozygous variant c.286C > T, p.Q96∗in the FERMT3 gene, which might be the causative mutation for LAD3 patients of Pakistani origin.	0
Objective:Quality of life (QoL) has so far seldom been taken into account by default in decision-making for surgical indication in thyroid surgery. Therefore, we compared pre- and postoperative QoL of patients using the EuroQoL-5D (EQ-5D) questionnaire. The influence of certain socio-economic factors on QoL as a second end-point was considered. Design:Prospective cohort study. Patients:About 153 patients with euthyroid symptomatic benign goitre after hemi- and total thyroidectomy (follow-up 83.6%) have been included. Measurements:The EQ-5D questionnaire was used prior to and 1 year after surgery. In addition, a questionnaire for assessment of socio-economic status was collected. Results:For n = 90 (n = 67 female, n = 23 male), total thyroidectomy (TT) and, for n = 63 (n = 45 female, n = 18 male), hemithyroidectomy (HT) were performed. None permanent dysfunction of the vocal cord was recorded. Transient symptomatic hypocalcaemia was detected in 9% of the thyroidectomy group (8/90 patients). At follow-up, 86% of patients showed either no change or improved QoL. About 14% of patients complained of deteriorated QoL, regardless of the extent of surgery. Socio-economic factors did not influence postoperative QoL. Conclusions:Results indicate that in pre-operative consultation of patients with benign goitre, the improvement of QoL should be taken into account for decision-making in cases of ambiguous surgical indication. Contrary to current discussions that too much thyroid surgery is performed in Germany, we can recommend presenting surgery as an equivalent option to watchful waiting as QoL is at least preserved or improved. The extension of the resection should, however, be decided individually.	0
RPGR exon ORF15 variants are one of the most frequent causes for inherited retinal disorders (IRDs), in particular retinitis pigmentosa. The low sequence complexity of this mutation hotspot makes it prone to indels and challenging for sequence data analysis. Whole-exome sequencing generally fails to provide adequate coverage in this region. Therefore, complementary methods are needed to avoid false positives as well as negative results. In this study, next-generation sequencing (NGS) was used to sequence long-range PCR amplicons for an IRD cohort of African ancestry. By developing a novel secondary analysis pipeline based on de novo assembly, we were able to avoid the miscalling of variants generated by standard NGS analysis tools. We identified pathogenic variants in 11 patients (13% of the cohort), two of which have not been reported previously. We provide a novel and alternative end-to-end secondary analysis pipeline for targeted NGS of ORF15 that is less prone to false positive and negative variant calls.	0
BACKGROUND:Dominant-intermediate Charcot-Marie-Tooth neuropathy subtype C (DI-CMTC) is associated with mutations in the YARS gene. The aim of this study is to investigate the long-term natural history of the disease. METHODS:In a 5-generation DI-CMTC family, we compared data from 2016 to that of 2000 in 13 of 21 original participants. RESULTS:Five women and 8 men were examined. While most symptoms and signs progressed, only gait progression was statistically significant (P = .016). The median CMT Neuropathy Score was 6.08 in 2000 and 11 in 2016 (P = .001). Quality of life (QOL) deteriorated in mobility (P = .008), pain/discomfort (P = .011), and anxiety/depression (P = .014). Median and ulnar compound muscle action potential amplitudes decreased from 9.35 ± 2.90 mV to 6.0 ± 2.9 mV (P = .002), and from 9.24 ± 2.10 mV to 6.06 ± 1.81 mV (P = .004), respectively, whereas motor nerve conduction velocities remained unchanged. CONCLUSIONS:DI-CMTC in this family is a slowly progressive disease with axonal degeneration, deteriorating mobility and QOL.	0
A comparison of epidemiological and clinical features of trigeminal neuralgia (TN) and glossopharyngeal neuralgia (GN) in Rochester, Minn., reveals several differences. The overall age- and sex-adjusted annual incidence rates were significantly higher for TN than for GN (4.7 vs. 0.8 per 100,000 population). The TN:GN ratio was increased for both men and women and was 5.9:1 for both sexes combined. This ratio is greater than reported in previous non-population-based studies. GN is a milder disease than TN, as indicated by the number of episodes, treatment, and characterization of pain. The right side is affected more often with TN than with GN. Bilaterality was noted less often in TN than in GN cases.	1
Hirschsprung's disease (HD) is a congenital disease manifesting various degrees of functional bowel obstruction caused by the absence of enteric ganglion cells, which are usually absent in the colonic segment of the HD patient. Because the aganglionic segment of HD always includes the rectum, pathological diagnosis can be made using a rectal sample. HD should be diagnosed as early as possible because serious complications, such as acute enterocolitis or toxic megacolon, can develop without a definitive diagnosis and appropriate treatment. In the mid-1900s, HD was diagnosed by HE staining of specimens obtained by full-thickness biopsy. Since then, the combination of rectal mucosal biopsy and rubeanic acid-amplificated AChE staining has been brought about by the following milestones: the discovery that the submucosal plexus and the intermuscular plexus had the same level of nerve migration; the findings of research on acetylcholine (ACh) and acetylcholinesterase (AChE) in the intestinal tract; and the establishment of a rubeanic acid amplification method. Consequently, the diagnostic rate of HD improved dramatically in the 1980s. This review outlines the history of diagnostic methods for HD, the roles of ACh and AChE in the intestine, and the method of AChE staining.	0
Microdeletion of the entire interferon regulatory factory 6 (IRF 6) gene is a rare cause of Van der Woude syndrome (VDW) with only few cases reported in medical literature. Its occurrence in multiple affected members of a family is exceptional. The aim of this presentation was to describe a Central African family with typical VDW phenotype carrying an IRF6 gene deletion. Here we reported phenotype features of members of a Central African family with VDW syndrome consisting of labioalveolar cleft, depressions of the lower lip with labial fistulae (lip pits), submucosal clefts and cleft palate. Mutation analysis by means of multiplex ligation-dependent probe amplification and chromosomal microarray revealed a 374.070 kb, deletion encompassing the entire IRF6 gene in four affected family members. Microdeletion of the entire IRF6 gene causes the classical VDW syndrome phenotype.	0
The saccharopine pathway (SACPATH) involves the conversion of lysine into α-aminoadipate by three enzymatic reactions catalyzed by the bifunctional enzyme lysine-ketoglutarate reductase/saccharopine dehydrogenase (LKR/SDH) and the enzyme α-aminoadipate semialdehyde dehydrogenase (AASADH). The LKR domain condenses lysine and α-ketoglutarate into saccharopine, and the SDH domain hydrolyzes saccharopine to form glutamate and α-aminoadipate semialdehyde, the latter of which is oxidized to α-aminoadipate by AASADH. Glutamate can give rise to proline by the action of the enzymes Δ1-pyrroline-5-carboxylate synthetase (P5CS) and Δ1-pyrroline-5-carboxylate reductase (P5CR), while Δ1-piperideine-6-carboxylate the cyclic form of α-aminoadipate semialdehyde can be used by P5CR to produce pipecolate. The production of proline and pipecolate by the SACPATH can help plants face the damage caused by osmotic, drought, and salt stress. AASADH is a versatile enzyme that converts an array of aldehydes into carboxylates, and thus, its induction within the SACPATH would help alleviate the toxic effects of these compounds produced under stressful conditions. Pipecolate is the priming agent of N-hydroxypipecolate (NHP), the effector of systemic acquired resistance (SAR). In this review, lysine catabolism through the SACPATH is discussed in the context of abiotic stress and its potential role in the induction of the biotic stress response.	0
A new type of congenital disorders of glycosylation, designated CDG-Ip, is caused by the deficiency of GDP-Man:Man3GlcNAc2-PP-dolichol-alpha1,2-mannosyltransferase, encoded by the human ortholog of ALG11 from yeast. The patient presented with a multisystemic disorder characterized by muscular hypotonia, seizures, developmental retardation and death at the age of 2 years. The isoelectric focusing pattern of the patient's serum transferrin showed the partial loss of complete N-glycan side chains, which is a characteristic sign for CDG-I. Analysis of dolichol-linked oligosaccharides in patient-derived fibroblasts revealed an accumulation of Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol. Determination of mannosyltransferase activities of early steps of lipid-linked oligosaccharide biosynthesis in fibroblasts indicated that the patient was deficient in elongating Man3GlcNAc2-PP-dolichol. These findings gave rise to genetic analysis of the hALG11 cDNA, in which homozygosity for mutation c.T257C (p.L86S) was identified. Verification of the mutation as a primary cause for the genetic defect was proved by retroviral expression of human wild-type and mutated ALG11 cDNA in patient-derived fibroblasts as well as using a yeast alg11 deletion strain as a heterologous expression system for hALG11 variants. Immunofluorescence examinations combined with western blotting showed no differences of intracellular localization or expression of ALG11 between control and patient fibroblasts, respectively, indicating no mislocalization or degradation of the mutated transferase.	0
FtsK protein contains a fast DNA motor that is involved in bacterial chromosome dimer resolution. During cell division, FtsK translocates double-stranded DNA until both dif recombination sites are placed at mid cell for subsequent dimer resolution. Here, we solved the 3.6-Å resolution electron cryo-microscopy structure of the motor domain of FtsK while translocating on its DNA substrate. Each subunit of the homo-hexameric ring adopts a unique conformation and one of three nucleotide states. Two DNA-binding loops within four subunits form a pair of spiral staircases within the ring, interacting with the two DNA strands. This suggests that simultaneous conformational changes in all ATPase domains at each catalytic step generate movement through a mechanism related to filament treadmilling. While the ring is only rotating around the DNA slowly, it is instead the conformational states that rotate around the ring as the DNA substrate is pushed through.	0
OBJECTIVE: To determine the sensitivity of ultrasonography in screening for foetal malformations in the pregnant women of the Swiss Canton of Vaud. STUDY DESIGN: Retrospective study over a period of five years. METHOD: We focused our study on 512 major or minor clinically relevant malformations detectable by ultrasonography. We analysed the global sensitivity of the screening and compared the performance of the tertiary centre with that of practitioners working in private practice or regional hospitals. RESULTS: Among the 512 malformations, 181 (35%) involved the renal and urinary tract system, 137 (27%) the heart, 71 (14%) the central nervous system, 50 (10%) the digestive system, 42 (8%) the face and 31 (6%) the limbs. Global sensitivity was 54.5%. The lowest detection rate was observed for cardiac anomalies, with only 23% correct diagnoses. The tertiary centre achieved a 75% detection rate in its outpatient clinic and 83% in referred patients. Outside the referral centre, the diagnostic rate attained 47%. CONCLUSIONS: Routine foetal examination by ultrasonography in a low-risk population can detect foetal structural abnormalities. Apart from the diagnosis of cardiac abnormalities, the results in the Canton of Vaud are satisfactory and justify routine screening for malformations in a low-risk population. A prerequisite is continuing improvement in the skills of ultrasonographers through medical education.	1
X-linked Charcot-Marie-Tooth disease type 4 (CMTX4), caused by AIFM1 (Apoptosis-Inducing Factor, Mitochondrion associated 1) mutations and associated with deafness and cognitive impairment, is a rare subtype of Charcot-Marie-Tooth disease. Here, we report a novel missense variant of AIFM1 in a X-linked recessive Chinese family with childhood-onset, slowly progressive, isolated axonal motor and sensory neuropathy. Calf magnetic resonance imaging revealed fatty infiltration and atrophy severely involving the muscles of peroneal compartment. Pathologies exhibited abnormal mitochondrial morphology and accumulation in axoplasm of nerve fiber and subsarcolemmal area of muscle. A hemizygous variant (c.513G>A, p.Met171Ile) in the family was identified and was classified as likely pathogenic according to the standards and guidelines of the American College of Medical Genetics and Genomics. Our report expands the genetic spectrum of diseases related to AIFM1 mutations and indicates that fatty infiltration and atrophy of muscles in the peroneal compartment may be a feature of CMTX4 in early stage.	0
PURPOSE:To report the observation of a triple corneal dystrophy association consisting of keratoconus (KC), epithelial basement membrane corneal dystrophy (EBMCD) and Fuchs' endothelial corneal dystrophy (FECD). METHODS:A 55-year-old male patient was referred to our cornea service for blurred vision and recurrent foreign body sensation. He reported bilateral recurrent corneal erosions with diurnal visual fluctuations. He underwent corneal biomicroscopy, Scheimpflug tomography, in vivo HRT confocal laser scanning microscopy and genetic testing for TGFBI and ZEB1 mutations using direct DNA sequencing. RESULTS:Biomicroscopic examination revealed the presence of subepithelial central and paracentral corneal opacities. The endothelium showed a bilateral flecked appearance, and the posterior corneal curvature suggested a possible concomitant ectatic disorder. Corneal tomography confirmed the presence of a stage II KC in both eyes. In vivo confocal laser scanning microscopy revealed a concomitant bilateral EBMCD with hyperreflective deposits in basal epithelial cells, subbasal Bowman's layer microfolds and ridges with truncated subbasal nerves as pseudodendritic elements. Stromal analysis revealed honeycomb edematous areas, and the endothelium showed a strawberry surface configuration typical of FECD. The genetic analysis resulted negative for TGFBI mutations and positive for a heterozygous mutation in exon 7 of the gene ZEB1. CONCLUSION:This is the first case reported in the literature in which KC, EBMCD and FECD are present in the same patient and associated with ZEB1 gene mutation. The triple association was previously established by means of morphological analysis of the cornea using corneal Scheimpflug tomography and in vivo HRT II confocal laser scanning microscopy.	0
Pemphigus is a group of autoimmune intraepidermal blistering diseases caused by immunoglobulins directed against keratinocyte cell surface components. In this case report, we identify a non-classical paraneoplastic pemphigus (PNP) foliaceous related to an undifferentiated uterine sarcoma. The patient is a 54-year-old Chinese female with a past medical history of arthritis who presented with worsening fatigue in November 2017 and an itchy, blistering, erythematous annular plaque that first appeared on her chest in February 2018. Given high suspicion for primary immunobullous disease despite negative immunofluorescence and lack of subepidermal split on initial biopsy, a repeat biopsy was performed from the right thigh showing positive intraepidermal "net-like" staining for C3 and IgG, but was negative for IgA, IgM, and fibrinogen. IgG antibodies against desmoglein 1 were elevated at 280u (reference range <18), but none resulted against desmoglein 3, consistent with pemphigus foliaceus. This patient's PNP was resistant to treatment with azathioprine, dapsone, mupirocin cream, or betamethasone ointment, but responded to prednisone and rituximab per lymphoma protocol at 375 mg/m2 weekly for one month in December 2018. In February 2019, the patient had 2-3 episodes of postmenopausal vaginal bleeding and subsequent hysteroscopy with dilation and curettage revealed an undifferentiated uterine sarcoma. The patient underwent an exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic lymph node sampling. After surgical staging, she noted significant improvement in her baseline skin lesions and has had no new lesions since surgery. Repeat desmoglein antibodies showed anti-Dsg1 antibodies of 32u (reference range <18) and anti-Dsg3 antibodies of 1u (reference range <19), as compared to the anti-Dsg1 antibodies of 280u in June 2018. She has since completed 4 cycles of adjuvant gemcitabine and docetaxel for her stage IIB undifferentiated uterine sarcoma with no recurrence of the pemphigus lesions.	0
PURPOSE:Microcephaly is a sign of many genetic conditions but has been rarely systematically evaluated. We therefore comprehensively studied the clinical and genetic landscape of an unselected cohort of patients with microcephaly. METHODS:We performed clinical assessment, high-resolution chromosomal microarray analysis, exome sequencing, and functional studies in 62 patients (58% with primary microcephaly [PM], 27% with secondary microcephaly [SM], and 15% of unknown onset). RESULTS:We found severity of developmental delay/intellectual disability correlating with severity of microcephaly in PM, but not SM. We detected causative variants in 48.4% of patients and found divergent inheritance and variant pattern for PM (mainly recessive and likely gene-disrupting [LGD]) versus SM (all dominant de novo and evenly LGD or missense). While centrosome-related pathways were solely identified in PM, transcriptional regulation was the most frequently affected pathway in both SM and PM. Unexpectedly, we found causative variants in different mitochondria-related genes accounting for ~5% of patients, which emphasizes their role even in syndromic PM. Additionally, we delineated novel candidate genes involved in centrosome-related pathway (SPAG5, TEDC1), Wnt signaling (VPS26A, ZNRF3), and RNA trafficking (DDX1). CONCLUSION:Our findings enable improved evaluation and genetic counseling of PM and SM patients and further elucidate microcephaly pathways.	0
We report on 2 sisters and one brother with severe dental anomalies, trichodysplasia, onychodysplasia, and slight skin alterations. Four other relatives have only mild dental anomalies. Differential diagnosis includes 3 other ectodermal dysplasias: hypodontia and nail dysgenesis, dermoodontodysplasia, and trichodermodysplasia with dental alterations. Cause is unknown.	0
The epidemic strain of Venezuelan equine encephalitis virus (VEE) 1B invaded south Texas in 1971. The success of the eventual containment and control of the virus invasion was the early recognition and immediate detection, cooperation, coordination, and participation among multiple federal agencies. There were 4739 wild vertebrate animals trapped on a ranch in the area with only 1 VEE virus isolation from a Virgina opossum (Didelphis virginiana). A large number of mosquitoes were also collected on the ranch and tested, resulting in 240 VEE virus isolations. Virus isolations were obtained from 58% of the 33 equines tested. Wild vertebrates did not play a significant role in the outbreak.	0
BACKGROUND:Pseudodiastrophic dysplasia (PDD) is a severe skeletal dysplasia associated with prenatal manifestation and early lethality. Clinically, PDD is classified as a 'dysplasia with multiple joint dislocations'; however, the molecular aetiology of the disorder is currently unknown. METHODS:Whole exome sequencing (WES) was performed on three patients from two unrelated families, clinically diagnosed with PDD, in order to identify the underlying genetic cause. The functional effects of the identified variants were characterised using primary cells and human cell-based overexpression assays. RESULTS:WES resulted in the identification of biallelic variants in the established skeletal dysplasia genes, B3GAT3 (family 1) and CANT1 (family 2). Mutations in these genes have previously been reported to cause 'multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects' ('JDSCD'; B3GAT3) and Desbuquois dysplasia 1 (CANT1), disorders in the same nosological group as PDD. Follow-up of the B3GAT3 variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstream in vitro functional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of the CANT1 variant showed impaired nucleotidase activity, which results in inhibition of glycosaminoglycan synthesis through accumulation of uridine diphosphate. CONCLUSION:For the families described in this study, the PDD phenotype was caused by mutations in the known skeletal dysplasia genes B3GAT3 and CANT1, demonstrating the advantage of genomic analyses in delineating the molecular diagnosis of skeletal dysplasias. This finding expands the phenotypic spectrum of B3GAT3-related and CANT1-related skeletal dysplasias to include PDD and highlights the significant phenotypic overlap of conditions within the proteoglycan biosynthesis pathway.	0
BACKGROUND:Infantile cortical hyperostosis (ICH)/Caffey disease is an inflammatory collagenopathy of infancy, manifested by subperiosteal bone hyperplasia. Genetically, ICH was linked with heterozygosity for an R836C mutation in the COL1A1 gene. Although an autosomal-recessive trait is also suspected, it has not been proven thus far. METHODS:A case of an infant male born to consanguineous parents is reported, presenting with classical findings, course, and clinical outcome of ICH. Whole-exome sequencing (WES) was performed in order to identify a possible underlying genetic defect. RESULTS:WES analysis revealed a novel homozygous nonsense mutation in lysine 2 of fetuin-A, encoded by the ALPHA-2-HS-GLYCOPROTEIN (AHSG) gene (c.A4T; p.K2X). Fetuin-A is an important regulator of bone remodeling and an inhibitor of ectopic mineralization. By enzyme-linked immunosorbent assay (ELISA), we show a complete deficiency of this protein in the patient's serum, compared to controls. CONCLUSION:A novel homozygous nonsense mutation in AHSG gene has been found in ICH patient with a typical phenotype, resulting in fetuin-A deficiency. This finding postulates an autosomal-recessive mode of inheritance in ICH, which, unlike the autosomal-dominant inheritance associated with COL1A1, is associated with AHSG and fetuin-A deficiency.	0
Brachydactyly type A2 (BDA2) is an autosomal dominant disease characterized by the deformation of the middle phalanx of the second fingers and toes. It has been reported to be associated with three genes regulating the osteogenesis, including BMPR1B, GDF5 and BMP2.10 BDA2 patients and 7 unaffected individuals in a Chinese family were identified through clinical signs and radiographs. The mutation analyses of BMPR1B, GDF5 and BMP2 gene was performed in all the available family members and 100 control subjects. The duplication analysis for the downstream of BMP2 was also performed in all the samples.A novel 4671bp duplication downstream the BMP2 gene was identified in all the patients undergoing molecular analysis but not in the unaffected individuals and healthy controls, with a 28bp microhomology flanking it. There was no mutation in all the exons of BMPR1B, GDF5 and BMP2 in all the tested family members.The novel duplication has different breakpoints compared with the previous ones but highly overlapped with them. The duplication narrows the range of the potential cis-regulatory sequence, and further supports the association between BDA2 and the duplication downstream BMP2.	0
Purpose:To report two cases of retinal vasculitis associated with CREST syndrome, a novel ocular finding. Observations:We report two cases of patients with CREST syndrome with ocular inflammatory disease. Patient 1 presented with a right unilateral panuveitis with extensive retinal vasculitis and evidence of prior uveitis in the contralateral eye. Patient 2 presented with a left branch retinal artery occlusion and bilateral retinal vasculitis. Both patients underwent treatment with prednisone and mycophenolate motefil. Conclusions and importance:Retinal vasculitis has not been previously reported in CREST syndrome. Prompt therapy with immunomodulatory therapy can potentially minimize ocular morbidity.	0
Agaricus blazei Murrill (ABM) is an edible fungus. This study investigated the protective role of ABM fruiting body against streptozotocin (STZ)-induced diabetic rats. After 4 weeks of ABM supplement, glucose homeostasis was improved in diabetic rats. Quantitative real-time and Western blot analyses suggested that ABM could promote the gene and protein expression level of insulin receptor, pyruvate dehydrogenase kinase, phospho-kinase B, kinase B, phosphatidylinositol 3-kinase, insulin receptor substrate 1, glucose transporter-4, and glutamine synthetase, while inhibiting the expression of glycogen synthase kinase 3β and c-jun N-terminal kinase 1 and 2. According to multivariate and univariate statistical analysis, liver metabolite profiles of the normal and diabetic rats fed basal and experimental diet were clearly separated. The differential liver metabolites from diabetic rats fed basal and ABM diet-related pathways including the glycolysis pathway, pentose phosphate pathway, tricarboxylic acid cycle, and oxidative phosphorylation were analyzed. A total of 18 potential biomarker metabolites were identified as differential biomarkers associated with ABM supplement diet.	0
PURPOSE:To report the spectrum of posterior segment findings in tubulointerstitial nephritis and uveitis syndrome (TINU) and discuss the abnormalities that can be seen on imaging. DESIGN:Retrospective, consecutive case series. PARTICIPANTS:Patients with TINU and posterior segment manifestations on examination or imaging. METHODS:Patients with elevated urine beta-2 microglobulin (Uβ2M) and a diagnosis of TINU were included if they were evaluated at the Cole Eye Institute and did not have alternative etiologies for uveitis. Electronic medical records were reviewed for abnormal findings on ultra-widefield fluorescein angiography (UWFFA) and OCT. MAIN OUTCOME MEASURES:Presence of peripheral vascular leakage, optic disc leakage, chorioretinal lesions, or leakage within the macula on UWFFA. For OCT findings, patients were categorized as having intraretinal fluid, epiretinal membrane, or optic nerve edema. RESULTS:Twenty eyes from 10 patients (6 female, 4 male) with a bimodal age distribution (10-46 years and 77-83 years) were included. Eighteen of 20 eyes (90%) underwent UWFFA; 13 eyes demonstrated the presence of peripheral vascular leakage, 5 eyes showed optic disc leakage, and 6 eyes had leakage within the macula. All eyes underwent OCT imaging; 7 eyes demonstrated intraretinal fluid, 4 eyes were found to have an epiretinal membrane, and 1 eye had optic nerve edema. Six eyes lacked anterior uveitis on initial or follow-up examination but had abnormal findings on UWFFA or OCT. CONCLUSIONS:Tubulointerstitial nephritis and uveitis syndrome is under-recognized in the clinical setting. It can manifest in patients of all ages, and posterior segment involvement is not uncommon. Abnormalities may be seen on posterior segment examination or imaging in the absence of anterior segment inflammation. Tubulointerstitial nephritis and uveitis syndrome should be considered in the differential diagnosis for patients presenting with bilateral uveitis without evidence of infection or other clear etiology for intraocular inflammation.	0
Cystic fibrosis is the most common lethal genetic disease in white populations. The outlook for patients with the disease has improved steadily over many years, largely as a result of earlier diagnosis, more aggressive therapy, and provision of care in specialised centres. Researchers now have a more complete understanding of the molecular-biological defect that underlies cystic fibrosis, which is leading to new approaches to treatment. One of these treatments, hypertonic saline, is already in use, whereas others are in advanced stages of development. We review clinical care for cystic fibrosis and discuss recent advances in the understanding of its pathogenesis, implementation of screening of neonates, and development of therapies aimed at treating the basic defect.	1
Reticulohistiocytoses (RH) are rare and clinically heterogeneous histiocytic disorders of dermatological interest. Three clinical entities with superimposable histopathological features are currently considered, namely solitary reticulohistiocytoma, diffuse/generalized reticulohistiocytosis and multicentric reticulohistiocytosis. Although in the last decade, RH studies have only minimally progressed, histiocytosis research has advanced considerably: the prognostic and therapeutic importance of the clinical subclassification of histiocytosis patients as well as of the detection of genetic alterations in the genes of the ERK pathway has been highlighted. According to these insights, we previously reported the presence of molecular alteration RH and described a subset of patients with disseminated multisystem involvement lacking arthritis. In the present review, we aim to update and revise the knowledge regarding RH. We first reviewed their histopathological, immunophenotypical and ultrastructural features, discussed their histopathological differential diagnosis with other conditions characterized by infiltrates made of oncocytic or epithelioid cells (with special regard to Destombes-Rosai-Dorfman disease) and finally summarized the molecular landscape of RH. We therefore tried to adjust the clinical subclassification of Langerhans cell histiocytosis to the clinical phenotypes of RH, outlining five clinically different groups of patients. Finally, we reconsidered the clinical workflow to the evaluation of RH patients, in light of the 5 different clinical groups and discussed the different therapeutic approaches and the possible role of target inhibitors.	0
Neonatal severe hyperparathyroidism (NSHPT) is a rare autosomal recessive disease. Children present within the first 6 months of life and more commonly in the first few weeks. Common presentation is poor feeding, polyuria, dehydration, lethargy, failure to thrive, hypotonia, gastrointestinal dysmotility, osteopenia and symptoms of respiratory distress due to a poorly developed chest cage. We present a case of a 2-month old girl with severe hypercalcemia and hyperparathyroidism. She was found to have a novel homozygous mutation in the acceptor splicing site of intron 4 (c.1378 -2A>G) of the calcium sensing receptor gene (CASR). This mutation causes frame shift deletion of exon 5 and insensitivity of CASR to calcium. The patient was treated with intravenous fluids, fruosemide, calcitonin, intravenous pamidronate and oral cinacalcet. She did not respond to medical treatment. Parathyroid gland imaging including ultrasound, MRI and sestamibi nuclear scan were not helpful in localizing the glands. Her symptoms resolved following total parathyroidectomy. She is being treated with alfacalcidiol and calcium supplements to maintain normal serum calcium and phosphate. She achieved her normal developmental milestones.	0
Graves' disease is seen in the majority of patients diagnosed with hyperthyroidism. The usual symptoms of Graves' disease are tremors, weight loss, sweating, exophthalmos, pretibial edema, anxiety, and palpitations. However, there could be unusual manifestations such as hepatic failure and pulmonary hypertension. We present the case of a 31-year-old female with Graves' disease with these two rare complications, which resolved with medical management in about three months. To the author's knowledge, this is the second case of a patient with this type of presentation.	0
There is a recognized association between silica exposure and Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV); however, no clear association between silica exposure and Immunoglobulin A (IgA) nephropathy. We describe the case of a 26-year-old male stonemason who presents with hilar lymphadenopathy, haematuria and acute kidney injury related to silica exposure, AAV and IgA nephropathy. He was asymptomatic on presentation; urinalysis revealed glomerular haematuria (>1000 red blood cells/L) and proteinuria (protein-to-creatinine ratio 84 mg/mmol). ANCA anti-myeloperoxidase serology was strongly positive. Mediastinal lymph node biopsy revealed multiple necrotizing granulomas with silica inclusions, and renal biopsy demonstrated crescentic glomerulonephritis and mesangial IgA staining. The patient was treated with cyclophosphamide and high-dose prednisolone with subsequent improvement in renal function. To our knowledge, this is the first report of both ANCA vasculitis and IgA nephropathy in the setting of silica exposure. This case highlights the relevance of occupational exposures in renal disease, and the immune-stimulatory effect of silica.	0
We present the case of a 64-year-old woman who has suffered from pustulosis palmaris et plantaris for 10 years. At the first examination, many erythematous lesions with purpura, blood crusts, and blisters were present in the lower legs and dorsum of the feet. Painful swelling in the sternal region and dorsal pain were also noted. Elevation of the CRP and myogenic enzyme levels, and liver and renal dysfunctions were noted on blood testing. Histopathologically, leukocytoclastic vasculitis was noted in small blood vessels in the whole dermal layers, and deposition of IgM and C3 in the vascular wall was detected by the direct immunofluorescence techniques. Based on these findings, cutaneous small vessel vasculitis was diagnosed. Because the patient complained of a toothache during the clinical course, an X-ray examination was performed. On pantomography, a radicular cyst and apical periodontitis were noted. The tooth symptoms changed with exacerbation and remission of the skin symptoms. These findings indicate that odontogenic infection is very likely to be a cause of cutaneous small vessel vasculitis in a manner similar to pustulosis palmaris et plantaris.	0
Malformations of cortical development encompass heterogeneous groups of structural brain anomalies associated with complex neurodevelopmental disorders and diverse genetic and nongenetic etiologies. Recent progress in understanding the genetic basis of brain malformations has been driven by extraordinary advances in DNA sequencing technologies. For example, somatic mosaic mutations that activate mammalian target of rapamycin signaling in cortical progenitor cells during development are now recognized as the cause of hemimegalencephaly and some types of focal cortical dysplasia. In addition, research on brain development has begun to reveal the cellular and molecular bases of cortical gyrification and axon pathway formation, providing better understanding of disorders involving these processes. New neuroimaging techniques with improved resolution have enhanced our ability to characterize subtle malformations, such as those associated with intellectual disability and autism. In this review, we broadly discuss cortical malformations and focus on several for which genetic etiologies have elucidated pathogenesis.	0
Schizencephaly is a rare congenital brain defect characterized by gray matter lined clefts of the cerebral mantle, frequently accompanied by other defects of the CNS such as absence of the corpus callosum. This study in a California population of >4 million births from 1985-2001 found a population prevalence of 1.54/100,000. Among 63 cases, there was an association with young parental age in isolated schizencephaly (RR 3.9 mothers; 5.8 fathers), which was also seen in mothers but not fathers of non-isolated cases (RR 3.2). Monozygotic twins may also be at increased risk for schizencephaly (RR 2.1). One third of cases had a non-CNS abnormality, over half of which could be classified as secondary to vascular disruption, including gastroschisis, bowel atresias, and amniotic band disruption sequence. Other apparent rare causes included chromosomal aneuploidy, non-random associations, and unusual syndromes. Our observations suggest that schizencephaly has heterogeneous etiologies many of which are vascular disruptive in origin.	1
Throughout history, many medical milestones have been achieved to prevent and treat human diseases. Man's early conception of illness was naturally holistic or integrative. However, scientific knowledge was atomized into quantitative and qualitative research. In the field of medicine, the main trade-off was the creation of many medical specialties that commonly treat patients in advanced stages of disease. However, now that we are immersed in the post-genomic era, how should we reevaluate medicine? Genomic medicine has evoked a medical paradigm shift based on the plausibility to predict the genetic susceptibility to disease. Additionally, the development of chronic diseases should be viewed as a continuum of interactions between the individual's genetic make-up and environmental factors such as diet, physical activity, and emotions. Thus, personalized medicine is aimed at preventing or reversing clinical symptoms, and providing a better quality of life by integrating the genetic, environmental and cultural factors of diseases. Whether using genomic medicine in the field of gastroenterology is a new approach or a new medical specialty remains an open question. To address this issue, it will require the mutual work of educational and governmental authorities with public health professionals, with the goal of translating genomic medicine into better health policies.	0
Boerhaave syndrome is a perforation of the esophagus caused by a sudden increase in intraluminal pressure. It is known to be associated with left-sided pleural effusion and mediastinitis, but rarely presents with bilateral effusion. Its association with the presence of a hiatal hernia is unclear. We present a patient with a hiatal hernia who developed bilateral empyemas because of Boerhaave syndrome and was treated with an endoscopically placed esophageal stent.	0
Cerebellar agenesis (CA) is an extremely rare entity. We present two adult patients with CA. The 61-year-old man had ataxia, dysarthria, abnormalities in cerebellar tests, severe cognitive impairment, and moderate mental retardation. The 26-year-old woman had dysmetria, dysdiadochokinesia, and dysarthria as well as mild cognitive impairment and mild mental retardation. Magnetic resonance imaging (MRI) showed complete absence of the cerebellum with small residual vermis. Brainstem was hypoplastic and structures above tentorium were normal. Supratentorial white matter bundles were unaffected in diffusion tensor tractography. Only few adult patients with CA have so far been published. These cases show that patients with CA present with a variety of developmental, clinical, and mental abnormalities; and emphasize the role of the cerebellum in normal motor, language, and mental development.	0
Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms characterized by increased rate of cardiovascular events, a varying burden of symptoms, and an intrinsic risk of evolution to secondary forms of myelofibrosis and acute leukemia; however, survival is only modestly reduced in most instances. In the last few years, following the description of driver mutations in JAK2, MPL and CALR, the diagnostic criteria for PV and ET were revised, making the identification of very early stages feasible. Scores for identifying patients at different risk of thrombosis were refined, and they largely guide therapeutic decisions. Treatment is therefore mainly focused on reduction of thrombosis risk, control of myeloproliferation, improvement of symptomatic burden, and management of disease-associated complications. New drugs recently entered the clinical arena, with the promise to improve overall patients' management. However, evidence of a disease-modifying potential is largely missing and represents a still unmet clinical need.	0
The major causes of rare extracranial carotid artery aneurysms are arteriosclerosis, trauma, and radiation therapy. Here, we describe a patient with an extracranial carotid artery aneurysm caused by a myeloproliferative neoplasm. A 67-year-old woman underwent excision of an irregularly shaped aneurysm in the left common carotid artery and a saphenous vein graft without major complications. The pathologic findings revealed abscess formation and atypical megakaryocyte infiltration, which was also seen in her bone marrow, indicating that the aneurysm was caused by a myeloproliferative neoplasm.	0
Ethylmalonic encephalopathy (EE) is caused by mutations in the ETHE1 gene. ETHE1 is vital for the catabolism of hydrogen sulfide (H2S). Patients with pathogenic mutations in ETHE1 have markedly increased thiosulfate, which is a reliable index of H2S levels. Accumulation of H2S is thought to cause the characteristic metabolic derangement found in EE. Recently introduced treatment strategies in EE, such as combined use of metronidazole (MNZ) and N-acetylcysteine (NAC), are aimed at lowering chronic H2S load. Experience with treatment strategies directed against acute episodes of metabolic decompensation (e.g., hemodialysis) is limited. Here we present an unusually mild, molecularly confirmed, case of EE in a 19-year-old male on chronic treatment with MNZ and NAC. During an acute episode of metabolic decompensation, we employed continuous renal replacement therapy (CRRT) to regain metabolic control. On continuous treatment with NAC and MNZ during the months preceding the acute event, plasma thiosulfate levels ranged from 1.6 to 4 μg/mL (reference range up to 2 μg/mL) and had a mean value of 2.5 μg/mL. During the acute decompensation, thiosulfate levels were 6.7 μg/mL, with hyperlactatemia and perturbed organic acid, acylglycine, and acylcarnitine profiles. CRRT decreased thiosulfate within 24 h to 1.4 μg/mL. Following discontinuation of CRRT, mean thiosulfate levels were 3.2 μg/mL (range, 2.4-3.7 μg/mL) accompanied by clinical improvement with metabolic stabilization of blood gas, acylcarnitine, organic acid, and acylglycine profiles. In conclusion, CRRT may help to regain metabolic control in patients with EE who have an acute metabolic decompensation on chronic treatment with NAC and MNZ.	0
AIM, STUDY AND BACKGROUND: The erosive-atrophic form of Oral lichen Planus (OLP) is often associated with severe pain and burning sensation. This study investigated the efficacy of CO2 laser surgery for management of refractory erosive-atrophic OLP.Ten patients with thirteen erosive-atrophic OLP resistant to standard therapy participated in this study. The size and clinical scores of the lesions and the level of pain/discomfort were recorded before treatment. The lesions were then removed with a CO2 laser device (10600 nm, continuous wave, 5 W, slightly defocused). The subjects were evaluated 1 month and 3 months later and the response rate was assessed according to the decrease in pain, sign scores and size of the lesions.There was a significant reduction in pain and lesion size at 1 and 3 months following laser treatment (p<0.05). The sign scores of the lesions were also significantly improved at follow-up periods compared to the pretreatment state (p<0.05). At the end of the follow-up period, 54% of the lesions showed 3 or 4 degrees of improvement in the clinical score and 23% improved 1 or 2 degrees, whereas 23% remained unchanged post-operatively compared to the pretreatment evaluation.The present results indicate that the CO2 laser surgery is an effective modality for management of erosive-atrophic OLP and can be considered as a suitable alternative to standard treatment.	0
Carney triad is a synchronous or metachronous association of gastric gastrointestinal stromal tumors (GIST), pulmonary chondroma and extra-adrenal paraganglioma. The majority of patients have only one or two components of the triad, all three tumors being found in only about 2% of the patients at the time of the first diagnosis. The most common combination is gastric and pulmonary tumors. We report a case of Carney triad which was diagnosed at Masaryk Memorial Cancer Institute. A 57-year-old female patient with a history of gastric resection for leiomyosarcoma at the age of 14 and with an unclear pulmonary lesion evident on chest X-ray since as early as 2003. She was referred to our Clinic of Comprehensive Cancer Care after being diagnosed with unspecified tumors of the stomach, the left retroperitoneum and two liver metastases. Biopsy of the retroperitoneal mass was performed and histological examination showed pheochromocytoma. The patient underwent resection of the retroperitoneal tumor and wedge resection of the gastric tumor, left hemihepatectomy and left adrenalectomy (in two separate operations). The excised gastric tumor was a gastrointestinal stromal tumor (GIST) with a low risk of malignancy. Analysis of a liver specimen, however, showed two GIST metastases. No pathology was found in the left adrenal gland and the retroperitoneal tumor was positive for chromogranin A. Paraganglioma was thus diagnosed. Subsequently, mutational analysis of genes coding for succinate dehydrogenase subunits B, C and D (SDHB, SDHC, SDHD) and analysis of DNA methylation at the gene locus of SDHC was made. Carney triad was thus confirmed and the unclear pulmonary lesion could be described as benign chondroma. This report demonstrates the difficulty in distinguishing between Carney triad and Carney-Stratakis syndrome. Molecular information should improve the diagnosis of Carney triad.Key words: Carney triad - GIST pulmonary chondroma extraadrenal paragangliomaCarney-Stratakis syndrome.	0
DRAM2-associated retinopathy is a rare inherited retinal dystrophy, and its outcome has not been determined. A single retinal involvement by a mutation of the DRAM2 gene is unexplained. We found three unrelated patients with a disease-causing DRAM2 variant in a biallelic state from 1555 Japanese individuals of 1314 families with inherited retinal dystrophy. We reviewed their medical records and examined their peripheral lymphocytes by transmission electron microscopy (TEM). Patient 1 was a 38-year-old woman who complained of night blindness and reduced vision. She developed macular degeneration at age 43 years. Patients 2 and 3 were a man and a woman both of whom noticed night blindness in their 30s. Both had a degeneration in the macula and midperiphery in their 40s, which progressed to a diffuse retinal degeneration in their 60s when their vision was reduced to hand motions. Three novel DRAM2 variants were identified. TEM of the lymphocytes of Patients 1 and 2 showed abnormal structures in 40.6% and 0.3% of the peripheral lymphocytes, respectively. We concluded that the DRAM2-associated retinopathy of our patients was a progressive rod-cone dystrophy, and the visual outcome was poor. The systemic effect of DRAM2 mutations may be compensable and have variations.	0
Isolated hand syndactyly is a common limb malformation with limited known genetic etiology. We used exome sequencing to discover two novel variants, chr11 g.46896373C>G; p.D1403H and chr11 g.46893078G>T; p.Q1564K, in LRP4 in a child with isolated bilateral syndactyly of the third and fourth fingers. Each variant was inherited from a different parent and neither parent was affected. Variants in LRP4 have been previously associated with syndactyly in Cenani-Lenz syndactyly syndrome and Sclerosteosis 2, but have not been reported in individuals with isolated syndactyly. LRP4 inhibits LRP6/LRP5-mediated activation of canonical Wnt signaling and mediates sclerostin-dependent inhibition of bone formation. p.D1403H and p.Q1564K are located within the fourth β-propeller of the extracellular protein domain that has yet to be associated with human disease. Functional analyses of p.D1403H and p.Q1564K show that they significantly decrease LRP4's inhibition of Wnt signaling. These results suggest that variants in the fourth β-propeller of the extracellular protein domain may cause a phenotype distinct from previously characterized LRP4 variants.	0
BACKGROUND:The double outlet right ventricle is uncommon and usually makes patients have haemodynamic and structural complications. Having a hyperdynamic state, such as pregnancy, with volume overload is very risky for a patient with complex CHD (CCHD). The diagnosis in early stages can prevent cardiac complications. The multi-disciplinary assessment of the disease lets patients make choices in treatment and reproductive life. OBJECTIVE:Present a case of a successful pregnancy in a patient with a rare CCHD. PARTICIPANT:A pregnant 19-year-old patient with a double outlet right ventricle without haemodynamic or structural complications and no fetal abnormalities.	0
PURPOSE:To evaluate the efficacy of corticosteroid-sparing immunomodulatory therapy (IMT) in patients with recurrent and/or sight-threatening central multifocal choroiditis (MFC). METHODS:This was a retrospective cohort study in a tertiary uveitis centre including all patients with MFC who have been treated with IMT for at least 12 months. Clinical data and imaging results were collected regarding the period prior to the start of IMT and at 3, 6, 12 and - where available - 24 months after the start of IMT. Main outcome measure was the number of annual recurrences of choroiditis with or without active choroidal neovascularization before and after the start of IMT. Secondary outcomes were the percentage of patients with (steroid-free) remission and the median time between the start of IMT and (steroid-free) remission. RESULTS:Thirty-two patients (39 eyes) were included. At the start of IMT, none of the patients were in (steroid-free) remission. At 24 months, the probability of achieving remission and steroid-free remission was 88,5% and 50%, respectively. The median time to achieve remission and steroid-free remission was 21 and 83 weeks, respectively. In 17 patients (20 eyes) with available clinical data and imaging results for ≥ 12 months prior to the start of IMT, the mean number of recurrences/year decreased significantly from 1.40 ± 0.81 at baseline to 0.49 ± 0.47 (p = 0.001) after the start of IMT. CONCLUSIONS:Preventive therapy with IMT should be considered in patients with recurrent and/or sight-threatening MFC to decrease the number of recurrences/year and to increase the prospects of achieving either remission or steroid-free remission.	0
BACKGROUND AND OBJECTIVES:Milroy disease is a form of congenital primary lymphedema affecting the lower limbs. When conservative management is ineffective, surgical treatment becomes necessary. The purpose of this study was to investigate the efficacy of vascularized lymph node transfer (VLNT) associated with extensive therapeutic lipectomy in the treatment of these patients. METHODS:In China Medical University Hospital, four patients have been diagnosed with Milroy disease and treated over an 8 year-period time. All patients presented with hereditary bilateral legs swelling since birth. All patients were treated with VLNT from the gastroepiploic region bilaterally associated with extensive therapeutic lipectomy. RESULTS:All procedures have been executed bilaterally and have been successful, without complications. The average follow-up of the patients was 20.2 ± 2.8 months. The limbs treated presented an average circumference reduction of a 4.0 ± 2.1 cm and patients did not experience cellulitis during follow-up. Patients expressed satisfaction with the procedure. CONCLUSIONS:VLNT together with therapeutic lipectomy proved to be a reliable technique in moderate cases of Milroy disease, providing an alternative path for lymph drainage, and reducing the lymph load and the excess of subcutaneous adipose tissues, thus improving patients' quality of life.	0
Rupture of aneurysm of sinus of Valsalva into the right atrium mimicking tricuspid valve endocarditis is a rare presentation. We review a case of spontaneous rupture of aneurysm of sinus of Valsalva into the right atrium presenting as a murmur. Transthoracic echocardiogram showed a mobile mass that appeared to be attached to the tricuspid valve leaflet with moderate tricuspid regurgitation suggestive of tricuspid valve endocarditis. The diagnosis was confirmed as spontaneous rupture of noncoronary sinus in to the right atrium by transesophageal echocardiogram. Patient recovered completely after surgical repair.	0
We report on a 4-month-old boy with manifestations of both the oculo-auriculovertebral spectrum and the caudal regression sequence. He has preauricular appendages, thoracic and lumbar hemivertebrae, anomalies of the ribs, dextrocardia, sacral "dysplasia," dislocated hips, bilateral talipes equinovarus, imperforate anus, recto-vesical fistula, malformed scrotum, and undescended testes. As suggested by Russell et al. [1981], who reported a patient with similar anomalies, the spectrum of anomalies probably is due to a generalized alteration in mesodermal cell migration during the primitive streak period. The term "axial mesodermal dysplasia spectrum" best describes the widespread anomalies in the cranial and caudal regions.	0
In the Original publication of the article, there are two minor errors in Fig. 2 and these include one missing arrow in Fig. 2d and appears as an incorrectly drawn solid lines as dashed line in Fig. 2d.	0
Synpolydactyly type 1 (SPD1, OMIM 186000) is inherited as autosomal dominant and is caused by HOXD13 mutations. The condition is rare and is known for its phenotypic heterogeneity. In the homozygous state, the phenotype is generally more severe and is characterized by three main features: a more severe degree of syndactyly, a more severe degree of brachydactyly, and the frequent loss of the normal tubular shape of the metacarpals/metatarsals. Due to the phenotypic heterogeneity and the phenotypic overlap with other types of syndactyly, no pathognomonic feature has been described for the homozygous phenotype of SPD1. In the current communication, the author reviews the literature on the phenotypes of SPD1 in homozygous patients. The review documents that not all homozygous patients show a severe hand phenotype. The review also defines the "relatively long and medially deviated big toe with/without cupping of the forefoot" as a pathognomonic feature in the phenotype. Illustration of this feature is done through a demonstrative clinical report in a multigeneration family with SPD1 and HOXD13 polyalanine repeat expansion. Finally, the pathogenesis of the clinical features is reviewed.	0
Background:The focused assessment with sonography for trauma (FAST) examination is helpful for the identification of pericardial effusion in trauma. However, in a cardiac rupture with a pericardial perforation, pericardial effusion is not always detected by FAST. We experienced the case that FAST and enhanced CT failed to detect pericardial effusion. Case presentation:A 51-year old woman injured after falling from a height of 3 m was brought to our institute. Focused assessment with sonography for trauma and enhanced computed tomography did not reveal any pericardial effusion; however, a massive hemothorax was revealed. Because the patient's hemodynamic state had become unstable, we performed an urgent left anterolateral thoracotomy. A left pericardial perforation was detected. By performing a clamshell thoracotomy, we found a rupture of 1 cm in diameter at the left atrial appendage. The hemodynamic state was stabilized by suturing the injury site. The postoperative course was uneventful, and the patient was transferred to another hospital after 31 days of admission. Conclusions:Cardiac injury in the left atrial appendage is rare and sometimes difficult to diagnose and to repair. In the case of a blunt chest trauma with a massive hemothorax, although focused assessment with sonography for trauma gives negative results for pericardial effusion, a cardiac rupture with pericardial perforation should be considered.	0
Mitochondrial membrane protein associated neurodegeneration (MPAN) belongs to the Neuronal brain iron accumulation (NBIA) spectrum disorder. It is caused by mutation in the C19orf12 gene. A 13-y-old previously healthy girl born to non-consanguineous marriage couple presented with regression of motor and cognitive milestones and decreased vision in both eyes, since 8 y of age. Examination revealed pyramidal signs, dystonia, dysarthria and pale optic disc. Neuroimaging showed streaking of medial medullary lamina of Globus pallidus. Genetic analysis revealed a novel p. G55 W in exon 3 of C19orf12 gene in homozygous state. Mitochondrial membrane protein associated neurodegeneration should be considered in any child presenting with neuronal brain iron accumulation spectrum disorder with findings of streaking of medial medullary lamina of Globus pallidus and absent retinitis pigmentosa.	0
Takayasu arteritis (TA) is a rare inflammatory arteritis that is usually affecting young women and causes ischemic changes in the vessel wall. In this report of TA leading to an acute ischemic stroke, we describe a treatment-resistant case, with short interval flares and the challenge of defining the stroke etiology as a large vessel occlusive disease vs. an arteritis flare. We have used CT and MRI modalities to show the active disease and got diagnostic answers from this tool.	0
Hiccups are common; however, hiccups caused by sarcoidosis have rarely been reported. An unusual case involving a patient with persistent hiccups possibly caused by hilar/mediastinal lymph node enlargement due to sarcoidosis prompted us to perform a literature search. Eight case reports relating hiccups to sarcoidosis were found and in only one case were the hiccups thought to be due to thoracic lymphadenopathy (LAD). Most cases were attributed to involvement of the central nervous system (CNS) with sarcoidosis. Management of hiccups in general is unclear and only chlorpromazine is approved by the Food and Drug Administration (FDA) for treatment; multiple other pharmacological agents have been advocated mostly being ineffective. This case report describes a patient whose hiccups were likely caused by thoracic sarcoidosis. It reviews the mechanisms of hiccups, explores co-morbid conditions associated with hiccups (including sarcoidosis), and provides some recommended treatments.	0
Germline CDH1 mutation carriers are at risk for early-onset diffuse gastric cancer (DGC) and female carriers have an additional risk of lobular breast cancer. The reported literature GC risk of 70% has led to the recommendation for germline mutation carriers to undergo prophylactic total gastrectomy (PTG). The objective of this research was to examine post-surgical clinical outcomes and to identify which of the domains/symptoms from the European Organisation for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30) were determinants of overall quality of life (QOL) in individuals undergoing PTG. Participants were recruited through multiple sources. Postsurgical clinical outcomes were obtained from hospital records. Participants completed validated questionnaires measuring generic and condition specific QOL (PROMIS, EORTC and SF 36v.II) at a single point in time. The mean QOL in this cohort was 70.6 (SD = 25.6), which is better than reference values from the general populations in USA and Canada Role and social function plus the symptoms anxiety, pain, taste, dyspnea and diarrhea were significant predictor variables for QOL (p < 0.05). Although this study reveals good overall QOL for individuals after PTG, attention should be given to managing symptoms as part of long term care to further enhance QOL. The function/symptom scores were associated with worse overall health and global health status and thus may mark a real need for more attentive post-surgical care.	0
Skeletal dysplasia (SD) is a complex group of bone and cartilage disorders often detectable by fetal ultrasound, but the definitive diagnosis remains challenging because the phenotypes are highly variable and often overlap among different disorders. The molecular mechanisms underlying this condition are also diverse. Hundreds of genes are involved in the pathogenesis of SD, but most of them are yet to be elucidated, rendering genotyping almost infeasible except those most common such as fibroblast growth factor receptor 3 (FGFR3), collagen type I alpha 1 chain (COL1A1), collagen type I alpha 2 chain (COL1A2), diastrophic dysplasia sulfate transporter (DTDST), and SRY-box 9 (SOX9). Here, we report the use of trio-based whole exome sequencing (trio-WES) with comprehensive gene set analysis in two Taiwanese non-consanguineous families with fetal SD at autopsy. A biparental-origin homozygous c.509G>A(p.G170D) mutation in peptidylprolyl isomerase B (PPIB) gene was identified. The results support a diagnosis of a rare form of autosomal recessive SD, osteogenesis imperfecta type IX (OI IX), and confirm that the use of a trio-WES study is helpful to uncover a genetic explanation for observed fetal anomalies (e.g., SD), especially in cases suggesting autosomal recessive inheritance. Moreover, the finding of an identical PPIB mutation in two non-consanguineous families highlights the possibility of the founder effect, which deserves future investigations in the Taiwanese population.	0
Creatine stores high-energy phosphate bonds in muscle, which is critical for muscle activity. In animals, creatine is synthesized in the liver from guanidinoacetic acid (GAA) with methylation by S-adenosylmethionine. Because methyl groups are used for the conversion of GAA to creatine, methyl group deficiency may occur as a result of GAA supplementation. With this study, the metabolic responses of cattle to post-ruminal supplementation of GAA were evaluated with and without methionine (Met) supplementation as a source of methyl groups. Six ruminally cannulated Holstein heifers (520 kg) were used in a split-plot design with treatments arranged as a 2 × 5 factorial. The main plot treatments were 0 or 12 g/d of l-Met arranged in a completely randomized design; three heifers received each main plot treatment throughout the entire experiment. Subplot treatments were 0, 10, 20, 30, and 40 g/d of GAA, with GAA treatments provided in sequence from lowest to highest over five 6-d periods. Treatments were infused continuously to the abomasum. Heifers were limit-fed twice daily a diet consisting of (dry matter basis) 5.3 kg/d rolled corn, 3.6 kg/d alfalfa hay, and 50 g/d trace-mineralized salt. Plasma Met increased (P < 0.01) when Met was supplemented, but it was not affected by supplemental GAA. Supplementing GAA linearly increased plasma arginine (% of total amino acids) and plasma concentrations of GAA and creatinine (P < 0.001). Plasma creatine was increased at all levels of GAA except when 40 g/d of GAA was supplemented with no Met (GAA-quadratic × Met, P = 0.07). Plasma homocysteine was not affected by GAA supplementation when heifers received 12 g/d Met, but it was increased when 30 or 40 g/d of GAA was supplemented without Met (GAA-linear × Met, P = 0.003); increases were modest and did not suggest a dangerous hyperhomocysteinemia. Urinary concentrations of GAA and creatine were increased by all levels of GAA when 12 g/d Met was supplemented; increasing GAA supplementation up to 30 g/d without Met increased urinary GAA and creatine concentrations, but 40 g/d GAA did not affect urine concentrations of GAA and creatine when no Met was supplemented. Overall, post-ruminal GAA supplementation increased creatine supply to cattle. A methyl group deficiency, demonstrated by modest increases in plasma homocysteine, became apparent when 30 or 40 g/d of GAA was supplemented, but it was ameliorated by 12 g/d Met.	0
Neurexins are presynaptic cell adhesion molecules critically involved in synaptogenesis and vesicular neurotransmitter release. They are encoded by three genes (NRXN1-3), each yielding a longer alpha (α) and a shorter beta (β) transcript. Deletions spanning the promoter and the initial exons of the NRXN1 gene, located in chromosome 2p16.3, are associated with a variety of neurodevelopmental, psychiatric, neurological and neuropsychological phenotypes. We have performed a systematic review to define (a) the clinical phenotypes most associated with mono-allelic exonic NRXN1 deletions, and (b) the phenotypic features of NRXN1 bi-allelic deficiency due to compound heterozygous deletions/mutations. Clinically, three major conclusions can be drawn: (a) incomplete penetrance and pleiotropy do not allow reliable predictions of clinical outcome following prenatal detection of mono-allelic exonic NRXN1 deletions. Newborn carriers should undergo periodic neuro-behavioral observations for the timely detection of warning signs and the prescription of early behavioral intervention; (b) the presence of additional independent genetic risk factors should always be sought, as they may influence prognosis; (c) children with exonic NRXN1 deletions displaying early-onset, severe psychomotor delay in the context of a Pitt-Hopkins-like syndrome 2 phenotype, should undergo DNA sequencing of the spared NRXN1 allele in search for mutations or very small insertions/deletions.	0
Atrioventricular canal defect (AVCD) represents a quite common congenital heart defect (CHD) accounting for 7.4% of all cardiac malformations. AVCD is a very heterogeneous malformation that can occur as a phenotypical cardiac aspect in the context of different genetic syndromes but also as an isolated, non-syndromic cardiac defect. AVCD has also been described in several pedigrees suggesting a pattern of familiar recurrence. Targeted Next Generation Sequencing (NGS) techniques are proved to be a powerful tool to establish the molecular heterogeneity of AVCD.Given the complexity of cardiac embryology, it is not surprising that multiple genes deeply implicated in cardiogenesis have been described mutated in patients with AVCD. This review attempts to examine the recent advances in understanding the molecular basis of this complex CHD in the setting of genetic syndromes or in non-syndromic patients.	0
BACKGROUND AND AIM: We have described a novel Mahvash disease of hyperglucagonemia and pancreatic neuroendocrine tumors (PNETs) associated with an inactivating glucagon receptor mutation, and identified the glucagon receptor-deficient (Gcgr(-/-)) mice as its murine model. We aim to elucidate the natural history of the rare Mahvash disease by long-term observation of the Gcgr(-/-) mice. MATERIALS AND METHOD: Wild type (WT) (n=52), heterozygous (n=127), and Gcgr(-/-) (n=56) mice living under standard vivarium conditions were observed without specific treatments over 22 months. Autopsy was performed on dead animals. RESULTS: The WT and heterozygous mice did not exhibit any measurable differences. The Gcgr(-/-) mice became progressively lethargic and cachexic after 12 months. Random glucose levels were stable in WT and heterozygous mice but decreased with age in the Gcgr(-/-) mice. At the end of observation, 28/56 Gcgr(-/-), 7/52 WT, and 24/127 heterozygous mice died. The survival curve of Gcgr(-/-) mice began to separate from those of WT and heterozygous mice at 12 months and the survival difference widened with age. At 18 months, survival probability was 17% for Gcgr(-/-) mice but 77% for WT and 81% for heterozygous mice. Autopsy revealed numerous PNETs up to 15 mm in diameter in most well-preserved Gcgr(-/-) pancreata (17/20) but none in WT or heterozygous ones. Four Gcgr(-/-) mice developed liver or subcutaneous metastasis. CONCLUSION: The untreated Mahvash disease may cause cachexia, severe hypoglycemia, and early death. Patients with Mahvash disease need to undergo life-long surveillance for PNETs. Functional glucagon receptor is thus required for long-term survival.	0
BACKGROUND:Dextrocardia with situs inversus is a rare genetic condition in which the heart and internal organs are positioned on the opposite side of the body. Diagnosing and treating acute myocardial infarction correctly in a patient with dextrocardia is a difficult task. CASE REPORT:We present the case of an acute anterior wall ST elevation myocardial infarction (STEMI) in a patient with dextrocardia with situs inversus diagnosed after a lead reversal electrocardiogram (ECG). The patient then successfully underwent percutaneous coronary intervention and subsequent multivessel coronary artery bypass grafting. We discuss the original diagnosis and decision-making, clinical features, ECG characteristics, and disposition of the patient, as well as a review of the relevant literature. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians must identify and recognize the typical ECG of dextrocardia, especially when presenting with pathology, as its identification can lead to proper diagnosis and treatment.	0
Osteopoikilosis (OP) is a very rare benign sclerosing bony dysplasia with an autosomal dominant inheritance. We describe the morphology of an osteopoikilosis male patient, associated with severe pain on wrist and hand joints, report on the relative literature and focus on clinical significance, due to mimicking capability of other more severe conditions such as bone metastases.	0
Charles Bonnet syndrome (CBS) is a condition of visual hallucinations or disturbances occurring in patients with visual pathway pathology not due to underlying psychiatric, metabolic, or neurologic disease. A patient with Parkinson's disease experiencing visual hallucinations was evaluated by the ophthalmology service and found to have decreased vision due to bilateral reversible posterior capsular opacification. The patient's hallucinations did not improve on clozapine, a medication requiring careful monitoring due to potentially severe systemic side effects. However, the hallucinations resolved and vision improved after bilateral treatment of the posterior capsular opacification. Clozapine was then discontinued, and the patient was able to resume his previous Parkinson's disease therapy. This case highlights the importance of considering visual pathway pathology as a contributing factor to visual hallucinations, even in patients with previously diagnosed underlying psychiatric, metabolic, or neurologic disease that could additionally be the etiology of the visual disturbances.	0
Down syndrome (DS) is related to constitutional trisomy 21 and is characterized by typical dysmorphic features and various congenital abnormalities. DS is also associated with a broad spectrum of hematological findings, such as transient thrombocytopenia in the neonatal period and acute leukemia. Of those hematological abnormalities, transient abnormal myelopoiesis (TAM) and acute myeloid leukemia (AML) have common genetic abnormalities, i.e., trisomy 21 and GATA1 mutation, and form a continuous spectrum, referred to as myeloid proliferations related to DS. Recent studies have demonstrated interactions between trisomy 21 and GATA1 mutations. Trisomy 21 promotes the expansion of early hematopoietic progenitors and upregulates short form GATA1, resulting in the accelerated production of aberrantly differentiated cells and development of TAM. Following spontaneous remission of TAM, subsequent AML can evolve from a preexisting residual TAM clone through the acquisition of additional mutations involving multiple cohesion components and epigenetic regulators.	0
Differential diagnosis of mycosis fungoides (MF) in the early stages can be challenging. Dermoscopy has been reported to be useful in the evaluation of early MF. However, to our knowledge, there is no study that specifies these early stages as stage IA, IB or IIA. The present study aims to evaluate the dermoscopic findings of stage IIA MF in comparison with plaque psoriasis (PP). Thirty-four patients aged between 16-70 years with stage IIA MF (n=17) and PP (n=17) were evaluated in this prospective study. Dermoscopic examinations were performed by manual dermatoscopy (Dermlite DL4). χ2 test was used. In patients with stage IIA MF, orange-yellow patches (88.2%), short, fine and linear vessels (82.3%), geometric white scales (70.5%), perifollicular white scales (47%) and white patches (35.2%) were common, while dotted vessels (94.1%), diffuse lamellar white scales (88.2%) and dotted and globular vessels (70.5%) were common in patients with PP. Although spermatozoa-like structures, purpuric dots, collarette white scales and Y-shaped arborizing vessels were common in patients with MF, this was not statistically significant. Geometric white scales (clinically; cigarette paper-like wrinkly scales) correlated with alternating parakeratosis and orthokeratosis in the stratum corneum histopathologically. A unique aspect of our study is that this study provides insights about the importance of scales in differentiating MF from PP. Orange-yellow and white patches, short, fine and linear vessels, geometric and perifollicular white scales may be useful in distinguishing stage IIA MF from PP by hand-held dermoscopy.	0
The serum insulin-like growth factor-I (IGF-I) concentration is commonly used as a screening tool for growth hormone deficiency (GHD), but there is no consensus on the cut-off limit of IGF-I standard deviation score (SDS) to perform GH stimulation tests for confirmation or exclusion of GHD. We argue that the cut-off limit is dependent on the clinical pre-test likelihood of GHD and propose a diagnostic strategy in which the cut-off limit varies between zero to -2 SDS.	0
Femoral vein access is the first choice for percutaneous atrial septal defect closure, and when it cannot be used due to anatomic reasons, the alternative sites should be considered, frequently increasing the complexity of the procedure. Here we report the case of a 3-year-old boy, with situs inversus and dextrocardia, electively referred for percutaneous closure of an ostium secundum atrial septal defect. During the procedure, agenesis of the infra-hepatic segment of the inferior caval vein was diagnosed, and no double inferior caval vein or right superior caval vein were identified by ultrasound or angiography. Therefore, we opted to perform the procedure through the left internal jugular vein, with fluoroscopy and transesophageal echocardiographic guidance. Catheters were navigated through a hydrophilic guidewire, and a Stiff guidewire was positioned in the left ventricle for better support. An Amplatzer septa occluder 19 was successfully deployed without major difficulties and the patient was discharged after 24 hours in good clinical condition. Percutaneous atrial septal defect closure through alternative access sites, especially in the presence of situs inversus, may pose significant challenges to the interventional team. In this case, the left internal jugular vein has shown to be a feasible option, allowing the navigation and manipulation of devices without complications. Provided the expertise of the interventional team, and awareness of the risks involved, alternative access sites can be successfully used for paediatric structural interventions.	0
BACKGROUND: Well known for its gene density and the large number of mapped diseases, the human sub-chromosomal region Xq28 has long been a focus of genome research. Over 40 of approximately 300 X-linked diseases map to this region, and systematic mapping, transcript identification, and mutation analysis has led to the identification of causative genes for 26 of these diseases, leaving another 17 diseases mapped to Xq28, where the causative gene is still unknown. To expedite disease gene identification, we have initiated the functional characterisation of all known Xq28 genes. RESULTS: By using a systematic approach, we describe the Xq28 genes by RNA in situ hybridisation and Northern blotting of the mouse orthologs, as well as subcellular localisation and data mining of the human genes. We have developed a relational web-accessible database with comprehensive query options integrating all experimental data. Using this database, we matched gene expression patterns with affected tissues for 16 of the 17 remaining Xq28 linked diseases, where the causative gene is unknown. CONCLUSION: By using this systematic approach, we have prioritised genes in linkage regions of Xq28-mapped diseases to an amenable number for mutational screens. Our database can be queried by any researcher performing highly specified searches including diseases not listed in OMIM or diseases that might be linked to Xq28 in the future.	0
Linear and whorled nevoid hypermelanosis (LWNH) is a pigmentation disorder characterized by macular hyperpigmentation following the lines of Blaschko. Dermatoscopy can be used in the differential diagnosis of this pigmentation disorder. To our knowledge, the dermatoscopic features of pigmented lesions in LWNH have not been described previously. Here, a case of LWNH is discussed together with its dermatoscopic findings. An 11-year-old girl presented to our department with hyperpigmentation along the lines of Blaschko over the entire body. The mental status of the patient was normal and no associated anomaly was detected in the physical examination or genetic analysis. Dermatologic examination revealed a whorled-like configuration of hyperpigmented macules on the neck, trunk, and buttocks, and a linear configuration of hyperpigmented macules, some of which were arranged in a parallel linear fashion on the extremities along the lines of Blaschko. Histopathologic examination confirmed the diagnosis. Dermatoscopic examination revealed linear or circular arrangement of streak-like pigmentations arranged in a parallel manner. This is the first known reported case of LWNH that describes its dermatoscopic findings. Dermatoscopy may be used to facilitate the differential diagnosis of melanotic lesions of this pigmentation disorder.	0
In vitro fertilization (IVF) procedures have been frequently associated with antithrombotic treatments, in particular, to aspirin or low-molecular-weight heparin (LMWH). The rationale of this treatment is based on the increase of thrombotic risk occurring in this clinical context. Indeed, both prothrombotic changes of coagulation parameters specifically related to IVF procedures as well as the presence of potential thrombophilic alterations may concur to increase the risk in these women. Furthermore, the presence of thrombophilia has been suggested as a potential cause of recurrent IVF failures. Therefore, antithrombotic treatments have been historically planned to prevent thrombotic disorders during pharmacological ovarian stimulation and/or to increase a successful rate of pregnancy and live births after IVF with embryo transfer. However, up to date, the role of inherited and\or acquired thrombophilia is still debated as well as a univocal therapeutic approach is lacking in women with infertility. The administration of antithrombotic drugs differs in several studies and even the dosages of aspirin and\or low-molecular-weight heparin are different. This review focuses on underlining current evidence on the role of thrombophilia and thromboprophylaxis in women selected for IVF with embryo transfer.	0
Newborn screening (NBS) can detect 21-hydroxylase deficiency (21-OHD), allowing for early treatment initiation. However, many patients present with adrenal crises or hyponatremia at their first visit. Age (in days) of hyponatremia development in infants with salt-wasting (SW)-type 21-OHD remains unclear. Therefore, we determined the earliest age of hyponatremia diagnosis in this retrospective observational study using medical records of 40 patients with classic 21-OHD in Niigata Prefecture, Japan, from April 1989 to March 2019. We determined the earliest diagnosis of hyponatremia (serum sodium levels < 130 mEq/L) and created a sodium decrease rate model to estimate hyponatremia development age. Of 23 patients with SW-type 21-OHD, 10 (43.5%) were identified during NBS; the earliest case to present with hyponatremia was at day 7. Serum sodium levels were significantly and negatively correlated with age in days, and hyponatremia was estimated to develop at 6.6 d after birth. Genotype or serum 17-hydroxyprogesterone levels were not associated with sodium decrease rate. Thus, hyponatremia development age is earlier (within 7 d) than the previously described time-point (10-14 d) in infants with SW-type 21-OHD. Efforts to reduce the time lag from obtaining results to consultation may be required in patients with high 17-hydroxyprogesterone levels on NBS.	0
Immunodeficiency 10 is an autosomal recessive disorder presenting with iris hypoplasia, muscular hypotonia and nonprogressive myopathy, recurrent bacterial infections, autoimmune hemolytic anemia, hypohidrosis and nail dysplasia caused by the mutation of stromal interaction molecule 1 gene (STIM1). Herein, we present a new case of STIM1 mediated immunodeficiency, carrying a novel frameshift mutation. Our patient presented with nephrotic syndrome, hypotonia, myopathy, recurrent bacterial infections, thrombocytopenia and autoimmune hemolytic anemia. She is now 23 months old and is on steroid, cyclosporine and monthly IVIG. She has had no recent significant infections and is receiving rehabilitation therapy to improve her motor skills. Rare genetic syndromes should be suspected in patients of consanguineous parents, who present with a set of different manifestations. Gathering all the patient's manifestations together and looking them as one disease should be encouraged.	0
BACKGROUND:Friedreich's ataxia (FA) is a rare autosomal recessive mitochondrial disease resulting of a triplet repeat expansion guanine-adenine-adenine (GAA) in the frataxin (FXN) gene, exhibiting progressive cerebellar ataxia, diabetes and cardiomyopathy. We aimed to determine the relationship between cardiac biomarkers, serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and serum cardiac high-sensitivity troponin (hsTnT) concentrations, and the extent of genetic abnormality and cardiac parameters. METHODS:Between 2013 and 2015, 85 consecutive genetically confirmed FA adult patients were prospectively evaluated by measuring plasma hsTnT and NT-proBNP concentrations, electrocardiogram, and echocardiography. RESULTS:The 85 FA patients (49% women) with a mean age of 39 ± 12 years, a mean disease onset of 17 ± 11 years had a mean SARA (Scale for the Assessment and Rating of Ataxia) score of 26 ± 10. The median hsTnT concentration was 10 ng/L (3 to 85 ng/L) and 34% had a significant elevated hsTnT ≥ 14 ng/L. Increased septal wall thickness was associated with increased hsTnT plasma levels (p < 0.001). The median NT-proBNP concentration was 31 ng/L (5 to 775 ng/L) and 14% had significant elevated NT-proBNP ≥ 125 ng/L. Markers of increased left ventricular filling pressure (trans mitral E/A and lateral E/E' ratio) were associated with increased NT-proBNP plasma levels (p = 0.01 and p = 0.01). Length of GAA or the SARA score were not associated with hsTnT or NT-proBNP plasma levels. CONCLUSION:hsTnT was increased in 1/3 of the adult FA and associated with increased septal wall thickness. Increased NT-proBNP remained a marker of increased left ventricular filling pressure. This could be used to identify patients that should undergo a closer cardiac surveillance.	0
OBJECTIVE:This study was undertaken to identify pathological conditions within the population living at Atalla (1000-500 BCE), an important early village site and ritual center located in Huancavelica, Peru. MATERIALS:Articulated burials (N = 3) and commingled human remains excavated during the 2015 and 2016 field seasons. METHODS:Osteological remains were analyzed for macroscopic evidence of pathological changes. RESULTS:A case of bilateral proximal radioulnar fusion was observed in an Early Horizon (ca. 800 BCE) subadult skeleton (Individual 1). A differential diagnosis of this pathology supports congenital radioulnar synostosis (CRUS), a rare developmental condition. Enamel hypoplasia was also identified in the same individual. CONCLUSIONS:Burial treatment of Individual 1 does not provide any indication that CRUS was afforded an exceptional social significance. CONTRIBUTION TO PALEOPATHOLOGY:This example of CRUS is notable as it represents the second published archaeological case of CRUS from Peru and the earliest reported case globally. LIMITATIONS OF THIS STUDY:The osteological sample currently available from this site is limited. SUGGESTIONS FOR FUTURE RESEARCH:Increased fieldwork in this region is recommended to further clarify the distribution and social significance of CRUS in the prehistoric Andes.	0
Context:Subependymal nodular heterotopia is a cortical development malformation that is commonly associated with refractory epilepsy. Patients with heterotopia show a wide spectrum of clinical manifestations, from being asymptomatic to presenting with intractable seizures and intellectual impairment. Case Report:We report a case of refractory epilepsy with normal intelligence, having bilateral subependymal heterotopic nodules in brain, presenting to us with a movement disorder in the form of myoclonus of bilateral lower limbs which is an unusual manifestation of gray matter heterotopias. Conclusion:Though rare, gray matter heterotopias may present as movement disorder and should be considered in differential diagnosis while work up of movement disorders.	0
Dermatitis herpetiformis (DH) is a genetically determined, gluten sensitive autoimmune bullous dermatosis related to celiac disease in which granular, insoluble aggregates in the papillary dermis of epidermal transglutaminase (TG3), immunoglobulin A (IgA), and fibrinogen are present. Detection of the dermal IgA-TG3 immune complex is the gold standard of diagnosis. DH develops in a subpopulation of patients with gluten sensitive enteropathy, characterized by itching, erythematous, excoriated papules showing characteristic distribution over the knees, elbows and buttocks; vesicles are rarely seen. The primary therapy of DH is a strict, lifelong gluten-free diet, and it may be necessary to temporarily give dapsone in case of severe symptoms.	0
Toriello-Carey syndrome is rare condition characterized by agenesis of the corpus callosum, the Pierre Robin sequence, and facial anomalies such as telecanthus, short palpebral fissures, and a small nose with anteverted nares [Toriello and Carey, 1988]. In addition, tracheal and laryngeal anomalies are common complications in patients with Toriello-Carey syndrome, and these anomalies can lead to death [Kataoka et al., 2003]. Congenital tracheal stenosis is a life-threatening condition with high mortality. Even if surgery is successful, several serious complications can result in a high risk of mortality. We describe a case of a Japanese boy with Toriello-Carey syndrome who had severe congenital tracheal stenosis, in whom surgical tracheal plasty was avoided because of adequate respiratory care, allowing the patient to be alive at 18 months of age.	0
Variegate porphyria (VP) is an autosomal dominant disease caused by mutations of the protoporphyrinogen oxidase (PPOX) gene. This porphyria has unique characteristics which can induce acute neurovisceral attacks and cutaneous lesions that may occur separately or together. We herin report a 58-years-old VP patient complicated with cholelithiasis. A sequencing analysis indicated a novel c.40G>C mutation (p.G14R) in the PPOX gene. His cutaneous photosensitivity had been worsening for 3 years before the emergence of cholecystitis and it then gradually improved after cholecystectomy and ursodeoxycholic acid treatment with a slight decline in the porphyrin levels in his blood, urine and stool. In VP patients, a worsening of photosensitivity can thus be induced due to complications associated with some other disease, thereby affecting their porphyrin-heme biosynthesis.	0
Primary cardiac angiosarcoma (PCAS) is a malignancy seldom seen in pregnancy. A 23-year-old G1P0 Chinese female was found to have PCAS during her first trimester when she presented with tamponade physiology. The transthoracic echocardiography (TTE) results did not indicate the presence of an intracardiac lesion, and pericardial fluid cytology analysis showed no evidence of malignancy. Cardiac magnetic resonance imaging (CMRI) exhibited a right atrial mass, and tissue biopsy indicated a high-grade angiosarcoma. MRI of the abdomen was suggestive of liver metastasis. She underwent an abortion and was started on combination chemotherapy, with a reduction in both the cardiac and liver masses. In cardiac angiosarcomas, advanced imaging modalities such as MRI should be utilised when there is high clinical suspicion or in the case of pregnancy when trying to minimise foetal harm. Prognosis is poor, and a standardised treatment protocol regardless of pregnancy continues to elude the medical community.	0
BACKGROUND:Joubert syndrome is a recessive neurodevelopmental disorder characterized by clinical and genetic heterogeneity. Clinical hallmarks include hypotonia, ataxia, facial dysmorphism, abnormal eye movement, irregular breathing pattern cognitive impairment and, the molar tooth sign is the pathognomonic midbrain-hindbrain malformation on magnetic resonance imaging. The disorder is predominantly caused by biallelic mutations in more than 30 genes encoding proteins with a pivotal role in morphology and function of the primary cilium. Oligogenic inheritance or occurrence of genetic modifiers has been suggested to contribute to the variability of the clinical phenotype. We report on a family with peculiar clinical spectrum Joubert syndrome molecularly and clinically dissecting a complex phenotype, in which hypogonadism, pituitary malformation and growth hormone deficiency occur as major features. CASE PRESENTATION:A 7 year-old male was enrolled in a dedicated "Undiagnosed Patients Program" for a peculiar form of Joubert syndrome complicated by iris and retinochoroidal coloboma, hypogonadism pituitary malformation, and growth hormone deficiency. The molecular basis of the complex phenotype was investigated by whole exome sequencing. The concomitant occurrence of homozygosity for mutations in KIF7 and KIAA0556 was identified, and the assessment of major clinical features associated with mutations in these two genes provided evidence that these two independent events represent the cause underlying the complexity of the present clinical phenotype. CONCLUSION:Beside the clinical variability of Joubert syndrome, co-occurrence of mutations in ciliopathy-associated genes may contribute to increase the clinical complexity of the trait.	0
A mother and son are reported with bilateral, symmetrical syndactyly of the third, fourth, and fifth toes, mild craniosynostosis of the coronary sutures, and small pinnae. The same combination of malformations was recently described as a new syndrome by Kurczynsky and Casperson in a mother and her daughter. In addition, in the present family, the mother had fusion of two cervical vertebrae and a partial duplication of the first metatarsal. The child had a bilateral cleft lip and palate. The question is raised whether these patients represent a new syndrome or a variant of the Saethre-Chotzen syndrome.	0
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pulmonary condition characterized by diffuse proliferation of neuroendocrine cells in the epithelium of the bronchial wall. DIPNECH may be easily missed in daily clinical practice and diagnosis is often delayed, which may impair prognosis since this condition is considered a pre-invasive lesion for lung carcinoid tumours. We report a clinical case of DIPNECH in order to discuss the diagnostic and therapeutic approach for this entity, the management of which is not yet well established in the literature. LEARNING POINTS:DIPNECH is a poorly understood lung condition characterized histologically by diffuse proliferation of pulmonary neuroendocrine cells in the bronchial wall, clinically by obstructive respiratory symptoms and radiologically by small airway disease features and pulmonary nodules.DIPNECH is considered to be a preneoplastic lesion within the spectrum of pulmonary neuroendocrine tumours.Treatment is usually guided by the symptoms and prognosis is highly variable.	0
We herein reported a patient with acute ischemic stroke in the bilateral medial medullary and the left tegmentum of the pons who presented with various neurological symptoms. Fusing digital subtraction angiography (DSA) and MRI (DSA-MR fusion imaging) could reveal the infarct-relevant arteries. A 41-year-old male presented with headache, bilateral arm's dysesthesia, quadriplegia, left Horner's syndrome, upbeat nystagmus, internuclear ophthalmoplegia and left peripheral facial paralysis. Diffusion weighted MRI (DWI) revealed the high intensity lesion in the bilateral medial medullary and the left tegmentum of the pons. MRA showed right vertebral artery (VA) occlusion. A high intensity on T1 weighted imaging was shown on the right VA vessel wall. DSA-MR fusion imaging revealed the anterior spinal artery (ASA) occlusion proximal to the infarction. The stenosis was located at the origin of the right VA perforating branch distributing into the infarct lesion. The steno-occlusive lesion of ASA and VA perforating branch due to VA dissection resulted in infarction in the pontomedullary junction and caused various neurological symptoms. DSA-MR fusion imaging would prove the radiological anatomy of infarct-relevant arteries and clarify the etiology of ischemic stroke.	0
Cole disease is a genodermatosis of pigmentation following a strict dominant mode of inheritance. In this study, we investigated eight patients affected with an overlapping genodermatosis after recessive inheritance. The patients presented with hypo- and hyperpigmented macules over the body, resembling dyschromatosis universalis hereditaria in addition to punctuate palmoplantar keratosis. By homozygosity mapping and whole-exome sequencing, a biallelic p.Cys120Arg mutation in ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was identified in all patients. We found that this mutation, like those causing dominant Cole disease, impairs homodimerization of the ENPP1 enzyme that is mediated by its two somatomedin-B-like domains. Histological analysis revealed structural and molecular changes in affected skin that were likely to originate from defective melanocytes because keratinocytes do not express ENPP1. Consistently, RNA-sequencing analysis of patient-derived primary melanocytes revealed alterations in melanocyte development and in pigmentation signaling pathways. We therefore conclude that germline ENPP1 cysteine-specific mutations, primarily affecting the melanocyte lineage, cause a clinical spectrum of dyschromatosis, in which the p.Cys120Arg allele represents a recessive and more severe form of Cole disease.	0
Angiosarcoma is a rare malignant neoplasm of the liver. The various morphologic patterns seen with angiosarcomas of the liver have not been systematically studied and their recognition remains a major diagnostic challenge. In order to provide more comprehensive data on the morphologic patterns, angiosarcomas that had been diagnosed between 1996 and 2016 at a large medical referral center were reviewed. The major growth patterns were classified as sinusoidal (non-mass forming) versus mass forming. The mass-forming cases were further subdivided into epithelioid, spindled, or vasoformative. The study identified 21 patients with primary hepatic angiosarcoma: 13 men and 8 women. The ages ranged from 26 to 89 years. Seventeen angiosarcomas were mass-forming tumors, of which 9 showed predominantly vasoformative growth. Most of these vasoformative cases (6/9) were composed of small vessels, 2 cases had slit-like vascular spaces, and one case showed a mixture of small and large vessels. There were 7 mass-forming angiosarcomas without vasoformation: 3 had an epithelioid morphology and 4 were composed primarily of spindled cells. The final mass-forming tumor showed a mixture of vasoformative and nonvasoformative areas. Four of 21 cases were non-mass forming and showed either diffuse sinusoidal infiltration (N=2) or prominent peliotic changes (N=2). Finally, 3 uncommon patterns were identified. One case showed nodules of spindle cells arranged in prominent whorls in a background of loose connective tissue with abundant inflammation. A second case arose in the setting of the Blue Rubber Bleb Nevus Syndrome and showed numerous tumor nodules with an architectural pattern that resembled infantile hemangioma, some with areas of atypia consistent with malignant transformation to angiosarcoma. The third unusual pattern showed multiple nodules of thin walled large caliber vascular proliferations, some of which showed atypia that reached the level of angiosarcoma. The results from this study indicate that the majority of hepatic angiosarcomas are mass forming (two third of cases), a pattern that is recognizable on H&E when vasoformative, but can mimic carcinoma or undifferentatied sarcomas when nonvasoformative (one third of cases). The sinusoidal patterns are particularly challenging and are frequently missed on initial review. Finally, we describe several unsual patterns of angiosarcoma. Awareness of these classic and rare morphologic patterns can help make the diagnosis of angiosarcoma.	0
Objective:To report a case of diabetes mellitus (DM) associated with partial pancreatic agenesis and congenital heart disease (CHD) in a patient found to have a nonsense mutation of the GATA6 gene. Methods:We present the imaging, laboratory, and genetic findings, and describe the clinical course of a patient with an atypical presentation of DM as well as CHD, who was found to have partial pancreatic agenesis on computed tomography (CT) imaging. Genetic testing was performed to identify monogenic DM. Results:A 30-year-old nonobese female with a waxing and waning pattern of insulin-dependent DM diagnosed at the age of 20 was found to have partial pancreatic agenesis on CT scan. It was unclear whether the patient was experiencing undetected hyperglycemia prior to initial diagnosis of DM. She had no history of diabetic ketoacidosis (DKA) despite poorly-controlled diabetes and years without insulin treatment. The patient also had congenital tricuspid atresia, ventricular septal defect, and transposition of the great vessels with surgical correction in childhood. Partial pancreatic agenesis and CHD with atypical DM prompted genetic testing for monogenic DM, and a nonsense mutation of the GATA6 (c.1242C>A, p.C414*) gene was found. Conclusion:GATA6 mutations are associated with a broad spectrum of diabetic phenotypes, pancreatic agenesis, and a variety of CHDs. This case highlights the importance of considering monogenic diabetes in young, nonobese patients with diabetes, particularly with negative pancreatic antibodies and no history of DKA. Further, this case demonstrates the importance of testing for GATA6 mutations in any young patient with diabetes and CHD.	0
Mutations in retinoid isomerase (RPE65) or lecithin-retinol acyltransferase (LRAT) disrupt 11-cis-retinal synthesis and cause Leber congenital amaurosis (LCA). Despite the success of recent RPE65 gene therapy, follow-up studies show that patients continue to experience photoreceptor degeneration and lose vision benefit over time. In Lrat-/- mouse model, mislocalized medium (M)-wavelength opsin was degraded, whereas mislocalized short (S)-wavelength opsin accumulated before the onset of cone degeneration. The mechanism for the foveal M/long-wavelength cone photoreceptor degeneration in LCA is unknown. By crossing Lrat-/- mice with a proteasome reporter mouse strain, this study showed that M-opsin-enriched dorsal cones in Lrat-/- mice exhibit proteasome stress because of the degradation of large amounts of M-opsin. Deletion of M-opsin relieves the proteasome stress and completely prevents M cone degeneration in Lrat-/-Opn1sw-/- mice (a pure M cone LCA model, Opn1sw encoding S-opsin) for at least 12 months. These results suggest that M-opsin degradation-associated proteasome stress plays a major role in M cone degeneration in Lrat-/- model. This finding may represent a general mechanism for M cone degeneration in multiple forms of cone degeneration because of M-opsin mislocalization and degradation. These results have important implications for the current gene therapy strategy for LCA that emphasizes the need for combinatorial therapies to both improve vision and slow photoreceptor degeneration.	0
To evaluate the efficacy of colchicine in reducing the frequency of attacks in patients with PFAPA.We conducted a 6-month open label, randomized, controlled study among patients with PFAPA who attend the Pediatric Rheumatology Clinic at the Rambam Medical Center in Israel. A total of 18 patients aged4 -11 years (males:females ratio = 11:7) were randomized into a control group (I, 10 children) and a study group (II, 8 children). Group I was followed for 6 months without any intervention, and group II was initially followed for 3 months and was thereafter treated with colchicine for 3 additional months, according to standard regimen. During the 6-month period of the study the patients and their physician recorded all the episodes of PFAPA in a constructed log. DNA analyses for the 5 common FMF mutations in Israel were performed in 17 out of the 18 patients.The number of episodes during the first 3 months was similar in both groups (group I 3.2 ± 1.5, group II 4.9 ± 2.3; p ≤ 0.12). Group II had significantly less PFAPA attacks in the second period while on colchicine therapy (4.9 ± 2.3 vs. 1.6 ± 1.2; p ≤ 0.01), in opposition to group I, where no difference in the number of attacks was noted between the first and second period of follow-up (3.2 ± 1.5 vs. 2.7 ± 1.5; p = 0.33). Of the 17 patients tested, 8 were carriers for FMF mutations (2 in group I and 6 in group II).Colchicine prophylaxis seems to be effective in reducing the number of attacks in PFAPA.	0
Introduction: Adult-onset Still's disease (AOSD) is a rare multisystem autoinflammatory disorder of unknown etiology, with clinical and biological similarities with the juvenile form (sJIA).The pivotal role of interleukin (IL)-1 gives rise to the use of IL-1 inhibitors in treating resistant cases.Areas covered: This review focuses on canakinumab, a fully human anti-IL-1β antibody, as treatment for AOSD. The data obtained from case reports and case series on AOSD and two double-blind, randomized, placebo-controlled Phase III trial on sJIA are analyzed. Efficacy and safety profiles of canakinumab are discussed.Expert opinion: There is no unanimous consensus on how to treat with IL-1 inhibitors. Many reviews have focused primarily on anakinra, but the accumulating data for canakinumab have emerged. The choice of treatment is a relevant issue for patients and the national health services. The available data for canakinumab indicate that this drug in AOSD patients is effective and well tolerated.	0
Autosomal recessive hyper-IgE syndrome is a primary immunodeficiency that results from a mutation in the DOCK8 gene. We report a case of a patient presenting with severe eczema, atopy, and recurrent skin infections since the first months of life. The diagnosis of autosomal recessive hyper-IgE syndrome was made at the age of 7 by a positive DOCK8 genetic test. The patient underwent hematopoietic stem cell transplantation, with complete remission of the various manifestations.	0
AIMS:Pudendal neuralgia (PN) due to pudendal nerve entrapment is a well-known disease in medical community but both diagnostic and treatment may be delayed for patients. The goal of this study was to achieve a systematic review of the published treatments of PN in order to help physician to take their decision to treat PN. METHODS:A Systematic review based on MEDLINE, Embase, and Cochrane databases was performed to identify articles related to PN. Studies involving ≥ 10 patients presenting PN according to Nantes's criteria who were managed with an intervention for their pain were reviewed. Data were extracted manually for qualitative analysis. RESULTS:Fifteen studies involving 672 patients (mean age 53.2 +/-5.1, SD 95%) were included. Nine different types of treatments were evaluated. Effectiveness of the treatments was heterogeneously assessed. Pain improvement was achieved in 41% to 100%, 13.4% to 100%, 60% to 100%, 12.2% to 100% in immediate, 3-month, 6-month, and 1-year post procedure, respectively. Complications reported were all grade ≤ II of Dindo-Clavien classification's. Given the heterogeneity of the outcomes measures and the lack of homogeneous prospective studies, no recommendation could be established to choose in between treatments. Methodological quality of the studies was heterogeneous. CONCLUSION:Many treatments seems available for drug-resistant PN. Given the heterogeneity of the outcomes measures and the lack of homogeneous prospective studies, no recommendation could be established to determine the best management strategy. Further studies about PN management are needed and should have common endpoint and follow-up.	0
Klippel Trenaunay syndrome (KTS) is a vascular malformation syndrome comprising of varying involvement of cutaneous capillaries, veins, and lymphatics with hypertrophy of soft tissue and bones of the affected limb. This syndrome is also referred to as capillary-lymphatic-venous malformation (CLVM), reflecting the changes seen in those vessels. This condition was first described in 1900 by 2 French Physicians-Maurice Klippel and Paul Trenaunay. KTS is a clinical diagnosis made by the presence of at least two of the three classic findings of localized cutaneous capillary malformations, venous abnormalities, and limb hypertrophy. The presence of arteriovenous malformations is now considered as a separate entity named as Parkes-Weber syndrome distinct from KTS.[1][2]	0
BACKGROUND:Carcinosarcoma of the ovary (CSO) is a rare and aggressive variant of ovarian cancer. Due to the rare nature of the disease there is insufficient evidence to make recommendations regarding standard management and overall prognosis. METHODS:An Institutional Review Board-approved study identified all our patients with CSO between January 2011 and May 2018. Demographic and outcome measures were abstracted from the medical records and tumor board files. Cox proportional hazard models, log rank tests, and comparisons of means were used to calculate significance (p < 0.05). RESULTS:27 women with CSO were identified. The median age at diagnosis was 65 years (range 48-91). Five women (18%) presented with early stage disease (Stage I or II) and 22 patients (82%) presented with late stage III or IV disease. Twenty patients (74%) received intravenous platinum-based combination chemotherapy. Seven patients did not receive chemotherapy during their treatment course. The median overall survival was 23 months (range 2-68 months). Overall survival was not significantly worsened by the stage of disease at diagnosis. There was no difference in survival based on the age at diagnosis, tobacco status or ethnicity (p > 0.05). CONCLUSION:This is one of the largest single institution experiences with CSO. The majority of our patients presented with advanced stage disease and received adjuvant platinum-based chemotherapy after cytoreductive surgery. The median overall survival of 23 months was not affected by the stage of the disease. The optimal management of this rare disease needs further study with collaborative, prospective multi-institutional trials.	0
Deficiency of the transcription factor GATA2 is a highly penetrant genetic disorder predisposing to myelodysplastic syndromes (MDS) and immunodeficiency. It has been recognized as the most common cause underlying primary MDS in children. Triggered by the discovery of a recurrent synonymous GATA2 variant, we systematically investigated 911 patients with phenotype of pediatric MDS or cellular deficiencies for the presence of synonymous alterations in GATA2. In total, we identified nine individuals with five heterozygous synonymous mutations: c.351C>G, p.T117T (N = 4); c.649C>T, p.L217L; c.981G>A, p.G327G; c.1023C>T, p.A341A; and c.1416G>A, p.P472P (N = 2). They accounted for 8.2% (9/110) of cases with GATA2 deficiency in our cohort and resulted in selective loss of mutant RNA. While for the hotspot mutation (c.351C>G) a splicing error leading to RNA and protein reduction was identified, severe, likely late stage RNA loss without splicing disruption was found for other mutations. Finally, the synonymous mutations did not alter protein function or stability. In summary, synonymous GATA2 substitutions are a new common cause of GATA2 deficiency. These findings have broad implications for genetic counseling and pathogenic variant discovery in Mendelian disorders.	0
Metastasis is the main cause of cancer-associated deaths, yet this complex process is still not well understood. Many studies have shown that acetate is involved in cancer metastasis, but the molecular mechanisms remain to be elucidated. In the present study, we first measured the effect of acetate on zinc finger transcriptional repressor SNAI1 and acetyl-CoA synthetase 2 (ACSS2) under glucose limitation in renal cell carcinoma cell lines, 786-O and ACHN. Then, RNA interference and overexpression of ACSS2 were used to detect the role of acetate on SNAI1 expression and cell migration. Finally, chromatin immunoprecipitation assay (ChIP) was used to investigate the regulatory mechanism of acetate on SNAI1 expression. The results showed that acetate increased the expressions of SNAI1 and ACSS2 under glucose limitation. ACSS2 knockdown significantly decreased acetate-induced SNAI1 expression and cell migration, whereas overexpression of ACSS2 increased SNAI1 level and histone H3K27 acetylation (H3K27ac). ChIP results revealed that acetate increased H3K27ac levels in regulatory region of SNAI1, but did not increase ACSS2-binding ability. Our study identified a novel inducer, acetate, which can promote SNAI1 expression by ACSS2-mediated histone acetylation in partly. This finding has important implication in treatment of metastatic cancers.	0
INTRODUCTION:Superior mesenteric artery syndrome (SMAS) is rare cause of small bowel obstruction and is characterized by an extrinsic vascular compression of the duodenum. The most common cause of SMAS is known as rapid and significant weight loss. PATIENT CONCERNS:A 61-year-old man who was diagnosed with amyotrophic lateral sclerosis and maintained a stable diet before admission. When the patient re-started feeding by gastrostomy tube after 5 days of therapeutic fasting due to gastric ulcer caused by gastrostomy tube irritation, he presented postprandial vomiting, abdominal distention, and tachycardia. Since fasting, his weight has been reduced by about 3 kg. DIAGNOSIS:Based on clinical symptoms and radiological findings, diagnose of SMAS was finally made. Abdomen computed tomography confirmed decreased aortomesenteric distance and tubography confirmed gastric and proximal duodenum distension above the compressed part. INTERVENTIONS:We performed jejunal tube insertion and the amount of feeding through the jejunal tube was gradually increased while maintaining parenteral nutrition. OUTCOMES:The presenting symptoms of the patient gradually improved. Follow-up abdomen computed tomography and tubography showed improvement in duodenal narrowing and stomach distension. CONCLUSION:SMAS should be considered when there is an abrupt observation of symptom of gastrointestinal obstruction in patients with predisposing condition such as a low body weight, even if the weight loss is relatively small.	0
Aside from well-characterized immune-mediated ataxias with a clear trigger and/or association with specific neuronal antibodies, a large number of idiopathic ataxias are suspected to be immune mediated but remain undiagnosed due to lack of diagnostic biomarkers. Primary autoimmune cerebellar ataxia (PACA) is the term used to describe this later group. An International Task Force comprising experts in the field of immune ataxias was commissioned by the Society for Research on the Cerebellum and Ataxias (SRCA) in order to devise diagnostic criteria aiming to improve the diagnosis of PACA. The proposed diagnostic criteria for PACA are based on clinical (mode of onset, pattern of cerebellar involvement, presence of other autoimmune diseases), imaging findings (MRI and if available MR spectroscopy showing preferential, but not exclusive involvement of vermis) and laboratory investigations (CSF pleocytosis and/or CSF-restricted IgG oligoclonal bands) parameters. The aim is to enable clinicians to consider PACA when encountering a patient with progressive ataxia and no other diagnosis given that such consideration might have important therapeutic implications.	0
BACKGROUND: As part of EUROCAT's surveillance of congenital anomalies in Europe, a statistical monitoring system has been developed to detect recent clusters or long-term (10 year) time trends. The purpose of this article is to describe the system for the identification and investigation of 10-year time trends, conceived as a "screening" tool ultimately leading to the identification of trends which may be due to changing teratogenic factors. METHODS: The EUROCAT database consists of all cases of congenital anomalies including livebirths, fetal deaths from 20 weeks gestational age, and terminations of pregnancy for fetal anomaly. Monitoring of 10-year trends is performed for each registry for each of 96 non-independent EUROCAT congenital anomaly subgroups, while Pan-Europe analysis combines data from all registries. The monitoring results are reviewed, prioritized according to a prioritization strategy, and communicated to registries for investigation. Twenty-one registries covering over 4 million births, from 1999 to 2008, were included in monitoring in 2010. CONCLUSIONS: Significant increasing trends were detected for abdominal wall anomalies, gastroschisis, hypospadias, Trisomy 18 and renal dysplasia in the Pan-Europe analysis while 68 increasing trends were identified in individual registries. A decreasing trend was detected in over one-third of anomaly subgroups in the Pan-Europe analysis, and 16.9% of individual registry tests. Registry preliminary investigations indicated that many trends are due to changes in data quality, ascertainment, screening, or diagnostic methods. Some trends are inevitably chance phenomena related to multiple testing, while others seem to represent real and continuing change needing further investigation and response by regional/national public health authorities.	1
BACKGROUND: Gestational diabetes insipidus is a rare, transient complication of pregnancy typically characterized by polyuria and polydipsia that may lead to mild electrolyte abnormalities. More severe sequelae of gestational diabetes insipidus are uncommon. CASE: We present a case of a 25-year-old woman at 23 weeks of gestation in a dichorionic-diamniotic twin pregnancy who developed severe symptomatic gestational diabetes insipidus complicated by rhabdomyolysis and death of both fetuses. CONCLUSION: Maternal rhabdomyolysis caused by gestational diabetes insipidus is extremely rare. Early recognition and treatment of gestational diabetes insipidus is necessary to prevent maternal and fetal morbidity and mortality.	0
BACKGROUND:Based on phenotypic similarities between age-related macular degeneration and the autosomal disorder Doyne honeycomb retinal dystrophy, we report on a single nanolaser treatment of a patient with genotype Doyne honeycomb retinal dystrophy confirmation and evidence of disease progression over 12 months. The case study is the first report of short-term results of subthreshold nanolaser treatment in a patient with Doyne honeycomb retinal dystrophy. CASE PRESENTATION:A 43-year-old Caucasian man with moderate loss of visual acuity in his left eye (20/40) and normal visual acuity in his right eye (20/20), with clinical Doyne honeycomb retinal dystrophy diagnosis and genetic confirmation of the common heterozygous mutation (EFEMP1) by genetic testing, underwent nanopulse subthreshold laser treatment in his left eye. A safety examination, carried out 7 days after treatment, and clinical follow-up, conducted 60 days following laser treatment, showed improvement of visual acuity from baseline by two letters and a subjective improvement of blurring. While no apparent morphological changes were found on fundoscopy, increased autofluorescence in the treated eye was observed on imaging. In addition, 2 months after nanopulse subthreshold laser treatment, rod-mediated and cone-mediated full-field electroretinography b-wave amplitudes showed an increase from baseline in both the treated eye (300%) and untreated eye (50%). At 2 months after nanopulse subthreshold laser treatment, multifocal electroretinograms showed improvement. Acuity and full-field electroretinography improvement persisted at 6-month follow-up. CONCLUSIONS:Sustained improvements in retinal function on electroretinography persisted in both eyes 6 months after treatment, suggesting an enhancement of phototransduction and retinoid recycling induced by nanopulse subthreshold laser treatment. The functional improvement observed in the untreated eye is hypothesized to arise from an increased expression and release of metalloproteinases that circulate systemically.	0
PURPOSE:Retinal degeneration in birdshot chorioretinopathy can be quantified using spectral domain optical coherence tomography by measuring the photoreceptor outer segment (PROS) volume. The purpose of this study was to determine if the PROS volume in BSCR responds to systemic immunomodulatory therapy (IMT). METHODS:Retrospective chart review with analysis of PROS volume derived from spectral domain optical coherence tomography. RESULTS:We identified a total of three patients who met our inclusion criteria. At baseline, all patients had abnormal PROS and/or ellipsoid layer findings on spectral domain optical coherence tomography. After systemic immunomodulatory therapy, these abnormalities improved, and PROS volume increased, in all patients (P < 0.05). CONCLUSION:PROS volume can increase after systemic treatment of birdshot chorioretinopathy. This SD-OCT parameter may serve as a useful marker of retinal degeneration in BSCR, and may be a useful outcome measure in monitoring treatment response in birdshot chorioretinopathy.	0
Playing an important role in the etiology of substance use disorder (SUD), dopamine (DA) neurons are subject to various regulations but transcriptional regulations are largely understudied. For the first time, we report here that the Human Immunodeficiency Virus Type I Enhancer Binding Protein 2 (HIVEP2) is a dopaminergic transcriptional regulator. HIVEP2 is expressed in both the cytoplasm and nuclei of DA neurons. Therein, HIVEP2 can target the intronic sequence GTGGCTTTCT of SLC6A3 and thereby activate the gene. In naive rats from the bi-directional selectively bred substance-preferring P vs -nonpreferring NP rat model of substance abuse vulnerability, increased gene activity in males was associated with the vulnerability, whereas decreased gene activity in the females was associated with the same vulnerability. In clinical subjects, extensive and significant HIVEP2-SLC6A3 interactions were observed for SUD. Collectively, HIVEP2-mediated transcriptional mechanisms are implicated in dopaminergic pathophysiology of SUD.	0
No reports on the frequency of X-linked ichthyosis (XLI) in the Italian general population and few surveys on the frequency of XLI in large communities in the world are available.The aim of this study was the assessment of the frequency of XLI in a large representative sample of the Italian male population.This study involved young men who enlisted as conscripts in the Italian Navy from January 1998 through February 2002, examined, prior to enlistment, at the Draft Council's Medical Unit of the Italian Navy in Taranto, Italy, to evaluate their psychophysical fitness. All the patients with an ichthyosiform condition were referred to the Department of Dermatology of the Navy Hospital, underwent a thorough dermatological examination and completed a questionnaire regarding their personal and familial history. Pertinent results of the other clinical investigations were recorded and the final diagnosis was formulated on the basis of all these data.From January 1998 through February 2002, of 75,653 young men examined, 15 cases of XLI were diagnosed, with a frequency of 1:5,043 or 1.98 per 10,000 (95% confidence interval based on the Poisson distribution 1.01-2.90). Four out of 15 cases (26.6%) showed corneal opacities. No other significant associated pathological change was observed.As this study is a survey involving a large male sample, homogeneous with reference to age, race and country of origin (southern Italy), the frequency of XLI could be estimated at about 1.98 per 10,000 males. These data are roughly in agreement with estimates from other European surveys.	1
Perinatal lethal Gaucher disease (PLGD), a particular and serious form of type 2 Gaucher disease (GD), often causes lethality in utero or death within hours after birth. The typical clinical manifestations include non-immune hydrops fetalis (NIHF), premature birth, fetal growth restriction, fetal intrauterine death, or neonatal distress and rapid death after birth. Here, we present a premature neonate with GD whose main clinical manifestations included intrauterine growth retardation, anasarca, facial dysmorphia, ichthyosis, respiratory distress, hepatosplenomegaly, joint contractures, myoclonus, refractory thrombocytopenia, anemia, elevated levels of liver enzymes, bile acid and direct bilirubin, cholestasis, pulmonary hypoplasia, intracranial hemorrhage, and abnormal electroencephalogram. The activity of β- glucocerebrosidase was 0 in the peripheral white blood cells of the neonate. The sequencing analysis identified the presence of missense G234E and H413P heterozygous mutations in glucerebrosidase (GBA) exon 7 and 10, with the latter first observed to be associated with PLGD. This infant died at 73 days of age.	0
INTRODUCTION:CLOVES syndrome is characterized by lipomatous overgrowth associated with vascular malforma tions, representing a diagnostic and a therapeutic challenge. Rapamycin, an mTOR inhibitor, has proved to be a good therapeutic option in some vascular anomalies. In this article, we report two ca ses of CLOVES syndrome with good response to oral rapamycin treatment. OBJECTIVE:To report the outcome of two patients with CLOVES syndrome treated with oral rapamycin. CLINICAL CASES:Case 1: A three-year-old female preschooler with CLOVES syndrome and history of repeated hospita lizations due to severe infections resulting from macrocystic lymphatic malformations and due to thrombotic episodes. The patient evolved with poor quality of life, multiple hospitalizations, surgical risk and progression of the lesions, therefore, oral rapamycin was indicated. After six months of treatment, clinical and radiological reduction in the size of the lipomatous and lymphatic masses, cutaneous lymphorrhea absence and a significant improvement of her quality of life were observed, without requiring new hospitalizations. Case 2: a ten-year-old female schooler with CLOVES syndro me, who developed scoliosis and deterioration of her motor skills, becoming wheelchair-dependent. Oral rapamycin was indicated, showing improvement in her physical capacity, independence and au tonomy, and absence of lymphorrhea after four months of treatment. CONCLUSION:We propose oral rapamycin for the treatment of patients with CLOVES syndrome who present with complications and deterioration in the quality of life as a result of the disease.	0
Context:Brain white matter hyperintensities are seen on routine clinical imaging in 46% of adults with congenital adrenal hyperplasia (CAH). The extent and functional relevance of these abnormalities have not been studied with quantitative magnetic resonance imaging (MRI) analysis. Objective:To examine white matter microstructure, neural volumes, and central nervous system (CNS) metabolites in CAH due to 21-hydroxylase deficiency (21OHD) and to determine whether identified abnormalities are associated with cognition, glucocorticoid, and androgen exposure. Design, Setting, and Participants:A cross-sectional study at a tertiary hospital including 19 women (18 to 50 years) with 21OHD and 19 age-matched healthy women. Main Outcome Measure:Recruits underwent cognitive assessment and brain imaging, including diffusion weighted imaging of white matter, T1-weighted volumetry, and magnetic resonance spectroscopy for neural metabolites. We evaluated white matter microstructure by using tract-based spatial statistics. We compared cognitive scores, neural volumes, and metabolites between groups and relationships between glucocorticoid exposure, MRI, and neurologic outcomes. Results:Patients with 21OHD had widespread reductions in white matter structural integrity, reduced volumes of right hippocampus, bilateral thalami, cerebellum, and brainstem, and reduced mesial temporal lobe total choline content. Working memory, processing speed, and digit span and matrix reasoning scores were reduced in patients with 21OHD, despite similar education and intelligence to controls. Patients with 21OHD exposed to higher glucocorticoid doses had greater abnormalities in white matter microstructure and cognitive performance. Conclusion:We demonstrate that 21OHD and current glucocorticoid replacement regimens have a profound impact on brain morphology and function. If reversible, these CNS markers are a potential target for treatment.	0
We studied activities of antioxidant system enzymes in tissues of rats with experimental allergic encephalomyelitis. It was shown that the development of pathology is accompanied by deformation of the neurons and axonal degeneration, intensification of free radical oxidation, exhaustion of the reduced glutathione pool, and multidirectional changes in activities of antioxidant enzymes in rat tissues. The observed imbalance in the antioxidant defense system can be associated with excessive glutathione utilization in the glutathione transferase reaction and different severity of the pathological process in the brain and spinal cord. The received data necessitate the search for compounds that can prevent inhibition of antioxidant system components in order to analyze the possibility of their use in the treatment of multiple sclerosis.	0
Parsonage Turner syndrome (otherwise known as PTS, neuralgic amyotrophy or acute brachial neuritis) is a rare, but clinically significant cause of atraumatic shoulder girdle pain and weakness. Diagnosis is primarily clinical and can be challenging due to its heterogeneous presentation. A case of PTS following systemic infection from Staphylococcus aureus spondylodiscitis is presented. Timely consideration of the diagnosis prevented unnecessary investigation and allowed effective rehabilitation. This is the first case of PTS preceded by S. aureus infection. PTS should be considered in those presenting with acute, atraumatic shoulder dysfunction after systemic infection.	0
Patients with multiple myeloma (MM) accumulate adverse copy number aberrations (CNAs), gains of 1q21, and 17p deletions during disease progression. A subset of these patients develops heightened 1q12 pericentromeric instability and jumping translocations of 1q12 (JT1q12), evidenced by increased copy CNAs of 1q21 and losses in receptor chromosomes (RC). To understand the progression of these aberrations we analyzed metaphase cells of 50 patients with ≥4 CNAs of 1q21 by G-banding, locus specific FISH, and spectral karyotyping. In eight patients with ≥5 CNAs of 1q21 we identified a chromosome instability phenotype similar to that found in ICF syndrome (immunodeficiency, centromeric instability, and facial anomalies). Strikingly, the acquired instability phenotype identified in these patients demonstrates the same transient structural aberrations of 1q12 as those found in ICF syndrome, suggesting similar underlying pathological mechanisms. Four types of clonal aberrations characterize this phenotype including JT1q12s, RC deletions, 1q12-21 breakage-fusion-bridge cycle amplifications, and RC insertions. In addition, recurring transient aberrations include 1q12 decondensation and breakage, triradials, and 1q micronuclei. The acquired self-propagating mobile property of 1q12 satellite DNA drives the continuous regeneration of 1q12 duplication/deletion events. For patients demonstrating this instability phenotype, we propose the term "Jumping 1q Syndrome."	0
Disabling hearing loss impacts ∼466 million individuals worldwide with 34 million children affected. Gene and pharmacotherapeutic strategies to rescue auditory function in mouse models of human deafness are most effective when administered before hearing onset, after which therapeutic efficacy is significantly diminished or lost. We hypothesize that preemptive correction of a mutation in the fetal inner ear prior to maturation of the sensory epithelium will optimally restore sensory function. We previously demonstrated that transuterine microinjection of a splice-switching antisense oligonucleotide (ASO) into the amniotic cavity immediately surrounding the embryo on embryonic day 13-13.5 (E13-13.5) corrected pre-mRNA splicing in the juvenile Usher syndrome type 1c (Ush1c) mouse mutant. Here, we show that this strategy only marginally rescues hearing and partially rescues vestibular function. To improve therapeutic outcomes, we microinjected ASO directly into the E12.5 inner ear. A single intra-otic dose of ASO corrects harmonin RNA splicing, restores harmonin protein expression in sensory hair cell bundles, prevents hair cell loss, improves hearing sensitivity, and ameliorates vestibular dysfunction. Improvements in auditory and vestibular function were sustained well into adulthood. Our results demonstrate that an ASO pharmacotherapeutic administered to a developing organ system in utero preemptively corrects pre-mRNA splicing to abrogate the disease phenotype.	0
CONTEXT:Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are caused by inactivating mutations in the exons of GNAS that encode the alpha-subunit of the stimulatory G protein (Gsα). In some cases abnormal methylation of exon A/B of GNAS, a hallmark of PHP1B, has been reported. OBJECTIVE:To identify the underlying genetic basis for PHP1A/PPHP in patients in whom molecular defects were not detected by GNAS sequencing and microarray-based analysis of copy number variations. METHODS:Whole genome sequencing (WGS) and pyrosequencing of differentially methylated regions (DMRs) of GNAS using genomic deoxyribonucleic acid from affected patients. RESULTS:We identified 2 novel heterozygous GNAS deletions: a 6.4 kb deletion that includes exon 2 of GNAS in the first proband that was associated with normal methylation (57%) of exon A/B DMR, and a 1438 bp deletion in a second PHP1A patient that encompasses the promoter region and 5' untranslated region of Gsα transcripts, which was inherited from his mother with PPHP. This deletion was associated with reduced methylation (32%) of exon A/B DMR. CONCLUSIONS:WGS can detect exonic and intronic mutations, including deletions that are too small to be identified by microarray analysis, and therefore is more sensitive than other techniques for molecular analysis of PHP1A/PPHP. One of the deletions we identified led to reduced methylation of exon A/B DMR, further refining a region needed for normal imprinting of this DMR. We propose that deletion of this region can explain why some PHP1A patients have reduced of methylation of the exon A/B DMR.	0
Emery-Dreifuss muscular dystrophy (EDMD), a rare inherited disease, is characterized clinically by humero-peroneal muscle atrophy and weakness, multijoint contractures, spine rigidity and cardiac insufficiency with conduction defects. There are at least six types of EDMD known so far, of which five have been associated with mutations in genes encoding nuclear proteins. The majority of the EDMD cases described so far are of the emerinopathy (EDMD1) kind, with a recessive X-linked mode of inheritance, or else laminopathy (EDMD2), with an autosomal dominant mode of inheritance. In the work described here, the authors have sought to describe the history by which EDMD came to be distinguished as a separate entity, as well as the clinical and genetic characteristics of the disease, the pathophysiology of lamin-related muscular diseases and, finally, therapeutic issues, prevention and ethical aspects.	0
INTRODUCTION:We assessed whether celiac disease-associated mortality is increased in Finland among patients diagnosed in the 21st century, given recent improvements in diagnostic and treatment facilities. METHODS:Biopsy-proven patients with celiac disease (Marsh III) and dermatitis herpetiformis aged 20-79 years (median 50 years) diagnosed 2005-2014 (n = 12,803) were identified from the national dietary grant registry. Dates and causes of death were obtained from Statistics Finland. Overall mortality and causes of death were compared with reference individuals (n = 38,384) matched for age, sex, and area of residence (at the time of celiac disease diagnosis) selected from the Population Information System. RESULTS:During a mean follow-up of 7.7 years (SD ±3.0 years), 884 (6.9%) and 2,613 (6.8%) deaths occurred among the celiac cohort and reference group, respectively. Overall mortality (hazard ratio [HR] 1.01, 95% confidence intervals [CIs] 0.94-1.09), mortality from all malignancies (HR 1.11, 95% CI 0.96-1.27), gastrointestinal tract malignancies (HR 1.21, 95% CI 0.56-1.71), or cardiovascular diseases (HR 0.91, 95% CI 0.77-1.07) were not increased among patients with celiac disease. Overall, mortality from lymphoproliferative diseases (HR 2.36, 95% CI 1.65-3.39) and nonmalignant digestive diseases (HR 2.19, 95% CI 1.40-3.43) was increased, but HRs decreased after the exclusion of the first 2 years of follow-up (HR 1.71, 95% CI 1.10-2.66 and HR 1.75, 95% CI 1.01-3.05, respectively). DISCUSSION:The overall mortality in adult celiac disease diagnosed 2005-2014 was not increased. Mortality from lymphoproliferative diseases was increased but lower than previously reported.	0
OBJECTIVES:Neutral lipid storage disease with myopathy (NLSDM) is a rare metabolic myopathy occurring owing to mutations in the patatin like phospholipase domain containing 2 (PNPLA2) gene. Till date, less than 50 patients with PNPLA2 mutations have been reported. In this study, we describe the clinical, pathological, and genetic findings, and muscle magnetic resonance imaging (MRI) changes in four Chinese patients with NLSDM. PATIENTS AND METHODS:Peripheral blood smears were stained using Wright's stain. Muscle biopsies, muscle MRI, and sequence analysis of PNPLA2 gene were performed. RESULTS:All patients exhibited slowly progressive myopathy during adulthood. Cardiomyopathy, sensorineural hearing loss, hepatic adipose infiltration, and hypertriglyceridemia were observed in some patients. Jordan's anomaly was detected in the blood smears of all patients. Muscle biopsies revealed the presence of massive lipid droplets and rimmed vacuoles in two patients. MR images of the lower lumbar, pelvis, and lower extremities showed the involvement of posterior compartment muscles. The anterior compartment muscles were found to be less affected. Gene analysis for PNPLA2 revealed an identical homozygous mutation c.757 + 1G > T in all patients. CONCLUSION:Patients with NLSDM display clinical heterogeneities despite sharing the same mutation (c.757 + 1G > T) of the PNPLA2 gene, may suggest a founder effect in the region.	0
Although C1q nephropathy (C1qN) was introduced three decades ago, the clinical significance and renal outcomes of C1qN remain unclear. This study aimed to evaluate the clinical characteristics of C1qN, including renal outcomes, by performing a matched comparison within a multicenter cohort. We enrolled 6,413 adult patients who underwent kidney biopsy between January 2000 and January 2018 at three tertiary hospitals in Korea. We compared the clinical characteristics of 23 patients with C1qN with those of patients with focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) who were matched by age, sex, diabetic status, and a period of biopsy. Histological and clinical parameters in patients with C1qN were also evaluated according to the different pathological phenotypes. For a mean follow-up period of 92 months, 4 patients with C1qN (17.4%) developed end-stage renal disease (ESRD). None of the matched patients with MCD had ESRD, but 7 (30.4%) of patients with FSGS progressed to ESRD, which was not different from that of C1qN patients (p = 0.491). Laboratory and pathological findings, except segmental glomerulosclerosis, were not notably different between FSGS and C1qN. The presence of segmental glomerulosclerosis, mesangial hypercellularity, and podocyte effacement did not affect both the short- and long-term renal outcomes in patients with C1qN. Our study showed that the renal outcomes of C1qN are comparable with those of FSGS, and not with MCD. Specific pathological findings, including segmental glomerulosclerosis in C1qN, were not associated with renal outcomes, which may suggest homogeneity in the clinical features of C1qN.	0
BACKGROUND:Focal dermal hypoplasia (FDH) is rare X-linked dominant disease characterized by atrophy and linear pigmentation of the skin, split hand/foot deformities and ocular anomalies. FDH is caused by mutations of the Porcupine (PORCN) gene, which encodes an enzyme that catalyzes the palmitoylation of Wnt ligands required for their secretion. High resolution melting analysis (HRM) is a technique that allows rapid, labor-efficient, low-cost detection of genomic variants. In the present study, we report the successful implementation of HRM in the molecular diagnosis of FDH. METHODS:Polymerase chain reaction and HRM assays were designed and optimized for each of the coding exons of the PORCN gene, processing genomic DNA samples form a non-affected control and a patient complying with the FDH diagnostic criteria. The causal mutation was characterized by Sanger sequencing from an amplicon showing a HRM trace suggesting heterozygous variation and was validated using an amplification-refractory mutation system (ARMS) assay. RESULTS:The melting profiles suggested the presence of a variant in the patient within exon 1. Sanger sequencing revealed a previously unknown C to T transition replacing a glutamine codon for a premature stop codon at position 28, which was validated using ARMS. CONCLUSIONS:Next-generation sequencing facilitates the molecular diagnosis of monogenic disorders; however, its cost-benefit ratio is not optimal when a single, small or medium size causal gene is already identified and the clinical diagnostic presumption is strong. Under those conditions, as it is the case for FDH, HRM represents a cost- and labor-effective approach.	0
This report details a family in whom there is autosomal dominantly inherited uveal colobomata, associated eye defects, and cleft lip and palate occurring in twelve subjects over three generations. Considerable variability in expression of the gene is apparent, uveal colobomata being the most constant feature, and the full syndrome probably includes mental retardation of varying degree. The possibility of association with neural tube defect is discussed.	0
Fibroblasts of a patient with Infantile Liver Failure Syndrome 2 (OMIM #616483) due to a homozygous missense variant in the neuroblastoma amplified sequence gene (NBAS; c.[2708T>G]; c.[2708T>G]/p.[Leu903Arg]; p.[Leu903Arg]) were reprogrammed to iPSCs using the Cytotune®-iPS 2.0 Sendai Reprogramming Kit (Invitrogen) delivering the reprogramming factors Oct3/4, Sox2, c-Myc and Klf4. Cells showed a normal karyotype. Pluripotency of DHMCi004-A was proven using immunohistochemistry, RT-PCR analysis, flow cytometry and differentiation into all three germ layers using the STEMdiff™ Trilineage Differentiation Kit (Stemcell Technologies). DHMCi004-A represents the first iPS-based cell model system to elucidate the pathomechanism underlying this disease.	0
BACKGROUND:One of most accepted principles for treating Kienböck's disease before wrist degeneration settles in is to decompress the lunate by an osteotomy. Several osteotomies have been proposed since 1935. However, they are based on biomechanical hypotheses that are sometimes conflicting: This study compares the decompression effect of radius transverse shortening, radius lateral closing and medial closing wedge osteotomies, capitate shortening - with and without hamate shortening - and a Camembert-type radius wedge osteotomy with and without ulnar head shortening according to Sennwald. METHODS:We built a 3D wrist model using finite elements that included the metacarpal, carpal and forearm bones. All wrist ligaments and Triangular Fibrocartilage Complex were incorporated in the simulation. Load was applied on the metacarpals with the forearm bones fixed. We then applied the different osteotomies to the model. FINDINGS:When load was applied to the wrist, the osteotomies that best unloaded the lunate were the capitate shortening osteotomy combined with hamate shortening and the Camembert osteotomy combined with ulna shortening; the latter was the only osteotomy that completely unloaded the lunate. INTERPRETATION:We think the association of the radius Camembert osteotomy and ulna Sennwald's shortening osteotomy is the most effective procedure to propose in Kienböck's disease.	0
OBJECTIVE: Comparative study of the incidence of classic 21-hydroxylase deficiency congenital adrenal hyperplasia (21ase-def CAH) and clinical findings of affected infants diagnosed via newborn screening versus case survey only in the Emilia-Romagna region of Italy. METHODS: Neonatal mass screening (from March 1980 to September 1983-Period A, and from March 1991 to August 1995-Period C) and case survey study (from 1980 to June 1995; case survey alone from October 1983 to February 1991--Period B) were performed by the Regional Referral Center for Neonatal Screening for Endocrine-Metabolic Disease with a laboratory (Central Laboratory, S. Orsola Hospital, Bologna) and clinical (First Pediatric Clinic, University of Bologna, S. Orsola Hospital, Bologna) component. A population-based sample of 420 960 newborns consecutively born in the Emilia-Romagna region from March 1980 to August 1995 were studied. Spot 17-OH-progesterone (nmol/L blood) was tested by the radioimmunoassay method after sample extraction during Period A and by fluoroimmunometric time resolved method without sample extraction during Period C. Serum 17-OH-progesterone (ng/dL or nmol/L) was tested by the radioimmunoassay method (Diagnostic Product Corporation Kit, Los Angeles, CA). The case survey was performed by means of a questionnaire sent to all regional centers dealing with pediatrics, neonatology, endocrinology, and pediatric surgery. RESULTS: Thirteen classic 21ase-def CAH were diagnosed by means of neonatal screening (combined A and C periods). One true and one questionable false-negative cases were identified. The incidence of classical 21-hydroxylase deficiency for the white population was 1:15 518 (95% confidence limits 1:9249-1:28 400) by neonatal screening plus case survey, 1:18 105 (95% confidence limits 1:10 365-1:35 041) by neonatal screening alone and 1:25 462 (95% confidence limits 1:12 925-1:59 043) by case survey alone. The sensitivity and specificity of screening for classic CAH were 83% and 99.8% for Period A and 90% and 99.2% for Period C, respectively. The percentage of salt-wasting forms and the male/female ratio were higher during the neonatal screening period than during the case survey only. Sixty-one percent of classic CAH patients benefited from a prompt diagnosis. Nonclassical 21ase-def CAH cases detected via screening and case survey were also reported. CONCLUSIONS: Even in a region with adequate neonatal services, clinical diagnosis alone of classic CAH might be delayed or misinterpreted and salt-wasting crises could cause neonatal deaths. CAH screening is thus an effective tool for diagnosing affected male infants without a family history of CAH and for preventing salt loss. However, to achieve maximal benefit from screening, quick procedures are necessary for notification of positive results and beginning prompt treatment. The possibility of false-negative cases indicates that clinical observation should never be abandoned, even with ongoing screening programs.	1
Purpose:The purpose of this study was to establish and analyze a cell model of Leber congenital amaurosis type 16 (LCA16), which is caused by mutations in the KCNJ13 gene encoding Kir7.1, an inward-rectifying potassium ion channel. Methods:The two guide RNAs specific to the target sites in the KCNJ13 gene were designed and KCNJ13 knock-out (KO) human-induced pluripotent stem cells (hiPSCs) were generated using the CRISPR/Cas9 system. The KCNJ13-KO hiPSCs were differentiated into retinal pigment epithelial cells (hiPSC-RPEs). The KCNJ13-KO in hiPSC-RPEs was confirmed by immunostaining. Phagocytic activity of hiPSC-RPEs was assessed using the uptake of fluorescently labeled porcine photoreceptor outer segments (POSs). Phagocytosis-related genes in RPE cells were assessed by quantitative polymerase chain reaction. Results:Most of the translated region of the KCNJ13 gene was deleted in the KCNJ13-KO hiPSCs by the CRISPR/Cas9 system, and this confirmed that the Kir7.1 protein was not present in RPE cells induced from the hiPSCs. Expression of RPE marker genes such as BEST1 and CRALBP was retained in the wild-type (WT) and in the KCNJ13-KO hiPSC-RPE cells. However, phagocytic activity and expression of phagocytosis-related genes in the KCNJ13-null hiPSC-RPE cells were significantly reduced compared to those of WT. Conclusions:We succeeded in generating an RPE model of LCA16 using hiPSCs. We suggest that Kir7.1 is required for phagocytosis of POSs by RPE cells and that impaired phagocytosis in the absence of Kir7.1 would be involved in the retinal degeneration found in LCA16.	0
Cohen syndrome (CS) is a rare, autosomal recessive disorder characterized by intellectual disability, postnatal microcephaly, facial abnormalities, abnormal truncal fat distribution, myopia, and pigmentary retinopathy. It is often considered an underdiagnosed condition, especially in children with developmental delay and intellectual disability. Here we report on four individuals from a large Jordanian family clinically diagnosed with CS. Using Trio Exome Sequencing (Trio-WES) and MLPA analyses we identified a maternally inherited novel intronic nucleotide substitution c.3446-23T>G leading to the activation of a cryptic splice site and a paternally inherited multi-exon deletion in VPS13B (previously termed COH1) in the index patient. Expression analysis showed a strong decrease of VPS13B mRNA levels and direct sequencing of cDNA confirmed splicing at a cryptic upstream splice acceptor site, resulting in the inclusion of 22 intronic bases. This extension results in a frameshift and a premature stop of translation (p.Gly1149Valfs*9). Segregation analysis revealed that three affected maternal cousins were homozygous for the intronic splice site variant. Our data show causality of both alterations and strongly suggest the expansion of the diagnostic strategy to search for intronic splice variants in molecularly unconfirmed patients affected by CS.	0
Revertant mosaicism, or "natural gene therapy", is the phenomenon in which germline mutations are corrected by somatic events. In recent years, revertant mosaicism has been identified in all major types of epidermolysis bullosa, the group of heritable blistering disorders caused by mutations in the genes encoding epidermal adhesion proteins. Moreover, revertant mosaicism appears to be present in all patients with a specific subtype of recessive epidermolysis bullosa. We therefore hypothesized that revertant mosaicism should be expected at least in all patients with recessive forms of epidermolysis bullosa. Naturally corrected, patient-own cells are of extreme interest for their promising therapeutic potential, and their presence in all patients would open exciting, new treatment perspectives to those patients. To test our hypothesis, we determined the probability that single nucleotide reversions occur in patients' skin using a mathematical developmental model. According to our model, reverse mutations are expected to occur frequently (estimated 216x) in each patient's skin. Reverse mutations should, however, occur early in embryogenesis to be able to drive the emergence of recognizable revertant patches, which is expected to occur in only one per ~10,000 patients. This underestimate, compared to our clinical observations, can be explained by the "late-but-fitter revertant cell" hypothesis: reverse mutations arise at later stages of development, but provide revertant cells with a selective growth advantage in vivo that drives the development of recognizable healthy skin patches. Our results can be extrapolated to any other organ with stem cell division numbers comparable to skin, which may offer novel future therapeutic options for other genetic conditions if these revertant cells can be identified and isolated.	0
Marcus Gunn jaw-winking syndrome (MGJWS) is noted in congenital blepharoptosis. MGJWS was first described by a Scottish ophthalmologist Dr.Robert Marcus Gunn in the year 1883. This syndrome was initially reported in a 15-year-old girl as unilateral ptosis associated with the upper eyelid contraction on the same side.[1] Other names of MGJWS include Marcus-Gunn jaw winking phenomenon (MGP), Marcus Gunn ptosis, Marcus Gunn jaw winking trigemino-oculomotor synkinesis, Maxillopalpebral synkinesis, and Pterygoid-levator synkinesis. It is one of the congenital cranial dysinnervation disorders (CCDD), and these individuals have variable degrees of blepharoptosis in the resting, primary position.[2] It is associated with synkinetic movements of the upper eyelid during masticating movements of the jaw. It is usually unilateral but may present bilaterally also.[3][4]	0
Idiopathic Juvenile Osteoporosis (IJO) is a very rare disease, self restrictive and shows marked, spontaneous improvement during adolescence. The major clinical features were pain with difficulty walking, growth retardation, oral and dental abnormalities with radiographically porous bone structure. A 13-year-old male referred to paediatric dentistry clinic for toothache. The observations made with extra-intraoral clinic examination that one revealed short and skinny stature, diffuse caries in deciduous teeth, abraded lower incisor, deep bite and dysmorphic appearance in permanent incisor. This report emphasizes the recognized features of IJO as well as describes facio-dental findings that could aid in the diagnosis and management of these patients.	0
An increasing number of adult patients have been diagnosed with fatty acid β-oxidation disorders with the rising use of diagnostic technologies. In this study, clinical, biochemical, and molecular characteristics of 2 Japanese patients with adult-onset glutaric acidemia type II (GA2) were investigated and compared with those of pediatric cases.The patients were a 58-year-old male and a 31-year-old male. In both cases, episodes of myopathic symptoms, including myalgia, muscle weakness, and liver dysfunction of unknown cause, had been noted for the past several years. Muscle biopsy, urinary organic acid analysis (OA), acylcarnitine (AC) analysis in dried blood spots (DBS) and serum, immunoblotting, genetic analysis, and an in vitro probe acylcarnitine (IVP) assay were used for diagnosis and investigation.In both cases, there was no obvious abnormality of AC in DBS or urinary OA, although there was a increase in medium- and long-chain ACs in serum; also, fat deposits were observed in the muscle biopsy. Immunoblotting and gene analysis revealed that both patients had GA2 due to a defect in electron transfer flavoprotein dehydrogenase (ETFDH). The IVP assay indicated no special abnormalities in either case.Late-onset GA2 is separated into the intermediate and myopathic forms. In the myopathic form, episodic muscular symptoms or liver dysfunction are primarily exhibited after later childhood. Muscle biopsy and serum (or plasma) AC analysis allow accurate diagnosis in contrast with other biochemical tests, such as analysis of AC in DBS, urinary OA, or the IVP assay, which show fewer abnormalities in the myopathic form compared to intermediate form.	0
To date, all the familial hyperaldosteronism type III (FH-III) patients reported presenting with typical primary aldosteronism (PA), without showing other adrenal hormone abnormalities.This study characterized a novel phenotype of FH-III and explored the possible pathogenesis.A male patient presented with severe hypertension and hypokalemia at the age of 2 years and developed Cushing's syndrome at 20 years. He was diagnosed with PA and Cushing's syndrome on the basis of typical biochemical findings. He had massive bilateral adrenal hyperplasia and underwent left adrenalectomy. KCNJ5 was sequenced, and secretion of aldosterone and cortisol were observed both in vivo and in vitro.A heterozygous germline p.Glu145Gln mutation of KCNJ5 was identified. ARMC5, PRKAR1A, PDE8B, PDE11A, and PRKACA genes and β-catenin, P53 immunoactivity were normal in the adrenal. CYP11B2 was highly expressed, whereas mRNA expression of CYP11B1, CYP17A1, and STAR was relatively low in the hyperplastic adrenal, compared with normal adrenal cortex and other adrenal diseases. In the primary cell culture of the resected hyperplastic adrenal, verapamil and nifedipine, two calcium channel blockers, markedly inhibited the secretion of both aldosterone and cortisol and the mRNA expression of CYP11B1, CYP11B2, CYP17A1, and STAR.We presented the first FH-III patient who had both severe PA and Cushing's syndrome. Hypersecretion of cortisol might be ascribed to overly large size of the hyperplastic adrenal because CYP11B1 expression was relatively low in his adrenal. Like aldosterone, synthesis and secretion of cortisol in the mutant adrenal may be mediated by voltage-gated Ca2+ channels.	0
BACKGROUND:Cell-free fetal DNA (cffDNA) has opened up new approaches for non-invasive prenatal testing (NIPT), and it is often used as the second-tier test for high-risk pregnant women in detecting trisomy (T) 21, T18, and T13 after serum biochemistry screening. This study aims to discuss the clinical performance of NIPT as an alternative first-tier screening test for pregnant women in detecting T21, T18, T13, and sex chromosome aneuploidies (SCAs) in China. METHODS:A total of 42,924 samples were recruited. The cell-free plasma DNA was directly sequenced. Each of the chromosome aneuploidies of PPV was analyzed. A total of 22 placental samples were acquired, including 14 FP and 8 TP samples. The placental verification of FP NIPT results was performed. RESULTS:Among 42,924 samples, 281 (0.65%) positive cases, including 87 of T21, 31 of T18, 22 of T13, and 141 of SCAs were detected. For the detection of T21, the positive predictive value (PPV) was 78.46%, for trisomy 18, 62.96%, for trisomy 13, 10.00%, for SCAs, 47.22% in the total samples. For trisomy 21, the PPV was 86.67%, for trisomy 18, 80.00%, for trisomy 13, 20.00%, for SCAs, 56.52% in advanced maternal age (AMA) women. The PPV of T21 increased with age. For T18, the PPV showed an overall upward trend. For T13 and SCAs, PPV was raised first and then lowered. Placental verification of false positive (FP) NIPT results confirmed confined placental mosaicism(CPM) was the reason for false positives. CONCLUSIONS:This study represents the first time that NIPT has been used as a first-tier screening test for fetal aneuploidies in a pilot city with large clinical samples in China. We propose that NIPT could replace serum biochemistry screening as a first-tier test.	0
Hereditary spastic paraplegias are heterogeneous disorders with diversified clinical manifestations, and genetic testing is important for the diagnosis and typing of hereditary spastic paraplegias.Gene panel sequencing containing 55 hereditary spastic paraplegias-related genes was performed to screen the pathogenic genes for hereditary spastic paraplegias. Sanger sequencing was adopted to validate if the family member carried the same pathogenic gene as the proband.Fifteen out of 53 patients carried mutation(s) in the screened hereditary spastic paraplegias-related genes. Among the 23 identified mutations, only one mutation had been previously reported as a pathogenic mutation. In the pedigree of case 6, the proband, his mother and uncle all carried the same novel deletion mutation (c.1459delA) at SPAST gene. Based on the pedigree, the disease was inherited in an AD pattern. In the pedigree of case 53, the family disease may be in an X-linked recessive inheritance pattern. The proband (case 53) carried two novel mutations in ALT1 gene and L1CAM gene (c.2511C>A), respectively. The L1CAM gene is the causative gene for the SPG1 X-linked recessive-hereditary spastic paraplegias.Our data confirm the genetic heterogeneity of hereditary spastic paraplegias, and SPG4/SPAST were the most frequent forms. The pathogenicity of the novel mutations is worth to be further investigated.	0
This is a report of an infant born near term with neonatal stroke and haematuria. Changes were noted on foetal magnetic resonance images, and these persisted postnatally. A routine renal ultrasound scan during follow-up detected haematuria with no associated proteinuria. A likely pathogenic genetic mutation was identified. This case highlights a relatively newly discovered cause for hereditary nephropathy affecting the basement membrane, initially affecting the glomerular but later the renal tubular basement membranes. The renal phenotype, pathogenic genotype and pathological findings on renal biopsy are discussed.	0
Prune belly syndrome (PBS) is a rare but morbid congenital disease, classically defined by a triad of cardinal features that includes cryptorchidism, urinary tract dilation and laxity of the abdominal wall musculature. Children often require numerous surgical interventions including bilateral orchidopexy as well as individually tailored urinary tract and abdominal wall reconstruction. Along with the classic features, patients with PBS often experience gastrointestinal, orthopedic, and cardiopulmonary comorbidities.	0
Although congenital herpes simplex virus (HSV) infection is rare, it is associated with severe morbidity. We report a 36-week gestational age infant who presented with atypical skin lesions, presumably mitigated by exposure to maternal antiviral suppressive therapy. The initial absence of typical herpetic vesicles and lack of viral detection in skin lesions delayed the correct diagnosis, highlighting the importance of differentiating HSV from other neonatal rashes.	0
The efficacy and safety of thoracoscopic atrial fibrillation (AF) ablation and minimally invasive direct coronary artery bypass grafting have been previously reported. Herein, we describe the successful combination of both procedures in a high-risk patient with symptomatic drug-refractory paroxysmal AF and a proximal left main stenosis. This innovative procedure offers patients an all-in-one, truly minimally invasive approach to treat AF and left anterior descending artery disease. Based on our initial experience, the procedure is safe and feasible.	0
Although selective IgM deficiency (SIGMD) was described almost five decades ago, it was largely ignored as a primary immunodeficiency. SIGMD is defined as serum IgM levels below two SD of mean with normal serum IgG and IgA. It appears to be more common than originally realized. SIGMD is observed in both children and adults. Patients with SIGMD may be asymptomatic; however, approximately 80% of patients with SIGMD present with infections with bacteria, viruses, fungi, and protozoa. There is an increased frequency of allergic and autoimmune diseases in SIGMD. A number of B cell subset abnormalities have been reported and impaired specific antibodies to Streptococcus pneumoniae responses are observed in more than 45% of cases. Innate immunity, T cells, T cell subsets, and T cell functions are essentially normal. The pathogenesis of SIGMD remains unclear. Mice selectively deficient in secreted IgM are also unable to control infections from bacterial, viral, and fungal pathogens, and develop autoimmunity. Immunological and clinical similarities and differences between mouse models of deficiency of secreted IgM and humans with SIGMD have been discussed. Patients with SIGMD presenting with recurrent infections and specific antibody deficiency responses appear to improve clinically on immunoglobulin therapy.	0
Segmental stiff skin syndrome (SSSS) is a rare genetic connective tissue disease, which is often misdiagnosed. High-frequency ultrasonography can represent a useful clinical adjunct in the differential diagnosis of this condition, in conjunction with the clinical and histopathological findings. Treatment options are limited and evidence is scarce. We present the clinical, sonographic and histological features of 5 paediatric patients diagnosed at our institution and we discuss their response to treatment.	0
Amelogenesis imperfecta type IG (AI1G) is caused by mutations in FAM20A. Genotypic and phenotypic features of AI1G are diverse and their full spectra remain to be characterized. The aim of this study was to identify and summarize variants in FAM20A in a broad population of patients with AI1G. We identified a Thai female (Pt-1) and a Saudi male (Pt-2) affected with AI1G. Both had hypoplastic enamel, gingival hyperplasia, and intrapulpal calcification. Pt-1 also had rapidly progressive embedding of unerupted teeth, early eruption of permanent teeth, and spontaneous dental infection. Uniquely, Pt-2 had all permanent teeth erupted which was uncommon in AI1G patients. Whole exome sequencing (WES) identified that Pt-1 was heterozygous for FAM20A, c.758A > G (p.Tyr253Cys), inherited from her father. The mutation on maternal allele was not detected by WES. Pt-2 possessed compound heterozygous mutations, c.1248dupG (p.Phe417Valfs*7); c.1081C > T (p.Arg361Cys) in FAM20A. Array comparative genomic hybridization (aCGH), cDNA sequencing, and whole genome sequencing successfully identified 7531 bp deletion on Pt-1's maternal allele. This was the largest FAM20A deletion ever found. A review of all 70 patients from 50 independent families with AI1G (including two families in this study) showed that the penetrance of hypoplastic enamel and gingival hyperplasia was complete. Unerupted permanent teeth were found in all 70 patients except Pt-2. Exons 1 and 11 were mutation-prone. Most mutations were frameshift. Certain variants showed founder effect. To conclude, this study reviews and expands phenotypic and genotypic spectra of AI1G. A large deletion missed by WES can be detected by WGS. Hypoplastic enamel, gingival hyperplasia, and unerupted permanent teeth prompt genetic testing of FAM20A. Screening of nephrocalcinosis, early removal of embedded teeth, and monitoring of dental infection are recommended.	0
Applications of transdominant mutants of human immunodeficiency virus type 1 (HIV-1) regulatory proteins, especially Rev mutant, have been attempted for gene therapy against AIDS, because the Rev protein is essential for viral replication. We have previously reported that a mutant Rev protein (dRev) lacking its nucleolar targeting signal remained out of nuclei in expressed cells and strongly inhibited the function of Rev. To investigate the effects of dRev on HIV-1 replication, we established several dRev-expressing human cell lines with two different vector systems and examined virus production in these cells. An HIV-1-derived vector containing drev cDNA was constructed and introduced into CD4-positive HeLa cells and cells of the human T-cell line CCRF-CEM (CEM). In dRev-expressing HeLa cells, virus replication, syncytium formation, and cell death caused by HIV-1 infection were remarkably suppressed, and the same vector also conferred a resistant phenotype on CEM cells. The production was also suppressed in CEM cells containing the drev gene driven by a cytomegalovirus promoter. In addition, we found that dRev did not cause nucleolar dysfunction in a transient assay, in contrast to other transdominant mutants and wild-type Rev. Since dRev cannot migrate into the nuclei, it is expected not to interfere with nuclear/nucleolar functions of the host cell. We conclude that dRev is one promising candidate as an antiviral molecule for gene therapy against AIDS.	0
Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100,000 births.To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia, and document early institution of effective treatments.Epidemiological and retrospective observational study.Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data, and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3,030,083 newborns screened with a TREC test.Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked.Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58,000 infants (95% CI, 1/46,000-1/80,000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87% (45/52), 92% (45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up practices influenced the rates of detection of non-SCID T-cell lymphopenia.Newborn screening in 11 programs in the United States identified SCID in 1 in 58,000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.	1
We describe an infant with clinically apparent oto-palatal-digital syndrome Type II (OPD II), who, in addition, also has hydrocephalus and cerebellar hypoplasia. This second X-linked disorder has not been reported previously to occur in association with OPD II. This patient had 2 maternal uncles who died neonatally with congenital hydrocephalus and digital abnormalities consistent with OPD II. We suggest that these 2 entities may be located near one another on the X chromosome, and that both loci are affected in this family.	0
BACKGROUND:Nonimmune hydrops fetalis (NIHF) is still a challenging diagnosis. The differential diagnosis is extensive and the success of identifying a cause depends on the thoroughness of efforts to establish a diagnosis. For the early diagnosis of NIHF, a virtual gene panel diagnostic tool was developed. The female premature baby in question was delivered via emergency cesarean at 30 + 1 weeks of gestational age (GA) due to rapidly developing NIHF to a healthy mother. The family history was noncontributory. METHODS:DNA of the family was extracted and sequenced by the virtual hydrops panel with whole-exome sequencing. RESULTS:The hydrops panel revealed Noonan syndrome (NS) with a germline mutation in PTPN11 c.218C>T (p.Thr73Ile). CONCLUSION:The diagnosis of our patient was rapidly confirmed by the hydrops panel. The variant of c.218C>T (p.Thr73Ile) has not yet been described in literature relating to NIHF. Only a few case reports of this variant are known. This particular mutation is associated with Noonan syndrome, congenital heart defect and persistent thrombocytopenia. Few reveal juvenile myelomonocytic leukemia.	0
Autoimmune polyglandular syndrome (APS) type 1 is a rare autoimmune disorder inherited in an autosomal recessive pattern due to loss of function of the AIRE gene and defective removal of self-reactive T-lymphocytes during the process of thymic T cell maturation. Its manifestation starts early in life with the cardinal clinical disorders being one of muco-cutaneous candidiasis, Addison's disease, and hypoparathyroidism. Recognizing the syndromic nature of one autoimmune disease will facilitate an active search for other conditions which would allow early detection, management, follow-up, and most importantly patient education and counselling to avoid potential complications. We present the case of a young immigrant with multiple endocrinopathies and mucocutaneous candidiasis who presented with features of adrenal insufficiency. Our aim was to briefly review APS type 1 as a disease entity and to highlight the importance of patient education in its management.	0
Parkinson's disease (PD) is a neurodegenerative disease characterized by selective dopaminergic (DAergic) neuronal degeneration in the substantia nigra (SN) and proteinaceous α-synuclein-positive Lewy bodies and Lewy neuritis. As a chemical chaperone to promote protein stability and an autophagy inducer to clear aggregate-prone proteins, a disaccharide trehalose has been reported to alleviate neurodegeneration in PD cells and mouse models. Its trehalase-indigestible analogs, lactulose and melibiose, also demonstrated potentials to reduce abnormal protein aggregation in spinocerebellar ataxia cell models. In this study, we showed the potential of lactulose and melibiose to inhibit α-synuclein aggregation using biochemical thioflavin T fluorescence, cryogenic transmission electron microscopy (cryo-TEM) and prokaryotic split Venus complementation assays. Lactulose and melibiose further reduced α-synuclein aggregation and associated oxidative stress, as well as protected cells against α-synuclein-induced neurotoxicity by up-regulating autophagy and nuclear factor, erythroid 2 like 2 (NRF2) pathway in DAergic neurons derived from SH-SY5Y cells over-expressing α-synuclein. Our findings strongly indicate the potential of lactulose and melibiose for mitigating PD neurodegeneration, offering new drug candidates for PD treatment.	0
Microphthalmia, anophthalmia, and anterior segment dysgenesis are severe ocular developmental defects. There is a wide genetic heterogeneity leading to these ocular malformations. By using whole genome, exome and targeted sequencing in patients with ocular developmental anomalies, six biallelic pathogenic variants (including five novel variants) were identified in the PXDN gene in four families with microphthalmia and anterior segment dysgenesis. Only 11 different mutations (11 families) have been described in this gene to date. The phenotype of these patients is variable in severity, ranging from cataract and developmental glaucoma to complex microphthalmia. Interestingly, two unrelated patients of our series presented with an ocular phenotype including aniridia and microspherophakia. However, despite various phenotypic presentations and types of mutations, no genotype-phenotype correlation could be made. Thus, this work improves our knowledge of the recessive phenotype associated with biallelic variants in this gene and highlights the importance of screening PXDN in patients with anterior segment dysgenesis with or without microphthalmia.	0
BACKGROUND: La Crosse viral encephalitis (LACVE) is associated with residual epilepsy and neurocognitive deficits in survivors. This report summarizes 3 phases of clinical studies of children treated with intravenous (IV) ribavirin (RBV), each one exploring a different phase (I, IIA, IIB) of clinical trial development. METHODS: In phase I, 7 children with life-threatening LACVE were treated with emergency use RBV using a moderate IV dose (8.33 mg/kg/dose q 8 hours day 1, 5 mg/kg/dose q 8 hours days 2-10). In phase IIA, 12 children with severe LACVE were enrolled: 8 treated with RBV (same dose as phase I) and 4 with placebo. In phase IIB an escalated dose was used (33 mg/kg dose 1, then 16 mg/kg/dose q 6 hours for 4 days, and 8 mg/kg/dose q 8 hours for 3 days). RESULTS: In a group of 15 children treated in phase I and phase IIA, RBV appeared safe at moderate dose, but based on steady-state RBV levels of 9.3 μM, estimated cerebrospinal fluid levels were less than 20% of the EC50 of RBV for LACVE. At the escalated dose used in phase IIB, adverse events occurred, likely related to RBV, and therefore the trial was discontinued. Nevertheless, valuable pharmacokinetic (PK) and safety data were obtained at moderate dose, with potential treatment implications for other indications. CONCLUSIONS: Although the results do not support the use of RBV for LACVE, this nevertheless is the largest study of antiviral treatment for LACVE to date and the largest pharmacokinetic analysis of IV RBV in children for any indication.	0
Kallmann syndrome is a genetically heterogeneous disease characterized by hypogonadotropic hypogonadism and anosmia. Six families in which the disorder followed an X-linked inheritance were investigated by linkage analysis. Diagnostic criteria were uniformly applied and included tests for hypogonadotropic hypogonadism and anosmia. Close linkage was found by using the hypervariable repeated sequence CRI-S232 (DXS278) previously mapped to Xp22.3. At a maximum lod score of 6.5, the recombination fraction was calculated as .03. Of 30 fully informative meioses, one recombination between the disease locus and the loci recognized by probe CRI-S232 was observed. When an independent approach is used, these results confirm the X-linked Kallmann syndrome assignment previously made by deletion mapping, and allow definitive localization of the syndrome assignment previously made by deletion mapping, and allow definitive localization of the syndrome to the Xp22.3 region. This opens the way to carrier detection and to the identification of a gene responsible for this disorder.	0
Urinary dysfunctions are not considered symptoms of spinocerebellar ataxias (SCAs). However, given that a patient with SCAs without a family history might be misdiagnosed as MSA-C when having urinary dysfunctions, characterization of urinary dysfunctions in SCAs is needed not only to understand SCAs but also to correctly diagnosis patients with ataxia. We retrospectively reviewed medical records of 143 patients with genetically confirmed SCA1, 2, 3, 6, 7, 17, and DRPLA. Twenty-two patients (men n = 9; age 62.1 ± 10.9; disease duration 8.2 ± 2.9 years) who had lower urinary track symptoms (LUTS) were included in this study. Six patients underwent urodynamic study (UDS), and 2 underwent uroflowmetry. LUTS was present in 1 of 11 patients with SCA1, in 4 of 51 with SCA2, in 2 of 26 with SCA3, in 3 of 20 with SCA6, in 2 of 4 with SCA7, in 8 of 26 with SCA17, and in 2 of 5 with DRPLA. Overall, urinary frequency was the most common symptom (16 patients, 72.7%) followed by voiding difficulty. In three of the 6 patients with UDS, post-micturition residuals were > 100 ml. Detrusor overactivity was noted in three patients. Detrusor areflexia was observed in one. Four patients were diagnosed with a neurogenic bladder, 3 with a storage problem, and 1 with both storage and voiding problems. Fifteen percent of the patients with SCAs had LUTS, and LUTS occurred in various types of SCAs. Our results indicate that SCAs should be considered in patients with progressive cerebellar ataxia and urinary dysfunctions.	0
Cardiovascular diseases (CVDs) are the first cause of death in the World. Mediator (MED) is an evolutionarily conserved protein complex, which mediates distinct protein-protein interactions. Pathogenic events in MED subunit have been associated with human diseases. Novel increasing evidence showed that missense mutations in MED13L gene are associated with transposition of great arteries while MED12, MED13, MED15, and MED30, have been correlated with heart development. Moreover, MED23 and MED25 have been associated with heart malformations in humans. Relevantly, MED1, MED13, MED14, MED15, MED23, MED25, and CDK8, were found modify glucose and/or lipid metabolism. Indeed, MED1, MED15, MED25, and CDK8 interact in the PPAR- and SREBP-mediated signaling pathways. MED1, MED14 and MED23 are involved in adipocyte differentiation, whereas MED23 mediates smooth muscle cell differentiation. MED12, MED19, MED23, and MED30 regulate endothelial differentiation by alternative splicing mechanism. Thus, MEDs have a central role in early pathogenic events involved in CVDs representing novel targets for clinical prevention and therapeutic approaches.	0
Disorders of Sex Development (DSD) are congenital anomalies in which there is a discordance between chromosomal, genetic, gonadal, and/or internal/external genital sex. In XY individuals, the process of fetal sex differentiation can be disrupted at the stage of gonadal differentiation, resulting in gonadal dysgenesis, a form of early fetal-onset primary hypogonadism characterized by insufficient androgen and anti-Müllerian hormone (AMH) production, which leads to the development of ambiguous or female genitalia. The process of sex differentiation can also be disrupted at the stage of genital differentiation, due to isolated defects in androgen or AMH secretion, but not both. These are forms of fetal-onset hypogonadism with dissociated gonadal dysfunction. In this review, we present a perspective on impaired testicular endocrine function, i.e., fetal-onset male hypogonadism, resulting in incomplete virilization at birth.	0
Purpose:To compare the efficacy of topical 5-FU as monotherapy to combined therapy of topical 5-FU and Er:YAG (2940 nm) laser in the treatment of non-segmental vitiligo (NSV). Methods:This is a prospective randomized comparative study. Thirty patients diagnosed with NSV were recruited from the dermatology outpatient clinics of the Medical Research Centre of Excellence, the National Research Centre and the National Institute of Laser Enhanced Sciences. Our study group was divided into two subgroups, Group 1 was subjected to ablative Er:YAG and 5-FU cream and Group 2 applied topical 5-FU cream. Three treatment sessions were repeated every 4 to 6 weeks and patients were followed up to 9 months. Repigmentation was assessed by digital photography and subsequent computer based image analysis. Results:Repigmentation of Group 1 patients ranged from 0 to 70% (mean 12±7%) whilst in Group 2 this ranged from 0 to 5% (mean 1.4±0.8%). In Group 1 repigmentation was mild in 22/30 (73.3%) and moderate to severe in 3/30 (10%) starting after 3 months and persisted or increased during the period of follow up to 9 months. Groups 1 and 2 were subdivided into A and B, vitiligo involving non-resistant and resistant areas respectively. Group 1A showed more repigmentation (mean 13.8±8.5%) than Group 1B (mean 9.8±4.5%) and Group 2A showed more repigmentation (mean 1.5±1%) than Group 2B (mean 1.3±0.5%). Conclusion:The combination of Er:YAG with 5-FU is safe and effective in treating and improving outcome in vitiligo especially of non-resistant areas. Computer based image analysis of vitiliginous lesions and assessing post-therapy response is an easy, quick, and reliable method.	0
Objectives: The present study was to isolate the biflavonoid (a bimolecular kaemferol structured molecule) and test its efficacy on oxidative stress and carbohydrate metabolic key enzymes in control and high fat diet and streptozotocin -induced diabetic rats.Methods: Type 2 diabetes was induced in male albino wistar rats by feeding them with high fat diet comprising of 84.3% standard laboratory chow, 5% lard, 10% yolk powder, cholesterol 0.2%, and 0.5% bile salt for 2 weeks. After 2 weeks, the animals were kept in an overnight fast and injected with low dose of streptozotocin (35 mg/kg, dissolved in 0.1 M sodium citrate buffer, pH 4.5).Results: At the end of the experimental period, diabetic control rats showed significant increase in plasma glucose, homeostatic model assessment of insulin resistance (HOMA-IR), glycosylated hemoglobin (HbA1c) with concomitant decrease in plasma insulin, total hemoglobin and body weight. The activities of key enzymes of carbohydrate metabolism, lipid peroxidation markers, antioxidant enzymes, glycogen content and glycogen synthase and glycogen phosphorylase were also altered in diabetic rats.Discussion: Oral administration of biflavonoid to diabetic rats significantly ameliorated all the biochemical alterations to near normal levels. The effect produced by the biflavonoid on various parameters was comparable to that of metformin.	0
BACKGROUND:Genetic mosaics arise through new mutations occurring after fertiliza- tion (i.e., postzygotic mutations). Mosaics have been described in recent years as the cause of many different disorders; many of these are neurocutaneous diseases and syndromal developmental disorders, each with a characteristic phenotype. In some of these disorders, there is a genetic predisposition to the development of tumors. This article is intended as an overview of selected mosaic diseases. METHODS:This review is based on publications retrieved by a selective search in PubMed, with particular attention to recent articles in high-ranking journals dealing with asymmetric growth disturbances, focal brain malformations, mosaic diseases due to dysregulation of the RAS/RAF signaling pathway (mosaic RASopathies), and vascular malformations. RESULTS:The identification of postzygotic mutations has led to the reclassification of traditional disease entities and to a better understanding of their pathogenesis. Diagnosis is aided by modern next-generation sequencing (NGS) techniques that allow the detection even of low-grade mosaics. Many mosaic mutations are not detectable in blood, but only in the affected tissue, e.g., the skin. Genetic mosaic diseases often manifest themselves in the skin and brain, and by facial dysmorphism, asymmetrical growth disturbances, and vascular malformations. CONCLUSION:The possibility of a mosaic disease should be kept in mind in the diag- nostic evaluation of patients with asymmetrical growth disturbances, focal neuronal migration disturbances, vascular malformations, and linear skin abnormalities. The demonstration of a postzygotic mutation often affords relief to the parents of an affected child, since this means that there is no increased risk for recurrence of the same disorder in future children. Correct classification is important, as molecular available for certain mosaic diseases, e.g., PIK3CA-related overgrowth spectrum (PROS) disorder.	0
High-risk human papillomavirus has been suggested as a risk factor for esophageal adenocarcinoma. Tumor human papillomavirus status has been reported to confer a favorable prognosis in esophageal adenocarcinoma. The size of the primary tumor and degree of lymphatic spread determines the prognosis of esophageal carcinomas. Lymph node status has been found to be a predictor of recurrent disease as well as 5-year survival in esophageal malignancies. In human papillomavirus driven cancers, e.g. cervical, anogenital, head and neck cancers, associated lymph nodes with a high viral load suggest metastatic lymph node involvement. Thus, human papillomavirus could potentially be useful as a marker of micro-metastases. To date, there have been no reported studies regarding human papillomavirus involvement in lymph nodes of metastatic esophageal adenocarcinoma. This review highlights the importance of investigating human papillomavirus in lymph node metastasis of esophageal adenocarcinoma based on data derived from other human papillomavirus driven cancers.	0
OBJECTIVE: To use new data to make a revised estimate of the global burden of typhoid fever, an accurate understanding of which is necessary to guide public health decisions for disease control and prevention efforts. METHODS: Population-based studies using confirmation by blood culture of typhoid fever cases were sought by computer search of the multilingual scientific literature. Where there were no eligible studies, data were extrapolated from neighbouring countries and regions. Age-incidence curves were used to model rates measured among narrow age cohorts to the general population. One-way sensitivity analysis was performed to explore the sensitivity of the estimate to the assumptions. The burden of paratyphoid fever was derived by a proportional method. FINDINGS: A total of 22 eligible studies were identified. Regions with high incidence of typhoid fever (>100/100,000 cases/year) include south-central Asia and south-eastAsia. Regions of medium incidence (10-100/100,000 cases/year) include the rest of Asia, Africa, Latin America and the Caribbean, and Oceania, except for Australia and New Zealand. Europe, North America, and the rest of the developed world have low incidence of typhoid fever (<10/100,000 cases/year). We estimate that typhoid fever caused 21,650,974 illnesses and 216,510 deaths during 2000 and that paratyphoid fever caused 5,412,744 illnesses. CONCLUSION: New data and improved understanding of typhoid fever epidemiology enabled us to refine the global typhoid burden estimate, which remains considerable. More detailed incidence studies in selected countries and regions, particularly Africa, are needed to further improve the estimate.	1
The association of ataxia, hypergonadotropic hypogonadism and hearing loss is extremely rare. Considerable heterogeneity exists in the literature of the neurological manifestations, age of onset, clinical severity and associated abnormalities. We describe a 24-year-old woman with secondary hypergonadotropic amenorrhea, early-onset progressive spinocerebellar ataxia (SCA), late-onset sensorineural hearing loss and normal intelligence and compare it with reported cases.	0
Cataracts are the principal cause of treatable blindness worldwide. Inherited congenital cataract (CC) shows all types of inheritance patterns in a syndromic and nonsyndromic form. There are more than 100 genes associated with cataract with a predominance of autosomal dominant inheritance. A cataract is defined as an opacity of the lens producing a variation of the refractive index of the lens. This variation derives from modifications in the lens structure resulting in light scattering, frequently a consequence of a significant concentration of high-molecular-weight protein aggregates. The aim of this review is to introduce a guide to identify the gene involved in inherited CC. Due to the manifold clinical and genetic heterogeneity, we discarded the cataract phenotype as a cardinal sign; a 4-group classification with the genes implicated in inherited CC is proposed. We consider that this classification will assist in identifying the probable gene involved in inherited CC.	0
Geleophysic dysplasia (GPHYSD1, MIM231050; GPHYSD2, MIM614185; GPHYSD3, MIM617809) is an autosomal disorder characterized by short-limb dwarfism, brachydactyly, cardiac valvular disease, and laryngotracheal stenosis. Mutations in ADAMTSL2, FBN1, and LTBP3 genes are responsible for this condition. We found that three previously described cases of GPHYSD diagnosed clinically were homozygote or compound heterozygotes for five ADAMTSL2 variants, four of which not being previously reported. By electron microscopy, skin fibroblasts available in one case homozygote for an ADAMTSL2 variant showed a defective intracellular localization of mutant ADAMTSL2 protein that did not accumulate within lysosome-like intra-cytoplasmic inclusions. Moreover, this mutant ADAMTSL2 protein was less secreted in medium and resulted in increased SMAD2 phosphorylation in transfected HEK293 cells.	0
A spectacular but poorly recognized nuclear repatterning is the association of heterochromatic domains during interphase. Using base-specific fluorescence and extended-depth-of-focus imaging, we show that the association of heterochromatic pericentromeres composed of AT- and GC-rich chromatin occurs on a large scale in cycling meiotic and somatic cells and during development in ring- and bivalent-forming Tradescantia spathacea (section Rhoeo) varieties. The mean number of pericentromere AT-rich domains per root meristem nucleus was ca. half the expected diploid number in both varieties, suggesting chromosome pairing via (peri)centromeric regions. Indeed, regular pairing of AT-rich domains was observed. The AT- and GC-rich associations in differentiated cells contributed to a significant reduction of the mean number of the corresponding foci per nucleus in relation to root meristem. Within the first 10 mm of the root, the pericentromere attraction was in progress, as if it was an active process and involved both AT- and GC-rich associations. Complying with Rabl arrangement, the pericentromeres preferentially located on one nuclear pole, clustered into diverse configurations. Among them, a strikingly regular one with 5-7 ring-arranged pericentromeric AT-rich domains may be potentially engaged in chromosome positioning during mitosis. The fluorescent pattern of pachytene meiocytes and somatic nuclei suggests the existence of a highly prescribed ring/chain type of chromocenter architecture with side-by-side arranged pericentromeric regions. The dynamics of pericentromere associations together with their non-random location within nuclei was compared with nuclear architecture in other organisms, including the widely explored Arabidopsis model.	0
Multiparametric magnetic resonance (MR) imaging combines anatomic and functional imaging techniques for evaluating the prostate and is increasingly being used in diagnosis and management of prostate cancer. A wide spectrum of anatomic and pathologic processes in the prostate may masquerade as prostate cancer, complicating the imaging interpretation. The histopathologic and imaging findings of these potential mimics are reviewed. These entities include the anterior fibromuscular stroma, surgical capsule, central zone, periprostatic vein, periprostatic lymph nodes, benign prostatic hyperplasia (BPH), atrophy, necrosis, calcification, hemorrhage, and prostatitis. An understanding of the prostate zonal anatomy is helpful in distinguishing the anatomic entities from prostate cancer. The anterior fibromuscular stroma, surgical capsule, and central zone are characteristic anatomic features of the prostate with associated low T2 signal intensity due to dense fibromuscular tissue or complex crowded glandular tissue. BPH, atrophy, necrosis, calcification, and hemorrhage all have characteristic features with one or more individual multiparametric MR imaging modalities. Prostatitis constitutes a heterogeneous group of infective and inflammatory conditions including acute and chronic bacterial prostatitis, infective and noninfective granulomatous prostatitis, and malacoplakia. These entities are associated with variable clinical manifestations and are characterized by the histologic hallmark of marked inflammatory cellular infiltration. In some cases, these entities are indistinguishable from prostate cancer at multiparametric MR imaging and may even exhibit extraprostatic extension and lymphadenopathy, mimicking locally advanced prostate cancer. It is important for the radiologists interpreting prostate MR images to be aware of these pitfalls for accurate interpretation. Online supplemental material is available for this article.	0
Human dentition development is a long and complex process which involves a series of reciprocal and sequential interactions between the embryonic stomodeal epithelium and the underlying neural crest-derived mesenchyme. Despite environment disturbances, tooth development is predominantly genetically controlled. To date, more than 200 genes have been identified in tooth development. These genes implied in various signaling pathways such as the bone morphogenetic protein, fibroblast growth factor, sonic hedgehog homolog, ectodysplasin A, wingless-type MMTV integration site family (Wnt), and transform growth factor pathways. Mutations in any of these strictly balanced signaling cascades may cause arrested odontogenesis and/or other dental defects. This article aims to review current knowledge about the genetic mechanisms responsible for selective nonsyndromic tooth agenesis in humans and to present a detailed summary of syndromes with hypodontia as regular features and their causative genes.	0
Elizabethkingia spp. are a group of non-fermentative, Gram-negative, catalase-positive, and non-motile bacilli. They can cause meningitis in neonates and immunosuppressed patients, and lead to high mortality. Considering the rising trend of drug resistance among bacteria pathogens, bacteriophage (phage) therapy is a potential alternative to antibiotics for treating multidrug-resistant bacterial infections. However, so far, no phages specific for Elizabethkingia spp. have been reported. Using a clinically isolated Elizabethkingia anophelis as the host, the phage TCUEAP1 was isolated from wastewater of Hualien Tzu Chi hospital. The phage particle of TCUEAP1 under electron microscopy was revealed to belong to the siphoviridae family, with a head size of 47 nm, and a tail dimension 12 nm in diameter and 172 nm in length. The one-step growth analysis showed that the latent period of TCUEAP1 was about 40 min with a rise period lasting about 20 min, yielding a burst size of approximately 10 PFU/cell. The adsorption rate of TCUEAP1 reached about 70% in 20 min. Using 20 isolates of Elizabethkingia spp. to test the host range of TCUEAP1, it displayed narrow spectrum infecting three strains of E. anophelis, but forming spot lysis on 16 strains. The sequence result showed that the genome of TCUEAP1 is a double-stranded DNA of 49,816 bp, containing 73 predicted open reading frames. Further genomic analysis showed TCUEAP1 to be a new phage with no resemblance to publicly available phage genomes. Finally, in a mouse intraperitoneal infection model, at 6 h after the bacterial injection, TCUEAP1 decreased the bacterial load by fivefold in blood. Also, TCUEAP1 rescued 80% of mice heavily infected with E. anophelis from lethal bacteremia. We hope that the isolation and characterization of TCUEAP1, the first phage infecting Elizabethkingia spp., can promote more studies of the phages targeting this newly emerging bacterial pathogen.	0
Variants in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and progeroid syndromes. Cardiovascular laminopathic involvement is classically described as cardiomyopathy in striated muscle laminopathies, and arterial wall dysfunction and/or valvulopathy in lipodystrophic and/or progeroid laminopathies. We report unexpected cardiovascular phenotypes in patients with LMNA-associated lipodystrophies, illustrating the complex multitissular pathophysiology of the disease and the need for specific cardiovascular investigations in affected patients. A 33-year-old woman was diagnosed with generalized lipodystrophy and atypical progeroid syndrome due to the newly identified heterozygous LMNA p.(Asp136Val) variant. Her complex cardiovascular phenotype was associated with atherosclerosis, aortic valvular disease and left ventricular hypertrophy with rhythm and conduction defects. A 29-year-old woman presented with a partial lipodystrophy syndrome and a severe coronary atherosclerosis which required a triple coronary artery bypass grafting. She carried the novel heterozygous p.(Arg60Pro) LMNA variant inherited from her mother, affected with partial lipodystrophy and dilated cardiomyopathy. Different lipodystrophy-associated LMNA pathogenic variants could target cardiac vasculature and/or muscle, leading to complex overlapping phenotypes. Unifying pathophysiological hypotheses should be explored in several cell models including adipocytes, cardiomyocytes and vascular cells. Patients with LMNA-associated lipodystrophy should be systematically investigated with 24-h ECG monitoring, echocardiography and non-invasive coronary function testing.	0
Phosphoinositide 3-kinase delta (PI3Kδ) mediates signaling transduction downstream of diverse immune receptors, including the T cell receptor (TCR), the B cell receptor (BCR), costimulatory molecules and cytokine receptors. Our understanding of the role of PI3Kδ in the immune system comes primarily from mice, and especially from the consequences of pharmacological inhibition of PI3Kδ in mouse models of human disease as well as the consequences of genetic manipulation, resulting in hyperactivation or loss of PI3Kδ function. In case of humans, in vitro studies with PI3Kδ-specific inhibitors, the consequences of treatment of hematologic malignancies with the PI3Kδ-specific inhibitor idelalisib and primary immunodeficiency disorders due to germline variants hyper- or underactivating PI3Kδ provide most of our knowledge on the role of PI3Kδ in immunity and immune regulation. In this review, we summarize the physiological and pathophysiological roles of PI3Kδ in the human immune system, focusing on immunodeficiency due to defects in PI3Kδ signaling and especially on the recently reported cases with mutations resulting in loss of PI3Kδ activity.	0
Common variable immunodeficiency (CVID) has a heterogenous clinical presentation and can be challenging to diagnose. Distinct histologic changes have been linked with CVID in several organ systems, which can help identify the correct diagnosis. In this study we review a cohort of hepatic CVID biopsies, to better define the spectrum of histologic and biochemical alterations. We reviewed 26 liver biopsies from 24 patients with CVID, obtained at 4 institutions between 2010 and 2019. Histologic slides were examined, and pathologic, biochemical, and clinical features were recorded. A control cohort of 21 patients with nodular regenerative hyperplasia (NRH) but lacking CVID was also examined. Liver function tests were frequently abnormal, especially alkaline phosphatase (median: 193 IU/L) and aspartate transaminase (median: 56 U/L), elevated in 23 and 17 of 25 biopsies, respectively. Fifteen patients had CVID involvement of other organs. Histologic features of primary biliary cholangitis were present in 2 patients, with florid duct lesions and prominent bile duct injury, in association with positive antimitochondrial antibodies. Among the other 24 biopsies, mild to moderate portal and lobular inflammation were present in 18 and 17 of 24 biopsies, respectively. Overall, 22 of 24 biopsies showed NRH-like changes. Plasma cell were absent. A distinct pattern of pericellular fibrosis was present in 23 of 26 biopsies overall. Involvement ranged from focal centrizonal fibrosis to bridging fibrosis and was accompanied by increased intrasinusoidal lymphocytes in 13 of 24 biopsies. Pericellular fibrosis was identified in 1 of 21 biopsies in the control cohort. Additional findings included granulomatous inflammation or nonhepatocellular foreign body-type multinucleate giant cells, identified in 4 biopsies. Three of 6 examined biopsies also demonstrated focal hepatocellular copper deposition. Hepatic disease in CVID is often associated with elevated alkaline phosphatase and aspartate transaminase and is characterized histologically by the mild nonspecific portal and lobular hepatitis, absence of plasma cells, NRH-like changes, and less commonly, typical histologic features of primary biliary cholangitis. We have also identified a distinctive pattern of delicate pericellular fibrosis that is a helpful clue to the diagnosis of hepatic disease in CVID, especially when accompanied by NRH-like changes.	0
Ring chromosome 14 syndrome is a rare genetic disorder. Typically, children with this syndrome have distinct facial features, development delay, microcephaly, seizures, ocular abnormalities, and recurrent respiratory infections. Epilepsy associated with ring chromosome 14 generally shows intractable seizures. We describe a six-month-old girl with ring chromosome 14 syndrome who presented with early-onset and drug-resistant seizures.	0
AIM:Umbilical cord ulceration (UCU) is a disease in which an ulcer forms in the umbilical cord in the pregnant uterus and is accompanied by hemorrhaging from the same site. UCU occurs in fetuses with congenital upper-intestinal atresia (CUIA); however, its onset mechanism remains unclear. Here, we report our investigation of cases of UCU in our hospital. METHODS:Among the 9825 deliveries performed between 2007 and 2016 at this hospital, 20 fetuses were diagnosed with CUIA, 4 (20%) of which had UCU. There was no difference in the backgrounds of the fetuses with UCU (UCU group: 4 fetuses) and those without (non-UCU group: 16 fetuses). RESULTS:There was no intergroup difference in gestational age at delivery. Four cases in the UCU group had maternal age 35 weeks (26-39), weeks of delivery 35 weeks (35-36) and weight 2178.5 g (1600-2640); three out of four fetuses were female; and the location of gastrointestinal obstruction was in the duodenum in one case and in the jejunum in three cases. Death occurred in three of four fetuses in the UCU group versus none in the non-UCU group. CONCLUSION:We performed a retrospective statistical investigation on the risk of UCU onset in cases from this hospital; however, we could not identify any prognostic factors for its onset. We investigated a total of 27 past reported UCU cases and the 4 cases in this study. Mean gestational age at onset was 33.3 ± 2.7 for all 27 cases. Various methods for the early discovery of UCU have been reported in the past; however, there is currently no gold standard. Based on this report and a review of past papers, for CUIA, it is desirable to perform in-hospital management from gestational week 30 onward and decide proper delivery timing on a case-by-case basis.	1
Among the congenital heart disease (CHD) population, intra-atrial reentrant tachycardia (IART) is a common sequela resulting from anatomical anomalies and surgical scars that significantly increases morbidity and mortality. Atrial antitachycardia pacing (ATP) delivered by atrial antitachycardia devices (ATDs) has been used to treat IART in the CHD population. However, there remains limited data on the safety and efficacy of ATP, as well as on comparisons of its effects amongst different CHD subtypes. The purpose of the current study is to describe the clinical history and ATP efficacy in three patients with unique forms of complex CHD. During this study, a single-center review of three patients with ATDs was performed. One patient with each of the following CHD anomalies was selected for inclusion: systemic left ventricle, systemic right ventricle, and single ventricle. Data collected included ATP success rates, medications in use, direct current (DC) cardioversions, and any complications related to the ATDs. Study findings revealed the patient with a systemic left ventricle had an ATD implanted for approximately 9.5 years, with 695 of 956 (73%) episodes successfully converted. Unsuccessfully treated episodes were generally asymptomatic and self-terminating in this patient. The patient with a systemic right ventricle had an ATD implanted for approximately 16 years, with 333 of 348 (96%) episodes being successfully converted. The patient with a single ventricle had an ATD implanted for approximately 12.5 years, with 404 of 416 (97%) episodes successfully converted. The patients with biventricular physiology were able to forgo DC cardioversion after receiving their ATDs. However, due to medical noncompliance as well as multiple episodes of IART, which presented with 1:1 conduction or low rates, the single-ventricle patient still required DC cardioversions post-ATD implantation. In conclusion, this study's findings demonstrate that, while ATP can be effective in a wide variety of CHDs, experiences can vary based on individual arrhythmia substrates, cardiac anatomy, and medical compliance. Additionally, challenges remain in IART detection in patients with especially complex CHD anatomies.	0
In previous years, several kinases, such as phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and extracellular-signal-regulated kinase (ERK), have been linked to important human diseases, although some kinase families remain neglected in terms of research, hiding their relevance to therapeutic approaches. Here, a review regarding the NEK family is presented, shedding light on important information related to NEKs and human diseases. NEKs are a large group of homologous kinases with related functions and structures that participate in several cellular processes such as the cell cycle, cell division, cilia formation, and the DNA damage response. The review of the literature points to the pivotal participation of NEKs in important human diseases, like different types of cancer, diabetes, ciliopathies and central nervous system related and inflammatory-related diseases. The different known regulatory molecular mechanisms specific to each NEK are also presented, relating to their involvement in different diseases. In addition, important information about NEKs remains to be elucidated and is highlighted in this review, showing the need for other studies and research regarding this kinase family. Therefore, the NEK family represents an important group of kinases with potential applications in the therapy of human diseases.	0
INTRODUCTION:Crush syndrome (CS) is a condition with a high morbidity and mortality due to severe electrolyte disorders, circulatory dysfunction and multiple organ failure, secondary to severe rhabdomyolysis and reperfusion injuries. There is controversy about the role of fasciotomy in the treatment of compartment syndromes due to crush injuries and it is still unknown if early amputation has patient-centered benefits. CASE PRESENTATION:This is a 29-year-old patient whose lower body was trapped for 50 h under a 40-meter landslide. Upon admission the left thigh was edematous and painful. Laboratories revealed a creatinine of 1.58 mg/dL, hyperkalemia, metabolic acidosis, hyperlactatemia and creatinine phosphokinase (CPK) of 88,700 U/L, suggesting CS. Despite fluid and bicarbonate infusion his renal function worsened, CPK rose and left thigh became more tense, so a fasciotomy was performed. He developed a distributive shock refractory to vasopressors, steroids and methylene blue so amputation was proposed. Two hours after amputation the vasopressor support was nearly withdrawn. DISCUSSION:This case suggests a potential benefit of amputation in patients with CS and progressive deterioration despite aggressive resuscitation. It also invites to think if this is a decision that should be considered before the establishment or in the initial stages of the syndrome, even if the viability of the extremity is still questionable. CONCLUSION:The presence of risk factors for poor prognosis can favor amputation despite the apparent viability of the limb and the morbidity of losing an extremity.	0
Holt-Oram syndrome (HOS) is a rare, autosomal dominant disorder caused by heterozygous pathogenic variants in cardiac T-box transcription factor, TBX5. Classically, it is associated with upper limb malformations and variable cardiac abnormalities. Limb manifestations are considered to be invariably present, ranging in severity from limitation in movement, to triphalangeal thumbs, absent thumbs, shortened forearms, or phocomelia. Cardiac involvement is characterized by congenital heart defects, most commonly septal structural malformations, and conduction system disease. Recently, novel TBX5 variants have also been reported in association with dilated cardiomyopathy (DCM). In this context, we report eight individuals from four unrelated families, in whom pathogenic variants in TBX5 segregated with an atypical HOS phenotype. Affected individuals exhibit relatively mild skeletal features of HOS, with a predominant cardiac phenotype, which includes several individuals affected by non-ischaemic DCM. To our knowledge, these represent the first reported cases of DCM in families with skeletal features of HOS, some of whom also harbored variants previously linked to a classical HOS phenotype (p. Arg279* and p.Arg237Gln). This finding supports diverse roles of TBX5 in cardiovascular development and function, and confirms the importance of long-term cardiac surveillance for individuals affected by HOS. Furthermore, these families highlight the wide phenotypic variability of HOS, which may include comparatively mild upper limb findings in respect to cardiac manifestations.	0
Venezuelan equine encephalitis virus (VEEV) is an important pathogen of medical and veterinary importance in the Americas. In this report, we present the complete genome sequences of five VEEV isolates obtained from pools of Culex (Melanoconion) gnomatos (4) or Culex (Melanoconion) pedroi (1) from Iquitos, Peru. Genetic and phylogenetic analyses showed that all five isolates grouped within the VEEV complex sister to VEEV IIIC and are members of subtype IIID. This is the first report of full-length genomic sequences of VEEV IIID.	0
BACKGROUND:Fabry disease (FD) is a rare X-linked lysosomal storage disorder and is included in the Specified Disease Treatment Research Program in Japan, which subsidizes medical care for beneficiaries with rare and other, designated diseases. However, no report on the epidemiologic features of Fabry disease has been published in Japan. METHODS:We used clinical research data reports submitted to the program between 2003 and 2008 to assess the epidemiologic features of 315 beneficiaries with FD. RESULTS:Of the 315 program beneficiaries, 198 were men (mean age, 37.4 years) and 117 were women (mean age, 51.2 years). The overall incidence in Japan was 0.25 cases per 100,000 individuals, and prevalence among men was 1.78 times that among women. More than 80% of beneficiaries were capable of working, going to school, or doing housework; however, 46 beneficiaries (14.6%) required home care, and 9 (2.9%) were living in hospitals or other medical facilities. As compared with the previous year, the clinical course of FD at beneficiary registration was unchanged for 178 of 290 beneficiaries (61.4%), worse for 81 (27.9%), and improved or cured for 31 (10.7%). The distribution of beneficiary-related characteristics was similar between men and women, and no significant difference was observed. CONCLUSIONS:The high percentage (>80%) of individuals with FD who were able to work, attend school, and perform tasks such as housework could reflect an improvement in the clinical course of FD after enzyme replacement therapy. We must continue data collection and conduct further studies to improve our understanding of the descriptive epidemiology of FD.	1
BACKGROUND:Syndactyly is a clinical feature of split-hand foot malformation (SHFM), ectodermal-dysplasia-syndactyly (EDSS1) and Cenani-Lenz syndactyly syndromes (CLSS). In EDSS1, only cutaneous syndactyly is observed, with sparse hair, abnormal nails and dentition. In SHFM, bony syndactyly may vary from hypoplasia of one phalanx to aplasia of central digits, extending to complete fusion of all fingers and toes in CLSS. Several genes have been assigned to these syndromes. Performing a single step molecular diagnostics becomes a challenge when a phenotype has overlaps with several syndromes or when some of the clinical features are not fully expressed in patients. METHODS:Whole exome sequencing (WES) analysis on one sample derived from a consanguineous family was performed. A causative variant in WES data was prioritized via standard bioinformatics tools. The selected variant was Sanger sequenced in all the available family members for autosomal recessive segregation. RESULTS:A novel missense variant (c.1151A>G; p.Tyr384Cys) was identified in the LRP4 gene. Sanger validation confirmed that all affected individuals were homozygous and the obligate carriers were heterozygous for this variant. The variant is neither reported in 1000 human genomes, nor in 60 706 exomes databases, and is predicted as "pathogenic" by SIFT, Polyphen-2 and MutationTaster software. CONCLUSIONS:The present study broadens the pathogenic spectrum of the LRP4 gene in syndactyly syndromes. WES is a powerful tool for genetic analysis in research and can be readily used as a first-line diagnostic test in syndactyly and related phenotypes.	0
Mullerian adenosarcoma following tamoxifen therapy is a rare condition. Our aim was to report the youngest patient in the literature with uterine mullerian adenosarcoma who was undergoing tamoxifen therapy for breast cancer. A premenopausal woman aged 38 years who was undergoing tamoxifen therapy for breast cancer, was admitted with symptoms of lower abdominal pain and irregular vaginal bleeding and malodorous vaginal discharge that had continued for at least 6 months. A pelvic examination revealed a large and malodorous polypoid mass protruding through the cervix and an enlarged uterus. A biopsy from the protruding polypoid mass was reported as a large area of necrosis with neoplastic mesenchymal cells. The patient underwent a total abdominal hysterectomy, bilateral salpingo-oopherectomy, pelvic-paraaortic lymph node dissection, and omentectomie. The histologic diagnosis was Mullerian adenosarcoma. As a result, she was discharged to the oncology department. The woman is alive and her chemoradiotherapy treatment is ongoing. The role of tamoxifen therapy in the development of endometrial neoplasms remains unclear, but all cases of endometrial thickening and vaginal bleeding must be investigated for Mullerian adenosarcoma in tamoxifen users.	0
Background:Mutations of GDAP1 gene cause autosomal dominant and autosomal recessive Charcot-Marie-Tooth (CMT) disease and over 80 different mutations have been identified so far. This study analyzed the clinical and genetic characteristics of a Vietnamese CMT family that was affected by a novel GDAP1 mutation. Methods:We present three children of a family with progressive weakness, mild sensory loss, and absent tendon reflexes. Electrodiagnostic analyses displayed an axonal type of neuropathy in affected patients. Sequencing of GDAP1 gene was requested for all members of the family. Results:All affected individuals manifested identical clinical symptoms of motor and sensory impairments within the first three years of life, and nerve conduction study indicated the axonal degeneration. A homozygous GDAP1 variant (c.667_671dup) was found in the three affected children as recessive inheritance pattern. The mutation leads to a premature termination codon that shortens GDAP1 protein (p.Gln224Hisfs∗37). Further testing showed heterozygous c.667_671dup variant in the parents. Discussion:Our study expands the mutational spectrum of GDAP1-related CMT disease with the new and unreported GDAP1 variant. Alterations in GDAP1 gene should be evaluated as CMT causing variants in the Vietnamese population, predominantly axonal form of neuropathy in CMT disease.	0
BACKGROUND:Studies have shown marked improvements in survival between 1981 and 2000 for Ewing sarcoma patients but not for osteosarcoma. This study aimed to explore socio-economic patterning in early mortality rates for both tumours. PROCEDURE:The study analysed all 2432 osteosarcoma and 1619 Ewing sarcoma cases, aged 0-49 years, diagnosed in Great Britain 1985-2008 and followed to 31/12/2009. Logistic regression models were used to calculate risk of dying within three months, six months, one year, three years and five years after diagnosis. Associations with Townsend deprivation score and its components were examined at small-area level. Urban/rural status was studied at larger regional level. RESULTS:For osteosarcoma, after age adjustment, mortality at three months, six months and one year was associated with higher area unemployment, OR = 1.05 (95% CI 1.00, 1.10), OR = 1.04 (95% CI 1.01, 1.08) and OR = 1.04 (95% CI 1.02, 1.06) respectively per 1% increase in unemployment. Mortality at six months was associated with greater household non-car ownership, OR = 1.02 (95% CI 1.00, 1.03). For Ewing sarcoma, there were no significant associations between mortality and overall Townsend score, nor its components for any time period. For both tumours increasing mortality was associated with less urban and more remote rural areas. CONCLUSIONS:This study found that for osteosarcoma, early mortality was associated with residence at diagnosis in areas of higher unemployment, suggesting risk of early death may be socio-economically determined. For both tumours, distance from urban centres may lead to greater risk of early death.	0
The diagnosis of acute autoimmune rheumatic disorders in sickle cell disease (SCD) can be challenging. Polymyositis is an inflammatory myopathy which, like SCD, may present with myalgia but is usually associated with proximal muscle weakness. We describe an adolescent boy presenting with limb pain, difficulty in mobilisation, with progressive loss of motor function and later bulbar weakness. Investigations showed massive elevation of creatine kinase, and MRI and muscle biopsy findings consistent with severe polymyositis. The patient was treated with corticosteroids, intravenous immunoglobulin and intensive rehabilitation therapy. He made a good recovery and was discharged on azathioprine and prednisolone. In the context of SCD, multisystem symptoms, unexplained muscle pain and weakness, unresponsive to conventional treatment in the presence of steady state haemoglobin, should alert the clinician to autoimmune phenomena. Key factors in making a diagnosis are an autoimmune screen and early discussion with a rheumatology expert.	0
Female-restricted syndromic intellectual disability (ID) is a neurodevelopmental disorder with developmental delay (DD)/ID, facial dysmorphism, and diverse congenital anomalies comprising heart defects, anal anomalies, choanal atresia, postaxial polydactyly, scoliosis, and brain abnormalities. Loss-of-function mutations in the USP9X gene inherited as X-linked dominance were identified as its etiology in females of different ethnic groups. Here, we report a 15-year-old Thai girl harboring a novel de novo heterozygous one-base pair deletion (c.3508delG, p.Val1170TrpfsX9) in exon 23 of USP9X. Her profound DD, dysmorphic face including attached earlobes, short stature, and congenital malformations including s-shaped thoracolumbar scoliosis, hip dislocation, and generalized brain atrophy shared common characteristics of X-linked syndromic ID. We have observed severely malformed oro-dental organs and a choledochal cyst, which have never been reported. Our study presents the first patient from Thailand expanding the phenotypic and mutational spectra of the syndrome.	0
BACKGROUND:Retinitis punctata albescens is a form of retinitis pigmentosa characterized by white fleck-like deposits in the fundus, in most cases caused by pathogenic variants in RLBP1 gene. The purpose of this work is to report the phenotypic and genotypic data of a patient with retinitis punctata albescens carrying a deletion in the RLBP1 gene. RESULTS:An 8-year-old Caucasian female has been complaining of nyctalopia for the last 2 years. No other ocular symptoms were present. No relevant past medical or familiar history was described. At clinical examination, the patient's best-corrected visual acuity was 20/20 in both eyes. Anterior segment evaluation and intraocular pressure were normal in both eyes. At fundoscopy, multiple punctate whitish-yellow fleck-like lesions were observed in the proximity of temporal superior and inferior vascular arcades. Scotopic electroretinogram demonstrated severely reduced rod response, without improvement or recovery of rod system function after prolonged dark adaptation. Blood DNA samples of this patient and from her parents were screened for causal variants in RLBP1, RDH5, and PRPH2. CONCLUSION:A probable pathogenic frameshift variant was identified in homozygosity in the RLBP1 gene with an autosomal recessive transmission as another cause of retinitis punctata albescens. This DNA variant will aid ongoing functional studies and add to our understanding of the molecular pathology about RLBP1-associated retinopathies.	0
The human X and Y chromosomes evolved from a pair of autosomes approximately 180 million years ago. Despite their shared evolutionary origin, extensive genetic decay has resulted in the human Y chromosome losing 97% of its ancestral genes while gene content and order remain highly conserved on the X chromosome. Five 'stratification' events, most likely inversions, reduced the Y chromosome's ability to recombine with the X chromosome across the majority of its length and subjected its genes to the erosive forces associated with reduced recombination. The remaining functional genes are ubiquitously expressed, functionally coherent, dosage-sensitive genes, or have evolved male-specific functionality. It is unknown, however, whether functional specialization is a degenerative phenomenon unique to sex chromosomes, or if it conveys a potential selective advantage aside from sexual antagonism. We examined the evolution of mammalian orthologs to determine if the selective forces that led to the degeneration of the Y chromosome are unique in the genome. The results of our study suggest these forces are not exclusive to the Y chromosome, and chromosomal degeneration may have occurred throughout our evolutionary history. The reduction of recombination could additionally result in rapid fixation through isolation of specialized functions resulting in a cost-benefit relationship during times of intense selective pressure.	0
BACKGROUND:Multiple system atrophy (MSA) is a serious progressive neurodegenerative disease. Early diagnosis of MSA is very difficult, and diagnostic biomarkers are limited. Growth differentiation factor 15 (GDF15) is involved in the differentiation and progression of the central nervous system, and is widely distributed in peripheral blood, which may be a novel biomarker for MSA. AIM:To determine serum GDF15 levels, related factors and their potential diagnostic value in MSA patients, compared with Parkinson's disease (PD) patients and healthy controls. METHODS:A case-control study was conducted, including 49 MSA patients, 50 PD patients and 50 healthy controls. Serum GDF15 levels were measured by human enzyme-linked immunosorbent assay, and the differences between the MSA, PD and control groups were analyzed. Further investigations were performed in different MSA subgroups according to age of onset, sex, clinical subtypes, diagnostic criteria, and disease duration. Receiver-operating characteristic curve analysis was used to evaluate the diagnostic value of GDF15, especially for the differential diagnosis between MSA and PD. RESULTS:Serum GDF15 levels were significantly higher in MSA patients than in PD patients and healthy controls (P = 0.000). Males and those with a disease duration of more than three years showed higher serum GDF15 levels (P = 0.043 and 0.000; respectively). Serum GDF15 levels may be a potential diagnostic biomarker for MSA patients compared with healthy controls and PD patients (cutoff: 470.42 pg/mL, sensitivity: 85.7%, specificity: 88.0%; cutoff: 1075.91 pg/mL, sensitivity: 51.0%, specificity: 96.0%; respectively). CONCLUSION:Serum GDF15 levels are significantly higher in MSA patients and provide suggestions on the etiology of MSA.	0
Complete sternal cleft is a very rare congenital midline defect of the sternum. It is not uncommonly associated with intracardiac defects. We report a case of a 2-year-old child with complete sternal cleft and tetralogy of Fallot who presented with cyanotic spells. The child underwent total correction, followed by chest wall reconstruction on the next day.	0
RATIONALE:Intestinal hypoganglionosis most commonly presents in infancy or childhood, with only a few cases reported in adults. Those are mainly diagnosed after elective surgery for long-standing constipation and megacolon. PATIENT CONCERNS:We report a case of a 48-year-old female from China who presented with symptoms of discontinuation of bowel movements for 2 months. A hard, round mass could be felt in her right lower abdomen. DIAGNOSIS:The following examination methods diagnosed acquired segmental sigmoid hypoganglionosis. An abdominal computed tomography revealed a dilatation of the colon and suspicious wall thickening of the sigmoid colon. Anorectal manometry revealed relaxation of the anal sphincter. Histological examination revealed lower numbers and the degeneration of ganglion cells. INTERVENTIONS:Sigmoidectomy and transverse colostomy. OUTCOMES:The patient recovered well from surgery. Three months after the surgery, barium enema revealed a recovery in colorectal dilatation. LESSONS:This case could help raise awareness of acquired segmental hypoganglionosis. Resection of TZ and enterostomy presents an effective remission strategy for patients at risk of anastomotic leakage due to poor intestinal conditions.	0
INTRODUCTION:Xanthoma disseminatum is a very rare disease classified as a benign non-Langerhans cell histiocytosis, which is rarely associated with osteoarticular lesions. There is only a report of tumor abrasion during treatment of osteoarticular lesions of this disease, artificial joint replacement has not been reported. We describe a patient in whom bilateral total joint replacement was performed for disseminated xanthoma lesions of the hip joints. CASE PRESENTATION:A 34-year-old Japanese woman had a chief complaint of bilateral coxalgia. She had been diagnosed as having disseminated xanthoma. Radiographs showed numerous 5-mm radiolucent bands that resembled worm-eaten tracks in the lower part of the femoral heads adjacent to the joint surface. In addition, short tau inversion recovery imaging scans showed high-intensity areas from the femoral head to the neck in both femurs, suggesting bone marrow edema. Total hip arthroplasty was performed for hip arthrosis on both hip joints caused by disseminated xanthoma. Deflection of the implants was a concern from the early stages postoperatively, but both the imaging and clinical findings have been satisfactory for 4 years of follow-up. CONCLUSIONS:A very unusual hip joint lesion of xanthoma disseminatum was replaced with a total artificial joint replacement, and the course over 4 years was good. Our patient's course will continue to be followed carefully.	0
The parasitic copepod Sinergasilus polycolpus was identified on the gills of bighead carp Aristichthys nobilis from 2 localities (Kladovo and Slankamen) in the Serbian part of the River Danube. This parasite is species-specific for 2 Chinese carp, the bighead carp and the silver carp Hypophthalmichthys molitrix. It was accidentally introduced into Serbia and Montenegro together with fry of these herbivorous carp intended for aquaculture and control of phytoplankton blooms. There is no record in the available literature of this parasite for European freshwaters. Our identification of S. polycolpus signals the possible spread of the infectious disease sinergasilosis in natural freshwaters and in fishponds, similar to bothriocephalosis, caused by Bothriocephalus opsariichthydis, which was introduced with the fry of various herbivorous species from the Amour River basin (USSR) into almost all countries throughout the world.	0
Polycytemia vera (PV) is a rare myeloproliferative neoplasm associated with microcirculatory disturbances, thrombosis and bleeding. Patients suffering from PV have a high risk of perioperative adverse events, but the literature regarding on-pump procedures in PV patients is scarce. We report two cases of acute and severe oxygenator failure during cardiopulmonary bypass and present valid exit scenarios.	0
BACKGROUND:Segmental progeroid syndromes (SPS) are rare hereditary diseases in which the affected individuals show signs of premature aging in more than one organ or type of tissue. We review the clinical and genetic features of some of these syndromes and discuss the extent to which their study affords a complementary opportunity to study aging processes in general. METHODS:This review is based on publications retrieved by a selective search in PubMed. RESULTS:Segmental progeroid syndromes are a clinically and genetically heterogeneous group of hereditary diseases. They can be categorized, for example, by the age of onset of manifestations (congenital vs. infantile vs. juvenile/adult forms). They are diagnosed on clinical grounds supplemented by genetic testing on the basis of next-generation sequencing, which is of central importance in view of the marked heterogeneity and complexity of their overlapping clinical features. The elucidation of the genetic and molecular causes of these diseases can lead to causally directed treatment, as shown by the initial clinical trials in Hutchinson- Gilford progeria syndrome. The molecular features of SPS are identical in many ways to those of "physiological" aging. Thus, studying the molecular mechanisms of SPS may be helpful for the development of molecularly defined treatment approaches for age-associated diseases in general. CONCLUSION:Segmental progeroid syndromes are a complex group of diseases with overlapping clinical features. Current research efforts focus on the elucidation of the molecular mechanisms of these diseases, most of which are very rare. This should enable the development of treatments that might be applicable to general processes of aging as well.	0
We studied 21 patients with Sanjad-Sakati syndrome (SSS) from 16 families. Parental consanguinity was recorded in 2 families (12.5%). All patients had severe intrauterine growth retardation, short stature, small hands and feet, blue sclera, deep-set eyes, microcephaly, persistent hypocalcaemia and hypoparathyroidism. Medullary stenosis was detected in 2 patients. Cytogenetic and fluorescent in situ hybridization studies were normal. All affected persons had homozygous deletion of 12 bp (155-166del) in exon 3 of the TBCE gene. All of the parents were heterozygous carriers of this mutation. The high frequency of SSS and low frequency of consanguineous marriages in this study may reflect a high rate of heterozygous carriers.	0
Craniosynostosis, the premature fusion of one or more cranial sutures of the skull, provides a paradigm for investigating the interplay of genetic and environmental factors leading to malformation. Over the past 20 years molecular genetic techniques have provided a new approach to dissect the underlying causes; success has mostly come from investigation of clinical samples, and recent advances in high-throughput DNA sequencing have dramatically enhanced the study of the human as the preferred "model organism." In parallel, however, we need a pathogenetic classification to describe the pathways and processes that lead to cranial suture fusion. Given the prenatal onset of most craniosynostosis, investigation of mechanisms requires more conventional model organisms; principally the mouse, because of similarities in cranial suture development. We present a framework for classifying genetic causes of craniosynostosis based on current understanding of cranial suture biology and molecular and developmental pathogenesis. Of note, few pathologies result from complete loss of gene function. Instead, biochemical mechanisms involving haploinsufficiency, dominant gain-of-function and recessive hypomorphic mutations, and an unusual X-linked cellular interference process have all been implicated. Although few of the genes involved could have been predicted based on expression patterns alone (because the genes play much wider roles in embryonic development or cellular homeostasis), we argue that they fit into a limited number of functional modules active at different stages of cranial suture development. This provides a useful approach both when defining the potential role of new candidate genes in craniosynostosis and, potentially, for devising pharmacological approaches to therapy.	0
BACKGROUND:The present study sought to introduce clinical characteristics and stepwise surgical strategies of isolated complete cryptophthalmos, a rare, congenital ocular anomaly. CASE PRESENTATION:Retrospective, noncomparative, clinical study. Six patients with isolated complete cryptophthalmos were diagnosed at the Beijing Tongren Hospital between 2010 to 2018. The presentation age of patients ranged from 1 month to 68 years. This study includes two males and four females, and involvement was noted to be bilateral in two cases and unilateral in four cases. According to orbital CT scan and ocular CDI results, two patients were combined with ocular cyst. Reconstruction surgeries were performed in three patients, involving the eyeball enucleation, creation of fornix, eyelid reconstruction with skin flaps/amniotic membrane, and implantation of prosthesis. Besides, implantation of hydroxyapatite was performed in one pediatric patient to promote orbit development. Good outcomes in terms of cosmetic satisfaction were achieved in all patients during follow-up. CONCLUSIONS:Surgical intervention could only improve the cosmetic appearance in isolated complete cryptophthalmos. The surgical strategies may be planned to use three-stage approaches described in this study. Meanwhile, orbital development must be taken into consideration in pediatric cases.	0
PURPOSE: Ehlers-Danlos syndrome (EDS), comprising a variety of inherited connective tissue disorders, has already been described in association with various neurological features, particularly with epilepsy and periventricular heterotopia (PH). Until now, there are reports of only bilateral periventricular heterotopia associated with Ehlers-Danlos syndrome. METHODS AND RESULTS: Here we describe a 1-year, 4-month-old female who came under our care in the Pediatric Emergency Room because of prolonged afebrile generalized seizures, whose clinical picture allowed us to suspect a diagnosis of Ehlers-Danlos syndrome. Neuroradiological investigations showed unilateral periventricular heterotopias, and genetic analyses confirmed the hypothesized diagnosis, identifying in particular a mutation in the COL5A1 gene. After starting anticonvulsant therapy, her seizures showed a good response with seizure control and she had a favorable long-term course. CONCLUSION: To our knowledge, this is the first report of unilateral periventricular heterotopia associated with Ehlers-Danlos syndrome. We first hypothesized a mosaicism as the cause of both, a unilateral localization of the heterotopias and a favorable long-term course with good response to anticonvulsant therapy; however, intriguingly, we could not demonstrate a mosaicism as the genetic condition in our patient and the neuroradiological findings and the favorable clinical outcome still remain unexplained.	0
SHIP2 is a phosphatase that acts at the 5-position of phosphatidylinositol 3,4,5-trisphosphate. It is one of several enzymes that catalyse dephosphorylation at the 5-position of phosphoinositides or inositol phosphates. SHIP2 has a confirmed role in opsismodysplasia, a disease of bone development, but also interacts with proteins involved in insulin signalling, cytoskeletal function (thus having an impact on endocytosis, adhesion, proliferation and apoptosis) and immune system function. The structure of three domains (constituting about 38 % of the protein) is known. Inhibitors of SHIP2 activity have been designed to interact with the catalytic domain with sub-micromolar IC50 values: these come from a range of structural classes and have been shown to have in vivo effects consistent with SHIP2 inhibition. Much remains unknown about the roles of SHIP2, and possible future directions for research are indicated.	0
PITX1 is a homeobox transcription factor essential for hindlimb morphogenesis. Two PITX1-related human disorders have been reported to date: PITX1 ectopic expression causes Liebenberg syndrome, characterized by malformation of upper limbs showing a "lower limb" appearance; PITX1 deletions or missense variation cause a syndromic picture including clubfoot, tibial hemimelia, and preaxial polydactyly. We report two novel PITX1 missense variants, altering PITX1 transactivation ability, in three individuals from two unrelated families showing a distinct recognizable autosomal dominant syndrome, including first branchial arch, pelvic, patellar, and male genital abnormalities. This syndrome shows striking similarities with the Pitx1-/- mouse model. A partial phenotypic overlap is also observed with Ischiocoxopodopatellar syndrome caused by TBX4 haploinsufficiency, and with the phenotypic spectrum caused by SOX9 anomalies, both genes being PITX1 downstream targets. Our study findings expand the spectrum of PITX1-related disorders and suggest a common pattern of developmental abnormalities in disorders of the PITX1-TBX4-SOX9 signaling pathway.	0
A total of 28 Norwegians have been diagnosed with hereditary tyrosinaemia type I (HT1) over the last 30 years. In this study, 19 of these patients were investigated. Three novel small deletions were found (NM_000137.1(FAH): c.615delT, p.Phe205LeufsX2, NM_000137.1(FAH): c.744delG, p.Pro249HisfsX55 and NM_000137.1(FAH):c835delC) pGln279ArgfsX25, all of them leading to a change in the reading frame and a premature stop codon. We hereby genetically characterized 51 of the 56 disease-causing alleles, identifying nine different disease-causing mutations in the Norwegian population. We found that 65% of the Norwegian HT1 patients are compound heterozygous for different mutations. Thus, the relatively high incidence of HT1 in Norway of 1 in 74,800 live births is not due to single founder effects or high incidence of parental consanguinity.	1
Elizabethkingia spp are Gram-negative bacteria associated with neonatal meningitis. In 2015-2016, an outbreak of Elizabethkingia anophelis infection that involved 63 patients and 18 deaths occurred in Wisconsin. Despite a multistate investigation, as of September 2016 the source remained undetermined, and experts warned of reemergence. We describe here the first cases of E anophelis infection in New York, including the case of a healthy infant without previous healthcare contact.	0
PURPOSE:To report our experience with oral miltefosine (MLT) as an adjunct treatment for progressive Acanthamoeba keratitis (AK). METHODS:Retrospective case series of all patients who underwent treatment with oral MLT for AK at Bascom Palmer Eye Institute from 2017 to 2020. RESULTS:Six females from 16 to 55 years old, with a microbiologic diagnosis of Acanthamoeba, were treated with MLT and standard medical treatment. Four of the six cases deteriorated after initiating treatment and three required a therapeutic keratoplasty. Two patients improved after 1 week of MLT and optical penetrating keratoplasty was performed after clinical resolution. Microbiologic culture of corneal buttons was negative in all cases. All corneal grafts remain clear at last follow-up with best-corrected visual acuity of 20/40 or better. CONCLUSION:Oral MLT may be a viable adjunctive therapy for recalcitrant AK; however, its use may be associated with a severe inflammatory reaction. Further studies are needed to evaluate its efficacy and variable clinical response.	0
INTRODUCTION:We present a patient with co-existence of 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) deficiency and Bartter syndrome, a unique dual combination of opposing pathologies that has not been reported previously in the literature. CASE:A female infant (46,XX) born at 34/40 weeks' gestation, weighing 2.67 kg (-1.54 standard deviation score) to non-consanguineous parents presented on day 4 of life with significant weight loss. Subsequent investigations revealed hyponatraemia, hypochloraemia, metabolic alkalosis, elevated 17-hydroxyprogesterone, ACTH, and renin. Urine steroid profile suggested HSD3B2 deficiency, which was confirmed by the identification of a homozygous HSD3B2 mutation. Due to the persistence of the hypochlo-raemic and hypokalemic alkalosis, an underlying renal tubulopathy was suspected. Sequence analysis of a targeted tubulopathy gene panel revealed a homozygous deletion in CLCNKB, consistent with Bartter syndrome type 3. The mother was found to be heterozygous for both mutations in -HSD3B2 and CLCNKB, and the father was negative for both. Single-nucleotide polymorphism microarray analysis confirmed 2 segments of homozygosity on chromosome 1 of maternal ancestry, encompassing both HSD3B2 and CLCKNB. DISCUSSION:Identification of a homozygous rare mutation in an offspring of non-consanguineous parents should raise suspicion of uniparental disomy, especially if the phenotype is unusual, potentially encompassing more than one disorder. The persistence of hypokalemic alkalosis, the biochemical fingerprint of hyperaldosteronism in a child with a form of CAH in which aldosterone production is severely impaired, challenges our current understanding of mineralocorticoid-mediated effects in the collecting duct.	0
Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease that is pathologically characterized by the presence of eosinophilic hyaline intranuclear inclusions in neurons, astrocytes, and specific somatic cells. Previously reported cases of NIID displayed various neurological symptoms, including dementia, muscle weakness, ataxia, etc. However, dysphagia associated with NIID have rarely been reported. Here, we report on three cases of NIID with dysphagia. Bolus mastication and transport were impaired in all three cases. Delay of the initiation of pharyngeal swallowing and silent aspiration was observed in two cases. Combined with the brain magnetic resonance imaging (MRI) findings, oropharyngeal dysphagia associated with NIID was suggested to be attributed to diffuse subcortical lesions.	0
Pulmonary venoocclusive disease (PVOD) is a rare cause of pulmonary hypertension characterized by a progressive clinical course and poor outcomes if not treated by early lung transplantation. The pathogenesis of PVOD remains poorly understood. We report PVOD that developed in 2 young women soon after the initiation of oral contraceptives (OCs). The first patient is a 14-year-old girl, with no medical history, who started taking an OC 3 weeks before the onset of symptoms. The second patient is an 18-year-old girl, diagnosed 2 years previously with systemic lupus erythematosus and lupus anticoagulant, who started taking an OC 4 months before the onset of symptoms. Both patients required lung transplantation. Radiographic and histopathologic findings in both patients showed features of PVOD. Only 1 prior patient with PVOD and a handful of unclassified patients with pulmonary hypertension in association with OCs have been documented. The importance of PVOD as the basis of pulmonary hypertension in patients with connective tissue disease has been recently proposed, as well as the role of thrombogenesis, in the development of PVOD. The temporal sequence in these 2 patients suggests the thrombogenic action of OCs may contribute to the development of PVOD, with or without underlying connective tissue disease.	0
BACKGROUND:Interstitial deletions of 2q are rare. Those that have been reported show varying clinical manifestations according to the size of the deletion and the genomic region involved. METHOD AND RESULTS:We describe a preterm male harboring a novel interstitial deletion encompassing the 2q21.2-q23.3 region of 2q, a deletion that has not been described previously. The patient had multiple congenital anomalies including agenesis of the corpus callosum, congenital cardiac defects, bilateral hydronephrosis, spontaneous intestinal perforation, hypospadias and cryptorchidism, sacral dimple and rocker-bottom feet. Array comparative genomic hybridization (aCGH) analysis revealed a de novo >18 Mb deletion at 2q21.1-q23.3, a region that included (605802, 611472 and 604593) OMIM genes. CONCLUSION:To the best of our knowledge this is the first report of a de novo interstitial deletion at 2q21.1-q23.3 in which haploinsufficiency of dose-sensitive genes is shown to contribute to the patient's phenotype.	0
Niemann-Pick disease type C1 (NPC1) is a rare, fatal neurodegenerative disorder characterized by lysosomal accumulation of unesterified cholesterol and glycosphingolipids. These subcellular pathologies lead to phenotypes of hepatosplenomegaly, neurological degeneration and premature death. NPC1 is extremely heterogeneous in the timing of clinical presentation and is associated with a wide spectrum of causative NPC1 mutations. To study the genetic architecture of NPC1, we have generated a new NPC1 mouse model, Npc1em1Pav Npc1em1Pav/em1Pav mutants showed notably reduced NPC1 protein compared to controls and displayed the pathological and biochemical hallmarks of NPC1. Interestingly, Npc1em1Pav/em1Pav mutants on a C57BL/6J genetic background showed more severe visceral pathology and a significantly shorter lifespan compared to Npc1em1Pav/em1Pav mutants on a BALB/cJ background, suggesting that strain-specific modifiers contribute to disease severity and survival. QTL analysis for lifespan of 202 backcross N2 mutants on a mixed C57BL/6J and BALB/cJ background detected significant linkage to markers on chromosomes 1 and 7. The discovery of these modifier regions demonstrates that mouse models are powerful tools for analyzing the genetics underlying rare human diseases, which can be used to improve understanding of the variability in NPC1 phenotypes and advance options for patient diagnosis and therapy.This article has an associated First Person interview with the first author of the paper.	0
Early development of extensive acanthosis nigricans (AN) is a key feature in some patients who have hypochondroplasia (HCH) in association with FGFR3 mutations. We here report regarding five new patients with HCH who exhibited AN, and we compare their characteristics to the eight patients previously described in the literature. In these patients, the AN lesions began in childhood, and they were extensive. These lesions were located on the torso, the abdomen, and the face, in addition to the typical skin fold sites. Other skin lesions were frequently reported: café-au-lait macules, melanocytic nevi, lentigines, and seborrheic keratosis. The Lys650Thr mutation was the predominant reported mutation of FGFR3.	0
To identify novel genetic causes of syndromic hearing loss in Brazil.To map a candidate chromosomal region through linkage studies in an extensive Brazilian family and identify novel pathogenic variants using sequencing and array-CGH.Brazilian pedigree with individuals affected by BO syndrome characterized by deafness and malformations of outer, middle and inner ear, auricular and cervical fistulae, but no renal abnormalities.Whole genome microarray-SNP scanning on samples of 11 affected individuals detected a multipoint Lod score of 2.6 in the EYA1 gene region (chromosome 8). Sequencing of EYA1 in affected patients did not reveal pathogenic mutations. However, oligonucleotide-array-CGH detected a duplication of 71.8Kb involving exons 4 to 10 of EYA1 (heterozygous state). Real-time-PCR confirmed the duplication in fourteen of fifteen affected individuals and absence in 13 unaffected individuals. The exception involved a consanguineous parentage and was assumed to involve a different genetic mechanism.Our findings implicate this EYA1 partial duplication segregating with BO phenotype in a Brazilian pedigree and is the first description of a large duplication leading to the BOR/BO syndrome.	0
Recombinant chromosome 8 syndrome is caused by duplication of 8q and deletion of 8p. A fetus with anomalies was misdiagnosed with this syndrome based on an amniocyte karyotype. Postnatal chromosomal microarray and other studies identified a de novo derivative chromosome 8. For fetal anomalies, detailed genetic studies may be required.	0
Pathogenic MAGEL2 variants result in the phenotypes of Chitayat-Hall syndrome (CHS), Schaaf-Yang syndrome (SYS) and Prader-Willi syndrome (PWS). We present five patients with mutations in MAGEL2, including the first patient reported with a missense variant, adding to the limited literature. Further, we performed a systematic review of the CHS and SYS literature, assess the overlap between CHS, SYS and PWS, and analyze genotype-phenotype correlations among them. We conclude that there is neither a clinical nor etiological difference between CHS and SYS, and propose that the two syndromes simply be referred to as MAGEL2-related disorders.	0
We performed shallow single-cell sequencing of genomic DNA across 1475 cells from a cell-line, COLO829, to resolve overall complexity and clonality. This melanoma tumor-line has been previously characterized by multiple technologies and is a benchmark for evaluating somatic alterations. In some of these studies, COLO829 has shown conflicting and/or indeterminate copy number and, thus, single-cell sequencing provides a tool for gaining insight. Following shallow single-cell sequencing, we first identified at least four major sub-clones by discriminant analysis of principal components of single-cell copy number data. Based on clustering, break-point and loss of heterozygosity analysis of aggregated data from sub-clones, we identified distinct hallmark events that were validated within bulk sequencing and spectral karyotyping. In summary, COLO829 exhibits a classical Dutrillaux's monosomic/trisomic pattern of karyotype evolution with endoreduplication, where consistent sub-clones emerge from the loss/gain of abnormal chromosomes. Overall, our results demonstrate how shallow copy number profiling can uncover hidden biological insights.	0
The TKI avapritinib showed preliminary evidence of efficacy in gastrointestinal stromal tumors.	0
B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessments of 34 patients with B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex (≥3 abnormalities) in 73% of the patients and highly complex (≥5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving MYC [t(MYC)] (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six (76%) of the 34 patients exhibited an MYC aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1. The majority of B-PLL used the IGHV3 or IGHV4 subgroups (89%) and displayed significantly mutated IGHV genes (79%). We identified 3 distinct cytogenetic risk groups: low risk (no MYC aberration), intermediate risk (MYC aberration but no del17p), and high risk (MYC aberration and del17p) (P = .0006). In vitro drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif inhibitor targeting MYC) was associated with significantly lower viability of B-PLL cells harboring a t(MYC). We concluded that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting MYC may be a useful treatment option in this disease.	0
We sought to determine the incidence, prevalence, and life expectancy of Aicardi syndrome from 408 cases compiled from multiple international sources. Last known age ranged from less than 1 month to 42 years. The incidence rates per live births for the United States and The Netherlands were 1 per 105 000 and 1 per 93 000, respectively. The prevalence in the United States is greater than 853 cases, and the worldwide estimate is several thousand. Forty-five cases were deceased (age range, 1 month to 33 years), and the risk of death peaked at age 16. The probability of survival at 27 years of age was 0.62 (95% CI, 0.47-0.77). The risk of death by age follows other congenital neurological disorders with a wide range in severity of functional disability. The longer life expectancy found in our study hints at a higher functioning capacity in Aicardi syndrome and may inform counseling to families.	1
Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA), though a well-established method for specimen acquisition from pancreatic neoplasm, has a limited role for non-focal benign pancreatic diseases such as autoimmune pancreatitis (AIP) due to sample inadequacy and architectural distortion. Core biopsies through EUS-trucut biopsy (EUS-TCB) or newer generation EUS-fine needle biopsy (EUS-FNB) enable better histopathologic review through greater tissue specimen size and visualization of the histologic milieu. We systematically reviewed EUS-guided sample acquisition (FNA or core biopsy) and the role of EUS-guided needle biopsy in evaluation of AIP. EUS-guided needle biopsy provided significantly higher adequacy of specimen (96.8% vs 79.8%; p = 0.016) and higher diagnostic sensitivity (60.20% vs 42.02%; p < 0.0001) compared to EUS-FNA for AIP. More evidence is imperative in evaluating the feasibility, safety, and diagnostic utility of EUS-guided needle biopsy for AIP.	0
Over the last three decades, measuring and modulating cerebellar activity and its connectivity with other brain regions has become an emerging research topic in clinical neuroscience. The most important connection is the cerebellothalamocortical pathway, which can be functionally interrogated using a paired-pulse transcranial magnetic stimulation paradigm. Cerebellar brain inhibition reflects the magnitude of suppression of motor cortex excitability after stimulating the contralateral cerebellar hemisphere and therefore represents a neurophysiological marker of the integrity of the efferent cerebellar tract. Observations that cerebellar noninvasive stimulation techniques enhanced performance of certain motor and cognitive tasks in healthy individuals have inspired attempts to modulate cerebellar activity and connectivity in patients with cerebellar diseases in order to achieve clinical benefit. We here comprehensively explore the therapeutic potential of these techniques in two movement disorders characterized by prominent cerebellar involvement, namely the degenerative ataxias and essential tremor. The article aims to illustrate the (patho)physiological insights obtained from these studies and how these translate into clinical practice, where possible by addressing the association with cerebellar brain inhibition. Finally, possible explanations for some discordant interstudy findings, shortcomings in our current understanding, and recommendations for future research will be provided. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.	0
Williams-Beuren syndrome is a multisystem genetic disorder associated with cardiovascular abnormalities, the most common of which is some variation of arterial stenosis. We describe a case of Williams-Beuren syndrome with multiple cardiovascular structural and arterial abnormalities and demonstrate the unique role of cardiac computed tomography in diagnosis.	0
Aplasia cutis congenita (ACC) is a rare condition that presents at birth as an absence of skin that does not usually involve underlying structures. Occurring in 3/10,000 live births, ACC is evenly distributed between males and females; the risk of ACC increases to 7 percent in consanguineous marriages. Up to 86 percent of lesions are found on the scalp in the midline vertex position. Lesions can also be found on the trunk and limbs, as with Adams-Oliver syndrome or accompanying epidermolysis bullosa. ACC is associated with chromosomal abnormalities and 35-50 percent of the time with trisomy 13 (Patau syndrome). This case study presents an infant with multiple ACC lesions of the scalp. The pathophysiology, treatment, potential long-term complications, and nursing considerations are discussed.	0
Congenital hemifacial hyperplasia is a rare developmental disorder of unknown etiology, characterized by a marked unilateral facial asymmetry. It involves the hard (bones and teeth) and soft tissues of the face. We report an interesting case of true hemifacial hyperplasia in a 25-year-old male highlighting the clinical and computed tomography imaging findings.	0
Biallelic loss-of-function mutations in the RNA-binding protein EIF4A3 cause Richieri-Costa-Pereira syndrome (RCPS), an autosomal recessive condition mainly characterized by craniofacial and limb malformations. However, the pathogenic cellular mechanisms responsible for this syndrome are entirely unknown. Here, we used two complementary approaches, patient-derived induced pluripotent stem cells (iPSCs) and conditional Eif4a3 mouse models, to demonstrate that defective neural crest cell (NCC) development explains RCPS craniofacial abnormalities. RCPS iNCCs have decreased migratory capacity, a distinct phenotype relative to other craniofacial disorders. Eif4a3 haploinsufficient embryos presented altered mandibular process fusion and micrognathia, thus recapitulating the most penetrant phenotypes of the syndrome. These defects were evident in either ubiquitous or NCC-specific Eif4a3 haploinsufficient animals, demonstrating an autonomous requirement of Eif4a3 in NCCs. Notably, RCPS NCC-derived mesenchymal stem-like cells (nMSCs) showed premature bone differentiation, a phenotype paralleled by premature clavicle ossification in Eif4a3 haploinsufficient embryos. Likewise, nMSCs presented compromised in vitro chondrogenesis, and Meckel's cartilage was underdeveloped in vivo. These findings indicate novel and essential requirements of EIF4A3 for NCC migration and osteochondrogenic differentiation during craniofacial development. Altogether, complementary use of iPSCs and mouse models pinpoint unique cellular mechanisms by which EIF4A3 mutation causes RCPS, and provide a paradigm to study craniofacial disorders.	0
Primary biliary cholangitis is a slowly progressive immune-mediated cholestatic disease that causes a destruction of the intrahepatic bile ducts and may lead to cirrhosis of the liver, end-stage liver disease, and the need for liver transplantation. The disease is among the most common reasons why adults require liver transplantation. The primary signs of the disease include the presence of antimitochondrial and antinuclear antibodies, elevated alkaline phosphatase, hyperbilirubinemia, hypercholesterolemia, and histologic features, such as intense inflammation with a florid duct lesion and hepatic fibrosis. The patient's quality of life is impacted by fatigue, pruritus, malabsorption syndrome, sicca syndrome, osteoporosis, and challenges coping with chronic illness. Advanced practice registered nurses need to understand the pathophysiology, clinical presentation, diagnostic approaches, disease and symptom management, and priority nursing assessment and care in patients with this rare disease to differentiate it from primary sclerosing cholangitis, autoimmune hepatitis, obstructed bile duct lesions, drug-induced cholestasis, cholestasis in pregnancy, cholangiocarcinoma, hepatic malignancy, and peptic ulcer disease.	0
Background: Mutations in CEP290 cause autosomal recessive conditions with a wide range of severity and the lack of strong genotype-phenotype data makes it difficult to provide accurate prognostic data to patients and families.Methods: A retrospective chart review was conducted on a patient with a clinical diagnosis of Senior-Loken Syndrome, molecularly confirmed biallelic nonsense mutations in CEP290,and a recent finding of infertility secondary to non-motile sperm.Results: Here we present the case of a patient with a long-standing diagnosis of Senior-Loken syndrome due to findings of early-onset retinitis pigmentosa and renal disease. This is a patient who has been followed by ophthalmology and genetics for over 20 years and so provides valuable information on the natural history of CEP290-related ciliopathies. Additionally, we consider how this patient's biallelic nonsense variants in CEP290 affect phenotype severity through nonsense-mediated alternative splicing and how understanding this process could lead to future therapeutic options.Conclusions: CEP290 mutations are associated with a variety of overlapping clinical phenotypes, some of which will become better understood as more patients with these conditions survive to reproductive age. Similarly, increased understanding of the molecular mechanisms that underlie differences in phenotype may provide avenues to consider in future therapies.	0
Central intraosseous adenoid cystic carcinoma (ACC) of the mandible, formerly known as cylindroma, is a rare neoplasm with only 47 cases reported in the literature. We present a case of central ACC involving the mandible of a 55-year-old male patient.	0
BACKGROUND:Dense Deposit Disease is a rare condition affecting the Bruch's membrane and the glomerular basement membrane. We report the progression of the ocular manifestations over a 30 year follow up period, longer than any previous report. CASE PRESENTATION:A 44 year old male presented with pigmentary changes at the macula noted by his optician. Best corrected visual acuity at presentation was good in both eyes. Fundoscopy showed pigmentary changes and drusen, and investigation using intravenous fundus fluorescein angiography did not demonstrate any choroidal neovascular membrane. The patient subsequently developed renal failure and received a dual renal transplant. The transplanted kidneys also failed over the coming year. The patient's vision gradually deteriorated and comparison between the images in 2010 and 1985 demonstrated a clear progression of the macula changes. Optical coherence tomography showed multiple subretinal hyper reflective drusenoid deposits. These deposits were also noted to be autofluorescent on blue auto-fluorescence. The young age at presentation of drusen, combined with the history of recurrent kidney failure and progression of subretinal deposits led to a diagnosis of dense deposit disease. CONCLUSIONS:Dense deposit disease is a rare condition affecting Bruch's membrane, but should be considered in the differential diagnosis of any patient under the age of 50 years presenting with drusen.	0
Pleuropulmonary blastoma is a rare and aggressive childhood tumor of mesenchymal origin. It has a poor prognosis and mainly classified as cystic (type 1), mixed type (type 2), and solid (type 3). Herein, we present two cases of pleuropulmonary blastoma type 3 presenting with pneumothorax, a rare clinical presentation of pleuropulmonary blastoma, which was successfully treated with surgery.	0
Actinic cheilitis (AC) is one of the most frequent pathologies to affect the lips. Studies show that the most commonplace oral malignancy, squamous cell carcinoma (SCC), often emerges from AC lesions. Invasive diagnostic techniques performed on the lips carry a high risk of complications, but reflectance confocal microscopy (RCM), a non-invasive skin imaging technique, may change the current diagnostic pathway. This retrospective study was aimed at consolidating the RCM diagnostic criteria for AC and lip SCC. The study was conducted in two tertiary care centers in Bucharest, Romania. We included adults with histopathologically confirmed AC and SCC who also underwent RCM examination. Of the twelve lesions included in the study, four were AC and eight were SCC. An atypical honeycomb pattern and the presence of target cells in the epidermis were RCM features associated with AC. SCC was typified by the presence of complete disruption of the epidermal architecture and dermal inflammatory infiltrates. The mean blood vessel diameter in SCC was 18.55 µm larger than that in AC (p = 0.006) and there was no significant difference (p = 0.64) in blood vessel density, as measured by RCM, between SCC and AC. These data confirm that RCM can be useful for the in vivo distinction between AC and lip SCC.	0
Background:Uncoupling protein 1 (UCP1) is a mitochondral protein transporter that uncouples electron transport from ATP production. UCP1 is highly expressed in brown adipose tissue (BAT), including hibernomas, but its expression in other adipose tumours is uncertain. UCP1 has also been found in other tissues (e.g. smooth muscle) but whether it is expressed in non-adipose benign and malignant soft tissue tumours is unknown. Methods:Immunohistochemical staining of normal (axillary) BAT and subcutaneous/abdominal white adipose tissue (WAT) as well as a wide range of benign and malignant primary soft tissue tumours (n = 171) was performed using a rabbit polyclonal antibody to UCP1. BAT and hibernomas were also stained by immunohistochemistry with monoclonal and polyclonal antibodies to adipose/non-adipose tumour markers in order to characterise the immunophenotype of BAT cells. Results:UCP1 was strongly expressed in the cytoplasm of brown fat cells in BAT and hibernomas, both of which also expressed aP2, S100, CD31, vimentin and calponin. UCP1 was not expressed in WAT or other adipose tumours with the exception a few tumour cells in pleomorphic liposarcoma. UCP1 was variably expressed by tumour cells in a few non-adipose sarcomas including leiomyosarcoma, rhabdomyosarcoma, alveolar soft part sarcoma, synovial sarcoma and clear cell sarcoma. Conclusions:UCP1 is strongly expressed in BAT but not WAT and is found in all hibernomas and a few pleomorphic liposarcomas but not in other adipose tumours. UCP1 expression in a few non-adipose soft tissue sarcomas may possibly reflect origin of tumour cells from a common mesenchymal stem cell precursor and/or developmental pathway.	0
Bosma arhinia microphthalmia syndrome (Bosma syndrome)(OMIM 603457) is a congenital condition characterized by microphthalmia with coloboma, arhinia and endocrine findings in the setting of normal intelligence and brain structure. This condition is quite rare with fewer than 50 case reports and series. Although pathogenesis is presumed to be genetic, the cause remains unknown. We report an individual with Bosma syndrome who had bilateral colobomatous microphthalmia, arhinia, high arched palate, mild ear malformations, and hypogonadotropic hypogonadism requiring growth hormone treatment in childhood, and normal intelligence. Clinical evaluation was significant for a geometrically abnormal aorta with effacement of the sinotubular ridge, a finding not previously reported in this condition. An MRI revealed absent olfactory bulbs. Suggested criteria for diagnosis of Bosma should include arhinia, hypoplastic maxilla, normal cognition, and hypogonadotropic hypogonadism in males.	0
Premature ovarian insufficiency (POI) is a major cause of female infertility. It is a heterogeneous disease that affects about 1% of women under 40 years of age. POI may be due to abnormal follicle stock formation, increased follicular atresia, impaired recruitment of dominant follicles, blocked follicular maturation or rapid depletion of the follicular stock. It remains idiopathic in most cases but the existence of familial cases shows that it can have a genetic origin. Next generation sequencing (NGS) strategies have allowed the identification of new genes involved in the etiology of POI. Here, I briefly describe some studies demonstrating that pathogenic variants in 'DNA repair and meiotic genes' underlie POI. Some of the examples show the power of the combination of classical genetics and NGS in the discovery of novel 'POI genes'.	0
Baylisascaris procyonis is a zoonotic nematode whose main definitive host is the raccoon, an invasive carnivore in Europe introduced from the United States. B. procyonis causes larva migrans with poor prognosis in humans. This parasite was unexpectedly detected in France for the first time upon molecular screening of wolf faecal samples. Because no patent infection was found, the wolf cannot be considered as a definitive host. This discovery of B. procyonis in France nonetheless raises questions about the parasite status of the expanding raccoon populations in the country, which will be investigated in the future.	0
Hyperostosis frontalis interna (HFI) is a bone overgrowth on the inside of the frontal bone. This alteration can occur in isolation or together with neuropsychiatric symptoms, metabolic and endocrine manifestations which together form the Morgagni-Stewart-Morel syndrome. In this regard, the case of a patient who meets criteria for this syndrome is presented and a review of the literature is performed with focus on its pathophysiology.A 74 years old female with a history of exposure to wood smoke, vitiligo, type 2 diabetes mellitus, hypertension and cognitive impairment who enters the hospital by malaise, dizziness, anxiety, confusion, disorientation and difficulty walking. In she were performed imaging of the skull where was observed the presence of extensive hyperostosis frontalis interna, cortical atrophy and a left thalamic lacunar infarction. During this hospital stay the presence of grade I obesity, hyperglycemia, hypertriglyceridemia and hyperuricemia was documented.The patient met the criteria of Morgagni-Stewart-Morel syndrome to manifest the presence of hyperostosis frontalis interna with metabolic, endocrine and neuropsychiatric manifestations. The pathophysiological origin of the syndrome is unknown, although it has been postulated that an endocrine imbalance motivated by genetic and environmental factors may be the cause.	0
BACKGROUND:Henoch-Schönlein purpura (HSP) is the most common vasculitis of childhood. It has a characteristic rash described as palpable purpura that most frequently affects the distal lower extremities and buttocks. HSP rarely presents with bullous rash nor pulmonary nodules. CASE PRESENTATION:We present a novel case of a 12-years-old female with recurrent pediatric HSP with a combination of the rare manifestations of bullous rash and pulmonary nodules. She initially presented with the bullous rash, chest pain, cough, and abdominal pain. Patient was successfully treated with intravenous pulse corticosteroids followed by a high dose oral corticosteroid taper, with resolution of the bullous rash and pulmonary nodules. CONCLUSION:The rare manifestations of scarring bullous rash and pulmonary nodules can be presenting features of pediatric HSP, the combination of which has not been previously reported. The treatment of intravenous corticosteroid resolved patient's abdominal symptoms, rash and pulmonary nodules.	0
Wallerian degeneration (WD) is a process of autonomous distal degeneration of axons upon injury. Macrophages (MPs) of the peripheral nervous system (PNS) are the main cellular agent controlling this process. Some evidence suggests that resident PNS-MPs along with MPs of hematogenous origin may be involved, but whether these two subsets exert distinct functions is unknown. Combining MP-designed fluorescent reporter mice and coherent anti-Stokes Raman scattering (CARS) imaging of the sciatic nerve, we deciphered the spatiotemporal choreography of resident and recently recruited MPs after injury and unveiled distinct functions of these subsets, with recruited MPs being responsible for efficient myelin stripping and clearance and resident MPs being involved in axonal regrowth. This work provides clues to tackle selectively cellular processes involved in neurodegenerative diseases.	0
Primary extrarenal Wilms tumor of the gynecologic tract is extremely rare with scattered case reports occurring in the ovary, uterine corpus and cervix. Only 9 cases of primary ovarian Wilms tumor have been reported to date. Here, we provide an extensive literature review and describe 2 patients with ovarian Wilms tumor: a 36-yr-old female (patient 1) and a 16-yr-old female (patient 2), both presenting with abdominal pain and suspected ovarian torsion. They were each found to have unilateral ovarian masses measuring >15 cm in size which were removed by unilateral salpingo-oophorectomy. Microscopically, the tumors exhibited the typical triphasic histology of Wilms tumor. In addition, the tumor from patient 1 contained elements of mature cystic teratoma, while an extensive rhabdomyosarcomatous component was identified in patient 2. Both tumors were diffusely and strongly positive for WT1 with variable staining for other biomarkers. The cases were diagnostically challenging and referred to our center for an expert opinion. Teratoid Wilms tumor in patient 1 is the second reported case of ovarian Wilms tumor arising in association with teratoma. Recognition of primary ovarian Wilms tumor requires a high index of suspicion and exclusion of other entities based on tumor morphology and immunohistochemical studies.	0
BACKGROUND:Gorlin-Chaudhry-Moss syndrome (GCMS) and Fontaine-Farriaux syndrome (FFS) are extremely rare genetic disorders that share similar clinical manifestations. Because a de novo missense mutation of the solute carrier family 25 member 24 (SLC25A24) gene was suggested to be the common genetic basis of both syndromes, it has been proposed recently that they be integrated into a single disorder under the name of Fontaine progeroid syndrome (FPS). CASE PRESENTATION:A 9-year-old Korean girl presented with typical clinical features of FPS. She had generalized loose skin with decreased subcutaneous fat, skin wrinkling on the forehead and limbs, skull deformities and a peculiar facial appearance with microphthalmia and midface hypoplasia, anomalies of the digits and nails, a large umbilical hernia and a nearly normal developmental outcome. She exhibited prenatal and postnatal growth retardation together with short stature, and records showed that her height and weight were invariably under - 2.0 SD from birth to the age of 10 years. SLC25A24 analysis revealed a heterozygous mutation reported previously, NM_013386:c.650G > A, p.[Arg217His]. After screening her family for the identified mutation, she was confirmed as being a de novo case of FPS caused by an SLC25A24 mutation. CONCLUSION:We describe a Korean girl with typical clinical findings of FPS and a de novo mutation in SLC25A24, as well as 10 years of clinical follow-up, including growth and developmental achievements.	0
SPONASTRIME dysplasia is a rare, recessive skeletal dysplasia characterized by short stature, facial dysmorphism, and aberrant radiographic findings of the spine and long bone metaphysis. No causative genetic alterations for SPONASTRIME dysplasia have yet been determined. Using whole-exome sequencing (WES), we identified bi-allelic TONSL mutations in 10 of 13 individuals with SPONASTRIME dysplasia. TONSL is a multi-domain scaffold protein that interacts with DNA replication and repair factors and which plays critical roles in resistance to replication stress and the maintenance of genome integrity. We show here that cellular defects in dermal fibroblasts from affected individuals are complemented by the expression of wild-type TONSL. In addition, in vitro cell-based assays and in silico analyses of TONSL structure support the pathogenicity of those TONSL variants. Intriguingly, a knock-in (KI) Tonsl mouse model leads to embryonic lethality, implying the physiological importance of TONSL. Overall, these findings indicate that genetic variants resulting in reduced function of TONSL cause SPONASTRIME dysplasia and highlight the importance of TONSL in embryonic development and postnatal growth.	0
Potocki-Shaffer syndrome (PSS, OMIM #601224) is a rare contiguous gene deletion syndrome caused by haploinsufficiency of genes located on the 11p11.2p12. Affected individuals have a number of characteristic features including multiple exostoses, biparietal foramina, abnormalities of genitourinary system, hypotonia, developmental delay, and intellectual disability. We report here on the first Korean case of an 8-yr-old boy with PSS diagnosed by high resolution microarray. Initial evaluation was done at age 6 months because of a history of developmental delay, hypotonia, and dysmorphic face. Coronal craniosynostosis and enlarged parietal foramina were found on skull radiographs. At age 6 yr, he had severe global developmental delay. Multiple exostoses of long bones were detected during a radiological check-up. Based on the clinical and radiological features, PSS was highly suspected. Subsequently, chromosomal microarray analysis identified an 8.6 Mb deletion at 11p11.2 [arr 11p12p11.2 (Chr11:39,204,770-47,791,278)×1]. The patient continued rehabilitation therapy for profound developmental delay. The progression of multiple exostosis has being monitored. This case confirms and extends data on the genetic basis of PSS. In clinical and radiologic aspect, a patient with multiple exostoses accompanying with syndromic features, including craniofacial abnormalities and mental retardation, the diagnosis of PSS should be considered.	0
BACKGROUND:Cerebellar liponeurocytoma is a rare tumor of the central nervous system occurring mainly in the posterior fossa, which shows neuronal and variable astrocytic differentiation with foci of lipomatous differentiation. Liponeurocytoma develops in adult patients and is defined in the World Health Organization classification of 2016 as a rare benign grade II tumor. CASE PRESENTATION:A 39-year-old Italian man presented to our department suffering from headache and nausea. Magnetic resonance imaging revealed a right-sided cerebellar lesion showing poor contrast enhancement without an obstructive hydrocephalus. Surgery was indicated and total tumor resection was achieved. He was discharged without any neurological deficits. Histopathological examinations revealed a cerebellar liponeurocytoma. A neurological follow-up examination revealed no neurological deficit directly after surgery and 1 year later. Radiotherapy was recommended at the neurooncological board despite the total removal of the tumor, but our patient refused adjuvant radiotherapy. Magnetic resonance imaging of his neurocranium with and without contrast enhancement 48 hours after surgery and 15 months after surgery showed no residual tumor. CONCLUSIONS:Liponeurocytomas are rare benign tumors occurring in the majority of cases in the cerebellum. The therapy of choice is surgery. Postoperative radiotherapy has to be discussed individually, but seems to be sufficient if complete tumor resection is not achieved or in cases of a tumor recurrence.	0
BACKGROUND:To evaluate oral, craniofacial and systemic characteristics of eight patients with Kabuki syndrome (KS), aged between 3 and 16 years old. MATERIAL AND METHODS:in this retrospective study, medical records of all patients were reviewed for information on family history, growth and development, medications in use, general systemic complications and oral and craniofacial characteristics. RESULTS:the medical alterations found included recurrent infections such as pneumonia and otitis media (n = 6), cardiovascular malformations (n = 4), kidney abnormalities (n = 2), epilepsy (n = 2) and visual deficiency (n = 2). The individuals exhibited dental caries (n = 5), agenesis (n = 5), delayed tooth eruption (n = 4), cleft lip/palate (n = 2) enamel hypoplasia (n = 2), fusion (n = 1) and microdontia (n = 1). CONCLUSIONS:There was a great diversity of oral, craniofacial and systemic characteristic among the KS patients, suggesting that an inter-disciplinary approach should be taken for their dental treatment.	0
Antiepileptic drug side effects are frequent, 42% of them corresponding to cosmetic changes. The most frequent effects are weight gain, gingival hyperplasia, and hair loss. Hair changes in texture or colour are rarely reported in the literature. We present a case of hair curling after the introduction of perampanel. A 13-year-old girl with genetically confirmed Pitt-Hopkins syndrome with uncontrolled seizures, while on treatment with levetiracetam and valproic acid, was started on perampanel, reaching seizure control. After a few weeks of the introduction of the new antiepileptic drug, she developed hair curling. Hair curling is a rare cosmetic side effect, reported mainly in patients under valproic acid treatment. Perampanel is a recently introduced pharmaceutical molecule with no prior reports of hair changes as a side effect. There is no clear explanation for this side effect, but it should be discussed with patients taking valproate whenever perampanel is added to the treatment.	0
BACKGROUND/PURPOSE:Hepatoblastoma diagnoses require liver biopsies. We aimed to investigate factors affecting the success of liver biopsy for hepatoblastoma diagnoses. METHODS:Data from patients with hepatoblastoma, including their demographic and clinical data, biopsy procedure information, pathologic diagnoses and subclassification, and surgical complications, were retrospectively reviewed. RESULTS:Of 153 patients who underwent liver biopsy, 28, 93, and 31 underwent computed tomography-guided, digital subtraction angiography-guided, and ultrasound-guided percutaneous biopsies, respectively, and one underwent a laparoscopic liver biopsy. One patient developed postoperative bleeding requiring a blood transfusion. The median number of specimens collected was 3. One-hundred and forty-four (94.1%) patients' HB diagnoses were confirmed through biopsies, and 96 (62.7%) patients' HB diagnoses were subclassified. Seven surgeons and eight interventional radiologists performed the biopsies. The diagnostic success rate did not correlate with the biopsy technique or the specialist who performed the biopsy. Significantly more specimens were biopsied from the patients whose diagnoses were subclassified (3.34 ± 1.08) than from those whose diagnoses were not subclassified (2.81 ± 0.79). Surgeons tended to collect more specimens than the interventional radiologists. CONCLUSION:Percutaneous liver biopsy is safe and effective for diagnosing hepatoblastoma, and its complication rate is very low. Collecting >3 pieces of tissue is preferred. LEVEL OF EVIDENCE:III.	0
BACKGROUND:Hereditary spastic paraplegia is a large group of degenerative, neurological disorders characterized by progressive lower limb spasticity and weakness. The disease was investigated precisely but still clinicians often make incorrect or late diagnosis. Our aim was to investigate the genetic background and clinical phenotype of spastic paraplegia in large Polish family. CASE PRESENTATION:A 37 years old woman presented with 4-year history of walking difficulties. On neurological examination, she had signs of upper motor lesion in lower extremities. She denied sphincter dysfunction and her cognition was normal. Her family history was positive for individuals with gait problems. The initial diagnosis was familial spastic paraplegia. Genetic testing identified a novel mutation in SPAST gene. All available family members were examined and had genetic testing. The same mutation in SPAST gene was identified in other affected family members. All patients caring the mutation presented with different phenotypes. CONCLUSION:This study presents a family with spastic paraplegia due to a novel mutation c.1390G›T(p.Glu464Term) in SPAST gene. Affected individuals showed a range of phenotypes that varied in their severity. This case report demonstrates, the signs of hereditary spastic paraplegia can be often misdiagnosed with other diseases. Therefore genetic testing should always be considered in patients with lower limb spasticity and positive family history in order to help to establish the correct diagnosis.	0
BACKGROUND/PURPOSE:Idiopathic pulmonary hemosiderosis (IPH) is a rare but fatal disease characterized by a triad of anemia, hemoptysis, and increased pulmonary infiltration. This study is aimed to review the clinical manifestations, diagnostic tools, medication and outcome of childhood IPH in Taiwan. METHODS:We retrospectively enrolled the patients less than 18 years old in National Taiwan University Hospital in the past 30 years. The clinical data were collected and analyzed. RESULTS:All of the twelve children diagnosed with IPH had anemia and increased pulmonary infiltration, eight had hemoptysis, and ten were confirmed with detection of hemosiderin-laden macrophages. The mean age at diagnosis were 4.9 (interquartile range 2.5-6.3) years old. Patients with high dose corticosteroid (CS, ≥ 1 mg/kg/day prednisolone equivalent) treatment had lower odds ratio for ICU admission and significant higher Hb recovery rate than those with mild disease activity not receiving high dose CS treatment (p = 0.011). The only factor that is significantly associated with persistent anemia is the usage of high dose CS (p < 0.001) after adjusting for hemoptysis, fulfilling triad, serum ferritin level, and ICU admission by multiple regression. The only factor that is significantly associated with ICU admission is the presence of microorganism yielded in sputum (p < 0.001) after adjusting for fever, serum ferritin level, usage of invasive MV, and high dose CS treatment days. CONCLUSION:The aggressive high dose CS therapy might prevent ICU admission and improve anemia. Aggressive high dose CS treatment is suggested in IPH patients regardless of the disease activity.	0
BACKGROUND:The pandemic of Novel Coronavirus Disease 2019 (COVID-19) is challenging, given the large number of hospitalized patients. Cardiovascular co-morbidities are linked to a higher mortality risk. Thus, patients with Congenital Heart Disease (CHD) might represent a high-risk population. Nevertheless, no data about them are available, yet. Hence, we conducted a nationwide survey to assess clinical characteristics and outcomes in patients with congenital heart disease affected by COVID-19. METHODS AND RESULTS:This is a multi-centre, observational, nationwide survey, involving high-volume Italian CHD centres. COVID-19 diagnosis was defined as either "clinically suspected" or "confirmed", where a severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) test had been performed and was positive. Cardiovascular comorbidities were observed among adult patients-atrial fibrillation (seven; 9%), hypertension (five; 7%), obesity (seven; 9%) and diabetes (one; 1%)-but were absent among children. Cardiovascular complications were mainly observed in the "confirmed" COVID-19+ group, consisting of heart failure (9%), palpitations/arrhythmias (3%), stroke/TIA (3%) and pulmonary hypertension (3%). Cardiovascular symptoms such as chest pain (1%), myocardial injury (1%) and pericardial effusion (1%) were also recorded. On the contrary, CHD patients from the clinically suspected COVID-19 group presented no severe symptoms or complications. CONCLUSIONS:Despite previous reports pointing to a higher case-fatality rate among patients with cardiovascular co-morbidities, we observed a mild COVID-19 clinical course in our cohort of CHD patients. Although these results should be confirmed in larger cohorts to investigate the underlying mechanisms, the findings of low cardiovascular complications rates and no deaths are reassuring for CHD patients.	0
Vascular oxidative stress and inflammation play a major role in vascular diseases. This study was aimed at determining the protective roles of fibronectin type III domain-containing 5 (FNDC5) in angiotensin II- (Ang II-) induced vascular oxidative stress and inflammation and underlying mechanisms. Wild-type (WT) and FNDC5-/- mice, primary mouse vascular smooth muscle cells (VSMCs), and the rat aortic smooth muscle cell line (A7R5) were used in the present study. Subcutaneous infusion of Ang II caused more serious hypertension, vascular remodeling, oxidative stress, NLRP3 inflammasome activation, AMPK phosphorylation inhibition, and SIRT1 downregulation in the aorta of FNDC5-/- mice than those of WT mice. Exogenous FNDC5 attenuated Ang II-induced superoxide generation, NADPH oxidase 2 (NOX2) and NLRP3 upregulation, mature caspase-1, and interleukin-1β (IL-1β) production in A7R5 cells. The protective roles of FNDC5 were prevented by SIRT-1 inhibitor EX527, AMPK inhibitor compound C, or integrin receptor inhibitor GLPG0187. FNDC5 attenuated the Ang II-induced inhibition in SIRT1 activity, SIRT1 protein expression, and AMPKα phosphorylation in A7R5 cells, which were prevented by compound C, EX527, and GLPG0187. FNDC5 deficiency deteriorated Ang II-induced oxidative stress, NLRP3 inflammasome activation, AMPK phosphorylation inhibition, and SIRT1 downregulation in primary aortic VSMCs of mice, which were prevented by exogenous FNDC5. These results indicate that FNDC5 deficiency aggravates while exogenous FNDC5 alleviates the Ang II-induced vascular oxidative stress and NLRP3 inflammasome activation via the AMPK-SIRT1 signal pathway in VSMCs.	0
Myotonic dystrophy (MD) or Steinert's disease is the most frequent hereditary myopathy in the adult. The aim of this study was to determine the rate of prevalence of MD on the island of Mallorca. Patients diagnosed with MD were studied in all public and private surgeries and centres able to diagnose this disease on the island of Mallorca. Therefore, this study included the whole population of Mallorca (551,129 inhabitants). A total of 60 cases were studied representing a prevalence rate of 110 cases per one million inhabitants. The patients were further classified according to the existence of family history and were geographically located into the different towns. The prevalence rate found was much higher than that described in the literature which oscillates between 30 and 50 cases per million inhabitants. Furthermore, there was a concentration of cases in 10 of the 52 towns of the island with the presence of 2 cases in 6 being significant. The rate of prevalence of the disease in the city of Palma (295,136 inhabitants) representing more than half of the population of the island was very similar (120 per million) to that found for the population as a whole.	1
Hearing impairment is a neurological symptom of hypophosphatasia (HPP), which leads to a reduced quality of life. However, the pathomechanism of hearing impairment and the effects of asfotase alfa enzyme replacement therapy on hearing function in HPP have not been clarified. Here we report a case and present clinical data of a patient with perinatal HPP whose hearing impairment improved after asfotase alfa treatment.	0
To investigate the prevalence and genetic characteristics of myotonic dystrophy type 1 (DM1) in Taiwan, DM-suspected patients and their families identified during the period of 1990-2001 had their clinical records reevaluated and the CTG repeat sizes at the DM1 locus examined. A total of 96 subjects belonging to 26 families were identified as DM1 patients, which gave a minimal disease prevalence of 0.46/100,000 inhabitants. Clinical anticipation was frequently observed in affected families, even in some parent-child pairs with transmission contraction of the CTG repeat size. The inverse correlation between age at onset and CTG repeat length was significant only in patients with small expansions. In addition, a DM1 carrier with a childhood-onset son was found to have CTG length heterogeneity in the range of 40-50, indicating that premutation alleles could be unstable during gametogenesis as well as in somatic tissues. Our data demonstrated that DM1 is a rare disease in Taiwan and showed that transmission contraction of repeat size is more likely to occur in alleles with large repeats.	1
Care of individuals with syndromes affecting craniofacial and dental structures are mostly treated by an interdisciplinary team from early childhood on. In addition to medical and dental specialists that have a vivid interest in these syndromes and for whom these syndromes are of evident interest, experts of scientific background-like molecular and developmental geneticists, but also computational biologists and bioinformaticians-, become more frequently involved in the refined diagnostic and etiological processes of these patients. Early diagnosis is often crucial for the effective treatment of functional and developmental aspects. However, not all syndromes can be clinically identified early, especially in cases of absence of known family history. Moreover, the treatment of these patients is often complicated because of insufficient medical knowledge, and because of the dental and craniofacial developmental variations. The role of the team is crucial for the prevention, proper function, and craniofacial development which is often combined with orthognathic surgery. Although the existing literature does not provide considerable insight into this topic, this descriptive review aims to provide tools for the interdisciplinary team by giving an update on the genetics and general features, and the oral and craniofacial manifestations for early diagnosis. Clinical phenotyping together with genetic data and pathway information will ultimately pave the way for preventive strategies and therapeutic options in the future. This will improve the prognosis for better functional and aesthetic outcome for these patients and lead to a better quality of life, not only for the patients themselves but also for their families. The aim of this review is to promote interdisciplinary interaction and mutual understanding among all specialists involved in the diagnosis and therapeutic guidance of patients with these syndromal conditions in order to provide optimal personalized care in an integrated approach.	0
Cysteine residues are reactive amino acids that can undergo several modifications driven by redox reagents. Mitochondria are the source of an abundant production of radical species, and it is surprising that such a large availability of highly reactive chemicals is compatible with viable and active organelles, needed for the cell functions. In this work, we review the results highlighting the modifications of cysteines in the most abundant proteins of the outer mitochondrial membrane (OMM), that is, the voltage-dependent anion selective channel (VDAC) isoforms. This interesting protein family carries several cysteines exposed to the oxidative intermembrane space (IMS). Through mass spectrometry (MS) analysis, cysteine posttranslational modifications (PTMs) were precisely determined, and it was discovered that such cysteines can be subject to several oxidization degrees, ranging from the disulfide bridge to the most oxidized, the sulfonic acid, one. The large spectra of VDAC cysteine oxidations, which is unique for OMM proteins, indicate that they have both a regulative function and a buffering capacity able to counteract excess of mitochondrial reactive oxygen species (ROS) load. The consequence of these peculiar cysteine PTMs is discussed.	0
OBJECTIVES:Assessment of bisphosphonates efficiency in the therapy of NSAIDs-refractory Chronic Recurrent Multifocal Osteomyelitis. METHODS:Retrospective analysis of records of patients treated for Chronic Recurrent Multifocal Osteomyelitis between 2012 and 2018. RESULTS:Between 2012 and 2018, 76 children and adolescents were diagnosed with Chronic Recurrent Multifocal Osteomyelitis in our department. All patients underwent an initial course of NSAIDs therapy that provided a remission in 46% of cases. Of 41 NSAIDs-resistant cases, 7 patients were male and 34 were female. Disease started meanly in the age of 10. Most frequently pain localised in foot, clavicle and hip. In presented group, pamidronate was administered intravenously in the dose of 1mg/kg/day for 3 days. Patients received 6 series (1-17 series) on average with mean interval of 10 weeks (4-14 weeks). Our observations demonstrated rapid decrease of symptoms intensity after first dose of pamidronate with relapse of pain after 3-4 weeks. The frequency of pamidronate dosage was dependent of patient's symptoms. No serious adverse effects were reported. We finished the therapy after complete remission of symptoms and complete bone remodelling in imaging. Of 41 patients, 32 achieved remission and 9 continue their therapy. In remission group patients received 7 series of pamidronate on average and their treatment lasted meanly 20 months. CONCLUSIONS:Pamidronate is a safe and efficient method of CRMO therapy, particularly in cases refractory to NSAIDs treatment. Treatment with pamidronate provides both symptomatic relief as well as normalisation of bone morphology.	0
The polyglutamine disease spinocerebellar ataxia type 17 (SCA17) is a neurodegenerative disease leading to severe neurological symptoms during development. Additionally, patients affected by SCA17 display psychosis earlier than their motor disorders.Here the putative psychotic phenotype and endophenotype of transgenic SCA17 rats was examined.The expression of schizophrenia-like symptoms was evaluated over a longitudinal period before and after the onset of neurological symptoms in SCA17. To this end, transgenic SCA17 rats' monoamine neurotransmission was investigated along with their locomotion at baseline and in response to amphetamine using in-vivo microdialysis in free moving conditions, their sensorimotor gating using pre-pulse inhibition of startle reaction, and their object memory using the novel object recognition test as an index of cognitive impairments.Presymptomatic SCA17 rats displayed dysregulated monoamine levels at baseline and in response to amphetamine compared with control wild-type (wt) rats. At that stage, neither amphetamine-induced hyperlocomotion nor sensorimotor gating differed from that in wt rats. Symptomatic SCA17 rats developed sensorimotor gating deficits and also showed an impaired object memory, while their monoaminergic responses remained supersensitive to amphetamine.The data of the present study demonstrate a neurochemical endophenotype in SCA17 rats resembling that of prodromal schizophrenia. These findings suggest that a sensitization of the monoamine systems arises early in adulthood in SCA17 rats and may predispose them to express schizophrenia-like symptoms later in life.	0
Episodic angioedema with eosinophilia (Gleich syndrome) is a rare disorder characterized by episodes of angioedema and eosinophilia that occur at monthly intervals and resolve spontaneously without therapy. Despite the striking periodicity of this disorder, its similarity to other cyclic hematopoietic disorders with multilineage involvement has not been assessed. To characterize the involvement of cell lineages in the etiology and pathogenesis of episodic angioedema with eosinophilia, four subjects were evaluated by blood counts and other analyses over the course of 1-2 months. Surface marker expression was assessed on T cells by flow cytometry and clonality by polymerase chain reaction. Intracellular cytokine evaluation, bone marrow and skin biopsies were performed during different parts of the cycle. Cycling of multiple cell lineages, including neutrophils, lymphocytes and eosinophils, was observed in the four subjects with the disorder with a periodicity of 25-35 days. An aberrant CD3(-)CD4(+) T-cell population was detected in all four subjects, and T-cell receptor rearrangement studies showed a clonal pattern in three subjects. A peak of type II cytokines was detected in the serum of subjects prior to the onset of symptoms and eosinophil cycling and corresponded to ex-vivo type II cytokines detected intracellularly in CD3(+)CD4(+)CD154(+) T cells. Although the etiology of episodic angioedema with eosinophilia is not yet known, multiple lineages, including lymphocytes, neutrophils and mast cells, are involved and may be related to disease pathogenesis. Whether these cells act directly or promote eosinophilia and eosinophil activation remains to be elucidated. All subjects gave informed consent and were evaluated under an Institutional Review Board-approved protocol (NCT00001406).	0
This study was performed to describe the clinical features, risk factors, and treatment methods of uterine torsion in pregnancy. The most common symptoms are abdominal pain, fetal heart rate changes, and failure of cervical dilatation and are often accompanied by complete or partial placental abruption. Preoperative diagnosis is challenging even with the use of ultrasound. Uterine torsion in the third trimester is correlated with the presence of multiple uterine fibroids. The causes of gravid uterine torsion vary and the clinical manifestations are nonspecific. Early diagnosis and improved detection approaches are the keys to treatment of patients with uterine torsion. However, the preoperative diagnosis remains difficult and the diagnosis is often made during cesarean section.	0
The mitochondrial tRNALys (mt-tRNALys) mutation is initially associated with myoclonic epilepsy and ragged-red fibers (MERRF). The clinical, laboratory, morphologic and molecular findings from 22 mt-tRNALys mutation carriers from local database in East China were analyzed retrospectively. We identified 13 symptomatic and 9 asymptomatic individuals with a known pathogenic mitochondrial tRNALys mutation. The most common mutations were m.8344 A>G (81.8%), m.8363G>A (9.1%), m.8356 T>C (4.5%) and m.8356 T>G (4.5%). The degree of mutation heteroplasmy in blood was high both in symptomatic (mean 64.5%, range 41-82%) and asymptomatic individuals (mean 53.1%, range 21-78%). Age at onset ranged from 6 year-old to the age of 66 years (mean 35.8 ± 16.4 years old). The most frequent symptoms were muscle weakness (76.9%), exercise intolerance (76.9%), elevated creatine kinase levels (61.5%), peripheral neuropathy (69.2%) and cerebellar ataxia (61.5%), while myoclonus was only present in 23.1% of symptomatic patients. A diagnosis of mitochondrial myopathy (MM) and neuropathy ataxia and retinitis pigmentosa (NARP/NARP-like) syndrome was made in 77% of symptomatic patients, whereas the classic syndrome of myoclonic epilepsy with ragged-red fibers (MERRF) was rare (23%). In this cohort of patients with mt-tRNALys mutation, more than one third of our patients did not develop signs and symptoms of central nervous system involvement even in later stages of the disease, indicating the necessity to investigate the mt-tRNALys gene in 'pure' mitochondrial 'myo-neuropathy'.	0
Context: Cisplatin-based chemotherapy was widely used in treating human malignancies. However, side effects and chemoresistance remains the major obstacle.Objective: To verify whether natural borneol (NB) can enhance cisplatin-induced glioma cell apoptosis and explore the mechanism.Materials and methods: Cytotoxicity of cisplatin and/or NB towards U251 and U87 cells were determined with the MTT assay. Cells were treated with 0.25-80 μg/mL cisplatin and/or 5-80 μM NB for 48 h. The effects of NB and/or cisplatin on apoptosis and cell cycle distribution were quantified by flow cytometric analysis. Protein expression was detected by western blotting. ROS generation was conducted by measuring and visualising an oxidation-sensitive fluorescein DCFH-DA.Results: NB synergistically enhanced the anticancer efficacy of cisplatin in human glioma cells. Co-treatment of 40 μg/mL NB and 40 μg/mL cisplatin significantly inhibited U251 cell viability from 100% to 28.2% and increased the sub-G1 population from 1.4% to 59.3%. Further detection revealed that NB enhanced cisplatin-induced apoptosis by activating caspases and triggering reactive oxygen species (ROS) overproduction as evidenced by the enhancement of green fluorescence intensity from 265% to 645%. ROS-mediated DNA damage was observed as reflected by the activation of ATM/ATR, p53 and histone. Moreover, MAPKs and PI3K/AKT pathways also contributed to co-treatment-induced U251 cell growth inhibition. ROS inhibition by antioxidants effectively improved MAPKs and PI3K/AKT functions and cell viability, indicating that NB enhanced cisplatin-induced cell growth in a ROS-dependent manner.Discussion and conclusions: Natural borneol had the potential to sensitise human glioma cells to cisplatin-induced apoptosis with potential application in the clinic.	0
Orofaciodigital syndrome 1 (OFD-1) is a rare, X-linked, dominantly inherited disorder caused by an OFD1 mutation that can cause polycystic kidneys. A 37-year-old woman on hemodialysis therapy was admitted to our hospital for trans-catheter arterial embolization therapy for enlarged polycystic kidneys. Lobulated tongue and brachydactyly were noticed, prompting an OFD1 sequencing analysis. Sequencing revealed a causal four-base-pair deletion in exon 13, both in the patient and in her mother, whose renal function had been retained. The peripheral leukocyte X chromosome inactivation pattern was skewed in the patient but not in her mother, suggesting some role in their phenotypic difference.	0
BACKGROUND:Bi-allelic loss of function variations in genes encoding proteins of the renin-angiotensin system (AGT, ACE, REN, AGTR1) are associated with autosomal recessive renal tubular dysgenesis, a severe disease characterized by the absence of differentiated proximal tubules leading to fetal anuria and neonatal end-stage renal disease. CASE-DIAGNOSIS/TREATMENT:We identified bi-allelic loss of function mutations in ACE, the gene encoding angiotensin-converting enzyme, in 3 unrelated cases displaying progressive chronic renal failure, whose DNAs had been sent for suspicion of juvenile hyperuricemic nephropathy, nephronophthisis, and cystic renal disease, respectively. In all cases, patients were affected with anemia whose severity was unexpected regarding the level of renal failure and with important polyuro-polydipsia. CONCLUSIONS:Bi-allelic loss of function mutation of ACE can have atypical and sometimes late presentation with chronic renal failure, anemia (out of proportion with the level of renal failure), and polyuro-polydipsia. These data illustrate the usefulness of next generation sequencing and "agnostic" approaches to elucidate cases with chronic kidney disease of unknown etiology and to broaden the spectrum of phenotypes of monogenic renal diseases. It also raises the question of genetic modifiers involved in the variation of the phenotypes associated with these mutations.	0
AIMS:Microcystic adnexal carcinoma is a distinctive sweat duct carcinoma of low-grade malignant potential with a risk for locally destructive growth and local recurrence. Distant metastases and disease-related mortality are exceptional. The histological hallmarks of these tumours are the diffusely infiltrative growth within the dermis, the frequent invasion of subcutaneous structures, the presence of perineurial invasion, and the bland cytological features. The tumours are organised in cords and strands, and show keratocyst formation and duct differentiation in varying proportions. Marked cytological atypia, nuclear pleomorphism, brisk and atypical mitotic activity and necrosis are not typically seen in these tumours. METHODS AND RESULTS:We report two patients presenting with large, slowly growing tumours on the face showing areas of morphologically high-grade carcinoma arising on a background of unequivocal microcystic adnexal carcinoma. Both patients are alive with follow-up of up to 6 years, with no evidence of disease. CONCLUSIONS:Morphologically high-grade transformation in microcytic adnexal carcinoma is a rare phenomenon that does not appear to confer a risk for aggressive behaviour. Recognition depends on sampling of the areas of conventional microcystic adnexal carcinoma.	0
Since 2013, the International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) has published an updated phenotypic classification of IEI, which accompanies and complements their genotypic classification into ten tables. This phenotypic classification is user-friendly and serves as a resource for clinicians at the bedside. There are now 430 single-gene IEI underlying phenotypes as diverse as infection, malignancy, allergy, autoimmunity, and autoinflammation. We herein report the 2019 phenotypic classification, including the 65 new conditions. The diagnostic algorithms are based on clinical and laboratory phenotypes for each of the ten broad categories of IEI.	0
Two siblings presented with clinical and histopathological findings of familial cutaneous collagenoma which is a rare connective tissue nevus, inherited in an autosomal-dominant pattern. A 13-year-old girl had oval-round, soft, painless papules, 5-10 mm in size and a total of 9-10 on her abdomen and flanks. Skin biopsy demonstrated dense, coarse collagen fibers in the dermis and a decrease in elastic fibers. Doppler echocardiography indicated an atrioseptal defect of the secundum type. Her 9-year-old brother was also examined; four lesions were discovered on his back but he was otherwise normal. Our cases comprise the sixth affected family to be reported in the medical published work and all lesions had appeared prepubertally.	0
Fox-Fordyce disease (FFD) is a rare pruritic dermatosis whose etiology has not been fully explored. It is mostly seen in women and presents as pruritic follicular papules at the apocrine (gland-bearing) regions, including the axilla, groins, perineum, and areola mammae, as well as the umbilicus. Treatment for FFD is extremely challenging in that there is no curative treatment for it. We report the case of a 26-year-old woman who was refractory to many treatments but who responded to calcipotriol betamethasone with rapid remission of her symptoms.	0
Deficiency of dolichyl-P-Glc:Man9GlcNAc2-PP-dolichyl glucosyltransferase is the cause of an additional type of carbohydrate-deficient glycoprotein syndrome (CDGS type V). Clinically this type resembles the classical type Ia of CDGS caused by the deficiency of phosphomannomutase. As a result of the glucosyltransferase deficiency in CDGS type V nonglucosylated lipid-linked oligosaccharides accumulate. The defect is leaky and glucosylated oligosaccharides are found on nascent glycoproteins. The limited availability of glucosylated lipid-linked oligosaccharides explains the incomplete usage of N-glycosylation sites in glycoproteins. This finding is reflected in the presence of transferrin forms in serum that lack one or both of the two N-linked oligosaccharides and the reduction of mannose incorporation to about one-third of control in glycoproteins of fibroblasts.	0
OBJECTIVE:To report on clinical characteristics and genetic findings in 15 Chinese patients with methylmalonic acidemia (MMA). METHODS:For the 15 MMA patients detected by tandem mass spectrometry, genetic analysis was carried out in twelve pedigrees. Clinical characteristics, genetic finding, treatment and outcomes were retrospectively analyzed. RESULTS:The main features of the patients included poor feeding, recurrent vomiting, lethargy, seizure and development retardation. Blood propionylcarnitine (except for 3 patients), its ratio with acetylcarnitine, and urine methylmalonic acid were increased in all patients. Twelve patients were diagnosed genetically, which included 7 with MUT variants, 4 with MMACHC variants, and 1 with MMAB variant. Nine MUT variants were detected, among which c.1159A>C, 753+1delGinsTGGTTATTA and c.504del were novel. Six known pathogenic MMACHC variants and two novel MMAB variants (c.289_290delGG, c.566G>A) were also detected. Seven patients died of metabolic crises within a year, others had improved effectively following the treatment, but had mild to severe growth delay and/or developmental retardation. CONCLUSION:The clinical manifestation of MMA are complex. Most patients have variants of the MUT and MMACHC genes. High mortality may occur before one year of age.	0
Xia-Gibbs syndrome (XGS) is a rare neurological disorder characterized by global developmental delay, hypotonia, intellectual disability, seizures, and sleep apnea. XGS is defined by monoallelic pathogenic variants in AHDC1. In this study, we identified a Brazilian patient carrying a likely de novo AHDC1 nonsense mutation (c.451C>T; p.Arg151*) which was absent in both parents. All disease-causative variants already associated with XGS have been reviewed and the mutation described here corresponds to the closest one to the N-terminal region. Our findings were discussed based on the suggested genotype-phenotype correlation of the disease.	0
Background: Exaggerated pulmonary arterial hypertension (PAH) is a hallmark of high-altitude pulmonary edema (HAPE). The objective of this study was therefore to investigate genetic predisposition to HAPE by analyzing PAH candidate genes in a HAPE-susceptible (HAPE-S) family and in unrelated HAPE-S mountaineers. Materials and Methods: Eight family members and 64 mountaineers were clinically and genetically assessed using a PAH-specific gene panel for 42 genes by next-generation sequencing. Results: Two otherwise healthy family members, who developed re-entry HAPE at 3640 m during childhood, carried a likely pathogenic missense mutation (c.1198T>G p.Cys400Gly) in the Janus Kinase 2 (JAK2) gene. One of them progressed to a mild form of PAH at the age of 23 years. In two of the 64 HAPE-S mountaineers likely pathogenic variants have been detected, one missense mutation in the Cytochrome P1B1 gene, and a deletion in the Histidine-Rich Glycoprotein (HRG) gene. Conclusions: This is the first study identifying an inherited missense mutation of a gene related to PAH in a family with re-entry HAPE showing a progression to borderline PAH in the index patient. Likely pathogenic variants in 3.1% of HAPE-S mountaineers suggest a genetic predisposition in some individuals that might be linked to PAH signaling pathways.	0
This case report describes a patient with ankyloglossia, oligodontia, unilateral hypoplasia of the zygoma and mandible, along with bilateral distal reduction anomalies of his limbs without long bone abnormalities. This may represent a mild variant of oromandibular limb hypogenesis syndrome, expanding the phenotypic spectrum, or a previously unrecognized malformation syndrome.	0
Eccrine porocarcinoma is a rare malignant skin appendage tumor of sweat gland origin. Eccrine porocarcinoma arising in a patient of oculocutaneous albinism is extremely rare and only two cases have been reported in English literature to the best of our knowledge. Out of the two cases of eccrine porocarcinoma in oculocutaneous albinism, one case had squamous differentiation. We report a case of eccrine porocarcinoma with squamous differentiation in a 39-year-old male, who presented with a nodular lesion on the upper left chest wall. He also had nodal and distant cutaneous metastasis.	0
OBJECTIVE: Studies of Wegener's granulomatosis (WG) since the late 1980s indicate a probable increase in incidence of unknown cause and significance, possibly related to antineutrophil cytoplasmic antibody (ANCA) testing. To extend these observations and to include calendar periods before ANCA was introduced, we assessed time trends in the incidence of WG in Sweden in the period 1975-2001. METHODS: In the population-based Swedish Inpatient Register, we identified 1938 individuals diagnosed with WG in the period 1975-2001, and calculated the annual age and sex adjusted incidences. RESULTS: The incidence increased from 0.33 (95% CI 0.28-0.39) in the period 1975-85 to 0.77 (95% CI 0.69-0.85) in 1986-90, to 1.19 (95% CI 1.12-1.26) in 1991-2001, resulting in a mean incidence of 0.78 (95% CI 0.74-0.82). CONCLUSION: WG displays a strong temporal trend. While the increase coincides to some extent with the implementation of ANCA testing, suggestive of increased disease recognition, ANCA testing remains an incomplete explanation as increasing incidences were noted before as well as after their introduction.	1
  67-year-old female patient developed drug-induced liver dysfunction after taking oral itraconazole (ITCZ) for the treatment of kerion celsi. Red papules appeared on the temporal area of the patient one month prior to her visit to our clinic. The patient presented with a nodule with yellow crust, erosion, infiltration, and hair loss on the area. Diagnosis of kerion celsi caused by Trichophyton rubrum was made from clinical, pathological, and mycological findings. Laboratory data showed normal liver function, and the patient was not taking any other medication, thus, daily oral ITCZ 100 mg was started. The skin lesion improved, but severe liver dysfunction was found 1 month after starting ITCZ. Oral ITCZ was therefore terminated, and the patient was admitted to a medical ward for the treatment of liver dysfunction. Hepatobiliary enzymes increased after admission: AST 232 IU/L, ALT 465 IU/L, T-bil 6.1 mg/dL, and D-bil 3.9 mg/dL. The patient was kept at rest and was given oral ursodeoxycholic acid. Hepatobiliary enzymes returned to normal level 2 1/2 months after starting ITCZ. The skin lesion healed without further treatment. No recurrence was observed. It is noteworthy that liver function has to be carefully monitored during treatment with oral ITCZ.	0
Aim:To report a case of radiation-induced brachial plexopathy (RIBP) with significant radiographic and clinical improvement after a course of hyperbaric oxygen (HBO). Background:RIBP is a rare complication after radiotherapy to the neck and axilla. There are no standard treatment options, with empirical use pharmacotherapy being predominately used, which has had mixed results.HBO is efficacious for the treatment of other severe radiation-induced side effects, however, its benefit in RIBP has conflicting reports. Case Presentation:A 45-year-old male, with a 33 pack-year smoking history, presented with a 6-month history of a progressive left neck mass. The final diagnosis was unknown primary squamous cell carcinoma of the head and neck. He received intensity-modulated radiation therapy (IMRT) with 70 Gy prescribed to the gross tumor volume (PTV HR) and 56 Gy to the oropharynx, nasopharynx, and bilateral lymphatics (PTV SR) in 35 daily fractions with three cycles of concurrent cisplatin at 100 mg/m2.Fifteen months following therapy completion, the patient began to endorse symptoms of left brachial plexopathy. Decadron was prescribed for 2 weeks, trental and vitamin E for 6 months, and HBO. The patient returned for follow-up 2 months after completing 30 dives of HBO at 2.4 atmospheres for 2 hours per session. He reported pain resolution and full range of motion of his left arm. Conclusions:The best management strategy of RIBP is prevention by reducing total RT doses and close follow-up. However, when RIBP occurs, we recommend treatment with HBO therapy, steroids, trental, and vitamin E as tolerable.	0
PURPOSE OF REVIEW:Light chain (AL) amyloidosis is an insidious progressive disease which results in significant morbidity and inevitable mortality if not diagnosed and treated promptly. This review will highlight recent developments and summarize critical clinical points and updated practice changes for the clinician in 2020. RECENT FINDINGS:Comparative analyses of staging systems, updated prognostic tools, and treatment response criteria now allow for improved patient stratification and treatment decisions; the role of minimal residual disease in response assessment is still being assessed. Clinical and genetic predictors for long-term survivors have been highlighted. Standard-of-care front-line bortezomib and the integration of anti-CD38 monoclonal antibodies in the relapsed disease have transformed treatment approach in recent years. Various clinical trials in the pipeline include novel anti-plasma cell therapies and therapies directed against amyloid deposits which promise to further advance the treatment landscape. Diagnosis, response assessment, and treatment paradigms for AL amyloidosis have evolved significantly in the past 15 years, translating into superior outcomes and increased chances of long-term survival for AL amyloidosis.	0
Tietze syndrome is an uncommon disease of unknown etiology that manifests as pain and tenderness of the parasternal joints. To date, however, there has been no report on ultrasonographic findings concerning swelling of the costochondral joint in Tietze syndrome. Moreover, there has been no research investigating images of ultrasound-guided corticosteroid injection, although corticosteroid injection is one of the most important treatments for Tietze syndrome. Therefore, we report a case of Tietze syndrome where ultrasound images were used in the diagnostic and therapeutic process. A 70-yr-old man was seen for left chest pain that had lasted for several weeks. Physical examination at our clinic revealed a focal tenderness of the left third costochondral joint, and an ultrasound showed a swelling of the left third costochondral joint. Considering both the radiological and the clinical examination, the patient received a diagnosis of Tietze syndrome with costochondral joint swelling. Then, the patient agreed to an ultrasound-guided left third costochondral corticosteroid injection after receiving a detailed explanation of the disease and treatment. After receiving three ultrasound-guided corticosteroid injections, his chest pain subsided, and the swelling and tenderness also disappeared completely. Collectively, our case suggests that ultrasound is important in the diagnosis and treatment of Tietze syndrome.	0
We report four sibs with Kenny-Caffey syndrome in a consanguineous Bedouin family. The first two died in the neonatal period while the remaining affected brother and sister had all the characteristic clinical, biochemical, and radiological abnormalities of the syndrome. These included severe pre- and postnatal growth retardation, cortical thickening of the tubular bones with medullary stenosis, eye abnormalities, facial dysmorphism, hypocalcaemia, and low levels of parathyroid hormone. The children also showed intracranial calcification, impaired neutrophil phagocytosis, increased proportion of B lymphocytes, reduced CD4 and CD8 subpopulations of T lymphocytes, and inhibited transformation in response to Candida antigen. Fluorescence in situ hybridisation (FISH) was applied to blood lymphocyte metaphase spreads from these two Bedouin sibs and their parents using probe D22S75 (Oncor), specific for the DiGeorge critical region on chromosome 22q11.2. The presence of 22q11.2 haploinsufficiency was identified in the affected sibs, which was transmitted from the phenotypically normal mother. The present report widens the spectrum of CATCH 22 microdeletion to accommodate Kenny-Caffey syndrome.	0
Peutz-Jeghers syndrome (PJS) is a hereditary polyposis syndrome characterized by hamartomatous Peutz-Jeghers polyps in the gastrointestinal tract, mucocutaneous pigmentations, and increased risk for intestinal and extraintestinal cancer. In more than two-third of patients it is possible to detect pathogenic variants in the serine/threonine kinase 11 (STK11) gene, but so far is knowledge about genetic causes in the remaining part of patients limited. Reports of STK11 mosaicism are rare but may be an explanation in some patients without initial findings of pathogenic variants in STK11. We report two Danish patients with STK11 mosaicism detected in blood when using Next-Generation Sequencing. This is only the sixth and seventh patient reported in the literature, and we compare phenotypes of the reported cases. The results indicate that STK11 mosaicism is more frequent than anticipated and highlight that mosaicism should be considered in patients with clinical suspicion of PJS or patients fulfilling the diagnostic criteria.	0
BACKGROUND:Athletes and coaches believe in the ergogenic effect of vitamin B12 (which results from enhanced erythropoiesis) and they often insist on its unjustified supplementation. Therefore, our study aimed to assess the vitamin B12 status in Polish elite athletes and its influence on red blood cell parameters. METHODS:In total, 1131 blood samples were collected during six years from 243 track and field athletes divided into strength and endurance groups, as well as according to the declared use of vitamin B12 injections. RESULTS:An average vitamin B12 concentration in all subjects was 739 ± 13 pg/mL, with no cases of deficiency. A weak but significant relationship was found between vitamin B12 and hemoglobin concentrations. A significant increase in hemoglobin appeared from very low vitamin B12 concentration and up to approx. 400 pg/mL, while hemoglobin did not significantly change from 700 pg/mL and onwards. Vitamin B12 injections were used by 34% of athletes, significantly more often by endurance than by strength athletes. In athletes who declared no use of injections, a higher concentration of vitamin B12 was observed in the endurance group. CONCLUSION:The main finding of the present study is the determination of the range of vitamin B12 concentration which may favor better hemoglobin synthesis in athletes. They should regularly monitor vitamin B12 concentration and maintain the range of 400-700 pg/mL as it may improve red blood cell parameters. We might suggest application of a supplementation if necessary. Special attention is required in athletes with a vitamin B12 concentration below 400 pg/mL.	0
Studies conducted in human and rodent models have suggested that preexisting neurodevelopmental defects could predispose immature brains to febrile seizures (FS). However, the impact of the anatomical extent of preexisting cortical malformations on FS susceptibility was never assessed. Here, we induced hyperthermic seizures (HS) in rats with bilateral subcortical band heterotopia (SBH) and found variable degrees of HS susceptibility depending on inter-individual anatomical differences in size and extent of SBH. This indicates that an association exists between the overall extent or location of a cortical malformation, and the predisposition to FS. This also suggests that various predisposing factors and underlying causes may contribute to the etiology of complex FS.	0
Since the first description of galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an inborn error of carbohydrate metabolism caused by deficient activity of any of the galactose metabolising enzymes. The current standard of care, a galactose-restricted diet, fails to prevent long-term complications. Studies in cellular and animal models in the past decades have led to an enormous progress and advancement of knowledge. Summarising current evidence in the pathophysiology underlying hereditary galactosemia may contribute to the identification of treatment targets for alternative therapies that may successfully prevent long-term complications. A systematic review of cellular and animal studies reporting on disease complications (clinical signs and/or biochemical findings) and/or treatment targets in hereditary galactosemia was performed. PubMed/MEDLINE, EMBASE, and Web of Science were searched, 46 original articles were included. Results revealed that Gal-1-P is not the sole pathophysiological agent responsible for the phenotype observed in galactosemia. Other currently described contributing factors include accumulation of galactose metabolites, uridine diphosphate (UDP)-hexose alterations and subsequent impaired glycosylation, endoplasmic reticulum (ER) stress, altered signalling pathways, and oxidative stress. galactokinase (GALK) inhibitors, UDP-glucose pyrophosphorylase (UGP) up-regulation, uridine supplementation, ER stress reducers, antioxidants and pharmacological chaperones have been studied, showing rescue of biochemical and/or clinical symptoms in galactosemia. Promising co-adjuvant therapies include antioxidant therapy and UGP up-regulation. This systematic review provides an overview of the scattered information resulting from animal and cellular studies performed in the past decades, summarising the complex pathophysiological mechanisms underlying hereditary galactosemia and providing insights on potential treatment targets.	0
While genetic causes are known for many syndromes involving developmental anomalies, a large number of individuals with overlapping phenotypes remain undiagnosed. Using exome-sequencing analysis and review of matchmaker databases, we have discovered four de novo missense variants predicted to affect the N-terminal region of WDR37-p.Ser119Phe, p.Thr125Ile, p.Ser129Cys, and p.Thr130Ile-in unrelated individuals with a previously unrecognized syndrome. Features of WDR37 syndrome include the following: ocular anomalies such as corneal opacity/Peters anomaly, coloboma, and microcornea; dysmorphic facial features; significant neurological impairment with structural brain defects and seizures; poor feeding; poor post-natal growth; variable skeletal, cardiac, and genitourinary defects; and death in infancy in one individual. WDR37 encodes a protein of unknown function with seven predicted WD40 domains and no previously reported human pathogenic variants. Immunocytochemistry and western blot studies showed that wild-type WDR37 is localized predominantly in the cytoplasm and mutant proteins demonstrate similar protein levels and localization. CRISPR-Cas9-mediated genome editing generated zebrafish mutants with novel missense and frameshift alleles: p.Ser129Phe, p.Ser129Cys (which replicates one of the human variants), p.Ser129Tyr, p.Lys127Cysfs, and p.Gln95Argfs. Zebrafish carrying heterozygous missense variants demonstrated poor growth and larval lethality, while heterozygotes with frameshift alleles survived to adulthood, suggesting a potential dominant-negative mechanism for the missense variants. RNA-seq analysis of zebrafish embryos carrying a missense variant detected significant upregulation of cholesterol biosynthesis pathways. This study identifies variants in WDR37 associated with human disease and provides insight into its essential role in vertebrate development and possible molecular functions.	0
BACKGROUND:Spinal muscular atrophy (SMA) is a genetic motor neuron disease related to deletions in the SMN1 gene. There is mounting evidence that the disease is not restricted to motor neurons. In this neuroimaging study, we aimed to investigate the presence of in-vivo cerebellar damage in adult SMA patients not treated with disease-modifying treatment. METHODS:Twenty-five molecularly confirmed patients with SMA type III or IV and 25 healthy controls underwent MRI with cerebellar focused structural analysis by the CERES automated pipeline. Volumetry (total and gray matter-GM) as well as cortical thickness of the cerebellar lobules were compared in both groups. Full clinical and demographic data were then assessed for correlations with cerebellar imaging findings. RESULTS:Volumes of cerebellar lobules VIIIB (right), IX and X were significantly smaller in patients with SMA. Lobule IX also had GM atrophy in comparison to controls. We found no significant correlation between clinical findings and cerebellar damage. CONCLUSIONS:Neuroimaging detects cerebellar structural changes in adult SMA patients, suggesting that neurodegeneration is not confined to the lower motor neurons in the disease.	0
Erosive pustular dermatosis of the scalp (EPDS) occurs in elderly individuals with significant actinic damage. EPDS also occurs in association with surgery; however, significant studies determining an association of EPDS with type of surgical closure is absent. This review examines whether the closure method following cutaneous surgery performed on the scalp is associated with development of EPDS. Databases were reviewed and studies describing EPDS after cutaneous surgery met inclusion criteria. Articles were excluded if EPDS developed after trauma or non-surgical procedures. Descriptive analyses were performed on the data. Thirteen case reports and 6 case series involving 32 patients met inclusion criteria. Fourteen articles (73.7%) stated that EPDS developed in the same location as, or near to, the closure site. Thirteen patients (40.6%) developed EPDS following skin grafting. Three patients (9.4%) developed EPDS following secondary intention healing, two patients (6.3%) following repair by primary intention, and one patient (3.1%) following repair with a local skin flap. Thirteen cases (40.6%) did not specify closure type. This review revealed that surgical procedures performed on the scalp utilizing skin grafts for closure may be increasingly associated with the development of EPDS compared to other closure types.	0
The objective of this review is to summarize the pharmacology, efficacy, and safety of cerliponase alfa for the treatment of late infantile neuronal ceroid lipofuscinosis type 2 (CLN2). Cerliponase alfa is recombinant human tripeptidyl peptidase 1 enzyme replacement therapy. A phase 1/2 trial established the efficacy and safety of cerliponase alfa for treatment of neuronal ceroid lipofuscinosis type 2. Treatment with intracerebroventricular cerliponase alfa resulted in slower decline of motor and language functions compared with natural history controls. Common adverse events include convulsions, electrocardiography abnormalities, pyrexia, vomiting, and upper respiratory tract infections. Intracerebroventricular device-related adverse events also occur. Cerliponase alfa is the first therapy for neuronal ceroid lipofuscinosis type 2 that targets the disease etiology. Cerliponase alfa is effective in delaying the progression of motor language decline for patients with neuronal ceroid lipofuscinosis type 2.	0
Erythroid colony growth in the presence and absence of erythropoietin was compared in 23 patients with primary proliferative polycythaemia (PPP), nine with idiopathic erythrocytosis, 10 with secondary polycythaemia, 15 with pseudopolycythaemia and in 76 normal subjects. Erythroid colonies growing without erythropoietin stimulation (endogenous erythroid colonies) from peripheral blood (BFU-E) were found in 20 of 22 patients with PPP and in two of seven with idiopathic erythrocytosis. None was found in secondary polycythaemia, pseudopolycythaemia, or in normal subjects. Small numbers of endogenous colony forming units-erythroid (CFU-E) (though not BFU-E) were cultured from the bone marrow of three of 24 normal subjects, suggesting that peripheral blood cultures provide a more specific indicator of clonal erythropoiesis. Peripheral blood endogenous erythroid colony growth is an effective and convenient means of distinguishing patients with clonal erythrocytosis and may be of particular value when iron deficiency obscures the diagnosis of PPP on conventional criteria.	0
OBJECTIVE:To report a rare case of maculopapular rash on the scalp in a patient with Mediterranean spotted fever (MSF). CLINICAL PRESENTATION AND INTERVENTION:A 58-year-old woman with breast cancer and chemotherapy-induced alopecia contracted MSF. Her clinical features were typical, except for a maculopapular rash covering the scalp. The diagnosis of MSF was confirmed by immunofluorescent assay. The disease had a favorable course and the patient was discharged in good condition. CONCLUSION:The rash on the scalp described in this report enriches our knowledge on the clinical characteristics of MSF.	0
BACKGROUND:Haemophagocytic lymphohistiocytosis is a life-threatening disease resulting from primary or secondary hyper-inflammatory disorders. The typical symptoms include persistent fever, splenomegaly, cytopenia and significant elevation of serum ferritin. CASE PRESENTATION:We report a 30-year-old Chinese female patient who was diagnosed with chronic active Epstein-Barr virus infection more than 9 months prior and has since been presenting with cutaneous lymphoproliferative disorders mimicking hydroa vacciniforme and subsequent haemophagocytic lymphohistiocytosis. Exome sequencing suggested novel digenic heterozygous STXBP2 (c.592A > C, p.Thr198Pro) and LYST (c.830A > T, p.His277Leu) mutations. CONCLUSIONS:This is the first case report in which adult HLH was associated with novel digenic mutations of STXBP2 and LYST combined with Epstein-Barr virus infection. It could also be the first polygenic model report, given that the pathogenicity of other mutated genes still remains unclear. We additionally conducted an in-depth, two-generation pedigree analysis to further illustrate the mode of inheritance in this case.	0
Hair loss in early childhood represents a broad differential diagnosis which can be a diagnostic and therapeutic challenge for a physician. It is important to consider the diagnosis of a genetic hair disorder. Genetic hair disorders are a large group of inherited disorders, many of which are rare. Genetic hair abnormalities in children can be an isolated phenomenon or part of genetic syndromes. Hair changes may be a significant finding or even the initial presentation of a syndrome giving a clue to the diagnosis, such as Netherton syndrome and trichothiodystrophy. Detailed history including family history and physical examination of hair and other ectodermal structures such as nails, sweat glands, and sebaceous glands with the use of dermoscopic devices and biopsy all provide important clues to establish the correct diagnosis. Understanding the pathophysiology of genetic hair defects will allow for better comprehension of their treatment and prognosis. For example, in patients with an isolated hair defect, the main problem is aesthetic. In contrast, when the hair defect is associated with a syndrome, the prognosis will depend mainly on the associated condition. Treatment of many genetic hair disorders is focused on treating the primary cause and minimizing trauma to the hair.	0
CASE:Congenital vertical talus (CVT) is a rare rigid flatfoot disorder with a rocker-bottom flatfoot appearance. It is characterized by hindfoot valgus and equinus, with associated midfoot dorsiflexion and forefoot abduction. We describe a patient who was born with dysmorphic features and subsequently was diagnosed with Beals contractural arachnodactyly. After the diagnosis of bilateral CVT was made, it was treated with a single-stage open reduction. There was a unilateral recurrence, which was treated with revision surgery. The patient had an excellent functional outcome. CONCLUSION:CVT often requires surgical management and may recur. To our knowledge, this is the first reported case of CVT associated with Beals contractural arachnodactyly.	0
Mutations in STUB1 have been identified to cause autosomal recessive spinocerebellar ataxia type 16 (SCAR16), also named as Gordon Holmes syndrome, which is characterized by cerebellar ataxia, cognitive decline, and hypogonadism. Additionally, several heterozygous mutations in STUB1 have recently been described as a cause of autosomal dominant spinocerebellar ataxia type 48. STUB1 encodes C-terminus of HSC70-interacting protein (CHIP), which functions as an E3 ubiquitin ligase and co-chaperone and has been implicated in several neurodegenerative diseases. In this study, we identified two SCAR16 pedigrees from 512 Taiwanese families with cerebellar ataxia. Two compound heterozygous mutations in STUB1, c.[433A>C];[721C>T] (p.[K145Q];[R241W]) and c.[433A>C];[694T>G] (p.[K145Q];[C232G]), were found in each SCAR16 family by Sanger sequencing, respectively. Among them, STUB1 p.R241W and p.C232G were novel mutations. SCAR16 seems to be an uncommon ataxic syndrome, accounting for 0.4% (2/512) of our cohort with cerebellar ataxia. Clinically, the three patients from the two SCAR16 families presented with cerebellar ataxia alone or in combination with cognitive impairment. The brain MRIs showed a marked cerebellar atrophy of the patients. In conclusion, SCAR16 is an important but often neglected diagnosis of cerebellar ataxia of unknown cause, and the isolated cerebellar ataxia without involvement of other systems cannot be a basis to exclude the possibility of STUB1-related disease.	0
BACKGROUND:Pancreatoblastoma is a rare malignancy that occurs predominantly in children. Less than 50 adult cases, including 17 patients with metastatic disease, have been published to date. Recent outcome data from children with advanced-stage disease suggest an intensive multimodal treatment approach; however, little is known about the most beneficial therapy in adults. Molecular characterization of pancreatoblastoma is limited to a small number of pediatric cases and revealed few recurrent genetic events without immediate clinical relevance. METHODS:Patients were treated between 2013 and 2018 at a high-volume German university cancer center. Molecular analyses included whole genome, exome, transcriptome, and fusion gene panel sequencing. Molecularly guided treatment recommendations were discussed within a dedicated molecular tumor board (MTB) embedded in a precision oncology program (NCT MASTER). RESULTS:We identified four adult patients with metastatic pancreatoblastoma. In three patients, local approaches were combined with systemic treatment. Oxaliplatin-containing protocols showed an acceptable tumor control as well as an adequate toxicity profile. Overall survival was 15, 17, 18 and 24 months, respectively. Three tumors harbored genetic alterations involving the FGFR pathway that included an oncogenic FGFR2 fusion. CONCLUSION:Oxaliplatin-containing chemotherapy seems to be a reasonable approach in adult patients with advanced pancreatoblastoma, whereas the benefit of intensified treatment including local ablative techniques or surgical resection remains unclear. Our finding of FGFR alterations in three of four cases indicates a potential role of FGFR signaling in adult pancreatoblastoma whose clinical significance warrants further study.	0
AIMS: Wolfram syndrome, also known as DIDMOAD, is a relatively rare inherited neurodegenerative disorder, first evident in childhood as an association of juvenile-onset diabetes mellitus and optic atrophy, followed by diabetes insipidus and deafness. The aim of the study was to examine the clinical profile of patients with DIDMOAD syndrome presenting to a tertiary care hospital in north India. METHODS: Clinical presentation of juvenile-onset diabetes mellitus fulfilling the diagnosis of Wolfram syndrome was studied using a prepared standardized form. RESULTS: Subjects with juvenile-onset non-autoimmune diabetes mellitus attending the diabetic clinic at a tertiary care centre in north India were followed for 10 years and a diagnosis of fully developed Wolfram syndrome was confirmed in seven individuals. The series consisted of five male and two female patients with a mean age of 17.5 ±7.34 years. Two subjects had consanguinity and none had any other family member affected. Optic atrophy was present in all, sensorineural hearing loss in 4/7, central diabetes insipidus in 4/7 and nephrogenic diabetes insipidus in 2/7 subjects. The new associations found were: spastic myoclonus, short stature with pancreatic malabsorption, nephrogenic diabetes insipidus, cyanotic heart disease and choledocholithiasis with cholangitis. Genetic analysis revealed mutation in exon 8 of the WFS1 gene in all the cases studied. CONCLUSIONS: The present clinical series of Wolfram syndrome reveals a varied clinical presentation of the syndrome and some new associations.	1
AIM:To determine whether the presence of internal calcifications on perinatal post-mortem skeletal surveys (PMSS) are associated with certain diagnoses of fetal loss. METHODS AND MATERIALS:A 6-month retrospective, single-centre, cohort study was conducted on PMSS performed for perinatal death assessment. One reader re-reviewed all PMSS images for the presence and location of internal calcifications, and noted whether these were included within the original radiology report. Findings at autopsy were then reviewed independently by a second researcher and cause of fetal loss or main diagnosis recorded. Chi-squared tests were conducted to identify differences between those with and without internal calcifications at PMSS. RESULTS:Two hundred and thirty perinatal deaths (mean gestational age 18 weeks; average 12-35 weeks) were included in the study, of which 42 (18.3%) demonstrated intra-abdominal calcifications, and 16/42 (38.1%) were mentioned in the radiology reports. Most calcifications were found to be within the lumen of the gastrointestinal tract, and in the left upper quadrant of the abdomen. There was no statistical difference between identifiable causes for fetal loss at autopsy in cases with and without calcification at PMSS (59.5% versus 58.5% respectively, p=0.904). Nevertheless, where calcification and a cause for fetal loss were found, the aetiology was more likely to be due a fetal rather than placental issue. CONCLUSION:The presence of internal calcifications on PMSS was not associated with an increased likelihood of explainable fetal loss or particular diagnosis at autopsy.	0
CHARGE syndrome is an autosomal dominant condition caused by mutations in the chromodomain helicase DNA binding protein 7 (CHD7) gene. The present study reported on the case of a 16-month-old female with plurimalformative syndrome, whose etiology was identified by clinical whole-exome sequencing (WES) analysis. Clinical and follow-up assessments identified multiple craniofacial dysmorphisms, congenital defects and functional symptoms, including dysphagia and Marcus Gunn jaw winking synkinesis. Trio-WES analysis was performed for the patient and their parents and the presence of CHARGE syndrome was further indicated using single-molecule real-time sequencing. A de novo pathogenic variant, c.4379_4380del (p.Ile1460Argfs*15), was identified in exon 19 of the CHD7 gene, which resulted in a premature translational stop signal. Trio-WES analysis was used for further investigation, indicating that neither of the patient's parents had the mutation and confirming its de novo nature. To the best of our knowledge, the case of the present study was the first reported case of CHARGE syndrome in Romania with congenital defects including an aberrant right subclavian artery and a horseshoe kidney. CHARGE syndrome was diagnosed in the patient based on the pathogenic mutation in the CHD7 gene. To the best of our knowledge, the present case report is the first to suggest that the CHD7 gene variant is associated with CHARGE syndrome.	0
AIMS:The aim of this study was the genetic diagnosis by next generation sequencing (NGS) of a patient diagnosed with Usher syndrome type 2 and the functional evaluation of the identified genetic variants to establish a phenotype-genotype correlation. METHODS:Whole exome sequencing (WES) analysis identified two heterozygous intronic variants in CDH23, a gene responsible of Usher syndrome type 1. Evaluation of the putative splicing effects was performed in vivo, in whole blood samples, and in vitro, by transfection of midigene constructs in HEK293T cells. RESULTS:Two intronic variants were identified in intron 45 of CDH23-one novel, c.6050-15G>A, and the other, c.6050-9G>A, already reported as a noncanonical splice site (NCSS) mutation-with partial functional characterization. In vivo and in vitro analyses showed aberrant transcripts by the addition of 13 and 7 nucleotides to exon 46, respectively. Transcript degradation by nonsense mediated decay (NMD) in blood cells could only be prevented by cycloheximide treatment. Midigene constructs showed that the two variants contributed to exon skipping and generated aberrantly spliced transcripts. CONCLUSIONS:A combination of in vivo and in vitro assays provided a comprehensive view of the physiological effects of NCSS variants, which in this case led to a clinical reassignment of the proband as affected with atypical USH1 syndrome.	0
Bjornstad syndrome is a rare condition characterized by pili torti and sensorineural hearing loss associated with pathological variations in BCS1L. Mutations in this gene are also associated with the more severe complex III deficiency and GRACILE syndrome. We report the first Italian patients with Bjornstad syndrome, two siblings with pili torti and sensorineural hearing loss, in whom we detected two novel compound heterozygous mutations in BCS1L. A thorough clinical evaluation did not reveal any features consistent with complex III deficiency or GRACILE syndrome.	0
T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare aggressive lymphoma characterized by a paucity of neoplastic B-cells and a majority of reactive T-cells with or without histiocytes. In the 'Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas' trial (clinicaltrials.gov NCT00554164; EudraCT 2006-001641-33), its frequency was less than 3%. While cancer cell content by quantitative histology was 10-times lower, baseline total metabolic tumor volume (TMTV) by 18-fluorodesoxyglucose positron emission tomography was 10-times higher in THRLBCL than in diffuse large B-cell lymphoma (DLBCL). When THRLBCL and DLBCL populations were matched for TMTV, the survival curves were superimposable. However, when the populations were matched for cancer cell volume by multiplying TMTV by cancer cell fraction, outcome in THRLBCL was worse than in DLBCL. Whether genetic differences between cancer cells, tumor-promoting properties of non-neoplastic cells, or both are responsible for inferior cancer cell volume-related outcome in THRLBCL, remains to be elucidated.	0
Gracile bones are a frequent abnormality associated with fetal hypokinesia of any cause. With the exception of thin, undermineralized bones, the chondro-osseous structure is usually normal in these cases. We present a lethal skeletal dysplasia comprising minor anomalies, central nervous system abnormalities, gracile long bones, and abnormal chondro-osseous morphology. In addition to a short, disordered growth plate, the chondrocytes contained dilated loops of rough endoplasmic reticulum, suggesting an abnormality of an extracellular matrix protein. This protein appears to have effects on chondro-osseous and on facial and central nervous system development. We suggest the term "gracile bone dysplasia" to describe this disorder.	0
Ring chromosome 10 is a rare cytogenetic finding. Only a few cases with molecular cytogenetic definition have been reported. We report here on a child with a ring chromosome 10, which is associated with prenatal and postnatal growth retardation, microcephaly, dysmorphic features, hypotonia, heart defect, severe pes equinovarus, and bronchial asthma. The chromosomal aberration was defined by chromosome microarray analysis, which revealed two deletions at 10pter (3.68 Mb) and 10qter (4.26 Mb). The clinical features are very similar to those reported in other clinical cases with ring chromosome 10, excluding bronchial asthma, which has not been previously reported in individuals with ring chromosome 10.	0
Upper airway obstruction is a common feature in pycnodysostosis and may cause obstructive sleep apnea (OSA). The aim of our study was to analyze sleep-disordered breathing and respiratory management in children with pycnodysostosis. A retrospective review of the clinical charts and sleep studies of 10 consecutive children (three girls and seven boys) with pycnodysostosis seen over a time period of 10 years was performed. Six patients had severe OSA and/or nocturnal hypoventilation and were started on continuous positive airway pressure (CPAP) as a first treatment at a median age of 3.4 ± 2.6 years, because of the lack of indication of any surgical treatment. Three patients could be weaned after several years from CPAP after spontaneous improvement (two patients) or multiple upper airway surgeries (one patient). Three patients had upper airway surgery prior to their first sleep study with two patients still needing CPAP during their follow-up. Only one patient never developed OSA. Patients with pycnodysostosis are at a high risk of severe OSA, underlying the importance of a systematic screening for sleep-disordered breathing. Multidisciplinary care is mandatory because of the multilevel airway obstruction. CPAP is very effective and well accepted for treating OSA.	0
The serotonin-1A receptor (5-HT1AR) represents a viable target in the treatment of disorders of the brain. However, development of psychiatric drugs continues to be hindered by the relative inaccessibility of brain tissue. Although the efficacy of drugs selective for the 5-HT1AR has not been proven, research continues to focus on drugs that influence this receptor subtype. To further knowledge on this topic, we investigated the topological coexpression patterns of the 5-HT1AR. We calculated Spearman's rho for the correlation of positron emission tomography-binding potentials (BPND) of the 5-HT1AR assessed in 30 healthy subjects using the tracer [carbonyl-11C]WAY-100635 and predicted whole-brain mRNA expression of 18 686 genes. After applying a threshold of r > 0.3 in a leave-one-out cross-validation of the prediction of mRNA expression, genes with ρ ≥ 0.7 were considered to be relevant. In cortical regions, 199 genes showed high correlation with the BPND of the 5-HT1AR, in subcortical regions 194 genes. Using our approach, we could consolidate the role of BDNF and implicate new genes (AnxA8, NeuroD2) in serotonergic functioning. Despite its explorative nature, the analysis can be seen as a gene prioritization approach to reduce the number of genes potentially connected to 5-HT1AR functioning and guide future in vitro studies.	0
OBJECTIVES:The financial burdens and subsequent related distress of medical care, referred to as financial toxicity, may limit access to beneficial treatments. However, financial toxicity after acute care is less described-and may be an important but underexplored mechanism preventing full recovery after critical illnesses such as acute respiratory distress syndrome. We sought to identify the mechanisms by which financial toxicity manifested in patients with acute respiratory distress syndrome, protective factors against such toxicity, and the consequences of financial toxicity to survivors' lives following acute respiratory distress syndrome. DESIGN:We conducted semistructured interviews following patients' hospitalization and during recovery as an ancillary study to a multicenter randomized clinical trial in acute respiratory distress syndrome. Patients were 9-16 months post randomization at the time of interview. SETTING AND PARTICIPANTS:The Reevaluation Of Systemic Early Neuromuscular Blockade trial examined the use of early neuromuscular blockade in mechanically ventilated patients with moderate/severe acute respiratory distress syndrome. We recruited consecutive surviving patients who were English speaking, consented to follow-up, and were randomized between December 11, 2017, and May 4, 2018 (n = 79) from 29 U.S. sites. MEASUREMENTS AND MAIN RESULTS:We asked about patients' perceptions of financial burden(s) that they associated with their acute respiratory distress syndrome hospitalization. Forty-six of 79 eligible acute respiratory distress syndrome survivors (58%) participated (from 22 sites); their median age was 56 (interquartile range 47-62). Thirty-one of 46 reported at least one acute respiratory distress syndrome-related financial impact. Financial toxicity manifested via medical bills, changes in insurance coverage, and loss of employment income. Respondents reported not working prior to acute respiratory distress syndrome, using Medicaid or Medicare, or, conversely, generous work benefits as factors which may have limited financial burdens. Patients reported multiple consequences of acute respiratory distress syndrome-related financial toxicity, including harms to their mental and physical health, increased reliance on others, and specific material hardships. CONCLUSIONS:Financial toxicity related to critical illness is common and may limit patients' emotional, physical, and social recovery after acute respiratory distress syndrome hospitalization for at least a year.	0
CONTEXT:Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are caused by inactivating mutations in the exons of GNAS that encode the alpha-subunit of the stimulatory G protein (Gsα). In some cases abnormal methylation of exon A/B of GNAS, a hallmark of PHP1B, has been reported. OBJECTIVE:To identify the underlying genetic basis for PHP1A/PPHP in patients in whom molecular defects were not detected by GNAS sequencing and microarray-based analysis of copy number variations. METHODS:Whole genome sequencing (WGS) and pyrosequencing of differentially methylated regions (DMRs) of GNAS using genomic deoxyribonucleic acid from affected patients. RESULTS:We identified 2 novel heterozygous GNAS deletions: a 6.4 kb deletion that includes exon 2 of GNAS in the first proband that was associated with normal methylation (57%) of exon A/B DMR, and a 1438 bp deletion in a second PHP1A patient that encompasses the promoter region and 5' untranslated region of Gsα transcripts, which was inherited from his mother with PPHP. This deletion was associated with reduced methylation (32%) of exon A/B DMR. CONCLUSIONS:WGS can detect exonic and intronic mutations, including deletions that are too small to be identified by microarray analysis, and therefore is more sensitive than other techniques for molecular analysis of PHP1A/PPHP. One of the deletions we identified led to reduced methylation of exon A/B DMR, further refining a region needed for normal imprinting of this DMR. We propose that deletion of this region can explain why some PHP1A patients have reduced of methylation of the exon A/B DMR.	0
INTRODUCTION: The aim of this study was to assess population-based changes in incidence, treatment, and in short- and long-term survival of patients with acute respiratory distress syndrome (ARDS) over 23 years. MATERIALS AND METHODS: Analysis of all patients in Iceland who fulfilled the consensus criteria for ARDS in 1988-2010. Demographic variables, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores and ventilation parameters were collected from hospital charts. RESULTS: The age-standardised incidence of ARDS during the study period was 7.2 cases per 100,000 person-years and was increased by 0.2 cases per year (P < 0.001). The most common causes of ARDS were pneumonia (29%) and sepsis (29%). The use of pressure-controlled ventilation became almost dominant from 1993. The peak inspiratory pressure (PIP) has significantly decreased (-0.5 cmH(2) O/year), but the peak end-expiratory pressure (PEEP) has increased (0.1 cmH(2) O/year) during the study period. The hospital mortality decreased by 1% per year (P = 0.03) during the study period, from 50% in 1988-1992 to 33% in 2006-2010. A multivariable logistic regression model revealed that higher age and APACHE II score increased the odds of hospital mortality, while a higher calendar year of diagnosis reduced the odds of mortality. This was unchanged when dominant respiratory treatment, PIP and PEEP were added to the model. The 10-year survival of ARDS survivors was 68% compared with 90% survival of a reference population (P < 0.001). CONCLUSION: The incidence of ARDS has almost doubled, but hospital mortality has decreased during the 23 years of observation. The 10-year survival of ARDS survivors is poor compared with the reference population.	1
Polyposis associated with mutations in the gene MYH is an autosomal recessive syndrome characterized by the development of colorectal adenomas and cancer. Two common mutations, p.Tyr165Cys (exon 7) and p.Glu382Asp (exon 13), have been shown to account for the majority of the mutations occurring in individuals of Caucasian ancestry. Other mutations have been found throughout the gene and many have been shown to have very low frequencies. Ethnic differences in the mutation spectrum have also been observed. Thus, in order to achieve the highest clinical sensitivity, it is necessary to perform whole-gene sequencing of the MYH gene. The sequencing protocol described allows one to identify mutations throughout the MYH gene.	0
Horizontal gaze palsy with progressive scoliosis (HGPPS) is an autosomal recessive disorder caused by ROBO3 gene mutations. To date, the number of confirmed HGPPS cases caused by gene mutations is estimated at 76. However, HGPPS caused by ROBO3 gene mutation has not been reported in the Chinese population. In this study, the clinical data, brain imaging features, somatosensory evoked potentials (SEP), and ROBO3 gene mutations were obtained for two Chinese patients with HGPPS. The proband was an 11-year-old boy. He developed horizontal eye movement disorder at the age of 1 year and scoliosis at the age of 11 years. Two eyeballs fixed in the midline position were revealed by neurological examination. A dorsal cleft in the pons and a butterfly-shaped medulla were shown by brain magnetic resonance imaging. Again, most corticospinal bundles did not cross in the brainstem, as revealed by diffusion tensor imaging. SEP confirmed that most somatosensory projections were uncrossed. The proband's 7-year-old brother exhibited similar clinical manifestations and imaging features. The brothers had compound heterozygous mutations c.3165G>A (p.W1055X) and c.955G>A (p.E319K) of the ROBO3 gene. The c.3165G>A mutation is a novel nonsense mutation that has not been previously reported. This study reports the first two cases of HGPPS carrying a novel ROBO3 gene mutation in patients from a Chinese family, thereby expanding the disease spectrum. Reports from the literature show that missense mutation is the most common mutational type in the ROBO3 gene. Early ROBO3 gene detection is required for patients exhibiting early-onset eyeball movement disorder to confirm HGPPS disease.	0
Reduced hepatic Na+/K+-ATPase (NKA) activity and NKAα1 expression are engaged in the pathologies of metabolism diseases. The present study was designed to investigate the potential roles of NKAα1 in hepatic gluconeogenesis and glycogenesis in both hepatocytes and obese diabetic mice. Methods: Insulin resistance was mimicked by glucosamine (GlcN) in either human hepatocellular carcinoma (HepG2) cells or primary mouse primary hepatocytes. Obese diabetic mice were induced by high-fat diet (HFD) feeding for 12 weeks. Results: We found that both NKA activity and NKAα1 protein level were downregulated in GlcN-treated hepatocytes and in the livers of obese diabetic mice. Pharmacological inhibition of NKA with ouabain worsened, while activation of NKAα1 with an antibody against an extracellular DR region of NKAα1 subunit (DR-Ab) prevented GlcN-induced increase in gluconeogenesis and decrease in glycogenesis. Likewise, the above results were also corroborated by the opposite effects of genetic knockout/overexpression of NKAα1 on both gluconeogenesis and glycogenesis. In obese diabetic mice, hepatic activation or overexpression of NKAα1 stimulated the PI3K/Akt pathway to suppress hyperglycemia and improve insulin resistance. More importantly, loss of NKA activities in NKAα1+/- mice was associated with more susceptibility to insulin resistance following HFD feeding. Conclusions: Our findings suggest that NKAα1 is a physiological regulator of glucose homoeostasis and its DR-region is a novel target to treat hepatic insulin resistance.	0
Mutations in the ATPase family 3-like gene (AFG3L2) have been linked to autosomal-dominant spinocerebellar ataxia type 28 and autosomal recessive spastic ataxia-neuropathy syndrome. Here, we describe the case of a child carrying bi-allelic mutations in AFG3L2 and presenting with ictal paroxysmal episodes associated with neuroimaging suggestive of basal ganglia involvement. Studies in skin fibroblasts showed a significant reduction of AFG3L2 expression. The relatively mild clinical presentation and the benign course, in spite of severe neuroimaging features, distinguish this case from data reported in the literature, and therefore expand the spectrum of neurological and neuroradiological features associated with AFG3L2 mutations.	0
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is an autosomal recessive mitochondrial fatty acid oxidation disorder that manifests in three clinical forms: (a) severe, (b) milder, and (c) myopathic. Patients with the myopathic form present intermittent muscular symptoms such as myalgia, muscle weakness, and rhabdomyolysis during adolescence or adulthood. Here, the clinical symptoms and serum creatine kinase (CK) levels of a pregnant 31-year-old woman with the myopathic form of VLCAD deficiency were reduced during pregnancy. Clinical symptoms rarely appeared during pregnancy, although she had sometimes suffered from muscular symptoms before pregnancy. When ritodrine was administered for threatened premature labor at 35 weeks of gestation, her CK level was elevated to over 3900 IU/L. She delivered a full-term baby via cesarean section but suffered from muscle weakness with elevated CK levels soon after delivery. It has been reported that an unaffected placenta and fetus can improve maternal β-oxidation during pregnancy. However, in our case, the baby was also affected by VLCAD deficiency. These suggest that the clinical symptoms of a woman with VLCAD deficiency might be reduced during pregnancy even if the fetus is affected with VLCAD deficiency.	0
Femoral artery aneurysms (FAAs) are very rare, and their natural history is not well understood. In this study, we sought to analyze the pathogenesis of inflammatory FAAs in interleukin-1 receptor antagonist-deficient (IL-1Ra(-/-)) B6 mice. Systolic arterial pressures and plasma lipid levels of IL-1Ra(-/-) mice and wild-type (WT) mice did not differ significantly. However, IL-1Ra(-/-) mice spontaneously developed fusiform FAAs. Real-time PCR of 9-month-old IL-1Ra(-/-) mice revealed significantly increased mRNA levels of IL-1β (6.6-fold), tumor necrosis factor-α (TNF-α) (12.4-fold), and matrix metalloproteinase-9 (6.0-fold) compared with WT mice. Histological analysis revealed numerous inflammatory cells around the FAAs in IL-1Ra(-/-) mice, and elastin staining showed destruction of both the internal and external elastic lamina in IL-1Ra(-/-) mice. Afterward, macrophage function was studied. After lipopolysaccharide (1 μg/mL) stimulation, IL-1Ra-deficient macrophages produced much higher levels of TNF-α than those from WT mice. Finally, we performed bone marrow cell transplantation. FAAs with many inflammatory cells in the adventitia were detected in several WT mice that received bone marrow cells from IL-1Ra(-/-) mice (44%), but not from WT mice (0%). Our study is the first to demonstrate that IL-1Ra deficiency in inflammatory cells disrupts immune system homeostasis and induces inflammatory FAAs in IL-1Ra(-/-) B6 mice. We believe that these mice will provide much information about the natural history and management of FAAs.	0
Neuronal ceroid lipofuscinosis (NCL) is a lysosomal storage disorder that causes progressive neurodegenerative disease as a result of storage in neurons and other cells. Late infantile type (NCL Type 2) of NCL, which is the most common neurodegenerative disease in childhood, is characterised by a homozygous mutation in the tripeptidyl peptidase-1 (TPP-1) gene. A male infant was referred to our neonatal intensive care unit (NICU) on 26th day of life with a diagnosis of metabolic disease. He was intubated. He was hypotonic and newborn reflexes were not present. Cranial magnetic resonance (MR) imaging revealed severe atrophy and delayed myelination of cerebellum and cerebral hemispheres. A novel homozygous pathological mutation was detected in exon 9 of the TPP-1 gene. With this case, it should be kept in mind that NCL may rarely start early in neonatal period and should be suspected in newborns with cerebral and cerebellar atrophy for early diagnosis. Key Words: Hypotonia, Lysosomal storage diseases, Metabolic disease, Neuronal ceroid lipofuscinosis, Newborn.	0
OBJECTIVE:Sudden arrhythmia death syndrome (SADS) accounts for about 30% of causes of sudden cardiac death (SCD) in young people. In Hong Kong, there are scarce data on SADS and a lack of experience in molecular autopsy. We aimed to investigate the value of molecular autopsy techniques for detecting SADS in an East Asian population. METHODS:This was a two-part study. First, we conducted a retrospective 5-year review of autopsies performed in public mortuaries on young SCD victims. Second, we conducted a prospective 2-year study combining conventional autopsy investigations, molecular autopsy, and cardiac evaluation of the first-degree relatives of SCD victims. A panel of 35 genes implicated in SADS was analysed by next-generation sequencing. RESULTS:There were 289 SCD victims included in the 5-year review. Coronary artery disease was the major cause of death (35%); 40% were structural heart diseases and 25% were unexplained. These unexplained cases could include SADS-related conditions. In the 2-year prospective study, 21 SCD victims were examined: 10% had arrhythmogenic right ventricular cardiomyopathy, 5% had hypertrophic cardiomyopathy, and 85% had negative autopsy. Genetic analysis showed 29% with positive heterozygous genetic variants; six variants were novel. One third of victims had history of syncope, and 14% had family history of SCD. More than half of the 11 first-degree relatives who underwent genetic testing carried related genetic variants, and 10% had SADS-related clinical features. CONCLUSION:This pilot feasibility study shows the value of incorporating cardiac evaluation of surviving relatives and next-generation sequencing molecular autopsy into conventional forensic investigations in diagnosing young SCD victims in East Asian populations. The interpretation of genetic variants in the context of SCD is complicated and we recommend its analysis and reporting by qualified pathologists.	0
Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is a rare, early-onset retinal dystrophy characterised by distinct bands of circumferential pigmentary degeneration in the peripheral retina and developmental eye defects. ADVIRC is caused by mutations in the Bestrophin1 (BEST1) gene, which encodes a transmembrane protein thought to function as an ion channel in the basolateral membrane of retinal pigment epithelial (RPE) cells. Previous studies suggest that the distinct ADVIRC phenotype results from alternative splicing of BEST1 pre-mRNA. Here, we have used induced pluripotent stem cell (iPSC) technology to investigate the effects of an ADVIRC associated BEST1 mutation (c.704T > C, p.V235A) in patient-derived iPSC-RPE. We found no evidence of alternate splicing of the BEST1 transcript in ADVIRC iPSC-RPE, however in patient-derived iPSC-RPE, BEST1 was expressed at the basolateral membrane and the apical membrane. During human eye development we show that BEST1 is expressed more abundantly in peripheral RPE compared to central RPE and is also expressed in cells of the developing retina. These results suggest that higher levels of mislocalised BEST1 expression in the periphery, from an early developmental stage, could provide a mechanism that leads to the distinct clinical phenotype observed in ADVIRC patients.	0
PURPOSE:This study was performed to clarify the clinical features of Japanese patients with PRRT2 mutations. METHODS:The PRRT2 gene was analyzed in 135 patients with benign infantile epilepsy (BIE) or paroxysmal kinesigenic dyskinesia (PKD) using a direct sequencing method: 92 patients had BIE alone, 25 had both BIE and PKD, and 18 had PKD alone. Of the cases, 105 were familial, and 30 were sporadic. Clinical information was collected using a structured questionnaire. RESULTS:PRRT2 mutations were identified in 104 patients. Among the familial cases, PRRT2 mutations were found in at least one individual in 21 of 28 families with BIE alone, in 26 of 27 families with infantile convulsions and choreoathetosis, and in 2 of 3 families with PKD alone. Among the sporadic cases, PRRT2 mutations were observed in 7 of 25 patients with BIE alone, in 1 of 1 patient with BIE and PKD, and in 3 of 4 patients with PKD alone. The c.649dupC mutation was the most frequent, followed by the c.981C > G mutation. Among the patients with epilepsy, the median age at BIE onset was 5 months, the median age at the last seizure was 6 months, and the median number of seizures was 5. CONCLUSION:PRRT2 mutations were found in 68% of Japanese probands with BIE or PKD. The phenotypes of BIE associated with PRRT2 mutations were consistent with those of BIE diagnosed clinically.	0
Tropical splenomegaly is often associated with malaria and schistosomiasis. In 2014 and 2015, 145 Congolese refugees in western Uganda diagnosed with splenomegaly during predeparture medical examinations underwent enhanced screening for various etiologies. After anecdotal reports of unresolved splenomegaly and complications after U.S. arrival, patients were reassessed to describe long-term clinical progression after arrival in the United States. Post-arrival medical information was obtained through medical chart abstraction in collaboration with state health partners in nine participating states. We evaluated observed splenomegaly duration and associated clinical sequelae between 130 case patients from eastern Congo and 102 controls through adjusted hierarchical Poisson models, accounting for familial clustering. Of the 130 case patients, 95 (73.1%) had detectable splenomegaly after arrival. Of the 85 patients with records beyond 6 months, 45 (52.9%) had persistent splenomegaly, with a median persistence of 14.7 months (range 6.0-27.9 months). Of the 112 patients with available results, 65 (58.0%) patients had evidence of malaria infection, and the mean splenomegaly duration did not differ by Plasmodium species. Refugees with splenomegaly on arrival were 43% more likely to have anemia (adjusted relative risk [aRR]: 1.43, 95% CI: 1.04-1.97). Those with persistent splenomegaly were 60% more likely (adjusted relative risk [aRR]: 1.60, 95% CI: 1.15-2.23) to have a hematologic abnormality, particularly thrombocytopenia (aRR: 5.53, 95% CI: 1.73-17.62), and elevated alkaline phosphatase (aRR: 1.57, 95% CI: 1.03-2.40). Many patients experienced persistent splenomegaly, contradicting literature describing resolution after treatment and removal from an endemic setting. Other possible etiologies should be investigated and effective treatment, beyond treatment for malaria and schistosomiasis, explored.	0
Leukodystrophies (LDs) are heterogeneous genetic disorders characterized by abnormal white matter in the central nervous system. Some of the LDs are progressive and often fatal. In general, LD is primarily diagnosed based on the neuroimaging; however, definitive diagnosis of the LD type is done using genetic testing such as next-generation sequencing. The aim of this study is to identify the genetic causes of LD in two independent Jordanian cases that exhibit MRI findings confirming LD with no definitive diagnosis using whole exome sequencing (WES). The most likely causative variants were identified. In one case, the homozygous pathogenic variant NM_000049.2:c.914C>A;p.Ala305Glu, which is previously reported in ClinVar, in the gene ASPA was identified causing Canavan disease. In the second case, the homozygous novel variant NM_000487.5:c.256C>G;p.Arg86Gly in the gene ARSA was identified causing metachromatic leukodystrophy. The two variants segregate in their families. The phenotypes of the two studied cases overlap with assigned diseases. The present study raises the importance of using WES to identify the precise neurodevelopmental diseases in Jordan.	0
Complement deficiencies are rare and often underdiagnosed primary immunodeficiencies that may be associated with invasive bacterial diseases. Serious infections with encapsulated organisms (mainly Streptococcus pneumoniae, but also Neisseria meningitides and Haemophilus influenzae type B) are frequent in patients with a deficiency of the second component of complement (C2), but no data are available on long-term follow-up. This study aimed to evaluate the long-term clinical outcome and the importance of an early diagnosis and subsequent infection prophylaxis in C2 deficiency. Here, we report the 21-year follow-up of a whole family which was tested for complement parameters, genetic analysis and biochemical measurements, due to recurrent pneumococcal meningitis in the elder brother. The two sons were diagnosed with homozygous type 1 C2 deficiency, while their parents were heterozygous with normal complement parameters. For the two brothers, a recommended vaccination program and antibiotic prophylaxis were prescribed. During the long-term follow-up, no severe/invasive infections were observed in either patient. At the age of 16, the younger brother developed progressive hypogammaglobulinemia of all three classes, IgA, IgM and IgG. A next generation sequencing panel excluded the presence of gene defects related to primary antibody deficiencies. Our data show that early diagnosis, use of vaccinations and antibiotic prophylaxis may allow a normal life in hereditary C2 deficiency, which can be characterized using functional and genetic methods. Moreover, a periodical check of immunoglobulin serum levels could be useful to detect a possible hypogammaglobulinemia.	0
: Retinal dystrophies (RDs) comprise relatively rare but devastating causes of progressive vision loss. They represent a spectrum of diseases with marked genetic and clinical heterogeneity. Mutations in the same gene may lead to different diagnoses, for example, retinitis pigmentosa or cone dystrophy. Conversely, mutations in different genes may lead to the same phenotype. The age at symptom onset, and the rate and characteristics of peripheral and central vision decline, may vary widely per disease group and even within families. For most RD cases, no effective treatment is currently available. However, preclinical studies and phase I/II/III gene therapy trials are ongoing for several RD subtypes, and recently the first retinal gene therapy has been approved by the US Food and Drug Administration for RPE65-associated RDs: voretigene neparvovec-rzyl (Luxturna). With the rapid advances in gene therapy studies, insight into the phenotypic spectrum and long-term disease course is crucial information for several RD types. The vast clinical heterogeneity presents another important challenge in the evaluation of potential efficacy in future treatment trials, and in establishing treatment candidacy criteria. This perspective describes these challenges, providing detailed clinical descriptions of several forms of RD that are caused by genes of interest for ongoing and future gene or cell-based therapy trials. Several ongoing and future treatment options will be described.	0
OBJECTIVE:To present the development of the first custom gene panel for the diagnosis of male and female infertility in Latin America. METHODS:We developed a next-generation sequencing (NGS) panel that assesses genes associated with infertility. The panel targeted exons and their flanking regions. Selected introns in the CFTR gene were also included. The FMR1 gene and Y chromosome microdeletions were analyzed with other recommended methodologies. An in-house developed bioinformatic pipeline was applied for the interpretation of the results. Clear infertility phenotypes, idiopathic infertility, and samples with known pathogenic variants were evaluated. RESULTS:A total of 75 genes were selected based on female (primary ovarian insufficiency, risk of ovarian hyperstimulation syndrome, recurrent pregnancy loss, oocyte maturation defects, and embryo development arrest) and male conditions (azoospermia, severe oligospermia, asthenozoospermia, and teratozoospermia). The panel designed was used to assess 25 DNA samples. Two of the variants found were classified as pathogenic and enable the diagnosis of a woman with secondary amenorrhea and a man with oligoasthenoteratozoospermia. Targeted NGS assay metrics resulted in a mean of 180X coverage, with more than 98% of the bases covered ≥20X. CONCLUSION:Our custom gene sequencing panel designed for the diagnosis of male and female infertility caused by genetic defects revealed the underlying genetic cause of some cases of infertility. The panel will allow us to develop more precise approaches in assisted reproduction.	0
Objectives:To describe the clinical presentation of lymphatic malformations (LM) and genotypically associated disorders and to summarize the recent literature regarding the genetic etiology of LM and provide a biologic correlation to medical and surgical management. Results:LM are congenital lesions derived from a developmental abnormality of the lymphatic vessels. The severity of disease varies widely and complications can occur with higher staged disease and those associated with a known constellation of symptoms. Somatic mutations of the PIK3CA gene have been found to be an etiologic factor in the development of LM and associated overgrowth syndromes. Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor that inhibits the pathway downstream of PIK3CA. Preliminary studies in select groups of patients suggest that sirolimus has a role in the medical management of certain aspects of this disease. Conclusions:Discovery of LM molecular genetics has led to the possibility of targeted therapies and highlights the importance of precision medicine in rare diseases. Identifying genetic mutations in larger cohorts of patients with LM will lead to additional insights. Knowledge of the genetic basis for disease can then lead to discovery of directed medical therapy. A specific molecular diagnosis can also help families understand better why their child is different and provide accurate counseling for subsequent pregnancies. Level of Evidence:6.	0
BACKGROUND:Patients with mucopolysaccharidosis type I (MPS I) have a good life expectancy due to early therapeutic options, such as stem cell therapy. Stem cell therapy can prevent the progression of some skeletal malformations. In contrast, the progression of thoracolumbar kyphoscoliosis, genua vara, and hip dysplasia cannot be influenced. We present 3 cases of children with MPS I with thoracolumbar kyphosis/kyphoscoliosis treated with a growing rod system. CASE DESCRIPTION:The medical records and radiologic imaging of 3 children with a diagnosis of MPS I and kyphosis/kyphoscoliosis of the lumbar spine treated between 2007 and 2019 were retrospectively analyzed. Two children presented with a kyphoscoliosis, and 1 child had a combination of severe anterolisthesis and kyphoscoliosis. Surgery to correct the kyphosis and dorsal stabilization was performed in all patients after exhausted conservative treatment. There were no neurologic complications. Postoperative treatment and aftercare included a corset for 4 months and physical therapy. In all 3 patients, distraction surgery of the lumbar stabilization was done twice at a mean interval of 1 year. CONCLUSIONS:If conservative treatment fails and surgery is necessary, an individual approach is needed. Dorsal stabilization with pedicle screws using a growing rod technique is an option for the correction of thoracolumbar/lumbar kyphosis in children with MPS I. However, fusion should be prevented initially or should be kept as short as possible. We achieved acceptable correction of the spinal deformity using the growing rod technique. Finally, surgery with correction and fusion is necessary after exhausted correction potential.	0
Despite widespread use of lactulose and rifaximin for the treatment of hepatic encephalopathy, this complication of advanced liver disease remains a major burden on the health care system in the United States and continues to predispose to high morbidity and mortality. Several agents have surfaced over recent years with promise to treat hepatic encephalopathy and mitigate the cognitive impairment associated with this disease process. The purpose of this article is to highlight the leading emerging therapies in hepatic encephalopathy as well as their therapeutic targets.	0
We describe a case of hereditary hypophosphatemic rickets with hypercalciuria (HHRH) in a 32-year-old female with short stature, chronic pathologic genu valgum deformity, and knee pain who was referred to endocrinology clinic after previous inconclusive workups. We present imaging spanning 10 years of untreated disease. Biochemical studies showed hypophosphatemia with undetectable fibroblast growth factor 23 (FGF23.) Renal ultrasound revealed bilateral medullary nephrocalcinosis despite no apparent hypercalciuria. Due to concern for HHRH, genetic testing was performed that determined this patient to be homozygous in the SLC34A3 gene for a previously described missense variant (c.1402C > T, p.Arg468Trp). There was no known family history of rickets. A bone biopsy with metabolic studies was performed for diagnostic and prognostic reasons. The histopathological findings along with tetracycline uptake studies were consistent with a diagnosis of HHRH. Treatment with phosphorous supplementation and surgical correction of her valgum deformity resulted in resolution of pain, but no change in bone histomorphometry.	0
PURPOSE:To describe abnormalities in choroidal and retinal vasculature associated with Val30Met familial transthyretin amyloidosis (V30M-FTA) using fluorescein and indocyanine green (ICG) angiography. DESIGN:Prospective, cross-sectional study. METHODS:This study was conducted at the French National Reference Center for FTA. We included 18 consecutive genetically confirmed V30M-FTA patients (36 eyes) who underwent complete neurologic examination, including staging with polyneuropathy disability (PND) score, and complete ophthalmic evaluation, including staging of intraocular amyloid deposits and fluorescein and ICG angiograms (ICG-A). The grading of choroidal and retinal angiopathy, and their association with neurologic functional impairment, were the main outcome measures. RESULTS:Eleven men and 7 women, mean age 61.6 ± 12.1 years, were included. Retinal amyloid angiopathy (RAA) was detected in 24 eyes (92%) of 13 patients, with microaneurysms, retinal hemorrhages, and retinal ischemia of variable extent. Three patients (5 eyes) had neovascular glaucoma and 2 (2 eyes) had preretinal neovascularization. ICG-A indicated choroidal amyloid angiopathy (CAA) in all patients, with 3 distinct patterns-diffuse (9/18 patients), focal (5/18 patients), or punctiform (4/18 patients)-based on the extent of late hypercyanescence along the choroidal arteries. PND scores were significantly higher in patients with diffuse CAA (firework pattern) compared to those with limited CAA (focal and punctiform patterns) (2.89 vs 1.78, P = .045). CONCLUSION:RAA is a frequent and severe complication of V30M-FTA that may lead to anterior and posterior segment neovascularization. CAA was detected in all patients, with a late hypercyanescent delineation of the choroidal arterial vasculature, which was more extensive with increased disease severity.	0
The increasing incidence of thyroid cancer in the United States is well documented. In this study, we assessed the incidence patterns by histologic type according to demographic and tumor characteristics to further our understanding of these cancers.We used the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program for cases diagnosed during 1992-2006 to investigate patterns for the four major histologic types of thyroid cancer by gender, race/ethnicity, and age as well as registry, tumor stage, and size.Among women, papillary thyroid cancer rates were highest among Asians (10.96 per 100,000 woman-years) and lowest among blacks (4.90 per 100,000 woman-years); follicular cancer rates did not vary substantially by race/ethnicity (p-values >0.05), medullary cancer rates were highest among Hispanics (0.21 per 100,000 woman-years) and whites (0.22 per 100,000 woman-years), and anaplastic rates were highest among Hispanics (0.17 per 100,000 woman-years). Among men, both papillary and follicular thyroid cancer rates were highest among whites (3.58 and 0.58 per 100,000 man-years, respectively), medullary cancer rates were highest among Hispanics (0.18 per 100,000 man-years), and anaplastic rates were highest among Asians (0.11 per 100,000 man-years). Racial/ethnic-specific rates did not vary notably across registries. In contrast to age-specific rates of papillary thyroid cancer that peaked in midlife (age 50), especially pronounced among women, rates for follicular, medullary, and anaplastic types continued to rise across virtually the entire age range, especially for anaplastic carcinomas. Female-to-male incidence rate ratios among whites decreased with age most steeply for the follicular type and least steeply for the medullary type; it was <1 until the very oldest ages for the anaplastic type.We conclude that the similar age-specific patterns and lack of geographical variation across the SEER racial/ethnic groups indicate that detection effects cannot completely explain the observed thyroid cancer incidence patterns as variation in the amount or quality of healthcare provided has been shown to vary by SEER racial/ethnic groups, gender, and age. We find that the variations in age-specific patterns by gender and across histologic types are intriguing and recommend that future etiologic investigation focus on exogenous and endogenous exposures that are experienced similarly by racial/ethnic groups, more strongly among women, and distinctively by age.	1
Loose anagen hair syndrome is an uncommon hair disorder, particularly in non-Caucasian children. We report the case of a 13-year-old Thai boy who presented with a single patch of hair thinning on the frontal scalp with excessive shedding, and the hairs did not grow long. Microscopic examination showed naked anagen bulbs with ruffling of the cuticle, which is compatible with loose anagen hair syndrome. To our knowledge, there is no reported case in Southeast Asian children.	0
Purpose:We report two cases of Wyburn-Mason syndrome that illustrate the spectrum of peripheral retinal ischemia seen in this condition. Observations:A 12-year-old female presented with a retinal arteriovenous malformation and sclerotic vessels associated with retinal ischemia on fluorescein angiography, as well as an ipsilateral ophthalmic arteriovenous malformation on magnetic resonance imaging. An 11-year-old male presented with retinal vascular engorgement and tortuosity along with a central retinal vein occlusion and secondary neovascularization. Conclusions and Importance:Retinal ischemia in Wyburn-Mason syndrome is heterogeneous and may be progressive, with secondary complications that result in neovascularization. Furthermore, it is necessary to recognize that this is a systemic condition that requires neurological evaluation.	0
Lymphoma is one of the most curable types of cancer. However, drug resistance is the main challenge faced in lymphoma treatment. Peroxisomal acyl-CoA oxidase 1 (ACOX1) is the rate-limiting enzyme in fatty acid β-oxidation. Deregulation of ACOX1 has been linked to peroxisomal disorders and carcinogenesis in the liver. Currently, there is no information about the function of ACOX1 in lymphoma. In this study, we found that upregulation of ACOX1 promoted proliferation in lymphoma cells, while downregulation of ACOX1 inhibited proliferation and induced apoptosis. Additionally, overexpression of ACOX1 increased resistance to doxorubicin, while suppression of ACOX1 expression markedly potentiated doxorubicin-induced apoptosis. Interestingly, downregulation of ACOX1 promoted mitochondrial location of Bad, reduced mitochondrial membrane potential and provoked apoptosis by activating caspase-9 and caspase-3 related apoptotic pathway. Overexpression of ACOX1 alleviated doxorubicin-induced activation of caspase-9 and caspase-3 and decrease of mitochondrial membrane potential. Importantly, downregulation of ACOX1 increased p73, but not p53, expression. p73 expression was critical for apoptosis induction induced by ACOX1 downregulation. Also, overexpression of ACOX1 significantly reduced stability of p73 protein thereby reducing p73 expression. Thus, our study indicated that suppression of ACOX1 could be a novel and effective approach for treatment of lymphoma. [BMB Reports 2019; 52(9): 566-571].	0
BACKGROUND:Liddle syndrome (LS), an autosomal dominant disorder, is a common monogenic hypertension in pediatrics. In this study, we reported a novel SCNN1G variant in a Chinese family with pediatric LS, and conduct a systematic review of epithelial sodium channel (ENaC)-gene-positive LS cases to conclude the clinical genetic features of LS in childhood. METHODS:Next-generation sequencing and in silico analysis were performed in the proband to discover candidate variants. Sanger sequencing was used to identify the predicted likely pathogenic variant. LS patients in this family were treated with amiloride. The Medline database was searched to summarize clinical features of pediatric LS cases whose age at genetic diagnosis was not more than 18 years. RESULTS:Genetic analysis identified a novel SCNN1G missense variant (c.1874C>T, p.Pro625Leu) in the proband with LS in childhood. In silico analysis revealed this heterozygous variant was highly conserved and deleterious. A total of 38 publications described pediatric LS associated with 25 pathogenic variants in SCNN1B and SCNN1G in 54 children. Despite the phenotypic heterogeneity, early-onset hypertension is the most common feature. All LS patients in this family or the reviewed cases showed significantly improvements in hypertension and hypokalemia after treatment with ENaC inhibitors. CONCLUSIONS:This study identified a novel SCNN1G missense variant in a patient with pediatric LS, expanding the genetic spectrum of SCNN1G and demonstrating the PY motif of γ-ENaC as a potential mutant region. Early identification and specific management of LS in children and adolescents are important to prevent the development of hypertensive end-organ disease.	0
Distinction of paraganglioma (PGL) from epithelial neuroendocrine tumors (NETs) can be difficult as they can mimic each other by nested architecture and expression of neuro-endocrine markers. In this study we examined differential diagnostic markers in 262 PGLs (142 adrenal pheochromocytomas and 120 extra-adrenal PGLs), 9 duodenal gangliocytic PGLs and 3 cauda equina PGLs, and 286 NETs (81 GI, 78 pancreatic, 42 thoracic, 37 medullary thyroid carcinomas, and 48 high-grade NETs including 32 small cell carcinomas of lung). While keratin-expression was nearly uniform in NETs with the exception of few tumors, extensive keratin expression was seen in only one PGL (<1%), and focal expression in 5% PGLs. GATA 3 was present in >90% of PGLs but only in 2% of NETs, usually focally. Tyrosine hydroxylase (TH) was expressed in >90% of adrenal, abdominal, and thoracic PGLs but only in 37% of head and neck PGLs reflecting their variable catecholamine synthesis. Focal or occasional extensive TH-expression was detected in 10% of NETs. CDX2 was a helpful discriminator seen in 28% of pancreatic and most GI NETs but in no PGLs. SOX10 detected sustentacular cells in 85% of PGLs and 7% of NETs, while GFAP detected sustentacular cells mainly in PGLs of neck and was absent in NETs. Duodenal gangliocytic PGLs (n = 9) and all cauda equina PGLs (n = 3) expressed keratins, lacked GATA3, showed no or minimal TH expression as some NETs, and contained SOX10 and S100 protein-positive spindle cells negative for GFAP. Ganglion-like epithelioid cells were keratin-positive and negative for TH and SOX10 differing from true ganglion cells. We conclude that duodenal gangliocytic and cauda equina PGLs have a NET-like immunoprofile and differ from ordinary PGLs. NETs can be distinguished from PGLs by their expression of keratins and general lack of GATA3, TH, and GFAP-positive sustentacular cells, and sometimes by expression of CDX2 or TTF1.	0
Background: X-linked Charcot-Marie-Tooth type 1 (CMTX1) is the second most frequent form of CMT, which is caused by mutations in the gap junction beta 1 gene (GJB1) coding for connexin 32 protein. In addition to typical peripheral neuropathy, central nervous system (CNS) involvement in patients with CMTX1 has been reported as a special feature, but female patients are rarely affected. Case presentation: We describe a 29-year-old female who had a history of two cesarean deliveries. After each delivery, she presented transient and recurrent slurred speech and limb weakness. Magnetic resonance imaging (MRI) showed diffuse abnormal signals in the corpus callosum, posterior limbs of bilateral internal capsule, and centrum semiovale. Electromyogram showed sensorimotor peripheral neuropathy with the characteristics of intermediate CMT. The C.622G>A mutation (p.Glu208Lys) in the GJB1 gene was detected by PCR-sequencing. Conclusion: The diagnosis of CMTX1 should be considered, even in female patients, when the disease presents with recurrent stroke-like symptoms and abnormal white matter signals on MRI. The puerperium after delivery may be one of the precipitating factors.	0
To date, 70 different TGFBI mutations that cause epithelial-stromal corneal dystrophies have been described. At present one commercially available test examines for the five most common of these mutations: R124H, R124C, R124L, R555W, and R555Q. To expand the capability of identifying the causative mutation in the remaining cases, 57 mutations would need to be added. The aim of this study was to obtain a better understanding of the worldwide distribution and population differences of TGFBI mutations and to assess which mutations could be included or excluded from any potential assay. A total of 184 published papers in Human Gene Mutation Database (HGMD) and PubMed from 34 countries worldwide reporting over 1600 corneal dystrophy cases were reviewed. Global data from 600,000 samples using the commercially available test were analyzed. Case studies by University College of London (UCL), Moorfield's Corneal Dystrophy Study data and 19 samples from patients with clinical abnormality or uncertainty for which the current test detected no mutation were used to predict an achievable detection rate. Data from the literature search showed no difference in the spectrum and frequency of each mutation in different populations or geographical locations. According to our analysis, an increase to the worldwide detection rate in all populations from 75 to 90% could be achieved by the addition of six mutations-H626R, A546D, H572R, G623D, R124S, and M502V-to the currently available test and that may be beneficial for LASIK pre-screening worldwide.	0
In 1993, Jabs et al. were the first to describe a genetic origin of craniosynostosis. Since this discovery, the genetic causes of the most common syndromes have been described. In 2015, a total of 57 human genes were reported for which there had been evidence that mutations were causally related to craniosynostosis. Facilitated by rapid technological developments, many others have been identified since then. Reviewing the literature, we characterize the most common craniosynostosis syndromes followed by a description of the novel causes that were identified between January 2015 and December 2017.	0
Purpose:To describe two cases of retinal artery occlusion followed by contralateral amaurosis fugax associated with eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome). Observations:Case 1 is a 57 year-old male who presented with transient vision loss in the right eye two weeks after a cilioretinal artery occlusion in the left eye. Evaluation eventually led to a diagnosis of EGPA. The patient was treated with high-dose steroids followed by systemic immunomodulatory therapy. Vision in the right eye recovered to 20/20 with no further episodes of vision loss. Case 2 is a 55 year-old male with a known diagnosis of EGPA who presented with transient vision loss in the right eye four weeks after a central retinal artery occlusion of the left eye. This patient also successfully recovered vision in the right eye after treatment with high-dose steroids following a change in his systemic immunomodulatory therapy. Conclusions and Importance:While ANCA-vasculitides are an uncommon cause of retinal artery occlusion and amaurosis fugax, it is important that they remain in the differential diagnosis, as good visual outcomes can be achieved with prompt initiation of appropriate therapies.	0
BACKGROUND:Granular cell tumor (GCT) of the thyroid is a rare benign tumor of Schwann cell origin with a favorable prognosis and only 10 cases have been reported so far in scientific literature. The present case study describes the first case of recurrent thyroid GCT. CASE PRESENTATION:Our case describes a 20-year-old woman who had undergone lobectomy for GCT of the thyroid 4 years ago. Hematoxylin-eosin (HE) staining revealed that the lesion was composed of epithelioid cells with an abundance of eosinophilic granular cytoplasm. Immunohistochemical analysis showed that tumor cells tested positive for S-100 protein and negative for desmin. Both histological and immunohistochemical analyses supported the diagnosis of recurrent GCT of the thyroid. CONCLUSIONS:Our case suggested that a tumor-free margin excision and post-operative follow-up are necessary for the treatment of GCT of the thyroid.	0
White sponge nevus (WSN) is an interesting hereditary oral mucosal disorder that commonly manifests as bilaterally symmetrical, thickened white, corrugated or velvety, diffuse plaques that predominantly affects the buccal mucosa. The lesions may develop at birth or later in childhood or adolescence. Because it is asymptomatic and benign, WSN requires no treatment. Recognition of this disorder is important due to its potential confusion with other lesions that may be found in the oral cavity. Emphasis should be given to the early and correct diagnosis of this disorder to avoid unnecessary treatment. This report presents three affected members of a single family.	0
BACKGROUND:Deletion of the long (q) arm of chromosome 18 causes a rare genetic disease termed 18q- syndrome. This syndrome has varying clinical presentation, depending on the extent of the deletion and the percentage of cells with abnormal chromosomes. One of the most common disorders in children affected by the disease is short stature, usually associated with growth hormone deficiency. Numerous reports on patients with 18q- syndrome show growth hormone treatment has significant therapeutic benefits, not only in terms of final body height but also cognitive functions and psychosocial development. CASE PRESENTATION:Here we describe the case of a 10-year-old girl with 18q- syndrome treated with recombinant human growth hormone from the age of 2. This is the first report of such a patient in Poland. After 8 years of observation, the child showed a clear benefit from recombinant human growth hormone treatment in terms of height and possibly mental development. The girl remains under cardiac care due to congenital heart disease and under neurological care for epilepsy. CONCLUSIONS:This case indicates the need for early diagnosis and multidisciplinary action to achieve satisfactory quality of life in patients with 18q- syndrome.	0
Data regarding the epidemiology of callosal anomalies are contradictory. We performed a population-based retrospective survey to study the birth prevalence and clinical features of agenesis/hypoplasia of the corpus callosum and accompanying central nervous system and somatic abnormalities in southeastern Hungary between July 1, 1992 and June 30, 2006. Among 185,486 live births, 38 patients (26 boys and 12 girls) manifested agenesis/hypoplasia of the corpus callosum, corresponding to a prevalence of 2.05 per 10,000 live births (95% confidence interval, 1.4-2.7). Callosal anomalies were isolated in 18 patients, and were associated with other central nervous system malformations in five children. Both central nervous system and noncentral nervous system abnormalities were evident in seven patients, whereas callosal dysgenesis was accompanied only by somatic anomalies in eight children. Five of 18 patients with isolated agenesis/hypoplasia of the corpus callosum remained asymptomatic. Developmental delay, intellectual disability, or epilepsy occurred in all patients, except one, when callosal anomalies were combined with other brain or somatic abnormalities. Five patients with multiplex malformations died. Callosal anomalies form a clinically significant and relatively frequent group of central nervous system malformations.	1
Spastic paraplegia type 4 (SPG4) is caused by mutations of the SPAST gene and is the most common form of autosomal-dominantly inherited pure hereditary spastic paraplegia (HSP). We herein report a Japanese patient with SPG4 with a confirmed de novo mutation of SPAST. On exome sequencing and Sanger sequencing, we identified the heterozygous missense mutation p.R460L in the SPAST gene. This mutation was absent in the parents, and the paternity and maternity of the parents were both confirmed. The patient showed a pure SPG4 phenotype with an infantile onset. This study may expand the clinical and genetic findings for SPG4.	0
In the pregnant patient, hypotonic polyuria in the setting of elevated serum osmolality and polydipsia should narrow the differential to causes related to diabetes insipidus (DI). Gestational DI, also called transient DI of pregnancy, is a distinct entity, unique from central DI or nephrogenic DI which may both become exacerbated during pregnancy. These three different processes relate to vasopressin, where increased metabolism, decreased production or altered renal sensitivity to this neuropeptide should be considered. Gestational DI involves progressively rising levels of placental vasopressinase throughout pregnancy, resulting in decreased endogenous vasopressin and resulting hypotonic polyuria worsening through the pregnancy. Gestational DI should be distinguished from central and nephrogenic DI that may be seen during pregnancy through use of clinical history, urine and serum osmolality measurements, response to desmopressin and potentially, the newer, emerging copeptin measurement. This review focuses on a brief overview of osmoregulatory and vasopressin physiology in pregnancy and how this relates to the clinical presentation, pathophysiology, diagnosis and management of gestational DI, with comparisons to the other forms of DI during pregnancy. Differentiating the subtypes of DI during pregnancy is critical in order to provide optimal management of DI in pregnancy and avoid dehydration and hypernatremia in this vulnerable population.	0
BACKGROUND:Neural tube defects (NTDs) are failure of neural tube closure, which includes multiple central nervous system phenotypes. More than 300 mouse mutant strains exhibits NTDs phenotypes and give us some clues to establish association between biological functions and subphenotypes. However, the knowledge about association in human remains still very poor. METHODS:High throughput targeted genome DNA sequencing were performed on 280 neural tube closure-related genes in 355 NTDs cases and 225 ethnicity matched controls, RESULTS: We explored that potential damaging rare variants in genes functioning in chromatin modification, apoptosis, retinoid metabolism and lipid metabolism are associated with human NTDs. Importantly, our data indicate that except for planar cell polarity pathway, craniorachischisis is also genetically related with chromatin modification and retinoid metabolism. Furthermore, single phenotype in cranial or spinal regions displays significant association with specific biological function, such as anencephaly is associated with potentially damaging rare variants in genes functioning in chromatin modification, encephalocele is associated with apoptosis, retinoid metabolism and one carbon metabolism, spina bifida aperta and spina bifida cystica are associated with apoptosis; lumbar sacral spina bifida aperta and spina bifida occulta are associated with lipid metabolism. By contrast, complex phenotypes in both cranial and spinal regions display association with various biological functions given the different phenotypes. CONCLUSIONS:Our study links genetic variant to subphenotypes of human NTDs and provides a preliminary but direct clue to investigate pathogenic mechanism for human NTDs.	0
OBJECTIVE: To describe prevalence, prenatal diagnosis and epidemiological data on oesophageal atresia from 23 well-defined European regions and compare the prevalence between these regions. DESIGN: Population-based study using data from a large European database for surveillance of congenital anomalies (EUROCAT) for two decades (1987-2006). SETTINGS: Twenty-three participating registries based on multiple sources of information including information about live births, fetal deaths with gestational age ≥20 weeks and terminations of pregnancy. PATIENTS: 1222 cases of oesophageal atresia in a population of 5 019 804 births. RESULTS: The overall prevalence was 2.43 cases per 10 000 births (95% CI 2.30 to 2.57). There were regional differences in prevalence ranging from 1.27 to 4.55. Prenatal detection rates varied by registry from >50% of cases to <10% of cases. A total of 546 cases (44.7%) had an isolated oesophageal anomaly, 386 (31.6%) were multiple malformed and 290 (23.7%) had an association or a syndrome. There were 1084 live born cases (88.7%), 43 cases were fetal deaths and 95 cases were terminations of pregnancy. One-week survival for live births was 86.9% and 99.2% if the gestational age was ≥38 weeks and isolated oesophageal atresia was present. Males accounted for 57.3% of all cases and 38.5% of live born cases were born with gestational age <37 weeks. CONCLUSION: There were regional differences in prevalence of oesophageal atresia in Europe. Half of all cases had associated anomalies. Prenatal detection rate increased from 26% to 36.5% over the two decades. Survival in infants with isolated oesophageal atresia born at term is high.	1
This review provides an updated summary of the state of our knowledge of the genetic contributions to the pathogenesis of congenital heart disease. Since 2007, when the initial American Heart Association scientific statement on the genetic basis of congenital heart disease was published, new genomic techniques have become widely available that have dramatically changed our understanding of the causes of congenital heart disease and, clinically, have allowed more accurate definition of the pathogeneses of congenital heart disease in patients of all ages and even prenatally. Information is presented on new molecular testing techniques and their application to congenital heart disease, both isolated and associated with other congenital anomalies or syndromes. Recent advances in the understanding of copy number variants, syndromes, RASopathies, and heterotaxy/ciliopathies are provided. Insights into new research with congenital heart disease models, including genetically manipulated animals such as mice, chicks, and zebrafish, as well as human induced pluripotent stem cell-based approaches are provided to allow an understanding of how future research breakthroughs for congenital heart disease are likely to happen. It is anticipated that this review will provide a large range of health care-related personnel, including pediatric cardiologists, pediatricians, adult cardiologists, thoracic surgeons, obstetricians, geneticists, genetic counselors, and other related clinicians, timely information on the genetic aspects of congenital heart disease. The objective is to provide a comprehensive basis for interdisciplinary care for those with congenital heart disease.	0
OBJECTIVE:To evaluate infant survival according to the Doppler pattern of impedance to blood flow in the umbilical arteries (UAs) prior to laser surgery, in pregnancies with twin-to-twin transfusion syndrome (TTTS). METHODS:This was a retrospective study of women with a monochorionic diamniotic twin pregnancy who underwent laser surgery for TTTS between January 2012 and May 2018 at a single institution. Absolute intertwin difference in UA pulsatility index (DUAPI) was measured within 48 h prior to laser surgery. Twins with intermittent or persistent absent/reversed end-diastolic flow (EDF) in the UA (UA-EDF) were analyzed separately. Survival of both or at least one infant at birth and at 30 days postpartum was compared between pregnancies with an intertwin DUAPI of ≥ 0.4 and those with an intertwin DUAPI of < 0.4, as well as between fetuses with intermittent and those with persistent absent/reversed UA-EDF. Parametric and non-parametric tests were used for analysis. Regression analysis was performed to determine if intertwin DUAPI and intermittent or persistent absent/reversed UA-EDF were associated independently with infant survival, while controlling for gestational age at delivery, Quintero stage and other important confounding variables. RESULTS:Of 231 TTTS pregnancies that underwent laser surgery during the study period, UA Doppler information could be retrieved for 206 and delivery information was available for 184, which comprised the study population. Rates of double-twin survival at birth were significantly higher in pregnancies with an intertwin DUAPI of < 0.4 than in those with an intertwin DUAPI of ≥ 0.4 (83.9% (78/93) vs 50.0% (12/24); P < 0.001). Double-infant survival at birth was higher in pregnancies with intermittent compared to those with persistent absent/reversed UA-EDF (73.0% (27/37) vs 36.7% (11/30); P = 0.003). Regression analysis demonstrated that an intertwin DUAPI of < 0.4 was associated with increased survival of both twins at delivery (P < 0.001) and at 30 days postpartum (P = 0.002), as well as increased survival of at least one twin at delivery (P = 0.009). Similarly, intermittent absent/reversed UA-EDF was associated with increased survival of both twins at delivery (P = 0.007) and at 30 days after birth (P = 0.015). CONCLUSIONS:Evaluation of intertwin differences in UA impedance to blood flow as well as identification of intermittent or persistent absent or reversed UA-EDF prior to laser surgery could help in the prediction of double-infant survival at birth and to 30 days in twin pregnancies with TTTS. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.	0
BACKGROUND:Intellectual disability (ID) is a heterogeneous neurodevelopmental disorder with a complex genetic underpinning in its etiology. Chromosome microarray (CMA) is recommended as the first-tier diagnostic test for ID due to high detection rate of copy number variation (CNV). METHODS:To identify an appropriate clinical detection scheme for ID in Han Chinese patients, whole genome low-coverage sequencing was performed as the first-tier diagnostic test, and medical exome sequencing (MES) as the second-tier diagnostic test for patients with negative results of CNVs. RESULTS:A total of 19 pathogenic CNVs in 16/95(16.84%) ID patients and 10 pathogenic single-nucleotide variations (SNVs), including 6 novel mutations in 8/95(8.42%) ID patients were identified on whom no pathogenic CNVs were discovered. The detection rate of CNVs in ID with multiple congenital anomalies (MCA) subgroup was significantly higher than ID with autism spectrum disorders and other IDs subgroups. And the single-nucleotide variations showed a higher occurrence rate in the other IDs subgroup. CONCLUSIONS:There were differences in the diagnostic yields of different variation types among the three ID subgroups. Our findings provided a new perspective on appropriate clinical detection scheme in different ID subgroups based on statistically significant differences among the three ID subgroups. The application of whole genome low-coverage sequencing as the first-tier diagnostic test for ID with MCA subgroup and MES as the first-tier diagnostic test for other ID subgroup was considered as an efficient clinical detection scheme.	0
Herein, a new fluorimetric procedure for analysis of milnacipran in its bulk, tablets dosage forms as well as biological human samples as plasma and urine. The suggested method relay on the construction of a derivative having strong fluorescence called dihydropyridine derivative. This derivative resulted from the interaction of the primary amino group in the studied drug and acetylacetone/formaldehyde in Mcllvaine buffer (pH 5). The fluorescent dihydropyridine derivative was measured at 470 nm. The influences of the experimental variables namely pH, reagent concentration and temperature were examined and optimized. The calibration curve showed linearity over the range of 0.15-1.25 μg mL-1 of milancipran with R2 of 0.9998. The detection limit was 0.02 μg mL-1 and the determination limit was 0.07 μg mL-1 . The developed procedure was successfully used in the assay of the studied drug in Avermilan® tablets with excellent selectivity. In addition, the reaction was applied for estimating the drug in spiked human plasma and urine with mean percentage recoveries of 100.04 ± 1.61 and 99.78 ± 0.81% for urine and plasma, respectively.	0
In most instances, delayed emergence from anesthesia is attributed to residual anesthetic or analgesic medications. However, delayed emergence can be secondary to unusual causes and present diagnostic dilemmas. Data from clinical studies is scarce and most available published material is comprised of case reports. In this review, we summarize and discuss less common and difficult to diagnose reasons for delayed emergence and present cases from our own experience or reference published case reports/case series. The goal is to draw attention to less common reasons for delayed emergence, identify patient populations that are potentially at risk and to help anesthesiologists identifying a possible cause why their patient is slow to wake up.	0
Topical minoxidil is a well-known and often-utilized drug in dermatological practice for the treatment of alopecia. It was approved by the United States Food and Drug Administration for the treatment of androgenetic alopecia in 1988. Since its approval, minoxidil has been used off-label for the treatment of many other types of alopecia, with minimal formal evidence of efficacy. Conditions for which the use of topical minoxidil has been reported include telogen effluvium, alopecia areata (AA), scarring alopecia, eyebrow hypotrichosis, monilethrix, and chemotherapy-induced alopecia (CIA). The evidence for the use of minoxidil in each condition is derived from a variety of studies, including clinical trials, case series, and case reports. A comprehensive review of the literature indicates that while minoxidil is routinely used in the management of many alopecic conditions, there is mixed evidence for its efficacy. For certain conditions, including AA and most scarring alopecias, the evidence seems to be inconclusive. For others, such as eyebrow hypotrichosis, monilethrix, early traction alopecia, and CIA, there is more support for the efficacy of minoxidil. Although the favorable safety profile of minoxidil is established in adults, its use in the treatment of pediatric alopecia may require heightened monitoring and patient education.	0
BACKGROUND:Fertility in men with hypospadias may be affected due to anatomical, surgical, or etiological factors and associated conditions. Fertility is further influenced by psychosocial and genetic factors, often shared within families. OBJECTIVE:To evaluate fertility in men born with hypospadias and assess confounding by familial factors. MATERIALS AND METHODS:A population-based cohort of 1.2 million men born in Sweden 1964-1998, identified through national demographic and healthcare registers. Associations between hypospadias and (a) being a biological father, (b) conceiving through ART, and (c) diagnosis of male infertility were investigated in the full cohort with logistic regression models and Cox proportional hazard models, expressed as odds ratios (ORs) and hazard ratios (HRs), respectively, with 95% confidence intervals (CIs). A stratified proportional hazard model, conditional on sibling group, was used to control for shared familial confounding. RESULTS:Men with hypospadias, as a whole group, had a lower probability of having biological children (adjusted HR 0.87, 95% CI 0.83-0.92). A significant association was present in both distal (adjusted HR 0.90, 95% CI 0.85-0.96) and proximal hypospadias (HR 0.59, 95% CI 0.42-0.81). Men with hypospadias more often became fathers through ART, regardless of concomitant cryptorchidism. The initial association between hypospadias and the diagnosis of infertility disappeared in sensitivity analyses excluding cryptorchidism. DISCUSSION:Men with hypospadias displayed lower birthrates as compared to their brothers and the general population. Mere birthrates may, however, be a questionable measure of fertility in a population using family planning. However, men with hypospadias were also at higher risk of reproducing through ART and did more often receive a diagnosis of male infertility. Altogether, these findings indicate impaired fertility in men with hypospadias. CONCLUSIONS:Fertility in men with hypospadias is impaired, as shown by lower birthrates, increased use of ART and higher risk of receiving a diagnosis of male infertility.	0
Hyperphosphatasia with mental retardation syndrome (HPMRS), an autosomal-recessive form of intellectual disability characterized by facial dysmorphism, seizures, brachytelephalangy, and persistent elevated serum alkaline phosphatase (hyperphosphatasia), was recently shown to be caused by mutations in PIGV, a member of the glycosylphosphatidylinositol (GPI)-anchor-synthesis pathway. However, not all individuals with HPMRS harbor mutations in this gene. By exome sequencing, we detected compound-heterozygous mutations in PIGO, a gene coding for a membrane protein of the same molecular pathway, in two siblings with HPMRS, and we then found by Sanger sequencing further mutations in another affected individual; these mutations cosegregated in the investigated families. The mutant transcripts are aberrantly spliced, decrease the membrane stability of the protein, or impair enzyme function such that GPI-anchor synthesis is affected and the level of GPI-anchored substrates localized at the cell surface is reduced. Our data identify PIGO as the second gene associated with HPMRS and suggest that a deficiency in GPI-anchor synthesis is the underlying molecular pathomechanism of HPMRS.	0
The coordination of tissue function is mediated by gap junctions (GJs) that enable direct cell-cell transfer of metabolic and electric signals. GJs are formed by connexins of which Cx43 is most widespread in the human body. In the brain, Cx43 GJs are mostly found in astroglia where they coordinate the propagation of Ca(2+) waves, spatial K(+) buffering, and distribution of glucose. Beyond its role in direct intercellular communication, Cx43 also forms unapposed, non-junctional hemichannels in the plasma membrane of glial cells. These allow the passage of several neuro- and gliotransmitters that may, combined with downstream paracrine signaling, complement direct GJ communication among glial cells and sustain glial-neuronal signaling. Mutations in the GJA1 gene encoding Cx43 have been identified in a rare, mostly autosomal dominant syndrome called oculodentodigital dysplasia (ODDD). ODDD patients display a pleiotropic phenotype reflected by eye, hand, teeth, and foot abnormalities, as well as craniofacial and bone malformations. Remarkably, neurological symptoms such as dysarthria, neurogenic bladder (manifested as urinary incontinence), spasticity or muscle weakness, ataxia, and epilepsy are other prominent features observed in ODDD patients. Over 10 mutations detected in patients diagnosed with neurological disorders are associated with altered functionality of Cx43 GJs/hemichannels, but the link between ODDD-related abnormal channel activities and neurologic phenotype is still elusive. Here, we present an overview on the nature of the mutants conveying structural and functional changes of Cx43 channels and discuss available evidence for aberrant Cx43 GJ and hemichannel function. In a final step, we examine the possibilities of how channel dysfunction may lead to some of the neurological manifestations of ODDD.	0
Peroxisomes exist in most cells, where they participate in lipid metabolism, as well as scavenging the reactive oxygen species (ROS) that are produced as by-products of their metabolic functions. In certain tissues such as the liver and kidneys, peroxisomes have more specific roles, such as bile acid synthesis in the liver and steroidogenesis in the adrenal glands. In the brain, peroxisomes are critically involved in creating and maintaining the lipid content of cell membranes and the myelin sheath, highlighting their importance in the central nervous system (CNS). This review summarizes the peroxisomal lifecycle, then examines the literature that establishes a link between peroxisomal dysfunction, cellular aging, and age-related disorders that affect the CNS. This review also discusses the gap of knowledge in research on peroxisomes in the CNS.	0
N-glycanase 1 deficiency is a congenital disorder of deglycosylation, which has been diagnosed in 27 patients, including 2 of them from Poland. The most characteristic symptoms include global developmental disability, hyperkinetic movement disorder, hypo-/alacrimia, and elevated serum transaminases. We reported on a patient in whom the liver biopsy done at the age of 3 years revealed the presence of steatosis, fibrosis, and an amorphous periodic acid-Schiff staining positive diastases-digested material in the cytoplasm.	0
Limb-girdle muscular dystrophy 2A (LGMD2A) is considered to be the most frequent LGMD. Our study surveyed an area in northeastern Italy where an almost complete ascertainment was possible. To identify LGMD2A patients we used a new diagnostic approach, including several molecular and biochemical methods. In 84 screened patients from northeastern Italy, we identified 39 LGMD2A patients, the prevalence of LGMD2A being 9.47 per million. In the Venezia district it appears higher than in other districts of the Veneto region, and in the Friuli region it is three times higher than in Veneto, due to the recurrence of single mutation. Haplotype analysis suggested a founder effect. The population from Venezia and Friuli has a higher risk of being heterozygote for these two mutant alleles than people from the rest of northeastern Italy. Our results indicate that LGMD2A is one of the most frequent autosomal recessive disorders, thus finding its molecular characterization becoming increasingly important.	1
BACKGROUND:Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is a common disorder of fatty acid oxidation in north west Europe. It is very variable in its clinical consequences and is believed to be considerably underdiagnosed. OBJECTIVE:To investigate the diagnosis and outcome of MCAD deficiency in the UK. METHOD:A prospective surveillance study through the British Paediatric Surveillance Unit. RESULTS:Of 62 affected individuals identified, 57 were from England, giving an incidence of 4.5 cases/100,000 births. Forty six cases presented with an acute illness (10 of whom died), 13 cases were identified because of family history, and three for other reasons. Six of the survivors were neurologically impaired. CONCLUSIONS:Despite increased clinical awareness, the mortality and morbidity from MCAD deficiency remain high. The frequency and severity of the disease support the case for the introduction of universal neonatal screening in England and Scotland.	1
OBJECTIVE:Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and multisystem abnormalities. Many TTD patients have a defect in known DNA repair genes. This report systematically evaluates the ocular manifestations of the largest-to-date cohort of TTD patients and xeroderma pigmentosum (XP)/TTD patients. DESIGN:Case series. PARTICIPANTS:Thirty-two participants, ages 1 to 30 years, referred to the National Eye Institute for examination from 2001 to 2010; 25 had TTD and 7 had XP/TTD. METHODS:Complete, age- and developmental stage-appropriate ophthalmic examination. MAIN OUTCOME MEASURES:Visual acuity (VA), best-corrected VA, ocular motility, state of the ocular surface and corneal endothelial cell density, corneal diameter, and lens assessment. RESULTS:Developmental abnormalities included microcornea (44% TTD), microphthalmia (8% TTD, 14% XP/TTD), nystagmus (40% TTD), and infantile cataracts (56% TTD, 86% XP/TTD). Corrective lenses were required by 65% of the participants, and decreased best-corrected VA was present in 28% of TTD patients and 71% of XP/TTD patients. Degenerative changes included dry eye (32% TTD, 57% XP/TTD) and ocular surface disease identified by ocular surface staining with fluorescein (32% TTD) that usually are exhibited by much older patients in the general population. The 2 oldest TTD patients exhibited clinical signs of retinal/macular degeneration. Four XP/TTD patients presented with corneal neovascularization. CONCLUSIONS:These TTD and XP/TTD study participants had a wide variety of ocular findings including refractive error, infantile cataracts, microcornea, nystagmus, and dry eye/ocular surface disease. Although many of these can be ascribed to abnormal development--likely owing to abnormalities in basal transcription of critical genes--patients may also have a degenerative course. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosures may be found after the references.	0
Circular RNAs (circRNAs) are ubiquitously expressed, covalently closed rings, produced by pre-mRNA splicing in a reversed order during post-transcriptional processing. Circularity endows 3'-5'-linked circRNAs with stability and resistance to exonucleolytic degradation which raises the question whether circRNAs may be relevant as potential therapeutic targets or agents. High stability in biological systems is the most remarkable property and a major criterion for why circRNAs could be exploited for a range of RNA-centred medical applications. Even though various biological roles and regulatory functions of circRNAs have been reported, their in-depth study is challenging because of their circular structure and sequence-overlap with linear mRNA counterparts. Moreover, little is known about their role in viral infections and in antiviral immune responses. We believe that an in-depth and detailed understanding of circRNA mediated viral protein regulations will increase our knowledge of the biology of these novel molecules. In this review, we aimed to provide a comprehensive basis and overview on the biogenesis, significance and regulatory roles of circRNAs in the context of antiviral immune responses and viral infections including hepatitis C virus infection, hepatitis B virus infection, hepatitis delta virus infection, influenza A virus infection, Epstein-Barr virus infection, kaposi's sarcoma herpesvirus infection, human cytomegalovirus infection, herpes simplex virus infection, human immunodeficiency virus infection, porcine epidemic diarrhoea virus infection, ORF virus infection, avian leukosis virus infection, simian vacuolating virus 40 infection, transmissible gastroenteritis coronavirus infection, and bovine viral diarrhoea virus infection. We have also discussed the critical regulatory role of circRNAs in provoking antiviral immunity, providing evidence for implications as therapeutic agents and as diagnostic markers.	0
This article provides an overview of selected genetic skin conditions where multiple inherited cutaneous tumours are a central feature. Skin tumours that arise from skin structures such as hair, sweat glands and sebaceous glands are called skin appendage tumours. These tumours are uncommon, but can have important implications for patient care. Certain appendageal tumours, particularly when multiple lesions are seen, may indicate an underlying genetic condition. These tumours may not display clinical features that allow a secure diagnosis to be made, necessitating biopsy and dermatopathological assessment. Coupled with robust clinical assessment, biopsy findings can guide genetic testing as, increasingly, the causative genes are known for these conditions. Here we review illustrative examples of appendageal tumours and relevant advances made in genetic discovery, and suggest when referral to a geneticist may need to be considered.	0
Inflammation of renal interstitium and uveal tissue establishes the two components of tubulointerstitial nephritis and uveitis (TINU) syndrome. Although believed to occur more frequently in young females, a broad spectrum of patients can be affected. Both renal and eye disease can be asymptomatic and may not manifest simultaneously, having independent progressions. Renal disease manifests as acute kidney injury and may cause permanent renal impairment. Eye inflammation can manifest in different anatomical forms, most commonly as bilateral anterior uveitis and may progress to a chronic course. TINU syndrome accounts for approximately 1%-2% of uveitis in tertiary referral centres. A literature review covering the clinical features, pathogenesis, diagnosis and treatment is presented.	0
A 19-year-old African American woman presented to the emergency department with a history of left upper quadrant pain for a week, associated with nausea, malaise, loss of appetite, subjective fevers and chills. Her family history is significant for thalassemia in her maternal aunt, and hereditary spherocytosis in her brother, sister and cousin. A contrast-enhanced CT scan of the abdomen and pelvis revealed massive splenomegaly and multiple splenic infarcts. On the second day of admission, she developed a fever of 103°F. Further evaluation revealed acute Epstein-Barr virus (EBV) infection and hereditary spherocytosis. Her condition improved after 4 days on piperacillin/tazobactam, intravenous fluids, analgesics and antipyretics. Our case report describes a thorough clinical evaluation of a patient with fever, anaemia, massive splenomegaly and multiple splenic infarcts. It highlights the need for careful interpretation of multiple positive IgM results on viral serological testing that often accompanies acute EBV infections.	0
Homocysteine and related thiols (cysteine, cysteinylglycine, and glutathione) in the urine of a cystathionine β-synthase (CBS)-deficient mouse model were quantified using hydrophilic interaction chromatography with fluorescence detection. Urine samples were incubated with tris(2-carboxyethyl) phosphine to reduce disulfide bonds into thiols. After deproteinization, thiols were fluorescently derivatized with ammonium 7-fluoro-2,1,3-benzoxadiazole-4-sulfonate (SBD-F). Homocysteine, cysteine, cysteinylglycine, and glutathione in mouse urine were analyzed using an amide-type column with a mobile phase of acetonitrile/120 mM ammonium formate buffer (pH 3.0) (81:19). The developed method was well-validated. Thiol concentrations in the urine of CBS-wild type (-WT), -heterozygous (-Hetero), and -knockout (-KO) mice were quantified using the developed method. As expected, total homocysteine concentration in CBS-KO mice was significantly higher than that in CBS-WT and CBS-Hetero mice. The developed method shows promise for diagnoses in preclinical and clinical studies.	0
There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers.	0
This review provides an updated summary of the state of our knowledge of the genetic contributions to the pathogenesis of congenital heart disease. Since 2007, when the initial American Heart Association scientific statement on the genetic basis of congenital heart disease was published, new genomic techniques have become widely available that have dramatically changed our understanding of the causes of congenital heart disease and, clinically, have allowed more accurate definition of the pathogeneses of congenital heart disease in patients of all ages and even prenatally. Information is presented on new molecular testing techniques and their application to congenital heart disease, both isolated and associated with other congenital anomalies or syndromes. Recent advances in the understanding of copy number variants, syndromes, RASopathies, and heterotaxy/ciliopathies are provided. Insights into new research with congenital heart disease models, including genetically manipulated animals such as mice, chicks, and zebrafish, as well as human induced pluripotent stem cell-based approaches are provided to allow an understanding of how future research breakthroughs for congenital heart disease are likely to happen. It is anticipated that this review will provide a large range of health care-related personnel, including pediatric cardiologists, pediatricians, adult cardiologists, thoracic surgeons, obstetricians, geneticists, genetic counselors, and other related clinicians, timely information on the genetic aspects of congenital heart disease. The objective is to provide a comprehensive basis for interdisciplinary care for those with congenital heart disease.	0
Perlecan, a highly conserved and ubiquitous basement membrane heparan sulfate proteoglycan, is essential for life, inasmuch as its absence results in embryonic lethality in mice and C. elegans, and neonatal lethality in humans. Perlecan plays an essential role in vasculogenesis and chondrogenesis, as well as in pathological states where these processes are maladapted. Although a large body of evidence supports a pro-angiogenic role for perlecan, recent findings suggests that portions of the perlecan protein core can be antiangiogenic, requiring a further evaluation of the functioning of this complex molecule. This review is focused on the genetics of mammalian and nonmammalian perlecan, the elucidation of its novel interacting partners and its role in angiogenesis. By more fully understanding perlecan's functioning in angiogenesis, we may gain invaluable insight that could lead to therapeutic interventions in cancer and other pathologic states.	0
Tumefactive multiple sclerosis (TMS) often presents a diagnostic challenge because it can mimic neoplastic, infectious, or ischemic disease. We describe 2 patients with TMS with retinal findings of venous sheathing and bone spicule pigmentation. Mechanisms for such findings are discussed.	0
OBJECTIVE:In 2008 the European Society for the Study of Interstitial Cystitis (ESSIC) established the diagnostic criteria and classification of Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC), based on clinical features and cystoscopy results. The present study aims to assess the relevance of the endoscopic evaluation in clinically suspected cases of BPS/IC, using ESSIC criteria. METHODS:. We included all patients who underwent endoscopic evaluation between 01/01/2015 and 31/10/2019 for clinical suspicion of BPS/IC. Collected data included demographic and baseline clinical features, endoscopic appearance (prior and after hydrodistension) and bladder wall biopsy results, both defined according to ESSIC criteria. Data were cross tabulated to define ESSIC phenotypes, while subgroups and multivariate analyses were carried out to assess the influence of clinical variables on ESSIC phenotypes. RESULTS:. Fifty-two subjects were included, mainly women (92%). Median age at evaluation was 45 (32.9-58.2) years. At hydrodistension, 21 patients (42%) had positive and 29 (58%) had negative findings. Grade 2-3 glomerulations were found in 18 patients, while Hunner lesions were reported only in 1 patient. Positive results at biopsy were found in 24 pts (51.1%), while negative in 23 (48.9%). Overall, the positive and negative concordance between hydrodistension and biopsy results was 78%. No significant differences in ESSIC subtypes were found after stratification based on clinical features and at multivariate analysis. Retrospective design is the main limitation. CONCLUSION:cystoscopy with hydrodistension and biopsy do have a role in the diagnostic pathway of BPS/IC. However, results should be considered in the clinical context of the individual patient.	0
Soft-tissue sarcoma (sts) is a rare mesenchymal malignancy that accounts for less than 1% of all adult tumours. Despite the successful advancement of localized therapies such as surgery and radiotherapy, these tumours can, for many, recur-often with metastatic disease. In the advanced setting, the role of systemic therapies is modest and is associated with poor survival. With the discovery of immunotherapies in other tumour types such as melanoma and lung cancer, interest has been renewed in exploring immunotherapy in sts. The biology of some stss makes them ripe for immunotherapy intervention; for example, some stss might have chromosomal translocations resulting in pathognomonic fusion products that have been shown to express cancer/testis antigens. Here, we present a targeted review of the published data and ongoing clinical trials for immunotherapies in patients with sarcoma, which comprise immune checkpoint inhibitors, adoptive cell therapies, and cancer vaccines.	0
Mutations in MYH2 that encodes myosin heavy chain IIa cause both dominant and recessively inherited myopathies. Patients with dominantly inherited MYH2 missense mutations present with ophthalmoplegia and progressive proximal limb weakness. Muscle biopsy reveals rimmed vacuoles and inclusions, prompting this entity to initially be described as hereditary inclusion body myopathy 3. In contrast, patients with recessive MYH2 mutations have early onset, non-progressive, diffuse weakness and ophthalmoplegia. Muscle biopsy reveals near or complete absence of type 2A fibers with no vacuole or inclusion pathology. We describe a patient with childhood onset ophthalmoplegia, progressive proximal muscle weakness beginning in adolescence, and muscle biopsy with myopathic changes and rimmed vacuoles. Although this patient's disease course and histopathology is consistent with dominant MYH2 mutations, whole exome sequencing revealed a c.737 G>A p.Arg246His homozygous MYH2 variant. These findings expand the clinical and pathologic phenotype of recessive MYH2 myopathies.	0
Aggrecan, encoded by ACAN, is a major proteoglycan component of the extracellular matrix in the growth plate and articular cartilage. Aggrecan provides the hydrated gel structure important for the load-bearing properties of joints and plays a key role in cartilage and bone morphogenesis. At least 25 pathological ACAN mutations have been identified in patients with highly variable phenotypes of syndromic or non-syndromic short stature. This review provides an overview of the current understanding of ACAN and the clinical and genetic findings concerning aggrecan-associated diseases.	0
Patients with multiple myeloma (MM) accumulate adverse copy number aberrations (CNAs), gains of 1q21, and 17p deletions during disease progression. A subset of these patients develops heightened 1q12 pericentromeric instability and jumping translocations of 1q12 (JT1q12), evidenced by increased copy CNAs of 1q21 and losses in receptor chromosomes (RC). To understand the progression of these aberrations we analyzed metaphase cells of 50 patients with ≥4 CNAs of 1q21 by G-banding, locus specific FISH, and spectral karyotyping. In eight patients with ≥5 CNAs of 1q21 we identified a chromosome instability phenotype similar to that found in ICF syndrome (immunodeficiency, centromeric instability, and facial anomalies). Strikingly, the acquired instability phenotype identified in these patients demonstrates the same transient structural aberrations of 1q12 as those found in ICF syndrome, suggesting similar underlying pathological mechanisms. Four types of clonal aberrations characterize this phenotype including JT1q12s, RC deletions, 1q12-21 breakage-fusion-bridge cycle amplifications, and RC insertions. In addition, recurring transient aberrations include 1q12 decondensation and breakage, triradials, and 1q micronuclei. The acquired self-propagating mobile property of 1q12 satellite DNA drives the continuous regeneration of 1q12 duplication/deletion events. For patients demonstrating this instability phenotype, we propose the term "Jumping 1q Syndrome."	0
Hyperimmunoglobulinemia D Syndrome (HIDS) has rarely been reported in Arabs. Moreover, the simultaneous presence of mutations in MEFV and MVK segregating in the same family is exceptional. We report an Arabic girl presenting since the age of 8-years with two patterns of recurrent episodes of fever, and associated with a spectrum of clinical features suggestive of overlap between familial Mediterranean fever (FMF) and HIDS. Her 19-year old brother presented since the age of 1 year with prolonged episodes of fever and was diagnosed with HIDS at the age of 7 years based on clinical features and homozygosity for p.V377I mutation in MVK. Shorter episodes of fever and abdominal pain more consistent with FMF ensued since the age of 17 years. Genetic testing done for both patients and all other family members revealed simultaneous presence of mutations in MEFV and MVK but with a variable clinical spectrum ranging from asymptomatic to severe manifestations. Both of our patients are homozygous for p.V377I MVK mutation; the girl is a compound heterozygote for p.E148Q/p.P369S/p.R408G and p.E167D/p.F479L MEFV mutations whereas the brother is a compound heterozygote for p.E148Q/p.P369S/p.R408G and p.M680I MEFV mutations. The clinical implications of having more than one mutation in different genes of monogenic autoinflammatory diseases in the same individual are not clear but may explain atypical clinical manifestations such as the overlap features of both FMF and HIDS in this family.	0
This study aims to characterize the epidemiology of immunocompetent Primary central nervous system lymphoma (PCNSL) diagnosed 2000-2013 in Sweden.Cases were identified in the population-based Swedish Lymphoma Register. Incidence per 100 000 person-years and 95% confidence intervals (CI) were calculated, and PCNSL-specific survival was estimated using relative survival. Tests for temporal trends were performed using Poisson regression. Population incidence of all brain tumors was retrieved for comparison.With 359 identified PCNSL cases (median age 66 years), overall incidence was 0.26 (95% CI: 0.24-0.29) and the average annual increase 4% (P = .002). The increasing trend was primarily observed among elderly individuals (70+ years). Similarly, an increase in incidence of all brain tumors was noted only among the elderly. There was no significant improvement in relative survival across the study period although, among fit patients (with Eastern Cooperative Oncology Group, EGOC 0), survival plateaued 6 years after diagnosis.The increasing PCNSL incidence in the elderly was consistent with an increasing incidence of brain tumors of any type and may in part be attributable to improved diagnostics and reporting in this group. New treatment options have not yet translated into general survival improvements in a population-based setting, although the presence of long-term survivors among fit patients is encouraging.	1
A syndrome characterized by progeroid facies, multiple nevi, mild mental retardation, skin hyperextensibility, bruisability, moderate skin fragility, joint hypermobility principally in digits, is described in two unrelated patients. Electron microscopy of the skin showed some fragmentation of the elastic fibers' portion and moderate electrodensity in the amorphous portion. Since a practically identical constellation of clinical features was previously reported in three patients, the individualization of a distinct connective tissue disorder, probably autosomal dominant, with variable expressivity is concluded.	0
Four cases of Aicardi's syndrome are reported. The constant features of this syndrome are infantile spasms, chorioretinopathy, and agenesis of the corpus callosum. The chorioretinopathy appears to be a defect of the pigment epithelium and choroid without significant retinal involvement. Additional ocular features include microphthalmia, colobomas of the optic nerve and choroid, persistent pupillary membrane, and glial tissue extending from the disc. The cause of the syndrome is uncertain. It occurs only in females and is nonfamilial. A male lethal syndrome resulting from a gene on the X chromosome occurring as a spontaneous mutation has been suggested. The possible role of intrauterine infection needs further investigation.	0
The TGF-β signaling pathway controls cellular proliferation, growth and differentiation and regulates several functions of the connective tissue. Disruption of genes coding for components of the TGF-β signaling pathway or its interactors, such as fibrillin-1, has been shown to cause several human pathologies. Large deletions and non-sense mutations in TGFB2 gene have been recently described in patients with aortic aneurysm, scoliosis, arachnodactyly, chest deformities, joint hyper-flexibility, and mild intellectual disability; this condition has been called Loeys-Dietz syndrome, type 4. In this paper we describe an 18-year-old girl with borderline mental impairment, seizures, retinal degeneration, short stature, congenital hip dysplasia, severe and worsening joint hypermobility, scoliosis, progressive deformation of the long bones, aortic dilatation and platelet disorder. Molecular study of DNA by Array-CGH demonstrated four de novo microdeletions: TGFB2 is among the genes deleted and we consider it the obvious candidate for the clinical phenotype. The multiple chromosomal rearrangements detected in the current patient can be ascribed to an event of constitutional chromothripsis.	0
To report 2 cases of pediatric vitreoretinal disease in the setting of Turner's syndrome. A 4-year-old girl with Turner's syndrome was referred for evaluation of a tractional retinal detachment in the right eye. Fundoscopic examination disclosed temporal dragging of the macula in the right eye, and vascular nonperfusion in the right and left eyes. Genetic testing revealed a novel frameshift mutation in the LRP5 gene consistent with familial exudative vitreoretinopathy (FEVR). The patient was treated with laser. A 14-year-old girl with Turner's syndrome presented with nyctalopia. Dilated fundus exam disclosed peri-foveal pigmentary changes and peripheral bone spicules. Full-field electroretinography demonstrated decreased rod and cone responses, consistent with retinitis pigmentosa (RP). Vitreoretinal disease, including RP and FEVR, is rarely observed in patients with Turner's syndrome.	0
BACKGROUND:Maternal uniparental disomy of chromosome 6 (upd(6)mat) is a rare finding and its clinical relevance is currently unclear. Based on clinical data from two new cases and patients from the literature, the pathogenetic significance of upd(6)mat is delineated. METHODS:Own cases were molecularly characterized for isodisomic uniparental regions on chromosome 6. For further cases with upd(6)mat, a literature search was conducted and genetic and clinical data were ascertained. RESULTS:Comparison of isodisomic regions between the new upd(6)mat cases and those from four reports did not reveal any common isodisomic region. Among the patients with available cytogenetic data, five had a normal karyotype in lymphocytes, whereas a trisomy 6 (mosaicism) was detected prenatally in four cases. A common clinical picture was not obvious in upd(6)mat, but intrauterine growth restriction (IUGR) and preterm delivery were frequent. CONCLUSION:A common upd(6)mat phenotype is not obvious, but placental dysfunction due to trisomy 6 mosaicism probably contributes to IUGR and preterm delivery. In fact, other clinical features observed in upd(6)mat patients might be caused by homozygosity of recessive mutations or by an undetected trisomy 6 cell line. Upd(6)mat itself is not associated with clinical features, and can rather be regarded as a biomarker. In case upd(6)mat is detected, the cause for the phenotype is identified indirectly, but the UPD is not the basic cause.	0
Purpose:To report a case of non-paraneoplastic autoimmune retinopathy (npAIR) treated with intravenous immunoglobulin (IVIG). Case report:A 12-year-old boy presented with progressive visual field loss, nyctalopia, and flashing for three months. He had suffered from common cold two weeks before the onset of these symptoms. On the basis of clinical history and paraclinical findings, he was diagnosed with npAIR, and IVIG without immunosuppressive therapy was started. During the one-year follow-up period after the first course of IVIG, flashing disappeared completely. Visual acuity remained 10/10, but nyctalopia did not improve. Multimodal imaging showed no disease progression. Conclusion:Although established retinal degenerative changes seem irreversible in npAIR, IVIG may be a suitable choice to control the disease progression.	0
A syndrome is described, consisting of severe neurogenic distal wasting, generalised muscle weakness, absent ankle reflexes, pyramidal signs, mental retardation, optic atrophy and retinal colloid bodies. A sural nerve biopsy from one case showed loss of nerve fibres suggesting the diagnosis of hereditary motor and sensory neuropathy. Progression of the disorder was very slow, all patients still being able to walk more than 20 years after the onset. The persons affected with this syndrome were two brothers and their female cousin from a large Gujerati pedigree where consanguinity was high. Autosomal recessive inheritance is therefore suggested.	0
BACKGROUND:Theory of mind (ToM) has been shown to be impaired in Clinical High Risk (CHR) for psychosis populations and is linked to functional outcomes and symptom severity. Implicit versus explicit ToM has seldom been differentiated in this group, and underlying neural networks have also gone unexplored. METHODS:24 CHR and 26 healthy volunteers (HV) completed a behavioral ToM measure called the Short Story Task (SST), as well as a resting state functional MRI scan. SST performance was correlated to attenuated psychosis symptoms. Interactions between group and ToM variables (implicit, explicit, and comprehension) on global efficiency in the Mentalizing (MENT) and Mirror Neuron System (MNS) were also examined. RESULTS:CHR individuals made significantly fewer spontaneous mental state inferences. There were trend-level associations between ToM variables and symptoms, such that greater ToM performance predicted less severe symptoms. There was an interaction of group by spontaneous mental state inference within MENT bilateral dorsomedial prefrontal cortex (dmPFC), such that CHR individuals that made spontaneous mental state inferences showed greater global efficiency within the MENT network's bilateral dmPFC. DISCUSSION:Findings suggest implicit ToM deficits are observable prior to psychotic disorder onset, and that these deficits implicate MENT network dmPFC efficiency. Explicit ToM performance was unaltered in the CHR group, and there were no interactions observed within MNS, suggesting specificity of implicit ToM associations with MENT network dmPFC global efficiency. Results identify potential treatment targets for the neural underpinnings of ToM, thus informing prevention and intervention efforts.	0
OBJECTIVE:To summarize the experience of diagnosis and surgical treatment of renal oncocytoma, and to evaluate the surgical results based on follow-up results, in order to find the best strategy. METHODS:In the study, 21 cases with renal oncocytoma from December 2003 to April 2016 in Peking University Third Hospital were retrospectively analyzed, including 4 males, and 17 females, with 10 cases on the right side and 11 cases on the left side. Their age was between 15 to 80 years (average: 58 years). Ultrasound or CT examination after admission was conducted. Ultrasound examination showed solid nodules. CT manifestations were solid masses with enhancement, and the tumor size was between 1.5 cm to 6.5 cm (average: 3.3 cm). Of the 21 cases, 9 were located in the middle of kidney, 7 were located in the upper pole, and 5 were located in the lower pole. After preoperative examination, according to the size and location of the tumor, laparoscopic partial nephrectomy or laparoscopic nephrectomy was performed, respectively. RESULTS:All the operations were successful, in which 17 cases underwent laparoscopic partial nephrectomy (including 3 cases which were converted to open surgery), and 4 cases underwent laparoscopic radical nephrectomy. The operation time ranged from 75 to 274 min (mean: 144 min), and the blood loss ranged from 10 to 1 000 mL (mean: 115 mL). The postoperative hospital stay time ranged from 6 to 13 d (average: 8.2 d). The pathological results were all renal oncocytoma. In the study, 17 cases were followed up while 4 cases were lost to follow-up. The follow-up time ranged from 12 to 175 months (mean: 44 months). One case died in 20 months after operation with unknown reason, and there were no recurrence or metastasis in the other 16 cases. CONCLUSION:Renal oncocytoma is a benign tumor with good prognosis. Enhanced CT is an effective diagnostic method in assistant examination, but it is difficult to differentiate clear cell carcinoma only from the naked eye. It is worthwhile to measure CT value at different stages of the tumor by picture archiving and communication systems (PACS), and to compare with CT value of adjacent kidney tissue may improve the diagnostic efficiency of CT. Laparoscopic surgery is an effective treatment for renal oncocytoma. We recommend laparoscopic partial nephrectomy for the patients with renal oncocytoma as the best choice if conditions permit.	0
Developmental and epileptic encephalopathies (DEEs) can be primarily attributed to genetic causes. The genetic landscape of DEEs has been largely shaped by the rise of high-throughput sequencing, which led to the discovery of new DEE-associated genes and helped identify de novo pathogenic variants. We discuss briefly the contribution of de novo variants to DEE and also focus on alternative inheritance models that contribute to DEE. First, autosomal recessive inheritance in outbred populations may have a larger contribution than previously appreciated, accounting for up to 13% of DEEs. A small subset of genes that typically harbor de novo variants have been associated with recessive inheritance, and often these individuals have more severe clinical presentations. Additionally, pathogenic variants in X-linked genes have been identified in both affected males and females, possibly due to a lack of X-chromosome inactivation skewing. Collectively, exome sequencing has resulted in a molecular diagnosis for many individuals with DEE, but this still leaves many cases unsolved. Multiple factors contribute to the missing etiology, including nonexonic variants, mosaicism, epigenetics, and oligogenic inheritance. Here, we focus on the first 2 factors. We discuss the promises and challenges of genome sequencing, which allows for a more comprehensive analysis of the genome, including interpretation of structural and noncoding variants and also yields a high number of de novo variants for interpretation. We also consider the contribution of genetic mosaicism, both what it means for a molecular diagnosis in mosaic individuals and the important implications for genetic counseling.	0
Background and Objectives: Demodex species are common obligatory parasites and normally present in low number in human beings. Immunosuppression was suggested to be associated with increased density of Demodex mites. Systemic glucocorticoids, cyclosporine, methotrexate, and azathioprine are commonly used immunosuppressive agents. We aim to determine the pre- and post-treatment Demodex densities in patients receiving immunosuppressive therapy and compare with those of healthy subjects. Materials and Methods: Demodex density was investigated at the beginning, first, and third months of the immunosuppressive therapy in 45 patients who received methotrexate, cyclosporine, systemic steroid, or azathioprine treatments and in 45 healthy subjects at the same time as the patients. Five standardized skin surface biopsies were taken from cheeks, forehead, nose, and chin of the patients and control group. The presence of five or more parasites in 1 cm2 area was considered as positive. Results: Demodex test was negative at the beginning of the treatment in all patients. Demodex test was positive in one patient in the first and third months of treatment and in three patients only in the third month of treatment. In the control group, Demodex test was determined as positive in just one healthy individual at the beginning, first and third months of the study. When the patient and control groups were evaluated in terms of Demodex number, there was a statistically significant difference in Demodex density in patients treated with immunosuppressive treatment in the first and third months when compared with the control group (p < 0.05). Conclusion: Immunosuppressive treatment might increase the number of Demodex mites and demodicidosis should be kept in mind in patients on immunosuppressive treatment.	0
Important insights into the etiology of osteoporosis have been gained by the study of single gene disorders, including osteogenesis imperfecta. We report on the genetic mapping of geroderma osteodysplastica (GO), a rare autosomal recessive disorder of the connective tissue, characterized by wrinkly skin and severe osteoporosis. We undertook autozygosity mapping in one Libyan and four consanguineous Pakistani families with a total of 10 affected individuals to define a 4 Mb homozygous region on chromosome 1q24, which harbors the GO causative gene. No obvious candidate genes that encode known protein constituents of the extracellular matrix are found in the linked region. Importantly, our study demonstrates that GO is not allelic to wrinkly skin syndrome caused by mutations in ATP6V0A2.	0
RATIONALE:Alien Hand syndrome (AHS) is characterized in most patients by seemingly purposeful, involuntary movements of the extremities. It is not well known among physicians on account of its diverse clinical manifestations. PATIENT CONCERNS:We present a 57-year-old Chinese man who could not stop or turn himself around as he involuntarily and uncontrollably walked forward, which had happened frequently in the month prior to treatment. He had been a heavy drinker for thirty years before the onset of the disease, with an alcohol intake of 600 to 800 ml/day. DIAGNOSES:History of alcohol intake and the brain magnetic resonance imaging findings indicated a diagnosis of Marchiafava-Bignami disease. The patient was additionally diagnosed with Alien Hand Syndrome according to his clinical symptoms. INTERVENTIONS:The patient was treated with high doses of vitamin B for 1 month. OUTCOMES:The patient's abnormal behaviors never appeared during the treatment, and no instance of recurrence was observed during the 6 months of follow-up. LESSONS:The clinical manifestation of AHS is non-specific. Only by considering its diverse manifestation can doctors better understand the disease and achieve early intervention.	0
BACKGROUND:Spondyloepiphyseal dysplasia congenita (SEDC) is an extremely rare inherited chondrodysplasia characterized by abnormal epiphyses, short stature, and flattened vertebral bodies. We investigate the phenotypes and the disease-associated variants of SEDC in two unrelated Chinese families. METHODS:We identified disease-associated variants in two nonconsanguineous families with SEDC using targeted next-generation sequencing and confirmed the variants using Sanger sequencing. We investigated the phenotypes of the patients, including clinical manifestations, bone turnover biomarkers, bone mineral density and skeletal radiographic features. RESULTS:Two probands were diagnosed as SEDC according to the phenotypes of disproportionately short-trunk stature, kyphosis, lumbar lordosis and adduction deformity of hips. Radiographs revealed kyphosis and lumbar lordosis, flattened vertebral bodies, compressed femoral heads and shortening of the femurs. Bone mineral density of the probands was lower than that of age- and gender-matched normal children, but bone turnover biomarker levels were within normal range. Two novel heterozygous missense variants (NM_001844.5: c.1654 G>A, NP_001835.3: p.Gly552Arg; NM_001844.5: c.3518G>T, NP_001835.3: p.Gly1173Val) in collagen type II alpha 1 chain (COL2A1) were detected in the two families, which would impair the formation of stable triple-helical type II collagen. CONCLUSIONS:We identified two novel disease-associated variants in COL2A1, which led to severe SEDC. Our findings expanded the gene variant spectrum and phenotypic spectrum of extremely rare type II collagenopathies.	0
Unlike systemic anaplastic large cell lymphoma, the vast majority of primary cutaneous anaplastic large cell lymphomas (C-ALCL) do not carry translocations involving the ALK gene and do not express ALK. Expression of ALK protein therefore strongly suggests secondary cutaneous involvement of a systemic anaplastic large cell lymphoma. Recent studies described a small subgroup of ALK-positive C-ALCL, but information on frequency, prognosis, and translocation partners is virtually lacking. A total of 6/309 (2%) C-ALCL patients included in the Dutch registry for cutaneous lymphomas between 1993 and 2019 showed immunohistochemical ALK expression. Clinical and histopathologic characteristics, immunophenotype and disease course were evaluated. Underlying ALK translocations were analyzed with anchored multiplex polymerase chain reaction-based targeted next-generation sequencing. Median age at diagnosis was 39 years (range: 16 to 53 y). All patients presented with a solitary lesion. Treatment with radiotherapy (n=5) or anthracycline-based chemotherapy (n=1) resulted in complete responses in all 6 patients. Three patients developed a relapse, of whom 2 extracutaneous. After a median follow-up of 41 months, 5 patients were alive without disease and 1 patient died of lymphoma. Immunohistochemically, 3 cases (50%) showed combined nuclear and cytoplasmic ALK expression with underlying NPM1-ALK fusions, while 3 cases (50%) showed solely cytoplasmic ALK expression with variant ALK fusion partners (TRAF1, ATIC, TPM3). ALK-positive C-ALCL is extremely uncommon, has a comparable favorable prognosis to ALK-negative C-ALCL, and should be treated in the same way with radiotherapy as first-line treatment.	0
The core axoneme structure of both the motile cilium and sperm tail has the same ultrastructural 9 + 2 microtubular arrangement. Thus, it can be expected that genetic defects in motile cilia also have an effect on sperm tail formation. However, recent studies in human patients, animal models and model organisms have indicated that there are differences in components of specific structures within the cilia and sperm tail axonemes. Primary ciliary dyskinesia (PCD) is a genetic disease with symptoms caused by malfunction of motile cilia such as chronic nasal discharge, ear, nose and chest infections and pulmonary disease (bronchiectasis). Half of the patients also have situs inversus and in many cases male infertility has been reported. PCD genes have a role in motile cilia biogenesis, structure and function. To date mutations in over 40 genes have been identified cause PCD, but the exact effect of these mutations on spermatogenesis is poorly understood. Furthermore, mutations in several additional axonemal genes have recently been identified to cause a sperm-specific phenotype, termed multiple morphological abnormalities of the sperm flagella (MMAF). In this review, we discuss the association of PCD genes and other axonemal genes with male infertility, drawing particular attention to possible differences between their functions in motile cilia and sperm tails.	0
We present an unusual case of melanoma in a 76-year-old female covering approximately 80% of her scalp. Partial sampling of the lesion revealed focal blue nevus-like features at the microscopic level. We discuss issues related to blue nevus-like melanomas and highlight the unique clinical presentation of the current case.	0
Cramp-fasciculation syndrome is a peripheral nerve hyperexcitability disorder, which could be caused by inflammatory neuropathy.We describe a 51-year-old woman who presented with a 4- to 5-year history of fasciculations and painful cramping of the right thenar eminence.Electrophysiological studies showed motor conduction block in the right median nerve between the axilla and the elbow with fasciculation potentials and cramp discharges on electromyography in the right abductor pollicis brevis muscle. High titers of serum anti-GM1 immunoglobulin M antibodies were detected.Monofocal motor neuropathy of the right median nerve was diagnosed. Intravenous immunoglobulin treatment led to significant improvement of symptoms and signs. Although fasciculations and cramps have been reported in multifocal motor neuropathy and are considered supporting criteria for the diagnosis, the occurrence of cramp-fasciculation syndrome as the presenting feature and predominant manifestation in monofocal motor neuropathy, a variant of multifocal motor neuropathy, is unique. Muscle Nerve 56: 828-832, 2017.	0
Sialin, encoded by the SLC17A5 gene, is a lysosomal sialic acid transporter defective in Salla disease, a rare inherited leukodystrophy. It also enables metabolic incorporation of exogenous sialic acids, leading to autoantibodies against N-glycolylneuraminic acid in humans. Here, we identified a novel class of human sialin ligands by virtual screening and structure-activity relationship studies. The ligand scaffold is characterized by an amino acid backbone with a free carboxylate, an N-linked aromatic or heteroaromatic substituent, and a hydrophobic side chain. The most potent compound, 45 (LSP12-3129), inhibited N-acetylneuraminic acid 1 (Neu5Ac) transport in a non-competitive manner with IC50 ≈ 2.5 μM, a value 400-fold lower than the KM for Neu5Ac. In vitro and molecular docking studies attributed the non-competitive character to selective inhibitor binding to the Neu5Ac site in a cytosol-facing conformation. Moreover, compound 45 rescued the trafficking defect of the pathogenic mutant (R39C) causing Salla disease. This new class of cell-permeant inhibitors provides tools to investigate the physiological roles of sialin and help develop pharmacological chaperones for Salla disease.	0
Steatocystoma multiplex is an uncommon benign skin disease, which typically manifests as numerous intradermal cysts that can be scattered anywhere on the body. Although usually asymptomatic, it can be significantly disfiguring. One type of steatocystoma multiplex is known to be associated with the autosomal dominant inheritance of a mutation in the gene coding for keratin 17 (KRT17). In such cases, it is often concurrent with other developmental abnormalities of the ectoderm-derived tissues, such as the nails, hair, and teeth. To the best of our knowledge, few cases have been reported of steatocystoma multiplex of the oral and maxillofacial region. This report describes a case of steatocystoma multiplex of both sides of the neck and multiple dental anomalies, with a focus on its clinical, radiological, and histopathological characteristics, as well as the possibility that the patient exhibited the familial type of this condition.	0
Ongoing Ebola virus disease outbreaks in the Democratic Republic of the Congo follow the largest recorded outbreak in Western Africa (2013-2016). To combat outbreaks, testing of medical countermeasures (therapeutics or vaccines) requires a well-defined, reproducible, animal model. Here we present Ebola virus disease kinetics in 24 Chinese-origin rhesus monkeys exposed intramuscularly to a highly characterized, commercially available Kikwit Ebola virus Filovirus Animal Non-Clinical Group (FANG) stock. Until reaching predetermined clinical disease endpoint criteria, six animals underwent anesthesia for repeated clinical sampling and were compared to six that did not. Groups of three animals were euthanized and necropsied on days 3, 4, 5, and 6 post-exposure, respectively. In addition, three uninfected animals served as controls. Here, we present detailed characterization of clinical and laboratory disease kinetics and complete blood counts, serum chemistries, Ebola virus titers, and disease kinetics for future medical countermeasure (MCM) study design and control data. We measured no statistical difference in hematology, chemistry values, or time to clinical endpoint in animals that were anesthetized for clinical sampling during the acute disease compared to those that were not.	0
BACKGROUND:Monosomy 1p36 is the most common terminal deletion syndrome with an autosomal dominant pattern of inheritance. This syndrome is defined by an extremely wide spectrum of characteristics; however, developmental delay and intellectual disability of various degree are present in all patients and about the 90% of patients have a severe intellectual disability. Dental agenesis or other dental anomalies have not been described in previous reports. CASE PRESENTATION:We report the case of two little sisters born from healthy and non-consanguineous parents, presenting with dental anomalies and one of them with epilepsy, dilated cardiomyopathy with left-ventricular non-compaction, strabismus, history of poor growth, hypotonia and mild language delay. Patients were evaluated in several departments (genetic, child neuropsychiatric, cardiology, odontostomatology, ophthalmology, otorhinolaryngology) of Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy. They underwent investigations such as electrocardiogram, echocardiogram, dental orthopantomography X-Ray and Computed Tomography, electroencephalograms, abdomen ultrasound, blood tests, IQ tests, genetic analysis. They both have an Intelligence Quotient greater than 70 and a negative neurologic exam. Each sister carries the same 1p36 deletion of about 2.3 Mb. Genetic analysis of the parents' blood samples (Single Nucleotide Polymorphism- array, karyotype and Fluorescent In Situ Hybridization) did not reveal any deletion, translocation or inversion and confirmed the paternity. A third sib of the probands does not carry the 1p36 deletion or other quantitative alterations. CONCLUSION:This report describes a new trait linked to monosomy 1p36, namely a mild intellectual outcome associated with significant dental anomalies. Our finding suggests that 1p36 deletion syndrome may present with a mild cognitive impairment or even with a normal intellectual development: this is very important for the genetic counselling, especially in a prenatal setting. Moreover, we report the third study with recurrent 1p36 deletion syndrome in two siblings, likely due to germline mosaicism. Finally, we believe that the dental anomalies should be investigated in 1p36 deletion syndrome and that the spectrum of the condition could be broader than we assume.	0
We report a case of Hashimoto encephalopathy initially presented as a drug-resistant depression with predominant apathy and asthenia, successfully treated with cyclophosphamide. We suspected that the psychiatric symptoms were due to a deficit in neurotransmitter synthesis related to immune activation. We hypothesized that the immunomodulatory treatment helped to restore the neurotransmitter synthesis and thus decreased the patient's depressive symptoms. In this case report we propose an innovative model in which immunity might disturbs neurotransmitters synthesis leading to depressive symptoms.	0
Mandatory accurate and specific diagnosis demands have brought about increased challenges for radiologists in pediatric posterior fossa tumor prediction and prognosis. With the development of high-performance computing and machine learning technologies, radiomics provides increasing opportunities for clinical decision-making. Several studies have applied radiomics as a decision support tool in intracranial tumors differentiation. Here we seek to achieve preoperative differentiation between ependymoma (EP) and pilocytic astrocytoma (PA) using radiomics analysis method based on machine learning. A total of 135 Magnetic Resonance Imaging (MRI) slices are divided into training sets and validation sets. Three kinds of radiomics features, including Gabor transform, texture and wavelet transform based ones are used to obtain 300 multimodal features. Kruskal-Wallis test score (KWT) and support vector machines (SVM) are applied for feature selection and tumor differentiation. The performance is investigated via accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) analysis. Results show that the accuracy, sensitivity, specificity, and AUC of the selected feature set are 0.8775, 0.9292, 0.8000, and 0.8646 respectively, having no significantdifferencescomparedwiththe overall feature set. For different types of features, texture features yield the best differentiation performance and the significance analysis results are consistent with this. Our study demonstrates texture features perform better than the other features. The radiomics approach based on machine learning is efficient for pediatric posterior fossa tumors differentiation and could enhance the application of radiomics methods for assisted clinical diagnosis.	0
Benign recurrent intrahepatic cholestasis represents a rare class of autosomal recessive chronic cholestasis disorders, usually presenting with recurrent episodes of intense pruritus and jaundice. We report a 27-year-old woman presenting with benign recurrent intrahepatic cholestasis type 2 due to heterozygosity in ABCB11. Interestingly, she was also found to be heterozygous in cystic fibrosis transmembrane conductance regulator, NPHP4, and A1ATD (SERPINA1), which may explain the severe nature of her disease expression because heterozygosity in each of these genes has been associated with cholestasis. Finally, she exhibited a response to steroids that may have implications for future treatment of bile salt export pump-related diseases.	0
Osteopetrosis is a rare congenital bone disorder, characterized by systemic osteosclerosis due to a deficiency of or functional defect in osteoclasts. Autosomal dominant osteopetrosis (ADOP) is the most common form with a late onset, a stable condition, relatively few symptoms and a good prognosis. Few studies to date have reported successful total hip arthroplasty (THA) in patients with ADOP and its operative difficulties. We herein describe a case of left hip osteoarthritis in a patient with OP via THA in order to share our experience during the treatment process. The patient was a 52-years-old female with osteopetrosis who was referred to our department due to a history of left hip pain with activity limitation for 20 years. The patient reported no history of fracture or family history. The patient underwent THA in the left hip. At the 6-month, 1- and 2-year follow-up, the components were in a good position and the patient remained asymptomatic and pain-free. Therefore, THA may be a feasible treatment option when patients with ADOP suffer from painful hip osteoarthritis.	0
Severe immunodeficient mice are widely used to examine human and animal cells behaviour in vivo. However, mice are short-lived and small in size; while large animals require specific large-scale equipment. Rabbits are also commonly employed as experimental models and are larger than mice or rats, easy to handle, and suitable for long-term observational and pre-clinical studies. Herein, we sought to develop and maintain stable strains of rabbits with X-linked severe combined immunodeficiency (X-SCID) via the CRISPR/Cas9 system targeting Il2rg. Consequently, X-SCID rabbits presented immunodeficient phenotypes including the loss of T and B cells and hypoplasia of the thymus. Further, these rabbits exhibited a higher success rate with engraftments upon allogeneic transplantation of skin tissue than did wild type controls. X-SCID rabbits could be stably maintained for a minimum of four generations. These results indicate that X-SCID rabbits are effective animals for use in a non-rodent model of severe immunodeficiency.	0
We report the case of a Caucasian Spanish boy, who showed profound neonatal hypotonia, feeding difficulties, apnea, severe developmental delay, epilepsy, bilateral convergent strabismus, poor verbal language development and a large brainstem. Whole-exome sequence uncovered a novel de novo mutation in the purine-rich element binding protein A gene (PURA; NM_005859.4:c.72del:p.(-Gly25AlafsTer53)) that encodes the transcriptional activator protein Pur-alpha (PURA). Mutations in this gene have been identified in patients with PURA syndrome, a rare disorder characterized by an early hypotonia, developmental delay, severe intellectual disability with or without epilepsy, and disability in expressive language development. Although, up to 75 cases have been identified worldwide, to the best of our knowledge, this is the first patient described with a brainstem larger than normal. In conclusion, our data expand both geneticand phenotypic spectrum associated with PURA gene mutations.	0
A 51-year-old woman who presented with a large cystic liver tumor with mural nodules in the lateral segment developed Trousseau's syndrome. A mural nodule directly invaded her liver parenchyma. Metastatic nodules were detected in the right lobe and portal/paraaortic lymph nodes. The pathological findings showed mucin-producing adenocarcinoma cells to have invaded the fibrous stroma forming a micropapillary cluster. She developed obstructive jaundice due to tumor progression and subsequently died of hepatic failure. Invasive biliary mucinous cystic neoplasm (MCN) is a rare form of a malignant tumor with a relatively favorable prognosis. This is a very rare case biliary MCN with invasive carcinoma that showed intrahepatic and lymph node metastases.	0
HFE-related Hemochromatosis is the most common genetic iron overload disease in European populations, particularly of Nordic or Celtic ancestry. It is reported that the HFE p.C282Y mutation is present in 1/10 people of northern European descent, resulting in one in two hundred people will be homozygous. However, the HFE p.C282Y heterozygosity is virtually absent among East Asians, including Japanese, Koreans, and Chinese. In this article, we report a case of HFE-related hemochromatosis caused by compound heterozygosity HFE p.C282Y/p.R71X. This is the first report of hemochromatosis associated with HFE p.C282Y mutation in China.	0
Reactive arthritis (ReA) with the classic triad of arthritis, conjunctivitis and urethritis, previously termed Reiter's syndrome, is a systemic illness, usually induced by genitourinary or gastrointestinal infections. However, it can be a rare complication of intravesical Bacillus Calmette-Guérin instillation (iBCG), a therapy prepared from attenuated strains of Mycobacterium bovis, a common and effective treatment for carcinoma in situ of the bladder (CisB). We report a case of a patient with CisB who developed ReA after iBCG. The symptoms resolved completely with corticosteroids. iBCG was stopped with no recurrence of carcinoma within 2 years. LEARNING POINTS:ReA is an aseptic arthritis, usually triggered by genitourinary or gastrointestinal infections, generally in individuals positive for HLA-B27.Septic arthritis and microcrystalline arthritis can mimic ReA and they must be ruled out with arthrocentesis.ReA may be considered as a complication in patients under iBCG.	0
Lecitin cholesterol acyltransferase (LCAT) deficiency comprises a group of rare disorders related to HDL metabolism. These disorders are characterized by ophthalmologic, hematologic, and renal findings. Case diagnosis/treatment: A 15-year-old female who presented with nephrotic syndrome and hypertension was diagnosed with LCAT deficiency by renal biopsy and LCAT enzyme activity. Her edema and hypertension improved with diuretic and antihypertensive therapies. Continued care of her LCAT deficiency is ongoing.Although rare, LCAT deficiency should be in the differential diagnosis of nephrotic syndrome in the setting of abnormally low HDL cholesterol levels.	0
Wiskott-Aldrich Syndrome (WAS) is a rare X-linked recessive Primary Immunodeficiency (PID) caused by mutations in WAS gene which encodes a protein known as WASp. WASp plays important roles in cytoskeletal functions that compromise multiple aspects of normal cellular activity including proliferation, phagocytosis, immune synapse formation, adhesion and directed migration. WASp defect particularly causes platelets abnormality which is presented in forms of decrease of Mean Platelet Volume (MPV) and thrombocytopenia in most WAS conditions; nevertheless, some studies reported WAS patients with a normal or large size of platelets in recent years. This phenomenon is unique and the exact mechanism of thrombocytopenia with a normal or large size of platelets is still unknown. In this study, Next Generation Sequencing (NGS) was utilized to discover the causing mutation in WAS gene; furthermore, an attempt was made to evaluate the possibility of other mutations or genes especially WASp interacting proteins and inherited platelet disorder genes in patient clinical symptoms for the purpose of understanding the origin of such unique symptom and to perform further analysis if it is required. Therefore, clinical manifestations and immunologic functions of the patient were checked and Whole Exome Sequencing (WES) was performed to analyze all exonic variations which can be associated with patient phenotypes. Finally, a novel de novo mutation in WAS gene which truncates WASp to half of its normal size was determined as the only cause of clinical manifestation.	0
The combination of a sixth nerve palsy and ipsilateral Horner's syndrome localises the disease process to the posterior cavernous sinus and can be a result of various pathologies in this region. A 74-year-old Chinese woman presented with a 9-month history of binocular horizontal diplopia worse when looking left. She was found to have a left sixth nerve palsy and Horner's syndrome and MRI revealed an enhancing soft tissue mass in the nasopharynx with involvement of the bones of the skull base and invasion of the left cavernous sinus. Endoscopic biopsy of the mass confirmed the diagnosis of non-keratinising squamous cell carcinoma, which was Epstein-Barr virus positive. She was treated with radiation therapy. Patients with a sixth nerve palsy and ipsilateral Horner's syndrome should have urgent neuroimaging with careful attention to the cavernous sinus since sympathetic fibres join the sixth nerve for a short distance in this location.	0
Sporadic late-onset Alzheimer disease (LOAD) preceded by mild cognitive impairment (MCI) is the most common type of dementia. Long-term studies of immunity to pathogenic amyloid-β (Aβ) in LOAD are lacking. Innate immunity of LOAD patients is malfunctioning in phagocytosis and degradation of Aβ and LOAD patients' macrophage transcriptome and metabolome are deregulated. We previously showed omega-3 fatty acid (ω-3)-mediated repair of unfolded protein response and here we show much broader transcriptomic effects. ω-3 treatment in vitro and ω-3 supplementation by the drink Smartfish (SMF) in vivo increased the transcripts of the genes and pathways of immunity, glycolysis, tricarboxylic acid cycle, OX-PHOS, nicotinamide dinucleotide (NAD+ ) synthesis, and reversed the defects in Aβ phagocytosis. In both peripheral blood mononuclear cells (PBMC) and macrophages, ω-3 increased ATP-linked oxygen consumption rate (OCR) and ω-3 with carnitine was superior to ω-3. ω-3 treatment in vitro and supplementation by the ω-3 drink SMF in vivo rescued macrophage phagocytosis when glycolysis or glycosylation were blocked. ω-3 provide flexible energy for immune clearance of the brain throughout the diurnal cycle, even in hypo- or hyper-glycemia. In certain LOAD patients, ω-3 may delay progression to dementia.	0
BACKGROUND Long noncoding RNA (lncRNA) acts as key regulator in human cancers, including retinoblastoma. However, the function of LINC00152 remains largely unknown in retinoblastoma. Thus, this study aimed to explore the role and molecular mechanisms of LINC00152 in retinoblastoma. MATERIAL AND METHODS The real-time quantitative polymerase chain reaction (RT-qPCR) was used to quantify the expression levels of LINC00152, miR-613 and yes-associated protein 1 (YAP1). The target genes of LINC00152 and miR-613 were identified by dual-luciferase reporter analysis, RNA immunoprecipitation (RIP) and RNA pulldown assays. The viability, apoptosis, and invasion of retinoblastoma cells were assessed by Cell Counting Kit-8, flow cytometry, and Transwell assays, respectively. In addition, western blot was used to test the protein expression in retinoblastoma cells or tissues. Cell sensitivity to carboplatin and adriamycin was analyzed by computing IC₅₀ value. The effects of LINC00152 silencing in vivo were measured by a xenograft experiment. RESULTS LINC00152 was obviously upregulated, while miR-613 was decreased in retinoblastoma tissues and cells. MiR-613, a target of LINC00152, was negatively regulated by LINC00152. Functional experiment further illustrated that silencing of LINC00152 evidently repressed proliferation, invasion, and autophagy while reinforced apoptosis of retinoblastoma cells, besides, retinoblastoma cells were more sensitive to carboplatin and adriamycin after knockdown of LINC00152. Importantly, knockdown of LINC00152-induced effects on retinoblastoma cells could be overturned by introducing miR-613 inhibitor. Downregulation of miR-613 abolished silencing of YAP1-effects on proliferation, apoptosis, invasion, autophagy, and chemoresistance of retinoblastoma cells. The results of the xenograft experiment indicated that LINC00152 silencing impeded tumor growth in vivo. CONCLUSIONS Mechanistically, LINC00152 enhanced the aggressiveness of retinoblastoma and boosted carboplatin and adriamycin resistance by regulating YAP1 by sponging miR-613 in human retinoblastoma.	0
Invasive meningococcal disease (IMD) is usually associated with intense inflammatory response that is correlated with severe infection. Corticosteroids may regulate this inflammatory response through an early but transient induction of IL-10 that is suggested to improve the outcome of IMD. We explored the mechanism of action of corticosteroids as an adjuvant treatment to antibiotics. Transgenic mice expressing the human transferrin were infected by a hyperinvasive meningococcal strain and transcriptomic analysis were then performed in the blood for all conditions of infection and treatment. Infected untreated mice, infected antibiotic-treated mice and infected amoxicillin and dexamethasone-treated mice were compared. Treatment using both corticosteroids and antibiotics was associated with differential gene expression in the blood especially in Monocytes-Macrophages pathways. Depletion of these cells in infected mice was associated with a more severe bacterial infection and uncontrolled production of both pro-inflammatory and anti-inflammatory cytokines. Accordingly, children suffering from severe IMD had low counts of monocytes at admission. Our data are in favor of a role of corticosteroids in enhancing a polarization from pro-inflammatory to anti-inflammatory phenotypes of Monocytes-Macrophages axis that may help controlling meningococcal invasive infections.	0
A 70-year-old man with lower right quadrant abdominal discomfort was admitted to our hospital. Colonoscopy identified a villous tumor protruding into the cecal lumen from the appendiceal orifice. Abdominal computed tomography(CT)revealed a cecal tumor with a swollen appendix. An appendiceal cecal tumor with obliterative appendicitis was diagnosed, and we performed an appendicectomy with removal of part of the cecum. On pathological examination, well to moderately differentiated adenocarcinoma with infiltration of the proper muscular layer was diagnosed. No additional treatment was given as the patient refused further surgery and chemotherapy. However, a metastatic tumor in S4/8 of the liver was seen on CT 5 months after the initial surgery. A resection of liver metastasis was performed after chemotherapy. We report herein a rare case of primary appendiceal adenocarcinoma reoccurring shortly after surgery.	0
Enamel hypoplasia secondary to amelogenesis imperfect (AI) is one of the common developmental disturbances associated with the oral cavity. AI in association with multiple unerupted teeth is a rare entity, and in adolescence it not only has an affect on esthetics but also has an impact on the psychological status of the person. AI has been reported with other systemic anomalies previously. We report a case of AI in association with multiple unerupted teeth and nephrocalcinosis in siblings. The present case also highlights the importance of systemic examination and investigations in planning the treatment of a patient with AI.	0
AIM:To evaluate the effects of maturation and sex on glucose metabolism during glucose tolerance (GTT) and insulin tolerance tests (ITT) in young and adult male and female rats by using two different approaches - the conventional, which uses area under the curve and glucose curve, and mathematical modeling that identifies parameters necessary for determining the function that models glucose metabolism. METHODS:Male and female rats at 3.5 and 12 months of age underwent standard GTT and ITT after overnight fasting. The parameters were identified by using Mathematica-module NonlinearModelFit [] for experimentally obtained data. RESULTS:When data were statistically analyzed, both sexes and age groups had similar glucose and insulin tolerance. In the mathematical model of GTT, parameters describing the rate of glucose concentration increase G'(0) and decrease G'I multiplied with maturation, with a concomitant decrease in the time point (tmax, tI) of reaching maximum and minimum glucose concentration (Gmax, G0). The mathematical model of ITT for males was independent of age, unlike of that for females, which had increased G'(0) and G'I, and more quickly recovered from hypoglycemia after maturation. CONCLUSION:The mathematical model revealed female susceptibility to large glucose excursions, which are better reflected by ITT in young animals and by GTT in adults.	0
BACKGROUND:Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. There is considerable heterogeneity in management strategies and a lack of evidence-based treatment guidelines. Consensus treatment plans (CTPs) are standardized treatment regimens that are derived based upon best available evidence and current treatment practices that are a way to enable comparative effectiveness studies to identify optimal therapy and are less costly to execute than randomized, double blind placebo controlled trials. The purpose of this project was to develop CTPs and response criteria for PFAPA. METHODS:The CARRA PFAPA Working Group is composed of pediatric rheumatologists, infectious disease specialists, allergists/immunologists and otolaryngologists. An extensive literature review was conducted followed by a survey to assess physician practice patterns. This was followed by virtual and in-person meetings between 2014 and 2018. Nominal group technique (NGT) was employed to develop CTPs, as well as inclusion criteria for entry into future treatment studies, and response criteria. Consensus required 80% agreement. RESULTS:The PFAPA working group developed CTPs resulting in 4 different treatment arms: 1. Antipyretic, 2. Abortive (corticosteroids), 3. Prophylaxis (colchicine or cimetidine) and 4. Surgical (tonsillectomy). Consensus was obtained among CARRA members for those defining patient characteristics who qualify for participation in the CTP PFAPA study. CONCLUSION:The goal is for the CTPs developed by our group to lead to future comparative effectiveness studies that will generate evidence-driven therapeutic guidelines for this periodic inflammatory disease.	0
The clinical features, neuroimaging, and neuropathologic findings of a new syndrome, characterized by onset in early infancy, progressive course, choreiform movements, hypotonia, and dysphagia, are described in 2 siblings originating from a consanguineous marriage. The serial neuroimaging studies indicated progressive loss of volume of both caudate nuclei and change in signal intensity in putamina. Pathologically, there was severe neuronal loss and gliosis in the striatum and thalamus. This pathologic pattern in association with clinical and radiologic correlates, to our knowledge, has not been previously described. It appears that this syndrome is an autosomal recessive disorder.	0
Context:Anti-pituitary-specific transcriptional factor-1 (anti-PIT-1) antibody syndrome is characterized by acquired and specific deficiencies in growth hormone, prolactin, and thyroid-stimulating hormone. Although PIT-1-reactive cytotoxic T lymphocytes (CTLs) have been speculated to recognize anterior pituitary cells and to cause the injury in the pathogenesis of the syndrome, it remains unclear whether endogenous PIT-1 protein is processed through the proteolytic pathway and presented as an antigen on anterior pituitary cells. Objective:To examine how PIT-1 protein is processed and whether its epitope is presented by major histocompatibility complex (MHC)/HLA class I on anterior pituitary cells. Materials and Methods:Immunofluorescence staining and proximity ligation assay (PLA) were performed using anti-PIT-1 antibody and patients' sera on PIT-1-expressing cell line GH3 cells and human induced pluripotent stem cell (iPSC)-derived pituitary tissues. Results:PIT-1 was colocalized with MHC class I molecules, calnexin, and GM130 in the cytosol. PLA results showed that PIT-1 epitope was presented by MHC/HLA class I molecules on the cell surface of GH3 cells and iPSC-derived pituitary cells. The number of PIT-1/HLA complexes on the cell surface of pituitary cells in the patient was comparable with that in the control subject. Conclusions:Our data indicate that PIT-1 protein is processed in the antigen presentation pathway and that its epitopes are presented by in MHC/HLA class I on anterior pituitary cells, supporting the hypothesis that PIT-1-reactive CTLs caused the cell-specific damage. It is also suggested that number of epitope presentation was not associated with the pathogenesis of anti-PIT-1 antibody syndrome.	0
PURPOSE:To describe in detail the phenotype of two siblings with biallelic NMNAT1 mutations. METHODS:A 4-year-old male patient (P1) and his 7-year-old sister (P2), product of a nonconsanguineous union of Egyptian ancestry, underwent a comprehensive ophthalmic examination, retinal imaging with spectral domain optical coherence tomography and near infrared (NIR) fundus autofluorescence (FAF), and full-field electroretinograms (ERG). RESULTS:Patients had blurred vision and nystagmus at ∼3 years of age. P2 was hyperopic (+6D). Visual acuity in P1 was 20/100 at age 3 and remained at ∼20/125 at age 4; P2 visual acuity was 20/70 at age 4 and declined to ∼20/200 at age 7. ERGs recorded in P1 showed relatively large rod-mediated responses but nearly undetectable cone signals. There was foveal/parafoveal depigmentation. Spectral domain optical coherence tomography showed hypoplastic foveas, a thin outer nuclear layer centrally but normal thickness beyond the vascular arcades. At the foveal center, cone outer segments were absent and the outer nuclear layer was further hyporreflective. The inner retina was mostly within normal limits. There was central depigmentation on near infrared fundus autofluorescence. Biallelic mutations were identified in NMNAT1: One was previously reported (c.769 G>A; pGlu257Lys), and the other one (c.245T>C; pVal82Ala) was novel. CONCLUSION:NMNAT1 mutations cause a consistent phenotype characterized by early-onset, progressive, cone>rod retinawide dysfunction and predominantly central abnormalities ranging from a hypoplastic to an atrophic fovea, supporting a critical role for NMNAT1 in central retinal development and maintenance. Relatively preserved inner retina and detectable photoreceptors may become therapeutic targets.	0
Fragile X syndrome (FXS) results from a CGG-repeat expansion that triggers hypermethylation and silencing of the FMR1 gene. FXS is referred to as the most common form of inherited intellectual disability, yet its true incidence has never been measured directly by large population screening. Here, we developed an inexpensive and high-throughput assay to quantitatively assess FMR1 methylation in DNA isolated from the dried blood spots of 36,124 deidentified newborn males. This assay displays 100% specificity and 100% sensitivity for detecting FMR1 methylation, successfully distinguishing normal males from males with full-mutation FXS. Furthermore, the assay can detect excess FMR1 methylation in 82% of females with full mutations, although the methylation did not correlate with intellectual disability. With amelogenin PCR used for detecting the presence of a Y chromosome, this assay can also detect males with Klinefelter syndrome (KS) (47, XXY). We identified 64 males with FMR1 methylation and, after confirmatory testing, found seven to have full-mutation FXS and 57 to have KS. Because the precise incidence of KS is known, we used our observed KS incidence as a sentinel to assess ascertainment quality and showed that our KS incidence of 1 in 633 newborn males was not significantly different from the literature incidence of 1 in 576 (p = 0.79). The seven FXS males revealed an FXS incidence in males of 1 in 5161 (95% confidence interval of 1 in 10,653-1 in 2500), consistent with some earlier indirect estimates. Given the trials now underway for possible FXS treatments, this method could be used in newborn or infant screening as a way of ensuring early interventions for FXS.	1
Diagnostic Exome Sequencing (DES) has been shown to be an effective tool for diagnosis individuals with suspected genetic conditions.We report a male infant born with multiple anomalies including bilateral dysplastic kidneys, cleft palate, bilateral talipes, and bilateral absence of thumbs and first toes. Prenatal testing including chromosome analysis and microarray did not identify a cause for the multiple congenital anomalies. Postnatal diagnostic exome studies (DES) were utilized to find a molecular diagnosis for the patient. Exome sequencing of the proband, mother, and father showed a previously unreported maternally inherited RNA binding motif protein 10 (RBM10) c.1352_1353delAG (p.E451Vfs*66) alteration. Mutations in RBM10 are associated with TARP syndrome, an X-linked recessive disorder originally described with cardinal features of talipes equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena cava.DES established a molecular genetic diagnosis of TARP syndrome for a neonatal patient with a poor prognosis in whom traditional testing methods were uninformative and allowed for efficient diagnosis and future reproductive options for the parents. Other reported cases of TARP syndrome demonstrate significant variability in clinical phenotype. The reported features in this infant including multiple hemivertebrae, imperforate anus, aplasia of thumbs and first toes have not been reported in previous patients, thus expanding the clinical phenotype for this rare disorder.	0
Noonan syndrome (NS), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and LEOPARD syndrome (now also referred to as Noonan syndrome with multiple lentigines or NSML) are clinically overlapping dominant disorders that are caused by mutations in RAS signaling pathway genes. The spectrum of cancer susceptibility in this group of disorders has not been studied in detail. We identified more than 1900 cases of NS, CS, CFCS, or NSML reported in the literature between 1937 and 2010; 88 cancers were reported. The most common cancers reported in 1051 NS subjects were neuroblastoma (n = 8), acute lymphoblastic leukemia (n = 8), low grade glioma (n = 6), and rhabdomyosarcoma (n = 6). These associations are biologically plausible, given that somatic RAS pathway mutations are known to occur in these specific cancers. In addition, 40 childhood cases of myeloproliferative disease were described in individuals with NS, several of whom experienced a benign course of this hematologic condition. We confirmed the previously described association between CS and cancer in 268 reported individuals: 19 had rhabdomyosarcoma, 4 had bladder cancer, and 5 had neuroblastoma. By age 20, the cumulative incidence of cancer was approximately 4% for NS and 15% for CS; both syndromes had a cancer incidence peak in childhood. The cancers described in CFCS and NSML overlapped with those reported in NS and CS. Future epidemiologic studies will be required to confirm the described cancer spectrum and to estimate precise cancer risks.	1
The present study aimed to identify potentially important biomarkers associated with polycystic ovary syndrome (PCOS) by integrating DNA methylation with transcriptome profiling. The transcription (E‑MTAB‑3768) and methylation (E‑MTAB‑3777) datasets were retrieved from ArrayExpress. Paired transcription and methylation profiling data of 10 cases of PCOS and 10 healthy controls were available for screening differentially expressed genes (DEGs) and differentially methylated genes (DMGs). Genes with a negative correlation between expression levels and methylation levels were retained by correlation analysis to construct a protein‑protein interaction (PPI) network. Subsequently, functional and pathway enrichment analyses were performed to identify genes in the PPI network. Additionally, a disease‑associated pathway network was also established. A total of 491 overlapping genes, and the expression levels of 237 genes, were negatively correlated with their methylation levels. Functional enrichment analysis revealed that genes in the PPI network were mainly involved with biological processes of cellular response to stress, negative regulation of the biosynthetic process, and regulation of cell proliferation. The constructed pathway network associated with PCOS led to the identification of four important genes (SPP1, F2R, IL12B and RBP4) and two important pathways (Jak‑STAT signaling pathway and neuroactive ligand‑receptor interaction). Taken, together, the results from the present study have revealed numerous important genes with abnormal DNA methylation levels and altered mRNA expression levels, along with their associated functions and pathways. These findings may contribute to an improved understanding of the possible pathophysiology of PCOS.	0
BACKGROUND:Nonimmune hydrops fetalis (NIHF) is still a challenging diagnosis. The differential diagnosis is extensive and the success of identifying a cause depends on the thoroughness of efforts to establish a diagnosis. For the early diagnosis of NIHF, a virtual gene panel diagnostic tool was developed. The female premature baby in question was delivered via emergency cesarean at 30 + 1 weeks of gestational age (GA) due to rapidly developing NIHF to a healthy mother. The family history was noncontributory. METHODS:DNA of the family was extracted and sequenced by the virtual hydrops panel with whole-exome sequencing. RESULTS:The hydrops panel revealed Noonan syndrome (NS) with a germline mutation in PTPN11 c.218C>T (p.Thr73Ile). CONCLUSION:The diagnosis of our patient was rapidly confirmed by the hydrops panel. The variant of c.218C>T (p.Thr73Ile) has not yet been described in literature relating to NIHF. Only a few case reports of this variant are known. This particular mutation is associated with Noonan syndrome, congenital heart defect and persistent thrombocytopenia. Few reveal juvenile myelomonocytic leukemia.	0
BACKGROUND:Purine nucleoside phosphorylase (PNP) deficiency accounts for about 4% of severe combined immunodeficiency diseases. PNP deficiency is a variable disease with recurrent infections and neurodevelopmental delay. Autoimmunity and malignancy can still occur in one-third of patients. METHODS:Case report. CASE PRESENTATION:An 8-year-old Saudi female who was apparently healthy presented at the age of 7 years with confirmed systemic lupus erythematosus (SLE) and lupus nephritis that were poorly controlled with conventional therapy. She also had frequent sinopulmonary and varicella infections. Preliminary immunological workup showed severe lymphopenia and depressed lymphocyte proliferation assay. The uric acid was within normal levels at 179 μmol/L (normal range, 150 to 350 μmol/L) 6 weeks after blood transfusion. Genetic study revealed a homozygous missense mutation c.265G>A in the PNP gene, resulting in a substitution of glutamic acid to lysine at amino acid 89 of the encoded protein (E89K). The PNP serum level was 798 nmol/h/mg (normal level 1354 ± 561 nmol/h/mg) 6 weeks after blood transfusion. Hematopoietic stem cell transplantation (HSCT) was planned from a matched unrelated donor; however, she developed an EBV and varicella meningoencephalitis. Atypical malignant cells suggestive of lymphoma were discovered, likely induced by EBV, and suspicious lesions were shown on brain MRI and PET scan. Unfortunately, she passed away before HSCT due to multiorgan failure. CONCLUSION:This report emphasizes the challenges in recognizing PNP deficiency in a patient suffering from SLE.	0
It is presumed that tracheobronchomalacia in adults is caused by airway pressure-induced injury due to chronic cough related to pulmonary emphysema or chronic bronchitis. Commonly, a posterolateral approach using stabilizing materials is the surgical technique of choice for treating tracheobronchomalacia. We report a case in which thoracoscopic plication of the membranous portion was performed instead of airway stent placement for tracheobronchomalacia in an elderly individual. An 87-year-old man who had been treated for bronchial asthma, pulmonary emphysema, and tracheobronchomalacia was admitted to our hospital with acute exacerbation of dyspnea. The patient underwent tracheal intubation, which was followed by tracheostomy 16 days later. Insertion of the tip of the adjustable-length tracheostomy tube to the end of the stenotic lesion enabled him to breathe spontaneously. However, conservative management failed due to recurrent pneumonia caused by the tracheobronchomalacia. Crescent-type tracheobronchomalacia (Johnson's classification grade III) was diagnosed, and the main narrowed area of the trachea was assumed to be approximately 3-10 cm from the tracheal bifurcation. A thoracoscopic approach was selected because a posterolateral approach was considered too invasive considering the patient's age and general condition. We placed eight stitches on the tracheal membranous portion and four stitches on the membranous portion of the right main bronchus, using the horizontal mattress suture technique. The use of foreign materials was avoided because meropenem-resistant Pseudomonas aeruginosa was cultured in a tracheal specimen. Immediately after the operation, the expiratory airway stenosis improved, and subsequently, spontaneous ventilation was possible using a normal type of tracheostomy tube instead of an adjustable-length tracheostomy tube. Tracheobronchomalacia is not a rare condition in patients with chronic obstructive pulmonary disease. The thoracoscopic approach is less invasive than the posterolateral approach and is suitable in cases that are otherwise refractory to medical treatment. We believe that thoracoscopy may be a useful treatment option in cases where conservative treatment is not appropriate.	0
We describe a 5-year-old boy and a 33-year-old woman with spondyloepimetaphyseal dysplasia with joint laxity leptodactylic form (spondyloepimetaphyseal dysplasia with multiple dislocations) (MIM 6003546), and two 12-year-old girls with the disorder who were previously reported as examples of a variant of sponatrime dysplasia. Their clinical manifestations included midface hypoplasia, micromelic short stature, and generalized joint laxity that caused multiple joint problems, including thoracolumbar scoliosis, hip subluxation, progressive genu valgum with knee and patellar subluxation, elbow subluxation, and malalignment of the wrist. Laryngotracheomalacia was present in two individuals, and myopathy was noted in one. The radiological findings in the four individuals included mild platyspondyly most conspicuous in infancy, narrow interpediculate distances of the lumbar spine evident in infancy, retarded epiphyseal ossification that evolved to epiphyseal dysplasia and later to degenerative joint disease, metaphyseal irregularities and striations present in early childhood, and leptodactylic appearance (slender short tubular bones) of the hand.	0
Trichorhinophalangeal syndrome type 1 is a rare skeletal dysplasia of autosomal-dominant inheritance due to defects in the TRPS-1 gene. The syndrome is characterised by sparse slow-growing hair, a bulbous pear-shaped nose, cone-shaped epiphyses and deformities of the interphalangeal joints resembling those in rheumatoid arthritis. We present a case of trichorhinophalangeal syndrome in a 23-year-old man who presented with symmetrical painless progressive deformity of the fingers in both hands.	0
BACKGROUND:Research suggests that acute alcohol consumption impairs processing of emotional faces. As emotion processing plays a key role in effective social interaction, these impairments may be one mechanism by which alcohol changes social behaviour. This study investigated the effect of individual differences on this relationship by comparing emotion recognition performance after acute alcohol consumption in individuals with high and low trait aggression. METHODS:Regular non-dependent drinkers, either high or low in trait aggression participated in a double-blind placebo-controlled experiment (N = 88, 50% high trait aggressive). Participants attended two sessions. In one they consumed an alcoholic drink (0.4 g/kg) and in the other they consumed a matched placebo. They then completed two computer-based tasks: one measured global and emotion-specific recognition performance across six primary emotions (anger, sadness, happiness, disgust, fear, surprise), the other measured processing bias of two ambiguously expressive faces (happy-angry/happy-sad). RESULTS:There was evidence of poorer global emotion recognition after alcohol. In addition, there was evidence of poorer sensitivity to sadness and fear after alcohol. There was also evidence for a reduced bias towards happiness following alcohol and weak evidence for an increased bias towards sadness. CONCLUSIONS:These findings suggest that alcohol impairs global emotion recognition. They also highlight a reduced ability to detect sadness and fearful facial expressions. As sadness and fear are cues of submission and distress (i.e. function to curtail aggression), failure to successfully detect these emotions when intoxicated may increase the likelihood of aggressive responding. This coupled with a reduced bias towards seeing happiness may collectively contribute to aggressive behaviour.	0
Primary adrenal insufficiency (PAI) occurs in 1/5000-1/7000 individuals in the general population. Autoimmune Addison's disease (AAD) is the major cause of PAI and is a major component of autoimmune polyendocrine syndrome type 1 (APS1) and type 2 (APS2). Presence of 21-hydroxylase autoantibodies (21OHAb) identifies subjects with ongoing clinical or pre-clinical adrenal autoimmunity. AAD requires life-long substitutive therapy with two-three daily doses of hydrocortisone (HC) (15-25 mg/day) or one daily dose of dual-release HC and with fludrocortisone (0.5-2.0 mg/day). The lowest possible HC dose must be identified according to clinical and biochemical parameters to minimize long-term complications that include osteoporosis and cardiovascular and metabolic alterations. Women with AAD have lower fertility and parity as compared to age-matched healthy controls. Patients must be educated to double-triple HC dose in the case of fever or infections and to switch to parenteral HC in the case of vomiting, diarrhoea or acute hypotension.	0
BACKGROUND:Due to its rarity, information on pulmonary metastasectomy for pulmonary metastasis from ovarian cancer is limited. METHODS:Cases of pulmonary metastasectomy for ovarian cancer were collected in a multi-institutional setting and the outcomes were analyzed. RESULTS:Among 1508 cases in which pulmonary resection was performed to treat pulmonary metastasis from tumors of various organs, 6 cases (0.4%) involved pulmonary metastasis from ovarian cancer. The mean age was 61 years (range, 39-75 years). The histological types were undifferentiated carcinoma in 2 patients, and clear cell adenocarcinoma, serous papillary cystadenocarcinoma, serous adenocarcinoma, and endometroid adenocarcinoma in 1 patient each. One patient (17%) had a history of liver metastasis at the time of pulmonary resection. The median disease-free interval was 22 months (range, 0 [synchronous]-188 months). The tumor was solitary in 5 patients (83%). The mean tumor size was 15 mm (range, 5-23 mm). All 6 patients underwent complete resection. The type of resection was wide wedge resection in 3 patients, segmentectomy in 2 patients, and lobectomy in 1 patient. Four patients (67%) received postoperative chemotherapy. Thus far, 4 patients (67%) have experienced recurrence after pulmonary resection. In terms of outcomes, 1 patient who had synchronous pulmonary metastasis with the primary tumor died in the early period after pulmonary resection, 1 patient is alive without recurrence after a short follow-up period (5 months), 3 patients have achieved mid- to long-term survival and are alive with disease (38-61 months), and 1 patient achieved long-term (61 months) disease-free survival. CONCLUSIONS:Patients with pulmonary metastasis from ovarian cancer who fulfill the eligibility criteria for pulmonary metastasectomy are rare. Pulmonary metastasectomy for ovarian cancer can provide favorable outcomes in highly selected patients. Patients with synchronous pulmonary metastasis from ovarian cancer are not good candidates for pulmonary metastasectomy.	0
External root resorption (ERR) of permanent teeth is a pathological process that can lead to their loss. There are several systemic and/or genetic abnormalities that have been associated with ERR. Among them, familial expansile osteolysis (FEO) is an autosomal dominant disease characterized by skeletal defects, middle ear deafness, and abnormal root resorption. The purpose of this paper was to describe the case of a 10-year-old female with familial expansile osteolysis born with missing ossicles and, therefore, deafness. The patient was not diagnosed with FEO until the age of 10 years, when she presented to the dental clinic with advanced ERR in several permanent teeth. The series of tests she underwent for diagnosis and the treatments rendered are presented and discussed. It is recommended that when ERR cannot be explained by local etiologic factors, systemic abnormalities and genetic testing should be considered.	0
BACKGROUND:Primary rhinoplasty has not been universally adopted because the potential for nasal growth impairment remains an unsolved issue in cleft care. This study's purpose was to assess the long-term effects of primary rhinoplasty performed by a single surgeon in a cohort of patients with a unilateral cleft lip nose deformity. METHODS:Three-dimensional nasal morphometric measurements (linear, angular, proportional, surface area, and volume) were collected from consecutive patients (cleft group, n = 52; mean age, 19 ± 1 year) who had undergone primary rhinoplasty with the use of the Noordhoff approach between 1995 and 2002 and reached skeletal maturity. Normal age-, sex-, and ethnicity-matched subjects (control group, n = 52) were identified for comparative analyses. RESULTS:No significant differences (all p > 0.05) were observed for most measures, including nasal height, alar width, nasal dorsum angle, columellar angle, columellar-labial angle, nasal tip/height ratio, nasal index, alar width/intercanthal distance ratio, nasal surface area, and nasal volume. The cleft group displayed significantly (all p < 0.05) lower nasal bridge length and nasal tip projection, and greater nasal protrusion, tip/midline deviation, nasal tip angle, nasal tip protrusion width index, and alar width/mouth ratio values than the control group. CONCLUSIONS:Primary rhinoplasty does not interfere with nasal growth as measured by three-dimensional photogrammetric analysis. Further imaging studies are required for the assessment of development in other anatomical nasal structures. CLINICAL QUESTION/LEVEL OF EVIDENCE:Therapeutic, IV.	0
Missense mutations in the MYH3 gene encoding myosin heavy chain-embryonic (MyHC-embryonic) have been reported to cause two skeletal muscle contracture syndromes, Freeman Sheldon Syndrome (FSS) and Sheldon Hall Syndrome (SHS). Two residues in MyHC-embryonic that are most frequently mutated, leading to FSS, R672 and T178, are evolutionarily conserved across myosin heavy chains in vertebrates and Drosophila. We generated transgenic Drosophila expressing myosin heavy chain (Mhc) transgenes with the FSS mutations and characterized the effect of their expression on Drosophila muscle structure and function. Our results indicate that expressing these mutant Mhc transgenes lead to structural abnormalities in the muscle, which increase in severity with age and muscle use. We find that flies expressing the FSS mutant Mhc transgenes in the muscle exhibit shortening of the inter-Z disc distance of sarcomeres, reduction in the Z-disc width, aberrant deposition of Z-disc proteins, and muscle fiber splitting. The ATPase activity of the three FSS mutant MHC proteins are reduced compared to wild type MHC, with the most severe reduction observed in the T178I mutation. Structurally, the FSS mutations occur close to the ATP binding pocket, disrupting the ATPase activity of the protein. Functionally, expression of the FSS mutant Mhc transgenes in muscle lead to significantly reduced climbing capability in adult flies. Thus, our findings indicate that the FSS contracture syndrome mutations lead to muscle structural defects and functional deficits in Drosophila, possibly mediated by the reduced ATPase activity of the mutant MHC proteins.	0
BACKGROUND:Chromosome deletions of the long arm of chromosome 4 in 4q syndrome are characterized by mild facial and digital dysmorphism, developmental delay, growth retardation, and skeletal and cardiac anomalies, which is regarded as an autism spectrum disorder. Moreover, some scarce reports indicate that patients with 4q interstitial deletion and 7p duplication may present symptoms associated with hearing loss. CASE PRESENTATION:A boy with a severe developmental delay not only post-natal but also intrauterine and several dysmorphic features including microcephaly, ocular hypertelorism, exophthalmos, low-set ears, single palmar flexion crease, and overlapping toes presented discontinued cyanosis and recurrent respiratory infections. MRI, BAEP, echocardiogram and bronchoscopy revealed that he had persistent falcine sinus with a thin corpus callosum, left auditory pathway disorder, patent foramen ovale (2 mm), and tracheobronchomalacia with the right superior bronchus arising from the lateral posterior wall of the right main bronchus. Finally, the patient died with severe pneumonia at 10 months. Array CGH revealed a 23.62 Mb deletion at chromosome 4q27, arr [hg19] 4q27-q31.21 (121, 148, 089-144, 769, 263) × 1, and a 0.85 Mb duplication at chromosome 7q36.1, arr [hg19] 7q36.1-q36.2 (152, 510, 685-153, 363,5 98) × 3. It is rare for 4q syndrome cases or 7q duplications previously reported to have a hearing disorder, pulmonary dysplasia, and pulmonary arterial hypertension. CONCLUSIONS:The phenotype of our patient mainly reflects the effects of haploinsufficiency of FGF2, SPATA5, NAA15, SMAD1, HHIP genes combined with a microduplication of 7q36.1.	0
The exotoxin TcsL is a major virulence factor in Paeniclostridium (Clostridium) sordellii and responsible for the high lethality rate associated with P. sordellii infection. Here, we present a genome-wide CRISPR-Cas9-mediated screen using a human lung carcinoma cell line and identify semaphorin (SEMA) 6A and 6B as receptors for TcsL. Disrupting SEMA6A/6B expression in several distinct human cell lines and primary human endothelial cells results in reduced TcsL sensitivity, while SEMA6A/6B over-expression increases their sensitivity. TcsL recognizes the extracellular domain (ECD) of SEMA6A/6B via a region homologous to the receptor-binding site in Clostridioides difficile toxin B (TcdB), which binds the human receptor Frizzled. Exchanging the receptor-binding interfaces between TcsL and TcdB switches their receptor-binding specificity. Finally, administration of SEMA6A-ECD proteins protects human cells from TcsL toxicity and reduces TcsL-induced damage to lung tissues and the lethality rate in mice. These findings establish SEMA6A and 6B as pathophysiologically relevant receptors for TcsL.	0
Ellis-van Creveld syndrome (EvC MIM. #225500) is an autosomal recessive skeletal dysplasia characterised by thoracic hypoplasia, cardiac anomalies, acromesomelic limb shortening, and postaxial polydactyly. Affected individuals commonly manifest with cardiorespiratory failure as neonates but generally survive neonatal difficulties. We report here on affected Japanese sibs with a lethal phenotype of EvC caused by novel compound heterozygous mutations of EVC2, c.871-3 C > G and c.1991dupA.	0
BACKGROUND:X-linked hydrocephalus (XLH), characterized by mental retardation and bilateral adducted thumbs, often come out to be a genetic disorder of L1CAM. It codes the protein L1 cell adhesion molecule (L1CAM), playing a crucial role in the development of the nervous system. The objective of the study was to report a new disease-causing mutation site of L1CAM, and gain further insight into the pathophysiology of hydrocephalus. METHODS:We collect the samples of a couple and their second hydrocephalic fetus. Then, the whole-exome sequencing and in-depth mutation analysis were performed. RESULTS:The variant c.2491delG (p.V831fs), located in the exon 19 of L1CAM (chrX:153131214), could damage the L1CAM function by producing a frameshift in the translation of fibronectin type-III of L1CAM. CONCLUSION:We identified a novel disease-causing mutation in L1CAM for the first time, which further confirmed L1CAM as a gene underlying XLH cases.	0
Osteogenesis imperfecta (OI) is a heterogeneous bone disorder characterized by recurrent fractures. Although most cases of OI have heterozygous mutations in COL1A1 or COL1A2 and show autosomal dominant inheritance, during the last years there has been an explosion in the number of genes responsible for both recessive and dominant forms of this condition. Herein, we have analyzed a cohort of patients with OI, all offspring of unaffected parents, to determine the spectrum of variants accounting for these cases. Twenty patients had nonrelated parents and were sporadic, and 21 were born to consanguineous relationships.Mutation analysis was performed using a next-generation sequencing gene panel, homozygosity mapping, and whole exome sequencing (WES).Patients offspring of nonconsanguineous parents were mostly identified with COL1A1 or COL1A2 heterozygous changes, although there were also a few cases with IFITM5 and WNT1 heterozygous mutations. Only one sporadic patient was a compound heterozygote for two recessive mutations. Patients offspring of consanguineous parents showed homozygous changes in a variety of genes including CRTAP,FKBP10,LEPRE1,PLOD2,PPIB,SERPINF1,TMEM38B, and WNT1. In addition, two patients born to consanguineous parents were found to have de novo COL1A1 heterozygous mutations demonstrating that causative variants in the collagen I structural genes cannot be overlooked in affected children from consanguineous couples. Further to this, WES analysis in probands lacking mutations in OI genes revealed deleterious variants in SCN9A,NTRK1, and SLC2A2, which are associated with congenital indifference to pain (CIP) and Fanconi-Bickel syndrome (FBS).This work provides useful information for clinical and genetic diagnosis of OI patients with no positive family history of this disease. Our data also indicate that CIP and FBS are conditions to be considered in the differential diagnosis of OI and suggest a positive role of SCN9A and NTRK1 in bone development.	0
Dowling-Degos disease (DDD) is a rare genodermatosis primarily presenting with reticulated pigmentation of the flexures. Secondary features include comedones and atrophic scarring. We present a patient with histologically confirmed DDD whose predominant clinical finding was of comedones and scarring, with less prominent pigmentation, thus expanding the clinical spectrum of DDD.	0
BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) results from mutations in the SERPINA1 gene and classically presents with early-onset emphysema and liver disease. The most common mutation presenting with clinical evidence is the Z mutation, while the S mutation is associated with a milder plasma deficiency. AATD is an under-diagnosed condition and the World Health Organisation recommends targeted detection programmes for AATD in patients with chronic obstructive pulmonary disease (COPD), non-responsive asthma, cryptogenic liver disease and first degree relatives of known AATD patients. METHODS: We present data from the first 3,000 individuals screened following ATS/ERS guidelines as part of the Irish National Targeted Detection Programme (INTDP). We also investigated a DNA collection of 1,100 individuals randomly sampled from the general population. Serum and DNA was collected from both groups and mutations in the SERPINA1 gene detected by phenotyping or genotyping. RESULTS: The Irish National Targeted Detection Programme identified 42 ZZ, 44 SZ, 14 SS, 430 MZ, 263 MS, 20 IX and 2 rare mutations. Analysis of 1,100 randomly selected individuals identified 113 MS, 46 MZ, 2 SS and 2 SZ genotypes. CONCLUSION: Our findings demonstrate that AATD in Ireland is more prevalent than previously estimated with Z and S allele frequencies among the highest in the world. Furthermore, our targeted detection programme enriched the population of those carrying the Z but not the S allele, suggesting the Z allele is more important in the pathogenesis of those conditions targeted by the detection programme.	1
Background:Turner syndrome (TS), a relatively rare chromosomal disease, is associated with multiple cardiovascular risk factors that possibly lead to increased left ventricular afterload and functional impairment. The aim of this study was to investigate whether alterations in myocardial work and work efficiency can be found in TS patients through left ventricular pressure-strain loop analysis (PSL). Methods:Thirty-eight patients with TS and 19 healthy, age-matched controls were recruited for this study. Global peak systolic strain (GLPS) and PSL of the left ventricle was assessed in study participants. TS patients whose history included coarctation of the aorta or prior cardiac surgery were excluded from GLPS and PSL analyses (n=5). Results:Median age was 16.00 years in the TS group and 16.35 years in the control group (P=0.236). GLPS did not show significant differences between both groups (P=0.524). TS patients demonstrated, compared to controls, a significantly higher global myocardial work index (BSA) (mean ± SD: 1,497±505 vs. 1,214±245 mmHg*%/m2; P=0.027). Heart rate was significantly increased in TS patients, compared to controls (mean ± SD: 90.08±14.79 vs. 73.95±15.05 bpm; P<0.001), and correlated significantly with global myocardial work index [body surface area (BSA)] within the TS cohort (r=0.558, P=0.001). Conclusions:TS patients showed signs of increased myocardial workload that were only detectable through the novel PSL analysis method and not through GLPS. Moreover, elevated resting heart rate was linked with increased myocardial workload in TS patients. Further studies will have to investigate whether TS patients may develop advanced left ventricular systolic dysfunction later in life.	0
Leptospirosis is a spirochetal zoonotic disease with a wide clinical spectrum, often underdiagnosed especially when presented as an acute neurological manifestation. We report a case of a 24-year-old man with serologically positive leptospirosis, who presented with altered sensorium, seizures and subsequently developed cortical blindness. His brain MRI revealed bilateral occipital and later parietal lobe cerebritis.	0
Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are responsible for a significant disease burden amongst Māori and Pacific populations in New Zealand (NZ). However, contemporary data are lacking regarding circulating group A Streptococcal (GAS) strains in NZ. Such information is important in guiding vaccine development.GAS isolates from April to June 2015 were recovered from skin and pharyngeal samples from children living in areas of high social deprivation in Auckland, NZ, a significant proportion of which are Māori or Pacific. These children are among the highest risk group for developing ARF. Isolates were compared to concurrently collected pharyngeal isolates from Dunedin, NZ, where both the proportion of Māori and Pacific children and risk of developing ARF is low. Emm typing, emm cluster typing and theoretical coverage of the 30-valent vaccine candidate were undertaken as previously described.A high diversity of emm types and a high proportion of emm-pattern D and cluster D4 isolates were detected amongst both skin and pharyngeal isolates in children at high risk of ARF. Pharyngeal isolates from children at low risk of ARF within the same country were significantly less diverse, less likely to be emm pattern D, and more likely to be theoretically covered by the 30-valent M protein vaccine.The high proportion of emm pattern D GAS strains amongst skin and pharyngeal isolates from children at high risk of ARF raises further questions about the role of skin infection in ARF pathogenesis. Emm types and emm clusters differed considerably between ARF endemic and non-endemic settings, even within the same country. This difference should be taken into account for vaccine development.	0
OBJECTIVES:Biallelic variants in solute carrier family 24 member 4 (SLC24A4) have been previously reported to cause non-syndromic autosomal recessive amelogenesis imperfecta (AI) of the pigmented hypomaturation type (MIM #615887). We here describe a novel variant in SLC24A4 causing mild enamel hypomaturation defects also in heterozygous individuals. MATERIALS AND METHODS:In the present pedigree analysis, a large consanguineous Syrian family with AI of the hypomaturation type was investigated by clinical and dental evaluation, and exome and Sanger sequencing. Dental histological investigations of seven primary and two permanent teeth were performed. RESULTS:Homozygous variants in SLC24A4 (c.1604G>A; p.Gly535Asp) were identified in five individuals with brown discolorations and irregular pits and grooves of the teeth. Severe attritions, occlusal abfractions, and the radiological lack of contrast between enamel and dentin point out a mineralization defect. Histological dental investigations confirmed the clinical diagnosis of AI of the hypomaturation type. In two heterozygous individuals, a mild hypomaturation defect was present with white and light brown enamel discolorations. CONCLUSIONS:This is the first report of heterozygous SLC24A4 variants causing mild hypomaturation defects, providing confirmatory evidence that the function of SLC24A4 in calcium transport has a crucial role in the maturation stage of amelogenesis. CLINICAL RELEVANCE:The present report is expanding the clinical phenotype of SLC24A4 variants to more severe forms of amelogenesis imperfecta. An autosomal-dominant inheritance pattern with mild clinical phenotypes in heterozygotes has to be considered.	0
Becker nevus syndrome is a phenotype characterized by the fundamental presence of Becker's nevus with ipsilateral hypoplasia of the breast or other skin, skeletal and/or muscular disorders. This syndrome generally originates at birth, intensifies significantly in adolescence and is one of the syndromes that constitute epidermal nevus syndrome. To the best of our knowledge, this is the first case published in the Brazilian literature of Becker nevus syndrome associated with Becker's nevus, ipsilateral breast hypoplasia and scoliosis in a 14-year-old girl.	0
UNLABELLED: The recent epidemiology and outcomes of primary biliary cirrhosis (PBC) in North America are incompletely described, partly due to difficulties in case ascertainment. In light of their availability, broad coverage, and limited expense, administrative databases may facilitate such investigations. We used population-based administrative data (inpatient, ambulatory care, and physician billing databases) and a validated International Classification of Diseases coding algorithm to describe the epidemiology and natural history of PBC in the Calgary Health Region (population approximately 1.1 million). Between 1996 and 2002, the overall age/sex-adjusted annual incidence of PBC was 30.3 cases per million (48.4 per million in women, 10.4 per million in men). Although the incidence remained stable, the prevalence increased from 100 per million in 1996 to 227 per million in 2002 (P < 0.0005). Among 137 incident cases with a total follow-up of 801 person-years from diagnosis (median 5.8 years), 27 patients (20%) died and six (4.4%) underwent liver transplantation. The estimated 10-year probabilities of survival, liver transplantation, and transplant-free survival were 73% (95% confidence interval [CI] 60%-83%), 6% (95% CI 2.5%-12.6%), and 68% (95% CI 55%-78%), respectively. Survival in PBC patients was significantly lower than that of the age/sex-matched Canadian population (standardized mortality ratio 2.87; 95% CI 1.89-4.17); male sex (hazard ratio [HR] 3.80; 95% CI 1.85-7.82) and an older age at diagnosis (HR per additional year, 1.06; 95% CI 1.03-1.10) were independent predictors of mortality. CONCLUSION: This population-based study demonstrates that the burden of PBC in Canada is high and growing. Survival of PBC patients is significantly lower than that of the general population, emphasizing the importance of developing new therapies for this condition.	1
BACKGROUND: Kohlschütter-Tönz syndrome is a rare neurodegenerative disorder presenting with intractable seizures, developmental regression, and characteristic hypoplastic dental enamel indicative of amelogenesis imperfecta. Recently, mutations in ROGDI were identified in part of Kohlschütter-Tönz syndrome cases, but the siblings reported here do not have a mutation in the ROGDI gene, showing that there is genetic heterogeneity in Kohlschütter-Tönz syndrome. AIM: Report two siblings that have Kohlschütter-Tönz syndrome. CONCLUSION: Early onset of seizures and lack of the ability to walk without support may be signs of non-ROGDI mutations in Kohlschütter-Tönz syndrome patients.	0
Following the first isolation of nuclear receptor (NR) genes, genetic disorders caused by NR gene mutations were initially discovered by a candidate gene approach based on their known roles in endocrine pathways and physiologic processes. Subsequently, the identification of disorders has been informed by phenotypes associated with gene disruption in animal models or by genetic linkage studies. More recently, whole exome sequencing has associated pathogenic genetic variants with unexpected, often multisystem, human phenotypes. To date, defects in 20 of 48 human NR genes have been associated with human disorders, with different mutations mediating phenotypes of varying severity or several distinct conditions being associated with different changes in the same gene. Studies of individuals with deleterious genetic variants can elucidate novel roles of human NRs, validating them as targets for drug development or providing new insights into structure-function relationships. Importantly, human genetic discoveries enable definitive disease diagnosis and can provide opportunities to therapeutically manage affected individuals. Here we review germline changes in human NR genes associated with "monogenic" conditions, including a discussion of the structural basis of mutations that cause distinctive changes in NR function and the molecular mechanisms mediating pathogenesis.	0
Background:A large deletion in Xp22.3 can result in contiguous gene syndromes, including X-linked ichthyosis (XLI) and Kallmann syndrome (KS), presenting with short stature, chondrodysplasia punctata, intellectual disability, and strabismus. XLI and KS are caused by the deletion of STS and ANOS1, respectively. Method:Two KS patients with XLI were screened to identify possible pathogenic mutations using whole exome sequencing. The clinical characteristics, molecular genetics, treatment outcomes, and genotype-phenotype association for each patient were analyzed. Results:We identified a novel 3,923 kb deletion within the Xp22.31 region (chrX: 5810838-9733877) containing STS, ANOS1, GPR143, NLGN4X, VCX-A, PUDP, and PNPLA4 in patient 1, who presented with KS, XLI, obesity, hyperlipidemia, and strabismus. We identified a novel 5,807 kb deletion within the Xp22.31-p22.33 regions (chrX: 2700083-8507807) containing STS, ANOS1, and other 24 genes in patient 2, who presented with KS, XLI, obesity, and strabismus. No developmental delay, abnormal speech development, or autistic behavior were noticed in either patient. Conclusion:We identified two novel microdeletions in the X chromosome leading to KS and XLI. These findings contribute to the understanding of the molecular mechanisms that drive contiguous gene syndromes. Our research confirmed that the Kallmann-Ichthyosis phenotype is caused by microdeletions at the chromosome level.	0
The impact of lenalidomide treatment on long-term outcomes of patients with lower risk myelodysplastic syndromes (MDS) and chromosome 5q deletion (del(5q)) is unclear. This study used time-dependent multivariate methodology to analyse the influence of lenalidomide therapy on overall survival (OS) and acute myeloblastic leukaemia (AML) progression in 215 patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk and del(5q). There were significant differences in several relevant characteristics at presentation between patients receiving (n = 86) or not receiving lenalidomide (n = 129). The 5-year time-dependent probabilities of OS and progression to AML were 62% and 31% for patients receiving lenalidomide and 42% and 25% for patients not receiving lenalidomide; differences were not statistically significant in multivariate analysis that included all variables independently associated with those outcomes (OS, P = 0·45; risk of AML, P = 0·31, respectively). Achievement of RBC transfusion independency (P = 0·069) or cytogenetic response (P = 0·021) after lenalidomide was associated with longer OS in multivariate analysis. These data clearly show that response to lenalidomide results in a substantial clinical benefit in lower risk MDS patients with del(5q). Lenalidomide treatment does not appear to increase AML risk in this population of patients.	0
We performed shallow single-cell sequencing of genomic DNA across 1475 cells from a cell-line, COLO829, to resolve overall complexity and clonality. This melanoma tumor-line has been previously characterized by multiple technologies and is a benchmark for evaluating somatic alterations. In some of these studies, COLO829 has shown conflicting and/or indeterminate copy number and, thus, single-cell sequencing provides a tool for gaining insight. Following shallow single-cell sequencing, we first identified at least four major sub-clones by discriminant analysis of principal components of single-cell copy number data. Based on clustering, break-point and loss of heterozygosity analysis of aggregated data from sub-clones, we identified distinct hallmark events that were validated within bulk sequencing and spectral karyotyping. In summary, COLO829 exhibits a classical Dutrillaux's monosomic/trisomic pattern of karyotype evolution with endoreduplication, where consistent sub-clones emerge from the loss/gain of abnormal chromosomes. Overall, our results demonstrate how shallow copy number profiling can uncover hidden biological insights.	0
Genomic analyses have revolutionized our understanding of the biology of B-progenitor acute lymphoblastic leukemia (ALL). Studies of thousands of cases across the age spectrum have revised the taxonomy of B-ALL by identifying multiple new subgroups with diverse sequence and structural initiating events that vary substantially by age at diagnosis and prognostic significance. There is a growing appreciation of the role of inherited genetic variation in predisposition to ALL and drug responsiveness and of the nature of genetic variegation and clonal evolution that may be targeted for improved diagnostic, risk stratification, disease monitoring, and therapeutic intervention. This review provides an overview of the current state of knowledge of the genetic basis of B-ALL, with an emphasis on recent discoveries that have changed our approach to diagnosis and monitoring.	0
Zika virus (ZIKV) infection during pregnancy has been causally linked to a constellation of neurodevelopmental deformities in the fetus resulting in a disease termed congenital Zika syndrome (CZS). Here we detail how ZIKV infection produces extensive neuropathology in the developing mouse brain and spinal cord of both sexes. Surprisingly, neuropathology differs depending on viral strain with a French Polynesian isolate producing primarily excitotoxicity and a Brazilian isolate being almost exclusively apoptotic but occurring over a prolonged period that is more likely to produce severe hypoplasia. We also show exposure can produce a characteristic pattern of infection that mirrors neuropathology and ultimately results in gross morphological deformities strikingly similar to CZS. This research provides a valuable mouse model mirroring the clinical course of disease that can be used to test potential therapies to improve treatment and gain a better understanding of the disabilities associated with CZS.SIGNIFICANCE STATEMENT Zika virus (ZIKV) infection during pregnancy has been causally linked to a constellation of neurodevelopmental deformities in the fetus resulting in a disease termed congenital Zika syndrome. Despite its devastating effects, very little is known about how ZIKV infection produces fetal neuropathology. Here we detail the temporal progression of ZIKV infection in the mouse brain and spinal cord resulting in massive neurodegeneration of infected regions. We also report a ZIKV strain from a region of Brazil with high levels of microcephaly (abnormally small head circumference) produces particularly devastating neuropathology.	0
OBJECTIVES:The diagnostic utility of En1 in the histopathologic differentiation of eccrine porocarcinoma (EPC) from invasive squamous cell carcinoma (SCC) was investigated. METHODS:Expression of En1 and CK19 in 16 cases of EPC was immunohistochemically examined and compared with that in 32 cases of SCC. RESULTS:In all 16 EPCs, En1 was expressed in 3% to 100% of tumor cells. In 20 of the 32 SCCs, En1 was expressed in 3% to 90% of tumor cells. A total of 13 of the 16 EPCs and five of the 32 SCCs were judged as En1 positive, with a cutoff value of 25%. In addition, 11 of the 16 EPCs and four of the 32 SCCs were CK19 positive. The frequencies of En1- and CK19-positive cases were significantly higher in EPCs than in SCCs. In a logistic regression analysis for predicting EPC, En1 and CK19 were independent markers. When expression patterns of En1 and CK19 were combined, none of the 32 SCCs was both positive. In contrast, 15 of the 16 EPCs were positive for either En1 or CK19. CONCLUSIONS:A combination of En1 and CK19 expression can improve the accuracy of histologic diagnosis of EPC.	0
Introduction:Osteochondromas are usually found in the long bones of patients with hereditary multiple exostoses (HME). The spine is reported to be involved in over 50% of cases, but few of these patients are symptomatic as the result of an existing spinal exostosis. Methods:We reviewed the current literature in order to find the right approach to patients with HME-complicated spinal exostosis and describe three paediatric patients that were diagnosed late with spinal cord compression due to cervical exostosis. Results:Our three cases were all late presentations with neurology and unfortunately had minimal improvement of neurology after the lesion was surgically removed. There is general agreement that late presentation of spinal cord injury due to osteochondromas involving the cervical spine may cause severe and irreversible neurological sequelae. Our literature review revealed that there are no clear-cut guidelines to develop more comprehensive screening measures for these patients. Conclusions:A high index of suspicion is the most important factor for correct diagnosis and appropriate management. Physicians who treat HME should bear in mind that thorough history taking and a neurological examination at follow up are essential for these patients. Clearer guidelines for the development of more comprehensive screening programmes are essential. Level of evidence:IV.	0
Brugada syndrome (BrS) is classically a malignant, genetically determined, arrhythmic syndrome manifesting as syncope or sudden cardiac death (SCD) in individuals with structurally normal hearts. An exceedingly rare cause of an induced electrocardiogram (ECG) pattern mimicking BrS is secondary to loperamide abuse. The following case describes the onset of a transient Brugada pattern secondary to loperamide abuse in a young healthy male.	0
Movement disorders in childhood comprise a heterogeneous group of conditions that lead to impairment of voluntary movement, abnormal postures, or inserted involuntary movements. Movement disorders in children are frequently caused by metabolic disorders, both inherited and acquired. Many of these respond to vitamin supplementation. Examples include infantile tremor syndrome, biotinidase deficiency, biotin-thiamine-responsive basal ganglia disease, pyruvate dehydrogenase deficiency, aromatic amino acid decarboxylase deficiency, ataxia with vitamin E deficiency, abetalipoproteinemia, cerebral folate deficiency, and cobalamin metabolism defects. Recognition of these disorders by pediatricians and neurologists is imperative as they are easily treated by vitamin supplementation. In this review, we discuss vitamin-responsive movement disorders in children.	0
Non-arteritic anterior ischemic optic neuropathy (NAION) is the most common cause of optic nerve swelling and optic neuropathy in adults over 50 years of age.[1]. Risk factors that have been strongly associated with NAION include hypertension, hypercholesterolemia, diabetes mellitus, cardio- and cerebrovascular disease, and obstructive sleep apnea.[2]. While the exact pathogenesis of a NAION has not been elucidated, the prevailing theory is that it is caused by hypoperfusion of the short posterior ciliary arteries supplying the optic nerve, which then causes ischemia which induces swelling of the portion of the optic nerve traveling through the small opening in a scleral canal.[2] This, in turn, leads to the compartment syndrome involving neighboring axons that are now compressed in a space limited by the small opening in the scleral canal, leading to apoptosis and death of the ganglion cells whose axons comprise the optic nerve. The natural history of NAION has been elucidated in Ischemic Optic Neuropathy Decompression Trial which demonstrated that about 30% of patients would regain 3 or more lines of vision at 2 years follow up, 20% will lose 3 or more lines of vision and in the majority of patients, the vision will remain unchanged after the onset.[3] In reality, visual acuity will not change in the vast majority of patients after the acute event has resolved, and the ones who are able to see a few lines better likely learned to improve their fixation.	0
Protein phosphatase 1 catalytic subunit beta (PPP1CB) is a disease-causing gene of Noonan-like syndrome, which acts via the RAS/MAPK pathway. To date, only 17 patients diagnosed with PPP1CB-related Noonan-like syndrome have been reported around the world, with few reports in Asia. Twelve reported patients are of short stature and only one patient was treated with growth hormone (GH); however, follow-up data is lacking. To the best of our knowledge, this is the first reported patient with complete recombinant human growth hormone (rhGH) treatment follow-up data; the patient has a de novo c.146C>G (p.Pro49Arg) mutation in the PPP1CB gene. The hair pattern of the patient (coarse, curly, slow growing, and fragile) combined with Noonan dysmorphic features, developmental delay, and congenital heart disease, are highly consistent with the typical features observed in Noonan syndrome-like disorder with loose anagen hair 2 (NSLH2). rhGH treatment, administered for 3 years and 8 months, promoted the patient's linear growth. Our findings expand the data regarding the treatment of short stature in patients with NSLH2 caused by PPP1CB mutation. Clinical manifestation, growth and development process, and rhGH therapy effect data will aid in future revision of the relevant diagnosis and treatment guidelines.	0
Camurati-Engelmann disease is a rare autosomal dominant inherited condition belonging to the group of craniotubular hyperostosis with characteristic radiological features of the diaphyses of the long bones and the skull. A 35-year-old female is reported presenting with bone pain and waddling gait, since the age of 20 years. Motor activities were limited since the age of 10 years. Palpable bones, muscle weakness and protrusion of eyes were noted. Radiologically, hyperostosis of long bones was seen. Based on history, clinical and radiological features Camurati-Engelmann disease was diagnosed. Sequence analysis of the transforming growth factor β1 (TGFB1) gene revealed a missense mutation (c.652C>T; p.Arg218Cys). She is the first molecularly confirmed case in sub-Saharan Africa. It is emphasized that Camurati-Engelmann disease is included in the differential diagnosis of persistent bone pain, but also of abnormal childhood motor development in order to avoid unnecessary investigations and inadequate management.	0
Fractures of the midface pose a serious medical problem as for their complexity, frequency and their socio-economic impact. Interdisciplinary approaches and up-to-date diagnostic and surgical techniques provide favorable results in the majority of cases though. Traffic accidents are the leading cause and male adults in their thirties are affected most often. Treatment algorithms for nasal bone fractures, maxillary and zygomatic fractures are widely agreed upon whereas trauma to the frontal sinus and the orbital apex are matter of current debate. Advances in endoscopic surgery and limitations of evidence based gain of knowledge are matters that are focused on in the corresponding chapter. As for the fractures of the frontal sinus a strong tendency towards minimized approaches can be seen. Obliteration and cranialization seem to decrease in numbers. Some critical remarks in terms of high dose methylprednisolone therapy for traumatic optic nerve injury seem to be appropriate. Intraoperative cone beam radiographs and preshaped titanium mesh implants for orbital reconstruction are new techniques and essential aspects in midface traumatology. Fractures of the anterior skull base with cerebrospinal fluid leaks show very promising results in endonasal endoscopic repair.	0
Quebec Platelet disorder (QPD) is a unique bleeding disorder that markedly increases urokinase plasminogen activator (uPA) in megakaryocytes and platelets but not in plasma or urine. The cause is tandem duplication of a 78 kb region of chromosome 10 containing PLAU (the uPA gene) and C10orf55, a gene of unknown function. QPD increases uPA in platelets and megakaryocytes >100 fold, far more than expected for a gene duplication. To investigate the tissue-specific effect that PLAU duplication has on gene expression and transcript structure in QPD, we tested if QPD leads to: 1) overexpression of normal or unique PLAU transcripts; 2) increased uPA in leukocytes; 3) altered levels of C10orf55 mRNA and/or protein in megakaryocytes and leukocytes; and 4) global changes in megakaryocyte gene expression. Primary cells and cultured megakaryocytes from donors were prepared for quantitative reverse polymerase chain reaction analyses, RNA-seq and protein expression analyses. Rapidly isolated blood leukocytes from QPD subjects showed only a 3.9 fold increase in PLAU transcript levels, in keeping with the normal to minimally increased uPA in affinity purified, QPD leukocytes. All subjects had more uPA in granulocytes than monocytes and minimal uPA in lymphocytes. QPD leukocytes expressed PLAU alleles in proportions consistent with an extra copy of PLAU on the disease chromosome, unlike QPD megakaryocytes. QPD PLAU transcripts were consistent with reference gene models, with a much higher proportion of reads originating from the disease chromosome in megakaryocytes than granulocytes. QPD and control megakaryocytes contained minimal reads for C10orf55, and C10orf55 protein was not increased in QPD megakaryocytes or platelets. Finally, our QPD megakaryocyte transcriptome analysis revealed a global down regulation of the interferon type 1 pathway. We suggest that the low endogenous levels of uPA in blood are actively regulated, and that the regulatory mechanisms are disrupted in QPD in a megakaryocyte-specific manner.	0
Objectives: To investigate the ability of radiomics features from MRI in differentiating anaplastic oligodendroglioma (AO) from atypical low-grade oligodendroglioma using machine-learning algorithms. Methods: A total number of 101 qualified patients (50 participants with AO and 51 with atypical low-grade oligodendroglioma) were enrolled in this retrospective, single-center study. Forty radiomics features of tumor images derived from six matrices were extracted from contrast-enhanced T1-weighted (T1C) images and fluid-attenuation inversion recovery (FLAIR) images. Three selection methods were performed to select the optimal features for classifiers, including distance correlation, least absolute shrinkage and selection operator (LASSO), and gradient boosting decision tree (GBDT). Then three machine-learning classifiers were adopted to generate discriminative models, including linear discriminant analysis, support vector machine, and random forest (RF). Receiver operating characteristic analysis was conducted to evaluate the discriminative performance of each model. Results: Nine predictive models were established based on radiomics features from T1C images and FLAIR images. All of the classifiers represented feasible ability in differentiation, with AUC more than 0.840 when combined with suitable selection method. For models based on T1C images, the combination of LASSO and RF classifier represented the highest AUC of 0.904 in the validation group. For models based on FLAIR images, the combination of GBDT and RF classifier showed the highest AUC of 0.861 in the validation group. Conclusion: Radiomics-based machine-learning approach could potentially serve as a feasible method in distinguishing AO from atypical low-grade oligodendroglioma.	0
BACKGROUND:Biotin-thiamine responsive basal ganglia disease (BTBGD) is an autosomal recessive disorder caused by mutations in the SLC19A3 gene and characterized by recurrent sub-acute episodes of encephalopathy that typically starts in early childhood. This study describes characteristic clinical and magnetic resonance imaging (MRI) findings of six cases of BTBGD diagnosed with newly identified mutations and genetically confirmed, with very early and different presentations compared to cases in the previous literature. METHODS:Six patients referred from different centers with similar clinical findings were diagnosed with BTBGD with newly identified mutations in the SLC19A3 gene. Two novel mutations in the SLC19A3 gene were identified in two patients at whole exome sequencing analysis. The clinical characteristics, responses to treatment, and electroencephalography (EEG) and MRI findings of these patients were examined. The other four patients presented with similar clinical and cranial MRI findings. These patients were therefore started on high-dose biotin and thiamine therapy, and mutation analysis concerning the SLC19A3 gene was performed. Responses to treatment, clinical courses, EEG findings and follow-up MRI were recorded for all these patients. RESULTS:Age at onset of symptoms ranged from 1 to 3 months. The first symptoms were generally persistent crying and restlessness. Seizures occurred in five of the six patients. Cranial magnetic resonance imaging revealed involvement in the basal ganglia, brain stem, and the parietal and frontal regions in general. The first two patients were siblings, and both exhibited a novel mutation of the SLC19A3 gene. The third and fourth patients were also siblings and also exhibited a similar novel mutation of the SLC19A3 gene. The fifth and sixth patients were not related, and a newly identified mutation was detected in both these subjects. Three novel mutations were thus detected in six patients. CONCLUSION:BTBGD is a progressive disease that can lead to severe disability and death. Early diagnosis of treatable diseases such as BTBGD is important in order to prevent long-term complications and disability.	0
Introduction LEOPARD syndrome is a rare genetic disorder characterised by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth and sensorineural deafness. Clinical manifestations are often mild, which may result in difficult and late diagnosis. Cardiac involvement may have a significant impact on the prognosis, however, appearance of severe abnormalities such as hypertrophic cardiomyopathy usually precedes the occurrence of multiple lentigines and may be asymptomatic. Case presentation We report two cases of LEOPARD syndrome with hypertrophic cardiomyopathy in a 10-year-old girl and an 18-year-old boy. In both cases, multiple lentigines, ocular hypertelorism and growth retardation were present. The first patient was followed up at the paediatric cardiology clinic due to the risk of progression of septal hypertrophy and pressure gradient across the left ventricular outflow tract, the second patient underwent surgery for a moderate obstruction of the left ventricular outflow tract with uncomplicated post-operative follow-up. Conclusion In both presented patients, hypertrophic cardiomyopathy was clinically silent and the murmur over the precordium was the sole cardiac abnormality revealed during routine visit. A detailed cardiologic examination should be considered in the patients with suspicion of LEOPARD syndrome since the ventricular hypertrophy is thought to precede the occurrence of lentigines and progress over time.	0
Induced pluripotent stem cells (iPSCs) obtained by reprogramming primary somatic cells have revolutionized the fields of cell biology and disease modeling. However, the number protocols for generating mature muscle fibers with sarcolemmal organization using iPSCs remain limited, and partly mimic the complexity of mature skeletal muscle. Methods: We used a novel combination of small molecules added in a precise sequence for the simultaneous codifferentiation of human iPSCs into skeletal muscle cells and motor neurons. Results: We show that the presence of both cell types reduces the production time for millimeter-long multinucleated muscle fibers with sarcolemmal organization. Muscle fiber contractions are visible in 19-21 days, and can be maintained over long period thanks to the production of innervated multinucleated mature skeletal muscle fibers with autonomous cell regeneration of PAX7-positive cells and extracellular matrix synthesis. The sequential addition of specific molecules recapitulates key steps of human peripheral neurogenesis and myogenesis. Furthermore, this organoid-like culture can be used for functional evaluation and drug screening. Conclusion: Our protocol, which is applicable to hiPSCs from healthy individuals, was validated in Duchenne Muscular Dystrophy, Myotonic Dystrophy, Facio-Scapulo-Humeral Dystrophy and type 2A Limb-Girdle Muscular Dystrophy, opening new paths for the exploration of muscle differentiation, disease modeling and drug discovery.	0
Purpose:To describe a unique presentation of Central Nervous System Burkitt Lymphoma. Observations:A 59-year-old male presented with new onset binocular horizontal diplopia five days after initial presentation with abdominal distension, weight loss, and night sweats. He was diagnosed with Burkitt Lymphoma with base of skull metastasis that was initially visible only on PET scan and subsequently resolved with chemotherapy. Conclusions and Importance:Burkitt Lymphoma (BL) is an aggressive type of B-cell, non-Hodgkin, lymphoma that arises due to a translocation of the MYC proto-oncogene. Although central nervous system (CNS) involvement has been described previously with BL, isolated sixth nerve palsy as the initial sign of CNS metastasis is rare. Suspicion should remain high for metastatic disease in patients presenting with acute-onset neurologic complaints even when initial imaging is negative as timely treatment can prevent poor outcomes.	0
BACKGROUND:Isolated complex II deficiency is a rare form of mitochondrial disease, accounting for approximately 2% of all respiratory chain deficiency diagnoses. The succinate dehydrogenase (SDH) genes (SDHA, SDHB, SDHC and SDHD) are autosomally-encoded and transcribe the conjugated heterotetramers of complex II via the action of two known assembly factors (SDHAF1 and SDHAF2). Only a handful of reports describe inherited SDH gene defects as a cause of paediatric mitochondrial disease, involving either SDHA (Leigh syndrome, cardiomyopathy) or SDHAF1 (infantile leukoencephalopathy). However, all four SDH genes, together with SDHAF2, have known tumour suppressor functions, with numerous germline and somatic mutations reported in association with hereditary cancer syndromes, including paraganglioma and pheochromocytoma. METHODS AND RESULTS:Here, we report the clinical and molecular investigations of two patients with histochemical and biochemical evidence of a severe, isolated complex II deficiency due to novel SDH gene mutations; the first patient presented with cardiomyopathy and leukodystrophy due to compound heterozygous p.Thr508Ile and p.Ser509Leu SDHA mutations, while the second patient presented with hypotonia and leukodystrophy with elevated brain succinate demonstrated by MR spectroscopy due to a novel, homozygous p.Asp48Val SDHB mutation. Western blotting and BN-PAGE studies confirmed decreased steady-state levels of the relevant SDH subunits and impairment of complex II assembly. Evidence from yeast complementation studies provided additional support for pathogenicity of the SDHB mutation. CONCLUSIONS:Our report represents the first example of SDHB mutation as a cause of inherited mitochondrial respiratory chain disease and extends the SDHA mutation spectrum in patients with isolated complex II deficiency.	0
Spinal and bulbar muscular atrophy or Kennedy disease (KD) is an X-linked recessive disorder caused by a pathogenic CAG expansion in the first exon of the androgen receptor. Proximal muscle atrophy, weakness, contraction fasciculations, bulbar involvement, and sensory disturbances are part of the clinical picture of KD. We report the unusual genetic and phenotypic expression in 2 monozygotic twins. Genetic analysis has shown abnormal expansion of CAG repeat in the first exon of the androgen receptor gene on chromosome X different between the twin brothers (44, respectively, 46) but with large phenotypical differences including onset age, evolution, and clinical features. Disease began at age 31 for the first brother, respectively, and at 56 years for the second one and consisted of muscle wasting and progressive impairment of walking. In addition, the second brother did not manifest bulbar involvement 3 years after clinical onset and has more sensory features. Besides classical EMG testing, we evaluate sensory participation in spinal and bulbar muscular atrophy with sudoscan device and confirmed the sensory deficit. We discussed epigenetic factors potentially involved in KD that could play a role in the phenotypical differences. To the best of our knowledge, this is the first case describing CAG trinucleotide repeats in monozygotic twins and also the first sudoscan diagnostic of sensory disturbances in Kennedy syndrome.	0
Inborn errors of metabolism (IEM) are a rare cause of epilepsy, but seizures and epilepsy are frequently encountered in patients with IEM. Since these disorders are related to inherited enzyme deficiencies with resulting effects on metabolic/biochemical pathways, the term "metabolic epilepsy" can be used to include these conditions. These epilepsies can present across the life span, and share features of refractoriness to anti-epileptic drugs, and are often associated with co-morbid developmental delay/regression, intellectual, and behavioral impairments. Some of these disorders are amenable to specific treatment interventions; hence timely and appropriate diagnosis is critical to improve outcomes. In this review, we discuss those disorders in which epilepsy is a dominant feature and present an approach to the clinical recognition, diagnosis, and management of these disorders, with a greater focus on primarily treatable conditions. Finally, we propose a tiered approach that will permit a clinician to systematically investigate, identify, and treat these rare disorders.	0
Albright hereditary osteodystrophy (AHO) is a complex disorder defined by the presence of a short adult stature relative to the height of an unaffected parent and brachydactyly type E, as well as a stocky build, round face, and ectopic calcifications. AHO and pseudohypoparathyroidism (PHP) have been used interchangeably in the past. The term PHP describes end-organ resistance to parathyroid hormone (PTH), occurring with or without the physical features of AHO. Conversely, pseudopseudohypoparathyroidism (PPHP) describes individuals with AHO features in the absence of PTH resistance. PHP and PPHP are etiologically linked and caused by genetic and/or epigenetic alterations in the guanine nucleotide-binding protein alpha-stimulating (Gs α) locus (GNAS) in chromosome 20q13. Another less-recognized group of skeletal dysplasias, termed acrodysostosis, partially overlap with skeletal, endocrine, and neurodevelopmental features of AHO/PHP and can be overlooked in clinical practice, causing confusion in the literature. Acrodysostosis is caused by defects in two genes, PRKAR1A and PDE4D, both encoding important components of the Gs α-cyclic adenosine monophosphate-protein kinase A signaling pathway. We describe the clinical course and genotype of two adult patients with overlapping AHO features who harbored novel pathogenic variants in GNAS (c.2273C > G, p.Pro758Arg, NM_080425.2) and PRKAR1A (c.803C > T, p.Ala268Val, NM_002734.4), respectively. We highlight the value of expert radiological opinion and molecular testing in establishing correct diagnoses and discuss phenotypic features of our patients, including the first description of subcutaneous ossification and spina bifida occulta in PRKAR1A-related acrodysostosis, in the context of the novel inactivating PTH/PTH related peptide signaling disorder classification system.	0
Hereditary spastic paraplegias are heterogeneous disorders with diversified clinical manifestations, and genetic testing is important for the diagnosis and typing of hereditary spastic paraplegias.Gene panel sequencing containing 55 hereditary spastic paraplegias-related genes was performed to screen the pathogenic genes for hereditary spastic paraplegias. Sanger sequencing was adopted to validate if the family member carried the same pathogenic gene as the proband.Fifteen out of 53 patients carried mutation(s) in the screened hereditary spastic paraplegias-related genes. Among the 23 identified mutations, only one mutation had been previously reported as a pathogenic mutation. In the pedigree of case 6, the proband, his mother and uncle all carried the same novel deletion mutation (c.1459delA) at SPAST gene. Based on the pedigree, the disease was inherited in an AD pattern. In the pedigree of case 53, the family disease may be in an X-linked recessive inheritance pattern. The proband (case 53) carried two novel mutations in ALT1 gene and L1CAM gene (c.2511C>A), respectively. The L1CAM gene is the causative gene for the SPG1 X-linked recessive-hereditary spastic paraplegias.Our data confirm the genetic heterogeneity of hereditary spastic paraplegias, and SPG4/SPAST were the most frequent forms. The pathogenicity of the novel mutations is worth to be further investigated.	0
The sideroblastic anemias (SAs) are a group of inherited and acquired bone marrow disorders defined by pathological iron accumulation in the mitochondria of erythroid precursors. Like most hematological diseases, the molecular genetic basis of the SAs has ridden the wave of technology advancement. Within the last 30 years, with the advent of positional cloning, the human genome project, solid-state genotyping technologies, and next-generation sequencing have evolved to the point where more than two-thirds of congenital SA cases, and an even greater proportion of cases of acquired clonal disease, can be attributed to mutations in a specific gene or genes. This review focuses on an analysis of the genetics of these diseases and how understanding these defects may contribute to the design and implementation of rational therapies.	0
Etiologic diagnosis of seizure requires proper consideration of apparently unrelated clinical features of the patient. Here, we report the case of a patient of status epilepticus with moderate-to-severe bilateral sensorineural deafness. Investigations showed extensive intracranial calcification, hypoparathyroidism and unilateral renal agenesis. The features were consistent with Barakat syndrome, a rare developmental disorder associated with mutations in the GATA3 gene. To the best of our knowledge, this is the first reported case of Barakat syndrome from India.	0
BACKGROUND:Brachydactyly type A1(BDA-1) is an autosomal dominant disorder which is caused by heterozygous pathogenic variants in a specific region of the N-terminal active fragment of Indian Hedgehog (IHH). The disorder is mainly characterized by shortening or missing of the middle phalanges. In this study, Our purpose is to identify the pathogenic variations associated with BDA-1 involved in a five-generation Chinese family. METHODS:A BDA-1 family with 8 affected and 14 unaffected family members was recruited. Whole exome sequencing (WES) was performed to identify the pathogenic variant in the proband, and which was later confirmed and segregated by Sanger sequencing. The significance of variants were assessed using several molecular and bioinformatics analysis methods. RESULTS:We uncovered a novel heterozygous missense variant c.299A > G (p.D100G) at the mutational hotspot of IHH gene following whole-exome sequencing of a Chinese family with BDA-1. The variant co-segregated with BDA-1 in the pedigree, showed 100% penetrance for phalange phenotype with variable expressivity. CONCLUSIONS:In conclusion, this study reports a five-generation Chinese family with BDA-1 due to a novel pathogenic variant (c.299A > G (p.D100G)) of IHH and expands the clinical and genetic spectrum of BDA-1.	0
Albright's hereditary osteodystrophy is a rare disease, characterized by phosphocalcic balance abnormalities related to peripheral resistance to parathyroid hormone. It is an hereditary affection with autosomal dominant inheritance pattern caused by mutation in GNAS gene1. It combines specific morphotype, subcutaneous calcifications, bone and renal resistance to parathyroid hormone. We report a new case of Albright's hereditary osteodystrophy in a 9-month old infant followed up for significant hypocalcaemia which occurred at 10 days of life. The purpose of this study was to remind clinicians of the clinical, biological, genetic and therapeutic features of this disease.	0
BACKGROUND:An early diagnosis of CHARGE syndrome is challenging, especially for the primary care physicians who often take care of neonates with multiple congenital anomalies. Here we report eight cases of CHARGE syndrome whose diagnosis was made early in life with the intent to identify the most helpful features allowing a prompt clinical diagnosis. METHODS:Medical records of patients with CHARGE syndrome whose diagnosis was made at the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico in Milan, Italy were retrospectively reviewed. RESULTS:Taken together, these patients reflect the considerable phenotypic variability of the syndrome; in one patient, the diagnosis was made immediately after birth because all the major criteria were met. In six patients, presenting with relatively nonspecific defects, a temporal bone computerized tomography scan was essential to achieve the correct diagnosis. In one patient, the diagnosis was made later than the others were. A careful examination revealed the presence of outer, middle, and inner ear anomalies: these elements, in the absence of any additional major criteria, represented for us an important diagnostic clue. CONCLUSIONS:This article suggests that an accurate evaluation of the ear should be made every time CHARGE syndrome is considered as a likely diagnosis even when the standard criteria are not fulfilled.	0
To present clinical, chromosomal and hormonal features of ten cases with SRY-positive 46,XX testicular disorder of sex development who were admitted to our infertility clinic.Records of the cases who were admitted to our infertility clinic between 2004 and 2015 were investigated. Ten 46,XX testicular disorder of sex development cases were detected. Clinical, hormonal and chromosomal assessments were analized.Mean age at diagnosis was 30.4, mean body height was 166.9cm. Hormonal data indicated that the patients had a higher FSH, LH levels, lower TT level and normal E2, PRL levels. Karyotype analysis of all patients confirmed 46,XX karyotype, and FISH analysis showed that SRY gene was positive and translocated to Xp. The AZFa, AZFb and AZFc regions were absent in 8 cases. In one case AZFb and AZFc incomplete deletion and normal AZFa region was present. In the other one all AZF regions were present.Gonadal development disorders such as SRY-positive 46,XX testicular disorder of sex development can be diagnosed in infertility clinics during infertility workup. Although these cases had no chance of bearing a child, they should be protected from negative effects of testosterone deficiency by replacement therapies.	0
Coexistence of the Poland syndrome and gynecomastia is a rare condition. Poland syndrome requires soft tissue augmentation of the affected side, whereas gynecomastia necessitates reduction of the breast tissue. To provide symmetry, breast reduction and fat grafting techniques should be combined. We report a 29-year-old male patient with left gynecomastia and right sided Poland syndrome. In order to correct his asymmetry on the anterior chest wall, left breast tissue resection and fat grafting to the right breast were performed. Having these two opposite conditions at the same time and on the same patient makes the deformities look more dramatic than they are separately. Accurate planning and selection of proper techniques enable to provide symmetry in such cases.	0
OBJECTIVE:Niemann-Pick disease type C1 (NPC1) is a lysosomal storage disease characterized by progressive neurodegeneration, with the age of diagnosis ranging from the prenatal period through adulthood. Although neurological symptoms usually precede genetic diagnosis, they do not necessarily prompt diagnosis in the early years. Few prospective data are available to describe neurological onset, including neurodevelopmental delays, in children with NPC1. This dearth of information hinders the planning and implementation of adequate monitoring and treatment for the neurodevelopmental sequelae of NPC1. METHOD:Twenty-nine infants, toddlers, and preschoolers younger than 6 years participated in a natural history study and were administered neurodevelopmental assessments using instruments commonly used for early intervention screening in the community. RESULTS:Twenty-two of 29 participants met the criteria for a significant delay of at least 1.5 SDs below the mean in at least one domain of development; the youngest children often met these criteria for a significant delay based on motor delays, but cognitive and language delays were also common. However, only 11 of the 22 participants were reported to receive early intervention services before study entry. CONCLUSION:Although neurological symptoms may not prompt the genetic diagnosis of NPC1, the current findings support the use of a multimethod approach to repeated assessments for young children with the diagnosis because of the frequency of developmental delays or decline in multiple domains. The diagnosis of NPC1 alone should qualify children for evaluation for early intervention services and consideration of investigational therapeutic interventions.	0
Hyaline fibromatosis syndrome (HFS) is the unifying term for infantile systemic hyalinosis and juvenile hyaline fibromatosis. HFS is a rare autosomal recessive disorder of the connective tissue caused by mutations in the gene for anthrax toxin receptor-2 (ANTXR2). It is characterized by abnormal growth of hyalinized fibrous tissue with cutaneous, mucosal, osteoarticular, and systemic involvement. We reviewed the 84 published cases and their molecular findings, aiming to gain insight into the clinical features, prognostic factors, and phenotype-genotype correlations. Extreme pain at minimal handling in a newborn is the presentation pattern most frequently seen in grade 4 patients (life-limiting disease). Gingival hypertrophy and subcutaneous nodules are some of the disease hallmarks. Though painful joint stiffness and contractures are almost universal, weakness and hypotonia may also be present. Causes of death are intractable diarrhea, recurrent infections, and organ failure. Median age of death of grade 4 cases is 15.0 months (p25-p75: 9.5-24.0). This review provides evidence to reinforce the previous hypothesis that missense mutations in exons 1-12 and mutations leading to a premature stop codon lead to the severe form of the disease, while missense pathogenic variants in exons 13-17 lead to the mild form of the disease. Multidisciplinary team approach is recommended.	0
BACKGROUND: Large-scale mitochondrial DNA (mtDNA) deletions are associated with clinical conditions such as Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia in adults and Pearson syndrome in children. Reported case series have suggested that deletions are not uncommon in the population, but their prevalence has not been documented. METHODS: The authors ascertained patients with clinical features associated with mtDNA deletions in a defined adult population in northern Finland. Buccal epithelial samples were requested from each patient fulfilling the selection criteria, and full-length mtDNA was amplified using the long PCR method. Deletion breakpoints were identified using sequencing. Patients with deletions were examined clinically. RESULTS: The authors identified four patients with single large-scale mtDNA deletions. The prevalence of deletions was calculated to be 1.6/100,000 in the adult population in the province of Northern Ostrobothnia (0.0 to 3.2; 95% CI). Analysis of incident cases from a neighboring province revealed two patients with deletions and yielded a similar population frequency. CONCLUSIONS: The frequency of large-scale mitochondrial DNA deletions is similar among populations, suggesting that there is a constant rate of new deletions.	1
We sequenced the complete coding genome of the western equine encephalitis virus (WEEV) strain Fleming. This strain was originally isolated in 1938 from a human WEEV case.	0
NEDD4L encodes an ubiquitin ligase which is expressed in the cortex and ventricular zone of the fetal brain. Missense variants in NEDD4L have been reported in nine patients with periventricular nodular heterotopia (PNH), polymicrogyria, cleft palate, and syndactyly. All reported variants are located in the HECT domain, causing deregulation of signaling pathways, including the AKT/mTOR pathway. Here we describe a first familial case with four affected members with a high degree of intra-familial phenotypic variability. Phenotypic features in the proband consisted of severe neurodevelopmental delay, refractory seizures, bilateral PNH, and perisylvian polymicrogyria. The other family members were less severely affected with mild developmental delay and isolated bilateral PNH. All family members had syndactyly. An unrelated patient presented with severe neurodevelopmental delay, seizures, and hypospadias, expanding the phenotypic spectrum. MRI revealed bilateral PNH and perisylvian polymicrogyria. All tested patients carry the recurrent variant c.623G > A, p.(Arg208Gln) in the WW domain of NEDD4L. The variant in the unrelated patient occurred de novo. This is the first report of a NEDD4L variant located in the WW domain which is probably involved in the recognition of substrates for ligation suggesting a loss of function variant.	0
Celiac disease (CD) is an immune-mediated enteropathy triggered by dietary ingestion of gluten in genetically susceptible patients. CD is often diagnosed by a "case-finding" approach of symptomatic patients. In recent times, the diagnostic paradigm has shifted to investigate patients who may be asymptomatic, but are at high risk of developing CD due to shared genetic susceptibilities. These high-risk groups include first-degree relatives of CD patients and patients with Type 1 diabetes mellitus, autoimmune thyroid disease, Down's syndrome, and Turner syndrome. Moreover, CD is often diagnosed as the cause of iron deficiency anemia or unexplained chronic diarrhea. Although screening for CD with serological tests is not recommended for the general population, it should be considered in these special populations. In this review, we explore screening for CD among high-risk groups in light of recent research and development in the CD arena.	0
We report a case of osteogenesis imperfecta (OI) (OMIM166210) type II, in which a prenatal diagnosis was made by three-dimensional computed tomography (3D-CT). Subsequent molecular analysis revealed a recurrent, heterozygous mutation in COL1A2. Fetal CT is a powerful tool for visualizing the fetal skeleton and can provide a definitive diagnosis of fetal skeletal dysplasias; however, whether or not its employment for prenatal diagnosis is warranted in terms of fetal radiation risks remains controversial, both medically and ethically. Based on our experience, we review the current state of fetal CT for the diagnosis of skeletal dysplasias, with a discussion of the relevant literature.	0
The glycosylation of microbial natural products often dramatically influences the biological and/or pharmacological activities of the parental metabolite. Over the past decade, crystal structures of several enzymes involved in the biosynthesis and attachment of novel sugars found appended to natural products have emerged. In many cases, these studies have paved the way to a better understanding of the corresponding enzyme mechanism of action and have served as a starting point for engineering variant enzymes to facilitate to production of differentially-glycosylated natural products. This review specifically summarizes the structural studies of bacterial enzymes involved in biosynthesis of novel sugar nucleotides.	0
Objective:To analyze the potential role of colchicine monotherapy in patients with tumor necrosis factor receptor associated periodic syndrome (TRAPS) in terms of control of clinical and laboratory manifestations. Methods:Patients with TRAPS treated with colchicine monotherapy were retrospectively enrolled; demographic, clinical and therapeutic data were collected and statistically analysed after having clustered patients according to different times at disease onset, penetrance of mutations, dosage of colchicine, and different disease manifestations. Results:24 patients (14 males; 15 with pediatric disease onset) treated with colchicine monotherapy were enrolled. Colchicine resulted in a complete response in 3 (12.5%) cases, partial response in 14 (58.3%) patients, and lack of response in 7 (29.2%) patients. There were not significant differences in colchicine response between pediatric and adult disease onset (p = 0.42), between low- and high-penetrance mutations (p = 0.62), and according to different dosages (p = 0.66). No significant differences were identified in the frequency of specific disease manifestations between patients experiencing any response to colchicine and patients with lack of response. Conclusions:Colchicine monotherapy is useful in a low percentage of TRAPS patients; nevertheless, it could be attempted in patients with milder phenotypes and at a lower risk of developing reactive amyloidosis.	0
Nigrostriatal dopaminergic systems govern physiological functions related to locomotion, and their dysfunction leads to movement disorders, such as Parkinson's disease and dopa-responsive dystonia (Segawa disease). Previous studies revealed that expression of the gene encoding nigrostriatal tyrosine hydroxylase (TH), a rate-limiting enzyme of dopamine biosynthesis, is reduced in Parkinson's disease and dopa-responsive dystonia; however, the mechanism of TH depletion in these disorders remains unclear. In this article, we review the molecular mechanism underlying the neurodegeneration process in dopamine-containing neurons and focus on the novel degradation pathway of TH through the ubiquitin-proteasome system to advance our understanding of the etiology of Parkinson's disease and dopa-responsive dystonia. We also introduce the relation of α-synuclein propagation with the loss of TH protein in Parkinson's disease as well as anticipate therapeutic targets and early diagnosis of these diseases.	0
Spinocerebellar ataxia type 21 (SCA21/ATX-TMEM240) is a rare form of cerebellar ataxia that commonly presents with motor, cognitive, and behavioral impairments. Although these features have been identified as part of the clinical manifestations of SCA21, the neurodevelopmental disorders associated with SCA21 have not been well studied or described. Here we present extensive phenotypic data for 3 subjects from an SCA21 family in the United States. Genetic testing demonstrated the c.196 G>A (p.Gly66Arg) variant to be a second recurrent mutation associated with the disorder. Standardized developmental assessment revealed significant deficits in cognition, adaptive function, motor skills, and social communication with 2 of the subjects having diagnoses of autism spectrum disorder, which has never been described in SCA21. Quantitative gait analysis showed markedly abnormal spatiotemporal gait variables indicative of poor gait control and cerebellar as well as noncerebellar dysfunction. Clinical evaluation also highlighted a striking variability in clinical symptoms, with greater ataxia correlating with greater severity of neurodevelopmental disorder diagnoses. Notably, neurodevelopmental outcomes have improved with intervention over time. Taken together, this case series identifies that the manifestation of neurodevelopmental disorders is a key feature of SCA21 and may precede the presence of motor abnormalities. Furthermore, the coexistence of ataxia and neurodevelopmental disorders in these subjects suggests a role for spinocerebellar pathways in both outcomes. The findings in this study highlight the importance of evaluation of neurodevelopmental concerns in the context of progressive motor abnormalities and the need for timely intervention to ultimately improve quality of life for individuals with SCA21.	0
The case of a 2-year-old Puerto Rican boy is presented. Clinical and histologic features are detailed because he showed peculiar jet black patches of pigmentation on the fingers of the right hand. This case, except for the lack of progression of the disease after a 2-year period of follow-up, shows many similarities to the case of a Japanese child reported by Furuya and Mishima as "acromelanosis progressiva." This condition is viewed as the epidermal counterpart of pigmentary disorders composed of dermal melanocytes, "epidermal melanocytosis."	0
Purpose:To assess retinal function in young patients with X-linked juvenile retinoschisis (XLRS), a disorder that is known to alter ERG postreceptor retinal components and also possibly photoreceptor components. Methods:ERG responses to full-field stimuli were recorded under scotopic and photopic conditions in 12 XLRS patients aged 1 to 15 (median 8) years. A- and b-wave amplitudes and implicit times were examined over a range of stimulus intensities. Rod and cone photoreceptor (SROD, RROD, SCONE, RCONE) and rod-driven postreceptor (log σ, VMAX) response parameters were calculated from the a- and b-waves. Data from XLRS patients were evaluated for significant change with age. Results:A- and b-wave amplitudes were smaller in XLRS patients compared with controls under both scotopic and photopic conditions. Saturated photoresponse amplitude (RROD), postreceptor b-wave (log σ), and saturated b-wave amplitude (VMAX) were significantly lower in XLRS patients than in controls; SROD did not differ between the two groups. SCONE and RCONE values were normal. In XLRS patients, neither a- and b-wave amplitudes nor calculated parameters (SROD, RROD, log σ, VMAX,SCONE, and RCONE) changed with age. Conclusions:In these young XLRS patients, RROD and a-wave amplitudes were significantly smaller than in controls. Thus, in addition to XLRS causing postreceptor dysfunction, an effect of XLRS on rod photoreceptors cannot be ignored.	0
Three cases of severe odontogenic infections due to nontuberculous mycobacteria (NTM) in Venezuela that were directly associated with dental procedures and the finding of dental unit waterlines (DUWLs) in dental offices that were colonized with mycobacteria species was the reason for assessing the water quality of DUWLs in dental offices in two capital cities in South America, namely, Quito and Caracas. The main water supplies and the water from 143 DUWLs in both cities were sampled and especially checked for contamination with NTM. To measure the overall bacteriological quality of the water also the presence of heterotrophic bacteria, coliform bacteria, and Pseudomonas was determined. Results showed that respectively 3% and 56% of the DUWLs in Quito and Caracas yielded NTM species (up to 1000 colony-forming units (CFU)/mL). Furthermore, high and unacceptable total viable counts of heterotrophic bacteria and/or coliform bacteria and Pseudomonas were detected in 73% of the samples. We conclude that, in both cities, the water in the majority of DUWLs was contaminated with NTM and other potential pathogens, presenting a risk to human health. The detection of NTM in DUWL water with acceptable heterotrophic bacteria counts shows the need to include NTM in water quality testing. Mycobacteria are more resistant to disinfection procedures than other types of vegetative bacteria, and most testing protocols for DUWLs do not assess mycobacteria and thus do not guarantee risk-free water.	0
We describe a brother and sister who both had holoprosencephaly, polydactyly, cardiac lesions and a normal karyotype. The parents were first cousins and a diagnosis of pseudotrisomy 13 syndrome is suggested. This report provides further support that the inheritance of pseudotrisomy 13 syndrome is autosomal recessive.	0
We measured the performance of exposure screening questions to identify Nipah virus encephalitis in hospitalized encephalitis patients during the 2012-13 Nipah virus season in Bangladesh. The sensitivity (93%), specificity (82%), positive predictive value (37%), and negative predictive value (99%) results suggested that screening questions could more quickly identify persons with Nipah virus encephalitis.	0
Spondylocostal dysostosis (SCDO) is a heterogeneous group of skeletal disorders characterized by multiple segmentation defects involving vertebrae and ribs. Seven disease genes have been reported as causal genes for SCDO: DLL3, MESP2, TBX6, HES7, RIPPLY2, DMRT2, and LFNG. Here we report a Japanese SCDO case with multiple severe vertebral anomalies from cervical to sacral spine. The patient was a compound heterozygote for c.372delG (p.K124Nfs*) and c.601G>A (p.D201N) variants of LFNG, which encodes a glycosyltransferase (O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase). The missense variant was in the DxD motif, an active-site motif of the glycosyltransferase, and its loss of the enzyme function was confirmed by an in vitro enzyme assay. This is the second report of LFNG mutations in SCDO.	0
Inner ear anomalies diagnosed using a radiological study are detected in almost 30% of cases with congenital or prelingual-onset sensorineural hearing loss. Inner ear anomalies can be isolated or occur along with a part of a syndrome involving other systems. Although astonishing progress has been made in research aimed at revealing the genetic causes of hearing loss in the past few decades, only a few genes have been linked to inner ear anomalies. The aim of this review is to discuss the known genetic causes of inner ear anomalies. Identifying the genetic causes of inner ear anomalies is important for guiding clinical care that includes empowered reproductive decisions provided to the affected individuals. Furthermore, understanding the molecular underpinnings of the development of the inner ear in humans is important to develop novel treatment strategies for people with hearing loss.	0
Noonan and LEOPARD syndromes (NS and LS) belong to a group of related disorders called RASopathies characterized by abnormalities of multiple organs and systems including hypertrophic cardiomyopathy and dysmorphic facial features. There are no approved drugs for these two rare diseases, but it is known that a missense mutation in PTPN11 genes is associated with approximately 50% and 70% of NS and LS cases, respectively. In this study, we implemented a hybrid computational drug repositioning framework by integrating transcriptomic and structure-based approaches to explore potential treatment options for NS and LS. Specifically, disease signatures were derived from the transcriptomic profiles of human induced pluripotent stem cells (iPSCs) from NS and LS patients and reverse correlated to drug transcriptomic signatures from CMap and L1000 projects on the basis that if disease and drug transcriptomic signatures are reversely correlated, the drug has the potential to treat that disease. The compounds that were ranked top based on their transcriptomic profiles were docked to mutated and wild-type 3D structures of PTPN11 by an adjusted Induced Fit Docking (IFD) protocol. In addition, we prioritized repositioned candidates for NS and LS by a consensus ranking strategy. Network analysis and phenotypic anchoring of the transcriptomic data could discriminate the two diseases at the molecular level. Furthermore, the adjusted IFD protocol was able to recapitulate the binding specificity of potential drug candidates to mutated 3D structures, revealing the relevant amino acids. Importantly, a list of potential drug candidates for repositioning was identified including 61 for NS and 43 for LS and was further verified from literature reports and on-going clinical trials. Altogether, this hybrid computational drug repositioning approach has highlighted a number of drug candidates for NS and LS and could be applied to identifying drug candidates for other diseases as well.	0
Epilepsy is a condition marked by abnormal neuronal discharges or hyperexcitability of neurons with synchronicity and is recognized as a major public health concern. The pathology is categorized into three subgroups: acquired, idiopathic, and epilepsy of genetic or developmental origin. There are approximately 1000 associated genes and the role of γ-aminobutyric acid (GABA) mediated inhibition, as well as glutamate mediated excitation, forms the basis of pathology. Epilepsy is further classified as being of focal, general or unknown onset. Genetic predisposition, comorbidities and novel biomarkers are useful for prediction. Prevalent postictal symptoms are postictal headache and migraine, postictal psychosis and delirium, postictal Todd's paresis and postictal automatisms. Diagnostic methods include electroencephalography (EEG), computed tomography scan, magnetic resonance imaging (MRI), positron emission tomography, single photon emission computed tomography and genetic testing; EEG and MRI are the two main techniques. Clinical history and witness testimonies combined with a knowledge of seizure semiology helps in distinguishing between seizures. Clinical information and patient history do not always lead to a clear diagnosis, in which case EEG and 24-hour EEG monitoring with video recording (video-EEG/vEEG) help in seizure differentiation. Treatment includes first aid, therapeutics such as anti-epileptic drugs, surgery, ketogenic diet and gene therapy. In this review, we are focusing on summarizing published literature on epilepsy and epileptic seizures, and concisely apprise the reader of the latest cutting-edge advances and knowledge on epileptic seizures.	0
Rhabdomyomatous mesenchymal hamartoma (RMH) is a benign, potentially pigmented lesion that occurs in the head and neck region. It generally consists of haphazardly arranged skeletal muscle with adipose tissue, blood vessels, collagen and nerve fibers and is largely asymptomatic. Trigeminal neuralgia is pain due to compression of the trigeminal nerve. TN may be idiopathic or associated with lesion-mediated compression.We describe the case of a 14-year-old female presenting with trigeminal neuralgia (TN) associated with RMH. On initial consultation, the patient presented with a history of right-sided lower facial swelling, numbness, and pain. Evaluation by various specialists confirmed TN. Surgical resection of the lesion resolved the condition and pathology confirmed RMH.This is the first case report demonstrating RMH-mediated TN. Surgical resection of the RMH is a safe management approach for this diagnosis.	0
Granular cell tumors of the pituitary gland are rare, slow-growing lesions arising from the neurohypophysis or pituitary stalk. We describe an extremely rare presentation of a pituitary granular cell tumor mimicking an anterior communicating artery aneurysmal rupture with ventricular hemorrhage. The patient was admitted in a comatose state and underwent urgent bilateral external ventricular drainage. Further diagnostic investigation revealed a sellar tumoral mass with suprasellar extension. No vascular anomalies, hormonal abnormalities, or visual disturbances were observed. Macroscopic complete resection without neurologic impairment was obtained via a right pterional approach. Posthemorrhagic hydrocephalus necessitated ventriculoperitoneal shunt placement, and hormonal substitution for panhypopituitarism was provided. The 5-year follow-up examination showed no tumor recurrence. The clinical course of these benign World Health Organization grade I lesions will normally correspond to nonsecreting pituitary adenomas with an insidious development of visual disturbances, hypopituitarism, or hydrocephalus. Sudden onset with potential catastrophic intratumoral and intraventricular hemorrhage is very uncommon.	0
Juvenile amyotrophic lateral sclerosis (JALS) occurs at an age of onset below 25 years with a heterogeneous disease onset location, variable progression and survival time. To investigate whether an ALS gene profile could resolve any aspects of clinical symptom heterogeneity, we have used targeted sequencing technology in a cohort of 12 JALS patients of Chinese descent. We detected 5 likely pathogenic mutations, 2 in familial probands and 3 in sporadic patients. One was a known TARDBP mutation (p.G348V) and 4 were FUS frameshift mutations including a known p.Gln519Ilefs*9 mutation and 3 novel mutations, p.Gly515Valfs*14, p.Gly486Profs*30, and p.Arg498Alafs*32. Of the 4 FUS mutations, 2 were able to be confirmed as de novo mutations. The TARDBP mutation carrier showed a classic ALS phenotype. All patients with FUS mutations experienced limb weakness at an early age and developed bulbar symptoms during the disease course. FUS mutations have previously been associated with increased JALS disease progression, however, we found a large range 12 to 84 months in disease survival (mean 58.2 months). Our results justify future screening for variants in FUS as it remains the most frequent genetic determinant of early onset, JALS (found in 30% of our patients).	0
Hyperinsulinism/hyperammonemia (HI/HA) syndrome is considered as the second most common type of hereditary HI. Correlation of genotype and phenotype in HI/HA syndrome has been described in several studies. We present three Serbian patients with HI/HA syndrome with emphasis on a possible correlation between genotype and clinical manifestations. Patient 1 was heterozygous for a de novo mutation p.S445L in the GLUD1 gene, while patients 2 and 3 (son and mother) both carry the p.R221C mutation. Early onset of hypoglycaemia with generalized seizures was recorded in infancy in all three patients. The two male patients had mild developmental delay, while the female patient presented with epilepsy. Analysis of Serbian patients with HI/HA syndrome confirms the association of p.S445L and p.R221C mutations with hypoglycaemic seizures noted within the first three months of life and with subsequent risk for cognitive impairment and/or epilepsy.	0
An acute illness (Jamaican vomiting sickness) which affected two adults after eating unripe ackee fruit was investigated. Analyses of serum and urine samples were performed to compare the patterns of organic acidaemia and aciduria with those reported from childhood cases. The main conclusion from the comparison is that the toxic ackee constitutent, hypoglycin, produces essentially the same metabolic effects in adults as in children.	0
We report 8 cases of coccidioidomycosis associated with ruxolitinib treatment. Among 135 patients living in the coccidioidal-endemic region receiving ruxolitinib, 5 cases were diagnosed after starting and 4 had extrathoracic dissemination. Periodic serological screening while on ruxolitinib is warranted for patients residing in the coccidioidal-endemic region.	0
Distal arthrogryposis (DA) is a skeletal muscle disorder which can be classified under a broader term as Arthrogryposis multiplex contractures. DA is characterized by the presence of joint contractures at various parts of the body, particularly in distal extremities. It is identified as an autosomal dominant and a rare X-linked recessive disorder associated with increased connective tissue formation around joints in such way that immobilizes muscle movement causing deformities. DA is again classified into various types since it manifests as a range of conditions representing different etiologies. Myopathy is one of the most commonly listed etiologies of DA. The mutations in sarcomeric protein-encoding genes lead to decreased sarcomere integrity, which is often associated with this disorder. Also, skeletal disorders are often associated with cardiac disorders. Some studies mention the presence of cardiomyopathy in patients with skeletal dysfunction. Therefore, it is hypothesized that the congenitally mutated protein that causes DA can also lead to cardiomyopathy. In this review, we will summarize the different forms of DA and their clinical features, along with gene mutations responsible for causing DA in its different forms. We will also examine reports that list mutations also known to cause heart disorders in the presence of DA.	0
PURPOSE OF REVIEW:Currently, there is a rapid expansion of novel, efficacious therapies for the treatment of patients with myelodysplastic syndromes (MDS) at a rate never seen to date. In this review, we will outline new treatment strategies in MDS focusing on novel hypomethylating agents (HMA) and combinations in addition to targeted and immune-based therapies. RECENT FINDINGS:Large-scale gene sequencing and immune-based research has given us a great deal of information regarding the complexity and heterogeneity of MDS. This rapid improvement in our knowledge has provided a framework for development of novel therapies with specific gene and immune-based targets. Additionally, expanding and optimizing our current HMA-based strategies has led us to potentially not only ease administration but also improve outcomes. SUMMARY:Novel therapies in MDS are greatly needed is a disease state where few options are currently available, particularly in the HMA failure setting. Fortunately, through comprehensive genetic profiling, characterization of novel underlying pathogenic drivers, and understanding of the immune microenvironment, the treatment paradigm of patients with MDS is encouraging.	0
Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by deficient β-glucuronidase (β-gluc) activity. Significantly reduced β-gluc activity leads to accumulation of glycosaminoglycans (GAGs) in many tissues, including the brain. Numerous combinations of mutations in GUSB (the gene that codes for β-gluc) cause a range of neurological features that make disease prognosis and treatment challenging. Currently, there is little understanding of the molecular basis for MPS VII brain anomalies. To identify a neuronal phenotype that could be used to complement genetic analyses, we generated two iPSC clones derived from skin fibroblasts of an MPS VII patient. We found that MPS VII neurons exhibited reduced β-gluc activity and showed previously established disease-associated phenotypes, including GAGs accumulation, expanded endocytic compartments, accumulation of lipofuscin granules, more autophagosomes, and altered lysosome function. Addition of recombinant β-gluc to MPS VII neurons, which mimics enzyme replacement therapy, restored disease-associated phenotypes to levels similar to the healthy control. MPS VII neural cells cultured as 3D neurospheroids showed upregulated GFAP gene expression, which was associated with astrocyte reactivity, and downregulation of GABAergic neuron markers. Spontaneous calcium imaging analysis of MPS VII neurospheroids showed reduced neuronal activity and altered network connectivity in patient-derived neurospheroids compared to a healthy control. These results demonstrate the interplay between reduced β-gluc activity, GAG accumulation and alterations in neuronal activity, and provide a human experimental model for elucidating the bases of MPS VII-associated cognitive defects.	0
Tctn3 belongs to the Tectonic (Tctn) family and is a single-pass membrane protein localized at the transition zone of primary cilia as an important component of ciliopathy-related protein complexes. Previous studies showed that mutations in Tctn1 and Tctn2, two members of the tectonic family, have been reported to disrupt neural tube development in humans and mice, but the functions of Tctn3 in brain development remain elusive. In this study, Tctn3 knockout (KO) mice were generated by utilizing the piggyBac (PB) transposon system. We found that Tctn3 KO mice exhibited abnormal global development, including prenatal lethality, microphthalmia, polysyndactyly, and abnormal head, sternum, and neural tube, whereas Tctn3 heterozygous KO mice did not show abnormal development or behaviors. Further, we found that the mRNA levels of Gli1 and Ptch1, downstream signaling components of the Shh pathway, were significantly reduced. Likewise, neural tube patterning-related proteins, such as Shh, Foxa2, and Nkx2.2, were altered in their distribution. Interestingly, Tctn3 KO led to significant changes in apoptosis-related proteins, including Bcl-2, Bax, and cleaved PARP1, resulting in reduced numbers of neuronal cells in embryonic brains. Tctn3 KO inhibited the PI3K/Akt signaling pathway but not the mTOR-dependent pathway. The small molecule SC79, a specific Akt activator, blocked apoptotic cell death in primary mouse embryonic fibroblasts from Tctn3 KO mice. Finally, NPHP1, a protein with anti-apoptotic ability, was found to form a complex with Tctn3, and its levels were decreased in Tctn3 KO mice. In conclusion, our results show that Tctn3 KO disrupts the Shh signaling pathway and neural tube patterning, resulting in abnormal embryonic development, cellular apoptosis, and prenatal death in mice.	0
Limb development is clinically and biologically important. Polydactyly is common and caused by aberrant anterior-posterior patterning. Human disorders that include polydactyly are diverse. To facilitate an understanding of the biology of limb development, cataloging the genes that are mutated in patients with polydactyly would be useful. In 2002, I characterized human phenotypes that included polydactyly. Subsequently, many advances have occurred with refinement of clinical entities and identification of numerous genes. Here, I update human polydactyly entities by phenotype and mutated gene. This survey demonstrates phenotypes with overlapping manifestations, genetic heterogeneity, and distinct phenotypes generated from mutations in single genes. Among 310 clinical entities, 80 are associated with mutations in 99 genes. These results show that knowledge of limb patterning genetics is improving rapidly. Soon, we will have a comprehensive toolkit of genes important for limb development, which will lead to regenerative therapies for limb anomalies.	0
Pineal parenchymal tumors of intermediate differentiation (PPTID) are extremely rare tumor entities, and only limited data are available regarding their pathologic features and biologic behaviors. Because grading criteria of pineal parenchymal tumors (PPTs) have yet to be established, the treatment strategy and prognosis of PPTIDs remain controversial. We describe the clinicopathologic study of six patients with PPTID and compare responses for the treatment and prognosis with cases of pineocytoma (PC) and pineoblastoma (PB). From this analysis, we attempt to clarify the treatment strategy for PPTIDs.This study included 15 patients with PPTs, consisting of 6 PCs, 6 PPTIDs, and 3 PBs. We focused on the 6 patients with PPTIDs. All PPTID cases were treated surgically, and radiotherapy and chemotherapy were administered as adjuvant therapies in some cases. We have earlier reported the histopathologic study (Neuropathology 32:647-653, 2012). Briefly, we examined mitotic figures and necrosis by hematoxylin-eosin staining and immunohistochemical markers such as neuronal markers (synaptophysin, neurofilament (NF), and neuronal nuclear antigen), and an MIB-1 labeling index was determined.In the PPTID cases, the extent of resection was variable and the recurrence rates among patients varied according to stage and treatment. All PC patients underwent total resection with no recurrence. All PB patients underwent resection and adjuvant therapy with radiotherapy and chemotherapy. There were no recurrences in patients with PC or PB. The results of histopathologic findings have been already reported as mentioned above. Briefly, the results indicated no mitotic figure or necrosis in any of the six cases of PPTID, but those features were observed in PB cases. All cases even including PC and PB were immunopositive for neuronal markers. The MIB-1 labeling index of PPTID was 3.5%, whereas it was 0% in PC and 10.5% in PB.Good radiosensitivity of PPTIDs was observed in our series. Because there are cases with discrepancies between images and pathologic findings, it is very difficult to determine the proper treatment strategy for PPTIDs. Proliferative potential was correlated with World Health Organization grade, although the immunoreactivity of neuronal markers did not correlate with the histologic grade.	0
This article shortly examines the biography, scientific activity and scientific work on neuromuscular diseases of the famous Russian neurologist Vladimir Roth who was the founder of neuromuscular disorders study in Russia. In 1876 he was the first in Russia who performed an autopsy and a detailed histological study of a case of progressive muscular atrophy, in which he did not find changes in the nervous system. He called this disease "muscular tabes" i.e. myopathy. In 1884 Vladimir Roth expressed his opinion about the nosological place of the peripheral type of muscular tabes to be considered as a distal myopathy. Dr. Roth became well-known for his monograph of the neuromuscular diseases, published in Moscow in 1895 under the name "Muscular Tabes" in which he described the history of neuromuscular diseases in a very detailed way, analyzing 1014 cases published in the world literature from 1830 to 1893 and 125 personal observations in the period 1874-1894. He performed a thorough analysis of the pattern of muscle involvement using both electrodiagnostic and histological study of muscles and central/peripheral nervous system. We report a short review of this monograph and two cases of peripheral (distal) myopathy.	0
Nail diseases in children do not account for a significant proportion of pediatric consultations, and most of the time the nails are not observed by the clinician, overlooking their importance. Specific examination of the nails is neglected, while localization to the nails could be an initial sign of a syndrome or a systemic disorder. Nail diseases in the pediatric population differ from those in adults in terms of diagnostic approach and management; some of them even are manifested mainly or exclusively in children. Pediatric patients with underlying systemic disorders are more likely to manifest acquired disorders of the nails. Although rare, nail diseases in children are a source of anxiety for the parents. Examination of the nails is an essential part of pediatric physical examination. A correct clinical history and careful examination help the clinician to distinguish the different conditions and to decide on the correct management of nail diseases in young patients. A classification of nail dystrophies according to age is somewhat arbitrary and a unique classification does not exist. Nail diseases in the pediatric population can be divided according to age groups where a predilection appears in most of the cases. Moreover, certain abnormalities may be lifelong once acquired, but their presentation may be modified by age, worsening or improving during life. This review describes many of the nail conditions that are seen in the pediatric population aging from newborn to toddler, starting with physiological aspects to better recognize the pathological conditions.	0
Malformations are significant contributions to childhood mortality and disability. Their co-occurrence with intellectual disability may compound the health burden, requiring additional evaluation and management measures. Overall, malformations of greater or lesser severity occur in at least some cases of almost half of the 153 XLID syndromes. Genitourinary abnormalities are most common, but tend to contribute little or no health burden and occur in only a minority of cases of a given XLID syndrome. Some malformations (e.g., lissencephaly, hydranencephaly, long bone deficiency, renal agenesis/dysplasia) are not amenable to medical or surgical intervention; others (e.g., hydrocephaly, facial clefting, cardiac malformations, hypospadias) may be substantially corrected.	0
BACKGROUND:Many studies show the occurrence of several multiple endocrine neoplasia syndromes caused by different mutations, for example, in MEN1 and RET genes. Nevertheless, there are less common mutations causing multiple endocrine glands tumors. Examples of such mutations are CHEK2 gene mutations, causing breast, kidney, gastric, colorectal, prostate, lung, ovarian, and thyroid cancers. CASE DESCRIPTION:In 2005, a 30-year-old woman was admitted to the hospital due to uncontrolled hypertension and obesity. Performed tests have shown ACTH (adrenocorticotropic hormone)-independent micronodular adrenal hyperplasia (AIMAH) as a cause. In 2010, the further diagnostic analysis revealed Cushing's disease caused by ACTH-secreting pituitary microadenoma. Additionally, in 2011, the patient underwent the strumectomy of multinodular struma. Papillary thyroid carcinoma was found in the excised tissue. In 2018, transvaginal ultrasonography revealed a tumor of the right ovary. After a performed hysterectomy with bilateral salpingo-oophorectomy, the histopathology result has shown female adnexal tumors of probable Wolffian origin (FATWO) located in the broad ligament of the uterus. Due to the history of multiglandular diseases, the patient was referred to genetic testing. We found a positive pathogenic mutation in CHEK2-suppressor gene involved in DNA repair, cell cycle arrest, and apoptosis in response to DNA damage. CONCLUSION:CHEK2 variants may predispose to a range of endocrine glands tumors, including those identified in our patient. Multiple endocrine glands tumors, as in the presented patient, are a serious problem of public health, due to numerous hospitalizations and necessary repeated surgical treatments. Moreover, the association between CHEK2 and ovarian cancer can be a serious problem with reproductive health.	0
Leukodystrophies and genetic leukoencephalopathies are a heterogeneous group of heritable disorders that affect the glial-axonal unit. As more patients with unsolved leukodystrophies and genetic leukoencephalopathies undergo next generation sequencing, causative mutations in genes leading to central hypomyelination are being identified. Two such individuals presented with arthrogryposis multiplex congenita, congenital hypomyelinating neuropathy, and central hypomyelination with early respiratory failure. Whole exome sequencing identified biallelic mutations in the CNTNAP1 gene: homozygous c.1163G>C (p.Arg388Pro) and compound heterozygous c.967T>C (p.Cys323Arg) and c.319C>T (p.Arg107*). Sural nerve and quadriceps muscle biopsies demonstrated progressive, severe onion bulb and axonal pathology. By ultrastructural evaluation, septate axoglial paranodal junctions were absent from nodes of Ranvier. Serial brain magnetic resonance images revealed hypomyelination, progressive atrophy, and reduced diffusion in the globus pallidus in both patients. These 2 families illustrate severe progressive peripheral demyelinating neuropathy due to the absence of septate paranodal junctions and central hypomyelination with neurodegeneration in CNTNAP1-associated arthrogryposis multiplex congenita.	0
Emery-Dreifuss muscular dystrophy (EDMD) is a rare muscular dystrophy, but is particularly important to diagnose due to frequent life-threatening cardiac complications. EDMD classically presents with muscle weakness, early contractures, cardiac conduction abnormalities and cardiomyopathy, although the presence and severity of these manifestations vary by subtype and individual. Associated genes include EMD, LMNA, SYNE1, SYNE2, FHL1, TMEM43, SUN1, SUN2, and TTN, encoding emerin, lamin A/C, nesprin-1, nesprin-2, FHL1, LUMA, SUN1, SUN2, and titin, respectively. The Online Mendelian Inheritance in Man database recognizes subtypes 1 through 7, which captures most but not all of the associated genes. Genetic diagnosis is essential whenever available, but traditional diagnostic tools can help steer the evaluation toward EDMD and assist with interpretation of equivocal genetic test results. Management is primarily supportive, but it is important to monitor patients closely, especially for potential cardiac complications. There is a high potential for progress in the treatment of EDMD in the coming years.	0
This article reports a case of limb-girdle muscular dystrophy type 1B (LGMD1B) caused by a novel splicing heterozygous mutation in the LMNA gene. The proband presented with progressive aggravation of weakness in walking. There was no atrophy of the scapular muscles and the lower-extremity proximal muscles, with normal muscle tension of the extremities, grade 4 muscle strength in the upper and lower extremities, and positive Gower sign. The level of creatine kinase was 779 U/L. Muscle hematoxylin-eosin staining showed muscular dystrophy, and there was no significant reduction in the expression of Lamin A protein. Second-generation sequencing revealed a novel splicing heterozygous mutation, c.810+2T>C, in the LMNA gene, while this locus was normal in his parents. GERP++RS software predicted that the mutation site was highly conservative. Human Splice Finder and Spliceman software predicted that the mutation might be a pathogenic mutation. ExPASy software predicted that the new amino acid sequence became shorter. There were two sequences of mRNA in the patient's muscle: one was the normal sequence, which accounted for 92.2%; the other was partial intron 4 retention, which was the abnormal splice variant accounting for 7.8%. LGMD1B is a type of autosomal dominant inherited myopathy caused by a mutation in the LMNA gene located on the autosomal 1q22. This study extends the mutation spectrum of the LMNA gene and provides help to the diagnosis of LGMD1B.	0
Cholecystectomy is one of the most frequently done procedures in general surgery. There are few reports of amputation neuromas following this procedure. This presentation describes a case of obstructive jaundice due to amputation neuroma in a patient with a history of cholecystectomy.We report about a 53 y o lady who presented with obstructive jaundice, 8 years following open cholecystectomy. Paraclinical investigations were in favor of cholangicarcinoma, however the final pathology revealed an amputation neuroma of the CBD.Amputation neuromas are rarely seen in the era of laparoscopic cholecystectomy. They are benign reparative lesions of the CBD following surgery or manipulation of the extra hepatic biliary tree. It is very difficult to diagnose them pre-operatively. Surgical resection is the first choice of treatment.Traumatic neuromas should always be among the differential diagnosis, when assessing a CBD mass in patients with a previous history of open cholecystectomy or surgery to the gastrointestinal tract.	0
Trisomy 13 (T13) is a congenital chromosomal disorder that is usually fatal within 2 years of birth, and only a few patients have been reported to reach adolescence. Here, we report a male long-term survivor of T13, currently 15 years of age, with a several-year history of extensive acne conglobata (AC) with abscesses on the face and neck. Methicillin-resistant Staphylococcus aureus was consistently isolated from the pustular lesions. Serum IgM levels were extremely low at 10 mg/dl. There were no abnormalities in neutrophil and total B cell number, or in serum IgA and IgG levels. Increased CD8+ T cell counts and inversion of the CD4/CD8 ratio were observed repeatedly. The patient's clinical features and laboratory data support a diagnosis of selective IgM deficiency (SIgMD) with concurrent AC. Immunoglobulin replacement therapy elevated serum IgM levels to the normal range and reduced the severity of AC. We suggest that T13 may represent a syndromic disorder associated with multiple organ malformation and a risk of developing immunodeficiency involving SIgMD. Because pediatric SIgMD is rare and an immunological abnormality in T13 patients has not previously been reported, we describe the patient's clinical course.	0
Systemic amyloidosis can be hereditary or acquired. The autosomal dominant hereditary transthyretin amyloidosis and the acquired light-chain amyloidosis, the result of a plasma cell dyscrasia, are multisystem disorders with cardiovascular, autonomic and peripheral nerve involvement. There are numerous investigational modalities available to diagnose systemic amyloidosis and to assess the extent of organ involvement, but it is frequently misdiagnosed due to its heterogeneous clinical presentations and misleading investigation findings. An accurate and timely diagnosis of amyloid neuropathy can greatly impact on the outcomes for patients, especially as there will soon be new gene-silencing treatments for hereditary transthyretin amyloidosis.	0
Periodic paralysis (PP) is a rare disease caused by abnormal excitability of the sarcolemma, resulting in the episodic weakness in extremities. Two major subtypes have been identified: primary/familial PP showing Mendelian inheritance of a mutation in the ion channel genes expressed in skeletal muscle, and secondary/sporadic PP which does not show Mendelian inheritance. Thyrotoxic periodic paralysis (TPP) contributes to the majority of secondary PP cases in Asians and Latin Americans, suggesting that genetic factors may underlie the pathogenesis. In contrast, sporadic periodic paralysis (SPP) has no familial history and no secondary factors. The genetic features associated with SPP in Japanese patients remain unexplored. Here, we investigate whether nine single nucleotide variants (SNVs), rs623011, rs312691, rs393743, rs312692, rs312736, rs992072, rs312732, rs723498, and rs312707, found in TPP and/or SPP in other Asian populations are also associated with Japanese SPP cases. The study cohort included 43 Japanese periodic paralysis patients with no mutations in causative genes (SCN4A, CACNA1S, and KCNJ2), no myotonia, and with euthyroid function. The results showed disease susceptibility for all nine SNVs in our Japanese SPP cohort. One of them, rs312691, was newly confirmed to show susceptibility to SPP. Our results suggest the genetic background underlies periodic paralysis.	0
Objectives:This article reviews the current role of genetics in pediatric hearing loss (HL). Methods:A review of the current literature regarding the genetic basis of HL in children was performed. Results:To date, 119 nonsyndromic genes have been associated with HL. There are also hundreds of syndromic causes that have HL as part of the clinical phenotype. Conclusions:Identifying HL genes coupled with clinical characteristics ("genotype-phenotype") yields a more accurate diagnosis and prognosis. Although the complexity of the auditory apparatus presents challenges, gene therapy is emerging and may be a viable management option in the future.	0
PURPOSE:The purpose of this study was to describe the spectral domain-optical coherence tomography findings in a patient with cone-rod dystrophy 6. METHODS:This is a case report of a 13-year-old girl who presented with progressive loss of vision. Fundus photography, a fluorescein angiogram, an electroretinogram, autofluorescence imaging, spectral domain-optical coherence tomography, and genetic testing were performed. RESULTS:The patient's fundi showed mild granularity of the perifoveal retinal pigment epithelium. An electroretinogram showed cone dysfunction and normal rod function. Genetic testing showed a heterozygous CGC>CAC nucleotide substitution at codon 838 of the GUCY2D gene. This results in an amino acid change of Arg838His and provides a molecular diagnosis of cone-rod dystrophy 6. The spectral domain-optical coherence tomography showed abnormalities at the inner segment/outer segment junction and the outer segment layer suggestive of loss or disease of photoreceptor outer segments. Autofluorescence imaging showed a perifoveal ring of hyperfluorescence that correlated with abnormallities on spectral domain-optical coherence tomography. CONCLUSION:Spectral domain-optical coherence tomography can show photoreceptor abnormalities that correlate with the perifoveal ring seen with autofluorescence imaging of patients with cone-rod dystrophy 6. Spectral domain-optical coherence tomography has significant potential for understanding and following the natural history of diseases such as cone-rod dystrophy 6.	0
PURPOSE:The exocyst complex is a conserved protein complex that mediates fusion of intracellular vesicles to the plasma membrane and is implicated in processes including cell polarity, cell migration, ciliogenesis, cytokinesis, autophagy, and fusion of secretory vesicles. The essential role of these genes in human genetic disorders, however, is unknown. METHODS:We performed homozygosity mapping and exome sequencing of consanguineous families with recessively inherited brain development disorders. We modeled an EXOC7 splice variant in vitro and examined EXOC7 messenger RNA (mRNA) expression in developing mouse and human cortex. We modeled exoc7 loss-of-function in a zebrafish knockout. RESULTS:We report variants in exocyst complex members, EXOC7 and EXOC8, in a novel disorder of cerebral cortex development. In EXOC7, we identified four independent partial loss-of-function (LOF) variants in a recessively inherited disorder characterized by brain atrophy, seizures, and developmental delay, and in severe cases, microcephaly and infantile death. In EXOC8, we found a homozygous truncating variant in a family with a similar clinical disorder. We modeled exoc7 deficiency in zebrafish and found the absence of exoc7 causes microcephaly. CONCLUSION:Our results highlight the essential role of the exocyst pathway in normal cortical development and how its perturbation causes complex brain disorders.	0
Renal medullary carcinoma is a rare and highly aggressive tumor seen almost exclusively in young individuals of African descent with sickle cell disease. Here, we describe a case of a 29-year-old man, who did not have sickle cell disease, with pathologically confirmed renal medullary carcinoma using dual-time FDG PET/CT.	0
Mutations in small heat shock protein beta-1 (HspB1) have been linked to Charcot-Marie-Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole-exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1-related disorders.	0
The large majority of cases with intellectual disability are syndromic (i.e. occur with other well-defined clinical phenotypes) and have been studied extensively. Autosomal recessive nonsyndromic intellectual disability is a group of genetically heterogeneous disorders for which a number of potentially causative genes have been identified although the molecular basis of most of them remains unexplored. Here, we report the clinical characteristics and genetic findings of a family with two male siblings affected with autosomal recessive nonsyndromic intellectual disability. Whole exome sequencing was carried out on two affected male siblings and unaffected parents. A potentially pathogenic variant identified in this study was confirmed by Sanger sequencing to be inherited in an autosomal recessive fashion. We identified a novel nonsense mutation (p.Gln368Ter) in the LINS1 gene which leads to loss of 389 amino acids in the C-terminus of the encoded protein. The truncation mutation causes a complete loss of LINES_C domain along with loss of three known phosphorylation sites and a known ubiquitylation site in addition to other evolutionarily conserved regions of LINS1. LINS1 has been reported to cause MRT27 (mental retardation, autosomal recessive 27), a rare autosomal recessive nonsyndromic intellectual disability, with limited characterization of the phenotype. Identification of a potentially pathogenic truncating mutation in LINS1 in two profoundly intellectually impaired patients also confirms its role in cognition.	0
INTRODUCTION:The AP4B1 gene encodes a subunit of adaptor protein complex-4 (AP4), a component of intracellular transportation of proteins which plays important roles in neurons. Bi-allelic mutations in AP4B1 cause autosomal recessive spastic paraplegia-47(SPG47). CASE PRESENTATION:Here we present a Chinese patient with spastic tetraplegia, moderate psychomotor development delay and febrile seizures plus. Brain MRIs showed dilated supratentorial ventricle, thin posterior and splenium part of corpus callosum. The patient had little progress through medical treatments and rehabilitating regimens. Whole exome sequencing identified novel compound heterozygous truncating variants c.1207C > T (p.Gln403*) and c.52_53delAC (p.Cys18Glnfs*7) in AP4B1 gene. Causal mutations in AP4B1 have been reported in 29 individuals from 22 families so far, most of which are homozygous mutations. CONCLUSIONS:Our study enriched the genetic and phenotypic spectrum of SPG47. Early discovery, diagnosis and proper treatment on the conditions generally increase chances of improvement on the quality of life for patients.	0
An acquired, transient bleeding disorder that predominantly affects children in Southeast Asia has been reported for the last 4 decades. The condition has been named idiopathic purpura with gray platelets (IPGP) or acquired platelet dysfunction with eosinophilia. In a retrospective review from a private pediatric clinic over an 8-year period, 10 consecutive children were diagnosed as IPGP with a mean age of 8.4 (3.7 to 16.2) years. Eosinophilia (>0.5×10/L) was absent in 1, while gray platelets were consistently found in all cases with a mean proportion of 64.5% (40% to 80%). Platelet aggregation tests were performed in 9 patients with abnormal responses consistent with platelet storage pool defect. All children recovered completely and spontaneously from 1 to 4 months after diagnosis without specific therapy. In an otherwise well child who presents abruptly with easy bruising and a platelet count >100×10/L, IPGP can be readily recognized as an acquired form of gray platelet syndrome. Eosinophilia is common but not mandatory for diagnosis.	0
PURPOSE:To systematically observe and analyze the signs of deficient posterior capsule in posterior polar cataracts. DESIGN:Ambispective observational study. PARTICIPANTS:Cases with posterior polar cataracts. METHODS:Eyes with diagnosed posterior polar cataracts were imaged on anterior segment optical coherence tomography. A detailed assessment was performed to note the morphology of the posterior opacity, posterior capsule, and the common patterns to indicate their abnormality. In addition, generalized observation of the morphology was also performed with respect to intraoperative surgical experiences. RESULTS:A total of 101 eyes were included. The average patient age was 52.85 ± 10.72 years. The posterior capsule integrity was identified as intact in 91 eyes and abnormal/deficient in 10 eyes (9 had intraoperative defective capsule). These deficient/abnormal morphologies were classified into 3 categories: conical (n=2), moth-eaten (n=5), and (3) ectatic (n=3). Similarly, depending on the presence of hypoechoic spaces between the opacity and the capsule, remaining posterior polar cataracts were categorized into 2 generalized morphological types: without hypoechoic areas (n=40) and with hypoechoic areas (n=51). In the without hypoechoic areas group, 6 cases developed capsular rent; in the with hypoechoic areas group, 1 case developed capsular rent. CONCLUSIONS:In posterior polar cataracts, the deficient/abnormal capsular morphology could be specifically categorized into 3 categories, conical, moth-eaten, and ectatic types. In addition, to predict the ease of intraoperative separation between the opacity and the capsule, generalized categorization might help in better case management.	0
Introduction:Mutations in ABCC9 are associated with Cantú syndrome (CS), a very rare genetic disorder characterized by congenital hypertrichosis, acromegaloid facial appearance (AFA), cardiomegaly, and skeletal anomalies. Case report:We report an 8-year-old female patient with congenital generalized hypertrichosis and coarse facial appearance but without cardiovascular or skeletal compromise. Whole exome sequencing revealed a novel de novo heterozygous mutation in ABCC9. In addition, the genotype and phenotype of the patient were compared with those of the patients reported in the literature and with other related conditions that include AFA, hypertrichosis and AFA, and CS. Conclusion:This is the first report of a South-American patient with mutation in ABCC9. We propose that her phenotype is a part of a spectrum of features associated with congenital hypertrichosis and mutations in ABCC9, which differs from CS and related disorders. Whole exome sequencing enabled the identification of the causality of this disease characterized by high clinical and genetic heterogeneity.	0
Mirror syndrome, also called Ballantyne syndrome, is a rare condition in pregnancy, defined by the presence of the clinical triad of fetal hydrops, placentomegaly and maternal oedema. Any aetiology of fetal hydrops, including rhesus iso-immunization, congenital infection, twin-to-twin transfusion, structural anomalies and fetal malignancies, can lead to the syndrome. The pathogenesis, although not well established, mimics trophoblastic damage and maternal vascular endothelial dysfunction, as is also seen in pre-eclampsia, and, hence, the two conditions may have a similar clinical presentation. They may even co-exist, where a patient with maternal mirror syndrome develops features of pre-eclampsia. A timely, accurate diagnosis and prompt interventions are needed to prevent fetal mortality and maternal morbidity.	0
Sporotrichosis is a sporadic and rare mycotic infection in most of the developed world. In many parts of the developing world, sporotrichosis is much more commonly recognized, but epidemiological data are generally lacking from these regions. We report epidemiological, clinical, and treatment data from 238 cases of culture-proven sporotrichosis occurring in a relatively remote area of the south central highlands of Peru that were retrospectively collected during 1995-1997. Most cases (60%) occurred in children aged </=14 years, and the most commonly affected anatomic site was the face. Disease was clinically confined to the skin and subcutaneous tissue in all patients. The incidence of sporotrichosis in this region ranged from 48 to 60 cases per 100,000 persons and was highest among children aged 7-14 years, approaching 1 case per 1000 persons. Sporotrichosis is a significant mycosis in the rural highlands of Peru, with an incidence exceeding those of other invasive mycoses in individuals without human immunodeficiency virus infection.	1
Danon disease (OMIM 300257) is an X-linked lysosomal storage disorder, characterized by hypertrophic cardiomyopathy (HCM), skeletal myopathy, variable intellectual disability, and other minor clinical features. This condition accounts for ~ 4% of HCM patients, with a more severe and early onset phenotype in males, causing sudden cardiac death (SCD) in the first three decades of life. Genetic alterations in the LAMP2 gene are the main cause of this inherited fatal condition. Up to date, more than 100 different pathogenic variants have been reported in the literature. However, the majority of cases are misdiagnosed as HCM or have a delay in the diagnosis. Here, we describe a young boy with an early diagnosis of HCM. After 2 episodes of ventricular fibrillation within 2 years, genetic testing identified a novel LAMP2 pathogenic variant. Subsequently, further clinical evaluations showing muscle weakness and mild intellectual disability confirmed the diagnosis of Danon disease. This report highlights the role of genetic testing in the rapid diagnosis of Danon disease, underscoring the need to routinely consider the inclusion of LAMP2 gene in the genetic screening for HCM, since an early diagnosis of Danon disease in patients with a phenotype mimicking HCM is essential to plan appropriate treatment, ie cardiac transplantation.	0
To examine the effectiveness of a family-based behavioral group intervention (Positively Fit; PF) for pediatric obesity relative to a brief family intervention (BFI) in a sample of treatment-seeking children and adolescents.Families (n = 93) were randomized to treatment condition. Assessments were conducted at pre- and posttreatment and at 12-month follow-up. Outcome indices included standardized body mass index (BMI) and quality of life (QOL).Results indicated a significant reduction in zBMI at posttreatment and follow-up across both conditions. At follow-up, BFI and PF participants evidenced average reductions of .12 and .19 zBMI units, respectively. Children demonstrated better outcomes than adolescents across both conditions. Results indicated clinically significant improvements in parent-reported QOL at postintervention and in self-reported QOL at follow-up for PF participants.Results suggest the effectiveness of family-based interventions for pediatric obesity in clinical settings among younger children. Neither intervention was effective in terms of reducing zBMI among adolescents.	0
Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype-phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7.	0
BACKGROUND:Neuronal ceroid lipofuscinosis type 5 (CLN5) is a rare form of neuronal ceroid lipofuscinoses (NCLs) which are a group of inherited neurodegenerative diseases characterized by progressive intellectual and motor deterioration, visual failure, seizures, behavioral changes and premature death. CLN5 was initially named Finnish variant late infantile NCL, it is now known to be present in other ethnic populations and with variable age of onset. Few CLN5 patients had been reported in Chinese population. CASE PRESENTATION:In this paper, we report the symptoms of a Chinese patient who suffer from developmental regression and grand mal epilepsy for several years. The DNA was extracted from peripheral blood of proband and both parents, and then whole exome sequencing was performed using genomic DNA. Both sequence variants and copy number variants (CNVs) were analyzed and classified according to guidelines. As the result, a novel frameshift mutation c.718_719delAT/p.Met240fs in CLN5 and a de novo large deletion at 13q21.33-q31.1 which unmasked the frameshift mutation were identified in the proband. Despite the large de novo deletion, which can be classified as a pathogenic copy number variant (CNV), the patient's clinical presentation is mostly consistent with that of CLN5, except for early developmental delay which is believed due to the large deletion. Both variants were detected simultaneously by exome sequencing. CONCLUSIONS:This is the first report of whole gene deletion in combination with a novel pathogenic sequence variant in a CLN5 patient. The two mutations detected with whole exome sequencing simultaneously proved the advantage of the sequencing technology for genetic diagnostics.	0
INTRODUCTION:Pericallosal artery aneurysms are rare. Very few cases of this vascular anomaly have been published from West Africa. We report the first case of a ruptured pericallosal artery (PCA) aneurysm managed in a Nigerian neurosurgical facility, with the aim to add to the limited documentation on vascular brain lesions in our sub-region. The management outcome of the index patient and a literature review on these unusual aneurysms were also discussed. CASE REPORT:A middle-aged known hypertensive woman who presented with clinical features of a WFNS grade I subarachnoid hemorrhage (SAH). A plain cranial computerized tomography (CT) scan revealed SAH, a supracallosal intracerebral hematoma and intraventricular hemorrhage. Cranial computerized tomography angiography (CTA) showed a small right pericallosal artery aneurysm, which was treated (with clipping via an interhemispheric approach) in a resource-constrained neurosurgical facility. The patient has remained well over a six-year follow-up period. DISCUSSION:PCA aneurysms have a high tendency to bleed compared with other supratentorial intracranial aneurysms in spite of their small size. Microsurgical approach, although difficult, is an effective treatment option for these rare aneurysms. CONCLUSION:Surgical clipping remains a safe and useful treatment option for pericallosal artery aneurysms in a low-resource neurosurgical facility.	0
OBJECTIVE: To assess the risks and benefits associated with caesarean delivery compared with vaginal delivery. DESIGN: Prospective cohort study within the 2005 WHO global survey on maternal and perinatal health. SETTING: 410 health facilities in 24 areas in eight randomly selected Latin American countries; 123 were randomly selected and 120 participated and provided data PARTICIPANTS: 106,546 deliveries reported during the three month study period, with data available for 97,095 (91% coverage). MAIN OUTCOME MEASURES: Maternal, fetal, and neonatal morbidity and mortality associated with intrapartum or elective caesarean delivery, adjusted for clinical, demographic, pregnancy, and institutional characteristics. RESULTS: Women undergoing caesarean delivery had an increased risk of severe maternal morbidity compared with women undergoing vaginal delivery (odds ratio 2.0 (95% confidence interval 1.6 to 2.5) for intrapartum caesarean and 2.3 (1.7 to 3.1) for elective caesarean). The risk of antibiotic treatment after delivery for women having either type of caesarean was five times that of women having vaginal deliveries. With cephalic presentation, there was a trend towards a reduced odds ratio for fetal death with elective caesarean, after adjustment for possible confounding variables and gestational age (0.7, 0.4 to 1.0). With breech presentation, caesarean delivery had a large protective effect for fetal death. With cephalic presentation, however, independent of possible confounding variables and gestational age, intrapartum and elective caesarean increased the risk for a stay of seven or more days in neonatal intensive care (2.1 (1.8 to 2.6) and 1.9 (1.6 to 2.3), respectively) and the risk of neonatal mortality up to hospital discharge (1.7 (1.3 to 2.2) and 1.9 (1.5 to 2.6), respectively), which remained higher even after exclusion of all caesarean deliveries for fetal distress. Such increased risk was not seen for breech presentation. Lack of labour was a risk factor for a stay of seven or more days in neonatal intensive care and neonatal mortality up to hospital discharge for babies delivered by elective caesarean delivery, but rupturing of membranes may be protective. CONCLUSIONS: Caesarean delivery independently reduces overall risk in breech presentations and risk of intrapartum fetal death in cephalic presentations but increases the risk of severe maternal and neonatal morbidity and mortality in cephalic presentations.	0
PURPOSE OF REVIEW:To review the recent advances and current controversies in patients with Zollinger-Ellison syndrome (ZES). RECENT FINDINGS:Recent advances in the management of ZES include: improved understanding of the pathogenesis of gastrinoma and pancreatic neuroendocrine tumors, new prognostic classification systems, new diagnostic algorithms, more sensitive localization studies, new treatment strategies including improved control of gastric acid secretion and role for surgery, and new approaches to patients with advanced disease. Controversies include: the best approach to a patient with hypergastrinemia suspected of possibly having ZES, the appropriate gastrin assay to use, the role of surgery in patients with ZES, especially those with multiple endocrine neoplasia type 1, and the precise order of therapeutic modalities in the treatment of patients with advanced disease. SUMMARY:This review updates clinicians regarding important advances and controversies required to optimally diagnose and manage patients with ZES.	0
Hyperammonia due to ornithine transcarbamylase deficiency (OTCD) can cause a range of deficiencies in domains of executive function and working memory. Only a few fMRI studies have focused on neuroimaging data in a population with OTCD. Yet, there is a need for monitoring the disease progression and neurocognitive function in this population. In this study, we used a non-invasive neuroimaging technique, functional Near Infrared Spectroscopy (fNIRS), to examine the hemodynamics of prefrontal cortex (PFC) based on neural activation in an OTCD population. Using fNIRS, we measured the activation in PFC of the participants while performing the Stroop task. Behavioral assessment such as reaction time and correct response were recorded. We investigated the difference in behavioral measures as well as brain activation in left and right PFC in patients with OTCD and controls. Results revealed a distinction in left PFC activation between controls and patients with OTCD, where control subjects showed higher task related activation increase. Subjects with OTCD also exhibited bilateral increase in PFC activation. There was no significant difference in response time or correct response between the two groups. Our findings suggest the alterations in neurocognitive function of PFC in OTCD compared to the controls despite the behavioral profiles exhibiting no such differences. This is a first study using fNIRS to examine a neurocognitive function in OTCD population and can provide a novel insight into the screening of OTCD progression and examining neurocognitive changes.	0
RATIONALE:It is rare to find 22q11.2 deletion syndrome with pseudohypoparathyroidism in children. Furthermore, the phenotypic spectrum of this disorder varies widely. PATIENT CONCERNS:A patient was diagnosed with pseudohypoparathyroidism at age 14 years because of convulsions, hypocalcemia, hyperphosphatemia, normal parathyroid hormone levels, and basal ganglia calcifications. Thereafter, the child presented with symptoms of nephrotic syndrome; subsequently, he was diagnosed with nephrotic syndrome at the local hospital. DIAGNOSIS:At our hospital, multiplex ligation-dependent probe amplification confirmed that the patient had 22q11.2 deletion syndrome. INTERVENTIONS:The patient continued to be treated with calcium supplements. OUTCOMES:Seizure activity and proteinuria ceased. LESSONS:Signs of this syndrome include delayed speech development due to velofacial dysfunction, recurrent croup attacks during early childhood due to latent hypocalcemia, and mild dysmorphic features. The findings of this patient indicated that 22q11.2 deletion syndrome may include a wide spectrum of clinical findings and that this diagnosis needs to be considered for all patients presenting with hypocalcemia, regardless of age.	0
In Central Europe, classical alveolar echinococcosis (AE) is endemic. Annual incidences in Austria were 2.4 and 2.8 cases/100,000 population during 1991-2000 and 2001-2010, respectively. Hence, the registration of 13 new AE patients in 2011 was unexpected. Increasing fox populations and past AE underreporting might have caused this increase.	1
Detailed comprehensive knowledge of the structures of individual long-range telomere-terminal haplotypes are needed to understand their impact on telomere function, and to delineate the population structure and evolution of subtelomere regions. However, the abundance of large evolutionarily recent segmental duplications and high levels of large structural variations have complicated both the mapping and sequence characterization of human subtelomere regions. Here, we use high throughput optical mapping of large single DNA molecules in nanochannel arrays for 154 human genomes from 26 populations to present a comprehensive look at human subtelomere structure and variation. The results catalog many novel long-range subtelomere haplotypes and determine the frequencies and contexts of specific subtelomeric duplicons on each chromosome arm, helping to clarify the currently ambiguous nature of many specific subtelomere structures as represented in the current reference sequence (HG38). The organization and content of some duplicons in subtelomeres appear to show both chromosome arm and population-specific trends. Based upon these trends we estimate a timeline for the spread of these duplication blocks.	0
Hereditary spastic paraplegias are heterogeneous disorders with diversified clinical manifestations, and genetic testing is important for the diagnosis and typing of hereditary spastic paraplegias.Gene panel sequencing containing 55 hereditary spastic paraplegias-related genes was performed to screen the pathogenic genes for hereditary spastic paraplegias. Sanger sequencing was adopted to validate if the family member carried the same pathogenic gene as the proband.Fifteen out of 53 patients carried mutation(s) in the screened hereditary spastic paraplegias-related genes. Among the 23 identified mutations, only one mutation had been previously reported as a pathogenic mutation. In the pedigree of case 6, the proband, his mother and uncle all carried the same novel deletion mutation (c.1459delA) at SPAST gene. Based on the pedigree, the disease was inherited in an AD pattern. In the pedigree of case 53, the family disease may be in an X-linked recessive inheritance pattern. The proband (case 53) carried two novel mutations in ALT1 gene and L1CAM gene (c.2511C>A), respectively. The L1CAM gene is the causative gene for the SPG1 X-linked recessive-hereditary spastic paraplegias.Our data confirm the genetic heterogeneity of hereditary spastic paraplegias, and SPG4/SPAST were the most frequent forms. The pathogenicity of the novel mutations is worth to be further investigated.	0
Congenital lactase deficiency (CLD) is a severe autosomal recessive genetic disorder that affects the functional capacity of the intestinal protein lactase-phlorizin hydrolase (LPH). This disorder is diagnosed already during the first few days of the newborn's life due to the inability to digest lactose, the main carbohydrate in mammalian milk. The symptoms are similar to those in other carbohydrate malabsorption disorders, such as congenital sucrase-isomaltase deficiency, and include severe osmotic watery diarrhea. CLD is associated with mutations in the translated region of the LPH gene that elicit loss-of-function of LPH. The mutations occur in a homozygote or compound heterozygote pattern of inheritance and comprise missense mutations as well as mutations that lead to complete or partial truncations of crucial domains in LPH, such as those linked to the folding and transport-competence of LPH and to the catalytic domains. Nevertheless, the identification of the mutations in CLD is not paralleled by detailed genotype/protein phenotype analyses that would help unravel potential pathomechanisms underlying this severe disease. Here, we review the current knowledge of CLD mutations and discuss their potential impact on the structural and biosynthetic features of LPH. We also address the question of whether heterozygote carriers can be symptomatic for CLD and whether genetic testing is needed in view of the severity of the disease.	0
Potassium channels are a heterogeneous group of membrane-bound proteins, whose functions support a diverse range of biological processes. Genetic disorders arising from mutations in potassium channels are classically recognized by symptoms arising from acute channel dysfunction, such as periodic paralysis, ataxia, seizures, or cardiac conduction abnormalities, often in a patient with otherwise normal examination findings. In this chapter, we review a distinct subgroup of rare potassium channelopathies whose presentations are instead suggestive of a developmental disorder, with features including intellectual disability, craniofacial dysmorphism or other physical anomalies. Known conditions within this subgroup are: Andersen-Tawil syndrome, Birk-Barel syndrome, Cantú syndrome, Keppen-Lubinsky syndrome, Temple-Baraitser syndrome, Zimmerman-Laband syndrome and a very similar disorder called Bauer-Tartaglia or FHEIG syndrome. Ion channelopathies are unlikely to be routinely considered in the differential diagnosis of children presenting with developmental concerns, and so detailed description and photographs of the clinical phenotype are provided to aid recognition. For several of these disorders, functional characterization of the genetic mutations responsible has led to identification of candidate therapies, including drugs already commonly used for other indications, which adds further impetus to their prompt recognition. Together, these cases illustrate the potential for mechanistic insights gained from genetic diagnosis to drive translational work toward targeted, disease-modifying therapies for rare disorders.	0
The hedgehog (Hh) family comprises sonic hedgehog (Shh), Indian hedgehog (Ihh), and desert hedgehog (Dhh), which are versatile signaling molecules involved in a wide spectrum of biological events including cell differentiation, proliferation, and survival; establishment of the vertebrate body plan; and aging. These molecules play critical roles from embryogenesis to adult stages; therefore, alterations such as abnormal expression or mutations of the genes involved and their downstream factors cause a variety of genetic disorders at different stages. The Hh family involves many signaling mediators and functions through complex mechanisms, and achieving a comprehensive understanding of the entire signaling system is challenging. This review discusses the signaling mediators of the Hh pathway and their functions at the cellular and organismal levels. We first focus on the roles of Hh signaling mediators in signal transduction at the cellular level and the networks formed by these factors. Then, we analyze the spatiotemporal pattern of expression of Hh pathway molecules in tissues and organs, and describe the phenotypes of mutant mice. Finally, we discuss the genetic disorders caused by malfunction of Hh signaling-related molecules in humans.	0
In the recent years, the progress in genetic analysis and next-generation sequencing technologies have opened up exciting landscapes for diagnosis and study of molecular mechanisms, allowing the determination of a particular mutation for individual patients suffering from hereditary red blood cell-related diseases or anemia. However, the huge amount of data obtained makes the interpretation of the results and the identification of the pathogenetic variant responsible for the diseases sometime difficult. Moreover, there is increasing evidence that the same mutation can result in varying cellular properties and different symptoms of the disease. Even for the same patient, the phenotypic expression of the disorder can change over time. Therefore, on top of genetic analysis, there is a further request for functional tests that allow to confirm the pathogenicity of a molecular variant, possibly to predict prognosis and complications (e.g., vaso-occlusive pain crises or other thrombotic events) and, in the best case, to enable personalized theranostics (drug and/or dose) according to the disease state and progression. The mini-review will reflect recent and future directions in the development of diagnostic tools for red blood cell-related diseases and anemias. This includes point of care devices, new incarnations of well-known principles addressing physico-chemical properties, and interactions of red blood cells as well as high-tech screening equipment and mobile laboratories.	0
Syringocystadenoma papilliferum is a very rare, benign adnexal tumor that originates from the apocrine sweat glands. Herein, we report a 25-year-old male who presented with a 10-year history of an asymptomatic slowly growing skin lesion on his face. Skin examination revealed a solitary rounded 3 × 3 cm erythematous plaque with central crustation on the right side of his face. Punch skin biopsy was taken from the lesion. The epidermis showed downward papillomatous extensions. The dermis showed multiple epithelial sheets and dilated ducts that were lined by columnar cells. On the basis of the above clinicopathological findings, the diagnosis of syringocystadenoma papilliferum was made. The patient was reassured and referred to a surgeon for surgical excision of the lesion.	0
The X-linked WTX/AMER1 protein constitutes an important component of the β-catenin destruction complex that can both enhance and suppress canonical β-catenin signaling. Somatic mutations in WTX/AMER1 have been found in a proportion of the pediatric kidney cancer Wilms' tumor. By contrast, germline mutations cause the severe sclerosing bone dysplasia osteopathia striata congenita with cranial sclerosis (OSCS), a condition usually associated with fetal or perinatal lethality in male patients. Here we address the developmental and molecular function of WTX by generating two novel mouse alleles. We show that in addition to the previously reported skeletal abnormalities, loss of Wtx causes severe midline fusion defects including cleft palate and ectopic synostosis at the base of the skull. By contrast, deletion of the C-terminal part of the protein results in only mild developmental abnormalities permitting survival beyond birth. Adult analysis, however, revealed skeletal defects including changed skull morphology and an increased whole-body bone density, resembling a subgroup of male patients carrying a milder, survivable phenotype. Molecular analysis in vitro showed that while β-catenin fails to co-immunoprecipitate with the truncated protein, partial recruitment appears to be achieved in an indirect manner using AXIN/AXIN2 as a molecular bridge. Taken together our analysis provides a novel model for WTX-caused bone diseases and explains on the molecular level how truncation mutations in this gene may retain some of WTX-protein functions. © 2018 American Society for Bone and Mineral Research.	0
BACKGROUND:Abnormalities of chromosome 3 in myelodysplastic syndromes (MDS), that is, inversion 3 (inv[3]), translocation 3q (t[3q]), or deletion 3q (del[3q]), are defined as poor-risk karyotypes in the Revised International Prognostic Scoring System (IPSS-R). The objective of this study was to further define the outcomes of patients with MDS with chromosome 3 abnormalities and address the impact of hypomethylating agent (HMA) therapy on this patient subset. PATIENTS AND METHODS:Through the MDS Clinical Research Consortium, we identified 411 patients with chromosome 3 abnormalities and MDS or oligoblastic acute myeloid leukemia (20%-30% blasts). RESULTS:Specific chromosome 3 aberrations and cytogenetic complexity were predictive of survival; patients with t(3q) and isolated chromosome 3 had improved overall survival (OS), albeit still poor, whereas patients with complex cytogenetics, including those with 3p abnormalities, had inferior OS. Overall response rates to HMAs among this patient population were similar to those of patients with nonchromosome 3-MDS (52%, with a 25% complete remission rate), although with higher response rates in decitabine-treated patients (69% vs. 45%, P = .008). HMA therapy improved the OS of patients with higher-risk MDS compared with intensive chemotherapy (median OS of 15.5 vs. 8.2 months; P  =  .017). This improvement remained significant in multivariate analyses (hazard ratio, 0.60; P  =  .018); however, there were no chromosome 3 aberrations among this subgroup predictive of improved response rates to or survival from HMAs. CONCLUSION:Patients with MDS with chromosome 3 abnormalities represent a cytogenetic cohort with poor OS, and there is an urgent need for novel therapeutic strategies.	0
BACKGROUND:Congenital disorders of glycosylation (CDG) represent 1 of the largest groups of metabolic disorders with >130 subtypes identified to date. The majority of CDG subtypes are disorders of N-linked glycosylation, in which carbohydrate residues, namely, N-glycans, are posttranslationally linked to asparagine molecules in peptides. To improve the diagnostic capability for CDG, we developed and validated a plasma N-glycan assay using flow injection-electrospray ionization-quadrupole time-of-flight mass spectrometry. METHODS:After PNGase F digestion of plasma glycoproteins, N-glycans were linked to a quinolone using a transient amine group at the reducing end, isolated by a hydrophilic interaction chromatography column, and then identified by accurate mass and quantified using a stable isotope-labeled glycopeptide as the internal standard. RESULTS:This assay differed from other N-glycan profiling methods because it was free of any contamination from circulating free glycans and was semiquantitative. The low end of the detection range tested was at 63 nmol/L for disialo-biantennary N-glycan. The majority of N-glycans in normal plasma had <1% abundance. Abnormal N-glycan profiles from 19 patients with known diagnoses of 11 different CDG subtypes were generated, some of which had previously been reported to have normal N-linked protein glycosylation by carbohydrate-deficient transferrin analysis. CONCLUSIONS:The clinical specificity and sensitivity of N-glycan analysis was much improved with this method. Additional CDGs can be diagnosed that would be missed by carbohydrate-deficient transferrin analysis. The assay provides novel biomarkers with diagnostic and potentially therapeutic significance.	0
BACKGROUND:Animal-model studies have demonstrated less group B streptococcal (GBS) invasive disease and gastrointestinal colonization after enteral administration of serotype-specific capsular antibodies. There is, however, a paucity of information on the association of breast milk GBS serotype-specific capsular antibodies and risks for invasive disease in infants. The aim of this study was to explore the association between natural secretory immunoglobulin A (sIgA) capsular antibodies in breast milk and the occurrence of late-onset disease (LOD) in young infants. METHODS:A matched case-control study was undertaken in infants <3 months of age in Johannesburg, South Africa. Breast milk samples were collected on cases and controls matched for gestational age, maternal age, and human immunodeficiency virus status at time of enrollment. Capsular serotype Ia, Ib, III, and V sIgA antibody concentrations were measured using the fluorescence-based micro-bead immunosorbent assay. RESULTS:Breast milk samples were available for 31 LOD cases (8 serotype Ia and 23 serotype III), 21 recto-vaginally colonized matched controls (10 serotype Ia and 11 serotype III), and 84 serotype Ia and 105 serotype III noncolonized matched controls. Using a Bayesian model to estimate the probability of disease, there were 90% reductions in the risks of developing serotypes Ia and III LOD with sIgA concentrations ≥0.14 µg/mL and ≥2.52 µg/mL, respectively. CONCLUSIONS:Breast milk sIgA capsular antibodies were associated with lower risks for LOD in young infants. The ability of GBS polysaccharide-protein conjugate vaccines currently under development to induce sIgA responses warrant investigation as potential mediators of protection against LOD.	0
Objective:To investigate the effects of the long-term use of a maxillary protraction facemask with miniplate (FM-MP) on pharyngeal airway dimensions in growing patients with cleft lip and palate (CLP). Methods:The study included 24 boys with CLP (mean age, 12.2 years; mean duration of FM-MP therapy, 4.9 years), divided into two groups according to the amount of A point advancement to the vertical reference plane (VRP): Group 1, > 4 mm; Group 2, < 2 mm; n = 12/group. After evaluating the skeletodental and airway variables using lateral cephalograms acquired before and after FM-MP therapy, statistical analyses were performed. Results:Group 1 showed greater forward and downward displacements of the posterior maxilla (posterior nasal spine [PNS]-horizontal reference plane [HRP]; PNSVRP), greater increase in ANB, more forward tongue position (tongue tip-Pt vertical line to Frankfort horizontal plane), and greater increase in the oropharynx (superior posterior airway space [SPAS]; middle airway space [MAS]) and upper nasopharynx (PNS-adenoid2) than did Group 2. While maxillary advancement (A-VRP and PNS-VRP) correlated with increases in SPAS, MAS, and PNS-adenoid2, downward displacement of the PNS (PNS-HRP) correlated with increases in SPAS, MAS, PNSadenoid1, and PNS-adenoid2, and with a decrease in vertical airway length (VAL). Mandibular forward displacement and decrease in mandibular plane correlated with increases in MAS. Conclusions:FM-MP therapy had positive effects on the oropharyngeal and nasopharyngeal airway spaces without increases in VAL in Group 1 rather than in Group 2. However, further validation using an untreated control group is necessary.	0
Abdominal ultrasound in a 50-year-old Japanese man revealed a cystic lesion on the caudate lobe of the liver. Four-month follow-up imaging showed a rapid increase in the size of the cystic lesion. The patient underwent laparoscopic partial hepatectomy because of a suspicion and perceived risk that the lesion might be malignant. The initial histological diagnosis was a hepatic cyst. Eleven months later, computed tomography showed a giant cystic lesion in the abdominal cavity and multiple liver metastases. The patient underwent excision of the giant cystic lesion and a partial hepatectomy. Immunohistochemistry for the recurring lesion revealed undifferentiated embryonal sarcoma of the liver.	0
To produce bioethanol from model cyanobacteria such as Synechocystis, a two gene cassette consisting of genes encoding pyruvate decarboxylase (PDC) and alcohol dehydrogenase (ADH) are required to transform pyruvate first to acetaldehyde and then to ethanol. However the partition of pyruvate to ethanol comes at a cost, a reduction in biomass and pyruvate availability for other metabolic processes. Hence strategies to divert flux to ethanol as a biofuel in Synechocystis are of interest. PDC from Zymobacter palmae (ZpPDC) has been reported to have a lower Km then the Zymomonas mobilis PDC (ZmPDC), which has traditionally been used in metabolic engineering constructs. The Zppdc gene was combined with the native slr1192 alcohol dehydrogenase gene (adhA) in an attempt to increase ethanol production in the photoautotrophic cyanobacterium Synechocystis sp. PCC 6803 over constructs created with the traditional Zmpdc. Native (Zppdc) and codon optimized (ZpOpdc) versions of the ZpPDC were cloned into a construct where pdc expression was controlled via the psbA2 light inducible promoter from Synechocystis sp. PCC 6803. These constructs were transformed into wildtype Synechocystis sp. PCC 6803 for expression and ethanol production. Ethanol levels were then compared with identical constructs containing the Zmpdc. While strains with the Zppdc (UL071) and ZpOpdc (UL072) constructs did produce ethanol, levels were lower compared to a control strain (UL070) expressing the pdc from Zymomonas mobilis. All constructs demonstrated lower biomass productivity illustrating that the flux from pyruvate to ethanol has a major effect on biomass and ultimately overall biofuel productivity. Thus the utilization of a PDC with a lower Km from Zymobacter palmae unusually did not result in enhanced ethanol production in Synechocystis sp. PCC 6803.	0
Mycetoma is one of the badly neglected tropical diseases, characterised by subcutaneous painless swelling, multiple sinuses, and discharge containing aggregates of the infecting organism known as grains. Risk factors conferring susceptibility to mycetoma include environmental factors and pathogen factors such as virulence and the infecting dose, in addition to host factors such as immunological and genetic predisposition. Epidemiological evidence suggests that host genetic factors may regulate susceptibility to mycetoma and other fungal infections, but they are likely to be complex genetic traits in which multiple genes interact with each other and environmental factors, as well as the pathogen, to cause disease. This paper reviews what is known about genetic predisposition to fungal infections that might be relevant to mycetoma, as well as all studies carried out to explore host genetic susceptibility to mycetoma. Most studies were investigating polymorphisms in candidate genes related to the host immune response. A total of 13 genes had allelic variants found to be associated with mycetoma, and these genes lie in different pathways and systems such as innate and adaptive immune systems, sex hormone biosynthesis, and some genes coding for host enzymes. None of these studies have been replicated. Advances in genomic science and the supporting technology have paved the way for large-scale genome-wide association and next generation sequencing (NGS) studies, underpinning a new strategy to systematically interrogate the genome for variants associated with mycetoma. Dissecting the contribution of host genetic variation to susceptibility to mycetoma will enable the identification of pathways that are potential targets for new treatments for mycetoma and will also enhance the ability to stratify 'at-risk' individuals, allowing the possibility of developing preventive and personalised clinical care strategies in the future.	0
The world health organisation has declared neurological disorders as one of the greatest public health risks in the world today. Yet, despite this growing concern, the mechanisms underpinning many of these conditions are still poorly understood. This may in part be due to the seemingly diverse nature of the initiating insults ranging from genetic (such as the Ataxia's and Lysosomal storage disorders) through to protein misfolding and aggregation (i.e. Prions), and those of a predominantly unknown aetiology (i.e. Alzheimer's and Parkinson's disease). However, efforts to elucidate mechanistic regulation are also likely to be hampered because of the complexity of the human nervous system, the apparent selective regional vulnerability and differential degenerative progression. The key to elucidating these aetiologies is determining the regional molecular cascades, which are occurring from the early through to terminal stages of disease progression. Whilst much molecular data have been captured at the end stage of disease from post-mortem analysis in humans, the very early stages of disease are often conspicuously asymptomatic, and even if they were not, repeated sampling from multiple brain regions of "affected" patients and "controls" is neither ethical nor possible. Model systems therefore become fundamental for elucidating the mechanisms governing these complex neurodegenerative conditions. However, finding a model that precisely mimics the human condition can be challenging and expensive. Whilst cellular and invertebrate models are frequently used in neurodegenerative research and have undoubtedly yielded much useful data, the comparatively simplistic nature of these systems makes insights gained from such a stand alone model limited when it comes to translation. Given the recent advances in gene editing technology, the options for novel model generation in higher order species have opened up new and exciting possibilities for the field. In this review, we therefore explain some of the reasons why larger animal models often appear to give a more robust recapitulation of human neurological disorders and why they may be a critical stepping stone for effective therapeutic translation.	0
The clinical outcomes of primary immunodeficiencies (PIDs) are greatly improved by accurate diagnosis early in life. However, it is not common to consider PIDs before the manifestation of severe clinical symptoms. Including PIDs in the nation-wide newborn screening programs will potentially improve survival and provide better disease management and preventive care in PID patients. This calls for the detection of disease biomarkers in blood and the use of dried blood spot samples, which is a part of routine newborn screening programs worldwide. Here, we developed a newborn screening method based on multiplex protein profiling for parallel diagnosis of 22 innate immunodeficiencies affecting the complement system and respiratory burst function in phagocytosis. The proposed method uses a small fraction of eluted blood from dried blood spots and is applicable for population-scale performance. The diagnosis method is validated through a retrospective screening of immunodeficient patient samples. This diagnostic approach can pave the way for an earlier, more comprehensive and accurate diagnosis of complement and phagocytic disorders, which ultimately lead to a healthy and active life for the PID patients.	0
Charcot-Marie-Tooth neuropathy type 1 (CMT1) is an inherited demyelinating neuropathy characterized by distal muscle weakness and atrophy. Charcot-Marie-Tooth disease type 1C (CMT1C) is a rare form of CMT1 caused by mutations in the lipopolysaccharide-induced tumor necrosis factor (LITAF) or small integral membrane protein of the lysosome/late endosome (SIMPLE) gene. Phenotypically, CMT1C is characterized by sensory loss and slow conduction velocity, and is typically slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. A 42-year-old female presented with a 10-year history of slowly progressive bilateral calf pain and cramps. After multiple electromyography/nerve conduction studies (EMG/NCS) and genetic testing, the patient was revealed to have CMT1C with a heterozygous pathogenic variant, c.334G>A (p.Gly112Ser). However, the presentation of the patient's CMT1C phenotype was unusual compared to patients with similar diagnosis in a previous study, including a normal sensory exam with the exception of high arches and mildly reduced vibratory sense. Additionally, the patient's teenage son already started showing symptoms of CMT1C despite the fact that the onset of the disease typically occurs at an older age. This particular case further highlights the idea that the phenotype related to CMT1C may have a wide spectrum of disease severity.	0
Lymphoedema is the build-up of lymphatic fluid leading to swelling in the tissues. Most commonly it affects the peripheries. Diagnosis is based on clinical assessment and imaging with lymphoscintigraphy. Treatment is supportive with compression garments, massage, good skin hygiene and prompt use of antibiotics to avoid the complication of cellulitis. Most commonly, lymphoedema occurs as a result of damage to the lymphatic system following surgery, trauma, radiation or infection. However, it can be primary, often associated with a genetic defect that causes disruption to the development of the lymphatic system. Common genetic conditions associated with lymphoedema include Turner syndrome and Noonan syndrome; however, there are numerous others that can be classified based on their clinical presentation and associated features. Herein we discuss how to diagnose and classify the known primary lymphoedema conditions and how best to investigate and manage this group of patients.	0
BACKGROUND:The non-lethal variant of the Escobar or multiple pterygium syndrome is an entity of autosomal recessive inheritance linked to the X chromosome; it is characterized by multiple pterygia (hence its name) located mainly in the neck (95%) and armpits (55%), as well as other orthopedic malformations such as a vertical talus, congenital hip dislocation, and congenital scoliosis. OBJECTIVE:To present an optional surgical technique for the management of severe spinal deformities. CASE REPORT:Twelve-year-old female diagnosed with Escobar syndrome with severe scoliosis which conditions malformations of the chest with lung involvement, producing mechanical ventilatory restriction and increasing the risk of severe lower respiratory tract infection. We performed a hands-free posterior instrumentation with PASS LP system and Smith-Petersen osteotomies. CONCLUSIONS:The Cobb angle improved from 62° to 23° and the sagittal balance from 125 mm to 73 mm.	0
Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder characterized by pyramidal weakness and spasticity of the lower limbs. SPG46, one of autosomal recessive HSP, is clinically characterized by spasticity and pyramidal weakness of the lower limbs, mental retardation, congenital bilateral cataract, thin corpus callosum, and hypogonadism in males. Mutations in the nonlysosomal glucosylceramidase β2 (GBA2) gene have been identified in patients with SPG46. A Japanese woman was identified with bilateral cataracts when she was in an elementary school. She felt falling easily, speaking unclearness, and difficulty in walking and raising her left leg in her 30s. Her neurological examination at the age of 44 revealed dysarthria, spasticity in the upper and lower extremities, increased jaw jerk and tendon reflexes in the extremities, bilateral extensor plantar reflexes, ataxia, and pollakiuria. Magnetic resonance imaging showed thinning of the corpus callosum body as well as atrophy in the pons and cerebellum. A novel homozygous c.1838A > G (p.D613G) missense mutation was detected at exon 12 in GBA2. We diagnosed her illness as an autosomal-recessive form of hereditary SPG46. The clinical features matched previously reported phenotype of SPG46. This is the first report of a Japanese patient with SPG46 with a novel mutation in GBA2. We presume that the novel GBA2 missense mutation found in our patient would cause loss of GBA2 activity, resulting in the neurological manifestations of SPG46.	0
We report a rare case of oligodendroglioma with gangliocytic differentiation. A 31-year-old male without a past medical history was admitted with a sudden seizure. On magnetic resonance imaging, an approximately 7-cm mass with necrosis was noted in the right frontal lobe. The patient underwent surgical resection. On microscopy, two morphologically distinct areas with oligodendroglioma- and ganglioglioma-like features were found. Immunohistochemistry showed an absence of CD34 expression, whereas isocitrate dehydrogenase 1 (IDH1) was positive in the glial component. Moreover, IDH1 was positive in the ganglion-like cells as well as in the glial component. Subsequent 1p/19q co-deletion was confirmed by fluorescence in situ hybridization. Finally, a diagnosis of oligodendroglioma with gangliocytic differentiation was made. IDH1/2 molecular test would be basic and essential diagnostic tool in central nervous system tumor of young patients.	0
The breast cancer susceptibility protein 1 (BRCA1) plays a central role in the suppression of human breast and ovarian cancer. Germ line mutations of the BRCA1 gene are responsible for the hereditary breast and ovarian cancer (HBOC) syndrome. Here were report 1H, 13C, and 15N resonance assignments for the intrinsically disordered BRCA1 fragment 219-504, which contains important interaction sites for the proto-oncogenic transcription factor MYC as well as for p53. A nuclear magnetic resonance assignment was achieved at 18.8 T magnetic field strength using a 5D HN(CA)CONH experiment and its associated 4D H(NCA)CONH and 4D (H)N(CA)CONH experiments. 13Cα and 13Cβ assignments were obtained using a 5D HabCabCONH experiment. With this strategy, 90% of 1H/15N backbone pairs could be assigned. Similarly, 264 C' resonances were assigned corresponding to 86% of the total number of C' atoms. In addition, 252 Cβ resonances (i.e. 85%) were assigned, together with 461 attached Hβ nuclei, as well as 264 (i.e. 86%) Cα resonances, together with 275 attached Hα nuclei.	0
Dubin-Johnson syndrome is an autosomal recessive condition characterized by recurrent episodes of jaundice and conjugated hyperbilirubinemia. It exacerbates during pregnancy and needs to be differentiated from other causes of jaundice. A 30-year-old patient presented to us with jaundice in her fourth pregnancy. She had intermittent episodes of jaundice earlier, with exacerbation in each pregnancy during the second trimester. The diagnosis of Dubin-Johnson syndrome was made on detailed evaluation along with histopathological confirmation on liver biopsy tissue. The patient was managed conservatively and had a good perinatal outcome.	0
Acral lentiginous melanoma (ALM) is one of the four major subtypes of cutaneous melanoma (CM) and occurs on the palms, soles, and nail beds of the body. CM has often been associated with sun exposure1 , but ALM occurs in generally unexposed anatomic sites. While the aetiology remains largely unknown, melanocytic nevi, trauma, pressure, ultraviolet light, and gene mutations have been postulated in ALM development.2 ALM represents about 2-3% of all melanomas but represents a much higher proportion of CM in darker-skinned individuals.3 Racial and ethnic differences have been shown in CM.4 Due to its rarity, few studies have closely examined the racial differences in ALM.3 Our study aims to investigate racial and ethnic differences in clinical presentation and outcomes in patients with ALM.	0
Littoral-cell angioma (LCA), a primary angioma which clinically belongs to splenic hemangioma, can be mostly found in normal spleen red sinus shore cells of reticuloendothelial cell system. The cells of LCA strongly express endothelial and tissue cell associated antigens that indicate a dual differentiation characteristic; whereas only endothelial cell markers are positive in normal spleen red sinus shore cells. Diagnosis of LCA relies on histopathology. Regular follow-up is needed to monitor recurrence and metastasis.	0
BACKGROUND:OFD1 has long been recognized as the gene implicated in the classic dysmorphology syndrome, oral-facial-digital syndrome type I (OFDSI). Over time, pathogenic variants in OFD1 were found to be associated with X-linked intellectual disability, Joubert syndrome type 10 (JBTS10), Simpson-Golabi-Behmel syndrome type 2 (SGBS2), and retinitis pigmentosa. Recently, OFD1 pathogenic variants have been implicated in primary ciliary dyskinesia (PCD), a disorder of the motile cilia with a phenotype that includes recurrent oto-sino-pulmonary infections, situs abnormalities, and decreased fertility. METHODS:We describe three male patients with PCD who were found to have hemizygous pathogenic variants in OFD1, further supporting that PCD is part of a clinical spectrum of OFD1-related disorders. In addition, we provide a review of the available clinical literature describing patients with OFD1 variants and highlight the phenotypic variability of OFD1-related disease. RESULTS:Some individuals with hemizygous OFD1 variants have PCD, either apparently isolated or in combination with other features of OFD1-related disorders. CONCLUSION:As clinicians consider the presence or absence of conditions allelic at OFD1, PCD should be considered part of the spectrum of OFD1-related disorders. Understanding the OFD1-related disease spectrum may allow for more focused genetic testing and more timely management of treatable sequelae.	0
Movement disorders in childhood comprise a heterogeneous group of conditions that lead to impairment of voluntary movement, abnormal postures, or inserted involuntary movements. Movement disorders in children are frequently caused by metabolic disorders, both inherited and acquired. Many of these respond to vitamin supplementation. Examples include infantile tremor syndrome, biotinidase deficiency, biotin-thiamine-responsive basal ganglia disease, pyruvate dehydrogenase deficiency, aromatic amino acid decarboxylase deficiency, ataxia with vitamin E deficiency, abetalipoproteinemia, cerebral folate deficiency, and cobalamin metabolism defects. Recognition of these disorders by pediatricians and neurologists is imperative as they are easily treated by vitamin supplementation. In this review, we discuss vitamin-responsive movement disorders in children.	0
Background:The rare presence of malignant cancerous cells afar any type of pregnancy is known as gestational trophoblastic neoplasia (GTN). GTN are benign lesions which mostly happen due to the activity of extravillous trophoblast cells and the placental villous tree development. These kinds of diseases would be occurring mainly due to the following clinicopathologic conditions: (I) existence of epithelioid trophoblastic tumor (ETT), (II) rare type of choriocarcinoma cancer, (III) gestational trophoblastic tumor of mole, and (IV) the rare malignant tumor of placental site trophoblastic tumor. Objective:This comprehensive study is trying to review the most recent approaches in comprehension of pathogenesis, more precise diagnosis, and also the most effective therapeutic procedures for patients who suffer from GTN disorders. Materials and Method:A comprehensive research was carried out on scientific databases of Science Citation Index (SCI), MEDLINE, EMBASE, HMIC, PubMed, CINAHL, Google Scholar, Cochrane Database of Systematic Reviews (CDSR), and PsycINFO over the time period of 2005 to 2019. The keywords which applied for discovering more related records were including: Gestational trophoblastic diseases (GTD), Gestational trophoblastic neoplasia (GTN), molar pregnancy, choriocarcinoma, human chorionic gonadotropin (hCG), diagnosis, management and treatment. Conclusion:In spite of the fact that GTN patients are treated with conventional surgical therapies or/and chemotherapy, in some patients with resistant disease, these therapies may not be effective and patients may die. Some novel remedial agents are required for decreasing the level of toxicity caused through administering conventional chemotherapy and also treating the patients who suffer from refractory or resistant disease. The newest issues are related to GTN diagnosis, process of progression of hydatidiform mole (HM) to GTN, and the issue of GTN drug resistance. In this regard, we should have a comprehensive knowledge on GTN genetics for answering all the available questions about this disorder.	0
Desbuquois dysplasia (DBQD) is a severe condition characterized by short stature, joint laxity, and advanced carpal ossification. Based on the presence of additional hand anomalies, we have previously distinguished DBQD type 1 and identified CANT1 (calcium activated nucleotidase 1) mutations as responsible for DBQD type 1. We report here the identification of five distinct homozygous xylosyltransferase 1 (XYLT1) mutations in seven DBQD type 2 subjects from six consanguineous families. Among the five mutations, four were expected to result in loss of function and a drastic reduction of XYLT1 cDNA level was demonstrated in two cultured individual fibroblasts. Because xylosyltransferase 1 (XT-I) catalyzes the very first step in proteoglycan (PG) biosynthesis, we further demonstrated in the two individual fibroblasts a significant reduction of cellular PG content. Our findings of XYLT1 mutations in DBQD type 2 further support a common physiological basis involving PG synthesis in the multiple dislocation group of disorders. This observation sheds light on the key role of the XT-I during the ossification process.	0
BACKGROUND:Nonimmune hydrops fetalis (NIHF) is still a challenging diagnosis. The differential diagnosis is extensive and the success of identifying a cause depends on the thoroughness of efforts to establish a diagnosis. For the early diagnosis of NIHF, a virtual gene panel diagnostic tool was developed. The female premature baby in question was delivered via emergency cesarean at 30 + 1 weeks of gestational age (GA) due to rapidly developing NIHF to a healthy mother. The family history was noncontributory. METHODS:DNA of the family was extracted and sequenced by the virtual hydrops panel with whole-exome sequencing. RESULTS:The hydrops panel revealed Noonan syndrome (NS) with a germline mutation in PTPN11 c.218C>T (p.Thr73Ile). CONCLUSION:The diagnosis of our patient was rapidly confirmed by the hydrops panel. The variant of c.218C>T (p.Thr73Ile) has not yet been described in literature relating to NIHF. Only a few case reports of this variant are known. This particular mutation is associated with Noonan syndrome, congenital heart defect and persistent thrombocytopenia. Few reveal juvenile myelomonocytic leukemia.	0
Familial hypertrophic cardiomyopathy is an autosomal dominant genetic disease considered the most common cause of sudden cardiac death in individuals under 35 years old, especially the athletes. This study aimed to investigate the association between the presence of late potentials and a family history of sudden death, syncope, and complex ventricular arrhythmias on patients with hypertrophic cardiomyopathy. A case series study was carried out from March 2001 to December 2002, including 22 patients with hypertrophic cardiomyopathy according to transthoracic echocardiogram criteria. Patients on a cardiac pacemaker, right bundle branch block, cardiac transplant, and under no possibilities to realize the exams were excluded. The results showed that asymmetric septal hypertrophy was the most common type (73%), 63% had a positive familial history of hypertrophic cardiomyopathy, 55% sudden cardiac death, and 23% syncope. Also, complex ventricular arrhythmias were detected in 14% and late potentials in 23% of patients. According to this study, the presence of late potentials was not associated with familial sudden death, syncope, and complex ventricular arrhythmias.	0
OBJECTIVES:Nonimmune hydrops fetalis (NIHF) accounts for 90% of hydrops fetalis cases. About 15% to 29% of unexplained NIHF cases are caused by lysosomal storage diseases (LSD). We review the spectrum of LSD and associated clinical findings in NIHF in a cohort of patients referred to our institution. METHODS:We present a retrospective case-control study of cases with NIHF referred for LSD biochemical testing at a single center. Cases diagnosed with LSD were matched to controls with NIHF and negative LSD testing and analyzed according to the STROBE criteria to the extent the retrospective nature of this study allowed. RESULTS:Between January 2006 and December 2018, 28 patients with NIHF were diagnosed with a LSD. Eight types of LSD were diagnosed: galactosialidosis 8/28 (28.6%), sialic acid storage disease (SASD) 5/28 (17.9%), mucopolysaccharidosis VII 5/28 (17.9%), Gaucher 4/28 (14.3%), sialidosis 2/28 (7.1%), GM1 gangliosidosis 2/28 (7.1%), Niemann-Pick disease type C 1/28 (3.6%), and mucolipidosis II/III 1/28 (3.6%). Associated clinical features were hepatomegaly 16/21 (76.2%) vs 22/65 (33.8%), P < .05, splenomegaly 12/20 (60.0%) vs 14/58 (24.1%), P < .05, and hepatosplenomegaly 10/20 (50.0%) vs 13/58 (22.4%) P < .05. CONCLUSION:The most common LSD in NIHF were galactosialidosis, SASD, mucopolysaccharidosis VII, and Gaucher disease. LSD should be considered in unexplained NIHF cases, particularly if hepatomegaly, splenomegaly, or hepatosplenomegaly is visualized on prenatal ultrasound.	0
OBJECTIVE: To clinically and genetically characterize a large Brazilian family with autosomal dominant partial epilepsy with auditory features (ADPEAF) not related to leucine-rich, glioma-inactivated 1 (LGI1) gene. METHODS: Seventy family members (four married-ins) participating in the study were assessed by a detailed clinical interview and a complete neurologic examination. Genetic mapping was conducted through autosome-wide single nucleotide polymorphism (SNP) genotyping and subsequent linkage analysis on 16 and haplotype analysis on 25 subjects, respectively. RESULTS: The pedigree comprised 15 affected members, of whom 11 were included in the study (male/female: 6/5; mean age 39.5 years). All but two (III:22 and IV:92) had focal seizures with auditory aura followed by secondary generalization in 44.4%. The mean age at onset of epilepsy seizures was 13.7 years. Initial autosome-wide SNP linkage analysis conducted on 12 subjects (8 affected) pointed to a single genomic region on chromosome 19 with a maximum multipoint logarithm of the odds (LOD) score of 2.60. Further refinement of this region through SNP and microsatellite genotyping on 16 subjects (11 affected) increased the LOD score to 3.41, thereby establishing 19q13.11-q13.31 as a novel ADPEAF locus. Haplotype analysis indicated that the underlying mutation is most likely located in a 9.74 Mb interval between markers D19S416 and D19S420. Sequence analysis of the most prominent candidate genes within this critical interval (SCN1B, LGI4, KCNK6, and LRFN1) did not reveal any mutation. SIGNIFICANCE: This study disclosed a novel ADPEAF locus on chromosome 19q13.11-q13.31, contributing to future identification of a second dominant gene for this epileptic syndrome. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.	0
Three siblings with inhalational elemental mercury toxicity presented with fever, rash, and upper respiratory tract symptoms. The patients were heavily exposed to elemental mercury that was spilled in their home and then vacuumed. Initial whole blood mercury levels were elevated at >200 µg/L, 153 µg/L and 130 µg/L (Mayo Clinic Laboratories lab reference range <9 µg/L) for Cases 1, 2, and 3, respectively. All three required chelation with succimer. Clinically significant elemental mercury toxicity can resemble an infectious illness. Severe morbidity and mortality can be prevented if heavy metal poisoning is considered early, through a detailed history including an environmental exposure history. For elemental mercury spills in the home, safe and effective clean-up steps are needed. Improved public health education is needed to prevent similar household exposures.	0
To determine the cortical mechanism that underlies the cognitive impairment and motor disability in hereditary spastic paraplegia (HSP), nine HSP patients from a Chinese family were examined using clinical evaluation, cognitive screening, and genetic testing. Controls were matched healthy subjects. White-matter fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD; tract-based spatial statistics), cortical thickness (FreeSurfer), and subcortical gray matter (FIRST) based on T1-weighted MRI and diffusion tensor imaging were analyzed. A novel mutation in the SPAST gene (NM_014946.3, c.1321+2T>C) was detected. Patients had motor disability and low Montreal Cognitive Assessment (MoCA) scores. Patients showed significantly decreased total gray- and white-matter volumes, corpus callosum volume, cortical thickness, and subcortical gray-matter volume as well as significantly lower FA and AD values and significantly higher MD and RD values in the corpus callosum and corticospinal tract. Cortical thickness, subcortical gray-matter volume, and MoCA score were negatively correlated with disease duration. Cortical thickness in the right inferior frontal cortex was negatively correlated with Spastic Paraplegia Rating Scale score. Cortical thickness and right hippocampus volume were positively correlated with the MoCA score and subscores. In conclusion, brain damage is not restricted to the white matter in SPG4-HSP patients, and widespread gray-matter damage may account for the disease progression, cognitive impairment, and disease severity in SPG4-HSP.	0
BACKGROUND:Lactic acidosis is a common finding in neonates, in whom mitochondrial dysfunction is often secondary to tissue hypoperfusion, respiratory failure, and/or sepsis. Primary (non-physiological) lactic acidosis is comparatively rare, and suggests the presence of an inborn error of mitochondrial energy metabolism. Optimal medical management and accurate prognostication requires the correct determination of the etiology of lactic acidosis in a given patient. Unfortunately, genetic diagnoses are rare and highly variable for neonates presenting with primary lactic acidosis; individual case reports may offer the most promise for treatment considerations. The mitochondrion is a complex molecular machine incorporating the products of > 1000 distinct nuclear genes. Primary lactic acidoses are therefore characterized by high genetic heterogeneity and a specific genetic diagnosis currently remains out of reach in most cases. Most mitochondriopathies with neonatal onset follow autosomal recessive inheritance and carry a poor prognosis. Here we detail the case of a father and daughter with dominantly-inherited, resolving (i.e. transient) neonatal hyperlactatemia due to complex IV deficiency. We found no other published descriptions of benign transient complex IV deficiency with autosomal dominant inheritance. CASE PRESENTATION:Both individuals presented as neonates with unexplained, marked lactic acidosis suggesting a primary mitochondrial disorder. Within the first weeks of life, elevated blood lactate levels normalized. Their clinical and developmental outcomes were normal. Biochemical studies in the proband showed multiple abnormalities consistent with a complex IV respiratory chain defect. Cultured skin fibroblasts showed an elevated lactate-to-pyruvate ratio, deficient complex IV activity, and normal pyruvate dehydrogenase and pyruvate carboxylase activities. Whole-exome sequencing of the proband and both parents did not identify a causative mutation. CONCLUSION:We conclude that the proband and her father appear to have a dominant form of transient neonatal hyperlactatemia due to heterozygous changes in an as-yet unidentified gene. This transient neonatal complex IV deficiency should be considered in the differential diagnosis of primary neonatal hyperlactatemia; notable clinical features include autosomal-dominant inheritance and an apparently benign postnatal course. This report exemplifies the growing differential diagnosis for neonatal lactic acidosis and highlights the importance of both physician counselling and the use of family history in communicating with parents.	0
We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.	0
The morphogenesis of midfacial processes requires the coordination of a variety of cellular functions of both mesenchymal and epithelial cells to develop complex structures. Any failure or delay in midfacial development as well as any abnormal fusion of the medial and lateral nasal and maxillary prominences will result in developmental defects in the midface with a varying degree of severity, including cleft, hypoplasia, and midline expansion. Despite the advances in human genome sequencing technology, the causes of nearly 70% of all birth defects, which include midfacial development defects, remain unknown. Recent studies in animal models have highlighted the importance of specific signaling cascades and genetic-environmental interactions in the development of the midfacial region. This review will summarize the current understanding of the morphogenetic processes and molecular mechanisms underlying midfacial birth defects based on mouse models with midfacial developmental abnormalities.	0
PURPOSE:Newborn screening (NBS) programs are important for appropriate management of susceptible neonates to prevent serious clinical problems. Neonates admitted to neonatal intensive care units (NICU) are at a potentially high risk of false-positive results, and repetitive NBS after total parenteral nutrition is completely off results in delayed diagnosis. Here, we present the usefulness of a targeted next-generation sequencing (TNGS) panel to complement NBS for early diagnosis in high-risk neonates. MATERIALS AND METHODS:The TNGS panel covered 198 genes associated with actionable genetic and metabolic diseases that are typically included in NBS programs in Korea using tandem mass spectrometry. The panel was applied to 48 infants admitted to the NICU of Severance Children's Hospital between May 2017 and September 2017. The infants were not selected for suspected metabolic disorders. RESULTS:A total of 13 variants classified as likely pathogenic or pathogenic were detected in 11 (22.9%) neonates, including six genes (DHCR7, PCBD1, GAA, ALDOB, ATP7B, and GBA) associated with metabolic diseases not covered in NBS. One of the 48 infants was diagnosed with an isobutyl-CoA dehydrogenase deficiency, and false positive results of tandem mass screening were confirmed in two infants using the TNGS panel. CONCLUSION:The implementation of TNGS in conjunction with conventional NBS can allow for better management of and earlier diagnosis in susceptible infants, thus preventing the development of critical conditions in these sick infants.	0
MURCS (Mullerian duct aplasia, Renal anomalies, and Cervicothoracic Somite dysplasia) association is a group of congenital genito-urinary and skeletal malformations. We report an adolescent girl with the cardinal features of MURCS association, obesity, and clinical findings of hyperandrogenism who did not show any exonic mutation of the WNT4 gene. Our finding excludes WNT4 gene as a candidate for MURCS association and suggests the need for further genetic studies.	0
Papillary cystadenomas of the epididymis are known to occur in association with Von Hippel-Lindau (VHL) disease. The development of a papillary cystadenocarcinoma, its malignant counterpart, is rare with only a few sporadic cases reported in the literature. Metastatic deposits are exceedingly uncommon; in fact, only a single case report has documented metastases to the paraureteral region, but metastases to the testis have never been reported. A 43-year-old gentleman with VHL disease presented with non-obstructive azoospermia, a right epididymal mass, and an atrophic surgically corrected undescended left testis. The epididymal mass was reported as a papillary cystadenocarcinoma on biopsy. The patient was managed with a radical inguinal orchidectomy and bench microTeSE with successful sperm retrieval. Metastatic papillary cystadenocarcinoma of the epididymis to the testis has never been previously reported. This case was managed by radical orchidectomy and subsequent onco-microTeSE, allowing safe oncological treatment and optimal fertility preservation.	0
Viruses are the most abundant and diverse biological entities in the planet. Historically, our main interest in viruses has focused on their pathogenic role, recognized by pandemics that have decimated the world population. However, viral infections have also played a major role in the evolution of cellular organisms, both through interchanging of genes with novel functions and shaping the immune system. Examples abound of infections that seriously compromise the host integrity, but evidence of plant and insect viruses mutualistic relationships have recently surfaced in which infected hosts are better suited for survival, arguing that virus-host interactions are initially parasitic but become mutualistic over years of co-evolution. A similar mutual help scenario has emerged with commensal gut bacteria. EBV is a herpesvirus that shares more than a hundred million years of co-evolution with humans, today successfully infecting close to 100% of the adult world population. Infection is usually acquired early in childhood persisting for the host lifetime mostly without apparent clinical symptoms. Disturbance of this homeostasis is rare and results in several diseases, of which the best understood are infectious mononucleosis and several EBV-associated cancers. Less understood are recently found inborn errors of the immune system that result in primary immunodeficiencies with an increased predisposition almost exclusive to EBV-associated diseases. Puzzling to these scenarios of broken homeostasis is the co-existence of immunosuppression, inflammation, autoimmunity and cancer. Homologous to EBV, HCMV, HHV-6 and HHV-7 are herpesviruses that also latently infect most individuals. Several lines of evidence support a mutualistic equilibrium between HCMV/EBV and hosts, that when altered trigger diseases in which the immune system plays a critical role. Interestingly, these beta and gamma herpesviruses persistently infect all immune lineages and early precursor cells. In this review, we will discuss the evidence of the benefits that infection of immune cells with these herpesviruses brings to the host. Also, the circumstances in which this positive relationship is broken, predisposing the host to diseases characterized by an abnormal function of the host immune system.	0
The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.	0
Purpose: To present the ocular findings of the members of a family that has the diagnosis of Muckle Wells syndrome, a form of cryopyrin associated periodic syndrome (CAPS).Materials and Methods: Nine patients with MWS were included in this study. Each study participant underwent a systemic evaluation, comprehensive ophthalmic examination, and auxillary testings.Results: In this study, conjunctivitis was the most prominent ocular finding. Other relatively common ocular findings included band keratopathy, clinical signs of past uveitis, and corneal topography abnormalities. Nystagmus, corneal leukoma, and optic nerve pallor with epiretinal membrane were also detected. Rare ocular manifestations were posterior stromal corneal opacification with edema, anterior iris snychecia, and mild cataract.Conclusion: MWS is a rare systemic autoinflammatory disorder that presents with a variety of ocular findings. Exacerbation of systemic and ocular findings with cold is a hallmark of the disease.	0
Laugier-Hunziker syndrome is a rare benign idiopathic condition characterized by acquired macular pigmentation of the lips and buccal mucosa, often accompanied by melanonychia. Although the etiopathogenesis is not fully known, tyrosine is thought to be responsible for the pathogenesis of enzyme hyperactivity in melanin biosynthesis. We present the case of a 66-year-old woman diagnosed with Laugier-Hunziker syndrome and rheumatoid arthritis.	0
Embryology of normal web space creation and the genetics of syndactyly in humans and experimental animals are well described in the literature. In this review, the author offers a 3-step pathway of pathogenesis for syndactyly. The first step is initiated either by the overactivation of the WNT canonical pathway or the suppression of the Bone Morphogenetic Protein (BMP) canonical pathway. This leads to an overexpression of Fibroblast Growth Factor 8 (FGF8). The final step is the suppression of retinoic acid in the interdigital mesenchyme leading to suppression of both apoptosis and extracellular matrix (ECM) degradation, resulting in syndactyly.	0
A 47-year-old Vietnamese woman presented with dystrophic fingernails and toenails that had been present since infancy. She also had developed, in the third decade, pretibial pruritus with vesicle formation and progressive localized papules and scars. Multiple family members were similarly affected. Physical examination showed lichenoid papules that coalesced into large plaques that were studded with milia over the pretibial areas and 20 nail dystrophy. A biopsy specimen showed milia-like structures and dermal fibrosis. Pretibial epidermolysis bullosa is a rare variant of dystrophic epidermolysis bullosa that shows appreciable clinical overlap with dystrophic epidermolysis bullosa pruginosa. Both disease subsets are characterized by the late age of onset, nail dystrophy, and predominantly pretibial pruritic lichenoid skin lesion; they are associated with glycine substitution mutations in COL7A1.	0
β-Glucans have long been used as an immunostimulant in aquaculture. However, the relationship of its structure to its immunomodulatory properties are poorly understood. In this study, the particle size and chemical structure of β-glucans extracted from wild-type strain of baker's yeast (Saccharomyces cerevisiae) and its null-mutant yeasts Gas1 were characterised. Using Sigma β-glucan as a reference, the immunomodulatory properties of these polysaccharides in the germ-free Artemia franciscana model system in the presence of Vibrio harveyi bacterial challenge were investigated. The survival of the A. franciscana nauplii, upon challenge with V. harveyi, was significantly higher in all three glucan-treated groups compared to the control. The glucan Gas1 with a lower degree of branching and shorter side chain length had the most prominent V. harveyi-protective effects. The particle size did not affect the nauplii survival when challenged with V. harveyi. Results also showed that the salutary effect of the tested glucans was associated with the upregulation of innate immune genes such as lipopolysaccharide and β-1,3-glucan-binding protein (lgbp), high mobility group box protein (hmgb), and prophenoloxidase (proPO). Interestingly, the up-regulation of superoxidase dismutase (sod) and glutathione-s-transferase (gst) was only observed in Gas1 treated group, indicating that Gas1 could function to induce higher reactive oxygen species and stronger immunomodulatory function in A. franciscana, and therefore higher survival rate. The expression of heat shock protein 70 (hsp70), peroxinectin (pxn), and down syndrome cell adhesion molecule (dscam) remain unaltered in response to glucan treatment. Taken together, this study provides insights into the structure-function relationship of β-glucan and the results confirmed that β-glucan can be an effective immunostimulant in aquaculture, especially the Gas1 glucan.	0
Background:Methanol, an industrial solvent, can cause illness and death if ingested. In June 2017, the Uganda Ministry of Health was notified of a cluster of deaths which occurred after drinking alcohol. We investigated to determine the cause of outbreak, identify risk factors, and recommend evidence-based control measures. Methods:We defined a probable case as acute loss of eyesight and ≥1 of the following symptoms: profuse sweating, vomiting, dizziness, or loss of consciousness in a resident of either Nabweru or Nangabo Subcounty from 1 to 30 June 2017. In a case-control study, we compared exposures of case-patients and controls selected among asymptomatic neighbors who drank alcohol and matched by age and sex. We collected alcohol samples from implicated bars and wholesaler X for testing. Results:We identified 15 cases; 12 (80%) died. Among case-patients, 12 (80%) were men; the median age was 43 (range: 23-66) years. Thirteen (87%) of 15 case-patients and 15 (25%) of 60 controls last drank a locally distilled alcohol at one of the three bars supplied by wholesaler X (ORM-H = 15; 95% CI: 2.3-106). We found that alcohol sellers sometimes added methanol to drinking alcohol to increase their profit margin. Among the 10 alcohol samples from wholesaler X, the mean methanol content (1200 mg/L, range: 77-2711 mg/L) was 24 times higher than the safe level. Conclusion:This outbreak was caused by drinking a locally distilled alcohol adulterated with methanol from wholesaler X. We recommended enforcing existing laws governing alcohol manufacture and sale. We recommended timely intravenous administration of ethanol to methanol poisoning victims.	0
BACKGROUND:Pancreaticoduodenectomy (PD) is a procedure associated with significant morbidity and mortality. Initially described as gastropancreaticoduodenectomy (GPD), the possibility of preservation of the gastric antrum and pylorus was described in the 1970s. AIM:To evaluate the mortality and operative variables of PD with or without pyloric preservation and to correlate them with the adopted technique and surgical indication. METHOD:Retrospective cohort on data analysis of medical records of individuals who underwent PD from 2012 through 2017. Demographic, anthropometric and operative variables were analyzed and correlated with the adopted technique (GPD vs. PD) and the surgical indication. RESULTS:Of the 87 individuals evaluated, 38 (43.7%) underwent GPD and 49 (53.3%) were submitted to PD. The frequency of GPD (62.5%) was significantly higher among patients with pancreatic neoplasia (p=0.04). The hospital stay was significantly shorter among the individuals submitted to resection due to neoplasias of less aggressive behavior (p=0.04). Surgical mortality was 10.3%, with no difference between GPD and PD. Mortality was significantly higher among individuals undergoing resection for chronic pancreatitis (p=0.001). CONCLUSION:There were no differences in mortality, surgical time, bleeding or hospitalization time between GPD and PD. Pancreas head neoplasm was associated with a higher indication of GPD. Resection of less aggressive neoplasms was associated with lower morbidity and mortality.	0
OBJECTIVE:To correlate the nutritional status with variables associated to the type of diet and feeding route of children and adolescents with spastic quadriplegic cerebral palsy (CP). METHODS:This cross-sectional study included 28 patients aged ≤13 years old who presented a diagnosis of spastic quadriplegic CP and were followed by the nutrition team of the Outpatient Clinic for Special Patients of Hospital de Clínicas de Uberlândia - Universidade Federal de Uberlândia (HC-UFU), between July/2016 and January/2017. Consent forms were signed by the legal guardians. The nutritional status was evaluated and data on dietary complications food route and type of diet were collected. For the description of data, average and median values were used. Correlation was tested with Spearman's index. Significance was set at p<0.05. RESULTS:75% of patients used alternative feeding routes (nasoenteral, catheter or gastrostomy), 57% were eutrophic. The most frequent complications were oropharyngeal dysphagia, reflux and intestinal constipation. No correlation was found between the occurrence of complications and the nutritional status. There was a positive correlation between the diet received and the patient's nutritional status (0.48; p=0.01), i.e. individuals with adequate caloric and macronutrients intake had a better nutritional status. CONCLUSIONS:The results reinforce the need for continued nutritional guidance for the children's parents/caregivers, as well as the choice of an adequate rout of feeding to each child by the multi-professional team, in order to contribute to improved nutritional status and adequate dietary intake.	0
BACKGROUND Thoracoschisis is a very rare congenital birth defect defined by the herniation of intra-abdominal organs through a defect in the thoracic wall. Though often associated with other birth defects as a part of the "limb-body wall complex" deformities, thoracoschisis has very rarely been reported as an isolated finding. CASE REPORT Here we present the case of a 30-day-old term male infant with an isolated left thoracoschisis managed successfully by primary closure. The patient was monitored postnatally in the Neonatal Intensive Care Unit (NICU) of Maputo Central Hospital because of the presence of a herniated mass through a left chest wall defect below the left nipple. Computed tomography (CT) scans suggested the presence of a left diaphragmatic hernia, left rib agenesis, and herniation of an unidentifiable intra-abdominal organ through the anterior left chest wall. On day of life (DOL) 30, when global health outreach pediatric surgeons arrived at the hospital, the decision was made to operate on the child. The mass was found to be of liver origin, the exposed tissue was excised, and primary closure of the chest wall was accomplished. The patient's postoperative course involved a wound infection that resolved favorably with treatment, allowing for discharged home on postoperative day (POD) 17 in stable condition. CONCLUSIONS Our case report highlights the importance of recognizing this rare condition and directing appropriate surgical care.	0
Fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling plays essential roles in bone development and diseases. Missense mutations in FGFs and FGFRs in humans can cause various congenital bone diseases, including chondrodysplasia syndromes, craniosynostosis syndromes and syndromes with dysregulated phosphate metabolism. FGF/FGFR signaling is also an important pathway involved in the maintenance of adult bone homeostasis. Multiple kinds of mouse models, mimicking human skeleton diseases caused by missense mutations in FGFs and FGFRs, have been established by knock-in/out and transgenic technologies. These genetically modified mice provide good models for studying the role of FGF/FGFR signaling in skeleton development and homeostasis. In this review, we summarize the mouse models of FGF signaling-related skeleton diseases and recent progresses regarding the molecular mechanisms, underlying the role of FGFs/FGFRs in the regulation of bone development and homeostasis. This review also provides a perspective view on future works to explore the roles of FGF signaling in skeletal development and homeostasis.	0
Adenine phosphoribosyltransferase (APRT) deficiency, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and primary hyperoxaluria (PH) are rare but important causes of severe kidney stone disease and/or chronic kidney disease in children. Recurrent kidney stone disease and nephrocalcinosis, particularly in pre-pubertal children, should alert the physician to the possibility of an inborn error of metabolism as the underlying cause. Unfortunately, the lack of recognition and knowledge of the five disorders has frequently resulted in an unacceptable delay in diagnosis and treatment, sometimes with grave consequences. A high index of suspicion coupled with early diagnosis may reduce or even prevent the serious long-term complications of these diseases. In this paper, we review the epidemiology, clinical features, diagnosis, treatment, and outcome of patients with APRT deficiency, cystinuria, Dent disease, FHHNC, and PH, with an emphasis on childhood manifestations.	1
PURPOSE:Intraoperative chest tubes (IOCTs) can be placed during esophageal atresia/tracheoesophageal fistula (EA/TEF) repair to control pneumothoraces and detect esophageal leaks, potentially preventing the need for postoperative chest tubes (POCTs). However, data are lacking regarding IOCTs' effect. We hypothesized that IOCT placement would not reduce the risk of POCT placement and would increase hospital length of stay (LOS). METHODS:This was a single-center case-control study of type C EA/TEF patients repaired at a tertiary referral center between 2006 and 2017. Postoperative complications of patients who received IOCTs (n = 83) were compared to that of patients who did not receive IOCTs (n = 26). Patients were compared via propensity score matching. Additionally, sensitivity analyses excluding low birth weight (LBW) patients and patients undergoing delayed esophageal anastomosis were also performed. RESULTS:There was no significant difference in rates of pneumothoraces or esophageal leaks between the IOCT and no-IOCT groups, nor were either of these complications detected earlier in the IOCT group. Rates of POCT placement and mortality also did not differ between groups. IOCT patients were associated with increased hospital LOS (28 vs 15.5 days, p < 0.001) and esophageal strictures (30% vs 8%, p = 0.04) requiring a return to the operating room (RTOR). CONCLUSION:IOCTs did not improve outcomes in EA/TEF repair. IOCTs seem associated with increased LOS and ROTR for esophageal stricture, suggesting that IOCTs may not be beneficial after EA/TEF repair.	0
LEOPARD syndrome with multiple lentigines (cardiomyopathic lentiginosis) is a rare, genetically predetermined disease with autosomal dominant inheritance. Prevalence of this syndrome is unknown. One of pathognomonic clinical manifestations of this syndrome is the presence of multiple lentiginous pigment spots all over the body. The most common cardiac manifestation (approximately 80%) is myocardial hypertrophy. We presented a rare clinical case of detecting LEOPARD syndrome with multiple lentigines in a 32-year old female patient with major manifestations evident as pronounces morpho-functional alterations, myocardial hypertrophy, and heart rhythm disorders.	0
To analyze the clinical manifestations and mutation of MYH9 gene in a large Chinese family affected with MYH9-related thrombocytopenia.After informed consent was obtained; clinical examination and history investigation was performed on 29 members of the family. DNA was extracted using a standard method, then exons 1 to 40 and their corresponding exon-intron junctions of the MYH9 gene were amplified with PCR and subjected to Sanger sequencing. The results were compared to reference sequence from the University of California, Santa Cruz (UCSC) to screen the mutation. PCR and Sanger sequencing was performed on genome DNA of all family members to confirm the identified mutation.The clinical manifestations of family members were prominently heterogeneous. Four affected members showed hearing loss or deafness, two affected members showed nephritis or kidney failure, and other affected members was only characterized by mild bleeding or with no obvious symptoms. A heterozygous missense mutation c.4270G>A (p.Aspl841Asn) in exon 30 of the MYH9 gene was identified in all affected members from this family, which also co-segregated with the phenotype.A missense mutation c.4270G>A (p.Aspl841Asn) within the exon 30 of the MYH9 gene was identified to be associated with MYH9-related thrombocytopenia in a Chinese family.	0
This report describes a case of a 32-year-old woman who had been diagnosed with a facial arteriovenous malformation during childhood. Because this patient possessed a major risk of perioperative hemorrhage, the use of several local hemostatic measures was thoroughly explored before routine exodontia.Selective embolization of the right superior thyroid artery was performed intraoperatively and a novel hemostatic technique using a combination of a packing of Gelfoam wrapped in Surgicel was placed within the extraction sites and sealed with SwiftSet.Local hemostasis was achieved with a novel technique using a combination of cyanoacrylate and local hemostatic agents despite aggressive hemorrhaging after routine exodontia.By exploiting the local properties of these agents, local hemostasis can be achieved with this novel technique even in the most challenging cases of vascular anomalies.	0
Cystic neoplasms arising from the prostate are rare, and stromal tumours of uncertain malignant potential and the spectrum of cystic epithelial tumours of the prostate are the major differential diagnoses of a cystic prostatic neoplasm. We report a case of a stromal tumour of uncertain malignant potential, which showed a multilocular cystic mass with some solid components. The solid component of the tumour did not show substantial diffusion restriction and uptake of 18F-FDG-PET, and this could be the critical finding suggesting a stromal tumour of uncertain malignant potential rather than a malignant cystic epithelial tumour.	0
Objective: To summarize the clinical features of leukoencephalopathy with vanishing white matter disease (VWM) in children. Methods: A retrospective cohort study was performed on 54 genetically diagnosed VWM patients in Peking University First Hospital from January 2007 to March 2019. Paper registration form and electronic medical record system were used to collect the data,and the children were divided into five groups according to the age of disease onset:<1 year, 1-<2 years, 2-<4 years, 4-<8 years and 8-<18 years respectively. The progression of motor function, episodic aggravation, epileptic seizures, survival time, brain magnetic resonance imaging (MRI) and genotype features were analyzed and compared. Non-parametric test, χ(2) test or Fisher's exact test were used for comparison among groups; Kaplan-Meier survival curve was adopted to delineate the survival status of the children. Results: Fifty-four VWM patients were included in the study, including 34 males and 20 females.The age of disease onset was 2 years and 8 months (ranged from 6 months to 9 years and 7 months). Onset age was less than 1 year in 5 cases; onset age was 1-<2 years in 12 cases; onset age was 2-<4 years in 25 cases; onset age was 4-<8 years, in 10 cases; onset age was 8-<18 years in 2 cases; 94% (51/54) of patients had complaint of motor regression at the first visit; 87% (47/54) of patients suffered from episodic aggravation. Episodic seizures occurred in 43% (23/54) patients. In survivors with disease durations of 1-3 years, in 38% (9/24) patients the disease was classified as grades Ⅳ-Ⅴ by gross motor function classification system (GMFCS). For the onset age 1-<2 years group, 1 patient was classified as GMFCS Ⅳ among 3 survivors with disease durations of 1-3 years. As for the 2-<4 years group, 6 patients were classified as GMFCS Ⅳ-Ⅴ among 15 patients with disease durations of 1-3 years, whereas 1 patient was classified as GMFCS Ⅳ-Ⅴ among 4 patients with disease durations of 1-3 years in the 4-<8 years group. Lesions, liquefaction and diffusion restriction in brain MRI were compared among different groups, and it was revealed that the earlier the age of disease onset was, the more likely the subcortical white matter (frontal lobe P<0.01,temporal and parieto-occipital lobe both P=0.002), internal capsule (anterior limb P<0.01, posterior limb P=0.00) and brain stem (midbrain P=0.001, pons P<0.01) were to be involved. In addition, internal capsule (anterior limb P=0.002, posterior limb P=0.005) and brain stem (midbrain P=0.001, pons P=0.003) showed more diffuse restricted diffusion. Moreover, the subcortical white matter (frontal and parieto-occipital lobe both P<0.01, temporal lobe P=0.005) showed earlier rarefaction. The 1-year and 2-year survival rates of the overall patients were 81% and 75% respectively, while the 15-year survival rate was 45%. EIF2B5 gene variation was the most common, which accounts for 43% (23/54), followed by EIF2B3 (22%, 12/54). Conclusions: The majority of VWM patients complained of motor regression at the first visit, episodic aggravation and epileptic seizures are common in the course. Earlier age at onset is associated with more rapid clinical progression, shorter survival time as well as more extensive lesions, liquefaction and diffusion restriction in brain MRI. The most common variant gene is EIF2B5, followed by EIF2B3.	0
Ossified spinal meningiomas are a rare form of spinal tumors. These tumors increase surgical morbidities due to their hard consistency and strong adhesion to the neural tissue and relatively narrow surgical space. Here, the authors describe the clinical findings, surgical strategies, and histological findings of a patient with an ossified meningioma. Preoperative diagnosis of these tumors can prevent surgical morbidities. Total resection can be curative with the application of meticulous microsurgical techniques.	0
Hyperinsulinism-hyperammonemia syndrome (HI/HA) is the second most common form of persistent hyperinsulinemic hypoglycemia of infancy (PHHI). The main clinical characteristics of HI/HA syndrome are repeated episodes of symptomatic hypoglycemia, but not usually severe. Consequently, children with HI/HA syndrome are frequently not recognized in the first months of life. An 8-month-old boy was admitted to a hospital due to hypoglycemia seizures. He also had asymptomatic hyperammonemia with no signs of lethargy or headaches. Genetic testing revealed autosomal dominant syndrome, a mutation in the GLUD1 gene (p.Arg274Cys). The boy started treatment with diazoxide. Subsequent growth and neurological development were normal. Hypoglycemic symptoms in HI/HA syndrome may vary from being non specific to severe. As hypoglycemia could lead to brain injury and impairment of neurological development, timely diagnosis and management are essential. If transient hypoglycemia is ruled out, metabolic disorders must be taken into account.	0
The clinical phenotype of 1q21.1 microdeletion syndrome is highly heterogeneous. It is characterized by dysmorphic facial features, microcephaly, and developmental delay. Several congenital defects, including cardiac, ocular, skeletal anomalies, and psychiatric or behavioural abnormalities, have also been described. Here, we report on two siblings with substantial intrafamilial phenotypic variability carrying a heterozygous deletion of the 1q21.1 region spanning a known critical genomic area (~1.35 Mb). The microdeletion was inherited from the unaffected father. Patients described here show a spectrum of clinical features, a portion of which overlap with those previously reported in patients with 1q21.1 microdeletions. In addition, we review the clinical reports of 66 individuals with this condition. These findings extend and substantiate the current clinical understanding of recurrent copy number variations in the 1q21.1 region.	0
Glycine encephalopathy (GE) or nonketotic hyperglycinemia is an autosomal recessive disorder due to a primary defect in glycine cleavage enzyme system. It is characterized by elevated levels of glycine in plasma and cerebrospinal fluid usually presenting with seizures, hypotonia, and developmental delay. In our case, paradoxical increase in seizure frequency on starting sodium valproate led us to diagnose GE.	0
Hemochromatosis is a clinical syndrome characterized by iron overload in various organs. We present here a case of type 4 hereditary hemochromatosis due to heterozygous mutation in SLC40A1 gene (p.D157A). SLC40A1 encodes ferroportin, a macromolecule only known as iron exporter from mammalian cells. He first presented symptoms correlated with hypopituitarism. Furthermore, marked hyperferritinemia and high transferrin saturation were revealed in combination with the findings of iron overload in the liver, spleen and pituitary gland by computed tomography and magnetic resonance imaging. Liver biopsy revealed iron deposition in both hepatocytes and Kupffer cells. SLC40A1 mutations are considered to cause wide heterogeneity by various ferroportin mutations. Thus, clinicopathological examinations seem to be very important for diagnosing phenotype of type 4 hemochromatosis in addition to the gene analysis. We diagnosed him as type 4B hereditary hemochromatosis (ferroportin-associated hemochromatosis) by the findings of high transferrin saturation and iron deposition in hepatocytes, and then started iron chelating treatment. We should suspect the possibility of hereditary hemochromatosis even in Japanese with severe iron overload. Although the same mutation in SLC40A1 gene (p.D157A) had been reported to cause "loss of function" phenotype, we considered that the mutation of our case caused "gain of function" phenotype.	0
BACKGROUND/AIMS:Glucocorticoids are essential in modulating memory processes of emotionally arousing experiences and we have shown that corticosteroid-binding globulin (CBG) influences glucocorticoid delivery to the brain. Here, we investigated the role of CBG in contextual and recognition long-term memory according to stress intensity. METHOD:We used adult male mice totally deficient in CBG (Cbg KO) or brain-specific Cbg KO (CbgCamk KO) to examine their performance in contextual fear conditioning (CFC) and au-ditory fear conditioning, both at short (1 h) and long-term (24 h). Long-term memory in Cbg KO was further analyzed in conditioned odor aversion and in novel object recognition task (NORT) with different paradigms, that is, with and without prior habituation to the context, with a mild or strong stressor applied during consolidation. In the NORT experiments, total and free glucocorticoid levels were measured during consolidation. RESULTS:Impaired memory was observed in the Cbg KO but not in the CbgCamk KO in the CFC and the NORT without habituation when tested 24 h later. However, Cbg KO displayed normal behavior in the NORT with previous habituation and in the NORT with a mild stressor. In condition of the NORT with a strong stressor, Cbg KO retained good 24 h memory performance while controls were impaired. Total and free glucocorticoids levels were always higher in controls than in Cbg KO except in NORT with mild stressor where free glucocorticoids were equivalent to controls. CONCLUSIONS:These data indicate that circulating but not brain CBG influences contextual and recognition long-term memory in relation with glucocorticoid levels.	0
Dermatofibrosarcoma protuberans is a slowly progressive, locally aggressive fibroblastic tumor which can be misdiagnosed in the early stage. Reflectance confocal microscopic features of dermatofibrosarcoma protuberans has been scarcely described in the literature. We described the dermoscopic and reflectance confocal microscopic findings of 12 × 15 cm sized tumoral lesion of 45-year-old man.	0
OBJECTIVES:Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy characterized by chronic lung disease and cyclic vomiting due to hyper-adrenergic crises. Most FD patients are in a depleted nutritional state; however, the phenotype of the disease is quite different between patients, as for the severity of lung disease and the intensity and frequency of these pathognomonic crises. In this study we wanted to investigate whether resting energy expenditure (REE) levels are increased in this population, and if correlations exist between REE levels and phenotype severity. METHODS:Data was collected from 12 FD patients (6/6 m/f). REE measurements were conducted by indirect calorimeter. Measured REE % predicted were correlated with pulmonary function, severity of the scoliosis, serum C-reactive protein, yearly frequency of hyperadrenergic crisis, hospital admissions and the use of nocturnal noninvasive positive pressure ventilation. RESULTS:Mean REE was 112 ±13% predicted with 50% being in a hypermetabolic state (REE/HB > 110%). Body mass index (BMI) was below normal range in 75% of patients, and reduced energy intake was also decreased in 75%. No significant correlations to disease severity factors were found. When dividing the subjects to REE levels above or below 125% predicted, Patients with REE above 125% predicted presented with significantly lower inspiratory capacity (42.7% predicted vs 62.8% predicted; P = 0.04). CONCLUSIONS:Hypermetabolic state was described in 50% of FD patients. The Low BMI is explained by combination of relative anorexia and increased REE. The REE levels are related to the underling respiratory disease.	0
Single gene mutations have been implicated in the pathogenesis of a form of diabetes mellitus (DM) known as the maturity-onset diabetes of the young (MODY). However, there are diverse opinions on the suspect genes and pathophysiology, necessitating the need to review and communicate the genes to raise public awareness. We used the Google search engine to retrieve relevant information from reputable sources such as PubMed and Google Scholar. We identified 14 classified MODY genes as well as three new and unclassified genes linked with MODY. These genes are fundamentally embedded in the beta cells, the most common of which are HNF1A, HNF4A, HNF1B, and GCK genes. Mutations in these genes cause β-cell dysfunction, resulting in decreased insulin production and hyperglycemia. MODY genes have distinct mechanisms of action and phenotypic presentations compared with type 1 and type 2 DM and other forms of DM. Healthcare professionals are therefore advised to formulate drugs and treatment based on the causal genes rather than the current generalized treatment for all types of DM. This will increase the effectiveness of diabetes drugs and treatment and reduce the burden of the disease.	0
We studied 18 patients (15 men and three women) evaluated for a destructive sinonasal lesion that had been diagnosed as "polymorphic reticulosis." The histologic features of each lesion were those of angiocentric immunoproliferative lesions," characterized by atypical lymphoid infiltrates with polymorphous, angiocentric, and necrotic features; 13 were grade 2 and five were grade 3. The neoplastic cells in each patient had a T-cell phenotype. Epstein-Barr virus RNA was detected in the neoplastic cells of 17 of the 18 T-cell lesions. Initial treatment consisted of local radiation therapy in each patient, chemotherapy in two patients, and prednisone in another patient. Two patients were lost to follow-up and the other 16 had a median follow-up of 14 years, 2 months (range, 4 months to 32 years, 5 months). Four patients are alive and disease free, four patients died not of disease or complication of therapy, and eight patients died of disease. The Kaplan-Meier estimate of survival was 63% at 5 years and 50% at 15 years. Histologic progression of angiocentric immunoproliferative lesions from grade 2 to grade 3 was observed in two patients, and a correlation between angiocentric immunoproliferative grade and survival could not be detected. These data suggest that polymorphic reticulosis is an Epstein-Barr virus-related angiocentric T-cell lymphoma.	0
Telomeropathies are a group of phenotypically heterogeneous diseases molecularly unified by pathogenic mutations in telomere-maintenance genes causing critically short telomeres. X-linked dyskeratosis congenita (DC), the prototypical telomere disease, manifested with ectodermal dysplasia, cancer predisposition, and severe bone marrow failure, is caused by mutations in DKC1, encoding a protein responsible for telomerase holoenzyme complex stability. To investigate the effects of pathogenic DKC1 mutations on telomere repair and hematopoietic development, we derived induced pluripotent stem cells (iPSCs) from fibroblasts of a DC patient carrying the most frequent mutation: DKC1 p.A353V. Telomeres eroded immediately after reprogramming in DKC1-mutant iPSCs but stabilized in later passages. The telomerase activity of mutant iPSCs was comparable to that observed in human embryonic stem cells, and no evidence of alternative lengthening of telomere pathways was detected. Hematopoietic differentiation was carried out in DKC1-mutant iPSC clones that resulted in increased capacity to generate hematopoietic colony-forming units compared to controls. Our study indicates that telomerase-dependent telomere maintenance is defective in pluripotent stem cells harboring DKC1 mutation and unable to elongate telomeres, but sufficient to maintain cell proliferation and self-renewal, as well as to support the primitive hematopoiesis, the program that is recapitulated with our differentiation protocol.	0
GABAergic interneurons are emerging as prominent substrates in the pathophysiology of multiple neurodevelopmental disorders, including autism spectrum disorders, schizophrenia, intellectual disability, and epilepsy. Interneuron excitatory activity is influenced by 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid receptors (AMPARs), which in turn affects excitatory transmission in the central nervous system. Yet how dysregulation of interneuronal AMPARs distinctly contributes to the molecular underpinning of neurobiological disease is drastically underexplored. Contactin-associated protein-like 2 (CNTNAP2) is a neurexin-related adhesion molecule shown to mediate AMPAR subcellular distribution while calcium/calmodulin-dependent serine protein kinase (CASK) is a multi-functional scaffold involved with glutamate receptor trafficking. Mutations in both genes have overlapping disease associations, including autism spectrum disorders, intellectual disability, and epilepsy, thus suggesting converging perturbations of excitatory/inhibitory balance. Our lab has previously shown that CNTNAP2 stabilizes interneuron dendritic arbors through CASK and that CNTNAP2 regulates AMPAR subunit GluA1 trafficking in excitatory neurons. The interaction between these three proteins, however, has not been studied in interneurons. Using biochemical techniques, structured illumination microscopy (SIM) and shRNA technology, we first confirm that these three proteins interact in mouse brain, and then examined relationship between CNTNAP2, CASK and GluA1 in mature interneurons. Using SIM, we ascertain that a large fraction of endogenous CNTNAP2, CASK, and GluA1 molecules collectively colocalize together in a tripartite manner. Finally, individual knockdown of either CNTNAP2 or CASK similarly alter GluA1 levels and localization. These findings offer insight to molecular mechanisms underlying GluA1 regulation in interneurons.	0
In 2007, Romania, the largest southeastern European country, reported the highest notification rate of botulism cases in the European Union (0.18 per 100,000 inhabitants), which was 18 times higher than the reported rate in the United States (0.01 per 100,000 inhabitants). This report aims to analyze published and unpublished surveillance data on foodborne botulism in Romania from 1980 to 2009 in the context of political and economical changes that occurred in the former communist countries. The mean annual incidence rate of botulism cases was significantly lower during the late communist period, 1980-1989 (0.06±0.03 cases per 100,000 inhabitants), than during the years 1990-1999 (0.1±0.04 cases per 100,000 inhabitants, p=0.01) and 2000-2009 (0.12±0.04 cases per 100,000 inhabitants, p<0.01). The highest incidence rates were registered in 1998 and 2007 (0.18 cases per 100,000 inhabitants), whereas the lowest incidence rate was registered in 1983 (0.02 cases per 100,000 inhabitants). The disease was usually associated with the consumption of home prepared meat products (mainly raw sausages, smoked-dried meat). Most of the laboratory-confirmed cases tested positive for type B toxin (99%). During 2007-2009, the incidence was particularly high in northwestern and western Romania (0.5 and 0.3 cases per 100,000 inhabitants, respectively). The fatality rate was 60% before 1995 and decreased to 12.2±8.5% during 1999-2009. The general ascending trend of infection rates throughout the period studied demonstrates the need for the implementation of correct public health and educational measures to fully prevent this severe disease.	1
We report on two sib fetuses with radiological and morphological findings similar to those of the recently described lethal skeletal dysplasia termed Pacman dysplasia (McKusick, 167220, Am J Med Genet 1993, 45:558-561). The first fetus, a male, was electively terminated after a routine ultrasound study at 20 weeks showed short-limb dwarfism. The second fetus, a female sib, was also electively terminated after similar, abnormal ultrasound findings were noted at 16 weeks of gestation. Similar to Pacman dysplasia, the radiographic appearance was characterized by under-mineralized bone, stippling, rhizomelic and mesomelic shortness, platyspondyly, and a short, broad pelvis. The metaphyses were dense, but the diaphyseal cortices were thin with undermodeled long bones, and there was a deficient trabecular pattern suggesting marrow replacement. Chondro-osseous structure was characterized by deficient trabecular bone formation, a fibrous marrow, and numerous, large, multinucleated osteoclasts lining the endosteal surfaces of the metaphyseal bone. The occurrence of this dysplasia in sibs of differing sex suggests autosomal recessive inheritance.	0
Metabolic disorders, although rare, can involve multiple organ systems and have a varied presentation. Renal involvement has been reported in several metabolic disorders in the pediatric age group. We report a rare metabolic disorder, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, in a child who developed steroid-resistant nephrotic syndrome at the age of 5 years. Renal biopsy showed features of collapsing glomerulopathy. The child had progressive chronic kidney disease. Alternative immunosuppressants including tacrolimus failed to show any clinical improvement. There have been no reports of children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency developing steroid-resistant nephrotic syndrome and collapsing glomerulopathy. This case highlights the need to monitor renal function and proteinuria among this group of children.	0
BACKGROUND:Paeoniae Radix Alba, the root of the plant Paeonia lactiflora Pall, is a common blood-enriching drug in traditional Chinese medicine. Its effectiveness in the clinical treatment of anaemia is remarkable, but its potential pharmacologic mechanism has not been clarified. METHODS:In this study, the potential pharmacologic mechanism of Paeoniae Radix Alba in the treatment of iron-deficiency anaemia was preliminarily elucidated through systematic and comprehensive network pharmacology. RESULTS:Specifically, we obtained 15 candidate active ingredients from among 146 chemical components in Paeoniae Radix Alba. The ingredients were predicted to target 77 genes associated with iron-deficiency anaemia. In-depth analyses of these targets revealed that they were mostly associated with energy metabolism, cell proliferation, and stress responses, suggesting that Paeoniae Radix Alba helps alleviate iron-deficiency anaemia by affecting these processes. In addition, we conducted a core target analysis and a cluster analysis of protein-protein interaction (PPI) networks. The results showed that four pathways, the p53 signalling pathway, the IL-17 signalling pathway, the TNF signalling pathway and the AGE-RAGE signalling pathway in diabetic complications, may be major pathways associated with the ameliorative effects of Paeoniae Radix Alba on iron-deficiency anaemia. Moreover, molecular docking verified the credibility of the network for molecular target prediction. CONCLUSIONS:Overall, this study predicted the functional ingredients in Paeoniae Radix Alba and their targets and uncovered the mechanism of action of this drug, providing new insights for advanced research on Paeoniae Radix Alba and other traditional Chinese medicines.	0
AIM:Evaluation of pediatric palliative home care of families with children suffering from neurodegeneration with brain iron accumulation (NBIA) and their parents. MATERIAL AND METHODS:The children were treated at home by a multidisciplinary team. Densitometry was used to evaluate the condition of the skeletal system. Botulinum toxin was injected into the muscles in doses between 22 and 50 units/kg. The quality of palliative care was assessed on the basis of a specially designed questionnaire for parents. RESULTS:The observations were performed on a group of 9 patients with NBIA. On admission, the median age of patients was 9 years (7-14). The average time of palliative home care was 1569 days (34 days-17 years). The median age at death (6 patients) was 11 years (7-15). The botulinum toxin injections gave the following results: reduction of spasticity and dystonia, reduction of spine and chest deformation, relief of pain and suffering, facilitation of rehabilitation and nursing, prevention of permanent contractures, and reduction of excessive salivation. Bone mineral density and bone strength index were reduced. Two patients experienced pathological fracture of the femur. The body mass index at admission varied between 9.8 and 14.9. In 7 cases, introduction of a ketogenic diet resulted in the increase of body mass and height. The ketogenic diet did not worsen the neurological symptoms. The parents positively evaluated the quality of care. CONCLUSION:Palliative home care is the optimal form of treatment for children with NBIA.	0
We report on the occurrence of coronal craniosynostosis, anal anomalies, and porokeratosis in two male sibs. A third male sib was phenotypically normal as were the parents. The occurrence of these three clinical features has, to our knowledge, not been reported before. Cutaneous or anal anomalies or both have been reported in a number of syndromes associated with craniosynostosis, including Crouzon, Pfeiffer, Apert, and Beare-Stevenson syndromes. These syndromes are associated with mutations in the fibroblast growth factor receptor genes FGFR1, FGFR2, and FGFR3. They are inherited in an autosomal dominant fashion. In contrast, the cases we report do not carry any of the common FGFR mutations and the pedigree suggests autosomal or X linked recessive inheritance.	0
In 1993, Jabs et al. were the first to describe a genetic origin of craniosynostosis. Since this discovery, the genetic causes of the most common syndromes have been described. In 2015, a total of 57 human genes were reported for which there had been evidence that mutations were causally related to craniosynostosis. Facilitated by rapid technological developments, many others have been identified since then. Reviewing the literature, we characterize the most common craniosynostosis syndromes followed by a description of the novel causes that were identified between January 2015 and December 2017.	0
Purpose: To report a case with monocular transient vision loss (TVL) associated with Hyperhomocysteinemia. Methods: We present a case with persistent TVL attacks and high level of homocysteine. Results: A 32-year-old male had a history of episodes of recurrent monocular TVL. Extensive ophthalmic, systemic and laboratory studies were unremarkable with the exception of high plasma homocysteine level. He never experienced TVL during the 36-month follow-up after starting folate, B12 and B6 except for one episode in which he had discontinued the treatment for three months. Conclusion: This case may suggest hyperhomocysteinemia as one of the underlying causes of recurrent attacks of TVL without any known source of emboli.	0
BACKGROUND:Filaggrin is a key structural epidermal protein in terminal differentiation and formation of skin barrier. The important role of filaggrin and its effects in various cutaneous and noncutaneous disorders initiated a cascade of considerable research in recent years. Loss-of-function mutations in FLG, the human gene encoding profilaggrin/filaggrin, is the cause of the common skin condition ichthyosis vulgaris (IV) and major genetic predisposing factor for atopic dermatitis (AD). Several null mutations in the FLG gene that lead to a decrease or absence of filaggrin in skin and predispose these conditions have been described. OBJECTIVE:The aim of this study was to investigative genetic polymorphism of FLG in Iranian patients with IV and AD. METHODS:In the current study, we carried out full sequencing of the entire FLG coding region in 30 IV patients and 30 AD patients, and also 60 healthy controls. RESULTS:In our research, we identified 43 variants reported previously and two novel variants. CONCLUSION:In our study, in the AD and IV patients, loss-of-function FLG mutation was not found. This means that another mechanism other than FLG nonsense mutation is involved in the pathogenesis of these patients.	0
BACKGROUND:Little data are available concerning the outcome of rituximab (RTX) therapy in pediatric patients with autoimmune bullous diseases (AIBDs). OBJECTIVE:We sought to evaluate safety and efficacy of RTX administration in pediatric patients with AIBDs and to assess first-line RTX therapy in pemphigus patients. METHODS:AIBD patients consisting of 12 pemphigus patients and a patient with bullous pemphigoid who received RTX before the age of 18 were enrolled. Detailed information regarding patients' outcome after the first RTX cycle was assessed. RESULTS:The mean age of the patients at RTX infusion was 15 ± 2 years. Six patients in the pemphigus group received RTX as first-line therapy. In pemphigus patients: complete remission (on minimal therapy) was achieved by seven patients, partial remission (on minimal therapy) and complete remission (off therapy) were achieved by three patients and one, respectively. Relapse occurred in nine patients, which were mostly mild. Likewise, the BP patient received RTX with a good clinical response. The observed adverse events were mostly mild infusion reactions and a case of sepsis. CONCLUSION:Rituximab is safe and effective in childhood/juvenile patients with AIBDs. Furthermore, RTX can be used as first-line treatment in pediatric patients with pemphigus.	0
Patients with chronic abdominal pain occasionally suffer from the anterior cutaneous nerve entrapment syndrome (ACNES). A substantial number of patients report previous visits to an emergency department (ED) with acute pain. Aim of this study was to obtain the incidence of ACNES in patients presenting with abdominal pain in the ED of a Dutch teaching hospital.In this observational study, data sets of all patients visiting Máxima Medical Center's (MMC) ED in 2011-2012 were searched for key terms 'ACNES', 'intercostal neuralgia' or 'abdominal wall pain'. Files of potential patients living within hospital's adherence area were checked using accepted criteria indicating the presence of ACNES. Disease incidence was calculated as a ratio to the hospital's adherence data. The ACNES MMC 2013's incidence in patients evaluated in the surgical outpatient department was also calculated.During the study period, 473 ED patient files met inclusion criteria. A total of 88 patients belonging to MMC's adherence area were diagnosed with ACNES leading to a mean 22/100.000 ACNES yearly incidence rate. About one of 50 patients with abdominal pain visiting the ED suffered from ACNES. A 35/100.000 outpatient department ACNES incidence rate was calculated in the year of 2013. Combining these two ratios, a 1:1800 ACNES incidence in the general population was obtained.In an ED setting of a Dutch teaching hospital, approximately 2% of patients presenting with acute abdominal pain suffered from ACNES. ED physicians should consider ACNES in abdominal pain patients with normal laboratory or imaging tests.	1
Langerhans cell histiocytosis (LCH) is a diagnostic and therapeutic challenge. We report on a rare case of its primary oral manifestation that was treated successfully with the BRAF-specific agent, vemurafenib, after insufficient standard LCH treatment. This case underlines the importance of proper diagnosis and the evaluation of targeted therapy as a valuable tool in LCH treatment. Furthermore, the close collaboration of surgeons, oncologists, and dentists is mandatory to ensure adequate treatment, restore the stomatognathic system in debilitating post-treatment situations, improve quality of life, and ensure effective disease control in infants and young patients.	0
To determine the cortical mechanism that underlies the cognitive impairment and motor disability in hereditary spastic paraplegia (HSP), nine HSP patients from a Chinese family were examined using clinical evaluation, cognitive screening, and genetic testing. Controls were matched healthy subjects. White-matter fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD; tract-based spatial statistics), cortical thickness (FreeSurfer), and subcortical gray matter (FIRST) based on T1-weighted MRI and diffusion tensor imaging were analyzed. A novel mutation in the SPAST gene (NM_014946.3, c.1321+2T>C) was detected. Patients had motor disability and low Montreal Cognitive Assessment (MoCA) scores. Patients showed significantly decreased total gray- and white-matter volumes, corpus callosum volume, cortical thickness, and subcortical gray-matter volume as well as significantly lower FA and AD values and significantly higher MD and RD values in the corpus callosum and corticospinal tract. Cortical thickness, subcortical gray-matter volume, and MoCA score were negatively correlated with disease duration. Cortical thickness in the right inferior frontal cortex was negatively correlated with Spastic Paraplegia Rating Scale score. Cortical thickness and right hippocampus volume were positively correlated with the MoCA score and subscores. In conclusion, brain damage is not restricted to the white matter in SPG4-HSP patients, and widespread gray-matter damage may account for the disease progression, cognitive impairment, and disease severity in SPG4-HSP.	0
Distal arthrogryposis (DA) is a skeletal muscle disorder which can be classified under a broader term as Arthrogryposis multiplex contractures. DA is characterized by the presence of joint contractures at various parts of the body, particularly in distal extremities. It is identified as an autosomal dominant and a rare X-linked recessive disorder associated with increased connective tissue formation around joints in such way that immobilizes muscle movement causing deformities. DA is again classified into various types since it manifests as a range of conditions representing different etiologies. Myopathy is one of the most commonly listed etiologies of DA. The mutations in sarcomeric protein-encoding genes lead to decreased sarcomere integrity, which is often associated with this disorder. Also, skeletal disorders are often associated with cardiac disorders. Some studies mention the presence of cardiomyopathy in patients with skeletal dysfunction. Therefore, it is hypothesized that the congenitally mutated protein that causes DA can also lead to cardiomyopathy. In this review, we will summarize the different forms of DA and their clinical features, along with gene mutations responsible for causing DA in its different forms. We will also examine reports that list mutations also known to cause heart disorders in the presence of DA.	0
Intellectual disability (ID) is a neurodevelopmental condition affecting 1-3% of the world's population. Genetic factors play a key role causing the congenital limitations in intellectual functioning and adaptive behavior. The heterogeneity of ID makes it more challenging for genetic and clinical diagnosis, but the advent of large-scale genome sequencing projects in a trio approach has proven very effective. However, many variants are still difficult to interpret. A combined approach of next-generation sequencing and functional, electrophysiological, and bioinformatics analysis has identified new ways to understand the causes of ID and help to interpret novel ID-causing genes. This approach offers new targets for ID therapy and increases the efficiency of ID diagnosis. The most recent functional advancements and new gene editing techniques involving the use of CRISPR-Cas9 allow for targeted editing of DNA in in vitro and more effective mammalian and human tissue-derived disease models. The expansion of genomic analysis of ID patients in diverse and ancient populations can reveal rare novel disease-causing genes.	0
Dentin dysplasia (DD) is an uncommon developmental disturbance affecting dentin, resulting in enamel with atypical dentin formation and abnormal pulpal morphology. Type I (radicular) and Type II (coronal) are the two types of DD. Type I is more common, and both types include single or multiple teeth in primary and permanent dentition. Combinations of both types have also been described in literature. Four distinct forms of Type I and one form of Type II were identified. This case report documents one such rarity of DD in an 11-year-old female with clinical and radiographical findings and management aspects.	0
Background: Previous studies have indicated that non-motor symptoms are primary problems in focal dystonia, but limited data are available about non-motor problems and their correlation with motor severity in generalized dystonia (GD). Methods: In the present study, we performed a case-control study and enrolled isolated inherited or idiopathic GD patients and age- and sex-matched healthy controls (HC). Clinical characteristics, motor symptoms, non-motor problems, including psychiatric co-morbidity, sleep problems, fatigue, and quality of life (QoL) were assessed in both groups using various rating scales and assessments. Results: Thirty-three patients with GD and 33 controls were enrolled. Significant higher scores on depression and anxiety (p < 0.001) were shown in GD compared with HC, whereas the frequency of obsessive-compulsive disorders approached that of HC (p = 0.238). Patients with GD also had significantly higher Pittsburg Sleep Quality Index (PSQI) and fatigue scores than HC, whereas no difference was observed in excessive daytime somnolence. In GD, QoL was more impaired, with statistically lower scores in both physical and mental components. Psychiatric rating scales did not correlate to motor severity or disease duration but might influence quality of sleep. Subgroup analysis suggests non-motor manifestations differ with different etiologies in GD. Conclusion: This study suggests that non-motor symptoms in GD, such as psychiatric problems, are likely to be primary determinants not correlated to motor severity, which may also affect quality of sleep and fatigue.	0
In the current study, Myxobolus episquamalis Egusa, Maeno & Sorimachi, 1990 (Myxozoa: Bivalvulida) is reported from the Lebranche mullet Mugil liza Valenciennes, 1836 in the estuarine region of the Maricá Lagoon, State of the Rio de Janeiro, southeastern Brazil. To date, this myxozoan species was reported in mullets from Asia, Africa, Europe, and Oceania. The characteristics of M. episquamalis previously reported are similar to the findings of the present study. DNA sequences of the nuclear small subunit ribosomal DNA (SSU rDNA) had 99.7-100% similarity with the sequences of M. episquamalis from North Africa and Asia. Therefore, strong morphological and molecular similarities ensure the identification of M. episquamalis in the current study. Finally, this finding records a new host and locality, revealing the worldwide distribution of this myxozoan species.	0
In this video, we demonstrate microsurgical resection of IV ventricle subependymoma. To the best of our knowledge, this is the first video case report of a microsurgical resection of subependymoma of the IV ventricle in the peer-reviewed English literature. Subependymomas are benign central nervous system tumors, typically arising in ventricular spaces, mostly in the IV and lateral ventricles.1-3 They are isointense on T1 and hyperintense on T2-weighted magnetic resonance imaging (MRI) with minimal or no enhancement.4 Microsurgery remains the mainstay treatment. Complete tumor resection is possible and curative with excellent prognosis.1,5-7 Although the clinical course appears benign, the inability to diagnose them radiographically with certainty and the possibility of an alternative malignant lesion support a low threshold for early and safe resection.8 A 39-yr-old man presented with severe headache and balance problems. Pre- and postcontrast neuroaxis MRI revealed a centrally located IV ventricle lesion without hydrocephalus. The aim of the surgery was complete tumor resection. Surgery was performed in the prone position by the senior author (KIA) with intraoperative neurophysiology monitoring. A small suboccipital craniotomy and C1 posterior arch removal was done. After opening the dura and arachnoid membrane, the tumor was identified and meticulously dissected from the adjacent posterior inferior cerebellar artery and the floor of the fourth ventricle and from brain stem white matter at the tumor-neural tissue interface to avoid brainstem interference. Histological analysis revealed subependymoma (World Health Organization Grade I). Postoperative pre- and postcontrast MRI revealed complete resection. Headache and balance problems completely resolved; the patient was neurologically intact. The patient provided written consent and permission to publish his image.	0
Low circulating high-density lipoproteins (HDL) are not only a defining criteria for metabolic syndrome, but are more generally associated with atherosclerotic cardiovascular disease (ASCVD) and other chronic diseases. Oxidative stress, a hallmark of cardio-metabolic disease, further influences HDL activity by suppressing their function. Especially the leukocyte-derived enzyme myeloperoxidase (MPO) has recently attracted great interest as it catalyzes the formation of oxidizing reactive species that modify the structure and function of HDL, ultimately increasing cardiovascular risk. Contrariwise, paraoxonase-1 (PON1) is an HDL-associated enzyme that protects HDL from lipid oxidation, and then acts as a protective factor against ASCVD. Noteworthy, recent studies have demonstrated how MPO, PON1 and HDL form a functional complex in which PON1 partially inhibits the MPO activity, while MPO in turn partially inactivates PON1.In line with that, high MPO/PON1 ratio characterizes patients with ASCVD and metabolic syndrome and has been suggested as a potential marker of dysfunctional HDL as well as a predictor of ASCVD. In this review, we summarize the evidence on the interactions between MPO and PON1 with regard to their structure, function and interaction with HDL activity. We also provide an overview on in vitro and experimental animal models, finally focusing on clinical evidence from cohort of patients with ASCVD and metabolic syndrome.	0
Wolfram syndrome is a rare multisystem disease characterized by childhood-onset diabetes mellitus and progressive neurodegeneration. Most cases are attributed to pathogenic variants in a single gene, Wolfram syndrome 1 (WFS1). There currently is no disease-modifying treatment for Wolfram syndrome, as the molecular consequences of the loss of WFS1 remain elusive. Because diabetes mellitus is the first diagnosed symptom of Wolfram syndrome, we aimed to further examine the functions of WFS1 in pancreatic β cells in the context of hyperglycemia. Knockout (KO) of WFS1 in rat insulinoma (INS1) cells impaired calcium homeostasis and protein kinase B/Akt signaling and, subsequently, decreased cell viability and glucose-stimulated insulin secretion. Targeting calcium homeostasis with reexpression of WFS1, overexpression of WFS1's interacting partner neuronal calcium sensor-1 (NCS1), or treatment with calpain inhibitor and ibudilast reversed deficits observed in WFS1-KO cells. Collectively, our findings provide insight into the disease mechanism of Wolfram syndrome and highlight new targets and drug candidates to facilitate the development of a treatment for this disorder and similar diseases.	0
The Sultanate of Oman is a rapidly developing Muslim country with well-organized government-funded health care services, and expanding medical genetic facilities. The preservation of tribal structures within the Omani population coupled with geographical isolation has produced unique patterns of rare mutations. In order to provide diagnosticians and researchers with access to an up-to-date resource that will assist them in their daily practice we collated and analyzed all of the Mendelian disease-associated mutations identified in the Omani population. By the 1 (st) of August 2015, the dataset contained 300 mutations detected in over 150 different genes. More than half of the data collected reflect novel genetic variations that were first described in the Omani population, and most disorders with known mutations are inherited in an autosomal recessive fashion. A number of novel Mendelian disease genes have been discovered in Omani nationals, and the corresponding mutations are included here. The current study provides a comprehensive resource of the mutations in the Omani population published in scientific literature or reported through service provision that will be useful for genetic care in Oman and will be a starting point for variation databases as next-generation sequencing technologies are introduced into genetic medicine in Oman.	0
A lack of understanding of the processes determining the absorption and subsequent metabolism of coenzyme Q10 (CoQ10) has resulted in some manufacturers' making incorrect claims regarding the bioavailability of their CoQ10 supplements, with potential consequences for the use of such products in clinical trials. The purpose of the present review article is, therefore, to describe the various stages of exogenous CoQ10 metabolism, from its first ingestion, stomach transit, absorption from the small intestine into the lymphatic system, transport in blood, and access into cells. In particular, the importance of CoQ10 crystal dispersion in the initial formulation is emphasised, the absence of which reduces bioavailability by 75%. In addition, evidence comparing the relative bioavailability and efficacy of ubiquinone and ubiquinol forms of CoQ10 has been reviewed.	0
PURPOSE:In this article, we will review the mechanisms and natural history of hearing loss in neurofibromatosis type 2 (NF2) and discuss the hearing outcomes with different rehabilitation options. METHODS:Review of the published literature. RESULTS:NF2 is a rare autosomal dominant syndrome characterized by vestibular schwannomas and other intracranial and spinal tumors. Bilateral vestibular schwannomas are the hallmark of the disease which occur in 90 to 95% of the patients. As a result, hearing loss will eventually occur in almost all NF2 patients. Deafness can occur from tumor progression or from treatment of vestibular schwannomas and is among the most debilitating aspects of NF2. A number of surgical and non-surgical rehabilitation options are available for these patients including cochlear and auditory brainstem implants. The audiologic outcomes with surgical rehabilitation options have been variable but most patients are able to achieve sound awareness and benefit from auditory cues in lip reading. CONCLUSION:Early identification and treatment of NF2 patients can help in achieving better hearing outcomes in the pediatric population. An increasing number of NF2 patients are receiving open set word understanding with refinement in surgical techniques.	0
Skin manifestations are a reflection of many of the internal diseases. Sometimes, skin disease may be the only manifestation of the internal disease. Internal malignancies may give rise to a number of cutaneous manifestations through their immunological, metabolic, and metastatic consequences. Curth proposed criteria to establish a causal relationship between a dermatosis and a malignant internal disease. Malignancy can present with a plethora of cutaneous manifestations. Here, we describe in brief about various skin manifestations of internal malignancies.	0
Hamartomatous polyposis is a rare cause of intussusception in adults. But this complication is the most frequent for patient with Peutz Jeghers syndrome. Small bowel screening is recommended for those patients in order to prevent emergency repetitive surgeries. We report here the case of a 20-year-old patient with confirmed Peutz Jeghers syndrome since eight years for whom a scheduled laparotomy was indicated. Asymptomatic intestinal intussusception was discovered intraoperatively. The patient was treated successfully with enterectomy and side to side anastomosis. Postoperative course was uneventful. Regular assessment as recommended for those patients is performed. Gastrointestinal intussusception in adults is rare and is often diagnosed preoperatively in a context of bowel obstruction. In the case of our patient, intussusception was diagnosed intraoperatively. This fact confirms the necessity of well-timed polypectomy in order to prevent this complication and the risk of extended resection in patients who are exposed to short gut syndrome by requiring iterative resections.	0
Focal musculoskeletal anomalies vary, and can manifest as part of a syndrome or be accompanied by numerous other conditions such as genetic disorders, karyotype abnormalities, central nervous system anomalies and other skeletal anomalies. Isolated focal musculoskeletal anomaly does, however, also occur; its early prenatal diagnosis is important in deciding prenatal care, and also helps in counseling parents about the postnatal effects of numerous possible associated anomalies. We have encountered 50 cases involving focal musculoskeletal anomalies, including focal limb dysplasia [radial ray abnormality (n=3), mesomelic dysplasia (n=1)]; anomalies of the hand [polydactyly (n=8), syndactyly (n=3), ectrodactyly (n=1), clinodactyly (n=6), clenched hand (n=5)]; anomalies of the foot [clubfoot (n=10), rockerbottom foot (n=5), sandal gap deformity (n=1), curly toe (n=2)]; amniotic band syndrome (n=3); and anomalies of the focal spine [block vertebra (n=1), hemivertebra (n=1)]. Among these 50 cases, five [polydactyly (n=1), syndactyly (n=2) and curly toe (n=2)] were confirmed by postnatal physical evaluation, two (focal spine anomalies) were diagnosed after postnatal radiologic examination, and the remaining 43 were proven at autopsy. For each condition, we describe the prenatal sonographic findings, and include a brief review.	0
The IκBKinase (IKK) complex represents a central signaling nexus in the TNF-dependent activation of the pro-inflammatory NF-κB pathway. However, recent studies suggested that the distinct IKK subunits (IKK, IKK, and NEMO) might withhold additional NF-κB-independent functions in inflammation and cancer. Here, we generated mice lacking all three IKK subunits in liver parenchymal cells (LPC) (IKK//NEMOLPC-KO) and compared their phenotype with mice lacking both catalytic subunits (IKK/LPC-KO), allowing to functionally dissect putative I-κB-Kinase-independent functions of the regulatory subunit NEMO. We show that the additional deletion of NEMO rescues IKK/LPC-KO mice from lethal cholestasis and biliary ductopenia by triggering LPC apoptosis and inducing a strong compensatory proliferation of LPC including cholangiocytes. Beyond this beneficial effect, we show that increased hepatocyte cell-death and compensatory proliferation inhibit the activation of LPC-necroptosis but trigger spontaneous hepatocarcinogenesis in IKK//NEMOLPC-KO mice. Collectively, our data show that free NEMO molecules unbound to the catalytic IKK subunits control LPC programmed cell death pathways and proliferation, cholestasis and hepatocarcinogenesis independently of an IKK-related function. These findings support the idea of different functional levels at which NEMO controls inflammation and cancer in the liver.	0
KBG syndrome (MIM #148050) is an autosomal dominant disorder characterized by developmental delay, intellectual disability, distinct craniofacial anomalies, macrodontia of permanent upper central incisors, skeletal abnormalities, and short stature. This study describes clinical features of 28 patients, confirmed by molecular testing of ANKRD11 gene, and three patients with 16q24 deletion encompassing ANKRD11 gene, diagnosed in a single center. Common clinical features are reported, together with uncommon findings, clinical expression in the first years of age, distinctive associations, and familial recurrences. Unusual manifestations emerging from present series include juvenile idiopathic arthritis, dysfunctional dysphonia, multiple dental agenesis, idiopathic precocious telarche, oral frenula, motor tics, and lipoma of corpus callosum, pilomatrixoma, and endothelial corneal polymorphic dystrophy. Facial clinical markers suggesting KBG syndrome before 6 years of age include ocular and mouth conformation, wide eyebrows, synophrys, long black eyelashes, long philtrum, thin upper lip. General clinical symptoms leading to early genetic evaluation include developmental delay, congenital malformations, hearing anomalies, and feeding difficulties. It is likely that atypical clinical presentation and overlapping features in patients with multiple variants are responsible for underdiagnosis in KBG syndrome. Improved knowledge of common and atypical features of this disorder improves clinical management.	0
Introduction:Dentinogenesis imperfecta type 1 (OIDI) is considered a relatively rare genetic disorder (1:5000 to 1:45,000) associated with osteogenesis imperfecta. OIDI impacts the formation of collagen fibrils in dentin, leading to morphological and structural changes that affect the strength and appearance of teeth. However, there is still a lack of understanding regarding the nanoscale characterization of the disease, in terms of collagen ultrastructure and mechanical properties. Therefore, this research presents a qualitative and quantitative report into the phenotype and characterization of OIDI in dentin, by using a combination of imaging, nanomechanical approaches. Methods:For this study, 8 primary molars from OIDI patients and 8 primary control molars were collected, embedded in acrylic resin and cut into longitudinal sections. Sections were then demineralized in 37% phosphoric acid using a protocol developed in-house. Initial experiments demonstrated the effectiveness of the demineralization protocol, as the ATR-FTIR spectral fingerprints showed an increase in the amide bands together with a decrease in phosphate content. Structural and mechanical analyses were performed directly on both the mineralized and demineralized samples using a combination of scanning electron microscopy, atomic force microscopy, and Wallace indentation. Results:Mesoscale imaging showed alterations in dentinal tubule morphology in OIDI patients, with a reduced number of tubules and a decreased tubule diameter compared to healthy controls. Nanoscale collagen ultrastructure presented a similar D-banding periodicity between OIDI and controls. Reduced collagen fibrils diameter was also recorded for the OIDI group. The hardness of the (mineralized) control dentin was found to be significantly higher (p<0.05) than that of the OIDI (mineralized) dentine. Both the exposed peri- and intratubular dentinal collagen presented bimodal elastic behaviors (Young's moduli). The control samples presented a stiffening of the intratubular collagen when compared to the peritubular collagen. In case of the OIDI, this stiffening in the collagen between peri- and intratubular dentinal collagen was not observed and the exposed collagen presented overall a lower elasticity than the control samples. Conclusion:This study presents a systematic approach to the characterization of collagen structure and properties in OIDI as diagnosed in dentin. Structural markers for OIDI at the mesoscale and nanoscale were found and correlated with an observed lack of increased elastic moduli of the collagen fibrils in the intratubular OIDI dentin. These findings offer an explanation of how structural changes in the dentin could be responsible for the failure of some adhesive restorative materials as observed in patients affected by OIDI.	0
Epidermal barrier integrity could be influenced by various factors involved in epidermal cell differentiation and proliferation, cell-cell adhesion, and skin lipids. Dysfunction of this barrier can cause skin disorders, including eczema. Inversely, eczema can also damage the epidermal barrier. These interactions through vicious cycles make the mechanism complicated in connection with other mechanisms, particularly immunologic responses. In this article, the molecular mechanisms concerning epidermal barrier abnormalities are reviewed in terms of the following categories: epidermal calcium gradients, filaggrin, cornified envelopes, desquamation, and skin lipids. Mechanisms linked to ichthyoses, atopic dermatitis without exacerbation or lesion, and early time of experimental irritation were included. On the other hand, the mechanism associated with epidermal barrier abnormalities resulting from preceding skin disorders was excluded. The molecular mechanism involved in epidermal barrier dysfunction has been mostly episodic. Some mechanisms have been identified in cultured cells or animal models. Nonetheless, research into the relationship between the causative molecules has been gradually increasing. Further evidence-based systematic data of target molecules and their interactions would probably be helpful for a better understanding of the molecular mechanism underlying the dysfunction of the epidermal barrier.	0
Despite optimal medical management (OMM), low back pain (LBP) can be disabling, particularly after spinal surgery. Spinal cord stimulation (SCS) is effective in reducing neuropathic leg pain; however, evidence is limited for LBP. This prospective, open-label, parallel-group trial randomized (1:1) failed back surgery syndrome (FBSS) patients with predominant LBP to SCS plus OMM (SCS group) or OMM alone (OMM group) at 28 sites in Europe and the Americas. If trial stimulation was successful, a multicolumn SCS system was implanted. Outcomes were assessed at baseline (before randomization) and at 1, 3, 6, and 12 months after randomization. Patients could change treatment groups at 6 months. The primary outcome was the proportion of patients with ≥50% reduction in LBP (responder) at 6 months. Secondary outcomes included change in pain intensity, functional disability, and health-related quality of life (HRQoL). The results are posted at ClinicalTrials.gov under registration number NCT01697358. In the intent-to-treat analysis, there were more responders in the SCS group than in the OMM group (13.6%, 15/110 vs 4.6%, 5/108, difference 9% with 95% confidence interval 0.6%-17.5%, P = 0.036) at 6 months. The SCS group improved in all secondary outcomes compared with the OMM group. The OMM group only improved in HRQoL. In the SCS group, 17.6% (18/102) experienced SCS-related adverse events through 6 months, with 11.8% (12/102) requiring surgical reintervention. Adding multicolumn SCS to OMM improved pain relief, HRQoL, and function in a traditionally difficult-to-treat population of failed back surgery syndrome patients with predominant LBP. Improvements were sustained at 12 and 24 months.	0
The discovery of genetic causes of inherited skin disorders has been pivotal to the understanding of epidermal differentiation, function, and renewal. Here we show via exome sequencing that mutations in ASPRV1 (aspartic peptidase retroviral-like 1) cause a dominant Mendelian disorder featuring palmoplantar keratoderma and lamellar ichthyosis, a phenotype that has otherwise been exclusively recessive. ASPRV1 encodes a mammalian-specific and stratified epithelia-specific protease important in processing of filaggrin, a critical component of the uppermost epidermal layer. Three different heterozygous ASPRV1 missense mutations in four unrelated ichthyosis kindreds segregate with disease and disrupt protein residues within close proximity to each other and autocatalytic cleavage sites. Expression of mutant ASPRV1 proteins demonstrates that all three mutations alter ASPRV1 auto-cleavage and filaggrin processing, a function vital to epidermal barrier integrity.	0
Steroid-resistant nephrotic syndrome (SRNS) is a common cause of chronic kidney disease in children, and a considerable number of patients progress to end-stage renal disease. SRNS is a highly heterogeneous disorder, both clinically and genetically, and more than 50 monogenic causes of SRNS, including isolated and syndromic forms, have been identified. Recent large-cohort studies indicate that at least 30% of childhood-onset SRNS cases are genetic. The benefits of definitive molecular diagnosis by genetic testing include the avoidance of unnecessary and potentially harmful diagnostic procedures (e.g., kidney biopsy) and treatment (e.g., steroid and immunosuppressants), detection of rare and potentially treatable mutations (e.g., coenzyme Q10 biosynthesis pathway defect), prediction of prognosis (e.g., posttransplant recurrence), and providing precise genetic counseling. Furthermore, the identification of novel disease-causing genes could provide new insights into the pathogenic mechanisms of SRNS. Therefore, whenever accessible and affordable, genetic testing is recommended for all pediatric patients with SRNS, and should certainly be performed in patients with a higher probability of genetic predisposition based on genotype-phenotype correlation data. The genetic testing approach should be determined for each patient, and clinicians should, therefore, be aware of the advantages and disadvantages of methods currently available, which include Sanger sequencing, gene panel testing, and whole-exome or whole-genome sequencing. Importantly, the need for precise and thorough phenotyping by clinicians, even in the era of genomics, cannot be overemphasized. This review provides an update on recent advances in genetic studies, a suggested approach for the genetic testing of pediatric patients with SRNS.	0
Background: Greig cephalopolysyndactyly syndrome (GCPS) is a disorder of autopod and craniofacial abnormalities. Autopod anomalies include preaxial and/or postaxial polydactyly together with or without syndactyly while craniofacial features include hypertelorism and macrocephaly. GCPS is inherited in an autosomal dominant manner and is caused by sequence variants in GLI3. Methodology and Results: In this study, we examined four unrelated families with GCPS segregating in an autosomal dominant manner. Sanger sequencing revealed three novel (p.Tyr146Leufs*19, p.Glu99Serfs*60, and p.Thr541Arg) and one previously reported non-sense variant (p.Arg792*) in GLI3. Conclusion: The study expands the spectrum of the variants in the GLI3 gene linked to GCPS, and should also facilitate genetic counseling of GCPS patients in the Pakistani population.	0
A significant portion of paragangliomas (PGL) and pheochromocytomas (PCC) occur in patients with hereditary PGL/PCC syndromes, including those with germline mutations in succinate dehydrogenase (SDHx) subunit genes. Recently, germline fumarate hydratase (FH) mutations have been identified in a subset of PGL/PCC, and patients with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) may have an increased risk of developing PGL/PCC. SDHB immunohistochemistry (IHC) has previously been shown to be useful for identifying SDHx-deficient PGL/PCC, however, FH IHC has never been explored in these tumors. Thus, we characterized SDHB and FH IHC in a large cohort of PGL/PCC patients (n = 41) at our institution who were evaluated for hereditary PGL/PCC syndromes. Overall, there was strong, positive correlation between germline SDHx subunit gene mutation status and SDHB IHC status (rφ = 0.77; P < .0001), with high corresponding sensitivity, specificity, positive predictive value, and negative predictive value (95.0%, 81.8%, 82.6%, and 94.7%, respectively). Although SDHB loss by IHC was highly correlated with germline SDHx gene mutations, its utility in this population was dependent on clinicopathologic context: while all head and neck PGL patients with SDHB-deficient tumors had germline SDHx gene mutations, only a small subset (25.0%) of PCC patients with SDHB-deficient tumors harbored a germline SDHx gene mutation. Finally, although our cohort contained only one HLRCC patient, their tumor was FH-deficient by IHC, and all other PGL/PCC showed retained FH IHC. Thus, in the appropriate clinical setting, SDHB and FH IHC may be useful for identifying PGL/PCC patients for Medical Genetics evaluation.	0
Lamellar sclerokeratoplasty is a surgical procedure described since 1979 by Lim in China and reported by different surgeons in the world. Our purpose is to report a modified technique in which not only the whole cornea with a scleral rim is utilized, but the importance of including the whole Schlemm's canal area is also insisted; therefore, a new aqueous humor drainage pathway can be restored. The technique is designed for cases in which not only the whole cornea is decompensated, but also have untreatable glaucoma. This procedure replaces the entire anterior segment with a clear donor cornea including the limbus and part of the trabecular meshwork. We present the results of visual acuity by the logMAR scale of 55 cases from 110 patients receiving this surgical technique. The results describe 39 cases that had visual improvement after more than 1 year of follow-up and 16 cases that did not improve in their visual acuity. Large-diameter sclerokeratoplasty is an alternative and therapeutic option to eliminate the entire corneal pathology, while obtaining structural and even optical results with a lower immunological reaction. It can be considered an option in cases that are not suitable for standard grafting procedures.	0
A reagent-free colorimetric method for galactose quantification using a composite of cerium oxide nanoparticles (nanoceria) and galactose oxidase (Gal Ox) entrapped in an agarose gel was developed. In the presence of galactose, the Gal Ox entrapped within the agarose gel catalyzed the oxidation of galactose to generate H2O2, which induced a color change from white to intense yellow. This reaction occurred without any chromogenic substrate. This color transition is presumed to be due to the H2O2-mediated alteration of the oxidation state of cerium ions present on the surface of the nanoceria. The intensity of color change was quantified by acquiring an image with a conventional smartphone, converting the image to cyan-magenta-yellow-black (CMYK) mode, and subsequently analyzing the image using the ImageJ software. Using this strategy, galactose concentration was specifically determined with excellent sensitivity of as low as 0.05 mM. The analytical utility of the assay was successfully verified by correctly determining diverse levels of galactose in human serum, which is enough to diagnose galactosemia, a genetic disorder characterized by the malfunctioning of enzymes responsible for galactose metabolism. The assay employing a hydrogel composite with entrapped nanoceria and Gal Ox, is a simple, cost-effective, and rapid colorimetric assay for galactose quantification, without using any chromogenic reagent. This cost-effective method has great potential for the diagnosis of galactosemia and is highly promising in comparison to the laborious instrumentation-based methods currently in use.	0
Innate defense mechanisms are aimed at quickly containing and removing infectious microorganisms and involve local stromal and immune cell activation, neutrophil recruitment and activation and the induction of host defense peptides (defensins and cathelicidins), acute phase proteins and complement activation. As an alternative to antibiotics, innate immune mechanisms are highly relevant as they offer rapid general ways to, at least partially, protect against infections and enable the build-up of a sufficient adaptive immune response. This review describes two classes of promising alternatives to antibiotics based on components of the innate host defense. First we describe immunoglobulins applied to mimic the way in which they work in the newborn as locally acting broadly active defense molecules enforcing innate immunity barriers. Secondly, the potential of host defense peptides with different modes of action, used directly, induced in situ or used as vaccine adjuvants is described.	0
Painful legs and moving toes syndrome is rare. It is predominantly diagnosed in middle-aged adults following a history of spinal cord surgery or trauma. The syndrome consists of abnormal repetitive movements, most commonly in the lower extremities, accompanied by pain in the affected limb. Pain usually precedes the movements. We report a case in a young patient that we believe was induced by the intake of a low-potency neuroleptic, which was prescribed to him for anxiety. The patient was treated with carbamazepine with mild relief of pain and later on with botulinum injection, which significantly reduced the movements and mildly improved the pain. After stopping the treatment, the beneficial effect lasted for about 3 months after which his condition gradually returned to its initial state.	0
Background  Although indomethacin and ibuprofen are the standard treatments for hemodynamically significant patent ductus arteriosus (hsPDA), they are associated with renal impairment and gastrointestinal complications. Paracetamol for hsPDA closure does not provoke a peripheral vasoconstrictive effect and seems to have effects similar to those of indomethacin and ibuprofen. We have previously reported the safety of low-dose (7.5 mg/kg) intravenous paracetamol for preterm infants with hsPDA, who were indomethacin-resistant or -contraindicated but did not affect the need for surgical PDA ligation. However, reports considering the use of higher-dose (15 mg/kg) paracetamol for hsPDA have not been published in Japan. Cases  In 16 premature infants in whom indomethacin or ibuprofen was contraindicated or ineffective, 15 mg/kg of paracetamol was intravenously administered every 6 hours for 3 days after obtaining parental consent. hsPDA closure or narrowing was observed in 14 infants (88%), with the need for surgical closure totally avoided in nine cases (56%). High plasma paracetamol levels were observed in three cases. No paracetamol-related side effects or adverse events were reported. Conclusion  The intravenous administration of higher dose paracetamol was safe and feasible in premature infants with hsPDA. Future clinical trials to explore the optimized dose and timing of administration are needed.	0
Although differentiation between central chondroid tumors is important, their parallelism makes it a diagnostic conundrum for clinicians and radiologists. The objective of this study was to evaluate the efficiency of quantitative single photon emission computed tomography (SPECT)/computed tomography (CT) in differentiating grade I chondrosarcomas from enchondromas. We reviewed SPECT/CT images of patients with enchondromas and grade I chondrosarcomas arising in the long bones. Volume, mean standardized uptake value (SUVmean), and maximum standardized uptake value (SUVmax) of tumors were calculated from SPECT/CT images. In addition, clinical characteristics and radiological information were assessed. Of a total of 34 patients, 14 had chondrosarcomas. Chondrosarcoma group had significantly larger volume, and higher SUVmean and SUVmax of tumors than enchondroma group. There was no significant difference in age and tumor size between two groups. Areas under the receiver-operating characteristic curve (AUCs) for tumor volume, SUVmean, and SUVmax were 0.727, 0.757, and 0.875. In pairwise analyses, SUVmax had larger AUC than SUVmean (p = 0.0216). With a cut-off value of 15.6 for SUVmax, its sensitivity and specificity were 86% and 75% for differentiating between enchondroma and grade I chondrosarcoma. Quantitative SPECT/CT is a potential method to differentiate grade I chondroarcomas from enchondromas in patients with central chondroid tumors.	0
This report describes the microscopical, immunohistochemical and ultrastructural findings in the first ovine cases of the Herlitz type of inherited junctional epidermolysis bullosa. Sixteen German black-headed mutton lambs and one crossbred lamb had blisters and ulceration of the skin and mucous membranes in addition to alterations of the horn of the hooves. Microscopically, there was separation of the dermoepidermal junction, which was confirmed to be located in the lamina lucida of the basement membrane by electron microscopy. In areas of subepidermal splitting the hemidesmosomes were missing and in adjacent areas they appeared to be rudimentary and reduced in number. Immunohistochemistry for laminin 5 revealed a markedly reduced expression of this molecule on the dermal side of the blisters, while expression of collagen VII was normal.	0
BACKGOUND:Idiopathic pulmonary arterial hypertension (IPAH) is a rare condition that requires lung transplantation in patients' refractory to medical therapy. Pulmonary artery aneurysm (PAA) is a documented complication of IPAH however, optimal management and timing of intervention for this rare entity is not well understood. CASE REPORT:We report a case of a 51-year-old female who underwent heart-lung transplantation for IPAH and giant PAA. The extreme size of the PAA and underlying pathology encountered in this case precluded both lung transplantation and conventional aneurysm repair. CONCLUSION:This case demonstrates that heart-lung transplantation is a good surgical option for IPAH complicated by giant sized PAA and right heart failure.	0
BACKGROUND:Cerebral Palsy (CP) Football is a para-sport performed by individuals with physical impairments of athetosis, ataxia, or hypertonia. However, little is known about the physical demands of para-footballers with CP, and no previous study has analysed those demands in a small-sided game (SSG). This study aims to describe physical parameters using a Global Positioning System device in an SSG played by CP Football players. METHODS:Fourteen male international para-footballers with CP took part in this study, which analysed their performance in an SSG of 3 vs. 3 players plus a goalkeeper per team. Also, a group of 12 football players participated as a control group. RESULTS:The total distance covered by the CP footballers during the SSG was 1931.1 ± 213.6 m, and the distance covered per minute was 71.2 ± 9.3 m·min-1, having lower scores than the control group. The maximum speed reached was 20.1 ± 1.8 km·h-1, with a metabolic power of 6.2 ± 0.9 W·kg-1 and lower scores than the control group. Players with the minimal eligible impairment in this para-sport (i.e., sport class FT8) covered a greater distance in high-speed zones compared to players with more severe impairments. CONCLUSIONS:This study demonstrated that para-footballers with CP exhibited lower physical performance in an SSG compared to regular football players. Additional studies are necessary to identify the best format of an SSG for football players with CP and its application for training and evidence-based classification.	0
Implant based reconstruction is still the most commonly employed method of post mastectomy reconstruction in the United States and internationally. Mastectomy techniques are improving, and adjuncts such as tissue perfusion technology and biologic implants allow for re-evaluation of traditional reconstructive methods. Subpectoral implant placement is used in a large majority of patients undergoing implant based reconstruction. However, with the advent of acellular dermal matrix (ADM), a "sling" for the expander and implant can be placed with surgical precision to create the optimal breast pocket. This has allowed for placement of the breast prosthesis in a prepectoral anatomic plane. The benefits are clear: avoidance of animation deformities and a significant decrease in pain that results from pectoralis mobilization and spasm. Here, we discuss specific techniques to avoid pitfalls and optimize aesthetic results with prepectoral breast reconstruction. Patient selection, intra-operative mastectomy flap evaluation, modifications in expander and implant fill, and technique specifics all play a critical role in this new, and rapidly growing method for implant based breast reconstruction.	0
Phosphorylation of Munc18-1 (Stxbp1), a presynaptic organizer of synaptic vesicle fusion, is a powerful mechanism to regulate synaptic strength. Munc18-1 is a proposed substrate for the Down Syndrome-related kinase dual-specificity tyrosine phosphorylation-regulate kinase 1a (Dyrk1a) and mutations in both genes cause intellectual disability. However, the functional consequences of Dyrk1a-dependent phosphorylation of Munc18-1 for synapse function are unknown. Here, we show that the proposed Munc18-1 phosphorylation site, T479, is among the highly constrained phosphorylation sites in the coding regions of the gene and is also located within a larger constrained coding region. We confirm that Dyrk1a phosphorylates Munc18-1 at T479. Patch-clamp physiology in conditional null mutant hippocampal neurons expressing Cre and either wildtype, or mutants mimicking or preventing phosphorylation, revealed that synaptic transmission is similar among the three groups: frequency/amplitude of mEPSCs, evoked EPSCs, paired pulse plasticity, rundown kinetics upon intense activity and the readily releasable pool. However, synapses expressing the phosphomimic mutant responded to intense activity with more pronounced facilitation. These data indicate that Dyrk1a-dependent Munc18-1 phosphorylation has a minor impact on synaptic transmission, only after intense activity, and that the role of genetic variation in both genes in intellectual disability may be through different mechanisms.	0
Angiosarcomas are highly malignant and rare tumors of vascular or lymphatic endothelial cell origin with a poor prognosis. Lymphangiosarcoma associated with chronic lymphedema is known as Stewart-Treves syndrome. Stewart-Treves syndrome is primarily described in patients with lymphedema of an upper extremity occurring after breast cancer surgery including radical axillary lymph node dissection and subsequent radiotherapy. It is rarely described in the presence of idiopathic chronic lymphedema of the lower extremities. We present a case of lymphangiosarcoma visualized on F-FDG PET/CT, where Stewart-Treves syndrome is secondary to probably a combination of idiopathic chronic lymphedema of the lower extremities and systemic immunosuppressive treatment.	0
BACKGROUND:The authors present an institutional experience treating congenital and acquired temporomandibular joint (TMJ) ankylosis, detailing outcomes and potential risk factors of recurrence. METHODS:Retrospective chart review identified patients with TMJ ankylosis (1976-2019). Clinical records, operative reports, and imaging studies were reviewed for demographics, surgical operations, and ankylosis including maximal interincisal opening (MIO) and re-ankylosis. RESULTS:Forty-four TMJs with bony ankylosis were identified in 28 patients (mean age at any initial mandibular surgery: 3.7; range:0-14 years). Follow-up was 13.7 ± 5.9 years. Sixteen (57.1%) patients had bilateral ankylosis; 27(96.4%) had syndromes. Nine patients had congenital ankylosis, 16 had iatrogenic ankylosis (4.5 ± 3.7 years from initial distraction osteogenesis or autologous mandibular reconstruction) referred from outside institutions in 6 instances, and 3 had post-infectious ankylosis. Patients having their first mandibular operation at a younger age had more frequent reoperations for recurrent TMJ ankylosis, although this did not reach statistical significance. Mean improvement in MIO was 21.4 ± 7.3 mm. Ankylosis recurred in 21 (75%) patients. Five patients with congenital TMJ ankylosis required gastrostomy and remained at least partially dependent. Five patients had tracheostomy at the time of TMJ ankylosis surgery: 2 were eventually decannulated and 3 required repeat tracheostomy after ankylosis recurrence and remained tracheostomy-dependent. CONCLUSION:The clinical course of TMJ ankylosis in children affected by craniofacial differences is complex and typically involves a high rate of recurrence and multiple reoperations despite initial improvement in postoperative MIO. Younger age at initial mandibular surgery and number of operations require further investigation as potential predictors of recurrent TMJ ankylosis as well as tracheostomy and gastrostomy dependence.	0
Progressive cardiac conduction defect (PCCD) is an inherited autosomal dominant cardiac disorder characterized by an age‑dependent cardiac electrical conduction block. Several genes have been associated with the genetic pathogenesis of PCCD. The present study aimed to identify the causal mutation of PCCD and to investigate the association between genotype and phenotype in a Chinese family with PCCD. A total of 39 family members were included in the present study. All subjects participated in physical, biochemical, electrocardiography and echocardiography examinations. Whole‑exome sequencing was performed for four individuals from the same generation, including three patients with PCCD and one normal control with no cardiovascular disease. Sanger sequencing and in silico analysis were used to identify the causal mutation. Whole‑exome sequencing and variant identification revealed a candidate nonsense mutation (c.1443C>A, p.Tyr481*) in lamin A/C (LMNA). The mutation was identified in seven patients (including the proband) and two asymptomatic mutation carriers, but it was not detected in 100 control subjects of matched ancestry. Clinical examinations identified typical symptoms in patients with PCCD, including bradycardia and various types of conduction defect, and excluded other phenotypes related to the LMNA mutation. The genotype and phenotype were co‑associated among all participants. In the present study, the c.1443C>A mutation in the LMNA gene was identified as a potential cause of PCCD. In silico analysis predicted that the identified mutation was damaging through its effect on the lamin tail domain of LMNA. From the present study, it could be suggested that genetic screening and family counseling, early pacemaker implantation or a sudden death in the family may be essential for risk stratification and treatment of patients with PCCD.	0
The association between encephalocele and radial defects is considered uncommon. These features have been occasionally described separately in certain recurrent conditions such as VACTERL association, oculo-auriculo-vertebral spectrum and Edwards syndrome (trisomy 18). DK-phocomelia is a rare syndrome characterized by both findings. However, Froster-Iskenius and Meinecke [1992, Clin Dysmorphol 1: 37-41] and Kunze et al. [1992, Eur J Pediatr 151: 467-468] reported patients presenting similar malformations. We proposed, through the description of an additional case, that these last patients present the same condition and thus represent a new syndrome. The fetus presented a cranial vault deformity associated with an exuberant herniation of brain content, compatible with occipital encephalocele. Other uncommon features were also identified: microtia of the left ear with atresia of the external auditory canal; radial defect with aplasia of left radius and thumb; findings suggestive of a congenital heart defect and esophageal atresia; hypoplastic lungs and adrenals; thoracolumbar scoliosis; atrophic right kidney; and single umbilical artery. Thus, based on our review, we believe that these patients represent a new condition characterized by encephalocele and radial defects associated with multiple malformations. We propose, that the name "Encephalocele-radial, cardiac, gastrointestinal, anal/renal anomalies," as suggested by the London Medical Database, or even the name, "Froster-Iskenius and Meinecke syndrome" should be used to indicate these cases. © 2014 Wiley Periodicals, Inc.	0
INTRODUCTION:Enteropathy-associated T-cell lymphoma (EATL) is a very rare form of lymphoma in the gastrointestinal tract. The proximal jejunum and ileum are the most common sites of EATL, whereas EATL rarely arises in the duodenum, and EATL involving metastasis of the bilateral ovaries is even rarer. PATIENT CONCERNS:A 43-year-old female suffered from upper abdominal pain and weight loss for 3 months. DIAGNOSIS:Type II EATL. INTERVENTIONS:The patient was initially treated with chemotherapies, including 4 cycles of the CHOP-E and 2 cycles of the DHAP+ chidamide chemotherapy regimens. However, the patient did not respond well to chemotherapy. Surgical treatment of the duodenal obstruction, with perforation of small intestine and the duodenum, was performed successively. OUTCOMES:The patient died of septic shock only 1 day after the surgery for the second perforation. Her overall survival was 11 months from the time of initial diagnosis. CONCLUSION:This case suggests that EALT is highly invasive and its clinical course is very aggressive. Intestinal perforation, intestinal obstruction, or involvement of extraintestinal organs may occur in EALT patients. Additionally, EALT patients respond poorly to chemotherapy and have an extremely unfavorable prognosis.	0
INTRODUCTION: The epidemiology of multifocal motor neuropathies (MMNs) is unknown. Prevalence is estimated at 1-2/100,000 population. METHODS: The objective of this study was to gain knowledge on MMN diagnosis and treatment in metropolitan France. An opinion survey was conducted by SOFRES from November 2004 to March 2005 on 4,040 hospital and private practice physicians (215 interviewed directly and 3,825 contacted only by mail) using two questionnaires (one for hospital physicians [HPs] and the other for physicians working for the most part in private practice [PPPs]). SOFRES received 424 questionnaires, 392 of which were included in the study, 32 having been excluded for incomplete responses, giving a high response rate for this type of survey. RESULTS: The 392 responses were made up of 296 for the HPs and 96 for the PPPs. The HPs were neurologists (56 percent), followed by internists (23 percent), and rheumatologists (13 percent), while the PPPs were nearly all neurologists (96 percent). One of the most interesting results was the number of patients seen during a physician's career: 1,964, comprising 1,557 for the HPs, and 407 for the PPPs. The responses describing care in terms of diagnosis and treatment generally complied with good practices as well as the recommendations and guidelines published in the field of MMN. CONCLUSION: MMN is a rare disorder whose prevalence in France, estimated by this survey, comes close to that published in the literature; diagnosis and treatment seem globally satisfactory.	1
Pyoderma gangrenosum (PG) is a skin disease characterized by painful ulcers that, when not appropriately treated, can lead to permanent disfigurement. Pyoderma gangrenosum has been observed in a multitude of autoimmune disorders such as rheumatoid arthritis, inflammatory bowel disease (IBD), and sarcoidosis (Feld et al. J Rheumatol. 39(1):197, 2012; Herrero et al. J Rheumatol. 36:7:1557-1558, 2009). It is rarely associated with autoimmune disorders such as systemic sclerosis. We report a case of a patient with known limited cutaneous systemic sclerosis who developed an ulcerated lesion on the 2nd digit of the left hand. The lesion was initially thought to be cellulitis and the patient underwent superficial wound debridement. Postoperatively, the patient's lesions worsened. The patient was treated with intravenous (IV) methylprednisolone and 0.05% topical clobetasol due to high suspicion for PG with complete resolution of ulcerated lesions and minimal scarring.	0
Light chain deposition disease (LCDD) is a rare clinical disorder. The deposition of light chain immunoglobulins mainly affects the kidneys, which have different characteristics than other tissues. To date, the therapeutic approach for the treatment of LCDD has no evidence-based consensus, and clinical experience of reported cases guides current disease management strategies. The present systematic review investigates and summarizes the pathological mechanisms of renal injury and the subsequent treatments for LCDD.	0
The clinical translation of next-generation sequencing has created a paradigm shift in the diagnostic assessment of individuals with suspected rare genetic diseases. Whole-exome sequencing (WES) simultaneously examines the majority of the coding portion of the genome and is rapidly becoming accepted as an efficient alternative to clinical Sanger sequencing for diagnosing genetically heterogeneous disorders. Among reports of the clinical and diagnostic utility of WES, few studies to date have directly compared its concordance to Sanger sequencing, which is considered the clinical "gold standard". We performed a direct comparison of 391 coding and noncoding polymorphisms and variants of unknown significance identified by clinical Sanger sequencing to the WES results of 26 patients. Of the 150 well-covered coding variants identified by Sanger sequencing, 146 (97.3%) were also reported by WES. Nine genes were excluded from the comparison due to consistently low coverage in WES, which might be attributed to the use of older exome capture kits. We performed confirmatory Sanger sequencing of discordant variants; including five variants with discordant bases and four with discordant zygosity. Confirmatory Sanger sequencing supported the original Sanger report for three of the five discordant bases, one was shown to be a false positive supporting the WES data, and one result differed from both the Sanger and WES data. Two of the discordant zygosity results supported Sanger and the other two supported WES data. We report high concordance for well-covered coding variants, supporting the use of WES as a screening tool for heterogeneous disorders, and recommend the use of supplementary Sanger sequencing for poorly-covered genes when the clinical suspicion is high. Importantly, despite remaining difficulties with achieving complete coverage of the whole exome, 10 (38.5%) of the 26 compared patients were diagnosed through WES.	0
Pitt Hopkins syndrome (PTHS) is a very rare condition and until now, approximately 500 patients were reported worldwide, of which not all are genetically confirmed. Usually, individuals with variants affecting exons 1 to 5 in the TCF4 gene associate mild intellectual disability (ID), between exons 5 to 8, moderate to severe ID and sometimes have some of the characteristics of PTHS, and variants starting from exon 9 to exon 20 associate a typical PTHS phenotype. In this report, we describe the clinical and molecular findings of a Caucasian boy diagnosed with PTHS. PTHS phenotype is described including craniofacial dysmorphism with brachycephaly, biparietal narrowing, wide nasal bridge, thin and linear lateral eyebrows, palpebral edema, full cheeks, short philtrum, wide mouth with prominent and everted lips, prominent Cupid's bow, downturned corners of the mouth, microdontia and also the clinical management of the patient. The previously and the current diagnosis scores are described in this report and also the challenges and their benefits for an accurate and early diagnosis.	0
PURPOSE:Among patients with familial amyloidosis, mutation in the transthyretin (TTR) protein is the most common type. Patients with TTR amyloidosis have been noted to have ocular, especially vitreous, involvement. In this report, an analysis of the types and frequency of ocular manifestations in TTR amyloidosis is presented. DESIGN:Observational case series. METHODS:Two hundred and sixty-three patients who presented to Mayo Clinic with TTR amyloidosis between January 1, 1970, and November 1, 2014, consented to be included in the Mayo Clinic amyloidosis database maintained by the Department of Hematology. Fifty-four patients had ocular examinations at a mean of 4.25 ± 3.93 months after systemic symptoms. RESULTS:Of 108 examined eyes in 54 patients with TTR amyloidosis, there were 26 eyes (24%) in 13 patients with ocular involvement. Patients with ocular involvement were more likely to be women than those without ocular involvement (46% vs 15%, respectively, P = .008) and have significantly worse visual acuity (VA) at presentation (logMAR 0.24 [Snellen equivalent 20/30] vs logMAR 0.00 [Snellen equivalent 20/20], P = .017). The ophthalmic findings included vitreous amyloid (26/26, 100%), neurotrophic keratitis (2/26, 8%), glaucoma (5/26, 19%), and tortuous retinal vessels (4/26, 15%). The glaucoma was classified as open-angle (2/26), exfoliative (2/26), and neovascular following central retinal vein occlusion from amyloidosis (1/26). Ten patients underwent vitrectomy for visually significant vitreous amyloidosis, which significantly improved VA from a baseline of logMAR 0.70 (Snellen equivalent 20/100) to logMAR 0.05 (Snellen equivalent ∼20/20), P = .003. Three TTR mutations, Glu89Lys, Gly47Arg, and homozygous Gly6Ser, not previously described, were associated with vitreous amyloid. CONCLUSION:In this large cohort of patients with TTR amyloidosis, female sex and decreased VA were associated with ocular amyloid. Three mutations that have not been previously reported to have vitreous involvement were described: Glu89Lys, Gly47Arg, and homozygous Gly6Ser.	0
Diagnosed cases of tick-borne encephalitis (TBE) and Lyme disease (LD) have been reportable infectious diseases in Hungary since 1977 and 1998, respectively. Clinically diagnosed cases have been registered in the National Database of Epidemiological Surveillance System (NDESS). All reported TBE cases are confirmed by laboratory serological and, if necessary, PCR tests, whereas the registered cases of LD are mainly based on the appearance of erythema migrans concurring with possible exposure of tick bite. Our work is the first comparative epidemiological and geographical information analysis of these 2 diseases together. The following demographic data from each individual case (703 TBE and 13,606 LD) recorded in the NDESS were used: Sex, age, the starting date and place of the onset of disease, and a short report from the affected person. The descriptive epidemiological analysis of incidence was carried out using directly standardized rates, and smoothed indirectly standardized incidence ratios were calculated by hierarchical Bayesian methods at the municipality level using a Rapid Inquiry Facility (RIF). The average yearly incidence rate of TBE was 0.64 per 100,000 inhabitants (range, 0.46-0.84) and of LD was 12.37 per 100,000 inhabitants (range, 9.9-18.1), with the highest incidence rates in 1998 for TBE and 2008 for LD. The most affected age groups were men between 15 and 59 years of age for TBE, and women between 45 and 64 years of age for LD. Seasonality, based on the starting date of the illness, was also characterized. Extended areas of high risk were identified in western and northern Hungary, illustrated on high-resolution (municipality level) maps. On the basis of our analysis, it is possible to associate areas and periods of high-risk with characteristics (sex, age, residence) of groups most affected by tick-borne diseases in Hungary.	1
Background:Carriers of balanced reciprocal chromosomal translocations are at known reproductive risk for offspring with unbalanced genotypes and resultantly abnormal phenotypes. Once fertilization of a balanced translocation gamete with a normal gamete, the partial monosomy or partial trisomy embryo will undergo abortion, fetal arrest or fetal malformations. We reported a woman with chromosomal balanced translocation who had two adverse pregnancies. Prenatal diagnosis was made for her third pregnancy to provide genetic counseling and guide her fertility. Case presentation:We presented a woman with chromosomal balanced translocation who had three adverse pregnancies. Routine G banding and CNV-seq were used to analyze the chromosome karyotypes and copy number variants of amniotic fluid cells and peripheral blood. The karyotype of the woman was 46,XX,t(4;5)(q33;p15). During her first pregnancy, odinopoeia was performed due to fetal edema and abdominal fluid. The umbilical cord tissue of the fetus was examined by CNV-seq. The results showed a genomic gain of 24.18 Mb at 4q32.3-q35.2 and a genomic deletion of 10.84 Mb at 5p15.2-p15.33 and 2.36 Mb at 15q11.1-q11.2. During her second pregnancy, she did not receive a prenatal diagnosis because a routine prenatal ultrasound examination found no abnormalities. In 2016, she gave birth to a boy. The karyotype the of the boy was 46,XY,der(5)t(4;5)(q33;p15)mat. The results of CNV-seq showed a deletion of short arm of chromosome 5 capturing regions 5p15.2-p15.33, a copy gain of the distal region of chromosome 4 at segment 4q32.3q35.2, a duplication of chromosome 1 at segment 1q41q42.11 and a duplication of chromosome 17 at segment 17p12. During her third pregnancy, she underwent amniocentesis at 17 weeks of gestation. Chromosome karyotype hinted 46,XY,der(5)t(4;5)(q33;p15)mat. Results of CNV-seq showed a deletion of short arm (p) of chromosome 5 at the segment 5p15.2p15.33 and a duplication of the distal region of chromosome 4 at segment 4q32.3q35.2. Conclusions:Chromosomal abnormalities in three pregnancies were inherited from the mother. Preimplantation genetic diagnosis is recommended to prevent the birth of children with chromosomal abnormalities.	0
BACKGROUND:Klippel-Feil syndrome (KFS) represents a rare anomaly characterized by congenital fusion of the cervical vertebrae. The underlying molecular etiology remains largely unknown because of the genetic and phenotypic heterogeneity. METHODS:We consecutively recruited a Chinese cohort of 37 patients with KFS. The clinical manifestations and radiological assessments were analyzed and whole-exome sequencing (WES) was performed. Additionally, rare variants in KFS cases and controls were compared using genetic burden analysis. RESULTS:We primarily examined rare variants in five reported genes (GDF6, MEOX1, GDF3, MYO18B and RIPPLY2) associated with KFS and detected three variants of uncertain significance in MYO18B. Based on rare variant burden analysis of 96 candidate genes related to vertebral segmentation defects, we identified BAZ1B as having the highest probability of association with KFS, followed by FREM2, SUFU, VANGL1 and KMT2D. In addition, seven patients were proposed to show potential oligogenic inheritance involving more than one variants in candidate genes, the frequency of which was significantly higher than that in the in-house controls. CONCLUSIONS:Our study presents an exome-sequenced cohort and identifies five novel genes potentially associated with KFS, extending the spectrum of known mutations contributing to this syndrome. Furthermore, the genetic burden analysis provides further evidence for potential oligogenic inheritance of KFS.	0
Objective: To compare and analyze the curative effect of three surgical methods in the treatment of small intestine atresia, and to provide evidence for individualized surgical treatment of children with small intestine atresia. Methods: The clinical diagnosis and treatment of 168 children with small intestine Ⅱ, Ⅲ, Ⅳ type atresia in our hospital from January 2008 to September 2017 were retrospectively analyzed and they were divided into different types according to the operation. The three groups were end-to-end anastomosis group (EEA, n=58), end oblique anastomosis group (EOA, n=68), and proximal end-end anastomosis group (PEA, n=42). The EEA group and the EOA group were further divided into group a (EEA-a/EOA-a) with a proximal intestinal tube diameter greater than 4.0 times the distal end and a group b ((EEA-b/EOA-b) with a diameter less than or equal to 4.0 times the distal intestinal tube diameter. The gender, gestational age, birth weight, type of atresia, and postoperative defecation time, postoperative feeding time, postoperative hospital stay and postoperative follow-up complications were compared. Results: There was no significant difference in gender, gestational age and birth weight between the groups (P>0.05). The PEA group was better than EEA-a group and EOA-a group in postoperative defecation time, postoperative feeding time, postoperative hospital stay and complications (P<0.05). The postoperative defecation time, postoperative feeding time, postoperative hospital stay and complications of the EOA-a group were better than those of the EEA-a group (P<0.05). There was no statistically significant difference in postoperative defecation time, postoperative feeding time, and complications between the EEA-b group and the EOA-b group (P>0.05), but the postoperative hospital stay in the EEA-b group was longer than that in the EOA-b group (P<0.05). Conclusion: PEA is recommended for children with a proximal intestinal canal diameter greater than 4.0 times greater than the distal end because of the rapid recovery and fewer complications; EOA is recommended for children with a proximal intestinal canal diameter of 4.0 or less because of its advantage of shorter hospital stay than EEA surgery. Congenital intestinal atresia has a better effect according to the specific conditions of the child.	0
Interdigitating dendritic cell tumor/sarcoma (IDCT) is a very rare and aggressive neoplasm arising from antigen-presenting cells. It usually involves lymph nodes, but extranodal sites can also be involved. Because of the rarity of the disease, consistent standard treatment guidelines have not been established till date. We report a case of a 35-year-old female who presented with right-sided neck swelling and anterior mediastinal mass. Histopathology revealed large mononucleated cells with background of mixed polymorphous inflammatory cells suspicious of Hodgkin's lymphoma. Hence, to confirm the diagnosis, immunohistochemistry was done. Immunohistochemistry revealed that the tumor was CD30 - negative, CD10 - negative, CD2 - negative, leukocyte common antigen - positive, vimentin - positive, and S-100 - positive, diagnostic of IDCT. Patient was treated with eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone regimen chemotherapy followed by involved field radiotherapy and showed dramatic response with complete resolution of mediastinal mass.	0
Splenomegaly is a key clinical manifestation of myelofibrosis, and splenectomy is currently indicated in patients with drug refractory, symptomatic splenomegaly or with the aim of improving refractory cytopenias. Transformation to acute myeloid leukemia occurs in up to 20% of patients with myelofibrosis, while cases of myeloid sarcoma have been reported very unfrequently. In this manuscript, we report the case of a 60-year-old man with a history of primary myelofibrosis who underwent splenectomy because of drug-refractory massive splenomegaly, systemic symptoms and anemia. At the opening of the peritoneal cavity, the spleen resulted massively enlarged and tenaciously entrapped by a pervasive neoplastic-like tissue. The extensive involvement of the abdomen fatally complicated the surgical procedure. At postmortem examination, the spleen showed a diffuse infiltration of immature cells that were also found in the peritoneum, bowel, liver, lungs and myocardium. After immunohistochemical, cytogenetic, flow cytometric and molecular characterization of neoplastic population, a diagnosis of disseminated myeloid sarcoma of the spleen was made. This case report highlights a very unusual case of myeloid sarcoma originating from the spleen in a patient with myelofibrosis who had no evidence of bone marrow or peripheral blood involvement by leukemic cells. Molecular characterization showed that leukemic cells originated from the founding clone of the chronic phase. The sarcoma could not be suspected based on clinical findings and was diagnosed only at the time of surgical procedure and autopsy. This case suggests that leukemic transformation of myelofibrosis can originate outside the bone marrow and, presumably rarely, present as a granulocytic sarcoma.	0
BACKGROUND Epidermolysis bullosa acquisita is a rare, subepithelial bullous disorder, which is distinguished from other autoimmune blistering diseases by the production of antibodies against type VII collagen. CASE REPORT Here, we describe the case of a 79-year-old male resident of the Northern Mariana Islands who presented to the clinic with multiple blistering skin lesions. CONCLUSIONS The primary focus of treatment is to prevent disease progression and serious complications of scarring (including blindness and respiratory obstruction) by avoiding physical trauma and suppressing the immune systems with agents, including corticosteroids, colchicine, dapsone, methotrexate, and cyclophosphamide. Successful treatment of the condition should involve a multidisciplinary team of medical professionals with regular monthly follow-ups during periods of active disease.	0
Most pituitary adenomas are sporadic, but 3-5% can occur in a family and hereditary context. This is the case of multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC) and familial isolated pituitary adenomas (FIPA). FIPA is an infrequent condition that occurs in a family context, not associated with MEN type1 or CNC. FIPA kindred can be homogeneous (all adenomas affected in the family having the same tumor phenotype) or heterogeneous (different tumor phenotypes in the affected members). We describe a Congolese family in which two sisters and a cousin were diagnosed with a prolactinoma (homogenous FIPA) at the ages of 29, 32 and 40 years, respectively. The patients presented with macroadenomas at the time of diagnosis, non-invasive tumors and good biological response to cabergoline treatment (maximum dose of 1.5 mg/weekly). Of these two sisters, one went through a pregnancy without complications. Because no MEN1 and CNC clinical and biochemical features were detected during the 12-year follow-up, these genes were not investigated. The genetic analysis of the aryl hydrocarbon receptor interacting protein (AIP) was normal. As nearly 80% of patients with FIPA do not have a mutation in the AIP gene, future studies in these families are required to identify other affected genes involved in their physiopathology.	0
The study of inherited retinal diseases has advanced our knowledge of the cellular and molecular mechanisms involved in sensory neural signaling. Dysfunction of two specific sensory modalities, vision and proprioception, characterizes the phenotype of the rare, autosomal-recessive disorder posterior column ataxia and retinitis pigmentosa (PCARP). Using targeted DNA capture and high-throughput sequencing, we analyzed the entire 4.2 Mb candidate sequence on chromosome 1q32 to find the gene mutated in PCARP in a single family. Employing comprehensive bioinformatic analysis and filtering, we identified a single-nucleotide coding variant in the feline leukemia virus subgroup C cellular receptor 1 (FLVCR1), a gene encoding a heme-transporter protein. Sanger sequencing confirmed the FLVCR1 mutation in this family and identified different homozygous missense mutations located within the protein's transmembrane channel segment in two other unrelated families with PCARP. To determine whether the selective pathologic features of PCARP correlated with FLVCR1 expression, we examined wild-type mouse Flvcr1 mRNA levels in the posterior column of the spinal cord and the retina via quantitative real-time reverse-transcriptase PCR. The Flvcr1 mRNA levels were most abundant in the retina, followed by the posterior column of the spinal cord and other brain regions. These results suggest that aberrant FLVCR1 causes a selective degeneration of a subpopulation of neurons in the retina and the posterior columns of the spinal cord via dysregulation of heme or iron homeostasis. This finding broadens the molecular basis of sensory neural signaling to include common mechanisms that involve proprioception and vision.	0
Background:Tufted angioma is a rare benign lesion with vascular proliferation. Aim:To retrospectively analyze the clinicopathological manifestations and immunohistochemical features of tufted angioma. Methods:Clinical and histopathological features of tufted angioma (n = 54) were evaluated and analyzed retrospectively in the Department of Dermatology, Xijing Hospital from 2003 to 2014. Results:Clinically, tufted angioma usually presented as erythematous plaques and papules on the head and neck (n = 11), trunk (n = 21) and extremities (n = 22), mainly in children (n = 48), without gender difference (24 males and 30 females). A total of 45 cases showed solitary lesions and nine cases showed multiple lesions. Common symptoms included pain (n = 11), tenderness (n = 7), itching (n = 1), hypertrichosis (n = 7), hyperhidrosis (n = 6) and Kasabach-Merritt phenomenon (n = 1). Histopathologically, typical tufted angioma (n = 37) showed proliferation of endothelial cells in a so-called cannonball pattern, while in the early (n = 4) and regressed (n = 13) stages the tufted appearance was not prominent. The proliferated endothelial cells were diffusely positive for CD31 and Wilms tumor 1, focally positive for D2-40 and Prox1, and negative for Glut-1. Limitations:Our research was confined to patients of Chinese origin and our sample size was limited. Conclusions:Tufted angioma is a rare vascular neoplasm with diverse clinical manifestations and unique pathological features. It should be recognized as a vascular tumor with lymphatic differentiation. We emphasize the importance of considering tufted angioma in the differential diagnoses of any congenital or acquired vascular tumor.	0
Adrenal corticotropin (ACTH) -independent macronodular adrenal hyperplasia (AIMAH) is a rare cause of Cushing's syndrome. Bilateral adrenalectomy is the treatment of choice, but lifetime steroid replacement is essential. Here we report a case of AIMAH whose hyperglycemia was improved following unilateral adrenalectomy. A 42-year-old woman with serious intellectual disability and intractable epilepsy presented with polydipsia. Casual blood glucose and hemoglobin A1c (HbA1c) were 322 mg/dl and 8.5%, respectively. The cortisol level was high and ACTH level was low. Abdominal computed tomography and magnetic resonance imaging revealed unsuspected macronodular enlargement of bilateral adrenal glands (left 8 cm, right 4 cm in maximal diameter) and she was diagnosed with AIMAH. Both adrenal glands showed intense 131 I-adosterol accumulation predominantly in the left side and left-unilateral laparoscopic adrenalectomy was performed. Both insulin and oral antidiabetic drugs could be cancelled postoperatively, and HbA1c decreased to 5.7%. Steroid was not replaced but she never experienced adrenal crisis. We conclude that unilateral adrenalectomy is a safe and effective treatment for certain cases of AIMAH.	0
PURPOSE OF REVIEW:Immune dysfunction, including severe combined immunodeficiency, has been described in genetic disorders affecting the metabolism of the vitamins cobalamin (vitamin B12) and folate. We have reviewed reports of clinical findings in patients with a number of inborn errors of cobalamin or folate metabolism, specifically looking for immune problems. RECENT FINDINGS:There is little evidence that immune function is affected in most of the disorders. Exceptions are Imerslund-Gräsbeck syndrome and hereditary folate malabsorption (affecting intestinal absorption of cobalamin and folate, respectively), transcobalamin deficiency (affecting transport of cobalamin in blood and cellular cobalamin uptake), and methylenetetrahydrofolate dehydrogenase 1 deficiency (catalyzing cytoplasmic interconversion of reduced folate coenzyme derivatives). SUMMARY:Although some inborn errors of cobalamin or folate can be associated with immune dysfunction, the degree and type of immune dysfunction vary with no obvious pattern.	0
Tube-shaped blood vessel models that mimic their geometries and mechanical properties can deliver reliable and realistic behavioral information such as deformation and rupture during procedures such as insertion of medical devices. Thickness of vessel walls is an important parameter for fabricating the blood vessel models owing to their strong influence on the model behavior, especially during deformation. The dip-coating method is used to fabricate blood vessel models; however, non-uniform wall thicknesses are observed using this method. This study aimed at finding the characteristics of stereo "angular control dip-coating" (ACDC) system to develop a dip-coating system that can produce tubular models with uniformed wall thickness. The system developed here enables an observation of the substrate behavior from two different views. The conditions of dip-coating used in this study produce 1.36-1.82 mm in the maximum and 0.188-0.435 mm in minimum wall thickness and the fabricated walls cover the realistic range of carotid arterial dimensions. The characteristics of the ACDC system indicate that ACDC is effective for fabricating the uniform wall thickness particularly in the strong curved parts.	0
Cytochrome c oxidase deficiency is caused by mutations in any of at least 30 mitochondrial and nuclear genes involved in mitochondrial complex IV biogenesis and structure, including the recently identified PET100 gene. Here, we report two families, of which one is consanguineous, with two affected siblings each. In one family, the siblings presented with developmental delay, seizures, lactic acidosis, abnormal brain magnetic resonance imaging, and low muscle mitochondrial complex IV activity at 30%. In the other family, the two siblings, now deceased, had a history of global developmental delay, failure to thrive, muscular hypotonia, seizures, developmental regression, respiratory insufficiency, and lactic acidosis. By whole exome sequencing, a missense mutation in exon 1 of the PET100 gene (c.3G > C; [p.Met1?]) was identified in both families. A review of the clinical description and literature is discussed, highlighting the importance of this variant in the Lebanese population.	0
Significant progress in the molecular pathology of melanocytic tumors have revealed that benign neoplasms, so-called nevi, are initiated by gain-of-function mutations in one of several primary oncogenes, such as BRAF in acquired melanocytic nevi, NRAS in congenital nevi or GNAQ/GNA11 in blue nevi, with consequent MAPK and PI3K/AKT/mTOR activation. Secondary genetic alterations overcome tumor suppressive mechanisms and allow the progression to intermediate lesions characterized by TERT-p mutation or to invasive melanomas displaying disruption of tumor suppressor genes. Currently, melanoma is molecularly regarded as four different diseases, namely BRAF, NRAS, NF1 and the "triple wild type" subtypes, which are associated with particular clinicopathological features. Melanocytic Spitzoid lesions include benign Spitz nevus, atypical Spitz tumor (AST) and Spitzoid melanoma. This is a challenging diagnostic group, particularly with regard to the distinction between AST and Spitzoid melanoma on clinical and histological grounds. Molecular analysis has identified the presence of HRAS mutation, BAP1 loss (often accompanying by BRAF mutations) or several kinase fusions in distinct categories of Spitz tumors. These aberrations account for the rapid growth characteristic of Spitz nevi. Subsequent growth is halted by various tumor suppressive mechanisms abrogation of which allow the development of AST, now better classified as low-grade melanocytic tumor. Although at present ancillary genetic techniques have not been very helpful in the prediction of biological behavior of AST, they have defined distinct tumor subsets differing with regard to biology and histology. Finally, we discuss how novel molecular markers may assist the differential diagnosis of melanoma, particularly from malignant peripheral nerve sheath tumor (MPNST). It is anticipated that the significant progress in the field of molecular pathology regarding the various types of melanocytic tumors, will eventually contribute to a more accurate histologic categorization, prediction of biologic behavior and personalized treatment.	0
Over the last 10 years an increasing amount of data regarding the prevalence of chronic daily headache (CDH) has been published. The economic implications of chronic daily headache have now grown in importance in view of the increasingly limited financial resources in the health care system. In addition to recording data regarding the prevalence of this disease, epidemiological studies have also dealt with analysing and evaluating the quality of life of the afflicted patients. According to population-based data from the USA, Europe and Asia, approx. 4-5% of the population suffer from chronic daily headache. These have been equated up until now with chronic tension-type headache (CTTH). More recent epidemiological studies have resulted in an adaptation of this point of view. Currently it is assumed that approx. 2-3% of the population suffer CTTH, which preferably affects females (approximately twice as frequently); approx. 2 % suffer chronic migraine (transformed migraine = TM) and 0.2 % are afflicted with a so-called  new daily persistent headache  or very rarely a hemicrania continua.	1
BACKGROUND:Preterm delivery and low birth weight (LBW) are generally associated with worse outcomes in hypoplastic left heart syndrome (HLHS), but an individual preterm or small neonate may do well. We sought to explore the interactions between gestational age, birth weight, and birth weight for gestational age with intermediate outcomes in HLHS. METHODS:We analyzed survival, growth, neurodevelopment, length of stay, and complications to age 6 years in subjects with HLHS from the Single Ventricle Reconstruction trial. Univariate and multivariable survival and regression analyses examined the effects and interactions of LBW (<2500 g), weight for gestational age, and gestational age category. RESULTS:Early-term delivery (n = 234) was more common than term (n = 219) delivery. Small for gestational age (SGA) was present in 41% of subjects, but only 14% had LBW. Preterm, compared with term, delivery was associated with an increased risk of death or transplant at age 6 years (all: hazard ratio = 2.58, confidence interval = 1.43-4.67; Norwood survivors: hazard ratio = 1.96, confidence interval = 1.10-3.49) independent of LBW and weight for gestational age. Preterm delivery, early-term delivery, LBW, and SGA were each associated with lower weight at 6 years. Neurodevelopmental outcomes were worst in the LBW cohort. CONCLUSIONS:Preterm delivery in HLHS was associated with worse survival, even beyond Norwood hospitalization. LBW, SGA, and early-term delivery were associated with worse growth but not survival. LBW was associated with worse neurodevelopment, despite similar length of stay and complications. These data suggest that preterm birth and LBW (although often concomitant) are not equivalent, impacting clinical outcomes through mechanisms independent of perioperative course complexity.	0
Juvenile Parkinson's disease (JPD) is a rare movement disorder that presents before the age of 21 years. Kufor-Rekab syndrome (KRS) is one of the distinct types of JPD caused by the ATP13A2 mutation and inherited as an autosomal recessive. The pathogenesis of KRS is related to an interrelated metabolism of ATP13A2 with Mn+2 and Zn+2, bioenergetics of mitochondria, autophagy lysosomal dysfunction, and synuclein metabolism. Clinically, KRS has a variable phenotype and may present with pyramidal or extrapyramidal symptoms and cognitive impairment. Early diagnosis of KRS is important as most of these patients are levodopa-responsive and genetic counseling and screening is important for the whole family. We present a case of a 16-year-old boy who presented with tremors and walking difficulty. His physical examination showed an expressionless face, decrease in eye blink frequency, and slow vertical saccadic eye movements. His movements were slow. All laboratory investigations were normal, except the genetic study, which led to the diagnosis of KRS.	0
Short root anomaly (SRA) is a poorly understood developmental disorder and can significantly compromise the patient's dental treatment. This case report describes the treatment of a 15-year-old girl with SRA and discusses the implication of this disorder on orthodontic and orthognathic treatment of patients.	0
Porphyria refers to a group of fascinating diseases from a metabolic and nutritional standpoint as it provides an example of how metabolic manipulation can be used for therapeutic purposes. It is characterized by defects in heme synthesis, particularly in the erythrocytes and liver. Specific enzymes involved in heme biosynthesis directly depend on adequate levels of vitamins and minerals in the tissues. Moreover, micronutrients that are required for producing succinyl CoA and other intermediates in the Krebs (TCA) cycle are indirectly necessary for heme metabolism. This review summarizes articles that describe the nutritional status, supplements intake, and dietary practices of patients affected by porphyria, paying special attention to the therapeutic use of nutrients that may help or hinder this group of diseases.	0
Epileptic encephalopathy can be induced by inborn metabolic defects that may be rare individually but in aggregate represent a substantial clinical portion of child neurology. These may present with various epilepsy phenotypes including refractory neonatal seizures, early myoclonic encephalopathy, early infantile epileptic encephalopathy, infantile spasms, and generalized epilepsies which in particular include myoclonic seizures. There are varying degrees of treatability, but the outcome if untreated can often be catastrophic. The importance of early recognition cannot be overemphasized. This paper provides an overview of inborn metabolic errors associated with persistent brain disturbances due to highly active clinical or electrographic ictal activity. Selected diseases are organized by the defective molecule or mechanism and categorized as small molecule disorders (involving amino and organic acids, fatty acids, neurotransmitters, urea cycle, vitamers and cofactors, and mitochondria) and large molecule disorders (including lysosomal storage disorders, peroxisomal disorders, glycosylation disorders, and leukodystrophies). Details including key clinical features, salient electrophysiological and neuroradiological findings, biochemical findings, and treatment options are summarized for prominent disorders in each category.	0
Patients with herpes zoster oticus (HZO) may commonly show symptoms associated with 7th and 8th cranial nerve (CN VII and CN VIII) dysfunction. The aim of this study is to investigate the characteristics of hearing loss in patients with HZO and discuss possible mechanisms.Ninety-five HZO patients who showed at least one of the symptoms of CN VII and CN VIII dysfunction between January 2007 and October 2014 were included in this study. Hearing loss was defined when the mean thresholds of pure tone audiometry (PTA) in speech frequency (0.5 kHz + 1 kHz + 2 kHz/3) or isolated high frequency (4 kHz + 8 kHz/2) were greater than 10 dB in the affected ear compared with the healthy ear, and a total of 72 patients were classified as the hearing loss group.The difference of mean PTA thresholds between affected and healthy ears was significantly greater in the high frequency range than in low range (20.0 ± 11.5 dB vs. 12.9 ± 15.7 dB, P = 0.0026) in patients with hearing loss (n = 72). The difference between affected and healthy ear was significantly greater in patients with vertigo (n = 34) than those without vertigo (n = 38) in both the high (P = 0.033) and low (P = 0.024) frequency ranges. In contrast, the differences between affected and healthy ears were not significantly different between patients with facial palsy (n = 50) and those without facial palsy (n = 22) in both the high (P = 0.921) and low (P = 0.382) frequency ranges.In patients with HZO, hearing loss is more severe in the high frequency range than in the low frequency range. Hearing impairment is more severe in patients with vertigo than in those without vertigo in both the high and low frequency ranges, even though the degree of hearing impairment is not significantly different between patients with and without facial palsy. These findings indicate that the mechanisms of viral spread from CN VII to CN VIII may differ between vestibular and audiologic deficits.	0
Innate and adaptive immune involvement in hemolysis, elevated liver enzymes and low platelet (HELLP) syndrome is an understudied field, although it is of high clinical importance. This syndrome implies a risk of serious morbidity and mortality to both the mother and the fetus during pregnancy. It was proposed that HELLP syndrome occurs in a circulatory inflammatory milieu, that might in turn participate in a complex interplay between the secreted inflammatory immunomodulators and immune cell surface receptors. Meanwhile, reported immune cell attenuation during HELLP may consequently lead to a prolonged immunoactivation and tissue damage. In this regard, learning more about the immune components of this syndrome should widen the understanding of the HELLP pathophysiology and eventually enable development of novel immune-based therapeutics. This review aims to summarize and discuss the recent and previous findings of the innate and adaptive immune responses during HELLP in order to update the current knowledge of the immune involvement in HELLP pathogenesis.	0
Background Ribbing disease, or multiple diaphyseal sclerosis, is a rare benign bone dysplasia. Purpose To systematically review the literature to determine the clinical and radiological presentation of patients with Ribbing disease as well as the effects of attempted treatments. Material and Methods We considered individual patient data of patients diagnosed with Ribbing disease derived from patient reports and patient series. All stages of the review were performed by two reviewers independently. Standard descriptive statistics were used for quantitative analyses and mixed model analyses were used when appropriate Results The literature search yielded 420 unique hits of which 23 studies were included, covering a total of 40 patients of whom 29 had bilateral involvement. The mean age at diagnosis was 35 years and the mean time between diagnosis and onset of symptoms, mostly pain, was five years (range = 1-16 years). The tibial diaphysis was the most commonly involved bone in 35 of 36 patients. Non-surgical treatment consisted of non-steroidal anti-inflammatory drugs (NSAIDs), prednisone, and bisphophonates with mixed results. Surgical treatment consisted of intramedullary reaming and fenestration and was very effective to reduce pain. Conclusion The clinical presentation and imaging findings of patients with Ribbing disease are becoming more apparent. However, there is paucity of evidence on the natural disease progression and effectiveness of treatment modalities.	0
This report aims to enhance the understanding of early longitudinal neuroimaging features of progressive multifocal leukoencephalopathy (PML) in human immunodeficiency virus (HIV). Neuroimaging has become crucial in the diagnosis and early recognition of PML. Recognition of magnetic resonance imaging (MRI) features in the early stages of PML is paramount to avoid misdiagnosis and facilitate the delivery of treatments aimed at reducing disease progression. A 49-year-old white man with HIV presented with 4-month progressive left-sided weakness. Neurological examination revealed mild cognitive impairment, left-sided hemiparesis, and somatosense impairment to all modalities. Brain MRI revealed a punctate pattern with innumerable T2-FLAIR (fluid attenuated inversion recovery) hyperintensities in the cortex, brainstem, cerebellum, subcortical, and periventricular areas. Susceptibility-weighted imaging (SWI) revealed hypointensities involving subcortical U-fibers and cortical architecture. A comprehensive diagnostic evaluation was inconclusive. John Cunningham virus (JCV) PCR in cerebrospinal fluid (CSF) was indeterminate. He was started on antiretroviral therapy. Repeat brain MRI performed 1.5 months later, in the setting of further neurological decline, demonstrated progression of the T2-hyperintensities into a large confluent white matter lesion in the right frontoparietal lobe. Despite an indeterminate JCV PCR, the appearance and characteristic progression of the lesions in successive imaging in the setting of severe immunosuppression, with extensive negative infectious workup, was indicative of PML. This clinical experience illustrates unique neuroimaging features of HIV-PML in early stages and its progression over time. It especially highlights the relevance of the SWI sequence in the diagnosis and features observed with disease evolution. Short-term imaging follow-up may assist with the recognition of MRI features consistent with the biology of the infection.	0
The inherited bone marrow failure syndromes (IBMFS) are a rare yet clinically important cause of neonatal hematological and non-hematological manifestations. Many of these syndromes, such as Fanconi anemia, dyskeratosis congenita and Diamond-Blackfan anemia, confer risks of multiple medical complications later in life, including an increased risk of cancer. Some IBMFS may present with cytopenias in the neonatal period whereas others may present only with congenital physical abnormalities and progress to pancytopenia later in life. A thorough family history and detailed physical examination are integral to the work-up of any neonate in whom there is a high index of suspicion for an IBMFS. Correct detection and diagnosis of these disorders is important for appropriate long-term medical surveillance and counseling not only for the patient but also for appropriate genetic counselling of their families regarding recurrence risks in future children and generations.	0
We here report a neonate with prenatal echocardiographic diagnosis of tricuspid atresia, with normally related great vessels, and large ventricular septal defect. This diagnosis could be confirmed with echocardiography at birth. An additional double mitral orifice was also seen. This is a very rare association.	0
Xanthogranulomatous cholecystitis (XGC) is a rare inflammatory disease of the gallbladder with distinct histopathological characteristics. Laparoscopic cholecystectomy (LC) is currently the standard treatment for gallbladder disease. However, the outcomes of LC for XGC have not been completely investigated, due to the rarity of XGC. The present study aimed to assess the surgical outcomes of LC for XGC. Among 3,037 patients undergoing cholecystectomy between 2005 and 2017 at our institution, 58 patients (1.9%) were diagnosed with XGC based on histopathology. Of the patients, LC was performed in 38 (65.5%), and they were enrolled in the present study. The outcome of LC for XGC in the cases was assessed, and was compared with outcomes of LC for other diseases. The average operation time was 109±36 min, and average intraoperative blood loss was 58±85 ml. LC was converted to open cholecystectomy in 6 (15.8%) of the 38 cases. No operative mortality occurred. One patient developed postoperative complications greater than grade II in the Clavien-Dindo classification, and the mean postoperative hospital stay was 6.1±5.8 days. Based on previous reports and the nature of XGC itself, the outcomes reported herein of LC for XGC seemed acceptable. It should be also noted that LC for XGC exhibited a higher conversion rate compared with LC than other benign gallbladder diseases, implying that LC for XGC remains challenging.	0
BACKGROUND:Data suggest that pregnant women are not at elevated risk of acquiring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or developing severe disease compared with nonpregnant patients. However, management of pregnant patients who are critically ill with coronavirus disease 2019 (COVID-19) infection is complicated by physiologic changes and other pregnancy considerations and requires balancing maternal and fetal well-being. CASE:We report the case of a patient at 28 weeks of gestation with acute respiratory distress syndrome (ARDS) from COVID-19 infection, whose deteriorating respiratory condition prompted delivery. Our patient's oxygenation and respiratory mechanics improved within hours of delivery, though she required prolonged mechanical ventilation until postpartum day 10. Neonatal swabs for SARS-CoV-2 and COVID-19 immunoglobulin (Ig) G and IgM were negative. CONCLUSION:We describe our multidisciplinary management of a preterm pregnant patient with ARDS from COVID-19 infection and her neonate.	0
Interstitial deletions involving 6q25 are rare chromosomal abnormalities associated with distinctive phenotypic features. We describe a 9-year-old boy who was followed from his infancy due to his multiple congenital anomalies and complex medical history. Over the years, a number of diagnoses were considered including Cornelia de Lange syndrome, Rubinstein-Taybi syndrome, as well as "a novel genetic disorder." Various genetic tests, including a BAC-based array-CGH analysis, were reported as normal. Recently, a SNP-based microarray analysis was performed and showed an 11.1-Mb deletion from 6q25.2 to 6q26, including ARID1B and ZDHHC14. Recent literature suggests that the 6q25 deletion syndrome is a recognizable entity characterized by growth delay, developmental disabilities, microcephaly, hearing loss, and variable other malformations including cleft palate. These features overlap with those of Coffin-Siris syndrome, which is caused by deletions and loss-of-function mutations of ARID1B. Retrospectively, this patient has features resembling both Coffin-Siris and 6q25 microdeletion syndromes.	0
BACKGROUND: Lenz microphthalmia syndrome is an X-linked recessive disorder characterized by microphthalmia and dental, urogenital, and skeletal anomalies. This case report represents the first detailed account of congenital kyphoscoliosis in the Lenz microphthalmia literature. METHODS: We present a case of Lenz microphthalmia syndrome with progressive kyphosis, spinal stenosis, and late-onset tibia vara along with many of the typical features of the disorder. In addition, we provide insight into the syndrome by reviewing the existing Lenz microphthalmia literature. RESULTS: Congenital kyphoscoliosis that is prone to reoccurrence after posterior spinal fusion is an unusual entity that may be associated with Lenz microphthalmia. CONCLUSIONS: We recommend close monitoring and early surgical intervention with posterior spinal fusion for congenital kyphosis in patients diagnosed with Lenz microphthalmia syndrome. However, more data on similar patients are necessary to define the optimal treatment strategy. LEVEL OF EVIDENCE (FOR CLINICAL ARTICLES): Level V.	0
The clinical phenotype of patients with ring chromosomes usually reflects the loss of genomic material during ring formation. However, phenotypic alterations can also be found in the presence of complete ring chromosomes, in which the breakage and rejoining in terminal regions of both chromosome arms result in no gene loss. Here, we present a patient with a ring chromosome 14 that lost nothing but the telomeres. Since he and other patients with a similar chromosome abnormality present certain abnormal characteristics, we investigated the gene expression of eight chromosome 14 genes to find out whether the configuration of the ring had changed it, possibly producing some of these clinical features. The expression of these eight genes was studied by quantitative real-time polymerase chain reaction (qPCR) in the patient and in seven controls matched for gender and age. Two of them were found to be downregulated in the patient compared to the controls, indicating that his phenotype might be related to alterations in the expression of genes located in the abnormal chromosome, even when the copy number is normal. Thus, the phenotypic alterations found in the presence of complete ring chromosomes may be related to changes in the chromatin architecture, bringing about a change of expression by position effect. These results may explain some of the characteristics presented by our patient.	0
The role of X-inactivation is often ignored as a prime cause of sex differences in disease. Yet, the way males and females express their X-linked genes has a major role in the dissimilar phenotypes that underlie many rare and common disorders, such as intellectual deficiency, epilepsy, congenital abnormalities, and diseases of the heart, blood, skin, muscle, and bones. Summarized here are many examples of the different presentations in males and females. Other data include reasons why women are often protected from the deleterious variants carried on their X chromosome, and the factors that render women susceptible in some instances.	0
Congenital hemifacial hyperplasia is a rare developmental disorder of unknown etiology, characterized by a marked unilateral facial asymmetry. It involves the hard (bones and teeth) and soft tissues of the face. We report an interesting case of true hemifacial hyperplasia in a 25-year-old male highlighting the clinical and computed tomography imaging findings.	0
A 2-year-old girl with a 1-year history of photophobia presented with bilateral eye redness and was found to have dendriform corneal ulcers, which were initially managed with acyclovir ointment, without improvement. Clinical inspection revealed small cutaneous lesions on the fingers and toes. The association of pseudodendritic keratitis with palmo-plantar hyperkeratotic lesions was suspicious for tyrosinemia type 2, which was confirmed by high levels of plasmatic tyrosine (2134 μmol/L). A protein-restricted diet led to the complete resolution of the corneal and cutaneous lesions and avoided the potential toxicity of tyrosine on central nervous system.	0
OBJECTIVE:To assess functional organization of the motor cortex in patients with Unverricht-Lundborg disease (EPM1A) using a combined neurophysiologic and imaging approach. METHODS:EPM1A patients underwent transcranial magnetic stimulation (TMS)-based cortical mapping of the motor hand area. Moreover, they performed neuroimaging studies to assess functional magnetic resonance imaging (fMRI) activation maps related to motor hand task and cortical thickness (CTH) on T1-weighted 3D images. RESULTS:The hand cortical representation was different in EPM1A patients from that of the control subjects both in TMS and in fMRI brain mapping, characterized by a posterior dislocation and a mild reduction in the activation of motor areas. CTH analysis revealed a thinning of both precentral and paracentral areas in the patients. CONCLUSIONS:We hypothesize that the altered cortical motor map reflects a functional reorganization of the residual cortical neuronal pool of the sensorimotor hand areas driven by plastic reorganization and/or pathophysiological mechanisms. SIGNIFICANCE:Both pathophysiological process and plastic changes may represent two sides of the same phenomenon in the EPM1A patients; structural and functional brain mapping may help to identify functional reorganization of the cortical motor system.	0
BACKGROUND:Particles and fibres affect human health as a function of their properties such as chemical composition, size and shape but also depending on complex interactions in an organism that occur at various levels between particle uptake and target organ responses. While particulate pollution is one of the leading contributors to the global burden of disease, particles are also increasingly used for medical purposes. Over the past decades we have gained considerable experience in how particle properties and particle-bio interactions are linked to human health. This insight is useful for improved risk management in the case of unwanted health effects but also for developing novel medical therapies. The concepts that help us better understand particles' and fibres' risks include the fate of particles in the body; exposure, dosimetry and dose-metrics and the 5 Bs: bioavailability, biopersistence, bioprocessing, biomodification and bioclearance of (nano)particles. This includes the role of the biomolecule corona, immunity and systemic responses, non-specific effects in the lungs and other body parts, particle effects and the developing body, and the link from the natural environment to human health. The importance of these different concepts for the human health risk depends not only on the properties of the particles and fibres, but is also strongly influenced by production, use and disposal scenarios. CONCLUSIONS:Lessons learned from the past can prove helpful for the future of the field, notably for understanding novel particles and fibres and for defining appropriate risk management and governance approaches.	0
BACKGROUND Epidermolysis bullosa acquisita is a rare, subepithelial bullous disorder, which is distinguished from other autoimmune blistering diseases by the production of antibodies against type VII collagen. CASE REPORT Here, we describe the case of a 79-year-old male resident of the Northern Mariana Islands who presented to the clinic with multiple blistering skin lesions. CONCLUSIONS The primary focus of treatment is to prevent disease progression and serious complications of scarring (including blindness and respiratory obstruction) by avoiding physical trauma and suppressing the immune systems with agents, including corticosteroids, colchicine, dapsone, methotrexate, and cyclophosphamide. Successful treatment of the condition should involve a multidisciplinary team of medical professionals with regular monthly follow-ups during periods of active disease.	0
Mining potential drug-disease associations can speed up drug repositioning for pharmaceutical companies. Previous computational strategies focused on prior biological information for association inference. However, such information may not be comprehensively available and may contain errors. Different from previous research, two inference methods, ProbS and HeatS, were introduced in this paper to predict direct drug-disease associations based only on the basic network topology measure. Bipartite network topology was used to prioritize the potentially indicated diseases for a drug. Experimental results showed that both methods can receive reliable prediction performance and achieve AUC values of 0.9192 and 0.9079, respectively. Case studies on real drugs indicated that some of the strongly predicted associations were confirmed by results in the Comparative Toxicogenomics Database (CTD). Finally, a comprehensive prediction of drug-disease associations enables us to suggest many new drug indications for further studies.	0
Interstitial and terminal deletions of chromosome 4q have been described for many years and have variable phenotypes depending on the size of the deletion present. Clinical features can include developmental delay, growth difficulty, digital differences, dysmorphic features, and cardiac anomalies. Here, we present an infant with pseudohypoaldosteronism found to have a deletion of 4q31.21q31.23, including NR3C2. Heterozygous mutations in NR3C2 have been reported to cause autosomal dominant pseudohypoaldosteronism type 1 (PHA1A). This represents a rare case of PHA1A due to a contiguous interstitial deletion and highlights the importance of evaluating patients with overlapping deletions for PHA1A.	0
Introduction: Myotonic dystrophy type 2 (DM2) lacks disease-specific, validated, motor outcome measures (OMs), and patients' reported outcomes (PROs). This represents a limit for the monitoring of disease progression and treatment response. Our aim was to identify the most appropriate OMs to be translated in clinical practice and clinical trials on DM2. This study has been registered on clinicaltrials.gov NCT03603171 (https://clinicaltrials.gov/ct2/show/NCT03603171). Methods: Sixty-six patients with genetically confirmed DM2 underwent a baseline and a follow-up visit after 1 year. The tested OMs included: hand opening time, pressure pain threshold (PPT), manual muscle testing (MMT), hand held dynamometry (HHD), scale for the assessment and rating of ataxia (SARA), quantitative motor function test (QMFT), gait stairs Gowers chair (GSGC), 30-s sit to stand test, functional index 2 (FI-2) and 6MWT. The PROs included DM1-Active-C, Rasch-built Pompe-specific activity scale (R-Pact), fatigue and daytime sleepiness (FDSS), brief pain inventory short form (BPI-sf), myotonia behavior scale (MBS), and the McGill pain questionnaire. Results: All patients completed the MBS and the results correlated well with the hand-opening time. The PPT showed a low reliability, no correlation with pain questionnaires, and did not differentiate patients with or without myalgia. Both muscle strength assessments, MMT and HHD, showed good construct validity. The QMFT showed an acceptable ceiling effect (14.5%), good convergent and differential validity and performed overall better than GSGC. The SARA score showed high flooring effect and is not useful in DM2. 6MWT proved a valid outcome measure in DM2. The 30-s sit to stand is a feasible test with good convergent validity, showing a flooring effect of 20% as it cannot be used in more severely affected patients. The FI-2 is time-consuming and has a high ceiling effect. At the 1-year visit the only assessments able to detect a worsening of DM2 were HHD, QMFT, and 6MWT, which are the most sensitive to change, and therefore clinically meaningful OMs in DM2. Conclusion: The clinical meaningful motor outcome measures that best depict the multifaceted phenotype of DM2 and its slow progression are MBS, MMT, or HHD (depending on the clinical setting), QMFT, and the 6MWT.	0
INTRODUCTION:X-linked hyper-IgM syndrome is a type of primary combined immunodeficiency disorder caused by mutations in CD40 ligand. Opportunistic infections caused by P jirovecii, cytomegalovirus (CMV), or fungi are frequently the first presenting symptom of the patients with X-linked hyper-IgM syndrome. PATIENT CONCERNS:Here, we report a 10-month-old infant who presented with cyanosis and shortness of breath. The infant exhibited no medical or birth history indicating a primary immune deficiency and was first diagnosed with interstitial pneumonia and acute respiratory failure on admission. DIAGNOSES:The infant was diagnosed with Pneumocystis jirovecii pneumonia combined with CMV and fungal infection through gene sequencing by nasopharyngeal swab and G-test. Whole-exome sequencing from a blood sample was performed and identified a functional mutation across the CD40 ligand gene (NM_000074;exon1;C.86_87del) resulting in an amino acid change (P.T29Sfl*18) attributed to X-linked hyper IgM syndrome. INTERVENTIONS:The infant received continuous positive airway pressure ventilation treatment combined with trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia, ganciclovir for CMV, voriconazole for fungal infection and substitution of high-dose immunoglobulin. OUTCOMES:Six months after discharge from our hospital, the infant remained well. CONCLUSION:Opportunistic infections should be suspected in infants presenting with severe interstitial pneumonia. Primary immune deficiency diseases should also be considered in infants diagnosed with opportunistic infections.	0
We report three cases of ring chromosome 5 [r(5)], two familial (mother and daughter) and one sporadic. The phenotype resembled that of the "ring syndrome" with prenatal onset of short stature, growth retardation, mild facial dysmorphism and normal psychomotor development. Extended metaphase and prometaphase chromosome preparations using G-, R- and Q-banding and scanning electron microscopy (SEM) failed to demonstrate deletion in the ring 5. Flow karyotype using the FACS cell sorter and peak area analysis showed the r(5) to be in the same position as the normal chromosome 5. The deletion that is presumably associated with ring formation appears to involve less that one megabase of DNA. In the "complex" rings, high resolution SEM showed fragile sites at the 5q34 and 5q35 region with frequent deletions at that site. A literature survey suggests that when a parent carries a ring chromosome about 80% of recognised pregnancies result in live birth. Of these, about half have a normal phenotype and karyotype, and half inherit the parental ring; about half of those acquiring the ring (20%) show significant mental retardation.	0
Gardner-Diamond syndrome (GDS) is a rare psychodermatological condition characterized by the formation of spontaneous, painful skin lesions that develop into ecchymosis following episodes of severe physiological or psychological stress. The majority of GDS cases occur in young adult females, and although the etiology of this rare disorder is unknown, there appears to be a psychological component correlated with the coexistence of previous psychiatric diagnoses. Due to the rare nature of this disorder, there exist few guidelines for prompt clinical diagnosis and optimal treatment. Here, a systematic review was conducted to include 45 cases of patients with GDS to better understand clinical presentation as well as current treatment options. Ultimately, GDS is a diagnosis of exclusion after other coagulopathies and causes of purpura are ruled out. High clinical suspicion following laboratory and clinical exclusion of known physiological causes is necessary for diagnosis. Selective serotonin reuptake inhibitors (SSRIs) and corticosteroids are cost effective first line treatments for GDS with proven efficacy in symptomatic relief. GDS refractory to initial treatment may require regular psychotherapy and titrated SSRI dosages to achieve long-term success. This review of available case studies serves to comprehensively describe the clinical presentation and available treatment approaches to this rare psychodermatological disorder.	0
Dihydropyrimidinase deficiency is an autosomal recessive inborn error of metabolism characterised by the presence of dihydropyrimidinuria. Its clinical presentation is variable and has also been reported in asymptomatic subjects. We report the first case of dihydropyrimidinase deficiency in Hong Kong, which is also the first reported in a Chinese subject. The patient was a 32-month-old boy who presented with language development delay. Biochemical analysis confirmed markedly increased urinary excretion of dihydrouracil and dihydrothymine, whilst DNA testing confirmed that the patient was compound heterozygous for two missense mutations, one known (p.R302Q) and the other was novel (p.N16K).	0
Biochemical and biological properties of glycoconjugates are strongly determined by the specific structure of its glycan parts. Glycosylation, the covalent attachment of sugars to proteins and lipids, is very complex and highly-coordinated process involving > 250 gene products. Deficiency of glycosylation enzymes or transporters results in impaired glycosylation, and consequently pathological modulation of many physiological processes. Inborn defects of glycosylation enzymes, caused by the specific mutations, lead to the development of rare, but severe diseases - congenital disorders of glycosylation (CDGs). Up today, there are more than 45 known CDGs. Their clinical manifestations range from very mild to extremely severe (even lethal) and unfortunately, only three of them can be effectively treated nowadays. CDG symptoms highly vary, though some are common for several CDG types but also for other unrelated diseases, especially neurological ones, leaving the possibility that many CDGs cases are under- or misdiagnosed. Glycan analysis of serum transferrin (by isoelectric focusing or more sophisticated methods, such as HPLC (high-performance liquid chromatography) or MALDI (matrix-assisted laser desorption/ionization)) or serum N-glycans (by MS), enzyme activity assays and DNA sequence analysis are the most frequently used methods for CDG screening and identification, since no specific tests are available yet. In this review we summarize the current knowledge on the clinical, biochemical and genetic characteristic of distinct CDGs, as well as existing diagnostic and therapeutic procedures, aiming to contribute to the awareness on the existence of these rare diseases and encourage the efforts to elucidate its genetic background, improve diagnostics and develop new strategies for their treatment.	0
We describe a diastrophic dysplasia (DTDST) gene mutation in a Japanese male fetus with achondrogenesis type 1B and his relatives. Diagnosis in the fetus was based on roentgenographic data and pathological findings of bones and cartilage. Nucleotide sequencing of the DTDST gene demonstrated that the fetus was homozygous for both delVal340 and Thr689Ser and his parents and a healthy brother were heterozygous for the mutations. The former mutation was reported previously in patients with achondrogenesis type 1B, and the latter was detected in 5 alleles of 26 healthy Japanese individuals. These data suggest that delVal340 is associated with achondrogenesis type 1B in the Japanese, whereas a serine to threonine substitution is most likely polymorphic.	0
Undifferentiated embryonal sarcoma of the liver is a rare entity. It is a malignant primitive mesenchymal tumor seen in the pediatric age group often between 6 to 10 years of age. It involves the right lobe of the liver commonly and is usually asymptomatic. Acute presentation in these cases is secondary to its rupture/ wall dehiscence. Alfa fetoprotein, a tumor marker elevated in most of the hepatic malignant tumors is however normal in undifferentiated embryonal sarcoma. Imaging wise it is a large encapsulated multiseptated lesion. It shows a "paradoxical appearance" with a predominantly solid appearance on ultrasonography and cystic appearance on CT/MRI. This is a peculiar feature that can help in the early diagnosis of this entity. Besides, normal serum alfa fetoprotein levels favor its diagnosis. Hereby we present a case of a 5-year-old female child, presented with complaints of acute onset abdominal pain and distension which on imaging investigation showed a liver mass with typical paradoxical appearance on ultrasonography, CT and MRI as described.	0
Crigler Najjar syndrome is associated with indirect hyperbilirubinemia due to a deficiency of enzyme Uridine Di Phospho Glucoronosyl Transferase (UDPGT). Presented here is a case of a female in the first trimester of pregnancy, who was diagnosed to have type 2 Crigler Najjar syndrome. We also discuss the management of this rare disease especially in pregnancy. Unconjugated bilirubin can cross the placental barrier causing neurological damage in the newborn. Patient was carefully monitored during pregnancy and treatment with phenobarbitone in low doses was adjusted such that the serum bilirubin levels were below 10 mg/dL. Crigler Najjar syndrome being rare needs to be diagnosed early in pregnancy to avoid adverse fetal outcomes. Phenobarbitone being an inducer of enzyme UDPGT is used as the first line of treatment and is not teratogenic in the low doses used. Treatment protocol followed was on the basis of previous reported cases and successful perinatal outcome was achieved.	0
BACKGROUND:Laron syndrome (LS) is an autosomal recessive hereditary condition affecting only 1/1000000 births. The cause is associated with mutations in the growth hormone (GH) receptor (GHR), leading to GH insensitivity. LS patients typically present with severe growth retardation, obesity, and abnormal sexual maturation. Currently, LS diagnosis is performed post-delivery. Therefore, we assessed the efficiency of Pre-implantation Genetic Testing (PGT) coupled with monoplex-polymerase chain reaction (PCR) technology for detecting this monogenic disease in embryos from a couple confirmed as LS heterozygous carriers. CASE SUMMARY:The couple LS-carriers were confirmed by the presence of a first child born with LS. The couple underwent a standard in vitro fertilization (IVF) protocol. DNA was collected from trophectoderm cells from day 5 embryos. Whole genome amplification (WGA) was performed using a Sureplex DNA Amplification System and analyzed by PCR, targeting the deletion of the exons 5 and 6 in the GHR gene as well as PGT by Next-generation Sequencing (Illumina). Eleven embryos were collected and analyzed. 27.3% were the wild type for GHR, 45.5% were heterozygotes, and 18.2% homozygous mutants. One embryo yielded no results. Three 2-embryos transfers were performed; 2 normal homozygous and four heterozygous carriers were selected for transfer. The first two transfers were unsuccessful, whereas the final transfer with two heterozygous embryos resulted in clinical pregnancy. The genomic composition of the fetus was verified, applying the same techniques using amniocytes, extracted after 21 wk of the ongoing pregnancy. The fetus was confirmed as GHR deletion in exon 5-6, carrier. A non-affected baby was born. CONCLUSION:Here, we present a case demonstrating that using WGA as a template in addition to PCR targeting specific gene regions, exons 5 and 6 on the GHR gene, could identify LS carrier embryos. This provides evidence that WGA and PCR serve as an excellent tool to detect this specific monogenic disease in IVF embryos, thus allowing selection of candidate embryos for transfer successfully when a specific inherited genetic mutation/disease is suspected.	0
In this article, distal myopathy syndromes are discussed. A discussion of the more traditional distal myopathies is followed by discussion of the myofibrillar myopathies. Other clinically and genetically distinctive distal myopathy syndromes usually based on single or smaller family cohorts are reviewed. Other neuromuscular disorders that are important to recognize are also considered, because they show prominent distal limb weakness.	0
Acquired pediatric Brown syndrome is rarely associated with sinusitis. Children may present with diplopia, elevation deficiency in adduction, and a head tilt or chin-up position. Magnetic resonance imaging can confirm the diagnosis. Antibiotic treatment is often insufficient for resolution. Surgical correction can effectively prevent amblyopia and restore binocular vision. [J Pediatr Ophthalmol Strabismus. 2019;56:e17-e19.].	0
BACKGROUND:National newborn screening programmes based on tandem-mass spectrometry (MS/MS) and other newborn screening (NBS) technologies show a substantial variation in number and types of disorders included in the screening panel. Once established, these methods offer the opportunity to extend newborn screening panels without significant investment and cost. However, systematic evaluations of newborn screening programmes are rare, most often only describing parts of the whole process from taking blood samples to long-term evaluation of outcome. METHODS:In a prospective single screening centre observational study 373 cases with confirmed diagnosis of a metabolic disorder from a total cohort of 1,084,195 neonates screened in one newborn screening laboratory between January 1, 1999, and June 30, 2009 and subsequently treated and monitored in five specialised centres for inborn errors of metabolism were examined. Process times for taking screening samples, obtaining results, initiating diagnostic confirmation and starting treatment as well as the outcome variables metabolic decompensations, clinical status, and intellectual development at a mean age of 3.3 years were evaluated. RESULTS:Optimal outcome is achieved especially for the large subgroup of patients with medium-chain acyl-CoA dehydrogenase deficiency. Kaplan-Meier-analysis revealed disorder related patterns of decompensation. Urea cycle disorders, organic acid disorders, and amino acid disorders show an early high and continuous risk, medium-chain acyl-CoA dehydrogenase deficiency a continuous but much lower risk for decompensation, other fatty acid oxidation disorders an intermediate risk increasing towards the end of the first year. Clinical symptoms seem inevitable in a small subgroup of patients with very early disease onset. Later decompensation can not be completely prevented despite pre-symptomatic start of treatment. Metabolic decompensation does not necessarily result in impairment of intellectual development, but there is a definite association between the two. CONCLUSIONS:Physical and cognitive outcome in patients with presymptomatic diagnosis of metabolic disorders included in the current German screening panel is equally good as in phenylketonuria, used as a gold standard for NBS. Extended NBS entails many different interrelated variables which need to be carefully evaluated and optimized. More reports from different parts of the world are needed to allow a comprehensive assessment of the likely benefits, harms and costs in different populations.	1
Acute lung injury is the main causative factor in paraquat dichloride (PQ)-induced mortality. The innate immune system-triggered detrimental inflammatory cascade plays a vital role in PQ-induced acute lung injury. However, the role of natural killer (NK) cells, which are essential for innate response, in PQ-induced acute lung injury remains largely unknown. Here, we found that in an acute PQ poisoning model, depletion of NK cells attenuated PQ-induced lung injury by inhibiting macrophage polarization towards the M1 type. Specifically, the percentages of NK cells were reduced in the lung, spleen, and peripheral blood in a murine model of acute PQ poisoning. NK cells were aberrantly activated, evidenced by upregulation of the activating markers CD69, CD107a, and NKG2D and downregulation of the inhibitive marker KLRG1. Further, NK-specific depletion in mice greatly prolonged the survival time and ameliorated reactive oxygen species-induced damage following PQ treatment compared with the control group. Importantly, NK cell depletion alleviated macrophage and neutrophil infiltration in the lung and reversed PQ induced-macrophage polarization towards the pro-inflammatory M1 type. Our study demonstrates a crucial role of NK cells and NK cell-to-macrophage interaction in PQ-induced acute lung injury.	0
Woolly Hair is an uncommon congenital anomaly of the scalp hair presenting with strongly coiled hair involving a localized area of the scalp or covering the entire side and occurring in non-black people. Isolated or localized wooly hair is usually benign and is not related to other disorders and/or complications. On the contrary, the generalized type may be related to disorders and syndromes affecting heart, cutis, liver and gastrointestinal organs. Among the syndromes presenting with wooly hair, the most known are the Naxos syndrome, the Carvajal-Huerta syndrome, the wooly hair/hypotrichosis, the ectodermal dysplasia-skin fragility, the tricho-hepato-enteric syndrome.To our knowledge, no cases of wooly hair syndromes has been associated to neurologic involvement. Among the clinical notes of patients admitted in the Pediatric Units of the Catania University, we have selected four individuals presenting wooly hair, who showed different clinical features and course: case 1 presenting with a localized wooly hair type; case 2, member of a family affected by WH with autosomal dominant inheritance, not associated to complications; case 3, a wooly hair patient who displayed a progressive, severe form of Rasmussen's encephalitis with fatal evolution, and case 4, wooly hair associated to brain malformation and drug-resistant epilepsy.With this report, we aim to underline the wide spectrum of clinical presentation of individuals with WH and in particular we wish to give an annotation on a possible association of WH with severe neurologic disorders.	0
Roberts Syndrome is an extremely rare syndrome reporting about 150 cases in the literature, with a very low survival rate. The authors present a case of a female patient with Roberts Syndrome who also had a coronal craniosynostosis. The aim of this case report is to present a case of a patient with Roberts Syndrome with a brachycephaly that required management of fronto-orbital advancement. In conclusion Roberts Syndrome is a rare disease, which can have different skeletal variations. This syndrome can manifest itself with craniosynostosis, with the requirement of a comprehensive management to correct it and avoid compression of the brain with endocranial hypertension.	0
The syndrome of the windblown hand deformity is a complex constellation of malformations affecting not only the head and the feet but also the hands in a quite distinct manner. In the hand, it involves congenital bilateral flexion contracture with ulnar deviation of the metacarpophalangeal joints. The thumb is characteristically adducted (reaching the palm; "thumb-in-palm deformity") with flexion of the MP joint and hyperextension of the IP joint. The etiology is basically unknown. We present two theories based on knowledge derived from the disciplines of evolution biology and embryology. We believe that the atavistic appearance of phylogenetically primitive muscle groups in conjunction with an impaired rotation of the extremities during embryological development account for this malformation syndrome.	0
Introduction:Posterior fossa brain tumor is the most devastating forms of human illness, primarily because of the limited space within the posterior fossa, the potential involvement of vital brain stem nuclei, and the mass effect causes obstructive hydrocephalus. Posterior fossa tumors are more common in children than adults. The Objective of the Study:To find out the satisfactory surgical outcome of posterior fossa brain tumors in children at Civil hospital, Karachi. Materials and Methods and Duration of Study Setting:This prospective observational, case series study was conducted from February 2015 to February 2105 in the Department of neurosurgery, Dow University of Health Sciences, Civil Hospital, Karachi, Karachi. Postoperative patients with the diagnosis of posterior fossa tumor were enrolled in the study. Detailed history, physical examination, anthropometrics, and biochemical measurements were recorded. Magnetic resonance imaging was done to determine the satisfactory surgical outcome. Patients were followed up at the third postoperative month to determine the satisfactory surgical outcome. Results:Seventy-one patients fulfilling the inclusion criteria, the mean ± standard deviation age of the study population was 6.63 ± 3.181 years. 29 (40.8%) were <7 years of age and 42 (59.2%) were of age 7 years and above. 50 (70.4%) were males and 21 (29.6%) were females. 49 (69%) patients presented with vomiting. 34 (47.9%) presented with seizures. (40.8%) had papilledema. (25.4%) presented with hemiparesis. 8 (11.3%) had meningismus. On analysis of the frequency of outcome variables (80.3%) achieved the satisfactory surgical outcome. Conclusions:There has been no major study to determine satisfactory surgical outcome in postoperative patients with posterior fossa brain tumor in our population. The study was to provide local data in our population and compare it to the international data. This may help in proper patient management. Majority of the patients had satisfactory surgical outcome. The absence of papilledema, hemiparesis, and meningismus had more chances of satisfactory surgical outcome.	0
Despite the significant brain abnormalities, the neurotoxic mechanisms of brain injury in hypertryptophanemia are virtually unknown. In this work, we determined the thiobarbituric acid-reactive substances, 2',7'-dihydrodichlorofluorescein oxidation, reduced glutathione and the activities of catalase, superoxide dismutase and glutathione peroxidase in cerebral cortex from rats loaded with L-tryptophan. High L-tryptophan concentrations, similar to those found in hypertryptophanemic patients were induced by three subcutaneous injections of saline-buffered tryptophan (2 micromol/g body weight) to 30-day-old Wistar rats. The parameters were assessed 1 h after the last injection. It was observed that tryptophan significantly increased thiobarbituric acid-reactive substances, 2',7'-dihydrodichlorofluorescein oxidation and reduced glutathione, whereas it reduced catalase activity. Pre-treatment with taurine (1.6 micromol/g of body weight), or alpha-tocopherol plus ascorbic acid (40 and 100 microg/g body weight, respectively) prevented those effects of tryptophan, reinforcing the hypothesis that tryptophan induces oxidative stress in brain cortex of the rats. Therefore, these findings also occur in human hypertryptophanemia or in other neurodegenerative diseases in which tryptophan accumulates, then oxidative stress may be involved in the mechanisms leading to the brain injury observed in patients affected by these disorders.	0
Hereditary diffuse gastric cancer (HDGC) is a rare autosomal dominant syndrome associated with an increased risk of developing Laurén's diffuse-type gastric carcinoma and lobular breast carcinoma. Although signet-ring cell carcinoma (SRCC) in situ (SRCC-pTis) has been reported as a characteristic lesion in HDGC cases with CDH1 germline mutations (CDH1 pathogenic variant), and a precursor of conventional intramucosal SRCC (SRCC-pT1a), its histopathologic features and specificity have not been sufficiently clarified. Here, we examined gastrectomy samples from 6 Japanese HDGC patients with CDH1 germline mutation, belonging to 4 families, and analyzed SRCC lesions histologically and immunohistochemically. Of the 274 foci found in the 6 samples, SRCC-pT1a accounted for 225 lesions (range: 8 to 107, mean 45.7 lesions per patient), while 46 foci were of SRCC-pTis (range: 1 to 15, mean 7.67 foci per patient). All SRCC-pTis foci were observed in the fundic gland area and on the superficial side of the mucosa. Histologically, tumor cells of SRCC-pTis were found between normal foveolar epithelial cells and the basement membrane, following a typical pagetoid spread pattern. Immunohistochemically, E-cadherin expression was lost in SRCC-pTis (27/28, 96.4%) more frequently than in SRCC-pT1a (95/197, 48.2%; P<0.001). To elucidate the specificity of SRCC-pTis for HDGC, 60 samples (range: 0.12 to 1.49 m, total 28.8 m of mucosal length) from gastric cancer cases were analyzed as controls, in which no SRCC-pTis were identified. Our results indicate that SRCC-pTis is a distinct histologic feature with high specificity for HDGC cases with CDH1 germline mutations.	0
The immune response is essential to protect organisms from infection and an altered self. An organism's overall metabolic status is now recognized as an important and long-overlooked mediator of immunity and has spurred new explorations of immune-related metabolic abnormalities. Peroxisomes are essential metabolic organelles with a central role in the synthesis and turnover of complex lipids and reactive species. Peroxisomes have recently been identified as pivotal regulators of immune functions and inflammation in the development and during infection, defining a new branch of immunometabolism. This review summarizes the current evidence that has helped to identify peroxisomes as central regulators of immunity and highlights the peroxisomal proteins and metabolites that have acquired relevance in human pathologies for their link to the development of inflammation, neuropathies, aging and cancer. This review then describes how peroxisomes govern immune signaling strategies such as phagocytosis and cytokine production and their relevance in fighting bacterial and viral infections. The mechanisms by which peroxisomes either control the activation of the immune response or trigger cellular metabolic changes that activate and resolve immune responses are also described.	0
Treatment in IRIDA focuses on use of intravenous iron preparations to circumvent oral absorptive defect resulting from high levels of hepcidin due to TMPRSS6 gene variations. However, recent case reports and recommendations on atypical microcytic hypochromic anemias advocate use of oral iron and vitamin c trial before parenteral iron, as the same results in comparable improvement in haemoglobin. We prospectively evaluated our IRIDA cohort (n = 7) with oral iron and vitamin c dose over a period of 10 weeks and noted complete response in majority (6/7 = 86%) with >2 g/dL rise in Hb along with significant improvement of other iron related indices.	0
BACKGROUND:Lemierre syndrome is characterized by head/neck vein thrombosis and septic embolism usually complicating an acute oropharyngeal bacterial infection in adolescents and young adults. We described the course of Lemierre syndrome in the contemporary era. METHODS:In our individual-level analysis of 712 patients (2000-2017), we included cases described as Lemierre syndrome if these criteria were met: (i) primary site of bacterial infection in the head/neck; (ii) objectively confirmed local thrombotic complications or septic embolism. The study outcomes were new or recurrent venous thromboembolism or peripheral septic lesions, major bleeding, all-cause death and clinical sequelae. RESULTS:The median age was 21 (Q1-Q3: 17-33) years, and 295 (41%) were female. At diagnosis, acute thrombosis of head/neck veins was detected in 597 (84%) patients, septic embolism in 582 (82%) and both in 468 (80%). After diagnosis and during in-hospital follow-up, new venous thromboembolism occurred in 34 (5.2%, 95% CI 3.8-7.2%) patients, new peripheral septic lesions became evident in 76 (11.7%; 9.4-14.3%). The rate of either was lower in patients who received anticoagulation (OR: 0.59; 0.36-0.94), higher in those with initial intracranial involvement (OR: 2.35; 1.45-3.80). Major bleeding occurred in 19 patients (2.9%; 1.9-4.5%), and 26 died (4.0%; 2.7-5.8%). Clinical sequelae were reported in 65 (10.4%, 8.2-13.0%) individuals, often consisting of cranial nerve palsy (n = 24) and orthopaedic limitations (n = 19). CONCLUSIONS:Patients with Lemierre syndrome were characterized by a substantial risk of new thromboembolic complications and death. This risk was higher in the presence of initial intracranial involvement. One-tenth of survivors suffered major clinical sequelae.	0
Purpose:To study the demographic details, risk factors, microbiological profile, and clinical outcomes of pediatric infectious keratitis cases in North India. Methods:This retrospective case series included review of medical records of pediatric patients (0-16 years) diagnosed with infectious keratitis in a tertiary care center of North India during December 2011 to January 2017 was done. Demographic details, predisposing factors, microbiological investigations, and clinical outcomes were analyzed. Results:In this time period, 104 eyes of 104 children had a diagnosis of infectious keratitis. Culture was obtained for all 104 eyes and was positive in eighty eight eyes (84.2%). The most common causative factor was trauma, seen in 77 eyes (74%). Bacteria was the most common agent isolated in culture (54.2%) followed by fungi (40.8%) and acanthamoeba (2.1%). Successful healing of the keratitis with appropriate medical treatment occurred in 84 (80.7%) eyes, while 13 (12.5%) eyes required therapeutic keratoplasty. Of the 80 eyes with documentation of both preliminary and final visual acuity, improvement of two lines was seen in 35 eyes (43.7%), stayed the same in and worsened in 17 eyes (21%). Mean time to resolution of infection on medical treatment for bacteria was 23.65 ± 4.78 days, fungi 32 ± 5.19 days, and acanthamoeba 53.67 ± 4.78 days. Conclusion:Gram positive organism is the most common etiological agent of keratitis in children in our study population which is in contrast to pediatric infective keratitis study conducted by Aruljyothi et al. in South India (2011--2013). Though less in number than bacterial keratitis, fungus also remains an important causative agent. Along with early diagnosis and immediate medical intervention, it is important to identify regional profile of organisms and risk factors for good visual and anatomical outcome.	0
Hypomagnesemia has been associated with a variety of abnormalities, including neurological, cardiac and secondary electrolyte abnormalities. We present the case of a 77-year-old male who presented to the emergency department with tremor and difficulty walking and was found to have severe hypomagnesemia necessitating hospital admission. After thorough workup, the patient's hospital course concluded that the profound hypomagnesemia was secondary to proton pump inhibitor use. Physicians should be aware of proton pump inhibitor-induced hypomagnesemia as a rare, but easily correctable etiology of hypomagnesemia.	0
Objective: Elevated homocysteine concentrations are a risk factor for stroke. A common genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR 677 C→T) results in elevated levels of homocysteine. MTHFR plays a critical role in the synthesis of S-adenosylmethionine (SAM), a global methyl donor. Our previous work has demonstrated that Mthfr+/- mice, which model the MTHFR polymorphism in humans, are more vulnerable to ischemic damage. The aim of this study was to investigate the cellular mechanisms by which the MTHFR-deficiency changes the brain in the context of ischemic stroke injury.Methods: In the present study, three-month-old male Mthfr+/- and wild-type littermate mice were subjected to photothrombosis (PT) damage. Four weeks after PT damage, animals were tested on behavioral tasks, in vivo imaging was performed using T2-weighted MRI, and brain tissue was collected for histological analysis.Results: Mthfr+/- animals used their non-impaired forepaw more to explore the cylinder and had a larger damage volume compared to wild-type littermates. In brain tissue of Mthfr+/- mice methionine adenosyltransferase II alpha (MAT2A) protein levels were decreased within the damage hemisphere and increased levels in hypoxia-induced factor 1 alpha (HIF-1α) in non-damage hemisphere. There was an increased antioxidant response in the damage site as indicated by higher levels of nuclear factor erythroid 2-related factor 2 (Nrf2) in neurons and astrocytes and neuronal superoxide dismutase 2 (SOD2) levels.Conclusions: Our results suggest that Mthfr+/- mice are more vulnerable to PT-induced stroke damage through the regulation of the cellular response. The increased antioxidant response we observed may be compensatory to the damage amount.	0
Mitochondria are highly plastic and dynamic organelles that have graded responses to the changing cellular, environmental, and developmental cues. Mitochondria undergo constant mitochondrial fission and fusion, mitochondrial biogenesis, and mitophagy, which coordinately control mitochondrial morphology, quantity, quality, turnover, and inheritance. Mitophagy is a cellular process that selectively removes the aged and damaged mitochondria via the specific sequestration and engulfment of mitochondria for subsequent lysosomal degradation. It plays a pivotal role in reinstating cellular homeostasis in normal physiology and conditions of stress. Damaged mitochondria may either instigate innate immunity through the overproduction of ROS or the release of mtDNA, or trigger cell death through the release of cytochrome c and other apoptogenic factors when mitochondria damage is beyond repair. Distinct molecular machineries and signaling pathways are found to regulate these mitochondrial dynamics and behaviors. It is less clear how mitochondrial behaviors are coordinated at molecular levels. BCL2 family proteins interact within family members to regulate mitochondrial outer membrane permeabilization and apoptosis. They were also described as global regulators of mitochondrial homeostasis and mitochondrial fate through their interaction with distinct partners including Drp1, mitofusins, PGAM5, and even LC3 that involved mitochondrial dynamics and behaviors. In this review, we summarize recent findings on molecular pathways governing mitophagy and its coordination with other mitochondrial behaviors, which together determine cellular fate.	0
BACKGROUND:Adenine phosphoribosyltransferase (APRT) deficiency is a rare, hereditary cause of kidney stones and chronic kidney disease (CKD), characterized by 2,8-dihydroxyadenine (DHA) renal parenchymal crystal deposition. The aim of this study was to examine outcomes of kidney transplantation in APRT deficiency patients. METHODS:Included were 13 patients in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, 2 from Westmead Hospital in Sydney, Australia, and 2 from Necker Hospital in Paris, France. The CKD-EPI and CKiD equations were used to calculate glomerular filtration rate estimates (eGFR). Allograft survival was analyzed employing the Kaplan-Meier method. The Wilcoxon-Mann-Whitney test was used to compare alllograft outcomes by xanthine oxidoreductase (XOR) inhibitor treatment status at transplantation. RESULTS:Seventeen patients (9 females) received 22 kidney transplants. Age at first transplantation was 47.2 (14.9-67.0) years. Ten patients received XOR inhhibitor therapy pretransplant (11 allografts), while 8 patients did not receive such treatment prior to transplantation (11 allografts). Two-year allograft survival was 91% and 55% in the 2 groups, respectively (p=0.16). The median (range) eGFR at 2 years posttransplant was 61.3 (24.0-90.0) mL/min/1.73 m when XOR inhibitor therapy was initiated before transplantation and 16.2 (10.0-39.0) mL/min/1.73 m (p=0.009) when such treatment was not administered pretransplant. CONCLUSIONS:Kidney allograft outcomes are good in APRT deficiency patients beginning XOR inhibitor therapy pretransplant. Delay in such treatment is a major cause of premature graft loss in these patients. Increased awareness among clinicians is imperative, promoting early diagnosis of APRT deficiency and pharmacotherapy initiation before kidney transplantation.	0
Marden-Walker syndrome (MWS) is characterized by multiple joint contractures, a mask-like face with blepharophimosis, micrognathia, high-arched or cleft palate, low-set ears, decreased muscular bulk, arachnodactyly, and kyphoscoliosis. We report a case of MWS along with unusual manifestation of neurological, cardiovascular, and genitourinary system.	0
Klippel-Trenaunay syndrome (KTS) is a rare congenital disorder characterised by cutaneous capillary malformations, soft tissue and bone hypertrophy and venous varicosities. The coexistence of Chiari 1 malformation and an intracranial tumour has been rarely reported in the literature. Multisystem involvement of this syndrome mandates adequate preparation and planning, with meticulous conduct of anaesthesia to achieve favourable outcomes. We report a case of KTS syndrome with Chiari 1 malformation who had presented for craniotomy, and thereby discuss the challenges faced during anaesthetic management of these patients for major surgeries.	0
Perrault syndrome is a rare autosomal recessive disorder that affects both males and females. The syndrome causes deafness in males, however females display gonadal dysgenesis along with sensorineural hearing loss. Herein, we present a 27-year-old female patient who is deaf and mute along with primary amenorrhea. Hormonal assays revealed hypergonadotropic hypogonadism and the karyotype was 46 XX. Pelvic ultrasound described a hypoplastic uterus and streak ovaries. MRI of the spine showed degenerative discs and Tarlov cysts. Whole exome sequencing identified a LARS2 mutation and the patient was diagnosed with Perrault syndrome type four (PRLTS4).	0
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a type of mitochondrial disorder and stroke-like lesions are observed prominently in the brain magnetic resonance imaging. Those stroke-like lesions of MELAS patients are usually located in the posterior quadrants and do not correspond to typical vascular territories. This case illustrates that focal cerebellar infarction can be the sole initial sign of MELAS.	0
BACKGROUND:Congenital disorders of glycosylation (CDG) represent 1 of the largest groups of metabolic disorders with >130 subtypes identified to date. The majority of CDG subtypes are disorders of N-linked glycosylation, in which carbohydrate residues, namely, N-glycans, are posttranslationally linked to asparagine molecules in peptides. To improve the diagnostic capability for CDG, we developed and validated a plasma N-glycan assay using flow injection-electrospray ionization-quadrupole time-of-flight mass spectrometry. METHODS:After PNGase F digestion of plasma glycoproteins, N-glycans were linked to a quinolone using a transient amine group at the reducing end, isolated by a hydrophilic interaction chromatography column, and then identified by accurate mass and quantified using a stable isotope-labeled glycopeptide as the internal standard. RESULTS:This assay differed from other N-glycan profiling methods because it was free of any contamination from circulating free glycans and was semiquantitative. The low end of the detection range tested was at 63 nmol/L for disialo-biantennary N-glycan. The majority of N-glycans in normal plasma had <1% abundance. Abnormal N-glycan profiles from 19 patients with known diagnoses of 11 different CDG subtypes were generated, some of which had previously been reported to have normal N-linked protein glycosylation by carbohydrate-deficient transferrin analysis. CONCLUSIONS:The clinical specificity and sensitivity of N-glycan analysis was much improved with this method. Additional CDGs can be diagnosed that would be missed by carbohydrate-deficient transferrin analysis. The assay provides novel biomarkers with diagnostic and potentially therapeutic significance.	0
AIM:To describe the complex, overlapping phenotype of four Chinese patients with inherited retinal dystrophies (IRDs) who harbored two pathogenic genes simultaneously. METHODS:This retrospective study included 4 patients affected with IRDs. Medical and ophthalmic histories were obtained, and clinical examinations were performed. A specific Hereditary Eye Disease Enrichment Panel (HEDEP) based on exome capture technology was used for genetic screening. RESULTS:Four patients were identified to harbor disease-causing variants in two different genes. Patient retinitis pigmentosa (RP) 01-II:1 exhibited both classical ABCA4-induced Stargardt disease (STGD) 1 and USH2A-associated RP, patient RP02-III:2 exhibited both classical ABCA4-induced STGD1 and CDH23-associated RP, patient RP03-II:1 exhibited both USH2A-induced autosomal recessive retinitis pigmentosa (arRP) syndrome and SNRNP200-induced autosomal dominant retinitis pigmentosa (adRP), and patient RP04-II:2 exhibited USH2A-induced arRP syndrome and EYS-induced arRP at the same time. CONCLUSION:Our study demonstrates that genotype-phenotype correlations and comprehensive genetic screening is crucial for diagnosing IRDs and helping family planning for patients suffering from the disease.	0
Mucopolysaccharidosis Type VII (MPS7, also called β-glucuronidase deficiency or Sly syndrome; MIM 253220) is an extremely rare autosomal recessive lysosomal storage disease, caused by mutations in the GUSB gene. β-glucuronidase (GUSB) is a lysosomal hydrolase involved in the stepwise degradation of glucuronic acid-containing glycosaminoglycans (GAGs). Patients affected with MPS VII are not able to completely degrade glucuronic acid-containing GAGs, including chondroitin 4-sulfate, chondroitin 6-sulfate, dermatan sulfate, and heparan sulfate. The accumulation of these GAGs in lysosomes of various tissues leads to cellular and organ dysfunctions. Characteristic features of MPS VII include short stature, macrocephaly, hirsutism, coarse facies, hearing loss, cloudy cornea, short neck, valvular cardiac defects, hepatosplenomegaly, and dysostosis multiplex. Oral manifestations in patients affected with MPS VII have never been reported. Oral manifestations observed in three patients consist of wide root canal spaces, taurodontism, hyperplastic dental follicles, malposition of unerupted permanent molars, and failure of tooth eruption with malformed roots. The unusual skeletal features of the patients include maxillary hypoplasia, hypoplastic midface, long mandibular length, mandibular prognathism, hypoplastic and aplastic mandibular condyles, absence of the dens of the second cervical vertebra, and erosion of the cortex of the lower border of mandibles. Dogs affected with MPS VII had anterior and posterior open bite, maxillary hypoplasia, premolar crowding, and mandibular prognathism. Unlike patients with MPS VII, the dogs had unremarkable mandibular condyles. This is the first report of oral manifestations in patients affected with MPS VII.	0
Congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA) is a recently identified neurodevelopmental syndrome which has only 8 reported cases to date since its existence was proposed in 2007. We report a case of CHEDDA syndrome identified in a newborn female with congenital anomalies including Pierre-Robin sequence, arthrogryposis, craniosynostosis, cleft palate, and cardiac abnormalities who subsequently developed epilepsy at 1 month of life. Diagnosis was identified by whole-exome sequencing identifying mutations in a conserved histidine-rich motif within the gene Atrophin-1. Radiologic findings of cerebral atrophy, hypoplasia of the cerebellum, and thinning of the corpus callosum were identified in this patient, consistent with other reported cases. Given the rarity of this condition, we report this case and its findings to increase awareness of CHEDDA syndrome as a possible underlying diagnosis for neonates who present with this constellation of symptoms and radiologic findings.	0
Acquired hypoganglionosis (HG) is a rare enteric gastrointestinal neuromuscular disorder previously associated with chronic inflammation that can lead to constipation, ileus, and even death. There is little known about the pathophysiology of acquired hypoganglionosis, and it is unclear if medications are related to the development of the disease. Clozapine is an atypical antipsychotic used to treat refractory schizophrenia that is well known for its side effects including agranulocytosis and gastrointestinal dysmotility. This is an unusual case of acquired hypoganglionosis in a patient with anticholinergic toxicity on clozapine therapy.	0
Background:Atypical hemolytic uremic syndrome (aHUS) is an extremely rare, heterogeneous disease of uncontrolled activation of the alternative complement pathway that is difficult to diagnose. We have evaluated the Canadian patients enrolled in the Global aHUS Registry to provide a Canadian perspective regarding the diagnosis and management of aHUS and the specific challenges faced. Objective:To evaluate Canadian patients enrolled in the Global aHUS Registry to provide a Canadian perspective regarding the diagnosis and management of aHUS and the specific challenges faced. Methods:The Global aHUS Registry is an observational, noninterventional, multicenter study that has prospectively and retrospectively collected data from patients of all ages with an investigator-made clinical diagnosis of aHUS, irrespective of treatment. Patients of all ages with a clinical diagnosis of aHUS were eligible and invited for enrollment, and those with evidence of Shiga toxin-producing Escherichia coli infection, or with ADAMTS13 activity ≤10%, or a subsequent diagnosis of thrombotic thrombocytopenic purpura were excluded. Data were collected at enrollment and every 6 months thereafter and were analyzed descriptively for categorical and continuous variables. End-stage renal disease (ESRD)-free survival was evaluated using Kaplan-Meier estimates, and ESRD-associated risk factors of interest were assessed using Cox proportional hazards regression models. Patients were censored at start of eculizumab for any outcome measures. Results:A total of 37 Canadian patients were enrolled (15 pediatric and 22 adult patients) between February 2014 and May 2017; the median age at initial aHUS presentation was 25.9 (interquartile range = 6.7-51.7) years; 62.2% were female and 94.6% had no family history of aHUS. Over three-quarters of patients (78.4%) had no conclusive genetic or anti-complement factor H (CFH) antibody information available, and most patients (94%) had no reported precipitating factors prior to aHUS diagnosis. Nine patients (8 adults and 1 child) experienced ESRD prior to the study. After initial presentation, there appears to be a trend that children are less likely to experience ESRD than adults, with 5-year ESRD-free survival of 93 and 56% (P = .05) in children and adults, respectively. Enrolling physicians reported renal manifestations in all patients at initial presentation, and 68.4% of patients during the chronic phase (study entry ≥6 months after initial presentation). Likewise, extrarenal manifestations also occurred in more patients during the initial presenting phase than the chronic phase, particularly for gastrointestinal (61.1% vs 15.8%) and central nervous system sites (38.9% vs 5.3%). Fewer children than adults experienced gastrointestinal manifestations (50.0% vs 70.0%), but more children than adults experienced pulmonary manifestations (37.5% vs 10.0%). Conclusions:This evaluation provides insight into the diagnosis and management of aHUS in Canadian patients and the challenges faced. More genetic or anti-CFH antibody testing is needed to improve the diagnosis of aHUS, and the management of children and adults needs to consider several factors such as the risk of progression to ESRD is based on age (more likely in adults), and that the location of extrarenal manifestations differs in children and adults.	0
Pediatric cutaneous mastocytosis (CM) is mainly attributed to gain-of-function mutations in KIT in mast cells. On the other hand, growing evidence suggests that CM patients exist without KIT mutations. To date, the association between the KIT mutation status and clinical phenotype has not been elucidated in pediatric CM, especially in patients with wild-type KIT. Nevertheless, genetic analysis has yet to be performed with whole KIT sequence of mast cells in Japanese patients with pediatric CM. In the present study, 11 Japanese patients with pediatric CM were analyzed to determine whether they had KIT mutations in their skin, and their clinical phenotypes were observed. The approximate frequency of patients with KIT mutation and that of wild-type KIT was almost consistent with the European analysis. The distribution of overall macules was similar between the patients with and without KIT mutations.	0
Deficiency of interleukin-1 receptor antagonist (DIRA) is a rare life-threatening autoinflammatory disease caused by autosomal recessive mutations in IL1RN. DIRA presents clinically with early onset generalized pustulosis, multifocal osteomyelitis, and elevation of acute phase reactants. We evaluated and treated an antibiotic-unresponsive patient with presumed DIRA with recombinant IL-1Ra (anakinra). The patient developed anaphylaxis to anakinra and was subsequently desensitized.Genetic analysis of IL1RN was undertaken and treatment with anakinra was initiated.A 5-month-old Indian girl born to healthy non-consanguineous parents presented at the third week of life with irritability, sterile multifocal osteomyelitis including ribs and clavicles, a mild pustular rash, and elevated acute phase reactants. SNP array of the patient's genomic DNA revealed a previously unrecognized homozygous deletion of approximately 22.5 Kb. PCR and Sanger sequencing of the borders of the deleted area allowed identification of the breakpoints of the deletion, thus confirming a homozygous 22,216 bp deletion that spans the first four exons of IL1RN. Due to a clinical suspicion of DIRA, anakinra was initiated which resulted in an anaphylactic reaction that triggered desensitization with subsequent marked and sustained clinical and laboratory improvement.We report a novel DIRA-causing homozygous deletion affecting IL1RN in an Indian patient. The mutation likely is a founder mutation; the design of breakpoint-specific primers will enable genetic screening in Indian patients suspected of DIRA. The patient developed anaphylaxis to anakinra, was desensitized, and is in clinical remission on continued treatment.	0
We report two patients with Panayiotopoulos syndrome (PS) who developed encephalopathy related to status epilepticus during slow sleep (ESES) at the peak of their clinical course. Clinical charts and EEG data were reviewed. The patients exhibited nocturnal autonomic seizures and occipital EEG foci, the latter of which later evolved into multifocal EEG foci with synchronous frontopolar and occipital spikes (Fp-O EEG foci), and finally into continuous spikes-waves during sleep (CSWS; spike-wave index >85% based on whole-night sleep recording) at eight years and seven years of age, respectively. The occipital spikes always preceded frontopolar spikes by 30∼50 mseconds based on the analysis of CSWS. Neuropsychological ability, including IQ, deteriorated during the CSWS period in both patients. The autonomic seizures and focal to bilateral tonic-clonic seizures were initially resistant to antiepileptic drugs (AEDs), and occurred more than 10 times in both patients. However, the seizures and EEG findings gradually resolved, and AEDs were successfully terminated in both patients. PS can progress to ESES if the clinical course exhibits atypical evolution. The initial autonomic symptom of the seizures and interictal Fp-O EEG foci should be carefully monitored in patients with CSWS or ESES.	0
Background and objectives: Loeys-Dietz syndrome 3, also known as aneurysms--osteoarthritis syndrome, is an autosomal dominant genetic connective tissue disease caused by pathogenic variants in SMAD3, a transcription factor involved in TGF-β signaling. This disorder is characterized by early-onset osteoarthritis and arterial aneurysms. Common features include scoliosis, uvula abnormalities, striae, and velvety skin. Materials and Methods: The pathogenicity of a variant of uncertain significance in the SMAD3 gene was evaluated (variant c.220C > T) through personalized protein informatics and molecular studies. Results: The case of a 44-year-old male, who was originally presumed to have Marfan syndrome, is presented. An expanded gene panel determined the probable cause to be a variant in SMAD3, c.220C > T (p.R74W). His case was complicated by a history of stroke, but his phenotype was otherwise characteristic for Loeys-Dietz syndrome 3. Conclusion: This case emphasizes the importance of comprehensive genetic testing to evaluate patients for connective tissue disorders, as well as the potential benefit of utilizing a protein informatics platform for the assessment of variant pathogenicity.	0
Eosinophilic cystitis is a rare manifestation of hypereosinophilia and a cause of morbidity, including dysuria and hematuria. Although some cases can be attributed to infection or allergy, most cases are assessed to be idiopathic and treated with corticosteroids. However, hypereosinophilia can also be due to actionable clonal molecular alterations in the haematopoietic cells, similar to other myeloproliferative neoplasms. Common mutations associated with eosonophilic syndromes are of platelet-derived growth factor receptor α or β or c-kit, though other pathogenic mutations have been found by next generation sequencing. Determination of a specific mutation may therefore identify clonality and refine treatment of some cases. Here we review the molecular features of eosinophilic disorders. We also describe the use of a liquid biopsy of circulating cell-free DNA in the workup of a case of eosinophilic cystitis in which next generation sequencing of cell-free DNA showed a BRAF I463T mutation. In silico modeling supports the functional impact and potential clinical relevance of BRAF I463T.	0
This study shows accommodative accuracy and distance accommodation facility in myopic children do not play a role in myopia progression. In 144 subjects, the monocular distance accommodative facility (DAF) and continuous accommodative stimulus-response curves (ASRCs) were measured at the enrolment. Retrospective and prospective refraction with regard to the enrolment visit were obtained from the outpatient database system based on noncycloplegic subjective spherical equivalent refraction (SER). The rate of myopic progression at enrolment was the first derivative of the Gompertz function, which was fitted with each subject's longitudinal refractive error data, including at least four records of SER with an interval of more than 6 months between each visit. A mixed linear model for multilevel repeated-measures data was used to explore the associations between the rate of myopia progression and accommodative parameters. The mean rate of myopia progression at enrolment was -0.61 ± 0.31 D/y with a mean age of 12.27 ± 1.61 years. By adjusting for age and SER, it was shown that the myopic progression rate was not associated with the accommodative lag (F = 0.269, P = 0.604), accommodative lag area (F = 0.086, P = 0.354), slope of ASRC (F = 0.711, P = 0.399), and DAF (F = 0.619, P = 0.432).	0
PURPOSE:The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion in humans, with highly variable phenotypic expression. Whereas congenital heart defects, palatal anomalies, immunodeficiency, hypoparathyroidism, and neuropsychiatric conditions are observed in over 50% of patients with 22q11DS, a subset of patients present with additional "atypical" findings such as craniosynostosis and anorectal malformations. Recently, pathogenic variants in the CDC45 (Cell Division Cycle protein 45) gene, located within the LCR22A-LCR22B region of chromosome 22q11.2, were noted to be involved in the pathogenesis of craniosynostosis. METHODS:We performed next-generation sequencing on DNA from 15 patients with 22q11.2DS and atypical phenotypic features such as craniosynostosis, short stature, skeletal differences, and anorectal malformations. RESULTS:We identified four novel rare nonsynonymous variants in CDC45 in 5/15 patients with 22q11.2DS and craniosynostosis and/or other atypical findings. CONCLUSION:This study supports CDC45 as a causative gene in craniosynostosis, as well as a number of other anomalies. We suggest that this association results in a condition independent of Meier-Gorlin syndrome, perhaps representing a novel condition and/or a cause of features associated with Baller-Gerold syndrome. In addition, this work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to pathogenic variants on the nondeleted chromosome.	0
Teebi and Shaltout [1989: Am J Med Genet 33: 58-60] described a new syndrome of craniofacial anomalies, abnormal hair, camptodactyly, and caudal appendage in children born to a consanguineous couple. We report on a second family with the same pattern of anomalies occurring in a liveborn female and 3 spontaneously aborted fetuses, and include autopsy findings. As additional findings 2 of our cases had unilateral microphthalmia and kidney anomalies. Our observation confirms that this pattern of anomalies is a distinct syndrome with autosomal recessive inheritance; we suggest the synonym Teebi-Shaltout syndrome.	0
This is a case series of 3 children from a single family who developed symptomatic elemental mercury poisoning requiring hospitalization and chelation. The mercury exposure primarily occurred in the home but the mercury was also tracked to one of their schools requiring environmental cleanup at both the home and school. The clinical assessment and management, as well as public health investigation and response, are discussed. There are many lessons learned in this difficult, often delayed, diagnosis. Early recognition of this environmental toxic exposure is essential. Communication between the clinicians and public health officials played a critical role. Public education prevented panic. Proper environmental sampling, and assessment and management of those exposed, were a few of the many challenges faced in this complicated case series.	0
INTRODUCTION:Lymphangiomas are benign cystic tumors which arise from congenital malformations of the lymphatic system and are extremely rare in adulthood. We report a case of adult lymphangioma of the axilla that was removed after identifying the feeding lymphatic vessel using an indocyanine green (ICG) fluorescence imaging system. PRESENTATION OF CASE:A 35-year old woman presented to our hospital with a rapidly growing mass on her left axilla. She had been pregnant once before and delivered at 34 years of age. Mammography, ultrasonography, and magnetic resonance imaging revealed a tumor that consisted of multiple cysts, which led to a diagnosis of cystic lymphangioma. The ICG fluorescence imaging system indicated that only one lymphatic vessel, which was completely removed with ligation of the feeding lymphatic vessel, was flowing to the tumor. An immunohistological study demonstrated that the cystic endothelia were positive for podoplanin (D2-40), a marker of lymphatic vessels. DISCUSSION:In addition to congenital factors, mechanical obstruction to lymphatic vessels by an external force, such as trauma or congestion of the lymphatic flow caused by increasing venous pressure during pregnancy or delivery might lead to lymphangioma in adulthood. Therefore, our patient's pregnancy and delivery one year prior to discovery of the tumor seems to be the cause of her lymphangioma. CONCLUSION:Based on our findings, we recommend the complete excision to successfully treat adult-onset lymphangioma. We also suggest that visualization with ICG fluorescence imaging system is very useful for detecting the feeding lymphatic vessel and performing complete excision of the lymphangioma.	0
Mycobacterium gordonae is a slow growing, pigmented, nontuberculous mycobacterium. It is commonly associated with environmental contamination of clinical specimens, but it is also a recognized pathogen in immunocompromised hosts. We describe an immunocompetent child with a spontaneously occurring skin ulcer on the face caused by M. gordonae infection.	0
Congenital dyserythropoietic anemias are a rare group of inherited anemias characterized by ineffective erythropoiesis and distinct morphological abnormalities in the erythroblasts. Interferon alpha has been shown to be effective in type 1 congenital dyserythropoietic anemia but the optimal duration of therapy is undefined. We present here a 32-years-old female patient diagnosed with type 1 congenital dyserythropoietic anemia precipitated by pregnancy and treated successfully with a short course of interferon alpha resulting in a durable response. A literature search including PubMed database on previously published articles regarding congenital dyserythropoietic anemia type 1 patients treated with interferon is conducted.	0
In a national retrospective register study 112 patients with ocular albinism (OA) were identified, including 60 male patients with proven or presumed X-linked ocular albinism (XLOA). Based on the birth year cohorts 1960-1989, an XLOA point prevalence at birth of 1 in 60,000 live-born was calculated. We identified 14 XLOA families in the Danish population, and obtained DNA from affected persons in nine families. Mutation analysis of the OA1 gene demonstrated seven presumed pathogenic mutations in the nine families with XLOA: five single nucleotide substitutions predicting a change of conserved amino acids (G35D, L39R, D78V, W133R and E233K) when compared with the mouse OA1 homologue, one deletion leading to the skipping of exon 2, and one single nucleotide substitution expected to affect the 5' splice site of intron 2 were found. Subsequent genealogical investigations in the three families harbouring the same mutation disclosed that two of the three pedigrees belonged to the same family. All mutations predict crucial changes in the protein structure. Clinical examination failed to identify any phenotype-genotype pattern except a milder phenotype devoid of iris translucency in the patient with the 5'splice site mutation of intron 2.	1
We present two half siblings with significant short stature who proved a diagnostic challenge for several years. Radiological findings included subtle epiphyseal changes. The diagnosis was made through whole genome sequencing via the 100,000 genome project. A maternally inherited pathogenic heterozygous CDKN1C variant was found in the PCNA (proliferating cell nuclear antigen) domain. Mutations of the PCNA domain of the CDKN1C gene are known to be associated with IMAGe syndrome thus with adrenal disease, although neither affected patient in our case had evidence of adrenal dysfunction. This report supports the previously reported findings of Russell-Silver syndrome (RSS) like phenotype caused by this unusual mechanism (CDKN1C mutations in the PCNA domain), highlights subtle radiological features not described previously and the phenotypic variability between two affected siblings. Additionally it reminds clinicians of the importance of considering associated adrenal disease/diabetes mellitus for variants within the PCNA domain. Finally it confirms RSS-like disorders should be considered in patients who have epiphyseal or metaphyseal changes and short stature, since CDKN1C PCNA domain mutations can result in this phenotype.	0
Oculoauriculovertebral spectrum (OAVS) or Goldenhar syndrome is a wide spectrum of congenital anomalies that involves structures arising from the first and second branchial arches. It is characterized by a wide spectrum of symptoms and physical features. These abnormalities mainly involve the cheekbones, jaws, mouth, ears, eyes, or vertebrae. Other conditions with ear and/or radial involvement, such as, the Nager syndrome, Holt-Oram syndrome, Radial-renal syndrome, facioauriculoradial dysplasia, Fanconi anemia, and Vertebral, Anal atresia, Cardiac, Trachea, Esophageal, Renal, and Limb (VACTERL) association should be considered for differential diagnosis. Here we report a child who had facial asymmetry, microsomia, microtia, congenital facial nerve palsy, conductive hearing loss, skin tags, iris coloboma, and preaxial polydactyly.	0
Patients with Klippel-Feil syndrome may present with neurologic complaints such as neck pain, radiculopathy and gait instability. Here we describe surgical management of a patient with congenital fusion of the occipital-cervical region and also block circumferential fusion of dens to T3 with spinal cord compression. This report is the first of its kind with such extensive fusion. Our patient was a 56 year-old female, who presented with neck pain and tingling in all extremities. On exam, she had a short neck, prominent jaw with extremely limited range of motion in neck and features of myelopathy. CT showed fusion of the dens to T3 vertebrae. Patient underwent sub-occipital craniectomy, C1 laminectomy and Occiput to T5 posterior fixation and fusion with neurologic improvement.	0
BACKGROUND:Currently, serum concentrations of sitosterol above 10 μg/ml are considered to be one of the major diagnostic criteria of sitosterolemia. METHODS:We retrospectively investigated consecutive 206 Japanese dyslipidemic subjects (mean age = 46 yr, male n = 94) with the assessments of serum sitosterol level and the presence of ABCG5 or ABCG8 genetic mutations in our institute since 2009-2018. We divided the subjects into 3 groups based on the number of pathogenic mutations in ABCG5 or ABCG8 genes. We compared serum lipids and serum sitosterol among those groups, and tried to validate the cutoff value discriminating patients of sitosterolemia with double mutations from others. RESULTS:We identified 8 individuals with sitosterolemia with double mutations (affected), 26 individuals with a single mutation (carrier), and 172 individuals without any mutations (wildtype control). Serum sitosterol level of patients with sitosterolemia with double mutations (affected) exhibited significantly higher than those of any other groups (45.2. vs. 7.9 μg/ml, p = 2.5 × 10-2, 45.2 vs. 3.1 μg/ml, p = 1.8 × 10-2). Under these conditions, a cutoff value of sitosterol 10 μg/ml could discriminate the patients with sitosterolemia with double mutations in ABCG5 or ABCG8 gene from no mutation carrier (wildtype control) perfectly, although 6 heterozygous mutation carries exhibited sitosterol level greater than 10 μg/ml. Receiver-operating characteristic (ROC) analysis predicting double mutation status showed that the best cut-off value was 14.81 μg/ml. CONCLUSION:We suggest a cutoff value of sitosterol 15 μg/ml that shows higher positive predictive value than 10 μg/ml.	0
BACKGROUND:A considerable proportion of patients with angina-like symptoms in an emergency department have very low pretest probability for acute myocardial infarction (AMI). Numerous algorithms exist for the exclusion of AMI, usually including laboratory tests. We aimed to investigate whether patients with very low risk can safely be identified by ECG and clinical information without biomarker testing, contributing to saving time and costs. METHODS:Prospective diagnostic test accuracy study. We included all consecutive patients presenting with angina at the department of emergency medicine of a tertiary care hospital during a 1-year period. Using clinical information without biomarker testing and ECG, the "Mini-GRACE score," based on the well-established GRACE-score without using laboratory parameters was calculated. In a cohort design we compared the index test Mini-GRACE to AMI as reference standard in the final diagnosis using standard measures of diagnostic test accuracy. RESULTS:We included 2755 patients (44% female, age 44 ± 17 years). AMI was diagnosed in 103 (4%) patients, among those 44% with STEMI. Overall 2562 patients (93%) had a negative "Mini-GRACE," four (0.2%) of these patients had myocardial infarction, and this results in a sensitivity of 96.1% (95% CI 90.4%-98.9%), specificity 96.5% (95.7%-97.1%), positive predictive value 51.3% (46.3%-56.3%) and negative predictive value 99.8% (99.6%-99.9%). Model performance according to C statistic (0.90) and Brier score (0.0045) was excellent. In rule-out patients 30-day mortality was 0.3% and 1-year mortality was 0.8%. CONCLUSIONS:Patients with very low risk of AMI can be identified with high certainty using clinical information without biomarker testing and ECG. Cardiac biomarkers might be avoided in such cases, potentially leading to a significant cost reduction.	0
Joubert syndrome (JBTS) is a recessive neurodevelopmental ciliopathy characterized by a pathognomonic hindbrain malformation. All known JBTS genes encode proteins involved in the structure or function of primary cilia, ubiquitous antenna-like organelles essential for cellular signal transduction. Here, we used the recently identified JBTS-associated protein armadillo repeat motif-containing 9 (ARMC9) in tandem-affinity purification and yeast 2-hybrid screens to identify a ciliary module whose dysfunction underlies JBTS. In addition to the known JBTS-associated proteins CEP104 and CSPP1, we identified coiled-coil domain containing 66 (CCDC66) and TOG array regulator of axonemal microtubules 1 (TOGARAM1) as ARMC9 interaction partners. We found that TOGARAM1 variants cause JBTS and disrupt TOGARAM1 interaction with ARMC9. Using a combination of protein interaction analyses, characterization of patient-derived fibroblasts, and analysis of CRISPR/Cas9-engineered zebrafish and hTERT-RPE1 cells, we demonstrated that dysfunction of ARMC9 or TOGARAM1 resulted in short cilia with decreased axonemal acetylation and polyglutamylation, but relatively intact transition zone function. Aberrant serum-induced ciliary resorption and cold-induced depolymerization in ARMC9 and TOGARAM1 patient cell lines suggest a role for this new JBTS-associated protein module in ciliary stability.	0
Atrioventricular canal defect (AVCD) represents a quite common congenital heart defect (CHD) accounting for 7.4% of all cardiac malformations. AVCD is a very heterogeneous malformation that can occur as a phenotypical cardiac aspect in the context of different genetic syndromes but also as an isolated, non-syndromic cardiac defect. AVCD has also been described in several pedigrees suggesting a pattern of familiar recurrence. Targeted Next Generation Sequencing (NGS) techniques are proved to be a powerful tool to establish the molecular heterogeneity of AVCD.Given the complexity of cardiac embryology, it is not surprising that multiple genes deeply implicated in cardiogenesis have been described mutated in patients with AVCD. This review attempts to examine the recent advances in understanding the molecular basis of this complex CHD in the setting of genetic syndromes or in non-syndromic patients.	0
A 3-year-old 49,XXXXX girl, the seventeenth case in medical literature, is described. A typical characteristic of the syndrome is the round face with epicanthal folds, hypertelorism, broad flat nasal bridge, upward slant of the palpebral fissures, enlarged round mandible and pointed chin, somewhat resembling trisomy 21. The apparent stronger selection against 49,XXXXX aneuploidy versus the 49,XXXXY suggested by the much higher frequency of the latter is probably due to the more severe congenital cardiopathy which may be related to the number of inactivated X chromosomes.	0
Epidermolysis bullosa (EB) is characterized by blistering of the skin and mucosal erosions caused by hemidesmosomal abnormalities. EB is divided into 3 major subgroups depending on the particular location of tissue separation: EB simplex, dystrophic EB, and junctional EB. Junctional EB (JEB) can further be broken down into Herlitz, non-Herlitz, and JEB with pyloric atresia (Carmi syndrome) depending on genetic and histologic testing. When extensive, management of a patient with EB can be challenging due to not only cutaneous but also extracutaneous manifestations as well. Families and health care teams are often faced with difficult decisions in their infant's best interest. We report a case of a preterm neonate with Carmi syndrome and unique findings on immunofluorescence studies. The patient's course was complicated by multisystem involvement and ultimately death. A multidisciplinary approach was crucial in the light of diagnostic, therapeutic, and ethical challenges.	0
BACKGROUND:The Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders with several recognised types. Patients with a type of EDS have connective tissue abnormalities resulting in a varying degree of joint hypermobility, skin and vascular fragility and generalised tissue friability. Classical EDS (cEDS) typically occurs as a result of dominant pathogenic variants in COL5A1 or COL5A2. The cardinal features of cEDS are hyperextensible skin, atrophic scarring and joint hypermobility. Arterial complications are more characteristically a feature of vascular EDS although individual cases of arterial events in cEDS have been reported. METHODS:A cohort of 154 patients with a clinical diagnosis of cEDS from the UK was analysed. RESULTS:Seven patients (4.5%) with a diagnosis of cEDS (four pathogenic, one likely pathogenic and two variants of uncertain significance in COL5A1) who had experienced arterial complications were identified. Arterial complications mostly involved medium-sized vessels and also two abdominal aortic aneurysms. No unique clinical features were identified in this group of patients. CONCLUSION:There is a possible increased risk of arterial complications in patients with cEDS, although not well-defined. Clinicians need to be aware of this possibility when presented with a patient with an arterial complication and features of cEDS. Long-term management in families with cEDS and a vascular complication should be individually tailored to the patient's history and their family's history of vascular events.	0
BACKGROUND:The tumor microenvironment can be classified into immunologically active "inflamed" tumors and inactive "non-inflamed" tumors based on the infiltration of cytotoxic immune cells. Previous studies on liver cancer have reported a superior prognosis for inflamed tumors compared to non-inflamed tumors. However, liver cancer is highly heterogeneous immunologically and genetically, and a finer classification of the liver cancer microenvironment may improve our understanding of its immunological diversity and response to immune therapy. METHODS:We characterized the immune gene signatures of 234 primary liver cancers, mainly virus-related, from a Japanese population using RNA-Seq of tumors and matched non-tumorous hepatitis livers. We then compared them with the somatic alterations detected using the whole-genome sequencing. FINDINGS:Liver cancers expressed lower levels of immune marker genes than non-tumorous hepatitis livers, indicating immunosuppression in the tumor microenvironment. Several immunosuppression mechanisms functioned actively and mutually exclusively, resulting in four immune subclasses of liver cancer: tumor-associated macrophage (TAM), CTNNB1, cytolytic activity (CYT), and regulatory T cell (Treg). The CYT and Treg subclasses represented inflamed tumors, while the TAM and CTNNB1 subclasses represented non-inflamed tumors. The TAM subclass, which comprised 31% of liver cancers, showed a poor survival, expressed elevated levels of extracellular matrix genes, and was associated with somatic mutations of chromatin regulator ARID2. The results of cell line experiments suggested a functional link between ARID2 and chemokine production by liver cancer cells. INTERPRETATION:Primary liver cancer was classified into four subclasses based on mutually exclusive mechanisms for immunosuppression. This classification indicate the importance of immunosuppression mechanisms, such as TAM and Treg, as therapeutic targets for liver cancer. FUNDING:The Japan Agency for Medical Research and Development (AMED).	0
Central hypoventilation (CH) is a quite rare disorder caused by some congenital or acquired conditions. It is featured by increased arterial concentration of serum carbon dioxide related to an impairment of respiratory drive. Patients affected by CH need to be treated by mechanical ventilation in order to achieve appropriate ventilation and oxygenation both in sleep and wakefulness. In fact, in severe form of Congenital Central Hypoventilation Syndrome (CCHS) hypercarbia can be present even during the day. Positive pressure ventilation via tracheostomy is the first therapeutic option in this clinical condition, especially in congenital forms. Non-Invasive ventilation is a an option that must be reserved for more stable clinical situations and that requires careful monitoring over time.	0
Mesotherapy is sometimes responsible for dermal and subcutaneous infections caused by nontuberculous mycobacteria. Mycobacterium chelonae, M abscessus, and M fortuitum are usually involved. We present two cases of deep skin infections caused by M chelonae following mesotherapy. A review of the literature is included.	0
Nuclear receptor coactivators (NCOAs) and corepressors (NCORs) bind to nuclear hormone receptors in a ligand-dependent manner and mediate the transcriptional activation or repression of the downstream target genes in response to hormones, metabolites, xenobiotics, and drugs. NCOAs and NCORs are widely expressed in the mammalian brain. Studies using genetic animal models started to reveal pivotal roles of NCOAs/NCORs in the brain in regulating hormonal signaling, sexual behaviors, consummatory behaviors, exploratory and locomotor behaviors, moods, learning, and memory. Genetic variants of NCOAs or NCORs have begun to emerge from human patients with obesity, hormonal disruption, intellectual disability, or autism spectrum disorders. Here we review recent studies that shed light on the function of NCOAs and NCORs in the central nervous system.	0
OBJECTIVE:To report clinical and ancillary findings in a kindred with spinocerebellar ataxia 38 (SCA38). PATIENTS AND METHODS:Five family members spanning two generations developed gait ataxia and intermittent diplopia. On examination, a cerebellar syndrome accompanied by downbeat nystagmus and a saccadic head impulse test (HIT) were found. RESULTS:Whole-exome sequencing demonstrated a heterozygous variant in ELOVL5, c.779A > G (p.Tyr260Cys), in four tested patients. Intermittent concomitant esotropia and hypertropia caused transient diplopia in one individual each. Saccadic HIT responses were found in four subjects. Sensorineural hypoacusis was present in every case. Electrophysiological studies demonstrated a sensory neuronopathy in patients from the first generation, with prolonged disease duration. Baseline serum docosahexaenoic acid (DHA) percent was diminished in four individuals. Oral 26-week dietary DHA supplementation, 650 mg/day, raised serum DHA percent and induced a statistically significant reduction in Scale for the Assessment and Rating of Ataxia (SARA) total scores, and in stance and heel-shin slide item scores. CONCLUSION:The mentioned ELOVL5 variant segregated with disease in this kindred. Downbeat nystagmus, intermittent heterotropia causing transient diplopia, vestibular impairment demonstrated by abnormal HIT, and sensory neuronopathy were part of the clinical picture in this series. DHA supplementation raised serum DHA percent in cases with diminished levels, and induced a clinical amelioration and a statistically significant reduction in SARA scores in the study group. Further studies are needed to investigate the role of these findings in SCA38, and to determine the response to prolonged DHA supplementation.	0
Background: Endolymphatic sac tumor (ELST) is an extremely rare disease that does not have established clinical guidelines.Objective: To provide guidance for the diagnosis and management of ELSTs.Methods: We retrospectively reviewed the medical records of patients who were suspected to have a lesion in the location of endolymphatic sac. Seven patients were included. Histopathologic diagnosis confirmed five ELSTs and two other diseases.Results: All of the enrolled patients had hearing impairment. Facial palsy was found in four out of five patients with ELST, whereas none of the patients in other disease group showed facial palsy. CT and MRI findings were consistent with those in previous literatures; however, angiographic findings were not consistent with those previously reported. All patients underwent surgery. Recurrence occurred in two patients with ELST, although there was no visible remnant tumor after the operation. These patients were treated with stereotactic radiosurgery.Conclusion: Hearing impairment and facial palsy were representative symptoms of ELST. All ELSTs showed 'salt and pepper' signal in MRI T1-weighted images, and smaller tumors could have blood supply from AICA in the radiologic study. Complete surgical resection with optional stereotactic radiosurgery should be considered in ELST.HighlightsHearing impairment and facial weakness are remarkable symptoms of ELST compared to other diseases that invade the endolymphatic sac.All ELSTs showed 'salt and pepper' signal in MRI T1-weighted images.ELST less than 3 cm in diameter could have blood supply from AICA.A complete surgical excision with optional stereotactic radiosurgery is required.	0
The use of theragnostic radiopharmaceuticals in nuclear medicine has grown rapidly over the years to combine the diagnosis and therapy of tumors. In this review, we performed web-based and desktop literature research to investigate and explain the potential role of theragnostic imaging in pediatric oncology. We focused primarily on patients with aggressive malignancies such as neuroblastoma and brain tumors, to select patients with the highest chance of benefit from personalized therapy. Moreover, the most critical and groundbreaking applications of radioimmunotherapy in children's oncology were examined in this peculiar context. Preliminary results showed the potential feasibility of theragnostic imaging and radioimmunotherapy in pediatric oncology. They revealed advantages in the management of the disease, thereby allowing an intra-personal approach and adding new weapons to conventional therapies.	0
Extramedullary involvement of the gastrointestinal tract (GIT) is a rare entity as most patients present with lymphoreticular organ involvement. Its detection and diagnosis can be extremely challenging, as these patients would present with unusual clinical symptoms. We diagnosed and managed a patient with leukemic infiltration of GIT who presented with perianal pain. Prompt use of MRI played an important role in detecting underlying pathology, and effective tissue sampling confirmed the diagnosis. This resulted in overall successful management of the patient.	0
Background:The current study evaluates the validity and performance of the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for small intestinal adenocarcinoma patients. Methods:Surveillance, Epidemiology and End Results (SEER) database [2004-2015] was explored and AJCC 6th, 7th, and 8th versions were assigned for each patient. Through Kaplan-Meier estimates, overall survival analyses were conducted. Cox regression analysis (adjusted for age, race, gender, sub-site, grade and surgical treatment) was conducted for cancer-specific survival and additionally, pairwise hazard ratio comparisons were performed. Results:A total of 2,997 small intestinal adenocarcinoma patients were eligible and included in the analysis. Overall survival was compared according to the three AJCC staging systems. For the three versions, the P value for the trend in overall survival was significant (P<0.0001). Cancer-specific Cox regression hazard was calculated for the three staging systems. Pairwise hazard ratio comparisons between different AJCC 6th stages were conducted and all P values for comparisons were significant (P<0.0001). Pairwise hazard ratio comparisons between different AJCC 7th and 8th stages were also performed, and all comparisons were significant (P<0.05) except for stage IIB vs. IIIA. C-statistic (using death from small intestinal adenocarcinoma as the dependent variable) for AJCC 6th staging system was: 0.645 [standard error (SE): 0.011; 95% CI: 0.623-0.668]; for c-statistic for AJCC 7th staging system was 0.658 (SE: 0.011; 95% CI: 0.637-0.680); while c-statistic for AJCC 8th staging system was 0.660 (SE: 0.011; 95% CI: 0.638-0.682). Multivariate analysis of factors affecting cancer-specific survival suggested that older age (P=0.005), higher lymph node ratio (P<0.0001) and duodenal localization of the primary are associated with worse outcomes (P=0.008). Conclusions:There is no evidence that AJCC 8th system provided better prognostic characterization compared to previous AJCC staging systems for small intestinal adenocarcinoma. Subsite-specific staging paradigms should be explored in future editions of the staging system.	0
The Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder caused by pathogenic variants in the ALDH3A2 gene, which codes for fatty aldehyde dehydrogenase (FALDH). FALDH prevents the accumulation of toxic fatty aldehydes by converting them into fatty acids. Pathogenic ALDH3A2 variants cause symptoms such as ichthyosis, spasticity, intellectual disability, and a wide range of less common clinical features. Interpreting patient-to-patient variability is often complicated by inconsistent reporting and negatively impacts on establishing robust criteria to measure the success of SLS treatments. Thus, with this study, patient-centered literature data was merged into a concise genotype-based, open-access database (www.LOVD.nl/ALDH3A2). One hundred and seventy eight individuals with 90 unique SLS-causing variants were included with phenotypic data being available for more than 90%. While the three lead symptoms did occur in almost all cases, more heterogeneity was observed for other frequent clinical manifestations of SLS. However, a stringent genotype-phenotype correlation analysis was hampered by the considerable variability in reporting phenotypic features. Consequently, we compiled a set of recommendations of how to generate comprehensive SLS patient descriptions in the future. This will be of benefit on multiple levels, for example, in clinical diagnosis, basic research, and the development of novel treatment options for SLS.	0
Heterozygous missense or in-frame insertion/deletion mutations in complement 1 subunits C1r and C1s cause periodontal Ehlers-Danlos Syndrome (pEDS), a specific EDS subtype characterized by early severe periodontal destruction and connective tissue abnormalities like easy bruising, pretibial haemosiderotic plaques, and joint hypermobility. We report extensive functional studies of 16 C1R variants associated with pEDS by in-vitro overexpression studies in HEK293T cells followed by western blot, size exclusion chromatography and surface plasmon resonance analyses. Patient-derived skin fibroblasts were analyzed by western blot and Enzyme-linked Immunosorbent Assay (ELISA). Overexpression of C1R variants in HEK293T cells revealed that none of the pEDS variants was integrated into the C1 complex but cause extracellular presence of catalytic C1r/C1s activities. Variants showed domain-specific abnormalities of intracellular processing and secretion with preservation of serine protease function in the supernatant. In contrast to C1r wild type, and with the exception of a C1R missense variant disabling a C1q binding site, pEDS variants had different impact on the cell: retention of C1r fragments inside the cell, secretion of aggregates, or a new C1r cleavage site. Overexpression of C1R variants in HEK293T as well as western blot analyses of patient fibroblasts showed decreased levels of secreted C1r. Importantly, all available patient fibroblasts exhibited activated C1s and activation of externally added C4 in the supernatant while control cell lines secreted proenzyme C1s and showed no increase in C4 activation. The central elements in the pathogenesis of pEDS seem to be the intracellular activation of C1r and/or C1s, and extracellular presence of activated C1s that independently of microbial triggers can activate the classical complement cascade.	0
Inpatients are threatened by global malnutrition, but also by specific micronutrient (i.e., trace element and vitamins) deficiencies that frequently are overseen in the differential diagnosis of major organ dysfunctions. Some of them are related to specific geographic risks (iodine, iron, selenium, zinc, vitamin A), while others are pathology related, and finally many are associated with specific feeding patterns, including low dose enteral feeding. Among the pathologies in which laboratory blood investigations should include a micronutrient outwork, anemia is in the front line, followed by obesity with bariatric surgery, chronic liver disease, kidney disease, inflammatory bowel disease, cardiomyopathies and heart failure. The micronutrients at the highest risk are iron, zinc, thiamine, vitamin B12 and vitamin C. Admission to hospital has been linked with an additional risk of malnutrition-feeding below 1500 kcal/day was frequent and has been associated with a structural additional risk of insufficient micronutrient intake to cover basal needs. Although not evidence based, systematic administration of liberal thiamine doses upon admission, and daily complementation of inpatients' food and enteral feeding solutions with multi-micronutrient tablets might be considered.	0
Lysosomal storage diseases (LSDs) are a group of about 50 inborn errors of metabolism characterized by the lysosomal accumulation of partially or non-degraded molecules due to mutations in proteins involved in the degradation of macromolecules, transport, lysosomal biogenesis or modulators of lysosomal environment. Significant advances have been achieved in the diagnosis, management, and treatment of LSDs patients. In terms of approved therapies, these include enzyme replacement therapy (ERT), substrate reduction therapy, hematopoietic stem cell transplantation, and pharmacological chaperone therapy. In this review, we summarize the Colombian experience in LSDs thorough the evidence published. We identified 113 articles published between 1995 and 2019 that included Colombian researchers or physicians, and which were mainly focused in Mucopolysaccharidoses, Pompe disease, Gaucher disease, Fabry disease, and Tay-Sachs and Sandhoff diseases. Most of these articles focused on basic research, clinical cases, and mutation reports. Noteworthy, implementation of the enzyme assay in dried blood samples, led to a 5-fold increase in the identification of LSD patients, suggesting that these disorders still remain undiagnosed in the country. We consider that the information presented in this review will contribute to the knowledge of a broad spectrum of LSDs in Colombia and will also contribute to the development of public policies and the identification of research opportunities.	0
BACKGROUND & AIMS:Treatments are needed for gastroparesis; antagonists of tachykinin receptor 1 (TACR1, also called NK1R) can reduce symptoms of nausea and vomiting. We investigated the safety and efficacy of tradipitant, an antagonist of NK1R, in patients with idiopathic or diabetic gastroparesis. METHODS:We performed a double-blind trial of 152 adults with gastroparesis at 47 sites in the United States from November 2016 through December 2018. Participants were randomly assigned to groups given oral tradipitant (85 mg, n=77) or placebo (n=75) twice daily for 4 weeks. Symptoms were assessed by a daily symptom dairy, gastroparesis cardinal symptom index scores, and other patient-reported questionnaires. The primary outcome from the intent to treat analysis was change from baseline to week 4 in average nausea severity, measured by the gastroparesis core symptom daily diary. RESULTS:Patients receiving tradipitant had a significant decrease in nausea score (reduction of 1.2) at week 4 compared with placebo (reduction of 0.7) (P=.0099), and a significant increase in of nausea-free days at week 4 (28.8% increase on tradipitant vs 15.0% on placebo; P=.0160). Patients with nausea and vomiting at baseline (n=101) had an even greater decrease in nausea in when given tradipitant (reduction of 1.4) compared with those given placebo (reduction of 0.4) (P<.0001), as well as an increase in nausea-free days at week 4 (32.3% improvement on tradipitant vs 7.6% on placebo; P=.0003). Average nausea score was 1 or less at week 4 in 32.9% of patients given tradipitant compared with 11.8% of patients given placebo (P=.0013). A greater than 1-point improvement in gastroparesis cardinal symptom index score was observed in 46.6% of patients given tradipitant compared with 23.5% of patients given placebo (P=.0053). CONCLUSIONS:Tradipitant resulted in statistically and clinically meaningful improvements in nausea and reduced vomiting, compared with placebo, in patients with idiopathic or diabetic gastroparesis.	0
Maturity-onset diabetes of the young is frequently misdiagnosed as type 1 or type 2 diabetes. A correct diagnosis of MODY is important for determining treatment, but can only be confirmed by molecular genetic testing. We aimed to compare the regional distribution of confirmed MODY cases in the UK and to estimate the minimum prevalence.UK referrals for genetic testing in 2,072 probands and 1,280 relatives between 1996 and 2009 were examined by region, country and test result. Referral rate and prevalence were calculated using UK Census 2001 figures.MODY was confirmed in 1,177 (35%) patients, with HNF1A (52%) and GCK mutations (32%) being most frequent in probands confirmed with MODY. There was considerable regional variation in proband referral rates (from <20 per million in Wales and Northern Ireland to >50 per million for South West England and Scotland) and patients diagnosed with MODY (5.3 per million in Northern Ireland, 48.9 per million in South West England). Referral rates and confirmed cases were highly correlated (r = 0.96, p < 0.0001). The minimum prevalence of MODY was estimated to be 108 cases per million.Assuming this minimal prevalence throughout the UK then >80% of MODY is not diagnosed by molecular testing. The marked regional variation in the prevalence of confirmed MODY directly results from differences in referral rates. This could reflect variation in awareness of MODY or unequal access to genetic testing. Increased referral for diagnostic testing is required if the majority of MODY patients are to have the genetic diagnosis necessary for optimal treatment.	1
Usher syndrome type 1B is a combined deaf-blindness condition caused by mutations in the MYO7A gene. Loss of functional myosin VIIa in the retinal pigment epithelia (RPE) and/or photoreceptors leads to blindness. We evaluated the impact of subretinally delivered UshStat, a recombinant EIAV-based lentiviral vector expressing human MYO7A, on photoreceptor function in the shaker1 mouse model for Usher type 1B that lacks a functional Myo7A gene. Subretinal injections of EIAV-CMV-GFP, EIAV-RK-GFP (photoreceptor specific), EIAV-CMV-MYO7A (UshStat) or EIAV-CMV-Null (control) vectors were performed in shaker1 mice. GFP and myosin VIIa expression was evaluated histologically. Photoreceptor function in EIAV-CMV-MYO7A treated eyes was determined by evaluating α-transducin translocation in photoreceptors in response to low light intensity levels, and protection from light induced photoreceptor degeneration was measured. The safety and tolerability of subretinally delivered UshStat was evaluated in macaques. Expression of GFP and myosin VIIa was confirmed in the RPE and photoreceptors in shaker1 mice following subretinal delivery of the EIAV-CMV-GFP/MYO7A vectors. The EIAV-CMV-MYO7A vector protected the shaker1 mouse photoreceptors from acute and chronic intensity light damage, indicated by a significant reduction in photoreceptor cell loss, and restoration of the α-transducin translocation threshold in the photoreceptors. Safety studies in the macaques demonstrated that subretinal delivery of UshStat is safe and well-tolerated. Subretinal delivery of EIAV-CMV-MYO7A (UshStat) rescues photoreceptor phenotypes in the shaker1 mouse. In addition, subretinally delivered UshStat is safe and well-tolerated in macaque safety studies These data support the clinical development of UshStat to treat Usher type 1B syndrome.	0
Treating patients with hemophilia and inhibitors is often problematic. The presence of inhibitors negatively impacts the effectiveness of treatment to achieve hemostasis especially in patients with hemophilia B, owing mainly to allergic reactions to factor IX (FIX) concentrates and the low success rate of immune tolerance therapy. A 9-month-old boy had intracranial hemorrhage and was diagnosed with hemophilia B. After replacement therapy, he developed inhibitors and an allergic reaction to FIX. Prophylactic therapy was initiated with recombinant activated factor VII (rFVIIa) and later switched to pdFVIIa/factor X (FX; 120 μg/kg as the FVII dose, every other day) because of a recurrence of intracranial hemorrhage. Since then, he remained well without life-threatening bleeding for more than 2 years. Our case suggests that pdFVIIa/FX may be useful for prophylactic therapy in hemophilia B complicated by inhibitors and allergic reaction to FIX concentrates.	0
Despite extensive investigation, the causes and nature of developmental prosopagnosia (DP)-a severe face identification impairment in the absence of acquired brain injury-remain poorly understood. Drawing on previous work showing that individuals identified as being neurotypical (NT) show robust individual differences in where they fixate on faces, and recognize faces best when the faces are presented at this location, we defined and tested four novel hypotheses for how atypical face-looking behavior and/or retinotopic face encoding could impair face recognition in DP: (a) fixating regions of poor information, (b) inconsistent saccadic targeting, (c) weak retinotopic tuning, and (d) fixating locations not matched to the individual's own face tuning. We found no support for the first three hypotheses, with NTs and DPs consistently fixating similar locations and showing similar retinotopic tuning of their face perception performance. However, in testing the fourth hypothesis, we found preliminary evidence for two distinct phenotypes of DP: (a) Subjects characterized by impaired face memory, typical face perception, and a preference to look high on the face, and (b) Subjects characterized by profound impairments to both face memory and perception and a preference to look very low on the face. Further, while all NTs and upper-looking DPs performed best when faces were presented near their preferred fixation location, this was not true for lower-looking DPs. These results suggest that face recognition deficits in a substantial proportion of people with DP may arise not from aberrant face gaze or compromised retinotopic tuning, but from the suboptimal matching of gaze to tuning.	0
The innate immune system is involved in the pathophysiology of systemic autoinflammatory diseases (SAIDs), an enlarging group of disorders caused by dysregulated production of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α, in which autoreactive T-lymphocytes and autoantibodies are indeed absent. A widely deranged innate immunity leads to overactivity of proinflammatory cytokines and subsequent multisite inflammatory symptoms depicting various conditions, such as hereditary periodic fevers, granulomatous disorders, and pyogenic diseases, collectively described in this review. Further research should enhance our understanding of the genetics behind SAIDs, unearth triggers of inflammatory attacks, and result in improvement for their diagnosis and treatment.	0
Hereditary mucoepithelial dysplasia is a rare desmosomal gap junction abnormality known to produce keratitis and cataracts in addition to multiple systemic problems. It generally carries a poor visual prognosis due to corneal scarring, amblyopia, and side effects of the treatment. The authors present a sporadic case of hereditary mucoepithelial dysplasia with an unusually good visual outcome and suggest that timely and appropriate intervention can improve the visual prognosis of this rare disorder.	0
Nearly all pediatric murmurs are heard in normal hearts and are not due to cardiac disorders. These murmurs usually can be classified by distinctive features and distinguished from organic murmurs by skillful clinical examination. This article reviews the various types of innocent heart murmurs in children, discusses their differential diagnoses, and suggests an approach to sorting out pediatric murmurs.	0
Background:Although it is well known that most choroid plexus cysts (CPCs) are asymptomatic, previous studies have reported that they can infrequently cause progressive hydrocephalus along with their increasing sizes. Among those cases, some patients needed cyst fenestration or cerebrospinal fluid (CSF) diversion to recover neurological deterioration. Meanwhile, some CPCs revealed spontaneous resolution, and in rare cases, they developed re-accumulation. Some reports have described series of radiological findings about their changes in location. Case Description:We present a 47-year-old male with CPC manifesting obstructive hydrocephalus. Radiological findings of the lateral and the third ventricles changed along with their different obstructive points, leading to their own symptoms. Because the patient's symptoms were not resolved completely, he underwent endoscopic fenestration for the cyst at the third ventricle. We could perform near-total resection, resulting in recovery of normal CSF flow. Postoperatively, the size of the ventricles decreased, with histological confirmation of a CPC. His symptoms resolved clearly without any complications. Conclusions:It seems quite unusual that shift of the CPC location in the ventricle systems could induce not only different types of hydrocephalus but also their own symptoms. We need to consider that the location of CPCs might change when patients present with fluctuating symptoms over time.	0
Case summary:A 3.5-year-old domestic shorthair cat presented with a 6 month history of weight loss and polyphagia. Clinical examination revealed a markedly reduced body condition score (2/9) and a quiet demeanour. Laboratory abnormalities comprised a mild non-regenerative anaemia, stress leukogram, hypoproteinaemia due to hypoalbuminaemia, azotaemia, hypokalaemia, total hypocalcaemia and sub-maximally concentrated urine (specific gravity 1.020). Abdominal ultrasonography revealed marked thickening of the gastric mucosa within the fundus, body and pylorus; the most dorsal portion of the fundus was spared. The thickened mucosa contained multiple small, anechoic cyst-like structures. The gastric submucosa, muscularis and serosa appeared normal. Histopathology, performed on a full-thickness gastric biopsy, revealed mucosal hypertrophy and markedly dilated gastric glands in areas; not all gastric glands were affected, with some appearing normal or atrophic. Focal interstitial fibrosis was present in some areas. The findings of hypoproteinaemia, gastric ultrasonographic changes and histopathology results share several similarities to those reported with Ménétrier disease. Relevance and novel information:Ménétrier disease is a rare condition of the stomach in humans. A similar condition, giant hypertrophic gastritis (or Ménétrier-like disease), has also been described rarely in dogs. To our knowledge, Ménétrier-like disease has not been previously described cats. This case shares features of Ménétrier-like disease, raising the suspicion of a similar aetiopathogenesis.	0
This study includes a retrospective analysis of the diagnosis and treatment of a case of severe pneumonia from fulminant psittacosis with multiple organ failure. Next-generation sequencing (NGS) of the pathogen was conducted. The purpose of this study was to summarize the clinical, laboratory, and imaging characteristics of the case and to improve understanding of the value of NGS in the diagnosis of severe community-acquired pneumonia (CAP). Fulminant psittacosis can be manifested as severe pneumonia with rapid progression, acute respiratory distress syndrome, sepsis, and multiple organ failure. Imaging shows unilateral lung consolidation, which is difficult to differentiate from CAP caused by common pathogens. The NGS technology can early detect rare pathogens, thus reducing unnecessary use of antibiotics and shortening the course of the disease.	0
We aimed to understand the etiology behind the abnormal craniofacial contour and other clinical presentations in a number of children with Robinow syndrome. Seven children with Robinow syndrome were enrolled in this study (autosomal recessive caused by homozygous mutations in the ROR2 gene on chromosome 9q22, and the autosomal dominant caused by heterozygous mutation in the WNT5A gene on chromosome 3p14). In the autosomal recessive (AR) group, the main clinical presentations were intellectual, disability, poor schooling achievement, episodes of headache/migraine, and poor fine motor coordinative skills, in addition to massive restrictions of the spine biomechanics causing effectively the development of kyposcoliosis and frequent bouts of respiratory infections. Three-dimensional reconstruction computed tomography scan revealed early closure of the metopic and the squamosal sutures of skull bones. Massive spinal malsegmentation and unsegmented spinal bar were noted in the AR group. In addition to severe mesomelia and camptodactyly, in the autosomal dominant (AD) group, no craniosynostosis but few Wormian bones and the spine showed limited malsegemetation, and no mesomelia or camptodactyly have been noted. We wish to stress that little information is available in the literature regarding the exact pathology of the cranial bones, axial, and appendicular malformations in correlation with the variable clinical presentations in patients with the 2 types of Robinow syndrome.	0
BACKGROUND:Mitochondrial DNA depletion syndromes (MDS) are clinically and phenotypically heterogeneous disorders resulting from nuclear gene mutations. The affected individuals represent a notable reduction in mitochondrial DNA (mtDNA) content, which leads to malfunction of the components of the respiratory chain. MDS is classified according to the type of affected tissue; the most common type is hepatocerebral form, which is attributed to mutations in nuclear genes such as DGUOK and MPV17. These two genes encode mitochondrial proteins and play major roles in mtDNA synthesis. CASE PRESENTATION:In this investigation patients in three families affected by hepatocerebral form of MDS who were initially diagnosed with tyrosinemia underwent full clinical evaluation. Furthermore, the causative mutations were identified using next generation sequencing and were subsequently validated using sanger sequencing. The effect of the mutations on the gene expression was also studied using real-time PCR. A pathogenic heterozygous frameshift deletion mutation in DGUOK gene was identified in parents of two affected patients (c.706-707 + 2 del: p.k236 fs) presenting with jaundice, impaired fetal growth, low-birth weight, and failure to thrive who died at the age of 3 and 6 months in family I. Moreover, a novel splice site mutation in MPV17 gene (c.461 + 1G > C) was identified in a patient with jaundice, muscle weakness, and failure to thrive who died due to hepatic failure at the age of 4 months. A 5-month-old infant presenting with jaundice, dark urine, poor sucking, and feeding problems was also identified to have another novel mutation in MPV17 gene leading to stop gain mutation (c.277C > T: p.(Gln93*)). CONCLUSIONS:These patients had overlapping clinical features with tyrosinemia. MDS should be considered a differential diagnosis in patients presenting with signs and symptoms of tyrosinemia.	0
OBJECTIVE: To examine the occurrence of arthrogryposis multiplex congenita (AMC) in Europe and to identify possible risk factors. STUDY DESIGN: Retrospective population-based epidemiological study using EUROCAT congenital anomaly registries. The study population included all cases of AMC (based on WHO ICD-9 or ICD-10 codes) that were livebirths (LB), fetal deaths (FD) from 20 weeks gestation and underwent termination of pregnancy for fetal anomaly (TOPFA), 1980-2006. RESULTS: Among 8.9 million births covered by 24 EUROCAT congenital anomaly registries, 757 AMC cases were reported. This gives a prevalence of 8.5 per 100,000. Five hundred and four (67%) AMC cases were LB, 199 (26%) cases were TOPFA, and FD occurred in 54 (7%) cases. First week survival status was known for 381 of the 504 LB (76%), of whom 87 (23%) died within the first week of life. Perinatal mortality associated with AMC was 32%. Two hundred and eighty-two (37%) cases had isolated AMC, 90 (12%) had additional syndrome or chromosomal anomalies and 385 (51%) had other major malformations. The same or similar anomaly was reported in 13% of siblings and in 12% of the mother's own family background. Information on prenatal testing was available for 521 cases of which 360 tested positive for a congenital anomaly, representing a sensitivity of 69%. Information on maternal illness before and during pregnancy and medication use in the first trimester was available for approximately a third of the mothers, of whom the vast majority reported no maternal illness or medication use. CONCLUSION: AMC is a rare occurrence, with a reported prevalence of 1:12,000. In this study, while information on potential risk factors such as maternal disease or maternal use of drugs was limited, they did not appear to be associated with the occurrence of AMC. AMC was lethal in a third of cases, either in utero or during the first week of life, although this may not be solely attributed to AMC as most cases had additional malformations.	1
Background:Primary coenzyme Q10 (CoQ10) deficiencies are clinically and genetically heterogeneous group of disorders associated with defects of genes involved in the CoQ10 biosynthesis pathway. COQ7-associated CoQ10 deficiency is very rare and only two cases have been reported. Methods and Results:We report a patient with encephalo-myo-nephro-cardiopathy, persistent lactic acidosis, and basal ganglia lesions resulting in early infantile death. Using whole exome sequencing, we identified compound heterozygous variants in the COQ7 gene consisting of a deletion insertion resulting in frameshift [c.599_600delinsTAATGCATC, p.(Lys200Ilefs*56)] and a missense substitution [c.319C>T, p.(Arg107Trp), NM_016138.4]. Skin fibroblast studies showed decreased combined complex II + III activity and reduction in CoQ10 level. Conclusion:This third patient presenting with lethal encephalo-myo-nephro-cardiopathy represents the severe end of this ultra-rare mitochondrial disease caused by biallelic COQ7 mutations. The response to CoQ10 supplement is poor and alternative treatment strategies should be developed for a more effective management of this disorder.	0
The comorbidity between multiple sclerosis (MS) and progressive familial intrahepatic cholestasis type-3 (PFIC3) has never been described yet. ABCB4 gene encodes the multidrug resistant protein 3 (MDR3) and its mutations induce PFIC3 as well as intrahepatic cholestasis of pregnancy (ICP) and drug-induced liver injury (DILI). We describe the case of a 32-year-old female with MS and PFIC3 who was effectively treated with natalizumab and ursodeoxycholic acid (UCDA), in contrast to glatiramer acetate, dimethylfumarate, and IFNb1a associated with DILI. Our findings clarify the pharmacodynamics of MS therapies and suggest natalizumab plus UDCA as the effective treatment of PFIC3/MS phenotype, unlike the others that should be avoided.	0
Sphingosine-1-phosphate (S1P) lyase is a vitamin B6-dependent enzyme that degrades sphingosine-1-phosphate in the final step of sphingolipid metabolism. In 2017, a new inherited disorder was described caused by mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). This condition is referred to as SPL insufficiency syndrome (SPLIS) or alternatively as nephrotic syndrome type 14 (NPHS14). Patients with SPLIS exhibit lymphopenia, nephrosis, adrenal insufficiency, and/or neurological defects. No targeted therapy for SPLIS has been reported. Vitamin B6 supplementation has therapeutic activity in some genetic diseases involving B6-dependent enzymes, a finding ascribed largely to the vitamin's chaperone function. We investigated whether B6 supplementation might have activity in SPLIS patients. We retrospectively monitored responses of disease biomarkers in patients supplemented with B6 and measured SPL activity and sphingolipids in B6-treated patient-derived fibroblasts. In two patients, disease biomarkers responded to B6 supplementation. S1P abundance and activity levels increased and sphingolipids decreased in response to B6. One responsive patient is homozygous for an SPL R222Q variant present in almost 30% of SPLIS patients. Molecular modeling suggests the variant distorts the dimer interface which could be overcome by cofactor supplementation. We demonstrate the first potential targeted therapy for SPLIS and suggest that 30% of SPLIS patients might respond to cofactor supplementation.	0
BACKGROUND:Barakat syndrome is an autosomal dominant disorder characterized by the triad of hypoparathyroidism, sensorineural deafness, and renal anomalies and is caused by mutations in GATA3 gene. SLC34A3 is the cause gene of hypophosphatemic rickets with hypercalciuria, and heterozygous carriers may have milder clinical symptoms. The aim of this study was to identify the underlying genetic cause of a patient who initially presented with renal failure, hypercalciuria, kidney stone, and bilateral sensorineural deafness. METHODS:A 6-year-old boy with complex clinical presentations was investigated. Comprehensive medical evaluations were performed including auditory function tests, endocrine function tests, metabolic studies, and imaging examinations. Molecular diagnoses were analyzed by trio whole-exome sequencing. RESULTS:One novel de novo deleterious variant (c. 324del) of the GATA3 gene was identified in the patient. The patient can be diagnosed with Barakat syndrome. In addition, one novel variant (c. 589A>G) of the SLC34A3 gene was detected, which was inherited from the father. This heterozygous variant can explain the hypercalciuria and kidney stone that occurred in both the patient and his father. CONCLUSION:This study provides a special case which is phenotype-driven dual diagnoses, and the two novel variants can parsimoniously explain the complex clinical presentations of this patient.	0
The incidence of West syndrome (WS) was determined by a search of reports of electroencephalograms (EEG) recorded in 1998 and 1999 in all public hospitals in Singapore. Amongst records of patients born in 1998, nine were found with EEG features of hypsarrhythmia or modified hypsarrhythmia with onset of seizures between January 1,1998 and December 31, 1999. The medical records of these patients were reviewed. The population of children born in 1998 was 43,664. In 1998 and 1999, 67% of all hospital admissions for patients 2 years or younger in Singapore were in public hospitals. The cumulative incidence of WS in Singapore corrected for the percentage of hospital admissions to public hospitals was 3.1/10,000 live births. The corrected cumulative incidences in Chinese, Malays and Indians were 2.7, 3.1 and 3.3 per 10,000, respectively. Three cases were idiopathic; three were due to congenital structural lesions of the brain; one each had periventricular leucomalacia, intracranial hemorrhage and severe intrauterine growth retardation. None of the patients were normal at follow up. The three patients with idiopathic WS had mild global developmental delay and the other six cases had cerebral palsy and severe mental retardation. With the best modern medical treatment, possibly only two of the nine cases of WS may have been prevented.	1
Porphyrias, is a general term for a group of metabolic diseases that are genetic in nature. In each specific porphyria the activity of specific enzymes in the heme biosynthetic pathway is defective and leads to accumulation of pathway intermediates. Phenotypically, each disease leads to either neurologic and/or photocutaneous symptoms based on the metabolic intermediate that accumulates. In each porphyria the distinct patterns of these substances in plasma, erythrocytes, urine and feces are the basis for diagnostically defining the metabolic defect underlying the clinical observations. Porphyrias may also be classified as either erythropoietic or hepatic, depending on the principal site of accumulation of pathway intermediates. The erythropoietic porphyrias are congenital erythropoietic porphyria (CEP), and erythropoietic protoporphyria (EPP). The acute hepatic porphyrias include ALA dehydratase deficiency porphyria, acute intermittent porphyria (AIP), hereditary coproporphyria (HCP) and variegate porphyria (VP). Porphyria cutanea tarda (PCT) is the only porphyria that has both genetic and/or environmental factors that lead to reduced activity of uroporphyrinogen decarboxylase in the liver. Each of the 8 enzymes in the heme biosynthetic pathway have been associated with a specific porphyria (Table 1). Mutations affecting the erythroid form of ALA synthase (ALAS2) are most commonly associated with X-linked sideroblastic anemia, however, gain-of-function mutations of ALAS2 have also been associated with a variant form of EPP. This overview does not describe the full clinical spectrum of the porphyrias, but is meant to be an overview of the biochemical steps that are required to make heme in both erythroid and non-erythroid cells.	0
Tolosa-Hunt syndrome is a rare disorder characterized by severe peri-orbital headache and ophthalmoplegia resulting from pseudotumour in the cavernous sinus compressing structures within it, namely cranial nerves III, IV, and VI and the superior divisions of cranial nerve V. We report the case of a 47 year old female who presented with painless left unilateral ptosis and complete external ophthalmoplegia. Magnetic Resonance Imaging (MRI) identified an enhancing heterogeneous mass filling the left cavernous sinus, following the course of the oculomotor nerve. After 2 weeks symptoms and signs resolved and there was a parallel resolution of the MRI findings, without the administration of corticosteroids. As far as we are aware this is one of the first reports of Tolosa-Hunt syndrome variant, with painless neurological involvement confined solely to the oculomotor nerve, and with complete resolution without pharmacological intervention.	0
Idiopathic granulomatous mastitis (IGM) rarely occurs with erythema nodosum (EN) as a systemic finding. However, the impact of their coexistence on disease severity and response to steroids has not been investigated yet. Patients diagnosed with IGM between September 2014 and October 2018 were divided into two groups according to the presence or absence of EN during the first admission retrospectively. The IGM was more severe in patients with EN as it was presented more often as bilateral and diffuse involvement of the breast. Findings of mastitis did not resolve with steroids in 50% of this group. Repetitive excisions and mastectomy with reconstructions were required to control the disease. Coexistence of EN and IGM was found to be related to bilateral and aggressive involvement, which could be associated with insufficient response to steroids. Associated patients should be informed in terms of the aggressive course, and surgery can be highlighted as a first-line treatment.	0
OBJECTIVE: To present prenatal diagnosis and molecular genetic analyses of mosaic trisomy 9. MATERIALS, METHODS AND RESULTS: A 35-year-old woman, gravida 3, para 1, underwent amniocentesis at 17 weeks of gestation because of her advanced maternal age. Amniocentesis revealed a karyotype of 47,XX,+9[3]/46,XX[6]. Repeat amniocentesis at 19 weeks of gestation revealed a karyotype of 47,XX,+9[6]/46,XX[19]. At 22 weeks of gestation, she was referred to a tertiary medical center for genetic counseling, and amniocentesis revealed a karyotype of 47,XX,+9[2]/46,XX[22]. Array comparative genomic hybridization analysis of uncultured amniocytes revealed no genomic imbalance in chromosome 9. However, interphase fluorescence in situ hybridization analysis of uncultured amniocytes showed that nine (18%) of 50 cells were trisomic for chromosome 9. Polymorphic DNA marker analyses also revealed a diallelic pattern with unequal biparental inheritance of chromosome 9 and a dosage ratio of 1:18 (paternal allele:maternal allele) in the uncultured amniocytes and a dosage ratio of 1:36 in the cultured amniocytes, indicating that the euploid cell line had maternal uniparental isodisomy for chromosome 9. Level II ultrasound demonstrated bilateral ventriculomegaly. The pregnancy was subsequently terminated, and a malformed fetus was delivered. Postnatal cytogenetic and polymorphic DNA marker analyses of the fetal and extraembryonic tissues confirmed the prenatal diagnosis. CONCLUSION: Mosaic trisomy 9 carries a high risk of fetal abnormalities warranting detailed sonographic investigation of congenital malformations. Mosaic trisomy 9 can be associated with maternal uniparental disomy for chromosome 9 in euploid cell lines. Array comparative genomic hybridization is limited for the detection of low-level mosaicism.	0
Juvenile myelomonocytic leukemia (JMML) is a pediatric myelodysplastic/myeloproliferative neoplasm overlap syndrome with sustained peripheral blood monocytosis, aggressive features, and poor outcomes. In >90% of cases JMML is driven by germline or somatic mutations involving the canonical RAS pathway (PTPN11, NRAS, CBL, KRAS and NF1), with somatic mutations/alterations in RAS pathway genes (second hit), SETBP1, ASXL1 and JAK3 resulting in disease progression. While spontaneous regression has been seen in germline PTPN11 and CBL mutant JMML, in most patients, allogeneic stem cell transplant is the only curative modality. JMML shares several phenotypic features with its adult counterpart proliferative, chronic myelomonocytic leukemia (pCMML). pCMML largely occurs due to RAS pathway mutations that occur in the context of age related clonal hematopoiesis (TET2, SRSF2, ASXL1), while JMML is a bona fide RASopathy, with additional somatic mutations, including in epigenetic regulators genes resulting in disease progression.	0
We report on the case of a 12-year-old girl, who presented with an ovarian germ cell tumor and cytopenia (anemia and thrombocytopenia) as an associated paraneoplastic syndrome, which gradually regressed after the tumor's removal. This report adds to the previously described paraneoplastic syndromes potentially associated with ovarian germ cell tumor.	0
The ridged skin of the palms and soles has several unique features: (i) presence of dermatoglyphics created by alternating ridges and grooves forming a unique pattern, (ii) presence of the highest density of eccrine sweat glands and absence of pilosebaceous units, and (iii) differential expression of keratins compared to the glabrous skin. These features explain the preferential localization of palmoplantar keratoderma (PPK) and several of its characteristic clinical features. PPK develops as a compensatory hyperproliferation of the epidermis and excessive production of stratum corneum in response to altered cornification of the palmoplantar skin due to mutations in the genes encoding several of the proteins involved in it. PPK can manifest as diffuse, focal, striate, or punctate forms per se or as a feature of several dermatological or systemic diseases. There is a wide genetic and phenotypic heterogeneity in hereditary PPK, due to which reaching an accurate diagnosis only on the basis of clinical features may be sometimes challenging for the clinicians in the absence of molecular studies. Nevertheless, recognizing the clinical patterns of keratoderma, extent of involvement, degree of mutilation, and associated appendageal and systemic involvement may help in delineating different forms. Molecular studies, despite high cost, are imperative for accurate classification, recognizing clinical patterns in resource poor settings is important for appropriate diagnosis, genetic counseling, and management. This review intends to develop a practical approach for clinical diagnosis of different types of hereditary PPK with reasonable accuracy.	0
The megakaryocyte/erythroid Transient Myeloproliferative Disorder (TMD) in newborns with Down Syndrome (DS) occurs when N-terminal truncating mutations of the hemopoietic transcription factor GATA1, that produce GATA1short protein (GATA1s), are acquired early in development. Prior work has shown that murine GATA1s, by itself, causes a transient yolk sac myeloproliferative disorder. However, it is unclear where in the hemopoietic cellular hierarchy GATA1s exerts its effects to produce this myeloproliferative state. Here, through a detailed examination of hemopoiesis from murine GATA1s ES cells and GATA1s embryos we define defects in erythroid and megakaryocytic differentiation that occur relatively late in hemopoiesis. GATA1s causes an arrest late in erythroid differentiation in vivo, and even more profoundly in ES-cell derived cultures, with a marked reduction of Ter-119 cells and reduced erythroid gene expression. In megakaryopoiesis, GATA1s causes a differentiation delay at a specific stage, with accumulation of immature, kit-expressing CD41hi megakaryocytic cells. In this specific megakaryocytic compartment, there are increased numbers of GATA1s cells in S-phase of cell cycle and reduced number of apoptotic cells compared to GATA1 cells in the same cell compartment. There is also a delay in maturation of these immature GATA1s megakaryocytic lineage cells compared to GATA1 cells at the same stage of differentiation. Finally, even when GATA1s megakaryocytic cells mature, they mature aberrantly with altered megakaryocyte-specific gene expression and activity of the mature megakaryocyte enzyme, acetylcholinesterase. These studies pinpoint the hemopoietic compartment where GATA1s megakaryocyte myeloproliferation occurs, defining where molecular studies should now be focussed to understand the oncogenic action of GATA1s.	0
Chronic progressive external ophthalmoplegia (CPEO) is one of the most common mitochondrial disorders. It is characterized by bilateral, slowly progressing loss of extraocular muscle mobility, orbicularis oculi weakness, ptosis, and other neuromuscular symptoms, which are caused by the accumulation of multiple mitochondrial DNA (mtDNA) deletions. Many mutations in different nuclear genes, such as POLG1, POLG2, ANT1, and others, have been described as causing autosomal-inherited CPEO with multiple mtDNA deletions. Most causative genes are involved in mtDNA replication impairment. Here, we report a family with CPEO-like symptoms characterized by multiple muscle mtDNA deletions, ptosis, diabetes, hearing loss, mental retardation, and emotional instability. We performed genetic analyses to identify nuclear gene mutations in the family. DNA from the proband was analyzed by whole-exome sequencing. In addition to possible pathogenic mutations, rare variants were prioritized for gene-functional phenotype interpretation. We found possible pathogenetic mutations in the PRIMPOL, BRCA1, CPT2, and GJB2 genes, and functional polymorphisms in the CARD8, and MEFV genes. Multiple functional polymorphisms and possible pathogenic mutations may contribute to mitochondrial-disease-like phenotypes in a composite manner.	0
coats disease is an uncommon form of retinal telangiectasis. Published case series mostly originate from tertiary referrals centres and may provide a skewed view of disease severity. We conducted a prospective population-based study of Coats disease in the United Kingdom to ascertain the incidence and provide a more representative picture.the study was conducted through the British Ophthalmological Surveillance Unit. This first paper reports the features at presentation; gender, mode of presentation, visual acuity, anterior and posterior segment findings, amount of retinal exudation, and disease staging.a total of 55 eligible cases of Coats disease were identified giving an estimated population incidence of 0.09 per 100.000 of the population. All cases were unilateral and 85% were male. Mean age at presentation was 146 months (median 96 months). The mean age of diagnosis was markedly different with differing mechanisms of presentation. Cases presenting with leucocoria or strabismus presented early whereas subjective visual loss presented much later. A large proportion of eyes (44%) were blind at diagnosis. The great majority of eyes (71%) had 6 or fewer clock hours of retinal exudation. More severe forms/stages of Coats disease were more common in the youngest patients.compared with published studies of Coats disease, we have found milder disease severity at presentation. This is most likely because of the population-based nature of our study reflecting the full disease spectrum. A large proportion of eyes with Coats have poor visual acuity and disease severity is worse in younger patients.	1
Glucagonoma, a rare neuroendocrine tumor of the pancreas, which is often misdiagnosed because of non-characteristic clinical manifestations. In addition, the treatment has not been well established for this disease so far. We here report a case of glucagonoma previous misdiagnosed as recurrent erythema. In this case, necrolytic migratory erythema was the main clinical manifestation, and he received surgical resection after admission although with liver metastasis. Postoperative pathological results showed that the heterogeneity of proliferative index in primary (Ki-67: 5~10%) and metastatic (Ki-67: 25~30%) tumors were obviously observed. One month postoperatively, abdominal CT and MRI showed multiple liver metastasis (type III) again. Interestingly, the skin rash was obviously improved after treatment with somatostatin combined with chemotherapy (octreotide, temozolomide and capecitabine). Subsequently, the patient received transarterial embolization (TAE). Up to now, no progression was noted for liver metastasis. Due to its rarity, clinical diagnosis is challenging; thus, further understanding of the disease by clinicians is helpful for early diagnosis and treatment, so as to improve the prognosis of patients.	0
CNS germinomas have an excellent prognosis with radiation therapy alone. However, in children, volume and dose of CNS radiation are associated with neurocognitive and neuroendocrine sequelae. Our objective was to determine long-term outcomes of our cohort who received chemotherapy and reduced radiation. This retrospective cohort study analyzed treatment and outcome of intracranial germinoma patients consecutively treated at Sick Kids, Toronto, Canada, from January 2000 to December 2013. 24 children (13 male, 11 female; median age 13.36 years) were identified. Median follow up was 61 months (range 1-144 months). Tumor location was suprasellar (n = 9), bifocal (8), pineal (6), and basal ganglia (1). Three children showed dissemination on imaging. 2/24 had only elevated serum human chorionic gonadotropin, 3/24 only elevated lumbar cerebrospinal fluid (CSF) hCG, and 2/24 had both elevated serum and lumbar CSF hCG. 23/24 children completed treatment and received multi-agent chemotherapy followed by either ventricular radiation (2340-2400 cGy) (n = 9), ventricular radiation + boost (1600 cGy) (n = 8), whole brain (2340 cGy) (n = 3), focal (4000 cGy) (n = 2) or craniospinal radiation (2340 cGy) (n = 1). Five-year progression free and overall survival was 96 and 100 % respectively. 8/24 patients with ventricular radiation ± boost (2340/4000 cGy) displayed stable full scale intelligence quotient over a mean interval of 3 years following radiation, but showed declined processing speed. In this limited experience, excellent 5-year overall survival rates were achieved with chemotherapy followed by reduced whole ventricular radiation even if ventricular radiation was delivered without boost.	0
BACKGROUND:Greig cephalopolysyndactyly syndrome is a rare multiple congenital anomaly syndrome characterized by the triad of polysyndactyly (preaxial or mixed preaxial and postaxial), macrocephaly, and ocular hypertelorism. Little is known about the neuropsychological phenotype and the developmental features of this syndrome. CASE PRESENTATION:We describe the clinical features of a 7-year-old Italian white boy affected by Greig cephalopolysyndactyly syndrome in comorbidity with autism spectrum disorder and the case of his 45-year-old white father, carrying the same point deletion (c.3677del) in the GLI3 gene and showing subclinical autistic symptoms. We performed a neuropsychiatric assessment of cognitive, adaptive, socio-communicative, and behavioral skills of the child. Concurrently, the father underwent his first psychiatric evaluation of cognitive skills and autistic symptoms. CONCLUSIONS:We report the first clinical description of an association between autistic symptoms and Greig cephalopolysyndactyly syndrome in two members of the same family with the same genetic point deletion. Further research is required in order to draw an accurate conclusion regarding the association between Greig cephalopolysyndactyly syndrome and autism.	0
A cross-sectional study was performed in the Netherlands to define the clinical characteristics of the various subtypes within the broad and heterogeneous entity of limb girdle muscular dystrophy (LGMD). An attempt was made to include all known cases of LGMD in the Netherlands. Out of the reported 200 patients, 105 who fulfilled strictly defined criteria were included. Forty-nine patients, mostly suffering from dystrophinopathies and facioscapulohumeral muscular dystrophy, appeared to be misdiagnosed. Thirty-four cases were sporadic, 42 patients came from autosomal recessive and 29 from autosomal dominant families. The estimated prevalence of LGMD in the Netherlands was at least 8.1 x 10(-6). The clinical features of the autosomal recessive and sporadic cases were indistinguishable from those of the autosomal dominant patients, although calf hypertrophy was seen more frequently, and the course of the disease was more severe in autosomal recessive and sporadic cases. The pectoralis, iliopsoas and gluteal muscles, hip adductors and hamstrings were the most affected muscles. Distal muscle involvement occurred late in the course of the disease. Facial weakness was a rare phenomenon. The severity of the clinical picture was correlated with a deteriorating lung function. All autosomal dominantly inherited cases showed a mild course, although in two families life-expectancy was reduced because of concomitant cardiac involvement.	1
Jaundice caused by intraluminal bile duct obstruction in infancy is rare but may occur in association with biliary sludge, inspissated bile plugs, or gall stones. Nine boys (aged 2 weeks-6 months) with obstruction caused by inspissated bile (n = 7) or gall stones (n = 2) are presented. Haemolysis was not a factor in the patients' histories but an abnormal entry of the common bile duct into the third part of the duodenum was demonstrated in two and one had an asymptomatic haemangioma. Ultrasonography was the most useful investigation. Surgical removal of the bile duct obstruction was necessary in eight cases and included biliary tract drainage in six and cholecystectomy for changes of cholecystitis in four. Obstruction resolved spontaneously in one infant after percutaneous cholangiography. There were no postoperative complications.	0
BACKGROUND:Coinfection with avian leukosis virus subgroup J (ALV-J) and reticuloendotheliosis virus (REV) is common in chickens, and the molecular mechanism of the synergistic pathogenic effects of the coinfection is not clear. Exosomes have been identified as new players in the pathogenesis of retroviruses. The different functions of exosomes depend on their cargo components. OBJECTIVES:The aim of this study was to investigate the function of co-regulation differentially expressed proteins in exosomes on coinfection of ALV-J and REV. METHODS:Here, viral replication in CEF cells infected with ALV-J, REV or both was detected by immunofluorescence microscopy. Then, we analyzed the exosomes isolated from supernatants of chicken embryo fibroblast (CEF) cells single infected and coinfected with ALV-J and REV by mass spectrometry. KEGG pathway enrichment analyzed the co-regulation differentially expressed proteins in exosomes. Next, we silenced and overexpressed tripartite motif containing 62 (TRIM62) to evaluate the effects of TRIM62 on viral replication and the expression levels of NCK-association proteins 1 (NCKAP1) and actin-related 2/3 complex subunit 5 (ARPC5) determined by quantitative reverse transcription polymerase chain reaction. RESULTS:The results showed that coinfection of ALV-J and REV promoted the replication of each other. Thirty proteins, including TRIM62, NCK-association proteins 1 (NCKAP1, also known as Nap125), and Arp2/3-5, ARPC5, were identified. NCKAP1 and ARPC5 were involved in the actin cytoskeleton pathway. TRIM62 negatively regulated viral replication and that the inhibition of REV was more significant than that on ALV-J in CEF cells coinfected with TRIM62. In addition, TRIM62 decreased the expression of NCKAP1 and increased the expression of ARPC5 in coinfected CEF cells. CONCLUSIONS:Collectively, our results indicated that coinfection with ALV-J and REV competitively promoted each other's replication, the actin cytoskeleton played an important role in the coinfection mechanism, and TRIM62 regulated the actin cytoskeleton.	0
Mucopolysaccharidoses (MPS) are rare genetic lysosomal storage disorders caused by a deficiency of enzymes that catalyze the breakdown of glycosaminoglycans. MPS-III, also known as Sanfilippo syndrome, is caused by a deficiency of one of four enzymes that catalyze heparan sulfate proteoglycan degradation. MPS-IIIA results from a deficiency of heparan sulfatase. The natural history of MPS-IIIA is marked by progressive neurodegeneration. A nine-year-old boy with developmental delay presented with progressive three-month functional decline culminating in emergency department presentation for lethargy and immobility. Laboratory workup revealed hepatic and renal failure, coagulopathy, pancytopenia, hypernatremia, and uremia requiring emergent dialysis. He developed hyperkalemia during the second month of hospitalization, the workup of which led to a diagnosis of hyperreninemic hypoaldosteronism with normal cortisol. Blood chemistry consistent with renal hypoperfusion prompted exploration of adrenal ischemia, specifically affecting the zona glomerulosa and sparing the zona fasciculata, to explain low aldosterone with normal cortisol. Heparan sulfate (HS) normally acts as a storage site for basic fibroblast growth factor (bFGF), a paracrine stimulator of aldosterone, but accumulates in MPS-IIIA due to deficiency of heparan sulfatase. If bFGF is sequestered in HS deposits in MPS-III, then paracrine signaling is reduced, accounting for the state of hypoaldosteronism. To our knowledge, this is the first reported case of hyperreninemic hypoaldosteronism caused by an MPS disorder.	0
CDK10/CycM is a protein kinase deficient in STAR (toe Syndactyly, Telecanthus and Anogenital and Renal malformations) syndrome, which results from mutations in the X-linked FAM58A gene encoding Cyclin M. The biological functions of CDK10/CycM and etiology of STAR syndrome are poorly understood. Here, we report that deficiency of CDK10/Cyclin M promotes assembly and elongation of primary cilia. We establish that this reflects a key role for CDK10/Cyclin M in regulation of actin network organization, which is known to govern ciliogenesis. In an unbiased screen, we identified the RhoA-associated kinase PKN2 as a CDK10/CycM phosphorylation substrate. We establish that PKN2 is a bone fide regulator of ciliogenesis, acting in a similar manner to CDK10/CycM. We discovered that CDK10/Cyclin M binds and phosphorylates PKN2 on threonines 121 and 124, within PKN2's core RhoA-binding domain. Furthermore, we demonstrate that deficiencies in CDK10/CycM or PKN2, or expression of a non-phosphorylatable version of PKN2, destabilize both the RhoA protein and the actin network architecture. Importantly, we established that ectopic expression of RhoA is sufficient to override the induction of ciliogenesis resulting from CDK10/CycM knockdown, indicating that RhoA regulation is critical for CDK10/CycM's negative effect on ciliogenesis. Finally, we show that kidney sections from a STAR patient display dilated renal tubules and abnormal, elongated cilia. Altogether, these results reveal CDK10/CycM as a key regulator of actin dynamics and a suppressor of ciliogenesis through phosphorylation of PKN2 and promotion of RhoA signaling. Moreover, they suggest that STAR syndrome is a ciliopathy.	0
BACKGROUND:Complement activation plays a substantial role in the pathogenesis of primary membranous nephropathy (pMN). C5b-9, C3c, MBL, and factor B have been documented in the subepithelial immune deposits. However, the changing of complement activation products in circulation and urine is not clear. METHODS:We measured the circulating and urinary levels of C1q, MBL, C4d, Bb, properdin, C3a, C5a, and sC5b-9, in 134 patients with biopsy-proven pMN, by enzyme-linked immunosorbent assay. All the plasma values were corrected by eGFR and all the urinary values were corrected by urinary creatinine and urinary protein excretion. Anti-PLA2R antibodies were measured in all patients. RESULTS:The plasma complement activation products were elevated both in the patients with and without anti-PLA2R antibodies. C3a levels were remarkably increased in the circulation and urine, much higher than the elevated levels of C5a. C5b-9 was in normal range in plasma, but significantly higher in urine. The urinary C5a had a positive correlation with anti-PLA2R antibody levels and urinary protein. The plasma level of C4d was elevated, but C1q and MBL were comparable to healthy controls. Positive correlations were observed between plasma C4d/MBL and urinary protein, only in the patients with positive anti-PLA2R antibodies but not in those without. The plasma level of Bb was elevated and had positive correlation with urinary protein only in the patients without anti-PLA2R antibodies. CONCLUSION:Complement activation products were remarkable increased in pMN and may serve as sensitive biomarkers of disease activity. The complement may be activated through lectin pathway with the existence of anti-PLA2R antibodies, while through alternative pathway in the absence of antibody.	0
BACKGROUND:Spondyloepiphyseal dysplasia congenita (SEDC) is an extremely rare inherited chondrodysplasia characterized by abnormal epiphyses, short stature, and flattened vertebral bodies. We investigate the phenotypes and the disease-associated variants of SEDC in two unrelated Chinese families. METHODS:We identified disease-associated variants in two nonconsanguineous families with SEDC using targeted next-generation sequencing and confirmed the variants using Sanger sequencing. We investigated the phenotypes of the patients, including clinical manifestations, bone turnover biomarkers, bone mineral density and skeletal radiographic features. RESULTS:Two probands were diagnosed as SEDC according to the phenotypes of disproportionately short-trunk stature, kyphosis, lumbar lordosis and adduction deformity of hips. Radiographs revealed kyphosis and lumbar lordosis, flattened vertebral bodies, compressed femoral heads and shortening of the femurs. Bone mineral density of the probands was lower than that of age- and gender-matched normal children, but bone turnover biomarker levels were within normal range. Two novel heterozygous missense variants (NM_001844.5: c.1654 G>A, NP_001835.3: p.Gly552Arg; NM_001844.5: c.3518G>T, NP_001835.3: p.Gly1173Val) in collagen type II alpha 1 chain (COL2A1) were detected in the two families, which would impair the formation of stable triple-helical type II collagen. CONCLUSIONS:We identified two novel disease-associated variants in COL2A1, which led to severe SEDC. Our findings expanded the gene variant spectrum and phenotypic spectrum of extremely rare type II collagenopathies.	0
The implantation of left ventricular assist devices (LVADs) is often complicated by arrhythmias and right ventricular failure (RVF). Today, the pump speed is titrated to optimize device support using single observations of interventricular septum (IVS) positioning with echocardiographic ultrasound (US). The study demonstrates the applicability of three integrated US transducers in the LVAD cannula to monitor IVS positioning continuously and robustly in real time. In vitro, the predictor of the IVS shift shows an overall prediction error for all volume states of less than 20% and provides a continuous assessment for 99% of cases in four differently sized heart phantoms. The prediction of IVS shift depending on the cannula position is robust for azimuthal and polar deviations of ± 20° and ± 8°, respectively. This intracardiac US concept results in a viable predictor for IVS positioning and represents a promising approach to continuously monitor the IVS and ventricular loading in LVAD patients. Graphical abstract.	0
We describe additional phenotypic features in a boy and his mother. Both manifested the phenotypic/genotypic correlation of oto-palato-digital syndrome type II. The mother's radiographs showed wormian bones of the skull, and paranasal bossing, her feet showed bilateral fusion of the cuboid with the lateral cuneiform bone with subsequent development of metatarsus varus associated with dysplastic distal phalanges.	0
Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder in which the adrenal cortex fails to respond appropriately to stimulation by adrenocorticotropic hormone (ACTH) to produce cortisol. The disease is characterized in laboratory testing by glucocorticoid deficiency and markedly elevated ACTH levels. FGD may present in infancy or early childhood with symptoms related to low cortisol and high ACTH, such as hyperpigmentation, severe hypoglycemia, failure to thrive and recurrent infections. Mutations in the MC2R accessory protein (MRAP) cause FGD types 2, which accounts for approximately 15-20% of FGD cases. Here, we report a female neonate of Chinese Han origin, who presented with noted hyperpigmentation at birth. Laboratory investigations revealed hypocortisolaemia (cortisol < 1.0 μg/dl) and elevated plasma ACTH (1051 pg/ml). She responded to hydrocortisone treatment. Genetic studies confirmed the diagnosis showing homozygous deletion (c. 106 + 1delG) in intron 3 of MRAP gene, a mutation already reported as responsible for FDG type 2. This mutation can cause complete lack of ACTH response thus explaining the early presentation in this case. Her parents and maternal grandmother were heterozygous for the same mutation. To our knowledge, this is the first Chinese Han patient reported with FGD type 2 due to a known MRAP mutation.	0
Truncating variants of the MAGEL2 gene, one of the protein-coding genes within the Prader-Willi syndrome (PWS) critical region on chromosome 15q11, cause Schaaf-Yang syndrome (SYS)-a neurodevelopmental disorder that shares several clinical features with PWS. The current study sought to characterize the neurobehavioral phenotype of SYS in a sample of 9 patients with molecularly-confirmed SYS. Participants received an assessment of developmental/intellectual functioning, adaptive functioning, autism symptomatology, and behavioral/emotional functioning. Compared to individuals with PWS, patients with SYS manifested more severe cognitive deficits, no obsessions or compulsions, and increased rates of autism spectrum disorder.	0
Ehlers-Danlos syndrome (EDS) comprises a series of rare hereditary connective tissue diseases characterized by musculoskeletal, skin, and cardiovascular involvements. EDS may be associated with physical as well as psychological pain that can lead to psychiatric problems. EDS imposes substantial psychological burden on patients, and recent large-scale studies have suggested that patients with EDS have a higher risk of mood disorders than the general population. To the best of our knowledge, we describe, for the first time, the cases of two Japanese patients with EDS complicated with mood disorders who secondarily developed transvestism that was judged strongly related to early stressful situations through childhood and adolescence. The first case was of a man in his mid-30s and the second of a woman in her late 20s. We report on detailed psychosocial data to further discuss the medical management and genetic counseling of such infrequent but challenging conditions. Physicians are advised to be aware of various potential psychological and psychiatric issues that may accompany EDS.	0
Our objective is to review the initial presentation, evolution, progression, final stage, and images in the follow up of an adult patient who presented an uncommon peroxisomal disease (1/20,000 males) that occurred by ABCD1 gene mutation in the Xq28 chromosome; to bring forward the imaging features (which nowadays is the most useful and accessible diagnostic tool) and clinical presentation of adrenoleukodystrophy in adulthood; to propose a differential diagnosis in aid of a prompt recognition of the disease hereafter from a neurologist approach. In relation of a clinical case we reviewed the literature to correlate the principal findings and evolution of the disease. This thrilling but at the same time unfortunate disease is not only a diagnostic problem is also a therapeutic quest besides all the related familial, labor, and social related problems. The very-long chain fatty acids (VLCFA) accumulation leads to a not completely understood mechanisms that precipitate the specific malfunction of the nervous system and adrenal gland. The initial corticospinal bilateral involvement provokes a spastic paraparesis but with the affection of others pathways multiple manifestations appears, with dementia and finally loss of the most of cortical functions secondary to the white matter affection. Since the hematopoietic stem cell transplantation can be treated with variable results, other treatments, as the Lorenzo's oil, have not been consistent with a substantial improvement of the affected individual. The genetic advice and support to the patient and the family are essentials as well as the screening in individuals at risk before the onset of the disease.	0
Differentiating glaucoma from myopic eye is a challenge to ophthalmologists. We try to develop a new discrete Fourier transform (DFT) model for analyzing optical coherence tomography data for the circumpapillary retinal nerve fiber layer (cpRNFL), and investigate DFT as a new diagnostic tool for glaucomatous myopic eyes. The thicknesses of 12 equidistant cpRNFL points were transformed into 6 signals in the frequency domain, ranging from 1 to 6 Hz. In all 232 eyes, generalized linear model showed that 1 Hz, 2 Hz, and 4 Hz were associated with glaucoma, high myopia, and the interaction between glaucoma and high myopia. The 3 Hz signal was associated with glaucoma and high myopia exclusively. A receiver operating characteristic curve analysis of the 3 Hz signals showed areas under the curves of 0.93 (95% CI 0.90-0.96) and 0.93 (95% CI 0.88-0.98), for diagnosing glaucoma in all subjects and in the highly myopic group, respectively. The DFT model is useful to differentiate glaucoma from non-glaucomatous change and showed potential as a diagnostic tool for glaucomatous myopic eyes.	0
Congenital hand malformations is rare and characterized by hand deformities. It is highly heterogeneous, both clinically and genetically, which complicates the identification of causative genes and mutations. Recently, targeted next-generation (NGS) sequencing has been successfully used for the detection of heterogeneous diseases, and the use of NGS also has contributed significantly in evaluating the etiology of heterogeneous disease. Here, we employed targeted NGS to screen 248 genes involved in genetic skeletal disorders, including congenital hand malformations. Three pathogenic mutations located in the GJA1, ROR2 and TBX5 genes were detected in three large Chinese families with congenital hand malformations. Two novel mutations were reported, and a known causative mutation was verified in this Chinese population. This is also the first report that the same panel of targeted NGS was employed to perform molecular diagnosis of different subtypes of congenital hand malformations. Our study supported the application of a targeted NGS panel as an effective tool to detect the genetic cause for heterogeneous diseases in clinical diagnosis.	0
Niemann Pick disease Type C (NPC) is a recessive rare disease caused by the mutation on NPC1 and/or NPC2 genes changing the processing of the Low-density proteins (LDL) resulting in an accumulation of lipids in the cells. Until today there is not a cure, the current treatment is based on palliative affairs to reduce the symptoms and prevent its appearance. Among all the treatments proposed the use of cyclodextrins (CDs), nanocarriers which can complex cholesterol, is one of the most useful alternatives. Indeed, for several years 2-hydroxypropyl-β-CD (HPβ-CD) is approved as orphan drug for FDA and EMA to the treatment. However, different CDs based materials are created each year to improve the cholesterol uptake. This review is focused on the novelty of CD based materials for NPC treatment.	0
A case with ocular (corneal crystals and retinal pigment epithelial mottling), muscle (oropharyngeal and hand weakness and atrophy), and renal (proteinuria and hypertension) abnormalities is described. We believe that this represents a previously unrecognized syndrome.	0
Myotonic dystrophies (DM) are slowly progressing multisystemic disorders caused by repeat expansions in the DMPK or CNBP genes. The multisystemic involvement in DM patients often reflects the appearance of accelerated aging. This is partly due to visible features such as cataracts, muscle weakness, and frontal baldness, but there are also less obvious features like cardiac arrhythmia, diabetes or hypogammaglobulinemia. These aging features suggest the hypothesis that DM could be a segmental progeroid disease. To identify the molecular cause of this characteristic appearance of accelerated aging we compare clinical features of DM to "typical" segmental progeroid disorders caused by mutations in DNA repair or nuclear envelope proteins. Furthermore, we characterize if this premature aging effect is also reflected on the cellular level in DM and investigate overlaps with "classical" progeroid disorders. To investigate the molecular similarities at the cellular level we use primary DM and control cell lines. This analysis reveals many similarities to progeroid syndromes linked to the nuclear envelope. Our comparison on both clinical and molecular levels argues for qualification of DM as a segmental progeroid disorder.	0
BackgroundAniridia is a severe autosomal dominant panocular disorder associated with pathogenic sequence variants of the PAX6 gene or 11p13 chromosomal aberrations encompassing the coding and/or regulatory regions of the PAX6 gene in a heterozygous state. Patients with aniridia display several ocular anomalies including foveal hypoplasia, cataract, keratopathy, and glaucoma, which can vary in severity and combination.MethodsA cohort of 155 patients from 125 unrelated families with identified point PAX6 pathogenic variants (118 patients) or large chromosomal 11p13 deletions (37 patients) was analyzed. Genetic causes were divided into 6 types. The occurrence of 6 aniridic eye anomalies was analyzed. Fisher's exact test was applied for 2×2 contingency tables assigning numbers of patients with/without each sign and each type of the PAX6 variants or 11p13 deletions with Benjamini-Hochberg correction. The age of patients with different types of mutation did not differ.ResultsPatients with 3'-cis-regulatory region deletions had a milder aniridia phenotype without keratopathy, nystagmus, or foveal hypoplasia. The phenotypes of the patients with other rearrangements involving 11p13 do not significantly differ from those associated with point pathogenic variants in the PAX6 gene. Missense mutations and genetic variants disrupting splicing are associated with a severe aniridia phenotype and resemble loss-of-function mutations. It is particularly important that in all examined patients, PAX6 mutations were found to be associated with multiple eye malformations. The age of patients with keratopathy, cataract, and glaucoma was significantly higher than the age of patients without these signs.ConclusionWe got clear statistically significant genotype-phenotype correlations in congenital aniridia and evident that aniridia severity indeed had worsened with age.	0
A 36-year-old man from presented with an 11-year history of progressive stiffness and painful spasms of his both legs, with recent worsening of his condition overthe last year resulting in a considerable difficulty of standing up and walking. As the patient developed phobic symptoms, he was considered as having a psychiatric illness and treated with antianxiety and antidepressant drugs. As no real improvement was observed, the patient was referred to internal medicine. Neurological examination showed paraspinal, abdominal and lower limbs muscle contraction with lumbar rigidity. These symptoms were associated to adrenergic symptoms: profuse sweating, tachycardia and high bloodpressure. Initial routine investigations revealed high blood glucose level. Polygraphic electromyographic (EMG) evaluation from paraspinal and leg muscles showed continuous motor unit activity in agonist and antagonist muscle. Electroencephalography and brain magnetic resonance imaging were normal. Immunologic tests according to radio immune assay technique revealed high level of serum anti-glutamic acid decarboxylase (anti-GAD65) antibodies. Diagnosis of autoimmune SPS was retained based on clinical, electrophysiological, and immunological findings. Pregabalin at the dose of 150 mg, three times a day was prescribed with satisfying response.	0
Hereditary congenital facial paresis (HCFP) consists of the paralysis or weakness of facial muscles caused by a maldevelopment of the facial branchiomotor (FBM) nucleus and its nerve. Linkage analyses have related this disorder to two loci, HCFP1 and HCFP2, placed respectively in human chromosomes 3q21.2-q22.1 and 10q21.3-q22.1, but the causative genes are still unknown. In this work we aimed to identify which genes from these loci are expressed in the developing hindbrain and particularly in the FBM nucleus. To this end, we retrieved from the ENSEMBL genomic database the list of these genes as well as their respective mouse orthologs. Subsequently we examined their respective expression patterns in the mouse embryo by using the GenePaint gene expression database. As a result of this screening, we found a new gene (Mgll) from the HCFP1 locus that has strong and specific expression in the developing FBM nucleus. In its turn, the HCFP2 locus appeared as a large gene-desert region, flanked by two genes, Reep3, with specific expression in the FBM nucleus, and Lrrtm3, broadly expressed in the brainstem, including the same nucleus. The concurrence of genomic position and neural expression pattern makes these genes new potential candidates for HCFP.	0
A patient with stigmata of both the Möbius syndrome and the Poland syndrome is presented. This is now the twelfth well-documented patient with a combination of the two syndromes. The association of the Poland syndrome and the Möbius syndrome occurs with sufficient frequency that the combination probably represents a formal genesis malformation syndrome of unknown aetiology that should be designated the Poland-Möbius syndrome.	0
Background: The VATER/VACTERL association (VACTERL) is defined as the non-random occurrence of the following congenital anomalies: Vertebral, Anal, Cardiac, Tracheal-Esophageal, Renal, and Limb anomalies. As no unequivocal candidate gene has been identified yet, patients are diagnosed phenotypically. The aims of this study were to identify patients with monogenic disorders using a genetics-first approach, and to study whether variants in candidate genes are involved in the etiology of VACTERL or the individual features of VACTERL: Anorectal malformation (ARM) or esophageal atresia with or without trachea-esophageal fistula (EA/TEF). Methods: Using molecular inversion probes, a candidate gene panel of 56 genes was sequenced in three patient groups: VACTERL (n = 211), ARM (n = 204), and EA/TEF (n = 95). Loss-of-function (LoF) and additional likely pathogenic missense variants, were prioritized and validated using Sanger sequencing. Validated variants were tested for segregation and patients were clinically re-evaluated. Results: In 7 out of the 510 patients (1.4%), pathogenic or likely pathogenic variants were identified in SALL1, SALL4, and MID1, genes that are associated with Townes-Brocks, Duane-radial-ray, and Opitz-G/BBB syndrome. These syndromes always include ARM or EA/TEF, in combination with at least two other VACTERL features. We did not identify LoF variants in the remaining candidate genes. Conclusions: None of the other candidate genes were identified as novel unequivocal disease genes for VACTERL. However, a genetics-first approach allowed refinement of the clinical diagnosis in seven patients, in whom an alternative molecular-based diagnosis was found with important implications for the counseling of the families.	0
Skeletal dysplasia (SD) is a complex group of bone and cartilage disorders often detectable by fetal ultrasound, but the definitive diagnosis remains challenging because the phenotypes are highly variable and often overlap among different disorders. The molecular mechanisms underlying this condition are also diverse. Hundreds of genes are involved in the pathogenesis of SD, but most of them are yet to be elucidated, rendering genotyping almost infeasible except those most common such as fibroblast growth factor receptor 3 (FGFR3), collagen type I alpha 1 chain (COL1A1), collagen type I alpha 2 chain (COL1A2), diastrophic dysplasia sulfate transporter (DTDST), and SRY-box 9 (SOX9). Here, we report the use of trio-based whole exome sequencing (trio-WES) with comprehensive gene set analysis in two Taiwanese non-consanguineous families with fetal SD at autopsy. A biparental-origin homozygous c.509G>A(p.G170D) mutation in peptidylprolyl isomerase B (PPIB) gene was identified. The results support a diagnosis of a rare form of autosomal recessive SD, osteogenesis imperfecta type IX (OI IX), and confirm that the use of a trio-WES study is helpful to uncover a genetic explanation for observed fetal anomalies (e.g., SD), especially in cases suggesting autosomal recessive inheritance. Moreover, the finding of an identical PPIB mutation in two non-consanguineous families highlights the possibility of the founder effect, which deserves future investigations in the Taiwanese population.	0
INTRODUCTION OR BACKGROUND:Congenital insensitivity to pain (CIP) is caused by extremely rare Mendelian genetic disorders. CIP individuals demonstrate the unexpectedly severe consequences of painlessness. Although only a small number of causative conditions and genes are known, most have led to profound insights into human nociception. CIP gene discovery is catalyzing the manufacture of completely new classes of analgesics, and these are needed as alternatives to synthetic highly potent opioids. SOURCES OF DATA:Pubmed.gov peer-reviewed journal articles and reviews. AREAS OF AGREEMENT:The importance of nerve growth factor-tropomyosin receptor kinase A (NGF-TRKA) signalling for nociceptor genesis and subsequent pain sensing.New analgesics can be generated from knowledge of the NGF-TRKA nociceptor pathway.Increased susceptibility to Staphylococcus aureus infection is a consequence of deficient NGF-TRKA signalling.Mutations in the voltage-gated sodium channels SCN9A and SCN11A can cause congenital painlessness, and in contradistinction, other mutations can cause episodic neuropathic pain. SCN9A/Nav1.7 is an analgesic target. SCN11A/Nav1.9 is unlikely to be an analgesic target.There are further Mendelian causes of painlessness to be discovered. AREAS OF CONTROVERSY:Which NGF-TRKA intracellular signalling pathways operate in nociceptor development and which in post-natal pain sensing?Why have no clinically effective Nav1.7 antagonist been generated? SCN9A-CIP causes analgesia, at least in part, through endogenous opioids.Why do all CIP phenotypes involve a complete loss of all types of nociception? AREAS TIMELY FOR DEVELOPING RESEARCH:PRDM12 as an analgesic target.Discovery of the function and analgesic potential of new CIP genes.Can NGF-TRKA be used in the treatment of S. aureus?	0
BACKGROUND:Gorlin syndrome, also known as basal cell nevus syndrome (BCNS), is a rare autosomal dominant genetic condition, characterized by the presence of multiple basal cell carcinomas at a young age, odontogenic keratocysts, skeletal anomalies, macrocephaly, and dysmorphisms. BCNS is mainly caused by mutations in PTCH1, an onco-suppressor gene that maps at 9q22.3 region. A disease related to BCNS is the 9q22.3 microdeletion syndrome. This condition has an overlapping clinical phenotype with the BCNS, but it can present in addition: metopic craniosynostosis, overgrowth, obstructive hydrocephalus, developmental delay, intellectual disability, and seizures. This syndrome is caused by the deletion of a genomic region containing the PTCH1 and the FANCC. METHODS AND RESULTS:We report the case of an 11-year-old girl that came to our attention for overgrowth, dysmorphic features of the face, and craniosynostosis, but with a normal intellectual and motor development. At first we performed an array-comparative genomic hybridization (aCGH) analysis. The analysis showed no copy number changes. Then, we performed the analysis of the PTCH1 by next-generation sequencing. This analysis showed a heterozygous frameshift mutation. CONCLUSION:This is the first case with a PTCH1 point mutation with a 9q22.3 microdeletion syndrome phenotype. This finding may strengthen the importance of the role of the PTCH1, especially regarding the metopic craniosynostosis.	0
PURPOSE:We observed four individuals in two unrelated but consanguineous families from Portugal and Brazil affected by early-onset retinal degeneration, sensorineural hearing loss, microcephaly, intellectual disability, and skeletal dysplasia with scoliosis and short stature. The phenotype precisely matched that of an individual of Azorean descent published in 1986 by Liberfarb and coworkers. METHODS:Patients underwent specialized clinical examinations (including ophthalmological, audiological, orthopedic, radiological, and developmental assessment). Exome and targeted sequencing was performed on selected individuals. Minigene constructs were assessed by quantitative polymerase chain reaction (qPCR) and Sanger sequencing. RESULTS:Affected individuals shared a 3.36-Mb region of autozygosity on chromosome 22q12.2, including a 10-bp deletion (NM_014338.3:c.904-12_904-3delCTATCACCAC), immediately upstream of the last exon of the PISD (phosphatidylserine decarboxylase) gene. Sequencing of PISD from paraffin-embedded tissue from the 1986 case revealed the identical homozygous variant. In HEK293T cells, this variant led to aberrant splicing of PISD transcripts. CONCLUSION:We have identified the genetic etiology of the Liberfarb syndrome, affecting brain, eye, ear, bone, and connective tissue. Our work documents the migration of a rare Portuguese founder variant to two continents and highlights the link between phospholipid metabolism and bone formation, sensory defects, and cerebral development, while raising the possibility of therapeutic phospholipid replacement.	0
In this study, we report a four-year-old male with D-2-hydroxyglutaric aciduria (D2HA) and enchondromatosis with a prior history of hyperpigmented, segmental whorls and streaks on his abdomen who later presented with an eruption of angiokeratoma circumscriptum within a similar distribution. His condition can likely be explained by underlying somatic mosaicism; however, a unifying culprit gene mutation has not yet been identified. To date, only 10 reported cases of D2HA with enchondromatosis are available in the literature with three reported skin findings. This is the first reported case of angiokeratoma circumscriptum associated with the rare condition of D2HA and enchondromatosis.	0
Primary thyroid teratomas are exceedingly rare. Mature and immature variants recapitulate their gonadal counterparts (predilection for infants/children, triphasic germ layer differentiation, and favorable outcome). On the other hand, the so-called malignant teratomas affect predominantly adults and elderly, are highly aggressive, and, according to a few published cases, harbor DICER1 mutations. We describe three highly aggressive sporadic malignant teratoid thyroid tumors in 2 females (17 and 45 years) and one male (17 years). Histology showed triphasic neoplasms composed of solid nests of small primitive monomorphic cells embedded in a cellular stroma with primitive immature rhabdomyosarcoma-like (2) or pleomorphic sarcoma-like (1) phenotype. The third component was represented by TTF1+/PAX8+ primitive teratoid epithelial tubules reminiscent of primitive thyroid follicles and/or Wilms tumor, admixed with scattered respiratory- or enteric-type tubules, neuroepithelial rosettes, and fetal-type squamoid nests. Foci of cartilage were seen in two cases, but none contained mature organoid adult-type tissue or skin adnexa. SALL4 was expressed in the small cell (2) and stromal (1) component. Other germ cell markers were negative. Molecular testing revealed a known "hotspot" pathogenic DICER1 mutation in two cases. In addition, case 1 had a missense TP53 variant. This type of thyroid malignancy is distinct from genuine teratomas. The immunoprofile suggests primitive thyroid- or branchial cleft-like differentiation. Given that "blastoma" is a well-accepted terminology in the spectrum of DICER1-associated malignancies, the term "thyroblastoma" might be more convenient for these malignant teratoid tumors of the thyroid gland. Relationship of thyroblastoma to the DICER1 syndrome remains to be addressed.	0
SARS-CoV-2, a new virus that appeared in Wuhan, China, in 2019 has approximately an 80% genomic match to the Severe Acute Respiratory Symptom (SARS) virus, which is known to come from a bat virus. Symptoms of Kawasaki disease in general and incomplete Kawasaki disease have been seen in a subset of pediatric patients having a current or previous infection of SARS-CoV-2. A viral infection, such as a SARS-CoV-2 virus infection, could result in extensive antigen-antibody immune complexes that cannot be quickly cleared in a subset of patients and thus create a type III hypersensitivity immune reaction and cause Kawasaki disease or Kawasaki disease symptoms (also known as multisystem inflammatory syndrome) in a subset of patients. Extensive binding of antibodies to viral antigens can create antigen-antibody immune complexes, which, if not eliminated in certain individuals having dysfunctional complement systems, can start inflammatory type III hypersensitivity symptoms, including protease releases that can disrupt epithelium, mesothelium, and endothelium basement membranes, and induce pervasive inflammation throughout the body. This could continue after SARS-CoV-2 infections end if the first wave of protease attacks on basement membranes created new secondary autoantibodies and new uncleared antigen-antibody immune complexes.	0
RATIONALE: Pulmonary arterial hypertension (PAH) is an orphan disease for which the trend is for management in designated centers with multidisciplinary teams working in a shared-care approach. OBJECTIVE: To describe clinical and hemodynamic parameters and to provide estimates for the prevalence of patients diagnosed for PAH according to a standardized definition. METHODS: The registry was initiated in 17 university hospitals following at least five newly diagnosed patients per year. All consecutive adult (> or = 18 yr) patients seen between October 2002 and October 2003 were to be included. MAIN RESULTS: A total of 674 patients (mean +/- SD age, 50 +/- 15 yr; range, 18-85 yr) were entered in the registry. Idiopathic, familial, anorexigen, connective tissue diseases, congenital heart diseases, portal hypertension, and HIV-associated PAH accounted for 39.2, 3.9, 9.5, 15.3, 11.3, 10.4, and 6.2% of the population, respectively. At diagnosis, 75% of patients were in New York Heart Association functional class III or IV. Six-minute walk test was 329 +/- 109 m. Mean pulmonary artery pressure, cardiac index, and pulmonary vascular resistance index were 55 +/- 15 mm Hg, 2.5 +/- 0.8 L/min/m(2), and 20.5 +/- 10.2 mm Hg/L/min/m(2), respectively. The low estimates of prevalence and incidence of PAH in France were 15.0 cases/million of adult inhabitants and 2.4 cases/million of adult inhabitants/yr. One-year survival was 88% in the incident cohort. CONCLUSIONS: This contemporary registry highlights current practice and shows that PAH is detected late in the course of the disease, with a majority of patients displaying severe functional and hemodynamic compromise.	1
OBJECTIVES:Sporadic endolymphatic sac tumor (ELST) is rare. The purpose of this study was to analyze the clinical feature and surgical outcome of a single-center series of sporadic ELSTs. PATIENTS AND METHODS:We retrospectively reviewed all cases of sporadic ELSTs operated at the Tiantan hospital between 2010 and 2020. RESULTS:Retrospective record revealed 14 patients with sporadic ELSTs who underwent surgical management. Serum VEGF(vascular endothelial growth factor)values of 6 patients were measured on admission, and the levels were all higher than normal(0-160 ng/L, Enzyme-Linked ImmunoSorbent Assay). All patients underwent surgical treatments, and there was no significant difference in KPS before and after the operation(KPS = 88:88). The average maximum diameter of the tumor was 41 mm (range28-56 mm). After surgery, Two patients received radiation therapy, We did not encounter any case with metastatic dissemination. No deaths occurred during follow-up. CONCLUSION:ELST is defined as an aggressive or low-grade malignant tumor, with the characteristics of local recurrence and invasion of bone growth. Sporadic cases are common, and this rare tumor provides insight into the relationship between ELST and VHL syndrome. Early surgical resection can prevent or reduce the disability of auditory vestibular symptoms, and improve the chance of complete resection and retention of hearing. As far as possible complete resection of the tumor can prolong the disease-free survival of patients. Preoperative radiotherapy or stereotactic therapy cannot control tumor growth. Postoperative radiotherapy may have a positive effect on tumor control. The high expression of VEGF in patients may be related to tumor occurrence and development.	0
PURPOSE OF REVIEW:Osteogenesis imperfecta (OI) is a chronic disease with few treatment options available. The purpose of this review is to provide an overview on treating OI with mesenchymal stem cells (MSC). RECENT FINDINGS:Off-the-shelf MSC have a good safety profile and exhibit multilineage differentiation potential and a low immunogenic profile and are easy to manufacture. Their ability to migrate, engraft, and differentiate into bone cells, and also to act via paracrine effects on the recipient's tissues, makes MSC candidates as a clinical therapy for OI. Due to their high osteogenic potency, fetal MSC offer an even higher therapeutic potential in OI compared with MSC derived from adult sources. Preclinical and initial clinical data support the use of MSC in treating OI. The characteristics of MSC make them of great interest in treating OI. MSC may be safely transplanted via intravenous administration and show potential positive clinical effects.	0
BACKGROUND:Fibrous dysplasia is a rare, benign fibro-osseous malformation whose occurrence in the craniofacial area can result in optic nerve compression, a cerebral mass effect, and cosmetic deformity. Most lesions will progress slowly, and the risk of malignant progression is rare. CASE DESCRIPTION:We present the case of a 21-year-old woman who had presented with acute worsening visual loss secondary to hemorrhagic fibrous dysplasia with ensuing optic nerve compression. Emergent surgical decompression resulted in rapid improvement of her visual dysfunction. The pathological features demonstrated a mixed pattern of woven bone in a fibrous background and secondary aneurysmal bone cyst-like changes. CONCLUSIONS:Hemorrhagic transformation of craniofacial FD remains rare but can present with acute neurologic deterioration. Rapid diagnosis and treatment can allow reversal of patient morbidity. We have also included Supplementary Video 1 to illustrate the surgical principles, and we review the reported data of similar cases.	0
Hereditary folate malabsorption is a rare autosomal recessive disorder caused by impaired active folate transport across membranes and into the central nervous system due to loss-of-function mutations in proton-coupled folate transporter (PCFT). Newborns with this condition have initially normal folate stores, but as they are unable to absorb dietary folate and use rapidly their stores because of their growth demands, symptoms appear in the early infancy. Significant neurological morbidity usually follows the initial non-specific clinical presentation and delayed initiation of treatment. High dose oral and parenteral folinic acid treatment have been previously reported in literature to improve the clinical outcome without achieving optimal cerebrospinal fluid (CSF) folate levels though. The active isomer of 5-formyltetrahydrofolate, also known as levofolinic acid, is available for administration. We report our experience in achieving normal (age dependent) CSF 5-Methyltetrahydrofolate (5-MTHF) levels following daily intramuscular administration of levofolinic acid in three patients with HFM. Follow-up assessment with repeated lumbar punctures has shown a stabilization of 5-MTHF levels within normal range. Clinical features and brain MRI findings had as well either improvement or stabilization. To the best of our knowledge, we provide as well for the first time data in regard to the im levofolinate treatment dosage.	0
BACKGROUND:The Houge type of X-linked syndromic mental retardation is an X-linked intellectual disability (XLID) recently recorded in the Online Mendelian Inheritance in Man (OMIM) and only 8 cases have been reported in literature thus far. CASE PRESENTATION:We present two brothers with intractable seizures and syndromic intellectual disability with symptoms consisting of delayed development, intellectual disability, and speech and language delay. The mother was a symptomatic carrier with milder clinical phenotype. Whole exome sequencing identified a small fragment deletion spanning four exons, about 9.5 kilobases (kb) in length in the CNKSR2 gene in the patients. The mutation co-segregation revealed that exon deletions occurred de novo in the proband's mother. CONCLUSION:Although large deletions have been reported, no small deletions have yet been identified. In this case report, we identified a small deletion in the CNKSR2 gene. This study enhances our knowledge of the CNKSR2 gene mutation spectrum and provides further information about the phenotypic characteristics of X-linked syndromic intellectual disability.	0
The current status and future prospects of glioblastoma treatment were explained through the understanding of the pivotal and important papers from the brain tumor guideline.	0
The liver is a major organ in lipid metabolism, and its malfunction leads to various diseases. Nonalcoholic fatty liver disease, the most common chronic liver disorder in developed countries, is characterized by the abnormal retention of excess lipid within hepatocytes and predisposes individuals to liver cancer. We previously reported that the levels of Lissencephaly 1 (LIS1, also known as PAFAH1B1) are down-regulated in human hepatocellular carcinoma. Following up on this observation, we found that genetic deletion of Lis1 in the mouse liver increases lipid accumulation and inflammation in this organ. Further analysis revealed that loss of Lis1 triggers endoplasmic reticulum (ER) stress and reduces triglyceride secretion. Attenuation of ER stress by addition of tauroursodeoxycholic acid (TUDCA) diminished lipid accumulation in the Lis1-deficient hepatocytes. Moreover, the Golgi stacks were disorganized in Lis1-deficient liver cells. Of note, the Lis1 liver-knockout mice exhibited increased hepatocyte ploidy and accelerated development of liver cancer after exposure to the liver carcinogen diethylnitrosamine (DEN). Taken together, these findings suggest that reduced Lis1 levels can spur the development of liver diseases from steatosis to liver cancer and provide a useful model for delineating the molecular pathways that lead to these diseases.	0
INTRODUCTION:Guillain-Barré syndrome (GBS) is one of the most common causes of acute flaccid paralysis, with up to 20%-30% of patients requiring mechanical ventilation. The aim of our study was to develop and validate a mechanical ventilation risk nomogram in a Chinese population of patients with GBS. METHODS:A total of 312 GBS patients were recruited from January 1, 2015, to June 31, 2018, of whom 17% received mechanical ventilation. The least absolute shrinkage and selection operator (LASSO) regression model was used to select clinicodemographic characteristics and blood markers that were then incorporated, using multivariate logistic regression, into a risk model to predict the need for mechanical ventilation. The model was characterized and assessed using the C-index, calibration plot, and decision curve analysis. The model was validated using bootstrap resampling in a prospective study of 114 patients recruited from July 1, 2018, to July 10, 2019. RESULTS:The predictive model included hospital stay, glossopharyngeal and vagal nerve deficits, Hughes functional grading scale scores at admission, and neutrophil/lymphocyte ratio (NLR). The model showed good discrimination with a C-index value of 0.938 and good calibration. A high C-index value of 0.856 was reached in the validation group. Decision curve analysis demonstrated the clinical utility of the mechanical ventilation nomogram. CONCLUSIONS:A nomogram incorporating hospital stay, glossopharyngeal and vagal nerve deficits, Hughes functional grading scale scores at admission, and NLR may reliably predict the probability of requiring mechanical ventilation in GBS patients.	0
Intellectual disability (ID) is one of most frequent reasons for genetic consultation. The complex molecular anatomy of ID ranges from complete chromosomal imbalances to single nucleotide variant changes occurring de novo, with thousands of genes identified. This extreme genetic heterogeneity challenges the molecular diagnosis, which mostly requires a genomic approach. CXorf56 is largely uncharacterized and was recently proposed as a candidate ID gene based on findings in a single Dutch family. Here, we describe nine cases (six males and three females) from three unrelated families. Exome sequencing and combined database analyses, identified family-specific CXorf56 variants (NM_022101.3:c.498_503del, p.(Glu167_Glu168del) and c.303_304delCTinsACCC, p.(Phe101Leufs*20)) that segregated with the ID phenotype. These variants are presumably leading to loss-of-function, which is the proposed disease mechanism. Clinically, CXorf56-related disease is a slowly progressive neurological disorder. The phenotype is more severe in hemizygote males, but might also manifests in heterozygote females, which showed skewed X-inactivation patterns in blood. Male patients might present previously unreported neurological features such as epilepsy, abnormal gait, tremor, and clonus, which extends the clinical spectrum of the disorder. In conclusion, we confirm the causative role of variants in CXorf56 for an X-linked form of intellectual disability with additional neurological features. The gene should be considered for molecular diagnostics of patients with ID, specifically when family history is suggestive of X-linked inheritance. Further work is needed to understand the role of this gene in neurodevelopment and intellectual disability.	0
INTRODUCTION:Babesiosis is a tick-borne hemo-parasitic disease of domestic and wild animals. Parasites causing babesiosis are considered to infect only specific hosts but some sporadic reports in recent past are in strong disagreement with their host specificity. This is the first report of a domestic cat being naturally infected with a novel Babesia sp. in India. METHODS:Blood samples collected from dogs (n = 6) and a 3-month-old cat, with clinical symptoms of babesiosis, were submitted to two different laboratories for hematology analysis, light microscopical examination, and molecular confirmation of Babesia sp. using PCR, sequencing, and phylogenetic analysis. RESULTS:Hematological alterations noticed in canine and feline samples were severe anemia and thrombocytopenia. Pear-shaped merozoites were visualized on light microscopic examination of both canine and feline blood smears. Size of the merozoites in feline blood sample was smaller when compared to canine samples. Molecular analysis using Babesia species-specific primers showed that all canine samples were positive for B. vogeli and feline sample was negative for B. canis, B. rossi, and B. vogeli infecting dogs. Amplification and sequencing of full-length ssrRNA using universal apicomplexan primers followed by molecular and phylogenetic analysis revealed that the Indian domestic cat was infected with a novel Babesia sp. CONCLUSION:This work presents the first molecular and phylogenetic evidence of a novel Babesia sp. causing feline babesiosis in a naturally infected domestic cat in India. We propose to name this novel species as Babesia panickeri sp. nov.	0
Importance:Although intraocular lenses (IOLs) are often implanted in children, little is known whether primary IOL implantation or aphakia and contact lens correction results in better long-term visual outcomes after unilateral cataract surgery during infancy. Objective:To compare long-term visual outcomes with contact lens vs IOL correction following unilateral cataract surgery during infancy. Design, Setting, and Participants:This multicenter randomized clinical trial enrolled 114 infants with a unilateral congenital cataract who underwent cataract surgery with or without primary IOL implantation between 1 and 6 months of age. Data on long-term visual outcomes were collected when the children were age 10.5 years (July 14, 2015, to July 12, 2019) and analyzed from March 30 through August 6, 2019. Interventions:Intraocular lens implantation at the time of cataract surgery. Main Outcomes and Measures:Best-corrected visual acuity using the electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) testing protocol. Analysis was performed on an intention-to-treat basis. Results:Best-corrected visual acuity was measured at age 10.5 years for 110 of the 114 patients (96%) enrolled as infants. The participants included 58 girls (53%) and 52 boys (47%). Overall, 27 of the children (25%) had good (logMAR 0.30 [Snellen equivalent, 20/40] or better) visual acuity in the treated eye (12 [22%] in the IOL group and 15 [27%] in the aphakia group), but 50 children (44%) had a visual acuity of logMAR 1.00 (Snellen equivalent, 20/200) or worse (25 [44%] in the IOL group and 25 [44%] in the aphakia group). The median logMAR acuity in the treated eye was similar in children randomized to receive an IOL at the time of cataract extraction (0.89; interquartile range [IQR], 0.33-1.43 [Snellen equivalent, 20/159]) and those who remained aphakic (0.86; IQR, 0.30-1.46 [Snellen equivalent, 20/145]) (IQR, 0.30-1.46; P = .82). Although the overall difference in median visual acuity between the 2 groups was small, the estimate was imprecise (99% CI for the difference in medians was -0.54 to 0.47). Conclusions and Relevance:As in previous phases of the study, visual acuity outcomes were highly variable with only 27 children (25%) achieving excellent visual acuity in their treated eye and 50 children (44%) having poor vision in the treated eye. Implanting an IOL at the time of cataract extraction was neither beneficial nor detrimental to the visual outcome. Trial Registration:ClinicalTrials.gov Identifier: NCT00212134.	0
Butterfly vertebrae are rare developmental anomalies representing failure of formation of the vertebral body. There have only been 8 previous reports of a butterfly vertebra occurring at S1. This is the first described case of a butterfly vertebra presenting with a sacral fracture and pelvic ring injury.	0
BACKGROUND:Sotos syndrome is caused by a gene deletion with an autosomal dominant pattern of inheritance. The Sotos syndrome was first described by Juan Sotos. Cole and Hughes identified the clinical characteristics of this syndrome. This syndrome is characterized by macrocephaly, frontal bossing, ocular hypertelorism, overgrowth, subdural hygroma, ventricular dilatation, agenesis of the corpus callosum. This syndrome is associated with mutations in NSD 1 (nuclear receptor SET domain-containing protein 1) gene, protein insufficiency, and a 5q35 microdeletion. Sotos syndrome is reported to occur in approximately 1/10,000-15,000 births. CASE PRESENTATION:We present a patient with Sotos syndrome who is harboring a sacral lipoma and tethered cord syndrome and she had growth retardation, frontal bossing and hypertelorism. After a standard approach for tethered cord syndrome, the patient was discharged 3 days after without any additional neurodeficits. CONCLUSION:In the literature, sacral lipoma and tethered cord syndrome with Sotos syndrome have not been published yet.	0
Biogenesis of F1Fo ATP synthase, the key enzyme of mitochondrial energy provision, depends on transmembrane protein 70 (TMEM70), localized in the inner mitochondrial membrane of higher eukaryotes. TMEM70 absence causes severe ATP-synthase deficiency and leads to a neonatal mitochondrial encephalocardiomyopathy in humans. However, the exact biochemical function of TMEM70 remains unknown. Using TMEM70 conditional knockout in mice, we show that absence of TMEM70 impairs the early stage of enzyme biogenesis by preventing incorporation of hydrophobic subunit c into rotor structure of the enzyme. This results in the formation of an incomplete, pathologic enzyme complex consisting of F1 domain and peripheral stalk but lacking Fo proton channel composed of subunits c and a. We demonstrated direct interaction between TMEM70 and subunit c and showed that overexpression of subunit c in TMEM70-/- cells partially rescued TMEM70 defect. Accordingly, TMEM70 knockdown prevented subunit c accumulation otherwise observed in F1-deficient cells. Altogether, we identified TMEM70 as specific ancillary factor for subunit c. The biologic role of TMEM70 is to increase the low efficacy of spontaneous assembly of subunit c oligomer, the key and rate-limiting step of ATP-synthase biogenesis, and thus to reach an adequately high physiologic level of ATP synthase in mammalian tissues.-Kovalčíková, J., Vrbacký, M., Pecina, P., Tauchmannová, K., Nůsková, H., Kaplanová, V., Brázdová, A., Alán, L., Eliáš, J., Čunátová, K., Kořínek, V., Sedlacek, R., Mráček, T., Houštěk, J. TMEM70 facilitates biogenesis of mammalian ATP synthase by promoting subunit c incorporation into the rotor structure of the enzyme.	0
Diffuse gastric cancer (DGC) is characterized by frequent missense mutations in the small GTPase RHOA, but the effects of this mutation on enzyme activity and signaling have been widely debated. In this issue, Zhang and colleagues show that the most common RHOA mutation in DGC, encoding RHOAY42C, represents a gain of function; that a mouse model incorporating this mutation in association with loss of the E-cadherin gene CDH1 recapitulates many aspects of DGC; and that rationally designed therapeutics based on our understanding of RHOA signaling are promising agents for treating DGC.See related article by Zhang et al., p. 288.	0
Estrogen receptor-α (ERα) is a steroid hormone-sensitive transcription factor that plays a critical role in development of breast cancer. The binding of estrogen to ERα triggers the recruitment of transcriptional co-activators as well as chromatin remodeling factors to estrogen-responsive elements (ERE) of ERα target genes. This process is tightly associated with post-translational modifications (PTMs) of ERα and its co-activators for promotion of transcriptional activation, which leads to proliferation of a large subset of breast tumor cells. These PTMs include phosphorylation, acetylation, methylation, and conjugation by ubiquitin and ubiquitin-like proteins. Ubiquitin-fold modifier 1 (UFM1), one of ubiquitin-like proteins, has recently been shown to be ligated to activating signal co-integrator 1 (ASC1), which acts as a transcriptional co-activator of nuclear receptors. Here, we discuss the mechanistic connection between ASC1 modification by UFM1 and ERα transactivation, and highlight how the interplay of these processes is involved in development of breast cancer. We also discuss potential use of UFM1-conjugating system as therapeutic targets against not only breast cancer but also other nuclear receptor-mediated cancers.	0
PURPOSE:To report a case of melanoma-associated retinopathy (MAR) with autoantibodies against the transient receptor potential cation channel, subfamily M, member 1 (TRPM1) with asymmetric severe vision loss. METHODS:We evaluated a patient with heel skin melanoma showing progressive vision loss in both eyes confirmed with a baseline ophthalmic examination, fluorescein angiography, spectral domain optical coherence tomography (OCT), visual field test, and full-field electroretinogram (ERG). Immunofluorescence assays and western blot analysis revealed autoantibodies in the patient's serum. RESULTS:The patient's best-corrected visual acuities were 20/50 in the right eye and hand motion in the left eye. Visual field test showed severely depressed visual fields especially in the left eye. Fluorescein angiography and OCT revealed extrafoveal choroidal neovascularization in the left eye. The patient had an electronegative ERG, suggesting MAR, and autoantibodies against TRPM1 and aldolase C were detected in the patient's blood sample. CONCLUSIONS:The clinical features of MAR patients with positive anti-TRPM1 autoantibodies can be manifested as severe vision loss, and the identification of autoantibodies can be helpful for confirming the diagnosis.	0
miR-143-3p is correlated with inflammatory pain responses, such as hsa-miR-143-3p expression reduction in fibromyalgia. The present study aimed to explore the effects of miR-143-3p and Toll-like receptor (TLR) 4/myeloid differentiation factor 88 (MyD88)/NF-κB signaling pathway on pulmonary inflammatory factors levels and alveolar epithelial cell apoptosis in mycoplasmal pneumonia mice. Twenty mice were selected as normal group. The 120 successfully modeled Mycoplasma pneumoniae (MP) infection mice were randomly divided into model group (without any treatment), negative control (NC) group (injected with NC mimic), miR-143-3p mimic group (injected with miR-143-3p mimic), miR-143-3p inhibitor group (injected with miR-143-3p inhibitor), TAK-242 group (treatment with TAK-242), and miR-143-3p inhibitor + TAK-242 group (treatment with miR-143-3p inhibitor + TAK-242). Compared with model group, model mice had up-regulated miR-143-3p expression and decreased MyD88 and p-NF-κB p50 protein expressions (all P<0.05); Model mice treated with miR-143-3p mimic and TAK-242 had reduced interleukin (IL)-2 and tumor necrosis factor (TNF)-α contents and protein expressions of MyD88, p-NF-κB p50, increased IL-10 content, fewer alveolar epithelial cell apoptosis, lower Bax expression and higher Bcl-2 expression (all P<0.05); however, mice with miR-143-3p inhibitor treatment showed opposite trends in terms of above indicators. The exacerbation of mycoplasmal pneumonia caused by miR-143-3p inhibitor was partly improved by miR-143-3p inhibitor + TAK-242 combination treatment (all P<0.05). Therefore, up-regulation of miR-143-3p expression may ameliorate pulmonary inflammatory factors levels and reduce alveolar epithelial cell apoptosis in mycoplasmal pneumonia mice by inhibiting TLR4/MyD88/NF-κB signaling pathway.	0
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive malignancy derived from the plasmacytoid dendritic cell that commonly involves the skin. Cutaneous involvement is often the initial presentation, with deep purple or red-brown macules, plaques, or tumors. As such, dermatologists may be the first to see these patients and, in addition to oncologists, should be familiar with its presentation to facilitate early diagnosis, helping to distinguish it from acute myelogenous leukemia cutis.	0
Metastasis is the leading cause of cancer-related death. This multistage process involves contribution from both tumour cells and the tumour stroma to release metastatic cells into the circulation. Circulating tumour cells (CTCs) survive circulatory cytotoxicity, extravasate and colonise secondary sites effecting metastatic outcome. Reprogramming the transcriptomic landscape is a metastatic hallmark, but detecting underlying master regulators that drive pathological gene expression is a key challenge, especially in childhood cancer. Here we used whole tumour plus single-cell RNA-sequencing in primary bone cancer and CTCs to perform weighted gene co-expression network analysis to systematically detect coordinated changes in metastatic transcript expression. This approach with comparisons applied to data collected from cell line models, clinical samples and xenograft mouse models revealed mitogen-activated protein kinase 7/matrix metallopeptidase 9 (MAPK7/MMP9) signalling as a driver for primary bone cancer metastasis. RNA interference knockdown of MAPK7 reduces proliferation, colony formation, migration, tumour growth, macrophage residency/polarisation and lung metastasis. Parallel to these observations were reduction of activated interleukins IL1B, IL6, IL8 plus mesenchymal markers VIM and VEGF in response to MAPK7 loss. Our results implicate a newly discovered, multidimensional MAPK7/MMP9 signalling hub in primary bone cancer metastasis that is clinically actionable.	0
BACKGROUND:L-2-hydroxyglutaric aciduria (L2HGA) is a rare neurometabolic disorder characterized by a slowly progressive clinical course, psychomotor and mental retardation, macrocephaly, dysarthria, seizures, and cerebellar and extrapyramidal findings. The diagnosis depends on the presentation of increased levels of L-2-hydroxyglutaric acid in the urine, plasma, and cerebrospinal fluids. Patients with L2HGA have an increased risk for the development of cerebral neoplasms which, though rarely, can be the initial presentation of the disease. Moreover, patients with L2HGA have an increased risk for the development of cerebral neoplasms. CASES PRESENTATION:Although psychomotor and mental retardation, macrocephaly, dysarthria, seizures, and cerebellar and extrapyramidal findings are the most common characteristics of the disease, we present two rare cases admitted with tumoral symptoms. CONCLUSION:Patients with L2HGA have an increased risk for the development of cerebral neoplasms.	0
BACKGROUND:Cerebrospinal fluid (CSF) collection is currently the only feasible means to obtain biological fluid for the quantitative determination of biomarkers that may reflect disease activity within the brain. Studies in mouse models of human neurological disease benefit from ascertainment and subsequent analysis of brain tissue that is not afforded in human patients. The CSF provides a translational forum, however, due to the practical constraints presented by the mouse's small size, CSF is often ignored in experimental mouse models. NEW METHOD:Here we report a method for the controlled, precise and predictable collection of 10 μL of CSF from the lateral ventricles of adult mice using stereotaxic equipment and a micro-syringe pump. RESULTS:Collected CSF was clear and manifested the consistency of water and moreover, quantification of a disease-specific biomarker for the neurodegenerative disorder, mucopolysaccharidosis type IIIA (MPS IIIA) was possible in this small volume of CSF. In the naturally occurring mouse model of MPS IIIA, that faithfully recapitulates the human form of the disease, this biomarker was present at concentrations of >100 pmol/mL and undetectable in wild-type mice. COMPARISON WITH EXISTING METHOD:Advantages of this method over the most commonly used cisterna magna collection technique include increased CSF sample volume (10 μL) and reduced blood contamination. CONCLUSION:The ability to collect CSF from mouse models of neurological disease enables a forum for translating research outcomes in experimental models to the human equivalent in which CSF collection is also possible.	0
Regulatory interaction networks are often studied on their dynamical side (existence of attractors, study of their stability). We focus here also on their robustness, that is their ability to offer the same spatiotemporal patterns and to resist to external perturbations such as losses of nodes or edges in the networks interactions architecture, changes in their environmental boundary conditions as well as changes in the update schedule (or updating mode) of the states of their elements (e.g., if these elements are genes, their synchronous coexpression mode versus their sequential expression). We define the generic notions of boundary, core, and critical vertex or edge of the underlying interaction graph of the regulatory network, whose disappearance causes dramatic changes in the number and nature of attractors (e.g., passage from a bistable behaviour to a unique periodic regime) or in the range of their basins of stability. The dynamic transition of states will be presented in the framework of threshold Boolean automata rules. A panorama of applications at different levels will be given: brain and plant morphogenesis, bulbar cardio-respiratory regulation, glycolytic/oxidative metabolic coupling, and eventually cell cycle and feather morphogenesis genetic control.	0
Costello syndrome (CS), a rare syndrome with multisystemic involvement inherited as a dominant trait, is characterized by developmental delay, coarse facial appearance, cardiac defects including hypertrophic cardiomyopathy, skin abnormalities, brain complications, and a predisposition to certain malignancies. The musculoskeletal system is particularly affected in CS, with peculiar orthopedic anomalies that impact posture and gait. Dystonia has been recently documented to contribute to abnormal postures and musculoskeletal anomalies characterizing CS, suggesting the possible use of pharmacological treatments to treat these complications. We report the case of a child affected by CS displaying a particularly severe musculoskeletal involvement with dystonic posture especially in the arms and legs. The Movement Disorder-Childhood Rating Scale (MD-CRS) and a gait analysis were used to assess clinical patterns of hyperkinetic movement disorder and dystonia. The child was further treated with trihexyphenidyl for six months with a final dosage of 14 mg. MD-CRS and gait analysis assessments provided evidence for a significant improvement of posture and the related musculoskeletal problems with no side effects. Our preliminary study report provides first evidence that pharmacological anti-dystonia treatment significantly improves movement and posture disorders in patients with CS. Further studies enrolling larger cohorts of patients should be performed to validate these preliminary observations.	0
Multiple familial trichoepithelioma type 1 (MFT1; MIM 601606), a rare monogenic skin disease with autosomal dominant inheritance, is characterized by the development of multiple skin-colored papules on the central area of the face, frequently occurring in the nasolabial area. The disease is associated with various mutations in the cylindromatosis (CYLD; MIM 605018) gene that are also responsible for familial cylindromatosis (FC) and Brooke-Spiegler syndrome (BSS).Recently we have identified a Spanish MFT1 pedigree with two affected family members (father and daughter). Direct sequencing of the CYLD gene revealed a worldwide recurrent heterozygous nonsense mutation (c.2272C/T, p.R758X) in the patients.This mutation has already been detected in patients with all three clinical variants - BSS, FC and MFT1 - of the CYLD-mutation spectrum. Haplotype analysis was performed for the Spanish patients with MFT1, Dutch patients with FC and an Austrian patient with BSS, all of whom carry the same heterozygous nonsense p.R758X CYLD mutation.Our results indicate that this position is a mutational hotspot on the gene and that patients carrying the mutation exhibit high phenotypic diversity.	0
Despite a lot of research on antiphospholipid antibodies (aPL), standardization of test systems, and better definition of its clinical symptoms, the pathomechanism of this acquired autoimmune disease is not yet fully explained. Progress in treatment increased the live birth rate in 70 to 80% of women suffering from obstetric antiphospholipid syndrome (OAPS). However, still 20 to 30% will develop adverse pregnancy outcome. Lack of awareness of this disorder as the cause for pregnancy complications is very harmful to mothers and to their newborns. Complications can be avoided or minimized by proper treatment. The aim of this article is to increase the awareness of gynecologists and medical personal for OAPS.	0
BACKGROUND:The incidence, survival, and prevalence of neuroendocrine tumors (NETs) in children were determined as a first step in improving diagnosis and therapy. Outcomes were compared with neuroblastoma, a pediatric malignancy that shares several biomarkers. METHODS:Incidence rates, observed survival rates and 31-year limited duration prevalence counts were obtained from SEER*Stat for diagnosis years 1975 to 2006. These rates were compared between and within NETs and neuroblastoma for demographic and tumor-related variables from nine standard SEER registries for ages 0-29 years. Multivariate Cox regression was performed to identify prognostic factors for survival in NETs. RESULTS:The number of NETs was 1,073 compared to 1,664 neuroblastomas. The most common NET sites were lung, breast, and appendix. NET 5-year observed survival rates increased from 83% between 1975 and 1979 to 84% for the 2000-2006 period, while analogous neuroblastoma survival rates steadily increased from 45-73%. Five-year observed survival was less than 30% in females with NETs of the cervix and ovary. The estimated 31-year limited duration prevalence for NETs as of January 1, 2006 in the U.S. population was 7,724 compared to 9,960 for neuroblastomas. Age-adjusted multivariate Cox Regression demonstrated small cell histology, primary location in the breast, and distant stage as major predictors of decreased survival. CONCLUSIONS:While survivorship has significantly increased for neuroblastoma, those diagnosed with NETs have shown no increase in survival during this 31-year period. NETs constitute an unrecognized cancer threat to children and young adults comparable to neuroblastoma in both number of affected persons and disease severity.	1
BACKGROUND: The aim of the study was to determine the epidemiology of primary systemic vasculitis in the Australian Capital Territory and the surrounding rural region between 1995 and 2005. METHODS: Cases were ascertained by a medical record search according to international consensus classification criteria. For antineutrophil cytoplasmic antibody-associated vasculitides, ascertainment was corroborated by a search of all positive antineutrophil cytoplasmic antibody serology during the study period. Denominators were obtained from region-specific census data collected during the study period. Prevalence, incidence and patient characteristics for primary systemic vasculitides were determined for two 5-year periods, 1995-1999 and 2000-2004. RESULTS: We identified 41 cases of primary systemic vasculitides (Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), Churg-Strauss syndrome or polyarteritis nodosa) between 1995 and 1999 and 67 between 2000 and 2004, giving prevalences of 95/million (95% confidence interval (CI) 76.9-116.1) and 148/million (95%CI 125.1-173.9), respectively. Annual incidence was similar in both periods (approximately 17/year per million adult population). Disease-specific incidences (per million per year) for each of the two periods were 8.8 and 8.4 for WG, 2.3 and 5.0 for MPA, 2.3 and 2.2 for Churg-Strauss syndrome and 2.3 and 1.1 for polyarteritis nodosa. The rural incidence of MPA was 13.9 (95%CI 7.7-23.5) compared with 1.6 (95%CI 0.2-7.2) in the city and there was a trend towards a higher incidence of WG in rural than urban areas. CONCLUSION: The overall incidence of primary systemic vasculitides is similar to that reported from other developed countries. WG is more common in south-eastern Australia than in southern Europe, whereas MPA is less common. There was a trend towards higher incidence of antineutrophil cytoplasmic antibody-associated vasculitides in rural than urban areas.	1
Fibrous dysplasia is an unusual pathologic condition caused by abnormal bone metabolism. Temporal bone involvement is often seen, but it is uncommon to find fibrous dysplasia limited to the middle ear, especially originating in and confined to a single ossicle. Here we report a case of osteofibrous dysplasia limited exclusively to an ossicle (malleus) causing gradual conductive hearing loss, which recovered after eventual complete removal of the dysplastic area. The lesion showed firm attachment to adjacent structures and initial removal was not possible. This report provides information to help other otologic surgeons facing similar conditions.	0
In this study, a Vohwinkel syndrome case is presented where in 5th digit constriction bands in the right hand were reconstructed using a distant abdominal skin flap. Vohwinkel syndrome, or keratoderma hereditarium mutilans, is a rare, autosomal dominant genetic skin condition that causes palmoplantar hyperkeratosis and constricts finger and/or toe bands. In a typical manifestation, the finger and toe constriction bands lead to progressive strangulation and autoamputation, which requires immediate clinical treatment. Topical keratolytics and systemic retinoids have been used to treat hyperkeratosis but without consistent results. Only 1 effective approach for autoamputation has been accepted, reconstructive surgery.Applying a distant abdominal skin flap produced satisfying postoperative effects at the 18-month follow-up.	0
PURPOSE:Genetic factors have been implicated in the pathogenesis of renal cell carcinoma (RCC), with around 3% of cases having a family history. A greater knowledge of the genetics of inherited RCC has the potential to translate into novel therapeutic targets for sporadic RCC. METHODS:A literature review was performed summarising the current knowledge on hereditary RCC diagnosis, surveillance and management. RESULTS:Familial RCC is usually inherited in an autosomal dominant manner, although inherited RCC may present without a relevant family history. A number of familial RCC syndromes have been identified. Familial non-syndromic RCC is suspected when ≥ 2 relatives are affected in the absence of syndromic features, although clear diagnostic criteria are lacking. Young age at onset and bilateral/multicentric tumours are recognised characteristics which should prompt molecular genetic analysis. Surveillance in individuals at risk of inherited RCC aims to prevent morbidity and mortality via early detection of tumours. Though screening and management guidelines for some inherited RCC syndromes (e.g. von Hippel-Lindau disease, Birt-Hogg-Dube syndrome, hereditary leiomyomatosis) are well defined for rare cause of inherited RCC (e.g. germline BAP1 mutations), there is limited information regarding the lifetime RCC risks and the most appropriate screening modalities. CONCLUSION:Increasing knowledge of the natural history and genetic basis has led to characterisation and tailored management of hereditary RCC syndromes. International data sharing of inherited RCC gene variant information may enable evidence-based improvements in the diagnosis, surveillance protocols and management of these rare conditions.	0
OBJECTIVE: McKusick-Kaufman syndrome (MKS) is a rare autosomal recessive syndrome characterized by hydrometrocolpos (HMC) and postaxial polydactyly (PAP). It is very difficult to diagnose MKS prenatally because of overlapping manifestations and associated anomalies with other syndromes. Herein, we present a case of MKS with prenatal ultrasound illustrating a fetal abdominal cystic mass. CASE REPORT: A 33-year-old woman, gravida 3 para 2, was referred to our obstetrics clinic at 34 weeks' gestation for fetal abdominal cyst detected by prenatal ultrasound. Our ultrasound illustrated a fetal abdominal cystic mass with two communicating components (suspected HMC) and polydactyly involving both hands and feet. At birth, the gross appearance revealed abdominal distention, vulva edema, and PAP. MKS was highly suspected. Abdominal computed tomography (CT) at 3 days of life showed HMC with a transverse vaginal septum. At 3 months of age, she received colpotomy and vaginal reconstruction to relieve the abdominal distension by HMC. Then she accepted corrections of PAP of both hands and feet at 8 months and 10 months. At 5 years of age, her body and mental development did not show any retardation. Pediatric ophthalmologic examination revealed no specific findings. Given the above evidences, the diagnosis of MKS was finally made at 5 years of age. CONCLUSION: Rare syndromes like MKS may need early comprehensive evaluations and consultations. Although prenatal diagnosis might be impossible for MKS, prenatal awareness by fetal ultrasound is very helpful to assist early management and maternal transfer. The final diagnosis and appropriate management of MKS requires the collaboration of obstetricians, geneticists, pediatricians, and ophthalmologists as soon as abnormal signs are detected in utero.	0
Tubular apocrine adenoma is a rare benign adnexal neoplasm most commonly identified in the scalp, composed of a dermal proliferation of apocrine tubules in a background of hyalinized stroma. Tubular apocrine adenoma can be a component of various sweat gland tumors and can also morphologically overlap with other sweat gland neoplasms. Isolated tubular apocrine adenoma arising in the glands of Moll is exceedingly rare, with only 4 previously reported cases. We present a 63-year-old male with tubular apocrine adenoma of the left upper eyelid, which recurred following initial incomplete excision. Although the lesion showed focal morphologic similarity to the apocrine variant of pleomorphic adenoma (chondroid syringoma), the diagnosis of tubular apocrine adenoma was supported by fluorescence in situ hybridization studies, which demonstrated absence of PLAG1 and HMGA2 gene rearrangements seen in pleomorphic adenoma. This case illustrates the clinical, microscopic and immunohistochemical features of tubular apocrine adenoma. The recent advances in our understanding of the molecular genetics of tubular apocrine adenoma and related tumors, and how these advances shape the evolving classification of sweat gland tumors are reviewed.	0
The International League Against Epilepsy (ILAE) has been working to standardize the epilepsy classifications for over a hundred years.The latest epilepsy classification has been recently carried out with a careful overview on several topics including the "epileptic encephalopathies" concept and several constructive discussions on this topic have taken place in the international community of epileptologists.Here we wish to share our reflection on a statement of the ILAE commission on the "epileptic encephalopathy" concept, which in our opinion pays less attention to the "electroclinical syndromes" concept in favor of the new and very rapid genetic advances, thus generating confusion.Our aim is both to preserve the role of electroclinical syndromes, while allowing for the association of the phenotype with specific gene mutations, and to underline the importance of bringing electroclinical syndromes back to the forefront of epileptology.We believe the "match" is still open and for this reason we would like to share our considerations and to open a constructive debate on the "epileptic encephalopathy" concept.	0
INTRODUCTION:Idiopathic pulmonary fibrosis (IPF) is an age-related disease of unknown cause. The disease is characterized by relentless scarring of the lung parenchyma resulting in respiratory failure and death. Two antifibrotic drugs (pirfenidone and nintedanib) are approved for the treatment of IPF worldwide, but they do not offer a cure and are associated with tolerability issues. Owing to its high unmet medical need, IPF is an area of dynamic research activity. AREAS COVERED:There is a growing portfolio of novel therapies that target different pathways involved in the complex pathogenesis of IPF. In this review, we discuss the mechanisms of action and available data for compounds in the most advanced stages of clinical development. We searched PubMed for articles on this topic published from 1 January 2000, to 6 June 2020. EXPERT OPINION:The approval of pirfenidone and nintedanib has fueled IPF drug discovery and development. New drugs are likely to reach the clinic in the near future. However, numerous challenges remain; the lack of animal models that reproduce the complexity of human disease and the poor translation of preclinical and early-phase positive effects to late stage clinical trials must be tackled.	0
Epidermolytic palmoplantar keratoderma (EPPK, OMIM 144200) is an autosomal dominant inherited disease, clinically characterized by diffuse yellowish thickening of the skin on the palms and soles, usually with erythematous borders developing during the first weeks or months after birth. Pathogenesis of EPPK is determined by mutations in the keratin gene (KRT9). Thirty three mutations in the KRT9 gene from 100 EPPK families have been identified. Among these, 23 mutations are located in the 1A region (a mutation hot spot region), 7 are located in the 2B region, and the remaining 3 are synonymous mutations. In this study, three heterozygous mutations (p.N161S, p.R163W, and p.R163Q), located in regions of the gene encoding the conserved central a-helix rod domain, were detected in the KRT9 gene of the three large Chinese families. This study confirms that codon 163 (48 of 100 cases) is a hot spot mutation site for KRT9. Additional findings identified p.N161S (4%) and p.R163W (4%) as potential hot spot mutations for EPPK associated with knuckle pads, and p.R163Q (15 of 100 cases) as the hot spot mutation of EPPK not occurring in combination with knuckle pads. In conjunction with future studies, this research may help lay the foundation for genetics counseling, prenatal diagnosis and clinical treatment of EPPK.	0
OBJECTIVES:We evaluated epidemiology of myotonic dystrophy in Istria, Croatia including direct mutation analysis as an additional, specific diagnostic criterion. MATERIAL AND METHODS:Patients were ascertained in the period 1980-1994 from multiple sources under established clinical criteria with a special reference to congenital and minimal forms of the disease. Additionally, patients and their relatives were evaluated by direct mutation analysis. The prevalence, corrected for underascertainment, was estimated on July 1, 1989. RESULTS:A total of 33 DM patients from nine families were ascertained. In all families the diagnosis was confirmed by mutation analysis of the DM gene. After correction for underascertainment the prevalence of 18.1/100,000 was calculated. CONCLUSION:One of the highest prevalence estimates of DM in the populations without evidence of founder effect or genetic isolation was found. Our results imply the importance of ascertainment of patients with all forms of DM and utilization of specific diagnostic tests for estimation of genetic epidemiology in DM.	1
BACKGROUND:Canine hemorrhagic gastroenteritis (also canine gastrointestinal hemorrhagic syndrome) is commonly associated with Clostridium perfringens, although in some cases the etiology remains unclear. This report describes a fatal acute hemorrhagic and necrotizing gastroenteropathy in a dog associated with Clostridium sordellii, a bacterial species never before identified as the etiological agent of hemorrhagic and necrotizing gastroenteropathy in dogs. CASE PRESENTATION:A fully vaccinated, eight-year-old, female neutered Labrador presented with a history of vomiting without diarrhea. Clinical examination revealed pink mucous membranes, adequate hydration, normothermia, and normocardia. The dog was discovered deceased the following day. Post-mortem examination showed moderate amounts of dark red, non-clotted fluid within the stomach that extended into the jejunum. Discoloration was noted in the gastric mucosa, liver, lungs, and kidneys, with small petechial hemorrhages present in the endocardium over the right heart base and thymic remnants. Histological analysis demonstrated that the gastric fundic mucosa, the pyloric region, small intestine, and large intestine exhibited superficial coagulative necrosis and were lined with a layer of short Gram-positive rods. Anaerobic culture of the gastric content revealed C. sordellii as the dominant bacterial species and neither Salmonella spp., Campylobacter spp., C. perfringens, nor C. difficile were isolated. Unexpectedly, whole genome sequencing of the C. sordellii isolate showed that it lacked the main plasmid-encoded virulence factors typical of the species, indicating that the genetic determinants of pathogenicity of this strain must be chromosomally encoded. Further phylogenetic analysis revealed it to be genetically similar to C. sordellii isolates associated with gastroenteric disease in livestock, indicating that the infection may have been acquired from the environment. CONCLUSIONS:This case demonstrates that C. sordellii can associate with a canine hemorrhagic and necrotizing gastroenteropathy in the absence of C. perfringens and illustrates the benefits of using bacterial whole genome sequencing to support pathological investigations in veterinary diagnostics. These data also update the molecular phylogeny of C. sordellii, indicating a possible pathogenic clade in the environment that is distinct from currently identified clades.	0
Orofaciodigital syndrome 1 (OFD-1) is a rare, X-linked, dominantly inherited disorder caused by an OFD1 mutation that can cause polycystic kidneys. A 37-year-old woman on hemodialysis therapy was admitted to our hospital for trans-catheter arterial embolization therapy for enlarged polycystic kidneys. Lobulated tongue and brachydactyly were noticed, prompting an OFD1 sequencing analysis. Sequencing revealed a causal four-base-pair deletion in exon 13, both in the patient and in her mother, whose renal function had been retained. The peripheral leukocyte X chromosome inactivation pattern was skewed in the patient but not in her mother, suggesting some role in their phenotypic difference.	0
Intestinal amebiasis is the disease caused by the extracellular protozoan parasite Entamoeba histolytica (Eh) that induces a dynamic and heterogeneous interaction profile with the host immune system during disease pathogenesis. In 90% of asymptomatic infection, Eh resides with indigenous microbiota in the outer mucus layer of the colon without prompting an immune response. However, for reasons that remain unclear, in a minority of the Eh-infected individuals, this fine tolerated relationship is switched to a pathogenic phenotype and advanced to an increasingly complex host-parasite interaction. Eh disease susceptibility depends on parasite virulence factors and their interactions with indigenous bacteria, disruption of the mucus bilayers, and adherence to the epithelium provoking host immune cells to evoke a robust pro-inflammatory response mediated by inflammatory caspases and inflammasome activation. To understand Eh pathogenicity and innate host immune responses, this review highlights recent advances in our understanding of how Eh induces outside-in signaling via Mϕs to activate inflammatory caspases and inflammasome to regulate pro-inflammatory responses.	0
Acute parvovirus B19 infection may lead to erythroblastopenia crisis in patients with underlying red blood cells disorders. We report herein an uncommon concomitant transient aplastic crisis in a mother and her daughter, both affected by hereditary spherocytosis. The diagnosis was confirmed by the detection of a very high parvovirus B19 DNA load in both the mother's and daughter's sera, associated with the presence of parvovirus B19 specific immunoglobulin-M antibodies. This rapid etiologic diagnosis allowed to save bone marrow sampling, although blood transfusion was required regarding the severe anemia associated with pancytopenia. Our observation illustrates first line parvovirus B19 hypothesis in the context of transient aplastic crisis and that contagiousness in household contacts should be considered in family with a medical history of red blood cell pathology.	0
Background Central serous chorioretinopathy (CSCR) is a chorioretinal disorder resulting from choroidal hyperpermeability. Its comorbidities as hypertension, coronary disease and psychological stress, suggest that it might reflect a more generalized vascular dysfunction. Objectives To assess the cerebrovascular regulation integrity, using cerebral autoregulation (CA), carbon dioxide vasoreactivity (VR) and neurovascular coupling (NVC) in CSCR. Methods This observational pilot study included 20 CSCR patients and 14 age and sex-matched controls. A State-Trait Anxiety Inventory (STAI) inquiry was full-filled. Continuous measurement of cerebral blood flow velocity (CBFV), arterial blood pressure, heart rate and end-tidal carbon dioxide was performed. VR was assessed during hypercapnia (inhaling carbogen gas) and hypnocapnia (hyperventilation). For NVC, the CBFV relative increase during mental activation using the N-Back Task was calculated. Results No significant differences in systemic hemodynamic parameters, CA or VR were found between both groups. During the NVC performance, the average CBFV rise during mental stress was significantly lower in CSCR (p=0.011). A significant negative correlation was found between STAI scores and NVC. Conclusions CSCR patients presented a significantly impaired cerebral NVC compared to controls, supporting the theory of a potential systemic vascular dysfunction. Stress could be related to this NVC impairment.	0
Numerous multiple malformation syndromes associated with pathologic overgrowth have been described and, for many, their molecular bases elucidated. This review describes the characteristic features of these overgrowth syndromes, as well as the current understanding of their molecular bases, intellectual outcomes, and cancer predispositions. We review syndromes such as Sotos, Malan, Marshall-Smith, Weaver, Simpson-Golabi-Behmel, Perlman, Bannayan-Riley-Ruvalcaba, PI3K-related, Proteus, Beckwith-Wiedemann, fibrous dysplasia, Klippel-Trenaunay-Weber, and Maffucci.	0
Corticomuscular and intermuscular coherence (CMC, IMC) reflect connectivity between neuronal activity in the motor cortex measured by electroencephalography (EEG) and muscular activity measured by electromyography (EMG), or between activity in different muscles, respectively. There is an ongoing debate on the appropriateness of EMG rectification prior to coherence estimation. This work examines the effects of EMG rectification in CMC and IMC estimation in 20 spinocerebellar ataxia type 2 (SCA2) patients, 16 prodromal SCA2 gene mutation carriers, and 26 healthy controls during a repetitive upper or lower limb motor task. Coherence estimations were performed using the non-rectified raw EMG signal vs. the rectified EMG signal. EMG rectification decreases the level of significance of lower beta-frequency band CMC and IMC values in SCA2 patients and prodromal SCA2 mutation carriers vs. healthy controls, and also results in overall lower coherence values. EMG rectification is detrimental for beta-frequency band CMC and IMC estimation. One likely reason for this effect is distortion of coherence estimation in high-frequency signals, where the level of amplitude cancelation is high.	0
INTRODUCTION:Hyponatraemia is one of the most frequent laboratory findings in hospitalised patients. We present an unusual case of hyponatraemia in a 23-year-old female secondary to acute intermittent porphyria (AIP), a rare inborn error of metabolism. CASE REPORT:The patient presented with upper respiratory tract infection, fever, seizures and abdominal pain. An initial diagnosis of encephalitis was made. In view of the unexplained abdominal pain with other clinical findings such as posterior reversible encephalopathy syndrome by CT brain, temporary blindness as well as hyponatraemia, acute intermittent porphyria was suspected. Urine delta aminolaevulinic acid (δ-ALA) and porphobilinogen were elevated confirming the diagnosis of AIP. Genetic studies were done for this patient. The patient had a complete resolution of her symptoms with carbohydrate loading and high caloric diet. CONCLUSION:Although rare, AIP should be considered as a cause of hyponatraemia in a patient who presents with signs and/or symptoms that are characteristic of this disease.	0
Pretibial epidermolysis bullosa (PEB) is an extremely rare subtype of dominant dystrophic epidermolysis bullosa (DDEB), in which recurrent blistering with scarring predominantly involves the pretibial skin. Nail dystrophy, albopapuloid lesions, and hypertrophic scars may also occur. In PEB, immunohistochemical and electron microscopic studies demonstrate the complete or partial loss of the anchoring fibril (AF) in the basement membrane zone, suggesting disturbed synthesis or excessive degradation of collagen VII, the main component of AF. Interestingly, we report a case of PEB with unusual results of joint loss of types IV and VII collagen.	0
PURPOSE:To review the outcomes in a series of patients with long anterior lens zonular fibers associated with late-onset retinal degeneration who had phacoemulsification cataract surgery. SETTING:Newcastle Eye Centre, Newcastle upon Tyne, United Kingdom. DESIGN:Retrospective case series. METHODS:Inclusion criteria were patients with genetically confirmed late-onset retinal degeneration requiring cataract surgery. Perioperative data relating to surgery were collected. In addition, the corrected distance visual acuity (CDVA) and retinal imaging data were recorded. Selected lens capsules were examined using immunohistochemistry or scanning electron microscopy (SEM). RESULTS:Eleven eyes of 7 patients were included. The long anterior lens zonular fibers made capsulorhexis challenging; however, it was completed safely in all cases. There were no intraoperative or postoperative issues with lens stability. The CDVA improved postoperatively in those cases with intact foveal photoreceptors and retinal pigment epithelium. Over the longer term, the CDVA slowly declined because of progressive atrophy of the macula. Most patients noticed a subjective improvement in vision, even those with advanced disease at baseline. Immunohistochemistry showed that the C1QTNF5 protein was expressed within the lens capsule epithelial cells, although SEM of the long anterior lens zonular fibers showed them to be smaller in diameter than normal anterior lens zonular fibers and to be composed of a helix of fibers. CONCLUSIONS:In this small series of patients with late-onset retinal degeneration, cataract surgery was successfully performed without long-term complications involving intraocular lens stability. The objective improvement in CDVA seemed to be limited to patients with good foveal photoreceptor architecture.	0
A 61-year-old female was diagnosed with multiple endocrine neoplasia type 2A (MEN2A), caused by a heterozygous point mutation in the RET gene (TGC to TAC at codon 634) resulting in the substitution of cytosine with leucine (C634Y). The patient had pheochromocytoma (PCC) in the left adrenal gland and medullary thyroid carcinoma (MTC) with liver metastasis. Primary hyperparathyroidism (PHP) was not evident. Family history data suggested that the RET gene mutation was inherited from the father. The PCC was removed laparoscopically, but the MTC was observed conservatively for 7 years because the status of the MTC was compatible with T1N1M1 and stage IVC; therefore, it was not curable with surgery. The MTC liver metastasis increased in size. Lenvatinib, an oral multi-tyrosine kinase inhibitor, was administered until the patient had received a total dose of 1336mg, and then administration was stopped because of nausea. The reduction rate of the MTC liver metastasis was 31%, which was considered partial response. At this point, the patient was doing well, suggesting that lenvatinib was effective in treating the MTC liver metastasis and may be one of the treatment for advanced MTC caused by C634Y mutation in the RET gene.	0
Worster-Drought syndrome (WDS) (congenital bilateral perisylvian syndrome, congenital pseudobulbar paresia) is characterized by neuronal migration defect, pseudobulbar paralysis, epilepsy, neuromotor retardation and perisylvian dysplasia. Pituitary abnormalities are rare disorders. We describe one case with an interesting association of congenital bilateral perisylvian syndrome with pituitary hypoplasia and posterior pituitary ectopia.	0
BACKGROUND:MECP2 duplication syndrome (MDS) is a rare X-linked genomic disorder primarily affecting males which is caused by interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene. Core clinical features of MDS include choreiform movements, progressive spasticity, recurrent respiratory infections, developmental delays in the first 6 months of life, hypotonia, vasomotor disturbances, constipation, drooling, and bruxism. Prior studies suggest that HPA axis activity may be altered in MDS and measures of HPA axis activity may offer insight into disease severity. METHODS:To ascertain whether cortisol profiles are a potential biomarker of clinical severity, diurnal profiles of cortisol and the cortisol awakening response were examined from saliva samples in 31 participants with MDS (ages 2-24 years), and 27 of these samples were usable. Documentation of a positive diagnostic test for MECP2 duplication was required for entry into the study. Samples were collected on each of two consecutive weekdays at four time points during the day: immediately after waking, 30 min after waking, between 3 and 4 PM, and in the evening before bedtime. Correlations with duplication size, clinical severity, sleep problems, and behavior were also examined. RESULTS:Results revealed that a majority of participants with MDS exhibit a declining cortisol awakening response (n = 17). A declining CAR was significantly associated with increased clinical severity scores (r = - .508; p = .03), larger duplication size, waking later, and an increased number of hospitalizations for infections. CONCLUSIONS:Future mechanistic studies will have to determine whether the declining CAR in MDS is attributable to problems with "flip-flop switching" of regional brain activation (involving the suprachiasmatic nucleus and the hippocampus, and the HPA axis) that is responsible for the switch from reduced to increased adrenal sensitivity. Taken together, results suggest the possibility that cortisol profiles could potentially be a biomarker of clinical severity and utilized for the purposes of patient stratification for future clinical trials in MDS.	0
CHARGE syndrome is a rare and complex disorder, causing multiple birth defects and sensory deficits. The CHD7 gene was proved to be the major pathogenic gene in CHARGE syndrome. To date, the phenotype of neonatal CHARGE syndrome is still poorly recognized. In this paper, we report a Chinese neonate with typical CHARGE syndrome. During his stay in the neonatal intensive care unit of our hospital, the patient presented with various appearance abnormalities, severe dyspnea, dysphagia and recurrent infection. Integrated analysis of the clinical manifestations and examinations suggested a diagnosis of CHARGE syndrome. Later, the genetic analysis revealed a de novo null heterozygous pathogenic mutation in the patient's CHD7 gene [c.6292C>T (p.Arg2098*)]. Taken together, the patient was diagnostic confirmed as typical CHARGE syndrome. The physicians provided symptomatic treatments for the patient which significantly alleviated his condition, including infection control, laryngoplasty, nasogastric tube feeding and respiratory support. To our knowledge, this case broadens the clinical phenotypic spectrum of typical CHARGE syndrome in neonatal period due to the null mutation of CHD7 gene [c.6292C>T (p.Arg2098*)]. It also demonstrates that genetic analysis is essential in the diagnosis of CHARGE syndrome early in life. Clinicians should focus on providing supportive and corrective therapies in early treatment, particularly in controlling infection, and improving breathing and feeding.	0
The authors report a case of a 6-week-old girl with microphthalmia, posterior lenticonus, persistent fetal vasculature, and coloboma of the right eye, with morning glory disc anomaly and falciform retinal folds of the left eye. Genetic testing revealed a previously unreported mutation (c.1471A>G [p.T491A]) in the gene ZNF408, which has been associated with autosomal recessive retinitis pigmentosa and autosomal dominant familial exudative vitreoretinopathy. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:253-256.].	0
BACKGROUND:Coronary interventions in patients of achondroplasia have been reported rarely in the medical literature. Due to short stature and kyphoscoliosis, endovascular access (Cannulation) of the coronary arteries is usually extremely difficult in such patients. CASE PRESENTATION:A 33 years old patient, a known case of achondroplasia, presented with epigastric pain for 3 h duration to a university hospital, Sudan. Her height was 95 cm and her weight was 38 Kg. A trans-femoral approach for coronary angioplasty was preferred. After it has been extremely difficult to cannulate the left system at first, the cannulation has been performed successfully using 5F, JL3.5 catheter. The angiogram depicted total occlusion of the proximal right coronary artery which was found to be originating from the left coronary sinus of the aorta. Successful trans-femoral coronary angioplasty has been performed with stent placement, and no complications encountered. During her last follow up, 1 year after the procedure, she appeared to be free of symptoms and with no further ischemic attacks or procedure-related complications. CONCLUSIONS:To the best of our knowledge, this is the first reported case of successful coronary angioplasty in achondroplasia patient in whom the occluded artery is an anomalous coronary artery. Literature review, description of the achondroplasia, development of the coronary arteries and the hypothesized theory for the anomaly have been described in this case report. The PCI performed has also been clearly and comprehensively described.	0
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is the most common genetic disorder of fatty acid oxidation, which presents before the age of 2 with the onset of acute hypoketotic hypoglycemia, and is typically precipitated by stress.We report serial brain magnetic resonance imaging (MRI) changes, including MR spectroscopy (MRS) and diffusion weighted imaging (DWI), in a patient with a classical MCAD presentation, compared with five healthy controls.Through this unique case we analyze the evolution of radiological findings during the first month of illness and we highlight the pivotal role of MRI, especially DWI, in the early diagnosis of the decompensated state of the disease.	0
Dentin dysplasia, a rare hereditary disorder of dentin formation, is characterized by normal enamel but atypical dentin formation along with abnormal pulpal morphology. It is inherited as an autosomal dominant trait. It has been divided into two clinical entities: type I (radicular) and type II (coronal). Early diagnosis and initiation of effective regular dental treatments may help the patients with this condition to delay or prevent the loss of the entire dentition and help them in cope up with edentulous state in early ages. The condition undoubtedly has a negative impact on the physical and psychological well-being of the affected individual. Numerous factors have to be considered during the prosthetic rehabilitation of patients with dentin dysplasia. Treatment protocol varies according to clinical case. Although literature reports suggest general guidelines for treatment planning, the present case report describes a full mouth rehabilitation of an 8-year-old female patient with dentin dysplasia. How to cite this article: Khandelwal S, Gupta D, Likhyani L. A Case of Dentin Dysplasia with Full Mouth Rehabilitation: A 3-year Longitudinal Study. Int J Clin Pediatr Dent 2014;7(2): 119-124.	0
Copy number variants at the chromosomal locus 16p11.2 contribute to neurodevelopmental disorders such as autism spectrum disorders, epilepsy, schizophrenia, and language and articulation disorders. Here, we provide detailed findings on the disrupted structural brain connectivity in 16p11.2 deletion syndrome (patients: N = 21, age range: 8-16 years; typically developing (TD) controls: 18, 9-16 years) using structural and diffusion MRI. We performed global short-, middle-, long-range, and interhemispheric connectivity analysis in the whole brain using gyral topology-based cortical parcellation. Using region of interest analysis, we studied bilateral dorsal (3 segments of arcuate fasciculus (AF)) and ventral (inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), uncinate fasciculus (UF)) language pathways. Our results showed significantly increased axial (AD) and radial (RD) diffusivities in bilateral anterior AF, decreased volume for left long AF, increased mean diffusivity (MD) and RD for right long AF, and increased AD for bilateral UF in the 16p11.2 deletion group in the absence of significant abnormalities in the whole-brain gyral and interhemispheric connectivity. The selective involvement of the language networks may aid in understanding effects of altered white matter connectivity on neurodevelopmental outcomes in 16p11.2 deletion.	0
Epidermolysis bullosa (EB) comprises a group of genetic disorders with the hallmark of fragility of the skin and mucosal surfaces. The severity of different types of EB varies markedly as does the occurrence of extra-cutaneous involvement and complications. A number of emergency situations may occur in the context of EB including obstruction to oral intake from oral or esophageal blisters or scarring, acute airway obstruction, acute urinary retention, sepsis and corneal erosions. Whilst general management principles apply in each of these settings, specific considerations are essential in managing EB to avoid undue trauma or damage to delicate tissues. These recommendations have been developed from a literature review and consensus from experts of the European Network for Rare Skin Disorders (ERN-Skin) to aid decision-making and optimize clinical care by non-EB expert health professionals encountering emergency situations in babies, children and adults with EB.	0
Mounier-Kuhn Syndrome (MKS) is a rare disease characterised by recurrent chest infections, and dilation of the trachea and main bronchi, most likely to due to atrophy of elastic fibres https://bit.ly/3azhDjr.	0
AIM OF THE STUDY:Multiple system atrophy (MSA) and spinocerebellar ataxia (SCA) share similar symptomatology. We describe a rare occurrence of familial MSA that proved to be SCA6 upon genetic analysis. MATERIALS AND METHODS:Eighty MSA patients were enrolled in our study; blood samples were collected and genetic screening of the familial case for known SCA loci was performed. RESULTS:A 68-year-old woman presented with recurrent and severe episodes of light-headedness, imbalance, frequent falls, neck and lower back stiffness, subjective arm and leg weakness, and numbness and tingling in both feet. One year later, her condition had declined; she experienced more falls, worsening instability, again more generalised but still subjective weakness, impaired fine motor movements, slurred speech, difficulty swallowing, episodes of choking, bladder incontinence, and constipation. Clinical suspicion included parkinsonism, MSA, and SCA. The patient was enrolled in our MSA study and was found to have 22 and 12 CAG repeats in CACNA1A. The other 79 clinical MSA patients were negative for SCA6 screening. CONCLUSIONS AND CLINICAL IMPLICATIONS:While MSA and SCA may have similar presentations during early disease stages, the presence of both conditions on the list of differential diagnoses can be a diagnostic dilemma. Further analysis will aid in developing a biomarker to distinguish between the two conditions and guide proper management.	0
The measurement of head circumference (HC) represents a useful and reliable tool to monitor brain growth. Many genetic conditions are associated with an abnormal pattern of head growth, but no specific pattern has been described in Dravet Syndrome (DS). To investigate the head growth trajectories in a pediatric population with DS, a retrospective analysis of medical records of patients with DS was performed in 2 epilepsy centers. Quantitative data were compared with z-score growth curve of standard population, and an independent samples t-test was performed using 6-month ranges. A total of 137 subjects aged less than 18 years were included, with a total of 529 HC values and a mean of 3.9 measures per patient. From birth until 24 months of life, HC values were almost equally distributed around the mean trajectory of the reference population from each side of the curve. This trend line deflects from the mean curve after 24 months showing a head growth slowdown reaching a statistical significance (p < .05) from 48 months for males and 60 for females. Future prospective studies are needed to assess factors that can impact head growth and explore possible phenotype-genotype correlation with HC.	0
A nationwide neonatal screening program for phenylketonuria (PKU), maple syrup urine disease (MSUD), homocystinuria, histidinemia and galactosemia was started in Japan in 1977. The total number of infants screened had reached 6,311,754 by March, 1982. A follow-up study revealed the incidence of the disease in Japan: 1/108,823 for PKU; 1/450,840 for hyperphenylalaninemia (HPA); 1/1,577,939 for biopterin deficiency; 1/525,980 for MSUD; 1/1,051,959 for homocystinuria; 1/8,371 for histidinemia, and 1/788,969 for galactosemia type 1. The incidences of PKU, HPA, homocystinuria, and galactosemia (type 1) were found to be markedly low in Japan as compared with those in Caucasian countries. There was no great difference in the incidence of MSUD between both. On the other hand, the incidence of histidinemia was higher in Japan. It was found that most of the patients with PKU, HPA, MSUD, homocystinuria, or galactosemia are developing normally due to the early initiation of dietary treatment. These results clearly indicate that the neonatal mass screening program plays a great role in preventing the occurrence of handicapped children.	1
Cartilage serves multiple functions in the developing embryo and in postnatal life. Genetic mutations affecting cartilage development are relatively common and lead to skeletal malformations, dysfunction or increased susceptibility to disease or injury. Characterization of these mutations and investigation of the molecular pathways in which these genes function have contributed to an understanding of the mechanisms regulating skeletal patterning, chondrogenesis, endochondral ossification and joint formation. Extracellular growth and differentiation factors including bone morphogenetic proteins, fibroblast growth factors, parathyroid hormone-related peptide, extracellular matrix components, and members of the hedgehog and Wnt families provide important signals for the regulation of cell proliferation, differentiation and apoptosis. Transduction of these signals within the developing mesenchymal cells and chondrocytes results in changes in gene expression mediated by transcription factors including Smads, Msx2, Sox9, signal transducer and activator of transcription (STAT), and core-binding factor alpha 1. Further investigation of the interactions of these signaling pathways will contribute to an understanding of cartilage growth and development, and will allow for the development of strategies for the early detection, prevention and treatment of diseases and disorders affecting the skeleton.	0
Léri-Weill dyschondrosteosis (LWD) is usually caused by haploinsufficiency of the short stature homeobox-containing gene (SHOX). The clinical manifestation of this disease is classic triad which are short stature, mesomelia, and Madelung deformity. LWD also includes other features such as high body mass index (BMI). Short stature and high BMI are risk factors of Type 2 diabetes mellitus and cardiovascular disease (CVD), however, LWD combined with type 2 diabetes mellitus or metabolic syndrome have not been described in the literature. In this paper, we report a case of LWD caused by an M1T mutation of the start codon of the SHOX gene. She also has type 2 diabetes mellitus, hypertension, and dyslipidemia. It is suggested that patients with LWD should be identified promptly and the prevention and treatment of metabolic diseases and CVD should be taken into consideration in patients with LWD.	0
BACKGROUND:It is of utmost importance to investigate novel therapies for cancer, as it is a major cause of death. In recent years, immunotherapies, especially those against immune checkpoints, have been developed and brought significant improvement in cancer management. However, on the other hand, immune checkpoints blockade (ICB) by monoclonal antiboties may cause common and severe adverse reactions (ADRs), the cause of which remains largely undetermined. We hypothesize that ICB-agents may induce adverse reactions through off-target protein interactions, similar to the ADR-causing off-target effects of small molecules. In this study, we propose a hybrid phenotype mining approach which integrates molecular level information and provides new mechanistic insights for ICB-associated ADRs. METHODS:We trained a conditional random fields model on the TAC 2017 benchmark training data, then used it to extract all drug-centric phenotypes for the five anti-PD-1/PD-L1 drugs from the drug labels of the DailyMed database. Proteins with structure similar to the drugs were obtained by using BlastP, and the gene targets of drugs were obtained from the STRING database. The target-centric phenotypes were extracted from the human phenotype ontology database. Finally, a screening module was designed to investigate off-target proteins, by making use of gene ontology analysis and pathway analysis. RESULTS:Eventually, through the cross-analysis of the drug and target gene phenotypes, the off-target effect caused by the mutation of gene BTK was found, and the candidate side-effect off-target site was analyzed. CONCLUSIONS:This research provided a hybrid method of biomedical natural language processing and bioinformatics to investigate the off-target-based mechanism of ICB treatment. The method can also be applied for the investigation of ADRs related to other large molecule drugs.	0
Ventilator-associated pneumonia is a hospital-acquired infection that is commonly encountered in intubated patients in the intensive care unit (ICU). It is associated with significant morbidity and mortality. The causative organisms include gram-negative rods (Escherichia coli, Klebsiella pneumoniae, or Acinetobacter species) or gram-positive cocci (Staphylococcus aureus). Described here is a case of ventilator-associated pneumonia caused by a relatively unknown gram-negative bacterium, Cupriavidus (C.) pauculus that was successfully treated with intravenous cefepime.	0
Swedish type Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS-S) is a severe adult-onset leukoencephalopathy with the histopathological hallmark of neuraxonal degeneration with spheroids, described in a large family with a dominant inheritance pattern. The initial stage of the disease is dominated by frontal lobe symptoms that develop into a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms. Median survival is less than 10 years. Recently, pathogenic mutations in CSF1R were reported in a clinically and histologically similar leukoencephalopathy segregating in several families. Still, the cause of HDLS-S remained elusive since its initial description in 1984, with no CSF1R mutations identified in the family. Here we update the original findings associated with HDLS-S after a systematic and recent assessment of several family members. We also report the results from exome sequencing analyses indicating the p.Cys152Phe variant in the alanyl tRNA synthetase (AARS) gene as the probable cause of this disease. The variant affects an amino acid located in the aminoacylation domain of the protein and does not cause differences in splicing or expression in the brain. Brain pathology in one case after 10 years of disease duration showed the end stage of the disease to be characterized by widespread liquefaction of the white matter leaving only some macrophages and glial cells behind the centrifugally progressing front. These results point to AARS as a candidate gene for rapidly progressing adult-onset CSF1R-negative leukoencephalopathies.	0
INTRODUCTION:Bcl-2-associated athanogene-3 (BAG3) mutations have been described in rare cases of rapidly progressive myofibrillar myopathies. Symptoms begin in the first decade with axial involvement and contractures and are associated with cardiac and respiratory impairment in the second decade. Axonal neuropathy has been documented but usually not as a key clinical feature. METHODS:We report a 24-year-old woman with severe rigid spine syndrome and sensory-motor neuropathy resembling Charcot-Marie-Tooth disease (CMT). RESULTS:Muscle MRI showed severe fat infiltration without any specific pattern. Deltoid muscle biopsy showed neurogenic changes and discrete myofibrillar abnormalities. Electrocardiogram and transthoracic echocardiography results were normal. Genetic analysis of a panel of 45 CMT genes showed no mutation. BAG3 gene screening identified the previously reported c.626C>T, pPro209Leu, mutation. DISCUSSION:This case indicates that rigid spine syndrome and sensory-motor axonal neuropathy are key clinical features of BAG3 mutations that should be considered even without cardiac involvement. Muscle Nerve, 57: 330-334, 2018.	0
BACKGROUND:Little is known about real-world treatment and outcomes of patients with anaplastic lymphoma kinase-positive (ALK+) advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS:This retrospective study of the Flatiron Health EHR-derived deidentified database included patients with a lung cancer diagnosis and confirmed advanced NSCLC who received ALK tyrosine kinase inhibitor (TKI) therapy (January 1, 2011, to June 30, 2018). Patient characteristics and treatment patterns were characterized. Real-world progression-free survival (rwPFS) and time to discontinuation were calculated using the Kaplan-Meier method. RESULTS:First-line ALK TKI therapy was administered to 581 patients (27.5% had brain metastasis on or prior to initiation) and second-line ALK TKI therapy to 254 patients postcrizotinib (45.7% had brain metastasis on or prior to second-line ALK TKI initiation). Crizotinib (84.6%; n = 492) was the most commonly administered first-line ALK TKI therapy. For second-line ALK TKI postcrizotinib (n = 254), 49.6% received ceritinib, 41.7% received alectinib, 5.9% received crizotinib retreatment, and 2.8% received brigatinib. Median (95% confidence interval [CI]) rwPFS was 7.47 (6.48-8.32) months for first-line and 7.30 (5.72-8.42) months for second-line ALK TKI. Median (95% CI) rwPFS was significantly longer among first-line ALK TKI patients without than with brain metastasis (8.52 [7.57-10.59] vs. 4.97 [3.75-5.99] months; p < .0001) and patients with brain metastasis on or prior to first-line ALK TKI therapy had a significantly increased risk of progression (hazard ratio ± SE, 1.976 ± 0.112; p < .0001). CONCLUSION:Median rwPFS in patients with advanced ALK+ NSCLC was < 8 months for first- and second-line ALK TKI therapy and was even shorter in patients with brain metastasis, highlighting the need for more effective treatments in this patient population. IMPLICATIONS FOR PRACTICE:Results presented herein describe real-world treatment of advanced ALK+ NSCLC with ALK TKI therapies from January 2011 through June 2018. Crizotinib was the most commonly prescribed first-line ALK TKI therapy in this patient population, but the majority of data analyzed were obtained prior to Food and Drug Administration approval of alectinib and ceritinib in the first-line ALK TKI setting. Physicians should monitor patients closely to help identify when a change in treatment should occur.	0
An 85-year-old man with cardiac history notable for atrial fibrillation diagnosed 10 years ago which was being treated with atenolol and warfarin presented to our institution with persistent atrial fibrillation. His echocardiogram showed ejection fraction (EF) of 56%, no regional wall motion abnormalities, mild mitral and pulmonary regurgitation, and trivial tricuspid regurgitation. Despite this treatment, he had recurrent episodes of paroxysmal symptomatic atrial fibrillation with a rapid rate requiring multiple emergency department visits and hospital admissions. Given difficulty to control the rate, he underwent atrioventricular (AV) nodal ablation and leadless pacemaker insertion. Fifteen days after the procedure, he was found to have a severe mitral regurgitation murmur.	0
A 16-year-old girl with history of treated congenital mitral valve disease and signs of respiratory infection was admitted to our paediatric cardiology department. She was tested positive for severe acute respiratory syndrome coronavirus 2. Despite her severe pre-existing cardiac conditions with pulmonary hypertension, atrial arrhythmias and mitral valve stenosis, the infection did not lead to any cardiac or pulmonary deterioration. In adults, cardiac co-morbidities are known risk factors for a severe course of coronavirus disease 2019 infections. This case illustrates that in children even severe cardiac disease is not necessarily associated with a severe course of coronavirus disease 2019.	0
AIM:To report an analysis of ~1 year of setmelanotide treatment for obesity and hunger, as well as metabolic and cardiac outcomes, in individuals with Bardet-Biedl syndrome (BBS). MATERIALS AND METHODS:Individuals aged 12 years and older with BBS received once-daily setmelanotide. The dose was titrated every 2 weeks to establish the individual therapeutic dose (≤3 mg); treatment continued for an additional 10 weeks. Participants who lost 5 kg or more (or ≥5% of body weight if <100 kg at baseline) continued into the 52-week extension phase. The primary outcome was mean percent change from baseline in body weight at 3 months. Hunger scores and safety were secondary outcomes. RESULTS:From February 2017 and February 2018, 10 individuals were screened; eight completed the 3-month treatment phase and seven completed the extension phase. Mean percent change in body weight from baseline to 3 months was -5.5% (90% CI, -9.3% to -1.6%; n = 8); change from baseline was -11.3% (90% CI, -15.5% to -7.0%; n = 8) at 6 months and -16.3% (90% CI, -19.9% to -12.8%; n = 7) at 12 months. All participants reported at least one treatment-emergent adverse event (AE), most commonly injection-site reaction. No AEs led to study withdrawal or death. Most, morning, and average hunger scores were reduced across time points. CONCLUSIONS:Setmelanotide reduced body weight and hunger in individuals with BBS and had a safety profile consistent with previous reports. Setmelanotide may be a treatment option in individuals with BBS-associated obesity and hyperphagia.	0
BACKGROUND:Müllerian aplasia or Mayer-Rokitansky-Küster-Hauser syndrome is described as congenital absence of the proximal vagina with or without absence of the cervix and uterus, most often recognized after the onset of primary amenorrhea. CASE:An 18-year-old woman presented to a free medical clinic in Arcahaie, Haiti with primary amenorrhea, abdominal distention, and cyclic monthly abdominal pain. Physical exam was significant for uterus palpable superior to the umbilicus, absence of vagina, and rectal exam without palpable vagina or cervix. Transabdominal and transperineal ultrasound examinations did not reveal hematocolpos. Exploratory laparotomy revealed severe endometriosis with bilateral hematosalpinx, markedly distended uterus, no proximal vagina, and normal ovaries. Uterine specimen was filled with blood and no clear cervix was present. SUMMARY AND CONCLUSION:Diagnosis of vaginal and cervical agenesis is complicated in low-resource settings and treatment must be modified when subspecialty care and consistent follow-up are not available.	0
Tabes dorsalis is a slowly progressive parenchymatous degenerative disease of the dorsal column and dorsal root of the spinal cord as a result of syphilis caused by infection with Treponema pallidum pallidum, one of three subspecies of Treponema pallidum that can cause sexually transmitted disease in humans. It generally occurs in the late tertiary stage of syphilis, but early involvement is reported. It may be accompanied by meningitis or meningomyelitis.[1] Although CSF invasion often occurs early in syphilis, the clinical syndrome of tabes dorsalis, one of two manifestations of late neurosyphilis, usually occurs years, often two to three decades later. The pathogenesis of tabes dorsalis follows the pattern of syphilis elsewhere: a perivascular inflammatory response against the treponeme along with gummas (caseous necrosis in granulomata). Some studies support the invasion of the large myelinated nerve fibers by Treponema pallidum and subsequent neuronal degeneration. The cellular infiltration in the spinal cord displays T-helper cells, macrophages that produce cytokines that intensify the inflammatory process.  Men who have sex with men and patients with HIV infection, or PLWH (patients living with HIV), are at a higher risk of neurosyphilis, especially the early types.[2] HIV coinfection commonly occurs with neurosyphilis in the U.S. Thus, the clinical suspicion of neurosyphilis in PLWH must always remain strong with neurological, visual, or otologic signs or symptoms.   Neurosyphilis can be both symptomatic and asymptomatic; in asymptomatic neurosyphilis, which is inflammation without symptoms, a lumbar puncture for CSF evaluation is controversial, but many feel it is important, especially in PLWH, to establish the diagnosis when present since treatment with penicillin at higher and longer doses than used for primary and secondary syphilis can retard or prevent the development of clinically evident and debilitating neurosyphilis, which, when it develops as late neurosyphilis is not as amenable to symptom reversal.	0
Lymphatic malformations in neonates often manifest as a chylothorax, and although rare, morbidity and mortality can be significant. First-line treatment with medium-chain triglyceride-enriched formulas, or enteric rest with total parenteral nutrition, are not always successful. We describe the case of a premature neonate with trisomy 21 who presented with bilateral pleural effusions and a pericardial effusion that worsened with the initiation of enteral nutrition. Clinical improvement was not seen until the initiation of treatment with oral propranolol at a maximum dosage of 0.5 mg/kg/day divided every 8 hours with extubation 8 days after propranolol initiation. Two case reports have described the use of propranolol in similar patients receiving 2 mg/kg/day; however, our experience is the first to report treatment success at a much lower dose. A review of the literature for alternative medication treatments uncovered numerous case reports and series documenting variable results with incongruent definitions of treatment success in a diverse patient population. The rarity of this disease state makes accrual of patients difficult and more robust treatment data unlikely. Therefore, selection of the optimal adjunctive treatment must be based on individual patient and disease state characteristics as well as safety and efficacy profile of the medication.	0
Dysregulated metabolism accelerates reduced decision-making and locomotor ability during aging. To identify mechanisms for delaying behavioral decline, we investigated how C. elegans males sustain their copulatory behavior during early to mid-adulthood. We found that in mid-aged males, gluco-/glyceroneogenesis, promoted by phosphoenolpyruvate carboxykinase (PEPCK), sustains competitive reproductive behavior. C. elegans' PEPCK paralogs, pck-1 and pck-2, increase in expression during the first 2 days of adulthood. Insufficient PEPCK expression correlates with reduced egl-2-encoded ether-a-go-go K+ channel expression and premature hyper-excitability of copulatory circuits. For copulation, pck-1 is required in neurons, whereas pck-2 is required in the epidermis. However, PCK-2 is more essential, because we found that epidermal PCK-2 likely supplements the copulation circuitry with fuel. We identified the subunit A of succinate dehydrogenase SDHA-1 as a potent modulator of PEPCK expression. We postulate that during mid-adulthood, reduction in mitochondrial physiology signals the upregulation of cytosolic PEPCK to sustain the male's energy demands.	0
BACKGROUND:Patients with existing or anticipated indications for cardiac resynchronisation therapy (CRT), bradycardia, or anti-tachycardia pacing should not be offered subcutaneous defibrillators (SQIDs) but it remains unclear how clinicians should predict future need for these therapies. METHODS:We applied three SQID selection policies to data collected retrospectively from transvenous implantable cardioverter defibrillator (TV-ICD) implants: (a) approach A, SQID used in inherited channelopathies and idiopathic ventricular fibrillation only; (b) approach B, as above, plus all hypertrophic cardiomyopathy and grown-up congenital heart disease patients; (c) approach C, as above, plus primary and secondary prevention (for ventricular fibrillation only) of SCD in patients with QRS <150 ms. Approach C reflects current ESC and AHA/ACC/HRS guidelines. RESULTS:338 of 951 patients with TV-ICD were considered for SQID after excluding 613 patients with contraindications. Approaches A, B, and C yielded 45 (4.7%), 89 (9.4%), and 338 (35.5%) patients suitable for SQID, respectively. Use of SQID resulted in more frequent ICD shocks compared to TV-ICD with approach C only (0.43 vs 0.23 per 1000 patient-days; P = .03). Rates of CRT upgrade were comparable across selection criteria (0, 0.03, and 0.07 per 1000 patient-days for approaches A, B, and C, respectively; P = NS). Risk of early mortality was higher when more liberal inclusion criteria were used (P = .003). CONCLUSIONS:One in three patients receiving ICDs may be suitable for SQID under current ESC and AHA/ACC/HRS guidelines. This proportion is influenced significantly by the selection criteria used, and the criteria used by a physician should be informed by the estimated survival of the patient, risk of shocks for MVT, future pacing, and CRT requirements.	0
OBJECTIVE:To assess real-world effectiveness of initial treatment with newer compared to injectable disease-modifying therapies (DMTs) on disease activity in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS). METHODS:This is a cohort study of children with MS/CIS followed at 12 clinics in the US Network of Pediatric MS Centers, who received initial therapy with newer (fingolimod, dimethyl fumarate, teriflunomide, natalizumab, rituximab, ocrelizumab) or injectable (interferon-β, glatiramer acetate) DMTs. Propensity scores (PSs) were computed, including preidentified confounders. Relapse rate while on initial DMT was modeled with negative binomial regression, adjusted for PS-quintile. Time to new/enlarging T2-hyperintense and gadolinium-enhancing lesions on brain magnetic resonance imaging were modeled with midpoint survival analyses, adjusted for PS-quintile. RESULTS:A total of 741 children began therapy before 18 years, 197 with newer and 544 with injectable DMTs. Those started on newer DMTs were older (15.2 vs injectable 14.4 years, p = 0.001) and less likely to have a monofocal presentation. In PS-quintile-adjusted analysis, those on newer DMTs had a lower relapse rate than those on injectables (rate ratio = 0.45, 95% confidence interval (CI) = 0.29-0.70, p < 0.001; rate difference = 0.27, 95% CI = 0.14-0.40, p = 0.004). One would need to treat with newer rather than injectable DMTs for 3.7 person-years to prevent 1 relapse. Those started on newer DMTs had a lower rate of new/enlarging T2 (hazard ratio [HR] = 0.51, 95% CI = 0.36-0.72, p < 0.001) and gadolinium-enhancing lesions (HR = 0.38, 95% CI = 0.23-0.63, p < 0.001) than those on injectables. INTERPRETATION:Initial treatment of pediatric MS/CIS with newer DMTs led to better disease activity control compared to injectables, supporting greater effectiveness of newer therapies. Long-term safety data for newer DMTs are required. ANN NEUROL 2020 ANN NEUROL 2020;88:42-55.	0
BACKGROUND:Fraser syndrome or "cryptophthalmos syndrome" is a rare autosomal recessive disease. It is characterized by a group of congenital malformations such as: crytophthalmos, syndactyly, abnormal genitalia, and malformations of the nose, ears, and larynx. Although cryptophthalmos is considered as a main feature of Fraser syndrome, its absence does not exclude the diagnosis. Clinical diagnosis can be made by Thomas Criteria. Here we present the first documented case of Fraser Syndrome in Aleppo, Syria that is characterized by bilateral anophthalmia and intrahepatic biliary atresia. CASE PRESENTATION:During pregnancy, several ultrasound scans revealed hyperechoic lungs, ascites, and unremarkable right kidney at the 19th-week visit; bilateral syndactyly on both hands and feet at the 32nd-week visit. On the 39th week of gestation, the stillborn was delivered by cesarean section due to cephalopelvic disproportion. Gross examination showed bilateral anophthalmia, bilateral syndactyly on hands and feet, low set ears, and ambiguous genitalia. Microscopic examination of the lung, spleen, liver, ovary, and kidneys revealed abnormalities in these organs. CONCLUSION:The diagnosis of Fraser syndrome can be made prenatally and postnatally; prenatally by ultrasound at 18 weeks of gestation and postnatally by clinical examination using Thomas criteria. Moreover, intrahepatic biliary atresia was not described previously with Fraser syndrome; this recommends a more detailed pathologic study for Fraser syndrome cases.	0
BACKGROUND:Pontocerebellar hypoplasia (PCH) describes a rare, heterogeneous group of neurodegenerative disorders mainly with a prenatal onset. Patients have severe hypoplasia or atrophy of cerebellum and pons, with variable involvement of supratentorial structures, motor and cognitive impairments. Based on distinct clinical features and genetic causes, current classification comprises 11 types of PCH. MAIN TEXT:In this review we describe the clinical, neuroradiological and genetic characteristics of the different PCH subtypes, summarize the differential diagnosis and reflect on potential disease mechanisms in PCH. Seventeen PCH-related genes are now listed in the OMIM database, most of them have a function in RNA processing or translation. It is unknown why defects in these apparently ubiquitous processes result in a brain-specific phenotype. CONCLUSIONS:Many new PCH related genes and phenotypes have been described due to the appliance of next generation sequencing techniques. By including such a broad range of phenotypes, including non-degenerative and postnatal onset disorders, the current classification gives rise to confusion. Despite the discovery of new pathways involved in PCH, treatment is still symptomatic. However, correct diagnosis of PCH is important to provide suitable care and counseling regarding prognosis, and offer appropriate (prenatal) genetic testing to families.	0
An elderly male was admitted to the Department of Neurology for slowly progressive dysarthria and right-sided atactic hemiparesis. Magnetic resonance imaging (MRI) revealed a small contrast-enhanced focus of malignant glioma in the left parietal lobe - with the growth pattern of cerebral gliomatosis - involving the whole left cerebral hemisphere, the corpus callosum, and spreading into the right frontal hemisphere. Diagnostic biopsy was deferred until the exclusion of other possible causes of the brain lesion. A follow-up brain MRI was planned in 6 weeks. In the interim, the patient was treated with dexamethasone, with mild improvement of the neurological symptoms. He was discharged home with a date for a follow-up brain MRI. One week later, the patient was readmitted due to a deterioration of speech and severe respiratory distress. The repeat brain MRI showed regression of contrast enhancement and no progression of the diffuse growth. Laboratory tests demonstrated tracheal candidiasis, invasive aspergillosis, and disseminated strongyloidiasis, including the brain. The patient rapidly deteriorated and died 11 days after the 2nd admission. The autopsy confirmed a small focus of glioblastoma in the left parietal lobe with the diffuse growth pattern of cerebral gliomatosis, laryngeal candidiasis, diffuse alveolar damage, with angioinvasive aspergillosis in the lungs and heart, and disseminated strongyloidiasis.	0
In this issue of ckj, Tabibzadeh et al. report one of the largest series of patients with MYH9 mutations and kidney disease. The cardinal manifestation of MYH9-related disease is thrombocytopenia with giant platelets. The population frequency of pathogenic MYH9 mutations may be at least 1 in 20 000. The literature abounds in misdiagnosed cases treated for idiopathic thrombocytopenic purpura with immune suppressants and even splenectomy. Additional manifestations include neurosensorial deafness and proteinuric and hematuric progressive kidney disease (at some point, it was called Alport syndrome with macrothrombocytopenia), leucocyte inclusions, cataracts and liver enzyme abnormalities, resulting in different names for different manifestation combinations (MATINS, May-Hegglin anomaly, Fechtner, Epstein and Sebastian syndromes, and deafness AD 17). The penetrance and severity of kidney disease are very variable, which may obscure the autosomal dominant inheritance. A correct diagnosis will both preclude unnecessary and potentially dangerous therapeutic interventions and allow genetic counselling and adequate treatment. Morphological erythrocyte, granulocyte and platelet abnormalities may allow the future development of high-throughput screening techniques adapted to clinical peripheral blood flow cytometers.	0
Necrobiosis lipoidica (NL), one of a group of "necrobiotic" granulomatous cutaneous disorders, is characterized histologically by layers of poorly defined, horizontally oriented, altered "necrobiotic" collagen surrounded by, and alternating with, layers of chronic inflammatory cells, histiocytes, and giant cells throughout the full thickness of the dermis. It is a rare disease associated mostly with diabetes mellitus in whom it may affect 0.3%-1.2% although it has also been associated with other cutaneous and systemic disorders and may occur in otherwise normal people. NL has been reported from all over the world, but there appears to be very few reports of NL in Black Africans. We report the case of a 55-year-old diabetic Nigerian woman who presented with typical NL lesions on the lower legs and who responded very well to topical betamethasone dipropionate 0.05% cream. We also briefly review the probable underlying mechanisms leading to the condition and the various treatments that have been found useful.	0
Chudley-McCullough syndrome (CMS) is an autosomal-recessive disorder characterized by a complex brain malformation and profound congenital sensorineural hearing loss. Postnatal brain imaging findings include ventriculomegaly, partial agenesis of corpus callosum, inferior cerebellar dysplasia, arachnoid cysts, and malformations of cortical development including frontal subcortical heterotopia and polymicrogyria. Prenatal diagnosis of CMS is important due to the markedly less severe neurodevelopmental prognosis compared to disorders with similar brain imaging findings. We report prenatal imaging features that help distinguish CMS from other disorders, including slit-like frontal horns, agenesis of the corpus callosum, frontal subcortical heterotopia, arachnoid cysts, and cerebellar dysplasia. © 2016 Wiley Periodicals, Inc.	0
Normophosphatemic familial tumoral calcinosis (NFTC) is an autosomal recessive disorder characterized by calcium deposition in skin and mucosae and associated with unremitting pain and life-threatening skin infections. A homozygous missense mutation (p.K1495E), resulting in SAMD9 protein degradation, was recently shown to cause NFTC in five families of Jewish-Yemenite origin. In this study, we evaluated another Jewish-Yemenite NFTC kindred. All patients were compound heterozygous for two mutations in SAMD9: K1495E and a previously unreported nonsense mutation, R344X, predicted to result in a markedly truncated molecule. Screening of unaffected population-matched controls revealed heterozygosity for K1495E and R344X only in individuals of Jewish-Yemenite ancestry, but not in more than 700 control samples of other origins, including 93 non-Jewish Yemenite. These data may be suggestive of positive selection, considering the rarity of NFTC and the small size of the Jewish-Yemenite population; alternatively, they may reflect genetic drift or the effect of a population-specific modifier trait. Calcifications in NFTC generally develop over areas subjected to repeated trauma and are associated with marked inflammatory manifestations, indicating that SAMD9 may play a role in the inflammatory response to tissue injury. We therefore assessed the effect of cellular stress and tumor necrosis factor-alpha (TNF-alpha), a potent pro-inflammatory cytokine, on SAMD9 gene expression. Whereas exogenous hydrogen peroxide and heat shock did not affect SAMD9 transcription, osmotic shock was found to markedly upregulate SAMD9 expression. In addition, incubation of endothelial cells with TNF-alpha caused a dose-related, p38-dependant increase in SAMD9 expression. These data link NFTC and SAMD9 to the TNF-alpha signaling pathway, suggesting a role for this system in the regulation of extra-osseous calcification.	0
Mucopolysaccharindosis type II (MPS II) is a rare lysosomal storage disorder caused by deficient or absent activity of the iduronate-2-sulfatase (IDS) enzyme, which leads to pathological accumulation of the glycosaminoglycans(GAGs). The absence of early diagnosis can result in irreversible developmental, neurological, and physiological damage. The lack of clear understanding of the etiology of physiological dysfunction in MPS II has been a major obstacle to the development of new treatment. Therefore, a reliable biomarker for early diagnosis and exploration of pathogenic mechanism are of great importance. Proteomics provides powerful tool for protein expression alterations and study of complicated pathological process. This study was performed to identify the differential protein profile in urine of MPS II patients using two-dimensional gel electrophoresis(2D-PAGE)combining with MALDI-TOF/TOF and a total of 15 differentially expressed proteins were identified. Content of alpha1-antitrypsin, Gm2 activator and lipocalin-type prostaglandin D synthase was measured by ELISA method. The value of urinary α1-AT/Cr in MPS II group was 0.79 ± 0.10 mg/mmol, significantly higher than 0.42 ± 0.05 mg/mmol in healthy control group; whereas the value of GM2A/Cr and L-PGDS/Cr in MPS II group was 1.30 ± 0.12 μg/mmol and 9.86 ± 1.16 ng/mmol respectively, which was significantly lower than 2.19 ± 0.19 μg/mmol and 13.98 ± 1.48 ng/mmol in healthy control group. The proteins can be considered as accessory diagnostic biomarkers for MPS II. This approach helped to discover early diagnostic markers and provided a better understanding of the pathogenic mechanism of MPS II.	0
PURPOSE:A key property to consider in all genetic tests is clinical utility, the ability of the test to influence patient management and health outcomes. Here we assess the current clinical utility of genetic testing in diverse pediatric inherited eye disorders (IEDs). METHODS:Two hundred one unrelated children (0-5 years old) with IEDs were ascertained through the database of the North West Genomic Laboratory Hub, Manchester, UK. The cohort was collected over a 7-year period (2011-2018) and included 74 children with bilateral cataracts, 8 with bilateral ectopia lentis, 28 with bilateral anterior segment dysgenesis, 32 with albinism, and 59 with inherited retinal disorders. All participants underwent panel-based genetic testing. RESULTS:The diagnostic yield of genetic testing for the cohort was 64% (ranging from 39% to 91% depending on the condition). The test result led to altered management (including preventing additional investigations or resulting in the introduction of personalized surveillance measures) in 33% of probands (75% for ectopia lentis, 50% for cataracts, 33% for inherited retinal disorders, 7% for anterior segment dysgenesis, 3% for albinism). CONCLUSION:Genetic testing helped identify an etiological diagnosis in the majority of preschool children with IEDs. This prevented additional unnecessary testing and provided the opportunity for anticipatory guidance in significant subsets of patients.	0
Multifocal fibrosclerosis(MFS) is a rare disorder of unknown etiology, characterized by chronic inflammation with dense fibrosis and lymphoplasmacytic infiltration into the connective tissue of various organs. Recently, MFS was classified as IgG4-related systemic disease. In this paper, we report a 60-year-old man with no history of head injury presenting with chronic subdural hematoma(CSDH). After surgery, he complained of severe, continuous headache and persistent high-grade fever. Extensive evaluation, including ⁶⁷Ga scintigraphy suggesting inflammations in various organs, liver needle biopsy showing sclerosing cholangitis, and blood examination showing elevated serum IgG4 levels, led to the diagnosis of MFS. To our knowledge this is the first report of MFS causing CSDH. The mechanism of the formation of CSDH is presumed to involve reactive granular membrane together with exudative subdural collection caused by MFS, which gives rise to minor and repeated bleeding. In this case, oral corticosteroid therapy was dramatically effective in the treatment of the condition.	0
To summarize the experience of 40 patients with pancreatic adenocarcinoma treated with irreversible electroporation ablation (IRE), their experiences with surgical nurses, and to explore the best nursing methods before and during IRE ablation. Preoperative visits were conducted to assess the condition of patients, and psychological counseling was subsequently given to them. All material and medication required for the operation were prepared in advance, and placed in appropriate locations. All 40 patients were treated successfully. The mean time of IRE ablation was 63.33±12.26 (range, 37-87) minutes, and mean blood loss was 2.09±0.49 (range: 1.0-2.8) mL. There were no ablation-related deaths. Skillful mastery of nanoknife usage and troubleshooting methods, intensive observation of patients' vital signs during ablation, and active cooperation with surgeons can ensure successful ablation and can reduce the influence of improper nursing during ablation on patients' prognosis.	0
A narrow thorax with shortening of long bones is usually pointing to dysfunction of the primary cilia corresponding clinically to ciliopathies with major skeletal involvement. Mutations in at least 23 genes are likely to correspond to this clinical presentation: IFT43/52/80/81/122/140/172, WDR19/34/35/60, DYNC2H1, DYNC2LI1, CEP120, NEK1, TTC21B, TCTEX1D2, INTU, TCTN3, EVC 1/2 and KIAA0586. In addition to these, KIAA0753 variants were recently described in seven patients with Jeune asphyxiating thoracic dystrophy (ATD) (two first cousins, one unrelated patient and one fetus), Joubert syndrome (two siblings) and orofaciodigital syndrome type 6 (one patient). We present the clinical characteristics of a eighth such patient. This 4 year-old boy with narrow thorax, short limbs, severe respiratory and feeding difficulties from birth on had a history of hypotonia and developmental delay. On skeletal survey, short tubular bones (height - 5,5 SD) and a trident appearance of the pelvis were seen. Brain MRI showed cervical canal stenosis. Renal function was normal and moderate hepatomegaly was noted. A homozygous c.943C > T mutation in KIAA0753 was identified on whole exome sequencing, resulting in Gln315Ter premature termination of the corresponding protein. This case provides confirmation of an additional molecular basis for skeletal dysplasia and illustrates how ciliopathies due to mutations in a single gene may present as apparently distinct syndromes.	0
Brittle cornea syndrome (BCS) is a rare autosomal recessive connective tissue disorder characterised by severe corneal thinning, with the major ocular risk being spontaneous ocular perforation due to progressive stromal thinning and ectasia. It is a complex condition with limited treatment options. The purpose of this review is to highlight the difficulties associated with the condition and examine the available published evidence with regards to management.	0
Short stature is a common reason for referral to pediatric endocrinologists. Multiple factors, including genetic, prenatal, postnatal, and local environmental factors, can impair growth. The majority of children with short stature, which can be defined as a height less than 2 standard deviation score below the mean, are healthy. However, in some cases, they may have an underlying relevant disease; thus, the aim of clinical evaluation is to identify the subset of children with pathologic conditions, for example growth hormone deficiency or other hormonal abnormalities, Turner syndrome, inflammatory bowel disease, or celiac disease. Prompt identification and management of these children can prevent excessive short stature in adulthood. In addition, a thorough clinical assessment may allow evaluation of the severity of short stature and likely growth trajectory to identify the most effective interventions. Consequently, appropriate diagnosis of short stature should be performed as early as possible and personalized treatment should be started in a timely manner. An increase in knowledge and widespread availability of genetic and epigenetic testing in clinical practice in recent years has empowered the diagnostic process and appropriate treatment for short stature. Furthermore, novel treatment approaches that can be used both as diagnostic tools and as therapeutic agents have been developed. This article reviews the diagnostic approach to children with short stature, discusses the main causes of short stature in children, and reports current therapeutic approaches and possible future treatments.	0
The genetic architecture of schizophrenia is complex and highly polygenic. This article discusses key findings from genetic studies of childhood-onset schizophrenia (COS) and the more common adult-onset schizophrenia (AOS), including studies of familial aggregation and common, rare, and copy number variants. Extant literature suggests that COS is a rare variant of AOS involving greater familial aggregation of schizophrenia spectrum disorders and a potentially higher occurrence of pathogenic copy number variants. The direct utility of genetics to clinical practice for COS is currently limited; however, identifying common pathways through which risk genes affect brain function offers promise for novel interventions.	0
Intellectual disability encompasses a large set of neurodevelopmental disorders of cognition that are more common in males than females. Although mutations in over 100 X-linked genes associated to intellectual disability have been identified, only a few X-linked intellectual disability proteins have been intensively studied. Hence, the molecular mechanisms underlying the majority of X-linked intellectual disability disorders remain poorly understood. A substantial fraction of X-linked intellectual disability genes encode nuclear proteins, suggesting that elucidating their functions in the regulation of transcription may provide novel insights into the pathogenesis of intellectual disability. Recent studies have uncovered mechanisms by which mutations of the gene encoding plant homeodomain (PHD)-like finger protein 6 (PHF6) contribute to the pathogenesis of the X-linked intellectual disability disorder Börjeson-Forssman-Lehmann syndrome (BFLS). PHF6 plays a critical role in the migration of neurons in the mouse cerebral cortex in vivo, and patient-specific mutations disrupt the ability of PHF6 to promote neuronal migration. Interestingly, PHF6 physically associates with the PAF1 transcriptional elongation complex and thereby drives neuronal migration in the cerebral cortex. PHF6 also interacts with the NuRD chromatin remodeling complex and with the nucleolar transcriptional regulator UBF, though the biological role of these interactions remains to be characterized. In other studies, PHF6 mRNA has been identified as the target of the microRNA miR-128 in the cerebral cortex, providing new insights into regulation of PHF6 function in neuronal migration. Importantly, deregulation of PHF6 function in neuronal migration triggers the formation of white matter heterotopias that harbor neuronal hyperexcitability, which may be relevant to the pathogenesis of intellectual disability and seizures in BFLS. Collectively, these studies are beginning to provide key insights into the molecular pathogenesis of BFLS.	0
Androgens and anti-Müllerian hormone (AMH), secreted by the foetal testis, are responsible for the development of male reproductive organs and the regression of female anlagen. Virilization of the reproductive tract in association with the absence of Müllerian derivatives in the XX foetus implies the existence of testicular tissue, which can occur in the presence or absence of SRY. Recent advancement in the knowledge of the opposing gene cascades driving to the differentiation of the gonadal ridge into testes or ovaries during early foetal development has provided insight into the molecular explanation of XX maleness.	0
The study of imprinting disorders in the context of infertility and its treatment is important, as studies have indicated an increased risk. In this study, we evaluated the risk of transient neonatal diabetes mellitus (TNDM), defined here as diabetes mellitus presenting within the first six weeks of life, in children born to women with fertility problems.This nationwide register-based cohort study comprised all 2,107,837 children born in Denmark between 1977 and 2010. Of these, 121,044 (5.7%) children were born to women with fertility problems. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between maternal fertility status and the risk for TNDM.A total of 103 children developed TNDM during the follow-up period. Children born to women with fertility problems had an elevated risk for TNDM, after adjustment for birth year, maternal age at birth and parental history of diabetes, although this was not statistically significant (HR = 1.49; 95% CI 0.73-3.03). The risk of children born in the period 1994-2010 (a period with more comprehensive information on maternal fertility problems and with more invasive fertility treatment procedures) was increased almost twofold (HR = 1.92; 95% CI 0.92-4.00) but was still not statistically significant.Our results indicate that children born to women with fertility problems, particularly after 1993, may be at an elevated risk for TNDM. As the increased risks were not statistically significant, however, the finding may be due to chance.	0
OBJECTIVES:Preparatory to a community trial investigating how best to deliver rectal artesunate as pre-referral treatment for severe malaria; local understanding, perceptions of signs/symptoms of severe malaria and treatment-seeking patterns for and barriers to seeking biomedical treatment were investigated. METHODOLOGY/PRINCIPAL FINDINGS:19 key informant interviews, 12 in-depth interviews and 14 focus group discussions targeting care-givers, opinion leaders, and formal and informal health care providers were conducted. Monthly fever episodes and danger signs or symptoms associated with severe malaria among under-fives were recorded. Respondents recognized convulsions, altered consciousness and coma, and were aware of their risks if not treated. But, these symptoms were perceived to be caused by supernatural forces, and traditional healers were identified as primary care providers. With some delay, mothers eventually visited a health facility when convulsions were part of the illness, despite pressures against this. Although vomiting and failure to eat/suck/drink were associated with malaria, they were not considered as indicators of danger signs unless combined with another more severe symptom. Study communities were familiar with rectal application of medicines. CONCLUSIONS/SIGNIFICANCE:Communities' recognition and awareness of major symptoms of severe malaria could encourage action, but perceptions of their causes and poor discrimination of other danger signs - vomiting and failure to feed - might impede early treatment. An effective health education targeting parents/guardians, decision-makers/advisors, and formal and informal care providers might be a prerequisite for successful introduction of rectal artemisinins as an emergency treatment. Role of traditional healers in delivering such medication to the community should be explored.	0
The complement system is an ancient arm of the innate immune system that plays important roles in pathogen recognition and elimination. Upon activation by microbes, complement opsonizes bacterial surfaces, recruits professional phagocytes, and causes bacteriolysis. Borreliella species are spirochetal bacteria that are transmitted to vertebrate hosts via infected Ixodes ticks and are the etiologic agents of Lyme disease. Pathogens that traffic in blood and other body fluids, like Borreliella, have evolved means to evade complement. Lyme disease spirochetes interfere with complement by producing a small arsenal of outer-surface lipoproteins that bind host complement components and manipulate their native activities. Here we review the current landscape of complement evasion by Lyme disease spirochetes and provide an update on recent discoveries.	0
Particular sonographic fetal malformations are common in chromosome 18 aberrations, requiring invasive prenatal tests to confirm the diagnosis. Karyotyping is the gold standard assay in these cases, although it is a high complexity, expensive and approximately 2 weeks turnaround time test. On the contrary, quantitative fluorescent PCR is considered an accurate, simple, low cost and rapid assay, particularly useful for the diagnosis of aneuploidies of chromosomes 13, 18 and 21 and for the detection of maternal cell contamination of the sample. Clinical presentation of two cases of rare chromosome 18 defects, diagnosed using both techniques. One case was an isochromosome and the other was a partial duplication. Quantitative fluorescent PCR was an invaluable tool for the cytogenetics laboratory.	0
Appendiceal malakoplakia masquerading as a cecal mass is uniquely rare. The presence of an infiltrate of granular eosinophilic macrophages containing Michaelis-Gutmann bodies on histopathology is pathognomonic of malakoplakia. Cutaneous, gastrointestinal and most commonly urogenital malakoplakia is reported in association with an immunocompromised state, infectious, inflammatory and neoplastic processes. Presentation varies from microscopic disease to plaques, nodules, polypoid lesions and small masses. However, a cecal mass postea proven appendiceal malakoplakia deserves special attention. We could not find similar case reports in the English literature. The pathogenesis of malakoplakia is poorly understood, and it is unclear if it is a harbinger of malignancy, a precursor lesion or an inflammatory marker. In the setting of a dominant appendiceal mass, post-treatment endoscopic and tumor marker surveillance is paramount but, however, undefined in contemporary literature.	0
NGLY1 encodes the enzyme N-glycanase that is involved in the degradation of glycoproteins as part of the endoplasmatic reticulum-associated degradation pathway. Variants in this gene have been described to cause a multisystem disease characterized by neuromotor impairment, neuropathy, intellectual disability, and dysmorphic features. Here, we describe four patients with pathogenic variants in NGLY1. As the clinical features and laboratory results of the patients suggested a multisystem mitochondrial disease, a muscle biopsy had been performed. Biochemical analysis in muscle showed a strongly reduced ATP production rate in all patients, while individual OXPHOS enzyme activities varied from normal to reduced. No causative variants in any mitochondrial disease genes were found using mtDNA analysis and whole exome sequencing. In all four patients, variants in NGLY1 were identified, including two unreported variants (c.849T>G (p.(Cys283Trp)) and c.1067A>G (p.(Glu356Gly)). Western blot analysis of N-glycanase in muscle and fibroblasts showed a complete absence of N-glycanase. One patient showed a decreased basal and maximal oxygen consumption rates in fibroblasts. Mitochondrial morphofunction fibroblast analysis showed patient specific differences when compared to control cell lines. In conclusion, variants in NGLY1 affect mitochondrial energy metabolism which in turn might contribute to the clinical disease course.	0
TEMPI syndrome, a disease entity comprising telangiectasia, erythrocytosis with high erythropoietin, monoclonal gammopathy, perinephric fluid collection, and intrapulmonary shunting, was first described by Sykes et al. in 2011. To our knowledge, only 15 cases have been reported worldwide, none of which were in Japan. We herein report a 47-year-old man who had intractable ascites for 2 and a half years and was referred to our department for a peritoneovenous shunt. In addition to ascites, he had telangiectasia, high erythropoietin, monoclonal gammopathy, and perinephric fluid collection. Thus, this is the first case of TEMPI syndrome in Japan.	0
OBJECTIVE:Cerebrospinal fluid hypovolemia (CSFH) is usually treated via an epidural blood patch (EBP). Accurate placement of the EBP at the site of cerebrospinal fluid (CSF) leakage is required for the successful treatment of CSFH. The thoracolumbar spine is evidently a common site of leakage, but because rates of detection of the leakage site via conventional imaging have historically not been high, there may be other common leakage sites. In the present study CSF leakage sites were identified via a combination of conventional imaging, a new method called the overflow leak test, and patient interviews. METHODS:CSF leakage sites were identified using computed tomography myelography, radioisotope cisternography, and the overflow leak test in 14 patients with CSFH. The patients were also asked about their history with regard to potential trauma. EBP was performed and the accuracy of leakage site identification was assessed. RESULTS:Conventional imaging identified a leakage site in 7/14 patients, and in most cases it was in the lumbar spine. In the remaining 7 cases the overflow leak test and ascertaining a history of trauma facilitated identification of the cervical spine as a leakage site. The sites of EBP included 10 in the cervical spine and 4 in the lumbar spine. Complete recovery was observed in 13/14 patients. CONCLUSIONS:In the present study the cervical spine was a common leakage site. Leakage in the cervical spine was undetectable via conventional imaging, suggesting that many cases of cervical spine leakage may remain undetected.	0
We report a 16-year-old girl with agenesis of the corpus callosum, congenital heart disease (ventricular septal defect and abnormal venous return), 5th digit camptodactyly and obesity, born to first cousin Italian parents. Although this child shares features with acrocallosal syndrome and Camera-Marugo-Cohen syndrome, we think that this combination of anomalies allows the delineation of a new MCA/MR syndrome, possibly recessively inherited.	0
Freiberg's disease is osteonecrosis of the dorsal side of a metatarsal head. The gold-standard surgical treatment is the osteotomy procedure first described by Gauthier.Gauthier osteotomy for Freiberg's disease will restore the joint space and lead to long-term clinical improvement. A retrospective study was carried out to verify this hypothesis.This study involved 30 consecutive cases treated by a single surgeon in 28 patients having a mean age of 61.2 years. These patients underwent the Gauthier osteotomy procedure with one or two dorsal staples used for fixation. Patients were reviewed 15 days, 45 days and 3 months after the procedure, and then at the last follow-up to look for any complications and determine patient satisfaction, the AOFAS score, metatarsophalangeal range of motion (ROM), sphericity of the metatarsal head, bone union and metatarsal shortening.The average follow-up was 6.5 years ± 2.2. The second metatarsal was affected in 27 cases and the third metatarsal in 3 cases. Discomfort related to the staples was noted in five cases; the staples were removed in three of them. There was one case of severe stiffening (< 20° ROM). At the last follow-up, 17 cases were very satisfied, 11 were satisfied and 2 were moderately satisfied. The average AOFAS score was 83.8 points ± 11.8 at the last follow-up. A mean loss of 15° plantar flexion and 10° dorsiflexion was noted. Bone union and metatarsal head sphericity were achieved in all cases. The average shortening was 2 mm ± 1.4.The Gauthier osteotomy procedure results in recovery of the metatarsal head's sphericity in every case of this series, with good clinical results and low morbidity.	0
Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is an autosomal dominant disorder caused by heterozygous mutations in RASA1 and EPHB4. Capillary stains in CM-AVM are compatible with Schöbinger's phase I AVMs. Vascular laser has been classically contraindicated for the treatment of AVMs, as there is a fear of accelerating their progression. In this study, we have treated capillary stains in five CM-AVM patients with pulsed dye laser, with improvement and without worsening or recurrence of the lesions after 1 year of clinical and ultrasound follow-up.	0
We report on a 2-month-old girl whose parents are first cousins. The patient has severe craniofacial anomalies characterized by: encephalocele, hypertelorism, midface hypoplasia, hypoplasia of frontal bone on the left side, malformed left eye, absent inner eyelashes, irregular S-shaped palpebral fissures, deformed nostrils, hypoplastic right nasal wing and cleft lip, and clefts of premaxilla, palate and uvula. No other malformations were observed. This association of anomalies suggests the diagnosis of frontofacionasal dysplasia. Parental consanguinity suggests autosomal recessive inheritance.	0
BACKGROUND:Congenital portosystemic shunt (cPSS) is one of the most common congenital disorders diagnosed in dogs. Hepatic encephalopathy (HE) is a frequent complication in dogs with a cPSS and is a major cause of morbidity and mortality. Despite HE been a major cause of morbidity in dogs with a cPSS, little is known about the cellular changes that occur in the central nervous system of dogs with a cPSS. OBJECTIVES:The objective of this study was to characterise the histological changes in the cerebral cortex and cerebellum of dogs with cPSS with particular emphasis on astrocyte morphology. METHODS:Eight dogs with a confirmed cPSS were included in the study. RESULTS:Six dogs had substantial numbers of Alzheimer type II astrocytes and all cases had increased immunoreactivity for glial fibrillary acidic protein in the cerebral cortex, even if there were minimal other morphological changes. CONCLUSIONS:This study demonstrates that dogs with a cPSS have marked cellular changes in the cerebral cortex and cerebellum. The cellular changes that occur in the cerebral cortex and cerebellum of dogs with spontaneously arising HE are similar to changes which occur in humans with HE, further validating dogs with a cPSS as a good model for human HE.	0
The 3q29 microdeletion syndrome is a rare, recurrent genomic disorder, associated with a variable phenotype, despite the same deletion size, consisting in neurodevelopmental features, such as intellectual disability (ID), schizophrenia, autism, bipolar disorder, depression and mild facial morphological anomalies/congenital malformations. A thorough neuropsychiatric evaluation has never been reported in patients with such syndrome. We analyzed the clinical phenotype of four individuals with 3q29 microdeletion syndrome, with special emphasis on the cognitive and behavioral assessment, in order to delineate the neuropsychiatric phenotype related to this condition. We assessed these patients with standardized scales or checklists measuring the cognitive (WISC III or LIPS-R), behavioral (CBCL) and adaptive (VABS) performances. An accurate evaluation in our sample highlights different degrees of ID, variable behavioral disorders, and a preservation of communicative skills among remaining adaptive areas, as the neuropsychiatric hallmark of 3q29 microdeletion syndrome.	0
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by variable and diverse symptoms including the classic triad of hemolytic anemia, thrombosis, and bone marrow failure. It is a disorder primarily seen in the adult population. The authors report a unique case of an 8-year-old girl diagnosed with PNH after initially presenting with a febrile illness and acute kidney injury. Though rare in children, PNH should remain in the differential diagnosis of a child presenting with acute kidney injury. The disease has serious long-term complications, mandating timely diagnosis and appropriate therapy.	0
Floating-Harbor syndrome (FHS) is an autosomal dominant genetic disease caused by SRCAP mutation. This article reports the clinical features of a boy with FHS. The boy, aged 11 years and 7 months, attended the hospital due to short stature for more than 8 years and had the clinical manifestations of unusual facial features (triangularly shaped face, thin lips and long eyelashes), skeletal dysplasia (curvature finger), expressive language disorder, and retardation of bone age. Genetic detection revealed a novel heterozygous mutation, c.7330 C>T(p.R2444X), in the SRCAP gene. The boy was diagnosed with FHS based on these clinical manifestations and gene detection results. FHS is rare in clinical practice, which may lead to missed diagnosis and misdiagnosis, and gene detection may help with the clinical diagnosis of FHS in children.	0
Rationale: Currently available imaging techniques have limited specificity for the detection of active myocardial inflammation. Aluminum fluoride-18-labeled 1,4,7-triazacyclononane-N,N',N″-triacetic acid conjugated folate (18F-FOL) is a positron emission tomography (PET) tracer targeting folate receptor β (FR-β) that is expressed on activated macrophages at sites of inflammation. We evaluated 18F-FOL PET for the detection of myocardial inflammation in rats with autoimmune myocarditis and studied expression of FR-β in human cardiac sarcoidosis specimens. Methods: Myocarditis was induced by immunizing rats (n = 18) with porcine cardiac myosin in complete Freund's adjuvant. Control rats (n = 6) were injected with Freund's adjuvant alone. 18F-FOL was intravenously injected followed by imaging with a small animal PET/computed tomography (CT) scanner and autoradiography. Contrast-enhanced high-resolution CT or 2-deoxy-2-18F-fluoro-D-glucose (18F-FDG) PET images were used for co-registration. Rat tissue sections and myocardial autopsy samples of 6 patients with cardiac sarcoidosis were studied for macrophages and FR-β. Results: The myocardium of 10 out of 18 immunized rats showed focal macrophage-rich inflammatory lesions with FR-β expression occurring mainly in M1-polarized macrophages. PET images showed focal myocardial 18F-FOL uptake co-localizing with inflammatory lesions (SUVmean, 2.1 ± 1.1), whereas uptake in the remote myocardium of immunized rats and controls was low (SUVmean, 0.4 ± 0.2 and 0.4 ± 0.1, respectively; P < 0.01). Ex vivo autoradiography of tissue sections confirmed uptake of 18F-FOL in myocardial inflammatory lesions. Uptake of 18F-FOL to inflamed myocardium was efficiently blocked by a non-labeled FR-β ligand folate glucosamine in vivo. The myocardium of patients with cardiac sarcoidosis showed many FR-β-positive macrophages in inflammatory lesions. Conclusion: In a rat model of autoimmune myocarditis, 18F-FOL shows specific uptake in inflamed myocardium containing macrophages expressing FR-β, which were also present in human cardiac sarcoid lesions. Imaging of FR-β expression is a potential approach for the detection of active myocardial inflammation.	0
Lipoid pneumonia is an uncommon disease caused by the presence of lipid in the alveoli. Here we described a case of a 50-year-old woman with haemoptysis, cough and tachypnea, who was diagnosed with cholesterol pneumonia accompanying with pulmonary artery hypertension. The extremely high pulmonary artery pressure achieved, in this case, is alarming and should alert the physicians that the cholesterol pneumonia may be one of the underlying causes of pulmonary artery hypertension. After a treatment of methylprednisolone, her clinical symptoms were significantly improved, which suggested that steroid might be a promising therapeutic for patients with cholesterol pneumonia.	0
Background:Nuclear receptor subfamily 0, group B, member 1 (NR0B1) gene previously known as DAX1 is a transcription factor that plays a key role in the development of hypothalamo-pituitary-gonadal and adrenal axis. Primary adrenal failure may result from metabolic, infection, autoimmune or developmental causes resulting in a life-threatening condition needing immediate intervention. This study aimed to analyse NR0B1 (DAX1) gene mutation resulting in adrenal hypoplasia congenita (AHC) in three brothers presenting with hypogonadotropic hypogonadism and primary adrenal failure either in infancy or in early childhood. Methods:We studied three boys with primary adrenal failure and hypogonadotropic hypogonadism presenting at different ages at the Paediatric Endocrinology Clinic. Muta- tional analysis of NR0B1 gene was carried out by bidirectional sequencing. Results:All the three boys had deletion of G in exon 1 at position 189 (c.189_189delG) of the gene resulting in frame shift mutation (Y64Tfs*21). Conclusion:Novel mutation in NR0B1 detected by this study explained the cause ofhypogonadotropic hypogonadism with primary adrenal failure in this Indian family. Intrafamilial variability was seen in this family. Early diagnosis by genetic testing, genetic counselling and family screening can help to manage this life-threatening condition.	0
BACKGROUND:FGF8-FGFR1 signalling is involved in multiple biological processes, while impairment of this signalling is one of the main reasons for isolated hypogonadotropic hypogonadism (IHH). Recently, several negative modulators of FGF8-FGFR1 signalling were also found to be involved in IHH, including DUSP6, IL17RD, SPRY2 and SPRY4. The aim of this study was to investigate the genotypic and phenotypic spectra of these genes in a large cohort of Chinese patients with IHH. METHODS:A total of 196 patients with IHH were enrolled in this study. Whole-exome sequencing was performed to identify variants, which was verified by PCR and Sanger sequencing. RESULTS:Four heterozygous DUSP6 variants (p.S157I, p.R83Q, p.P188L and p.N355I) were found in six patients. Cryptorchidism, dental agenesis, syndactyly and blue colour blindness were commonly observed in patients with DUSP6 mutations. Six heterozygous IL17RD variants (p.P191L, p.G35V, p.S671L, p.A221T, p.I329M and p.I329V) were found in seven patients. Segregation analysis indicated that 100% (5/5) of probands inherited the IL17RD variants from their unaffected parents, and oligogenicity was found in 4/7 patients. One rare SPRY4 variant (p.T68S) was found in a female patient with Kallmann syndrome who also carried a PLXNA1 mutation. CONCLUSION:Our study greatly enriched the genotypic and phenotypic spectra of DUSP6, IL17RD and SPRY4 in IHH. Mutations in DUSP6 alone seem sufficient to cause IHH in an autosomal dominant manner, whereas IL17RD or SPRY4 mutations may cause IHH phenotypes in synergy with variants in other IHH-associated genes.	0
Obtaining reliable and high fidelity next-generation sequencing (NGS) data requires to choose a suitable sequencing platform and a library preparation approach, which both have their inherent assay-specific limitations. Here, we present the results of successful adaptation of SureSelect hybridisation-based target enrichment protocol for the sequencing on the Ion Torrent S5 platform, which is designed to work preferably with amplicon-based panels. In our study, we applied a custom NGS panel to screen a cohort of 16 unrelated patients affected by premature fusion of the cranial sutures, i.e. craniosynostosis (CS). CS occurs either as an isolated malformation or in a syndromic form, representing a genetically heterogeneous and clinically variable group of disorders. The approach presented here allowed us to achieve high quality NGS data and confirmed molecular diagnosis in 19% of cases, reaching the diagnostic yield similar to some of the published research reports. In conclusion, we demonstrated that an alternative enrichment strategy for library preparations can be successfully applied prior to sequencing on the Ion Torrent S5 platform. Also, we proved that the custom NGS panel designed by us represents a useful and effective tool in the molecular diagnostics of patients with CS.	0
BACKGROUND:Effects of malnutrition on patients with infective endocarditis (IE) have not been fully studied. Because malnutrition is associated with poor health, we hypothesized that among patients with IE, those with malnutrition would have more negative in-hospital outcomes. METHODS:The National Inpatient Sample was used to identify adults ≥18 years old with IE. We compared outcomes of in-hospital mortality, morbidity, valvular interventions, and utilization of resources between individuals with and without malnutrition. RESULTS:11,939 adults ≥18 years were hospitalized with IE, 2035 had a secondary diagnosis for malnutrition. There were no significant differences in age (mean age ± SEM: 55.6 ± 1.0 vs 54.3 ± 0.4 years, P = .21) or sex (female: 36.7%; 743/2,035 vs 37.5%; 3,717/9,904, P = .69) in patients with and without malnutrition. Patients with malnutrition had more comorbidities (Charlson comorbidity score ≥3: 36%; 732/2,035 vs 30.7%; 3,040/9,904, P = .04). Despite similar adjusted in-hospital mortality (adjusted odds ratio [aOR], 1.4; 95% CI, 0.8-1.5; P = .23), malnourished patients were more likely to develop sepsis (aOR, 1.7; 95% CI, 1.2-2.4; P < .01) and had higher odds of mitral-valve (aOR, 1.7; 95% CI, 1.2-2.4; P < .01) repairs/replacements. Patients with malnutrition also had increased lengths of stay (adjusted mean difference [aMD], 4.7 days; 95% CI, 2.9-6.5 days; P < .01) and hospital charges (aMD, $36,052; 95% CI, $14,935-$57,168; P < .01). CONCLUSIONS:Patients with malnutrition and IE are at risk for high morbidity, valvular repairs/replacements, and use of hospital resources.	0
We report three further patients of the recently described new bone dysplasia-dominantly inherited pseudorheumatoid arthritis. The patients of this report have a similar clinical history, the same distinctive phenotype and almost identical radiographic findings. The only major difference is absence of weather dependent articular pain which characterized the family of the previous study. This report expands the clinical data of this bone dysplasia. All patients are Caucasians and originate from different parts of the Czech Republic. It seems that this disorder is quite a common constitutional bone disorder in this country. We propose the name of Czech Dysplasia Metatarsal Type for this unique disease.	0
Sanfilippo syndrome is a rare lysosomal storage disorder caused by an impaired degradation of heparan sulfate (HS). It presents severe and progressive neurodegeneration and currently there is no effective treatment. Substrate reduction therapy (SRT) may be a useful option for neurological disorders of this kind, and several approaches have been tested to date. Here we use different siRNAs targeting EXTL2 and EXTL3 genes, which are important for HS synthesis, as SRT in Sanfilippo C patients' fibroblasts in order to decrease glycosaminoglycan (GAG) storage inside the lysosomes. The results show a high inhibition of the EXTL gene mRNAs (around 90%), a decrease in GAG synthesis after three days (30-60%) and a decrease in GAG storage after 14 days (up to 24%). Moreover, immunocytochemistry analyses showed a clear reversion of the phenotype after treatment. The in vitro inhibition of HS synthesis genes using siRNAs shown here is a first step in the development of a future therapeutic option for Sanfilippo C syndrome.	0
Kimura disease (KD) is a rare, chronic inflammatory disease of unknown cause and is characterized by painless s.c. swellings and lymphadenopathy commonly affecting the head and neck region. Much therapeutics has been used to treat KD, but is not satisfactory because of frequent relapse. Imatinib has been reported previously to be useful for treatment of hypereosinophilic syndrome and may work by selectively blocking protein-tyrosine kinases, such as platelet-derived growth factor receptor, and c-Kit. We carried out immunohistochemical examination of platelet-derived growth factor receptor-alpha and c-Kit in tissues from patients with KD. The results were positive and suggested that Imatinib might be an effective drug for the treatment of the disease. We have also briefly reviewed the epidemiology, aetiology, clinical manifestations, laboratory and pathological examinations, differential diagnoses, treatment and prognosis of KD in this manuscript.	1
OBJECTIVES:Transient myeloproliferative disorder (TMD), now more commonly known as transient abnormal myelopoiesis (TAM), is a condition closely associated with Down syndrome. Ninety-five percent of Down syndrome cases occur as a result of chromosomal nondisjunction and are rarely due to mosaicism or translocation. TMD is found exclusively in neonates and is most commonly characterized by trisomy 21, somatic GATA1 mutation, and the increased presence of megakaryoblasts. TMD often does not manifest clinically, but patients may show hepatomegaly, splenomegaly and other symptoms. While TMD is almost always present with trisomy 21, there are not many other cytogenetic abnormalities associated with TMD, with a few rare cases such as monosomy 7 and trisomy 8. Recent studies have suggested liver hematopoietic progenitor cells as the candidate for TMD origin. Furthermore, GATA1 mutations associated with TMD are found to encode for a stop codon in the N-terminal activation region of gene sequences. It has been shown that those mutations can cause overproliferation of megakaryocytes, which can cooperate with Down syndrome cells, which have trisomy 21, in the progression of TMD into acute megakaryoblastic leukemia (AMKL). Since GATA1 mutations are present in all cases of myeloid leukemia of Down Syndrome, monitoring GATA1 in patients with trisomy 21 may assist with earlier diagnosis of TMD. Another likely cause of TMD is the amplification of the RUNX1 transcription factor gene located on chromosome 21. It has been shown that RUNX1 is associated with leukemias of myeloid lineage. While most cases of TMD will spontaneously resolve, some will evolve into acute myeloid leukemia (AML). In this review, we will discuss the cytogenetic, molecular genetics and clinical aspects of TMD.	0
Steatocystoma multiplex is an uncommon benign skin disease, which typically manifests as numerous intradermal cysts that can be scattered anywhere on the body. Although usually asymptomatic, it can be significantly disfiguring. One type of steatocystoma multiplex is known to be associated with the autosomal dominant inheritance of a mutation in the gene coding for keratin 17 (KRT17). In such cases, it is often concurrent with other developmental abnormalities of the ectoderm-derived tissues, such as the nails, hair, and teeth. To the best of our knowledge, few cases have been reported of steatocystoma multiplex of the oral and maxillofacial region. This report describes a case of steatocystoma multiplex of both sides of the neck and multiple dental anomalies, with a focus on its clinical, radiological, and histopathological characteristics, as well as the possibility that the patient exhibited the familial type of this condition.	0
Background: The aim of this study was to investigate the genetic and clinical features of dopa-responsive dystonia (DRD) in China. Method: Characteristics of gene mutations and clinical manifestations of 31 patients diagnosed with DRD were analyzed retrospectively. Result: From January 2000 to January 2019, 31 patients were diagnosed with DRD. Twenty (64.5%) were male, and 11 (35.5%) were female. Ten patients (32.3%) had classic DRD, 19 (61.3%) had DRD-plus, and 2 (6.4%) patients had mutations in the dopamine synthetic pathway (PTS gene mutation) without a typical phenotype (not DRD or DRD-plus). Twenty-eight (90.3%) patients underwent genetic testing. Homozygous or compound heterozygous TH gene mutations were found in 22 patients. GCH1 and PTS gene mutations were found in 2 patients. Heterozygous TH mutation and genetic testing were negative in 1 patient. They took different doses of L-dopa, ranging from 0.4 to 8.7 mg/kg/d. Patients with classic DRD responded well. In patients with DRD-plus, 94.7% (18/19) responded well with residual symptoms. One patient (5.3%) did not show any improvement. Conclusion: DRD can be divided into classic DRD and DRD-plus. In this cohort, the most common pathogenic gene was TH. Fever was the important inducing factor of the disease. L-dopa has sustained and stable effects on patients with classic DRD. In patients with DRD-plus, treatment with L-dopa could ameliorate most of the symptoms.	0
Enchondroma protuberans (EP) is a rare form of enchondroma which demonstrates exophytic growth outside the margins of the bony cortex. A previously healthy 18-year-old male presented with chronic painless palpable mass of the left third finger. Radiograph showed a well-circumscribed expansile lucent lesion in the middle phalanx of the left third finger. The magnetic resonance imaging confirmed an expansile cortical-based lesion extending through the cortex into the soft tissues, which demonstrated high T2 signal with internal foci with low to intermediate signal suggestive of internal chondroid matrix. The patient underwent surgical excision, curettage and bone grafting, and surgical pathology study confirmed the diagnosis of EP. A rare case of EP involving a phalanx of the hand was described in this study. Imaging, particularly magnetic resonance imaging, plays a key role for accurate preprocedural diagnosis.	0
OBJECTIVE:Placental cytogenetic studies may reveal the origin of discordant noninvasive prenatal testing (NIPT). We performed placental studies to elucidate discordances between NIPT showing a structural chromosome aberration and the fetus having a different chromosome aberration in three cases. METHOD:Diagnostic testing with genomic SNP microarray was performed in three cases with NIPT showing a duplication on 4q (case 1), a terminal deletion of 13q (case 2), and a terminal deletion of 15q (case 3). Placental studies involved SNP array analysis of cytotrophoblast and mesenchymal core of chorionic villi of four placental quadrants. Clinical follow-up was performed as well. RESULTS:Amniotic fluid revealed a different structural chromosome aberration than predicted by NIPT: a terminal 2q deletion (case 1), a segmental uniparental isodisomy of 13q (case 2), and a terminal duplication of 15q and of 13q (case 3). Placental studies revealed the aberration detected with NIPT in the cytotrophoblast, whereas the fetal karyotype was confirmed in the placental mesenchymal core. CONCLUSION:Our study shows that targeted cytogenetic investigations for confirmation of NIPT showing a microscopically visible structural chromosome aberration should be avoided, since another aberration, even a submicroscopic one or one involving another chromosome, may be present in the fetus.	0
Cole disease is a rare autosomal dominant genodermatosis with only five cases published in literature since its first description in 1976. We report a case of a 3-year-old boy of Italian ancestry who presented with hypopigmented skin patches on the upper extremities and multiple yellowish, firm papules and small plaques on his palms and soles. There were similar findings in the family, extending back at least four generations. Whole exome sequence analysis revealed a novel variant of the ENPP1 gene mutation, which has not been previously reported to be associated with Cole disease. Although there is no extracutaneous involvement associated with this condition, accurate diagnosis and variant identification is nevertheless important so that appropriate medical and genetic counseling can be offered to affected individuals and their at-risk relatives.	0
BACKGROUND:To evaluate the feasibility and clinical outcomes of vaginoplasties using a neovaginal polylactic acid prosthesis made with 3-dimensional (3D) printing technology as an intraneovaginal mould. METHODS:This was an interventionist, prospective, and multicentre clinical pilot investigation of a sanitary product (PACIENA prosthesis®) aiming to recruit and operate on 8 patients over 6 months with a follow-up period of 6 months. Only six patients with Rokitansky syndrome and one patient with Morris syndrome (7 patients in total) were operated on in two university hospitals: "La Fe", Valencia (H1) and "Arrixaca", Murcia (H2). INTERVENTIONS:Extensive surgical dissection of a defined space between the urethra and bladder in the front and of the rectum in the back as well as insertion of the PACIENA prosthesis® covered with Interceed® were performed. After 12 days, the prosthesis was changed to the silicone-covered version for daily application. RESULTS:In the 6 patients with Rokitansky syndrome (86%), the primary endpoint (satisfactory vaginal outcome in terms of appearance, function, and sensation without relevant additional morbidity) was achieved, although only 2 patients (28%) were sexually active at the end of 6 months of follow-up. The patient with Morris syndrome withdrew from the study after 1 month. Patients without bacterial colonization showed positive Schiller tests at 1 month, and subsequent biopsies showed adequate keratinization and epidermization. Epithelization and iodopositivity were delayed in the patients who developed inflammatory granulomas. CONCLUSIONS:Good anatomical and functional results can be achieved with the PACIENA prosthesis® for vaginoplasties without skin grafts. However, adequate patient selection and education, good surgical techniques and haemostasis, postoperative support, and prevention of bacterial colonization are important. TRIAL REGISTRATION:This clinical study was approved by the Ethical Clinical Investigation Committee of San Juan University Hospital on September 27, 2016, to be conducted in the participating centres; it was authorized by the Spanish Agency of Medicines and Health Products (AEMPS) on April 24, 2017 (exp. no. 585/16/EC), to be carried out in that hospitals.	0
Isolated Crohn's disease of the esophagus is rare, and accurate diagnosis and treatment in its early course are difficult. Most cases are often found very late, when severe strictures or other complications have occurred. We report the case of a male 60-year-old patient with complaints of progressive dysphagia for more than two months and the sudden appearance of heartburn for seven consecutive days. Clinical examination revealed severe esophageal stricture with a suspected fistula and mediastinitis. The patient received a successful esophagectomy. The resected specimen and pathological results confirmed a deep linear ulcer, chronic and noncaseating granulomatous inflammation, as well as a circular stricture of the esophagus with fistula into the mediastinum due to isolated esophageal Crohn's disease.	0
Thymomas are slow-growing neoplasia arising from the epithelial cells of the thymus that usually present with respiratory symptoms, superior vena cava syndrome, or parathymic syndromes. Approximately 30% of thymomas develop myasthenia gravis. An additional 5% of patients with thymomas have other systemic syndromes, including rheumatoid arthritis, thyroiditis, red cell aplasia, systemic lupus erythematosus, and Cushing syndrome. Rarely, patients can present with diarrhea due to thymoma-associated autoimmune gastrointestinal pathologies that include Good syndrome (acquired hypogammaglobulinemia), thymoma- associated multiorgan autoimmunity, and autoimmune enteropathy. We present an uncommon and interesting case of an invasive metastatic thymoma with right upper lobe endobronchial lesion and autoimmune enteropathy in a 27-year-old female. The novelty of this case lay in the findings of extensive metastatic thymoma with right upper lobe endobronchial disease and autoimmune diarrhea.	0
It is a great challenge to cure symptomatic lesions and considerable defects of hyaline cartilage due to its complex structure and poor self-repair capacity. If left untreated, unmatured degeneration will cause significant complications. Surgical intervention to repair cartilage may prevent progressive joint degeneration. A series of surgical techniques, including biological augmentation, microfracture and bone marrow stimulation, autologous chondrocyte implantation (ACI), and allogenic and autogenic chondral/osteochondral transplantation, have been used for various indications. However, the limited repairing capacity and the potential pitfalls of these techniques cannot be ignored. Increasing evidence has shown promising outcomes from ACI and cartilage transplantation. Nevertheless, the morbidity of autologous donor sites and limited resource of allogeneic bone have considerably restricted the wide application of these surgical techniques. Costal cartilage, which preserves permanent chondrocytes and the natural osteochondral junction, is an ideal candidate for the restoration of cartilage defects. Several in vitro and in vivo studies have shown good performance of costal cartilage transplantation. Although costal cartilage is a classic donor in plastic and cosmetic surgery, it is rarely used in skeletal cartilage restoration. In this review, we introduce the fundamental properties of costal cartilage and summarize costa-derived chondrocyte implantation and costal chondral/osteochondral transplantation. We will also discuss the pitfalls and pearls of costal cartilage transplantation. Costal chondral/osteochondral transplantation and costa-based chondrocytotherapy might be up-and-coming surgical techniques for recalcitrant cartilage lesions.	0
Perineural invasion, or neurotropism, is defined by the presence of cancer cells either within the neuronal sheath or found along the nerves. In melanoma, it is most commonly associated with invasive desmoplastic melanoma, a melanoma that is most commonly associated with malignant melanoma in situ, lentigo maligna type. Initially, perineural invasion was included in the reported Breslow thickness; however, recent data suggest that it should not be included. In this report, we describe a case of malignant melanoma in situ, lentigo maligna type, with associated neurotropism in the absence of invasive component.	0
Cardiac rhythm abnormalities are a leading cause of morbidity and mortality in developed countries. Loss-of-function variants in the ANK2 gene can cause a variety of cardiac rhythm abnormalities including sinus node dysfunction, atrial fibrillation and ventricular arrhythmias (called the "ankyrin-B syndrome"). ANK2 encodes ankyrin-B, a molecule critical for the membrane targeting of key cardiac ion channels, transporters, and signalling proteins.Here, we describe a family with a reciprocal chromosomal translocation between chromosomes 4q25 and 9q26 that transects the ANK2 gene on chromosome 4 resulting in loss-of-function of ankyrin-B. Select family members with ankyrin-B haploinsufficiency due to the translocation displayed clinical features of ankyrin-B syndrome. Furthermore, evaluation of primary lymphoblasts from a carrier of the translocation showed altered levels of ankyrin-B as well as a reduced expression of downstream ankyrin-binding partners.Thus, our data conclude that, similar to previously described ANK2 loss-of-function "point mutations", large chromosomal translocations resulting in ANK2 haploinsufficiency are sufficient to cause the human cardiac ankyrin-B syndrome. The unexpected ascertainment of ANK2 dysfunction via the discovery of a chromosomal translocation in this family, the determination of the familial phenotype, as well as the complexities in formulating screening and treatment strategies are discussed.	0
Trichinosis is a worldwide zoonotic disease closely related to cultural and dietary habits caused by a nematode Trichinella spp. The drugs for its prevention and treatment are still not thoroughly defined. Wortmannilactone F was used to value the therapeutic effects on the worm reduction rates, change of the intestinal mucosa, and the host's body's immune activity in this experiment. BALB/c mice were orally fed with 200 infective Trichinella spiralis larvae. Then, T. spiralis-infected mice were treated with wortmannilactone F (50, 100, and 200 mg/kg). The number and morphological analysis of adult worm, the expression of Factor associated suicide (Fas), and the level of SIgA in the mice were investigated. Wortmannilactone F showed dose-dependent anthelmintic effects by causing mortality of worms, obvious damaging effects on mature T. spiralis' surface and their digestive systems, decreasing the expression of mice's intestinal mucosa's Fas protein, and reducing intestinal mucosa's level of SIgA secretions. Wortmannilactone F is expected to be a potential therapeutic drug for trichinellosis treatment.	0
The etiology of severe hemolytic anemia in most patients with recessive hereditary spherocytosis (rHS) and the related disorder hereditary pyropoikilocytosis (HPP) is unknown. Whole exome sequencing of DNA from probands of 24 rHS or HPP kindreds identified numerous mutations in erythrocyte membrane α-spectrin (SPTA1). Twenty-eight mutations were novel, with null alleles frequently found in trans to missense mutations. No mutations were identified in a third of SPTA1 alleles (17/48). Whole genome sequencing revealed linkage disequilibrium between the common rHS-linked α-spectrinBug Hill polymorphism and a rare intron 30 variant in all 17 mutation-negative alleles. In vitro minigene studies and in vivo splicing analyses revealed the intron 30 variant changes a weak alternate branch point (BP) to a strong BP. This change leads to increased utilization of an alternate 3' splice acceptor site, perturbing normal α-spectrin mRNA splicing and creating an elongated mRNA transcript. In vivo mRNA stability studies revealed the newly created termination codon in the elongated transcript activates nonsense mediated decay leading to spectrin deficiency. These results demonstrate a unique mechanism of human genetic disease contributes to the etiology of a third of cases of rHS, facilitating diagnosis and treatment of severe anemia, and identifying a new target for therapeutic manipulation.	0
We present a case to demonstrate the feasibility of transapical beating heart mitral valve repair in a patient with dextrocardia. This minimally invasive technique provides simple, safe and satisfactory mitral repair. The surgical technique, outcome and prognosis are not affected by the condition.	0
Emery-Dreifuss muscular dystrophy (EDMD) is a rare genetic disorder characterised by the early development of muscle contractures, progressive muscle weakness, and heart abnormalities. The latter may result in serious complications, or in severe cases, sudden death. Currently, there are very few effective treatment options available for EDMD and so there is a high clinical need for new therapies. Various genetic mutations have been identified in the development and causation of EDMD, each encoding proteins that are components of the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, which spans the nuclear envelope and serves to connect the nuclear lamina to the cytoskeleton. Within this review, we examine how mutations in the genes encoding these proteins, including lamins A/C, emerin, nesprins 1/2, FHL1, and SUN1/2 lead to muscle cell differentiation and development pathway defects. Further work to identify conserved molecular pathways downstream of these defective proteins may reveal potential targets for therapy design.	0
Dyschromatosis universalis hereditaria (DUH) is a rare, autosomal dominant genodermatosis with a peculiar reticulate pigmentary change, consisting of hyperpigmented macules mingled with hypopigmented lesions to give an overall impression of mottling. We herein report a case of DUH with adermatoglyphia in a young male with family history of the disorder.	0
We review genetic diseases with identified molecular bases that include abnormal, reduced (hypoplasia), or absent (aplasia) patellae as a significant aspect of the phenotype. The known causal genes can be broadly organized according to three major developmental and cellular processes, although some genes may act in more than one of these: limb specification and pattern formation; DNA replication and chromatin structure; bone development and differentiation. There are also several genes whose phenotypes in mice indicate relevance to patellar development, for which human equivalent syndromes have not been reported. Developmental studies in mouse and chick embryos, as well as patellar involvement in human diseases with decreased mobility, document the additional importance of local environmental factors in patellar ontogenesis. Patellar anomalies found in humans can be an important clue to a clinical genetic diagnosis, and a better knowledge of the genetics of patellar anomalies will improve our understanding of limb development.	0
The specific temporal evolution of bacterial and phage population sizes, in particular bacterial depletion and the emergence of a resistant bacterial population, can be seen as a kinetic fingerprint that depends on the manifold interactions of the specific phage-host pair during the course of infection. We have elaborated such a kinetic fingerprint for a human urinary tract Klebsiella pneumoniae isolate and its phage vB_KpnP_Lessing by a modeling approach based on data from in vitro co-culture. We found a faster depletion of the initially sensitive bacterial population than expected from simple mass action kinetics. A possible explanation for the rapid decline of the bacterial population is a synergistic interaction of phages which can be a favorable feature for phage therapies. In addition to this interaction characteristic, analysis of the kinetic fingerprint of this bacteria and phage combination revealed several relevant aspects of their population dynamics: A reduction of the bacterial concentration can be achieved only at high multiplicity of infection whereas bacterial extinction is hardly accomplished. Furthermore the binding affinity of the phage to bacteria is identified as one of the most crucial parameters for the reduction of the bacterial population size. Thus, kinetic fingerprinting can be used to infer phage-host interactions and to explore emergent dynamics which facilitates a rational design of phage therapies.	0
A 5-y-old female Golden Retriever was presented with a 2-wk history of hyporexia, vomiting, diarrhea, lethargy, weight loss, polyuria, and polydipsia. Clinical examination and ultrasonography revealed multiple organ enlargement with gallbladder and kidney nodules suggestive of disseminated neoplasia. Hematologic and biochemical analyses revealed pancytopenia, hypercalcemia, and monoclonal IgA gammopathy suspicious for a plasma cell neoplasm. Bone marrow and blood smear examination revealed neoplastic atypical cells highly suggestive of lymphoid origin. Autopsy confirmed the presence of homogeneous white masses and multifocal pale infiltrates in the spleen, kidney, small intestine, gallbladder, and urinary tract. Histologic features were consistent with a multicentric atypical plasma cell tumor. Tumor cells were negative for CD204, IBA-1, E-cadherin, CD3, CD5, CD79a, CD20, and PAX5, and positive for MUM1, consistent with plasma cell origin. The presence of > 20% of circulating blastic plasma cells was consistent with primary plasma cell leukemia with plasmablastic morphology, a disease rarely described in veterinary medicine.	0
Peters' anomaly accounts for the highest type of Anterior Segment Dysgenesis (ASD). The main features of Peters' anomaly are: congenital corneal opacity centrally, defect in the posterior stroma and absence of Descemet's membrane and the endothelium. However, this condition has wide clinical and histopathological variations in appearance, associations and severity. In this case series, we summarize 6 corneas in 5 Saudi cases of Peters' anomaly (and describe 2 in detail) with unique histopathological findings that are additional to the typical known ones, shedding some light on the nomenclature of these variants according to the reported cases in the English-written literature. This will widen the spectrum of findings known to ophthalmic pathologists and ophthalmologists about this anomaly. This is also of importance in the assessment of the congenital glaucoma cases commonly seen in Saudi Arabia that often happens in association with ASD.	0
OBJECTIVE:To review acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) in light of recent information about the definitions, epidemiology, pathophysiology, management, and outcome of these conditions. DATA SOURCES:The author's personal files as well as the computerized MEDLINE database. STUDY SOLUTION: Studies were selected for their relevance to the conditions of ALI and ARDS. DATA EXTRACTION:The author extracted all applicable data. DATA SYNTHESIS:The diagnostic criteria for ALI and ARDS include a) acute onset; b) bilateral chest radiographic infiltrates; c) a pulmonary artery occlusion pressure of < or =18 mm Hg or no evidence of left atrial hypertension; and d) impaired oxygenation manifested by a PaO2/FIO2 ratio of < or =300 torr (< or =40 kPa) for ALI and < or =200 torr (< or =27 kPa) for ARDS. The incidence of ALI and ARDS are approximately 70 and 7 patients out of 100,000 of the total U.S. population per year, respectively. The conditions result from direct or indirect injury to the pulmonary epithelium and endothelium that causes edema, atelectasis, inflammation, and fibrosis. This "diffuse alveolar damage" is actually patchy in many patients. Therapy of ALI and ARDS is largely supportive, although new approaches in mechanical ventilation, patient positioning, and pharmacologic therapy have been introduced. The mortality rate of ARDS has improved to <50%, but the reasons for this improvement are unclear. CONCLUSION:ALI and ARDS are better defined and understood than ever before, and their outcome has improved for unclear reasons.	1
Lymphedema distichiasis syndrome (LDS) is a rare, autosomal dominant genetic condition, characterized by lower limb lymphedema and distichiasis. Other associated features that have been reported include varicose veins, cleft palate, congenital heart defects, and ptosis. We update a previously reported family with a pathogenic variant in FOXC2 (c.412-413insT) where five affected individuals from the youngest generation had congenital renal anomalies detected on prenatal ultrasound scan. These included four fetuses with hydronephrosis and one with bilateral renal agenesis. A further child with LDS had prominence of the left renal pelvis on postnatal renal ultrasound. We also describe a second family in whom the proband and his affected son had congenital renal anomalies; left ectopic kidney, right duplex kidney, and bilateral duplex collecting systems with partial duplex kidney with mild degree of malrotation, respectively. Foxc2 is expressed in the developing kidney and therefore congenital renal anomalies may well be associated, potentially as a low penetrance feature. We propose that all individuals diagnosed with LDS should have a baseline renal ultrasound scan at diagnosis. It would also be important to consider the possibility of renal anomalies during prenatal ultrasound of at risk pregnancies, and that the presence of hydronephrosis may be an indication that the baby is affected with LDS.	0
INTRODUCTION:The short arm of chromosome 17 is characterized by a high density of low copy repeats, creating the opportunity for non-allelic homologous recombination to occur. Microdeletions of the 17p13.3 region are responsible for neuronal migration disorders including isolated lissencephaly sequence and Miller-Dieker syndrome. CASE REPORT:We describe the case of a 4-year and 2-month-old female with peculiar somatic traits and neurodevelopmental delay. At the age of 6 months, she started to present with infantile spasms syndrome; therefore, we administered vigabatrin followed by two cycles of adrenocorticotropic hormone, with good response. The coexistence of epileptic activity, neuropsychological delay, brain imaging abnormalities, and peculiar somatic features oriented us towards the hypothesis of a genetic etiology that could explain her clinical picture. Array CGH identified a 730 Kb deletion in the p13.3 region of the short arm of chromosome 17 including eleven genes, among these are YWHAE and CRK. DISCUSSION:Microdeletions of the 17p13.3 region involving only YWHAE and CRK, sparing PAFAH1B1, result in neurodevelopmental delay, growth retardation, craniofacial dysmorphisms, and mild structural brain abnormalities. Differently from the previously described patients carrying YWHAE and CRK deletions, the main complaint of our patient was represented by seizures. The absence of clear neuronal migration defects and mutations of the PAFAH1B1 gene in our patient underlines the central role of additional genes located in the 17p13.3 chromosomal region in the pathogenesis of epilepsy and helps to expand the phenotype of 17p13.3 microdeletion syndrome.	0
We report a patient with Muenke syndrome who had repetitive apneic spell followed by focal status epilepticus in the early infancy. Ictal EEG showed focal spikes bursts originated from the left hemisphere and sifted to the right hemisphere, during which he had migrating tonic seizures from right side of the body to the left side of the body. Brain MRI showed abnormal development of bilateral hippocampus, which was characterized as abnormal folding of hippocampal gyri. However, the long-term seizure prognosis was favorable. Results from this and previous studies failed to support the notion that FGFR3 (P250) mutation results in epileptic encephalopathy.	0
BACKGROUND:Collecting duct carcinoma (CDC) of the kidney is a rare and highly aggressive malignant tumor with the worst prognosis among all renal cancers. Nevertheless, the first-line treatments, including chemotherapy and target therapy, usually show poor response to CDC. Recent studies have suggested that immunotherapy targeting personal tumor-specific neoantigens could be a promising strategy for several solid cancers. However, whether it has therapeutic potential in CDC remains unclear. CASE PRESENTATION:Here, we report a case of an Asian patient who underwent personalized neoantigen-based immunotherapy. The patient was diagnosed with metastatic CDC and suffered extensive tumor progression following sorafenib treatment. Based on the patient's own somatic mutational profile, a total of 13 neoantigens were identified and corresponding long-peptide vaccine and neoantigen-reactive T cells (NRTs) were prepared. After six cycles of neoantigen-based vaccination and T-cell immunotherapy, the patient was reported with stable disease status in tumor burden and significant alleviation of bone pain. Ex vivo interferon-γ enzyme-linked immunospot assay proved the reactivity to 12 of 13 neoantigens in peripheral blood mononuclear cells collected after immunotherapy, and the preferential reactivity to mutant peptides compared with corresponding wild-type peptides was also observed for 3 of the neoantigens. Surprisingly, biopsy sample collected from CDC sites after 3 months of immunotherapy showed decreased mutant allele frequency corresponding to 92% (12/13) of the neoantigens, indicating the elimination of tumor cells carrying these neoantigens. CONCLUSIONS:Our case report demonstrated that the combined therapy of neoantigen peptide vaccination and NRT cell infusion showed certain efficacy in this CDC case, even when the patient carried only a relatively low tumor mutation burden. These results indicated that the personalized neoantigen-based immunotherapy was a promising new strategy for advanced CDC. TRIAL REGISTRATION NUMBER:ChiCTR1800017836.	0
Alaskan Husky encephalopathy (AHE(1) ) is a fatal brain disease associated with a mutation in SLC19A3.1 (c.624insTTGC, c.625C>A). This gene encodes for a thiamine transporter 2 with a predominately (CNS) central nervous system distribution. Considering that brain is particularly vulnerable to thiamine deficiency because of its reliance on thiamine pyrophosphate (TPP)-dependent metabolic pathways involved in energy metabolism and neurotransmitter synthesis, we characterized the impact of this mutation on thiamine status, brain bioenergetics and the contribution of oxidative stress to this phenotype. In silico modeling of the mutated transporter indicated a significant loss of alpha-helices resulting in a more open protein structure suggesting an impaired thiamine transport ability. The cerebral cortex and thalamus of affected dogs were severely deficient in TPP-dependent enzymes accompanied by decreases in mitochondrial mass and oxidative phosphorylation (OXPHOS) capacity, and increases in oxidative stress. These results along with the behavioral and pathological findings indicate that the phenotype associated with AHE is consistent with a brain-specific thiamine deficiency, leading to brain mitochondrial dysfunction and increased oxidative stress. While some of the biochemical deficits, neurobehavior and affected brain areas in AHE were shared by Wernicke's and Korsakoff's syndromes, several differences were noted likely arising from a tissue-specific vs. that from a whole-body thiamine deficiency.	0
OBJECT: There are a variety of treatment options for the management of vestibular schwannomas (VSs), including microsurgical resection, radiotherapy, and observation. Although the choice of treatment is dependent on various patient factors, physician bias has been shown to significantly affect treatment choice for VS. In this study the authors describe the current epidemiology of VS and treatment trends in the US in the modern era. They also illustrate patient and tumor characteristics and elucidate their effect on tumor management. METHODS: Patients diagnosed with VS were identified through the Surveillance, Epidemiology, and End Results database, spanning the years 2004-2009. Age-adjusted incidence rates were calculated and adjusted using the 2000 US standard population. The chi-square and Student t-tests were used to evaluate differences between patient and tumor characteristics. Multivariate logistic regression was performed to determine the effects of various patient and tumor characteristics on the choice of tumor treatment. RESULTS: A total of 6225 patients with VSs treated between 2004 and 2009 were identified. The overall incidence rate was 1.2 per 100,000 population per year. The median age of patients with VS was 55 years, with the majority of patients being Caucasian (83.16%). Of all patients, 3053 (49.04%) received surgery only, with 1466 (23.55%) receiving radiotherapy alone. Both surgery and radiation were only used in 123 patients (1.98%), with 1504 patients not undergoing any treatment (24.16%). Increasing age correlated with decreased use of surgery (OR 0.95, 95% CI 0.95-0.96; p<0.0001), whereas increasing tumor size was associated with the increased use of surgery (OR 1.04, 95% CI 1.04-1.05; p<0.0001). Older age was associated with an increased likelihood of conservative management (OR 1.04, 95% CI 1.04-1.05; p<0.0001). Racial disparities were also seen, with African American patients being significantly less likely to receive surgical treatment compared with Caucasians (OR 0.50, 95% CI 0.35-0.70; p<0.0001), despite having larger tumors at diagnosis. CONCLUSIONS: The incidence of vestibular schwannomas in the US is 1.2 per 100,000 population per year. Although many studies have demonstrated improved outcomes with the use of radiotherapy for small- to medium-sized VSs, surgery is still the most commonly used treatment modality for these tumors. Racial disparities also exist in the treatment of VSs, with African American patients being half as likely to receive surgery and nearly twice as likely to have their VSs managed conservatively despite presenting with larger tumors. Further studies are needed to elucidate the reasons for treatment disparities and investigate the nationwide trend of resection for the treatment of small VSs.	1
Erythema ab igne is a thermal-associated skin condition that can occur secondary to persistent direct or indirect contact with heat. Historically, erythema ab igne has been linked to fireplace and stove exposures; more recently, it has been associated with heaters, hot water bottles, and laptops. A 48-year-old woman presented for the evaluation of hyperpigmented, reticulated macular lesions on her distal legs. Additional history revealed that she had developed erythema ab igne secondary to the use of a space heater underneath her desk at work. Her skin condition stopped progressing with removal of the causative agent. In addition to erythema ab igne, heat-related skin conditions include basal cell carcinomas and squamous cell carcinomas, burns, erythromelalgia, subtypes of urticaria, and ultraviolet-associated disorders. Awareness of thermal-associated skin conditions enables the clinician to establish the appropriate diagnosis based on the associated history of the condition, the morphology of the skin lesion, and, if necessary, correlation with the skin biopsy findings of the cutaneous condition.	0
Congenital adrenal hyperplasia (CAH) is the most common cause of primary adrenal insufficiency in children and adolescents. It comprises several clinical entities associated with mutations in genes, encoding enzymes involved in cortisol biosynthesis. The mutations lead to considerable (non-classic form) to almost complete (classic form) inhibition of enzymatic activity, reflected by different phenotypes and relevant biochemical alterations. Up to 95% cases of CAH are due to mutations in CYP21A2 gene and subsequent 21α-hydroxylase deficiency, characterized by impaired cortisol synthesis and adrenal androgen excess. In the past two decades an alternative ("backdoor") pathway of androgens' synthesis in which 5α-androstanediol, a precursor of the 5α-dihydrotestosterone, is produced from 17α-hydroxyprogesterone, with intermediate products 3α,5α-17OHP and androsterone, in the sequence and with roundabout of testosterone as an intermediate, was reported in some studies. This pathway is not always considered in the clinical assessment of patients with hyperandrogenism. The article describes the case of a 17-year-old female patient with menstrual disorders and androgenization (persistent acne, advanced hirsutism). Her serum dehydroepiandrosterone sulfate and testosterone were only slightly elevated, along with particularly high values for 5α-dihydrotestosterone. In 24 h urine collection, an increased excretion of 16α-OHDHEA-a dehydroepiandrosterone metabolite-and pregnanetriolone-a 17α-hydroxyprogesterone metabolite-were observed. The investigations that we undertook provided evidence that the girl suffered from non-classic 21α-hydroxylase deficiency with consequent enhancement of the androgen "backdoor" pathway in adrenals, peripheral tissues or both, using adrenal origin precursors. The paper presents diagnostic dilemmas and strategies to differentiate between various reasons for female hyperandrogenism, especially in childhood and adolescence.	0
The phenotypic characters of X -linked Hypohidrotic Ectodermal Dysplasia (XLHED) are the dysplasia of epithelial- and mesenchymal-derived organs. Ectodysplasin (EDA) is the causative gene of XLHED.The current study reported a large Chinese XLHED pedigree. The genomic DNA of adult and fetus was extracted from peripheral blood and shed chorion cell respectively. The nucleotide variation in EDA gene was screened through direct sequencing the coding sequence. The methylation state of EDA gene's promoter was evaluated by pyrosequencing.This Chinese XLHED family had two male patients and three carriers. All of them were with a novel EDA frameshift mutation. The mutation, c.172-173insGG, which leads to an immediate premature stop codon in exon one caused severe structural changes of EDA. Prenatal diagnosis suggested that the fetus was a female carrier. The follow-up observation of this child indicated that she had mild hypodontia of deciduous teeth at age six. The methylation level of EDA gene's promoter was not related to carriers' phenotype changes in this family.We reported a new frameshift mutation of EDA gene in a Chinese family. Prenatal diagnosis can help to predict the disease status of the fetus.	0
Porcine pleuropneumonia caused by Actinobacillus pleuropneumoniae (APP) is a swine respiratory disease with an important impact around the world either as a single infection or part of the porcine respiratory disease complex. The data of interaction between hosts and pathogens has becoming more crucial for exploration of the mechanism. However, up to now, comparatively little information is available on the systemic and dynamic changes that occur in pig serum in response to APP infection. This study used iTRAQ to identify differentially expressed proteins (DEPs) in pig serum in response to APP infection. Compared with the APP un-infected group (S0),there were 137 up-regulated and 68 down-regulated proteins at 24 h (S24), and 81 up-regulated and 107 down-regulated proteins at 120 h (S120). At 24 h, the immune response was not significantly enriched, but cell adhesion, cytosol, Golgi apparatus, GTP and ATP binding and regulation of cell cycle were extremely active, implying host preparation of immune response starting. Subsequently, innate immune response, negative regulation of apoptotic process, immunological synapse, adaptive immune response, the regulation of inflammatory response, positive regulation of T cell proliferation were more enhanced at 120 h then that of 24 h, representing innate immunity transferring to the adaptive, while endocytosis, cell adhesion and platelet aggregation showed obvious decline. The pathways of T cell receptor signaling pathway, cytokine-cytokine receptor interaction, complement and coagulation cascades, leukocyte transendothelial migration were active remarkably during all infection period, and more pathways could connect to form innate immune defense networks. Surprisingly, the pathways like amoebiasis, rheumatoid arthritis and malaria had been found up-regulated. As a conclusion, APP could delay host inflammatory response to the infection at early stage, and induced innate immunity to convert from adhesion, interaction into complement activation, proteasome digestion, bacterial invasion at later stage. This would increase our understanding of the porcine distinct response to APP infection.	0
The natural outcome of abdominal aortic aneurysm (AAA) is that of slow progression and ultimate rupture, then a life-threatening hemorrhage consequently. Ruptured AAA is a dramatic catastrophe and constitutes one of the leading causes of acute death in elderly men. However, the mechanism of AAA is still unclear. Transient receptor potential vanilloid (TRPV) family has protective effects in cardiovascular diseases. In this study, we revealed the expression and the pathogenesis of TRPV1 in a mouse AAA model. The results presented here identify TRPV1 could be a potential therapeutic target for AAA treatment.	0
Otofaciocervical syndrome (OFCS) is a rare disorder characterized by facial anomalies, cup-shaped low-set ears, preauricular fistulas, hearing loss, branchial defects, skeletal anomalies, and mild intellectual disability. Autosomal dominant cases are caused by deletions or point mutations of EYA1. A single family with an autosomal recessive form of OFCS and a homozygous missense mutation in PAX1 gene has been described. We report whole exome sequencing of 4 members of a consanguineous family in which 2 children, showing features of OFCS, expired from severe combined immunodeficiency (SCID). To date, the co-occurrence of OFCS and SCID has never been reported. We found a nonsense homozygous mutation in PAX1 gene in the 2 affected children. In mice, Pax1 is required for the formation of specific skeletal structures as well as for the development of a fully functional thymus. The mouse model strongly supports the hypothesis that PAX1 depletion in our patients caused thymus aplasia responsible for SCID. This report provides evidence that bi-allelic null PAX1 mutations may lead to a multi-system autosomal recessive disorders, where SCID might represent the main feature.	0
Phenotypic variability in maturity-onset diabetes of the young (MODY) makes screening criteria for genomic analysis challenging. We describe the clinical spectrum in a large pedigree with HNF1A-MODY; as generations progressed, the course and outcome became poorer. Although uncommon, pancreatic autoantibodies and diabetes ketoacidosis should not exclude the diagnosis of MODY.	0
PURPOSE:To compare disease severity in detail between patients carrying variants in exons 1-14 and ORF15 of retinitis pigmentosa GTPase regulator (RPGR). METHODS:Systematic next-generation sequencing data analysis, Sanger sequencing validation and segregation analysis were utilised to identify the pathogenic variants. Detailed ophthalmic examinations, including electroretinograms, fundus photography, fundus autofluorescence and optical coherence tomography were performed. Statistical analysis, including age adjustment and comparison, were performed based on cross-sectional level to compare disease severity between variants in the two RPGR variant groups. RESULTS:Sixty-two variants were identified in RPGR in 86 patients from 77 unrelated families. Twenty-nine (37.7%) had variants in RPGR-exons 1-14 (group 1) and 48 (62.3%) in RPGR-ORF15 (group 2). Eighty-four patients were diagnosed with X-linked retinitis pigmentosa and only two patients with cone-rod dystrophy. LogMAR visual acuity increased 0.035 and 0.022 each year on average in group 1 and group 2, respectively. Group 2 patients had better visual acuity with a mean logMAR difference of 0.4378, which is significant after age adjustment (P < 0.01). Neither the value of log (ellipsoid zone width) nor central retinal thickness was significantly correlated with variant grouping after considering the effect of the age variable (P = 0.56 and 0.40, respectively). Spherical refractive error did not differ significantly between the two variant groups (P = 0.17). Patterns of autofluorescence included a hyperfluorescent ring at the posterior pole, diffuse hyperfluorescence in the macular area, and dark macular autofluorescence with or without fovea hyperfluorescence. The age and proportion of fundus autofluorescence patterns between the two variant groups were significantly different (P < 0.01). CONCLUSIONS:Patients with variants in exons 1-14 retained less visual acuity than patients with ORF15 variants and deteriorated faster. However, the ellipsoid zone widths, central retinal thickness and refractions were comparable between the two groups. Autofluorescence pattern relates to the age and the variant grouping.	0
There has been a growing interest toward mitochondrial fatty acid synthesis (mtFAS) since the recent discovery of a neurodegenerative human disorder termed MEPAN (mitochondrial enoyl reductase protein associated neurodegeneration), which is caused by mutations in the mitochondrial enoyl-CoA/ACP (acyl carrier protein) reductase (MECR) carrying out the last step of mtFAS. We show here that MECR protein is highly expressed in mouse Purkinje cells (PCs). To elucidate mtFAS function in neural tissue, here, we generated a mouse line with a PC-specific knock-out (KO) of Mecr, leading to inactivation of mtFAS confined to this cell type. Both sexes were studied. The mitochondria in KO PCs displayed abnormal morphology, loss of protein lipoylation, and reduced respiratory chain enzymatic activities by the time these mice were 6 months of age, followed by nearly complete loss of PCs by 9 months of age. These animals exhibited balancing difficulties ∼7 months of age and ataxic symptoms were evident from 8-9 months of age on. Our data show that impairment of mtFAS results in functional and ultrastructural changes in mitochondria followed by death of PCs, mimicking aspects of the clinical phenotype. This KO mouse represents a new model for impaired mitochondrial lipid metabolism and cerebellar ataxia with a distinct and well trackable cellular phenotype. This mouse model will allow the future investigation of the feasibility of metabolite supplementation approaches toward the prevention of neurodegeneration due to dysfunctional mtFAS.SIGNIFICANCE STATEMENT We have recently reported a novel neurodegenerative disorder in humans termed MEPAN (mitochondrial enoyl reductase protein associated neurodegeneration) (Heimer et al., 2016). The cause of neuron degeneration in MEPAN patients is the dysfunction of the highly conserved mitochondrial fatty acid synthesis (mtFAS) pathway due to mutations in MECR, encoding mitochondrial 2-enoyl-CoA/ACP reductase. The report presented here describes the analysis of the first mouse model suffering from mtFAS-defect-induced neurodegenerative changes due to specific disruption of the Mecr gene in Purkinje cells. Our work sheds a light on the mechanisms of neurodegeneration caused by mtFAS deficiency and provides a test bed for future treatment approaches.	0
Background:To demonstrate the long-term results of enhanced cosmetic pterygium surgery with extensive Tenonectomy, adjunctive fibrin-glued amniotic membrane transplantation (AMT), and mitomycin C (MMC). Methods:Retrospective chart review of patients who had pterygium surgery with AMT and MMC between January 2001 to July 2017 and had completed at least 6 months of follow-up. Early and long-term postoperative cosmetic outcomes, recurrence rate, and complications were analyzed. Cosmetic outcomes were evaluated based on patient and surgeon reported outcome measures. Results:The study was conducted on a total of 603 eyes of 578 patients (316 males, 262 females) with an average age of 52.9 ± 15.1 years. At post-op day 1, patients reported no discomfort and could not tell which eye had surgery based on patient reported subjective grading scales. Over an average follow-up period of 23.1 ± 35 months (range: 6-216 months), there was one pterygium recurrence (0.2%), eighteen granulomas (2.9%), one self-resolving scleral melt (0.2%), one correctable restricted ocular motility (0.2%), one pupil abnormality (0.2%), one dellen (0.2%) and one correctable upper lid abnormality (0.2%). Planned laser vision correction was used for residual corneal scar in eleven eyes (1.8%) as a staged refractive approach. Conclusion:This study highlights an improved technique of an old concept of pterygium surgery that not only reduces the recurrence but also enhances cosmetic excellence and improves the quality of vision.	0
OBJECTIVE:To evaluate the pathological and radiological features, hormone profiles, surgery and treatment methods of metaplastic breast carcinoma cases diagnosed at our center in the light of current literature. MATERIAL AND METHOD:A total of 38 metaplastic breast cancer cases diagnosed between 2006-2018 at our center were included in the study. The patients were evaluated in terms of age, tumor size, localization, histological grade, hormone profiles (ER, PR, Her2-neu), American Joint Committee on Cancer (AJCC) Tumor, Lymph node status, Metastases (TNM) stage, progression, survival, radiological features, types of surgery and therapy modalities (chemotherapy and / or radiotherapy). RESULTS:The age of the patients ranged between 32 and 95 years. Pathological evaluation of cases showed that 14 were pure epithelial (IC-NST + squamous cell carcinoma) and 24 were metaplastic carcinomas with mesenchymal differentiation. Ductal carcinoma in situ (DCIS) was accompanying an invasive component in twenty cases. Seventeen patients had lymph node metastasis. Twelve patients developed distant metastasis. Thirty patients were triple negative for hormone receptors. The mean follow-up period of the patients was 34 months. The estimated life expectancy was 116 months. All of the patients received chemotherapy and 28 patients received adjuvant radiotherapy. There was no correlation between tumor size and lymph node or distant metastasis in our series. Our findings are consistent with the literature. CONCLUSION:Metaplastic breast carcinoma is a rare entity among breast carcinomas. Metaplastic carcinomas of the breast draw attention with the differences in their clinical course and the radiological and pathological heterogeneity.	0
Peroxiredoxins (PRXs) are intracellular anti-oxidative enzymes but work as inflammatory amplifiers under the extracellular condition. To date, the function of PRXs in the pathogenesis of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is not fully understood. The aim of this study was to investigate whether PRXs play a role in the pathogenesis of MS and NMOSD. We analyzed levels of PRXs (PRX1, PRX5 and PRX6) in the cerebrospinal fluid (CSF) and serum of 16 patients with MS, 16 patients with NMOSD and 15 patients with other neurological disorders (ONDs). We identified potential correlations between significantly elevated PRXs levels and the clinical variables in patients with MS and NMOSD. Additionally, pathological analyses of PRXs (PRX1-6) in the central nervous system (CNS) were performed using the experimental autoimmune encephalomyelitis (EAE), animal model of MS. We found that serum levels of PRX5 and PRX6 in patients with MS and NMOSD were higher compared with those in patients with ONDs (P < 0·05). Furthermore, high levels of PRX5 and PRX6 were partly associated with blood-brain barrier dysfunction and disease duration in NMOSD patients. No significant elevation was found in CSF PRXs levels of MS and NMOSD. Spinal cords from EAE mice showed remarkable PRX5 staining, especially in CD45+ infiltrating cells. In conclusion, PRX5 and PRX6 may play a role in the pathogeneses of MS and NMOSD.	0
The filamin A gene (FLNA) on Xq28 encodes the filamin A protein. Mutation in FLNA causes a wide spectrum of disease including skeletal dysplasia, neuronal migration abnormality, cardiovascular malformation, intellectual disability and intestinal obstruction. Recently, childhood-onset interstitial lung disease associated with a range of FLNA mutations has been recognised and reported. We document our personal experience of this emerging disorder and compile a comprehensive overview of clinical features and molecular changes in all identifiable published cases. Reviewing the emerging dataset, we underline this unanticipated phenotypic consequence of pathogenic FLNA mutation-associated pulmonary disease.Conclusion: From the emerging data, we suggest that while reviewing complex cases with a sustained oxygen requirement against a clincial background of cardiac concerns or intestinal obstruction to have a high index of suspicion for FLNA related pathology and to instigate early MRI brain scan and FLNA mutation analysis. What is Known: • FLNA gene on Xq28 encodes the filamin A protein and mutation therein is associated with variable phenotypes depending on its nature of mutation. • Loss-of-function mutation of filamin A is associated with X-linked inherited form of periventricular nodular heterotopia with or without epilepsy with most individuals affected being female. There is a recently recognised associated respiratory phenotype. What is New: • The respiratory phenotype in the form of childhood interstitial lung disease is a recently recognised clinical consequence of loss-of-function FLNA mutation. • Rare male patients with loss-of-function FLNA mutation-associated lung disease with residual protein function can survive into infancy with a severe form of the phenotype.	0
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of clinically aggressive diseases associated with poor outcome. Studies that focus specifically on PTCL are emerging, with the ultimate goal of improved understanding of disease biology and the development of more effective therapies. However, one of the difficulties in classifying and studying treatment options in clinical trials is the rarity of these subtypes. Various groups have developed lymphoma classifications over the years, including the World Health Organization, which updated its classification in 2008. This article briefly reviews the major lymphoma classification schema, highlights contributions made by the collaborative International PTCL Project, discusses prognostic issues and gene expression profiling, and outlines therapeutic approaches to PTCL. These include the standard chemotherapeutic regimens and other modalities incorporating antifolates, conjugates, histone deacetylase inhibitors, monoclonal antibodies, nucleoside analogs, proteasome inhibitors, and signaling inhibitors. As this review emphasizes, the problem has now evolved into an abundance of drugs and too few patients available to test them. Collaborative groups will aid in future efforts to find the best treatment strategies to improve the outcome for patients with PTCL.	1
Liver regeneration requires intrahepatic and extrahepatic metabolic reprogramming to meet the high hepatic bioenergy demand for liver cell repopulation. This study aims to elucidate how pyruvate dehydrogenase kinase 4 (PDK4), a critical regulator of glucose and lipid metabolism, coordinates metabolic regulation with efficient liver growth. We found that hepatic Pdk4 expression was elevated after two-thirds partial hepatectomy (PHx). In Pdk4 -/- PHx mice, the liver/body weight ratio was more rapidly restored, accompanied by more aggressive hepatic DNA replication; however, Pdk4 -/- mice developed more severe hypoglycemia. In Pdk4 -/- PHx livers, the pro-regenerative insulin signaling was potentiated, as demonstrated by early peaking of the phosphorylation of insulin receptor, more remarkable induction of the insulin receptor substrate proteins, IRS1 and IRS2, and more striking activation of Akt. The hepatic up-regulation of CD36 contributed to the enhanced transient regeneration-associated steatosis in Pdk4 -/- PHx mice. Notably, CD36 overexpression in mice promoted the recovery of liver/body weight ratio and elevated intrahepatic adenosine triphosphate after PHx. CD36 expression was transcriptionally suppressed by FOXO1 (forkhead box protein O1), which was stabilized and translocated to the nucleus following AMPK (adenosine monophosphate-activated protein kinase) activation. PHx remarkably induced AMPK activation, which became incompetent to respond in Pdk4 -/- livers. Moreover, we defined that PDK4-regulated AMPK activation directly depended on intracellular adenosine monophosphate in vitro and in regenerative livers. Conclusion: PDK4 inhibition reprograms glucose and lipid metabolism to promote liver regeneration by enhancing hepatic insulin/Akt signaling and activating an AMPK/FOXO1/CD36 regulatory axis of lipid. These findings may lead to potential therapeutic strategies to prevent hepatic insufficiency and liver failure.	0
Genetic factors have been implicated in osteoarthritis (OA), particularly in OA of the hip joint (hip OA). Several instances of familial hip OA that show distinctive modes of inheritance but that differ from chondrodysplasia have been reported. Here, we report the characterization of a large Japanese family with an inherited disease of the hip that is indistinguishable from common hip OA, as evidenced by clinical symptoms and radiographs of the joint. This family contained eight patients in 4 generations. Affected individuals develop pain in the hip joint during adolescence, and the disease progresses to severe crippling before age 60 years. Patients generally are in good health, height is not reduced, and there is no extraskeletal involvement suggestive of chondrodysplasia. The skeletal change is bilateral acetabular dysplasia followed by OA, which occurs after age approximately 40 years and is indistinguishable from idiopathic nonfamilial dysplastic hip OA. This trait shows autosomal dominant inheritance, with a considerably consistent phenotype. Genomewide screening revealed linkage at chromosome 13q22, and haplotype analysis narrowed the locus to a 6.0-cM interval between markers D13S1296 and D13S162, with a maximal multipoint LOD score of 3.57. The family described here represents a novel genetic entity as a monogenic form of hip OA. Its further characterization can aid in elucidating the etiology and pathogenesis of a common idiopathic form of OA.	0
7q11.23 duplication syndrome is a disease caused by duplication of a region of chromosome 7 comprising 26 genes. The first case described in the literature was reported by Somerville et al. in 2005, who described a patient with dolichocephaly, high and narrow forehead, long eyelashes, high and wide nose, short philtrum, high arched palate, dental malocclusion, retrognathia, and severe language delay. We report the case of a Colombian patient with 7q11.23 duplication by comparative genomic hybridization techniques, and classical clinical findings, this being the first reported case in Colombia and Latin America.	0
Novel pathogens can cause massive declines in populations, and even extirpation of hosts. But disease can also act as a selective pressure on survivors, driving the evolution of resistance or tolerance. Bat white-nose syndrome (WNS) is a rapidly spreading wildlife disease in North America. The fungus causing the disease invades skin tissues of hibernating bats, resulting in disruption of hibernation behavior, premature energy depletion, and subsequent death. We used whole-genome sequencing to investigate changes in allele frequencies within a population of Myotis lucifugus in eastern North America to search for genetic resistance to WNS. Our results show low FST values within the population across time, i.e., prior to WNS (Pre-WNS) compared to the population that has survived WNS (Post-WNS). However, when dividing the population with a geographical cut-off between the states of Pennsylvania and New York, a sharp increase in values on scaffold GL429776 is evident in the Post-WNS samples. Genes present in the diverged area are associated with thermoregulation and promotion of brown fat production. Thus, although WNS may not have subjected the entire M. lucifugus population to selective pressure, it may have selected for specific alleles in Pennsylvania through decreased gene flow within the population. However, the persistence of remnant sub-populations in the aftermath of WNS is likely due to multiple factors in bat life history.	0
Idiopathic spinal cord herniation (ISCH) is displacement of spinal cord through a dural or arachnoidal defect. Most patients present with back pain or myelopathy, paresthesia, and sensory or motor weakness. Imaging findings include anterior displacement of the cord with possible kink, no filling defect on CT myelography, and no restricted diffusion/mass lesion on magnetic resonance imaging. Abrupt kink in the spinal cord or widened cerebrospinal fluid (CSF) space can be caused by a variety of reasons. The differential considerations include arachnoid web, intradural extramedullary epidermoid or arachnoid cyst, abscess or cystic schwannoma. We discuss the features, imaging, differentials, and treatment of ISCH as a rare cause of such kink in the cord. While reading such cases, a radiologist should include the location, segments involved, cord signal abnormality, visible defect, scalpel sign or C-sign, ventral cord kink, nuclear trail sign, the ventral CSF space preservation, or obliteration and the type.	0
Heterozygous mutations in the ATP1A3 gene, coding for an alpha subunit isoform (α3) of Na+/K+-ATPase, are the primary genetic cause for rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). Recently, cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss (CAPOS), early infantile epileptic encephalopathy (EIEE), childhood rapid onset ataxia (CROA) and relapsing encephalopathy with rapid onset ataxia (RECA) extend the clinical spectrum of ATP1A3 related disorders. AHC and RDP demonstrate distinct clinical features, with AHC symptoms being generally more severe compared to RDP. Currently, it is largely unknown what determines the disease severity, and whether severity is linked to the degree of functional impairment of the α3 subunit. Here we compared the effect of twelve different RDP and AHC specific mutations on the expression and function of the α3 Na+/K+-ATPase in transfected HEK cells and oocytes. All studied mutations led to functional impairment of the pump, as reflected by lower survival rate and reduced pump current. No difference in the extent of impairment, nor in the expression level, was found between the two phenotypes, suggesting that these measures of pump dysfunction do not exclusively determine the disease severity.	0
PURPOSE: This study evaluates the incidence trends and clinical outcomes of children with hepatocellular carcinoma (HCC) and assesses factors predictive of patient survival. METHODS: The Surveillance, Epidemiology, and End Results registry was queried from 1973 to 2009 for all patients between ages 0 and 19 with primary HCC. Demographics, tumor histology, surgical intervention, and patient survival were collected. RESULTS: Overall, 218 patients were identified. The annual age-adjusted incidence was 0.05 cases per 100,000 in 2009. Fibrolamellar subtype tumors were exclusive to children >5years old and exhibited greater survival compared to non-fibrolamellar subtype (57% vs. 28%, respectively, p=0.002). Tumor extirpation for patients with resectable disease significantly improved overall survival at 5years compared to no surgery (60% vs. 0%, respectively, p<0.0001). Overall 5-, 10- and 20-year survival for the entire cohort was 24%, 23%, and 8%, respectively. Independent prognostic factors of lower mortality according to multivariate analysis were surgical resection (hazard ratio (HR)=0.18), non-Hispanic ethnicity (HR=0.52), and local disease at presentation (HR=0.46). CONCLUSION: Over the past four decades, the incidence of HCC has remained relatively stable. Children of Hispanic ethnicity have high mortality rates. However, HCC resection for curative intent significantly improves outcomes.	1
Members of the International Skeletal Society compiled a glossary of terms for musculoskeletal radiology. The authors also represent national radiology or pathology societies in Asia, Australia, Europe, and the USA. We provide brief descriptions of musculoskeletal structures, disease processes, and syndromes and address their imaging features. Given the abundance of musculoskeletal disorders and derangements, we chose to omit most terms relating to neoplasm, spine, intervention, and pediatrics. Consensus agreement was obtained from 19 musculoskeletal radiology societies worldwide.	0
BACKGROUND:Panel-based targeted exome sequencing was used to analyze the genetic and clinical findings of targeted genes in a cohort of northeast Chinese with retinitis pigmentosa. METHODS:A total of 87 subjects, comprising 23 probands and their family members (total patients: 32) with confirmed retinitis pigmentosa were recruited in the study. Panel-based targeted exome sequencing was used to sequence the patients and family members, all subjects with retinitis pigmentosa underwent a complete ophthalmologic examination. RESULTS:Of the 23 probands, the clinical manifestations include night blindness, narrowing of vision, secondary cataracts, choroidal atrophy, color blindness, and high myopia, the average age of onset of night blindness is 12.9 ± 14 (range, 0-65; median, 8). Posterior subcapsular opacities is the most common forms of secondary cataracts (nine cases, 39.1%), and peripheral choroidal atrophy is the most common form of secondary choroidal atrophy (12 cases, 52.2%). Of these probands with complication peripheral choroidal atrophy, there were eight probands (66.7%, 8/12) caused by the pathogenic variation in USH2A gene. A total of 17 genes and 45 variants were detected in 23 probands. Among these genes, the commonest genes were USH2A (40%; 18/45), RP1 (15.6%; 7/45), and EYS (8.9%; 4/45), and the top three genes account for 56.5% (13/23) of diagnostic probands. Among these variants, comprising 22 (48.9%) pathogenic variants, 14 (31%) likely pathogenic variants, and nine (20%) uncertain clinical significance variants, and 22 variants was discovered first time. Most of the mutations associated with RP were missense (53.3%, 24/45), and the remaining mutation types include frameshift (35.6%, 16/45), nonsense (6.7%, 3/45), and spliceSite (4.4%, 2/45). Among the probands with mutations detected, compound heterozygous forms was detected in 13 (56.5%, 13/23) probands, and digenic inheritance (DI) forms was detected in five (21.7%, 5/23) probands. CONCLUSION:Panel-based targeted exome sequencing revealed 23 novel mutations, recognized different combinations forms of variants, and extended the mutational spectrum of retinitis pigmentosa and depicted common variants in northeast China.	0
Objectives:This study aimed to analyze the clinical and imaging findings as well as the outcomes of patients with Mullerian duct anomalies. Materials and Methods:A retrospective analysis of 41 patients with Mullerian development anomalies treated in a tertiary care center in the past 9 years was done. The presenting symptoms, radiological findings, management, and the outcomes were evaluated. Results:According to the American Fertility Society's classification, 11 patients presented in Class I, 6 in Class II, and 24 in Class III of the classification. It was found that some of the defects such as the unicornuate uterus, a unicornuate uterus with noncommunicating rudimentary horn, and longitudinal vaginal septum were usually asymptomatic whereas disorders such as Mayer-Rokitansky-Küster-Hauser (MRKH), cervicovaginal atresia, and transverse vaginal septum presented with the absence of menarche, cyclical abdominal pain, and abdominal mass, respectively. Defects such as the bicornuate uterus, didelphys uterus, and septate uterus present with poor reproductive performance. Unicornuate uterus with communicating horn presented with rupture of the horn in the antenatal period, which was managed vigorously. Vaginoplasty with a skin graft and amnion graft had excellent results in MRKH syndrome. Patients with cervicovaginal atresia had a poor prognosis and ultimately required a hysterectomy. Hysteroscopic septal resection improved the reproductive performance in the patients with septate uterus. Conclusion:This study concluded that the management of uterine malformations is individualized depending on the symptoms and fertility concerns. Cervicovaginal atresia was associated with restenosis after surgery ultimately required a hysterectomy. MRKH had excellent results with McIndoe vaginoplasty. Optimal and timely management may lead to better outcomes.	0
Downbeat nystagmus (DBN) is a frequent form of acquired persisting central fixation nystagmus, often associated with other cerebellar ocular signs, such as saccadic smooth pursuit or gaze-holding deficits. Despite its distinct clinical features, the underlying etiology of DBN often remains unclear. Therefore, a genome-wide association study (GWAS) was conducted in 106 patients and 2609 healthy controls of European ancestry to identify genetic variants associated with DBN. A genome-wide significant association (p < 5 × 10-8) with DBN was found for a variation on chromosome 13 located within the fibroblast growth factor 14 gene (FGF14). FGF14 is expressed in Purkinje cells (PCs) and a reduction leads to a decreased spontaneous firing rate and excitability of PCs, compatible with the pathophysiology of DBN. In addition, mutations in the FGF14 gene cause spinocerebellar ataxia type 27. Suggestive associations (p < 1 × 10-05) could be detected for 15 additional LD-independent loci, one of which is also located in the FGF14 gene. An association of a region containing the dihydrofolate reductase (DHFR) and MutS Homolog 3 (MSH3) genes on chromosome 5 was slightly below the genome-wide significance threshold. DHFR is relevant for neuronal regulation, and a dysfunction is known to induce cerebellar damage. Among the remaining twelve suggestive associations, four genes (MAST4, TPPP, FTMT, and IDS) seem to be involved in cerebral pathological processes. Thus, this GWAS analysis has identified a potential genetic contribution to idiopathic DBN, including suggestive associations to several genes involved in postulated pathological mechanisms of DBN (i.e., impaired function of cerebellar PCs).	0
Waldenström macroglobulinemia (WM) is an uncommon lymphoma characterized by the infiltration of the bone marrow by clonal lymphoplasmacytic cells that produce monoclonal immunoglobulin M (IgM). The disease may have an asymptomatic phase, or patients may present with symptoms and complications resulting from marrow or other tissue infiltration, or from physicochemical or immunological properties of the monoclonal IgM. Diagnosis of WM has been clearly defined, and genetic testing for somatic mutation of MYD88L265P is a useful tool for differential diagnosis from other conditions. Specific criteria that define symptomatic disease that needs treatment offer clinical guidance. The treatment of WM has evolved rapidly, with treatment options that include anti-CD20 monoclonal antibody-based combinations and BTK inhibitors. The choice of therapy is based on the need for rapid disease control, presence of specific disease complications, and patient's age. With the use of BTK inhibitors, the use of continuous therapy has been introduced as another option over fixed-duration chemoimmunotherapy. In this review, we focus on different clinical scenarios and discuss treatment options, based on the available data.	0
The aim of this review is to summarize and discuss recent findings and new insights in the etiology and phenotype of metabolic myopathies. The review relies on a systematic literature review of recent publications. Metabolic myopathies are a heterogeneous group of disorders characterized by mostly inherited defects of enzymatic pathways involved in muscle cell metabolism. Metabolic myopathies present with either permanent (fixed) or episodic abnormalities, such as weakness, wasting, exercise-intolerance, myalgia, or an increase of muscle breakdown products (creatine-kinase, myoglobin) during exercise. Though limb and respiratory muscles are most frequently affected, facial, extra-ocular, and axial muscles may be occasionally also involved. Age at onset and prognosis vary considerably. There are multiple disease mechanisms and the pathophysiology is complex. Genes most recently related to metabolic myopathy include PGM1, GYG1, RBCK1, VMA21, MTO1, KARS, and ISCA2. The number of metabolic myopathies is steadily increasing. There is limited evidence from the literature that could guide diagnosis and treatment of metabolic myopathies. Treatment is limited to mainly non-invasive or invasive symptomatic measures. In conclusion, the field of metabolic myopathies is evolving with the more widespread availability and application of next generation sequencing technologies worldwide. This will broaden the knowledge about pathophysiology and putative therapeutic strategies for this group of neuromuscular disorders.	0
Acute graft-versus-host disease (GVHD) is initially triggered by alloreactive T cells, which damage peripheral tissues and lymphoid organs. Subsequent transition to chronic GVHD involves the emergence of autoimmunity, although the underlying mechanisms driving this process are unclear. Here, we tested the hypothesis that acute GVHD blocks peripheral tolerance of autoreactive T cells by impairing lymph node (LN) display of peripheral tissue-restricted antigens (PTAs). At the initiation of GVHD, LN fibroblastic reticular cells (FRCs) rapidly reduced expression of genes regulated by DEAF1, an autoimmune regulator-like transcription factor required for intranodal expression of PTAs. Subsequently, GVHD led to the selective elimination of the FRC population, and blocked the repair pathways required for its regeneration. We used a transgenic mouse model to show that the loss of presentation of an intestinal PTA by FRCs during GVHD resulted in the activation of autoaggressive T cells and gut injury. Finally, we show that FRCs normally expressed a unique PTA gene signature that was highly enriched for genes expressed in the target organs affected by chronic GVHD. In conclusion, acute GVHD damages and prevents repair of the FRC network, thus disabling an essential platform for purging autoreactive T cells from the repertoire.	0
Adults with sickle cell disease (SCD) experience acute and chronic complications and die prematurely. When taken at maximum tolerated dose (MTD), hydroxyurea prolongs survival; however, it has not consistently reversed organ dysfunction. Patients also frequently do not take hydroxyurea, at least in part because of physician discomfort with prescribing hydroxyurea. We sought to develop a computer program that could easily titrate hydroxyurea to MTD. This was a single-arm, open-label pilot study. Fifteen patients with homozygous SCD were enrolled in the protocol, and 10 patients were followed at baseline and then for 1 year after hydroxyurea initiation or dose titration. Fetal hemoglobin significantly increased in all 10 patients from 8.3% to 25.1% (P < .001). Nine patients were titrated to MTD in an average of 7.9 months, and the tenth patient's hydroxyurea dose was increased to 33 mg/kg/day. Computer program dosing recommendations were the same as manual dosing decisions made using the same algorithm for all patients and at all times. We also evaluated markers of cardiopulmonary, liver and renal damage. Although cardiopulmonary function did not significantly improve, direct bilirubin and alanine aminotransferase levels significantly decreased (P < .001 and P < .01, respectively). Last, although kidney function did not improve, degree of proteinuria was significantly reduced (P < .05). We have developed a computer program that reliably titrates hydroxyurea to MTD. A larger study is indicated to test the program either as a computer program or a downloadable application.	0
Ciliopathy disorders due to abnormalities of motile cilia encompass a range of autosomal recessive conditions typified by chronic otosinopulmonary disease, infertility, situs abnormalities and hydrocephalus. Using a combination of genome-wide SNP mapping and whole exome sequencing (WES), we investigated the genetic cause of a form of situs inversus (SI) and male infertility present in multiple individuals in an extended Amish family, assuming that an autosomal recessive founder variant was responsible. This identified a single shared (2.34 Mb) region of autozygosity on chromosome 15q21.3 as the likely disease locus, in which we identified a single candidate biallelic frameshift variant in MNS1 [NM_018365.2: c.407_410del; p.(Glu136Glyfs*16)]. Genotyping of multiple family members identified randomisation of the laterality defects in other homozygous individuals, with all wild type or MNS1 c.407_410del heterozygous carriers being unaffected, consistent with an autosomal recessive mode of inheritance. This study identifies an MNS1 variant as a cause of laterality defects and male infertility in humans, mirroring findings in Mns1-deficient mice which also display male infertility and randomisation of left-right asymmetry of internal organs, confirming a crucial role for MNS1 in nodal cilia and sperm flagella formation and function.	0
Femoral-facial syndrome (FFS) is a congenital disorder, characterized by facial dysmorphism and femoral hypoplasia. We describe the prenatal ultrasound and autopsy findings of FFS in 2 female fetuses born to diabetic mothers. Prenatal ultrasound showed micrognathia, low-set dysplastic ears and very short femora. Autopsy also demonstrated cleft palate, hypoplastic genitalia and visceral malformations including interventricular communication and posthemorrhagic hydrocephalus. Histologic study showed hyperplasia of the islets of Langerhans and femoral cartilage abnormalities. The growth plate displayed poor columnar organization of the growth plate with small zones of chondrocyte hypertrophy. Our case reports and the previously published cases of FFS allow discussing the variable expression of this challenging condition, its strong association with maternal diabetes mellitus and the main differential diagnoses.	0
H syndrome (histiocytosis lymph adenopathy plus syndrome) is an autosomal recessive disorder caused by mutations in the SLC29A3 gene, encoding the human equilibrative nucleoside transporter (hENT3), characterized by cutaneous hyperpigmentation and hypertrichosis, hepatosplenomegaly, hearing loss, heart anomalies, hypogonadism, low height, hyperglycemia/insulin-dependent diabetes mellitus, and hallux valgus/flexion contractures. Exophthalmos, malabsorption, renal anomalies, flexion contractions of interphalangeal joints and hallux valgus, and lytic bone lesions, as well as osteosclerosis, are also seen. If these are lacking, the constellation of additional findings should raise suspicion for H syndrome. As most of the patients reported to date with H syndrome are from traditional, low-income populations, where consanguinity is common, it is highly important to develop a cheap and affordable technique for a mutation analysis. Two siblings presented to us, diagnosed as having insulin-dependent diabetes mellitus (IDDM) since the age of eight years and progressive flexion contracture of the small joints for seven-eight years. On examination, both had short stature. One also had bilateral cervical lymphadenopathy. The female had the Tanner stage of B3P3A2 M0 and the male had the Tanner stage of prepuberty. Laboratory workup, including antinuclear antibodies, rheumatoid factor, erythrocyte sedimentation rate, thyroid profile, and Celiac serology were negative. Genetic studies confirmed the diagnosis of H syndrome.	0
Frontonasal dysplasia is an uncommon congenital anomaly with diverse clinical phenotypes and highly variable clinical characteristics, including hypertelorism, a broad nasal root, median facial cleft, a missing or underdeveloped nasal tip, and a widow's peak hairline. Frontonasal dysplasia is mostly inherited and caused by the ALX genes (ALX1, ALX3, and ALX4). We report a rare case of a frontonasal dysplasia patient with mild hypertelorism, a broad nasal root, an underdeveloped nasal tip, an accessory nasal tag, and a widow's peak. We used soft tissue re-draping to achieve aesthetic improvements.	0
Winchester syndrome (WS) is a rare autosomal recessive syndrome resulting in multicentric osteolysis. Only a few cases of WS have been described in the literature worldwide. It has recently been shown to be caused by mutation in the gene encoding matrix metalloproteinase-2 (MMP2). We report a patient affected by WS with a proven mutation of the MMP2 gene and describe the progression of radiological findings over a 23-year period. To our knowledge there is no comparable article concerning the WS in the literature.	0
Cystic fibrosis (CF) lung disease is characterized by unconventional mechanisms of inflammation, implicating a chronic immune response dominated by innate immune cells. Historically, therapeutic development has focused on the mutated cystic fibrosis transmembrane conductance regulator (CFTR), leading to the discovery of small molecules aiming at modulating and potentiating the presence and activity of CFTR at the plasma membrane. However, treatment burden sustained by CF patients, side effects of current medications, and recent advances in other therapeutic areas have highlighted the need to develop novel disease targeting of the inflammatory component driving CF lung damage. Furthermore, current issues with standard treatment emphasize the need for directed lung therapies that could minimize systemic side effects. Here, we summarize current treatment used to target immune cells in the lungs, and highlight potential benefits and caveats of novel therapeutic strategies.	0
BACKGROUND:Zinc is a trace element and is thus commonly known to be indispensable for regular cellular function. Until today, zinc deficiency is a widespread health problem, affecting approximately one sixth of the world's population. Especially the immune system has proven to be highly dependent on zinc. Interferon-γ (IFN-γ) is a key element in the defense against intracellular pathogens. A lack of this cytokine results in immunological impairment, whereas an excess can lead to autoimmunity, highlighting the importance of a well-regulated IFN-γ expression. In a state of zinc deficiency, the production of this cytokine has long been shown to be reduced. Providing further insight into the molecular mechanisms responsible for this interaction is the primary objective of this study. METHODS:Zinc-deficient or -supplemented cell culture, ELISA, quantitative PCR, methylation analysis. RESULTS:Promoter methylation is a typical mechanism of gene silencing and a strong regulating factor for IFN-γ production. An analysis of the methylation status of IFN-γ and its transcription factor IRF4 in human PBMC in a state of cellular zinc deficiency or excess showed no dependency on the trace metal. Unexpectedly, zinc-deficient PBMC, which secreted significantly less IFN-γ protein, showed significantly higher mRNA levels of the cytokine compared to cells with high total zinc levels. CONCLUSION:This report is the first about this unconventional ratio of IFN-γ mRNA to protein. Such a mismatch is highly relevant to the study of protein production in general and that of IFN-γ in particular. Based on our results and the latest research, we hypothesize a strong post-transcriptional effect of zinc on IFN-γ.	0
OBJECTIVE:The recessive disease arterial calcification due to deficiency of CD73 (ACDC) presents with extensive nonatherosclerotic medial layer calcification in lower extremity arteries. Lack of CD73 induces a concomitant increase in TNAP (tissue nonspecific alkaline phosphatase; ALPL), a key enzyme in ectopic mineralization. Our aim was to investigate how loss of CD73 activity leads to increased ALPL expression and calcification in CD73-deficient patients and assess whether this mechanism may apply to peripheral artery disease calcification. Approach and Results: We previously developed a patient-specific disease model using ACDC primary dermal fibroblasts that recapitulates the calcification phenotype in vitro. We found that lack of CD73-mediated adenosine signaling reduced cAMP production and resulted in increased activation of AKT. The AKT/mTOR (mammalian target of rapamycin) axis blocks autophagy and inducing autophagy prevented calcification; however, we did not observe autophagy defects in ACDC cells. In silico analysis identified a putative FOXO1 (forkhead box O1 protein) binding site in the human ALPL promoter. Exogenous AMP induced FOXO1 nuclear localization in ACDC but not in control cells, and this was prevented with a cAMP analogue or activation of A2a/2b adenosine receptors. Inhibiting FOXO1 reduced ALPL expression and TNAP activity and prevented calcification. Mutating the FOXO1 binding site reduced ALPL promoter activation. Importantly, we provide evidence that non-ACDC calcified femoropopliteal arteries exhibit decreased CD73 and increased FOXO1 levels compared with control arteries. CONCLUSIONS:These data show that lack of CD73-mediated cAMP signaling promotes expression of the human ALPL gene via a FOXO1-dependent mechanism. Decreased CD73 and increased FOXO1 was also observed in more common peripheral artery disease calcification.	0
Singleton-Merten syndrome (SMS) is a type I interferonopathy characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma, and psoriasis. A missense mutation in IFIH1 encoding a cytoplasmic viral RNA sensor MDA5 has recently been identified in the SMS patients as well as in patients with a monogenic form of lupus. We previously reported that Ifih1gs/+ mice express a constitutively active MDA5 and spontaneously develop lupus-like nephritis. In this study, we demonstrate that the Ifih1gs/+ mice also exhibit SMS-like bone abnormalities, including decreased bone mineral density and thin cortical bone. Histological analysis revealed a low number of osteoclasts, low bone formation rate, and abnormal development of growth plate cartilages in Ifih1gs/+ mice. These abnormalities were not observed in Ifih1gs/+ ・Mavs-/- and Ifih1gs/+ ・Ifnar1-/- mice, indicating the critical role of type I IFNs induced by MDA5/MAVS-dependent signaling in the bone pathogenesis of Ifih1gs/+ mice, affecting bone turnover. Taken together, our findings suggest the inhibition of type I IFN signaling as a possible effective therapeutic strategy for bone disorders in SMS patients.	0
Airway management for patients with craniofacial disorders poses many challenges. Congenital infiltrating lipomatosis of the face (CILF) is an extremely rare disorder in which mature lipocytes invade adjacent tissues in the head and neck. The manifestations are typically unilateral, often with associated hypertrophy of both the hard and soft tissues of the face. This is a case report regarding the anesthetic management for a 5-year-old intellectually disabled female with CILF involving the right side of her face who underwent a successful intubated general anesthetic for dental treatment. Awake fiber-optic intubations are recommended and routinely used for patients with suspected or confirmed difficult airways. In this case, substantial distortion of the normal facial anatomy was observed clinically with noted hypertrophy of the right maxilla, mandible, and right side of the tongue. Further complicating matters was the patient's inability to fully cooperate because of her intellectual disability, precluding the option of an awake fiber-optic intubation. To secure the airway following mask induction of anesthesia, spontaneous ventilation was carefully maintained using sevoflurane, nitrous oxide, and oxygen combined with the application of a nasopharyngeal airway. Despite compression of the oral cavity and upper pharyngeal space by the hypertrophic tissues due to CILF, the space in and around the glottis was preserved. Intubation was completed easily with the use of a fiber-optic scope without any serious complications.	0
Broadly neutralizing, anti-HIV-1 gp120 mAbs have been isolated from infected individuals, and there is considerable interest in developing these reagents for Ab-based immunoprophylaxis and treatment. As a means to identify potentially new anti-HIV Abs, we exploited humanized NOD-scid IL2rγnull mice systemically infected with HIV-1 to generate a wide variety of Ag-specific human mAbs. The Abs were encoded by a diverse range of variable gene families and Ig classes, including IgA, and several showed significant levels of somatic mutation. Moreover, the isolated Abs not only bound target Ags with similar affinity as broadly neutralizing Abs, they also demonstrated neutralizing ability against multiple HIV-1 clades. The use of humanized mice will allow us to use our knowledge of HIV-1 gp120 structure and function, and the immune response targeting this protein, to generate native human prophylactic Abs to reduce the infection and spread of HIV-1.	0
Adiposis dolorosa or Dercum's disease is a rare lipomatous disorder characterized by painful lipomas. In this article, we report a case of rather large exophytic adiposis dolorosa causing difficulties with ambulation, and our surgical management of the disorder. To our knowledge, this is the first reported case of a large exophytic adiposis dolorosa of the upper medial thigh causing problems with mobility. This is also the first reported case of the use of a delayed split-thickness skin graft (STSG) after interval use of wound vacuum-assisted closure (VAC) following dermolipectomy. A 77-year-old female presented with a chronic mass on the medial aspect of her right thigh for over 40-50 years. She had noticed a recent rapid increase in size, causing some discomfort and interference with mobility and activities of daily living. The patient underwent an MRI with finding consistent with adiposis dolorosa. She underwent dermolipectomy and reconstruction of the resulting defect with a combination of partial primary closure, wound VAC, and delayed closure using STSG. Dermolipectomy with interval application of a wound VAC combined with delayed reconstruction with STSG is a feasible option for patients with large lesions of the extremity that causes difficulty with mobility and activities of daily living.	0
Organizing pneumonia (OP) is a common interstitial lung disease, pathologically characterized by polypoid granulation tissue in the alveolar ducts and alveoli. In clinical practice, OP occasionally presents as non-resolving pneumonia. The typical radiographic pattern of OP is characterized by dense consolidation with ground-glass opacities. Diffuse micronodular pattern of OP (MNOP) is a rare radiographic manifestation that mimics non-resolving bronchiolar diseases such as pulmonary tuberculosis or hypersensitivity pneumonitis. Steroid therapy is usually effective for MNOP; however, spontaneous remission in MNOP has never been reported. Herein, we report a case of a diffuse micronodular form of cryptogenic OP (COP) that was diagnosed via transbronchial biopsy (TBB) and resolved spontaneously within a few months. Our case highlights that MNOP may resolve spontaneously similar to other forms of OP, and mild cases may be under-recognized. Furthermore, careful observation could be an option for managing MNOP with mild and non-progressive symptoms.	0
Human herpesvirus 6 (HHV-6) encephalitis has a high mortality rate. Among those who survive, ~80% develop some type of permanent neurologic disorder. Early diagnosis and treatment may help prevent long-term sequelae. There have been several case reports as well as retrospective and prospective studies associating HHV-6 encephalitis with some form of sodium imbalance, either hyponatremia or hypernatremia; however, the exact frequency post-HCT is unknown, with reports ranging from 30% to 100%. We performed a systematic review of the literature and found 34 cases of HHV-6 encephalitis reported in conjunction with sodium imbalance that documented the timing of that imbalance relative to the onset of encephalitis. Sodium imbalance occurred before or at the onset of HHV-6 encephalitis in all but 2 cases (94%). This finding supports previous suggestions that sodium imbalance can be considered an early indicator of the potential development or presence of HHV-6 encephalitis in at-risk patient populations.	0
Cyclic thrombocytopenia (CTP) is rarely seen and characterized by periodic fluctuations in platelet counts. In some cases, it occurs in phase with menstrual cycle. A 40-year-old female, presented firstly on June 30, 2012, with a 40-day history of appearance of purpuric skin rash and bruising, was readmitted on Aug 14, when she noted bruise on her lips. The platelet count was 24×10(9)/L on June 30, 32×10(9)/L on Aug 14, while it was 161×10(9)/L on July 1, 110×10(9)/L on Aug 16. Physical examination show skin purpuric spots and bruise over the limbs and truck. Liver, spleen, lymph nodes were not enlarged. Antinuclear antibody and rheumatoid factor (RF) were positive. Results of immune complex levels, serum complements, Hp antibody and Thrombopoietin (TPO) were all within normal ranges. Bone marrow aspiration and biopsy shown there was no change in megakaryocyte number. Fluorescence-activated cell sorter (FACS) performed normal. JAK2-V617F gene mutational and platelet-associated antibodies were not detected. We observed the patient over two complete cycles, and continued investigating her blood counts for six months follow up. During the entire process, her menstrual was regular without heavy blood loss and prolonged period. Her hemoglobin and white cell counts remained normal without cyclic change. Even if the patient was not on any therapy designed to increase the platelet count, her platelet level was back to normal. Follow up to December, 2012; her platelet count continued to fluctuation, 20×10(9)/L-40×10(9)/L in the middle of menstrual cycle while 105×10(9)/L-197×10(9)/L at the menses.	0
Spiradenoma and cylindroma are related sweat gland tumors. To delineate their histogenesis, gene profiles, and their potential drivers, we performed a whole-transcriptome sequencing analysis of fourteen samples of spiradenoma/cylindroma in comparison to normal samples. A total of 12 spiradenomas, 5 cylindromas, 3 hybrid spiradenomas/cylindromas and 2 adnexal carcinomas were included in this study. 1335 characteristic genes and transcripts expressed over all 14 spiradenoma/cylindroma tumors were identified, and two groups of expression profiles were observed. Highest upregulated top 7 gene signatures characterized benign tumors with developmental and differentiation related genes, and carcinomas with top 7 genes mainly related to signaling, reorganization and metabolism of membranes. Immunohistochemistry of protein expressions validated 4 upregulated genes (ODAM, HOXB13, MYB and SOX10) considered important and as potential biomarkers for spiradenomas and cylindromas. We further compared the transcriptome of eccrine adnexal tumors with the transcriptome of adenoid cystic carcinoma (ACC) to identify the overlapping genes that may indicate histogenesis. There were 36 specific genes overlapping between adnexal carcinomas and the epithelial-dominant subtype of ACC, and 27 specific genes overlapping benign adnexal tumors with the myoepithelial-dominant subtype of ACC, At this point there is no known specific biomarker to aid in the diagnosis of eccrine spiradenoma and cylindroma in small samples or biopsies within the context of morphological overlap with ACC. In conclusion, spiradenomas and cylindromas are characterized by overexpressed developmental genes, where LHX2 and activated WNT signaling possibly drive associated carcinomas.	0
The neurodiagnostic criteria of Leigh syndrome have not yet been clearly redefined based on the expanding of molecular etiologies. We aimed to analyze 20 years of clinical, genetic, and magnetic resonance studies from our Leigh syndrome cohort to provide a detailed description of central nervous system lesions in Leigh syndrome and their biological evolution in view of their genetic and clinical findings. Our study adds new neurodiagnostic insights to the current knowledge of Leigh syndrome, including association with overlapping syndromes, and the correlation of pathogenic genetic variants with neuroimaging phenotypes. ANN NEUROL 2020.	0
BACKGROUND:Conventional treatment options for trochlear pain arising from trochleitis or primary trochlear headache include oral anti-inflammatory medications and/or local injection of corticosteroids and local anesthetic. Trochleaectomy is an additional option to consider for monocular patients with intractable trochlear pain. METHODS:We report 3 patients undergoing trochleaectomy for refractory trochlear pain syndromes. RESULTS:Trochleaectomy resulted in resolution of their periocular discomfort. CONCLUSIONS:Trochleaectomy is an effective procedure to treat trochlear pain syndrome in functionally monocular patients.	0
Purpose:To report a severe phenotype of retinitis pigmentosa associated with novel mutations in CNGB1. Observations:Six siblings, age range 50-75 years old, were examined using optical coherence tomography and fundus autofluorescene, electroretinogram testing, Goldman visual field testing, and genetic testing using next generation sequencing.In four affected siblings, two novel compound heterozygous variants in CNGB1 were detected: in exon 26 the missense variant c.2603G > A (p.(Gly868Asp)), and in exon 21, the in-frame 12-bp duplication c.2093_2104dupGCGACCTCATCT (p.(Cys698_lle701dup)). One sibling was unaffected and carried neither of the variants, while another sibling had mild macular degeneration changes and carried the latter variant in heterozygous status. The affected siblings presented with a phenotype showing markedly constricted visual field, flat scotopic and photopic electroretinogram responses and generalized retinal atrophy. Conclusions and importance:This is the first report of a 12bp in-frame duplication and a missense variant (in compound heterozygous status) in CNGB1, being associated with a severe form of retinitis pigmentosa featuring extensive peripheral and central retinal degeneration. This study expands the molecular genetic basis of CNGB1-related disease.	0
Pleomorphic xanthoastrocytoma (PXA) is an astrocytic neoplasm that is typically well circumscribed and can have a relatively favorable prognosis. Tumor progression to anaplastic PXA (WHO grade III), however, is associated with a more aggressive biologic behavior and worse prognosis. The factors that drive anaplastic progression are largely unknown. We performed comprehensive genomic profiling on a set of 23 PXAs from 19 patients, including 15 with anaplastic PXA. Four patients had tumor tissue from multiple recurrences, including two with anaplastic progression. We find that PXAs are genetically defined by the combination of CDKN2A biallelic inactivation and RAF alterations that were present in all 19 cases, most commonly as CDKN2A homozygous deletion and BRAF p.V600E mutation but also occasionally BRAF or RAF1 fusions or other rearrangements. The third most commonly altered gene in anaplastic PXA was TERT, with 47% (7/15) harboring TERT alterations, either gene amplification (n = 2) or promoter hotspot mutation (n = 5). In tumor pairs analyzed before and after anaplastic progression, two had increased copy number alterations and one had TERT promoter mutation at recurrence. Less commonly altered genes included TP53, BCOR, BCORL1, ARID1A, ATRX, PTEN, and BCL6. All PXA in this cohort were IDH and histone H3 wildtype, and did not contain alterations in EGFR. Genetic profiling performed on six regions from the same tumor identified intratumoral genomic heterogeneity, likely reflecting clonal evolution during tumor progression. Overall, anaplastic PXA is characterized by the combination of CDKN2A biallelic inactivation and oncogenic RAF kinase signaling as well as a relatively small number of additional genetic alterations, with the most common being TERT amplification or promoter mutation. These data define a distinct molecular profile for PXA and suggest additional genetic alterations, including TERT, may be associated with anaplastic progression.	0
Fibrous dysplasia (FD) is a benign bone disease characterized by expansile lesions that typically stabilize with age. Rarely, FD can undergo malignant transformation, presenting with atypical, rapid growth and destruction of adjacent bone. Other potential causes of rapid FD expansion include secondary lesions, such as aneurysmal bone cysts. We describe a case of an aggressive occipital lesion that presented with pain associated with diplopia and tinnitus, raising concern for malignant transformation. A massive intraosseous arteriovenous fistula was identified giving rise to an anomalous vein coursing to the cavernous sinus with compression of the abducens nerve. The vascular anomaly was mapped and after embolization symptoms resolved; a biopsy with extensive genetic analyses excluded malignancy. The differential diagnosis for expanding FD lesions includes aggressive FD, malignant transformation, and secondary vascular anomalies. In cases when traditional radiographic and histologic assessments are nondescript, use of additional radiographic modalities and genetic analyses are required to make an accurate diagnosis and guide treatment. When vascular anomalies are suspected, detailed angiography with embolization is necessary to define and treat the lesion. However, to rule out malignant transformation, genetic screening is recommended.	0
PURPOSE OF REVIEW:Functional anorectal pain syndromes are a neglected yet often disabling clinical entity resulting in significant economic and psychological burden to the patient. The aim of this review is to update the practicing gastroenterologist/coloproctologist on the diagnosis and management of these complicated disorders. RECENT FINDINGS:The updated Rome foundation diagnostic criteria (Rome IV) for functional anorectal pain subgroups chronic proctalgia (levator ani syndrome and unspecified functional anorectal pain) and acute proctalgia (proctalgia fugax) on the basis of symptom duration and digital rectal examination findings. Chronic proctalgia is thought to be secondary to paradoxical pelvic floor contraction in many patients and biofeedback to improve the defecation effort has proven effective for over 90% in the short term. Unfortunately, management of proctalgia fugax remains challenging and treatment outcomes modest at best. A number of therapies to relax the pelvic floor may be employed to improve symptoms in functional anorectal pain syndromes; however, only biofeedback to improve defaecatory dynamics in patients with levator ani syndrome has proven effectiveness in a randomized setting. Further investigation of treatment approaches in proctalgia fugax is required.	0
BACKGROUND:Brown-Vialetto-Van Laere Syndrome (BVVLS), a rare neurological disorder characterized by motor, sensory, and cranial neuronopathies, is mainly associated with defective riboflavin transporters encoded by SLC52A2 and SLC52A3 genes. Clinical outcomes have been shown to be improved significantly by high-dose riboflavin supplementation. The aim of this study was to identify genetic causes and further evaluate the clinical course and response to riboflavin in a Chinese pedigree with BVVLS. CASE PRESENTATION:We report the novel compound heterozygous variants c.1328G>A p.(Cys443Tyr) and c.1022_1023insC p. (Leu341Profs*103) of SLC52A2 gene in a female proband who presented in our out-patient clinic at the age of one-year-old with progressive mental and motor regression, breath holding, and brain stem dysfunction including facial weakness, hearing loss, dysphagia. Following high-dose riboflavin supplementation, the respiratory insufficiency and mental, motor, and bulbar function improved. However, sensorineural hearing loss was not improved. The missense variant site was highly conserved. Both variants were not found in the population database gnomAD. The two variants were inherited from her mother and father, respectively. Both variants were predicted to be deleterious by Polyphen2, Mutation taster, and SIFT and were classified as likely pathogenic according to the ACMG guideline. CONCLUSIONS:Two novel pathogenic variations of SLC52A2 gene were firstly found from a Chinese pedigree with BVVLS. Clinical outcomes could be improved by early diagnosis and riboflavin supplementation.	0
Short stature is a common and heterogeneous condition that is often genetic in etiology. For most children with genetic short stature, the specific molecular causes remain unknown; but with advances in exome/genome sequencing and bioinformatics approaches, new genetic causes of growth disorders have been identified, contributing to the understanding of the underlying molecular mechanisms of longitudinal bone growth and growth failure. Identifying new genetic causes of growth disorders has the potential to improve diagnosis, prognostic accuracy, and individualized management, and help avoid unnecessary testing for endocrine and other disorders.	0
We report on a novel variant of the dicentric chromosome 17;20 (dic (17;20)(p11.2;q11.2) in a patient with de novo myelodysplastic syndrome (MDS). Based on FISH and array-CGH, the variant turns out to be an insertion of chromosome 17 (17p11.2-telomere 17) into chromosome 20 with breakpoints at 20q11.22 and 20q13.33. Based on conventional chromosome analysis and G-banding patterns, the region 17p11.2-17q25 was directly inserted between 20q11.22 and 20q13.33. The breakpoint junctions occurred within KCNJ12 (17p11.2), UQCC1 (20q11.2), and CDH4 (20q13.3), leading to 5' deletions of all the genes and positioning the 3' of UQCC1 next to KCNJ12 at 17p11.2 and CDH4 next to an unknown gene at 17q25-20q13.3. In addition, the centromere of chromosome 17 was not active, transforming the primary constriction to a flat band. Therefore, the novel insertion variant is a pseudo dicentric derivative chromosome with one functional centromere: 45,XX,der(17;20)del(20)(q11.22q13.33)ins(20;17)(q11.2;p11.2q25). A review of the literature of all dic(17;20) cases is presented. For the first time, we report an array-CGH characterization of such rare variant that revealed to be an insertion.	0
Background. Impairments in postural control in Huntington disease (HD) have important consequences for daily functioning. This observational study systematically examined baseline postural control and the effect of sensory attenuation and sensory enhancement on postural control across the spectrum of HD. Methods. Participants (n = 39) included healthy controls and individuals in premanifest (pHD) and manifest stages (mHD) of HD. Using wearable sensors, postural control was assessed according to (1) postural set (sit vs stand), (2) sensory attenuation using clinical test of sensory integration, and (3) sensory enhancement with gaze fixation. Outcomes included sway smoothness, amplitude, and frequency. Results. Based on postural set, pHD reduced postural sway in sitting relative to standing, whereas mHD had pronounced sway in standing and sitting, highlighting a baseline postural deficit. During sensory attenuation, postural control in pHD deteriorated relative to controls when proprioceptive demands were high (eyes closed on foam), whereas mHD had significant deterioration of postural control when proprioception was attenuated (eyes open and closed on foam). Finally, gaze fixation improved sway smoothness, amplitude, and frequency in pHD; however, no benefit was observed in mHD. Conclusions. Systematic examination of postural control revealed a fundamental postural deficit in mHD, which further deteriorates when proprioception is challenged. Meanwhile, postural deficits in pHD are detectable when proprioceptive challenge is high. Sensory enhancing strategies using gaze fixation to benefit posture may be useful when introduced well before motor diagnosis. These findings encourage further examination of wearable sensors as part of routine clinical assessments in HD.	0
Background and Aims:PCDH19 gene, which encodes protocadherin 19, is associated with epilepsy and intellectual disability, mainly in affected females. The clinical manifestations are heterogeneous and the main features include early onset seizure, generalized or focal seizures sensitive to fever, and brief seizures occurring in clusters. The disorders exhibit a unique and unusual X-linked pattern of expression. We aimed to investigate PCDH19 mutations/deletions in patients with epilepsy and describe the clinical/molecular features. Methods:PCDH19 gene was analyzed in 35 Turkish female patients from 34 families with early-onset epilepsy via direct sequencing and multiplex ligation-dependent probe amplification analysis. Additionally, array comparative genomic hybridization analysis was performed in patients with whole gene deletion. Results:We identified 2 different heterozygous mutations in 2 unrelated probands (5. 7%) which were located in exon 1. Additionally, whole gene deletions were detected in dizygotic twin girls (5. 7%), who had distinct clinical features and the deletion was inherited from the unaffected father. The second twin suffered more severe clinical manifestations including autistic features, behavioral problems, mild-moderate mental retardation and seizures, which were under control with multidrug regimen when compared with the first twin. Conclusion:PCDH19 is a major causative gene in patients with epilepsy and further data is required to gain a better understanding of phenotype-genotype correlation. In addition to gene sequencing, deletion/duplication analysis will improve the molecular diagnosis in patients with clinical findings.	0
OBJECTIVE:To study the potential significance and clinical application of FGFR1 gene abnormality in the diagnosis, clinical features, pathological mechanism and treatment in hematological tumors. METHODS:Clinical data of total of 29 patient with chromosome of 8 short arm (8P) abnormality who had more comprehensive medical history from 2013 to 2018 were collected. The karyotype analysis of bone marrow chromosomes in patients was carried out by using chromosome R band banding technique. FGFR1 gene was detected by using fluorescence in situ hybridization (FISH). RESULTS:Seven cases of FGFR1 gene abnormalities were decteted, including 3 cases of FGFR1 gene amplification, 2 cases of translocation, and 2 cases of deletion. Five patients with FGFR1 gene amplification or deletion not accompaned with eosinophilia, moreover the chromosome was a complex karyotype with poor prognosis; Two cases of FGFR1 gene translocation were non-complex chromosomal translocation and one of which survived for 6 years after bone marrow transplantation, the other chromosome karyotype showed no rearrangement of 8 short arm. However, FGFR1 gene rearrangement was confirmed by FISH analysis, which was a rare insertional translocation. CONCLUSION:FGFR1 gene amplification or deletion often occur in cases with complex karyotype, which not accompany eosinophilia, moreover have poor prognosis. The patients with FGFR1 gene translocation accompany eosinophilia which is consistent with the clinical characteristics of myeloid / lymphoid neoplasms with FGFR1 abnormality. Karyotype analysis combined with FISH method can improve the detection of abnormal clones.	0
The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.1.	0
AIMS:To define an unusual macular appearance found in association with nanophthalmos. METHODS:A case review. RESULTS:Seven children (aged 8 months to 17 years) with nanophthalmos were examined. They all exhibited the same clinical findings of an unusual yellow macula appearance with retinal folds and crowded optic discs. Visual electrophysiology performed in four cases was normal. CONCLUSION:A distinctive yellow macular pigmentation with associated chorioretinal folds and crowded optic discs is present in nanophthalmos. It is proposed that the retinal folds are due to a disparity between scleral and retinal growth while the macula discoloration is due to a congenital abnormality in arrangement or position of the luteal pigment and is not degenerative. Included in this case series is the second case in the literature of nanophthalmos associated with Kenny's syndrome. Inheritance of nanophthalmos appears to be autosomal recessive.	0
Glutathione synthetase deficiency (GSSD) is a rare inborn error of glutathione metabolism with autosomal recessive inheritance. The severe form of the disease is characterized by acute metabolic acidosis, usually present in the neonatal period with hemolytic anemia and progressive encephalopathy. A case of a male newborn infant who had severe metabolic acidosis with high anion gap, hemolytic anemia, and hyperbilirubinemia is reported. A high level of 5-oxoproline was detected in his urine and a diagnosis of generalized GSSD was made. DNA sequence analysis revealed the infant to be compound heterozygous with two mutations, c.738dupG in exon 8 of GSS gene resulting in p.S247fs and a repetitive sequence in exon 3 of GSS gene. Treatment after diagnosis of GSSD included supplementation with antioxidants and oral sodium hydrogen bicarbonate. However, he maintained a variable degree of metabolic acidosis and succumbed shortly after his parents requested discontinuation of therapy because of dismal prognosis and medical futility when he was 18 days old.	0
Fibroblast growth factor receptor 2 (FGFR2) promotes osteoprogenitor proliferation and differentiation during bone development, yet how the receptor elicits these distinct cellular responses remains unclear. Analysis of the FGFR2-skeletal disorder bent bone dysplasia syndrome (BBDS) demonstrates that FGFR2, in addition to its canonical signaling activities at the plasma membrane, regulates bone formation from within the nucleolus. Previously, we showed that the unique FGFR2 mutations that cause BBDS reduce receptor levels at the plasma membrane and diminish responsiveness to extracellular FGF2. In this study, we find that these mutations, despite reducing canonical signaling, enhance nucleolar occupancy of FGFR2 at the ribosomal DNA (rDNA) promoter. Nucleolar FGFR2 activates rDNA transcription via interactions with FGF2 and UBF1 by de-repressing RUNX2. An increase in the nucleolar activity of FGFR2 in BBDS elevates levels of ribosomal RNA in the developing bone, consequently promoting osteoprogenitor cell proliferation and decreasing differentiation. Identifying FGFR2 as a transcriptional regulator of rDNA in bone unexpectedly reveals a nucleolar route for FGF signaling that allows for independent regulation of osteoprogenitor cell proliferation and differentiation.	0
Bilateral microtia, absent patellae, short stature, poor weight gain, and characteristic facial features are described in two female sibs. Other skeletal anomalies included complete habitual dislocation of the elbow, slender ribs and long bones, abnormal modelling of the glenoid fossae with hooked clavicles, and clinodactyly. Bone age was significantly delayed and there was flattening of the epiphyses. This unusual combination of features has many similarities to the syndrome described by Hurst et al.	0
Background:Pfeiffer syndrome (PS) is a very rare condition with a wide clinical spectrum. There are only a few studies that address the classification and treatment of PS and take into account the most commonly presented clinical features. Thus, the objectives of this study are to propose an algorithm for PS management based on a modified severity scale and correlate PS severity with tracheostomy placement. Methods:An observational retrospective study was performed on consecutive patients with PS (n = 12), who underwent surgery between 2008 and 2018. Clinical features and findings of all included patients with PS were classified as types A, B, and C, which guided treatment workflow. The Fisher test was used to correlate the severity of patients with PS with tracheostomy placement. Results:There were 12 patients, classified as type A (n = 3), type B (n = 6), and type C (n = 3). All patients who received tracheostomies (n = 6) were stratified into the severe category (n = 9; types B and C) (P < 0.05). There were 4 minor complications, and 1 major complication according to a modified Clavien-Dindo surgical complication scale. Conclusion:A treatment algorithm based on the 3 different Pfeiffer types was proposed. Severity of PS statistically correlates to tracheostomy placement.	0
Idiopathic nephrotic syndrome newly affects 1-3 per 100,000 children per year. Approximately 85% of cases show complete remission of proteinuria following glucocorticoid treatment. Patients who do not achieve complete remission within 4-6 weeks of glucocorticoid treatment have steroid-resistant nephrotic syndrome (SRNS). In 10-30% of steroid-resistant patients, mutations in podocyte-associated genes can be detected, whereas an undefined circulating factor of immune origin is assumed in the remaining ones. Diagnosis and management of SRNS is a great challenge due to its heterogeneous etiology, frequent lack of remission by further immunosuppressive treatment, and severe complications including the development of end-stage kidney disease and recurrence after renal transplantation. A team of experts including pediatric nephrologists and renal geneticists from the International Pediatric Nephrology Association (IPNA), a renal pathologist, and an adult nephrologist have now developed comprehensive clinical practice recommendations on the diagnosis and management of SRNS in children. The team performed a systematic literature review on 9 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, formulated recommendations and formally graded them at a consensus meeting, with input from patient representatives and a dietician acting as external advisors and a voting panel of pediatric nephrologists. Research recommendations are also given.	0
The "Jumping Frenchmen of Maine" were described by George Beard in 1878. They had an excessive startle response, sometimes with echolalia, echopraxia, or forced obedience. In 1885, Gilles de la Tourette concluded that "jumping" was similar to the syndrome that now bears his name. Direct observations of jumpers have been scarce. We studied eight jumpers from the Because region of Quebec. In our opinion, this phenomenon is not a neurologic disease, but can be explained in psychological terms as operant conditioned behavior. Our cases were related to specific conditions in lumber camps in the 19th and the beginning of the 20th century.	0
Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative lysosomal storage disease (LSD) caused by inactivating mutations in the CLN1 gene. CLN1 encodes palmitoyl-protein thioesterase-1 (PPT1), a lysosomal enzyme that catalyzes the deacylation of S-palmitoylated proteins to facilitate their degradation and clearance by lysosomal hydrolases. Despite the discovery more than two decades ago that CLN1 mutations causing PPT1-deficiency underlies INCL, the precise molecular mechanism(s) of pathogenesis has remained elusive. Here, we report that autophagy is dysregulated in Cln1 -/- mice, which mimic INCL and in postmortem brain tissues as well as cultured fibroblasts from INCL patients. Moreover, Rab7, a small GTPase, critical for autophagosome-lysosome fusion, requires S-palmitoylation for trafficking to the late endosomal/lysosomal membrane where it interacts with Rab-interacting lysosomal protein (RILP), essential for autophagosome-lysosome fusion. Notably, PPT1-deficiency in Cln1 -/- mice, dysregulated Rab7-RILP interaction and preventing autophagosome-lysosome fusion, which impaired degradative functions of the autolysosome leading to INCL pathogenesis. Importantly, treatment of Cln1 -/- mice with a brain-penetrant, PPT1-mimetic, small molecule, N-tert (butyl)hydroxylamine (NtBuHA), ameliorated this defect. Our findings reveal a previously unrecognized role of CLN1/PPT1 in autophagy and suggest that small molecules functionally mimicking PPT1 may have therapeutic implications.	0
OBJECTIVE:To describe an unusual phenotype of a case with rare homozygous ALPL gene mutation that results in mild form of hypophosphatasia. METHODS:Case presentation, description of biochemical profiles, genetic testing and a brief review of literature are presented. RESULTS:A 13-year-old male presented with chronic left knee pain. Radiogram of the left knee indicated two oval radiolucent lesions in the femoral metaphysis. Serum alkaline phosphatase activity (17 U/L) was markedly below normal (42 to 362 U/L). Serum pyridoxal 5' phosphate (258 μg/L) was above normal (5 to 50 μg/L). Sequence analysis of ALPL gene indicated a homozygous missense mutation c.1077 C>G (p. I359M). The mutation was previously identified in a case of perinatal hypophosphatasia with severe skeletal abnormalities in contrast to the mild phenotype of the patient we present. CONCLUSION:The case of homozygous mutation of ALPL gene but mild form of hypophosphatasia suggests that functions of the mutated protein may be modified by other factors.	0
Receptor tyrosine kinases (RTKs) are a family of ligand-binding cell surface receptors that regulate a wide range of essential cellular activities, including proliferation, differentiation, cell-cycle progression, survival and apoptosis. As such, these proteins play an important role during development and throughout life; germline mutations in genes encoding RTKs cause several developmental syndromes, while somatic alterations contribute to the pathogenesis of many aggressive cancers. This creates an interesting paradigm in which mutation timing, type and location in a gene leads to different cell signaling and biological responses, and ultimately phenotypic outcomes. In this review, we highlight the roles of RTKs in developmental disorders and cancer. The multifaceted roles of these receptors, their genetic signatures and their signaling during developmental morphogenesis and oncogenesis are discussed. Additionally, we propose that comparative analysis of RTK mutations responsible for developmental syndromes may shed light on those driving tumorigenesis.	0
Objective: To review the efficacy and safety of caplacizumab and ravulizumab for thrombotic microangiopathy. Data Sources: A literature search from January 2011 to May 2020 was performed using the key terms caplacizumab (or ALX-0681), ravulizumab (or ALXN1210), atypical hemolytic uremic syndrome (aHUS), acquired thrombotic thrombocytopenic purpura (aTTP), and thrombotic microangiopathy. Study Selection and Data Extraction: Relevant clinical trials and articles in the English language were identified and reviewed. Data Synthesis: aTTP and aHUS are syndromes of thrombotic microangiopathy manifested by excessive platelet aggregation and endothelial cell destruction, with subsequent thrombocytopenia, hemolysis, and multiorgan failure. Current standard therapy for aTTP is therapeutic plasma exchange (TPE) to remove von Willebrand factor (vWF) multimers and anti-ADAMTS13 autoantibodies. As an adjunctive therapy to TPE, caplacizumab inhibits binding of vWF to platelets and prevents new microthrombi formation. It reduces thromboembolic event rate and days of TPE and delays relapse. Headache and epistaxis were the most common adverse events. aHUS develops because of dysregulation of the alternative complement pathway, followed by constitutive activation of complement components that causes thrombosis and end-organ damage. Short-term initial evaluation with ravulizumab, a long-acting complement inhibitor, demonstrates rapid hematological and renal improvement, with sustained complement inhibition and tolerable adverse effects. Relevance to Patient Care and Clinical Practice: This review describes the pharmacology, pharmacokinetics, cost consideration, and clinical studies for caplacizumab and ravulizumab for thrombotic microangiopathy. Place of therapy is also discussed. Conclusion: Targeted therapies with caplacizumab and ravulizumab are expected to reduce the burden of exacerbation, refractory disease, recurrence, and possibly death for thrombotic microangiopathy.	0
INTRODUCTION:Invasive fetal cardiac intervention (FCI) for pulmonary atresia with intact ventricular septum (PAIVS) and critical pulmonary stenosis (PS) has been performed with small single-institution series reporting technical and physiological success. We present the first multicenter experience. OBJECTIVES:Describe fetal and maternal characteristics of those being evaluated for FCI, including pregnancy/neonatal outcome data using the International Fetal Cardiac Intervention Registry (IFCIR). METHODS:We queried the IFCIR for PAIVS/PS cases evaluated from January 2001 to April 2018 and reviewed maternal/fetal characteristics, procedural details, pregnancy and neonatal outcomes. Data were analyzed using standard descriptive statistics. RESULTS:Of the 84 maternal/fetal dyads in the registry, 58 underwent pulmonary valvuloplasty at a median gestational age of 26.1 (21.9-31.0) weeks. Characteristics of fetuses undergoing FCI varied in terms of tricuspid valve (TV) size, TV regurgitation, and pulmonary valve patency. There were fetal complications in 55% of cases, including 7 deaths and 2 delayed fetal losses. Among those who underwent successful FCI, the absolute measurement of the TV increased by 0.32 (±0.17) mm/week from intervention to birth. Among 60 liveborn with known outcome, there was a higher percentage having a biventricular circulation following successful FCI (87 vs. 43%). CONCLUSIONS:Our data suggest a possible benefit to fetal therapy for PAIVS/PS, though rates of technically unsuccessful procedures and procedure-related complications, including fetal loss were substantial. FCI criteria are extremely variable, making direct comparison to nonintervention patients challenging and potentially biased. More uniform FCI criteria for fetuses with PAIVS/PS are needed to avoid unnecessary procedures, expose only fetuses most likely to sustain a benefit, and to enable comparisons to be made with nonintervention patients.	0
BACKGROUND This paper aims to highlight the presence of primary congenital glaucoma (PCG) in a patient with chromosome 1 q31 and q42.1 deletion of the distal long arm. The characteristic combination of phenotypic features in this deletion include dysmorphic features, psychomotor retardation and neurological signs; however, PCG has never been recognized as part of these features before. CASE REPORT This is a case of an 8-year-old female with chromosome 1 q31 and q42.1 deletion with congenital glaucoma since birth. She was found to have bilateral buphthalmos and large cloudy corneas and was also unable to follow or fixate in any directional gaze with either eye. Family history was negative for congenital glaucoma and both parents are healthy and non-consanguineous. Karyotyping showed chromosome 1 microdeletion, 46, XX, del (1) (q31q42.1) on high resolution G-banding. Further genetic testing showed no mutations in the CYP1B1 gene. CONCLUSIONS In summary, we describe a rare presentation of congenital bilateral glaucoma in the context of chromosome 1 q31 and q42.1 deletion. This clinical manifestation is uncommon when compared with that of other subsets of chromosome 1 deletions. Thus, we emphasize the need to explore factors contributing to the development of PCG in patients with chromosomal 1 deletion.	0
Background: ATR-X syndrome is an X-linked clinical condition usually associated with profound intellectual disability, facial dysmorphism and alpha-thalassemia. The syndrome is clinically heterogeneous with a broad phenotypic spectrum. Although, alpha-thalassaemia is commonly present, it may not manifest in some patients. Case report: A novel missence mutation (NM_000489: ATRX; c.6130C > T; p.Leu2044Phe) was detected in the ATR-X gene in two male siblings with severe intellectual disability, dysmorphic facial appearance and skeletal anomalies. Severe kyphoscoliosis was the main finding. Hematologic findings, one of the well-known clinical entities, were not present. Conclusion: The missense mutation we have described in our patients has not been previously reported. This finding enriches mutation spectrum of ATRX (OMIM #300032) gene. This missense mutation, which is associated with ID and kyphoscoliosis and without alpha-thalassemia, contributes to genotype-phenotype correlation of the ATR-X spectrum. This case report provides further evidence that reverse genetics is a useful approach in diagnostic process of syndromic patients in adulthood.	0
Dubin-Johnson syndrome is a rare, benign disorder that results in conjugated hyperbilirubinemia. The disease manifests as intermittent jaundice without long-term hepatic or other clinical complications. This article reports a case of Dubin-Johnson syndrome, which was identified during cardiac transplant evaluation for cardiomyopathy secondary to a polyglycogen storage disease. The patient successfully underwent an orthotopic heart transplant. Postoperatively, her conjugated hyperbilirubinemia increased as compared to her baseline but resolved after several weeks. This report briefly reviews the hepatic manifestations in patients with Dubin-Johnson syndrome undergoing major surgery and highlights urinary coproporphyrin as a useful diagnostic test for Dubin-Johnson syndrome.	0
Left ventricular (LV) mechanical dyssynchrony assessed with phase analysis of electrocardiogram (ECG) -gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is useful for predicting major cardiac events (MCEs) in patients with cardiac dysfunction. However, there is no report on its usefulness in Japanese patients with known or suspected stable coronary artery disease (CAD) with preserved LV ejection fraction (LVEF).We retrospectively investigated 3,374 consecutive patients with known or suspected CAD who underwent rest 201Tl and stress 99mTc-tetrofosmin ECG-gated SPECT MPI and had preserved LVEF (≥ 45%), and followed them up to confirm their prognosis for three years. The composite endpoint was the onset of MCEs consisting of cardiac death, non-fatal myocardial infarction (MI), unstable angina pectoris, and severe heart failure requiring hospitalization. LV mechanical dyssynchrony was evaluated with phase analysis with the Heart Risk View-F software to obtain the phase bandwidth and standard deviation.During the follow-up, 179 patients experienced MCEs: cardiac death (n = 42); non-fatal MI (n = 34); unstable angina pectoris (n = 54); and severe heart failure (n = 49). Results of the multivariate analysis showed age, a history of MI, diabetes mellitus, summed stress score, and stress phase bandwidth to be independent predictors for MCEs. In Kaplan-Meier analysis, prognoses were significantly stratified with the tertiles of stress phase bandwidth.LV mechanical dyssynchrony assessed with ECG-gated SPECT MPI is useful for predicting a prognosis and stratifying the risk of MCEs in Japanese patients with known or suspected stable CAD with preserved LVEF.	0
A fragment of a Dracunculus-like worm was extracted from the hind limb of a 2-year-old dog from Toledo, Spain. Cytochrome oxidase I and rRNA sequences confirmed an autochthonous mammalian Dracunculus worm infection in Europe. Sequence analyses suggest close relation to a parasite obtained from a North American opossum.	0
Osteopetrosis is a rare group of bone disorders characterized by defective osteoclast bone resorption causing high bone mineral density. A high bone mineral density in combination with defective skeletal mineralization results in a phenotype of osteopetrorickets. We present a rare presentation of infantile osteopetrorickets in an 8-week-old female who presented with failure to thrive, hypophosphatemia, anemia, and thrombocytopenia. A skeletal survey showed increased bone density with rachitic changes. She was found to have a homozygous T-cell immune regulator 1 (TCIRG1) pathogenic mutation consistent with osteopetrosis. This highlights the importance of a clinical suspicion of osteopetrosis with this symptom constellation.	0
Czech dysplasia metatarsal type is an autosomal-dominant disorder characterized by an early-onset, progressive spondyloarthropathy with normal stature. Shortness of third and/or fourth toes is a frequently observed clinical feature. Similarities between individuals with this dysplasia and patients with an R275C mutation in the COL2A1 gene, prompted us to analyze the COL2A1 gene in the original families reported with Czech dysplasia. Targeted sequencing of exon 13 of the COL2A1 gene was performed, followed by sequencing of the remaining exons in case the R275C mutation was not identified. We identified the R275C substitution in two of the original patients reported with Czech dysplasia and three additional patients. All affected individuals had a similar phenotype characterized by normal height, spondyloarthropathy, short postaxial toes and absence of ocular and orofacial anomalies. The R275C mutation was excluded in a third patient reported with Czech dysplasia. However, the identification of the Y1391C mutation in this patient with disproportionate short stature made the diagnosis of spondyloperipheral dysplasia (SPD) more probable. The Y1391C mutation is located in the C-propeptide of the procollagen chain and has been reported before in a patient with the Torrance type of lethal platyspondylic skeletal dysplasia (PLSD-T). Our observation of the same Y1391C mutation in an additional unrelated patient with SPD further supports the evidence that PLSD-T and SPD represent a phenotypic continuum. The R275C mutation in the COL2A1 gene causes a specific type II collagen disorder that was recently delineated as Czech dysplasia.	0
OBJECTIVE:To explore the genetic basis for fetus with short limbs detected by prenatal ultrasonography. METHODS:Results of clinical imaging of the fetus was collected. Amniotic fluid sample was collected through amniocentesis for the extraction of fetal DNA. Whole exome sequencing was carried out to detect variants related to the clinical phenotypes. Candidate variant was verified by Sanger sequencing. RESULTS:Prenatal ultrasound showed that the fetus had short limbs but no other abnormality. Whole exome sequencing has identified that the fetus carried two heterozygous pathogenic variants c.484G>T and c.1436dupA of the SLC26A2 gene, for which its mother and father were heterozygous carriers, respectively. CONCLUSION:The fetus was diagnosed with atelosteogenesis type 2 by combined prenatal ultrasonography and whole exome sequencing, which may be attributed to the compound heterozygous variants of the SLC26A2 gene. Above findings provided evidence for the diagnosis of the fetus and genetic counseling.	0
INTRODUCTION:Non-invasive prenatal testing (NIPT) using cell-free foetal DNA has been widely accepted in recent years for detecting common foetal chromosome aneuploidies, such as trisomies 13, 18 and 21, and sex chromosome aneuploidies. In this study, the practical clinical performance of our foetal DNA testing was evaluated for analysing all chromosome aberrations among 7113 pregnancies in Italy. METHODS:This study was a retrospective analysis of collected NIPT data from the Ion S5 next-generation sequencing platform obtained from Altamedica Medical Centre in Rome, Italy. RESULTS:In this study, NIPT showed 100% sensitivity and 99.9% specificity for trisomies 13, 18 and 21. Out of the 7113 samples analysed, 74 cases (1%) were positive by NIPT testing; foetal karyotyping and follow-up results validated 2 trisomy 13 cases, 5 trisomy 18 cases, 58 trisomy 21 cases and 10 sex chromosome aneuploidy cases. There were no false-negative results. CONCLUSION:In our hands, NIPT had high sensitivity and specificity for common chromosomal aneuploidies such as trisomies 13, 18 and 21.	0
Arterial tortuosity syndrome (ATS) is a recessively inherited connective tissue disorder, mainly characterized by tortuosity and aneurysm formation of the major arteries. ATS is caused by loss-of-function mutations in SLC2A10, encoding the facilitative glucose transporter GLUT10. Former studies implicated GLUT10 in the transport of dehydroascorbic acid, the oxidized form of ascorbic acid (AA). Mouse models carrying homozygous Slc2a10 missense mutations did not recapitulate the human phenotype. Since mice, in contrast to humans, are able to intracellularly synthesize AA, we generated a novel ATS mouse model, deficient for Slc2a10 as well as Gulo, which encodes for L-gulonolactone oxidase, an enzyme catalyzing the final step in AA biosynthesis in mouse. Gulo;Slc2a10 double knock-out mice showed mild phenotypic anomalies, which were absent in single knock-out controls. While Gulo;Slc2a10 double knock-out mice did not fully phenocopy human ATS, histological and immunocytochemical analysis revealed compromised extracellular matrix formation. Transforming growth factor beta signaling remained unaltered, while mitochondrial function was compromised in smooth muscle cells derived from Gulo;Slc2a10 double knock-out mice. Altogether, our data add evidence that ATS is an ascorbate compartmentalization disorder, but additional factors underlying the observed phenotype in humans remain to be determined.	0
In this report, we present a new case of mosaic trisomy 13 with prolonged survival, firstly detected by array-CGH analysis which was carried out because of moderate intellectual disability with postaxial hexadactyly, dermatologic features, ventricular septal defect, bicuspid aortic valve, and aortic dystrophy in a 19-year-old male patient. In a subset of 15% of the cells, the patient carried a derivative chromosome 10 generated by a nonreciprocal (10;13) translocation inherited from his healthy mother who carried the translocation in a balanced and homogeneous state. FISH analyses showed interstitial telomeric sequences at the breakpoints. To our knowledge, this is the second report of a patient with trisomy 13 mosaicism displaying a severe aortic root dilatation. We also discuss the mechanisms which could explain the mosaic state, the most likely one being related to the instability of the interstitial telomere.	0
Thrombocytopenia absent radii (TAR) syndrome is clearly defined by the combination of radial aplasia and reduced platelet counts. The genetics of TAR syndrome has recently been resolved and comprises a microdeletion on Chromosome 1 including the RBM8A gene and a single nucleotide polymorphism (SNP) either at the 5' untranslated region (5'UTR) or within the first intron of RBM8A. Although phenotypically readily diagnosed after birth, the genetic determination of particular SNPs in TAR syndrome harbours valuable information to evaluate disease severity and treatment decisions. Here, we present clinical data in a cohort of 38 patients and observed that platelet counts in individuals with 5'UTR SNP are significantly lower compared to patients bearing the SNP in intron 1. Moreover, elevated haemoglobin values could only be assessed in patients with 5'UTR SNP whereas white blood cell count is unaffected, indicating that frequently observed anaemia in TAR patients could also be SNP-dependent whereas leucocytosis does not correlate with genetic background. However, this report on a large cohort provides an overview of important haematological characteristics in TAR patients, facilitating evaluation of the various traits in this disease and indicating the importance of genetic validation for TAR syndrome.	0
Importance:Pityriasis rubra pilaris is a rare and disabling cutaneous disease that is frequently recalcitrant to conventional therapies and appears to involve interleukin (IL)-17 overexpression. Objective:To investigate the clinical response and safety of ixekizumab in treating pityriasis rubra pilaris. Design, Setting, and Participants:Single-arm, investigator-initiated trial conducted in adult patients with moderate to severe pityriasis rubra pilaris at a single-center academic university from June 2018 to January 2020. A total of 41 patients were screened, 12 were enrolled, and 11 completed the full duration of therapy. A referred, consecutive sample was used during participant selection. The treatment period and primary outcome occurred over 24 weeks with additional patient follow-up through 36 weeks. Intervention:Subcutaneous administration of ixekizumab, a humanized IgG4 antibody that binds IL-17A, at the US Food and Drug Administration-approved dosing schedule for treatment of psoriasis for 24 weeks. Main Outcomes and Measures:The primary outcome was the mean change in Psoriasis Area and Severity Index at 24 weeks. Secondary outcomes included change in affected body surface area, quality of life, induction of sustained remission, and association of improvement with CARD14 genetic variations and cutaneous cytokine expression. Results:A total of 12 white patients (mean [SD] age, 49.8 [15.1] years; 8 male [67%]) were enrolled between June 2018 and April 2019, with 11 completing the full course of intervention. The mean (SEM) improvements in Psoriasis Area and Severity Index, affected body surface area, and Dermatology Life Quality Index were 15.2 (2.1) (P < .0001), 29.8% (9.3%) (P = .009), and 9.5 (2.5) (P = .004), respectively. The 4 participants with the most improvement in Psoriasis Area and Severity Index at week 24 stayed in remission at week 36 (defined as lack of increase in Psoriasis Area and Severity Index from week 24 through week 36), off therapy. Relative dermal IL-17A expression decreased by a 1.9 log-fold change. No participants had known pathogenic CARD14 variations. There were no serious adverse events. Conclusions and Relevance:In this single-armed trial, ixekizumab was associated with reduced clinical signs and symptoms of pityriasis rubra pilaris in a subset of patients, including those in whom other systemic therapies have failed. Trial Registration:ClinicalTrials.gov Identifier: NCT03485976.	0
The oculocerebrorenal (OCRL) syndrome, also known as Lowe syndrome (LS), is an X-linked recessive disorder that predominantly affects males and is characterized by growth and mental retardation, congenital cataract and renal Fanconi syndrome. OCRL1 is the gene responsible for LS and encodes an inositol polyphosphate-5-phosphatase. We report a male child from North India, with LS with missense mutation in exon 14 of the OCRL gene.	0
A 19-year-old female presented with pain, deformity, and slightly restricted left wrist motion for five years with gradual progression. Physical examination revealed volar subluxation of the left hand, dorsally prominent ulnar styloid, radial and dorsal bowing of the distal forearm, and mild restriction in wrist dorsiflexion. Radiographs showed a failure of ossification of the ulnar side of the distal radial epiphysis, increased radial inclination angle, dorsal subluxation of the distal ulna, V-shaped proximal carpal row due to proximal migration of the lunate, and increased interosseous space. A diagnosis of Madelung deformity of the left wrist was made. Conservative management with oral analgesics, activity restriction, and a volar splint was done as the patient was skeletally mature, had only mild pain with no functional limitation or gross deformity. At the six-month follow-up, she was doing well with decreased pain and no new complaints.	0
Chronic low-grade inflammation drives atherosclerosis and despite optimal pharmacological treatment of classical cardiovascular risk factors, one third of the patients with atherosclerotic cardiovascular disease has elevated inflammatory biomarkers. Additional anti-inflammatory strategies to target this residual inflammatory cardiovascular risk are therefore required. T-cells are a dominant cell type in human atherosclerotic lesions. Modulation of T-cell activation is therefore a potential strategy to target inflammation in atherosclerosis. Ubiquitination is an important regulatory mechanism of T-cell activation and several E3 ubiquitin ligases, including casitas B-lineage lymphoma proto-oncogene B (Cbl-B), itchy homolog (Itch), and gene related to anergy in lymphocytes (GRAIL), function as a natural brake on T-cell activation. In this review we discuss recent insights on the role of Cbl-B, Itch, and GRAIL in atherosclerosis and explore the therapeutic potential of these E3 ubiquitin ligases in cardiovascular medicine.	0
Background:We describe this case of a young gentleman presenting with acute dyspnoea on a background history of known, long-standing asthma. His dramatic presentation, notable for profound hypoxia and cyanosis, led to an unexpected additional diagnosis of type one congenital methaemoglobinaemia. Case presentation:A 26-year-old Irish gentleman was transferred urgently to the emergency department resuscitation room with marked cyanosis and tachypnoea. His oxygen saturation was 70% on 100% high flow oxygen. His arterial blood gas (On Fi02 90%) demonstrated a PaO2 = 76.8 kPa, SpO2 = 99%, pCO2 = 3 kPa and pH = 7.51. A saturation gap was evident and on further analysing the arterial blood gas, the methaemoglobin level was noted to be 28%. No contributing drugs were identified. Our patient was diagnosed with type one congenital methaemoglobinaemia. He recovered well from this admission, however, has had recurrent presentations to hospital since with high methaemoglobin levels noted on each occasion. Discussion:Congenital methemoglobinemia is a rare, often overlooked differential diagnosis in patients presenting with cyanosis and dyspnoea. This is the only case, to our knowledge, of a patient with both asthma and congenital methaemoglobinaemia. Congenital methaemoglobinaemia was first described in 1943 by Dr Deeny who described two siblings as suffering from 'Familial Idiopathic Methaemoglobinaemia'. The case we present is the first reported Irish case of congenital methaemoglobinaemia, we are aware of, since 1943.Current treatment strategies include high-flow oxygen, methylene blue infusion (contraindicated in glucose-6-phosphate-dehydrogenase deficiency) and red cell exchange transfusions in the emergency setting whilst oral ascorbic acid and riboflavin are preventative.	0
The aim of this study was to explore the association between alpha-thalassemia, fetal hemoglobin, hematological indices, and clinical adverse events in Angolan sickle cell disease pediatric patients. A total of 200 sickle cell disease (SCD) children were sampled in Luanda and Caxito. A venous blood sample was collected and used for hematological analyses, fetal hemoglobin quantification, and genotyping of 3.7 kb alpha-thalassemia deletion by GAP-PCR. The frequency of the 3.7 kb alpha-thalassemia deletion in homozygosity was 12.5% and in heterozygosity was 55.0%. An increase in alpha-thalassemia frequency was observed in children older than 5 years old (11.7% vs. 13.00%). Furthermore, 3.7 kb alpha-thalassemia deletion homozygotes had a significantly higher age of the first manifestation, lower number of blood transfusions by year, higher hemoglobin, lower mean corpuscular volume, mean corpuscular hemoglobin, and lower hemolytic rate observed by a lower number of reticulocytes count. There were no differences in fetal hemoglobin between the three genotypes. Moreover, the number of stroke events, osteomyelitis, splenomegaly, splenectomy, and hepatomegaly were lower when alpha-thalassemia was co-inherited. For the first time in Angolan population, the effect of alpha-thalassemia deletion in sickle cell disease was analyzed and results reinforce that this trait influences the hematological and clinical aspects and produces a milder phenotype.	0
Background:Oligohydramnios sequence can be caused by renal tubular dysgenesis (RTD), a rare condition resulting in pulmonary and renal morbidity. Besides typical features of Potter-sequence, the infants present with severe arterial hypotension and anuria as main symptoms. Establishing an adequate arterial blood pressure and sufficient renal perfusion is crucial for the survival of these infants. Case presentation:We describe a male preterm infant of 34 + 0 weeks of gestation. Prenatally oligohydramnios of unknown cause was detected. After uneventful delivery and good adaptation the infant developed respiratory distress due to a spontaneous right-sided pneumothorax and required thoracocentesis and placement of a chest tube; he showed no major respiratory concerns thereafter and needed only minimal ventilatory support. Echocardiography revealed no abnormalities, especially no pulmonary hypertension. However, he suffered from severe arterial hypotension and anuria refractory to catecholamine therapy (dobutamine, epinephrine and noradrenaline). After 36 h of life, vasopressin therapy was initiated resulting in an almost immediate stabilization of arterial blood pressure and subsequent onset of diuresis. Therapy with vasopressin was necessary for three weeks to maintain adequate arterial blood pressure levels and diuresis. Sepsis and adrenal insufficiency were ruled out as inflammation markers, microbiological tests and cortisol level were normal. At two weeks of age, our patient developed electrolyte disturbances which were successfully treated with fludrocortisone. He did not need renal replacement therapy. Genetic analyses revealed a novel compound hyterozygous mutation of RTD. Now 17 months of age, the patient is in clinically stable condition with treatment of fludrocortisone and sodium bicarbonate. He suffers from stage 2 chronic kidney disease; blood pressure, motor and cognitive development are normal. Conclusions:RTD is a rare cause of oligohydramnios sequence. Next to pulmonary hypoplasia, severe arterial hypotension is responsible for poor survival. We present the only second surviving infant with RTD, who did not require renal replacement therapy during the neonatal period. It can be speculated whether the use of vasopressin prevents renal replacement therapy as vasopressin increases urinary output by improving renal blood flow.	0
Hereditary iron overload includes several disorders characterized by iron accumulation in tissues, organs, or even single cells or subcellular compartments. They are determined by mutations in genes directly involved in hepcidin regulation, cellular iron uptake, management and export, iron transport and storage. Systemic forms are characterized by increased serum ferritin with or without high transferrin saturation, and with or without functional iron deficient anemia. Hemochromatosis includes five different genetic forms all characterized by high transferrin saturation and serum ferritin, but with different penetrance and expression. Mutations in HFE, HFE2, HAMP and TFR2 lead to inadequate or severely reduced hepcidin synthesis that, in turn, induces increased intestinal iron absorption and macrophage iron release leading to tissue iron overload. The severity of hepcidin down-regulation defines the severity of iron overload and clinical complications. Hemochromatosis type 4 is caused by dominant gain-of-function mutations of ferroportin preventing hepcidin-ferroportin binding and leading to hepcidin resistance. Ferroportin disease is due to loss-of-function mutation of SLC40A1 that impairs the iron export efficiency of ferroportin, causes iron retention in reticuloendothelial cell and hyperferritinemia with normal transferrin saturation. Aceruloplasminemia is caused by defective iron release from storage and lead to mild microcytic anemia, low serum iron, and iron retention in several organs including the brain, causing severe neurological manifestations. Atransferrinemia and DMT1 deficiency are characterized by iron deficient erythropoiesis, severe microcytic anemia with high transferrin saturation and parenchymal iron overload due to secondary hepcidin suppression. Diagnosis of the different forms of hereditary iron overload disorders involves a sequential strategy that combines clinical, imaging, biochemical, and genetic data. Management of iron overload relies on two main therapies: blood removal and iron chelators. Specific therapeutic options are indicated in patients with atransferrinemia, DMT1 deficiency and aceruloplasminemia.	0
Purpose:Primary congenital glaucoma (PCG) is a genetically heterogeneous disorder caused by developmental defects in the anterior chamber and trabecular meshwork. This disease is an important cause of childhood blindness. In this study, we aim to identify the genetic determinants of PCG in three consanguineous families of Pakistani descent. Methods:Affected members of all three families underwent detailed ophthalmological examination including slit-lamp biomicroscopy. Blood samples were collected from affected and healthy members of all three families, and genomic DNA was extracted. Linkage analysis was performed for the known or reported loci of PCG to localize the disease interval, and logarithm of odds (LOD) scores were calculated. All protein-coding exons of the candidate gene, latent transforming growth factor-beta binding protein 2 (LTBP2), were bidirectionally sequenced to identify the disease-causing mutation. Results:Short tandem repeat (STR) marker-based linkage analysis localized the critical interval to chromosome 14q with a maximum two-point LOD score of 2.86 (PKGL076), 2.8 (PKGL015), and 2.92 (PKGL042). Bidirectional Sanger sequencing of LTBP2 revealed three novel pathogenic variants, i.e., c.3028G>A (p.Asp1010Asn), c.3427delC (p.Gln1143Argfs*35), and c.5270G>A (p.Cys1757Tyr) in PKGL076, PKGL015, and PKGL042, respectively. All three mutations segregated with the disease phenotype in their respective families and were absent in 200 ethnically matched normal chromosomes. Conclusions:We identified three novel mutations, p.D1010N, p.Q1143Rfs*35, and p.C1757Y, in LTBP2 responsible for PCG.	0
The KCNT1 gene encodes for subunits contributing to the Na(+)-activated K(+) current (KNa), expressed in many cell types. Mutations in KCNT1 have been found in patients affected with a wide spectrum of early-onset epilepsies, including Malignant Migrating Partial Seizures in Infancy (MMPSI), a severe early-onset epileptic encephalopathy characterized by pharmacoresistant focal seizures migrating from one brain region or hemisphere to another and neurodevelopment arrest or regression, resulting in profound disability. In the present study we report identification by whole exome sequencing (WES) of two de novo, heterozygous KCNT1 mutations (G288S and, not previously reported, M516V) in two unrelated MMPSI probands. Functional studies in a heterologous expression system revealed that channels formed by mutant KCNT1 subunits carried larger currents when compared to wild-type KCNT1 channels, both as homo- and heteromers with these last. Both mutations induced a marked leftward shift in homomeric channel activation gating. Interestingly, the KCNT1 blockers quinidine (3-1000μM) and bepridil (0.03-10μM) inhibited both wild-type and mutant KCNT1 currents in a concentration-dependent manner, with mutant channels showing higher sensitivity to blockade. This latter result suggests two genotype-tailored pharmacological strategies to specifically counteract the dysfunction of KCNT1 activating mutations in MMPSI patients.	0
CDKL5 deficiency disorder (CDD) is a severe neurodevelopmental encephalopathy caused by mutations in the X-linked CDKL5 gene that encodes a serine/threonine kinase. CDD is characterised by the early onset of seizures and impaired cognitive and motor skills. Loss of CDKL5 in vitro and in vivo affects neuronal morphology at early and late stages of maturation, suggesting a link between CDKL5 and the neuronal cytoskeleton. Recently, various microtubule (MT)-binding proteins have been identified as interactors of CDKL5, indicating that its roles converge on regulating MT functioning. MTs are dynamic structures that are important for neuronal morphology, migration and polarity. The delicate control of MT dynamics is fundamental for proper neuronal functions, as evidenced by the fact that aberrant MT dynamics are involved in various neurological disorders. In this review, we highlight the link between CDKL5 and MTs, discussing how CDKL5 deficiency may lead to deranged neuronal functions through aberrant MT dynamics. Finally, we discuss whether the regulation of MT dynamics through microtubule-targeting agents may represent a novel strategy for future pharmacological approaches in the CDD field.	0
Split-hand/split-foot malformation (SHFM) is mainly inherited as an autosomal dominant trait with incomplete penetrance and characterized by malformation of the limb involving the central rays of the autopod. It presents with a deep median cleft of the hand and/or foot, aplasia/hypoplasia of the phalanges, metacarpals, and metatarsals. Pathogenic mechanism is a failure to maintain signaling from the median apical ectodermal ridge. Without this signaling, cells of the underlying progress zone stop proliferation and differentiation which in turn results in defects of the central rays. We describe a case of SHFM in 10-year-old boy.	0
Hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP) is a recently identified autosomal dominant genetic syndrome with mutations in FAM111B. Herein, we report a 14-month-old girl who presented with progressive poikiloderma on the face. Her 24-year-old mother had an identical facial poikiloderma, hyperpigmentation, mottling and Blaschko line hypopigmentation on the trunk and limbs, as well as severe tendon contractures. Next-generation sequencing based on a targeted gene capture panel revealed a missense mutation in the FAM111B gene p.Phe416Ser (c.1247T>C). Her mother had the same mutation as the proband. Moreover, this mutation was absent in the unaffected father and maternal grandparents. Based on the clinical manifestations and genetic analysis, the proband and her mother were diagnosed with POIKTMP. Protein modeling indicated that the mutation p.Phe416Ser dramatically changed the protein structure, especially its structural stability, and affected the protein function. This is the first report of POIKTMP in a Chinese family due to a novel FAM111B mutation. Furthermore, we have reviewed the genotype-phenotype correlation, differential diagnoses and management of POIKTMP.	0
Congenital vertebral malformations (CVM) pose a significant health problem because they can be associated with spinal deformities, such as congenital scoliosis and kyphosis, in addition to various syndromes and other congenital malformations. Additional information remains to be learned regarding the natural history of congenital scoliosis and related health problems. Although significant progress has been made in understanding the process of somite formation, which gives rise to vertebral bodies, there is a wide gap in our understanding of how genetic factors contribute to CVM development. Maternal diabetes during pregnancy most commonly contributes to the occurrence of CVM, followed by other factors such as hypoxia and anticonvulsant medications. This review highlights several emerging clinical issues related to CVM, including pulmonary and orthopedic outcome in congenital scoliosis. Recent breakthroughs in genetics related to gene and environment interactions associated with CVM development are discussed. The Klippel-Feil syndrome which is associated with cervical segmentation abnormalities is illustrated as an example in which animal models, such as the zebrafish, can be utilized to provide functional evidence of pathogenicity of identified mutations.	0
BACKGROUND:Karyomegalic interstitial nephritis (KIN) is a rare hereditary cause of chronic kidney disease. It typically causes progressive renal impairment with haemoproteinuria requiring renal replacement therapy before 50 years of age. It has been associated with mutations in the Fanconi anaemia-associated nuclease 1 (FAN1) gene and has an autosomal recessive pattern of inheritance. Leukocyte chemotactic factor 2 amyloidosis (ALECT2) is the third most common cause of amyloid nephropathy presenting with chronic kidney disease and variable proteinuria. We report a novel mutation in the FAN1 gene causing KIN and to our knowledge, the first case of concurrent KIN and ALECT. CASE PRESENTATION:We describe the case of 44 year old Pakistani woman, presenting with stage four non-proteinuric chronic kidney disease, and a brother on dialysis. Renal biopsy demonstrated KIN and concurrent ALECT2. Genetic sequencing identified a novel FAN1 mutation as the cause of her KIN and she is being managed conservatively for chronic kidney disease. Her brother also had KIN with no evidence of amyloidosis and is being worked up for kidney transplantation. CONCLUSION:This case highlights two rare causes of chronic kidney disease considered underdiagnosed in the wider population due to their lack of proteinuria, and may contribute to the cohort of patients reaching end stage renal disease without a renal biopsy. We report a novel mutation of the FAN1 gene causing KIN, and report the first case of concurrent KIN and ALECT2. This case highlights the importance of renal biopsy in chronic kidney disease of unclear aetiology which has resulted in a diagnosis with implications for kidney transplantation and family planning.	0
BACKGROUND:Danon disease (DD) is an X-linked dominant multisystem disorder that is associated with cardiomyopathy, skeletal myopathy, and varying degrees of intellectual disability. It results from mutations in the lysosome-associated membrane protein 2 (LAMP2) gene. METHODS:Herein, a proband with a mild DD case presenting with a familial hypertrophic cardiomyopathy (HCM) phenotype and additional family members were evaluated. Exome sequencing and Sanger sequencing were performed to explore the genetic basis of DD in the proband. Segregation, in silico, and functional analyses were carried out to explore potential pathogenicity in the candidate mutation. RESULTS:Exome sequencing and Sanger sequencing identified one novel missense mutation (p.G93R) in the LAMP2 gene in the proband, and this mutation was also identified in three other family members. In silico analysis of LAMP2 predicted that the mutation causes a conformational change and subsequent protein destabilization. Furthermore, functional examination showed that mutation carriers have a significant reduction in LAMP2 expression, which supports that the mutation is pathogenic. Moreover, skewed X chromosome inactivation (XCI) was identified in one female mutation carrier, thus suggesting that skewed XCI may be the reason why this individual escaped the pathogenic influence of the mutation. CONCLUSION:These findings will aid in diagnosing DD patients carrying this LAMP2 mutation that presents with a HCM phenotype. Furthermore, this study illustrates the importance of utilizing a molecular diagnostic approach in HCM patients and is the first study to report a LAMP2 p.G93R mutation associated with mild DD and identify that XCI serves a protective role in DD etiology.	0
INTRODUCTION:Sporotrichosis is a rare fungal infection in transplant patients; among these patients, it occurs mostly in renal transplant patients. Sporothrix schenkii is the primary pathogen responsible. A high index of suspicion is required to make the diagnosis keeping important differential diagnoses in mind. History of trauma through recreational or occupational exposure to the fungus may assist in making the diagnosis. Treatment is difficult, with long-term use of potentially nephrotoxic and cytochrome P450 inhibitor antifungal agents leading to potential calcineurin inhibitors toxicity. We describe two renal transplant patients presenting with distinct sporotrichosis infection: "Case 2" being only the second reported case ever of meningeal sporotrichosis. We subsequently review the general aspects of sporotrichosis, specifically in renal transplant patients as described in the medical literature. CASE PRESENTATION:Case 1, a 43-year-old mixed ancestry male patient presented with a non-healing ulcer on the left arm for 1 year, he was diagnosed with cutaneous sporotrichosis and was successfully treated with itraconazole monotherapy. Case 2, a 56-year-old mixed ancestry male patient presented with a slow decline in functions, confusion, inappropriate behavior, rigors and significant loss of weight and appetite over the past 4 months, he was diagnosed with meningeal sporotrichosis and was successfully treated with a combination of deoxycholate amphotericin B and itraconazole. CONCLUSION:Physicians taking care of renal transplant patients should have a high index of suspicion for sporotrichosis infection particularly when conventional therapy for common conditions fails. Susceptibility testing is recommended to identify the most effective antifungal agent and its dose. The slow nature of growth of Sporothrix schenkii necessitates patients to be on amphotericin B until the time results are available. Finally, there is a need to be aware of potential drug-drug interactions of the azoles with calcineurin inhibitors and the required dose adjustments to prevent therapy related adverse events.	0
Transaldolase (TALDO) deficiency has various clinical manifestations including liver dysfunction, hepatosplenomegaly, anemia, thrombocytopenia, and dysmorphic features. We report a case presenting prenatally with hyperechogenic bowel and intrauterine growth restriction. The infant was born small for gestational age, with cutis laxa and hypertrichosis. Postnatally, meconium plug was identified, complicated with intestinal obstruction necessitating laparotomy, partial resection of the intestine, and ileostomy. Liver biopsy revealed cholangiolar proliferation and portal fibrosis. He also suffered from persistent congenital thrombocytopenia requiring platelet transfusions and severe hypothyroidism with normal anatomical and structural gland responding only to the combination of T3 and T4 treatment. Neurologically, severe hypotonia and anisocoria were noted at the age of 2 months. Brain MRI was normal. Shortly after the abdominal surgery, a rapid liver failure ensued, which eventually led to his death. Specific metabolic tests ruled out glycosylation disorders, yet urine analysis using 1H NMR showed accumulation of sedoheptulose which was previously described in patients with transaldolase deficiency. Sequencing of the gene-encoding transaldolase (TALDO1) revealed a homozygous stop mutation c.669C>G; p.Tyr223*. In conclusion, we present an infant with a novel homozygous mutation in TALDO1, causing TALDO deficiency, and extend the clinical characteristics of this rare syndrome.	0
Background: In a small series, it has been postulated that delayed release of complex syndactyly of the 3rd web in Apert syndrome patients causes compression on epiphyses, with early epiphyseal closure, leading to symphalangism and reduced capitate ossification. We wished to see whether this remains true in a larger series. Methods: We reviewed radiographs of 48 patients (86 hands) with Apert syndrome seen in the department of Plastic and Reconstructive Surgery, Great Ormond Street Hospital, between the years 2001-2012. Patients underwent surgical release of syndactyly in a staged fashion with the 3rd web release left until last. We measured the size of the capitate ossification center relative to that of the hamate and determined the relative position of the middle finger metacarpal relative to the ring finger metacarpal. Results: We found agreement with many findings, however we weren't able to demonstrate the catch-up growth of the capitate after release of the third web. The failure of normal distal migration of the 3rd metacarpal appeared to occur until the 3rd web release is performed. Conclusions: Consistent findings of delayed ossification of the capitate and failure of normal distal migration of the third metacarpal add support to the initial hypothesis, however, we cannot fully conclude that an earlier release of the third web is recommended, further research is still needed.	0
Purpose:We comprehensively evaluated the mutational spectrum of Leber congenital amaurosis (LCA) and investigated the molecular diagnostic rate and genotype-phenotype correlation in a Korean cohort. Methods:This single-center retrospective case series included 50 Korean patients with LCA between June 2015 and March 2019. Molecular analysis was conducted using targeted panel-based next-generation sequencing, including deep intronic and regulatory variants or whole exome sequencing. The molecular diagnosis was made based on the inheritance pattern, zygosity, and pathogenicity. Results:Among the 50 patients, 27 patients (54%) were male, and 11 (22%) showed systemic features. Genetic variants highly likely to be causative were identified in 78% (39/50) of cases and segregated into families. We detected two pathogenic or likely pathogenic variants in a gene linked to a recessive trait without segregation analysis in three cases (6.0%). GUCY2D (20%), NMNAT1 (18%), and CEP290 (16%) were the most frequently mutated genes in Korean LCA. Copy number variations were found in three patients, which accounted for 6% of LCA cases. A possible dual molecular diagnosis (Senior-Løken syndrome along with Leigh syndrome, and Joubert syndrome with transposition of the great arteries) was made in two patients (4%). Three of 50 patients were medically or surgically actionable: one patient for RPE65 gene therapy and two patients with WDR19 Senior-Løken syndrome for early preparation for kidney and liver transplantations. Conclusions:This study demonstrated that approximately 4% of patients may have dual molecular diagnoses, and 6% were surgically or medically actionable in LCA. Therefore, accurate molecular diagnosis and careful interpretation of next-generation sequencing results can be of great help in patients with LCA.	0
BACKGROUND:Amelogenesis imperfecta (AI) is a highly heterogeneous group of hereditary developmental abnormalities which mainly affects the dental enamel during tooth development in terms of its thickness, structure, and composition. It appears both in syndromic as well as non-syndromic forms. In the affected individuals, the enamel is usually thin, soft, rough, brittle, pitted, chipped, and abraded, having reduced functional ability and aesthetics. It leads to severe complications in the patient, like early tooth loss, severe discomfort, pain, dental caries, chewing difficulties, and discoloration of teeth from yellow to yellowish-brown or creamy type. The study aimed to identify the disease-causing variant in a consanguineous family. METHODS:We recruited a consanguineous Pashtun family of Pakistani origin. Exome sequencing analysis was followed by Sanger sequencing to identify the pathogenic variant in this family. RESULTS:Clinical analysis revealed hypomaturation AI having generalized yellow-brown or creamy type of discoloration in affected members. We identified a novel nonsense sequence variant c.1192C > T (p.Gln398*) in exon-12 of SLC24A4 by using exome sequencing. Later, its co-segregation within the family was confirmed by Sanger sequencing. The human gene mutation database (HGMD, 2019) has a record of five pathogenic variants in SLC24A4, causing AI phenotype. CONCLUSION:This nonsense sequence variant c.1192C > T (p.Gln398*) is the sixth disease-causing variant in SLC24A4, which extends its mutation spectrum and confirms the role of this gene in the morphogenesis of human tooth enamel. The identified variant highlights the critical role of SLC24A4 in causing a rare AI type in humans.	0
Oculocerebrorenal syndrome of Lowe is a rare X-linked metabolic disorder complicated by Fanconi's syndrome. Anaesthetic management of Lowe syndrome with Fanconi's syndrome is challenging to the anaesthesiologists in view of difficult airway due to microcephaly, metabolic abnormalities, and risk of peri-operative seizures. We report a successful anaesthetic management of a case of 2-year-old child scheduled for evaluation under anaesthesia following bilateral lens aspiration surgery.	0
Background:Hyperprolactinaemia is a common adverse effect of antipsychotics (APs). The results of Peony-Glycyrrhiza decoction (PGD) as a potentially useful adjunctive treatment for hyperprolactinaemia are inconsistent. Aim:This meta-analysis of randomised controlled trials (RCTs) examined the efficacy and safety of adjunctive PGD therapy for AP-induced hyperprolactinaemia. Methods:English (PubMed, Embase, Cochrane Library, PsycINFO) and Chinese (Chinese National Knowledge Infrastructure, Wanfang Data) databases were systematically searched up to 10 June 2018. The inclusion criteria were based on PICOS-Participants: adult patients with schizophrenia; Intervention: PGD plus APs; Comparison: APs plus placebo or AP monotherapy; Outcomes: efficacy and safety; Study design: RCTs. The weighted mean difference (WMD) and risk ratio (RR) along with their 95% CIs were calculated using Review Manager (RevMan) V.5.3 software. Results:Five RCTs (n=450) were included and analysed. Two RCTs (n=140) were double-blind and four RCTs (n=409) reported 'random' assignment with specific description. The PGD group showed a significantly lower serum prolactin level at endpoint than the control group (n=380, WMD: -32.69  ng/mL (95%  CI -41.66 to 23.72), p<0.00001, I 2 =97%). Similarly, the superiority of PGD over the control groups was also found in the improvement of hyperprolactinaemia-related symptoms. No difference was found in the improvement of psychiatric symptoms assessed by the Positive and Negative Syndrome Scale (n=403, WMD: -0.62 (95% CI -2.38 to 1.15), p=0.49, I 2 =0%). There were similar rates of all-cause discontinuation (n=330, RR 0.93 (95% CI 0.63 to 1.37), p=0.71, I 2 =0%) and adverse drug reactions between the two groups. According to the Grading of Recommendations Assessment, Development and Evaluation approach, the level of evidence of primary and secondary outcomes ranged from 'very low' (14.3%), 'low' (42.8%), 'moderate' (14.3%), to 'high' (28.6%). Conclusions:Current evidence supports the adjunctive use of PGD to suppress elevated prolactin and improve prolactin-induced symptoms without significant adverse events in adult patients with AP-induced hyperprolactinaemia. High-quality RCTs with longer duration are needed to confirm these findings. Trial registration number:42016037017.	0
A 28 year old male who complained of abdominal pain over the past several months was found on CT to have lymphadenopathy along the right aspect of the inferior vena cava. The patient was subsequently seen by an oncologist where further work up of the lymphadenopathy was performed. A MR of the abdomen demonstrated right aortocaval and para-caval lymph nodes measuring to 3.7cm. A testicular ultrasound was then performed, which demonstrated an apparent peripheral focal hypoechoic region with no associated internal vascularity within the right testes. Biopsy of the retroperitoneal lymph nodes pathologically confirmed the diagnosis of seminoma. Keywords: Seminoma, Testicular Cancer, Retroperitoneal Adenopathy, Oncology, Burned-Out Tumor.	0
Interest in how proline contributes to cancer biology is expanding because of the emerging role of a novel proline metabolic cycle in cancer cell survival, proliferation, and metastasis. Proline biosynthesis and degradation involve the shared intermediate Δ1-pyrroline-5-carboxylate (P5C), which forms l-glutamate-γ-semialdehyde (GSAL) in a reversible non-enzymatic reaction. Proline is synthesized from glutamate or ornithine through GSAL/P5C, which is reduced to proline by P5C reductase (PYCR) in a NAD(P)H-dependent reaction. The degradation of proline occurs in the mitochondrion and involves two oxidative steps catalyzed by proline dehydrogenase (PRODH) and GSAL dehydrogenase (GSALDH). PRODH is a flavin-dependent enzyme that couples proline oxidation with reduction of membrane-bound quinone, while GSALDH catalyzes the NAD+-dependent oxidation of GSAL to glutamate. PRODH and PYCR form a metabolic relationship known as the proline-P5C cycle, a novel pathway that impacts cellular growth and death pathways. The proline-P5C cycle has been implicated in supporting ATP production, protein and nucleotide synthesis, anaplerosis, and redox homeostasis in cancer cells. This Perspective details the structures and reaction mechanisms of PRODH and PYCR and the role of the proline-P5C cycle in cancer metabolism. A major challenge in the field is to discover inhibitors that specifically target PRODH and PYCR isoforms for use as tools for studying proline metabolism and the functions of the proline-P5C cycle in cancer. These molecular probes could also serve as lead compounds in cancer drug discovery targeting the proline-P5C cycle.	0
The epithelium represents the first and most extensive line of defence against pathogens, toxins and pollutant agents in humans. In general, pathogens have developed strategies to overcome this barrier and use it as an entrance to the organism. Entamoeba histolytica, Naegleria fowleri and Acanthamoeba spp. are amoebae mainly responsible for intestinal dysentery, meningoencephalitis and keratitis, respectively. These amoebae cause significant morbidity and mortality rates. Thus, the identification, characterization and validation of molecules participating in host-parasite interactions can provide attractive targets to timely intervene disease progress. In this work, we present a compendium of the parasite adhesins, lectins, proteases, hydrolases, kinases, and others, that participate in key pathogenic events. Special focus is made for the analysis of assorted molecules and mechanisms involved in the interaction of the parasites with epithelial surface receptors, changes in epithelial junctional markers, implications on the barrier function, among others. This review allows the assessment of initial host-pathogen interaction, to correlate it to the potential of parasite invasion.	0
Movement disorders in childhood comprise a heterogeneous group of conditions that lead to impairment of voluntary movement, abnormal postures, or inserted involuntary movements. Movement disorders in children are frequently caused by metabolic disorders, both inherited and acquired. Many of these respond to vitamin supplementation. Examples include infantile tremor syndrome, biotinidase deficiency, biotin-thiamine-responsive basal ganglia disease, pyruvate dehydrogenase deficiency, aromatic amino acid decarboxylase deficiency, ataxia with vitamin E deficiency, abetalipoproteinemia, cerebral folate deficiency, and cobalamin metabolism defects. Recognition of these disorders by pediatricians and neurologists is imperative as they are easily treated by vitamin supplementation. In this review, we discuss vitamin-responsive movement disorders in children.	0
Venezuelan Equine Encephalitis Virus (VEEV) is the causative viral pathogen of Venezuelan Equine Encephalitis (VEE). Outbreaks frequently involve both equines – including horses, donkeys, mules, zebras – and humans.[1][2] Outbreaks may range over a large geographic area and may last for several months to years.[1] Sporadic epidemic outbreaks occur most commonly in Central and South America. VEEV exists as both a natural pathogen and a laboratory-developed biologic weapon.[1] Outbreaks have been reported in several South and Central American countries, including Venezuela, Colombia, Peru, Ecuador, Costa Rica, Nicaragua, Honduras, El Salvador, Guatemala, Panama, Mexico, and the United States.[3] Previous outbreaks of epizootic strains have affected up to 75,000 people during a single epidemic.	0
Background: REEP1 is a common cause of autosomal dominant hereditary spastic paraplegia (HSP) but is rare in China. The pathological mechanism of REEP1 is not fully understood. Methods: We screened for REEP1 mutations in 31 unrelated probands from Chinese HSP families using next-generation sequencing targeting pathogenic genes for HSP and other related diseases. All variants were validated by Sanger sequencing. The proband family members were also screened for variants for the segregation analysis. All previously reported REEP1 mutations and cases were reviewed to clarify the genetic and clinical features of REEP1-related HSP. Results: A pathogenic mutation, REEP1c. 125G>A (p.Trp42*), was detected in a pure HSP family from North China out of 31 HSP families (1/31). This locus, which is located in the second hydrophobic domain of REEP1, is detected in both Caucasian patients with complicated HSP phenotypes and Chinese pure HSP families. Conclusion: REEP1-related HSP can be found in the Chinese population. The 42nd residue is a novel transethnic mutation hotspot. Mutations in this spot can lead to both complicated and pure form of HSP. Identification of transethnic hotspot will contribute to clarify the underlying pathological mechanisms.	0
BACKGROUND:Fanconi anemia (FA) is phenotypically diverse, hereditary condition associated with bone marrow failure, multiple physical abnormalities, and an increased susceptibility to the development of malignancies. Less recognized manifestations of FA include endocrine abnormalities. International discourse has highlighted that these abnormalities are widespread among children and adults with FA. To date there has been no systematic study that has evaluated the endocrine abnormalities in a cohort of patients with FA, homozygous for a founder mutation (c.637_643del (p.Tyr213Lysfs*6)) in FANCG. The objectives of the study were to evaluate endocrine gland function in patients with FA of a single FA genotype, and to determine the frequency and nature of endocrine abnormalities in this group. METHODS:Cross-sectional, descriptive study of 24 South African patients of African ancestry with FA (homozygous for a FANCG founder mutation). Outcomes measured included growth, pubertal status, growth hormone axis screening, thyroid gland function, glucose and insulin metabolism and bone age (BA). RESULTS:Endocrine dysfunction was present in 70.8% (17 of 24), including abnormal insulin-like growth factor 1 (IGF-1)/insulin-like growth factor-binding protein 3 (IGFBP-3) in 25.0% (6 of 24), insulin resistance in 41.7% (10 of 24), abnormal thyroid function in 16.7% (4 of 24) and short stature in 45.8% (11 of 24). No abnormalities of glucose metabolism were identified. Abnormal pubertal status was seen in three males (12.5%). Abnormal BAs were present in 34.8% (8 of 23). CONCLUSION:Endocrine abnormalities occur at a high frequency in patients with FA, homozygous for a FANCG founder mutation, similar to other FA cohorts. Our data are specific to FA patients with a single genotype, and therefore provide the first genotype-phenotype information on endocrine abnormalities in South African patients, homozygous for a FANCG founder mutation. Recommendations regarding endocrine screening in this patient subgroup are made, including, but not limited to, baseline testing of thyroid function, fasted insulin and glucose, and IGF-1 and IGFBP-3.	0
Scleroderma, "en coup de sabre" is a rare disorder, characterized by linear depressed scarring at frontoparietal area of the face, seldom associated with ophthalmological findings. Extraocular muscle involvement and paralytic strabismus are rarely associated with linear scleroderma. Here we are reporting a case of unilateral linear scleroderma in an 8-year-old child, with features of strabismus fixus secondary to fibrosed medial rectus (MR) muscle, enophthalmos and en coup de saber (sword-like scar) on the eyebrow. MRI orbit was suggestive of the bulky MR and the inferior rectus muscle. MR recession along with partial loop myopexy resulted in cosmetically acceptable ocular alignment in this case. Histopathology of the portion of muscle and intermuscular septum showed diffuse fibrosis of the muscle. Linear scleroderma may be the causative etiology of strabismus fixus in our case, never reported before in literature.	0
Chromosomal microarray (CMA) analysis for discovery of copy number variants (CNVs) is now recommended as a first-line diagnostic tool in patients with unexplained developmental delay/intellectual disability (DD/ID) and autism spectrum disorders. In this study, we present the results of CMA analysis in patients with DD/ID. Of 210 patients, pathogenic CNVs were detected in 26 (12%) and variants of uncertain clinical significance in 36 (17%) children. The diagnosis of well-recognized genetic syndromes was achieved in 12 patients. CMA analysis revealed pathogenic de novo CNVs, such as 11p13 duplication with new clinical features. Our results support the utility of CMA as a routine diagnostic test for unexplained DD/ID.	0
L1 syndrome is a group of overlapping, X-linked disorders caused by mutations in L1CAM. Clinical phenotypes within L1 syndrome include X-linked hydrocephalus with stenosis of the aqueduct of sylvius (HSAS); mental retardation, adducted thumbs, shuffling gait, and aphasia (MASA) syndrome; spastic paraplegia type 1; and agenesis of the corpus callosum. Over 200 mutations in L1CAM have been reported; however, only a few large gene deletions have been observed. We report on a 4-month-old male with a de novo whole gene deletion of L1CAM presenting with congenital hydrocephalus, aqueductal stenosis, and adducted thumbs. Initial failure of L1CAM gene sequencing suggested the possibility of a whole gene deletion of L1CAM. Further investigation through chromosome microarray analysis showed a 62Kb deletion encompassing the first exon of the PDZD4 gene and the entire L1CAM gene. Investigations into genotype-phenotype correlations have suggested that mutations leading to truncated or absent L1 protein cause more severe forms of L1 syndrome. Based on the presentation of the proband and other reported patients with whole gene deletions, we provide further evidence that L1CAM whole gene deletions result in L1 syndrome with a severe phenotype, deletions of PDZD4 do not cause additional manifestations, and that X-linked nephrogenic diabetes insipidus reported in a subset of patients with large L1CAM deletions results from the loss of AVPR2.	0
Pulmonary arteriovenous malformations (PAVMs) are abnormal vascular structures that most often connect a pulmonary artery to a pulmonary vein, bypassing the normal pulmonary capillary bed and resulting in an intrapulmonary right-to-left shunt. As a consequence, patients with PAVM can have hypoxemia and paradoxical embolization complications, including stroke and brain abscess. PAVMs may be single or multiple, unilateral or bilateral, and simple or complex. Most PAVMs are hereditary and occur in hereditary hemorrhagic telangiectasia, an autosomal dominant vascular disorder, and screening for PAVM is indicated in this subgroup. PAVMs may also be idiopathic, occur as a result of trauma and infection, or be secondary to hepatopulmonary syndrome and bidirectional cavopulmonary shunting. Diagnostic testing involves identifying an intrapulmonary shunt, with the most sensitive test being transthoracic contrast echocardiography. Chest CT scan is useful in characterizing PAVM in patients with positive intrapulmonary shunting. Transcatheter embolotherapy is the treatment of choice for PAVM. Lifelong follow-up is important because recanalization and collateralization may occur after embolization therapy. Surgical resection is rarely necessary and reserved for patients who are not candidates for embolization. Antibiotic prophylaxis for procedures with a risk of bacteremia (eg, dental procedures) is recommended in all patients with PAVM because of the risk of cerebral abscess.	1
PURPOSE:Congenital adrenal hyperplasia (CAH) is rare autosomal recessive disease. CAH due to 21-hydroxylase deficiency accounts for 95% of cases. We aimed to share the first case of coexistence of simple virilizing-type congenital adrenal hyperplasia [I172N mutation in the CYP21A], triple translocation [t(9;11;12)], and ovarian granulose cell tumor. METHODS:A 59-year-old female patient was presented to our clinic, complaining with abdominal pain and distension. Physical examination revealed palpable abdominal mass, virilism, ambiguous genitalia, clitoramegaly, and hyperpigmentation. Contrast-enhanced abdominal computed tomography showed a giant mass originating from the right tubo-ovarian structure. RESULTS:The patient was operated in the light of the clinico-radiological features mentioned above. A giant mass weighing 3500 g was detected on the right tubo-ovarian structure during laparotomy, and mass was excised with right tubo-ovarian structure. Immunohistochemical examination revealed ovarian granulosa cell tumor. The high serum concentration of 17-OH progesterone was measured at baseline and after 250-μg bolus of synthetic ACTH. In genetic analysis, we screened for six-point mutations, large deletions, and non-common mutations using restriction fragment length polymorphism (RFLP) methods, PCR, and sequencing of CYP21 gene respectively. The patient was detected to be homozygous for the I172N mutation. In addition, 50% of the metaphases examined had triple translocation [t(9;11;12)]. CONCLUSION:The coexistence of congenital adrenal hyperplasia, triple chromosomal translocations, and ovarian granulosa cell tumor has not been described previously. This coexistence may be a sign of a new syndrome.	0
Margarita Island ectodermal dysplasia (ED4) is an autosomal recessive disorder characterized by unusual facies, dental anomalies, hypotrichosis, palmoplantar hyperkeratosis and onychodysplasia, syndactyly, and cleft lip/cleft palate. We have used an affected-only DNA-pooling strategy to carry out linkage disequilibrium mapping of the ED4 gene to 11q23. Haplotype analysis of four complex Margarita Island ED4 families localized the ED4 gene to an approximately 1-2-Mb interval spanned by just two YACs.	0
Hydrolysis of glucosylceramides (GlcCer) by beta-glucocerebrosidase generates ceramides, critical components of the epidermal permeability barrier. Ceramides also are involved in the regulation of cellular proliferation and differentiation in a variety of cell types. Whereas most studies have focused on ceramides and their sphingoid base metabolites as growth inhibitors, GlcCer apparently acts oppositely (i.e., as a mitogen). To determine whether enhancement of GlcCer content stimulates epidermal mitogenesis, we examined the response of hairless mouse epidermis to alterations in endogenous and/or exogenous GlcCer. Topical applications of conduritol B epoxide, a specific irreversible inhibitor of beta-glucocerebrosidase, increased epidermal GlcCer levels twofold, an alteration localized largely to the basal, proliferative cell layer (fourfold increase); and stimulated epidermal proliferation (2.3-fold elevation in [3H]thymidine incorporation; P < or = 0.001), localized autoradiographically again to the basal layer, and resulting in epidermal hyperplasia. Intracutaneous administration of GlcCer (2.0 mg) also stimulated epidermal DNA synthesis, while simultaneous treatment with conduritol B epoxide plus GlcCer resulted in an additive increase in DNA synthesis. These increases in epidermal proliferation could not be attributed either to altered epidermal permeability barrier function, or to nonspecific irritant effects, as determined by four separate criteria. These results strongly suggest that GlcCer directly stimulates epidermal mitogenesis.	0
We herein report a 62-year-old man with idiopathic pulmonary fibrosis who developed remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome during follow-up. Pulmonary infiltrations were detected concomitantly with the development of RS3PE syndrome, and prednisolone improved both the pulmonary and extrapulmonary lesions. Recognizing the pulmonary manifestations of RS3PE syndrome is necessary to provide an appropriate diagnosis and disease management.	0
Gestational psittacosis is a rare disease that is associated with significant maternal and fetal morbidity and mortality. Currently, there is no examination method which allows for a quick diagnosis. We report a case of gestational psittacosis that could not be diagnosed as psittacosis during treatment and resulted in maternal and fetal death despite intensive treatment. We also reviewed 23 cases of gestational psittacosis. Fetal and maternal mortality was 82.6% (19/23) and 8.7% (2/23), respectively. In pregnant women with high fever and flu-like symptoms, we should suspect Chlamydia psittaci infection if at least one of the following is present; contact with sheep, parrots, parakeets or goats; normal or moderately decreased leucocyte count, thrombocytopenia and hepatic and/or renal dysfunction; cough and/or lobe consolidation or infiltration on chest X-ray. Antibiotic therapy with macrolide prenatally, macrolide or tetracycline postnatally and termination of pregnancy should be considered.	0
Infection-induced acute encephalopathies (IIAEs) are a group of neurologic disorders caused post infection. They are of 8 types, 6 of which are herpes specific, whereas IIAE3 and IIAE4 can be triggered by infections additional to herpeslike influenza, enterovirus, etc. IIAE3 is also known as acute necrotizing encephalopathy type 1, which is a rare type of encephalopathy that occurs following an infection in infancy or early childhood. Symptoms include fever, cough, congestion, vomiting, and diarrhea followed by seizures, hallucination, ataxia, and abnormal muscle tone, and sometimes it leads to untimely death. Here, we describe a familial case where 3 siblings were clinically diagnosed with acute necrotizing encephalopathy 1. Genetic testing revealed 2 heterozygous variations: RANBP2 c.5249C>G, p.P1750 R, and CPT2 c.365C>T, p.S122F. Variants in RANBP2 and CPT2 have been individually known to be associated with IIAE3 and IIAE4, respectively. Segregation analysis revealed that the RANBP2 variant was inherited from the father and the CPT2 variant from the mother. This case qualifies to be the first of its kind where digenic inheritance (ie, DNA sequence variants in 2 genes are required for the pathogenic phenotypes) appears to cause a lethal class of acute necrotizing encephalopathy.	0
BACKGROUND:In recent years, the elucidation of splicing abnormalities as a cause of hereditary diseases has progressed. However, there are no comprehensive reports of suspected splicing variants in the CLCN5 gene in Dent disease cases. We reproduced gene mutations by mutagenesis, inserted the mutated genes into minigene vectors, and investigated the pathogenicity and onset mechanisms of these variants. METHODS:We conducted functional splicing assays using a hybrid minigene for six suspected splicing variants (c.105G>A, c.105+5G>C, c.106-17T>G, c.393+4A>G, c.517-8A>G, c.517-3C>A) in CLCN5. We extracted information on these variants from the Human Gene Mutation Database. We reproduced minigene vectors with the insertion of relevant exons with suspected splicing variants. We then transfected these minigene vectors into cultured cells and extracted and analyzed the mRNA. In addition, we conducted in silico analysis to confirm our minigene assay results. RESULTS:We successfully determined that five of these six variants are pathogenic via the production of splicing abnormalities. One showed only normal transcript production and was thus suspected of not being pathogenic (c.106-17T>G). CONCLUSION:We found that five CLCN5 variants disrupted the original splice site, resulting in aberrant splicing. It is sometimes difficult to obtain mRNA from patient samples because of the fragility of mRNA or its low expression level in peripheral leukocytes. Our in vitro system can be used as an alternative to in vivo assays to determine the pathogenicity of suspected splicing variants.	0
γ-Secretase is a multisubunit membrane protein complex containing catalytic presenilin (PS1 or PS2) and cofactors such as nicastrin, Aph-1, and Pen2. γ-Secretase hydrolyzes the transmembrane domains of type-I membrane proteins, which include the amyloid precursor protein (APP). APP is cleaved by γ-secretase to produce amyloid β peptide (Aβ), which is deposited in the brains of Alzheimer disease patients. However, the mechanism of this unusual proteolytic process within the lipid bilayer remains unknown. We have established a yeast transcriptional activator Gal4p system with artificial γ-secretase substrates containing APP or Notch fragments to examine the enzymatic properties of γ-secretase. The γ-secretase activities were evaluated by transcriptional activation of reporter genes upon Gal4 release from the membrane bound substrates as assessed by growth of yeast or β-galactosidase assay. We also established an in vitro yeast microsome assay system which identified different Aβ species produced by trimming. The yeast system allows for the screening of mutations and chemicals that inhibit or modulate γ-secretase activity. Herein we describe the genetic and biochemical methods used to analyze γ-secretase activity using the yeast reconstitution system. By studying the loss-of-function properties of PS1 mutants, it is possible to successfully screen FAD suppressor mutations and identify γ-secretase modulators (GSMs), which are promising Alzheimer disease therapeutic agents.	0
Blau syndrome (BS) is a rare autosomal dominant familial granulomatous inflammatory disease presenting in early childhood with dermatitis, arthritis and uveitis. Early-onset sarcoidosis represents the sporadic form, and both are characterised by mutations in the CARD15/NOD2 gene on chromosome 16. We describe a 38-year-old man with known BS who presented for orthopaedic review following right-sided patellar dislocation. MRI of the injured knee demonstrated diffuse synovitis and prominent fatty tissue resembling lipoma arborescens with evidence of recent patellar dislocation. Synovectomy was performed and confirmed granulomatous synovitis. Knee imaging findings are described for the first time. Combining distinct morphological bone changes with synovitis which resembles lipoma arborescens and histology which includes sarcoidal-type granulomatous synovitis should lead the radiologist and pathologist to consider the diagnosis of BS.	0
Background: Chronic acrodermatitis continua of Hallopeau (ACH) is a rare form of pustular psoriasis predominantly affecting the distal phalanges of the fingers and toes. The disease manifests by pustular rash with marked infiltration, fissures, and often results into severe dystrophy of nail plates. ACH is refractory to most of psoriasis standard of care (SOC) therapies. Objective: The objective of this study is to assess the prospects of secukinumab therapy of ACH based on current clinical observation. Methods: We observed a female patient with ACH. Number of SOC treatments were applied in that case including local PUVA therapy, systemic retinoids, methotrexate, and biologic agents. Result: Secukinumab, a IL-17 inhibitor, demonstrated pronounced clinical effect in the case of ACH refractory to other SOC therapies. Conclusion: IL-17 inhibition provided by secukinumab was linked to clinically meaningful improvement in the heavily pretreated ACH. Further exploration and clinical studies may be important to provide more data on secukinumab effects in ACH.	0
The musculoskeletal system is critical for movement and the protection of organs. In addition to abrupt injuries, daily physical demands inflict minor injuries, necessitating a coordinated process of repair referred to as the acute-phase response (APR). Dysfunctional APRs caused by severe injuries or underlying chronic diseases are implicated in pathologic musculoskeletal repair, resulting in decreased mobility and chronic pain. The molecular mechanisms behind these phenomena are not well understood, hindering the development of clinical solutions. Recent studies indicate that, in addition to regulating intravascular clotting, the coagulation and fibrinolytic systems are also entrenched in tissue repair. Although plasmin and fibrin are considered antithetical to one another in the context of hemostasis, in a proper APR, they complement one another within a coordinated spatiotemporal framework. Once a wound is contained by fibrin, activation of plasmin promotes the removal of fibrin and stimulates angiogenesis, tissue remodeling, and tissue regeneration. Insufficient fibrin deposition or excessive plasmin-mediated fibrinolysis in early convalescence prevents injury containment, causing bleeding. Alternatively, excess fibrin deposition and/or inefficient plasmin activity later in convalescence impairs musculoskeletal repair, resulting in tissue fibrosis and osteoporosis, while inappropriate fibrin or plasmin activity in a synovial joint can cause arthritis. Together, these pathologic conditions lead to chronic pain, poor mobility, and diminished quality of life. In this review, we discuss both fibrin-dependent and -independent roles of plasminogen activation in the musculoskeletal APR, how dysregulation of these mechanisms promote musculoskeletal degeneration, and the possibility of therapeutically manipulating plasmin or fibrin to treat musculoskeletal disease.	0
Catel-Manzke syndrome is characterized by hyperphalangism with bilateral deviation of the index fingers and micrognathia with or without cleft palate. Some atypical patients present with additional malformations. No molecular basis is yet available. Most patients have an unremarkable family history but autosomal recessive inheritance has been recently suggested in a consanguineous family with recurrence in sibs. Catel-Manzke syndrome has overlapping features with Desbuquois dysplasia type 1 due to CANT1 (calcium-activated nucleotidase 1) mutations and also with "chondrodysplasia with joint dislocations, gPAPP type" due to IMPAD1 (Inositol Monophosphatase Domain containing 1) mutations recently reported in four patients, all characterized by short stature, joint dislocations, brachydactyly and cleft palate. The aim of our study was to screen CANT1 and IMPAD1 in Catel-Manzke patients. Three patients were diagnosed as classical Catel-Manzke syndrome and two as Catel-Manzke like patients, based on the presence of additional features. We identified two homozygous loss-of-function IMPAD1 mutations in the two Catel-Manzke like patients (p.Arg187X and p.Ser108ArgfsX48). The phenotype was characterized by severe growth retardation with short and abnormal extremities, cleft palate with micrognathia and knee hyperlaxity. Radiographs of hands and feet revealed numerous accessory bones with abnormally shaped phalanges and carpal synostosis. Based on this report, we concluded that IMPAD1 should be screened for patients with Catel-Manzke and additional features.	0
Nivolumab induces several immune-related adverse events. Isolated adrenocorticotropic hormone(ACTH)deficiency has low frequency. A 73-year-old woman with gastric cancer metastasis of the peritoneum was treated with nivolumab as the third-line chemotherapy. After 5 courses of nivolumab, she developed hypothyroidism. After completing 12 courses, peritoneal metastasis increased. We evaluated the metastasis as progression of disease, so treatment with nivolumab was discontinued. Two weeks after the last dosage of nivolumab, she developed general fatigue and appetite loss. At first, we considered that these symptoms were caused by peritoneal metastasis, but progression was not indicated in the CT. Blood levels of cortisol and ACTH were very low. We suspected secondary adrenocortical insufficiency induced by nivolumab. Endocrinological examinations and the results of brain MRIsuggested isolated ACTH deficiency. This is the first report of isolated ACTH deficiency induced by nivolumab in a patient with gastric cancer metastasis of the peritoneum. The symptoms of adrenocortical insufficiency induced by nivolumab overlap with those of peritoneal metastasis, and thus, it may be difficult to confirm a differential diagnosis. When adrenocortical insufficiency is suspected, we should check the blood levels of cortisol and ACTH.	0
The main energy substrate of adult cardiomyocytes for their contractility are the fatty acids. Its metabolism generates high ATP levels at the expense of high oxygen consumption in the mitochondria. Under low oxygen supply, they can get energy from other substrates, mainly glucose, lactate, ketone bodies, etc., but the mitochondrial dysfunction, in pathological conditions, reduces the oxidative metabolism. In consequence, fatty acids are stored into epicardial fat and its accumulation provokes inflammation, insulin resistance, and oxidative stress, which enhance the myocardium dysfunction. Some therapies focused on improvement the fatty acids entry into mitochondria have failed to demonstrate benefits on cardiovascular disorders. Oppositely, those therapies with effects on epicardial fat volume and inflammation might improve the oxidative metabolism of myocardium and might reduce the cardiovascular disease progression. This review aims at explain (a) the energy substrate adaptation of myocardium in physiological conditions, (b) the reduction of oxidative metabolism in pathological conditions and consequences on epicardial fat accumulation and insulin resistance, and (c) the reduction of cardiovascular outcomes after regulation by some therapies.	0
OBJECTIVE:The aim of this study is to evaluate surgical outcomes for patients with sagittal craniosynostosis undergoing open cranial vault remodeling with a modified pi procedure comparing subgaleal versus subperiosteal dissection. METHODS:A retrospective chart review was performed for children between the ages of 3 and 7 months with sagittal craniosynostosis undergoing open cranial vault expansion at Seattle Children's Hospital. Patient demographics, operative variables, and post-operative outcomes including the surface area of bony cranial defects at 2-year follow up were evaluated. RESULTS:Over a 3-year period, 35 patients between the ages of 3-7 months underwent surgical correction of sagittal craniosynostosis using our institutional adaptation of the modified pi technique. Twenty-five patients underwent exposure via a sub-galeal (SG) approach, 10 patients had a sub-pericranial (SP) exposure. Compared to the SP group, the SG group had significant lower estimated blood loss and a shorter operating time (p < 0.05). There were no significant differences with regard to hospital length of stay or post-operative complications (p > 0.48). At two-years post-operatively, there were no significant differences in the size of the largest cranial defects (SG: 1.1 + 0.1 cm2 versus 3.7 + 0.1 cm2, p = 0.40); no patients required a secondary cranioplasty. CONCLUSIONS:Open posterior and middle cranial vault expansion is a safe and efficient method of open cranial vault expansion in sagittal craniosynostosis regardless of the plane of dissection. Elevation of the scalp flaps in the subgaleal plane is a minor technical modification that can reduce blood loss and operative times.	0
Background: Postoperative hydrocephalus and subdural fluid collection (SFC) have been reported as the rare complications following foramen magnum decompression in patients with Chiari malformation.Case Description: The paper reports the case of a 63-year-old female patient who underwent foramen magnum decompression for basilar invagination. The patient developed a shifting, bilateral SFC and subsequent acute hydrocephalus. A ventriculoperitoneal shunting was performed and the clinical symptom resolved. The dramatic change in CSF distribution supported the diagnosis of external hydrocephalus, which was associated with a postoperative cervical pseudomeningocele.Conclusions: Postoperative SFC in patients underwent foramen magnum decompression may harbor different mechanisms. Subdural drainage for patients having external hydrocephalus may have a higher recurrence rate.	0
Purpose:Two diabetic case reports of serous retinal detachment (SRD) accompanied by pachychoroid in hypotony maculopathy after trabeculectomy for neovascular glaucoma (NVG). Observations:Case 1: A 66-year-old female with stage 3 NVG and decreased vision acuity in the left eye. After trabeculectomy, postoperative laser suture lysis (LSL) resulted in development of hypotony maculopathy, followed by pachychoroid and SRD. Injection of C3F8 gas in the anterior chamber was unsuccessful and transconjunctival scleral re-suturing was performed. Intraocular pressure (IOP) consequently increased and SRD improved. Case 2: A 60-year-old man with stage 2 NVG and decreased vision acuity in the right eye. Trabeculectomy was uneventful, but postoperative LSL also resulted in development of hypotony maculopathy followed by pachychroid and SRD. Intravitreal bevacizumab injection had no effect and transconjunctival flap re-suturing was performed. IOP consequently increased and SRD improved. Conclusions:SRD accompanied by pachychoroid was observed in hypotony maculopathy in diabetic cases. VEGF-independent exudative change in hypotony maculopathy may be due to hydrostatic pressure elevation in choroidal blood vessels based on Starling's hypothesis with the consequent breakdown of retinal pigment epithelium barrier in diabetic patients.	0
Variations in genes encoding for the enzymes responsible for synthesizing the linker region of proteoglycans may result in recessive conditions known as "linkeropathies". The two phenotypes related to mutations in genes B4GALT7 and B3GALT6 (encoding for galactosyltransferase I and II respectively) are similar, characterized by short stature, hypotonia, joint hypermobility, skeletal features and a suggestive face with prominent forehead, thin soft tissue and prominent eyes. The most outstanding feature of these disorders is the combination of severe connective tissue involvement, often manifesting in newborns and infants, and skeletal dysplasia that becomes apparent during childhood. Here, we intend to more accurately define some of the clinical features of B4GALT7 and B3GALT6-related conditions and underline the extreme hypermobility of distal joints and the soft, doughy skin on the hands and feet as features that may be useful as the first clues for a correct diagnosis.	0
There is no available measuring protocol and reference range for the normal canine trigeminal nerve. This can be problematic in cases of suspected bilateral trigeminal neuropathy since contralateral nerves cannot be a usefully compared. Trigeminal nerves and brain measurements were retrospectively assessed via multiplanar reconstruction (MPR) of 3DT1 post-contrast MR sequences from 137 dogs with no signs or diagnosis of trigeminal disease. Direct measurements of vertical brain height (BH), trigeminal nerves transverse height (TTH) and trigeminal nerves width in dorsal reconstruction (TDW) were made in a plane immediately caudal to the foramen ovale and used to derive trigeminal nerve-to-brain (NB) ratios, including height-to-brain ratio (HBR) and width-to-brain ratio (WBR). HBR (0.09, IQR = 0.08-0.09) and WBR (0.10, IQR = 0.09-0.11) maintained more consistent values across the study population compared to direct measurements of TTH (3.72, IQR = 3.42-4.07) and TDW (4.35 +/- 0.63). Calculated normal reference intervals for HBR and WBR were 0.07-0.11 and 0.08-0.13, respectively and the largest NB ratios recorded in normal dogs were 0.13 and 0.14 for HBR and WBR, respectively. All measurements varied proportionally with weight, including HBR (r = 0.41, p < 0.0001) and small dogs had a significantly smaller HBRs compared to medium (p = 0.0294), large (p < 0.0049) and giant dogs (p < 0.0044). Median HBR was the same across skull types (0.09), however post-hoc analysis detected significantly smaller HBRs in brachycephalic compared to mesaticephalic dogs (p = 0.0494). In conclusion, trigeminal NB ratios may allow for accurate, objective assessment of the canine trigeminal nerves on MRI but further quantification of the effects of weight and skull type on suggested reference intervals is needed.	0
OBJECTIVE:Genetic subtypes of dystonia may respond differentially to deep brain stimulation of the globus pallidus pars interna (GPi DBS). We sought to compare GPi DBS outcomes among the most common monogenic dystonias. METHODS:This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology guidelines. We searched PubMed for studies on genetically confirmed monogenic dystonia treated with GPi DBS documenting pre-surgical and post-surgical assessments using the Burke-Fahn-Marsden Dystonia Rating Scale Motor Score (BFMMS) and Burke-Fahn-Marsden Disability Score (BFMDS). We performed (i) meta-analysis for each gene mutation; (ii) weighted ordinary linear regression analyses to compare BFMMS and BFMDS outcomes between DYT-TOR1A and other monogenic dystonias, adjusting for age and disease duration and (iii) weighted linear regression analysis to estimate the effect of age, sex and disease duration on GPi DBS outcomes. Results were summarised with mean change and 95% CI. RESULTS:DYT-TOR1A (68%, 38.4 points; p<0.001), DYT-THAP1 (37% 14.5 points; p<0.001) and NBIA/DYT-PANK2 (27%, 21.4 points; p<0.001) improved in BFMMS; only DYT-TOR1A improved in BFMDS (69%, 9.7 points; p<0.001). Improvement in DYT-TOR1A was significantly greater than in DYT-THAP1 (BFMMS -31%), NBIA/DYT-PANK2 (BFMMS -35%; BFMDS -53%) and CHOR/DYT-ADCY5 (BFMMS -36%; BFMDS -42%). Worse motor outcomes were associated with longer dystonia duration and older age at dystonia onset in DYT-TOR1A, longer dystonia duration in DYT/PARK-TAF1 and younger age at dystonia onset in DYT-SGCE. CONCLUSIONS:GPi DBS outcomes vary across monogenic dystonias. These data serve to inform patient selection and prognostic counselling.	0
Dyggve-Melchior-Clausen syndrome (DMC) (MIM 223800) and Smith-McCort dysplasia (SMC) (MIM 607326) are rare allelic autosomal recessive spondylo-epi-metaphyseal dysplasias (SEMDs) characterized by similar skeletal manifestations. Both phenotypes have been mapped to chromosome 18q21.1 and mutations in the DYM (dymeclin) gene were identified in 13 families with DMC and in two families with SMC. Most mutations identified in DMC predict a loss of function, while those identified in SMC are mainly missense mutations, presumably associated with residual DYM activity and a less severe phenotype. We studied three consanguineous families from Turkey, Lebanon, and Georgia, one with SMC and two with DMC and identified different homozygous DYM mutations (IVS3 194-1G > A, 938_942delTGTCT) in the DMC families. No mutation was identified in the SMC family, possibly suggesting genetic heterogeneity of this disorder.	0
North Carolina macular dystrophy (NCMD) has a variable phenotype (Fig. 21.1). Patients are usually infants, in whom the fundus shows a cluster of yellowish-white lesions (like drusen) at the macula (grade 1); sometimes the lesions are confluent (grade 2). As the disease progresses, retinal pigment epithelial (RPE) atrophy sets in, and the lesion may appear excavated like a coloboma (grade 3) or a toxoplasmosis scar with a thick, white, fibrotic rim.	0
The current definition of cough headache includes provocation of the symptom by Valsalva manoeuvre, and it is generally believed that all cough headache results from a sudden increase in intracranial pressure. We sought to question that presumption and to determine whether the Valsalva test might distinguish primary from secondary cough headache.We examined 16 consecutive cough headache patients using a modified Valsalva test (exhalation into the connecting tube of a standard anaeroid sphygmomanometer to 60 mm Hg for 10 seconds). A positive response was recorded if the manoeuvre provoked headache. All patients subsequently underwent brain MRI.None of the patients had neurological signs. Eleven had positive modified Valsalva tests. Ten were found subsequently to have posterior fossa pathologies (secondary cough headache: 8 Chiari Type 1 malformations, 2 posterior fossa meningiomas). The cough headache was relieved following surgery in all cases. One patient with a positive Valsalva test had an apparently normal brain MRI but measurements of hindbrain and posterior fossa dimensions were consistent with 'posterior fossa crowdedness'. The remaining 5 patients had negative (4 patients) or equivocal (1 patient) Valsalva tests and normal MRI scans (primary cough headache).These findings suggest that secondary cough headache results from a transient increase in intracranial CSF pressure during exertion in the presence of obstruction to normal cerebrospinal fluid dynamics. The modified Valsalva test can also determine whether tonsillar herniation found on brain MRI is symptomatic. Primary cough headache appears to be caused by a different mechanism, possibly through congestion of the orbital venous plexus in the presence of jugular venous incompetence and a reduced threshold for trigeminal sensory activation.	0
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Prognosis is highly variable, ranging from few months to more than 30 years. 25OH vitamin D (25OH VD) blood levels have been associated with worse prognosis of ALS, but these results remain in dispute. We addressed this controversy with a prospective study and multivariate analysis to study the influence of known clinical prognostic factors of the disease and 25OH VD levels on Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) severity score (ALS-SS), as defined by the monthly rate of decline of ALSFRS-R score, to identify the factors most closely linked to the risk of worsening of the disease. Results:This prospective cohort of ALS patients recruited 127 individuals, and 105 of them met inclusion criteria. Mean age of onset was 62.2 ± 12.1 years, 32% of subjects had bulbar onset, and gender ratio was 1.44 (male/female). Mean 25OH VD level was 26.8 ± 10.8 ng/ml and was similar between males and females. Patients with 25OH VD levels <15 ng/ml had significantly higher ALS-SS at inclusion (ALS-SSi) than those with normal levels (>30 ng/ml), p = 0.011. The study of ALS-SS as calculated at the end of follow-up (ALS-SSe) was not found correlated to initial 25OH VD levels (r = -0.19; p = 0.084). Univariate analysis showed that ALS-SSe correlated with 25OH VD levels, ALS duration at inclusion, slow vital capacity (SVC) at inclusion, and SVC loss. Multivariate model showed that 25OH VD levels were independently associated with ALS-SSe: r = -0.0125, p = 0.033. Log rank test with Kaplan-Meier curves did not show significant differences of survival between the groups defined by 25OH VD levels: <15, >15 and <30, and > 30 ng/ml, p = 0.88. Conclusions: This prospective study in ALS patients confirmed previous retrospective results: ALS-SSi is significantly higher in patients with severe VD deficiency. For the first time, multivariate analysis showed that 25OH VD level was an independent prognostic factor correlated to ALS-SSe, suggesting that discrepancies between previous works could be due to confounders. It would be important that the present work be replicated in larger samples to confirm the present findings.	0
Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM) is a rare platelet disorder caused by mutations in RUNX1. We generated an iPSC line (GENYOi005-A) from a FPDMM patient with a non-previously reported variant p.Thr196Ala. Non-integrative Sendai viruses expressing the Yamanaka reprogramming factors were used to reprogram peripheral blood mononuclear cells from this FPDMM patient. Characterization of GENYOi005-A included genetic analysis of RUNX1 locus, Short Tandem Repeats profiling, alkaline phosphatase enzymatic activity, expression of pluripotency-associated factors and differentiation studies in vitro and in vivo. This iPSC line will provide a powerful tool to study developmental alterations of FPDMM patients.	0
Background:Sickle cell hemoglobinopathies are associated with end organ damage but very rarely present with a clinical and laboratory picture of microangiopathic hemolytic anemia (MAHA) and thrombocytopenia, characteristic of thrombotic microangiopathy (TMA). Case presentation:We present a patient with HbSC disease who developed thrombotic microangiopathy, needing both RBC exchange transfusion and therapeutic plasma exchange (TPE) for complete clinical recovery. Conclusion:Although literature showed therapeutic plasma exchange alone can abrogate a similar clinical scenario, we did an in-depth review which concluded that in most of the TMA cases secondary to sickle cell disease, treatment with both with plasma exchange and red cell exchange transfusion are necessary.	0
Purpose: This is the first review article examining literature specific to the use of corneal cross-linking (CXL) to treat pellucid marginal degeneration (PMD). Results: CXL appears to be an effective treatment that may halt the progression of PMD to stabilize vision. This could postpone or eliminate the need for corneal transplantation in the management of these patients. Furthermore, combining CXL with keratorefractive surgery in a single procedure has been shown to be safe and successful in improving vision in PMD patients. Conclusions: The data reported in literature is limited at this time, consisting mostly of retrospective studies with short term follow up. Further research is needed to evaluate refractive effects of combined CXL and excimer laser procedures.	0
PURPOSE:While there is an urgent need for diagnosis and therapeutic intervention in patients with primary immunodeficiency diseases (PIDs), current genetic tests have drawbacks. We retrospectively reviewed the usefulness of flow cytometry (FCM) as a quick tool for immunophenotyping and functional assays in patients suspected to have PIDs at a single tertiary care institute. METHODS:Between January 2001 and June 2018, patients suspected of having PIDs were subjected to FCM tests, including lymphocyte subset analysis, detection of surface- or intracellular-target proteins, and functional analysis of immune cells, at Samsung Medical Center, Seoul, Korea. The genetic diagnosis was performed using Sanger or diagnostic exome sequencing. RESULTS:Of 60 patients diagnosed with definite or probable PID according to the European Society of Immune Deficiencies criteria, 24 patients were provided with useful information about immunological dysfunction after initial FCM testing. In 10 patients, the PID diagnosis was based on abnormal findings in FCM testing without genetic tests. The FCM findings provided strong evidence for the diagnosis of severe combined immunodeficiency (n = 6), X-linked chronic granulomatous diseases (CGD) (n = 6), leukocyte adhesion deficiency type 1 (n = 3), X-linked agammaglobulinemia (n = 11), autoimmune lymphoproliferative syndrome-FASLG (n = 1), and familial hemophagocytic lymphohistiocytosis type 2 (n = 1), and probable evidence for autosomal recessive-CGD (n = 2), autosomal dominant-hyper-immunoglobulin E (IgE)-syndrome (n = 1), and STAT1 gain-of-function mutation (n = 1). In PIDs derived from PIK3CD (n = 2), LRBA (n = 2), and CTLA4 mutations (n = 3), the FCM test provided useful evidence of immune abnormalities and a tool for treatment monitoring. CONCLUSIONS:The initial application of FCM, particularly with known protein targets on immune cells, would facilitate the timely diagnosis of PIDs and thus would support clinical decisions and improve the clinical outcome.	0
Background:The importance of fetal nuchal translucency was highlighted in the early 1990s as a useful first-trimester marker to identify fetal chromosomal abnormalities. Here, we report the prenatal diagnosis of a fetus with Niemann-Pick disease type C initially identified by first-trimester ultrasonographic markers and eventually confirmed by extensive genetic evaluation. Case presentation:The fetus of a 30-year-old woman exhibited a cystic hygroma in the first trimester of pregnancy. The woman underwent chorionic villus sampling with extensive genetic investigations to identify the genetic cause of the ultrasonographic findings. Owing to normal karyotype results, further evaluation of 1,024 genes underlying structural abnormalities was performed. This test identified a homozygous mutation of the NPC2 gene (OMIM 601015), which has been reported to be pathogenic and responsible for Niemann-Pick disease type C2 (NPD-C2). Genetic evaluation of the parents found them to be carriers. Considering the poor prognosis, the parents decided to terminate the pregnancy. Ultrasonographic screening during the subsequent pregnancy showed normal findings; however, molecular testing for the previous familial mutation c.441 + 1G>A identified the fetus as homozygous for this mutation. Therefore, the parent chose to terminate the subsequent pregnancy as well. Conclusion:We report the first prenatal diagnosis of NPD-C2 based on a cystic hygroma found during the first trimester of pregnancy as the sole indicator.	0
Ascertainment of cases of classical galactosaemia over a three year period in the UK and the Republic of Ireland, through the British Paediatric Surveillance Unit, identified 58 proved cases and two in whom the diagnosis was strongly suspected. One patient died at 4 days, and severe morbidity was no more frequent in babies diagnosed clinically because of their symptoms compared with those who were screened for galactosaemia. Treatment of four babies in the non-screened group was delayed until after 5 weeks of age, but it is concluded that all cases of galactosaemia could be diagnosed in an acceptable time without screening, providing clinical vigilance is maintained.	1
Deletions within chromosome region 5q14.3q15 have been associated with a spectrum of disorders including developmental delay, hypotonia, absent speech, mild facial dysmorphism, seizures, and brain anomalies. Some cases of concomitant neurologic abnormalities and cutaneous vascular malformation associated with 5q14.3 deletion have been reported. Previously reported cases had similar features, including multiple capillary malformations, and neurologic abnormalities, including epilepsy, hypotonia, and developmental delay. We report a case of 5q14.3 neurocutaneous syndrome presenting with multiple capillary malformations, neurologic abnormalities, and microdeletion in chromosome 5q14.3.	0
The atrophy of the periodontal ligament places the tooth very close to the bone or another tooth, as occurs in unerupted teeth. The absent interdental bone and the lack of functional periodontal stimulus may lead to the fusion of the appositional layers of cement between the roots of the teeth. Concrescence almost always occurs in the region of the maxillary molars. Asymptomatic, it should always be remembered when the proper response to orthodontic movement is not obtained, and there is no apparent explanation. When surgically extracting a tooth and there is resistance, insisting will not be the best strategy. Moving the teeth with concrescence is not convenient, as it requires very intense forces. Once separated, these teeth can be considered normal for movement. It is possible to separate two teeth presenting concrescence, but it depends on the extension of the area, the surgical access and, especially, the clinical convenience. The tooth to be extracted will be repaired with new cement deposited in the sectioned area. The simple separation with the maintenance of the proximity and the lack of function of one of the teeth will cause a new concrescence. After a period of 1 to 3 months, the separated teeth are biologically prepared to be moved. The most important detail in this separation of teeth presenting concrescence is that the diagnosis should be made in advance, and not at the time of the intervention.	0
Capillary malformation-arteriovenous malformations (CM-AVMs) caused by a RASA-1 or EPHB4 mutation are characterized as hereditary sporadic or multifocal capillary malformations (CMs), associated with potential fast-flow vascular anomalies underlying erythema lesions. Because of the similar phenotype, CM-AVMs should be considered in the differential diagnosis of isolated CMs as well as other disorders with an erythema phenotype, such as hereditary hemorrhagic telangiectasia (HHT).Herein, we report a male patient with facial erythema. Red lesions were located in the V1 region of his left face, the V2 and V3 regions on his right side, and the nasal back. The patient was initially thought to have PWSs because of the unilateral and segmental distribution of his red facial lesions. In contrast to a previous diagnosis, we diagnosed the child with capillary malformation-arteriovenous malformation type 2 (CM-AVM2) based on a family history of erythema, the results of physical examination and ultrasound raising potential fast-flow lesions, and a genetic study revealing a germline EPHB4 mutation. This study emphasizes the importance of differential diagnosis for PWS and CM-AVM. A single clinical diagnosis can be limited, and molecular diagnosis is recommended to provide more information for the evaluation of the potential risk of fast-flow lesions underlying erythema lesions if necessary.	0
Stachybotrys chartarum is a fungal contaminant within the built environment and a respiratory health concern in the United States. The objective of this study was to characterize the mechanisms influencing pulmonary immune responses to repeatedly inhaled S. chartarum. Groups of B6C3F1/N mice repeatedly inhaled viable trichothecene-producing S. chartarum conidia (strain A or strain B), heat-inactivated conidia, or high-efficiency particulate absolute-filtered air twice per week for 4 and 13 weeks. Strain A was found to produce higher amounts of respirable fragments than strain B. Lung tissue, serum, and BAL fluid were collected at 24 and 48 hours after final exposure and processed for histology, flow cytometry, and RNA and proteomic analyses. At 4 weeks after exposure, a T-helper cell type 2-mediated response was observed. After 13 weeks, a mixed T-cell response was observed after exposure to strain A compared with a T-helper cell type 2-mediated response after strain B exposure. After exposure, both strains induced pulmonary arterial remodeling at 13 weeks; however, strain A-exposed mice progressed more quickly than strain B-exposed mice. BAL fluid was composed primarily of eosinophils, neutrophils, and macrophages. Both the immune response and the observed pulmonary arterial remodeling were supported by specific cellular, molecular, and proteomic profiles. The immunopathological responses occurred earlier in mice exposed to high fragment-producing strain A. The rather striking induction of pulmonary remodeling by S. chartarum appears to be related to the presence of fungal fragments during exposure.	0
Beckwith-Wiedemann Syndrome (BWS) is the most common overgrowth syndrome. The condition was named after American pediatric pathologist John Bruce Beckwith in 1963, and German pediatrician Hans-Rudolf Wiedemann in 1964, reported the syndrome independently.[1] Etiologically, BWS is a human imprinting disorder caused by genetic and epigenetic changes affecting the regulation of genes on chromosome 11p15 region. It presents with a wide and varied clinical spectrum, which can make the diagnosis challenging in some cases. Among the clinical signs, macrosomia, macroglossia, and abdominal wall defects stand out as the most common features. BWS is also a cancer predisposition syndrome. Thus, early recognition of the condition in the prenatal or neonatal period is critical for monitoring and timely treatment of complications.[2][3]	0
The case of a 20 year old woman with a right coronary-right atrial fistula is reported. The diagnosis was made during investigation of a continuous murmur and the tolerance was excellent. Aortic root angiography demonstrated a fistula between the initial part of the right coronary artery and a right heart cavity. Selective coronary angiography visualised pseudo-aneurysmal dilatation of the first segment of the right coronary artery, the calibre and trajectory of which was then normal. The medical literature suggests surgical correction even in asymptomatic cases because of the risk of spontaneous complications (cardiac failure 15 p. 100, endocarditis 7 p. 100, infection 4 p. 100). Since 1968, there has been no operative mortality in 145 subjects with isolated coronaro-cardiac fistulae without cardiac failure. In the case presented, the fistula was successfully closed under cardiopulmonary bypass and endoaneurysmorrhaphy was performed to remodel the lumen of the right coronary artery.	0
We describe a brother and sister and an unrelated boy with congenital cerebellar hypoplasia and endosteal sclerosis. All 3 children presented with ataxia and developmental delay, and were found to have microcephaly, short stature, oligodontia, strabismus, nystagmus, and congenital hip dislocation. A previously published case is reviewed. The disorder appears to represent a newly recognized autosomal recessive syndrome.	0
The term linkeropathies (LKs) refers to a group of rare heritable connective tissue disorders, characterized by a variable degree of short stature, skeletal dysplasia, joint laxity, cutaneous anomalies, dysmorphism, heart malformation, and developmental delay. The LK genes encode for enzymes that add glycosaminoglycan chains onto proteoglycans via a common tetrasaccharide linker region. Biallelic variants in XYLT1 and XYLT2, encoding xylosyltransferases, are associated with Desbuquois dysplasia type 2 and spondylo-ocular syndrome, respectively. Defects in B4GALT7 and B3GALT6, encoding galactosyltransferases, lead to spondylodysplastic Ehlers-Danlos syndrome (spEDS). Mutations in B3GAT3, encoding a glucuronyltransferase, were described in 25 patients from 12 families with variable phenotypes resembling Larsen, Antley-Bixler, Shprintzen-Goldberg, and Geroderma osteodysplastica syndromes. Herein, we report on a 13-year-old girl with a clinical presentation suggestive of spEDS, according to the 2017 EDS nosology, in whom compound heterozygosity for two B3GAT3 likely pathogenic variants was identified. We review the spectrum of B3GAT3-related disorders and provide a comparison of all LK patients reported up to now, highlighting that LKs are a phenotypic continuum bridging EDS and skeletal disorders, hence offering future nosologic perspectives.	0
Hereditary folate malabsorption (HFM) is an autosomal recessive disorder characterized by impaired intestinal folate absorption and impaired folate transport across the choroid plexus due to loss of function of the proton-coupled folate transporter (PCFT-SLC46A1). We report a novel mutation, causing HFM, affecting a residue located in the 11th transmembrane helix within the external gate. The mutant N411K-PCFT was stable, trafficked to the cell membrane, and had sufficient residual activity to characterize the transport defect and the structural requirements at this site for gate function. The influx Vmax of the N411K mutant was markedly decreased, as was the affinity for most, but not all, folate/antifolate substrates. The greatest loss of activity was for 5-methyltetrahydrofolate. Substitutions with positive charged residues resulted in a loss of activity (arginine > lysine > histidine). Function was retained for the negative charged aspartate, but not the larger glutamate substitutions, whereas the bulky hydrophobic (leucine), or polar (glutamine) substitutions, were tolerated. Homology models of PCFT, in the inward and outward open conformations, based upon the mammalian Glut5 fructose transporter structures, localize Asn411 protruding into the aqueous pathway. This is most prominent when the carrier is in the inward open conformation when the external gate is closed. Mutations at this site likely result in highly specific steric and electrostatic interactions between the Asn411-substituted, and other, residues in the gate region that impede carrier function. The substrate specificity of the N411K mutant may be due to alterations of substrate flows through the external gate, downstream allosteric alterations in the folate-binding pocket, or both.	0
Proteoglycans (PGs) are macromolecules present on the cell surface and in the extracellular matrix that confer specific mechanical, biochemical, and physical properties to tissues. Sulfate groups present on glycosaminoglycans, linear polysaccharide chains attached to PG core proteins, are fundamental for correct PG functions. Indeed, through the negative charge of sulfate groups, PGs interact with extracellular matrix molecules and bind growth factors regulating tissue structure and cell behavior. The maintenance of correct sulfate metabolism is important in tissue development and function, particularly in cartilage where PGs are fundamental and abundant components of the extracellular matrix. In chondrocytes, the main sulfate source is the extracellular space, then sulfate is taken up and activated in the cytosol to the universal sulfate donor to be used in sulfotransferase reactions. Alteration in each step of sulfate metabolism can affect macromolecular sulfation, leading to the onset of diseases that affect mainly cartilage and bone. This review presents a panoramic view of skeletal dysplasias caused by mutations in genes encoding for transporters or enzymes involved in macromolecular sulfation. Future research in this field will contribute to the understanding of the disease pathogenesis, allowing the development of targeted therapies aimed at alleviating, preventing, or modifying the disease progression.	0
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare monogenic disease caused by mutations in the ABCB4 gene, resulting in a reduction in biliary phosphatidylcholine. Reduced biliary phosphatidylcholine cannot counteract the detergent effects of bile salts, leading to cholestasis, cholangitis, cirrhosis and ultimately liver failure. Here, we report results from treating two- or five-week-old Abcb4-/- mice with an AAV vector expressing human ABCB4, resulting in significant decreases of PFIC3 disease biomarkers. All male mice achieved a sustained therapeutic effect up through 12 weeks, but the effect was achieved in only 50% of females. However, two-week-old females receiving a second inoculation three weeks later maintained the therapeutic effect. Upon sacrifice, markers of PFIC3 disease such as, hepatosplenomegaly, biliary phosphatidylcholine and liver histology were significantly improved. Thus, AAV-mediated gene therapy successfully prevented PFIC3 symptoms in a clinically relevant mouse model, representing a step forward in improving potential therapy options for PFIC3 patients.	0
BACKGROUND:Although, the diagnostic criteria for enlarged vestibular aqueduct syndrome (EVAS) were determined by years. On the shoulders of predecessors, we still detected some new discoveries about EVAS by using 3D-real IR MRI. AIMS/OBJECTIVES:To analyze the signal intensity of membranous and osseous labyrinths of vestibular aqueduct (VA) and endolymphatic sac (ES) in EVAS using three-dimensional real inversion recovery (3D-Real-IR) magnetic resonance imaging (MRI) after intratympanic injection of gadolinium. MATERIAL AND METHODS:The study is a prospective trial, diagnosed EVAS patients (n = 10) and none- patients (n = 10) were included. 3D-real-IR MRIs were performed to assess the endolymphatic hydrops (EH) and differentiated the endolymphatic and perilymphatic signal intensities of VA and ES. RESULTS:Compared to control group, EVAS group had VA osseous labyrinths middle diameter >1.5 mm different from membranous labyrinths. The cochlear EH was correlated with Mondini malformation and irrelation with the level of hearing loss (HL). CONCLUSIONS AND SIGNIFICANCE:Interspace of osseous labyrinths of VA and ES are much larger than their membranous labyrinths, which is not consistance with previous research. And cochlear Mondini malformation may cause endolymphatic fluid malabsorption, inducing cochlear EH. Osteal ampliative of VA and ES and cochlear EH, which are morphogenetic anomalies, may not the direct cause of HL in EVAS.	0
BACKGROUND:Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added. METHODS:We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care. RESULTS:A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes. CONCLUSIONS:The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.).	0
Epidermolysis bullosa is a rare disorder with several variants. Included in this disorder is epidermolysis bullosa with mottled pigmentation (EBS-MP). We report a case of a young child with this rare disorder and explain the genetic cause.	0
Pretibial epidermolysis bullosa (PEB) is an extremely rare subtype of dominant dystrophic epidermolysis bullosa (DDEB) caused by mutation of the COL7A1 gene. More than 730 mutations have been identified in patients with DDEB, but only five mutations have been found to be related to PEB. In this study, a novel heterozygous nucleotide G>T transition at position 6101 in exon 73 of COL7A1 was detected, which resulted in a glycine to valine substitution (G2034V) in the triple-helical domain of type-VII collagen. This is the first report to show that one mutation caused a broad range of severity of disease in one family with PEB. These data suggest that c.6101G>T may influence the phenotype of PEB. They also contribute to the expanding database on COL7A1 mutations.	0
The Holmes-Adie Syndrome (HAS) is a disorder of unknown aetiology comprising unilateral or bilateral tonic pupils with near light dissociation and tendon areflexia. Although considered to be benign, troublesome symptoms may result from autonomic disturbances, affecting vasomotor, sudomotor and respiratory function. It is unclear if the autonomic manifestations of the disease remain stable or progress, as longitudinal studies with detailed autonomic assessments have not been described. The authors report four HAS patients studied at intervals over 16, 8, 4 and 2&emsp14;years with cardiovascular autonomic tests (head-up tilt, isometric exercise, mental arithmetic, cutaneous cold, deep breathing, Valsalva manoeuvre and standing). In each, there was progression of cardiovascular autonomic deficits with time, accompanied by symptomatic worsening. These observations in HAS, for the first time, indicate progression of cardiovascular autonomic dysfunction of clinical significance. This has a number of implications, including those relating to aetiology and prognosis. The authors recommend regular clinical and laboratory follow-up, especially of cardiovascular autonomic function, in patients with HAS.	0
Background:Glycogen storage disease type IV (GSD IV; Andersen's disease) is a rare autosomal recessive disease caused by mutation in the GBE1 gene. Presentation of GSD IV varies on a continuum of severity and symptomatology ranging from neonatal death to mild adult-onset disease with variable involvement of hepatic, muscular, neurologic, dermatologic, and cardiac systems. Cardiomyopathy seen in GSD IV is also heterogeneous and its appearance on cardiac magnetic resonance imaging (CMR) is rarely described. Case summary:A 29-year-old man without previous medical history was admitted to our facility multiple times over 2 years for focal sensorimotor deficits, gout arthropathy, chronic hyperlactataemia and hyperuricaemia, and severe decompensated non-ischaemic cardiomyopathy complicated by episodes of thromboembolic organ infarction. Echocardiography and CMR showed severe biventricular failure with the presence of intraventricular thrombi with increased right ventricular trabeculation and absent late gadolinium enhancement. He underwent muscle biopsy which showed prominent glycogen in skeletal muscle followed by genetic testing showing a single heterozygous splicing mutation c.993-1G>T found at the junction of intron 7 and exon 8 of the GBE1 gene which had not previously been reported and was predicted to be pathologic. He was referred to a tertiary care centre with glycogen storage disease specialists but expired prior to establishing care at that facility. Discussion:Discovery of GSD IV in our patient was unexpected due to a highly variant clinical presentation. Our case stresses the clinical heterogeneity of GSD IV and the importance of genetic sequencing studies in the evaluation of potential glycogen storage disease.	0
Cilia are microtubule-based organelles, protruding from the apical cell surface and anchoring to the cytoskeleton. Primary (nonmotile) cilia of the kidney act as mechanosensors of nephron cells, responding to fluid movements by triggering signal transduction. The impaired functioning of primary cilia leads to formation of cysts which in turn contribute to development of diverse renal diseases, including kidney ciliopathies and renal cancer. Here, we review current knowledge on the role of ciliary genes in kidney ciliopathies and renal cell carcinoma (RCC). Special focus is given on the impact of mutations and altered expression of ciliary genes (e.g., encoding polycystins, nephrocystins, Bardet-Biedl syndrome (BBS) proteins, ALS1, Oral-facial-digital syndrome 1 (OFD1) and others) in polycystic kidney disease and nephronophthisis, as well as rare genetic disorders, including syndromes of Joubert, Meckel-Gruber, Bardet-Biedl, Senior-Loken, Alström, Orofaciodigital syndrome type I and cranioectodermal dysplasia. We also show that RCC and classic kidney ciliopathies share commonly disturbed genes affecting cilia function, including VHL (von Hippel-Lindau tumor suppressor), PKD1 (polycystin 1, transient receptor potential channel interacting) and PKD2 (polycystin 2, transient receptor potential cation channel). Finally, we discuss the significance of ciliary genes as diagnostic and prognostic markers, as well as therapeutic targets in ciliopathies and cancer.	0
Coenzyme Q10 (CoQ10 or ubiquinone) deficiency can be due either to mutations in genes involved in CoQ10 biosynthesis pathway, or to mutations in genes unrelated to CoQ10 biosynthesis. CoQ10 defect is the only oxidative phosphorylation disorder that can be clinically improved after oral CoQ10 supplementation. Thus, early diagnosis, first evoked by mitochondrial respiratory chain (MRC) spectrophotometric analysis, then confirmed by direct measurement of CoQ10 levels, is of critical importance to prevent irreversible damage in organs such as the kidney and the central nervous system. It is widely reported that CoQ10 deficient patients present decreased quinone-dependent activities (segments I + III or G3P + III and II + III) while MRC activities of complexes I, II, III, IV and V are normal. We previously suggested that CoQ10 defect may be associated with a deficiency of CoQ10-independent MRC complexes. The aim of this study was to verify this hypothesis in order to improve the diagnosis of this disease.To determine whether CoQ10 defect could be associated with MRC deficiency, we quantified CoQ10 by LC-MSMS in a cohort of 18 patients presenting CoQ10-dependent deficiency associated with MRC defect. We found decreased levels of CoQ10 in eight patients out of 18 (45 %), thus confirming CoQ10 disease.Our study shows that CoQ10 defect can be associated with MRC deficiency. This could be of major importance in clinical practice for the diagnosis of a disease that can be improved by CoQ10 supplementation.	0
CONTEXT:Hypoglycemia is emerging as a risk for cardiovascular events in diabetes. We hypothesized that hypoglycemia activates the innate immune system, which is known to increase cardiovascular risk. OBJECTIVE:To determine whether hypoglycemia modifies subsequent innate immune system responses. DESIGN AND SETTING:Single-blinded, prospective study of three independent parallel groups. PARTICIPANTS AND INTERVENTIONS:Twenty-four healthy participants underwent either a hyperinsulinemic-hypoglycemic (2.5 mmol/L), euglycemic (6.0 mmol/L), or sham-saline clamp (n = 8 for each group). After 48 hours, all participants received low-dose (0.3 ng/kg) intravenous endotoxin. MAIN OUTCOME MEASURES:We studied in-vivo monocyte mobilization and monocyte-platelet interactions. RESULTS:Hypoglycemia increased total leukocytes (9.98 ± 1.14 × 109/L vs euglycemia 4.38 ± 0.53 × 109/L, P < 0.001; vs sham-saline 4.76 ± 0.36 × 109/L, P < 0.001) (mean ± SEM), mobilized proinflammatory intermediate monocytes (42.20 ± 7.52/μL vs euglycemia 20.66 ± 3.43/μL, P < 0.01; vs sham-saline 26.20 ± 3.86/μL, P < 0.05), and nonclassic monocytes (36.16 ± 4.66/μL vs euglycemia 12.72 ± 2.42/μL, P < 0.001; vs sham-saline 19.05 ± 3.81/μL, P < 0.001). Following hypoglycemia vs euglycemia, platelet aggregation to agonist (area under the curve) increased (73.87 ± 7.30 vs 52.50 ± 4.04, P < 0.05) and formation of monocyte-platelet aggregates increased (96.05 ± 14.51/μL vs 49.32 ± 6.41/μL, P < 0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51 ± 1.42/μL vs euglycemia 4.19 ± 1.08/μL, P < 0.05; vs sham-saline 3.81± 1.42/μL, P < 0.05) and nonclassic monocytes (9.53 ± 1.08/μL vs euglycemia 2.86 ± 0.72/μL, P < 0.01; vs sham-saline 3.08 ± 1.01/μL, P < 0.05), with platelets compared with controls. Hypoglycemia led to greater leukocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96 ± 0.97 vs euglycemia 8.21 ± 0.85 × 109/L, P < 0.05). CONCLUSIONS:Hypoglycemia mobilizes monocytes, increases platelet reactivity, promotes interaction between platelets and proinflammatory monocytes, and potentiates the subsequent immune response to endotoxin. These changes may contribute to increased cardiovascular risk observed in people with diabetes.	0
Background: Not only an association between benign paroxysmal positional vertigo (BPPV) and migraine have been recognized in the literature, but also, there are close similarities between BPPV and vestibular migraine (VM) presentations as both can be presented by very similar positional nystagmus.Aims/objectives: To prescribe relatively uncommon cases of positional nystagmus caused by VM that mimics positioning nystagmus of BPPV.Material and method: 12 patients were reviewed retrospectively in this study. All were subjected to full history taking, videonystagmography testing (VNG) and brain magnetic resonance imaging (MRI) with contrast. Provisionally, they were diagnosed with BPPV. After three attempts of repositioning sessions none of them improved. After exclusion of central insults using brain MRI, trial of anti-migraine medical treatment (50-100 Topiramate tablets once per day) for at least one month was prescribed to them.Results: 10 patients were completely cured on medical treatment and finally were diagnosed VM. Only 2 patients did not improve on medical treatment (for one month), were managed again by repeated repositioning maneuvers till finally improved and were diagnosed as resistant BPPV.Conclusions/significance: VM positional nystagmus can mimic BPPV nystagmus in some patients.	0
The urofacial syndrome, also known as Ochoa syndrome, is a rare autosomal recessive condition that occurs in both genders and characterized by uropathy and facial abnormalities. Early diagnosis is crucial for the management and prognosis of urinary problems due to a dysfunctional bladder. We report 11 patients with urofacial syndrome in five families from Turkey with a median follow up of 32 months (range, 2-44 months).	0
PURPOSE:To evaluate the role of selected modalities of Storz Professional Image Enhancement System (IMAGE1 S) in differentiating cholesteatoma during endoscopic ear surgery (EES); to assess the potential usefulness of IMAGE1 S in recognition of cholesteatoma residuals at the end of EES. METHODS:A retrospective study on 45 consecutive patients who underwent EES for cholesteatoma between March 2019 and November 2019 at a tertiary referral center was performed. For each case, Spectra A and Spectra B filters were applied intra-operatively. When examining the surgical field, a switch from white light (WL) to IMAGE1 S was performed to detect cholesteatoma and differentiate it from non-cholesteatomatous tissue. When the IMAGE1 S pattern was suspicious for the presence of cholesteatoma, images of the field under both enhancement modalities were taken and the targeted lesions were sent for histologic analysis. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of IMAGE1 S were calculated. A final recognition of the surgical field using the selected filters was performed to detect any possible cholesteatomatous residuals. RESULTS:Detection of cholesteatoma by IMAGE1 S selected filters revealed the following data: sensitivity 97%, specificity 95%, PPV 95%, NPV 97%. On three occasions, there was no correspondence between enhanced endoscopy and histology. In 5 out of 45 cases (11%), cholesteatoma residuals, which had not been identified at WL inspection at the end of the procedure, were detected by IMAGE1 S. CONCLUSION:Our results suggest a potential role for IMAGE1 S Spectra A and B filters in EES for cholesteatoma surgery. We propose the integration of IMAGE1 S as a final overview of the surgical cavity for recognition of cholesteatomatous residuals.	0
Cartilage comprises a single cell type, the chondrocyte, embedded in a highly complex extracellular matrix. Disruption to the cartilage growth plate leads to reduced bone growth and results in a clinically diverse group of conditions known as genetic skeletal diseases (GSDs). Similarly, long-term degradation of articular cartilage can lead to osteoarthritis (OA), a disease characterised by joint pain and stiffness. As professionally secreting cells, chondrocytes are particularly susceptible to endoplasmic reticulum (ER) stress and this has been identified as a core disease mechanism in a group of clinically and pathologically related GSDs. If unresolved, ER stress can lead to chondrocyte cell death. Recent interest has focused on ER stress as a druggable target for GSDs and this has led to the first clinical trial for a GSD by repurposing an antiepileptic drug. Interestingly, ER stress markers have also been associated with OA in multiple cell and animal models and there is increasing interest in it as a possible therapeutic target for treatment. In summary, chondrocyte ER stress has been identified as a core disease mechanism in GSDs and as a contributory factor in OA. Thus, chondrocyte ER stress is a unifying factor for both common and rare cartilage-related diseases and holds promise as a novel therapeutic target.	0
Osteopetrosis is a rare genetic disease characterized by increased bone density and bone fractures due to defective osteoclast function. Autosomal dominant osteopetrosis type 2 (ADO-2), Albers-Schonberg disease, is characterized by the sclerosis of bones, predominantly involving the spine, pelvis and the base of the skull. Here, we report a typical case of osteopetrosis in a 17.7-year-old male who carries a heterozygous c.746C>T mutation in exon 9 in the chloride voltage-gated channel 7 (CLCN7) gene. The patient’s spine showed multiple sclerotic changes including sandwich vertebra. His father had the same mutation but his skeletal radiographs were normal. This is the first reported case of ADO-2, confirmed by genetic testing in a Korean patient.	0
The rare association of pontocerebellar hypoplasia with anterior horn cell involvement has been classified as pontocerebellar hypoplasia type 1. Its classic phenotype is usually severe. However, the pontocerebellar hypoplasia type 1 may have wider variability in clinical and radiological features. There may be a genetic heterogeneity as well. We described here a young girl with relatively milder clinical phenotype with cerebellar atrophy with absent pontine involvement, further adding to the clinical phenotype.	0
BACKGROUND:Early-onset epileptic encephalopathies with burst suppression (EOEE-BS) are a group of neonatal epileptic syndromes characterized by intractable epilepsy and severe psychomotor delay with structural and metabolic factors accounting for major etiologies. However, recent advances in gene sequencing have identified that genetic factors might also play a significant role in the development of EOEE-BS. Herein, we used various genetic tests to identify pathogenic genetic variants in EOEE-BS irrespective of structural malformations and analyzed the clinical features associated with each different etiology. METHODS:A total of 48 patients with EOEE-BS were included. Except for patients with severe hypoxic damage, patients with structural malformations were included in our patient cohort. Clinical features of the patients were reviewed, and etiological diagnoses were made based on several genetic tests, metabolic studies, and radiological findings. RESULT:A genetic diagnosis was made in 31 (64.6 %) patients, with the most commonly diagnosed gene being STXBP1 (n = 13, 27.1 %), followed by KCNQ2 (n = 5, 10.4 %), SCN2A (n = 5, 10.4 %), DEPDC5 (n = 3, 6.3 %), CASK (n = 1, 2.1 %), CDKL5 (n = 1, 2.1 %), GNAO1 (n = 1, 2.1 %), SLC6A8 (n = 1, 2.1 %), and LIS1 deletion (n = 1, 2.1 %). Other than the classification of epilepsy syndrome, no clinical features were associated with the genetically diagnosed group. Among eight patients with structural malformations, genetic diagnosis was achieved in five (62.5 %), and those patients had pathogenic mutations in DEPDC5 and CASK or LIS1 deletion, indicating the significance of gene sequencing irrespective of structural abnormalities. Treatment responses to a variety of medications and the ketogenic diet differed by etiology, and surgical resection proved to be effective in patients with cortical dysplasia. CONCLUSION:Genetic etiologies are an important factor in EOEE-BS irrespective of structural malformations and the treatment options may differ by etiology.	0
Lewis-Sumner syndrome (LSS) is a rare disease characterized by asymmetrical and multifocal mononeuropathy commonly located in the upper limbs. Some rare cases affecting cranial nerve have been described, but LSS is unknown to affect especially laryngeal nerves. This paper presents the first case of unilateral vocal fold paresis caused by an LSS in a 59-year-old man complaining of dysphonia, breathy voice, and vocal fatigue. Epidemiology, clinical features, diagnosis, and treatment will be described.	0
BACKGROUND: Amyloidosis is a heterogeneous disease caused by deposition of amyloid fibrils in organs and thereby interfering with physiological functions. Hardly any incidence data are available and most survival data are limited to specialist clinics. METHODS: Amyloidosis patients were identified from the Swedish Hospital Discharge and Outpatients Registers from years 2001 through 2008. RESULTS: The incidence of non-hereditary amyloidosis in 949 patients was 8.29 per million person-years and the diagnostic age with the highest incidence was over 65 years. Secondary systemic amyloidosis showed an incidence of 1 per million and a female excess and the largest number of subsequent rheumatoid arthritis deaths; the median survival was 4 years. However, as rheumatoid arthritis deaths also occurred in other diagnostic subtypes, the incidence of secondary systemic amyloidosis was likely to be about 2.0 per million. The median survival of patients with organ-limited amyloidosis was 6 years. Most myeloma deaths occurred in patients diagnosed with unspecified or 'other' amyloidosis. These subtypes probably accounted for most of immunoglobulin light chain (AL) amyloidosis cases; the median survival time was 3 years. CONCLUSIONS: The present diagnostic categorization cannot single out AL amyloidosis in the Swedish discharge data but, by extrapolation from myeloma cases, an incidence of 3.2 per million could be ascribed to AL amyloidosis. Similarly, based on rheumatoid arthritis death rates, an incidence of 2.0 could be ascribed to secondary systemic amyloidosis.	1
There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers.	0
OBJECTIVES: To assess overall and malformation-specific trends in the prevalence and prenatal diagnosis of congenital anomalies in the Parisian population. METHODS: The Paris Registry of Congenital Malformations is population-based and since 1981 has registered all cases with structural birth defects or chromosomal anomalies in the Parisian population. The total and livebirth prevalence and the proportion of cases with prenatal diagnosis were calculated for all anomalies and 20 malformations selected based on their higher frequency and their impact on health outcomes. RESULTS: The overall prevalence was 3.30% (95% CI 3.27-3.33), and the livebirth prevalence 2.42% (95% CI 2.39-2.45). The proportion of cases diagnosed prenatally increased from 16.5% (95% CI 14.1-19.1) in 1983 to 70.7% (95% CI 68.3-73.1) in 2007. Terminations of pregnancy for fetal anomaly (TOPFA) increased from 8.8% (95% CI 7.0-10.8) in 1983 to 35.6% (95% CI 33.1-38.1) in 2007. These results varied substantially for the 20 congenital anomalies studied. CONCLUSION: We found an increase in the overall prevalence of all anomalies, especially for chromosomal abnormalities. The observed increase is at least to a large extent due to trends in delayed childbearing and an increase in both pre- and postnatal diagnosis of congenital anomalies in our population.	1
Prion diseases are neurodegenerative and invariably fatal conditions that affect humans and animals. In particular, Creutzfeldt-Jakob disease (CJD) and bovine spongiform encephalopathy (BSE) are paradigmatic forms of human and animal prion diseases, respectively. Human exposure to BSE through contaminated food caused the appearance of the new variant form of CJD (vCJD). These diseases are caused by an abnormal prion protein named PrPSc (or prion), which accumulates in the brain and leads to the onset of the disease. Their definite diagnosis can be formulated only at post-mortem after biochemical and neuropathological identification of PrPSc. Thanks to the advent of an innovative technique named protein misfolding cyclic amplification (PMCA), traces of PrPSc, undetectable with the standard diagnostic techniques, were found in peripheral tissues of patients with vCJD, even at preclinical stages. The technology is currently being used in specialized laboratories and can be exploited for helping physicians in formulating an early and definite diagnosis of vCJD using peripheral tissues. However, this assay is currently unable to detect prions associated with the sporadic CJD (sCJD) forms, which are more frequent than vCJD. This review will focus on the most recent advances and applications of PMCA in the field of vCJD and other human prion disease diagnosis.	0
BACKGROUND:Transient receptor potential cation channel subfamily V member 4 (TRPV4) is an ion channel permeable to Ca2+ that is sensitive to physical, hormonal, and chemical stimuli. This protein is expressed in many cell types, including osteoclasts, chondrocytes, and sensory neurons. As such, pathogenic variants of this gene are associated with skeletal dysplasias and neuromuscular disorders. Pathogenesis of these phenotypes is not yet completely understood, but it is known that genotype-phenotype correlations for TRPV4 pathogenic variants often are not present. METHODS:Newly characterized, suspected pathogenic variant in TRPV4 was analyzed using protein informatics and personalized protein-level molecular studies, genomic exome analysis, and clinical study. RESULTS:This statement is demonstrated in the family of our proband, a 47-year-old female having the novel c.2401A>G (p.K801E) variant of TRPV4. We discuss the common symptoms between the proband, her father, and her daughter, and compare her phenotype to known TRPV4-associated skeletal dysplasias. CONCLUSIONS:Protein informatics and molecular modeling are used to confirm the pathogenicity of the unique TRPV4 variant found in this family. Multiple data were combined in a comprehensive manner to give complete overall perspective on the patient disease and prognosis.	0
Congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA) is a recently identified neurodevelopmental syndrome which has only 8 reported cases to date since its existence was proposed in 2007. We report a case of CHEDDA syndrome identified in a newborn female with congenital anomalies including Pierre-Robin sequence, arthrogryposis, craniosynostosis, cleft palate, and cardiac abnormalities who subsequently developed epilepsy at 1 month of life. Diagnosis was identified by whole-exome sequencing identifying mutations in a conserved histidine-rich motif within the gene Atrophin-1. Radiologic findings of cerebral atrophy, hypoplasia of the cerebellum, and thinning of the corpus callosum were identified in this patient, consistent with other reported cases. Given the rarity of this condition, we report this case and its findings to increase awareness of CHEDDA syndrome as a possible underlying diagnosis for neonates who present with this constellation of symptoms and radiologic findings.	0
Granulomatous rosacea is a rare chronic inflammatory skin disease with an unknown origin. The role of Demodex follicularum in its pathogenesis is currently proved.We report a case of a 54-year-old Moroccan man with a 3-month history of erythematous, nonpruritic papules on the lateral side around the eyes. Dermoscopy and histology confirmed the diagnosis of granulomatous rosacea.We describe another clinical presentation of granulomatous rosacea with a clinical-dermoscopic-pathological correlation.	0
Objectives:To evaluate the early and midterm results of a modified sliding anastomosis technique in patients with aortic coarctation. Materials and Methods:In this study, we reported a new repair method and compared the early and midterm outcome(s) with a conventional surgical approach for the management of patients with aortic coarctation. Forty-eight aortic coarctation patients with a narrowed segment length longer than 2 cm were operated at our department's pediatric surgical division. Excision of the coarctation and end-to-end anastomosis was carried out in twenty-five patients (control group). In contrast, a modified sliding technique was used for twenty-three cases in the observation group. Other accompanying cardiac anomalies simultaneously repaired included ventricular septal defect and patent ductus arteriosus. All patients received 1.5-10 years of postoperative echocardiographic follow-up. Results:This is a retrospective study carried out between January 2005 and June 2018. The study population consisted of forty-eight patients, which included twenty-six male and twenty-two female patients, with an average age of 5.2 ± 1.9 months (range, 28 days to 1 year). There was no mortality. The operative time, the number of intercostal artery disconnection, the drainage volume, and arm-leg systolic pressure gradient postoperation were less in the observation group as compared to the control group (p < 0.05). Also, cases with an anastomotic pressure gradient exceeding 10 mmHg during follow-up were less in the observation group as compared to the control group (p < 0.05). The postoperative complications encountered were chylothorax (control group 2 cases vs. observation group 0) and pulmonary atelectasis (control group 4 cases vs. observation group 1). They all, however, recovered after conservative treatment. Three patients in the control group underwent balloon angioplasty (reintervention) postoperative 2-4 years due to an increase in the anastomotic pressure gradient (>20 mmHg). After reintervention, the anastomotic pressure gradient reduced to 14 mmHg, 15 mmHg, and 17 mmHg, respectively. Conclusions:For long segment aortic coarctation patients (longer than 2 cm), the use of the modified sliding anastomotic technique effectively helps to retain more autologous tissues, enlarge the diameter of the anastomosis, and decrease anastomotic tension and vascular injury. Therefore, this technique provides a new idea for the surgical treatment of aortic coarctations.	0
Nevus of Ota and nevus of Ito are rare dermal melanocytoses. Nevus of Ota may be very rarely associated with the nevus of Ito and other extra cutaneous features. Both nevi are similar in all respect apart from the area of distribution. Bilateral distribution of nevus of Ito is seldom reported in the literature. A 24-year-old male patient reported with nevus of Ota of the right side of his face since his infancy and nevus of Ito on both shoulder regions since early childhood. He had bluish lesions on the right side of his hard palate. Systemic examination was normal. Relevant laboratory investigations were non contributory. The histopathological examination of the skin from the affected areas showed the presence of elongated dendritic dermal melanocytes. The present case is the first report of an association of bilateral nevus of Ito with nevus of Ota and palatal lesions. Tanino classified Nevus of Ota into four groups. As both the nevi are similar in all respect except the area of distribution, a minor modification of the existing Tanino's classification to incorporate the nevus of Ito into the classification for the Ota's nevus may be appropriate.	0
Mid-life stage adults are at higher risk of developing venous thrombosis (VT)/thromboembolism (VT/E). Aging is characterized by an overproduction of reactive oxygen species (ROS), which could evoke a series of physiological changes involved in thrombosis. Here, we focus on the critical role of ROS within the red blood cell (RBC) in initiating venous thrombosis during aging. Growing evidence has shifted our interest in the role of unjustifiably unvalued RBCs in blood coagulation. RBCs can be a major source of oxidative stress during aging, since RBC redox homeostasis is generally compromised due to the discrepancy between prooxidants and antioxidants. As a result, ROS accumulate within the RBC due to the constant endogenous hemoglobin (Hb) autoxidation and NADPH oxidase activation, and the uptake of extracellular ROS released by other cells in the circulation. The elevated RBC ROS level affects the RBC membrane structure and function, causing loss of membrane integrity, and decreased deformability. These changes impair RBC function in hemostasis and thrombosis, favoring a hypercoagulable state through enhanced RBC aggregation, RBC binding to endothelial cells affecting nitric oxide availability, RBC-induced platelet activation consequently modulating their activity, RBC interaction with and activation of coagulation factors, increased RBC phosphatidylserine exposure and release of microvesicles, accelerated aging and hemolysis. Thus, RBC oxidative stress during aging typifies an ultimate mechanism in system failure, which can affect major processes involved in the development of venous thrombosis in a variety of ways. The reevaluated concept of the critical role of RBC ROS in the activation of thrombotic events during aging will help identify potential targets for novel strategies to prevent/reduce the risk for VT/E or VT/E recurrences in mid-life stage adults.	0
Goldenhar syndrome, also known as oculo-auriculo-vertebral syndrome, has been described since 1952. Traditionally, the syndrome has been described as having eye, ear, facial and vertebral anomalies. However, numerous case reports and reviews have highlighted multi-organ involvement, including cardiovascular, gastrointestinal, respiratory system and urinary abnormalities. We describe a 13 years old who has a reproductive tract abnormality, which has not been reported previously as a finding of Goldenhar syndrome.	0
BACKGROUND:Inherited retinal dystrophies (IRDs) are characterized by extreme genetic and clinical heterogeneity. There are many genes that are known to cause IRD which makes the identification of the underlying genetic causes quite challenging. And in view of the emergence of therapeutic options, it is essential to combine molecular and clinical data to correctly diagnose IRD patients. In this study, we aimed to identify the disease-causing variants (DCVs) in four consanguineous Jordanian families with IRDs and describe genotype-phenotype correlations. METHODS:Exome sequencing (ES) was employed on the proband patients of each family, followed by segregation analysis of candidate variants in affected and unaffected family members by Sanger sequencing. Simulation analysis was done on one novel CLRN1 variant to characterize its effect on mRNA processing. Clinical evaluation included history, slit-lamp biomicroscopy, and indirect ophthalmoscopy. RESULTS:We identified two novel variants in CLRN1 [(c.433+1G>A) and (c.323T>C, p.Leu108Pro)], and two recurrent variants in ABCA4 [(c.1648G>A, p.Gly550Arg) and (c.5460+1G>A)]. Two families with the same DCV were found to have different phenotypes and another family was shown to have sector RP. Moreover, simulation analysis for the CLRN1 splice donor variant (c.433+1G>A) showed that the variant might affect mRNA processing resulting in the formation of an abnormal receptor. Also, a family that was previously diagnosed with nonsyndromic RP was found to have Usher syndrome based on their genetic assessment and audiometry. CONCLUSION:Our findings extend the spectrum of CLRN1- and ABCA4-associated IRDs and describe new phenotypes for these genes. We also highlighted the importance of combining molecular and clinical data to correctly diagnose IRDs and the utility of simulation analysis to predict the effect of splice donor variants on protein formation and function.	0
RATIONALE:Late complement deficiency increases susceptibility to meningococcal disease and recurrent infections. In Korea, 5 case reports have described meningococcal disease with complement deficiency. However, C6 deficiency has not been described previously. PATIENT CONCERNS:A 21-year-old police trainee presented with recurrent meningococcal meningitis. He was housed in communal living quarters until 20 days before the initial symptom onset. DIAGNOSIS:He was diagnosed with meningococcal meningitis with C6 deficiency. INTERVENTIONS:He was treated with intravenous ceftriaxone. An additional dose of quadrivalent meningococcal conjugate vaccine was administered after discharge. OUTCOMES:He was discharged without complications. LESSONS:Screening for complement deficiency is necessary in patients with a history of recurrent meningococcal infections to provide appropriate care and prevent recurrent infections.	0
OBJECTIVES: To estimate the point prevalence (p.p.) of Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), polyarteritis nodosa (PAN) and Churg-Strauss syndrome (CSS) within a defined population in southern Sweden. METHOD: A cross-sectional p.p. study using multiple sources for case identification. The study area, a healthcare district around the city of Lund in southern Sweden (Mellersta Skånes sjukvårdsdistrikt), had, on 31 December 2002, a total population of 287 479 inhabitants. All the identified cases were verified by medical record review. The patients were classified according to an algorithm based on the American College of Rheumatology classification criteria 1990 and the Chapel Hill Consensus Conference definitions 1994. RESULTS: Eighty-six patients (49% female) with a median age of 64.8 yrs (range 15-90.5) fulfilled the study criteria. There were 46 patients with WG; 27 with MPA; nine with PAN; and four with CSS. The p.p. per million inhabitants was estimated on 1 January 2003 to be 160 (95% confidence interval 114-206) for WG, 94 (58-129) for MPA, 31 (11-52) for PAN and 14 (0.3-27) for CSS. Capture-recapture analysis estimated the completeness of the case finding to 96%. CONCLUSIONS: The prevalence of WG, MPA, PAN and CSS in our district is the highest figure reported so far. Explanations for this finding may include high incidence, extensive ANCA-testing, good survival as well as sensitive search methods for case identification.	1
OBJECTIVE:We present prenatal diagnosis of concomitant distal 5q duplication and terminal 10q deletion in a fetus with intrauterine growth restriction (IUGR), congenital diaphragmatic hernia (CDH) and congenital heart defects (CHD). CASE REPORT:A 34-year-old, gravida 4, para 2, woman was referred for amniocentesis at 21 weeks of gestation because of advanced maternal age and IUGR. There was no congenital malformation in the family. Amniocentesis revealed a derivative chromosome 10 with an additional maternal on the terminal region of 10q. Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from the cultured amniocytes revealed a result of arr 5q31.3q35.5 (142, 548, 354-180,696,806) × 3.0, arr 10q26.3 (132, 932, 808-135,434,178) × 1.0 [GRCh37 (hg19)] with a 2.50-Mb deletion of 10q26.3 encompassing 19 [Online Mendelian Inheritance in Man (OMIM)] genes and a 38.15-Mb duplication of 5q31.3-q35.5 encompassing 195 OMIM genes including four CDH candidate genes of NDST1, ADAM19, NSD1 and MAML1. The mother was found to have a karyotype of 46,XX,t(5; 10) (q31.3; q26.3). Therefore, the fetal karyotype was 46,XX,der(10)t(5; 10)(q31.3; q26.3)mat. Prenatal ultrasound showed IUGR, right CDH, transposition of great artery, double outlet of right ventricle and right atrial isomerism. The pregnancy was terminated, and a malformed fetus was delivered with facial dysmorphism. CONCLUSION:Fetuses with concomitant distal 5q duplication and terminal 10q deletion may present IUGR, CDH and CHD on prenatal ultrasound.	0
A swine acute diarrhea syndrome coronavirus (SADS-CoV) that causes severe diarrhea in suckling piglets was identified in Southern China in 2017. To develop an antigen that is specific, sensitive, and easy to prepare for serological diagnosis, antigenic sites in the SADS-CoV nucleocapsid (N) protein were screened. We generated and characterized an N-reactive monoclonal antibody (mAb) 3E9 from mice immunized with recombinant N protein. Through fine epitope mapping of mAb 3E9 using a panel of eukaryotic-expressed polypeptides with GFP-tags, we identified the motif 343DAPVFTPAP351 as the minimal unit of the linear B-cell epitope recognized by mAb 3E9. Protein sequence alignment indicated that 343DAPVFTPAP351 was highly conserved in different SADS-CoV strains and SADS-related coronaviruses from bat, with one substitution in this motif in HKU2-related bat coronavirus. Using mAb 3E9, we observed that N protein was expressed in the cytoplasm and was in the nucleolus during SADS-CoV replication. N protein was immunoprecipitated from SADS-CoV-infected Vero E6 cells. Taken together, our results indicated that 3E9 mAb could be a useful tool to investigate the structure and function of N protein during viral replication.	0
Isolated hemichorea (HC) in adults has a relatively restricted differential diagnosis including stroke of contralateral basal ganglia nuclei, nonketotic hyperglycemia, and basal ganglia toxoplasmosis in HIV infection. Hypoparathyroidism-related basal ganglia calcification can potentially cause neurological problems, including movement disorders, that are usually bilateral in keeping with bilateral symmetric lesions. We report a patient with video-documented isolated, adult-onset HC due to iatrogenic hypoparathyroidism and bilateral basal ganglia calcification. A 47-year-old woman presented with isolated adult-onset HC of 2 years' duration as the presenting and only neurological feature of hypoparathyroidism and bilateral extensive basal ganglia calcification, 20 years after thyroidectomy-induced hypoparathyroidism. Significant improvement in the unilateral hyperkinesia was noted after correction of hypocalcemia and hypoparathyroidism at 3 months. Isolated HC in adults is a rare presenting feature of hypoparathyroidism with bilateral basal ganglia calcification and is treatable with correction of the underlying metabolic abnormality. In all cases with a movement disorder and brain calcification, hypoparathyroidism should be actively sought as this treatable condition must not be missed.	0
Introduction: Xanthogranulomatous cholecystitis (XGC) is a rare inflammatory disease of the gallbladder (GB). XGC surgery is a difficult process due to its clinical, radiological, and intraoperative findings. In this study, our aim is to show the difficulties of XGC surgery and to find out if laparoscopic surgery is a sufficient procedure. Materials and Methods: Histological findings of 3339 cholecystectomy patients, who were operated between January 2015 and January 2020, were retrospectively reviewed. Age, gender, radiological results, clinical features, intraoperative findings, and surgical management of the patients with XGC were recorded. Results: XGC was observed in 70 patients (2.09%). The average age was 53.75. M:F ratio was 1.2. In radiological examinations, gallstones were found in 94.2% of the patients and GB wall thickness (≥3 mm) was increased in 58.5% of the patients. Around 45.7% of the patients came to the clinic with chronic cholecystitis and 32.9% with acute cholecystitis. In the intraoperative period, adhesions were observed in 80% and increase in GB wall thickness was observed in 77.1% of the patients. The operation started laparoscopically in 66 patients. In 14 patients (21.2%), it was converted to open surgery usually due to insufficient dissection of Calot's triangle. Gallbladder carcinoma (GBC) was suspected in 6 patients, but none of them had malignancy in frozen sections or histology. Conclusions: XGC surgery is difficult due to its radiological, clinical, and intraoperative features and mimicking GBC. It can be converted to open cholecystectomy due to difficulties in laparoscopic dissection. However, since conversion cholecystectomy rates are reasonable, laparoscopic surgery is recommended in patients with suspected XGC.	0
In this report we describe two siblings, a 17-year-old male and his deceased sister, born to consanguineous parents, and presenting an oculocerebral syndrome with hypopigmentation as first delineated by Cross in 1967. In addition to the cutaneous hypopigmentation, both presented deep mental retardation and spastic tetraplegia with athetoid movements. A remarkable finding in this family is that a third sibling, an otherwise normal 23-year-old male, presents the same hypopigmentation with white-grey hair colour as his two severely affected siblings.	0
Sixteen cases of verified Cushing's syndrome, and twelve cases of probable Cushing's syndrome were reviewed and data on them were compared with various reports on Cushing's syndrome in the literature. The diagnosis hinges upon a high index of suspicion, and one or several of the major criteria may be lacking. Ultimate establishment of correct diagnosis should be based largely on the clinical features, although stimulation and suppression tests may help to confirm a clinical diagnosis. In well-established clinical cases, with borderline laboratory confirmation, exploration may be justified, especially if tests fail to identify a specific cause. In cases of adrenal cortical tumor, all pathological tissue should be removed if possible, with great care to support and stimulate the remaining atrophic adrenal gland during and following operation. In cases of bilateral adrenal cortical hyperplasia, the problem is one of how much to remove. At present most investigators advocate radical subtotal resection, leaving less than 10 per cent of one side.	0
Dicarbonyl/L-xylulose reductase (DCXR) is a highly conserved and phylogenetically widespread enzyme converting L-xylulose into xylitol. It also reduces highly reactive α-dicarbonyl compounds, thus performing a dual role in carbohydrate metabolism and detoxification. Enzymatic properties of DCXR from yeast, fungi and mammalian tissue extracts are extensively studied. Deficiency of the DCXR gene causes a human clinical condition called pentosuria and low DCXR activity is implicated in age-related diseases including cancers, diabetes, and human male infertility. While mice provide a model to study clinical condition of these diseases, it is necessary to adopt a physiologically tractable model in which genetic manipulations can be readily achieved to allow the fast genetic analysis of an enzyme with multiple biological roles. Caenorhabditis elegans has been successfully utilized as a model to study DCXR. Here, we discuss the biochemical properties and significance of DCXR activity in various human diseases, and the utility of C. elegans as a research platform to investigate the molecular and cellular mechanism of the DCXR biology.	0
In the past century, dramatic shifts in demographics, globalization and urbanization have facilitated the rapid spread and transmission of infectious diseases across continents and countries. In a matter of weeks, the 2019 coronavirus pandemic devastated communities worldwide and reinforced the human perception of frailty and mortality. Even though the end of this pandemic story has yet to unfold, there is one parallel that is undeniable when a comparison is drawn between the 2019 coronavirus and the 1918 influenza pandemics. The public health response to disease outbreaks has remained nearly unchanged in the last 101 years. Furthermore, the role of environments and human behaviors on the effect and response to the coronavirus pandemic has brought to light many of the historic and contemporaneous inequalities and injustices that plague the United States. Through a reflection of these pandemic experiences, the American burden of disparity and disproportionality on morbidity, mortality and overall social determinants of health has been examined. Finally, a reimagination of a post-coronavirus existence has also been presented along with a discussion of possible solutions and considerations for moving forward to a new and better normal.	0
Among children with recessive metaphyseal dysplasia involving the knees and extremities, two types can be distinguished. In true cartilage-hair hypoplasia, as described by McKusick, many patients show clinical hair involvement and variable immunodeficiency. We present a series of six patients with the same radiological changes, but without apparent hypotrichosis. We suggest that they should be considered as having a variant form of cartilage-hair hypoplasia, with a clinically distinct phenotype, which could be as common as 'true' cartilage-hair hypoplasia among non-Amish populations. Microscopic examination of the hair may show reduction in the diameter of the hair shaft. This form of metaphyseal dysplasia may result from allelic heterogeneity.	0
Ulnar-mammary syndrome (UMS) is a rare syndromic limb malformation caused by heterozygous mutations in TBX3. The name highlights the two commonly involved body parts i.e. mammary gland and ulnar ray of the upper limbs, although a more extensive systemic involvement is also known to occur. Here, we report the surprising finding of a patient with a de novo mutation in TBX3 whose clinical presentation is limited to dorsalization of both little fingers and slightly deep 4th web spaces. We review the literature to confirm that this should be considered as a forme fruste phenotype of UMS.	0
UNLABELLED:Cholesteryl ester storage disease (CESD) and Wolman disease are autosomal recessive later-onset and severe infantile disorders, respectively, which result from the deficient activity of lysosomal acid lipase (LAL). LAL is encoded by LIPA (10q23.31) and the most common mutation associated with CESD is an exon 8 splice junction mutation (c.894G>A; E8SJM), which expresses only ∼3%-5% of normally spliced LAL. However, the frequency of c.894G>A is unknown in most populations. To estimate the prevalence of CESD in different populations, the frequencies of the c.894G>A mutation were determined in 10,000 LIPA alleles from healthy African-American, Asian, Caucasian, Hispanic, and Ashkenazi Jewish individuals from the greater New York metropolitan area and 6,578 LIPA alleles from African-American, Caucasian, and Hispanic subjects enrolled in the Dallas Heart Study. The combined c.894G>A allele frequencies from the two cohorts ranged from 0.0005 (Asian) to 0.0017 (Caucasian and Hispanic), which translated to carrier frequencies of 1 in 1,000 to ∼1 in 300, respectively. No African-American heterozygotes were detected. Additionally, by surveying the available literature, c.894G>A was estimated to account for 60% (95% confidence interval [CI]: 51%-69%) of reported mutations among multiethnic CESD patients. Using this estimate, the predicted prevalence of CESD in the Caucasian and Hispanic populations is ∼0.8 per 100,000 (∼1 in 130,000; 95% CI: ∼1 in 90,000 to 1 in 170,000). CONCLUSION:These data indicate that CESD may be underdiagnosed in the general Caucasian and Hispanic populations, which is important since clinical trials of enzyme replacement therapy for LAL deficiency are currently being developed. Moreover, future studies on CESD prevalence in African and Asian populations may require full-gene LIPA sequencing to determine heterozygote frequencies, since c.894G>A is not common in these racial groups.	1
Goblet cell carcinoids (GCC) are extremelyrare neuroendocrine tumours, and characterised by their unique combination of two types of cancer cells âÃÂ" neuroendocrine (carcinoid) and epithelial (adeno-carcinoma). In spite of the fact that GCC is regarded as Neuro-Endocrine Tumour (NET), it does not illicit carcinoid syndrome. GCC usually arises in the appendix and accounting for less than 14% of all appendiceal tumours.Primary extra-appendiceal GCC have been reported as stomach, duodenum, small intestine, colon and rectum. The paper presents a rare case of GCC of the ascending colon in a 57-year-old male.	0
PURPOSE:To investigate the longitudinal morphologic choroidal changes in eyes with acute zonal occult outer retinopathy. METHODS:In this retrospective observational case series, we studied 10 patients (11 eyes) with unilateral acute zonal occult outer retinopathy at the first visit who were followed more than 12 months by enhanced depth optical coherence tomography. The retinal and choroidal thicknesses (CTs) were measured at six sites in the macula. RESULTS:The integrity of the ellipsoid zone was lost 1,500 μm and 3,000 μm nasally in all 11 eyes at the first visit. Compared with the unaffected fellow eyes, the mean total retinal thickness at the first visit was significantly (P = 0.03) thinner 3,000 μm nasal to the fovea in the affected eyes. The mean CTs in the affected eyes did not differ from that in the unaffected eyes at any evaluation; the mean subfoveal CT in the affected eyes gradually decreased during the follow-up period. Compared with the first visit, the mean subfoveal CT decreased significantly (P = 0.011) at the foveal center and nasal, superior, and temporal to the fovea 12 months after disease onset. CONCLUSION:The subfoveal CT in eyes with acute zonal occult outer retinopathy can decrease during follow-up.	0
Human disorganization syndrome (HDS) is an extremely rare congenital syndrome characterized by a seemingly random distribution of multiple developmental anomalies involving all three germinal layers. Case Report:We report a rare case of a female child whose congenital anomalies are consistent with HDS. The orthopaedic features of this patient include a popliteus pterygium with an associated flexion contracture secondary to an elongated biceps femoris tendon that attached to the gastrocnemius-soleus muscle complex, two finger-like appendages, a tethered cord, a lipomeningomyelocele at the level of L5, and a leglength discrepancy. The patient was treated with a splinting program, release of the biceps femoris tendon at its erroneous insertion from the gastrocs-soleus, and surgical excision of the finger-like appendages. She underwent three subsequent soft-tissue releases to address recurrence of the knee flexion contracture and an anteromedial and lateral distal femoral eight plate procedure for guided growth and slow correction of the remaining flexion deformity. Conclusion:The treatment of HDS can be quite complex and can present with a variety of anomalies with distinctive orthopaedic features correctable with surgical management, including soft-tissue releases, excision of appendages, and growth modulation.	0
BACKGROUND:Thoracic aortic aneurysm and dissection (TAA/D) represents a potentially lethal disease group characterized by an increased risk of dissection or rupture. Only a small percentage (approximately 30%) of individuals with nonsyndromic familial TAA/D have a pathogenic variant in one of the genes that have been found to be associated with the disease. METHODS:A targeted sequencing panel and direct sequencing approach were used to identify causative mutations in the index patients and other family members. RESULTS:In this study we report two apparently unrelated Cypriot families with nonsyndromic familial TAA/D. The proband A is a female patient diagnosed with TAA/D and intracranial aneurysm and opted for an elective intervention. The proband B is a male patient who was diagnosed with TAA/D and underwent cardiac surgery. Sequencing analysis identified a novel splice site variant (c.871+1G>A) in SMAD3 which is shown to be associated with the disease. Analysis of mRNA from the patient's tissue confirmed aberrant splicing and exon 6 skipping. CONCLUSION:Our findings expand the mutation spectrum of variants that have been shown to be associated with nonsyndromic familial TAA/D. This study demonstrates the importance of a comprehensive clinical and genetic evaluation aiming at early diagnosis and intervention.	0
Patients with multiple myeloma (MM) accumulate adverse copy number aberrations (CNAs), gains of 1q21, and 17p deletions during disease progression. A subset of these patients develops heightened 1q12 pericentromeric instability and jumping translocations of 1q12 (JT1q12), evidenced by increased copy CNAs of 1q21 and losses in receptor chromosomes (RC). To understand the progression of these aberrations we analyzed metaphase cells of 50 patients with ≥4 CNAs of 1q21 by G-banding, locus specific FISH, and spectral karyotyping. In eight patients with ≥5 CNAs of 1q21 we identified a chromosome instability phenotype similar to that found in ICF syndrome (immunodeficiency, centromeric instability, and facial anomalies). Strikingly, the acquired instability phenotype identified in these patients demonstrates the same transient structural aberrations of 1q12 as those found in ICF syndrome, suggesting similar underlying pathological mechanisms. Four types of clonal aberrations characterize this phenotype including JT1q12s, RC deletions, 1q12-21 breakage-fusion-bridge cycle amplifications, and RC insertions. In addition, recurring transient aberrations include 1q12 decondensation and breakage, triradials, and 1q micronuclei. The acquired self-propagating mobile property of 1q12 satellite DNA drives the continuous regeneration of 1q12 duplication/deletion events. For patients demonstrating this instability phenotype, we propose the term "Jumping 1q Syndrome."	0
Sixty-four infants and children showing signs of decerebrate rigidity admitted to a paediatric unit have been studied. Cases of head injury, myelomeningocoele, and tumours were excluded from the series. The aetiological factors causing decerebration in the remainder fell into four main groups: infections, hypoxia, metabolic disease, and intracranial haemorrhage. Increased intracranial pressure was diagnosed in 87%. Defects in homeostasis occurred in 75%, respiratory abnormalities were present in 66%, cardiovascular in 33%, hypothermia in 30%, and hyponatraemia in 17%. Early recognition and treatment of raised intracranial pressure and defects in homeostasis are of the utmost importance if morbidity and mortality are to be minimized. There was a 31% mortality from the acute illness: 30% of the survivors were normal at follow-up examination; the remainder showed varying degrees of handicap. The severity of decerebration showed no correlation with aetiology or prognosis. The study shows that a wide range of disorders can lead to the clinical picture of decerebration in the young child, and that the prognosis is probably much better than in adults showing the same symptoms and signs.	0
OBJECTIVE:To explore the clinical and genetic characteristics of five pedigrees affected with hereditary spastic paraplegia(HSP). METHODS:Clinical data of the five pedigrees was collected, and high-throughput sequencing was carried out to detect potential variants. Sanger sequencing were used to verify the results. RESULTS:The probands of pedigree 1 and 2 were found to harbor heterozygous SPAST gene variants, namely c.1196C>T and c.1523T>A. The proband of pedigree 3 harbored compound heterozygous variants of FA2H gene (c.61G>C and c.688G>A). Proband from pedigree 4 harbored compound heterozygous variants of SPG11 gene (c.6812+4_6812+7delAGTA and c.915delT). The proband of pedigree 5 harbored compound heterozygous variants of SPG7 gene (c.1703_1704delAG and c.1937-1G>C). Based on the American College of Medical Genetics and Genomics(ACMG) guidelines, all variants were predicted to be likely pathogenic. Among these, SPAST gene c.1523T>A, FA2H gene c.61.G>C, SPG11 gene splicing region c.6812+4_6812+7delAGTA, c.915delT, SPG7 gene c.1703_1704delAG and splicing region c.1937-1G>C variants were unreported previously. CONCLUSION:The probands of pedigrees 1 and 2 were diagnosed with autosomal dominant hereditary spastic paraplegia type 4, for which pedigree 2 showed incompletely penetrance. Pedigrees 3, 4, and 5 were diagnosed with autosomal recessive hereditary spastic paraplegia type 35, 11 and 7, respectively. Above result provided a reference for clinical diagnosis and genetic counseling for the affected pedigrees.	0
We report on three male newborn infants of a highly inbred Lebanese family presenting with a characteristic phenotype: arthrogryposis multiplex, deafness, large inguinal hernia, hiccup-like diaphragmatic contractions, and inability to suck, requiring nasogastric gavage feeding. All three boys died from respiratory failure during the first 3 months of life. Intra vitam or post mortem examinations revealed myopathic changes and elevated glycogen content of muscle tissue. This new syndrome is probably transmitted in an autosomal recessive mode, although X-linked inheritance cannot be excluded.	0
In this article, distal myopathy syndromes are discussed. A discussion of the more traditional distal myopathies is followed by discussion of the myofibrillar myopathies. Other clinically and genetically distinctive distal myopathy syndromes usually based on single or smaller family cohorts are reviewed. Other neuromuscular disorders that are important to recognize are also considered, because they show prominent distal limb weakness.	0
Purpose: To report a case of a patient who suffered from Sweet's syndrome with panuveitis in both eyes.Materials & Methods: Retrospective interventional case report.Results: A 54-year-old Chinese male patient complained of fever, painful skin lesions and blurry vision in both eyes lasting for 4 days. His visual acuity was hand motion in both eyes. Slit-lamp examination showed the hypopyon and severe vitreous opacification in both eyes. A skin pathology from head skin lesion demonstrated diffuse neutrophilic infiltration in the dermis with karyorrhexis. Based on the inspection above, the patient was diagnosed with Sweet's syndrome and given systemic corticosteroids therapy. However, he developed secondary rhegmatogenous retinal detachment in the right eye during his treatment.Conclusion: The association of bilateral uveitis with Sweet's syndrome has been described in this report.	0
RATIONALE:Castleman disease (CD) is a rare lymphoproliferative disease with a poorly understood etiology. The occurrence of CD in the abdominal cavity is very rare, especially in the retroperitoneal peripancreatic region. PATIENT CONCERNS:A 33-year-old woman was referred to our department on March 1, 2018 for a detailed physical examination due to retroperitoneal peripancreatic lymph node enlargement over 15 days. DIAGNOSIS:Enhanced magnetic resonance imaging of the epigastrium showed the mass with abundant blood supply is located between the liver and the stomach in the upper margin of the pancreas. Postoperative pathological examination revealed CD, type of unicentric Castleman disease. INTERVENTIONS:We performed an open surgery on this patient and completely removed the mass. There was no postoperative radiochemotherapy. OUTCOMES:The patient was followed-up for more than 12 months after the operation and showed good recovery. LESSONS:CD is a rare disorder that is hard to diagnose early and complete resection of the tumor is still the most effective treatment.	0
The goal of screening programs for inborn errors of metabolism (IEM) is early detection and timely intervention to significantly reduce morbidity, mortality and associated disabilities. Phenylketonuria exemplifies their success as neonates are identified at birth and then promptly treated allowing normal neurological development. Lysosomal diseases comprise about 50 IEM arising from a deficiency in a protein required for proper lysosomal function. Typically, these defects are in lysosomal enzymes with the concomitant accumulation of the enzyme's substrate as the cardinal feature. None of the lysosomal diseases are screened at birth in Australia and in the absence of a family history, traditional laboratory diagnosis of the majority, involves demonstrating a deficiency of the requisite enzyme. Diagnostic confusion can arise from interpretation of the degree of residual enzyme activity causative of disease and is impractical when the disorder is not due to an enzyme deficiency per se. Advances in mass spectrometry technologies has enabled simultaneous measurement of the enzymes' substrates and their metabolites which facilitates the efficiency of diagnosis. Employing urine chemistry as a reflection of multisystemic disease, individual lysosomal diseases can be identified by a characteristic substrate pattern complicit with the enzyme deficiency. Determination of lipids in plasma allows the diagnosis of a further class of lysosomal disorders, the sphingolipids. The ideal goal would be to measure biomarkers for each specific lysosomal disorder in the one mass spectrometry-based platform to achieve a diagnosis. Confirmation of the diagnosis is usually by identifying pathogenic variants in the underlying gene, and although molecular genetic technologies can provide the initial diagnosis, the biochemistry will remain important for interpreting molecular variants of uncertain significance.	0
BACKGROUND:There are two types of esophageal varices (EVs): high-risk EVs (HEVs) and low-risk EVs, and HEVs pose a greater threat to patient life than low-risk EVs. The diagnosis of EVs is mainly conducted by gastroscopy, which can cause discomfort to patients, or by non-invasive prediction models. A number of non-invasive models for predicting EVs have been reported; however, those that are based on the formula for calculation of liver and spleen volume in HEVs have not been reported. AIM:To establish a non-invasive prediction model based on the formula for liver and spleen volume for predicting HEVs in patients with viral cirrhosis. METHODS:Data from 86 EV patients with viral cirrhosis were collected. Actual liver and spleen volumes of the patients were determined by computed tomography, and their calculated liver and spleen volumes were calculated by standard formulas. Other imaging and biochemical data were determined. The impact of each parameter on HEVs was analyzed by univariate and multivariate analyses, the data from which were employed to establish a non-invasive prediction model. Then the established prediction model was compared with other previous prediction models. Finally, the discriminating ability, calibration ability, and clinical efficacy of the new model was verified in both the modeling group and the external validation group. RESULTS:Data from univariate and multivariate analyses indicated that the liver-spleen volume ratio, spleen volume change rate, and aspartate aminotransferase were correlated with HEVs. These indexes were successfully used to establish the non-invasive prediction model. The comparison of the models showed that the established model could better predict HEVs compared with previous models. The discriminating ability, calibration ability, and clinical efficacy of the new model were affirmed. CONCLUSION:The non-invasive prediction model for predicting HEVs in patients with viral cirrhosis was successfully established. The new model is reliable for predicting HEVs and has clinical applicability.	0
Steroid cell tumors (SCTs) (not otherwise specified (NOS)) are rare sex cord-stromal tumors of the ovary. These are associated with hormonal disturbances resulting in menstrual bleeding patterns and androgenic effects. We report the case of a 36-year-old female presented with hirsutism, signs of virilization, and elevated androgen levels. Transvaginal ultrasound showed a solid-appearing right ovarian mass. She underwent fertility-sparing surgery with a laparoscopic left oophorectomy. Histological examination showed a benign steroid cell tumor, NOS. These tumors often small can then present a problem of positive diagnosis responsible for a delay in the diagnosis.	0
COVID-19 can severely affect pregnant women Furthermore, issues regarding vertical transmission of severe acute respiratory syndrome coronavirus 2 are emerging. In patients and neonates who are showing symptoms of coronavirus disease 2019, real-time polymerase chain reaction of nasal and throat swabs, sputum, and feces is performed to detect the presence of severe acute respiratory syndrome coronavirus 2. In addition, real-time polymerase chain reaction of vaginal swabs, amniotic fluid, placenta, cord blood, neonatal blood, or breast milk for the detection of severe acute respiratory syndrome coronavirus 2 did not show substantial results. Viremia was present in 1% of adult patients who were showing symptoms of coronavirus disease 2019. Here, we reviewed 12 articles published between Feb. 10, 2020, and April 4, 2020, that reported on 68 deliveries and 71 neonates with maternal infection in the third trimester of pregnancy. To determine whether infection occurred congenitally or perinatally, perinatal exposure, mode of delivery, and time interval from delivery to the diagnosis of neonatal infection were considered. Neonates with severe acute respiratory syndrome coronavirus 2 infection are usually asymptomatic. In 4 cases, a diagnostic test for severe acute respiratory syndrome coronavirus 2 infection was performed within 48 hours of life. Furthermore, detection rates of real-time polymerase chain reaction and the interpretation of immunoglobulin M and immunoglobulin G antibodies levels in cord and neonatal blood were discussed in relation with the immaturity of the fetal and neonatal immune system.	0
OBJECTIVES:Chondroblastoma is an uncommon benign neoplasm of cartilaginous origin usually involving the long bones. The temporal bone is a rare location for this tumor. As such, the clinical profile, optimal medical and surgical management, and outcomes of treatment for temporal bone chondroblastoma remain unknown. MATERIALS AND METHODS:We performed a systematic review of the SCOPUS, PubMed, and CENTRAL databases for case reports and case series on patients with histopathologically proven temporal bone chondroblastoma. Data on demographics, clinical manifestation, surgical management, adjuvant treatment, and outcome on last follow-up were collected. RESULTS:A total of 100 cases were reported in the literature, including one described in the current study. The mean age of patients was 42.3 years (2 - 85 years), with a slight male predilection (1.3:1). The most common clinical manifestations were otologic complaints such as hearing loss (65%), tinnitus, and otalgia, and a palpable mass. Surgical excision was done in all cases, with gross total excision achieved in 58%. Radiation therapy was performed in 18% of cases, mostly as adjuvant treatment after subtotal excision. There were no deaths at a median follow-up of 2 years. Among the patients with detailed status on follow-up, 58% had complete neurologic recovery, 38% had partial recovery, while 4% had progression of symptoms due to tumor recurrence. CONCLUSION:Temporal bone chondroblastoma has a distinct clinical profile from chondroblastoma of long bones. Surgery is the mainstay of treatment, and radiation therapy may be given after subtotal excision. Outcomes are generally favorable after treatment.	0
Ph+ chronic myeloid leukemia (CML) is a clonal myeloproliferative disease whose clinical course is characterized by progression disease from the early chronic phase (CP) to the fatal blastic phase (BP). This programmed course is closely related to the translocation t(9;22)(q22;q11) and the resulting BCR-ABL1 fusion protein (p210) that drives the leukemic transformation of hematopoietic stem cells. Therefore, the cure of CML can only pass through the abrogation of the Ph+ clone. Allogeneic stem cell transplantation (allo-SCT) and interferon-alpha (IFNα) have been proven to reduce the Ph+ clone in a limited proportion of CML population and this translated in a lower rate of progression to BP and in a significant prolongation of survival. Tyrosine-kinase inhibitors (TKIs), lastly introduced in 2000, by preventing the disease blastic transformation and significantly prolonging the survival in up to 90% of the patient population, radically changed the fate of CML. The current therapy with TKIs induces a chronicization of the disease but several criticisms still persist, and the most relevant one is the sustainability of long-term therapy with TKIs in terms of compliance, toxicity and costs. The perspectives concern the optimization of therapy according to the age, the risk of disease, the potency and the safety profiles of the TKIs. The prolongation of survival is the most important end point which should be guaranteed to all patients. The treatment free remission (TFR) is the new goal that we would like to give to an increasing number of patients. The cure remains the main objective of CML therapy.	0
Aims: To determine the clinical characteristics and genetic cause of Waardenburg syndrome type 1 (WS1) in a Chinese family. Materials and Methods: Evaluations, including history, clinical features, and audiological tests, were performed on the proband and her parents. Genetic analyses were performed targeting 144 known deafness genes using a next-generation sequencing panel. Bioinformatic analyses were used to analyze the candidate mutation. Results: The proband and her parents suffered from congenital bilateral profound hearing loss. Her mother exhibited bilateral blue irides. WS1 was diagnosed in the proband and her mother according to the Waardenburg syndrome consortium criteria: the calculated W index of the proband was 2.39 and that of her mother was 2.31. A novel mutation c.1076_1077del (p.Thr359fs) in exon 7 of the PAX3 gene (paired box 3) was identified in the proband and her mother that was absent in the father and controls. Conclusion: Mutations in exon 7 of the PAX3 gene are rare. We identified a novel frameshift mutation in exon 7 of the PAX3 gene that we determined was responsible for WS1 in this family.	0
RATIONALE:Chilaiditi syndrome is a rare disorder characterized by a broad spectrum of (gastro-intestinal) symptoms caused by interposition of a segment of bowel between the liver and the diaphragm. Most cases present with abdominal symptoms and the morbidity tend to increase with age. PATIENT CONCERNS:Here we present a rare case of Chilaiditi syndrome. An elderly postmenopausal woman developed unresolved postoperative respiratory symptoms and chest pain. Chest auscultation revealed considerable attenuation of respiratory sounds. She showed postoperative increase in D-dimer level and sudden onset of dyspnea. DIAGNOSES:Considering the presence of atelectasis in the middle and lower lobes of the right lung, bedside fiberoptic bronchoscopy was performed immediately to rule out bronchial phlegm embolism. However, no phlegm embolism was found in the left lung, and a small amount of yellow-white mucus was seen in the upper lobe of the right lung. Due to external pressure, the lumen of the middle and lower lobes of the right lung was obviously narrowed. INTERVENTIONS:The patient was placed in a semi-sitting position and a tube was passed through the anus to decompress the intestinal cavity; in addition, she received potassium supplementation. OUTCOMES:The patient's symptoms improved markedly. Chest and semi-supine abdominal plain radiographs showed enhanced lung markings, shadows in the left lower lung lobes, elevation of the right diaphragm, and small amount of pneumoperitoneum. The patient recovered after 5 days of continuous treatment and was discharged. LESSONS:Emergency computed tomographic pulmonary angiography may facilitate the diagnosis of Chilaiditi syndrome, especially in the postoperative setting. Occurrence of Chilaiditi syndrome in this patient was likely associated with surgical factors. Appropriate investigations and clear identification of etiology are essential for successful treatment.	0
Electrophysiological studies can provide objective and quantifiable assessments of movement disorders. They are useful in the diagnosis of hyperkinetic movement disorders, particularly tremors and myoclonus. The most commonly used measures are surface electromyography (sEMG), electroencephalography (EEG) and accelerometry. Frequency and coherence analyses of sEMG signals may reveal the nature of tremors and the source of the tremors. The effects of voluntary tapping, ballistic movements and weighting of the limbs can help to distinguish between organic and functional tremors. The presence of Bereitschafts-potentials and beta-band desynchronization recorded by EEG before movement onset provide strong evidence for functional movement disorders. EMG burst durations, distributions and muscle recruitment orders may identify and classify myoclonus to cortical, subcortical or spinal origins and help in the diagnosis of functional myoclonus. Organic and functional cervical dystonia can potentially be distinguished by EMG power spectral analysis. Several reflex circuits, such as the long latency reflex, blink reflex and startle reflex, can be elicited with different types of external stimuli and are useful in the assessment of myoclonus, excessive startle and stiff person syndrome. However, limitations of the tests should be recognized, and the results should be interpreted together with clinical observations.	0
α-Synucleinopathies are characterized by autonomic dysfunction and motor impairments. In the pure autonomic failure (PAF), α-synuclein (α-Syn) pathology is confined within the autonomic nervous system with no motor features, but mouse models recapitulating PAF without motor dysfunction are lacking. Here, we show that in TgM83+/- mice, inoculation of α-Syn preformed fibrils (PFFs) into the stellate and celiac ganglia induces spreading of α-Syn pathology only through the autonomic pathway to both the central nervous system (CNS) and the autonomic innervation of peripheral organs bidirectionally. In parallel, the mice develop autonomic dysfunction, featured by orthostatic hypotension, constipation, hypohidrosis and hyposmia, without motor dysfunction. Thus, we have generated a mouse model of pure autonomic dysfunction caused by α-Syn pathology. This model may help define the mechanistic link between transmission of pathological α-Syn and the cardinal features of autonomic dysfunction in α-synucleinopathy.	0
Purpose: The experiences of parents caring for the complex care needs of children with rare neurodevelopmental disorders are not well understood. Parents struggle to meet their children's medical, behavioural, and social needs within and across health, social, and family systems. The purpose of this study was to explore the parents' experience of caring for medical and social care needs for children with rare neurodevelopmental disorders.Methods: Hermeneutic phenomenology was used for the data analysis. Fifteen parents participated in semi-structured interviews.Results: Interpretive analysis revealed four insights: (a) difference in children's behaviours and disease manifestations led to misunderstanding and vulnerability within social domains, (b) social taboo and stigma were experienced with rarity, (c) fragmented disconnected care from health and social systems impacted families, and (d) incomprehension from friends and family occurs when managing daily care.Conclusion: New interpretations and increased understanding of parents' experiences are required in supporting parents caring for children with complex needs. Understanding parents' experiences could reduce social isolation and exclusion, and mitigate appropriate and supportive practices and services within and across medical, social, and family systems.	0
BACKGROUND:Health researchers are increasingly using electronic health records (EHRs) to study the health care needs of people with neurodevelopmental disorders (NDDs). However, little is known about the preferences of people with NDDs for sharing EHRs for research. OBJECTIVE:To explore preferences for sharing EHRs for research among young adults ages 18-40 who make their own legal decisions and who have autism spectrum disorder (ASD), fragile X syndrome (FXS), or no NDDs. METHODS:We conducted a qualitative study with seven focus groups: 2 ASD groups, 3 FXS groups, and 2 no-NDD groups. We asked participants about factors that could affect their willingness to share their EHRs for research: type of organization, type of information, study purpose, duration, contact frequency, return of results, benefits, and risks. We analyzed the qualitative data using directed content analysis. RESULTS:Participants with NDDs valued personally relevant and directly beneficial EHR research. Participants with NDDs expressed willingness to share sensitive data if the study was personally relevant. Most participants wanted to receive results, but only participants with FXS indicated it would affect their willingness to participate. Participants were concerned about privacy risks, discrimination, researcher misconduct, and financial conflicts of interest. CONCLUSION:This study provides initial evidence suggesting that young adults with NDDs prefer EHR research that is personally relevant, benefits themselves and their communities, and is conducted in the context of trusting, reciprocal participant-researcher relationships. The findings point to the need for researchers to improve the informed consent process and to better engage individuals with NDDs in research.	0
Acromesomelic dysplasia is genetically heterogeneous group of skeletal disorders characterized by short stature and acromelia and mesomelia of limbs. Acromesomelic dysplasia segregates in an autosomal recessive pattern and is caused by biallelic sequence variants in three genes (NPR2, GDF5, and BMPR1B). A consanguineous family of Pakistani origin segregating a subtype of acromesomelic dysplasia called Hunter-Thompson was clinically and genetically evaluated. Genotyping of microsatellite markers and linkage analysis revealed a 7.78 Mb homozygous region on chromosome 4q22.3, which harbors BMPR1B. Sequence analysis of the gene revealed a novel homozygous missense variant (c.1190T > G, p.Met397Arg) that segregates with the disease phenotype within the family and produced a Logarithm of odds (LOD) score of 3.9 with the disease phenotype. This study reports on the first familial case of acromesomelic dysplasia Hunter-Thompson type. It is also the first report of BMPR1B underlying the etiology of acromesomelic dysplasia Hunter-Thompson type.	0
A 39-year-old man was admitted to our university hospital because of diffuse pulmonary infiltrates on chest X-ray. He had been diagnosed with T-acute lymphoblastic leukaemia/lymphoblastic lymphoma three years before and had been treated with chemotherapy and cord blood stem cell transplantation twice. Although he had neither blast cells in the peripheral blood nor leucocytosis, urgent bronchoscopy findings demonstrated blast cells invading both the alveolar spaces/alveolar septa and the vein walls. These pathological findings corresponded to ground-glass opacities and thickening of the interlobular septa on thoracic computed tomography (CT). In acute lymphoblastic leukaemia/lymphoblastic lymphoma patients presenting with infiltrates on thoracic CT, leukaemic pulmonary involvement should be considered in the differential diagnoses, even in the absence of hyperleucocytosis or blast cells in the blood, similar to pulmonary involvement in myeloid leukaemias.	0
Ubiquitination is a versatile and dynamic post-translational modification in which single ubiquitin molecules or polyubiquitin chains are attached to target proteins, giving rise to mono- or poly-ubiquitination, respectively. The majority of research in the ubiquitin field focused on degradative polyubiquitination, whereas more recent studies uncovered the role of single ubiquitin modification in important physiological processes. Monoubiquitination can modulate the stability, subcellular localization, binding properties, and activity of the target proteins. Understanding the function of monoubiquitination in normal physiology and pathology has important therapeutic implications, as alterations in the monoubiquitin pathway are found in a broad range of genetic diseases. This review highlights a link between monoubiquitin signaling and the pathogenesis of genetic disorders.	0
Approximately half of all cases of Hoyeraal-Hreidarsson syndrome (HHS), a multisystem disorder characterized by bone marrow failure, developmental defects and very short telomeres, are caused by germline mutations in genes related to telomere biology. However, the varying symptoms and severity of the disease indicate that additional mechanisms are involved. Here, a 3-year-old boy with HHS was found to carry biallelic germline mutations in WRAP53 (WD40 encoding RNA antisense to p53), that altered two highly conserved amino acids (L283F and R398W) in the WD40 scaffold domain of the protein encoded. WRAP53β (also known as TCAB1 or WDR79) is involved in intracellular trafficking of telomerase, Cajal body functions and DNA repair. We found that both mutations cause destabilization, mislocalization and faulty interactions of WRAP53β, defects linked to misfolding by the TRiC chaperonin complex. Consequently, WRAP53β HHS mutants cannot elongate telomeres, maintain Cajal bodies or repair DNA double-strand breaks. These findings provide a molecular explanation for the pathogenesis underlying WRAP53β-associated HHS and highlight the potential contribution of DNA damage and/or defects in Cajal bodies to the early onset and/or severity of this disease.	0
BACKGROUND:Relatively little attention has been given to the epidemiology and management of cancer of the ampulla of Vater. SETTING:A series of 111 patients with a cancer of the ampulla of Vater diagnosed over a 20-year period (1976-1995) in a well-defined French population was used to analyse its incidence, management and prognosis as well as to determine time trends. Prognosis was determined by using crude and relative survival rates. Factors predictive of survival were also identified using a relative survival model in a multivariate analysis. RESULTS:Age-standardized incidence rates were 3.8 per 1000000 inhabitants in men and 2.7 per 1000000 inhabitants in women. Incidence increased over time in men from 1.9 during the first period (1976-1980) to 5.9 during the last period (1991-1995). In women, incidence rates remained stable. A resection for cure was performed in 52 cases (48.1%). Overall, 9.9% of these cancers were classified TNM stage I and 54.1% stage IV. There was no significant variation in treatment modalities and in stage at diagnosis over the study period. The overall operative mortality rate was 7.5%. Relative survival rates were 58.9% at 1 year, 30.9% at 3 years and 20.9% at 5 years. Five-year relative survival rates varied from 72.8% in TNM stage I cancers to 6.6% in TNM stage IV cancers. Age, treatment procedure and stage at diagnosis significantly influenced the prognosis of cancer of the ampulla of Vater. In a multivariate analysis, stage at diagnosis remained the major prognostic factor (P<0.01). CONCLUSIONS:Although its incidence is increasing in men, cancer of the ampulla of Vater remains a rare tumour in both sexes. No improvements in the management and care of patients have been achieved. Further studies are needed to enhance the understanding of this cancer.	1
INTRODUCTION:The subdivision into two entities of papillary renal cell carcinoma (PRCC) was established on histological criteria. It's in fact possible to distinguish the two subtypes by the means of radiological and progressive data. The subtype 1 is associated with the favorable profile. The ultrasound and especially CT urography ensure an accurate diagnostic approach with substantial therapeutic and prognostic involvement. The aim of the study is to define the radiological features that distinguish the two subtypes of renal papillary carcinoma, and to study the radiological predictive factors of locoregional recurrence, metastases free survival and specific survival. METHODS:It's about a monocentric, retrospective study led between January 2005 and June 2017, gathering 49 cases of operated PRCC. The study concerned patients over the age of 18, who were diagnosed after anatomopathological examination of the operative specimen (enlarged nephrectomy or conservative surgery). Cases in which diagnosis was made by renal biopsy were excluded. The comparative study concerned ultrasound and CT scan data. Univariate and multivariate analysis were performed to determine factors having a prognostic value in terms of locoregional recurrence, metastases-free and specific survival. RESULTS:On the ultrasound, the subtype 1 tumors were significantly homogenous with regular contours. Tumors were globally spontaneously hypodense and hypo vascular in 97,8% of cases. Enhancement was significantly more heterogonous for subtype 2 (p=0,01). Intratumoral necrosis and adenomegalies were associated with subtype 2 (p=0,0001 and 0,005). The predictive factors of locoregional recurrence, metastases-free survival and specific survival in univariate analysis were the contours' aspect, moderate enhancement and the presence of adenomegalies. On multivariate analysis, only the irregular contours were retained for locoregional recurrence-free survival and specific survival. CONCLUSIONS:Significant differences between the PRCC subtypes were observed when studying the radiological data. Irregular contours, adenomegalies and enhancement degree seemed to predict the progression of PRCC after curative surgery.	0
OBJECTIVES:Developmental dysplasia of the hip (DDH) is a common skeletal disorder. This study was conducted to demonstrate the association between DDH and a polymorphism rs9277935 of COL11A2 gene. RESULTS:A significant difference in genotype distribution in a recessive model (TT+GT vs. GG) between two groups (P=0.017) was demonstrated. Analysis in female patients showed significantly greater frequency of minor allele G(0.49 vs. 0.43, p=0.024) and significantly higher distribution of GG genotype (p=0.006). DDH patients were found to have significantly lower COL11A2 expression than controls. Moreover, DDH patients with rs9277935 genotype TT have a significantly increased expression of COL11A2 than those with genotype GG. COL11A2 demonstrated chondrogenic properties in vitro. CONCLUSION:Polymorphism rs9277935 of gene COL11A2 is a functional variant regulating the expression and the chondrogenic properties of COL11A2 in DDH in Chinese Han population. METHODS:A case-control candidate gene association study was conducted in 945 patients (350 radiologically confirmed DDH patients and 595 healthy controls). Difference of COL11A2 expression in hip joint tissue was compared between the patients and the controls. Allelic difference in Col11a2 expression by rs9277935 was assessed with luciferase activity. Chondrogenic effects of Col11a2 signaling on BMSCs were also determined in vitro.	0
The term congenital hypopigmentary disorders refers to a wide group of heterogeneous hereditary diseases, clinically characterized by inborn pigmentary defects of the iris, hair, and/or skin. They include Gray Hair Syndromes (GHSs), a rare group of autosomal recessive genodermatosis hallmarked by inborn silvery gray hair. GHSs encompass Griscelli, Chediak⁻Higashi, Elejalde, and Cross syndromes, which are all characterized by a broad spectrum of severe multisystem disorders, including neurological, ocular, skeletal, and immune system impairment. In this manuscript, we describe in detail the clinical, trichoscopic, and genetic features of a rare case of Griscelli syndrome; moreover, we provide an overview of all the GHSs known to date. Our report highlights how an accurate clinical examination with noninvasive methods, like trichoscopy, may play a crucial rule in diagnosis of rare and potentially lethal genetic syndromes such as Griscelli syndrome, in which timely diagnosis and therapy may modify the clinical course, quality of life, and likelihood of survival.	0
This dominantly inherited disease begins with fine, pale, drusen-like deposits or confluent faint yellow material or sheets beneath the retinal pigment epithelium (RPE), but it eventually progresses to either geographic atrophy with pigmentary clumps or scar due to choroidal neovascular membrane (at about 40 years of age) (Figs. 20.1, 20.2 and 20.3). The patient usually becomes symptomatic, with loss of central vision (about 20/200 or less), in the fourth to sixth decade of life. When neovascular membrane develops, it mimics age-related macular degeneration (AMD), but the age of onset is much earlier.	0
Allgrove syndrome or triple A (3A) syndrome is a multisystem disorder which classically involves the triad of esophageal achalasia, alacrima, and adrenal insufficiency due to adrenocorticotropin hormone insensitivity. It follows an autosomal recessive pattern of inheritance and is associated with mutations in the AAAS (achalasia-addisonianism-alacrima syndrome) gene. Since its first description in 1978, the knowledge on clinical and genetic characteristics has been expanding; however, the current literature is limited to case reports and case reviews. Early recognition of the syndrome is challenging, given the rarity of the condition and high phenotypic heterogeneity even among members of kin. The coordination of care for these patients requires a multidisciplinary team of specialists, including endocrinologists, neurologists, gastroenterologists, ophthalmologists, developmental specialists, dentists, geneticists, and surgeons. In this review, we aim to summarize the current recommendations for the diagnosis, management, and follow-up of patients with 3A syndrome.	0
OBJECTIVE:We present prenatal diagnosis of mosaic trisomy 22 at amniocentesis in a pregnancy with facial cleft, oligohydramnios and intrauterine growth restriction (IUGR), and we review the literature. CASE REPORT:A 37-year-old woman underwent amniocentesis at 19 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XX,+22[9]/46,XX[9]. Array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes showed a result of arr(22) × 3 [0.8]. Prenatal ultrasound revealed fetal median facial cleft, oligohydramnios and IUGR. Repeat amniocentesis at 22 weeks of gestation using uncultured amniocytes revealed an aCGH result of arr 22q11.1q13.33 (17,397,498-51,178,264) × 2.8 compatible with 80% mosaicism for trisomy 22, and a fluorescence in situ hybridization (FISH) result of mosaic trisomy 22 with trisomy 22 in 54/100 interphase cells. The cultured amniocytes at repeat amniocentesis had a karyotype of 47,XX,+22[12]/46,XX[8]. The parental karyotypes were normal. Polymorphic DNA marker analysis confirmed a maternal origin of the extra chromosome 22. The pregnancy was terminated, and a 256-g female fetus was delivered with facial dysmorphism and median facial cleft. Cytogenetic analysis of the skin fibroblasts revealed a karyotype of 47,XX,+22[33]/46,XX[7]. CONCLUSION:Fetuses with high level mosaicism for trisomy 22 at amniocentesis may present IUGR, facial cleft and oligohydramnios on prenatal ultrasound.	0
BACKGROUND: REVEAL (The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) provides current demographics of patients with group 1 pulmonary arterial hypertension (PAH) in the United States. METHODS: A total of 2,967 patients with PAH diagnosed based on right-sided heart catheterization were enrolled in REVEAL between March 2006 and September 2007. Demographics from the REVEAL patient cohort and REVEAL subpopulations (matched by inclusion criteria to other registries) were compared with historic US registry data and other contemporary US and non-US national PAH registries by inclusion criteria, including the National Institutes of Health (NIH) PAH registry and the French PAH registry. RESULTS: REVEAL patients matched to NIH registry patients were older at diagnosis (mean ± SE, 44.9 ± 0.6 years vs 36.4 ± 1.1 years; difference, 8.5 ± 1.4; P < .001) and more likely to be women (78.7 ± 1.2% vs 63.1 ± 3.5%; P < .001). REVEAL patients matched to French registry patients had similar age and severity at diagnosis, but REVEAL patients were more likely to be women (79.8 ± 0.8% vs 65.3 ± 1.8%; P < .001) and obese (BMI, ≥ 30 kg/m(2), 32.5 ± 1.0% vs 14.8 ± 1.4%; P < .001), whereas French patients were more likely to have HIV-associated PAH (6.2% vs 2.3%). The female preponderance is similar to that in other US-based contemporary registries. CONCLUSIONS: At diagnosis, REVEAL patients were older than NIH registry patients and similar in age to patients enrolled in contemporary registries. Compared with NIH and contemporary European and UK registries, there was a striking preponderance of women, and REVEAL patients were more likely to be obese. These observations and the difference in HIV-associated PAH between REVEAL and other non-US contemporary registries warrant further investigation. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00370214; URL: clinicaltrials.gov.	1
Publicly available data on racial and ethnic disparities related to coronavirus disease 2019 (COVID-19) are now surfacing, and these data suggest that the novel virus has disproportionately sickened Hispanic communities in the United States. We discuss why Hispanic communities are highly vulnerable to COVID-19 and how adaptations were made to existing infrastructure for Penn State Project ECHO (Extension for Community Healthcare Outcomes) and Better Together REACH (a community-academic coalition using grant funds from Racial and Ethnic Approaches to Community Health) to address these needs. We also describe programming to support COVID-19 efforts for Hispanic communities by using chronic disease prevention programs and opportunities for replication across the country.	0
BACKGROUND:Upper gastrointestinal bleeding (UGIB) after an acute myocardial infarction (AMI) is not an uncommon complication. Acute UGIB caused by Mallory-Weiss syndrome (MWS) is usually a dire situation with massive bleeding and hemodynamic instability. Acute UGIB caused by MWS after an AMI has not been previously reported. CASE SUMMARY:A 57-year-old man with acute inferior wall ST elevation myocardial infarction underwent a primary coronary intervention of the acutely occluded right coronary artery. Six hours after the intervention, the patient had a severe UGIB, followed by vomiting. His hemoglobin level dropped from 15.3 g/dL to 9.7 g/dL. In addition to blood transfusion and a gastric acid inhibition treatment, early endoscopy was employed and MWS was diagnosed. Bleeding was stopped by endoscopic placement of titanium clips. CONCLUSION:Bleeding complications after stent implantation can pose a dilemma. MWS is a rare but severe cause of acute UGIB after an AMI that requires an early endoscopic diagnosis and a hemoclip intervention to stop bleeding.	0
The 4q deletion syndrome is a rare chromosome deletion syndrome with a wide range of clinical phenotypes. There is limited clinical phenotype and molecular correlation for congenital heart defects (CHDs) reported so far for this region primarily because many cases are large deletions, often terminal, and because high-resolution array has not been reported in the evaluation of this group of patients. CHDs are reported in about 60% of patients with 4q deletion syndrome, occurring in the presence or absence of dHAND deletion, implying the existence of additional genes in 4q whose dosage influences cardiac development. We report an 8-month-old patient with a large mid-muscular to outlet ventricular septal defect (VSD), moderate-sized secundum-type atrial septal defect (ASD), thickened, dysplastic pulmonary valve with mild stenosis and moderate pulmonic regurgitation, and patent ductus arteriosus (PDA). Illumina CytoSNP array analysis disclosed a de novo, heterozygous, interstitial deletion of 11.6 Mb of genomic material from the long arm of chromosome 4, at 4q32.3-q34.3 (Chr4:167236114-178816031; hg18). The deleted region affects 37 RefSeq genes (hg18), including two provisional microRNA stemloops. Three genes in this region, namely TLL1 (Tolloid-like-1), HPGD (15-hydroxyprostaglandin dehydrogenase), and HAND2 (Heart and neural crest derivatives-expressed protein 2), are known to be involved in cardiac morphogenesis. This report narrows the critical region responsible for CHDs seen in 4q deletion syndrome.	0
BACKGROUND:Lactic acidosis is a common finding in neonates, in whom mitochondrial dysfunction is often secondary to tissue hypoperfusion, respiratory failure, and/or sepsis. Primary (non-physiological) lactic acidosis is comparatively rare, and suggests the presence of an inborn error of mitochondrial energy metabolism. Optimal medical management and accurate prognostication requires the correct determination of the etiology of lactic acidosis in a given patient. Unfortunately, genetic diagnoses are rare and highly variable for neonates presenting with primary lactic acidosis; individual case reports may offer the most promise for treatment considerations. The mitochondrion is a complex molecular machine incorporating the products of > 1000 distinct nuclear genes. Primary lactic acidoses are therefore characterized by high genetic heterogeneity and a specific genetic diagnosis currently remains out of reach in most cases. Most mitochondriopathies with neonatal onset follow autosomal recessive inheritance and carry a poor prognosis. Here we detail the case of a father and daughter with dominantly-inherited, resolving (i.e. transient) neonatal hyperlactatemia due to complex IV deficiency. We found no other published descriptions of benign transient complex IV deficiency with autosomal dominant inheritance. CASE PRESENTATION:Both individuals presented as neonates with unexplained, marked lactic acidosis suggesting a primary mitochondrial disorder. Within the first weeks of life, elevated blood lactate levels normalized. Their clinical and developmental outcomes were normal. Biochemical studies in the proband showed multiple abnormalities consistent with a complex IV respiratory chain defect. Cultured skin fibroblasts showed an elevated lactate-to-pyruvate ratio, deficient complex IV activity, and normal pyruvate dehydrogenase and pyruvate carboxylase activities. Whole-exome sequencing of the proband and both parents did not identify a causative mutation. CONCLUSION:We conclude that the proband and her father appear to have a dominant form of transient neonatal hyperlactatemia due to heterozygous changes in an as-yet unidentified gene. This transient neonatal complex IV deficiency should be considered in the differential diagnosis of primary neonatal hyperlactatemia; notable clinical features include autosomal-dominant inheritance and an apparently benign postnatal course. This report exemplifies the growing differential diagnosis for neonatal lactic acidosis and highlights the importance of both physician counselling and the use of family history in communicating with parents.	0
BACKGROUND:Neuromuscular disorders (NMDs) comprise a group of heterogeneous genetic diseases with a broad spectrum of overlapping the clinical presentations that makes diagnosis challenging. Notably, the recent introduction of whole-exome sequencing (WES) is introducing rapid changes on the genetic diagnosis of NMDs. We aimed to investigate the diagnostic value of WES for pediatric-onset NMDs. METHODS:We applied integrated diagnostic approach and performed WES in 50 Chinese subjects (30 males, 20 females) with undiagnosed pediatric-onset NMDs despite previous specific tests. The patients were categorized in four subgroups according to phenotyping and investigation findings. Variants on NMDs gene list and open exome analysis for those with initial negative findings were identified. RESULTS:WES identified causative variants in ACTA1 (n = 2), POMT1, COL6A1 (n = 2), MTMR2, LMNA, SELENON, DNM2, TGFB1, MPZ, IGHMBP2, and LAMA2 in 13 patients. Two subjects have variants of uncertain significance (VUSs) in TTN and SCN11A, unlikely to be pathogenic due to incompatible phenotypes. The mean interval time from symptom onset to genetic diagnosis was 10.4 years (range from 1 month to 33 years). The overall diagnostic yield of WES in our cohort was 26%. Open exome analysis was necessary to identify the pathogenic variant in TGFB1 that caused skeletal dysplasia with neuromuscular presentation. CONCLUSION:Our study shows a clear role of WES in the pathway of integrated diagnostic approach to shorten the diagnostic odyssey in patients with rare NMDs.	0
Short anagen syndrome (SAS) is a recently described entity characterized by idiopathic shortening of anagen phase. The condition is poorly described in Indian population. We describe the 1(st) Indian case with clinico-pathological features of a 30-year-old woman diagnosed with SAS. Case was diagnosed on the basis of clinical examination, trichogram, microscopic examination of the hair shaft, histopathologic examination of scalp, and measurement of hair growth rate.	0
We present the case of a 39-year-old male with sectoral chorioretinal atrophy similar to that seen in gyrate atrophy (GA) but with a normal plasma ornithine level. Unlike previously reported cases of GA, he had below-normal plasma taurine concentration. Much remains unknown about the pathophysiologic mechanism underlying gyrate-like chorioretinal atrophy. The concomitant occurrence of GA-like phenotype and hypotaurinemia suggests a possible future avenue for research on this matter.	0
Rett syndrome (RTT) is a pervasive neurodevelopmental disorder associated with mutation in MECP2 gene. Despite a well-defined genetic cause, there is a growing consensus that a metabolic component could play a pivotal role in RTT pathophysiology. Indeed, perturbed redox homeostasis and inflammation, i.e. oxinflammation, with mitochondria dysfunction as the central hub between the two phenomena, appear as possible key contributing factors to RTT pathogenesis and its clinical features. While these RTT-related changes have been widely documented by transcriptomic profiling, proteomics studies supporting these evidences are still limited. Here, using primary dermal fibroblasts from control and patients, we perform a large-scale proteomic analysis that, together with data mining approaches, allow us to carry out the first comprehensive characterization of RTT cellular proteome, showing mainly changes in expression of proteins involved in the mitochondrial network. These findings parallel with an altered expression of key mediators of mitochondrial dynamics and mitophagy associated with abnormal mitochondrial morphology. In conclusion, our proteomic analysis confirms the pathological relevance of mitochondrial dysfunction in RTT pathogenesis and progression.	0
BACKGROUND: The characterizations of primary lymphedemas in different hereditary diseases are often published as case reports. In this study, 17 out of 20 Norweigian adult patients with lymphedema cholestasis syndrome 1 (LCS1)/Aagenaes syndrome were examined. The patients exhibited lymphedema and sporadic cholestasis. Individual clinical variations are described. METHODS AND RESULTS: Lymphedema was classified from Grade I to IV by clinical examinations and ultrasound B-mode scanning. To support the clinical findings, direct segmental multifrequency bioelectrical impedance analysis (DSM-BIA) was included and was compared to healthy matched controls. The lymphedema was similar to other hereditary lymphedemas, with more pronounced fluid retention in the lower extremities. It was generally more extensive, as it also included lymphedema in the arms, face, and trunk. Limited tissue fibrosis was observed, even after long-standing lymphedema. CONCLUSIONS: Approximately one-third of the patients had severe forms of lymphedema in the limbs (grades III and IV) and their conditions required close followup. A more frequent use of compression in the upper extremities is advised.	0
BACKGROUND:Shapiro syndrome is extremely rare and is characterized by the triad of spontaneous periodic hypothermia, hyperhidrosis and agenesis of the corpus callosum, resulting in neurological and psychological disorders. The exact mechanism of this syndrome is unknown and treatment consists of controlling the periodic attacks. This case report describes a case of Shapiro syndrome presenting with ventricular fibrillation (VF) who was treated with dual chamber implantable cardioverter defibrillator (ICD) therapy. CASE SUMMARY:A 45-year-old man, suffering from Shapiro syndrome with frequent hypothermic attacks, was admitted to the emergency department with an out of hospital cardiac arrest caused by VF due to hypothermia. To prevent cardiac death during future hypothermic attacks with VF, the patient was treated with a dual chamber ICD. Within 1 month after ICD implantation the patient had two events of ventricular tachycardia/VF during hypothermia, which were both successfully terminated by an ICD shock. One year after ICD implantation the patient suffered from an uncontrolled urinary tract infection and the patient passed away. Post-mortem interrogation of the ICD did not reveal further episodes of VF and showed a higher supraventricular heartrate in the last days before his death, probably due to a sinus tachycardia driven by the infection. It was concluded that the most likely cause of death was an uncontrolled sepsis. DISCUSSION:The current case showed that ICD therapy can be successful in treating VF episodes in patients with unexpected periods of hypothermia.	0
At present, mostly case-control and retrospective studies have investigated the association between etiologic risk factors and the development of histologic subtypes of renal cell carcinoma (RCC). Therefore, we assessed the heterogeneity between body mass index (BMI), cigarette smoking, alcohol consumption and hypertension across clear-cell RCC (ccRCC) and papillary RCC (pRCC) risk in the prospective Netherlands Cohort Study on diet and cancer. In 1986, 120 852 participants aged 55 to 69 completed a self-administered questionnaire on diet and other risk factors for cancer. Participants were followed up for cancer through record linkage. Tumor histology was assessed through centralized revision by two experienced uropathologists. After 20.3 years of follow-up, 384 histologically verified RCC cases, including 315 ccRCC and 46 pRCC cases and 4144 subcohort members were eligible for case-cohort analysis. Hazard ratios and 95% confidence intervals were estimated by multivariable-adjusted proportional hazards models. Overall, BMI was associated positively with ccRCC risk, but inversely with pRCC risk. Cigarette smoking was associated with an increased ccRCC, but a decreased pRCC risk. Alcohol consumption was inversely associated with both ccRCC and pRCC risk. Hypertension was associated with an increased risk of both ccRCC and pRCC. Statistically significant etiologic heterogeneity was observed for BMI, BMI change since age 20, and smoking duration in current smokers across ccRCC and pRCC risk. In conclusion, we observed potential heterogeneity for BMI, BMI change and smoking duration across ccRCC and pRCC risk.	0
A 6-month-old, female intact terrier mixed breed puppy was presented to the Atlantic Veterinary College cardiology service for evaluation of a subclinical heart murmur. Echocardiography identified severe pulmonic stenosis (PS) and a concurrent left-to-right shunting patent ductus arteriosus (PDA). Correction via minimally invasive transcatheter techniques, including placement of an Amplatz canine duct occluder device and balloon valvuloplasty, repaired the PDA and PS, respectively. The patient recovered uneventfully and continues to show complete PDA occlusion and significant improvement in severity of PS with no clinical signs. This dog had 2 potentially life-threatening congenital heart conditions that were corrected via minimally invasive therapeutic techniques and now has excellent expected long-term prognosis as a result.	0
Sotos syndrome is one of the overgrowth syndromes, and can present with intellectual disability, behavioral problems and tall stature. In some cases, seizures, pectus deformity, cardiac and renal anomalies may be identified. Here we report two Indian children with Sotos syndrome whose initial presentation was macrocephaly and behavioral problems, respectively. The pathogenic variants in NSD1 gene were confirmed by next generation sequencing. The gene variants in the two children, one male and one female; were NSD1: c.2362C>T and NSD1: c.5474dup, respectively, leading to premature termination of protein formation.	0
Primrose syndrome is characterized by variable intellectual deficiency, behavior disorders, facial features with macrocephaly, and a progressive phenotype with hearing loss and ectopic calcifications, distal muscle wasting, and contractures. In 2014, ZBTB20 variants were identified as responsible for this syndrome. Indeed, ZBTB20 plays an important role in cognition, memory, learning processes, and has a transcription repressive effect on numerous genes. A more severe phenotype was discussed in patients with missense single nucleotide variants than in those with large deletions. Here, we report on the clinical and molecular results of 14 patients: 6 carrying ZBTB20 missense SNVs, 1 carrying an early truncating indel, and 7 carrying 3q13.31 deletions, recruited through the AnDDI-Rares network. We compared their phenotypes and reviewed the data of the literature, in order to establish more powerful phenotype-genotype correlations. All 57 patients presented mild-to-severe ID and/or a psychomotor delay. Facial features were similar with macrocephaly, prominent forehead, downslanting palpebral fissures, ptosis, and large ears. Hearing loss was far more frequent in patients with missense SNVs (p = 0.002), ectopic calcification, progressive muscular wasting, and contractures were observed only in patients with missense SNVs (p nonsignificant). Corpus callosum dysgenesis (p = 0.00004), hypothyroidism (p = 0.047), and diabetes were also more frequent in this group. However, the median age was 9.4 years in patients with deletions and truncating variant compared with 15.1 years in those with missense SNVs. Longer follow-up will be necessary to determine whether the phenotype of patients with deletions is also progressive.	0
Gynandroblastoma is an extremely rare sex cord-stromal tumor with both female (granulosa cell tumor) and male (Sertoli-Leydig cell tumor) elements. Juvenile granulosa cell tumors are also very rare and are so named because they usually occur in children and adolescents. A 71-year-old woman with right upper quadrant abdominal pain visited our hospital. Pelvic computed tomography showed a large multilocular cystic mass, suspected to be of ovarian origin. We performed a total abdominal hysterectomy (total abdominal hysterectomy was performed) with bilateral salpingooophorectomy. A 13-cm multilocular cystic mass with serous fluid was observed in her right ovary. Upon microscopic examination, the solid component of the mass showed both Sertoli-Leydig cell and juvenile granulosa cell differentiation, which we diagnosed as gynandroblastoma. Gynandroblastoma with a juvenile granulosa cell tumor component is extremely rare and, until now, only six cases have been reported in the English literature. We report the first gynandroblastoma with a juvenile granulosa cell tumor component diagnosed in an elderly patient, along with a literature review.	0
Nail-patella syndrome (NPS) is a rare disorder characterized by abnormal development of ectodermal and mesodermal tissues. Classically, NPS presents as a triad of nail dysplasia, dysplastic patellae, and bony exostoses of the ilia known as "iliac horns." Apart from dermatological and skeletal abnormalities, patients may also have involvement of ophthalmologic and renal systems. The underlying molecular etiology in NPS is the mutation of LMX1B homeobox gene which results in loss of function of its protein also called LMX1B, a DNA-binding protein belonging to the larger LIM-homeodomain transcription factor family. Normal LMX1B gene and protein function are essential for dorsalization of the vertebrate limb bud, development of anterior eye structures, skull formation, and differentiation and migration of neurons in the central nervous system. We report a case of confirmed NPS presenting with congenital aplasia of the internal carotid artery and believe this is the first report of cerebrovascular developmental abnormality associated with NPS.	0
The amniotic band syndrome is a congenital condition. It is characterized by the presence of fibrous amniotic bands that may entangle or entrap different foetal parts in utero, resulting in deformation, malformation or disruption. We report on a female piglet presenting amniotic band adherences in the right abdominal flank, several body wall defects (gastroschisis, abdominoschisis with omphalocele), severe scoliosis, anomalous umbilical cord with single umbilical artery, anal atresia, anomalous liver and absent gall bladder, hypoplastic genitalia, ankylosis and arthrogryposis in pelvic limbs, and bilateral patellar agenesia. The ethiopatogenia is discussed, as well as the comparative and embryological implications.	0
Neonatal brain sonography is part of routine clinical practice in neonatal intensive care units, but ultrasound imaging of the posterior fossa has gained increasing attention since the burden of perinatal acquired posterior fossa abnormalities and their impact on motor and cognitive neurodevelopmental outcome have been recognized. Although magnetic resonance imaging (MRI) is often superior, posterior fossa abnormalities can be suspected or detected by optimized cranial ultrasound (CUS) scans, which allow an early and bed-side diagnosis and monitoring through sequential scans over a long period of time. Different ultrasound appearances and injury patterns of posterior fossa abnormalities are described according to gestational age at birth and characteristics of the pathogenetic insult. The aim of this review article is to describe options to improve posterior fossa sequential CUS image quality, including the use of supplemental acoustic windows, to show standard views and normal ultrasound anatomy of the posterior fossa, and to describe the ultrasound characteristics of acquired posterior fossa lesions in preterm and term infants with effect on long-term outcome. The limitations and pitfalls of CUS and the role of MRI are discussed.	0
Skeletal dysplasias are a diverse group of heritable diseases affecting bone and cartilage growth. Throughout the years, the molecular defect underlying many of the diseases has been identified. These identifications led to novel insights in the mechanisms regulating bone and cartilage growth and homeostasis. One of the pathways that is clearly important during skeletal development and bone homeostasis is the Wingless and int-1 (WNT) signaling pathway. So far, three different WNT signaling pathways have been described, which are all activated by binding of the WNT ligands to the Frizzled (FZD) receptors. In this review, we discuss the skeletal disorders that are included in the latest nosology of skeletal disorders and that are caused by genetic defects involving the WNT signaling pathway. The number of skeletal disorders caused by defects in WNT signaling genes and the clinical phenotype associated with these disorders illustrate the importance of the WNT signaling pathway during skeletal development as well as later on in life to maintain bone mass. The knowledge gained through the identification of the genes underlying these monogenic conditions is used for the identification of novel therapeutic targets. For example, the genes underlying disorders with altered bone mass are all involved in the canonical WNT signaling pathway. Consequently, targeting this pathway is one of the major strategies to increase bone mass in patients with osteoporosis. In addition to increasing the insights in the pathways regulating skeletal development and bone homeostasis, knowledge of rare skeletal dysplasias can also be used to predict possible adverse effects of these novel drug targets. Therefore, this review gives an overview of the skeletal and extra-skeletal phenotype of the different skeletal disorders linked to the WNT signaling pathway.	0
Dystrophic epidermolysis bullosa is a major form of epidermolysis bullosa and may be inherited as an autosomal dominant or recessive trait, with associated mutations in the COL7A1 gene. Here, we describe a consanguineous Pakistani family with four affected individuals suffering from recessive dystrophic epidermolysis bullosa. Exome sequencing of the proband's DNA revealed a homozygous missense variant (c.8038G>A:p.Gly2680Ser) in COL7A1 which cosegregated with disease in the family. The emergence of this particular glycine substitution in patients from diverse ethnic backgrounds such as China, United Kingdom, Poland, Iran, and Pakistan indicates that this variant most likely constitutes a recurrent mutational hotspot in the COL7A1 gene, rather than a germline mutation present at low levels in the general population.	0
OBJECTIVES:To use computer-assisted quantitative measurements of upper airway changes during drug-induced sleep endoscopy (DISE) and to correlate these parameters with disease severities and physiologic changes in patients with obstructive sleep apnea/hypopnea syndrome (OSA). DESIGN:A retrospective study. SETTING:Tertiary academic medical center. PATIENTS AND METHODS:A total of 170 patients who failed continuous positive airway pressure therapy and then underwent upper airway surgery were enrolled. All patients received polysomnography and DISE preoperatively. We used ImageJ 1.48v to obtain maximal and minimal measurements, including cross-sectional areas and anterior-posterior and lateral diameters at 4 anatomic levels (retropalatal, oropharyngeal, retroglossal, and retroepiglottic) under DISE, and then computed the percentage changes. We analyzed the clinical values of DISE changes by computer-assisted analysis in patients with OSA and any correlations between these changes and polysomnography parameters. RESULTS:The percentage changes of upper airway showed significant collapses at all 4 anatomic levels (all P < .0001). We also found that the changes at retropalatal levels were significantly greater and that retroglossal levels were significantly smaller, while the changes of anterior-posterior diameters at retroglossal levels showed a significant positive association with apnea-hypopnea index and desaturation index. However, there were no statistically significant correlations between upper airway changes and obesity. CONCLUSION:Computer-assisted quantitative analysis could evaluate upper airway changes of OSA in an objective way and may help identify the sites of obstruction during DISE more accurately. Upper airway showed multilevel collapse with independent significant changes in patients with OSA, with the retropalatal and retroglossal levels playing important roles in particular.	0
OBJECTIVES: Neural tube defects (NTDs), (including anencephaly, meningomyelocele and encephalocele), are among the most common birth defects, with high associated mortality and morbidity. NTDs occur in 1-5 per 1,000 births, with marked geographic and ethnic variations. However, there are few data concerning the incidence, associated anomalies, treatment and outcome of NTDs in Thailand. The objective of this study is to analyze data on NTD cases from 1990-1999 at Siriraj Hospital, a hospital with 18,000-20,000 deliveries annually. MATERIAL AND METHOD: A retrospective chart review of patients with NTDs who were born at or referred to Siriraj Hospital 1990-1999 was performed. RESULTS: During the 10 year period we examined, there were 115 patients with NTDs treated in the Department of Pediatrics as well as in other Departments at Siriraj Hospital. The incidence of NTD is 0.67 per 1,000 births. The sex distribution was equal among NTD cases, 55 (48%) females, 59 (51%) males and one (1%) unidentified sex. Isolated NTDs accounted for 105 (91%) cases, and 10 (8.7%) had at least 1 other structural anomaly such as cleft lip/palate, imperforate anus, amniotic band sequence, or ambiguous genitalia. Among all NTD cases, there were 55 (48%) with myelomeningocele, 45 (39%) with anencephaly, and 14 (12%) with encephalocele. Seventeen (15%) cases died; among these, 7 (41% of deaths) died in utero, 8 (47% of deaths) died in the early neonatal period, and 2 (12%) died after 1 year of age. Regarding treatment, 95 surgical corrections, 47 excisions and repairs, 45 excisions and VP shunts, 1 laminectomy and 2 club feet corrections were performed. CONCLUSIONS: In this hospital-based study of 115 patients with NTD, we found an incidence of 0.67/1000 births; however, as this was a hospital-based study, the community incidence is likely higher. Most cases were isolated NTDs, and almost half of NTDs were meningomyelocele. There was a high rate of mortality. Further studies are warranted to better elucidate the health burden from NTDs in Thailand. Public health interventions aimed at increasing the periconceptional consumption of folic acid should be implemented or enhanced to reduce the incidence of NTDs in Thailand.	1
Cold-induced sweating syndrome (CISS) is a rare autosomal recessive disease due to mutation in the Cytokine receptor-like factor 1 (CRLF1). The characteristic symptom of CISS is the tendency to sweat profusely especially in the upper body and hands when the patient is exposed to cold temperature. We sought to first report the findings of autonomic reflex screen in a case of CISS type 1 with Cytokine receptor-like factor 1 mutation. Valsalva morphology, Valsalva ratio, and heart rate response to deep breathing were normal for the patient's age. Quantitative sudomotor axon reflex test showed nonlength dependent decrease in the sweat volume. Tilt table revealed evidence of reflex (vasovagal) "syncope," however, the patient was asymptomatic without loss of consciousness.	0
Monilethrix is a rare hereditary disorder affecting hair resulting in hair fragility and alopecia. We report three patients of monilethrix who presented with complaints of sparse and brittle hair from early childhood. All three patients had multiple discrete hyperkeratotic papules over the scalp. Dermoscopy revealed beaded appearance of hair with the presence of elliptical nodes and intermittent constrictions on the hair shafts as well as broken hairs, which were confirmed with routine microscopic examination of hair. Dermoscopy helps in easier and faster diagnosis of monilethrix.	0
We present three children who presented with papules and plaques over the knuckles, mimicking Gottron's papules of juvenile dermatomyositis, as well as subcutaneous nodules over the joints of the extremities that were initially thought to represent calcinosis cutis. However, thorough clinical and laboratory evaluation, as well as imaging, failed to support this diagnosis. Skin biopsies were consistent with a diagnosis of subcutaneous granuloma annulare. This unique phenotype of granuloma annulare should be recognized in order to prevent erroneous diagnosis and treatment.	0
Microcephalic primordial dwarfism (MPD) is a group of rare single-gene disorders characterized by the extreme reduction in brain and body size from early development onwards. Proteins encoded by MPD-associated genes play important roles in fundamental cellular processes, notably genome replication and repair. Here we report the identification of four MPD individuals with biallelic variants in DNA2, which encodes an adenosine triphosphate (ATP)-dependent helicase/nuclease involved in DNA replication and repair. We demonstrate that the two intronic variants (c.1764-38_1764-37ins(53) and c.74+4A>C) found in these individuals substantially impair DNA2 transcript splicing. Additionally, we identify a missense variant (c.1963A>G), affecting a residue of the ATP-dependent helicase domain that is highly conserved between humans and yeast, with the resulting substitution (p.Thr655Ala) predicted to directly impact ATP/ADP (adenosine diphosphate) binding by DNA2. Our findings support the pathogenicity of these variants as biallelic hypomorphic mutations, establishing DNA2 as an MPD disease gene.	0
An unusual case of a post operative wound infection involving Flavimonas oryzihabitans is described. This organism is rarely isolated from human sources. It can cause infections in patients having continuous ambulatory peritoneal dialysis. Our patient developed a wound infection 2 months after femoro-popliteal bypass grafting. The source of the organism was unknown.	0
INTRODUCTION:The Pierre-Robin sequence (PRS) is a pattern of congenital facial abnormalities comprising micrognathia, glossoptosis, and airway obstruction. Associated spinal pathologies have rarely been reported with PRS. METHODS:We explore the molecular genetic basis of this association through a systematic review of spinal disease in patients with PRS. We also present an illustrative case of a PRS patient with tethered cord in the setting of chromosome 10q terminal deletion. RESULTS:Our systematic literature review of spinal disease in patients with PRS revealed several patterns in the underlying genetic syndromes causing these conditions to co-occur. These principles are illustrated in the case of a 6-month-old female with PRS and a 14.34-Mb terminal deletion of chromosome 10q, who was found to have a sacral dimple during a routine outpatient checkup. Magnetic resonance imaging of the spine revealed a lumbar syrinx associated with tethered spinal cord. Surgical de-tethering was undertaken, with subsequent improvement in motor function and decrease in the size of the syrinx. The deletion of chromosome 10q in our patient had not previously been described in association with tethered cord or PRS. CONCLUSION:Spinal pathologies are understudied contributors to disease burden in patients with PRS. The range of predisposing syndromes and mutations in patients with both PRS and spinal disorders remains poorly characterized but may be more defined than previously conceived. Clinical screening is most critical during neonatal and adolescent developmental periods with continued neurological assessment. This study emphasizes the need for early genetic testing and counseling in this patient population, in parallel with research efforts to develop molecular classifications to guide clinical management.	0
Osteopetrosis is a heritable bone condition featuring increased bone density due to defective osteoclastic bone resorption. Exome sequencing and Sanger sequencing were conducted in Han Chinese family members, some of whom had typical osteopetrosis, and a novel missense variant c.2350A>T (p.R784W) in the chloride channel 7 gene (CLCN7) was identified. This variant cosegregated with the disorder in the family but was not observed in 800 controls. The data indicate that exome sequencing is a powerful and effective molecular diagnostic tool for detecting mutations in osteopetrosis, which is a genetically and clinically heterogeneous disorder. This discovery broadens the CLCN7 gene mutation spectrum and has important implications for clinical therapeutic regimen decisions, prognosis evaluations, and antenatal diagnoses.	0
A canine rabies epidemic started in early 2015 in Arequipa, Peru and the rabies virus continues to circulate in the dog population. Some city residents who suffer dog bites do not seek care or do not complete indicated post-exposure prophylaxis (PEP) regimens, increasing the risk of human rabies. The objectives of our study are to qualitatively assess knowledge about rabies, and preventive practices, such as rabies vaccine administration, following a dog bite. We conduct eight focus group discussions in peri-urban and urban communities with 70 total participants. In our results, we observe low awareness of rabies severity and fatality, and different practices following a dog bite, depending on the community type: for example, whereas participants in the urban communities report cleaning the wound with hydrogen peroxide rather than soap and water, participants in peri-urban areas cover the wound with herbs and hair from the dog that bit them. Misconceptions about rabies vaccines and mistreatment at health centers also commonly prevent initiating or completing PEP. We identify important behavioral and structural barriers and knowledge gaps that limit evidence-based preventive strategies against rabies and may threaten successful prevention of dog-mediated human rabies in this setting.	0
INTRODUCTION:The Pierre-Robin sequence (PRS) is a pattern of congenital facial abnormalities comprising micrognathia, glossoptosis, and airway obstruction. Associated spinal pathologies have rarely been reported with PRS. METHODS:We explore the molecular genetic basis of this association through a systematic review of spinal disease in patients with PRS. We also present an illustrative case of a PRS patient with tethered cord in the setting of chromosome 10q terminal deletion. RESULTS:Our systematic literature review of spinal disease in patients with PRS revealed several patterns in the underlying genetic syndromes causing these conditions to co-occur. These principles are illustrated in the case of a 6-month-old female with PRS and a 14.34-Mb terminal deletion of chromosome 10q, who was found to have a sacral dimple during a routine outpatient checkup. Magnetic resonance imaging of the spine revealed a lumbar syrinx associated with tethered spinal cord. Surgical de-tethering was undertaken, with subsequent improvement in motor function and decrease in the size of the syrinx. The deletion of chromosome 10q in our patient had not previously been described in association with tethered cord or PRS. CONCLUSION:Spinal pathologies are understudied contributors to disease burden in patients with PRS. The range of predisposing syndromes and mutations in patients with both PRS and spinal disorders remains poorly characterized but may be more defined than previously conceived. Clinical screening is most critical during neonatal and adolescent developmental periods with continued neurological assessment. This study emphasizes the need for early genetic testing and counseling in this patient population, in parallel with research efforts to develop molecular classifications to guide clinical management.	0
Malignant SMARCB1/INI1-deficient extrarenal rhabdoid tumors are aggressive tumors that are extremely rare in adults. A 56-year-old male presented with the chief complaints of unilateral lower abdominal and pelvic pain. He underwent urgent surgical intervention and mass resection with tissue sampling. After pathology confirmed the diagnosis, systemic chemotherapy with vincristine, doxorubicin plus ifosfamide, and mesna was administered. Following treatment, he experienced a durable and long-lasting response to therapy for this aggressive and rare soft tissue sarcoma. To date, the patient remains in complete remission following the cessation of chemotherapy. Malignant SMARCB1/INI1-deficient extrarenal rhabdoid tumors are aggressive neoplasms that are extremely rare in adults. We report a rare case of such a tumor and review the literature for its molecular, clinical, and imaging features.	0
Fowlpox (FP) is a common epitheliotropic disease in chickens that is usually controlled by live attenuated vaccines. However, there have been some reports of outbreaks of FP in recent years, even in vaccinated flocks, presenting as atypical lesions and feathering abnormalities in chickens. These findings can be associated with fowlpox virus (FPV) with the reticuloendotheliosis virus (REV) integrated into its genome. In the present study, outbreaks of atypical FP were explored in vaccinated commercial laying hen flocks to determine the nature of the causative agent by histopathologic and molecular approaches. FPV and REV were detected and classified into subclade A1 of the genus Avipoxvirus and subtype 3 of REV (REV3), respectively. Additionally, heterogeneous populations of FPV with partial (containing only a remnant long terminal repeat-LTR) or total (all functional genes) integration of REV were identified by heterologous PCRs and detected considering reference integration sites. These results indicate the mechanism of chimeric genome FPV-REV associated with outbreaks and atypical clinicopathological manifestations in commercial laying hens for the first time in Brazil and in South America. In addition, this study demonstrates the emergence of REV integrated in the FPV genome in Brazilian chicken flocks.	0
The outer and inner dynein arms (ODAs and IDAs) are composed of multiple subunits including dynein heavy chains possessing a motor domain. These complex structures are preassembled in the cytoplasm before being transported to the cilia. The molecular mechanism(s) controlling dynein arms' preassembly is poorly understood. Recent evidence suggests that canonical R2TP complex, an Hsp-90 co-chaperone, in cooperation with dynein axonemal assembly factors (DNAAFs), plays a crucial role in the preassembly of ODAs and IDAs. Here, we have summarized recent data concerning the identification of novel chaperone complexes and their role in dynein arms' preassembly and their association with primary cilia dyskinesia (PCD), a human genetic disorder.	0
The extracellular matrix (ECM) is a complex network of proteins and proteoglycans secreted by keratinocytes, fibroblasts and immune cells. The function of the skin ECM has expanded from being a scaffold that provides structural integrity, to a more dynamic entity that is constantly remodeled to maintain tissue homeostasis. The ECM functions as ligands for cell surface receptors such as integrins, dystroglycans, and toll-like receptors (TLRs) and regulate cellular signaling and immune cell dynamics. The ECM also acts as a sink for growth factors and cytokines, providing critical cues during epithelial morphogenesis. Dysregulation in the organization and deposition of ECMs lead to a plethora of pathophysiological conditions that are exacerbated by aberrant ECM-immune cell interactions. In this review, we focus on the interplay between ECM and immune cells in the context of skin diseases and also discuss state of the art therapies that target the key molecular players involved.	0
The type 2 lysine methyltransferases KMT2C and KMT2D are large, enzymatically active scaffold proteins that form the core of nuclear regulatory structures known as KMT2C/D COMPASS complexes (complex of proteins associating with Set1). These evolutionarily conserved proteins regulate DNA promoter and enhancer elements, modulating the activity of diverse cell types critical for embryonic morphogenesis, central nervous system development, and post-natal survival. KMT2C/D COMPASS complexes and their binding partners enhance active gene expression of specific loci via the targeted modification of histone-3 tail residues, in general promoting active euchromatic conformations. Over the last 20 years, mutations in five key COMPASS complex genes have been linked to three human congenital syndromes: Kabuki syndrome (type 1 [KMT2D] and 2 [KDM6A]), Rubinstein-Taybi syndrome (type 1 [CBP] and 2 [EP300]), and Kleefstra syndrome type 2 (KMT2C). Here, we review the composition and biochemical function of the KMT2 complexes. The specific cellular and embryonic roles of the KMT2C/D COMPASS complex are highlight with a focus on clinically relevant mechanisms sensitive to haploinsufficiency. The phenotypic similarities and differences between the members of this new family of disorders are outlined and emerging therapeutic strategies are detailed.	0
Chromosomal rearrangements, such as duplications/deletions, can lead to a variety of genetic disorders. Herein, we reported a prenatal case with right aortic arch and aberrant left subclavian artery, consisting of a complex chromosomal copy number variations. Routine cytogenetic analysis described the chromosomal karyotype as 46,XY, add (2)(q37) for the fetus. However, the chromosomal microarray analysis (CMA) identified a 22.4 Mb duplication in chromosome 4p16.3p15.2, a 3.96 Mb microduplication in 12p11.1q11, and a 1.68 Mb microdeletion in Xp22.31. Fluorescence in situ hybridization (FISH) using a chromosome 4 painting probe was found to hybridize to the terminal of chromosome 2q on the fetus, thus confirming that the extra genetic materials of chromosome 2 was actually trisomy 4p detected through CMA. Meanwhile, the parental karyotypes were normal, which proved that the add (2) was de novo for fetus. The duplication of Wolf-Hirschhorn syndrome critical region (WHSCR) and X-linked recessive ichthyosis associated with Xp22.31 deletion separately were considered potentially pathogenic causes although other abnormalities involving these syndromes were not observed. For prenatal cases, the combined utilization of ultrasonography, traditional cytogenetic, and molecular diagnosis technology will enhance better diagnostic benefits, offer more detailed genetic counselling, and assess the prognosis of the fetuses.	0
The most common cardiomyopathies often present to primary care physicians with similar symptoms, despite the fact that they involve a variety of phenotypes and etiologies (1). Many have signs and symptoms common in heart failure, such as reduced ejection fraction, peripheral edema, fatigue, orthopnea, exertion dyspnea, paroxysmal nocturnal dyspnea, presyncope, syncope and cardiac ischemia (1). In all cardiomyopathies, the cardiac muscle (myocardium) may be structurally and/or functionally impaired. They can be classified as hypertrophic, dilated, left-ventricular non compaction, restrictive and arrhythmogenic right ventricular cardiomyopathies.	0
BACKGROUND:The association of atrioventricular septal defect and transposition of the great arteries is very rare. As a rule, these patients have unbalanced ventricles. However, there have been no studies describing the results of single-ventricle palliation in these children. METHODS:All children who underwent surgery with a diagnosis of atrioventricular septal defect and transposition of the great arteries were included in the study. Data were obtained from medical records. RESULTS:A total of 38 patients with atrioventricular septal defect and transposition of the great arteries underwent single-ventricle palliation at the study institution between 1971 and 2016. The mean follow-up was 12.4 years (median: 14.6 years, range 2-43.3 years). Most children had unbalanced atrioventricular septal defect (94.7%, 36/38). Survival was 67.6% (95% confidence interval [CI]: 50.0-80.2%) at 10 years and 57.8% (95% CI: 38.0-73.4%) at 20 years. By 10 years, 58.6% (95% CI: 40.8-72.7%) had progressed to Fontan completion, while 32.5% (95% CI: 18.2-47.6%) had died. In patients achieving Fontan completion, 20-year event-free survival was 73.3% (95% CI: 34.8-91.3%), while 5.0% (95% CI: 0.4-20.5%) had undergone cardiac transplantation and 21.7% (95% CI: 3.2-50.8%) had undergone takedown of the Fontan circulation. Freedom from atrioventricular valve surgery was 57.0% (95% CI: 37.2-72.7%) at 10 and 20 years. CONCLUSIONS:The association of atrioventricular septal defect and transposition of the great arteries is very rare, and most of these children have unbalanced ventricles. Single-ventricle palliation results in 25-year overall survival of 50%. However, in patients, who had Fontan completion, survival was 75% at 25 years after Fontan operation.	0
Köhler disease is a childhood condition of pain and swelling of the medial midfoot with associated osteochondrosis or avascular necrosis of the tarsal navicular. The age at presentation is between 2 and 10 years, with boys more likely to be affected than girls. Radiographs show increased sclerosis and sometimes flattening and fragmentation of the navicular. Long-term outcomes for Köhler disease are favorable regardless of the type of treatment, although a short period of immobilization with a short leg walking cast may reduce the duration of symptoms.	0
Hereditary hearing loss is one of the most common sensory disabilities worldwide. Mutation of POU domain class 4 transcription factor 3 (POU4F3) is considered the pathogenic cause of autosomal dominant nonsyndromic hearing loss (ADNSHL), designated as autosomal dominant nonsyndromic deafness 15. In this study, four novel variants in POU4F3, c.696G>T (p.Glu232Asp), c.325C>T (p.His109Tyr), c.635T>C (p.Leu212Pro), and c.183delG (p.Ala62Argfs∗22), were identified in four different Chinese families with ADNSHL by targeted next-generation sequencing and Sanger sequencing. Based on the American College of Medical Genetics and Genomics guidelines, c.183delG (p.Ala62Argfs∗22) is classified as a pathogenic variant, c.696G>T (p.Glu232Asp) and c.635T>C (p.Leu212Pro) are classified as likely pathogenic variants, and c.325C>T (p.His109Tyr) is classified as a variant of uncertain significance. Based on previous reports and the results of this study, we speculated that POU4F3 pathogenic variants are significant contributors to ADNSHL in the East Asian population. Therefore, screening of POU4F3 should be a routine examination for the diagnosis of hereditary hearing loss.	0
Homozygous and compound heterozygous mutations in GNB5 gene have been associated with a wide spectrum of clinical presentations, ranging from neurodevelopmental issues with or without cardiac arrhythmia (LADCI) to severe developmental delay with epileptic encephalopathy, retinal dystrophy, and heart rhythm abnormalities (IDDCA). While missense or missense/non-sense mutations usually lead to milder form, the biallelic loss of function of GNB5 gene causes the severe multisystemic IDDCA phenotype. So far, only 27 patients have been described with GNB5-associated disease. We report the first case of a patient carrying a homozygous 15q21.2 microdeletion, encompassing GNB5 and the two contiguous genes BCL2L10 and MYO5C. The clinical features of the child are consistent with the severe IDDCA phenotype, thus confirming the GNB5 loss-of-function mechanism in determining such presentation of the disease.	0
Autosomal recessive renal tubular dysgenesis (ARRTD) is a rare and lethal disorder that causes stillbirth or early neonatal death. Most of the reported cases are diagnosed postnatally by a histopathological hallmark of the absence or paucity of differentiated proximal tubules in kidneys. Prenatal diagnosis of ARRTD is challenging because only a few fetal features (e.g., oligohydramnios/anhydramnios, anuria) are associated with this condition. In this study, we report a fetus with ARRTD, which showed anhydramnios and invisible urinary bladder since the second trimester, followed by growth restriction and reversed end diastolic flow in the middle cerebral artery (MCA-REDF). No morphological anomaly was detected on the fetal kidneys during an ultrasound scan. The baby died of refractory hypotension the day after their birth. Genetic analysis of genes that are involved in the renin-angiotensin-aldosterone system (RAAS), which are the known genetic causes of ARRTD, identified a novel, biparental-origin homozygous c.857-619_1269+243delinsTTGCCTTGC mutation in the AGT gene. The mutation is considered as pathogenic because it is cosegregated with ARRTD and detected in other unrelated ARRTD families. Our findings link the fetal ultrasound manifestations to the ARRTD, highlighting clues that are useful for prenatal diagnosis, which warrants confirmatory genotyping of the RAAS genes including oligohydramnios/anhydramnios, anuria (absent filling of a fetal urinary bladder), MCA-REDF, and a morphologically normal kidney.	0
Pontocerebellar hypoplasia (PCH) is a diverse group of autosomal recessive genetic conditions presenting with hypoplastic changes in the brainstem, cerebellum, and spinal cord. It clinically manifests with neurological symptoms, respiratory failure, and often in a combination with other malformations of the internal organs and musculoskeletal system. In this report, we present an autopsy case report of a two-month-old female patient with blood-relative parents. The patient presented clinically with neonatal-onset respiratory failure, mild neurological symptoms, facial dysmorphism, and developmental delay. On autopsy, the cerebellum and brainstem were severely hypoplastic, and the diagnosis of PCH was established grossly. The central nervous system (CNS) revealed specific hypoplastic changes in the structures, with a decreased neuronal count, stratification disturbances of the cortex of the cerebellum, and cellular misarrangement. The morphological findings in the CNS and their associated parenchymal organ changes, even in the absence of a genetic test, were specific enough to identify PCH type 1B as the main condition.	0
INTRODUCTION AND OBJECTIVES:Although pulmonary valve stenosis (PVS) is considered a low risk congenital heart disease, there have been reports of complications and the need for reintervention throughout follow-up. The aims of this study were to evaluate the long-term outcome of repaired PVS and to identify predictors of cardiovascular complications and reintervention. METHODS:We studied 158 adult patients with repaired PVS (repair procedures performed from 1957 to 2010) receiving active follow-up in a tertiary referral center. RESULTS:A total of 95 patients (60%) received surgical treatment, and 63 patients (40%) received percutaneous pulmonary balloon valvuloplasty. At the end of follow-up (27 years, IQR, 20-33 years), most patients (n=134, 84.8%) were in New York Heart Association functional class I, but 61 patients (38.6%) required a reintervention, mainly pulmonary valve replacement (17.7%, n=28), and 19 patients (12%) had at least one cardiovascular complication: 13 (8.2%) supraventricular arrhythmias, 6 (3.8%) heart failure, 5 (3.2%) stroke, 1 (0.6%) death, 1 (0.6%) thromboembolism, and 1 (0.6%) ventricular arrhythmia. Multivariate analysis showed that age at PVS repair (HR, 1.08; 95%CI, 1.04-1.12; P <.001) and the presence of cyanosis before PVS repair (HR, 5.23; 95%CI, 1.99-13.78; P=.001) were independent predictors for cardiovascular complications. CONCLUSIONS:Good long-term outcome can be expected after PVS repair, but complications and the need for reintervention may appear. Older age and the presence of cyanosis at PVS repair emerged as predictors of cardiovascular complications and identified a population that may merit stricter control.	0
A second case of a novel rabies variant described once in a capuchin monkey from Mato Grosso, Brazil, was discovered in a rabid wild kinkajou from the same region, indicating a public health risk following exposure to either of the two animals.	0
PURPOSE OF REVIEW:Tyrosine kinase inhibitors (TKIs) are the backbone for advanced gastrointestinal stromal tumor (GIST) treatment. The increasing knowledge concerning the structure and the changing conformational status because of some mutations in KIT and PDGFRα, allowed the development of new efficient compounds, with the main goal to overcome resistance in GIST. This review summarizes the latest developments in the treatment of GIST patients. RECENT FINDINGS:Amongst the several TKIs currently being studied in GIST, ripretinib, avapritinib and crenolanib had shown promising potent activity in preclinical studies and clinical trials. Ripretinib is a type II inhibitor that exerts its main action in the switch pocket of the activation loop, by mimicking the inhibition exerted by the regulatory region in this domain. Ripretinib is considered the new standard in the fourth line in advanced GIST. Avapritinib is a type I inhibitor synthesized to exerts its activity in the active conformation of the activation loop of KIT and PDFGRα. The relevant activity reported with avapritinib in patients carrying the D842 v mutation represents, for first time, an active therapeutic option in this resistant mutant. Crenolanib is a type I selective inhibitor of PDGFRα-resistant mutants, mainly D842 V, which is currently under clinical trial. SUMMARY:New potent TKIs are being approved, adding value to the already three registered drugs. Other agents, such as MEK inhibitors, immunotherapy and TRK-targeted therapy are potential new options in specific subsets of GIST patients.	0
Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506∗ and p.Glu496∗ were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.	0
INTRODUCTION:Determining the risk of recurrence of primary spontaneous pneumothorax is challenging. The objective of this study was to develop a risk assessment model to predict the probability of recurrence in patients with spontaneous pneumothorax. METHODS:A retrospective study was performed of all episodes of pneumothorax diagnosed in the last 12 years in a hospital, in patients not initially submitted to surgery. Logistic regression was used to estimate the probability of recurrence. Based on a set of variables, a predictive model was built with its corresponding ROC curve to determine its discrimination power and diagnostic precision. RESULTS:Of the 253 patients included, 128 (50.6%) experienced recurrence (37% within the first year). Recurrence was detected within 110 days in 25% of patients. The median of time to recurrence for the whole population was 1120 days. The presence of blebs/bullae was found to be a risk factor of recurrence (OR: 5.34; 95% CI: 2.81-10.23; p=0.000), whereas chest drainage exerted protective effect (OR: 0.19; 95% CI: 0.08-0.40; p=0.000). The variables included in the regression model constructed were hemoglobin and leukocyte count in blood, treatment received, and presence of blebs/bullae, with a fair discriminative power to predict recurrence [AUC=0.778 (95% CI: 0.721-0.835)]. CONCLUSION:The overall recurrence rate was high and was associated with the presence of blebs/bullae, failure to perform an active intervention (chest drainage) and low levels of hemoglobin and leukocytes in blood. Recurrence rarely occurs later than three years after the first episode. Once validated, this precision model could be useful to guide therapeutic decisions.	0
We describe a 29-year-old Para 1 post-Emergency Lower Segment Caesarean Section (EMLSCS) for fetal distress and Preterm Rupture of the Membrane (PROM) referred by the Obstetric team for persistent bradycardia. She had the typical features of Albright's Hereditary Osteodystrophy (AHO). The laboratory investigation revealed hypocalcemia, hyperphosphatemia with a high Parathyroid hormone (PTH) level and low free Thyroxine 4 (fT4) with high Thyroid Stimulating Hormone (TSH). The patient was diagnosed with Pseudohypoparathyroidism (PHP) Type 1A associated with TSH resistance based on the somatic features of AHO present as well as biochemical and radiological abnormalities.	0
EGR2 (Early Growth Response 2) is one of the most important transcription factors involved in myelination in the peripheral nervous system. EGR2 mutations typically cause different forms of demyelinating neuropathy, that is, Charcot-Marie-Tooth type 1D (CMT1D), Dejerine-Sottas Syndrome (DSS), and Congenital Hypomyelinating Neuropathy (CHN). However, the EGR2 gene has been recently associated with an axonal phenotype (CMT2) in a large CMT family. Here, we report another CMT family exhibiting an axonal phenotype associated with a missense change (c.1235A>G, p.E412G) in the EGR2 gene. Neurological evaluation of five affected members of the family showed a classical CMT phenotype including distal muscle atrophy and weakness, absence of deep tendon reflexes, pes cavus, and scoliosis. Electrophysiological examination was consistent with a motor-sensory axonal neuropathy. Sural nerve biopsy performed in one patient showed a loss of myelinated and unmyelinated nerve fibers without de-remyelinating signs and onion bulbs. This study confirms the phenotypical heterogeneity of EGR2-related neuropathy, indicating a role for EGR2 in primary axonal degeneration.	0
Retinal development is under the coordinated control of overlapping networks of signaling pathways and transcription factors. The paper was conceived as a review of the data and ideas that have been formed to date on homeobox genes mutations that lead to the disruption of eye organogenesis and result in inherited eye/retinal diseases. Many of these diseases are part of the same clinical spectrum and have high genetic heterogeneity with already identified associated genes. We summarize the known key regulators of eye development, with a focus on the homeobox genes associated with monogenic eye diseases showing retinal manifestations. Recent advances in the field of genetics and high-throughput next-generation sequencing technologies, including single-cell transcriptome analysis have allowed for deepening of knowledge of the genetic basis of inherited retinal diseases (IRDs), as well as improve their diagnostics. We highlight some promising avenues of research involving molecular-genetic and cell-technology approaches that can be effective for IRDs therapy. The most promising neuroprotective strategies are aimed at mobilizing the endogenous cellular reserve of the retina.	0
Rabson-Mendenhall syndrome (RMS) is a rare genetic disorder characterized by growth retardation, dysmorphisms, lack of subcutaneous fat, acanthosis nigricans, enlarged genitalia, hirsutism, dysplastic dentition, coarse facial features, abnormal glucose homeostasis, hyperinsulinemia and pineal hyperplasia. Herein, we describe a 13-year-old girl with physical features of RMS who presented to us on account of acanthosis nigricans.	0
Purpose:To compare the efficacies of mirabegron 50 mg addition after alpha-adrenoreceptor blocker in terms of reducing storage symptoms in patients with BPH. Materials and Methods:Fifty-eight patients that had been taking alpha-adrenoreceptor blocker for more than 8 weeks, but had an OABSS of greater than 3 points, were initially enrolled. One group added any alpha-adrenoreceptor blocker with mirabegron 50 mg (n=39; the mirabegron group) and the other group received alpha-adrenoreceptor blocker only (n=19; the control group) for 8 weeks. Results:In the control group, mean total IPSS decreased from 15.7 to 13.1 (p=0.298) and in mirabegron group, mean total IPSS decreased from 19.4 to 16.5 (p=0.024). Mean storage symptom scores reduced in the control and mirabegron groups from 8.5 to 7.9 (p=0.584) and from 9.1 to 7.6 (p=0.015), respectively, and mean QoL scores from 3.7 to 3.1 (p=0.052) and 3.6 to 3.2 (p=0.027), respectively. Mean overall OABSS in the control and mirabegron groups reduced from 8.4 to 7.2 (p=0.173) and from 8.8 to 7.3, respectively (p=0.005); mean OABSS Q3 from 3.6 to 2.9 (p=0.073) and from 3.5 to 2.7 (p=0.002), respectively; and mean OABSS Q4 from 2.4 to 2.0 (p=0.306) and from 2.7 to 2.0 (p=0.016), respectively. The change of mean Qmax and PVR was insignificant in 2 groups. Conclusions:IPSS total scores, storage symptom scores, QoL, overall OABSS, OABSS Q3 and Q4 were more improved significantly by alpha-adrenoreceptor blocker with mirabegron 50 mg in BPH patients with persistent overactive symptoms. Mirabegron 50 mg addition is considered to patients with persistent storage symptoms after alpha-adrenoreceptor blocker.	0
The International Mouse Phenotyping Consortium (IMPC) continues to expand the catalogue of mammalian gene function by conducting genome and phenome-wide phenotyping on knockout mouse lines. The extensive and standardized phenotype screens allow the identification of new potential models for human disease through cross-species comparison by computing the similarity between the phenotypes observed in the mutant mice and the human phenotypes associated to their orthologous loci in Mendelian disease. Here, we present an update on the novel disease models available from the most recent data release (DR10.0), with 5861 mouse genes fully or partially phenotyped and a total number of 69,982 phenotype calls reported. With approximately one-third of human Mendelian genes with orthologous null mouse phenotypes described, the range of available models relevant for human diseases keeps increasing. Among the breadth of new data, we identify previously uncharacterized disease genes in the mouse and additional phenotypes for genes with existing mutant lines mimicking the associated disorder. The automated and unbiased discovery of relevant models for all types of rare diseases implemented by the IMPC constitutes a powerful tool for human genetics and precision medicine.	0
BACKGROUND: Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by the presence of anti-mitocondrial autoantibodies (AMA) which has an essential role also for diagnosis. In addition, also some anti-nuclear antibodies (ANA) have been shown to be highly specific PBC. The purpose of this study was to assess the prevalence of PBC among the adults referring hospital for annual health check-up in Southern China by screening sera for PBC-specific autoantibodies. METHODS: AMA and ANA were screened in 8,126 adults (mean age 44 ± 15 years, 48% females) by indirect immunofluorenscence (IIF). Positive sera were tested by ELISA/immunoblotting for AMA-M2, anti-sp100 and anti-gp210. A diagnosis of PBC was re-assessed six months after the initial testing. RESULTS: Out of 8,126 individuals 35 were positive for AMA and 79 positive for ANA. Nineteen, 4, and 3 of the subjects positive for AMA and/or ANA showed reactivity for AMA-M2, anti-sp100 or gp210, respectively, further tested with ELISA/immunoblotting. Fourteen in the 39 individuals positive for AMA at IIF, AMA-M2, anti-gp210, or anti-sp100 had abnormal cholestatic liver functional indices. One definite and 3 probable PBC diagnosis could be made in 4 cases including 3 females and 1 male after half a year. CONCLUSIONS: We found a point prevalence rate of PBC among Southern Chinese adults attending for yearly health check-up of 492 cases per million (95% CI, 128 to 1,093) and 1,558 cases per million (95% CI, 294 to 3,815) for women over 40, a finding similar to prevalence reported in other geographical areas.	1
Langerhans cell sarcoma (LCS) is rare and aggressive and patients have an overall survival rate of less than 50%. We present a 62-year old man with a history of superficial spreading melanoma of the upper back with sentinel lymph node metastasis, Langerhans cell histiocytosis and LCS. The patient presented with erythematous papules and scaly areas on his face, neck, arms, chest, abdomen, and legs. A skin biopsy revealed a proliferation of large neoplastic cells involving the dermis with epidermotropism. These cells had atypical bean-shaped nuclei, with ample cytoplasm and abundant mitotic figures including atypical forms. Immunohistochemical studies showed the tumor to be diffusely positive for CD1a, S100 protein, and langerin (CD207) and negative for melanocytic markers. Some tumor cells were positive for cyclin D1. A diagnosis of LCS involving the skin was established. The present is a very unusual case of LCS showing epidermotropism. The patient's history of metastatic melanoma posed additional challenges for diagnosis, underlying the need of immunophenotyping in these cases. Consensus for optimal standard therapy has not been established in LCS and thus, early recognition is important since these neoplasms tend to recur and metastasize. LCS in skin is discussed and published cases are comprehensively reviewed. This article is protected by copyright. All rights reserved.	0
Recent molecular genetic studies have revealed that Schimmelpenning-Feuerstein-Mims syndrome (SFMS), which presents as sebaceous nevi, is a mosaic RASopathy caused by postzygotic somatic activating mutations in HRAS, NRAS, or KRAS Some patients with SFMS also have hypophosphatemic rickets, called cutaneous skeletal hypophosphatemia syndrome (CSHS). We here report a pediatric case of biopsy-proven CSHS with mosaic mutation in the HRAS gene. A girl who showed extensive nevus sebaceous since birth had suffered progressive lower extremity deformity since the age of 5 years. We found hypophosphatemic rickets in laboratory and radiological studies. From the molecular study with skin tissue with nevus sebaceous, we identified a heterozygous mutation, c.182A>G (p.Gln61Arg), in exon 3 of HRAS by Sanger sequencing. However, we did not find this mutation in the peripheral blood and unaffected tissue, which demonstrated mosaic distribution of the mutation throughout the body. Given the rarity of the previous genetically proven CSHS cases, accumulation of more cases is needed to establish the role of Ras activation in skeletal manifestations in CSHS, which is likely due to excessive production of fibroblast growth factor 23.	0
: Heparin-induced thrombocytopenia (HIT) syndrome is an immune-mediated disorder producing thrombocytopenia and thrombosis, with or without prior exposure to heparin. Although avoidance of heparin products and nonheparin anticoagulants are used, immune-based therapies including intravenous immunoglobulin (IVIg) have been tried when the thrombocytopenia persists or there is breakthrough thrombosis. We sought to systematically review and analyze the published literature on use of IVIg in the treatment of HIT. A systematic search of PubMed, Google Scholar, EMBASE and SCOPUS for all study designs and reports were carried out from inception until April 2019. Statistical analysis was done using Microsoft Excel and Stata version 13. In 34 patients with HIT, the mean age was 60 years. About 70% cases were by unfractionated heparin exposure and 30% by low-molecular weight heparin. The most common precipitant in the patients without heparin exposure was recent surgery. Average nadir platelet count for which IVIg was used was 28 000/μl. Time from resolution of the thrombocytopenia after IVIg treatment was 3 days with average platelet count recovery to 159 000/μl. Mean time from diagnosis to administration of IVIg was day 18. Thrombosis was identified in 32% of patients. About 77% patients improved (platelet count >100 000/μl or cessation of thrombosis) following use of IVIg. Logistic regression did not identify any factors that predicted IVIg response (P > 0.05). No thrombotic events or other adverse events were noted with use of IVIg. IVIg appears to be a safe and effective treatment option for HIT-related thrombocytopenia and for refractory thrombosis.	0
Spondylometaphyseal dysplasias (SMD) are a heterogeneous group of bone dysplasias characterized by vertebral and metaphyseal changes of various severities. We report two unrelated patients of east African origin with a skeletal disorder consisting of 1) severe metaphyseal dysplasia of early onset, sparing hand bones, with bracket-shaped metaphyses; 2) dysplastic pelvis with irregular iliac rim; and 3) oval-shaped vertebral bodies. Contrasting with most types of SMD, the spinal dysplasia is limited to mild changes in the vertebral body shape that tend to soften with time, whereas the iliac rims have a striking lacy appearance. Except for the most common types (Kozlowski type and Schmidt type), most of the literature on SMD deals with single case reports, without longitudinal data, for which molecular definition is still lacking and classification remains unclear. These two patients could belongs to the A4 group in the classification of Maroteaux and Spranger [1991: Pediatr Radiol 2l:293-297], and illustrate the difficulties of a clinical classification of SMD.	0
Dyschromatosis Universalis Hereditaria (DUH) belongs to a group of congenital diffuse reticulate pigmentary disorders characterised by both hypo and hyper pigmented macules. It is both hereditary and sporadic. A number of associated cutaneous and systemic diseases have been reported. The recent discovery of the mutation in ATP binding cassette protein, ABCB6 in DUH attempts to explain the reason behind the pigmentary abnormalities and varied associations. We add a new association by reporting a case of DUH with primary ovarian failure (POF) and hypothyroidism.	0
BACKGROUND AND AIMS:Recent adult evidence suggests that infliximab (IFX) trough levels (TL) in patients with severe ulcerative colitis (UC) may be decreased. The aims of our study were to compare post-induction IFX TL of children with severe versus moderate UC and to evaluate short- and long-term outcomes. METHODS:In this single-center retrospective study, children with a diagnosis of UC starting IFX with a Pediatric Ulcerative Colitis Activity Index (PUCAI) ≥35 and with available post-induction TL were recruited. UC characteristics, IFX dosage and interval, primary non-response, IFX failure, and surgery after 24 months were collected. Post induction TL, anti-IFX antibodies, and laboratory evaluations at the time of starting IFX were also acquired. RESULTS:A total of 90 children were enrolled, of whom 39 (43.3%) were classified as severe UC and 51 (56.6%) as moderate UC. Median post-induction IFX TL were lower in severe UC versus moderate group (5.5 vs 10.3; p = 0.03), despite a more frequently intensified IFX regimen. Children in the higher TL quartiles showed increased rates of clinical, biological, and combined remission (p = 0.04, p < 0.001, and p = 0.01, respectively). In a multivariate analysis, a PUCAI ≥65 and time interval from last IFX infusion were the only predictors associated with IFX TL. At 24 months, children in the higher TL quartiles had a decreased risk of IFX failure (p = 0.002). The severe UC group showed a higher risk of IFX failure at 24 months (16/23 (41%) vs. 11/40 (21.6%); p = 0.05). Kaplan-Meier methods demonstrated a trend toward statistical significance, with a two-year cumulative colectomy rate of 15.38% (95% confidence interval (CI) 8.1-15.6%) in children with severe UC and 3.92% (95% CI 2.9-10.8%) in patients with moderate UC (logrank test p = 0.06). CONCLUSIONS:Children starting IFX with severe UC showed lower post-induction TL and poor disease outcomes. Achieving adequate TL was associated with better efficacy outcomes.	0
Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome is a rare disease, linked to an auto-inflammatory pathway. We report a 7-year-old boy with recurrent suppurative knee arthritis without signs of suppurative skin infection or ulcer; his younger brother had the same symptom. Genetic testing indicated the presence of proline-serine-threonine phosphatase interacting protein 1 gene mutation in both boys. Our patient's grandfather had a history of recurrent pyoderma, and his father though a genetic carrier had no symptoms. Interestingly, our patient displayed markedly high levels of interleukin-6, while interleukin-1 and other cytokines were not elevated. These lab findings led to the treatment of pyogenic arthritis, pyoderma gangrenosum, and acne syndrome with tocilizumab. Previously reported cases of similar phenotypes of the syndrome have not presented in this fashion, nor have there been reported cases of pyogenic arthritis, pyoderma gangrenosum, and acne syndrome with a positive family history and an elevation in interleukin-6. The mutation site of proline-serine-threonine phosphatase interacting protein 1 in this incomplete pyogenic arthritis, pyoderma gangrenosum, and acne syndrome has not been reported before. It is possible that there are other pathogenic ways to trigger these auto-inflammatory disorders. Tocilizumab, which specifically targets interleukin-6, was effective in this case.	0
Coronavirus disease 2019 (COVID-19) is a viral disease, also known as severe acute respiratory syndrome coronavirus 2, was first reported in Wuhan, China, December 2019. Respiratory manifestations from the induced acute lung injury were the most common reported findings. Few cases showed extrapulmonary manifestations. COVID-19-associated neurological manifestations have not been widely reported. In this report, we describe a case of encephalopathy in a patient with COVID-19 infection.	0
BACKGROUND:Pneumoperitoneum poses an important diagnostic sign determining the urgency of management of patients in an emergency department. Chilaiditi sign is a rare radiologic finding of large intestines transposition between the diaphragm and the liver. If the patient becomes symptomatic, then the condition is called Chilaiditi syndrome. CASE PRESENTATION:We present a rare case of a 49-year-old Egyptian man who presented to our emergency department complaining of cough and vague abdominal discomfort who was found to have Chilaiditi syndrome diagnosed radiologically by computed tomography scan. He was conservatively managed rather than undergoing invasive non-warranted diagnostic and therapeutic testing that may have resulted in increased morbidity. CONCLUSIONS:A review of the current literature on Chilaiditi syndrome is provided with a focus on increasing the familiarity of health care professionals with the conditions and stressing the importance of a physical examination in evaluating patients with what appears to be air under the diaphragm.	0
Objectives:This article reviews the current role of genetics in pediatric hearing loss (HL). Methods:A review of the current literature regarding the genetic basis of HL in children was performed. Results:To date, 119 nonsyndromic genes have been associated with HL. There are also hundreds of syndromic causes that have HL as part of the clinical phenotype. Conclusions:Identifying HL genes coupled with clinical characteristics ("genotype-phenotype") yields a more accurate diagnosis and prognosis. Although the complexity of the auditory apparatus presents challenges, gene therapy is emerging and may be a viable management option in the future.	0
BACKGROUND:Steatocystoma multiplex (SM) is a disorder of the pilosebaceous unit characterized by multiple sebum-containing dermal cysts. Psychological distress of patients is always derived from these undesirable lesions. Although various treatments have been attempted to improve cosmetic outcomes, no optimal treatment strategy has been established to date.. AIMS:To provide a facile and practical surgical technique combined with tissue adhesive for the treatment of steatocystoma multiplex. METHOD:Forty patients diagnosed as SM were treated with simple modified surgical technique. After local anesthesia, the surface skin was incised about 1-2 mm using a No. 11 blade. When the wall was punctured, the cyst should be squeezed to cause the contents to come out first. Then, we used single toothed forceps which were inserted through the narrow incision. When the cyst was exposed, the mosquito forceps grasp the portion of the cyst and pull it out gently. Then, the incisions were pressed locally, and tissue adhesive was employed to align them when there was no bleeding. We just took approximately 1-2 minutes to excise one cyst completely. RESULT:We successfully treated forty SM patients with our simple modified surgical technique. After treatment, excellent clinical outcomes and minimal adverse effects were observed in this study. And more importantly, no recurrence was found 12 months after the surgery. CONCLUSION:Our simple modified surgical technique was proved to be practical and have excellent results in the long run. We highly recommend this treatment technique as the first-line therapy for SM.	0
The heterogeneous nuclear ribonucleoprotein (HNRNP) genes code for a set of RNA-binding proteins that function primarily in the spliceosome C complex. Pathogenic variants in these genes can drive neurodegeneration, through a mechanism involving excessive stress-granule formation, or developmental defects, through mechanisms that are not known. Here, we report four unrelated individuals who have truncating or missense variants in the same C-terminal region of hnRNPR and who have multisystem developmental defects including abnormalities of the brain and skeleton, dysmorphic facies, brachydactyly, seizures, and hypoplastic external genitalia. We further identified in the literature a fifth individual with a truncating variant. RNA sequencing of primary fibroblasts reveals that these HNRNPR variants drive significant changes in the expression of several homeobox genes, as well as other transcription factors, such as LHX9, TBX1, and multiple HOX genes, that are considered fundamental regulators of embryonic and gonad development. Higher levels of retained intronic HOX sequences and lost splicing events in the HOX cluster are observed in cells carrying HNRNPR variants, suggesting that impaired splicing is at least partially driving HOX deregulation. At basal levels, stress-granule formation appears normal in primary and transfected cells expressing HNRNPR variants. However, these cells reveal profound recovery defects, where stress granules fail to disassemble properly, after exposure to oxidative stress. This study establishes an essential role for HNRNPR in human development and points to a mechanism that may unify other "spliceosomopathies" linked to variants that drive multi-system congenital defects and are found in hnRNPs.	0
We report the case of a 45-year-old female who presented with acute left abdominal pain and subsequently developed a left partial Brown-Séquard syndrome. Spinal fluid, inflammatory and prothrombotic tests were unremarkable. Magnetic resonance showed a left intraforaminal disc prolapse at the T9-T10 level and a hyperintense lesion on T2-weighted images in the left postero-lateral cord at the T8-T9 level with restricted diffusion on DWI imaging. A diagnosis of spinal cord infarction due to compromise of the left T8 thoracic radicular artery was made. The patient was managed conservatively and at the 3 months follow-up, she was ambulant and able to walk small distances without a walker.	0
Background: X-linked Charcot-Marie-Tooth type 1 (CMTX1) is the second most frequent form of CMT, which is caused by mutations in the gap junction beta 1 gene (GJB1) coding for connexin 32 protein. In addition to typical peripheral neuropathy, central nervous system (CNS) involvement in patients with CMTX1 has been reported as a special feature, but female patients are rarely affected. Case presentation: We describe a 29-year-old female who had a history of two cesarean deliveries. After each delivery, she presented transient and recurrent slurred speech and limb weakness. Magnetic resonance imaging (MRI) showed diffuse abnormal signals in the corpus callosum, posterior limbs of bilateral internal capsule, and centrum semiovale. Electromyogram showed sensorimotor peripheral neuropathy with the characteristics of intermediate CMT. The C.622G>A mutation (p.Glu208Lys) in the GJB1 gene was detected by PCR-sequencing. Conclusion: The diagnosis of CMTX1 should be considered, even in female patients, when the disease presents with recurrent stroke-like symptoms and abnormal white matter signals on MRI. The puerperium after delivery may be one of the precipitating factors.	0
A 39-year-old man was admitted to our university hospital because of diffuse pulmonary infiltrates on chest X-ray. He had been diagnosed with T-acute lymphoblastic leukaemia/lymphoblastic lymphoma three years before and had been treated with chemotherapy and cord blood stem cell transplantation twice. Although he had neither blast cells in the peripheral blood nor leucocytosis, urgent bronchoscopy findings demonstrated blast cells invading both the alveolar spaces/alveolar septa and the vein walls. These pathological findings corresponded to ground-glass opacities and thickening of the interlobular septa on thoracic computed tomography (CT). In acute lymphoblastic leukaemia/lymphoblastic lymphoma patients presenting with infiltrates on thoracic CT, leukaemic pulmonary involvement should be considered in the differential diagnoses, even in the absence of hyperleucocytosis or blast cells in the blood, similar to pulmonary involvement in myeloid leukaemias.	0
Zellweger spectrum disorders (ZSD) are rare autosomal recessive inherited metabolic disorders and include severe (Zellweger syndrome) and milder phenotypes [neonatal adrenoleukodystrophy and infantile Refsum disease (IRD)]. ZSD are characterized by impaired peroxisomal functions and lack of peroxisomes detected by electron microscopy (EM). ZSD are caused by mutations in any of the 14 PEX genes. Patients with ZSD commonly demonstrate nonspecific hepatic symptoms within the first year, often without clinical suspicion of ZSD. Thus, recognition of pathologic findings in the liver is critical for the early diagnosis. We herein demonstrate the histologic and ultrastructural features in liver biopsies in the early and advanced phases from a 16-year-old male with IRD. The initial biopsy at 5 months of age showed a lack of peroxisomes by EM, and this finding played a critical role in the early diagnosis. In contrast, the second biopsy at 14 years of age, after long-term diet therapy, demonstrated significant disease progression with near-cirrhotic liver. In addition to lack of peroxisomes, EM revealed abundant trilamellar inclusions within large angulated lysosomes in many of the hepatocytes and Kupffer cells. Mitochondrial abnormalities were identified only in the second biopsy and were mainly identified in damaged cells; thus they were likely nonspecific secondary changes. This is the first report demonstrating histological and ultrastructural features of liver biopsies in the early and advanced phases from a child with ZSD. Trilamellar inclusions are considered to be an ultrastructural hallmark of ZSD, but they may not be apparent in the early phases.	0
Background:Morquio-B disease (MBD) is a distinct GLB1-related dysostosis multiplex involving the trabecular parts of long bones and spine, presenting a mild phenocopy of GALNS-related Morquio-A disease. Methods:We analyzed 63 (n = 62 published) cases with MBD to describe their clinical, biochemical and genetic features. Results:Forty-one of 51 cases with informative clinical data had pure MBD including progressive growth impairment, kyphoscoliosis, coxa/genua valga, joint laxity, platyspondyly, odontoid hypoplasia. Ten of 51 had MBD plus neuronopathic manifestations including intellectual/developmental/speech delay, spasticity, ataxia dystonia. Corneal clouding, cardiac valve pathology, hepatosplenomegaly, spinal cord compression were infrequent and atlantooccipital dislocation, cardiomyopathy and cherry red spot were never reported. Urinary glycosaminoglycan and oligosaccharide excretion was consistently abnormal. Keratan sulphate-derived oligosaccharides were only detected using LC-MS/MS-based methods. Residual β-galactosidase activities measured against synthetic substrates were 0%-17%.Among 28 GLB1 variants, W273 L (34/94 alleles) and T500A (11/94 alleles) occurred most frequently. W273L was invariably associated with pure MBD. Pure MBD also was reported in a case homozygous for R201H, and in the majority of cases carrying the T500A variant. Homozygous Y333C and G438E were associated with MBD plus neuronopathic manifestations. T82M, R201H, and H281Y, observed in seven alleles, previously have been found sensitive to experimental chaperones. Conclusion:Data provide a basis for future systematic collection of clinical, biochemical, morphologic, and genetic data of this ultra-rare condition.	0
Background: Spinocerebellar ataxia type 3 (SCA3) is an inherited form of ataxia that leads to progressive neurodegeneration. Fatigue is a common non-motor symptom in SCA3 and other neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Although risk factors to fatigue in these diseases have been thoroughly studied, whether or not fatigue can affect clinical phenotypes has yet to be investigated. Methods: Ninety-one molecularly confirmed SCA3 patients and 85 age- and sex-matched controls were recruited for this study. The level of fatigue was measured using the 14-item Fatigue Scale (FS-14), and the risk factors to fatigue and how fatigue correlates with clinical phenotypes were studied using multivariable linear regression models. Results: We found that the severity was significantly higher in the SCA3 group than in the control group (9.30 ± 3.04% vs. 3.94 ± 2.66, P = 0.000). Daytime somnolence (β = 0.209, P = 0.002), severity of ataxia (β = 0.081, P = 0.006), and poor sleep quality (β = 0.187, P = 0.037) were found to have a positive relationship with fatigue. Although fatigue had no relationship with age at onset or ataxic progression, we found that it did have a positive relationship with the severity of ataxia (β = 7.009, P = 0.014). Conclusions: The high level of fatigue and the impact of fatigue on the clinical manifestation of SCA3 patients suggest that fatigue plays a large role in the pathogenesis of SCA3, thus demonstrating the need for intervention and treatment options in this patient cohort.	0
Pyruvate kinase deficiency (PKD) is a monogenic metabolic disease caused by mutations in the PKLR gene that leads to hemolytic anemia of variable symptomatology and that can be fatal during the neonatal period. PKD recessive inheritance trait and its curative treatment by allogeneic bone marrow transplantation provide an ideal scenario for developing gene therapy approaches. Here, we provide a preclinical gene therapy for PKD based on a lentiviral vector harboring the hPGK eukaryotic promoter that drives the expression of the PKLR cDNA. This therapeutic vector was used to transduce mouse PKD hematopoietic stem cells (HSCs) that were subsequently transplanted into myeloablated PKD mice. Ectopic RPK expression normalized the erythroid compartment correcting the hematological phenotype and reverting organ pathology. Metabolomic studies demonstrated functional correction of the glycolytic pathway in RBCs derived from genetically corrected PKD HSCs, with no metabolic disturbances in leukocytes. The analysis of the lentiviral insertion sites in the genome of transplanted hematopoietic cells demonstrated no evidence of genotoxicity in any of the transplanted animals. Overall, our results underscore the therapeutic potential of the hPGK-coRPK lentiviral vector and provide high expectations toward the gene therapy of PKD and other erythroid metabolic genetic disorders.	0
Facioscapulohumeral muscular dystrophy (FSHD) is a genetic illness, inherited in an autosomal dominant fashion, that affects skeletal muscle tissue in affected individuals. Muscle groups involved include those of the face, shoulder girdle, and lower extremity that are affected asymmetrically.[1][2] FSHD characteristically starts proximally in the face and spreads distally to affected muscle groups. Beyond musculature, 50% of FSHD patients also present with subclinical high-frequency hearing loss and retinovasculopathy.[3]	0
Pelger-Huet anomaly is usually autosomal dominant, although it is likely that new mutations are common. This condition is characterized by granulocytes that are either bilobed or completely unsegmented. Here is a report of a 46 year old Indian lady who presented with fever to the hospital and on evaluation, her peripheral blood smear showed extreme hypolobation of granulocytes. Along with normal appearing neutrophils there were many neutrophils with bilobed and single monolobated nuclei which accounted for 82 % of the neutrophils. After identifying these neutrophilic abnormalities which were suggestive of Pelgeroid changes, the other family members were also screened and were found to be having similar morphologic abnormalities in granulocytes. As these changes were evident in granulocytic leucocytes of the patient as well as her mother, both her sisters and her son, with exception of her brother, the diagnosis of familial Pelger-Huet Anomaly was considered in this case.	0
BACKGROUND:Ribonucleases (RNases) are crucial for degradation of ribosomal RNA (rRNA). RNASET2 as a subtype of RNASEs is a 256 amino acid protein, encoded by RNASET2 gene located on chromosome six. Defective RNASET2 leads to RNASET2-deficient leukoencephalopathy, a rare autosomal recessive neurogenetic disorder with psychomotor delay as its main clinical symptom. The clinical findings can be similar to congenital cytomegalovirus (CMV) infection and Aicardi-Goutieres syndrome (AGS). METHODS:Herein, we presented a patient with motor delay, neurological regression, infrequent seizures and microcephaly at 5 months of age. Brain imaging showed white matter involvement, calcification and anterior temporal cysts. Basic metabolic tests, serum and urine CMV polymerase chain reaction (PCR) were requested. According to clinical and imaging findings, screening of RNASET2 and RMND1 genes were performed. The clinical data and magnetic resonance imaging (MRI) findings of previous reported individuals with RNASET2-deficient leukodystrophy were also reviewed and compared to the findings of our patient. RESULTS:Brain MRI findings were suggestive of RNASET2-deficient leukoencephalopathy, AGS and CMV infection. Basic metabolic tests were normal and CMV PCR was negative. Molecular study revealed a novel homozygous variant of c.233C > A; p.Ser78Ter in exon 4 of RNASET2 gene compatible with the diagnosis of RNASET2-deficient leukoencephalopathy. CONCLUSIONS:RNASET2-deficiency is a possible diagnosis in an infant presented with a static leukoencephalopathy and white matter involvement without megalencephaly. Due to overlapping clinical and radiologic features of RNASET2-deficient leukoencephalopathy, AGS and congenital CMV infections, molecular study as an important and helpful diagnostic tool should be considered to avoid misdiagnosis.	0
Femoral-facial syndrome (FFS) is a very rare multiple congenital anomaly syndrome. The authors describe a case of FFS in a 2-day-old infant of a diabetic mother. The phenotypic features include bilateral symmetrical femoral involvement with completely aplastic right-sided femur, severely hypoplastic left femur and unusual facial dysmorphic features without other skeleton/spinal and genitourinary anomalies. Cases of FFS need to be carefully evaluated because of the similarity between FFS and caudal dysgenesis, a condition frequently related to maternal diabetes and with other syndromes characterised by femoral hypoplasia and associated anomalies, which can pose a diagnostic challenge.	0
Background:A large deletion in Xp22.3 can result in contiguous gene syndromes, including X-linked ichthyosis (XLI) and Kallmann syndrome (KS), presenting with short stature, chondrodysplasia punctata, intellectual disability, and strabismus. XLI and KS are caused by the deletion of STS and ANOS1, respectively. Method:Two KS patients with XLI were screened to identify possible pathogenic mutations using whole exome sequencing. The clinical characteristics, molecular genetics, treatment outcomes, and genotype-phenotype association for each patient were analyzed. Results:We identified a novel 3,923 kb deletion within the Xp22.31 region (chrX: 5810838-9733877) containing STS, ANOS1, GPR143, NLGN4X, VCX-A, PUDP, and PNPLA4 in patient 1, who presented with KS, XLI, obesity, hyperlipidemia, and strabismus. We identified a novel 5,807 kb deletion within the Xp22.31-p22.33 regions (chrX: 2700083-8507807) containing STS, ANOS1, and other 24 genes in patient 2, who presented with KS, XLI, obesity, and strabismus. No developmental delay, abnormal speech development, or autistic behavior were noticed in either patient. Conclusion:We identified two novel microdeletions in the X chromosome leading to KS and XLI. These findings contribute to the understanding of the molecular mechanisms that drive contiguous gene syndromes. Our research confirmed that the Kallmann-Ichthyosis phenotype is caused by microdeletions at the chromosome level.	0
Carcinoma showing thymic-like differentiation (CASTLE) is a rare tumor most commonly occurring in the thyroid and soft tissues of the neck. We report the first case of CASTLE occurring in the sublingual gland. The patient, a 35-year-old healthy man, presented with a submucosal lesion located in the anterior right floor of the oral cavity and an ipsilateral neck mass. The lesion had been previously investigated by neck computed tomography and ultrasound-guided fine needle aspiration cytology and diagnosed as metastatic squamous cell carcinoma. After oral cavity magnetic resonance imaging, positron emission tomography, and a non-diriment, fine needle aspiration cytology of the sublingual mass, the patient was treated as affected by a sublingual gland malignancy with removal of primary tumor and neck dissection. Morphological and immunohistochemical findings were diagnostic for primary sublingual gland CASTLE. The patient received adjuvant radiotherapy and is free of disease 2 years after treatment. We describe the pathological features of the lesion and discuss the possible differential diagnoses.	0
One hundred and forty-four patients with hereditary motor and sensory neuropathy (HMSN) were selected from within a defined area (Cantabria) in Northern Spain, from 1974 to 1984. The series comprises 49 index cases and 95 affected relatives. The prevalence ratio was 28.2 cases per 100,000. The results of the study indicate that the majority of the cases were hereditary as a dominant trait. The prevalence for the Type I HMSN cases did not differ from that of Type II cases. Previous population-surveys of these disorders are compared.	1
BACKGROUND:Wolcott-Rallison syndrome (WRS) is characterized by permanent early-onset diabetes, skeletal dysplasia and several additional features, e.g. recurrent liver failure. This is the first multicentre approach that focuses on diabetes management in WRS. We searched the German/Austrian Diabetes-Patienten-Verlaufsdokumentation (DPV) registry and studied anthropometric characteristics, diabetes treatment, glycaemic control and occurrence of severe hypoglycaemia (SH) and diabetic ketoacidosis (DKA) in 11 patients with WRS. Furthermore, all local treatment centres were personally contacted to retrieve additional information on genetic characteristics, migration background and rate of consanguinity. RESULTS:Data were analysed at diabetes onset and after a median follow-up period of 3 (1.5-9.0) years (time from diagnosis to latest follow-up). Median age at diabetes onset was 0.2 (0.1-0.3) years, while onset was delayed in one patient (aged 16 months). Seventy percent of patients manifested with DKA. At follow-up, 90% of patients were on insulin pump therapy requiring 0.7 [0.5-1.0] IU of insulin/kg/d. More than two third of patients had HbA1c level ≥ 8%, 40% experienced at least one episode of SH in the course of the disease. Three patients died at 0.6, 5 and 9 years of age, respectively. To the best of our knowledge three patients carried novel mutations in EIF2AK3. CONCLUSION:Insulin requirements of individuals with WRS registered in DPV appear to be comparable to those of preschool children with well-controlled type 1 diabetes, while glycaemic control tends to be worse and episodes of SH tend to be more common. The majority of individuals with WRS in the DPV registry does not reach glycaemic target for HbA1c as defined for preschool children (< 7.5%). International multicentre studies are required to further improve our knowledge on the care of children with WRS.	0
Untangling the complex interplay between phenotype and genotype is crucial to the effective characterization and subtyping of diseases. Here we build and analyze the multiplex network of 779 human diseases, which consists of a genotype-based layer and a phenotype-based layer. We show that diseases with common genetic constituents tend to share symptoms, and uncover how phenotype information helps boost genotype information. Moreover, we offer a flexible classification of diseases that considers their molecular underpinnings alongside their clinical manifestations. We detect cohesive groups of diseases that have high intra-group similarity at both the molecular and the phenotypic level. Inspecting these disease communities, we demonstrate the underlying pathways that connect diseases mechanistically. We observe monogenic disorders grouped together with complex diseases for which they increase the risk factor. We propose potentially new disease associations that arise as a unique feature of the information flow within and across the two layers.	0
Aim: To investigate the expression of embryonic stem cell (ESC) markers in microcystic lymphatic malformation (mLM). Methods and Results: Cervicofacial mLM tissue samples from nine patients underwent 3,3'-diaminobenzidine (DAB) immunohistochemical (IHC) staining for ESC markers octamer-binding protein 4 (OCT4), homeobox protein NANOG, sex determining region Y-box 2 (SOX2), Krupple-like factor (KLF4), and proto-oncogene c-MYC. Transcriptional activation of these ESC markers was investigated using real-time polymerase chain reaction (RT-qPCR) and colorimetric in situ hybridization (CISH) on four and five of these mLM tissue samples, respectively. Immunofluorescence (IF) IHC staining was performed on three of these mLM tissue samples to investigate localization of these ESC markers. DAB and IF IHC staining demonstrated the expression of OCT4, SOX2, NANOG, KLF4, and c-MYC on the endothelium of lesional vessels with abundant expression of c-MYC and SOX2, which was also present on the cells within the stroma, in all nine mLM tissue samples. RT-qPCR and CISH confirmed transcriptional activation of all these ESC markers investigated. Conclusions: These findings suggest the presence of a primitive population on the endothelium of lesional vessels and the surrounding stroma in mLM. The abundant expression of the progenitor-associated markers SOX2 and c-MYC suggests that the majority are of progenitor phenotype with a small number of ESC-like cells.	0
BACKGROUND:Autosomal recessive nail dysplasia is characterized by thick and hard nails with a very slow growth on the hands and feet. Mutations in FZD6 gene were found to be associated with autosomal recessive nail dysplasia in 2011. Presently, only seven mutations have been reported in FZD6 gene; five mutations are clustered in the C-terminus, one is at the seventh transmembrane domain, and another is at the very beginning of third extracellular loop. METHODS:Whole exome sequencing (WES) was applied to the index case, her one affected sister and her healthy consanguineous parents. The mutation was verified via Sanger sequencing. Molecular dynamics simulations of the predicted structures of native and mutant proteins were compared to gain insight into the pathogenicity mechanism of the mutation. RESULTS:Here, we report a homozygous 8 bp deletion mutation, p.Gly559Aspfs*16; c.1676_1683delGAACCAGC, in FZD6 gene which causes a frameshift and creates a premature stop codon at position 16 of the new reading frame. Our molecular dynamics calculations predict that the pathogenicity of this frameshift mutation may be caused by the change in entropy of the protein with negative manner, disturbing the C-terminal domain structure, and hence interaction partners of FZD6. CONCLUSION:We identified a homozygous deletion mutation in FZD6 in a consanguineous Turkish family with nail dysplasia. We also provide a molecular mechanism about the effects of the deletion on the protein structure and its possible motions. This study provides a pathogenicity mechanism for this mutation in nail dysplasia for the first time.	0
Methylmalonic aciduria (MMA) cblB type is caused by mutations in the MMAB gene. This encodes the enzyme ATP:cob(I)alamin adenosyltransferase (ATR), which converts reduced cob(I)alamin to an active adenosylcobalamin cofactor. We recently reported the presence of destabilizing pathogenic mutations that retain some residual ATR activity. The aim of the present study was to seek pharmacological chaperones as a tailored therapy for stabilizing the ATR protein. High-throughput ligand screening of over 2000 compounds was performed; six were found to enhance the thermal stability of purified recombinant ATR. Further studies using a well-established bacterial system in which the recombinant ATR protein was expressed in the presence of these six compounds, showed them all to increase the stability of the wild-type ATR and the p.Ile96Thr mutant proteins. Compound V (N-{[(4-chlorophenyl)carbamothioyl]amino}-2-phenylacetamide) significantly increased this stability and did not act as an inhibitor of the purified protein. Importantly, compound V increased the activity of ATR in patient-derived fibroblasts harboring the destabilizing p.Ile96Thr mutation in a hemizygous state to within control range. When cobalamin was coadministrated with compound V, mutant ATR activity further improved. Oral administration of low doses of compound V to C57BL/6J mice for 12 days, led to increase in steady-state levels of ATR protein in liver and brain (disease-relevant organs). These results hold promise for the clinical use of pharmacological chaperones in MMA cblB type patients harboring chaperone-responsive mutations.	0
Metatropic dysplasia (MD), is a rare skeletal dysplasia occurring predominantly in infants characterized by a distinctive long torso and short limbs; it is as a result of mutations in the TRPV4 gene. However, a clear distinction between various forms of skeletal dysplasias caused by the transient receptor potential vanilloid 4 (TRPV4) gene is difficult but could be achieved by a combination of gene sequencing, medical and radiological criteria. We hereby report a case of a 14-month old girl who presented with an abnormal stature. The diagnosis of nonlethal MD was confirmed by X-ray with dumbbell-shaped long bones, platyspondyly, and delayed carpal ossification, as well as broadened pelvis with marginally widened ilia, epiphyseal plates, and slightly flattened acetabula. Furthermore, gene sequencing confirmed gene mutation on exon 15 of the TRPV4 gene with a heterozygous missense mutation (c.2396C > T), but no mutation was present in her parents. Our findings recorded metatropic dysplasia with the c.2396C > T mutation in the TRPV4 gene in China. This mutation caused changes in amino acid of TRPV4, which can induce growth retardation in children.	0
BACKGROUND/OBJECTIVES:To determine whether iron was being enterally absorbed in anemic patients with recessive dystrophic epidermolysis bullosa (RDEB). METHODS:Anemic patients with RDEB who were refractory or had poor adherence to oral or gastrostomy-given iron underwent enteral iron absorption challenges. Subjects were given 2 mg/kg of elemental iron. Successful iron absorption was defined as a two- to threefold increase of serum iron or a rise to above 100 µg/dL. RESULTS:Nine of 12 iron challenges did not show increased iron absorption. Only three of the ten subjects demonstrated elevated iron absorption. All patients had elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), low serum albumin, and hemoglobin levels. Eight challenges were in patients with elevated soluble transferrin receptor (STFR)/log ferritin levels, indicating iron deficiency. The three challenges with elevated iron absorption also had elevated STFR/log ferritin as well as elevated ESR and CRP, but these inflammatory markers were, in general, less elevated than those in non-absorbers. CONCLUSIONS:Enteral iron is routinely prescribed for anemic patients with RDEB assuming a component of iron deficiency. Adherence to enteral iron tends to be unreliable due to unpalatable taste and gastrointestinal complaints. Enteral iron absorption tests are relatively noninvasive and appear to be well tolerated. Poor gastrointestinal iron absorption may be an important factor in failure to improve anemia in RDEB enterally. It may be prudent to test patients with RDEB who are anemic and not responding well to conventional iron supplements with iron absorption tests and to consider replacement with intravenous iron in iron-deficient patients.	0
Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease due to motor neuron loss variably associated with frontotemporal dementia (FTD). Next generation sequencing technology revealed an increasing number of rare and novel genetic variants and interpretation of their pathogenicity represents a major challange in the diagnosis of ALS. We selected 213 consecutive patients with sporadic or familial (16%) ALS, tested negative for SOD1, FUS, TARDBP, and C9orf72 mutations. To reveal rare forms of genetic ALS, we performed a comprehensive multi-gene panel screening including 46 genes associated with ALS, hereditary motor neuronopathies, spastic paraplegia, and FTD. Our study allowed the identification of pathogenic or likely pathogenic variants in 4.2% of patients. The genes with the highest percentage of pathogenic variants were OPTN (1%), VCP (1%) SQSTM1(1%), SETX (0.4%), FIG4 (0.4%), and GARS1 (0.4%) genes. We also found 49 novel or rare gene variants of unknown significance in 30 patients (14%), 44 unlikely pathogenic variants (39%), and 48 variants in ALS susceptibility genes. The results of our study suggest the screening of OPTN, VCP, and SQSTM1 genes in routine diagnostic investigations for both sporadic and familial cases, and confirm the importance of diagnosis and couselling for patients and their relative family members.	0
BACKGROUND:Wieacker-Wolff syndrome (WWS) is a congenital X-linked neuromuscular disorder, which was firstly reported in 1985. Zinc finger C4H2-type containing (ZC4H2) gene has been found to be associated with the disease pathogenesis. However, the underlying mechanism remains elusive. METHODS:Whole-exome sequencing was performed to identify the mutations. Expression plasmids were constructed and cell culture and immune-biochemical assays were used to examine the effects of the mutation. RESULTS:We reported a female patient with classical symptoms of WWS and discovered a novel nonsense heterozygous mutation (p.R67X; c.199C>T) in ZC4H2 gene in the patient but not in her parents. The mutation resulted in a 66 amino-acid truncated ZC4H2 protein. The mutation is located in the key helix domain and it altered the subcellular locations of the mutant ZC4H2 protein. X-chromosome inactivation (XCI) pattern analysis revealed that the XCI ratio of the proband was 22:78. CONCLUSION:Female heterozygous carriers with nonsense mutation with a truncated ZC4H2 protein could lead to the pathogenesis of Wieacker-Wolff syndrome and our study provides a potential new target for the disease treatment.	0
The objective of this retrospective study was to evaluate the efficacy of high-energy focused extracorporeal shock wave therapy (HF-ESWT) on painful bone marrow edema syndrome (BMES) of the hip and shorten the natural course of disease.Thirty-four consecutive patients with BMES of the hip were treated with HF-ESWT in our department between August 2017and July 2018. The progression and treatment results of BMES were evaluated by imaging examination and clinical outcomes. The clinical outcomes include hip pain and function which were measured using the visual analog scale (VAS) and Harris hip score (HHS), respectively, and the VAS and HHS of all patients were calculated and evaluated before treatment (s0), at 1 month (s1), 3 months (s2), 6 months (s3)post-treatment. Imaging examination including Pelvic radiographs and frog views and double hip magnetic resonance imaging (MRI) were also obtained and scheduled before treatment, at 1, 3, 6, and the final follow-up post-treatment to exclude avascular necrosis and other pathology.All patients successfully completed the treatment and follow-up. Compared with pretherapy, the pain was alleviated to varying degrees and the HHS was significantly improved, and the VAS was significantly reduced at S1-2 (1- and 3-months post-treatment) after therapeutic intervention (P < .05). The mean improvements were strongly statistically significant between S0 and S1 and between S1 andS2 (P < .0001) and less significant between S2 and S3 (P < .01). The mean improvement between 6 months (S3) and final follow-up (more than 12 months) was not statistically significant. The MRI findings demonstrated that the diffuse BMES in the femoral head and neck disappeared completely.HF-ESWT is a safe, effective, reliable, and noninvasive treatment in patients with painful BMES of the hip, and it can accelerate the recovery of BMES of the hip, shorten the treatment time and course of disease, improve hip joint function and the quality of life of patients.	0
We present the unique case of adult hyperinsulinism hyperammonemia syndrome (HI/HA). This condition is rarely seen in children and even more infrequently in adults. A 27-year-old female with HI/HA, generalized tonic-clonic seizures, staring spells, and gastroesophageal reflux disease presented with diffuse abdominal pain, hypoglycemia, confusion, and sweating. She reported a history of significant nausea, vomiting, and diarrhea, which had been present intermittently over the past year. On examination, she was found to have a soft, nontender, and mildly distended abdomen without splenomegaly or masses. She had a normal blood pressure and was tachycardic (130 bpm). Her initial complete blood count and basic metabolic panel, excluding glucose, were within normal limits. She was found to have an elevated peripherally drawn venous ammonia (171 mmol/L) and near hypoglycemia (blood glucose 61 mg/dL), which were drawn given her history of HI/HA. She was continued on home carglumic acid and diazoxide, glucose was supplemented intravenously, and she was started on levetiracetam for seizure prophylaxis. An upper endoscopy (esophagogastroduodenoscopy [EGD]) was performed and was unremarkable, and biopsies taken were within normal limits. Following the EGD, she underwent a gastric emptying study that showed delayed emptying (216 minutes), consistent with a new diagnosis of gastroparesis, the likely etiology of her initial abdominal pain on presentation. This was subsequently treated with azithromycin oral solution. We present this case to raise awareness of this rarely encountered syndrome and to provide the basic principles of treatment.	0
​Multicentric osteolysis nodulosis and arthropathy (MONA) is an infrequently described autosomal recessive skeletal dysplasia characterized by progressive osteolysis and arthropathy. Inactivating mutations in MMP2, encoding matrix metalloproteinase-2, are known to cause this disorder. Fifteen families with mutations in MMP2 have been reported in literature. In this study we screened thirteen individuals from eleven families for MMP2 mutations and identified eight mutations (five novel and three known variants). We characterize the clinical, radiographic and molecular findings in all individuals with molecularly proven MONA from the present cohort and previous reports, and provide a comprehensive review of the MMP2 related disorders.	0
Oral potentially malignant disorders (OPMDs) are precursor lesions that may undergo malignant transformation to oral cancer. These lesions most commonly present clinically as white patches (leukoplakia). However, they may also be red (erythroplakia), or red and white (erythroleukoplakia). There are many risk factors associated with the development of an OPMD, and with the risk of malignant transformation of the lesion. A biopsy with subsequent microscopic examination from the lesional tissue is necessary in identification of OPMD. This article reviews the clinical appearance of OPMDs, associated risk factors, diagnosis and histologic appearance, and treatment.	0
BACKGROUND:Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative condition characterized by the loss of neurons and the presence of eosinophilic nuclear inclusions in the central and peripheral nervous system, skin and visceral organs. In this paper, we present a case of NIID with recurrent encephalitic attacks that remained stable and nonprogressive for seven years; no such case has previously been reported. CASE PRESENTATION:A 63-year-old female was hospitalized due to light-headedness, vomiting, unstable gait and cognitive impairment. Seven years prior, she had experienced an episode of light-headedness, central facial paralysis, unstable gait, aphasia, nausea, vomiting and loss of consciousness. She regained consciousness within 12 h, and her other symptoms were completely resolved within one week. During the present hospitalization, a brain magnetic resonance imaging (MRI) examination detected high signal intensity on diffusion-weighted imaging (DWI) of the bilateral frontal grey matter-white matter junction. We reviewed the patient's previous MRI results and found that she had also had high signal intensity on DWI of the bilateral frontal grey matter-white matter junction seven years prior. In the intervening seven years, the high signal intensity in the frontal lobes had spread along the grey matter-white matter junction, but the deep white matter remained unaffected. Skin biopsy was performed, and intranuclear inclusions were found in adipocytes, fibroblasts and sweat gland cells. GGC repeat expansions in the NOTCH2NLC (Notch 2 N-terminal like C) gene confirmed the diagnosis of NIID. She received supportive treatment such as nutrition support therapy and vitamin B and C supplementation, as well as symptomatic treatment during hospitalization. The patient's symptoms were completely relieved within one week. CONCLUSION:This is a detailed report of a case of NIID with multiple reversible encephalitic attacks, diagnosed by clinical symptoms, intranuclear inclusions, characteristic DWI signals, and genetic tests.	0
Ambiguous genitalia, known to be associated with sex chromosome disorders, may also be seen with autosomal chromosome anomalies. Herein, we report a case with ambiguous genitalia and ring chromosome 13. Ring chromosome 13 is a rare genetic anomaly in which the loss of genetic material determines the clinical spectrum.	0
Localization of metastases into the parotid gland is a very uncommon event. Usually they arise from primary tumors located in the head and neck, mainly melanoma or epidermoid carcinoma of the skin, while other histotypes, from others anatomical districts, hardly have a metastatic spread to the parotid. Myxoid Liposarcoma (MLS) is a rare malignant tumor of the soft tissue that mainly occurs in the extremities, representing the second most common subtype of liposarcoma. Although it is typical for liposarcomas to metastasize to the lungs, it is known that MLS can spread also to extra pulmonary sites. The authors report a case of myxoid liposarcoma of the left thigh in a 64-year-old man, with an unusual metastatic double presentation to the contralateral forearm first and to the parotid gland then. MLS with metastatic disease to the parotid gland is an extremely rare event with very few cases reported in the English literature.	0
Kidney diseases are becoming a major cause of global burden with high mortality and morbidity. The origins of most kidney diseases are known, but for some the exact aetiology is not yet understood. Dermatoglyphics is the scientific study of epidermal ridge patterns and it has been used as a non-invasive diagnostic tool to detect or predict different medical conditions that have foetal origin. However, there have been a limited number of studies that have evaluated a dermatoglyphic relationship in different kidney diseases. The aim of this review was to systematically identify, review and appraise available literature that evaluated an association of different dermatoglyphic variables with kidney diseases. This review is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. The PubMed(®) (Medline), POPLINE, Cochrane Library and Trip Database and grey literature sources such as OpenGrey, Google Scholar, and Google were searched to earliest date to 17 April 2014. Of the 36 relevant publications, 15 were included in the review. Of these studies, there are five case reports, seven case series and three comparative studies. Possible association of dermatoglyphics with Wilms tumor (WT) had been evaluated in two comparative studies and one case series that found fewer whorls and a lower mean total ridge count (TRC). Another study evaluated adult polycystic kidney disease (APCD) type III that revealed lower TRC means in all cases. All other case series and case reports describe dermatoglyphics in various kidney disease such as acro-renal-ocular syndrome, potter syndrome, kabuki makeup syndrome, neurofaciodigitorenal syndrome, syndactyly type V, ring chromosome 13 syndrome, trisomy 13 syndrome and sirenomelia. It is evident that whorl pattern frequency and TRC have been used widely to investigate the uncertainty related to the origin of several kidney diseases such as WT and APCD type III. However, small sample sizes, possibly methodological issues, and discrepancy in the make up between cases and control groups limits interpretation of any significant findings. Future studies with proper protocol, adequate cases, and control groups may provide stronger evidence to resolve uncertainty related to the aetiology of kidney diseases.	0
BACKGROUND:Multigene panel sequencing (MGPS) is the first-line option in diagnostic testing for genetically heterogeneous but clinically similar conditions, such as neuromuscular disorders (NMDs). In this study, we aimed to assess the utility of comprehensive NMD MGPS and the need for updated panels. METHODS:All patients were analyzed by either of two versions of the NMD MGPS and by chromosomal microarray and karyotype testing. Four patients with negative NMD MGPS results underwent whole exome sequencing. RESULTS:In total, 91 patients were enrolled, and a genetic diagnosis was made in 36 (39.6%); of these, 33 were diagnosed by the comprehensive NMD MGPS, two were confirmed by chromosomal microarray, and one was diagnosed by whole exome sequencing. For MGPS, the diagnostic yield of Version 2 (19/52; 36.5%) was a little higher than that of Version 1 (14/39; 35.9%), and one gene identified in Version 2 was not included in Version 1. A total of 36 definitive and nine possible causative variants were identified, of which 17 were novel. CONCLUSION:A more comprehensive panel for NMD MGPS can improve the diagnostic efficiency in genetic testing. The rapid discovery of new disease-causing genes over recent years necessitates updates to existing gene panels.	0
OBJECTIVE:Herpes simplex virus (HSV) infection during pregnancy can cause severe neonatal infections. It is also a rare cause of congenital infections. We aimed to describe fetal and neonatal abnormalities of congenital HSV infection in order to define the features that are accessible to prenatal diagnosis during ultrasound screening and/or during a work-up for congenital malformations. METHODS:We analysed all cases of congenital HSV infection (CHI) described before and/or after birth and identified in Pubed and classified the findings as accessible or not to prenatal diagnosis. RESULTS:Thirty-six cases of congenital herpes infection were reported, of which 15 were described prenatally and 21 postnatally. The most frequently reported malformations accessible to prenatal diagnosis were cerebral anomalies. The most common abnormalities described after birth were skin lesions and keratitis, which are not considered amenable to prenatal ultrasound detection. CHI can due to either HSV1 or HSV2 infection, whether primary or non-primary infection, with or without the presence of maternal symptoms. CONCLUSION:Prenatal ultrasound abnormalities due to CHI are rare, varied and non-specific. There is no clear role for fetal ultrasound in the routine management of women with primary or non-primary HSV infection in pregnancy. However, in fetuses with ultrasound abnormalities suggestive of congenital infection, HSV should still be considered as a differential diagnosis after the more common in utero infections, such as cytomegalovirus, are excluded.	0
Mutations in proteolipid protein 1 (PLP1) result in failure of myelination and neurological dysfunction in the X-linked leukodystrophy Pelizaeus-Merzbacher disease (PMD)1,2. Most PLP1 mutations, including point mutations and supernumerary copy variants, lead to severe and fatal disease. PLP1-null patients and mice, however, can display comparatively mild phenotypes, suggesting that PLP1-suppression might provide a general therapeutic strategy for PMD1,3-5. Here we show effective in vivo Plp1-suppression in the severe jimpy (Plp1jp) point mutation mouse model of PMD. CRISPR-Cas9 mediated germline suppression of Plp1 in jimpy mice increased myelination and restored nerve conduction velocity, motor function, and lifespan to wild-type levels, validating PLP1-suppression as a therapeutic approach. To evaluate the translational potential of this strategy we identified antisense oligonucleotides (ASOs) that stably decrease Plp1 mRNA and protein throughout the neuraxis, in vivo. Administration of a single dose of Plp1-targeting ASOs to postnatal jimpy mice fully restored oligodendrocyte numbers, increased myelination, improved motor performance, normalized respiratory function, and extended lifespan through an 8-month endpoint. These results support the development of PLP1-suppression as a treatment for PMD. More broadly, we demonstrate that oligonucleotide therapeutics can be delivered to oligodendrocytes in vivo to modulate neurological function and lifespan, establishing a new pharmaceutical modality for myelin disorders.	0
This article focuses on primary ovarian insufficiency and the experimental models used in recent years to explain the probable mechanisms of autoimmune oophoritis and idiopathic primary ovarian insufficiency. The relationship between the immune system and the neuroendocrine system is also an important focus of this article. Activation of the immune system is necessary for maintaining homeostasis and this requires multiple interactions and regulation between the immune system and the neuroendocrine system. Neuropeptides, neuroendocrine mediators, are expressed and released primarily, but not exclusively, by the nervous system and have profound effects on the immune system. As an example of one of these peptides we describe the α-melanocyte-stimulating hormone and its anti-inflammatory properties.	0
Acquired hemophilia A (AHA), a rare bleeding disorder caused by neutralizing autoantibodies against coagulation factor VIII (FVIII), occurs in both men and women without a previous history of bleeding. Patients typically present with an isolated prolonged activated partial thromboplastin time due to FVIII deficiency. Neutralizing antibodies (inhibitors) are detected using the Nijmegen-modified Bethesda assay. Approximately 10% of patients do not present with bleeding and, therefore, a prolonged activated partial thromboplastin time should never be ignored prior to invasive procedures. Control of acute bleeding and prevention of injuries that may provoke bleeding are top priorities in patients with AHA. We recommend treatment with bypassing agents, including recombinant activated factor VII, activated prothrombin complex concentrate, or recombinant porcine FVIII in bleeding patients. Autoantibody eradication can be achieved with immunosuppressive therapy, including corticosteroids, cyclophosphamide and rituximab, or combinations thereof. The median time to remission is 5 weeks, with considerable interindividual variation. FVIII activity at presentation, inhibitor titer and autoantibody isotype are prognostic markers for remission and survival. Comparative clinical studies to support treatment recommendations for AHA do not exist; therefore, we provide practical consensus guidance based on recent registry findings and the authors' clinical experience in treating patients with AHA.	0
Keratoconus (KC), though one of the most common corneal degeneration, still continues to be a mystique regarding its pathogenesis, diagnosis, associations, and management; with newer discoveries and evolutions being reported. We report, what we believe to be another new association of KC- Cogan Reese syndrome with secondary glaucoma. A 32-year-old male, diagnosed as bilateral KC, presented for examination. Unilateral Cogan-Reese syndrome and associated secondary glaucoma was identified. These associations had been missed by previous ophthalmologists. The patient was managed with a rigid contact lens for KC and topical antiglaucoma agents for glaucoma. He was advised regular reviews and is under observation till date. We describe the first case known to us of a new association with KC. This case not only highlights the ophthalmologist's need to look for multiple entities linked to KC; but may also pave way for future insights regarding pathogenesis and genetics of these associated diseases.	0
BACKGROUND:Skeletal dysplasias are a heterogeneous group of >400 genetic disorders characterized by abnormal bone growth. Many individuals experience joint pain and limitation, coming to require joint replacement much earlier than the average-statured population. In addition, prosthesis survival rate is less in the dysplastic population. The purpose of this study is to identify risk factors for surgery and provide recommendations to improve surgical outcomes. METHODS:This a retrospective review of 29 individuals with a skeletal dysplasia who had 64 joint replacements between April 1985 and January 2019 at a single institution. We collected demographics, physical examination, medical history, imaging studies, surgical indication, and complications. RESULTS:Spondyloepiphyseal dysplasia was the most common skeletal dysplasia (7), followed by pseudoachondroplasia (4) and multiple epiphyseal dysplasia (4). Average age of the cohort was 40.6 years (range 14-64). Hip arthroplasty (34) was the most commonly performed surgery. The majority of arthroplasties (75%) required custom components. Complication rate was 37.3%, most commonly pulmonary embolism (3) and pneumonia (3). Most complications (81.8%) occurred in individuals with either a pre-existing cardiopulmonary comorbidity or lumbar/sacral deformity. Body mass index did not correlate with complication severity (R = -0.042, P = .752) or rate (R = 0.006, P = .963). CONCLUSION:Surgical complications are highest in patients with pre-existing cardiopulmonary conditions. Body mass index does not predict complications in this cohort. Preoperative evaluations for individuals with skeletal dysplasias should include comprehensive work-up of spine issues and extraskeletal systems that present an operative risk. Intraoperative protocol should include special consideration for placement on the table, airway maintenance, and spinal cord monitoring in select cases.	0
Complex regional pain syndrome (CRPS) and fibromyalgia are chronic pain conditions of unexplained origins. In addition to symptoms in the diagnostic criteria, patients can report changes to vision and other sensations or bodily functions. It is unclear whether these are greater than would be expected due to normal ageing, living with chronic pain generally, or common comorbidities of chronic pain such as depression or anxiety. We administered an on-line survey evaluating the frequencies and types of self-reported somatic symptoms, bodily changes, and sensory sensitivity in respondents with CRPS (n = 390), fibromyalgia (n = 425), and both CRPS and fibromyalgia ("CRPS+fibromyalgia"; n = 88) compared to respondents with other chronic pain conditions (n = 331) and pain-free controls (n = 441). The survey assessed somatic symptoms (Patient Health Questionnaire-15), bodily changes, pain/discomfort/distress triggers, and pain intensifiers. We conducted analysis of covariance's with age, sex, Patient Health Questionnaire-9 (measuring depression), Generalized Anxiety Disorder-7, pain duration in years, hours of pain per day, and number of pain-related medical diagnoses as covariates. After controlling for covariates, respondents with CRPS and/or fibromyalgia reported more somatic symptoms, changes in movement and biological responses, pain/discomfort/distress triggers, and pain intensifiers than pain(-free) control groups. Fibromyalgia specifically related to changes in vision and hearing, urinary/intestinal function, and drinking and eating. Complex regional pain syndrome related to changes in hair, skin, and nails; and infection and healing. The CRPS+fibromyalgia group presented with features of both disorders with minimal additional stressors or symptoms over and above these. Our findings suggest that CRPS and fibromyalgia share underlying pathophysiologies, although specific mechanisms might be different.	0
The descriptive epidemiology of hairy cell leukaemia is reported from a specialized register of haematological malignancies covering approximately one-third of England and Wales. The overall incidence of hairy cell leukaemia at 2.9 per million persons per year is similar to that recorded in America. There is a marked male preponderance (4.0 compared with 1.7 per million per year for females). A case-control study on hairy cell leukaemia was conducted in the Yorkshire and Trent Regional Health Authority areas. 50 cases and 95 controls were identified, and interviewed using a structured questionnaire. Previous results on the aetiology of hairy cell leukaemia were not supported by this study, with the exception of an association between hairy cell leukaemia and exposure to organic solvents, petrochemicals and related products.	1
Keipert syndrome is a rare condition comprising sensorineural deafness associated with facial and digital abnormalities. To date, Keipert syndrome has been reported in six male patients including two sib pairs; however the genetic basis of Keipert syndrome is yet to be elucidated. We report on the diagnosis of Keipert syndrome in the nephew of the brothers in the first report of Keipert syndrome, with a pedigree consistent with X-linked recessive inheritance. Linkage analysis using microsatellite markers along the X-chromosome suggests that the gene for Keipert syndrome is located in the region Xq22.2-Xq28. We postulate the Keipert syndrome is caused by a novel gene at Xq22.2-Xq28.	0
Rubinstein-Taybi syndrome (RSTS) is an autosomal-dominant disorder characterized by intellectual disability, skeletal abnormalities, growth deficiency and an increased risk of tumors. RSTS is predominantly caused by mutations in CREBBP or EP300 genes encoding for CBP and p300 proteins, two lysine acetyl-transferases (KAT) playing a key role in transcription, cell proliferation and DNA repair. However, the efficiency of these processes in RSTS cells is still largely unknown. Here, we have investigated whether pathways involved in the maintenance of genome stability are affected in lymphoblastoid cell lines (LCLs) obtained from RSTS patients with mutations in CREBBP or in EP300 genes. We report that RSTS LCLs with mutations affecting CBP or p300 protein levels or KAT activity, are more sensitive to oxidative DNA damage and exhibit defective base excision repair (BER). We have found reduced OGG1 DNA glycosylase activity in RSTS compared to control cell extracts, and concomitant lower OGG1 acetylation levels, thereby impairing the initiation of the BER process. In addition, we report reduced acetylation of other BER factors, such as DNA polymerase β and Proliferating Cell Nuclear Antigen (PCNA), together with acetylation of histone H3. We also show that complementation of CBP or p300 partially reversed RSTS cell sensitivity to DNA damage. These results disclose a mechanism of defective DNA repair as a source of genome instability in RSTS cells.	0
Advances in podocytology and genetic techniques have expanded our understanding of the pathogenesis of hereditary steroid-resistant nephrotic syndrome (SRNS). In the past 20 years, over 45 genetic mutations have been identified in patients with hereditary SRNS. Genetic mutations on structural and functional molecules in podocytes can lead to serious injury in the podocytes themselves and in adjacent structures, causing sclerotic lesions such as focal segmental glomerulosclerosis or diffuse mesangial sclerosis. This paper provides an update on the current knowledge of podocyte genes involved in the development of hereditary nephrotic syndrome and, thereby, reviews genotype-phenotype correlations to propose an approach for appropriate mutational screening based on clinical aspects.	0
Pediatric patients with systemic-onset juvenile idiopathic arthritis (SOJIA) may be treated with tacrolimus. However, the therapeutic range for tacrolimus is narrow with considerable inter- and intra-individual variability, making it difficult to formulate an ideal dosage regimen for personalized treatment. The purpose of the present study was to set up a population pharmacokinetics (PPK) model of tacrolimus treatment for SOJIA to determine the optimal initial dosage. Patients with SOJIA were analyzed using non-linear mixed-effects modeling. Different regimens were analyzed using Monte Carlo simulation with concentration profiles. A first-order absorption and elimination one-compartment model was selected as the most appropriate model for SOJIA. Based on initial dosage recommendations, the regimen of 0.5 mg every 24 h (q24h) appeared to be most suitable for subjects with a body weight of 5 kg, while the 0.5 mg q12h regimen was most suitable for subjects with a body weight of 15-25 kg, the 1/0.5 mg q24h regimen was appropriate for the 26-35 kg group and the 1 mg q12h regimen was suitable for the subjects with a body weight of 36-50 kg. To the best of our knowledge, the present study established the first PPK model of tacrolimus treatment that may be used for the selection of the initial dose based on body weight of pediatric patients with SOJIA.	0
The identification of rare disease-causing variants in humans by large-scale next-generation sequencing (NGS) studies has also provided us with new insights into the pathophysiological role of de novo missense variants in the CACNA1D gene that encodes the pore-forming α1-subunit of voltage-gated Cav1.3 L-type Ca2+ channels. These CACNA1D variants have been identified somatically in aldosterone-producing adenomas as well as germline in patients with neurodevelopmental and in some cases endocrine symptoms. In vitro studies in heterologous expression systems have revealed typical gating changes that indicate enhanced Ca2+ influx through Cav1.3 channels as the underlying disease-causing mechanism. Here we summarize the clinical findings of 12 well-characterized individuals with a total of 9 high-risk pathogenic CACNA1D variants. Moreover, we propose how information from somatic mutations in aldosterone-producing adenomas could be used to predict the potential pathogenicity of novel germline variants. Since these pathogenic de novo variants can cause a channel-gain-of function, we also discuss the use of L-type Ca2+ channel blockers as a potential therapeutic option.	0
Objectives: To explore barriers in access to dementia care in Turkish, Pakistani and Arabic speaking minority ethnic groups in Denmark.Method: Semi-structured qualitative individual- and group interviews with minority ethnic family carers, primary care dementia coordinators, staff in elderly daycare, and multicultural link workers. Hermeneutic phenomenology was used as theoretical framework.Results: A total of 21 individual- and 6 group interviews were conducted, including a total of 35 participants. On the service user side, barriers in access to dementia care were related to lacking language proficiency and strong cultural norms, including familial responsibility for the care of older family members and stigma associated with mental illness and dementia. On the care provider side, the available formal services were rarely tailored to the specific needs of minority ethnic service users and were often considered inadequate or unacceptable.Conclusion: Care practices and perceived consequences of dementia in minority ethnic communities were heavily influenced by cultural factors leading to a number of persisting barriers to accessing dementia care services. There is a simultaneous need to raise awareness about dementia and the existence of dementia care services in minority ethnic groups, to reduce stigma, and to develop culturally appropriate dementia care options.	0
Heterozygous pathogenic variants in the FN1 gene, encoding fibronectin (FN), have recently been shown to be associated with a skeletal disorder in some individuals affected by spondylometaphyseal dysplasia with "corner fractures" (SMD-CF). The most striking feature characterizing SMD-CF is irregularly shaped metaphyses giving the appearance of "corner fractures". An array of secondary features, including developmental coxa vara, ovoid vertebral bodies and severe scoliosis, may also be present. FN is an important extracellular matrix component for bone and cartilage development. Here we report five patients affected by this subtype of SMD-CF caused by five novel FN1 missense mutations: p.Cys123Tyr, p.Cys169Tyr, p.Cys213Tyr, p.Cys231Trp and p.Cys258Tyr. All individuals shared a substitution of a cysteine residue, disrupting disulfide bonds in the FN type-I assembly domains located in the N-terminal assembly region. The abnormal metaphyseal ossification and "corner fracture" appearances were the most remarkable clinical feature in these patients. In addition, generalized skeletal fragility with low-trauma bilateral femoral fractures was identified in one patient. Interestingly, the distal femoral changes in this patient healed with skeletal maturation. Our report expands the phenotypic and genetic spectrum of the FN1-related SMD-CF and emphasizes the importance of FN in bone formation and possibly also in the maintenance of bone strength.	0
Limb development is clinically and biologically important. Polydactyly is common and caused by aberrant anterior-posterior patterning. Human disorders that include polydactyly are diverse. To facilitate an understanding of the biology of limb development, cataloging the genes that are mutated in patients with polydactyly would be useful. In 2002, I characterized human phenotypes that included polydactyly. Subsequently, many advances have occurred with refinement of clinical entities and identification of numerous genes. Here, I update human polydactyly entities by phenotype and mutated gene. This survey demonstrates phenotypes with overlapping manifestations, genetic heterogeneity, and distinct phenotypes generated from mutations in single genes. Among 310 clinical entities, 80 are associated with mutations in 99 genes. These results show that knowledge of limb patterning genetics is improving rapidly. Soon, we will have a comprehensive toolkit of genes important for limb development, which will lead to regenerative therapies for limb anomalies.	0
Nemaline myopathies are a heterogenous group of congenital myopathies caused by de novo, dominantly or recessively inherited mutations in at least twelve genes. The genes encoding skeletal α-actin (ACTA1) and nebulin (NEB) are the commonest genetic cause. Most patients have congenital onset characterized by muscle weakness and hypotonia, but the spectrum of clinical phenotypes is broad, ranging from severe neonatal presentations to onset of a milder disorder in childhood. Most patients with adult onset have an autoimmune-related myopathy with a progressive course. The wide application of massively parallel sequencing methods is increasing the number of known causative genes and broadening the range of clinical phenotypes. Nemaline myopathies are identified by the presence of structures that are rod-like or ovoid in shape with electron microscopy, and with light microscopy stain red with the modified Gömöri trichrome technique. These rods or nemaline bodies are derived from Z lines (also known as Z discs or Z disks) and have a similar lattice structure and protein content. Their shape in patients with mutations in KLHL40 and LMOD3 is distinctive and can be useful for diagnosis. The number and distribution of nemaline bodies varies between fibres and different muscles but does not correlate with severity or prognosis. Additional pathological features such as caps, cores and fibre type disproportion are associated with the same genes as those known to cause the presence of rods. Animal models are advancing the understanding of the effects of various mutations in different genes and paving the way for the development of therapies, which at present only manage symptoms and are aimed at maintaining muscle strength, joint mobility, ambulation, respiration and independence in the activities of daily living.	0
BACKGROUND:Hepatocerebral mitochondrial DNA depletion syndrome (MTDPS) is a disease caused by defects in mitochondrial DNA maintenance and leads to liver failure and neurological complications during infancy. Liver transplantation (LT) remains controversial due to poor outcomes associated with extrahepatic symptoms. The purposes of this study were to clarify the current clinical and molecular features of hepatocerebral MTDPS and to evaluate the outcomes of LT in MTDPS patients in Japan. RESULTS:We retrospectively assessed the clinical and genetic findings, as well as the clinical courses, of 23 hepatocerebral MTDPS patients from a pool of 999 patients who were diagnosed with mitochondrial diseases between 2007 and 2019. Causative genes were identified in 18 of 23 patients: MPV17 (n = 13), DGUOK (n = 3), POLG (n = 1), and MICOS13 (n = 1). Eight MPV17-deficient patients harbored c.451dupC and all three DGUOK-deficient patients harbored c.143-307_170del335. The most common initial manifestation was failure to thrive (n = 13, 56.5%). The most frequent liver symptom was cholestasis (n = 21, 91.3%). LT was performed on 12 patients, including nine MPV17-deficient and two DGUOK-deficient patients. Among the 12 transplanted patients, five, including one with mild intellectual disability, survived; while seven who had remarkable neurological symptoms before LT died. Five of the MPV17-deficient survivors had either c.149G > A or c.293C > T. CONCLUSIONS:MPV17 was the most common genetic cause of hepatocerebral MTDPS. The outcome of LT for MTDPS was not favorable, as previously reported, however, patients harboring MPV17 mutations associated with mild phenotypes such as c.149G > A or c.293C > T, and exhibiting no marked neurologic manifestations before LT, had a better prognosis after LT.	0
A 20 year old male patient presented with lack of sexual development. On examination he was eunuchoidal and hypogonadal, and olfactory function testing showed he was anosmic. Biochemical investigations proved he was hypogonadotrophic. Kallmann's syndrome was therefore diagnosed. His appearance was very different from his alleged identical twin who had undergone a normal puberty and had normal plasma testosterone and gonadotrophin levels. However, the twin was hyposmic. Genetic fingerprinting confirmed the twins were identical. Why Kallman's syndrome was incompletely expressed in one of them is unexplained. The parents and a normally menstruating sister had normal olfactory function.	0
INTRODUCTION:Perry syndrome, also recognized as Perry disease, is a rare autosomal dominant disorder characterized by midlife-onset atypical parkinsonism, apathy or depression, respiratory failure and weight loss caused by a mutation in the Dynactin (DCTN1) gene. CASE DESCRIPTION:A fifty-six years-old adopted male presented with atypical parkinsonism with bradykinesia and postural instability, apathy, weight loss, and recurrent respiratory failure due to central hypoventilation requiring tracheostomy. METHODS AND RESULTS:Clinical workup revealed a novel DCTN1 p.Tyr78His variant. Using bioinformatic protein structure modeling, we compare our patient's variant to known DCTN1 mutations and predict protein stability of each variant at the CAP-Gly domain of p150Glued. All eight variants causing Perry syndrome, as well as Tyr78His, are located at site expected to interact with MAPRE1 tail and are predicted to be destabilizing. Variants causing atypical parkinsonism with incomplete Perry syndrome phenotype (K56R and K68E) are not significantly destabilizing in silico. CONCLUSION:We propose p.Tyr78His as the ninth pathogenic DCTN1 variant causing Perry syndrome. Bioinformatic protein modeling may provide additional window to understand and interpret DCTN1 variants, as we observed non-destabilizing variants to have different phenotype than destabilizing variants.	0
The field of primary immunodeficiencies (PIDs) is rapidly evolving. Indeed, the number of described diseases is constantly increasing thanks to the rapid identification of novel genetic defects by next-generation sequencing. PIDs are now rather referred to as "inborn errors of immunity" due to the association between a wide range of immune dysregulation-related clinical features and the "prototypic" increased infection susceptibility. The phenotypic spectrum of PIDs is therefore very large and includes several orofacial features. However, the latter are often overshadowed by severe systemic manifestations and remain underdiagnosed. Patients with impaired innate immunity are predisposed to a variety of oral manifestations including oral infections (e.g., candidiasis, herpes gingivostomatitis), aphthous ulcers, and severe periodontal diseases. Although less frequently, they can also show orofacial developmental abnormalities. Oral lesions can even represent the main clinical manifestation of some PIDs or be inaugural, being therefore one of the first features indicating the existence of an underlying immune defect. The aim of this review is to describe the orofacial features associated with the different PIDs of innate immunity based on the new 2019 classification from the International Union of Immunological Societies (IUIS) expert committee. This review highlights the important role played by the dentist, in close collaboration with the multidisciplinary medical team, in the management and the diagnostic of these conditions.	0
RATIONALE:Wiedemann-Steiner syndrome (WDSTS, online mendelian inheritance in man 605130) is a rare autosomal dominant disorder characterized by hypertrichosis cubiti. Here, we report a Chinese boy who do not show the characteristic of hypertrichosis cubiti, and was misdiagnosed as blepharophimosis-ptosis-epicanthus inversus syndrome at first. We found a de novo frameshift mutation (p.Glu390Lysfs*10) in the KMT2A gene, which was not reported before. Our study increases the cohort of Chinese WDSTS patients, and expand the WDSTS phenotypic and variation spectrum. PATIENT CONCERNS:The patient demonstrated typical craniofacial features of blepharophimosis-ptosis-epicanthus inversus syndrome, including small palpebral fissures, ptosis, telecanthus, and epicanthus inversus, besides he had congenital heart disease (ventricular septal defects), strabismus, hypotonia, amblyopia, delayed speech and language development, delayed psychomotor development, and amblyopia (HP:0000646) which was not reported before. DIAGNOSIS:FOXL2 gene was cloned and sequenced, however, there was no mutation detected in this patient. The result of Chromosomal microarray analysis was normal. The patient was diagnosed as WDSTS by whole exome sequencing. INTERVENTIONS:The patient received cardiac surgery, frontalis suspension and regular speech and occupational therapy. He also treated with growth hormone (GH). OUTCOMES:The patient's symptoms are improved after cardiac surgery and frontalis suspension, he can express himself well now and had a 10 cm gain in height. LESSONS:As the relationship between genotype and phenotype becomes more and more clear, WES is incredibly powerful tool to diagnose the disease of WDSTS.	0
BACKGROUND:Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis caused by a mutation in any one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16 or KRT17). Characteristic features of PC are painful palmoplantar keratoderma, variable nail dystrophy, cysts, follicular hyperkeratosis and often oral leukokeratosis. Although oral leukokeratosis can go unnoticed, mucosal involvement of the oral cavity and upper airways can manifest with pain during feeding, hoarseness, stridor and, occasionally, life-threatening obstruction. OBJECTIVES:To characterize patients with PC with symptomatic mucosal involvement. METHODS:We present a case series of nine children with PC with symptomatic mucosal involvement, all with heterozygous mutations in KRT6A. Seven patients complained of painful feeding problems. Four patients were diagnosed with failure to thrive, three of whom required a feeding tube. Simple feeding solutions were beneficial in most cases. Seven patients had laryngeal involvement and one patient died at 4 years of age from acute laryngeal obstruction. CONCLUSIONS:It is important for dermatologists and otolaryngologists to be aware that symptomatic mucosal involvement, and very rarely laryngeal obstruction, can occur in patients with PC. Usually simple feeding solutions may prevent complications and failure to thrive. What's already known about this topic? Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis due to a mutation in any one of five keratin genes. Symptomatic mucosal involvement is an important clinical feature of PC and appears to be more pronounced in KRT6A mutation carriers. Only leukokeratosis is frequently seen in PC and can be one of the earliest signs of disease. Laryngeal involvement is a less common feature. It might be symptomatic but usually presents as hoarseness, stridor and, occasionally, as a life-threatening respiratory distress. What does this study add? In most cases of laryngeal involvement, there is no need for any intervention. Although pain and feeding difficulties are usually attributed to the oral leukokeratosis, they can be related to a phenomenon called 'first bite syndrome' (FBS). Symptomatic mucosal involvement with feeding difficulty is important but can be managed in most cases with simple feeding solutions (e.g. softer nipple with a larger hole, thicker formula and feeding with a syringe). Linked Comment: Youssefian and Vahidnezhad. Br J Dermatol 2020; 182:536-537.	0
A mutation in the epithelial morphogen gene ectodysplasin-A1 (EDA1) is responsible for the disorder X-linked hypohidrotic ectodermal dysplasia (XLHED), the most common form of ectodermal dysplasia. XLHED is characterized by impaired development of hair, eccrine sweat glands, and teeth. This study aimed to identify potentially pathogenic mutations in four Chinese XLHED families.Genomic DNA was extracted from the peripheral blood and sequenced. Sanger sequencing was used to carry out mutational analysis of the EDA1 gene, and the three-dimensional structure of the novel mutant residues in the EDA trimer was determined. Transcriptional activity of NF-κB was tested by Dual luciferin assay.We identified a novel EDA1 mutation (c.1046C>T) and detected 3 other previously-reported mutations (c.146T>A; c.457C>T; c.467G>A). Our findings demonstrated that novel mutation c.1046C>T (p.A349 V) resulted in XLHED. The novel mutation could cause volume repulsion in the protein due to enlargement of the amino acid side chain. Dual luciferase assay revealed that transcriptional NF-κB activation induced by XLHED EDA1 protein was significantly reduced compared with wild-type EDA1.These results extend the spectrum of EDA1 mutations in XLHED patients and suggest a functional role of the novel mutation in XLHED.	0
AIM:Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare neurodegenerative disorder presenting in children aged 2-4 years with seizures and loss of motor and language skills, followed by blindness and death in late childhood. Initial presenting features are similar to a range of common epilepsies. We aim to highlight typical clinical and radiological features that may prompt diagnosis of CLN2 disease in early disease stages. METHODS:We present a series of 13 Australian patients with CLN2 disease, describing clinical features, disease evolution, neuroimaging, electroencephalogram, biochemical and genetic results. Expert neuroradiological magnetic resonance imaging (MRI) analysis was retrospectively performed on 10 cases. RESULTS:Twelve patients presented with seizures, with initial seizures being focal (n = 4), generalised tonic-clonic (n = 3), absence (n = 3) and febrile (n = 2). Eleven patients (85%) had a language delay before the onset of seizures. Cerebellar or cerebral atrophy was noted in all patients on centralised MRI review, with abnormalities of the brain-stem, ventricles, corpus callosum and hippocampi. CONCLUSIONS:Early language delay with the onset of seizures at 2-4 years of age is the hallmark of CLN2 disease. MRI findings of early subtle atrophy in the cerebellum or posterior cortical regions should hasten testing for CLN2 disease to enable early initiation of enzyme replacement therapy.	0
Shahgholi E. A case series of hematohidrosis: A puzzling medical phenomenon. Turk J Pediatr 2018; 60: 757-761. Hematohidrosis (bloody sweat), also known as hematidrosis, is a rare clinical entity characterized by recurrent, spontaneous, self-limited episodes of blood oozing from intact skin or mucosa that are witnessed by medical personnel. We hereby report three healthy children with the history of recurrent episodes of bleeding from the intact skin over their various parts of the body. Most of these bleeding episodes occurred after stressful situations. On the basis of clinical presentation and normal investigation, they were diagnosed with hematohidrosis. We treated them with non-specific beta-blocker (propranolol). Follow-up observation of these patients demonstrated marked diminish in the frequency and severity of their episodes. In spite of the rarity of hematohidrosis, it should be considered as a differential diagnosis of bleeding episodes in patients with normal physical and laboratory investigations.	0
BACKGROUND:Weakness is the primary impairment in paediatric neuromuscular diseases, impacting gait and gait-related functional activities in ambulant children affected by these rare and often degenerative diseases. Gait speed is an indicator of health and disability, yet gait is a complex, multi-faceted activity. Using the International Classification of Function, Health and Disability (ICF) model, assessment of gait and functional ambulation should consider the impairments, activity limitations and participation restrictions due to disease, and factors related to the environment and the individual person. METHODS:This narrative review involved a literature search of databases including Medline, Embase and Pubmed from 1946 to October 2019. Inclusion criteria included assessments of gait, endurance and ambulatory function in paediatric (0-18 years) neuromuscular diseases. RESULTS:Fifty-two papers were identified reporting assessments of gait speed, timed function, endurance and ambulatory capacity, gait-related balance and qualitative descriptive assessments of gait function and effect of disease on gait and gait-related activities. Gait speed is an indicator of disability and children with neuromuscular disease walk slower than typically developing peers. Increasing disease severity and age were associated with slower walking in children with Duchenne muscular dystrophy and Charcot-Marie-Tooth disease. The six-minute walk test is used widely as a test of endurance and ambulatory capacity; six-minute walk distance was substantially reduced across all paediatric neuromuscular diseases. Endurance and ambulatory capacity was more limited in children with spinal muscular atrophy type 3, congenital muscular dystrophy and older boys with Duchenne muscular dystrophy. Only a few papers considered normalisation of gait parameters accounting for the effect on gait of height in heterogeneous groups of children and linear growth in longitudinal studies. Balance related to gait was considered in five papers, mainly in children with Charcot-Marie-Tooth disease. There was limited investigation of factors including distance requirements and terrain in children's typical environments and personal factors related to self-perception of disease effect on gait and gait-related function. CONCLUSION:Assessments of gait and functional ambulation are important considerations in documenting disease progression and treatment efficacy in the clinical setting; and in clinical trials of disease-modifying agents and physiotherapeutic interventions in paediatric neuromuscular diseases. There is a need for expert consensus on core gait and functional ambulation assessments for use in clinical and research settings.	0
A young female patient suffering from Satoyoshi syndrome had the first characteristic signs and symptoms of hair loss and progressive spontaneous intermittent painful spasms of limb muscles at age 6.5 years. Thereafter, she developed chronic diarrhea, amenorrhea, and skeletal deformities. In the orofacial region, she suffered from painful spasms of the masseter (jaw closing) muscles, progressive tooth loss, and degeneration of the mandibular condyles. Treatment with steroids and provision of complete dentures improved the signs and symptoms. Early diagnosis and timely provision of multidisciplinary care can minimize complications in these patients and improve their orofacial functions and quality of life.	0
Pili annulati is a disorder that produces a spangled appearance to the hair, caused by alternating light and dark banding of hair shafts. This phenomenon is created by abnormal cavities in the cortex of the hair shaft, which produces lighter bands seen on clinical examination. Complications of pili annulati are limited; the most noteworthy complication is increased breakage secondary to weathering of the abnormal hair shafts. We report a case of a 14-year-old adolescent girl with pili annulati and progressive hair loss of 2 months' duration. Most of her hairs were notably short, spangled, and lusterless with light and dark banding observed with handheld magnification. Light microscopy demonstrated alternating light and dark bands, and the dark bands had the typical appearance of air-filled spaces. Gentler hair grooming practices were recommended, and at a follow-up visit, the appearance of the hair had improved with darker and longer shafts. This case should alert clinicians to look for pili annulati when hair fragility is present.	0
Urethral duplication is a rare congenital anomaly and presents as a spectrum of varying severity. This report present three cases of duplication of urethra whose presentation ranged from prepubic sinus to a complete urethral duplication. They were investigated using ultrasonography, retrograde urethrography and cystoscopy. They were treated depending on the severity of the anomaly. The management of these cases is discussed and the current literature on this rare entity reviewed.	0
Currarino triad is a rare syndrome that may be occasionally encountered during managing cases of anorectal anomalies. The triad consists of anorectal anomaly, sacral bony defect, and a presacral mass. It may be familial or sporadic, with a reported female predominance. Identification of the characteristic notched sacrum (sacral scimitar) in plain X-ray (anteroposterior view) is considered the key for the diagnosis; however, not infrequently, this radiological sign is overlooked, especially with a small sacral defect. Excision of the presacral cyst is usually performed concomitantly during anorectoplasty. The prone position is the standard approach for posterior sagittal anorectoplasty (PSARP) in males; however, in females, the supine position can be used as an alternative (anterior sagittal anorectoplasty). In this case report, excision of the presacral cyst took place in two steps: the first excision during the PSARP procedure in the prone position, and a second operation in the supine lithotomy position to remove a residual component of the lesion that was missed during the primary operation. It was clear that the supine lithotomy position provided better access to explore the presacral space than the prone position, especially with a deeply located cyst as in our case. The role of magnetic resonance imaging (MRI) in the identification of the exact nature and extent of the lesion before surgery is crucial and should be performed in all cases.	0
The Integrator complex subunit 1 (INTS1) is a component of the integrator complex that comprises 14 subunits and associates with RPB1 to catalyze endonucleolytic cleavage of nascent snRNAs and assist RNA polymerase II in promoter-proximal pause-release on protein-coding genes. We present five patients, including two sib pairs, with biallelic sequence variants in INTS1. The patients manifested absent or severely limited speech, an abnormal gait, hypotonia and cataracts. Exome sequencing revealed biallelic variants in INTS1 in all patients. One sib pair demonstrated a missense variant, p.(Arg77Cys), and a frameshift variant, p.(Arg1800Profs*20), another sib pair had a homozygous missense variant, p.(Pro1874Leu), and the fifth patient had a frameshift variant, p.(Leu1764Cysfs*16) and a missense variant, p.(Leu2164Pro). We also report additional clinical data on three previously described individuals with a homozygous, loss of function variant, p.(Ser1784*) in INTS1 that shared cognitive delays, cataracts and dysmorphic features with these patients. Several of the variants affected the protein C-terminus and preliminary modeling showed that the p.(Pro1874Leu) and p.(Leu2164Pro) variants may interfere with INTS1 helix folding. In view of the cataracts observed, we performed in-situ hybridization and demonstrated expression of ints1 in the zebrafish eye. We used Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 to make larvae with biallelic insertion/deletion (indel) variants in ints1. The mutant larvae developed typically through gastrulation, but sections of the eye showed abnormal lens development. The distinctive phenotype associated with biallelic variants in INTS1 points to dysfunction of the integrator complex as a mechanism for intellectual disability, eye defects and craniofacial anomalies.	0
Baraitser-Winter cerebrofrontofacial syndrome (BWCFF) is a rare autosomal dominant developmental disorder associated with missense mutations in the genes ACTB or ACTG1. The classic presentation of BWCFF is discerned by the combination of unique craniofacial characteristics including ocular coloboma, intellectual disability, and hypertelorism. Congenital contractures and organ malformations are often present, including structural defects in the brain, heart, renal, and musculoskeletal system. However, there is limited documentation regarding its prenatal presentation that may encourage healthcare providers to be aware of this disorder when presented throughout pregnancy. Herein we describe a case of a pregnancy with large cystic hygroma and omphalocele. Whole exome sequencing (WES) was performed and a de novo, heterozygous, likely pathogenic mutation in ACTB was detected, c.1004G>A (p.Arg335His), conferring a diagnosis of BWCFF.	0
Malignant migrating partial seizures in infancy is a devastating pharmacoresistent epileptic encephalopathy of unknown etiology characterized by onset in the first 6 months of life, continuous migrating focal seizures with corresponding multifocal electroencephalographic discharges, developmental deterioration, and early mortality. Recent widespread interest in the nonpsychoactive component of the cannabis plant, cannabidiol, as a potential treatment for refractory devastating epilepsies has led to individual trials initiated by families or physicians in states that have legalized medical marijuana with anecdotal success.We describe a now 10-month-old boy with malignant migrating partial seizures in infancy who made developmental gains and demonstrated sustained seizure reduction with the addition of cannabidiol to his antiepileptic regimen.This report supports a role for cannabidiol in the treatment of malignant migrating partial seizures in infancy.	0
Human skin fibroblasts were isolated from a 48-year-old patient carrying compound heterozygous mutations (c.610+364G>A and c.1311A>G) in OPA1, responsible for early onset optic atrophy complicated by ataxia and pyramidal signs (Behr syndrome; OMIM #210000). Fibroblasts were reprogrammed using episomal plasmids carrying hOCT4, hSOX2, hKLF4, hL-MYC and hLIN28. The generated transgene-free line iPS-OPA1-BEHR showed no additional genomic aberrations, maintained the disease-relevant mutations, expressed important pluripotency markers and was capable to differentiate into cells of all three germ layers in vitro. The generated iPS-OPA1-BEHR line might be a useful platform to study the pathomechanism of early onset complicated optic atrophy syndromes.	0
Primary aldosteronism is the most common form of endocrine hypertension. This disorder comprises both sporadic and familial forms. Four familial forms of primary aldosteronism (FH-I to FH-IV) have been described. FH-III is caused by germline mutations in KCNJ5, encoding the potassium channel Kir3.4 (also called GIRK4). These mutations alter the selectivity filter of the channel and lead to abnormal ion currents with loss of potassium selectivity, sodium influx and consequent increased intracellular calcium that causes excessive aldosterone biosynthesis. To date, eleven families have been reported, carrying six different mutations. Although the clinical features are variable, FH-III patients often display severe hyperaldosteronism with an early onset, associated with hypokalemia and diabetes insipidus-like symptoms. In most cases FH-III patients are resistant to pharmacological therapy and require bilateral adrenalectomy to control symptoms. In the present manuscript, we review the genetics and pathological basis of FH-III, the diagnostic work-up, clinical features and therapeutic management. Finally, we will describe a new case of FH-III of an Italian patient carrying a Gly151Arg mutation.	0
OBJECTIVES:Nonimmune hydrops fetalis (NIHF) accounts for 90% of hydrops fetalis cases. About 15% to 29% of unexplained NIHF cases are caused by lysosomal storage diseases (LSD). We review the spectrum of LSD and associated clinical findings in NIHF in a cohort of patients referred to our institution. METHODS:We present a retrospective case-control study of cases with NIHF referred for LSD biochemical testing at a single center. Cases diagnosed with LSD were matched to controls with NIHF and negative LSD testing and analyzed according to the STROBE criteria to the extent the retrospective nature of this study allowed. RESULTS:Between January 2006 and December 2018, 28 patients with NIHF were diagnosed with a LSD. Eight types of LSD were diagnosed: galactosialidosis 8/28 (28.6%), sialic acid storage disease (SASD) 5/28 (17.9%), mucopolysaccharidosis VII 5/28 (17.9%), Gaucher 4/28 (14.3%), sialidosis 2/28 (7.1%), GM1 gangliosidosis 2/28 (7.1%), Niemann-Pick disease type C 1/28 (3.6%), and mucolipidosis II/III 1/28 (3.6%). Associated clinical features were hepatomegaly 16/21 (76.2%) vs 22/65 (33.8%), P < .05, splenomegaly 12/20 (60.0%) vs 14/58 (24.1%), P < .05, and hepatosplenomegaly 10/20 (50.0%) vs 13/58 (22.4%) P < .05. CONCLUSION:The most common LSD in NIHF were galactosialidosis, SASD, mucopolysaccharidosis VII, and Gaucher disease. LSD should be considered in unexplained NIHF cases, particularly if hepatomegaly, splenomegaly, or hepatosplenomegaly is visualized on prenatal ultrasound.	0
Aim:Achondrogenesis type II is a rare, lethal osteochondrodysplasia with considerable phenotypic heterogeneity. We describe our experience in diagnosing prenatal-onset achondrogenesis type II by a multidisciplinary assessment. Methods:Two cases of fetal achondrogenesis type II were analyzed retrospectively using prenatal ultrasound evaluation, postnatal radiographic diagnosis, and molecular genetic testing of COL2A1. Results:A causative mutation in the COL2A1 gene was found in both patients. Combined with postnatal radiographic examination, the final diagnosis of achondrogenesis type II was made. Conclusion:Our findings emphasize the importance of a multidisciplinary assessment for the definitive diagnosis of achondrogenesis type II, which is paramount for proper genetic counseling.	0
Objective:Non-palpable testes remain a diagnostic challenge, often involving exploratory laparoscopy. We evaluated the diagnostic value of a wide range of reproductive hormones in order to distinguish between bilateral cryptorchidism and bilateral anorchia. Design:In this retrospective study, we identified and included 36 boys with non-palpable testes (20 with cryptorchidism, 3 with congenital hypogonadotropic hypogonadism (CHH), and 13 with anorchia) at first examination during childhood. Methods:Information on karyotype, phenotype, surgical results from laparoscopy, and biochemistry was retrieved from patient files. We compared serum concentrations of AMH, inhibin B, FSH, LH, testosterone, estradiol, and hCG stimulation testing in cryptorchid and anorchid boys to serum concentrations in a large, age-matched control group. Receiver-operating characteristic curves were used to determine the cut-off values of each reproductive hormone as a predictor of the presence of functional testicular tissue. Results:Concentrations of AMH in 0-1 year olds: ≥155 pmol/L and >1-15 year olds: ≥19 pmol/L, inhibin B (≥22 pg/mL and ≥4 pg/mL), FSH (≤28.9 IU/L and ≤20.3 IU/L) and hCG-induced testosterone (>1-15 year olds: ≥2 nmol/L) were significantly sensitive and specific markers in predicting the presence of functional testicular tissue in boys with non-palpable testes. In infancy, anorchid infants had significantly elevated gonadotropin levels, while CHH had low levels. Conclusion:Our findings suggest that laparoscopy may not be necessary in all boys with non-palpable testes if reproductive hormones unequivocally confirm the presence of functional testicular tissue. However, proving the absence may still be a diagnostic challenge.	0
Objectives:Recently, defects in the protein kinase mTOR (mammalian target of rapamycin) and its associated pathway have been correlated with hemimegalencephaly (HME). mTOR acts as a central regulator of important physiological cellular functions such as growth and proliferation, metabolism, autophagy, death, and survival. This study was aimed at identifying specific variants in mTOR signaling pathway genes in patients diagnosed with HME. Methods:Using amplicon and whole exome sequencing (WES) of resected brain and paired blood samples from five HME patients, we were able to identify pathogenic mosaic variants in the mTOR pathway genes MTOR, PIK3CA, and DEPDC5. Results:These results strengthen the hypothesis that somatic variants in PI3K-Akt-mTOR pathway genes contribute to HME. We also describe one patient presenting with a pathogenic variant on DEPDC5 gene, which reinforces the role of DEPDC5 on cortical structural changes due to mTORC1 hyperactivation. These findings also provide insights into when in brain development these variants occurred. An early developmental variant is expected to affect a larger number of cells and to result in a larger malformation, whereas the same variant occurring later in development would cause a minor malformation. Significance:In the future, numerous somatic variants in known or new genes will undoubtedly be revealed in resected brain samples, making it possible to draw correlations between genotypes and phenotypes and allow for a genetic clinical diagnosis that may help to predict a given patient's outcome.	0
A case of multiple occurrences of benign metastasizing leiomyoma in the lung, left thigh, left ilium and pelvis in a 43-year-old woman who underwent twice myomectomy in 1999 and 2004 and had hysterectomy in 2009 was reported. She was complained of chest distress as well as the pain of left hip and back of thigh. Computed tomography, X-ray and positron emission tomography-computed tomography (PET-CT) demonstrated multiple nodules in lung, masses of left thigh and pelvis. Biopsy of these nodules indicated benign metastasizing leiomyomas according to pathologic and immunohistochemical results. The patient received gonadotropin-releasing hormone agonist injection and regular follow-up. Up to now, all the symptoms have been alleviated.	0
PURPOSE:Sjögren's syndrome (SS) is an autoimmune disease associated with ocular surface inflammation. The goals of this study were to establish a novel bead-based protein microarray for simultaneous analysis of 11 cytokines from tear fluid collected with Schirmer strips from patients with SS. METHODS:Three to ten microliter of tear fluid was collected with Schirmer strips from both eyes of 13 healthy controls and 12 SS patients. Tear fluid was eluted from the Schirmer strips, total protein and concentrations of 11 different cytokines were analyzed. RESULTS:The multiplex assay demonstrated high assay sensitivity with LoDs between 1.4 and 55.3 pg/µl with mean CVs between 3.7% and 9.7%. Statistically significant upregulation (p < .005) of eight cytokines was observed in SS patients compared to controls. Additionally, four patient cytokine values showed a significant inverse correlation (r<-0.7) with Schirmer strip readings. CONCLUSION:The assay offers analytical reliability for quantification of biomarkers in small amounts of tear fluid with potential utility for treatment monitoring of SS and other types of Dry Eye Disease.	0
Cornelia de Lange spectrum (CdLSp) is a rare genetic condition characterized by intellectual disability, facial dysmorphisms, major malformations, growth impairment, and development delay. Approximately 80% of CdLSp patients have gastroesophageal reflux disease (GERD) with a varied clinical presentation. The aim of this study is to define potential clinical/genetic risk factors based on the clinical phenotype description of CdLSp patients with severe GERD who underwent surgical treatment. We retrospectively collected data from 23 CdLSp patients, 13 females and 10 males. Mean age of the patients undergoing surgical treatment was of 4 years. 21/23 (91%) had a molecular characterization, of which 21/21 (100%) had a NIPBL gene mutation, while 2/23 (9%) did not have a genetical characterization, only a clinical diagnosis. Most of our patients presented a moderate-severe severity score (21/23, 91%) with limb malformations evidenced in 10/23 (44%) of our patients and a moderate-severe intellectual disability in 20/23 (87%). Therefore, CdLSp patients harboring NIPBL variants, upper limb malformations and severe psychomotor delay are more likely to suffer from severe GERD, not responsive to proton pump inhibitors treatment. These features should be considered as clinical markers for potentially severe GERD that might require surgical treatment.	0
Short rib-polydactyly syndromes (SRPS) are a heterogeneous group of recessively inherited lethal skeletal dysplasias. Four types have been recognised. However, overlap in the clinical and radiological features of the four types has led to difficulties in distinguishing between them. The congenital infection-like syndrome is an autosomal recessive syndrome characterised by mental retardation, microcephaly, seizures, and intracranial calcifications. We report a complex consanguineous family of Baluchi origin in whom short rib-polydactyly type III and congenital infection-like syndrome are segregating. Four children inherited SRPS III, one inherited congenital infection-like syndrome, and one inherited both. Although the radiological features in all the children with SRPS in this report were typical of type III, there was overlap in the clinical features with the other types of SRP syndromes. Furthermore, the child who inherited both SRPS III and congenital infection-like syndrome had CNS malformations in addition to periventricular calcification. CNS malformations have been described in SRPS types II and IV but not type III. This report further highlights the overlap between the different types of SRP syndrome. Moreover, it draws attention to the importance of considering the possibility of two recessive syndromes in the same child in complex consanguineous families when features overlap two syndromes.	0
Incidence and prevalence estimates of acromegaly in the United States (US) are limited. Most existing reports are based on European data sources. The objective of this study was to estimate the annual incidence and prevalence of acromegaly in a large US managed care population, overall and stratified by age, sex, and geographic region, using data from 2008 to 2012.Using administrative claims data, commercial health plan enrollees were identified with acromegaly if they had two or more medical claims with an acromegaly diagnosis code (ICD-9-CM: 253.0×) or one medical claim with an acromegaly diagnosis code in combination with one other claim for a pituitary tumor or pituitary procedure. The first date for an acromegaly-related claim set the index year. Incidence rates for each year were calculated by dividing the number of new acromegaly cases by the calculated person-time at risk. Annual prevalence estimates were calculated by dividing the number with any evidence of acromegaly by the total number of health plan enrollees enrolled for at least 1 day during each calendar year. Incidence and prevalence estimates were stratified by age (0-17, 18-44, 45-64, 65+ years), sex (male, female), and US geographic region of the health plan (Midwest, Northeast, South, West).Overall annual incidence rates of acromegaly were relatively constant across 2008-2012 with ~11 cases per million person-years (PMPY). Rates increased with age, ranging from 3-8 cases PMPY among children aged 0-17 years old to 9-18 cases PMPY among adults aged 65 and older. Females had 12 cases PMPY on average compared to 10 cases PMPY among men. On average, the Midwest had the lowest incidence rates (7 cases PMPY) compared to the Northeast, South and West (14, 12, and 10 cases PMPY, respectively). The overall annual prevalence of acromegaly was relatively constant across the 5 years from 2008 to 2012 with approximately 78 cases per million each year. Annual prevalence estimates increased with age, ranging from 29-37 cases per million among children aged 0-17 years old to 148-182 cases per million among adults aged 65 years and older. Males and females were similarly affected; each with approximately 77 cases per million each year. The Northeast and South had the highest prevalence estimates (92 and 89 cases per million, respectively); while the estimates for the West and Midwest were lower (65 and 57 cases per million, respectively) each year.This study examined 5 years of recent data to estimate the incidence and prevalence of acromegaly in a large geographically-diverse managed care population. The incidence rates were higher on average than published rates outside the US (11 vs. 3.3 PMPY), but prevalence estimates were consistent with previous reports. Incidence and prevalence both increased by age, did not differ for males and females, and varied slightly by US geographic region. The age and sex distribution of the selected population matched the known epidemiology of the disease. Using a claims-based approach, this analysis only captured acromegaly cases with an acromegaly-related medical claim. As a result, these estimates may underestimate the incidence and prevalence of acromegaly in US commercial health plans as they did not include individuals who were undiagnosed, in remission, undertreated, or not monitored during the study period. At the same time, these estimates may be viewed as an upper bound on the incidence of acromegaly in the US as the estimates did not include individuals who were in other health plans or uninsured during the study period. Additional evaluations are needed to identify the full extent of acromegaly in the US.	1
Hemolytic uremic syndrome (HUS) is defined by the triad of mechanical hemolytic anemia, thrombocytopenia and renal impairment. Atypical HUS (aHUS) defines non Shiga-toxin-HUS and even if some authors include secondary aHUS due to Streptococcus pneumoniae or other causes, aHUS designates a primary disease due to a disorder in complement alternative pathway regulation. Atypical HUS represents 5 -10% of HUS in children, but the majority of HUS in adults. The incidence of complement-aHUS is not known precisely. However, more than 1000 aHUS patients investigated for complement abnormalities have been reported. Onset is from the neonatal period to the adult age. Most patients present with hemolytic anemia, thrombocytopenia and renal failure and 20% have extra renal manifestations. Two to 10% die and one third progress to end-stage renal failure at first episode. Half of patients have relapses. Mutations in the genes encoding complement regulatory proteins factor H, membrane cofactor protein (MCP), factor I or thrombomodulin have been demonstrated in 20-30%, 5-15%, 4-10% and 3-5% of patients respectively, and mutations in the genes of C3 convertase proteins, C3 and factor B, in 2-10% and 1-4%. In addition, 6-10% of patients have anti-factor H antibodies. Diagnosis of aHUS relies on 1) No associated disease 2) No criteria for Shigatoxin-HUS (stool culture and PCR for Shiga-toxins; serology for anti-lipopolysaccharides antibodies) 3) No criteria for thrombotic thrombocytopenic purpura (serum ADAMTS 13 activity > 10%). Investigation of the complement system is required (C3, C4, factor H and factor I plasma concentration, MCP expression on leukocytes and anti-factor H antibodies; genetic screening to identify risk factors). The disease is familial in approximately 20% of pedigrees, with an autosomal recessive or dominant mode of transmission. As penetrance of the disease is 50%, genetic counseling is difficult. Plasmatherapy has been first line treatment until presently, without unquestionable demonstration of efficiency. There is a high risk of post-transplant recurrence, except in MCP-HUS. Case reports and two phase II trials show an impressive efficacy of the complement C5 blocker eculizumab, suggesting it will be the next standard of care. Except for patients treated by intensive plasmatherapy or eculizumab, the worst prognosis is in factor H-HUS, as mortality can reach 20% and 50% of survivors do not recover renal function. Half of factor I-HUS progress to end-stage renal failure. Conversely, most patients with MCP-HUS have preserved renal function. Anti-factor H antibodies-HUS has favourable outcome if treated early.	1
Abscisic acid is a phytohormone found in fruits and vegetables and is endogenously produced in mammals. In humans and mice, lanthionine synthetase C-like 2 (LANCL2) has been characterized as the natural receptor for ABA. Herein, we characterize the efficacy of a fig fruit extract of ABA in promoting glycemic control. This ABA-enriched extract, at 0.125 µg ABA/kg body weight, improves glucose tolerance, insulin sensitivity and fasting blood glucose in diet-induced obesity (DIO) and db/db mouse models. In addition to decreasing systemic inflammation and providing glycemic control without increasing insulin, ABA extract modulates the metabolic activity of muscle. ABA increases expression of important glycogen synthase, glucose, fatty acid and mitochondrial metabolism genes and increases direct measures of fatty acid oxidation, glucose oxidation and metabolic flexibility in soleus muscle cells from ABA-treated mice with DIO. Glycolytic and mitochondrial ATP production were increased in ABA-treated human myotubes. Further, ABA synergized with insulin to dramatically increase the rate of glycogen synthesis. The loss of LANCL2 in skeletal muscle abrogated the effect of ABA extract in the DIO model and increased fasting blood glucose levels. This data further supports the clinical development of ABA in the treatment of pre-diabetes, type 2 diabetes and metabolic syndrome.	0
Pituitary stalk interruption syndrome (PSIS) consisting of the triad: ectopic posterior pituitary (EPP), thin or absent pituitary stalk and anterior pituitary hypoplasia is a rare pituitary malformation with variable degrees of pituitary insufficiency, from isolated growth hormone deficiency to TSH, gonadotropin and ACTH deficiency which may occur in time, with normo, hyper or hypoprolactinemia and central diabetes insipidus in up to 10% of cases. Also, extrapituitary malformations have been described in some cases. Genetic defects were identified only in 5% of cases. MRI findings are considered predictive for the endocrine phenotype. We aim to describe two cases with PSIS without central diabetes insipidus, anosmia and extrapituitary malformations, except for minor head dysmorphic features. The first case was referred at the age of 4 years for short stature (-4SDS for height, bone age 2 years), diagnosed with severe GH deficiency and developed central hypothyroidism and hypoprolactinemia during five-years follow-up. The second case, a 26 year old male with birth asphyxia, cryptorchidism, poor growth in childhood and adolescence (-3 to -4 height SDS), absent puberty and normal adult height (-1.18 SDS; bone age 15.5 years and active growth plates) had GH, TSH, ACTH deficiency and low normal PRL levels. Increasing medical awareness on PSIS clinical and endocrine heterogeneity may help a more early and accurate diagnosis. Corroboration of neuroimaging and endocrine data will improve our knowledge and understanding and will create premises for molecular diagnosis, genetic counseling and a better patients' management.	0
Rhizomelic chondrodysplasia punctata (RCDP) is a rare genetic disorder caused by mutations in peroxisomal genes essential for plasmalogen biosynthesis. Plasmalogens are a class of membrane glycerophospholipids containing a vinyl-ether-linked fatty alcohol at the sn-1 position that affect functions including vesicular transport, membrane protein function and free radical scavenging. A logical rationale for the treatment of RCDP is therefore the therapeutic augmentation of plasmalogens. The objective of this work was to provide a preliminary characterization of a novel vinyl-ether synthetic plasmalogen, PPI-1040, in support of its potential utility as an oral therapeutic option for RCDP. First, wild-type mice were treated with 13C6-labeled PPI-1040, which showed that the sn-1 vinyl-ether and the sn-3 phosphoethanolamine groups remained intact during digestion and absorption. Next, a 4-week treatment of adult plasmalogen-deficient Pex7 hypo/null mice with PPI-1040 showed normalization of plasmalogen levels in plasma, and variable increases in plasmalogen levels in erythrocytes and peripheral tissues (liver, small intestine, skeletal muscle and heart). Augmentation was not observed in brain, lung and kidney. Functionally, PPI-1040 treatment normalized the hyperactive behavior observed in the Pex7 hypo/null mice as determined by open field test, with a significant inverse correlation between activity and plasma plasmalogen levels. Parallel treatment with an equal amount of ether plasmalogen precursor, PPI-1011, did not effectively augment plasmalogen levels or reduce hyperactivity. Our findings show, for the first time, that a synthetic vinyl-ether plasmalogen is orally bioavailable and can improve plasmalogen levels in an RCDP mouse model. Further exploration of its clinical utility is warranted.This article has an associated First Person interview with the joint first authors of the paper.	0
We provide a nationwide population study of patients with congenital muscular dystrophy in Italy.Cases were ascertained from the databases in all the tertiary referral centers for pediatric neuromuscular disorders and from all the genetic diagnostic centers in which diagnostic tests for these forms are performed.The study includes 336 patients with a point prevalence of 0.563 per 100,000. Mutations were identified in 220 of the 336 (65.5%). The cohort was subdivided into diagnostic categories based on the most recent classifications on congenital muscular dystrophies. The most common forms were those with α-dystroglycan glycosylation deficiency (40.18%) followed by those with laminin α2 deficiency (24.11%) and collagen VI deficiency (20.24%). The forms of congenital muscular dystrophy related to mutations in SEPN1 and LMNA were less frequent (6.25% and 5.95%, respectively).Our study provides for the first time comprehensive epidemiologic information and point prevalence figures for each of the major diagnostic categories on a large cohort of congenital muscular dystrophies. The study also reflects the diagnostic progress in this field with an accurate classification of the cases according to the most recent gene discoveries.	1
The aim of this retrospective study was to determine the prevalence of lysosomal storage disorders (LSDs) in the Czech Republic. The data on cases diagnosed between 1975 and 2008 were collected and analyzed. The overall prevalence of LSDs in the Czech population (12.25 per 100,000) is comparable to that reported for the countries with well-established and advanced diagnostics of LSDs such as the Netherlands (14 per 100,000), Australia (12.9 per 100,000) and Italy (12.1 per 100,000). Relatively higher prevalence of LSDs was reported in the north of Portugal (25 per 100,000). Thirty-four different LSDs were diagnosed in a total of 478 individuals. Gaucher disease was the most frequent LSD with a birth prevalence of 1.13 per 100,000 births. The most frequent LSD groups were lipidoses, mucopolysaccharidoses, and neuronal ceroid lipofuscinoses, with combined prevalences of 5.0, 3.72, and 2.29 per 100,000 live births, respectively. Glycoproteinoses (0.57 per 100,000 live births), glycogenosis type II (0.37), and mucolipidoses (0.31) rarely occur in the Czech population, and a range of other LSDs have not been detected at all over the past three decades. Knowledge of the birth prevalence and carrier frequency of particular disorders is important in genetic counselling for calculation of the risk for the disorder in the other members of affected families. Earlier diagnosis of these disorders will permit timely intervention and may also result in lowering of the number of newborns with LSDs.	1
This study examined the health-related quality of life (HRQoL) and psychological functioning of children and young adults with Gaucher disease, type 1 (GD1). Thirty-two (17 pediatric, 15 young adult) patients with GD1 and one parent completed age-appropriate assessments of HRQoL, emotional, and behavioral health. The HRQoL of children with GD1 was compared with a healthy sample and to children diagnosed with Fabry disease (FD; another lysosomal storage disease), while young adults were compared to a healthy sample and to patients with self-reported chronic illnesses. Children with GD1 reported significantly lower HRQoL across all domains relative to healthy counterparts yet comparable HRQoL compared to children with FD. Young adults reported mildly lower physical functioning than healthy peers, but no differences in HRQoL relative to the chronic illness sample. Parent-reported symptom severity was associated with poorer HRQOL in children but not young adults. Few group differences in psychological functioning were observed, except young children showed more school problems than the normative average and there was a trend toward internalizing symptoms. Overall, results consistently identified younger patients with GD1 as more affected than older patients in HRQoL and psychological domains. Implementation of psychosocial interventions may be particularly beneficial during early childhood.	0
OBJECTIVE:To carry out genetic testing for a male infant suspected for Menkes disease. METHODS:Genomic DNA of the proband and his parents were extracted and subjected to family trio whole exome sequencing (WES). Microduplication and microdeletion of the ATP7A gene were detected by multiplex ligation-dependent probe amplification (MLPA). Suspected variants were subjected to bioinformatic analysis and verified by Sanger sequencing. RESULTS:The proband was found to harbor a de novo c.1870 -13T>G variation of the ATP7A gene, which may alter a splice site and affect its protein product. CONCLUSION:The patient was diagnosed with Menkes disease due to the c.1870 -13T>G variant of the ATP7A gene. Whole exome sequencing of family trios is a powerful tool for the diagnosis of diseases with strong phenotypic heterogeneity.	0
Synovial sarcoma is a type of soft tissue sarcoma that commonly occurs around large joints. However, primary intra-articular synovial sarcoma is considered an extremely rare variant of synovial sarcoma. We present a case of synovial sarcoma arising from the hip joint in a 17-year-old female patient. Clinical, radiographic, magnetic resonance imaging and histopathology findings are described. The patient underwent neoadjuvant chemoradiation therapy followed by right hemipelvectomy, and there was no local recurrence in the subsequent follow ups. Unfortunately, the patient had pleural metastasis, and she was treated with palliative chemotherapy. To the best of our knowledge, there is only one published case report in the English literature on intra-articular synovial sarcoma from the hip joint.	0
'Polar gigantism' describes a biogeographic pattern in which many ectotherms in polar seas are larger than their warmer-water relatives. Although many mechanisms have been proposed, one idea-the oxygen-temperature hypothesis-has received significant attention because it emerges from basic biophysical principles and is appealingly straightforward and testable. Low temperatures depress metabolic demand for oxygen more than supply of oxygen from the environment to the organism. This creates a greater ratio of oxygen supply to demand, releasing polar organisms from oxygen-based constraints on body size. Here we review evidence for and against the oxygen-temperature hypothesis. Some data suggest that larger-bodied taxa live closer to an oxygen limit, or that rising temperatures can challenge oxygen delivery systems; other data provide no evidence for interactions between body size, temperature, and oxygen sufficiency. We propose that these findings can be partially reconciled by recognizing that the oxygen-temperature hypothesis focuses primarily on passive movement of oxygen, implicitly ignoring other important processes including ventilation of respiratory surfaces or internal transport of oxygen by distribution systems. Thus, the hypothesis may apply most meaningfully to organisms with poorly developed physiological systems (eggs, embryos, egg masses, juveniles or adults without mechanisms for ventilating internal or external surfaces). Finally, most tests of the oxygen-temperature hypothesis have involved short-term experiments. Many organisms can mount effective responses to physiological challenges over short time periods; however, the energetic cost of doing so may have impacts that appear only in the longer term. We therefore advocate a renewed focus on long-term studies of oxygen-temperature interactions.	0
PURPOSE:To evaluate multimodal imaging findings of solitary idiopathic choroiditis (SIC; also known as unifocal helioid choroiditis) to clarify its origin, anatomic location, and natural course. DESIGN:Multicenter retrospective observational case series. PARTICIPANTS:Sixty-three patients with SIC in 1 eye. METHODS:Demographic and clinical data were collected. Multimodal imaging included color fundus photography, OCT (including swept-source OCT), OCT angiography (OCTA), fundus autofluorescence, fluorescein and indocyanine green angiography, and B-scan ultrasonography. MAIN OUTCOME MEASURES:Standardized grading of imaging features. RESULTS:Mean age at presentation was 56 ± 15 years (range, 12-83 years). Mean follow-up duration in 39 patients was 39 ± 55 months (range, 1 month-25 years). The lesions measured a mean of 2.4 × 2.1 mm in basal diameter, were located inferior (64%) or nasal to the optic disc, and appeared yellow (53%). No systemic associations were found. The lesions all appeared as an elevated subretinal mass, with OCT demonstrating all lesions to be confined to the sclera, not the choroid. On OCT, the deep lesion margin was visible in 12 eyes with a mean lesion thickness of 0.6 mm. Overlying choroidal thinning or absence was seen in 95% (mean choroidal thickness, 28 ± 35 μm). Mild subretinal fluid was observed overlying the lesions in 9 patients (14%). Retinal pigment epithelial disruption and overlying retinal thinning was observed in 56% and 57%, respectively. OCT angiography was performed in 13 eyes and demonstrated associated choroidal and lesional flow voids. Four lesions (6%) were identified at the macula, leading to visual loss in 1 patient. One lesion demonstrated growth and another lesion showed spontaneous resolution. CONCLUSIONS:In this largest series to date, multimodal imaging of SIC demonstrated a scleral location in all patients. The yellow and white clinical appearance may be related to scleral unmasking resulting from atrophy of overlying tissues. Additional associated features included documentation of deep margin on swept-source OCT, trace subretinal fluid in a few patients, and OCTA evidence of lesional flow voids. Because of the scleral location of this lesion in every patient, a new name, focal scleral nodule, is proposed.	0
Galactosemia is the inherited inability to metabolise galactose. The most common results from a lack of galactose 1-phosphate uridylyltransferase activity. The current treatment, removal of galactose from the diet, is inadequate and often fails to prevent long-term complications. Since 2015, three patents have been filed describing novel therapies. These are: the use of aldose reductase inhibitors to reduce cataracts and, possibly, other symptoms; salubrinal to stimulate cellular stress responses; mRNA therapy to increase cellular galactose 1-phosphate uridylyltransferase activity. The viability of all three is supported by academic studies. The potential and drawbacks of all three are discussed and evaluated.	0
We investigated the genetic origin of the phenotype of three children from two unrelated Italian families presenting with a previously-unrecognized, seemingly autosomal recessive disorder that included a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability, and Leber congenital amaurosis (SHILCA), as well as some brain anomalies that were visible at the MRI. Autozygome-based analysis showed that these children shared a 4.6 Mb region of homozygosity on chromosome 1, with an identical haplotype. Nonetheless, whole-exome sequencing failed to identify any shared rare coding variants, in this region or elsewhere. We then determined the transcriptome of patients' fibroblasts by RNA sequencing, followed by additional whole-genome sequencing experiments. Gene expression analysis revealed a 4-fold downregulation of the gene NMNAT1, previously associated with Leber congenital amaurosis (LCA) and residing in the shared autozygous interval. Short- and long-read whole-genome sequencing highlighted a duplication involving 2 out of the 5 exons of NMNAT1 main isoform (NM_022787.3), leading to the production of aberrant mRNAs. No other pathogenic variants in NMNAT1 have been previously shown to cause non-syndromic LCA. However, no patient with null biallelic variants has ever been described, and murine Nmnat1 knockouts show embryonic lethality. We hypothesize that complete absence of NMNAT1 activity is not compatible with life. The rearrangement found in our cases, presumably causing a strong but not complete reduction of enzymatic activity, may therefore result in an intermediate syndromic phenotype, between non-syndromic LCA and lethality.	0
Dermochondrocorneal dystrophy (François' syndrome) is an extremely rare disorder characterized by firm, nodular lesions involving the hands and the face; osteochondrodystrophy of the peripheral extremital bones, resulting in limitation of movement; and corneal dystrophy marked by white or brownish opacities. A nonfamilial case of dermochondrocorneal dystrophy was studied in a 45-year-old woman who had severe involvement of the gingival and palatal mucous membranes.	0
OBJECTIVE:To investigate the presence of the Angiopoietin 1 (ANGPT1) and Plasminogen (PLG) mutations in patients with Hereditary Angioedema (HAE) and normal C1 esterase inhibitor (C1-INH) levels, who do not harbor the F12 gene mutation. METHODS:Patients clinically diagnosed with HAE but without C1-INH deficiency or dysfunction and F12 gene mutation were evaluated. DNA extraction, quantification, and dilution were performed at a concentration of 100 ng/µL, followed by a DNA amplification (PCR) for molecular evaluation of exon 2 of the ANGPT1 gene and exon 9 of the PLG gene for identification of mutations c.807G>T / p.A119S and c.988A>G / p.K330E, respectively. The PCR product was evaluated in 1% agarose gel electrophoresis. Sequencing was performed using the Sanger method. The electropherograms were analyzed using the FASTA® program. RESULTS:DNA samples from 15 women were sequenced. Their ages ranged from 10 to 60 years and the normal C1 esterase and C4 inhibitor serum levels ranged from 22 to 39 mg/dL and from 10 to 40 mg/dL, respectively. No mutations were detected in the analyzed exons of ANGPT1 and PLG. However, a single-nucleotide polymorphism (SNP) was detected in two homozygotic and five heterozygotic patients. CONCLUSION:Further studies are needed to evaluate these SNPs and scrutinize their potential for use as molecular markers of HAE and as novel therapeutic targets.	0
Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the acid β-glucosidase gene (GBA1). Besides causing GD, GBA1 mutations constitute the main genetic risk factor for developing Parkinson's disease. The molecular basis of neurological manifestations in GD remain elusive. However, neuroinflammation has been proposed as a key player in this process. We exploited CRISPR/Cas9 technology to edit GBA1 in the human monocytic THP-1 cell line to develop an isogenic GD model of monocytes and in glioblastoma U87 cell lines to generate an isogenic GD model of glial cells. Both edited (GBA1 mutant) cell lines presented low levels of mutant acid β-glucosidase expression, less than 1% of residual activity and massive accumulation of substrate. Moreover, U87 GBA1 mutant cells showed that the mutant enzyme was retained in the ER and subjected to proteasomal degradation, triggering unfolded protein response (UPR). U87 GBA1 mutant cells displayed an increased production of interleukin-1β, both with and without inflammosome activation, α-syn accumulation and a higher rate of cell death in comparison with wild-type cells. In conclusion, we developed reliable, isogenic, and easy-to-handle cellular models of GD obtained from commercially accessible cells to be employed in GD pathophysiology studies and high-throughput drug screenings.	0
PURPOSE:To report a case of a drug-induced anterior uveitis secondary to the use of intracameral moxifloxacin. CASE REPORT:A 64-year-old Colombian male patient presented with severe ocular pain and photophobia in his left eye 15 days after cataract surgery. In the ophthalmology and glaucoma specialist evaluation, pigment dispersion in the anterior chamber and camerular angle, severe anterior segment inflammation, and elevated intraocular pressure were observed. Poor response to treatment for a suspected viral origin and exclusion of other possible etiologies, led to the conclusion of intracameral moxifloxacin induced anterior uveitis. CONCLUSION AND IMPORTANCE:We present the second published case worldwide about anterior uveitis secondary to intracameral moxifloxacin, which may rarely cause hypertensive uveitis that may be confused with viral uveitis. This provides evidence on the importance of postoperative follow-up by the surgeon for an early referral and treatment of these cases.	0
Primary liver cancer includes hepatocellular carcinoma (HCC, 75-85%) and intrahepatic cholangiocarcinoma (10-15%). The vast majority of patients with primary HCC are not candidates for surgical treatment. Surgical resection, liver transplantation and percutaneous puncture are effective potentially curable treatments for patients with early stage liver cancer. Radiation therapy is a non-surgical alternative treatment that has generally been used to treat patients with advanced liver cancer, although it's use in the potentially curative setting is increasing. Radiotherapy is a non-invasive local treatment which works through ionizing radiation. This review summarizes the efficacy and safety of commonly used radiotherapy methods, and reviews three-dimensional conformal radiotherapy (3DCRT), intensity modulated radiation therapy (IMRT), stereotactic body radiotherapy (SBRT), volume-modulated arc therapy (VMAT), and internal radiation therapies, for primary liver cancer (in particular for HCC).	0
The acetylcholine receptor (AChR) is a member of the superfamily of transmitter-gated ion channels having a critical role in controlling electrical signals between nerves and muscle cells. Disruptive mutations in genes encoding different subunits of AChR result in multiple pterygium syndrome (MPS), which can be associated with a severe prenatally lethal presentation. This study aimed to investigate the etiology of lethal MPS (LMPS) in two consanguineous families with a history of miscarriages. DNA was extracted from a tissue sample of two aborted fetuses (probands) from two different families with a history of spontaneous miscarriages. Parental peripheral blood samples were collected for confirmatory analysis and follow-up testing. Whole-exome sequencing (WES) was performed on DNA from the probands. The results were confirmed and segregated by Sanger sequencing. Moreover, protein structure evaluations were accomplished. We identified a homozygous frameshift mutation of c.753_754delCT (p.V253fs*44) and a homozygous missense mutation of c.715C>T (p.Arg239Cys) in the CHRNG gene. Both aborted fetuses had pterygium, severe arthrogryposis, and fetal hydrops with cystic hygroma, being compatible with LMPS. The heterozygous state was confirmed in parents for both CHRNG variants. Likewise, CHRNG mutation was predicted to display the damaging effects by lowering the number of helixes and modifying the surface electrostatic potential. The present study identified rare sequence variants in the CHRNG gene in aborted fetuses from consanguineous couples with recurrent miscarriage history. WES is a comprehensive and cost-effective approach to study heterogeneous diseases including MPS. Such findings can improve our knowledge of MPS databases, particularly for genetic counseling of high-risk families and preimplantation genetic diagnosis.	0
Pyle's disease is an extremely rare skeletal disorder characterized by a benign course and an autosomal recessive genetic pattern of inheritance. Its causal mutation is still unknown. In the medical literature, fewer than 30 cases have been described to date. We report the case of two female siblings, daughters of consanguineous parents, referred to the radiology department complaining of genu valgum. Laboratory tests showed no other relevant findings. Conventional radiography plain films revealed Erlenmeyer flask deformity in bilateral femorotibial metaphyses, metaphyseal flaring of long bones, and mild sclerosis of the skull base. The clinicoradiological dissociation, along with the characteristic imaging findings, was consistent with the diagnosis of Pyle's disease. Intervention is not required in most cases, but orthopedic treatment may be required for genu valgum or fractures. Therefore, these cases emphasize the pivotal role conventional radiography plays in the correct diagnosis of this rare entity, allowing for appropriate genetic counseling.	0
The human induced pluripotent stem cell (iPSC) line ZJUCHi002-A was established from renal epithelial cells present in urine (urinary cells) collected from an 8-year-old Charcot-Marie-Tooth disease type 2A (CMT2A) patient carrying point mutation in MFN2 (c.752C > T). Urinary cells were reprogrammed by retrovirus vectors containing reprogramming factors: OCT4, SOX2, KLF4 and c-MYC. The pluripotency, capacity of differentiation into 3 germ layers, silence of reprogramming factors and normal karyotype were all confirmed in this study.	0
Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disease affecting mainly the salivary and lacrimal glands characterized by lymphocytic infiltration which results in gland destruction and impairment of functions. SS rarely affects pediatric patients, and there are no clear diagnostic criteria as there are with adult SS. The present case reports an atypical case of SS in a 3-year-old female who was closely followed up with for 5 years. The important role of salivary gland ultrasonography (SGUS) in early diagnosis, the change in clinical picture, as well as fluctuation of serology, are noticed.	0
A20 is a ubiquitin-editing enzyme that is known to regulate inflammatory signaling and cell death. However, A20 mutations are also frequently found in multiple malignancies suggesting a potential role as a tumor suppressor as well. We recently described a novel role for A20 in regulating the wnt-beta-catenin signaling pathway and suppressing colonic tumor development in mice. The underlying mechanisms for this phenomenon are unclear. To study this, we first generated A20 knockout cell lines by genome-editing techniques. Using these cells, we show that loss of A20 causes dysregulation of wnt-dependent gene expression by RNAseq. Mechanistically, A20 interacts with a proximal signaling component of the wnt-signaling pathway, receptor interacting protein kinase 4 (RIPK4), and regulation of wnt-signaling by A20 occurs through RIPK4. Finally, similar to the mechanism by which A20 regulates other members of the receptor interacting protein kinase family, A20 modifies ubiquitin chains on RIPK4 suggesting a possible molecular mechanism for A20's control over the wnt-signaling pathway.	0
Pattern recognition, using a group of characteristic, or discriminating features, is a powerful tool in metabolic diagnostic. A classic example of this approach is used in biochemical analysis of urine organic acid analysis, where the reporting depends more on the correlation of pertinent positive and negative findings, rather than on the absolute values of specific markers. Similar uses of pattern recognition in the field of biochemical genetics include the interpretation of data obtained by metabolomics, like glycomics, where a recognizable pattern or the presence of a specific glycan sub-fraction can lead to the direct diagnosis of certain types of congenital disorders of glycosylation. Another indispensable tool is the use of clinical pattern recognition-or syndromology-relying on careful phenotyping. While genomics might uncover variants not essential in the final clinical expression of disease, and metabolomics could point to a mixture of primary but also secondary changes in biochemical pathways, phenomics describes the clinically relevant manifestations and the full expression of the disease. In the current review we apply phenomics to the field of congenital disorders of glycosylation, focusing on recognizable differentiating findings in glycosylation disorders, characteristic dysmorphic features and malformations in PMM2-CDG, and overlapping patterns among the currently known glycosylation disorders based on their pathophysiological basis.	0
Adult-onset Still's disease (AOSD) is a rare disease that is classified among the multifactorial autoinflammatory disorders. It is characterised by fever, arthritis and, a typical salmon-coloured rash, and is accompanied by fever at nights. Currently, there is limited data on the prevalence of AOSD.Patients diagnosed with AOSD at the Department of Rheumatology of Trakya University Medical Faculty, between 2003 to 2014 were reviewed retrospectively. Patients' clinical features, laboratory measurements, demographics, treatments, follow-up durations, disease courses, outcomes and complications were evaluated.Our study included 42 patients with AOSD of whom, 32 (76.2%) were females and 10 (23.8%) were males (female to male ratio: 3.2). Over the course of the study, the annual incidence of AOSD was 0.62/100,000; and the overall prevalence was 6.77/100,000. The most common findings were fever (97.6%), arthralgia (95.2%), arthritis (76.2%), rash (73.8%) and sore throat (40.5%).In our hospital-based study on AOSD which is a disease with very limited epidemiological data, the frequency of AOSD was found to be significantly higher than in other series. Female gender was more common in our series; and polycyclic pattern was more common in patients with longer follow-ups.	1
Lymphogranuloma venereum is a sexually transmitted infection caused by serotypes L1-3 of Chlamydia trachomatis and may present as hemorrhagic proctocolitis. The diagnosis of an active infection is difficult to establish, as confirmatory testing can be unreliable or unavailable. Imaging findings can be nonspecific and mimic malignancy or other chronic infectious and inflammatory disorders. In this report, we present a case of lymphogranuloma venereum proctocolitis and its computed tomography features to highlight the relevant imaging findings and importance of timely diagnosis.	0
Spinocerebellar ataxia type 28 (SCA28) is related to mutations of the ATPase family gene 3-like 2 gene (AFG3L2). To date, 13 private missense mutations have been identified in families of French, Italian, and German ancestry, but overall, the disorder seems to be rare in Europe. Here, we report a kindred of German ancestry with four affected family members presenting with slowly progressive ataxia, mild pyramidal tract signs and slow saccades.After excluding repeat expansions in the genes for SCA1-3, 6-8, 10, 12, and 17, Sanger sequencing of the coding regions of TTBK2 (SCA11), KCNC3 (SCA13), PRKCG (SCA14), FGF14 (SCA27) and AFG3L2 (SCA28) was performed. The 17 coding exons of AFG3L2 with flanking intronic sequences were amplified by PCR and sequenced on both strands.Sequencing detected a novel potential missense mutation (p.Y689N) in the C-terminal proteolytic domain, the mutational hotspot of AFG3L2. The online programme "PolyPhen-2" classifies this amino acid exchange as probably damaging (score 0.990). Similarly to most of the published SCA28 mutations, the novel mutation is located within exon 16. Mutations in exon 16 alter the proteolytic activity of the protease AFG3L2 that is highly expressed in Purkinje cells.Genetic testing should be considered in dominant ataxia with pyramidal tract signs and saccadic slowing.	0
Budd-Chiari syndrome (BCS), or hepatic venous outflow obstruction, is a rare cause of liver disease that should not be missed. Variable clinical presentation among patients with BCS necessitates a high index of suspicion to avoid missing this life-threatening diagnosis. BCS is characterized as primary or secondary, depending on etiology of venous obstruction. Most patients with primary BCS have several contributing risk factors leading to a prothrombotic state. A multidisciplinary stepwise approach is integral in treating BCS. Lifelong anticoagulation is recommended. Long-term monitoring of patients for development of cirrhosis, complications of portal hypertension, hepatocellular carcinoma, and progression of underlying diseases is important.	0
Brain malformations such as agenesis and dysgenesis of corpus callosum, pituitary hypoplasia, hypothalamic hamartoma, mesial temporal periventricular heterotopia, and abnormally oriented and misshapen hippocampi have been described with SOX2 gene mutations. A neocortical malformation is presented here in association with SOX2 deletion that over time underwent spontaneous evolution and decrease in size.	0
BACKGROUND:Greenberg dysplasia is a rare, autosomal recessive, prenatal lethal bone dysplasia caused by biallelic pathogenic variants in the lamin B receptor (LBR) gene. Pathogenic variants in LBR are also associated with Pelger-Huët anomaly, an autosomal dominant benign abnormality of the nuclear shape and chromatin organization of blood granulocytes, and Pelger-Huët anomaly with variable skeletal anomalies, a mild, regressing to moderate-severe autosomal recessive condition. Conditions with abnormal sterol metabolism and different genetic basis have clinical and radiographic features similar to Greenberg dysplasia, for example X-linked dominant chondrodysplasia punctata, Conradi-Hünermann type, and CHILD syndrome, and other conditions with unknown genetic etiology display very similar features, for example, dappled diaphyseal dysplasia and Astley-Kendall dysplasia. METHODS:We present a fetus with typical clinical and radiographic features of Greenberg dysplasia, and review the literature. RESULTS:Genetic testing confirmed the diagnosis Greenberg dysplasia: homozygosity for a pathogenic variant in LBR. CONCLUSION:Comparing the clinical and radiographic phenotypes of Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia, we suggest that these are allelic disorders.	0
Purpose:To investigate the clinical and virologic-associated and predictive factors of intraocular pressure (IOP) evolution over time and its severity in Fuchs' heterochromic iridocyclitis (FHC). Methods:Consecutive patients with both clinical FHC and intraocular synthesis of rubella virus (RV)-specific antibodies were included in this study. Specific ocular production of RV antibodies was confirmed using the quotient of serum/aqueous humor ratio of RV IgGs (Crv) and control antiviral IgGs (Cctl), using quantitative serology methods. Epidemiologic, clinical, biological, and virologic data at referral were collected and correlated with IOP values over time, occurrence, and severity of glaucoma. Results:Sixty-eight eyes of 68 patients were included. Mean age at diagnosis was 40.7 ± 11.1 years. Mean follow-up was 4.3 ± 4.3 years. Mean baseline Crv and Cctl values were 12.34 ± 14.67 and 216.70 ± 98.4, respectively. Mean baseline IOP was 17.2 ± 7.2 mm Hg (range, 9-40) and 15.6 ± 5.6 (range, 3-30) 5 years after referral. The predictive factors for pejorative IOP evolution over time and glaucoma severity were male sex (P = 0.03) and decreased Crv (P = 0.04) and presence of iris nodules (P < 0.001) and decreased Cctl (P = 0.02), respectively. Diagnostic delay was associated with increased likelihood of undergoing glaucoma surgery (P = 0.02). Conclusions:Time to diagnosis, male sex, presence of iris nodules at baseline, and decreased Crv and Cctl ratios were associated with increased likelihood of pejorative IOP evolution over time. Given the aggressiveness of glaucoma in FHC, these results provide interesting insight into what category of patients should need the closest screening.	0
A 25-year-old Canadian male with a history of 3-methylglutaconyl-coenzyme-A hydratase deficiency, also known as 3-methylglutaconic aciduria type I, a very rare inborn error of metabolism, presented with respiratory distress, nausea, vomiting and signs of multisystem organ failure due to a suspected underlying infectious process. An electrocardiogram revealed bilateral atrial enlargement and an elevated brain natriuretic peptide on the initial laboratory studies, which prompted a more thorough cardiac workup. The transthoracic echocardiogram revealed a dilated cardiomyopathy with severe systolic dysfunction. The deficient enzyme present in this patient is involved in the pathway of leucine catabolism and is particularly important in various tissues for energy production and sterol synthesis. The dilated cardiomyopathy in this patient possibly had a variety of potential mechanisms including: a mitochondrial myopathy due to the deficiency of this enzyme leading to a defect in energy production inside cardiac myocytes; or a direct toxicity from 3-methylglutaconic acid (3-MGA) and its toxic metabolites; or a cardiac dysfunction due to a variety of other potential mechanisms. In conclusion, this patient's clinical presentation suggested that 3-methylglutaconyl-CoA hydratase deficiency could cause a severe dilated cardiomyopathy and heart failure.	0
OBJECTIVE:Juvenile-onset mixed connective tissue disease (JMCTD) is a chronic inflammatory disease. We have previously demonstrated preclinical atherosclerosis in these patients, now exploring this further by assessing markers of endothelial dysfunction. METHODS:Thirty-three patients with JMCTD and 33 age-and sex-matched controls were included. Soluble intercellular adhesion molecule-1 (sICAM-1), Il-6 and, von Willenbrand factor (vWF) were assayed from blood taken at the time of carotid ultrasound. RESULTS:Our major findings were: (1) Levels of sICAM-1 (P < .001), IL-6 (P = .004), and vWF (P = .001) were higher, whereas (2) high density lipoprotein cholesterol (<.01) and apolipoprotein A1 (P < .01) were lower in the patient group compared to controls. CONCLUSIONS:Patients with JMCTD had significantly increased levels of markers of endothelial dysfunction.	0
INTRODUCTION:Alkaptonuria (AKU) is a rare inherited disorder of tyrosine metabolism resulting in an accumulation of homogentisic acid oxidation products in the joints and cardiovascular system. Aortic distensibility may be a non-invasive indicator of cardiovascular complications. Descending thoracic aortic distensibility in alkaptonuria has not been studied. METHODS:Patients diagnosed with alkaptonuria underwent Magnetic Resonance Imaging (MRI) and gated non-contrast and contrast-enhanced cardiovascular computed tomography. Using MRI cine images, aortic distensibility of the descending thoracic aorta was determined. RESULTS:Seventy-six patients with alkaptonuria were imaged. When compared to literature normal values, aortic distensibility in AKU was impaired (5.2 vs 6.2 × 10-3, p < .001). Aortic distensibility was inversely related to age (r = -0.6, p = .0001). Hypertensive patients with alkaptonuria had impaired distensibility compared to normotensive patients with alkaptonuria (4.6 vs 5.6 × 10-3, p = .03), and hyperlipidemic patients with alkaptonuria had impaired distensibility compared to non-hyperlipidemic patients with alkaptonuria (4.1 vs 6.0 × 10-3, p = .001). Male hypertensive patients with alkaptonuria had greater distensibility than their female counterparts (5.3 vs 2.9 × 10-3, p = .02). Similarly, male hyperlipidemic patients with alkaptonuria had greater distensibility than their female counterparts (4.8 vs 2.5 × 10-3, p < .01). Of patients with alkaptonuria, those with a coronary artery calcium (CAC) score greater than 100 had more impaired distensibility than those with a CAC score less than 100 (3.5 vs 5.1 × 10-3, p = .01) and those with aortic calcium score greater than 100 had impaired distensibility compared to those with an aortic calcium score less than 100 (3.2 vs 4.9 × 10-3, p = .02). Univariate analysis revealed age, aortic calcification, and hyperlipidemia to be significant factors of distensibility, and multiple regression analysis showed age as the only significant risk factor of distensibility. CONCLUSIONS:Patients with alkaptonuria have impaired aortic distensibility, which is likely an early marker for reduced cardiovascular health. Variables such as age, hypertension, hyperlipidemia, and aortic and coronary calcification were associated with impaired distensibility.	0
Peeling skin syndrome is a relatively rare clinical case with pathology of apparently normal skin that needs clinical details to reach accurate diagnoses. Hence, this case was used as examples to declare how it is important for both the pathologist and the dermatologist to cooperate to reach an accurate diagnosis.	0
OBJECTIVES:Too little is known about hearing loss rehabilitation in patients with Alström syndrome (AS). Benefits of hearing aids (HA) have not been fully documented and only one case treated with a Cochlear Implant (CI) has been described in the proceedings of a conference. Furthermore, comorbidities and risk of complications following surgical intervention may contraindicate Cochlear Implant procedures in these patients.The present case report concerns the first AS patient with CI in the literature. METHODS:After reporting a concise description of the audiological profile of patients with AS described in the literature, the case of a 22-year-old woman with genetically confirmed Alström syndrome who underwent a sequential bilateral CI (Bi-CI) rehabilitation is reported. Audiological results before and after cochlear implantation are described. RESULTS:The patient showed an excellent functional outcome with CIs, which enabled her to achieve communicative, social and academic results comparable with her peers, and no complications occurred. CONCLUSIONS:AS is not necessarily an absolute contraindication to CI. For many AS patients, a good cognitive function and adequate life expectancy represent a clear indication to prompt and adequate hearing rehabilitation with CIs. The description of this type of clinical cases could in the future also generate indications for a tailored audiological treatment of patients with very specific needs, such as patients with Alström Syndrome.	0
To determine the cortical mechanism that underlies the cognitive impairment and motor disability in hereditary spastic paraplegia (HSP), nine HSP patients from a Chinese family were examined using clinical evaluation, cognitive screening, and genetic testing. Controls were matched healthy subjects. White-matter fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD; tract-based spatial statistics), cortical thickness (FreeSurfer), and subcortical gray matter (FIRST) based on T1-weighted MRI and diffusion tensor imaging were analyzed. A novel mutation in the SPAST gene (NM_014946.3, c.1321+2T>C) was detected. Patients had motor disability and low Montreal Cognitive Assessment (MoCA) scores. Patients showed significantly decreased total gray- and white-matter volumes, corpus callosum volume, cortical thickness, and subcortical gray-matter volume as well as significantly lower FA and AD values and significantly higher MD and RD values in the corpus callosum and corticospinal tract. Cortical thickness, subcortical gray-matter volume, and MoCA score were negatively correlated with disease duration. Cortical thickness in the right inferior frontal cortex was negatively correlated with Spastic Paraplegia Rating Scale score. Cortical thickness and right hippocampus volume were positively correlated with the MoCA score and subscores. In conclusion, brain damage is not restricted to the white matter in SPG4-HSP patients, and widespread gray-matter damage may account for the disease progression, cognitive impairment, and disease severity in SPG4-HSP.	0
BACKGROUND:Double aneuploidies - especially in combination with structural aberrations - are extremely rare among liveborns. The most frequent association is that of Down (DS) and Klinefelter syndromes (KS). We present the case of a male newborn with a unique 47,XY,+ 21[80%]/48,XY,+i(X)(q10),+ 21[20%] karyotype, hypothesize about his future phenotype, discuss the aspects of management and review the literature. CASE PRESENTATION:The additional association of isochromosome Xq (i(X)(q10)) could be the result of a threefold non-disjunction event. 47,XY,+i(X)(q10) KS is not common and its symptoms differ from the classical KS phenotype. In combined DS and i(X)(q10) KS, the anticipatory phenotype is not simply the sum of the individual syndromic characteristics. This genotype is associated with higher risk for several diseases and certain conditions with more pronounced appearance: emotional and behavioral disorders; poorer mental and physical quality of life; lower muscle mass/tone/strength; connective tissue weakness; muscle hypotonia and feeding difficulties; osteopenia/-porosis with earlier beginning and faster progression; different types of congenital heart diseases; more common occurrence of hypertension; increased susceptibility to infections and female predominant autoimmune diseases; higher risk for hematological malignancies and testicular tumors. CONCLUSIONS:In multiple aneuploidies, the alterations have the potential to weaken or enhance each other, or they may not have modifying effects at all. Prenatal ultrasound signs are not obligatory symptoms of numerous chromosomal anomalies (specifically those involving supernumerary sex chromosomes), therefore combined prenatal screening has pertinence in uncomplicated pregnancies as well.	0
We present a case of mild, adult-onset dopa-responsive dystonia (DRD) with a heterozygous mutation in the tyrosine hydroxylase (TH) gene. We propose that this genetic state may have led to partial enzyme deficiency. Future studies should attempt to identify and characterize the phenotype of other patients with single TH variants.	0
BACKGROUND:The relation between brain functional connectivity of patients with neuromyelitis optica spectrum disorder (NMOSD) and the degree of disability remains unclear. OBJECTIVE:Compare brain functional connectivity of patients with NMOSD to healthy subjects in resting-state functional MRI (rs-fMRI). METHODS:We compared the rs-fMRI connectivity in 12 NMOSD patients with 20 healthy subjects matched for age and sex. Graph theory analysis was used to quantify the role of each node using a set of metrics: degree, global efficiency, clustering and modularity. To summarize the abnormal connectivity profile of brain regions in patients compared to healthy subjects, we defined a hub disruption index κ. RESULTS:Concerning the global organization of networks in NMOSD, a small-world topology was preserved without significant modification concerning all average metrics. However, visual networks and the sensorimotor network showed decreased connectivity with high interindividual variability. The hub disruption index κ was correlated to the Expanded Disability Status Scale (EDSS). CONCLUSION:These results demonstrate a correlation between disability according to the EDSS and neuronal reorganization using the rs-fMRI graph methodology. The conservation of a normal global topological structure despite local modifications in functional connectivity seems to show brain plasticity in response to the disability.	0
Cryoelectron microscopy and mutational analyses have shown that type 1 ryanodine receptor (RyR1) amino acid residues RyR1-E3893, -E3967, and -T5001 are critical for Ca2+-mediated activation of skeletal muscle Ca2+ release channel. De novo missense mutation RyR1-Q3970K in the secondary binding sphere of Ca2+ was reported in association with central core disease (CCD) in a 2-yr-old boy. Here, we characterized recombinant RyR1-Q3970K mutant by cellular Ca2+ release measurements, single-channel recordings, and computational methods. Caffeine-induced Ca2+ release studies indicated that RyR1-Q3970K formed caffeine-sensitive, Ca2+-conducting channel in HEK293 cells. However, in single-channel recordings, RyR1-Q3970K displayed low Ca2+-dependent channel activity and greatly reduced activation by caffeine or ATP. A RyR1-Q3970E mutant corresponds to missense mutation RyR2-Q3925E associated with arrhythmogenic syndrome in cardiac muscle. RyR1-Q3970E also formed caffeine-induced Ca2+ release in HEK293 cells and exhibited low activity in the presence of the activating ligand Ca2+ but, in contrast to RyR1-Q3970K, was activated by ATP and caffeine in single-channel recordings. Computational analyses suggested distinct structural rearrangements in the secondary binding sphere of Ca2+ of the two mutants, whereas the interaction of Ca2+ with directly interacting RyR1 amino acid residues Glu3893, Glu3967, and Thr5001 was only minimally affected. We conclude that RyR1-Q3970 has a critical role in Ca2+-dependent activation of RyR1 and that a missense RyR1-Q3970K mutant may give rise to myopathy in skeletal muscle.	0
This article reviews the majority of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) with emphasis in Pediatric Pathology describing and illustrating lesions as varied as ureteral duplications, ureteropelvic junction obstruction, horseshoe kidney, posterior urethral valve and prune belly syndrome, obstructive renal dysplasia, nonmotile ciliopathies and several syndromes associated with renal malformations (Meckel-Joubert, short rib, Bardet-Biedl, asplenia/polysplenia, hereditary renal adysplasia, Zellweger, trisomies, VACTER-L, Potter, caudal dysplasia, and sirenomelia), as well as ADPK, and ARPK. The purpose of this review is not only to describe the congenital renal anomalies, but also to analyze the more recent therapeutic interventions that may modify the natural history of some of these severe conditions.	0
Introduction: An increase of serum dehydroepiandrosterone (DHEA) sulfate (DHEAS) is observed in premature adrenarche and congenital adrenal hyperplasia. Very high DHEAS levels are typical for adrenal tumors. Approximately 74% of DHEAS is hydrolyzed to DHEA by the steroid sulfatase (STS). The reverse reaction is DHEA sulfation. Besides these two enzyme reactions, the DHEAS transported through the cell membrane is important for its distribution and excretion. Case Presentation: We present a female adolescent with overweight and a very high DHEAS. The presence of a DHEAS-producing tumor was rejected using ultrasonography, Magnetic Resonance Tomography (MRT), and dexamethasone suppression. STS deficiency was suspected. Sequence analysis revealed a heterozygous nonsense mutation which predicts a truncation of the carboxyl region of the STS that is implicated in substrate binding. No partial gene deletion outside exon 5 was detected by multiplex ligation-dependent probe amplification. The bioassay revealed normal enzyme activity in the patient's leukocytes. A defect of transporter proteins was suggested. Both efflux [multidrug-resistance protein (MRP)2 and breast cancer-resistance protein (BCRP)] and uptake [organic anion-transporting polypeptide (OATP) and organic anion transporter (OAT) carriers] transporters were studied. Sequence analysis of exons revealed a heterozygous Q141K variant for BCRP. Conclusions: A novel heterozygous nonsense mutation in the STS gene and a known heterozygous missense variant in the BCRP gene were found. The heterozygous nonsense mutation in the STS gene is not supposed to be responsible for STS deficiency. The BCRP variant is associated with reduced efflux transport activity only in its homozygous state. The combination of the two heterozygous mutations could possibly explain the observed high levels of DHEAS and other sulfated steroids.	0
Phytosphingosine (PHS) is the major long-chain base component of sphingolipids in Saccharomyces cerevisiae The PHS metabolic pathway includes a fatty acid (FA) α-oxidation reaction. Recently, we identified the novel protein Mpo1, which is involved in PHS metabolism. However, the details of the FA α-oxidation reaction and the role of Mpo1 in PHS metabolism remained unclear. In the present study, we revealed that Mpo1 is involved in the α-oxidation of 2-hydroxy (2-OH) palmitic acid (C16:0-COOH) in the PHS metabolic pathway. Our in vitro assay revealed that not only the Mpo1-containing membrane fraction but also the soluble fraction was required for the α-oxidation of 2-OH C16:0-COOH. The addition of Fe2+ eliminated the need for the soluble fraction. Purified Mpo1 converted 2-OH C16:0-COOH to C15:0-COOH in the presence of Fe2+, indicating that Mpo1 is the enzyme body responsible for catalyzing the FA α-oxidation reaction. This reaction was also found to require an oxygen molecule. Our findings indicate that Mpo1 catalyzes the FA α-oxidation reaction as 2-OH fatty acid dioxygenase, mediated by iron(IV) peroxide. Although numerous Mpo1 homologs exist in bacteria, fungi, protozoa, and plants, their functions had not yet been clarified. However, our findings suggest that these family members function as dioxygenases.	0
Isolated limb reduction defects occur in approximately 1 in 2000 live births within which central ray anomalies are an important subgroup. Most affected persons have mild or moderate functional impairment. Considerable psychological morbidity may also occur. While there have been major strides forwards in our understanding of vertebrate limb development, the mechanisms responsible for central ray deformities remain poorly understood. Several case reports of central clefting anomalies associated with chromosomal rearrangements or interstitial deletions of 7q21.2-q21.3 suggest that this chromosomal region is important for limb development.	0
Seckel syndrome (SS) is a rare spectrum of congenital severe microcephaly and dwarfism. One SS-causative gene is Ataxia Telangiectasia and Rad3-Related Protein (ATR), and ATR (c.2101 A>G) mutation causes skipping of exon 9, resulting in a hypomorphic ATR defect. This mutation is considered the cause of an impaired response to DNA replication stress, the main function of ATR, contributing to the pathogenesis of microcephaly. However, the precise behavior and impact of this splicing defect in human neural progenitor cells (NPCs) is unclear. To address this, we established induced pluripotent stem cells (iPSCs) from fibroblasts carrying the ATR mutation and an isogenic ATR-corrected counterpart iPSC clone. SS-patient-derived iPSCs (SS-iPSCs) exhibited cell type-specific splicing; exon 9 was dominantly skipped in fibroblasts and iPSC-derived NPCs, but it was included in undifferentiated iPSCs and definitive endodermal cells. SS-iPSC-derived NPCs (SS-NPCs) showed distinct expression profiles from ATR non-mutated NPCs with negative enrichment of neuronal genesis-related gene sets. In SS-NPCs, abnormal mitotic spindles occurred more frequently than in gene-corrected counterparts, and the alignment of NPCs in the surface of the neurospheres was perturbed. Finally, we tested several splicing-modifying compounds and found that TG003, a CLK1 inhibitor, could pharmacologically rescue the exon 9 skipping in SS-NPCs. Treatment with TG003 restored the ATR kinase activity in SS-NPCs and decreased the frequency of abnormal mitotic events. In conclusion, our iPSC model revealed a novel effect of the ATR mutation in mitotic processes of NPCs and NPC-specific missplicing, accompanied by the recovery of neuronal defects using a splicing rectifier.	0
In patients with the behavioral variant of frontotemporal dementia, the core clinical phenotype of frontotemporal lobar degeneration, various social behaviors such as disinhibition, apathy, lack of empathy, stereotypy, and changes in eating behavior occur from the onset of the disease, and progresses slowly with frontal lobe damage. Because there are no disease-specific biomarkers, the diagnosis of frontotemporal dementia is based on the evaluation of behavioral symptoms, with neuroimaging methods and cognitive tests as assisting methods. Although diagnostic criteria are useful, frontotemporal dementia may be difficult to differentiate from other conditions, including mental illnesses. We need to be careful to avoid overdiagnosis and underdiagnosis.	0
BACKGROUND:The "nonclassic" apparent mineralocorticoid excess (NC-AME) has been identified in approximately 7% of general population. This phenotype is characterized by low plasma renin activity (PRA), high serum cortisol (F) to cortisone (E) ratio, low cortisone, high Fractional Excretion of potassium (FEK) and normal-elevated systolic blood pressure (SBP). An early detection and/or identification of novel biomarkers of this phenotype could avoid the progression or future complications leading to arterial hypertension. Isolation of extracellular vesicles, such as exosomes, in specific biofluids support the identification of tissue-specific RNA and miRNA, which may be useful as novel biomarkers. Our aim was to identify miRNAs within urinary exosomes associated to the NC-AME phenotype. METHODS:We perform a cross-sectional study in a primary care cohort of 127 Chilean subjects. We measured BP, serum cortisol, cortisone, aldosterone, PRA. According to the previous reported, a subgroup of subjects was classified as NC-AME (n = 10). Urinary exosomes were isolated and miRNA cargo was sequenced by Illumina-NextSeq-500. RESULTS:We found that NC-AME subjects had lower cortisone (p < 0.0001), higher F/E ratio (p < 0.0001), lower serum potassium (p = 0.009) and higher FEK 24 h (p = 0.03) than controls. We found miR-204-5p (fold-change = 0.115; p 0.001) and miR-192-5p (fold-change = 0.246; p 0.03) are both significantly downregulated in NC-AME. miR-192-5p expression was correlated with PRA (r = 0.45; p 0.028) and miR-204-5p expression with SBP (r = - 0.48, p 0.027) and F/E ratio (r = - 0.48; p 0.026). CONCLUSIONS:These findings could support a potential role of these miRNAs as regulators and novel biomarkers of the NC-AME phenotype.	0
Neutrophils are the most abundant innate cell population and a key immune player against invading pathogens. Neutrophils can kill both bacterium and spores of Bacillus anthracis, the causative anthrax pathogen. Unlike interactions with professional phagocytes, the molecular recognition of anthrax by neutrophils is largely unknown. In this study, we investigated the role of complement C3 deposition on anthrax particles for neutrophil recognition of bacterium and/or its cell wall peptidoglycan, an abundant pathogen-associated molecular pattern that supports anthrax sepsis. C3 opsonization and recognition by complement receptors accounted for 70-80% of the affinity interactions between neutrophils and anthrax particles at subphysiologic temperatures. In contrast, C3 supported up to 50% of the anthrax particle ingestion under thermophysiologic conditions. Opsonin-dependent low affinity interactions and, to a lower extent, opsonin-independent mechanisms, provide alternative entry routes. Similarly, C3 supported 58% of peptidoglycan-induced degranulation and, to a lower extent, 23% of bacterium-induced degranulation. Interestingly, an opsonin independent mechanism mediated by complement C5, likely through C5a anaphylatoxin, primes azurophilic granules in response to anthrax particles. Overall, we show that C3 deposition supports anthrax recognition by neutrophils but is dispensable for pathogen ingestion and neutrophil degranulation, highlighting immune recognition redundancies that minimize the risk of pathogen evasion.	0
Background:Glutaric acidemia (GAI) and mucopolysaccharidosis type IIIB (MPSIIIB) are two rare genetic disorders caused by pathogenic variants in two different genes. Here, we report a coexistence of these two different rare disorders in an individual. Methods:A four-year-old Iranian boy born to first-cousin parents suspected to have MPSIIIB and/or GAI was investigated in this study. Targeted genomic enrichment and next-generation sequencing were used to examine genes related to MPS and GA. Sanger sequencing was performed to confirm the results. Results:Two homozygous likely pathogenic variants in α-N-acetylglucosaminidase (NAGLU) and GCDH genes were found and confirmed in the proband. Conclusion:A combination of specific features of two different diseases in a patient has been reported here. More studies on this case and similar cases can provide more information about the effect of simultaneous pathogenic variants in different genes.	0
Mutations in the ATPase family 3-like gene (AFG3L2) have been linked to autosomal-dominant spinocerebellar ataxia type 28 and autosomal recessive spastic ataxia-neuropathy syndrome. Here, we describe the case of a child carrying bi-allelic mutations in AFG3L2 and presenting with ictal paroxysmal episodes associated with neuroimaging suggestive of basal ganglia involvement. Studies in skin fibroblasts showed a significant reduction of AFG3L2 expression. The relatively mild clinical presentation and the benign course, in spite of severe neuroimaging features, distinguish this case from data reported in the literature, and therefore expand the spectrum of neurological and neuroradiological features associated with AFG3L2 mutations.	0
Congenital Dyserythropoietic Anemia (CDA) is a heterogeneous group of hematological disorders characterized by chronic hyporegenerative anemia and distinct morphological abnormalities of erythroid precursors in the bone marrow. In many cases, a final diagnosis is not achieved due to different levels of awareness for the diagnosis of CDAs and lack of use of advanced diagnostic procedures. Researchers have identified five major types of CDA: types I, II, III, IV, and X-linked dyserythropoietic anemia and thrombocytopenia (XLDAT). Proper management in CDA is still unsatisfactory, as the different subtypes of CDA have different genetic causes and different but overlapping patterns of signs and symptoms. For this reason, we developed a new telemedicine tool that will help doctors to achieve a faster diagnostic for this disease. Using open access code, we have created a responsive webpage named CoDysAn (Congenital Dyserythropoietic Anemia) that includes practical information for CDA awareness and a step-by-step diagnostic tool based on a CDA algorithm. The site is currently available in four languages (Catalan, Spanish, Italian, and English). This telemedicine webpage is available at http://www.codysan.eu.	0
Laminin-α2-related congenital muscular dystrophy (LAMA2-CMD) is a devastating neuromuscular disease caused by mutations in the LAMA2 gene. These mutations result in the complete absence or truncated expression of the laminin-α2 chain. The α2-chain is a major component of the laminin-211 and laminin-221 isoforms, the predominant laminin isoforms in healthy adult skeletal muscle. Mutations in this chain result in progressive skeletal muscle degeneration as early as neonatally. Laminin-211/221 is a ligand for muscle cell receptors integrin-α7β1 and α-dystroglycan. LAMA2 mutations are correlated with integrin-α7β1 disruption in skeletal muscle. In this review, we will summarize laminin-211/221 interactions with integrin-α7β1 in LAMA2-CMD muscle. Additionally, we will summarize recent developments using upregulation of laminin-111 in the sarcolemma of laminin-α2-deficient muscle. We will discuss potential mechanisms of action by which laminin-111 is able to prevent myopathy. These published studies demonstrate that laminin-111 is a disease modifier of LAMA2-CMD through different methods of delivery. Together, these studies show the potential for laminin-111 therapy as a novel paradigm for the treatment of LAMA2-CMD.	0
Objective To observe the correlation of hepatocyte growth factor (HGF) and Hepato- cyte growth factor receptor (c-Met ) in serum and gastric mucosa tissues of chronic erosive gastritis pa- tients. Methods Totally 70 patients with chronic erosive gastritis were selected and assigned to turbidity toxin intrinsic syndrome group and Gan-wei disharmony syndrome group, HGF expression level of ser- um,and HGF,c-Met expression level of gastric mucosa tissues were measured;the correlation of HGF and c-Met in gastric mucosa tissues, and the correlation of HGF in serum and gastric mucosa tissues were analyzed. Results The expression level of HGF and c-Met in turbidity toxin intrinsic syndrome group was higher than that in Gan-wei disharmony syndrome group (P <0. 05) ; the expression level of HGF in gastric mucosa tissues was positively correlated with c-Met(r =0. 831 , P <0. 05) ; the expression level of HGF in serum was positively correlated with that of gastric mucosa tissues(r =0. 656, P <0. 05). Conclusions There was correlation between turbidity toxin intrinsic syndrome of Chronic Erosive Gastri- tis patients and the expression level of HGF and c-Met.	0
Background:Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes, being characterized by beta-cell disfunction, early onset, and autosomal dominant inheritance. Despite the rapid evolution of molecular diagnosis methods, many MODY cases are misdiagnosed as type 1 or type 2 diabetes. High costs of genetic testing and limited knowledge of MODY as a relevant clinical entity are some of the obstacles that hinder correct MODY diagnosis and treatment. We present a broad review of clinical syndromes related to most common MODY subtypes, emphasizing the role of biomarkers that can help improving the accuracy of clinical selection of candidates for molecular diagnosis. Main body:To date, MODY-related mutations have been reported in at least 14 different genes. Mutations in glucokinase (GCK), hepatocyte nuclear factor-1 homeobox A (HNF1A), and hepatocyte nuclear factor-4 homeobox A (HNF4A) are the most common causes of MODY. Accurate etiological diagnosis can be challenging. Many biomarkers such as apolipoprotein-M (ApoM), aminoaciduria, complement components, and glycosuria have been tested, but have not translated into helpful diagnostic tools. High-sensitivity C-reactive protein (hs-CRP) levels are lower in HNF1A-MODY and have been tested in some studies to discriminate HNF1A-MODY from other types of diabetes, although more data are needed. Overall, presence of pancreatic residual function and absence of islet autoimmunity seem the most promising clinical instruments to select patients for further investigation. Conclusions:The selection of diabetic patients for genetic testing is an ongoing challenge. Metabolic profiling, diabetes onset age, pancreatic antibodies, and C-peptide seem to be useful tools to better select patients for genetic testing. Further studies are needed to define cut-off values in different populations.	0
AIMS:Adult-onset inherited errors of metabolism can be difficult to diagnose. Some cases of potentially treatable myopathy are caused by autosomal recessive acid α-1,4 glucosidase (acid maltase) deficiency (Pompé disease). This study investigated whether screening of asymptomatic patients with elevated creatine kinase (CK) could improve detection of Pompé disease. METHODS:Pathology databases in six hospitals were used to identify patients with elevated CK results (>2× upper limit of normal). Patients were recalled for measurement of acid α-1,4 glucosidase activity in dried blood spot samples. RESULTS:Samples were obtained from 812 patients with elevated CK. Low α-glucosidase activity was found in 13 patients (1.6%). Patients with neutropaenia (n=4) or who declined further testing (n=1) were excluded. Confirmation plasma specimens were obtained from eight individuals (1%) for a white cell lysosomal enzyme panel, and three (0.4%) were confirmed to have low α-1,4-glucosidase activity. One patient was identified as a heterozygous carrier of an acid α-1,4 glucosidase c.-32-13 G>T mutation. Screening also identified one patient who was found to have undiagnosed Fabry disease and one patient with McArdle's disease. One patient later presented with Pompé's after an acute illness. Including the latent case, the frequency of cases at 0.12% was lower than the 2.5% found in studies of patients with raised CK from neurology clinics (p<0.001). CONCLUSIONS:Screening pathology databases for elevated CK may identify patients with inherited metabolic errors affecting muscle metabolism. However, the frequency of Pompé's disease identified from laboratory populations was less than that in patients referred for neurological investigation.	0
Aetiologies of bronchiectasis in mainland China and their comparisons with those in western countries are unknown. We aimed to investigate bronchiectasis aetiologies in Guangzhou, southern China, and to determine ethnic or geographic differences with reports from western countries.Consecutive patients with steady-state bronchiectasis were randomly recruited. Past history was meticulously extracted. Patients underwent physical examination, saccharine test, humoral immunity assays, gastroesophageal reflux scoring and sputum culture. Fiberoptic bronchoscopy, total immunoglobin E (IgE) and Aspergillus fumigatus-specific IgE measurement, 24-h gastroesophageal pH monitoring and miscellaneous screening tests were performed, if indicated. This entailed comparisons on aetiologies with literature reports.We enrolled 148 patients (44.6 ± 13.8 years, 92 females), most of whom had mild to moderate bronchiectasis. Idiopathic (46.0%), post-infectious (27.0%) and immunodeficiency (8.8%) were the most common aetiologies. Miscellaneous aetiologies consisted of asthma (5.4%), gastroesophageal reflux (4.1%), aspergillosis (2.7%), congenital lung malformation (2.0%), Kartagener syndrome (1.4%), rheumatoid arthritis (1.4%), chronic obstructive pulmonary disease (0.7%), Young's syndrome (0.7%), yellow nail's syndrome (0.7%), eosinophilic bronchiolitis (0.7%) and foreign bodies (0.7%). No notable differences in clinical characteristics between idiopathic and known aetiologies were found. Ethnic or geographic variations of aetiologies were overall unremarkable.Idiopathic, post-infectious and immunodeficiency constitute major bronchiectasis aetiologies in Guangzhou. Clinical characteristics of patients between known aetiologies and idiopathic bronchiectasis were similar. Ethnicity and geography only account for limited differences in aetiologic spectra. These findings will offer rationales for early diagnosis and management of bronchiectasis in future studies and clinical practice in China.	0
Mice lacking plasminogen activator inhibitor-1 (PAI-1) did not affect lung injury induced by gram-positive bacteria pneumococcal pneumonia but worsened lung injury induced by gram-negative bacteria Klebsiella. The exact mechanisms have not been completely elucidated. In this study, we examined the signaling pathway of Toll-like receptor 4 (TLR4) with/without PAI-1 in acute lung injury (ALI) induced by lipopolysaccharides (LPS) in mice. PAI-1 knockout mice (n=60) and wild-type mice (n=60) were exposed to LPS intratracheal instillation. Different groups of mice were then sacrificed at 0 and 8 h after LPS instillation. PAI-1-/- mice showed increased excess lung water and elevated cytokines production and release. In addition, expression of TLR4 was up-regulated and the phosphorylation activation of extracellular regulating kinase (ERK) and c-Jun N-terminal kinase (JNK) were also increased in PAI-1 knockout mice compared to wild-type mice. Inversely, interleukin (IL)-1 receptor-associated kinase-M (IRAK-M) and suppressor of cytokine signaling 1 (SOCS1) were both significantly reduced in PAI-1-/-mice after LPS challenge. PAI-1 deletion increased lung injury induced by LPS through up-regulation of TLR4, ERK and C-JNK and down-regulation of TLR4 negative regulators.	0
A previously unrecognised form of acute porphyria has been identified in a large family in Chester, UK. Patients presented with attacks of neurovisceral dysfunction and none had experienced cutaneous photosensitivity. Biochemically, the excretion pattern of haem precursors varied between individuals; some had a pattern typical of acute intermittent porphyria, others showed that of variegate porphyria, and some had an intermediate pattern. Studies of the enzymes of haem biosynthesis in peripheral blood cells showed a dual enzyme deficiency, with reduced activity of both porphobilinogen deaminase, as seen in acute intermittent porphyria, and protoporphyrinogen oxidase, as seen in variegate porphyria. The genetic basis of this dual form of acute porphyria and its relation to the other acute porphyrias are not clear.	0
Autoimmune gastrointestinal dysmotility is a limited autoimmune dysautonomia occurring idiopathically or in the context of an anatomically remote neoplasm, previously documented or unsuspected. Here we report 24 Mayo Clinic patients in whom the profile of serum autoantibodies aided this diagnosis.All patients were ascertained serologically in the course of service evaluation for autoantibodies consistent with neurologic autoimmunity. Review of their histories, motility studies, and laboratory findings revealed that all had presented with subacute gastrointestinal dysmotility.Recorded motility abnormalities included esophageal dysmotility 8 (6 had achalasia), delayed gastric emptying 12, slow small intestinal transit 7, slow colonic transit 4, and pelvic floor dyssynergia 4. Four patients underwent abdominal surgery; 2 commenced total parenteral nutrition. Plasma membrane cation channel autoantibodies were detected in 23 patients: neuronal voltage-gated calcium channel (5 N-type and 1 P/Q-type), acetylcholine receptor (11 ganglionic-type and 4 muscle-type), and neuronal voltage-gated potassium channel autoantibodies (4). Two patients had antineuronal nuclear autoantibodies, type 1. Approximately half of the patients had neural autoantibodies (including skeletal muscle striational and glutamic acid decarboxylase, 65kd isoform) or other antibody markers of organ-specific autoimmunity (thyroid or gastric parietal cell specificities). Neoplasia was diagnosed in 11 patients (9 recent, 2 remote): lung, breast and endometrial, gastrointestinal and thymoma. Moderate to dramatic improvement in gastrointestinal symptoms was reported after immunotherapy in 4 of 4 patients treated and after pyridostigmine treatment in 2 of 2 patients treated.Autoimmune serology aids the diagnosis of autoimmune gastrointestinal dysmotility, both paraneoplastic and idiopathic, and might guide management.	0
Gestational vitamin D deficiency is associated with pulmonary diseases. This study aimed to investigate the effect of gestational vitamin D deficiency on fetal lung development in mice. Absolute and relative weights of fetal lungs were reduced in vitamin D deficient (VDD) group. Incrassate mesenchyme, measured by septal wall thickness, accompanied by lessened saccular space, was shown in VDD group. Numerous immature type II pneumocytes, as determined by PAS staining, were observed in VDD group. Moreover, increased Ki67-positive cells, a marker of cell proliferation, was detected in VDD group. The additional experiments showed that Sftpa, Sftpb, Sftpc and Sftpd, four surfactant genes, were downregulated and pro-surfactant protein B was reduced in VDD group. FoxA1, FoxA2 and TTF-1, three transcription factors that regulate surfactant genes, and VEGF, a key regulator for pulmonary maturation, were downregulated in VDD group. These results suggest that gestational vitamin D deficiency impairs fetal lung development partially through suppressing type II pneumocyte differentiation.	0
Context: The relationship between resveratrol and histone acetylation in renal cell carcinoma (RCC) has not yet been reported.Objective: To explore the functional role of resveratrol in RCC.Materials and methods: Functional experiments were performed to determine proliferatio n of ACHN cells with treatment of resveratrol (0, 7.8125, 15.625, 31.25 and 62.5 μg/mL, for 12, 24 and 48 h of culture) or 0.1 μM SAHA. The enzyme activities of MMP-2/-9 were measured by gelatine zymography and histone acetylation by Western blot.Results: When the cells were treated with 15.625, 31.25 and 62.5 μg/mL resveratrol, ACHN cells viability was 73.2 ± 3.5%, 61.4 ± 3.1%, 50.2 ± 4.7% for 12 h, 62.7 ± 4.5%, 52.4 ± 5.5%, 40.2 ± 3.8% for 24 h, and 60.8 ± 3.7%, 39.4 ± 5.1%, 37.6 ± 2.7% for 48 h, and the wound closure (%) of migration was increased from 0.6 to 0.7, 0.85, 0.9 for 12 h and from 0.23 to 0.3, 0.48, 0.59 for 24 h. The invasion rate was 8.5 ± 0.9%, 7.4 ± 0.3% and 5.8 ± 0.6%, and cell cycle was arrested at G1 from 42.5 ± 2.9% to 55.3 ± 5.7%, 59.8 ± 3.4%, 68.7 ± 4.6%. MMP-2/-9 expression (p < 0.05) was inhibited by resveratrol. The protein levels of histone acetylation (p < 0.01) was increased by resveratrol.Discussion and conclusions: Our results suggest that these effects might be related to a high level of histone acetylation, and resveratrol can be considered as an alternative treatment for RCC.	0
BACKGROUND:Xeroderma pigmentosum (XP) is a rare photosensitive syndrome, which is divided into eight complementation groups (XP-A to XP-G and XPV) and characterized by skin cancers diagnosed at early age. A family of seven members (age range between 5 and 47 years) with carriers of the novel nonsense mutation that causes XP-E type were included in the current study. METHODS:DNA was isolated from peripheral blood samples of the proband, and cancer predisposition genes were sequenced with next-generation sequencing. The demographic features and the laboratory, clinical, and histopathological findings of patients were evaluated. RESULTS:In the proband, squamous cell carcinoma was first diagnosed in the right-eye cornea at the age of 13 years and then in the left-eye cornea at the age of 15 years. Later, the patient was diagnosed with basosquamous cell carcinoma on the dorsum of the nose at the age of 18 years. After genetic analysis, a novel nonsense c.1063C>T(p.Arg355Ter) pathogenic variation that causes XP-E type was detected as homozygous in the DDB2 gene of the proband and her siblings, 11 and 5 years of age, and as heterozygous in her parents and a 22-year-old brother. CONCLUSION:Because of the occurrence of early termination codon, truncated nonfunctional proteins or proteins with deleterious loss or gain-of-function activities are synthesized in nonsense mutation. Thus, to avoid the development of pathological lesions, it is important that such patients with nonsense mutation stay away from agents that might cause DNA damage and develop an appropriate lifestyle according to this condition.	0
Background: Drooling related to bulbar weakness and dysfunction is a common concern in patients with neuromuscular disease. While there are numerous medications to manage sialorrhea, they are often limited by side effects and lack of efficacy. Botulinum toxin has shown to benefit ALS patients in a few studies, but there is scant data on the benefit in other neuromuscular conditions. Objective: To assess the effectiveness of Botulinum toxin in reducing sialorrhea in patients with various neuromuscular disease. Design/Methods: 25 patients (19M, 6F; 54.36 ± 17.09 yr) with documented neuromuscular illness and concern for drooling was followed for 6 weeks after Botulinum toxin injection. These patients had one of the following diagnoses: Duchenne muscular dystrophy (3), myotonic dystrophy (3), oculopharyngeal muscular dystrophy (1), inclusion body myositis (2), primary lateral sclerosis (1), amyotrophic lateral sclerosis (9), spinal muscular atrophy type 2 and 3 (2), spinal-bulbar muscular atrophy (2), and Becker's muscular dystrophy (2). A subjective drooling scale (1: markedly worse, 5: markedly better) and drooling thickness score (0=normal, 100=thick) was calculated on these patients prior to the injection and 4 and 6 weeks after the injection. Botulinum toxin 20-30 units were injected into bilateral parotid gland (70% of the dose) and submandibular gland (30% of the dose). Results: The drooling thickness score at before the injection was 75.2 ± 10.46. At 4 and 6 weeks, average scores reduced to 47.2 ± 6.14 and 18.8 ± 5.26, respectively (p < 0.05). The average pre injection perception about drooling was 3.0 (p < 0.05). The average change in perception was +0.84 and +1.28 at 4 and 6 weeks, respectively, (p < 0.05) implying significant improvement. There were no reported adverse effects. Conclusion: This study provides preliminary evidence for the use of botulinum toxin for refractory sialorrhea for a variety of neuromuscular conditions.	0
Congenital disorders of glycosylation (CDG) are a rapidly expanding group of inherited metabolic disorders with highly variable clinical presentations caused by deficient glycosylation of proteins and/or lipids. CDG-IIh is a very rare subgroup of CDG caused by mutations in the conserved oligomeric Golgi (COG) complex gene, COG8, and so far, only two cases have been reported in the medical literature. Here, we describe an 8-year-old Korean boy with psychomotor retardation, hypotonia, failure to thrive, elevated serum liver enzymes, microcephaly, and talipes equinovarus. A liver biopsy of the patient showed only interface hepatitis with mild lobular activity, and brain magnetic resonance imaging revealed cerebellar atrophy. Compared with the previous two reported cases, our patient showed relatively mild psychomotor retardation without a seizure history. The transferrin isoelectric focusing profiles in the patient showed a CDG type II pattern with increased disialo- and trisialo-transferrin. Targeted exome sequencing was performed to screen all CDG type II-related genes, and two novel frameshift mutations were found: c.171dupG (p.Leu58Alafs*29) and c.1656dupC (p.Ala553Argfs*15) in COG8. The parents were heterozygous carriers of each variant. CDG should be included in the initial differential diagnosis for children with a suspected unknown syndrome or unclassified inherited metabolic disorder or children with diverse clinical presentations, such as psychomotor retardation, hypotonia, skeletal deformity, microcephaly, cerebellar atrophy, and unexplained transient elevated liver enzyme.	0
Mitochondrial trifunctional protein (TFP) deficiency is a rare inherited metabolic disorder caused by defects in fatty acid β-oxidation (FAO) of long-chain fatty acids, leading to impaired energy production. Fasting avoidance, fatty acid-restricted diets, and supplementation with medium-chain triglycerides are recommended as a treatment, but there are no pharmaceutical treatments available with strong evidence of efficacy. Bezafibrate, which enhances the transcription of FAO enzymes, is a promising therapeutic option for FAO disorders (FAODs). The effectiveness of bezafibrate for FAODs has been reported in some clinical trials, but few clinical studies have investigated its in vivo efficacy toward TFP deficiency. Herein, we describe two Japanese patients with TFP deficiency. Patient 1 presented with recurrent myalgia since the age of 5 years. Laboratory findings showed increased serum levels of long-chain fatty acids and reduced expression of TFPα and TFPβ in his skin fibroblasts. Based on these findings, he was diagnosed with the myopathic type of TFP deficiency. Patient 2 suddenly exhibited cardiopulmonary arrest one day after birth. Elevated levels of creatine kinase and long-chain acylcarnitines were observed. Genetic analysis identified compound heterozygous variants in HADHB (c.1175C>T/c.1364T>G). He was diagnosed with the lethal type of TFP deficiency. Although both patients were treated with dietary therapy and l-carnitine supplementation, they experienced frequent myopathic attacks associated with respiratory infections and exercise. After the initiation of bezafibrate, their myopathic manifestations were markedly reduced, leading to an improvement in quality of life without any side effects. Our clinical findings indicate that bezafibrate combined with other treatments such as dietary therapy may be effective in improving myopathic manifestations in TFP deficiency.	0
Background:Angle closure glaucoma (ACG) whether primary or secondary lens induced has rare occurrence in cases with retinitis pigmentosa (RP). Method:Five patients with history of diminished vision, ocular pain, and nyctalopia were clinically evaluated. Four patients had unilateral presentations of circumciliary congestion, corneal edema, and high intraocular pressure (IOP), while one had bilateral presentation, respectively. Anterior chambers were shallow; fundoscopy revealed the features of RP and gonioscopy affirmed closed angles in all the cases. The management strategies were individualized based on the specific ocular condition. Result:The raised IOP were not well controlled with conventional medical treatment. Neodymium yttrium aluminium garnet laser peripheral iridotomy (LPI) was performed in two patients and in the fellow eye in other two patients as a prophylactic measure. Phacoemulsification surgery with implantation of intraocular lens (IOL) was performed in three patients, whereas phacoemulsification only without IOL and trabeculectomy performed in one patient. Among them, two patients had subluxated lens, where one was managed with capsular tension ring and the other was left aphakic, respectively. However, the vision was not improved significantly in these patients. Conclusion:RP may be associated with ACG in rare instances. In these patients, angle closure-related high IOP can have a detrimental effect on the pre-existing visual impairment. However, this can be prevented by thorough clinical examination and timely intervention in those susceptible eyes.	0
Normal red blood cells maturation depends on many different hematological factors, including vitamin (vit.) B12. Megaloblastic anemias are basically caused by vit. B12 deficiency. In childhood the deficiency of this vitamin is extremely rare. The article captures findings of observation of the patient with rare form congenital vit. B12 deficiency anemia - Imerslund-Gräsbeck syndrome. The disease is characterized with selective intestinal malabsorption of vit. B12 and permanent proteinuria, without sings of kidney disease. The diagnosis was confirmed by our team in early childhood and based on the history, clinical and paraclinical data. After two weeks of specific treatment with vit. B12 , complete clinical - hematological remission was achieved. Treatment includes lifelong vit. B12 injections once per month. Cathamnesic observation for 18 months revealed that the patient is in remission, but there was continued macrocytosis of red blood cells and mild proteinuria. The presented case is interesting as a rare case of megaloblastic anemia caused by vit. B12 deficiency in childhood. Such patients often treated under different diagnosis. In such cases early diagnosis, treatment and prevention are crucial for the good prognosis.	0
Undiagnosed and rare conditions are collectively common and affect millions of people worldwide. The NIH Undiagnosed Diseases Program (UDP) strives to achieve both a comprehensive diagnosis and a better understanding of the mechanisms of disease for many of these individuals. Through the careful review of records, a well-orchestrated inpatient evaluation, genomic sequencing and testing, and with the use of emerging strategies such as matchmaking programs, the UDP succeeds nearly 30 percent of the time for these highly selective cases. Although the UDP process is built on a unique set of resources, case examples demonstrate steps genetic professionals can take, in both clinical and research settings, to arrive at a diagnosis for their most challenging cases.	0
Defects in somitogenesis result in vertebral malformations at birth known as spondylocostal dysostosis (SCDO). Somites are formed with a species-specific periodicity controlled by the "segmentation clock," which comprises a group of oscillatory genes in the presomitic mesoderm. Here, we report that a segmentation clock model derived from human embryonic stem cells shows many hallmarks of the mammalian segmentation clock in vivo, including a dependence on the NOTCH and WNT signaling pathways. The gene expression oscillations are highly synchronized, displaying a periodicity specific to the human clock. Introduction of a point of mutation into HES7, a specific mutation previously associated with clinical SCDO, eliminated clock gene oscillations, successfully reproducing the defects in the segmentation clock. Thus, we provide a model for studying the previously inaccessible human segmentation clock to better understand the mechanisms contributing to congenital skeletal defects.	0
This case report describes the clinical characteristics of a 50-year-old woman that developed SARS-CoV-2 pneumonia and was admitted at the COVID-19 dedicated unit where she developed neurological symptoms 10 days after admission. After neurological examination, including a panel of blood cerebrospinal fluid biomarkers, a diagnosis of Miller Fisher syndrome (MFS) was hypothesized and intravenous immunoglobulin therapy (IVIG) was initiated. Fourteen days after the start of IVIG treatment, the patient has been discharged at home with the resolution of respiratory symptoms and only minor hyporeflexia at the lower limbs, without any side effect.	0
OBJECTIVE: To assess the natural history of congenital myopathies (CMs) due to different genotypes. METHODS: Retrospective cross-sectional study based on case-note review of 125 patients affected by CM, followed at a single pediatric neuromuscular center, between 1984 and 2012. RESULTS: Genetic characterization was achieved in 99 of 125 cases (79.2%), with RYR1 most frequently implicated (44/125). Neonatal/infantile onset was observed in 76%. At birth, 30.4% required respiratory support, and 25.2% nasogastric feeding. Twelve percent died, mainly within the first year, associated with mutations in ACTA1, MTM1, or KLHL40. All RYR1-mutated cases survived and did not require long-term ventilator support including those with severe neonatal onset; however, recessive cases were more likely to require gastrostomy insertion (p = 0.0028) compared with dominant cases. Independent ambulation was achieved in 74.1% of all patients; 62.9% were late walkers. Among ambulant patients, 9% eventually became wheelchair-dependent. Scoliosis of variable severity was reported in 40%, with 1/3 of (both ambulant and nonambulant) patients requiring surgery. Bulbar involvement was present in 46.4% and required gastrostomy placement in 28.8% (at a mean age of 2.7 years). Respiratory impairment of variable severity was a feature in 64.1%; approximately half of these patients required nocturnal noninvasive ventilation due to respiratory failure (at a mean age of 8.5 years). CONCLUSIONS: We describe the long-term outcome of a large cohort of patients with CMs. While overall course is stable, we demonstrate a wide clinical spectrum with motor deterioration in a subset of cases. Severity in the neonatal/infantile period is critical for survival, with clear genotype-phenotype correlations that may inform future counseling.	0
OBJECTIVE:To describe the nutritional profile of newborns with microcephaly and factors associated with worse outcomes during the first 14 days of life. METHODS:This investigation is a longitudinal, descriptive study carried out in 21 full-term neonates exposed vertically to the Zika virus and hospitalized in a neonatal intensive care unit from February to September 2016. Patients receiving parenteral nutrition were excluded. Data analysis was performed using a generalized estimating equation model and Student's t-test to evaluate the association between worsening weight-for-age z-scores and independent clinical, sociodemographic and nutritional variables during hospitalization, with p<0.05 indicating significance. RESULTS:During hospitalization, there was a decrease in the mean values of the weight-for-age z-scores. The factors associated with worse nutritional outcomes were symptomatic exposure to the Zika virus, low maternal schooling, absence of maternal income and consumption of infant formula (p<0.05). Calcification and severe microcephaly were also associated with poor nutritional outcomes. Energy and macronutrient consumption remained below the recommendations and had an upward trend during hospitalization. CONCLUSION:The presence of cerebral calcification, the severity of microcephaly and symptomatic maternal exposure to Zika virus affected the nutritional status of newborns. In terms of nutritional factors, human milk intake had a positive impact, reducing weight loss in the first days of life. Other known factors, such as income and maternal schooling, were still associated with a poor nutritional status.	0
Hypomandibular faciocranial dysostosis is a condition heretofore described only in a single case. We report the birth of an affected sister along with follow-up information on the initial surviving patient. While a primary error in neural crest development was postulated in this syndrome, subsequently discovered anatomical abnormalities suggest a more complex pathogenesis.	0
In the report "Progress Toward Global Eradication of Dracunculiasis - January 2018-June 2019," on page 979, a sentence was omitted from the first paragraph. The paragraph should have read as follows.	0
Purpose:Paediatric radial neck fractures are challenging to treat. Multiple strategies exist for reduction and fixation; there is no clear consensus on the best surgical technique to achieve reduction. The percutaneous leverage technique is a method for reduction of radial neck fractures that has previously been described by Wallace, though there is a lack of published literature on this technique. We present a technical note and a modest case series on our modification to the percutaneous leverage technique accompanied by intramedullary fixation. Methods:We describe a retrospective series of patients who underwent the modified percutaneous leverage technique for paediatric radial neck fracture reduction followed by flexible intramedullary nail fixation at a single Level I trauma centre from 2008 to 2016. This technique involves making a small incision over the dorsal border of the ulna and using a blunt curved surgical forceps to dissect towards the ulnar border of the radius just distal to the radial neck fracture site. The curved forceps is then used to push the radial shaft away from the ulnar shaft which reduces the radial neck fracture. Intramedullary fixation is then utilized to stabilize the reduction. Pre- and postoperative radiographs and clinical data from the medical record were reviewed, and patient, injury and treatment characteristics as well as complication rates are summarized. Results:We successfully treated a series of eight radial neck fractures with the modified percutaneous leverage technique. This technique allows for a small incision and a minimally invasive method for the reduction of paediatric radial neck fractures. This allowed for subsequent intramedullary fixation and early postoperative elbow mobilization. In our series, no patients developed synostoses or sustained peripheral nerve injuries using this technique. Conclusion:The modified percutaneous leverage technique followed by intramedullary fixation is a safe and effective technique for fixation of displaced paediatric radial neck fractures. Level of Evidence:Level IV.	0
BACKGROUND:An early diagnosis of CHARGE syndrome is challenging, especially for the primary care physicians who often take care of neonates with multiple congenital anomalies. Here we report eight cases of CHARGE syndrome whose diagnosis was made early in life with the intent to identify the most helpful features allowing a prompt clinical diagnosis. METHODS:Medical records of patients with CHARGE syndrome whose diagnosis was made at the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico in Milan, Italy were retrospectively reviewed. RESULTS:Taken together, these patients reflect the considerable phenotypic variability of the syndrome; in one patient, the diagnosis was made immediately after birth because all the major criteria were met. In six patients, presenting with relatively nonspecific defects, a temporal bone computerized tomography scan was essential to achieve the correct diagnosis. In one patient, the diagnosis was made later than the others were. A careful examination revealed the presence of outer, middle, and inner ear anomalies: these elements, in the absence of any additional major criteria, represented for us an important diagnostic clue. CONCLUSIONS:This article suggests that an accurate evaluation of the ear should be made every time CHARGE syndrome is considered as a likely diagnosis even when the standard criteria are not fulfilled.	0
Charcot-Marie-Tooth type 4 (CMT4) is an autosomal recessive severe form of neuropathy with genetic heterogeneity. CMT4B1 is caused by mutations in the myotubularin-related 2 (MTMR2) gene and as a member of the myotubularin family, the MTMR2 protein is crucial for the modulation of membrane trafficking. To enable future clinical trials, we performed a detailed review of the published cases with MTMR2 mutations and describe four novel cases identified through whole-exome sequencing (WES). The four unrelated families harbor novel homozygous mutations in MTMR2 (NM_016156, Family 1: c.1490dupC; p.Phe498IlefsTer2; Family 2: c.1479+1G>A; Family 3: c.1090C>T; p.Arg364Ter; Family 4: c.883C>T; p.Arg295Ter) and present with CMT4B1-related severe early-onset motor and sensory neuropathy, generalized muscle atrophy, facial and bulbar weakness, and pes cavus deformity. The clinical description of the new mutations reported here overlap with previously reported CMT4B1 phenotypes caused by mutations in the phosphatase domain of MTMR2, suggesting that nonsense MTMR2 mutations, which are predicted to result in loss or disruption of the phosphatase domain, are associated with a severe phenotype and loss of independent ambulation by the early twenties. Whereas the few reported missense mutations and also those truncating mutations occurring at the C-terminus after the phosphatase domain cause a rather mild phenotype and patients were still ambulatory above the age 30 years. Charcot-Marie-Tooth neuropathy and Centronuclear Myopathy causing mutations have been shown to occur in proteins involved in membrane remodeling and trafficking pathway mediated by phosphoinositides. Earlier studies have showing the rescue of MTM1 myopathy by MTMR2 overexpression, emphasize the importance of maintaining the phosphoinositides equilibrium and highlight a potential compensatory mechanism amongst members of this pathway. This proved that the regulation of expression of these proteins involved in the membrane remodeling pathway may compensate each other's loss- or gain-of-function mutations by restoring the phosphoinositides equilibrium. This provides a potential therapeutic strategy for neuromuscular diseases resulting from mutations in the membrane remodeling pathway.	0
Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy. Mutations in the periaxin gene (PRX) can cause CMT type 4F, an autosomal recessive neuropathy, which is clinically characterized by slowly progressive distal muscle atrophy and weakness, with pes cavus deformity of the foot, and the absence of deep tendon reflexes. To date, dozens of reports of PRX mutations have been published worldwide, but none have been reported in Chinese patients. Here, we describe a 14-year-old Chinese boy with neuropathy characterized by slowly progressive limb weakness and atrophy, as well as sensory ataxia, whose cerebrospinal protein levels were 1627 mg/L. Genetic analysis identified a novel homozygous mutation, c.1174C>T (p.R392X), in exon 6 of PRX, which is the first case of its kind recorded in China.	0
We report the case of a 81-year-old man presenting with stable exercise angina pectoris. The stress test is positive and the coronaro-angiographic evaluation demonstrates a coronary fistula between the left anterior descending (LAD) artery and the pulmonary artery trunk. The mid LAD presents a significant lesion after the origin of the fistula. A cardiac computed tomography is used before surgical treatment. Coronary artery fistulas are unusual congenital or acquired coronary artery abnormalities in which blood is shunt into a cardiac chamber, great vessel or other structure. Low-pressure structure is the most common site of drainage of the coronary fistula. The clinical presentation of coronary fistulas is mainly dependent on the severity of the left-to-right shunt. Various cardiac imaging modalities are used for diagnosis and anatomical exploration before surgical or percutaneous intervention if the closure of the fistula is indicated.	0
PURPOSE OF REVIEW:Commonly categorized as a rare disease, alpha-1 antitrypsin deficiency (AATD) is neither rare, when compared to many other genetic disorders, nor an actual disease, but rather a predisposition toward a wide variety of diseases. It is one of the most common genetic disorders which can lead to a spectrum of clinical manifestations, ranging from no symptoms to progressively debilitating systemic disease, most commonly affecting the lung and liver. It is therefore imperative for clinicians to recognize and be familiar with the spectrum of presentations, methods of diagnosis, and clinical management of AATD. It is also imperative for scientists to recognize the potential for progress in the management of this disorder. RECENT FINDINGS:This review focuses on the current state of knowledge of AATD, including the wide range of presentations, diagnosis, and clinical management. In addition to the clinical implications of severe AATD, we discuss the relevance of heterozygous state with mild or moderate AATD in the development of both lung and liver disease. While our understanding of the multiple roles of alpha-1 antitrypsin (AAT) is on the rise, with appreciation of its immunomodulatory, anti-infective, and anti-inflammatory properties, this knowledge has yet to impact our ability to predict outcomes. We discuss nuances of augmentation therapy and review novel therapeutic approaches currently under investigation. With the expanding knowledge about the complexities of AAT function and its clinical relevance, and with the increasing ability to diagnose early and intervene on AATD, it should be our goal to change the perception of AATD as a correctable inherited disorder rather than a fatal disease.	0
BACKGROUND:Nontuberculous mycobacteria are mycobacteria, other than those in the Mycobacterium tuberculosis complex, and are commonly found in the environment. Nontuberculous mycobacteria species (most commonly Mycobacterium avium complex and Mycobacterium abscessus) are isolated from the respiratory tract of approximately 5% to 40% of individuals with cystic fibrosis; they can cause lung disease in people with cystic fibrosis leading to more a rapid decline in lung function and even death in certain circumstances. Although there are guidelines for the antimicrobial treatment of nontuberculous mycobacteria lung disease, these recommendations are not specific for people with cystic fibrosis and it is not clear which antibiotic regimen may be the most effective in the treatment of these individuals. This is an update of a previous review. OBJECTIVES:The objective of our review was to compare antibiotic treatment to no antibiotic treatment, or to compare different combinations of antibiotic treatment, for nontuberculous mycobacteria lung infections in people with cystic fibrosis. The primary objective was to assess the effect of treatment on lung function and pulmonary exacerbations and to quantify adverse events. The secondary objectives were to assess treatment effects on the amount of bacteria in the sputum, quality of life, mortality, nutritional parameters, hospitalizations and use of oral antibiotics. SEARCH METHODS:We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and hand searching of journals and conference abstract books. Date of last search: 24 February 2020. We also searched a register of ongoing trials and the reference lists of relevant articles and reviews. Date of last search: 21 March 2019. SELECTION CRITERIA:Any randomized controlled trials comparing nontuberculous mycobacteria antibiotics to no antibiotic treatment, as well as one nontuberculous mycobacteria antibiotic regimen compared to another nontuberculous mycobacteria antibiotic regimen, in individuals with cystic fibrosis.   DATA COLLECTION AND ANALYSIS: Data were not collected because in the one trial identified by the search, data specific to individuals with cystic fibrosis could not be obtained from the pharmaceutical company. MAIN RESULTS:One completed trial was identified by the searches, but data specific to individuals with cystic fibrosis could not be obtained from the pharmaceutical company. AUTHORS' CONCLUSIONS:This review did not find any evidence for the effectiveness of different antimicrobial treatment for nontuberculous mycobacteria lung disease in people with cystic fibrosis. Until such evidence becomes available, it is reasonable for clinicians to follow published clinical practice guidelines for the diagnosis and treatment of nodular or bronchiectatic pulmonary disease due to Mycobacterium avium complex or Mycobacterium abscessus in patients with cystic fibrosis.	0
BACKGROUND:Autosomal dominant GCH1 mutations are known to cause dopa-responsive dystonia (DRD). In this case series, we confirm a variant phenotype, characterized by predominant spastic paraplegia at disease onset with development of dystonia and/or parkinsonism only decades later. METHODS:Clinical trajectories of four patients from three families with pathogenic variants in GCH1 are described, illustrated by videos of the motor phenotype before and during treatment with levodopa. An extensive literature review was performed on previous reports of spasticity in patients with autosomal dominant GCH1 mutations. RESULTS:All patients presented during childhood or early adolescence with gait and leg spasticity. Three patients developed basal ganglia signs only in the fifth decade; the youngest patient has not yet developed dystonia, bradykinesia or hypokinesia. All patients responded to levodopa/carbidopa with improvement of gait and of dystonia, hypokinesia and/or rigidity. In all patients, spasticity decreased but did not disappear. Spasticity has been described previously in DRD, but in most cases co-existent basal ganglia signs were identified early in the disease course. CONCLUSION:GCH1 mutations may cause a phenotype initially resembling hereditary spastic paraplegia (HSP) rather than DRD, with basal ganglia signs developing only after decades. In order not to miss this treatable condition, GCH1 should be included in HSP gene panels and its testing is pivotal in patients with spastic paraplegia, especially if there are concomitant basal ganglia signs and/or diurnal fluctuation.	0
TRIpartite motif (TRIM) proteins are part of the largest subfamilies of E3 ligases that mediate the transfer of ubiquitin to substrate target proteins. In this review, we focus on TRIM37 in the normal cell and in pathological conditions, with an emphasis on the MULIBREY (MUscle-LIver-BRain-EYe) genetic disorder caused by TRIM37 mutations. TRIM37 is characterized by the presence of a RING domain, B-box motifs, and a coiled-coil region, and its C-terminal part includes the MATH domain specific to TRIM37. MULIBREY nanism is a rare autosomal recessive caused by TRIM37 mutations and characterized by severe pre- and postnatal growth failure. Constrictive pericarditis is the most serious anomaly of the disease and is present in about 20% of patients. The patients have a deregulation of glucose and lipid metabolism, including type 2 diabetes, fatty liver, and hypertension. Puzzlingly, MULIBREY patients, deficient for TRIM37, are plagued with numerous tumors. Among non-MULIBREY patients affected by cancer, a wide variety of cancers are associated with an overexpression of TRIM37. This suggests that normal cells need an optimal equilibrium in TRIM37 expression. Finding a way to keep that balance could lead to potential innovative drugs for MULIBREY nanism, including heart condition and carcinogenesis treatment.	0
We report two siblings with bowed tibia, hypoplastic thumbs, multiple fractures, a distinctive facial phenotype and developmental delay. These children share some features with other cases reported in the literature but we consider that they represent a new syndrome.	0
BACKGROUND:13q33-q34 microdeletions are rare chromosomal aberrations associated with a high risk of developmental disability, facial dysmorphism, cardiac defects and other malformation of organs. It is necessary to collect and report evidence of this rare chromosome mutation to improve the prognosis of this rare disease. CASE PRESENTATION:We report a patient harboring an 11.56 Mb microdeletion at 13q33.1-34 region, which contains about 30 OMIM genes. Besides the common clinical manifestations such as facial dysmorphism, developmental delay, intellectual disability, epilepsy, and congenital heart disease, she also suffered from a reduced anogenital distance, hematuria and left renal hypoplasia. Most related cases were characterized by facial deformity and heart defects, but there were few reports on renal malformation, especially regarding renal hypoplasia with hematuria. CONCLUSION:We have reported a patient suffering from a reduced anogenital distance, hematuria and left renal hypoplasia. A de novo 11.56 Mb deletion ranging from 13q33.1 to 13q34 (Chr13:103542220-115,106,996) was found by SNP-array analysis. It might be the first time for hematuria and renal hypoplasia to be reported as symptoms of 13q33-q34 deletion syndrome Neurodevelopmental disability, heart defects and urogenital/anorectal anomalies may be resulted from common or overlapping regions of deletion in chromosome bands 13q33.1-q34 and may share a common molecular mechanism.	0
Background and aims:Several studies highlighted how the ameloblasts, secretory cells responsible of the tooth enamel formation, are highly sensitive to changes in their environment. Due to enamel maturation, their dysfunctions during a limited period of tooth development may lead to permanent morphological consequences, namely Developmental Enamel Defects (DED). The aim of this study was to show the advantages of Er:YAG laser for DED treatment. Subjects and methods:The case report presented describes the treatment, by Er:YAG laser, of some DED lesions present in the upper incisors of a young patient. The settings used were: 1W power, 100mJ energy, 10 Hz frequency corresponding to a Fluence of 0.318 J/cm2 per pulse or 3, 18 J/cm2. Results:The patient, even in absence of local anesthesia, did not feel any pain or discomfort during and after intervention. Follow-up at 2, 6 and 12 months did not show any problems in an aesthetic point of view as well as regarding hypersensitivity. Conclusions:The use of Er:YAG laser for the treatment of developmental enamel defects in frontal teeth is a safe, painless and minimally invasive; moreover, it is able to assure a good aesthetic result.	0
Originally, locus symbols (e.g., DYT1) were introduced to specify chromosomal regions that had been linked to a familial disorder with a yet unknown gene. Symbols were systematically assigned in a numerical series to designate mapped loci for a specific phenotype or group of phenotypes. Since the system of designating and using locus symbols was originally established, both our knowledge and our techniques of gene discovery have evolved substantially. The current system has problems that are sources of confusion, perpetuate misinformation, and misrepresent the system as a useful reference tool for a list of inherited disorders of a particular phenotypic class. These include erroneously assigned loci, duplicated loci, missing symbols, missing loci, unconfirmed loci in a consecutively numbered system, combining causative genes and risk factor genes in the same list, and discordance between phenotype and list assignment. In this article, we describe these problems and their impact, and propose solutions. The system could be significantly improved by creating distinct lists for clinical and research purposes, creating more informative locus symbols, distinguishing disease-causing mutations from risk factors, raising the threshold of evidence prior to assigning a locus symbol, paying strict attention to the predominant phenotype when assigning symbols lists, and having a formal system for reviewing and continually revising the list that includes input from both clinical and genetics experts.	0
BACKGROUND:Bainbridge-Ropers syndrome (BRPS) is a recently described developmental disorder caused by de novo truncating mutations in the Additional sex combs-like 3 (ASXL3) gene. Only four cases have been reported in China and are limited to the analysis of its clinical abnormalities, medical imaging features and gene variation. The aim of this study was to investigate the clinical phenotype, imaging manifestations and genetic characteristics of BPRS syndrome caused by ASXL3 gene mutation. Clinical data, medical imaging data and gene test results of BRPS in infant patients were retrospectively analyzed, and related literature was summarized. CASE PRESENTATION:At the age of 8 months, brain MRI showed that the subarachnoid space of the forehead was widened, part of the sulci was deepened, and the corpus callosum was thin. The development quotient (DQ) was determined using the 0~6-year-old pediatric examination table of neuropsychological development at 6 months and 8 months. The DQ of both tests was less than 69. Whole-exome sequencing revealed a heterozygous frameshift mutation c.3493_3494deTG in exon 12 of the ASXL3 gene, resulting in the amino acid change p. (Cys1165Ter). No variation was present at this site in her parents. Sanger sequencing of family members validated this analysis, suggesting a de novo mutation. The de novo ASXL3 mutations generated stop codons and were predicted, in silico, to generate a truncated ASXL3. CONCLUSIONS:The main clinical features of the patient included psychomotor development retardation, difficulty in feeding, hypotonia, and special facial features. MRI features showed that brain development lagged behind that of normal children. Genetic testing is helpful in the early diagnosis of BRPS.	0
The human X and Y chromosomes evolved from a pair of autosomes approximately 180 million years ago. Despite their shared evolutionary origin, extensive genetic decay has resulted in the human Y chromosome losing 97% of its ancestral genes while gene content and order remain highly conserved on the X chromosome. Five 'stratification' events, most likely inversions, reduced the Y chromosome's ability to recombine with the X chromosome across the majority of its length and subjected its genes to the erosive forces associated with reduced recombination. The remaining functional genes are ubiquitously expressed, functionally coherent, dosage-sensitive genes, or have evolved male-specific functionality. It is unknown, however, whether functional specialization is a degenerative phenomenon unique to sex chromosomes, or if it conveys a potential selective advantage aside from sexual antagonism. We examined the evolution of mammalian orthologs to determine if the selective forces that led to the degeneration of the Y chromosome are unique in the genome. The results of our study suggest these forces are not exclusive to the Y chromosome, and chromosomal degeneration may have occurred throughout our evolutionary history. The reduction of recombination could additionally result in rapid fixation through isolation of specialized functions resulting in a cost-benefit relationship during times of intense selective pressure.	0
PURPOSE OF REVIEW:Congenital muscular dystrophies and congenital myopathies are a heterogeneous group of disorders resulting in hypotonia, muscle weakness, and dystrophic or myopathic features on muscle biopsy. This article summarizes the clinical and genetic aspects of these disorders. RECENT FINDINGS:Historically, diagnoses of congenital muscular dystrophy and congenital myopathy have been made by clinical features and histopathology; however, recent advances in genetics have changed diagnostic practice by relying more heavily on genetic findings. This article reviews the clinical and genetic features of the most common congenital muscular dystrophies including laminin subunit alpha 2 (LAMA2)-related (merosin deficient), collagen VI-related, and α-dystroglycan-related congenital muscular dystrophies and reviews the most common congenital myopathies including nemaline rod, core, and centronuclear myopathies. With the increasing accessibility of genetic testing, the number of genes found to be associated with these disorders has increased dramatically. A wide spectrum of severity and onset (from birth to adulthood) exist across all subtypes. Progression and other features are variable depending on the subtype and severity of the specific genetic mutation. SUMMARY:Congenital muscular dystrophy and congenital myopathy are increasingly recognized disorders. A growing appreciation for the breadth of phenotypic variability and overlap between established subtypes has challenged long-standing phenotypic and histopathologic classifications of these disorders but has driven a greater understanding of pathogenesis and opened the door to the development of novel treatments.	0
Cutaneous mastocytosis is characterized by the abnormal accumulation of mast cells in the skin. However, mast cell counting is not always easy and reproducible with classical methods. This work aims to demonstrate the reliability, usability, and virtues of a new software used on digital tablets for counting mast cells in cutaneous specific lesions of mastocytosis, to assess differences in mast cell counts between clinical subtypes of mastocytosis in the skin, and to consider the feasibility of applying a diagnostic mast cell count cutoff to urticaria pigmentosa, which is the most frequent form of cutaneous mastocytosis. Using a new digital tablet software that was accessible by multiple observers through its own wireless network and allowed high resolution of the image without data compression, we counted the number of mast cells on slides of patients and control skins immunostained for CD117. We found that our counting method was highly reproducible and that the new software allowed very quick counting. We evidenced strong differences in the mast cell count between most of the clinical subtypes of mastocytosis in the skin. However, when applied to a subset of patients with urticaria pigmentosa, a diagnostic cutoff in the mast cell count lacked sensitivity. Thus, our digital method for counting CD117-immunostained mast cells was highly accurate and was of a significant value for the diagnosis of mastocytosis in the skin. However, some subtypes with low mast cell counts will still require the application of additional diagnostic criteria.	0
Ectodermal dysplasia (ED) is a rare genetic disorder occurring as a consequence of gene mutations that code for the ectoderm of the developing embryo and results in numerous disorders of varying severity. The lack of functioning sweat glands in those affected with ED leads to high infant mortality and frequent complaints of hyperthermia. Temperature control of two adolescents affected with ED was assessed by conducting heat and exercise exposures while monitoring insulated auditory canal (Tac) and skin temperatures, sweating rates, and skin blood flow. One participant was able to sweat and regulate his Tac while a second participant could not regulate Tac without a cooling intervention. The heterogeneous nature of ED, and these cases highlight the need for a case-by-case review of temperature control of individuals affected with ED. This will determine cooling strategies that would be of most benefit to the individual.	0
The article presents a case report and literature review of hemifacial microsomia with cervical vertebral anomalies. Unilateral hypoplasia of the mandible, congenital anomalies of the external ear and cervical spine pathology identified in this case are common major signs/symptoms of Goldenhar (Goldenhar-Gorlin) syndrome. Complete fusion of bodies and spinous processes of the second and third cervical vertebrae as well as atlantooccipital assimilation and anterior cleft of the atlas were also found. All abnormalities were accidentally identified and not accompanied by clinical symptoms.	0
ARID1B mutations in Coffin-Siris syndrome are a cause of intellectual disability (0.5-1%), with various degrees of autism and agenesis of the corpus callosum (10%). Little is known regarding the cognitive and motor consequences of ARID1B mutations in humans and no link has been made between corpus callosum anomalies and visuospatial and neuromotor dysfunctions. We have investigated the visuospatial and neuromotor phenotype in eight patients with ARID1B mutations. A paramedian sagittal section of the brain MRI was selected, and corpus callosum was measured in anteroposterior length, genu and trunk width. Spearman's rank order coefficients were used to explore correlations between visuospatial and social cognitive variables and dimensions of the corpus callosum. A significant correlation between genu width size and visual cognition was observed. Retrocerebellar cysts were associated with corpus callosum anomalies. Here, we show that corpus callosum anomalies caused in ARID1B mutations may be predictive of the visuospatial and motor phenotype in Coffin-Siris syndrome.	0
Maturity-onset diabetes of the young (MODY) classically describes dominantly inherited forms of monogenic diabetes diagnosed before 25 years of age due to pancreatic β-cell dysfunction. In contrast, mutations in certain MODY genes can also present with transient or persistent hyperinsulinemic hypoglycemia in newborn infants, reflecting instead β-cell dysregulation. Of the MODY genes described to date, only hepatocyte nuclear factor-4-alpha (HNF4A; MODY1) and hepatocyte nuclear factor-1-alpha (HNF1A; MODY3) mutations may result in a biphasic phenotype of hypoglycemia in early life and hyperglycemia in later life. We report a family with a novel HNF4A mutation with diverse phenotypic presentations of glucose dysregulation. The proband was a term, appropriate-for-gestational age male infant with symptomatic hypoglycemia on day 3 of life needing high glucose infusion rate to maintain normoglycemia. He was born to a non-obese and non-diabetic mother. Glucose regulation was optimized using diazoxide upon confirmation of hyperinsulinism. Cascade genetic screening identified the same mutation in his father and elder sister, but mother was negative. Father was diagnosed with Type 1 diabetes at 15 years of age that required insulin therapy. Proband's elder sister, born at term appropriate for gestational age, presented with transient neonatal hypoglycemia needing parenteral glucose infusion for a week followed by spontaneous resolution. The paternal grandparents were negative for this mutation, confirming a paternal de novo mutation and autosomal dominant inheritance in this family. This pedigree suggests that the presence of early-onset paternal diabetes should prompt molecular testing in infants presenting in the newborn period with diazoxide-responsive hyperinsulinemic hypoglycemia, even in the absence of maternal diabetes and macrosomia.	0
Auriculo-condylar syndrome (ACS) is a rare condition affecting first branchial arch structures. The types of hearing loss and temporal bone findings in ACS have not been reported. We describe a 14-year-old male with constricted pinnae, mandibular dysostosis, glossoptosis, a high-arched palate, hearing loss, and cholesteatoma. Computed tomography imaging demonstrated malleoincudal joint ankylosis. The fused malleoincudal complex was removed during mastoidectomy for cholesteatoma. Electron microscopy and histopathology of the joint suggested the fusion was congenital. This is the first report of ossicular fusion and cholesteatoma in ACS and the most detailed in vivo evidence of disruption of embryogenesis during malleoincudal joint formation.	0
INTRODUCTION:X-linked hyper-IgM syndrome is a type of primary combined immunodeficiency disorder caused by mutations in CD40 ligand. Opportunistic infections caused by P jirovecii, cytomegalovirus (CMV), or fungi are frequently the first presenting symptom of the patients with X-linked hyper-IgM syndrome. PATIENT CONCERNS:Here, we report a 10-month-old infant who presented with cyanosis and shortness of breath. The infant exhibited no medical or birth history indicating a primary immune deficiency and was first diagnosed with interstitial pneumonia and acute respiratory failure on admission. DIAGNOSES:The infant was diagnosed with Pneumocystis jirovecii pneumonia combined with CMV and fungal infection through gene sequencing by nasopharyngeal swab and G-test. Whole-exome sequencing from a blood sample was performed and identified a functional mutation across the CD40 ligand gene (NM_000074;exon1;C.86_87del) resulting in an amino acid change (P.T29Sfl*18) attributed to X-linked hyper IgM syndrome. INTERVENTIONS:The infant received continuous positive airway pressure ventilation treatment combined with trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia, ganciclovir for CMV, voriconazole for fungal infection and substitution of high-dose immunoglobulin. OUTCOMES:Six months after discharge from our hospital, the infant remained well. CONCLUSION:Opportunistic infections should be suspected in infants presenting with severe interstitial pneumonia. Primary immune deficiency diseases should also be considered in infants diagnosed with opportunistic infections.	0
Catastrophic antiphospholipid syndrome (CAPS) is a rare condition characterized by multiple thromboses affecting mainly small vessels in a short period of time in patients with antiphospholipid antibodies. A high suspicion index is mandatory in order to initiate rapidly aggressive immunomodulatory therapy to avoid a very poor prognosis. Systemic lupus erythematosus (SLE) is often associated with antiphospholipid syndrome, with a worse outcome when the catastrophic features occur. We report the case of a 64-year-old woman with a clinical debut of SLE who presented concomitantly with CAPS with several thrombosis affecting the kidney, spleen and bilateral limbs with blue toe syndrome in both legs. Furthermore, she presented with aortitis, with a malaise and myalgias and general syndrome (asthenia, hyporexia and mild weight loss). Fortunately, she had a good response to multi-target combination therapy (anticoagulants, corticosteroids, hydroxychloroquine, intravenous immunoglobulins, plasma exchange and rituximab). Here, we discuss the association between aortitis and CAPS secondary to SLE, and review the literature regarding similar conditions.	0
BACKGROUND:Greenberg dysplasia is a rare, autosomal recessive, prenatal lethal bone dysplasia caused by biallelic pathogenic variants in the lamin B receptor (LBR) gene. Pathogenic variants in LBR are also associated with Pelger-Huët anomaly, an autosomal dominant benign abnormality of the nuclear shape and chromatin organization of blood granulocytes, and Pelger-Huët anomaly with variable skeletal anomalies, a mild, regressing to moderate-severe autosomal recessive condition. Conditions with abnormal sterol metabolism and different genetic basis have clinical and radiographic features similar to Greenberg dysplasia, for example X-linked dominant chondrodysplasia punctata, Conradi-Hünermann type, and CHILD syndrome, and other conditions with unknown genetic etiology display very similar features, for example, dappled diaphyseal dysplasia and Astley-Kendall dysplasia. METHODS:We present a fetus with typical clinical and radiographic features of Greenberg dysplasia, and review the literature. RESULTS:Genetic testing confirmed the diagnosis Greenberg dysplasia: homozygosity for a pathogenic variant in LBR. CONCLUSION:Comparing the clinical and radiographic phenotypes of Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia, we suggest that these are allelic disorders.	0
Fifty one infants who were oxygen dependent after treatment for neonatal respiratory disease were entered into a study programme where 100% oxygen was delivered at low flow through a nasal catheter. Thirty five (69%) of the infants were discharged home and the remainder were either discharged to a convalescent hospital or back to their peripheral referring hospital. Excluding repeat admissions for monitoring or for the treatment of acute infections, 2760 hospital days (79 days/patient) were saved, representing a financial saving of $11990 (pounds 6500) per treated infant. A home low flow oxygen therapy programme has benefits to the infant/parent relationship, provides a more constant flow of oxygen than conventional methods, and the early hospital discharge represents a considerable financial saving.	0
Lichen planus pigmentosus is uncommon in childhood and its treatment is often challenging. We report a case of cutaneous lichen planus pigmentosus in a 10-year-old boy, without oral mucosal involvement, two months after an amalgam dental restoration. The diagnosis was based on the histopathological examination of a skin biopsy, the positive patch test to mercury, and the improvement after amalgam removal. Our case report suggests that metal allergy may play a role, and amalgam replacement may be followed by clinical improvement.	0
There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers.	0
Mutations in the insulin receptor (INSR) gene underlie rare severe INSR-related insulin resistance syndromes (SIR), including insulin resistance type A, Rabson⁻Mendenhall syndrome and Donohue syndrome (DS), with DS representing the most severe form of insulin resistance. Treatment of these cases is challenging, with the majority of DS patients dying within the first two years of life. rhIGF-I (mecasermin) has been reported to improve metabolic control and increase lifespan in DS patients. A case report and literature review were completed. We present a case involving a male patient with DS, harbouring a homozygous mutation in the INSR gene (c.591delC). Initial rhIGF-I application via BID (twice daily) injection was unsatisfactory, but continuous subcutaneous rhIGF-I infusion via an insulin pump improved weight development and diabetes control (HbA1c decreased from 10 to 7.6%). However, our patient died at 22 months of age during the course of a respiratory infection in in Libya. Currently available data in the literature comprising more than 30 treated patients worldwide seem to support a trial of rhIGF-I in SIR. rhIGF-I represents a treatment option for challenging SIR cases, but careful consideration of the therapeutic benefits and the burden of the disease is warranted. Continuous application via pump might be advantageous compared to single injections.	0
We present the anaesthetic management of a parturient with kyphomelic dysplasia and Pierre Robin Sequence who underwent elective caesarean delivery. Potential anaesthetic issues and management strategies are discussed.	0
Uterine gas gangrene caused by Clostridium perfringens is a serious, often life-threatening infection that is rarely encountered in the practice of gynecologic oncology. However, the hypoxic nature of gynecologic cancers due to necrosis and/or prior radiation therapy creates a microenvironment optimal for proliferation of anaerobic bacteria such as the Clostridium species. Early recognition and aggressive treatment with IV antibiotics and surgical debridement remain the cornerstones of management in order to decrease morbidity and mortality. Here we present the case of a 52 year-old woman with a remote history of cervical cancer who was previously treated at our institution with primary chemotherapy and radiation and was then admitted decades later with Clostridium perfringens bacteremia and CT evidence of intrauterine abscess. The patient received a prolonged course of IV antibiotic therapy and subsequently underwent definitive surgical management with a total abdominal hysterectomy, bilateral salpingo-oophorectomy, small bowel resection with anastomosis for a utero-ileal fistula identified intraoperatively. Pathology from the uterine specimen demonstrated a primary poorly differentiated uterine adenocarcinoma. The patient recovered fully from her Clostridium perfringens infection and was discharged from the hospital shortly after surgical intervention.	0
The Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder caused by pathogenic variants in the ALDH3A2 gene, which codes for fatty aldehyde dehydrogenase (FALDH). FALDH prevents the accumulation of toxic fatty aldehydes by converting them into fatty acids. Pathogenic ALDH3A2 variants cause symptoms such as ichthyosis, spasticity, intellectual disability, and a wide range of less common clinical features. Interpreting patient-to-patient variability is often complicated by inconsistent reporting and negatively impacts on establishing robust criteria to measure the success of SLS treatments. Thus, with this study, patient-centered literature data was merged into a concise genotype-based, open-access database (www.LOVD.nl/ALDH3A2). One hundred and seventy eight individuals with 90 unique SLS-causing variants were included with phenotypic data being available for more than 90%. While the three lead symptoms did occur in almost all cases, more heterogeneity was observed for other frequent clinical manifestations of SLS. However, a stringent genotype-phenotype correlation analysis was hampered by the considerable variability in reporting phenotypic features. Consequently, we compiled a set of recommendations of how to generate comprehensive SLS patient descriptions in the future. This will be of benefit on multiple levels, for example, in clinical diagnosis, basic research, and the development of novel treatment options for SLS.	0
Background:The programmed cell death 1 (PD-1) inhibitor pembrolizumab is a promising agent for treatment of several different malignancies, but as with all immunotherapy there is a potential risk of immune-related adverse events. Adrenocorticotropic hormone (ACTH) deficiency and hypophysitis have been reported in patients treated with a different PD-1 inhibitor, nivolumab. However, clinical characteristics of these side effects associated with pembrolizumab have yet to be described in detail. Case presentation:An 85-year-old Japanese woman was diagnosed with advanced squamous cell lung cancer. The patient was treated with 200 mg pembrolizumab every three weeks as first-line therapy. Routine examination including thyroid function, complete blood count, serum cortisol and sodium levels before each pembrolizumab infusion had shown no significant changes up to the eighth cycle. However, 8 days after the eighth cycle of single-agent pembrolizumab, she presented with rapidly worsening general fatigue and appetite loss over two days. Laboratory data revealed a low serum cortisol level (0.92 μg/dL) with inappropriately low ACTH (8.3 pg/mL), hyponatremia (122 mmol/L) and hypoglycemia (68 mg/dL). Standard-dose short ACTH testing showed an unsatisfactory cortisol response, indicating adrenal insufficiency. Pituitary magnetic resonance imaging showed diffuse substantial gadolinium enhancement, T2 hyperintensity, loss of pituitary bright spot, but no pituitary enlargement. Serum cortisol and ACTH levels were low throughout the day, and urinary free cortisol excretion fell below the lower normal limit. There was no ACTH and cortisol response in the corticotropin-releasing hormone test, despite significant responses of other anterior pituitary hormones to their corresponding challenge tests. Thus, isolated ACTH deficiency was diagnosed, and hypophysitis was suspected as the etiology. After administration of 15 mg/day hydrocortisone, the patient's debilitation, hyponatremia, and hypoglycemia swiftly disappeared. Conclusion:This is a case of isolated ACTH deficiency possibly due to hypophysitis in a patient with advanced lung cancer, in whom recent routine examinations had shown unremarkable results. We therefore conclude that isolated ACTH deficiency can suddenly arise during pembrolizumab monotherapy, albeit probably only rarely. Caution should be exercised to make sure that adrenal insufficiency is recognized immediately in order to achieve swift recovery by steroid replacement.	0
Human eye development is coordinated through an extensive network of genetic signalling pathways. Disruption of key regulatory genes in the early stages of eye development can result in aborted eye formation, resulting in an absent eye (anophthalmia) or a small underdeveloped eye (microphthalmia) phenotype. Anophthalmia and microphthalmia (AM) are part of the same clinical spectrum and have high genetic heterogeneity, with >90 identified associated genes. By understanding the roles of these genes in development, including their temporal expression, the phenotypic variation associated with AM can be better understood, improving diagnosis and management. This review describes the genetic and structural basis of eye development, focusing on the function of key genes known to be associated with AM. In addition, we highlight some promising avenues of research involving multiomic approaches and disease modelling with induced pluripotent stem cell (iPSC) technology, which will aid in developing novel therapies.	0
L-histidine (HIS) is an essential amino acid with unique roles in proton buffering, metal ion chelation, scavenging of reactive oxygen and nitrogen species, erythropoiesis, and the histaminergic system. Several HIS-rich proteins (e.g., haemoproteins, HIS-rich glycoproteins, histatins, HIS-rich calcium-binding protein, and filaggrin), HIS-containing dipeptides (particularly carnosine), and methyl- and sulphur-containing derivatives of HIS (3-methylhistidine, 1-methylhistidine, and ergothioneine) have specific functions. The unique chemical properties and physiological functions are the basis of the theoretical rationale to suggest HIS supplementation in a wide range of conditions. Several decades of experience have confirmed the effectiveness of HIS as a component of solutions used for organ preservation and myocardial protection in cardiac surgery. Further studies are needed to elucidate the effects of HIS supplementation on neurological disorders, atopic dermatitis, metabolic syndrome, diabetes, uraemic anaemia, ulcers, inflammatory bowel diseases, malignancies, and muscle performance during strenuous exercise. Signs of toxicity, mutagenic activity, and allergic reactions or peptic ulcers have not been reported, although HIS is a histamine precursor. Of concern should be findings of hepatic enlargement and increases in ammonia and glutamine and of decrease in branched-chain amino acids (valine, leucine, and isoleucine) in blood plasma indicating that HIS supplementation is inappropriate in patients with liver disease.	0
This paper reviews the molecular basis of the clinical features of Al-Awadi-Raas-Rothschild (limb/pelvis/uterus-hypoplasia-aplasia) (AARRS) syndrome and Fuhrmann syndrome. Human WNT7A mutations are also reviewed. Based on this review, these mutations will be classified into two main groups of phenotypes: Fuhrmann and AARRS phenotypes in which there is partial and complete loss of WNT7A functions, respectively.	0
Leigh syndrome is a clinically and radiologically heterogeneous condition with approximately 75 genes, nuclear and mitochondrial, known to be implicated in its pathogenesis. Leigh syndrome due to complex II deficiency constitutes 2% to 7% of these cases. Previously, nine individuals with Leigh syndrome have been reported with pathogenic variants in SDHB, which encodes for the iron-sulfur cluster subunit of mitochondrial respiratory chain complex II. The proband presented with Leigh syndrome. Exome sequencing revealed a homozygous missense variant p.(Ala102Thr) in SDHB. In silico protein modeling of the wild-type and mutant proteins showed potentially decreased protein stability. We hereby report another individual with Leigh syndrome due to SDHB-related mitochondrial complex II deficiency and review the phenotype and genotype associated with this condition.	0
OBJECTIVES:To compare patient-graded facial and social/well-being function with physician-graded facial function in Bell's palsy over time. STUDY DESIGN:A prospective follow-up study at two tertiary otorhinolaryngological centers. METHODS:A total of 96 patients, 36 women and 60 men, aged 18-77 years, were included. Facial Clinimetric Evaluation (FaCE) scale and Facial Disability Index (FDI) scores were compared with Sunnybrook and House-Brackmann scores. RESULTS:Inclusion was on mean day 7 (96 patients) and follow-up on days 53 (81 patients) and 137 (32 patients). Initially, correlations between FaCE total score, FaCE domains, FDI physical function, FDI social/well-being function and Sunnybrook and House-Brackmann scores were low to fair, except for FaCE facial movement (r = 0.55). Correlations between FaCE total score and Sunnybrook score were very good to excellent at visits 2 (r = 0.83) and 3 (r = 0.81). Women scored FaCE social and FDI social/well-being function lower than men, despite similar Sunnybrook scores. CONCLUSION:In early stages of Bell's palsy, there were low to fair correlations between FaCE/FDI (except for facial movement) and Sunnybrook score. This implies that the design of the quality of life (QoL) instruments is less suited for the acute phase. The high correlations at follow-ups suggest that the questionnaires can be used for evaluation of QoL over time. Our results indicate that women experience more facial palsy-related psychosocial dysfunction. LEVEL OF EVIDENCE:4 Laryngoscope, 2020.	0
Cervical lipomyelomeningocele is a very rare form of spina bifida occulta, which can cause some complications following tethered cord syndrome. We report a 10-year-old female with a history of progressive upper-extremity weakness, a very small soft-tissue mass at the posterior aspect of her neck, and evidence of lipomyelomeningocele in her radiological study. The patient underwent laminectomy of C6 and C7 together with resection of lipomatous tissue attaching to the cord from superficial tissue and cord untethering, which resulted in progressive improvement of her weakness.	0
To the central nervous system (CNS) belong a heterogeneous group of glial and non glial rare cancers. The aim of the present study was to estimate the burden (incidence, prevalence, survival and proportion of cured) for the principal CNS cancers in Europe (EU27) and in European regions using population-based data from cancer registries participating in the RARECARE project. We analysed 44,947 rare CNS cancers diagnosed from 1995 to 2002 (with follow up at 31st December 2003): 86.0% astrocytic (24% low grade, 63% high grade and 13% glioma NOS), 6.4% oligodendroglial (74% low grade), 3.6% ependymal (85% low grade), 4.1% Embryonal tumours and 0.1% choroid plexus carcinoma. Incidence rates vary widely across European regions especially for astrocytic tumours ranging from 3/100,000 in Eastern Europe to 5/100,000 in United Kingdom and Ireland. Overall, about 27,700 new rare CNS cancers were estimated every year in EU27, for an annual incidence rate of 4.8 per 100,000 for astrocytic, 0.4 for oligodendroglial, 0.2 for ependymal and embryonal tumours and less than 0.1 for choroid plexus carcinoma. More than 154,000 persons with rare CNS were estimated alive (prevalent cases) in the EU at the beginning of 2008. Five-year relative survival was 14.5% for astrocytic tumours (42.6% for low grade, 4.9% for high grade and 17.5% for glioma NOS), 54.5% for oligodendroglial (64.9% high grade and 29.6% low grade), 74.2% for ependymal (80.4% low grade and 36.6% high grade), 62.8% for choroid plexus carcinomas and 56.8% for embryonal tumours. Survival rates for astrocytic tumours were relatively higher in Northern and Central Europe than in Eastern Europe and in UK and Ireland. The different availability of diagnostic imaging techniques and/or radiation therapy equipment across Europe may contribute to explain the reported survival differences. The estimated proportion of cured patients was 7.9% for the 'glial' group to which belong astrocytic tumours. Overall results are strongly influenced by astrocytic tumours that are the most common type. This is the first study to delineate the rare CNS cancer burden in Europe by age, sex and European region.	1
Glycosylphosphatidylinositol biosynthesis defects cause rare genetic disorders characterised by developmental delay/intellectual disability, seizures, dysmorphic features, and diverse congenital anomalies associated with a wide range of additional features (hypotonia, hearing loss, elevated alkaline phosphatase, and several other features). Glycosylphosphatidylinositol functions as an anchor to link cell membranes and protein. These proteins function as enzymes, adhesion molecules, complement regulators, or co-receptors in signal transduction pathways. Biallelic variants involved in the glycosylphosphatidylinositol anchored proteins biosynthetic pathway are responsible for a growing number of disorders, including multiple congenital anomalies-hypotonia-seizures syndrome; hyperphosphatasia with mental retardation syndrome/Mabry syndrome; coloboma, congenital heart disease, ichthyosiform dermatosis, mental retardation, and ear anomalies/epilepsy syndrome; and early infantile epileptic encephalopathy-55. This review focuses on the current understanding of Glycosylphosphatidylinositol biosynthesis defects and the associated genes to further understand its wide phenotype spectrum.	0
The purpose of this article is to review the evidence linking background exposure to endocrine-disrupting chemicals (EDCs) with insulin resistance in children. Although evidence in children is scarce since very few prospective studies exist even in adults, evidence that EDCs might be involved in the development of insulin resistance and related diseases such as obesity and diabetes is accumulating. We reviewed the literature on both cross-sectional and prospective studies in humans and experimental studies. Epidemiological studies show a statistical link between exposure to pesticides, polychlorinated bisphenyls, bisphenol A, phthalates, aromatic polycyclic hydrocarbides, or dioxins and insulin resistance.	0
The case of thiamine-responsive megaloblastic anemia (TRMA) presented here speculates the need early diagnosis, continuous monitoring, follow-up, and regulated treatment plan for the patients. Complications and systemic manifestations are likely to enhance in otherwise circumstances.	0
The etiology of epilepsy is variable and sometimes multifactorial. Clinical course and response to treatment largely depend on the precise etiology of the seizures. Along with the electroencephalogram (EEG), neuroimaging techniques, in particular, magnetic resonance imaging (MRI), are the most important tools for determining the possible etiology of epilepsy. Over the last few years, there have been many developments in data acquisition and analysis for both morphological and functional neuroimaging of people suffering from this condition. These innovations have increased the detection of underlying structural pathologies, which have till recently been classified as "cryptogenic" epilepsy. Cryptogenic epilepsy is often refractory to anti-epileptic drug treatment. In drug-resistant patients with structural or consistent functional lesions related to the epilepsy syndrome, surgery is the only treatment that can offer a seizure-free outcome. The pre-operative detection of the underlying structural condition increases the odds of successful surgical treatment of pharmacoresistant epilepsy. This article provides a comprehensive overview of neuroimaging techniques in epilepsy, highlighting recent advances and innovations and summarizes frequent etiologies of epilepsy in order to improve the diagnosis and management of patients suffering from seizures, especially young patients and children.	0
Tumour-induced osteomalacia (TIO) is a rare disease characterised by hypophosphataemia and clinical symptoms of osteomalacia. Herein we report the case of a 29-year-old man who was admitted to hospital with progressive bone pain and was diagnosed with TIO caused by maxillary sinus tumours. In the preoperative evaluation, it was found that the patient had thyroid malignant tumours at the same time. Two operations were performed separately on the left maxillary sinus tumour and thyroid tumour after complete examination. After tumour resections, the symptoms of bone pain were relieved and the level of blood phosphorus was restored, long-term replacement therapy was needed for thyroid. When a patient is diagnosed with TIO, it is necessary to screen for the presence of other malignant tumours and explore the treatment options in order to benefit patients preferably.	0
Galactosialidosis (GS) is a rare form of lysosomal storage disease that involves a broad spectrum of skeletal and soft tissue abnormalities. We report here on a 4-year 7-month-old boy with mild mental retardation, exhibiting multiple caries cavities and associated infectious foci and macroglossia. A huge abdominal enlargement due to peritoneal ascites was evident. Behavioral management and patient positioning on the dental chair represented a true challenge. The patient was treated under general anesthesia. However, life-threatening postoperative complications occurred because of the impossibility of extubating the patient. A very careful preanesthetic assessment is crucial in children affected by general conditions associated with airway anomalies, such as GS.	0
A 1q42 deletion is a rare structure variation that commonly harbours various deletion breakpoints along with diversified phenotypes. In our study, we found a de novo 1q42 deletion in a boy who did not have a cleft palate or a congenital diaphragmatic hernia but presented with psychomotor retardation. A 1.9 Mb deletion located within 1q42.11-q42.12 was validated at the molecular cytogenetic level. This is the first report of a 1q42.11-q42.12 deletion in a patient with onlypsychomotor retardation. The precise break points could facilitate the discovery of potential causative genes, such as LBR, EPHX1, etc. The correlation between the psychomotor retardation and the underlying genetic factors could not only shed light on the diagnosis of psychomotor retardation at the genetic level but also provide potential therapeutic targets.	0
Harlequin ichthyosis (HI) is a rare and severe form of ichthyosis and is characterized by thickened, hard, armor-like plates of skin that cover the entire body. This disease is caused by mutations in the adenosine triphosphate-binding cassette transporter protein A12 gene, and the pattern of inheritance is autosomal recessive. Prenatal sonographic diagnosis of HI has not been frequently reported. Here, we report a case of HI detected at 28 weeks of gestation and discuss with the sonographic findings and a brief review of literature. The diagnosis was reached mainly based on 2-dimensional and 3-dimensional ultrasound findings. Three-dimensional ultrasound applications help recognize facial morphology, and thus, greatly contributes to prenatal diagnoses.	0
Fibrillary glomerulonephritis (FGN) was previously defined by glomerular deposition of haphazardly-oriented fibrils that stain with antisera to immunoglobulins and are negative for Congo red. We report the first series of immunoglobulin-negative FGN. The cohort consisted of 9 adults (7 females, 2 males), with a mean age at diagnosis of 66 years. Patients presented with proteinuria (100%, mean 3 g/day), hematuria (100%), and renal insufficiency (100%). Co-morbidities included carcinoma in 3 and hepatitis C infection in 2; no patient had hypocomplementemia or monoclonal gammopathy. Histologically, glomeruli were positive for DNAJB9, showed mostly mild mesangial hypercellularity and/or sclerosis, and were negative for immunoglobulins by immunofluorescence on frozen and paraffin tissue. Ultrastructurally, randomly-oriented fibrils measuring 13-20 nm in diameter were seen intermingling with mesangial matrix in all and infiltrating the glomerular basement membranes in 5. On follow up (mean 21 months), 2 had disease remission, 4 had persistent decreased kidney function, and 3 required kidney replacement therapy. Thus, rare cases of FGN are not associated with glomerular immunoglobulin deposition, and the diagnosis of FGN in these cases can be confirmed by DNAJB9 immunostaining. Pathogenesis remains to be elucidated.	0
Distal deletions and duplications of 3p are individually well-characterized chromosome abnormalities. Here, we report an inverted duplication of 3p with an adjacent terminal 3p deletion in a 17-month-old girl who had prenatal intrauterine growth restriction and cardiac defects. Other findings included hemangiomas, neutropenia, umbilical hernia, hypotonia, gross motor delay, microcephaly, and ptosis. Family history was noncontributory. Microarray analysis revealed a 5.37 Mb deletion of chromosome bands 3p26.1 to 3p26.3 and a 13.68 Mb duplication of 3p24.3 to 3p26.1. FISH analysis confirmed that the duplication was inverted. Upon literature review, only one postnatal patient and one second trimester pregnancy have been reported with this finding. Many of our patient's features are present in both 3p deletion and 3p duplication syndromes, including congenital heart disease, growth restriction, microcephaly, hypotonia, and developmental delay. Our patient has additional features not commonly reported in 3p deletion or duplication patients, such as aortic dilation, hemangiomas, and neutropenia. The identification of this patient contributes to additional understanding of features associated with concurrent deletion and inverted duplication in the distal 3p chromosome. This report may assist clinicians working with patients who have constellations of similar features or similar cytogenomic abnormalities.	0
β thalassemia major is a common hemoglobinopathy in Sri Lanka. Klebsiella pneumoniae (KP) is a Gram-negative capsulated organism responsible for various nosocomial and community-acquired infections. Transfusion-dependent splenectomized thalassemia patients are at risk of infections. Liver abscess is an infection to suspect in such patients, and, among the organisms, KP is an organism to watch out for. Furthermore, KP could cause multiple liver abscesses, which makes it difficult to treat, as it cannot be drained. We report a 16-year-old splenectomized transfusion-dependent thalassemia major patient who presented with multiple liver abscesses with KP bacteremia.	0
Neonatal herpes simplex virus (HSV) infection is a life-threatening infection with high morbidity and mortality rates. Neonatal herpes, most commonly due to HSV type 2, is a multi-system disease; however, initial pulmonary presentation is extremely unusual. We describe an infant presenting with progressive respiratory distress, which was the dominant clinical feature of HSV infection during the first days of life. Sepsis work-up and antibiotic treatment were immediately initiated; however, antiviral treatment was not given until the infant's death. HSV type 1 was isolated in nasopharyngeal and endotracheal aspirates. HSV pneumonia should be considered in a newborn with respiratory deterioration not compatible with common neonatal respiratory diseases.	0
Megaconial congenital muscular dystrophy (OMIM 602541) is characterized with early-onset hypotonia, muscle wasting, proximal weakness, cardiomyopathy, mildly elevated serum creatine kinase (CK) levels, and mild-to-moderate intellectual disability. We report two siblings in a consanguineous family admitted for psychomotor delay. Physical examination revealed proximal muscle weakness, contractures in the knee of elder sibling, diffuse mild generalized muscle atrophy, and dry skin with ichthyosis together with multiple nummular eczema in both siblings. Serum CK values were elevated up to 500 U/L. For genetic work-up, we performed whole exome sequencing (WES) after Nimblegen enrichment on the Illumina platform. The WES revealed a novel homozygous missense mutation in the Choline Kinase-Beta (CHKB) gene c.1031G>A (p.R344Q) in exon 9. Ichthyosis-like skin changes with intense pruritus and nummular eczema may lead to clinical diagnosis in cases with megaconial congenital muscular dystrophy.	0
Schwannoma is a slow-growing benign tumor, which originates from Schwann cells and is usually asymptomatic. The most common sites of schwannomas are the head, neck, and extremities. However, a schwannoma located in the liver is extremely rare. Here, we report a 53-year-old woman with a hepatic lesion accidentally found by ultrasound. It was highly suggestive of hepatic cholangiocarcinoma by MRI. F-FDG PET/CT could not exclude hepatic malignant tumor due to its high metabolism. Finally, it was confirmed as hepatic schwannoma by postoperative pathology.	0
BACKGROUND:In the last few years trio-whole exome sequencing (WES) analysis has demonstrated its potential in obtaining genetic diagnoses even in nonspecific clinical pictures and in atypical presentations of known diseases. Moreover WES allows the detection of variants in multiple genes causing different genetic conditions in a single patient, in about 5% of cases. The resulting phenotype may be clinically discerned as variability in the expression of a known phenotype, or as a new unreported syndromic condition. METHODS:Trio-WES was performed on a 4-month-old baby with a complex clinical presentation characterized by skeletal anomalies, congenital heart malformation, congenital hypothyroidism, generalized venous and arterial hypoplasia, and recurrent infections. RESULTS:WES detected two different homozygous variants, one in CEP57, the gene responsible for mosaic variegated aneuploidy syndrome 2, the other in DYNC2H1, the main gene associated with short-rib thoracic dysplasia. CONCLUSION:The contribution of these two different genetic causes in determining the phenotype of our patient is discussed, including some clinical signs not explained by the detected variants. The report then highlights the role of WES in providing complete and fast diagnosis in patients with complex presentations of rare genetic syndromes, with important implications in the assessment of recurrence risk.	0
An amendment to this paper has been published and can be accessed via a link at the top of the paper.	0
BACKGROUND:Turner syndrome (TS) occurs in approximately 1 in 2500 live female births and is caused by the partial or complete loss of one of the X chromosomes, resulting in abnormalities such as ovarian failure and infertility. However, pregnancy in women with TS may still occur via spontaneous pregnancy or through oocyte donation. Limited data exists on pregnancy in women with TS that could aid in clinical care. METHODS:We conducted a population-based cross-sectional study using data from the Discharge Abstract Database (2004-2015), which contains all labor and delivery hospitalizations across Canada (excluding Quebec) where women delivered a live or stillborn infant. The odds of adverse maternal and neonatal outcomes for women with and without TS were calculated using backwards multivariable logistic regression with generalized estimating equations, adjusting for the Obstetric Comorbidity Index, mode of delivery, and year. RESULTS:Overall, 2,682,284 women delivered a live or stillborn infant during the study period and 44 birth events occurred for women with TS. No severe maternal morbidity or adverse cardiovascular events occurred for women with TS at their labor and delivery hospitalization. However, infants born to women with TS were 3.6 times more likely (95% CI: 1.7-7.8) to experience neonatal morbidity than those born to women without TS. These infants also were more likely to have had a preterm birth (aOR: 2.9, 95% CI: 1.6-5.4) and to be small-for-gestational-age (aOR: 4.5, 95% CI: 2.4-8.4). CONCLUSION:This study adds further understanding of the likelihood of adverse outcomes for pregnant women with TS.	0
Advanced fetal sonographic equipment has contributed to the increase in prenatal diagnosis of congenital thoracic malformations. Among these anomalies is congenital lobar emphysema (CLE), a rare congenital anomaly characterized by over distention and overexpansion of the involved fetal pulmonary lobe. Several studies addressed the prenatal diagnosis of CLE in mid second or early third trimester. The early prenatal diagnosis and the outcome of a case of CLE are reported in this study.	0
A coronary angiography performed for the occurrence of atypical chest pain allowed us to discover a coronary-right ventricular fistula as a rare complication of myocardial penetration by a tined ventricular catheter implanted some years earlier.	0
Rhabdomyomas are rare benign mesenchymal tumors of striated muscle origin. These are classified as cardiac and extracardiac types. Extracardiac type is further classified as adult, fetal and genital types. Adult rhabdomyoma represents <2% of all muscular tumors. It mostly occurs in adults (median: 60 years). Males are more commonly affected (M:F = 3:1) and usually present as solitary lesion. We report a rare case of multinodular adult rhabdomyoma arising from the floor of the mouth. A 55-year-old female presented with a painless, soft, mobile, nontender and multinodular swelling in the right submandibular region and the floor of the mouth for 2 months. Fine-needle aspiration cytology showed cellular smears of large elongated to round cells with abundant eosinophilic granular cytoplasm, small nuclei and occasionally prominent nucleoli. Histology revealed partially encapsulated lesion showing sheets of large, oval to polygonal cells with abundant deeply eosinophilic and granular cytoplasm, with small peripherally placed nuclei with few cells showing prominent nucleoli. Prominent cytoplasmic vacuolations (periodic acid-Schiff positive) were present. The cells were positive for desmin and myogenin. This case is an extremely rare presentation of multinodular adult rhabdomyoma in a female. The correct identification of this lesion is important to avoid an unnecessarily aggressive resection, yet providing potentially curative therapy.	0
Robin sequence with cleft mandible and limb anomalies, known as Richieri-Costa-Pereira syndrome (RCPS), is an autosomal recessive acrofacial dysostosis characterized by mandibular cleft and other craniofacial anomalies and respiratory complications. The aim of this cross-sectional study was to describe the hyoid and head posture of 9 individuals with RCPS using cephalometric measurements and provide a discussion about its implications in obstructive sleep apnea syndrome (OSAS). The study was conducted on lateral cephalograms of patients with RCPS and 9 selected age-matched controls in tertiary cleft center in Brazil. The cephalograms were digitized and analyzed on a software to obtain the vertical and horizontal hyoid position, its relationship with the mandible and the relation of the cranial base and postvertebral line. The t test was used for analysis of means and Levene's test for equality of variances.Cephalometric measurements H-S (vertical distance between hyoid bone and sella) (Supplemental Digital Content, Figure 1, http://links.lww.com/SCS/B247) and H-C4lp (horizontal position of the hyoid in relation to the post-pharyngeal space) showed statistically significant difference compared to controls (P < 0.05). Therefore, the hyoid bone was more inferiorly and posteriorly positioned in the study group compared with the control group. The vertebrae measurements did not present differences compared to controls. The described position of hyoid bone could be involved in the severe OSAS of RCPS patients.	0
OBJECTIVE:To explore the clinical and genetic characteristics of five pedigrees affected with hereditary spastic paraplegia(HSP). METHODS:Clinical data of the five pedigrees was collected, and high-throughput sequencing was carried out to detect potential variants. Sanger sequencing were used to verify the results. RESULTS:The probands of pedigree 1 and 2 were found to harbor heterozygous SPAST gene variants, namely c.1196C>T and c.1523T>A. The proband of pedigree 3 harbored compound heterozygous variants of FA2H gene (c.61G>C and c.688G>A). Proband from pedigree 4 harbored compound heterozygous variants of SPG11 gene (c.6812+4_6812+7delAGTA and c.915delT). The proband of pedigree 5 harbored compound heterozygous variants of SPG7 gene (c.1703_1704delAG and c.1937-1G>C). Based on the American College of Medical Genetics and Genomics(ACMG) guidelines, all variants were predicted to be likely pathogenic. Among these, SPAST gene c.1523T>A, FA2H gene c.61.G>C, SPG11 gene splicing region c.6812+4_6812+7delAGTA, c.915delT, SPG7 gene c.1703_1704delAG and splicing region c.1937-1G>C variants were unreported previously. CONCLUSION:The probands of pedigrees 1 and 2 were diagnosed with autosomal dominant hereditary spastic paraplegia type 4, for which pedigree 2 showed incompletely penetrance. Pedigrees 3, 4, and 5 were diagnosed with autosomal recessive hereditary spastic paraplegia type 35, 11 and 7, respectively. Above result provided a reference for clinical diagnosis and genetic counseling for the affected pedigrees.	0
Butterfly vertebrae are rare developmental anomalies representing failure of formation of the vertebral body. There have only been 8 previous reports of a butterfly vertebra occurring at S1. This is the first described case of a butterfly vertebra presenting with a sacral fracture and pelvic ring injury.	0
Background:Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes, being characterized by beta-cell disfunction, early onset, and autosomal dominant inheritance. Despite the rapid evolution of molecular diagnosis methods, many MODY cases are misdiagnosed as type 1 or type 2 diabetes. High costs of genetic testing and limited knowledge of MODY as a relevant clinical entity are some of the obstacles that hinder correct MODY diagnosis and treatment. We present a broad review of clinical syndromes related to most common MODY subtypes, emphasizing the role of biomarkers that can help improving the accuracy of clinical selection of candidates for molecular diagnosis. Main body:To date, MODY-related mutations have been reported in at least 14 different genes. Mutations in glucokinase (GCK), hepatocyte nuclear factor-1 homeobox A (HNF1A), and hepatocyte nuclear factor-4 homeobox A (HNF4A) are the most common causes of MODY. Accurate etiological diagnosis can be challenging. Many biomarkers such as apolipoprotein-M (ApoM), aminoaciduria, complement components, and glycosuria have been tested, but have not translated into helpful diagnostic tools. High-sensitivity C-reactive protein (hs-CRP) levels are lower in HNF1A-MODY and have been tested in some studies to discriminate HNF1A-MODY from other types of diabetes, although more data are needed. Overall, presence of pancreatic residual function and absence of islet autoimmunity seem the most promising clinical instruments to select patients for further investigation. Conclusions:The selection of diabetic patients for genetic testing is an ongoing challenge. Metabolic profiling, diabetes onset age, pancreatic antibodies, and C-peptide seem to be useful tools to better select patients for genetic testing. Further studies are needed to define cut-off values in different populations.	0
Background:Overdrainage and collapse of the hemispheres is a potential severe complication after surgical treatment of internal hydrocephalus using ventriculoperitoneal shunts. Here we describe a case of a spontaneous hemispheric ventricular collapse in an untreated dog with congenital hydrocephalus internus. Case presentation:A twelve-week-old, male, intact Golden Retriever was presented with a history of peracute obtundation, impaired vision, and progressive gait abnormalities of all limbs for three days. Neurological examination revealed a dome shaped skull, a broad-based stance and a moderate cerebellar ataxia. The postural responses were markedly delayed in all limbs. Moderate ventro-lateral strabismus, vertical nystagmus and absent menace response were observed bilaterally. Clinical signs indicated multifocal localisation (forebrain, cerebellum). Magnetic resonance imaging (MRI) showed dilation of all cerebral ventricles, irregular thinning of the periventricular white and grey matter, consistent with internal hydrocephalus. In addition, the hemispheres were collapsed at the right temporal and left frontal lobe with haemorrhage filling the adjacent subarachnoid space. The dog underwent left frontal and right temporal craniotomy for removal of the haemorrhage. The dog improved on all neurological signs and was discharged after seven days. A repeat MRI three months postsurgical intervention showed reexpansion of the cerebral hemispheres. Subarachnoid haemorrhages were markedly reduced. Conclusions:Collapse of the hemispheres can occur spontaneously in dogs with hydrocephalus internus. Removal of the haemorrhage can improve clinical signs.	0
Spondylometaphyseal dysplasia (SMD) comprises a heterogeneous group of heritable skeletal dysplasias characterized by modifications of the vertebral bodies of the spine and metaphyses of the tubular bones. The genetic etiology of SMD is currently unknown; however, the type X collagen gene (COL10A1) is considered an excellent candidate, for two reasons: first, Schmid metaphyseal chondrodysplasia, a condition known to result from COL10A1 mutations, shows a significant phenotypic overlap with SMD; and, second, transgenic mice carrying deletions in type X collagen show SMD phenotypes. Hence, we examined the entire coding region of COL10A1 by direct sequencing of DNA from five unrelated patients with SMD and found a heterozygous missense mutation (Gly595Glu) cosegregating with the disease phenotype in one SMD family. This initial documented identification of a mutation in SMD expands our knowledge concerning the range of the pathological phenotypes that can be produced by aberrations of type X collagen (type X collagenopathy).	0
Aristolochic acids (AAs) have been known as potent nephrotoxins since the use of AA-containing herbal medicines was linked with a series of sporadic renal fibrotic nephropathy cases, and yet an estimated 100 million people worldwide are still at risk today because of continued use of similar medicines. However, a similar nephropathic condition is endemic in the rural Balkan regions (e.g., Serbian farming villages) and AAs were again found to be the causative agents. In the case of this Balkan endemic nephropathy, AAs were found to have originated from a widespread local weed Aristolochia clematitis L. In this study, we tested the hypothesis that AAs released from decomposition of A. clematitis were also being leached into groundwater, thus polluting the drinking water of local residents. We initiated the study by developing a dispersive solid-phase extraction-based sample preparation method for water samples suspected of AA contamination. The validated method was then coupled with a liquid chromatography-tandem mass spectrometric method to measure AAs in groundwater samples collected from Serbia. Our study revealed for the first time that groundwater in Serbia is extensively contaminated with AA-I, at ng/L levels. Results also showed that AAs are long-lived water contaminants, with no observable concentration changes over a 2-month period of sample storage.	0
Eleven missense mutations have been describe in human triosephosphate isomerase (TPI), affecting its catalytic function. Several of these mutations generate triosephosphate isomerase deficiency, the consequences of which can in some cases be lethal. The missense F240L mutation was found in a Hungarian patient showing symptoms of chronic hemolytic anemia and neuromuscular dysfunction. In vitro studies using a recombinant version of this mutant showed that it affects kinetic parameters, thermal stability and dimeric stability. Using X-ray crystal structures, the present paper describes how this mutation affected the flexibility of catalytic residues K13 and part of the (β/α) 8-barrel fold facing the dimeric interface in the TPI.	0
In mammals, the iron storage and detoxification protein ferritin is composed of two functionally and genetically distinct subunit types, H (heavy) and L (light). The two subunits co-assemble in various ratios, with a tissue specific distribution, to form shell-like protein structures of 24 subunits within which a mineralized iron core is stored. The H-subunits possess ferroxidase centers that catalyze the rapid oxidation of ferrous ions, whereas the L-subunit does not have such centers and is believed to play an important role in electron transfer reactions that occur during the uptake and release of iron. Pathogenic mutations on the L-chain lead to neuroferritinopathy, a neurodegenerative disease characterized by abnormal accumulation of ferritin inclusion bodies and iron in the central nervous system. Here, we have characterized the thermal stability, iron loading capacity, iron uptake, and iron release properties of ferritin heteropolymers carrying the three pathogenic L-ferritin mutants (L154fs, L167fs, and L148fs, which for simplicity we named Ln1, Ln2 and Ln3, respectively), and a non-pathogenic variant (L135P) bearing a single substitution on the 3-fold axes of L-subunits. The UV-Vis data show a similar iron loading capacity (ranging between 1800 to 2400 Fe(iii)/shell) for all ferritin samples examined in this study, with Ln2 holding the least amount of iron (i.e. 1800 Fe(iii)/shell). The three pathogenic L-ferritin mutants revealed higher rates of iron oxidation and iron release, suggesting that a few mutated L-chains on the heteropolymer have a significant effect on iron permeability through the ferritin shell. DSC thermograms showed a strong destabilization effect, the severity of which depends on the location of the frameshift mutations (i.e. wt heteropolymer ferritin ≅ homopolymer H-chain > L135P > Ln2 > Ln1 > Ln3). Variant L135P had only minor effects on the protein functionality and stability, suggesting that local melting of the 3-fold axes in this variant may not be responsible for neuroferritinopathy-like disorders. The data support the hypothesis that hereditary neuroferritinopathies are due to alterations of ferritin functionality and lower physical stability which correlate with the frameshifts introduced at the C-terminal sequence and explain the dominant transmission of the disorder.	0
BACKGROUND AND OBJECTIVES:The development of desmoid fibromatosis after tumor resection may mimic local recurrence. To our knowledge, this phenomenon has not been reported after extremity sarcoma resection. We report four cases of desmoid-type fibromatosis ("desmoid tumors") mimicking local recurrence after extremity sarcoma resection. METHODS:We retrospectively reviewed the records of patients treated for extremity sarcoma by our orthopedic oncology service from 2014 to 2019 and identified four patients with biopsy-proven desmoid tumors. We extracted clinical, pathologic, radiographic, and operative data for the primary neoplasms and desmoid tumors. RESULTS:Four patients with postresection surveillance magnetic resonance imaging suspicious for local recurrence underwent further analysis showing desmoid tumors. Patients underwent image-guided needle biopsy, with specimens demonstrating fibromatosis-type histologic characteristics. Two cases were β-catenin positive. Desmoid tumors were managed with observation. No patient had experienced local or distant recurrence of the primary tumor at a mean follow-up of 30 months after resection (range, 23-34 months); none underwent surgery for symptoms of desmoid tumors. CONCLUSIONS:Desmoid tumors should be considered part of the differential diagnosis when assessing patients with radiographic concern for postresection local recurrence of extremity bone and soft-tissue sarcoma. An image-guided needle biopsy can inform diagnosis and management.	0
BACKGROUND:Syndactyly is a clinical feature of split-hand foot malformation (SHFM), ectodermal-dysplasia-syndactyly (EDSS1) and Cenani-Lenz syndactyly syndromes (CLSS). In EDSS1, only cutaneous syndactyly is observed, with sparse hair, abnormal nails and dentition. In SHFM, bony syndactyly may vary from hypoplasia of one phalanx to aplasia of central digits, extending to complete fusion of all fingers and toes in CLSS. Several genes have been assigned to these syndromes. Performing a single step molecular diagnostics becomes a challenge when a phenotype has overlaps with several syndromes or when some of the clinical features are not fully expressed in patients. METHODS:Whole exome sequencing (WES) analysis on one sample derived from a consanguineous family was performed. A causative variant in WES data was prioritized via standard bioinformatics tools. The selected variant was Sanger sequenced in all the available family members for autosomal recessive segregation. RESULTS:A novel missense variant (c.1151A>G; p.Tyr384Cys) was identified in the LRP4 gene. Sanger validation confirmed that all affected individuals were homozygous and the obligate carriers were heterozygous for this variant. The variant is neither reported in 1000 human genomes, nor in 60 706 exomes databases, and is predicted as "pathogenic" by SIFT, Polyphen-2 and MutationTaster software. CONCLUSIONS:The present study broadens the pathogenic spectrum of the LRP4 gene in syndactyly syndromes. WES is a powerful tool for genetic analysis in research and can be readily used as a first-line diagnostic test in syndactyly and related phenotypes.	0
In order to build a common data pool and estimate the disease burden of primary immunodeficiencies (PID) in Europe, the European Society for Immunodeficiencies (ESID) has developed an internet-based database for clinical and research data on patients with PID. This database is a platform for epidemiological analyses as well as the development of new diagnostic and therapeutic strategies and the identification of novel disease-associated genes. Since its start in 2004, 13,708 patients from 41 countries have been documented in the ESID database. Common variable immunodeficiency (CVID) represents the most common entity with 2880 patients or 21% of all entries, followed by selective immunoglobulin A (sIgA) deficiency (1424 patients, 10·4%). The total documented prevalence of PID is highest in France, with five patients per 100,000 inhabitants. The highest documented prevalence for a single disease is 1·3 per 100,000 inhabitants for sIgA deficiency in Hungary. The highest reported incidence of PID per 100,000 live births was 16·2 for the period 1999-2002 in France. The highest reported incidence rate for a single disease was 6·7 for sIgA deficiency in Spain for the period 1999-2002. The genetic cause was known in 36·2% of all registered patients. Consanguinity was reported in 8·8%, and 18·5% of patients were reported to be familial cases; 27·9% of patients were diagnosed after the age of 16. We did not observe a significant decrease in the diagnostic delay for most diseases between 1987 and 2010. The most frequently reported long-term medication is immunoglobulin replacement.	1
Krabbe disease is a progressive neurologic disorder caused by deficiency of the lysosomal enzyme galactocerebrosidase. The disease commonly has an early-infantile onset, but can have late-infantile, juvenile, or adult-onset phenotypes. Classic computed tomography (CT) and magnetic resonance imaging (MRI) findings in Krabbe have been well described. We report a patient, ultimately diagnosed with juvenile-onset Krabbe, who presented with atypical CT imaging and rapid disease progression. Our patient was a previously healthy and developmentally appropriate female who presented at 3 years 4 months of age with ataxia and motor regression that had progressed over the course of 6 weeks without an identifiable catalyst. CT, performed in the emergency setting, demonstrated extensive white matter hyperdensity. Subsequent MRI showed T2 hyperintensity of the white matter corresponding to the areas of hyperdensity on the CT, as well as enhancement of multiple cranial nerves bilaterally, suggestive of Krabbe disease. Enzymatic testing demonstrated low galactocerebrosidase activity and molecular testing of GALC revealed compound heterozygosity for 2 known pathogenic mutations, consistent with a diagnosis of Krabbe Disease. This included the common 30-kb deletion and a known pathogenic mutation associated with juvenile/adult-onset disease. Our patient's diffuse hyperdensity on CT offers a new radiographic finding to include in the repertoire of Krabbe imaging, and thus aide in the diagnostic evaluation. The rapidity of progression our patient demonstrated is additionally unique and should be considered in the identification of juvenile Krabbe as well as the complicated decision-making process regarding potential treatments.	0
INTRODUCTION:Charcot-Marie-Tooth (CMT) phenotypes can be distinguished by electrophysiology and genetic analysis but few can be identified by their clinical characteristics. Distinctive phenotypes are useful in identifying affected individuals and providing additional clues about the mechanism of the neuropathy. Cranial neuropathies are uncommon features of CMT, and few reports of familial hemifacial spasm (HFS) and trigeminal neuralgia (TN) have been published. METHODS:Sixty-three members of a large CMT 1B kindred were assessed for signs of peripheral neuropathy and cranial neuropathies then tested for the G163R mutation in the myelin protein zero (MPZ) gene. RESULTS:Of 27 individuals with the G163R mutation in MPZ, 10 had HFS or TN. Co-existing HFS and TN were found in 3 of these and 4 had bilateral HFS or TN. CONCLUSIONS:This kindred exhibits a distinct CMT phenotype characterized by the development of HFS or TN decades after clinical signs of hereditary neuropathy are manifest. Muscle Nerve, 2019.	0
BACKGROUND:Homozygous protein C (PC) deficiency is a potentially fatal disease with ocular blinding presentation or sequela. CASE PRESENTATION:A 5 month-old boy was presented for evaluation of leukocoria. He had a history of frequent bruises and PC deficiency, treated with warfarin. His intraocular pressure was normal. In the left eye leukoma with anterior segment dysgenesis, shallow anterior chamber, and cataract were observed. Fundus was not visible. B-scan revealed a closed funnel retinal detachment. His right eye had a normal anterior segment and a thin retina with anomalous retinal vascular branching at equator and peripheral retina. A fibrovascular tuft on the optic nerve head with induced traction on superior arcade was visible. Total loss of a and b wave of both were appreciated in electroretinography (ERG). Fluorescein angiography (FA) showed very severe leakage at the junction of the vascularized and non-vascularized retina and optic nerve head. Favorable outcome was achieved with lasering of avascular retina in the right eye. CONCLUSION:The potential for protein C deficiency should be assessed in all infants with leukocoria, anterior segment dysgenesis, retinal detachment and retinal dysplasia. Early diagnosis could save the child's life and vision.	0
Congenitally corrected transposition of the great arteries (CCTGA) is a rare congenital heart lesion with varied morphological presentation and can often by asymptomatic. A failing systemic right ventricle (RV) or increasing tricuspid regurgitation are generally indications for surgical intervention. The surgical approach depends upon the age of the patient and morphology of the lesion. Anatomical correction is associated with satisfactory long-term results.	0
Complete penoscrotal transposition is an extremely rare congenital anomaly and is usually associated with other urinary system abnormalities. Prenatal diagnosis is feasible by demonstrating perineal anatomy and its relation with scrotum and phallus. We describe two prenatal cases presenting with oligohydramniosis and megacystis due to lower urinary tract obstruction. Postnatal diagnosis was confirmed in both cases. Considering the dismal perinatal outcome, an accurate prenatal diagnosis is required for counseling the parents and preparing for postnatal care.	0
Budd-Chiari syndrome (BCS) is an uncommon condition, caused by obstruction to hepatic venous outflow. It is largely underdiagnosed, and a high index of suspicion is required for any patient with unexplained portal hypertension. The understanding of its etiology and pathology is improving with advances in diagnostic techniques. Recent studies reported an identifiable etiology in > 80% of cases. Myeloproliferative neoplasm (MPN) is the most common etiology, and genetic studies help in diagnosing latent MPN. Better cross-sectional imaging helps delineate the site of obstruction accurately. The majority of BCS patients are now treated by endovascular intervention and anticoagulation which have improved survival in this disease. Angioplasty of hepatic veins/inferior vena cava remains under-utilized at present. While surgical porto-systemic shunts are no longer done for BCS, liver transplantation is reserved for select indications. Some of the unresolved issues in the current management of BCS are also discussed in this review.	0
Background:Glycogen storage disease type IV (GSD IV; Andersen's disease) is a rare autosomal recessive disease caused by mutation in the GBE1 gene. Presentation of GSD IV varies on a continuum of severity and symptomatology ranging from neonatal death to mild adult-onset disease with variable involvement of hepatic, muscular, neurologic, dermatologic, and cardiac systems. Cardiomyopathy seen in GSD IV is also heterogeneous and its appearance on cardiac magnetic resonance imaging (CMR) is rarely described. Case summary:A 29-year-old man without previous medical history was admitted to our facility multiple times over 2 years for focal sensorimotor deficits, gout arthropathy, chronic hyperlactataemia and hyperuricaemia, and severe decompensated non-ischaemic cardiomyopathy complicated by episodes of thromboembolic organ infarction. Echocardiography and CMR showed severe biventricular failure with the presence of intraventricular thrombi with increased right ventricular trabeculation and absent late gadolinium enhancement. He underwent muscle biopsy which showed prominent glycogen in skeletal muscle followed by genetic testing showing a single heterozygous splicing mutation c.993-1G>T found at the junction of intron 7 and exon 8 of the GBE1 gene which had not previously been reported and was predicted to be pathologic. He was referred to a tertiary care centre with glycogen storage disease specialists but expired prior to establishing care at that facility. Discussion:Discovery of GSD IV in our patient was unexpected due to a highly variant clinical presentation. Our case stresses the clinical heterogeneity of GSD IV and the importance of genetic sequencing studies in the evaluation of potential glycogen storage disease.	0
Isolated patellofemoral arthritis is a common debilitating condition in adults older than 40 years of age. Surgical options such as patellofemoral arthroplasty exist for those who failed to respond to nonoperative treatment. However, early patellofemoral arthroplasty techniques often resulted in poor outcomes due to mal-tracking and malalignment of components. Robotic-assisted surgery recently has been introduced as an alternative to classic patellofemoral arthroplasty, with the potential to improve the anatomical fit and reproducibility of implant positioning. We present the technique for minimally invasive robotic-assisted patellofemoral arthroplasty system.	0
AIM:Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare neurodegenerative disorder presenting in children aged 2-4 years with seizures and loss of motor and language skills, followed by blindness and death in late childhood. Initial presenting features are similar to a range of common epilepsies. We aim to highlight typical clinical and radiological features that may prompt diagnosis of CLN2 disease in early disease stages. METHODS:We present a series of 13 Australian patients with CLN2 disease, describing clinical features, disease evolution, neuroimaging, electroencephalogram, biochemical and genetic results. Expert neuroradiological magnetic resonance imaging (MRI) analysis was retrospectively performed on 10 cases. RESULTS:Twelve patients presented with seizures, with initial seizures being focal (n = 4), generalised tonic-clonic (n = 3), absence (n = 3) and febrile (n = 2). Eleven patients (85%) had a language delay before the onset of seizures. Cerebellar or cerebral atrophy was noted in all patients on centralised MRI review, with abnormalities of the brain-stem, ventricles, corpus callosum and hippocampi. CONCLUSIONS:Early language delay with the onset of seizures at 2-4 years of age is the hallmark of CLN2 disease. MRI findings of early subtle atrophy in the cerebellum or posterior cortical regions should hasten testing for CLN2 disease to enable early initiation of enzyme replacement therapy.	0
Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.	0
A large pedigree with erythrokeratodermia variabilis (EKV) and erythema gyratum repens-like lesions is described. Clinical, laboratory, and histologic findings of this family are presented. The differential diagnoses of the following dermatoses with an erythematous and a hyperkeratotic component are discussed: erythrokeratodermia variabilis (Mendes da Costa), progressive symmetric erythrokeratoderma (Gottron), loricrin keratoderma, erythrokeratoderma en cocardes (Degos), Netherton syndrome, keratitis-ichthyosis-deafness (KID) syndrome, erythrokeratolysis hiemalis (Oudtshoorn disease), and nonbullous congenital ichthyosiform erythroderma.	0
BACKGROUND:Although endoscopic approaches are widely used for resection of colloid cysts because of the lower invasiveness, removal of the recurrent colloid cyst is still challenging. Total removal is sometimes difficult to achieve with single-port endoscopy because of the restricted access and working space. To compensate for these limitations, the dual endoscope technique via the bilateral transforaminal approach was chosen. CASE DESCRIPTION:A 34-year-old woman with recurrent colloid cyst of the third ventricle was admitted to our department. She had a history of endoscopic subtotal removal at another institution. Reoperation was scheduled and the endoscopic bilateral transforaminal approach was chosen to ensure total removal with minimum complication risk. After decompression, the cyst was retracted toward the third ventricle floor via the right foramen of Monro. Under direct inspection with an angled scope via the right foramen of Monro, the cyst attachment on the third ventricle roof was sharply dissected via the left foramen of Monro, resulting in total removal. CONCLUSIONS:The dual endoscope technique via the bilateral transforaminal approach can achieve better surgical outcome by obtaining direct visualization of the cyst attachment. Although the indication should be limited, this approach can be considered especially for patients with recurrent lesions involving possible adhesion to vital structures.	0
Electrocardiogram showing a regular wide QRS tachycardia with left branch block (LBBB) like in morphology at 200 beats per minute (bpm). During electrophysiology study, it suddenly gets narrow and faster. What is the mechanism of the switch from a broad complex to a narrow complex tachycardia?	0
Thrombocytopenia absent radius (TAR) syndrome is a very rare and infrequently seen congenital disorder with an approximate frequency of 0.42/100,000 live births. It is associated with bilateral absence of radii, hypo-megakaryocytic thrombocytopenia, and presence of both thumbs. The other systems which are affected by TAR syndrome include skeletal, hematologic, and cardiac systems. Intracranial hemorrhages due to thrombocytopenia and cardiac disorders are a common association usually seen with this syndrome and are usual cause of death. We describe a 3-month-old infant who was diagnosed with TAR syndrome on the basis of clinical features (thrombocytopenia and bilateral absent radius bone and confirmed by genetic analysis). The patient was diagnosed to have Tetralogy of Fallot, for which the infant was managed with definitive repair and thrombocytopenia was managed with platelet transfusion. Infants with TAR syndrome should be assessed for other associated malformations of various systems and followed up regularly and parents should be counseled for associated expected complications in these patients. We report an infant with TAR syndrome with Tetralogy of Fallot, which has not been reported in medical literature until now and this is the first case of its type.	0
Thoracic aortic aneurysm is typically clinically silent, with a natural history of progressive enlargement until a potentially lethal complication such as rupture or dissection occurs. Underlying genetic predisposition strongly influences the risk of thoracic aortic aneurysm and dissection. Familial cases are more virulent, have a higher rate of aneurysm growth, and occur earlier in life. To date, over 30 genes have been associated with syndromic and non-syndromic thoracic aortic aneurysm and dissection. The causative genes and their specific variants help to predict the disease phenotype, including age at presentation, risk of dissection at small aortic sizes, and risk of other cardiovascular and systemic manifestations. This genetic "dictionary" is already a clinical reality, allowing us to personalize care based on specific causative mutations for a substantial proportion of these patients. Widespread genetic sequencing of thoracic aortic aneurysm and dissection patients has been and continues to be crucial to the rapid expansion of this dictionary and ultimately, the delivery of truly personalized care to every patient.	0
Mucolipidosis type II (ML-II, I-cell disease) is a fatal inherited lysosomal storage disease caused by a deficiency of the enzyme N-acetylglucosamine-1-phosphotransferase. A characteristic skeletal phenotype is one of the many clinical manifestations of ML-II. Since the mechanisms underlying these skeletal defects in ML-II are not completely understood, we hypothesized that a defect in osteogenic differentiation of ML-II bone marrow mesenchymal stem cells (BM-MSCs) might be responsible for this skeletal phenotype. Here, we assessed and characterized the cellular phenotype of BM-MSCs from a ML-II patient before (BBMT) and after BM transplantation (ABMT), and we compared the results with BM-MSCs from a carrier and a healthy donor. Morphologically, we did not observe differences in ML-II BBMT and ABMT or carrier MSCs in terms of size or granularity. Osteogenic differentiation was not markedly affected by disease or carrier status. Adipogenic differentiation was increased in BBMT ML-II MSCs, but chondrogenic differentiation was decreased in both BBMT and ABMT ML-II MSCs. Immunophenotypically no significant differences were observed between the samples. Interestingly, the proliferative capacity of BBMT and ABMT ML-II MSCs was increased in comparison to MSCs from age-matched healthy donors. These data suggest that MSCs are not likely to cause the skeletal phenotype observed in ML-II, but they may contribute to the pathogenesis of ML-II as a result of lysosomal storage-induced pathology.	0
PIGT encodes a subunit of the glycosylphosphatidylinositol transamidase complex, which catalyzes the attachment of proteins to GPI-anchors. A homozygous PIGT variant c.550G>A (p. E184K) in a Chinese boy with multiple malformations, hypotonia, seizure and profound development delay was identified by panel sequencing. Pathogenicity of the variant was confirmed by flow cytometry. The expression of CD16 and CD24 of this proband reduced to 16.92 and 22.16% compare with normal control respectively while which of his parents and sister were normal. This mutation raised the mRNA level on the peripheral blood mono nuclear cells of this patient. This study expanded the variant spectrum of MCAHS3, and CD16 could be an effective marker to evaluate the pathogenicity of PIGT mutation.	0
BACKGROUND:Wolcott-Rallison Syndrome (WRS) is a rare autosomal recessive disease that is the most common cause of neonatal diabetes in consanguineous families. WRS is caused by various genetic alterations of the Eukaryotic Translation Initiation Factor 2-Alpha Kinase 3 (EIF2AK3) gene. METHODS:Genetic analysis of a consanguineous family where two children were diagnosed with WRS was performed by Sanger sequencing. The altered protein was investigated by in vitro cloning, expression and immunohistochemistry. RESULTS:The first cases in Hungary, - two patients in one family, where the parents were fourth-degree cousins - showed the typical clinical features of WRS: early onset diabetes mellitus with hyperglycemia, growth retardation, infection-induced multiple organ failure. The genetic background of the disease was a novel alteration in the EIF2AK3 gene involving the splice site of exon 11- intron 11-12 boundary: g.53051_53062delinsTG. According to cDNA sequencing this created a new splice site and resulted in a frameshift and the development of an early termination codon at amino acid position 633 (p.Pro627AspfsTer7). Based on in vitro cloning and expression studies, the truncated protein was functionally inactive. Immunohistochemistry revealed that the intact protein was absent in the islets of pancreas, furthermore insulin expressing cells were also dramatically diminished. Elevated GRP78 and reduced CHOP protein expression were observed in the liver. CONCLUSIONS:The novel genetic alteration causing the absence of the EIF2AK3 protein resulted in insufficient handling of severe endoplasmic reticulum stress, leading to liver failure and demise of the patients.	0
Abnormal development of the ocular anterior segment may lead to a spectrum of clinical phenotypes ranging from primary congenital glaucoma (PCG) to variable anterior segment dysgenesis (ASD). The main objective of this study was to identify the genetic alterations underlying recessive congenital glaucoma with ASD (CG-ASD). Next-generation DNA sequencing identified rare biallelic CPAMD8 variants in four patients with CG-ASD and in one case with PCG. CPAMD8 is a gene of unknown function and recently associated with ASD. Bioinformatic and in vitro functional evaluation of the variants using quantitative reverse transcription PCR and minigene analysis supported a loss-of-function pathogenic mechanism. Optical and electron microscopy of the trabeculectomy specimen from one of the CG-ASD cases revealed an abnormal anterior chamber angle, with altered extracellular matrix, and apoptotic trabecular meshwork cells. The CPAMD8 protein was immunodetected in adult human ocular fluids and anterior segment tissues involved in glaucoma and ASD (i.e., aqueous humor, non-pigmented ciliary epithelium, and iris muscles), as well as in periocular mesenchyme-like cells of zebrafish embryos. CRISPR/Cas9 disruption of this gene in F0 zebrafish embryos (96 hpf) resulted in varying degrees of gross developmental abnormalities, including microphthalmia, pharyngeal maldevelopment, and pericardial and periocular edemas. Optical and electron microscopy examination of these embryos showed iridocorneal angle hypoplasia (characterized by altered iris stroma cells, reduced anterior chamber, and collagen disorganized corneal stroma extracellular matrix), recapitulating some patients' features. Our data support the notion that CPAMD8 loss-of-function underlies a spectrum of recessive CG-ASD phenotypes associated with extracellular matrix disorganization and provide new insights into the normal and disease roles of this gene.	0
Congenital sensorineural hearing loss may occur in association with inborn pigmentary defects of the iris, hair, and skin. These conditions, named auditory-pigmentary disorders (APDs), represent extremely heterogeneous hereditary diseases, including Waardenburg syndromes, oculocutaneous albinism, Tietz syndrome, and piebaldism. APDs are part of the neurocristopathies, a group of congenital multisystem disorders caused by an altered development of the neural crest cells, multipotent progenitors of a wide variety of different lineages, including those differentiating into peripheral nervous system glial cells and melanocytes. We report on clinical and genetic findings of two monozygotic twins from a large Albanian family who showed a complex phenotype featured by sensorineural congenital deafness, severe neuropsychiatric impairment, and inborn pigmentary defects of hair and skin. The genetic analyzes identified, in both probands, an unreported co-occurrence of a new heterozygous germline pathogenic variant (c.2484 + 5G > T splicing mutation) in the KIT gene, consistent with the diagnosis of piebaldism, and a heterozygous deletion at chromosome 15q13.3, responsible for the neuropsychiatric impairment. This case represents the first worldwide report of dual locus inherited syndrome in piebald patients affected by a complex auditory-pigmentary multisystem phenotype. Here we also synthesize the clinical and genetic findings of all known neurocristopathies characterized by a hypopigmentary congenital disorder.	0
OBJECTIVE: To allow early recognition of cystathionine beta-synthase by newborn screening. STUDY DESIGN: Total homocysteine was determined in dried blood spots with a novel, robust high-performance liquid chromatography method with tandem mass spectrometry. Quantification of homocysteine was linear over a working range up to 50 micromol/L. For mutation analysis, DNA was tested for 2 mutations common in Qatar. RESULTS: Both methods proved to be suitable for high throughput processing. In 2 years, 7 infants with classic homocystinuria were identified of 12,603 native Qatari infants, yielding an incidence of 1:1800. Molecular screening would have missed 1 patient homozygous for a mutation not previously identified in the Qatari population. Over a period of 3 years, a total of 14 cases of classic homocystinuria were detected by screening of homocysteine from all newborn infants born in Qatar (n = 46 406). Homocysteine was always elevated, whereas methionine was elevated in only 7 cases. CONCLUSIONS: The study offers a reliable method for newborn screening for cystathionine beta-synthase deficiency, reaching a sensitivity of up to 100%, even if samples are taken within the first 3 days of life.	1
PURPOSE:Stargardt disease (STGD) is the most frequent cause of hereditary macular dystrophy in childhood. Variants in the ABCA4, ELOVL4, PROM1, BEST1, and PRPH2 genes have been detected in patients with autosomal recessive or dominant STGD. This study was aimed at identifying the novel disease-associated variants in Chinese patients with STGD. METHODS:Ten Chinese families and two sporadic cases with STGD (n = 32) were enrolled in the study. All subjects underwent genetic analysis with next-generation sequencing (NGS), which was based on a specially customized capture panel targeting exons and untranslated regions (UTRs) of 792 genes related to common hereditary ophthalmopathy. Variants were analyzed to assess possible pathogenicity. RESULTS:Fourteen disease-associated variants of ABCA4 were detected in 9 Chinese families with autosomal recessive STGD, including 11 pathogenic variants and 3 likely pathogenic variants. Variant c.4253 + 4C > T in ABCA4 was identified as one de novo variant. Of the 14 distinct variants in ABCA4, 7 novel variants were found. In addition, one known variant of PROM1, c.1117C > T (p.Arg373Cys), was detected in one family and one sporadic case with autosomal dominant STGD, respectively. One novel missense variant of ELOVL4, c.59A > G (p.Asn20Ser), was found in one sporadic case with autosomal dominant STGD. The potential deleterious effects of these novel variants were confirmed through intensive analysis. CONCLUSION:By panel-based NGS, 8 novel disease-associated variants are identified in two genes responsible for STGD, including ABCA4 and ELOVL4. Our results further extend the mutation spectrum of these two genes in Chinese patients with STGD. One ABCA4 c.4253 + 4C > T variant is identified as a de novo splicing variant.	0
Premature ovarian insufficiency (POI) defined by the cessation of ovarian function before the age of 40 years and the increase of gonadotropins (> 25 UI/l) occurs in approximately 1-5% of women. Different mechanisms are responsible for POI: chemotherapy, radiotherapy, environmental factors or genetic causes but most frequently no cause is identified. In order to determine the etiology of POI, cytogenetic analyses such as karyotype are performed. The karyotype allows to identify abnormalities of the number of chromosomes as well as abnormalities of the structure such as translocations, deletions or insertions of a size greater than 5-10 Mb… Turner syndrome is the most frequent genetic cause of POI and deletions of the long arm of the X chromosome are other causes of POI identified by the karyotype. However, the resolution of the karyotype is low and other cytogenetic techniques were developed such as all genome microarray analysis. This technique includes CGH-array and SNP-array and allows to identify gain or loss of chromosomal material as small as 10 kb but not the balanced structural rearrangements. Different studies using microarray analysis in cohorts of patients presenting with POI identify candidate genes responsible for POI. Furthermore, they allowed to identify a recurrent microdeletion, which includes the CPEB1 gene, located in 15q25.2 in about 1.5% of patients with POI.	0
Congenital maxillomandibular fusion or syngnathia is a rare craniofacial disorder with only 26 cases reported in the literature. We present a case of a congenital complex zygomatico-mandibular syngnathia associated with a palatal cleft, posterior maxilla and turbinate agenesia, mild hemifacial microsomia, and a disordered dental eruption. The patient has the highest age (15 years) at diagnosis described in the literature. 3D planning of the surgery was performed to study the patient's anatomy and design the necessary osteotomies to separate the jaws. En bloc removal of the fused fragment with bilateral coronoidectomy and aggressive long-term physiotherapy for 3 months led to a stable increase in mouth opening from 0 to 21 mm inter-incisor distance. The patient reported an improvement in speech, was able to eat without restriction regarding food consistency, and could maintain a good oral hygiene.	0
A 42-year-old man was referred to our hospital with heart failure and unoperated tricuspid atresia with pulmonary valve stenosis. His condition was initially managed with medical therapy; however, he required repeat hospitalisations for congestive heart failure. We diagnosed the chief cause of his heart failure as aortic valve regurgitation secondary to aortic root dilatation. Aortic root replacement was performed and then his heart failure was controlled.	0
BACKGROUND: Recent literature has shown increasing incidence and prevalence rates of eosinophilic esophagitis (EoE). However, data are mainly based on small studies and come from centers dedicated to EoE. Aim of this study was to estimate the incidence rates of EoE by using a large database. METHODS: We performed a cross-sectional study of the pathology reports describing esophageal eosinophilia from 1996 through 2010, using the nationwide network and registry of histo- and cytopathology in The Netherlands (PALGA). All histopathology reports nationwide enter this database. We classified cases according to the diagnosis made by the pathologist. Annual incidence rates of EoE were estimated. KEY RESULTS: Our search criteria yielded 8838 positive pathology reports. Eosinophilic esophagitis was diagnosed in 674 patients, of which 74% were men. In another 174 patients, no distinction was made between eosinophilia caused by gastro-esophageal reflux disease or EoE. The incidence of EoE increased considerably over the years, being 0.01 in 1996, 0.01 in 2000, 0.14 in 2005, and 1.31 per 100,000 persons in 2010. Eosinophilic esophagitis was diagnosed in all age groups, but in 2010 the highest incidence was seen in 20-29 years old males, in whom it was estimated to be 3.23 per 100,000 persons. The incidence in children was 0.73 per 100,000 in 2010. No seasonal variation in diagnosis of EoE was observed. CONCLUSIONS & INFERENCES: In this large study, we found robust data on increasing incidence rates of pediatric and adult EoE in the past 15 years. This rapidly increasing incidence has not reached a plateau yet.	1
In the original publication, introduction section under Abstract was published incorrectly. The correct version is given below.	0
To determine the cortical mechanism that underlies the cognitive impairment and motor disability in hereditary spastic paraplegia (HSP), nine HSP patients from a Chinese family were examined using clinical evaluation, cognitive screening, and genetic testing. Controls were matched healthy subjects. White-matter fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD; tract-based spatial statistics), cortical thickness (FreeSurfer), and subcortical gray matter (FIRST) based on T1-weighted MRI and diffusion tensor imaging were analyzed. A novel mutation in the SPAST gene (NM_014946.3, c.1321+2T>C) was detected. Patients had motor disability and low Montreal Cognitive Assessment (MoCA) scores. Patients showed significantly decreased total gray- and white-matter volumes, corpus callosum volume, cortical thickness, and subcortical gray-matter volume as well as significantly lower FA and AD values and significantly higher MD and RD values in the corpus callosum and corticospinal tract. Cortical thickness, subcortical gray-matter volume, and MoCA score were negatively correlated with disease duration. Cortical thickness in the right inferior frontal cortex was negatively correlated with Spastic Paraplegia Rating Scale score. Cortical thickness and right hippocampus volume were positively correlated with the MoCA score and subscores. In conclusion, brain damage is not restricted to the white matter in SPG4-HSP patients, and widespread gray-matter damage may account for the disease progression, cognitive impairment, and disease severity in SPG4-HSP.	0
Leukodystrophies and genetic leukoencephalopathies are a heterogeneous group of heritable disorders that affect the glial-axonal unit. As more patients with unsolved leukodystrophies and genetic leukoencephalopathies undergo next generation sequencing, causative mutations in genes leading to central hypomyelination are being identified. Two such individuals presented with arthrogryposis multiplex congenita, congenital hypomyelinating neuropathy, and central hypomyelination with early respiratory failure. Whole exome sequencing identified biallelic mutations in the CNTNAP1 gene: homozygous c.1163G>C (p.Arg388Pro) and compound heterozygous c.967T>C (p.Cys323Arg) and c.319C>T (p.Arg107*). Sural nerve and quadriceps muscle biopsies demonstrated progressive, severe onion bulb and axonal pathology. By ultrastructural evaluation, septate axoglial paranodal junctions were absent from nodes of Ranvier. Serial brain magnetic resonance images revealed hypomyelination, progressive atrophy, and reduced diffusion in the globus pallidus in both patients. These 2 families illustrate severe progressive peripheral demyelinating neuropathy due to the absence of septate paranodal junctions and central hypomyelination with neurodegeneration in CNTNAP1-associated arthrogryposis multiplex congenita.	0
The authors used magnetic resonance imaging (MRI) to study extraocular muscles (EOMs) and nerves in Duane-radial ray (Okihiro) syndrome (DRRS) caused by mutations in the transcription factor SALL4.The authors examined four male and two female affected members of a pedigree previously reported to cosegregate DRRS and a heterozygous SALL4 mutation. Coronal T1-weighted magnetic resonance images of the orbits and heavily T2-weighted images in the plane of the cranial nerves were obtained in four subjects. MRI findings were correlated with motility examinations and published norms obtained using identical technique.Five of the six subjects with DRRS had radial ray abnormalities including thumb, radial artery, radial bone, and pectoral muscle hypoplasia. Three had bilateral and three had unilateral ocular involvement. Seven eyes had limitation of both abduction and adduction, whereas two had limitations only of abduction. Most affected eyes had lid fissure narrowing and retraction in adduction. Intraorbital and intracranial abducens nerves (CN6) were small to absent, particularly ipsilateral to abduction deficiency. All subjects undergoing MRI had normal intracranial oculomotor nerves (CN3). Optic nerve (ON) cross-section findings were similar to normal. EOMs and pulleys were structurally normal in most subjects. In some affected orbits, a branch of CN3 closely approximated and presumably innervated the LR.DRRS encompasses a Duane syndrome phenotype, with a variable and asymmetric endophenotype including marked CN6 hypoplasia and probable innervation or coinnervation of the LR by CN3. This endophenotype is more limited than reported in DURS2-linked Duane syndrome (On-line Mendelian Inheritance in Man, OMIM 604356) and CFEOM1 (OMIM 135700), which are clinically similar congenital cranial dysinnervation disorders that also feature CN3 hypoplasia and more widespread EOM abnormalities.	0
The role of X-inactivation is often ignored as a prime cause of sex differences in disease. Yet, the way males and females express their X-linked genes has a major role in the dissimilar phenotypes that underlie many rare and common disorders, such as intellectual deficiency, epilepsy, congenital abnormalities, and diseases of the heart, blood, skin, muscle, and bones. Summarized here are many examples of the different presentations in males and females. Other data include reasons why women are often protected from the deleterious variants carried on their X chromosome, and the factors that render women susceptible in some instances.	0
West Nile virus (WNV) is an important neurotropic flavivirus that is widely distributed globally. WNV strain XJ11129 was first isolated in Xinjiang, China, and its genetic and biological characteristics remain largely unknown. In this study, phylogenetic and sequence analyses revealed that XJ11129 belongs to lineage 1a and shares high genetic identity with the highly pathogenic strain NY99. Then, the full-length genomic cDNA of XJ11129 was amplified and assembled using a modified Gibson assembly (GA) method. The virus (named rXJ11129) was successfully rescued in days following this method. Compared with other wild-type WNV isolates, rXJ11129 exhibited virulence indistinguishable from that of the NY99 strain in vivo. In summary, the genomic and virulence phenotypes of rXJ11129 were characterized in vivo and in vitro, and these data will improve the understanding of the spread and pathogenesis of this reemerging virus.	0
STUDY OBJECTIVES:Due to a limited number of pediatric sleep centers, the aim was to test the feasibility of ambulatory polysomnography (PSG-home) in a group of French children suspected of OSA. METHODS:Children undergoing one-night PSG-home, with the device installed at the pediatric sleep physician's office, were prospectively included. General failure was considered when PSG-home recording captured < 5 h of artifact-free sleep or when ≥ 1 channel (nasal flow, thoraco-abdominal belts, oximetry) presented artifacts > 75% of the recording time. No-OSA was defined as an obstructive apnea-hypopnia index (OAHI) < 1 event/h and respiratory-related arousals index (RAI) < 1 event/h. OSA was defined as upper airways resistance syndrome (UARS) with OAHI < 1 event/h with RAI ≥ 1 event/h, or mild OSA (OAHI ≥ 1 event/h-5 events/h), moderate OSA (OAHI ≥ 5 events/h-10 events/h), or severe OSA (OAHI ≥ 10 events/h). Parents completed a severity hierarchy score questionnaire, Conners Parent Rating Scale, and an adapted Epworth Sleepiness Scale. RESULTS:Fifty-seven children aged 3 through 16 years were included. PSG-home was technically acceptable in 46 (81%). Failure due to nasal cannula was observed in 11% (n = 6), oximetry in 7% (n = 4), and both in 2% (n = 1) of cases. No difference in feasibility was found according to age, sex, OSA severity, or comorbidities. There were 14 (25%) children categorized as no-OSA, 43 (75%) as OSA, 4 (7%) as UARS, 26 (46%) as mild, 6 (10%) as moderate, and 7 (12%) as severe OSA. Neither questionnaires nor clinical and physical examination predicted OSA diagnosis. CONCLUSIONS:When equipment is installed at the professional's office and a parent monitors the child, PSG-home is feasible and technically acceptable in children aged 3 through 16 years old. The short delay and feasibility provided by PSG-home could improve the management of children suspected of OSA.	0
Recurrent respiratory papillomatosis (RRP) is a chronic disease caused by human papillomavirus (HPV). RRP is a clinical challenge because of the high recurrence rate, poor surgery response, extension to tracheobronchial tree and because of the risk of malignancy in some cases. There is no consensus on which adjuvant therapy is better for those patients with highly recurrent course. Because papilloma cells overexpress the epidermal growth factor receptor (EGFR), together with an increased expression of COX-2 and prostaglandin E2, the combination of erlotinib and celecoxib seems plausible, and could be proposed for patients with poor response to previous lines of treatment.	0
Chromosome 6pter-p24 deletion syndrome (OMIM #612582) is a recognized chromosomal disorder. Most of the individuals with this syndrome carry a terminal deletion of the short arm of chromosome 6 (6p) with a breakpoint within the 6p25.3p23 region. An approximately 2.1 Mb terminal region has been reported to be responsible for some major features of the syndrome. The phenotypic contributions of other deleted regions are unknown. Interstitial deletions of the region are uncommon, and reciprocal interstitial duplication in this region is extremely rare.We present a family carrying an interstitial deletion and its reciprocal duplication within the 6p25.1p24.3 region. The deletion is 5.6 Mb in size and was detected by array comparative genomic hybridization (aCGH) in a 26-month-old female proband who presented speech delay and mild growth delay, bilateral conductive hearing loss and dysmorphic features. Array CGH studies of her family members detected an apparently mosaic deletion of the same region in the proband's mildly affected mother, but a reciprocal interstitial duplication in her phenotypically normal brother. Further chromosomal and fluorescence in situ hybridization (FISH) analyses revealed that instead of a simple mosaic deletion of 6p25.1p24.3, the mother actually carries three cell populations in her peripheral blood, including a deletion (~70 %), a duplication (~8 %) and a normal (~22 %) populations. Therefore, both the deletion and duplication seen in the siblings were apparently inherited from the mother.Interstitial deletion within the 6p25.1p24.3 region and its reciprocal duplication may co-exist in the same individual and/or family due to mitotic unequal sister chromatid exchange. While the deletion causes phenotypes reportedly associated with the chromosome 6pter-p24 deletion syndrome, the reciprocal duplication may have no or minimal phenotypic effect, suggesting possible triploinsensitivity of the same region. In addition, the cells with the duplication may compensate the phenotypic effect of the cells with the deletion in the same individual as implied by the maternal karyotype and her mild phenotype. Chromosomal and FISH analyses are essential to verify abnormal cytogenomic array findings.	0
Hyalinosis is a vascular lesion affecting the renal vasculature and contributing to aging-related renal function decline. We assessed whether arteriolar hyalinosis is caused by Klotho deficiency, a state known to induce both renal and vascular phenotypes associated with aging. Histochemistry was used to assess hyalinosis in Klotho-/- kidneys, compared with Klotho+/- and wild-type littermates. Immunohistochemistry was used to investigate vascular lesion composition and the different layers of the vascular wall. Finally, spironolactone was used to inhibit calcification in kl/kl mice, and vascular lesions were characterized in the kidney. Arteriolar hyalinosis was detected in Klotho-/- mice, which was present up to the afferent arterioles. Hyalinosis was accompanied by loss of α-smooth muscle actin expression, whereas the endothelial lining was mostly intact. Hyalinous lesions were positive for IgM and iC3b/c/d, indicating subendothelial leakage of plasma proteins. The presence of extracellular matrix proteins suggested increased production by smooth muscle cells (SMCs). Finally, in Klotho-/- mice with marked vascular calcification, treatment with spironolactone allowed for replacement of calcification by hyalinosis. Klotho deficiency potentiates both endothelial hyperpermeability and SMC dedifferentiation. In the absence of a calcification-inducing stimulus, SMCs assume a synthetic phenotype in response to subendothelial leakage of plasma proteins. In the kidney, this results in arteriolar hyalinosis, which contributes to the decline in renal function. Klotho may play a role in preventing aging-related arteriolar hyalinosis.	0
Increasing evidence points to the respiratory Complex II (CII) as a source and modulator of reactive oxygen species (ROS). Both functional loss of CII as well as its pharmacological inhibition can lead to ROS generation in cells, with a relevant impact on the development of pathophysiological conditions, i.e. cancer and neurodegenerative diseases. While the basic framework of CII involvement in ROS production has been defined, the fine details still await clarification. It is important to resolve these aspects to fully understand the role of CII in pathology and to explore its therapeutic potential in cancer and other diseases.	0
We have evaluated a 3 2/12 year old girl who presented with unilateral blepharophimosis, ptosis of the eyelid, and mental retardation. Additional dysmorphic features include microcephaly, high, narrow forehead, short stubby fingers, and adduction of the right first toe. Cytogenetic analysis showed an unbalanced karyotype consisting of 46,XX,add(7)(q+) that was de novo in origin. Fluorescence in situ hybridisation (FISH) using microdissected library probe pools from chromosomes 1,2,3,7, and 3q26-qter showed that the additional material on 7q was derived from the distal end of the long arm of chromosome 3. Our results indicate that the patient had an unbalanced translocation, 46,XX,der(7)t(3;7)(q26-qter;q+) which resulted in trisomy for distal 3q. All currently reported cases of BPES (blepharophimosis-ptosis-epicanthus inversus syndrome) with associated cytogenetic abnormalities show interstitial deletions or balanced translocations involving 3q22-q23 or 3p25.3. Our patient shares similar features to BPES, except for the unilateral ptosis and absence of epicanthus inversus. It is possible that our patient has a contiguous gene defect including at least one locus for a type of blepharophimosis, further suggesting that multiple loci exist for eyelid development.	0
PURPOSE OF REVIEW:To provide a current review of the embryology, classification, evaluation, surgical management, and clinical outcomes related to preaxial polydactyly. RECENT FINDINGS:Recent studies include a proposed embryologic link between preaxial polydactyly and other congenital abnormalities, an evaluation of long-term postsurgical outcomes, and an examination of important predictors for postsurgical outcomes. Preaxial polydactyly, while relatively uncommon, is a complex congenital hand abnormality that requires careful preoperative classification and proper surgical intervention timing to yield optimal outcomes.	0
Feingold syndrome-2 has been recently shown to be caused by germline heterozygous deletions of MIR17HG with 10 reported patients to date. Manifestations common to both Feingold syndrome-1 and Feingold syndrome-2 include microcephaly, short stature, and brachymesophalangy; but those with Feingold syndrome-2 lack gastrointestinal atresias. Here we describe a 14-year-old male patient who presented to our Cardiovascular Genetics Clinic with a history of a bicuspid aortic valve with aortic stenosis, short stature, hearing loss, and mild learning disabilities. Upon examination he was noted to have dysmorphic features and brachydactyly of his fingers and toes. His head circumference was 54.5 cm (25th-50th centile) and his height was 161.3 cm (31st centile) after growth hormone therapy. A skeletal survey noted numerous abnormalities prompting suspicion for Feingold syndrome. A comparative genomic hybridization microarray was completed and a ∼3.6 Mb interstitial heterozygous deletion at 13q31.3 including MIR17HG was found consistent with Feingold syndrome-2. Clinically, this patient has the characteristic digital anomalies and short stature often seen in Feingold syndrome-2 with less common features of a congenital heart defect and hearing loss. Although non-skeletal features have been occasionally reported in Feingold syndrome-1, only one other patient with a 13q31 microdeletion including MIR17HG has had non-skeletal manifestations. Additionally, our patient does not have microcephaly and, to our knowledge, is the first reported pediatric patient with Feingold syndrome-2 without this feature. This report illustrates significant phenotypic variability within the clinical presentation of Feingold syndrome-2 and highlights considerable overlap with Feingold syndrome-1.	0
OBJECTIVE: To assess the efficiency of the French national screening program for 21-hydroxylase deficiency (21-OHD). Neonatal screening for congenital adrenal hyperplasia due to 21-OHD is mainly intended to prevent death due to salt wasting but remains controversial because of the number of false-positive results and the ease with which most female cases can be identified by virilized genitalia at birth. DESIGN: Population-based study. SETTING: National neonatal screening program, pediatric endocrinologists nationwide, and reference center for genotyping. PARTICIPANTS: All neonates screened for 21-OHD in mainland France between January 1, 1996, and December 31, 2003. OUTCOME MEASURES: Screening efficiency indicators, disease severity, contribution of screening to early diagnosis, and disease-specific mortality before and during the study period. RESULTS: A total of 6,012,798 neonates were screened; results in 15,407 were considered positive for 21-OHD. Three hundred eighty-three cases were identified, giving a prevalence of 1 for every 15,699 births. The positive predictive value of screening was 2.3% (95% CI, 2.1%-2.6%), with a sensitivity of 93.5% (90.9%-95.9%) and a specificity of 99.7% (99.7%-99.7%). The false-positive rate was particularly high in preterm infants, for which the positive predictive value was 0.4% (95% CI, 0.2%-0.5%). Screening allowed clinical diagnosis in 162 of 383 cases (42.3%), with the others being detected clinically or through family history. There was a trend toward declining neonatal mortality due to 21-OHD. CONCLUSIONS: In this large population-based study, the efficiency of routine 21-OHD screening was moderate in neonates born at term and very low in preterm neonates. We recommend the discontinuation of screening, as currently performed in France, in preterm neonates.	1
Dyskerin is a protein involved in the formation of small nucleolar and small Cajal body ribonucleoproteins. These complexes participate in RNA pseudouridylation and are also components of the telomerase complex required for telomere elongation. Dyskerin mutations cause a rare disease, X-linked dyskeratosis congenita, with no curative treatment. The social amoeba Dictyostelium discoideum contains a gene coding for a dyskerin homologous protein. In this article D. discoideum mutant strains that have mutations corresponding to mutations found in dyskeratosis congenita patients are described. The phenotype of the mutant strains has been studied and no alterations were observed in pseudouridylation activity and telomere structure. Mutant strains showed increased proliferation on liquid culture but reduced growth feeding on bacteria. The results obtained indicated the existence of increased DNA damage response and reactive oxygen species, as also reported in human Dyskeratosis congenita cells and some other disease models. These data, together with the haploid character of D. discoideum vegetative cells, that resemble the genomic structure of the human dyskerin gene, located in the X chromosome, support the conclusion that D. discoideum can be a good model system for the study of this disease.	0
BACKGROUND:Hypoparathyroidism in children is a heterogeneous group with diverse genetic etiologies. To aid clinicians in the investigation and management of children with hypoparathyroidism, we describe the phenotype of a 6-year-old child with hypoparathyroidism and short stature diagnosed with Kenny-Caffey syndrome (KCS) Type 2 and the subsequent response to growth hormone (GH) treatment. CASE PRESENTATION:The proband presented in the neonatal period with hypocalcemic seizures secondary to hypoparathyroidism. Her phenotype included small hands and feet, hypoplastic and dystrophic nails, hypoplastic mid-face and macrocrania. Postnatal growth was delayed but neurodevelopment was normal. A skeletal survey at 2 years of age was suggestive of KCS Type 2 and genetic testing revealed a novel de novo heterozygous mutation c.1622C > A (p.Ser541Tyr) in FAM111A. At 3 years and 2 months, her height was 80cms (SDS -3.86). She had normal overnight GH levels. GH therapy was commenced at a dose of 4.9 mg/m2/week for her short stature and low height velocity of 5cms/year. At the end of the first and second years of GH treatment, height velocity was 6.5cms/year and 7.2cms/year, respectively with maximal dose of 7.24 mg/m2/week. CONCLUSION:This case highlights the phenotype and the limited response to GH in a child with genetically proven KCS type 2. Long-term registries monitoring growth outcomes following GH therapy in patients with rare genetic conditions may help guide clinical decisions regarding the use and doses of GH in these conditions.	0
Carcinoma of unknown primary accounts for 2%-5% of all head and neck tumors. Identification of the primary site is challenging. We present a case report of a 43-year-old man with metastatic cervical lymphadenopathy for 3 year, and the primary tumor was unknown after routine examinations, including positron emission tomography/computed tomography. Whole-body diffusion-weighted imaging was performed to detect small lesions in the nasopharynx, and a biopsy confirmed the lesions as squamous cell carcinoma. Therefore, the primary tumor site was found in a patient with carcinoma of unknown primary, suggesting that whole-body diffusion-weighted imaging can be very helpful in detecting small occult cancer.	0
PURPOSE:To investigate photoreceptor degeneration in retinitis pigmentosa (RP) by quantitatively analysing optical intensity of ellipsoid zone (EZ) on optical coherence tomography (OCT). METHODS:We conducted OCT line scans of the horizontal meridian in 24 eyes of 24 RP patients and 30 eyes of 30 healthy controls and obtained longitudinal reflectance profiles using ImageJ at every 5 pixels. Relative optical intensity was calculated from dividing the peak of EZ by the mean of the whole retina. RESULTS:The optical intensity of EZ variation followed a similar pattern in all patients. It decreased with eccentricity and then vanished, regardless whether it was normal or reduced at the fovea. The mean relative optical intensity of EZ in RP patients was 0.69 ± 0.13 to that of control subjects at the location just before it disappeared. The relative optical intensity of EZ at fovea was significantly correlated with the best-corrected visual acuity in patients (r = -0.617, p = 0.001). CONCLUSION:The optical intensity of EZ detected by OCT can serve as a biomarker for early detection of photoreceptor degeneration in RP.	0
We report on a probably new form of spondyloepimetaphyseal dysplasia (SEMD) with an X linked inheritance pattern. Eight males were affected in the same family. We were able to examine three adult patients and we studied the skeletal radiological aspect of one of these patients at 2 years 6 months and at 9 years of age. The main clinical features are severe short trunked dwarfism, brachydactyly, normal facies, and normal intelligence. Radiologically, the diaphyses of all the long bones are short and broad. The epiphyses of the distal portion of the femora and those of the proximal and distal portions of the tibia are embedded in their metaphyses and there is marked narrowing of the intercondylar groove. There is moderate platyspondyly. Several vertebrae show an anterior tongue in infancy and severe irregularities of the upper and lower surfaces are present in adulthood. The 11th or 12th thoracic vertebra is wedge shaped. The pelvis is narrow. The distal ulnae and fibulae are disproportionately long. The hands show radial deviation and brachydactyly is present in the hands and feet. This X linked SEMD was not detectable at birth.	0
Oculodentodigital dysplasia (ODDD) is a rare genetic disorder associated with a characteristic craniofacial profile with variable dental, limb, eye, and ocular adnexa abnormalities. We performed an extensive literature review to highlight key eye features in patients with ODDD and report a new case of a female patient with a heterozygous missense GJA1 mutation (c.65G>A, p.G22E) and clinical features consistent with the condition. Our patient presented with multiple congenital anomalies including syndactyly, microphthalmia, microcornea, retrognathia, and a small nose with hypoplastic alae and prominent columella; in addition, an omphalocele defect was present, which has not been reported in previous cases. A systematic review of the published cases to date revealed 91 literature reports of 295 individuals with ODDD. There were 73 different GJA1 mutations associated with these cases, of which the most common were the following missense mutations: c.605G>A (p.R202H) (11%), c.389T>C (p.I130T) (10%), and c.119C>T (p.A40V) (10%). Mutations most commonly affect the extracellular-1 and cytoplasmic-1 domains of connexin-43 (gene product of GJA1), predominately manifesting in microphthalmia and microcornea. The syndrome appears with an approximately equal sex ratio. The most common eye features reported among all mutations were microcornea, microphthalmia, short palpebral fissures, and glaucoma.	0
Primary aldosteronism is one of the most common causes of secondary hypertension. This condition is characterized by autonomous hypersecretion of aldosterone which produces sodium retention and potassium excretion, resulting in high blood pressure and potential hypokalemia. Transient postoperative hyporeninemic hypoaldosteronism with an increased risk of hyperkalemia may occur in some patients. We report the case of a 63-year-old patient with persistent hypokalemia, periodic paralysis, and refractory hypertension who was diagnosed with primary hyperaldosteronism due to elevated aldosterone, undetectable plasmatic renin concentration, and the presence of a left adrenal mass. One month after the surgery, the patient was admitted with signs of severe hyperkalemia (8 mmol/L) and worsened renal function, thus requiring hemodialysis. Fluid resuscitation, loop diuretic, and sodium bicarbonate treatment decreased his potassium. Zona glomerulosa insufficiency was confirmed by hormonal tests which exposed low aldosterone-renin axis. The fludrocortisone treatment was initiated and maintained, with consequent potassium and creatinine stabilization. Old age, long duration of hypertension, impaired renal function, severe hypokalemia before surgery, and large size of the aldosterone-producing adenoma are important risk factors for serious potassium imbalance after removal of the adenoma. We have to consider monitoring the patients after surgery for primary hyperaldosteronism in order to prevent severe hyperkalemia; therefore, postoperative immediate follow-up (arterial pressure, potassium, and renal function) is mandatory.	0
PURPOSE:To investigate complex and different phenotypes in seven Chinese patients diagnosed with Bardet-Biedl syndrome (BBS) and carrying pathogenic mutations. METHODS:Seven unrelated BBS patients were enrolled. Their medical and ophthalmic histories were reviewed, and comprehensive clinical examinations, such as fundus photography, optical coherence tomography, and medical imaging, were performed. A specific hereditary eye disease enrichment panel based on exome-capture technology was used to collect and amplify the protein-coding regions of 441 targeted hereditary eye disease genes, followed by high-throughput sequencing using the Illumina HiSeq platform. RESULTS:All patients exhibited the primary clinical phenotype of BBS. Seven BBS mutations were found in five patients (BBS7 in two patients, BBS10 in two patients, BBS12 in one patient), for a detection rate of 71% (5/7). The ratio of novel to known BBS mutations was 5:2. CONCLUSIONS:This study showed the phenotypic and genotypic spectrum of BBS patients from China, and the findings underscore the importance of obtaining comprehensive clinical observations and molecular analyses for ciliopathies.	0
Serpiginous choroiditis (SC) is an asymmetrically bilateral inflammation of the choroid that leads to loss of choriocapillaris atrophy or loss of overlying retinal pigment epithelium. Over the last few decades, SC has passed through a long evolution of nomenclature, etiologies and morphological variations. Initially diagnosed in patients with tuberculosis and syphilis, SC was predominantly considered as autoimmune process. With the advancement of molecular diagnosis, a new aspect of infectious subtypes of SC has emerged out. The terminologies such as serpiginous-like choroiditis (SLC) and multifocal serpiginoid choroiditis are now used to denote the subtypes of SC which are associated with infectious etiologies especially tuberculosis. In a country endemic for tuberculosis such as India, it is very important to differentiate between classic SC and SLC before initiating aggressive immunomodulatory therapy. Also, management of paradoxical worsening of the clinical condition with antitubercular treatment is another challenge in SLC and ophthalmologists should be aware of such situations. With advent of newer imaging modalities, monitoring the patient with choroiditis and identification of complications such as choroidal neovascular membrane have become much easier. This article aims to review the existing literature on SC with a special emphasis on management of SC and SLC.	0
Infantile myofibromatosis, a rare, nonmalignant disease seen almost exclusively in the pediatric population, can involve skin, muscle, soft tissues, bone, or viscera in either solitary or multicentric pattern. Although nonmalignant, visceral involvement in infantile myofibromatosis is a key prognostic indicator, which is associated with mortality in 75% of patients. Those with pulmonary involvement have a particularly poor outcome. This case illustrates the diagnostic utility of F-FDG PET/CT in defining disease extent in this unusual entity and compares it to other commonly used imaging modalities.	0
Parkes Weber Syndrome (PWS) is a congenital disorder characterized by the presence of arteriovenous malformations (AVMs) in upper or lower extremities. We herein present a 35 year-old male with PWS with complex AVMs in the right upper extremity; he had been previously treated with multiple sessions of vessel embolization, sclerotherapy and AVM resections. The patient presented to our clinic with two month history of progressive hand ischemia, digit necrosis and infection. Angiography was performed demonstrating numerous AVMs and filiform flow through the ulnar artery with poor opacification of arterial structures in the hand. Because of advanced ischemia, soft tissue infection and osteomyelitis, a distal forearm amputation was indicated. Hand threatening ischemia secondary to steal phenomenon associated to AVMs in PWS is rarely encountered and reported. This case illustrates a complex clinical presentation with advanced disease that required limb amputation.	0
BACKGROUND:The non-invasive prenatal screening (NIPS) has been introduced into clinical practice with a high sensitivity and specificity. Although the false-negative results are inevitable and important, limited false-negative NIPS results have been reported and studied previously. In this study, we aim to report and analyze false-negative results detected in the NIPS cases with a low-risk result. METHODS:NIPS was performed using whole-genome massively parallel shotgun sequencing for screening common trisomies, rare autosomal aneuploidies, and subchromosome copy number variants. All the NIPS cases with a low-risk result performed in our center in 2017 were followed-up using medical records and telephone interview at 3 months after delivery. Fetal ultrasound results and available genetic diagnostic testing results were collected for pregnancies with adverse outcomes. The genetic diagnostic testing referred to chromosomal microarray analysis or fluorescent in situ hybridization on amniotic fluid cells, fetal skin tissue, neonatal peripheral blood, or available placental biopsies. RESULTS:By following-up 10,975 low-risk results, we found 166 NIPS cases with adverse pregnancy outcomes, in which eight cases had diagnostic testing. Among them, four false-negative cases were confirmed, including one trisomy 18 caused by placental mosaicism, one mosaic tetrasomy 12p, and 2 microdeletion/microduplication cases. CONCLUSION:Our results revealed that mosaicism contributes to a major cause of false negative in NIPS, and highlighted the importance of ultrasound in identifying these false-negative results.	0
To delineate the clinical, biochemical and genetic mutational characteristics of a child with mitochondrial complex III deficiency.Clinical information and results of auxiliary examination of the patient were analyzed. Next-generation sequencing of the mitochondrial genome and related nuclear genes was carried out. Suspected mutation was confirmed in both parents with Sanger sequencing. Heterozygous deletion was mapped with chromosomal microarray analysis and confirmed with real-time PCR.The patient presented with vomiting, polypnea, fever, metabolic acidosis, hyperlactatemia, hypoglycemia, dysfunction of coagulation and immune system, in addition with increased lactate dehydrogenase and creatine kinase isoenzyme. Elevation of blood alanine and acylcarnitines as well as urinary ketotic dicarboxylic acid were also noted. The patient also presented development delay, mental retardation and hypotonia. Sequence analysis revealed two mutations in the nuclear gene UQCRB, which included a previously reported frameshift mutation c.306_309delAAAA(p.Arg105Lysfs*22) and a novel large deletion encompassing the entire UQCRB gene.The clinical, biochemical and gene mutation characteristics of a child with mitochondrial complex III deficiency caused by mutations of the UQCRB gene have been delineated.	0
Intestinal vascular malformations in children and adolescents are rare but must be considered in the differential diagnosis of gastrointestinal bleeding and chronic anemia. We report a 16-year-old girl who developed chronic iron-deficiency anemia due to recurrent bleeding from multiple angiodysplastic lesions of the stomach, duodenum, and jejunum. The cause of blood loss remained unclear for several years while the girl received numerous blood transfusions. Diagnosis was finally established by capsule endoscopy and double-balloon enteroscopy. Treatment was effectively carried out by argon plasma coagulation. Many systemic vascular malformation syndromes are associated with gastrointestinal lesions. However, as no extraintestinal vascular lesions were present in our patient, diagnosis of a known vascular malformation syndrome seemed unlikely. In addition to the microvascular intestinal malformations, we found a familial congenital asplenia without apparent infectious complications. Thus, the reported case possibly constitutes a so far unpublished variant of the Ivemark syndrome without macrovascular malformations but instead with microvascular malformations. We therefore envison that in times of refined diagnostic techniques the phenotype of the Ivemark syndrome might be expanded by including microvascular malformations.	0
OBJECTIVE:To assess birth and gene frequencies of specific autosomal recessively inborn errors of metabolism (IEM) within different ethnic groups. DESIGN:Retrospective study in a regional centre for investigation and treatment of IEM. SUBJECTS:All children born within the West Midlands NHS Region, UK, during the decade immediately preceding the 1991 National Census. METHODS:Birth frequencies for individual IEM were calculated separately for the main ethnic groups in the West Midlands using data from the West Midlands Neonatal Screening Programme, the regional register of IEM patients, and population frequencies from the National Census. Gene frequencies were calculated using previously documented observations on parental consanguinity rates and inbreeding coefficients. RESULTS:The overall incidence of recorded IEM was tenfold higher among Pakistanis compared to white children (1:318 v 1:3760), whereas only one AfroCaribbean child was identified (incidence 1:16 887). Tyrosinaemia type 1, cystinosis, mucopolysaccharidosis type 1, non-ketotic hyperglycinaemia, and hyperchylomicronaemia all occurred more frequently among Pakistanis. An increased gene frequency was only confirmed for tyrosinaemia. The incidence of phenylketonuria was similar in Pakistani and white children (1:14 452 v 1:12 611), but the gene frequency was significantly lower in Pakistanis (1:713 v 1:112). These results illustrate the interplay between gene frequency and parental consanguinity in determining disease frequencies in different populations, and indicate anticipated disease frequencies in the absence of consanguineous marriage. These figures have implications for the organisation of services for management of inborn errors, for genetic counselling, and for the assessment of gene flow in world populations.	1
Cockayne syndrome is an uncommon autosomal recessive disease characterized by microcephaly, abnormal growth, and pathologic premature aging. The purpose of this report is to evaluate liver failure in children with Cockayne syndrome following metronidazole administration. The first case was a 2-year-old boy with Cockayne syndrome. He had been treated with metronidazole for gastroenteritis. 48 hours after treatment initiation, he was hospitalized due to jaundice, intractable vomiting, and agitation. Unfortunately, he died of acute liver failure. The second case was a 5-year-old boy with Cockayne syndrome as well, who had been treated with amoxicillin and metronidazole for a dental infection. He developed jaundice, drowsiness, lethargy, and anorexia after treatment. At hospital, the child received supportive treatment, and his general condition gradually improved. The liver enzyme levels decreased. He was finally discharged in good general condition. The mortality after metronidazole consumption in patients with Cockayne syndrome due to liver failure is very high. The awareness of the dangers of using metronidazole in these patients is valuable.	0
BACKGROUND: Since 1988, three nonrelated fatal cases of congenital ichthyosis associated with Gaucher disease have been described in Australia. CASE: We present a case of Gaucher disease with congenital ichthyosis and restrictive dermopathy and describe the associated prenatal sonographic findings and pathology of this new syndrome. CONCLUSION: The unusual association of congenital ichthyosis with lipid storage disease may be suspected prenatally. A high index of suspicion may prove this condition to be more common than previously thought.	0
The ubiquitin-proteasome system degrades ubiquitin-modified proteins to maintain protein homeostasis and to control signalling. Whole-genome sequencing of patients with severe deafness and early-onset cataracts as part of a neurological, sensorial and cutaneous novel syndrome identified a unique deep intronic homozygous variant in the PSMC3 gene, encoding the proteasome ATPase subunit Rpt5, which lead to the transcription of a cryptic exon. The proteasome content and activity in patient's fibroblasts was however unaffected. Nevertheless, patient's cells exhibited impaired protein homeostasis characterized by accumulation of ubiquitinated proteins suggesting severe proteotoxic stress. Indeed, the TCF11/Nrf1 transcriptional pathway allowing proteasome recovery after proteasome inhibition is permanently activated in the patient's fibroblasts. Upon chemical proteasome inhibition, this pathway was however impaired in patient's cells, which were unable to compensate for proteotoxic stress although a higher proteasome content and activity. Zebrafish modelling for knockout in PSMC3 remarkably reproduced the human phenotype with inner ear development anomalies as well as cataracts, suggesting that Rpt5 plays a major role in inner ear, lens and central nervous system development.	0
The management of osteochondritis dissecans (OCD) continues to baffle even the savviest of surgeons, with unclear etiology, unknown relationship of presentation to outcome, bewildering response to various treatments, and frustratingly difficult-to-predict prognosis. Whether skeletal immaturity may be indicative of surgical success, at least when it comes to lesions requiring screw fixation, remains debatable. Treatment may include activity modification, drilling, fixation, or osteochondral replacement of OCD lesions in the knee. Regardless, each OCD lesion must be followed until osseous integration is confirmed by imaging -otherwise, progression of disease to osteoarthritis is likely.	0
In order to investigate the mechanism of genistein (Gen) in the treatment of climacteric syndrome, an in vivo study was performed to investigate the beneficial effects of genistein on the expression of P450 aromatase (P450 arom) and follicle-stimulating hormone receptor (FSHR) in the mouse ovary and uterus. Fifty female ICR mice (45 ± 5g, n = 50), aged 12 months, were divided into the following five groups with 10 animals in each: blank control group (CG), low-dose genistein group (L-Gen), middle-dose genistein group (M-Gen) and high-dose genistein group (H-Gen) (received 15, 30 and 60 mg/kg of genistein, respectively), and oestrogen group (EG; received 0.5 mg/kg diethylstilbestrol). The expression levels of the FSHR protein were determined by an immunohistochemical staining method. The expression of P450 arom, Cytochrome P450 19 (CYP19) and FSHR was quantified by real-time PCR. Immunohistochemical results showed that the expression levels of the FSHR protein in the M-Gen (average stained area: 20.79) and the H-Gen (average stained area: 21.21) groups were significantly stronger than in the CG (average area was 17.24) group (p < .05). The expression levels of CYP19 mRNA and P450 arom were positively correlated with the dose of genistein. Specifically, the relative expression levels in the H-Gen and EG groups were more than 1.5 times higher than in the CG group (p < .05). Genistein played a significant role in regulating aromatase and FSHR gene expression to improve perimenopausal ovarian and uterine function.	0
BACKGROUND:Myoclonic epilepsy with ragged-red fibers (MERRF, OMIM, #545000) is a rare neurological condition mostly caused by the m.8344A>G mitochondrial DNA pathogenic variant, which can variably affect multiple tissues, including the retina and optic nerve. We report detection of visually asymptomatic neuroretinal loss in 3 patients with genetically confirmed MERRF, using spectral domain optical coherence tomography (SD-OCT). METHODS:All patients underwent a complete ophthalmic examination including assessments of visual acuity, color vision, pupillary reactions, extraocular movements, applanation tonometry, slit-lamp, and dilated fundus examinations. Standard automated perimetry or Goldmann kinetic perimetry was performed, as well as fundus photographs and SD-OCT of the optic nerve head and macula. RESULTS:Despite the absence of visual symptoms in all patients, and normal visual acuity and visual fields in 1 patient, the 3 genetically confirmed patients (point mutations m.8344A>G; age range: 18-62 years) with MERRF-related neurological manifestations, displayed thinning of the retinal nerve fiber layer and variable alterations of the macular ganglion cell complex. CONCLUSIONS:Visually asymptomatic patients with genetically confirmed MERRF can display features of structural neuroretinal loss, quantifiable with SD-OCT. Further investigations are needed to establish whether OCT can assess early neurodegeneration in MERRF.	0
Warburg Micro syndrome is a rare autosomal recessive disease due to mutation in the RAB3GAP1, RAB3GAP2, RAB18 and TBC1D20 genes. It is commonly seen in consanguineous marriages, characterized by optic (microcornea, microphthalmia, congenital cataracts), neurologic )microcephaly, corpus callosum hypoplasia, severe mental retardation( and hypogonadism; some non-typical findings could be present (cardiomyopathy, peripheral neuropathy). We report a novel homozygous mutation in the RAB3GAP1 gene in a 7-month-old boy from healthy nonconsanguineous parents from the same village in Syria, with bilateral congenital cataracts, hypogonadism, muscular hypotonia and severe developmental delay. Whole exome sequencing (WES) showed a homozygous mutation in the c.2195del p.(Pro732Glnfs*6) in exon 19 of the RAB3GAP1 gene, which is likely pathogenic and correlates with Warburg Micro syndrome type 1.	0
A 49-year-old man presented with progressive, painful, ulcerative, retiform purpuric patches on the torso and extremities. Multiple skin biopsies revealed a prominent pan-dermal vascular proliferation but no occlusive vasculopathy or cutaneous vasculitis. Diffuse dermal angiomatosis should be considered in the differential diagnosis of retiform purpura, especially in patients with atherosclerotic disease or underlying hypercoagulable states.	0