abstract
stringlengths 101
4.14k
| label
class label 2
classes |
|---|---|
Diseases of the pediatric nose and nasal sinuses as well as neighboring anatomical structures encompass a variety of pathologies, especially of inflammatory nature. Congenital disease, such as malformations and structural deviations of the nasal septum, as well as systemic metabolic pathologies affecting the nose and sinuses, rarely require medical therapy from an Otolaryngologist. The immunological function of the mucosa and genetic factors play a role in the development of disease in the pediatric upper airway tract, especially due to the constantly changing anatomy in this growth phase. Disease description of the nose and nasal sinuses due to mid-facial growth must also take developmental age differences (infant, toddler, preschool, and school age) into account. Epidemiological examinations and evidence based studies are often lacking in the pediatric population. The wide range of inflammatory diseases of the nose and paranasal sinuses, such as the acute and chronic rhinosinusitis, the allergic rhinitis, and adenoid disease, play a role in the susceptibility of a child to infection. The susceptibility to infection depends on the pediatric age structure (infant, young child) and has yet to be well defined. The acute rhinosinusitis in children develops after a viral infection of the upper airways, also referred to as the "common cold" in the literature. It usually spontaneously heals within ten days without any medical therapy. Antibiotic therapy is prudent in complicated episodes of ARS. The antibiotic therapy is reserved for children with complications or associated disease, such as bronchial asthma and/or chronic bronchitis. A chronic rhinosinusitis is defined as the inflammatory change in the nasal mucosa and nasal sinus mucosa, in which the corresponding symptoms persist for over 12 weeks. The indication for CT-imaging of the nasal sinuses is reserved for cases of chronic rhinosinusitis that have been successfully treated with medication. A staged therapeutic concept is followed in CRS based on conservative and surgical methods. Nasal sinus surgery is considered nowadays as effective and safe in children. Based on the assumption that adenoids are a reservoir for bacteria, from which recurrent infections of the nose and nasal sinus originate, the adenoidectomy is still defined as a cleansing procedure in rhinosinusitis. 69.3% of the children had benefit from adenoidectomy. Comorbidities, such as pediatric bronchial asthma, presently play an even more important role in the therapy of rhinosinusitis; therefore, it is often wise to have the support of pediatricians. In western European countries 40% of children presently suffer from allergic rhinitis, in which pronounced nasal obstruction can cause disturbed growth in facial bones. An early therapy with SIT may prevent the development of bronchial asthma and secondary sensitization to other allergens. Therefore, SIT is recommended in treatment of allergic rhinitis whenever, if possible. The assessment of diagnostic tools is for the examiner not often possible due to the lack of evidence. Rhinosurgical approaches are often described in study reports; however, they lack the standard prospective randomized long-term study design required nowadays and can only be evaluated with caution in the literature. | 01 = IsEpi
|
BACKGROUND:Vici syndrome is a rare autosomal recessive disease with phenotypically heterogeneous presentation. Characteristic features of the disease are oculocutaneous albinism, corpus callosum agenesis, cataract, cardiomyopathy, and immunodeficiency. CASE:Here we report two Turkish patients with Vici syndrome. One of these patients had a novel mutation in EPG5 and presented with idiopathic thrombocytopenic purpura (ITP) and maculopapular rashes similar to Stevens-Johnson syndrome, which has been previously reported in only a few cases in the literature. CONCLUSION:Vici syndrome presents with a typical phenotype which may facilitate diagnosis for infants with multisystemic disorders. ITP and maculopapular rashes might be added to the spectrum of findings of patients with Vici syndrome. | 01 = IsEpi
|
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. | 01 = IsEpi
|
Subglottic papillomatous growths were observed on routine tracheal intubation for a scheduled colorectal procedure. Fibreoptic bronchoscopy revealed that the lesions extended down to the carina and into the main bronchi. The diagnosis of tracheobronchopathia osteoplastica was made after subsequent bronchoscopy and biopsy in the post-operative period. A brief review of this rare benign condition is given. | 01 = IsEpi
|
OBJECTIVE:The authors' objective was to better understand the anatomical load-bearing relationship between the atlantooccipital joint and the upper cervical spine and its influence on the clinical behavior of patients with Chiari malformation type I (CM-I) and craniocervical pathology. METHODS:In a single-center prospective study of patients younger than 18 years with CM-I from 2015 through 2017 (mean age 9.91 years), the authors measured the occipital condyle-C2 sagittal vertebral alignment (C-C2SVA; defined as the position of a plumb line from the midpoint of the occiput (C0)-C1 joint relative to the posterior aspect of the C2-3 disc space), the pB-C2 (a line perpendicular to a line from the basion to the posteroinferior aspect of the C2 body on sagittal MRI), and the CXA (clivoaxial angle). Control data from 30 patients without CM-I (mean age 8.97 years) were used for comparison. The primary outcome was the need for anterior odontoid resection and/or occipitocervical fusion with or without odontoid reduction. The secondary outcome was the need for two or more Chiari-related operations. RESULTS:Of the 60 consecutive patients with CM-I identified, 7 underwent anterior odontoid resection or occipitocervical fusion and 10 underwent ≥ 2 decompressive procedures. The mean C-C2SVA was greater in the overall CM-I group versus controls (3.68 vs 0.13 mm, p < 0.0001), as was the pB-C2 (7.7 vs 6.4 mm, p = 0.0092); the CXA was smaller (136° vs 148°, p < 0.0001). A C-C2SVA ≥ 5 mm was found in 35% of CM-I children and 3.3% of controls (p = 0.0006). The sensitivities and specificities for requiring ventral decompression/occipitocervical fusion were 100% and 74%, respectively, for C-C2SVA ≥ 5 mm; 71% and 94%, respectively, for CXA < 125°; and 71% and 75%, respectively, for pB-C2 ≥ 9 mm. The sensitivities and specificities for the need for ≥ 2 decompressive procedures were 60% and 70%, respectively, for C-C2SVA ≥ 5 mm; 50% and 94%, respectively, for CXA < 125°; and 60% and 76%, respectively, for pB-C2 ≥ 9 mm. The log-rank test demonstrated significant differences between C-C2SVA groups (p = 0.0007) for the primary outcome. A kappa value of 0.73 for C-C2SVA between raters indicated substantial agreement. CONCLUSIONS:A novel screening measurement for craniocervical bony relationships, the C-C2SVA, is described. A significant difference in C-C2SVA between CM-I patients and controls was found. A C-C2SVA ≥ 5 mm is highly predictive of the need for occipitocervical fusion/ventral decompression in patients with CM-I. Further validation of this screening measurement is needed. | 01 = IsEpi
|
Cylindrical spirals are a rare ultrastructural finding on muscle biopsy, with fewer than 20 reported cases since its first description in 1979. These structures are sometimes observed with tubular aggregates and are thought to comprise longitudinal sarcoplasmic reticulum. While mutations in genes encoding key components of Ca2+ handling (ORAI1 and STIM1) underlie tubular aggregate myopathy, no causative genes have been associated with cylindrical spirals. Here we describe two families with cylindrical spirals on muscle biopsy with a suspected genetic cause. In one family we identified a known truncating variant in EBF3, previously associated with a neurodevelopmental disorder. The affected individuals in this family present with clinical features overlapping with those described for EBF3 disease. An isolated proband in the second family harbours bi-allelic truncating variants in TTN and her clinical course and other features on biopsy are highly concordant for titinopathy. From experimental studies, EBF3 is known to be involved in Ca2+ regulation in muscle, thus EBF3 dysregulation may represent a novel mechanism of impaired Ca2+ handling leading to cylindrical spirals. Additional cases of EBF3 disease or titinopathy with cylindrical spirals need to be identified to support the involvement of these genes in the pathogenesis of cylindrical spirals. | 01 = IsEpi
|
BACKGROUND:Congenital hemolytic anemia constitutes a heterogeneous group of rare genetic disorders of red blood cells. Diagnosis is based on clinical data, family history and phenotypic testing, genetic analyses being usually performed as a late step. In this study, we explored 40 patients with congenital hemolytic anemia by whole exome sequencing: 20 patients with hereditary spherocytosis and 20 patients with unexplained hemolysis. RESULTS:A probable genetic cause of disease was identified in 82.5% of the patients (33/40): 100% of those with suspected hereditary spherocytosis (20/20) and 65% of those with unexplained hemolysis (13/20). We found that several patients carried genetic variations in more than one gene (3/20 in the hereditary spherocytosis group, 6/13 fully elucidated patients in the unexplained hemolysis group), giving a more accurate picture of the genetic complexity of congenital hemolytic anemia. In addition, whole exome sequencing allowed us to identify genetic variants in non-congenital hemolytic anemia genes that explained part of the phenotype in 3 patients. CONCLUSION:The rapid development of next generation sequencing has rendered the genetic study of these diseases much easier and cheaper. Whole exome sequencing in congenital hemolytic anemia could provide a more precise and quicker diagnosis, improve patients' healthcare and probably has to be democratized notably for complex cases. | 01 = IsEpi
|
Objective:Acute necrotizing encephalopathy of childhood (ANEC) is a fast growing disease, accompanied by progressive encephalopathy. The aim of this study was to report a rare case of ANEC in a four-year-old boy with bilateral thalamic necrosis and non-fatal outcomes. Case Report:The patient was a four-year-old Iranian boy, without any history of health problems or hospitalization, except for jaundice and phototherapy in the neonatal period. He had no neurological signs or symptoms during admission, and he was admitted only with chief complaints of acute onset of fever, coryza, and icterus. In the neurological consultation, brain MRI was requested to analyze the possibility of brain damage. The results indicated the involvement of cerebellum, thalamus, and basal ganglia, which led to the diagnosis of ANEC. Conclusion:Based on our findings, although ANEC is a rare disease, it should not be underestimated. | 01 = IsEpi
|
RATIONALE:Cole-Carpenter syndrome-1 (CLCRP1) is an independent osteogenesis imperfect (OI)-like disorder that manifests as bone fragility, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features. Only 2 types of mutation sites in the P4HB and CRTAP genes have been reported. PATIENT CONCERNS:A 14-month-old Chinese girl presented with prominent ocular proptosis, frontal bossing, craniosynostosis, plump anterior fontanel, growth retardation, osteopenia, and distinctive facial features that were strikingly similar to those in the original 2 cases. DIAGNOSES:Whole-exome sequencing revealed a novel deletion variation in exons 5 to 8 of the P4HB gene, which was found to be heterozygous using fluorogenic quantitative-polymerase chain reaction. LESSONS:This de novo deletion mutation in exons 5 to 8 of the P4HB gene advances our understanding of CLCRP1, expands the mutation spectrum of P4HB, and diversifies the cases reported for this condition. | 01 = IsEpi
|
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. | 01 = IsEpi
|
BACKGROUND:A lack or dysfunction of the anchoring protein laminin-332 in the basement membrane leads to the skin blistering disorder junctional epidermolysis bullosa (JEB). The mutation c.628G>A in the gene LAMB3 encoding the laminin β3-chain is associated with generalized intermediate JEB; it may introduce an amino acid substitution (p.Glu210Lys) or disrupt splicing. OBJECTIVE:This retrospective study aimed at determining the effects of aberrant splicing on the JEB phenotype. METHODS:LAMB3 transcription was analysed in two siblings compound heterozygous for the LAMB3 mutations p.Glu210Lys and p.Arg635* with a diverging JEB phenotype from late childhood on. Laminin-332 levels in skin sections and in cultured keratinocytes were investigated by immunofluorescence staining. Real-time PCR was used to quantify LAMB3 expression in keratinocytes. RNA splice variants were identified by subcloning of a LAMB3 cDNA fraction and subsequent DNA sequencing. Structural models of laminin-332 helped to assess the impact of certain mutations on laminin-332 folding. RESULTS:Both siblings showed diminished LAMB3 expression. Laminin-332 was equally reduced in skin sections obtained during infancy but differed in keratinocytes isolated during adolescence. Although aberrant LAMB3 splicing with 26 variants was detected in both patients, splicing differed significantly: the full-length LAMB3 transcript harbouring the p.Glu210Lys mutation was found more often in the patient affected less severely (14/108 vs. 5/106 clones; P = 0.03). Structural modelling predicted that several deletions in LAMB3, but not the point mutation p.Glu210Lys, have an effect on laminin-332 folding and secretion. CONCLUSIONS:Differential LAMB3 mRNA splicing in the patients may explain the disparate JEB phenotype. By elucidating the regulation of laminin-332 gene expression, these findings may contribute to the development of therapeutic strategies for JEB and might help to understand phenotype modification by splice-site mutations in other hereditary diseases. | 01 = IsEpi
|
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. | 01 = IsEpi
|
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. | 01 = IsEpi
|
AIMS: To evaluate the incidence of congenital adrenal hyperplasia (CAH) in the Northern Italian population and the efficiency of the North-Eastern Italy screening program. To adjust cut-off levels for 17-hydroxyprogesterone (17-OHP) in relation to gestational age and birth weight, comparing the benefits in terms of reduction of recall rates with the two approaches and ultimately choosing the better of the two. SUBJECTS AND METHODS: Since September 2001, blood samples from neonates born in North-Eastern Italy have been screened with a fluoroimmunoassay method for 17-OHP determination (DELFIA). A preliminary cut-off level of > or = 30 nmol/l was set both for term and preterm newborns. The values of 17-OHP were analysed using statistical methods in relation to gestational age and birth weight in order to modify the cut-off on the basis of our data. RESULTS: After 33 months of screening we screened 128,282 newborns and detected 6 affected babies. During the first 8 months of screening among the recalled babies, 89.6 and 78.1% were preterm and low-birth-weight newborns, respectively, with a recall rate of 2.59% for premature neonates and of 4.94% for babies with birth weights < 2,500 g. We chose a new cut-off value of 50 nmol/l for preterm newborns only and, after 4 months, the recall rate was reduced to 0.83% for these infants and to 1.83% for low-birth-weight infants. CONCLUSION: After 33 months of screening for CAH in North-Eastern Italy, we report an incidence of 1:21,380. In 5 out of 6 affected babies, the diagnosis was established only after a positive screening test, which prevented a severe salt-wasting crisis in these babies. The cut-off level related to gestational age led to a significant reduction in the number of false-positives among preterm babies.We therefore intend to continue with the screening program for CAH in North-Eastern Italy, keeping a gestational-age-related cut-off in the hope that our data may encourage a national screening program for CAH. | 10 = IsNotEpi
|
PURPOSE:Ocular cicatricial pemphigoid (OCP) is a rare systemic autoimmune disease and a potentially blinding subepithelial blistering disorder. The purpose of this study was to describe the clinical spectrum of the disease and to assess the efficacy and safety of immunosuppressive agents in a cohort of patients with OCP. METHODS:We conducted a monocentric retrospective cross-sectional cohort study of all unselected consecutive patients diagnosed with progressive OCP. Ocular and extra ophthalmological involvement as well as histological findings were gathered. Other outcomes were exposures to immunosuppressive agents defined by the use of a particular treatment. For each exposure, success in controlling ocular inflammation was graded as a complete response, response, or failure. Relapses and adverse events (AE) were also recorded. RESULTS:Seventeen patients (34 affected eyes), 35% of whom were women, were included, with an age at diagnosis of 75 ± 11 years. Corneal involvement was diagnosed in 30 of 34 eyes, and 22 of 34 eyes had progressive fibrosing conjunctival involvement. Sixty-two exposures to immunosuppressive agents or biologics were recorded: dapsone, n = 26; mycophenolate mofetil, n = 6; azathioprine, n = 4; cyclophosphamide, n = 10; rituximab, n = 14; and intravenous immunoglobulin, n = 2. Rates of response and of complete response achievement during the first 3 months were 84% and 45%, respectively. Response rates were 100%, 100%, 86%, 85%, and 80% for intravenous immunoglobulin, mycophenolate mofetil, rituximab, dapsone, and cyclophosphamide, respectively. Thirteen percent of those drugs were discontinued because of an adverse event in 4 patients. CONCLUSIONS:This study describes the efficacy of immunosuppressants or biologics with an acceptable safety profile for OCP. | 01 = IsEpi
|
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. | 01 = IsEpi
|
Few spatial ecological studies on hair selenium (Se) and Keshan disease (KD) have been reported. To investigate the relationships of hair Se with KD and economic indicators and to visualize the evidence for KD precise prevention. An ecological study design was employed. The levels of hair Se of 636 adult men (≥ 18 years old) living in rural, general cities and developed cities in 15 KD endemic provinces and 11 KD non-endemic provinces in mainland China were measured using hydride generation atomic fluorescence spectrometry. Spatial description and spatial analysis of hair Se were conducted. The subjects were adults aged. The hair Se level of the residents of KD endemic areas was 0.30 mg/kg, statistically significantly lower than that of non-endemic areas 0.34 mg/kg (Mann-Whitney U test, p = 0.007). The hair Se level of the 636 people was 0.33 mg/kg. The hair Se levels of the residents of the developed cities, general cities, and rural were 0.35 mg/kg, 0.33 mg/kg, and 0.32 mg/kg, respectively, with statistical significance (Kruskal-Wallis H test, P = 0.032). Spatial regression analysis showed that the spatial distribution of hair Se was positively correlated with per capita GDP. Selenium deficiency may still exist among residents living in the KD endemic areas. The results of spatial description and analysis of hair Se provided visualized evidence for targeting key provinces for precise prevention of Keshan disease, including assessment of KD elimination. The hair Se level of the mainland Chinese males was probably between 0.31 and 0.33 μg/g in 2015. | 01 = IsEpi
|
Background Atrial fibrillation (AF) has been shown to be associated with an increased risk of dementia as well as Alzheimer disease in observational studies. Whether this association reflects causal association is still unclear. The purpose of this study was to examine the causal association of AF with Alzheimer disease. Methods and Results We used a 2-sample Mendelian randomization approach to evaluate the causal effect of AF on Alzheimer disease. Summary data on the association of single nucleotide polymorphisms with AF were obtained from a recently published genome-wide association study with up to 1 030 836 individuals and data on single nucleotide polymorphism-Alzheimer disease association from another genome-wide association study with up to 455 258 individuals. AF was mainly diagnosed according to International Classification of Diseases, Ninth Revision (ICD-9 or ICD-10) and Alzheimer disease was mainly diagnosed according to clinical criteria (eg, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association [NINCDS-ADRDA] criteria). Effect estimates were calculated using the inverse-variance weighted method. The Mendelian randomization analysis showed nonsignificant association of genetically predicted AF with risk of Alzheimer disease (odds ratio=1.002, 95% CI: 0.996-1.009, P=0.47) using 93 single nucleotide polymorphisms as the instruments. Mendelian randomization-Egger indicated no evidence of genetic pleiotropy (intercept=0.0002, 95% CI: -0.001 to 0.001, P=0.70). Conclusions This Mendelian randomization analysis found no evidence to support causal association between AF and Alzheimer disease. | 01 = IsEpi
|
Understanding the categorization of human diseases is critical for reliably identifying disease causal genes. Recently, genome-wide studies of abnormal chromosomal locations related to diseases have mapped >2000 phenotype-gene relations, which provide valuable information for classifying diseases and identifying candidate genes as drug targets. In this article, a regularized non-negative matrix tri-factorization (R-NMTF) algorithm is introduced to co-cluster phenotypes and genes, and simultaneously detect associations between the detected phenotype clusters and gene clusters. The R-NMTF algorithm factorizes the phenotype-gene association matrix under the prior knowledge from phenotype similarity network and protein-protein interaction network, supervised by the label information from known disease classes and biological pathways. In the experiments on disease phenotype-gene associations in OMIM and KEGG disease pathways, R-NMTF significantly improved the classification of disease phenotypes and disease pathway genes compared with support vector machines and Label Propagation in cross-validation on the annotated phenotypes and genes. The newly predicted phenotypes in each disease class are highly consistent with human phenotype ontology annotations. The roles of the new member genes in the disease pathways are examined and validated in the protein-protein interaction subnetworks. Extensive literature review also confirmed many new members of the disease classes and pathways as well as the predicted associations between disease phenotype classes and pathways. | 01 = IsEpi
|
Lesch-Nyhan disease (LND) is a rare monogenic disease caused by deficiency of the salvage pathway enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). LND is characterized by severe neuropsychiatric symptoms that currently cannot be treated. Predictive in vivo models are lacking for screening and evaluating candidate drugs because LND-associated neurological symptoms are not recapitulated in HGPRT-deficient animals. Here, we used human neural stem cells and neurons derived from induced pluripotent stem cells (iPSCs) of children affected with LND to identify neural phenotypes of interest associated with HGPRT deficiency to develop a target-agnostic-based drug screening system. We screened more than 3000 molecules and identified 6 pharmacological compounds, all possessing an adenosine moiety, that corrected HGPRT deficiency-associated neuronal phenotypes by promoting metabolism compensations in an HGPRT-independent manner. This included S-adenosylmethionine, a compound that had already been used as a compassionate approach to ease the neuropsychiatric symptoms in LND. Interestingly, these compounds compensate abnormal metabolism in a manner complementary to the gold standard allopurinol and can be provided to patients with LND via simple food supplementation. This experimental paradigm can be easily adapted to other metabolic disorders affecting normal brain development and functioning in the absence of a relevant animal model. | 01 = IsEpi
|
We describe a patient with the unusual association of cleft palate, bilateral choanal atresia, curly hair, and congenital hypothyroidism. This association has been reported before in two brothers and may represent a new syndrome. | 01 = IsEpi
|
Primary ovarian insufficiency (POI) resulting from ovarian autoimmunity is a poorly understood clinical condition lacking in effective treatments. Understanding the targets of the autoimmune response and induction of ovarian-specific tolerance would allow development of focused therapies to preserve fertility in an at-risk population. MATER (maternal antigen that embryos require) is a known ovarian autoantigen targeted in autoimmune syndromes of POI. We attempt to induce ovarian-specific tolerance via transgenic expression of the MATER antigen on potentially tolerogenic antigen-presenting cells (APC), which typically present antigen via the major histocompatibility complex (MHC) class II molecule. We hypothesize that expression of MATER in a MHC class II-dependent manner on APC can mediate induction of ovarian tolerance. We utilized a well-characterized murine model of ovarian autoimmunity, whereby oophoritis develops after d 3 neonatal thymectomy (NTx). Wild-type and transgenic mice, carrying an MHC Class II-driven Mater gene (IE-Mater), were subjected to NTx and assessed for evidence of autoimmune oophoritis. After disease induction by NTx, female mice carrying the IE-Mater transgene had significant reductions in histological oophoritis (56%) and circulating ovarian autoantibodies (28%) compared with wild-type females (94% and 82%, respectively). Incidence of other autoimmunity was unaffected as assessed by antinuclear autoantibodies. Transgenic expression of MATER in APC can induce antigen-specific tolerance with a significant reduction in ovarian autoimmunity. Lack of complete disease protection suggests that other antigens may also play a role in autoimmune oophoritis. As a known autoantigen in the human APS1 (autoimmune polyglandular syndrome type 1), which is associated with POI, MATER may represent a relevant target for future diagnostic and therapeutic clinical interventions. | 01 = IsEpi
|
Genetic investigation of inherited skin disorders has informed the understanding of skin self-renewal, differentiation, and barrier function. Erythrokeratodermia variabilis et progressiva (EKVP) is a rare, inherited skin disease that is characterized by transient figurate patches of erythema, localized or generalized scaling, and frequent palmoplantar keratoderma. By using exome sequencing, we show that de novo missense mutations in GJA1 (gap junction protein alpha 1) cause EKVP. The severe, progressive skin disease in EKVP subjects with GJA1 mutations is distinct from limited cutaneous findings rarely found in the systemic disorder oculodentodigital dysplasia, also caused by dominant GJA1 mutations. GJA1 encodes connexin 43 (Cx43), the most widely expressed gap junction protein. We show that the GJA1 mutations in EKVP subjects lead to disruption of Cx43 membrane localization and aggregation within the Golgi. These findings reveal a critical role for Cx43 in epidermal homeostasis, and they provide evidence of organ-specific pathobiology resulting from different mutations within GJA1. | 01 = IsEpi
|
T4 is a prohormone secreted by the thyroid. T4 has a long half life in circulation and it is tightly regulated to remain constant in a variety of circumstances. However, the availability of iodothyronine selenodeiodinases allow both the initiation or the cessation of thyroid hormone action and can result in surprisingly acute changes in the intracellular concentration of the active hormone T3, in a tissue- specific and chronologically-determined fashion, in spite of the constant circulating levels of the prohormone. This fine-tuning of thyroid hormone signaling is becoming widely appreciated in the context of situations where the rapid modifications in intracellular T3 concentrations are necessary for developmental changes or tissue repair. Given the increasing availability of genetic models of deiodinase deficiency, new insights into the role of these important enzymes are being recognized. In this review, we have incorporated new information regarding the special role played by these enzymes into our current knowledge of thyroid physiology, emphasizing the clinical significance of these new insights. | 01 = IsEpi
|
Loin Pain Hematuria Syndrome (LPHS) remains a rare disease but has a significant impact on those affected by it. Patients diagnosed with LPHS experience severe, constant or intermittent flank pain that radiates to the groin and may be exacerbated even by a gentle touch. These patients often require significant narcotic regimens for pain control and are unable to maintain a functional lifestyle. Previously, diagnosis has been made based on clinical presentation. One treatment for this syndrome is renal autotransplant; however, success rates are varied. Therefore, patient selection for this procedure is important. We have developed the UW-LPHS test as a diagnostic maneuver in order to determine which patients with LPHS would benefit from renal autotransplant. To perform this diagnostic test, bupivacaine is instilled into the ureter on the affected side and left to dwell. Patients who experience pain relief following this test are deemed to benefit from renal autotransplant. Here we describe this novel diagnostic test and initial success rates following renal autotransplant. | 01 = IsEpi
|
Marfan syndrome and dominant ectopia lentis are part of type 1 fibrillinopathies that are caused by FBN1 pathogenic variants. Making a diagnosis could be challenging due to the clinical overlap between these disorders. The revised Ghent criteria used for Marfan syndrome diagnosis helped in resolving some of the confusion, especially in younger children. We report on a case of bilateral ectopia lentis in a 2-year-old child with a normal echocardiogram. FBN1 sequencing revealed a novel likely pathogenic variant described as c.385T > A (p.Cys129Ser). The patient's father also has a history of bilateral ectopia lentis and his genetic analysis detected the same FBN1 variant as the proband. | 01 = IsEpi
|
We describe a case of a large simple neonatal ovarian cyst, which was managed successfully using "wait and watch" approach and serial ultrasound monitoring. A cystic lesion arising from right ovary was noted in antenatal ultrasound (USG) which was followed up with postnatal USG which revealed a large simple ovarian cyst without any complications. Patient was kept on expectant management with close clinical and USG monitoring. Cyst resolved spontaneously at 10 wk of age. A brief review of literature for likely aetio-pathogenesis and management is also presented. | 01 = IsEpi
|
In humans a chromosomal hemideletion of the 16p11.2 region results in variable neurodevelopmental deficits including developmental delay, intellectual disability, and features of autism spectrum disorder (ASD). Serotonin is implicated in ASD but its role remains enigmatic. In this study we sought to determine if and how abnormalities in serotonin neurotransmission could contribute to the behavioral phenotype of the 16p11.2 deletion syndrome in a mouse model (Del mouse). As ASD is frequently associated with altered response to acute stress and stress may exacerbate repetitive behavior in ASD, we studied the Del mouse behavior in the context of an acute stress using the forced swim test, a paradigm well characterized with respect to serotonin. Del mice perseverated with active coping (swimming) in the forced swim test and failed to adopt passive coping strategies with time as did their wild-type littermates. Analysis of monoamine content by HPLC provided evidence for altered endogenous serotonin neurotransmission in Del mice while there was no effect of genotype on any other monoamine. Moreover, we found that Del mice were highly sensitive to the 5-HT2A antagonists M100907, which at a dose of 0.1 mg/kg normalized their level of active coping and restored the gradual shift to passive coping in the forced swim test. Supporting evidence for altered endogenous serotonin signaling was provided by observations of additional ligand effects including altered forebrain Fos expression. Taken together, these observations indicate notable changes in endogenous serotonin signaling in 16p11.2 deletion mice and support the therapeutic utility of 5-HT2A receptor antagonists. | 01 = IsEpi
|
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. | 01 = IsEpi
|
Marburg virus (MARV), a close relative of Ebola virus, is the causative agent of a severe human disease known as Marburg hemorrhagic fever (MHF). No licensed vaccine or therapeutic exists to treat MHF, and MARV is therefore classified as a Tier 1 select agent and a category A bioterrorism agent. In order to develop countermeasures against this severe disease, animal models that accurately recapitulate human disease are required. Here we describe the development of a novel, uniformly lethal Syrian golden hamster model of MHF using a hamster-adapted MARV variant Angola. Remarkably, this model displayed almost all of the clinical features of MHF seen in humans and non-human primates, including coagulation abnormalities, hemorrhagic manifestations, petechial rash, and a severely dysregulated immune response. This MHF hamster model represents a powerful tool for further dissecting MARV pathogenesis and accelerating the development of effective medical countermeasures against human MHF. | 01 = IsEpi
|
Cystic fibrosis (CF), an autosomal recessive disorder, occurs due to mutations in CFTR gene resulting in impaired cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel function in various epithelia. In addition to the well-known pulmonary and pancreatic morbidities, CF is characterized by electrolyte and acid-base abnormalities- hypochloremia, hyponatremia, hypokalemia and metabolic alkalosis. These are collectively known as Pseudo-Bartter syndrome, as similar abnormalities are seen in Bartter syndrome- an inherited tubulopathy affecting thick ascending limb of loop of Henle. There may be a significant clinical overlap between the Classic Bartter syndrome, Gitelman syndrome and CF presenting as Pseudo-Bartter syndrome, especially in early childhood. This review focuses on Pseudo-Bartter syndrome in CF, its pathogenesis and differentiation from Bartter/Gitelman syndrome. Other causes of metabolic abnormalities resembling Bartter syndrome are also highlighted. | 01 = IsEpi
|
Opitz syndrome is a rare genetic disorder which has been well defined; however, the surgical treatment of the anomalies has not been codified. The objective is to review the literature and describe the surgical priorities in the treatment of Opitz syndrome. This report is unique in the fact that it describes a surgical approach to the treatment of the deformities. Better outcomes are achieved with preoperative analysis of the deformities and surgical planning. Simultaneous soft tissues and bony reconstruction with grafts can achieve long lasting results and decrease recurrence rates. | 01 = IsEpi
|
BACKGROUND:Neuroleptic malignant syndrome (NMS) may be induced by atypical antipsychotic drugs (AAPDs) such as aripiprazole, olanzapine, risperidone and quetiapine, either as a single treatment or in combination with other drugs. A case of NMS following the administration of lamotrigine, aripiprazole and quetiapine in a patient with bipolar disorder, and with renal failure caused by toxic lithium levels has not been reported. CASE PRESENTATION:A 51-year-old female patient with a 27-year history of bipolar disorder, being treated with lithium, fluoxetine, olanzapine, gabapentine, perazine and biperiden, was admitted to the hospital due to depressed mood and delusions. A urinary tract infection was diagnosed and antibiotic therapy was initiated. After 5 days of treatment her physical state deteriorated and she developed a fever of 38.4 °C. Her laboratory results revealed a toxic level of lithium (2.34 mmol/l). Acute renal failure was diagnosed and the lithium was withdrawn. After stabilization of her condition, and despite her antipsychotic treatment, further intensification of delusions and depressed mood were observed. All drugs being taken by the patient were withdrawn and lamotrigine and aripiprazole were initiated. Due to the insufficient effectiveness of aripiprazole treatment and because of problems with sleep, quetiapine was added, however further treatment with this drug combination and an increase of quetiapine to 400 mg/d eventually caused NMS. Amantadine, lorazepam and bromocriptine were therefore initiated and the patient's condition improved. CONCLUSION:This case report indicates that concurrent use of multiple antipsychotic drugs in combination with mood stabilizers in patients with organic disorders confers an increased risk of NMS development. | 01 = IsEpi
|
Leiomyoma are commonly seen as benign smooth muscle tumors of the uterus. Smooth muscle tumors with unusual growth pattern are rare and include 3 primary neoplasms: intravenous leiomyomatosis (IVL), benign metastasizing leiomyoma (BML) and disseminated peritoneal leiomyomatosis (DPL). DPL is a rare benign disease, often giving the appearance of metastatic ovarian or peritoneal carcinoma. It is a disease that predominately affects women at their reproductive age. The risk of malignant transformation is 2-5%. There are no standard treatment guidelines for the management of the DPL. The unusual presentation of the disease delays the diagnosis or is often misdiagnosed and thus over treated, which may lead to increased morbidity and mortality. Therefore careful consideration and high index of suspicion is required for the proper management of such cases. | 01 = IsEpi
|
Munchausen by proxy syndrome (MBPS) is a form of child abuse wherein the mother fabricates or produces illness in her child. The condition is hard to diagnose and few successful interventions have been described. Long-term outcome is associated with high family disruption, reabuse, mortality and morbidity. We report on a six-month-old girl that experienced eight hospital admissions within five months. Symptoms of repeated vomiting, bloody diarrhoea and acute life-threatening events (ALTE) were never substantiated. Finally, blood in diapers and napkins presented by the mother was shown to be of maternal origin. When confronted, the mother agreed to psychiatric admission. Following five months of treatment, her mental state stabilised and she entered supported living. She remained separated from the child, who was given to the father and developed normally on close paediatric follow-up. We report a definite diagnosis and successful intervention in MBPS. The case highlights characteristic features of this entity and illustrates that a favourable outcome depends on early intervention with separation of the child and perpetrator, as well as concomitant long-term psychiatric treatment. | 01 = IsEpi
|
The Food and Drug Administration has recently approved the off-label use of hydroxychloroquine (HCQ) for the treatment of coronavirus disease 2019 (COVID-19) infections. However, a recent study not only failed to demonstrate HCQ efficacy but also documented a serious side effect of COVID-19 therapy with HCQ: QT prolongation and secondary arrhythmia. HCQ has been used as an off-label drug and deemed safe and effective for the treatment of oral lesions, such as Sjogren syndrome (SS), chronic ulcerative stomatitis (CUS), and oral lichen planus (OLP). Because HCQ may be appropriately used for the off-label treatment of SS, CUS, and OLP, relevant safety concerns regarding HCQ therapy with regard to dosage, drug-to-drug interactions, and QT prolongation and secondary arrhythmia are discussed here. Because of the possibility of decreased pharmacy supplies of HCQ, replacement drugs with respect to patients with SS, CUS, and OLP being successfully treated with HCQ are also discussed. | 01 = IsEpi
|
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. | 10 = IsNotEpi
|
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. | 01 = IsEpi
|
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. | 01 = IsEpi
|
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. | 01 = IsEpi
|
Fertile eunuch syndrome is caused by isolated LH deficiency, but its pathophysiology still remains controversial. We report a case of fertile eunuch syndrome with homozygous Trp8Arg and Ile15Thr mutations in the LH beta subunit gene. An 18-year-old man was admitted to our hospital for hypogonadism. Examination of genitalia revealed Tanner G1PH1, whereas both testes were elastically palpated and developed up to 18 ml. Endocrinological evaluations revealed normogonadotropic hypogonadism and there were normal responses after GnRH and hCG stimulation. Intratesticular testosterone concentration was almost normal (1.34 x 10(3) ng/g). By PCR direct sequencing, homozygous Trp (8) Arg and Ile (15) Thr mutations in exon 2 of LH beta were detected. Normal virilization and improved semen parameters were achieved after hCG supplementation. To our knowledge, this is the first case of fertile eunuch syndrome with homozygous Trp (8) Arg and Ile (15) Thr mutations in beta subunit of LH gene. | 01 = IsEpi
|
The 17q12 deletion syndrome is a chromosomal anomaly resulting from the interstitial microdeletion of the long arm of chromosome 17. The aim of this study was to present the experience on prenatal diagnosis of 17q12 deletion to further define the prenatal phenotypes of this syndrome. Eleven pregnancies with foetal 17q12 deletion detected by chromosomal microarray (CMA) were retrospectively included at a single Chinese tertiary medical centre. Clinical data were reviewed for these cases, including the maternal demographics, foetal ultrasound findings, CMA results and pregnancy outcomes. The deletion sizes of 17q12 ranged from 1.42 to 1.94 Mb. The deletion had arisen de novo in 10 cases and inherited from one of the parents in one case. Variable kidney abnormalities were found by ultrasound in all of the cases, with bilateral or unilateral hyperechogenic kidneys being the most common findings. This study indicates that a strikingly high correlation between prenatal hyperechogenic kidneys and 17q12 deletion, and prenatal testing with CMA should be offered to the foetal cases of hyperechogenic kidneys. Impact statement What is already known on this subject? 17q12 deletion syndrome is a cause of renal abnormalities, maturity-onset diabetes of the young and neurodevelopmental disorders. Prenatal diagnosis has been reported in several isolated cases with the use of microarray-based technologic means. What do the results of this study add? The results provide further evidence that a strikingly high correlation between prenatal hyperechogenic kidneys and 17q12 deletion, and genetic testing should be offered to foetal cases with hyperechogenic kidneys. A rare prenatal case of 17q12 deletion with multiple structural malformations and anhydramnios is presented. What are the implications of these findings for clinical practice and/or further research? There should be a high index of suspicion of carriers in parents when 17q12 deletion is confirmed prenatally. An extremely wide phenotype spectrum of this deletion should be emphasised in the prenatal counselling. | 01 = IsEpi
|
BACKGROUND:Congenital hyperinsulinism (CHI) is a neuroendocrine disease with focal or diffuse abnormalities in pancreas. While drug-resistant diffuse forms require near-total pancreatectomy or prolonged pharmacotherapy, focal CHI may be treated by targeted surgical resection. We evaluated the usefulness of 18F-DOPA PET/CT to identify the focal pancreatic form. SUBJECTS AND METHODS:Nineteen children (11 boys, 8 girls, aged 2-54 months) with clinical signs of neonatal CHI and positive genetic examinations were enrolled in the study. After i.v. administration of 18F-DOPA, early PET and late PET/CT acquisition covering one-bed length over thoraco-abdominal region were performed. Both acquisitions were done in dynamic mode to allow exclusion of frames with motion artefacts. Standardized uptake values were adjusted to bodyweight (SUVbw). The finding was considered as focal when the ratio of SUVbwmax between the suspicious region and the rest of pancreas was greater than 1.2. RESULTS:Focal forms were recorded in 10/19 children and 4 of them underwent surgical resection with complete recovery. Focal uptake was significantly higher than the uptake in the normal pancreatic tissue (p=0.0059). Focal and diffuse forms of CHI did not differ significantly in normal pancreatic tissue uptake. We found no advantage in the measurement of SUVbwmean ratio compared to SUVbwmax ratio (p=0.50). CONCLUSION:18F-DOPA PET/CT is a useful tool for the localization of focal CHI and planning of surgical treatment. | 01 = IsEpi
|
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. | 01 = IsEpi
|
Endodontic treatment of fused teeth needs special care and attention due to its complex anatomy. The aim of this article is to highlight the problems encountered and the strategy in treating such cases. We report a case of unilateral fusion of the left mandibular central incisor and lateral incisor, with a single pulp chamber. The single pulp chamber separates into two root canals and a large communication exists at the apical third of the root canals. This is the first time fused teeth with a large communication is reported. CBCT analysis was effective in confirming the morphological aberrations and aided in accurate planning and treatment. Chemomechanical preparation with manual dynamic irrigation coupled with passive ultrasonic activation of the irrigant and obturation with thermoplasticised gutta percha helped in successful outcome of the case. | 01 = IsEpi
|
Follicular mucinosis (FM) is a rare disorder of the skin characterized by follicular degeneration due to the accumulation of mucin within the pilosebaceous unit, with associated inflammatory changes. We report a case of an 11-year-old female with widespread lesions showing distinct clinical and histological features of FM with a brief review of the literature. | 01 = IsEpi
|
Guanidinoacetate methyltransferase (GAMT) deficiency is a rare inherited disorder characterized by creatine (Cr) depletion and guanidinoacetate (GAA) accumulation in body fluids. We report the first identified Chinese case, diagnosed in a 4-year-old girl with onset of global developmental. Low Cr and high GAA levels were detected in her serum and urine, and low Cr level in her brain. Compound heterozygous variants in GAMT gene were found, including a previously reported variant at c.491dupG which was inherited from her mother and a novel variant at c.564G>T, which was inherited from her father. The Cr and GAA levels returned back to normal after 3 months of treatment. After one year of treatment, the patient stopped taking antiepileptic drugs and her electroencephalogram (EEG) was also back to normal. The girl was followed up for five years and exhibited good results beyond our expectation. The results have shown that protein restriction with high-dose ornithine and creatine supplements have strong therapeutic potential for our patient. | 01 = IsEpi
|
Poland syndrome refers to a chest wall disorder in which there is a deficiency of the pectoral musculature. Möbius syndrome is a rare disorder in which there is absence or hypoplasia of the facial or abducens nerve, either unilaterally or bilaterally. Described here is a case in a newborn male in which both conditions manifest simultaneously as Poland-Möbius syndrome. The imaging findings here serve as a useful guide for the radiologist and ordering providers by reinforcing the need for dedicated cranial nerve imaging in patients who have deficiencies in anterior chest wall musculature. | 01 = IsEpi
|
Congenital disorders of glycosylation (CDG) are a rapidly expanding group of inborn errors of metabolism with around 100 types described so far. Because of the limited number of reported cases in each type except PMM2-CDG, the complete clinical picture of other types is not known. RFT1-CDG is a rare type, with ten cases reported in the literature. Our patient presented as a floppy neonate with severe respiratory insufficiency and ventilator dependence in the newborn period. He had fetal growth restriction, facial dysmorphism, high arched palate, bilateral cryptorchidism, hypoplastic pons and cerebellum and probable hearing impairment. He succumbed to the illness on day 24 of life. There was a similar history of two previous sibling deaths in the early neonatal period due to respiratory insufficiency and history of multiple neonatal and infant deaths in the extended family. Transferrin iso-electric focusing was normal. Clinical exome sequencing revealed a novel homozygous missense mutation (c.1018 G > A) in RFT1 gene [NM_052859; c.1018G > A; p.G340S; ENST00000296292] and the parents were heterozygous for the same (ClinVar SVC000778540). The pathogenic variants so far reported are all missense variants affecting the luminal loops; whereas the variant in our case is in the trans-membrane helical domain. A strong family history of neonatal deaths and similar presentations in the previous 2 siblings suggests the homogenous phenotype of this mutation. Severe respiratory insuffiency and ventilator dependence shows the lethality of the disease phenotype and incompatibility with survival beyond the neonatal period. | 01 = IsEpi
|
BACKGROUND:Hyperprolinemia type 2 (HPII) is a rare autosomal recessive disorder of the proline metabolism, that affects the ALDH4A1 gene. So far only four different pathogenic mutations are known. The manifestation is mostly in neonatal age, in early infancy or early childhood. CASE PRESENTATION:The 64-years female patient had a long history of abdominal pain, and episode of an acute neuritis. Ten years later she was admitted into the neurological intensive-care-unit with acute abdominal pain, multiple generalized epileptic seizures, a vertical gaze palsy accompanied by extensive lactic acidosis in serum 26.0 mmol/l (reference: 0.55-2.2 mmol/l) and CSF 12.01 mmol/l (reference: 1.12-2.47 mmol/l). Due to repeated epileptic seizures and secondary complications a long-term sedation with a ventilation therapy over 20 days was administered. A diagnostic work-up revealed up to 400-times increased prolin-level in urine CSF and blood. Furthermore, a low vitamin-B6 serum value was found, consistent with a HPII causing secondary pyridoxine deficiency and seizures. The ALDH4A1 gene sequencing confirmed two previously unknown compound heterozygous variants (ALDH4A1 gene (NM_003748.3) Intron 1: c.62 + 1G > A - heterozygous and ALDH4A1 gene (NM_003748.3) Exon 5 c.349G > C, p.(Asp117His) - heterozygous). Under high-dose vitamin-B6 therapy no further seizures occurred. CONCLUSION:We describe two novel ALDH4A1-variants in an adult patient with hyperprolinemia type II causing secondary pyridoxine deficiency and seizures. Severe and potentially life-threatening course of this treatable disease emphasizes the importance of diagnostic vigilance and thorough laboratory work-up including gene analysis even in cases with atypical late manifestation. | 01 = IsEpi
|
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. | 01 = IsEpi
|
Introduction: Subependymal ependymal giant cell astrocytomas (SEGAs) occur almost exclusively in the setting of tuberous sclerosis (TSC). They are low-grade gliomas which typically produce clinical symptoms through either mass effect or hydrocephalus. As do other manifestations of tuberous sclerosis, these lesions result from mutations in either the TSC1 or the TSC2 gene. These mutations cause hyperactivation of the mechanistic target of rapamycin (mTOR). In view of their tendency to grow slowly, clinical symptoms usually only occur when the tumors reach a considerable size. Therapy can involve surgical resection, cerebrospinal fluid diversion, or medical therapy with an mTOR inhibitor.Areas covered: Herein, the authors discuss the diagnosis, symptoms, and practical management of SEGAs as well as providing their expert opinion.Expert opinion: mTOR inhibitors have largely replaced surgery as the primary modality for the management of SEGAs. Surgical treatment is largely limited to tumors that present with acute hydrocephalus and increased intracranial pressure. Patients with TSC should undergo periodic screening with CT or preferably MRI scans of the brain from childhood to approximately age 25 to identify SEGAs which require treatment. In addition to avoiding potential morbidity associated with surgical resection, mTOR inhibitors have the potential to improve the clinical status of tuberous sclerosis patients generally. | 01 = IsEpi
|
BACKGROUND:To describe a case of a rare association of bilateral keratoconus and unilateral essential iris atrophy and to conduct a literature review of the current strategies of treatment of the corneal disease and glaucoma in patients with Iridocorneal Endothelial Syndrome (ICE). CASE PRESENTATION:We report a rare association of bilateral keratoconus and unilateral essential iris atrophy in a 38-year-old man. Diagnosis of bilateral keratoconus was confirmed by corneal topography. Slit-lamp examination showed extensive iris atrophy with corectopia and policoria in one eye. Corneal specular microscopy revealed an abnormal endothelium morphology in the same eye with extensive peripheral anterior synechiae and closure of the drainage angle at gonioscopy. Intraocular pressure was 26 mmHg, despite maximal topical therapy. Optic disc examination showed severe glaucomatous cupping. Surgery by glaucoma drainage device implantation was performed. CONCLUSION:Essential iris atrophy is a rare clinical variant of ICE syndrome characterized by profound anatomical alterations of the anterior segment associated with corneal edema and secondary glaucoma. In these patients, selective keratoplasties have replaced penetrating keratoplasty to treat corneal decompensation and glaucoma drainage devices are preferred to conventional trabeculectomy for the treatment of secondary glaucoma. | 01 = IsEpi
|
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. | 01 = IsEpi
|
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. | 01 = IsEpi
|
Co-deletion of 1p/19q is a hallmark of oligodendroglioma and predicts better survival. However, little is understood about its metabolic characteristics. In this study, we aimed to explore the extracellular acidity of WHO grade II and III gliomas associated with 1p/19q co-deletion. We included 76 glioma patients who received amine chemical exchange saturation transfer (CEST) imaging at 3 T. Magnetic transfer ratio asymmetry (MTRasym) at 3.0 ppm was used as the pH-sensitive CEST biomarker, with higher MTRasym indicating lower pH. To control for the confounder factors, T2 relaxometry and L-6-18F-fluoro-3,4-dihydroxyphenylalnine (18F-FDOPA) PET data were collected in a subset of patients. We found a significantly lower MTRasym in 1p/19q co-deleted gliomas (co-deleted, 1.17% ± 0.32%; non-co-deleted, 1.72% ± 0.41%, P = 1.13 × 10-7), while FDOPA (P = 0.92) and T2 (P = 0.61) were not significantly affected. Receiver operating characteristic analysis confirmed that MTRasym could discriminate co-deletion status with an area under the curve of 0.85. In analysis of covariance, 1p/19q co-deletion status was the only significant contributor to the variability in MTRasym when controlling for age and FDOPA (P = 2.91 × 10-3) or T2 (P = 8.03 × 10-6). In conclusion, 1p/19q co-deleted gliomas were less acidic, which may be related to better prognosis. Amine CEST-MRI may serve as a non-invasive biomarker for identifying 1p/19q co-deletion status. | 01 = IsEpi
|
BACKGROUND:Children with spastic hemiplegic cerebral palsy have deficits in eye-hand coordination. This limits manual actions performed with the affected hand, especially fine motor skills such as grasping and manipulation. Visual-motor integration, grasping skills, and visual perception are collectively involved in eye-hand coordination. AIMS:We investigated the effects of augmented biofeedback training on eye-hand coordination in children with spastic hemiplegic cerebral palsy. METHODS AND PROCEDURES:Forty-five spastic hemiplegic cerebral palsy children (5-8 years old) were included. Children were assigned randomly into three equal groups. One group received traditional physical therapy to facilitate visual-motor integration and grasping skills for 3 months. The second group received augmented biofeedback training. The third group received a combination of augmented biofeedback training and traditional physical therapy. Children were evaluated with the Peabody Developmental Motor Scale (2nd edition) (PDMS-2). Treatment sessions were conducted for 60 min, three times a week, for 3 consecutive months. OUTCOMES AND RESULTS:Children that received augmented biofeedback training alongside traditional physical therapy had significantly improved scores in the Visual-Motor Integration and grasping subtests compared to children that received only one intervention. CONCLUSIONS AND IMPLICATIONS:Augmented biofeedback training alongside physical therapy improved eye-hand coordination in children with spastic hemiplegic cerebral palsy. | 01 = IsEpi
|
Leigh syndrome (LS) is a progressive neurodegenerative disease caused by either mitochondrial or nuclear DNA mutations resulting in dysfunctional mitochondrial energy metabolism. The onset of clinical features is typically between 3 and 12 months of age; however, a later onset has been described in a few patients. Complex I deficiency is reported to be the most common cause of mitochondrial disorders. We described a patient with a late-onset LS, who presented with gait ataxia, caused by complex I deficiency (NDUFV1 gene). | 01 = IsEpi
|
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. | 01 = IsEpi
|
MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) (OMIM 540000) is the most dominant subtype of mitochondrial myopathy. The aim of this study was to determine the prevalence, natural course, and severity of MELAS.A prospective cohort study of 96 Japanese patients with MELAS was followed between June 2003 and April 2008. Patients with MELAS were identified and enrolled based on questionnaires administered to neurologists in Japan. MELAS was defined using the Japanese diagnostic criteria for MELAS. Two follow-up questionnaires were administered to neurologists managing MELAS patients at an interval of 5years.A prevalence of at least 0.58 (95% confidential interval (CI), 0.54-0.62)/100,000 was calculated for mitochondrial myopathy, whereas the prevalence of MELAS was 0.18 (95%CI, 0.02-0.34)/100,000 in the total population. MELAS patients were divided into two sub-groups: juvenile form and adult form. Stroke-like episodes, seizure and headache were the most frequent symptoms seen in both forms of MELAS. Short stature was significantly more frequent in the juvenile form, whereas hearing loss, cortical blindness and diabetes mellitus were significantly more frequent in the adult form. According to the Japanese mitochondrial disease rating scale, MELAS patients showed rapidly increasing scores (mean±standard deviation, 12.8±8.7) within 5years from onset of the disease. According to a Kaplan-Meier analysis, the juvenile form was associated with a higher risk of death than the adult form (hazard ratio, 3.29; 95%CI, 1.32-8.20; p=0.0105).We confirmed that MELAS shows a rapid degenerative progression within a 5-year interval and that this occurs in both the juvenile and the adult forms of MELAS and follows different natural courses. This article is part of a Special Issue entitled: Biochemistry of Mitochondria. | 10 = IsNotEpi
|
We report on a Brazilian girl, born to consanguineous parents and presenting a multiple congenital anomaly (MCA) syndrome, mainly characterized by blepharophimosis, cleft palate, and arachnodactyly. The clinical aspects involving this patient suggest an apparently undescribed "new" autosomal recessive syndrome. | 01 = IsEpi
|
In Europe, dietary management of isovaleric acidemia (IVA) may vary widely. There is limited collective information about dietetic management.To describe European practice regarding the dietary management of IVA, prior to the availability of the E-IMD IVA guidelines (E-IMD 2014).A cross-sectional questionnaire was sent to all European dietitians who were either members of the Society for the Study of Inborn Errors of Metabolism Dietitians Group (SSIEM-DG) or whom had responded to previous questionnaires on dietetic practice (n = 53). The questionnaire comprised 27 questions about the dietary management of IVA.Information on 140 patients with IVA from 39 centres was reported. 133 patients (38 centres) were given a protein restricted diet. Leucine-free amino acid supplements (LFAA) were routinely used to supplement protein intake in 58% of centres. The median total protein intake prescribed achieved the WHO/FAO/UNU [2007] safe levels of protein intake in all age groups. Centres that prescribed LFAA had lower natural protein intakes in most age groups except 1 to 10 y. In contrast, when centres were not using LFAA, the median natural protein intake met WHO/FAO/UNU [2007] safe levels of protein intake in all age groups. Enteral tube feeding was rarely prescribed.This survey demonstrates wide differences in dietary practice in the management of IVA across European centres. It provides unique dietary data collectively representing European practices in IVA which can be used as a foundation to compare dietary management changes as a consequence of the first E-IMD IVA guidelines availability. | 01 = IsEpi
|
There are currently five compounds (clobazam, felbamate, lamotrigine, topiramate, rufinamide) available for prescription with a demonstrated efficacy on drop seizures for Lennox-Gastaut syndrome (LGS). There are also currently new and under-investigation compounds. This paper gives an overview on these novel developments for LGS based on the lecture given at the French Chapter meeting of the International League Against Epilepsy (ILAE) held in Paris in October 2019. Five compounds were discussed. Epidiolex (cannabidiol) has been approved recently based on positive randomized control trials in LGS patients. Four drugs are under investigation according to a search on the 'clinicaltrials.gov' database. Perampanel and fenfluramine are both being studied in ongoing phase 3 studies. Two compounds are in an earlier stage of development with ongoing phase 1 and 2 studies: carisbamate and OV953. We summarized the publicly available data. Based on these drug development programs, we can expect that new compounds will become available for LGS in the next years, possibly resulting in new treatment paradigms. | 01 = IsEpi
|
Omsk hemorrhagic fever virus (OHFV) is a tick-borne flavivirus classified as a biosafety level-4 (BSL4) pathogen. Studies of OHFV are restricted to be conducted within BSL4 laboratories. Currently, no commercial vaccines or antiviral drugs are available against OHFV infection. In this study, we recovered a replication-deficient OHFV with an NS1 deletion (OHFV-ΔNS1) and reporter virus replacing NS1 with the Gaussia luciferase (Gluc) (OHFV-ΔNS1-Gluc). Both the defective OHFV-ΔNS1 and OHFV-ΔNS1-Gluc virus could only replicate efficiently in the BHK21 cell line expressing NS1 (BHK21NS1) but not in naïve BHK21 cells. The Gluc reporter gene of OHFV-ΔNS1-Gluc virus was maintained stably after serial passaging of BHK21NS1 cells and was used to surrogate the replication of OHFV. Using NITD008, OHFV-ΔNS1-Gluc virus was validated for antiviral screening, and high-throughput screening parameters were optimized in a 96-well plate format with a calculated Z' value above 0.5. The OHFV-ΔNS1-Gluc reporter virus is a powerful tool for antiviral screening as well as viral replication and pathogenesis studies in BSL2 laboratories. | 01 = IsEpi
|
Hereditary neuropathies form a heterogeneous group of disorders for which over 40 causal genes have been identified to date. Recently, dominant mutations in the transient receptor potential vanilloid 4 gene were found to be associated with three distinct neuromuscular phenotypes: hereditary motor and sensory neuropathy 2C, scapuloperoneal spinal muscular atrophy and congenital distal spinal muscular atrophy. Transient receptor potential vanilloid 4 encodes a cation channel previously implicated in several types of dominantly inherited bone dysplasia syndromes. We performed DNA sequencing of the coding regions of transient receptor potential vanilloid 4 in a cohort of 145 patients with various types of hereditary neuropathy and identified five different heterozygous missense mutations in eight unrelated families. One mutation arose de novo in an isolated patient, and the remainder segregated in families. Two of the mutations were recurrent in unrelated families. Four mutations in transient receptor potential vanilloid 4 targeted conserved arginine residues in the ankyrin repeat domain, which is believed to be important in protein-protein interactions. Striking phenotypic variability between and within families was observed. The majority of patients displayed a predominantly, or pure, motor neuropathy with axonal characteristics observed on electrophysiological testing. The age of onset varied widely, ranging from congenital to late adulthood onset. Various combinations of additional features were present in most patients including vocal fold paralysis, scapular weakness, contractures and hearing loss. We identified six asymptomatic mutation carriers, indicating reduced penetrance of the transient receptor potential vanilloid 4 defects. This finding is relatively unusual in the context of hereditary neuropathies and has important implications for diagnostic testing and genetic counselling. | 01 = IsEpi
|
BACKGROUND:When evaluating patients' profile, surgeons usually note the lack of the chin projection and may suggest chin augmentation, but they rarely discuss reduction of an over-projecting chin. This is unfortunate, since there are quite many individuals who have macrogenia and would aesthetically benefit from corrective surgery, but the chin reduction is seldom offered. The reason for this is the lack of experience, lack of the technical equipment necessary, or sometimes lack of knowledge. The present study conveys 25 years of experience with the reduction genioplasty. METHODS:From 1994 to 2019, 47 patients (39 females, 6 males, and 2 male to female transsexuals) underwent 49 chin reduction procedures. All patients were operated and followed up by the author. The transoral approach was used in 23 patients, and in 24 patients the procedure was done through the straight 4- to 6-cm-long submental incision. The air-driven pneumatic chisel was employed for reduction of the mandibular bone (MicroAire, Charlottesville, VA, USA). Forty-eight operations were carried out under dissociative and local anaesthesia on an outpatient basis, and one procedure was done under general endotracheal anaesthesia. RESULTS:Both mandibular bone and the soft tissues of the chin were reduced, or modulated according to the needs of each patient. Operations were technically easier when executed by the submental approach because of better exposure of the mandibular rim and the higher precision in the remodelling of the soft tissues. Thirty-six patients (77%) could be followed up for a mean of 2.5 years (range 9 months to 12 years). Twenty-eight of evaluated patients (78%) described the outcome as very good or good. Four patients described the result as acceptable and another 4 as bad. In the majority of cases the evaluation by the surgeon correlated well with the opinion of patients, but in five cases surgeon estimated result with the higher score than the patient. Overall good results were illustrated by the photographs of the clinical examples. Complications were few and manageable. Transient neuropathies were common and more frequent with the transoral approach. Five patients required minor intervention for skin indentations at the jaw line developed during the healing phase. CONCLUSIONS:Skilful chin reduction surgery is safe and the aesthetic improvement could be quite spectacular, which is also rewarding for the patients. Complications in this patient series were few and manageable. More surgeons should include chin reduction in their repertoire. | 01 = IsEpi
|
Bone is a dynamic organ that undergoes constant remodeling, an energetically costly process by which old bone is replaced and localized bone defects are repaired to renew the skeleton over time, thereby maintaining skeletal health. This review provides a general overview of bone's main players (bone lining cells, osteocytes, osteoclasts, reversal cells, and osteoblasts) that participate in bone remodeling. Placing emphasis on the family of extracellular matrix metalloproteinases (MMPs), we describe how: (i) Convergence of multiple protease families (including MMPs and cysteine proteinases) ensures complexity and robustness of the bone remodeling process, (ii) Enzymatic activity of MMPs affects bone physiology at the molecular and cellular levels and (iii) Either overexpression or deficiency/insufficiency of individual MMPs impairs healthy bone remodeling and systemic metabolism. Today, it is generally accepted that proteolytic activity is required for the degradation of bone tissue in osteoarthritis and osteoporosis. However, it is increasingly evident that inactivating mutations in MMP genes can also lead to bone pathology including osteolysis and metabolic abnormalities such as delayed growth. We argue that there remains a need to rethink the role played by proteases in bone physiology and pathology. | 01 = IsEpi
|
RATIONALE:Pulmonary arterial hypertension (PAH) is a serious lung condition characterized by vascular remodeling in the precapillary pulmonary arterioles. We and others have demonstrated chromosomal abnormalities and increased DNA damage in PAH lung vascular cells, but their timing and role in disease pathogenesis is unknown. OBJECTIVES:We hypothesized that if DNA damage predates PAH, it might be an intrinsic cell property that is present outside the diseased lung. METHODS:We measured DNA damage, mutagen sensitivity, and reactive oxygen species (ROS) in lung and blood cells from patients with Group 1 PAH, their relatives, and unrelated control subjects. MEASUREMENTS AND MAIN RESULTS:Baseline DNA damage was significantly elevated in PAH, both in pulmonary artery endothelial cells (P < 0.05) and peripheral blood mononuclear cells (PBMC) (P < 0.001). Remarkably, PBMC from unaffected relatives showed similar increases, indicating this is not related to PAH treatments. ROS levels were also higher (P < 0.01). DNA damage correlated with ROS production and was suppressed by antioxidants (P < 0.001). PBMC from patients and relatives also showed markedly increased sensitivity to two chemotherapeutic drugs, bleomycin and etoposide (P < 0.001). Results were consistent across idiopathic, heritable, and associated PAH groups. CONCLUSIONS:Levels of baseline and mutagen-induced DNA damage are intrinsically higher in PAH cells. Similar results in PBMC from unaffected relatives suggest this may be a genetically determined trait that predates disease onset and may act as a risk factor contributing to lung vascular remodeling following endothelial cell injury. Further studies are required to fully characterize mutagen sensitivity, which could have important implications for clinical management. | 01 = IsEpi
|
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. | 01 = IsEpi
|
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. | 01 = IsEpi
|
The present study aimed to investigate the extent to which the severity of misophonia symptoms is linked with cognitive control under misophonia symptom-provocation circumstances in the general population sample. Participants (N = 79) completed a measure of cognitive control-a Stroop color naming task, which consists of congruent and incongruent stimuli, and requires inhibition of a prepotent response (reading a word) in the service of a less predominant response (naming a color), while listening to misophonia symptom-provocation or universally unpleasant sounds. Participants' misophonia sound sensitivity, and emotional behaviors towards trigger sounds were assessed using the Misophonia Questionnaire. Stronger emotional behavioral reactions to misophonia trigger sounds were significantly associated with the larger Stroop effect when participants were exposed to the misophonia trigger sounds, but not when they were exposed to the universally unpleasant sounds. This effect held when controlling for the personality trait of Neuroticism and for baseline levels of anxiety. Both elevated misophonia sound sensitivity and emotional behaviors towards trigger sounds significantly correlated with higher self-reported anxiety when performing the Stroop task. However, only elevated emotional behaviors towards trigger sounds were linked with higher anxiety levels at baseline, suggesting that people who experience stronger emotions and behavioral reactions to misophonia trigger sounds may have higher anxiety at a trait level. Limitations and future directions are discussed. | 01 = IsEpi
|
Bowen-Conradi syndrome (BCS) is a common autosomal recessive condition in the Hutterite population. In 2012, when BCS clinical testing was not available, we reported two babies believed to have BCS based upon their clinical features. Diagnostic molecular testing is now available for this condition. We describe here a brother born to the parents of one of the infants in our previous report. Although clinically both babies in the 2012 report appeared to have the same condition, this current infant was found to have a normal EMG1 gene sequence, and thus, lacks the Hutterite mutation for BCS. We discuss the importance of molecular testing in the Hutterite population. | 01 = IsEpi
|
BACKGROUND:Nutcracker syndrome is an easily missed cause of hematuria in children. It is characterized by left renal vein entrapment between the abdominal aorta and the superior mesenteric artery causing renal venous hypertension. Intermittent hematuria and orthostatic proteinuria with or without abdominal or flank pain are the common clinical manifestations. Presence of variable non-specific symptoms and non-significant physical findings results in a delayed diagnosis. CASE PRESENTATION:We present a ten -year -old girl with four episodes of painless gross hematuria and recurrent microscopic hematuria since the age of two years. Doppler ultrasound showed left renal vein compression while 3 D computerized tomography angiography confirmed the diagnosis of an anterior nutcracker. The patient was conservatively treated with nutritional support (pediasure complete formula and high calorie food), iron supplements and followed up, monitored for anemia, hypertension and renal insufficiency. CONCLUSION:Nutcracker syndrome is a rare cause of recurrent gross hematuria in children. A high index of suspicion and proper imaging is needed to reach a proper diagnosis and avoid the psychological and financial stress on the family. | 01 = IsEpi
|
We describe the first patient with a left ventricular assist device (LVAD) driveline infection caused by Mycobacterium chelonae presenting with persistent infection despite conventional antibiotics. Treatment was successful with surgical debridement, driveline exit relocation, and a 4-month period of antibiotics. In the case of a culture-negative LVAD driveline infection, non-tuberculous mycobacteria should be considered. This case illustrates that multidisciplinary collaboration is essential in providing optimal care for LVAD patients. | 01 = IsEpi
|
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. | 01 = IsEpi
|
Introduction:In this study, we aimed to investigate the effect of uric acid on the disease, its severity and progression in ET patients with partially co-clinical features with Parkinson's disease (PD). Methods:Serum UA levels of 87 consecutive ET patients were measured and were matched according to age and sex with 87 healthy controls. Fahn-Tolosa-Marin scale was used for the severity of tremor. Sociodemographic characteristics, type of ET, duration of disease, and treatment modalities were evaluated. Results:The mean uric acid level was calculated as 4.986±2.1458 mg/dL and 6.004±1.523 mg/dL in the patient and control groups, respectively (p≤0.005). The blood UA level of patients with sporadic (n: 61) ET was found to be lower than the familial ET (n: 26) (p≤0.005). The tremor severity of the family ET patients was lower than the sporadic ET. (n: 61) (p≤0.005). The mean blood UA level (4.429±1.216 mg/dL) in the patients with high total tremor severity scores (n: 48) was found lower than in the patients with low total tremor severity scores (n: 39) (5.673±2.106 mg/dL) (P=0.000). The serum UA level was significantly lower in the patients whose disease duration longer than 5 years than in patients whose duration of the disease was shorter than 5 years. 5.732±1.240 for ≥5 years; 6.438±0.286≤5 years) (P=0.001). Conclusion:We hypothesize that as a result of high antioxidant properties of high serum uric acid levels, it is a biomarker that can show disease risk and progression in patients with ET as well as PD. | 01 = IsEpi
|
Recent narrative reviews have described the potential efficacy of providing individuals infected with coronavirus disease 2019 (COVID-19) with additional micronutrients to reduce disease severity. Although there are compelling reasons why providing additional micronutrients or conditional amino acids may affect COVID-19-related outcomes, evidence is lacking. The objective of this scoping review is to explore and describe the literature examining the effect of providing additional micronutrients or conditional amino acids (glutamine, arginine) in adults with conditions or infections similar to COVID-19 infection on COVID-19-related health outcomes. A literature search of the MEDLINE database and hand search of Cochrane Database of systematic reviews retrieved 1,423 unique studies, and 8 studies were included in this scoping review. Four studies examined a target population with ventilator-related pneumonia and acute respiratory distress syndrome, and the other 4 studies included patients who were at risk for ventilator-associated pneumonia. Interventions included intravenous ascorbic acid, intramuscular cholecalciferol, enteral and intramuscular vitamin E, enteral zinc sulfate, and oral and parenteral glutamine. In 6 of the 8 included studies, baseline status of the nutrient of interest was not reported and, thus, it is uncertain how outcomes may vary in the context of nutrient deficiency or insufficiency compared with sufficiency. In the absence of direct evidence examining efficacy of providing additional micronutrients or conditional amino acids to standard care, registered dietitian nutritionists must rely on clinical expertise and indirect evidence to guide medical nutrition therapy for patients infected with COVID-19. | 01 = IsEpi
|
BACKGROUND:Genetic familiar causes of oro-facial dyskinesia are usually restricted to Huntington's disease, whereas other causes are often missed or underestimated. Here, we report the case of late-onset oro-facial dyskinesia in an elderly patient with a genetic diagnosis of Spinocerebellar Ataxia type 2 (SCA2). CASE PRESENTATION:A 75-year-old man complained of progressive balance difficulty since the age of 60 years, associated with involuntary movements of the mouth and tongue over the last 3 months. No exposure to anti-dopaminergic agents, other neuroleptics, antidepressants, or other drugs was reported. Family history was positive for SCA2 (brother and the son of the brother). At rest, involuntary movements of the mouth and tongue were noted; they appeared partially suppressible and became more evident during stress and voluntary movements. Cognitive examination revealed frontal-executive dysfunction, memory impairment, and attention deficit. Brain magnetic resonance imaging (MRI) disclosed signs of posterior periventricular chronic cerebrovascular disease and a marked ponto-cerebellar atrophy, as confirmed by volumetric MRI analysis. A dopamine transporter imaging scan demonstrated a bilaterally reduced putamen and caudate nucleus uptake. Ataxin-2 (ATXN2) gene analysis revealed a 36 cytosine-adenine-guanine (CAG) repeat expansion, confirming the diagnosis of SCA2. CONCLUSIONS:SCA2 should be considered among the possible causes of adult-onset oro-facial dyskinesia, especially when the family history suggests an inherited cerebellar disorder. Additional clinical features, including parkinsonism and motor neuron disease, may represent relevant cues for an early diagnosis and adequate management. | 01 = IsEpi
|
Electrolyte homeostasis is maintained by the kidney through a complex transport function mostly performed by specialized proteins distributed along the renal tubules. Pathogenic variants in the genes encoding these proteins impair this function and have consequences on the whole organism. Establishing a genetic diagnosis in patients with renal tubular dysfunction is a challenging task given the genetic and phenotypic heterogeneity, functional characteristics of the genes involved and the number of yet unknown causes. Part of these difficulties can be overcome by gathering large patient cohorts and applying high-throughput sequencing techniques combined with experimental work to prove functional impact. This approach has led to the identification of a number of genes but also generated controversies about proper interpretation of variants. In this article, we will highlight these challenges and controversies. | 01 = IsEpi
|
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. | 01 = IsEpi
|
Mutations in the RMRP gene lead to a wide spectrum of autosomal recessive skeletal dysplasias, ranging from the milder phenotypes metaphyseal dysplasia without hypotrichosis and cartilage hair hypoplasia (CHH) to the severe anauxetic dysplasia (AD). This clinical spectrum includes different degrees of short stature, hair hypoplasia, defective erythrogenesis, and immunodeficiency. The RMRP gene encodes the untranslated RNA component of the mitochondrial RNA-processing ribonuclease, RNase MRP. We recently demonstrated that mutations may affect both messenger RNA (mRNA) and ribosomal RNA (rRNA) cleavage and thus cell-cycle regulation and protein synthesis. To investigate the genotype-phenotype correlation, we analyzed the position and the functional effect of 13 mutations in patients with variable features of the CHH-AD spectrum. Those at the end of the spectrum include a novel patient with anauxetic dysplasia who was compound heterozygous for the null mutation g.254_263delCTCAGCGCGG and the mutation g.195C-->T, which was previously described in patients with milder phenotypes. Mapping of nucleotide conservation to the two-dimensional structure of the RMRP gene revealed that disease-causing mutations either affect evolutionarily conserved nucleotides or are likely to alter secondary structure through mispairing in stem regions. In vitro testing of RNase MRP multiprotein-specific mRNA and rRNA cleavage of different mutations revealed a strong correlation between the decrease in rRNA cleavage in ribosomal assembly and the degree of bone dysplasia, whereas reduced mRNA cleavage, and thus cell-cycle impairment, predicts the presence of hair hypoplasia, immunodeficiency, and hematological abnormalities and thus increased cancer risk. | 01 = IsEpi
|
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. | 01 = IsEpi
|
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. | 01 = IsEpi
|
Papillon-Lefèvre syndrome (PLS; MIM#245000) is a rare recessive autosomal disorder characterized by palmar and plantar hyperkeratosis, and aggressively progressing periodontitis leading to premature loss of deciduous and permanent teeth. PLS is caused by loss-of-function mutations in the CTSC gene, which encodes cathepsin C. PLS clinical expressivity is highly variable and no consistent genotype-phenotype correlation has been demonstrated yet. Here we report the clinical and genetic features of five PLS patients presenting a severe periodontal breakdown in primary and permanent dentition, hyperkeratosis over palms and soles, and recurrent sinusitis and/or tonsillitis. Mutation analysis revealed two novel homozygous recessive mutations (c.947T>C and c.1010G>C) and one previous described homozygous recessive mutation (c.901G>A), with parents carrying them in heterozygous, in three families (four patients). The fourth family presented with the CTSC c.628C>T mutation in heterozygous, which was inherited maternally. Patient carrying the CTSC c.628C>T mutation featured classical PLS phenotype, but no PLS clinical characteristics were found in his carrier mother. All mutations were found to affect directly (c.901G>A, c.947T>C, and c.1010G>C) or indirectly (c.628C>T, which induces a premature termination) the heavy chain of the cathepsin C, the region responsible for activation of the lysosomal protease. Together, these findings indicate that both homozygous and heterozygous mutations in the cathepsin C heavy chain domain may lead to classical PLS phenotype, suggesting roles for epistasis or gene-environment interactions on determination of PLS phenotypes. | 01 = IsEpi
|
The use of traditional American Joint Committee on Cancer (AJCC) staging alone has limitations in predicting patient survival with nodular melanoma (NM). We aimed to establish a comprehensive prognostic nomogram and compare its prognostic value with the AJCC staging system.A nomogram was constructed to predict the 3-year and 5-year survival rates of NM patients by Cox regression. Several common model-validation parameters were used to evaluate the performance of our survival model.The multivariate analyses demonstrated that the age at diagnosis; being divorced, separated, or widowed; AJCC stages II, III, and IV; a regional SEER stage and the lymph-node density (LND) were risk factors for survival. The concordance index, the area under the time-dependent receiver operating characteristic curve, and calibration plots indicated that the nomogram performed well, while the net reclassification improvement and the integrated discrimination improvement showed that the nomogram performed better than the AJCC staging system. Finally, the decision curve analyses curves of the nomogram yielded net benefits that were higher than when using AJCC staging system with either the training or the validation cohort.The prognostic value of the nomogram is better than that of the AJCC staging system alone. In addition, we found that LND is an important risk factor for the survival of NM patients. The nomogram developed in this study may be a valuable tool for clinical practice when advising patients about their survival risk over the next 3 to 5 years. | 01 = IsEpi
|
OBJECTIVE: Studies on the epidemiology of primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) show variable outcome. We aimed at systematically reviewing the incidence and prevalence rates, as well as geographical distribution and temporal trends of PSC and PBC. DATA SOURCES: A systematic search of literature was performed in Medline and EMBASE (search last conducted January 10th, 2011). STUDY SELECTION: Population-based epidemiological studies reporting incidence and/or prevalence rates for PSC or PBC in a defined geographical area of at least 100,000 adult inhabitants were considered relevant. DATA EXTRACTION: Study area, study period, number of patients, number of inhabitants, incidence per 100,000 inhabitants per year, prevalence per 100,000 inhabitants, method of case-finding, method of case-ascertainment, male/female ratio and in case of PSC, occurrence of inflammatory bowel diseases (IBD) were extracted from retrieved articles. RESULTS: The literature search yielded 2286 abstracts of which 31 articles fulfilled all inclusion criteria. Studies varied in size from 10 to 770 patients in catchment areas from 100,312 to 19,230,000 inhabitants. The incidence and prevalence rates for PSC range from 0 to 1.3 per 100,000 inhabitants/year and 0-16.2 per 100,000 inhabitants, respectively. PBC incidence rates range from 0.33 to 5.8 per 100,000 inhabitants/year and prevalence rates range from 1.91 to 40.2 per 100,000 inhabitants; prevalence rates are increasing in time. CONCLUSIONS: Incidence and prevalence rates of both PSC and PBC vary widely and seem to be increasing. True population-based studies are scarce and therefore large population-based studies combining meticulous case-finding and case-ascertainment strategies are necessary. | 10 = IsNotEpi
|
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. | 01 = IsEpi
|
Cyclic thrombocytopenia is often misdiagnosed as immune thrombocytopenia due to similar clinical features, a fact of significance because cyclic thrombocytopenia generally responds poorly to treatments used successfully in immune thrombocytopenia. A precise diagnosis must establish the statistical significance of periodicity of the platelet counts using statistical methods (eg, Lomb-Scargle periodogram). | 01 = IsEpi
|
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. | 01 = IsEpi
|
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. | 01 = IsEpi
|
Background: We report a unique case of renal cholesterol crystal embolism (CCE) induced by carotid artery stenting that was successfully treated with evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9).Case presentation: A 77-year-old man with hypertension, hyperlipidemia, and chronic kidney disease was referred to our department for decreased estimated glomerular filtration rate (eGFR)-from 32.0 to 13.9 mL/min/1.73 m2-5 weeks after carotid artery stenting. Further examination revealed livedo reticularis in the bilateral toes and eosinophilia (723/μL). Skin biopsy from livedo reticularis tissue in the bilateral toes showed cholesterol clefts in the small arteries. The patient was therefore diagnosed with CCE. After 25 weeks' administration of evolocumab at a dose of 140 mg subcutaneously administered every 2 weeks, his eGFR had improved from 10.7 to 18.1 mL/min/1.73 m2.Conclusion: Evolocumab may have a beneficial effect on renal involvement in patients with CCE. | 01 = IsEpi
|
BACKGROUND:Silver-Russell syndrome (SRS) is characterized by growth failure and dysmorphic features. Major (epi)genetic causes of SRS are loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (upd(7)mat). However, IGF2, CDKN1C, HMGA2, and PLAG1 mutations infrequently cause SRS. In addition, other imprinting disturbances, pathogenic copy number variations (PCNVs), and monogenic disorders sometimes lead to SRS phenotype. This study aimed to clarify the frequency and clinical features of the patients with gene mutations among etiology-unknown patients with SRS phenotype. RESULTS:Multigene sequencing was performed in 92 out of 336 patients referred to us for genetic testing for SRS. The clinical features of the patients were evaluated based on the Netchine-Harbison clinical scoring system. None of the patients showed 11p15 LOM, upd(7)mat, abnormal methylation levels for six differentially methylated regions (DMRs), namely, PLAGL1:alt-TSS-DMR on chromosome 6, KCNQ1OT1:TSS-DMR on chromosome 11, MEG3/DLK1:IG-DMR on chromosome 14, MEG3:TSS-DMR on chromosome 14, SNURF:TSS-DMR on chromosome 15, and GNAS A/B:TSS-DMR on chromosome 20, PCNVs, or maternal uniparental disomy of chromosome 16. Using next-generation sequencing and Sanger sequencing, we screened four SRS-causative genes and 406 genes related to growth failure and/or skeletal dysplasia. We identified four pathogenic or likely pathogenic variants in responsible genes for SRS (4.3%: IGF2 in two patients, CDKN1C, and PLAG1), and five pathogenic variants in causative genes for known genetic syndromes presenting with growth failure (5.4%: IGF1R abnormality (IGF1R), SHORT syndrome (PIK3R1), Floating-Harbor syndrome (SRCAP), Pitt-Hopkins syndrome (TCF4), and Noonan syndrome (PTPN11)). Functional analysis indicated the pathogenicity of the CDKN1C variant. The variants we detected in CDKN1C and PLAG1 were the second and third variants leading to SRS, respectively. Our patients with CDKN1C and PLAG1 variants showed similar phenotypes to previously reported patients. Furthermore, our data confirmed IGF1R abnormality, SHORT syndrome, and Floating-Harbor syndrome are differential diagnoses of SRS because of the shared phenotypes among these syndromes and SRS. On the other hand, the patients with pathogenic variants in causative genes for Pitt-Hopkins syndrome and Noonan syndrome were atypical of these syndromes and showed partial clinical features of SRS. CONCLUSIONS:We identified nine patients (9.8%) with pathogenic or likely pathogenic variants out of 92 etiology-unknown patients with SRS phenotype. This study expands the molecular spectrum of SRS phenotype. | 01 = IsEpi
|
BACKGROUND:The congenital Zika syndrome involves structural brain changes, including ventriculomegaly, thin cerebral cortices, abnormal gyral pattern, cortical malformations, hypoplasia of the corpus callosum, myelination delay, subcortical diffuse calcifications, brainstem hypoplasia, and microcephaly in newborns. OBJECTIVE:This study aimed to describe the clinical characteristics of children with congenital Zika syndrome; to compare the outcomes of infants infected in the first (1T, n=20) and second trimesters of pregnancy (2T, n=11); to investigate correlations between birth weight, birth and follow-up head circumference, birth gestational age, and gross motor scores. METHODS:Participants were evaluated with Alberta Infant Motor Scale (AIMS) and part A of the Gross Motor Function Measure (GMFM-A). ANOVA compared head circumference, birth gestational age, birth weight, and gross motor performance of 1T and 2T. RESULTS:The correlations were investigated by Pearson correlation coefficients. ANOVA showed differences in birth and follow-up head circumferences. Head circumference was smaller in 1T, compared to 2T. Motor performance was classified as below the fifth percentile in AIMS in all children and 1T showed lower scores in prone, sitting, and total AIMS score, compared to 2T. Children ranged from 8 to 78% on GMFM-A and there was a poorer motor performance of 1T. Nineteen children showed hypertonia, six showed normal tone and six showed hypotonia. Birth head circumference was correlated with AIMS prone postural control. Follow-up head circumference was correlated to prone, supine and total AIMS scores. Smaller head circumference at birth and follow-up denoted poorer postural control. DISCUSSION:Children with congenital Zika syndrome showed microcephaly at birth and follow-up. Smaller head circumferences and poorer motor outcomes were observed in 1T. Infants showed poor visual and motor outcomes. Moderate positive correlations between birth and follow-up head circumference and gross motor function were found. | 01 = IsEpi
|
BACKGROUND:Telomeric DNA is typically comprised of G-rich tandem repeat motifs and maintained by telomerase (Greider CW, Blackburn EH; Cell 51:887-898; 1987). In eukaryotes lacking telomerase, a variety of DNA repair and DNA recombination based pathways for telomere maintenance have evolved in organisms normally dependent upon telomerase for telomere elongation (Webb CJ, Wu Y, Zakian VA; Cold Spring Harb Perspect Biol 5:a012666; 2013); collectively called Alternative Lengthening of Telomeres (ALT) pathways. By measuring (TTAGGG) n tract lengths from the same large DNA molecules that were optically mapped, we simultaneously analyzed telomere length dynamics and subtelomere-linked structural changes at a large number of specific subtelomeric loci in the ALT-positive cell lines U2OS, SK-MEL-2 and Saos-2. RESULTS:Our results revealed loci-specific ALT telomere features. For example, while each subtelomere included examples of single molecules with terminal (TTAGGG) n tracts as well as examples of recombinant telomeric single molecules, the ratio of these molecules was subtelomere-specific, ranging from 33:1 (19p) to 1:25 (19q) in U2OS. The Saos-2 cell line shows a similar percentage of recombinant telomeres. The frequency of recombinant subtelomeres of SK-MEL-2 (11%) is about half that of U2OS and Saos-2 (24 and 19% respectively). Terminal (TTAGGG) n tract lengths and heterogeneity levels, the frequencies of telomere signal-free ends, and the frequency and size of retained internal telomere-like sequences (ITSs) at recombinant telomere fusion junctions all varied according to the specific subtelomere involved in a particular cell line. Very large linear extrachromosomal telomere repeat (ECTR) DNA molecules were found in all three cell lines; these are in principle capable of templating synthesis of new long telomere tracts via break-induced repair (BIR) long-tract DNA synthesis mechanisms and contributing to the very long telomere tract length and heterogeneity characteristic of ALT cells. Many of longest telomere tracts (both end-telomeres and linear ECTRs) displayed punctate CRISPR/Cas9-dependent (TTAGGG) n labeling patterns indicative of interspersion of stretches of non-canonical telomere repeats. CONCLUSION:Identifying individual subtelomeres and characterizing linked telomere (TTAGGG) n tract lengths and structural changes using our new single-molecule methodologies reveals the structural consequences of telomere damage, repair and recombination mechanisms in human ALT cells in unprecedented molecular detail and significant differences in different ALT-positive cell lines. | 01 = IsEpi
|
BACKGROUND:Few manuscripts have reported phenotypes of skeletal muscle myopathies caused by mutations in the head region of slow/cardiac beta-myosin heavy chain (MyHCI). Among the patients, some of them showed the phenotype of skeletal muscle weakness with the obvious clinical features of cardiomyopathy while others showed pure skeletal muscle weakness with no symptoms of cardiac involvement. Genotype-phenotype relationship regarding the effect of a mutation on MyHCI is complex. Questions regarding why some mutations cause cardiomyopathy or skeletal muscle disorders alone or a combination of both still need to be answered. More findings in genetic variation are needed to extend knowledge of mutations in the MYH7 gene linked to skeletal muscle disorders. CASE PRESENTATION:Here we present a female adult patient with a phenotype of childhood onset of muscular disorders and predominant involvement of thigh muscles with biopsy showing intrasarcoplasmic inclusion bodies. Whole exome sequencing showed that variant c.1370 T > G (p.Ile457Arg) in the MYH7 gene is a missense mutation possibly linked to the clinical findings. Our patient likely shows an uncharacteristic myosin storage myopathy associated with respiratory and cardiac involvement linked to a missense mutation in the head of MyHCI. CONCLUSIONS:Given this mutation is located within the motor domain of MyHCI, this might affect the regulation of myosin mechano-chemical activity during the contractile cycle. Consequently, this potentially damaging effect can be easily amplified within the network of ~ 300-myosin molecules forming the thick filament and therefore become cumulatively deleterious, affecting, in turn, the overall organization and performance of sarcomere. | 01 = IsEpi
|
Increased blood ammonium concentrations cause neurological complications. Existing drugs are not always sufficiently effective. Alternatively, erythrocytes-bioreactors (EBRs) loaded with enzymes utilizing ammonium, were suggested for ammonium removal from blood. However all they worked only for a short period of time. The reasons for this were not investigated. In this study, EBR mathematical models were developed and analysed based on the reactions of glycolysis and different enzymes utilizing ammonium, which showed that the efficiency and duration of EBRs' functioning could be limited due to low permeability of the cell membrane for some key substrates and products. A new enzyme system including glutamate dehydrogenase and alanine aminotransferase was proposed and realised experimentally, which was not limited by cell membrane permeability for glutamate and α-ketoglutarate due to creating metabolic pathway where these metabolites were produced and consumed cyclically. New bioreactors removed ammonium in vitro at the rate of 1.5 mmol/h × lRBCs (for human bioreactors) and in vivo in a model of hyperammoniemia in mice at the rate of 2.0 mmol/h × lRBCs (for mouse bioreactors), which correlated with model calculations. Experimental studies proved the proposed mathematical models are correct. Mathematical simulation of erythrocyte-bioreactors opens new opportunities for analysing the efficiency of any enzyme included in erythrocytes. | 01 = IsEpi
|
We describe an adult case of radiation-induced meningioma(RIM)that was identified within a short interval from the initial treatment for brain tumor. A 45-year-old woman, who had tumor resection followed by radiation therapy for right frontal oligodendroglioma, showed a small enhanced lesion on the right frontal region 3 years and 6 months after the initial radiation therapy. The pathological diagnosis was meningioma(World Health Organization(WHO)grade I)and the Ki-67 labeling index was 3.2%. Most RIMs occur after a long period of time(18.7-24.0 years on average)following radiation therapy. Several studies have suggested that the period before the occurrence of RIM is correlated with both the age of a patient and the radiation dose at the time of radiation therapy. A patient that receives a higher dose of radiation at a younger age has a higher risk of RIM occurrence. In this case, the patient was middle aged;however, she was exposed to a high dose of radiation(54 Gy). High-dose radiation might induce the early onset of RIM. Recently, treatments for glioma have been developed, thus resulting in an increased long-term survival rate among patients. Physicians must pay attention not only to the recurrence of gliomas but also to the occurrence of RIMs. | 01 = IsEpi
|
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. | 01 = IsEpi
|
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. | 01 = IsEpi
|
BACKGROUND:Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive lysosomal lipid storage disorder that results in an early-onset, severe, and lethal phenotype, known as Wolman disease, or a late-onset, attenuated phenotype, cholesteryl ester storage disease (CESD). The aim of our study was to describe the clinical presentation of CESD, focusing on the first noted abnormalities in patients. A diagnostic algorithm of CESD was also proposed. METHODS:This is an observational, 1-center study of 19 Polish patients with late-onset LAL-D. RESULTS:The mean age at which the first symptoms were reported was 4 years and 6 months. A mild hepatomegaly was the most common initial abnormality observed in all (100%) patients. Seven (37%) patients were noted to have mildly to moderately elevated serum transaminases. At the time of first hospitalization all (100%) patients presented with hepatomegaly, 15 (79%) patients presented with elevated serum transaminases and all (100%) patients had dyslipidemia. The mean age at the time of CESD diagnosis was 7 years and 2 months. Diagnoses were based on a deficient LAL activity in leukocytes (in all patients) and the LIPA gene mutations (in 47% of them). All the patients were carriers for the mutation c.894G>A in the LIPA gene. There was approximately a 3-year delay from initial symptoms to final diagnosis. CONCLUSIONS:Hepatomegaly constitutes the most common presenting clinical sign of CESD. Hepatomegaly and dyslipidemia defined as elevated serum total and LDL cholesterol, elevated triglycerides and normal to low HDL cholesterol, comprises the most characteristic findings at CESD diagnosis. | 01 = IsEpi
|