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Background:Congenital anomalies of the kidney and urinary tract (CAKUT) constitute 20-30% of all congenital malformations. Within the CAKUT phenotypic spectrum, renal hypodysplasia (RHD) is particularly severe. This study aimed to evaluate the applicability of single-nucleotide polymorphism (SNP) array test in prenatal diagnosis of RHD for improving prenatal genetic counseling and to search for evidence of a possible causative role of copy-number variations (CNVs) in RHD. Results:We performed a systematic survey of CNV burden in 120 fetuses with RHD: 103 cases were isolated RHD and 17 were non-isolated RHD. Single-nucleotide polymorphism (SNP) array test was performed using the Affymetrix CytoScan HD platform. All annotated CNVs were validated by fluorescence in situ hybridization. We identified abnormal CNVs in 15 (12.5%) cases of RHD; of these CNVs, 11 were pathogenic and 4 were variants of uncertain significance. The detection rate of abnormal CNVs in non-isolated RHD was higher (29.4%, 5/17) than that in isolated RHD (9.7%, 10/103) (P = 0.060). Parents are more inclined to terminate the pregnancy if the fetuses have pathogenic results of the SNP-array test. Conclusions:The variable phenotypes that abnormal CNVs may cause indicate the genetic counseling is needed for RHD cases. | 01 = IsEpi
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BACKGROUND:Woven coronary artery (WCA) is an extremely rare congenital anomaly in which a part of epicardial coronary artery is divided into thin channels, that twist along the axis of the coronary arteries and then merge again as the main coronary lumen. This anomaly is regarded as a benign condition because the blood flow is normal. Very few cases of WCA have been reported. CASE PRESENTATION:Herein we report a case of a 44-year-old man who was admitted to our hospital due to 20 years of repeated episodes of heart palpitations, 2 years of shortness of breath after activity, and the symptoms were aggravated for 1 month. He had history of inferior myocardial infarction and atrial fibrillation. Color Doppler echocardiography revealed rheumatic heart disease, severe mitral regurgitation, mild-moderate tricuspid regurgitation, moderate pulmonary hypertension. Coronary angiography revealed 60-85% diffuse stenosis in the middle of left anterior descending artery, 60-90% diffuse stenosis in the middle of left circumflex artery, 30-40% diffuse stenosis in the proximal segment of right coronary artery, and WCA anomaly in the middle, and distal segments of right coronary artery. CONCLUSION:The patient successfully underwent prosthetic valve replacement and left anterior descending coronary artery bypass grafting, and had a good recovery after surgery. Further studies are needed to fully understand the disease and determine appropriate treatment options. | 01 = IsEpi
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The term congenital hypopigmentary disorders refers to a wide group of heterogeneous hereditary diseases, clinically characterized by inborn pigmentary defects of the iris, hair, and/or skin. They include Gray Hair Syndromes (GHSs), a rare group of autosomal recessive genodermatosis hallmarked by inborn silvery gray hair. GHSs encompass Griscelli, Chediak⁻Higashi, Elejalde, and Cross syndromes, which are all characterized by a broad spectrum of severe multisystem disorders, including neurological, ocular, skeletal, and immune system impairment. In this manuscript, we describe in detail the clinical, trichoscopic, and genetic features of a rare case of Griscelli syndrome; moreover, we provide an overview of all the GHSs known to date. Our report highlights how an accurate clinical examination with noninvasive methods, like trichoscopy, may play a crucial rule in diagnosis of rare and potentially lethal genetic syndromes such as Griscelli syndrome, in which timely diagnosis and therapy may modify the clinical course, quality of life, and likelihood of survival. | 01 = IsEpi
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Protein tyrosine kinases have been recognized as important actors of cell transformation and cancer progression, since their discovery as products of viral oncogenes. SRC-family kinases (SFKs) play crucial roles in normal hematopoiesis. Not surprisingly, they are hyperactivated and are essential for membrane receptor downstream signaling in hematological malignancies such as acute myeloid leukemia (AML) and mastocytosis. The precise roles of SFKs are difficult to delineate due to the number of substrates, the functional redundancy among members, and the use of tools that are not selective. Yet, a large num ber of studies have accumulated evidence to support that SFKs are rational therapeutic targets in AML and mastocytosis. These two pathologies are regulated by two related receptor tyrosine kinases, which are well known in the field of hematology: FLT3 and KIT. FLT3 is one of the most frequently mutated genes in AML, while KIT oncogenic mutations occur in 80-90% of mastocytosis. Studies on oncogenic FLT3 and KIT signaling have shed light on specific roles for members of the SFK family. This review highlights the central roles of SFKs in AML and mastocytosis, and their interconnection with FLT3 and KIT oncoproteins. | 01 = IsEpi
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We describe a patient with thrombocytopenia-absent radius (TAR) syndrome, multisystemic Langerhans cell histiocytosis and multiple reticulohistiocytomas. A mutational study by massive sequencing identified the Val600Glu (V600E) BRAF mutation in the Langerhans cell histiocytosis lesions, but no molecular alterations were found in the reticulohistiocytoma lesions. The concomitant presence in the same patient of more than one type of histiocytosis from two different groups recognized in the most recent Histiocyte Society classification is an extremely rare event. Our case is the first reported case of multisystemic Langerhans cell histiocytosis and multiple reticulohistiocytomas in a patient with TAR syndrome. | 01 = IsEpi
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Objective: To compare and analyze the curative effect of three surgical methods in the treatment of small intestine atresia, and to provide evidence for individualized surgical treatment of children with small intestine atresia. Methods: The clinical diagnosis and treatment of 168 children with small intestine Ⅱ, Ⅲ, Ⅳ type atresia in our hospital from January 2008 to September 2017 were retrospectively analyzed and they were divided into different types according to the operation. The three groups were end-to-end anastomosis group (EEA, n=58), end oblique anastomosis group (EOA, n=68), and proximal end-end anastomosis group (PEA, n=42). The EEA group and the EOA group were further divided into group a (EEA-a/EOA-a) with a proximal intestinal tube diameter greater than 4.0 times the distal end and a group b ((EEA-b/EOA-b) with a diameter less than or equal to 4.0 times the distal intestinal tube diameter. The gender, gestational age, birth weight, type of atresia, and postoperative defecation time, postoperative feeding time, postoperative hospital stay and postoperative follow-up complications were compared. Results: There was no significant difference in gender, gestational age and birth weight between the groups (P>0.05). The PEA group was better than EEA-a group and EOA-a group in postoperative defecation time, postoperative feeding time, postoperative hospital stay and complications (P<0.05). The postoperative defecation time, postoperative feeding time, postoperative hospital stay and complications of the EOA-a group were better than those of the EEA-a group (P<0.05). There was no statistically significant difference in postoperative defecation time, postoperative feeding time, and complications between the EEA-b group and the EOA-b group (P>0.05), but the postoperative hospital stay in the EEA-b group was longer than that in the EOA-b group (P<0.05). Conclusion: PEA is recommended for children with a proximal intestinal canal diameter greater than 4.0 times greater than the distal end because of the rapid recovery and fewer complications; EOA is recommended for children with a proximal intestinal canal diameter of 4.0 or less because of its advantage of shorter hospital stay than EEA surgery. Congenital intestinal atresia has a better effect according to the specific conditions of the child. | 01 = IsEpi
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Nephronophthisis-related ciliopathies (NPHP-RC) are a group of inherited diseases that affect genes encoding proteins that localize to primary cilia or centrosomes. With few exceptions, ciliopathies are inherited in an autosomal recessive manner, and affected individuals manifest early during childhood or adolescence. NPHP-RC are genetically very heterogeneous, and, currently, mutations in more than 90 genes have been described as single-gene causes. The phenotypes of NPHP-RC are very diverse, and include cystic-fibrotic kidney disease, brain developmental defects, retinal degeneration, skeletal deformities, facial dimorphism, and, in some cases, laterality defects, and congenital heart disease. Mutations in the same gene can give rise to diverse phenotypes depending on the mutated allele. At the same time, there is broad phenotypic overlap between different monogenic genes. The identification of monogenic causes of ciliopathies has furthered the understanding of molecular mechanism and cellular pathways involved in the pathogenesis. | 01 = IsEpi
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Tyrosinemia type II is a genetic disorder characterized by elevated blood levels of the amino acid tyrosine caused by the deficiency of tyrosine aminotransferase enzyme, resulting in neurologic and developmental difficulties in the patients. Although neurological sequelae are common in Tyrosinemia type II patients, the mechanisms involved are still poorly understood. The oxidative stress appears to be, at least in part, responsible for neurological complication in this inborn error metabolism. We observed that an acute injection of tyrosine in rats caused a massive oxidative stress in different brain structures. The glutathione system and superoxide dismutase enzyme are relevant antioxidant strategies of the cells and tissues, including in the brain. Other important point is the strong relation between oxidative damage and inflammatory events. Herein, we investigated the effects of chronic administration of tyrosine in the hippocampus of young rats, with emphasis in the activity of GSH related enzymes and superoxide dismutase enzyme, and the astrocytosis. We observed that rats exposed to high levels of tyrosine presented an increased content of tyrosine, which was associated with an increment in the activity of glutathione peroxidase and glutathione reductase as well as with a diminished activity of superoxide dismutase. This antioxidant imbalance was accompanied by enhanced glial fibrillary acidic protein immunoreactivity, a marker of astrocytes, in the brain area studied. In conclusion, hippocampus astrogliosis is also a characteristic of brain alteration in Tyrosinemia. In addition, the chronic exposition to high levels of tyrosine is associated with an alteration in the activity of fundamental antioxidant enzymes. | 01 = IsEpi
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Gordon syndrome is a rare inherited monogenic form of hypertension, which is associated with hyperkalaemia and metabolic acidosis. Since the recognition of this predominantly autosomal dominant condition in the 1960s, the study of families with Gordon syndrome has revealed four genes WNK1, WNK4, KLHL3, and CUL3 to be implicated in its pathogenesis after a phenotype-genotype correlation was realised. The encoded proteins Kelch-like 3 and Cullin 3 interact to form a ring-like complex to ubiquitinate WNK-kinase 4, which, in normal circumstances, interacts with the sodium chloride co-symporter (NCC), the epithelial sodium channel (ENaC), and the renal outer medullary potassium channel (ROMK) in an inhibitory manner to maintain normokalaemia and normotension. WNK-kinase 1 has an inhibitory action on WNK-kinase 4. Mutations in WNK1, WNK4, KLHL3, and CUL3 all result in the accumulation of WNK-kinase 4 and subsequent hypertension, hyperkalaemia, and metabolic acidosis. This review explains the clinical aspects, disease mechanisms, and molecular genetics of Gordon syndrome. | 01 = IsEpi
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Primary Whipple disease of the Central Nervous System is a rare entity whose outcome might be fatal if not promptly diagnosed and treated. Few cases are reported in the literature with heterogeneous clinical and radiological presentations which often make the diagnosis extremely challenging. We report a case of primary Whipple disease of the Central Nervous System presenting with rhombencephalitis in a female patient in immunosuppressive treatment for rheumatoid arthritis. We describe the management of our patient and discuss the features of this rare clinical entity. | 01 = IsEpi
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BACKGROUND:Mutations of human androgen receptor (AR) gene are responsible for androgen insensitivity syndrome (AIS). Variable phenotypes and androgen receptor binding activity have permitted the classification of AIS into complete (CAIS), partial (PAIS), and minimal or mild (MAIS) forms. Somatic mosaicism in AIS is a rare condition which happened when de novo mutations occur after the zygotic stage. METHODS:Clinical evaluation, hormone measurements, and molecular analysis were performed to diagnose the patient in the study. RESULTS:A 46, XY girl who conceived through in vitro fertilization (IVF), presented with partial virilization of external genitalia, was found to have the p.C620R in heterozygosity. The variant p.C620R of AR has been previously reported in a patient with completely feminized external genitalia, which was inherited from the heterozygote carrier mother. Mutation analysis of the mother of our patient revealed that the variant was de novo and presented as a somatic mosaicism which indicated an insufficient amount of wild-type AR in our patient. CONCLUSION:This is the first case that AIS was caused by de novo mutation of AR in a 46, XY Disorder of Sexual Development (DSD) patient by the assisted reproduction technique (ART). The phenotype of partial virilization could be explained by AR mutation in somatic mosaicism. | 01 = IsEpi
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We report on a child with bilateral anophthalmia, esophageal atresia, and cryptorchidism. This is the first case observed in the Spanish Collaborative Study of Congenital Malformations (ECEMC) with this constellation of congenital anomalies, and it is similar to that described in 1988 by Rogers. We think that it may constitute a new syndrome. | 01 = IsEpi
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PURPOSE:To investigate complex and different phenotypes in seven Chinese patients diagnosed with Bardet-Biedl syndrome (BBS) and carrying pathogenic mutations. METHODS:Seven unrelated BBS patients were enrolled. Their medical and ophthalmic histories were reviewed, and comprehensive clinical examinations, such as fundus photography, optical coherence tomography, and medical imaging, were performed. A specific hereditary eye disease enrichment panel based on exome-capture technology was used to collect and amplify the protein-coding regions of 441 targeted hereditary eye disease genes, followed by high-throughput sequencing using the Illumina HiSeq platform. RESULTS:All patients exhibited the primary clinical phenotype of BBS. Seven BBS mutations were found in five patients (BBS7 in two patients, BBS10 in two patients, BBS12 in one patient), for a detection rate of 71% (5/7). The ratio of novel to known BBS mutations was 5:2. CONCLUSIONS:This study showed the phenotypic and genotypic spectrum of BBS patients from China, and the findings underscore the importance of obtaining comprehensive clinical observations and molecular analyses for ciliopathies. | 01 = IsEpi
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Mouse models have greatly helped in elucidating the molecular mechanisms involved in hair formation and regeneration. Recent publications have reviewed the genes involved in mouse hair development based on the phenotype of transgenic, knockout and mutant animal models. While much of this information has been instrumental in determining molecular aspects of human hair development and cycling, mice exhibit a specific pattern of hair morphogenesis and hair distribution throughout the body that cannot be directly correlated to human hair. In this mini-review, we discuss specific aspects of human hair follicle development and present an up-to-date summary of human genetic disorders associated with abnormalities in hair follicle morphogenesis, structure or regeneration. | 01 = IsEpi
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Stenotrophomonas maltophilia (S. maltophilia) is an important nosocomial bacterial pathogen. However, the clinical features of children with S. maltophilia infection, the predisposing factors, and the antibiotic susceptibility of the bacteria have not been fully evaluated.In this study, the data of children with S. maltophilia infection from the West China Second University Hospital of Sichuan University (Chengdu, China) between July 2010 and October 2017 were collected and analyzed. The clinical features of enrolled children, the predisposing factors, and the antibiotic susceptibility were reported.In total, infection of S. maltophilia was identified in 128 patients. Most of these patients were under 1 year old (67.2%) and were mainly diagnosed as pneumonia (69%). A large proportion had underlying diseases (45.3%), received immunosuppressive therapy (53.1%), had undergone invasive operations (41.4%), had a history of carbapenem antibiotics use within 7 days before culture acquisition (54.7%), history of intensive care unit (ICU) hospitalization within previous 30 days (34.4%), and other risk factors. In particular, invasive operation (95% confidence interval [CI]: 1.125-14.324, P = .032), especially mechanical ventilation (95% CI: 1.277-20.469, P = .021), and ICU admission (95% CI: 1.743-22.956, P = .005) were independent risk factors for the children to develop severe S. maltophilia infection. As for antibiotic susceptibility, trimethoprim sulfamethoxazole (TMP-SMX), piperacillin tazobactam, ticarcillin clavulanate, and ceftazidime exhibited strong antibacterial activities against S. maltophilia, the susceptibility rates were 97.5%, 86.7%, 92.9%, and 81.5%, respectively.We report the clinical features of children with S. maltophilia infection, the predisposing factors and the antibiotic susceptibility. TMP-SMX can continue to be the first choice for the treatment of S. maltophilia infection. Piperacillin tazobactam, ticarcillin clavulanate, and the third generation cephalosporins can be used as alternative drugs. | 01 = IsEpi
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Thiamine metabolism dysfunction syndrome (THMD) comprises a group of clinically and genetically heterogeneous encephalopathies with autosomal recessive inheritance. Four genes, SLC19A3, SLC25A19, SLC19A2, and TPK1, are associated with this disorder. This study aimed to explore the clinical, biochemical and molecular characteristics of seven Chinese patients with THMD. Targeted next-generation sequencing of mitochondrial DNA and nuclear DNA was used to identify the causative mutations. The patients presented with subacute encephalopathy between the ages of 1-27 months. Brain magnetic resonance imaging (MRI) revealed abnormalities in the basal ganglia, indicating Leigh syndrome. Urine α-ketoglutarate in five patients was elevated. In four patients, five novel mutations (c.1276_1278delTAC, c.265A > C, c.197T > C, c.850T > C, whole gene deletion) were found in SLC19A3, which is associated with THMD2. In two patients, four novel mutations (c.194C > T, c.454C > A, c.481G > A, and c.550G > C) were identified in SLC25A19, supporting a diagnosis of THMD4. In one patient, two novel mutations (c.395T > C and c.614-1G > A) were detected in TPK1, which is indicative of THMD5. The patients received thiamine, biotin, and symptomatic therapy, upon which six patients demonstrated clinical improvement. Our findings expanded the phenotypic and genotypic spectrum of THMD, with eleven novel mutations identified in seven Chinese patients. Early diagnosis and treatment have a significant impact on prognosis. | 01 = IsEpi
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A case of a baby born preterm with an antenatal diagnosis of aortic coarctation for which prostin was electively started at birth. The baby was found to be profoundly anaemic with no clear obstetric cause. Features consistent with antenatal intracerebral haemorrhage were noted on cranial ultrasonography in the context of severe coagulopathy, prompting investigations which confirmed fetal-maternal haemorrhage. It transpired that, following aortic and mitral valve replacements, the mother was anticoagulated with warfarin at conception, having misunderstood her cardiologist's advice that: 'you cannot get pregnant whilst on warfarin'. Following conversion to low molecular weight heparin, she suffered a stroke, thus warfarin was restarted, with an international normalised ratio of 3-4.7 during pregnancy. Following transfer to the paediatric intensive care unit, fetal warfarin syndrome was diagnosed. The coagulopathy and anaemia were corrected and aortic coarctation was excluded. The baby returned to the neonatal intensive care unit for ongoing care and was discharged home in good condition around his due date. At the present time, there is no clinically overt neurological deficit. | 01 = IsEpi
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Purpose:To report the outcomes of pars-plana approach for the management of brunescent cataract in eyes with severe microcornea and associated chorio-retinal coloboma. Methods:This was a retrospective, single center, interventional case series performed in a tertiary eyecare center in central Medical records of consecutive cases of microcornea with coloboma who underwent pars-plana vitrectomy with phacofragmentation (PF) between January 2015 and December 2017 were reviewed. Results:The study group comprised of 30 eyes of 30 patients, of which 18 (60%) were males and 12 (40%) were females. The mean age of the patients was 41.9 years (range of 17-70 years). The mean corneal diameter was 6.7 mm with a range of 4-8 mm and all the eyes had dense cataract with nuclear sclerosis of grade 4 or more. The mean preoperative visual acuity was 1.97 (+/-0.067) Log MAR and the mean postoperative vision at 1 month was 1.6 (+/-0.39) Log MAR. Postoperatively, 21 patients (70%) gained ambulatory vision. The visual gain in all the patients was maintained over a mean follow-up period of 15.5 months. Conclusion:Pars-plana vitrectomy with PF can be considered in eyes with severe microcornea and brunescent cataracts, where cataract surgery through the limbal (anterior) approach is not only difficult but at times impossible due to anatomical restraints. | 01 = IsEpi
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Two patients with auditory neuropathy spectrum disorder (ANSD) considered to be associated with Charcot-Marie-Tooth (CMT) are reported. In case 1, a 23-year-old man presented with progressive bilateral sensorineural hearing loss (SNHL) from 10 years of age and was diagnosed with ANSD. He was later diagnosed with CMT by neurological testing. In case 2, a 16-year-old girl, the younger sister of the patient in case 1, presented with progressive SNHL with similar auditory findings since 6 years of age as those of her brother. Both cases underwent bilateral cochlear implantation. In case 1, the maximum discrimination score improved to 45% 24 months after the first side of cochlear implantation from 5% before the surgery. In case 2, the score was 5% 10 months after cochlear implant (CI) surgery from 0% before the surgery. CI treatment for CMT patients has been considered difficult because of both failure in synchronization of nerve conduction due to demyelination and axonal failure of the auditory nerve. Though slower progress compared to the average subset of patients receiving CI was seen, significant improvement was gradually observed in the present patients after bilateral cochlear implantations. CI is thus a viable option for rehabilitation of SNHL in CMT patients. | 01 = IsEpi
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Varicella-zoster virus (VZV) is a teratogen that can cross the placenta and cause the congenital varicella syndrome (CVS), which is characterised by multi-system anomalies. There have been 130 reported cases of CVS from 1947 to 2013. The estimated incidence of CVS was 0.59% and 0.84% for women infected with VZV during the entire pregnancy and for those infected the first 20 weeks of pregnancy, respectively. Nine cases were reported at 21-27 weeks of gestation and one case was identified at 36 weeks. Herpes zoster caused CVS in two cases. Regarding treatment, varicella zoster immunoglobulin treatment, irrespective of gestational age, should be considered in addition to antiviral drugs for women who have been exposed to or infected with virus. | 10 = IsNotEpi
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BACKGROUND:Arthrogryposis-Renal dysfunction-Cholestasis syndrome (ARC, MIM#208085) is a rare multisystem disease due to mutations in the VPS33B and VIPAR genes, both involved in maintaining apical-basolateral cell polarity. The correlation between mutations and phenotype in the ARC Syndrome is not well described. We report on a 6 year old patient who presented with severe renal Fanconi as first manifestation of ARC related to a combined de novo mutation in the VPS33B gene. CASE PRESENTATION:A 6 year old girl presented during the first year of life with severe renal Fanconi as the first manifestation of ARC-Syndrome. This case presents all defining features of ARC syndrome (including liver, skin and articular manifestations) with predominantly renal impairment at presentation. This novel mutation may be associated with a pronounced renal phenotype in ARC. Furthermore, we report on the successful use of LDL-Apheresis and biliodigestive derivation for treatment of cholestatic pruritus with encouraging results. CONCLUSION:ARC is a heterogeneous disorder with early mortality. This case report contributes to a better understanding of this rare disorder, describes a novel mutation in the VPS33B gene and presents an innovative rescue treatment approach. | 01 = IsEpi
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Testicular neuroendocrine tumors, commonly called carcinoid, are extremely rare and account for less than 1% of all testicular neoplasms. The most common type is primary carcinoid followed by testicular metastasis from another primary and rarely carcinoid within a testicular teratoma. To date, less than 25 cases of carcinoid associated teratomas have been reported in the literature. Herein, we present a unique case of testicular carcinoid tumor arising in association with mature teratoma in a patient with contralateral classic seminoma. | 01 = IsEpi
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Delayed neutrophil engraftment (NE) has been reported in cord blood transplantation (CBT) compared with other stem cell transplantation methods. The numbers of total nucleated cells (TNCs), CD34+ cells (generally ≥ 1 × 105/kg), and granulocyte/macrophage colony-forming units (CFU-GM) significantly impact NE. Splenomegaly exerts negative effects on NE, but the appropriate cell dose for the patients with splenomegaly has not yet been determined, especially in CBT. We retrospectively investigated the effect of splenomegaly and number of CD34+ cells infused on NE through the analysis of outcomes of 502 consecutive patients who underwent single CBT for the first time at Toranomon Hospital between 2011 and 2018. Spleen index, Lmax × Hvert (SI Lmax × Hvert), was defined as maximal length at any transverse section, (Lmax) × vertical height (Hvert), and splenomegaly was defined as SI Lmax × Hvert ≥ 115 cm2. Our results show that splenomegaly (hazard ratio [HR], .60; P < .01) and low dose of infused CD34+ cells (HR, .58; P < .01) had significant negative impact on NE, whereas neither CFU-GM dose nor TNC dose had any impact on NE in multivariate analysis. Other factors with a significant negative impact on NE in multivariate analysis were myeloid disease (HR, .62; P < .01), nonremission status at CBT (HR, .71; P < .01), low Eastern Cooperative Oncology Group Performance Status (HR, .68; P < .01), and graft-versus-host disease prophylaxis (other than tacrolimus alone) (HR, .76; P < .01). Without splenomegaly, even patients infused with < .8 × 105/kg CD34+ cells achieved up to 94.3% NE, with the median value observed at 21 days post-CBT. This study shows that splenomegaly has a significant negative impact on NE after CBT. Cord blood units with < .8 × 105/kg CD34+ cells may still be a suitable choice for patients without splenomegaly. | 01 = IsEpi
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Trigeminal trophic syndrome (TTS) is a rare condition in which there is the involvement of the skin innervated by branches of the trigeminal nerve. Because of an alteration in the sensory function of the trigeminal nerve, an exaggerated manipulation of the skin by the patient occurs, with secondary ulcers in the affected areas. They are usually unilateral and located mainly at the beginning of the nose wing. There are very few publications in the current literature, so it is in the interest of doctors to know this rare pathology. | 01 = IsEpi
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Heterozygous mutations in the gene encoding fibroblast growth factor 10 (FGF10) or its cognate receptor, FGF-receptor 2 IIIb result in two human syndromes - LADD (lacrimo-auriculo-dento-digital) and ALSG (aplasia of lacrimal and salivary glands). To date, the partial loss-of-FGF10 function in these patients has been attributed solely to perturbed paracrine signalling functions between FGF10-producing mesenchymal cells and FGF10-responsive epithelial cells. However, the functioning of a LADD-causing G138E FGF10 mutation, which falls outside its receptor interaction interface, has remained enigmatic. In the present study, we interrogated this mutation in the context of FGF10's protein sequence and three-dimensional structure, and followed the subcellular fate of tagged proteins containing this or other combinatorial FGF10 mutations, in vitro We report that FGF10 harbours two putative nuclear localization sequences (NLSs), termed NLS1 and NLS2, which individually or co-operatively promote nuclear translocation of FGF10. Furthermore, FGF10 localizes to a subset of dense fibrillar components of the nucleolus. G138E falls within NLS1 and abrogates FGF10's nuclear translocation whilst attenuating its progression along the secretory pathway. Our findings suggest that in addition to its paracrine roles, FGF10 may normally play intracrine role/s within FGF10-producing cells. Thus, G138E may disrupt both paracrine and intracrine function/s of FGF10 through attenuated secretion and nuclear translocation, respectively. | 01 = IsEpi
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Gray platelet syndrome (GPS) is a rare (<1/1 000 000) and inherited platelet function disorder characterized by macrothrombocytopenia, α-granule deficiency, and hemorrhages. Bleeding intensity does not correlate with platelet count nor with functional test results. We hereby describe the perioperative bleeding prevention and management of a patient with GPS requiring multiple redo cardiac surgeries. | 01 = IsEpi
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We describe 27 individuals of 7 families related to each other with high probability who showed manifestations of ectodermal dysplasia and other anomalies affecting females as severely as males with variable expressivity. All parents were normal. These families were detected in a relatively isolated and inbred population with very small neighbouring communities from a Caribbean Sea island, Margarita Island, in Northeastern Venezuela (Nueva Esparta State). The clinical picture common to all patients could not be classified within the heterogeneous group of known ectodermal dysplasias and the published cases do not resemble our patients. We believe that this condition constitutes a newly recognized autosomal recessive dysplasia/malformation syndrome of ectodermal dysplasia. | 01 = IsEpi
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We report two sibs with features overlapping those of orofaciodigital syndrome type VI (Varadi syndrome). Both presented at birth with oculomotor abnormalities, dysmorphic facial features, and dysgenesis of the cerebellar vermis. There were minimal oral manifestations (high arched palate) in both of them and one had postaxial polydactyly of both hands and one foot. In addition, there was evidence of aplasia of the pituitary gland on MRI scan in both of them with evidence of hypopituitarism. Both responded well to hormone replacement therapy with improvement in their linear growth and mental ability. These cases may represent a new autosomal recessive midline defect syndrome with features overlapping OFDS VI. Alternatively the features in these children could represent variability within OFDS VI. | 01 = IsEpi
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Purpose:To describe the diagnosis and management of a patient with rupture of the posterior capsule (PC) following blunt trauma to the left eye. Observation:68 year-old man presented with complaints of left eye pain, blurry vision and photophobia after getting hit in the left eye with a baseball. He was found to have a posterior capsule rupture, as well as mydriasis and zonular dialysis without formation of intumescent traumatic cataract. Femtosecond laser associated cataract surgery (FLACS) was performed to facilitate creation of an anterior capsulotomy and segmentation of the nucleus without additional strain on the posterior capsule, facilitating placement of a capsular tension ring segment and a 3-piece IOL in the sulcus. At three-month post-operative visit, his BCVA was 20/30 in the left eye with a well-centered IOL. Conclusions and Importance:Isolated PC tear following high-speed blunt trauma is relatively rare and prior reports have managed these cases using standard phacoemulsification and IOL insertion. Our case highlights the advantages of using FLACS in management of traumatic PC tears and outlines modifications to this technique for such cases. | 01 = IsEpi
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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
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Recovery from alopecia is rare in autoimmune polyglandular syndrome (APS). A 41-year-old male was admitted to our hospital with hyperglycemia. He developed alopecia areata (AA) 5 months before admission and developed thirst, polyuria, and anorexia in 2 weeks. His plasma glucose level upon admission was 912 mg/dl (50.63 mmol/l) and HbA1c was 13.7%. Although urinary and plasma C-peptide levels showed that insulin secretion was not depleted, anti-insulinoma-associated antigen 2 antibody was present. In addition, measurement of thyroid autoantibodies revealed the presence of Hashimoto's thyroiditis. These findings suggested a diagnosis of APS type 3. The patient has showed signs of improvement with the continuation of insulin therapy. During the successful control of diabetes, he had total hair regrowth within 2-3 months. Human leukocyte antigen typing showed that DRB1*1501-DQB1*0602 and DQB1*0301 were present. Similar cases should be accumulated to clarify the association of APS type 3 with recovery from AA.Alopecia in diabetic patients is a suspicious manifestation of autoimmune type 1 diabetes.Patients with autoimmune type 1 diabetes specifically manifesting alopecia should be further examined for diagnosis of APS.Insulin-mediated metabolic improvement may be a factor, but not the sole factor, determining a favorable outcome of alopecia in patients with autoimmune type 1 diabetes. | 01 = IsEpi
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Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare neonatal disorder that is caused by alloimmunization against platelet antigens during pregnancy. Although rare, affecting only 1 in 1000 live births, it can cause intracranial hemorrhage and other bleeding complications that can lead to miscarriage, stillbirth and life-long neurological complications. One of the gold-standard therapies for at risk pregnancies is the administration of IVIg. Although IVIg has been used in a variety of different disorders for over 40 years, its exact mechanism of action is still unknown. In FNAIT, the majority of its therapeutic effect is thought the be mediated through the neonatal Fc receptor, however other mechanisms cannot be excluded. Due to safety, supply and other concerns that are associated with IVIg use, alternative therapies that could replace IVIg are additionally being investigated. This includes the possibility of a prophylaxis regimen for FNAIT, similarly to what has been successfully used in hemolytic disease of the fetus and newborn for over 50 years. | 01 = IsEpi
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Nuclear receptor coactivators (NCOAs) and corepressors (NCORs) bind to nuclear hormone receptors in a ligand-dependent manner and mediate the transcriptional activation or repression of the downstream target genes in response to hormones, metabolites, xenobiotics, and drugs. NCOAs and NCORs are widely expressed in the mammalian brain. Studies using genetic animal models started to reveal pivotal roles of NCOAs/NCORs in the brain in regulating hormonal signaling, sexual behaviors, consummatory behaviors, exploratory and locomotor behaviors, moods, learning, and memory. Genetic variants of NCOAs or NCORs have begun to emerge from human patients with obesity, hormonal disruption, intellectual disability, or autism spectrum disorders. Here we review recent studies that shed light on the function of NCOAs and NCORs in the central nervous system. | 01 = IsEpi
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Double-outlet left ventricle (DOLV) is a rare cardiac malformation in which both great arteries originate from the morphological left ventricle. DOLV is associated with high mortality, generally due to heart failure, myocardial infarction, or aortic thrombosis. With surgery, the 5-year survival rate is estimated at 70%-75%. Most patients will continue to present with residual cardiac anomalies, such as aortic or mitral valve regurgitation, arrhythmias, or hypertension. Here, we report a 25-year-old male with DOLV with pulmonary stenosis and patent ductus arteriosus who presented to us with hemoptysis, which was due to respiratory tract infection. He improved with standard therapy. | 01 = IsEpi
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Triphalangeal thumb is a rare congenital anomaly in which the thumb has three phalanges. Clinical presentation of triphalangeal thumb can vary considerably and can be present in both hands or unilateral. The thumb can be long with a finger-like appearance. The presence of clinodactyly depends on the shape of the extra phalanx varying from wedge-shaped to rectangular. Various joints, ligaments, muscles, and tendons of the first ray can be hypoplastic or absent, with varying degrees of stiffness or instability. The aim of surgical treatment is to reconstruct or correct the anatomic anomalies to obtain greater function and a more acceptable appearance. In our series, operations varied from removal of the delta phalanx with ligament reconstruction to multiple osteotomies and rebalancing of soft tissues. Results in these often complex cases can be rewarding if the surgeon has sufficient knowledge of the underlying anatomic differences. This review summarizes our current concepts of presentation and management of the triphalangeal thumb. | 01 = IsEpi
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Spinocerebellar ataxia 17 (SCA17) belongs to the family of 9 genetically inherited, late-onset neurodegenerative diseases, which are caused by polyglutamine (polyQ) expansion in different proteins. In SCA17, the polyQ expansion occurs in the TATA box binding protein (TBP), which functions as a general transcription factor. Patients with SCA17 suffer from a broad array of motor and non-motor defects, and their life expectancy is normally within 20 y after the initial appearance of symptoms. Currently there is no effective treatment, but remarkable efforts have been devoted to tackle this devastating disorder. In this review, we will summarize our current knowledge about the molecular mechanisms underlying the pathogenesis of SCA17, with a primary focus on transcriptional dysregulations. We believe that impaired transcriptional activities caused by mutant TBP with polyQ expansion is a major form of toxicity contributing to SCA17 pathogenesis, and rectifying the altered level of downstream transcripts represents a promising therapeutic approach for the treatment of SCA17. | 01 = IsEpi
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In autoimmune/lymphoproliferative syndrome (ALPS), defective Fas death receptor function causes lymphadenomegaly/splenomegaly, the expansion of T-cell receptor αβ(+) CD4/CD8 double-negative T cells, and frequent development of hematologic autoimmunity. Dianzani autoimmune lymphoproliferative disease (DALD) has a similar phenotype but lacks the expansion of double-negative T cells. This work shows that patients with ALPS and DALD have high serum levels of interleukin 17A (IL-17A), IL-17F, and IL-17AF, which are involved in several autoimmune diseases, and that their T cells show increased secretion of these cytokines upon activation in vitro. The following data indicate that these cytokines may contribute to ALPS and DALD: (1) recombinant IL-17A and IL-17F significantly inhibit Fas-induced cell death in Fas-sensitive T cells from healthy donors; (2) this inhibitory effect is also induced by the patients' serum and is reversed by anti-IL-17A antibodies; (3) IL-17A neutralization substantially increases Fas-induced cell death in T cells from ALPS and DALD patients in vitro; and (4) treatment with anti-IL-17A antibodies ameliorates the autoimmune manifestations and, at a lesser extent, the lymphoproliferative phenotype and prolongs survival in MRLlpr/lpr mice, which are an animal model of ALPS. These data suggest that IL-17A and IL-17F could be targeted therapeutically to improve Fas function in ALPS and DALD. | 01 = IsEpi
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Monostotic fibrous dysplasia is a rare osteodystrophy that typically affects adolescents, manifests later in life, and may be associated with subclinical hormonal imbalances. It can lead to serious complications, including visual compromise. We report a case of presumed monostotic sphenoid fibrous dysplasia presenting with transient abducens nerve palsy and esotropia in an otherwise healthy infant. The mechanism of transient, noncompressive abducens nerve palsy is not clearly understood but has been theorized to be secondary to localized inflammation during a cycle of florid bone remodeling that includes cyst formation, microhemorrhage, and resorption. | 01 = IsEpi
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Lymphomatoid papulosis (LyP) is a benign chronic often relapsing skin condition that belongs to the CD30-positive cutaneous lymphoproliferative disorders. LyP typically presents as crops of lesions with a tendency to self-resolve, and morphology can range from solitary to agminated or diffuse papules and plaques to nodules or tumours. The clinical-histological spectrum can range from borderline cases to overlap with primary cutaneous anaplastic cell lymphoma (pcALCL). Histology and immunophenotype commonly show overlap with other CD30-positive disorders and sometimes may be identical to pcALCL, making its diagnosis more difficult. Patients with LyP have an increased risk of developing a second neoplasm such as mycosis fungoides, pcALCL and/or Hodgkin lymphoma. Clinical correlation allows its proper classification and diagnosis, which is fundamental for treatment and prognosis. This review focuses on the clinical appearance, histopathological features, diagnosis, differential diagnosis and management of LyP. | 01 = IsEpi
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External root resorption (ERR) of permanent teeth is a pathological process that can lead to their loss. There are several systemic and/or genetic abnormalities that have been associated with ERR. Among them, familial expansile osteolysis (FEO) is an autosomal dominant disease characterized by skeletal defects, middle ear deafness, and abnormal root resorption. The purpose of this paper was to describe the case of a 10-year-old female with familial expansile osteolysis born with missing ossicles and, therefore, deafness. The patient was not diagnosed with FEO until the age of 10 years, when she presented to the dental clinic with advanced ERR in several permanent teeth. The series of tests she underwent for diagnosis and the treatments rendered are presented and discussed. It is recommended that when ERR cannot be explained by local etiologic factors, systemic abnormalities and genetic testing should be considered. | 01 = IsEpi
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This article describes the inter- and intra-familial phenotypic variability in four families with WNT10A mutations. Clinical characteristics of the patients range from mild to severe isolated tooth agenesis, over mild symptoms of ectodermal dysplasia, to more severe syndromic forms like odonto-onycho-dermal dysplasia (OODD) and Schöpf-Schulz-Passarge syndrome (SSPS). Recurrent WNT10A mutations were identified in all affected family members and the associated symptoms are presented with emphasis on the dentofacial phenotypes obtained with inter alia three-dimensional facial stereophotogrammetry. A comprehensive overview of the literature regarding WNT10A mutations, associated conditions and developmental defects is presented. We conclude that OODD and SSPS should be considered as variable expressions of the same WNT10A genotype. In all affected individuals, a dished-in facial appearance was observed which might be helpful in the clinical setting as a clue to the underlying genetic etiology. | 01 = IsEpi
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The new coronavirus infection COVID-19 has quickly become a global health emergency. Mortality is principally due to severe Acute Respiratory Distress Syndrome (ARDS) which relays only on supportive treatment. Numerous pathological, clinical and laboratory findings rise the similarity between moderate to severe COVID-19 and haemophagocytic lymphohistiocytosis (HLH). Etoposide-based protocol including dexametasone is the standard of care for secondary HLH. The protocol has been successfully used in HLHs that are secondary to EBV and H1N1 infections by inducing complete response and prolonged survival. These observations prompt to consider this cytotoxic therapy in HLH associated to moderately severe to severe forms of COVID-19. | 01 = IsEpi
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Myopathies typically present with proximal or generalised muscle weakness, but it is important for clinicians to recognise they may also have other distributions. This paper describes a case of distal myopathy that was confirmed genetically as ZASP (Z-band alternatively spliced PDZ motif-containing protein) myofibrillar myopathy (MFM). MFMs are particularly topical because the genetic basis of several have recently been established, enabling diagnosis of conditions previously labelled 'idiopathic myopathy', and shedding new light on their pathophysiology. This paper describes a purely distal lower limb phenotype of ZASP MFM, the pathophysiology of ZASP and other MFMs, and the differential diagnosis of late-onset distal symmetrical weakness. The case includes several learning points: ZASP MFM is a new diagnosis; it should be included in differential diagnoses for late-onset myopathy, especially if there is a distal pattern or autosomal dominant inheritance; testing for cardiomyopathy is recommended, and a genetic test is now available. | 01 = IsEpi
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BACKGROUND: Terminal deletions of chromosome 4q are associated with a broad spectrum of phenotypes including cardiac, craniofacial, digital, and cognitive impairment. The rarity of this syndrome renders genotype-phenotype correlation difficult, which is further complicated by the widely different phenotypes observed in patients sharing similar deletion intervals. CASE PRESENTATION: Herein, we describe a boy with congenital hearing impairment and a variety of moderate syndromic features that prompted SNP array analysis disclosing a heterozygous 6.9 Mb deletion in the 4q35.1q35.2 region, which emerged de novo in the maternal germ line. CONCLUSION: In addition to the index patient, we review 35 cases from the literature and DECIPHER database to attempt genotype-phenotype correlations for a syndrome with great phenotypic variability. We delineate intervals with recurrent phenotypic overlap, particularly for cleft palate, congenital heart defect, intellectual disability, and autism spectrum disorder. Broad phenotypic presentation of the terminal 4q deletion syndrome is consistent with incomplete penetrance of the individual symptoms. | 01 = IsEpi
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INTRODUCTION: Esophageal cancer is the 6th most common cause of cancer death in the world. During the past two decades some changes have occurred in histologic type and primary tumor location in some parts of the world but there is a little information about histopathological aspect of disease in Iran. The purpose of the present study was to clarify the features of histopathological of esophageal cancer in Iran. METHODS: This study designed as a cross sectional study. Data analysis was performed with descriptive and univariate methods. Information required for this study extracted from cancer registry forms. The cases were all patients who received a histopathological diagnosis of EC that were referred to this center from January 2003 to October 2008. RESULTS: A total of 264 EC cases were recruited in the study the lower third of the esophagus was the most frequent site of origin of these tumors. Squamus cell carcinoma was commonest histologic type of tumor. In 15.2% of cases tumor was metastasis to other organs. In 46.6% were in advanced stage at diagnosis. DISCUSSION: Based on result of present study, esophageal cancer in our country more presented in Squamus cell carcinoma histology type, in advanced stage. Since Squamus cell carcinoma have a poorer prognosis and given that these patients have vague symptomatology for approximately several months, therefore, early diagnosis and treatment led to better prognosis. | 10 = IsNotEpi
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OBJECTIVE:This study aimed to summarize our experience with the diagnosis and treatment of intravenous leiomyomatosis (IVL) involving the inferior vena cava (IVC) or right cardiac chambers. METHODS:This study retrospectively analyzed clinical data from 10 patients diagnosed with IVL involving the IVC or right cardiac chambers between May 2009 and October 2019 at one medical center. RESULTS:All patients were females aged 35 to 56 years (average, 46.8 years) with a history of uterine leiomyoma. Of these 10 patients, 8 manifested clinical symptoms and 2 were asymptomatic. Four were diagnosed with lesions involving the right cardiac chambers, four had lesions that extended into the suprahepatic IVC, and an additional two had lesions extending into the infrarenal IVC. All patients underwent surgery. Three of the four patients with extension into the right cardiac chambers underwent a two-stage operation, and an additional patient was managed with a one-stage operation. Patients who underwent a two-stage operation experienced less hemorrhaging and a shorter intensive care unit stay than the patient who underwent a one-stage operation. Six patients with intracaval extension alone underwent laparotomy, including four with a lesion extending into the suprahepatic IVC, under transesophageal echocardiography monitoring. Bilateral adnexectomy and ovariectomy were performed in seven patients, and unilateral adnexectomy and ovariectomy were performed in two patients; antiestrogen therapy was administered to two patients who retained a unilateral ovary and to one patient who retained bilateral ovaries. One patient suffered deep vein thrombosis in the left lower extremity after surgery that improved after treatment. All patients received conventional anticoagulant treatment postoperatively. All pathologic findings confirmed IVL, and the follow-up period ranged from 27 to 120 months (average, 57.5 months). Recurrence was not observed in the iliac vein or IVC, excluding one case of pelvic leiomyoma that recurred at one year postoperatively. CONCLUSIONS:IVL should be highly suspected when an IVC mass occurs in a patient with a history of uterine leiomyoma. Surgery is the gold standard treatment for IVL; a two-stage operation is more beneficial for patient recovery if the lesion exhibits intracardiac involvement, and transesophageal echocardiography is a helpful tool to monitor safety during surgical procedure for patients with a lesion invading the IVC above the level of the renal vein. | 01 = IsEpi
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Hypertrophic cardiomyopathy is known as Leopard syndrome, which is a mnemonic rule for multiple lentigines (L), electrocardiographic conduction abnormalities (E), ocular hypertelorism (O), pulmonary stenosis (P), abnormalities of genitalia (A), retardation of growth (R), and deafness (D). We report the case of a 12-year-old patient with some of the abovementioned characteristics: hypertelorism, macroglossia, lentigines, hypospadias, cryptorchidism, subaortic stenosis, growth retardation, and hearing impairment. Due to this set of symptoms, we diagnosed Leopard syndrome. | 01 = IsEpi
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A 17-month-old girl with no medical history presented at our emergency room with abnormal vaginal bleeding and vaginal tissue loss with a "grape bunch" appearance. Physical examination showed no abnormalities, but gynaecological examination showed abnormal vaginal tissue protruding through the vagina introitus. Given the typical clinical presentation, the age of the girl and the location and aspect of the lesion, there was a high suspicion of the botryoid variant of embryonal rhabdomyosarcoma of the vagina. Histology of a biopsy of the lesion was consistent with embryonal rhabdomyosarcoma. As no metastases were detected, the girl received chemotherapy. This case report describes the importance of early recognition of the typical clinical symptoms of sarcoma botryoides, since a rapid diagnosis followed by treatment is necessary to prevent death. | 01 = IsEpi
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BACKGROUND:Aim of this work was to describe a rare inheritance pattern of Primary Failure of Eruption (PFE) in a small family with incomplete penetrance of PFE and a novel nonsense PTH1R variant. CASE PRESENTATION:The proband, a 26 year-old man with a significant bilateral open-bite, was diagnosed with PFE using clinical and radiographic characteristics. DNA was extracted from the proband and his immediate family using buccal swabs and the entire PTH1R coding sequence was analyzed, revealing a novel heterozygous nonsense variant in exon 7 of PTH1R (c.505G > T). This variant introduces a premature stop codon in position 169, predicted to result in the production of a truncated and non-functional protein. This variant has never been reported in association with PFE and is not present in the Genome Aggregation Database (gnomAD). Interestingly, the c.505G > T variant has also been identified in the unaffected mother of our proband, suggesting incomplete penetrance of PFE. CONCLUSIONS:In this study, we report a new PTH1R variant that segregates in an autosomal dominant pattern and causes PFE with incomplete penetrance. This underlines the diagnostic value of a thorough clinical and genetic analysis of all family members in order to estimate accurate recurrence risks, identify subtle clinical manifestations and provide proper management of PFE patients. | 01 = IsEpi
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The neuronal ceroid lipofuscinoses (NCLs) are a group of devastating monogenetic lysosomal disorders that affect children and young adults with no cure or effective treatment currently available. One of the more severe infantile forms of the disease (INCL or CLN1 disease) is due to mutations in the palmitoyl-protein thioesterase 1 (PPT1) gene and severely reduces the child's lifespan to approximately 9 years of age. In order to better translate the human condition than is possible in mice, we sought to produce a large animal model employing CRISPR/Cas9 gene editing technology. Three PPT1 homozygote sheep were generated by insertion of a disease-causing PPT1 (R151X) human mutation into the orthologous sheep locus. This resulted in a morphological, anatomical and biochemical disease phenotype that closely resembles the human condition. The homozygous sheep were found to have significantly reduced PPT1 enzyme activity and accumulate autofluorescent storage material, as is observed in CLN1 patients. Clinical signs included pronounced behavioral deficits as well as motor deficits and complete loss of vision, with a reduced lifespan of 17 ± 1 months at a humanely defined terminal endpoint. Magnetic resonance imaging (MRI) confirmed a significant decrease in motor cortical volume as well as increased ventricular volume corresponding with observed brain atrophy and a profound reduction in brain mass of 30% at necropsy, similar to alterations observed in human patients. In summary, we have generated the first CRISPR/Cas9 gene edited NCL model. This novel sheep model of CLN1 disease develops biochemical, gross morphological and in vivo brain alterations confirming the efficacy of the targeted modification and potential relevance to the human condition. | 01 = IsEpi
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Background:Classical heterozygous pathogenic variants of the lamin A/C (LMNA) gene cause autosomal dominant familial partial lipodystrophy type 2 (FPLD2). However, recent reports indicate phenotypic heterogeneity among carriers of LMNA pathogenic variants, and a few patients have been associated with generalized fat loss. Case presentation:Here, we report a patient with a lamin A specific pathogenic variant in exon 11, denoted LMNA (c.1745G > A; p.R582H), present in the homozygous state. Fat distribution was compared radiographically to an unrelated heterozygote LMNA p.R582H patient from another pedigree, a healthy female control, a series of adult female subjects with congenital generalized lipodystrophy type 1 (CGL1, n = 9), and typical FPLD2 (n = 8). The whole-body MRI of the index case confirmed near-total loss of subcutaneous adipose tissue with well-preserved fat in the retroorbital area, palms and soles, mons pubis, and external genital region. This pattern resembled the fat loss pattern observed in CGL1 with only one difference: strikingly more fat was observed around mons pubis and the genital region. Also, the p.R582H LMNA variant in homozygous fashion was associated with lower leptin level and earlier onset of metabolic abnormalities compared to heterozygous p.R582H variant and typical FPLD2 cases. On the other hand, the heterozygous LMNA p.R582H variant was associated with partial fat loss which was similar to typical FPLD2 but less severe than the patients with the hot-spot variants at position 482. Conclusions:Our observations and radiological comparisons demonstrate an additive effect of LMNA pathogenic variants on the severity of fat loss and add to the body of evidence that there may be complex genotype-phenotype relationships in this interesting disease known as FPLD2. Although the pathological basis for fat loss is not well understood in patients harboring pathogenic variants in the LMNA gene, our observation suggests that genetic factors modulate the extent of fat loss in LMNA associated lipodystrophy. | 01 = IsEpi
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Patient with Refsum disease present with nyctalopia, and the fundus shows progressive panretinal degeneration. Vision gradually decreases, with progressive peripheral constriction. The pupil usually does not dilate well. | 01 = IsEpi
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Purpose:A subgroup of uveal melanoma (UM) gives rise to metastases at a late stage. Our objective was to identify patient and tumor characteristics that are associated with UM-related death in patients who survived 5 years following enucleation. Methods:A retrospective analysis was performed in 583 primary UM cases, enucleated at the Leiden University Medical Center between 1983 and 2013. Univariable and multivariable Cox regression analyses were performed in the total cohort and separately in those surviving more than 5 years (n = 297). Results:In the total cohort, the median age was 62.6 years, and the median tumor diameter was 12.0 mm. Monosomy 3 was detected in 53% of cases and gain of 8q in 47%. In the cohort surviving 5 years, the median age was 59.5 years, and the median tumor diameter was 11.0 mm. Monosomy 3 and gain of 8q were detected in 33% and 31% of cases, respectively. In the total cohort, male gender (P = 0.03), tumor diameter (P < 0.001), mitotic count (P < 0.001), extravascular matrix loops (P = 0.03), extraocular growth (P < 0.001), and gain of 8q (P < 0.001) were independently associated with UM-related death. In patients surviving 5 years after enucleation, univariable analysis revealed that age (P = 0.03), tumor diameter (P < 0.001), monosomy 3 (P = 0.04), and 8q gain (P = 0.003) were associated with subsequent UM-related death. Using a multivariable analysis, only male gender (P = 0.03) and gain of 8q (P = 0.01) remained significant. Conclusions:Predictors of UM-related death change over time. Among UM patients who survived the initial 5 years following enucleation, male gender and chromosome 8q status were the remaining factors related to UM-related death later on. | 01 = IsEpi
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STUDY QUESTION:How did the field of stem cell research develop in the years following the derivation of the first human embryonic stem cell (hESC) line? SUMMARY ANSWER:Supported by the increasing number of clinical trials to date, significant technological advances in the past two decades have brought us ever closer to clinical therapies derived from pluripotent cells. WHAT IS KNOWN ALREADY:Since their discovery 20 years ago, the use of human pluripotent stem cells has progressed tremendously from bench to bedside. Here, we provide a concise review of the main keystones of this journey and focus on ongoing clinical trials, while indicating the most relevant future research directions. STUDY DESIGN SIZE DURATION:This is a historical narrative, including relevant publications in the field of pluripotent stem cells (PSC) derivation and differentiation, recounted both through scholarly research of published evidence and interviews of six pioneers who participated in some of the most relevant discoveries in the field. PARTICIPANTS/MATERIALS SETTING METHODS:The authors all contributed by researching the literature and agreed upon body of works. Portions of the interviews of the field pioneers have been integrated into the review and have also been included in full for advanced reader interest. MAIN RESULTS AND THE ROLE OF CHANCE:The stem cell field is ever expanding. We find that in the 20 years since the derivation of the first hESC lines, several relevant developments have shaped the pluripotent cell field, from the discovery of different states of pluripotency, the derivation of induced PSC, the refinement of differentiation protocols with several clinical trials underway, as well as the recent development of organoids. The challenge for the years to come will be to validate and refine PSCs for clinical use, from the production of highly defined cell populations in clinical grade conditions to the possibility of creating replacement organoids for functional, if not anatomical, function restoration. LIMITATIONS REASONS FOR CAUTION:This is a non-systematic review of current literature. Some references may have escaped the experts' analysis due to the exceedingly diverse nature of the field. As the field of regenerative medicine is rapidly advancing, some of the most recent developments may have not been captured entirely. WIDER IMPLICATIONS OF THE FINDINGS:The multi-disciplinary nature and tremendous potential of the stem cell field has important implications for basic as well as translational research. Recounting these activities will serve to provide an in-depth overview of the field, fostering a further understanding of human stem cell and developmental biology. The comprehensive overview of clinical trials and expert opinions included in this narrative may serve as a valuable scientific resource, supporting future efforts in translational approaches. STUDY FUNDING/COMPETING INTERESTS:ESHRE provided funding for the authors' on-site meeting and discussion during the preparation of this manuscript. S.M.C.S.L. is funded by the European Research Council Consolidator (ERC-CoG-725722-OVOGROWTH). M.P. is supported by the Special Research Fund, Bijzonder Onderzoeksfonds (BOF01D08114). M.G. is supported by the Methusalem grant of Vrije Universiteit Brussel, in the name of Prof. Karen Sermon and by Innovation by Science and Technology in Flanders (IWT, Project Number: 150042). A.V. and B.A. are supported by the Plataforma de Proteomica, Genotipado y Líneas Celulares (PT1770019/0015) (PRB3), Instituto de Salud Carlos III. Research grant to B.H. by the Research Foundation-Flanders (FWO) (FWO.KAN.2016.0005.01 and FWO.Project G051516N). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER:Not applicable.ESHRE Pages are not externally peer reviewed. This article has been approved by the Executive Committee of ESHRE. | 01 = IsEpi
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Mutations in CASK cause X-linked intellectual disability, microcephaly with pontine and cerebellar hypoplasia, optic atrophy, nystagmus, feeding difficulties, GI hypomotility, and seizures. Here we present a patient with a de novo carboxyl-terminus splice site mutation in CASK (c.2521-2A>G) and clinical features of the rare FG syndrome-4 (FGS4). We provide further characterization of genotype-phenotype correlations in CASK mutations and the presentation of nystagmus and the FGS4 phenotype. There is considerable variability in clinical phenotype among patients with a CASK mutation, even among variants predicted to have similar functionality. Our patient presented with developmental delay, nystagmus, and severe gastrointestinal and gastroesophageal complications. From a cognitive and neuropsychological perspective, language skills and IQ are within normal range, although visual-motor, motor development, behavior, and working memory were impaired. The c.2521-2A>G splice mutation leads to skipping of exon 26 and a 9 base-pair deletion associated with a cryptic splice site, leading to a 28-AA and a 3-AA in-frame deletion, respectively (p.Ala841_Lys843del and p.Ala841_Glu868del). The predominant mutant transcripts contain an aberrant guanylate kinase domain and thus are predicted to degrade CASK's ability to interact with important neuronal and ocular development proteins, including FRMD7. Upregulation of CASK as well as dysregulation among a number of interactors is also evident by RNA-seq. This is the second CASK mutation known to us as cause of FGS4. © 2017 Wiley Periodicals, Inc. | 01 = IsEpi
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Background:Menkes disease is an X-linked neurodegenerative disease caused by mutation in ATP7A gene, which codes for copper-transporting ATPase. It usually presents in early infancy with neuro-regression, hypotonia, seizures, and kinky hair. Magnetic resonance imaging (MRI) of the brain shows cerebral atrophy, subdural effusions, and tortuous cerebral blood vessels. Case Characteristics:We report the case of a 7-month-old boy who presented with global developmental delay, seizures, and increasing head size since 2 months of age and history of sibling death. He had macrocephaly, sparse, hypopigmented hair, seborrheic dermatitis of scalp, hypotonia, and brisk reflexes. Brain MRI was suggestive of megalencephalic leukodystrophy. Careful reexamination of films revealed tortuous blood vessels. Serum copper and ceruloplasmin levels were significantly reduced, leading to diagnosis of Menkes disease. Conclusion:This case exemplifies a rare presentation of Menkes disease, simulating a leukodystrophy with macrocephaly. Tortuosity of cerebral blood vessels is an important finding, which can help in differentiating Menkes disease from white matter disorders. | 01 = IsEpi
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Marie-Unna type of hereditary hypotrichosis is a rare autosomal dominant disorder that has a distinctive type of hair loss pattern that varies with child's age. It is characterized by sparse or absent hair at birth with regrowth of coarse, wiry twisted hair from childhood, followed by progressive loss on approaching puberty. We report a 12-year-old male child with characteristic clinical features suggestive of hereditary hypotrichosis of Marie-Unna type. | 01 = IsEpi
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ERLIN2-related disorders are rare conditions of the motor system and clinical details are limited to a small number of prior descriptions. We here presented clinical and genetic details in five individuals (four different families) where three subjects carried a common homozygous p.Asn292ArgfsX26, associated also with sensorineural hearing loss in one child. One further subject had a de novo p.Gln63Lys and one harbors the homozygous p.Val136Gly because of maternal isodisomy of chromosome 8. Overall, we expanded the clinical and genetic spectrum of ERLIN2-related disorders and we reiterate that autosomal-dominant transmission is a potential mode of inheritance. Future research will elucidate disease mechanisms. | 01 = IsEpi
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Nanoparticle-based drug delivery system offers a promising platform for combination cancer therapy. However, the inefficient drug release in cells reduces the therapeutic efficacy of cancer nanomedicines. Herein, a PEGylated poly(α-lipoic acid) copolymer (mPEG-PαLA) was prepared and used as a reduction/pH dual responsive nanocarrier to simultaneously deliver paclitaxel (PTX) and doxorubicin (DOX) for osteosarcoma therapy. The amphiphilic mPEG-PαLA could efficiently encapsulate both PTX and DOX during its self-assembly into micelles in aqueous solution to generate PTX and DOX co-loaded nanoparticles (NP-PTX-DOX). The as-prepared NP-PTX-DOX showed enhanced PTX and DOX release in response to reductive and acidic stimuli. Moreover, the dual-drug loaded nanoparticles were efficiently internalized by K7 osteosarcoma cells and released drugs intracellularly, as confirmed by flow cytometry analysis and confocal laser scanning microscopy. Consequently, NP-PTX-DOX exhibited synergistic therapeutic effects and induced enhanced cell apoptosis in K7 cells. Furthermore, NP-PTX-DOX presented improved biodistribution and higher tumor growth inhibition efficacy compared to the control groups in a murine osteosarcoma model. Altogether, the results of this work indicate that the proposed strategy is promising for osteosarcoma therapy using mPEG-PαLA copolymer as a dual-responsive nanocarrier to co-deliver anticancer drugs. | 01 = IsEpi
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The Ehlers-Danlos syndromes (EDS) constitute a clinically and genetically heterogeneous group of connective tissue disorders. Tenascin X (TNX) deficiency is a rare type of EDS, defined as classical-like EDS (clEDS), since it phenotypically resembles the classical form of EDS, though lacking atrophic scarring. Although most patients display a well-defined phenotype, the diagnosis of TNX-deficiency is often delayed or overlooked. Here, we described an additional patient with clEDS due to a homozygous null-mutation in the TNXB gene. A review of the literature was performed, summarizing the most important and distinctive clinical signs of this disorder. Characterization of the cellular phenotype demonstrated a distinct organization of the extracellular matrix (ECM), whereby clEDS distinguishes itself from most other EDS subtypes by normal deposition of fibronectin in the ECM and a normal organization of the α5β1 integrin. | 01 = IsEpi
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A 65-year-old woman presented with mycosis fungoides and an anterior mediastinal tumor. Stage Ⅱa mycosis fungoides was treated with bath psoralen plus ultraviolet A, topical corticosteroids, and oral bexarotene. One month later, a surgical resection was performed for the anterior mediastinal tumor, which was a stage Ⅱ thymoma with membrane invasion. Furthermore, adjuvant radiotherapy was performed for anterior mediastinum. The mycosis fungoides lesion exacerbated after 3 months;thus, chemotherapies were performed. The patient died of respiratory insufficiency due to multiple pulmonary metastases of mycosis fungoides 1 year after the operation. | 01 = IsEpi
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Non-ossifying fibromas are seen in different disorders recognizable by specific features. Indeed, osteoglophonic dysplasia (OD) is characterized by radiolucent bone lesions associated with severe short stature, dysmorphism and failure of dental eruption. This syndrome is caused by heterozygous activating mutations in the immunoglobulin-like D3 domain of the FGFR1 gene, encoding a tyrosine kinase. Here, we report three patients from the same family presenting with radiolucent bone lesions and teeth retentions. Exome sequencing allowed identification of a novel mutation c.917C > T, p. Pro306Leu in exon 7 of the FGFR1 gene. Our patients present with normal stature and no severe dysmorphism. This report describes a mild form of OD and expands the phenotype related to FGFR1 mutations. These findings emphasize the need to consider FGFR1 variants in the case of multiple non-ossifying bone lesions associated with dental eruption anomalies. | 01 = IsEpi
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BACKGROUND: The presence of a branchial fistula with communication both internally and externally: a 'true' branchial fistula is rare, and may arise in the context of autosomal dominant conditions such as branchiootic syndrome and branchiootorenal syndrome. STUDY: We discuss the case of a true branchial fistula, which recurred after initial surgical excision, in a patient with branchiootic syndrome. The residual tract was dissected in a second operation through stepladder neck incisions and removed in toto via an intraoral approach. No renal abnormalities were detected on investigation with ultrasound. DISCUSSION: Incomplete excision of a branchial sinus is likely to cause recurrence however intraoperative visualisation of the tract can can sometimes prove challenging. An combined intraoral and external approach aids delineation and tract definition when there is a true branchial fistula and can therefore facilitate a complete excision. Suspicion of an hereditary aetiology should be raised in patients with bilateral or preauricular features, or a positive family history, which may then prompt additional renal and genetic investigation. | 01 = IsEpi
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In response to the coronavirus disease 2019 (COVID-19) outbreak, caused by SARS-CoV-2, multiple diagnostic tests are required for acute disease diagnosis, contact tracing, monitoring asymptomatic infection rates and assessing herd immunity. While PCR remains the frontline test of choice in the acute diagnostic setting, serological tests are urgently needed. Unlike PCR tests which are highly specific, cross-reactivity is a major challenge for COVID-19 antibody tests considering there are six other coronaviruses known to infect humans. SARS-CoV is genetically related to SARS-CoV-2 sharing approximately 80% sequence identity and both belong to the species SARS related coronavirus in the genus Betacoronavirus of family Coronaviridae. We developed and compared the performance of four different serological tests to comprehensively assess the cross-reactivity between COVID-19 and SARS patient sera. There is significant cross-reactivity when N protein of either virus is used. The S1 or RBD regions from the spike (S) protein offers better specificity. Amongst the different platforms, capture ELISA performed best. We found that SARS survivors all have significant levels of antibodies remaining in their blood 17 years after infection. Anti-N antibodies waned more than anti-RBD antibodies, and the latter is known to play a more important role in providing protective immunity. | 01 = IsEpi
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Background: Though Todd's phenomenon (TP) is a relatively rare occurrence, its correct identification is of key diagnostic and therapeutic importance as a stroke mimic. Here we describe a case of isolated gaze palsy as a manifestation of TP, discuss periictal gaze abnormalities as lateralizing sign involving the frontal eye field (FEF), and present a narrative literature review. Methods: We reviewed the main features of the case and conducted a structured literature search of TP and gaze palsy using PubMed. We restricted the search to publications in English, Spanish, French, and German. Case presentation: A 71-year-old male with a history of right frontotemporal subarachnoid hemorrhage was admitted to the Emergency Department of our institution after suffering a first unprovoked focal to bilateral tonic-clonic seizure with ictal gaze deviation to the left. Cranial imaging showed no signs of ischemia, intracerebral hemorrhage, or tumor. The patient presented the following postictal features: involuntary eye deviation to the right due to left-sided gaze palsy and disorientation in time with preserved responsiveness. Eye movements were normal three days later. We concluded that the patient suffered from new-onset epilepsy due to sequelae following the right frontotemporal subarachnoid hemorrhage, affecting the FEF with contralateral ictal gaze deviation, and postictal gaze palsy with ipsilateral eye deviation as an unusual Todd's phenomenon. Conclusion: Unusual manifestations of TP are uncommon but clinically highly relevant, as they can mimic stroke or epileptic status and are decisive in the diagnostic and therapeutic decision-making process. Though postictal gaze palsy has been reported associated with other deficits, this constitutes, to our knowledge, the first report of isolated gaze palsy as a form of TP. Further research into the underlying causes is needed. Ictal contralateral gaze and head deviation, and probably postictal ipsilateral gaze deviation if present, are very helpful for the lateralization of the seizure-onset zone. | 01 = IsEpi
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Mast cells (MCs) are being increasingly implicated as a possible contributor to symptoms in diarrhea predominant irritable bowel syndrome (IBS). The term "mastocytic enterocolitis" was proposed to describe an increase in mucosal MCs in patients with chronic diarrhea due to functional gastrointestinal disease (FGID). The efficacy of anti-MC mediator therapy (antihistamines and MC stabilizers) has been well documented in this setting. Here we describe the treatment with oral budesonide of mastocytic enterocolitis refractory to standard anti-MC therapy. | 01 = IsEpi
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The formation of human enamel is highly regulated at the molecular level and involves thousands of genes. Requisites for development of this highly mineralized tissue include cell differentiation; production of a unique extracellular matrix; processing of the extracellular matrix; altering of cell function during different stages of enamel formation; cell movement and attachment; regulation of ion and protein movement; and regulation of hydration, pH, and other conditions of the microenvironment, to name just a few. Not surprising, there is a plethora of hereditary conditions with an enamel phenotype. The objective of this review was to identify the hereditary conditions listed on Online Mendelian Inheritance in Man (OMIM) that have an associated enamel phenotype and whether a causative gene has been identified. The OMIM database was searched with the terms amelogenesis, enamel, dental, and tooth, and all results were screened by 2 individuals to determine if an enamel phenotype was identified. Gene and gene product function was reviewed on OMIM and from publications identified in PubMed. The search strategy revealed 91 conditions listed in OMIM as having an enamel phenotype, and of those, 71 have a known molecular etiology or linked genetic loci. The purported protein function of those conditions with a known genetic basis included enzymes, regulatory proteins, extracellular matrix proteins, transcription factors, and transmembrane proteins. The most common enamel phenotype was a deficient amount of enamel, or enamel hypoplasia, with hypomineralization defects being reported less frequently. Knowing these molecular defects allows an initial cataloging of molecular pathways that lead to hereditary enamel defects in humans. This knowledge provides insight into the diverse molecular pathways involved in enamel formation and can be useful when searching for the genetic etiology of hereditary conditions that involve enamel. | 01 = IsEpi
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In the present study, we described the phenotype, histologic morphology, and molecular etiology of a mouse model of unstable hemoglobin Santa Ana. Hematologic evaluation of anemic mice (Anem/+) discovered after N-ethyl-N-nitrosourea mutagenesis revealed moderate anemia with intense reticulocytosis and polychromasia, followed by anisocytosis, macrocytosis, hypochromia, and intraerythrocytic inclusion and Heinz bodies. The mice also demonstrated hemoglobinuria, bilirubinemia, and erythrocytic populations with differing resistance to osmotic lysis. Splenomegaly (particularly in older mutant mice) and jaundice were apparent at necropsy. Histopathologic examination revealed dramatically increased hematopoiesis and hemosiderosis in hematopoietic organs and intracellular iron deposition in tubular renal cells. These data are characteristic of a congenital hemolytic regenerative anemia, similar to human anemias due to unstable hemoglobin. Genetic mapping assigned the affected gene to mouse chromosome 7, approximately 50 cM from the Hbb locus. The sequence of the mutant Hbb gene exhibited a T→C transversion at nucleotide 179 in Hbb-b1, leading to the substitution of proline for leucine at amino acid residue 88 and thus homologous to the genetic defect underlying Santa Ana anemia in humans. | 01 = IsEpi
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The relation between hair growth and levels of sex hormones in serum and saliva was investigated in 256 !Kung San and Kavango men (ages 18 to 39 years) from Namibia/Southern Africa. Serum concentrations of total testosterone (Tser), 5 alpha-dihydrotestosterone (DHT), and estradiol (E2) as well as the level of bioavailable non-SHBG-bound testosterone in the saliva (Tsal) were determined by radioimmunoassay. The distribution and density of scalp and facial hair as well as the development of terminal hair on the chest, abdomen, pubic area, arms, fingers, and legs were categorized using objective criteria. Covariance analyses revealed marked differences in the distribution of body hair in the San and the Negro sample. This is partly explained by a significant influence of androgen and estrogen levels on the growth of terminal hair. DHT and the ratio DHT/Tser are significantly positively related to midphalangeal hair growth and negatively to pubic hair development. Tsal, the bioavailable fraction of total testosterone, exerts a weak positive influence on the degree of arm and leg hair growth; the most significant positive effect on the growth of abdominal, arm, and leg hair in our samples is caused by E2. The ratio Tser/E2 correlates significantly negatively with the arm and leg hair development and the ratio DHT/E2 with the degree of abdominal, pubic, arm, and leg hair, whereas lower DHT concentrations occur in men with stronger hair development. | 01 = IsEpi
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Two Turkish sibs, products of a second cousin marriage, with tetramelic syndactyly, ectodermal dysplasia, cleft lip and palate, renal anomalies, and mental retardation are reported. Similarities between these two brothers and previously reported cases and their mode of transmission are discussed. | 01 = IsEpi
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POEMS syndrome is a rare multi-system disorder, which sometimes involves the kidney. Immunotactoid glomerulopathy (ITG) is an uncommon glomerular disease resulted from deposits of immunoglobulins and its derivatives. ITG caused by POEMS syndrome is rarely reported.A 63-year-old man was presented with acute kidney injury. In addition, it's found that he had abnormal serum free κ /λ ratio, polyneuropathy, Castleman's disease, organomegaly, endocrinopathy and skin changes.POEMS syndrome was diagnosed, Renal biopsy revealed an ITG.Dexamethasone and thalidomide were given, as well as hemodialysis and other supportive treatments.The patient's extrarenal manifestations improved gradually and his renal function also showed slight improvement.ITG caused by POEMS syndrome is rare, however, it makes sense that the monoclonal proteins produced by the plasma cells could cause ITG. Chemotherapy similar to that employed in multiple myeloma may be beneficial for these patients. | 01 = IsEpi
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BACKGROUND:Epidermolytic palmoplantar keratoderma (EPPK) is a rare skin disorder and its pathogenesis and inheritability are unknown. OBJECTIVE:To investigate the inheritance and pathogenesis of EPPK. METHODS:Two EPPK cases occurred in a three-generation Chinese family. Patient-parents trio EPPK was carried out and the identified candidate variants were confirmed by Sanger sequencing. RESULTS:A heterozygous missense pathogenic variant, c.488G > A (p.Arg163Gln), in the keratin (KRT) 9 gene was detected in the proband and his son via targeted exome sequencing, and then validated by Sanger sequencing. This pathogenic variant cosegregated with the EPPK in extended family members, and was predicted to be pathogenic by SIFT, PolyPhen2, PROVEAN, and Mutation Taster. This heterozygous variation was not evident in 100 healthy controls. CONCLUSION:This report describes a KRT9 c.488G > A (p.Arg163Gln) variant causing a diffuse phenotype of Chinese EPPK. The current results broaden the spectrum of KRT9 pathogenic variants responsible for EPPK and have important implications for molecular diagnosis, treatment, and genetic counseling for this family. | 01 = IsEpi
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OBJECTIVE:Retinal prostheses aim to restore vision in patients with retinal degenerative diseases, such as age-related macular degeneration and retinitis pigmentosa. By implanting an array of microelectrodes, such a device creates percepts in patients through electrical stimulation of surviving retinal neurons. A challenge for retinal prostheses when trying to return high quality vision is the unintended activation of retinal ganglion cells through the stimulation of passing axon bundles, which leads to patients reporting large, elongated patches of light instead of focal spots. APPROACH:In this work, we used calcium imaging to record the responses of retinal ganglion cells to electrical stimulation in explanted retina using rectangular electrodes placed with different orientations relative to the axon bundles. MAIN RESULTS:We showed that narrow, rectangular electrodes oriented parallel to the axon bundles can achieve focal stimulation. To further improve the strategy, we studied the impact of different stimulation waveforms and electrode configurations. We found the selectivity for focal stimulation to be higher when using short (33 μs), anodic-first biphasic pulses, with long electrode lengths and at least 50 μm electrode-to-retinal separation. Focal stimulation was, in fact, less selective when the electrodes made direct contact with the retinal surface due to unwanted preferential stimulation of the proximal axon bundles. SIGNIFICANCE:When employed in retinal prostheses, the proposed stimulation strategy is expected to provide improved quality of vision to the blind. | 01 = IsEpi
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INTRODUCTION:Mutations of the voltage-gated sodium channel gene (SCN4A), which encodes Nav1.4, cause nondystrophic myotonia that occasionally is associated with severe apnea and laryngospasm. There are case reports of nondystrophic myotonia due to mutations in the C-terminal tail (CTerm) of Nav1.4, but the functional analysis is scarce. METHODS:We present two families with nondystrophic myotonia harboring a novel heterozygous mutation (E1702del) and a known heterozygous mutation (E1702K). RESULTS:The proband with E1702K exhibited repeated rhabdomyolysis, and the daughter showed laryngospasm and cyanosis. Functional analysis of the two mutations as well as another known heterozygous mutation (T1700_E1703del), all located on EF hand-like motif in CTerm, was conducted with whole-cell recording of heterologously expressed channel. All mutations displayed impaired fast inactivation. DISCUSSION:The CTerm of Nav1.4 is vital for regulating fast inactivation. The study highlights the importance of accumulating pathological mutations of Nav1.4 and their functional analysis data. | 01 = IsEpi
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Skeletal muscle is a major organ for glucose disposal and thermogenesis. While hepatic fructose-1,6-bisphosphatase is well known as a key enzyme for gluconeogenesis, the role of muscle fructose-1,6-bisphosphatase 2 (Fbp2) in glucose disposal and thermogenesis is unknown. Here, using Fbp2 knockout (KO) mice, we assessed the physiological role of Fbp2 in energy and glucose metabolism and thermogenesis. In vivo assessments of energy metabolism, glucose metabolism, and thermogenesis were performed by indirect calorimetry, hyperinsulinemic-euglycemic clamp, and cold challenge studies, respectively. Under both feeding and fasting conditions, Fbp2 KO mice showed similar phenotypes regarding energy and glucose metabolism compared to wild-type (WT) mice. However, Fbp2 KO mice were severely intolerant to cold challenge under fasting conditions. Mechanistically, the cold-induced intramuscular conversion of lactate to glycogen (glyconeogenesis) is completely abolished in the KO muscle, which leads to a lack of glycogen source for thermogenesis in Fbp2 KO mice. The cold-intolerant phenotype of KO mice disappeared after feeding, and the KO mice were equally as cold tolerant as the WT mice and survived during the cold challenge for three weeks. Taken together, these data demonstrate that Fbp2 is essential for muscle thermogenesis by replenishing the intramuscular glycogen pool through glyconeogenesis when the exogenous glucose source is limited. These data imply the physiological importance of Fbp2 in thermal homeostasis and suggest a potential novel therapy targeted to increase glycogen replenishment upon cold stress. | 01 = IsEpi
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BACKGROUND Dyslipidemia is the most frequent comorbidity in patients with cardiovascular disease. However, studies examining the relationship between blood lipid profiles and AF have produced inconsistent results. MATERIAL AND METHODS A total of 651 patients were enrolled into 3 groups: Healthy controls (n=64), Paroxysmal AF (PAF; n=270), and Continuous AF (CAF; n=317). All enrolled patients underwent routine baseline 12-lead electrocardiography (ECG) and 24-h dynamic ECG along with blood testing, which included the following: complete metabolic panel, hepatic function, renal function, circulating thyroxine, fasting high-density lipoprotein cholesterol (HDL -C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and total cholesterol (TC). RESULTS Patients with AF had significantly higher levels of triglycerides (TG), lower levels of LDL-C-c, and lower levels of HDL-C (p<0.05). TC (OR 0.979, p<0.9247) and TG (OR 0.945, p<0.6496) were negatively and linearly associated with PAF, while TG (OR 0.807, p=0.2042), LDL-C (OR 0.334, p=0.0036), and HDL-C (OR 0.136, p=0.0002) were negatively and linearly associated with CAF. CONCLUSIONS Compared to healthy controls, patients with AF had lower blood lipid levels, especially LDL-c and HDL-c levels. Hypolipoproteinemia may increase patient susceptibility to developing AF. | 01 = IsEpi
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Objective: This study was to investigate the perioperative safety of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for pseudomyxoma peritonei (PMP), and analyze the risk factors of serious adverse events (SAEs). Methods: The occurrences of perioperative SAEs were retrospectively analyzed in 254 PMP patients treated with CRS plus HIPEC. Univariate and multivariate analysis were performed to identify independent risk factors. Results: Among the 272 CRS plus HIPEC procedures for 254 PMP patients, a total of 93 (34.2%) perioperative SAEs occurred, including 26 in infection, 22 in digestive system, 17 in respiratory system, 15 in cardiovascular system, 8 in hematological system, and 4 in urinary system. In terms of severity, the vast majority was grade Ⅲ with 76 cases, followed by grade Ⅳ with 13 cases and grade Ⅴ with 4 cases. Univariate analysis revealed 3 risk factors of perioperative SAEs: HIPEC regimen (P=0.020), intraoperative red blood cell transfusion volume (P=0.004), and intraoperative blood loss volume (P=0.002). Multivariate analysis by logistic regression model analysis revealed that intraoperative red blood cell transfusion volume was an independent risk factor for perioperative SAEs (OR=1.160, P=0.001). Conclusion: In conclusion, the perioperative safety of CRS plus HIPEC was acceptable. Moreover, intraoperative blood loss volume and red blood cell transfusion volume are expected to be reduced in order to prevent SAEs for PMP patients. | 01 = IsEpi
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Pulmonary hypoplasia or agenesis is a rare congenital disorder that results in lung underdevelopment. This disease is usually found in children but rarely encountered in adults. We describe the case of an 84-year-old woman diagnosed with a unilateral pulmonary hypoplasia presenting simultaneously with left pulmonary artery hypoplasia. Due to this condition, the patient had a lifelong history of pulmonary infections that resulted in several bronchiectases in the affected lung. Moreover, the pulmonary artery hypoplasia led to the development of pulmonary hypertension and collateral circulation causing hemoptysis, giving rise to the patient attending the emergency department. Although we were able to medically manage the hemoptysis, it can be fatal and require surgical intervention. Hence, an early diagnosis is essential so that appropriate follow-up and prompt prevention and treatment of complications, such as pulmonary infections, hemoptysis and pulmonary hypertension, are achieved. LEARNING POINTS:Although rare and typically associated with childhood, lung and pulmonary artery hypoplasia can in exceptional cases be present in adult life.The diagnosis of lung and pulmonary artery hypoplasia is challenging in adults as they can easily be mistaken for more common diseases.Symptoms and complications may be life-threatening, including dyspnea, hemoptysis, recurrent pulmonary infections and pulmonary hypertension.An early diagnosis is extremely important because it allows a close follow-up with consequent timely detection and treatment of serious complications, especially pulmonary hypertension. | 01 = IsEpi
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Biotinidase deficiency is an autosomal recessive inherited neurocutaneous disorder. Clinically untreated patients with BD can present with variable neurological and dermatological signs, such as seizures, hypotonia, feeding problems, developmental delay, hearing loss, optic atrophy ataxia, alopecia, and skin rash. Clinical findings of patients with partial BD reported in the literature show that it can occur from infancy to adulthood. Outcomes of newborn screening programs support the fact that biotin treatment started after birth prevents patients with biotinidase deficiency from developing symptoms. Presence of late-onset cases with different clinical findings indicates that there is still much to learn about BD. | 01 = IsEpi
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BACKGROUND:Tumours are known to increase the risk of infections, especially those occurring in the central nervous system where insertion of surgical hardware/shunts such as in craniopharyngiomas may be required. However, infections are surprisingly scarce in craniopharyngioma cases. In this study, we explored the possibility of antimicrobial effects of craniopharyngioma cystic fluid. METHODS:The antibacterial effect of craniopharyngioma cystic fluid samples against selected human pathogens: Escherichia. coli, S. aureus and S. pneumoniae were determined using the agar disc diffusion method. Streptomycin and ampicillin were used as controls. The test organisms were cultured in Mueller-Hinton broth overnight at 37 °C. McFarland standard was used as a reference to adjust the inoculum size of each test organism to a concentration of 1 × 106 CFU/ml using sterile broth. RESULTS:The craniopharyngioma cystic fluid inhibited growth of Gram-positive bacteria S. aureus and S. pneumoniae, but not the Gram-negative bacteria, E. coli. The samples showed the highest zones of S. pneumoniae growth inhibition of up to 20.0 ± 1.0 mm compared with 18.0 ± 1.0 mm of streptomycin and 9.0 ± 0.0 mm of ampicillin. CONCLUSION:Craniopharyngioma cystic fluid showed significant antibacterial properties against Gram-positive bacteria. This novel finding has implications in the way we view infections in craniopharyngioma patients. More studies need to be carried out to further elucidate this unique finding and possibly exploit these antimicrobial properties. | 01 = IsEpi
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Context: Berberine is an alkaloid that possesses various pharmacologic effects.Objective: To explore the mechanism of berberine to improve insulin sensitivity in fructose-fed mice.Materials and methods: Sixty male ICR mice were randomly divided into 6 groups (10 mice in each group): control, fructose, pioglitazone (10 mg/kg) and berberine (50, 100, and 200 mg/kg). Except for the control group, the mice received 20% fructose drinking for 10 weeks. Pioglitazone and berberine were orally administered once daily during the last 4 weeks. The insulin sensitivity was evaluated using an oral glucose tolerance test (OGTT). The serum levels of fasting glucose and insulin, blood lipids, and hormones were determined. The hepatic AMP and ATP contents were detected using high performance liquid chromatography (HPLC) analysis, and the protein expression was examined by immunoblotting.Results: Berberine significantly reversed the insulin resistance induced by fructose, including lowering fasting insulin levels (from 113.9 to 67.4) and area under the curve (AUC) during OGTT (from 1310 to 1073), decreasing serum leptin (from 0.28 to 0.13) and increasing serum adiponectin levels (from 1.50 to 2.80). Moreover, berberine enhanced the phosphorylation levels of protein kinase B (PKB/AKT; 2.27-fold) and glycogen synthase kinase-3β (GSK3β; 2.56-fold), and increased hepatic glycogen content (from 0.19 to 1.65). Furthermore, berberine upregulated the protein expression of peroxisome proliferator activated receptor gamma coactivator 1α (PGC1α; 2.61-fold), phospho-AMP-activated protein kinase (p-AMPK; 1.35-fold) and phospho-liver kinase B1 (p-LKB1; 1.41-fold), whereas it decreased the AMP/ATP ratio (from 4.25 to 1.82).Conclusion: The present study demonstrated the protective effects of berberine against insulin resistance induced by fructose. Our findings may provide an experimental basis for the application of berberine in the treatment of insulin resistance. | 01 = IsEpi
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PURPOSE:Spinal cord involvement in Kearns-Sayre (KSS) syndrome could be more frequent than commonly thought. Our aims were to evaluate the involvement of the spinal cord in patients with KSS by means of MRI and to investigate possible correlations of spinal and brain disease with patient disability. METHODS:Eleven patients with KSS disease and spinal cord MRI were retrospectively recruited. The severity of spinal disease was defined as follows: grade 0 (none), grade 1 (focal), and grade 2 (extensive). We calculated a radiologic score of brain involvement based on typical features. We performed a chi-square test to correlate spinal cord and brain MRI involvement to patient disability. For significant variables, a contingency coefficient, phi factor, and Cramer's V were also computed. RESULTS:Spinal cord lesions were detected in 6/11 patients, showing four patterns: involvement of gray matter, gray matter and posterior columns, posterior columns, and anterior columns. The severity of spinal disease was grade 1 in two and grade 2 in four patients. All patients showed brain involvement (9-point average for patients with spinal involvement and 10 for the others). A significant correlation was found between disability score and spinal cord involvement (χ2 = 7.64; p = 0.022) or brain score (χ2 = 26.85; p = 0.043). Significance for brain score-disability correlation increased with the spinal cord as a cofactor (χ2 = 24.51; p = 0.017, phi factor = 1.201, Cramer's V = 0.849, contingency effect = 0.767; p = 0.017). CONCLUSION:Spinal cord lesions are common in KSS. Patients with spinal disease show higher disability than patients without spinal cord lesions, supporting the inclusion of dedicated acquisitions to routine MRI of the brain in patients with KSS. | 01 = IsEpi
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BACKGROUND:The Registry of Adult and Paediatric Patients Treated with Cystadane® - Homocystinuria (RoCH) is a non-interventional, observational, multi-centre, post-authorization safety study that aimed to identify safety of betaine anhydrous (Cystadane®) in the treatment of patients with inborn errors of homocysteine metabolism (homocystinuria) in order to minimise the treatment associated risks and establish better knowledge on its clinical use. The registry included patients of all ages with homocystinuria who were treated with betaine anhydrous in conjunction with other therapies. Clinical data were collected retrospectively from 2007 to 2013, then prospectively up to February 2014. All adverse events (AEs) reported during the study were recorded. The clinical and biological status of patients was monitored at least once a year. RESULTS:A total of 125 patients with homocystinuria (adults [> 18 years]: 50; paediatric [≤18 years]: 75) were enrolled at 29 centres in France and Spain. Patients were treated with betaine anhydrous for a mean duration of 7.4 ± 4.3 years. The median total daily dose of betaine anhydrous at the first and last study visits was 6 g/day for cystathionine β-synthase (CBS)-deficient vitamin B6 responders and 9 g/day for methylenetetrahydrofolate reductase-deficient patients, while the median daily dose increased in CBS-deficient B6 non-responders (from 6 to 9 g/day) and cobalamin metabolism-defective patients (from 3 to 6 g/day) between the first and last visits. Treatment caused a mean overall reduction of 29% in plasma homocysteine levels in the study population. A total of 277 AEs were reported during the study, of which two non-serious AEs (bad taste and headache) and one serious AE (interstitial lung disease) were considered to be drug related. Overall, betaine anhydrous was well tolerated with no major safety concerns. CONCLUSIONS:Data from the RoCH registry provided real-world evidence on the clinical safety and efficacy of betaine anhydrous in the management of homocystinuria in paediatric and adult patients. | 01 = IsEpi
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BACKGROUND:Granulomatous lobular mastitis (GM) is a rare chronic benign inflammatory breast condition. It can present a diagnostic challenge and mimic inflammatory carcinoma. It causes significant morbidity for affected patients. OBJECTIVE:The aim of this article is to provide a clinical update and case study for general practitioners, who are usually the first to see the patient. DISCUSSION:GM is usually idiopathic. The condition presents with a large painful lump with erythema. There is often ulceration, abscess and sinus formation. Triple assessment is needed to confirm diagnosis. GM may last for 12 months or more before healing occurs. Options for management are conservative/supportive care, oral prednisone or methotrexate, or surgical excision. At present, there is no universally accepted management strategy for GM; therefore, treatment will depend on the symptoms, extent of disease and patient preferences. Supporting the patient in coping with the long-term nature of GM and the chronic discharging lesions is essential. | 01 = IsEpi
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Whole-exome sequencing was used to identify the genetic etiology of a rapidly progressing neurological disease present in two of six siblings with early childhood onset of severe progressive spastic paraparesis and learning disabilities. A homozygous mutation (c.2005G>T, p, V669L) was found in VAC14, and the clinical phenotype is consistent with the recently described VAC14-related striatonigral degeneration, childhood-onset syndrome (SNDC) (MIM#617054). However, the phenotype includes a distinct clinical presentation of retinitis pigmentosa (RP), which has not previously been reported in association with VAC14 mutations. Brain magnetic resonance imaging (MRI) revealed abnormal magnetic susceptibility in the globus pallidus, which can be seen in neurodegeneration with brain iron accumulation (NBIA). RP is a group of inherited retinal diseases with phenotypic/genetic heterogeneity, and the pathophysiologic basis of RP is not completely understood but is thought to be due to a primary retinal photoreceptor cell degenerative process. Most cases of RP are seen in isolation (nonsyndromic); this is a report of RP in two siblings with VAC14-associated syndrome, and it is suggested that a connection between RP and VAC14-associated syndrome should be explored in future studies. | 01 = IsEpi
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Diffuse leptomeningeal glioneuronal tumor (DLGNT) was introduced, for the first time, as a provisional entity in the 2016 WHO classification of central nervous system tumors. DLGNT mainly occur in children and characterized by a widespread leptomeningeal growth occasionally associated with intraspinal tumor nodules, an oligodendroglial-like cytology, glioneuronal differentiation and MAP-Kinase activation associated with either solitary 1p deletion or 1p/19q codeletion in the absence of IDH mutation.We report here two unexpected DLGNTs adult cases, characterized by a unique supratentorial circumscribed intraparenchymal tumor without leptomeningeal involvement in spite of long follow-up. In both cases, the diagnosis of DLGNT was made after DNA-methylation profiling which demonstrated that one case belonged to the DLGNT class whereas the other remained not classifiable but showed on CNV the characteristic genetic findings recorded in DLGNT. Both cases harbored 1p/19q codeletion associated with KIAA1549:BRAF fusion in one case and with BRAF V600E and PIK3CA E545A mutations, in the other.Our study enlarges the clinical and molecular spectrum of DLGNTs, and points out that the terminology of DLGNTs is not fully appropriate since some cases could have neither diffuse growth nor leptomeningeal dissemination. This suggests that DLGNTs encompass a wide spectrum of tumors that has yet to be fully clarified. | 01 = IsEpi
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Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes. | 01 = IsEpi
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Waardenburg syndrome (WS) is an autosomal dominant inherited neurogenic disorder with the combination of various degrees of sensorineural deafness and pigmentary abnormalities affecting the skin, hair and eye. The four subtypes of WS were defined on the basis of the presence or absence of additional symptoms. Mutation of human microphthalmia-associated transcription factor (MITF) gene gives rise to WS2. Here, we identified a novel WS-associated mutation at the stop codon of MITF (p.X420Y) in a Chinese WS2 patient. This mutation resulted in an extension of extra 33 amino-acid residues in MITF. The mutant MITF appeared in both the nucleus and the cytoplasm, whereas the wild-type MITF was localized in the nucleus exclusively. The mutation led to a reduction in the transcriptional activities, whereas the DNA-binding activity was not altered. We show that the foremost mechanism was haploinsufficiency for the mild phenotypes of WS2 induced in X420Y MITF. | 01 = IsEpi
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Mounier-Kuhn Syndrome (MKS) is a rare disease characterised by recurrent chest infections, and dilation of the trachea and main bronchi, most likely to due to atrophy of elastic fibres https://bit.ly/3azhDjr. | 01 = IsEpi
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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
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BACKGROUND:Scurvy, the disease resulting from vitamin C deficiency, is perceived as being rare and occurring predominantly in the past. However, scurvy continues to exist and may be encountered in children with medical/developmental conditions and/or restricted diet. Diagnosis can be challenging given the perceived rarity of the condition and nonspecific symptoms, including gingival disease. METHODS:We present a series of two cases of scurvy in which the affected children presented to medical attention with dental complaints. Additional cases of scurvy are described, based on the literature review of case reports/series published in the last 10 years. RESULTS:Literature review yielded 77 relevant case reports published in the English language since 2009. Most affected children had a previous diagnosis of a medical or developmental condition (especially autism spectrum disorder). Intraoral features (gingival swelling, pain, and bleeding) were noted in most of the identified cases of scurvy. Improvement in the oral features of scurvy occurred within days of vitamin C therapy initiation. CONCLUSIONS:Recognizing classic signs and symptoms of scurvy enables prompt diagnosis and avoids invasive investigations. Dentists may be in a unique position to facilitate prompt and accurate diagnosis of a condition that is relatively easy and safe to treat once identified. | 01 = IsEpi
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Factor H (fH) and properdin both modulate complement; however, fH inhibits activation, and properdin promotes activation of the alternative pathway of complement. Mutations in fH associate with several human kidney diseases, but whether inhibiting properdin would be beneficial in these diseases is unknown. Here, we found that either genetic or pharmacological blockade of properdin, which we expected to be therapeutic, converted the mild C3 GN of an fH-mutant mouse to a lethal C3 GN with features of human dense deposit disease. We attributed this phenotypic change to a differential effect of properdin on the dynamics of alternative pathway complement activation in the fluid phase and the cell surface in the fH-mutant mice. Thus, in fH mutation-related C3 glomerulopathy, additional factors that impact the activation of the alternative pathway of complement critically determine the nature and severity of kidney pathology. These results show that therapeutic manipulation of the complement system requires rigorous disease-specific target validation. | 01 = IsEpi
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BACKGROUND:The spotted fever rickettsioses (SFR), including Rocky Mountain spotted fever, are tick-borne infections with frequent neurologic involvement. High morbidity and mortality make early recognition and empiric treatment critical. Most literature on SFR meningoencephalitis predates widespread magnetic resonance imaging (MRI) utilization. To better understand the contemporary presentation and outcomes of this disease, we analyzed clinical and radiographic features of patients with SFR meningoencephalitis. METHODS:Patients were identified through hospital laboratory-based surveillance or through the Tennessee Unexplained Encephalitis Study. Cases meeting inclusion criteria underwent medical records review and, when available, independent review of the neuroimaging. RESULTS:Nineteen cases (11 children, 8 adults) met criteria for SFR meningoencephalitis. Rash was significantly more common in children than adults (100% vs 50%, respectively), but other clinical features were similar between the 2 groups. Cerebrospinal fluid pleocytosis and protein elevation were each seen in 87.5% of cases, and hypoglycorrhachia was present in 18.8% of cases. The "starry sky" sign (multifocal, punctate diffusion restricting or T2 hyperintense lesions) was seen on MRI in all children, but no adults. Ninety percent of patients required intensive care unit admission and 39% were intubated. Outcomes were similar between adults and children, with only 46% making a complete recovery by the time of discharge. CONCLUSIONS:SFR meningoencephalitis is a life-threatening infection. The clinical presentation varies between adults and children based on the presence of rash and brain MRI findings. The starry sky sign was ubiquitous in children and should prompt consideration of empiric treatment for SFR when present. | 01 = IsEpi
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Phacomatosis pigmentokeratotica is a recently identified disease characterized by the coexistence of an epidermal nevus with sebaceous differentiation arranged along Blaschko lines and a speckled lentiginous nevus showing a checkerboard pattern, mostly in association with various extracutaneous defects. A 52-year-old man presented with asymptomatic ulcerative plaque on his left side of perioral area. A 2 × 2-cm-sized fleshy colored ulceration on his left perioral area was consistent with basal cell carcinoma with nevus sebaceous. Next to the ulceration, there was a light pinkish to fleshy colored papule on his left cheek that showed syringocystadenoma papilliferum. On his chin area, there was a 2 × 0.3-cm-sized skin colored papule that was consistent with trichilemmoma. Moreover, various sized light brownish macules and dark brownish papules were also located on his left side of the chest wall, back, and arm. Biopsy specimens from macules on the left side of the trunk confirmed the clinical diagnosis of speckled lentiginous nevus and multiple black papules beside that a speckled lentiginous nevus also revealed basal cell carcinomas. Herein, we present a rare case of a patient with phacomatosis pigmentokeratotica who had no extracutaneous abnormalities and who developed basal cell carcinoma, syringocystadenoma papilliferum, and trichilemmoma in nevus sebaceous on the face and speckled lentiginous nevus on the trunk. This syndrome needs adequate follow-up due to the possibility of malignant transformation. | 01 = IsEpi
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Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant inherited disease caused by mutations in the folliculin (FLCN) gene. It is characterized by lung cysts, skin fibrofolliculomas and an increased risk for the development of renal cancer, especially chromophobe. Lung cysts in the context of BHDS are typically lower lobe predominant, paramediastinal, in relation to the fissures and often elliptical shaped. Skin manifestations can easily go unnoticed. Respiratory physicians need to have a high degree of vigilance as they can be the first to suspect the disease in the setting of diffuse cystic lung disease. Meticulous skin examination and referral to a dermatologist is of utmost importance as it can establish the diagnosis in the least invasive way. Correct diagnosis is crucial as it may allow for genetic counseling to the affected family and the implementation of a monitoring strategy for early detection of renal cancer. | 01 = IsEpi
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Currently, offering whole-exome sequencing (WES) via collaboration with an external laboratory is increasingly common. However, the receipt of a WES report can be merely the beginning of a continuing exploration process rather than the end of the diagnostic odyssey. The laboratory often does not have the information the physician has, and any discrepancies in variant interpretation must be addressed by a medical geneticist. In this study, we performed diagnostic WES of 104 patients with paediatric-onset genetic diseases. The post-exome review of WES reports by the clinical geneticist led to a more comprehensive assessment of variant pathogenicity in 16 cases. The overall diagnostic yield was 41% (n = 43). Among these 43 diagnoses, 51% (22/43) of the pathogenic variants were nucleotide changes that have not been previously reported. The time required for the post-exome review of the WES reports varied, and 26% (n = 27) of the reports required an extensive amount of time (>3 h) for the geneticist to review. In this predominantly Chinese cohort, we highlight the importance of discrepancies between global and ethnic-specific frequencies of a genetic variant that complicate variant interpretation and the significance of post-exome diagnostic modalities in genetic diagnosis using WES. The challenges faced by geneticists in interpreting WES reports are also discussed. | 01 = IsEpi
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The Anderson-Fabry disease (AFD, or simply Fabry Disease, FD; MIM #301500) is a rare X-linked lysosomal storage disorder (Xq22.1) characterized by progressive renal failure, leading to morbidity through cardio- and cerebro-vascular involvement. Despite the classic phenotype, only cardiac involvement (cardiac variant of AFD; MIM 301500) is frequent in about 40% of male and 28% of female AFD patients, as reported by the Fabry Registry ( https://www.registrynxt.com ). Morphologically, the cardiac characteristic of the disease, occurs as left ventricular hypertrophy, is accompanied by myocardial fibrosis. Cardiologists may come across these patients during clinical and instrumental evaluation in individuals with non-specific symptoms such as chest pain and arrhythmias, or after instrumental evidence of left ventricular hypertrophy/hypertrophic cardiomyopathy (HCM; MIM 192600). A comprehensive cardiological work-up, including a cardiological visit, a baseline electrocardiogram (ECG) and imaging by both echocardiography (ECHO) and magnetic resonance (MRI) enables identification of the cardiac involvement in patients with a proven diagnosis of AFD. The heart involvement is present in up to 75% of AFD patients irrespective of their sex. Involvement includes ECG and echocardiography features which suggest AFD and not HCM. Cardiac imaging plays an important role in detecting this sub-type of cardiomyopathy, which, since 2001, has benefited from the introduction of the enzyme replacement therapy (ERT) in symptomatic and pre-symptomatic patients. | 01 = IsEpi
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The core axoneme structure of both the motile cilium and sperm tail has the same ultrastructural 9 + 2 microtubular arrangement. Thus, it can be expected that genetic defects in motile cilia also have an effect on sperm tail formation. However, recent studies in human patients, animal models and model organisms have indicated that there are differences in components of specific structures within the cilia and sperm tail axonemes. Primary ciliary dyskinesia (PCD) is a genetic disease with symptoms caused by malfunction of motile cilia such as chronic nasal discharge, ear, nose and chest infections and pulmonary disease (bronchiectasis). Half of the patients also have situs inversus and in many cases male infertility has been reported. PCD genes have a role in motile cilia biogenesis, structure and function. To date mutations in over 40 genes have been identified cause PCD, but the exact effect of these mutations on spermatogenesis is poorly understood. Furthermore, mutations in several additional axonemal genes have recently been identified to cause a sperm-specific phenotype, termed multiple morphological abnormalities of the sperm flagella (MMAF). In this review, we discuss the association of PCD genes and other axonemal genes with male infertility, drawing particular attention to possible differences between their functions in motile cilia and sperm tails. | 01 = IsEpi
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Hypercortisolemia in females may lead to menstrual cycle disturbances, infertility, hirsutism and acne. Herewith, we present a 18-year-old patient, who was diagnosed due to weight gain, secondary amenorrhea, slowly progressing hirsutism, acne and hot flashes. Thorough diagnostics lead to a conclusion, that the symptoms was the first manifestation of primary pigmented nodular adrenocortical disease (PPNAD). All symptoms of Cushing syndrome including hirsutism and menstrual disturbances resolved after bilateral adrenalectomy. Our report indicates that oligo- or amenorrhea, hirsutism, acne in combination with weight gain, growth failure, hypertension and slightly expressed cushingoid features in a young woman requires diagnostics towards hypercortisolemia. Despite PPNAD is a very rare cause of ACTH-independent Cushing syndrome, it has to be taken into consideration, especially when adrenal glands appear to be normal on imaging and paradoxical rise in cortisol level in high-dose dexamethasone test is observed. Unlike in our patient, in vast majority of patients, PPNAD is associated with Carney complex (CC). Therefore, these patients and their first-degree relatives should be always carefully screened for symptoms of PPNAD, CC and genetic mutations of PRKAR1A, PDE11A, and PDE8B genes. | 01 = IsEpi
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BACKGROUND:The Clinica del Lavoro of Milan provided several contributions to industrial hygiene and occupational toxicology during the twentieth century. OBJECTIVES:Describe the first years of the laboratory of industrial hygiene of Milan through three figures who played a leading role: Enrico Carlo Vigliani, Nicola Zurlo and Gianmario Cavagna. METHODS:Scientific literature of the period 1948-1970 was investigated, also interviewing first-hand witnesses of that period. RESULTS:Enrico Vigliani was the first European scholar to understand the importance of a laboratory of industrial hygiene within his institution. Thanks to the support of private (Montecatini) and public (INAIL) institutions he succeeded in creating a laboratory in 1948. Nicola Zurlo, who directed this structure in the first thirty years, conducted innovative studies on chronic mercury intoxication, lead intoxication and silicosis, designing and creating instruments for capturing and analyzing atmospheric dust and protection devices. He conducted analysis of the health effects of organophosphorus insecticides and started to study the air pollution. Zurlo also provided an epistemological and methodological content to the discipline. Gianmario Cavagna, one of the first Italian toxicologists, contributed to the discovery of the origin of fevers caused by the inhalation of metal fumes and to the studies on the pathogenesis of byssinosis, hypothesizing a role of bacterial endotoxins in the genesis of this disease. CONCLUSIONS:The contributions provided by these three protagonists to industrial hygiene and occupational toxicology were relevant and made in those years the Clinica del Lavoro of Milan as a landmark, not only in Italy but also abroad. | 01 = IsEpi
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