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The ectodermal dysplasias (ED) are a large and complex group of diseases characterized by anomalies of the ectoderm and its derivates, often associated with malformations in other organs. We report a patient with an ectodermal dysplasia affecting hair, teeth, and nails and malformations of all four extremities including absence of several rays in the hands and feet. This patient shares many similarities with odontotrichomelic syndrome, a rare ectodermal dysplasia syndrome that has so far only been described in three individuals. However, some differences exist and this patient might also represent a separate ectodermal dysplasia syndrome. p63, a gene that is mutated in a number of syndromes associated with ectodermal dysplasia and limb malformations, was considered a possible candidate gene. However, no mutation in p63 was identified. | 01 = IsEpi
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Hand-Foot-Genital syndrome is a rare condition caused by mutations in the HOXA13 gene and characterized by limb malformations and urogenital defects. While the role of Hoxa13 in limb development has been extensively studied, its function during the development of the urogenital system remains elusive mostly due to the embryonic lethality of Hoxa13 homozygous mutant mice. Using a conditional inactivation strategy, we show that mouse fetuses lacking Hoxa13 function develop megaureters, hydronephrosis and malformations of the uterus, reminiscent of the defects characterizing patients with Hand-Foot-Genital syndrome. Our analysis reveals that Hoxa13 plays a critical role in Müllerian ducts fusion and in ureter remodeling by regulating the elimination of the caudal common nephric duct, eventually preventing the separation from the nephric duct. Our data also reveal a specific role for Hoxa13 in the urogenital sinus, which is in part mediated by Gata3, as well as Hoxa13 requirement for the proper organization of the ureter. Finally, we provide evidence that Hoxa13 provides positional and temporal cues during the development of the lower urogenital system, a sine qua non condition for the proper function of the urinary system. | 01 = IsEpi
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Anomalies of pyramidal tract decussation are rare phenomena that can be caused by ectodermal dysplasia. Herein, we describe a patient with ichthyosis who exhibited ipsilateral hemiparesis after stroke and whose neuroimaging results showed evidence of motor control being provided by the ipsilateral motor cortex. A 24-year-old right-handed man presented with skin abnormalities, sudden-onset left hemiparesis, and dysarthria. He exhibited a mild-to-moderate left-sided weakness (grade 4 on the Medical Research Council scale). Magnetic resonance imaging revealed an acute infarct in the left corona radiata. Diffusion tensor imaging revealed uncrossed corticospinal tracts. Next-generation sequencing identified heterozygous FLG mutations. The patient was diagnosed with cerebral infarction and ichthyosis vulgaris and was treated with aspirin (100 mg/d). His symptoms gradually dissipated. This case suggests that pyramidal decussation anomalies can be associated with ichthyosis. Patients with ichthyosis should therefore be evaluated for nerve involvement. | 01 = IsEpi
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BACKGROUND:Non-target embolization is a well-known complication of endovascular procedures for arteriovenous malformation. However, few reports have described non target encephalic embolization, detailing its temporal evolution. CASE PRESENTATION:A 41-year-old man presented with a massive hemorrhage in the oral cavity due to an arteriovenous malformation involving the left hemiface and tongue. Under conscious sedation, selective angiography was followed by endovascular embolization with a mixture of n-butyl-cyanoacrylate-methacryloxy-sulfolane (NBCA-MS) with Lipiodol. The hemorrhage was successfully arrested, but the procedure was complicated with a reflux of embolic material from the right external carotid artery into the common carotid, caused by strong unexpected coughing. Non-target embolization was confirmed by emergency CT and subsequent MRI. After initial neurological impairment, the patient recovered fully and was discharged after one week. No sequelae were confirmed by 9-months follow-up with CT and MRI. We describe technical aspects, multimodality imaging, clinical presentation, and follow-up of this peculiar case. CONCLUSION:Endovascular embolization of AVM fed by the external carotid is at risk for non-target brain embolization and general anesthesia should be considered to prevent inadvertent movements and master the delivery of the embolic agent A small amount of Lipiodol / NBCA-MS may be fully tolerated by the brain matter and partially reabsorbed without permanent deficit. | 01 = IsEpi
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Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases with progressive weakness of skeletal and respiratory muscles, leading to significant disability. The disorder is caused by mutations in the survival motor neuron 1 (SMN1) gene and a consequent decrease in the SMN protein leading to lower motor neuron degeneration. Recently, Food and Drug Administration (FDA) and European Medical Agency (EMA) approved the antisense oligonucleotide nusinersen, the first SMA disease-modifying treatment and gene replacement therapy by onasemnogene abeparvovec. Encouraging results from phase II and III clinical trials have raised hope that other therapeutic options will enter soon in clinical practice. However, the availability of effective approaches has raised up ethical, medical and financial issues that are routinely faced by the SMA community. This review covers the available data and the new challenges of SMA therapeutic strategies. | 01 = IsEpi
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We present a case of a patient with Anton's syndrome due to decompression illness (DCI) after recreational scuba diving. Visual anosognosia, or denial of loss of vision, which is associated with lack of awareness regarding visual loss in the setting of cortical blindness, is known as Anton's syndrome (also termed Anton-Babinski syndrome). Our patient presented with progressive neurological DCI treated with repeated recompression. The anosogosia resolved after 48 h. Subsequent echocardiography revealed a persistent (patent) foramen ovale. | 01 = IsEpi
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Objective: To investigate the clinical features and genetic characteristics of cases with X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia (XMEN). Methods: Characteristics of clinical material, immunological data and gene mutation of two cases with XMEN in the same family in China were retrospectively analyzed. The related reports literature were searched by using search terms'MAGT1 gene'or'XMEN'. Results: The proband, a 2-year-eight-month old boy, was admitted due to 'Urine with deepened color for two days and yellow stained skin for one day'. He had suffered from recurrent upper respiratory tract infection and sinusitis previously. Hemoglobin level was 38 g/L. The absolute count of reticulocytes was 223.2×10(9)/L. Urobilinogen level was 38 μmol/L (3-16 μmol/L). Coomb's test was positive. Both total (77.2 μmol/L) and indirect bilirubin (66 μmol/L) levels were elevated. There was an inverted CD4(+)/CD8(+)T cell ratio (0.89). The gene sequencing results showed MAGT1 gene c.472delG, p.D158Mfs*6 mutation. His 1-year-6-month old brother, was also identified to have MAGT1 gene c.472delG, p.D158Mfs*6 mutation.The younger brother mainly suffered from recurrent upper respiratory tract infection, accompanied by an inverted CD4(+)/CD8(+)T cell ratio (0.45), an elevated ratio and number of total B cells (45.7%). A total of 7 reports were retrieved including 11 male cases caused by MAGT1 gene mutation. These 11 cases were characterized by EBV viremia (11 cases), recurrent upper respiratory tract infection, otitis media or sinusitis (10 cases), secondary neoplasia diseases (8 cases), reduction of CD4(+)/CD8(+) T cell ratio (7 cases),and autoimmune thrombocytopenia or hemolytic anemia (2 cases). Conclusion: XMEN often manifests as male onset, recurrent upper respiratory tract infection, otitis media or sinusitis, EBV viremia, lymphoproliferative disease or lymphoma, autoimmune diseases and reduction of CD4(+)/CD8 (+)T cell ratio. NKG2D expression in NK cells is significantly reduced, and gene sequencing analysis shows a pathogenic mutation in MAGT1 gene. | 01 = IsEpi
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We report the case of a 75-year-old woman who developed band keratopathy following denosumab therapy. The patient was referred for evaluation of progressive vision loss and new-onset band keratopathy in both eyes following denosumab therapy. She had no prior ocular history. On examination, she had calcific deposits in a horizontal band in the interpalpebral superficial cornea. Laboratory workup was negative. Denosumab was discontinued, and she was treated with keratectomy with ethylene-diamine-tetra-acetic acid. Denosumab influences calcium metabolism and consequently reduces bone turnover and increases bone density. It is commonly used for treatment of osteoporosis at high-risk for fracture. Very few cases of ocular adverse drug reactions have been reported. However, because of temporal association and biological plausibility, we believe our patient developed progressive band keratopathy after administration of denosumab. | 01 = IsEpi
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Lateral meningocele syndrome (LMS) is a rare genetic connective tissue disorder. It is associated with morphological changes similar to those of other connective tissue disorders, with the unique distinction of multiple, often bilateral and large, lateral meningoceles herniating through the spinal foramina. In some cases, these lateral meningoceles can cause pain and discomfort due to their presence within retroperitoneal tissues or cause direct compression of the spinal nerve root exiting the foramen; in some cases compression may also involve motor weakness. The presence of lateral meningoceles imposes unique challenges related to CSF flow dynamics, especially with concurrent Chiari malformation, which also occurs with increased frequency in individuals with LMS. The authors present the case of a 6-month-old female with LMS with multiple lateral meningoceles throughout the thoracic and lumbar spine. The infant experienced a focal neurological abnormality due to enlargement of her lateral meningoceles following decompression of a symptomatic Chiari malformation and endoscopic third ventriculostomy. The finding was reversed through implantation of a ventriculoperitoneal shunt, which reduced the burden of CSF upon the lateral meningoceles. Such a case compels consideration that CSF flow dynamics in addition to altered connective tissue play a role in the presence of lateral meningoceles in patients within this and similar patient populations. | 01 = IsEpi
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Producing speech that is clear, audible, and intelligible to others is a challenge for many children with cerebral palsy (CP) and children with Down syndrome (DS). Previous studies have demonstrated the effectiveness of using the Lee Silverman Voice Treatment (LSVT LOUD®) to increase vocal loudness and improve speech intelligibility in individuals with dysarthria secondary to Parkinson's disease (PD), and some research suggests that it also may be effective for individuals with dysarthria secondary to other conditions, including CP and DS. Although LSVT LOUD targets healthy vocal loudness, there is some evidence of spreading effects to the articulatory system. Acoustic data from two groups of children with secondary motor speech disorders [one with CP (n = 17) and one with DS (n = 9)] who received a full dose of LSVT LOUD and for whom post-treatment intelligibility gains have been previously reported, were analyzed for treatment effects on: 1) vowel duration, 2) acoustic vowel space and 3) the ratio of F2/i/ to F2/u/. Statistically significant changes in vowel duration and acoustic vowel space occurred pre-treatment to 12 weeks post-treatment in the CP group, and increased acoustic vowel space was observed in 5 of the DS participants. The present study provides preliminary evidence of intensive voice treatment spreading effects to the articulatory system in some children with CP and children with DS consistent with previous findings in other populations. | 01 = IsEpi
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Type 2 multiple endocrine neoplasia (MEN2A) is a variant of hereditary medullary thyroid carcinoma (MTC). MEN2A is characterized by the presence of the following: MTC, hyperparathyroidism, and pheochromocytoma (PHEO). The pathogenesis includes RET proto-oncogene mutation; the most frequently observed mutation is in exon 11 codon 634. We report pedigree of a large Indian family involving three generations including 21 members with MEN2A, in whom RET mutation status was determined. We then analyzed their clinical follow-up details, with a median duration of follow-up of 60 months (range: 9-276 months). Calcitonin (Ctn) levels were routinely checked during the follow-up. The index case was found to carry p.C634R mutation involving exon 11 of the RET gene. RET mutation was positive in 12 members in the family (12/21, i.e., 57%), was negative in 7 patients, and was not tested in 2 patients, as they were not available for the genetic test. Thirteen were clinically affected with MTC and 10 members had PHEO. At the last follow-up, the median Ctn level was 14.3 pg/mL (range: 2-12655 pg/mL). Four patients developed lymph nodal recurrence during follow-up, for which they underwent re-operations with median duration to recurrence being 48 months (range: 9-156 months). We highlight in this article that early diagnosis, adequate surgery, and appropriate genetic counseling with genetic screening are essential to improve the outcome of persons with MTC. Every case of MTC should be seen as familial or index case of hereditary MTC unless otherwise RET mutation excludes it. | 01 = IsEpi
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Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) are poor outcome leukemias. Its diagnosis is based on clinical, cytogenetic, and cytomorphologic criteria, last criterion being sometimes difficult to assess. A high frequency of ASXL1 mutations have been described in this leukemia. We sequenced ASXL1 gene mutations in 61 patients with AML-MRC and 46 controls with acute myeloid leukemia without other specifications (AML-NOS) to identify clinical, cytomorphologic, and cytogenetic characteristics associated with ASXL1 mutational status. Mutated ASXL1 (ASXL1+) was observed in 31% of patients with AML-MRC compared to 4.3% in AML-NOS. Its presence in AML-MRC was associated with older age, a previous history of myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN), leukocytosis, presence of micromegakaryocytes in bone marrow, lower number of blasts in bone marrow, myelomonocytic/monocytic morphological features and normal karyotype. ASXL1 mutation was not observed in patients with myelodysplastic syndrome-related cytogenetic abnormalities or TP53 mutations. Differences in terms of overall survival were found only in AML-MRC patients without prior MDS or MDS/MPN and with intermediate-risk karyotype, having ASXL1+ patients a worst outcome than ASXL1-. We conclude that the ASXL1 mutation frequency is high in AML-MRC patients being its presence associated with specific characteristics including morphological signs of dysplasia. This association raises the possible role of ASXL1 as a surrogate marker in AML-MRC, which could facilitate the diagnosis of patients within this group when the karyotype is normal, and especially when the assessment of multilineage dysplasia morphologically is difficult. This mutation could be used as a worst outcome marker in de novo AML-MRC with intermediate-risk karyotype. | 01 = IsEpi
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Hypersensitivity pneumonitis (HP) is an immunologically mediated lung disease resulting from exposure to inhaled environmental antigens. Prognosis is variable, with a subset of patients developing progressive fibrosis leading to respiratory failure and death. Therefore, there is an urgent need to identify factors which predict prognosis and survival in patients with HP. We undertook a narrative review of existing evidence to identify prognostic factors in patients with chronic HP. Patient demographics, smoking history, extent of antigen exposure and comorbidities all have reported associations with disease outcome, and physiological, radiological and laboratory markers have been shown to predict overall survival. While no single marker has been demonstrated to accurately and reliably predict prognosis, older age, more severe impairment of pulmonary function at baseline and established fibrosis on either biopsy or high-resolution computed tomography are consistently associated with worse survival. The vast majority of existing studies are retrospective, and this review identifies a need for prospective longitudinal studies with serial assessment of respiratory health to ascertain factors associated with nonfatal deterioration. Future developments, including the development of HP-specific composite scores may help further improve our ability to predict outcomes for individual patients. | 01 = IsEpi
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In 1993, Jabs et al. were the first to describe a genetic origin of craniosynostosis. Since this discovery, the genetic causes of the most common syndromes have been described. In 2015, a total of 57 human genes were reported for which there had been evidence that mutations were causally related to craniosynostosis. Facilitated by rapid technological developments, many others have been identified since then. Reviewing the literature, we characterize the most common craniosynostosis syndromes followed by a description of the novel causes that were identified between January 2015 and December 2017. | 01 = IsEpi
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β thalassemia major is a common hemoglobinopathy in Sri Lanka. Klebsiella pneumoniae (KP) is a Gram-negative capsulated organism responsible for various nosocomial and community-acquired infections. Transfusion-dependent splenectomized thalassemia patients are at risk of infections. Liver abscess is an infection to suspect in such patients, and, among the organisms, KP is an organism to watch out for. Furthermore, KP could cause multiple liver abscesses, which makes it difficult to treat, as it cannot be drained. We report a 16-year-old splenectomized transfusion-dependent thalassemia major patient who presented with multiple liver abscesses with KP bacteremia. | 01 = IsEpi
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Cyclical intravenous treatment with pamidronate is widely used to treat osteogenesis imperfecta (OI) types I, III, and IV, which are due to dominant mutations affecting collagen type I alpha chains. There is no information about the effects of pamidronate in children with OI type VII, an autosomal-recessive form of OI caused by a mutation in the cartilage-associated protein gene. In this retrospective single-center study, we compared the effects of pamidronate in four girls with OI type VII (age range 3.9-12.7 years) to those in eight girls with OI types caused by collagen type I mutations who were matched for age and disease severity. During 3 years of pamidronate therapy, lumbar spine areal bone mineral density increased and lumbar vertebral bodies improved in shape in patients with OI type VII. Other outcomes such as fracture rates and mobility scores did not show statistically significant changes in this small study cohort. There were no significant side effects noted during the time of follow-up. Thus, intravenous treatment with pamidronate seems to be safe and of some benefit in patients with OI type VII. | 01 = IsEpi
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This study describes the optical coherence tomography and optical coherence tomography angiography features of three eyes of three patients affected by contractile morning glory syndrome. Optical coherence tomography angiography scans of the peripapillary retina revealed a dense microvascular network without any vascular difference between the superficial vascular plexus and the deep vascular plexus around the optic nerve. These optical coherence tomography angiography findings confirm that the contractile movement could be due to the presence of an autonomic cholinergic muscular mechanism in the posterior part of the globe. In fact in our cases, the contractile movement seemed to be induced by massage of the eyeball. Optical coherence tomography angiography is a valid, non-invasive, dyeless, and reliable method that could shed light on the pathogenesis of this rare disease of the optic disk. | 01 = IsEpi
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Heart-hand syndrome is a broad category of diseases. The most common form is Holt-Oram syndrome (HOS) that occurs in approximately 1:100 000 live births. It is characterized by upper limb defects (carpal bone defects, triphalangeal thumbs, hypoplasia or absence of the thumb and the radial ray) and cardiac septal defects (atrial septal defects or ventricular septal defects). There are three main types of "heart-hand" syndromes. "Heart-hand" syndrome type I--HOS is characterised by atrial septal defect and thumb anomaly, type II (Tabatznik syndrome) by short distal phalanx of the thumb, upper limb abnormalities and cardiac arrhythmias, type III by cardiac conduction diseases and shortening of the middle phalanges. The aim of this report is to present a new case of the "heart-hand" syndrome in the family. This diagnosis was established on the base of clinical examination, radiological findings, and echocardiography. Our patient demonstrates congenital bilateral absence of a radial bone and thumbs, dextrocardia and patent foramen ovale. | 01 = IsEpi
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PURPOSE:Lymphatic malformations (LMs) compromising the upper airway is a life-threatening and intractable disease. Here, we establish a novel method to perform intralesional focal sclerotherapy targeting the culprit for airway stenosis. METHODS:Between July 2015 and February 2020, 11 patients with airway-compromising LMs were enrolled. To yield maximal effects on the compromised airway with minimal adverse effects, ultrasound-guided intralesional bleomycin sclerotherapy assisted by balloon was performed, aimed at the most responsible lesion around the airway. A retrospective analysis was performed. RESULTS:Ten patients presented with respiratory symptoms, eight of whom required airway support. The last asymptomatic patient showed airway compression on magnetic resonance imaging. The dose of bleomycin injected ranged from 1.3-9 mg per patient per course. A median of one course was required for withdrawal from airway support, and the median time was 15 days. A median of two courses was required to eliminate the lesion adjacent to the airway, which would have potential risk of airway stenosis. No complications were observed. CONCLUSIONS:Our intralesional focal sclerotherapy technique with bleomycin targeting the culprit lesion is dose-sparing, safe, and effective in achieving rapid shrinkage of LMs compromising the upper airway in children, thereby avoiding tracheostomy. | 01 = IsEpi
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Waldenström macroglobulinemia (WM) is an uncommon lymphoma characterized by the infiltration of the bone marrow by clonal lymphoplasmacytic cells that produce monoclonal immunoglobulin M (IgM). The disease may have an asymptomatic phase, or patients may present with symptoms and complications resulting from marrow or other tissue infiltration, or from physicochemical or immunological properties of the monoclonal IgM. Diagnosis of WM has been clearly defined, and genetic testing for somatic mutation of MYD88L265P is a useful tool for differential diagnosis from other conditions. Specific criteria that define symptomatic disease that needs treatment offer clinical guidance. The treatment of WM has evolved rapidly, with treatment options that include anti-CD20 monoclonal antibody-based combinations and BTK inhibitors. The choice of therapy is based on the need for rapid disease control, presence of specific disease complications, and patient's age. With the use of BTK inhibitors, the use of continuous therapy has been introduced as another option over fixed-duration chemoimmunotherapy. In this review, we focus on different clinical scenarios and discuss treatment options, based on the available data. | 01 = IsEpi
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Crouzon syndrome is a genetic disease that is transferred by autosomal dominant inheritance. Patients with this syndrome have craniosynostosis, hypertelorism, orbital proptosis, mid-face hypoplasia, mandibular prognathism, and concave facial profile. A number of surgical treatments are used to improve facial contours, and to correct dental and maxillary relationships. Orthognathic surgery is routinely used in the treatment of these patients. We present a female patient with Crouzon syndrome treated with Le Fort I and bilateral sagittal split osteotomy. Previously, surgically assisted rapid maxillary expansion (SARME) surgery was performed to the patient by separating the pterygomaxillary junction under general anesthesia. Down fracture was performed during the Le Fort I osteotomy without the need to separate the pterygomaxillary junction again. The facial appearance was improved with bilateral sagittal split osteotomy, and skeletal malocclusion between the jaws was treated. | 01 = IsEpi
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PURPOSE:total removal of spinal hemangioblastomas with satisfactory clinical outcomes remains a challenge. We aimed to evaluate the surgical outcomes of our spinal hemangioblastomas patients, summarize our experiences with this condition and review-related literature. METHODS:records of 18 spinal hemangioblastoma patients who underwent microsurgical resection were analyzed retrospectively. Clinical features, surgical procedures and outcomes were reviewed to assess the prognosis of their spinal hemangioblastomas. The McCormick classification method was used to evaluate spinal function and MR scans used to assess location and features of the tumor pre-surgically, tumor recurrence and syringomyelia status post-surgically. RESULTS:total resection of 37 tumors was achieved in all 18 cases. Of those patients, two (11%) were accompanied with von Hippel-Lindau (VHL). Of the 37 tumors, 3 (8.1%) were completely intramedullary, 16 (43.2%) intramedullary-extramedullary and 18 (48.6%) primarily extramedullary. Tumors accompanied with syringomyelia were present in 17 (94.4%) patients. Clinical symptoms such as pain were reduced within 48 h after surgery in 16 patients. Post-operative neurological functions improved in all cases at 3 months post-surgery. Over the subsequent 3-18 month follow-up period, pre-operative symptoms improved in all 18 patients and no tumor recurrence was present. Syringomyelia was reduced or absent within 3-6 months. CONCLUSIONS:our results indicated that a complete microscopic resection was effective in eliminating symptoms in these spinal hemangioblastoma patients, who showed a good prognosis after surgery. These improvements in clinical symptoms may be associated with the blood flow changes, but not with reductions and/or eliminations of syrinx after surgery. | 01 = IsEpi
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Autosomal dominant optic atrophy (ADOA) is a neuro-ophthalmic condition characterized by bilateral degeneration of the optic nerves. Although heterozygous mutations in OPA1 represent the most common genetic cause of ADOA, a significant number of cases remain undiagnosed.Here, we describe a family with a strong ADOA history with most family members spanning three generation having childhood onset of visual symptoms. The proband, in addition to optic atrophy, had neurological symptoms consistent with relapsing remitting multiple sclerosis. Clinical exome analysis detected a novel mutation in the AFG3L2 gene (NM_006796.2:c.1010G > A; p.G337E), which segregated with optic atrophy in family members. AFG3L2 is a metalloprotease of the AAA subfamily which exerts quality control in the inner mitochondrial membrane. Interestingly, the identified mutation localizes close to the AAA domain of AFG3L2, while those localized in the proteolytic domain cause dominant spinocerebellar ataxia type 28 (SCA28) or recessive spastic ataxia with epilepsy (SPAX5). Functional studies in patient fibroblasts demonstrate that the p.G337E AFG3L2 mutation strongly destabilizes the long isoforms of OPA1 via OMA hyper-activation and leads to mitochondrial fragmentation, thus explaining the family phenotype. This study widens the clinical spectrum of neurodegenerative diseases caused by AFG3L2 mutations, which shall be considered as genetic cause of ADOA. | 01 = IsEpi
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OBJECTIVE: There is limited information on the prevalence of autoimmune liver disease in nonwhite populations. We conducted a population-based study on the prevalence of autoimmune liver diseases in Alaska natives. METHODS: Clinical records from 1984 to July, 2000 were reviewed to identify Alaska natives with autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis, autoimmune cholangitis, and overlap syndromes of two of the above. AIH was defined as definite or probable, based on criteria established by the International Autoimmune Hepatitis Group. The diagnosis of PBC was based on a positive antimitochondrial antibody of > or = 1: 40, biochemical evidence of cholestasis, and compatible liver biopsy. Autoimmune cholangitis was defined as PBC but without a positive antimitochondrial antibody. Primary sclerosing cholangitis was diagnosed on the basis of cholangiogram. RESULTS: Seventy-seven patients with possible autoimmune liver disease were identified. Of these, 42 had definite and seven probable AIH. At presentation, 34.7% of patients with AIH presented with acute icteric hepatitis, and 65.3% were asymptomatic. Persons presenting with mild or no symptoms were more likely to have moderate to severe fibrosis on liver biopsy than those presenting with jaundice. Eighteen persons were diagnosed with PBC, five with autoimmune cholangitis, five with overlap syndrome, and none with primary sclerosing cholangitis. The combined point prevalence of AIH Alaska natives was 42.9/100,000 (95% CI = 31-57.7). The prevalence of PBC was 16/100,000 (95% CI = 12.9-25.4). CONCLUSIONS: This population-based study demonstrates that the prevalence rates of AIH and PBC in Alaska natives are comparable with reported rates in other populations. | 10 = IsNotEpi
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The transfer of metabolites through the mitochondrial membranes is a vital process that is highly controlled and regulated by the inner membrane. A variety of metabolites, nucleotides, and cofactors are transported across the inner mitochondrial membrane (IMM) by a superfamily of membrane transporters which are known as the mitochondrial carrier family (MCF) or the solute carrier family 25 (SLC25 protein family). In humans, the MCF has 53 members encoded by nuclear genes. Members of the SLC25 family of transporters, which is the largest group of solute carriers, are also known as mitochondrial carriers (MCs). Because MCs are nuclear-coded proteins, they must be imported into the IMM. When compared with normal cells, the mitochondria of cancer cells exhibit significantly increased transmembrane potentials and a number of their transporters are altered. SLC25 members were identified as potential biomarkers for various cancers. The objective of this review is to summarize what is currently known about the involvement of mitochondrial SLC25 carriers in associated diseases. This review suggests that the SLC25 family could be used for the development of novel points of attack for targeted cancer therapy. | 01 = IsEpi
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Robinow syndrome is a clinically and genetically heterogeneous disorder characterized by mesomelic limb shortening, distinctive facial features, and variable oral, cardiac, vertebral, and urogenital malformations. We identified the novel de novo splice acceptor mutation c.1715-2A > C in DVL3 in a 15-year-old female patient with typical features of Robinow syndrome. By studying DVL3 transcripts in this patient, we confirmed expression of both wild-type and mutant alleles. Mutant DVL3 mRNAs were found to harbor a deletion of four nucleotides at the beginning of exon 15 and encode a protein product with a distinct -1 reading-frame C-terminus. The data demonstrate that mutant DVL3 proteins associated with Robinow syndrome show truncation of the C-terminus and share 83 novel amino acid residues before the stop codon confirming highly specific DVL3 alterations to be associated with this syndrome. The phenotype of the Robinow syndrome-affected female reported here is typical as she shows mesomelia and mild hand anomalies as well as characteristic facial anomalies. She also exhibited a supraumbilical midline abdominal raphe which has not been observed in other patients with Robinow syndrome. In contrast to the clinical data of four previously reported individuals with DVL3-related Robinow syndrome, short stature was not present in this individual at the age of 15 years. These findings expand the clinical spectrum of Robinow syndrome associated with DVL3 mutations. To date, comparison of clinical data of DVL3 mutation-positive individuals with those of patients with genetically different forms did not allow delineation of gene-specific phenotypes. | 01 = IsEpi
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The authors describe the 20th known case of cervical cancer with metastasis in an episiotomy scar, being the first case describing an implant of malignant cells in the episiotomy scar associated with glassy cell carcinoma.One case report.We describe the case of a 34-year-old woman, with cervical cancer diagnosed 1 month after delivery. Four months later, a radical hysterectomy was performed. During surgery, a nodule at the site of the episiotomy scar was identified and removed. The histologic diagnosis revealed a glassy cell carcinoma of the cervix, with metastasis in the episiotomy scar. After surgery, chemotherapy and radiotherapy were performed. The disease progressed rapidly, and the patient died 9 months after surgery.The implantation of neoplastic cells in the perineum is a potential risk of vaginal delivery, with a 40% mortality rate. It thus seems advisable to avoid vaginal delivery as much as possible when cervical cancer is diagnosed during pregnancy. Given the rarity, there are no studies on the most effective treatment in such situations. | 01 = IsEpi
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Canavan disease is an autosomal recessive disorder with spongy degeneration of white matter of the brain. It presents with developmental delay, visual problems and macrocephaly.We report a ten-month old boy with Canavan disease who presented with global developmental delay, seizures, abnormal eye movements and microcephaly.MRI brain revealed diffuse involvement of the supra tentorial white matter, globus pallidi, thalami, dentate nuclei and brainstem with sparing of the corpus callosum. The genetic testing revealed homozygous mutation of aspartoacylase gene [c.859 G>A (p.Ala287Thr)] in Exon 6.Possibility of Canavan disease should be considered even in the presence of microcephaly. | 01 = IsEpi
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We report a patient with severe mental retardation (MR), microcephaly, Dandy-Walker malformation, bilateral lip/palate clefts, hypertrophied sublingual frenulum, lobular tongue, absent thumbs, and other skeletal abnormalities, including Y-shaped metacarpals and urogenital abnormalities. High-resolution karyotype and subtelomeric fluorescence in situ hybridization were normal. We propose that his clinical picture is most consistent with Juberg-Hayward or orocraniodigital syndrome. Several clinical features present in our patient (unilateral distal displacement of elbow position, second-site radioulnar synostosis, bilateral Y-shaped metacarpal, lobular tongue, hypertrophic frenuli, Dandy-Walker malformation) have not previously been reported in this condition, thus expanding the phenotypic spectrum of this rare condition. The presence of these novel findings suggests possible overlap with other syndromes, such as orofaciodigital and Malpuech syndromes. | 01 = IsEpi
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Hereditary hyperferritinemia-cataract syndrome is an autosomal dominant genetic disorder associated with mutations in the 5'UTR region of the ferritin light chain gene. These mutations cause the ferritin levels to increase even in the absence of iron overload. Patients also develop bilateral cataract early due to accumulation of ferritin in the lens, and many are misdiagnosed as having hemochromatosis and thus not properly treated. The first cases were described in 1995 and several mutations have already been identified. However, this syndrome is still a poorly understood. We report two cases of unrelated Brazilian families with clinical suspicion of the syndrome, which were treated in our department. For the definitive diagnosis, the affected patients, their parents and siblings were submitted to Sanger sequencing of the 5'UTR region for detection of the ferritin light gene mutation. Single nucleotide polymorphism-like mutations were found in the affected patients, previously described. The test assisted in making the accurate diagnosis of the disease, and its description is important so that the test can be incorporated into clinical practice. | 01 = IsEpi
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Hypospadias is a common congenital malformation. The prevalence of hypospadias has a large geographical variation, and recent studies have reported both increasing and decreasing temporal trends. It is unclear whether hypospadias prevalence is associated with maternal age.To analyze the prevalence and trends of total hypospadias, isolated hypospadias, hypospadias with multiple congenital anomalies, hypospadias with a known cause, and hypospadias severity subtypes in Europe over a 10-year period and to investigate whether maternal age is associated with hypospadias.We included all children with hypospadias born from 2001 to 2010 who were registered in 23 EUROCAT registries. Information on the total number of births and maternal age distribution for the registry population was also provided. We analyzed the total prevalence of hypospadias and relative risks by maternal age.From 2001 to 2010, 10,929 hypospadias cases were registered in 5,871,855 births, yielding a total prevalence of 18.61 per 10,000 births. Prevalence varied considerably between different registries, probably due to differences in ascertainment of hypospadias cases. No significant temporal trends were observed with the exceptions of an increasing trend for anterior and posterior hypospadias and a decreasing trend for unspecified hypospadias. After adjusting for registry effects, maternal age was not significantly associated with hypospadias.Total hypospadias prevalence was stable in 23 EUROCAT registries from 2001 to 2010 and was not significantly influenced by maternal age. | 10 = IsNotEpi
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BACKGROUND:Bobble-head doll syndrome is a rare neurological syndrome presenting with repetitive anteroposterior head movements. It is usually associated with expansile cystic lesions in the third ventricular region. CASE DESCRIPTION:An 8-year-old boy presented with involuntary bobbling head movements. Magnetic resonance imaging of the brain revealed an extensive suprasellar cyst resulting in obstructive hydrocephalus. Endoscopic ventriculo-cysto-cisternostomy resulted in improved clinical outcome. CONCLUSIONS:Endoscopic ventriculo-cysto-cisternostomy is an effective, less-invasive technique in the treatment of suprasellar cysts that results in resolution of the bobbling head movements. | 01 = IsEpi
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The aim of this study was to investigate hidden hearing loss in patients with Charcot-Marie-Tooth disease type 1 A (CMT1A), a common inherited demyelinating neuropathy. By using pure-tone audiometry, 43 patients with CMT1A and 60 healthy controls with normal sound detection abilities were enrolled. Speech perception in quiet and noisy backgrounds, spectral ripple discrimination (SRD), and temporal modulation detection (TMD) were measured. Although CMT1A patients and healthy controls had similar pure-tone thresholds and speech perception scores in a quiet background, CMT1A patients had significantly (p < 0.05) decreased speech perception ability in a noisy background compared to controls. CMT1A patients showed significantly decreased temporal and spectral resolution (both p < 0.05). Also, auditory temporal processing of CMT1A patients was correlated with speech perception in a noisy background (r = 0.447, p < 0.01) and median motor conduction velocity (r = 0.335, p < 0.05). Therefore, we assumed that demyelination of auditory nerve in CMT1A causes defective cochlear neurotransmission, which reduces temporal resolution and speech perception in a noisy background. Because the temporal resolution test was well correlated with the degree of demyelination in auditory and peripheral motor nerves, temporal resolution testing could be performed as an additional marker for CMT1A. | 01 = IsEpi
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Osteoma is a benign tumor which is composed of mature compact or cancellous bone. Osteoma may be periosteal (arising from surface of the bone) or endosteal (develop in the medullary bone) or combination of both. Here, we present a case of unusually large osteoma present on the lingual surface of the mandible in a 40-year-old female patient. The lesion had grown slowly for 15 years and caused intra-oral swelling leading to difficulty in mastication, speech and tongue movements. Under general anesthesia, local complete surgical excision was performed. | 01 = IsEpi
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BACKGROUND:Athletes and coaches believe in the ergogenic effect of vitamin B12 (which results from enhanced erythropoiesis) and they often insist on its unjustified supplementation. Therefore, our study aimed to assess the vitamin B12 status in Polish elite athletes and its influence on red blood cell parameters. METHODS:In total, 1131 blood samples were collected during six years from 243 track and field athletes divided into strength and endurance groups, as well as according to the declared use of vitamin B12 injections. RESULTS:An average vitamin B12 concentration in all subjects was 739 ± 13 pg/mL, with no cases of deficiency. A weak but significant relationship was found between vitamin B12 and hemoglobin concentrations. A significant increase in hemoglobin appeared from very low vitamin B12 concentration and up to approx. 400 pg/mL, while hemoglobin did not significantly change from 700 pg/mL and onwards. Vitamin B12 injections were used by 34% of athletes, significantly more often by endurance than by strength athletes. In athletes who declared no use of injections, a higher concentration of vitamin B12 was observed in the endurance group. CONCLUSION:The main finding of the present study is the determination of the range of vitamin B12 concentration which may favor better hemoglobin synthesis in athletes. They should regularly monitor vitamin B12 concentration and maintain the range of 400-700 pg/mL as it may improve red blood cell parameters. We might suggest application of a supplementation if necessary. Special attention is required in athletes with a vitamin B12 concentration below 400 pg/mL. | 01 = IsEpi
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HistoryA 13-year-old girl was born to consanguineous parents. She presented with mild intellectual impairment, convergent strabismus, horizontal gaze palsy, and bilateral abducens palsy. Vertical gaze was preserved, and no abnormalities suggesting facial paralysis were noted. In addition, she reported progressive back pain since she was 5 years old. Other symptoms were denied. No medications or related drugs had been administered thus far. The patient underwent brain MRI for further evaluation. Current and previous spine radiographs were also reviewed. | 01 = IsEpi
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Purpose:To evaluate the phenotypic spectrum of autosomal recessive RP1-associated retinal dystrophies and assess genotypic associations. Methods:A retrospective multicenter study was performed of patients with biallelic RP1-associated retinal dystrophies. Data including presenting symptoms and age, visual acuity, kinetic perimetry, full field electroretinogram, fundus examination, multimodal retinal imaging, and RP1 genotype were evaluated. Results:Nineteen eligible patients from 17 families were identified and ranged in age from 10 to 56 years at the most recent evaluation. Ten of the 21 unique RP1 variants identified were novel, and mutations within exon 2 accounted for nearly half of alleles across the cohort. Patients had clinical diagnoses of retinitis pigmentosa (13), cone-rod dystrophy (3), Leber congenital amaurosis (1), early-onset severe retinal dystrophy (1), and macular dystrophy (1). Macular atrophy was a common feature across the cohort. Symptom onset occurred between 4 and 30 years of age (mean 14.9 years, median 13 years), but there were clusters of onset age that correlated with the effects of RP1 mutations at a protein level. Patients with later-onset disease, including retinitis pigmentosa, had at least one missense variant in an exon 2 DCX domain. Conclusions:Biallelic RP1 mutations cause a broad spectrum of retinal disease. Exon 2 missense mutations are a significant contributor to disease and can be associated with a considerably later onset of retinitis pigmentosa than that typically associated with biallelic RP1 mutations. | 01 = IsEpi
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BACKGROUND:Neuronal ceroid lipofuscinosis type 5 (CLN5) is a rare form of neuronal ceroid lipofuscinoses (NCLs) which are a group of inherited neurodegenerative diseases characterized by progressive intellectual and motor deterioration, visual failure, seizures, behavioral changes and premature death. CLN5 was initially named Finnish variant late infantile NCL, it is now known to be present in other ethnic populations and with variable age of onset. Few CLN5 patients had been reported in Chinese population. CASE PRESENTATION:In this paper, we report the symptoms of a Chinese patient who suffer from developmental regression and grand mal epilepsy for several years. The DNA was extracted from peripheral blood of proband and both parents, and then whole exome sequencing was performed using genomic DNA. Both sequence variants and copy number variants (CNVs) were analyzed and classified according to guidelines. As the result, a novel frameshift mutation c.718_719delAT/p.Met240fs in CLN5 and a de novo large deletion at 13q21.33-q31.1 which unmasked the frameshift mutation were identified in the proband. Despite the large de novo deletion, which can be classified as a pathogenic copy number variant (CNV), the patient's clinical presentation is mostly consistent with that of CLN5, except for early developmental delay which is believed due to the large deletion. Both variants were detected simultaneously by exome sequencing. CONCLUSIONS:This is the first report of whole gene deletion in combination with a novel pathogenic sequence variant in a CLN5 patient. The two mutations detected with whole exome sequencing simultaneously proved the advantage of the sequencing technology for genetic diagnostics. | 01 = IsEpi
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Pseudomembranous conjunctivitis is commonly associated with infections. However, the normal flora of the human conjunctiva has been proven to harbour many of the microorganisms presumed to cause infective pseudomembranous conjunctivitis. We aimed to evaluate firstly the aetiology of pseudomembranes, and secondly the treatment of pseudomembranes. This case series exhibited foreign body as a common factor in the formation of pseudomembranous conjunctivitis requiring repeated foreign body and pseudomembrane removal with an early, sustained course of topical steroid for effective recovery. | 01 = IsEpi
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Branchio-oculo-facial syndrome (BOFS), a rare, multiple-malformation congenital disorder, is characterized by facial anomalies, including associated cutaneous and ocular abnormalities. We report a new case of BOFS in an 11-year-old male child with bilateral cervical erythematous scaly linear plaque associated with scar formation and erosion. Although BOFS is very rare, physicians, especially dermatologists, should be aware of the cutaneous and histopathological features of BOFS due to impacts of the associated anomalies. | 01 = IsEpi
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Twenty patients, selected on the basis of simultaneous existence of overt diabetes and marked hirsutism, were submitted to clinical and biological investigations. Obesity, hypertension and angiopathy were present in most of these patients. Metabolic investigations afforded valuable proof of hypercorticism associated with depressed activity of insulin. Nevertheless, increased steroiduria was also observed in groups of non-hirsute diabetic women carefully paired for age. Thus the Achard-Thiers syndrome cannot be separated with certainty from common overt diabetes. | 01 = IsEpi
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Context. Denosumab is a monoclonal antibody against RANK ligand. Its administration in giant cell tumor of bone (GCTB) cases results in elimination of giant cells and new bone formation. Neoplastic stromal cells of GCTB harbor mutation of histone 3.3 and have pre-osteoblastic properties and thus express SATB2. Objectives. To (1) analyze histological changes in post-denosumab-treated GCTB, (2) analyze expression of H3.3G34W and SATB2 in pre- and post-denosumab-treated samples, and (3) to discuss why changes occur in the expression of not only H3.3G34W but also SATB2. Materials and Methods. Hematoxylin and eosin slides of 19 cases of denosumab-treated GCTB were reviewed. Immunohistochemical stains H3.3G34W and SATB2 were performed. The number of positive mononuclear cells were counted and graded. Results. Complete absence of osteoclast-like giant cells (OCLGCs) was noted in most cases along with a fibro-osseous component merging with peripheral shell of reactive bone. Irregular trabeculae of woven bone and osteoid with focal osteoblastic rimming was seen. Spindle cells were arranged predominantly in fascicular pattern. Morphometric analysis of H3.3G34W showed a mean of 68.8% positive stromal cells in pretreatment and a mean of 26.9% positive stromal cells in posttreated specimens with a statistically significant P value (.001). Mean percentage of SATB2-positive stromal cells in the pre- and posttreatment specimens was 36.46% and 20.8%, respectively. Conclusions. Our study validates that denosumab treatment results in marked reduction of OCLGCs with increased osteoblastic activity. Decreased expression of H3.3G34W in posttreatment may be a result of decreased antigenicity of neoplastic mononuclear cells. No significant change in SATB2 expression was noted. | 01 = IsEpi
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BACKGROUND:Multiple epiphyseal dysplasia (MED) is a heterogeneous genetic condition characterized by variable phenotypes, such as short stature (mild to moderate), joint deformities, abnormal gait, scoliosis, and brachydactyly. Recessive mutations in the SLC26A2 gene cause a phenotype of multiple epiphyseal dysplasia-4 (MED-4). In the present study, we identified novel compound heterozygous mutations in the SLC26A2 gene in a Chinese family with two affected sibs with MED-4. CASE PRESENTATION:Radiographs revealed hip dysplasia, brachydactyly and scoliosis in patient 1. Radiological examinations in patient 2 also showed hip dysplasia recently. Both of them were diagnosed with MED-4. SLC26A2 c.824 T > C and SLC26A2 c.1198C > T were identified in two siblings in this family, which were inherited from both parents, one mutation from each. CONCLUSIONS:This is the first Chinese MED-4 family attributed to SLC26A2 mutations, and these results show that these novel compound heterozygous mutations in SLC26A2 contribute to MED-4. | 01 = IsEpi
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BACKGROUND Transformation of primary cutaneous follicle center lymphoma (PCFCL), a low-grade B-cell non-Hodgkin lymphoma (NHL), into a high-grade NHL is rare with uncertain prognosis and treatment. A case is reported of a 40-year-old man who presented with a scalp mass that was diagnosed histologically as PCFCL. Imaging of the head and neck identified diffuse large B-cell lymphoma (DLBCL) involving the parotid gland and cervical lymph nodes, which responded well to radiation therapy. CASE REPORT A 40-year-old African American man presented with a two-year history of a progressively enlarging scalp mass that measured 10.5×7.1×6.6 cm. Histology showed a low-grade lymphoma with a follicular pattern. Immunohistochemistry was positive for B-cell markers and Bcl-6, consistent with a diagnosis of PCFCL. Computed tomography (CT) identified a 4.9×3.7×3.4 cm mass in the left parotid gland with bilateral cervical lymphadenopathy that had been present for the previous two or three months. The diagnosis of DLBCL was made on histology from a needle biopsy. Treatment began with rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH) chemotherapy, followed by radiation therapy to the scalp, both sides of the neck, and left parotid gland. At four-month follow-up, combined positron emission tomography (PET) and CT showed only diffuse low-level uptake in the scalp and parotid gland. CONCLUSIONS Transformation of low-grade PCFCL to high-grade DLBCL is rare, and the approach to treatment varies. This case showed a good response to chemotherapy and radiation therapy. | 01 = IsEpi
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Delusional infestation is the conviction that one is infested with pathogens-either animate or inanimate-despite medical or microbiologic evidence to the contrary. Infestation with inanimate pathogens, specifically fibers or filaments, has been controversially termed Morgellons disease by the patients themselves, who believe that this is not a psychiatric disease but rather a new organic condition or a skin manifestation of an infection, such as Lyme disease. A large-scale study by the Centers of Disease Control and Prevention on patients presenting with Morgellons clinical manifestations did not find evidence of fibers in the skin nor an association with any infection, including Lyme disease. Once the diagnosis of delusional infestation is made, the cornerstone of treatment is antipsychotics, although this is often quite challenging, as patients are reluctant to take these medications. | 01 = IsEpi
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Caudal duplication syndrome is a rare entity that describes the association between congenital anomalies involving caudal structures and may have a wide spectrum of clinical manifestations. A full-term male presented with combination of anomalies including anorectal malformation, duplication of the colon and lower urinary tract, split of the lower spine, and lipomyelomeningocele with tethering of the cord. We report this exceptional case of caudal duplication syndrome with special emphasis on surgical strategy and approach combining all disciplines involved. The purpose of this report is to present the pathology, assessment, and management strategy of this complex case. | 01 = IsEpi
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Homocysteine (Hcy) is a sulfur-containing amino acid that is generated during methionine metabolism. Physiologic Hcy levels are determined primarily by dietary intake and vitamin status. Elevated plasma levels of Hcy can be caused by deficiency of either vitamin B12 or folate. Hyperhomocysteinemia (HHcy) can be responsible of different systemic and neurological disease. Actually, HHcy has been considered as a risk factor for systemic atherosclerosis and cardiovascular disease (CVD) and HHcy has been reported in many neurologic disorders including cognitive impairment and stroke, independent of long-recognized factors such as hyperlipidemia, hypertension, diabetes mellitus, and smoking. HHcy is typically defined as levels >15 micromol/L. Treatment of hyperhomocysteinemia with folic acid and B vitamins seems to be effective in the prevention of the development of atherosclerosis, CVD, and strokes. However, data from literature show controversial results regarding the significance of homocysteine as a risk factor for CVD and stroke and whether patients should be routinely screened for homocysteine. HHcy-induced oxidative stress, endothelial dysfunction, inflammation, smooth muscle cell proliferation, and endoplasmic reticulum (ER) stress have been considered to play an important role in the pathogenesis of several diseases including atherosclerosis and stroke. The aim of our research is to review the possible role of HHcy in neurodegenerative disease and stroke and to understand its pathogenesis. | 01 = IsEpi
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Most pituitary adenomas are sporadic, but 3-5% can occur in a family and hereditary context. This is the case of multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC) and familial isolated pituitary adenomas (FIPA). FIPA is an infrequent condition that occurs in a family context, not associated with MEN type1 or CNC. FIPA kindred can be homogeneous (all adenomas affected in the family having the same tumor phenotype) or heterogeneous (different tumor phenotypes in the affected members). We describe a Congolese family in which two sisters and a cousin were diagnosed with a prolactinoma (homogenous FIPA) at the ages of 29, 32 and 40 years, respectively. The patients presented with macroadenomas at the time of diagnosis, non-invasive tumors and good biological response to cabergoline treatment (maximum dose of 1.5 mg/weekly). Of these two sisters, one went through a pregnancy without complications. Because no MEN1 and CNC clinical and biochemical features were detected during the 12-year follow-up, these genes were not investigated. The genetic analysis of the aryl hydrocarbon receptor interacting protein (AIP) was normal. As nearly 80% of patients with FIPA do not have a mutation in the AIP gene, future studies in these families are required to identify other affected genes involved in their physiopathology. | 01 = IsEpi
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A previously independent 66-year-old right-handed male presented with right-sided weakness, preferring the lower-extremities with additional impaired gait and dysarthria for 1-day duration. Imaging found a large left hemispheric anterior cerebral artery ischemic infarction with multiple lacunar infarcts. He exhibited frontal, callosal, and posterior variants of Alien Hand Syndrome which impeded activities of daily living. Although limited in evidence, a trial of clonazepam was initiated based on previous case reports describing suspected efficacy. Botulinum toxin A was not used given the patient's immediate need and limited hospital length of stay. Right upper extremity constricting therapies improved intermanual conflict and spontaneous grasping and levitation (arm elevation in retroflexion) activity; however, concomitant left upper extremity motor apraxia complicated task-oriented activities. The combination of pharmaceutical and therapeutic interventions improved the patient's quality of life as assessed by clinical observation, functional independence measures from 41 to 57, and patient-reporting. This case report aims to increase awareness of a potential barrier to rehabilitation of a debilitating and rare condition and to discuss current assessment tools and treatment options supported by available evidence. | 01 = IsEpi
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We present two half siblings with significant short stature who proved a diagnostic challenge for several years. Radiological findings included subtle epiphyseal changes. The diagnosis was made through whole genome sequencing via the 100,000 genome project. A maternally inherited pathogenic heterozygous CDKN1C variant was found in the PCNA (proliferating cell nuclear antigen) domain. Mutations of the PCNA domain of the CDKN1C gene are known to be associated with IMAGe syndrome thus with adrenal disease, although neither affected patient in our case had evidence of adrenal dysfunction. This report supports the previously reported findings of Russell-Silver syndrome (RSS) like phenotype caused by this unusual mechanism (CDKN1C mutations in the PCNA domain), highlights subtle radiological features not described previously and the phenotypic variability between two affected siblings. Additionally it reminds clinicians of the importance of considering associated adrenal disease/diabetes mellitus for variants within the PCNA domain. Finally it confirms RSS-like disorders should be considered in patients who have epiphyseal or metaphyseal changes and short stature, since CDKN1C PCNA domain mutations can result in this phenotype. | 01 = IsEpi
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BACKGROUND:Susac syndrome is a very rare cerebral small vessel disease, which can leave patients with cognitive impairment. We aimed at evaluating processing speed slowing, executive dysfunction and apathy and their relationships with whole brain and callosal atrophy. METHODS:Patients with Susac syndrome included in a prospective observational cohort study were evaluated, while clinically steady-state, with standardized brain MRI and a neuropsychological battery specifically designed to capture minimal cognitive alterations in non-disabled young patients. Brain volume and corpus callosum area were measured using 3D-T1 sequences, repeatedly overtime. Relationships between neuropsychological data and brain volumetric measures obtained the same day were tested with linear regression while controlling for sex, age, level of education, scores of depression and of apathy. RESULTS:Nineteen patients aged 37.5 ± 10.5 years were included. Mean follow-up time was 2.6 ± 1.3 years (5.8 ± 2.2 evaluations). While Montreal Cognitive Assessment scores were 25.1 ± 3.6, processing speed slowing was obvious (Trail Making Test version A: 43.1 ± 16.2 s; version B: 95.5 ± 67.9 s; reaction time: 314.6 ± 79.6 ms). Brain and corpus callosum atrophy was striking. No relationship was found between cognitive performances and brain volume or corpus callosum area. CONCLUSION:Patients with Susac syndrome show largely preserved global cognitive functions but important processing speed alterations. Although brain and corpus callosum area atrophy is prominent and evolving, we did not find any relationship with cognitive alterations, questioning the mechanisms underlying cognitive alterations in these patients. TRIAL REGISTRATION:Clinical Trial Registration-URL: https://www.clinicaltrials.gov Unique Identifier: NCT01481662. | 01 = IsEpi
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Beare-Stevenson syndrome (BSS) is an extremely rare genetic disorder characterized by a broad range of congenital malformations including craniosynostosis, cutis gyrata, facial deformities, and abnormal genitalia. The authors report a case of a 7 month old female who developed a mechanical ptosis secondary to dermatochalasis as a complication of fronto-orbital advancement and remodeling (FOAR) surgery which subsequently required multiple lid surgeries to reverse ptosis. This is the first report of blepharoptosis correction in a child with BSS as a complication of FOAR. | 01 = IsEpi
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We report on the case of a child who presented with recurrent, multiple, and voluminous bladder diverticula. Bladder diverticula are defined as a herniation of the mucosa through the bladder muscle or the detrusor. Causes are numerous and diverticula can be classified into primary congenital diverticula (para-ureteral - or Hutch diverticula - and posterolateral diverticula); secondary diverticula (resulting from chronic mechanical obstruction or from neurological disease; and diverticula secondary to connective tissue or muscle fragility. The latter is seen in disease entities such as prune belly syndrome, Ehlers-Danlos syndrome, cutis laxa syndrome, OHS (occipital horn syndrome), Menkes disease, and Williams-Beuren syndrome. In this patient, the cause of these diverticula was OHS, a genetic, recessive X-chromosome-linked syndrome, responsible for abnormal tissue caused by a disorder in copper metabolism. This case reminds us of the importance of pushing the diagnostic workup when presented with multiple and/or large bladder diverticula, and in particular to search for rare malformation syndromes after exclusion of an obstacle. | 01 = IsEpi
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Succinic semialdehyde dehydrogenase deficiency (SSADH-D) is a genetic disorder that results from the aberrant metabolism of the neurotransmitter γ-amino butyric acid (GABA). The disease is caused by impaired activity of the mitochondrial enzyme succinic semialdehyde dehydrogenase. SSADH-D manifests as varying degrees of mental retardation, autism, ataxia, and epileptic seizures, but the clinical picture is highly heterogeneous. So far, there is no approved curative therapy for this disease. In this review, we briefly summarize the molecular genetics of SSADH-D, the past and ongoing clinical trials, and the emerging features of the molecular pathogenesis, including redox imbalance and mitochondrial dysfunction. The main aim of this review is to discuss the potential of further therapy approaches that have so far not been tested in SSADH-D, such as pharmacological chaperones, read-through drugs, and gene therapy. Special attention will also be paid to elucidating the role of patient advocacy organizations in facilitating research and in the communication between researchers and patients. | 01 = IsEpi
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BACKGROUND:Several studies have employed animal models to explore the association between microbiota and interleukin (IL) 10 signaling; however, limited information is available about the human microbiome. AIM:To characterize the microbiome in patients with IL10RA mutations and to explore the association between gut dysbiosis and disease severity. METHODS:Fecal samples were collected from patients who were diagnosed with loss-of-function mutations in the IL10RA gene between January 2017 and July 2018 at the Children's Hospital of Fudan University. Age-matched volunteer children were recruited as healthy controls. Patients with Crohn's disease (CD) were used as disease controls to standardize the antibiotic exposure. Microbial DNA was extracted from the fecal samples. All analyses were based on the 16S rRNA gene sequencing data. RESULTS:Seventeen patients with IL10RA mutations (IL10RA group), 17 patients with pediatric CD, and 26 healthy children were included. Both patients with IL10RA mutations and those with CD exhibited a reduced diversity of gut microbiome with increased variability. The relative abundance of Firmicutes was substantially increased in the IL10RA group (P = 0.02). On further comparison of the relative abundance of taxa between patients with IL10RA mutations and healthy children, 13 taxa showed significant differences. The IL10RA-specific dysbiosis indices exhibited a significant positive correlation with weighted pediatric CD activity index and simple endoscopic score for CD. CONCLUSION:In patients with IL10RA mutations and early onset inflammatory bowel disease, gut dysbiosis shows a moderate association with disease severity. | 01 = IsEpi
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Injectable hydrogels are one of the most widely investigated and versatile technologies for drug delivery and tissue engineering applications. Hydrogels' versatility arises from their tunable structure, which has been enabled by considerable advances in fields such as materials engineering, polymer science, and chemistry. Advances in these fields continue to lead to invention of new polymers, new approaches to crosslink polymers, new strategies to fabricate hydrogels, and new applications arising from hydrogels for improving healthcare. Various hydrogel technologies have received regulatory approval for healthcare applications ranging from cancer treatment to aesthetic corrections to spinal fusion. Beyond these applications, hydrogels are being studied in clinical settings for tissue regeneration, incontinence, and other applications. Here, we analyze the current clinical landscape of injectable hydrogel technologies, including hydrogels that have been clinically approved or are currently being investigated in clinical settings. We summarize our analysis to highlight key clinical areas that hydrogels have found sustained success in and further discuss challenges that may limit their future clinical translation. | 01 = IsEpi
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OBJECTIVE:To identify initial parameters that predict worsening of skin thickening in patients with diffuse cutaneous systemic sclerosis (dcSSc) using a multicentre, prospective, observational cohort in Japan. METHODS:A total of 171 patients with dcSSc were selected from a prospective cohort database based on the following criteria: dcSSc, modified Rodnan total skin thickness score (mRSS) ≥7, disease duration <60 months, and valid mRSS data at one year. Worsening of skin thickness was defined as an increase in mRSS ≥3 points and an increase ≥25% from baseline to one year. Initial demographic and clinical parameters useful for predicting the progression of skin thickness were identified using univariate and multivariable analysis, and prediction models of skin thickening progression were built based on combinations of independent predictive parameters. RESULTS:Only 23 patients (13.5%) experienced worsening mRSSs at one year. Short disease duration, low mRSS, absence of nailfold bleeding, arthritis, and a high erythrocyte sedimentation rate at diagnosis were identified as predictors of subsequent worsening of the mRSS even after adjusting for the treatment. Assessment of the best predictive model revealed that patients with a disease duration ≤12 months and mRSS ≤19 had a risk of mRSS worsening within one year, with a sensitivity of 73.9% and specificity of 81.1%. CONCLUSION:Identification of predictors of subsequent worsening of skin thickness in dcSSc patients is useful for identifying patients who require intensive treatment with potential disease-modifying agents and for improving clinical trial design by characterizing eligible progressors in the Japanese population. | 01 = IsEpi
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Human skeletal muscles express three major myosin heavy chain (MyHC) isoforms: MyHCIIx (MYH1) in fast type 2B muscle fibers, MyHCIIa (MYH2) in fast type 2A fibers and MyHCI/β-cardiac MyHC (MYH7) in slow type I skeletal fibers and cardiac ventricles. In line with its expression pattern, MYH7 mutations have been reported in association with hypertrophic or dilated cardiomyopathy, skeletal myopathies or a combination of both. We analyzed the clinical and molecular phenotype of two unrelated families of Jewish Moroccan ancestry that presented with apparently autosomal dominant inheritance of progressive Laing-like distal myopathy with non-specific myopathic changes, but uncommon marked contractures and wasting of the neck extensors.Clinical phenotyping, whole exome sequencing and restriction analysis, generation of mutants followed by cell culture transfection and imaging.Using whole exome sequencing we identified in both families two novel heterozygous proline substitutions located in exon 31 of MYH7 within its rod domain: c.4309G>C (p.Ala1437Pro) and c.4301G>C (p.Arg1434Pro). Here we show that the phenotype caused by these mutations includes marked cervical muscle contracture, and report that the severity of the phenotype varies significantly, to the extent of non-penetrance in one of the families. Finally, we provide evidence that both proline substitutions impair myosin self-assembly in non-muscle cells transfected with β-myosin constructs carrying the mutations, but do not prevent incorporation of the mutant molecules into the sarcomere.This study expands our clinical and molecular knowledge of MYH7 rod mutations causing skeletal myopathies, and underscores the importance of discussing disease penetrance during genetic counseling. | 01 = IsEpi
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Cap disease is a rare congenital myopathy associated with skeletal malformations and respiratory involvement. Abnormally arranged myofibrils taking the appearance of a "cap" are the morphological hallmark of this entity. We report a case of cap disease concerning a 42-year-old man, without any family history and presenting a p.Arg168His mutation on the TPM3 gene. His first biopsy at 7years had only shown selective type I hypotrophy. Mutations of TPM3 gene have been found in nemaline myopathy, congenital fiber type disproportion, but never before in cap disease. | 01 = IsEpi
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Most state-of-the-art biomedical entity normalization systems, such as rule-based systems, merely rely on morphological information of entity mentions, but rarely consider their semantic information. In this paper, we introduce a novel convolutional neural network (CNN) architecture that regards biomedical entity normalization as a ranking problem and benefits from semantic information of biomedical entities.The CNN-based ranking method first generates candidates using handcrafted rules, and then ranks the candidates according to their semantic information modeled by CNN as well as their morphological information. Experiments on two benchmark datasets for biomedical entity normalization show that our proposed CNN-based ranking method outperforms traditional rule-based method with state-of-the-art performance.We propose a CNN architecture that regards biomedical entity normalization as a ranking problem. Comparison results show that semantic information is beneficial to biomedical entity normalization and can be well combined with morphological information in our CNN architecture for further improvement. | 01 = IsEpi
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PURPOSE:To systematically observe and analyze the signs of deficient posterior capsule in posterior polar cataracts. DESIGN:Ambispective observational study. PARTICIPANTS:Cases with posterior polar cataracts. METHODS:Eyes with diagnosed posterior polar cataracts were imaged on anterior segment optical coherence tomography. A detailed assessment was performed to note the morphology of the posterior opacity, posterior capsule, and the common patterns to indicate their abnormality. In addition, generalized observation of the morphology was also performed with respect to intraoperative surgical experiences. RESULTS:A total of 101 eyes were included. The average patient age was 52.85 ± 10.72 years. The posterior capsule integrity was identified as intact in 91 eyes and abnormal/deficient in 10 eyes (9 had intraoperative defective capsule). These deficient/abnormal morphologies were classified into 3 categories: conical (n=2), moth-eaten (n=5), and (3) ectatic (n=3). Similarly, depending on the presence of hypoechoic spaces between the opacity and the capsule, remaining posterior polar cataracts were categorized into 2 generalized morphological types: without hypoechoic areas (n=40) and with hypoechoic areas (n=51). In the without hypoechoic areas group, 6 cases developed capsular rent; in the with hypoechoic areas group, 1 case developed capsular rent. CONCLUSIONS:In posterior polar cataracts, the deficient/abnormal capsular morphology could be specifically categorized into 3 categories, conical, moth-eaten, and ectatic types. In addition, to predict the ease of intraoperative separation between the opacity and the capsule, generalized categorization might help in better case management. | 01 = IsEpi
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PURPOSE:Schnyder corneal dystrophy (SCD) is a rare inherited disease that leads to gradual vision loss by the deposition of lipids in the corneal stroma. The aim of this study is to report a novel pathogenic variant in the UBIAD1 gene and present clinical and molecular findings in Polish patients with SCD. METHODS:Individuals (n = 37) originating from four Polish SCD families were subjected for a complete ophthalmological check-up and genetic testing. Corneal changes were visualized by slit-lamp examination, anterior segment optical coherent tomography (AS-OCT), and in vivo confocal microscopy (IVCM). RESULTS:In a proband with primarily mild SCD that progressed rapidly at the end of the fifth decade of life, a novel missense pathogenic variant in UBIAD1 (p.Thr120Arg) was identified. The other studied SCD family represents the second family reported worldwide with the UBIAD1 p.Asp112Asn variant. SCD in the remaining two families resulted from a frequently identified p.Asn102Ser pathogenic variant. All affected subjects presented a crystalline form of SCD. The severity of corneal changes was age-dependent, and their morphology and localization are described in detail. CONCLUSION:The novel p.Thr120Arg is the fourth SCD-causing variant lying within the FARM motif of the UBIAD1 protein, which underlines a high importance of this motif for SCD pathogenesis. The current study provides independent evidence for the pathogenic potential of UBIAD1 p.Asp112Asn and new information useful for clinicians. | 01 = IsEpi
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Skeletal dysplasias are a diverse group of heritable diseases affecting bone and cartilage growth. Throughout the years, the molecular defect underlying many of the diseases has been identified. These identifications led to novel insights in the mechanisms regulating bone and cartilage growth and homeostasis. One of the pathways that is clearly important during skeletal development and bone homeostasis is the Wingless and int-1 (WNT) signaling pathway. So far, three different WNT signaling pathways have been described, which are all activated by binding of the WNT ligands to the Frizzled (FZD) receptors. In this review, we discuss the skeletal disorders that are included in the latest nosology of skeletal disorders and that are caused by genetic defects involving the WNT signaling pathway. The number of skeletal disorders caused by defects in WNT signaling genes and the clinical phenotype associated with these disorders illustrate the importance of the WNT signaling pathway during skeletal development as well as later on in life to maintain bone mass. The knowledge gained through the identification of the genes underlying these monogenic conditions is used for the identification of novel therapeutic targets. For example, the genes underlying disorders with altered bone mass are all involved in the canonical WNT signaling pathway. Consequently, targeting this pathway is one of the major strategies to increase bone mass in patients with osteoporosis. In addition to increasing the insights in the pathways regulating skeletal development and bone homeostasis, knowledge of rare skeletal dysplasias can also be used to predict possible adverse effects of these novel drug targets. Therefore, this review gives an overview of the skeletal and extra-skeletal phenotype of the different skeletal disorders linked to the WNT signaling pathway. | 01 = IsEpi
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BACKGROUND:Twin reversed arterial perfusion (TRAP) sequence consists of acardiac twin (A) paradoxically perfused by pump twin (P) through an umbilical artery (UA). We proposed characterization of acardiac twins with intrafetal vascular pattern (IVP), and assessed its correlation with morphology and UA Doppler indices. METHODS:We prospectively evaluated 21 cases of TRAP sequence. Morphology (acardia vs hemicardia) and IVP (simple vs complex) of acardiac twins were characterized with ultrasound and color Doppler. Twins weight ratio (A/P Wt) and UA Doppler indices of acardiac and pump twins including (1) difference of systolic/diastolic ratio (UA ∆S/D), (2) difference of resistance index (UA ∆RI), and (3) ratio of pulsatility index (UA PI A/P) were calculated. RESULTS:The median (min, max) gestational age at diagnosis was 18 (11, 27) weeks. Acardia (n = 14) were associated with simple IVP (n = 16) (P < .05). After exclusion of acardia with complex IVP (n = 1), the A/P Wt, UA ∆S/D, UA ∆RI, and UA PI A/P of acardia with simple IVP (n = 13), hemicardia with simple IVP (n = 3), and hemicardia with complex IVP (n = 4) were not significantly different (P > .05). CONCLUSIONS:Most of acardiac twins were acardia with simple IVP. Morphology and IVP of acardiac twins were not associated with UA Doppler indices. | 01 = IsEpi
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CONTEXT:Low serum adiponectin and high-density lipoprotein-cholesterol (HDL-C) levels are risk factors for cardiovascular disease. Patients with primary adrenal insufficiency are at higher risk of cardiovascular complications compared with healthy subjects. However, there is no information on the relationship between adiponectin and glucocorticoid replacement therapy in patients with secondary adrenal insufficiency (SAI). OBJECTIVE:To determine the effects of intrinsic adrenal function and glucocorticoid replacement therapy on serum adiponectin levels and lipid profile in patients with SAI. DESIGN:Part 1: a cross-sectional study. Part 2: a randomized, double-blind, crossover study. SETTING:Osaka University Hospital, Osaka, Japan. PATIENTS:Part 1: 58 patients diagnosed with nonfunctioning pituitary adenoma who underwent insulin tolerance test (ITT) for assessment of adrenal function. Part 2: 12 SAI patients randomly received hydrocortisone replacement therapy at a dose of 10, 20, or 30 mg/d for 4 weeks per term for three terms. OUTCOME MEASUREMENTS:Part 1: we analyzed the relationship between serum cortisol levels during ITT and serum adiponectin levels and the lipid profile. Part 2: serum adiponectin levels and lipid profile were measured every 4 weeks. RESULTS:Serum levels of adiponectin and HDL-C correlated significantly with peak cortisol levels after ITT. Serum adiponectin and HDL-C levels were significantly lower in patients with SAI than non-SAI. Serum levels of adiponectin and HDL-C increased in a hydrocortisone dose-dependent manner. CONCLUSIONS:Glucocorticoid replacement therapy increased serum levels of adiponectin, an adipose-derived anti-atherogenic factor, and HDL-C in patients with SAI. | 01 = IsEpi
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We report on a 74-year-old man with a cutaneous B-cell follicle center lymphoma, which was treated upfront with systemic rituximab and suffered several local relapses. The first of the local recurrences, 10 months after completion of treatment, was characterized by a dense T-cell infiltrate that obscured a minor population of B-cell lymphoma cells, suggesting a second primary cutaneous T-cell lymphoma. This represents a previously not reported diagnostic pitfall and underscores the importance of performing sequential biopsies when dealing with lymphoma recurrences in this setting. | 01 = IsEpi
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Hereditary spastic paraplegias (HSPs) is a rare heterogeneous group of neurodegenerative diseases, with upper and lower limb spasticity motor neuron disintegration leading to paraplegias. NT5C2 gene (OMIM: 600417) encode a hydrolase enzyme 5'-nucleotidase, cytosolic II play an important role in maintaining the balance of purine nucleotides and free nucleobases in the spinal cord and brain. In this study we have identified a large consanguineous Saudi family segregating a novel homozygous splice site donor alteration in NT5C2 gene leading to spastic diplegia cerebral palsy, developmental delay and microcephaly. Whole exome sequencing (WES) was performed for the affected members of the family to study the novel mutation. WES data analysis, confirmed by Sanger sequencing analysis, identifies a homozygous splice site donor alteration of possible interest in NT5C2 (ENST00000343289: c.539+1G > T) at the sixth exon/intron boundaries. The mutation was further ruled out in 100 healthy control from normal population. The novel homozygous mutation observed in this study has not been reported in the literature or variant databases. The identified splicing alteration broadens the mutation spectrum of NT5C2 gene in neurodevelopmental disorders. To the best of our knowledge this is the first report from Saudi Arabia. | 01 = IsEpi
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Objective:This study presents the neurologic phenotypes of 2 brothers with a novel homozygous COL4A1 mutation that was identified in a large Turkish consanguineous cohort of neurogenetic diseases. Methods:Whole-exome sequencing and bioinformatic analysis of consanguineous families with children affected by early-onset, neurogenetic disorders was performed using the RD-Connect Genome-Phenome Analysis Platform. We also performed clinical, EEG, and neuroimaging analyses in unaffected siblings and parents. Results:We have identified a homozygous missense mutation in COL4A1 (p.Gly1278Ser, NM_001845.5:c.3832G>T) in 2 siblings affected by small vessel brain disease with periventricular leukoencephalopathy and ocular defects. Presenting symptoms included mild weakness, hemiparetic gait, pyramidal findings, and seizures, whereas their intellectual and behavioral functions were normal. Both parents and 5 of the siblings (3 boys and 2 girls) were heterozygous for the variant. They did not show any clinical or laboratory signs of small vessel disease. Conclusions:COL4A1 has previously been associated with dominant small vessel disease of the brain and other organs, manifesting with high penetrance in heterozygous mutation carriers. Our findings provide evidence that COL4A1-related encephalopathy can be inherited in an autosomal recessive manner, which is important for counseling, prognosis, and treatment. Genotype-phenotype correlations remain to be established. | 01 = IsEpi
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Background:Tarlov cyst disease is a collection of cerebrospinal fluid between the endoneurium and perineurium of spinal, usually sacral, nerve roots. These cysts can become symptomatic in 20% of patients, causing lower back pain, radiculopathy, bladder and bowel dysfunction necessitating medical or surgical intervention. Different surgical and non-surgical modalities have been described for the treatment of symptomatic Tarlov cysts. However, there has been no published study that examined types of surgical techniques side by side. Our study presents a preliminary experience in the surgical management of symptomatic Tarlov cysts using two surgical techniques: cyst fenestration and nerve root imbrication. Methods:Retrospective chart review and analysis was done for all patients who underwent surgical intervention for symptomatic Tarlov cyst(s) in the period 2007-2013. Operative reports, preoperative and postoperative clinic visit reports were reviewed. The surgical techniques of cyst fenestration and nerve root imbrication were each described in terms of intraoperative parameters, hospital course and outcome. Modified MacNab criteria were used for evaluation of the final clinical outcome. Results:Thirty-six surgical patients were identified. Three had repeat surgery (total of 39 operations). The median age was 51 years (range, 26-84 years). Eighty-six percent were females. The presenting symptoms were low back pain (94%), sensory radiculopathy (69%), bladder and bowel dysfunction (61%), sexual dysfunction (17%) and motor dysfunction (8%). Cyst fenestration was performed in 12 patients (31%) and nerve root imbrication was done in 27 (69%). All patients in the fenestration group but only 67% in the imbrication group had fibrin glue injection into the cyst or around the reconstructed nerve root. The overall surgery-related complication rate was 28%. The complication rate was 5/12 (42%) in the fenestration group and 6/27 (22%) in the imbrication group. At the time of the last clinic visit, improved clinical outcome was noted in 9/11 (82%) and 20/25 (80%) in the fenestration and the imbrication group, respectively. Conclusions:Cyst fenestration and nerve root imbrication are both surgical techniques to treat symptomatic Tarlov cyst(s), and both can result in clinical improvement. | 01 = IsEpi
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Paroxysmal movement disorders (PMDs) are rare neurological diseases typically manifesting with intermittent attacks of abnormal involuntary movements. Two main categories of PMDs are recognized based on the phenomenology: Paroxysmal dyskinesias (PxDs) are characterized by transient episodes hyperkinetic movement disorders, while attacks of cerebellar dysfunction are the hallmark of episodic ataxias (EAs). From an etiological point of view, both primary (genetic) and secondary (acquired) causes of PMDs are known. Recognition and diagnosis of PMDs is based on personal and familial medical history, physical examination, detailed reconstruction of ictal phenomenology, neuroimaging, and genetic analysis. Neurophysiological or laboratory tests are reserved for selected cases. Genetic knowledge of PMDs has been largely incremented by the advent of next generation sequencing (NGS) methodologies. The wide number of genes involved in the pathogenesis of PMDs reflects a high complexity of molecular bases of neurotransmission in cerebellar and basal ganglia circuits. In consideration of the broad genetic and phenotypic heterogeneity, a NGS approach by targeted panel for movement disorders, clinical or whole exome sequencing should be preferred, whenever possible, to a single gene approach, in order to increase diagnostic rate. This review is focused on clinical and genetic features of PMDs with the aim to (1) help clinicians to recognize, diagnose and treat patients with PMDs as well as to (2) provide an overview of genes and molecular mechanisms underlying these intriguing neurogenetic disorders. | 01 = IsEpi
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Background:Light chain deposition disease (LCDD) is a systemic disorder typically characterized by non-amyloid monoclonal immunoglobulin light chain deposition in tissues. LCDD is recognized as a multisystem disease, in which the kidneys and liver are often affected. However, it is rarely encountered as a localized pulmonary disease. This study set out to characterize the clinical manifestations and features of pulmonary light-chain deposition disease (PLCDD) by conducting a retrospective analysis of clinical data obtained from patients, with the aim of improving clinical understanding of PLCDD. Methods:Data from inpatients diagnosed with PLCDD at Shanghai Pulmonary Hospital (Shanghai, China) between January 2010 and December 2018 were retrospectively collected and analyzed. Results:A total of 4 PLCDD patients confirmed with PLCDD by pulmonary tissue biopsy were analyzed. All of the patients were female and were found by physical examination. Chest images of each patient's lungs showed multiple cystic cavities with nodules. A history of Sjogren's syndrome was present with 1 patient, 2 patients were diagnosed with Sjogren's syndrome after surgery (including 1 diagnosed with Sjogren's syndrome in the 8th year of follow up), and 3 patients had leukopenia. The longest follow-up period was 8 years. During the follow-up period, 2 patients developed pulmonary lesions (1 patient had an enlarged original cystic lesion in basal segment of right lower lobe 2 years after surgery, while the other developed new nodules 7 years after surgery). Conclusions:PLCDD is characterized by multiple cystic changes with nodules in both lungs and can be easily complicated by lymphoid diseases such as Sjogren's syndrome. The clinical symptoms cannot be characterized, and the diagnosis depends on lung biopsy. | 01 = IsEpi
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Lipodystrophies are a heterogeneous group of congenital or acquired disorders, characterized by partial or generalized loss of adipose tissue. Familial partial lipodystrophy (FPLD) presents with genetic and phenotypic variability with insulin resistance, hypertriglyceridemia and hepatic steatosis being the cardinal metabolic features. The severity of the metabolic derangements is in proportion with the degree of lipoatrophy. The underpinning pathogenetic mechanism is the limited capacity of adipose tissue to store lipids leading to lipotoxicity, low-grade inflammation, altered adipokine secretion and ectopic fat tissue accumulation. Advances in molecular genetics have led to the discovery of new genes and improved our knowledge of the regulation of adipose tissue biology. Diagnosis relies predominantly on clinical findings, such as abnormal fat tissue topography and signs of insulin resistance and is confirmed by genetic analysis. In addition to anthropometry and conventional imaging, new techniques such as color-coded imaging of fat depots allow more accurate assessment of the regional fat distribution and differentiation of lipodystrophic syndromes from common metabolic syndrome phenotype. The treatment of patients with lipodystrophy has proven to be challenging. The use of a human leptin analogue, metreleptin, has recently been approved in the management of FPLD with evidence suggesting improved metabolic profile, satiety, reproductive function and self-perception. Preliminary data on the use of glucagon-like peptide 1 receptor agonists (GLP1 Ras) and sodium-glucose co-transporter 2 (SGLT2) inhibitors in cases of FPLD have shown promising results with reduction in total insulin requirements and improvement in glycemic control. Finally, investigational trials for new therapeutic agents in the management of FPLD are underway. | 01 = IsEpi
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Background:Hemifacial microsomia (HFM) is a congenital disorder characterized by facial asymmetry, but no midline reference has been established for evaluating facial morphology in patients with HFM. The purpose of this study was to develop a 3-dimensional coordinate system unaffected by the deformity of the external acoustic aperture or orbital circumference and to quantitatively evaluate craniofacial morphology in such patients. Methods:We quantitatively evaluated craniofacial morphology using 3-dimensional measurements with the skull base as a reference. Using computed tomography data from 15 patients with HFM and 15 controls, a coordinate system was created for each patient, and left-right differences between measurement points were compared. Results:When mandibular deformity was severe, the deformity of the posterior part of the palatine bone and lateral part of the orbit increased, but this trend was not evident for other measurement points. Thus, craniofacial deformity in HFM was not always related to mandibular deformity. Moreover, no difference was evident in the position of the hypoglossal canal between controls and patients with HFM. Conclusions:Quantitative assessments are possible using the coordinate system devised in this study, irrespective of the severity of HFM. The degree of mandibular deformity detailed in the Pruzansky classification was associated with the superoinferior deformity of the posterior part of the palatine bone and anteroposterior deformity of the lateral part of the orbit. | 01 = IsEpi
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OBJECTIVE: To give an epidemiological description of the clinical entity given the name Pierre Robin sequence, defined by retro- and micrognathia, cleft palate, and respiratory distress and describe other malformations and possible intrauterine impairment. METHODS: Using the inclusion criteria of micrognathia, cleft palate, and neonatal respiratory distress, a retrospective population-based study of all Danish live births during 1990 through 1999 were carried out. We found 50 children, 25 boys and 25 girls, fulfilling the inclusion criteria, giving an incidence of 1 in 14,000 live births. RESULTS: Two-thirds (n = 33) of the children had the classical U-shaped cleft palate. More than one-third (n = 19) had one or several other malformations, and in five patients the triad of Pierre Robin was a minor feature of a complex syndrome. The most common noncomplex syndrome was the Stickler syndrome found in 6 of the 50 patients. More than one-fourth (n = 17) had some kind of intrauterine impairment, with no specific obstetric diagnosis predominant. Consistent with this, the average birth weight was well below normal. CONCLUSIONS: Several authors have stated that the triad of Pierre Robin is not a nosological entity, in that it has diverse etiology and diverse pathogenesis. We conclude that the triad of Pierre Robin still can be regarded as a clinical entity, readily defined at birth, experiencing the same neonatal problems in varying degrees and hence the possibility of designing treatment protocols for later scientific evaluation. | 10 = IsNotEpi
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BACKGROUND:The most common infection in patients positive for anti-interferon-gamma autoantibodies (anti-IFN-γ AAbs) is disseminated nontuberculous mycobacterial (dNTM) infection. Here, we report a rare case of triple infection caused by Cryptococcus, varicella-zoster virus (VZV), and nontuberculous mycobacterium in a patient with anti-IFN-γ AAbs. CASE PRESENTATION:A 53-year-old Thai man presented with a progressively enlarging right cervical mass with low-grade fever and significant weight loss for 4 months. He also developed a lesion at his left index finger. A biopsy of that lesion showed granulomatous inflammation with yeast-like organisms morphologically consistent with cryptococcosis. Serum cryptococcal antigen was positive. Histopathology of a right cervical lymph node revealed chronic granulomatous lymphadenitis, and the lymph node culture grew Mycobacterium abscessus. One month later, he complained of vision loss in his left eye and subsequently developed a group of painful vesicles at the right popliteal area of S1 dermatome. Lumbar puncture was performed and his cerebrospinal fluid was positive for VZV DNA. His blood test for anti-HIV antibody was negative. Anti-IFN-γ AAbs was positive, but test for anti-granulocyte-macrophage colony-stimulating factor autoantibodies (anti-GM-CSF AAbs) was negative. He was treated with amphotericin B plus fluconazole for cryptococcosis; a combination of amikacin, imipenem, azithromycin, and levofloxacin for dNTM infection; and, intravenous acyclovir for disseminated VZV infection. After treatment, our patient's fever and cervical lymphadenopathy were subsided, and his vision and visual acuity were both improved. CONCLUSIONS:This is the first case of triple infection with cryptococcosis, VZV, and dNTM in a patient who tested positive for anti-IFN-γ AAbs and negative for anti-GM-CSF AAbs. This case will increase awareness and heighten suspicion of these infections in patients with the described presentations and clinical characteristics, and this will accelerate diagnosis and treatment. | 01 = IsEpi
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BACKGROUND:Fraser syndrome or "cryptophthalmos syndrome" is a rare autosomal recessive disease. It is characterized by a group of congenital malformations such as: crytophthalmos, syndactyly, abnormal genitalia, and malformations of the nose, ears, and larynx. Although cryptophthalmos is considered as a main feature of Fraser syndrome, its absence does not exclude the diagnosis. Clinical diagnosis can be made by Thomas Criteria. Here we present the first documented case of Fraser Syndrome in Aleppo, Syria that is characterized by bilateral anophthalmia and intrahepatic biliary atresia. CASE PRESENTATION:During pregnancy, several ultrasound scans revealed hyperechoic lungs, ascites, and unremarkable right kidney at the 19th-week visit; bilateral syndactyly on both hands and feet at the 32nd-week visit. On the 39th week of gestation, the stillborn was delivered by cesarean section due to cephalopelvic disproportion. Gross examination showed bilateral anophthalmia, bilateral syndactyly on hands and feet, low set ears, and ambiguous genitalia. Microscopic examination of the lung, spleen, liver, ovary, and kidneys revealed abnormalities in these organs. CONCLUSION:The diagnosis of Fraser syndrome can be made prenatally and postnatally; prenatally by ultrasound at 18 weeks of gestation and postnatally by clinical examination using Thomas criteria. Moreover, intrahepatic biliary atresia was not described previously with Fraser syndrome; this recommends a more detailed pathologic study for Fraser syndrome cases. | 01 = IsEpi
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Recognition of antigens displayed on the surface of an antigen-presenting cell (APC) by T-cell receptors (TCR) of a T lymphocyte leads to the formation of a specialized contact between both cells named the immune synapse (IS). This highly organized structure ensures cell-cell communication and sustained T-cell activation. An essential lipid regulating T-cell activation is diacylglycerol (DAG), which accumulates at the cell-cell interface and mediates recruitment and activation of proteins involved in signaling and polarization. Formation of the IS requires rearrangement of the cytoskeleton, translocation of the microtubule-organizing center (MTOC) and vesicular compartments, and reorganization of signaling and adhesion molecules within the cell-cell junction. Among the multiple players involved in this polarized intracellular trafficking, we find sorting nexin 27 (SNX27). This protein translocates to the T cell-APC interface upon TCR activation, and it is suggested to facilitate the transport of cargoes toward this structure. Furthermore, its interaction with diacylglycerol kinase ζ (DGKζ), a negative regulator of DAG, sustains the precise modulation of this lipid and, thus, facilitates IS organization and signaling. Here, we review the role of SNX27, DAG metabolism, and their interplay in the control of T-cell activation and establishment of the IS. | 01 = IsEpi
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Anaplastic (undifferentiated) thyroid carcinoma (ATC) is a rare malignancy which may arise from transformation of a pre-existing differentiated carcinoma. We report the unique case where a lesion of thyroid origin presented with the histological features of mature plasma cells. Immunohistochemistry confirmed the lesion to be an anaplastic thyroid carcinoma arising from papillary thyroid carcinoma. A tumor mimicking a malignancy of a different cellular origin can lead clinicians to incorrect treatment approaches. Careful correlation with clinical details and knowledge of these unique presentations is important for reaching the correct diagnosis. | 01 = IsEpi
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Variants in TGFBR1 have been reported to induce two completely distinct diseases, namely Loeys-Dietz syndrome (LDS) and multiple self-healing squamous epithelioma (MSSE). However, detailed mechanisms underlying this effect remain unknown. We report a Japanese familial case of LDS with a novel splice donor site variant in TGFBR1 gene (c.973 + 1 G > A; NG_007461.1). The intronic variant was predicted to mediate in-frame exon 5 skipping within the serine/threonine kinase (STK) domain, which may also be mediated by a similar TGFBR1 variant of a splice acceptor site in intron 4 (c.806-2 A > C), identified in a British familial case of MSSE. Therefore, ex vivo splicing and functional assays were performed in mammalian cells to evaluate the effect of these sequence variants. The MSSE variant activated a cryptic acceptor site at 76 bp downstream of the 3' natural splice acceptor site, which produced an out-of-frame transcript (r.807_882del, p.Asn270Thrfs*8). In contrast, the LDS variant generated two types of in-frame transcription products, r.[806_973del, 965_973 del], and produced two functionally inactivated proteins, p.[Asp269_Gln324del, Thr323_Gly325del], as a result of exon 5 skipping and the activation of a cryptic donor splice site at 9 bp upstream of the 5' natural splice donor site, respectively. Our results support the previously proposed but not yet approved mechanism that dominant-negative and truncating variants in STK domain induce LDS and MSSE, respectively. | 01 = IsEpi
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Pain is one of the most significant causes of suffering and disability world-wide, and arguably the most burdensome global health challenge. The growing number of patients suffering from chronic pain conditions such as fibromyalgia, complex regional pain syndrome, migraine and irritable bowel syndrome, not only reflect the complexity and heterogeneity of pain types, but also our lack of understanding of the underlying mechanisms. Sensory neurons within the dorsal root ganglia (DRG) have emerged as viable targets for effective chronic pain therapy. However, DRG's contain different classes of primary sensory neurons including pain-associated nociceptive neurons, non-nociceptive temperature sensing, mechanosensory and chemoreceptive neurons, as well as multiple types of immune and endothelial cells. This cell-population heterogeneity makes investigations of individual subgroups of DRG neurons, such as nociceptors, difficult. In attempts to overcome some of these difficulties, a limited number of immortalized DRG-derived cell lines have been generated over the past few decades. In vitro experiments using DRG-derived cell lines have been useful in understanding sensory neuron function. In addition to retaining phenotypic similarities to primary cultured DRG neurons, these cells offer greater suitability for high throughput assays due to ease of culture, maintenance, growth efficiency and cost-effectiveness. For accurate interpretation and translation of results it is critical, however, that phenotypic similarities and differences of DRG-derived cells lines are methodically compared to native neurons. Published reports to date show notable variability in how these DRG-derived cells are maintained and differentiated. Understanding the cellular and molecular differences stemming from different culture methods, is essential to validate past and future experiments, and enable these cells to be used to their full potential. This review describes currently available DRG-derived cell lines, their known sensory and nociceptor specific molecular profiles, and summarize their morphological features related to differentiation and neurite outgrowth. | 01 = IsEpi
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Two analytical methods; high performance liquid chromatography and gas chromatography were used to determine the content of 2-methylquinoxaline, a methylglyoxal-derived agent in sera from cattle with fascioliasis. Methylglyoxal is a highly mutagenic and cytotoxic reactive dicarbonyl compound formed by non-enzymatic fragmentation of triose phosphate GAP and DHAP during glycolysis which regularly contributes to repositioning the energetic balance between physiological and pathological situations. The aim of this study was to propose the MGO as a new biomarker in the bovine fasciolosis. Strongly infected animals showed a correlation between the relatively high levels of Fasciola hepatica anti-f2 antibody and methylglyoxal compared to unharmed animals. Also, an acute hyperglycemia was recorded and closely related to hepatic parenchyma hyperplasia, inflammation, bile ducts obstruction and scléro-fibrous foci formation.Unlike HPLC, which has shown analytical flaws and irregularities, GC-MS remains an excellent diagnostic tool for detecting and quantifying methylglyoxal in biological fluids. The developed method has been validated under FDA guidelines. A full scan-range was set from m/z 39 to 144/999 and the molecular weight of the 2-methylquinoxaline was identified according to NIST Database and ES. Methylglyoxal was the only analyte successfully quantified in a relatively short run time. It was linear over a concentration range of 0.057-5.7 μg.ml-1with mean recoveries and RSD of 118% and 3.63% respectively. The intra and inter-day assays were satisfying and not exceed 3.00%. Results reflect the degree of precision of our method and indicate that MGO was an important contributor to understand the hepatic failure independently of other serum markers. | 01 = IsEpi
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OBJECTIVE:We identified a pedigree over five generations with 49 members, some of whom had chronic megacolon presenting in adolescence or adulthood. We aimed to assess the genetic cause of chronic megacolon through clinical and DNA studies. DESIGN:After ethical approval and informed consent, family members provided answers to standard bowel disease questionnaires, radiological or surgical records, and DNA (buccal mucosal scraping). Exome DNA sequencing of colon tissue or blood DNA from seven family members with colon or duodenal dilatation, or no megacolon (n = 1) was carried out. Sanger sequencing was performed in 22 additional family members to further evaluate candidate variants. The study focused on genes of potential relevance to enteric nerve (ENS) maturation and Hirschsprung's disease or megacolon, based on the literature (GFRA1, NKX2-1, KIF26A, TPM3, ACTG2, SCN10A, and C17orf107 [CHRNE]) and other genetic variants that co-segregated with megacolon in the six affected family members. RESULTS:Information was available in all except five members alive at time of study; among 30 members who provided DNA, six had definite megacolon, one megaduodenum, seven significant constipation without bowel dilatation, and 16 normal bowel function by questionnaire. Among genes studied, SEMA3F (g.3:50225360A>G; c1873A>G) was found in 6/6 family members with megacolon. The SEMA3F gene variant was assessed as potentially pathogenic, based on M-CAP in silico prediction. SEMA3F function is associated with genes (KIT and PDGFRB) that impact intestinal pacemaker function. CONCLUSION:Familial chronic megacolon appears to be associated with SEMA3F, which is associated with genes impacting enteric nerve or pacemaker function. | 01 = IsEpi
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Acquired deficiencies in platelet glycoprotein VI are rare and have not been found associated with other defects. Here we report the case of a 64-year old male patient presenting an immune GPVI deficiency associated to a mutation in the alpha-actinin gene and who has been treated with dual anti platelet therapy without bleeding. Introduction: Glycoprotein (GP) VI, a pluripotent receptor interacting with collagen and fibrin(ogen) is responsible for thrombus formation, growth and stability (1-4). It is co-expressed with the Fc receptor γ (FcRγ) chain (5). GPVI is not critical for haemostasis since subjects with a GPVI deficiency usually present low or even no bleeding tendency (6, 7). Acquired GPVI deficiency due to antibody-induced GPVI depletion is the most frequent finding. At least 10 patients have been described with an acquired GPVI deficiency, most often associated to immune thrombocytopenia, moderate bleeding and impaired collagen-induced platelet aggregation (7). Several mechanisms leading to the GPVI deficiency are proposed including antibody-triggered GPVI internalization and/or shedding of the extracellular domain (8, 9).We report the case of a patient presenting an acquired GPVI deficiency different from those previously described: (i) he is male whereas all previous cases were female, (ii) he is heterozygous for a mutation in α (alpha)-actinin-1 gene and (iii) he was treated with dual antiplatelet therapy with no haemorrhagic manifestation. | 01 = IsEpi
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We performed a study to estimate the point prevalence of progressive supranuclear palsy (PSP) in the UK at national, regional and community levels. A 'Russian doll' design was used in which the population denominator for each of the three studies was successively smaller, whilst the method of case ascertainment became increasingly more rigorous. The NINDS-SPSP (National Institute of Neurological Disorders and the Society for Progressive Supranuclear Palsy) diagnostic criteria for PSP were applied throughout the study for case definition. The national study identified cases using passive referral mechanisms [e.g. the British Neurological Surveillance Unit (BNSU), PSP (Europe) Association patient register]. We identified 577 cases of PSP, giving a national prevalence estimate of 1.0 per 100 000 [95% confidence interval (CI) 0.9-1.1]. The North of England regional study used active 'multiple source' case ascertainment from a collaborative network of neurologists and non-neurologists. We identified 80 cases of PSP in this study, giving a crude and age-adjusted prevalence of 3.1 (95% CI 2.4-3.8) and 2.4 (1.9-3.0) per 100 000, respectively. Of these 80 cases, 51 patients (65%) were referred initially to non-neurologists and 10 patients (13%) had not seen a neurologist at any stage of their illness. The proportion of female cases was significantly greater in the regional than in the national study (61% versus 44%; P < 0.02). Cases referred to non-neurologists were significantly older than those referred to neurologists in the regional study (median age 73 versus 69.5 years; P < 0.01). Patients in the community study were identified via diagnostic and therapeutic registers from a representative sample of general practices in Newcastle upon Tyne. We identified 17 cases of PSP, yielding crude and age-adjusted prevalences of 6.5 (95% CI 3.4-9.7) and 5.0 (95% CI 2.5-7.5) per 100 000, respectively. Seven of the 17 cases (41%) had not previously been diagnosed as PSP. This study suggests that PSP is more common than previously considered, is commonly misdiagnosed and that the majority of cases are not initially referred to neurologists. The study also confirms the importance of active and detailed case ascertainment in ensuring reliable prevalence estimates. | 10 = IsNotEpi
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Creatine transporter deficiency (CTD) is a metabolic disorder resulting in cognitive, motor, and behavioral deficits. Cyclocreatine (cCr), a creatine analog, has been explored as a therapeutic strategy for the treatment of CTD. We developed a rapid, selective, and accurate HILIC ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to simultaneously quantify the intracellular concentrations of cCr, creatine (Cr), creatine-d3 (Cr-d3), phosphocyclocreatine (pcCr), and phosphocreatine (pCr). Using HILIC-UPLC-MS/MS, we measured cCr and Cr-d3 uptake and their conversion to the phosphorylated forms in primary human control and CTD fibroblasts. Altogether, the data demonstrate that cCr enters cells and its dominant intracellular form is pcCr in both control and CTD patient cells. Therefore, cCr may replace creatine as a therapeutic strategy for the treatment of CTD. | 01 = IsEpi
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Heterozygous mutations in MECOM (MDS1 and EVI1 complex locus) have been reported to be causative of a rare association of congenital amegakaryocytic thrombocytopenia and radioulnar synostosis. Here we report on 12 patients with congenital hypomegakaryocytic thrombocytopenia caused by MECOM mutations (including 10 novel mutations). The mutations affected different functional domains of the EVI1 protein. The spectrum of phenotypes was much broader than initially reported for the first 3 patients; we found familial as well as sporadic cases, and the clinical spectrum ranged from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormality. The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss. No single clinical manifestation was detected in all patients affected by MECOM mutations. Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1. We propose the term MECOM-associated syndrome for this heterogeneous hereditary disease and inclusion of MECOM sequencing in the diagnostic workup of congenital bone marrow failure. | 01 = IsEpi
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Megalocytic interstitial nephritis is a rare form of kidney disease caused by chronic inflammation. We report a case of megalocytic interstitial nephritis occurring in a 45-yrold woman who presented with oliguric acute kidney injury and acute pyelonephritis accompanied by Escherichia coli bacteremia. Her renal function was not recovered despite adequate duration of susceptible antibiotic treatment, accompanied by negative conversion of bacteremia and bacteriuria. Kidney biopsy revealed an infiltration of numerous histiocytes without Michaelis-Gutmann bodies. The patient's renal function was markedly improved after short-term treatment with high-dose steroid. | 01 = IsEpi
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BACKGROUND & AIMS:The epidemiology of primary biliary cirrhosis (PBC) has not been studied systematically in the United States. We report the incidence and prevalence of this condition in the general population. We also examined the validity of the Mayo natural history model for PBC among these unselected patients from the community. METHODS:The Rochester Epidemiology Project entails a computerized index of diagnoses from the health care encounters of residents of Olmsted County, Minnesota. For potential cases identified using this database, the complete (inpatient and outpatient) medical records were reviewed to verify the diagnosis and extract information necessary for the application of the Mayo model. We estimated the incidence and prevalence of PBC in this population and compared the actual survival of patients with PBC in the community with the survival predicted for PBC patients by the Mayo natural history model. RESULTS:The age-adjusted (to 1990 U.S. whites) incidence of PBC per 100,000 person-years for years 1975-1995 was 4.5 (95% confidence interval [CI], 3.1-5.9) for women, 0.7 (95% CI, 0.1-1.3) for men, and 2.7 (95% CI, 1.9-3.5) overall. The age- and sex-adjusted prevalence per 100,000 persons as of 1995 was 65.4 (95% CI, 43.0-87.9) for women, 12.1 (95% CI, 1.1-23.1) for men, and 40.2 (95% CI, 27.2-53.1) overall. The Mayo natural history model accurately predicted the actual survival of these patients. CONCLUSIONS:This first description of the epidemiology of PBC in the United States indicates that its incidence and prevalence in this country are among the highest reported. Outcomes among these unselected patients from a community population further validated the Mayo natural history model of PBC. | 10 = IsNotEpi
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Hereditary hemorrhagic telangiectasia (HHT) can be clinically diagnosed, but children often lack characteristic features. We report a family with homozygous growth differentiation factor 2 (GDF2)-related HHT diagnosed by genetic testing. A boy aged 5 years and 2 months presented with isolated hypoxemia. He was the product of a consanguineous marriage; his parents were second cousins. Physical examination revealed cyanosis of nail beds and clubbed fingers. Pulse oxygen saturation was 84% to 89%. Lung function, contrast-enhanced lung computed tomography, and noncontrast echocardiography were normal. A pulmonary perfusion scan revealed radioactivity in the brain and bilateral kidney, suggesting the existence of a intrapulmonary shunt. Whole-exome sequencing revealed a homozygous variant [c.1060_1062delinsAG (p.Tyr354ArgfsTer15)] in GDF2, which was found to be inherited from his heterozygous parents. At the age of 8 years, he developed epistaxis, and an angiogram revealed diffuse pulmonary arteriovenous malformations. At the age of 9 years, he was treated with sirolimus, and his condition improved significantly. However, his now 7-year-old sister with the same homozygous variant currently has no symptoms. Physical examinations revealed 1 pinpoint-sized telangiectasia on the chest of his mother and a vascular lesion on the forehead of his sister. Additionally, the patient's father and great-uncle had a history of mild to moderate epistaxis. Mutation in GDF2 is a rare cause of HHT. Ours is the first report of homozygous GDF2-related HHT; in addition, this variant has not been reported previously. In our report, we also confirm variable expressivity, even with the same pathogenic variant in GDF2-related HHT. | 01 = IsEpi
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RATIONALE:Autosomal recessive distal renal tubular acidosis (dRTA) is a rare condition, most cases of which are caused by genetic mutations. Several loss-of-function mutations in the ATP6V0A4 gene have been recently reported. PATIENT CONCERNS:A 2-month, 24-day-old Chinese girl presenting with vomiting and diarrhea. DIAGNOSIS:dRTA was established by metabolic acidosis and hypokalemia. Mutational analysis of the ATP6V0A4 gene revealed a homozygous deletion of exons 13 and 14. The father was found to have a heterozygous loss of both exons, whereas the mother was normal. INTERVENTIONS:Patient was treated with potassium citrate. OUTCOMES:The patient has shown normal pH and potassium levels. LESSONS:This is the first case of a homozygous deletion in ATP6V0A4 reported in the literature. Although the initial auditory screening was normal in this case, this patient will nevertheless undergo long-term auditory testing. | 01 = IsEpi
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BACKGROUND:Infant death in keratitis-ichthyosis-deafness (KID) syndrome is recognized; its association with specific genotypes and pathophysiology is inadequately understood. OBJECTIVE:We sought to discover characteristics that account for poor outcomes in lethal KID syndrome. METHODS:We collected 4 new cases and 9 previously reported, genotyped cases of lethal KID syndrome. We performed new molecular modeling of the lethal mutants GJB2 p.A88V and GJB2 p.G45E. RESULTS:Infant death occurred in all patients with GJB2 p.G45E and p.A88V; it is unusual with other GJB2 mutations. Early death with those 2 "lethal" mutations is likely multifactorial: during life all had ≥1 serious infection; most had poor weight gain and severe respiratory difficulties; many had additional anatomic abnormalities. Structural modeling of GJB2 p.G45E identified no impact on the salt bridge previously predicted to account for abnormal central carbon dioxide sensing of GJB2 p.A88V. LIMITATIONS:This clinical review was retrospective. CONCLUSION:GJB2 p.G45E and p.A88V are the only KID syndrome mutations associated with uniform early lethality. Those electrophysiologically severe mutations in GJB2 reveal abnormalities in many organs in lethal KID syndrome. All patients with KID syndrome may have subtle abnormalities beyond the eyes, ears, and skin. Early genotyping of KID syndrome births will inform prognostic discussion. | 01 = IsEpi
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In this study we sought to identify magnetic resonance imaging (MRI) signs of selective muscle involvement and disease progression in patients with spinal muscular atrophy type 3b (SMA3b).Twenty-five patients with genetically confirmed SMA3b underwent MRI on a 1.5-Tesla MR scanner.MRI showed significantly more severe involvement of the iliopsoas than of the gluteus maximus muscles, and more severe involvement of the triceps brachii than of the biceps brachii muscles. The quadriceps femoris muscles were severely involved. The deltoid, adductor longus, portions of the hamstrings, gracilis, sartorius, and rectus abdominis muscles were well preserved. We found a significant positive correlation between MRI changes and disease duration for gluteus maximus and triceps brachii. Follow-up MRIs of 4 patients showed disease progression.This study confirms the pattern of selective muscle involvement suggested by previous studies and further refines muscle MRI changes in SMA3b. Progressive muscle involvement is implicated. Muscle Nerve 55: 651-656, 2017. | 01 = IsEpi
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Kallmann syndrome is a rare genetic disorder marked by hypogonadotropic hypogonadism (HH) and anosmia, affecting 1 in 50,000 females. It is due to a defect of gonadotropin-releasing hormone (GnRH)-secreting neurons migration from the nasal olfactory epithelium to the basal hypothalamus. Non-reproductive, non-olfactory symptoms can also be present, depending on the genetic form of disease. The management includes hormone replacement therapy and fertility treatment. We report a case of Kallmann syndrome in an 18-year girl who presented with primary amenorrhea with poor, secondary sexual characteristics' development, poor sense of smell and syndactyly. The plasma levels of luteinising hormone, follicle stimulating hormone, and estradiol were very low, while chromosome analysis showed 46, XX karyotype. Pelvic MRI confirmed the presence of uterus and ovaries. MRI of brain was normal. Treatment was started with cyclic conjugated estrogen and progestin with good response. She is now on regular follow-up to monitor treatment. | 01 = IsEpi
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We performed whole-exome sequencing in two autopsy-confirmed cases and an elderly unaffected control from a multigenerational family with autosomal dominant neuronal ceroid lipofuscinosis (ANCL). A novel single-nucleotide variation (c.344T>G) in the DNAJC5 gene was identified. Mutational screening in an independent family with autosomal dominant ANCL found an in-frame single codon deletion (c.346_348 delCTC) resulting in a deletion of p.Leu116del. These variants fulfill all genetic criteria for disease-causing mutations: they are found in unrelated families with the same disease, exhibit complete segregation between the mutation and the disease, and are absent in healthy controls. In addition, the associated amino acid substitutions are located in evolutionarily highly conserved residues and are predicted to functionally affect the encoded protein (CSPα). The mutations are located in a cysteine-string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of CSPα. We performed a comprehensive in silico analysis of the functional and structural impact of both mutations on CSPα. We found that these mutations dramatically decrease the affinity of CSPα for the membrane. We did not identify any significant effect on palmitoylation status of CSPα. However, a reduction of CSPα membrane affinity may change its palmitoylation and affect proper intracellular sorting. We confirm that CSPα has a strong intrinsic aggregation propensity; however, it is not modified by the mutations. A complementary disease-network analysis suggests a potential interaction with other NCLs genes/pathways. This is the first replication study of the identification of DNAJC5 as the disease-causing gene for autosomal dominant ANCL. The identification of the novel gene in ANCL will allow us to gain a better understanding of the pathological mechanism of ANCLs and constitutes a great advance toward the development of new molecular diagnostic tests and may lead to the development of potential therapies. | 01 = IsEpi
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Hürthle cell thyroid cancer (HCTC) is a less common form of differentiated thyroid cancer. It rarely metastasizes to the liver, and when it does, the metastasis is almost never isolated. Here we report a 62-year-old male with widely invasive Hürthle cell thyroid cancer, who underwent total thyroidectomy and received adjuvant treatment with I-131 with posttreatment scan showing no evidence of metastatic disease. His thyroglobulin however continued to rise after that and eventually an isolated liver metastasis was identified. He underwent laparoscopic microwave ablation of the liver metastasis, with dramatic decline in thyroglobulin and no structural disease identified to date. This case highlights the rare occurrence of isolated liver metastasis from HCTC and also illustrates the utility of thermoablation as an alternative to surgical resection in the treatment of small isolated liver metastases from HCTC. | 01 = IsEpi
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Bare lymphocyte syndrome (BLS) is a rare immunodeficiency disorder manifested by the partial or complete disappearance of major histocompatibility complex (MHC) proteins from the surface of the cells. Based on this specific feature, it is categorized into three different types depending on which type of MHC protein is affected. These proteins are mainly involved in generating the effective immune responses by differentiating 'self' from 'non-self' antigens through a process referred to as antigen presentation. Investigations on BLS have immensely contributed to our understanding of the transcriptional regulation of these molecules and have led to the discovery of several important proteins of the antigen presentation pathway. Reviews on this subject consistently project type II BLS, MHC II deficiency as BLS syndrome, although literatures' document cases of other types of BLS too. Therefore, in this article, we have assembled information on the BLS syndrome to produce a systematic narration while emphasizing the importance of BLS system in studying various aspects of immune biology. | 01 = IsEpi
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Malakoplakia is a characteristic inflammatory condition, which is usually seen in the urogenital tract, and less frequently in the gastrointestinal tract. We present a case of colonic malakoplakia in an immunocompromised patient. A 55-year-old female visited the outpatient clinic for routine cancer surveillance. Her past medical history was significant for kidney transplantation 11 years ago, and she had been taking immunosuppressants. A colonoscopy revealed several depressed flat lesions and elevated polyps, which were 0.3 to 0.4 cm in size and accompanied by whitish exudates. A biopsy revealed an infiltration of histiocytes with ample granular eosinophilic cytoplasm, with some lymphocytes and plasma cells. Many histiocytes had the characteristic morphology, described as Michaelis-Gutmann bodies: one or several round basophilic structures of approximately 1 to 10 µm in size with some being laminated, some appearing homogeneous, and others having a dense central core with a targetoid appearance. These Michaelis-Gutmann bodies were positively stained on von Kossa stain, and were diagnostic for malakoplakia. | 01 = IsEpi
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BACKGROUND:An early diagnosis of CHARGE syndrome is challenging, especially for the primary care physicians who often take care of neonates with multiple congenital anomalies. Here we report eight cases of CHARGE syndrome whose diagnosis was made early in life with the intent to identify the most helpful features allowing a prompt clinical diagnosis. METHODS:Medical records of patients with CHARGE syndrome whose diagnosis was made at the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico in Milan, Italy were retrospectively reviewed. RESULTS:Taken together, these patients reflect the considerable phenotypic variability of the syndrome; in one patient, the diagnosis was made immediately after birth because all the major criteria were met. In six patients, presenting with relatively nonspecific defects, a temporal bone computerized tomography scan was essential to achieve the correct diagnosis. In one patient, the diagnosis was made later than the others were. A careful examination revealed the presence of outer, middle, and inner ear anomalies: these elements, in the absence of any additional major criteria, represented for us an important diagnostic clue. CONCLUSIONS:This article suggests that an accurate evaluation of the ear should be made every time CHARGE syndrome is considered as a likely diagnosis even when the standard criteria are not fulfilled. | 01 = IsEpi
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A subset of acute myeloid leukemia (AML) arises either from an antecedent myeloid malignancy (secondary AML, sAML) or as a complication of DNA-damaging therapy for other cancers (therapy-related myeloid neoplasm, t-MN). These secondary leukemias have unique biological and clinical features that distinguish them from de novo AML. Over the last decade, molecular techniques have unraveled the complex subclonal architecture of sAML and t-MN. In this review, we compare and contrast biological and clinical features of de novo AML with sAML and t-MN. We discuss the role of genetic mutations, including those involved in RNA splicing, epigenetic modification, tumor suppression, transcription regulation, and cell signaling, in the pathogenesis of secondary leukemia. We also discuss clonal hematopoiesis in otherwise healthy individuals, as well as in the context of another malignancy, and how it challenges the conventional notion of sAML/t-MN. We conclude by summarizing the current and emerging treatment strategies, including allogenic transplant, in these complex scenarios. | 01 = IsEpi
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BACKGROUND: In 1972, Fuhrmann et al. (Humangenetik 1972;14:196-203) described a novel syndrome consisting of cleft palate (CP) and lateral synechiae (LS) between the palate and the floor of the mouth. This constellation of malformations, since denoted as cleft-palate lateral synechiae syndrome (CPLS), is a rare syndrome; only five cases have been reported since the original description. Because of the paucity of recognized cases, little is known regarding the phenotypic spectrum of this presumably autosomal dominant condition. CASES: We report two unrelated patients who presented with remarkably similar phenotypic features, including multiple intraoral synechiae (filiforme intraalveolar bands), cleft palate, micrognathia, and redundant lower lip tissue. Their phenotypic findings indicate a diagnosis of CPLS; however, case 3 (the monozygotic twin of case 2) had classic phenotypic features of Fryns syndrome. CONCLUSIONS: This report presents two new cases of CPLS, and suggests that the CPLS phenotype may represent the mild end of the Fryns syndrome phenotypic spectrum. Supplementary material for this article can be found on the Birth Defects Research (Part A) website (http://www.interscience.wiley.com/ jpages/1542-0752/suppmat/67/fig5.xls). | 01 = IsEpi
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