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Melanoma-associated retinopathy (MAR) is a rare paraneoplastic autoimmune manifestation of cutaneous malignant melanoma. Patients classically present with acute onset night blindness, positive visual phenomena and visual field defects, and typically have significantly reduced quality of life as a result. Early recognition of MAR is of prognostic significance as it can precede the diagnosis of primary or metastatic malignant melanoma, and early treatment can lower the risk of irreversible immunological damage to the retinal cells with improved visual outcomes. The focus of our review article is therefore to raise awareness of MAR and present the latest evidence relating to the investigation and management of this condition. | 01 = IsEpi
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Trichoepithelioma is a benign hair follicle tumor that can undergo malignant transformation into basal cell carcinoma in rare cases. Due to the similar clinical and histological features of trichoepithelioma and basal cell carcinoma, distinguishing between these types of tumors can be a diagnostic challenge. Punch biopsy obtains only a small sample of the entire lesion, and thus inherently involves a risk of misdiagnosis between histologically similar diseases. Therefore, if the possibility of misdiagnosis can reasonably be suspected, clinicians should conduct an excisional biopsy or immunohistochemical staining (e.g., CD10 and Bcl-2) to ensure an exact diagnosis. Although trichoepithelioma is benign, the surgical excision of solitary trichoepithelioma should be considered in order to avoid the possibility of malignant transformation, which has occasionally been documented for multiple familial trichoepitheliomas. Herein, we report a case that was initially misdiagnosed as trichoepithelioma before ultimately being diagnosed as basal cell carcinoma through excision and immunohistochemical staining. | 01 = IsEpi
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Malformations of cortical development (MCD) represent a major cause of developmental disabilities, severe epilepsy, and reproductive disadvantage. Genes that have been associated to MCD are mainly involved in cell proliferation and specification, neuronal migration, and late cortical organization. Lissencephaly-pachygyria-severe band heterotopia are diffuse neuronal migration disorders causing severe global neurological impairment. Abnormalities of the LIS1, DCX, ARX, RELN, VLDLR, ACTB, ACTG1, TUBG1, KIF5C, KIF2A, and CDK5 genes have been associated with these malformations. More recent studies have also established a relationship between lissencephaly, with or without associated microcephaly, corpus callosum dysgenesis as well as cerebellar hypoplasia, and at times, a morphological pattern consistent with polymicrogyria with mutations of several genes (TUBA1A, TUBA8, TUBB, TUBB2B, TUBB3, and DYNC1H1), regulating the synthesis and function of microtubule and centrosome key components and hence defined as tubulinopathies. MCD only affecting subsets of neurons, such as mild subcortical band heterotopia and periventricular heterotopia, have been associated with abnormalities of the DCX, FLN1A, and ARFGEF2 genes and cause neurological and cognitive impairment that vary from severe to mild deficits. Polymicrogyria results from abnormal late cortical organization and is inconstantly associated with abnormal neuronal migration. Localized polymicrogyria has been associated with anatomo-specific deficits, including disorders of language and higher cognition. Polymicrogyria is genetically heterogeneous, and only in a small minority of patients, a definite genetic cause has been identified. Megalencephaly with normal cortex or polymicrogyria by MRI imaging, hemimegalencephaly and focal cortical dysplasia can all result from mutations in genes of the PI3K-AKT-mTOR pathway. Postzygotic mutations have been described for most MCD and can be limited to the dysplastic tissue in the less diffuse forms. | 01 = IsEpi
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Synovial chondromatosis (SC) is a rare benign cartilaginous neoplasm in which recurrent fibronectin 1 (FN1) and activin receptor 2A (ACVR2A) gene rearrangements have been recently reported. Triggered by a case of malignant transformation in SC (synovial chondrosarcoma) showing a novel KMT2A-BCOR gene fusion by targeted RNA sequencing, we sought to evaluate the molecular abnormalities in a cohort of 27 SC cases using a combined methodology of fluorescence in situ hybridization (FISH) and/or targeted RNA sequencing. Results showed that FN1 and /or ACVR2A gene rearrangements were noted in 18 cases (67%), with an FN1-ACVR2A fusion being confirmed in 15 (56%) cases. Two cases showed only FN1 gene rearrangement, without other abnormalities. A novel FN1-NFATc2 gene fusion was noted in one case by RNA sequencing. The remaining nine cases showed no abnormalities in FN1 and ACVR2A genes. No additional cases showed BCOR gene alterations. In conclusion, this study confirms that FN1-ACVR2A fusion is the leading pathogenetic event in SC, at even higher frequency than previously reported. FISH methodology emerges as an appropriate tool in the identification of FN1 and ACVR2A gene abnormalities, which can be used in challenging cases. Further studies are needed to determine the recurrent potential of BCOR abnormalities in this disease. | 01 = IsEpi
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Ketamine is used widely in emergency departments for a variety of purposes, including procedural sedation and pain management. A major benefit of using ketamine is the rapid onset and lack of respiratory depression. The known side effects include emergence reactions, hallucinations, hypertension, dizziness, nausea, and vomiting. Recent studies have shown the benefit of ketamine for refractory status epilepticus; however, this application of the drug is still being studied. We present a case where ketamine likely induced a seizure in a patient on whom it was used as a single agent in procedural sedation. Seizure is not a known side effect of ketamine in patients without a seizure history. Given the eagerness over additional uses for ketamine, this novel case of a seizure following procedural sedation with ketamine should be of interest to emergency providers. | 01 = IsEpi
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OPINION STATEMENT:Denosumab is a RANK ligand inhibitor approved for the treatment of giant cell tumor of bone. While the role of denosumab in the setting of advanced and unresectable disease is well established, its role in surgically resectable disease is currently under discussion. Several prospective and retrospective series on neoadjuvant therapy in potentially resectable tumor with high morbidity surgery reported a relapse rate of 10-20% after resection and 30-40% after curettage. At the same time, less morbid surgery has obvious clinical advantages for the patient, and several studies have shown the efficacy of denosumab in downgrading of the surgical procedure. Currently, the role of neoadjuvant denosumab in operable GCTB is limited to selected cases in which a diffuse reactive bone formation and peripheral ossification can make an easier surgical procedure, for example, in tumors with a large soft tissue component. A planned resection may become less morbid when preoperative denosumab is administered. Whenever a segmental resection is thought to be indicated at diagnosis, denosumab may be considered in the neoadjuvant setting. A preoperative course of 6 months is considered safe and effective. Two case scenarios are presented and critically discussed. Because of the high recurrence rates after denosumab treatment followed by curettage, we discourage the use of denosumab when curettage is considered feasible. In this setting, a short course of preoperative denosumab (2-6 months) may be considered for highly selected cases, for example in pathological fractures. The role of adjuvant denosumab needs further investigation. Long-term disease control has been reported in case of non-surgical lesions, even after treatment interruption, but there is no consensus on ideal treatment duration and dosage for these scenarios. In all cases, multidisciplinary discussion with oncology, pathologist, radiologist, and surgeons is mandatory. Patient's comorbidities, dental conditions, and preferences, including family planning, should always be taken into account. | 01 = IsEpi
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BACKGROUND AND OBJECTIVES:The development of desmoid fibromatosis after tumor resection may mimic local recurrence. To our knowledge, this phenomenon has not been reported after extremity sarcoma resection. We report four cases of desmoid-type fibromatosis ("desmoid tumors") mimicking local recurrence after extremity sarcoma resection. METHODS:We retrospectively reviewed the records of patients treated for extremity sarcoma by our orthopedic oncology service from 2014 to 2019 and identified four patients with biopsy-proven desmoid tumors. We extracted clinical, pathologic, radiographic, and operative data for the primary neoplasms and desmoid tumors. RESULTS:Four patients with postresection surveillance magnetic resonance imaging suspicious for local recurrence underwent further analysis showing desmoid tumors. Patients underwent image-guided needle biopsy, with specimens demonstrating fibromatosis-type histologic characteristics. Two cases were β-catenin positive. Desmoid tumors were managed with observation. No patient had experienced local or distant recurrence of the primary tumor at a mean follow-up of 30 months after resection (range, 23-34 months); none underwent surgery for symptoms of desmoid tumors. CONCLUSIONS:Desmoid tumors should be considered part of the differential diagnosis when assessing patients with radiographic concern for postresection local recurrence of extremity bone and soft-tissue sarcoma. An image-guided needle biopsy can inform diagnosis and management. | 01 = IsEpi
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Mirror foot is a rare abnormality which presents as a preaxial, postaxial, or central polydactyly of the foot. The latter is encountered infrequently. We describe the case of a central mirror foot. Our patient had eight digits of a central ray pattern type with fully developed metatarsal, proximal, middle, and distal phalanges, as well as a medial toe syndactyly. He had no tarsal bone duplications. He was treated by central ray resection via double V-shaped incisions on the dorsal and plantar aspects of the foot, while preserving the medial and lateral rays. The results were satisfactory. We describe the technique and attempt a review of the literature. | 01 = IsEpi
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A 64-year-old man presented to the emergency department with generalised fatigue and dizzy spells. His background history includes a previous admission with right leg deep vein thrombosis, provoked by pneumonia. Laboratory results showed evidence of hyponatremia and hyperkalaemia. A synacthen test was performed that indicated hypoadrenalism. CT of his abdomen revealed enlarged adrenal glands bilaterally. Adrenal antibodies and positron emission tomography (PET) scan were performed to assess the cause of enlarged adrenals. PET scan showed no evidence of increased uptake. Adrenal antibodies were found to be negative. Tuberculous (TB) adrenalitis was the principle differential diagnosis. TB QuantiFERON was strongly positive. Following 9 months of TB treatment, surveillance CT scan indicated a significant reduction in adrenal gland size. However, subsequent events culminated in a retrospective review of CT scans questioning the initial clinical diagnosis and suggesting that the observed adrenal gland enlargement was secondary to bilateral adrenal infarction and haemorrhage. Equally, the subsequently observed marked reduction in adrenal gland size was not secondary to an assumed response to TB therapy, but rather the sequela of infracted atrophied adrenal glands, as a manifestation of the underlying antiphospholipid syndrome (APS). The case highlights the importance of recognising adrenal insufficiency in patients with a history of APS. It also illustrates the role of multidisciplinary meetings in the management of such complex cases. | 01 = IsEpi
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BACKGROUND:Primary distal renal tubular acidosis (dRTA) is a rare genetic condition characterized by an impaired acid excretion by the intercalated cells in the renal collecting duct. Recessive forms of this disease are caused by mutations in tow major genes: ATP6V1B1 and ATP6V0A4. Causal mutations in ATP6V1B1 gene are classically associated with early sensorineural hearing loss, however cases of tubular acidosis with early deafness have also been described in patients with mutations in the ATP6V0A4 gene. METHODS:The phenotype and genotype of three Moroccan consanguineous families with dRTA and deafness were assessed. Molecular analysis was performed by PCR amplification and direct sequencing of exon 12 of ATP6V1B1 gene. RESULTS:A novel c.1169dupC frameshift mutation of ATP6V1B1 gene was identified in one family and the c.1155dupC North African mutation in the tow other families. DISCUSSION AND CONCLUSION:In this report, we propose first line genetic testing based on screening of these two mutations both located in exon 12 of ATP6V1B1 gene in Moroccan patients with recessive form of dRTA associated to precocious hearing loss. Molecular diagnosis of dRTA leads to appropriate treatment and prevention of renal failure in affected individuals and to provide genetic counseling for families at risk. | 01 = IsEpi
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Introduction:White matter signal changes are common in wide spectrum of disorders other than primary demyelinating diseases. Knowledge into their characteristics is of great relevance as treatment options are available in most cases, if diagnosed early. Patient and methods:Patients both children and adults who showed radiological evidences of leukoencephalopathy which was not due to primary demyelinating disorders were evaluated in detail. Results:There were a total of 55 patients in the last 2 years. 58% patients were <10 years, 16% were <20years, 9% were <30 years and the rest of the patients were 40 and above. Commonest condition was ALD, followed by SSPE and Unclassified group. There were 3 cases each of MLD, Krabbe's, Vanishing White Matter Disease and Hypomyelination. Discussion and Conclusion:White matter disorders belong to a wide spectrum of illnesses which varies from degeneration to a spectrum of other disorders. Correlating the clinical, radiological and other laboratory data are mandatory for proper diagnosis. Those who belong to older age with shorter duration and uncharacterized radiological features suffered from acquired treatable causes. | 01 = IsEpi
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Holt-Oram syndrome (HOS) is a rare monogenic disorder characterized by upper limb abnormalities, congenital heart defects and/or conduction abnormalities. It is determined by mutations of TBX5 gene and is inherited in an autosomal dominant manner. Penetrance is complete, but variable expressivity is present, which gives sometimes diagnostic difficulties. Our case is a young adult with a personal history of preaxial polydactyly operated in infancy, multiple cardiac malformations (atrial septal defect, bicuspid aortic valve, left ventricular non-compaction) and radiologic findings consistent with HOS. Family history is negative for HOS. In conclusion, we present a case of HOS diagnosed in the adult period to highlight the diagnostic problems for the proband and the family and the importance of an early diagnostic. | 01 = IsEpi
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Mutations in EFTUD2 are responsible for the autosomal dominant syndrome named MFDM (mandibulofacial dysostosis with microcephaly). However, it is not clear how reduced levels of EFTUD2 cause abnormalities associated with this syndrome. To determine if the mouse can serve as a model for uncovering the etiology of abnormalities found in MFDM patients, we used in situ hybridization to characterize expression of Eftud2 during mouse development, and used CRISPR/Cas9 to generate a mutant mouse line with deletion of exon 2 of the mouse gene. We found that Eftud2 was expressed throughout embryonic development, though its expression was enriched in the developing head and craniofacial regions. Additionally, Eftud2 heterozygous mutant embryos had reduced EFTUD2 mRNA and protein levels. Moreover, Eftud2 heterozygous embryos were born at the expected Mendelian frequency, and were viable and fertile despite being developmentally delayed. In contrast, Eftud2 homozygous mutant embryos were not found post-implantation but were present at the expected Mendelian frequency at embryonic day (E) 3.5. Furthermore, only wild-type and heterozygous E3.5 embryos survived ex vivo culture. Our data indicate that Eftud2 expression is enriched in the precusor of structures affected in MFDM patients and show that heterozygous mice carrying deletion of exon 2 do not model MFDM. In addition, we uncovered a requirement for normal levels of Eftud2 for survival of pre-implantation zygotes. | 01 = IsEpi
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BACKGROUND:Osteopetrosis is a rare hereditary metabolic bone disorder characterized by generalized skeletal sclerosis caused by a defect in bone resorption and remodelling. Infantile autosomal recessive osteopetrosis is one of three subtypes of osteopetrosis and the most severe form. The correct and early diagnosis of infantile osteopetrosis is important for management of complications and for future genetic counselling. Diagnosis is largely based on clinical and radiographic evaluation, confirmed by gene testing where applicable. METHODS:Therefore, in this case study the classical clinical and radiological signs of a boy with infantile osteopetrosis will be presented with a comprehensive literature update. The differentiating signs from other causes of hereditary osteosclerosing dysplasias are discussed. RESULTS:This case study and review of available literature show that there tends to be a highly unique clinical and skeletal radiographic pattern of affection in infantile osteopetrosis. CONCLUSION:Although tremendous advances have been made in the elucidation of the genetic defect of osteopetrosis over the past years, the role of accurate clinical and radiological assessment remains an important contributor to the diagnosis of infantile osteopetrosis. | 01 = IsEpi
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BACKGROUND:Disseminated superficial actinic porokeratosis (DSAP) is a rare autosomal dominant disease. In our previous research, we found that a linkage region of DSAP in a large family is located at 12q23·2-q24·1. Subsequently, the mevalonate kinase gene (MVK) was shown to be pathogenic in DSAP. OBJECTIVES:To elucidate the mechanism by which MVK mutations lead to keratinocyte apoptosis and DSAP, and to report a new missense mutation, c.566 C>T (p.A189V), in MVK in a Chinese DSAP pedigree. METHODS:The half-life of wild-type (WT) MVK protein and mutants was assessed using cycloheximide treatment of cells. Dimerization of MVK was analysed by coimmunoprecipitation and glutathione S transferase pull-down assay. MVK kinase activity, production of cell cholesterol, mitochondrial complex activity and apoptosis were detected, using the corresponding commercial kits, in cells overexpressing MVK WT and mutants. RESULTS:Mechanically, we demonstrated that both the pathogenic p.A189V mutant and a sporadic mutation p.H312R (c.935A>G), which we reported previously, have rapid degradation, decreased kinase activity and reduced production of cell cholesterol. Also, we found the p.H312R mutation confers on the MVK protein an inability to dimerize. Further, we demonstrated that the mutants are impaired in mitochondrial function and lead to increased apoptosis. CONCLUSIONS:Our results provide an important basis for elucidating the mechanism by which MVK missense mutations contribute to DSAP. | 01 = IsEpi
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Two siblings from a Mexican family who carried lethal Raine syndrome are presented. A newborn term male (case 1) and his 21 gestational week brother (case 2), with a similar osteosclerotic pattern: generalized osteosclerosis, which is more evident in facial bones and cranial base. Prenatal findings at 21 weeks and histopathological features for case 2 are described. A novel combination of biallelic FAM20C pathogenic variants were detected, a maternal cytosine duplication at position 456 and a paternal deletion of a cytosine in position 474 in exon 1, which change the reading frame with a premature termination at codon 207 and 185 respectively. These changes are in concordance with a negative detection of the protein in liver and kidney as shown in case 2. Necropsy showed absence of pancreatic Langerhans Islets, which are reported here for the first time. Corpus callosum absence is added to the few reported cases of brain defects in Raine syndrome. This report shows two new FAM20C variants not described previously, and negative protein detection in the liver and the kidney. We highlight that lethal Raine syndrome is well defined as early as 21 weeks, including mineralization defects and craniofacial features. Pancreas and brain defects found here in FAM20C deficiency extend the functional spectrum of this protein to previously unknown organs. | 01 = IsEpi
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We report a case of a manicurist who developed an allergic skin reaction to acrylates, manifested by itchy erythema, papules, vesicles and fissures on her hands, fingertips, forearm and eyelids. Patch tests showed positive reactions to three nail products used: ethylene glycol dimethacrylate, 2-hydroxyethyl methacrylate, ethyl acrylate and 2-hydroxyethyl acrylate in (meth)acrylate series. By using gel nail products, our patient became sensitized to 2-hydroxyethyl methacrylate. We assume that this had been the trigger, leading to the occurrence of cross-reactions between numerous acrylates including ethylene glycol dimethacrylate, ethyl acrylate and 2-hydroxyethyl acrylate. When handling nail products, it is necessary to prevent airway sensitization, contact sensitization and cross-reaction between various acrylates. | 01 = IsEpi
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Erdheim-Chester disease (ECD) is a rare but increasingly recognized multi-system disorder. Its diagnosis and treatment require integration of clinical information, imaging studies, and pathology studies. Of note, ECD can now be defined as a clonal myeloid disorder due to mutations which activate mitogen-activated protein kinase (MAPK) pathways and where an inflammatory milieu is important in the pathogenesis and clinical manifestations of the disease. Biopsy demonstrating characteristic histopathologic features in addition to clinical and radiographic features, most often sclerosing long bone involvement, is required to establish a diagnosis. Detection of somatic MAPK pathway mutations can also assist in the differential diagnosis of ECD and related histiocytic neoplasms. Also, genetic analysis establishing BRAF and RAS mutational status is critical in all ECD patients, as these features will impact therapy with MAPK inhibition. Therapy is recommended at diagnosis in all patients, except for those patients with minimally symptomatic disease. Prospective therapeutic trials are essential to furthering therapeutic progress in ECD. | 01 = IsEpi
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A ring chromosome replacing a normal chromosome could involve variable structural rearrangements and mitotic instability. However, most previously reported cases lacked further genomic characterization. High-resolution oligonucleotide array comparative genomic hybridization with single-nucleotide polymorphism typing (aCGH+SNP) was used to study 2 unrelated cases with a ring chromosome 21. Case 1 had severe myopia, hypotonia, joint hypermobility, speech delay, and dysmorphic features. aCGH detected a 1.275-Mb duplication of 21q22.12-q22.13 and a 6.731-Mb distal deletion at 21q22.2. Case 2 showed severe growth and developmental retardations, intractable seizures, and dysmorphic features. aCGH revealed a contiguous pattern of a 3.612- Mb deletion of 21q22.12-q22.2, a 4.568-Mb duplication of 21q22.2-q22.3, and a 2.243-Mb distal deletion at 21q22.3. Mitotic instability was noted in 13, 30, and 76% of in vitro cultured metaphase cells, interphase cells, and leukocyte DNA, respectively. The different phenotypes of these 2 cases are likely associated with the unique genomic structure and distinct mitotic behavior of their ring chromosome 21. These 2 cases represent a subtype of ring chromosome 21 probably involving somatic dicentric ring breakage and reunion. A cytogenomic approach is proposed for characterizing the genomic structure and mitotic instability of ring chromosome abnormalities. | 01 = IsEpi
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PURPOSE:Early clinical recognition of sepsis can be challenging. With the advancement of machine learning, promising real-time models to predict sepsis have emerged. We assessed their performance by carrying out a systematic review and meta-analysis. METHODS:A systematic search was performed in PubMed, Embase.com and Scopus. Studies targeting sepsis, severe sepsis or septic shock in any hospital setting were eligible for inclusion. The index test was any supervised machine learning model for real-time prediction of these conditions. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, with a tailored Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) checklist to evaluate risk of bias. Models with a reported area under the curve of the receiver operating characteristic (AUROC) metric were meta-analyzed to identify strongest contributors to model performance. RESULTS:After screening, a total of 28 papers were eligible for synthesis, from which 130 models were extracted. The majority of papers were developed in the intensive care unit (ICU, n = 15; 54%), followed by hospital wards (n = 7; 25%), the emergency department (ED, n = 4; 14%) and all of these settings (n = 2; 7%). For the prediction of sepsis, diagnostic test accuracy assessed by the AUROC ranged from 0.68-0.99 in the ICU, to 0.96-0.98 in-hospital and 0.87 to 0.97 in the ED. Varying sepsis definitions limit pooling of the performance across studies. Only three papers clinically implemented models with mixed results. In the multivariate analysis, temperature, lab values, and model type contributed most to model performance. CONCLUSION:This systematic review and meta-analysis show that on retrospective data, individual machine learning models can accurately predict sepsis onset ahead of time. Although they present alternatives to traditional scoring systems, between-study heterogeneity limits the assessment of pooled results. Systematic reporting and clinical implementation studies are needed to bridge the gap between bytes and bedside. | 01 = IsEpi
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Isolated sulfite oxidase deficiency (ISOD) is a life-threatening, autosomal recessive disease characterized by severe neurological impairment. As no long-term effective treatment is available, distinction from other treatable diseases, such as molybdenum cofactor deficiency (MoCD) type A, should be made. We reviewed 47 patients (45 previously reported in the literature). Cases were reviewed for consanguinity, sex, age at onset, death, clinical findings (including spasticity, seizures, psychomotor retardation, feeding difficulties, ectopia lentis, microcephaly), laboratory findings [urinary sulfite, S-sulfocysteine (in plasma and urine), plasma cystine, total homocysteine, uric acid, and oxypurines in urine] and radiological findings (including cerebral/cerebellar atrophy, cystic white matter changes, ventriculomegaly). We also aligned the published SUOX gene mutations to the reference sequence NM_000456.2. Onset occurred mostly during the first 72 h of life (57%) and within the first year of life in all but two patients (96%). All patients presented with neurological abnormalities, such as neonatal axial hypotonia and/or peripheral hypertonia (100%), (pharmacoresistant) seizures (84%), or developmental delay (97%). Feeding problems were also common. As found in our review, measurement of homocysteine in plasma, amino acids in plasma/urine, and sulfite in fresh urine supports the diagnosis of ISOD. Analysis of uric acid (plasma) and oxypurines (urine) is useful to rule out MoCD. In all patients in whom brain magnetic resonance imaging/computed tomography (MRI/CT) was performed, brain abnormalities were found. The purpose of this literature review is to provide a thorough overview of clinical, neuroimaging, biochemical, and genetic findings of patients with ISOD. | 01 = IsEpi
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Spondylocostal dysostosis is a very rare combination of complex vertebra and rib malformations, accompanied occasionally by other disorders. A 3-year-old girl presented kyphoscoliosis, foot deformities, gate disturbance, and urinary incontinence. The CT and MRI examination revealed kyphosis and scoliosis with a double curve, some absent, broadened, bifurcating and fused ribs, hemivertebrae, butterfly and cleft vertebrae in thoracic and lumbar region, sporadic cleft or absent vertebral arches or pedicles, and hypoplastic sacrum with a cleft of the S2 vertebra. Spina bifida occulta extended from T10 to T11, and from L3 to the end of the sacrum. Two hemicords, separated by a bony septum and surrounded by their own dural tubes (type I), were present from the level of T9 to the conus medullaris. Filum terminale was thick and duplicated. Syringomyelia was present in the thoracic cord from T5 to T8. Finally, a small meningocele was seen at the T10-T11 level, and a subcutaneous lipoma in the thoracolumbar region. To our knowledge, such a combination of vertebra, rib, and cord malformations, including the mentioned additional disorders, has never been reported. | 01 = IsEpi
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PURPOSE OF REVIEW:Tyrosine kinase inhibitors (TKIs) are the backbone for advanced gastrointestinal stromal tumor (GIST) treatment. The increasing knowledge concerning the structure and the changing conformational status because of some mutations in KIT and PDGFRα, allowed the development of new efficient compounds, with the main goal to overcome resistance in GIST. This review summarizes the latest developments in the treatment of GIST patients. RECENT FINDINGS:Amongst the several TKIs currently being studied in GIST, ripretinib, avapritinib and crenolanib had shown promising potent activity in preclinical studies and clinical trials. Ripretinib is a type II inhibitor that exerts its main action in the switch pocket of the activation loop, by mimicking the inhibition exerted by the regulatory region in this domain. Ripretinib is considered the new standard in the fourth line in advanced GIST. Avapritinib is a type I inhibitor synthesized to exerts its activity in the active conformation of the activation loop of KIT and PDFGRα. The relevant activity reported with avapritinib in patients carrying the D842 v mutation represents, for first time, an active therapeutic option in this resistant mutant. Crenolanib is a type I selective inhibitor of PDGFRα-resistant mutants, mainly D842 V, which is currently under clinical trial. SUMMARY:New potent TKIs are being approved, adding value to the already three registered drugs. Other agents, such as MEK inhibitors, immunotherapy and TRK-targeted therapy are potential new options in specific subsets of GIST patients. | 01 = IsEpi
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BACKGROUND:Waardenburg syndrome (WS) is a dominantly inherited, genetically heterogeneous auditory-pigmentary syndrome characterized by nonprogressive sensorineural hearing loss and iris discoloration. This study aimed to investigate the underlying molecular pathology in Chinese WS families. METHODS:A total of 13 patients with Waardenburg syndrome type II (WS2) from six unrelated Chinese families were enrolled. We investigated the mutation profile of genes related to congenital deafness in these families through a targeted sequencing technology and validated the candidate variants by Sanger sequencing. RESULTS:We identified six novel variants in microphthalmia-associated transcription factor (MITF) and SRY-box 10 (SOX10), which were predicted to be disease causing by in silico analysis. Our results showed that mutations in SOX10 and MITF are two major causes of deafness associated with WS, and de novo mutations were frequently found in probands with SOX10 mutations but not in those with MITF mutations. CONCLUSION:Results showed that targeted next-generation sequencing (NGS) enabled us to detect disease-causing mutations with high accuracy, stability, speed and throughput. Our study extends the pathogenic mutation spectrum of MITF and SOX10. | 01 = IsEpi
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The four R-spondin secreted ligands (RSPO1-RSPO4) act via their cognate LGR4, LGR5 and LGR6 receptors to amplify WNT signalling1-3. Here we report an allelic series of recessive RSPO2 mutations in humans that cause tetra-amelia syndrome, which is characterized by lung aplasia and a total absence of the four limbs. Functional studies revealed impaired binding to the LGR4/5/6 receptors and the RNF43 and ZNRF3 transmembrane ligases, and reduced WNT potentiation, which correlated with allele severity. Unexpectedly, however, the triple and ubiquitous knockout of Lgr4, Lgr5 and Lgr6 in mice did not recapitulate the known Rspo2 or Rspo3 loss-of-function phenotypes. Moreover, endogenous depletion or addition of exogenous RSPO2 or RSPO3 in triple-knockout Lgr4/5/6 cells could still affect WNT responsiveness. Instead, we found that the concurrent deletion of rnf43 and znrf3 in Xenopus embryos was sufficient to trigger the outgrowth of supernumerary limbs. Our results establish that RSPO2, without the LGR4/5/6 receptors, serves as a direct antagonistic ligand to RNF43 and ZNRF3, which together constitute a master switch that governs limb specification. These findings have direct implications for regenerative medicine and WNT-associated cancers. | 01 = IsEpi
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Neonatal screening is helpful to prevent serious disability and sufferings caused by congenital or inherited disease. This study was to review the status of neonatal screening for congenital hypothyroidism (CH) and phenylketonuria (PKU) in China.We analyzed data of neonatal screening for CH and PKU in the past two decades which were obtained from the national network of neonatal screening centers collected by the National Center for Clinical Laboratory.Of 18.8 million newborns screened from 1985 to 2007, 9198 were identified with CH, giving a prevalence of 1/2047. In 19.0 million newborns screened in the same period, 1638 had PKU, with a prevalence of 1/11 572. An increasing number of neonates have been subjected to neonatal screening in China annually during this period. Data from Zhejiang Neonatal Screening Center showed that the recall rate of neonates suspected with CH and PKU was 95.52% in 2007. Confirmatory tests were performed and treatments were initiated in most of the neonates with CH and PKU within a month after birth.More governmental support at different levels is needed to make neonatal screening more efficient. The screening should be improved with a satisfactory control system including shorter time of report and a higher recall rate. | 10 = IsNotEpi
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To evaluate whether the adult patients with acquired pure red cell aplasia (PRCA) could benefit more from cyclosporine A (CsA) combined with corticosteroids (CS) than CsA or CS alone.Seventy-three patients were evaluated in 2 institutions (6 patients lost to follow-up).The induction therapy included CsA (n = 21), CS (n = 21), or CsA combined with CS (n = 31), and remission was achieved in 16/21 (76.2%), 10/21 (47.6%), and 21/31 (71.0%) patients, respectively. Higher complete remission (CR) rate was achieved in CsA combined with CS group than in CS group (61.3% vs 19.0%, P = .003). Patients achieved CR faster in CsA combined with CS group than in CS group or CsA group (median time, 1 month vs 2 month vs 3 month, P = .010). By multivariate analysis, CsA combined with CS therapy and primary PRCA were the influence factors for CR rate. Twenty-seven patients relapsed due to discontinuation or tapering therapy, and 19 patients regained response by increasing the dose of original regimens or changing to other immunosuppressive therapy. Complete remission to induction therapy was a correlative factor for death (P = .035).CsA combined with CS produced faster and higher CR rate in treating adult patients with PRCA than did CsA or CS alone. | 01 = IsEpi
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Pena-Shokeir syndrome (PSS) type 1, also known as fetal akinesia deformation sequence, is a rare genetic syndrome that almost always results in intrauterine or early neonatal death. It is characterized by markedly decreased fetal movements, intrauterine growth restriction, joint contractures, short umbilical cord, and features of pulmonary hypoplasia. Antenatal diagnosis can be difficult. Ultrasound features are varied and may overlap with those of Trisomy 18. The poor prognosis of PSS is due to pulmonary hypoplasia, which is an important feature that distinguishes PSS from arthrogryposis multiplex congenital without pulmonary hypoplasia, which has a better prognosis. If diagnosed in the antenatal period, a late termination of pregnancy can be considered following ethical discussion (if the law allows). In most cases, a diagnosis is only made in the neonatal period. Parents of a baby affected with PSS require detailed counseling that includes information on the imprecise recurrence risks and a plan for subsequent pregnancies. | 01 = IsEpi
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BACKGROUND:To study the histological structure and immunohistochemical (IHC) parameters of the plasmacytoma tumour substrate in patients with multiple myeloma (MM). METHODS:The study included 21 patients (10 men/11 women) aged 23 to 73 years old with newly diagnosed MM complicated by plasmacytoma. Bone plasmacytoma was diagnosed in 14 patients, and extramedullary plasmacytoma was diagnosed in 7 patients. Plasmacytoma tissue specimens were examined using a LEICA DM4000B microscope. Anti-CD56, anti-CD166, anti-CXCR4, anti-Ki-67, and anti-c-MYC antibodies were used for IHC study of plasmacytoma biopsies. RESULTS:When comparing the morphology of bone and extramedullary plasmacytoma, no significant differences were revealed; however, the substrate of extramedullary plasmacytoma was more often represented by tumour cells with an immature morphology than was the bone plasmacytoma substrate (57.1% vs. 28.6%, respectively). We revealed a significant difference in the expression of CD166 between bone and extramedullary plasmacytoma. The mean values of CD166 expression in bone plasmacytoma cells were significantly higher (36.29 ± 7.61% versus 9.57 ± 8.46%, respectively; p = 0.033) than those in extramedullary plasmacytoma cells. We noticed that in extramedullary plasmacytoma cells, there were higher values for the Ki-67 index than in bone plasmacytoma cells, and this result was independent of cell morphology. CONCLUSION:The mechanisms involved in the dissemination of tumour plasma cells are currently unexplored. Even in such a small sample, some differences in expression could be identified, which may indicate that different mechanisms lead to the formation of bone and extramedullary plasmacytomas. Specifically, the expression of CD166 in extramedullary plasmacytoma cells was almost 4 times lower than that in bone plasmacytoma cells, which may indicate the involvement of CD166 in the mechanisms of bone destruction. The proliferative activity of extramedullary plasmacytoma cells was shown to be higher than that of bone plasmacytoma cells. | 01 = IsEpi
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We have analyzed a mouse model of Charcot-Marie-Tooth disease 2E (CMT2E) harboring a heterozygous p.Asn98Ser (p.N98S) Nefl mutation, whose human counterpart results in a severe, early-onset neuropathy. Behavioral, electrophysiological, and pathological analyses were done on separate cohorts of NeflN98S/+ mutant mice and their wild type Nefl+/+ littermates between 8 and 48 weeks of age. The motor performance of NeflN98S/+ mice, as evidenced by altered balance and gait measures, was impaired at every age examined (from 6 to 25 weeks of age). At all times examined, myelinated axons were smaller and contained markedly fewer neurofilaments in NeflN98S/+ mice, in all examined aspects of the PNS, from the nerve roots to the distal ends of the sciatic and caudal nerves. Similarly, the myelinated axons in the various tracts of the spinal cord and in the optic nerves were smaller and contained fewer neurofilaments in mutant mice. The myelinated axons in both the PNS and the CNS of mutant mice had relatively thicker myelin sheaths. The amplitude and the nerve conduction velocity of the caudal nerves were reduced in proportion with the diminished sizes of myelinated axons. Conspicuous aggregations of neurofilaments were only seen in primary sensory and motor neurons, and were largely confined to the cell bodies and proximal axons. There was evidence of axonal degeneration and regeneration of myelinated axons, mostly in distal nerves. In summary, the p.N98S mutation causes a profound reduction of neurofilaments in the myelinated axons of the PNS and CNS, resulting in substantially reduced axonal diameters, particularly of large myelinated axons, and distal axon loss in the PNS. | 01 = IsEpi
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Charcot-Marie-Tooth disease Type 2E/1F (CMT2E/1F) is a peripheral neuropathy caused by mutations in neurofilament protein L (NFL), which is one of five neurofilament subunit proteins that co-assemble to form neurofilaments in vivo. Prior studies on cultured cells have shown that CMT2E/1F mutations disrupt neurofilament assembly and lead to protein aggregation, suggesting a possible disease mechanism. However, electron microscopy of axons in peripheral nerve biopsies from patients has revealed accumulations of neurofilament polymers of normal appearance and no evidence of protein aggregates. To reconcile these observations, we reexamined the assembly of seven CMT2E/1F NFL mutants in cultured cells. None of the mutants assembled into homopolymers in SW13vim- cells, but P8R, P22S, L268/269P, and P440/441L mutant NFL assembled into heteropolymers in the presence of neurofilament protein M (NFM) alone, and N98S, Q332/333P, and E396/397K mutant NFL assembled in the presence of NFM and peripherin. P8R, P22S, N98S, L268/269P, E396/397K, and P440/441L mutant NFL co-assembled into neurofilaments with endogenous NFL, NFM, and α-internexin in cultured neurons, although the N98S and E396/397K mutants showed reduced filament incorporation, and the Q332/333P mutant showed limited incorporation. We conclude that all the mutants are capable of assembling into neurofilaments, but for some of the mutants this was dependent on the identity of the other neurofilament proteins available for co-assembly, and most likely also their relative expression level. Thus, caution should be exercised when drawing conclusions about the assembly capacity of CMT2E/1F mutants based on transient transfections in cultured cells. | 01 = IsEpi
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Phthiocerol dimycocerosates (PDIMs) are a class of mycobacterial lipids that promote virulence in Mycobacterium tuberculosis and Mycobacterium marinum. It has recently been shown that PDIMs work in concert with the M. tuberculosis Type VII secretion system ESX-1 to permeabilize the phagosomal membranes of infected macrophages. As the zebrafish-M. marinum model of infection has revealed the critical role of PDIM at the host-pathogen interface, we set to determine if PDIMs contributed to phagosomal permeabilization in M. marinum. Using an ΔmmpL7 mutant defective in PDIM transport, we find the PDIM-ESX-1 interaction to be conserved in an M. marinum macrophage infection model. However, we find PDIM and ESX-1 mutants differ in their degree of defect, with the PDIM mutant retaining more membrane damaging activity. Using an in vitro hemolysis assay-a common surrogate for cytolytic activity, we find that PDIM and ESX-1 differ in their contributions: the ESX-1 mutant loses hemolytic activity while PDIM retains it. Our observations confirm the involvement of PDIMs in phagosomal permeabilization in M. marinum infection and suggest that PDIM enhances the membrane disrupting activity of pathogenic mycobacteria and indicates that the role they play in damaging phagosomal and red blood cell membranes may differ. | 01 = IsEpi
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OBJECTIVE:The activities of tumor-infiltrating immune cells (TIICs) play an important role in the outcomes of many types of cancers. Here, we sought to describe the landscape of TIICs in testicular germ cell tumors (TGCT) and to develop a prognostic model based on this information. METHODS:The Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to determine the proportions of 22 types of TIICs in a TGCT dataset (n = 74). Univariate and multivariate Cox regression analysis were used to develop an immune risk score (IRS) based on the association between TIICs and disease-free survival (DFS). The predictive accuracy of the IRS was evaluated using receiver operating characteristic curves, and the predictive accuracy of a prognostic nomogram was assessed using C-index and calibration curves. The biological functions of IRS-associated genes were evaluated by gene set enrichment analysis. RESULTS:The relative abundances of three TIICs (plasma cells, M2 macrophages, and resting mast cells) were significantly associated with DFS in TGCT patients. In receiver operating characteristic curve analysis, the resulting IRS had areas under the curve of 0.70, 0.793, and 0.827, for predicting 1-, 2-, and 3-year DFS, respectively. Kaplan-Meier analysis confirmed that DFS was shorter for patients with high IRS compared with low IRS. IRS was an independent predictor of disease recurrence (hazard ratio 1.306, 95% confidence interval 1.022-1.668; P = 0.033). The C-index for the nomogram was 0.733. Genes involved in cancer-associated and immunity-associated pathways were enriched in TGCT samples from patients in the high- and low-risk groups, respectively, and expression of four immune checkpoint regulators was significantly lower in the high IRS group compared with the low IRS group. CONCLUSIONS:A TIIC-based IRS may have utility as a complementary tool to predict relapse in patients with TGCT. | 01 = IsEpi
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BACKGROUND AND AIMS:In recent years, with the development of endoscopic techniques, endoscopic resection is widely used for duodenal papillary adenomas, but conventional endoscopic resection has a high rate of incomplete resection and recurrence. On this basis, we have employed a novel modified endoscopic papillectomy (ESP). In this study, we evaluated the feasibility and advantages of this ESP for the treatment of duodenal major papilla adenoma. METHODS:A total of 56 patients with duodenal major papilla adenoma confirmed by endoscopic ultrasonography, intraluminal ultrasound and gastroscopic biopsy from October 2007 to June 2017 were collected in the Department of Gastroenterology, Nanjing Drum Tower Hospital. The diameter of the adenoma ranged from 1.41 to 2.02 cm. 16 cases were given the conventional method and 40 cases underwent the modified ESP procedure in which a small incision was made by cutting current when anchoring the snare tip on the distal side of the adenoma. RESULTS:En bloc resection rate was significantly higher in the modified group (100%, 40/40) than that in the conventional group (81.3%, 13/16; P = 0.02). However, no significance was seen between the modified group and the conventional group in complete resection rate (92.5%, 37/40 vs 93.8%, 15/16; P = 1.00). There was no significant difference in the number and difficulty of postoperative pancreatic and biliary stents placement between the two groups (P = 0.20). Total bleeding occurrence was much lower in the modified group (37.5%, 15/40 vs 87.5%, 14/16; P = 0.001), and no significant differences were found in other short-term complications and the 3, 6, 12 and 24 months recurrences rate between the conventional and modified ESP groups. CONCLUSIONS:The modified ESP improves the treatment outcome of duodenal major papilla adenoma with higher en bloc resection rate and lowering bleeding rate. | 01 = IsEpi
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Myotonic Dystrophy type 1 (DM1) is a neuromuscular disease showing strong genetic anticipation, and is caused by the expansion of a CTG repeat tract in the 3'-UTR of the DMPK gene. Congenital Myotonic Dystrophy (CDM1) represents the most severe form of the disease, with prenatal onset, symptoms distinct from adult onset DM1, and a high rate of perinatal mortality. CDM1 is usually associated with very large CTG expansions, but this correlation is not absolute and cannot explain the distinct clinical features and the strong bias for maternal transmission. This review focuses upon the molecular and epigenetic factors that modulate disease severity and might be responsible for CDM1. Changes in the epigenetic status of the DM1 locus and in gene expression have recently been observed. Increasing evidence supports a role of a CTCF binding motif as a cis-element, upstream of the DMPK CTG tract, whereby CpG methylation of this site regulates the interaction of the insulator protein CTCF as a modulating trans-factor responsible for the inheritance and expression of CDM1. | 01 = IsEpi
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Sociability entails some of the most complex behaviors processed by the central nervous system. It includes the detection, integration, and interpretation of social cues and elaboration of context-specific responses that are quintessentially species-specific. There is an ever-growing accumulation of molecular associations to autism spectrum disorders (ASD), from causative genes to endophenotypes across multiple functional layers; these however, have rarely been put in context with the opposite manifestation featured in hypersociability syndromes. Genetic copy number variations (CNVs) allow to investigate the relationships between gene dosage and its corresponding phenotypes. In particular, CNVs of the 7q11.23 locus, which manifest diametrically opposite social behaviors, offer a privileged window to look into the molecular substrates underlying the developmental trajectories of the social brain. As by definition sociability is studied in humans postnatally, the developmental fluctuations causing social impairments have thus far remained a black box. Here, we review key evidence of molecular players involved at both ends of the sociability spectrum, focusing on genetic and functional associations of neuroendocrine regulators and synaptic transmission pathways. We then proceed to propose the existence of a molecular axis centered around the paradigmatic dosage imbalances at the 7q11.23 locus, regulating networks responsible for the development of social behavior in humans and highlight the key role that neurodevelopmental models from reprogrammed pluripotent cells will play for its understanding. | 01 = IsEpi
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Congenital Nail abnormalities are rare ectodermal defects. Autosomal recessive nail dysplasia is much rarer. Recently it has been recognized as a condition resulting in nail dystrophy in the absence of other cutaneous or extracutaneous disorders. Few case reports have identified mutations in the Frizzled 6 (FZD6) gene in families presenting with abnormal nails consistent with Non-Syndromic Congenital Nail Dysplasia. We report a family presenting, they lived in Namin a country of the Ardabil Province, northwestern Iran in 2016, for the first time in Iran in whom we identified mutations in FZD6 with abnormal nails formation. | 01 = IsEpi
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Compartment syndrome of the limb is a true orthopaedic emergency that warrants prompt evaluation and treatment. Acute compartment syndrome of the limb is not uncommon and has the potential to cause devastating morbidity and mortality. Failure to provide urgent surgical intervention once established can lead to irreversible tissue damage within hours of onset. Compartment syndrome can occur across all limbs, the buttocks and even the abdomen, but this article focuses solely on the diagnosis of acute compartment syndrome of the limb. Acute compartment syndrome can have a wide range of causes, with trauma representing approximately 70% of cases. | 01 = IsEpi
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In this study, the long-term patient survival after plaque brachytherapy of uveal melanoma is examined. All patients treated between 1980 and 1999 at a single institution were included (n = 677). 533 (79%) had deceased before the end of follow-up. The median follow-up for the 144 survivors was 25.4 years (SD 5.2). Uveal melanoma-related mortality was 18% by 5 years, 28% by 10 years, 32% by 15 years, 35% by 20 years, and 36% by 25 to 40 years. 172 of 209 (82%) uveal melanoma-related deaths occurred within the first decade after brachytherapy. Relative survival rates were 74% at 5 years, 64% at 10 years, 62% at 20 years, 83% at 30 years and ≥100% at 32 to 40 years. Tumor diameter and local recurrence were independent predictors of uveal melanoma-related mortality in multivariate Cox proportional hazards analysis. In conclusion, uveal melanoma has a high mortality rate and most uveal melanoma-related deaths occur in the first decade after treatment. Long-term survivors may have a survival advantage to individuals of the same sex and age from the general population. | 01 = IsEpi
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Primary distal renal tubular acidosis (dRTA) caused by mutations of the SLC4A1 gene, which encodes for erythroid and kidney isoforms of anion exchanger, shows marked difference in inheritance patterns and clinical features in different parts of the world. While the disease shows autosomal dominant inheritance without any red cell morphological abnormalities in the temperate countries, it is almost invariably recessive, and often accompanies red cell morphological abnormalities or hemolytic anemia in the tropics, especially in Southeast Asia. Here, we report three patients with autosomal recessive (AR) dRTA, presenting with typical findings of failure to thrive and rickets, from two unrelated Lao families. The mutational analyses revealed that all three patients harbored the same homozygous SLC4A1 mutation, p.Gly701Asp. Adequate supplementation of alkali and potassium resulted in remarkable improvement of growth retardation and skeletal deformities of the patients. This is the first case report of Lao patients with AR dRTA caused by SLC4A1 mutations. | 01 = IsEpi
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OBJECTIVE: To examine the functional neuroanatomy that could account for pure Gerstmann syndrome, which is the selective association of acalculia, finger agnosia, left-right disorientation, and agraphia. METHODS: We used structural and functional neuroimaging at high spatial resolution in healthy subjects to seek a shared cortical substrate of the Grundstörung posited by Gerstmann, ie, a common functional denominator accounting for this clinical tetrad. We construed a functional activation paradigm that mirrors each of the four clinical deficits in Gerstmann syndrome and determined cortical activation patterns. We then applied fiber tracking to diffusion tensor images and used cortical activation foci in the four functional domains as seed regions. RESULTS: None of the subjects showed parietal overlap of cortical activation patterns from the four cognitive domains. In every subject, however, the parietal activation patterns across all four domains consistently connected to a small region of subcortical parietal white matter at a location that is congruent with the lesion in a well-documented case of pure Gerstmann syndrome. INTERPRETATION: Our functional neuroimaging findings are not in agreement with Gerstmann's postulate of damage to a common cognitive function underpinning clinical semiology. Our evidence from intact functional neuroanatomy suggests that pure forms of Gerstmann's tetrad do not arise from lesion to a shared cortical substrate but from intraparietal disconnection after damage to a focal region of subcortical white matter. | 01 = IsEpi
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In 1596, the Niclas Mollyn (Nicolaus Mollinus; 1550/55-1625) printing house in Riga, published a book in Latin, authored by Prussian poet and humanist Daniel Hermann (1543-1601) with quite an intriguing title "De monstroso partu…" or "About the monstrous birth: on August 18 of the year 1595 in the district of Ascheraden on the other side of the Duna in Livonia and on things that happen against the laws of nature. An ethical, natural and historical discourse." The "Monstroso partu…" is among the earliest books printed in Riga and the first one dedicated to a medical topic. The book contains what could be seen as the earliest known description of syndromic cryptophthalmos aka Fraser syndrome. | 01 = IsEpi
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Linear and whorled nevoid hypermelanosis (LWNH) is a rare sporadic disorder, characterized by hyperpigmented, reticulated, streaky, and whorled macules along Blaschko lines. Herein we report a 33-year-old male presenting with linear and whorled nevoid hypermelanosis.There was no family history. Dermatoscopy revealed a net like pattern. This case is been presented for its rarity and for its dermatoscopic pattern. | 01 = IsEpi
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Chronic active Epstein-Barr virus infection (CAEBV) presents with mononucleosis-like symptoms such as chronic persistent or recurrent pyrexia, lymphadenopathy, and hepatosplenomegaly because of the reactivation of Epstein-Barr virus (EBV) as demonstrated by the recurrence of EBV-infected cells. The mechanism of CAEBV remains obscure, and CAEBV can lead to fatal conditions such as hemophagocytic syndrome and malignant lymphoma by clonal expansion of EBV-infected T- or NK-cells. Without hematopoietic stem cell transplantation, CAEBV has a poor prognosis. CAEBV is listed in the revised 2016 World Health Organization classification as a chronic active EBV infection of T- and NK-cell types, systemic form, among EBV-positive T- and NK-cell lymphoproliferative diseases of childhood. However, similar clinical conditions have been reported in adult patients. Therefore, we investigated the clinical features of adult patients with CAEBV-like features (adult-onset CAEBV) in a relatively small number of cases. Additionally, genetic alterations related to CAEBV development have also been reported. Along with these results, we reviewed the clinical characteristics of adult-onset CAEBV. | 01 = IsEpi
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Importance:Achromatopsia linked to variations in the CNGA3 gene is associated with day blindness, poor visual acuity, photophobia, and involuntary eye movements owing to lack of cone photoreceptor function. No treatment is currently available. Objective:To assess safety and vision outcomes of supplemental gene therapy with adeno-associated virus (AAV) encoding CNGA3 (AAV8.CNGA3) in patients with CNGA3-linked achromatopsia. Design, Setting, and Participants:This open-label, exploratory nonrandomized controlled trial tested safety and vision outcomes of gene therapy vector AAV8.CNGA3 administered by subretinal injection at a single center. Nine patients (3 per dose group) with a clinical diagnosis of achromatopsia and confirmed biallelic disease-linked variants in CNGA3 were enrolled between November 5, 2015, and September 22, 2016. Data analysis was performed from June 6, 2017, to March 12, 2018. Intervention:Patients received a single unilateral injection of 1.0 × 1010, 5.0 × 1010, or 1.0 × 1011 total vector genomes of AAV8.CNGA3 and were followed up for a period of 12 months (November 11, 2015, to October 10, 2017). Main Outcomes and Measures:Safety as the primary end point was assessed by clinical examination of ocular inflammation. Systemic safety was assessed by vital signs, routine clinical chemistry testing, and full and differential blood cell counts. Secondary outcomes were change in visual function from baseline in terms of spatial and temporal resolution and chromatic, luminance, and contrast sensitivity throughout a period of 12 months after treatment. Results:Nine patients (mean [SD] age, 39.6 [11.9] years; age range, 24-59 years; 8 [89%] male) were included in the study. Baseline visual acuity letter score (approximate Snellen equivalent) ranged from 34 (20/200) to 49 (20/100), whereas baseline contrast sensitivity log scores ranged from 0.1 to 0.9. All 9 patients underwent surgery and subretinal injection of AAV8.CNGA3 without complications. No substantial safety problems were observed during the 12-month follow-up period. Despite the congenital deprivation of cone photoreceptor-mediated vision in achromatopsia, all 9 treated eyes demonstrated some level of improvement in secondary end points regarding cone function, including mean change in visual acuity of 2.9 letters (95% CI, 1.65-4.13; P = .006, 2-sided t test paired samples). Contrast sensitivity improved by a mean of 0.33 log (95% CI, 0.14-0.51 log; P = .003, 2-sided t test paired samples). Conclusions and Relevance:Subretinal gene therapy with AAV8.CNGA3 was not associated with substantial safety problems and was associated with cone photoreceptor activation in adult patients, as reflected by visual acuity and contrast sensitivity gains. Trial Registration:ClinicalTrials.gov Identifier: NCT02610582. | 01 = IsEpi
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Introduction:It is routine practice to observe patients (pts) overnight in the hospital after atrial fibrillation (AF) ablation. We report single center experience comparing the rate of complications prior to and after implementing a strategy of same day discharge (SDD) following AF ablation. Objective:To assess the safety of SDD after AF ablation. Methods:We reviewed the charts of consecutive pts who underwent AF ablation between Jan 2005 to Dec 2015. Patients who were electively admitted to undergo AF ablation or left atrial flutter ablation (AFL) were included. Patients undergoing only right atrial flutter ablation and in-patients were excluded. In Sept 2012 SDD strategy was implemented. Complication rates were collected up to 3 months post ablation. Major complications were defined as death, pericardial tamponade, CVA, hematoma requiring intervention, pulmonary vein stenosis, diaphragmatic paralysis or atrioesophageal fistula formation. Minor complications were defined as hematoma not requiring intervention and procedure related readmissions. Comparisons were made using an intention to treat analysis. Results:Group A (between Jan 2005 to Feb 2010) included 145 patients (87 males; 60.2 yrs mean age; 103 paroxysmal AF) who were observed overnight. Group B (between Mar 2010 to Dec 2015) included 426 patients (298 males; 62.3 yrs mean age; 247 paroxysmal AF) undergoing ablation following implementation of the SDD strategy. Patients in Group B were contacted by phone next day. In Group B, 51/426 (12%) pts were not discharged same day due to non-ablation related medical care (15/50 pts), ablation related complications (17/50 pts), pt preference (14/50 pts) and late cases (5/50 pts). Rate of total complications was more frequent in Group A (Group A 11.7% vs Group B 4.4%; p 0.026). Major complications happened in 2 pts in Group A and 6 pts in Group B. None of the major complications in Group B happened within 24 hrs of discharge. Only one pt in Group B had pericardial effusion drained 10 days post procedure. Most common minor complication in Group A was hematoma not requiring intervention and Group B was procedure related readmissions. Conclusions:Our data suggest that SDD after AF or AFL ablation can be safely implemented in majority of pts with similar outcomes as pts observed overnight. | 01 = IsEpi
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Objectives:This article reviews the current role of genetics in pediatric hearing loss (HL). Methods:A review of the current literature regarding the genetic basis of HL in children was performed. Results:To date, 119 nonsyndromic genes have been associated with HL. There are also hundreds of syndromic causes that have HL as part of the clinical phenotype. Conclusions:Identifying HL genes coupled with clinical characteristics ("genotype-phenotype") yields a more accurate diagnosis and prognosis. Although the complexity of the auditory apparatus presents challenges, gene therapy is emerging and may be a viable management option in the future. | 01 = IsEpi
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Generalized lymphangiomatosis (GLA) is a rare lymphatic abnormality, mostly affects children and young individuals and can be a diagnostic challenge because of wide spectrum of clinical manifestations. A 26-year-old woman presented to the emergency department of our institution with respiratory distress and hypoxia. The patient reported similar episodes for the past 10 years without a definite diagnosis. The imaging study demonstrated findings suggestive of GLA with pulmonary, retroperitoneal and osseous involvements which was confirmed on pathological studies from a lung biopsy. A concise review of the clinical, imaging and pathological findings of GLA is provided in this study. A comprehensive history and physical examination, laboratory and pathological work up and imaging is required to make the diagnosis of GLA. The characteristic imaging findings play an essential role to rule out other possible diagnoses and raise the possibility of GLA. | 01 = IsEpi
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This report demonstrates the prevalence of primary congenital hypothyroidism (CH) in the Federation of Bosnia and Herzegovina and summarizes the laboratory data. Neonatal thyroid-stimulating hormone (TSH) was measured in whole blood drawn between the 3rd and 5th days of life and spotted on filter paper using the fluorometric assay. Among the 87,061 neonates, 22 had CH, 13 dysgenetic forms, and nine with thyroids in situ. No differences were found between the two types in terms of TSH and total T4 concentrations. However, thyroglobulin was significantly lower in patients with dysgenetic thyroid tissue (p=0.0023). We conclude that the prevalence of CH in the Federation of Bosnia and Herzegovina is 1:3,957 newborns. | 10 = IsNotEpi
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Ciliopathies are a class of clinically and genetically heterogeneous disorders characterized by deficits of the primary cilium, an important organelle for cellular signaling and development. Here we report on a patient from a consanguineous family presenting with renal cysts, short stature, distinctive facial features, missing teeth, brachydactyly, narrow chest, and abnormal ribs. His phenotype resembled a skeletal ciliopathy and the initial clinical differential diagnosis included Jeune thoracic dystrophy and cranioectodermal dysplasia. Due to the presence of parental consanguinity, a homozygous recessive mutation was the suspected cause and homozygosity mapping was used to direct candidate gene sequencing. WDR35, an intraflagellar transport protein previously associated with cranioectodermal dysplasia, the more severe short rib polydactyly syndrome type V and recently Ellis van Creveld syndrome, is present within a region of homozygosity and sequencing of all coding exons identified a novel homozygous nonsynonymous variant, p.Trp1153Cys. This variant affects a highly conserved tryptophan residue, is predicted to be deleterious, and is the most distal mutation yet reported in WDR35. This case expands the spectrum of phenotypes caused by WDR35 mutations, which we review herein. | 01 = IsEpi
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Enteric disease in horses may be caused by a variety of microorganisms, including several clostridial species. Paeniclostridium sordellii (previously Clostridium sordellii) has been frequently associated with gas gangrene in humans and several animal species, including horses. However, its role in enteric diseases of animals has not been fully determined. We describe herein 7 cases of enteric disease in horses associated with P. sordellii infection. Grossly, the small and/or large intestines were necrotic, hemorrhagic, and edematous. Microscopically, there was severe mucosal necrosis and hemorrhage of the small and/or large intestine of all horses. P. sordellii was isolated and/or demonstrated by immunohistochemistry and/or PCR in the intestine of all horses. All other known causes of enteric disease in horses were ruled out in these 7 cases. P. sordellii should be considered among the differential diagnoses in cases of enteric disease in horses. | 01 = IsEpi
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Sheehan syndrome, characterized by postpartum pituitary necrosis, is an important cause of hypopituitarism in developing countries. We report the case of a 50-year-old female with Sheehan syndrome, who had two spontaneous conceptions following severe postpartum hemorrhage in her first delivery and presented 27 years later with moderate pericardial effusion and features of pseudohypertrophic myopathy mimicking muscular dystrophy. | 01 = IsEpi
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Subependymal nodular heterotopia (SNH) is a cortical development malformation that is commonly associated with medically resistant epilepsy. Cases of SNH are challenging to treat surgically because there are typically multiple nodules, which may be involved in epileptogenesis. Moreover, dual pathology may exist in these patients. Here, we present a case with unilateral subependymal heterotopic nodules associated with ipsilateral hippocampal atrophy. Invasive and non-invasive work-ups revealed that the hippocampus was the actual ictal onset zone and that the SNH was not involved. An anterior temporal lobectomy was carried out, and postoperative seizure outcome was class Ia at the end of 2 years. The case demonstrates that SNH may not play a major role in patients with dual pathology. However, direct electroencephalography (EEG) recording from areas of SNH and other possible epileptogenic regions is indispensable in defining the ictal onset zone and avoiding poor surgical outcomes. | 01 = IsEpi
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Two new cases with the Tel-Hashomer camptodactyly syndrome have been ascertained in an Indian family. This report emphasizes the autosomal recessive nature of disease and documents an additional feature of hirsuitism not previously described. The gene for Tel-Hashomer camptodactyly syndrome is present in all populations around the world. | 01 = IsEpi
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We report here two brothers with an intellectual disability (ID), dysmorphic features, speech delay, and congenital hypotonia, with chromosomal microarray confirmed. However, two different de novo chromosomal aberrations; unbalanced translocations (13;18) (q34,q23) were found in the elder boys and de novo 6q25 deletion in the second boy. The boy with 13q34 microdeletion and 18q23 microduplication suffered from ID, obesity, dysmorphic features, speech delay, and seizure while the one with 6q25 deletion presented with ID and speech delay. Both parents were tested and were normal. The third child had mild hypotonia at infancy, which improved later. Whole-exome sequencing (WES) showed the three boys carried a likely benign variant in MED12, inherited from the healthy, asymptomatic mother. The father suffered from rheumatoid arthritis and was on chemotherapy during the conception of the first two affected boys. This report places emphasis on the use of a chromosomal microarray in patients with ID, even with familial cases, and reports the paternal use of methotrexate. | 01 = IsEpi
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Background:Microdeletion of 1q43q44 causes a syndrome characterized by intellectual disability (ID), speech delay, seizures, microcephaly (MIC), corpus callosum abnormalities (CCA) and characteristic facial features. Duplication of 4q is presented with minor to severe ID, MIC and facial dysmorphism. We aimed to verify the correlation between genotype/phenotype in a patient with 1q43q44 deletion associated with 4q32.1q35.2 duplication. Case presentation:We report on a 3 year-old female patient with delayed motor and mental milestones, MIC and facial dysmorphism. She is a child of non-consanguineous parents and no similarly affected family members. CT brain showed abnormal gyral patterns, hypogenesis of corpus callosum and bilateral deep Sylvian fissure. Electroencephalogram showed frontotemporal epileptogenic focus. Her karyotype was revealed as 46,XX,add(1)(q44). Fluorescence in situ hybridization (FISH) using whole chromosome paint (WCP1) and subtelomere 1q revealed that the add segment was not derived from chromosome 1 and there was the deletion of subtelomere 1q. Multiple ligation probe amplification (MLPA) subtelomere kit revealed the deletion of 1q and duplication of 4q. Array CGH demonstrated the 6.5 Mb deletion of 1q and 31 Mb duplication of chromosome 4q. Conclusion:The phenotype of our patient mainly reflects the effects of haploinsufficiency of AKT3, HNRNPU, ZBTB18 genes associated with duplication of GLRA3, GMP6A, HAND2 genes. Patients presented with ID, seizures, MIC together with CCA are candidates for prediction of 1q43q44 microdeletion and cytogenomic analysis. | 01 = IsEpi
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This article reports two cases of childhood-onset nemaline myopathy diagnosed by muscle pathology and genetic diagnosis. The two patients had onset in early childhood, with muscle weakness as the first manifestation, as well as long disease duration and slow progression. Gomori staining and hematoxylin-eosin staining showed red-stained rods in the sarcoplasmic cytoplasm and sarcolemma under a light microscope. Electron microscopy showed that the dense nemaline rods were located under the muscle fiber sarcolemma and parallel to the long axis of the muscle fibers, and some muscle fiber myofilaments were dissolved and necrotic. Gene testing found that one of the two patients had heterozygous mutation (c.1013A>C) in the ACTA1 gene, and the other had compound heterozygous mutation (c.18676C>T and c.9812C>A) in the NEB gene. The two mutations were more common in nemaline myopathy. Nemaline myopathy is a recessive or dominant inheritance myopathy, in which the nemaline rod in the cytoplasm of myocytes is a characteristic muscle pathological change. Pathological and genetic diagnosis is the gold standard for diagnosis of nemaline myopathy. | 01 = IsEpi
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Muenke syndrome (MIM #602849), the most common syndromic craniosynostosis, results from the recurrent pathogenic p.P250R variant in FGFR3. Affected patients exhibit wide phenotypic variability. Common features include coronal craniosynostosis, hearing loss, carpal and tarsal anomalies, and developmental/behavioral issues. Our study examined the phenotypic findings, medical management, and surgical outcomes in a cohort of 26 probands with Muenke syndrome identified at the Children's Hospital of Philadelphia. All probands had craniosynostosis; 69.7% had bicoronal synostosis only, or bicoronal and additional suture synostosis. Three male patients had autism spectrum disorder. Recurrent ear infections were the most common comorbidity, and myringotomy tube placement the most common extracranial surgical procedure. Most patients (76%) required only one fronto-orbital advancement. de novo mutations were confirmed in 33% of the families in which proband and both parents were genetically tested, while in the remaining 66% one of the parents was a mutation carrier. In affected parents, 40% had craniosynostosis, including 71% of mothers and 13% of fathers. We additionally analyzed the medical resource utilization of probands with Muenke syndrome. To our knowledge, these data represent the first comprehensive examination of long-term management in a large cohort of patients with Muenke syndrome. Our study adds valuable information regarding neuropsychiatric and medical comorbidities, and highlights findings in affected relatives. | 01 = IsEpi
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BACKGROUND AND AIMS:The Danish Polyposis Register was established in 1971 with the aim of improving the poor prognosis of familial adenomatous polyposis (FAP), and in 1975 the register became national. The aim of the present study was to evaluate the prevalence of colorectal cancer and survival rate in FAP patients before and after the establishment of the Danish Polyposis Register. PATIENTS AND METHODS:The Danish Polyposis Register was established by collecting information on probands and construction of their pedigrees. Family members at risk were offered prophylactic endoscopic and molecular genetic examination, and affected individuals were treated by colectomy. RESULTS:At the end of 2001, the Danish Polyposis Register included 434 patients from 165 families. The incidence rate was 1.90x10(-6) and the prevalence rate 4.65x10(-5). Colorectal cancer on the basis of FAP constituted 0.07% of all colorectal cancers in the 1990s. Colorectal cancer was diagnosed in 170/252 probands (67%) and in 5/182 call-up patients (3%) (p<0.001). The cumulative crude survival was 94% in call-up patients compared with 44% in probands (p<0.0001). A comparison of two periods, 1900-1975 and 1976-2001, demonstrated a decreased prevalence of colorectal cancer from 60% to 27% (p<0.0001), and an increased use of colectomy from 52% to 93% (p<0.00001). The cumulative crude survival in FAP showed substantial improvement with time (p<0.00001). CONCLUSION:Since the establishment of the Danish Polyposis Register, the prevalence of colorectal cancer has decreased considerably and the prognosis has improved substantially. The work of the Danish Polyposis Register is probably the main cause of this improvement. | 10 = IsNotEpi
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Congenital tufting enteropathy (CTE) is an autosomal recessive disease characterized by severe intestinal failure in infancy and mutations in the epithelial cell adhesion molecule (EPCAM) gene. Previous studies of CTE in mice expressing mutant EpCAM show neonatal lethality. Hence, to study the cellular, molecular, and physiological alterations that result from EpCAM mutation, a tamoxifen-inducible mutant EpCAM enteroid model has been generated. The presence of mutant EpCAM in the model was confirmed at both mRNA and protein levels. Immunofluorescence microscopy demonstrated the reduced expression of mutant EpCAM. Mutant enteroids had reduced budding potential as well as significantly decreased mRNA expression for epithelial lineage markers (Mucin 2, lysozyme, sucrase-isomaltase), proliferation marker Ki67, and secretory pathway transcription factors (Atoh1, Hnf1b). Significantly decreased numbers of Paneth and goblet cells were confirmed by staining. These findings were correlated with intestinal tissue from CTE patients and the mutant mice model that had significantly fewer Paneth and goblet cells than in healthy counterparts. FITC-dextran studies demonstrated significantly impaired barrier function in monolayers derived from mutant enteroids compared with control monolayers. In conclusion, we have established an ex vivo CTE model. The role of EpCAM in the budding potential, differentiation, and barrier function of enteroids is noted. Our study establishes new facets of EpCAM biology that will aid in understanding the pathophysiology of CTE and role of EpCAM in health and disease.NEW & NOTEWORTHY Here, we develop a novel ex vivo enteroid model for congenital tufting enteropathy (CTE) based on epithelial cell adhesion molecule (EPCAM) gene mutations found in patients. With this model we demonstrate the role of EpCAM in maintaining the functional homeostasis of the intestinal epithelium, including differentiation, proliferation, and barrier integrity. This study further establishes a new direction in EpCAM biology that will help in understanding the detailed pathophysiology of CTE and role of EpCAM. | 01 = IsEpi
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A 9-year-old boy presented with multiple hyperpigmented papules over flexors with polyuria, polydipsia and progressive loss of vision. Histopathology of papule suggested a diagnosis of non-Langerhans cell histiocytosis and systemic evaluation showed central diabetes insipidus and optic atrophy. With a diagnosis of xanthoma disseminatum with significant neurological involvement, he received cladribine therapy and showed significant improvement in both cutaneous and nervous system lesions. | 01 = IsEpi
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OBJECTIVE:Changes in prenatal diagnosis and maternal age are likely to have an impact on live born prevalence of trisomies 13 and 18. We investigated trends in diagnosis, prevalence, and survival in these conditions. METHODS:A population-based study of one UK health region in 1985-2007 using a well-established congenital abnormality register. Individual records were reviewed and live birth and maternal age data obtained. RESULTS:Pregnancies with trisomies 13 and 18 increased from 0.08 to 0.23 per 1000 registered births and 0.20 to 0.65 per 1000 registered births, respectively. Prenatal diagnosis increased and was associated with high termination rates. Live born prevalence with trisomy 13 decreased from 0.05 to 0.03 per 1000 live births and with trisomy 18 from 0.16 to 0.10 per 1000 live births. Postnatal survival remains poor: one baby (3%) with trisomy 13 and four (6%) with trisomy 18 survived the first year. The percentage of mothers over 35 years increased from 6 to 15%. CONCLUSIONS:Changes in prenatal screening and maternal age have had dramatic effects on the live born prevalence of trisomies 13 and 18. Infant survival remains largely unchanged with the majority dying in the neonatal period. | 10 = IsNotEpi
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There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers. | 01 = IsEpi
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BACKGROUND:Autosomal recessive or compound heterozygous mutations in KLHL40 cause nemaline myopathy 8, which is one of the most severe forms of nemaline myopathy. The KLHL40 c.1516A>C variant has recently been reported as a founder mutation in southern Chinese. METHODS:We report six cases of nemaline myopathy 8 which involves the c.1516A>C variant, from five unrelated families of non-consanguineous southern Chinese. The pre- and postnatal phenotypes of these cases were reviewed with emphasis on prenatal clinical features. Genetic testing for the founder mutation was performed on three patients with homozygous mutations. RESULTS:Common prenatal features included reduced fetal movement, polyhydramnios, breech presentation, and clubfeet. Two pregnancies were terminated. Four live-born patients had postnatal features typical of nemaline myopathy 8. The length of survival ranged from 49 days to 17 months, with respiratory failure and infections being the principal causes of death. Haplotype analysis in three patients with homozygous mutation showed a shared haplotype block of 1.1727 cM spanning over the c.1516A>C variant, suggesting it is a southern Chinese-specific founder mutation. CONCLUSION:Analysis of the KLHL40 c.1516A>C variant should be considered in prenatal diagnosis of Chinese pregnant patients with suspected congenital neuromuscular disorders or with significant family history of congenital myopathies. | 01 = IsEpi
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Ocular neuromyotonia (ONM) is a rare eye movement disorder, presenting as a paroxysmal involuntary spasm of one or more extra-ocular muscles, that can persist for a few seconds up to several minutes. The phenomenon is caused by the contraction of an extra-ocular muscle, excited by a damaged nerve, which leads to delayed muscle relaxation. We present eight patients with this rare condition together with an overview of the literature on all published ONM cases. One of the presented cases is possibly secondary to hypovitaminosis D. This association has not been reported previously in the literature. A possible underlying mechanism is given. | 01 = IsEpi
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PURPOSE:Recurrent respiratory papillomatosis is a disease caused by the human papilloma virus (HPV). HPV is frequently localised in the larynx. The disease tends to recur and frequent intervention is usually required. Management modules include surgical intervention using microdebriders or laser ablation as well as adjuvant treatments which aim mainly at maintaining an adequate airway and secondly to manage dysphonia caused by the growth on the vocal folds. In this pilot study, another surgical modality is trialled using plasma-mediated radio-frequency ablation (coblation). METHODS:Retrospective study examining management of 15 adult patients diagnosed with recurrent laryngeal papillomatosis and surgically treated using coblation. One patient required multiple procedures. Pre-operative assessment in voice clinic evaluating voice quality and its impact on patients' life-quality using voice parameters and self-assessment questionnaires. Follow-up post-operatively using the same parameters from 4 to 6 weeks after surgery until up to 2 years later to check recurrence rate. No other adjuvant treatment was used and all patients received post-operative voice therapy. RESULTS:78.6% of patients did not show evidence of recurrence during the study period. Improvement in voice handicap following first intervention is reported and recurrence rate in the rest of the sample reported. CONCLUSIONS:The results of this small sample seem to support the previous small studies' findings that coblation is a good excisional technique to use for removal of laryngeal papillomatosis. Recurrence rates seem to be slightly lower than rates reported in the literature for the other surgical modalities. LEVEL OF EVIDENCE:IV. | 01 = IsEpi
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BACKGROUND:Two cases with refractory macular edema secondary to adult-onset Coats' disease underwent unsatisfactory treatment by intravitreal injections of anti-vascular endothelial growth factor (VEGF) drugs and retinal photocoagulation. CASE PRESENTATION:The authors highlight the guiding effect of the measurement of cytokines in the aqueous humor for the treatment of adult-onset Coats' disease with refractory macular edema. In the two cases, typical Coats' disease changes, including telangiectasis, subretinal exudation and macular edema were observed. Initial treatment consisted of intravitreal anti-VEGF drugs and retinal laser photocoagulation; however, the response was poor. Then, the aqueous humor was acquired and the cytokine concentrations were measured (Flow Cytometry Analysis, Beijing Giantmed Medical Diagnostics Lab). When the cytokine levels were tested every time there would be quality control, with a fixed concentration of cytokines samples to detect before the results reported. A low level of VEGF and a high level of inflammatory cytokines were found. Then, treatment was switched to intravitreal injection of dexamethasone implant (Ozurdex®) (Allergan, Inc., Irvine, Calif., USA), which resulted in resolution of the refractory macular edema and improvement of visual acuity in both cases. CONCLUSIONS:For refractory macular edema secondary to adult-onset Coats' disease, measurement of the levels of VEGF and inflammatory cytokines can help clinic doctors precisely investigate the molecular mechanism of macular edema and thereby find a suitable treatment. | 01 = IsEpi
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OBJECTIVE:We present prenatal diagnosis and molecular cytogenetic characterization of Wolf-Hirschhorn syndrome (WHS) in a fetus with facial cleft and preaxial polydactyly. MATERIALS AND METHODS:A 37-year-old woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age, and the result showed an aberrant chromosome 4 or 46,XX,add(4) (p15.3). The woman consulted our clinics at 22 weeks of gestation and requested for repeat amniocentesis. Prenatal ultrasound revealed intrauterine growth restriction, facial cleft, vermian hypoplasia of cerebellum, micrognathia and absent stomach. Conventional cytogenetic analysis was performed on cultured amniocytes, parental bloods and cord blood. Array comparative genomic hybridization (aCGH) and quantitative fluorescent polymerase chain reaction (QF-PCR) were performed on the DNAs extracted from uncultured amniocytes and parental bloods. Fluorescence in situ hybridization (FISH) analysis was performed on cultured metaphase amniocytes. RESULTS:aCGH analysis on uncultured amniocytes revealed arr 4p16.3p16.1 (74,447-8,732,731) × 1.0 [GRCh37 (hg19)] with an 8.66-Mb deletion of 4p16.3-p16.1 encompassing 70 [Online Mendelian Inheritance of in Man (OMIM)] genes including ZNF141, FGFRL1, TACC3, LETM1, NSD2 and NELFA. QF-PCR revealed a paternal origin of the distal 4p deletion. Conventional cytogenetic analysis revealed 46,XX,del(4) (p16.1)dn in the fetus. Metaphase FISH analysis confirmed a 4p16 deletion. The parental karyotypes were normal. The pregnancy was subsequently terminated, and a malformed fetus was delivered with typical WHS facial dysmorphism, bilateral cleft lip and palate, and preaxial polydactyly on the right hand. CONCLUSION:aCGH, QF-PCR and FISH help to delineate the nature of a prenatally defected aberrant chromosome, and the acquired information is useful for genetic counseling. | 01 = IsEpi
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BACKGROUND: In the United States, birth defects affect approximately 3% of all births, are a leading cause of infant mortality, and contribute substantially to childhood morbidity. METHODS: Population-based data from the National Birth Defects Prevention Network were combined to estimate the prevalence of 21 selected defects for 1999-2001, stratified by surveillance system type. National prevalence was estimated for each defect by pooling data from 11 states with active case-finding, and adjusting for the racial/ethnic distribution of US live births. We also assessed racial/ethnic variation of the selected birth defects. RESULTS: National birth defect prevalence estimates ranged from 0.82 per 10,000 live births for truncus arteriosus to 13.65 per 10,000 live births for Down syndrome. Compared with infants of non-Hispanic (NH) white mothers, infants of NH black mothers had a significantly higher birth prevalence of tetralogy of Fallot, lower limb reduction defects, and trisomy 18, and a significantly lower birth prevalence of cleft palate, cleft lip with or without cleft palate, esophageal atresia/tracheoesophageal fistula, gastroschisis, and Down syndrome. Infants of Hispanic mothers, compared with infants of NH white mothers, had a significantly higher birth prevalence of anencephalus, spina bifida, encephalocele, gastroschisis, and Down syndrome, and a significantly lower birth prevalence of tetralogy of Fallot, hypoplastic left heart syndrome, cleft palate without cleft lip, and esophageal atresia/tracheoesophageal fistula. CONCLUSIONS: This study can be used to evaluate individual state surveillance data, and to help plan for public health care and educational needs. It also provides valuable data on racial/ethnic patterns of selected major birth defects. | 10 = IsNotEpi
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Wilson's disease is characterized by hepatic and extrapyramidal movement disorders (EPS) with variable manifestation primarily between age 5 and 45. This variability often makes an early diagnosis difficult. A classification defines different clinical variants of Wilson's disease, which enables classifying the current clinical findings and making an early tentative diagnosis. Until the unequivocal proof or an autosomal recessive disorder of the hepatic copper transporter ATP7B has been ruled out, differential diagnoses have to be examined. Laboratory-chemical parameters of copper metabolism can both be deviations from the norm not related to the disease as well as other copper metabolism disorders besides Wilson's disease. In addition to known diseases such as Menkes disease, occipital horn syndrome (OHS), Indian childhood cirrhosis (ICC) and ceruloplasmin deficiency, recently discovered disorders are taken into account. These include MEDNIK syndrome, Huppke-Brendel syndrome and CCS chaperone deficiency. Another main focus is on differential diagnoses of childhood icterus correlated with age and anaemia as well as disorders of the extrapyramidal motor system. The Kayser-Fleischer ring (KFR) is qualified as classical ophthalmologic manifestation. The recently described manganese storage disease presents another rare metabolic disorder with symptoms similar to Wilson's disease. As this overview shows, Wilson's disease fits into a broad spectrum of internal and neurological disease patterns with icterus, anaemia and EPS. | 01 = IsEpi
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Arguably, fingerprinting is the single most widely utilized method for individual identification and authentication (I&A). Dermatoglyphics form a vital portion of mass data collection, biometric scrutiny, and verification. Adermatoglyphia, or simply, loss of fingerprints attributed to a medical cause, represents a taxing situation for such biometric scrutiny systems requiring a fingerprint scan as a mandatory phase in I&A procedure. The scenario can be extremely debilitating for the adermatoglyphia patients, especially when the condition is permanent or irreversible. This article reviews different causes of adermatoglyphia, the challenge it poses to biometric identification, and the potential substitute modalities for fingerprinting technology. These modalities can function as a backup program for biometric surveillance in both medical and non-medical settings under circumstances when the fingerprinting method fails to comply. | 01 = IsEpi
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A two-year-old female presented with acutely altered mental status following eight days of fever and rash. She had been camping at an Indiana campground 11 days prior to the onset of illness and was evaluated twice for her fever and rash prior to admission. Laboratory evaluation on admission revealed thrombocytopenia, hyponatremia, and elevated transaminases. The patient developed diffuse cerebral edema, and despite intensive care, the edema led to brain death from Rocky Mountain spotted fever (RMSF). We present this case to highlight the importance of considering RMSF and other tick-borne illnesses in a child with prolonged fever and rash in a nonendemic area and also the difficulty of diagnosis in early stages of disease. A detailed travel history, evaluation of key laboratory findings (white blood count, platelet count, and transaminases), and close follow-up if rash and fevers persist may help to improve detection of RMSF. If a tick-borne illness such as RMSF is suspected, empiric doxycycline therapy should be started immediately, as lab confirmation may take several days and mortality increases greatly after five days of symptoms. | 01 = IsEpi
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Charcot-Marie-Tooth disease type 4H (CMT4H) is a rare variant of autosomal recessive hereditary neuropathy. It is caused by FGD4 mutations and characterized by early infantile onset, slowly progressive distal muscle weakness, scoliosis, and myelin outfoldings visible in nerve biopsy samples. Here, we report a 65-year-old male born to consanguineous parents, who carries a novel homozygous FGD4 c.724C>T nonsense mutation. He developed lower limb weakness in his teens, which progressed slowly and was accompanied by diplopia, bilateral hearing loss, and erectile dysfunction from his twenties. At the age of 65, he was wheelchair-bound and had mild scoliosis, bilateral ophthalmoplegia, facial muscle weakness, inner ear hearing loss, distal-dominant weakness, and sensory disturbance, but no cognitive deterioration. Magnetic resonance imaging revealed enlarged bilateral trigeminal and facial nerves. Accordingly, we believe that this mutation causes slowly progressive sensorimotor neuropathy with apparent cranial nerve involvement, thereby further expanding the clinical spectrum of CMT4H. | 01 = IsEpi
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Juvenile Xanthogranuloma (JXG), the most common pediatric non-Langerhans cell histiocytosis, may rarely occur in association with Neurofibromatosis (types 1 and 2), Juvenile Myelomonocytic Leukemia and Cutaneous Mastocytosis (CM) and, morphologically, mimics Erdheim-Chester Disease tissue lesions and ALK-positive histiocytosis. We describe a 4-year-old girl with Beta-Thalassemia Major who developed an hypopharyngeal BRAFV600E- and ALK-negative JXG and CM. JXG has been rarely reported in the aerodigestive tract and in association with CM. In this molecular era, knowledge of genetic heterogeneity of JXG and clinical scenarios in which it may develop is essential for the appropriate diagnosis and treatment of each individual patient. | 01 = IsEpi
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Progressive hemifacial atrophy (PHA) is mainly characterized by asymmetrical atrophy of craniofacial tissue; however, 10% to 30% of patients with PHA exhibit ocular manifestations. Here, we describe abnormal ocular findings in a Chinese patient with PHA. The patient was a 29-year-old Chinese man. Characteristic ocular findings in his affected eye included keratic precipitate, corneal endothelial degeneration, fundus tessellation, pupillary dilation, direct light reflex loss, and visual evoked potential alteration. Whole exosome sequencing revealed that the patient harbored a mutation in the CRB1 gene; this gene has been associated with various retinal dystrophies. During 10 years of follow-up, the patient's ocular status remained stable. To the best of our knowledge, this is the first report of ocular manifestations of PHA in a Chinese patient, and the first report of a CRB1 mutation in a patient with PHA; these findings may inform future research regarding PHA. | 01 = IsEpi
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CMT disease caused by NEFL gene mutations is rare. The mode of inheritance can be dominant or recessive and nerve conduction velocities can be normal, reduced (demyelinating) or presenting intermediate values. Two Portuguese adult related members in two successive generations were affected by peripheral neuropathy, one with a chronic ataxic peripheral neuropathy and the other with a classical Charcot-Marie-Tooth phenotype. An axonal sensorimotor peripheral neuropathy was described at neurophysiology. A missense heterozygous mutation, c.794A > G (p.Tyr265Cys), in the NEFL gene was found in both patients. This is the first Portuguese family reported with NEFL-related CMT type 2. | 01 = IsEpi
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Acute necrotizing encephalopathy of childhood (ANEC) is a disease, characterized by a respiratory or gastrointestinal infection, accompanied with fever, rapid alteration of consciousness, and seizures. The clinical characteristics of ANEC include acute encephalopathy following a viral infection, seizure, altered consciousness, and absence of cerebrospinal fluid (CSF) pleocytosis, with an occasional increase in the level of proteins. This disease is almost exclusively seen in previously healthy infants and children from East Asia. Serial magnetic resonance imaging (MRI) examinations have demonstrated symmetric lesions involving the thalami, brainstem, cerebellum, and white matter. ANEC has a poor prognosis with high morbidity and mortality rates. Herein, we present three cases of ANEC, who were referred to Bu-Ali Hospital of Ardabil, Iran during two weeks. Report of these three cases promoted the idea of an epidemic. The purpose of this case series was to raise the issue that ANEC may occur as an epidemic. | 01 = IsEpi
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Saguenay-Lac-St-Jean is a geographically isolated region located in northeastern Quebec. Opened to the white settlement in 1938, its immigrants mainly came from Charlevoix, another isolated region of Quebec. The prevalence and/or incidence of several autosomal dominant and recessive disorders are very high. The overall birth prevalence of the recessive disorders was calculated at 1/207 living births and the overall carrier rate at 1/7 inhabitants. This situation may be explained by migration and social factors. | 10 = IsNotEpi
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BACKGROUND:Many metabolites serve as important signalling molecules to adjust cellular activities and functions based on nutrient availability. Links between acetyl-CoA metabolism, histone lysine acetylation, and gene expression have been documented and studied over the past decade. In recent years, several additional acyl modifications to histone lysine residues have been identified, which depend on acyl-coenzyme A thioesters (acyl-CoAs) as acyl donors. Acyl-CoAs are intermediates of multiple distinct metabolic pathways, and substantial evidence has emerged that histone acylation is metabolically sensitive. Nevertheless, the metabolic sources of acyl-CoAs used for chromatin modification in most cases remain poorly understood. Elucidating how these diverse chemical modifications are coupled to and regulated by cellular metabolism is important in deciphering their functional significance. SCOPE OF REVIEW:In this article, we review the metabolic pathways that produce acyl-CoAs, as well as emerging evidence for functional roles of diverse acyl-CoAs in chromatin regulation. Because acetyl-CoA has been extensively reviewed elsewhere, we will focus on four other acyl-CoA metabolites integral to major metabolic pathways that are also known to modify histones: succinyl-CoA, propionyl-CoA, crotonoyl-CoA, and butyryl-CoA. We also briefly mention several other acyl-CoA species, which present opportunities for further research; malonyl-CoA, glutaryl-CoA, 3-hydroxybutyryl-CoA, 2-hydroxyisobutyryl-CoA, and lactyl-CoA. Each acyl-CoA species has distinct roles in metabolism, indicating the potential to report shifts in the metabolic status of the cell. For each metabolite, we consider the metabolic pathways in which it participates and the nutrient sources from which it is derived, the compartmentalisation of its metabolism, and the factors reported to influence its abundance and potential nuclear availability. We also highlight reported biological functions of these metabolically-linked acylation marks. Finally, we aim to illuminate key questions in acyl-CoA metabolism as they relate to the control of chromatin modification. MAJOR CONCLUSIONS:A majority of acyl-CoA species are annotated to mitochondrial metabolic processes. Since acyl-CoAs are not known to be directly transported across mitochondrial membranes, they must be synthesized outside of mitochondria and potentially within the nucleus to participate in chromatin regulation. Thus, subcellular metabolic compartmentalisation likely plays a key role in the regulation of histone acylation. Metabolite tracing in combination with targeting of relevant enzymes and transporters will help to map the metabolic pathways that connect acyl-CoA metabolism to chromatin modification. The specific function of each acyl-CoA may be determined in part by biochemical properties that affect its propensity for enzymatic versus non-enzymatic protein modification, as well as the various enzymes that can add, remove and bind each modification. Further, competitive and inhibitory effects of different acyl-CoA species on these enzymes make determining the relative abundance of acyl-CoA species in specific contexts important to understand the regulation of chromatin acylation. An improved and more nuanced understanding of metabolic regulation of chromatin and its roles in physiological and disease-related processes will emerge as these questions are answered. | 01 = IsEpi
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The Food and Drug Administration has recently approved the off-label use of hydroxychloroquine (HCQ) for the treatment of coronavirus disease 2019 (COVID-19) infections. However, a recent study not only failed to demonstrate HCQ efficacy but also documented a serious side effect of COVID-19 therapy with HCQ: QT prolongation and secondary arrhythmia. HCQ has been used as an off-label drug and deemed safe and effective for the treatment of oral lesions, such as Sjogren syndrome (SS), chronic ulcerative stomatitis (CUS), and oral lichen planus (OLP). Because HCQ may be appropriately used for the off-label treatment of SS, CUS, and OLP, relevant safety concerns regarding HCQ therapy with regard to dosage, drug-to-drug interactions, and QT prolongation and secondary arrhythmia are discussed here. Because of the possibility of decreased pharmacy supplies of HCQ, replacement drugs with respect to patients with SS, CUS, and OLP being successfully treated with HCQ are also discussed. | 01 = IsEpi
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We present the case of a 58-year-old woman who was diagnosed as having telangiectasia macularis eruptiva perstans (TMEP) and was successfully treated with PUVA photochemotherapy. During the 6-month follow-up, no recurrence of pruritus or skin lesions was observed. TMEP represents a rare form of cutaneous mastocytosis, which is clinically characterized by reddish-brown telangiectatic macules symmetrically distributed over the trunk and extremities. Although in the majority of cases the disease is limited to the skin, systemic involvement may occur. The treatment of TMEP is challenging and several therapeutic modalities have been proposed in the past. | 01 = IsEpi
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Typhoid fever transmission occurs through ingestion of food or water contaminated with Salmonella Typhi, and case-control studies are often conducted to identify outbreak sources and transmission vehicles. However, there is no current summary of the associations among water, sanitation, and hygiene (WASH); and food exposures and typhoid from case-control studies. We conducted a systematic review and meta-analysis of case-control studies to evaluate the associations among typhoid fever and predicted WASH or food exposure risk factors (13), and protective factors (7). Overall, 19 manuscripts describing 22 case-control studies were included. Two studies were characterized as having low risk of bias, one as medium risk, and 19 as high risk. In total, nine of 13 predicted risk factors were associated with increased odds of typhoid (odds ratio [OR] = 1.4-2.4, I 2 = 30.5-74.8%.), whereas five of seven predicted protective factors were associated with lower odds of typhoid (OR = 0.52-0.73, I 2 = 38.7-84.3%). In five types of sensitivity analyses, two (8%) of 26 summary associations changed significance from the original analysis. Results highlight the following: the importance of household hygiene transmission pathways, the need for further research around appropriate food interventions and the risk of consuming specific foods and beverages outside the home, and the absence of any observed association between sanitation exposures and typhoid fever. We recommend that typhoid interventions focus on interrupting household transmission routes and that future studies provide more detailed information about WASH and food exposures to inform better targeted interventions. | 01 = IsEpi
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This is a case report of a woman in her sixth decade of life diagnosed with primary angiosarcoma of the breast using mammography and ultrasound, confirmed with imaging-guided biopsy, and finally treated with surgery and radiation. Imaging studies obtained and discussed include mammography, ultrasonography, and MRI. Further discussion on the presenting symptoms, useful imaging modalities, and treatment options takes place. It is important to consider primary angiosarcoma of the breast, though rare, in any woman presenting with a palpable breast mass and, if feasible, an MRI will be most helpful in the diagnosis of this rare tumor. | 01 = IsEpi
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gamma-Cystathionase deficiency (cystathioninemia-cystathioninuria) is a disorder of the transsulfuration pathway characterized by the accumulation of cystathionine in blood and urine. There are probably no clinical consequences. However, maternal gamma-cystathionase deficiency has not been reported. We studied 2 pregnancies and the offspring of these pregnancies in a woman with the pyridoxine-nonresponsive form of the disorder. The outcomes were favorable, suggesting that maternal gamma-cystathionase deficiency may not be deleterious to the pregnant woman or the fetus. | 01 = IsEpi
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Ring chromosome 20 (r20) is characterized by intellectual impairment, behavioral disorders, and refractory epilepsy. We report a patient presenting nonmosaic ring chromosome 20 followed by duplication and deletion in 20q13.33 with seizures, delayed neuropsychomotor development and language, mild hypotonia, low weight gain, and cognitive deficit. Chromosomal microarray analysis (CMA) enabled us to restrict a chromosomal segment and thus integrate clinical and molecular data with systems biology. With this approach, we were able to identify candidate genes that may help to explain the consequences of deletions in 20q13.33. In our analysis, we observed five hubs (ARFGAP1, HELZ2, COL9A3, PTK6, and EEF1A2), seven bottlenecks (CHRNA4, ARFRP1, GID8, COL9A3, PTK6, ZBTB46, and SRMS), and two H-B nodes (PTK6 and COL9A3). The candidate genes may play an important role in the developmental delay and seizures observed in r20 patients. Gene ontology included microtubule-based movement, nucleosome assembly, DNA repair, and cholinergic synaptic transmission. Defects in these bioprocesses are associated with the development of neurological diseases, intellectual disability, neuropathies, and seizures. Therefore, in this study, we can explore molecular cytogenetic data, identify proteins through network analysis of protein-protein interactions, and identify new candidate genes associated with the main clinical findings in patients with 20q13.33 deletions. | 01 = IsEpi
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Diabetic mastopathy is a rare benign breast condition. It is strongly associated with type I diabetes mellitus and commonly presents similar to malignancy. Here, we report a case of a 29-year-old Saudi female with a long history of type I diabetes mellitus (DM) who presented with a painless hard breast mass and had a strong family history of breast cancer. Further evaluation with ultrasound (US) imaging revealed a highly suspicious, ill-defined hypoechoic lesion. Mammographic examination revealed that both breasts were of normal shape with bilateral dense glandular parenchyma. US-guided true-cut biopsy was carried out, which showed acellular fibro-sclerotic tissues with normal-looking lobules and ducts surrounding by a dense lymphocytic infiltrate. Subsequently, a diagnosis of diabetic mastopathy was established. Results were discussed with the patient, and an agreement was reached to proceed with an excisional biopsy for further reassurance and exclusion of malignancy. Local surgical excision of the lesion was performed and histopathological examination revealed extensive fibrosis of the specimen with no cellular atypia. Awareness of such a condition, with its clinical, radiographical, and histopathological characteristics, is essential in order to alleviate the patient's anxiety and avoid unnecessary surgical interventions. | 01 = IsEpi
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Despite significant advances in the treatment of thrombogenic diseases, antiplatelet therapies are still associated with a high bleeding risk. Consequently, potential benefits of preventing thromboembolic events by pharmacological agents need to be balanced with the potential harm of inducing hemorrhage. Glycoprotein VI (GPVI) is a platelet-specific receptor, which plays a crucial role in thrombus formation. GPVI deficiency has been identified in patients who suffer from significant reduction of collagen-induced thrombus formation, with a slight tendency for mild bleeding. However, an isolated GPVI deficiency can reduce thrombus formation while not resulting in severe bleeding. Together, these observations strongly suggest that physiological hemostasis does not require GPVI, but pharmacological GPVI modulation may provide novel "bleeding-free" antithrombotic therapies. In this review, we discuss recent findings regarding the biological role of GPVI in platelet-related disorders and highlight the efforts to develop potential therapeutic strategies based on its structure, signaling pathways, and biological effects. | 01 = IsEpi
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Drug studies on Rett syndrome (RTT) have drastically increased over the past few decades. This review aims to provide master data on bench-to-bedside drug studies involving RTT. A comprehensive literature review was performed by searching in PUBMED, MEDLINE and Google Scholar, international, national and regional clinical trial registries and pharmaceutical companies using the keywords "Rett syndrome treatment and/or drug or compound or molecule". Seventy drugs were investigated in non-clinical (N = 65 animal/cell line-based studies; N = 5 iPSC-based study) and clinical trials (N = 34) for ameliorating the symptoms of RTT. Though there is good progress in both clinical and non-clinical studies, none of these drugs entered phase III/IV for being launched as a therapeutic agent for RTT. | 01 = IsEpi
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Febrile ulceronecrotic Mucha-Habermann disease (FUMHD) is a rare fulminant variant of pityriasis lichenoides et varioliformis acuta (PLEVA) characterized by a rapidly progressive course with predominant ulceronecrotic lesions associated with fever and systemic manifestations. First described by Degos in 1966, it carries a high morbidity and is potentially fatal. The exact pathogenesis is not clear, but it is proposed to be the result of hypersensitivity reaction to an infection.Here we report the case of an 8-year-old boy with FUMHD in the eastern province of Saudi Arabia.The patient presented with pyrexia, fatigue, arthralgia, and worsening of his already existing skin lesions of PLEVA. There was an extensive painful erythematous maculopapular rash, some lesions ulcerated and necrotic, involving the face, trunk, limbs, and flexures. A diagnosis of FUMHD was made based on clinical and histological features. The skin lesions responded extremely well to oral methotrexate, with almost complete healing after 4 weeks.We describe a rare variant of PLEVA, namely FUMHD, in an 8-year-old boy who showed a remarkably favorable response to methotrexate, as manifested by near total clearance of the skin lesions without scarring or hyperpigmentation. | 01 = IsEpi
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BACKGROUND:Wolcott-Rallison syndrome (WRS) is characterized by permanent early-onset diabetes, skeletal dysplasia and several additional features, e.g. recurrent liver failure. This is the first multicentre approach that focuses on diabetes management in WRS. We searched the German/Austrian Diabetes-Patienten-Verlaufsdokumentation (DPV) registry and studied anthropometric characteristics, diabetes treatment, glycaemic control and occurrence of severe hypoglycaemia (SH) and diabetic ketoacidosis (DKA) in 11 patients with WRS. Furthermore, all local treatment centres were personally contacted to retrieve additional information on genetic characteristics, migration background and rate of consanguinity. RESULTS:Data were analysed at diabetes onset and after a median follow-up period of 3 (1.5-9.0) years (time from diagnosis to latest follow-up). Median age at diabetes onset was 0.2 (0.1-0.3) years, while onset was delayed in one patient (aged 16 months). Seventy percent of patients manifested with DKA. At follow-up, 90% of patients were on insulin pump therapy requiring 0.7 [0.5-1.0] IU of insulin/kg/d. More than two third of patients had HbA1c level ≥ 8%, 40% experienced at least one episode of SH in the course of the disease. Three patients died at 0.6, 5 and 9 years of age, respectively. To the best of our knowledge three patients carried novel mutations in EIF2AK3. CONCLUSION:Insulin requirements of individuals with WRS registered in DPV appear to be comparable to those of preschool children with well-controlled type 1 diabetes, while glycaemic control tends to be worse and episodes of SH tend to be more common. The majority of individuals with WRS in the DPV registry does not reach glycaemic target for HbA1c as defined for preschool children (< 7.5%). International multicentre studies are required to further improve our knowledge on the care of children with WRS. | 01 = IsEpi
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Background:Antimicrobial resistance is an increasing problem in human and veterinary medicine and is closely linked to the use of antimicrobials. The objective of this study was to describe antimicrobial prescriptions for selected canine diseases in Switzerland during 2016. Methods:Dogs presented to two university hospitals and 14 private practices for acute diarrhoea (AD; n=371), suspected or confirmed urinary tract infections (UTIs; n=245), respiratory tract infections (RTIs; n=274) or wound infections (WIs; n=175) were included. Clinical history, diagnostic work-up and antimicrobial prescription (class, dosage and duration) were retrospectively assessed. A justification score was applied to evaluate appropriateness of antimicrobial therapy based on available national and international consensus guidelines. Results:Antimicrobials were prescribed in 65 per cent of dogs with AD, 88 per cent with UTI, 62 per cent with RTI and 90 per cent with WI. The most prescribed antimicrobial classes (monotherapy and combination therapy) were potentiated aminopenicillins (59 per cent), nitroimidazoles (22 per cent), non-potentiated aminopenicillins (16 per cent) and fluoroquinolones (13 per cent). Overall, 38 per cent (95 per cent CI 0.35 to 0.41) of the prescriptions were in accordance with consensus guidelines. In dogs with AD, antimicrobial therapy was associated with the presence of haemorrhagic diarrhoea (P<0.05) and complied in 32 per cent with consensus guidelines, which recommend antimicrobial treatment only when sepsis is suspected. A bacterial aetiology was confirmed via culture and/or sediment examination in 36 per cent of dogs with suspected UTI. Conclusions:Overall, adherence to consensus guidelines was poor both, at university hospitals and private practices. Antimicrobial stewardship measures are therefore needed to improve prudent use. | 01 = IsEpi
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INTRODUCTION:Recently, a novel hypothesis has been proposed concerning the origin of craniovertebral junction (CVJ) abnormalities. Commonly found in patients with these entities, atlantoaxial instability has been suspected to cause both Chiari malformation type I and basilar invagination, which renders the tried and tested surgical decompression strategy ineffective. In turn, C1-2 fusion is proposed as a single solution for all CVJ abnormalities, and a revised definition of atlantoaxial instability sees patients both with and without radiographic evidence of instability undergo fusion, instead relying on the intraoperative assessment of the atlantoaxial joints to confirm instability. METHODS:The authors conducted a comprehensive narrative review of literature and evidence covering this recently emerged hypothesis. The proposed pathomechanisms are discussed and contextualized with published literature. CONCLUSION:The existing evidence is evaluated for supporting or opposing sole posterior C1-2 fusion in patients with CVJ abnormalities and compared with reported outcomes for conventional surgical strategies such as posterior fossa decompression, occipitocervical fusion, and anterior decompression. At present, there is insufficient evidence supporting the hypothesis of atlantoaxial instability being the common progenitor for CVJ abnormalities. Abolishing tried and tested surgical procedures in favor of a single universal approach would thus be unwarranted. | 01 = IsEpi
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Trisomy 13 is a chromosomal aneuploidy originally described by Patau et al. in 1960.[1] The occurrence of trisomy 13 is 1 in 10,000 to 20,000 live births with antenatal mortality of over 95% of gestations.[2][3] It can occur as complete, partial, or mosaic expression.[1] The complete trisomy is the most common presentation representing about 80% of all patients. This expression characteristically demonstrates the presence of three chromosomes 13 copies.[1] The partial expression is characterized by a Robertsonian translocation t(13;14), while only 5% of all cases present with mosaicism.[4] Mosaicism is characterized by a percentage of cells remaining trisomic while others maintain euploidy.[1] Trisomy 13 arises from the nondisjunction of germ cells during meiosis I or II of either parental cells.[5] Nonetheless, maternal germ cell nondisjunction correlated to the increased age of conception contributes to 91% of cases.[3] The mode of inheritance for the complete trisomy 13 is caused by spontaneous interference in meiosis, while vertical inheritance is hereditary in balanced translocations.[5] Phenotypic findings in trisomy 13 are associated with patterns of congenital anomalies and mental disabilities incompatible with life.[5] The embryological defects in trisomy 13 develop in the absence of fusion of prechordal mesoderm, which phenotypically presents as midline defects. These midline defects are associated with aberrant SHH genes.[6] Despite the accelerated mortality of trisomy 13, it remains clinically significant due to its variable expressivity in patients with compatible mosaicisms.[1] | 01 = IsEpi
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Objective: Using the method of the ultrasound and the noninvasive DNA to find the relationship between the choroid plexus cyst and the aneuploidy, and to provide the meaningful data for prenatal consultant. Methods: A total of 112 cases, that the gestational age were between 13 and 20 weeks, which were diagnosed with choroid plexus cyst in the Department of Gynecology and Obstetrics of the Second Hospital of Jilin University from January. 2016 to July. 2017 were tested by ultrasonography. They all accepted the noninvasive DNA. At the same time, a total of 100 normal fetuses were randomly involved in the control group by the combination of gestational age and the age of the pregnant woman, all of them had taken the non-invasive DNA examination and followed up until the birth. Those fetuses who combined with other malformations were induced labor in the two groups. If the results of noninvasive DNA indicated the high-risk, invasive examination for karyotype analysis were recommended. If the results were aneuploidy, they chose induced labor. The rest cases followed up until the birth. Results: Five cases of the 112 fetuses in the case group were found with obvious malformation (3 of them were found in the early trimester, 2 of them were found in the middle trimester). The numbers of high risk results of noninvasive DNA were 7, and 5 of them underwent the invasive karyotype analysis. When the aneuploidy had diagnosed definitely, induced labor had been taken. One case was found to be the aneuploidy in the control group, and took the induced labor. One case was diagnosed as right side aortic arch by ultrasound in the control group, with a good prognosis. The other cases were followed up until the birth with a good prognosis. Conclusions: (1)In the early trimester, the fetus with choroid plexus cyst has an increasing risk of aneuploidy. (2)When the maximum diameter of choroid plexus cyst is less than 1 cm and the cyst was single, most of them could disappear in the middle trimester, it has no effect on the fetus. (3)Noninvasive DNA test has a high accuracy, which can improve the positive rate of invasive examination. | 01 = IsEpi
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X-linked lissencephaly with abnormal genitalia (XLAG) is a rare disorder caused by mutations in the aristaless-related homeobox (ARX) gene. We report on the clinical data of a boy with a 1-bp deletion (790 delC) resulting in a frame shift in the ARX gene and prolonged survival until age 18 months. Similar to other patients, the boy showed postnatal microcephaly, hypothalamic dysfunction, intractable neonatal seizures, and chronic diarrhoea. In addition, he suffered from exocrine pancreatic insufficiency and renal phosphate wasting became apparent from age 5 months, both of which have not been described previously in XLAG. This allows us to speculate that the phenotype of XLAG is more complex than hitherto known and may include renal phosphate wasting which might not have been observed in other patients due to early death. | 01 = IsEpi
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This study represents the first national epidemiological survey of primary immunodeficiency diseases in Norway. Uniform questionnaires were sent out in April 1998 to all hospital departments considered relevant. As of February 1999, a total of 372 patients have been registered, of whom 69 patients are deceased. With a population of 4.45 million people, the total prevalence of primary immunodeficiency diseases in Norway February 1, 1999 is 6.82 per 100000 inhabitants. Distribution between the main immunodeficiency diagnoses is (a) antibody deficiencies 50.8%, (b) combined deficiencies included other immunodeficiency syndromes 12.4%, (c) complement deficiencies 21.0%, (d) phagocytic disorders 6.7%, (e) and immunodeficiency associated with other congenital diseases 9. 1%. Compared to previous reports from other European countries, there is a smaller proportion of antibody deficiencies due to few IgA deficiencies registered and a large proportion of complement deficiencies due to many patients with hereditary angioedema. | 10 = IsNotEpi
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Aquagenic urticaria (AQ) is a rare physical urticaria induced by contact with water. It may be distinctive clinically, evident as 1-2 mm folliculopapular urticaria, a pattern also characteristic of cholinergic urticaria. AQ has a truncal and upper extremity distribution within 20-30 minutes after contact with water, regardless of its temperature or source. AQ is usually symptomatic with mild to severe pruritus and a burning sensation. The mechanism by which water produces mast cell degranulation and histamine release remains unclear. We review its clinical presentation, diagnostic parameters, differential diagnosis, and treatment. | 01 = IsEpi
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BACKGROUND/OBJECTIVES:Bart syndrome was initially described as association of congenital absence of skin (CAS), nail abnormalities, and epidermolysis bullosa (EB). Further reports of patients with CAS and EB have been made with wide clinical heterogeneity among them. Current guidelines recommend the elimination of eponyms and use of the descriptive term EB with CAS. METHODS:We performed a PubMed and Medline database search of patients with Bart syndrome or EB with CAS. We included case reports or case series that contained clinical and demographic information. RESULTS:After review, 55 articles were included, reporting 96 patients. CAS involved the lower extremities in all patients, with additional upper limb, trunk, or head involvement in 17%. In all patients, the time to healing ranged from 2 weeks to 6 months; most received only conservative treatment. The subtype and frequency of associated EB most frequently reported were recessive dystrophic EB (41.4%) and dominant dystrophic EB (22.8%). Extracutaneous features were present in 29 patients; with pyloric atresia and ear malformations being the most common. The prognosis varied based on the subtype of EB and the presence of additional comorbidities; 50% of the patients with junctional EB with pyloric atresia and CAS died during the first months of life, while mortality among those with recessive dystrophic EB was 6.8%. CONCLUSION:Epidermolysis bullosa with CAS is a clinically heterogeneous disorder, most often associated with recessive dystrophic EB, but other EB subtypes may occur. Further investigations are necessary to better establish a pathological mechanism for CAS, and its association with EB. | 01 = IsEpi
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Dedicator of cytokinesis (DOCK) proteins constitute a family of evolutionarily conserved guanine nucleotide exchange factors (GEFs) for the Rho family of GTPases. Although DOCK family proteins do not contain the Dbl homology domain typically found in other GEFs, they mediate the GTP-GDP exchange reaction through the DOCK homology region-2 (DHR-2) domain. In mammals, this family consists of 11 members, each of which has unique functions depending on the expression pattern and the substrate specificity. For example, DOCK2 is a Rac activator critical for migration and activation of leukocytes, whereas DOCK8 is a Cdc42-specific GEF that regulates interstitial migration of dendritic cells. Identification of DOCK2 and DOCK8 as causative genes for severe combined immunodeficiency syndromes in humans has highlighted their roles in immune surveillance. In addition, the recent discovery of a naturally occurring DOCK2-inhibitory metabolite has uncovered an unexpected mechanism of tissue-specific immune evasion. On the other hand, GEF-independent functions have been shown for DOCK8 in antigen-induced IL-31 production in helper T cells. This review summarizes multifaced functions of DOCK family proteins in the immune system. | 01 = IsEpi
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INTRODUCTION:Primary hyperoxaluria type 1 (PH1) is a genetic autosomal recessively inherited disorder due to mutation in the alanine-glyoxylate aminotransferase (AGXT) gene. It usually presents in children with nephrolithiasis and/or nephrocalcinosis and progressive renal function impairment and end stage renal disease (ESRD). PATIENT CONCERNS:A 13 years old Saudi boy with history of recurrent urolithiasis since the age of 2 years presented to us with picture of ESRD. He has strong family history of urolithiasis. DIAGNOSIS:Working up the patient suggested the diagnosis of PH1 based on the typical clinical, laboratory, and imaging findings which was genetically proved by positive AXGT gene mutation. The mutation detected was not previously reported in literature. The mutation detected was not previously reported in literature. The novel mutation c. 799A>T p. (IIe267Phe) detected in our patient extend the spectrum of the known AGXT gene mutations. INTERVENTIONS AND OUTCOMES:Hemodialysis as a temporary step followed by renal transplantation which is the only cure. CONCLUSION:High index of suspicion of PH1 before ESRD should be considered in any patient who has recurrent urolithiasis since early life especially in presence of strong family history. | 01 = IsEpi
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