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Background Citrin deficiency (CD) is an autosomal recessive genetic disorder caused by a defect in the mitochondrial aspartate/glutamate antiporter, citrin. Three clinical manifestations have been described until today. Case presentation We reported 5 CD patients from two families. Four patients were male and one patient was female. Two of them have NICCD (neonatal intrahepatic cholestasis caused by citrin deficiency); three of them have CTLN2 (adult-onset type II citrullinemia). Both NICCD patients showed typical clinical and biochemical changes with a diagnosis confirmed by mutations in the SLC25A13 gene. We detected a previously unreported homozygous novel mutation c.478delC (L160Wfs*36 ) on the SLC25A13 gene. All of the CTLN2 patients were siblings. Proband was a 15-year-old mentally retarded and autistic male who had admitted to our emergency with disorientation. Laboratory data showed hyperammonemia and citrullinemia. Conclusions Two different profiles of age-related CD have been depicted with this article. It has been aimed to underline that the CD can be observed in different forms not only in neonatals or little infants but also in adolescents. This article is the first case series that covers both NICCD and CTLN2 cases together and that has been published in Turkey. Considering the fact that especially the majority of CTLN2 cases have been identified in Asian countries, our article has vital importance in terms of defining phenotypic features of the disease. | 01 = IsEpi
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Genetic defects of NKX2-1 are classically associated with hypothyroidism, benign chorea and neonatal respiratory distress. The purpose of this study was to identify the genetic pathogenesis of the "NKX2-1 triad" in a 10 year-old female presenting additional features barely described in the disorder. In the neonatal period, she presented with generalized hypotonia and respiratory distress, with later episodes of frequent wheezing. At 3 month-age developmental dysplasia of the hip was diagnosed and at 10 months, primary hypothyroidism was detected and treated. Subsequently, delayed achievement of developmental milestones and then subtle choreic movements of extremities were identified at 2 years of age. Furthermore, delayed teeth eruption and agenesis of some dental pieces, short stature and joint hyperlaxity were also noticed. At 10 years, a poor immune response to polysaccharide antigens and hypogammaglobulinemia, including all IgG subclasses were detected. Surprisingly, no mutations were identified in the complete coding region of NKX2-1 by PCR and Sanger sequencing. MLPA showed a de novo loss of gene dosage in all 3 probes located in NKX2-1 exons. A CGH-array identified a deletion of 3.32 Mb in chromosome 14q13.2-q21.1 containing 20 genes, including NKX2-1, PAX9 and two candidate genes (NFKB1A and PPP2R3C) involved in immune response. The Brain-Lung-Thyroid syndrome (OMIM#610978; ORPHA:209905) associated with other clinical phenotypes should suggest monoallelic deletions of chromosome 14 causing haploinsufficiency of NKX2-1, and other contiguous genes like PAX9 (hypodontia) or other dosage-sensitive genes in the chromosomal vicinity that emerge as candidates for hypogammaglobulinemia, mainly NFKBIA. | 01 = IsEpi
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Angiokeratoma corporis diffusum refers to symmetrical clusters of minute red papules in a "bathing trunk" distribution and is considered the cutaneous hallmark of Fabry disease. Acid sphingomyelinase deficiency is an autosomal recessive sphingolipidosis, which presents with massive hepatosplenomegaly, pulmonary infiltrates, and skeletal abnormalities. We present the unusual case of a 12-year-old girl with acid sphingomyelinase deficiency who developed characteristic lesions of angiokeratoma corporis diffusum. | 01 = IsEpi
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BACKGROUND:Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). OBJECTIVE:To identify pathogenic mutation in the Korean patients with CMT and distal hereditary motor neuronopathy (dHMN). METHODS:We screened AARS1 mutations in 373 unrelated CMT families including 318 axonal CMT, 36 dHMN, and 19 intermediate CMT (Int-CMT) who were negative for 17p12 (PMP22) duplication or deletion using whole exome sequencing and targeted sequencing of CMT-related genes. RESULTS:This study identified an early onset Int-CMT family harboring an AARS1 p.Arg329His mutation which was previously reported as pathogenic in French and Australian families. The mutation was located in the highly conserved tRNA binding domain and several in silico analyses suggested pathogenic prediction of the mutations. The patients harboring p.Arg329His showed clinically similar phenotypes of the early onset and electrophysiological intermediate type as those in Australian patients with same mutation. We also found a novel c.2564A>G (p.Gln855Arg) in a CMT2 patient, but its' pathogenic role was uncertain (variant of uncertain significance). CONCLUSION:This study suggests that the frequency of the AARS1 mutations appears to be quite low in Korean CMT. This is the first report of the AARS1 mutation in Korean CMT patients and will be helpful for the exact molecular diagnosis and treatment of Int-CMT patients. | 01 = IsEpi
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We used molecular tools to identify an autochthonous case of gnathostomiasis in Madagascar. This severe ocular infection, caused by Gnathostoma spinigerum nematodes, led to vision loss in the patient's left eye. Clinicians should be aware of this parasitosis in Madagascar and other countries in Africa. | 01 = IsEpi
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MYH-associated polyposis is a recessively inherited syndrome of colorectal cancer predisposition attributed to biallelic germline mutations in the base excision repair gene MYH. Clinically it overlaps with attenuated familial adenomatous polyposis, sporadic oligopolyposis, serrated polyposis, familial colorectal cancer type X, and Lynch syndrome. There is no specific phenotypic feature of MYH-associated polyposis. We have noticed that a proportion of patients with MYH-associated polyposis presenting for yearly colonoscopy surveillance have rectums that are studded with small hyperplastic polyps.We report this as a possible unique phenotypic feature of the syndrome.This was a descriptive study.The study was conducted at a department of colorectal surgery in a tertiary referral center.Patients affected with oligopolyposis or MYH-associated polyposis presenting for endoscopic surveillance and polyp control were included.Interventions included colonoscopy or proctoscopy with excision or biopsy of mucosal lesions.The presence of rectal studding was measured.There were 49 patients, 16 with biallelic germline mutations of MYH; 10 of these had rectal studding. A sampling of rectal polyps was biopsied and all were hyperplastic. Five patients with biallelic MYH mutations had no studding, and 1 had not been prospectively examined. The studding was independent of the nature of the MYH mutation(s). The 33 patients other patients included 21 with serrated polyposis, 2 with a germline APC mutation, 1 with a PTEN mutation, 2 with mixed polyposis, 3 with oligoadenomatous polyposis and no germline mutation, and 4 patients with oligoadenomatous polyposis who had not been genetically tested. Only 1 of these (oligoadenomatous polyposis, not tested) had studding.The study was limited by its small number of biallelic MYH mutation carriers.Rectal studding may be a sign of MYH-associated polyposis and raises questions about the biology of abnormal base excision repair. | 01 = IsEpi
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Split-hand/foot malformation (SHFM) is a genetic limb anomaly disturbing the central rays of the autopod. SHFM is a genetically heterogeneous disorder with variable expressivity inherited as syndromic and nonsyndromic forms. We provide an update of the clinical and molecular aspects of nonsyndromic SHFM. This rare condition is highly complex due to the clinical variability and irregular genetic inheritance observed in the affected individuals. Nonsyndromic SHFM types have been reviewed in terms of major molecular genetic alterations reported to date. This updated overview will assist researchers, scientists, and clinicians in making an appropriate molecular diagnosis, providing an accurate recurrence risk assessment, and developing a management plan. | 01 = IsEpi
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We described a heterozygous de novo mutation (G434V) in the frizzled class receptor 2 (FZD2) gene in a patient with distinct facial features including hypertelorism, bilateral cleft lip/palate, short nose with a broad nasal bridge, microretrognathia, and bilateral shortness of the upper limbs, first metacarpal bones, and middle phalanges of the 5th digits. The findings of our patient were compared to an autosomal dominant omodysplasia (OMOD2) family with FZD2 mutation reported in the literature. OMOD2 is a rare skeletal dysplasia and characterized by facial dysmorphism and shortness of the upper extremities and first metacarpal bones. This is the second report which supports the findings of the first family described and points out that heterozygous FZD2 mutations may be disease-causing for OMOD2. | 01 = IsEpi
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BACKGROUND:This case report highlights the rare occurrence of postpartum psychosis in the setting of peripartum cardiomyopathy, which can have rare presentations like arrhythmias and pulmonary edema; and the challenges one should anticipate while managing these conditions together. Caution is advised whenever antipsychotic drugs are to be administered to a patient with a cardiac condition as these drugs potentially increase the risk of arrhythmias and sudden death. CASE PRESENTATION:A 35 year old grand multiparous woman who was 1 week into puerperium was admitted with severe difficulty in breathing at rest, chest congestion and pain. She also had easy fatigability, orthopnea, paroxysmal nocturnal dyspnea, edema, tachycardia, tachypnea, irregularly irregular heart rate with a pulse deficit, elevated jugular venous pressure, cardiomegaly, hepatomegaly and pulmonary crepitations. On the sixth day while improving on standard drugs for heart failure, she developed bizarre behavior and confusion. She also had auditory, visual and olfactory hallucinations; violence to the baby and the husband; and refusal to feed and take medication. There was no altered sensorium and the vital signs were normal. She was diagnosed with puerperal psychosis during the management of peripartum cardiomyopathy. CONCLUSION:In the rare occurrence of puerperal psychosis in the course of management of peripartum cardiomyopathy one must be acutely aware of the risk of sudden cardiac death occasioned by use of antipsychotics, either directly or due to arrhythmias. Continuous electrocardiogram (ECG) monitoring or use of alternative management modalities is thus highly advised. | 01 = IsEpi
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SMARCA4 encodes a central ATPase subunit in the BRG1-/BRM-associated factors (BAF) or polybromo-associated BAF (PBAF) complex in humans, which is responsible in part for chromatin remodeling and transcriptional regulation. Variants in this and other genes encoding BAF/PBAF complexes have been implicated in Coffin-Siris Syndrome, a multiple congenital anomaly syndrome classically characterized by learning and developmental differences, coarse facial features, hypertrichosis, and underdevelopment of the fifth digits/nails of the hands and feet. Individuals with SMARCA4 variants have been previously reported and appear to display a variable phenotype. We describe here a cohort of 15 unrelated individuals with SMARCA4 variants from the Coffin-Siris syndrome/BAF pathway disorders registry who further display variability in severity and degrees of learning impairment and health issues. Within this cohort, we also report two individuals with novel nonsense variants who appear to have a phenotype of milder learning/behavioral differences and no organ-system involvement. | 01 = IsEpi
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BACKGROUND:Congenital hemangiomas are benign abnormal proliferation of blood vessels. Noninvoluting congenital hemangiomas are a rare variant which persist, and may become bigger. Hemangiomas are known to be associated with thrombocytopenia, microangiopathic hemolytic anemia and Kasabach-Merritt phenomenon. Kasabach-Merritt phenomenon is characterized by consumptive coagulopathy with microangiopathic haemolyic anemia and thrombocytopenia. Platelet sequestration in the hemangioma or increased destruction which may either be immune or non immune are also further contributors to thrombocytopenia. CASE PRESENTATION:A 45 year old female with a non involuting hemangioma and baseline thrombocytopenia was observed to develop repeated episodes of transient severe thrombocytopenia associated with a variety of infectious conditions. Laboratory investigations suggested a peripheral mechanism. Platelet counts always returned to baseline levels on resolution of the precipitating infection. CONCLUSION:The authors report this phenomenon as the first reported case of baseline thrombocytopenia complicated by recurrent episodes of transient severe thrombocytopenia following infections associated with a non involuting congenital hemangioma. The observations made in this patient were unique and hitherto unreported in medical literature. Both peripheral sequestration and destructive consumption were considered likely. Consumptive mechanisms were likely to encompass either or both immune and non immune causes. Further studies are needed to establish the precise pathogenesis. | 01 = IsEpi
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Musculocontractural Ehlers-Danlos syndrome caused by mutations in CHST14 (mcEDS-CHST14) is a recently delineated disorder, characterized by craniofacial, skeletal, visceral, and ocular malformations; and progressive cutaneous, skeletal, vascular, and visceral fragility-related manifestations. Spinal lesions, though one of the most serious complications, have not been investigated systematically. In this study, we report detailed and comprehensive information about spinal lesions of 12 patients with a mean age at the first visit of 13.4 years. Eight patients (66.7%) had scoliosis with a Cobb angle ≥10°, including one with severe scoliosis with a Cobb angle ≥45°. Five patients (41.7%) had kyphosis at the thoracolumbar junction with a kyphotic angle ≥20°. Three patients (25%) developed severe thoracolumbar kyphosis with a kyphotic angle ≥50° accompanied by thoracic lordosis with a wedge-like vertebral deformity and anterior vertebral osteophyte at the thoracolumbar junction, and two of them underwent surgical correction: complicated by fistula formation in one and performed safely and effectively through two-staged operation in the other. Six patients (50.0%) had cervical kyphosis, all of whom except one had kyphosis ≥20° at the thoracolumbar level. Two patients (16.7%) had atlantoaxial subluxation, and 10 patients (83.3%) had cervical vertebral malformations. Patients with mcEDS-CHST14 are susceptible to develop scoliosis, thoracolumbar kyphosis, and cervical kyphosis; and are recommended to have regular surveillance including total spine radiology. The present findings also suggest the critical role of dermatan sulfate in the development and maintenance of the spine. | 01 = IsEpi
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Next-generation sequencing (NGS) is helpful in diagnosing complex genetic disorders and phenotypes, particularly when more than one overlapping condition is present. From a large cohort of 362 families with clinical manifestations of skin and mucosal fragility, referred by several major medical centers, one patient was found by NGS to have two overlapping heritable skin diseases, recessive dystrophic epidermolysis bullosa (RDEB; COL7A1 mutations) and acrodermatitis enteropathica (AE; SLC39A4 mutations). The pathogenicity of the variants was studied at gene expression as well as ultrastructural and tissue levels. Although there is no specific treatment for RDEB except avoiding trauma, supplementation with oral zinc (3 mg·kg-1 ·day-1 ) for the AE resulted in rapid amelioration of the skin findings. This case demonstrates the power of NGS in identifying two genetically unlinked diseases that led to effective treatment with major clinical benefits as an example of genomics-guided treatment. | 01 = IsEpi
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SHORT syndrome is a rare genetic congenital defects condition. The frequency of the disease still remains unknown.We report the two-year-four-month old female with SHORT syndrome who present growth retardation and dysmorphic features (triangular-shaped face, prominent forehead, ocular depression, lipodystrophy at the lumbar region and around elbows), consistent with the phenotype described for this syndrome. The molecular analysis showed the presence of heterozygous variant c.1956dupT (p.Lys653*) in exon 15 of PIK3R1.The frequency of the disease still remains unknown; solely several dozen cases have been described worldwide. | 01 = IsEpi
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Desmin-related myopathy (DRM) is a rare heritable cardiac and skeletal muscle disease caused by mutations in the desmin gene (DES). DRM is generally characterized by skeletal muscle weakness, conduction disturbance, and dilated cardiomyopathy. However, the clinical cardiac phenotypes of DRM are not yet fully understood. Herein, we report the first case of DRM with the de novo missense DES mutation, R454W, that is characterized by left ventricular non-compaction cardiomyopathy, progressive cardiac conduction defect, spontaneous coronary artery dissection, and no skeletal muscle weakness. Our case findings suggest that clinicians should genetically test patients who have cardiomyopathy, progressive cardiac conduction defect, and coronary artery dissection, even if the patient has neither family history of DRM nor skeletal muscle symptoms. | 01 = IsEpi
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Since the 1950s, the Kingdom of Morocco has been and remains one of the pioneers in the fight against trachoma, a disease that has completely disappeared in the majority of its national territory, but some endemic pockets have persisted and pose a health risk, particularly for children and women. Morocco finds itself today, thanks to years of joint efforts, at the forefront of the world stage of the fight against trachoma. The country has demonstrated through its experience the effectiveness and relevance of the "SAFE" strategy - an extensive programme designed to tackle trachoma and its complications. The strategy is complex in its implementation and requires the synergy of a set of actors dedicated to specific activities, whether medico-surgical management activities aimed at setting up a physical project for local development, or information and awareness-raising activities. The key to the long-term success of eliminating blinding trachoma was not only to link distribution of drugs to the entire project area for several years to reduce substantially the reservoir of human- to-human transmission, but also to ensure permanence. In addition, services that provide quality palpebral surgery and especially repeat treatment campaigns with antibiotics, as well as health education campaigns and the promotion of personal and collective hygiene have generated sustainable changes in the living environment of receiving populations. | 01 = IsEpi
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Background:Pallister-Killian syndrome (PKS) (OMIM:#601803) is a rare sporadic genetic disorder characterized by multi-malformations which is caused by the presence of the extra isochromosome 12p. PKS is featured by the tissue-limited mosaicism of the isochromosome 12p [i(12p)]. There were a wide spectrum of prenatal ultrasound findings of PKS, which made it difficult to be found in first or second trimester. Polyhydramnios, diaphragmatic hernia, and rhizomelic limb shortening were the most common prenatal ultrasound abnormalities in PKS. This study retrospectively analyzed the ultrasound findings and molecular cytogenetic results of four PKS fetuses diagnosed by using cord blood samples. Results:The ultrasound anomalies of four PKS fetuses are described as follows: fetal macrosomia, cerebral ventriculomegaly, increased NT thickness, rhizomelic limbs shortening, polyhydramnios. Biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), femur length (FL) measurements were above the mean in three fetuses,while one fetus showed rhizomelic limbs shortening. Combined with this study and previous literature, polyhydramnios was the most frequent anomaly observed in prenatal ultrasound examination of PKS, which accounted for 48% (94/194). Fetal macrosomia was present in 15% (29/194), cerebral ventriculomegaly in 13% (25/194), thickened nuchal fold in 9% (18/194), rhizomelic limbs shortening in 26% (51/194). I(12p) was found in the karyotype analysis of cultured cord blood lymphocytes and the mosaic ratios ranged from 2 to 5%. Single nucleotide polymorphisms array (SNP-array) results suggested that the whole short arm of chromosome 12 was duplicated with 2~3 copies. Fluorescence in situ hybridization (FISH) was performed to confirm the results of karyotype and SNP-array. Conclusions:In case non-specific indicators such as fetal macrosomia, polyhydramnios and rhizomelic limbs shortening are observed meanwhile in prenatal ultrasound, targeted detection of PKS should be considered. In the prenatal diagnosis of PKS, the combination of SNP-array and FISH with conventional karyotype are the key to seek i(12p) and for precise diagnosis. | 01 = IsEpi
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Autosomal recessive congenital ichthyosis is a heterogenous group of disorders that are present at birth with generalized involvement of skin and lack of other organ systems. Clinical presentation, pattern of inheritance, and laboratory evaluation may establish a precise diagnosis, which can assist in prognosis and genetic counseling. There is a little knowledge about the oral manifestations of these disorders.This case report presents management and complete oral rehabilitation of a rare case of lamellar ichthyosis. | 01 = IsEpi
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Polydactyly, also known as hyperdactyly or hexadactyly is the most common hereditary limb anomaly characterized by extra fingers or toes, with various associated morphologic phenotypes as part of a syndrome (syndromic polydactyly) or may occur as a separate event (non-syndromic polydactyly). Broadly, the non-syndromic polydactyly has been classified into three types, i.e.; preaxial polydactyly (radial), central polydactyly (axial), and postaxial polydactyly (ulnar). Mostly inherited as an autosomal dominant entity with variable penetrance and caused by defects that occur in the anterior-posterior patterning of limb development. In humans, to-date at least 10 loci and six genes causing non-syndromic polydactyly have been identified, including the ZNF141, GLI3, MIPOL1, IQCE, PITX1, and the GLI1. In the present review, clinical, genetic and molecular characterization of the polydactyly types has been presented including the recent genes and loci identified for non-syndromic polydactyly. This review provides an overview of the complex genetic mechanism underlie polydactyly and might help in genetic counseling and quick molecular diagnosis. | 01 = IsEpi
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Pulmonary vein stenosis is a rare and poorly understood condition causing obstruction of the large pulmonary veins and of blood flow from the lungs to the left atrium. This results in elevated pulmonary venous pressure and pulmonary edema, pulmonary hypertension, potentially cardiac failure, and death. Clinical signs of the disease include failure to thrive, increasingly severe dyspnea, hemoptysis, respiratory difficulty, recurrent respiratory tract infections/pneumonia, cyanosis, and subcostal retractions. On chest radiograph, the most frequent finding is increased interstitial, ground-glass and/or reticular opacity. Transthoracic echocardiography with pulsed Doppler delineates the stenosis, magnetic resonance imaging and multislice computerized tomography are used for further evaluation. Interventional cardiac catherization, surgical techniques, and medical therapies have been used with varying success as treatment options. | 01 = IsEpi
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INTRODUCTION:X-linked adrenoleukodystrophy (X-ALD) encompasses several clinical and neuroimaging phenotypes, including cerebral X-ALD, the most common phenotype in children, and adrenomyeloneuropathy, the most common phenotype in adults. A spinocerebellar variant of X-ALD has been described in individuals from the Far East, but the criteria for its diagnosis are unclear. CASE REPORT:A 35-year-old man from Albania was assessed because of a familial, slowly progressive spastic-ataxic gait associated with neurogenic bladder, sexual dysfunctions, and manic-like behavior. There was no definite clinical feature that suggested cerebellar involvement (eg, cerebellar limb ataxia, nystagmus, and dysarthria). A few months earlier, he had received a diagnosis of Addison disease. Brain magnetic resonance imaging showed a leukoencephalopathy with predominant cerebellum and brainstem involvement, and FDG-PET revealed marked cerebellar hypometabolism. The diagnosis of X-ALD was made because we found an increase of very long chain fatty acids, and a new ABCD1 mutation (c.1627C>T, p.Pro543Ser). CONCLUSIONS:X-ALD should be included in the differential diagnosis of adult leukoencephalopathies with predominant involvement of infratentorial structures, that is, the cerebellum and brainstem. From a classification perspective, our patient (of white origin), like others (all of Asian origin), should be considered as suffering from a variant of adrenomyeloneuropathy rather than from spinocerebellar X-ALD. Actually, the term "spinocerebellar" or similar ones, such as "cerebello-brainstem dominant form," should be limited to those exceptional cases, in which both the clinical and neuroimaging findings point exclusively (or at least predominantly) to the involvement of infratentorial structures. | 01 = IsEpi
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Phenotypic manifestations of the autosomal recessive form of VACTERL-hydrocephaly syndrome (David-O'Callaghan syndrome) and the X-linked recessive form (Hunter-MacMurray) syndrome are almost identical. The absence of cardiovascular malformations in cases with undoubtedly X-linked inheritance may be the only exception. The comparison of patients with David-O'Callaghan syndrome and nonclassified sporadic cases of VACTERL-hydrocephaly showed two marked differences. First, radial involvement (usually bilateral) occurred in all familial but only in 22 of 36 sporadic cases. Therefore, radial noninvolvement may be evidence against a genetic origin of the complex in a sporadic case. Second, predominantly severe forms of cardiovascular malformations were found in cases of David-O'Callaghan syndrome, whereas in sporadic cases almost all cardiovascular malformations were simple defects with minimal, if any, hemodynamic disturbances. The similarity of the spectrum and frequency of main manifestations of David-O'Callaghan and von Voss-Cherstvoy syndromes allows us to think that both of these syndromes actually might be 2 forms of one genetic entity. There are some syndromes with abnormalities of the brain (different for each syndrome) sharing the same limb defects (mainly preaxial), congenital heart defects, abnormalities of kidneys, and anal atresia/ectopia. Baller-Gerold syndrome, Steinfeld syndrome, XK-aprosencephaly, and DK-phocomelia (von Voss-Cherstvoy) syndrome as well as Mendelian forms of VACTERL-hydrocephaly syndromes fit into this "cerebro-cardio-radio-reno-rectal community." | 01 = IsEpi
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Myeloid sarcoma is an isolated extramedullary tumor mass consisting of immature myeloid cells. It is characterized by highly variable outcomes and usually disrupts the normal architecture of the normal tissue in which it originates. It may occur de novo or be associated with other hematological malignancies. Clinical presentation of myeloid sarcomas can be highly variable based on the tumor site, size, and extent of tissue involvement. The diagnosis of myeloid sarcoma is challenging and requires a high index of suspicion. Tissue sampling followed by the use of auxiliary studies is essential for diagnosis. Moreover, bone marrow sampling is necessary to exclude morrow involvement. Currently, the recommended therapeutic regimens for myeloid sarcoma are similar to those for acute myeloid leukemia. Much work remains to be accomplished as myeloid sarcomas, if initially missed or misdiagnosed, have poor overall survival rates. Furthermore, prognostic factors for this malignancy remain poorly understood. | 01 = IsEpi
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Background:Cervical dystonia is mostly idiopathic in nature. However, a small subset of cases are mimics, leading to diagnostic pitfalls. There is paucity of literature on pseudodystonias affecting the cervical region. Method:We performed a retrospective review of patients attending a movement disorders clinic over a period of 7 years (2012-2018). Among them, those who were considered to have mimics of cervical dystonia based upon clinical and supportive investigations were included. Results:Six out of 2,412 patients (0.24%) were diagnosed as cervical dystonia mimics and the causes included isolated neck extensor myopathy (2), craniovertebral junction anomalies (2), sternocleidomastoid fibrosis (1) and post traumatic sequelae (1). Among these patients, three patients had received various treatments for cervical dystonia, including botulinum toxin injections. Discussion:Mimics of isolated cervical dystonia are rare. A high degree of suspicion and proper diligent clinical assessment assists management and prognostication. | 01 = IsEpi
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The nuclear lamina is a fibrous meshwork of proteins found adjacent to the inner nuclear membrane that plays a critical role in the maintenance of nuclear architecture. Made up of A and B type lamins, the nuclear lamina has recently been shown to contribute to numerous cellular functions such as chromatin organization, DNA replication, cellular proliferation, senescence, and aging. While at least a dozen disorders are associated with LMNA, the focus of this review is Autosomal Dominant Leukodystrophy (ADLD), the only disease associated with the lamin B1 gene (LMNB1). ADLD is a fatal, adult onset CNS demyelinating disorder that is caused by either genomic duplications involving LMNB1 or deletions upstream of the gene. Both mutation types result in increased LMNB1 gene expression. How the increased levels of this widely expressed nuclear structural component results a phenotype as specific as demyelination is a great mystery. This review summarizes what is currently known about the disease and describes recent work using animal and cell culture models that have provided critical insights into ADLD pathological mechanisms. The delineation of these pathways provides a fascinating glimpse into entirely novel roles for the nuclear lamina and will be critical for the identification of therapies for this fatal disease. | 01 = IsEpi
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Meromelia is a rare skeletal abnormality characterized by the partial absence of at least one limb. Several mechanisms have been postulated to explain the etiopathogenesis of the disorder. Most of the cases of meromelia are reported to be sporadic. It can occur either in isolation or with other congenital malformations. VACTERL association, gastroschisis, atrial septal defect, proximal femoral focal deficiency, and fibular hemimelia are the congenital abnormalities reported to be in association with meromelia. However, no other congenital abnormalities in association with meromelia have been recorded to date. We herein present an unusual case of bilateral upper limb meromelia accompanied by unilateral oligodactyly and brachymesophalangy of the foot. | 01 = IsEpi
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Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is an inborn error of ketone body metabolism and causes episodic ketoacidosis. We report clinical and molecular analyses of 5 patients with SCOT deficiency. Patients GS07, GS13, and GS14 are homozygotes of S405P, L327P, and R468C, respectively. GS17 and GS18 are compound heterozygotes for S226N and A215V, and V404F and E273X, respectively. These mutations have not been reported previously. Missense mutations were further characterized by transient expression analysis of mutant cDNAs. Among 6 missense mutations, mutants L327P, R468C, and A215V retained some residual activities and their mutant proteins were detected in immunoblot analysis following expression at 37°C. They were more stable at 30°C than 37°C, indicating their temperature sensitive character. The R468C mutant is a distinct temperature sensitive mutant which retained 12% and 51% of wild-type residual activities at 37 and 30°C, respectively. The S226N mutant protein was detected but retained no residual activity. Effects of missense mutations were predicted from the tertiary structure of the SCOT molecule. Main effects of these mutations were destabilization of SCOT molecules, and some of them also affected catalytic activity. Among 5 patients, GS07 and GS18 had null mutations in both alleles and the other three patients retained some residual SCOT activities. All 5 developed a first severe ketoacidotic crisis with blood gas pH <7.1, and experienced multiple ketoacidotic decompensations (two of them had seven such episodes). In general, the outcome was good even following multiple ketoacidotic events. Permanent ketosis or ketonuria is considered a pathognomonic feature of SCOT deficiency. However, this condition depends not only on residual activity but also on environmental factors. | 01 = IsEpi
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Background/Aims:Rosai-Dorfman disease (RDD) is a rare, self-limited disorder of unknown etiology that affects children and young adults worldwide and typically manifests as chronic, painless cervical lymphadenopathy. Orbital involvement is very rare and may be an isolated extranodal manifestation or associated with concurrent systemic disease. Adjacent bone involvement is most exceptional, and secondary optic neuropathy has never been reported. Methods:This is a case report with review of the literature. Results:We present a 32-year-old man who, over a 3-month period, developed worsening vision, headache, and vertical diplopia. On examination, there was decreased vision with dyschromatopsia, proptosis, and hypotropia of the left eye. CT scan of the orbits revealed a soft tissue mass inseparable from the lacrimal gland with adjacent bone erosion. Histopathologic evaluation revealed a diffuse infiltrate of histiocytes, lymphocytes, plasma cells, and neutrophils with peripolesis and emperipolesis (tunneling of lymphocytes and plasma cells in the histiocytes' cytoplasm without destruction), consistent with RDD. Resolution of symptoms as well as of the optic neuropathy was achieved with oral corticosteroids. Conclusion:RDD is an important diagnosis that must be considered in the differential diagnosis of an orbital mass. | 01 = IsEpi
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BACKGROUND:Death from bacterial meningitis is rarely attributed to the actual event causing death. The present study therefore categorized and characterized the cause and time of death due to bacterial meningitis. METHODS:In a cohort of patients > 15 years of age with community acquired bacterial meningitis the medical records were reviewed, and a clinical cause of death categorized into six main categories: 1) CNS complications, 2) Systemic complications, 3) Combination of systemic and CNS complications, 4) Sudden death, 5) Withdrawal of care, or 6) Unknown. RESULTS:We identified 358 patients of which 84 (23%) died in-hospital. Causes of death were ascribed to CNS complications in 43%, Systemic complications in 39%, Combined CNS and systemic complications in 4%, Sudden death in 7% and withdrawal of care in 5%. Brain herniation, circulatory failure, intractable seizures and other brain injury were the most common specific causes of death within 14 days from admission (55%). CONCLUSION:Fatal complications due to the primary infection - meningitis - is most common within 14 days of admission. The diversity of complications causing death in meningitis suggest that determining the clinical cause of death is essential to the evaluation of novel treatment strategies. | 01 = IsEpi
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Congenital Dyserythropoietic Anemia (CDA) is a heterogeneous group of hematological disorders characterized by chronic hyporegenerative anemia and distinct morphological abnormalities of erythroid precursors in the bone marrow. In many cases, a final diagnosis is not achieved due to different levels of awareness for the diagnosis of CDAs and lack of use of advanced diagnostic procedures. Researchers have identified five major types of CDA: types I, II, III, IV, and X-linked dyserythropoietic anemia and thrombocytopenia (XLDAT). Proper management in CDA is still unsatisfactory, as the different subtypes of CDA have different genetic causes and different but overlapping patterns of signs and symptoms. For this reason, we developed a new telemedicine tool that will help doctors to achieve a faster diagnostic for this disease. Using open access code, we have created a responsive webpage named CoDysAn (Congenital Dyserythropoietic Anemia) that includes practical information for CDA awareness and a step-by-step diagnostic tool based on a CDA algorithm. The site is currently available in four languages (Catalan, Spanish, Italian, and English). This telemedicine webpage is available at http://www.codysan.eu. | 01 = IsEpi
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BACKGROUND:Syndromic congenital heart disease accounts for 30% of cases and can be determined by genetic, environmental or multifactorial causes. In many cases the etiology remains uncertain. Many known genes are responsible for specific morphopathogenetic mechanisms during the development of the heart whose alteration can determine specific phenotypes of cardiac malformations. CASE PRESENTATION:We report on two cases of association of conotruncal heart defect with facial dysmorphisms in sibs. In both cases the malformations' identification occurred by ultrasound in the prenatal period. It was followed by prenatal invasive diagnosis. The genetic analysis revealed no rearrangements in Array-CGH test, while gene panel sequencing identified a new hemizygous variant of uncertain significance (c.887G > A; p.Arg296Gln) in the MED12 gene, located on the X chromosome and inherited from the healthy mother. CONCLUSION:No other reports about the involvement of MED12 gene in syndromic conotruncal heart defects are actually available from the literature and the international genomic databases. This novel variant is a likely pathogenic variant of uncertain significance and it could broaden the spectrum of genes involved in the development of congenital heart diseases and the phenotypic range of MED12-related disorders. | 01 = IsEpi
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OBJECTIVE:The association between birth weight and infants' neurodevelopment is not well understood. We aimed to examine the impact of birth weight on neurodevelopment of infants at age 1-6 months using data from the Wuhan Healthy Baby Cohort (WHBC) study. SETTING AND PARTICIPANTS:This is a prospective cohort study of 4026 infants from the WHBC study who were born at the Women and Children's Hospital of Wuhan, China between October 2012 and September 2013 and who had complete healthcare records within 6 months after birth. Participants were categorised into three groups according to their birth weight: low birth weight (LBW; birth weight <2500 g), normal birth weight (2500 g ≤ birth weight <4000 g) and macrosomia (birth weight ≥4000 g). MAIN OUTCOME MEASURES:The main outcomes were development quotient (DQ) and clinical diagnosis of neurodevelopmental delay. Both adjusted regression coefficients and ORs were estimated for LBW and macrosomia. RESULTS:Of the 4026 infants, 166 (4.12%) were of LBW and 237 (5.89%) were with macrosomia. Adjusted regression coefficients of LBW and macrosomia for gross motor DQ were -11.18 (95% CI -11.36 to 10.99) and 0.49 (95% CI 0.36 to 0.63), fine motor DQ -6.57 (95% CI -6.76 to -6.39) and -2.73 (95% CI -2.87 to -2.59), adaptability DQ -4.87 (95% CI -5.05 to -4.68) and -1.19 (95% CI -1.33 to -1.05), language DQ -6.23 (95% CI -6.42 to -6.05) and 0.43 (95% CI 0.29 to 0.57), and social behaviour DQ -6.82 (95% CI -7.01 to -6.64) and 1.10 (95% CI 0.96 to 1.24). Adjusted OR of LBW for clinical diagnosis of 'neurodevelopmental delay' in gross motor was 2.43 (95% CI 1.65 to 3.60), fine motor 1.49 (95% CI 1.01 to 2.19) and adaptability 1.56 (95% CI 1.06 to 2.31). LBW has no significant effects on 'neurodevelopmental delay' in language and social behaviour, and macrosomia has no significant effects on clinical diagnosis of 'neurodevelopmental delay' in all domains. CONCLUSION:Both LBW and macrosomia are associated with infants' DQ, and LBW increases the risk of being diagnosed with 'neurodevelopmental delay' in gross motor, fine motor and adaptability among infants aged 1-6 months. | 01 = IsEpi
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BACKGROUND:Fanconi anemia (FA) (OMIM #227650) is a rare hereditary disease characterized by genomic instability. The clinical phenotype involves malformations, bone marrow failure, and cancer predisposition. Genetic heterogeneity is a remarkable feature of FA; at least 22 FANC genes are known to cooperate in a unique FA/BRCA repair pathway. A common rule on the mutations found in these genes is allelic heterogeneity, except for mutations known to have arisen from a founder effect like the FANCC c.67delG in the Dutch Mennonite Community. Here, we present an 11-year-old male patient, member of the Mennonite Community of Tamaulipas México, with a clinical and cytogenetic diagnosis of FA. METHOD:Chromosome fragility test was performed in all siblings. Genomic DNA was obtained from peripheral blood samples. Sanger sequencing was used to identify the FANCC c.67delG mutation (NC_000009.11(NM_000136.2):c.67delG p.(Asp23IlefsTer23)) and its accompanying haplotype. RESULTS:The FANCC c.67delG mutation in 13 members of his family confirmed a FA diagnosis in two of his siblings and identified heterozygous carriers. Haplotype analysis supports that in this family, FA is caused by the founder mutation that initially appeared in Mennonite Dutch and followed this population's migrations through Canada and further to Mexico. CONCLUSION:The identification of the FANCC c.67delG mutation in this family not only allows proper genetic counseling, but it also grants the possibility to raise awareness of FA risk among the Mennonite community living in Mexico. | 01 = IsEpi
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BACKGROUND Paraneoplastic cerebellar degeneration (PCD) is a rare condition that can present as an acute or subacute cerebellar syndrome. PCD is most commonly associated with gynecological and breast cancer, small-cell lung cancer, and classical Hodgkin's lymphoma. The symptoms of PCD can arise several months before tumor diagnosis. This report is of a case of a 44-year-old man with PCD that preceded the diagnosis of classical Hodgkin's lymphoma by 16 months. CASE REPORT A 44-year-old man was admitted to hospital with a cerebellar syndrome that was initially diagnosed as vertebrobasilar insufficiency. Eight months later, cerebral magnetic resonance imaging (MRI) findings and serum anti-Tr antibodies supported the diagnosis of PCD, but no underlying malignancy was initially found. At 16 months after the initial diagnosis of PCD, the patient developed an enlarged inguinal lymph node. Histology of the excisional lymph node biopsy confirmed the diagnosis of classic mixed cellularity Hodgkin's lymphoma, Ann Arbor stage IIA. The patient responded to four cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy. CONCLUSIONS This case illustrates that in patients who present with PCD, an associated malignancy, such as classical Hodgkin's lymphoma, may emerge several months later, which supports long-term follow-up. The presence of anti-Tr antibodies may support a diagnosis of classical Hodgkin's lymphoma in a patient with a history of PCD who develops lymphadenopathy. | 01 = IsEpi
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Hyaline fibromatosis syndrome (HFS) is a rare autosomal recessive genetic disorder characterized by accumulation of hyalinized fibrous tissue with cutaneous, mucosal, osteoarticular, and systemic involvement. The condition is caused by a mutation of ANTXR2 gene that results in a faulty synthesis of a transmembrane protein which leads up to excessive deposition of hyaline material in extracellular space. The first signs may be present at birth or appear during infancy, and joint stiffness is the first, most common, symptom. Other manifestations include joint contractures, hyperpigmented macules over bony prominences of the joints, and gingival hypertrophy. The symptom that raises suspicion of HFS is present later, along with subcutaneous growths. The progression of the disease includes enteropathy with extensive protein loss, chronic diarrhea and frequent infections. We present a case of a five-year-old girl with severe gingival hypertrophy that caused difficulties in eating and speaking. To the best of our knowledge, this is also the first patient in Croatia with a confirmed ANTXR2 gene mutation described in the literature. | 01 = IsEpi
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Cilia are microtubule-based organelles, protruding from the apical cell surface and anchoring to the cytoskeleton. Primary (nonmotile) cilia of the kidney act as mechanosensors of nephron cells, responding to fluid movements by triggering signal transduction. The impaired functioning of primary cilia leads to formation of cysts which in turn contribute to development of diverse renal diseases, including kidney ciliopathies and renal cancer. Here, we review current knowledge on the role of ciliary genes in kidney ciliopathies and renal cell carcinoma (RCC). Special focus is given on the impact of mutations and altered expression of ciliary genes (e.g., encoding polycystins, nephrocystins, Bardet-Biedl syndrome (BBS) proteins, ALS1, Oral-facial-digital syndrome 1 (OFD1) and others) in polycystic kidney disease and nephronophthisis, as well as rare genetic disorders, including syndromes of Joubert, Meckel-Gruber, Bardet-Biedl, Senior-Loken, Alström, Orofaciodigital syndrome type I and cranioectodermal dysplasia. We also show that RCC and classic kidney ciliopathies share commonly disturbed genes affecting cilia function, including VHL (von Hippel-Lindau tumor suppressor), PKD1 (polycystin 1, transient receptor potential channel interacting) and PKD2 (polycystin 2, transient receptor potential cation channel). Finally, we discuss the significance of ciliary genes as diagnostic and prognostic markers, as well as therapeutic targets in ciliopathies and cancer. | 01 = IsEpi
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A reagent-free colorimetric method for galactose quantification using a composite of cerium oxide nanoparticles (nanoceria) and galactose oxidase (Gal Ox) entrapped in an agarose gel was developed. In the presence of galactose, the Gal Ox entrapped within the agarose gel catalyzed the oxidation of galactose to generate H2O2, which induced a color change from white to intense yellow. This reaction occurred without any chromogenic substrate. This color transition is presumed to be due to the H2O2-mediated alteration of the oxidation state of cerium ions present on the surface of the nanoceria. The intensity of color change was quantified by acquiring an image with a conventional smartphone, converting the image to cyan-magenta-yellow-black (CMYK) mode, and subsequently analyzing the image using the ImageJ software. Using this strategy, galactose concentration was specifically determined with excellent sensitivity of as low as 0.05 mM. The analytical utility of the assay was successfully verified by correctly determining diverse levels of galactose in human serum, which is enough to diagnose galactosemia, a genetic disorder characterized by the malfunctioning of enzymes responsible for galactose metabolism. The assay employing a hydrogel composite with entrapped nanoceria and Gal Ox, is a simple, cost-effective, and rapid colorimetric assay for galactose quantification, without using any chromogenic reagent. This cost-effective method has great potential for the diagnosis of galactosemia and is highly promising in comparison to the laborious instrumentation-based methods currently in use. | 01 = IsEpi
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Tetrasomy 18p syndrome (Online Mendelian Inheritance in Man 614290) is a rare chromosomal disorder that is seen in approximately 1 in every 180,000 live births. It is caused by the presence of isochromosome 18p, which is a supernumerary marker composed of two copies of the short arms of chromosome 18. Isochromosome 18p is one of the most commonly observed isochromosomes. We report tetrasomy 18p syndrome diagnosed prenatally after noninvasive prenatal testing (NIPT) was positive for trisomy 18. Tetrasomy 18p was finally diagnosed by G-banding and fluorescence in situ hybridization of chromosome 18p, before invasive confirmatory testing the karyotype findings by NIPT showed an increase in the DNA fragments from chromosome 18p, indicating duplication of chromosome 18p. NIPT can detect not only trisomy 13, 18, and 21, but also structural chromosomal anomalies, such as deletions and duplications. An NIPT report "positive for trisomy 18" indicates the possibility of tetrasomy 18p, and detailed analysis of NIPT data can reveal subchromosomal copy number variations, to a certain extent, before definitive diagnostic testing. | 01 = IsEpi
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Chromosomal abnormalities, consisting of numerical and structural chromosome abnormalities, are a common characteristic of cancer. Numerical chromosome abnormalities, mainly including aneuploidy and chromosome instability, are caused by chromosome segregation errors in mitosis, whereas structural chromosome abnormalities are a consequence of DNA damage and comprise focal/arm-level chromosome gain or loss. Recent advances have started to unveil the mechanisms by which chromosomal abnormalities can facilitate tumorigenesis and change the cellular fitness and the expression or function of RNAs and proteins. Accumulating evidence suggests that chromosome abnormalities represent a genomic signature that is linked to cancer prognosis and reaction to chemotherapy and immunotherapy. In this review, we discuss the most recent findings on the role of chromosome abnormalities in tumorigenesis and cancer progression, with a particular emphasis on how aneuploidy and chromosome instability influence cancer therapy and prognosis. We also highlight the distribution and clinical application of the structural chromosome abnormalities in various cancer types. A better understanding of the role of chromosome abnormalities will be beneficial to the development of precision oncology and suggest future directions for the field. | 01 = IsEpi
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BACKGROUND:Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro-mediated congenital heart block (CHB). OBJECTIVES:Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB. METHODS:This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon's optimal approach. Anti-SSA/Ro-positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash. RESULTS:By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4). CONCLUSIONS:These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573). | 01 = IsEpi
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Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized by obesity, mental impairment, rod-cone dystrophy, polydactyly, male hypogonadism, and renal abnormalities. This disorder is caused by mutations in BBS1-21. Alström syndrome (AS), caused solely by mutations in ALMS1, is another genetic obesity syndrome clinically similar to BBS. We previously conducted the first nationwide survey of BBS in Japan and found four patients with genetically definite BBS. In this study, exome analyses were performed on new patients whose symptoms fulfilled the diagnostic criteria for BBS. We identified one reported heterozygous mutation in BBS1 (p.R429*) in one patient, two novel mutations (p.L493R and p.H719Y) in BBS20 in a second patient, and one novel mutation (p.Q920*) and one reported mutation (p.R2928*) in ALMS1 in a third patient, who was subsequently diagnosed with AS. The first patient with BBS was previously considered to have digenic heterozygous mutations in BBS1 and BBS4. RT-PCR and long-range genomic PCR analyses identified a new heterozygous mutation in BBS1, the deletion of exons 10 and 11. Thus, this patient was compound heterozygous for mutations in BBS1. Many studies have described digenic heterozygous mutations in BBS. However, undetected mutations might have existed in either one of the mutated genes. | 01 = IsEpi
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Congenital microcoria (MCOR) is an eye anomaly characterized by a pupil with diameter below 2 mm, and is caused by underdevelopment or absence of the dilator muscle of the pupil. Two types have been described: a recessive, syndromic (Pierson syndrome OMIM 609049) and a dominant, isolated form (MCOR syndrome OMIM 156600). Fares-Taie and colleagues described inherited microdeletions in chromosome band 13q32.1 segregating with dominant microcoria in several families. The GPR180 gene is located within the smallest commonly deleted region and encodes a G protein-coupled receptor involved in smooth muscle cells growth. We here describe a patient with isolated, non-syndromic MCOR. The patient presented with a blue iris and small pupils, non-reactive to cycloplegic agents. Her mother had a milder ocular phenotype, namely a blue iris with hypoplastic crypts and mild myopia. We present a detailed clinical examination and follow up. DNA from the index patient was analyzed for the presence of chromosomal imbalances using molecular karyotyping. The genetic test revealed a small duplication of chromosome band 13q32.1. The duplication affected a 289 kb region, encompassing 11 genes including GPR180. Interestingly, the patient displays only MCOR in contrast to patients with the reciprocal deletion who present with MCOR and iridocorneal angle dysgenesis. This genetic anomaly was inherited from the mother who carries the duplication in mosaic form, which should be considered when offering genetic counselling. In summary, we describe the first 13q32.1 duplication encompassing GPR180 associated with MCOR. | 01 = IsEpi
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Bohring-Opitz syndrome (BOS) has been described as a clinically recognizable genetic syndrome since 1999. Clinical diagnostic criteria were established in 2011 and include microcephaly, trigonocephaly, distinctive craniofacial dysmorphic features, facial nevus flammeus, failure to thrive, and severe developmental delays. The same year, different de novo heterozygous nonsense mutations in the ASXL1 were found in affected individuals. Since then, several cases have been reported confirming the association between this chromatin remodeling gene and BOS. Most affected individuals die in early childhood because of unexplained bradycardia, obstructive apnea, or pulmonary infections. Those that survive usually cannot walk independently and are nonverbal. Some have had success using walkers and braces in late childhood. While few are able to speak, many have been able to express basic needs using communication devices as well as gestures with associated basic vocalizations. In this article, we present a mild case of BOS with a de novo pathogenic mutation c.1720-2A>G (p.I574VfsX22) in ASXL1 detected on whole-exome sequencing and confirmed by functional analysis of the messenger RNA splicing pattern on the patient's fibroblasts. She has typical dysmorphic features and is able to run and walk independently as well as to communicate with basic sign language. | 01 = IsEpi
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Mansonelliasis is a widespread yet neglected tropical infection of humans in Africa and South America caused by the filarial nematodes, Mansonella perstans, M. ozzardi, M. rodhaini and M. streptocerca. Clinical symptoms are non-distinct and diagnosis mainly relies on the detection of microfilariae in skin or blood. Species-specific DNA repeat sequences have been used as highly sensitive biomarkers for filarial nematodes. We have developed a bioinformatic pipeline to mine Illumina reads obtained from sequencing M. perstans and M. ozzardi genomic DNA for new repeat biomarker candidates which were used to develop loop-mediated isothermal amplification (LAMP) diagnostic tests. The M. perstans assay based on the Mp419 repeat has a limit of detection of 0.1 pg, equivalent of 1/1000th of a microfilaria, while the M. ozzardi assay based on the Mo2 repeat can detect as little as 0.01 pg. Both LAMP tests possess remarkable species-specificity as they did not amplify non-target DNAs from closely related filarial species, human or vectors. We show that both assays perform successfully on infected human samples. Additionally, we demonstrate the suitability of Mp419 to detect M. perstans infection in Culicoides midges. These new tools are field deployable and suitable for the surveillance of these understudied filarial infections. | 01 = IsEpi
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An 11-year-old girl with dystelephalangy (Kirner deformity) of the right middle, ring, and little, and the left index through little fingers is reported. To the author's best knowledge, such polytopic affection with dystelephalangy has not yet been reported. The parents, one of the siblings and maternal grandfather showed dystelephalangy of the little finger. So, the patient was considered to be a homozygous state of dystelephalangy gene. | 01 = IsEpi
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Ornithine transcarbamylase (OTC) deficiency is an X-linked recessive disorder that leads to hyperammonemia and liver damage. Hepatocellular adenoma in OTC deficiency patients has not been previously described. Here we report the first such case to be described in the English language scientific literature. | 01 = IsEpi
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Febrile ulceronecrotic Mucha-Habermann disease (FUMHD) is a rare severe variant of pityriasis lichenoides et varioliformis acuta characterized clinically by aggressive ulceronecrotic skin lesions associated with high fever and histologically by features typical of pityriasis lichenoides et varioliformis acuta. Despite the continuous addition of new case reports, no definite diagnostic criteria have been established, and an optimum treatment is still waiting. Herein, we review the different aspects of this rare entity, including pathogenesis, clinical and histopathological features, differential diagnosis, course, prognosis, and outcome. Different diagnostic and therapeutic challenges associated with FUMHD are also evaluated and discussed. We propose two sets of diagnostic criteria to define the disease more precisely and to avoid missing cases. The first comprises constant clinical and histopathological features that are always present in every case, the combination of which is necessary for diagnosis. The second set includes variable features that may be present in some cases and to which any emerging finding could be added. Although different therapeutic options have been used, there is no optimum therapy for FUMHD, and the disease still represents a therapeutic challenge. | 01 = IsEpi
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Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder characterized by impaired sexual development and infertility, caused by the deficiency of hypothalamic gonadotropin-releasing hormone neurons. IHH is named Kallmann's syndrome (KS) or normosmic IHH (nIHH) when associated with a defective or normal sense of smell. Variants in SEMA3A have been recently identified in patients with KS. In this study, we screened SEMA3A variants in a cohort of Chinese patients with IHH by whole exome sequencing. Three novel heterozygous SEMA3A variants (R197Q, R617Q and V458I) were identified in two nIHH and one KS patients, respectively. Functional studies indicated that R197Q and R617Q variants were ineffective in activating the phosphorylation of FAK (focal adhesion kinase) in GN11 cells, despite normal production and secretion in HEK293T cells. The V458I SEMA3A had defect in secretion as it was not detected in the conditioned medium from HEK293T cells. Compared with wild type SEMA3A protein, all three SEMA3A mutant proteins were ineffective in inducing the migration of GN11 cells. Our study further showed the contribution of SEMA3A loss-of-function variants to the pathogenesis of IHH. | 01 = IsEpi
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We report two Hong Kong children with severe generalized epidermolysis bullosa simplex (EBS), the most severe form of EBS, without a family history of EBS. EBS is a rare genodermatosis usually inherited in an autosomal dominant fashion although rare autosomal recessive cases have been reported. Genetic studies in these patients showed that the first case was due to a novel de novo heterozygous variant, c.377T>G (NM_000526.5 (c.377T>G, p.Leu126Arg)) in the KRT14 gene and the second case was due to a rare de novo heterozygous variant c.527A>G (NM_000424.4, c.527A>G, p.Asn176Ser) in the KRT5 gene. To our knowledge, the c.377T>G variant in the KRT14 gene has not been previously reported, and the c.527A>G variant in the KRT5 gene is a rare cause of severe generalized EBS. In severe generalized EBS, infants exhibit severe symptoms at the onset; however, they tend to improve with time. A precise genetic diagnosis in these two cases aided in counseling the families concerning the prognosis in their affected children and the recurrence risk for future pregnancies. | 01 = IsEpi
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Diagnosis and treatment of laryngeal clefts (LCs) particularly type I pose a challenge. Although rare, type I LCs are becoming increasingly identified in recent years, and this is perhaps due to both an increased awareness and better diagnostic modalities. We report a young infant presenting with feeding difficulty and respiratory distress related to LC. The pertinent literature is also reviewed. | 01 = IsEpi
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Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease across all age groups. Obesity, diabetes, and metabolic syndrome, are the primary causes that are closely linked with the development of NAFLD. However, in young children, rare inborn errors of metabolism are predominant secondary causes of NAFLD. Furthermore, inborn errors of metabolism causing hepatosteatosis are often misdiagnosed as NAFLD in adolescents and adults. Many inborn errors of metabolism are treatable disorders and therefore require special consideration. This review aims to summarize the basic characteristics and diagnostic clues of inborn errors of metabolism associated with fatty liver disease. A suggested clinical and laboratory diagnostic approach is also discussed. | 01 = IsEpi
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INTRODUCTION:Chromosome 18q deletion syndrome (18q-) is a rare chromosomal disorder with phenotypic variability, including mental deficiency, short stature, hypotonia, cleft palate, and hearing impairment. We present a case with features of 18q- syndrome who had combined 18q partial monosomy and 18p partial trisomy. MATERIAL AND METHODS:A 50-year-old female patient was examined during the genetic counseling of her brother. She had a history of congenital cleft palate and developmental deficiency with hypotonia, hearing loss, and epilepsy until adulthood. Her family history was free of related cases. Karyotype analysis and comparative genomic hybridization array (aCGH) were performed in patient's blood samples. RESULTS:Clinical examination showed features of 18q- syndrome including hypotonia and tremor. Neuropsychological deficiency of moderate cognitive disorder was noticed. The patient's karyotype was normal. The aCGH analysis revealed 8 Mb deletion (del18q22.3q23) and 7.2 Mb duplication (dup18p11.32p11.23). CONCLUSION:Almost all patients' clinical features were associated with 18q- syndrome. There are very few reported cases with similar genotype possibly caused by a de novo unequal recombination mechanism. | 01 = IsEpi
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We have reviewed all known UK cases of Smith-Lemli-Opitz syndrome. Among 49 cases with proven 7-dehydrocholesterol reductase deficiency, half had been terminated or had died in infancy. The minimum incidence is 1 in 60,000. The frequent occurrence of hypospadias may account for 71% of recognised cases being male. Important common features which emerged include short thumbs, severe photosensitivity, aggressive behaviour, and atrioventricular septal defect. The typical facial appearance becomes less obvious with age and 20% of cases did not have 2/3 toe syndactyly. Biochemical measurements of serum 7-dehydrocholesterol did not correlate with clinical severity. | 10 = IsNotEpi
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BACKGROUND:The European Reference Networks, ERNs, are virtual networks for healthcare providers across Europe to collaborate and share expertise on complex or rare diseases and conditions. As part of the ERNs, the Clinical Patient Management System, CPMS, a secure digital platform, was developed to allow and facilitate web-based, clinical consultations between submitting clinicians and relevant international experts. The European Reference Network on Intellectual Disability, TeleHealth and Congenital Anomalies, ERN ITHACA, was formed to harness the clinical and diagnostic expertise in the sector of rare, multiple anomaly and/or intellectual disability syndromes, chromosome disorders and undiagnosed syndromic disorders. We present the first year results of CPMS use by ERN ITHACA as an example of a telemedicine strategy for the diagnosis and management of patients with rare developmental disorders. RESULTS:ERN ITHACA ranked third in telemedicine activity amongst 24 European networks after 12 months of using the CPMS. Information about 28 very rare cases from 13 different centres across 7 countries was shared on the platform, with diagnostic or other management queries. Early interaction with patient support groups identified data protection as of primary importance in adopting digital platforms for patient diagnosis and care. The first launch of the CPMS was built to accommodate the needs of all ERNs. The ERN ITHACA telemedicine process highlighted a need to customise the CPMS with network-specific requirements. The results of this effort should enhance the CPMS utility for telemedicine services and ERN-specific care outcomes. CONCLUSIONS:We present the results of a long and fruitful process of interaction between the ERN ITHACA network lead team and EU officials, software developers and members of 38 EU clinical genetics centres to organise and coordinate direct e-healthcare through a secure, digital platform. The variability of the queries in just the first 28 cases submitted to the ERN ITHACA CPMS is a fair representation of the complexity and rarity of the patients referred, but also proof of the sophisticated and variable service that could be provided through a structured telemedicine approach for patients and families with rare developmental disorders. Web-based approaches are likely to result in increased accessibility to clinical genomic services. | 01 = IsEpi
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Haemoglobin C (HbC) is one of the commonest structural haemoglobin variants in human populations. Although HbC causes mild clinical complications, its diagnosis and genetic counselling are important to prevent inheritance with other haemoglobinopathies. Little is known about its contemporary distribution and the number of newborns affected. We assembled a global database of population surveys. We then used a Bayesian geostatistical model to create maps of HbC frequency across Africa and paired our predictions with high-resolution demographics to calculate heterozygous (AC) and homozygous (CC) newborn estimates and their associated uncertainty. Data were too sparse outside Africa for this methodology to be applied. The highest frequencies were found in West Africa but HbC was commonly found in other parts of the continent. The expected annual numbers of AC and CC newborns in Africa were 672,117 (interquartile range (IQR): 642,116-705,163) and 28,703 (IQR: 26,027-31,958), respectively. These numbers are about two times previous estimates. | 10 = IsNotEpi
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Angiokeratomas are variable sized hyperkeratotic vascular papules that are characterized histologically by superficial dilated capillaries in papillary dermis with epidermal proliferation. They can occur as a single lesion to a generalized form (angiokeratoma corporis diffusum). Angiokeratoma corporis diffusum though initially synonymous with Anderson Fabry disease, is now known to occur in a variety of lysosomal enzyme deficiencies. We report a case of 22 year old male with angiokeratoma corporis diffusum associated with acroparesthesias, febrile episodes, sensorineural hearing loss and renal involvement. Histopathological evaluation showed characteristic ectatic blood vessels with vacuolated endothelial cells in papillary dermis. Based on the clinical evaluation and available investigations, we suspected him to be having to Anderson fabry disease. Resource constraints limited our ability to confirm our diagnosis with enzyme assay and electron microscopy. We report this unusual case in desire of re emphasizing the importance of clinical evaluation for reaching a diagnosis in a resource poor setting. | 01 = IsEpi
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PURPOSE:Ocular cicatricial pemphigoid (OCP) is a rare systemic autoimmune disease and a potentially blinding subepithelial blistering disorder. The purpose of this study was to describe the clinical spectrum of the disease and to assess the efficacy and safety of immunosuppressive agents in a cohort of patients with OCP. METHODS:We conducted a monocentric retrospective cross-sectional cohort study of all unselected consecutive patients diagnosed with progressive OCP. Ocular and extra ophthalmological involvement as well as histological findings were gathered. Other outcomes were exposures to immunosuppressive agents defined by the use of a particular treatment. For each exposure, success in controlling ocular inflammation was graded as a complete response, response, or failure. Relapses and adverse events (AE) were also recorded. RESULTS:Seventeen patients (34 affected eyes), 35% of whom were women, were included, with an age at diagnosis of 75 ± 11 years. Corneal involvement was diagnosed in 30 of 34 eyes, and 22 of 34 eyes had progressive fibrosing conjunctival involvement. Sixty-two exposures to immunosuppressive agents or biologics were recorded: dapsone, n = 26; mycophenolate mofetil, n = 6; azathioprine, n = 4; cyclophosphamide, n = 10; rituximab, n = 14; and intravenous immunoglobulin, n = 2. Rates of response and of complete response achievement during the first 3 months were 84% and 45%, respectively. Response rates were 100%, 100%, 86%, 85%, and 80% for intravenous immunoglobulin, mycophenolate mofetil, rituximab, dapsone, and cyclophosphamide, respectively. Thirteen percent of those drugs were discontinued because of an adverse event in 4 patients. CONCLUSIONS:This study describes the efficacy of immunosuppressants or biologics with an acceptable safety profile for OCP. | 01 = IsEpi
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Childhood obesity is a modern worldwide epidemic with significant burden for health. It is a chronic metabolic disorder associated with multiple cardiovascular risk factors such as dyslipidemia, hypertension, stroke, and insulin resistance. Many obese adolescents remain obese into adulthood, with increased morbidity and mortality. As childhood obesity is a risk factor for adult obesity, the childhood obesity-related disorders account for an increased risk of cardiovascular consequences in adults, in addition to the effects already exerted by the fat mass in adulthood. Several papers have already described the cardiovascular implications of idiopathic obesity, while few data are available about syndromic obesity, due to the small sample size, not homogeneous phenotypes, and younger age at death. The aim of this mini-review is to give a comprehensive overview on knowledge about cardiovascular implications of idiopathic and syndromic obesity to allow the reader a quick comparison between them. The similarities and differences will be highlighted. | 01 = IsEpi
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BACKGROUND:Cutis marmorata telangiectatica congenita (CMTC) is a rare capillary malformation characterised by persistent reticulated marbled erythema. It tends to be associated with cutaneous atrophy, ulcerations and body asymmetry. CMTC is usually reported to be a benign condition; however, associated anomalies are not rare. Here, we have compiled information on published CMTC patients with the aim to evaluate the proposed diagnostic criteria by Kienast et al. and address the clinical manifestations, associated anomalies, differential diagnoses, management and prognosis. Our review is based on a search of the PubMed database which retrieved studies between 1922 and April 2019. The search yielded 148 original articles with a total of 485 patients. RESULTS:Of the identified patients, 24.5% had generalised CMTC, 66.8% had localised and 8.7% had a non-specified distribution of CMTC. Associated anomalies were observed in 42.5% of patients, predominantly body asymmetry and neurological defects like seizure and developmental delay. Fewer patients (10.1%) had ophthalmological defects, usually glaucoma. The major criterium "absence of venectasia" was not met in 20.4% of patients. CONCLUSION:We suggest that children with CMTC should be referred to an ophthalmologist for regular follow-up, and children with CMTC affecting the legs should be monitored for leg length discrepancy throughout the growth period. Furthermore, we suggest reconsideration of the major criterium "absence of venectasia" from the proposed diagnostic criteria, and instead include body asymmetry. | 01 = IsEpi
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BACKGROUND:Hypoxia delays brain maturation and contributes to neurodevelopmental morbidity in fetuses with congenital heart defects (CHDs). Maternal hyperoxygenation (MH) can, in theory, promote oxygen/nutrient delivery to the fetal brain, owing to an improved heart structure/function and increased fetal oxygen content. We aimed to determine whether MH alters fetal cerebral hemodynamics in fetuses with CHD. METHODS:Twenty-eight fetuses with borderline small left hearts and 28 age-matched normal fetuses were enrolled and subdivided by gestational age (GA): 23+ 0 ~ 27+ 6 weeks and 28+ 0 ~ 36+ 6 weeks. The middle cerebral artery pulsatility index (MCA-PI), vascular index (VI), flow index (FI) and vascular/flow index (VFI) were measured with baseline room air, after 10 min of MH and after 10 min of recovery for all subjects. RESULTS:MCA-PI, VI, FI and VFI did not differ with MH in the normal fetuses. In fetuses with borderline small left hearts, MCA-PI increased and VI, FI and VFI significantly decreased during the 3rd trimester (from 1.44 ± 0.27, 3.19 ± 0.87, 56.91 ± 9.19, and 1.30 ± 0.33 at baseline to 1.62 ± 0.15, 2.37 ± 0.37, 45.73 ± 4.59, and 0.94 ± 0.15 during MH, respectively, P < 0.05), but this response was not apparent during mid-gestation (p > 0.05). These parameters returned to the baseline levels during the recovery phase. The change in cerebral perfusion depended on the baseline MCA-PI and increased the combined cardiac index (CCOi). CONCLUSIONS:MH alters the cerebral hemodynamics of fetuses with borderline small left hearts during the third trimester. Further investigation is needed to determine whether MH may benefit brain growth and neurodevelopment in this high-risk population. | 01 = IsEpi
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Glycogen storage disease type XV (GSD XV) is a recently described muscle glycogenosis due to glycogenin-1 (GYG1) deficiency characterized by the presence of polyglucosan bodies on muscle biopsy (Polyglucosan body myopathy-2, PGBM2). Here we describe a 44 year-old man with limb-girdle muscle weakness mimicking a limb-girdle muscular dystrophy (LGMD), and early onset exertional myalgia. Neurologic examination revealed a waddling gait with hyperlordosis, bilateral asymmetric scapular winging, mild asymmetric deltoid and biceps brachii weakness, and pelvic-girdle weakness involving the gluteal muscles and, to a lesser extent, the quadriceps. Serum creatine kinase levels were slightly elevated. Electrophysiological examination showed a myopathic pattern. There was no cardiac or respiratory involvement. Whole-body muscle MRI revealed atrophy and fat replacement of the tongue, biceps brachii, pelvic girdle and erector spinae. A deltoid muscle biopsy showed the presence of PAS-positive inclusions that remained non-digested with alpha-amylase treatment. Electron microscopy studies confirmed the presence of polyglucosan bodies. A diagnostic gene panel designed by the Genetic Diagnosis Laboratory of Strasbourg University Hospital (France) for 210 muscular disorders genes disclosed two heterozygous, pathogenic GYG1 gene mutations (c.304G>C;p.(Asp102His) + c.164_165del). Considering the clinical heterogeneity found in the previously described 38 GYG-1 deficient patients, we suggest that GYG1 should be systematically included in targeted NGS gene panels for LGMDs, distal myopathies, and metabolic myopathies. | 01 = IsEpi
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Fabry disease is caused by deficient activity of α-galactosidase A and subsequent accumulation of glycosphingolipids (mainly globotriaosylceramide, Gb3), leading to multisystem organ dysfunction. Oxidative stress and nitric oxide synthase (NOS) uncoupling are thought to contribute to Fabry cardiovascular diseases. We hypothesized that decreased tetrahydrobiopterin (BH4) plays a role in the pathogenesis of Fabry disease. We found that BH4 was decreased in the heart and kidney but not in the liver and aorta of Fabry mice. BH4 was also decreased in the plasma of female Fabry patients, which was not corrected by enzyme replacement therapy (ERT). Gb3 levels were inversely correlated with BH4 levels in animal tissues and cultured patient cells. To investigate the role of BH4 deficiency in disease phenotypes, 12-month-old Fabry mice were treated with gene transfer-mediated ERT or substrate reduction therapy (SRT) for 6 months. In the Fabry mice receiving SRT but not ERT, BH4 deficiency was restored, concomitant with ameliorated cardiac and renal hypertrophy. Additionally, glutathione levels were decreased in Fabry mouse tissues in a sex-dependent manner. Renal BH4 levels were closely correlated with glutathione levels and inversely correlated with cardiac and kidney weight. In conclusion, this study showed that BH4 deficiency occurs in Fabry disease and may contribute to the pathogenesis of the disease through oxidative stress associated with a reduced antioxidant capacity of cells and NOS uncoupling. This study also suggested dissimilar efficacy of ERT and SRT in correcting pre-existing pathologies in Fabry disease. | 01 = IsEpi
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The review of over 800 references on aluminum (Al) published since the mid-fifties covers the occurrence of Al in soil, air, water, plants and food products, as well as air and water pollution problems. In addition, the existing quality criteria, the biology and toxicology of Al, and the therapeutic and medical uses are presented. It is concluded that absorption and retention or accumulation of Al in humans occurs at lower levels of intake than had been assumed formerly. However, levels of 5 to 50 times the normal daily intake do not appear to interfere with other metabolic processes. The adverse effects of Al reported in the more recent years resulted from the inhalation or ingestion of Al in concentrations many times greater than the amounts present under normal circumstances. As in the past, there is still no need for concern by the public or producers of Al or its products concerning hazards to human health derived from well established and extensively used products. | 01 = IsEpi
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BACKGROUND:Juvenile idiopathic arthritis (JIA) has been categorized into seven different categories according to the International League of Associations for Rheumatology (ILAR) criteria. Enthesitis-related arthritis (ERA) was found to represent the largest category in a Taiwanese cohort study. The aim in this study was to compare the clinical characteristics, treatments, and outcomes of ERA in a single tertiary center in Taiwan, as compared to those of other categories of JIA. Furthermore, we determined patients' characteristics and risk factors that can help assess the outcomes in ERA. METHODS:A retrospective chart review of all patients with JIA referred to a pediatric rheumatology clinic in the National Taiwan University Hospital between 1993 and 2018 were identified according to ILAR criteria. Outcomes were assessed based on the Wallace criteria to categorize patients into active and non-active, including inactive, remission on medication, and remission off medication, groups. A subset of samples was further tested by DNA sequencing to identify HLA-B27 subtypes. RESULTS:One-hundred and eighty-three patients were included in the study, with a mean of 8 years' follow-up. ERA was the single largest category of JIA (39.9%); psoriasis and undifferentiated JIA were both the least common type (0.5%). ERA was male predominant (86%), had a late age of onset (11.0 ± 3.2 years), and the majority of ERA patients was HLA-B27-positive (97%). Of 25 HLA-B27-positive ERA patients checked by HLA-B27 sequencing, 23 were B*27:04 and 2 were B*27:05. ERA patients were significantly less likely to achieve non-active status compared to patients with persistent oligoarthritis (P = 0.036). In terms of treatment response to TNF-α inhibitors in methotrexate-refractory ERA, 26 patients remained active and only 11 patients (30%) achieved a non-active status. Sacroiliitis was a risk factor contributing to poorer treatment response in ERA (P = 0.006). CONCLUSION:ERA represented the most common category of JIA in Taiwan. Those ERA patients with sacroiliitis were likely to have persistent active disease and may require a more aggressive treatment strategy to improve their outcomes. | 01 = IsEpi
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In 1993, Jabs et al. were the first to describe a genetic origin of craniosynostosis. Since this discovery, the genetic causes of the most common syndromes have been described. In 2015, a total of 57 human genes were reported for which there had been evidence that mutations were causally related to craniosynostosis. Facilitated by rapid technological developments, many others have been identified since then. Reviewing the literature, we characterize the most common craniosynostosis syndromes followed by a description of the novel causes that were identified between January 2015 and December 2017. | 01 = IsEpi
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Objective: Dental anomalies occurring in deciduous teeth can affect the eruption of the permanent dentition and the occlusion stability. The occurrence of dental anomalies such as double teeth during the primary dentition in the daily practice might be frequent. The study aimed to qualitatively summarize the therapeutic management of double teeth in primary incisors.Material and Methods: A systematic review regarding the therapy of primary fused incisors in the mandible was performed and the obtained data were assessed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The following electronic databases were screened from 1st January, 1996 until 30th July, 2019: PubMed, Scopus, EBSCO and the archives of paediatric dental journals. The search terms were grouped in anatomic entity: (tooth OR teeth OR incisor), pathological condition: (fused OR fusion OR geminated OR double), intervention: (treatment OR intervention OR therapy OR prevention OR control OR management OR restoration), observed parameters: (primary dentition OR primary tooth OR primary teeth).Results: Ten articles met all inclusion criteria. The data disclosed the occurrence of double teeth in mandibular incisors. The main management of this clinical condition is either preventive or surgical involving the extraction of fused teeth, based on the deciduous nature of the teeth, the degree of caries and malocclusion development risk.Conclusion: An early diagnosis of dental anomalies is fundamental for the application of proper preventive strategies to avoid a potential malocclusion in permanent dentition and to maintain these teeth sound and caries-free until the eruption of the permanent dentition. | 01 = IsEpi
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CONTEXT:Congenital pituitary hormone deficiencies with syndromic phenotypes and/or familial occurrence suggest genetic hypopituitarism; however, in many such patients the underlying molecular basis of the disease remains unknown. OBJECTIVE:To describe patients with syndromic hypopituitarism due to biallelic loss-of-function variants in TBC1D32, a gene implicated in Sonic Hedgehog (Shh) signaling. SETTING:Referral center. PATIENTS:A Finnish family of 2 siblings with panhypopituitarism, absent anterior pituitary, and mild craniofacial dysmorphism, and a Pakistani family with a proband with growth hormone deficiency, anterior pituitary hypoplasia, and developmental delay. INTERVENTIONS:The patients were investigated by whole genome sequencing. Expression profiling of TBC1D32 in human fetal brain was performed through in situ hybridization. Stable and dynamic protein-protein interaction partners of TBC1D32 were investigated in HEK cells followed by mass spectrometry analyses. MAIN OUTCOME MEASURES:Genetic and phenotypic features of patients with biallelic loss-of-function mutations in TBC1D32. RESULTS:The Finnish patients harboured compound heterozygous loss-of-function variants (c.1165_1166dup p.(Gln390Phefs*32) and c.2151del p.(Lys717Asnfs*29)) in TBC1D32; the Pakistani proband carried a known pathogenic homozygous TBC1D32 splice-site variant c.1372 + 1G > A p.(Arg411_Gly458del), as did a fetus with a cleft lip and partial intestinal malrotation from a terminated pregnancy within the same pedigree. TBC1D32 was expressed in the developing hypothalamus, Rathke's pouch, and areas of the hindbrain. TBC1D32 interacted with proteins implicated in cilium assembly, Shh signaling, and brain development. CONCLUSIONS:Biallelic TBC1D32 variants underlie syndromic hypopituitarism, and the underlying mechanism may be via disrupted Shh signaling. | 01 = IsEpi
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Aim:To report a case of radiation-induced brachial plexopathy (RIBP) with significant radiographic and clinical improvement after a course of hyperbaric oxygen (HBO). Background:RIBP is a rare complication after radiotherapy to the neck and axilla. There are no standard treatment options, with empirical use pharmacotherapy being predominately used, which has had mixed results.HBO is efficacious for the treatment of other severe radiation-induced side effects, however, its benefit in RIBP has conflicting reports. Case Presentation:A 45-year-old male, with a 33 pack-year smoking history, presented with a 6-month history of a progressive left neck mass. The final diagnosis was unknown primary squamous cell carcinoma of the head and neck. He received intensity-modulated radiation therapy (IMRT) with 70 Gy prescribed to the gross tumor volume (PTV HR) and 56 Gy to the oropharynx, nasopharynx, and bilateral lymphatics (PTV SR) in 35 daily fractions with three cycles of concurrent cisplatin at 100 mg/m2.Fifteen months following therapy completion, the patient began to endorse symptoms of left brachial plexopathy. Decadron was prescribed for 2 weeks, trental and vitamin E for 6 months, and HBO. The patient returned for follow-up 2 months after completing 30 dives of HBO at 2.4 atmospheres for 2 hours per session. He reported pain resolution and full range of motion of his left arm. Conclusions:The best management strategy of RIBP is prevention by reducing total RT doses and close follow-up. However, when RIBP occurs, we recommend treatment with HBO therapy, steroids, trental, and vitamin E as tolerable. | 01 = IsEpi
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Intellectual disability (ID) is a neurodevelopmental condition affecting 1-3% of the world's population. Genetic factors play a key role causing the congenital limitations in intellectual functioning and adaptive behavior. The heterogeneity of ID makes it more challenging for genetic and clinical diagnosis, but the advent of large-scale genome sequencing projects in a trio approach has proven very effective. However, many variants are still difficult to interpret. A combined approach of next-generation sequencing and functional, electrophysiological, and bioinformatics analysis has identified new ways to understand the causes of ID and help to interpret novel ID-causing genes. This approach offers new targets for ID therapy and increases the efficiency of ID diagnosis. The most recent functional advancements and new gene editing techniques involving the use of CRISPR-Cas9 allow for targeted editing of DNA in in vitro and more effective mammalian and human tissue-derived disease models. The expansion of genomic analysis of ID patients in diverse and ancient populations can reveal rare novel disease-causing genes. | 01 = IsEpi
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Wegener's granulomatosis (WG) is a systemic vasculitis of unknown etiology. The UK General Practice Research Database (GPRD) contains the complete primary care records of approximately 3.6 million people. There are no data on the incidence and prevalence of WG from primary care. The aim of the study was to estimate the incidence and prevalence of WG in the GPRD population.We identified all patients who had a first diagnosis of WG during 1990-2005, using Oxford Information System and Read codes. The diagnosis was verified by review of a randomly selected sample of 35 records that had identifying data removed. The annual incidence was calculated as the number of incident cases divided by the total person-years.A total of 295 patients (51.2% male) with a first diagnosis of WG were identified during 1990-2005. The median age was 59 years (interquartile range 47-70 years). The overall annual incidence of WG was 8.4 per million (95% confidence interval [95% CI] 7.5-9.4). The annual rate in women and men was 8.1 per million (95% CI 6.8-9.6), and 8.8 per million (95% CI 7.4-10.3), respectively. The incidence was stable throughout the study period. There was an increase in the annual prevalence from 28.8 per million in 1990 to 64.8 per million in 2005. The diagnosis was verified in 28 of 31 available case records.This is the first study of the incidence and prevalence of WG in a database from a primary care population. The results are similar to previous studies from secondary and tertiary care and suggest that these studies are representative of the general population. The increasing prevalence with a constant incidence suggests that survival is improving with modern treatment protocols. | 10 = IsNotEpi
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Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition, clinically characterized by boiled cysts, comedones, abscesses, hypertrophic scars, and/or sinus tracts typically in the apocrine-gland-rich areas such as the axillae, groin, and/or buttocks. Although its precise pathogenic mechanisms remain unknown, I herein emphasize the importance of the following three recent discoveries in the pathogenesis of HS: First, heterozygous loss-of-function mutations in the genes encoding γ-secretase, including NCSTN, PSENEN, and PSEN1, have been identified in some patients with HS. Such genetic alterations result in hyperkeratosis, dysregulated hair follicle differentiation, and cyst formation via aberrant Notch signaling. Furthermore, Psen1-/Psen2-, Psen1-, Ncstn+/-, and Notch1-/Notch2- mice share common phenotypes of human HS, suggesting a role of aberrant keratinization in the development of HS. Second, upregulation of interleukin 1β, interleukin-36, caspase-1, and NLRP3 and dysregulation of the Th17:Treg cell axis have been demonstrated in HS samples, suggesting that autoinflammation is a key event in the pathophysiology of the disease. Notably, HS may be complicated with other autoinflammatory diseases such as inflammatory bowel diseases and pyoderma gangrenosum, again highlighting the importance of autoinflammation in HS. Last, biologics such as adalimumab, infliximab, anakinra, ustekinumab, and secukinumab are reportedly effective for moderate-to-severe HS. These findings collectively suggest that HS is closely linked with aberrant keratinization and autoinflammation, raising the question whether it represents an autoinflammatory keratinization disease, a recently proposed disease entity. In this mini review, I introduce the concept of autoinflammatory keratinization disease and attempt to address this clinically important question. | 01 = IsEpi
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BACKGROUND AND OBJECTIVES:Non-healing corneal ulcers (NHCU) are a common problem in equine practice and several treatment options are available with different success and healing times. The aim of this retrospective study was to evaluate and to compare treatment protocols, clinical courses, corneal healing time and outcomes of NHCU. METHODS:From December 2001 to December 2017, a total of 57 horses with NHCU were presented at the Vetmeduni Vienna. Recorded data included affected eye, signalment, clinical symptoms, season of diagnosis, treatment protocols, complications and corneal healing rate. RESULTS:Sixty-three eyes were diagnosed with a NHCU. Follow-up information was available for 48/63 eyes. For those treated medically mean corneal healing time was 15.7 days (± SD 12.0). Medical treatment included topical antibiotics, antimycotics, cycloplegics, and systemic anti-inflammatory drugs. Twelve eyes received treatment with a poly-carboxymethylglucose-sulfate regenerating agent (Cacicol®; Thea Pharma GmbH, Wien, Austria). Other common additional treatments included debridement with an iodine drenched cotton tip (48 eyes; 76.2 %) and diamond burr debridement (30 eyes; 47.6 %). A bandage contact lens (BCL) was used for 10 eyes. Each eye received at least one additional treatment, although none of them led to a statistically significant alteration in healing time. Only usage of a BCL significantly increased healing time when compared to not using a BCL (p = 0.035). When all treatments failed, superficial keratectomy with placement of a conjunctival flap was performed. Secondary complications included stromal cellular infiltration, keratomycosis, keratomalacia, and corneal abscess formation. CONCLUSIONS:Results correlated with those previously described and thus demonstrated the difficulty and complexity of this disease. Further research is needed to determine an optimal treatment protocol for non-healing ulcers in horses. CLINICAL RELEVANCE:Since NHCUs are a commonly encountered problem in equine practice a reliable treatment protocol is required. This study reflects the problems with those ulcers and provides several protocols for possible treatments. | 01 = IsEpi
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PURPOSE:To review the current state of diagnosis and management of retinal hemangioblastoma and retinal vascular proliferation arising from von Hippel-Lindau (VHL) disease. METHODS:A review of the literature was performed. Consensus was reached among authors regarding current practice, with reference to published data where possible. RESULTS:von Hippel-Lindau disease and its ocular manifestations are relatively rare, and there is limited evidence in the literature on which to base management. There was consensus on core principles, including 1) recognition and diagnosis of von Hippel-Lindau disease when present, with appropriate referral for care of this potentially lethal systemic condition; 2) regular ophthalmic evaluation for individuals with von Hippel-Lindau disease, to identify and offer timely treatment for new or active retinal hemangioblastomas; 3) ablative treatment of retinal hemangioblastomas that can be safely destroyed, to lower risk of vision loss; 4) observation or consideration of nonablative treatments for retinal hemangioblastomas that cannot be safely destroyed; and 5) observation of asymptomatic retinal vascular proliferation, with consideration of vitrectomy for lesions exerting effects on vision. CONCLUSION:Ocular outcomes can be gratifying in many cases with appropriate management. Improved understanding of the molecular basis for the disease creates an opportunity for rational design of better therapies. | 01 = IsEpi
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Purpose:To report a case of peripheral elevated lesions mimicking retinal detachment which were ultimately ascertained to be giant pars plana cysts through ophthalmoscopy with scleral depression. Methods:This was a case report documented with ophthalmoscopy and Optos imaging. Results:Patient initially referred for assessment of bilateral retinal detachment was found by careful ophthalmoscopy with scleral depression to have bilateral giant pars plana cysts with no frank retinal breaks. Conclusion:Large pars plana cysts may mimic retinal detachment or other peripheral retinal pathology. The lesions in question were found to originate from the pars plana and overhang the retina. No frank retinal breaks or associated rhegmatogenous retinal detachments were noted in either eye. Ophthalmoscopy with a complete scleral depressed exam allowed for the differentiation. | 01 = IsEpi
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Hereditary spastic paraplegia (HSP) is a group of rare neurodegenerative disorder with genetic and clinical heterogeneity. It has autosomal dominant (AD), autosomal recessive (AR) and X-linked forms. HSPs are clinically classified into 'pure' and 'complicated' (complex) forms. SPG11 (KIAA1840) and SPG15 (ZFYVE26) are the most common ARHSPs with thin corpus callosum (TCC). They typically present with early cognitive impairment in childhood followed by gait impairment and spasticity in the second and third decades of life. Here, we present a patient girl, born to a couple who were first cousins, was admitted to the pediatric neurology outpatient clinic at 14 years of age because of walking with help, dysarthria and forgetfulness. Her examination revealed a motor mental retardation, bilateral leg spasticity, increased deep tendon reflexes in lower limbs, bilateral pigmentary retinopathy; TCC and white matter hyperintensities on brain MRI, sensorimotor axonal polyneuropathy findings in lower limbs on electromyography. Based on the clinical features and the imaging studies, the diagnosis of HSP was suspected. Targeted next generation sequencing (NGS) was performed using Inherited NGS Panel that consists of 579 gene associated with Mendelian disorders. Analysis of the patient revealed a c.6398_6401delGGGA(p.Arg2133Asnfs*15)(Exon35) homozygous novel change in ZFYVE26 gene. Genotype-phenotype correlation of HSP is complicated due to heterogeneity. The clinical similarity of HSP types increases the importance of genetic diagnosis. There are few reports about pathogenic variants in ZFYVE26 gene in the literature. This case report is one of the few studies that revealed a novel pathogenic variant in ZFYVE26 gene using NGS. | 01 = IsEpi
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Many human genetic disorders result from unbalanced chromosome abnormalities, in which there is a net gain or loss of genetic material. Such imbalances often disrupt large numbers of dosage-sensitive, developmentally important genes and result in specific and complex phenotypes. Alternately, some chromosomal syndromes may be caused by a deletion or duplication of a single gene with pleiotropic effects. Traditionally, chromosome abnormalities were identified by visual inspection of the chromosomes under a microscope. The use of molecular cytogenetic technologies, such as fluorescence in situ hybridization and microarrays, has allowed for the identification of cryptic or submicroscopic imbalances, which are not visible under the light microscope. Microarrays have allowed for the identification of numerous new syndromes through a genotype-first approach in which patients with the same or overlapping genomic alterations are identified and then the phenotypes are described. Because many chromosomal alterations are large and encompass numerous genes, the ascertainment of individuals with overlapping deletions and varying clinical features may allow researchers to narrow the region in which to search for candidate genes. | 01 = IsEpi
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A 4-year-old male Toy Poodle was presented with a history of status epilepticus. On presentation, neurological examination revealed a delay in postural reactions in the right pelvic limb. Magnetic resonance imaging showed a fluid-containing cystic lesion that compressed the mesencephalon, hippocampus, and amygdala. The cyst was surgically removed via left rostrotentorial craniotomy. The final diagnosis was an intracranial ectopic choroid plexus cyst. The patient has remained free of seizures for 18 months after surgery. This is the first case report of an intracranial ectopic choroid plexus cyst that was surgically removed in a dog. | 01 = IsEpi
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BACKGROUND:The lymph node (Ln) status of patients with resectable pancreatic ductal adenocarcinoma is an important predictor of survival. The survival benefit of extended lymphadenectomy during pancreatectomy is, however, disputed, and there is no true definition of the optimal extent of the lymphadenectomy. The aim of this study was to formulate a definition for standard lymphadenectomy during pancreatectomy. METHODS:During a consensus meeting of the International Study Group on Pancreatic Surgery, pancreatic surgeons formulated a consensus statement based on available literature and their experience. RESULTS:The nomenclature of the Japanese Pancreas Society was accepted by all participants. Extended lymphadenectomy during pancreatoduodenectomy with resection of Ln's along the left side of the superior mesenteric artery (SMA) and around the celiac trunk, splenic artery, or left gastric artery showed no survival benefit compared with a standard lymphadenectomy. No level I evidence was available on prognostic impact of positive para-aortic Ln's. Consensus was reached on selectively removing suspected Ln's outside the resection area for frozen section. No consensus was reached on continuing or terminating resection in cases where these nodes were positive. CONCLUSION:Extended lymphadenectomy cannot be recommended. Standard lymphadenectomy for pancreatoduodenectomy should strive to resect Ln stations no. 5, 6, 8a, 12b1, 12b2, 12c, 13a, 13b, 14a, 14b, 17a, and 17b. For cancers of the body and tail of the pancreas, removal of stations 10, 11, and 18 is standard. Furthermore, lymphadenectomy is important for adequate nodal staging. Both pancreatic resection in relatively fit patients or nonresectional palliative treatment were accepted as acceptable treatment in cases of positive Ln's outside the resection plane. This consensus statement could serve as a guide for surgeons and researchers in future directives and new clinical studies. | 01 = IsEpi
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X-linked Charcot-Marie-Tooth disease type 4 (CMTX4), caused by AIFM1 (Apoptosis-Inducing Factor, Mitochondrion associated 1) mutations and associated with deafness and cognitive impairment, is a rare subtype of Charcot-Marie-Tooth disease. Here, we report a novel missense variant of AIFM1 in a X-linked recessive Chinese family with childhood-onset, slowly progressive, isolated axonal motor and sensory neuropathy. Calf magnetic resonance imaging revealed fatty infiltration and atrophy severely involving the muscles of peroneal compartment. Pathologies exhibited abnormal mitochondrial morphology and accumulation in axoplasm of nerve fiber and subsarcolemmal area of muscle. A hemizygous variant (c.513G>A, p.Met171Ile) in the family was identified and was classified as likely pathogenic according to the standards and guidelines of the American College of Medical Genetics and Genomics. Our report expands the genetic spectrum of diseases related to AIFM1 mutations and indicates that fatty infiltration and atrophy of muscles in the peroneal compartment may be a feature of CMTX4 in early stage. | 01 = IsEpi
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Mutations in photoreceptor cilium genes CEP290 and NPHP5 cause a form of Leber congenital amaurosis (LCA) which typically lacks rods but retains central cones. The current study evaluated the transient pupillary light reflex (TPLR) as an objective outcome measure to assess efficacy of ongoing and future therapies. Eleven eyes of six patients selected for retained cone function were tested with TPLR using full-field stimuli in the dark-adapted state. Stimuli were red or blue with 1 s duration and spanned a 6-log unit dynamic range. TPLR response amplitude was quantified at fixed times of 0.9 and 2 s after stimulus onset and TPLR latency was defined as the time to reach 0.3 mm constriction. Full-field stimulus testing (FST) and static perimetry were used to correlate subjective perception with objective TPLR parameters. TPLR and FST thresholds with both red and blue stimuli were abnormally elevated in patients to near -1.25 log phot-cd·m-2 consistent with the lack of rods. TPLR latencies were delayed on average but showed some differences among patients. Remnant extrafoveal vision was correlated with faster TPLR latencies. Our results support the use of a short TPLR protocol with full-field red stimuli of 0.7 log phot-cd·m-2 or brighter as an objective and convenient outcome measure of cone function in CEP290- and NPHP5-LCA. The latency parameter of the TPLR would be expected to show a detectable change when an intervention modifies cone sensitivity in the extrafoveal region. | 01 = IsEpi
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Objective: To investigate the carrier frequency of pathogenic genes for methylmalonic acidemia and Wilson's disease in neonates in Qingdao. Methods: In this cross-sectional study, using computer random sampling, 5 020 neonates from the neonatal screening center in Qingdao area from June 2016 to December 2018 were selected, and 5 012 of them were included in the carrier screening study.DNA was extracted from dried blood stain specimens used in the screening of newborns. Multiplex PCR combined with next generation sequencing were used for gene detection of MMACHC gene, MUT gene and ATP7B gene. The carrying rate of hotspots of each gene were calculated, and binomial distribution method was used to calculate 95% confidence interval of pathogenic gene carrying rate. Results: A total of 5 012 neonates completed the screening for carriers of disease-causing genes, of which 5 006 neonates completed the screening of two diseases and the remaining 6 neonates completed the screening of Wilson disease only.For ATP7B gene, the carrier frequency of the 12 hot spot mutations was 1.46% (73/5 012),and the 95% confidence interval was 1.16%-1.83%. For MMACHC gene and MUT gene, carrier frequency of 18 hot spot mutations was 2.50% (125/5 006) , and the 95% confidence interval was 2.10%-2.97%, among which cblC type accounted for 87.2% and the MUT pathogenic gene accounted for 12.8%. Conclusion: The carrier frequency of methylmalonic acidemia and Wilson's disease are both high in the neonatal population in Qingdao. | 01 = IsEpi
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Prolidase is a metallopeptidase that cleaves iminodipeptides containing a proline (Pro) or hydroxyproline (Hyp) residue at their C-terminal end. The disease prolidase deficiency (PD) is a rare recessive human disorder characterized by reduced prolidase activity. PD manifests itself by a wide range of severe clinical symptoms, most commonly as skin ulceration, recurrent infections of the respiratory tract, and mental retardation. Several mutations in the PEPD gene have been identified that are responsible for the loss or the reduction of prolidase activity. In contrast, the structural basis of enzyme inactivation has so far remained elusive. In this study, we present high resolution crystal structures of a number of human prolidase (HsProl) variants, in which single amino acids are either substituted by others or deleted. The observed implications of the mutations on the three-dimensional structure of HsProl are reported and discussed and related to their enzymatic activity. The resulting structures may be divided into four groups depending on the presumed effect of the corresponding mutations on the reaction mechanism. The four possible inactivation mechanisms, which could be elucidated, are disruption of the catalytic Mn2 (OH- )-center, introduction of chain disorder along with the displacement of important active site residues, rigidification of the active site, and flexibilization of the active site. DATABASE:All refined structure coordinates as well as the corresponding structure factor amplitudes have been deposited in the PDB under the accession numbers 5MBY, 5MBZ, 5MC0, 5MC1, 5MC2, 5MC3, 5MC4, 5MC5, 6H2P, 6H2Q. | 01 = IsEpi
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Sütçü M, Aktürk H, Gülümser-Şişko S, Acar M, Erol OB, Somer A, Bilgiç B, Salman N. Granulomatous amebic encephalitis caused by Acanthamoeba in an immuncompetent child. Turk J Pediatr 2018; 60: 340-343. Acanthamoeba may lead to granulomatous amebic encephalitis (GAE) with high mortality rates generally in patients with immunosupression and/or chronic disease. Here, we present a rare GAE case, who was a previously healthy child. A Georgian 9 year old boy presented with focal seizure on his left arm and confusion. Since computed tomography (CT) demonstrated hypodense lesion on right occipital lobe, brain biopsy was performed. Histopathological examination of the biopsy material revealed Acanthamoeba cysts and trophozoites together with granulomatous inflammation. The patient, who had no clinical and laboratory findings consistent with immunedeficiency, was diagnosed as GAE. He was treated with a combination drug therapy. Even if it is very rare, amebic meningoencephalitis may also be seen in immunocompetent children, as in our case. Definitive diagnosis is made by microbiological and histopathological examination of brain biopsy material. | 01 = IsEpi
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Ring chromosome 6 is a rare chromosome abnormality that arises typically de novo. The phenotypes can be highly variable, ranging from almost normal to severe malformations and neurological defects. We report a case of a 3-year-old girl with mosaic ring chromosome 6 who presented with being small for gestational age and intellectual disability, and whose brain MRI later revealed periventricular heterotopia and white matter abnormalities. Mosaicism was identified in peripheral blood cells examined by standard G-bands, mos 46,XX,r(6)(p25q27)[67]/45,XX,-6[25]/46,XX,dic r(6:6)(p25q27:p25q27)[6]/47,XX,r(6)(p25q27) × 2[2]. Using array-comparative genomic hybridization, we identified terminal deletion of 6q27 (1.5 Mb) and no deletion on 6p. To our knowledge, this is the first report of periventricular heterotopia and white matter abnormalities manifested in a patient with ring chromosome 6. These central nervous system malformations are further discussed in relation to molecular genetics. | 01 = IsEpi
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Charcot-Marie-Tooth (CMT) disease comprises a heterogeneous group of peripheral neuropathies characterized by muscle weakness and wasting, and impaired sensation in the extremities. Four genes encoding an aminoacyl-tRNA synthetase (ARS) have been implicated in CMT disease. ARSs are ubiquitously expressed, essential enzymes that ligate amino acids to cognate tRNA molecules. Recently, a p.Arg329His variant in the alanyl-tRNA synthetase (AARS) gene was found to segregate with dominant axonal CMT type 2N (CMT2N) in two French families; however, the functional consequence of this mutation has not been determined. To investigate the role of AARS in CMT, we performed a mutation screen of the AARS gene in patients with peripheral neuropathy. Our results showed that p.Arg329His AARS also segregated with CMT disease in a large Australian family. Aminoacylation and yeast viability assays showed that p.Arg329His AARS severely reduces enzyme activity. Genotyping analysis indicated that this mutation arose on three distinct haplotypes, and the results of bisulfite sequencing suggested that methylation-mediated deamination of a CpG dinucleotide gives rise to the recurrent p.Arg329His AARS mutation. Together, our data suggest that impaired tRNA charging plays a role in the molecular pathology of CMT2N, and that patients with CMT should be directly tested for the p.Arg329His AARS mutation. | 01 = IsEpi
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Tarsal-carpal coalition syndrome (TCC, OMIM #186570) is an autosomal dominant disorder characterised by fusion of the carpals, tarsals, and phalanges, with the short first metacarpals causing brachydactyly and humeroradial fusion. Mutations in the NOG gene have been reported in many families. We describe a family with carpal tarsal fusion seen at a Skeletal Dysplasia Clinic and look at the differential diagnoses. | 01 = IsEpi
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Rhizomelic chondrodysplasia punctata (RCDP) is a rare peroxisomal disease characterised by punctate calcifications of non-ossified cartilage epiphyseal centres. The main biochemical marker of all RCDP types is a decrease in the levels of plasmalogens. Additionally, the accumulation of phytanic acid can be used as a differential marker between types of RDCP. Due to the biochemical overlap between types 1 and 5 RCDP, a genetic analysis of these genes should be performed in patients to identify the type.A 2-month-19-day-old male child presented with symptoms of limited movement and discomfort with movement in the extremities. His sister, who had similar clinical findings, was diagnosed with tetralogy of Fallot and died at 6 months of age. A physical examination revealed an atypical facial appearance, bilateral cataracts, sensitivity to touch in the extremities, shortness in the proximal segments of the long bones, limited movement in both knees and elbows and axial hypotonicity. Laboratory analyses revealed normal ammonia, lactate, plasma and urine amino acids, long chain fatty acids and phytanic acid levels. Rhizomelia, significant metaphyseal expansion, irregularities in the cortex, loss of ossification, fragmented appearance and punctate calcifications in both elbows, both knees and in the femoral epiphysis were seen on the skeletal survey. A homozygote p.L70W (c.209T>G) mutation was found in the PEX7 gene.Plasma phytanic acid levels can be normal in a patient with type 1 RCDP that develops as a result of a PEX7 gene mutation, as in our case. A molecular genetic analysis and/or fibroblast culture must be conducted in clinically suspicious cases. While no cardiac pathology was found in our case, tetralogy of Fallot was present in his sister with similar clinical findings. The presence of different cardiological phenotypes in the sibling suggested that the genotype-phenotype correlation may not be complete in this disorder. | 01 = IsEpi
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A genetic influence on spontaneous pneumothoraces-those occurring without a traumatic or iatrogenic cause-is supported by several lines of evidence: 1) pneumothorax can cluster in families (i.e., familial spontaneous pneumothorax), 2) mutations in the FLCN gene have been found in both familial and sporadic cases, and 3) pneumothorax is a known complication of several genetic syndromes. Herein, we review known genetic contributions to both sporadic and familial pneumothorax. We summarize the pneumothorax-associated genetic syndromes, including Birt-Hogg-Dubé syndrome, Marfan syndrome, vascular (type IV) Ehlers-Danlos syndrome, alpha-1 antitrypsin deficiency, tuberous sclerosis complex/lymphangioleiomyomatosis, Loeys-Dietz syndrome, cystic fibrosis, homocystinuria, and cutis laxa, among others. At times, pneumothorax is their herald manifestation. These syndromes have serious potential extrapulmonary complications (e.g., malignant renal tumors in Birt-Hogg-Dubé syndrome), and surveillance and/or treatment is available for most disorders; thus, establishing a diagnosis is critical. To facilitate this, we provide an algorithm to guide the clinician in discerning which cases of spontaneous pneumothorax may have a genetic or familial contribution, which cases warrant genetic testing, and which cases should prompt an evaluation by a geneticist. | 01 = IsEpi
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Aggressive natural killer-cell leukemia (ANKL) is a rare, lethal disease with pathologic features that are underdescribed in the literature, particularly in Western nations. In addition, although data on the molecular pathogenesis of ANKL has been reported, evaluation of such data in a clinicopathologic context remains limited. Patients diagnosed with ANKL were identified retrospectively. Detailed demographic and clinicopathologic data were analyzed. We assessed novel markers by immunohistochemistry and performed targeted next-generation sequencing analysis. The study group included 9 men and 3 women with a median age at diagnosis of 47.5 years (range, 20 to 75 y). Two distinct patterns of bone marrow involvement were identified: interstitial and sinusoidal. The neoplastic cells were positive for CD56 and CD94, and negative for surface CD3, CD5, and CD57 in all cases assessed. They were also positive for CD2 (10/12), c-MYC (6/8), BCL2 (6/8), CD16 (5/7), EBER (9/12), CD7 (6/11), pSTAT3 (3/8), CD8 (2/6), PD-L1 (2/8), CD4 (2/11), CD8 (2/6), and CD158 (1/5). Aberrant p53 expression was identified in most (7/8) cases; p53 was strongly expressed in 4 cases. Conventional cytogenetic analysis showed clonal abnormalities in 5 of 12 cases. TP53 mutations were detected in 3 of 6 cases, whereas ASXL1 and TET2 mutations were each detected in 2 of 6 cases. Patients had very poor outcomes despite intensive chemotherapy, with a median survival of 2 months. ANKL exhibits 2 distinct patterns of tissue involvement. Neoplastic cells in ANKL are commonly positive for c-MYC and EBER, and they have a high frequency of p53 overexpression, frequently with corresponding TP53 mutations. | 01 = IsEpi
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Clostridium septicum is a highly pathogenic microbe that causes gas gangrene in humans, and is the principal cause of spontaneous gas gangrene in patients with gastrointestinal maladies, including adenocarcinoma of the colon. Despite modern approaches to manage C. septicum infection, morbidity and mortality remain high (>60%). At present, no objective in-vivo data exist supporting the current antibiotic treatment recommendations for C. septicum infection. Utilizing an established murine model of clostridial myonecrosis, this study investigated the efficacy of standard antibiotics for anaerobic Gram-positive soft tissue infections (penicillin, clindamycin, tetracycline and vancomycin) in treating C. septicum gas gangrene. Following intramuscular challenge with 1 × 106 colony-forming units of C. septicum, antibiotics were administered by intraperitoneal injection every 4 h for a total of four doses. At 30 h, all animals in all treatment groups survived the C. septicum challenge, compared with no survivors in the untreated controls (100% mortality by 10 h). However, by 60 h, mice treated with vancomycin exhibited 40% mortality, with no mortality observed in any other antibiotic treatment group. Microbroth dilution minimum inhibitory concentration analyses for three strains of C. septicum also demonstrated high susceptibility to penicillin, clindamycin and tetracycline, but considerably lower susceptibility to vancomycin. This study suggests that penicillin, clindamycin and tetracycline are suitable alternatives for the treatment of C. septicum infection in humans. | 01 = IsEpi
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Proteoglycans (PGs) are macromolecules present on the cell surface and in the extracellular matrix that confer specific mechanical, biochemical, and physical properties to tissues. Sulfate groups present on glycosaminoglycans, linear polysaccharide chains attached to PG core proteins, are fundamental for correct PG functions. Indeed, through the negative charge of sulfate groups, PGs interact with extracellular matrix molecules and bind growth factors regulating tissue structure and cell behavior. The maintenance of correct sulfate metabolism is important in tissue development and function, particularly in cartilage where PGs are fundamental and abundant components of the extracellular matrix. In chondrocytes, the main sulfate source is the extracellular space, then sulfate is taken up and activated in the cytosol to the universal sulfate donor to be used in sulfotransferase reactions. Alteration in each step of sulfate metabolism can affect macromolecular sulfation, leading to the onset of diseases that affect mainly cartilage and bone. This review presents a panoramic view of skeletal dysplasias caused by mutations in genes encoding for transporters or enzymes involved in macromolecular sulfation. Future research in this field will contribute to the understanding of the disease pathogenesis, allowing the development of targeted therapies aimed at alleviating, preventing, or modifying the disease progression. | 01 = IsEpi
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This data article provides zircon U-Pb and Lu-Hf isotopic information along with whole-rock Sm-Nd, Sr and Pb isotopic geochemistry from granitoids in Thailand. The U-Pb ages are described and the classification of crystallisation and inherited ages are explained. The petrography of the granitoid samples is detailed. The data presented in this article are interpreted and discussed in the research article entitled "Probing into Thailand's basement: New insights from U-Pb geochronology, Sr, Sm-Nd, Pb and Lu-Hf isotopic systems from granitoids" (Dew et al., 2018). | 01 = IsEpi
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Based on attachment theory and a social-cognitive model of posttraumatic stress disorder (PTSD), this study examined the roles of parent-child communication, perceived parental depression, and intrusive rumination in the association between insecure attachment to parents and PTSD among adolescents following the Jiuzhaigou earthquake. In this study, 620 adolescents were recruited to complete self-report questionnaires. The results showed that the direct association between anxious attachment and PTSD was significant, but that between avoidant attachment and PTSD was non-significant. In addition, both anxious and avoidant attachment had indirect associations with PTSD via the mediating effects of parent-child communication openness and problems, perceived parental depression, and intrusive rumination. However, the specific paths between anxious and avoidant attachment and PTSD were different. The findings indicated that insecure attachment among adolescents following the earthquake was predictive for their PTSD, and the mechanisms underlying the association between anxious attachment and PTSD and the association between avoidant attachment and PTSD were distinct. To alleviate PTSD, more attention should be paid to improving the quality of parent-child communication for adolescents with avoidant attachment to parents, and to reducing negative cognition in adolescents with anxious attachment. | 01 = IsEpi
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The bric-a-brac, tramtrack and broad complex (BTB) superfamily of conserved proteins are involved in ubiquitin-proteasome system that contains the Kelch-like (KLHL) gene family. Kelch-like family member 7 (KLHL7), one of the KLHL gene family, consists of one BTB/POZ domain, one BACK domain and five or six Kelch motifs. Numerous variants in KLHL7 gene domains have been reported with Crisponi syndrome/cold-induced sweating syndrome type 1 (CS/CISS1)-like features and retinitis pigmentosa 42, and have recently been identified as causing Bohring-Opitz syndrome (BOS)-like features. We report two siblings with BOS-like phenotype with healthy parents and living in Qazvin province (Central Iran). We performed whole-exome sequencing (WES) on the older patient and Sanger sequencing was carried out for validation of potential causative variants in the close family. A novel homozygous frameshift mutation, p.(Phe83Leufs*3), was identified in the BTB domain of KLHL7 that caused a premature translation-termination codon (PTC) in the two siblings with severe developmental delay, microcephaly, facial dysmorphism, peripheral retinal and optic disc atrophy and cardiac septal defects. Our findings are in agreement with the clinical spectrum of KLHL7 mutations, which are associated with BOS-like features that reports for first time in our population. | 01 = IsEpi
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Human eye development is coordinated through an extensive network of genetic signalling pathways. Disruption of key regulatory genes in the early stages of eye development can result in aborted eye formation, resulting in an absent eye (anophthalmia) or a small underdeveloped eye (microphthalmia) phenotype. Anophthalmia and microphthalmia (AM) are part of the same clinical spectrum and have high genetic heterogeneity, with >90 identified associated genes. By understanding the roles of these genes in development, including their temporal expression, the phenotypic variation associated with AM can be better understood, improving diagnosis and management. This review describes the genetic and structural basis of eye development, focusing on the function of key genes known to be associated with AM. In addition, we highlight some promising avenues of research involving multiomic approaches and disease modelling with induced pluripotent stem cell (iPSC) technology, which will aid in developing novel therapies. | 01 = IsEpi
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Importance:Impairment of dopaminergic transmission may contribute to cognitive dysfunction in Alzheimer disease (AD). Objective:To investigate whether therapy with dopaminergic agonists may affect cognitive functions in patients with AD. Design, Setting, and Participants:This phase 2, monocentric, randomized, double-blind, placebo-controlled trial was conducted in Italy. Patients with mild to moderate AD were enrolled between September 1, 2017, and December 31, 2018. Data were analyzed from July 1 to September 1, 2019. Interventions:A rotigotine 2 mg transdermal patch for 1 week followed by a 4 mg patch for 23 weeks (n = 47) or a placebo transdermal patch for 24 weeks (n = 47). Main Outcomes and Measures:The primary end point was change from baseline on the Alzheimer Disease Assessment Scale-Cognitive Subscale. Secondary end points were changes in Frontal Assessment Battery, Alzheimer Disease Cooperative Study-Activities of Daily Living, and Neuropsychiatric Inventory scores. Prefrontal cortex activity was evaluated by transcranial magnetic stimulation combined with electroencephalography. Results:Among 94 patients randomized (mean [SD] age, 73.9 [5.6] years; 58 [62%] women), 78 (83%) completed the study. Rotigotine, as compared with placebo, had no significant effect on the primary end point: estimated mean change in Alzheimer Disease Assessment Scale-Cognitive Subscale score was 2.92 (95% CI, 2.51-3.33) for the rotigotine group and 2.66 (95% CI, 2.31-3.01) for the placebo group. For the secondary outcomes, there were significant estimated mean changes between groups for Alzheimer Disease Cooperative Study-Activities of Daily Living score (-3.32 [95% CI, -4.02 to -2.62] for rotigotine and -7.24 [95% CI, -7.84 to -6.64] for placebo) and Frontal Assessment Battery score (0.48 [95% CI, 0.31 to 0.65] for rotigotine and -0.66 [95% CI, -0.80 to -0.52] for placebo). There was no longitudinal change in Neuropsychiatric Inventory scores (1.64 [95% CI, 1.06-2.22] for rotigotine and 1.26 [95% CI, 0.77-1.75] for placebo group). Neurophysiological analysis of electroencephalography results indicated that prefrontal cortical activity increased in rotigotine but not in the placebo group. Adverse events were more common in the rotigotine group, with 11 patients dropping out compared with 5 in the placebo group. Conclusions and Relevance:In this randomized clinical trial, rotigotine treatment did not significantly affect global cognition in patients with mild to moderate AD; however, improvement was observed in cognitive functions highly associated with the frontal lobe and in activities of daily living. These findings suggest that treatment with the dopaminergic agonist rotigotine may reduce symptoms associated with frontal lobe cognitive dysfunction and thus may delay the impairment of activities of daily living. Trial Registration:ClinicalTrials.gov Identifier: NCT03250741. | 01 = IsEpi
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A 33-year-old woman presented with more than 100 flesh-colored papules and nodules centrally located on the face (Figure 1). Since their first appearance at the age of 7, the lesions had increased in number and spread laterally from the nasolabial folds. She underwent surgical removal at age 10 with recurrence afterward. Her mother, maternal grandmother, and maternal great aunt have similar lesions on the face. Histopathologic examination confirmed the diagnosis of trichoepitheliomas and multiple familial trichoepithelioma (MFT). | 01 = IsEpi
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Human dentition development is a long and complex process which involves a series of reciprocal and sequential interactions between the embryonic stomodeal epithelium and the underlying neural crest-derived mesenchyme. Despite environment disturbances, tooth development is predominantly genetically controlled. To date, more than 200 genes have been identified in tooth development. These genes implied in various signaling pathways such as the bone morphogenetic protein, fibroblast growth factor, sonic hedgehog homolog, ectodysplasin A, wingless-type MMTV integration site family (Wnt), and transform growth factor pathways. Mutations in any of these strictly balanced signaling cascades may cause arrested odontogenesis and/or other dental defects. This article aims to review current knowledge about the genetic mechanisms responsible for selective nonsyndromic tooth agenesis in humans and to present a detailed summary of syndromes with hypodontia as regular features and their causative genes. | 01 = IsEpi
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Tauopathies are neurodegenerative diseases characterized by the presence of aggregates of abnormally phosphorylated Tau. Deciphering the pathophysiological mechanisms that lead from the alteration of Tau biology to neuronal death depends on the identification of Tau cellular partners. Combining genetic and transcriptomic analyses in Drosophila, we identified 77 new modulators of human Tau-induced toxicity, bringing to 301 the number of Tau genetic interactors identified so far in flies. Network analysis showed that 229 of these genetic modulators constitute a connected network. The addition of 77 new genes strengthened the network structure, increased the intergenic connectivity and brought up key hubs with high connectivities, namely Src64B/FYN, Src42A/FRK, kuz/ADAM10, heph/PTBP1, scrib/SCRIB, and Cam/CALM3. Interestingly, we established for the first time a genetic link between Tau-induced toxicity and ADAM10, a recognized Alzheimer Disease protective factor. In addition, our data support the importance of the presynaptic compartment in mediating Tau toxicity. | 01 = IsEpi
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An aberrant right subclavian artery (ARSCA) is a relatively rare congenital anomaly of the aortic arch branches. A 63-year-old man suffered from dysphagia, and was referred to our hospital. Computed tomography (CT) revealed an aortic aneurysm (Kommerell's diverticulum) and ARSCA which routed behind the esophagus. We performed total arch replacement with the open stent-grafting technique via median sternotomy. ARSCA was anastomosed to 1 branch of the arch graft at the right side of the trachea, which released esophageal compression. Postoperatively dysphagia disappeared and CT scan indicated successful reconstruction of the distal arch and ARSCA. The open stent-grafting technique is considered to be effective for aortic disease with ARSCA. | 01 = IsEpi
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