A Recurrent Nonsense Mutation in NECTIN4 Underlying Ectodermal Dysplasia-Syndactyly Syndrome with a Novel Phenotype in a Consanguineous Kashmiri Family.

EDSS1, a syndrome characterized by ectodermal dysplasia-syndactyly, is inherited in an autosomal recessive manner due to mutations in the NECTIN4/PVRL4 gene. Clinical manifestations of the syndrome include defective nail plate, sparse to absent scalp and body hair, spaced teeth with enamel hypoplasia, and bilateral cutaneous syndactyly in the fingers and toes. Here, we report a consanguineous family of Kashmiri origin presenting features of EDSS1. Using whole exome sequencing, we found a recurrent nonsense mutation (NM_030916: c.181C > T, p.(Gln61 ∗)) in the NECTIN4 gene. The variant segregated perfectly with the disorder within the family. The candidate variant was absent in 50 in-house exomes pertaining to other disorders from the same population. In addition to the previously reported clinical phenotype, an upper lip cleft was found in one of the affected members as a novel phenotype that is not reported by previous studies in EDSS1 patients. Therefore, the study presented here, which was conducted on the Kashmiri population, is the first to document a NECTIN4 mutation associated with the upper lip cleft as a novel phenotype. This finding broadens the molecular and phenotypic spectrum of EDSS1.

Same Gene, Different Story (a Case Report of Congenital Long QT Syndrome Subtype 8 With a Novel Mutation).

Long QT syndrome (LQTS) 8 is a rare inherited channelopathy caused by CACNA1C gene mutations that affects calcium channels, and when combined with congenital heart defects, musculoskeletal defects, and neurodevelopmental defects, it is referred to as Timothy syndrome. A female patient, aged 17 years, presented with a witnessed episode of syncope secondary to ventricular fibrillation that was successfully cardioverted. Electrocardiogram showed sinus bradycardia 52/min, normal axis, and a QTc of 626 ms. In the hospital, she had another episode of asystole and Torsade de pointes and underwent successful cardiopulmonary resuscitation. Echocardiogram showed severely reduced left ventricular systolic function from postcardiac arrest myocardial dysfunction and no congenital heart defects. Long QT genetic test detected a missense mutation in the CACNA1C gene (NM_199460.3, variant c.2573G>A, p Arg858His, heterozygous, autosomal dominant), resulting in replacement of arginine with histidine at position 858(R858H), leading to the gain of function in the L-type calcium channel. Given the absence of congenital cardiac defects, musculoskeletal deformities, or neurodevelopmental delay a final diagnosis of LQTS subtype 8 was made. A cardioverter defibrillator was implanted. In conclusion, our case highlights the importance of genetic testing in the diagnosis of LQTS. Some CACNA1C mutations, such as R858H described here, cause LQTS without the extracardiac manifestations observed in classic Timothy syndrome and should be included in the genetic testing for LQTS. To the best of our knowledge, our case is the first one from United States with the R585H mutation. Three cases with similar mutations have been reported from Japan and one from New Zealand.

A novel homozygous nonsense mutation in NECTIN4 gene in a Pakistani family with ectodermal dysplasia syndactyly syndrome 1.

BACKGROUND: Ectodermal dysplasia syndactyly syndrome 1 (EDSS1) is a rare hereditary disorder characterized by defects in teeth, hair, and nails in association with a fusion of the digits. Genetically, the disease phenotypes are caused by homozygous and compound heterozygous variants in NECTIN4 gene. OBJECTIVE: The main objective of the study was to identify the pathogenic sequence variant(s) for family screening and identification of carriers. METHODS: In the present study, the authors have investigated a large consanguineous family of Pakistani origin segregating autosomal recessive EDSS1. All the coding exons of the NECTIN4 gene were directly sequenced using gene-specific primers. RESULTS: The affected individuals presented the classical EDSS1 clinical features including sparse hair, hypoplastic nails with thick flat discolored nail plates, peg-shaped, conical, and widely spaced teeth with enamel hypoplasia, proximal cutaneous syndactyly of fingers and toes. Sequence analysis of the coding region of the NECTIN4 identified a novel nonsense variant [c.163C>T; p.(Arg55*)] in exon-2 of the gene. Computational analysis of protein structure revealed that the variant induced premature termination at Arg55 located in Ig-like V-loop region leading to loss of Ig-C2 type domains and transmembrane region, and most likely Nectin-4 function will be lost. STUDY LIMITATION: Gene expression studies are absent that would have strengthened the findings of computational analysis. CONCLUSION: The present study expanded the phenotypic and mutation spectrum of the NECTIN4 gene. Further, the study would assist in carrier testing and prenatal diagnosis of the affected families.

Clinical and molecular characterizations of 11 new patients with type 1 Feingold syndrome: Proposal for selecting diagnostic criteria and further genetic testing in patients with severe phenotype.

Feingold Syndrome type 1 (FS1) is an autosomal dominant disorder due to a loss of function mutations in the MYCN gene. FS1 is generally clinically characterized by mild learning disability, microcephaly, short palpebral fissures, short stature, brachymesophalangy, hypoplastic thumbs, as well as syndactyly of toes, variably associated with organ abnormalities, the most common being gastrointestinal atresia. In current literature, more than 120 FS1 patients have been described, but diagnostic criteria are not well agreed upon, likewise the genotype-phenotype correlations are not well understood. Here, we describe 11 FS1 patients, belonging to six distinct families, where we have identified three novel MYCN mutations along with three pathogenetic variants, the latter which have already been reported. Several patients presented a mild phenotype of the condition and they have been diagnosed as being affected only after segregation analyses of the MYCN mutation identified in the propositus. We also describe here the first ever FS1 patient with severe intellectual disability having a maternally inherited MYCN variant together with an additional GNAO1 mutation inherited paternally. Mutations in the GNAO1 gene are associated with a specific form of intellectual disability and epilepsy, thus the finding of two different rare diseases in the same patient could explain his severe phenotype. Therein, a thorough investigation is merited into the possibility that additional variants in patients with a MYCN mutation and severe phenotype do exist. Finally, in order to guarantee a more reliable diagnosis of FS1, we suggest using both major and minor clinical-molecular diagnostic criteria.

Generalised hypomineralisation of enamel in oculodentodigital dysplasia: comprehensive dental management of a case.

Oculodentodigital dysplasia (ODDD) is a rare congenital disorder characterised by developmental abnormalities of the eye, dentition and digits of the hands and feet, with neurological symptoms reported in 30% of individuals. Dental anomalies associated with ODDD include enamel hypoplasia and subsequent caries, microdontia, missing teeth, amelogenesis imperfecta, pulp stones and delayed tooth development. Here, we describe the comprehensive dental management of a 3-year-old girl who presented with rapid deterioration of the primary dentition due to generalised enamel hypomineralisation. Conservative, comprehensive restorative management was performed under general anaesthesia. Within 6 months, further breakdown of the remaining unrestored enamel was noted. This case documents the challenges of conservative management in dental anomalies that are not well documented due to the extreme rarity of the disorder.

Patient-Reported Outcomes after Syndactyly Reconstruction.

BACKGROUND: There is scant literature regarding patient-reported outcomes after reconstruction for congenital hand syndactyly. Understanding patient perceptions of the postoperative outcome may facilitate a more evidence-based discussion of expectations after reconstruction. METHODS: All patients undergoing congenital syndactyly reconstruction at Ann and Robert H. Lurie Children's Hospital of Chicago between January of 2007 and December of 2015 were identified. Patient-Reported Outcomes Measurement Information System questionnaires were completed by patients; parent-proxy questionnaires were completed for patients 10 years of age and younger and those unable to complete the questionnaire independently. A retrospective chart review was also performed to capture demographic and clinical information. RESULTS: The authors identified 124 patients meeting inclusion criteria; 51 completed the Patient-Reported Outcomes Measurement Information System surveys (response rate, 41.1 percent). The survey score for upper extremity function was 41.8 ± 11. Upper extremity function was further impaired in patients with a documented history of developmental delay (23.8 ± 6.2 versus 44.2 ± 10.2). Parents completing surveys on behalf of their children reported higher pain interference scores than self-responders. CONCLUSIONS: The Patient-Reported Outcomes Measurement Information System is a valuable tool for measuring patient-reported outcomes in patients with syndactyly. Patients who have undergone reconstruction for syndactyly experience minor impairments in upper extremity function, but other aspects of their health-related quality of life are comparable to those of the general population. Developmental delay may be associated with additional impairments in upper extremity function and should be discussed when considering surgical reconstruction.

High Prevalence of Late-Appearing T-Wave in Patients With Long QT Syndrome Type 8.

BACKGROUND: Long QT syndrome type 8 (LQT8) is a rare genotype of long QT syndrome. Late-appearing T-waves (LaT) are often documented in patients with LQT8, as in long QT syndrome type 3 (LQT3); however, the frequency of LaT and its relevance to the clinical severity of LQT8 remains unclear. This study investigated T-wave morphology (TWM) in LQT3 and LQT8 patients and compared the phenotypes of different TWMs.Methods and Results:TWMs were classified into 3 types: early onset T-waves (EoT), LaT, and bifid T-waves (biT). Electrocardiogram (ECG) measurements, symptoms, and topology were compared among TWM types. The study cohort comprised 25 patients with LQT8 (14 mutations) and 25 patients with LQT3 (14 mutations). LaT was detected in 17 (68%) and 13 (52%) LQT8 and LQT3 patients, respectively. There were no significant differences in ECG measurements or the severity of symptoms between patients with LaT and those with other TWMs in either the LQT8 or LQT3 group. However, only patients with LaT experienced cardiopulmonary arrest. Compared with the LQT3 group, in the LQT8 group there was a tendency for mutations in patients with LaT to be located in domain-linking regions. CONCLUSIONS: In this study, two-thirds of patients with LQT8 exhibited LaT on ECG, and nearly one-third of those experienced cardiopulmonary arrest. Further investigations are warranted to differentiate between LQT3 and LQT8 in patients exhibiting LaT to optimize therapy.

A novel frameshift variant in BHLHA9 underlies mesoaxial synostotic syndactyly associated with postaxial polydactyly.

Mesoaxial synostotic syndactyly (MSSD) with phalangeal reduction is an uncommon congenital limb abnormality characterized by central osseous synostosis at a metacarpal level, mesoaxial reduction of the fingers, and preaxial cutaneous syndactyly in toes. In rare cases, the disease is also associated with fifth finger clinodactyly and postaxial polydactyly. It has autosomal recessive inheritance pattern caused by homozygous variants in the gene BHLHA9 mapped at chromosome 17p13.3. In the present study, a consanguineous family of Pakistani origin segregating MSSD in autosomal recessive form was characterized at clinical and genetic levels. Clinically, the diseased individuals have MSSD associated with clinodactyly and polydactyly. Homozygosity mapping followed by Sanger sequencing of BHLHA9 revealed a novel frameshift variant NM_001164405.1: c.409-409delC; p.(His137Thrfs*61) segregating with the disease phenotypes in the family. This is the second report providing evidence of association of polydactyly with MSSD caused by frameshift variant in the gene BHLHA9. The present molecular investigation will support genetic counselling of the local population carrying diseased variants.

GJA1 Variants Cause Spastic Paraplegia Associated with Cerebral Hypomyelination.

Oculodentodigital dysplasia is an autosomal dominant disorder due to GJA1 variants characterized by dysmorphic features. Neurologic symptoms have been described in some patients but without a clear neuroimaging pattern. To understand the pathophysiology underlying neurologic deficits in oculodentodigital dysplasia, we studied 8 consecutive patients presenting with hereditary spastic paraplegia due to GJA1 variants. Clinical disease severity was highly variable. Cerebral MR imaging revealed variable white matter abnormalities, consistent with a hypomyelination pattern, and bilateral hypointense signal of the basal ganglia on T2-weighted images and/or magnetic susceptibility sequences, as seen in neurodegeneration with brain iron accumulation diseases. Patients with the more prominent basal ganglia abnormalities were the most disabled ones. This study suggests that GJA1-related hereditary spastic paraplegia is a complex neurodegenerative disease affecting both the myelin and the basal ganglia. GJA1 variants should be considered in patients with hereditary spastic paraplegia presenting with brain hypomyelination, especially if associated with neurodegeneration and a brain iron accumulation pattern.

Orodental Findings in Patients with Lacrimo-Auriculo-Dento-Digital Syndrome.

Lacrimo-auriculo-dento-digital syndrome (LADD) is a rare autosomal dominant disorder arising from heterozygous mutations in the genes encoding fibroblast growth factor receptors two and three and the gene encoding the fibroblast growth factor 10. The characteristics associated with LADD are mainly related with hypoplasia or aplasia of lacrimal and salivary ducts, low cup-shaped ears, sensorineural or conductive hearing loss, abnormalities of teeth, and anomalies of the hands and feet. The purpose of this paper is to describe a 13-year-old female patient with a history of a blocked tear duct, mild hearing loss, congenitally missing teeth, tauro- dontism, and malformation of the fingers who was referred for a dental evaluation. She was diagnosed with LADD syndrome based on her clinical picture. (J Dent Child 2019;86(1):53-60)
Received August 16, 2018; Last Revision November 8, 2018; Accepted November 9, 2018.

Dental management of a child with ectrodactyly ectodermal dysplasia cleft lip/palate syndrome: A case report.

Ectrodactyly ectodermal dysplasia with clefting is a rare syndrome resulting from TP63 gene mutations. It is inherited in autosomal dominant manner or as a de novo transfiguration. It is characterized by a triad of ectodermal dysplasia, ectrodactyly, and facial clefts. This report represents a clinical case of 5 years and 6 months-old male child with ectrodactyly ectodermal dysplasia cleft lip and palate syndrome requiring treatment of his carious teeth. After history taking and clinical examination, the necessary treatment was provided under general anesthesia due to the definitely negative behavior of the child. The treatment outcomes had a positive impact on the behavior and acceptance to dental treatment. This was evidenced by completion of the prosthetic and space management appliances on the dental chair. The child's quality of life was consequently improved. This was evidenced by the reduced response scores of the child perception questionnaire (CPQ11-14 ) after treatment. This report highlighted the value of proper diagnosis and fulfillment of the unmet dental needs for patients with orofacial syndromes to improve their quality of life.

Enhanced oligodendrocyte maturation and myelination in a mouse model of Timothy syndrome.

To study the role of L-type voltage-gated Ca++ channels in oligodendrocyte development, we used a mouse model of Timothy syndrome (TS) in which a gain-of-function mutation in the α1 subunit of the L-type Ca++ channel Cav1.2 gives rise to an autism spectrum disorder (ASD). Oligodendrocyte progenitor cells (OPCs) isolated from the cortex of TS mice showed greater L-type Ca++ influx and displayed characteristics suggestive of advanced maturation compared to control OPCs, including a more complex morphology and higher levels of myelin protein expression. Consistent with this, expression of Cav1.2 channels bearing the TS mutation in wild-type OPCs triggered process formation and promoted oligodendrocyte-neuron interaction via the activation of Ca++ /calmodulin-dependent protein kinase II. To ascertain whether accelerated OPC maturation correlated with functional enhancements, we examined myelination in the TS brain at different postnatal time points. The expression of myelin proteins was significantly higher in the corpus callosum, cortex and striatum of TS animals, and immunohistochemical analysis for oligodendrocyte stage-specific markers revealed an increase in the density of myelinating oligodendrocytes in several areas of the TS brain. Along the same line, electron microscopy studies in the corpus callosum of TS animals showed significant increases both in the percentage of myelinated axons and in the thickness of myelin sheaths. In summary, these data indicate that OPC development and oligodendrocyte myelination is enhanced in the brain of TS mice, and suggest that this mouse model of a syndromic ASD is a useful tool to explore the role of L-type Ca++ channels in myelination.

Mice harbouring an oculodentodigital dysplasia-linked Cx43 G60S mutation have severe hearing loss.

Given the importance of connexin43 (Cx43, encoded by GJA1) function in the central nervous system and sensory organ processing, we proposed that it would also be crucial in auditory function. To that end, hearing was examined in two mouse models of oculodentodigital dysplasia that globally express GJA1 mutations resulting in mild or severe loss of Cx43 function. Although Cx43I130T/+ mutant mice, with ∼50% Cx43 channel function, did not have any hearing loss, Cx43G60S/+ mutant mice, with ∼20% Cx43 channel function, had severe hearing loss. There was no evidence of inner ear sensory hair cell loss, suggesting that the mechanism for Cx43-linked hearing loss lies downstream in the auditory pathway. Since evidence suggests that Cx26 function is essential for hearing and may be protective against noise-induced hearing loss, we challenged Cx43I130T/+ mice with a loud noise and found that they had a similar susceptibility to noise-induced hearing loss to that found in controls, suggesting that decreased Cx43 function does not sensitize the mice for environmentally induced hearing loss. Taken together, this study suggests that Cx43 plays an important role in baseline hearing and is essential for auditory processing.This article has an associated First Person interview with the first author of the paper.

A multicentre study of patients with Timothy syndrome.

Aims: Timothy syndrome (TS) is an extremely rare multisystem disorder characterized by marked QT prolongation, syndactyly, seizures, behavioural abnormalities, immunodeficiency, and hypoglycaemia. The aim of this study was to categorize the phenotypes and examine the outcomes of patients with TS. Methods and results: All patients diagnosed with TS in the United Kingdom over a 24-year period were reviewed. Fifteen centres in the British Congenital Arrhythmia Group network were contacted to partake in the study. Six patients with TS were identified over a 24-year period (4 boys and 2 girls). Five out of the six patients were confirmed to have a CACNA1C mutation (p.Gly406Arg) and the other patient was diagnosed clinically. Early presentation with heart block, due to QT prolongation was frequently seen. Four are still alive, two of these have a pacemaker and two have undergone defibrillator implantation. Five out of six patients have had a documented cardiac arrest with three occurring under general anaesthesia. Two patients suffered a cardiac arrest while in hospital and resuscitation was unsuccessful, despite immediate access to a defibrillator. Surviving patients seem to have mild developmental delay and learning difficulties. Conclusion: Timothy syndrome is a rare disorder with a high attrition rate if undiagnosed. Perioperative cardiac arrests are common and not always amenable to resuscitation. Longer-term survival is possible, however, patients invariably require pacemaker or defibrillator implantation.

A case report: Is mexiletine usage effective in the shortening of QTC interval and improving the T-wave alternans in Timothy syndrome?

Timothy syndrome (TS) is a multisystemic disease that occurs because of a mutation in CACN1C gene and is characterized by prolonged QT interval. Mexiletine is a Class 1B antiarrhythmic drug that causes the disappearance of T-wave alternans by shortening QTc and peak-to-end of the T wave. It may block the development of torsades de pointes in a prolonged QT. This study presented the case of a patient diagnosed with TS and had a cardiac arrest history, prolonged QT, and T-wave alternans. After mexiletine treatment, the QTc interval shortened and T-wave alternans disappeared. Such a case has rarely been seen in the literature, and hence considered rare. This case presentation was of particular importance because it highlighted the use of mexiletine besides an initial beta-blocker treatment in the cases with TS.

LADD syndrome with glaucoma is caused by a novel gene.

PURPOSE: Lacrimo-auriculo-dento-digital (LADD) syndrome is an autosomal dominant disorder displaying variable expression of multiple congenital anomalies including hypoplasia or aplasia of the lacrimal and salivary systems causing abnormal tearing and dry mouth. Mutations in the FGF10, FGFR2, and FGFR3 genes were found to cause some cases of LADD syndrome in prior genetic studies. The goal of this study is to identify the genetic basis of a case of LADD syndrome with glaucoma and thin central corneal thickness (CCT). METHODS: Whole exome sequencing was performed, and previously described disease-causing genes (FGF10, FGFR2, and FGFR3) were first evaluated for mutations. Fifty-eight additional prioritized candidate genes were identified by searching gene annotations for features of LADD syndrome. The potential pathogenicity of the identified mutations was assessed by determining their frequency in large public exome databases; through sequence analysis using the Blosum62 matrix, PolyPhen2, and SIFT algorithms; and through homology analyses. A structural analysis of the effects of the top candidate mutation in tumor protein 63 (TP63) was also conducted by superimposing the mutation over the solved crystal structure. RESULTS: No mutations were detected in FGF10, FGFR2, or FGFR3. The LADD syndrome patient's exome data was searched for mutations in the 58 candidate genes and only one mutation was detected, an Arg343Trp mutation in the tumor protein 63 (TP63) gene. This TP63 mutation is absent from the gnomAD sequence database. Analysis of the Arg343Trp mutation with Blosum62, PolyPhen2, and SIFT all suggest it is pathogenic. This arginine residue is highly conserved in orthologous genes. Finally, crystal structure analysis showed that the Arg343Trp mutation causes a significant alteration in the structure of TP63's DNA binding domain. CONCLUSIONS: We report a patient with no mutations in known LADD syndrome genes (FGF10, FGFR2, and FGFR3). Our analysis provides strong evidence that the Arg343Trp mutation in TP63 caused LADD syndrome in our patient and that TP63 is a fourth gene contributing to this condition. TP63 encodes a transcription factor involved in the development and differentiation of tissues affected by LADD syndrome. These data suggest that TP63 is a novel LADD syndrome gene and may also influence corneal thickness and risk for open-angle glaucoma.