Journal of pediatric genetics最新文献

The SCN encephalopathies are one of the rare early childhood intractable epileptic encephalopathies associated with pleomorphic seizures, cognitive decline, motor, and behavioral abnormalities that begin in early infancy. There is a dearth of data on phenotype and genotype of SCN encephalopathies from the Indian subcontinent, hence we are reporting clinical and molecular profile and outcome of SCN developmental and epileptic encephalopathies. This is a retrospective chart review of SCN developmental and epileptic encephalopathies in a tertiary care center, Bangalore, India between January 2015 and March 2020. All children with clinical features of SCN developmental and epileptic encephalopathies and confirmed with pathogenic variants were included. A total of 50 cases of SCN developmental and epileptic encephalopathies were analyzed, 31 of them were male and the mean age of presentation was 7.8 months. Precipitating factors for the first episode of seizure were fever and vaccination accounting for 33 and 8 children, respectively. Forty (80%) children had prolonged seizures and 15 (30%) had epileptic spasms. All children had a normal birth history and normal development before the onset of seizures, which was followed by developmental delay and regression. Thirty (60%) children had behavioral difficulties, notable hyperactivity, and autistic features. Neuroimaging and the initial electroencephalogram (EEG) were normal in all patients. The mean age of abnormal EEG was 14 months. The various subtypes of SCN variants were SCN1A in 31 children followed by SCN2A and SCN9A in eight children each and SCN1B in three children. Frameshift and nonsense mutations were associated with more severe phenotype and poor outcome compared with missense mutations. Thirty-four patients partially responded to treatment and the rest were refractory. The results of genetic testing were used to guide treatment; sodium channel blocking antiepileptic drugs were discontinued in 15 patients and sodium channel blocking agents were started in 3 patients with partial response. Three out of four children on stiripentol had a partial response. The SCN developmental and epileptic encephalopathies can present with epileptic spasms in addition to other types of seizures. Epileptic spasms are more common in nonsense and frameshift mutations. The outcome is poor in children with epileptic spasms compared with those without epileptic spasms. Genetic testing helps to select antiepileptic drugs that lead to seizure reduction.

[This corrects the article DOI: 10.1055/s-0040-1721384.].

Kindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. Besides these major features, many minor presentations have also been reported in the literature. We are reporting two cases with atypical features of the syndrome and a new feature of recurrent neutropenia. Whole exome sequencing analysis was done using next-generation sequencing which detected a homozygous loss-of-function (LOF) variant of FERMT1 in both patients. The variant is classified as a pathogenic variant as per the American College of Medical Genetics and Genomics guidelines. Homozygous LOF variants of FERMT1 are a common mechanism of KS and as such confirm the diagnosis of KS in our patients even though the presentation was atypical.

Cardiac defects presenting in childhood show significant phenotypic and genetic heterogeneity. With availability of advanced genetic technologies, these can be detected early using specialized testing. Prenatal testing is currently feasible with improved ultrasonography and fetal echocardiography. Here, we report two cases of Noonan's and cardiofaciocutaneous syndromes in patients seen in the genetic unit of a tertiary care center presenting with cardiac defect with or without developmental delay, short stature, and dysmorphism. In these conditions, there is also increased risk of malignancy such as juvenile myelomonocytic leukemia. With the advent of next-generation sequencing, definitive diagnosis and counseling is possible in this group of conditions.

Glycine encephalopathy (GE), also known as nonketotic hyperglycinemia (NKH) is an autosomal recessive disorder due to a primary defect in the glycine cleavage enzyme system. It is characterized by elevated levels of glycine in the plasma and cerebrospinal fluid (CSF) and increased CSF to plasma glycine ratio. Mutations in three genes of the mitochondrial glycine cleavage system have been found to cause NKH. Most patients have a mutation in the GLDC . In this report, we present five new patients from Middle Eastern families with NKH. They were all born to consanguineous parents and two of them have family history of similarly affected sibling(s). All patients presented with neonatal encephalopathy associated with seizures. Their diagnoses were suspected clinically and confirmed biochemically. DNA sequence analysis of the five patients revealed five different pathogenic or likely pathogenic variants in the GLDC . Three were missense variants (c.2675C > T; p.Ala892Val), (c.2512A > G; p.Asn838Asp), and (c.2943A > C; p.Lys981Asn); one was an intronic missense variant (c.1402-2A > T) leading to an exonic deletion, and one was a deletion of 42 amino acids (c.1927-?_2052 + ?del.) All variants were novel and homozygous. The pathogenicity of these variants was determined according to the American College of Medical Genetics (ACMG) variant classification and in silico analysis. Another novel homozygous variant (c.1384C > G; p.Leu462Val) was detected, which was classified as likely benign. The novel variants identified in the GLDC in these patients underlie the pathogenesis of NKH, specifically for the Middle Eastern population. This expands the mutation spectrum of NKH to include a distinct ethnic population that has not been studied before.

Pyridoxine-dependent epilepsy (PDE) (OMIM 266100) is an autosomal recessive disorder of lysine metabolism secondary to antiquitin deficiency. The prototypical presentation is intractable neonatal seizures that do not respond to conventional antiseizure medication but are well controlled by pyridoxine supplementation. Atypical forms account for one-third of the PDE spectrum and may escape early diagnosis. The common atypical presentations include the prenatal onset of seizures, seizures onset as delayed as 3 years of age, autism, arrested hydrocephalus, and fetal ventriculomegaly. Herein, we describe a 9-month-old child with neonatal-onset refractory seizures who failed two short trials of pyridoxine therapy and was later diagnosed with PDE by molecular studies. Regardless of the therapeutic response, a prolonged course of pyridoxine therapy is justified to identify delayed responders in infants with drug-refractory epilepsy of no apparent etiology.

KCNQ2 mutations encompass a wide range of phenotypes, ranging from benign familial neonatal seizure to a clinical spectrum of early-onset epileptic encephalopathy that occurs in the early neonatal period. We report an infant with KCNQ2 encephalopathy presenting as neonatal seizure, initially controlled by two anticonvulsants. Electroencephalogram (EEG) showed repetitive multifocal epileptiform discharges, which remained similar after administration of intravenous pyridoxine injection. Seizure recurred at the age of 3 months preceded by an episode of minor viral infection, which occurred multiple times per day. No significant change in seizure frequency was observed after 5-day oral pyridoxine trial, but subsequently, there was dramatic seizure improvement with oral pyridoxal-5'-phosphate (PLP). We hope to alert clinicians that in patients with neonatal epileptic encephalopathy, particularly with known KCNQ2 mutations, intravenous injection of pyridoxine (preferably with EEG monitoring), followed by both oral trial of pyridoxine and PLP should be considered. KCNQ2 mutations should also be considered in vitamin B6-responsive patients.

Achondroplasia is the most common autosomal dominant form of skeletal dysplasia and is caused by heterozygous mutations of the fibroblast growth factor receptor 3 ( FGFR3 ) gene at region 4p16.3. This study highlights the data of achondroplasia cases, clinical spectrum, and their outcome from small cities and the region around Rajasthan. The data for analysis were collected retrospectively from genetic records of rare disease clinic in Rajasthan. Clinical profile, radiographic features, molecular test results, and outcome were collected. There were 15 cases, including eight males and seven females, in this cohort. All had facial hypoplasia, depressed nasal bridge, prominent forehead, and characteristic radiographic features. A total of 14 cases were sporadic and one case was inherited from the mother. Mutation analysis showed 13 out of 15 cases with the p.Gly380Arg mutation in the FGFR3 gene. Hydrocephalus was developed in three cases, required shunting in two cases.

Knobloch syndrome (KS) is an autosomal recessive disorder caused by biallelic pathogenic variants in COL18A1 . KS clinically manifests with the typical eye findings (high myopia, vitreoretinal degeneration, retinal detachment, and lens subluxation), variable neurological findings (occipital encephalocele, polymicrogyria, cerebellar malformations, epilepsy, and intellectual disability), and the other uncommon clinical manifestations. Literature review of all KS patients (source PubMed) was done with special reference to cerebellar abnormalities. Here, we report two siblings with typical KS with posterior fossa malformations and novel cerebellar midline cleft abnormality analyzed by whole exome sequencing. Known pathogenic homozygous variant c.2908C > T; (p.Arg970Ter) in exon 26 of COL18A1 was found as a cause for KS. These two siblings presented with early-onset severe ocular manifestations, facial dysmorphism, and variable central nervous system manifestations along with novel cerebellar midline cleft abnormality. The presence or absence of structural brain malformations and genotypes does not absolutely predict cognitive functions in KS patients. However, the presence of posterior fossa abnormality may be predictive for the development of ataxia in later life and needs further studies.