Clinical and molecular characterisation of children with monogenic obesity: a case series.

INTRODUCTION: To study the clinical profile and molecular diagnosis of children with severe early-onset non-syndromic monogenic obesity. METHODS: The clinical and molecular data (performed using whole exome sequencing) of 7 children with early-onset (< 5 years) non-syndromic monogenic obesity were extracted from the Obesity Clinic files and analysed retrospectively. RESULTS: The median (IQR) age at presentation was 18 (10.5-27) months. Of the 7 patients, 5 were boys, 3 had a history of parental consanguinity, and 4 had a family history of severe early-onset obesity. All patients exhibited hyperphagia and showed signs of insulin resistance. Dyslipidaemia and fatty liver were observed in 4. The variants identified in 6 patients included 2 in leptin receptor, and one each in melanocortin 4 receptor, pro-opiomelanocortin, leptin, and neurotrophic tyrosine kinase receptor type 2 genes. Notably, 4 of these variants were novel. CONCLUSIONS: This case series provides valuable insights into the spectrum of genetic mutations associated with non-syndromic monogenic obesity in North Indian children. The findings underscore the significance of next-generation sequencing in identifying the aetiology of severe early-onset obesity.

Cost and cost-effectiveness of treatments for rheumatic heart disease in low- and middle-income countries: a systematic review protocol.

OBJECTIVE: This review will synthesize studies on costs, the impact of these costs, and the cost-effectiveness of treatments for rheumatic heart disease (RHD) in low- and middle-income countries. INTRODUCTION: RHD incurs high costs owing to its clinical complexity, surgical treatments, and prolonged hospital stays. Thus, the disease has a substantial economic impact on the health system, patients, and their families. No systematic review on economic evidence of treatments for RHD has been published to date. INCLUSION CRITERIA: This review will consider all cost and cost-effectiveness studies on RHD treatments for children and young adults (5─30 years), residing in low- and middle-income countries. METHODS: The review will follow the JBI methodology for systematic reviews of economic evaluation evidence. The search strategy will locate published and unpublished studies in English. Systematic searches will be conducted in MEDLINE (PubMed), MEDLINE (Ovid), Embase (Ovid), Scopus, CINAHL (EBSCOhost), National Health Service Economic Evaluation Databases, Pediatric Economic Database Evaluation, and Cost-Effectiveness Analysis Registry. Two independent reviewers will screen titles and abstracts, followed by a full-text review based on the inclusion criteria. Data will be extracted using a modified JBI data extraction form for economic evaluations. JBI's Dominance Ranking Matrix for economic evaluations will be used to summarize and compare the results of cost and cost-effectiveness studies. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach will be used to assess the certainty of economic evidence for outcomes related to resource use. REVIEW REGISTRATION NUMBER: PROSPERO CRD42023425850.

Severity Scoring Cutoff for MLPA and Its Diagnostic Yield in 332 North Indian Children with Developmental Delay.

Chromosomal aberrations/rearrangements are the most common cause of intellectual disability (ID), developmental delay (DD), and congenital malformations. Traditionally, karyotyping has been the investigation of choice in such cases, with the advantage of being cheap and easily accessible, but with the caveat of the inability to detect copy number variations of sizes less than 5 Mb. Chromosomal microarray can solve this problem, but again the problems of expense and poor availability are major challenges in developing countries. The purpose of this study is to find the utility of multiplex ligation-dependent probe amplification (MLPA) as a middle ground, in a resource-limited setting. We also attempted to establish an optimum cutoff for the de Vries score, to enable physicians to decide between these tests on a case-to-case basis, using only clinical data. A total of 332 children with DD/ID with or without facial dysmorphism and congenital malformations were studied by MLPA probe sets P245. Assessment of clinical variables concerning birth history, facial dysmorphism, congenital malformations, and family history was done. We also scored the de Vries scoring for all the patients to find a suitable cutoff for MLPA screening. In our study, the overall detection rate of MLPA was 13.5% (45/332). The majority of patients were DiGeorge's syndrome with probe deletion in 22q11.21 in 3.3% (11/332) followed by 15q11.2 del in 3.6% (12/332, split between Angelman's and Prader-Willi's syndromes). Also, 3.0% (10/332) of patients were positive for Williams-Beuren's syndrome 7q11.23, 1.8% (6/332) for Wolf--Hirschhorn's syndrome 4p16.3, 1.2% (4/332) for 1p36 deletion, and 1% for each trichorhinophalangeal syndrome type I 8q23.3 duplication syndrome and cri du chat syndrome. The optimum cutoff of de Vries score for MLPA testing in children with ID and/or dysmorphism came out to be 2.5 (rounded off to 3) with a sensitivity of 82.2% and specificity of 66.7%. This is the largest study from India for the detection of chromosomal aberrations using MLPA common microdeletion kit P245. Our study suggests that de Vries score with a cutoff of 3 or more can be used to offer MLPA as the first tier test for patients with unexplained ID, with or without facial dysmorphism and congenital malformations.

Pattern Recognition of Common Multiple Congenital Malformation Syndromes with Underlying Chromatinopathy.

Chromatinopathy is an emerging category of multiple malformation syndromes caused by disruption in global transcriptional regulation with imbalances in the chromatin states (i.e., open or closed chromatin). These syndromes are caused by pathogenic variants in genes coding for the writers, erasers, readers, and remodelers of the epigenetic machinery. Majority of these disorders (93%) show neurological dysfunction in the form of intellectual disability. Other overlapping features are growth abnormalities, limb deformities, and immune dysfunction. In this study, we describe a series of children with six common chromatinopathy syndromes with an aim to develop pattern recognition of this emerging category of multiple malformation syndromes.

Estrogen Receptor 1 Gene Polymorphism and its Association with Idiopathic Short Stature in North Indian Population.

Background: In the hypothalamic-pituitary-gonadotrophin (HPG) axis, estrogen plays a key role in the bone maturation regulation and growth plates closure. This study was designed to explore the link between single nucleotide polymorphisms (SNPs) in estrogen receptor 1 (ESR1) gene with idiopathic short stature (ISS) susceptibility in the North Indian population. Methods: Four SNPs of the ESR1 gene (rs543650, rs6557177, rs2234693 and rs9340799) were genotyped by Sanger sequencing in 52 ISS patients and 68 controls. Linkage disequilibrium (LD) and haplotyping were done by SNPstat and SHESISplus softwares. Extent of LD was determined by calculating D' and r2 values in SNPs paired combinations. Results: A significant positive association was found between rs6557177 and rs543650 genotype and ISS susceptibility as compared to controls. The frequencies of the rs6557177 CC genotype (p=0.030; OR=0.13; 95% CI:0.01-1.10) and rs543650 genotype TT (p =0.043; OR=0.29; 95% CI: 0.09-0.92) were observed to be increased in ISS group as compared with the control group. However, no significant correlation was observed between clinical parameters of patients and these SNPs. rs543650 shown strong LD with rs2234693 and rs9340799, similarly rs2234693 and rs9340799. Conclusion: Our study showed that CC genotype at rs6557177 and TT genotype of rs543650 of ESR1 constitutes risk factor for developing ISS in North Indian children. In the future, these findings may lead to a better understanding of the SNPs associated with ISS susceptibility.

Biallelic novel variants in ZNF469 causing Brittle Cornea Syndrome 1: a detailed report of an Indian patient.

BACKGROUND: Variations in ZNF469 have been associated with Brittle Cornea Syndrome that presents with bluish sclera, loss of vision after trivial trauma, arachnodactyly, and joint laxity. MATERIALS AND METHODS: Detailed medical and family history, physical examination, and molecular analysis. RESULTS: A 21-year-old female presented with bluish discoloration of sclera, diminution of vision following trivial trauma in childhood along with hearing loss and systemic features of arachnodactyly and joint laxity. Clinical diagnosis of brittle cornea syndrome was made which was molecularly proven using next-generation sequencing which identified compound heterozygosity in ZNF469 for pathogenic and likely pathogenic nonsense variants. One variant namely NM_001367624.2:c.5882dup was identified in the exon 3 which was novel and classified as likely pathogenic according to American College of Medical Genetics (ACMG) criteria for variant classification. Another variant NM_001367624.2:c.8992C>T in the exon 2 was classified as pathogenic for Brittle Cornea Syndrome 1. CONCLUSIONS: The report adds to the allelic heterogeneity in ZNF469 causative of Brittle Cornea Syndrome 1 and shall acquaint the physicians about this potentially vision threatening, underdiagnosed, rare syndrome.

Neurofibromatosis type 1: Clinical characteristics and mutation spectrum in a North Indian cohort.

Background: Neurofibromatosis type 1 (NF1) is a unique, highly penetrant neuro-cutaneous disorder with a wide range of manifestations. Though the clinical diagnosis of NF1 is straight forward, there can be other disorders which mimic NF1, especially its cutaneous features. Here we describe the clinical and mutation spectrum of a series of individuals whose primary diagnosis was NF1 or NF1 related disorders. Methods: We have screened 29 unrelated individuals who fulfilled the clinical criteria of NF1. Whole exome sequencing (WES) was done in all individuals except one with suspected microdeletion syndrome with NF1 in whom Cytogenetic microarray (CMA) was done. Results: Out of 29 suspected patients, 25 had germline pathogenic/likely pathogenic variants involving NF1 gene. Five novel and 20 known variants in coding and non-coding regions were identified, among them 7 variants were deletions (28%), 7 nonsense (28%), 3 splice-site (12%), 4 missense (16%), 2 duplications (8%) and 2 (8%) were contiguous deletions. In those where NF1 variants were not detected, 3 had neurofibromatosis type 2 (NF2) and 1 rare autosomal recessive form of Elher Danlos syndrome. Conclusion: We hereby present the wide range of manifestations in different age groups and the mutation spectrum ranging from small scale variants to contiguous gene deletion syndromes involving NF1 gene. We highlight the usefulness of molecular testing and its importance in tumor surveillance and genetic counseling in this disorder.

Characterization of the CYP21A2 Gene Mutations in Children with Classic Congenital Adrenal Hyperplasia.

OBJECTIVE: To characterize the CYP21A2 gene mutations in children with classic congenital adrenal hyperplasia (CAH). METHODS: A prospective, cross-sectional study was conducted on 24 children with classic CAH. Molecular characterization of the CYP21A2 gene was carried out by Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), or clinical exome sequencing. Another 21 previously mutation-proven CAH patients were also included and a combined result was drawn. RESULTS: Out of 45 children, pathogenic variants in the CYP21A2 gene were identified in 43 patients (95.5%). Homozygous, probable compound heterozygous, and heterozygous variants were seen in 69%, 22%, and 18% of patients, respectively. The most common variant was c.293-13C/A>G (33%), followed by deletion/duplication (24%), and c.955C>T (p.Gln319Ter) (21%), similar to previous Indian studies. Allelic frequencies of c.332_339del and c.518 T>A (p.Ile173Asn) were 9% and 4%, respectively. Less common variants were c.923dupT (p.Leu308PhefsTer6), c.92C>T (p.Pro31Leu), c.1069C>T (p.Arg357Trp), c.1267G>C (p.Gly423Arg), and c.710_719delins (p.Ile237_Met240delinsAsnGluGluLys). A good genotype-phenotype correlation was observed; only p.Pro31Leu and p.Ile173Asn variants showed discordance. The diagnostic yield of Sanger sequencing alone, Sanger sequencing with MLPA, and clinical exome alone was 85%, 100%, and 100%, respectively. CONCLUSIONS: All children, except two, diagnosed clinically as classic CAH, showed pathogenic variants in the CYP21A2 gene; the most common variant was c.293-13 C/A>G. The results suggest a broad mutation spectrum in the authors' single-center cohort of children with CAH. Clinical exome sequencing is the preferred stand-alone method for molecular diagnosis of CAH.

Health-related quality of life and fatigue perception in children with congenital adrenal hyperplasia: A Developing nation perspective.

INTRODUCTION: Disease chronicity, lifelong medications, Adrenal crisis, and genital surgeries affect the physical, mental, school and social aspects of a child's life and are a cause of great concern to parents regarding the future of their child with Congenital Adrenal Hyperplasia (CAH). The aim of the study was to assess quality of life (QoL) in children and parents of CAH and comparison with healthy children. MATERIAL AND METHODS: This was a questionnaire-based cross-sectional study in 28 children with classical CAH attending the Pediatric Endocrine clinic at a tertiary-care center in northern India. RESULTS: CAH children had poorer QoL in School domain (73.6 vs. 90.0; p = 0.034) and significantly lower scores than their healthy peers in General (83.1 vs. 91.7, p = 0.025), Sleep (74.4 vs. 84.2, p = 0.017) domains and total score (80.0 vs. 87.8, p = 0.008) of the Fatigue scale. Parents reported Social (72.4 vs. 84.5; p = 0.009), School (63.8 vs. 90.0; p 0.01) and Total (74.3 vs. 84.2; p = 0.024) QoL were scores significantly lower than parents of healthy children. Parents perceived scores of Fatigue scale were significantly worse in all domains when compared to parents of healthy children. Failure to thrive was found to be a significant risk factor for impaired school (r  = -0.533; p = 0.013) and overall (r = -0.563; p = 0.008) QoL as perceived by the child. CONCLUSIONS: Children and parents have different perception of QoL for their child. Routine periodic QoL assessment will help in better understanding of child and parent's hidden concerns which remain unaddressed in busy clinical practice.