Novel Mutation in CYP2R1 Causing Vitamin D-Dependent Rickets Type 1b.

Monogenic forms of rickets are being increasingly recognized. However, vitamin D-dependent rickets 1b (VDDR1b) due to CYP2R1 gene mutation is exceedingly rare. We report a 4.5-year-old girl and her younger sibling who presented with clinical, radiological, and biochemical features suggestive of nutritional rickets that did not resolve despite repeated therapeutic doses of vitamin D3. This led to evaluation for resistant rickets, which revealed a novel homozygous CYP2R1 c.50_51insTCGGCGGCGC; p.Leu18ArgfsTer79 variant in the affected siblings. The children were treated with oral calcium and cholecalciferol, dose titrated to maintain serum alkaline phosphatase, 25 hydroxy vitamin D, and parathyroid hormone levels in the normal range, with good clinical and radiological response. This case highlights the importance of genetic evaluation in patients with suspected nutritional rickets who have a family history of similar illness and require higher than usual doses of vitamin D for healing or relapse on stopping treatment. To the best of our knowledge this is the first case of VDDR1b reported from Asia.

High Frequency of Recessive WFS1 Mutations Among Indian Children With Islet Antibody-negative Type 1 Diabetes.

BACKGROUND: While the frequency of islet antibody-negative (idiopathic) type 1 diabetes mellitus (T1DM) is reported to be increased in Indian children, its aetiology has not been studied. We investigated the role of monogenic diabetes in the causation of islet antibody-negative T1DM. METHODS: We conducted a multicenter, prospective, observational study of 169 Indian children (age 1-18 years) with recent-onset T1DM. All were tested for antibodies against GAD65, islet antigen-2, and zinc transporter 8 using validated ELISA. Thirty-four islet antibody-negative children underwent targeted next-generation sequencing for 31 genes implicated in monogenic diabetes using the Illumina platform. All mutations were confirmed by Sanger sequencing. RESULTS: Thirty-five (21%) children were negative for all islet antibodies. Twelve patients (7% of entire cohort, 34% of patients with islet antibody-negative T1DM) were detected to have pathogenic or likely pathogenic genetic variants. The most frequently affected locus was WFS1, with 9 patients (5% of entire cohort, 26% of islet antibody-negative). These included 7 children with homozygous and 1 patient each with a compound heterozygous and heterozygous mutation. Children with Wolfram syndrome 1 (WS) presented with severe insulin-requiring diabetes (including 3 patients with ketoacidosis), but other syndromic manifestations were not detected. In 3 patients, heterozygous mutations in HNF4A, ABCC8, and PTF1A loci were detected. CONCLUSION: Nearly one-quarter of Indian children with islet antibody-negative T1DM had recessive mutations in the WFS1 gene. These patients did not exhibit other features of WS at the time of diagnosis. Testing for monogenic diabetes, especially WS, should be considered in Indian children with antibody-negative T1DM.