Endocrine Abstracts

Vitamin D-dependent rickets type-1 (VDDR1) is an autosomal recessive disorder characterised by onset of rickets by 2 years of age, accompanied by poor growth and hypotonia, muscle weakness, seizures, hypocalcaemia with secondary hyperparathyroidism, hypophosphataemia and normal plasma 25-hydroxyvitamin D (25(OH₂)D) concentration that distinguishes VDDR1 from vitamin D deficient rickets. VDDR1 is caused by loss-of-function mutations of the 25-hydroxyvitamin D 1-alpha-hydroxylase gene, also referred to as cytochrome P450 family 27 subfamily-B member-1 (CYP27B1), and this explains the occurrence of low plasma 1,25(OH₂)D concentrations, despite the normal 25(OH)D and elevated parathyroid hormone (PTH) concentrations. To date, 46 CYP27B1 mutations have been identified in VDDR1 patients and ~75% of these are missense, ~15% are small deletions or insertions, and ~10% are nonsense mutations. We report a consanguineous family, originating from the Indian subcontinent, in which two siblings have VDDR1 due to a novel homozygous CYP27B1 mutation (Phe80fsX157). The proband, at 21 months of age presented with bilateral pes plano valgus and flexion deformity of the knees in association with hypocalcaemia, and his sister presented at 6 weeks of age with a hypocalcaemic seizure. Treatment with calcitriol (i.e. 1,25(OH)₂D) restored normocalcaemia. DNA sequence analysis, using leukocyte DNA, of the CYP27B1 nine coding exons, and intron-exon boundaries, identified a novel homozygous 1 bp deletion of a T at codon 80 in exon 2 of the CYP27B1 gene. This mutation predicts a frameshift with 77 missense amino acids, followed by a premature stop codon at amino acid 157. Such a mutation, in which 351 amino acids are lost is likely deleterious. Thus, the VDDR1 in this family is due to a novel, frame-shifting CYP27B1 mutation.