Siblings with vitamin D‐dependent rickets type 1A: Importance of genetic testing and a review of genotype–phenotype correlations

Abstract

AbstractVitamin D‐dependent rickets type 1A (VDDR1A) is a rare condition caused by biallelic pathogenic variants in CYP27B1, which encodes 25‐hydroxyvitamin D3‐1‐α‐hydroxylase. Inadequate activity of this enzyme results in deficient 1α‐hydroxylation of inactive 25‐hydroxyvitamin D to biologically active 1,25‐dihydroxyvitamin D, with consequent adverse effects on calcium and phosphate metabolism. A female child was clinically diagnosed at 18 months old with hypophosphatemic rickets based on phenotype and biochemical testing, with neither parent affected. A subsequent affected male sibling led to the reconsideration of the diagnosis. Exome sequencing showed a homozygous CYP27B1 c.1040T>A (p.Ile347Asn) variant for both children. No variants were found in genes associated with hypophosphatemic rickets. A review of published cases of VDDR1A with homozygous CYP27B1 variants indicates variable clinical presentation, lack of genotype–phenotype correlation, and low serum phosphate at diagnosis in most cases. These findings emphasize the clinical importance of molecular testing as part of the diagnostic evaluation for cases of non‐nutritional rickets.