Do the heterozygous carriers of a CYP24A1 mutation display a different biochemical phenotype than wild types

Context Human cytochrome P450 24 subfamily A member 1 (CYP24A1) loss-of-function mutations result in impaired activity of the 24-hydroxylase involved in vitamin D catabolism, thus inducing a vitamin D-dependent hypercalcemia. Homozygotes often present an overt clinical phenotype named Idiopathic Infantile hypercalcemia (IIH), whereas it is debated whether heterozygotes display an abnormal phenotype. Objectives To compare the clinical and biochemical features of heterozygous carriers of CYP24A1 variant and healthy wild-type controls, sharing the same genetic and environmental exposure. Methods A large family harboring the nonsense c.667A>T, p.Arg223* pathogenic variant in the CYP24A1 gene was evaluated. All subjects underwent clinical and biochemical evaluation and complete analysis of vitamin D metabolites using mass-spectroscopy including 1,24,25(OH)3D3. Subjects were divided according to their genotype in two groups: heterozygotes and wild-type for the CYP24A1 variant. Results The proband, a 40-year-old man, homozygous for p.Arg223* pathogenic variant, had a history of mild hypercalcemia with a seasonal trend, recurrent nephrolithiasis, and no episodes of acute hypercalcemia. He showed the highest serum levels of FGF23, the highest 25(OH)D3/24,25(OH)2D3 ratio and undetectable levels of 1,24,25(OH)3D3 which represent indicators of a loss-of function CYP24A1. Compared to the wild-types, heterozygotes had higher serum calcium and 25(OH)D3 concentrations (P=0.017 and P=0.025, respectively), without any difference in the other biochemical parameters and in the rate of nephrolithiasis. Conclusions Heterozygotes exhibit a biochemical phenotype different from that of wild-type subjects. In clinical practice, these individuals might require surveillance because of the potential risk of developing hypercalcemia and related clinical manifestations if exposed to triggering factors.