Overlapping Phenotypes Associated With , , and Mutations: A Cohort Study of Patients With Hypersensitivity to Vitamin D.

Mutations in (vitamin D 24-hydroxylase) and (renal phosphate transporter NPT2a) cause autosomal recessive Infantile Hypercalcemia type 1 and 2, illustrating links between vitamin D and phosphate metabolism. Patients may present with hypercalciuria and alternate between chronic phases with normal serum calcium but inappropriately high 1,25-(OH)D and appropriately low PTH, and acute phases with hypercalcemia with suppressed PTH. Mutations in and have been associated with phosphate wasting without hypercalcemia. The aims of this study were to evaluate the frequency of mutations in these genes in patients with a medical history suggestive of mutation to search for a specific pattern. Using next generation sequencing, we screened for mutations in 185 patients with PTH levels < 20 pg/mL, hypercalcemia and/or hypercalciuria, and relatives. Twenty-eight (15%) patients harbored biallelic mutations in (25) and (3), mostly associated with renal disease (lithiasis, nephrocalcinosis) (86%). Hypophosphatemia was found in 7 patients with biallelic mutations in and a normal phosphatemia was reported in 2 patients with biallelic mutations in . Rare variations in and were mostly of uncertain significance. Fifteen patients (8%) carried only one heterozygous mutation. Heterozygous relatives carrying or variation may present with biochemical changes in mineral metabolism. Two patients' genotype may suggest digenism (heterozygous variations in different genes). No variation was found in As no specific pattern can be found, patients with medical history suggestive of mutation should benefit from and analysis.