AUTHOR=Molin Arnaud , Lemoine Sandrine , Kaufmann Martin , Breton Pierre , Nowoczyn Marie , Ballandonne Céline , Coudray Nadia , Mittre Hervé , Richard Nicolas , Ryckwaert Amélie , Lavillaureix Alinoe , Jones Glenville , Bacchetta Justine , Kottler Marie-Laure 

TITLE=Overlapping Phenotypes Associated With CYP24A1, SLC34A1, and SLC34A3 Mutations: A Cohort Study of Patients With Hypersensitivity to Vitamin D

JOURNAL=Frontiers in Endocrinology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.736240

DOI=10.3389/fendo.2021.736240

ISSN=1664-2392

ABSTRACT=<p>Mutations in <italic>CYP24A1</italic> (vitamin D 24-hydroxylase) and <italic>SLC34A1</italic> (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)<sub>2</sub>D and appropriately low PTH, and acute phases with hypercalcemia with suppressed PTH. Mutations in <italic>SLC34A3</italic> and <italic>SLC9A3R1</italic> 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 <italic>CYP24A1</italic> mutation to search for a specific pattern. Using next generation sequencing, we screened for mutations in 185 patients with PTH levels &lt; 20 pg/mL, hypercalcemia and/or hypercalciuria, and relatives. Twenty-eight (15%) patients harbored biallelic mutations in <italic>CYP24A1</italic> (25) and <italic>SLC34A3</italic> (3), mostly associated with renal disease (lithiasis, nephrocalcinosis) (86%). Hypophosphatemia was found in 7 patients with biallelic mutations in <italic>CYP24A1</italic> and a normal phosphatemia was reported in 2 patients with biallelic mutations in <italic>SLC34A3</italic>. Rare variations in <italic>SLC34A1</italic> and <italic>SLC34A3</italic> were mostly of uncertain significance. Fifteen patients (8%) carried only one heterozygous mutation. Heterozygous relatives carrying <italic>SLC34A1</italic> or <italic>SLC34A3</italic> 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 <italic>SLC9A3R1.</italic> As no specific pattern can be found, patients with medical history suggestive of <italic>CYP24A1</italic> mutation should benefit from <italic>SLC34A1</italic> and <italic>SLC34A3</italic> analysis.</p>