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

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

doi:10.3389/fendo.2021.736240

Abstract

Mutations in CYP24A1 (vitamin D 24-hydroxylase) and SLC34A1 (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)2D and appropriately low PTH, and acute phases with hypercalcemia with suppressed PTH. Mutations in SLC34A3 and SLC9A3R1 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 CYP24A1 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 CYP24A1 (25) and SLC34A3 (3), mostly associated with renal disease (lithiasis, nephrocalcinosis) (86%). Hypophosphatemia was found in 7 patients with biallelic mutations in CYP24A1 and a normal phosphatemia was reported in 2 patients with biallelic mutations in SLC34A3. Rare variations in SLC34A1 and SLC34A3 were mostly of uncertain significance. Fifteen patients (8%) carried only one heterozygous mutation. Heterozygous relatives carrying SLC34A1 or SLC34A3 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 SLC9A3R1. As no specific pattern can be found, patients with medical history suggestive of CYP24A1 mutation should benefit from SLC34A1 and SLC34A3 analysis.

Highlights

Hypersensitivity to vitamin D (HVD) may be defined as an inability to regulate vitamin D metabolism which leads to calcium homeostasis deregulation, especially in case of vitamin D supplementation [1]
This phenotype was classically associated with Idiopathic Infantile Hypercalcemia (IIH), a condition firstly described in the early fifties [2]
In 2011, mutations in CYP24A1 encoding the vitamin D 24-hydroxylase were identified as the cause of Infantile Hypercalcemia type 1 (IH1) (MIM 143880) with HVD phenotype [3, 4]

Summary

Introduction

Hypersensitivity to vitamin D (HVD) may be defined as an inability to regulate vitamin D metabolism which leads to calcium homeostasis deregulation, especially in case of vitamin D supplementation [1]. This phenotype was classically associated with Idiopathic Infantile Hypercalcemia (IIH), a condition firstly described in the early fifties [2]. In 2011, mutations in CYP24A1 encoding the vitamin D 24-hydroxylase were identified as the cause of Infantile Hypercalcemia type 1 (IH1) (MIM 143880) with HVD phenotype [3, 4]. Patients present with a lifelong susceptibility to acute hypercalcemia and hypercalciuria, especially in case of vitamin D supplementation [16] and sunshine exposure [17]

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