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

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.

The Vitamin D Metabolite Diagnostic Ratio Associates With Phenotypic Traits of Idiopathic Hypercalciuria

“… 37 Individuals with infantile hypercalcemia type 1 and very low CYP24A1 activity have high FGF23 levels. 38 , 39 In our analysis, a trend toward an association between lower CYP24A1 activity and higher 1,25 (OH) 2 vitamin D 3 was observed after adjusting for FGF23. Thus, we speculate that reduced CYP24A1 activity might lead to higher FGF23, which in turn reduces 1,25 (OH) 2 vitamin D 3 synthesis through inhibition of CYP27B1.…”

Case report: Two heterozygous pathogenic variants of CYP24A1: A novel cause of hypercalcemia and nephrocalcinosis in adulthood

“…However, the heterogeneity of 1,25OH levels is very high in patients with mild forms of IHH (and their adult relatives), ranging from near-normal levels to highly elevated ones ( 13 ). Furthermore, in the Molin's et al study ( 14 ) of patients with hypersensitivity to vitamin D, the levels of 1,25OHD did not significantly differ among patients with or without CYP24A1 mutation. We can just speculate that the combination of these pathogenic variants is not necessarily associated with elevated levels of 1,25OHD (although no functional studies were done to confirm this hypothesis and since it is the first described case of this combination of pathogenic variants, no literature data are available).…”

Mineral Metabolism in Children: Interrelation between Vitamin D and FGF23

“…These inactivating mutations of PHEX cause an increased concentration of FGF23, leading to hyperphosphaturia, hypophosphatemia and low or inappropriately normal serum 1,25(OH) 2 D concentrations [ 128 ]. Table 8 summarizes recent and significant studies published in humans with hypophosphatemic disorders about the effects of treatment and the possible interaction between FGF23, Klotho and vitamin D [ 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 ]. Several mechanisms are still currently unclear and further studies are needed to explore the selective targeting of the distinct biological processes involved in phosphate homeostasis with the exploration of Klotho-FGF23-FGFR1 complex [ 161 , 162 , 163 ].…”