25-Hydroxyvitamin D 24-hydroxylase (CYP24A1) deficiency is a rare cause of autosomal recessive infantile hypercalcemia due to vitamine D hypersensitivity. We report the case of a 2-year-old boy who presented with severe hypercalcemia-hypercalciuria and a bilateral nephrocalcinosis. Laboratory investigations detected a collapsed parathormone and a highly elevated 1α,25-dihydroxycholecalciferol along with an increased phosphate excretion (hypophosphatemia and hyperphosphaturia). An adapted management with two courses of palmidronic acid and an eviction of vitamin D and calcium allowed to stabilize him. A homozygous p.Leu409Ser pathogenic variant on CYP24A1 gene resulting in a collapsed 25-Hydroxyvitamin D24-hydroxylase activity was found. A normal development is possible with a meticulous clinical, biological and nutritional management and monitoring. Vitamin D hypersensitivity is challenging during childhood, especially due to the need to avoid vitamin D while requiring a close nutritional monitoring to maintain a normal growth. Biomarkers such as vitamin D metabolite ratio and 24,25(OH)2D3 along with ionized calcium and nutritional management can contribute to properly follow patients with vitamin D hypersensitivity. Le déficit en 25-hydroxyvitamine D 24-hydroxylase (CYP24A1) est une cause rare d’hypercalcémie infantile autosomique récessive due à une hypersensibilité à la vitamine D. Nous rapportons le cas d’un garçon de 2 ans qui a présenté une hypercalcémie-hypercalciurie sévère et une néphrocalcinose bilatérale. Les examens de laboratoire ont détecté une parathormone effondrée et un 1α,25-dihydroxycholécalciférol très élevé ainsi qu’une excrétion accrue de phosphate (hypophosphatémie et hyperphosphaturie). Une prise en charge adaptée avec deux cures d’acide palmidronique et une éviction de la vitamine D et du calcium a permis de le stabiliser. Un variant pathogène homozygote p.Leu409Ser sur le gène CYP24A1 entraînant un effondrement de l’activité de la 25-hydroxyvitamine D24-hydroxylase a été retrouvé. Un développement normal est possible avec une prise en charge et un suivi clinique, biologique et nutritionnel méticuleux. L’hypersensibilité à la vitamine D est un défi pendant l’enfance, notamment en raison de la nécessité d’éviter la vitamine D tout en exigeant un suivi nutritionnel étroit pour maintenir une croissance normale. Les biomarqueurs tels que le rapport des métabolites de la vitamine D et la 24,25(OH)2D3, ainsi que le calcium ionisé et la gestion nutritionnelle peuvent contribuer à un suivi adéquat des patients souffrant d’hypersensibilité à la vitamine D.

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.