Clinical and Molecular Spectrum of Infantile Hypercalcemia Type I: Insights Into CYP24A1 Variants

Background Inactivating pathogenic variants (PVs) in CYP24A1 (MIM*126065), which encodes the enzyme vitamin D‐24‐hydroxylase, were initially identified in patients with infantile hypercalcemia (IH). Although CYP24A1 PVs were originally associated with a recessive inheritance pattern, it is now understood that heterozygous (monoallelic) variants may also lead to milder phenotypes. Subjects and Methods Eight patients from six families, who presented with hypercalcemia, normal or elevated 25‐hydroxyvitamin D (25(OH)D 3 ), suppressed or low‐normal parathyroid hormone (PTH), and hypercalciuria and/or nephrocalcinosis were included in the study. Results Eight patients (five females) were diagnosed with IH based on clinical and laboratory assessment. The median age at presentation was 9.1 months (range: 5.0‐44.4 months). The most common reason for referral was vomiting, reported in 50% of patients. Four patients (50%) were born to consanguineous parents. The mean serum calcium 3.6 ± 0.7 mmol/L (median 3.5; range 2.8–4.6) and 25(OH)D 3 970.7 ± 880.5 nmol/L (median 845.4; range 89.9–2069) levels were elevated. Data on 1,25(OH)₂D₃ levels were available for three patients; two patients with biallelic PVs exhibited elevated concentrations, whereas the monoallelic patient showed a normal level. Hypercalciuria and/or nephrocalcinosis were present in 87.5% of the patients. Eight distinct CYP24A1 PVs were identified in eight patients. Of these, two patients were homozygous, four were compound heterozygous and two were heterozygous for the respective variants. We detected mild hypercalcemia and/or nephrocalcinosis/nephrolithiasis in 40% of monoallelic parents. Conclusions Monoallelic or biallelic PVs in the CYP24A1 gene play a significant role in the aetiology of hypercalcemia and/or nephrocalcinosis/nephrolithiasis. Early genetic diagnosis is essential for guiding clinical management, particularly to avoid inappropriate vitamin D supplementation and to minimize the risk of long‐term renal complications.