24-Hydroxylase Deficiency Due to CYP24A1 Sequence Variants: Comparison with Other Vitamin D-mediated Hypercalcemia Disorders

Context: CYP24A1 encodes 24-hydroxylase, which converts 25(OH)D3 and 1,25(OH)2D3 to inactive metabolites. Loss-of-function variants in CYP24A1 are associated with 24-hydroxylase deficiency (24HD), characterized by hypercalcemia, nephrolithiasis, and nephrocalcinosis. We retrospectively reviewed laboratory, imaging, and clinical characteristics of patients with suspected or confirmed 24HD and patients with other vitamin D-mediated hypercalcemia disorders: sarcoidosis, lymphoma, and exogenous vitamin D toxicity (EVT). Objective: To identify features that differentiate 24HD from other vitamin D-mediated hypercalcemia disorders. Methods: Patients seen at the Mayo Clinic (Rochester, MN) from January 1, 2008, to 31 December, 2016, with the following criteria were retrospectively identified: serum calcium ≥9.6 mg/dL, parathyroid hormone <30 pg/mL, and 1,25(OH)2D3 >40 pg/mL. Patients were considered to have 24HD if they had (1) confirmed CYP24A1 gene variant or (2) 25(OH)D3:24,25(OH)2D ratio ≥50. Patients with sarcoidosis, lymphoma, and EVT were also identified. Groups were compared using the Fisher exact test (categorical variables) or the Wilcoxon rank sum test (continuous variables). Results: We identified 9 patients with 24HD and 28 with other vitamin D-mediated disorders. Patients with 24HD were younger at symptom onset (median 14 vs 63 years; P =. 001) and had positive family history (88.9% vs 20.8%; P <. 001), nephrocalcinosis (88.9% vs 6.3%; P <. 001), lower lumbar spine Z-scores (median-0.50 vs 1.20; P =. 01), higher peak serum phosphorus (% of peak reference range, median 107 vs 84; P =. 01), and higher urinary calcium:creatinine ratios (median 0.24 vs 0.17; P =. 047). Conclusion: Patients with 24HD had clinical and laboratory findings that differed from other vitamin D-mediated hypercalcemia disorders. 24HD should be suspected in patients with hypercalcemia who present at younger age, have positive family history, and have nephrocalcinosis.