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

Sarah M. Azer, Lisa E. Vaughan, Peter J. Tebben, David J. Sas

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numberbvab119
JournalJournal of the Endocrine Society
Issue number9
StatePublished - Sep 2021


  • 24-hydroxylase
  • CYP24A1
  • Idiopathic infantile hypercalcemia
  • genetic
  • hypercalcemia
  • vitamin D

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism


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