OR36-04 Novel Heterozygous CYP24A1 Mutations (c.1226T>C and c.1513C>T) Leading to Adult-Onset Vitamin D-Mediated Hypercalcemia Unmasked by Supplement Use

Abstract Disclosure: L. O'Keefe: None. D. Beckman: None. Novel Heterozygous CYP24A1 Mutations (c.1226T>C and c.1513C>T) Leading to Adult-Onset Vitamin D-Mediated Hypercalcemia Unmasked by Supplement UseIntroductionIn this case of Vitamin D-mediated hypercalcemia, we examine how supplement use unmasked underlying 24-hydroxylase deficiency due to novel mutations in the CYP24A1 gene.Case ReportA 50 year-old female presented in fall 2024 for second opinion on hypercalcemia, as initial evaluation ruled out hyperparathyroidism, PTHrP-induced hypercalcemia, granulomatous disease, or lymphoma. Beginning in 2022, an insidious increase in serum calcium resulted in nephrolithiasis and polyuria. She completed a four-month “detox program” with unknown supplements at the time of the initial calcium increase. On presentation she was taking fourteen supplements including encapsulated beef organs, but denied calcium or vitamin D.Her prescription medications were levothyroxine, methocarbamol, and cetirizine. She denied thiazide use. Family history was negative for hypercalcemia or renal stones. Surgical history included lithotripsy and stent placement for a 1.3cm nephrolith in 2024. Physical exam was unremarkable with normal vital signs and no anterior neck nodules. Labs demonstrated calcium 10.9 mg/dL (normal range 8.6-10.0 mg/dL), 25-Vitamin D 97 ng/mL (30-100 ng/mL), 1,25-Vitamin D 105pg/mL (21-65 pg/mL), PTH 13pg/mL (15-65pg/mL), and 24-hr urine calcium 582.9mg (100-300mg). The elevated 1,25-Vitamin D suggested impaired degradation of 25-Vitamin D via 24-hydroxylase to its inactive metabolite 24,25-Vitamin D; inactivation of 24-hydroxylase results in shunting towards 1,25-Vitamin D. Testing revealed an elevated ratio of 25-Vitamin D to 24,25-Vitamin D of 50:1 (normal <25:1). Genetic testing confirmed two newly described heterozygous missense mutations in the CYP24A1 gene, c.1226T>C and c.1513C>T, which codes for 24-hydroxylase. The patient discontinued supplements. On follow up, labs showed calcium 9.7mg/dL, 25-Vitamin D 75 ng/mL, and 1,25-Vitamin D 66 pg/mL. DiscussionThe inappropriate 1,25-Vitamin D elevation was an important clue to her underlying 24-hydroxylase deficiency. Elevated 1,25-Vitamin D is associated with Idiopathic Infantile Hypercalcemia secondary to homozygous mutations of CYP24A1. As our patient had no hypercalcemia in childhood, genetic causes were not considered during initial evaluation. However, case reports of adult-onset hypercalcemia have been linked to heterozygous CYP24A1 mutations. We posit that her previously undescribed mutations in the CYP24A1 gene resulted in subclinical impairment of 24-hydroxylase, which compensated under normal conditions, but unmasked with supplement use.This case underscores the need to follow the implications of unusual lab results and consider genetic mutations in adults, as mildly pathogenic variants may have subclinical manifestations. Presentation: Monday, July 14, 2025