A Challenging Case of Hypercalcemia Caused by a Novel Homozygous Variant Missense Mutation in the <i>CYP24A1</i> Gene

Mild to moderate elevations of calcium may be asymptomatic and therefore remain undiagnosed until detected incidentally or when an aggravating factor exacerbates the hypercalcemia, causing recognizable symptoms. We report a unique case of a 26-year-old male with persistent hypercalcemia, nephrolithiasis, suppressed PTH, normal PTH-related protein, and hypercalciuria but no etiological diagnosis despite an exhaustive workup. Genetic analysis revealed a novel homozygous missense pathogenic variant of the <i>CYP24A1</i> gene, crucial for vitamin D metabolism. Mutations in this gene have been shown to cause hypercalcemia, due to decreased catabolism of 1,25-dihydroxyvitamin D3, resulting in increased calcium absorption, hypercalcemia, and hypercalciuria, without elevated PTH levels. Over 16 months of follow-up, the hypercalcemia remained mild to moderate, with instructions to restrict supplemental vitamin D and dietary calcium. He also received fluconazole 50 mg daily and magnesium glycinate 850 mg 12 hourly for 3 months. Calcium levels fell from 12.7 mg/dL (8.2-10.3 mg/dL) (SI: 3.1 mmol/L [2.1-2.6 mmol/L]) to 9.4 mg/dL (SI: 2.3 mmol/L). This case underscores the importance of considering <i>CYP24A1</i> pathogenic variant in unexplained hypercalcemia. Identification of a novel variant expands the genetic landscape of hypercalcemia and supports further exploration of targeted therapies.