A Challenging Case of Hypercalcemia Caused by a Novel Homozygous Variant Missense Mutation in the CYP24A1 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 CYP24A1 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 CYP24A1 pathogenic variant in unexplained hypercalcemia. Identification of a novel variant expands the genetic landscape of hypercalcemia and supports further exploration of targeted therapies.