Co-occurrence of pathogenic CYP24A1 gene variants and primary hyperparathyroidism: a diagnostic challenge

Abstract Hypercalcemia is mostly caused by primary hyperparathyroidism (PHPT) or malignancy. Less commonly, hypercalcemia results from vitamin D–dependent mechanisms. Pathogenic variants in CYP24A1, which encodes the 24-hydroxylase responsible for inactivating 1,25-dihydroxyvitamin D, can lead to hypercalciuria, nephrolithiasis/nephrocalcinosis, and hypercalcemia, typically with suppressed parathyroid hormone (PTH). When CYP24A1-related disease coexists with PHPT, their biochemical features may overlap, potentially masking a vitamin D catabolic defect and complicating postoperative interpretation of hypercalcemia. We report two unrelated patients with moderate-to-severe hypercalcemia in whom PHPT and CYP24A1 variants coexisted. The first patient was a 26-year-old man with longstanding nephrolithiasis who initially had hypercalcemia with an inappropriately normal PTH level and imaging consistent with a hyperfunctioning parathyroid lesion, treated with parathyroidectomy (PTx). Several years later, PTH-suppressed hypercalcemia and elevated 25(OH)D3 and 1,25(OH)2D3 concentrations was detected despite the absence of vitamin D supplementation. Genetic testing revealed a heterozygous pathogenic CYP24A1 variant (p.Leu409Ser), consistent with partial 24-hydroxylase deficiency. The second patient was a 59-year-old woman with severe PHPT requiring surgery and later experienced life-threatening hypercalcemia (19.8 mg/dL) requiring hemodialysis, marked calcium fluctuations, particularly after calcium and calcitriol exposure following a second surgery, nephrocalcinosis, and progressive renal impairment. Genetic testing identified compound heterozygous CYP24A1 variants (p.Glu143del and p.Gln82Arg). These cases broaden the clinical spectrum of combined PHPT and CYP24A1-related disease and highlight that persistent or recurrent hypercalcemia after PTx, particularly when PTH is suppressed, may prompt evaluation for CYP24A1 defects, with potential implications for vitamin D avoidance and long-term renal surveillance.