Endocrine Abstracts

JOINT2014

The CYP24A1 gene encodes the enzyme 24-hydroxylase, which plays a crucial role in the catabolism of 1, 25(OH)₂D₃ and 25-hydroxyvitamin D [25(OH)D₃]. A deficiency in this enzyme results in elevated circulating levels of both 25(OH)D₃ and 1, 25(OH)₂D₃, leading to enhanced vitamin D activity. This, in turn, increases serum calcium levels due to heightened intestinal calcium absorption and renal calcium reabsorption. Biallelic pathogenic variants in this gene are responsible for infantile idiopathic hypercalcemia, whereas heterozygous individuals may either maintain normocalcemia or develop mild hypercalcemia. To date, only six cases of patients with a heterozygous CYP24A1 variant and primary hyperparathyroidism (PHPT) has been documented in the literature. Here, we present the cases of two unrelated patients evaluated at our outpatient clinic. The first patient is a man with a history of recurrent nephrolithiasis since the age of 16. At 26, he was referred to our clinic for evaluation after presenting with a serum calcium level of 12. 5 mg/dL (reference range: 8. 6–10. 2), PTH of 24 pg/mL (10–40), 25(OH)D of 72. 8 mg/dL, 1, 25(OH)₂D₃ 64. 9 mg/dL and 24-hour urinary calcium of 558 mg/24h. Suspecting PHPT, a SPECT/CT scan revealed a hyperfunctioning parathyroid gland, leading to parathyroidectomy (PTx) with histological confirmation of a parathyroid adenoma. Six months postoperatively, the patient continued to have persistent hypercalcemia (10. 8 mg/dL) and suppressed PTH (7 pg/mL), raising suspicion for PTH-independent hypercalcemia. Genetic analysis revealed a heterozygous variant c. 1226T>C, p. (Leu409Ser) in the CYP24A1 gene. The second patient is a 59 years-old woman who presented with severe hypercalcemia (14. 3 mg/dL), PTH of 47 pg/mL and 25(OH)D of 30. 9 mg/dL. Suspecting PHPT, she underwent PTx of the left lower and upper glands, with histological confirmation of parathyroid adenomas. Four years later, after missing follow-up appointments, she was admitted to the emergency department with nausea and vomiting due to severe hypercalcemia (19 mg/dL) and an elevated PTH of 227 pg/mL. She was treated with hemodialysis, zoledronic acid, cinacalcet, and, subsequently, underwent PTx of the right lower parathyroid with histological confirmation of adenoma. Six months later, despite persistent hypercalcemia (10. 4 mg/dL) and suppressed PTH (7 pg/mL), genetic analysis revealed compound heterozygosity for the c. 428_430del, p. (Glu143del) and c. 245A>G, p. (Gln82Arg) variants in the CYP24A1 gene. These two cases illustrate the clinical presentation of PHPT in patients with CYP24A1 mutations, showing that these individuals can develop severe hypercalcaemia challenging-to-manage hypercalcemia. Whether this association is just by chance or depends on specific mechanisms remains to be explored.