Severe Hypercalcemia Due to Primary Hyperparathyroidism and Heterozygous Pathogenic Variant of CYP24A1

Abstract

Pathogenic variants of CYP24A1 are associated with hypercalcemia due to disruptions in the ability of 24-hydroxylase to break down 1,25-dihydroxyvitamin D (1,25-DHVD). A case involving a heterozygous pathogenic variant of CYP24A1 and primary hyperparathyroidism leading to severe hypercalcemia has not been previously reported. A 23-year-old woman presented with fatigue and was found to be hypercalcemic at 13.8 mg/dL [reference range, 8.4-10.2 pg/mL]. Her parathyroid hormone (PTH) was 62 pg/mL [reference range, 19-88 pg/mL] and 1,25-DHVD was elevated to 242.7 pg/mL [reference range, 18-72 pg/mL]. Other laboratory workup was unrevealing. She had a bone scan, whole body CT scan, and thyroid ultrasound that were normal. Her 25-hydroxy-vitamin D to 24,25-dihydroxy-vitamin D ratio was elevated at 25.18 (normal, < 25). Because of concern for primary hyperparathyroidism, she was referred to an endocrine surgeon and underwent a parathyroidectomy with the removal of a 3.5-gram adenoma. Pathology showed a parafibromin-deficient parathyroid neoplasm. Genetic testing demonstrated a heterozygous pathogenic variant in CYP24A1. Three weeks after surgery, PTH was 14 pg/mL (1.48 pmol/L), calcium and 1,25-DHVD normalized. In summary, we report a case where a patient with severe symptomatic hypercalcemia was found to have primary hyperparathyroidism exacerbated by an underlying heterozygous pathogenic variant in CYP24A1.

Persistent hypercalcaemia associated with two pathogenic variants in the CYP24A1 gene and a parathyroid adenoma—a case report and review

“…Pathological examination revealed hyperplasia in the parathyroid glands in 2 patients after total or partial parathyroidectomy ( 37 , 38 ). For the other subjects, adenomas were found; in one patient, a complete histopathology report was unavailable ( 36 , 37 , 39 , 40 ). In all patients, removal of autonomous parathyroid tissue resulted in a significant decrease in the serum calcium concentration.…”

“…In a recent case, low-normal PTH concentrations (23.6 pg/mL) before and after the first partial parathyroidectomy were observed, and after the second parathyroid surgery, PTH became undetectable ( 39 ). The only known patient with a heterozygous pathogenic variant in CYP24A1 had a preoperative PTH level of 63 pg/mL ( 40 ).…”

“…In most of the discussed cases, the 25(OH)D 3 :24.25(OH) 2 D 3 ratio was determined before genetic testing ( 37 , 38 , 40 ). Except for one patient with a heterozygous pathogenic variant in CYP24A1 (25(OH)D 3 :24.25(OH) 2 D 3 ratio of 25.18), the ratios were above 100 ( 37 , 38 , 40 ).…”

“…Hypercalcaemia due to a novel heterozygous pathogenic variant (p.Pro392Argfs*9) in the CYP24A1 gene and concomitant primary hyperparathyroidism were documented in the case of a 23-year-old female by Liu et al. ( 40 ).…”

“…To date, 6 cases of primary hyperparathyroidism coexisting with a CYP24A1 mutation have been reported in 5 publications (Table 2) (36)(37)(38)(39)(40). The diagnosis of PHPT was made due to elevated serum calcium and inadequate nonsuppressed PTH.…”