Hypervitaminosis D Secondary to a CYP24A1 Loss‐of‐Function Mutation: An Unusual Cause of Hypercalcemia in Two Siblings

Abstract

Hypervitaminosis D as a cause of hypercalcemia may be due to vitamin D intoxication, granulomatous diseases, or abnormalities of vitamin D metabolism. The CYP24A1 gene encodes for the 24‐hydroxylase enzyme, which is responsible for the catabolism of 25‐hydroxyvitamin D (25(OH)D) and 1,25‐dihydroxyvitamin D (1,25(OH)2D). Mutations in CYP24A1 can result in elevated 1,25(OH)2D causing parathyroid hormone (PTH)‐independent hypercalcemia, hypercalciuria, nephrolithiasis, and nephrocalcinosis. We present the cases of two siblings exhibiting hypercalcemia secondary to a CYP24A1 loss‐of‐function mutation. Case 1 presented initially with PTH‐dependent hypercalcemia, with localization of a left upper parathyroid adenoma on parathyroid technetium sestamibi (99mTc‐MIBI) uptake study. Despite parathyroidectomy (180 mg adenoma), hypercalcemia, hypercalciuria, and low normal PTH levels persisted. A repeat parathyroid 99mTc‐MIBI uptake study localized a second adenoma and a right inferior parathyroidectomy was performed (170 mg adenoma). PTH subsequently became undetectable, however hypercalcemia and hypercalciuria persisted. A new presentation of PTH‐independent hypercalcemia found to be secondary to a CYP24A1 loss‐of‐function mutation in his sibling, Case 2, signaled the underlying cause. Cascade testing confirmed both siblings were homozygous for the pathogenic variant c.1186C>T, p.Arg396Trp (R396W) of CYP24A1 (NM_000782.5). In clinical practice CYP24A1 loss‐of‐function mutations should be considered in patients presenting with PTH‐independent hypercalcemia, hypercalciuria, and 1,25(OH)2D levels in the upper normal or elevated range. Although in our case assays of 24,25(OH)2D were not available, calculation of the 25(OH)D:24,25(OH)2D ratio can assist in the diagnostic process. Possible treatments to manage the risk of hypercalcemia in patients with a CYP24A1 loss‐of‐function mutation include avoidance of vitamin D oversupplementation and excessive sun exposure. Hydration and bisphosphonate therapy can be useful in managing the hypercalcemia. Although not utilized in our cases, treatment with ketoconazole, fluconazole, and rifampicin have been described as potential therapeutic options. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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

“…The opposite condition in which parathyroid hyperplasia occurs as a result of hyperphosphatemia, calcitriol deficiency, or hypocalcaemia is renal failure. In our patient, as well as in the other 5 described patients with the CYP24A1 mutation and PHPT, mild renal failure was noted; however, the phosphate concentration remained low ( 36 – 39 ).…”

“…and Collins et al. ( 38 , 39 ). In most of the reported cases, the genetic panel was extended by the analysis of the genes associated with hyperparathyroidism, i.e., MEN1 (encoding the tumour suppressor protein menin; MEN1, Multiple Endocrine Neoplasia type 1), CaSR (encoding the G protein-coupled extracellular calcium-sensing receptor), HRPT2 (encoding the tumour suppressor parafibromin) and CDK (encoding the tumour suppressor cyclin-dependent kinase) ( 37 , 48 , 49 ).…”

“…In the case described by Collins et al., genetic testing confirmed that the patient was homozygous for the pathogenic variant c.1186C>T, p.Arg396Trp in the CYP24A1 gene ( 39 ). ( 39 ) Documented cases of primary hyperparathyroidism and missense p.Arg396Trp mutation raise the question of whether the described genetic alteration predisposes patients to parathyroid autonomy. The link between loss-of-function CYP24A1 mutations and the development of primary hyperparathyroidism has not been confirmed ( 50 ).…”

“…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.…”

“…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.…”