Hypercalcemia due to CYP24A1 variants in five unrelated patients: diagnostic and clinical considerations

Calcitriol-induced hypercalcemia is most frequently caused by granulomatous and inflammatory conditions such as sarcoidosis as well as lymphoma. Recently, pathogenic CYP24A1 variants resulting in inability of the 24-hydroxylase enzyme to deactivate 1,25(OH)2D has been found to be a cause of calcitriol-induced hypercalciuria and hypercalcemia in children and adults. Patients may present with hypercalcemia, suppressed PTH, hypercalciuria, and renal stones. We describe 4 young women and 1 man with calcitriol-associated hypercalcemia in whom pathogenic CYP24A1 variants were found to be the cause. In 2 of the 3 women who became pregnant, hypercalcemia worsened (the calcium was not checked during pregnancy in the third). Lactation was associated with worsened hypercalcemia in the 2 women who breast-fed. In the other woman who did not become pregnant, serum calcium levels varied from high normal to markedly elevated often without an explanation. The male patient was a middle-aged man with a long history of kidney stones and hypercalcemia as well as a family history of kidney stones. Gene sequencing confirmed that each patient had 2 variants in CYP24A1. We share 5 cases of a rare condition and further broaden the presentation of CYP24A1 variants to not only include worsening hypercalcemia in pregnancy, but also during lactation. Further calcium levels may vary markedly in patients with this condition. Physicians should consider pathogenic CYP24A1 variants in patients with unexplained calcitriol-associated hypercalcemia/hypercalciuria.