Hypercalcemia due to <i>CYP24A1</i> 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 <i>CYP24A1</i> 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 <i>CYP24A1</i> 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 <i>CYP24A1</i>. We share 5 cases of a rare condition and further broaden the presentation of <i>CYP24A1</i> 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 <i>CYP24A1</i> variants in patients with unexplained calcitriol-associated hypercalcemia/hypercalciuria.