Three Sisters With Heterozygous Gene Variants of CYP24A1: Maternal Hypercalcemia, New-Onset Hypertension, and Neonatal Hypoglycemia

Gene variants of CYP24A1, which encodes the enzyme 24-hydroxylase, are a most unusual cause of maternal hypercalcemia. Loss-of-function mutations in CYP24A1 result in impaired dehydroxylation of active vitamin D (calcitriol). Secondary to this hypercalcemia, hypercalciuria and suppressed parathyroid hormone (P-PTH) can develop. These gene-variants are most often detected in children exposed to vitamin D prophylaxis. These children develop failure to thrive, hypercalciuria, hypercalcemia, and low PTH levels. CYP24A1 variants have also been reported in adults with hypercalcemia and recurrent urolithiasis. This report describes gestational hypercalcemia in two of three sisters with combined CYP24A1 heterozygous variants. METHODS: We retrospectively investigated medical files, clinical information, and calcium levels during and after pregnancy in three sisters giving birth to nine children. All three sisters were also tested genetically. RESULTS: Two sisters developed hypercalcemia during all seven pregnancies and late-onset hypertension during pregnancy. These sisters had two heterozygote variants in the enzyme CYP24A1: c1186C>T and c443T>C. A third sister had the c1186C>T variant and was normocalcemic. Of the seven children born to the two sisters with combined variants, four had hypercalcemia and five had hypoglycemia as neonates. In these mothers, calcium levels slowly normalized postpartum. In the affected neonates, calcium and blood glucose levels became normal within weeks. CONCLUSION: Combined variants of CYP24A1 caused long-standing gestational hypercalcemia and late-onset hypertension. In neonates, elevated serum calcium and hypoglycemia can be consequences necessitating prompt measures. CYP24A1 mutations should be considered in unexplained gestational hypercalcemia. Their combined effects during pregnancy have not been observed previously.