Background:
CYP24A1 encodes a 24-hydroxylase involved in vitamin D catabolism. Loss-of-function mutations cause vitamin D-dependent hypercalcaemia, commonly manifesting during pregnancy due to upregulated placental and renal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, and empiric colecalciferol supplementation(1-3). We report a case of severe hypercalcaemia detected post-partum due to pathogenic CYP24A1 variants, with significant maternal and fetal sequelae, that had evaded diagnosis in prior pregnancies.
Case:
A G4P2 40-year-old woman was referred for hypercalcaemia discovered post-emergency delivery at 31-weeks’ gestation, with symptoms of polyuria, polydipsia, constipation, and abdominal pain while taking a multivitamin, colecalciferol 1000 IU/d and Caltrate 1800mg/d. Past medical history included pre-eclampsia and HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) during her first pregnancy with delivery at 34-weeks’ gestation while taking a multivitamin, and two subsequent miscarriages (11 and 8 weeks’ gestation) while taking a multivitamin, colecalciferol 1000 IU/d, and prophylactic Caltrate 1800mg/d and aspirin. In retrospect, the patient reported similar symptoms then, however calcium assessment wasn’t performed. Family history identified a paternal cousin with hypercalcaemia and nephrolithiasis. Serum calcium was 3.19mmol/L (2.15-2.65mmol/L), PTH 0.3pmol/L (2.0-8.5pmol/L), PTHrP undetectable, 25-hydroxyvitamin D 53nmol/L (>50nmol/L), 1,25-dihydroxyvitamin D 292pmol/L (50-190pmol/L), 24-hour urine calcium:creatinine ratio 0.94 (<0.7), with normal ACE, SPEP, CT Chest-Abdomen-Pelvis. Intravenous fluid and prednisolone were ineffective. Given suspicion of a 24-hydroxylase impairment, strategies to reduce vitamin D synthesis were implemented with resolution of hypercalcaemia (serum calcium 2.55mmol/L). Genetic testing identified two heterozygous pathogenic variants: CYP24A:c.1186C>T p.(Arg396Trp), CYP24A1:c.428_430del AAG p.(Glu143del), the latter a novel variant.
Conclusion:
Individuals with CYP24A1 pathogenic variants may develop hypercalcemia, exacerbated by colecalciferol supplementation and pregnancy. Our case highlights the seriousness of this condition, difficulties in diagnosis, and maternal and fetal complications, including pre-eclampsia and fetal death(4). Calcium should be checked prior to commencing supplementation and abnormal vitamin D metabolism must be considered in PTH-independent hypercalcaemia(5).