Introduction: Inactivating mutations in CYP24A1, encoding vitamin D-24-hydroxylase, can lead to an accumulation of active vitamin D metabolites and consequent hypercalcaemia. Patient (infantile and adult) presentation is varied and includes mild-severe hypercalcaemia, hypercalciuria, nephrocalcinosis and nephrolithiasis. This study aimed to characterize the clinical and biochemical phenotypes of a family with two CYP24A1 missense variants.
Methods: The proband and seven family members underwent detailed clinical and biochemical evaluation. Laboratory measurements included serum calcium, intact parathyroid hormone (iPTH), vitamin D metabolites and urine calcium and creatinine.
Results: The proband presented during the second trimester of a planned pregnancy with flu-like symptoms. Laboratory tests showed elevated adjusted calcium of 3.27 (upper reference limit (URL:2.30) mmol/L), suppressed iPTH (<6ng/L), elevated 25(OH)D (264 (URL:55) nmol/L) and elevated 1,25(OH)D (293 (URL:<280) pmol/L). Ionized calcium was 1.55 (URL:1.28) mmol/L. Sanger sequencing revealed two heterozygous missense variants in the CYP24A1: p.(Arg439Cys), R439C and p.(Trp275Arg), W275R. The proband’s brother and sister had the same genotype. The brother had intermittent hypercalcaemia and hypervitaminosis D. Only the sister had a history of nephrolithiasis. The proband’s daughter and two nephews were heterozygous for the R439C variant. The proband’s mother was heterozygous for the W275R variant and her father was homozygous for the R439C variant. All were normocalcaemic with normal 25(OH)D.
Conclusions: In this family, compound heterozygosity for a known pathogenic mutation R439C, in combination with a novel variant W275R was associated with hypercalcaemia and frequently elevated 25(OH)D:24,25 (OH)2D ratios (>50) and may be associated with a variable phenotype or incomplete penetrance.