Endocrine Abstracts

Idiopathic infantile hypercalcemia (IIH) constitutes a broad group of diseases with a common outcome namely, hypercalcemia. It is now recognized that mutations of the vitamin D catabolic cytochrome P450, CYP24A1 represent one of the major causes of IIH. Patients often present in neonatal life with transient hypercalcemia, but adults with hypercalciuria, renal stones & nephrocalcinosis also appear with CYP24A1 defects. Recently, there have been reports that pregnant females with IIH can suffer hypercalcemic episodes during pregnancy, presumably due to increased synthesis of 1,25-(OH)₂D₃ by the placenta, that abate after pregnancy. Estimates of the frequency of CYP24A1 gene mutations suggest 1:100 carriers and a 1:40 000 incidence of IIH. While genetic analysis of the CYP24A1 locus represents the definitive diagnosis of this form of IIH, we have devised a rapid, screening test for detecting IIH patients with two defective CYP24A1 mutations. It consists of simultaneously measuring vitamin D metabolites: 25-OH-D₃ and 24,25-(OH)₂D₃ in serum by LC-MS/MS and then expressing the results as a 25-OH-D₃:24,25-(OH)₂D₃ ratio. Heterozygotes and normal individuals have ratios between 5-25 while IIH patients have ratios >80. Refinements of this approach have further resolved IIH patients from individuals with a high ratio due to vitamin D deficiency and patients with chronic kidney disease on dialysis. Loss-of-function CYP24A1 mutations cause hypersensitivity to dietary vitamin D, so reduction of dietary vitamin D or exposure to UV light is recommended. Further insights into the causes of hypercalcemic episodes in IIH should come from studies of the CYP24A1-null mouse. Reintroduction of a BAC clone representing the full wild-type human or mouse CYP24A1 gene into the CYP24A1 null mouse restores normocalcemia.