Infantile hypercalcemia and hypercalciuria: new insights into a vitamin D-dependent mechanism and response to ketoconazole treatment.

Objective To analyze vitamin D metabolism and response to ketoconazole, an imidazole derivative that inhibits the vitamin D-1-hydroxylase, in infants with idiopathic hypercalcemia, and hypercalciuria. Study design Twenty infants (4 days-17 months) with hypercalcemia, severe hypercalciuria, and low parathyroid hormone level, (10 had nephrocalcinosis), including 10 treated with ketoconazole(3-9 mg/kg/day), were followed to the age of 2 to 51 months. VitaminD receptorexpression (VDR), 24-hydroxylase activity, and functional gene polymorphisms of vitamin D metabolism regulators VDR(rs4516035), 1-hydroxylase(rs10877012), 24-hydroxylase(rs2248359), FGF23(rs7955866), Klotho(rs9536314, rs564481, rs648202), were evaluated. Results Serum calcium levels, which occurred faster in the ketoconazolegroup (0.7 ± 0.2 versus 2.4 ± 0.6 months; P = .0076), and urinary calciumexcretion (2.5 ± 0.5 versus 4.2 ± 1.7 months) normalized in all patients. Serum 1,25-(OH)2D levels were high normal and positively correlated to 25-(OH)D levels. Serum 24,25-(OH)2D levels were low normal, and skin fibroblasts from 1 patient showed defective up-regulation of the 24-hydroxylase by 1,25-(OH)2D despite normal VDR binding ability. An abnormally low prevalence of haplotype CC/CC for H589H/A749A in Klothogene was found in patients and family members. Conclusions Ketoconazoleis a potentially useful and safe agent for treatment of infantile hypercalcemia. Abnormal vitamin D metabolism is suggested as the mechanism, possibly involving defective up-regulation of the 24-hydroxylase by 1,25-(OH)2D3, and the klotho-FGF23 axis.