title: Infantile hypercalcemia and hypercalciuria: new insights into a vitamin D-dependent mechanism and response to ketoconazole treatment.
abstract: 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.
  
  
  METHODS
  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. Vitamin D receptor expression (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 ketoconazole group (0.7 +/- 0.2 versus 2.4 +/- 0.6 months; P = .0076), and urinary calcium excretion (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 Klotho gene was found in patients and family members.
  
  
  CONCLUSIONS
  Ketoconazole is 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.
authors.affiliation: Inserm U561, Hôpital St Vincent de Paul, Paris, France.
authors.forename: Minh
authors.initials: M
authors.lastname: Nguyen
authors.forename: Henri
authors.initials: H
authors.lastname: Boutignon
authors.forename: Eric
authors.initials: E
authors.lastname: Mallet
authors.forename: Agnes
authors.initials: A
authors.lastname: Linglart
authors.forename: Huguette
authors.initials: H
authors.lastname: Guillozo
authors.forename: Frederic
authors.initials: F
authors.lastname: Jehan
authors.forename: Michele
authors.initials: M
authors.lastname: Garabedian
mesh_terms: D002118:Calcium / Q000097:blood; D005260:Female; D000089703:Fibroblast Growth Factor-23; D006239:Haplotypes; D006801:Humans; D006934:Hypercalcemia / Q000188:drug therapy* / Q000209:etiology*; D053565:Hypercalciuria / Q000188:drug therapy* / Q000209:etiology*; D007223:Infant; D007231:Infant, Newborn; D007654:Ketoconazole / Q000627:therapeutic use*; D008297:Male; D010281:Parathyroid Hormone / Q000378:metabolism; D011110:Polymorphism, Genetic; D018167:Receptors, Calcitriol / Q000096:biosynthesis; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014807:Vitamin D / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase
chemical_list: C000717427:FGF23 protein, human; D010281:Parathyroid Hormone; D018167:Receptors, Calcitriol; D014807:Vitamin D; D000089703:Fibroblast Growth Factor-23; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D007654:Ketoconazole; D002118:Calcium