title: Hypercalcemia, hypercalciuria, and elevated calcitriol concentrations with autosomal dominant transmission due to CYP24A1 mutations: effects of ketoconazole therapy.
abstract: BACKGROUND
  Mutations of the CYP24A1 gene, which encodes the 1,25-dihydroxyvitamin D-24-hydroxylase cytochrome P450, Cyp24A1, are predicted to result in elevated 1,25-dihydroxyvitamin D concentrations, hypercalcemia, hypercalciuria, nephrolithiasis, and bone disease. Treatment of hypercalcemia associated with CYP24A1 gene mutations has not been described.
  
  
  METHODS
  The genetic basis of a syndrome in a 44-yr-old Caucasian male characterized by intermittent hypercalcemia, hypercalciuria, elevated serum 1,25-dihydroxyvitamin D, undetectable serum 24,25-dihydroxyvitamin D, metabolically active nephrolithiasis, and reduced bone mineral density of the lumbar spine was examined. Sequencing of the CYP24A1 gene and biochemical and genetic analysis of seven family members in three generations was carried out. Because of hypercalcemia, hypercalciuria, and metabolically active nephrolithiasis, the patient was treated with a cytochrome 3A inhibitor, ketoconazole, 200 mg orally every 8 h, for 2 months.
  
  
  RESULTS
  The sequence of the CYP24A1 gene showed two canonical splice junction mutations in the proband. Analysis of family members showed a phenotype associated one or both mutations, suggesting autosomal dominant transmission with partial penetrance of the trait. After therapy with ketoconazole, statistically significant reductions in previously elevated urinary calcium into the normal range were noted. Previously elevated serum 1,25-dihydroxyvitamin D and calcium concentrations decreased, and previously decreased PTH concentrations increased into the normal range, but the differences were not statistically significant.
  
  
  CONCLUSIONS
  In a syndrome characterized by intermittent hypercalcemia, hypercalciuria, elevated 1,25-dihydroxyvitamin D, undetectable 24,25-dihydroxyvitamin D concentrations, splice junction mutations of the CYP24A1 gene, and autosomal dominant transmission of the trait, treatment with ketoconazole is useful in reducing urinary calcium.
authors.affiliation: Mercy Healthcare, Edmond, OK 73142, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tebben
authors.forename: Dawn S
authors.initials: DS
authors.lastname: Milliner
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Horst
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
authors.forename: Ravinder J
authors.initials: RJ
authors.lastname: Singh
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wu
authors.forename: John W
authors.initials: JW
authors.lastname: Foreman
authors.forename: Paul R
authors.initials: PR
authors.lastname: Chelminski
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000627:therapeutic use*; D000328:Adult; D002117:Calcitriol / Q000097:blood*; D005838:Genotype; D006801:Humans; D006934:Hypercalcemia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D053565:Hypercalciuria / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D007654:Ketoconazole / Q000627:therapeutic use*; D008297:Male; D009154:Mutation; D013250:Steroid Hydroxylases / Q000235:genetics*; D013577:Syndrome; D016896:Treatment Outcome; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D058888:14-alpha Demethylase Inhibitors; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol; D007654:Ketoconazole