title: Vitamin D receptor genotype in hypophosphatemic rickets as a predictor of growth and response to treatment.
abstract: BACKGROUND
  Treatment of X-linked hypophosphatemic rickets improves bone mineralization and bone deformities, but its effect on skeletal growth is highly variable.
  
  
  OBJECTIVE
  Genetic variants in the promoter region of the vitamin D receptor (VDR) gene may explain the response to treatment because this receptor mediates vitamin D action.
  
  
  METHODS
  We studied the VDR promoter haplotype structure in a large cohort of 91 patients with hypophosphatemic rickets including 62 patients receiving 1alpha-hydroxyvitamin D3 derivatives and phosphates from early childhood on.
  
  
  RESULTS
  Treatment improved bone deformities and final height, but 39% of treated patients still had short stature at the end of growth (-2 sd score or below). Height was closely associated with VDR promoter Hap1 genotype. Hap1(-) patients (35% of the cohort) had severe growth defects. This disadvantageous association of Hap1(-) status with height was visible before treatment, under treatment, and on to adulthood. Gender and age at initiation of treatment could not account for the Hap1 effect. No association with growth was found with a polymorphism of the PTH receptor gene otherwise found to be associated with adult height. Compared with Hap1(+) patients, those who were Hap1(-) had a higher urinary calcium response to 1alpha-hydroxyvitamin D3 and had significantly lower circulating FGF23 levels (C-terminal assay), taking into account their phosphate and 1alpha-hydroxyvitamin D3 intakes.
  
  
  CONCLUSIONS
  The present work identifies the VDR promoter genotype as a key predictor of growth under treatment with 1alpha-hydroxyvitamin D3 derivatives in patients with hypophosphatemic rickets, including those with established PHEX alterations. The VDR promoter genotype appears to provide valuable information for adjusting treatment and for deciding upon the utility of early GH therapy.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unit 561, Hôpital Saint Vincent de Paul, 82 Avenue Denfert-Rochereau, 75014 Paris, France. frederic.jehan@inserm.fr
authors.forename: Frédéric
authors.initials: F
authors.lastname: Jehan
authors.forename: Céline
authors.initials: C
authors.lastname: Gaucher
authors.forename: Thi Minh
authors.initials: TM
authors.lastname: Nguyen
authors.forename: Odile
authors.initials: O
authors.lastname: Walrant-Debray
authors.forename: Najiba
authors.initials: N
authors.lastname: Lahlou
authors.forename: Christiane
authors.initials: C
authors.lastname: Sinding
authors.forename: Michèle
authors.initials: M
authors.lastname: Déchaux
authors.forename: Michèle
authors.initials: M
authors.lastname: Garabédian
mesh_terms: D000293:Adolescent; D000328:Adult; D000375:Aging / Q000502:physiology; D002117:Calcitriol / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D053098:Familial Hypophosphatemic Rickets / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D040181:Genetic Diseases, X-Linked; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010755:Organophosphates / Q000627:therapeutic use; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic / Q000235:genetics; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics; D018167:Receptors, Calcitriol / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics; D055815:Young Adult
chemical_list: C000717427:FGF23 protein, human; D010755:Organophosphates; C473449:PTH1R protein, human; D044168:Receptor, Parathyroid Hormone, Type 1; D018167:Receptors, Calcitriol; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D004247:DNA; D002117:Calcitriol