This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jehan, F. Articles by Garabédian, M. Search for Related Content PubMed PubMed Citation Articles by Jehan, F. Articles by Garabédian, M. Related Collections Pediatric Endocrinology Calcium and Bone Metabolism

Vitamin D Receptor Genotype in Hypophosphatemic Rickets as a Predictor of Growth and Response to Treatment

Institut National de la Santé et de la Recherche Médicale Unit 561 (F.J., C.G., T.M.N., O.W.-D., C.S., M.G.), Laboratory for Hormone Biology (N.L.), and Department of Pediatric Endocrinology (C.S., M.G.), Hôpital Saint Vincent de Paul, 75014 Paris, France; and Service d’Explorations Fonctionnelles (M.D.), Hôpital Necker and Université Paris Descartes, 75015 Paris, France

Address all correspondence and requests for reprints to: Frédéric Jehan, Institut National de la Santé et de la Recherche Médicale Unit 561, Hôpital Saint Vincent de Paul, 82 Avenue Denfert-Rochereau, 75014 Paris, France. E-mail: frederic.jehan{at}inserm.fr.

Context: 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.

Design: We studied the VDR promoter haplotype structure in a large cohort of 91 patients with hypophosphatemic rickets including 62 patients receiving 1-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 1-hydroxyvitamin D3 and had significantly lower circulating FGF23 levels (C-terminal assay), taking into account their phosphate and 1-hydroxyvitamin D3 intakes.

Conclusions: The present work identifies the VDR promoter genotype as a key predictor of growth under treatment with 1-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.