Genetic advances, biochemical and clinical features and critical approach to treatment of patients with X-linked hypophosphatemic rickets

X-linked hypophosphatemic rickets (XLH) is an hereditary form of rickets due to isolated renal tubular phosphate wasting and impaired production of 1,25-dihydroxyvitamin D [1,25(OH)2D]. XLH is caused by mutations in the PHEX (phosphate regulating gene with homology to endopeptidases) gene, which is located on Xp22.1. The pathogenetic mechanisms by which mutations in the PHEX gene cause XLH are not completely known. Hypophosphatemia associated with disproportionate short stature and bone deformities of the lower limbs are the main findings in XLH patients. Some studies have shown that conventional treatment with vitamin D metabolites, such as 1,25(OH)2D3 or 1 alpha-hydroxyvitamin D3, combined with inorganic phosphate salts is able to improve serum phosphate concentrations and linear growth, as well as healing rickets. However, some patients may have poor beneficial effects by this therapy. On the other hand, some important treatment complications, such as hypervitaminosis D, nephrocalcinosis and secondary/tertiary hyperparathyroidism may occur during the current therapy. Despite conventional treatment, some patients may require surgical correction of bone deformities. In the light of the recent genetic advances the mechanisms that could be involved in the pathogenesis of XLH are discussed. Furthermore, the article reviews the effects of the medical treatment providing current recommendations for the management of XLH patients.