Heritable Renal Phosphate Wasting Disorders

Heritable disorders of disturbed renal phosphate handling are the most common causes of rickets and osteomalacia in developed countries. However, the molecular mechanisms underlying the biochemical abnormalities and abnormal bone/cartilage mineralization in these diseases are complex, and our current models are incomplete, albeit they have grown remarkably over the past decade. Isolated renal phosphate wasting and consequent low serum phosphorus concentrations may result from a variety of genetic disorders that include: autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemic rickets (XLH), and autosomal recessive hypophosphatemic rickets (ARHR). Seminal findings have confirmed a central role for the endocrine molecule, fibroblast growth factor 23 (FGF23), in the pathogenesis of these diseases. Understanding the inter-relationships between the gene mutations underlying these disorders and regulation of FGF23 production and proteolysis has provided new and unanticipated therapeutic targets for management of this constellation of diseases. These advances have resulted from ground-breaking studies in humans and animal models that promise to fuel further successful studies.