An update on the genetic causes and treatment of hypophosphatemic rickets

Hypophosphatemic rickets (HR) results from impaired renal phosphate reabsorption caused either by genetic defects in renal phosphate cotransporters or by increased levels of phosphaturic mediators (phosphatonins). Fibroblast growth factor 23 (FGF23) is the principal regulator of phosphate metabolism and interacts with several hormonal and molecular pathways to maintain phosphate homeostasis. Variants in genes such as <i>PHEX</i>, <i>FGF23</i>, <i>DMP1</i>, <i>ENPP1</i>, <i>FAM20C</i>, and others lead to inherited forms of HR, and HR may also occur as part of several syndromic conditions. Affected patients typically present with short stature, skeletal deformities, bone pain, muscle weakness, dental abnormalities, and characteristic radiographic abnormalities. Laboratory findings usually include hypophosphatemia, normal or mildly elevated parathyroid hormone levels, and markedly increased alkaline phosphatase. Conventional therapy with oral phosphate and active vitamin D improves many metabolic abnormalities but rarely leads to full correction. The development of burosumab, a monoclonal antibody targeting FGF23, has transformed treatment by improving biochemical parameters, rickets severity, growth, and quality of life. This review summarizes current knowledge regarding the molecular mechanisms, clinical manifestations, diagnostic work-up, classification, and treatment strategies for HR, with particular emphasis on advances in targeted therapy.