Background: Understanding X-linked Hypophosphatemia
X-linked hypophosphatemia (XLH) represents the most prevalent form of inherited rickets, affecting approximately 1 in 20,000 to 1 in 60,000 individuals worldwide. This rare genetic disorder stems from loss-of-function mutations in the PHEX gene, resulting in dysregulated phosphate homeostasis and impaired bone mineralization.
The pathophysiology of XLH centers on elevated fibroblast growth factor 23 (FGF23), a hormone produced by osteocytes and osteoblasts. Excess FGF23 suppresses renal phosphate reabsorption by downregulating sodium-phosphate cotransporters (NaPi-2a and NaPi-2c) in the proximal tubule. Additionally, FGF23 inhibits 1α-hydroxylase activity, reducing active vitamin D (1,25-dihydroxyvitamin D) synthesis. The resulting chronic hypophosphatemia leads to defective mineralization of the growth plate and bone matrix, manifesting as rickets in children and osteomalacia in adults.
