Hypophosphatemic rickets

Hypophosphatemic rickets is a group of rare genetic disorders characterized by renal phosphate wasting, leading to chronically low levels of phosphate in the blood (hypophosphatemia) and defective mineralization of bones and teeth. The most common form is X-linked hypophosphatemic rickets (XLH), caused by mutations in the PHEX gene, but autosomal dominant and autosomal recessive forms also exist (caused by mutations in FGF23, DMP1, ENPP1, CLCN5, and other genes). The condition is also known as vitamin D-resistant rickets because it does not respond to standard vitamin D supplementation. The disease primarily affects the skeletal system, leading to bowing of the legs, short stature, bone pain, and fractures. In children, the hallmark features include progressive leg bowing (genu varum or genu valgum), widening of the wrists and knees, delayed walking, waddling gait, and impaired growth. Dental manifestations are common and include spontaneous dental abscesses, enamel defects, and enlarged pulp chambers. Adults may experience osteomalacia, enthesopathies (calcification of tendons and ligaments), joint stiffness, pseudofractures, hearing loss, and chronic musculoskeletal pain. The kidneys are functionally involved as the primary site of phosphate loss, though kidney function is otherwise typically preserved. Traditional treatment has consisted of oral phosphate supplementation combined with active vitamin D analogs (calcitriol or alfacalcidol) to improve phosphate balance and promote bone mineralization. However, this regimen requires careful monitoring due to risks of nephrocalcinosis and secondary hyperparathyroidism. A major therapeutic advance came with the approval of burosumab (Crysvita), a monoclonal antibody targeting FGF23, which has been shown to significantly improve phosphate levels, rickets severity, growth, and pain in both children and adults with XLH. Orthopedic surgery may be needed for severe skeletal deformities that persist despite medical treatment.

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