The Diagnosis and Therapy of XLH
Ineke Böckmann, Dieter Haffner
Abstract
X-linked hypophosphatemia is a rare genetic disease caused by pathogenic variants in the PHEX (phosphate-regulating endopeptidase homolog X-linked) gene with X-linked dominant inheritance that causes metabolic bone disease and other severe complications. PHEX dysfunction results in increased production and secretion of the phosphaturic hormone fibroblast growth factor 23 (FGF23) from bone. The consequences of FGF23 excess are renal phosphate wasting and decreased calcitriol synthesis, leading to hypophosphatemia and subsequently rickets and osteomalacia. Children with XLH usually become symptomatic in the second year of life presenting with progressive disproportionate short stature, bone pain, frontal bossing, enlarged joints, bowed legs, and a waddling gait. Various other symptoms may develop later, including dental abscesses, peritonitis, hearing loss, pseudofractures, spinal stenosis, osteoarthritis, and enthesopathies, often leading to a diminished quality of life and ultimately disability. Here, we provide an overview of the current knowledge of the pathophysiology and treatment insights of this rare and challenging disease, including the targeting of FGF23 as a therapeutic approach that has significantly improved patient outcomes.