VOLUME 6 - NUMBER 1 - 2026

Congenital hypophosphatemia

  • Ineke Böckmann, Dieter Haffner
  • Concise reviews, 40-45
  • Full text PDF

  • Maintenance of phosphate homeostasis is crucial for proper bone and tooth mineralization. Congenital hypophosphatemia, mainly caused by pathogenic variants in genes involved in the regulation of phosphate homeostasis, leads to increased secretion of the phosphaturic hormone fibroblast growth factor 23 (FGF23) from bone, selective genetic defects in the sodium-dependent phosphate cotransporters in the proximal tubules, or generalized proximal renal tubular dysfunction, as in renal Fanconi syndrome. X-linked hypophosphatemia (XLH) is the most common form of congenital hypophosphatemia. Symptoms typically emerge in the first two years of life and include growth delay, rickets, osteomalacia, bone pain, leg deformities, and a waddling gait. Depending on the specific cause of congenital hypophosphatemia, patients may show additional complications or be asymptomatic for many years. New insights into the role of FGF23 in the pathogenesis of XLH have opened the way for novel therapies, such as FGF23 inhibition. Diagnosis rests on clinical features and biochemical findings; in the absence of a definite non-genetic cause or positive family history and clear clinical presentation, it should be confirmed by genetic testing. This review discusses the pathophysiology, clinical manifestations, differential diagnosis, and clinical management of patients with congenital hypophosphatemia.

  • KEY WORDS: Congenital hypophosphatemia, X-linked hypophosphatemia, rickets, osteomalacia, fibroblast growth factor 23, PHEX, SLC34A3, SLC34A1