The expanding family of hypophosphatemic syndromes

J Bone Miner Metab. 2012 Jan;30(1):1-9. doi: 10.1007/s00774-011-0340-2. Epub 2011 Dec 14.


Investigation of X-linked hypophosphatemia (XLH) has led to the identification of a novel phosphate-regulating homeostatic system. Initially considered vitamin D-refractory rickets, renal phosphate wasting was identified as the cardinal biochemical feature of XLH and several related disorders. Current therapy employs calcitriol and phosphate, which usually improves, but does not completely heal deformities and short stature. Later complications of XLH include development of osteophytes, entheses, and osteoarthritis. The mutated gene in XLH, PHEX, is expressed in osteocytes, but its role in the pathogenesis of phosphate wasting is poorly understood. Many hypophosphatemic disorders are mediated by FGF23, a unique fibroblast growth factor with endocrine properties. Renal action of FGF23 leads to reduced expression of type II sodium-phosphate co-transporters, as well as reduced expression of CYP27B1, which encodes vitamin D 1α-hydroxylase. FGF23-mediated hypophosphatemia is characterized by inappropriately normal circulating 1,25-dihydroxyvitamin D together with renal phosphate wasting. The FGF23 system serves as a novel mechanism by which the mineralizing skeleton can communicate phosphate supply to the kidney and thereby mediate excretion or conservation of this important skeletal component. Other forms of FGF23-mediated hypophosphatemia represent various aberrations in this axis. Secretion of excess FGF23 (as in tumor-induced osteomalacia), and mutations preventing proteolytic cleavage of FGF23 result in similar clinical features. Other hypophosphatemic disorders are discussed.

Publication types

  • Review

MeSH terms

  • Animals
  • Familial Hypophosphatemic Rickets / complications
  • Familial Hypophosphatemic Rickets / genetics
  • Familial Hypophosphatemic Rickets / pathology*
  • Familial Hypophosphatemic Rickets / therapy
  • Fibroblast Growth Factors / metabolism
  • Genetic Diseases, X-Linked*
  • Humans
  • Syndrome


  • Fibroblast Growth Factors
  • fibroblast growth factor 23