The gene associated with XLH was identified in 1995 and is now called PHEX. The PHEX protein is known to be an endopeptidase that is expressed on the surface of bone cells, including osteoblasts and osteocytes. When the gene encoding the PHEX protein is abnormal, XLH can result. The biochemical changes of XLH, including the renal phosphate wasting and limited capacity to produce activated vitamin D (1,25-dihydroxyvitamin D), are mediated by a separate protein, known as Fibroblast Growth Factor 23 (FGF23). It is not clear at this time how disruption of PHEX results in increased blood levels of FGF23, but that connection appears to be central to the disease process.
Current research in XLH is focused on the mechanism of action of FGF23, in a class of molecules referred to as "phosphatonins" because of their capacity to regulate phosphate homeostasis. The role of PHEX has eluded researchers as well, and is actively being studied. A protein called klotho, first considered to mediate changes in the aging process, appears to be essential for FGF23 to communicate to the kidney. The role of FGF23 in other tissues is also under investigation. Research on XLH is one of the very hottest areas in the field of bone metabolism, growth and development.
Another focus of contemporary research has been to determine other candidate phosphatonins. Related phosphate wasting disorders are also under investigation. Some of these appear to be FGF23 mediated, and others are not. Some of these disorders include:
- ADHR, or Autosomal Dominant Hypophosphatemic Rickets, which exhibits symptoms nearly identical to those in XLH. This disease is due to specific changes in FGF23 that prevent its degradation.
- TIO, or Tumor-Induced Osteomalacia, which is an acquired disease where phosphatonins are made in excess by small tumors.
- HHRH, or Hereditary Hypophosphatemic Rickets with Hypercalciuria, which is not FGF23 mediated, but rather a result of loss-of-function mutations in a kidney transporter. This results in excess urinary phosphate losses, but not the problem with vitamin D activation described in XLH and other FGF23-mediated forms of the disease.
Clinical trials have begun on a new form of treatment with the knowledge of FGF23's role, attempting to neutralize the activity of the increased levels of the protein.
These links supply more information:
- PHEX Locus Database contains a wealth of information relating to PHEX
- OMIM entry
- The XLH Research Citations
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The authors of this web site are not medical professionals, and this information does not substitute for medical care. Information on these pages is based on biomedical research, published in peer-reviewed journals, and international research conferences. Additionally, in some cases anecdotal information is provided by subscribers to a mailing list and/or members of a forum for The XLH Network Inc. A listing of XLH research is available. Please read our full disclaimer.