X-linked hypophosphatemia (XLH) is a genetic disorder characterized by low phosphate levels in the body.

Phosphate plays an essential role in many biological processes, including bone mineralization. Therefore, low levels of phosphate impair the mineralization of the bone matrix and lead to symptoms such as bowed legs and short stature, as well as dental problems including tooth abscess, cavities, and abnormal enamels.

XLH and genetics

XLH is caused by mutations in a gene called PHEX, which is situated on the X-chromosome. This gene encodes for an enzyme that is predominantly active in the bones and teeth, and that regulates the synthesis of a phosphate-regulating protein called fibroblast growth factor 23 (FGF23) by mechanisms not well-understood.

The mutations cause the circulating levels of FGF23 to be higher than normal, which decreases phosphate reabsorption in the kidneys. This results in the low phosphate levels in the body.

Role of FGF23

FGF23 is generally secreted by the bones as a glycosylated protein. It binds to FGF receptors 1 and 4 situated on the surface of kidney tubule cells and signals the cells to stop or lower the absorption of phosphate.

FGF23 also regulates the amount of dietary phosphate absorbed in the intestines.

Excessive FGF23 can also restrict the synthesis of the active vitamin D required for intestinal phosphate absorption and bone mineralization.

Inheritance of XLH

XLH can occur in males or females as only one mutant copy of the PHEX gene is sufficient to cause the disease.

Females carry two copies of the X-chromosome while males carry only one copy. Therefore, a woman with XLH has a 50% chance of passing the disease to her sons or daughters, whereas a man with the disease will pass it on to all his daughters but none of his sons.

XLH can also be the result of de novo mutations that occur during development. Individuals with these mutations do not have a family history of XLH but can still pass the disease to future generations.


Last updated: Jan. 21, 2020


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