X-linked hypophosphatemia (XLH) is a rare genetic disorder characterized by weakness in bones and teeth, among other symptoms. The condition affects about one in 20,000 newborns and is caused by mutations in a gene called PHEX.

XLH, PHEX, and FGF23

The PHEX gene provides genetic instructions for cells in the bones and teeth to make an enzyme that cleaves (cuts) some proteins. Most of the targets of the PHEX enzyme have not been identified. However, one protein that is cleaved by PHEX is called fibroblast growth factor 23 (FGF23). FGF23 is inactivated by this cleavage, which prevents it from functioning.

Mutations in the PHEX gene prevent the PHEX enzyme from cleaving FGF23, leading to the symptoms of the disease.

How is XLH inherited?

The PHEX is situated on the X-chromosome, one of two chromosomes that determine biological sex. Males have one X-chromosome and one Y-chromosome, while females have two X-chromosomes, one inherited from each parent.

XLH is inherited in an X-linked dominant pattern, meaning that a single copy of a disease-causing mutation situated on the X-chromosome will cause the disease.

If a male parent with XLH has children with a female partner who does not have the disease (i.e., does not carry the mutation on either of her X-chromosomes), their male children will not inherit the disease. But their female children will develop the disease.

If a female parent with XLH has children with a male without the disease, their children, both male, and female will have a 50% chance of developing the disease.

If both parents have XLH, then all of their female children will have XLH. Their male children will have a 50% chance of inheriting the disease-causing mutation from the mother and developing XLH.

Spontaneous mutations

Around 20–30% of XLH cases are due to spontaneous mutations. In these cases, neither parent has a copy of the disease-causing mutation, and the mutation arises spontaneously during the formation of gametes (egg and sperm cells) that give rise to the zygote (fertilized egg cell) or during early development.


Last updated: Jan. 23, 2020


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