What is X-linked hypophosphatemia (XLH)?

Todd and Heidi, with their daughter Ruby, living with XLH

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XLH, or X-linked hypophosphatemia, is a condition that affects bones, muscles, and teeth due to the excessive loss of phosphate. Phosphate is lost through the urine, which causes low levels of phosphorus in the blood, a condition called phosphate wasting or hypophosphatemia.

 

Phosphate is a molecule that is made up of phosphorus and oxygen. It is required for healthy bones, muscles, and teeth. Rickets is a hallmark of XLH and is caused by the softening of bones during growth in childhood. Rickets is a key feature of XLH in children and causes symptoms such as curving of the legs, or bowed legs, which become noticeable at 2 years of age when the legs begin to bear weight. New symptoms may also appear as children grow. While some might think that XLH is a condition that occurs only during childhood, adults with XLH continue to experience symptoms of an ongoing condition.

 

Who gets XLH?

XLH is an uncommon condition. Children and adults, male or female, can show varying signs and symptoms of XLH.

Phosphate is required for healthy bones, muscles, and teeth

XLH is an inherited condition. The “X” in XLH stands for “X-linked,” because the condition is due to a defect (a mutation) in the X chromosome that can be passed on to children. Males have XY chromosomes, and females have XX chromosomes.

Inheritance of XLH through a mother with XLH

If a mother has XLH, then her children (both boys and girls) each have a 50% chance of also having XLH. This is because all children inherit one X chromosome from their mother.

Inheritance of XLH through a father with XLH

If a father has XLH, all daughters will have XLH because daughters always inherit an X chromosome from their father. No sons will have XLH because sons get their X chromosome from their mother.

Inheritance of XLH through both mother and father with XLH

If a father and mother both have XLH, all daughters will have XLH, and sons have a 50% chance of having XLH.

About 20% to 30% of cases of XLH are “spontaneous”. This means that in some people with XLH, the condition is not inherited from their parents. Individuals who have a spontaneous case of XLH can still pass the condition to their children. Diagnosis of people with spontaneous cases of XLH is important.

If you suspect XLH, talk to your doctor.

Genetic testing can confirm a diagnosis of XLH.
Learn more about genetic testing for hypophosphatemia.

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Increased FGF23 activity is the cause of XLH

People with XLH have a mutation in the PHEX gene, which causes the body to produce too much of a hormone called fibroblast growth factor 23 (FGF23). FGF23 controls the amount of phosphate present in the blood.

  • Too much FGF23 causes phosphate wasting, the loss of phosphate through urine
  • Phosphate wasting leads to low levels of phosphorus in the blood, a condition called hypophosphatemia
  • This leads to weak and soft bones, the underlying cause of the symptoms of XLH

  • X-linked hypophosphatemic rickets
  • Hereditary hypophosphatemic rickets
  • Familial hypophosphatemic rickets
  • Vitamin D–resistant rickets (VDRR)
  • Vitamin D–resistant osteomalacia
  • X-linked vitamin D–resistant rickets
  • Hypophosphatemic rickets
  • Hypophosphatemic vitamin D–resistant rickets (HPDR)
  • X-linked rickets (XLR)
  • Genetic rickets
  • Familial hypophosphatemia