X-Linked Hypophosphatemia: Understanding this hereditary, progressive, and lifelong condition

Acknowledgment: This story is sponsored by Ultragenyx Pharmaceutical Inc. and is promoted through the Patient Worthy Collaborative Content program. We only publish content that embodies our mission of providing relevant, vetted, and valuable information to the rare disease community.

X-linked hypophosphatemia (XLH) is a rare, lifelong condition that can seriously affect bones, muscles, and teeth in children and adults due to the excessive loss of phosphorus. The “X” in XLH stands for “X-linked” because the condition is due to a change (a mutation) on the X chromosome, and it can be passed on to children.

XLH is inherited in most cases

Chromosomes are thread-like structures made up of DNA and are found inside cells of the body. Since males have XY chromosomes and females have XX chromosomes, this means that sons inherit an X from their mother and a Y from their father. Because XLH is carried on the X chromosome, a father cannot pass XLH on to his sons. Daughters inherit an X from their mother and an X from their father, so they can inherit XLH from either parent.

If a father has XLH, all of his daughters and no sons will have XLH.

If a mother has XLH, each of her children (boy or girl) has a 50% chance of inheriting XLH.

However, XLH is not always inherited. Children can sometimes be born with XLH, even if there’s no family history of the condition. This is called a spontaneous case, and it can happen in 20% to 30% of people with XLH. If someone has a spontaneous case, they can then pass XLH on to their children. To learn more about the inheritance patterns of XLH, click here.

The link between XLH and phosphorus levels

Increased FGF23

When someone has XLH, their body makes too much of a protein called fibroblast growth factor 23 (FGF23). FGF23 plays a role in controlling the amount of phosphorus present in the body.

Phosphorus wasting

Too much FGF23 causes phosphorus wasting, which is the loss of phosphorus through the urine.

Weak and soft bones

Phosphorus wasting leads to low levels of phosphorus in the blood (called hypophosphatemia), causing various symptoms of XLH.

Testing to confirm XLH

Your doctor may order the following laboratory tests of blood and urine samples to help identify XLH.

Type of test Reason for this test
Blood tests
Serum phosphorus Measures levels of phosphorus in the blood related to bone and dental health; normal ranges vary for children and adults
1,25 dihydroxy vitamin D (1,25(OH)2D) Measures active vitamin D levels (different from oral vitamin D)
25-hydroxy vitamin D (25(OH)D) Measures vitamin D levels
Alkaline phosphatase (ALP) Identifies a marker of rickets and osteomalacia that is usually elevated in children with XLH, but is less reliable as a measure of XLH in adults
Parathyroid hormone (PTH)

Serum calcium

Used to rule out other causes of rickets and monitor treatment effects
Urine test
Urinary calcium Used to rule out other causes of rickets and monitor treatment effects
Blood and urine test
TmP/GFR Measures serum phosphorus wasting

Your doctor may also include one of the tests below to help confirm a diagnosis of XLH.

Type of test Reason for this test
PHEX genetic test Provides a genetic diagnosis by detecting a mutation in the PHEX gene
FGF23 protein test Measures the protein that regulates serum phosphorus levels

Common symptoms of XLH

It’s important to keep in mind that no two people experience XLH exactly the same way, and each person living with XLH may have different symptoms. Symptoms can start during childhood and progress throughout life—so symptoms may change over time.

Rickets is a key feature of XLH in children and causes symptoms such as bowed legs, which become noticeable when the legs begin to bear weight.

Other common signs of XLH in children can include:

  • Delay in starting to walk
  • Falling behind on the growth chart
  • Tooth abscesses (infections) or other ongoing dental problems (half of children with XLH have dental abscesses)
  • Stiff, weak, or painful joints and muscles

Even though some symptoms may start during childhood, some people may not know they have XLH until they are well into adulthood. It’s possible the early onset of their symptoms was never confirmed to be XLH through genetic testing until later in life. Common symptoms that both children and adults can experience include:

  • Frequent dental problems
  • Osteomalacia (weakening of bones)
  • Bowed legs or knock-knees
  • Bone and/or joint pain or stiffness
  • Muscle pain or weakness
  • Short stature
4 out of 5 adults with XLH have dental abscesses.

Because osteomalacia continues into adulthood, new symptoms may keep appearing or existing symptoms may worsen over time, which can limit the body’s movements. In addition to ongoing dental problems, other common symptoms in adults with XLH can include:

  • Enthesopathy: damage to the connective tissues between bones and tendons or ligaments, causing pain, swelling, and inflammation
  • Spinal stenosis: narrowing of the spaces within the spine
  • Osteoarthritis: inflammation of the joints
  • A history of recurring and low-trauma fractures

Continue your journey

Visit XLHLink.com to learn more about XLH and the symptoms it may cause. XLHLink is an Ultragenyx-sponsored resource that offers information on XLH and educational events featuring a clinical specialist and a patient or caregiver. Here, you’ll also discover essential resources available to you, including the XLH Specialist Finder.

MRCP-KRN23-01800 08/2022

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