X-linked hypophosphatemia (XLH)
X-linked hypophosphatemia (XLH) is a rare genetic disorder that affects bone and dental health. It is characterized by low levels of the mineral phosphorus (sometimes referred to as “phosphate”) in the blood due to abnormal processing by the kidneys. When insufficient amounts of phosphorus reach the bones and teeth for absorption, bones can become deformed, soft and easy to fracture. Mobility and hearing may be impaired. Dental problems may occur, including abscesses, infections and tooth pain.
This condition is sometimes referred to as hypophosphatemic rickets, X-linked rickets, vitamin-D-resistant rickets and phosphate diabetes.
What causes XLH?
XLH is caused by a mutation in the PHEX gene, on the X chromosome. This mutation leads to an increase in a protein called FGF23, which results in an excess of excretion of phosphate by the kidneys, through the urine. This results in low phosphate levels in the blood (hypophosphatemia).
Because phosphorus, along with vitamin D, calcium and other minerals, is critical to the healthy development of bones and teeth, when it is lacking in the blood, too little is available to be absorbed by the bones and teeth. Without sufficient phosphorus, the bones and teeth can develop abnormally, without needed strength and hardness. As phosphate, like calcium, is an important mineral in our bones, XLH can result in weaker bones and skeletal deformities.
Diagnosis
It is essential to have an early and accurate diagnosis of XLH to manage it. XLH is typically diagnosed based on clinical symptoms, family history, and laboratory tests. It is generally diagnosed in childhood; however, those with milder symptoms may not have their XLH diagnosed until adulthood.
Key diagnostic tests include:
- Low phosphate in the blood
- High phosphate in the urine
- Elevated FGF23 levels in the blood
- Normal or low-normal calcium levels in the blood
- Increased alkaline phosphatase (in children)
- Genetic testing for PHEX mutations
More severe symptoms that can present in childhood can include:
- Short stature
- Bone and muscle pain
- Dental problems and abnormal tooth development
- Deformities in the legs
- Rickets (soft, weak bones)
Milder symptoms that can lead to an adulthood diagnosis can include:
- Joint and muscle pain
- Muscle weakness
- Multiple fractures
- Stiff ligaments and tendons
- Abnormal patterns of walking
- Impaired mobility from enthesopathy (disorder in tendons and ligaments)
- Hearing loss
Treatment For XLH
Conventional therapy
- As the blood phosphate level is low, this can be improved by increasing intake of phosphate through diet and/or supplementation.
- Activated vitamin D is also necessary to help with the absorption of phosphate.
(note, this is different from the vitamin D3 available over the counter)
Targeted therapy
- As XLH results in an elevation of the FGF23, Burosumab is a medication that directly blocks the action of FGF23.
As a result, the use of Burosumab can help correct the phosphate abnormalities with XLH, resulting in improved bone health.
Supportive therapy
- If there are severe bone deformities that significantly impairs mobility or function, orthopedic surgery may be considered.
- Pain management may also be required to improve mobility and reduce discomfort.
Regular dental care is vital as patients with XLH are prone to dental abscesses
Ongoing Care and Management
While there is no cure for XLH, early diagnosis and appropriate treatment may significantly improve outcomes and ultimately lead to a better quality of life for patients with XLH.
Ongoing management includes:
- Regular bloodwork and urine tests to assess phosphate, calcium, and FGF23 levels to monitor and detect complications associated with prolonged phosphate therapy
- Regular follow-up with a family doctor, endocrinologist or orthopedic surgeon is necessary to monitor growth, ensure proper skeletal development, and monitor bone health to prevent deformities.
Resource: Endocrine Society: XLH and Children’s Hospital of Philadelphia
