What is X-linked hypophosphatemia?

X-linked hypophosphatemia (XLH) is a rare inherited disorder that affects the bones and teeth. 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.

X-linked hypophosphatemia is a form of rickets and has also been called X-linked hypophosphatemic rickets.

Signs and symptoms of X-linked hypophosphatemia

The signs and symptoms of X-linked hypophosphatemia can vary widely, as can the severity of their effects. Symptoms of XLH are often noticed when a child begins to walk, when weakness and malformations in the legs become apparent. Early diagnosis and treatment can prevent some symptoms from worsening.

Symptoms of X-linked hypophosphatemia may include:

• Delayed ability to walk
• Bowed legs or knock knees
• Abnormal or waddling gait
• Short stature
• Bone or joint pain
• Enlarged or swollen wrists and ankles
• Abnormal head shape (caused by fused skull bones)
• Muscle weakness
• Fatigue
• Dental problems, including severe dental pain, tooth abscesses and abnormal tooth enamel

In adolescence and adulthood, additional symptoms may include:

• Hearing loss
• Chronic bone fractures
• Osteoarthritis in the knees
• Calcification of the tendons

Causes of X-linked hypophosphatemia

X-linked hypophosphatemia is caused by mutations in the PHEX gene on the X chromosome. The changes in the gene reduce the suppression of a hormone — fibroblast growth factor-23 (FGF23) — that regulates how the kidney filters phosphorus from the blood and excretes it in urine. High levels of FGF-23 lead to excessive secretion of phosphorus in the urine and insufficient levels of the mineral in the blood. This is known as “phosphate wasting.” High FGF-23 levels also reduce the amount of 1,25-dihydroxy vitamin D (the active form of vitamin D).

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.

Inheritance

Because the gene involved in the disorder is on the X chromosome, its inheritance pattern is affected by sex. Females have two X chromosomes, while males have one X chromosome and one Y chromosome. Males inherit one of their mother’s two X chromosomes and their father’s Y chromosome. Females inherit one of their mother’s two X chromosomes and their father’s X chromosome.

When a mother has an X-linked mutation (a mutation on one of her two X chromosomes), each of her children, whether males or females, has a 50% chance of inheriting the mutation.
When a father has an X-linked mutation (a mutation on his only X chromosome), all of his female children and none of his male children will inherit the mutation.

The gene mutation associated with X-linked hypophosphatemia can also, in rare cases, occur spontaneously (a de novo mutation), without inheriting it from either parent.

Anyone, either male or female, who has the mutated gene associated with XLP will have the disorder.

How is X-linked hypophosphatemia diagnosed?

If XLH or another type of rickets is suspected, your healthcare provider will:

• Take a complete medical history to understand the occurrence of symptoms.
• Perform a physical exam.
• Ask about any history of similar or related symptoms in other family members.
• Do blood and urine tests to check for raised or reduced levels of certain compounds and enzymes. Low blood levels phosphorus and high levels of the hormone FGF23 are characteristic of X-linked hypophosphatemia.

In infants and young children, X-rays or other imaging studies may be done to examine bone form and density.

Care must be taken to distinguish X-linked hypophosphatemia from other types of rickets. In children, a vitamin D deficiency may produce similar symptoms. In adults, similar symptoms, including elevations of FGF23, may be caused by a tumor.

Genetic testing confirms a diagnosis of XLH. Genetic testing can be valuable in understanding the inheritance pattern of the disorder.

Treatment for X-linked hypophosphatemia

Two treatments address the metabolic causes of X-linked hypophosphatemia:

• Giving phosphate supplements and vitamin D (in the form of calcitriol) can reduce or even reverse the effects of the disorder in children.
• Bursomab, a monoclonal antibody treatment approved by the Food and Drug Administration (FDA) for X-linked hypophosphatemia in adults and children older than 6 months, inactivates FGF-23. The result is a reduction in phosphate wasting and an increase in phosphate levels in the blood, with more phosphorus absorbed by the bones and teeth.

Other treatments can address specific symptoms and complications. These treatments may include:

• Growth hormones
• Non-steroidal anti-inflammatory drugs (NSAIDs) for relief of bone and joint pain
• Physical and occupational therapy
• Dental care to prevent abscesses and damage to weakened tooth enamel, or to replace lost teeth
• Orthopedic surgery to repair fractured bones or correct misaligned joints
• Hearing aids

Genetic counseling may be helpful for people diagnosed with X-linked hypophosphatemia and their families. Understanding how XLH is inherited and what testing is available can help people make informed decisions as they consider having more children.

Follow-up care

Ongoing care, coordinated by a primary care physician or specialist who is knowledgeable about X-linked hypophosphatemia is essential to the long-term health and well-being of patients. Because the disorder can affect different body functions, coordinated care by a team of appropriate specialists is needed.

Treatment of X-linked hypophosphatemia at Children’s Hospital of Philadelphia (CHOP) is managed by the Center for Bone Health, which provides comprehensive, coordinated care in collaboration with other specialty departments.

Depending on the patient’s diagnosis and condition, coordinated care might include specialists in:

• Orthopedics
• Endocrinology
• Pain management
• Dental care
• Physical and occupational therapy
• Nutrition
• Audiology
• Genetics