What Is X-linked Hypophosphatemia?

A hereditary medical condition that causes weak bones due to low phosphate levels, X-linked hypophosphatemia is a rare disease that affects approximately 1 out of every 20,000 people worldwide.

The symptoms begin during early childhood and include slow growth, bone deformities, and dental infections. Because X-linked hypophosphatemia is not common, it might not be the first diagnosis that comes to mind when a child has atypical bone development. Blood tests and imaging tests can help confirm the diagnosis. 

Treatment includes Crysvita (burosumab) injections as well as medical and/or surgical management of the medical and dental complications.

X-Linked Hypophosphatemia Symptoms 

This condition affects the bones and teeth. The most prominent effect is rickets, which is childhood softening and weakness of the bones. If your child has X-linked hypophosphatemia, you may notice the effects as they are growing and starting to walk, usually before they reach the age of 2.

And even after a child is fully-grown, the effects of the condition continue into adolescence and adulthood, causing bone, joint, and dental problems.

Early symptoms of X-linked hypophosphatemia include: 

• Slow growth
• Short stature and smaller body size
• Bowing of the legs, bones curving out
• Unusual walking
• Bone and/or muscle pain
• Problems with tooth development
• Dental problems
• Muscle weakness
• Muscle, joint, and bone pain
• Small head and skull
• Hearing deficit and inner ear abnormalities

Adults affected by this condition can expect to have effects as well. Adults can have osteomalacia, which is a condition characterized by weak, fragile bones. 

Symptoms that affect adults include:

• Dental problems, such as infections and abscesses 
• Pain and/or weakness of the bones, muscles, and joints
• Enthesopathy, which is abnormal attachment of ligaments, tendons, and/or bones in joints
• Increased risk of bone fractures
• Hyperparathyroidism, which is over activity of parathyroid hormone, a hormone that helps maintain a balance of phosphate and calcium levels in the body 

Causes 

The effects of X-linked hypophosphatemia are caused by a lack of phosphate in the bones. Your body uses this mineral (along with calcium) for building bones and teeth. Phosphate deficiency interferes with bone and tooth development in children and causes fragility of the bones and teeth in adults. Defects in bone formation result in weakness and malformed bones, especially in the legs and hips. 

Inheritance Pattern

X-linked hypophosphatemia is caused by a genetic defect that is usually inherited with an X-linked dominant pattern. The gene, which is called the PHEX gene, is located in the X chromosome. Because the genetic defect is dominant, a person who inherits it will develop the condition.

Males have one X-chromosome, which is inherited from their mother. Females have two X chromosomes, one inherited from their father and one from their mother. Any male or female who has the gene that causes X-linked hereditary hypophosphatemia on one X-chromosome will develop the condition. 

Genetics

The PHEX gene regulates the production of the fibroblast growth factor 23 (FGF23) protein. The genetic mutation that causes X-linked hypophosphatemia results in an increase FGF23 protein. This protein regulates the kidney’s management of phosphate.

Most of the time, the genetic defect is inherited, and it can rarely occur without a family history of the condition. 

The Kidneys in X-linked Hypophosphatemia

The kidneys detect the concentration of electrolytes like phosphate, and precisely regulate the body’s concentration of these electrolytes through reabsorption into the blood. Normally, FGF23 helps the kidneys eliminate excess phosphate in the urine by preventing the reabsorption of excess phosphate into the bloodstream.

But when there is too much FGF23, phosphate is lost in the urine, resulting in a phosphate deficiency. 

In addition, FGF23 suppresses the production of 1,25 dihydroxy vitamin D. This vitamin plays an important role in the absorption of the phosphate that you get from your diet, and a deficiency further lowers phosphorus levels. Both of these problems ultimately result in bone and tooth abnormalities.

Diagnosis 

There are several physical signs of childhood rickets and adult osteomalacia. Both of these conditions can be caused by factors besides X-linked hypophosphatemia. In fact, nutritional deficits cause these bone problems far more often than X-linked hypophosphatemia. The diagnosis is based first on recognizing the effects, and then on directed testing to identify the cause. 

Children who have a pattern of slow growth or a smaller than expected skull size may have this condition. Children may have bowed legs as they start to walk because their weight can be too heavy for their weak bones. For some children, the pediatrician may detect craniosynostosis, which is early closure of the skull bones.

Imaging Tests 

Imaging tests of the bones, including X-rays, computerized tomography (CT), and bone scan may show signs of insufficient bone mineralization due to rickets or osteomalacia. 

Blood Tests 

Blood tests are usually necessary at this stage because rickets and osteomalacia can be associated with other blood test abnormalities such as low calcium and vitamin D levels in the absence of X-linked hypophosphatemia.

If there is a concern about X-linked hypophosphatemia, a phosphate level and FGF23 level can be tested in the blood. Low levels of phosphate and high levels of FGF23 are consistent with this condition.

Vitamin D level may be low or normal, and parathyroid hormone level may be normal or elevated. This is because parathyroid hormone can become elevated due to low phosphorus levels.

Genetic Test 

A genetic test can identify the mutation that causes this condition, but you do not need to have a genetic test to be diagnosed with X-linked hypophosphatemia. 

Usually the family history can provide clues that someone might have X-linked hypophosphatemia.

Because the condition can cause a range in the severity of symptoms, some people who have it may have parents who weren’t necessarily diagnosed with it. Parents might have some of the signs, such as mild muscle weakness or aching. And those who do not have access to their parental health history may have inherited the condition as well.

Treatment 

One of the features of X-linked hypophosphatemia is that an affected person’s blood phosphate level doesn’t improve with phosphate supplements. That’s because even with phosphate supplements, the excess FGF23 causes phosphate to be lost in the urine. 

There are several treatment approaches for X-linked hypophosphatemia, including a prescription medication indicated for the condition and management of the effects. 

In 2018, Crysvita (burosumab) was approved for the treatment of X-linked hypophosphatemia in adults and children who are six months of of age and older. This medication is a monoclonal antibody that binds to FGF23, inhibiting its activity to restore normal renal phosphate reabsorption and increase the concentration of 1,25 dihydroxy vitamin D.

The adult dose is 1 milligram (mg) per kilogram (kg) of body weight up to a maximum dose of 90 mg administered every four weeks. For children who weigh less than 10 kg, the dose is 1 mg/kg of body weight administered every two weeks. For children who weigh more than 10 kg, the dose is 0.8 mg/kg of body weight administered every two weeks.

Because Crysvita is a new drug, not much is known about its long-term effects. Common side effects in children include fever, coughing, diarrhea, toothaches, and muscle pains. Among the potential side effects in adults are back pain, tooth infections, muscle spasms, and restless legs syndrome. (It is also worth noting that Crysvita is an extremely expensive medication. Check with your insurance company to find out to what extent they may cover the cost.)

Hormone Treatments 

Sometimes hormone treatment is used to help alleviate the effects of this condition. 

• Growth hormone: This hormone is used for children who have inadequate or slow growth due to hormonal issues. Growth hormone does not specifically treat phosphate levels, but its use can help some children who have growth problems due to X-linked hypophosphatemia to catch up on their lagging growth. 
• Calcitriol: This is a form of vitamin D that increases blood calcium levels by increasing the amount of calcium absorbed in the intestines and the amount of calcium maintained in the body by the kidneys

Bone, Joint, and Muscle Care 

The effects of this condition may need to be managed with procedures, surgery, and/or physical therapy. These approaches can correct bone and joint deformities, improve strength, and alleviate dental problems. 

• Joint or bone surgery: If joint structure is problematic, interventional procedures may be needed to repair these issues. Bone fractures may require surgery as well. Surgery may be needed at any age.
• Dental care: Cavities, infections, abscesses, and weak teeth are frequently treated with dental interventions. If you have X-linked hypophosphatemia, it is especially important that you have regular dental checkups so that your dentist can catch problems at an early stage. 
• Braces: When bone structure is affecting movements, an external brace may be placed to help promote more appropriate growth and muscle control and to prevent injuries. 
• Rehabilitation and physical therapy: An individualized physical therapy program can help build and strengthen your muscles. This can be beneficial throughout life.

A Word From Verywell

A hereditary cause of rickets and osteomalacia, X-linked hypophosphatemia is manageable, but it requires lifelong medical care. Be sure to see your healthcare provider and dentist on a regular basis to catch problems and avoid progression of serious issues, like tooth abscesses.