What is X-linked hypophosphatemia?

X-linked hypophosphatemia (XLH) is a rare inherited disease that affects approximately one in 20,000 to 60,000 children born each year. Although the exact number of people affected is unknown, it is estimated that around 250 people in Serbia live with this condition. In XLH, the kidneys excrete too much phosphate, leading to chronically low levels in the blood. In children, this most often results in bone deformities and slowed growth, while adults may experience chronic pain, stiffness, and joint problems.  The condition can develop as early as infancy, and timely diagnosis and treatment can significantly reduce symptoms and prevent serious complications.

What is X-linked hypophosphatemia?

XLH is a chronic condition in which the body cannot retain enough phosphate in the blood. Phosphate is essential for building and maintaining strong bones and teeth, but in people with XLH, the kidneys excrete it in greater amounts than needed. This leads to bone softening (osteomalacia in adults and rickets in children), pain, and reduced mobility.

The disease is caused by a mutation in the PHEX gene on the X chromosome. This mutation results in elevated levels of the hormone FGF23, which prevents the kidneys from retaining phosphate and reduces the activation of vitamin D. As a result, bones do not receive enough minerals, affecting their growth and structure.

Does XLH affect men or women more?

Because the mutation is located on the X chromosome, men, who have only one X chromosome, usually develop more severe symptoms. Women, who have two X chromosomes, may have milder or more severe symptoms depending on which chromosome they pass on to their children. The disease can be inherited from a parent, but in some cases, it occurs spontaneously (de novo mutation).

If one parent carries the mutation, there is a 50% chance of passing it on to a child, regardless of the child’s sex.

What are the symptoms of X-linked hypophosphatemia?

Symptoms of XLH can be present from early childhood and may change over the course of life.

In children:

• Slow growth and shorter height compared to peers
• Bowed legs or other bone deformities
• Pain in the legs, knees, and hips
• Delayed walking
• Dental problems – weak enamel, cavities, abscesses

In adults:

• Chronic pain in bones and joints
• Joint stiffness and reduced mobility
• Fragile bones and increased risk of fractures
• Enthesopathy (calcification of ligaments and tendons)
• Dental problems and tooth loss
• Fatigue and reduced stamina

Symptoms often worsen without treatment, and in some patients, they can lead to permanent deformities and mobility limitations.

How is X-linked hypophosphatemia diagnosed?

A doctor may suspect XLH if a patient has bone deformities, joint pain, and chronically low phosphate levels in the blood. The diagnosis is confirmed through:

• Blood and urine tests – low blood phosphate, increased phosphate excretion in urine
• Bone X-rays – changes typical of rickets or osteomalacia
• Genetic testing – identification of a mutation in the PHEX gene
• Measurement of FGF23 hormone – usually elevated in affected individuals

A doctor may suspect XLH if the patient has:

• Bone deformities and slow growth (in children)
• Bone and joint pain
• Chronically low phosphate levels in the blood
• Normal or low calcium levels
• Elevated FGF23 hormone

How is X-linked hypophosphatemia treated?

Treatment is individualized and long-term, with the goal of increasing blood phosphate levels, improving bone mineralization, and relieving symptoms. Common approaches include:

• Phosphate supplements in small, frequent doses throughout the day
• Active forms of vitamin D (calcitriol or alfacalcidol) to improve mineral absorption
• Burosumab – a monoclonal antibody that reduces the effect of the FGF23 hormone and helps retain phosphate
• Physical therapy to maintain mobility and strengthen muscles
• Orthopedic interventions for severe bone deformities
• Dental care to prevent and treat oral health problems

Treatment is long-term and carried out under the supervision of a medical team, which may include an endocrinologist, orthopedic surgeon, physical therapist, and dentist.

Possible complications and prognosis in X-linked hypophosphatemia

If XLH is left untreated or therapy is discontinued, the disease can lead to numerous complications:

• Permanent bone deformities
• Leg length discrepancy
• Chronic pain and joint stiffness
• Bone fractures due to reduced strength
• Enthesopathy (calcification of tendons and ligaments)
• Dental problems – frequent cavities, abscesses, tooth loss
• Reduced mobility and difficulty performing daily activities

XLH is a lifelong chronic condition, but with proper treatment it is possible to relieve symptoms, prevent the progression of deformities, and significantly improve quality of life. Early diagnosis and continuous therapy are crucial for preserving bone and joint function.

Living with XLH and lifestyle changes

Although X-linked hypophosphatemia cannot be cured, an adapted lifestyle can help ease symptoms and reduce the risk of complications.

• Proper nutrition – a balanced diet rich in calcium and phosphorus, while avoiding foods and drinks that hinder phosphate absorption (e.g., carbonated beverages with phosphoric acid)
• Regular physical activity – gentle stretching and muscle-strengthening exercises help maintain mobility and reduce pain, but activities that put excessive strain on the bones and joints should be avoided
• Dental care – regular dentist visits and good oral hygiene reduce the risk of cavities and infections
• Medical check-ups – monitoring phosphate levels, vitamin D, and kidney function, as well as orthopedic evaluations to check for deformities
• Psychological and social support – speaking with a psychologist or joining rare disease support groups can help in coping with a chronic condition

Timely therapy, regular check-ups, and healthy habits can greatly improve the quality of life for people with XLH.

Early recognition and proper treatment protect bone health

X-linked hypophosphatemia requires ongoing attention and collaboration with a team of specialists. Although it cannot be cured, early diagnosis and proper treatment can prevent severe deformities, reduce pain, and preserve mobility. Timely laboratory testing, such as that available at IntroLab in Belgrade, enables earlier detection of the disease and the start of treatment on time. With medical support, a tailored diet, regular physical activity, and appropriate dental care, it is possible to lead a fulfilling and active life.