X-linked hypophosphatemia (XLH) is a rare genetic disorder affecting how the body processes phosphate, a mineral important for bone and tooth health. This lifelong condition leads to abnormally low blood phosphate levels, known as hypophosphatemia. These low levels disrupt bone and tooth mineralization, causing them to become soft, weak, and prone to deformity. Symptoms can vary and evolve throughout a person’s life.
Causes and Genetic Inheritance
Phosphate plays a significant role in bodily functions, particularly in building strong bones and teeth, supporting nerve function, and enabling muscle movement. In XLH, a mutation in the PHEX gene on the X chromosome leads to overproduction of fibroblast growth factor 23 (FGF23).
Normally, FGF23 helps regulate phosphate levels by signaling the kidneys to excrete excess phosphate. However, excessive FGF23 from the PHEX gene mutation causes the kidneys to waste too much phosphate into the urine, leading to persistently low levels in the bloodstream. High FGF23 levels also reduce vitamin D activation, further impairing calcium and phosphate balance.
XLH follows an X-linked dominant inheritance pattern; a single copy of the mutated PHEX gene on the X chromosome is sufficient to cause the disorder. A male with XLH will pass the condition to all of his daughters but none of his sons. A female with XLH has a 50% chance of passing the gene to each child, regardless of sex. Males often experience more pronounced symptoms due to having only one X chromosome.
Signs and Symptoms of XLH
Symptoms of X-linked hypophosphatemia can differ significantly between children and adults, often becoming apparent as children begin to walk. In infants and young children, common signs include bowed legs or knock-knees, characteristic of rickets, a condition where bones soften and weaken. Children may also experience short stature, an abnormal or waddling gait, bone and joint pain, and dental problems such as abscesses, infections, and tooth pain.
As individuals with XLH age, adults often develop osteoarthritis, particularly in weight-bearing joints, and may experience stress fractures due to weakened bones. Progressive hearing loss is another common manifestation in adults. Enthesopathy, which involves the inflammation or degeneration of tendons and ligaments where they attach to bone, can also occur, causing pain and stiffness. Recurrent dental abscesses and premature tooth loss remain a concern throughout adulthood.
The Diagnostic Process
Diagnosing X-linked hypophosphatemia involves clinical evaluation and laboratory tests. Doctors assess medical history and conduct a physical examination, looking for characteristic signs such as bowed legs or short stature. They also inquire about any family history of similar symptoms, as XLH is an inherited condition.
Blood tests are a primary diagnostic tool, checking for low levels of phosphate in the blood. Calcium levels are usually within the normal range, which helps distinguish XLH from other conditions causing rickets. Urine tests confirm that the kidneys are excessively wasting phosphate, a key indicator of the disorder.
X-rays visualize the bones and identify signs of rickets in children or osteomalacia (adult rickets) in adults, such as bone deformities or impaired bone mineralization. Genetic testing can provide a definitive diagnosis by identifying the specific mutation in the PHEX gene. This genetic confirmation is particularly helpful in ambiguous cases or for family planning.
Treatment and Management Approaches
Managing X-linked hypophosphatemia involves a multi-faceted approach aimed at increasing phosphate levels and improving bone health. Conventional therapy involves daily high-dose oral phosphate supplements combined with calcitriol, an active form of vitamin D. This therapy helps the body absorb more phosphate and reduce its loss through the kidneys, supporting bone mineralization. However, this treatment can present challenges, including gastrointestinal side effects like diarrhea and abdominal discomfort, and a risk of kidney complications such as nephrocalcinosis (calcium deposits in the kidneys).
Burosumab, a modern targeted therapy, is a monoclonal antibody. It works by directly targeting and blocking excess fibroblast growth factor 23 (FGF23) that causes phosphate wasting. By neutralizing overactive FGF23, burosumab allows the kidneys to reabsorb more phosphate, leading to increased phosphate levels in the blood and improved bone mineralization. This targeted approach has shown promise in reducing the severity of XLH symptoms and promoting healing of rickets.
Beyond specific medications, supportive care is an important aspect of XLH management. Regular dental monitoring and interventions address frequent dental problems. Physical therapy helps improve muscle strength and mobility, while occupational therapy assists with daily activities affected by bone deformities or pain. Orthopedic surgeries may be required to correct severe bone deformities, such as bowed legs, improving alignment and reducing pain.