XLH, or X-linked hypophosphatemia, is a genetic condition where the body wastes phosphate through the kidneys, leaving too little in the blood for normal bone and tooth development. It is the most common form of inherited phosphate wasting, affecting roughly 4 to 5 people per 100,000, with an incidence of about 3.9 per 100,000 live births. In children, XLH typically causes bowed legs, short stature, and dental problems. In adults, it leads to chronic pain, joint stiffness, and softened bones.
How XLH Works in the Body
XLH is caused by mutations in a gene called PHEX, which sits on the X chromosome. This gene normally produces an enzyme that helps regulate levels of a hormone called FGF23. When PHEX doesn’t work properly, FGF23 builds up in the bloodstream. That excess FGF23 does two things: it tells the kidneys to dump phosphate into the urine instead of reabsorbing it, and it blocks the kidneys from activating vitamin D. Since active vitamin D is needed to absorb phosphate and calcium from food, both pathways of getting phosphate into the body are disrupted at once.
The result is chronically low blood phosphate, a state called hypophosphatemia. Phosphate is essential for mineralizing bones and teeth, so without enough of it, bones stay soft and don’t harden the way they should. The bone cells themselves seem to be affected too. Research in animal models shows that cells lacking normal PHEX function become overly sensitive to phosphate levels and keep producing excess FGF23 even when phosphate levels are corrected, which is one reason the condition is so persistent.
Inheritance Pattern
Because the PHEX gene is on the X chromosome, XLH follows an X-linked dominant inheritance pattern. A single copy of the mutated gene is enough to cause the disease. A woman with XLH has a 50% chance of passing it to each child, regardless of sex. A man with XLH will pass the condition to all of his daughters but none of his sons, since sons receive his Y chromosome instead. In some cases, XLH arises from a new spontaneous mutation with no family history, then gets passed to future generations from that point on.
Signs in Children
XLH usually becomes apparent when a child starts walking, typically between ages 1 and 2. The hallmark sign is bowing of the legs, which can bend inward (knock-kneed) or outward (bowlegged), sometimes with twisting of the shinbones. Children develop a waddling gait, delayed motor milestones, and grow more slowly than their peers, resulting in below-average stature. Bone pain, muscle weakness, and fatigue are common.
Some children develop craniosynostosis, where the skull bones fuse too early, giving the head an elongated shape. Hearing loss and tinnitus can also occur. X-rays typically show widened, irregular growth plates consistent with rickets, along with bowing and deformity of the long bones in the legs.
How XLH Affects Teeth
Dental problems are one of the most distinctive features of XLH and often go unrecognized. Children and adults with XLH develop spontaneous dental abscesses, meaning infections that appear without any cavity or injury. This happens because the teeth themselves are structurally flawed. The dentin, the hard layer beneath the enamel, contains large gaps and channels of unmineralized tissue that extend all the way to the junction with the enamel. Bacteria can travel through these defects and reach the inner pulp of the tooth without ever causing a visible cavity.
On dental X-rays, teeth in XLH patients show enlarged pulp chambers, prominent pulp horns, shortened roots, and thin walls of dentin. The enamel is slightly underdeveloped as well. Because bacteria have such easy access to the tooth interior, preventive dental care and early treatment of any wear or small cavities is critical to avoiding repeated abscesses.
Symptoms in Adults
Adults with XLH face a different set of challenges. The rickets of childhood transitions into osteomalacia, a condition where bones remain soft and poorly mineralized. This leads to chronic musculoskeletal pain, general weakness, and stiffness. Over time, the softened bones can develop pseudofractures, which are cracks that appear on X-rays in the long bones and sometimes progress to full fractures. One study found that over half of adult XLH patients had experienced fractures or pseudofractures.
A particularly troublesome complication in adults is enthesopathy, where the tendons and ligaments that attach to bone become calcified and inflamed. This causes chronic pain and stiffness around joints, restricts range of motion, and worsens with age. Adults with XLH often develop abnormal walking patterns, with a wider stance and leaning of the trunk to compensate for stiff, painful joints. Early-onset osteoarthritis is also common as a consequence of years of abnormal bone alignment and joint stress.
How XLH Is Diagnosed
Diagnosis starts with blood work showing persistently low serum phosphate, typically below 2.5 mg/dL in adults. The key distinction from other causes of low phosphate is that the kidneys are actively wasting it. This is measured by calculating how much phosphate the kidneys reabsorb relative to how much they filter. In XLH, reabsorption is abnormally low, and a fractional excretion of phosphate at or above 20% points to kidney-driven phosphate loss.
FGF23 levels help confirm the diagnosis. In XLH, FGF23 is elevated or “inappropriately normal,” meaning the hormone isn’t suppressed the way it should be when phosphate is low. Normal FGF23 runs between 30 and 100 RU/mL. Active vitamin D levels may be low or inappropriately normal for the degree of phosphate wasting, since excess FGF23 blocks its production. A family history consistent with X-linked inheritance strengthens the clinical picture, and genetic testing for PHEX mutations can provide definitive confirmation.
Conventional Treatment
Since the 1980s, the standard treatment for XLH has been a combination of oral phosphate supplements and active vitamin D. Children are typically given phosphate divided into four to five doses spread throughout the day, along with a daily dose of active vitamin D to help the body absorb calcium and counteract the effects of low phosphate. This regimen helps improve bone mineralization and supports growth, but it doesn’t fix the underlying problem of excess FGF23.
The treatment requires careful, ongoing monitoring because the supplements themselves carry risks. Oral phosphate can trigger secondary overactivity of the parathyroid glands, and the combination of phosphate and vitamin D can cause calcium to build up in the kidneys, a condition called nephrocalcinosis. Regular blood tests and kidney ultrasounds are part of the monitoring routine. Even with years of conventional treatment, many patients continue to have short stature, gait abnormalities, dental problems, and reduced physical function.
Newer Treatment With Burosumab
Burosumab is a newer therapy that works differently from conventional supplements. It’s an antibody that blocks FGF23 directly, targeting the root cause of the disease rather than replacing the phosphate that’s being lost. By neutralizing excess FGF23, burosumab allows the kidneys to reabsorb phosphate normally and restores the body’s ability to activate vitamin D on its own. It’s given as an injection rather than taken orally multiple times a day.
Results in real-world use have been striking. In a UK study of 136 adults starting burosumab, only 5% had normal serum phosphate levels at baseline. After six months of treatment, that number rose to 63%, and phosphate levels remained significantly improved through at least 18 months. In children, clinical trials showed improvements in both phosphate levels and healing of rickets on X-rays, without the need for phosphate supplements or active vitamin D alongside it.
Living With XLH
XLH is a lifelong condition that changes character over time. In childhood, the focus is on managing rickets, supporting growth, and preventing dental complications. Some children require orthopedic surgery to correct severe leg bowing that doesn’t improve with medical treatment. In adulthood, the priorities shift to managing pain, maintaining mobility, and addressing enthesopathy and osteoarthritis. Physical therapy and regular monitoring of bone health remain important throughout life.
Because XLH is rare, many people go years before receiving a correct diagnosis, particularly if they don’t have an obvious family history. Adults who were never diagnosed as children may present with unexplained fractures, chronic pain, or dental abscesses that finally prompt the right testing. Early diagnosis and treatment in childhood lead to better outcomes for growth and bone development, but treatment at any age can improve phosphate levels and reduce the burden of symptoms.