XLH is estimated to occur in 3.9-5 individuals per 100,000 live births. Males and females are equally affected.

XLH is caused by changes in the PHEX gene. The exact cause of XLH and the function of the protein encoded by PHEX is unknown, but this protein is found in cells responsible for bone formation. Changes in this gene lead to abnormally high levels of another protein called fibroblast growth factor 23 (FGF23). This protein increases the secretion of phosphate into the urine in the kidneys, leading to low phosphate levels due to its urinary excretion. In addition, FGF23 also decreases the activity of an enzyme in the kidney that activates vitamin D. Therefore, with high levels of FGF23, vitamin D is not activated adequately, impairing its function. Phosphate and vitamin D both have important functions in maintaining bone health, therefore, their dysregulation leads to skeletal symptoms.

Human cells contain 23 pairs of chromosomes, including sex chromosomes, which can be X or Y. An individual is genetically male if they have an X chromosome and Y chromosome and female if they have two X chromosomes. One copy of each chromosome pair is inherited from the mother and one copy from the father. The offspring becomes genetically male if they happen to inherit a Y chromosome from their father and female if they inherit an X chromosome from their father. While the other 22 pairs of chromosomes have very similar content, the X chromosome is much larger than the Y chromosome, and therefore, contains many more genes. XLH is inherited in an X-linked manner, as the responsible gene is located on the X chromosome. An implication of an X-linked pattern of inheritance is that an affected father will pass on XLH to all his daughters but none of his sons while an affected mother passes it on to 50% of her children. XLH is also a dominant disorder, meaning that having one defective X chromosome is enough to cause XLH.

Although in most cases XLH is inherited, and thus, runs in families, there are cases where it occurs in individuals with no family history.

XLH syndromes can range from asymptomatic hypophosphatemia that is only evident in blood tests measuring blood phosphate to severe bone abnormalities and pain. In most cases, symptoms become evident around 2 years of age as the individual starts walking and weight-bearing more. Abnormal development of the bones, particularly bowing or twisted growth of lower legs and slow growth are common early presentations. Other symptoms are bone pain, muscle pain and weakness, or an abnormal way of walking (gait). Pain may worsen at night or with prolonged walking. Sometimes, XLH may present in adulthood with symptoms such as short stature with disproportionately shorter legs, joint pain, or reduced joint immobility due to the hardening of tendons and ligaments (enthesopathy). Dental abnormalities are also common. Because teeth cannot mineralize properly, there is a higher risk for tooth abscesses and tooth pain. There might be craniosynostosis which is the early fusion of the bones that make up the skull before the brain has fully developed leading to irregularities in the shape of the skull or Chiari malformation which is when a part of the brain pushes down into the spinal canal because the space in the skull is too small for the brain, causing headaches. Hearing impairment is also possible as an abnormal skull may impinge in the auditory nerve.

Diagnosis of XLH is suspected based on family history, symptoms and clinical features such as slow growth velocity, worsening bowing of lower legs which starts when the child begins walking, or swelling around joints in children and short stature, bone and joint pain and immobility and dental issues in adults. Once there is a clinical suspicion due to the presence of these features, X-ray imaging of the bones and blood tests can confirm XLH. Genetic testing is also available but not necessary for diagnosis.

Biochemical tests that establish the diagnosis of XLH include blood tests measuring phosphate levels. In XLH, blood phosphate levels are abnormally low. As opposed to the vitamin D-related causes of disorders with a similar presentation, phosphate levels in XLH do not improve with vitamin D treatment. Additionally, while in healthy individuals, active vitamin D levels rise in the body in response to low phosphate levels, such a response is not observed in individuals with XLH, leading to vitamin D levels that do not correspond to the low phosphate levels. Urine tests are also done to check for phosphate wasting which is expected in XLH. This means that despite low phosphate levels in the blood, phosphate is being excreted in the urine while the body should be trying to reduce the amount of phosphate excreted in the urine to correct the low blood phosphate levels. Therefore, XLH is associated with low blood phosphate levels and elevated urine phosphate. Other test results that can assist an XLH diagnosis include elevated FGF23 levels in the blood and elevated ALP, particularly in children, which is a marker of activation of cells that form bones in response to poor bone mineralization. 

Another important investigation in XLH is an x-ray which may show bone abnormalities such as the enlargement of the wide end of the long bones.

Genetic testing can also identify mutations in PHEX but this is not necessary for diagnosis.

Treatment of XLH consists of active vitamin D (calcitriol) and phosphate supplements. This is associated with reduced pain and improved lower leg abnormalities. In children, treatment starts at the time of diagnosis and is continued until the completion of long bone growth. In adults, however, it is unclear whether medical treatment is beneficial and it is reserved for adults with significant symptoms such as severe pain, planned orthopedic procedure, test results indicating the softening of the bones or osteomalacia (elevated ALP), or multiple fractures that occur due to overuse and not trauma (stress fractures). 

Burosumab is another pharmacological option for XLH. Burosumab is a monoclonal anti-FGF23 antibody. Antibodies are proteins made by the immune system to attack foreign particles that are in the body. Monoclonal antibodies are engineered antibodies that attack a specific substance. Burosumab attacks FGF23 which is elevated in XLH and thus causes all the associated symptoms. The immune-mediated destruction of the extra FGF23 improves hypophosphatemia and many of the associated symptoms. 

In addition, children with short stature may benefit from growth hormone therapy to increase their final height if their XLH is well-controlled. This, however, is controversial. 

Some individuals with severe lower leg deformities that do not respond to pharmacologic treatment may benefit from surgical treatment. Although there are multiple surgical options, the effectiveness of these has not been compared. When choosing the surgical option, it is important to consider the age and the growth status of the individual. For example, corrective osteotomy or cutting of the bone to reshape and restore the correct alignment of the bone is typically not done until after peak growth velocity has been achieved. Peak growth velocity refers to a period of time in which a child experiences the fastest growth in height and is determined by following a child’s growth by charting their height at specific ages which tends to have a predictable pattern. 

Regular dental hygiene such as flossing and using a fluoride mouthwash is essential to prevent dental problems.

The prognosis of XLH varies significantly among individuals. Some may only have low phosphate levels with no associated symptoms while others may experience severe pain, complications, and persistent lower leg deformity despite treatment. The persistence of lower leg abnormalities in adulthood despite appropriate management is partially related to poor compliance with pharmacological therapy during childhood. In addition, early diagnosis and treatment also improve long-term outcomes.

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Fuente R, Gil-Peña H, Claramunt-Taberner D. X-linked hypophosphatemia and growth. Rev Endocr Metab Disord. 2017;18(1):107-115. DOI 10.1007/s11154-017-9408-1

Genetic and Rare Disease Information Center. X-Linked Hypophosphatemia. 2018. Available from  https://rarediseases.info.nih.gov/diseases/12943/x-linked-hypophosphatemia
 

Lambert AS, Zhukouskaya V, Rothenbuhler A, Linglart A. X-linked hypophosphatemia: Management and treatment prospects. Joint Bone Spine. 2019;86(6):731-738. https://doi.org/10.1016/j.jbspin.2019.01.012.

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