X-linked Hypophosphatemia (XLH) is a rare, inherited disorder that disrupts the body’s ability to maintain proper levels of phosphate, a mineral fundamental to bone and tooth structure. This chronic condition is characterized by renal phosphate wasting, where the kidneys excrete too much phosphate into the urine. This leads to chronic hypophosphatemia, or low phosphate in the blood. Since phosphate is necessary for bone mineralization, this deficiency results in skeletal abnormalities that manifest throughout life. The condition is progressive, affecting both children and adults, and requires continuous medical management.
The Genetic Cause and Biological Mechanism
The underlying mechanism of XLH is a mutation of the PHEX gene, located on the X chromosome. This gene produces an enzyme called Phosphate Regulating Gene with Homologies to Endopeptidases on the X Chromosome. The mutation is inherited in an X-linked dominant pattern, meaning a single copy of the altered gene is sufficient to cause the disorder. The defective PHEX protein leads to a malfunction in the regulation of the hormone Fibroblast Growth Factor 23 (\(FGF23\)).
The non-functional PHEX enzyme causes an overabundance of \(FGF23\), which is primarily produced by bone cells. High levels of \(FGF23\) instruct the kidneys to reduce the reabsorption of phosphate from the filtered blood, resulting in excessive phosphate loss in the urine. Elevated \(FGF23\) also suppresses the production of active vitamin D, impairing the body’s ability to absorb phosphate and calcium from the gut.
This combination of excessive phosphate loss and impaired vitamin D activation leads directly to chronic hypophosphatemia. Since the body cannot maintain adequate phosphate levels, the mineralization of bone and cartilage is significantly impaired. This molecular cascade explains the skeletal and dental symptoms that define XLH.
Recognizing the Physical Effects and Complications
The effects of chronic hypophosphatemia often appear early in life, typically when a child starts to walk. A hallmark pediatric manifestation is rickets, which is the softening and weakening of bones causing skeletal deformities. Children frequently develop bowing of the legs or knock-knees because soft bones bend under body weight.
Other symptoms in children include bone and muscle pain, short stature, and an abnormal gait. Dental issues are common, involving thin enamel and a propensity for dental abscesses. The progressive nature of the disorder requires continuous monitoring and care as symptoms can change and worsen over time.
As individuals transition into adulthood, manifestations continue as osteomalacia, the adult equivalent of rickets involving bone softening. Adults frequently experience chronic joint stiffness, generalized bone pain, and an increased risk of fractures. A common complication is enthesopathy, the calcification of tendons and ligaments where they attach to bone, leading to restricted movement and pain. Hearing loss and spinal stenosis are also reported.
Diagnosis and Current Treatment Approaches
Diagnosis of XLH begins with recognizing characteristic clinical signs, such as rickets and skeletal deformities, along with a detailed family history. Laboratory tests confirm the diagnosis by revealing persistently low serum phosphate levels and elevated levels of \(FGF23\). Genetic testing confirms a pathogenic mutation in the PHEX gene, which is the definitive diagnostic marker for the disorder.
For many decades, conventional therapy involved the multiple daily administration of oral phosphate supplements and active vitamin D analogs, such as calcitriol or alfacalcidol. The goal was to partially replace lost phosphate and improve intestinal absorption. However, this regimen presented challenges, including gastrointestinal side effects and the risk of secondary hyperparathyroidism. A concern with conventional therapy is the potential for kidney damage, specifically nephrocalcinosis and kidney stones, due to high calcium and phosphate loads.
A major development in XLH management is the introduction of burosumab, a targeted therapy addressing the root cause of the disorder. Burosumab is a human monoclonal antibody that specifically binds to and inhibits the excessive activity of \(FGF23\). By blocking the hormone, burosumab restores the kidneys’ ability to reabsorb phosphate and increases the production of active vitamin D, normalizing phosphate levels in the blood.
Burosumab is administered as a subcutaneous injection, typically every two weeks for children. This treatment has demonstrated superiority over conventional therapy in improving rickets and promoting bone healing. The targeted approach improves mobility, reduces pain, and enhances the quality of life for both children and adults with XLH.