X-linked hypophosphatemia (XLH) is a rare, inherited disorder that disrupts the body’s ability to maintain healthy levels of phosphate, a mineral essential for strong bones and teeth. It is the most common form of hereditary hypophosphatemic rickets, affecting approximately one in 20,000 people globally. XLH is defined by the chronic loss of phosphate through the kidneys (renal phosphate wasting), which leads to abnormally low phosphate levels in the bloodstream. This deficiency impairs bone tissue mineralization, causing a range of progressive skeletal and dental problems throughout life.
Genetic Basis and Underlying Mechanism
The root cause of X-linked hypophosphatemia is an inactivating mutation in the PHEX gene, which is located on the X chromosome and follows an X-linked dominant inheritance pattern. The PHEX gene encodes an endopeptidase primarily expressed in bone cells. This protein regulates the activity of Fibroblast Growth Factor 23 (FGF23), a hormone that controls phosphate metabolism.
The non-functional PHEX protein leads to excessively high circulating levels of FGF23. Elevated FGF23 blocks phosphate reabsorption in the kidneys, causing it to be lost in the urine (hypophosphatemia). High FGF23 also suppresses the enzyme 1-alpha-hydroxylase, which converts inactive Vitamin D to its active form, 1,25-dihydroxyvitamin D. Low levels of active Vitamin D reduce the intestine’s ability to absorb phosphate and calcium, compounding the mineral deficiency that impairs bone mineralization.
Physical Manifestations of XLH
The chronic lack of phosphate results in a spectrum of physical abnormalities that often manifest in early childhood. In growing children, the condition presents as rickets, characterized by poorly mineralized, soft bone tissue. This leads to skeletal deformities such as bowed legs (genu varum), knock knees (genu valgum), and a waddling gait, which typically become noticeable when a child begins to walk.
As individuals with XLH reach adulthood, the condition is referred to as osteomalacia. Adults commonly experience bone pain, muscle weakness, and joint stiffness. Pathologic fractures and pseudofractures are also frequent occurrences. Another common musculoskeletal complication is enthesopathy, the painful calcification of tendons and ligaments where they attach to bone.
XLH is also associated with dental abnormalities due to defects in dentin mineralization. Patients often suffer from spontaneous dental abscesses, which can occur even in teeth without caries or trauma. Defects in the dentin and thin enamel allow bacteria to easily penetrate the tooth pulp, causing these infections. Children with XLH often experience short stature because their growth plates cannot properly mineralize.
Identification and Monitoring
Diagnosis relies on clinical, biochemical, and genetic findings. A primary indicator is a low fasting serum phosphate level that is inappropriate for the patient’s age. Blood work will also reveal normal or low-normal serum calcium and elevated levels of the enzyme alkaline phosphatase, especially in children with active rickets.
A definitive biochemical signature includes high circulating levels of FGF23, confirming the underlying pathophysiology. Urinalysis demonstrates renal phosphate wasting, often quantified by measuring the tubular maximum reabsorption of phosphate per glomerular filtration rate (TmP/GFR). X-rays are used to visualize skeletal damage, showing evidence of rickets (widened, frayed growth plates) in children or osteomalacia (pseudofractures) in adults. The diagnosis is confirmed with molecular genetic testing that identifies a pathogenic variant in the PHEX gene. Once diagnosed, ongoing monitoring involves regular biochemical testing and imaging to assess disease activity, growth plate healing, and response to therapeutic management.
Therapeutic Management
The traditional approach to managing XLH involved high-dose oral phosphate supplements combined with activated Vitamin D, such as calcitriol. The goal of this conventional therapy was to replace the lost phosphate and enhance its intestinal absorption. However, this treatment requires frequent daily dosing (four to six times a day) and often fails to persistently normalize serum phosphate levels. Long-term use of this high-dose regimen is associated with serious side effects, including nephrocalcinosis (calcium deposits in the kidneys) and secondary hyperparathyroidism.
Burosumab, a targeted therapy administered via subcutaneous injection, represents a significant treatment advancement. Burosumab is a humanized monoclonal antibody that specifically binds to and neutralizes the excess FGF23. By inhibiting FGF23, this treatment allows the kidneys to retain phosphate more effectively, reversing renal phosphate wasting. It also leads to increased levels of active Vitamin D, thereby improving phosphate homeostasis and promoting better bone mineralization.
In addition to medical treatment, supportive care addresses the physical complications of the disorder. Orthopedic interventions, such as osteotomy, may be necessary to correct severe lower limb deformities that impair mobility. Specialized dental care is required to manage frequent dental abscesses and prevent premature tooth loss resulting from dentin defects. The integration of medical and supportive management is necessary to improve skeletal health and quality of life for individuals living with XLH.