X-linked Hypophosphatemia (XLH) is a rare, inherited disorder that disrupts the body’s normal management of phosphate, a mineral indispensable for healthy bones and energy metabolism. This genetic condition is characterized by chronic hypophosphatemia. Because phosphate is a building block for the skeleton and teeth, its reduced availability leads to skeletal and dental issues throughout a person’s life. XLH is the most common form of hereditary rickets, affecting approximately 1 in 20,000 individuals worldwide. The resulting lack of proper mineralization can lead to bone deformities and impaired growth.
The Genetic Cause and Inheritance Pattern
X-linked Hypophosphatemia is caused by an inactivating mutation in the PHEX gene, an acronym for Phosphate Regulating Endopeptidase Homolog, X-Linked. This gene is located on the X chromosome, which explains the “X-linked” part of the disorder’s name. The disorder is inherited in an X-linked dominant manner, meaning that inheriting just one copy of the mutated gene is sufficient to cause the condition.
Since females possess two X chromosomes and males have one X and one Y, the inheritance pattern is distinct for each sex. A mother with XLH has a 50% chance of passing the gene to any child, regardless of sex. A father with XLH will pass the gene to all his daughters but none of his sons.
XLH affects both males and females, though the clinical manifestations can be more severe in males. The gene mutation can also occur spontaneously in rare cases, meaning it appears in an individual without being inherited from either parent. The PHEX gene encodes an enzyme that is predominantly expressed in bone and teeth cells, and its malfunction sets off the cascade leading to phosphate depletion.
How Low Phosphate Levels Develop
The physiological problem begins when the PHEX gene is mutated and unable to function properly within bone cells, specifically osteocytes. Normally, the PHEX enzyme helps to regulate the levels of a hormone called Fibroblast Growth Factor 23 (FGF23). In XLH, the defective PHEX protein results in the overproduction or lack of breakdown of FGF23, leading to inappropriately high levels of this hormone circulating in the blood.
FGF23 acts as a powerful phosphate-regulating signal, and its excess causes the body to waste phosphate. The hormone travels to the kidneys, where it acts directly on the proximal tubules. This action prevents the kidneys from reabsorbing phosphate back into the bloodstream after it has been filtered.
The phosphate is excessively excreted in the urine, a process known as renal phosphate wasting. High FGF23 levels also impair the body’s ability to produce the active form of vitamin D, known as calcitriol. This reduction in active vitamin D further limits the absorption of phosphate from the digestive tract, compounding the problem of chronic low phosphate in the blood.
Physical Effects and Clinical Symptoms
The long-term state of chronic low phosphate directly impacts the skeletal system, which relies on this mineral for proper mineralization. In children, the lack of phosphate causes rickets, which manifests as skeletal deformities. These often include bowed legs or knock-knees, as well as an abnormal or waddling gait.
Children frequently experience impaired growth, resulting in short stature, and may suffer from bone and joint pain. In adults, the condition is referred to as osteomalacia, where bones are soft and prone to fracture. Adults may also experience pseudofractures, chronic bone pain, joint stiffness, and the calcification of ligaments and tendons, known as enthesopathy.
Beyond the skeleton, XLH can also cause distinct dental abnormalities, such as severe dental pain, abscesses, and defective enamel. Muscle weakness and fatigue are also commonly reported symptoms. Some patients also develop hearing loss, particularly as they age.
Identifying and Managing X-Linked Hypophosphatemia
XLH is often suspected in children presenting with slowed growth, rickets, or bowing of the legs. Diagnosis is confirmed through a combination of biochemical tests and genetic analysis. Blood tests reveal low serum phosphate levels and elevated or inappropriately normal levels of FGF23.
The goal of managing XLH is to raise the circulating phosphate levels to promote proper bone and dental health. Traditional management involves administering oral phosphate supplements multiple times a day to compensate for the kidney wasting. This approach is paired with active vitamin D supplements, such as calcitriol, to improve intestinal phosphate absorption and enhance bone mineralization.
A newer, targeted approach involves the use of monoclonal antibodies that directly inhibit the action of excess FGF23. This modern therapy, exemplified by burosumab, blocks the hormone, allowing the kidneys to reabsorb phosphate and increasing active vitamin D production. This targeted treatment represents a shift toward addressing the underlying mechanism of the disorder, offering a more effective way to increase phosphate levels and improve skeletal health throughout the patient’s life.