X-linked hypophosphatemia (XLH) is a rare and progressive inherited disorder characterized by the loss of phosphate from the kidneys, and subsequently low levels of phosphate in the blood.
Phosphorus, which exists as phosphate in the blood, is an important mineral required for the development and growth of bones and teeth. It is also involved in maintaining cellular integrity, and regulating many cellular processes.
In XLH, phosphate is abnormally processed and excreted by the kidneys, leading to low availability in the blood. This causes rickets-like symptoms such as osteomalacia (soft and weak bones), early osteoarthritis, fractures, pain, dental abscesses (buildup of pus in the teeth), and stunted growth.
XLH is estimated to occur in about 1 in 20,000 live births.
Cause of XLH
XLH is caused by mutations in the PHEX gene that is situated on the X-chromosome. This gene encodes for the PHEX enzyme, (phosphate regulating endopeptidase homolog X-linked enzyme), which is thought to regulate the functioning of another protein — called fibroblast growth factor 23 or FGF23 — that is produced on instructions from the FGF23 gene. The exact mechanism of action of PHEX is still being investigated.
The FGF23 protein inhibits the ability of the kidneys to reabsorb phosphate into the blood. Mutations in the PHEX gene cause FGF23 to be overly active, resulting in lesser phosphate reabsorption and its greater excretion in urine. This condition, sometimes called phosphate wasting, leads to the symptoms of XLH.
Inheritance of XLH
About 20%-30% of XLH cases develop as a result of spontaneous mutations, with patients having no previous family history of the disease. These people can pass XLH to their children.
Symptoms of XLH
Symptoms of XLH can vary among individuals. They usually start appearing in early childhood, and can last a person’s lifetime.
Common symptoms include hypophosphatemia (low levels of phosphorus in the blood), genu varum (outward bowing of the legs), osteomalacia (soft bones), joint dislocations, abnormalities in the dental enamel, and problems with the metaphysis of long bones (where bone growth occurs), dental abscesses, and rickets.
Some children also show craniosynostosis (early closure of skull joints, leading to problems with skull growth), while adults show enthesopathy (tendon or ligament attachment problems), osteoarthritis, and are of short stature.
XLH patients may also have hearing defects, increased rates of bone fracture, spinal stenosis (narrowing of the spinal canal that puts pressure on the spinal nerves), and abnormalities in the shape of the hip bone.
Diagnosis of XLH
XLH is diagnosed based on physical exams and the patient’s family history, imaging tests such as X-rays, biochemical tests, and molecular genetic tests.
Physical examination includes looking for evidence of impaired growth, bowing of the legs, knock-knees (angular deformities of the knees), an abnormal shape to the head, dental abscesses, and enlarged wrists and knees.
Imaging tests such as X-rays can help in understanding if bone metaphyses are affected and to what extent, and in determining the presence of rachitic rosary in the ribs.
Biochemical tests include measuring the levels of alkaline phosphatase, phosphate, and FGF23 protein in the blood and urine. Normal blood serum phosphate levels vary with age, and are usually between 4.8 to 8.2 mg/dL in newborns and 2.7 to 4.7 mg/dL in people starting at age 15.
Estimating the renal tubular reabsorption rate of phosphate is also useful in diagnosing the disease to evaluate the extent of phosphate wasting through the kidneys.
Molecular genetic tests to identify mutations in the PHEX gene can help in confirming XLH. Genetic testing may also be extended to other genes of interest to study their involvement.
XLH patients do not respond to vitamin D treatment alone, as is often given people with rickets. Giving XLH patients vitamin D, for this reason, can help in an overall diagnosis of this disease.
Currently, no cure is known for XLH and treatment aims to relieve pain and correct skeletal deformities. Phosphate supplements given three to five times daily and combined with a high dose of calcitriol is usually recommended for children. These supplements continue to be given until the bones are fully grown. Children may also be prescribed growth hormones to promote body growth, but this is only effective when done at infancy.
For adults, the primary goal of treatment is pain relief. Corrective surgery may be performed to better adjust bent legs and joints. Regular visits to the dentist can prevent dental abscesses from returning.
The U.S. Food and Drug Administration (FDA) recently approved an antibody called Crysvita (burosumab), by Ultragenyx, to treat XLH in both children and adults. Crysvita binds to excess FGF23 protein and helps to reduce phosphate wastage through the kidneys, thereby increasing phosphate availability in the blood.
Last updated: Dec. 9, 2019
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