X-linked hypophosphatemia

X-linked hypophosphatemia (XLH), is an X-linked dominant form of rickets (or osteomalacia) that differs from most cases of rickets in that vitamin D supplementation does not cure it.

X dominant affected father

Other Names

X-linked hypophosphatemic rickets; XLH; Hypophosphatemic rickets, X-linked dominant; See More

Clinical features

• X-linked hypophosphatemia (XLH) is an inherited disorder characterized by low levels of phosphate in the blood.
• Phosphate levels are low because phosphate is abnormally processed in the kidneys, which causes a loss of phosphate in the urine (phosphate wasting) and leads to soft, weak bones (rickets).
• XLH is usually diagnosed in childhood. Features include bowed or bent legs, short stature, bone pain, and severe dental pain.
• XLH is caused by mutations in the PHEX gene on the X chromosome, and inheritance is X-linked dominant.
• Treatment generally involves supplements of phosphate and high-dose calcitriol (the active form of Vitamin D), and may also include growth hormones, corrective surgery, and dental treatment.
• The long-term outlook varies depending on severity and whether complications arise.
• While some adults with XLH may have minimal medical problems, others may experience persistent discomfort or complications.

X dominant affected mother

Symptoms

The symptoms of XLH can vary in severity. Some people with XLH have no apparent bone-related symptoms and only hypophosphatemia, while others have severe symptoms. In many cases, symptoms become apparent within the first 18 months of life, when a child begins to bear weight on the legs. Early signs and symptoms may include abnormal bone development (leading to bowing or twisting of the lower legs) and short stature or a slowing growth rate.

Other symptoms that may be present early or may develop include:

• Bone pain.
• Muscle pain and weakness.
• A waddling gait (manner of walking).
• Joint pain caused by hardening (calcification) of tendons and ligaments.
• Abnormal tooth development.
• Tooth abscesses and dental pain.
• Rickets that does not improve with traditional Vitamin D therapy.

In some cases, symptoms of XLH do not begin until adulthood. Symptoms that may develop in adults with XLH include joint pain and impaired mobility from enthesopathy (calcification of the tendons, ligaments, and joint capsules), tooth abscesses, and hearing loss.

Cause

XLH is caused by mutations in the PHEX gene which is involved in regulating the amount of phosphate in the body. Mutations in this gene lead to an increased concentration of of a protein called fibroblast growth factor 23 (FGF23), which regulates the reabsorption of phosphate in the kidneys. Too much FGF23 reduces the amount of phosphate reabsorbed by the kidneys, leading to hypophosphatemia and the resulting symptoms of XLH.

Inheritance

XLH is inherited in an X-linked dominant manner.

• This is because the gene responsible for the condition is located on the X chromosome, and having only one mutated copy of the gene is enough to cause the condition in both males and females.
• A female with XLH has a 50% chance of passing XLH to each of her children. A male with XLH will pass XLH to all of his daughters, but to none of his sons.
• In some cases, XLH is not inherited from a parent, but occurs in a person with no family history of XLH, due to a new (de novo) mutation in the responsible gene (the PHEX gene).

Diagnosis

XLH is diagnosed based on a physical exam, blood tests, imaging tests such as X-rays, and family history. Specific factors considered for the diagnosis include:

• A slow growth rate and noticeable bowing of the legs or other skeletal abnormalities.
• Low levels of phosphate and high levels of FGF23 in the blood.
• Lack of response of phosphate levels to vitamin D treatment.
• Phosphate wasting in the kidneys.

Genetic testing for XLH

Genetic testing for XLH is available and may confirm the diagnosis if a mutation is identified, but it is not necessary for the diagnosis.

Genetic testing registry

• The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition.
• The intended audience for the GTR is health care providers and researchers.
• Patients and consumers with specific questions about a genetic test should contact a healthcare provider or a genetics professional.

Treatment

XLH is different from other types of rickets because it cannot be treated by increasing vitamin D alone. Phosphate supplements are generally required and are typically combined with high dose calcitriol. Calcitriol increases calcium levels by increasing the amount of calcium absorbed in the intestines and the amount of calcium kept in the kidneys. In children, treatment is usually started at the time of diagnosis and continues until bones stop growing. The main treatment goal for adults is to help improve pain. Other treatments for XLH, depending on symptoms and severity, may include:

• Growth hormone to improve growth in children.
• Corrective surgery to fix bowed or bent legs.
• Treatment to repair skull abnormalities, such as premature fusion of the skull bones (synostosis).
• Dental procedures to treat pain in the teeth and gums.

FDA-Approved Treatments

• Burosumab (Brand name: Crysvita) - Manufactured by Ultragenyx Pharmaceutical, Inc. is FDA-approved for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 1 year of age and older.

Prognosis

XLH is a lifelong condition that may require ongoing treatment and monitoring. While some people with XLH may have only short stature and otherwise good health, there can be significant morbidity associated with XLH as people with the disease get older. This may result from mobility impairment, pain, and discomfort, which may be caused by various complications including osteoarthritis, problems with the tendons and ligaments (enthesopathy) or stress fractures in weakened bones (insufficiency fractures). Furthermore, problems can arise due to incorrect or inadequate treatment or misdiagnosis, since there is a lack of accessible treatment guidelines and awareness of XLH. Additional problems in some people may include:

• Loss of permanent teeth from recurrent dental abscesses.
• Spinal stenosis due to calcification of the spinal ligaments.
• Persistent lower-limb bowing and twisting (torsion) which can lead to misalignment of the legs, requiring surgery.
• Repeated surgeries for bone deformities or complications from previous surgeries.
• Prolonged healing times after surgeries, sometimes requiring several months of immobilization.
• The need for total hip and knee arthroplasty from degenerative joint disease and enthesopathy.

Complications from medications

• Phosphate treatment can cause an upset stomach and diarrhea.
• While starting medical treatment very early in childhood can increase final adult height, it is not yet known whether (or how much) this can prevent later-onset complications, and additional (new) symptoms can develop during adulthood.

See also

• Hypophosphatemia