National Center for Advancing and Translational Sciences Genetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

X-linked hypophosphatemia


Other Names:
X-linked hypophosphatemic rickets; XLH; Hypophosphatemic rickets, X-linked dominant; X-linked hypophosphatemic rickets; XLH; Hypophosphatemic rickets, X-linked dominant; Hypophophatemia, X-linked; Vitamin D-Resistant Rickets, X-linked; Hypophophatemic vitamin D-resistant rickets; HPDR See More
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This disease is grouped under:
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.[1][2] 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.[3] 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 persistant discomfort or complications.[4][5]
Last updated: 2/23/2018
The symptoms of XLH can vary in severity.[3][6] Some people with XLH have no apparent bone-related symptoms and only hypophosphatemia, while others have severe symptoms.[6] 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:[6][7]
  • 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.[3]

Last updated: 2/26/2018

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Showing of 36 |
Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormality of dental enamel
Abnormal tooth enamel
Enamel abnormalities
Enamel abnormality
[ more ] 		0000682
Abnormality of the metaphysis
Abnormality of the wide portion of a long bone
0000944
Bone pain 0002653
Genu varum
Outward bow-leggedness
Outward bowing at knees
[ more ] 		0002970
Hypophosphatemia
Low blood phosphate level
0002148
Joint dislocation
Joint dislocations
Recurrent joint dislocations
[ more ] 		0001373
Osteomalacia
Softening of the bones
0002749
Rachitic rosary 0000897
Rickets
Weak and soft bones
0002748
Tooth abscess 0030757
30%-79% of people have these symptoms
Craniosynostosis 0001363
Enthesitis 0100686
Osteoarthritis
Degenerative joint disease
0002758
Short stature
Decreased body height
Small stature
[ more ] 		0004322
5%-29% of people have these symptoms
Hearing impairment
Deafness
Hearing defect
[ more ] 		0000365
Recurrent fractures
Increased fracture rate
Increased fractures
Multiple fractures
Multiple spontaneous fractures
Varying degree of multiple fractures
[ more ] 		0002757
Percent of people who have these symptoms is not available through HPO
Abnormality of pelvic girdle bone morphology
Abnormal shape of pelvic girdle bone
0002644
Arthralgia
Joint pain
0002829
Bowing of the legs
Bowed legs
Bowed lower limbs
[ more ] 		0002979
Elevated alkaline phosphatase
Greatly elevated alkaline phosphatase
High serum alkaline phosphatase
Increased alkaline phosphatase
Increased serum alkaline phosphatase
[ more ] 		0003155
Elevated circulating parathyroid hormone level 0003165
Femoral bowing
Bowed thighbone
0002980
Fibular bowing
Bowed calf bone
0010502
Flattening of the talar dome 0008144
Frontal bossing 0002007
Hypomineralization of enamel
Poorly mineralized tooth enamel
0006285
Hypophosphatemic rickets 0004912
Metaphyseal irregularity
Irregular wide portion of a long bone
0003025
Renal phosphate wasting 0000117
Renal tubular dysfunction
Abnormal function of filtrating structures in kidney
0000124
Shortening of the talar neck 0008117
Spinal canal stenosis
Narrow spinal canal
0003416
Spinal cord compression
Pressure on spinal cord
0002176
Tibial bowing
Bowed shankbone
Bowed shinbone
[ more ] 		0002982
Trapezoidal distal femoral condyles 0006432
X-linked dominant inheritance 0001423
Showing of 36 |
Last updated: 7/1/2020
XLH is caused by mutations in the PHEX  gene which is involved in regulating the amount of phosphate in the body.[3][8] 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.[7][8]
Last updated: 2/26/2018
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).[3]
Last updated: 2/26/2018
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:[2][3][7]
  • 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 is available and may confirm the diagnosis if a mutation is identified, but it is not necessary for the diagnosis.[3]

Last updated: 2/26/2018

Testing Resources

  • 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 health care provider or a genetics professional.
XLH is different from other types of rickets because it cannot be treated by increasing vitamin D alone.[1] 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.[5] In children, treatment is usually started at the time of diagnosis and continues until bones stop growing.[3] The main treatment goal for adults is to help improve pain. Other treatments for XLH, depending on symptoms and severity, may include:[3][5][9]
  • 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.
Last updated: 2/26/2018

FDA-Approved Treatments

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Learn more orphan products.

XLH is a lifelong condition that may require ongoing treatment and monitoring.[10] 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.[4][5] 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).[4] 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.[11] Additional problems in some people may include:[3][10][11][12][13]
  • 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 - for example, 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.[4][10]

Last updated: 2/23/2018

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet
Differential diagnosis includes autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), hereditary hypophosphatemic rickets with hypercalciuria (HHRH), fibrous dysplasia of bones, renal Fanconi syndrome (see these terms), vitamin D deficiency and tumor-induced osteomalacia.
Visit the Orphanet disease page for more information.

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Patient Registry

  • A registry supports research by collecting of information about patients that share something in common, such as being diagnosed with X-linked hypophosphatemia. The type of data collected can vary from registry to registry and is based on the goals and purpose of that registry. Some registries collect contact information while others collect more detailed medical information. Learn more about registries.

    Registries for X-linked hypophosphatemia:
    XLH CoRDS Registry
    X-Linked Hypophosphatemic Rickets International Registry
     

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on X-linked hypophosphatemia. This website is maintained by the National Library of Medicine.
  • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.
  • The XLH Network, a worldwide patient support organization for people living and dealing with X-linked hypophosphatemia, provides information about XLH.

In-Depth Information

  • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
  • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know.

  1. XLH Network Board of Directors. What is XLH?. XLH Network. April 20, 2012; https://xlhnetwork.org/index.php/what-is-xlh/.
  2. Harrold Juppner. X-linked hypophosphatemia. OrphaNet. January 2012; http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=89936.
  3. Ruppe MD. X-Linked Hypophosphatemia. GeneReviews. April 13, 2017; http://www.ncbi.nlm.nih.gov/books/NBK83985/#rickets-xlh.
  4. Chesher D, Oddy M, Darbar U et al. Outcome of adult patients with X-linked hypophosphatemia caused by PHEX gene mutations. J Inherit Metab Dis. February 19, 2018; [Epub ahead of print]:https://link.springer.com/article/10.1007%2Fs10545-018-0147-6.
  5. Chan JCM. Hypophosphatemic Rickets. Medscape Reference. May 1, 2017; https://emedicine.medscape.com/article/922305-overview.
  6. Symptoms of XLH. XLH Network. August 13, 2017; https://xlhnetwork.org/what-is-xlh/symptoms-of-xlh/.
  7. Melinda S Sharkey, Karl Grunseich, Thomas O Carpenter. Contemporary Medical and Surgical Management of X-linked Hypophosphatemic Rickets. The American Academy of Orthopaedic Surgeons. July 2015; http://www.ncbi.nlm.nih.gov/pubmed/26040953.
  8. Hereditary hypophosphatemic rickets. Genetics Home Reference. September, 2010; http://ghr.nlm.nih.gov/condition/hereditary-hypophosphatemic-rickets.
  9. Steven J Scheinman, Marc K Drezner. Hereditary Hypophosphatemic Rickets and Tumor-Induced Osteomalacia. UpToDate. December 1, 2015; http://www.uptodate.com/contents/hereditary-hypophosphatemic-rickets-and-tumor-induced-osteomalacia?source=search_result&search=x-linked+hypophosphatemia&selectedTitle=1~10.
  10. Effect of Medical Treatment. XLH Network. March 28, 2016; http://www.xlhnetwork.org/what-is-xlh/treating-xlh/effect-of-medical-treatment/.
  11. Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A Clinician's Guide to X-Linked Hypophosphatemia. J Bone Miner Res. July, 2011; 26(7):1381-1388. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157040/.
  12. Kawaguchi A, Miyamoto K, Wakahara K, Hosoe H, Miura A, Hanamoto T, Shimizu K. Surgical treatment of multiple spinal canal stenoses associated with vitamin D-resistant rickets. J Clin Neurosci. May, 2009; 16(5):717-719. https://www.ncbi.nlm.nih.gov/pubmed/19264492.
  13. Effect of Surgical Treatment. XLH Network. March 28, 2016; http://www.xlhnetwork.org/what-is-xlh/treating-xlh/effects-of-surgical-treatment/.
  14. James CM Chan, Karl S Roth. Hypophosphatemic Rickets: Treatment & Medication. eMedicine. December 2, 2015; http://emedicine.medscape.com/article/922305-treatment.