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Disease Profile

X-linked hypophosphatemia

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
1-9 / 1 000 000

331 - 2,979

US Estimated

1-9 / 1 000 000

514 - 4,622

Europe Estimated

Age of onset

Childhood

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ICD-10

E83.3

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

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

Categories

Congenital and Genetic Diseases; Endocrine Diseases; Kidney and Urinary Diseases;

Summary

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]

Symptoms

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]

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.

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

Cause

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]

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:[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]

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.

    Treatment

    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.

    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.

    Organizations

    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

      Learn more

      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.

          References

          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; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=89936.
          3. Ruppe MD. X-Linked Hypophosphatemia. GeneReviews. April 13, 2017; https://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; https://www.ncbi.nlm.nih.gov/pubmed/26040953.
          8. Hereditary hypophosphatemic rickets. Genetics Home Reference. September, 2010; https://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; https://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; https://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; https://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; https://emedicine.medscape.com/article/922305-treatment.

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