• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
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Wilson Disease

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Last updated: 5/12/2025
Years published: 1985, 1986, 1990, 1991, 1992, 1994, 1995, 1996, 1997, 1999, 2000, 2003, 2007, 2008, 2009, 2012, 2015, 2018, 2024, 2025


Acknowledgment

NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders and George J. Brewer, MD, Morton S. and Henrietta K. Sellner Emeritus Professor of Human Genetics, Emeritus Professor of Internal Medicine, Departments of Human Genetics and Internal Medicine, University of Michigan Medical School, for assistance in the preparation of this report.


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Disease Overview

Wilson disease is a rare genetic disorder characterized by excess copper stored in various body tissues, particularly the liver, brain and corneas of the eyes. The disease is progressive and, if left untreated, it may cause liver (hepatic) disease, central nervous system dysfunction and death. Early diagnosis and treatment may prevent serious long-term disability and life-threatening complications.

Wilson disease is caused by changes (variants) of the ATP7B gene. Inheritance is autosomal recessive.

Treatment is lifelong and aims to reduce the amount of copper that has accumulated in the body and to maintain normal copper levels thereafter.

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Synonyms

  • hepatolenticular degeneration
  • lenticular degeneration, progressive
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Signs & Symptoms

Wilson disease is a rare genetic disorder that affects the body’s ability to process and eliminate copper, leading to copper buildup in vital organs like the liver and brain. While the disease usually starts with liver problems in childhood, many symptoms may not appear until the teenage years or early adulthood.

For many people, especially children, Wilson disease first presents as liver disease. The symptoms can range from mild to severe, including:

  • Yellowing of the skin and eyes due to liver dysfunction (jaundice)
  • Swelling in the legs or abdomen due to fluid retention (edema)
  • Fluid buildup in the abdomen (ascites)
  • Enlarged veins in the esophagus that can bleed (esophageal varices)
  • Excessive tiredness (fatigue)
  • Tendency to bruise or bleed more easily

Some children may have asymptomatic liver injury, which means they show no symptoms but have abnormal liver tests. Over time, this can lead to cirrhosis scarring of the liver (cirrhosis) or even acute liver failure, a serious condition that requires immediate medical attention.

In teenagers and adults, the disease may shift to affect the brain and nervous system, often presenting with neurological or psychiatric symptoms:

  • Shaking (tremor)
  • Involuntary movements, which are uncontrolled movements or muscle contractions
  • Difficulty swallowing (dysphagia)
  • Slurred or poorly articulated speech (dysarthria)
  • Lack of coordination with difficulty with balance and movement (ataxia)
  • Stiffness or tightness in the muscles (muscle rigidity)
  • Abnormal body postures due to muscle spasms (dystonic postures)

Most people affected with Wilson Disease who have neurological symptoms will also have Kayser-Fleischer rings, which are rusty-brown rings around the corneas of the eyes caused by copper deposits. These can be seen by an ophthalmologist.

Psychiatric symptoms can vary widely and may include:

  • Depression
  • Personality changes both in mood and behavior
  • Cognitive issues such as difficulty concentrating or thinking clearly
  • Psychiatric symptoms can be confused with schizophrenia or may be misdiagnosed as substance abuse

In most people, psychiatric symptoms appear alongside neurological symptoms or develop within three years of their onset.

Some women (especially young women) present with menstrual and hormonal issues due to liver dysfunction, leading to:

  • Delayed onset of menstruation
  • Absence of menstruation (amenorrhea)
  • Menstrual irregularities
  • Difficulty conceiving (infertility)
  • Increased risk of pregnancy loss (miscarriage)

Wilson disease can also lead to other health complications including:

  • Kidney stones caused by the buildup of copper in the kidneys
  • Renal tubular damage which can affect the kidney function
  • Premature arthritis (early onset of joint problems)
  • Thinning of bones (osteoporosis) making them more fragile
  • Bony outgrowths at large joints (osteophytes)
  • Narrowing of the space between joints leading to stiffness and pain

Liver disease is the most common first sign, but some children may also experience neuropsychiatric symptoms.

During adolescence, liver disease can become severe, but neurological and psychiatric symptoms may also develop. Liver failure can occur more frequently in adolescence, particularly in young women.

In adults, neuropsychiatric symptoms tend to dominate, though liver disease is still common. Scarring of the liver (cirrhosis) is present in about 38% of children and 58% of adults at diagnosis.

Females are more likely to present with liver disease, especially in childhood while males more likely to develop neurological symptoms as they age.

As commented before, some people with Wilson disease may not show symptoms for many years or might never develop noticeable symptoms. Many people with Wilson disease are diagnosed because of abnormal liver function tests, even before other symptoms appear.

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Causes

Wilson disease is caused by changes (variants) of the ATP7B gene, which plays an important role in the movement of excess copper from the liver to the bile to eventually be excreted from the body through the intestines. More than 1,000 different variants of the ATP7B gene have been identified.

Wilson disease is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

Wilson disease is a rare disorder that affects males and females in equal numbers. The disease is found in all races and ethnic groups. Although estimates vary, it is believed that Wilson disease occurs in approximately one in 30,000 to 40,000 people worldwide. Approximately one in 90 people may be carriers of a gene variant for the disease. Although only about 2,000-3,000 people have been diagnosed in the United States, other affected individuals may be misdiagnosed with other neurological, liver or psychiatric disorders. According to one estimate, there may be 9,000 people affected by Wilson disease in the United States.

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Diagnosis

Diagnosis of Wilson disease requires an integrated approach combining clinical features, biochemical markers, genetic analysis and, if needed, liver biopsy. No single test is definitive in all patients. A high index of suspicion, especially in children or young adults with unexplained liver, neurologic, or psychiatric symptoms, is essential to ensure early diagnosis and treatment. Early diagnosis and treatment are essential to prevent permanent damage to the liver, brain and other organs.

Wilson disease should be suspected in the following situations:

  • Any child or young adult with unexplained liver disease, especially chronic hepatitis, fatty liver, or cirrhosis
    • In children, the first symptoms of liver disease are often yellowing of the skin, swelling and fatigue
    • Wilson disease should be considered in any child over one year of age who shows signs of liver dysfunction, though it is rare before the age of five
  • Teenagers and young adults with neuropsychiatric symptoms such as tremors, dystonia, speech difficulties and personality or mood disorders
  • People with Coombs-negative hemolytic anemia (Coombs negative means no antibodies are attached to red blood cells and hemolytic means that blood cells are broken down) due to copper-induced oxidative damage, particularly if accompanied by acute liver dysfunction
  • Family history of Wilson disease or known ATP7B gene variants
  • Unexplained liver failure in children or young adults, especially females

The suggested steps for diagnosis include:

Step 1

  • Clinical evaluation where doctors review the person’s symptoms, medical history and perform a physical exam
  • Physical exam should include a slit-lamp microscope examination of the eyes looking for Kayser-Fleischer rings which are rusty-brown deposits of copper around the corneas (hallmark of the disease). Kayser-Fleischer rings are less common in affected children with liver disease alone (50-60%) but are almost always present in people with Wilson disease who have neurological symptoms.
  • Neurologic and psychiatric evaluation: May reveal tremor, dystonia, dysarthria, cognitive decline, or psychiatric changes (e.g., depression, impulsivity)
  • Laboratory tests:
    • Liver function tests (hepatic panels) are blood tests that check for liver dysfunction by measuring levels of various proteins and enzymes.
      • Elevated AST, ALT and bilirubin may be present and suggest liver dysfunction. AST (aspartate transaminase) and ALT (alanine transaminase) are enzymes found in the liver and bilirubin is a byproduct of red blood cell breakdown.
    • INR (international normalized ratio) and albumin
      • Abnormal levels suggest abnormal liver function as they are indicators of the liver’s ability to produce essential proteins. INR measures the liver’s ability to produce clotting factors, and albumin is a primary protein produced by the liver.
    • Copper metabolism tests including:
      • Serum ceruloplasmin (measures the levels of ceruloplasmin, a protein that binds to copper): Levels are lower than normal in Wilson disease with values typically <14 mg/dL (normal >20 mg/dL) but can be normal in acute inflammation or low in other conditions.
      • 24-hour urinary copper excretion (measures the amount of copper excreted in urine):
        • 100 μg/24 hr in symptomatic patients is suggestive.
        • 40–100 μg/24 hr may indicate Wilson disease but it is indeterminate; repeat testing or further workup is needed.
        • In asymptomatic siblings, levels may be lower but still elevated compared to healthy controls.

Step 2

  • If initial tests suggest Wilson disease, genetic testing can be done to identify variants in the ATP7Bgene that cause Wilson disease.
    • Two disease-causing variants in the ATP7B gene confirm Wilson disease.
  • About 95% of people with symptoms have identifiable variants.
        • First-degree relatives (parents, siblings and children) should be offered genetic testing.
        • Genetic testing sometimes does not identify two ATP7B gene variants and is not required to confirm a diagnosis of Wilson disease. A diagnosis can be made in other ways, such as with the Leipzig scoring system (see below).

Step 3 (if needed)

  • Liver biopsy (hepatic copper quantification)
    • Indicated when diagnosis is uncertain despite biochemical/genetic testing
      • Copper content >250 μg/g dry liver weight (250 μg of copper per gram of liver tissue) is diagnostic.
      • Lower values may occur in early disease or due to sampling error.
      • Examination of liver tissue under a microscope (histology) may show fatty liver (steatosis), chronic liver inflammation (hepatitis), or severe scar tissue (cirrhosis).

Additional diagnostic tests may include:

  • D-penicillamine challenge test: This involves taking d-penicillamine which increases urinary copper excretion over 24 hours and measuring the urine copper afterward. The benefit of this test is controversial and not routinely recommended.
  • Non-ceruloplasmin-bound copper (NCC): This test measures the amount of copper that is not bound to ceruloplasmin. The levels are elevated in Wilson disease, especially with neurologic involvement. However, the calculation is prone to error, so it is not recommended as the only test and is primarily a research tool. It should not be used alone to confirm or rule out Wilson disease.
  • Exchangeable copper (CuEXC) and relative exchangeable copper (REC) is a promising new test that measures unbound copper in the blood independently of ceruloplasmin levels. It can be used to distinguish Wilson disease from other liver diseases with high accuracy. This test is not yet widely available and currently limited to research or specialized centers.
  • Neuroimaging (MRI) may show characteristic changes in the brain structures known as basal ganglia or brainstem (e.g., “face of the giant panda” sign). It is helpful for diagnosis and monitoring in people with Wilson disease who have neurologic symptoms.
  • Ultrasound and other non-invasive tools like transient elastography may be used to assess liver damage, including the presence of liver scarring (fibrosis). However, it cannot confirm or exclude a diagnosis of Wilson disease.

A diagnostic score for Wilson disease was developed in 2001, known as the Leipzig or Ferenci score. It is widely used when diagnosis is uncertain or incomplete. It is based on clinical features, laboratory tests, tissue analysis (histology) and genetics. The Leipzig (Ferenci) diagnostic score combines ceruloplasmin levels, Kayser-Fleischer rings, urinary and hepatic copper, genetic findings and neurologic symptoms. A score ≥4 indicates probable or definite Wilson disease.

The Wilson Disease Prognostic Index is used in people with acute liver failure to predict the need for urgent liver transplantation. It considers factors like bilirubin levels, liver enzymes, INR, white blood cell count and albumin.  A score >11 suggests poor prognosis without transplant.

Since many of the symptoms can overlap with other conditions, a high level of suspicion is necessary, especially in children and adolescents with unexplained liver or neurological issues.

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Standard Therapies

Treatment for Wilson disease focuses on lowering copper levels to stop damage to organs like the liver and brain, reverse symptoms where possible and prevent future copper buildup. Early diagnosis and consistent treatment are key to avoiding serious complications. It’s important to understand that treatment is lifelong.

Treatment for Wilson disease depends on the stage of the disease:

  1. Symptomatic treatment: For people with symptoms, treatment aims to reduce copper levels quickly to stop the damage.
  2. Maintenance therapy: After copper levels are reduced, long-term treatment is necessary to keep copper levels at non-toxic levels and prevent future buildup.
  3. Preventive maintenance: In people who are diagnosed before symptoms develop, maintenance therapy begins immediately to prevent the onset of symptoms.

There are three main types of medications used to manage Wilson disease. These either help the body get rid of copper or block its absorption from food. These include chelating agents and zinc salts.

  • Chelating agents (copper-removal medications): These drugs bind to copper and help remove it through urine. They are especially important during the initial phase of treatment and sometimes for long-term management.
    • Penicillamine (Cuprimine): This is often the first-line treatment. It effectively increases copper excretion by the urine but has a higher risk of side effects like rash, fever, joint pain and in some people, worsening neurological symptoms. Neurologic worsening is seen in up to 50% of neurologically symptomatic patients. It is recommended to start slowly and monitor closely.
    • Trientine: This works by binding to copper so it can be removed in urine. There are two main forms:
      • Trientine dihydrochloride (2HCl) (Syprine): This is a second-line option for people who can’t tolerate penicillamine. It removes copper similarly but tends to cause fewer side effects. It’s most often used during the symptomatic or early treatment phase. It is given as capsules that may need special handling/storage.
      • Trientine tetrahydrochloride (4HCl) (Cuvrior): This is a newer formulation that was FDA-approved in 2022. It is specific for adults who are already stable, have been de-coppered and can tolerate penicillamine. Cuvrior is not meant to be a starting treatment or for people with active symptoms but for long-term maintenance for a very specific group of patients. It is available as a tablet form that is room temperature stable and possibly easier to manage.
  • A concerning side effect for people treated with either penicillamine or trientine (of any type) is a rapid clinical worsening of neurologic symptoms within months after treatment onset, possibly caused by rapid mobilization of large amounts of copper.
    • Close monitoring and neurologic checks are essential during the early phase of treatment.
  • Zinc salts (e.g., zinc acetate such as Galzin) work by blocking the absorption of copper from food. It’s often used as long-term maintenance therapy after initial copper removal or for people who do not have any symptoms.
    • Zinc is preferred in children and pregnant women due to its minimal side effects.
    • Zinc is not typically used alone as the first treatment for people with Wilson disease who have neurological symptoms. This is because zinc works by blocking copper absorption in the gut which is a slower process and, therefore, not ideal when urgent copper removal is needed. It is considered a first-line option in some patients because it doesn’t usually worsen neurological symptoms.
      • Some clinicians advocate combining chelators and zinc (a combination of trientine and zinc), particularly in severe cases, but only if they are administered at different times of the day to avoid interference in absorption.
        • Combo therapy must be very carefully monitored in neurologic disease.

Regular follow-up is essential to ensure that copper levels remain controlled and to avoid side effects from the medications. Monitoring includes 24-hour urine copper testing (measures how much copper is being excreted in the urine), non-ceruloplasmin-bound copper (blood test that measures the amount of toxic copper not bound to ceruloplasmin), liver function tests to monitor liver health and check for signs of improvement or worsening and urine tests for people on chelating agents like penicillamine or trientine (to detect any protein or blood cells which could indicate kidney issues). Assessments twice per year are recommended including liver tests, INR, complete blood count and routine urinalysis, especially for patients on chelation therapy

Supportive treatments include management of the neurological and psychiatric symptoms, including medications and therapies like physical, occupational and speech therapy to address the different symptoms and improve the quality of life.

Stopping treatment can lead to a rapid buildup of copper and life-threatening complications, so it’s critical for patients to adhere to their medication regimen. By following the treatment plan and adhering to medication, most people with Wilson disease can lead healthy and active lives. However, diagnosis is often delayed and there is frequently a lack of adherence to the necessary lifelong treatment. Even in people with clinically stable and well-managed disease, Wilson disease may result in a decreased quality of life.

For people with severe liver failure or acute liver failure, a liver transplant may be the only option for long-term survival. Transplants can restore normal liver function and stop the progression of Wilson disease. However, the need for a liver transplant in neurological cases is controversial and this must be decided on a case-by-case basis.

The Wilson Disease Association offers updates in treatment and advances as well as many useful resources for patients and health professionals and has designated several Wilson Disease Centers of Excellence.

The American Association for the Study of Liver Diseases (AASLD) developed  recommendations for Wilson disease treatment that are available in the article: Wilson disease: a summary of the updated AASLD Practice Guidance. (Please note that this article has medical terms.)

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Clinical Trials and Studies

Tetrathiomolybdate (TTM) is an investigational drug currently undergoing clinical trials. It is a copper chelator that also prevents intestinal copper absorption and acts by slowing copper absorption from the gastrointestinal tract and binding circulating copper, reducing its toxic effects. Early clinical trials have shown promising results, particularly in people with neurological symptoms. However, tetrathiomolybdate (specifically bis-choline tetrathiomolybdate) is not yet FDA approved and is available only through clinical trial participation or compassionate use programs.

There is ongoing research to find better treatments for Wilson disease including:

  • Gene therapy: Researchers are exploring gene therapy to correct the ATP7B gene variants that cause Wilson disease.
  • Pharmacological approaches: Scientists are studying ways to repair the function of the altered ATP7B gene with drugs like curcumin and stress kinase inhibitors.

The Wilson Disease Association has a Patient Registry Study. Patient registries are important for the development of clinical research studies in rare diseases, in efforts to improve patient care as well as for healthcare planning and policy.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Basan NM, Sheikh Hassan M, Gökhan Z & cols. Usefulness of the Leipzig Score in the Diagnosis of Wilson’s Disease – A Diagnostically Challenging Case Report. Int Med Case Rep J. 2024 Sep 29;17:819-822. doi: 10.2147/IMCRJ.S491888. PMID: 39364335; PMCID: PMC11448466.

Kirk FT, Munk DE, Swenson ES, Quicquaro AM, Vendelbo MH, Larsen A, Schilsky ML, Ott P, Sandahl TD. Effects of tetrathiomolybdate on copper metabolism in healthy volunteers and in patients with Wilson disease. J Hepatol. 2024 Apr;80(4):586-595. doi: 10.1016/j.jhep.2023.11.023

Tudor Lucian and Alina Grama. New developments in the management of Wilson’s disease in children. Global Pediatrics 8. June 2024, 100142. https://www.sciencedirect.com/science/article/pii/S2667009724000101

Alkhouri N, Gonzalez-Peralta RP, Medici V. Wilson disease: a summary of the updated AASLD Practice Guidance. Hepatol Commun. 2023;7(6):e0150. Published 2023 May 15. doi:10.1097/HC9.0000000000000150

Beyzaei Z, Mehrzadeh A, Hashemi N, Geramizadeh B. The mutation spectrum and ethnic distribution of Wilson disease, a review. Mol Genet Metab Rep. 2023 Dec 6;38:101034. doi: 10.1016/j.ymgmr.2023.101034. PMID: 38149214; PMCID: PMC10750106.

Patel AH, Ghattu M, Mazzaferro N, Chen A, Catalano K, Minacapelli CD, Rustgi V. Demographics and outcomes related to Wilson’s disease patients: A nationwide inpatient cohort study. Cureus. 2023 Sep 5;15(9):e44714. doi: 10.7759/cureus.44714.

Schilsky ML, Roberts EA, Bronstein JM & cols. A multidisciplinary approach to the diagnosis and management of Wilson disease: Executive summary of the 2022 Practice Guidance on Wilson disease from the American Association for the Study of Liver Diseases. Hepatology. 2023 Apr 1;77(4):1428-1455. doi: 10.1002/hep.32805. Epub 2022 Dec 7. PMID: 36152019.

Abuduxikuer K, Wang JS. Zinc mono-therapy in pre-symptomatic Chinese children with Wilson disease: a single center, retrospective study [published correction appears in PLoS One. 2014;9(3):e92491]. PLoS One. 2014;9(1):e86168. Published 2014 Jan 24. doi:10.1371/journal.pone.0086168

Brewer, GJ. Treatment of Wilson’s Disease: Our patients deserve better. Expert Opin on Orphan Drugs 2014;2:12.

INTERNET
Online Mendelian Inheritance in Man (OMIM). Wilson Disease. Entry No: 277900. Last Edited 09/23/2024. Available at: https://omim.org/entry/277900?search=277900&highlight=277900 Accessed May 12, 2025.

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Programs & Resources

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RareCare® Assistance Programs

NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/

Patient Organizations


More Information

The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.

GARD Disease Summary

The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).

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Orphanet

Orphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.

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OMIM

Online Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.

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