NORD gratefully acknowledges Alexandra H Filipovich, MD, Professor of Pediatric Hematology/Oncology, Immunodeficiency and Histiocytosis Program, and Judith Johnson, MS, CGC, Genetic Counselor, Diagnostic Center for Heritable Immunodeficiencies at the Cincinnati Children's Hospital Medical Center, for assistance in the preparation of this report.
The WAS-related disorders are a spectrum of conditions affecting the immune system that are caused by mutations in the WAS gene. These disorders include Wiskott-Aldrich syndrome, X-linked thrombocytopenia and X-linked congenital neutropenia. The WAS gene abnormality results in a deficiency in the WASP protein that leads to a low platelet count (thrombocytopenia). WAS-related disorders usually present in infancy and are characterized by bloody diarrhea, recurrent infections, scaling, itchy, skin rashes (eczema), and the appearance of small purple spots on the skin (petechia). The development of Pneumocystis carinii pneumonia (PCP) and intracranial bleeding are possible early, life-threatening complications. Later potential complications include destruction of red blood cells (hemolytic anemia), arthritis, vasculitis and kidney and liver damage. Affected individuals have an increased risk of developing lymphomas, especially after exposure to Epstein-Barr virus. WAS-related disorders are extremely variable, even in individuals in the same family.
The WAS-related disorders are a spectrum of conditions affecting the immune system that are caused by mutations in the WAS gene. These disorders include Wiskott-Aldrich syndrome, X-linked thrombocytopenia and X-linked congenital neutropenia.
Symptoms of Wiskott Aldrich syndrome usually begin in infancy. The original description of this condition included a combination of three features: bloody diarrhea, abnormal bleeding episodes and/or small purple spots on the skin (petechia); scaling, itchy, skin rashes (eczema); recurrent ear infections. A low platelet count (thrombocytopenia), in association with small platelet size, is usually present at birth, but platelet counts may initially be near normal. Intracranial bleeding is a possible life-threatening complication of WAS. Eczema occurs in approximately 80% of affected individuals and can range from mild to severe. Boys with WAS have an increased risk for recurrent bacterial and viral infections. The development of Pneumocystis carinii pneumonia (PCP) is a possible life-threatening complication. Autoimmune disorders are common in those who survive and include destruction of red blood cells (hemolytic anemia), arthritis, vasculitis and kidney and liver damage. The risk for developing an autoimmune disorder increases with age. Boys with WAS have an increased risk of developing lymphomas, especially after exposure to Epstein-Barr virus. The lymphomas are often in unusual locations such as the brain, lung or gastrointestinal tract.
Males with X-linked thrombocytopenia have thrombocytopenia without eczema or immune dysfunction It is not always possible to classify a patient as having XLT or WAS because of the overlap of clinical symptoms, variabilities in WAS protein expression and overlap of mutations in these disorders.
X-linked congenital neutropenia is thought to be extremely rare and is characterized by recurrent bacterial infections, an abnormal decrease in the number of neutrophils (the most common type of white blood cells) in the blood, and abnormal development of bone marrow.
WAS-related disorders are X-linked recessive genetic diseases that occur almost exclusively in males. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. WAS-related disorders are caused by a mutation in the WAS gene on the X chromosome that leads to a deficiency of the WASP protein. The WASP protein is important in the structure and function of most blood cells.
Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.
The estimated prevalence of WAS-related disorders is 3/1,000,000 males. This condition has been described in many ethnic groups and in many countries.
A WAS-related disorder is suspected based on clinical features and laboratory testing. Testing shows a low platelet count and small platelet size, and sometimes shows abnormal levels of serum immunoglobulins: low IgM, elevated IgA and IgE, decreased absolute numbers of CD8+ T cells and decreased function of natural killer cells. Decreased or absent WASP protein in blood cells strengthens the diagnosis. Molecular genetic testing for the WAS gene is available to confirm the diagnosis.
The only treatment currently available to cure WAS-related disorders is bone marrow transplant from an allogeneic donor. Allogeneic donors must have human leukocyte antigens (HLA) that match the recipient. Human leukocyte antigens (HLA), which are a form of "histocompatability antigens," are present within the body's tissues and function as an essential part of the immune system. The specific type of HLA within a person's tissues is inherited and is known as the person's "tissue type.". When tissues are transplanted, a donor's and a recipient's HLA tissue types influence the outcome of transplantation. For example, if a donor can be located whose HLA tissue types are very close to those of the recipient, the histocompatability antigens in the donor tissue may not be recognized as foreign and therefore may not be attacked by the recipient's immune system, improving the chances of successful transplantation. Siblings or other blood relatives are the most likely to have HLA types very similar to those of the recipient. Boys with WAS who receive bone marrow transplantation from a matched healthy sibling or closely matched unrelated donor have a greater than 85% chance of being cured if the procedure is performed before five years of age.
Supportive care for WAS-related disorders includes prophylaxis against PCP and appropriate antimicrobial therapy for infections. intravenous immunoglobulin. routine childhood immunizations, and treating eczema with topical steroid therapy. Treatment of significant bleeding sometimes includes platelet transfusions. Splenectomy is no longer recommended as it increases the risk of late death following bone marrow transplantation.
Preclinical studies on the use of gene therapy to treat WAS-related disorders are ongoing.
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 National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., immune deficiency, thrombocytopenia, eczema, autoimmune-like symptoms, etc.].)
Filipovich AH. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:38-9.
Conley ME, Saragoussi D, Notarangela L, et al. An international study examing therapeutic options used in treatment of Wiskott-Aldrich syndrome. Clin Immunol 2003;109:272-7.
Derry JM, Ochs HD, and Franke U. Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. Cell 1994;78:635-644.
Devriendt K, Kim As, Mathijs G, et al. Constituitively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet 2001;27:313-7.
Dupuis-Girod S, Medioni J, Haddad E, et al. Autoimmunity in Wiskott-Aldrich syndrome: Risk factors, clinical features, and outcome in a single-center cohort of 55 patients. Pediatrics 2003;111:e622-7.
Filipovich AH, Stone J, Tomany SC, et al. Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich syndrome: Collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program. Blood 2001;97:1598-603.
Imai K, Morio T, Zhu Y, et al. Clinical course of patients with WASP gene mutations. Blood 2004;103:456-64.
Luthi JN, Gandhi MJ, Drachman JG, X-linked thrombocytopenia caused by a mutation in the Wiskott-Aldrich syndrome (WAS) gene that disrupts interaction with the WAS protein (WASP)-interacting protein (WIP). Exp Hematol 2003;31:150-8.
Ochs HD, Rosen FS. The Wiskott-Aldrich syndrome. Cell 1999;78:292-305.
Sullivan KE, Mullen CA, Blaese RM, et al. A multi-institutional survey of the Wiskott-Aldrich syndrome. J Pediatr 1994;125:876-885.
Villa A, Notarangelo L, Macchi P, et al. X-linked thrombocytopenia and Wiskott-Aldrich syndrome are allelic diseases with mutations in the WASP gene. Nat Genet 1995;9:414-417.
FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No. 301000; Last Update:11/30/06.
Filipovich AH, Johnson J and Zhand K. Updated 9/30/04. WAS-Related Disorders. In GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2006. Available at http://www.genetests.org Accessed 12/06.
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