Information on the following diseases can be found in the Related Disorders section of this report:

• Idiopathic thrombocytopenic purpura (ITP)
• X-linked agammaglobulinemia
• Severe combined immunodeficiency
• Nezelof syndrome
• Associated congenital disorders (General)
• .

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 isnot 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.

Symptoms of the following disorders may be similar to those of WAS-related disorders. Comparisons may be useful for a differential diagnosis:

Human immunodeficiency (HIV) infection should always be ruled out in any individual presenting with PCP or severe immune dysfunction.

Idiopathic thrombocytopenic purpura (ITP) is a rare autoimmune bleeding disorder characterized by the abnormally low levels of certain blood cells called platelets, creating a condition known as thrombocytopenia. Platelets are specialized blood cells that help prevent and stop bleeding by inducing clotting. In ITP, there is no readily apparent cause or underlying disease (idiopathic). The cells of the immune system, lymphocytes, produce anti-platelet antibodies that attach to the platelets. The presence of antibodies on platelets leads to their destruction in the spleen. The disorder is characterized by abnormal bleeding into the skin resulting in bruising, which is what the term purpura means. Bleeding from mucous membranes also occurs, and may subsequently result in low levels of circulating red blood cells (anemia). (For more information on this disorder, choose "ITP" as your search term in the Rare Disease Database.)

In males who initially present with Pneumocystis Carinii pneumonia, SCID and XHM should be considered. Neither is typically associated with persistent thrombocytopenia.

Severe Combined Immunodeficiency (SCID) is a group of rare congenital syndromes characterized by little if any immune responses. This results in frequent recurring infections. Cellular immune responses involve specialized white blood cells known as T lymphocytes which consist of "helper" and "killer cells." These cells assist other white blood cells (B lymphocytes) to respond to infectious, foreign agents that invade the body (i.e., bacteria or viruses). The B lymphocytes maintain immunity by enabling the body to produce and preserve circulating antibodies. People with SCID are unusually susceptible to recurrent infections with bacteria, viruses, fungi, and other infectious agents that can be life threatening.

There are several types of SCID. Each type of severe combined immune deficiency is caused by a different genetic defect, but the primary symptom is reduced or absent immune functions, and all types are hereditary. (For more information on this disorder, choose "SCID" as your search term in the Rare Disease Database.)

Hyper-IgM Syndrome (HIM) is a rare genetic (primary) immunodeficiency disorder that is typically inherited as an X-linked recessive genetic trait. Symptoms and physical findings associated with the disorder usually become apparent in the first or second year of life. Hyper-IgM Syndrome may be characterized by recurrent bacterial infections of the upper and lower respiratory tract including the sinuses and/or the lungs (pneumonitis or pneumonia); the middle ear (otitis media); the membrane that lines the eyelids and the white portions (sclera) of the eyes (conjunctivitis); the skin (pyoderma); and/or, in some cases, other areas. Individuals with Hyper-IgM Syndrome are also susceptible to "opportunistic" infections, i.e., infections caused by microorganisms that usually do not cause disease in individuals with fully functioning immune systems (non-immunocompromised) or widespread (systemic) overwhelming disease by microorganisms that typically cause only localized, mild infections. In addition, individuals with Hyper-IgM syndrome are prone to certain autoimmune disorders affecting particular elements of the blood, such as neutropenia, a condition in which there is an abnormal decrease of certain white blood cells (neutrophils). Additional physical findings often associated with the disorder may include enlargement (hypertrophy) of the tonsils, enlargement of the liver and spleen (hepatosplenomegaly), chronic diarrhea and impaired absorption of nutrients by the intestinal tract (malabsorption), and/or other symptoms. (For more information on this disorder, choose "hyper IgM" as your search term in the Rare Disease Database.)

Diagnosis
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.

Treatment
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
Email: prpl@cc.nih.gov

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