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Genetics of Wiskott-Aldrich Syndrome

written by: R. Elizabeth C. Kitchen•edited by: dianahardin•updated: 6/29/2011

This immune deficiency disorder primarily affects males. It is a genetic disorder related to a defect in immunoglobulin M production. There is no easy cure, but there are treatments available.

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    Wiskott-Aldrich syndrome is classified an as immune deficiency disorder. Patient's with this disorder do not produce enough immunoglobulin M (IgM). This condition also causes blood platelets to be small in size, low numbers of platelets, eczema and the increased risk of developing cancer or an autoimmune disease. Worldwide, somewhere between 1 and 10 cases per million males are noted. This condition almost exclusively affects males.

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    Related Genes

    This condition is caused by a WAS gene mutation. The WAS protein is located within cells made from hematopoietic stem cells. These include certain immune cells and blood cells. This protein plays a role in communicating signals from the surface of a cell to the actin cytoskeleton. The actin cytoskeleton has a variety of important functions, including allowing cells to move and determining cell shape.

    When the WAS gene is mutated it impairs the WAS protein's role in cell signaling, as well as disrupts the actin cytoskeleton's function in certain blood cells and immune cells. Immune cells without WAS protein function generally have difficulty responding to the factors that activate cell division and growth. These defective cells have issues with attaching to other cells and with cell movement. With this condition, when the normal immune cell function is disrupted, it may contribute to eczema, as well as the patient being at an increased risk for autoimmune disorders, lymphoma and infection associated with this condition. A characteristic sign of this condition is microthrombocytopenia, which may result from WAS protein function impairment interfering with normal platelet development.

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    Inheritance Pattern

    Patients inherit this condition in an X-linked recessive pattern. The associated gene is located on the X chromosome. Males only have to have a single altered copy of the gene within each cell for the condition to occur. Females would require two, which is why it is unlikely for females to be affected.

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    Symptoms and How this Condition Affects the Body

    Symptoms generally begin between birth and 25 years of age with the average onset being during the first two years of life. Male infants with this condition generally experience bleeding, commonly prolonged bleeding from circumcision, unusual bruising, bloody diarrhea and purpura. Intracranial hemorrhage may affect less than two percent of patients.

    Infections may occur and generally begin in the first three months of life. Streptococcus pneumoniae may cause meningitis, pneumonia or sinusitis. Staphylococcus aureus and Haemophilus influenzae type B may also occur. Otitis media is very common, and patients are also at risk for viral and fungal infections.

    Autoimmune diseases can occur at any age, with the most common being autoimmune hemolytic anemia. Glomerulonephritis may cause renal failure. Other possible issues may include neutropenia, skin vasculitis, inflammatory bowel disease, arthritis, cerebral vasculitis and renal disease.

    Eczema may occur and is clinically similar to atopic eczema. It generally develops during the patient's first year of life. It may be worse when the patient is experiencing an infection. Allergic rhinitis and other atopic conditions may also occur.

    Malignancy is more common in adults but may occur in children. Around 25 percent of patients with Wiskott-Aldrich syndrome older than 20 years of age develop lymphoma. Non-Hodgkins lymphoma is the most common malignancy, but leukemia may also occur.

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    Making the Diagnosis

    A chest X-ray may be done if the doctor suspects pneumonia. A CT scan may be done to help in ruling out malignancy, evaluate sinus infection, evaluate splenomegaly, help rule out intracranial bleeding or evaluate for pulmonary infections.

    To evaluate for hematologic malignancy or in complex cases, a bone marrow biopsy may be done. This will not be a necessity, though, for the majority of patients. Megakaryocytes typically appear normal with a bone marrow biopsy. A lumbar puncture may be necessary, if meningitis is considered. Tympanostomy tube placement may be required, if the patient experiences recurrent otitis media.

    Doctors may be looking for low platelet count, low IgM and IgG levels with elevated IgE and IgA levels, autoantibodies present, low platelet mean volume, impairment of cell-mediated immunity and thrombocytopenia.

    Other testing may include tissue typing, bacteriology and renal and liver function testing.

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    Aggressive and prompt treatment is necessary for bleeding and infections. Eczema can get severe for some patients. Moisturization, careful skin care and steroid therapy are used to treat it.

    Thrombocytopenia may be treated with corticosteroids and/or intravenous immunoglobulin. If the patient has bleeding, red blood cell and/or platelet transfusions may be necessary.

    If an appropriate histocompatible donor can be found, bone marrow transplantation may be curative; however, this carries significant risks, including mortality.

    To help control thrombocytopenia, a splenectomy may be beneficial for some patients. This may also help to normalize platelet counts and reduce bleeding risk.

    Different types of medications may be useful, depending on the symptoms and complications the patient may be experiencing. These may include antibiotics, antifungals, immunoglobulins, antivirals, chemotherapeutic agents and corticosteroids.

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    Genetics Home Reference. (2008). Wiskott-Aldrich Syndrome. Retrieved on June 11, 2011 from Genetics Home Reference.

    Dibbern Jr., D.A. MD, et al. (2010). Wiskott-Aldrich Syndrome. Retrieved on June 11, 2011 from eMedicine Medscape.