Wiskott-Aldrich syndrome

Description, Causes and Risk Factors:Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia). It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954. The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present similar but less severe symptoms and are caused by mutations of the same gene.The estimated incidence of Wiskott-Aldrich syndrome is between 1 and 10 cases per million males worldwide; this condition is rarer in females.Wiskott-Aldrich syndrome is characterized by abnormal immune system function (immune deficiency) and a reduced ability to form blood clots. This condition primarily affects males.Individuals with Wiskott-Aldrich syndrome have microthrombocytopenia, which is a decrease in the number and size of blood cells involved in clotting (platelets). This platelet abnormality, which is typically present from birth, can lead to easy bruising or episodes of prolonged bleeding following minor trauma.Wiskott-Aldrich syndrome causes many types of white blood cells, which are part of the immune system, to be abnormal or nonfunctional, leading to an increased risk of several immune and inflammatory disorders. Many people with this condition develop eczema, an inflammatory skin disorder characterized by abnormal patches of red, irritated skin. Affected individuals also have an increased susceptibility to infection. People with Wiskott-Aldrich syndrome are at greater risk of developing autoimmune disorders, which occur when the immune system malfunctions and attacks the body's own tissues and organs. The chance of developing some types of cancer, such as cancer of the immune system cells (lymphoma), is also greater in people with Wiskott-Aldrich syndrome.Mutations in the WAS gene cause Wiskott-Aldrich syndrome. The WAS gene provides instructions for making a protein called WASP. This protein is found in all blood cells. WASP is involved in relaying signals from the surface of blood cells to the actin cytoskeleton, which is a network of fibers that make up the cell's structural framework. WASP signaling activates the cell when it is needed and triggers its movement and attachment to other cells and tissues (adhesion). In white blood cells, this signaling allows the actin cytoskeleton to establish the interaction between cells and the foreign invaders that they target (immune synapse).WAS gene mutations that cause Wiskott-Aldrich syndrome lead to a lack of any functional WASP. Loss of WASP signaling disrupts the function of the actin cytoskeleton in developing blood cells. White blood cells that lack WASP have a decreased ability to respond to their environment and form immune synapses. As a result, white blood cells are less able to respond to foreign invaders, causing many of the immune problems related to Wiskott-Aldrich syndrome. Similarly, a lack of functional WASP in platelets impairs their development, leading to reduced size and early cell death.Symptoms:Due to its mode of inheritance, the overwhelming majority of patients are male. The first signs of WAS are usually petechiae and bruising, resulting from thrombocytopenia (low platelet counts). Spontaneous nose bleeds and bloody diarrhea are common. Eczema develops within the first month of life. Recurrent bacterial infections develop by three months. Splenomegaly is not an uncommon finding. The majority of WAS children develop at least one autoimmune disorder, and malignancies (mainly lymphoma and leukemia) develop in up to a third of patients.IgM levels are reduced, IgA and IgE are elevated, and IgG levels can be normal, reduced, or elevated.Diagnosis:The diagnosis is made on the basis of clinical parameters, the blood film and low immunoglobulin levels. Typically, immunoglobulin M (IgM) levels are low, IgA levels are elevated, and IgE levels may be elevated; paraproteins are occasionally observed. Skin immunologic testing (allergy testing) may reveal hyposensitivity. Not all patients will have a positive family history of the disorder, new mutations do occur. Often, leukemia may be suspected on the basis of low platelets and infections, and bone marrow biopsy may be performed. Decreased levels of Wiskott-Aldrich syndrome protein and/or confirmation of a causative mutation provides the most definitive diagnosis.Sequence analysis can detect the WAS-related disorders of Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN). Sequence analysis of the WASP gene can detect about 98% of mutations in males and 97% of mutations in female carriers. Because XLT and XLN symptoms may be less severe than full WAS and because female carriers are usually asymptomatic, clinical diagnosis can be elusive. In these cases, genetic testing can be instrumental in diagnosis of WAS-related disorders.Treatment:Treatment of Wiskott-Aldrich syndrome is currently based on correcting symptoms. Aspirin and other non-steroidal anti-inflammatory drugs should be avoided, since these may interfere with platelet function. A protective helmet can protect children from bleeding into the brain which could result from head injuries. For severely low platelet counts, patients may require platelet transfusions or a splenectomy. For patients with frequent infections, intravenous immunoglobulins (IVIG) can be given to boost the immune system. Anemia from bleeding may require iron supplementation or blood transfusion.As Wiskott-Aldrich syndrome is primarily a disorder of the blood-forming tissues, a hematopoietic stem cell transplant, accomplished through a cord blood or bone marrow transplant offers the only current hope of cure. This may be recommended for patients with HLA-identical donors, matched sibling donors, or even in cases of incomplete matches if the patient is age 5 or under.Studies of correcting Wiskott-Aldrich syndrome with gene therapy using a lentivirus have begun. Proof-of-principle for successful hematopoietic stem cell gene therapy has been provided for patients with Wiskott-Aldrich syndrome. Currently, many investigators continue to develop optimized gene therapy vectors.NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.DISCLAIMER: This information should not substitute for seeking responsible, professional medical care. 

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