Wiskott Aldrich syndrome

Alternate names

WAS; Eczema thrombocytopenia immunodeficiency syndrome; Immunodeficiency 2; IMD 2; Aldrich syndrome

Definition

Wiskott-Aldrich syndrome is characterized by abnormal immune system function (immune deficiency), eczema (an inflammatory skin disorder characterized by abnormal patches of red, irritated skin), and a reduced ability to form blood clots.

Summary

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, bloody diarrhea, or episodes of prolonged bleeding following nose bleeds or minor trauma. Microthrombocytopenia can also lead to small areas of bleeding just under the surface of the skin, resulting in purplish spots called purpura, or variably sized rashes made up of tiny red spots called petechiae. In some cases, particularly if a bleeding episode occurs within the brain, prolonged bleeding can be life-threatening. Wiskott-Aldrich syndrome is also characterized by abnormal or nonfunctional immune system cells known as white blood cells. Changes in white blood cells lead to an increased risk of several immune and inflammatory disorders in people with Wiskott-Aldrich syndrome. These immune problems vary in severity and include an increased susceptibility to infection from bacteria, viruses, and fungi. People with Wiskott-Aldrich syndrome are at greater risk of developing autoimmune disorders, such as rheumatoid arthritis, vasculitis, or hemolytic anemia. These disorder occur when the immune system malfunctions and attacks the body's own tissues and organs. The chance of developing certain types of cancer, such as cancer of the immune system cells (lymphoma), is also increased in people with Wiskott-Aldrich syndrome. Wiskott-Aldrich syndrome is often considered to be part of a disease spectrum with two other disorders: X-linked thrombocytopenia and severe congenital neutropenia. These conditions have overlapping signs and symptoms and the same genetic cause.

Epidemiology

The estimated incidence of Wiskott-Aldrich syndrome is between 1 and 10 cases per million males worldwide; this condition is rarer in females.

Cause

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 triggers the cell to move and attach to other cells and tissues (adhesion). In white blood cells, this signaling allows the actin cytoskeleton to establish interactions between cells and the foreign invaders that they target (immune synapses).

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. Additionally, the normal process of removing platelets from circulation and taking them to the spleen for destruction also likely contributes to microthrombocytopenia in individuals with Wiskott-Aldrich syndrome.

Because they all have the same genetic cause, Wiskott-Aldrich syndrome, X-linked thrombocytopenia, and severe congenital neutropenia are sometimes collectively referred to as WAS-related disorders.

Inheritance

X-linked recessive inheritance

This condition is inherited in an X-linked pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males, who have only one X chromosome, a mutation in the only copy of the gene in each cell is sufficient to cause the condition. In females, who have two copies of the X chromosome, one altered copy of the gene in each cell can lead to less severe features of the condition or may cause no signs or symptoms at all. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Symptoms

Common signs and symptoms of Wiskott-Aldrich syndrome include the following. Decreased numbers of platelets (thrombocytopenia), and very small platelets usually present at birth which can result in:

• Bleeding inside the brain, which can be very fatal
• Mucosal (such as insed the mouth) bleeding
• Bloody diarrhea
• Bruising or purplish areas on the skin or mucous membranes (purpura), caused by bleeding under the skin
• Pinpoint red spots on the skin (petechiae).
• Life-threatening bleeding (occurs in 30% of males prior to diagnosis)
• Red patches of red and irritated skin (eczema), occurs in about 80% of the cases and can be mild to severe
• Other skin diseases such as impetigo, cellulitis, and abscesses
• Increased risk of infections, especially to recurrent bacterial and viral infections, mostly recurrent ear infections and some viruses such as cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV).
• Increased risk of developing autoimmune disorders (when the immune system mistakenly attacks the body's own tissues and organs) specially when people get older, and that may include hemolytic anemia (destruction of red blood cells), immune thrombocytopenic purpura, rheumatoid arthritis, vasculitis of small and large vessels, and immune-mediated damage to the kidneys and liver
• Increased risk of developing some types of cancer, such as lymphoma, especially in people with WAS who had an EBV infection or are older and have an autoimmune disease.

Diagnosis

Wiskott-Aldrich syndrome should be suspected in a male with:

• Profound thrombocytopenia (<70,000 platelets/mm3)
• Small platelet size (mean platelet volume >2 SD below the mean for the laboratory)
• Recurrent bacterial or viral infection or opportunistic infection in infancy or early childhood
• Eczema
• Autoimmune disorder
• Lymphoma
• Family history of one or more maternally related males with a WAS-related phenotype or disorder
• Absent or decreased intracellular Wiskott-Aldrich syndrome protein (WASP) detection in hematopoietic cells as determined by flow cytometry or western blotting

Abnormal lymphocytes: Decreased T-cell subsets, especially proportion and absolute number of CD8+T cells Decreased NK cell function. Lymphocyte subsets, mitogen responses, and other tests of cell-mediated immunity can vary among individuals, and over time in the same individual. Note: (1) Some individuals, particularly children, have normal lymphocyte numbers and normal function. (2) Although the proportion of CD8+ cells is often decreased, it is occasionally increased.

Abnormal immunoglobulin levels: decreased IgM, normal or decreased IgG, increased IgA, increased IgE Absent isohemagglutinins

Absent or greatly decreased antibody responses to polysaccharide vaccines (e.g., Pneumovax®)

The diagnosis is made on the basis of clinical parameters, the peripheral blood smear, and low immunoglobulin levels. Typically, 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 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 WASp are typically observed.

The current gold standard for diagnosis is genomic DNA sequence analysis, which can detect WAS and the related disorders XLT and XLN in the vast majority of patients and carriers.

Treatment

Treatment may depend on severity and symptoms in each person, but hematopoietic cell transplantation is the only known cure. Hematopoietic cells are the blood-forming stem cells that can be found mainly in the sponge-like material found inside bones (bone marrow), but also in the bloodstream (peripheral blood stem cells (PBSCs), and in the umbilical cord.

Hematopoietic cell transplantation (HCT): The only curative treatment clinically available for Wiskott-Aldrich syndrome is allogeneic HCT. Affected males who receive HCT from a matched healthy sib or closely matched unrelated donor before their second birthday have a greater than 90% probability of being cured of the disorder.

Eczema: Topical steroids are the mainstay of therapy. When chronic infections of the skin worsen eczema, antibiotics may be useful.

Infection: For those individuals with clinical signs or symptoms of infection, prompt evaluation and treatment is necessary. The initiation of empiric parenteral antibiotic treatment is necessary in the majority of individuals.

Autoimmune disease: Treatment usually consists of judicious use of immunosuppressants tailored to the individual's diagnosis.

Studies of correcting Wiskott–Aldrich syndrome with gene therapy using a lentivirus have begun.

Prognosis

Prognosis have improved over time due to better management of the disease. People who have a successful and uncomplicated hematopoeitic cell transplantation, usually have normal immune function and, normal survival.

NIH genetic and rare disease info

• NIH info on Wiskott Aldrich syndrome

Wiskott Aldrich syndrome is a rare disease.

Wiskott Aldrich syndrome Resources
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