Wiskott-Aldrich syndrome

ALSO KNOWN AS: Aldrich syndrome, eczema-thrombocytopenia-immunodeficiency syndrome, Wiskott syndrome

ANATOMY OR SYSTEM AFFECTED: Blood, ears, immune system, lungs, skin

DEFINITION: An X-linked genetic disorder characterized by thrombocytopenia, infections, and eczema in childhood

CAUSES: Genetic protein deficiency affecting lymphocytes and platelets

SYMPTOMS: Thrombocytopenia; eczema; recurrent sinus and pulmonary infections; bleeding into skin, bowels, gums, or joints

DURATION: Chronic

TREATMENTS: Blood and platelet transfusions, antibiotics, intravenous immunoglobulins, removal of spleen, bone marrow transplantation, cord blood stem cell transplantation

Causes and Symptoms

Wiskott-Aldrich syndrome is a rare primary inherited immunodeficiency disorder, involving both T and Bdf lymphocytes. Also, the disease is characterized by the deficiency of platelets, which are integral cells required for blood clotting. In the classical form, it is manifested soon after birth and through the first year of life, with the symptoms of recurrent sinopulmonary infections (from a decreased immune system); bleeding into the skin, bowels, gums, or joints (from defective platelets); and eczematous scaly skin rash. Autoimmune manifestations in the form of and or malignancies such as lymphoma or leukemia later in adolescence or young adulthood are also reported.

The disease is seen in its classical form as a result of the ineffective production of Wiskott-Aldrich syndrome protein (WASP), which determines the severity of the disease—the greater the deficiency of the WASP, the more severe the disease. Defective production of WASP is caused by a or error in the WASP gene, located on the short arm of the X chromosome. This mutation is inherited in an X-linked recessive fashion, and therefore, primarily boys are affected by the disease. In extremely rare cases involving girls, similar genetic mutations have not been noted.

Wiskott-Aldrich syndrome is suspected in any male child who has bleeding, typically bloody in infancy. Older children may even have a low platelet count and abnormally small when a routine blood smear is done during an infection. Otitis media, sinusitis, and pneumonia are quite common infections for these children, and viral infections are also seen as a result of the abnormal immune response.

The clinical presentation depends on the severity of the WASP deficiency and may differ from patient to patient. It may range from just (low platelet count) to all three classic symptoms of eczema, recurrent infections (because of immunodeficiency), and bleeding (because of low platelets). The disease X-linked thrombocytopenia is considered a different form of Wiskott-Aldrich syndrome. The first presentation of the disease is usually within the first year of life, soon after birth, and most often is as a result of immunodeficiency or thrombocytopenia. The most characteristic feature of Wiskott-Aldrich syndrome is reduced platelets. Also, a defect in the function of platelets is noticed in some forms of the disease, manifested as bleeding gums, prolonged epistaxis (nosebleeds), or bleeding into joints or bowels.

Eczema is a common symptom of Wiskott-Aldrich syndrome. It may be localized or generalized, with itchy rashes all over the body. Scratching of such rashes might lead to bleeding and infections. Recurrent infections are common in the syndrome because of the deficiency of T and B lymphocytes (white blood cells). As both T and B cells are affected, the infections may be attributable to bacteria, fungi, or viruses. Other manifestations of the disease are autoimmune anemia, leukemia, and lymphoma, which are seen more often in older boys and adults.

A diagnosis of Wiskott-Aldrich syndrome must be considered in any boy with unusual bleeding, recurrent infections, and eczema. The characteristic platelet features of low count and abnormally small size are also evident in the cord blood of a newborn. The blood test for platelet count and size is, therefore, the most useful one. In older children, other tests such as serum immunological studies for antibodies and negative skin tests for T cell function are done. Confirmation of the diagnosis is by measuring the levels of WASP in the blood or by detecting WASP gene mutation through genetic studies.

In families with a boy diagnosed with Wiskott-Aldrich syndrome, prenatal testing of the mother before subsequent pregnancies should be performed by amniocentesis or chorionic villus sampling, as there is a 50 percent chance of a mother transferring the abnormal gene to her baby.

Treatment and Therapy

The treatment of Wiskott-Aldrich syndrome is prolonged and involves multiple approaches. Family support is of vital importance in the treatment of chronic illnesses. Bleeding often results in anemia that requires blood transfusions for correction. To counter recurrent infections, these boys require appropriate antibiotics, which must be determined after careful culture and tests. As a result of the abnormality of the immune system, vaccinations might not prove very effective. In fact, live virus vaccines are contraindicated in these patients and must be avoided. Instead, patients are given intravenous immunoglobulins (IVIGs), or preformed antibodies, to decrease the chances of bacterial infections. The treatment of eczema involves avoiding frequent bathing and applying bath oils and moisturizing creams after a bath; topical are often helpful. Systemic antibiotics are of help in some cases of eczema. Platelet deficiency is corrected by transfusing platelets into the bloodstream. Surgical removal of the is of some beneficial effect in checking the thrombocytopenia. Avoiding allergens is an important way to prevent the exacerbation of eczema. While bone marrow and cord blood transplantation are the only methods of curing the disease permanently, researchers have encouraging results regarding the long-term outcomes of gene therapy to treat severe cases of Wiskott-Aldrich syndrome. The researchers followed eight patients for four years and found that the gene-corrected cells grafted well and the patients had no severe side-effects from the treatment. The patients all experienced a significant reduction in their symptoms.

Perspective and Prospects

In 1937, Alfred Wiskott first discovered this disease in three brothers with low platelet counts. In 1954, Robert Anderson Aldrich identified it as an X-linked recessive disease. When the disease was first identified, the was dismal, with a life expectancy of just two to three years. The discovery of and advances in antibiotics, immunoglobulins, transplantations, and cord blood stem cell transplantation have improved the prognosis greatly. Today, it is not unusual to see patients with Wiskott-Aldrich syndrome lead productive lives as adults without developing the complications of the disease.

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