IDF PATIENT/FAMILY HANDBOOK | CHAPTER VII
The Wiskott Aldrich Syndrome
The Wiskott-Aldrich Syndrome is a primary immune deficiency disease involving both T and B-lymphocytes. In addition, the blood cells that help control bleeding, called platelets, are also affected. The Wiskott-Aldrich syndrome has a characteristic pattern of findings that may include one or more of the following: 1) an increased tendency to bleed caused by a reduced number of platelets, 2) recurrent bacterial, viral and fungal infections, and 3) eczema of the skin.
DEFINITION: In 1937, Dr. Wiskott described three brothers with low platelet counts (thrombocytopenia), bloody diarrhea, eczema and recurrent ear infections. Seventeen years later, in 1954, Dr. Aldrich demonstrated that this syndrome was inherited as an X-linked recessive trait (see chapter on Inheritance). In the 1960s, the features of the underlying immunodeficiency were identified and the Wiskott-Aldrich syndrome joined the list of Primary Immune Deficiency Diseases.
The Wiskott-Aldrich Syndrome (WAS) is a primary immune deficiency disease involving both T- and B-lymphocytes. In addition, another type of blood cell called platelets, which helps control bleeding, is also affected. In its classic form, the WAS has a characteristic pattern of findings that include 1) an increased tendency to bleed caused by a reduced number of platelets, 2) recurrent bacterial, viral and fungal infections, and 3) eczema of the skin. In addition, long term observations of patients with the WAS have revealed an increased incidence of malignancies, including lymphoma and leukemia, and an increased incidence of autoimmune diseases in some patients.
The WAS is caused by mutations (or mistakes) in the gene which produces a protein named in honor of the disorder, the Wiskott-Aldrich Syndrome Protein (WASP). The WASP gene is located on the short arm of the X chromosome. The majority of these mutations are “unique”. This means that almost every family has its own characteristic mutation of the WASP gene. If the mutation is severe and interferes almost completely with the gene’s ability to produce the WAS protein, the patient has the classic, more severe form of WAS. In contrast, if there is some production of mutated WAS protein, a milder form of the disorder may result.
CLINICAL PRESENTATIONS: The clinical presentation of the Wiskott-Aldrich Syndrome (WAS) varies from patient to patient. Some patients present with all three classic manifestations, including low platelets and bleeding, immunodeficiency and infection, and eczema. Other patients present just with low platelet counts (thrombocytopenia) and bleeding. In fact, in past years the patients who presented with just low platelet counts were felt to have a different disease called X-linked thrombocytopenia (XLT). However, after the identification of the WAS gene, it was realized that both the WAS and X-linked thrombocytopenia are due to mutations of the same gene, and thus are different clinical forms of the same disorder.
The initial clinical manifestations of WAS may be present soon after birth or develop in the first year of life. They usually are due to the low platelet count or the underlying immunodeficiency.
Bleeding Tendency: A reduced number of platelets is a characteristic hallmark of all patients with the WAS. In addition, the platelets are smaller than normal. The precise mechanism for the thrombocytopenia (low platelet count) is unknown but may include inefficient production of platelets by the bone marrow or increased removal of platelets by the spleen. Hemorrhage following circumcision may be an early clue to the presence of the disease. The bleeding into the skin caused by the thrombocytopenia may cause pinhead sized red spots, called petechiae, or may be larger and resemble bruises. Affected boys may also have bloody bowel movements (especially during infancy), bleeding gums, prolonged nose bleeds and bleeding into the joints. Hemorrhage into the brain is a dangerous complication; toddlers may benefit from wearing a helmet to prevent head injuries until treatment is able to raise their platelet count.
Infections: Because of the profound deficiency of T- and B-lymphocytes, infections are common in classic WAS. These infections may include upper and lower respiratory infections such as otitis media, sinusitis and pneumonia. More severe infections such as sepsis (blood stream infection or blood poisoning), meningitis and severe viral infections are less frequent. Some patients with classic WAS develop recurrent Herpes Simplex infections (cold sores) and some have Pneumocystis carinii pneumonia.
Eczema: Eczema is a very common finding in patients with classic WAS. In infants, the eczema may resemble “cradle cap”, a severe diaper rash, or be generalized. In older boys, eczema is usually limited to the skin creases around the front of the elbow, around the wrist and neck and behind the knees. Because the eczema is extremely pruritic or itchy, affected boys often scratch until they bleed, even while asleep. Eczema may be absent or mild in some patients.
Autoimmune Manifestations: A problem observed frequently in older boys and adults with WAS is a high incidence of “autoimmune-like” symptoms. The word “autoimmune” describes conditions that appear to be the result of a disregulated immune system reacting against part of the patient’s own body. The most common autoimmune manifestation observed in WAS patients is a form of anemia caused by antibodies which destroy red blood cells. Some patients have a more generalized disorder in which there may be fevers, in the absence of infection, associated with swollen joints, kidney inflammation, and gastrointestinal symptoms such as diarrhea. Occasionally, inflammation of arteries (vasculitis) in the skin, heart, brain or other internal organs develops and causes a wide range of symptoms. These autoimmune episodes may last only a few days or may occur in waves over a period of many years.
Malignancies: Malignancies can occur in young children with WAS, but are more frequent in adolescents and young adults. Most of these malignancies involve the lymphocytes, e.g. lymphoma and leukemia.
DIAGNOSIS: Because of the wide spectrum of findings, the diagnosis of Wiskott-Aldrich Syndrome (WAS) should be considered in any boy presenting with unusual bleeding and bruises, congenital or early onset thrombocytopenia and small platelets. In fact, the characteristic platelet abnormalities, low numbers and small size, are already present in the cord blood of newborns.
The simplest and most useful test to diagnose WAS is to obtain a platelet count and to carefully determine the platelet size. WAS platelets are significantly smaller than normal platelets. In older children, over the age of two years, a variety of immunologic abnormalities can also be identified and used to support the diagnosis. Certain types of serum antibodies are characteristically low or absent in boys with WAS. They often have low levels of antibodies to blood group antigens (antibodies against type A or B red cells) and fail to produce antibodies against certain vaccines that contain polysaccharides or complex sugars. Skin tests to test T-lymphocyte function may show a negative response and laboratory tests of T-lymphocytes function may be abnormal.
The diagnosis is confirmed by demonstrating a decrease or absence of the WAS protein in blood cells or by the presence of a mutation within the WASP gene. These tests are done in a few specialized laboratories and require blood or other tissue.
INHERITANCE: The Wiskott-Aldrich Syndrome (WAS) is inherited as an Xlinked recessive disorder. Therefore, only boys are affected with this disease. See the chapter on Inheritance for more complete information on how X-linked recessive disorders are passed on from generation to generation. Since this is an inherited disease transmitted as an Xlinked recessive trait, there may be brothers or maternal uncles (the patient’s mother’s brother) with similar findings. However, the family history may be entirely negative because of small family size or because of the occurrence of a new mutation.
If the precise mutation of WASP is known in a given family, it is possible to perform prenatal diagnosis.
TREATMENT: All children with serious chronic illness need the support of the parents and family. The demands on the parents of boys with the Wiskott-Aldrich Syndrome (WAS) and the decisions they have to make may be overwhelming. Progress in nutrition and antimicrobial therapy, prophylactic use of IVIG, and bone marrow transplantation have improved the life expectancy of patients with WAS.
Because of increased blood loss, iron deficiency anemia is common and iron supplementation may be necessary. When there are symptoms of infection, a thorough search for bacterial, viral and fungal infections is necessary to determine the most effective antimicrobial treatment. Because patients with WAS have abnormal antibody responses to vaccines and to invading microorganisms, the prophylactic infusion of intravenous immunoglobulin may be indicated for those patients who suffer from frequent bacterial infections.
The eczema can be severe and persistent, requiring constant care. Excessive bathing should be avoided because frequent baths cause drying of the skin and make the eczema worse. Bath oils should be used during the bath and a moisturizing cream should be applied after bathing, and several times daily to areas of dry skin/eczema. Steroid creams applied sparingly to areas of chronic inflammation are often helpful but their overuse should be avoided. Do not use strong steroid creams, e.g. fluorinated steroids, on the face. If certain foods make the eczema worse, and if known food allergies exist, attempts should be made to remove the offending food items. Systemic antibiotics may also improve the eczema in some cases.
Platelet transfusions may be used in some situations to treat the low platelet count and bleeding. For example, if serious bleeding occurs that cannot be stopped by conservative measures, platelet transfusions are usually indicated. Hemorrhages into the brain usually require immediate platelet transfusions. Surgical removal of the spleen (a lymphoid organ in the abdomen that “filters the blood”) has been performed in WAS patients and has been shown to correct the low platelet count, or thrombocytopenia, in over 90% of the cases. However, removal of the spleen increases the susceptibility of WAS patients to bacterial infections, especially infections of the blood stream and meningitis.
The symptoms of autoimmune diseases may require treatment with drugs that further suppress the patient’s immune system. High dose IVIG and systemic steroids may correct the problem; if possible, the steroid dose should be reduced to the lowest level that will control symptoms.
As with all children with primary immune deficiency diseases involving Tlymphocytes and/or B-lymphocytes, boys with WAS should not receive live virus vaccines because there is a possibility that a vaccine strain of the virus may cause disease.
Complications of chicken pox occur frequently and may require treatment with antiviral drugs, high dose IVIG or Herpes Zoster Hyper Immune Serum.
The only “permanent cure” for WAS is a bone marrow transplantation or cord blood stem cell transplantation (see chapter on Specific Medical Therapy). Because patients with WAS have some residual T-lymphocytes function in spite of their immune deficiency, immunosuppressive drugs and/or total body irradiation are required to condition the patient before transplantation. If the affected boy has healthy siblings with the same parents, the entire family should be tissue typed to determine whether there is an HLA-identical sibling (a good tissue match) who could serve as bone marrow transplant donor. The results with HLAidentical sibling donor bone marrow transplantation in WAS are excellent with an overall success (cure) rate of 80-90%. This procedure is therefore the treatment of choice for boys with significant clinical findings of the WAS. The decision to perform an HLA-matched sibling bone marrow transplant in patients with milder clinical forms, such as isolated thrombocytopenia, is more difficult, and should be discussed with an experienced immunologist.
Matched, unrelated donor (MUD) transplants are nearly as successful as matched sibling transplants if performed in younger children (up to 5-6 years of age). The success rate of MUD transplants decreases with age and the decision to transplant teenagers or adults with WAS may be difficult.
Cord blood stem cells, fully or partially matched, have successfully been used for immune reconstitution and the correction of platelet abnormalities. This strategy is especially promising if a matched sibling donor is not available.
In contrast to the excellent outcome of matched transplants, haploidentical bone marrow transplantation (the use of a parent) has not been as successful as HLA-matched transplants.
EXPECTATIONS: Three decades ago, the classic Wiskott-Aldrich Syndrome was one of the most severe primary immunodeficiency disorder with a life expectancy of only 2-3 years. Although it remains a serious disease in which life threatening complications may occur, many affected males go through puberty and enter adulthood, live productive lives and have families of their own. The oldest bone marrow transplanted patients are now in their twenties and thirties and seem to be cured, without developing malignancies or autoimmune diseases.