Definition
Wiskott-Aldrich syndrome (WAS) is a rare inherited disorder marked by a low level of blood platelets, eczema, recurrent infections, and a high risk of leukemia or lymph node tumors.
Description
Wiskott-Aldrich syndrome (WAS) was named for the two physicians who reported the disorder. In 1937, A. Wiskott, a physician working in Munich, described two affected boys of German ancestry who had repeated infections, a skin rash, and poor blood-clotting ability. Nearly twenty years later, R. A. Aldrich reported similar symptoms in members of an American family of Dutch ancestry.
WAS is inherited as an X-linked genetic disorder and thus only affects males. The gene responsible for WAS is located on the short arm of the X chromosome. Since males have only one X chromosome they only have one copy of the gene. If that copy carries the abnormal gene, they have WAS. In contrast, females have two X chromosomes. They have a normal copy of the gene on one chromosome even if an abnormal gene is on the other because the abnormal gene is very rare. The normal copy on one X chromosome is usually sufficient to prevent females from having WAS. However, women who have one abnormal copy of the WAS gene are designated as carriers. While they will not have WAS, they have a 50 percent risk of passing the gene to each of their sons who will have WAS. Carrier females also have a 50 percent risk of passing the defective copy of the gene to their daughters who also become carriers.
Researchers identified the gene for WAS in 1994 and pinpointed its location on the short arm of the X chromosome. As of 2000, over 100 different mutations had been found in the gene among WAS patients. The fact that there are many mutations explains some of the variability of symptoms among boys with WAS. However, even within the same family, affected individuals with the identical WAS gene mutation may have different degrees of severity of the disease. The mild form, X-linked thrombocytopenia, is also caused by mutations in this same gene.
Demographics
The WAS syndrome affects one in every 250,000 male children and occurs worldwide. In the year 2000, scientists estimated that about 500 Americans had WAS.
Causes and Symptoms
The syndrome is caused by a defect (mutation) in a specific gene called the WAS gene that normally codes for the protein named Wiskott-Aldrich syndrome protein (WASP). This vital protein is a component of cells that are important in the body's defense against infection (lymphocytes). The same protein also functions in the cells that help prevent bleeding (platelets). A less severe form of the disease, X-linked thrombocytopenia, affects mainly the platelets.
Increased susceptibility to infections, eczema, and excessive bleeding and bruising are the hallmarks of WAS, although the symptoms can vary significantly from one patient to another. The immune system of patients with WAS produces too few B and T cells. B cells are the cells in the body that make antibodies. There are many types of T cells. Both B and T cells are needed to defend the body against infection. Because both types of cells are affected, WAS patients are subject to repeated infections from bacteria, fungi, and viruses. Ear infections, meningitis, and pneumonia are common in boys with WAS.
WAS patients also have abnormal platelets, the specialized blood cells that help to form blood clots and control bleeding. In WAS, the platelets are often too few (called thrombocytopenia) and too small. Some of the earliest symptoms of the syndrome may be noted during early infancy, including excessive bleeding after a circumcision, bloody diarrhea, and a tendency to bruise very easily.
Some patients also have too few red blood cells (anemia) and an enlarged spleen (splenomegaly). About 10 percent of patients develop malignancies, usually leukemia or tumors in the lymph nodes (non-Hodgkin's lymphoma).
Diagnosis
The diagnosis of WAS is usually suspected in male infants who have excessive bleeding, eczema, and frequent bacterial or viral infections. Special blood tests can then be ordered to confirm WAS. The blood of Wiskott-Aldrich patients shows a low platelet count and a weak immune (antibody) response. Blood is analyzed to determine the quantity of immunoglobulins in the blood as well as the ability of the immune system to mount an antibody response against common pathogens. It is also possible to confirm the diagnosis by obtaining a small sample of the patient's blood and analyzing the DNA for a mutation in the WAS gene. Information about the exact mutation and the quantity of WAS protein the defective gene can produce may help predict the severity of the individual's condition.
Carrier Testing
If the specific WAS gene mutation is identified in an affected child, that child's mother can then be tested to confirm that she carries the gene. Other members of the mother's family may also want to consider testing to find out if they carry the same gene mutation. The first step in studying other family members is for a geneticist or genetic counselor to obtain a detailed family history and construct a pedigree (family tree) to determine which family members should be offered testing.
Prenatal Diagnosis
In families in which there one child has been born with WAS, prenatal testing should be offered in subsequent pregnancies. When the mother is a carrier, there is a 50 percent chance with each subsequent pregnancy that the new baby will receive the abnormal copy of the gene. The key is to first identify the particular WAS gene mutation in the child with WAS. Then, early in a pregnancy, cells can be obtained from the developing fetus by chorionic villus sampling or amniocentesis and checked for the same mutation. Women who carry the abnormal WAS gene and are considering prenatal diagnosis should discuss the risks and benefits of this type of testing with a geneticist or genetic counselor.
Treatment
Standard treatments for individuals with WAS include antibiotics for infections and platelet and red blood cell transfusions. Corticosteroids and immune globulin may be given in an attempt to improve thrombocytopenia. Eczema can be treated with corticosteroid creams applied directly to the skin. The spleen is sometimes removed to improve thrombocytopenia. In individuals with WAS, however, removal of the spleen also increases the risk of certain types of infections. About 50 percent of individuals with WAS are helped by treatment with transfer factor, which is a substance derived from the T cells of a healthy person. Transfer factor is given to improve both blood clotting and immune functions. Bone marrow transplantation has been successful in a number of cases. It has been most successful in boys under five years of age when the donor is a sibling whose tissue type closely matches that of the individual with WAS. As of 2000, attempts were also being made to treat individuals with WAS with umbilical cord blood from unrelated newborns in cases in which the individual diagnosed with WAS has no matched sibling donor.
Prognosis
The prognosis for males diagnosed with Wiskott-Adrich syndrome is poor. The average individual lives about eight years. Death usually occurs due to severe bleeding or overwhelming infection. Those who survive into adolescence often develop leukemia, lymphoma, or autoimmune diseases such as vasculitis, arthritis, inflammatory bowel disease, and kidney disease.
Prevention
Although there are no available treatments to prevent the development of WAS in an individual who receives the defective gene, prenatal genetic counseling can help couples determine their risk of having a baby with WAS.
Parental Concerns
Caring for a baby or child with WAS is a highly stressful task. The child's healthcare provider should help the parents decide what steps will be necessary in order to decrease the child's risk of infection. Excellent hand washing and careful food handling should always be followed, but the healthcare provider should also provide guidance about other ways to avoid exposure to infectious disease. The parents will need to balance their child's need for a normal life with peer interaction and the desire to reduce the chance of exposure to serious infection. Furthermore, parents of children with WAS need to maintain a high level of suspicion; when a child with WAS begins to act ill or develop a fever, it may be necessary to immediately begin antibiotic treatment in order to avoid a more serious infection.
Resources
Organizations
Immune Deficiency Foundation. 25 W. Chesapeake Ave., Suite 206, Towson, MD 21204. Web site: www.primaryimmune.org/inside.htm.
Web Sites
NORD—National Organization for Rare Disorders Inc. Available online at www.rarediseases.org (accessed January 9, 2005).
[Article by: Sallie Boineau Freeman, PhD Rosalyn Carson-DeWitt, MD]
