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
WAS was named for the two physicians who first reported the disorder. In 1937, Dr. 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, Dr. R.A. Aldrich reported similar symptoms in members of an American family of Dutch ancestry.
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.
Genetic profile
WAS is inherited as an X-linked genetic disorder and will therefore only affect 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 will have WAS. In contrast, females have two X chromosomes. They will 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% risk of passing the gene to each of their sons, who would then have WAS. Carrier females also have a 50% risk of passing the defective copy of the gene to their daughters, who then become carriers.
Researchers identified the gene for WAS in 1994 and pinpointed its location on the short arm of the X chromosome (Xp11.22-p11.23). As of 2000, over 100 different mutations have been found in the gene among WAS patients. The fact that there are many mutations may explain 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 have WAS.
Signs and symptoms
Increased susceptibility to infections, eczema, and excessive bleeding are the hallmarks of WAS, although the symptoms can vary signficantly 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 thrombocytopenia, a decreased number of platelets. Platelets are the specialized blood cells that help to form blood clots and prevent uncontrolled bleeding. The platelets may also be smaller
than normal. Some of the earliest symptoms of the syndrome are hemorrhage from circumcision, bloody diarrhea, and a tendency to bruise very easily.
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 patients with Wiskott-Aldrich will show a low platelet count and a weak immune (antibody) response. 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. Knowledge of the exact mutation combined with information about how much WAS protein the defective gene can produce may help predict how severe a form of the disease an individual will have.
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 has been one child born with WAS, prenatal testing should be offered in subsequent pregnancies. There is a 50% chance with each subsequent pregnancy that the mother, who is a carrier, will
transmit the abnormal copy of the gene to her baby. 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 and management
Standard treatments for individuals with WAS include antibiotics for infections and platelet transfusions to limit bleeding. Immune globulin is given to strengthen the individual's immune system. Eczema can be treated with corticosteroid creams applied directly to the skin. The spleen is sometimes removed to reduce the risk of bleeding. In individuals with WAS, however, removal of the spleen also increases the risk of infection unless antibiotics are given to prevent infections. About 50% 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 when 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 four years; those who survive into adolescence often develop cancer. Death usually occurs from severe
bleeding or overwhelming infection in the first few years of life.
BOOKS
Belmont, J. W., and J. M. Puck. "T Cell and Combined Immunodeficiency Disorders." In The Metabolic & Molecular Bases of Inherited Disease. Edited by C. R. Scriver, et al. New York: McGraw-Hill, 2001.
PERIODICALS
Kuska, B. "Wiskott-Aldrich Syndrome: Molecular Pieces Slide Into Place." Journal of the National Cancer Institute 92 (January 5, 2000): 9–11.
