Wiskott-Aldrich Syndrome

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

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.

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 will have WAS. Carrier females also have a 50% 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 have been found in the gene among WAS patients. The fact that there are many mutations many 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.

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.

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 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.

Anemia and an enlarged spleen (splenomegaly) are seen in some patients. About 10% 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 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 where there has been one child born with WAS, prenatal testing should be offered in subsequent pregnancies. There 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

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 where 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 where the individual diagnosed with WAS has no matched sibling donor.

KEY TERMS

Amniocentesis— A procedure performed at 16-18 weeks of pregnancy in which a needle is inserted through a woman's abdomen into her uterus to draw out a small sample of the amniotic fluid from around the baby. Either the fluid itself or cells from the fluid can be used for a variety of tests to obtain information about genetic disorders and other medical conditions in the fetus.

Anemia— A blood condition in which the level of hemoglobin or the number of red blood cells falls below normal values. Common symptoms include paleness, fatigue, and shortness of breath.

Chorionic villus biopsy— A procedure used for prenatal diagnosis at 10-12 weeks gestation. Under ultrasound guidance a needle is inserted either through the mother's vagina or abdominal wall and a sample of cells is collected from around the early embryo. These cells are then tested for chromosome abnormalities or other genetic diseases.

Eczema— Inflammation of the skin with redness and other variable signs such as crusts, watery discharge, itching.

Gene— A building block of inheritance, which contains the instructions for the production of a particular protein, and is made up of a molecular sequence found on a section of DNA. Each gene is found on a precise location on a chromosome.

Immune system— A major system of the body that produces specialized cells and substances that interact with and destroy foreign antigens that invade the body.

Mutation— A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease, and can be transmitted to offspring.

Platelets— Small disc-shaped structures that circulate in the blood stream and participate in blood clotting.

Prenatal diagnosis— The determination of whether a fetus possesses a disease or disorder while it is still in the womb.

Syndrome— A group of signs and symptoms that collectively characterize a disease or disorder.

Thrombocytopenia— A persistent decrease in the number of blood platelets usually associated with hemorrhaging.

X-linked— Located on the X chromosome, one of the sex chromosomes. X-linked genes follow a characteristic pattern of inheritance from one generation to the next.

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.

Resources

BOOKS

Belmont, J. W., and J. M. Puck. "T Cell and Combined Immunodeficiency Disorders." In The Metabolic & Molecular Bases of InheritedDisease, edited by C. R. Scriver, et al. New York: McGraw-Hill, 2001.

PERIODICALS

Kuska, B. "Wiskott-Aldrich Syndrome: Molecular Pieces SlideInto Place." Journal of the National Cancer Institute 92 (January 5, 2000): 9-11.

ORGANIZATIONS

Immune Deficiency Foundation. 25 W. Chesapeake Ave., Suite 206, Towson, MD 21204. (800) 296-4433. 〈http://www.primaryimmune.org/inside.htm〉.

OTHER

"Entry 301000: Wiskott-Aldrich Syndrome." OMIM—Online Mendelian Inheritance in Man. 〈http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=301000〉.

NORD—National Organization for Rare Disorders, Inc. 〈http://www.rarediseases.org〉.

Wiskott-Aldrich syndrome

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.

KEY TERMS

Amniocentesis —A procedure performed at 16–18 weeks of pregnancy in which a needle is inserted through a woman's abdomen into her uterus to draw out a small sample of the amniotic fluid from around the baby for analysis. Either the fluid itself or cells from the fluid can be used for a variety of tests to obtain information about genetic disorders and other medical conditions in the fetus.

Anemia —A condition in which there is an abnormally low number of red blood cells in the bloodstream. It may be due to loss of blood, an increase in red blood cell destruction, or a decrease in red blood cell production. Major symptoms are paleness, shortness of breath, unusually fast or strong heart beats, and tiredness.

Chorionic villus sampling —A procedure performed at 10 to 12 weeks of pregnancy in which a needle is inserted either through the mother's vagina or abdominal wall into the placenta to withdraw a small amount of chorionic membrane from around the early embryo. The amniotic fluid can be examined for signs of chromosome abnormalities or other genetic diseases.

Eczema —A superficial type of inflammation of the skin that may be very itchy and weeping in the early stages; later, the affected skin becomes crusted, scaly, and thick.

Immune system —The system of specialized organs, lymph nodes, and blood cells throughout the body that work together to defend the body against foreign invaders (bacteria, viruses, fungi, etc.).

Mutation —A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease. This change can be transmitted to offspring.

Platelet —A cell-like particle in the blood that plays an important role in blood clotting. Platelets are activated when an injury causes a blood vessel to break. They change shape from round to spiny, "sticking" to the broken vessel wall and to each other to begin the clotting process. In addition to physically plugging breaks in blood vessel walls, platelets also release chemicals that promote clotting.

Prenatal diagnosis —The determination of whether a fetus possesses a disease or disorder while it is still in the womb.

Syndrome —A group of signs and symptoms that collectively characterize a disease or disorder.

Thrombocytopenia —A persistent decrease in the number of blood platelets usually associated with hemorrhaging.

X-linked —A gene carried on the X chromosome, one of the two sex chromosomes.

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).

Sallie Boineau Freeman, PhD Rosalyn Carson-DeWitt, MD

Wiskott-Aldrich syndrome

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

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 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 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.

Anemia and an enlarged spleen (splenomegaly) are seen in some patients. About 10% 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 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 where 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.

Resources

BOOKS

Belmont, J. W., and J. M. Puck. "T Cell and Combined Immunodeficiency Disorders." The Metabolic & Molecular Bases of Inherited Disease. Ed. 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.

ORGANIZATIONS

Immune Deficiency Foundation. 40 W. Chesapeake Ave., Suite 308, Towson, MD 21204. (800) 296-4433. Fax: (410) 321-9165. <http://www.primaryimmune.org/inside.htm>.

WEBSITES

"Entry 301000: Wiskott-Aldrich Syndrome." OMIM—Online Mendelian Inheritance in Man. <http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=301000>.

NORD—National Organization for Rare Disorders, Inc. <http://www.rarediseases.org>.

Sallie Boineau Freeman, PhD

Wiskott-Aldrich syndrome

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

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.

Anemia and an enlarged spleen (splenomegaly) are seen in some patients. About 10% 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 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.

Resources

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.

ORGANIZATIONS

Immune Deficiency Foundation. 40 W. Chesapeake Ave., Suite 308, Towson, MD 21204. (800) 296-4433. Fax: (410) 321-9165. <http://www.primaryimmune.org/inside.htm>.

WEBSITES

"Entry 301000: Wiskott-Aldrich Syndrome." OMIM—Online Mendelian Inheritance in Man.<http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=301000>.

NORD—National Organization for Rare Disorders, Inc.<http://www.rarediseases.org>.

Sallie Boineau Freeman, PhD