Wiskott-Aldrich syndrome


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Related to Wiskott-Aldrich syndrome: Ataxia-telangiectasia, DiGeorge syndrome

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

 [wis´kot awl´drich]
a congenital platelet storage pool disease, transmitted as an X-linked recessive trait, characterized by the triad of eczema, thrombocytopenia, and recurrent purulent infection. There is an inability to produce antibodies to polysaccharide antigens and increased susceptibility to infection with encapsulated bacteria such as Haemophilus influenzae,meningococcus, or pneumococcus. Called also Aldrich syndrome.

Wis·kott-Ald·rich syn·drome

(wis'kot awl'drich), [MIM*301000 and MIM*277970]
an immunodeficiency disorder occurring in male children and characterized by thrombocytopenia, eczema, melena, and susceptibility to recurrent bacterial infections; death occurs from severe hemorrhage or overwhelming infection; X-linked recessive inheritance, caused by mutation in the Wiskott-Aldrich syndrome protein (WASP) on chromosome Xp.
Synonym(s): Aldrich syndrome

Wis·kott-Ald·rich syn·drome

(wis'kot awl'drich), [MIM*301000 and MIM*277970]
an immunodeficiency disorder occurring in male children and characterized by thrombocytopenia, eczema, melena, and susceptibility to recurrent bacterial infections; death occurs from severe hemorrhage or overwhelming infection; X-linked recessive inheritance, caused by mutation in the Wiskott-Aldrich syndrome protein (WASP) on chromosome Xp.
Synonym(s): Aldrich syndrome

Wiskott-Aldrich syndrome

(wĭs′kŏt-ôl′drĭch, -ŏl′-, vĭs′-)
n.
A hereditary sex-linked recessive disorder characterized by chronic eczema, recurring infections, and a decrease in the number of white blood cells and platelets.

Wiskott-Aldrich syndrome

[wis′ko tôl′drich]
Etymology: Alfred Wiskott, German pediatrician, 1898-1978; Robert Anderson Aldrich, American pediatrician, b. 1917
an immunodeficiency disorder inherited as a recessive X-linked trait, characterized by thrombocytopenia, eczema, inadequate T and B cell function, and an increased susceptibility to viral, bacterial, and fungal infections and to cancer. Treatment includes the prescription of appropriate antibiotics for specific infectious organisms and the administration of transfer factor from activated lymphocytes to increase the resistance to infection and to clear the eczema. See also transfer factor.

WAS

A gene on chromosome Xp11.4-p11.21 that encodes an eEffector protein for Rho-type GTPases, which regulates actin filament reorganisation by interacting with the Arp2/3 complex. WAS plays a key role in efficient actin polymerisation, and may regulate lymphocyte and platelet function; it mediates actin filament reorganisation and the formation of actin pedestals after infection by pathogenic bacteria.

Wiskott-Aldrich syndrome

Hematology An XR immunodeficiency Clinical Eczema, proneness to infection due to recurrent pyogenic infections, especially with encapsulated bacteria–eg, H influenzae, S pneumoniae, N meningiditis, thrombocytopenia, bloody diarrhea, ↑ susceptibility for lymphoproliferative disorders Lab ↓ IgM, ↑ IgA, ↑ IgE, ↓ platelets Management Splenectomy, kidney transplant, BMT Prognosis Death usually before age 10

Wis·kott-Ald·rich syn·drome

(wis'kot awl'drich sin'drōm)
Immunodeficiency disorder occurring in boys characterized by thrombocytopenia, eczema, melena, and susceptibility to recurrent bacterial infections; death occurs from severe hemorrhage or overwhelming infection.

Wiskott-Aldrich syndrome

An X-linked recessive immune deficiency disorder featuring recurrent infections, eczema and bleeding because of small platelets present in inadequate numbers. The affected gene, the product of which has been cloned, is on the short arm of the X chromosome. More than 160 mutations spanning all 12 EXONs of the gene have been found. Like other X-linked recessive diseases the condition is almost confined to males. In female carriers the unmutated chromosome is preferentially selected in haematoipoietic cells. The condition has been cured by bone marrow transplantation. (Arthur Wiskott, German-born American paediatrician, 1898–1978; and Robert Anderson Aldrich, 1917–1998, American professor of paediatrics and preventice medicine).

Aldrich,

Robert Anderson, U.S. pediatrician, 1917–.
Aldrich syndrome - Synonym(s): Wiskott-Aldrich syndrome
Wiskott-Aldrich syndrome - see under Wiskott

Wiskott,

Alfred, 20th century German pediatrician.
Wiskott-Aldrich syndrome - a fatal X-linked immunodeficiency disorder occurring in male children. Synonym(s): Aldrich syndrome
References in periodicals archive ?
Structure and function of the Wiskott-Aldrich syndrome protein.
In addition to the trial in Wiskott-Aldrich syndrome, Genethon is also continuing the gene therapy trial launched in 2006 for a neuromuscular disease.
The Normanby youngster faced a hugely uncertain future when he entered Newcastle's Royal Victoria Infirmary to prepare for the transplant, aged nine months, after being diagnosed with rare genetic condition Wiskott-Aldrich Syndrome which, if untreated, would have eventually robbed him of his immune system.
Gene Edition for Wiskott-Aldrich Syndrome Gene Therapy -- Abstract #342 Session: Gene Targeting and Gene Correction II Poster Session -- Thursday, May 14, 2015
Diagnosed with the rare genetic condition Wiskott-Aldrich Syndrome, as reported in the Gazette, the blood stem cell transplant was Danny's only hope as few people with the rare genetic condition survive into their teens.
These include but are not limited to congenital X-linked agammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome and severe combined immunodeficiencies.
Sangamo collaborators will also be discussing the use of Sangamo zinc finger nucleases in preclinical and research studies of SCID-X1, cancer and Wiskott-Aldrich Syndrome.
The transplant was his only hope after he was diagnosed with the rare genetic condition Wiskott-Aldrich Syndrome, as few people with it survive into their teens.