A previous article dealt with Chronic Granulomatous Disease, a disorder in which the immune cells that usually destroy invading pathogens do not function properly. This article now deals another genetic disease that also causes immunodeficiency, albeit in a very different manner. Wiskott-Aldrich Syndrome (WAS) is an x-linked genetic disorder in which male children experience recurrent infection, prolonged bleeding, bloody diarrhea, and an increased risk of malignancy (cancer). This is a very rare disease and one that is subject to variable expression. The phrase variable expression means that while the disease is caused by a disturbance in a particular gene, the nature of that disturbance has an effect on how severe the symptoms are in any given individual. For some, full-blown WAS leads to a very severe immunodeficiency and early death while other experience only mildly low platelets and no other issues. In this article, we will leave the pathophysiology of WAS to the end and begin with the clinical manifestations.
The symptoms of WAS vary widely from person to person for reasons that are explained in the section on pathophysiology. This section will discuss the symptoms of WAS in order of most to least common, with the most common symptoms being those that affect individuals with even the mildest forms of the disease and the least common symptoms being those that only affect those suffering from the most severe forms of WAS.
1. Thrombocytopenia: This is a term that refers to the low platelet count in patients with WAS. Platelets are specialized cells that circulate within the blood stream and help to stop bleeding. In fact, platelets are the first step to the long pathway of forming a clot to stop bleeding.
When platelets are either deficient or they do not work properly, the individual will experience easy bruising, prolonged bleeding, and recurrent bleeding from the mucous membranes (gums, nose, rectum, etc.). Having thrombocytopenia is similar to overdosing on aspirin (aspirin prevents platelets from performing their jobs properly).
Patients with WAS suffer from thrombocytopenia. A normal platelet count is somewhere between 150,000 to 450,000 platelets per microliter of blood (1). In general, bleeding issues do not begin until the platelet count drops below 100,000. At that point, a patient will recognize increased bruising and mild bleeding with his or her brushing teeth. As the platelet levels drops, the risk of bleeding increases and the length of time it takes for a wound to stop bleeding increases. At a level of 20,000 platelets, spontaneous bleeding can occur throughout the body. Platelet counts of 20,000 or less are considered life-threatening. Patients with thrombocytopenia due to WAS often experience prolonged bleeding from the circumcision site, bloody diarrhea, and excessive bruising (2).
2. Atopic Dermatitis: This is another term for eczema. It is estimated that 80% of patients will suffer from eczema during the early years of life (3). This is not to say, however, that if you suffer from eczema you have WAS. Eczema is a very common condition and is most likely not related to WAS. However, patients with WAS have a roughly 80% chance of developing eczema, which leaves them more susceptible to infection.
3. Immunodeficiency: Patients with more severe forms of WAS have an increased susceptibility due to immune dysfunction. The specific immune dysfunction varies with the severity of the disease but includes both cellular and humoral immunity (for more on these topics read the section on pathophysiology).
In early life, patients with WAS experience bacterial infections primarily from encapsulated bacteria. This includes the bacteria that cause pneumonia, ear infections, meningitis, and severe blood infections (sepsis). Later in life, infections with opportunistic organisms becomes more of a problem. Opportunistic organisms include certain fungi and viruses, such as the viruses that cause herpes. Currently, the most common cause of death in WAS is from the Epstein Barr virus (EBV). EBV is the same virus that causes Mono. In patients with WAS, EBV can lead to the development of lymphoreticular malignancy (2).
4. Malignancy: Patients with WAS are at an increased risk of developing a variety of different malignancies. The immune system, besides defending the body from outside invaders, also helps to monitor for and rid the body of cancerous cells. The diminished ability of the immune system to perform this function in those with more sever forms of WAS results in increased development of many cancers.
5. Autoimmune Complications: The immune dysfunction in WAS appears to increase the chances that patients will develop autoimmune diseases such as arthritis, vasculitis (inflammation of the blood vessels), inflammatory bowel disease (Chrohn’s and ulcerative colitis), and glomerulonephritis (kidney disease). In patients with WAS, increased difficulty with autoimmune syndromes portends an increased risk of developing malignancy (4).
The diagnosis of WAS is based upon clinical suspicion of the disease in male patients with recurrent infection and thrombocytopenia at an early age. The following is a list of tests that are performed to help rule out other diseases and to determine the severity of the WAS.
1. Complete Blood Count: Also called a CBC. This will demonstrate the platelet level as well as any other disruptions in the white and red blood cell counts.
2. Quantitative Serum Immunoglobulin Levels: This test measures the levels of antibodies circulatin gin the blood. The antibodies are broken down into five main categories and labeled as IgM, IgA, IgD, IgE, and IgG. In patients with WAS, IgM levels are low, IgG levels are generally normal, and IgA and IgE levels can be abnormally elevated (3).
3. Functional Immune Function Testing: These tests are used to determine how well the immune system is functioning and can be broken down into two different categories. In the first category, patiens are vaccinated with the normal vaccines of childhood. However, unlike most children, their response to these vaccinations will be tested. Patients with WAS do not develop the antibodies against these vaccines that the average child does.
The second test used to measure immune function is commonly referred to as the scratch test. In this case, proteins that would normally cause a skin reaction are injected under the surface of the skin. In patients with WAS, anergy (a lack of response) is present (3).
4. Genetic testing is usually carried out on the mother to determine if she is a carrier of the disease. The gen on the x-chromosome that causes WAS when dysfunctional can be damaged at two different points in time. I the damage occurred after conception, which the fetus was developing it is termed a spontaneous mutation and the mother will not pass the disease on to further offspring. If, however, the mutation occurred in the mother’s genes before conception took place, then she carriers the mutation with her (though she does not suffer from the disease because she has a second x-chromosome that works normally) and there is a 50% chance that every male child she has will be affected by WAS and a 50% chance that every female child she has will also carry the defective gene and the risk of passing the disease on to her male children.
The only cure for WAS involves complete removal and replacement of the defective bone marrow with healthy bone marrow. Bone marrow transplants are the only curative treatment available. In those patients who only suffer from thrombocytopenia, surgical removal of the spleen can correct the problem (2). Eczema associated with WAS must be carefully managed as the damage to the skin provides a portal of entry for infection.
In general, those patients who undergo splenectomy have an average survival of 25 years while those who undergo a successful bone marrow transplant can live relatively normal, average life spans. Without treatment, most patients will die before reaching their teens (3).
WAS is a genetic disease the results from a mutation on the x-chromosome. Specifically, the Wiskott-Aldrich Syndrome Protein gene (WASP gene) is found on the short arm of the x-chromsome at the location Xp11.22-p11.23. At least 150 different mutations have been noted in this gene, all of which lead to WAS of variable severity (2).
The reason that the severity of WAS is so variable is that different mutations in the WASP gene have different effects on the eventual protein that the gene codes for. Genetic mutations come in a variety of forms that include the following:
Null mutations: This type of mutation means that no functional protein is produced at all. These are the most severe mutations and often are not compatible with life.
Gene deletions: These mutations result is removal of varying amounts of DNA from the WASP gene. The severity of the mutation depends not just on how much of the gene is missing, but also what portion is gone. The severity of deletion ranges from severe to unnoticeable.
Insertions: In this type of mutation, extra DNA is added where it does not belong. Again, the severity of the mutation depends on how much is added and where the addition is located.
Null mutations are associated with the most severe forms of WAS. Null mutations have a higher association with mortality and result in death at an earlier age than any of the other mutations.
The WASP gene codes for a protein that helps to stabilize the membranes of cells. What is known is that when immune cells recognize an invading organism, they go through a structural change so that they can better fight off the infection and produce antibodies. It is thought that damage to the WASP gen,e and hence the cell stabilizing protein, prevents the cell from undergoing these changes properly, thus leading to immune deficiency and inadequate amounts of IgM. This same protein likely plays a role in stabilizing the cell membrane of platelets. Without this protein, the platelets are more prone to damage and thus early removal from the bloodstream. This early removal is not compensated for by the bone marrow because the platelets that are produced are just as inferior as those that we lost (2,3).
Besides stabilizing cell membranes, the protein coded for by the WASP gene also appears to play an important role in phagocytosis (the process by which immune cells engulf and kill invading organisms). This would account for the defects in cell-mediated immunity seen in WAS (3).
The above discussion makes reference to cell-mediated immunity. In the immune system, there are several different methods by which invading organisms are fended off. Two of these methods are referred to as humoral immunity and cell-mediated immunity. Humoral immunity is the production of antibodies. These antibodies attach themselves to invading organisms and mark them for removal from the body. Cell-mediated immunity is the process by which cells of the immune system actively hunt down and destroy invading organisms. Both of these processes depend on the structural protein encoded by the WASP gene and hence both are affected in WAS.
1. Platelet Count. On: Lab Tests Online. Updated March 18, 2009. Accessed August 12, 2009. http://www.labtestsonline.org/understanding/analytes/platelet/test.html.
2. Buckley RH. Chapter 431: Combined Immunodeficiency Diseases. In: McMillan JA, Feigin RD, DeAngelis CD, Jones MD. Oski’s Pediatrics Principles and Practice, 4th edition. Lippincott Williams & Wilkins: Philadelphia 2006. P 2467-8.
3. Dibbern DA Jr, Routes JM. Wiskott-Aldrich Syndrome. On eMedicine from WebMD. Updated Jun 5, 2009. Accessed Aug 12, 2009. http://emedicine.medscape.com/article/137015-overview
4. Wantanabe JM, Dale DC. Chapter 13: Congenital Neutropenia. In: Young NS, Gerson SL, High KA. Clinical Hematology. Mosby Elsevier: Philadelphia 2006. P 190 – 1.