Wiskott-Aldrich Syndrome

Wiskott-Aldrich syndrome is a primary immunodeficiency state that affects both T-lymphocytes and B-lymphocytes. In addition, platelets are affected – cells that help stop bleeding. For the classical form of the syndrome Wiskott-Aldrich characterized by a complex of disorders, which includes increased bleeding due to a decrease in the number of platelets, recurrent bacterial, viral and fungal infections, as well as skin eczema. After identifying the gene responsible for this disorder, we recognize that it is possible and easier forms of this condition with the presence of some, but not all of the above symptoms.
In 1937, Dr. Wiskott described three brothers with a low number of platelets (tromobocytopenia), bloody diarrhea, eczema and recurrent ear infections. Seventeen years later, in 1954, Dr. Aldrich showed that this syndrome is inherited as an X-linked recessive trait. In the 50’s and 60’s of the 20th century, signs of immune deficiency were detected, and Wiskott-Aldrich syndrome was included in the list of primary immunodeficiencies. Wiskott-Aldrich syndrome is a primary immunodeficiency state that affects both T-lymphocytes and B-lymphocytes. Thrombocytes are also hard to kill – cells that help stop bleeding. The classical form of NWO is a characteristic set of violations:
1. Increased bleeding, associated with a significant decrease in the number of platelets.
2. Recurrent bacterial, viral and fungal infections.
3. Skin eczema.
In addition, long-term follow-up of patients with SVO revealed in many patients an increased incidence of malignant tumors, for example, lymphomas and leukemias, as well as an increased incidence of different autoimmune diseases.
The cause of SVO are mutations (errors) in the structure of the gene responsible for protein production, the name of which corresponds to the name of the disorder – the protein of the syndrome Wiskott-Aldrich (Wiskott – Aldrich Syndrome Protein, WASP). The WASP gene is located in the short arm of the X chromosome. Most of these mutations are “unique.” This means that almost every family has its own characteristic mutation of the WASP gene. If the mutation is severe and almost completely eliminates the ability of the gene to produce a protein of the SVO, the patient develops a classic, heaviest form of SVO. On the contrary, if some ability to produce a mutant protein of CBO persists, an easier form of this disorder may develop.
CLINICAL MANIFESTATIONS
Clinical manifestations of the syndrome Wiskott-Aldrich (SVO) in different patients are different. Some patients have all three classic manifestations, including a decrease in the number of platelets and bleeding, immune deficiency and infections, and eczema.
In other patients, only a decrease in the number of platelets (thrombocytopenia) and bleeding is observed. In recent years, patients with only a decrease in the number of platelets were diagnosed with another disease – X-linked thrombocytopenia (X-CT). After identification of the SVO gene, it became clear that thrombocytopenia in SVO and X-ST is caused by a mutation of the same gene, and these diseases are different clinical forms of the same disorder. The first clinical manifestations of SVO can occur soon after birth or in the first year of life. These early clinical signs are directly related to any or all of the components of the classical clinical triad: bleeding due to low platelet count, pruritus, flaky skin rash and eczema and / or infection due to immunity disorders.
INCREASED BLEEDING
Reduction in the number of small platelets (thrombocytopenia) is a characteristic feature in all patients with NW. Since SVO is the only disorder in which small platelets are detected, their detection in the blood is a valuable test for the diagnosis of this disease. Intradermal hemorrhage caused by thrombocytopenia can lead to the formation of bluish-red spots the size of a pinhead, called petechiae, or larger spots resembling bruises. Patients with boys may also have blood in the stool (especially in the first year of life), bleeding from the gums and prolonged nasal bleeding. Hemorrhage in the brain is a dangerous complication, and some doctors recommend that young children with very low platelet counts (less than 15,000) wear a helmet to protect themselves from head injuries until treatment increases the number of platelets in their blood.
INFECTIONS
Because of the significant deficiency of the function of T- and B-lymphocytes, with classical SVO, infections that can be caused by any kind of microorganisms are frequent. These infections include upper respiratory tract and bronchial infections, otitis media, sinusitis and pneumonia. Heavier infections, for example, sepsis (circulatory blood infection or “blood poisoning”), meningitis and severe viral infections are less common. In infrequent cases in patients with classical SVO, pneumonia caused by Pneumocystis jiroveci (carinii) can develop. The skin can also be infected by various bacteria as a result of intense combing of the zones affected by eczema. In SVR also often there is a viral skin infection, called a contagious mollusk.
ECZEMA
Eczema is often observed with classical SVO. In the first year of life, the eczema may resemble seborrheic dermatitis, severe diaper dermatitis, or be generalized and affect the skin of the entire body and / or limbs. In older boys, eczema may be limited to folds of the skin in the elbow, around the hands or neck, and under the knee joints; in other cases, eczema can affect a significant part of the skin surface. Since eczema is accompanied by severe itching, sick boys often inflict bleeding bruises, even at night. In extremely severe cases, eczema can cause such a strong inflammation of the reddened skin that the boys emit heat into the environment, and they experience thermoregulatory disturbances. In some patients, eczema may be absent or have an easy form.
AUTOIMMUNE PROJECTS
In children of the first year of life, as well as in adults with SVO, “autoimmuno-like” symptoms are often observed. The term “autoimmune” refers to conditions resulting from a disorder in the regulation of the immune system, as a result of which it destroys the tissues of the patient’s own body. Among the most frequent autoimmune manifestations in patients with SVA is inflammation of the blood vessels (vasculitis), accompanied by fever and rash on the limbs; Sometimes these symptoms worsen after exercise. Another autoimmune disorder is anemia caused by antibodies that destroy the patient’s own red blood cells (hemolytic anemia). The decrease in the number of platelets can be enhanced by an autoimmune reaction in which the patient produces antibodies that attack the rest of the platelets (this condition is commonly called ITP or idiopathic thrombocytopenic purpura). Some patients have a more generalized disorder, in which periods of high fever can occur in the absence of infection, swelling of the joints, soreness of the lymph nodes and gastrointestinal disorders, for example diarrhea. In some cases, inflammation of the arteries (vasculitis), mainly in the muscles, heart, brain and other internal organs, which causes many symptoms. These episodes of autoimmune reactions can last only a few days or occur wavy for many years and are difficult to treat.
MALIGNANT NEOPLASMS
In young children, adolescents and adult patients with SVO can develop malignant tumors. Many of them affect B-lymphocytes and cause lymphoma or leukemia.
DIAGNOSIS
Due to the breadth of the spectrum of manifestations, the diagnosis of Wiskott-Aldrich syndrome (SVO) should be borne in mind when examining any boy with unusual bleeding and bruising congenital or beginning with thrombocytopenia and small platelets at an early age.
Typical platelet abnormalities, their low number and small size, can almost always be detected in the blood of the umbilical cord when the baby is born. The most simple and useful way to diagnose SVO is to count and carefully determine the size of platelets.
With SVO, platelets are usually smaller than normal. In older children (more than two years), it is also possible to detect various immunity disorders that can confirm the diagnosis. Some types of serum antibodies may be low or absent in boys with SVO. They usually have low levels of antibodies to group blood antigens (isogemagglutinins, for example, antibodies to A or B erythrocytes) and there is no production of antibodies for some vaccines containing polysaccharides or complex sugars, for example, the vaccine against Streptococcus pneumoniae (Pneumovax). Skin tests evaluating the function of T-lymphocytes may be negative, and laboratory studies of the function of T-lymphocytes may reveal abnormalities. The diagnosis is confirmed by the detection of a decrease in the level or absence of a protein in the blood vessels or the presence of a mutation in the WASP gene. These studies are conducted in a few very skilled laboratories using blood or other tissues.
INHERITANCE
SVO is inherited as a recessive trait linked to the X chromosome. They suffer only boys. Because this disease is hereditary and transmitted as a recessive trait linked to the X chromosome, similar manifestations can be found in the patient’s brothers or the mother’s brothers of the patient. Family history can be completely negative due to the small size of the family or in connection with the emergence of a new mutation. It is believed that about 1/3 of patients with newly diagnosed SVO cause the disease is a new mutation that occurs during the fertilization of the egg. If the exact nature of the WASP mutation in this family is not known, it is possible to perform prenatal DNA testing in cells obtained by amniocentesis, or in villi chorion.
TREATMENT
All children with severe chronic diseases need the support of parents and family members. The requirements for the parents of boys with CSEs, and the decisions they need to take, can be extremely serious. Progress in the field of therapeutic nutrition and antimicrobial therapy, the preventive use of replacement immunoglobulin and bone marrow transplantation significantly improved the prognosis of NWS regarding the life of patients. Because of increased blood loss, iron-deficient anemia is often encountered, requiring the addition of additional amounts of iron. In the presence of symptoms of infection, a thorough examination is necessary to detect a bacterial, viral or fungal infection and determine the most effective antimicrobial therapy.
Since the body’s reactions to vaccination and the invasion of microorganisms are violated during the CBO, prophylactic substitution administration of immunoglobulins can be shown to patients suffering from frequent bacterial infections. It should be noted that with a low number of platelets, most doctors prescribe intravenous immunoglobulins, since subcutaneous administration of immunoglobulins can cause intradermal or subcutaneous hemorrhage. The substitution of immunoglobulins is especially important if the patient underwent a therapeutic splenectomy. Eczema can be severe and persistent, so the patient may need constant help. Avoid excessive skin washing, as frequent washing can cause dry skin and worsen the course of eczema. Bathing should use bath oils, and after washing and several times a day, apply a moisturizer. Creams with steroid preparations often help with limited application to chronically inflamed areas, however their excessive use should be avoided. Do not apply strong steroid creams, for example, with fluorinated steroids, on the face. If any food substances lead to a worsening of eczema or food allergies are detected, it should be possible to exclude dangerous foods from the diet to the extent possible. In some cases, platelet transfusion may be required to treat a low platelet count and bleeding. For example, if severe bleeding can not be stopped by conservative measures, transfusion of platelets is indicated. With intracerebral hemorrhage, an immediate transfusion of platelets is usually required. Patients with NWS performed surgical removal of the spleen (lymphoid organ of the abdominal cavity, which “filters” the blood); It is shown that this operation eliminates the decrease in the number of platelets (thrombocytopenia) in more than 90% of cases. Surgical removal of the spleen does not cure other disorders characteristic of SVO and should be used only to eliminate thrombocytopenia in patients with a particularly low number of platelets. After removal of the spleen, the effectiveness of the substitution of high doses of immunoglobulins for the increase in the number of platelets in boys with SVE is significantly increased. Spleen removal increases the sensitivity of patients with CBO to certain infections, in particular circulatory blood infections and meningitis caused by encapsulated bacteria, for example, S pneumoniae or H influenzae. If removal of the spleen is performed, it is extremely important to prescribe a prophylactic introduction of antibiotics to the child and preferably a substitution of immunoglobulins, sometimes throughout life, to prevent these serious infections. Symptoms of autoimmune disorders may require the use of drugs that will further suppress the patient’s immune system. In this case, the substitutive administration of high doses of immunoglobulins and the systemic administration of steroids can help, and it is very important to reduce the dose of steroids as soon as possible to the lowest level that provides symptom control. Boys with SVR, like other children with primary immunodeficiencies with T- and / or B-lymphocyte lesions, should not be vaccinated with live viruses, since it is possible that the vaccine strain of the virus can cause disease. Sometimes complications arise after a chickenpox infection. They can be prevented by the appointment (immediately after contact with the patient) of antiviral drugs, the substitution of high doses of immunoglobulins or hyperimmune serum against herpes zoster. The only way to ensure a “permanent cure” from SVR is bone marrow transplantation or cord blood stem cells, and the search for an HLA-compatible donor should be started immediately after the diagnosis of SVO. Since some residual function of T-lymphocytes persists in patients with NDT, in spite of immunodeficiency, preparation of the patient with the help of drugs that suppress immunity and / or total irradiation is necessary before transplantation. If the sick boy has healthy siblings from the same parents, the whole family should perform typing of the tissues to identify HLA-identical sibling (with good tissue compatibility) that can become a donor for bone marrow transplantation. Bone marrow transplantation from HLA-identical sibling gives excellent results with SVO with a total success rate (cure) of 80-90%. This procedure is preferable for boys with severe clinical manifestations of CBO. The question of bone marrow transplantation from HLA-compatible sibling in patients with milder clinical forms, for example, with isolated thrombocytopenia, is more complex and requires discussion with an experienced immunologist. Success of transplantation from a compatible donor-non-relative has significantly increased over the past two decades. Transplantation from a fully compatible non-related donor is currently as successful as transplantation from a compatible sibling if performed at the age of the patient to 5-6 years and until significant complications, such as severe viral infection or cancer, occur. The frequency of transplant success from a fully compatible non-relative donor decreases with age, making it difficult to make decisions about such transplantation to adolescents or adult patients with NWS. Fully or partially compatible stem cells of the umbilical cord blood were successfully used to restore immunity and correct platelet abnormalities in several patients with CVD; One may consider the possibility of using this method in the absence of a compatible sibling or a fully compatible non-relative donor. In contrast to very good transplant outcomes from HLA-compatible donors, haploidentical bone marrow transplantation (as a donor is used by one of the parents) is much less successful than transplantation from HLA-compatible donors.
FORECAST
Thirty years ago the classical Wiskott-Aldrich Syndrome was one of the most severe primary immunity disorders with an expected life expectancy of only 2-3 years. Despite the fact that it remains a serious disease in which life-threatening complications are possible, many male patients live to adolescence or even adulthood, lead a productive life and have their own families. The oldest patient who has received bone marrow transplantation is now more than twenty or thirty years old and they seem to have recovered without the development of malignant tumors or autoimmune diseases.
The article is kindly provided by the worldwide organization IPOPI – working to improve the lives of people with primary immunodeficiency.
Copyright 2007 is owned by the Immune Deficiency Foundation, USA. “A guide to primary immunodeficiency diseases for patients and their families”, from which this material was taken under license, was developed by the Immune Deficiency Foundation with the support of Baxter Healthcare Corporation.
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