Wiskott-Aldrich syndrome is an immunodeficiency hereditary disease characterized by eczema, hemorrhagic syndrome, a high probability of developing tumors, infectious and autoimmune diseases. The key symptoms are prolonged bleeding from injuries, frequent nosebleeds and hematomas, recurrent bacterial, fungal and viral infections, skin rash, provoking itching and burning sensation. The diagnosis is established on the basis of a clinical and anamnestic examination, the results of a general blood test, an immunity study and a biogenetic test. Treatment includes hematopoietic cell transplantation and palliative therapy.
ICD 10
D82.0 Wiskott-Aldrich syndrome
General information
As a synonym for Wiskott-Aldrich syndrome (WAS), the term eczema-thrombocytopenia-immunodeficiency syndrome is used, as well as the abbreviation WAS, derived from the English “Wiskott-Aldrich syndrome”. The disease is named after the surnames of American researchers. E. Wiskott in 1937 described clinical cases of thrombocytopenia in combination with eczema and recurrent infections in boys from the same family, in which all the girls were healthy. R. Aldrich in the late 80s and early 90s established that the pathology is hereditary and linked to sex, determined the location of the gene with the defect. The prevalence of the syndrome is extremely low – 1 case per 1 million newborn boys. Isolated cases of this disease have been noted in girls, which is associated with insufficient inactivation of the defective X chromosome.
Causes
WAS is a hereditary disease. The reason for its development is a mutation in the WAS gene responsible for the synthesis of immune cell protein. The gene is localized on the X chromosome in the region Xp11.23. Currently, more than 300 variants of WAS gene mutations have been identified, which lead to the development of X-linked thrombocytopenia, most often to microthrombocytopenia and neutropenia. The degree of manifestation of symptoms depends on the nature of the mutation – from a decrease in platelet levels, detected only by laboratory method, to a severe form of Wiskott-Aldrich syndrome with the addition of blood cancer, autoimmune pathology.
The type of inheritance of the syndrome is X-linked recessive. Men have only one X chromosome, if it turns out to be defective, the disease manifests itself. The father passes the mutation to all daughters, the sons get a normal Y chromosome. Women have two X chromosomes. A defective gene located in one of them is inactivated because it is recessive. The syndrome does not manifest itself, but women remain carriers of the mutation and with a 50% probability can pass it on to children of both sexes (sons are ill, daughters are carriers).
Pathogenesis
The genetic defect is manifested by a violation of the synthesis of the WASP protein, which is present in the cells of the immune system. It is produced by hematopoietic stem cells – the earliest precursors of blood elements located in the red bone marrow. WASP is involved in the restructuring and restoration of the cytoskeleton, the formation of immunological synaptic transmissions, intracellular protein transport. In its absence or insufficient production, defective platelets are formed, the functions of cells responsible for the reactions of innate and adaptive immunity are pathologically altered.
The process of blood clotting worsens, progressive immunodeficiency develops. The severity of the clinical manifestations of the syndrome partially depends on the cellular concentration of WASP, and its amount is determined by the localization and type of mutation. The symptoms are variable, most patients are diagnosed with mild to moderate severity. Severe course is rare.
Classification
There is no unified classification of Wiskott-Aldrich syndrome. In clinical practice, it is common to use a point system, which is based on the statement that all patients have thrombocytopenia, most of them have an immunodeficiency condition, and the rest of the symptoms may be absent. Taking into account these parameters , three forms of the disease are distinguished:
1 Easy its. It is characterized by the absence of eczema or mild, treatable eczema, rare infections. It is estimated at 1-2 points.
2 Classic middleweight WAS. It is manifested by relapses of infectious diseases and eczema, moderate autoimmune reactions. Corresponds to the 3rd and 4th points.
3 Classic heavy WAS. Patients suffer from recurrent infections, severe eczema, autoimmune pathologies and malignant neoplasms. Palliative treatment is ineffective. The severity of the syndrome is 5 points.
Symptoms
Clinical signs of thrombocytopenia are detected from birth. In infants, a petechial rash is visible on the surface of the skin – small red spots formed due to the rupture of small blood vessels and slow blood clotting. Ecchymoses are detected – subcutaneous hemorrhages of purple and bluish-black with a diameter of 3 mm. The stool contains blood impurities. There are frequent nosebleeds, bloody vomiting. A decrease in blood clotting is noted during invasive medical procedures, for example, after blood sampling for analysis.
Eczema usually manifests itself from childhood, but may be absent throughout life. In babies up to a year old, it is similar to seborrheic or diaper dermatitis. It is possible to develop a generalized form in which the skin of the entire body of the child is affected, or a local one characterized by rashes on the extremities. In older age, eczema is often limited to areas in the elbow bends, around the hands, under the knee joints, in the folds of the neck skin. In some patients, the rash is absent or manifests itself extremely rarely and weakly, does not require treatment.
Immunological disorders are characteristic of most patients. A decrease in the protective functions of the body leads to frequent otitis media, pneumonia, candidiasis, meningitis, enterocolitis, herpes and skin infectious pathologies. Chronic forms of infections develop with frequent relapses, the effectiveness of standard therapy is low. Autoimmune diseases occur in adults – patients are susceptible to hemolytic anemia, vasculitis, thrombocytopenic purpura, inflammatory lesions of the kidneys and intestines. With a classic severe WAS, malignant neoplasms form in adolescents and young people, the most common variant is non-Hodgkin’s lymphoma.
Complications
With WAS, there is a high risk of death. In 59% of cases, infectious diseases are the cause of death. Severe pneumonia and sepsis (blood poisoning) prevail among them. Against the background of infections, hemorrhagic syndrome increases, and intensive combing of areas affected by eczema provokes the development of fungal and bacterial skin diseases. About 21% of patients die as a result of internal bleeding. Intracranial, gastrointestinal and intra-pulmonary hemorrhages are life-threatening. In 12% of patients, oncopathology becomes the cause of early death, lymphomas and leukemias are the most common.
Diagnostics
Symptoms of thrombocytopenia in children with Wiskott-Aldrich syndrome appear immediately after birth, but the diagnosis is confirmed in the first or second year of life. The primary diagnosis is carried out by neonatologists and pediatricians with the participation of geneticists. In the course of differential diagnosis, thrombocytopenic purpura, hereditary thrombocytopenia with thalassemia and X-linked congenital dyskeratosis are excluded. A distinction is made with leukoplakia, lacrimal gland atresia, anemia and non-hereditary thrombocytopenia. A comprehensive examination includes the following procedures:
1 Survey. In a conversation with parents, it turns out the presence of thrombocytopenia and severe recurrent infections among male relatives, deaths of boys at an early age due to infections, hemorrhages and blood cancer. Complaints include skin rash, bleeding, frequent infectious diseases.
2 Physical examination. On examination, petechiae, ecchymoses, manifestations of atopic dermatitis, infectious foci on the skin are noted. The palpation method determines the increase in the size of lymph nodes, liver and spleen (lymphadenopathy, hepatosplenomegaly).
3 Laboratory tests. Blood tests are the most informative diagnostic methods. A number of tests are performed:
- Blood test. Thrombocytopenia is diagnosed with a decrease in the size of platelets. This feature is unique, it allows you to differentiate IT with other types of thrombocytopenia.
- Study of the immune status. From an early age, lymphocytopenia is detected in the immunogram with the most pronounced decrease in the number of CD8 lymphocytes. There is a violation of delayed hypersensitivity reactions, a decrease in the B-lymphocyte index, a decrease in the level of immunoglobulins M and G, an increase in the concentration of immunoglobulins A and E.
- WASP research. Protein expression is determined in cell cultures. The result allows you to confirm the diagnosis with a high probability and make a prognosis of the disease. The complete absence of WASP production is noted in severe forms of the syndrome.
- Molecular genetic analysis. Detection of the WAS gene mutation is performed by PCR with subsequent sequencing of reaction products. The presence of a defective gene confirms the alleged diagnosis. In some cases, the nature of the mutation is taken into account when making a forecast.
Treatment
The therapy is performed by hematopoietic stem cell or bone marrow transplantation. Transplantation of biomaterial of a healthy person makes it possible to completely eliminate hematological and immunological defects. When selecting a histocompatible donor, the effectiveness of such treatment reaches 84-90%. Before the introduction of HSC transplantation into medical practice, most patients lived only up to 6-6.5 years.
Additionally, palliative therapy is prescribed, which is represented by intravenous administration of immunoglobulin, preventive use of antiviral and antimicrobial drugs. With severe hemorrhagic syndrome, splenectomy can be performed – surgical removal of the spleen. After the procedure, there is an increase in the number and size of platelets. In acute bacterial infections, treatment with broad-spectrum antibiotics is indicated.
New developments in the treatment of WAS include gene therapy using lentiviruses. The essence of the method is the collection of autologous stem cells from the patient, the subsequent correction of a genetic defect in these cells using a lentiviral vector and the introduction of modified material into the body. In the course of therapy, the cells of the defective immune system are destroyed. Experimental studies of this method are being conducted, reports of its high efficiency have been received.
Prognosis and prevention
Modern methods of treatment have significantly increased the duration and improved the quality of life of patients. With a comprehensive approach to treatment, the prognosis is favorable. Prevention of the syndrome is impossible because the disease is hereditary. To calculate the probability of the birth of a sick child, medical and genetic counseling of at-risk couples is necessary. To prevent complications, it is recommended to strictly observe hygiene rules, exclude contact with infectious patients, avoid injury, use special hypoallergenic products for baby skin care, adhere to a diet that excludes allergens from food.
