Symptoms of Wiskott-Aldrich syndrome.

The severity of symptoms in patients with Wiskott-Aldrich syndrome varies from intermittent thrombocytopenia with minimal hemorrhagic manifestations to severe disease with pronounced infectious and autoimmune syndromes. Thus, at present, it has not been possible to establish a clear correlation between the severity of the disease and the type of mutation. Discrepancies between several groups of researchers can be explained by the lack of a clear classification of WAS and, as a consequence, researchers classify patients with similar disease severity differently. However, in general, most missense mutations in exon 2 are accompanied by a mild course of disease, nonsense and SRS mutations lead to severe Wiskott-Aldrich syndrome.

Hemorrhagic syndrome

The mean age at diagnosis of Wiskott-Aldrich syndrome in a 1994 study was 21 months, and 90% of patients had hemorrhagic syndrome at diagnosis. Because thrombocytopenia is usually present at birth, the disease may present with bleeding from the umbilical cord, as well as symptoms such as melena, epistaxis, hematuria, petechial rash, and life-threatening intracranial and gastrointestinal bleeding. In 1994, bleeding was noted as the leading cause of death in Wiskott-Aldrich syndrome.

Patients with Wiskott-Aldrich syndrome are often diagnosed with idiopathic thrombocytopenic purpura (ITP), which significantly delays the actual diagnosis.

In some patients with Wiskott-Aldrich syndrome, thrombocytopenia and hemorrhagic manifestations are the only symptoms of the disease, and for many years, before the gene responsible for this syndrome was identified, these patients were classified as having X-linked thrombocytopenia. On closer examination, some of them were found to have laboratory abnormalities of the immune response in the absence or minimal clinical manifestations of immunodeficiency.

Eczema or atopic dermatitis of varying severity usually appears in the first year of life and is often accompanied by local infection. In patients with a mild course of WAS, eczema may be absent or be mild and transient.

Infectious manifestations

Most patients with Wiskott-Aldrich syndrome develop progressive signs of immunodeficiency with age. Due to impaired humoral and cellular immunity, patients with moderate to severe Wiskott-Aldrich syndrome have frequent infections, which often occur in the first six months of life. The most common of these are otitis media (78%), sinusitis (24%), and pneumonia (45%). The same retrospective study showed that 24% of patients had sepsis, 7% had meningitis, and 13% had gastrointestinal infections. The most common pathogens are H. influenzae, S. pneumoniae, P. carinii, and C. albicans. Less common are viral infections, including chickenpox and herpes infections. Fungal infections are rare. In patients with mild Wiskott-Aldrich syndrome, frequent infections may not be mentioned.

Autoimmune diseases

According to Sullivan, autoimmune disorders are observed in 40% of patients with Wiskott-Aldrich syndrome. The most common are hemolytic anemia, vasculitis, and renal damage. Autoimmune disorders are characteristic of severe disease. Some patients develop more than one autoimmune disease. Often, WAS patients develop immune thrombocytopenia, accompanied by an increased level of platelet IgG. In patients with Wiskott-Aldrich syndrome, who have a normal platelet count as a result of splenectomy, a repeated decrease in the platelet count is sometimes observed as a result of a secondary autoimmune process.

Malignant neoplasms

Malignant neoplasms most often develop in adults or adolescents with Wiskott-Aldrich syndrome, but can also occur in children. The average age of development of malignant neoplasms in patients with Wiskott-Aldrich syndrome is 9.5 years. Previously, in WAS patients over 5 years old, the incidence of tumor diseases averaged 18-20%. With the increase in the life expectancy of patients with Wiskott-Aldrich syndrome due to improved medical care, the proportion of patients who develop tumor diseases has increased. Most tumors are of lymphoreticular origin, among them non-Hodgkin's lymphomas are most common, while neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma, etc., typical of childhood, are absent. Lymphomas are often extranodal and are characterized by an unfavorable prognosis.

Laboratory pathology

As stated above, the most consistent manifestation of Wiskott-Aldrich syndrome is thrombocytopenia with decreased platelet volume. Decreased platelet volume is a virtually unique symptom that allows differential diagnosis with other thrombocytopenias. Determination of functional characteristics of platelets in a clinical laboratory setting is not recommended, since this study is complicated by the decreased platelet volume of WAS patients.

Immune disorders in Wiskott-Aldrich syndrome include both humoral and cellular disorders. T-cell immunity disorders primarily include lymphopenia, which is observed in WAS patients from an early age. CD8 lymphocytes are reduced to a greater extent in patients. In addition, WAS patients have a decreased response to mitogens, decreased proliferation in response to stimulation with allogeneic cells and monoclonal antibodies to CD3, and impaired delayed-type hypersensitivity reactions to specific antigens. Delayed-type hypersensitivity reactions are impaired in 90% of patients. In the humoral link, there is a moderate decrease in B-lymphocytes, decreased IgM levels, normal or decreased IgG levels, and an increase in IgA and GdE. An interesting feature of the immune status of WAS patients is the relative and absolute increase in natural killers. There is evidence that this fact has pathogenetic significance.

Wiskott-Aldrich syndrome is also characterized by the inability of patients to synthesize antibodies to polysaccharide antigens. This defect was first described as the absence of isogenagglutinins in these patients. Later, it was shown that patients with Wiskott-Aldrich syndrome are unable to produce antibodies in response to such antigens as pneumococcal polysaccharides, lipopolysaccharide VI E. coli antigens of salmonella.

Standard studies of the neutrophil and macrophage links of immunity, including studies of neutrophil mobility, phagocytic response, and granule release, did not reveal any abnormalities. There are reports of impaired neutrophil and monocyte chemotaxis.