Wiskott-Aldrich Syndrome

Wiscott-Aldrich syndrome (WAS) (OMIM # 301000) is an X-linked disease, the main manifestations of which are microthrombocytopenia, eczema and immunodeficiency. The incidence of the disease is approximately 1 in 250,000 newborn boys.

History of the disease

Wiscott in 1937 first described three brothers with manifestations of thrombocytopenia, melena, eczema and frequent infections. In 1995, Aldrich suggested the X-linked nature of disease inheritance on the basis of a description of several male patients from the same family. In 1994, in parallel in two laboratories (Derry, Kwan), a gene was mapped, the mutations of which lead to the disease. Despite the fact that by now more than 200 families with Wiskott-Aldrich syndrome have been described, the pathogenetic mechanisms of the disease have not been fully deciphered.

Pathogenesis of Wiskott-Aldrich Syndrome

At the moment, WAS is a disease with the defeat of a single gene, modeled by positional cloning and named WASP (Wiskott-Aldrich Syndrome Protein). The gene is located on Xp11.23 and consists of 12 exons.

The protein WASP is expressed exclusively in cells of the hematopoietic series. Its function is not fully known, it is suggested that WASP plays the role of an intermediary of activation cellular signals and subsequent reorganization of the cell skeleton.

Mutations of the WASP gene include the entire possible spectrum: missense, nonsense, deletions, insertions, mutation splicing sites, and large deletions. The distribution of mutations along the length of the gene is uneven, although mutations were found in all 12 exons of the gene. Some mutations are located in the "hot spots" (C290T, G257A, G431A) - these mutations are found in multiple families.

Thrombocytopenia occurs in all patients with Wiskott-Aldrich syndrome: the number of platelets usually does not exceed 50,000 / μl, and the platelet count is reduced to 3.8-5.0 tl. Available studies suggest that thrombocytopenia in Wiscott-Aldrich syndrome is mainly associated with increased platelet destruction.

Symptoms of Wiskott-Aldrich Syndrome

The severity of the manifestations of the disease in patients with Wiskott-Aldrich syndrome varies from intermittent thrombocytopenia with minimal hemorrhagic manifestations to a severe disease with marked infectious and autoimmune syndromes. Thus, at the moment, there is no clear correlation between the severity of the disease and the type of mutation. The discrepancies between several groups of researchers can be explained by the lack of a clear classification of the Wiskott-Aldrich syndrome and, as a consequence, researchers classify patients with similar disease severity in different ways. However, in general, most missense mutations in 2 exons are accompanied by mild disease, nonsense and CDS mutations lead to severe Wiskott-Aldrich syndrome.

Symptoms of Wiskott-Aldrich Syndrome

Classification of Wiskott-Aldrich Syndrome

At the moment there is no unified classification of Wiskott-Aldrich syndrome. The most commonly used is the scoring system described in the Ochs 1998 review. This system is based on the claim that all WAS patients have microthrombocytopenia, and that the majority, if not all, develop an immunodeficiency of varying severity. No history of eczema or mild, treatable eczema and mild, non-frequent infections that go without complications, correspond to an easy flow of Wiskott-Aldrich syndrome (1-2 points). Severe eczema, recurrent infections, non-treatable, autoimmune diseases and malignant neoplasms are characteristic of the so-called classic Wiskott-Aldrich Syndrome, which is estimated at 3-4 points (moderate) and 5 points (severe).

[1], [2], [3]

Diagnosis of Wiskott-Aldrich Syndrome

Since Wiscott-Aldrich syndrome is characterized by a wide range of clinical manifestations, this diagnosis should be considered in all boys with bleeding, congenital or early-identified thrombocytopenia. Infections and immunological disorders may be absent or, conversely, be strongly pronounced. Some patients may develop autoimmune diseases.

According to the diagnostic consensus adopted by the ESID (European Society of Immunodeficiencies), the absolute criterion for diagnosing WAS is to detect a significant decrease in the WASP protein concentration in the blood cells and / or to detect a gene mutation.

Diagnosis of Wiskott-Aldrich Syndrome

[4], [5], [6], [7], [8], [9]

Treatment of Wiskott-Aldrich Syndrome

The first choice of WAS is the transplantation of hematopoietic stem cells (TSCC). Survival of patients with WAS after TRNC from HLA-identical siblings reaches 80%. Transplantation from HLA-identical unrelated donors is most effective in children under 5 years of age. Unlike TSCC from an HLA-identical donor, the results of TSCS from partially compatible (haploidentical) related donors were not so impressive, although many angoras describe a 50-60% survival rate, which is quite acceptable, given the poor prognosis of the disease outside the TSCC.

Splenectomy reduces the likelihood of bleeding, but is accompanied by an increased risk of septicemia. Splenectomy leads to an increase in the number of circulating platelets and an increase in their size.

Treatment of Wiskott-Aldrich Syndrome