Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) (OMIM #301000) is an X-linked disorder characterized by microthrombocytopenia, eczema, and immunodeficiency. The incidence of the disease is approximately 1 in 250,000 male births.

History of the disease

In 1937, Wiskott first described three brothers with manifestations of thrombocytopenia, melena, eczema and frequent infections. In 1954, Aldrich suggested an X-linked inheritance pattern for the disease based on the description of several male patients from one family. In 1994, the gene whose mutations lead to the disease was mapped in two laboratories (Derry, Kwan). Despite the fact that more than 200 families with Wiskott-Aldrich syndrome have been described to date, the pathogenetic mechanisms of the disease have not been fully deciphered.

Pathogenesis of Wiskott-Aldrich syndrome

WAS is currently a disease involving a single gene, mapped by positional cloning and named WASP (Wiskott-Aldrich Syndrome Protein). The gene is located on Xp11.23 and consists of 12 exons.

The WASP protein is expressed exclusively in hematopoietic cells. Its function is not fully known, but it is assumed that WASP plays the role of a mediator of activating cellular signals and subsequent reorganization of the cellular skeleton.

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

Thrombocytopenia is found in all patients with Wiskott-Aldrich syndrome: the platelet count is usually less than 50,000/μl, and the platelet volume is reduced to 3.8-5.0 tl. Available studies suggest that thrombocytopenia in Wiskott-Aldrich syndrome is mainly due to increased platelet destruction.

Symptoms of Wiskott-Aldrich syndrome

The severity of disease manifestations 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 Wiskott-Aldrich syndrome and, as a result, 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.

Symptoms of Wiskott-Aldrich syndrome

Classification of Wiskott-Aldrich syndrome

There is currently no single classification system for WAS. The most commonly used is the scoring system described in the review by Ochs 1998. This system is based on the premise that all patients with WAS have microthrombocytopenia and that most, if not all, patients develop some degree of immunodeficiency. No history of eczema or mild, treatable eczema and mild, infrequent, uncomplicated infections correspond to a mild course of WAS (score 1–2). Severe eczema, recurrent infections that do not respond to treatment, autoimmune diseases, and malignancies are characteristic of the so-called classic WAS, which is scored at 3–4 (moderate) and 5 (severe).

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Diagnosis of Wiskott-Aldrich syndrome

Because Wiskott-Aldrich syndrome has a wide spectrum of clinical manifestations, the diagnosis should be considered in all boys with bleeding, congenital or early thrombocytopenia. Infections and immunological disorders may be absent or, conversely, pronounced. Some patients may develop autoimmune diseases.

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

Diagnosis of Wiskott-Aldrich syndrome

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Treatment of Wiskott-Aldrich syndrome

The first choice for treating WAS is hematopoietic stem cell transplantation (HSCT). Survival rates for WAS patients after HSCT from HLA-identical siblings are as high as 80%. Transplantation from HLA-identical unrelated donors is most effective in children under 5 years of age. In contrast to HSCT from an HLA-identical donor, the results of HSCT from partially matched (haploidentical) related donors have not been as impressive, although many Angoras report 50-60% survival, which is quite acceptable given the poor prognosis of the disease without HSCT.

Splenectomy reduces the risk of bleeding but is associated with an increased risk of septicemia. Splenectomy results in an increase in the number of circulating platelets and their size.

Treatment of Wiskott-Aldrich syndrome