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Wiskott–Aldrich Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Wiskott–Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency disorder that is attributable to mutations in the WAS gene on chromosome Xp11.23. Given its role in actin polymerization, receptor engagement, signaling transduction, and cytoskeletal rearrangement, truncation or absence of WASP caused by WAS missense or splicing variants, small or gross deletions/insertions, and complex rearrangements has serious consequences. This is exemplified by the decreased capacity of white blood cells to form immune synapses with foreign invaders, and the poor development and early death of platelets, leading to the triad of eczema, microthrombocytopenia, and recurrent middle ear infections, along with easy bruising/bleeding, bloody diarrhea, autoimmune disorders, and lymphoma, particularly in males. Establishment of WAS diagnosis requires the findings of congenital thrombocytopenia (<70,000 platelets/mm3), small platelets (platelet volume <7.5 fL), and at least one of other features (eczema, recurrent infections, autoimmune disease, malignancy, reduced WASP expression in a fresh blood sample, abnormal antibody response to polysaccharide antigens and/or low isohemagglutinins, or positive maternal family history of WAS). Further confirmation is obtained with molecular detection of a hemizygous WAS pathogenic variant. Management of WAS involves topical steroids for eczema, antibiotics for infections, immunomodulatory therapy for autoimmune disease, G-CSF and antibiotics for neutropenia, and HSCT for hematologic diseases [20,21].
Mucosal manifestations of immunodeficiencies
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Scott Snapper, Jodie Ouahed, Luigi D. Notarangelo
Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by eczema, congenital thrombocytopenia with small-sized platelets, and immune deficiency. The responsible gene, named WAS, maps at Xp11.2 and encodes for a protein involved in cytoskeleton reorganization in hematopoietic cells. Most patients with classical WAS have mutations that impair expression and/or function of Wiskott-Aldrich syndrome protein (WASp). However, some missense mutations are associated with a milder phenotype (isolated X-linked thrombocytopenia).
The Spleen
Published in E. George Elias, CRC Handbook of Surgical Oncology, 2020
Wiskott-Aldrich syndrome, a sex linked recessive disease seen in children is characterized by chronic thrombocytopenia, eczema, and immunological deficiencies both at the humoral and cellular levels. Patients with this syndrome may also have hereditary thrombocytopenia which differs from ITP in that the platelets in ITP have a near normal survival. In other words, hereditary thrombocytopenia is part of the Wiskott-Aldrich syndrome. The defective platelet production and their accelerated catabolism are considered the more likely causes of this chronic thrombocytopenia. These patients may benefit from splenectomy; however, they have a very high incidence of postoperative infections and all precautions should be made to avoid such complications.
Clinical, Laboratory Features and Clinical Courses of Patients with Wiskott Aldrich Syndrome and X–linked Thrombocytopenia–A single center study
Published in Immunological Investigations, 2022
Hacer Neslihan Bildik, Deniz Cagdas, Aysenur Ozturk Kura, Sevil Oskay Halacli, Ozden Sanal, Ilhan Tezcan
Wiskott Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disorder caused by mutations in the Wiskott Aldrich syndrome protein (WASp) gene, which is located on the short arm of the X chromosome (Xp11.22–p11.23) (Aldrich et al. 1954; Wiskott 1937). The classic form of WAS is characterized by microthrombocytopenia, severe immunodeficiency, and eczema (Aldrich et al. 1954; Orange et al. 2004; Sullivan et al. 1994; Wiskott 1937). Mutations result in decreased but not absent protein expression cause a milder presentation called X-linked thrombocytopenia (XLT) that is associated with thrombocytopenia and rarely with milder eczema and immunodeficiency (Ochs and Rosen 1999; Ochs et al. 1980). Additionally, activating mutation of the WASp gene on the GTPase-binding domain is defined as X-linked neutropenia (XLN), characterized by neutropenia and variable myelodysplasia.
Diagnosis of platelet function disorders: A standardized, rational, and modular flow cytometric approach
Published in Platelets, 2018
Oliver Andres, Katja Henning, Gabriele Strauß, Annerose Pflug, Georgi Manukjan, Harald Schulze
We then examined platelets of two non-related four year-old boys with Wiskott-Aldrich syndrome who had undergone allogeneic hematopoietic stem cell transplantation in their first year of life and whose donor chimerism in the platelet lineage fluctuated around 20%. Indeed, analysis revealed microthrombocytopenia characterised by reduced FSC and SSC signals (Figure 3A). While expression of the von Willebrand factor receptor, the collagen receptor and the integrin β1 subunit was widely normal, expression of the receptors for fibrinogen, laminin, or fibronectin was clearly diminished (Figure 3A). Whereas degranulation markers and PAC-1 binding reached normal values after ADP treatment, CD62P expression and fibrinogen receptor activation upon TRAP6 stimulation were markedly reduced (Figure 3B). Of note, values measured in infants and young children should be interpreted carefully due to altered receptor expression and function [17].
Clinical considerations in the hematopoietic stem cell transplant management of primary immunodeficiencies
Published in Expert Review of Clinical Immunology, 2018
Alexandra Laberko, Andrew R. Gennery
The importance of donor myeloid chimerism was also demonstrated in patients with Wiskott–Aldrich syndrome. Those with low levels of donor myeloid chimerism have an increased risk of developing autoimmune complications [11,48]. In patients with X-linked chronic granulomatous disease, 10–20% donor myeloid chimerism may be sufficient to prevent infection – and mixed donor/recipient T-lymphocyte chimerism does not seem to be important. However, given recent reports of significant autoinflammatory and autoimmune symptoms in female carriers of X-linked chronic granulomatous disease [33,34], full donor myeloid chimerism may be preferable, although to date there are no reports of similar symptoms in recipient partial chimeras. For other PIDs, such as hemophagocytic lymphohistiocytosis (HLH), low levels of donor chimerism are not associated with graft rejection or poor graft function [49]. Thus, 10–20% donor chimerism may be sufficient to prevent disease. In immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, very low levels of donor chimerism may be adequate as long as the defective immunological component is replaced by functional donor-derived cells [50]. For more recently described immunodeficiencies or PID with a strong predisposition to hematopoietic malignancies (e.g. DNA repair disorders), it is not clear what degree of myeloid chimerism is required to cure the disease, but the limited data suggest that high levels of chimerism are preferable [25,28,51].