X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment options

Albert, Michael H.; Bittner, Tanja C.; Nonoyama, Shigeaki; Notarangelo, Lucia Dora; Burns, Siobhan O.; Imai, Kohsuke; Español, Teresa; Fasth, Anders; Pellier, Isabelle; Strauß, Gabriele; Morio, Tomohiro; Gathmann, Benjamin; Noordzij, Jeroen G.; Fillat, Cristina; Hoenig, Manfred; Nathrath, Michaela; Meindl, Alfons; Pagel, Philipp; Wintergerst, Uwe; Fischer, Alain; Thrasher, Adrian J.; Belohradsky, Bernd H.; Ochs, Hans D.

doi:10.1182/blood-2009-09-239087

Cited by 180 publications

(188 citation statements)

References 39 publications

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“…In these subjects, splenectomy increases platelet count up to normal levels, but also results in higher incidence of severe infectious episodes [88]. These data indicate that the pros and cons of this treatment should be weighed for individual XLT patients.…”

Section: Splenectomymentioning

confidence: 96%

Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists

Pecci

2013

Int J Hematol

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Knowledge in the field of inherited thrombocytopenias (ITs) has considerably improved over the recent years. In the last 5 years, nine new genes whose mutations are responsible for thrombocytopenia have been identified, and this also led to the recognition of several novel nosographic entities, such as thrombocytopenias deriving from mutations in CYCS, TUBB1, FLNA, ITGA2B/ITGB3, ANKRD26 and ACTN1. The identification of novel molecular alterations causing thrombocytopenia together with improvement of methodologies to study megakaryopoiesis led to considerable advances in understanding pathophysiology of ITs, thus providing the background for proposing new treatments. Thrombopoietin-receptor agonists (TPO-RAs) represent an appealing therapeutic hypothesis for ITs and have been tested in a limited number of patients. In this review, we provide an updated description of pathogenetic mechanisms of thrombocytopenia in the different forms of ITs and recapitulate the current management of these disorders. Moreover, we report the available clinical and preclinical data about the role of TPO-RAs in ITs and discuss the rationale for the use of these molecules in view of pathogenesis of the different forms of thrombocytopenia of genetic origin.

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Section: Splenectomymentioning

confidence: 96%

Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists

Pecci

2013

Int J Hematol

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“…One of the 3 most common mutations is valine at position 75 (Val75Met), as was observed in the presented patients. This mutation was observed in 22 patients from 16 families in 7 countries [1]. A study that included 262 patients from 227 families (including Turkish cases) reported nonsense mutations 950 G>T at exon 9 and 1124 C>T at exon 10, missense mutations 138 T>A at exon 1, 290 C>T at exon 2, 1115C>A at exon 10, and 1542G>C at exon 12, as well as 1 splice mutation at exon 10 in the WASP gene of Turkish patients other than the mutation in the presented cases [8].…”

Section: Discussionmentioning

confidence: 99%

“…Splenectomized patients require life-long antibiotic prophylaxis. Stem cell transplantation must be considered on a patient-by-patient basis, as some XLT patients have excellent survival, where others have significant morbidity and mortality secondary to life threatening bleedings [1].…”

Section: Leblebisatan Et Al Familial Thrombocytopenia In a Turkish Fmentioning

confidence: 99%

“…XLT belongs to a disorder group related with the WAS gene family, which is expressed selectively in the hematopoietic stem cell-derived lineage that encodes WAS protein (WASP) functioning in cellular motility, the cytoskeleton, signaling, and apoptosis. According to the literature, the condition is common in Europe and Japan [1]; however, XLT with the detected mutational analysis is not common in Turkey. Herein we present 2 brothers with XLT mutation (223G>A, Val75Met), which to the best of our knowledge has not been previously described in a Turkish family.…”

Section: Introductionmentioning

confidence: 99%

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Wiskott-Aldrich syndrome mutation in two Turkish siblings with X-linked thrombocytopenia

Leblebisatan

Bay²,

Mitsuiki³

et al. 2011

Turk J Hematol

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Wiskott-Aldrich syndrome (WAS) is a clinical condition characterized by thrombocytopenia, eczema, and life-threatening infections. In some cases autoimmunity-related problems and even malignancy might be seen; however, some patients have milder clinical manifestations due to mutations in the same gene family, such as in X-linked thrombocytopenia (XLT), which is generally not associated with serious symptoms of disease, except for thrombocytopenia. Herein we report 2 siblings with chronic thrombocytopenia that were diagnosed with XLT based on a missense mutation in the WASP gene (223G>A, Val75Met). To the best of our knowledge this mutation has not been previously reported in a Turkish patient with XLT. (Turk J Hematol 2011; 28: 139-41) Key words: X-linked thrombocytopenia, Wiskott-Aldrich syndrome, WASP gene ÖzetWiskott Aldrich Sendromu (WAS) trombositopeni, egzema ve hayatı tehdit edici enfeksiyonlar ile karakterize klinik durumdur. Bazı vakalarda otoimmünite ile ilgili problemler hatta malign hastalıklar da görülebilmektedir. Bunların yanında aynı gen ailesinden köken alan bazı mutasyonlarda daha hafif klinik seyir görülmektedir. X'e bağlı trombositopeni bunlardan biri olup genellikle trombositopeni dışındaki ciddi semptomları taşımaz. Burada kronik trombositopenisi olan iki erkek kardeş, WASP geninde bir missens mutasyona bağlı X'e bağlı trombositopeni tanısı almaları nedeniyle sunulmuştur. Bu mutasyon bildiğimiz kadarıyla X'e bağlı trombositopeni tanılı Türk hastalarda daha önce bildirilmemiştir. (Turk J Hematol 2011; 28: 139-41)

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“…WAS mutations result in 3 distinct clinical phenotypes: classic WAS, XLT, and X-linked neutropenia, and a strong genotype phenotype correlation has been suggested. Mutations completely averting WAS protein (WASP) expression typically lead to the classic phenotype [3]. The classic WAS phenotype with microthrombocytopenia, severe eczema, increased susceptibility to pyogenic and opportunistic infections, and increased risk of autoimmune disease and cancer usually leads to death in early childhood or adolescence if left untreated.…”

Section: Introductionmentioning

confidence: 99%

Successful Haploidentical Transplantation with High Doses of CD34+-Selected Peripheral Blood Stem Cells in Wiskott-Aldrich Syndrome: A Case Report

Ae¹

2017

Ann Hematol Oncol

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Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive, primary immunodeficiency, characterized by eczema, microthrombocytopenia, recurrent infection, and increased susceptibility to autoimmune diseases and lymphoreticular malignancies. To date, HSCT is the only curative therapy. HSCT using HLA-matched related or unrelated donors is highly successful in treating WAS, but these donors may not always be available. We describe a 20 months-old-boy with WAS, who was transplanted by using highly-purified, 16.11x106/kg CD34 + stem cells from his HLA 2-loci mismatched mother, because of lacking donor and suffering life threatening, ongoing sinopulmonary infections. Conditioning consisted of busulfan (16 mg/kg), cyclophosphamide (200 mg/kg), rabbit anti-thymocyte globulin (10 mg/kg) and fludarabine (160 mg/m 2 ). He received methylprednisolone for graft-versus-host disease (GvHD) prophylaxis. The time for neutrophil, platelet and erythrocyte recovery was 11 days, 14 days and 19 days, respectively. He showed immunologic reconstitution by day +180. He developed grade II aGVHD on day +12, and grade I cGVHD on day +240, resolution achieved in aGVHD with i.v. methylprednisolone and cyclosporine, in cGVHD with oral prednisolone. He is well and alive up to now six years after transplantation. He didn't have any serious infection. Fluorescence in situ hybridization analysis revealed sustained full donor-type engraftment and flow cytometric analysis revealed sustained immunologic reconstitution. The convenient results in this patient can encourage further investigation of the role of using 'high doses' of related haploidentical CD34-selected peripheral blood stem cells in patients with WAS at early stages of disease, before the beginning of severe, life-threatening complications.

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X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment options

Cited by 180 publications

References 39 publications

Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists

Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists

Wiskott-Aldrich syndrome mutation in two Turkish siblings with X-linked thrombocytopenia

Successful Haploidentical Transplantation with High Doses of CD34+-Selected Peripheral Blood Stem Cells in Wiskott-Aldrich Syndrome: A Case Report

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