The clinical presentation of WAS includes several key findings [3]:

• Bleeding abnormalities - As a result of thrombocytopenia, petechiae, epistaxis, hematemesis and melena are seen in the majority of patients and one of the earliest diagnostic clues may be excessive hemorrhage after circumcision. In 30% of cases, life-threatening gastrointestinal or intracranial hemorrhage can occur.
• Skin changes - Eczema in infancy and childhood is a constitutive feature of WAS.
• Infections - Recurrent bacterial, viral or opportunistic infections, like eczema, are invariably reported by patients, examples being bacterial pneumonia, pneumocystis jiroveci pneumonia (PJP) and various skin infections.

The diagnosis mandates a thorough patient history regarding the course of symptoms, but establishing their presence in other family members may significantly aid in making the diagnosis. To confirm WAS, however, laboratory studies identifying thrombocytopenia and a smaller diameter of platelets is necessary, coupled with genetic testing to determine WASP mutations [3].

Hematopoietic cell transplantation (HCT) is currently the only therapeutic procedure for WAS, but it is associated with significant complications - an increased frequency of autoimmune events, development of hematologic malignancies (B-cell lymphoma, large-cell lymphoma, myelodysplasia and lymphoproliferative disorders have all been documented) and infections (particularly viral) [4]. Stem-cell gene therapy for WAS is a novel therapeutic modality that is still in the phase of research, but its application in clinical practice might substantially increase survival and reduce the burden of WAS [5] [6].

With current therapy, the prognosis of patients suffering from WAS is poor, as median survival rates are approximately 15 years and most common causes of death are an infection, bleeding and the appearance of malignant diseases (mainly lymphoproliferative disorders) [2].

X-linked mutations of WASP in hematopoietic cells is the underlying cause of WAS, but the events that trigger these mutations remain unknown [1] [4].

An incidence rate of 1-4 per 1 million patients is established and the diagnosis is most frequently made around 24 months of age in patients without a positive family history [4]. Given the fact that WAS is an X-linked disorder, virtually all patients are males and very few cases of female WAS have been described in the literature [7].

WAS protein (WASP) is one of the key proteins involved in the polymerization of actin in hematopoietic cells, influencing processes such as cell signaling, locomotion, and formation of immunologic synapses [6]. In the setting of mutations that impair its function, the activity of B and T cells, as well as the formation of platelets, is suppressed, leading to various forms of immunodeficiency, depending on the severity of mutations [4].

Current prevention strategies are aimed at reducing the risk of infections by prophylactic use of antibiotics and antiviral agents, immunosuppressive therapy if there is clinical suspicion of autoimmunity, and platelet transfusion to minimize the risk of bleeding [3].

Wiskott-Aldrich syndrome (WAS) is a rare form of primary immunodeficiency that stems from X-linked mutations in the WAS gene, coding for WAS protein (WASP) expressed only in hematopoietic cells [1]. WASP is involved in the polymerization of actin, which is essential for cell locomotion and signaling, but specific mutations lead to its dysfunction and absence in hematopoietic lineages [2]. As a result, impaired B and T cell activity, defects in phagocytosis and platelet abnormalities develop, causing immunodeficiency [2]. Hence, recurrent pyogenic, viral or opportunistic infections occurring exclusively in males are a clinical hallmark of WAS, as are thrombocytopenia, eczema and an increased incidence of lymphoproliferative disease [3]. The diagnosis is made based on clinical findings and laboratory studies, but it should be mentioned that a strong correlation between genotypes and phenotypes exist (milder mutations are associated with X-linked thrombocytopenia and X-linked neutropenia, or XLT and XLN, respectively) [4]. Hematopoietic cell transplantation is currently the mainstay of therapy [3], but the prognosis of WAS patients is rather poor, with median survival being around 15 years despite available therapy [2]. Gene therapy, however, has been evaluated in the treatment of WAS and is showing promising results [5] [6].

Wiskott-Aldrich syndrome is a rare genetic disorder seen in approximately 1-4 per 1 million individuals, and stems from mutations in WAS protein, one of the key molecules involved in maintaining the structure of red and white blood cells, as well as platelets. Because mutations are located on the X chromosome, only male individuals can develop WAS, as they carry only one copy of the genes that code for the aberrant protein. Consequences of mutations are a very early onset of eczema, recurrent infections (including viral, bacterial and fungal) and episodes of bleeding due to reduced platelet count, which may be life-threatening if not recognized on time. The initial diagnosis is made on clinical grounds and patient history, whereas confirmation requires laboratory studies to confirm low platelet count (and a very small size of platelets) and genetic tests. Transplantation of hematopoietic stem cells is the only therapeutic measure, but the overall prognosis is poor, as patients infrequently reach adulthood.

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5. Bosticardo M, Ferrua F, Cavazzana M, Aiuti A. Gene therapy for Wiskott-Aldrich Syndrome. Curr Gene Ther. 2014;14(6):413-21.
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7. Boonyawat B, Dhanraj S, Al Abbas F, Zlateska B, Grunenbaum E, Roifman CM, et al. Combined de-novo mutation and non-random X-chromosome inactivation causing Wiskott-Aldrich syndrome in a female with thrombocytopenia. J Clin Immunol. 2013;33(7):1150-1155.