Classic Wiskott-Aldrich Syndrome Research Articles

Impairment of cytokine production following immunological synapse formation in patients with Wiskott-Aldrich syndrome and leukocyte adhesion deficiency type 1

T cells following immunological synapse (IS) formation with antigen-presenting cells produce multiple cytokines through T cell receptor, integrin, and costimulatory signaling. Here, we investigated the cytokine profiles following IS formation in response to staphylococcal superantigen exposure in three adolescent patients with classical Wiskott-Aldrich syndrome (WAS) and in one patient with leukocyte adhesion deficiency (LAD) type 1. All WAS patients showed lower Th1 and Th2-skewed cytokine production; similar results were observed in the flow cytometric analysis of IFNγ- and IL-4-producing T cells. The patient with LAD type 1 with somatic mosaicism in 2% of CD8+ T cells showed lower Th1 and Th2 cytokine production than healthy controls. The patients with WAS were susceptible to infections and atopic manifestations, and the patients with LAD type 1 showed cold abscess on their skin, our findings using patient samples provide clinical insights into the mechanisms underlying immunodeficiency related to the symptoms of each disease.

Confirmed diagnosis of classic Wiskott–Aldrich syndrome in East Africa: a case report

IntroductionWiskott–Aldrich syndrome is a rare X-linked primary immunodeficiency that mostly presents with a classic triad of eczema, microthrombocytopenia, recurrent infections, and increased risk of autoimmunity/malignancies.Case presentationWe present an 8-month-old African male, born from nonconsanguineous parents and who presented with a history of eczematous skin rash since day 9 of life, with recurrent sinus infections, otitis media, and skin abscesses. An elder male sibling who had similar symptoms passed away during infancy. Investigations were consistent with microthrombocytopenia and significantly raised immunoglobulin E, while immunoglobulin A and immunoglobulin G were moderately elevated with normal immunoglobulin M. Genetic testing revealed the patient to be hemizygous for a pathogenic Wiskott–Aldrich syndrome gene variant (NM_000377.2:c.403C>T). He was managed conservatively with supportive treatment until he died a year later.ConclusionDespite Wiskott–Aldrich syndrome being a rare disease, it should be considered as a differential in any male child who presents with microthrombocytopenia and recurrent infections, especially in low-resource settings where genetic testing is not routinely available.

Clinical Features, Cancer Biology, Transplant Approach and Other Integrated Management Strategies for Wiskott-Aldrich Syndrome.

Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive inborn error of immunity (IEI) first described in 1937. Classic WAS is characterized by the triad of thrombocytopenia with small platelets, recurrent infections due to combined immunodeficiency, and eczema. Hematopoietic stem cell transplantation (HSCT) was the only curative option available for five decades, with excellent outcomes reported for matched sibling donors (MSD) and matched unrelated donors (MUD). More recently, alternative donor transplants such as umbilical cord blood (UCB) and haploidentical transplant have emerged as viable options due to improvements in better graft selection, cell dosing, and effective allograft manipulation measures. Gene therapy is another potential curative option with promising results, yet currently is offered only as part of a clinical trial.

Clinical and molecular characteristics of Wiskott-Aldrich Syndrome in five unrelated Chinese families.

Wiskott-Aldrich syndrome (WAS) also called the eczema-thrombocytopenia-immunodeficiency syndrome is a primary immunodeficiency disease with X-linked recessive inheritance caused by mutations in the WAS protein (WASp) gene and characterized by thrombocytopenia with reduced platelet volume, eczema, immunodeficiency, and increased risk of malignant tumours. The mutations will lead to separate WAS severity which can be typical severe 'classical' WAS or less severe 'non-classical' WAS. This article will review and analyse clinical and immune characteristics of five unrelated Chinese families harbouring classical and non-classical WAS. The expression of WASp was detected in the peripheral blood monocytes (PBMC) by flow cytometry, and five mutations were found by WAS gene sequencing, one of which had not been reported in the literature, namely frameshift mutation c.1240_1247delCCACTCCC (p. P414Sfs*41).

Outcome of Children with Wiskott-Aldrich Syndrome (WAS) Given TCR Alpha-Beta/CD19 Depleted Hematopoietic Stem Cell Transplantation (HSCT) from an HLA-Haploidentical Relative

Background: WAS is a rare X-linked recessive disorder, characterized by thrombocytopenia with low platelet volume, recurrent infections, eczema, autoimmunity, vasculitis and increased incidence of malignancies. Patients with classical WAS have chronic morbidities, severely impaired quality of life and a decreased life expectancy. Allogeneic HSCT is the only well-established curative treatment, gene therapy being still an experimental approach. Excellent outcome have been reported in patients transplanted at early age from either matched related and unrelated donors, with 5-year overall survival (OS) exceeding 90%. However, experience with HLA-haploidentical HSCT is limited and has been historically associated with inferior results. Haploidentical HSCT after selective depletion of α/β+ T-cells and CD19+ B-cells (TBdepl-haploHSCT) was shown to be safe and effective in children with multiple types of non-malignant disorders (Merli et al, Blood Adv 2021). To further optimize this approach and accelerate the recovery of adaptive immunity, we conducted a phase I/II trial evaluating the safety and efficacy of post-transplant infusion of a titrated number of donor T-cells transduced with the inducible caspase-9 (iC9) suicide gene (BPX-501, or rivogenlecleucel, cells) in children with either malignant or non-malignant disorders (ClinicalTrials.gov identifier: NCT02065869). We report the outcome of a cohort of 12 children affected by WAS who received a TBdepl-haploHSCT at our Center.Patients and methods: Between 2014 and 2021, 12 patients affected by WAS received a TBdepl-haploHSCT from an HLA-partially matched relative at Ospedale Pediatrico Bambino Gesù in Rome, Italy. Patients and transplant characteristics are depicted in Table 1. All patients received a myeloablative conditioning regimen, combining pharmacokinetic-adjusted busulfan with Thiotepa and Fludarabine. Pre-transplant anti-thymocyte globulins (from day -4 to day -2) were given to modulate bi-directional donor/recipient alloreactivity, while rituximab was administered on day -1 to prevent PTLD. No post-transplant pharmacological GvHD prophylaxis was employed. Eight subjects, enrolled in NCT02065869 trial, additionally received post-transplant infusion of BPX-501 cells (dose: 1x10 6 cells/kg) at a median time of 16 days after HSCT (range 12-20).Results: 11 patients achieved primary donor cell engraftment, while one patient experienced secondary graft failure (GF), likely triggered by CMV reactivation. Median time to neutrophil and platelet recovery was 15 (range 8-33) and 10 days (range 9-16), respectively. The patient with secondary GF was successfully re-transplanted with a second TBdepl-haploHSCT from the same donor. Grade I/II skin acute GvHD (aGvHD) occurred in 3 patients, the cumulative incidence of aGvHD being 25.9% (95% CI 0-47.7). None of these 3 patients required activation of iC9 with rimiducid and no cases of chronic GVHD (cGvHD) were observed. No patient died. With a median follow-up of 58 months (range 1 - 78), the 5-year probability of OS and event-free survival is 100% and 90.7% (95% CI 50.8-98.7), respectively. Considering the successful second allograft, the 5-year disease-free survival is 100%. Platelet recovery is reported in Figure 1A. Two months after the allograft, all evaluable subjects had a platelet count above 50.000/microL (median 202.000, range 53.000-353.000). All subjects but one have full donor chimerism at last follow-up, the remaining patient having stable mixed chimerism (40% of donor cells) without any WAS manifestation. All subjects with a follow-up of at least 6 months are independent of immunoglobulin replacement. Details on reconstitution of lymphocytes subsets are reported in Figure 1B,C,D.Conclusions: TBdepl-haploHSCT after Bu-based conditioning regimen is an highly-effective curative option for children with WAS, being characterized by high-engraftment rate with fast recovery of both neutrophils and platelets, low incidence of aGvHD and no occurrence of cGVHD. Given the prognostic impact of age in determining HSCT outcome in WAS and prompt availability of haploidentical family donors, our data suggest that this approach should be offered without delay to those patients with WAS who lack a matched donor. Infusion of BPX-501 cells contribute to accelerate the recovery of adaptive T-cell immunity, further increasing the safety of the procedure. [Display omitted] DisclosuresMerli: SOBI: Consultancy; JAZZ: Consultancy. Locatelli: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyl: Honoraria.

The WASP P460S Mutation Causes a New Phenotype of WASP Mutations Related Disorder: X-Linked Pancytopenia

Mutations of the Wiskott-Aldrich Syndrome Protein (WASP) are responsible for a rare and severe disease: Wiskott-Aldrich Syndrome (WAS), including classic Wiskott-Aldrich Syndrome (WAS), X-linked thrombocytopenia (XLT), and congenital X-linked neutropenia (XLN). Classic WAS patients present typical WAS manifestation: eczema, thrombocytopenia, small platelet and recurrent infection, while XLT patients present thrombocytopenia, and XLN patients present congenital neutropenia. Bone marrow failure (BMF) is a series diseases characterized by pancytopenia in peripheral-blood(PB), different degree of bone marrow hypocellularity. In this study, we present two unrelated boys with pancytopenia who were admitted to our hospital on account of declining blood cells and different degree of hematopoietic failure. We identified a new WAS gene mutation C1378T inducing the WASP P460S mutation in both penitents by the second generation sequencing. Furthermore, one case developed T cell acute lymphoblastic leukemia (T-ALL) after severe pancytopenia recovered for 4 years and relapsed in mediastinum transplanted with cord blood for 1 year, another case recovered after haploidentical transplantation and kept stable for 1 year. To date, the role of WAS gene mutation in aplastic anemia-like hematopoietic failure remains unknown. We further verified WASP P460S mutation in these two patients by Sanger sequencing. In patient's PB cells, normal expression level of total WASP proteins was detected. This notion was different from general WASP deficiency classic WAS or XLT patients. To test the function of WASP P460S mutation in pancytopenia, we examined the effect of WASP P460S mutation on cell proliferation. Human myelogenous leukemia K562 cell line, which lacks endogenous WASP, was transfected with lentivirus vectors carrying mutant or wild type of WAS gene. We found that the cells expressing WASP P460S grew significantly slower than the cells expressing the wild type. Moreover, actin polymerization assay showed that increased actin polymerization function in WASP P460S mutation compared with wild type. In addition, P460S mutation had no obvious effect on Daunorubicin-induced apoptosis response. Our findings revealed that the WASP P460S mutation played a role in the inhibition of cell proliferation and actin polymerization which may lead to a new phenotype for WASP mutation related X-linked pancytopenia. DisclosuresNo relevant conflicts of interest to declare.

Identification of a novel WAS mutation in a South African patient presenting with atypical Wiskott-Aldrich syndrome: a case report

BackgroundThe X-linked recessive primary immunodeficiency disease (PIDD) Wiskott-Aldrich syndrome (WAS) is identified by an extreme susceptibility to infections, eczema and thrombocytopenia with microplatelets. The syndrome, the result of mutations in the WAS gene which encodes the Wiskott-Aldrich protein (WASp), has wide clinical phenotype variation, ranging from classical WAS to X-linked thrombocytopaenia and X-linked neutropaenia. In many cases, the diagnosis of WAS in first affected males is delayed, because patients may not present with the classic signs and symptoms, which may intersect with other thrombocytopenia causes.Case presentationHere, we describe a three-year-old HIV negative boy presenting with recurrent infections, skin rashes, features of autoimmunity and atopy. However, platelets were initially reported as normal in numbers and morphology as were baseline immune investigations. An older male sibling had died in infancy from suspected immunodeficiency. Uncertainty of diagnosis and suspected severe PIDD prompted urgent further molecular investigation. Whole exome sequencing identified c. 397 G > A as a novel hemizygous missense mutation located in exon 4 of WAS.ConclusionWith definitive molecular diagnosis, we could target treatment and offer genetic counselling and prenatal diagnostic testing to the family. The identification of novel variants is important to confirm phenotype variations of a syndrome.

Lentiviral gene therapy corrects platelet phenotype and function in patients with Wiskott-Aldrich syndrome

BackgroundThrombocytopenia is a serious issue for all patients with classical Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) because it causes severe and life-threatening bleeding. Lentiviral gene therapy (GT) for WAS has shown promising results in terms of immune reconstitution. However, despite the reduced severity and frequency of bleeding events, platelet counts remain low in GT-treated patients.ObjectiveWe carefully investigated platelet defects in terms of phenotype and function in untreated patients with WAS and assessed the effect of GT treatment on platelet dysfunction.MethodsWe analyzed a cohort of 20 patients with WAS/XLT, 15 of them receiving GT. Platelet phenotype and function were analyzed by using electron microscopy, flow cytometry, and an aggregation assay. Platelet protein composition was assessed before and after GT by means of proteomic profile analysis.ResultsWe show that platelets from untreated patients with WAS have reduced size, abnormal ultrastructure, and a hyperactivated phenotype at steady state, whereas activation and aggregation responses to agonists are decreased. GT restores platelet size and function early after treatment and reduces the hyperactivated phenotype proportionally to WAS protein expression and length of follow-up.ConclusionsOur study highlights the coexistence of morphologic and multiple functional defects in platelets lacking WAS protein and demonstrates that GT normalizes the platelet proteomic profile with consequent restoration of platelet ultrastructure and phenotype, which might explain the observed reduction of bleeding episodes after GT. These results are instrumental also from the perspective of a future clinical trial in patients with XLT only presenting with microthrombocytopenia.

How I manage patients with Wiskott Aldrich syndrome.

Wiskott Aldrich syndrome (WAS) is a primary immunodeficiency disease resulting in recurrent infections, eczema and microthrombocytopaenia. In its classical form, significant combined immune deficiency, autoimmune complications and risk of haematological malignancy necessitate early correction with stem cell transplantation or gene therapy. Amilder form, X-linked thrombocytopaenia (XLT), shares similar bleeding risk from thrombocytopaenia but is not associated with other significant clinical features and is generally managed conservatively. Here, we detail our approach to the diagnosis and treatment of classical WAS and XLT.

Evaluation of Classic Wiskott Aldrich Syndrome with Mild Symptoms in Two Cousins: A Case Report

Introduction: Wiskott–Aldrich syndrome (WAS) is characterized by microthrombocytopenia, eczema, recurrent infections, and an increased incidence of autoimmunity. Commonly, classicWAS is presented with severe clinical symptoms. Case Presentation:We report a new phenotype of classic Wiskott–Aldrich syndrome with mild symptoms in two cousins who were 7 years old. They had not severe infections or hemorrhage, in spite of having genetic mutation in WAS gene. The symptoms and infections of the patients responded to treatment with IVIG and antibiotics. Conclusions: This report is presenting a novel clinical phenotype of classicWAS with milder symptoms.

Defective thymic output in WAS patients is associated with abnormal actin organization

Wiskott-Aldrich syndrome protein (WASp) is a key regulator of the actin cytoskeleton. Defective T - cell function is a major cause for immune deficiency in Wiskott-Aldrich syndrome (WAS) patients. T cells originate in the bone marrow and develop in the thymus, and then migrate to peripheral tissues. TCR excision circles (TRECs) present in thymic output cells stably, which is used as a molecular marker for thymic output. We found that CD8+ T naïve cells of classic WAS patients were significantly reduced, and TRECs in patients with classic WAS and X-linked thrombocytopenia (XLT) dramatically decreased compared with that of HCs. TRECs were also reduced in WAS (KO) mice. These suggest that defective thymic output partially accounts for T cell lymphopenia in WAS patients. However, the correlation between the defect of thymic output and actin organization still remains elusive. We found that the subcellular location and the levels of of F-actin were altered in T cells from both WAS and XLT patients compared to that of HCs with or without stimulation. Our study shows that WASp plays a critical role in thymic output, which highly correlates with the subcellular location and level of F-actin in T cells.

A risk factor analysis of outcomes after unrelated cord blood transplantation for children with Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome is a severe X-linked recessive immune deficiency disorder. A scoring system of Wiskott-Aldrich syndrome severity (0.5–5) distinguishes two phenotypes: X-linked thrombocytopenia and classic Wiskott-Aldrich syndrome. Hematopoietic cell transplantation is curative for Wiskott-Aldrich syndrome; however, the use of unrelated umbilical cord blood transplantation has seldom been described. We analyzed umbilical cord blood transplantation outcomes for 90 patients. The median age at umbilical cord blood transplantation was 1.5 years. Patients were classified according to clinical scores [2 (23%), 3 (30%), 4 (23%) and 5 (19%)]. Most patients underwent HLA-mismatched umbilical cord blood transplantation and myeloablative conditioning with anti-thymocyte globulin. The cumulative incidence of neutrophil recovery at day 60 was 89% and that of grade II–IV acute graft-versus-host disease at day 100 was 38%. The use of methotrexate for graft-versus-host disease prophylaxis delayed engraftment (P=0.02), but decreased acute graft-versus-host disease (P=0.03). At 5 years, overall survival and event-free survival rates were 75% and 70%, respectively. The estimated 5-year event-free survival rates were 83%, 73% and 55% for patients with a clinical score of 2, 4–5 and 3, respectively. In multivariate analysis, age <2 years at the time of the umbilical cord blood transplant and a clinical phenotype of X-linked thrombocytopenia were associated with improved event-free survival. Overall survival tended to be better in patients transplanted after 2007 (P=0.09). In conclusion, umbilical cord blood transplantation is a good alternative option for young children with Wiskott-Aldrich syndrome lacking an HLA identical stem cell donor.

A novel mutation of WAS gene in a boy with Mycobacterium bovis infection in spleen.

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disorder caused by mutations of the gene encoding WAS protein (WASp). A scoring system has been used to grade severity of the disease. However, the phenotype of the disease may progress over time, especially in children younger than 2 years of age. Here, we report a male child who presented with X-linked thrombocytopenia (XLT). Mutation analysis revealed a novel hemizygous 13-bp deletion (c.181_193delGCTGAGCACTGGA) on exon 2 of the WAS gene. This frameshift mutation resulted in a premature terminating codon at position 71 (p.A61fsX10). Molecular analysis of maternal DNA revealed a heterozygosity of the same mutation. The disease progressed to classic WAS within 8 months. Later, gastric varices as a consequence of Mycobacterium bovis infection in the spleen was detected. The rapid worsening of the disease may be due to the severe genotype of this patient.

Endovascular repair of descending thoracic aortic aneurysm in patient with Wiskott-Aldrich syndrome

An association has been reported between Wiskott-Aldrich syndrome and necrotizing vasculitis and aneurysmal arterial dilatation. We present here the first endovascular repair of descending thoracic aortic aneurysm in a 35-year-old male patient with the classical Wiskott-Aldrich syndrome phenotype. He had a successful endovascular repair with early discharge from hospital with no postoperative complications. His 1-year follow-up computed tomography scan confirmed appropriate stent position, aneurysm sac resolution with no evidence of endoleak, and no further aneurysm formation.

Clinical and Molecular Characterization of Thai Patients with Wiskott–Aldrich Syndrome

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive primary immunodeficiency disorder caused by mutations in the gene encoding the WAS protein (WASP). Classic WAS is characterized by thrombocytopenia with small-sized platelets, recurrent infections, eczema and increased susceptibility to autoimmune diseases and haematologic malignancies. Here, we reported on seven unrelated Thai individuals with classic WAS. In addition to clinical and immunologic characterization, mutation analysis by PCR-sequencing the entire coding region of WASP was performed. Recurrent and novel mutations were successfully identified. A nonsense mutation, the c.55C>T (p.Q19X), has not been previously described, expanding the mutational spectrum of WASP. The patient with this newly described mutation developed cow's milk allergy manifesting as angioedema and urticaria and had cytomegalovirus infection that was successfully treated with long-term ganciclovir. This study reported long-term follow-up of seven patients with molecular confirmation of WAS and infrequent features in the patient with classic WAS carrying the novel nonsense mutation.

IVS6+5G>A found in Wiskott-Aldrich syndrome and X-linked thrombocytopenia in a Korean family

Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) are caused by a mutation in the WAS gene on Xp11.22. We report two patients with IVS6+5G>A of WAS in a Korean family. The proband presented with classic WAS, whereas his maternal cousin had symptoms limited to XLT. Their mothers were proved to be carriers. The IVS6+5G>A mutation was reported to result in incomplete splicing of the donor site and typically associated with mild form of disease, XLT. Our observation of the intrafamilial variability of clinical manifestations of WAS further expands the genotype-phenotype correlations and suggests the presence of modifying genetic factors.

Clinical spectrum, pathophysiology and treatment of the Wiskott–Aldrich syndrome

The Wiskott-Aldrich syndrome (WAS), caused by mutations in the WAS gene, is a complex and diverse disorder with X-linked inheritance. This review focuses on recent developments in the understanding of its basic pathophysiology, diverse clinical phenotypes and optimal patient management including novel therapies. The protein encoded by the WAS gene is a multifunctional signaling element expressed in immune and hematopoietic cells that plays a critical role in cytoskeletal reorganization, immune synapse formation and intracellular signaling. The type of specific mutation, its location within the gene and its effect on protein expression play a major role in determining an individual patient's clinical phenotype. Recent clinical observations and molecular studies have created a sophisticated picture of the disease spectrum. The improved outcome of stem cell transplantation from related and unrelated matched donors and promising early results from the first clinical gene therapy trial have added new therapeutic options for these patients. Classic WAS, X-linked thrombocytopenia and X-linked neutropenia are caused by WAS gene mutations, each having a distinct pattern of clinical symptoms and disease severity. New developments in the understanding of these syndromes and novel therapeutic options will have a major impact on the treatment of individuals with WAS mutations.

Clinical Aspects and Genetic Analysis of Taiwanese Patients with Wiskott–Aldrich Syndrome Protein Mutation: The First Identification of X-Linked Thrombocytopenia in the Chinese with Novel Mutations

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by microthrombocytopenia, eczema, and recurrent infections. However, the more than 500 patient mutations described are mainly based on Caucasian and Japanese populations. This study investigated Taiwanese patients with WASP mutations since 1985 as part of a long-term comprehensive study in primary immunodeficiency diseases (PIDs) covering 23 million inhabitants. Clinical manifestations, immunologic functions, and WASP gene sequencing and expressions were analyzed in WAS patients. And, those patients with idiopathic thrombocytopenic purpura and "small" thrombocytopenia were enrolled. Of 16 patients studied in 1993-2009, 12 presented as classic WAS phenotype and four had X-linked thrombocytopenia (XLT). Almost all correlated to the WASP expression level and severity of infections. Causes of mortality in the 12 classic WAS patients were mass bleeding, Staphylococcus aureus sepsis, and cytomegalovirus (CMV) pneumonitis in three non-transplant cases, and EBV-associated lymphoproliferative disorder and CMV pneumonitis in two non-engrafted transplant patients. Splicing mutations of Int 8 (+5) G>A in cousins and insertion of 1023 C in unrelated families presented as both XLT and classic WAS phenotype in the same mutations. Four XLT patients, including two novel mutations of 1023 Ins C (in 2) and "double" missense mutations of 1378 C>T and 1421 T>C had relatively higher CD4+ memory cells and/or activated lymphocytes (CD3+CD69+) compared with those of classic WAS patients. The lower ratio of XLT to classic WAS patients underestimates the burden of Taiwanese patients with WASP mutations, especially the XLT phenotype. A clustering pattern on exon 1 and five unique mutations (deletion of 45-48 ACCA, IVS 1 (-1) G>C, large deletion of promoter and exon 1 and 2, insertion 1023 C, and 1378 C>T and 1421 T>C) explain the genetic variations in different ethnic groups, despite the possibility of selection and ascertainment bias.

Characterization of  Wiskott–Aldrich syndrome (WAS) mutants usingSaccharomyces cerevisiae

Wiskott-Aldrich syndrome (WAS) is caused by alterations in the WAS protein (WASP), and 80% of the missense mutations are located in the WH1 domain, the region essential for interaction with the WASP-interacting protein (WIP). It has been suggested that loss of WASP-WIP interaction is causal to the disease. Las17p (yeast WASP) is essential for growth at 37 degrees C. The growth defect of the las17Delta strain can be suppressed by the expression of human WASP together with WIP. Using the las17Delta strain, we have analyzed 52 missense mutations in the gene encoding WASP and found that 13 of these mutant proteins were unable to suppress the growth defect of the las17Delta strain. The majority of these 13 mutations cause the classic WAS in humans and are located within the WH1 domain, while none of the 12 mutations outside the WH1 domain abolished the activity of WASP in Saccharomyces cerevisiae cells. This suggests that some of the mutations (13 out of 40) in the WH1 domain cause the syndrome in humans by perturbing the WASP-WIP complex formation, while the rest of the mutations cause the syndrome without affecting the WASP-WIP complex formation, but may affect the activity of the complex.

Clinical and Molecular Characteristics of 35 Chinese Children with Wiskott–Aldrich Syndrome

Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency disease, with an incidence of 4/1,000,000 live male births. In China, an estimated number of 35 babies with WAS are born each year, but likely many remain undiagnosed. The objectives of study were to review the clinical and molecular characteristics of a cohort of Chinese children with WAS and to describe the long-term outcome of those who underwent hematopoietic stem cell transplant (HSCT). Records of 35 patients diagnosed with WAS during 1991-2008 were reviewed. Genetic diagnosis was established by direct gene sequencing. All patients had classical WAS phenotype. WASP mutations were identified in 33 patients from 29 families. Nine patients underwent HSCT at a mean age of 22.1 months (match-unrelated donor, n = 5; mismatched related donor, n = 2; matched-sibling donor, n = 2). Post-transplant immune hemolytic anemia and thrombocytopenia occurred in three patients with complete resolution. All patients survived without significant long-term complications and had full platelet, T and B lymphocyte recovery within 2 years post-transplant. In the past decade, there has been significant improvement in clinical and genetic diagnosis of WAS in Chinese. We demonstrated excellent long-term survival in patients who underwent HSCT. Early workup for transplant should be advocated for children with classical WAS before they suffer from major disease complications and morbidities.