A 2-Year-Old Boy With Difficulty Waking After Bone Marrow Transplantation.

We report a 2-year-old boy who was evaluated for difficult waking during prolonged intensive care unit admission associated with bone marrow transplant for Wiskott-Aldrich syndrome. Neurologic examination was found to be abnormal, with nuchal rigidity initially, then decreased extremity movement and areflexia developing over several days. Electromyogram showed length-dependent, axonal, sensorimotor polyneuropathy. Cerebrospinal fluid showed albuminocytologic dissociation suggestive of Guillain-Barre syndrome or acute motor and sensory axonal neuropathy variant. The patient was treated with immunotherapy and slowly showed signs of motor recovery over several months. A review of Wiskott-Aldrich syndrome, Guillain-Barre syndrome, immune-mediated complications of bone marrow transplantation, and acute weakness in the intensive care unit is provided in this case report.

Lung transplantation after haematopoietic stem cell transplantation for Wiskott-Aldrich syndrome.

The authors report the first case involving a patient with Wiskott-Aldrich syndrome who underwent single living-donor lobar lung transplantation after haematopoietic stem cell transplantation. Haematopoietic stem cell transplantation was performed at 1 year of age; however, he developed severe pulmonary complications. Although lung transplantation is generally contraindicated in patients with immunodeficiency disease, the patient was able to undergo living-donor lobar lung transplantation because his immunodeficiency and thrombocytopenia were well controlled as a result of haematopoietic stem cell transplantation. Currently, the patient is doing well and is free from oxygen supplementation.

Un-manipulated Haploidentical Transplant in Wiskott-Aldrich Syndrome.

BACKGROUND: Allogeneic stem cell transplant is the only curative treatment for Wiskott-Aldrich syndrome. CASE CHARACTERISTICS: 18-months-old boy with no sibling, cord blood or matched unrelated donor transplant options. OUTCOME: Doing well 7 years after haplo-identical stem cell transplantation using unmanipulated bone marrow as the stem cell source. MESSAGE: Father as a haplo-identical donor is a feasible option.

Impact of conditioning on outcome of hematopoietic stem cell transplantation for wiskott-Aldrich syndrome.

Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for Wiskott-Aldrich syndrome (WAS). The aim of this retrospective study is to report the effect of the conditioning regimen and donor source on disease-free survival (DFS) in children undergoing HSCT for WAS. Fourteen children who underwent HSCT at 4 Israeli centers from 1996 to 2011 were included in this study. Five children were transplanted from matched related donors (4/5 siblings, 1/5 fully matched uncle) and other donors were used in 9 children. Six patients were conditioned with full dose busulfan/cyclophosphamide (Bu/Cy) whereas 8 patients were conditioned with other regimens. Thirteen of 14 patients (92.8%) are alive with a median follow-up of 3.4 years (range, 5 mo to 12.5 y). Nine patients (64.3%) survive with complete clinical, immunologic, and hematologic recovery. Children conditioned with full dose Bu/Cy had a 100% DFS, compared with children conditioned with other regimens, 25%±19% (P=0.022). Donor source was not associated with DFS. Graft failure was related to the use of conditioning regimens other than full dose Bu/Cy and not to the donor source. Further studies are required to determine the best conditioning regimen and optimal donor source for children with WAS.

Outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome.

HLA-identical sibling donor transplantation remains the treatment of choice for Wiskott-Aldrich Syndrome (WAS). Since 1990, utilization of alternative donor sources has increased significantly. We report the hematopoietic cell transplantation (HCT) outcomes of 47 patients with WAS treated at a single center since 1990. Improved outcomes were observed after 2000 despite the increased number of alternative donors. Five-year OS improved from 62.5% (95% CI: 34.9% to 81.1%) to 90.8% (95% CI: 67.7% to 97.6%) for patients transplanted during 1990-2000 and 2001-2009, respectively. In multivariate analysis, transplant era significantly impacted OS (P=0.04), whereas age was only marginally significant (P=0.06, Cox proportional hazard analysis). No TRM occurred within the first 100 days among patients transplanted during 2001-2009 compared with 3/16 during 1990-2000, (P=0.03, Fisher's exact test). The extent of HLA mismatch did not significantly affect the incidence of acute GVHD, chronic GVHD or survival. Post-HCT autoimmune cytopenias were frequently diagnosed after 2001: 17/31 (55%) patients. Their occurrence was not associated with transplant donor type (P=0.53), acute GVHD (P=0.74), chronic GVHD (P=0.12), or post-transplant mixed chimerism (P=0.50).

Prolonged survival after splenectomy in Wiskott-Aldrich syndrome: a case report.

Wiskott-Aldrich syndrome is a rare X-linked immunodeficiency disorder that is characterized by a variable clinical phenotype. Matched donor bone marrow transplantation is currently the only curative therapeutic option. We present the case of a 24-year-old male who was diagnosed at the age of seven with Wiskott-Aldrich syndrome. He did not respond to intravenous gammaglobulin and he experienced recurrent pulmonary infections despite prophylactic antibiotics. The patient had no matched donor. At the age of nine, he was submitted to splenectomy and his platelet count was normalized. Fifteen years later, the patient remains asymptomatic with a normal platelet count. He is still receiving prophylactic antibiotics and no bleeding episodes or septic complications have been reported. This case demonstrates that splenectomy can represent a safe therapeutic option in selected WAS patients, provided that there is a tight follow-up program, patient education and adherence to guidelines regarding post-splenectomy prophylaxis.

Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study.

In this retrospective collaborative study, we have analyzed long-term outcome and donor cell engraftment in 194 patients with Wiskott-Aldrich syndrome (WAS) who have been treated by hematopoietic cell transplantation (HCT) in the period 1980- 2009. Overall survival was 84.0% and was even higher (89.1% 5-year survival) for those who received HCT since the year 2000, reflecting recent improvement of outcome after transplantation from mismatched family donors and for patients who received HCT from an unrelated donor at older than 5 years. Patients who went to transplantation in better clinical conditions had a lower rate of post-HCT complications. Retrospective analysis of lineage-specific donor cell engraftment showed that stable full donor chimerism was attained by 72.3% of the patients who survived for at least 1 year after HCT. Mixed chimerism was associated with an increased risk of incomplete reconstitution of lymphocyte count and post-HCT autoimmunity, and myeloid donor cell chimerism < 50% was associated with persistent thrombocytopenia. These observations indicate continuous improvement of outcome after HCT for WAS and may have important implications for the development of novel protocols aiming to obtain full correction of the disease and reduce post-HCT complications.

Congenital cytomegalovirus infection and Wiskott-Aldrich syndrome successfully treated with unrelated cord blood transplantation.

We report a successful umbilical cord blood transplantation (UCBT) in an 8-month male with Wiskott-Aldrich syndrome (WAS) and congenital cytomegalovirus (CMV) infection. The child presented at 3 months of age with symptomatic thrombocytopenia and CMV infection. Despite appropriate antiviral treatment no rise in the platelet count was observed. Genetic analysis confirmed the diagnosis of WAS. The clinical course was complicated by severe CMV retinitis with bilateral retinal hemorrhages and renal vasculitis. He underwent unrelated UCBT resulting in a rapid resolution of autoimmunity and thrombocytopenia.

New insights into the biology of Wiskott-Aldrich syndrome (WAS).

The Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disease with a characteristic clinical phenotype that includes thrombocytopenia with small platelets, eczema, recurrent infections due to immunodeficiency, and an increased incidence of autoimmune manifestations and malignancies. The identification of the molecular defect in the WAS gene has broadened the clinical spectrum of disease to include chronic or intermittent X-linked thrombocytopenia (XLT), a relatively mild form of WAS, and X-linked neutropenia (XLN) due to an arrest of myelopoiesis. The pathophysiological mechanisms relate to defective actin polymerization in hematopoietic cells as a result of deficient or dysregulated activity of the WAS protein (WASp). The severity of disease is variable and somewhat predictable from genotype. Treatment strategies therefore range from conservative through to early definitive intervention by using allogeneic hematopoietic stem cell transplantation and potentially somatic gene therapy. All aspects of the condition from clinical presentation to molecular pathology and basic cellular mechanisms have been reviewed recently.

Ten years of gene therapy for primary immune deficiencies.

Gene therapy with hematopoietic stem cells (HSC) is an attractive therapeutic strategy for several forms of primary immunodeficiencies. Current approaches are based on ex vivo gene transfer of the therapeutic gene into autologous HSC by vector-mediated gene transfer. In the past decade, substantial progress has been achieved in the treatment of severe combined immundeficiencies (SCID)-X1, adenosine deaminase (ADA)-deficient SCID, and chronic granulomatous disease (CGD). Results of the SCID gene therapy trials have shown long-term restoration of immune competence and clinical benefit in over 30 patients. The inclusion of reduced-dose conditioning in the ADA-SCID has allowed the engraftment of multipotent gene-corrected HSC at substantial level. In the CGD trial significant engraftment and transgene expression were observed, but the therapeutic effect was transient. The occurrence of adverse events related to insertional mutagenesis in the SCID-X1 and CGD trial has highlighted the limitations of current retroviral vector technology. For future applications the risk-benefit evaluation should include the type of vector employed, the disease background and the nature of the transgene. The use of self-inactivating lentiviral vectors will provide significant advantages in terms of natural gene regulation and reduction in the potential for adverse mutagenic events. Following recent advances in preclinical studies, lentiviral vectors are now being translated into new clinical approaches, such as Wiskott-Aldrich Syndrome.

[Successful treatment of a patient with Wiskott-Aldrich syndrome using hematopoietic stem cell transplantation--case report and literature review].

OBJECTIVE: Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency diseases. The patients with classical WAS have poor prognosis. The hematopoietic stem cell transplantation is the most effective method to cure WAS at present. In this report, a patient with WAS was cured with HLA identical sibling bone marrow transplantation (BMT). METHODS: Wiskott-Aldrich syndrome protein (WASP) was detected using flow cytometry and WASP were analyzed for the diagnosis. The bone marrow was collected from the elder sister who was the HLA identical sibling donor. A total of 4.38x10(8)/kg mononuclear cell (MNC) and 3.78x10(6)/kg CD34+ cells were collected and transfused into the patient after the conditioning regimen with busulfan/cyclophosphamide. Cyclosporine only was used for graft-versus-host disease prophylaxis. WASP and short tandem repeats (STR) were detected as the evidence of engraftment. RESULTS: The diagnosis was WAS: WASP (-IVS9+2T>C, WASP-negative). The patient received busulfan/cyclophosphamide 9 days before the transplantation. WBC decreased to 0.1x10(9)/L in d+4; The absolute number of neutrophils (ANC) was 0.8x10(9)/L in d+13, and exceeded 1.0x10(9)/L later on. From d(-9)-d+14 the patient was dependent on platelet transfusion. From d+15 the patient's PLT>50x10(9)/L and returned to normal after d+30. In d+9-d+10 mild GVHD (I degree) occurred but subsided after the steroid treatment. From d+50, WASP was detected positive and STR showed full donor DNA chimera. Follow-up for 510 d post-transplant, the patient suffered only from mild cold twice, no eczema, no bleeding occurred. The PLT is normal and no chronic GVHD occurred. The levels of IgG, IgM and IgA of the patient were approximately normal. CONCLUSION: The HLA-identical sibling's BMT seems to be the periorit treatment of choice for the WAS patient.

Spontaneous thrombosis of hepatic aneurysms in an infant with Wiskott-Aldrich syndrome.

Vasculitides and aneurysm formation are well-known complications in Wiskott-Aldrich syndrome (WAS), most often appearing later in life, usually in second decade. The authors report the case of a 5-month-old boy with a genetically and phenotypically severe Wiskott-Aldrich syndrome and sequential formation and spontaneous thrombosis of hepatic aneurysms. This case demonstrates that aneurysm formation may develop early in the course of severe WAS phenotypes. Because of the progressive nature of these manifestations, surgical or interventional procedures are not advisable. Early allogeneic hematopoietic stem cell transplantation (HSCT) should be considered before the manifestation of irreversible organ damage.

Clinical and molecular characteristics of 35 Chinese children with Wiskott-Aldrich syndrome.

BACKGROUND: 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. OBJECTIVES: 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). MATERIALS AND METHOD: Records of 35 patients diagnosed with WAS during 1991-2008 were reviewed. Genetic diagnosis was established by direct gene sequencing. RESULTS: 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. CONCLUSION: 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.

Aneurysm of the aortic root in the setting of Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome is a rare X-linked disease, associated with immunodeficiency, infections, thrombocytopaenia, and eczema. Aortitis and formation of aneurysms have also been described. We describe here our experience with a 7-year-boy with this syndrome. He survived replacement of the aortic root because of an aneurysmal ascending aorta, and subsequent bone marrow transplantation.

Results and long-term outcome in 39 patients with Wiskott-Aldrich syndrome transplanted from HLA-matched and -mismatched donors.

In this report, we present an analysis in 39 WAS patients treated by hematopoietic stem cell transplantation (HSCT) in our center since 1983. Fifteen patients received transplants from HLA-identical unrelated donors, 15 from nonidentical parental donors, and 9 from matched siblings. The overall survival rate is 90% in patients with matched donors and 50% in patients after nonidentical transplantation, with a mean follow-up time of 11 years. Treatment failures in the latter group were mainly related to graft rejections and to GvHD and infections following repeat transplants. Long-term survivors in both patient groups remain with few exceptions free of late complications and with stable graft function and complete donor cell chimerism. Based on our findings, we recommend early and prompt treatment of each diagnosed WAS patient if an HLA-matched, related or unrelated, donor can be identified. If this is not the case, HLA-nonidentical donor transplantation represents an alternative to be considered early in patients with severe disease.

Unrelated bone marrow transplantation with a reduced toxicity myeloablative conditioning regimen in Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is an X-linked congenital immune-deficiency syndrome, and bone marrow transplantation (BMT) has become a curative modality. However, the transplant with the alternative donor needed more intensive conditioning with increased treatment-related toxicities. Recently, fludarabine-based reduced toxicity myeloablative conditioning regimens have been developed for adult myeloid malignancies with promising results of good engraftment and low treatment-related toxicities. To increase the engraftment potential without serious complications, a boy with WAS received successful unrelated BMT with a reduced toxicity myeloablative conditioning regimen composed of fludarabine (40 mg/m2) on days -8, -7, -6, -5, -4, -3), busulfan (0.8 mg/kg i. v. q 6 hr on days -6, -5, -4, -3), and thymoglobulin (2.5 mg/kg on days -4, -3, -2). This novel conditioning regimen could improve the outcome of allogeneic transplantation for other non-malignant diseases such as congenital immune-deficiency syndromes or metabolic storage diseases.

Wiskott-Aldrich syndrome.

PURPOSE OF REVIEW: Wiskott-Aldrich syndrome is caused by mutations of the Wiskott-Aldrich syndrome protein gene, which codes for a cytoplasmic protein with multiple functions. This review will focus on recent progress in understanding the molecular basis of Wiskott-Aldrich syndrome and its ramifications for the cure of this lethal disease. RECENT FINDINGS: The discovery of the causative gene has revealed a spectrum of clinical phenotypes demonstrating a strong genotype/phenotype correlation. The discovery of unique functional domains of Wiskott-Aldrich syndrome protein has been instrumental in defining mechanisms that control activation of Wiskott-Aldrich syndrome protein. Long-term follow up of patients undergoing hematopoietic stem cell transplantation has led to important modifications of the procedure. Studies of Wiskott-Aldrich syndrome protein-deficient cell lines and wasp-knockout mice have paved the way for possible gene therapy. SUMMARY: Wiskott-Aldrich syndrome protein gene mutations result in four clinical phenotypes: classic Wiskott-Aldrich syndrome and X-linked thrombocytopenia, intermittent thrombocytopenia and neutropenia. Wiskott-Aldrich syndrome protein is a signaling molecule and instrumental for cognate and innate immunity, cell motility and protection against autoimmune disease. The success of hematopoietic stem cell transplantation is related to the recipient's age, donor selection, the conditioning regimen and the extent of reconstitution. Since Wiskott-Aldrich syndrome protein is expressed exclusively in hematopoietic stem cells, and because Wiskott-Aldrich syndrome protein exerts a strong selective pressure, gene therapy is expected to cure the disease.