Objective: To evaluate the therapeutic efficacy of hematopoietic stem cell transplantation (HSCT) for Wiskott-Aldrich syndrome (WAS), and to analyze the factors related to the outcomes. Methods: The clinical data of 60 children with WAS received HSCT in Shanghai Children's Medical Center from January 2006 to December 2020 were retrospectively analyzed. All cases were treated with a myeloablative conditioning regimen with busulfan and cyclophosphamide, and a graft-versus-host disease (GVHD) prevention regimen based on cyclosporine and methotrexate. Implantation, GVHD, transplant-related complications, immune reconstitution and survival rate were observed. Survival analysis was performed by Kaplan-Meier method, and Log-Rank method was used for univariate comparison. Results: The 60 male patients had main clinical features as infection and bleeding. The age at diagnosis was 0.4 (0.3, 0.8) years, and the age at transplantation was 1.1 (0.6, 2.1) years. There were 20 cases of human leukocyte antigen matched transplantation and 40 mismatched transplantation; 35 patients received peripheral blood HSCT, and 25 cord blood HSCT. All cases were fully implanted. The incidence of acute GVHD (aGVHD) was 48% (29/60) and only 2 (7%) developed aGVHD of grade Ⅲ; the incidence of chronic GVHD (cGVHD) was 23% (13/56), and all cases were limited. The incidence of CMV and EBV infection was 35% (21/60) and 33% (20/60) respectively; and 7 patients developed CMV retinitis. The incidence of sinus obstruction syndrome was 8% (5/60), of whom 2 patients died. There were 7 cases (12%) of autoimmune hemocytopenia after transplantation. Natural killer cells were the earliest to recover after transplantation, and B cells and CD4⁺T cells returned to normal at about 180 days post HSCT. The 5-year overall survival rate (OS) of this group was 93% (95%CI 86%-99%), and the event free survial rate (EFS) was 87% (95%CI 78%-95%). EFS of non-CMV reactivation group is higher than that of CMV reactivation group (95% (37/39) vs.71% (15/21), χ²=5.22, P=0.022). Conclusions: The therapeutic efficacy of HSCT for WAS is satisfying, and the early application of HSCT in typical cases can achieve better outcome. CMV infection is the main factor affecting disease-free survival rate, which can be improved by strengthening the management of complications.
Humans ; Male ; Child ; Retrospective Studies ; Wiskott-Aldrich Syndrome/therapy* ; China ; Hematopoietic Stem Cell Transplantation/methods* ; Graft vs Host Disease/prevention & control* ; Transplantation Conditioning

Humans ; Herpesvirus 4, Human ; Wiskott-Aldrich Syndrome ; Epstein-Barr Virus Infections/complications* ; Smooth Muscle Tumor/therapy* ; Hematopoietic Stem Cell Transplantation

OBJECTIVE: To study the clinical features of Wiskott-Aldrich syndrome (WAS) in children. METHODS: A retrospective analysis was performed for the clinical data of 13 children with WAS. RESULTS: All 13 children were boys, with a median age of onset of 3 months (range 1-48 months) and a median age of 24 months (range 1-60 months) at the time of diagnosis. Of the 13 children, only 3 had typical WAS and the remaining 10 children had X-linked thrombocytopenia (XLT). The mean WAS score was 2 (range 1-3), the mean platelet count was 20.5×10/L [range (13-46)×10/L], and the mean platelet volume was 8.1 fl (range 6.7-12.1 fl). Lymphocyte subsets and immunoglobulins were measured for 4 children, among whom 1 (25%) had a reduction in both the percentage of CD3T cells per lymphocyte and lymphocyte per nuclear cells, 1(25%) had a reduction in CD3CD56 NK cells. Among these 4 children, 1 (25%) had an increase in IgG, 2 (50%) had a reduction in IgM, 1 (25%) had a reduction in IgA, and 4 (100%) had an increase in IgE. A total of 14 gene mutations belonging to 13 types were found in 13 children, among which there were 9 missense mutations (65%), 2 splicing mutations (14%), 2 nonsense mutation (14%), and 1 frameshift mutation (7%). The median follow-up time was 39 months (range 3-62 months), and all 13 children survived. CONCLUSIONS Children with WAS often have a young age of onset, and most of them are boys. Major clinical features include thrombocytopenia with a reduction in platelet volume. Missense mutation is the main type of gene mutation.
Child, Preschool ; Humans ; Infant ; Male ; Mutation ; Retrospective Studies ; Thrombocytopenia ; Wiskott-Aldrich Syndrome ; Wiskott-Aldrich Syndrome Protein

OBJECTIVE: To investigate the gene mutation of patients with WAS gene defect and its correlation with clinical manifestations. METHODS: Thirty-one patients consulted in Children's Hospital of Soochow University from January 2013 to February 2018 were enrolled in this study. The hot pot mutations of WAS gene in 31 patients were detected and related clinical phenotypes were analyzed retrospectively. RESULTS: All patients were male. The median onset age was 1 month (range, 0-83 months). Nine mutants were reported as novel mutations among 25 mutants detected in 31 patients, including c.1234_1235dupCC, c.1093-1097delG, c.28-30dupC, c.436G>T, c.273 + 10_273 + 11dupCC, c.995_996insG, c.1010T>A, c.332_333delCC and c.683C>T mutations. There were 25 cases of classic WAS which mutations included missense mutation, deletion mutation, insertion mutation, splicing mutation and nonsense mutation, 2 cases of X-linked thrombocytopenia (XLT) were induced by missense mutation, 1 case of intermittent X-linked thrombocytopenia (IXLT) was induced by splicing mutation, 2 cases of X-linked pancytopenia were induced by missense mutation. Intravenous immunoglobulin (IVIG) and glucocorticoid therapy in IXLT patient was effective, and remission could be sustained, platelets could be increased in the short-term in treated XLT patients, but only a small part of classic WAS patients(8.0%) showed transient response to it, the IVIG and glucocorticoid therapy did not improve the status of platelet in XLP patients. Immune laboratory examination showed that CD3 was decreased in 60.0% patients, CD19 was decreased in 12.0% patients, and CD56CD16 in 4 patients was decreased, accounting for 16.0%. Out of 24 patients, 22 patients were alive after treated with hematopoietic stem cell transplantation (HSCT), 4 patients who were not given HSCT died of brain bleeding and severe infection, 1 patient diagnosed as IXLT got remission and survived. CONCLUSION WAS gene defect is an important basis for the diagnosis of WAS and related diseases. IVIG plus glucocorticoid therapy is less effective for fewer patients, the HSCT is an effective treatment for WAS.
Genetic Diseases, X-Linked ; Humans ; Male ; Mutation ; Phenotype ; Retrospective Studies ; Thrombocytopenia ; Wiskott-Aldrich Syndrome Protein ; genetics

OBJECTIVE: To explore the clinical efficacy and safety of unrelated umbilical cord blood transplantation (UCBT) for the treatment of Wiskott-Aldrich syndrome(WAS). METHODS: Five pediatric patients with WAS received single UCBT were retrospectively analyzed. The median age of these male patients was 268 days (range, 3 days -695 days). Among them, 2 patients were transplanted with a 6/6 matched cord blood graft，the other 3 patients received a 5/6 matched cord blood graft. Myeloablative conditioning regimen was applied, and all patients received a combination of cyclosporine and mycophenolate mofetil for the prophylaxis of graft versus host disease (GVHD). The recovery time of neutrophils and platelets as well as chimerism after transplantation were taken as the evidence of hematopoietic reconstruction. RESULTS: All the five pediatric patients had hematopoietic recovery. A median time of neutrophil cells after transplantation was at 15.8 days (range,11 days -25 days), and platelet recovery was at a median of 20.4 days(range,12 days-30 days). Chimerism data were available for 5 patients at 30 days after UCBT, 4 out of the 5 patients had full donor chimerism and only one patient had mixed chimerism. There were 2 cases with pre-engraftment syndrome, 3 cases with acute GVHD gradeⅠ-Ⅲ, 4 cases with pulmonary infection and cytomegalovirus infection, but chronic GVHD was not observed in 5 cases. Four patients were alive with a median follow-up of 12.3 months (range, 5 months-17 months), and one patient had died at 22 days after UCBT. CONCLUSION Unrelated umbilical cord blood transplantation is a safe and effective treatment method for Wiskott-Aldrich syndrome.
Cord Blood Stem Cell Transplantation ; Graft vs Host Disease ; Humans ; Infant ; Infant, Newborn ; Male ; Retrospective Studies ; Transplantation Conditioning ; Treatment Outcome ; Wiskott-Aldrich Syndrome

OBJECTIVETo detect potential mutation of the WAS gene in a Chinese family affected with Wiskott-Aldrich syndrome.

METHODSPeripheral blood samples were collected from the proband and his family members. All exons and flanking regions of the WAS gene were subjected to PCR amplification - Sanger sequencing as well as restriction endonuclease analysis. Plasma level of B-cell activating factor (BAFF) was also determined for all family members.

RESULTSA hemizygous mutation (c.257G>A) of the WAS gene was identified in all patients from the family, for which the patient's mother was heterozygous. The same mutation was not found among healthy members of the family. Compared with unaffected members, all patients had a higher level of BAFF.

CONCLUSIONThe c.257G>A mutation of the WAS gene probably underlies the Wiskott-Aldrich syndrome in this family.

B-Cell Activating Factor ; blood ; Child, Preschool ; Heterozygote ; Humans ; Male ; Mutation ; Wiskott-Aldrich Syndrome ; genetics ; Wiskott-Aldrich Syndrome Protein ; genetics

BACKGROUND: Wiskott-Aldrich syndrome (WAS) is a very rare disease and patients who do not receive timely treatment suffer from bleeding, infection, and malignancy. Hematopoietic stem cell transplantation (HSCT) has been recognized as an effective treatment, but the standard transplantation protocol has not been established. We report the outcomes of WAS patients who underwent HSCT in our institution. METHODS: We retrospectively studied patients who underwent HSCT at Seoul National University Children's Hospital from 2005 to 2018. Busulfan-based myeloablative conditioning regimen was used, and an intensive daily therapeutic drug monitoring (TDM) for busulfan dosing was started for effective myeloablation and to reduce toxicity since 2008. We collected and analyzed data regarding symptoms, engraftment, transplantation-related toxicities, and survival. RESULTS: Six WAS patients who received HSCT were evaluated. The median age of the patients at diagnosis was 5 years (range, 1–11). There were 2 matched unrelated donor bone marrow transplantations, 3 matched unrelated peripheral blood stem cell transplantations (PBSCT), and 1 haploidentical PBSCT. No patient experienced engraftment failure. Three patients developed grades II to IV acute graft-versus-host disease (GVHD). Two patients had veno-occlusive disease (VOD). Two patients died (due to VOD and acute GVHD). The 5-year overall survival was 66.7% with 8 years of median follow-up. Particularly, a patient who underwent haploidentical PBSCT using targeted busulfan is alive with a follow-up duration of 3 years after HSCT. CONCLUSION: In conclusion, WAS patients may be cured with HSCT with targeted busulfan-based myeloablative conditioning. But, long-term and multi-center studies are needed.
Bone Marrow ; Busulfan ; Diagnosis ; Drug Monitoring ; Follow-Up Studies ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation* ; Hematopoietic Stem Cells* ; Hemorrhage ; Humans ; Rare Diseases ; Retrospective Studies ; Seoul ; Stem Cell Transplantation ; Unrelated Donors ; Wiskott-Aldrich Syndrome

Humans ; Infant ; Male ; Phenotype ; Wiskott-Aldrich Syndrome ; diagnosis ; genetics ; immunology

OBJECTIVETo investigate the clinical and immunological laboratory features, gene mutations, treatment and prognosis in children with Wiskott-Aldrich syndrome (WAS).

METHODThe clinical, laboratory characteristics, treatment and prognosis of 132 children with WAS, who visited Children's Hospital of Chongqing Medical University from April 2000 to June 2015, were analyzed retrospectively.

RESULTAll patients were male. The median age of disease onset was 15 days and the median age at diagnosis was 10 months. Of the 132 cases, 112 had classic WAS, 20 had X-linked thrombocytopenia (XLT). The median platelet count was 23×10(9)/L. All cases had the clinical characteristics of WAS including bleeding, eczema, and being susceptible to infection. The initial symptoms include hemorrhage (75.0%) and eczema (16.7%). Twenty-one cases had autoimmune diseases and one patient had leukemia. WAS protein (WASP) expression in 115 cases were measured by flow cytometry, 88 cases were negative, in 12 cases WASP decreased, in 5 cases it was normal, 10 cases had bimodal distribution. Eighty-one kinds of mutations were found in 122 families, including eight kinds of hot-spot mutations, which were 290 C> N / 291G> N (R86C / H / L), 665 C> T (R211X), 155 C> T (R41X), 168 C> T (T45 M), IVS1+ 1 g> t/ a, IVS6 + 5 g> a, IVS8 + 1 g> a and IVS8 + 1to + 6del gtga. Meantime, 29 kinds of novel mutations were found, which were 321T>C, 415C>A, 471C>T, 102-105delC, 521 del C, 1330 del A, IVS2-2 a>c, 168 C>A/1412 C> T, exon1-2 del/1412 C>T, and so on. The proportion of CD3(+) T cells (31.3%), helper T cells (37.3%) and cytotoxic T cells (38.6%) in the peripheral blood declined. The serum levels of IgG (51.1%), IgA (43.3%) and IgE (40.0%) increased, IgM (25.6%) decreased. Of the 132 cases, 72 remain survived, of whom 36 cases received hematopoietic stem cell transplantation (HSCT), 14 patients with classic WAS received intravenous immunoglobulin (IVIG) therapy. With regular IVIG therapy, the frequency of infections was reduced and the patients' symptoms were improved.

CONCLUSIONThe clinical characteristics of Wiskott-Aldrich syndrome were early age of onset, microthrombocytopenia, eczema and recurrent infections. The proportion of T lymphocyte declined, the serum levels of IgG, IgA, and IgE increased, and level of IgM decreased in a part of patients. The detection of WAS gene mutation and WAS protein detection was the key diagnostic methods. Regular IVIG can gain more time for children who will receive HSCT and improve their quality of life.

Genetic Diseases, X-Linked ; genetics ; Genotype ; Hematopoietic Stem Cell Transplantation ; Humans ; Immunoglobulins, Intravenous ; therapeutic use ; Infant ; Infant, Newborn ; Male ; Mutation ; Platelet Count ; Retrospective Studies ; Thrombocytopenia ; genetics ; Wiskott-Aldrich Syndrome ; genetics ; Wiskott-Aldrich Syndrome Protein ; genetics

OBJECTIVETo investigate the history of a Wiskott- Aldrich syndrome (WAS) family with normal mean platelet volume (MPV), analyse the WASP gene mutation of to better understand its clinical characteristics.

METHODSA four- generation WAS family histories of 22 members were investigated. Peripheral blood samples were collected from propositus and his mother to analyse all exon mutations of WASP gene using sanger sequencing.

RESULTSThe MPV of both propositus and his elder brother were normal. The patient's clinical score was 5, antibodies to PM-Scl, PCNA and PO were positive with very high level of ASO, the patient co- suffered from autoimmune disease, anemia, abnormal renal function, fungal infection and scleritis. A homozygous mutation (C>T) was found at 173 bp of exon 2, corresponding to amino acids Pro (P) 58 abnormally changed to Leu (L). His mother was the carrier of the mutation. Of 112 blood diseases- related genes, mutation frequencies of CBL, CREBBP, DNM2 and ADAMTS13 were higher than normals.

CONCLUSIONThis was the first report the phenotype 173C>T mutation of WASP without eczema, but with normal MPV and autoimmune disease in Chinese, WAS should be recognized earlier and diagnosed correctly by genomic methods.

Asian Continental Ancestry Group ; DNA Mutational Analysis ; Exons ; Humans ; Male ; Mean Platelet Volume ; Mutation ; Phenotype ; Wiskott-Aldrich Syndrome ; genetics ; Wiskott-Aldrich Syndrome Protein ; genetics