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1.
Medicina (B Aires) ; 80(1): 81-83, 2020.
Artigo em Espanhol | MEDLINE | ID: mdl-32044744

RESUMO

Wiskott-Aldrich syndrome is a rare X chromosome-linked primary immunodeficiency syndrome associated with an increased incidence of infections, autoimmune disorders and neoplasms. We present the case of a 41-year-old man with a diagnosis of Wiskott-Aldrich syndrome with ileitis as a form of presentation of a lymphoproliferative syndrome. The ileitis, in the context of the patient, represents a clinical challenge given the large number of differential diagnoses (inflammatory bowel disease, infections, neoplasms and lymphoproliferative diseases), so it usually requires anatomopathological diagnosis and particular considerations regarding the subsequent specific treatment.


Assuntos
Neoplasias do Íleo/patologia , Ileíte/patologia , Linfoma/patologia , Síndrome de Wiskott-Aldrich/patologia , Adulto , Biópsia , Diagnóstico Diferencial , Humanos , Neoplasias do Íleo/diagnóstico , Ileíte/diagnóstico , Imuno-Histoquímica , Linfoma/diagnóstico , Masculino , Síndrome de Wiskott-Aldrich/diagnóstico
2.
Scand J Immunol ; 91(1): e12805, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31267543

RESUMO

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease caused by a mutation in the WAS gene that encodes the WAS protein (WASp); up to 5-10% of these patients develop inflammatory bowel disease (IBD). The mechanisms by which WASp deficiency causes IBD are unclear. Intestinal microbial dysbiosis and imbalances in host immune responses play important roles in the pathogenesis of polygenetic IBD; however, few studies have conducted detailed examination of the microbial alterations and their relationship with IBD in WAS. Here, we collected faecal samples from 19 children (all less than 2 years old) with WAS and samples from WASp-KO mice with IBD and subjected them to 16S ribosomal RNA sequencing. We found that microbial community richness and structure in WAS children were different from those in controls; WAS children revealed reduced microbial community richness and diversity. Relative abundance of Bacteroidetes and Verrucomicrobiain in WAS children was significantly lower, while that of Proteobacteria was markedly higher. WASp-KO mice revealed a significantly decreased abundance of Firmicutes. Faecal microbial dysbiosis caused by WASp deficiency is similar to that observed for polygenetic IBD, suggesting that WASp may play crucial function in microbial homoeostasis and that microbial dysbiosis may contribute to IBD in WAS. These microbial alterations may be useful targets for monitoring and therapeutically managing intestinal inflammation in WAS.


Assuntos
Disbiose , Fezes/microbiologia , Microbioma Gastrointestinal , Síndrome de Wiskott-Aldrich/etiologia , Animais , Biodiversidade , Biomarcadores , Estudos de Casos e Controles , Pré-Escolar , Modelos Animais de Doenças , Feminino , Humanos , Lactente , Doenças Inflamatórias Intestinais/etiologia , Masculino , Metagenoma , Metagenômica/métodos , Camundongos , Camundongos Knockout , Mutação , RNA Ribossômico 16S/genética , Síndrome de Wiskott-Aldrich/diagnóstico , Proteína da Síndrome de Wiskott-Aldrich/deficiência
3.
Zhonghua Er Ke Za Zhi ; 57(6): 429-433, 2019 Jun 02.
Artigo em Chinês | MEDLINE | ID: mdl-31216799

RESUMO

Objective: To explore the clinical value of genetic screening for early identification of WAS gene-related disorders in newborns. Methods: This was a retrospective study. Neonatal Genome Project from Children's Hospital of Fudan University collected 5 800 high-risk newborns in the neonatal intensive care unit to study the patients' genetic causes using high-throughput sequencing from January 2016 to December 2017. Eleven newborns (all were boys) with pathogenic or likely pathogenic variants in WAS gene were enrolled. Data of clinical characteristics,gene variants and genotype-phenotype correlation were collected and summarized. Results: Eleven patients included 5 cases with Wiskott-Aldrich syndrome (WAS) and 6 cases with X-linked thrombocytopenia (XLT).Two patients with WAS developed clinical manifestations in the early neonatal period,and 3 patients in 5-8 weeks after birth. Three neonates with XLT were hospitalized for other diseases in the first place.Their platelet count was found to be reduced after admission to hospital, and diagnosis was made after genetic testing. Eleven pathogenic or likely pathogenic variants in WAS gene were identified. Among them, 7 were first reported in this study, including 2 frame shift variants c.138delG and c.388_390del, 4 splicing variants c.1453+1G>A,c.734+1G>C,c.135G>A and c.1453+3G>C, and 1 missense variant c.1118C>T. The other 4 reported variants were c.777+1G>A,c.107_108delTT, c.436delC and c.1509_*3delAGTG. Conclusions: The clinical features of WAS gene-related disorders in neonatal period lack specificity. Genetic screening in newborns plays an important role in the early diagnosis of diseases and provides providing evidence for the early intervention.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X , Testes Genéticos/métodos , Trombocitopenia/diagnóstico , Proteína da Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/diagnóstico , Criança , Análise Mutacional de DNA , Diagnóstico Precoce , Humanos , Recém-Nascido , Masculino , Mutação , Estudos Retrospectivos , Trombocitopenia/genética , Síndrome de Wiskott-Aldrich/genética
5.
Lancet Haematol ; 6(5): e239-e253, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30981783

RESUMO

BACKGROUND: Wiskott-Aldrich syndrome is a rare, life-threatening, X-linked primary immunodeficiency characterised by microthrombocytopenia, infections, eczema, autoimmunity, and malignant disease. Lentiviral vector-mediated haemopoietic stem/progenitor cell (HSPC) gene therapy is a potentially curative treatment that represents an alternative to allogeneic HSPC transplantation. Here, we report safety and efficacy data from an interim analysis of patients with severe Wiskott-Aldrich syndrome who received lentiviral vector-derived gene therapy. METHODS: We did a non-randomised, open-label, phase 1/2 clinical study in paediatric patients with severe Wiskott-Aldrich syndrome, defined by either WAS gene mutation or absent Wiskott-Aldrich syndrome protein (WASP) expression or a Zhu clinical score of 3 or higher. We included patients who had no HLA-identical sibling donor available or, for children younger than 5 years of age, no suitable 10/10 matched unrelated donor or 6/6 unrelated cord blood donor. After treatment with rituximab and a reduced-intensity conditioning regimen of busulfan and fludarabine, patients received one intravenous infusion of autologous CD34+ cells genetically modified with a lentiviral vector encoding for human WAS cDNA. The primary safety endpoints were safety of the conditioning regimen and safety of lentiviral gene transfer into HSPCs. The primary efficacy endpoints were overall survival, sustained engraftment of genetically corrected HSPCs, expression of vector-derived WASP, improved T-cell function, antigen-specific responses to vaccinations, and improved platelet count and mean platelet volume normalisation. This interim analysis was done when the first six patients treated had completed at least 3 years of follow-up. The planned analyses are presented for the intention-to-treat population. This trial is registered with ClinicalTrials.gov (number NCT01515462) and EudraCT (number 2009-017346-32). FINDINGS: Between April 20, 2010, and Feb 26, 2015, nine patients (all male) were enrolled of whom one was excluded after screening; the age range of the eight treated children was 1·1-12·4 years. At the time of the interim analysis (data cutoff April 29, 2016), median follow-up was 3·6 years (range 0·5-5·6). Overall survival was 100%. Engraftment of genetically corrected HSPCs was successful and sustained in all patients. The fraction of WASP-positive lymphocytes increased from a median of 3·9% (range 1·8-35·6) before gene therapy to 66·7% (55·7-98·6) at 12 months after gene therapy, whereas WASP-positive platelets increased from 19·1% (range 4·1-31·0) to 76·6% (53·1-98·4). Improvement of immune function was shown by normalisation of in-vitro T-cell function and successful discontinuation of immunoglobulin supplementation in seven patients with follow-up longer than 1 year, followed by positive antigen-specific response to vaccination. Severe infections fell from 2·38 (95% CI 1·44-3·72) per patient-year of observation (PYO) in the year before gene therapy to 0·31 (0·04-1·11) per PYO in the second year after gene therapy and 0·17 (0·00-0·93) per PYO in the third year after gene therapy. Before gene therapy, platelet counts were lower than 20 × 109 per L in seven of eight patients. At the last follow-up visit, the platelet count had increased to 20-50 × 109 per L in one patient, 50-100 × 109 per L in five patients, and more than 100 × 109 per L in two patients, which resulted in independence from platelet transfusions and absence of severe bleeding events. 27 serious adverse events in six patients occurred after gene therapy, 23 (85%) of which were infectious (pyrexia [five events in three patients], device-related infections, including one case of sepsis [four events in three patients], and gastroenteritis, including one case due to rotavirus [three events in two patients]); these occurred mainly in the first 6 months of follow-up. No adverse reactions to the investigational drug product and no abnormal clonal proliferation or leukaemia were reported after gene therapy. INTERPRETATION: Data from this study show that gene therapy provides a valuable treatment option for patients with severe Wiskott-Aldrich syndrome, particularly for those who do not have a suitable HSPC donor available. FUNDING: Italian Telethon Foundation, GlaxoSmithKline, and Orchard Therapeutics.


Assuntos
Terapia Genética , Vetores Genéticos/genética , Células-Tronco Hematopoéticas/metabolismo , Lentivirus/genética , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/terapia , Criança , Pré-Escolar , Feminino , Terapia Genética/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Itália , Masculino , Mutação , Linfócitos T/imunologia , Linfócitos T/metabolismo , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Síndrome de Wiskott-Aldrich/sangue , Síndrome de Wiskott-Aldrich/diagnóstico , Proteína da Síndrome de Wiskott-Aldrich/genética
7.
BMJ Case Rep ; 20182018 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-29991546

RESUMO

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder, described as a clinical triad of microthrombocytopenia, eczema and recurrent infections. Different mutations in WAS gene have been identified, resulting in various phenotypes and a broad range of disease severity, ranging from classic WAS to X-linked thrombocytopenia and X-linked neutropenia. WAS in some cases can be fatal without haematopoietic stem cell transplantation early in life. In this particular case, we present a novel mutation with a unique presentation. An 18-year-old man incidentally found to have macrothrombocytopenia and neutropenia at 16 years of age later found to be hemizygous for c. 869T>C (p.Ile290Thr) mutation in WAS gene. The late presentation, absence of other manifestations of WAS and presence of macrothrombocytopenia, rather than microthrombocytopenia, which is usually a characteristic finding in WAS, misled the initial diagnosis. On review of literature, this mutation has not been reported as causing WAS.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação , Neutropenia/genética , Trombocitopenia/genética , Síndrome de Wiskott-Aldrich/genética , Adolescente , Humanos , Masculino , Síndrome de Wiskott-Aldrich/complicações , Síndrome de Wiskott-Aldrich/diagnóstico , Proteína da Síndrome de Wiskott-Aldrich/genética
9.
Cogn Behav Neurol ; 31(1): 13-17, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29561314

RESUMO

We report the neuropsychological profile of a 6-year-old girl with Wiskott-Aldrich syndrome, a rare X-linked immunodeficiency disorder associated with thrombocytopenia, eczema, recurrent infections, and malignancy. Wiskott-Aldrich syndrome occurs almost exclusively in males and is extremely rare in females, with no known research focused on cognitive and academic functioning in this population. Our patient was referred due to concerns about her memory and academic functioning. She had a history of progressive thrombocytopenia and hematopoietic stem cell transplantation at age 15 months. Standardized measures of intellectual ability, language, visual-spatial and visual-motor skills, attention, memory, and academic achievement were administered. The results showed average to above-average performance in multiple areas of cognitive and academic functioning, with weaknesses in phonological awareness and rapid naming. The advent of hematopoietic stem cell transplantation has led to considerable improvement in the long-term prognosis of children with Wiskott-Aldrich syndrome. Although the impact of this syndrome and related conditions on neurocognitive development is presently unknown, this case highlights both the importance of considering base rates for commonly occurring conditions and the significant role neuropsychology can play in identifying cognitive strengths and weaknesses in the context of the developing brain.


Assuntos
Testes Neuropsicológicos , Síndrome de Wiskott-Aldrich/diagnóstico , Criança , Feminino , Humanos , Síndrome de Wiskott-Aldrich/patologia
10.
J Pediatr Hematol Oncol ; 40(3): 240-242, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28859046

RESUMO

Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency characterized by various clinical phenotypes. We report the case of a 3-year-old immigrant boy presenting with persistent infant-onset thrombocytopenia treated for refractory immune thrombocytopenic purpura. Sequence analysis confirmed the diagnosis of WAS. The patient responded neither to IV infusions of immunoglobulin (Ig) nor a thrombopoietin receptor agonist and is currently planned for stem cell transplantation. Raised awareness is thus vital of this potentially misdiagnosed and lethal disorder. The diagnosis of WAS should be considered in all males with infant-onset immune thrombocytopenic purpura-like features, especially, if mean platelet volume is decreased (<7 fL) and good increment to platelet transfusions are evident.


Assuntos
Púrpura Trombocitopênica Idiopática/diagnóstico , Síndrome de Wiskott-Aldrich/diagnóstico , Pré-Escolar , Erros de Diagnóstico , Humanos , Masculino
15.
J Pediatr Hematol Oncol ; 39(8): e493-e496, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28859032

RESUMO

There are very few reports of reduced intensity conditioning (RIC) hematopoietic stem cell transplant (HSCT) with alternate donor for Wiskott-Aldrich syndrome (WAS) and there is no report of RIC with posttransplant cyclophosphamide (PTCy) in WAS. There is only 1 report of T cell receptor αß and CD19-depleted haploidentical HSCT for WAS. Here we report successful outcome in 3 children with WAS who underwent successful RIC alternate donor HSCT of whom 2 (matched unrelated donor and T-cell replete haploidentical) received PTCy and 1 underwent T cell receptor αß and CD19-depleted haploidentical HSCT. We modified conditioning used by Luznik for haploidentical HSCT by adding thiotepa 8 mg/kg and Campath or rabbit antithymoglobulin for 2 cases who received PTCy. In third case we gave fludarabine, thiotepa, and treosulfan-based conditioning. The mean duration of follow-up for these patients was 23.6 months posttransplant (range, 21 to 26 mo). All 3 patients are transfusion independent. Acute graft versus host disease (GVHD) grade I occurred in 1 and none had chronic GVHD. Chimerism of all 3 was fully donor (>95% donor) at D+30 and D+100 posttransplant. All are alive, healthy, and doing well. Our 3 cases highlight that with newer conditioning and GVHD prophylaxis approach alternate donor HSCT in WAS can become a safe and effective treatment option.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Doadores de Tecidos , Condicionamento Pré-Transplante , Síndrome de Wiskott-Aldrich/terapia , Adolescente , Adulto , Pré-Escolar , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Quimeras de Transplante , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento , Síndrome de Wiskott-Aldrich/diagnóstico
16.
Allergy ; 72(12): 1916-1924, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28600891

RESUMO

BACKGROUND: Food allergies are a growing health problem, and the development of therapies that prevent disease onset is limited by the lack of adjuvant-free experimental animal models. We compared allergic sensitization in patients with food allergy or Wiskott-Aldrich syndrome (WAS) and defined whether spontaneous disease in Was-/- mice recapitulates the pathology of a conventional disease model and/or human food allergy. METHODS: Comparative ImmunoCAP ISAC microarray was performed in patients with food allergy or WAS. Spontaneous food allergy in Was-/- mice was compared to an adjuvant-based model in wild-type mice (WT-OVA/alum). Intestinal and systemic anaphylaxis was assessed, and the role of the high-affinity IgE Fc receptor (FcεRI) in allergic sensitization was evaluated using Was-/- Fcer1a-/- mice. RESULTS: Polysensitization to food was detected in both WAS and food-allergic patients which was recapitulated in the Was-/- model. Oral administration of ovalbumin (OVA) in Was-/- mice induced low titers of OVA-specific IgE compared to the WT-OVA/alum model. Irrespectively, 79% of Was-/- mice developed allergic diarrhea following oral OVA challenge. Systemic anaphylaxis occurred in Was-/- mice (95%) with a mortality rate >50%. Spontaneous sensitization and intestinal allergy occurred independent of FcεRI expression on mast cells (MCs) and basophils. CONCLUSIONS: Was-/- mice provide a model of food allergy with the advantage of mimicking polysensitization and low food-antigen IgE titers as observed in humans with clinical food allergy. This model will facilitate studies on aberrant immune responses during spontaneous disease development. Our results imply that therapeutic targeting of the IgE/FcεRI activation cascade will not affect sensitization to food.


Assuntos
Hipersensibilidade Alimentar/etiologia , Hipersensibilidade Alimentar/metabolismo , Mastócitos/imunologia , Mastócitos/metabolismo , Receptores de IgE/metabolismo , Proteína da Síndrome de Wiskott-Aldrich/genética , Adulto , Alérgenos/imunologia , Anafilaxia , Animais , Modelos Animais de Doenças , Feminino , Hipersensibilidade Alimentar/diagnóstico , Expressão Gênica , Humanos , Imunização , Imunoglobulina E/imunologia , Masculino , Camundongos , Camundongos Knockout , Fenótipo , Síndrome de Wiskott-Aldrich/diagnóstico , Síndrome de Wiskott-Aldrich/imunologia , Adulto Jovem
17.
Rev. méd. hondur ; 85(1-2): 27-29, ene.-jun. 2017.
Artigo em Espanhol | LILACS | ID: biblio-884083

RESUMO

Introducción. Las inmunodeficiencias primarias son un grupo de enfermedades de origen genético que implican altera - ciones asociadas a la respuesta inmunológica. El infra diagnóstico de estas conlleva al retraso de tratamiento, evitables en gran parte; Entre estas existe el síndrome de Wiskott-Aldrich; es un trastorno raro, ligado al cromosoma X, recesivo, que se caracteriza por trom - bocitopenia, eczema e inmunodeficiencia donde su tratamiento curativo es el trasplante de medula ósea. CASO CLÍNICO : Paciente de 10 años, con antecedentes de múltiples hospitalizaciones por procesos infecciosos importantes: neumonías recurrentes, menin - gitis, diarreas, erupción cutánea generalizada y trombocitopenia de hasta 9,000 mm³. Después de múltiples estudios realizados, se confirma el diagnóstico de síndrome de Wiskott -Aldrich por inmunogenetica (mutación del gen WAS) y mediante colaboración médica internacional, se realiza trasplante de médula ósea con posterior resolución de su enfermedad. DISCUSION: Las inmunodeficiencias primarias son patologías más comunes de lo que se creía (prevalencia de hasta 1/1200), la evidencia de aparición y su importancia clínica deben ser tomadas en consideración. En este caso de Síndrome de Wiskot-Aldrich en donde el diagnóstico definitivo es in - munogenetico, (actualmente el país no cuenta), además de tratamiento inmuno-oncológico adecuado, el paciente pudo sobrevivir y mejorar su calidad de vida gracias a soporte investigativo y terapéutico multinacional. Existen colaboraciones multicentricas como el consorcio de tratamiento inmunodeficiencias primarias, que tienen como objetivo colaborar activamente en el diagnóstico y tratamien - to estos casos, salvaguardando la vida de estos pacientes y ayudando a comprender estas enfermedades raras...(AU)


Assuntos
Humanos , Doenças Autoimunes , Transplante de Medula Óssea/métodos , Trombocitopenia/complicações , Síndrome de Wiskott-Aldrich/diagnóstico , Cromossomo X
18.
Hum Immunol ; 78(9): 565-573, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28535968

RESUMO

Wiskott-Aldrich syndrome (WAS) is a severe and rare primary immunodeficiency. Several studies show that WAS protein (WASp) plays a key role in the function of certain lymphocyte subsets. So far, no study has described distinct immunophenotypic abnormalities associated with WAS; thus the prognostic significance of any such abnormalities is unclear. This study examined many differences in the percentage/absolute numbers of distinct lymphocyte subsets in 20 WAS patients and 20 age/sex-matched healthy controls, and analyzed the association between these abnormalities and clinical disease scores. The results showed that the numbers of CD4+ T cells, B cells, and CD8+ naïve T cells were significantly lower in WAS patients; furthermore, the numbers in WASp-negative patients were lower than those in WASp-positive patients. WAS patients showed a selective reduction in expression of CD19 by naïve and transitional B cells. There was a negative association between the number of B cells and the WAS clinical scores. Also, CD8+ naïve T cell numbers in patients with a score of 3-5A were lower than those in patients with a score of 2. The absence of WASp leads to a reduction in the population of specific lymphocyte subsets; therefore, these findings may help future management of patients with WAS.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Subpopulações de Linfócitos/imunologia , Síndrome de Wiskott-Aldrich/imunologia , Antígenos CD19/metabolismo , Células Cultivadas , Pré-Escolar , Humanos , Memória Imunológica , Imunofenotipagem , Lactente , Recém-Nascido , Contagem de Linfócitos , Síndrome de Wiskott-Aldrich/diagnóstico , Proteína da Síndrome de Wiskott-Aldrich/imunologia
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