湿疹、血小板减少伴免疫缺陷综合征的诊治进展
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摘要
湿疹、血小板减少伴免疫缺陷综合征又名Wiskott-Aldrich综合征(Wiskott-Aldrich syndrome,WAS),是一种罕见的X-连锁的原发性免疫缺陷病,以血小板减少、出现湿疹、反复感染及免疫缺陷和恶性肿瘤发生率增加为特点。该疾病由造血细胞的WAS基因突变引起,WAS基因突变影响WAS蛋白(Wiskott-Aldrich syndrome protein, WASp)表达水平,而WASp表达水平与疾病严重程度正相关。WAS基因突变除引起以湿疹、血小板减少及免疫缺陷为典型三联征表现的WAS外,还可引起以轻度血小板减少为主要表现的X-连锁血小板减少症(X-linked thrombocytopenia,XLT)。造血干细胞移植是目前治疗WAS最有效的手段。近年,基因治疗也开始进入临床研究中。本文就近年来WAS诊治进展作一综述。
Eczema thrombocytopenia with immunodeficiency syndrome is also known as Wiskott-Aldrich syndrome(WAS), which is a rare X-linked primary immunodeficiency disease characterized by thrombocytopenia, eczema, recurrent infections and increased incidence of autoimmune and malignant tumors. The disease is caused by the mutation of WAS gene in hematopoietic cells. The mutation of WAS gene affects the expression level of Wiskott-Aldrich syndrome protein(WASp), and the expression level of WASp is positively correlated with the severity of the disease. In addition to WAS,which is characterized by eczema, thrombocytopenia and immunodeficiency, WAS gene mutation can also cause X-linked thrombocytopenia(XLT), which is characterized by mild thrombocytopenia.Hematopoietic stem cell transplantation is the most effective treatment for WAS. In recent years, gene therapy has also begun to enter clinical trials. This article reviews the progress of WAS diagnosis and treatment in recent years.
Eczema thrombocytopenia with immunodeficiency syndrome is also known as Wiskott-Aldrich syndrome(WAS), which is a rare X-linked primary immunodeficiency disease characterized by thrombocytopenia, eczema, recurrent infections and increased incidence of autoimmune and malignant tumors. The disease is caused by the mutation of WAS gene in hematopoietic cells. The mutation of WAS gene affects the expression level of Wiskott-Aldrich syndrome protein(WASp), and the expression level of WASp is positively correlated with the severity of the disease. In addition to WAS,which is characterized by eczema, thrombocytopenia and immunodeficiency, WAS gene mutation can also cause X-linked thrombocytopenia(XLT), which is characterized by mild thrombocytopenia.Hematopoietic stem cell transplantation is the most effective treatment for WAS. In recent years, gene therapy has also begun to enter clinical trials. This article reviews the progress of WAS diagnosis and treatment in recent years.
引文
[1]Massaad MJ,Ramesh N,Geha RS.Wiskott-Aldrich syndrome:a comprehensive review[J].Ann N Y Acad Sci,2013,1285:26-43.
[2]Ariga T.Wiskott-Aldrich syndrome:an x-linked primary immunodeficiency disease with unique and characteristic features[J].Allergol Int,2012.61(2):183-189.
[3]Kawasaki Y,Toyoda H,Otsuki S,et al.A novel WiskottAldrich syndrome protein mutation in an infant with thrombotic thrombocytopenic purpura[J].Eur J Haematol2013,90(2):164-168.
[4]Worth AJ,Thrasher AJ.Current and emerging treatmen options for Wiskott-Aldrich syndrome[J].Expert Rev Clin Immunol,2015,11(9):1015-1032.
[5]Li W,Liu D,Zhang X,et al.Clinical features and genotype analysis of 132 patients with Wiskott-Aldrich syndrome[J]Zhonghua Er Ke Za Zhi, 2015,53(12):925-930.
[6]Kaneko R,Yamamoto S, Okamoto N, et al. WiskottAldrich syndrome that was initially diagnosed as immune thrombocytopenic purpura secondary to a cytomegalovirus infection[J].SAGE Open Med Case Rep,2018,9:6-6.
[7]Esmaeilzadeh H,Bordbar MR,Dastsooz H, et al. A nove splice site mutation in WAS gene in patient with WiskottAldrich syndrome and chronic colitis:a case report[J].BMC Med Genet,2018,19(1):123-123.
[8]Arwani M, Lee D, Haddad A,et al.A novel mutation in Wiskott-Aldrich gene manifesting as macrothrombocytopenia and neutropenia[J].Br Med J Case Rep,2018,doi:10.1136/bcr-2018-225123.
[9]Kamuran K,Cetin M, Geylan H,et al.Wiskott-Aldrich syndrome:two case reports with a novel mutation[J].Pediatr Hematol Oncol,2017,34(5):286-291.
[10]Medina SS,Siqueira LH,Colella MP,et al.Intermittent low platelet counts hampering diagnosis of X-linked thrombocytopenia in children:report of two unrelated cases and a novel mutation in the gene coding for the WiskottAldrich syndrome protein[J].BMC Pediatr,2017,17(1):151-151.
[11]Pacharn P,Boonyawat B,Tantemsapya N,et al.A novel mutation of WAS gene in a boy with Mycobacterium bovis infection in spleen[J].Asian Pac J Allergy Immunol,201735(3):166-170.
[12]Patiroglu T,Klein C,Gungor HE,et al. Clinical features andgenetic analysis of six patients with Wiskott-Aldrich syndrome reporting two novel mutations:experience of Erciyes University,Kayseri,Turkey[J].Genet Couns,2016,27(1):9-24.
[13]Brigida I, Scaramuzza S, Lazarevic D,et al. A novel genomic inversion in Wiskott-Aldrich-associated autoinflammation[J].J Allergy Clin Immunol,2016,138(2):619-622.
[14]Eghbali M,Sadeghi-Shabestari M,Najmi Varzaneh F,et al.Novel WASP mutation in a patient with Wiskott-Aldrich syndrome:case report and review of the literature[J].Allergol Immunopathol(Madr),2016,44(5):450-454.
[15]Yoonessi L,Randhawa I,Nussbaum E,et al. Wiskott-Aldrich syndrome:description of a new gene mutation with normal platelet volume[J].J Pediatr Hematol Oncol,2015,37(7):515-518.
[16]Gulacsy V,Soltesz B,Petrescu C,et al. A novel large deletion and single nucleotide insertion in the Wiskott-Aldrich syndrome protein gene[J].Eur J Haematol,2015,95(1):93-98.
[17]Mantadakis E,Sawalle-Belohradsky J,Tzanoudaki M,et al.X-linked thrombocytopenia in three males with normal sized platelets due to novel WAS gene mutations[J].Pediatr Blood Cancer,2014,61(12):2305-2306.
[18]Zhu X,Tang B,Zheng C, et al.A novel mutation in WiskottAldrich syndrome and successfully treated with umbilical cord blood transplantation[J].Blood Cells Mol Dis,2014,53(4):283-285.
[19]Wada T,Itoh M,Maeba H,et al.Intermittent X-linked thrombocytopenia with a novel WAS gene mutation[J].Pediatr Blood Cancer,2014,61(4):746-748.
[20]Lee EK,Eem YJ,Chung NG,et al.A case of familial X-linked thrombocytopenia with a novel WAS gene mutation[J].Korean J Pediatr,2013,56(6):265-268.
[21]Siminovitch KA.Prenatal diagnosis and genetic analysis of Wiskott-Aldrich syndrome[J].Prenatal diagnosis,2003,23(12):1014-1016.
[22]Simpson JL,Carson SA,Cisneros. Preimplantation genetic diagnosis(PGD)for heritable neoplasia[J].J Natl Cancer Inst Monogr,2005,34:87-90.
[23]Kahraman S,Beyazyurek C,Yesilipek MA,et al.Successful haematopoietic stem cell transplantation in 44 children from healthy siblings conceived after preimplantation HLA matching[J].Reprod Biomed Online,2014,29(3):340-35.
[24]Rivers E,Worth A,Thrasher AJ,et al. Bleeding and splenectomy in Wiskott-Aldrich syndrome:a single-centre experience[J].J Allergy Clin Immunol Pract,2019,7(3):1042-1044.
[25]Braun CJ,Boztug K,Paruzynski A,et al. Gene therapy for Wiskott-Aldrich syndrome-long-term efficacy anc genotoxicity[J].Sci Transl Med,2014,6(227):227-233.
[26]Hacein-Bey Abina S,Gaspar HB,Blondeau J,et al. Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome[J].J Am Med Assoc,2015,313(15):1550-1563.
[27]Aiuti A,Biasco L,Scaramuzza S, et al. Lentivira hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome[J].Science,2013,341(6148):1233151-1233151.
[28]Bosticardo M,Ferrua F,Cavazzana M,et al. Gene therapy for Wiskott-Aldrich syndrome[J].Curr Gene Ther,2014,14(6):413-421.
[29]Castiello MC,Scaramuzza S,Pala F,et al. B-cell reconstitution after lentiviral vector-mediated gene therapy in patients with Wiskott-Aldrich syndrome[J].J Allergy Clin Immunol,2015136(3):692-702.
[30]Ghosh S,Gaspar HB.Gene Therapy Approaches to Immunodeficiency[J].Hematol Oncol Clin North Am,201731(5):823-834.
[31]Sarkar K,Sadhukhan S, Han SS,et al. Disruption of hSWI/SNF complexes in T cells by WAS mutations distinguishe:X-linked thrombocytopenia from Wiskott-Aldrich syndrome[J].Blood,2014,124(23):3409-3419.
[32]Parkman R,Rappeport J,Geha R, et al. Complete correction of the Wiskott-Aldrich syndrome by allogeneic bone-marroy transplantation[J].N Engl J Med,1978,298(17):921-927.
[33]Hacein-Bey Abina S,Gaspar HB, Blondeau J,et al. Outcomesfollowing hematopoietic cell transplantation for WiskottAldrich syndrome[J].Bone Marrow Transplant,2012,47(11):1428-1435.
[34]Mahlaoui N,Pellier I,Mignot C,et al.Characteristics and outcome of early-onset,severe forms of Wiskott-Aldrich syndrome[J].Blood,2013,121(9):1510-1516.
[35]Gungor T,Teira P,Slatter M,et al.Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease:a prospective multicentre study[J].Lancet,2014,383(9915):436-448.
[36]Morio T,Atsuta Y,Tomizawa D,et al. Outcome of unrelated umbilical cord blood transplantation in 88 patients with primary immunodeficiency in Japan[J].Br J Haematol,2011,154(3):363-372.
[37]Chiesa R,Veys P.Reduced-intensity conditioning for allogeneic stem cell transplant in primary immune deficiencies[J].Expert Rev Clin Immunol,2012,8(3):255-266.
[37]Slatter MA,Rao K,Amrolia P,et al.Treosulfan-based conditioning regimens for hematopoietic stem cell transplantation in children with primary immunodeficiency:United Kingdom experience[J].Blood,2011,11 7(1 6):4367-4375.
[39]Yue Y,Shi X,Song Z,et al.Posttransplant cyclophosphamide for haploidentical stem cell transplantation in children with Wiskott-Aldrich syndrome[J].Pediatr Blood Cancer,2018,doi:10.1002/pbc.27092.
[40]Elfeky R,FurtadoSilva JM,Chiesa,R,et al.100%survival after transplantation of 34 Wiskott Aldrich syndrome patients over 20 years[J].J Allergy Clin Immunol,2018,doi:10.1016/j.jaci.201 8.06.042.
[2]Ariga T.Wiskott-Aldrich syndrome:an x-linked primary immunodeficiency disease with unique and characteristic features[J].Allergol Int,2012.61(2):183-189.
[3]Kawasaki Y,Toyoda H,Otsuki S,et al.A novel WiskottAldrich syndrome protein mutation in an infant with thrombotic thrombocytopenic purpura[J].Eur J Haematol2013,90(2):164-168.
[4]Worth AJ,Thrasher AJ.Current and emerging treatmen options for Wiskott-Aldrich syndrome[J].Expert Rev Clin Immunol,2015,11(9):1015-1032.
[5]Li W,Liu D,Zhang X,et al.Clinical features and genotype analysis of 132 patients with Wiskott-Aldrich syndrome[J]Zhonghua Er Ke Za Zhi, 2015,53(12):925-930.
[6]Kaneko R,Yamamoto S, Okamoto N, et al. WiskottAldrich syndrome that was initially diagnosed as immune thrombocytopenic purpura secondary to a cytomegalovirus infection[J].SAGE Open Med Case Rep,2018,9:6-6.
[7]Esmaeilzadeh H,Bordbar MR,Dastsooz H, et al. A nove splice site mutation in WAS gene in patient with WiskottAldrich syndrome and chronic colitis:a case report[J].BMC Med Genet,2018,19(1):123-123.
[8]Arwani M, Lee D, Haddad A,et al.A novel mutation in Wiskott-Aldrich gene manifesting as macrothrombocytopenia and neutropenia[J].Br Med J Case Rep,2018,doi:10.1136/bcr-2018-225123.
[9]Kamuran K,Cetin M, Geylan H,et al.Wiskott-Aldrich syndrome:two case reports with a novel mutation[J].Pediatr Hematol Oncol,2017,34(5):286-291.
[10]Medina SS,Siqueira LH,Colella MP,et al.Intermittent low platelet counts hampering diagnosis of X-linked thrombocytopenia in children:report of two unrelated cases and a novel mutation in the gene coding for the WiskottAldrich syndrome protein[J].BMC Pediatr,2017,17(1):151-151.
[11]Pacharn P,Boonyawat B,Tantemsapya N,et al.A novel mutation of WAS gene in a boy with Mycobacterium bovis infection in spleen[J].Asian Pac J Allergy Immunol,201735(3):166-170.
[12]Patiroglu T,Klein C,Gungor HE,et al. Clinical features andgenetic analysis of six patients with Wiskott-Aldrich syndrome reporting two novel mutations:experience of Erciyes University,Kayseri,Turkey[J].Genet Couns,2016,27(1):9-24.
[13]Brigida I, Scaramuzza S, Lazarevic D,et al. A novel genomic inversion in Wiskott-Aldrich-associated autoinflammation[J].J Allergy Clin Immunol,2016,138(2):619-622.
[14]Eghbali M,Sadeghi-Shabestari M,Najmi Varzaneh F,et al.Novel WASP mutation in a patient with Wiskott-Aldrich syndrome:case report and review of the literature[J].Allergol Immunopathol(Madr),2016,44(5):450-454.
[15]Yoonessi L,Randhawa I,Nussbaum E,et al. Wiskott-Aldrich syndrome:description of a new gene mutation with normal platelet volume[J].J Pediatr Hematol Oncol,2015,37(7):515-518.
[16]Gulacsy V,Soltesz B,Petrescu C,et al. A novel large deletion and single nucleotide insertion in the Wiskott-Aldrich syndrome protein gene[J].Eur J Haematol,2015,95(1):93-98.
[17]Mantadakis E,Sawalle-Belohradsky J,Tzanoudaki M,et al.X-linked thrombocytopenia in three males with normal sized platelets due to novel WAS gene mutations[J].Pediatr Blood Cancer,2014,61(12):2305-2306.
[18]Zhu X,Tang B,Zheng C, et al.A novel mutation in WiskottAldrich syndrome and successfully treated with umbilical cord blood transplantation[J].Blood Cells Mol Dis,2014,53(4):283-285.
[19]Wada T,Itoh M,Maeba H,et al.Intermittent X-linked thrombocytopenia with a novel WAS gene mutation[J].Pediatr Blood Cancer,2014,61(4):746-748.
[20]Lee EK,Eem YJ,Chung NG,et al.A case of familial X-linked thrombocytopenia with a novel WAS gene mutation[J].Korean J Pediatr,2013,56(6):265-268.
[21]Siminovitch KA.Prenatal diagnosis and genetic analysis of Wiskott-Aldrich syndrome[J].Prenatal diagnosis,2003,23(12):1014-1016.
[22]Simpson JL,Carson SA,Cisneros. Preimplantation genetic diagnosis(PGD)for heritable neoplasia[J].J Natl Cancer Inst Monogr,2005,34:87-90.
[23]Kahraman S,Beyazyurek C,Yesilipek MA,et al.Successful haematopoietic stem cell transplantation in 44 children from healthy siblings conceived after preimplantation HLA matching[J].Reprod Biomed Online,2014,29(3):340-35.
[24]Rivers E,Worth A,Thrasher AJ,et al. Bleeding and splenectomy in Wiskott-Aldrich syndrome:a single-centre experience[J].J Allergy Clin Immunol Pract,2019,7(3):1042-1044.
[25]Braun CJ,Boztug K,Paruzynski A,et al. Gene therapy for Wiskott-Aldrich syndrome-long-term efficacy anc genotoxicity[J].Sci Transl Med,2014,6(227):227-233.
[26]Hacein-Bey Abina S,Gaspar HB,Blondeau J,et al. Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome[J].J Am Med Assoc,2015,313(15):1550-1563.
[27]Aiuti A,Biasco L,Scaramuzza S, et al. Lentivira hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome[J].Science,2013,341(6148):1233151-1233151.
[28]Bosticardo M,Ferrua F,Cavazzana M,et al. Gene therapy for Wiskott-Aldrich syndrome[J].Curr Gene Ther,2014,14(6):413-421.
[29]Castiello MC,Scaramuzza S,Pala F,et al. B-cell reconstitution after lentiviral vector-mediated gene therapy in patients with Wiskott-Aldrich syndrome[J].J Allergy Clin Immunol,2015136(3):692-702.
[30]Ghosh S,Gaspar HB.Gene Therapy Approaches to Immunodeficiency[J].Hematol Oncol Clin North Am,201731(5):823-834.
[31]Sarkar K,Sadhukhan S, Han SS,et al. Disruption of hSWI/SNF complexes in T cells by WAS mutations distinguishe:X-linked thrombocytopenia from Wiskott-Aldrich syndrome[J].Blood,2014,124(23):3409-3419.
[32]Parkman R,Rappeport J,Geha R, et al. Complete correction of the Wiskott-Aldrich syndrome by allogeneic bone-marroy transplantation[J].N Engl J Med,1978,298(17):921-927.
[33]Hacein-Bey Abina S,Gaspar HB, Blondeau J,et al. Outcomesfollowing hematopoietic cell transplantation for WiskottAldrich syndrome[J].Bone Marrow Transplant,2012,47(11):1428-1435.
[34]Mahlaoui N,Pellier I,Mignot C,et al.Characteristics and outcome of early-onset,severe forms of Wiskott-Aldrich syndrome[J].Blood,2013,121(9):1510-1516.
[35]Gungor T,Teira P,Slatter M,et al.Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease:a prospective multicentre study[J].Lancet,2014,383(9915):436-448.
[36]Morio T,Atsuta Y,Tomizawa D,et al. Outcome of unrelated umbilical cord blood transplantation in 88 patients with primary immunodeficiency in Japan[J].Br J Haematol,2011,154(3):363-372.
[37]Chiesa R,Veys P.Reduced-intensity conditioning for allogeneic stem cell transplant in primary immune deficiencies[J].Expert Rev Clin Immunol,2012,8(3):255-266.
[37]Slatter MA,Rao K,Amrolia P,et al.Treosulfan-based conditioning regimens for hematopoietic stem cell transplantation in children with primary immunodeficiency:United Kingdom experience[J].Blood,2011,11 7(1 6):4367-4375.
[39]Yue Y,Shi X,Song Z,et al.Posttransplant cyclophosphamide for haploidentical stem cell transplantation in children with Wiskott-Aldrich syndrome[J].Pediatr Blood Cancer,2018,doi:10.1002/pbc.27092.
[40]Elfeky R,FurtadoSilva JM,Chiesa,R,et al.100%survival after transplantation of 34 Wiskott Aldrich syndrome patients over 20 years[J].J Allergy Clin Immunol,2018,doi:10.1016/j.jaci.201 8.06.042.