13例Wiskott-Aldrich综合征临床特征分析
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摘要
目的研究Wiskott-Aldrich综合征(WAS)患儿的临床特征。方法对13例WAS患儿的临床资料进行回顾性分析。结果 13例患儿均为男性,发病年龄3(1～48)月,确诊年龄24(1～60)月。13例患儿中仅3例为典型WAS,余10例均为X-连锁血小板减少症(XLT)。WAS评分为2(1～3)分,血小板计数为20.5(13～46)×10~9/L,平均血小板体积为8.1(6.7～12.1)fl。4例患儿行淋巴细胞亚群及免疫球蛋白检查,其中淋巴细胞占有核细胞百分比及CD3~+T细胞占淋巴细胞百分比均减低者1例(25%);CD3-CD56+NK细胞占淋巴细胞百分比减低者1例(25%);IgG升高者1例(25%),IgM下降者2例(50%),IgA下降者1例(25%),4例患儿IgE均升高(100%)。13例患儿共发现13种14个基因突变,其中错义突变9例(65%),剪接突变2例(14%),无义突变2例(14%),移码突变1例(7%)。随访39(3～62)个月,13例患儿均存活。结论 Wiskott-Aldrich综合征发病年龄小,男性为主,主要临床特征为血小板减少伴血小板体积缩小,基因突变以错义突变为主。[中国当代儿科杂志,2019,21(5):463-467]
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 20.5×109/L [range(13-46)×10~9/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 CD3+T cells per lymphocyte and lymphocyte per nuclear cells, 1(25%) had a reduction in CD3-CD56~+ 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.[Chin J Contemp Pediatr, 2019, 21(5): 463-467]
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 20.5×109/L [range(13-46)×10~9/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 CD3+T cells per lymphocyte and lymphocyte per nuclear cells, 1(25%) had a reduction in CD3-CD56~+ 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.[Chin J Contemp Pediatr, 2019, 21(5): 463-467]
引文
[1]Worth AJ,Thrasher AJ.Current and emerging treatment options for Wiskott-Aldrich syndrome[J].Expert Rev Clin Immunol,2015,11(9):1015-1032.
[2]Aldrich RA,Steinberg AG,Campbell DC.Pedigree demonstrating a sex-linked recessive condition characterized by draining ears,eczematoid dermatitis and bloody diarrhea[J].Pediatrics,1954,13(2):133-139.
[3]de Saint Basile G,Arveiler B,Fraser NJ,et al.Close linkage of hypervariable marker DXS255 to disease locus of WiskottAldrich syndrome[J].Lancet,1989,2(8675):1319-1321.
[4]Derry JM,Ochs HD,Francke U.Isolation of a novel gene mutated in Wiskott-Aldrich syndrome[J].Cell,1994,78(4):635-644.
[5]Massaad MJ,Ramesh N,Geha RS.Wiskott-Aldrich syndrome:a comprehensive review[J].Ann N Y Acad Sci,2013,1285:26-43.
[6]Zhu Q,Zhang M,Blaese RM,et al.The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene[J].Blood,1995,86(10):3797-3804.
[7]肖慧勤,张志勇,蒋利萍,等.Wiskott-Aldrich综合征10例临床特点与实验室诊断分析[J].免疫学杂志,2010,26(1):43-48.
[8]Zhu Q,Watanabe C,Liu T,et al.Wiskott-Aldrich syndrome/X-linked thrombocytopenia:WASP gene mutations,protein expression,and phenotype[J].Blood,1997,90(7):2680-2689.
[9]Ochs HD.The Wiskott-Aldrich syndrome[J].Isr Med Assoc J,2002,4(5):379-384.
[10]赵惠君.Wiskott-Aldrich综合征诊断治疗进展[J].中华实用儿科临床杂志,2016,31(15):1129-1132.
[11]Jin Y,Mazza C,Christie JR,et al.Mutations of the WiskottAldrich Syndrome Protein(WASP):hotspots,effect on transcription,and translation and phenotype/genotype correlation[J].Blood,2004,104(13):4010-4019.
[12]Notarangelo LD,Mazza C,Giliani S,et al.Missense mutations of the WASP gene cause intermittent X-linked thrombocytopenia[J].Blood,2002,99(6):2268-2269.
[13]李文言,刘大玮,张璇,等.Wiskott-Aldrich综合征132例临床特点及基因型分析[J].中华儿科杂志,2015,53(12):925-930.
[14]Blundell MP,Worth A,Bouma G,et al.The Wiskott-Aldrich syndrome:the actin cytoskeleton and immune cell function[J].Dis Markers,2010,29(3-4):157-175.
[15]Sullivan KE,Mullen CA,Blaese RM,et al.A multiinstitutional survey of the Wiskott-Aldrich syndrome[J].J Pediatr,1994,125(6 Pt 1):876-885.
[16]Worth AJ,Thrasher AJ.Current and emerging treatment options for Wiskott-Aldrich syndrome[J].Expert Rev Clin Immunol,2015,11(9):1015-1032.
[17]Moratto D,Giliani S,Bonfim C,et al.Long-term outcome and lineage-specific chimerism in 194 patients with WiskottAldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009:an international collaborative study[J].Blood,2011,118(6):1675-1684.
[18]Gerrits AJ,Leven EA,Frelinger AL 3rd,et al.Effects of eltrombopag on platelet count and platelet activation in WiskottAldrich syndrome/X-linked thrombocytopenia[J].Blood,2015,126(11):1367-1378.
[19]DupréL,Marangoni F,Scaramuzza S,et al.Efficacy of gene therapy for Wiskott-Aldrich syndrome using a WAS promoter/cDNA-containing lentiviral vector and nonlethal irradiation[J].Hum Gene Ther,2006,17(3):303-313.
[20]Astrakhan A,Sather BD,Ryu BY,et al.Ubiquitous high-level gene expression in hematopoietic lineages provides effective lentiviral gene therapy of murine Wiskott-Aldrich syndrome[J].Blood,2012,119(19):4395-4407.
[21]Boztug K,Schmidt M,Schwarzer A,et al.Stem-cell gene therapy for the Wiskott-Aldrich syndrome[J].N Engl J Med,2010,363(20):1918-1927.
[22]Hacein-Bey Abina S,Gaspar HB,Blondeau J,et al.Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome[J].JAMA,2015,313(15):1550-1563.
[2]Aldrich RA,Steinberg AG,Campbell DC.Pedigree demonstrating a sex-linked recessive condition characterized by draining ears,eczematoid dermatitis and bloody diarrhea[J].Pediatrics,1954,13(2):133-139.
[3]de Saint Basile G,Arveiler B,Fraser NJ,et al.Close linkage of hypervariable marker DXS255 to disease locus of WiskottAldrich syndrome[J].Lancet,1989,2(8675):1319-1321.
[4]Derry JM,Ochs HD,Francke U.Isolation of a novel gene mutated in Wiskott-Aldrich syndrome[J].Cell,1994,78(4):635-644.
[5]Massaad MJ,Ramesh N,Geha RS.Wiskott-Aldrich syndrome:a comprehensive review[J].Ann N Y Acad Sci,2013,1285:26-43.
[6]Zhu Q,Zhang M,Blaese RM,et al.The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene[J].Blood,1995,86(10):3797-3804.
[7]肖慧勤,张志勇,蒋利萍,等.Wiskott-Aldrich综合征10例临床特点与实验室诊断分析[J].免疫学杂志,2010,26(1):43-48.
[8]Zhu Q,Watanabe C,Liu T,et al.Wiskott-Aldrich syndrome/X-linked thrombocytopenia:WASP gene mutations,protein expression,and phenotype[J].Blood,1997,90(7):2680-2689.
[9]Ochs HD.The Wiskott-Aldrich syndrome[J].Isr Med Assoc J,2002,4(5):379-384.
[10]赵惠君.Wiskott-Aldrich综合征诊断治疗进展[J].中华实用儿科临床杂志,2016,31(15):1129-1132.
[11]Jin Y,Mazza C,Christie JR,et al.Mutations of the WiskottAldrich Syndrome Protein(WASP):hotspots,effect on transcription,and translation and phenotype/genotype correlation[J].Blood,2004,104(13):4010-4019.
[12]Notarangelo LD,Mazza C,Giliani S,et al.Missense mutations of the WASP gene cause intermittent X-linked thrombocytopenia[J].Blood,2002,99(6):2268-2269.
[13]李文言,刘大玮,张璇,等.Wiskott-Aldrich综合征132例临床特点及基因型分析[J].中华儿科杂志,2015,53(12):925-930.
[14]Blundell MP,Worth A,Bouma G,et al.The Wiskott-Aldrich syndrome:the actin cytoskeleton and immune cell function[J].Dis Markers,2010,29(3-4):157-175.
[15]Sullivan KE,Mullen CA,Blaese RM,et al.A multiinstitutional survey of the Wiskott-Aldrich syndrome[J].J Pediatr,1994,125(6 Pt 1):876-885.
[16]Worth AJ,Thrasher AJ.Current and emerging treatment options for Wiskott-Aldrich syndrome[J].Expert Rev Clin Immunol,2015,11(9):1015-1032.
[17]Moratto D,Giliani S,Bonfim C,et al.Long-term outcome and lineage-specific chimerism in 194 patients with WiskottAldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009:an international collaborative study[J].Blood,2011,118(6):1675-1684.
[18]Gerrits AJ,Leven EA,Frelinger AL 3rd,et al.Effects of eltrombopag on platelet count and platelet activation in WiskottAldrich syndrome/X-linked thrombocytopenia[J].Blood,2015,126(11):1367-1378.
[19]DupréL,Marangoni F,Scaramuzza S,et al.Efficacy of gene therapy for Wiskott-Aldrich syndrome using a WAS promoter/cDNA-containing lentiviral vector and nonlethal irradiation[J].Hum Gene Ther,2006,17(3):303-313.
[20]Astrakhan A,Sather BD,Ryu BY,et al.Ubiquitous high-level gene expression in hematopoietic lineages provides effective lentiviral gene therapy of murine Wiskott-Aldrich syndrome[J].Blood,2012,119(19):4395-4407.
[21]Boztug K,Schmidt M,Schwarzer A,et al.Stem-cell gene therapy for the Wiskott-Aldrich syndrome[J].N Engl J Med,2010,363(20):1918-1927.
[22]Hacein-Bey Abina S,Gaspar HB,Blondeau J,et al.Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome[J].JAMA,2015,313(15):1550-1563.