132例Wiskott-Aldrich综合征和两家系X连锁淋巴细胞异常增生症临床及免疫学研究
发布时间：2018-07-17 03:53
【摘要】：第一部分:132例Wiskott-Aldrich综合征患儿临床特点及基因型分析目的:总结分析WAS综合征患儿的临床资料和突变基因,对临床表型和基因型,治疗及预后情况进行探讨。方法:回顾性分析我院2000年4月至2015年6月诊治的WAS综合征临床资料,探讨其主要临床表现特点、免疫学相关实验室检查、流式检测WAS蛋白表达情况、Sanger测序法检测基因突变、静脉注射免疫球蛋白(IVIG)等治疗及预后情况。结果:(1)132例WAS患儿均为男性,中位发病年龄15天(1天~4岁4月龄),中位诊断年龄10月龄(1月~22岁1月龄)。132例中包括典型WAS 112例,XLT 20例。外周血中位血小板值23×109/L(1×109/L~80×109/L)。(2)临床始发症状以皮肤出血或消化道出血为主,占75.0%(99例),其次为皮肤湿疹,占16.7%(22例)。病程中132例患儿均有不同程度的出血、湿疹和感染表现,其中21例(15.9%)并发自身免疫性疾病,1例合并白血病。(3)115例患儿行流式细胞术WAS蛋白(WASp)检测,其中88例不表达,12例表达减少,5例表达正常,10例双峰表达。(4)125个无关家系中共发现81种突变,发现已报道的8种热点突变,即290CN/291GN(R86C/H/L)、665CT(R211X)、155 CT(R41X)、168 CT(T45M)、IVS1+1 gt/a、IVS6+5ga、IVS8+1 ga和IVS8+1_+6del gtga;同时发现新发突变29种,包括321TC、415CA、471CT、102-105 del C、521 del C、1330 del A、IVS2-2 ac、168 CA/1412 CT和exon1-2 del/1412 CT等。(5)免疫学检查发现部分患儿外周血CD3+T细胞(31.3%)、辅助性T细胞(37.3%)及细胞毒性T细胞(38.6%)比例下降;患儿外周血免疫球蛋白IgG增高(51.1%)、Ig A增高(43.3%)、Ig M减低(25.6%)及Ig E增高(40.0%)。(6)72例存活患儿中36例接受造血干细胞移植(HSCT),14例典型WAS患儿接受静脉注射免疫球蛋白(IVIG)治疗,感染频率降低。结论:我们诊治了全球单中心最大宗Wiskott-Aldrich综合征病例。该病起病年龄早,以血小板减少伴血小板体积减小、湿疹及反复感染为主要临床特征。部分患儿T淋巴细胞减少,可有Ig A增高、Ig M降低及Ig E增高表现。WAS基因突变类型和所处位置与临床表现密切相关。HSCT是根本治疗该病的手段。合理的IVIG治疗是为患儿赢取等待供者的时间及改善其生存质量的有效方法。第二部分:X连锁淋巴细胞异常增生症1型两家系临床特点及免疫学研究目的:探讨以丙种球蛋白缺乏血症为突出表现的两个家系4名X-连锁淋巴细胞异常增生症1型(XLP-1)患儿的临床和免疫学特点、SAP蛋白表达及SH2D1A基因突变情况。方法:以2016年1~6月在我医院风湿免疫科诊治的两家系4例(家系A例1、例2,家系B例3、例4)患儿及亲属为研究对象,分析临床特征。采用流式细胞术分析淋巴细胞亚群、T细胞增殖功能和SAP蛋白表达,采用PCR技术检测结合T细胞受体删除环(sj TRECs)、TCRVβ亚家族克隆谱和SH2D1A基因。结果:(1)4例患儿确诊为XLP-1,均为男性,发病年龄例1和例2为1岁余龄、例3为1月余龄、例4为6月龄,诊断年龄分别为9岁10月龄、16岁8月龄、14岁10月龄、4岁9月龄,4例患儿均有反复呼吸道感染,例1、例2、例3的IgG、Ig M、Ig A极低,例4稍降低。EBV-PCR检测均为阳性。4名患儿均有肺实质病变和肺不张。例3有明确支扩并确诊为咽部Burkitt淋巴瘤。(2)4名患儿有CD4/CD8比值倒置、耗竭细胞增多、NK细胞数量降低、B细胞总数正常、记忆B细胞数量减少、初始B细胞正常、sj TRECs值低、TCRVβ亚家族克隆谱轻度受限、T细胞增殖正常。(3)流式细胞术检测显示例1和例2无SAP蛋白,例3和例4的SAP蛋白量减少。(4)基因分析发现家系A中2例患儿为SH2D1A基因163 CT(p.R55X),其母及两个同胞姐妹为携带者。家族B中2例患儿为SH2D1A基因突变278GA(p.G93D),其母为携带者。4例患儿中其中例3放弃治疗,其余患儿开始接受规律静脉注射免疫球蛋白(IVIG)治疗,等待移植。结论:两个家系中4例患儿均以IgG、Ig M、Ig A降低为突出表现,易于与X-连锁无丙球血症(XLA)相混淆。但本组患儿同时具有EB病毒高度易感,免疫功能不同程度受损。流式检测SAP蛋白表达异常和SH2D1A基因发现致病突变。
[Abstract]:The first part: clinical features and genotype analysis of 132 children with Wiskott-Aldrich syndrome: the clinical data and mutant genes of children with WAS syndrome were summarized and analyzed. The clinical phenotype and genotype, treatment and prognosis were discussed. Methods: a retrospective analysis of the clinical data of WAS syndrome in our hospital from April 2000 to June 2015 was reviewed. To discuss the main clinical manifestations, immunological related laboratory tests, flow detection of WAS protein expression, Sanger sequencing and intravenous immunoglobulin (IVIG) and other treatment and prognosis. Results: (1) 132 children with WAS were male, the median age was 15 days (1 days ~4 years 4 month old), and median age was 10 month old (January). ~22 years old 1 month old).132 cases included typical WAS 112 cases, XLT 20 cases. The median blood platelet value of peripheral blood was 23 x 109/L (1 x 109/L~80 x 109/L). (2) the clinical initial symptoms were mainly skin bleeding or digestive tract bleeding, 75% (99 cases), followed by skin eczema, 16.7% (22 cases). In the course of disease, there were different degrees of bleeding, eczema and infection in children. Among them, 21 cases (15.9%) had autoimmune diseases and 1 cases with leukemia. (3) 115 cases were detected by flow cytometry WAS protein (WASp), of which 88 cases were not expressed, 12 cases were expressed, 5 cases expressed normal, 10 cases of Shuangfeng expression. (4) 125 unrelated families were present 81 kinds of mutation, found that 290CN/291GN (R86C/H/L) ), 665CT (R211X), 155 CT (R41X), 168 CT (T45M), IVS1+1 gt/a, IVS6+5ga, IVS8+1 GA and IVS8+1_+6del. The proportion of T cells (37.3%) and cytotoxic T cells (38.6%) decreased, the peripheral blood immunoglobulin IgG increased (51.1%), Ig A increased (43.3%), Ig M decreased (25.6%) and Ig E increased (40%). (6) 36 patients with 72 surviving children received hematopoietic stem cell transplantation (HSCT), 14 cases of typical WAS children received intravenous immunoglobulin (IVIG) treatment, infection. Conclusion: we have diagnosed the largest Wiskott-Aldrich syndrome in a single center of the world. The onset of the disease is early, thrombocytopenia with reduced platelet volume, eczema and recurrent infection as the main clinical features. The decrease of T lymphocyte in some children, the increase of Ig A, the decrease of Ig M and the increase of.WAS gene mutation in Ig E .HSCT, which is closely related to its location and clinical manifestations, is a fundamental treatment for the disease. Reasonable IVIG therapy is an effective way to win the time for the waiting for the donor and improve the quality of life for the children. The second part: the clinical characteristics and immunological purposes of the two lines of X linked lymphoblastic dysplasia (1): To explore the gamma globulin The clinical and immunological characteristics, SAP protein expression and SH2D1A gene mutation of two families with 4 X- linked lymphoblastic dysplasia (XLP-1) in children with deficiency syndrome. Methods: 4 cases (1 of family A cases, 2 of family, 3 of B cases, 4 of family B cases) and relatives were studied in the rheumatology Department of our hospital during 1~6 month of 2016. Analysis of the clinical features. Flow cytometry was used to analyze lymphocyte subsets, T cell proliferation and SAP protein expression. PCR technique was used to detect T cell receptor deletion ring (SJ TRECs), TCRV beta subfamily clone and SH2D1A gene. Results: (1) 4 cases were diagnosed as XLP-1, all were male, age 1, and 2 were 1 years old, Cases 3 were in January, 4 was 6 month old, and the diagnostic age was 9 and 10 month old, 16 years old and 8 month old, 14 years 10 month old, 4 years 9 month old, 4 cases were recurrent respiratory tract infection. Cases 1, case 2, IgG, Ig M, Ig A were very low. The cases of.EBV-PCR detection were all positive.4 children all had pulmonary parenchyma disease and atelectasis. Burkitt lymphoma. (2) 4 children had the inversion of CD4/CD8 ratio, the number of depleted cells, the decrease of the number of NK cells, the normal number of B cells, the decrease of the number of memory B cells, the normal B cells, the low SJ TRECs value, the mild restriction of the TCRV beta subfamily clone spectrum and the normal proliferation of T cells. (3) the flow cytometry showed 1 and 2 non SAP proteins, 3 cases and 4 cases. The amount of SAP protein decreased. (4) gene analysis found that 2 children in family A were SH2D1A gene 163 CT (p.R55X), their mother and two siblings were carriers. 2 children in the family B were SH2D1A gene mutation 278GA (p.G93D), and the mother was the carrier of the carrier, of which 3 gave up the treatment, the rest of the children began to receive the regular intravenous immunization eggs. White (IVIG) treatment, waiting for transplantation. Conclusion: 4 cases of two families with IgG, Ig M, Ig A decreased to be prominent, easy to be confused with X- linked non propanaemia (XLA), but the children were highly susceptible to EB virus, the immune function was damaged in varying degrees. Flow detection of SAP protein expression abnormality and SH2D1A gene discovery of pathogenic mutation.
【学位授予单位】：重庆医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R725.9
[Abstract]:The first part: clinical features and genotype analysis of 132 children with Wiskott-Aldrich syndrome: the clinical data and mutant genes of children with WAS syndrome were summarized and analyzed. The clinical phenotype and genotype, treatment and prognosis were discussed. Methods: a retrospective analysis of the clinical data of WAS syndrome in our hospital from April 2000 to June 2015 was reviewed. To discuss the main clinical manifestations, immunological related laboratory tests, flow detection of WAS protein expression, Sanger sequencing and intravenous immunoglobulin (IVIG) and other treatment and prognosis. Results: (1) 132 children with WAS were male, the median age was 15 days (1 days ~4 years 4 month old), and median age was 10 month old (January). ~22 years old 1 month old).132 cases included typical WAS 112 cases, XLT 20 cases. The median blood platelet value of peripheral blood was 23 x 109/L (1 x 109/L~80 x 109/L). (2) the clinical initial symptoms were mainly skin bleeding or digestive tract bleeding, 75% (99 cases), followed by skin eczema, 16.7% (22 cases). In the course of disease, there were different degrees of bleeding, eczema and infection in children. Among them, 21 cases (15.9%) had autoimmune diseases and 1 cases with leukemia. (3) 115 cases were detected by flow cytometry WAS protein (WASp), of which 88 cases were not expressed, 12 cases were expressed, 5 cases expressed normal, 10 cases of Shuangfeng expression. (4) 125 unrelated families were present 81 kinds of mutation, found that 290CN/291GN (R86C/H/L) ), 665CT (R211X), 155 CT (R41X), 168 CT (T45M), IVS1+1 gt/a, IVS6+5ga, IVS8+1 GA and IVS8+1_+6del. The proportion of T cells (37.3%) and cytotoxic T cells (38.6%) decreased, the peripheral blood immunoglobulin IgG increased (51.1%), Ig A increased (43.3%), Ig M decreased (25.6%) and Ig E increased (40%). (6) 36 patients with 72 surviving children received hematopoietic stem cell transplantation (HSCT), 14 cases of typical WAS children received intravenous immunoglobulin (IVIG) treatment, infection. Conclusion: we have diagnosed the largest Wiskott-Aldrich syndrome in a single center of the world. The onset of the disease is early, thrombocytopenia with reduced platelet volume, eczema and recurrent infection as the main clinical features. The decrease of T lymphocyte in some children, the increase of Ig A, the decrease of Ig M and the increase of.WAS gene mutation in Ig E .HSCT, which is closely related to its location and clinical manifestations, is a fundamental treatment for the disease. Reasonable IVIG therapy is an effective way to win the time for the waiting for the donor and improve the quality of life for the children. The second part: the clinical characteristics and immunological purposes of the two lines of X linked lymphoblastic dysplasia (1): To explore the gamma globulin The clinical and immunological characteristics, SAP protein expression and SH2D1A gene mutation of two families with 4 X- linked lymphoblastic dysplasia (XLP-1) in children with deficiency syndrome. Methods: 4 cases (1 of family A cases, 2 of family, 3 of B cases, 4 of family B cases) and relatives were studied in the rheumatology Department of our hospital during 1~6 month of 2016. Analysis of the clinical features. Flow cytometry was used to analyze lymphocyte subsets, T cell proliferation and SAP protein expression. PCR technique was used to detect T cell receptor deletion ring (SJ TRECs), TCRV beta subfamily clone and SH2D1A gene. Results: (1) 4 cases were diagnosed as XLP-1, all were male, age 1, and 2 were 1 years old, Cases 3 were in January, 4 was 6 month old, and the diagnostic age was 9 and 10 month old, 16 years old and 8 month old, 14 years 10 month old, 4 years 9 month old, 4 cases were recurrent respiratory tract infection. Cases 1, case 2, IgG, Ig M, Ig A were very low. The cases of.EBV-PCR detection were all positive.4 children all had pulmonary parenchyma disease and atelectasis. Burkitt lymphoma. (2) 4 children had the inversion of CD4/CD8 ratio, the number of depleted cells, the decrease of the number of NK cells, the normal number of B cells, the decrease of the number of memory B cells, the normal B cells, the low SJ TRECs value, the mild restriction of the TCRV beta subfamily clone spectrum and the normal proliferation of T cells. (3) the flow cytometry showed 1 and 2 non SAP proteins, 3 cases and 4 cases. The amount of SAP protein decreased. (4) gene analysis found that 2 children in family A were SH2D1A gene 163 CT (p.R55X), their mother and two siblings were carriers. 2 children in the family B were SH2D1A gene mutation 278GA (p.G93D), and the mother was the carrier of the carrier, of which 3 gave up the treatment, the rest of the children began to receive the regular intravenous immunization eggs. White (IVIG) treatment, waiting for transplantation. Conclusion: 4 cases of two families with IgG, Ig M, Ig A decreased to be prominent, easy to be confused with X- linked non propanaemia (XLA), but the children were highly susceptible to EB virus, the immune function was damaged in varying degrees. Flow detection of SAP protein expression abnormality and SH2D1A gene discovery of pathogenic mutation.
【学位授予单位】：重庆医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R725.9
【参考文献】
相关期刊论文 前2条
1 蒋金秋;唐茂芝;安云飞;赵晓东;;普通变异型免疫缺陷病研究进展[J];儿科药学杂志;2015年07期
2 杨曦;王晶;安云飞;金兼弘和;宫，
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