發(fā)布時間：2018-07-17 03:53

【摘要】：第一部分:132例Wiskott-Aldrich綜合征患兒臨床特點(diǎn)及基因型分析目的:總結(jié)分析WAS綜合征患兒的臨床資料和突變基因,對臨床表型和基因型,治療及預(yù)后情況進(jìn)行探討。方法:回顧性分析我院2000年4月至2015年6月診治的WAS綜合征臨床資料,探討其主要臨床表現(xiàn)特點(diǎn)、免疫學(xué)相關(guān)實(shí)驗(yàn)室檢查、流式檢測WAS蛋白表達(dá)情況、Sanger測序法檢測基因突變、靜脈注射免疫球蛋白(IVIG)等治療及預(yù)后情況。結(jié)果:(1)132例WAS患兒均為男性,中位發(fā)病年齡15天(1天~4歲4月齡),中位診斷年齡10月齡(1月~22歲1月齡)。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)臨床始發(fā)癥狀以皮膚出血或消化道出血為主,占75.0%(99例),其次為皮膚濕疹,占16.7%(22例)。病程中132例患兒均有不同程度的出血、濕疹和感染表現(xiàn),其中21例(15.9%)并發(fā)自身免疫性疾病,1例合并白血病。(3)115例患兒行流式細(xì)胞術(shù)WAS蛋白(WASp)檢測,其中88例不表達(dá),12例表達(dá)減少,5例表達(dá)正常,10例雙峰表達(dá)。(4)125個無關(guān)家系中共發(fā)現(xiàn)81種突變,發(fā)現(xiàn)已報道的8種熱點(diǎn)突變,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;同時發(fā)現(xiàn)新發(fā)突變29種,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)免疫學(xué)檢查發(fā)現(xiàn)部分患兒外周血CD3+T細(xì)胞(31.3%)、輔助性T細(xì)胞(37.3%)及細(xì)胞毒性T細(xì)胞(38.6%)比例下降;患兒外周血免疫球蛋白IgG增高(51.1%)、Ig A增高(43.3%)、Ig M減低(25.6%)及Ig E增高(40.0%)。(6)72例存活患兒中36例接受造血干細(xì)胞移植(HSCT),14例典型WAS患兒接受靜脈注射免疫球蛋白(IVIG)治療,感染頻率降低。結(jié)論:我們診治了全球單中心最大宗Wiskott-Aldrich綜合征病例。該病起病年齡早,以血小板減少伴血小板體積減小、濕疹及反復(fù)感染為主要臨床特征。部分患兒T淋巴細(xì)胞減少,可有Ig A增高、Ig M降低及Ig E增高表現(xiàn)。WAS基因突變類型和所處位置與臨床表現(xiàn)密切相關(guān)。HSCT是根本治療該病的手段。合理的IVIG治療是為患兒贏取等待供者的時間及改善其生存質(zhì)量的有效方法。第二部分:X連鎖淋巴細(xì)胞異常增生癥1型兩家系臨床特點(diǎn)及免疫學(xué)研究目的:探討以丙種球蛋白缺乏血癥為突出表現(xiàn)的兩個家系4名X-連鎖淋巴細(xì)胞異常增生癥1型(XLP-1)患兒的臨床和免疫學(xué)特點(diǎn)、SAP蛋白表達(dá)及SH2D1A基因突變情況。方法:以2016年1~6月在我醫(yī)院風(fēng)濕免疫科診治的兩家系4例(家系A(chǔ)例1、例2,家系B例3、例4)患兒及親屬為研究對象,分析臨床特征。采用流式細(xì)胞術(shù)分析淋巴細(xì)胞亞群、T細(xì)胞增殖功能和SAP蛋白表達(dá),采用PCR技術(shù)檢測結(jié)合T細(xì)胞受體刪除環(huán)(sj TRECs)、TCRVβ亞家族克隆譜和SH2D1A基因。結(jié)果:(1)4例患兒確診為XLP-1,均為男性,發(fā)病年齡例1和例2為1歲余齡、例3為1月余齡、例4為6月齡,診斷年齡分別為9歲10月齡、16歲8月齡、14歲10月齡、4歲9月齡,4例患兒均有反復(fù)呼吸道感染,例1、例2、例3的IgG、Ig M、Ig A極低,例4稍降低。EBV-PCR檢測均為陽性。4名患兒均有肺實(shí)質(zhì)病變和肺不張。例3有明確支擴(kuò)并確診為咽部Burkitt淋巴瘤。(2)4名患兒有CD4/CD8比值倒置、耗竭細(xì)胞增多、NK細(xì)胞數(shù)量降低、B細(xì)胞總數(shù)正常、記憶B細(xì)胞數(shù)量減少、初始B細(xì)胞正常、sj TRECs值低、TCRVβ亞家族克隆譜輕度受限、T細(xì)胞增殖正常。(3)流式細(xì)胞術(shù)檢測顯示例1和例2無SAP蛋白,例3和例4的SAP蛋白量減少。(4)基因分析發(fā)現(xiàn)家系A(chǔ)中2例患兒為SH2D1A基因163 CT(p.R55X),其母及兩個同胞姐妹為攜帶者。家族B中2例患兒為SH2D1A基因突變278GA(p.G93D),其母為攜帶者。4例患兒中其中例3放棄治療,其余患兒開始接受規(guī)律靜脈注射免疫球蛋白(IVIG)治療,等待移植。結(jié)論:兩個家系中4例患兒均以IgG、Ig M、Ig A降低為突出表現(xiàn),易于與X-連鎖無丙球血癥(XLA)相混淆。但本組患兒同時具有EB病毒高度易感,免疫功能不同程度受損。流式檢測SAP蛋白表達(dá)異常和SH2D1A基因發(fā)現(xiàn)致病突變。
[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.
【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R725.9

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