以丙种球蛋白缺乏血症为突出表现的X连锁淋巴细胞异常增生症1型两家系研究  

Two families of X-linked lymphoproliferative disease type 1 characterized by agammaglobulinemia

作　　者：李文言[1] 陈金淑[1] 赵芹[1] 戴荣欣[1] 王艳平[1] 赵宏意 陈学梅[1] 薛秀红[1] 孙晓宇[1] 唐雪梅[1] 张宇[1] 丁媛[1] 赵晓东[1] 张志勇[1] 

机构地区：[1]重庆医科大学附属儿童医院风湿免疫科儿童发育疾病研究教育部重点实验室儿童发育重大疾病国家国际科技合作基地儿童感染免疫重庆市重点实验室,400014

出　　处：《中华儿科杂志》2017年第5期377-382,共6页Chinese Journal of Pediatrics

基　　金：国家卫生计生委公益性行业科研专项（201402012）;国家自然科学基金（81202365、81172878）

摘　　要：目的 探讨以丙种球蛋白缺乏血症为突出表现的X连锁淋巴细胞异常增生症1型（XLP-1）的临床特点、免疫学特征、SAP蛋白表达及SH2D1A基因突变情况.方法 以2016年1-6月在重庆医科大学附属儿童医院风湿免疫科诊治的两家系4例（A家系例1、例2,B家系例3、例4）患儿及其亲属为研究对象,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技术检测信号结合T细胞受体删除环（sj TRECs）、TCRvβ亚家族克隆谱和SH2D1A基因.结果 （1）例1～4确诊为XLP-1,均为男性,发病年龄分别为1岁余、1岁余、1月龄余、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,均有反复严重呼吸道感染,例1、例2、例3为无丙种球蛋白血症,例4为低丙种球蛋白血症.EB病毒-PCR检测均阳性.胸部CT发现4例患儿均有肺实变不张,其中例3有支气管扩张.例3于14岁确诊为Burkitt淋巴瘤.（2）4例患儿的免疫学检查发现CD4/CD8比倒置、耗竭T细胞增多、NK细胞数量降低、B细胞总数正常,但记忆B细胞数量减少而初始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SAP蛋白表达显示例1和例2蛋白无表达,例3和例4蛋白表达减少.（4）基因分析发现家系A中2例患儿SH2D1A基因第2外显子无义突变（c.163C＞T;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基因第3外显子错义突变（c.278 G＞A;p.G93D）,其母为携带者.4例患儿目前均存活,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 两家系中4例患儿均以丙种球蛋白缺乏血症为突出表现,具有EB病毒高度易感,T细胞、B细胞及NK细胞免疫功能不同程度受损,流式检测SAP蛋白表达异常和SH2D1A基因发现致病突变为诊断XLP-1依据.Objective To investigate the clinical and immunological laboratory features,mutations in SH2D1A gene and SAP protein expression in four children of two families with X-linked lymphoproliferative disease type 1 （XLP-1）.Method Four patients （Family A including Patient 1 and Patient 2,Family B including Patient 3 and Patient 4） and their maternal relatives were enrolled in this study.The clinical manifestation,EBV infection status and chest CT scan were analyzed.The absolute and relative numbers of lymphocyte subsets,T lymphocyte proliferative response,SAP protein expression were assessed by flow cytometry.Quantification of signal joint TCR rearrangementexcision circle （sjTRECs）,CDR3 spectratyping of TCRv3 and gene mutation of SH2D1A were detected by PCR based on genomic DNA or cDNA.Result Four male patients from two families were diagnosed with XLP-1.The ages of disease onset were more than 1 year,more than 1 year,more than 1 month and 6 months.The ages at diagnosis were nine years and ten months,sixteen years and eight months,fourteen years and ten months,four years and nine months.All patients had recurrent infections and EBV infection.Patients 1,2,and 3 had agammaglobulinemia and Patient 4 had hypogammaglobulinemia.Chest CT scan showed all patients had atelectasis and pneumonia,and Patient 3 had bronchiectasis.Patient 3 was diagnosised as Burkitt lymphoma.For immunological function,all patients exhibited reduced CD4/CD8 ratios,increased numbers of exhausted T lymphocyte,decreased number of NK cell.The numbers of total B lymphocyte and naive B lymphocyte were normal,but the number of memory B lymphocyte declined in all cases.Four patients＇ copy numbers of sjTRECs were low and CDR3 spectratypings of TCRvβ showed mildly skewed.But their T lymphocyte proliferative response was normal.SAP protein expression in four cases were measured by flow cytometry.Two patients from Family A were absent and two patients from Family B showed decreased values.SH2D1A gene sequence analysis showed that the patients of

关 键 词：淋巴组织增殖性疾病 丙种球蛋白缺乏血症 基因 SH2D1A 诊断 

分 类 号：R725.9[医药卫生—儿科]