5例儿童X连锁无丙种球蛋白血症报告及基因特征分析
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摘要
目的总结X连锁无丙种球蛋白血症(XLA)患儿的临床和免疫学特征及基因突变特点,提高对该病的认识。方法对高度疑诊XLA的5例男童的临床和实验室资料进行回顾性总结,并采用二代测序+一代验证技术对患儿及父母进行BTK基因测序。结果 5例病儿均为男性、汉族,以反复下呼吸道感染为主要临床表现,并发鼻炎、鼻窦炎2例,关节炎1例,血小板减少性紫癜1例;体格检查显示浅表淋巴结和扁桃体缺如;血清免疫球蛋白和外周血B细胞显著降低;基因检测示5例患儿均存在人类酪氨酸激酶(BTK)基因半合子突变,均来自母亲,分别为c.1349+5G>T,c.1154deIC,p.(Pro386fs),c.1632-1G>T,c.110T>G和c.1751C>A。结论男性患儿、反复呼吸道感染、扁桃体及外周淋巴结缺如、血清免疫球蛋白和外周血B细胞显著降低或缺如是XLA的重要特征,BTK基因突变是确诊依据;BTK基因c.1632-1G>T和c.1751C>A突变为首次报道。
Objective To summarize the clinical and immunological characteristics and gene mutation characteristics of children with X-linked agagoglobulemia(XLA),so as to improve the understanding of the disease.Methods Carried on the retrospective analysis for the clinical and laboratory data of 5 boys who were highly suspected of XLA,and did the BTK gene sequencing for children and their parents with the two generation sequencing generation verification techniques.Results 5 cases were all males and Han nationality,with main clinical manifestations of recurrent lower respiratory tract infection,accompanying 2 cases with rhinitis and sinusitis,1 cases of arthritis,1 case of thrombocytopenic purpura.Physical examination revealed a superficial lymph node and tonsil deletion,and serum immunoglobulin and peripheral blood B cells significantly decreased;BTK gene hemizygous mutations were proved by the gene detection in 5 these cases,and they were all from the mother,which were c.1349+5 G>T,c.1154 deIC,p.(Pro386 fs),c.1632-1 G>T,c.110 T>G and c.1751 C>A respectively.Conclusion Male patients,the important feature of XLA could be summarized as recurrent respiratory tract infection,tonsil and absence of peripheral lymph nodes,significant decrease or absence of serum immunoglobulin and B cells in peripheral blood.BTK gene mutation is the basis of diagnosis;BTK gene c.1632-1 G>T and c.1751 C>A mutations were reported for the first time.
Objective To summarize the clinical and immunological characteristics and gene mutation characteristics of children with X-linked agagoglobulemia(XLA),so as to improve the understanding of the disease.Methods Carried on the retrospective analysis for the clinical and laboratory data of 5 boys who were highly suspected of XLA,and did the BTK gene sequencing for children and their parents with the two generation sequencing generation verification techniques.Results 5 cases were all males and Han nationality,with main clinical manifestations of recurrent lower respiratory tract infection,accompanying 2 cases with rhinitis and sinusitis,1 cases of arthritis,1 case of thrombocytopenic purpura.Physical examination revealed a superficial lymph node and tonsil deletion,and serum immunoglobulin and peripheral blood B cells significantly decreased;BTK gene hemizygous mutations were proved by the gene detection in 5 these cases,and they were all from the mother,which were c.1349+5 G>T,c.1154 deIC,p.(Pro386 fs),c.1632-1 G>T,c.110 T>G and c.1751 C>A respectively.Conclusion Male patients,the important feature of XLA could be summarized as recurrent respiratory tract infection,tonsil and absence of peripheral lymph nodes,significant decrease or absence of serum immunoglobulin and B cells in peripheral blood.BTK gene mutation is the basis of diagnosis;BTK gene c.1632-1 G>T and c.1751 C>A mutations were reported for the first time.
引文
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[5]邓朝晖,蒋丽蓉,张斌,等.抗体缺陷病并发肝硬化一例并文献复习[J].中华儿科杂志,2016,54(5):379-382.Deng ZH,Jiang LR,Zhang B,et al.Primary hypogammaglobulinemia complicated with liver cirrhosis and literature review[J].Chinese Journal of Pediatrics,2016,54(5):379-382.
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[8]李小琳,付四毛,刘玉玲,等.X-连锁无丙种球蛋白血症3例报告并文献复习[J].临床儿科杂志,2014,32(7):690-693.Li XL,Fu SM,Liu YL,et al.Three cases report and literature review of X-Linked agammaglobulinemia[J].J Clin Pediatr,2014,32(7):690-693.
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[11]Conley ME,Howard V.Clinical finding leading to the diagnosis of X-linked agammaglobulinemia[J].J Pediatr,2002,141(4):566-571.
[12]涂明辉,朱小燕.X连锁无丙种球蛋白血症一例误诊分析[J].临床误诊误治,2010,23(5):499.Tu MH,Zhu XY.A misdiagnosed case of X-linked agegammaglobulinemia[J].Clinical Misdiagnosis&Mistherapy,2010,23(5):499.
[13]Yang L,Wu EY,Tarrant TK,et al.Immune gamma globulin therapeutic indications in immune deficiency and autoimmunity[J].Curr Allergy Asthma Rep,2016,16(8):55.
[14]Corneth OBJ,Klein Wolterink RGJ,Hendriks RW.BTK signaling in B cell differentiation and autoimmunity[J].Curr Top Microbiol Immunol,2016,393(12):67-105.
[15]Garcia-Garcia E,Staines-Boone AT,Vargas-Hernandez A,et al.Clinical and mutational features of Xlinked agammaglobulinemia in Mexico[J].Clinical Immunology,2016(165):38-44.
[16]王晓川.X连锁无丙种球蛋白血症的临床特点[J].中华儿科杂志,2004,42(8):564-567.Wang XC.Clinical features of X-linked agammaglobulinemia:analysis of 8cases[J].Chinese Journal of Pediatrics,2004,42(8):564-567.
[17]王艳琼,崔玉霞,王予川,等.X-连锁无丙种球蛋白血症患儿临床表型和基因诊断分析[J].实用儿科临床杂志,2012,27(9):684-686.Wang YQ,Cui YX,Wang YC,et al.Clinical phenotype and genetic diagnosis analysis of X-linked agammaglobulinemia[J].Journal of Applied Clinical Pediatrics,2012,27(9):684-686.
[18]Lee KH,Shyur SD,Chu SH,et al.Clinical manifestations and BTK gene defect in 4unrelated Taiwanese families with Bruton’s disease[J].Asian Pac J Allergy Immunol,2011,29(3):260-265.
[19]Ikegame K,Imai K,Yamashita M,et al.Allogeneic stem cell transplantation for X-linked agammaglobulinemia using reduced intensity conditioning as a model of the reconstitution of humoral immunity[J].J Hematol Oncol,2016(9):9.
[20]凌瑶君,蔡家泉,王红霞,等.基因突变致非遗传性X连锁无丙种球蛋白血症1例[J].中国热带医学,2015,15(7):887-889.Ling YJ,Cai JQ,Wang HX,et al.A cases with non hereditary X-linked agammaglobulinemia caused by gene mutation[J].China Tropical Medicine,2015,15(7):887-889.
[21]孔祥东,莫桂玲,刘宁,等.X-连锁无丙种球蛋白血症家系BTK基因突变分析及产前诊断研究[J].中华医学杂志,2014,94(18):1405-1408.Kong XD,Mo GL,Liu N,et al.Mutation analysis and prenatal diagnosis in families of X-linked agammaglobulinemia caused by BTK gene mutation[J].National Medical Journal of China,2014,94(18):1405-1408.
[22]张晓敏,李虹,李强,等.六例X连锁无丙种球蛋白血症患儿BTK基因突变检测及临床分析[J].中华医学遗传学杂志,2014,31(1):29-33.Zhang XM,Li H,Li Q,et al.Detection of Bruton’s tyrosine kinase gene mutations and clinical analysis of 6patients with X-linked agammaglobulinemia[J].Chinese Journal of Medical Genetics,2014,31(1):29-33.
[23]王莹,应文静,孙金峤,等.中国X连锁无丙种球蛋白血症40例基因型表型相关性分析[J].中国循证儿科杂志,2012,7(1):4-10.Wang Y,Ying WJ,Sun JQ,et al.Characterization and correlation pf genotype with phenotype of 40cases of X-linked agmmaglobulinemia in China[J].Chinese Journal of Evidence-Based Pediatr,2012,7(1):4-10.
[2]Lindvall JM,Blomberg KE,V¨aoLiaho J,et al.Bruton’s tyrosine kinase:cell biology,sequence conservation,mutation spectrum,siRNA modifications,and expression profiling[J].Immunol Rev,2005,203(1):200-215.
[3]陶英博,陈慧珊,曾华松.X-连锁无丙种球蛋白血症BTK基因新发突变1例报告[J].中华临床免疫和变态反应杂志,2013,7(2):203-205.Tao YB,Chan HS,Zeng HS.X-linked agammaglobulinemia with BTK mutation:1cases report[J].Chinese Journal of Allergy and Clinical Immunology,2013,7(2):203-205.
[4]Sigmon JR,Kasasbeh E,Krishnaswamy G.X-linked agammaglobulinemia diagnosed late in life:case report and review of the literature[J].Clin Molr Allergy,2008,6(5):5.
[5]邓朝晖,蒋丽蓉,张斌,等.抗体缺陷病并发肝硬化一例并文献复习[J].中华儿科杂志,2016,54(5):379-382.Deng ZH,Jiang LR,Zhang B,et al.Primary hypogammaglobulinemia complicated with liver cirrhosis and literature review[J].Chinese Journal of Pediatrics,2016,54(5):379-382.
[6]Quartier P,DebréM,De Blic J,et al.Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia:a retrospective survey of 31patients[J].J Pediatr,1999,134(5):589-596.
[7]师丽晓,罗丹青,师晓东.X-连锁无丙种球蛋白血症BTK基因突变1例并文献复习[J].中国医刊,2017,52(2):57-60.Shi LX,Luo DQ,Shi XD.X-linked agammaglobulinemia with BTK mutations and literature review[J].Chinese Journal of Medicine,2017,15(2):57-60.
[8]李小琳,付四毛,刘玉玲,等.X-连锁无丙种球蛋白血症3例报告并文献复习[J].临床儿科杂志,2014,32(7):690-693.Li XL,Fu SM,Liu YL,et al.Three cases report and literature review of X-Linked agammaglobulinemia[J].J Clin Pediatr,2014,32(7):690-693.
[9]Sukumaran S,Marzan K,Shaham B,et al.A child with X-linked agammaglobulinemia and enthesitis-related arthritis[J].Int J Rheumatol,2011,2011:175973.
[10]Toth B,Volokha A,Mihas A,et al.Genetic and demographic features of X-linked agamagammaglobulinemia in Easternand Central Europe;a cohort study[J].Mol Immuno,2009,46(10):2140-2146.
[11]Conley ME,Howard V.Clinical finding leading to the diagnosis of X-linked agammaglobulinemia[J].J Pediatr,2002,141(4):566-571.
[12]涂明辉,朱小燕.X连锁无丙种球蛋白血症一例误诊分析[J].临床误诊误治,2010,23(5):499.Tu MH,Zhu XY.A misdiagnosed case of X-linked agegammaglobulinemia[J].Clinical Misdiagnosis&Mistherapy,2010,23(5):499.
[13]Yang L,Wu EY,Tarrant TK,et al.Immune gamma globulin therapeutic indications in immune deficiency and autoimmunity[J].Curr Allergy Asthma Rep,2016,16(8):55.
[14]Corneth OBJ,Klein Wolterink RGJ,Hendriks RW.BTK signaling in B cell differentiation and autoimmunity[J].Curr Top Microbiol Immunol,2016,393(12):67-105.
[15]Garcia-Garcia E,Staines-Boone AT,Vargas-Hernandez A,et al.Clinical and mutational features of Xlinked agammaglobulinemia in Mexico[J].Clinical Immunology,2016(165):38-44.
[16]王晓川.X连锁无丙种球蛋白血症的临床特点[J].中华儿科杂志,2004,42(8):564-567.Wang XC.Clinical features of X-linked agammaglobulinemia:analysis of 8cases[J].Chinese Journal of Pediatrics,2004,42(8):564-567.
[17]王艳琼,崔玉霞,王予川,等.X-连锁无丙种球蛋白血症患儿临床表型和基因诊断分析[J].实用儿科临床杂志,2012,27(9):684-686.Wang YQ,Cui YX,Wang YC,et al.Clinical phenotype and genetic diagnosis analysis of X-linked agammaglobulinemia[J].Journal of Applied Clinical Pediatrics,2012,27(9):684-686.
[18]Lee KH,Shyur SD,Chu SH,et al.Clinical manifestations and BTK gene defect in 4unrelated Taiwanese families with Bruton’s disease[J].Asian Pac J Allergy Immunol,2011,29(3):260-265.
[19]Ikegame K,Imai K,Yamashita M,et al.Allogeneic stem cell transplantation for X-linked agammaglobulinemia using reduced intensity conditioning as a model of the reconstitution of humoral immunity[J].J Hematol Oncol,2016(9):9.
[20]凌瑶君,蔡家泉,王红霞,等.基因突变致非遗传性X连锁无丙种球蛋白血症1例[J].中国热带医学,2015,15(7):887-889.Ling YJ,Cai JQ,Wang HX,et al.A cases with non hereditary X-linked agammaglobulinemia caused by gene mutation[J].China Tropical Medicine,2015,15(7):887-889.
[21]孔祥东,莫桂玲,刘宁,等.X-连锁无丙种球蛋白血症家系BTK基因突变分析及产前诊断研究[J].中华医学杂志,2014,94(18):1405-1408.Kong XD,Mo GL,Liu N,et al.Mutation analysis and prenatal diagnosis in families of X-linked agammaglobulinemia caused by BTK gene mutation[J].National Medical Journal of China,2014,94(18):1405-1408.
[22]张晓敏,李虹,李强,等.六例X连锁无丙种球蛋白血症患儿BTK基因突变检测及临床分析[J].中华医学遗传学杂志,2014,31(1):29-33.Zhang XM,Li H,Li Q,et al.Detection of Bruton’s tyrosine kinase gene mutations and clinical analysis of 6patients with X-linked agammaglobulinemia[J].Chinese Journal of Medical Genetics,2014,31(1):29-33.
[23]王莹,应文静,孙金峤,等.中国X连锁无丙种球蛋白血症40例基因型表型相关性分析[J].中国循证儿科杂志,2012,7(1):4-10.Wang Y,Ying WJ,Sun JQ,et al.Characterization and correlation pf genotype with phenotype of 40cases of X-linked agmmaglobulinemia in China[J].Chinese Journal of Evidence-Based Pediatr,2012,7(1):4-10.