新发BTK基因缺失突变1例并文献复习

doi:10.6040/j.issn.1671-7554.0.2022.0841

摘要/Abstract

摘要： 目的探讨1例BTK基因大片段缺失导致X-连锁无丙种球蛋白血症患儿的临床表现、检验及基因特点。方法对2016年8月山东第一医科大学附属省立医院收治的1例X-连锁无丙种球蛋白血症患儿的临床表现、检验检查、基因特点进行分析,并在万方、中国知网(CNKI)、PubMed数据库进行文献检索并文献复习。结果患儿,男,7岁7个月,自3岁起反复细菌感染病史。外周血免疫功能提示,CD19+ 0.06%,IgG<1.42 g/L,IgA<0.23 g/L,IgM 0.44 g/L,免疫功能明显降低;胸部CT提示支气管扩张、支气管肺炎表现。基因检测报告提示,患儿BTK基因第2~5号外显子缺失,患儿母亲相应位点疑似杂合缺失。因2~5号外显子整体缺失突变导致的X-连锁无丙种球蛋白血症在Human Gene Mutation Database(HGMD)专业数据库中尚无报道。随访5年,患儿每1~2个月应用7.5~10 g人免疫球蛋白,未再出现反复细菌性感染,复查胸部CT仍有轻度支气管扩张。患儿母亲再次怀孕后经羊水穿刺行基因检测,未发现胎儿BTK基因异常,患儿弟弟出生后免疫功能正常。结论对反复细菌性感染、支气管扩张患儿需常规进行免疫功能筛查,存在异常者需进行基因检测明确诊断,对于确诊XLA的患儿需规律行静脉输注丙种球蛋白替代治疗。母亲再次怀孕时需进行羊水BTK基因检测。

关键词: X-连锁无丙种球蛋白血症, BTK基因, 缺失突变, 产前诊断

Abstract: Objective To investigate the clinical manifestations, laboratory examinations and gene characteristics of a child with X-linked agammaglobulinemia(XLA)caused by a new BTK gene deletion. Methods The clinical manifestations, laboratory examinations and genetic characteristics of a child with XLA admitted to Shandong Provincial Hospital Affiliated to Shandong First Medical University in August 2016 were analyzed, and relevant literature was reviewed in Wanfang, CNKI and PubMed databases. Results The child, male, 7 years and 7 months old, had a history of repeated bacterial infection since the age of 3. Peripheral blood immune function showed CD19+ 0.06%, IgG <1.42 g/L, IgA <0.23 g/L, IgM 0.44 g/L, with significantly reduced immune function. Chest CT showed bronchiectasis and bronchopneumonia. Gene test report suggested deletion of exon 2-5 of BTK gene, and the mother of the child was suspect of heterozygous deletion. There are no reports in the Human Gene Mutation Database(HGMD)of X-linked gammaglobulinemia due to a deletion mutation in exons 2-5. In 5 years of follow-up, the patient received 7.5-10 g of human immunoglobulin every 1-2 months, and no repeated bacterial infection occurred. Chest CT showed mild bronchiectasis. The childs mother was pregnant again and genetic testing by amniocentesis revealed no fetal BTK gene abnormality, and the childs brother was born with normal immune function. Conclusion Children with recurrent bacterial infections and bronchiectasis should be routinely screened for immune function, and those with abnormalities should be genetically tested for a definitive diagnosis. Children with confirmed XLA should be treated regularly with intravenous gamma globulin replacement therapy. Genetic testing of amniotic fluid for BTK is required if the mother becomes pregnant again.

Key words: X-linked agammaglobulinemia, BTK gene, Deletion mutation, Prenatal diagnosis

中图分类号:

R593.31

魏俊杰,岳蔷薇,孙立锋. 新发BTK基因缺失突变1例并文献复习[J]. 山东大学学报 (医学版), 2023, 61(8): 74-78.

WEI Junjie, YUE Qiangwei, SUN Lifeng. New BTK gene deletion mutation: a case report and literature review[J]. Journal of Shandong University (Health Sciences), 2023, 61(8): 74-78.

参考文献

[1] Picard C, Bobby Gaspar H, Al-Herz W, et al. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee report on inborn errors of immunity [J]. J Clin Immunol, 2018, 38(1): 96-128.
[2] Bruton OC. Agammaglobulinemia [J]. Pediatrics, 1952, 9(6): 722-728.
[3] Kornfeld SJ, Kratz J, Haire RN, et al. X-linked agammaglobulinemia presenting as transient hypogammaglobulinemia of infancy [J]. J Allergy Clin Immunol, 1995, 95(4): 915-917.
[4] Ritis K, Speletas M, Tsironidou V, et al. Absence of Brutons tyrosine kinase(Btk)mutations in patients with acute myeloid leukaemia [J]. Br J Haematol, 1998, 102(5): 1241-1248.
[5] Wang Y, Kanegane H, Sanal O, et al. Bruton tyrosine kinase gene mutations in Turkish patients with presumed X-linked agammaglobulinemia [J]. Hum Mutat, 2001, 18(4): 356. doi:10.1002/humu.1200.
[6] Jo EK, Wang Y, Kanegane H, et al. Identification of mutations in the Brutons tyrosine kinase gene, including a novel genomic rearrangements resulting in large deletion, in Korean X-linked agammaglobulinemia patients [J]. J Hum Genet, 2003, 48(6): 322-326.
[7] Wattanasirichaigoon D, Benjaponpitak S, Techasaensiri C, et al. Four novel and three recurrent mutations of the BTK gene and pathogenic effects of putative splice mutations [J]. J Hum Genet, 2006, 51(11): 1006-1014.
[8] Sedivá A, Smith CI, Asplund AC, et al. Contiguous X-chromosome deletion syndrome encompassing the BTK, TIMM8A, TAF7L, and DRP2 genes [J]. J Clin Immunol, 2007, 27(6): 640-646.
[9] Jyonouchi H, Geng LE, Törüner GA, et al. Monozygous twins with a microdeletion syndrome involving BTK, DDP1, and two other genes; evidence of intact dendritic cell development and TLR responses [J]. Eur J Pediatr, 2008, 167(3): 317-321.
[10] Zhang ZY, Zhao XD, Jiang LP, et al. Clinical characteristics and molecular analysis of 21 Chinese children with congenital agammaglobulinemia [J]. Scand J Immunol, 2010, 72(5): 454-459.
[11] 赵培伟, 何学莲, 丁艳, 等. X连锁无丙种球蛋白血症的临床特点及基因检测[J]. 临床儿科杂志, 2013, 31(1): 19-21. ZHAO Peiwei, HE Xuelian, DING Yan, et al. The clinical features of X-linked agammaglobulinemia and gene testing [J]. Journal of Clinical Pediatrics, 2013, 31(1): 19-21.
[12] Chen XF, Wang WF, Zhang YD, et al. Clinical characteristics and genetic profiles of 174 patients with X-linked agammaglobulinemia: report from Shanghai, China(2000-2015)[J]. Medicine, 2016, 95(32): e4544. doi:10.1097/MD.0000000000004544.
[13] Sharma D, Gupta A, Goel S, et al. Large BTK gene mutation in a child with X-linked agammaglobulinemia and polyarthritis [J]. Clin Immunol, 2017, 183: 109-111. doi: 10.1016/j.clim.2017.08.005.
[14] Shaker M, Lorigiano TJ, Lucas A, et al. An X-linked agammaglobulinemia contiguous gene syndrome with metachronous coprimary testicular cancers [J]. Ann Allergy Asthma Immunol, 2018, 120(2): 215-217.
[15] Gao SS, Hu S, Duan HK, et al. Clinical characteristics and prenatal diagnosis for 22 families in Henan Province of China with X-linked agammaglobulinemia(XLA)related to Brutons tyrosine kinase(BTK)gene mutations [J]. BMC Med Genet, 2020, 21(1): 131. doi:10.1186/s12881-020-01063-5.
[16] Jain A, Govindaraj GM, Edavazhippurath A, et al. Whole genome sequencing identifies novel structural variant in a large Indian family affected with X-linked agammaglobulinemia [J]. PLoS One, 2021, 16(7): e0254407. doi: https://doi.org /10.1371/journal.pone.0254407.
[17] Liu N, Yang XM, Wang SL, et al. PBMC-derived integration-free iPSCs line SDQLCHi039-A from a patient with X-linked agammaglobulinemia carrying a novel 9-bp in-frame deletion in BTK gene [J]. Stem Cell Res, 2021, 51: 102165. doi: 10.1016/j.scr.2021.102165.
[18] Rendtorff ND, Karstensen HG, Lodahl M, et al. Identification and analysis of deletion breakpoints in four Mohr-Tranebjærg syndrome(MTS)patients [J]. Sci Rep, 2022, 12(1): 14959. doi:10.1038/s41598-022-18040-y.
[19] 沈文那, 孙欣荣. X连锁无丙种球蛋白血症患儿4例及相关文献分析[J]. 中国妇幼健康研究, 2020, 31(4): 475-482. SHEN Wenna, SUN Xinrong. 4 cases of X-linked agammaglobulinemia and related literature analysis: case report and literature review [J]. Chinese Journal of Woman and Child Health Research, 2020, 31(4): 475-482.
[20] Carrillo-Tapia E, García-García E, Herrera-González NE, et al. Delayed diagnosis in X-linked agammaglobulinemia and its relationship to the occurrence of mutations in BTK non-kinase domains [J]. Expert Rev Clin Immunol, 2018, 14(1): 83-93.
[21] 中华医学会儿科学分会免疫学组,中华儿科杂志编辑委员会.原发性免疫缺陷病免疫球蛋白G替代治疗专家共识[J].中华儿科杂志, 2019, 57(12): 909-912. doi: 10.3760/cma.j.issn.0578-1310.2019.12.003. The Subspecialty Group of Immunology, the Society of Pediatrics, Chinese Medical Association, the Editorial Board, Chinese Journal of Pediatrics. Expert consensus on immunoglobulin G replacement therapy for primary immunodeficiency [J]. Chinese Journal of Pediatrics, 2019, 57(12): 909-912. doi: 10.3760/cma.j.issn.0578-1310.2019.12.003.
[22] Quartier P, Debré M, De Blic J, et al. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients [J]. J Pediatr, 1999, 134(5): 589-596.
[23] 李亚文, 陈欢, 张宇, 等. 先天性无丙种球蛋白血症静脉丙种球蛋白替代治疗114例现状分析[J]. 中华儿科杂志, 2021, 59(6): 495-500. LI Yawen, CHEN Huan, ZHANG Yu, et al. Intravenous immunoglobulin replacement therapy in 114 cases of congenital agammaglobulinemia [J]. Chinese Journal of Pediatrics, 2021, 59(6): 495-500.

多维度评价

Viewed

Full text

Abstract

Cited

Shared

Discussed