目的 分析先天性纤维蛋白原病（congenital fibrinogen disorder, CFD）患儿临床表型和基因型的特征。 方法 回顾性分析16例CFD患儿的临床资料。聚合酶链反应技术扩增FGA、FGB、FGG基因全部外显子及侧翼序列并进行测序，分析变异特征。 结果 16例患儿，男9例（56%），女7例（44%），中位就诊年龄4岁。9例（56%）患儿因出血事件就诊，7例（44%）因术前检查发现。出血事件患儿的纤维蛋白原活性水平低于无出血事件患儿（P<0.05）。12例患儿完成基因检测，共检出12种变异，其中有4个新位点变异，分别为FGA基因c.80T>C和c.1368delC、FGG基因c.1007T>A和c.1053C>A。2例遗传性无纤维蛋白原血症均为FGA基因无效变异引起，有较重的出血症状。7例遗传性异常纤维蛋白原血症主要由FGG和FGA基因杂合错义变异引起，临床表型从无症状至不同程度出血。 结论 CFD患儿临床表现具有异质性，患儿出血的严重程度与纤维蛋白原活性水平有关，但临床表型与基因型之间的相关性较弱。
Abstract
Objective To investigate the clinical phenotypes and genotypes of children with congenital fibrinogen disorder (CFD). Methods A retrospective analysis was conducted on the clinical data of 16 children with CFD. Polymerase chain reaction was used to amplify all exons and flanking sequences of the FGA, FGB, and FGG genes, and sequencing was performed to analyze mutation characteristics. Results Among the 16 children, there were 9 boys (56%) and 7 girls (44%), with a median age of 4 years at the time of attending the hospital. Among these children, 9 (56%) attended the hospital due to bleeding events, and 7 (44%) were diagnosed based on preoperative examination. The children with bleeding events had a significantly lower fibrinogen activity than those without bleeding events (P<0.05). Genetic testing was conducted on 12 children and revealed a total of 12 mutations, among which there were 4 novel mutations, i.e., c.80T>C and c.1368delC in the FGA gene and c.1007T>A and C.1053C>A in the FGG gene. There were 2 cases of congenital afibrinogenemia caused by null mutations of the FGA gene, with relatively severe bleeding symptoms. There were 7 cases of congenital dysfibrinogenemia mainly caused by heterozygous missense mutations of the FGG and FGA genes, and their clinical phenotypes ranged from asymptomatic phenotype to varying degrees of bleeding. Conclusions The clinical phenotypes of children with CFD are heterogeneous, and the severity of bleeding is associated with the level of fibrinogen activity, but there is a weak association between clinical phenotype and genotype.
关键词
先天性纤维蛋白原病 /
FGA基因 /
FGB基因 /
FGG基因 /
儿童
Key words
Congenital fibrinogen disorder /
FGA gene /
FGB gene /
FGG gene /
Child
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
1 中华医学会血液学分会血栓与止血学组, 中国血友病协作组. 罕见遗传性出血性疾病诊断与治疗中国专家共识（2021年版）[J]. 中华血液学杂志, 2021, 42(2): 89-96. PMID: 33858037. PMCID: PMC8071661. DOI: 10.3760/cma.j.issn.0253-2727.2021.02.001.
2 Casini A, Moerloose P, Neerman-Arbez M. One hundred years of congenital fibrinogen disorders[J]. Semin Thromb Hemost, 2022, 48(8): 880-888. PMID: 36055263. DOI: 10.1055/s-0042-1756187.
3 Casini A, Undas A, Palla R, et al. Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH[J]. J Thromb Haemost, 2018, 16(9): 1887-1890. PMID: 30076675. DOI: 10.1111/jth.14216.
4 Neerman-Arbez M, de Moerloose P, Casini A. Laboratory and genetic investigation of mutations accounting for congenital fibrinogen disorders[J]. Semin Thromb Hemost, 2016, 42(4): 356-365. PMID: 27019463. DOI: 10.1055/s-0036-1571340.
5 Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. PMID: 25741868. PMCID: PMC4544753. DOI: 10.1038/gim.2015.30.
6 Li ZY, Wang S, Li DY, et al. Fibrinogen A alpha-chain amyloidosis in two Chinese patients[J]. Front Med (Lausanne), 2022, 9: 869409. PMID: 35572989. PMCID: PMC9096909. DOI: 10.3389/fmed.2022.869409.
7 尹自长, 陈莲, 王文献, 等. 肝纤维蛋白原贮积症2例临床病理学分析[J]. 中华病理学杂志, 2023, 52(12): 1275-1277. PMID: 38058048. DOI: 10.3760/cma.j.cn112151-20230727-00034.
8 黄丽颖, 张冬雷, 付荣凤, 等. 146例先天性纤维蛋白原病的基因突变谱及纤维蛋白原输注药代动力学分析[J]. 中华血液学杂志, 2021, 42(7): 555-562. PMID: 34455742. PMCID: PMC8408493. DOI: 10.3760/cma.j.issn.0253-2727.2021.07.005.
9 Wypasek E, Klukowska A, Zdziarska J, et al. Genetic and clinical characterization of congenital fibrinogen disorders in Polish patients: identification of three novel fibrinogen gamma chain mutations[J]. Thromb Res, 2019, 182: 133-140. PMID: 31479941. DOI: 10.1016/j.thromres.2019.08.012.
10 Brunclikova M, Simurda T, Zolkova J, et al. Heterogeneity of genotype-phenotype in congenital hypofibrinogenemia: a review of case reports associated with bleeding and thrombosis[J]. J Clin Med, 2022, 11(4): 1083. PMID: 35207353. PMCID: PMC8874973. DOI: 10.3390/jcm11041083.
11 Sucker C, Geisen C, Schmitt U, et al. Hypofibrinogenemia and miscarriage: report of a first successful pregnancy under fibrinogen substitution and short review of the literature[J]. Arch Clin Cases, 2022, 9(3): 100-103. PMID: 36176499. PMCID: PMC9512129. DOI: 10.22551/2022.36.0903.10211.
12 Casini A, Neerman-Arbez M, de Moerloose P. Heterogeneity of congenital afibrinogenemia, from epidemiology to clinical consequences and management[J]. Blood Rev, 2021, 48: 100793. PMID: 33419567. DOI: 10.1016/j.blre.2020.100793.
13 Peyvandi F, Palla R, Menegatti M, et al. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European network of rare bleeding disorders[J]. J Thromb Haemost, 2012, 10(4): 615-621. PMID: 22321862. DOI: 10.1111/j.1538-7836.2012.04653.x.
14 Casini A, Blondon M, Tintillier V, et al. Mutational epidemiology of congenital fibrinogen disorders[J]. Thromb Haemost, 2018, 118(11): 1867-1874. PMID: 30332696. DOI: 10.1055/s-0038-1673685.
15 Ramanan R, McFadyen JD, Perkins AC, et al. Congenital fibrinogen disorders: strengthening genotype-phenotype correlations through novel genetic diagnostic tools[J]. Br J Haematol, 2023, 203(3): 355-368. PMID: 37583269. DOI: 10.1111/bjh.19039.
16 Chapman J, Dogan A. Fibrinogen alpha amyloidosis: insights from proteomics[J]. Expert Rev Proteomics, 2019, 16(9): 783-793. PMID: 31443619. PMCID: PMC6788741. DOI: 10.1080/14789450.2019.1659137.
17 Asselta R, Paraboschi EM, Duga S. Hereditary hypofibrinogenemia with hepatic storage[J]. Int J Mol Sci, 2020, 21(21): 7830. PMID: 33105716. PMCID: PMC7659954. DOI: 10.3390/ijms21217830.
18 Casini A, de Moerloose P. Can the phenotype of inherited fibrinogen disorders be predicted?[J]. Haemophilia, 2016, 22(5): 667-675. PMID: 27293018. DOI: 10.1111/hae.12967.
基金
安徽省自然科学基金（2108085MH268）。
PDF(495 KB)
