Clinical phenotypes and factor VII genotype in congenital factor VII deficiency
Clinical phenotypes and factor VII genotype in congenital factor VII deficiency
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DOI：
10.1160/th04-10-0650
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发表时间：
2005-03-01
影响因子：
6.7
通讯作者：
Bernardi, F
中科院分区：
文献类型：
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作者：
Mariani, G;Herrmann, FH;Bernardi, F
为探讨临床表型、凝血活性(FVIIc)与FVII基因分型的关系，采用集中式基因分型和特异性功能分析的方法，对FVII基因先天缺陷进行了多中心研究。患者(n=313)的FVII基因突变具有极强的异质性(103个不同，22个新基因)。临床表型从无症状状态(包括15个纯合子和14个双杂合子)到与早期出现强烈相关的以危及生命和致残症状(中枢神经系统、消化道出血和关节出血)为特征的严重疾病的患者。根据症状的类型和数量，我们将90例患者分为“重度”(FVIIc中位数为1.4%，IQR为0.9-3.8)，83例为“中度”(FVIIc为3%，IQR为1-21.7)，140例为“轻度”出血(FVIIc为14%，IQR为3-31)。FVIIc水平的显著差异，以及重度(98%)、中度(84%)和轻度(56%)出血者中纯合子或双杂合子发生率的下降，进一步支持了我们的分类。在中度出血者(女性/男性比率=2.6)中，女性过多可归因于月经过多。没有证据表明频繁的功能多态改变了临床特征。相同突变(Ala294Val；11125delC)具有相似FVIIc和FXA世代水平的纯合子在临床表型上表现出显著差异。我们的研究描绘了这种罕见疾病的丰富临床图景，提出了严重程度的分类，并为重症患者的早期治疗提供了论据。基因型-表型关系表明存在调节FVII缺乏症表达的主要环境成分和/或基因外成分。
To investigate the relationship between clinical phenotype, clotting activity (FVIIc) and FVII genotype, a multi-center study of factor VII (FVII) congenital deficiency with centralized genotyping and specific functional assays was carried out. FVII mutations characterized in patients (n=313) were extremely heterogeneous (103 different, 22 novel). Clinical phenotypes ranged from asymptomatic condition, including 15 homozygotes and 14 double heterozygotes, to patients with a severe disease characterized by life-threatening and disabling symptoms (CNS, GI bleeding and hemarthrosis) strongly associated with an early age of presentation. Based on type and number of symptoms we classified 90 'severe' (median FVIIc 1.4%, IQR [Interquartile Range] 0.9-3.8),83 'moderate' (FVIIc 3%, IQR 1-21.7), and 140 'mild' bleeders (FVIIc 14%, IQR 3-31). The significantly different FVIIc levels, and the decreasing prevalence of homozygotes or double heterozygotes among severe (98%), moderate (84%) and mild (56%) bleeders, further support our classification. The excess of females among moderate bleeders (female/male ratio = 2.6) is attributable to menorrhagia. There was no evidence for modulation of clinical features by frequent functional polymorphisms. Homozygotes for the same mutation (Ala294Val; 11125delC) with similar FVIIc and FXa generation levels, showed striking differences in clinical phenotypes. Our study depicts the ample clinical picture of this rare disorder, proposes a severity classification and provides arguments for the early management of the disease in the severe cases. Genotype-phenotype relationships indicate the presence of major environmental and/or extragenic components modulating expressivity of FVII deficiency.