146名不符合马凡综合征临床诊断标准的成人患者中的致病性FBN1突变:1型原纤维蛋白病的进一步界定及对具有孤立主要标准患者的关注

Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion.

作者信息

Faivre L, Collod-Beroud G, Callewaert B, Child A, Loeys B L, Binquet C, Gautier E, Arbustini E, Mayer K, Arslan-Kirchner M, Kiotsekoglou A, Comeglio P, Grasso M, Beroud C, Bonithon-Kopp C, Claustres M, Stheneur C, Bouchot O, Wolf J E, Robinson P N, Adès L, De Backer J, Coucke P, Francke U, De Paepe A, Boileau C, Jondeau G

机构信息

Centre de Génétique, CHU Dijon, Dijon, France.

出版信息

Am J Med Genet A. 2009 May;149A(5):854-60. doi: 10.1002/ajmg.a.32809.

Abstract

Mutations in the FBN1 gene cause Marfan syndrome (MFS) and have been associated with a wide range of milder overlapping phenotypes. A proportion of patients carrying a FBN1 mutation does not meet diagnostic criteria for MFS, and are diagnosed with "other type I fibrillinopathy." In order to better describe this entity, we analyzed a subgroup of 146 out of 689 adult propositi with incomplete "clinical" international criteria (Ghent nosology) from a large collaborative international study including 1,009 propositi with a pathogenic FBN1 mutation. We focused on patients with only one major clinical criterion, [including isolated ectopia lentis (EL; 12 patients), isolated ascending aortic dilatation (17 patients), and isolated major skeletal manifestations (1 patient)] or with no major criterion but only minor criteria in 1 or more organ systems (16 patients). At least one component of the Ghent nosology, insufficient alone to make a minor criterion, was found in the majority of patients with isolated ascending aortic dilatation and isolated EL. In patients with isolated EL, missense mutations involving a cysteine were predominant, mutations in exons 24-32 were underrepresented, and no mutations leading to a premature truncation were found. Studies of recurrent mutations and affected family members of propositi with only one major clinical criterion argue for a clinical continuum between such phenotypes and classical MFS. Using strict definitions, we conclude that patients with FBN1 mutation and only one major clinical criterion or with only minor clinical criteria of one or more organ system do exist but represent only 5% of the adult cohort.

摘要

FBN1基因突变会导致马凡综合征(MFS),并与多种较为轻微的重叠表型相关。一部分携带FBN1突变的患者不符合MFS的诊断标准,被诊断为“其他类型的原纤维蛋白病”。为了更好地描述这一实体,我们从一项大型国际合作研究中分析了689例成年先证者中的146例亚组,这些先证者不符合“临床”国际标准(根特分类法),该研究共有1009例携带致病性FBN1突变的先证者。我们重点关注仅具有一项主要临床标准的患者[包括单纯晶状体异位(EL;12例患者)、单纯升主动脉扩张(17例患者)和单纯主要骨骼表现(1例患者)],或不具有主要标准但在1个或更多器官系统中仅有次要标准的患者(16例患者)。在大多数单纯升主动脉扩张和单纯EL患者中,发现了根特分类法中至少一个单独不足以构成次要标准的组成部分。在单纯EL患者中,涉及半胱氨酸的错义突变占主导,外显子24 - 32中的突变比例较低,且未发现导致过早截断的突变。对仅有一项主要临床标准的先证者的复发性突变和受影响家庭成员的研究表明,这些表型与经典MFS之间存在临床连续性。使用严格的定义,我们得出结论,携带FBN1突变且仅有一项主要临床标准或仅有一个或多个器官系统的次要临床标准的患者确实存在,但仅占成年队列的5%。

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