Clinical and genetic studies of Birt-Hogg-Dube syndrome
Clinical and genetic studies of Birt-Hogg-Dube syndrome
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DOI：
10.1136/jmg.39.12.906
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发表时间：
2002-12-01
影响因子：
4
通讯作者：
Richard, S
中科院分区：
文献类型：
--
作者：
Khoo, SK;Giraud, S;Richard, S
Birt-Hogg-Dube综合征（BHD）是一种常染色体显性遗传癌症综合征，其特征为良性皮肤肿瘤、肾肿瘤和自发性气胸。该基因已被定位在染色体17p11.2上，最近被发现，表达一种名为卵泡素的新型蛋白质。我们报告了四个散发性BHD病例和四个家庭共23个受影响的主题的临床和遗传学研究。这些家庭的单倍型分析使用BHD连锁标记显示，他们没有共享相同的受影响的等位基因，排除共同的祖先。BHD基因的突变分析鉴定了外显子11上的两个种系突变（c. 1733 insC和C. 1733 delC），以及四个散发病例中的两个。一个新的体细胞突变，C。1732 delTCinsAC在BHD相关的嫌色细胞肾癌中被检测到。我们的结果证实了外显子11中的（C）区是BHD的突变热点，应始终考虑用于未来的基因检测。我们的观察还表明，在某些BHD相关突变中的第二次打击（Knudson的两次打击理论）是以体细胞突变的形式出现的，而不是洛丢失。在一个法国大家庭中，有8名受影响的受试者携带C。1733 delC突变，鉴定出具有多次自发性气胸发作的表型。共有5名突变携带者（年龄在37岁至66岁之间）没有任何BHD特征的证据，这表明该疾病的发病率降低或发病年龄较晚。此外，8例生殖系突变阳性的受影响受试者中有6例已证实肿瘤性结肠息肉，表明结直肠肿瘤是某些家族中BHD的相关特征。我们的研究观察到BHD的几个有趣的遗传特征：（1）外显子11的poly（C）区作为突变热点;（2）表型的存在;（3）发病率降低或发病年龄晚;（4）在某些家族中与结直肠肿瘤有关;（5）体细胞突变而不是洛作为BHD转变的第二击。
Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant cancer syndrome characterised by benign skin tumours, renal tumours, and spontaneous pneumothorax. The gene has been mapped to chromosome 17p11.2 and recently identified, expressing a novel protein called folliculin. We report the clinical and genetic studies of four sporadic BHD cases and four families with a total of 23 affected subjects. Haplotype analysis of these families using BHD linked markers showed they did not share the same affected alleles, excluding common ancestry. Mutation analysis of the BHD gene identified two germline mutations on exon 11 (c. 1733insC and c. 1733delC) in three of four families as well as two of four sporadic cases. A novel somatic mutation, c. 1732delTCinsAC, was detected in a BHD related chromophobe renal carcinoma. Our results confirmed the (C), tract in exon 11 as a mutational hot spot in BHD and should always be considered for future genetic testing. Our observation also indicated that the second hit (of Knudson's two hit theory) in some BHD related turnours is in the form of somatic mutation rather than LOH. In a large French family in which eight affected subjects carry the c. 1733delC mutation, a phenocopy who has multiple episodes of spontaneous pneumothorax was identified. A total of five mutation carriers (aged between 37 to 66) did not have any evidence of BHD features, suggesting either reduced penetrance or late age of onset of the disease. In addition, six out of eight affected subjects who have positive germline mutation have confirmed neoplastic colonic polyps, indicating that colorectal neoplasia is an associated feature of BHD in some families. Our studies have observed several interesting genetic features in BHD: (1) the poly (C) tract in exon 11 as a mutational hot spot; (2) the existence of phenocopy; (3) reduced penetrance or late age of onset of disease; (4) association with colorectal neoplasia in some families; and (5) somatic mutation instead of LOH as the second hit in BHD turnours.