Occurrence of MEN 2a in familial Hirschsprung's disease:: A new indication for genetic testing of the RET proto-oncogene
Occurrence of MEN 2a in familial Hirschsprung's disease:: A new indication for genetic testing of the RET proto-oncogene
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DOI：
10.1016/s0022-3468(98)90433-x
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发表时间：
1998-02-01
影响因子：
2.4
通讯作者：
Peacock, ML
中科院分区：
文献类型：
--
作者：
Decker, RA;Peacock, ML
目的：最近报道了罕见的遗传性癌症综合征，多发性内分泌瘤2a型（MEN 2a）与巨结肠病的关联，两者都与RET原癌基因的种系突变有关。随着men2a基因筛查的广泛应用，有必要确定men2a基因检测的适应症和遗传该疾病的高危人群亚群。本研究的目的是评估男性2a先天性巨结肠病的患病率，并探讨男性2a基因分析在家族性先天性巨结肠病儿童中的价值。方法：种族多样化的研究组由未选择的有遗传性甲状腺髓样癌（MTC）风险的连续患者（n = 426）组成，这些患者被提交到单一实验室进行基因检测。使用基因组DNA和基于聚合酶链反应的异双工突变检测策略对RET原癌基因的外显子10,11,13和14进行分析，然后进行直接DNA测序。RET基因型-表型相关性的显著性通过Fisher双尾精确检验和2 × 2列联表确定。结果：鉴定出36个明显新的MEN 2a种类。在36个（17%）家庭中的6个家庭中，有15名患有先天性巨结肠病的兄弟姐妹共分离。15例肿大范围从直肠中部到十二指肠。在15例巨结肠病患者中，10例（6名男孩，4名女孩）在2至47岁（平均15.6岁）期间（平均15.6岁）因MTC （n = 5）或c细胞增生（n = 5）接受了甲状腺切除术，其余5例患者在儿童期死于与腺瘤病相关的并发症。回顾过去，6个家族中有5个家族以巨结肠病为MEN 2a的表现特征，而不是MTC或嗜铬细胞瘤。在所有表达巨结肠病的6个MEN 2a家族中，导致合并表型的RET突变发生在第10外显子609 （n = 2）、618 （n = 3）或620 （n = 1）的密码子位置。相比之下，在RET外显子11、13或14突变的22个家族中，没有发现具有Hirschsprung表型的MEN 2a （P= 0.0007）。结论：作者得出结论，巨结肠病是MEN 2a的一个表型标记，可能比最初认为的更常见。带有MEN 2a的巨结肠病的表达可能与RET外显子10突变有独特的联系。作者建议(1)应告知男性2a患者其后代患先天性巨结肠病的潜在风险；(2)对患有先天性巨结肠病的儿童进行MTC家族史调查，并考虑对男性2a进行遗传筛查。版权所有(C) 1998由W.B. Saunders公司。
Purpose: The association of the rare hereditary cancer syndrome, multiple endocrine neoplasia type 2a (MEN 2a) with Hirschsprung's disease, both linked to germline mutations in the RET proto-oncogene, has been reported recently. With the widespread availability of genetic screening for MEN 2a, it is necessary to define the indications for genetic testing of MEN 2a and population subgroups at high risk for inheriting the disease. The purpose of this study was to assess the prevalence of Hirschsprung's disease in MEN 2a and investigate the value of genetic analysis for MEN 2a in children with familial Hirschsprung's disease.Methods: The ethnically diverse study group consisted of unselected consecutive patients (n = 426) at risk for hereditary medullary thyroid cancer (MTC) referred to a single laboratory for genetic testing. Analysis used genomic DNA and a polymerase chain reaction-based heteroduplex mutation detection strategy for exons 10, 11, 13, and 14 of the RET proto-oncogene followed by direct DNA sequencing. Significance of RET genotype-phenotype correlation was determined by Fisher's two-tailed Exact test and a 2 x 2 contingency table.Results: Thirty-six distinctly new MEN 2a kindreds were identified. Hirschsprung's disease cosegregated among siblings with MEN 2a in 15 patients from 6 of the 36 (17%) families. The extent of aganglionosis in the 15 patients ranged from midrectum to duodenum. Of the 15 patients with Hirschsprung's disease, 10 (six boys, four girls) underwent thyroidectomy for MTC (n = 5) or C-cell hyperplasia (n = 5) at ages 2 to 47 years (mean, 15.6 years), and the remaining five patients died in childhood of complications related to the aganglionosis. In retrospect, Hirschsprung's disease was the presenting feature of MEN 2a in five of the six families rather than MTC or pheochromocytoma. In all six MEN 2a families expressing Hirschsprung's disease, the RET mutation predisposing to the combined phenotype occurred in exon 10 at codons 609 (n = 2), 618 (n = 3), or 620 (n = 1). By contrast, the MEN 2a with Hirschsprung's phenotype was not found in any of the 22 families with a RET exon 11, 13, or 14 mutation (P=.0007).Conclusions: The authors conclude that Hirschsprung's disease is a phenotypic marker for MEN 2a and possibly more common than originally appreciated. The expression of Hirschsprung's disease with MEN 2a may be uniquely linked to RET exon 10 mutations. The authors recommend that (1) patients affected with MEN 2a may be counseled regarding the potential risk of Hirschsprung's disease in offspring and (2) a family history of MTC be explored in children with familiar Hirschsprung's disease and genetic screening for MEN 2a be considered. Copyright (C) 1998 by W.B. Saunders Company.