Elisei Rossella, Romei Cristina, Cosci Barbara, Agate Laura, Bottici Valeria, Molinaro Eleonora, Sculli Mariangela, Miccoli Paolo, Basolo Fulvio, Grasso Lucia, Pacini Furio, Pinchera Aldo
Department of Endocrinology, University of Pisa, Via Paradisa 2, 56100 Pisa, Italy.
J Clin Endocrinol Metab. 2007 Dec;92(12):4725-9. doi: 10.1210/jc.2007-1005. Epub 2007 Sep 25.
Germline RET gene mutations are causative of multiple endocrine neoplasia (MEN) 2 and may be identified by genetic screening. Three different syndromes are distinguished: MEN 2A, when medullary thyroid carcinoma (MTC) is associated with pheochromocytoma and/or parathyroid adenomas; MEN 2B, when accompanied by a marfanoid habitus and/or pheochromocytoma; and familial medullary thyroid carcinoma (FMTC), when only MTC is present.
During the last 13 yr, we performed RET genetic screening in 807 subjects: 481 with apparently sporadic MTC, 37 with clinical evidence of MEN 2, and 289 relatives. Genomic DNA was extracted from the blood of all subjects, and exons 10, 11, 13, 14, 15, and 16 were analyzed by direct sequencing after PCR.
We unexpectedly discovered a germline RET mutation in 35 of 481 (7.3%) apparently sporadic MTC patients. A germline RET mutation was also found in 36 of 37 patients with clinical evidence of hereditary MTC. The distribution of RET mutations in cysteine and noncysteine encoding codons was significantly different in the two groups of patients, with the prevalence of RET mutations in noncysteine codons being higher in MTC that presented as apparently sporadic (P < 0.0001). A total of 34 FMTCs (75.5% of all FMTC) arrived with apparent sporadic MTC, with no familial history of other MTC cases. According to genetic screening and clinical data, our 72 families were classified as follows: 45 FMTC (62.5%), 22 MEN 2A (30.5%), and five MEN 2B (7%).
In this large series of MTC, hereditary forms, mainly FMTC, were clinically unsuspected in 7.3% of apparently sporadic cases. As a consequence, the prevalence of FMTC in our series is higher than that previously reported (60 vs. 10%). In these cases, RET mutations were more prevalently located in noncysteine codons. Data derived from our series helped elucidate the role of RET genetic screening for the identification of all forms of MEN 2, and especially for FMTC, which are frequently clinically misdiagnosed as nonheritable, sporadic cases.
生殖系RET基因突变是导致多发性内分泌腺瘤（MEN）2型的原因，可通过基因筛查来识别。可区分出三种不同的综合征：MEN 2A，即甲状腺髓样癌（MTC）与嗜铬细胞瘤和/或甲状旁腺腺瘤相关；MEN 2B，伴有类马凡氏体型和/或嗜铬细胞瘤；以及家族性甲状腺髓样癌（FMTC），即仅存在MTC。
在过去13年中，我们对807名受试者进行了RET基因筛查：481例明显散发型MTC患者、37例有MEN 2临床证据的患者以及289名亲属。从所有受试者的血液中提取基因组DNA，PCR后通过直接测序分析第10、11、13、14、15和16外显子。
我们意外地在481例（7.3%）明显散发型MTC患者中的35例发现了生殖系RET突变。在37例有遗传性MTC临床证据的患者中，也有36例发现了生殖系RET突变。两组患者中RET突变在编码半胱氨酸和非半胱氨酸密码子中的分布存在显著差异，在表现为明显散发型的MTC中，非半胱氨酸密码子中RET突变的发生率更高（P < 0.0001）。共有34例FMTC（占所有FMTC的75.5%）表现为明显散发型MTC，且无其他MTC病例的家族史。根据基因筛查和临床数据，我们的72个家系分类如下：45例FMTC（62.5%）、22例MEN 2A（30.5%）和5例MEN 2B（7%）。
在这一大系列MTC中，遗传性类型，主要是FMTC，在7.3%的明显散发型病例中临床未被怀疑。因此，我们系列中FMTC的患病率高于先前报道（60%对10%）。在这些病例中，RET突变更普遍地位于非半胱氨酸密码子中。我们系列的数据有助于阐明RET基因筛查在识别所有形式的MEN 2中的作用，尤其是对于FMTC，其在临床上经常被误诊为非遗传性散发病例。
