Chiefari E, Chiarella R, Crocetti U, Tardio B, Arturi F, Russo D, Trischitta V, Filetti S, Zingrillo M
Cattedra di Endocrinologia, Dipartimento di Medicina Sperimentale e Clinica, Catanzaro, Italy.
Horm Metab Res. 2001 Jan;33(1):52-6. doi: 10.1055/s-2001-12627.
Germline mutations of the RET proto-oncogene cause three different cancer syndromes: multiple endocrine neoplasia type 2A (MEN 2A), multiple endocrine neoplasia type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). In the absence of biochemical and/or clinical evidence of pheochromocytoma and hyperparathyroidism, patients with MEN 2A disease display the same phenotype of FMTC disease, although prognosis and clinical management in both affected and unaffected familial members are quite different. We studied a family with hereditary MTC, whose proband was referred to us because of enlarged cervical nodes and increased calcitonin serum levels 28 years after the total thyroidectomy for MTC. Cervical node dissection was carried out and subsequently the presence of MTC metastasis was histologically confirmed. A RET genomic mutation at codon 634 (TGC-->TTC) was identified in the proband and in seven out of 19 familial members studied. Accordingly, a hereditary disease was suggested. However, the strong association of RET mutation at codon 634 with the presence of pheochromocytoma in MEN 2 disease suggested a more rigorous management in all gene carriers. Indeed, during the follow-up pheochromocytoma was subsequently identified in the proband. This finding suggests that all families with a pedigree suggestive of FMTC should be regarded at risk from MEN 2A disease, at least when a critical mutation in the RET cysteine domain is detected.
RET原癌基因的种系突变可导致三种不同的癌症综合征：2A型多发性内分泌腺瘤病（MEN 2A）、2B型多发性内分泌腺瘤病（MEN 2B）和家族性甲状腺髓样癌（FMTC）。在没有嗜铬细胞瘤和甲状旁腺功能亢进的生化和/或临床证据的情况下，MEN 2A疾病患者表现出与FMTC疾病相同的表型，尽管受影响和未受影响的家族成员的预后和临床管理有很大不同。我们研究了一个遗传性甲状腺髓样癌（MTC）家族，该家族的先证者因甲状腺髓样癌全甲状腺切除术后28年颈部淋巴结肿大和血清降钙素水平升高而转诊至我们这里。进行了颈部淋巴结清扫，随后组织学证实存在MTC转移。在先证者和所研究的19名家族成员中的7名中鉴定出RET基因第634密码子（TGC→TTC）的基因组突变。因此，提示存在一种遗传性疾病。然而，MEN 2疾病中第634密码子的RET突变与嗜铬细胞瘤的存在密切相关，这表明对所有基因携带者应进行更严格的管理。事实上，在随访期间，在先证者中随后发现了嗜铬细胞瘤。这一发现表明，所有家系提示FMTC的家族都应被视为有患MEN 2A疾病的风险，至少在检测到RET半胱氨酸结构域的关键突变时如此。
