RET基因突变导致的多发性内分泌腺瘤病2B型患者的临床特点及诊治经验  

Clinical manifestations, therapeutic response to tyrosinase inhibitor and RET gene activatingmutation in a patient with multiple endocrine neoplasia 2B

作　　者：茅江峰[1] 王志新[1] 李梅[1] 童安莉[1] 连小兰[1] 邢小平[1] 

机构地区：[1]中国医学科学院北京协和医学院北京协和医院内分泌科卫生部内分泌重点实验室,100730

出　　处：《中华医学杂志》2013年第6期445-448,共4页National Medical Journal of China

基　　金：国家自然科学基金（81100416）

摘　　要：目的对1例多发性内分泌腺瘤病2B型患者的临床特点、酪氨酸抑制剂治疗反应和致病基因进行探讨，以提高对此疾病的认识和治疗水平。方法收集患者长期诊治的临床资料、生化检查及影像学资料进行临床特点和药物治疗反应分析。抽取患者及其父母的外周静脉血，提取基因组DNA，通过聚合酶链反应（PCR）方法，对RET原癌基因第10-16个外显子及相邻内含子进行测序，明确RET基因突变状态。结果（1）患者以甲状腺髓样癌（MTC）、双侧肾上腺嗜铬细胞瘤和多发黏膜神经纤维瘤为主要临床表现。（2）MTC，肺、肝和骨多处转移。病程中试用酪氨酸酶抑制剂——索拉非尼治疗MTC2个月，水样腹泻和咳嗽减少。因不能耐受脱发、疼痛性皮疹不良反应而停药。（3）即使已发生肿瘤多处转移，但患者长期接受静脉营养支持治疗，存活时间超过14年。（4）基因检测示RET原癌基因存在激活突变，918位蛋氨酸被苏氨酸取代（Met918Thr）。结论尽管手术是MTC主要治疗方式，但酪氨酸激酶抑制剂可能为晚期患者改善症状提供一个新选择。对已出现多处转移的患者，长期营养支持可能有助于延长生存时间。Objective To explore the clinical manifestations, therapeutic response and RET gene mutation in a patient with multiple endocrine neoplasia 2B （MEN2B） characterized by medullary thyroid carcinoma （MTC）, bilateral adrenal pheochromocytoma and multiple mucosal neuromas. Methods The clinical features, laboratory data and radiological manifestations of this patient were collected. Genomic DNA was extracted from her peripheral blood leukocytes and her parents. Tenth to sixteenth exons of RET proto- oncogene, including the flanking regions of introns, were amplified by polymerase chain reaction （PCR）. And the mutations of RET proto-oncogene were identified by direct sequencing. Results MEN-2B was diagnosed by the clinical presentations, laboratory tests and radiological findings. Gene analysis confirmed heterozygous mis-sense mutation at codon 918 in exon 16 of RET proto-oncogene in which thymine was replaced by cytosine （ATG→ACG）. Her thyroid medullary carcinoma was treated by radical operations and radiotherapy. Tyrosinase inhibitor sorafenib was administered for 2 months and watery diarrhea and cough were alleviated. The drug was withdrawn because of such intolerant side effects as hair loss and painful rashes. She had a survival time of over 14 years with multiple system tumor metastases. Conclusions The mutation analysis of RET proto-oncogene confirmed the diagnosis of MEN2B in respect of molecular genetics. For patients with advanced MTC, tyrosinase inhibitors may relieve the symptoms and provide a new therapeutic choice.

关 键 词：多发性内分泌瘤病2b型 原癌基因蛋白质c-ret 癌 髓样 酪氨酸激酶抑制剂 

分 类 号：R736[医药卫生—肿瘤]