三个多发性内分泌腺瘤2A型家系的临床诊治及RET原癌基因突变检测

The clinical diagnosis, treatment and RET proto-oncogene screening in three multiple endocrineneoplasia type 2A pedigrees

目的 探讨3个多发性内分泌腺瘤2A型（MEN2A）家系的诊治及RET基因检测的临床意义.方法 分析1990年4月至2011年12月诊治的3个家系10例MEN2A患者的临床资料.男4例,女6例.5例以颈部占位就诊：3例接受了不规范的甲状腺全切除术,2例接受双侧甲状腺全切＋双侧颈部改良淋巴结清扫；5例无甲状腺肿瘤症状的RET基因突变携带者行双侧甲状腺全切＋至少双侧颈部Ⅵ区淋巴结清扫.6例伴发肾上腺嗜铬细胞瘤（PHEO）：5例行双侧PHEO一期切除,1例行单侧PHEO切除.3个家系共23例成员接受外周血RET基因检测.结果 病理均明确诊断双侧甲状腺髓样癌（10/10）.有、无症状的甲状腺髓样癌（MTC）患者间的首次平均诊断年龄[39.0（31 ～64）岁比18.2（5.5 ～36）岁]、肿瘤最大直径[2.8（1.2～5.6） cm比0.7（0.2 ～ 1.3） cm]、淋巴结阳性转移率[100％ （5/5）比20％ （1/5）],差异均有统计学意义（均P＜0.05）.MTC随访7～ 66个月,术后降钙素有症状组均升高（5/5）,无症状组仅见1例升高（P＜0.05）.6例PHEO（60％）的平均诊断年龄42.0岁,5例为双侧多发,1例为单侧单发；3例双侧PHEO术后需终生口服激素替代.PHEO随访19 ～ 104个月,6例均无复发或转移.基因检测均为RET基因p.C634Y突变（10/23）,1个家系为RET基因p.C634Y新发突变（de novo）.结论 基于RET基因和血清降钙素检测及早进行规范手术可有效治愈MEN2A-MTC；对伴有双侧PHEO者,应优先选择保留肾上腺皮质功能的腹腔镜下双侧PHEO一期切除术.

Objective To discuss clinical characteristics,treatment and clinical significance for RET screening in 3 multiple endocrine neoplasia type 2A （MEN2A） pedigrees.Methods The clinical data of 10 MEN2A patients from 3 unrelated MEN2A pedigrees from April 1990 to December 2011 were analyzed.There were 4 males and 6 females.5 patients with symptomatic palpable neck masses underwent bilateral total thyroidectomy ＋ bilateral neck lymph node dissection.Other 5 RET screening detected asymptomatic thyroid cancer patients underwent bilateral total thyroidectomy ＋ bilateral level Ⅵ lymph node dissection.6 adrenal pheochromocytoma （PHEO） patients received bilateral adrenalectomy （5 cases） or unilateral adrenalectomy （1 case）.23 members from 3 families agreed to participate in biochemical testing,image examinations and RET screening.Results Histopathology revealed bilateral medullary thyroid carcinoma （MTC） in all 10 patients （100%）.The two groups （symptomatic and asymptomatic） have significantly differences from the first diagnostic age [39.0 （31-64） years vs.18.2 （5.5-36） years],tumor maximum diameter [2.8 （1.2-5.6） cm vs.0.7 （0.2-1.3） cm] and positive lymph node metastatic ratio [100% （5/5） vs.20% （1/5）] （P 〈 0.05）.These MTC cases were followed-up for 7-66 months,postoperative calcitonin still positive in all 5 preoperatively symptomatic patients,while in only 1 preoperatively asymptomatic patient （P 〈 0.05）.PHEO was bilateral,multiple in 5 patients and unilateral multiple in 1 patient.Postoperatively 3 patients need lifelong steroid substitution.19-104 months follow-up found no recurrence or metastasis.RET screening showed a missense mutations of TGC to TAC （p.C634Y）at codon 634 on exon 11 in all 10 patients,and a patient was diagnosed as having de novo MEN2A.Conclusions Based on RET screening and serum calcitonin monitoring,early and radical surgery can cure MEN2A related MTC; One stage bilateral laparoscopic cortical-sparing adrenalectomy is recommended for bilateral PHEO in MEN2A patients.