七个多发性内分泌腺瘤2A型伴皮肤苔藓淀粉样变家系的临床及遗传学分析

Clinical and genetic analysis of seven Chinese pedigrees affected with multiple endocrine neoplasia type 2A with cutaneous lichen amyloidosis

目的探讨伴皮肤苔藓淀粉样变(cutaneous lichen amyloidosis,CLA)的多发性内分泌腺瘤2A型(MEN2A)的临床特征和遗传学病因。方法对7个无血缘关系的MEN2A-CLA家系共51名成员进行家系调查、生化和RET基因等检测及相关组织病理学分析。结果基因检测发现28例MEN2A患者存在RET基因变异(C634G/F/R/S/W或C611Y),与临床诊断完全符合,平均诊断年龄为(41.1±18.3)岁,其甲状腺髓样癌、嗜铬细胞瘤、甲状旁腺功能亢进和CLA的发病率分别为89.3%、28.6%、7.1%和28.6%。基因型-表型分析发现C611Y与C634G/F/R/S/W的嗜铬细胞瘤和CLA发病率的差异具有统计学意义(P<0.05;P<0.05)。8例伴CLA病例的临床表现为肩胛区皮肤反复瘙痒,病损皮肤干燥增厚、棕色色素沉着伴鳞屑、片状丘疹和苔藓样改变;其CLA的平均发病年龄为(18.4±4.6)岁,与其CLA和MEN2A的平均诊断年龄相比差异均有统计学意义(P<0.001;P<0.001)。结论MEN2A-CLA可能是MEN2A的早期临床表现,且大多存在RET-C634变异。提高对MEN2A-CLA的认识,结合家系和RET变异筛查,有利于MEN2A相关内分泌疾病的早期规范诊治和预后。

Objective To explore the pathological characteristics and significance of RET proto-oncogene screening in multiple endocrine neoplasia type 2A(MEN2A)with cutaneous lichen amyloidosis(CLA).Methods Clinical data of 51 members from 7 unrelated pedigrees of MEN2A-CLA were collected.Systemic clinical investigations including biochemical testing,imaging examination,germline RET variant screening and histopathological examination were carried out.Results RET gene variants were detected in 28 patients with MEN2A(C634G/F/R/S/W and C611Y)including 12 males and 16 females,with the mean age of diagnosis being(41.1±18.3)years old,which were consistent with their clinical manifestations.The incidence of medullary thyroid carcinoma(MTC),pheochromocytoma(PHEO),hyperparathyroidism(HPTH)and CLA among 28 MEN2A patients were 89.3%,28.6%,7.1%and 28.6%,respectively.Comparison of the incidence of MTC/PHEO/HPTH and CLA between C611Y and C634G/F/R/S/W,only PHEO and CLA in C611Y were lower than those in C634G/F/R/S/W(P<0.05;P<0.05).Among 8 patients with CLA,the male to female ratio was 2:6.The clinical features included pruritus in the interscapular region and presence of dry,thickened,scaly,brown pigment,clustered or desquamate-like plaques.The mean onset age of CLA[(18.4±4.6)years]versus the mean age at diagnosis of CLA or MEN2A were significantly different(P<0.001;P<0.001).Conclusion MEN2A-CLA may be the early clinical manifestation of MEN2A and most frequently occurred along with RET-C634 variant.To facilitate the recognition of MEN2A-CLA,to combine family investigation and screening of RET variant are helpful for early diagnosis and standardized treatment,which can improve the long-term outcome of MEN2A-specific tumors.