Speak Rowena, Cook Jackie, Harrison Barney, Newell-Price John
Departments of Oncology and Metabolism , University of Sheffield.
Department of Genetics , Sheffield Children's Hospital, Sheffield , UK.
Endocrinol Diabetes Metab Case Rep. 2016;2016. doi: 10.1530/EDM-16-0093. Epub 2016 Nov 25.
Mutations of the rearranged during transfection () proto-oncogene, located on chromosome 10q11.2, cause multiple endocrine neoplasia type 2A (MEN2A). Patients with mutations at the codon 609 usually exhibit a high penetrance of medullary thyroid cancer (MTC), but a sufficiently low penetrance of phaeochromocytoma that screening for this latter complication has been called to question. Patients with other mutations are at higher risk of younger age onset phaeochromocytoma if they also possess other polymorphisms (L769L, S836S, G691S and S904S), but there are no similar data for patients with 609 mutations. We investigated the unusual phenotypic presentation in a family with MEN2A due to a C609Y mutation in . Sanger sequencing of the entire -coding region and exon-intron boundaries was performed. Five family members were C609Y mutation positive: 3/5 initially presented with phaeochromocytoma, but only 1/5 had MTC. The index case aged 73 years had no evidence of MTC, but presented with phaeochromocytoma. Family members also possessed the G691S and S904S polymorphisms. We illustrate a high penetrance of phaeochromocytoma and low penetrance of MTC in patients with a C609Y mutation and polymorphisms G691S and S904S. These data highlight the need for life-long screening for the complications of MEN2A in these patients and support the role for the screening of polymorphisms for the purposes of risk stratification.
C609Y mutations may be associated with a life-long risk of phaeochromocytoma indicating the importance of life-long screening for this condition in patients with MEN2A.C609Y mutations may be associated with a lower risk of MTC than often quoted, questioning the need for early prophylactic thyroid surgery discussion at the age of 5 years.There may be a role for the routine screening of polymorphisms, and this is greatly facilitated by the increasing ease of access to next-generation sequencing.
转染期间重排（RET）原癌基因位于10q11.2染色体上，其突变会导致2A型多发性内分泌肿瘤（MEN2A）。密码子609发生突变的患者通常甲状腺髓样癌（MTC）的外显率较高，但嗜铬细胞瘤的外显率足够低，以至于对后者并发症的筛查受到质疑。如果其他RET突变患者还具有其他RET多态性（L769L、S836S、G691S和S904S），则他们患早发性嗜铬细胞瘤的风险更高，但对于密码子609突变的患者没有类似数据。我们研究了一个因RET基因C609Y突变导致MEN2A的家族中不寻常的表型表现。对整个RET编码区和外显子 - 内含子边界进行了桑格测序。五名家族成员C609Y突变呈阳性：5人中有3人最初表现为嗜铬细胞瘤，但只有1人患有MTC。索引病例为一名73岁的患者，没有MTC的证据，但患有嗜铬细胞瘤。家族成员还具有G691S和S904S RET多态性。我们说明了C609Y突变以及G691S和S904S多态性的患者中嗜铬细胞瘤的高外显率和MTC的低外显率。这些数据突出了对这些患者进行MEN2A并发症终身筛查的必要性，并支持为风险分层目的筛查RET多态性的作用。
C609Y RET突变可能与嗜铬细胞瘤的终身风险相关，这表明对MEN2A患者进行这种疾病终身筛查的重要性。C609Y RET突变可能与MTC的风险低于通常引用的风险相关，这对5岁时进行早期预防性甲状腺手术讨论的必要性提出了质疑。常规筛查RET多态性可能有作用，而获取下一代测序的日益便利极大地促进了这一点。
