Casey Ruth T, Warren Anne Y, Martin Jose Ezequiel, Challis Benjamin G, Rattenberry Eleanor, Whitworth James, Andrews Katrina A, Roberts Thomas, Clark Graeme R, West Hannah, Smith Philip S, Docquier France M, Rodger Fay, Murray Vicki, Simpson Helen L, Wallis Yvonne, Giger Olivier, Tran Maxine, Tomkins Susan, Stewart Grant D, Park Soo-Mi, Woodward Emma R, Maher Eamonn R
Department of Medical Genetics, University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre, Cambridge CB2 OQQ, United Kingdom.
Department of Endocrinology, Cambridge University National Health Service (NHS) Foundation Trust, Cambridge CB2 OQQ, United Kingdom.
J Clin Endocrinol Metab. 2017 Nov 1;102(11):4013-4022. doi: 10.1210/jc.2017-00562.
The co-occurrence of pheochromocytoma (PC) and renal tumors was linked to the inherited familial cancer syndrome von Hippel-Lindau (VHL) disease more than six decades ago. Subsequently, other shared genetic causes of predisposition to renal tumors and to PC, paraganglioma (PGL), or head and neck paraganglioma (HNPGL) have been described, but case series of non-VHL-related cases of renal tumor and pheochromocytoma/paraganglioma tumor association syndrome (RAPTAS) are rare.
To determine the clinical and molecular features of non-VHL RAPTAS by literature review and characterization of a case series.
A review of the literature was performed and a retrospective study of referrals for investigation of genetic causes of RAPTAS.
Literature review revealed evidence of an association, in addition to VHL disease, between germline mutations in SDHB, SDHC, SDHD, TMEM127, and MAX genes and RAPTAS [defined here as the co-occurrence of tumors from both classes (PC/PGL/HNPGL and renal tumors) in the same individual or in first-degree relatives]. In both the literature review and our case series of 22 probands with non-VHL RAPTAS, SDHB mutations were the most frequent cause of non-VHL RAPTAS. A genetic cause was identified in 36.3% (8/22) of kindreds.
Renal tumors and PC/PGL/HNPGL tumors share common molecular features and their co-occurrence in an individual or family should prompt genetic investigations. We report a case of MAX-associated renal cell carcinoma and confirm the role of TMEM127 mutations with renal cell carcinoma predisposition.
六十多年前，嗜铬细胞瘤（PC）与肾肿瘤的同时出现就与遗传性家族性癌症综合征冯希佩尔-林道（VHL）病相关联。随后，人们又描述了其他一些导致肾肿瘤以及PC、副神经节瘤（PGL）或头颈部副神经节瘤（HNPGL）易感性的共同遗传原因，但非VHL相关的肾肿瘤与嗜铬细胞瘤/副神经节瘤肿瘤关联综合征（RAPTAS）的病例系列却很罕见。
通过文献综述和一个病例系列的特征分析，确定非VHL型RAPTAS的临床和分子特征。
进行了文献综述，并对因RAPTAS遗传原因进行调查的转诊病例进行了回顾性研究。
文献综述显示，除了VHL病之外，SDHB、SDHC、SDHD、TMEM127和MAX基因的种系突变与RAPTAS（在此定义为同一人或一级亲属中同时出现两类肿瘤（PC/PGL/HNPGL和肾肿瘤））之间存在关联。在文献综述以及我们的22例非VHL型RAPTAS先证者病例系列中，SDHB突变都是非VHL型RAPTAS最常见的病因。在36.3%（8/22）的家族中确定了遗传原因。
肾肿瘤与PC/PGL/HNPGL肿瘤具有共同的分子特征，它们在个体或家族中的同时出现应促使进行基因调查。我们报告了1例与MAX相关的肾细胞癌病例，并证实了TMEM127突变在肾细胞癌易感性中的作用。
