Mannelli M, Simi L, Gaglianò M S, Opocher G, Ercolino T, Becherini L, Parenti G
Department of Clinical Pathophysiology, Endocrinology Unit, University of Florence, Florence, Italy.
Exp Clin Endocrinol Diabetes. 2007 Mar;115(3):160-5. doi: 10.1055/s-2007-970407.
The familial forms of pheochromocytoma have recently been demonstrated to be more frequent than believed in the past. The genes currently known to be responsible for tumor formation are RET, VHL, NF1, SDHB, SDHC and SDHD. Germline mutations of these genes increase the risk of developing pheochromocytomas and/or paragangliomas which variably associate with other neoplasms and characterize diverse clinical syndromes such as MEN 2, von Hippel-Lindau (VHL), and neurofibromatosis type 1 (NF 1), or the PGL syndromes, respectively. Although the pathogenesis of pheochromocytoma/paraganglioma formation is still largely unknown, studies of the familial forms have started to uncover some pathways that favor tumor formation, such as activation of tyrosine-kinase, induction of hypoxia-inducible factors, activation of the oncogene Ras or reduced apoptosis. These studies have also demonstrated that various gene mutations can differently affect the biological characteristics of pheochromocytoma: for example, while the tumors are mostly adrenergic (epinephrine secreting) and episodically secreting in MEN 2, they are mostly noradrenergic (norepinephrine secreting) and continuously secreting in VHL. Biological variability can also be observed in the PGL syndromes where tumors develop in the head and neck and are parasympathetic in origin and non-secreting, or in the thorax and the abdomen, where they are sympathetic in origin and catecholamine secreting. Genetic testing in patients with pheochromocytomas or paragangliomas is, at present, strongly recommended and is mandatory in young patients or in cases of multiple or recurrent tumors. The clinical picture and the biological characteristics of the tumor may suggest the priority of the genes to be tested first.
最近已证实，家族性嗜铬细胞瘤比过去认为的更为常见。目前已知与肿瘤形成相关的基因有RET、VHL、NF1、SDHB、SDHC和SDHD。这些基因的种系突变会增加患嗜铬细胞瘤和/或副神经节瘤的风险，这些肿瘤与其他肿瘤有不同程度的关联，并分别表现出多种临床综合征的特征，如MEN 2、冯·希佩尔-林道病（VHL）和1型神经纤维瘤病（NF 1）或副神经节瘤综合征。尽管嗜铬细胞瘤/副神经节瘤形成的发病机制在很大程度上仍不清楚，但对家族性形式的研究已开始揭示一些有利于肿瘤形成的途径，如酪氨酸激酶的激活、缺氧诱导因子的诱导、癌基因Ras的激活或凋亡减少。这些研究还表明，各种基因突变可对嗜铬细胞瘤的生物学特性产生不同影响：例如，在MEN 2中，肿瘤大多为肾上腺素能（分泌肾上腺素）且呈间歇性分泌，而在VHL中，肿瘤大多为去甲肾上腺素能（分泌去甲肾上腺素）且持续分泌。在副神经节瘤综合征中也可观察到生物学变异性，其中肿瘤发生在头颈部，起源于副交感神经且不分泌，或发生在胸部和腹部，起源于交感神经且分泌儿茶酚胺。目前，强烈建议对嗜铬细胞瘤或副神经节瘤患者进行基因检测，对于年轻患者或多发或复发性肿瘤患者，基因检测是强制性的。肿瘤的临床表现和生物学特性可能提示首先检测的基因的优先级。
