Bryant Jennifer, Farmer Jennifer, Kessler Lisa J, Townsend Raymond R, Nathanson Katherine L
Division of Medical Genetics, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
J Natl Cancer Inst. 2003 Aug 20;95(16):1196-204. doi: 10.1093/jnci/djg024.
Pheochromocytomas and paragangliomas are tumors of the autonomic nervous system; pheochromocytomas are tumors of the adrenal medulla, and paragangliomas are extra-adrenal tumors arising from either the sympathetic nervous system or parasympathetic ganglia. It has previously been estimated that approximately 10%-15% of pheochromocytomas are due to hereditary causes. However, our increased understanding of the three hereditary syndromes (neurofibromatosis 1, multiple endocrine neoplasia type 2, and von Hippel-Lindau syndrome) in which pheochromocytoma is found and the recent discovery that mutations in genes in the succinate dehydrogenase family (SDHB and SDHD) predispose to pheochromocytoma have necessitated a re-evaluation of the genetic basis of pheochromocytoma. These studies indicate that the frequency of germline mutations associated with isolated pheochromocytoma is higher than previously estimated, with both hospital-based series and a large population-based series indicating that the frequency of germline mutations in RET, VHL, SDHB, and SDHD taken together approximates 20%. In all patients with pheochromocytoma, including those with known hereditary syndrome or a positive family history, the frequency of germline mutations in these four genes together approaches 30%. Given the frequency of germline mutations, consideration should be given to genetic counseling for all patients with pheochromocytoma and is particularly important for individuals with a positive family history, multifocal disease, or a diagnosis before age 50. Identification of patients with hereditary pheochromocytoma is important because it can guide medical management in mutation-positive patients and their families. This review provides an overview of the known genetic syndromes that are commonly associated with pheochromocytoma, examines recent data on the association of germline mutations in the succinate dehydrogenase gene family with pheochromocytoma, and suggests guidelines for the genetic evaluation of pheochromocytoma patients.
嗜铬细胞瘤和副神经节瘤是自主神经系统的肿瘤；嗜铬细胞瘤是肾上腺髓质的肿瘤，而副神经节瘤是起源于交感神经系统或副交感神经节的肾上腺外肿瘤。此前估计，约10%-15%的嗜铬细胞瘤是由遗传因素引起的。然而，我们对发现嗜铬细胞瘤的三种遗传综合征（神经纤维瘤病1型、多发性内分泌腺瘤2型和冯·希佩尔-林道综合征）的认识不断增加，以及最近发现琥珀酸脱氢酶家族（SDHB和SDHD）中的基因突变易患嗜铬细胞瘤，这就需要对嗜铬细胞瘤的遗传基础进行重新评估。这些研究表明，与孤立性嗜铬细胞瘤相关的种系突变频率高于先前估计，基于医院的系列研究和大型基于人群的系列研究均表明，RET、VHL、SDHB和SDHD的种系突变频率合计约为20%。在所有嗜铬细胞瘤患者中，包括那些患有已知遗传综合征或有阳性家族史的患者，这四个基因的种系突变频率合计接近30%。鉴于种系突变的频率，应对所有嗜铬细胞瘤患者进行遗传咨询，这对有阳性家族史、多灶性疾病或50岁前确诊的个体尤为重要。识别遗传性嗜铬细胞瘤患者很重要，因为它可以指导突变阳性患者及其家人的医疗管理。本综述概述了通常与嗜铬细胞瘤相关的已知遗传综合征，研究了琥珀酸脱氢酶基因家族种系突变与嗜铬细胞瘤关联的最新数据，并提出了嗜铬细胞瘤患者遗传评估的指导原则。
