目的：检测嗜铬细胞瘤/副神经节瘤患者的4种与该病相关基因（RET、VHL、SDHD、SDHB）的胚系遗传变异，以了解我国该病患者上述基因变异情况。方法：以2012年9月至2014年3月就诊于北京大学第一医院，并经病理确诊的嗜铬细胞瘤/副神经节瘤患者为研究对象，共入选12例，其中嗜铬细胞瘤患者11例，副神经节瘤患者1例。提取患者外周血白细胞DNA，采用PCR技术扩增RET基因的第10、11、13～16外显子，VHL、SDHD、SDHB基因的全部外显子，以及各外显子的邻近内含子（±20 bp），并对扩增产物进行测序。比对测序结果及野生型序列，确定基因变异。对1例诊断为多发性内分泌腺瘤病2A型的患者进行家系分析，在家族成员中检测相应基因变异。结果：共3例患者发现胚系基因变异：1例恶性嗜铬细胞瘤患者存在SDHB基因c.136C>T（p.R46X）变异；1例多发性内分泌腺瘤病2A型患者存在RET基因c.1901G>A（p.C634Y）变异及c.2071G>A（p.G691S）/ c.2712C>G（p.S904S）变异，其家系中发现其他5名成员携带上述变异；1例散发、无恶性表现的嗜铬细胞瘤患者存在RET基因c.2071G>A（p.G691S）/ c.2712C>G（p.S904S）变异。1例患者存在先天性单心室畸形合并嗜铬细胞瘤，其上述4个基因均未发现有临床意义的变异。结论：本研究在25%（3/12）的嗜铬细胞瘤/副神经节瘤患者中发现了错义或无义胚系基因变异，包括SDHB基因的c.136C>T（R46X）变异、RET基因的c.1901G>A（C634Y）变异以及RET基因的c.2071G>A（p.G691S）/ c.2712C>G（p.S904S）变异等，其中前两种变异具有明确的致病性。本研究验证了上述变异在嗜铬细胞瘤/副神经节瘤患者中的存在，临床工作中应该对嗜铬细胞瘤/副神经节瘤患者开展广泛的遗传基因筛查。

Objective： To analyze the germline variations of genes RET, VHL, SDHD and SDHB in patients with pheochromocytoma and/or paraganglioma and to evaluate variations of these genes in Chinese patients. Methods: Patients who were treated in Peking University First Hospital from September 2012 to March 2014 and diagnosed with pheochromocytoma and/or paraganglioma by pathologists were included in this study. Twelve patients were included in total, of whom 11 had pheochromocytoma, and 1 had paraganglioma. Deoxyribonucleic acid (DNA) was extracted from the leukocytes of peripheral blood of the patients. The exons 10, 11, 13-16 of the RET gene, and all exons of VHL, SDHB and SDHD genes and their nearby introns (±20 bp) were amplified with polymerase chain reactions, and the products were sent to a biotechnology company for sequencing. The sequencing results were compared with wildtype sequences of these genes to identify variations. One of the patients was diagnosed with multiple endocrine neoplasia type 2A. A family analysis was performed in his kindred, and his family members received genetic tests for the related variations. Results: Three patients were found to have germline gene variations. A c.136C>T (p.R46X) variation of the SDHB gene was found in a patient with malignant pheochromocytoma. A c.1901G>A (C634Y) variation, as well as c.2071G>A (p.G691S) and c.2712C>G (p.S904S) variations of the RET gene were found in a patient with multiple endocrine neoplasia type 2A. After a family analysis, five family members of this patient were found to have the same variations. c.2071G>A (p.G691S) and c.2712C>G (p.S904S) variations of the RET gene were also found in a clinical sporadic patient without evidence of malignancy. A patient with congenital single ven-tricle malformation and pheochromocytoma was included in this study, and no variation with clinical significance was found in the four genes of this patient. Conclusion: 25% (3/12) patients with pheochromocytoma or paraganglioma were found to have missense or nonsense germline gene variations in this study, including the c.136C>T (p.R46X) variation of the SDHB gene, the c.1901G>A (C634Y) variation of the RET gene, and c.2071G>A (p.G691S) and c.2712C>G (p.S904S) variations of the RET gene. The former two variations have already been confirmed to be pathogenic. The existence of these variations in Chinese patients with pheochromocytoma and/or paraganglioma was validated in this study, which supports the conclusion that genetic testing is necessary to be generally performed in patients with pheochromocytoma and/or paraganglioma.