目的：von Hippel-Lindau病（VHL病） 是一种少见的遗传性肿瘤综合征。本文对VHL病相关嗜铬细胞瘤及胰腺病变的临床特征进行总结，并首次报道一例VHL病相关的胰岛素瘤。

方法：对北京协和医院2007至2023年诊断的90例VHL病病例进行回顾性研究，收集存在胰腺病变以及嗜铬细胞瘤患者的临床表现、实验室检查及影像学检查结果。对于可获得外周血样本的患者，通过Sanger测序明确VHL突变位点。按照VHL基因突变位点对患者进行分组并比较临床特征差异。对VHL病相关胰岛素瘤患者的肿瘤及瘤周正常胰腺组织进行全外显子测序以及全基因组测序。通过SPSS 22进行数据分析。

结果：在90例VHL病患者中，54例（60.0%）患者存在胰腺病变（男：女=1.16:1，平均诊断年龄34岁），59例（65.6%）存在PPGLs（男：女=1.81:1，平均诊断年龄25岁）。VHL病胰腺病变可表现为囊肿（n=30，55.6%）、浆液性囊腺瘤（n=4，7.4%）和胰腺神经内分泌肿瘤（pNETs）（n=32，59.3%）。在32例pNETs中，1例为胰岛素瘤，其他31例为无功能瘤。存在胰腺病变的患者中共22例存在第3外显子区第161或167密码子的突变。相比其他位点突变的患者，这些患者更出现pNETs（21/22 vs 7/15，p=0.002）。VHL病相关胰岛素瘤的CNV分析提示拷贝数扩增。VHL病相关PPGLs患者中98.3%存在肾上腺病变，76.3%存在多发病变，45.0%出现术后复发。这些患者中91.4%存在错义突变，64.2%的错义突变发生在延长因子C结合区域。不同突变位点患者的临床特征无显著差异。与散发性PPGLs相比，VHL病相关PPGLs存在肾上腺病变（71.2% vs 49.0%，p<0.05）、多发病变（76.3% vs 11.0%，p<0.05）的比例更高，肿瘤以去甲肾上腺素分泌型为主（80.4% vs 43.2%，p<0.05），术后更易复发（45.0% vs 15.3%，p<0.05）。

结论：VHL病患者常存在胰腺病变以及PPGLs。在存在胰腺病变的VHL病患者中，VHL基因的热点突变为密码子161及167，临床常表现为胰腺无功能NET。本文首次报道一例VHL病相关胰岛素瘤。VHL病相关的PPGLs通常位于肾上腺、存在多发病变，一般为去甲肾上腺素分泌型，术后更易复发。突变位点对PPGLs的临床特征无显著影响。

Objective: von Hippel-Lindau (VHL) disease is a rare heritable syndrome with multiorgan involvement. In this study, we described the clinical features of pancreatic lesions and pheochromocytomas in VHL patients and first reported a case of insulinoma associated with VHL disease .

Methods: Clinical data of 90 VHL patients treated in a single center were retrospectively reviewed. Genetic testing for VHL mutation was conducted by Sanger sequencing. One patient with insulinoma underwent the whole exome sequencing (WES) and whole genome sequencing (WGS). Patients were grouped according to the mutation sites and the clinical charasteristics were compared between groups. Statistics were conducted using SPSS 22.

Results: In the 90 patients, 54 (60.0%) had pancreatic lesions (male: female, 1.16:1; average age at diagnosis, 34 years) and 59 (65.6%) had PPGLs (male: female, 1.81:1; average age at diagnosis 25 years). Pancreatic lesions presented as simple cysts (n=30, 55.6%), serous cystadenoma (n=4, 7.4%), or neuroendocrine tumors (pNETs)(n= 32, 59.3%). In 32 NETs, one was insulinoma, and others were nonfunctional. 22 patients had mutations of codon 161 or 167 in exon 3. pNETs were statistically more frequent in these patients compared to mutations in the rest of VHL (21/22 vs 7/15, p=0.002). An amplification pattern of copy-number variation was found in the WGS of the insulinoma. In patients with VHL-related PPGLs, 98.3% had adrenal lesions, 76.3% had multiple lesions, and 45.0% had recurrence. Missense mutations were present in 91.4% of patients with PPGLs, and 64.2% of which located in the elongin C binding domain. The clinical characteristics had no significant difference between groups with different mutation sites. Compared with sporadic PPGLs, VHL disease-related PPGLs were often in the adrenal (71.2% vs 49.0%, p<0.05), had multiple lesions (76.3% vs 11.0%, p<0.05), and secreted noradrenaline (80.4% vs 43.2%, p<0.05). They were also more likely to relapse after the surgery (45.0% vs 15.3%, p<0.05).

Conclusion: Patients with VHL disease often have pancreatic lesions and PPGLs.  Mutations of codon 161 and 167 were hotspots in patients with pancreatic lesions and were usually characterized by non-functional NETs. A case of VHL disease with insulinoma was first reported. VHL disease related PPGLs were usually multifocal, located in the adrenal gland and secret norepinephrine. They were more likely to relapse after surgery. The mutation site had no significant effect on the clinical characteristics of PPGLs.