Von Hippel-Lindau(VHL)综合征为临床十分罕见的家族性常染色体显性遗传性肿瘤综合征,表现为多发、多器官的良、恶性肿瘤征候群,包括中枢神经系统血管母细胞瘤、内脏肿瘤和囊肿等。发病率约1/3.6万,平均发病年龄为26.3～30.9岁。预后不...Von Hippel-Lindau(VHL)综合征为临床十分罕见的家族性常染色体显性遗传性肿瘤综合征,表现为多发、多器官的良、恶性肿瘤征候群,包括中枢神经系统血管母细胞瘤、内脏肿瘤和囊肿等。发病率约1/3.6万,平均发病年龄为26.3～30.9岁。预后不良,平均生存年龄<49岁,其主要死亡原因是中枢神经系统血管母细胞瘤破裂出血、肾细胞癌和嗜铬细胞引起的恶性高血压。现介绍1例经浙江湖州师范学院附属第一医院泌尿外科收治的中枢神经系统血管母细胞瘤伴发双侧肾癌,附睾、肝、胰腺多发囊肿病例。该患者经左侧保留肾单位的肾癌切除术,索尼替尼分子靶向治疗后效果较佳,随访30个月,生存良好。展开更多
The pancreatic manifestations seen in patients with von Hippel-Lindau(VHL) disease are subdivided into 2 categories:pancreatic neuroendocrine tumors(NET),and cystic lesions,including simple cyst and serous cystadenoma...The pancreatic manifestations seen in patients with von Hippel-Lindau(VHL) disease are subdivided into 2 categories:pancreatic neuroendocrine tumors(NET),and cystic lesions,including simple cyst and serous cystadenoma.The VHL-associated cystic lesions are generally asymptomatic and do not require any treatment,unless they are indistinguishable from other cystic tumor types with malignant potential.Because pancreatic NET in VHL disease are non-functioning and have malignant potential,it is of clinical importance to find and diagnose these as early as possible.It will be recommended that comprehensive surveillance using dynamic computed tomography for abdominal manifestations,including pancreatic NET,should start from the age of 15 years in VHL patients.Unlike sporadic non-functioning NET without VHL disease,in which surgical resection is generally recommended,VHL patients at lower metastatic risk of pancreatic NET should be spared the risks of operative resection.展开更多
Background：Von Hippel-Lindau （VHL） disease is a hereditary tumor disorder caused by mutations or deletions of the VHL gene.Few studies have documented the clinical phenotype and genetic basis of the occurrence of V...Background：Von Hippel-Lindau （VHL） disease is a hereditary tumor disorder caused by mutations or deletions of the VHL gene.Few studies have documented the clinical phenotype and genetic basis of the occurrence of VHL disease in China.This study armed to present clinical and genetic analyses of VHL within a five-generation VHL family from Northwestern China,and summarize the VHL mutations and clinical characteristics of Chinese families with VHL according to previous studies.Methods：An epidemiological investigation of family members was done to collect the general information.A retrospective study of clinical VHL cases was launched to collect the relative clinical data.Genetic linkage and haplotype analysis were used to make sure the linkage of VHL to disease in this family.The VHL gene screening was performed by directly analyzing DNA sequence output.At last,we summarized the VHL gene mutation in China by the literature review.Results：A five-generation North-western Chinese family afflicted with VHL disease was traced in this research.The family consisted of 38 living family members,of whom nine were affected.The individuals afflicted with VHL exhibited multi-organ tumors that included pheochromocytomas （8）,central nervous system hemangioblastomas （3）,pancreatic endocrine tumors （2）,pancreatic cysts （3）,renal cysts （4）,and paragangliomas （2）.A linkage analysis resulted in a high maximal LOD score of 8.26 （theta =0.0） for the marker D3S1263,which is in the same chromosome region as VHL.Sequence analysis resulted in the identification of a functional C〉T transition mutation （c.499 C〉T,p.R167W） located in exon 3 of the 16th codon of VHL.All affected individuals shared this mutation,whereas the unaffected family members and an additional 100 unrelated healthy individuals did not.To date,49 mutations have been associated with this disease in Chinese populations.The most frequent VHL mutations in China are p.S65 W,p.N78 S,p.R161Q and p.R167 W.Conclusions：The results suppo展开更多
Von Hippel-Lindau病(VHL病)是VHL基因变异导致的遗传肿瘤综合征。VHL病相关肿瘤常为多发,其常规治疗方法为手术,但术后易复发。VHL基因具有缺氧诱导因子(HIF)依赖及HIF非依赖的肿瘤抑制作用,关于VHL病遗传学机制的研究为该病的治疗奠...Von Hippel-Lindau病(VHL病)是VHL基因变异导致的遗传肿瘤综合征。VHL病相关肿瘤常为多发,其常规治疗方法为手术,但术后易复发。VHL基因具有缺氧诱导因子(HIF)依赖及HIF非依赖的肿瘤抑制作用,关于VHL病遗传学机制的研究为该病的治疗奠定了基础。近年来针对VHL病遗传学机制靶向药物的出现,为该病的治疗提供了新的思路,作用于缺氧诱导通路的小分子靶向药物,如belzutifan、酪氨酸激酶抑制剂,在临床试验中对VHL病的治疗展示了良好的应用前景。本文对VHL病遗传学机制及相关治疗进展进行总结。针对VHL病靶向药物更深入的临床研究将会为该病患者提供更多的治疗选择。展开更多
目的 von Hippel-Lindau(VHL)综合征是一组罕见的多器官受累的常染色体显性遗传性疾病,临床表现复杂、易误诊。本文探讨VHL综合征的临床特点、CT及MRI特征,提高对本病的早期诊断和综合治疗水平。资料与方法回顾性分析5例VHL综合征患者...目的 von Hippel-Lindau(VHL)综合征是一组罕见的多器官受累的常染色体显性遗传性疾病,临床表现复杂、易误诊。本文探讨VHL综合征的临床特点、CT及MRI特征,提高对本病的早期诊断和综合治疗水平。资料与方法回顾性分析5例VHL综合征患者的临床资料、CT及MRI表现,随访治疗后的结局。结果 5例VHL综合征患者中,小脑血管网织细胞瘤4例,其中1例合并脑干多发血管网织细胞瘤,颈髓多发血管网织细胞瘤1例,典型MRI表现为多发囊实性混杂信号,强化MRI呈实质部明显强化。肾透明细胞癌3例,典型CT表现为等或稍低密度肿块,强化CT可见肿块呈欠均匀强化。双侧附睾囊腺瘤1例,超声示双侧附睾囊实性肿物,实质部分回声不均匀且血流丰富。出院后随访至2015年1月,格拉斯哥预后评分恢复良好3例,死亡2例,均死于肾癌。结论 VHL综合征患者预后较差,肾癌为主要死亡原因。早期应对高度怀疑或已诊断为VHL综合征的患者行VHL基因检测分析并仔细询问其家族史,早期治疗、长期随访及定期影像学检查有助于改善患者预后。展开更多
基金Supported by The Health and Labor Sciences Research Grant for a nationwide clinical survey and establishment of guidelines in the diagnosis and treatment for von Hippel-Lindau disease in Japan
文摘The pancreatic manifestations seen in patients with von Hippel-Lindau(VHL) disease are subdivided into 2 categories:pancreatic neuroendocrine tumors(NET),and cystic lesions,including simple cyst and serous cystadenoma.The VHL-associated cystic lesions are generally asymptomatic and do not require any treatment,unless they are indistinguishable from other cystic tumor types with malignant potential.Because pancreatic NET in VHL disease are non-functioning and have malignant potential,it is of clinical importance to find and diagnose these as early as possible.It will be recommended that comprehensive surveillance using dynamic computed tomography for abdominal manifestations,including pancreatic NET,should start from the age of 15 years in VHL patients.Unlike sporadic non-functioning NET without VHL disease,in which surgical resection is generally recommended,VHL patients at lower metastatic risk of pancreatic NET should be spared the risks of operative resection.
基金This study was supported by funding from the National Science Foundation of China （No. 81072051 and No.81272644）.ACKNOWLEDGMENTS We are indebted to all individuals who participated in or helped with this research project.
文摘Background：Von Hippel-Lindau （VHL） disease is a hereditary tumor disorder caused by mutations or deletions of the VHL gene.Few studies have documented the clinical phenotype and genetic basis of the occurrence of VHL disease in China.This study armed to present clinical and genetic analyses of VHL within a five-generation VHL family from Northwestern China,and summarize the VHL mutations and clinical characteristics of Chinese families with VHL according to previous studies.Methods：An epidemiological investigation of family members was done to collect the general information.A retrospective study of clinical VHL cases was launched to collect the relative clinical data.Genetic linkage and haplotype analysis were used to make sure the linkage of VHL to disease in this family.The VHL gene screening was performed by directly analyzing DNA sequence output.At last,we summarized the VHL gene mutation in China by the literature review.Results：A five-generation North-western Chinese family afflicted with VHL disease was traced in this research.The family consisted of 38 living family members,of whom nine were affected.The individuals afflicted with VHL exhibited multi-organ tumors that included pheochromocytomas （8）,central nervous system hemangioblastomas （3）,pancreatic endocrine tumors （2）,pancreatic cysts （3）,renal cysts （4）,and paragangliomas （2）.A linkage analysis resulted in a high maximal LOD score of 8.26 （theta =0.0） for the marker D3S1263,which is in the same chromosome region as VHL.Sequence analysis resulted in the identification of a functional C〉T transition mutation （c.499 C〉T,p.R167W） located in exon 3 of the 16th codon of VHL.All affected individuals shared this mutation,whereas the unaffected family members and an additional 100 unrelated healthy individuals did not.To date,49 mutations have been associated with this disease in Chinese populations.The most frequent VHL mutations in China are p.S65 W,p.N78 S,p.R161Q and p.R167 W.Conclusions：The results suppo
文摘目的 von Hippel-Lindau(VHL)综合征是一组罕见的多器官受累的常染色体显性遗传性疾病,临床表现复杂、易误诊。本文探讨VHL综合征的临床特点、CT及MRI特征,提高对本病的早期诊断和综合治疗水平。资料与方法回顾性分析5例VHL综合征患者的临床资料、CT及MRI表现,随访治疗后的结局。结果 5例VHL综合征患者中,小脑血管网织细胞瘤4例,其中1例合并脑干多发血管网织细胞瘤,颈髓多发血管网织细胞瘤1例,典型MRI表现为多发囊实性混杂信号,强化MRI呈实质部明显强化。肾透明细胞癌3例,典型CT表现为等或稍低密度肿块,强化CT可见肿块呈欠均匀强化。双侧附睾囊腺瘤1例,超声示双侧附睾囊实性肿物,实质部分回声不均匀且血流丰富。出院后随访至2015年1月,格拉斯哥预后评分恢复良好3例,死亡2例,均死于肾癌。结论 VHL综合征患者预后较差,肾癌为主要死亡原因。早期应对高度怀疑或已诊断为VHL综合征的患者行VHL基因检测分析并仔细询问其家族史,早期治疗、长期随访及定期影像学检查有助于改善患者预后。
