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
Objective:The aim of the current review is to summarize the available evidence to aid clinicians in the surveillance,treatment and follow-up of the different primary tumors developed by patients diagnosed with von Hip...Objective:The aim of the current review is to summarize the available evidence to aid clinicians in the surveillance,treatment and follow-up of the different primary tumors developed by patients diagnosed with von Hippel-Lindau(VHL)syndrome.Methods:A non-systematic narrative review of original articles,meta-analyses,and random-ized trials was conducted,including articles in the pre-clinical setting to support relevant find-ings.Results:VHL disease is the most common rare hereditary disorder associated with clear cell renal cell carcinoma.Affected individuals inherit a germline mutation in one VHL allele,and any somatic event that disrupt the other allele can trigger mutations,chromosomal rearrange-ments,or epigenetic regulations leading to oncogenesis.From a clinical perspective,patients continuously develop multiple primary tumors.Conclusion:Because VHL is considered a rare disease,very limited evidence is available for diagnosis,surveillance,active treatment with local or systemic therapy and follow-up.展开更多
von Hippel-Lindau(VHL)disease is a rare autosomal dominant multiorgan disease characterized by several benign and malignant tumors rich in vascular,as well as cysts in other organs.A great clinical treatment strategy ...von Hippel-Lindau(VHL)disease is a rare autosomal dominant multiorgan disease characterized by several benign and malignant tumors rich in vascular,as well as cysts in other organs.A great clinical treatment strategy is significantly warranted for good prognosis of patients with VHL disease.Herein,we reported a case of a 45-year-old woman diagnosed with VHL disease with spinal hemangioblastoma(HB)and clear cell renal cell carcinoma(ccRCC).Four years after the resection of the right kidney,a recurrent RCC in the right kidney and a malignant lesion in the left kidney were observed.This patient was started on sorafenib(800 mg,daily)and tislelizumab(200 mg per 3 weeks).After 6 months of treatment,the size of renal cell carcinoma was dramatically reduced and renal function improved.More importantly,she achieved partial response during the whole treatment.Microscopically,intramedullary masses resection was done and the HB in T4-5 thoracic spinal was removed.Neurologic symptoms such as numbness and pain were remarkably alleviated.Additionally,tislelizumab-induced elevation in liver transaminase levels and hypothyroidism were revered by hepatoprotector and levothyroxine,respectively.In short,comprehensive treatment strategies may benefit patients with VHL disease,especially with HB and ccRCC.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 supported the notion that the genomic sequence that corresponds to the 167th residue of VHL is a mutational hotspot.Further research is needed to clarify the molecular role of VHL in the development of organ-specific tumors.展开更多
Von Hippel-Lindau (VHL) disease is an autosomal dominant here ditary familial neoplasm syndrome characte rized by development of a variety of benign and malignant tumors in multiple organ systems,such as the brain,kid...Von Hippel-Lindau (VHL) disease is an autosomal dominant here ditary familial neoplasm syndrome characte rized by development of a variety of benign and malignant tumors in multiple organ systems,such as the brain,kidney,pancreas,adrenalgland,and epididymis,with aprev a lence of one in 39000- 53000.1 4 Hallmarks of the condition in clude retinal angiomas,hem angioblastomas of the cerebellum and the spinal cord,renal cell carcinoma and cysts,and pheochrom ocytomas.In this article,we report imaging findings in three cases of VHLdisease.展开更多
Background Von HippeI-Lindau disease （VHL）,a heritable autosomal dominant disease characterized by neoplasia in multiple organ systems,has rarely been reported in Asia.We genetically investigated a unique Chinese fa...Background Von HippeI-Lindau disease （VHL）,a heritable autosomal dominant disease characterized by neoplasia in multiple organ systems,has rarely been reported in Asia.We genetically investigated a unique Chinese family with VHL disease and performed an analysis of the VHL protein stability.Methods Genomic deoxyribonucleic acid （DNA） extracted from peripheral blood was amplified by polymerase chain reaction （PCR） to three exons of the VHL gene in 9 members of the Chinese family with VHL disease.PCR products were directly sequenced.We estimated the effects of VHL gene mutation on the stability of pVHL,which is indicated by the free energy difference between the wild-type and the mutant protein （△△G）.Results The Chinese family was classified as VHL type 1.Three family members,including two patients and a carrier,had a T to G heterozygotic missense mutation at nucleotide 515 of the VHL gene exon 1.This missense mutation resulted in the transition from leucine to arginine in amino acid 101 of the VHL protein.There was low stability of the VHL protein （the △△G was 12.71 kcal/mol） caused by this missense mutation.Conclusions We first reported a family with this VHL gene mutation in Asia.This missense mutation is predicted to significantly reduce the stability of the VHL protein and contribute to the development of the renal cell carcinoma （RCC） phenotype displayed by this family.The genetic characterization and protein stability analysis of families with VHL disease are important for early diagnosis and prevention of the disease being passed on to their offspring.展开更多
Von Hippel-Lindau (VHL) is an inherited neoplasia syndrome caused by inactivation of the VHL tumor suppressor gene, characterized by the development of sporadic clear cell renal carcinoma, pheochromocytomas, retinal a...Von Hippel-Lindau (VHL) is an inherited neoplasia syndrome caused by inactivation of the VHL tumor suppressor gene, characterized by the development of sporadic clear cell renal carcinoma, pheochromocytomas, retinal angioma, pancreatic cysts, and CNS hemangioblastomas. Glomeruloid hemangioma is a vascular lesion, previously considered to be specifically associated with POEMS (polyneuropathy, organomegaly, endocrinopathy/edema, M-protein and skin abnormalities) syndrome. However, there are reports of solitary glomeruloid hemangioma in patients without POEMS syndrome. We report the case of a 39-year-old male with VHL disease, with known bilateral clear cell renal carcinomas, CNS hemangioblastoma and pancreatic cysts. The patient presented with a0.35 cmred papule on the left lateral neck, which was easily irritated, and bleed frequently. Histopathologically, there were irregular areas of ectatic vascular channels of small capillaries, resembling renal glomeruli, surrounded by actin-positive pericytes, within the dermis. These findings were consistent with a glomeruloid hemangioma. Fluorescent in-situ hybridization studies confirmed a deletion in the 3p25.3 region. As per clinical tests, no evidence of POEMS syndrome was found in this patient. Only six reports of glomeruloid hemangioma have been previously reported in patients without POEMS syndrome and this constitutes the first report of glomeruloid hemangioma in a patient with VHL.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.
文摘Objective:The aim of the current review is to summarize the available evidence to aid clinicians in the surveillance,treatment and follow-up of the different primary tumors developed by patients diagnosed with von Hippel-Lindau(VHL)syndrome.Methods:A non-systematic narrative review of original articles,meta-analyses,and random-ized trials was conducted,including articles in the pre-clinical setting to support relevant find-ings.Results:VHL disease is the most common rare hereditary disorder associated with clear cell renal cell carcinoma.Affected individuals inherit a germline mutation in one VHL allele,and any somatic event that disrupt the other allele can trigger mutations,chromosomal rearrange-ments,or epigenetic regulations leading to oncogenesis.From a clinical perspective,patients continuously develop multiple primary tumors.Conclusion:Because VHL is considered a rare disease,very limited evidence is available for diagnosis,surveillance,active treatment with local or systemic therapy and follow-up.
基金National Natural Scientific Foundation of China,Grant/Award Number:82172566Beijing Science and Technology Innovation Medical Development Foundation,Grant/Award Number:KC2021-JX-0186-101Tsinghua University Initiative Scientific Research Program of Precision Medicine,Grant/Award Number:2022ZLB004。
文摘von Hippel-Lindau(VHL)disease is a rare autosomal dominant multiorgan disease characterized by several benign and malignant tumors rich in vascular,as well as cysts in other organs.A great clinical treatment strategy is significantly warranted for good prognosis of patients with VHL disease.Herein,we reported a case of a 45-year-old woman diagnosed with VHL disease with spinal hemangioblastoma(HB)and clear cell renal cell carcinoma(ccRCC).Four years after the resection of the right kidney,a recurrent RCC in the right kidney and a malignant lesion in the left kidney were observed.This patient was started on sorafenib(800 mg,daily)and tislelizumab(200 mg per 3 weeks).After 6 months of treatment,the size of renal cell carcinoma was dramatically reduced and renal function improved.More importantly,she achieved partial response during the whole treatment.Microscopically,intramedullary masses resection was done and the HB in T4-5 thoracic spinal was removed.Neurologic symptoms such as numbness and pain were remarkably alleviated.Additionally,tislelizumab-induced elevation in liver transaminase levels and hypothyroidism were revered by hepatoprotector and levothyroxine,respectively.In short,comprehensive treatment strategies may benefit patients with VHL disease,especially with HB and ccRCC.
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 supported the notion that the genomic sequence that corresponds to the 167th residue of VHL is a mutational hotspot.Further research is needed to clarify the molecular role of VHL in the development of organ-specific tumors.
文摘Von Hippel-Lindau (VHL) disease is an autosomal dominant here ditary familial neoplasm syndrome characte rized by development of a variety of benign and malignant tumors in multiple organ systems,such as the brain,kidney,pancreas,adrenalgland,and epididymis,with aprev a lence of one in 39000- 53000.1 4 Hallmarks of the condition in clude retinal angiomas,hem angioblastomas of the cerebellum and the spinal cord,renal cell carcinoma and cysts,and pheochrom ocytomas.In this article,we report imaging findings in three cases of VHLdisease.
基金This research was supported by grants from the National Natural Science Foundation of China （No. 30901487, No. 81302223, No. 81070488 and No. 81172432）, the Guangdong Natural Science Foundation （No. 10251008901000005）, and the Guangdong Province Science and Technology Project （No. 2011 B031800115, No. 2011 B032000003 and No. 20101051500032）.
文摘Background Von HippeI-Lindau disease （VHL）,a heritable autosomal dominant disease characterized by neoplasia in multiple organ systems,has rarely been reported in Asia.We genetically investigated a unique Chinese family with VHL disease and performed an analysis of the VHL protein stability.Methods Genomic deoxyribonucleic acid （DNA） extracted from peripheral blood was amplified by polymerase chain reaction （PCR） to three exons of the VHL gene in 9 members of the Chinese family with VHL disease.PCR products were directly sequenced.We estimated the effects of VHL gene mutation on the stability of pVHL,which is indicated by the free energy difference between the wild-type and the mutant protein （△△G）.Results The Chinese family was classified as VHL type 1.Three family members,including two patients and a carrier,had a T to G heterozygotic missense mutation at nucleotide 515 of the VHL gene exon 1.This missense mutation resulted in the transition from leucine to arginine in amino acid 101 of the VHL protein.There was low stability of the VHL protein （the △△G was 12.71 kcal/mol） caused by this missense mutation.Conclusions We first reported a family with this VHL gene mutation in Asia.This missense mutation is predicted to significantly reduce the stability of the VHL protein and contribute to the development of the renal cell carcinoma （RCC） phenotype displayed by this family.The genetic characterization and protein stability analysis of families with VHL disease are important for early diagnosis and prevention of the disease being passed on to their offspring.
文摘Von Hippel-Lindau (VHL) is an inherited neoplasia syndrome caused by inactivation of the VHL tumor suppressor gene, characterized by the development of sporadic clear cell renal carcinoma, pheochromocytomas, retinal angioma, pancreatic cysts, and CNS hemangioblastomas. Glomeruloid hemangioma is a vascular lesion, previously considered to be specifically associated with POEMS (polyneuropathy, organomegaly, endocrinopathy/edema, M-protein and skin abnormalities) syndrome. However, there are reports of solitary glomeruloid hemangioma in patients without POEMS syndrome. We report the case of a 39-year-old male with VHL disease, with known bilateral clear cell renal carcinomas, CNS hemangioblastoma and pancreatic cysts. The patient presented with a0.35 cmred papule on the left lateral neck, which was easily irritated, and bleed frequently. Histopathologically, there were irregular areas of ectatic vascular channels of small capillaries, resembling renal glomeruli, surrounded by actin-positive pericytes, within the dermis. These findings were consistent with a glomeruloid hemangioma. Fluorescent in-situ hybridization studies confirmed a deletion in the 3p25.3 region. As per clinical tests, no evidence of POEMS syndrome was found in this patient. Only six reports of glomeruloid hemangioma have been previously reported in patients without POEMS syndrome and this constitutes the first report of glomeruloid hemangioma in a patient with VHL.
