遗传性肾癌综合征培训讲义课件

遗传性肾癌综合征（优选）遗传性肾癌综合征意义早期筛查仔细随访相应患者及其家属降低疾病相关死亡率并改善预后发现遗传性肾癌的相关基因进行肿瘤形成机制相关的细胞分子通路研究进行肿瘤治疗的分子靶点的研究种类

VHL综合征遗传性乳头状肾细胞癌(HPRC)遗传性平滑肌瘤病及肾细胞癌综合征(HLRCC)Birt–Hogg–Dube综合征结节性硬化病(TS)？2023/6/105VonHipple–Lindau综合征1895年由德国眼科教授EugenvonHipple首先发现1926年由瑞典病理学家AvidLindau再次确认1936年由Davison教授总结相关临床表现并命名为vonHippelLindausyndrome是一种相对罕见的常染色体显性遗传病，发病率1/36000主要表现包括肾透明细胞癌，嗜铬细胞瘤，视网膜成血管母细胞瘤，中枢神经系统成血管细胞瘤等基因学研究VHL基因定位在常染色体3p2625目前已被完全测序，并确认是存在于散发性和家族性肾透明细胞癌中的抑癌基因该基因的丢失、突变和甲基化失活导致正常的VHL蛋白合成障碍，是导致VHL综合征的重要分子学基础头颅MRI显示左侧延髓见类圆形混杂信号灶，大小约1.IsolatedcasesofuterineleiomyosarcomasPreoperativePETscansmayprovebeneficialincasesinwhichlymphnodeornonlocalizeddiseaseissuspectedIsolatedcasesofuterineleiomyosarcomasMeanageatdiagnosisisolder,nearage50yearsaggressivetumorfeaturesinyoungpatientsBemappedtoaregiononchromosome1(1q42.发病隐匿，多无明显临床表现其他病变如胰腺囊肿、附睾或阔韧带乳头状囊腺瘤、肾囊肿,多无明显症状，一般预后良好肾癌占VHL综合征患者死亡原因的50%，发生率为24～70%Birt–Hogg–DubesyndromeIsolatedcasesofuterineleiomyosarcomas仔细随访相应患者及其家属仔细随访相应患者及其家属仔细随访相应患者及其家属既往体健，否认高血压病史，否认家族史，体格检查血压轻度升高150/78mmHg仔细随访相应患者及其家属Morerecently,detailedhistologicdescriptionhasledtomorerefinedcharacterizationofthepathologicfeaturesnowtermedHLRCCrenaltumorsBirt–Hogg–Dubesyndrome2023/6/108该基因在VHL病家族成员中突变率几乎达100%散发的肾透明细胞癌患者中，VHL基因突变率为46%～70%肾脏其他病理类型肿瘤未发现VHL基因突变chromophobe嫌色细胞,oncocytoma,clearcellandhybridoncocytictumorscomposedofelementsofoncocytomaandchromophobeBirt–Hogg–Dubesyndrome一项研究对肾脏肿瘤小于3cm的108例VHL综合征患者与肿瘤大于3cm的73例患者做比较该基因的丢失、突变和甲基化失活导致正常的VHL蛋白合成障碍，是导致VHL综合征的重要分子学基础pulmonarymetastasesfromacaseoflocallyadvancedclearcellcarcinomaina20yearoldpatientIsolatedcasesofuterineleiomyosarcomasNephronsparingsurgeryislesswellestablishedinthissetting6cm，增强后边缘较前清晰。aggressivetumorfeaturesinyoungpatientsVHL基因定位在常染色体3p2625发现遗传性肾癌的相关基因Lungcystswerecommonandseenin83%VHL基因抑癌机制清楚，抑癌作用明显，而且VHL基因只有3个外显子，是基因治疗十分理想的目的基因interventionfortumors,whichgrowtoreach3cminsizeandincludetheuseofnephronsparingprocedureswhenpossiblePathologicanalysisof130tumorsobtainedfrom30surgicallymanagedcasesidentifiedproportionaldifferencesincludinghybridonco/chromo50%,chromophobe34%,conventionalclearcell9%,oncocytoma5%andpapillary2%chromophobe嫌色细胞,oncocytoma,clearcellandhybridoncocytictumorscomposedofelementsofoncocytomaandchromophobe与cMet原癌基因的突变有关，定位于染色体7q31pulmonarycysts阴囊B超提示双侧附睾头囊肿，左侧0.既往体健，否认高血压病史，否认家族史，体格检查血压轻度升高150/78mmHg44%beforetheageof30PreoperativePETscansmayprovebeneficialincasesinwhichlymphnodeornonlocalizeddiseaseissuspectedrenalcellcarcinoma仔细随访相应患者及其家属ClassictriadofskinfibrofolliculomasBemappedtoaregiononchromosome1(1q42.renaltumorswerediscoveredin1434%.仔细随访相应患者及其家属One39yearoldpatientwithBHDandmixedrenaltumor,includingclearcellcomponentsdevelopeddistantprogressionanddeathBirt–Hogg–Dubesyndrome结节性硬化病(TS)？Bemappedtoaregiononchromosome1(1q42.chromophobe嫌色细胞,oncocytoma,clearcellandhybridoncocytictumorscomposedofelementsofoncocytomaandchromophobe对最大径超过3cm的肿瘤行肾部分切除术，这样可以减低肿瘤的转移的风险而且保留肾脏的功能指的是病人易于罹患肾乳头状细胞癌的状态therelativeheterogeneityoftumorsubtypesCutaneousleiomyomasarecommonamongaffectedindividuals,thoughmaybedifficulttoidentifyrenaltumorsVHL综合征临床表现2023/6/1010VHL综合征诊断标准（1）中枢神经系统或视网膜成血管细胞瘤家族病史，有一种成血管细胞瘤或内脏病变（如肾肿瘤、胰腺肿瘤或囊肿、嗜铬细胞瘤、附睾乳头状囊腺瘤等）（2）对于无明确家族遗传史的孤立病例，若患有两种或两种以上成血管母细胞瘤,或一种成血管母细胞瘤和一种内脏病变类型I型不表现为肾上腺嗜铬细胞瘤，病变可累及中枢神经系统、肾脏、胰腺等Ⅱ型伴发肾上腺嗜铬细胞瘤ⅡA型，不伴有肾癌ⅡB型，伴有肾癌ⅡC型，仅有肾上腺嗜铬细胞瘤表现chromophobe嫌色细胞,oncocytoma,clearcellandhybridoncocytictumorscomposedofelementsofoncocytomaandchromophobeMeanageatdiagnosisisolder,nearage50years但是复杂的囊肿有可能包含肿瘤组织而逐渐生长，需要定期监测renaltumorswerediscoveredin1434%.目前已被完全测序，并确认是存在于散发性和家族性肾透明细胞癌中的抑癌基因与散发的肾癌相比并无特异性遗传性平滑肌瘤病及肾细胞癌Spontaneouspneumothoracesoccurredin23%:mostcommoninyoungerfamilymembers(<40years)renaltumorswerediscoveredin1434%.其他病变如胰腺囊肿、附睾或阔韧带乳头状囊腺瘤、肾囊肿,多无明显症状，一般预后良好降低疾病相关死亡率并改善预后44%beforetheageof30Pathologicanalysisof130tumorsobtainedfrom30surgicallymanagedcasesidentifiedproportionaldifferencesincludinghybridonco/chromo50%,chromophobe34%,conventionalclearcell9%,oncocytoma5%andpapillary2%对最大径超过3cm的肿瘤行肾部分切除术，这样可以减低肿瘤的转移的风险而且保留肾脏的功能1895年由德国眼科教授EugenvonHipple首先发现Lungcystswerecommonandseenin83%仔细随访相应患者及其家属IsolatedcasesofuterineleiomyosarcomasPreoperativePETscansmayprovebeneficialincasesinwhichlymphnodeornonlocalizeddiseaseissuspectedinterventionfortumors,whichgrowtoreach3cminsizeandincludetheuseofnephronsparingprocedureswhenpossible影像学表现为乏血供的肿瘤，CT增强仅表现为轻度强化（增加1030HU），MRI增强仅15%影像学表现为乏血供的肿瘤，CT增强仅表现为轻度强化（增加1030HU），MRI增强仅15%6cm，增强后边缘较前清晰。临床特点一般情况下，病变是视网膜成血管母细胞瘤最早出现，然后是中枢神经系统血管母细胞瘤，而肾癌出现较晚中枢神经系统血管母细胞瘤和肾脏透明细胞癌为该病最常见的致死原因嗜铬细胞瘤，临床上多因出现高血压症状而发现其他病变如胰腺囊肿、附睾或阔韧带乳头状囊腺瘤、肾囊肿,多无明显症状，一般预后良好VHL综合征是遗传性肾癌最常见的原因肾癌也是VHL综合征主要的恶性肿瘤与散发的肾癌相比并无特异性肾癌占VHL综合征患者死亡原因的50%，发生率为24～70%加上肾囊肿，VHL综合征患者中肾脏病变的发生率可达到60%肾脏病变的平均年龄为39岁(16～67)体积较小的肾脏肿瘤（<3cm）恶性度低VHL综合征肾脏病变为多灶性Walther等对VHL综合征患者的肾脏标本进行研究，显微镜下观察，发现有的标本中存在600个肿瘤病灶和1100个囊肿病灶随访研究表明由单纯囊肿变为肾癌的可能性很小所以VHL综合征的单纯肾囊肿若没有症状一般无需特殊治疗但是复杂的囊肿有可能包含肿瘤组织而逐渐生长，需要定期监测散发的肾癌一样，VHL综合征肾癌缺乏早期临床症状，通常在很长时间内都没有任何表现肾癌进展的病例可以表现为血尿，疼痛或肿块肾癌病理类型基本是透明细胞癌亚型，肿瘤体积越小倾向恶性程度越低与非VHL综合征肾癌相比，VHL综合征肾癌的发病年龄较早，通常表现为双侧多中心的实性和囊性的病变治疗VHL综合征患者肾癌的预后与肿瘤的大小密切相关对最大径超过3cm的肿瘤行肾部分切除术，这样可以减低肿瘤的转移的风险而且保留肾脏的功能对于直径较小的肿瘤（≤3cm）可以选择密切观察一项研究对肾脏肿瘤小于3cm的108例VHL综合征患者与肿瘤大于3cm的73例患者做比较中位时间超过5年随访结果显示肿瘤小于3cm患者中无病例发生转移，而肿瘤大于3cm组73例患者中有20例发生转移（27%）VHL综合征肾癌常为双侧多发，肿瘤生长较慢，转移较晚，肾脏肿瘤平均每年增长0.5cm一般不建议对VHL综合征行肾根治性切除术，即使为单侧肾癌，也应尽量行保留肾单位的肿瘤切除手术，因为对侧肾脏也有再发生肾癌的可能如果无法保留肾脏，可选择进行双侧肾根治性切除术，再透析或行肾移植术加服免疫抑制剂当VHL患者接受肾移植以后，移植肾无发展为肾囊肿或肾癌的倾向但长期服用免疫抑制剂是否增加VHL综合征其他系统肿瘤的发病率？VHL基因抑癌机制清楚，抑癌作用明显，而且VHL基因只有3个外显子，是基因治疗十分理想的目的基因目前VHL基因治疗还处在体外研究动物实验阶段VHL基因治疗将为VHL综合征治疗开辟一个新的方向随访VHL综合征合并肾癌的患者应每年复查一次CT或MRI如果最大肿瘤直径超过3cm，就应对所有肿瘤行肿瘤剜除术或肾部分切除术有VHL家族病史的人，也应该每年复查一次CT对于无肿瘤的单纯囊肿，不推荐手术切除遗传性乳头状肾细胞癌指的是病人易于罹患肾乳头状细胞癌的状态与cMet原癌基因的突变有关，定位于染色体7q31常染色体显性遗传临床表现发病隐匿，多无明显临床表现多为多灶性，双侧发病影像学表现为乏血供的肿瘤，CT增强仅表现为轻度强化（增加1030HU），MRI增强仅15%2023/6/1025治疗通常选择肾部分切除术术中仔细检查，防止遗漏病灶遗传性平滑肌瘤病及肾细胞癌Arelativelynew,rareandaggressiveformofHRCsyndromecutaneousleiomyomasuterineleiomyomasrenalcellcarcinomafumaratehydratase,aKrebscycleenzymeGeneticsBemappedtoaregiononchromosome1(1q42.343)encodesfortheHLRCCgeneproduct,fumaratehydrataseanautosomaldominantpatternthetumorsuppressorfunctionofthegeneClinicalfeaturesthefindingofseverelysymptomaticuterinefibroidsamongaffectedwomenwithinfamiliesoftenrequiringearlyhysterectomyduetodifficultiesfrommenometrorrhagia89%ofaffectedwomenunderwenthysterectomy44%beforetheageof30Clinicalfeatures89%ofaffectedwomenunderwenthysterectomypotentiallymisclassifiedascollectingducttumors1926年由瑞典病理学家AvidLindau再次确认Lungcystswerecommonandseenin83%遗传性乳头状肾细胞癌(HPRC)Pathologicanalysisof130tumorsobtainedfrom30surgicallymanagedcasesidentifiedproportionaldifferencesincludinghybridonco/chromo50%,chromophobe34%,conventionalclearcell9%,oncocytoma5%andpapillary2%thefindingofseverelysymptomaticuterinefibroidsamongaffectedwomenwithinfamiliesIsolatedcasesofuterineleiomyosarcomasBirt–Hogg–Dubesyndromepotentiallymisclassifiedascollectingducttumors散发的肾透明细胞癌患者中，VHL基因突变率为46%～70%但长期服用免疫抑制剂是否增加VHL综合征其他系统肿瘤的发病率？cutaneousleiomyomasthetumorsuppressorfunctionofthegene6cm，增强后边缘较前清晰。头颅MRI显示左侧延髓见类圆形混杂信号灶，大小约1.肾癌占VHL综合征患者死亡原因的50%，发生率为24～70%IsolatedcasesofuterineleiomyosarcomasCutaneousleiomyomasarecommonamongaffectedindividuals,thoughmaybedifficulttoidentifyRenalcancerswithaprevalenceestimatedbetween2and21%papillarytype2tumorspotentiallymisclassifiedascollectingducttumorsMorerecently,detailedhistologicdescriptionhasledtomorerefinedcharacterizationofthepathologicfeaturesnowtermedHLRCCrenaltumorsManagementRadiographicappearanceofHLRCCtumorsmayappearpartlycysticandpoorlydefinedNephronsparingsurgeryislesswellestablishedinthissettingSurgicalinterventionmustbeperformedwithcaretoensureminimalhandlingofthetumorandcompletewideresection,includinglymphnodedissectionPreoperativePETscansmayprovebeneficialincasesinwhichlymphnodeornonlocalizeddiseaseissuspectedBirt–Hogg–DubesyndromeThefamilialassociationofperifolliculardermatosisinvolvingthefaceandtrunkamongthreefirstdegreerelativeswasfirstdescribedbyHornsteinandKnickenbergin1975Twoyearslater,DrsBirt,HoggandDubedescribedclinicaldermatologicfindingsinvolving15familymemberswithsimilarskinnodulesdescribedasfibrofolliculomas纤维毛囊瘤,trichodiscomas毛盘状瘤acrochordons软垂疣GeneticsautosomaldominantpatternsofinheritancechromosomeThegeneproduct,folliculin,isthoughttobeinvolvedinregulationofthemammaliantargetofrapamycin(mTOR)pathwaybyactingthroughfolliculininteractingprotein(FNIP1)and50AMPactivatedproteinkinaseClinicalfeaturesClassictriadofskinfibrofolliculomaspulmonarycystsrenaltumorsrenaltumorswerediscoveredin1434%.Spontaneouspneumothoracesoccurredin23%:mostcommoninyoungerfamilymembers(<40years)Lungcystswerecommonandseenin83%Skinlesionsin90%therelativeheterogeneityoftumorsubtypesindolentformsofdiseasechromophobe嫌色细胞,oncocytoma,clearcellandhybridoncocytictumorscomposedofelementsofoncocytomaandchromophobeMeanageatdiagnosisisolder,nearage50yearsPathologicanalysisof130tumorsobtainedfrom30surgicallymanagedcasesidentifiedproportionaldifferencesincludinghybridonco/chromo50%,chromophobe34%,conventionalclearcell9%,oncocytoma5%andpapillary2%lessaggressivetumorhistologiesnotbeconsideredanindolentdiseaseprocessaggressivetumorfeaturesinyoungpatientspulmonarymetastasesfromacaseoflocallyadvancedclearcellcarcinomaina20yearoldpatientOne39yearoldpatientwithBHDandmixedrenaltumor,includingclearcellcomponentsdevelopeddistantprogressionanddeath既往体健，否认高血压病史，否认家族史，体格检查血压轻度升高150/78mmHgVHL基因抑癌机制清楚，抑癌作用明显，而且VHL基因只有3个外显子，是基因治疗十分理想的目的基因Thegeneproduct,folliculin,isthoughttobeinvolvedinregulationofthemammaliantargetofrapamycin(mTOR)pathwaybyactingthroughfolliculininteractingprotein(FNIP1)and50AMPactivatedproteinkinase与cMet原癌基因的突变有关，定位于染色体7q31Meanageatdiagnosisisolder,nearage50yearsPathologicanalysisof130tumorsobtainedfrom30surgicallymanagedcasesidentifiedproportionaldifferencesincludinghybridonco/chromo50%,chromophobe34%,conventionalclearcell9%,oncocytoma5%andpapillary2%6cm，增强后边缘较前清晰。一般情况下，病变是视网膜成血管母细胞瘤最早出现，然后是中枢神经系统血管母细胞瘤，而肾癌出现较晚发现遗传性肾癌的相关基因PreoperativePETscansmayprovebeneficialincasesinwhichlymphnodeornonlocalizeddiseaseissuspected仔细随访相应患者及其家属1895年由德国眼科教授EugenvonHipple首先发现结合上述临床表现诊断为VHL综合征。影像学表现为乏血供的肿瘤，CT增强仅表现为轻度强化（增加1030HU），MRI增强仅15%与cMet原癌基因的突变有关，定位于染色体7q31Birt–Hogg–Dubesyndrome但是复杂的囊肿有可能包含肿瘤组织而逐渐生长，需要定期监测降低疾病相关死亡率并改善预后2023/6/10402023/6/10412023/6/10422023/6/1043Managementinterventionfortumors,whichgrowtoreach3cminsizeandincludetheuseofnephronsparingprocedureswhenpossible该基因的丢失、突变和甲基化失活导致正常的VHL蛋白合成障碍，是导致VHL综合征的重要分子学基础该基因在VHL病家族成员中突变率几乎达100%VHL综合征诊断标准autosomaldominantpatternsofinheritancechromosome嗜铬细胞瘤，临床上多因出现高血压症状而发现renalcellcarcinomaPathologicanalysisof130tumorsobtainedfrom30surgicallymanagedcasesidentifiedproportionaldifferencesincludinghybridonco/chromo50%,chromophobe34%,conventionalclearcell9%,oncocytoma5%andpapillary2%Pathologicanalysisof130tumorsobtainedfrom30surgicallymanagedcasesidentifiedproportionaldifferencesincludinghybridonco/chromo50%,chromophobe34%,conventionalclearcell9%,oncocytoma5%andpapillary2%加上肾囊肿，VHL综合征患者中肾脏病变的发生率可达到60%Renalcancerswithaprevalenceestimatedbetween2and21%One39yearoldpatientwithBHDandmixedrenaltumor,includingclearcellcomponentsdevelopeddistantprogressionanddeath肾脏其他病理类型肿瘤未发现VHL基因突变chromophobe嫌色细胞,oncocytoma,clearcellandhybridoncocytictumorscomposedofelementsofoncocytomaandchromophobeBirt–Hogg–DubesyndromeBirt–Hogg–DubesyndromePreoperativePETscansmayprovebeneficialincasesinwhichlymphnodeornonlocalizeddiseaseissuspected但长期服用免疫抑制剂是否增加VHL综合征其他系统肿瘤的发病率？Twoyearslater,DrsBirt,HoggandDubedescribedclinicaldermatologicfindingsinvolving15familymemberswithsimilarskinnodulesdescribedasfibrofolliculomas纤维毛囊瘤,trichodiscomas毛盘状瘤acrochordons软垂疣VHL综合征肾癌常为双侧多发，肿瘤生长较慢，转移较晚，肾脏肿瘤平均每年增长0.interventionfortumors,whichgrowtoreach3cminsizeandincludetheuseofnephronsparingprocedureswhenpossible一般不建议对VHL综合征行肾根治性切除术，即使为单侧肾癌，也应尽量行保留肾单位的肿瘤切除手术，因为对侧肾脏也有再发生肾癌的可能Surgicalinterventionmustbeperformedwithcaretoensureminimalhandlingofthetumorandcompletewideresection,includinglymphnodedissection总结中、青年居多，有/无家族史肾肿瘤多为双侧、多发合并其它脏器病变染色体和基因异常治疗肾肿瘤直径小于3cm者观察等待，当肾肿瘤直径大于3cm时可手术，以NSS首选病例男性，21岁体检B超发现双肾占位，胰腺占位3周就诊患者无明显的症状，无血尿、心悸、出汗、头痛。既往体健，否认高血压病史，否认家族史，体格检查血压轻度升高150/78mmHg腹部CT显示双肾多个大小不等低密度影，部分边缘欠清晰，增强后，右肾上极及左肾门处见不均匀性强化，分别为3.3×3.6cm，2.6×3.4cm。内未见脂肪密度。双肾内亦可见多个不强化低密度影，最大者于右肾实质内，大小2.5×2.6cm，增强后边缘较前清晰。左肾上腺区类圆形软组织肿块影，密度均匀，边缘光滑，大小1.5×1.6cm，增强后见明显均匀强化。胰颈部、尾部见斑片状低密度影，增强后有轻度强化。CT影像表现提示双肾多发肿瘤、多发囊肿，左肾上腺肿瘤，胰腺囊腺瘤2023/6/1047头颅MRI显示左侧延髓见类圆形混杂信号灶，大小约1.5×1.4mm，增强扫描明显强化，符合血管母细胞瘤行眼底荧光血管造影提示双眼视网膜大动脉血管母细胞瘤阴囊B超提示双侧附睾头囊肿，左侧0.5×0.3cm，右侧0.3×0.2cm，精液囊肿可能结合上述临床表现诊断为VHL综合征。术前检查患者血清儿茶酚胺水平位于正常范围内Meanageatdiagnosisisolder,nearage50years6cm，增强后边缘较前清晰。chromophobe嫌色细胞,oncocytoma,clearcellandhybridoncocytictumorscomposedofelementsofoncocytomaandchromophobe对最大径超过3cm的肿瘤行肾部分切除术，这样可以减低肿瘤的转移的风险而且保留肾脏的功能6cm，增强后边缘较前清晰。renaltumors1936年由Davison教授总结相关临床表现并命名为vonHippelLindausyndrome行眼底荧光血管造影提示双眼视网膜大动脉血管母细胞瘤（2）对于无明确家族遗传史的孤立病例，若患有两种或两种以上成血管母细胞瘤,或一种成血管母细胞瘤和一种内脏病变影像学表现为乏血供的肿瘤，CT增强仅表现为轻度强化（增加1030HU），MRI增强仅15%Isolatedcasesofuterineleiomyosarcomas结合上述临床表现诊断为VHL综合征。interventionfortumors,whichgrowtoreach3cminsizeandincludetheuseofnephronsparingprocedureswhenpossiblepotentiallymisclassifiedascollectingducttumors但是复杂的囊肿有可能包含肿瘤组织而逐渐生长，需要定期监测potentiallymisclassifiedascollectingducttumorsCT影像表现提示双肾多发肿瘤、多发囊肿，左肾上腺肿瘤，胰腺囊腺瘤治疗肾肿瘤直径小于3cm者观察等待，当肾肿瘤直径大于3cm时可手术，以NSS首选进行肿瘤形成机制相关的细胞分子通路研究肾癌病理类型基本是透明细胞癌亚型，肿瘤体积越小倾向恶性程度越低Pathologicanalysisof130tumorsobtainedfrom30surgicallymanagedcasesidentifiedproportionaldifferencesincludinghybridonco/chromo50%,chromophobe34%,conventionalclearcell9%,oncocytoma5%andpapillary2%VHL基因抑癌机制清楚，抑癌作用明显，而且VHL基因只有3个外显子，是基因治疗十分理想的目的基因pulmonarycystsI型不表现为肾上腺嗜铬细胞瘤，病变可累及中枢神经系统、肾脏、胰腺等既往体健，否认高血压病史，否认家族史，体格检查血压轻度升高150/78mmHg仔细随访相应患者及其家属（2）对于无明确家族遗传史的孤立病例，若患有两种或两种以上成血管母细胞瘤,或一种成血管母细胞瘤和一种内脏病变IsolatedcasesofuterineleiomyosarcomasencodesfortheHLRCCgeneproduct,fumaratehydratase是一种相对罕见的常染色体显性遗传病，发病率1/360006cm，增强后边缘较前清晰。PreoperativePETscansmayprovebeneficialincasesinwhichlymphnodeornonlocalizeddiseaseissuspected但长期服用免疫抑制剂是否增加VHL综合征其他系统肿瘤的发病率？中、青年居多，有/无家族史发现遗传性肾癌的相关基因ClassictriadofskinfibrofolliculomasBemappedtoaregiononchromosome1(1q42.IsolatedcasesofuterineleiomyosarcomasVHL综合征患者肾癌的预后与肿瘤的大小密切相关肾脏其他病理类型肿瘤未发现VHL基因突变散发的肾透明细胞癌患者中，VHL基因突变率为46%～70%加上肾囊肿，VHL综合征患者中肾脏病变的发生率可达到60%PreoperativePETscansmayprovebeneficialincasesinwhichlymphnodeornonlocalizeddiseaseissuspected加上肾囊肿，VHL综合征患者中肾脏病变的发生率可达到60%PreoperativePETscansmayprovebeneficialincasesinwhichlymphnodeornonlocalizeddiseaseissuspected该基因的丢失、突变和甲基化失活导致正常的VHL蛋白合成障碍，是导致VHL综合征的重要分子学基础Isolatedcasesofuterineleiomyosarcomas结合上述临床表现诊断为VHL综合征。chromophobe嫌色细胞,oncocytoma,clearcellandhybridoncocytictumorscomposedofelementsofoncocytomaandchromophobeRenalcancerswithaprevalenceestimatedbetween2and21%chromophobe嫌色细胞,oncocytoma,clearcellandhybridoncocytictumorscomposedofelementsofoncocytomaandchromophobe（优选）遗传性肾癌综合征VHL综合征肾癌常为双侧多发，肿瘤生长较慢，转移较晚，肾脏肿瘤平均每年增长0.Lungcystswerecommonandseenin83%Birt–Hogg–Dubesyndrome其他病变如胰腺囊肿、附睾或阔韧带乳头状囊腺瘤、肾囊肿,多无明显症状，一般预后良好Thegeneproduct,folliculin,isthoughttobeinvolvedinregulationofthemammaliantargetofrapamycin(mTOR)pathwaybyactingthroughfolliculininteractingprotein(FNIP1)and50AMPactivatedproteinkinaseVHL基因定位在常染色体3p2625potentiallymisclassifiedascollectingducttumors肾癌占VHL综合征患者死亡原因的50%，发生率为24～70%加上肾囊肿，VHL综合征患者中肾脏病变的发生率可达到60%Bemappedtoaregiononchromosome1(1q42.1926年由瑞典病理学家AvidLindau再次确认Twoyearslater,DrsBirt,HoggandDubedescribedclinicaldermatologicfindingsinvolving15familymemberswithsimilarskinnodulesdescribedasfibrofolliculomas纤维毛囊瘤,trichodiscomas毛盘状瘤acrochordons软垂疣Cutaneousleiomyomasarecommonamongaffectedindividuals,thoughmaybedifficulttoidentify但是复杂的囊肿有可能包含肿瘤组织而逐渐生长，需要定期监测interventionfortumors,whichgrowtoreach3cminsizeandincludetheuseofnephronsparingprocedureswhenpossible嗜铬细胞瘤，临床上多因出现高血压症状而发现6cm，增强后边缘较前清晰。仔细随访相应患者及其家属对最大径超过3cm的肿瘤行肾部分切除术，这样可以减低肿瘤的转移的风险而且保留肾脏的功能Meanageatdiagnosisisolder,nearage50yearschromophobe嫌色细胞,oncocytoma,clearcellandhybridoncocytictumorscomposedofelementsofoncocytomaandchromophobe（优选）遗传性肾癌综合征遗传性平滑肌瘤病及肾细胞癌interventionfortumors,whichgrowtoreach3cminsizeandincludetheuseofnephronsparingprocedureswhenpossible（1）中枢神经系统或视网膜成血管细胞瘤家族病史，有一种成血管细胞瘤或内脏病变（如肾肿瘤、胰腺肿瘤或囊肿、嗜铬细胞瘤、附睾乳头状囊腺瘤等）PreoperativePETscansmayprovebeneficialincasesinwhichlymphnodeornonlocalizeddiseaseissuspectedClassictriadofskinfibrofolliculomas治疗肾肿瘤直径小于3cm者观察等待，当肾肿瘤直径大于3cm时可手术，以NSS首选Birt–Hogg–Dubesyndromepotentiallymisclassifiedascollectingducttumors1926年由瑞典病理学家AvidLindau再