认识结节性硬化综合症在腹部的表现.

影像医学部放射科Case1•女，25岁影像医学部放射科影像医学部放射科Case2•男，20岁影像医学部放射科(我是医生)结节性硬化综合征（TuberousSclerosisComplex，TSC）梁长虹影像医学部放射科TSC•概述•分子学研究•诊断标准•胸腹部异常表现影像医学部放射科TSC概述•常染色体显性多系统遗传性疾病，以不同器官的多种错构瘤样病变为特征•TSC可以累及男女及所有人种；估计发病率在1/6000-1/12000，约2/3的病例为散发•TSC预后很差，约40%死于35岁以前影像医学部放射科Source.—Reference3.Inthisarticle,wereviewthediagnosis,clinicalcourse,andclinicalandradiologicmanifestationsofTSinavarietyoforgans.Wediscussandillustratecentralnervoussystem(CNS),cardiovascular,pulmonary,renal,retroperitoneal,hepatic,gastrointestinal,andskeletalinvolvementofTS.MolecularConsiderationsTShasbeenconsideredtobecausedbymutationsoftwogenesknownasTSC1andTSC2.Linkageanalysisinmultigenerationalfamiliesandpositionalcloningwereusedtomapthesegenes(4,5).TheTSC1geneconsistsof23exonsandistranscribedintoan8.6-kbmessengerRNA.Itislocatedonthelongarmofchromosome9(9q34)andencodesa130-kDaproteincalledhamartin.TheTSC2geneconsistsof41exonsandisdistributedover44kbpofgenomicDNA.Itissituatedontheshortarmofchromosome16(16p13)andencodesa200-kDaproteincalledtuberin.ThelocationoftheTSC2geneiscontiguouswiththePKD1gene,whichcanexplainwhymultiplerenalcystsaresometimesfoundinpatientswithTS(6).TSC1andTSC2aretumorsuppressorgeneswhosefunctionistohelpregulatecellgrowthanddifferentiation.Iftheyarealteredbymutation,disturbedcontrolofcellgrowthresultsinformationoftumorsthroughoutthebody.AvarietyofmutationscanoccurinTSpatients:Morethan200TSC1andalmost700TSC2allelicvariantshavebeenreported(7,8).ThefrequencyofmutationsinTSC2ishigherthaninTSC1.ThereissomeevidencefromcaseseriesthatmutationsinTSC2tendtoresultinmoreseveredisease(7).Nomutationisidentifiablein15%–20%ofTSpatients,andthesepatientsgenerallyhavemilderclinicalmanifestations(9).Theproteinshamartinandtuberininteractwithhighaffinityandcoexistasacomplexincellsinavarietyoforgans,includingthekidneys,brain,lungs,andpancreas.Table2.MainCausesofDeathCorrelatedwithAgeGroup不同年龄阶段主要死亡原因UmeokaS,etal.Radiographics.2008;28(7)影像医学部放射科分子学研究•TSC是TSC1和TSC2两种基因的突变导致的•TSC1基因位于9号染色体的长臂（9q34），编码错构瘤蛋白；TSC2基因位于16号染色体的短臂（16p13），编码马铃薯蛋白•TSC1和TSC2是肿瘤抑制基因，如果它们因突变发生变化，会导致在身体多处形成肿瘤•TSC病人中有15-20%没有基因突变，这些病人通常临床症状较轻微影像医学部放射科血管平滑肌脂肪瘤和淋巴管平滑肌瘤病的发病机制CrinoPB,etal.NEnglJMed.2006;355:1345-56.影像医学部放射科诊断标准•典型三联征（Vogt三联征）–智力低下–癫痫–皮质腺瘤•约有一半的TSC智力正常，约1/4的TSC没有癫痫影像医学部放射科主要特征次要特征1.面部的纤维血管瘤或额部纤维斑块1.多发的、随机分布的牙釉质小凹2.非创伤性指（趾）甲或甲周纤维瘤2.错构瘤性直肠息肉3.色素脱失斑（3块或3块以上）3.骨囊肿4.鲨鱼皮样斑4.大脑白质放射状移行线5.多发性视网膜结节状错构瘤5.牙龈纤维瘤6.皮质结节6.非肾性错构瘤7.室管膜下结节7.视网膜无色性斑块8.室管膜下巨细胞星形细胞瘤8.“咖啡”牛奶斑9.单发或多发的心脏横纹肌瘤9.多囊肾10.淋巴血管肌瘤病11.肾血管平滑肌脂肪瘤肯定性诊断：两个主要特征或一个主要特征加上两个次要特征可能性诊断：一个主要特征加上一个次要特征怀疑性诊断：一个主要特征或两个、两个以上次要特征RoachES,etal.JChildNeurol.1998;13(12):624-628.1998年全美TS协会制定的诊断标准影像医学部放射科2012年更新的TSC诊断标准NorthrupH,etal.PediatrNeurol.2013;49(4):243-254.影像医学部放射科A.基因诊断标准–发现TSC1或TSC2致病性突变即可作出肯定性诊断–10-25%TSC患者传统基因测定中没有发现突变，一个正常的结果并不能排除TSC，也不能对使用临床诊断标准诊断TSC产生任何影响影像医学部放射科B.临床诊断标准主要特征次要特征1.皮肤脱色斑（≥3，至少5mm直径）1.“咖啡”牛奶斑2.纤维血管瘤（≥3）或纤维性头部斑块2.牙釉质小凹（3）3.指甲纤维瘤（≥2）3.口腔内纤维瘤（≥2）4.鲨革斑4.视网膜色素缺失斑5.多发视网膜错构瘤5.多发肾囊肿6.皮质发育不良*6.非肾性错构瘤7.室管膜下结节8.室管膜下巨细胞星形细胞瘤9.心脏横纹肌瘤10.淋巴管平滑肌瘤病（LAM）+11.血管平滑肌脂肪瘤（≥2）+肯定性诊断：两个主要特征或一个主要特征与≥2个次要特征怀疑性诊断：一个主要诊断或≥2个次要特征*包括结节和脑白质放射状迁移线+LAM和血管平滑肌脂肪瘤两个主要特征结合而没有其它特征，不能满足肯定诊断的标准影像医学部放射科2019/12/1716Recentadvancesincytogeneticsandpathophysiologyhavebeenmadetowardunderstandingthefunctionsofthehamartin-tuberincomplex(9).Normally,directphosphorylationorinactivationoftuberinregulatestheRashomologueexpressedinbrain(Rheb),whichisaspecificGTPasedownstreamoftuberin.Ifthefunctionsoftuberinarealtered,Rheb-GTPisexcessivelygenerated,resultinginenhancedstimulationofthemammaliantargetofrapamycin(mTOR),whichplaysanimportantroleinthecontrolofcellgrowthandproliferation.Althoughthepreciseroleofhamartinisnotclearlyknown,italsohasaninfluenceonmTORactivation(9).DermatologicInvolvementTScanpresentwithavarietyofskinlesions,includinghypopigmentedmacules,facialangiofibromas,shagreenpatches,andungulafibromas.Hypopigmentedmacules,whichhavebeencalled“ashleafspots”aftertheEuropeanmountainashtree,occurinmorethan90%ofpatientswithTS(10).Theyaregenerallydetectedininfancyorearlychildhoodandaretypicallyroundatoneendandtaperedattheother.Facialangiofibromas,alsoknownas“adenomasebaceum,”areseeninapproximately75%ofpatients(10).Thelesionstypicallyappearinadolescenceassmallredpapulesinthemalararea,withaso-called“butterflydistribution”(Fig1).Shagreenpatchesaretypicallyfoundasgrayish-greenorlightbrownareasinthelumbosacralregionin20%–30%ofpatients(10).Ungulafibromasarenodularlesionslocatedbeneaththenailsofthetoesorfingers.Thelesionscanbefoundinapproximately20%ofpatients,especiallyinadolescentsandadults(10).DetectionoftheseskinlesionscanbeafirststepindiagnosingTS,sincetheyaretheonlymajordiagnosticcriteriathatcanbeevaluatedatclinicalexamination(Table1).Figure1.Facialangiofibromaina19-year-oldman.Photographdemonstratesmultipledome-shapedpapulesinthemalararea,withabutterflydistribution.UmeokaS,etal.Radiographics.2008;28(7)NorthrupH,etal.PediatrNeurol.2013;49(4):243-254.影像医学部放射科胸腹部异常表现•心脏–横纹肌瘤•肺–淋巴管肌瘤病（Lymphangioleiomyomatosis，LAM）–错构瘤结节（MultifocalMicronodularPneumocyteHyperplasi