骨髓衰竭綜合征演示文稿

骨髓衰竭綜合征演示文稿當(dāng)前1頁(yè)，總共82頁(yè)。CasePresentation16yearoldmaleSeenbyfamilydoctorbecausetennisinstructornoticedthathewastiringeasilyHistoryoftripoutsidetheUSA5monthsearlierNotedtohavepallorandalargebruiseonarm(wherehitbytennisball)CBC:Hb8.5g/dL,platelets40,000/mL,WBC2000/mL(20%neutrophils)當(dāng)前2頁(yè)，總共82頁(yè)。NextStepLookatbloodsmearR/ocirculatingblastsDoabonemarrowAspirateCelltypesCytogeneticsBiopsyCellularity當(dāng)前3頁(yè)，總共82頁(yè)。PancytopeniawithHypocellularMarrowAcquiredaplasticanemiaInheritedbonemarrowfailuresyndromeHypocellularMyelodysplasticSyndromeAleukemicleukemiaMarrowlymphoma當(dāng)前4頁(yè)，總共82頁(yè)。PancytopeniawithCellularMarrowPrimarymarrowdiseaseLeukemiaMyelodysplasticsyndromeParoxysmalnocturnalhemoglobinuriaSystemicdiseaseLupusHypersplenismInfection,e.g.brucellosis,sarcoidosis,tuberculosis當(dāng)前5頁(yè)，總共82頁(yè)。BoneMarrow(BM)BiopsyNormalAplastic當(dāng)前6頁(yè)，總共82頁(yè)。AplasticAnemia:SignsandSymptomsAnemiafatigue,lassitude,dyspneaThrombocytopeniabruises,petechiaeseriousbleedingNeutropeniainfections當(dāng)前7頁(yè)，總共82頁(yè)。SeverityofAplasticAnemiaSevere2ofthefollowing3:neutrophils<500/mL,platelets<20,000/mL,reticulocytes<20,000/mLBMcellularity<25%with<30%hematopoieticcellsVerysevereNeutrophils<200/mLNon-severe(moderate)Betterthansevere當(dāng)前8頁(yè)，總共82頁(yè)。NosologyofAplasticAnemiaGeneticsAcquiredInheritedCellbiologyStemcellImmune當(dāng)前9頁(yè)，總共82頁(yè)。AcquiredAplasticAnemiaRadiationDrugs(cytotoxics,chloramphenicol,nonsteroidals,anticonvulsants,gold)Chemicals(benzene,insecticides,pesticides,fertilizer)Viruses(Epstein-Barr,hepatitis[non-A,B,C],humanimmunodeficiency)GeneticpolymorphismsindetoxifyingenzymesParoxysmalnocturnalhemoglobinuria(PNH)PregnancyImmunediseases(eosinophilicfasciitis,hypoimmunoglobulinemia,thymoma)IDIOPATHIC當(dāng)前10頁(yè)，總共82頁(yè)。EvidenceforImmuneDiseaseAutologousrecoveryafterimmunosuppressionfortransplantEvensyngeneictransplantsrequireconditioningResponsetoimmunosuppression(ATG/CsA;Cp)OligoclonalexpansionofVbsubfamiliesActivatedTcellsIncreasedfrequencyofHLA-DR2Increasedapoptosis當(dāng)前11頁(yè)，總共82頁(yè)。Copyright?2006AmericanSocietyofHematology.Copyrightrestrictionsmayapply.Young,N.S.etal.Blood2006;108:2509-2519ImmunePathophysiologyofAcquiredAplasticAnemiaIncitingevent(virusordrug),aberrantimmuneresponse,oligoclonalexpansionofcytotoxicTcells,destroysstemcells.BMTorISTeradicateorsuppresspathogenicT-cellclones.Immuneresponserecurs,selectionofPNH,MDS,orAMLcells.PNH,當(dāng)前12頁(yè)，總共82頁(yè)。TreatmentforAcquiredAplasticAnemiaStemcelltransplantATG/CsACyclophosphamideSupportTransfusionsPlatelets?G-CSF當(dāng)前13頁(yè)，總共82頁(yè)。OverlappingSyndromesAATERC,TERT,TINF2OtherFADCMDSAMLPNHAcquired當(dāng)前14頁(yè)，總共82頁(yè)。InheritedBoneMarrowFailureSyndromes(IBMFS):YoungChildren3yoFA4yoDBANBTAR2yoSDS10yoDC1.5yoSCN5yoAmega當(dāng)前15頁(yè)，總共82頁(yè)。IBMFS:AdultsandOlderChildren26FA23FA16SDS21DC32DBA42TAR當(dāng)前16頁(yè)，總共82頁(yè)。

IBMFS:BenignHematologyOncologySyndromeHematologyLeukemiaSolidTumorsFanconiAnemia(FA)AplasticAMLSCCDyskeratosisCongenita(DC)AplasticAMLSCCDiamond-BlackfanAnemia(DBA)PureanemiaAMLSarcomasShwachman-DiamondSyndrome(SD)NeutropeniaAML-SevereCongenitalNeutropenia(SCN)NeutropeniaAML-AmegakaryocyticThrombocytopeniaThrombocytopeniaAML-ThrombocytopeniaAbsentRadii(TAR)ThrombocytopeniaAML-Thesedisordersarethemajor“InheritedBoneMarrowFailureSyndromes.”當(dāng)前17頁(yè)，總共82頁(yè)。History:GuidoFanconiFanconiAnemia(Fanconipancytopeniasyndrome):1927-3brotherswithpancytopeniaandphysicalabnormalities,“perniziosiforme”FanconiSyndrome(renalFanconisyndrome):1936-proteinuria,glucosuria,phosphaturia,aminoaciduria,citraturia,andproximalrenaltubularacidosis當(dāng)前18頁(yè)，總共82頁(yè)。FanconiAnemia-ChildrenPhotoswithpermission當(dāng)前19頁(yè)，總共82頁(yè)。FanconiAnemia:AdultsAbsentradius,0Aplasticanemia,5?,6Aplasticanemia,16Cancer,30BMTdonor,55當(dāng)前20頁(yè)，總共82頁(yè)。Literature:PhysicalFindingsFinding%LowBirthWeight52Short45Skinhyperpigmented31Skincaféaulait18Thumbs32Radii7Gonadsmale26Gonadsfemale1Microcephaly22Finding%Eyes20Renal20Developmentaldelay10Ears,deaf8Legs,hips,feet6Cardiopulmonary6Gastrointestinaltract5Brain/pituitary3Shortorskinonly7Allfindingsbiasedbyunder-orover-reporting!當(dāng)前21頁(yè)，總共82頁(yè)。LaboratoryFindingsinFALowbloodcounts(pancytopenia)Largeredcells(macrocytosis)Increasedfetalhemoglobin(HbF)ChromosomebreakageinlymphocytesorfibroblastsculturedwithaDNAcrosslinker,e.g.diepoxybutane(DEB)ormitomycinC(MMC)當(dāng)前22頁(yè)，總共82頁(yè)。FanconiAnemia-DefinitionAutosomalrecessive(1X-linkedrecessivegene)PhysicalfindingsAplasticanemiaLeukemiaSolidtumorsChromosomeinstabilityDNArepairdefect>13genes當(dāng)前23頁(yè)，總共82頁(yè)。FANCGenesAdaptedfromJoenje,2006D1=BRCA2*JandNinteractwithBRCA1andBRCA2當(dāng)前24頁(yè)，總共82頁(yè)。FAComplementationGroups/GenesGroupLocuscDNAExonsAA%A16q24.35.5431455~70BXp22.312.810859RareC9q22.34.614558~10D1/BRCA213q12.311.4273418RareD23p25.35441451RareE6p21-222.510536~5F11p151.31374RareG/XRCC99p132.514622~10I/KIAA179415q25-264.5381328RareJ/BACH1/BRIP117q22.34.6201249RareL/PHF9/POG2p15-16.11.714375RareM/Hef14q21.36.5222014RareN/PALB216p12.13.5131186RareBRIP1is“BRCA1interactingprotein”;PALB2is“partnerandlocalizerofBRCA2”當(dāng)前25頁(yè)，總共82頁(yè)。FADNARepairPathwayBD2DNARepairDNADamageCEFIGMLAPCNANBS1RAD51J/BACH1BRCA1D2UbD1/BRCA2D2UbN/PALB2當(dāng)前26頁(yè)，總共82頁(yè)。WhoShouldbeTestedforFA?Characteristicbirthdefects(egthumbs,kidneys,poorgrowth,etc)AplasticAnemia(AA)MyelodysplasticSyndrome(MDS)AcuteMyeloidLeukemia(AML)DecreasedfertilityEarlycharacteristiccancerSiblingsofFApatients當(dāng)前27頁(yè)，總共82頁(yè)。WhataretheTestsforFA?Bloodchromosomebreakage(DEBorMMC)SkinfibroblastchromosomebreakageFlowcytometryforG2arrestWesternblotforubiquitinatedD2RetroviralFAgenecorrectionofFAphenotypeFAgenesequencing當(dāng)前28頁(yè)，總共82頁(yè)。D2UbiquitinationShimamuraetal,Blood,2002LIJ(BRIP1)BM當(dāng)前29頁(yè)，總共82頁(yè)。Retrovirus-mediatedCorrectionofTA0252'sT-cellsanalyzedbyflowcytometryafterfivedaysofMMC-Incubation0204060801001101001000c(MMC)[nM]cellsalive[%]S11EGSFAS11FCIEGS11FEIEG2S11FFIEGS11FGFANCARetrovirus-mediatedCorrectionofFACells當(dāng)前30頁(yè)，總共82頁(yè)。FAComplicationsAplasticAnemiaAcuteLeukemiaMyelodysplasticSyndromeSolidTumorsLivertumors當(dāng)前31頁(yè)，總共82頁(yè)。FAAplasticAnemiaAdaptedfromKutleretal,Blood,200380%byage~15,>90%overall當(dāng)前32頁(yè)，總共82頁(yè)。FALiterature:Cancer1927-2007179solidtumorsand163leukemiasin330/1865patients;29had2-4cancersAMLLiverHNSCCBrainVulvaWilmsALLEsophagus當(dāng)前33頁(yè)，總共82頁(yè)。RiskofCancerinFAbyO/ERatioFACohortsParameterNASGEFAISFARNCINumberofPatients145182Person-Years20002818AllCancers52x44xAllSolidTumors51x26xOralCavity/Pharynx706x240xVulvar4317x2411xAML785x868xMDS8559x4559xNorthAmericanSurvey;GermanFARegistry;IsraeliFARegistry;NationalCancerInstitute當(dāng)前34頁(yè)，總共82頁(yè)。NCIFACumulativeIncidenceandCause-specificHazards當(dāng)前35頁(yè)，總共82頁(yè)。CompetingRisksofCancer當(dāng)前36頁(yè)，總共82頁(yè)。FanconiAnemia:Phenotype/OutcomeRosenberg,Huang,Alter,Blood2004Phenotypepredictsageandincidenceofmarrowfailureandsolidtumors.NormalPhenotypeAbnormalPhenotypeAbnormalphenotype=radii,plusabnormaldevelopment,heartorlung,kidney,hearing,andhead.Competingriskanalyses.當(dāng)前37頁(yè)，總共82頁(yè)。TransplantandHeadandNeckCancerinFanconiAnemiaBMTNoBMTDATA:Transplantincreasedcancerby4.4-fold;Shiftedmedianageto16yearsyounger;Allcancerpatientshadgraftvshostdisease.ParisRosenberg,Socie,Gluckman,Alter:Blood,2005;BiolBlood&MarrowTranspl,2005LESSON:Improvetransplantpreparationtoreducegraftvshostdisease.USA當(dāng)前38頁(yè)，總共82頁(yè)。DiagnosisofFAafterCancerTongueSCCage30SkinSCCsage33Short,80lbs,hearingaids,menopauseage30XRTsideeffectsNormalbloodcountsPBchromosomesnobreaks;skinbreaksExon8:790C>T;Q264X;Gln264StopExon27:2585delCT;Frameshift,Cys846fsX20SkinGeneconversion,lossofexon27frameshift2585delCTBloodSomaticMosaicism,FANCAAlter,Joenje,Oostra,Pals,ArchOtolaryngol,2005當(dāng)前39頁(yè)，總共82頁(yè)。HematopoieticMosaicism當(dāng)前40頁(yè)，總共82頁(yè)。MosaicismfromRecombinationaAAaaAAaaAAa當(dāng)前41頁(yè)，總共82頁(yè)。FANCD1/BRCA2Proband;AdultFANCAPhotoswithparentalandpatientconsent當(dāng)前42頁(yè)，總共82頁(yè)。

OddsRatiosforComplicationsinFAandFANCD1/BRCA2GeneralPopulationFAFAvsGenlFA-D1FA-D1vsFAFA-D1vsGenlVATER2.6/1065/10019,0005/273.771,000AML1/1059/14580010/278.97,000AnyCancer10/10523/1455025/27663300FANCD1/BRCA2isassociatedwithextremelyhighincidencesofVACTERL-Hassociation,AML,andspecificSolidTumors(Wilms,medulloblastoma).Alter,Brody,Rosenberg:JMedGenet2007當(dāng)前43頁(yè)，總共82頁(yè)。Genotype/Phenotype/Outcome:27FAwithBiallelicMutationsinBRCA2Alter:BrJHaematol,2006Alter,Brody,Rosenberg:JMedGenet,200778%byage10(AML,ALL)HR7.7(CI2-29),p=0.00383%byage7(Wilms,Medulloblastoma)97%byage6當(dāng)前44頁(yè)，總共82頁(yè)。FANCD1/BRCA2MutationsMutationsUniformity1Cluster2MissenseNo,p=0.01Yes,p=<0.001DeleteriousYes,p=0.6No,p=0.3Whatistheriskofcancerincarriersofthesemissensemutations?1Chisquareofexpectedfrequencyacrossthegene.2Permutationtestofrangebetweentheextremes.Alter,Brody,Rosenberg:JMedGenet,2007Whydopatientswithbiallelicdeleterious/deleteriousordeleterious/missensemutationsinBRCA2bothdevelopFAandcancer?當(dāng)前45頁(yè)，總共82頁(yè)。FA:WhentoTreatCytopeniasHb<8g/dLorsymptomsPlatelets<30,000/mm3WBC<500/mm3MDSMorphologic+cytopeniasNotforclonealoneLeukemiaBlastsinblood>20%blastsinmarrowSolidtumorsorlivertumorsWhendetectedFA:GuidelinesforDiagnosisandManagement,2008當(dāng)前46頁(yè)，總共82頁(yè)。FA:HowtoTreatHematologicdisease(benignormalignant)StemcelltransplantAndrogensHematopoieticgrowthfactors(G-CSF,Ep)ChemotherapyFolicacidBloodproducts:notfamily;leukodeplete;irradiateGenetherapy?LivertumorsStopandrogensSolidtumorsConservative/focusedradiationChemotherapythatdoesnotcross-linkDNANewmodalities,e.g.cetuximabFA:GuidelinesforDiagnosisandManagement,2008當(dāng)前47頁(yè)，總共82頁(yè)。FASurveillance:CancerHematopoiesis–AA,MDS,aMLBloodcountsevery3-4monthsBonemarrowaspirate,biopsy,cytogeneticsannuallyOralcavityandpharynx-roleofHPVvaccine?Age>10yearsBMT>1yearGynecologic-roleofHPVvaccine?Age>16yearsMenarcheLiverLiverenzymesevery3-4monthsLiverultrasoundevery6-12monthsSkinAnnualexam當(dāng)前48頁(yè)，總共82頁(yè)。CasePresentation16yearoldmaleSeenbyfamilydoctorbecausetennisinstructornoticedthathewastiringeasilyHistoryoftripoutsidetheUSA5monthsearlierNotedtohavepallorandalargebruiseonarm(wherehitbytennisball)CBC:Hb8.5g/dL,platelets40,000/mL,WBC2000/mL(20%neutrophils)Diagnosis:FanconiAnemia,newlydiagnosedinanadolescent當(dāng)前49頁(yè)，總共82頁(yè)。DyskeratosisCongenita當(dāng)前50頁(yè)，總共82頁(yè)。DyskeratosisCongenita-Kids2yo,HH1.5yo,HH6yo,TINF210yo,TINF2當(dāng)前51頁(yè)，總共82頁(yè)。DyskeratosisCongenita-Adults22yo,DKC148and16yo,TERC27yo,TINF224yo,TINF2當(dāng)前52頁(yè)，總共82頁(yè)。PhysicalFindingsinDCDystrophicnails*Laceypigmentation*Leukoplakia*Epiphora,blepharitisDevelopmentaldelayPulmonarydiseaseShortstatureDentalcariesLiverdiseaseEsophagealstrictureEarlygreyhair,hairloss,sparseeyelashesHyperhidrosisCerebellarhypoplasiaHypogonadismMicrocephalyUrethralstrictureOsteoporosis,avascularnecrosis*DiagnosticTriad(need2/3).Or,1ofthetriad,+hypoplasticbonemarrow,+2oftheotherfindings.當(dāng)前53頁(yè)，總共82頁(yè)。X-linkedrecessive(XLR),Autosomaldominant(AD),Autosomalrecessive(AR)Mutationsintelomeraseandshelterinpathways:DKC1(XLR)TERC(AD)TERT(AD,AR)TINF2(AD)DCInheritance

NOLA2(AR)NOLA3(AR)Others(~50%)當(dāng)前54頁(yè)，總共82頁(yè)。MajorComplicationsinDCHematologicBonemarrowfailureMyelodysplasticsyndromeLeukemiaSolidtumorsHeadandneckAnogenitalPulmonaryfibrosis當(dāng)前55頁(yè)，總共82頁(yè)。44cancersin36/425patientsDCLiterature:Cancer1910-2007HNSCCRectalStomach當(dāng)前56頁(yè)，總共82頁(yè)。WhatistheEndoftheShoelace?Theaglet當(dāng)前57頁(yè)，總共82頁(yè)。TelomeresandChromosomalInstabilityLongTTAGGGrepeatsShortenwitheachcelldivisionManyproteinsinteracttoregulatetelomerelengthandstabilizestructureLackoftelomeremaintenanceleadstoerosionofchromosomeends,genomicinstability,cellcrisisandcelldeathFISH:telomeresCourtesyofPeterLansdorp當(dāng)前58頁(yè)，總共82頁(yè)。TelomereBiologyPathwayArmanios,AnnuRevGenomicsHumGenet,2009KirwanandDokal,BBA,2009當(dāng)前59頁(yè)，總共82頁(yè)。LaboratoryDiagnosticTest:

TelomereLengthbyflow-FISHAlter,Baerlocher,Savage,…Lansdorp:Blood,2007AlmostallpatientswithDChaveveryshorttelomeresinbloodcells,including3silentcarriersand6lackingthetriad.

MostpatientswithotherIBMFShavenormaltelomeres.當(dāng)前60頁(yè)，總共82頁(yè)。TelomereLengthinMultiplexFamilyEthics:Dennyetal:AJMG,2008Genediscovery:Savageetal:AJHG,2008當(dāng)前61頁(yè)，總共82頁(yè)。TINF2isMutatedinDCArg282SerLys280GluArg282HisHoyeraal-HreidarssonSyndromeReveszSyndromeSavageetal:AJHG,2008當(dāng)前62頁(yè)，總共82頁(yè)。NCIIBMFSCohort:

RelativeRiskofCancer(O/ERatio)ParameterFADCNumberPerson-YearsAllCancersAllSolidTumorsTongueAMLMDS當(dāng)前63頁(yè)，總共82頁(yè)。NCIDC

ComparedwithAllFA當(dāng)前64頁(yè)，總共82頁(yè)。DCSurveillanceandTreatmentSimilartoFanconiAnemiaRoleofHPVvaccine?StemcelltransplantcomplicatedbypulmonarydiseaseNoroleforimmunosuppressionFeaturesuniquetoDC:AndrogensensitiveSplenicpeliosisandruptureonandrogens+G-CSFPulmonaryfibrosisHepaticfibrosis,cirrhosisTelomerelengthassay:diagnosisofpatients,silentcarriers;surveillanceandgeneticcounseling當(dāng)前65頁(yè)，總共82頁(yè)。Diamond-BlackfanAnemia當(dāng)前66頁(yè)，總共82頁(yè)。Diamond-BlackfanAnemiaNormochromic,usuallymacrocyticanemia,developingininfancyReticulocytopeniaMarrowerythroblastopeniaNormalorslightlydecreasedleukocytesNormalorincreasedplateletsIncreasedfetalhemoglobin(HbF)Increasedredcelladenosinedeaminase(ADA)25%withphysicalfindings:short,abnormalthumbs,etc當(dāng)前67頁(yè)，總共82頁(yè)。DBALiterature2008:PhysicalFindingsFindingNumber%Anyabnormalityincludingshortstature22425Anyabnormalityotherthanshortstature15321Shortstatureonly354Thumbanomaly576Triphalangealthumb243Cleftpalate243Denominator=~900,butnodatainmanyreports.當(dāng)前68頁(yè)，總共82頁(yè)。DBAInheritanceAutosomaldominant~25%RPS19~2%RPS24~1%RPS1740sribosomebiogenesisHaploinsufficiency~7%RPL5~5%RPL11~2%RPL35a當(dāng)前69頁(yè)，總共82頁(yè)。30cancersin30/899patients;3MDSnotincludedDBALiterature:Cancer1936-2008當(dāng)前70頁(yè)，總共82頁(yè)。DBASurveillanceandTreatmentMonitorbloodcountsAnnualbonemarrows(noconsensus)TreatwhenHb<8g/dL,orsymptomsCorticosteroidsTransfuseduringfirstyearandpuberty(noconsensus)CyclosporinA(rare)Metoclopramide(rare)當(dāng)前71頁(yè)，總共82頁(yè)。Shwachman-DiamondSyndromeExocrinepancreaticinsufficiencyDecreasedtrypsinogenandisoamylase(age-dependent)PancreassmallorfattyonimagingBonemarrowfailureNeutropenia:<1500/mLAnemia:MacrocytosisThrombocytopeniaMyelodysplasticsyndrome/acuteleukemiaBonesMetaphysealdysostosisAutosomalrecessiveSBDS=Shwachman-Bodian-DiamondSyndrome60sribosomebiogenesis當(dāng)前72頁(yè)，總共82頁(yè)。SDSLiterature:Leukemia1949-200736leukemiasin36/510patients

AMLALL當(dāng)前73頁(yè)，總共82頁(yè)。SDSSurveillanceandTreatmentSimilartoFanconiAnemiaG-CSF-neutropeniaStemcelltransplant-cardiotoxicityfromcyclophosphamide?FeaturesuniquetoSDS:Malabsorption-pancreaticenzymes,ADEKMetaphysealdysostosis-surgeryasneededCytogeneticclones-monitor當(dāng)前74頁(yè)，總共82頁(yè)。SevereCongenitalNeutropeniaNophysicalphenotypeANC<500/mLPyogenicinfe