骨髓衰竭綜合征

關(guān)于骨髓衰竭綜合征CasePresentation16yearoldmaleSeenbyfamilydoctorbecausetennisinstructornoticedthathewastiringeasilyHistoryoftripoutsidetheUSA5monthsearlierNotedtohavepallorandalargebruiseonarm(wherehitbytennisball)CBC:Hb8.5g/dL,platelets40,000/mL,WBC2000/mL(20%neutrophils)第2頁,共83頁，星期六，2024年，5月NextStepLookatbloodsmearR/ocirculatingblastsDoabonemarrowAspirateCelltypesCytogeneticsBiopsyCellularity第3頁,共83頁，星期六，2024年，5月PancytopeniawithHypocellularMarrowAcquiredaplasticanemiaInheritedbonemarrowfailuresyndromeHypocellularMyelodysplasticSyndromeAleukemicleukemiaMarrowlymphoma第4頁,共83頁，星期六，2024年，5月PancytopeniawithCellularMarrowPrimarymarrowdiseaseLeukemiaMyelodysplasticsyndromeParoxysmalnocturnalhemoglobinuriaSystemicdiseaseLupusHypersplenismInfection,e.g.brucellosis,sarcoidosis,tuberculosis第5頁,共83頁，星期六，2024年，5月BoneMarrow(BM)BiopsyNormalAplastic第6頁,共83頁，星期六，2024年，5月AplasticAnemia:SignsandSymptomsAnemiafatigue,lassitude,dyspneaThrombocytopeniabruises,petechiaeseriousbleedingNeutropeniainfections第7頁,共83頁，星期六，2024年，5月SeverityofAplasticAnemiaSevere2ofthefollowing3:neutrophils<500/mL,platelets<20,000/mL,reticulocytes<20,000/mLBMcellularity<25%with<30%hematopoieticcellsVerysevereNeutrophils<200/mLNon-severe(moderate)Betterthansevere第8頁,共83頁，星期六，2024年，5月NosologyofAplasticAnemiaGeneticsAcquiredInheritedCellbiologyStemcellImmune第9頁,共83頁，星期六，2024年，5月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第10頁,共83頁，星期六，2024年，5月EvidenceforImmuneDiseaseAutologousrecoveryafterimmunosuppressionfortransplantEvensyngeneictransplantsrequireconditioningResponsetoimmunosuppression(ATG/CsA;Cp)OligoclonalexpansionofVbsubfamiliesActivatedTcellsIncreasedfrequencyofHLA-DR2Increasedapoptosis第11頁,共83頁，星期六，2024年，5月Copyright?2006AmericanSocietyofHematology.Copyrightrestrictionsmayapply.Young,N.S.etal.Blood2006;108:2509-2519ImmunePathophysiologyofAcquiredAplasticAnemiaIncitingevent(virusordrug),aberrantimmuneresponse,oligoclonalexpansionofcytotoxicTcells,destroysstemcells.BMTorISTeradicateorsuppresspathogenicT-cellclones.Immuneresponserecurs,selectionofPNH,MDS,orAMLcells.PNH,第12頁,共83頁，星期六，2024年，5月TreatmentforAcquiredAplasticAnemiaStemcelltransplantATG/CsACyclophosphamideSupportTransfusionsPlatelets?G-CSF第13頁,共83頁，星期六，2024年，5月OverlappingSyndromesAATERC,TERT,TINF2OtherFADCMDSAMLPNHAcquired第14頁,共83頁，星期六，2024年，5月InheritedBoneMarrowFailureSyndromes(IBMFS):YoungChildren3yoFA4yoDBANBTAR2yoSDS10yoDC1.5yoSCN5yoAmega第15頁,共83頁，星期六，2024年，5月IBMFS:AdultsandOlderChildren26FA23FA16SDS21DC32DBA42TAR第16頁,共83頁，星期六，2024年，5月

IBMFS:BenignHematologyOncologySyndromeHematologyLeukemiaSolidTumorsFanconiAnemia(FA)AplasticAMLSCCDyskeratosisCongenita(DC)AplasticAMLSCCDiamond-BlackfanAnemia(DBA)PureanemiaAMLSarcomasShwachman-DiamondSyndrome(SD)NeutropeniaAML-SevereCongenitalNeutropenia(SCN)NeutropeniaAML-AmegakaryocyticThrombocytopeniaThrombocytopeniaAML-ThrombocytopeniaAbsentRadii(TAR)ThrombocytopeniaAML-Thesedisordersarethemajor“InheritedBoneMarrowFailureSyndromes.”第17頁,共83頁，星期六，2024年，5月History:GuidoFanconiFanconiAnemia

(Fanconipancytopeniasyndrome):1927-3brotherswithpancytopeniaandphysicalabnormalities,“perniziosiforme”FanconiSyndrome

(renalFanconisyndrome):1936-proteinuria,glucosuria,phosphaturia,aminoaciduria,citraturia,andproximalrenaltubularacidosis第18頁,共83頁，星期六，2024年，5月FanconiAnemia-ChildrenPhotoswithpermission第19頁,共83頁，星期六，2024年，5月FanconiAnemia:AdultsAbsentradius,0Aplasticanemia,5?,6Aplasticanemia,16Cancer,30BMTdonor,55第20頁,共83頁，星期六，2024年，5月Literature:PhysicalFindingsFinding%LowBirthWeight52Short45Skinhyperpigmented31Skincaféaulait18Thumbs32Radii7Gonadsmale26Gonadsfemale1Microcephaly22Finding%Eyes20Renal20Developmentaldelay10Ears,deaf8Legs,hips,feet6Cardiopulmonary6Gastrointestinaltract5Brain/pituitary3Shortorskinonly7Allfindingsbiasedbyunder-orover-reporting!第21頁,共83頁，星期六，2024年，5月LaboratoryFindingsinFALowbloodcounts(pancytopenia)Largeredcells(macrocytosis)Increasedfetalhemoglobin(HbF)ChromosomebreakageinlymphocytesorfibroblastsculturedwithaDNAcrosslinker,e.g.diepoxybutane(DEB)ormitomycinC(MMC)第22頁,共83頁，星期六，2024年，5月FanconiAnemia-DefinitionAutosomalrecessive(1X-linkedrecessivegene)PhysicalfindingsAplasticanemiaLeukemiaSolidtumorsChromosomeinstabilityDNArepairdefect>13genes第23頁,共83頁，星期六，2024年，5月FANCGenesAdaptedfromJoenje,2006D1=BRCA2*JandNinteractwithBRCA1andBRCA2第24頁,共83頁，星期六，2024年，5月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”第25頁,共83頁，星期六，2024年，5月FADNARepairPathwayBD2DNARepairDNADamageCEFIGMLAPCNANBS1RAD51J/BACH1BRCA1D2UbD1/BRCA2D2UbN/PALB2第26頁,共83頁，星期六，2024年，5月WhoShouldbeTestedforFA?Characteristicbirthdefects(egthumbs,kidneys,poorgrowth,etc)AplasticAnemia(AA)MyelodysplasticSyndrome(MDS)AcuteMyeloidLeukemia(AML)DecreasedfertilityEarlycharacteristiccancerSiblingsofFApatients第27頁,共83頁，星期六，2024年，5月WhataretheTestsforFA?Bloodchromosomebreakage(DEBorMMC)SkinfibroblastchromosomebreakageFlowcytometryforG2arrestWesternblotforubiquitinatedD2RetroviralFAgenecorrectionofFAphenotypeFAgenesequencing第28頁,共83頁，星期六，2024年，5月D2UbiquitinationShimamuraetal,Blood,2002LIJ(BRIP1)BM第29頁,共83頁，星期六，2024年，5月Retrovirus-mediatedCorrectionofTA0252'sT-cellsanalyzedbyflowcytometryafterfivedaysofMMC-Incubation0204060801001101001000c(MMC)[nM]cellsalive[%]S11EGSFAS11FCIEGS11FEIEG2S11FFIEGS11FGFANCARetrovirus-mediatedCorrectionofFACells第30頁,共83頁，星期六，2024年，5月FAComplicationsAplasticAnemiaAcuteLeukemiaMyelodysplasticSyndromeSolidTumorsLivertumors第31頁,共83頁，星期六，2024年，5月FAAplasticAnemiaAdaptedfromKutleretal,Blood,200380%byage~15,>90%overall第32頁,共83頁，星期六，2024年，5月FALiterature:Cancer1927-2007179solidtumorsand163leukemiasin330/1865patients;29had2-4cancersAMLLiverHNSCCBrainVulvaWilmsALLEsophagus第33頁,共83頁，星期六，2024年，5月RiskofCancerinFAbyO/ERatioFACohortsParameterNASGEFAISFARNCINumberofPatients145182Person-Years20002818AllCancers52x44xAllSolidTumors51x26xOralCavity/Pharynx706x240xVulvar4317x2411xAML785x868xMDS8559x4559xNorthAmericanSurvey;GermanFARegistry;IsraeliFARegistry;NationalCancerInstitute第34頁,共83頁，星期六，2024年，5月NCIFACumulativeIncidenceandCause-specificHazards第35頁,共83頁，星期六，2024年，5月CompetingRisksofCancer第36頁,共83頁，星期六，2024年，5月FanconiAnemia:Phenotype/OutcomeRosenberg,Huang,Alter,Blood2004Phenotypepredictsageandincidenceofmarrowfailureandsolidtumors.NormalPhenotypeAbnormalPhenotypeAbnormalphenotype=radii,plusabnormaldevelopment,heartorlung,kidney,hearing,andhead.Competingriskanalyses.第37頁,共83頁，星期六，2024年，5月TransplantandHeadandNeckCancerinFanconiAnemiaBMTNoBMTDATA:Transplantincreasedcancerby4.4-fold;Shiftedmedianageto16yearsyounger;Allcancerpatientshadgraftvshostdisease.ParisRosenberg,Socie,Gluckman,Alter:Blood,2005;BiolBlood&MarrowTranspl,2005LESSON:Improvetransplantpreparationtoreducegraftvshostdisease.USA第38頁,共83頁，星期六，2024年，5月DiagnosisofFAafterCancerTongueSCCage30SkinSCCsage33Short,80lbs,hearingaids,menopauseage30XRTsideeffectsNormalbloodcountsPBchromosomesnobreaks;skinbreaksExon8:790C>T;Q264X;Gln264StopExon27:2585delCT;Frameshift,Cys846fsX20SkinGeneconversion,lossofexon27frameshift2585delCTBloodSomaticMosaicism,FANCAAlter,Joenje,Oostra,Pals,ArchOtolaryngol,2005第39頁,共83頁，星期六，2024年，5月HematopoieticMosaicism第40頁,共83頁，星期六，2024年，5月MosaicismfromRecombinationaAAaaAAaaAAa第41頁,共83頁，星期六，2024年，5月FANCD1/BRCA2Proband;AdultFANCAPhotoswithparentalandpatientconsent第42頁,共83頁，星期六，2024年，5月

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第43頁,共83頁，星期六，2024年，5月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第44頁,共83頁，星期六，2024年，5月FANCD1/BRCA2MutationsMutationsUniformity1Cluster2MissenseNo,p=0.01Yes,p=<0.001DeleteriousYes,p=0.6No,p=0.3Whatistheriskofcancerincarriersofthesemissensemutations?1Chisquareofexpectedfrequencyacrossthegene.2Permutationtestofrangebetweentheextremes.Alter,Brody,Rosenberg:JMedGenet,2007Whydopatientswithbiallelicdeleterious/deleteriousordeleterious/missensemutationsinBRCA2bothdevelopFAandcancer?第45頁,共83頁，星期六，2024年，5月FA:WhentoTreatCytopeniasHb<8g/dLorsymptomsPlatelets<30,000/mm3WBC<500/mm3MDSMorphologic+cytopeniasNotforclonealoneLeukemiaBlastsinblood>20%blastsinmarrowSolidtumorsorlivertumorsWhendetectedFA:GuidelinesforDiagnosisandManagement,2008第46頁,共83頁，星期六，2024年，5月FA:HowtoTreatHematologicdisease(benignormalignant)StemcelltransplantAndrogensHematopoieticgrowthfactors(G-CSF,Ep)ChemotherapyFolicacidBloodproducts:notfamily;leukodeplete;irradiateGenetherapy?LivertumorsStopandrogensSolidtumorsConservative/focusedradiationChemotherapythatdoesnotcross-linkDNANewmodalities,e.g.cetuximabFA:GuidelinesforDiagnosisandManagement,2008第47頁,共83頁，星期六，2024年，5月FASurveillance:CancerHematopoiesis–AA,MDS,aMLBloodcountsevery3-4monthsBonemarrowaspirate,biopsy,cytogeneticsannuallyOralcavityandpharynx-roleofHPVvaccine?Age>10yearsBMT>1yearGynecologic-roleofHPVvaccine?Age>16yearsMenarcheLiverLiverenzymesevery3-4monthsLiverultrasoundevery6-12monthsSkinAnnualexam第48頁,共83頁，星期六，2024年，5月CasePresentation16yearoldmaleSeenbyfamilydoctorbecausetennisinstructornoticedthathewastiringeasilyHistoryoftripoutsidetheUSA5monthsearlierNotedtohavepallorandalargebruiseonarm(wherehitbytennisball)CBC:Hb8.5g/dL,platelets40,000/mL,WBC2000/mL(20%neutrophils)Diagnosis:FanconiAnemia,newlydiagnosedinanadolescent第49頁,共83頁，星期六，2024年，5月DyskeratosisCongenita第50頁,共83頁，星期六，2024年，5月DyskeratosisCongenita-Kids2yo,HH1.5yo,HH6yo,TINF210yo,TINF2第51頁,共83頁，星期六，2024年，5月DyskeratosisCongenita-Adults22yo,DKC148and16yo,TERC27yo,TINF224yo,TINF2第52頁,共83頁，星期六，2024年，5月PhysicalFindingsinDCDystrophicnails*Laceypigmentation*Leukoplakia*Epiphora,blepharitisDevelopmentaldelayPulmonarydiseaseShortstatureDentalcariesLiverdiseaseEsophagealstrictureEarlygreyhair,hairloss,sparseeyelashesHyperhidrosisCerebellarhypoplasiaHypogonadismMicrocephalyUrethralstrictureOsteoporosis,avascularnecrosis*DiagnosticTriad(need2/3).Or,1ofthetriad,+hypoplasticbonemarrow,+2oftheotherfindings.第53頁,共83頁，星期六，2024年，5月X-linkedrecessive(XLR),Autosomaldominant(AD),Autosomalrecessive(AR)Mutationsintelomeraseandshelterinpathways:DKC1(XLR)TERC(AD)TERT(AD,AR)TINF2(AD)DCInheritanceNOLA2(AR)NOLA3(AR)Others(~50%)第54頁,共83頁，星期六，2024年，5月MajorComplicationsinDCHematologicBonemarrowfailureMyelodysplasticsyndromeLeukemiaSolidtumorsHeadandneckAnogenitalPulmonaryfibrosis第55頁,共83頁，星期六，2024年，5月44cancersin36/425patientsDCLiterature:Cancer1910-2007HNSCCRectalStomach第56頁,共83頁，星期六，2024年，5月WhatistheEndoftheShoelace?Theaglet第57頁,共83頁，星期六，2024年，5月TelomeresandChromosomalInstabilityLongTTAGGGrepeatsShortenwitheachcelldivisionManyproteinsinteracttoregulatetelomerelengthandstabilizestructureLackoftelomeremaintenanceleadstoerosionofchromosomeends,genomicinstability,cellcrisisandcelldeathFISH:telomeresCourtesyofPeterLansdorp第58頁,共83頁，星期六，2024年，5月TelomereBiologyPathwayArmanios,AnnuRevGenomicsHumGenet,2009KirwanandDokal,BBA,2009第59頁,共83頁，星期六，2024年，5月LaboratoryDiagnosticTest:

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

MostpatientswithotherIBMFShavenormaltelomeres.第60頁,共83頁，星期六，2024年，5月TelomereLengthinMultiplexFamilyEthics:Dennyetal:AJMG,2008Genediscovery:Savageetal:AJHG,2008第61頁,共83頁，星期六，2024年，5月TINF2isMutatedinDCArg282SerLys280GluArg282HisHoyeraal-HreidarssonSyndromeReveszSyndromeSavageetal:AJHG,2008第62頁,共83頁，星期六，2024年，5月NCIIBMFSCohort:

RelativeRiskofCancer(O/ERatio)ParameterFADCNumberPerson-YearsAllCancersAllSolidTumorsTongueAMLMDS第63頁,共83頁，星期六，2024年，5月NCIDC

ComparedwithAllFA第64頁,共83頁，星期六，2024年，5月DCSurveillanceandTreatmentSimilartoFanconiAnemiaRoleofHPVvaccine?StemcelltransplantcomplicatedbypulmonarydiseaseNoroleforimmunosuppressionFeaturesuniquetoDC:AndrogensensitiveSplenicpeliosisandruptureonandrogens+G-CSFPulmonaryfibrosisHepaticfibrosis,cirrhosisTelomerelengthassay:diagnosisofpatients,silentcarriers;surveillanceandgeneticcounseling第65頁,共83頁，星期六，2024年，5月Diamond-BlackfanAnemia第66頁,共83頁，星期六，2024年，5月Diamond-BlackfanAnemiaNormochromic,usuallymacrocyticanemia,developingininfancyReticulocytopeniaMarrowerythroblastopeniaNormalorslightlydecreasedleukocytesNormalorincreasedplateletsIncreasedfetalhemoglobin(HbF)Increasedredcelladenosinedeaminase(ADA)25%withphysicalfindings:short,abnormalthumbs,etc第67頁,共83頁，星期六，2024年，5月DBALiterature2008:PhysicalFindingsFindingNumber%Anyabnormalityincludingshortstature22425Anyabnormalityotherthanshortstature15321Shortstatureonly354Thumbanomaly576Triphalangealthumb243Cleftpalate243Denominator=~900,butnodatainmanyreports.第68頁,共83頁，星期六，2024年，5月DBAInheritanceAutosomaldominant~25%RPS19~2%RPS24~1%RPS1740sribosomebiogenesisHaploinsufficiency~7%RPL5~5%RPL11~2%RPL35a第69頁,共83頁，星期六，2024年，5月30cancersin30/899patients;3MDSnotincludedDBALiterature:Cancer1936-2008第70頁,共83頁，星期六，2024年，5月DBASurveillanceandTreatmentMonitorbloodcountsAnnualbonemarrows(noconsensus)TreatwhenHb<8g/dL,orsymptomsCorticosteroidsTransfuseduringfirstyearandpuberty(noconsensus)CyclosporinA(rare)Metoclopramide(rare)第71頁,共83頁，星期六，2024年，5月Shwachman-DiamondSyndromeExocrinepancreaticinsufficiencyDecreasedtrypsinogenandisoamylase(age-dependent)PancreassmallorfattyonimagingBonemarrowfailureNeutropenia:<1500/mLAnemia:MacrocytosisThrombocytopeniaMyelodysplasticsyndrome/acuteleukemiaBonesMetaphysealdysostosisAutosomalrecessiveSBDS=Shwachman-Bodian-DiamondSyndrome60sribosomebiogenesis第72頁,共83頁，星期六，2024年，5月SDSLiterature:Leukemia1949-200736leukemiasin36/510patients

AMLALL第73頁,共83頁，星期六，2024年，5月SDSSurveillanceandTreatmentSimilartoFanconiAnemiaG-CSF-neutropeniaStemcelltransplant-cardiotoxicityfromcyclophosphamide?FeaturesuniquetoSDS:Malabsorption-pancreaticenzymes,ADEKMetaphysealdysostosis-surgeryasneededCytogeneticclones-monitor第74頁,共83頁，星期六，2024年，5月SevereCongenitalNeutropeniaNophysicalphenotypeANC<500/mLPyogenicinfectionsRxG-CSFAutosomaldominant