畸变染色体引起的疾病课件

畸变染色体引起的疾病

Anysyndromecharacterizedbymalformationsormalfunctionsinanyofthebody'ssystems,andcausedbyabnormalchromosomenumberorconstitution.1.DownsyndromeA.ABriefHistoryTheformalstorybeganin1866,whenaphysiciannamedJohnLangdonDownpublishedanessayinEnglandinwhichhedescribedasetofchildrenwithcommonfeatureswhoweredistinctfromotherchildrenwithmentalretardation.DownwassuperintendentofanasylumforchildrenwithmentalretardationinSurrey,Englandwhenhemadethefirstdistinctionbetweenchildrenwhowerecretins(latertobefoundtohavehypothyroidism)andwhathereferredtoas"Mongoloids."DownbasedthisunfortunatenameonhisnotionthatthesechildrenlookedlikepeoplefromMongolia,whowerethoughtthentohaveanarresteddevelopment.Thisethnicinsultcameunderfireintheearly1960sfromAsiangeneticresearchers,andthetermwasdroppedfromscientificuse.Instead,theconditionbecamecalled"Down'ssyndrome."Inthe1970s,anAmericanrevisionofscientifictermschangeditsimplyto"Downsyndrome,"whileitstilliscalled"Down's"intheUKandsomeplacesinEurope.Inthefirstpartofthetwentiethcentury,therewasmuchspeculationofthecauseofDownsyndrome.ThefirstpeopletospeculatethatitmightbeduetochromosomalabnormalitieswereWaardenburgandBleyerinthe1930s.Butitwasn'tuntil1959thatJeromeLejeuneandPatriciaJacobs,workingindependently,firstdeterminedthecausetobetrisomy(triplication)ofthe21stchromosome.CasesofDownsyndromeduetotranslocationandmosaicismweredescribedoverthenextthreeyears.B.TheChromosomesTherearethreedifferenttypesofDownsyndrome:StandardTrisomy21,Translocation,andMosaicism.InDownsyndrome,95%ofallcasesarecausedbythisevent:onecellhastwo21stchromosomesinsteadofone,sotheresultingfertilizedegghasthree21stchromosomes.Hencethescientificname,trisomy21.Recentresearchhasshownthatinthesecases,approximately90%oftheabnormalcellsaretheeggs.Thecauseofthenondisjunctionerrorisn'tknown,butthereisdefinitelyconnectionwithmaternalage.Researchiscurrentlyaimedattryingtodeterminethecauseandtimingofthenondisjunctionevent.Threetofourpercentofallcasesoftrisomy21areduetoRobertsonianTranslocation.Inthiscase,twobreaksoccurinseparatechromosomes,usuallythe14thand21stor21stand22stchromosomes.Thereisrearrangementofthegeneticmaterialsothatsomeofthe14thchromosomeisreplacedbyextra21stchromosome.Sowhilethenumberofchromosomesremainnormal,thereisatriplicationofthe21stchromosomematerial.Someofthesechildrenmayonlyhavetriplicationofpartofthe21stchromosomeinsteadofthewholechromosome,whichiscalledapartialtrisomy21.Translocationsresultingintrisomy21maybeinherited,soit'simportanttocheckthechromosomesoftheparentsinthesecasestoseeifeithermaybea"carrier."

Mosaicismiswhenapersonhasamixofcells,somecontaining46chromosomesandsomecontaining47chromosomes.C.The21stChromosomeandDownSyndrome

Intrisomy21,thepresenceofanextrasetofgenesleadstooverexpressionoftheinvolvedgenes,leadingtoincreasedproductionofcertainproducts.Formostgenes,theiroverexpressionhaslittleeffectduetothebody'sregulatingmechanismsofgenesandtheirproducts.ButthegenesthatcauseDownsyndromeappeartobeexceptions.Whichgenesareinvolved?That'sbeenthequestionresearchershaveaskedeversincethethird21stchromosomewasfound.Fromyearsofresearch,onepopulartheorystatedthatonlyasmallportionofthe21stchromosomeactuallyneededtobetriplicatedtogettheeffectsseeninDownsyndrome;thiswascalledtheDownSyndromeCriticalRegion(DSCR).However,thisregionisnotonesmallisolatedspot,butmostlikelyseveralareasthatarenotnecessarilysidebyside.The21stchromosomemayactuallyhold200to250genes(beingthesmallestchromosomeinthebodyintermsoftotalnumberofgenes);butit'sestimatedthatonlyasmallpercentageofthosemayeventuallybeinvolvedinproducingthefeaturesofDownsyndrome.GenesthatmayhaveinputintoDownsyndromeinclude:SuperoxideDismutase(SOD1)--overexpressionmaycauseprematureaginganddecreasedfunctionoftheimmunesystem;itsroleinSenileDementiaoftheAlzheimer'stypeordecreasedcognitionisstillspeculativeCOL6A1--overexpressionmaybethecauseofheartdefectsETS2--overexpressionmaybethecauseofskeletalabnormalitiesCAF1A--overexpressionmaybedetrimentaltoDNAsynthesisCystathioneBetaSynthase(CBS)--overexpressionmaydisruptmetabolismandDNArepairDYRK--overexpressionmaybethecauseofmentalretardationCRYA1--overexpressionmaybethecauseofcataractsGART--overexpressionmaydisruptDNAsynthesisandrepairIFNAR--thegeneforexpressionofInterferon,overexpressionmayinterferewiththeimmunesystemaswellasotherorgansystemsOthergenesthatarealsosuspectsincludeAPP,GLUR5,S100B,TAM,PFKL,andafewothers.Again,itisimportanttonotethatnogenehasyetbeenfullylinkedtoanyfeatureassociatedwithDownsyndrome.OneofthemorenotableaspectsofDownsyndromeisthewidevarietyoffeaturesandcharacteristicsofpeoplewithtrisomy21:ThereisawiderangeofmentalretardationanddevelopmentaldelaynotedamongchildrenwithDownsyndrome.

Somebabiesarebornwithheartdefectsandothersaren't.Somechildrenhaveassociatedillnessessuchasepilepsy,hypothyroidismorceliacdisease,andothersdon't.Thefirstpossiblereasonisthedifferenceinthegenesthataretriplicated.Theeffectofoverexpressionofgenesmaydependonwhichalleleispresentinthepersonwithtrisomy21.Thesecondreasonthatmightbeinvolvediscalled"penetrance,"andthatappearstobewhathappenswithtrisomy21:theallelesdon'tdothesamethingtoeverypersonwhohasit.BothreasonsmaybewhythereissuchvariationinchildrenandadultswithDownsyndrome.D.ClinicalfeaturesGrowth:Shortstatureandobesityoccursduringadolescence.CNS:Moderate-to-severementalretardationoccurs,withanintelligencequotient(IQ)of20-85.CongenitalheartdefectsEars:Theearsaresmallwithanoverfoldedhelix.Dermatoglyphics:Distalaxialtriradiusinthepalms,transversepalmarcreases,asingleflexioncreaseinthefifthfinger,ulnarloops(often10),apatterninhypothenar,andinterdigitalIIIregionsareobserved.E.PrenatalTesting

Maternalserumalphafeto-protein(MSAFP)ismeasuredbyabloodtestinthepregnantwomanat15-18weeksofgestation.AFPismadeinthefetalliver,andsomeescapesintothematernalcirculation.ItiswidelyusedasascreeningtestforaDSfetus.MSAFPandatleast1otherscreeningtestarerecommendedforallpregnanciesnothavingamniocentesisbytheAmericanCollegeofObstetrics,andtheAmericanCollegeof.MSAFPtestingisbasedonthefactthatDSfetusestendtobealittlesmalleronaverage,havesmallerplacentas,andthussecretelessMSAFPandothermaterials,whicharedeterminedintheserumofthepregnantwoman.Factorsthataffectthistestincludegestationalage,maternalweight,diabetesandethnicity.MSAFPscreeningisnotadefinitivetest.IftheMSAFPtestislowitsuggeststheriskofaDSfetusequaltotheriskofawomanage35,andprenataltesting/chromosomestudiesaresuggestediftheparentswantthisinformation.IfMSAFPaloneistested,20percentofDSfetuseswilltestlow.IfMSAFPandhumanchorionicgonadotrophin(HCG)aredetermined,50-60%ofDSfetuseswillbeidentified.IfMSAFP,HCGandestradiol(E2)aretested,60-70%ofDSfetuseswillbeidentified.SomeHCGtestingemploysabetasubunitbutthisisnotwidespread.ApositivescreeningtestsuggestsonlythattheriskofDSisincreased,andthedefinitivetestingofamniocentesisisindicated.SomeultrasonographerscandeterminesuggestivefindingsofDSbychangesintheneck,orheart.Thisisnotyetconfirmedorinwidespreaduse.UltrasoundscanbenormalinaDSfetus.Amniocentesis,asamplingoftheamnioticfluidsurroundingthefetus,isroutinelydoneat14-16wks.Amniocentesistestingforchromosomedisordersis99.8percentreliableforchromosomenumber,andthereisariskofmiscarriage(usually1/250orless)aftertheprocedure.2.Trisomy18Trisomy18wasindependentlydescribedbyEdwardsetalandSmithetalin1960.Amonglivebornchildren,trisomy18isthesecondmostcommonautosomaltrisomyaftertrisomy21.Thedisorderischaracterizedbyseverepsychomotorandgrowthretardation,microcephaly,microphthalmia,malformedears,micrognathiaorretrognathia,microstomia,distinctivelyclenchedfingers,andothercongenitalmalformations.Synonymsandrelatedkeywords:EdwardssyndromeEdwards'syndrometrisomy18syndrometrisomyEsyndromeA.Pathophysiology

Trisomy18severelyaffectsallorgansystems.Intranslocationsthatresultinpartialtrisomyorincasesofmosaictrisomy18,clinicalexpressionislesssevereandlongersurvivalisusual.B.Frequency

IntheUS:Prevalenceisapproximately1in6000-8000livebirths.C.Mortality/Morbidity

Approximately95%ofconceptuseswithtrisomy18dieinembryonicorfetallife;5-10%ofaffectedchildrensurvivebeyondthefirstyearoflife.Thehighmortalityrateisusuallyduetothepresenceofcardiacandrenalmalformations,feedingdifficulties,sepsis,andapneacausedbyCNSdefects.Severepsychomotorandgrowthretardationareinvariablypresentforthosewhosurvivebeyondinfancy.D.SexApproximately80%ofcasesoccurinfemales.Thepreponderanceoffemaleswithtrisomy18inliveborninfants(sexratio0.63)comparedtofetuseswithprenataldiagnoses(sexratio0.90)indicatesaprenatalselectionagainstmaleswithtrisomy18afterthetimeofamniocentesis.E.CauseThecauseofEdwardssyndromeisfulltrisomy18in95%ofcases.Mosaicismandtranslocationscausefewcases.Anextrachromosome18isresponsibleforthephenotype.Incidenceincreaseswithadvancedmaternalage.Inapproximately90%ofcases,theextrachromosomeismaternalinorigin,withmeiosisIIerrorsoccurringtwiceasfrequentlyasmeiosisIerrors.Thisisincontrasttootherhumantrisomies,whichexhibitahigherfrequencyofnondisjunctioninmaternalmeiosisI.Amongcasesresultingfrompaternalnondisjunction,mostaretheresultofpostzygoticmitoticerrors.F.ClinicalfeaturesNeurologicalCranialFacialSkeletalCardiacPulmonaryGastrointestinalGenitourinaryEndocrineDermal

Thumbagenesis-Trisomy18.17weeks.3.PatausyndromeTrisomy13syndromeisadisorderofhumanchromosomeswhichoccursinapproximately1in10,000liveborninfants.Synonyms:

Trisomy13

PatauSyndrome

Trisomy13-15DTrisomySyndromeTrisomy13isduetothepresenceofanextra13rdchromosome.Approximately80%ofinfantswithTrisomy13syndromewillhaveafulltrisomywhiletheremainderwillhaveatrisomyduetoarearrangementcalledatranslocationorhavemosaicism(twodifferentcelllines).Findingsofsignificanceincludesmallheadsize(microcephaly);smalleyes(microphthalmia)orsometimesabsenteyeorfaultydevelopmentoftheretina.Cleftliporcleftpalateorbothoccurinabout60%ofchildren.Inaddition,thereareanumberoflessmedicallysignificantphysicalfindingsthatarehelpfulindiagnosis.Theseincludevariationsofearshape,changesonthepalmofthehand,andextrafingersandtoes.Changesinfootdevelopment,includingchangestotheheel,theso-calledrockerbottomfoot,canoccur.Aplasiacutiscongenitaonthescalp(mostcommonlocation)shortlyafterbirth.Tripletareasofaplasiacutiscongenitaarecommonininfantswithtrisomy13.4.criducatsyndromeIn1963,Lejeuneetaldescribedasyndromeofmultiplecongenitalanomalies,mentalretardation,microcephaly,abnormalface,andamewingcryininfantswithdeletionofaBgroupchromosome(Bp-),lateridentifiedas5p-.Cri-du-chatsyndromeisanautosomaldeletionsyndromecausedbyapartialdeletionofchromosome5p.Itischaracterizedbyadistinctive,high-pitched,catlikecryininfancywithgrowthfailure,microcephaly,facialabnormalities,andmentalretardationthroughoutlife.Synonymsandrelatedkeywordscatcrysyndromechromosomedeletion5psyndromemonosomy5psyndrome(Bp-)5p-partialdeletionofchromosome5p5pdeletion5pmonosomyA.PathophysiologyApartialdeletionoftheshortarmofchromosome5isresponsibleforthecharacteristicphenotype.Thecharacteristiccryisperceptuallyandacousticallysimilartothemewingofkittens.Thisunusualcryisbecauseofstructuralabnormalitiesofthelarynx(suchaslaryngealhypoplasia)andCNSdysfunction.Thelaryngealappearancemaybenormalormayexhibitmarkedanatomicalabnormalitiessuchasfloppyepiglottis,smalllarynx,andasymmetricvocalcords.However,thecauseofthecharacteristiccrycannotbeentirelyascribedtothelarynx.Adevelopmentalfieldconnectingthebrainandtheaffectedclivusregionofthecranialbasewiththelaryngealregionfromwhichthecharacteristiccryderivesmayexist.Thisareaofthebrainisprobablydeformedinpatientswithcri-du-chatsyndrome.Thecharacteristiccryusuallydisappearswithtime.B.Frequency

IntheUS:Theestimatedprevalenceisabout1in50,000livebirths.Theprevalenceamongindividualswithmentalretardationisabout1.5in1000.C.Mortality/MorbidityWithcontemporaryinterventions,thechanceofsurvivaltoadulthoodispossible.Currently,deathoccursin6-8%oftheoverallpopulationaffectedwiththesyndrome.Pneumonia,aspirationpneumonia,congenitalheartdefects,andrespiratorydistresssyndromearethemostcommoncausesofdeath.D.Sex

Asignificantfemalepredominanceexistsinaffectednewborns,withamale-to-femaleratioof0.72.E.CausesMostcases(80-85%)areduetosporadicdenovodeletionof5p(15.3->15.2).Approximately10-15%ofcasesresultfromtheunequalsegregationofaparentalbalancedtranslocationwherethe5pmonosomyisoftenaccompaniedbyatrisomicportionofthegenome.Thephenotypesintheseindividualsmaybemoreseverethaninthosewithisolatedmonosomyof5pbecauseofthisadditionaltrisomicportionofthegenome.Mostcasesinvolveterminaldeletionswith30-60%lossof5pmaterial.Fewerthan10%ofcaseshaveotherrarecytogeneticaberrations.Thedeletedchromosome5ispaternalinorigininabout80%ofthecases.Lossofasmallregioninband5p15.2(cri-du-chatcriticalregion)correlateswithalltheclinicalfeaturesofthesyndromewiththeexceptionofthecatlikecry,whichmapstoband5p15.3(catlikecriticalregion).High-resolutionmappingofgenotype-phenotyperelationshipsincri-du-chatsyndromeusingarraycomparativegenomichybridization(CGH)Localizedtheregionassociatedwiththecryto1.5Mbindistalband5p15.31,betweenbacterialartificialchromosomes(BACs)containingmarkersD5S2054andD5S676.Localizedtheregionassociatedwiththespeechdelayto3.2Mbinband5p15.32-15.33,betweenBACscontainingmarkersD5S417andD5S635.Localizedtheregionassociatedwiththefacialdysmorphologyto2.4Mbinband5p15.2-15.31,betweenBACscontainingmarkersD5S208andD5S2887.F.ClinicalfeaturesHistory:

CharacteristiccryDevelopmentalhistory:Earlyfeedingproblemsarepresentbecauseofswallowingdifficulties;poorsuck;failuretothrive;earlyearinfections;andseverecognitive,speech,andmotordelays.Almostallpatientshavetheseproblems.BehavioralhistoryPhysical:NeonatalperiodChildhood:Findingsincludeseverementalretardation;developmentaldelay;microcephaly;Imageisofaninfantwithcri-du-chatsyndrome.Notearoundfacewithfullcheeks,hypertelorism,epicanthalfolds,andapparentlylow-setears.Imageisofachildwithcri-du-chatsyndrome.Notehypertonicity,smallandnarrowface,droppedjaw,andopen-mouthexpressionsecondarytofaciallaxity.5.KlinefeltersyndromeIn1942,Klinefelteretalpublishedareporton9menwhohadenlargedbreasts,sparsefacialandbodyhair,smalltestes,andinabilitytoproducesperm.In1959,thesemenwithKlinefeltersyndromewerediscoveredtohaveanextrasexchromosome(genotypeXXY)insteadoftheusualmalesexcomplement(genotypeXY).Klinefeltersyndromeisthemostcommonchromosomaldisorderassociatedwithmalehypogonadismandinfertility.Itisdefinedclassicallybya47,XXYkaryotypewithvariantsdemonstratingadditionalXandYchromosomes.Thesyndromeischaracterizedbyhypogonadism(smalltestes,azoospermia/oligospermia),gynecomastiaatlatepuberty,psychosocialproblems,hyalinizationandfibrosisoftheseminiferoustubules,andelevatedurinarygonadotropins.A.PathophysiologyTheadditionofmorethan1extraXorYchromosometoamalekaryotyperesultsinvariablephysicalandcognitiveabnormalities.Ingeneral,theextentofphenotypicabnormalities,includingmentalretardation,isrelateddirectlytothenumberofsupernumeraryXchromosomes.AsthenumberofXchromosomesincreases,somaticandcognitivedevelopmentaremorelikelytobeaffected.Skeletalandcardiovascularabnormalitiescanbecomeincreasinglysevere.GonadaldevelopmentisparticularlysusceptibletoeachadditionalXchromosome,resultinginseminiferoustubuledysgenesisandinfertilityaswellashypoplasticandmalformedgenitaliainpolysomyXmales.Moreover,mentalcapacitydiminisheswithadditionalXchromosomes.TheIQisreducedbyapproximately15pointsforeachsupernumeraryXchromosome,butconclusionsaboutreducedmentalcapacitymustbedrawncautiously.Allmajorareasofdevelopment,includingexpressiveandreceptivelanguageandcoordination,are

affectedbyextraXchromosomematerial.B.Frequency

IntheUS:Approximately1in500-1,000malesisbornwithanextrasexchromosome;over3,000affectedmalesarebornyearly.Theprevalenceis5-20timeshigherinthementallyretardedthaninthegeneralnewbornpopulation.C.Mortality/Morbidity

About40%ofconceptiwithKlinefeltersyndromesurvivethefetalperiod.Ingeneral,severityofsomaticmalformationsinKlinefeltersyndromeisproportionaltothenumberofadditionalXchromosomes;mentalretardationandhypogonadismaremoreseverein49,XXXXYthanin48,XXXY.Mortalityrateisnotsignificantlyhigherthaninhealthyindividuals.D.CausesKlinefeltersyndromeiscausedbythepresenceofanadditionalXchromosomeinamale.About50-60%ofcasesareduetomaternalnondisjunction(75%meiosisIerrors).IncasesinwhichthesematernalmeiosisIerrorsareidentified,maternalageisincreased.Theremainingcasesareduetopaternalnondisjunction.Themostcommonkaryotypeis47,XXY(about80-90%ofallcases).Mosaicism(46,XY/47,XXY)isobservedinabout10%ofcases.Othervariantkaryotypes,including48,XXYY,48,XXXY,49,XXXYY,and49,XXXXY,arerare.ThemosaicformsofKlinefeltersyndromeThemosaicformsofKlinefeltersyndromeareduetomitoticnondisjunctionafterfertilizationofthezygote.Theseformscanarisefroma46,XYzygoteora47,XXYzygote.Thevariantformsareasfollows:48,XXXY49,XXXXY48,XXYY49,XXXYYE.ClinicalfeaturesGrowthCentralnervoussystemDentalSexualcharacteristicsCardiacandcirculatoryproblemsAdolescentmalewithgynecomastiawhohasKlinefeltersyndrome.ChildwithKlinefeltersyndrome.Otherthanathinbuildanddisproportionatelylongarmsandlegs,thephenotypeisnormal.AdolescentmalewithKlinefeltersyndromewhohasfemale-typedistributionofpubichairandtesticulardysgenesis.6.TurnersyndromeIn1938,HenryTurnerfirstdescribedTurnersyndrome,whichisoneofthemostcommonchromosomalabnormalities.