内分泌系统教学课件：三体唐氏综合症

TRISOMY21

SYNDROMEDownsyndrome(asweknowittoday)hasexistedsincethebeginningof

humankind.Dept.ofPediatrics,TongjiHospital,

HUSTTrisomy21

SyndromeZhouZhou,YizhouHU,DOBApril1,1978,IQ=

30Dept.ofPediatrics,TongjiHospital,

HUSTDown

syndrome:FirstdescribedinthemedicalliteraturebyDr.JohnLangdonDowninEnglandin

1866In1956,scientistsdiscoveredthatthetypicalhumancellhas46

chromosomesIn1958,LejeunediscoveredthatthecellsfromanindividualwithDShadanextrachromosome

21In1959,9peoplewithDSwerefoundtohaveanextrachromosome

21IncidenceGlobally1per700live

birth1/3ofmoderateandseveremental

handicapsRaceall

racesSexno

differenceDept.ofPediatrics,TongjiHospital,

HUST1Dept.ofPediatrics,TongjiHospital,

HUSTMaternal

age放射线RadiationInfectionChemicalsGenetic

factorsMother

cyesisEtiology(‰)The

incidence

of

DSMaternalage

(Y)Dept.ofPediatrics,TongjiHospital,

HUSTMaternal

ageThe

incidence<251:180025-291:150030-341:80035-391:25040-441:100>451:50Average1:650Maternal

AgeTheriskincreaseswiththematernal

ageNormalThegenesofchromosome21:whatdowe

know?Therearemorethan400genesonchromosome21(weusedtothinktherewere

fewer)Ofthese,~170codeforproteinsthatarealsoencodedbygenesinmiceandotheranimalsWhengenesareconservedacrossspecies,itistypicallybecausetheyare

importantChromosome21

proteins…ArepredictedtodirectlyandindirectlyaffectlearningandmemoryinDownsyndrome

byPreventingestrogenfromenteringbraincells(lowestrogeninbraincanpromoteearlymenopauseandAlzheimer

disease)Reducingsubstancesthatallowcellstocommunicatewithone

anotherReducingbraincellsurvivalinthe

adultStudyingchromosome21genesacrossspeciesallowsus

to…Understandtherolesofthesegenesinnormaldevelopmentand

functionLearnhowtheproteinsencodedbythesegenesinteractwithotherproteinsinthe

bodyPredictwaysinwhichtheextrainformationencodedbythesegenescanbe“turneddown”or“turnedoff”bymedications,genetherapy,

etc.2TypesofDown

Syndrome■Trisomy21

(92%~95%)MMoossaaiicc

DDoowwnn

Synnddrroommee((2.5%~5%)TranslocationTrisomy

21((2%~4%)Trisomy

21Foundin92%ofallDS

individualsCausedbynondisjuctioninmeiosis,causingeggstohavetrisomy

21Increasesinincidencewithmaternalage,butalsofoundinyounger

mothersChildrenbornimmediatelyafterDSchildrenhaveahigherchanceofalsohavingDS,however,forothersiblings,theriskforhavingDSdoesnot

increaseNondisjunctionMosaic

DS2-4%oftheDS

populationStartsoffwith23pairsofchromosomesineach

cellErroroccursinanearlycell

divisionDuringembryonicdevelopment,arandomcellwillacquiretrisomy21,creating2individualcelllines(normaland

trisomatic)Theearlierthemutationoccurs,themoreprofoundthe

effectsMosaic

DSTranslocation

DS3-4%oftheDS

populationARobertsoniantranslocationoccurswhenonechromosome21attachestoanotherchromosome,formingasinglenew,chromosomeTherecipientchromosomeisusuallychromosome14andthecombinationofthe2chromosomesiscalledafourteen,twentyonetranslocationCanalsoswitchwith13,15,or

223Translocation

DSAbout¼ofTranslocationDSis

inheritedTheparentisthencalledatranslocationcarrierParenthasonenormalcopyof21andonecopyof21attachedtoanother

chromosomeBothcopiesarethenpassed

onWhenfertilizationoccurs,embryocontainsbothcopiesof21fromthecarrierparent,andthenormalonecopyor21fromthenormalparentEffectsaresimilartoTrisomy21

DSTranslocation

DSRobertsonianTranslocationsCanresultinDown

syndromeClinical

Featuresmentalretardationgrowthfailurecharacteristic

faciesdermatoglyphicabnormalityother

malformationsDept.ofPediatrics,TongjiHospital,

HUSTFacialCharacteristicsQheadandface

Q

eye Q

noseQ

mouth Q

ear Q

othersDept.ofPediatrics,TongjiHospital,

HUSTDermatoglyphic

Abnormality50%palmarflexioncreaseslikesimian

linenormal SimiancreasetransitionaltransitionalSydney

typetype

I type

IIDept.ofPediatrics,TongjiHospital,

HUST4Dermatoglyphic

AbnormalityAxialtriradiusofpalmmovestothecenterAtdangle

increasesad tNormal

atd≈41° DS’s

atd＞58°Dept.ofPediatrics,TongjiHospital,

HUSTMedical

ComplicationsEpilepsyHypothyroidismCrossed

eyesCataractsHearing

impairmentHeart

defectsChildhoodleukemiais20%more

commonHerniasSterilityin

malesFemalesarefertilebutcanpasson

DSAcceleratedAgingwithhighchanceofAlzheimer’s

disease196819741983-81988NewTestforDown

Syndrome?1959196619331990Screening

milestonesTrisomy21identifiedascauseofDown

SyndromeFirstchromosomalanalysesfromamniotic

fluidAssociation

betweenmaternalageandDown

syndromeTripletest

introducedMaternalserummarkersforDown

syndromeNuchal

translucencyintroduced196819741983-819881959196619331990PrenataldiagnosisofDown

syndromeRaisedAF-AFPassociatedwith

NTD1864Langdon-Downfirstdescriptionoftheclinicalfeaturesof

“mongolism”Noninvasiveprenatalscreeningfor

DSDecember1,2008–Sequenom,Inc.announcedresultsfromacollaborativestudywithTheChineseUniversityshowingthatitispreliminarilypossibleto

diagnoseDownsyndromeonabloodsampletakenfromexpectantmothersduringthefirstandsecondtrimestersofpregnancy.-ThemethodusestechnologythatextractsfetalRNAfrommaternal

blood.-Studyisbeinglaunchedtoevaluateupto10,000pregnanciesatincreasedriskfor

DSNoninvasivetest

(cont.)Atfirst,womenwithpositivescreenswillssttiilllluunnddeerrggoochorionicvillisampling(CVS)oramniocentesistoconfirmresults,butthehopeisthatthenewtestwillultimatelyreplaceboth.Thereissomeconcernthatthistestingwillbemarketed/indemandbeforesufficientstudiesarecompletedtoprove

accuracy.5Noninvasivetest

(cont.)ResearchersatStanfordhavepublishedpreliminaryresultsonamaternalblood-basedDSscreenthatusesadifferenttechnologythan

SequenomOthercompaniesarealsoworkingonnoninvasive

testsTreatmentNoeffectivetreatmentsEducationandtrainingCorrectthemalformationPrevent

infectionsDrugsDept.ofPediatrics,TongjiHospital,

HUST196819741983-81988AlternativeTherapiesforChildrenwithDown

Syndrome1959196619331990Alternative

therapies--history1960’s:HenryTurkelclaimedthatamixtureof48ingredientscouldimprovetheintelligenceofchildrenwithDS,whichheadministeredtohispatientsformorethan40years.Nodouble-blindstudywaseverperformed.Noevidenceemergedthatthiswasbeneficial.Alternativetherapieshistory(cont.)1980’s:RuthHarrell,andassociatesreportedthatsupplementaryvitaminsandmineralsandthyroidhormoneimprovedIQscoresandnormalizedphysicalappearanceinchildrenwithmentaldeficiency.Reportedly,3childrenwithDSshowedthebestresults.Thestudywasnotperformedscientifically,and7studiesperformedinthenextdecadeusingthismixtureshowedno

benefit.Alternativetherapieshistory(cont.)1980’s:HapsCaps,anothermixtureofvitamins,minerals,andsupplementswaspromotedthroughtravelingclinicsrunbyJackWarner,MD,of

California6Alternativetherapieshistory(cont.)1995:ABC-TV’s“DayOne”promotedaformulacreatedbyDixieLawrenceTafoya,owner/operatorofanadoptionagencyspecializinginfindinghomesforspecialneedschildren.HerformulawasbasedonTurkel’sformulabuthadmoreingredients.Subsequently,piracetamwas

added.DixieLawrence

(cont.)ArrangedforherformulatobeproducedbyNutri-ChemLabsinCanada(MSB

Plus)1996-LawrencewithdrewsupportfromNutri-ChemandbeganpromotingNuTriVene-DmarketedbyInternationalNutritioninBaltimore(MSPPlusismadethere,

also)The

latest…ChangingMindsFoundation*ispromotinga“newtreatmentforDownsyndrome”thatleadsto“lifechanging

results.”Treatmentincludesregulardosesoffluoxetine(Prozac),Dexmethylphenidate(FocalinXR),andginkgobilobaaswellas“BodyBioBalancedOil”andfolinic

acid.Whatarethese

drugs?Ginkgobiloba(GB)–anherbthathasbeenusedmedicinallyformillennia,GBisaGABAantagonist.SupportersofitsuseinDSsaythatitpromotesimprovedmemory.Nocontrolledstudieshavebeendoneinanimalsorhumanstoestablishsafedosesortoprovea

benefit.Fluoxetine(Prozac)–anantidepressantthatinDSmiceincreasedthegrowthofnewnervecells.Notreplicatedinhumansandcandoharmto

fetuses.Whatarethesedrugs?

(cont.)Dexmethylphenidate(FocalinXR)–

astimulant

medicationusedtotreatADHD.Itsuseshouldbecarefullyconsideredinchildrenwithheartdefects,anditisnotrecommendedinbabiesandyoung

children.Folinicacid–hasvitaminactivitysimilartofolicacid(Bvitamin)andhasbeenproventohavenosignificanteffectondevelopmentinchildrenwith

DSWhat

is…BodyBioBalancedOil*–pertheChangingMinds

Foundation,“Thereisagrowingbodyofevidencethatinflammationanddegenerationgohandinhand.Thisoilprovidesthebodywithbuildingblockstoreduceinflammationandimprove

health.”*$26.35for180softgelsfornon-members7DiagnosisClinicalmanifestations：Final

diagnosis：karyotypingofperipheralblood

lymphocytePrenataldiagnosis：karyotypingofchorioniccellsTriplescreening

tests:AFP,FE3,

HCGDept.ofPediatrics,TongjiHospital,

HUSTPreventionThreelevelsofpreventionbyWHOprimary：pathogenesissecondary：delivery

tertiary：early

diagnosisand

therapyDept.ofPediatrics,TongjiHospital,

HUST100base

pairs105109CGHand

MLPADNA

sequencingFISHChromosome

bandingLive,dividingcellsScreenall

chromosomesTAT2–4weeksLabour

intensiveAny

tissueTestspecific

regionsTAT72

hoursCanbe

automatedCHROMOSOMESDNAShorttandemrepeats(STR)STR=microsatellite

markers10000’sacross

genomeStretchesofDNAofunitsof2-4

nucleotidesTGTG…TGCAACAA….CAADifferentallelesexistforeachSTRin

popn.Eachallelediffersinrepeat

lengthQuantitativefluorescentPCRaneuploidyscreen

(QF-PCR)Principle:TestSTRmarkerson

chromosomes4-5onautosomesofchoice(13,18,

21)FeweronXand

YUsedtodetectnumericalchromosomeabnormalitiesCantestblood,amnioticfluid,CVS,post-mortemtissue

etc.8QF-PCRAdvantagesRapidresult(48–72

hours)99%

accuracyNolivecells

requiredDisadvantagesWon’tdetectmosaicism

(<30%)Won’tdetectotherchromosome

abnormalitiesMechanismofaneuploidyremains

unknownBlood-stainedamniomaymaketesting

impossibleRiskofmaternalcontaminationifCVSnotcarefullyprepared/dissectedPast

…Pre-andpostnataltestingforDSbykaryotypingPrenataltestingforDSin

AMAwomen

by

QF-PCRPostnataltestingforDSbykaryotypingJanuary2007–May2008563requestsforDS

testingPast

…Pre-andpostnataltestingforDSbykaryotypingPrenataltestingforDSin

AMAwomen

by

QF-PCRPostnataltestingforDSbykaryotypingJanuary2007–May2008563requestsforDS

testing307confirmedDS

(54.5%)+79confirmed

DSonspecimensnotrequestedas

DS=

386

confirmed

DS185

not

DS(33%)67

no

result4otherchromosomeabnormalitiesPast

…Pre-andpostnataltestingforDSbykaryotypingPrenataltestingforDSin

AMAwomen

by

QF-PCRPostnataltestingforDSbykaryotypingJanuary2007–May2008563requestsforDS

testing307confirmedDS

(54.5%)+79confirmed

DSonspecimensnotrequestedas

DS=

386

confirmed

DS185

not

DS(33%)67

no

result366

trisomy95%6

mosaic1.5%14

translocation3.5%4otherchromosomeabnormalities…presentIndicationfor

DStestingPrenataltestingforDSin

AMAwomen

by

QF-PCRPostnataltestingforDSby

QF-PCRConfirmed

DS98%

RRrelates

to

trisomy~2%

RR

relates

toinheritedtranslocationOffer

parentalkaryotype