医学精品课件：21三体唐氏综合症.pptx

1、TRISOMY 21 SYNDROMEDr.Xiaoping Luo Professor and Chairman Department of PediatricsTongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan,ChinaDown syndrome(as we know it today)has existed since the beginning of humankind.Dept.of Pediatrics,Tongji Hospital,HUSTT

2、risomy 21 SyndromeZhou Zhou,Yizhou HU,DOB April 1,1978,IQ=30Dept.of Pediatrics,Tongji Hospital,HUSTDown syndrome:First described in the medical literature by Dr.John Langdon Down in England in 1866In 1956,scientists discovered that the typical human cell has 46 chromosomesIn 1958,Lejeune discovered

3、that the cells from an individual with DS had an extra chromosome 21In 1959,9 people with DS were found to have an extra chromosome 21IncidenceGlobally1 per 700 live birth1/3 of moderate and severe mental handicapsRaceall racesSexno differenceDept.of Pediatrics,Tongji Hospital,HUST1Dept.of Pediatric

4、s,Tongji Hospital,HUSTMaternal age放射线放射线RadiationInfectionChemicalsGenetic factorsMother cyesisEtiology()The incidence of DSMaternal age(Y)Dept.of Pediatrics,Tongji Hospital,HUSTMaternal ageThe incidence451:50Average1:650Maternal AgeThe risk increases with the maternal ageNormalThe genes of chromoso

5、me 21:what do we know?There are more than 400 genes on chromosome 21(we used to think there were fewer)Of these,170 code for proteins that are also encoded by genes in mice and other animalsWhen genes are conserved across species,it is typically because they are importantChromosome 21 proteinsAre pr

6、edicted to directly and indirectly affect learning and memory in Down syndrome byPreventing estrogen from entering brain cells(low estrogen in brain can promote early menopause and Alzheimer disease)Reducing substances that allow cells to communicate with one anotherReducing brain cell survival in t

7、he adultStudying chromosome 21 genes across species allows us toUnderstand the roles of these genes in normal development and functionLearn how the proteins encoded by these genes interact with other proteins in the bodyPredict ways in which the extra information encoded by these genes can be“turned

8、 down”or“turned off”by medications,gene therapy,etc.2Types of Down Syndrome Trisomy 21(92%95%)MMoossaaiicc DDoowwnn S y nnddrroommee(2.5%5%)Translocation Trisomy 21(2%4%)Trisomy 21Found in 92%of all DS individualsCaused by nondisjuction in meiosis,causing eggs to have trisomy 21Increases in incidenc

9、e with maternal age,but also found in younger mothersChildren born immediately after DS children have a higher chance of also having DS,however,for other siblings,the risk for having DS does not increaseNondisjunctionMosaic DS2-4%of the DS populationStarts off with 23 pairs of chromosomes in each ce

10、llError occurs in an early cell divisionDuring embryonic development,a random cell will acquire trisomy 21,creating 2 individual cell lines(normal and trisomatic)The earlier the mutation occurs,the more profound the effectsMosaic DSTranslocation DS3-4%of the DS populationA Robertsonian translocation

11、 occurs when one chromosome 21 attaches to another chromosome,forming a single new,chromosomeThe recipient chromosome is usually chromosome 14 and the combination of the 2 chromosomes is called a fourteen,twenty one translocationCan also switch with 13,15,or 223Translocation DSAbout of Translocation

12、 DS is inheritedThe parent is then called a translocation carrierParent has one normal copy of 21 and one copy of 21 attached to another chromosomeBoth copies are then passed onWhen fertilization occurs,embryo contains both copies of 21 from the carrier parent,and the normal one copy or 21 from the

13、normal parentEffects are similar to Trisomy 21 DSTranslocation DSRobertsonian TranslocationsCan result in Down syndromeClinical Featuresmental retardation growth failure characteristic faciesdermatoglyphic abnormality other malformationsDept.of Pediatrics,Tongji Hospital,HUSTFacial CharacteristicsQ

14、head and face Q eyeQ noseQ mouthQ earQ othersDept.of Pediatrics,Tongji Hospital,HUSTDermatoglyphic Abnormality50%palmar flexion creases like simian linenormalSimian crease transitional transitional Sydney typetype Itype IIDept.of Pediatrics,Tongji Hospital,HUST4Dermatoglyphic AbnormalityAxial trirad

15、ius of palm moves to the center Atd angle increasesadtNormal Normal atd41atd41DSDSs s atdatd5858Dept.of Pediatrics,Tongji Hospital,HUSTMedical Complications Epilepsy Hypothyroidism Crossed eyes Cataracts Hearing impairment Heart defects Childhood leukemia is 20%more common Hernias Sterility in males

16、 Females are fertile but can pass on DS Accelerated Aging with high chance of Alzheimers disease196819741983-81988New Test for Down Syndrome?1959196619331990Screening milestonesTrisomy 21 identified as cause of Down SyndromeFirst chromosomal analyses from amniotic fluidAssociation between maternal a

17、ge and Down syndromeTriple test introducedMaternal serum markers for Down syndromeNuchal translucency introduced196819741983-819881959196619331990Prenatal diagnosis of Down syndromeRaised AF-AFP associated with NTD1864Langdon-Down first description of the clinical features of“mongolism”Noninvasive p

18、renatal screening for DSDecember 1,2008 Sequenom,Inc.announced results from a collaborative study with The Chinese University showing that it is preliminarily possible to diagnose Down syndrome on a blood sample taken from expectant mothers during the first and second trimesters of pregnancy.-The me

19、thod uses technology that extracts fetal RNA from maternal blood.-Study is being launched to evaluate up to 10,000 pregnancies at increased risk for DSNoninvasive test(cont.)At first,women with positive screens will ssttiillll uunnddeerrggoo chorionic villi sampling (CVS)or amniocentesis to confirm

20、results,but the hope is that the new test will ultimately replace both.There is some concern that this testing will be marketed/in demand before sufficient studies are completed to prove accuracy.5Noninvasive test(cont.)Researchers at Stanford have published preliminary results on a maternal blood-b

21、ased DS screen that uses a different technology than SequenomOther companies are also working on noninvasive testsTreatmentNo effective treatments Education and training Correct the malformation Prevent infectionsDrugsDept.of Pediatrics,Tongji Hospital,HUST196819741983-81988Alternative Therapies for

22、 Children with Down Syndrome1959196619331990Alternative therapies-history1960s:Henry Turkel claimed that a mixture of 48 ingredients could improve the intelligence of children with DS,which he administered to his patients for more than 40 years.No double-blind study was ever performed.No evidence em

23、erged that this was beneficial.Alternative therapies history (cont.)1980s:Ruth Harrell,and associates reported that supplementary vitamins and minerals and thyroid hormone improved IQ scores and normalized physical appearance in children with mental deficiency.Reportedly,3 children with DS showed th

24、e best results.The study was not performed scientifically,and 7 studies performed in the next decade using this mixture showed no benefit.Alternative therapies history (cont.)1980s:HapsCaps,another mixture of vitamins,minerals,and supplements was promoted through traveling clinics run by Jack Warner

25、,MD,of California6Alternative therapies history (cont.)1995:ABC-TVs“Day One”promoted a formula created by Dixie Lawrence Tafoya,owner/operator of an adoption agency specializing in finding homes for special needs children.Her formula was based on Turkels formula but had more ingredients.Subsequently

26、,piracetam was added.Dixie Lawrence(cont.)Arranged for her formula to be produced by Nutri-Chem Labs in Canada(MSB Plus)1996-Lawrence withdrew support from Nutri-Chem and began promoting NuTriVene-D marketed by International Nutrition in Baltimore(MSP Plus is made there,also)The latestChanging Minds

27、 Foundation*is promoting a “new treatment for Down syndrome”that leads to“life changing results.”Treatment includes regular doses of fluoxetine(Prozac),Dexmethylphenidate (Focalin XR),and ginkgo biloba as well as “Body Bio Balanced Oil”and folinic acid.What are these drugs?Ginkgo biloba(GB)an herb t

28、hat has been used medicinally for millennia,GB is a GABA antagonist.Supporters of its use in DS say that it promotes improved memory.No controlled studies have been done in animals or humans to establish safe doses or to prove a benefit.Fluoxetine(Prozac)an antidepressant that in DS mice increased t

29、he growth of new nerve cells.Not replicated in humans and can do harm to fetuses.What are these drugs?(cont.)Dexmethylphenidate(Focalin XR)a stimulant medication used to treat ADHD.Its use should be carefully considered in children with heart defects,and it is not recommended in babies and young chi

30、ldren.Folinic acid has vitamin activity similar to folic acid(B vitamin)and has been proven to have no significant effect on development in children with DSWhat isBody Bio Balanced Oil*per the Changing Minds Foundation,“There is a growing body of evidence that inflammation and degeneration go hand i

31、n hand.This oil provides the body with building blocks to reduce inflammation and improve health.”*$26.35 for 180 softgels for non-members7DiagnosisClinical manifestations：Final diagnosis：karyotyping of peripheral blood lymphocytePrenatal diagnosis：karyotyping of chorionic cells Triple screening tes

32、ts:AFP,FE3,HCGDept.of Pediatrics,Tongji Hospital,HUSTPreventionThree levels of prevention by WHO primary：pathogenesis secondary：delivery tertiary：early diagnosis and therapyDept.of Pediatrics,Tongji Hospital,HUST100 base pairs105109CGH and MLPADNA sequencingFISHChromosome bandingLive,dividing cells

33、Screen all chromosomes TAT 2 4 weeks Labour intensiveAny tissueTest specific regions TAT 72 hoursCan be automatedCHROMOSOMESDNAShort tandem repeats(STR)STR=microsatellite markers10 000s across genomeStretches of DNA of units of 2-4 nucleotidesTGTGTGCAACAA.CAADifferent alleles exist for each STR in p

34、opn.Each allele differs in repeat lengthQuantitative fluorescent PCR aneuploidy screen(QF-PCR)Principle:Test STR markers on chromosomes4-5 on autosomes of choice(13,18,21)Fewer on X and YUsed to detect numerical chromosome abnormalitiesCan test blood,amniotic fluid,CVS,post-mortem tissue etc.8QF-PCR

35、AdvantagesRapid result(48 72 hours)99%accuracyNo live cells requiredDisadvantagesWont detect mosaicism(30%)Wont detect other chromosome abnormalitiesMechanism of aneuploidy remains unknownBlood-stained amnio may make testing impossibleRisk of maternal contamination if CVS not carefully prepared/diss

36、ectedPast Pre-and postnatal testing for DS by karyotypingPrenatal testing for DS in AMA women by QF-PCRPostnatal testing for DS by karyotypingJanuary 2007 May 2008 563 requests for DS testingPast Pre-and postnatal testing for DS by karyotypingPrenatal testing for DS in AMA women by QF-PCRPostnatal t

37、esting for DS by karyotypingJanuary 2007 May 2008 563 requests for DS testing307 confirmed DS(54.5%)+79 confirmed DSon specimens not requested as DS=386 confirmed DS185 not DS(33%)67 no result4 other chromosome abnormalitiesPast Pre-and postnatal testing for DS by karyotypingPrenatal testing for DS

38、in AMA women by QF-PCRPostnatal testing for DS by karyotypingJanuary 2007 May 2008 563 requests for DS testing307 confirmed DS(54.5%)+79 confirmed DSon specimens not requested as DS=386 confirmed DS185 not DS(33%)67 no result366 trisomy95%6 mosaic1.5%14 translocation3.5%4 other chromosome abnormalit

39、iespresentIndication for DS testingPrenatal testing for DS in AMA women by QF-PCRPostnatal testing for DS by QF-PCRConfirmed DS98%RRrelates to trisomy2%RR relates to inherited translocationOffer parental karyotypepresentIndication for DS testingPrenatal testing for DS in AMA women by QF-PCRPostnatal

40、 testing for DS by QF-PCRConfirmed DSNegative QF-PCRStrongly suspect DS?mosaicDysmorphic features Unknown diagnosisRequest karyotypeRefer to Genetics98%RRrelates to trisomy2%RR relates to inherited translocationOffer prenatal testing and/or parental karyotype if recurrence risk perceived as highGene

41、tic counselling9Baby with multiple congenital abnormalitiesStillbornMaceratedSkin snip (saline)QF-PCR T13,18,21,X,YRefer to GeneticsAliveBaby with multiple congenital abnormalitiesStillbornAliveFresh SBMaceratedSkin snip (saline)QF-PCR T13,18,21,X,YKaryotypeCardiac blood(heparin)Skin snip(saline)Ref

42、er to GeneticsBaby with multiple congenital abnormalitiesStillbornAliveFresh SBMaceratedSkin snip (saline)MCA-unknownQF-PCR T13,18,21,X,YSuspect trisomy 13 or 18KaryotypeBlood (EDTA)Blood (heparin)KaryotypeQF-PCRNegative PositiveRefer to GeneticsCardiac blood(heparin)Skin snip(saline)Mortality/MorbidityMortality25-30%die during the first year of lifeThe most frequent causesrespiratory infections congenital heart diseaseDept.of Pediatrics,Tongji Hospital,HUST10