1、染色體異常鄭博仁副教授 人類正常染色體組成於1956年正式確立,第一批染色體異常(Downs，Tunners，Klinefelters症候群)則定義於1959年。自此，由於培養與檢驗之遺傳科技日益精進，因染色體異常導致的數百種異常也逐一被發現。三倍體 17Nail hypoplasiaFetal wastage(95%)Hyotonia,followed by hypertonia,apnea,seizuresMicrophthalmia死胎 5Chromosome typesWilliams SyndromeMultiple pigmented neviDS:Major Malformati
2、onsSlanting palpebral fissures,small dysplastic ears,flattened faciesSkeletal anomalies:polydactyly,talipes equinovarusMales in institutions for the mentally retarded-1/100Advanced maternal age effectCub foot,cataracts,imperforate anus,cleft lip/palateMCA/MR caused by an extra copy of 18Otherwise no
3、rmal phenotype5-10%(parental translocation)Round face,hypertelorism,epicanthal folds,downward slanting of palpebral fissuresMicrocephaly,bitemporal depression,long philtrum,thin upper lip,mild micrognathia,ear dysplasia,anteverted nares定義：?整倍體（Euploid）染色體數目是單倍體的倍數 （2n）?多倍體（Polyploid）染色體數目超過二倍體（3n,三倍
4、體）?非整倍體（Aneuploid）染色體數目非單倍數的倍數 （2n1三體症，2n1單體症）?嵌合體（Mosaic）出現來自同一配子的二種不 同細胞來源（46XX/45X，Turners嵌合體）?交移體（Chimaera）出現來自二個配子融合形成 的二種不同細胞來源 （46XX/46XY，真性陰陽人）染色體報告形式?染色體總數後列出性染色體形式46,XX ，正常女性47,XXY ，Klinefelters症男性47,XXX ，三X症女性?增加或缺少的染色體以”或”表示 47,XY,21 ，21三染色體男性（Downs症）46,XX,12 p ，12染色體短臂多出一段不明染 色體?嵌合體列出所有
5、的細胞來源46,XX/47,XX,21 ，Downs嵌合體症46,XY/47,XXX/45,X ，Turnes/三X嵌合體症?描述構造上的異常，指出p，q及異常的部位46,XY,del 11(P13)11染色體短臂的13顯帶處缺失46,XX,t(X;7)(P21;q23)X與7染色體在P21及q23顯帶處 裂開而移位自然流產及死胎的染色體異常發生率%自然流產 所有 50 12週以內 60 1220週 20死胎 5Otherwise normal phenotypeHypercalcemia/hypercalcinuriaHirschprung diseaseTranslocation tris
6、omy(4%)Proportionate short statureKlinefelter Syndrome:HypogonadismThree active X chromosomes early in embryonic development(prior to X inactivation)Two of the three X chromosomes are inactivated.Advanced maternal age effectMicro/retrognathiaDeletion of a WH probe signalMicrocephalyMales in institut
7、ions for the mentally retarded-1/100Klinefelter Syndrome:BackgroundDel(5p)syndromeAbsent secondary sex characteristicsDel(5p)syndromeMultiple pigmented nevi47,XXX(1/1,000 female births)Microcephaly,trigonocephaly,glabellar hemangioma,punched-out scalp lesionThe great majority(99%)of 45,X conceptus a
8、re lost prenatally.自然流產的染色體異常種類%三體症 52X 單體症 18三倍體 17移位 2-4新生兒染色體異常比例%所有 91常染色體三體症 14常染色體重組 平衡性 52 非平衡性 6性染色體異常 19常見的染色體異常常染色體 21三體症Downs症 18三體症Edwards症 13三體症Pataus症性染色體 XO Turners症 XXX 三X症 XXX Klinefelters症 XYY XYY男性Down Syndrome(Trisomy 21)唐氏症(蒙古痴呆症)MCA/MR caused by an extra copy of chromosome 21 F
9、irst described by Langdon Down in 1866 Discovery of +21 by Lejeune in 1959DS:Epidemiology Incidence:1/800 to 1/1,000 live births Prevalence:1/3,000 in general population,reflecting high infant mortality rate Advanced maternal age effectDS Fetuses:Natural History Highly lethal in fetal life(65%of con
10、ceptuses aborted)Recognizable fetal phenotype:IUGR,thickened nuchal fold,septal cardiac defects,duodenal atresia,simian crease,clinodactyly,&short cord Decreased motor activityPsychosocial/behavioral problemsDel(7)(q11.Psychosocial/behavioral problemsAntimongoloid slantTrisomy 13(Patau Syndrome)Hirs
11、chprung diseaseGenu valgumFISH:Trisomy 21Mosaics or translocations(20%)Abnormal finger grasping pattern,increased digital arches,rocker-bottom feet,short sternumMother with 21/22 carrier-6%46,XY/47,XXY(15%)染色體總數後列出性染色體形式46,XX ，正常女性47,XXY ，Klinefelters症男性47,XXX ，三X症女性Deletion of 4pIncidence in male p
12、rison populations(1/30)Trisomy 18 fetusDe novo(90%)所有 50Abnormal earsShort philtrumWHS KaryotypeTranslocation trisomy(4%)Cardiac/genitourinary/skeletal anomaliesDel(4p)syndromeEpicanthal foldsKlinefelter Syndrome:HypogonadismCardiac/genitourinary/skeletal anomaliesDistinct finger grasping patternDel
13、(7)(q11.69,XXY(60%)Absent secondary sex characteristicsEpicanthal foldsProtruding tongueShort philtrumRecurrence risk-not increasedHypercalcemia/hypercalcinuriaLearning/speech disabilitiesTriploidy is a frequent cause of fetal wastage(20%)during 1st/2nd trimester.Most frequent sex chromosome abnorma
14、lity present at birth in femalesFemale type distribution of pubic hairXYY SyndromeMost cases(de novo)DS:Cardinal Signs Hypotonia Sloping forehead,brachycephaly Slanting palpebral fissures,small dysplastic ears,flattened facies Excess nuchal skin Simian crease with dysplastic middle phalanges of 5th
15、finger Hyperextensible joints Dysplastic pelvis DS:Infant Sloping forehead Upslanting eyes Epicanthal folds Flat nasal bridge Small nose Protruding tongue Small chin Small ears Proximated nipplesDS Brachycephaly Sloping forehead Woolley sign Flat nasal bridge Small nose Protruding tongue Cutis mamor
16、ata DS child Upslant eyes Brushfield spots Epicanthal folds Flat nasal bridge Small nose Open mouth Protruding tongue Small chin Small earsDS Ear Typical DS small ear Overfolded helixDermatoglyphicsDS Hand Transverse palmar crease(simian crease)Clinodactyly DS:Adult MR Upslanting eyes Mid-facial hyp
17、oplasia Mandibular prognathismDS:Major Malformations Congenital heart disease(29%of newborn;64%of necropsies)AV canal/endocardial cushion defect(most common),VSD,ASD,TOF,PDA,others Duodenal obstruction(2-3%)Hirschprung disease Others Cub foot,cataracts,imperforate anus,cleft lip/palateDS:Growth&Deve
18、lopment Developmental delay(MR)Atlantoaxial joint instability Males:Infertile due to testicular interstitial fibrosis and hypoplasia of seminiferous tubules Females:about 1/2 of offspring with Down syndromeDS:Immune System&Aging Increased incidence of hypothyroidism,thyroiditis,diabetes mellitus,and
19、 leukemia(10-to 30-folds)Depressed immune system Premature aging(Alzheimer)47,XYY SyndromeSecondary sexual characteristicsCardiac/genitourinary/skeletal anomaliesGenu valgumXO Turners症Microcephaly69,XYY(99%)of 45,X conceptus are lost prenatally.MicrocephalyTurner Syndrome:EpidemiologyPremature aging
20、(Alzheimer)A common cause of primary hypogonadism in malesRound face,hypertelorism,epicanthal folds,downward slanting of palpebral fissuresShort philtrumMost die within 1st few days of life.Abnormalities may result from:Incidence:1/2,500-1/5,000 liveborn females%MCA/MR caused by an extra copy of 18T
21、ranslocation trisomy(4%)Cubitus valgus性染色體異常 19Trisomy 21 Karyotype活產及羊膜穿刺檢查唐氏症發生率孕婦年齡(生產時 活產發生率 羊膜穿刺術發生率或羊膜穿刺術時)所有年齡 650分之1 30歲 900分之1 35歲 385分之1 256分之1 36歲 305分之1 200分之1 37歲 240分之1 156分之1 38歲 190分之1 123分之1 39歲 145分之1 96分之1 40歲 110分之1 75分之1 44歲 37分之1 29分之1 I(21q)KaryotypeFISH:Trisomy 21DS:Cytogenet
22、ic Basis Full trisomy(94%)Translocation trisomy(4%)Translocation between 21&other chromosome Mosaic trisomy(2%)Most commonly due to maternal non-disjunction(95%by molecular studies)21q22 to qter is responsible for the phenotypeDS:Genetic Counseling(Recurrence Risk)Full trisomy 21(irrespective of mat
23、ernal age)-1%Siblings,nieces,nephews,a aunts,or uncles of the proband with trisomy 21 probably no increased risk Mother with balanced D/G translocation-10%Father with balanced D/G translocation-4%Mother with 21/22 carrier-6%Father with 21/22 carrier-3%Parent with 21/21 carrier-100%A DS child with de
24、 novo translocation-1%Deletion of a WH probe signal所有年齡 650分之1Turner Syndrome:Cytogenetic BasisDel(5p)syndromeTrisomy 18(Edwards Syndrome)45,X represents 15-20%of chromosome abnormalities seen among spontaneous abortions.Woolley signSevere cystic hygromaEach additional X chromosome is accompanied by
25、 increased mental retardation&physical abnormalitiesGrowth Chart for Turner SyndromeMicrophthalmia嵌合體（Mosaic）出現來自同一配子的二種不 同細胞來源（46XX/45X，Turners嵌合體）Prevalence:one in 2,500-10,000 femalesFull trisomy 21(irrespective of maternal age)-1%Overfolded helixGrowth hormone therapy染色體總數後列出性染色體形式46,XX ，正常女性47,
26、XXY ，Klinefelters症男性47,XXX ，三X症女性Epidemiology:1/3,000 live birthsDescribed by Turner in 1938Renal/GI anomalies(cystic kidneys;TE fistula)Objectives:Students are required to study and understand羊膜穿刺判讀錯誤羊膜穿刺判讀錯誤 新光判賠七百多萬新光判賠七百多萬 婦人朱秀蘭高齡懷孕，到台北新光醫院作羊膜穿刺篩檢，因醫院僱用非專業的檢驗員判讀資料錯誤，致生下患有唐氏症的男孩，朱女經過八年訴訟，最近獲得確定勝訴
27、判決，最高法院前天判決新光醫院應賠償朱女七百廿五萬餘元。Trisomy 18(Edwards Syndrome)MCA/MR caused by an extra copy of 18 Epidemiology:1/3,000 live births Natural history:Fetal wastage(95%)Intrauterine growth retardation Polyhydramnios Small placenta with single umbilical artery 90%die before 1 year of age Severe growth and men
28、tal retardationTrisomy 18:Cardinal Signs Hyotonia,followed by hypertonia,apnea,seizures Microcephaly,prominent occiput Hypertelorism,epicanthal folds,microphthalmia,iris coloboma,micro/retrognathia,low set/malformed ears,choanal atresia Cardiac defects(polyvalvular,VSD)Renal/GI anomalies(cystic kidn
29、eys;TE fistula)Abnormal finger grasping pattern,increased digital arches,rocker-bottom feet,short sternumInfant with trisomy 18 Microcephaly Hypertelorism Microphthalmia Micro/retrognathia Low set,malformed ears Short sternum Abnormal finger grasping patternTrisomy 18 fetus Arthrogryposis Distinct f
30、inger grasping patternTrisomy 18 Arthrogryposis Abnormal finger grasping pattern Nail hypoplasia Increased number of digital archesTrisomy 18 Rocker-bottom feetTrisomy 13(Patau Syndrome)Epidemiology:1/6,000 live births Cytogenetics:Full trisomy(80%)Mosaics or translocations(20%)Natural history:90%di
31、e before 1 year of ageFTT,hypotonia,deafness,seizuresSevere psychomotor retardationTrisomy 13:Cardinal Signs Craniofacial:Microcephaly,trigonocephaly,glabellar hemangioma,punched-out scalp lesion Hypertelorism,anophthalmia/microphthalmia,coloboma of iris/retina,cleft lip/palate,micro/retrognathia CN
32、S:holoprosencephaly spectrum Cardiac/renal/GI anomalies:VSD,multicystic kidneys,omphalocele Skeletal anomalies:polydactyly,talipes equinovarusTrisomy 13 Microcephaly Microphthalmia Cleft lip/palate Holoprosencephaly Short neck Polydactyly86Trisomy 13 Infant with trisomy 13 Scalp defect PolydactylySe
33、x Chromosome Anomalies Turner syndrome Klinefelter syndrome Trisomy X syndrome XYY syndromeTurner Syndrome Described by Turner in 1938 Prevalence:one in 2,500-10,000 females Phenotypic female Proportionate short stature Normal intelligence Sexual infantilism&ovarian dysgenesisTurner Syndrome:Sexual
34、infantilism&ovarian dysgenesis The ovaries develop normally until the 15th week of gestation,but then ova begin to degenerate and disappear,so that at birth they are represented by streaks Primary amenorrhea(exception 5%)Infertility Absent secondary sex characteristics Low estrogen High gonadotropin
35、sTurner Syndrome:Characteristic Facies Antimongoloid slant Ptosis Strabismus High-arched palate Posteriorly rotated earsTurner Syndrome:Lymphatic Obstruction Webbed neck Low posterior hair line Redundant skin on the nape Cystic hygroma Rotated ears Lymphedema of hands/feet Nail hypoplasiaTurner Synd
36、rome Short neck Webbed neck Low posterior hair line Abnormal earsTurner Syndrome:Fetus Severe cystic hygromaTurner Syndrome Lymph edema Nail hypoplasiaTurner Syndrome Nail hypoplasiaTurner Syndrome:Skeletal Features Short stature Short neck Cubitus valgus Short metacarpals Madelung deformity Scolios
37、is Genu valgumGrowth Chart for Turner SyndromeTurner Syndrome:Miscellaneous Defects Shield-like chest,increased inter-nipple distance(optical illusion in some cases)Multiple pigmented nevi Cardiovascular anomalies/hypertension(COA most common)Renal anomalies Horse-shoe/ectopic/absent kidney Ureteral
38、 duplications)Hearing lossTurner Syndrome:Chest Shield-like chest Increased inter-nipple distanceTurner Syndrome:Associated Disorders Hashimoto thyroiditis Hypothyroidism Crohn disease Gastrointestinal bleeding(telangiectasia)Turner Syndrome:Epidemiology Incidence:1/2,500-1/5,000 liveborn females 45
39、,X represents 15-20%of chromosome abnormalities seen among spontaneous abortions.The great majority(99%)of 45,X conceptus are lost prenatally.Many chromosomal mosaicism or confined placental mosaicism do survive to term.Turner Syndrome:Karyotype(45,X)Monosomy X:Mechanism Monosomy X arises from non-d
40、isjunction 80%of cases have only maternal X chromosome,an error occurred in spermatogenesis or post-fertilizationTurner Syndrome:Cytogenetic Basis Karyotypes 45,X(50%)Mosaics(30-40%)Iso(Xq),r(X),iso(Xp)In general,del(Xp)is associated with the Turner phenotype,whilst del(Xq)alone produce streak ovari
41、es without the associated dysmorphic features(Turner stigmata)Turner Syndrome:Management Psychosocial approach Webbing resection(cosmetic)Sex hormone replacement Secondary sexual characteristics Stature Growth hormone therapy Stature Genetic counseling Recurrence risk-not increasedKlinefelter Syndro
42、me:Background In 1942,Klinefelter et al.reported 9 men who had:Enlarged breasts Sparse facial and body hair Small testes Inability to produce sperm In 1959,men with Klinefelter syndrome were discovered to have 47,XXY.Klinefelter Syndrome:Epidemiology Incidence Birth 1/1,000 male births Males in inst
43、itutions for the mentally retarded-1/100 Infertile males-1/10 Chromosome types 47,XXY(majority)46,XY/47,XXY(15%)48,XXXY,48,XXYY 49,XXXXY,49,XXXYYKlinefelter Syndrome:KaryotypeKlinefelter Syndrome:Growth/Development Tall with disproportionately long arms/legs Poorly developed secondary sex characteri
44、stics Learning/speech disabilities Psychosocial/behavioral problems Subnormal intelligenceKlinefelter Syndrome:A Child Slightly long arms and legs Otherwise normal phenotypeKlinefelter Syndrome:Hypogonadism A common cause of primary hypogonadism in males Gynecomastia(1/3),with increased risk for bre
45、ast cancer(20X)Small testes(10 ml),sterility(most patients),secondary to atrophic seminiferous tubulesKlinefelter syndrome:GynecomastiaKlinefelter Syndrome:External Genitalia Female type distribution of pubic hair Testicular dysgenesisKlinefelter syndrome:Management Androgen therapy(testosterone inj
46、ection)for hypogonadism Mastectomy for gynecomastia Multidisciplinary team approach Speech impairments Academic difficulties Psychosocial/behavioral problems Genetic counseling Recurrence risk-not increasedTrisomy X Syndrome First described by Jacobs et al.in 1959 Most frequent sex chromosome abnorm
47、ality present at birth in females 47,XXX(1/1,000 female births)Triple X Syndrome:Origin Most 47,XXX conceptions result from maternal nondisjunction at meiosis I(AMA).Two of the three X chromosomes are inactivated.Abnormalities may result from:Three active X chromosomes early in embryonic development
48、(prior to X inactivation)Genes on the X chromosome that escape inactivationTriple X Syndrome:Phenotype Benign phenotype Physically normal Late puberty Menstrual irregularity Majority are fertile Sterility Mild mental retardation(15-25%)Trisomy X:Karyotype(47,XXX)Triple X Syndrome Slender body habitu
49、sTriple X Syndrome:Genetic Counseling A small but slightly increase risk of XXX daughter or XXY son of an XXX mother Recurrence risk not increased unless mother is a 47,XXX or mosaic Pertinent to offer prenatal diagnosisPoly X Syndromes Females with 4 or 5 X chromosomes Each additional X chromosome
50、is accompanied by increased mental retardation&physical abnormalities 48,XXXX 49,XXXXX47,XYY Syndrome Incidence:one in 1,000 males Arise through nondisjunction at paternal meiosis II Incidence in male prison populations(1/30)XYY Karyotype47,XYY Syndrome Normal birth length and weight Tall when older
