四川大学学报(医学版)J Sichu an U niv(Med Sci Edi)　2010;41(2):312-315 胎儿染色体异常与不同先天性心脏病的关系研究3张 ,张晓红,任梅宏,宋桂宁北京大学人民医院产前诊断中心(北京100044) 【摘要】　目的　通过分析产前诊断中确诊的染色体异常并伴有先天性心脏病畸形患儿相关资料,总结心脏畸形不同分类和染色体异常的关系及比率,为探讨先天性心脏病病因、提高先天性心脏病产前诊断率提供理论依据。

方法　回顾性分析2006年1月至2009年12月间北京大学人民医院产前诊断中心确诊的染色体异常并伴有先天性心脏畸形病例资料,综合分析先天性心脏病畸形分类和染色体异常的关系及比率。

结果　49例染色体异常伴先天性心脏畸形患儿中,212三体11例,182三体6例,132三体6例,142三体1例,162三体3例,82三体1例,222三体1例,46,XY/XX,5p-2例,易位型部分三体8例,性染色体异常8例,三倍体2例。

相同的染色体异常可伴有不同的心脏畸形及心外畸形,同样的心脏畸形可存在不同的染色体异常。

结论　染色体异常可伴有众多基因的增加或减少,可同时伴有多种心脏或心外畸形,不同染色体异常伴发心脏畸形的类型及比率也各不同。

超声提示胎儿心脏畸形者,应进一步行产前细胞遗传学诊断以排除染色体异常,避免染色体异常综合征患儿出生。

【关键词】　先天性心脏病　染色体异常　产前诊断　羊水穿刺　脐带血穿刺【中图分类号】　R714.252Chromosome Abnorm alities and Congenital H eart Diseases:A R etrospective Study on49C ases　Z HA N G L in, Z HA N G X iao2hong,R EN Mei2hong,S O N G Gui2ning.　T he Center of Prenatal Diagnosis,B ei j ing Universit y People’s Hos pital,Beijing100044,China【Abstract】　Objective　To investigate the association between congenital heart diseases and chromosome abnormalities.Methods　Patients with congenital heart diseases who underwent chromosome examinations during J an2006and Dec2009in the Center of Prenatal Diagnosis of Beijing University People’s Hospital were recruited in the study.The association between chromosome karyotypes and types of congenital heart diseases was analyzed.R esults　Among the49patients with congenital heart diseases,trisomy21was established in11cases,trisomy18 in6cases,trisomy13in6cases,trisomy14in1cases,trisomy16in3cases,trisomy8in1cases,trisomy22in 1cases,sex chromosomal abnormalities in8cases,triploid in2cases,partial chromosomal trisomy in8cases,and 46,XX/XY,5p-in2cases.Conclusion　Chromosome abnormalities are associated with congenital heart diseases.Different abnormal chromosome karyotypes contribute to different types of congenital heart diseases.Prenatal chromosome examinations could be undertaken to detect congenital heart diseases.【K ey w ords】 Congenital heart disease Chromosome karyotype Prenatal diagnosis Amniocentesis Umbilical cord blood collection 先天性心脏病(congenital heart disease,CHD)是目前最常见的先天性畸形,约占出生缺陷疾病的1/3,在足月活产新生儿中发病率为4‰～8‰,在早产、死产或流产中的发病率更高,是目前婴幼儿死亡的首要原因[1,2]。

C HD为一种多基因遗传病,由于胚胎期遗传和环境因素导致某些基因在时间或空间的表达和相互作用出现异常,影响胎儿心脏发育导致CHD的发生[3-10]。

从遗传学和临床学角度对CHD进一步研究和总结,必将会对该病的认识、诊断和治疗达到一个新的水平。

现对2006年1月至2009年12月北京大学人民医院产前诊断中心产前3北京大学人民医院发展基金(RDP2008210)资助确诊的49例染色体异常伴先天性心脏畸形患儿,综合分析其心脏畸形分类及染色体异常的关系,报道如下。

1　对象与方法1.1　对象北京大学人民医院产前诊断中心B超提示胎儿为CHD伴或不伴心外畸形的孕妇,根据孕周不同,分别采用羊水穿刺和脐带血取样采集标本,行产前细胞遗传学诊断胎儿染色体核型。

继续妊娠者追踪妊娠结局并在新生儿出生后进一步超声诊断,终止妊娠者行胎儿尸体解剖,所有C HD病例均为确诊病例。

孕妇年龄22～49岁,平均年龄为33.83　J Sichuan Univ(Med Sci Edi)Vol.41No.22010 岁;丈夫年龄34～50岁,平均年龄为36.89岁;平均孕周为32+4周。

1.2　方法患者知情同意并签署知情同意书后,在超声引导下分别采集羊水和脐带血标本,培养、分析胎儿染色体核型,总结胎儿CHD不同类型与染色体核型异常的比例关系和胎儿心脏及心外畸形与不同染色体异常的发病比例。

1.2.1　羊水细胞检测(孕中期)　妊娠16～28周,取羊水20mL(最初取出的1～2mL羊水弃去), 1000r/min离心10min,弃上清,留2.5～3.0mL 细胞悬液,无菌条件下分别接种于5mL G ibco和以色列两种羊水专用培养基中,置于37℃含5%CO2的培养箱中静置培养6～7d,用培养液换液后每天观察细胞生长情况。

当羊水细胞贴壁生长旺盛、倒置显微镜下可见多个克隆、有较多中期分裂细胞时进行收获,以G带染色(必要时加做C带染色)制备染色体标本,每例标本按照ISCN(1985)标准,油镜下分析30个分散好、中等长度的中期分裂相,发现嵌合体或异常核型时加数到100个分裂相。

1.2.2　胎儿脐静脉血检测(孕中晚期)　妊娠16周至37周,经腹取脐静脉血1.5～2mL(肝素抗凝),首先用1/12mol/L NaO H鉴定取出的是否为胎儿血,确定为胎儿血后再接种于5mL1640培养基中(20～30滴血即可),37℃培养72h,收获、制备染色体标本,分析、计数标准同羊水细胞。

2　结果确诊的49例染色体异常伴C HD病例中,三体征29例,占所有异常59.18%,其中212三体11例, 182三体6例,132三体6例,142三体1例,162三体3例,82三体1例,222三体1例,46,XY/XX,5p-2例;易位型部分三体型8例,占所有异常16.33%;性染色体异常8例,占所有异常16.33%;三倍体2例,占所有异常4.08%。

212三体以心内膜垫缺损、瓣膜病变、室间隔缺损、主动脉肺动脉异常等为主,且72.73%同时存在心外畸形;182三体以室间隔缺损、单心房、单心室及瓣狭病变等为主,且66.67%同时存在心外畸形;132三体以室间隔缺损、房间隔缺损、二尖瓣返流、大动脉转位或狭窄、单心房、单心室等为主,且100%同时存在心外畸形;162三体以单心房、单心室、法乐四联症为主,且100%同时存在心外畸形;8例较为罕见的易位型部分三体患儿存在心内膜垫缺损、室间隔缺损、房间隔缺损、单心房、单心室、主动脉狭窄、动脉导管未闭、永存动脉干、右位心、右心发育不良、法乐四联征等心脏畸形,且100%同时存在心外畸形;性染色体异常以房间隔缺损、室间隔缺损和瓣膜病变为主,且87. 50%同时存在心外畸形;三倍体以心内膜垫缺损、大动脉转位、肺动脉主干缺如、永存动脉干等心脏异常为主,且50%同时存在心外畸形;46,XY/XX,5p-2例,以房间隔缺损、室间隔缺损、瓣膜异常等为主,且100%同时存在心外畸形。

详见附表。

附表　胎儿先心病与染色体异常的关系T able　The association bet w een congenital heart diseases and chromosome abnorm alitiesChromosome karyotypeof fetus CaseType ofheart diseasesType of ot herorganic malformation47,XX,+211Endocardial cushion defect s None47,XY,+211Endocardial cushion defect s Absence of nosebone,hypertelorism47,XX,+211Tricuspid valve backstreaming Nuchal translucency t hickening47,XX,+211Tricuspid valve backstreaming None47,XY,+211Ventricular septal defect,aorta saddle,pulmonary artery atresia and truncus arteriosusAbsence of nosebone and hypertelorism47,XY,+211Tetralogy of Fallot and double outlet rightventricleNone47,XY,+211Int racardiac echogenic focus Bilateral nephrauxe47,XX,+211Tetralogy of Fallot Nuchal translucency t hickening46,XX,t(15;21)1Endocardial cushion defect s Microcephaly46,XY,t(14;21)1Ventricular septal defect Absence of nosebone46,XX,t(14;21)1Tetralogy of Fallot Nuchal translucency t hickening and duodenalechogenic focus47,XY,+181Double outlet right ventricle,pulmonary arterystraitness and endaorty dilatation,ventricularseptal defectSpecial fist and t he foot of Edward syndrome47,XY,+181Single ventricle and single atria and ventricularseptal defect,mitral stenosi None313 四川大学学报(医学版)2010年第41卷第2期　(续附表)Chromosome karyotypeof fetus CaseType ofheart diseasesType of ot herorganic malformation47,XX+181Right isomerism,double outlet right ventricleand Absence of nosebone Absence of nosebone and bilateral cleft lip and palate47,XY,+181Single ventricle and single atria,transpositionof t he great arteriesNone47,XX+181Ventricular septal defect Bilateral cleft lip and widened lateralventricles47,XX+181Ventricular septal defect and patent ductusarteriosus Fetal growt h rest riction and bilateral choroid plexus cyst s47,XX,+131Patent ductus arteriosus and ventricular septaldefectBilateral cleft lip and palate47,XY,+131Absence of nosebone and atrial septal defect,mitral insufficiencyDuodenal atresia and hydronephrosis47,XX,+131Ventricular septal defect,coarctation of t heaortic arch and interrupted aorticarchBilateral cleft lip and duodenal atresia47,XX,+131Coarctation of t he aortic arch and ventricularseptal defect Bilateral cleft lip,Dandy2Walker malformation and hydronephrosis47,XY,+131Double outlet right ventricle and PulmonaryStenosisDuodenal atresia and polyhydramnios46,XX,t(13;14),+131Single ventricle and single atria,transpositionof t he great arteries and pulmonary atresiaPleural effusion46,XY,t(14;15),+141Endocardial cushion defect s Bilateral renal agensis and anorectal atresia47,XX,+161Right isomerism,single ventricle and singleat ria,hypoplastic left heart Bilateral polycystic kidney,peritoneal effusion,pleural effusion,great vessel malformation and internal organ ectropion47,XY,+161Tetralogy of Fallot,Coarctation of t he aorticarch double outlet right ventricle ventricularseptal defect,pulmonary artery straitnessOligohydramnios and bilateral renal agenesis47,XX,+161Complete transposition of t he great arteries Widened lateral ventricles,hydronephrosisand duodenal atresia47,XX,+81Atria septal defect and ventricular septal defect Dandy2Walker malformation,acromphalusand anorecta atresia47,XY,+221Endocardial cushion defect s Duodenal atresia and deformity of externalear47,XXY1Tetralogy of Fallot Uret hra dehisce47,XXY1Atria septal defect and ventri cular septal defect None47,XYY1Atria septal defect and ventricular septaldefect,mitral insufficiencyCryptorchidism45,X1Coarctation of t he aorta,ventricular septaldefectCubitus valgus,fetal anasarca45,X1Coarctation of t he aorta Fetal anasarca45,X1Ventricular septal defect,hypoplastic rightheart and tricuspid at resiaCubitus valgus45,X/46,X,del(X)1Hypoplastic left heart Cubitus valgus and nuchal translucencyt hickening45,X/46,X,i(X)(q10;q10)1Ventricular septal defect Fetal growt h rest riction and hydrops46,XX,5p-1Ventricular septal defect and patent ductusarteriosisBilateral cleft lip and palate46,XY,5p-1Ventricular septal defect.and atrial septaldefect,mitral insufficiencyHydrocephalus46,XX,-2,+t(2;6)1Truncus arteriosus and ventricular septal defect Dandy2Walker malformation,hydronephrosis46,XY,-18,+t(3;18)1Ventricular septal defect and coarctation of t heaortic arch Dandy2Walker malformation,widened lateral ventricles and omphalocele46,XY,-14,+t(13;14)(q21;p10)1Patent ductus arteriosis and atria septal defect Right hand syndactyly46,XY,-6,+t(2;6)(p11; q11)1Right isomerism,single ventricle and singleat riaPolycystic kidney and hydronephrosis46,XY,-22,+t(19;22)(p11;q13)1Yetralogy of Fallot Polyhydramnios and diaphragmatic hernia46,XY,-11,+t(5;11)(p15;q21)1Tetralogy of Fallot Polyhydramnios and diaphragmatic hernia46,XY,-14,+t(6;14)(q25;q13)1Endocardial cushion defect s Bilateral cleft lip46,XY,-15,+t(13;15)1Ventricular septal defect and truncus arteriosus Nuchal t ranslucency t hickening and widenedlateral ventricles69,XXX1Endocardial cushion defect s,transposition oft he great arteries,absence of pulmonary arteryand truncus arteriosusNone69,XXY1Left half heart agenesis Polyhydramnios,agenesis of t he corpuscallosum,diaphragmatic hernia andanopht halmos 413 结果显示:相同的染色体异常可伴有不同的心脏及心外畸形,且不同染色体异常发生心脏及心外畸形的比率也各不相同。