Familial pericentric inversion incidentally detected at prenatal diagnosis

Summary A case of familial heterozygous pericentric inversion of chromosome 1 [inv(1)(p13q23)] is presented. The inversion was incidentally detected in a fetus whose mother received prenatal chromosomal diagnosis due to her age (40 years old), and thereafter the same inversion was detected in the father whose phenotype was normal. No abnormalities were found in the phenotype of the newborn carrier. Semen analysis of the father revealed normal findings. The couple had no history of spontaneous abortion.     

Angelman综合征的诊断及其产前诊断

目的 对临床疑似Angelman综合征(Angelman syndrom,AS)的患者进行诊断并对已确诊的患儿家庭行产前诊断.方法 用高分辨染色体和荧光原位杂交(fluorescence in situ hybridization,FISH)技术对患者进行检测.结果 诊断出两例AS患者和一名正常胎儿.结论 结合临床症状、高分辨核型分析、FISH可确诊Ⅰ型AS患者,为临床提供准确的遗传咨询和产前咨询,并可对有AS生育史的家庭行产前诊断.     

B19病毒感染产前诊断方法探讨

目的同时用B超引导介入性查胎血病原体分子、免疫学、生理指标和非介入性B超形态学观察方法,对孕期B19病毒感染孕妇胎儿宫内诊断,探讨临床工作中B19病毒感染的产前诊断最佳方法。方法对93例孕12~34w诊断为B19病毒感染孕妇,同时用介入性产前诊断查胎血B19 IgM、PCR、血常规和B超检查胎儿生长各径线、胎盘厚度、胎儿心胸比例、大脑中动脉血流速度、胸腹腔是否积液等形态学指标,并定期观察等方法,进行B19病毒孕期感染胎儿宫内诊断。结果介入性查胎血病原体分子、免疫学方法检出6例(6/93),其中5例胎儿出现水肿,患者要求引产,另1例胎血B19 IgM、PCR( ),血常规,血色素血球压积正常,B超定期观察胎儿均无水肿征兆,至足月顺产,脐带血复查B19IgM( ):非介入性定期观察B超形态学方法,检出5例(5/93),5例胎儿均为水肿,引产证实。结论介入与非介入的B19病毒感染孕妇胎儿宫内诊断方法两两χ2四格表检验,无显著差异。     

Non-invasive prenatal diagnosis of osteogenesis imperfecta

The main mode of non-invasive prenatal diagnosis of osteogenesis imperfecta (OI) is fetal imaging, either by radiography or detailed ultrasonography. Radiography is more of historical interest and ultrasonography is in practice virtually exclusively used for non-invasive second trimester diagnosis of OI. Both methods have also been reported later in pregnancy when diagnosis allows the most appropriate method of delivery to be planned. For example, a caesarean section can be avoided if the fetus is shown to have a form of OI associated with limited survival. Ultrasonography is useful mainly for prenatal diagnosis of the severe forms of OI, especially the perinatally lethal forms (Sillence type II) and to a lesser extent for the severe progressively deforming forms (Sillence types III and III/IV). For the milder varieties of OI (Sillence types I and IV), many cases will be missed by scans. Invasive methods of prenatal diagnosis of OI (principally chorion villous sampling) are used for families with the milder dominant forms of OI and in severe forms of OI in which the actual biochemical or molecular defect in type I collagen is known. Many cases of type II OI and a few of type III have now been reported which were detected by scans before 20 weeks gestation, the earliest being at 15 weeks, for type IIA OI. These include cases not only at genetic risk but also sporadic cases in which scans were done either routinely or for obstetric indications. The ultrasonic abnormalities which are found include reduced echogenicity, multiple fractures, and deformity of the long bones, ribs and skull. There is a marked reduction of long bone length on measurement. The abnormalities are more severe in type II OI than in type III. No false negative diagnoses have yet been reported for severe OI. Ultrasonography is a reliable mode of prenatal diagnosis for a pregnancy at risk of type II OI and probably also for type III, although more reports for the latter are needed to give more information about the likelihood of false negative diagnoses in this form of OI. For pregnancies at risk of types II and III OI, serial scans from 14 weeks gestation can be offered. An experienced operator, using a good realitime scanner should be able to detect type II OI by at least 17 weeks gestation, and type III OI by 19 to 20 weeks. In future, it may be possible to diagnose type II OI in the first trimester by ultrasound using an intravaginal transducer.     

One hundred twin pregnancies in a prenatal diagnosis program

One hundred pairs of twins were encountered in 8,500 pregnancies having genetic amniocentesis. Only 5 of 27 (18.5%) pairs were recognized before the institution of routine ultrasonic examination, while 69 of 73 (94%) twin pairs were found after ultrasound use. Amniotic fluid was obtained from both sacs in 71 of the 73 (97%) identified twin gestations in which both twins were living at the time of amniocentesis.     

羊水细胞原位培养与产前诊断镶嵌体分析

目的了解载片培养瓶对羊水细胞原位培养的效果,并探讨产前诊断羊水染色体中镶嵌体不同分级水平与临床意义。方法使用载片培养瓶（研究组）与载片培养皿（对照组）对1274例有产前诊断指征的孕妇进行羊水细胞原位培养并G显带分析。结果研究组与对照组培养时间平均为6.7和8.9d,细胞克隆数平均为11.5和6.0个,两组培养天数和细胞克隆数比较差异有统计学意义（χ2=1814.4,P〈0.01;χ2=2049.04,P〈0.01）。羊水镶嵌体检出34例,Ⅰ级水平25例,Ⅱ级水平7例,Ⅲ级水平2例,其中真性镶嵌体3例。结论载片培养瓶对羊水细胞原位培养优于载片培养皿,羊水原位培养镶嵌体分级水平的研究对产前诊断有非常重要的临床意义,Ⅱ级水平不能认为全是假性镶嵌体。     

First trimester prenatal diagnosis using transcervical cells: an evaluation

Human trophoblastic cells can be retrieved by minimally invasiveprocedures from the endocervical canal between 6 and 15 weeksgestation. The incidence with which fetal cells can be detectedin transcervical cell (TCC) samples varies according to themethod of collection and the molecular techniques employed fortheir identification. Fluorescence in-situ hybridization (FISH)and polymerase chain reaction (PCR) assays have been successfullyused to detect aneuploidies and Y-derived DNA sequences in TCCsamples obtained from male fetuses. Chromosome specific polymorphicDNA sequences (small tandem repeats) have also been employedto identify, by quantitative fluorescent PCR, fetal cells inTCC samples. Furthermore, Rh(D) sequences have been amplifiedin samples retrieved from Rh(D) negative mothers. Preliminaryresults also suggest that prenatal diagnoses of thalassaemiaand sickle cell anaemia can be performed on clumps of cellsisolated from TCC samples. Overall systematic studies allowoptimism about the possibility of using TCC samples for theprenatal diagnosis of selected inherited disorders.     

母胎间差异甲基化片段在无创性产前诊断中的应用价值

目的探讨HLCS、RASSF1A片段在母胎间甲基化状态的差异并评估其在无创性产前诊断中的应用价值。方法收集388例孕妇血浆,其中126例同时收集外周血细胞及胎盘（或绒毛）组织,采用甲基化敏感性限制性酶切联合荧光定量PCR（MSRE＋PCR）技术,检测母胎间HLCS基因、RASSF1A基因甲基化状态的差异,分析其影响因素,并根据孕妇血浆中胎源性HLCS/RASSF1A浓度比值判断胎儿21号染色体数目。结果研究证实HLCS及RASSF1A在胎盘或绒毛组织中均呈高甲基化状态,而在母体外周血细胞呈现低甲基化状态,且这种甲基化差异不受孕妇年龄、孕周、胎儿性别的影响。采用MSRE＋PCR技术对孕妇血浆中HLCS、RASSF1A片段的检出率分别为97.4%和96.9%。计算274例正常妊娠孕妇血浆中胎源性HLCS/RASSF1A比值,确定其95%的参考值范围为0.34～2.02,以此为标准判断102例胎儿21号染色体数目,其中98例二倍体妊娠的准确率为95.9%（94/98）,4例21三体综合征妊娠均获正确诊断。结论高甲基化HLCS、RASSF1A基因可作为孕妇血浆中胎源DNA的标志物,且有望根据孕妇血浆中甲基化HLCS/RASSF1A浓度比值进行21三体综合征的无创性产前诊断。     

脊髓小脑性共济失调一家系的基因诊断和产前诊断

目的 确定一脊髓小脑性共济失调(spinocerehellar ataxia,SCA)家系具体分型,并开展症状前患者检测和产前诊断.方法 收集该脊髓小脑性共济失调家系中的2例患者的血液标本,结合该家系的临床表现和我国该类疾病的发病率,采用聚合酶链反应对SCA1、SCA2和SCA3/MJD 3个基因的三核苷酸重复片段进行扩增,并通过琼脂糖凝胶电泳和PCR产物测序的方法确定所有正常和异常扩增等位基因内三核苷酸重复次数.明确致病基因后,对患者子女进行症状前检测,并对1例怀孕症状前患者进行了产前诊断.结果 SCA1和SCA2基因内三核苷酸重复次数在正常范围内,SCA3/MJD的2个等位基因中1个等位基因三核苷酸重复次数在正常范围内,另1个等位基因三核苷酸重复次数在异常范围内.患者子女有1人携带异常等位基因,胎儿携带异常等位基因.结论 该家系经基因诊断确诊为SCA3/MJD型,有1人为症状前患者,该症状前患者所孕胎儿也为症状前患者.     

Infantile polycystic kindney disease: Observations from attempts at prenatal diagnosis

Three successive pregnancies of a couple at risk for infantile polycystic kidney disease were evaluated by sequential ultrasound examinations to attempt prenatal diagnosis of the disorder. The gestational age at which renal sonographic changes were noted varied from 20 to 34 weeks and resulted in both false-positive and false-negative diagnoses.     

Attitudes of Mexican geneticists towards prenatal diagnosis and selective abortion

Prenatal diagnosis (PD) provides the physician information on whether the unborn fetus has a genetic or chromosomal disorder, and offers patients a new option: selective abortion. In the present study, we analyzed the answers Mexican geneticists provided to a few selected questions from a multi-national survey designed by Wertz and Fletcher [1988: Am J Hum Genet 42:592–600]. The selected questions were related to the use of PD, the acceptance of selective abortion, and the self-reported directiveness of counselling following the diagnosis of a fetal anomaly. Our results show that the great majority of Mexican geneticists participating in the study agree with PD when medically indicated, but not on free demand. Specific cases stimulated the group on thinking more than the general statements provided in the survey. Although the majority agreed that PD should be available to all women, when faced with cases of nonmorbid maternal anxiety, paternity testing, and sex selection, the proportion of geneticists willing to perform the test decreased substantially. When counselling patients on a fetal anomaly, the minority would be as unbiased as possible, and this seems to be the tendency in developing countries where counselling, as stated in the respondents' comments, reflects the belief that the goal of genetics is the prevention of or opposition to abortion. Counselling was influenced by the severity of the disorder. The geneticists' personal attitude toward abortion in the same situations was stronger than when counselling others. Analysis of directiveness in counselling for fetal anomaly showed that older geneticists, with more years of experience in medical genetics, were more likely to be neutral. When counselling directively, the group showed an overall direction toward continuing affected pregnancies. However, older geneticists and those with more than 10 years of practice were more likely than their younger counterparts to counsel towards terminating affected pregnancies. In personal situations of fetal disorder, the general tendency was to abort; however, geneticists seeing more than 5 patients per week, and those who believe that religion is important, were more likely to reject abortion. The sample is representative of Mexican geneticists, and the main limitation of this study is that the geneticists have very little experience in PD, and that their responses were mostly based on theory. However, their opinions may influence the demand and the availability of PD and abortion, as well as the possibility of legalization of abortion on the basis of a fetal defect. Am. J. Med. Genet. 75:426-431, 1998. © 1998 Wiley-Liss, Inc.     

The usefulness of fetal MRI for prenatal diagnosis

PURPOSE: Fast MRI has provided detailed and reproducible fetal anatomy. This study was performed to evaluate the usefulness of fetal MRI for prenatal diagnosis. MATERIALS AND METHODS: Fifty-six fetuses with congenital abnormalities on ultrasonography were evaluated by fetal MRI from 2001 to 2004 in Severance Hospital. Final diagnosis was made by postnatal pathology, postnatal MRI, and other modalities (such as ultrasound, retrograde pyelogram). A 1.5-Tesla superconductive MR imaging unit was used to obtain half-Fourier acquisition single-shot turbo spin images. RESULTS: Of the 56 fetuses, intracranial abnormalities were found in 26 fetuses, intraabdominal abnormalities in 17 fetuses, intrathoracic in 6 fetuses, head and neck in 5 fetuses, and other sites in 2 fetuses. There were six cases in which the diagnoses of fetal MRI and ultrasonography differed. In such cases, fetal MRI provided more exact diagnosis than ultrasonography (5 vs. 0). Three fetuses with intracranial abnormalities on ultrasonography were diagnosed as normal by fetal MRI and in postnatal diagnosis. CONCLUSION: Although ultrasonography is known as a screening modality of choice in the evaluation of fetus because of the cost-effectiveness and safety, the sonographic findings are occasionally inconclusive or insufficient for choosing the proper management. Thus, in this study, we suggest that fetal MRI is more useful than ultrasonography for the evaluation of intracranial abnormalities in some instances. For prenatal counseling and postnatal treatment planning, fetal MRI can be informative when prenatal ultrasonography is inadequate and doubtful.     

First prenatal diagnosis of X-linked lymphoproliferative disease

A family study was performed in order to diagnose X-linked lymphoproliferative (XLP) disease in a fetus. The molecular genetic analysis indicated that the fetus, as well as its healthy 7-year-old brother, inherited XLP. Analysis of immunoglobulin subclasses from the 7-year-old brother supported the DNA-based diagnosis. This is the first XLP family of African descent. © 1992 Wiley-Liss, Inc.     

Routine prenatal diagnosis of aneuploidy by FISH studies in high‐risk pregnancies

This study is a prospective clinical trial with fluorescent in situ hybridization (FISH) as a “routine” test for prenatal detection of the most common aneuploidies in high‐risk pregnancies. Since April 1996, FISH studies with multicolor, commercially available, specific probes for chromosomes 13, 18, 21, X, and Y have been routinely performed in our cytogenetic laboratory on uncultured chorionic villous samplings (CVS), amniotic fluid samples, or fetal blood obtained by cordocentesis from patients with major or minor fetal anomalies detected by ultrasonography. Among the 4,193 prenatal samples analyzed between April 1996 and June 1998, routine FISH studies were ordered by the referring physicians on 301 (7.2%) cases. Aneuploidies were detected in 32 (10.6%) samples. Fourteen trisomy‐21, 10 trisomy‐18, 3 trisomy‐13, 4 monosomies of X, and 1 case of triploidy were diagnosed by FISH. All 1,505 hybridizations were informative, and all 301 results were available and reported to the referring physicians in 24–48 hr. All relevant FISH results were confirmed by subsequent cytogenetic analysis. In 10 (3.8%) cases with normal FISH results, the final cytogenetic analysis revealed abnormal chromosomal rearrangements that could not be detected by the routine FISH studies. We conclude that rapid FISH analysis of interphase, uncultured fetal cells is an accurate and very sensitive method for routine prenatal diagnosis of the most common aneuploidies in high‐risk pregnancies. Am. J. Med. Genet. 90:233–238, 2000. © 2000 Wiley‐Liss, Inc.     

Impact, logistics and prospects of traditional prenatal diagnosis

Traditional second trimester prenatal diagnosis (PD) by amniocentesis was introduced about 20 years ago. It is still the most frequently used procedure for this purpose. About 85% of all requests for PD are based on maternal age alone. The commonest indication is a maternal age of 35 or higher at delivery. Attempts are being made to improve utilization of the limited laboratory capacity by evaluating the indication for PD by combining age and other indicators, ie. maternal-serum-alpha-fetoprotein and unconjugated estriol. Chorionic villus sampling so far has appealed to an additional group of pregnant women rather than being a replacement for the older procedure. While the impact of PD on the individual woman and her family is great, it has limited impact on the prevalence of Down syndrome patients in the society. Of major concern is the impact of PD on the attitude to a pregnancy with a possibly affected child, on the attitude to induced abortion in general and on the acceptance of disabled individuals. The importance of proper genetic counseling including ethical issues is stressed.     

Germline mosaicism in Rett syndrome identified by prenatal diagnosis

Rett syndrome is an X-linked neurodevelopmental dominant disorder that affects almost exclusively girls. The vast majority of cases are sporadic and are caused by de novo mutations in the MECP2 gene, located in Xq28. Only few familial cases have been reported: in four cases, the mother was an asymptomatic carrier and in other four cases, the germline mosaicism in the mother was postulated. Owing to the above reported cases of germline mosaicism, we decided to offer prenatal diagnosis to all expectant mothers with a Rett daughter despite the absence of the causative mutation in parents' blood. We describe here the outcome of the first nine cases of prenatal diagnosis followed by our center. In eight cases, the fetus did not carry the mutation. In one case, the female fetus did carry the same mutation of the affected sister. The couple decided to interrupt the pregnancy and to devolve fetal tissues for research purposes. Our results indicate that prenatal diagnosis should be proposed to all couples with a Rett daughter, even when the mutation is apparently de novo. Moreover, one positive prenatal test among the first nine cases indicates that germline mosaicism may be seriously considered for the assessment of recurrence risk during genetic counseling.     

胎儿脑中线结构异常的产前超声诊断简

目的探讨产前常规超声检查对胎儿脑中线结构异常的临床应用价值。方法回顾性分析经常规超声检查怀疑有脑中线结构异常的胎儿178例,孕妇年龄19-43岁,平均年龄30．7岁,孕周14-38周。平均孕周28．4周。所有胎儿均经腹扫查．应用二维或三维超声扫查模式．总结并归纳其声像图特征。超声怀疑有脑中线结构异常的胎儿可行MRI检查或染色体检查,经生后随访或尸检证实超声检查结果。计算超声和MRI诊断胎儿脑中线结构异常的阳性预测值,采用卡方检验进行统计学分析。结果产前超声诊断胎儿脑中线结构异常178例,其中前脑无裂畸形27例,胼胝体发育不全53例,单纯透明隔腔缺如2例．Dandy-Walker畸形9例,小脑蚓部发育不良14例,巨大枕大池73例。178例胎儿失访9例．经生后随访或尸检证实的169例胎儿中,真阳性数为145例;178例胎儿中共有73例接受MRI检查,阳性60例,其中真阳性数为53例;超声和MRI诊断胎儿脑中线结构异常的阳性预测值分别为85．8％及88-3％．二者间差异无统计学意义（P〉0．05）。结论超声检查安全有效．方便省时,对胎儿脑中线结构异常确诊率较高．是产前筛查胎儿脑中线结构异常的可靠方法。     

Carrier detection and prenatal diagnosis of X-linked agammaglobulinemia

We investigated the pregnant mother of a boy with X-linked agammaglobulinemia (XLA) but with no family history of immune disease. The X-inactivation pattern was found, using a methylation-sensitive probe, to be skewed in the maternal B cells but random in the polymorphonuclear cells, indicating carrier status and a 50% risk of inheritance for her male fetus. Using probes assigned to regions on either side of the XLA locus and defining RFL polymorphism, we excluded for the first time a diagnosis of XLA on a chorionic villus sample, with a risk of error <0.003. Immunological studies performed at the 19th week of gestation and 3 days after birth confirmed normality. Carrier detection based on the X-chromosome inactivation pattern, together with prenatal studies using probes close to the disease locus, thus permits prenatal diagnosis in families with isolated cases of XLA. © 1992 Wiley-Liss, Inc.     

Evaluation of prenatal diagnosis of congenital anomalies diagnosable by prenatal ultrasound in patients in neonatal intensive care units of Cali,Colombia

Introduction:

The study aim was to determine the frequency of prenatal ultrasound diagnosis of congenital anomalies in Newborns (NB) with birth defects hospitalized in two Neonatal Intensive Care Units (NICU) of Cali (Colombia) and to identify socio-demographic factors associated with lack of such diagnosis.

Patients and methods:

It was an observational cross-sectional study. NB with congenital defects diagnosable by prenatal ultrasound (CDDPU), who were hospitalized in two neonatal intensive care units (NICU), were included in this study. A format of data collection for mothers, about prenatal ultra-sonographies, socio-demographic data and information on prenatal and definitive diagnosis of their conditions was applied. Multiple logistic and Cox regressions analyses were done.

Results:

173 NB were included, 42.8% of cases had no prenatal diagnosis of CDDPU; among them, 59.5% had no prenatal ultrasound (PNUS). Lack of PNUS was associated with maternal age, 25 to 34 years (Odds Ratio [OR]: 4.41) and 35 to 47 years (OR: 5.24), with low levels of maternal education (OR: 8.70) and with only a PNUS compared to having two or more PNUS (OR: 4.00). Mothers without health insurance tend to be delayed twice the time to access the first PNUS in comparison to mothers with payment health insurance (Hazard Ratio [HR]: 0.51). Among mothers who had PNUS, screening sensitivity of CDDPU after the 19^th gestational week was 79.2%.

Conclusions:

The frequency of prenatal diagnosis is low and is explained by lack of PNUS, or by lack of diagnostic in the PNUS. An association between lack of PNUS and late age pregnancy and low level of maternal education was found. In addition, uninsured mothers tend to delay twice in accessing to the first PNUS in comparison to mothers with health insurance. It is necessary to establish national policies which ensure access to appropriate, timely and good quality prenatal care for all pregnant women in Colombia.     

Transcervical cells and the prenatal diagnosis of haemoglobin (Hb) mutations

Prenatal diagnoses of haemoglobin (Hb) mutations were performed using transcervical cells, retrieved by aspiration from the endocervical canal of ten selected pregnant women at about 10 weeks of gestation, prior to chorionic villus sampling (CVS). Both parents were carriers of haemoglobinopathies (thalassaemia or HbS). Clumps of fetal cells were isolated by micromanipulation under an inverted microscope and aliquots of the extracted DNA tested separately for the presence of paternally derived chromosome markers and Hb mutations by quantitative fluorescent polymerase chain reaction (PCR). The correct prenatal diagnosis of Hb diseases, using selected single clumps of trophoblastic cellular elements free of maternal contaminating cells, was achieved in six out of ten cases.