A rare occurrence of trisomy 18 and trisomy 21 in a dizygotic twin pregnancy

Objective Case report of a rare combination of a trisomy 18 and 21 in a dizygotic twin pregnancy in a woman with a history of recurrent miscarriage, a neonatal death, no living offspring and Graves disease. Methods Case report and literature search. Results Only one other report in the literature of a combined trisomy 18 and 21 twin pregnancy was found. Conclusion The combination of a trisomy 18 and 21 in a dizygotic twin pregnancy is very rare. Despite the high frequency and clinical importance of aneuploidy, very little is known about the factors that may modulate meiotic non-disjunction.     

Examination of a first-trimester Down syndrome screening concept on a mix of 11,107 high- and low-risk patients at a private center for prenatal medicine in Germany

Objective

To assess the performance of a combined first-trimester screening concept for trisomies 21, 18 and 13 applied to a low- and high-risk patient sample in a specialized private center for prenatal medicine.

Study design

The quality of different first-trimester screening algorithms (risk calculation based on maternal age and nuchal translucency alone, maternal age and serum parameters (free β-hCG and PAPP-A) alone and a combination of both) was evaluated in a study population of low- and high-risk cases for fetal aneuploidies. All measurements were performed between the 11th + 0 and 13th + 6 weeks of gestation during the study period from November 2000 to December 2006, in accordance with the guidelines of the Fetal Medicine Foundation (FMF), London.

Results

Of 11,107 women included in the study, we had a complete follow-up on 10,668. The difference between the detection rate was insignificant for both the low-risk and the high-risk groups. In the overall study population, 52 of 59 cases of trisomy 21 were detected when a pre-defined cut-off of 1:300 was applied (detection rate (DR) 88.1%; 95% confidence interval (CI): 79.8–96.4 and false-positive rate (FPR) 4.9%; 95% CI: 4.5–5.3). For trisomies 13 and 18 with a pre-defined cut-off of 1:150, 26 of 32 cases were detected (DR 81.3%; 95% CI: 67.8–94.8 and FPR 0.7%; 95% CI: 0.5–0.9). The highest sensitivity was between 11 + 0 and 11 + 6 weeks of gestation with all cases of trisomy 21 detected with a FPR 5.1%; 95% CI: 3.7–6.5.

Conclusion

In our study population of different risk categories, the detection rate using the combined risk calculation based on maternal age, fetal NT, maternal PAPP-A and free β-hCG levels was superior to the application of either parameter alone.     

Stepwise sequential screening for trisomy 21 in assisted reproduction pregnancies

We offered a modified stepwise sequential integrated screening for Down syndrome to 72 singleton and 16 twin pregnancies obtained with assisted reproductive techniques, observing no cases of trisomy 21 and obtaining a false positive rate of 10% in singleton and 7% in twin pregnancies. In our population, this approach for regulating access to invasive karyotyping can avoid a substantial number of unnecessary procedures, comparing favourably with current practice even in spontaneous pregnancies.     

Prenatal sonographic findings in 207 fetuses with trisomy 21

OBJECTIVE: The objective was to evaluate the contribution of second trimester ultrasound examination to the prenatal diagnosis of trisomy 21 in 207 fetuses with this aneuploidy. The type and frequency of abnormal sonographic findings were determined. Possible multiple malformation patterns, characteristic of trisomy 21 were sought. STUDY DESIGN: Singleton fetuses that had prenatal sonography during the second trimester, then underwent cytogenetic evaluation in our institution, made up the study population. The sonographic findings of 207 fetuses with trisomy 21 were analyzed. RESULTS: Between 1990 and 2004, fetal karyotyping was performed in 22,150 patients for different indications. An abnormal karyotype was diagnosed in 514 cases (2.3%); among them 207 fetuses with trisomy 21 were detected (40.3%). Abnormal sonography was seen in 63.8% of the cases. Structural anomalies were detected in 28.5% of the trisomy 21 fetuses, among them cardiac defects (15.9%), central nervous system anomalies (14.5%), and cystic hygromas (6.8%) were the most common. Of the minor markers, increased nuchal translucency (28%), pyelectasis (20.3%), and shorter extremities (8.7%) were common findings. CONCLUSIONS: Appropriate diagnosis of structural anomalies, looking for relatively easily detectable minor markers and incorporating fetal echocardiography into the second trimester sonographic protocol, may increase the contribution of mid-trimester ultrasound examination to diagnosing trisomy 21.     

Resistin in mid-trimester amniotic fluid in trisomy 21

Abstract

Objective: The aim of this study was to examine whether resistin is present in second trimester amniotic fluid from trisomy 21 (also known as Down’s syndrome) pregnancies and whether its concentration differs compared with euploid pregnancies.

Methods: The study cohort consisted of 58 women in the mid-trimester of pregnancy who underwent amniocentesis for prenatal diagnosis, 31 of whom carried a single fetus with diagnosed trisomy 21 (study group) and the rest with normal karyotype (control group, n?=?27). Groups were matched for maternal and gestational age. Levels of resistin in amniotic fluid were measured by a commercially available enzyme-linked immunosorbent assay (ELISA) kit.

Results: Resistin was detected in all amniotic fluid samples. Its median concentration in the second trimester amniotic fluid of trisomy 21 pregnancies (2.1?ng/ml) was statistically significantly lower (p value <0.001) in comparison with that in euploid pregnancies (3.3?ng/ml).

Conclusions: Resistin is a physiologic constituent of second trimester amniotic fluid. Lower levels of amniotic fluid resistin in pregnancies with trisomy 21 may reflect altered metabolic pathways in utero that could possibly be related with phenotypic features of the syndrome.     

Perinatal cytogenetic discrepancy in a fetus with low-level mosaicism for trisomy 21 and a favorable outcome

ObjectiveWe present perinatal cytogenetic discrepancy in a fetus with low-level mosaicism for trisomy 21 and a favorable outcome.Case reportA 40-year-old woman underwent amniocentesis at 19 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XY,+21[7]/46,XY[14]. She underwent cordocentesis 21 weeks of gestation, and the karyotype of cord blood was 47,XY,+21[13]/46,XY[38]. The prenatal ultrasound findings were unremarkable. After genetic counseling of a favorable outcome of low-level mosaic trisomy 21 at amniocentesis, the parents decided to continue the pregnancy, and a 3128-g phenotypically normal male baby was delivered at 38 weeks of gestation without phenotypic features of Down syndrome. Postnatal cytogenetic analysis of cord blood revealed a karyotype of 47,XY,+21[3]/46,XY[47]. The placenta had a karyotype of 47,XY,+21[8]/46,XY[32], and the umbilical cord had a karyotype of 47,XY,+21[5]/46,XY[35]. Array comparative genomic hybridization analysis on the DNA extracted from cord blood revealed no genomic imbalance. Polymorphic DNA marker analysis excluded uniparental disomy 21. Interphase fluorescence in situ hybridization analysis on urinary cells revealed trisomy 21 signals in 2/102 (1.96%) cells compared with 2/103 (1.94%) cells in normal control.ConclusionThe cells of abnormal cell line in prenatally detected mosaic trisomy 21 may decrease in number or disappear in various tissues as the fetus grows, and there exists perinatal cytogenetic discrepancy in mosaic trisomy 21 detected at prenatal diagnosis.     

应用荧光原位杂交技术对胚胎植入前行21—三体检查的研究

目的 避免移植染色体异常胚胎及提高体外受精-胚胎移植（IVF-ET）的质量。方法 应用DSCRCosmidDNA特异性探针,借助于荧乐原位杂交技术对20对35岁以上行IVF助孕夫妇的植入前胚胎进行21-三体检查。结果 在20例对夫妇中10对夫妇的胚胎成功地进行了植入前胚胎21-三体检查,其中8对夫妇的胚胎被证明为正常,给予常规移植,移植的8例胚胎中2例妊娠,其中1例流产,另1例正在妊娠中;2对夫妇的胚胎被证明为正常,给予常规移植,移植的8例胚胎中2例妊娠,其中1例流产,另1例正在妊姑吉,2对夫妇的胚胎被检查出21-三体,未给予移植。结论 在行IVF助孕的高龄妇女中,进行胚胎植入前21-三体检查是必要的。     

Comprehensive investigation of DNA methylation and gene expression in trisomy 21 placenta

IntroductionTrisomy 21 (T21) is the most common aneuploidy affecting humans and is caused by an extra copy of all or part of chromosome 21 (chr21). DNA methylation is an epigenetic event that plays an important role in human diseases via regulation of gene expression. However, the integrative association between DNA methylation and gene expression in T21 fetal placenta has yet to be determined.MethodsWe profiled expression of 207 genes on chr21 and their DNA methylation patterns in placenta samples from normal and DS fetuses using microarray analysis and predicted the functions of differentially expressed genes using bioinformatics tools.ResultsWe found 47 genes with significantly increased expression in the T21 placenta compared to the normal placenta. Hypomethylation of the 47 genes was observed in the T21 placenta. Most of hypomethylated DNA positions were intragenic regions, i.e. regions inside a gene. Moreover, gene expression and hypomethylated DNA position showed significantly positive associations. By analyzing the properties of the gene-disease network, we found that increased genes in the T21 placenta were significantly associated with T21 and T21 complications such as mental retardation, neurobehavioral manifestations, and congenital abnormalities.DiscussionTo our knowledge, this is the first study to comprehensively survey the association between gene expression and DNA methylation in chr21 of the T21 fetal placenta. Our findings provide a broad overview of the relationships between gene expression and DNA methylation in the placentas of fetuses with T21 and could contribute to future research efforts concerning genes involvement in disease pathogenesis.     

Monozygotic twins discordant for trisomy 21: Discussion of etiological events involved

Objective

To elucidate the etiologies of discordant trisomy 21 in monozygotic twin pregnancy.

MicroRNAs as potential biomarkers for noninvasive detection of fetal trisomy 21

Purpose

The objective of this study was to discover a panel of microRNAs (miRNAs) as potential biomarkers for noninvasive prenatal testing (NIPT) of trisomy 21 (T21) and to predict the biological functions of identified biomarkers using bioinformatics tools.

Methods

Using microarray-based genome-wide expression profiling, we compared the expression levels of miRNAs in whole blood samples from non-pregnant women, whole blood samples from pregnant women with euploid or T21 fetuses, and placenta samples from euploid or T21 fetuses. We analyzed the differentially expressed miRNAs according to disease and tissue type (P value <0.05 and two-fold expression change). To predict functions of target genes of miRNAs, the functional annotation tools were used.

Results

We identified 299 miRNAs which reasonably separate the whole blood from the placenta. Among the identified miRNAs, 150 miRNAs were up-regulated in the placenta, and 149 miRNAs were down-regulated. Most of the up-regulated miRNAs in the placenta were members of the mir-498, mir-379, and mir-127 clusters. Among the up-regulated miRNAs in the placenta, mir-1973 and mir-3196 were expressed at higher levels in the T21 placenta than in the euploid placenta. The two miRNAs potentially regulate 203 target genes that are involved in development of brain, central nervous system, and nervous system. The genes are significantly associated with T21-related disorder such as congenital abnormalities, mental disorders, and nervous system diseases.

Conclusions

Our study indicates placenta-specific miRNAs that may be potential biomarkers for NIPT of fetal T21 and provides new insights into the molecular mechanisms of T21 via regulation of miRNAs.     

Late-onset fetal bilateral pleural effusions associated with Down syndrome

Objective

We present two cases of late-onset bilateral fetal pleural effusions associated with fetal Down syndrome.

Hypoechoic liver in fetuses with trisomy 21

The association between hypoechoic hepatomegaly in the third trimester and transient abnormal myelopoiesis (TAM) was reported previously in six fetuses with trisomy 21 (T21). We report a series of three cases of T21 in which hypoechoic liver (HL) was found in the second trimester but without evidence of TAM on both hematological and histological examination. We postulate that the hypo-echogenicity may be due to liver congestion secondary to hemodynamic disturbances seen in T21 fetuses. All three cases had negative first trimester Down syndrome screening and one case was detected solely because of the isolated finding of HL. HL per se may be associated with T21 and more positive cases are required to support this association.     

An outcomes analysis of five prenatal screening strategies for trisomy 21 in women younger than 35 years

OBJECTIVE: This study was undertaken to examine the cost-effectiveness and procedural-related losses associated with 5 prenatal screening strategies for fetal aneuploidy in women under 35 years old. STUDY DESIGN: Five prenatal screening strategies were compared in a decision analysis model: triple screen: maternal age and midtrimester serum alpha-fetoprotein, human chorionic gonadotropin (hCG), and unconjugated estriol; quad screen: triple screen plus serum dimeric inhibin A; first-trimester screen: maternal age, serum pregnancy-associated plasma protein A and free beta-hCG and fetal nuchal translucency at 10 to 14 weeks' gestation; integrated screen: first-trimester screen plus quad screen, but first-trimester results are withheld until the quad screen is completed when a composite result is provided; sequential screen: first-trimester screen plus quad screen, but the first-trimester screen results are provided immediately and prenatal diagnosis offered if positive; later prenatal diagnosis is available if the quad screen is positive. Model estimates were literature derived, and cost estimates also included local sources. The 5 strategies were compared for cost, the numbers of Down syndrome fetuses detected and live births averted, and the number of procedure-related euploid losses. Sensitivity analyses were performed for parameters with imprecise point estimates. RESULTS: In the baseline analysis, sequential screening was the least expensive strategy ($455 million). It detected the most Down syndrome fetuses (n=1213), averted the most Down syndrome live births (n=678), but led to the highest number of procedure-related euploid losses (n=859). The integrated screen had the fewest euploid losses (n=62) and averted the second most Down syndrome live births (n=520). If fewer than 70% of women diagnosed with fetal Down syndrome elect to abort, the quad screen became the least expensive strategy. CONCLUSION: Although sequential screening was the most cost-effective prenatal screening strategy for fetal trisomy 21, it had the highest procedure-related euploid loss rate. The patient's perspective on detection versus fetal safety may help define the optimal screening strategy.     

Ultrasonographically adjusted midtrimester risk of trisomy 21 and significant chromosomal defects in advanced maternal age

OBJECTIVE: Our purpose was to determine whether normal midtrimester ultrasonography results reduces the risk of fetal Down syndrome and any clinically significant chromosomal defects in pregnancies with advanced maternal age and to develop risk tables on the basis of age and ultrasonographic results. STUDY DESIGN: Biometry data were obtained in 4079 women between 15 and 24 weeks undergoing amniocentesis for maternal age. Expected values of humerus, femur, both combined, and abdominal circumference based on biparietal diameter were generated from a normal group. Observed/expected values of each parameter and nuchal thickness ≥6 mm was used to screen for Down syndrome and any clinically significant chromosome defects. Receiver-operator characteristic curves were used to determine threshold screening values for each parameter. By use of stepwise logistic regression the optimal measurements for detection of chromosome anomalies were established. An abnormal ultrasonography result was defined as either abnormal biometry choroid plexus cysts or a structural defect. RESULTS: The finding of shortened humerus (observed/expected <0.90), abnormal nuchal thickness, or an anatomic defect had the highest sensitivity for Down syndrome detection, 70.6%, p < 0.0001, whereas a short humerus, small abdominal circumference, (observed/expected <0.92), or an anatomic defect had a sensitivity of 46.7%, p < 0.0001, for any significant chromosome defect. With a normal ultrasonography the risk of Down syndrome in a 39-year-old woman falls from 1:100 to <1:292. CONCLUSION: A normal ultrasonography substantially reduces the risk of Down syndrome and any chromosome abnormality. This information is useful in counseling women who decline amniocentesis on the basis of maternal age. (Am J Obstet Gynecol 1996;175:1563-8.)     

Prospective first-trimester screening for trisomy 21 in 30,564 pregnancies

OBJECTIVE: This study was undertaken to evaluate the performance of a 1-stop clinic for first-trimester assessment of risk (OSCAR) for trisomy 21 by a combination of maternal age, fetal nuchal translucency (NT) thickness, and maternal serum-free ss- human chorionic gonadotrophin (hCG) and pregnancy-associated plasma protein-A (PAPP-A). STUDY DESIGN: OSCAR was carried out in 30,564 pregnancies at 11 to 13 + 6 weeks. Patient-specific risks for trisomy 21 and detection and false-positive rates were calculated. RESULTS: The median maternal age was 34 (range 15-49) years. Chromosomal abnormalities were identified in 330 pregnancies, including 196 cases of trisomy 21. The estimated risk for trisomy 21 was 1 in 300 or greater in 7.5% of the normal pregnancies, in 93.4% of those with trisomy 21 and in 88.8% of those with other chromosomal defects. CONCLUSION: The most effective method of screening for chromosomal defects is by first-trimester fetal NT and maternal serum biochemistry.