Chromosomal abnormalities associated with neural tube defects (II): partial aneuploidy

Fetuses with neural tube defects (NTDs) carry a risk of chromosomal abnormalities. The risk varies with maternal age, gestational age at diagnosis, association with other structural abnormalities, and family history of chromosome aberrations. This article provides a comprehensive review of structural chromosomal abnormalities associated with NTDs, such as del(13q), r(13), dup(2p), del(2q), del(1p), del(1q), dup(1q), del(3p), dup(3p), del(3q), dup(3q), del(4p), dup(4p), del(4q), dup(4q), del(5p), del(6p), dup(6q), del(6q), dup(7p), del(7q), dup(8q), del(9p), del(10q), del(11q), dup(11q), dup(12p), dup(14q), del(14q), del(15q), dup(16q), del(18q), r(18), dup(20p), +i(20p), del(22q), del(Xp), and dup(Xq). NTDs may be associated with aneuploidy. Perinatal identification of NTDs should alert one to the possibility of chromosomal abnormalities and prompt a thorough cytogenetic investigation and genetic counseling.     

Chromosomal abnormalities in fetuses with ultrasonographically detected neural tube defects

We analyzed the karyotype of fetuses with ultrasonographically detected neural tube defects (NTDs). In our study, we included a total of 194 fetuses with NTDs. We analyzed the type of NTD, the karyotype, maternal age, fetal gestational age at diagnosis, and fetal sex. Of the 194 fetuses with NTDs, 87 were anencephalic and 107 had other, nonanencephalic, NTDs. A total of 12 fetuses were shown to have chromosomal abnormalities. Three of 87 anencephalic fetuses (3.45%) had chromosomal abnormalities. The sex ratio for anencephalic fetuses was 65.5% : 34.5% for female and male fetuses. Nine of 107 fetuses with other NTDs (8.41%) had chromosomal abnormalities. Seven fetuses had isolated NTDs and a further seven fetuses had additional ultrasonographic anomalies. Two of the latter had abnormal karyotypes. The sex ratio of all other NTD cases was 67.3% : 32.7% for female and male fetuses. The high number of chromosomal abnormalities justifies prenatal karyotyping in all fetuses with ultrasonographically diagnosed NTDs.     

Choroid plexus cysts and trisomy 18: Risk modification based on maternal age and multiple-marker screening

Choroid plexus cysts are more common in fetuses with chromosomal aneuploidies, particularly trisomy 18. Although it is accepted that the risk of karyotypic abnormality justifies amniocentesis when associated abnormalities are present, disagreement continues as to the risk of trisomy 18 in a fetus with an isolated choroid plexus cyst. We propose consideration of maternal age and multiple-marker screening for chromosomal aneuploidy in the assessment of risk. Bayesian statistical modeling was used to calculate the risk of trisomy 18 from age-related risk figures for trisomy 18 and the incidence of isolated choroid plexus cysts in fetuses with trisomy 18. The risk was further modified on the basis of the ability of multiple-marker screening to detect fetuses with trisomy 18. From risk estimates calculated across maternal ages 20 to 45 years, the risk of trisomy 18 does not approach that of amniocentesis until a maternal age of ≥37 years. Therefore in the presence of an isolated choroid plexus cyst and normal multiple-marker screen results amniocentesis is justified only in the patient with advanced maternal age. (Am J Obstet Gynecol 1996;175:1493-7.)     

Prenatal diagnosis of trisomy 2 mosaicism: a case report

We report a case of trisomy 2 mosaicism detected upon amniocentesis in a woman with advanced maternal age. A mos 47,XY,+2(4)/46,XY(21) karyotype was revealed using standard GTG banding. There were no pathological sonographic findings and the fetal size was normal for gestational age at 16th week. The use of serial high-resolution ultrasound examination of the fetus to detect major abnormalities was offered as an option to the parents who, however, decided for termination of the pregnancy. Fetal autopsy did not reveal any malformations. Trisomy 2 mosaicism is associated with variable phenotypic abnormalities without a specific pattern, intrauterine growth restriction, fetal demise or stillbirth. The rarity of trisomy-2 mosaicism in prenatal diagnosis, as well as the increased risk of an abnormal outcome makes the diagnostic approach and genetic counseling difficult.     

Spontaneous abortion. Chromosome studies on 41 cases and an analysis of maternal age and duration of pregnancy in relation to karyotype

The relatively frequent occurrence of chromosomal abnormalities in spontaneous abortuses offers an opportunity to gain additional insight into the mechanisms and consequences of alterations in the karyotype. Studies on 41 successfully cultured specimens showed abnormalities belonging to each of the three major classes previously reported (autosomal trisomy, X-monosomy, and triploidy) as well as one case of mosaicism and one with a structural abnormality. Analyses of pooled data showed a higher mean maternal age and shorter mean period of gestation for trisomic abortuses than for abortuses associated with X-monosomy, triploidy, and normal chromosomes. No influence of maternal age could be demonstrated for X-monosomic or triploid abortions when these were compared with abortions having normal chromosomes. An association of triploidy with missed abortion was noted and may be significant.     

Chromosomal abnormalities associated with omphalocele

Fetuses with omphalocele have an increased risk for chromosomal abnormalities. The risk varies with maternal age, gestational age at diagnosis, association with umbilical cord cysts, complexity of associated anomalies, and the contents of omphalocele. There is considerable evidence that genetics contributes to the etiology of omphalocele. This article provides an overview of chromosomal abnormalities associated with omphalocele and a comprehensive review of associated full aneuploidy such as trisomy 18, trisomy 13, triploidy, trisomy 21, 45,X, 47,XXY, and 47,XXX, partial aneuploidy such as dup (3q), dup (11p), inv (11), dup (1q), del (1q), dup (4q), dup (5p), dup (6q), del (9p), dup (15q), dup(17q), Pallister-Killian syndrome with mosaic tetrasomy 12p and Miller-Dieker lissencephaly syndrome with deletion of 17p13.3, and uniparental disomy (UPD) such as UPD 11 and UPD 14. Omphalocele is a prominent marker for chromosomal abnormalities. Perinatal identification of omphalocele should alert chromosomal abnormalities and familial unbalanced translocations, and prompt thorough cytogenetic investigations and genetic counseling.     

Trisomy 14 Mosaicism: a case without evidence of neurodevelopmental delay and a review of the literature

Trisomy 14 mosaicism is a rare chromosomal defect with only 20 cases reported in the literature. We describe a child with trisomy 14 mosaicism who has some previously described and some novel phenotypic features. Trisomy 14 mosaicism was demonstrated in both blood lymphocytes and from skin fibroblasts, and with normal parents and siblings. This child had no evidence of neurodevelopmental delay at 6 years of age on formal testing, suggesting that mental retardation is not universal in this condition. This child did not demonstrate neurodevelopmental delay, which as been reported universally among children with trisomy 14 mosaicism.     

Prenatally detected trisomy 7 mosaicism in a dysmorphic child

Trisomy 7 mosaicism was detected prenatally in cultured amniocytes but not in fetal lymphocytes. The child that was born had pigmentary changes of the skin and facial asymmetry suggestive of a chromosomal mosaicism. Skin fibroblasts were studied and trisomy 7 mosaicism was confirmed. At 3 years of age the boy had developed mentally within normal limits. However, dysmorphic findings include sparse hair, short left palpebral fissure, ptosis of the left eyelid, strabismus, enamel dysplasia, low-set and posteriorly rotated ears and undescended testes. These findings share some common features with previously reported cases of trisomy 7 mosaicism.     

Sonographic features of chromosomal defects in the second trimester of pregnancy

Each chromosomal defect has its own syndromal pattern of detectable abnormalities. The authors describe the sonographic features of trisomy 21 and other major chromosomal defects in the second trimesters of pregnancy. It is recommended that, when an abnormality/marker is detected at routine ultrasound examination, a thorough check is made for the other features of the chromosomal defect known to be associated with that marker; should additional abnormalities be identified, the risk is dramatically increased. In the case of apparently isolated abnormalities, the decision whether to carry out an invasive test depends on the type of abnormality. Minor fetal abnormalities or soft markers are common and they are not usually associated with any handicap, unless there is an underlying chromosomal defect. Routine karyotyping of all pregnancies with these markers would have major implications, both in terms of miscarriage and in economic costs. It is best to base counseling on an individual estimated risk for a chromosomal defect, rather than the arbitrary advice that invasive testing is recommended because the risk is 'high\ The estimated risk can be derived by multiplying the a priori risk (based on maternal age, gestational age, history of previously affected pregnancies and, where appropriate, the results of previous screening by NT and/or biochemistry in the current pregnancy) by the likelihood ratio of the specific abnormality or marker.     

Assessment of risk for chromosomal abnormalities at 10-14 weeks of gestation by nuchal translucency and maternal age in 5,210 fetuses at a single centre

OBJECTIVE: To evaluate the screening of chromosomal abnormalities by nuchal translucency (NT) measurement. METHODS: Assessment of risk for chromosomal abnormalities by NT and maternal age in 5,210 single fetuses with karyotype and outcome already known. RESULTS: Risk was > or =1 in 300 in 640 (12.2%) of all fetuses, in 575 (11.1%) of the normal fetuses, in 38 (80.8%) of the fetuses affected by trisomy 21, and in 65 (89%) of the fetuses affected by chromosomal abnormalities. Risk was > or =1 in 200 in 477 (9.1%) of all fetuses, in 418 (8.1%) of the normal fetuses, in 35 (74.4%) of the fetuses affected by trisomy 21, and in 59 (80.8%) of the fetuses affected by chromosomal abnormalities. Risk was > or =1 in 100 in 270 (5.1%) of all fetuses, in 216 (4.2%) of the normal fetuses, in 33 (70.2%) of the fetuses affected by trisomy 21, and in 54 (73.9%) of the fetuses affected by chromosomal abnormalities. CONCLUSIONS: Risk generated by NT and maternal age is effective in screening for chromosomal abnormalities.     

Mosaic trisomy 16 in a fetus: the complex relationship between phenotype and genetic mechanisms

OBJECTIVES: This study was undertaken to discuss the workup of trisomy 16 pregnancies. STUDY DESIGN: This case study reports the prenatal detection and postnatal confirmation of mosaic trisomy 16, associated with uniparental disomy (UPD) 16, in a 34-year-old woman who showed elevated maternal serum alpha-fetoprotein and beta-HCG at a gestational age (GA) of 15.5 weeks. RESULTS: Amniotic fluid (AF) karyotyping at different GAs revealed various levels of trisomy 16 mosaicism (0 to level III). UPD studies at 21 weeks of gestation revealed maternal heterodisomy 16. Serial fetal ultrasonography showed fetal abnormalities: intrauterine growth restriction (IUGR), dilated digestive tract, and gallbladder agenesis. Postmortem examination confirmed the prenatal findings and revealed additional anomalies, such as hypoplastic cerebellum with abnormal gyration of the vermis. CONCLUSIONS: Workup following prenatal detection of trisomy 16 mosaicism in chorionic villi must include AF karyotyping and serial ultrasound examination of the fetus in order to approach postnatal developmental prognosis.     

Prenatally detected trisomy 4 and 6 mosaicism--cytogenetic results and clinical phenotype

We report on a live-born male with 46,XY/47,XY+4/47,XY,+6 mosaicism. Trisomy 4 mosaicism was detected by karyotyping chorionic villus samples (CVS) and was confirmed by the analysis of 16 metaphases obtained from cultured amniotic fluid cells. Eight metaphases were normal (46,XY), two had trisomy 4 (47,XY,+4), and two had trisomy 6 (47,XY,+6). Two postnatal chromosomal analyses of blood lymphocytes at birth and at the age of one week were normal. Chromosomal analysis of cultured skin fibroblasts from the right inguinal region at the age of 12 months revealed trisomy 4 (47,XY,+4) in 49 metaphases, trisomy 6 (47,XY,+6) in 2 metaphases, and a normal karyotype (46,XY) in 49 cells of the 100 analyzed metaphases, respectively. The main clinical findings consist of prenatal growth retardation, hypoplasia of the right side of the face, a dysplastic and posteriorly rotated right ear, a high vaulted palate, retrognathia, aplasia of the right thumb, hypoplasia of the fingernails, a deep sacral dimple, and patchy skin hypopigmentation of the right leg. When last seen at the age of 14 months, his development was nearly normal. Five patients with trisomy 4 mosaicism have been reported previously, but none with an additional trisomy 6 mosaicism.     

Apparent confined placental mosaicism of trisomy 16 and multiple fetal anomalies: case report

Trisomy 16 is frequently found confined to the placenta (confined placental mosaicism (CPM)), with a structurally normal fetus. In some cases of trisomy 16, the fetus has uniparental disomy for chromosome 16 (UPD16) which is associated with intrauterine growth restriction (IUGR) and fetal anomalies. We report a case of apparent confined placental mosaicism for trisomy 16, using standard cytogenetic techniques, but with multiple fetal abnormalities including congenital diaphragmatic hernia in which there was no evidence of UPD in the disomic tissues examined. Subsequent examination of fetal tissues using fluorescent in situ hybridization (FISH) demonstrated low levels of mosaicism for trisomy 16 in all the tissues examined. The use of FISH permits identification of mosaicism which conventional techniques may not identify.     

无创DNA检测在诊断高龄孕妇胎儿非整倍体中的应用

目的:探讨高龄妊娠胎儿染色体异常的风险以及无创DNA产前检测(NIPT)在诊断高龄孕妇胎儿非整倍体染色体病中的应用价值。方法:选择≥35岁的高龄孕妇2714例,按年龄分为35~39岁,≥40岁两组,采用NIPT高通量测序检测孕妇血浆游离DNA,并对检测结果提示21-三体、18-三体、13-三体及性染色体高风险者行羊膜腔穿刺术及胎儿染色体核型分析,对检测结果阴性者通过电话随访进行验证。计算NIPT检测的敏感度、特异度、阳性预测值、阴性预测值及Youden指数。结果:2714例高龄孕妇NIPT检测结果提示胎儿非整倍体染色体异常高风险47例,6例高风险孕妇拒绝侵入性产前诊断,余41例高风险孕妇行羊膜腔穿刺术及羊水细胞染色体核型分析,结果显示21-三体19例,18-三体1例,13-三体2例,性染色体异常7例。与现有的金标准羊膜腔穿刺术核型分析相比较,NIPT对高龄孕妇除外性染色体异常的胎儿非整倍体染色体异常检出敏感度为100.00%,特异度为99.93%,阳性预测值为90.91%,阴性预测值为100.00%,Youden指数为0.99。进一步通过年龄分组发现,40岁及以上年龄组异常率显著高于35~39岁年龄组(P=0.011)。结论:高龄孕妇可通过NIPT快速、安全地筛查出胎儿非整倍体染色体异常,减少侵入性产前检测比例,降低胎儿出生缺陷率。     

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.     

Fetal blood chromosome analysis: some new indications for prenatal karyotyping

Summary. Prenatal karyotyping using stimulated fetal blood lymphocytes was undertaken in 170 pregnancies between 16 and 36 weeks gestation for the following reasons-(1) mosaicism or marker chromo somes found in amniotic fluid culture; (2) a family history of X-linked mental retardation with fragile Xq28; (3) fetal abnormalities detected ultrasonographically; (4) late booking or amniotic fluid culture failure in patients with advanced age or balanced translocations; and ( 5 ) twin pregnancies discordant for a chromosomal anomaly. Forty-one karyotypic abnormalities were detected (24%). These were: 45,X (7 cases). trisomy 13 ( 5 cases), trisomy 18 (6 cases), trisomy 21 (4 cases), twin pregnancy where one twin had trisomy 21 (1 case), supernumerary marker chromosome (3 cases, one of which occurred in a twin pregnancy). triploidy (3 cases), X-linked mental retardation with fragile site at Xq28 in males (6 cases), fetal erythroleukaemia (3 cases including 2 cases with Turner's), Fanconi's anaemia (1 case), unbalanced chromosome translocation 47,XY+der22,t(l1;22) mat (1 case), mos 46,XXI8p-/46,XX.-18,+i(l8q) (1 case), 46,XXde1(2q) (1 case), and 46,XYt(5;17) de novo (1 case). In fetuses at high risk of a chromosome aberration. a rapidly obtaincd karyotype is helpful and fetoscopy and fetal blood sampling are justified in the second or third trimester.     

Management of prenatally detected trisomy 8 mosaicism.

We report on ten pregnancies with trisomy 8 mosaicism. Nine cases were prenatally detected in chorionic villi (n=6), amniotic fluid (AF) cells (n=2) or fetal blood (FB) lymphocytes (n=1). Follow-up laboratory investigations showed confined placental mosaicism (CPM) or pseudomosaicism in eight cases. In one case with ultrasound abnormalities, trisomy 8 mosaicism was detected in FB cells although cultured AF cells showed normal cells only. Another case of mosaic trisomy 8 was prenatally missed; cytogenetic analysis of short-term cultured villi revealed a normal male karyotype, while postnatally, trisomy 8 mosaicism was detected in peripheral blood lymphocytes and skin fibroblasts of the affected child. These findings indicate the difficulties in the prenatal diagnosis of trisomy 8 mosaicism. When found in chorionic villi, it mostly represented CPM, while in a case of true fetal trisomy 8 mosaicism, the cytotrophoblast cells showed a normal karyotype. So, the cytotrophoblast compartment of chorionic villi is a poor indicator of the presence or absence of fetal trisomy 8 mosaicism. Follow-up investigations including amniocentesis and especially fetal blood sampling are required to come to a definite prenatal diagnosis of trisomy 8 mosaicism.     

Warkany syndrome associated with agenesis of the corpus callosum

Trisomy of chromosome 8 (Warkany syndrome) is a rare chromosomal abnormality associated with retarded psycho-motor development, facial dysmorphism and other structural anomalies. We present a case report of fetal mosaicism of trisomy 8 at 30 weeks of gestation associated with agenesis of the corpus callosum as part of a larger polymalformation sequence.     

Sonographic Markers of Fetal Aneuploidy—A Review

The most effective sonographic marker of trisomy 21 and other chromosomal defects is increased nuchal translucency (NT) thickness at 11–14 weeks. Extensive studies over the last decade have examined the methodology of measuring NT, the development of the necessary algorithms for calculating the individual patient risk for trisomy 21 by NT in combination with maternal age and with various maternal serum biochemical markers, and the performance of this test. Another promising marker for trisomy 21, both in the first and second trimesters, is absence of the fetal nasal bone. There is also an extensive literature on the association between chromosomal abnormalities and a wide range of second trimester ultrasound findings. However, there are very few reports that have prospectively examined the screening performance of second trimester markers. This article reviews the association between sonographically detectable fetal abnormalities and chromosomal defects, and examines the value of incorporating these defects in screening policies.     

Trisomy 20 mosaicism in prenatal diagnosis--a review and update

A total of 66 cases with prenatal diagnosis of trisomy 20 mosaicism was reviewed. Since the majority of cases (85 per cent) was associated with grossly normal phenotype and the abnormalities noted in 15 per cent of cases were inconsistent and rather non-specific, no casual relationship between trisomy 20 mosaicism and a specific malformation syndrome can be established. The possibility of an association between an abnormal phenotype and a high percentage of trisomy 20 cells (greater than 60 per cent) must be considered preliminary and be viewed with caution. The fact that cells with trisomy 20 have not been recovered from blood cultures and were detected more frequently from specific fetal tissues, (such as kidney, rectum, oesophagus), and from placental tissues, suggests that trisomy 20 is more likely to be confined to certain fetal organs and to extra-embryonic tissues. This review calls for the collection of more data on all cases of trisomy 20 mosaicism diagnosed prenatally, in order to provide more accurate information to the prospective parents.