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. Copyright © 2003 John Wiley & Sons, Ltd.     

A chromosome 21-specific cosmid cocktail for the detection of chromosome 21 aberrations in interphase nuclei

Fluorescent in situ hybridization (FISH) with a 21q11-specific probe (CB21c1) consisting of three non-overlapping cosmids has been applied to interphase amniocytes of pregnancies at increased risk for fetal aneuploidy (N = 78) and to interphase lymphocytes, cultured and uncultured, of patients referred for Down syndrome (N = 19 and 28, respectively). In the uncultured amniocytes, six chromosome aberrations were detected: three cases of trisomy 21, a triploidy, a de novo 46,XX,t(21q21q), and a mosaic 46,XY/47,XY,+dic(21)(q11)/48,XY,+dic(21)(q11), +del(21)(q11). In 15 cultured and 20 uncultured blood samples, FISH correctly diagnosed trisomy 21 (full or mosaic) at the interphase level, which was confirmed in all cases by subsequent karyotyping. Because of specific and strong signals in interphase nuclei, CB21c1 appears to be a useful tool for the rapid detection of chromosome 21 abnormalities.     

Parental mosaic trisomy 21 detected following maternal cell contamination of an amniotic fluid specimen from a normal male pregnancy

We report a case of maternal mosaic trisomy 21 ascertained at prenatal diagnosis as a result of maternal cell contamination of an amniotic fluid sample. A 34 year old female was referred for karyotyping because of a previous trisomy 21 pregnancy. Chromosome analysis of primary in situ cultures showed a karyotype of 47,XX, + 21[6]/46,XY[32]/46,XX[2]. Molecular testing demonstrated maternal cell contamination of the amniotic fluid sample and G-banded karyotyping of maternal blood showed that 3/200 cells had trisomy 21, consistent with the mother being a Down syndrome mosaic. A normal male baby with a 46,XY chromosome complement was delivered at 30 weeks. This case emphasises the need for close collaboration between cytogenetic and molecular genetics laboratories in resolving unusual cases of mosaicism. Copyright © 2007 John Wiley & Sons, Ltd.     

Prenatal diagnosis of trisomy 20 by chorionic villus sampling (CVS): a case report with long-term outcome

A case of prenatally diagnosed non-mosaic trisomy 20 in cells cultured from a chorionic villus sample (CVS)is presented. The term placental karyotype was also non-mosaic trisomy 20. The karyotype of thenewborn was 46,XY/47,XY,+20 in foreskin cultures and in a second skin culture; blood lymphocyte culture was 46,XY. Aside from diffuse, hypopigmentary swirls along the lines of Blaschko observed on hisextremities and trunk, referred to as hypomelanosis of Ito, the patient is clinically normal at 8¾ years ofage. In addition, he is one of the oldest reported cases of mosaic trisomy 20 confirmed after birth forwhich the clinical outcome has been monitored. This case demonstrates that these trisomy 20 findings are compatible with normal psychomotor development and phenotype. Copyright © 2001 John Wiley & Sons, Ltd.     

The significance of trisomy 7 mosaicism in chorionic villus cultures

Two cases of mosaic trisomy 7 confined to the cultured cells and not found in direct preparation were detected from 200 consecutive first-trimester chorionic villus samples (CVS) analysed. The mosaicism was similar in the two cases, but the pregnancy outcome was different. In both cases, the direct metaphases from the CVS were 46, XY. Culture metaphases were mos46,XY/47,XY, + 7; the trisomy 7 was seen in 34 per cent of cells from case 1 and 53 per cent from case 2. A sonogram at 15¹/₂ weeks revealed fetal death in utero in case 1, and the patient declined amniocentesis. The fetal tissue failed to grow in culture, but the placental cultured cells were 47,XY, + 7 in 28 (100 per cent) cells analysed. In the second case, all the amniotic fluid cells were 46,XY and the pregnancy resulted in a normal male with a 46,XY karyotype in the cord blood and foreskin fibroblast cultures. The term placenta was mosaic with 13/163 (8 per cent) trisomy 7 cells. Extensive cytogenetic studies on the placenta for the first time confirmed trisomy 7 mosaicism confined to the villus cultures.     

Maternal uniparental isodisomy 10 and mosaicism for an additional marker chromosome derived from the paternal chromosome 10 in a fetus

An Erratum has been published for this article in Prenatal Diagnosis 22(11) 2002: 1056. We report a case of maternal isodisomy 10 combined with mosaic partial trisomy 10 (p12.31-q11.1). Chromosome examinations from a CVS sample showed a karyotype 47,XY,+mar/46,XY. The additional marker chromosome which was present in 6/25 interphase nuclei was shown by fluorescence in situ hybridization (FISH) to have been derived from a pericentromeric segment of chromosome 10. DNA analysis was performed from umbilical cord blood from the fetus after termination of the pregnancy at 18 weeks. The results showed that the two structurally normal chromosomes 10 were both of maternal origin, whereas the marker chromosome derived from the father. Autopsy of the fetus revealed hypoplasia of heart, liver, kidneys and suprarenal glands, but, apart from a right bifid ureter, no structural organ abnormalities. This fetus represents the second reported instance of a maternal uniparental disomy (UPD) 10. Copyright © 2002 John Wiley & Sons, Ltd.     

False-positive diagnosis of trisomy 21 using fluorescence in situ hybridisation (FISH) on uncultured amniotic fluid cells

An amniocentesis was performed on a 22-week pregnancy following the detection of foetal abnormalities on ultrasound. A rapid aneuploid screen using fluorescence in situ hybridisation on uncultured amniotic fluid cells revealed 3 signals for chromosome 21, consistent with trisomy 21. In situ metaphase cultures revealed a 46,XY normal male karyotype. These discordant results may be explained by a sub-standard batch of the commercially available probe or alternatively, a very specific variation within the sample interacting with the probe. Alternative strategies are proposed in order to safeguard against inappropriate clinical action as a consequence of discordant results. Copyright © 2003 John Wiley & Sons, Ltd.     

Significantly higher number of fetal cells in the maternal circulation of women with pre-eclampsia

Although the pathophysiology of pre-eclampsia is unknown, several studies have indicated that abnormal placentation early in pregnancy might play a key role. It has recently been suggested that this abnormal placentation may result in transfusion of fetal cells (feto-maternal transfusion) in women with pre-eclampsia. In the present study, fetal nucleated red blood cells were isolated from 20 women with pre-eclampsia and 20 controls using a very efficient magnetic activated cell sorting (MACS) protocol. The number of male cells was determined using two-color fluorescence in situ hybridization (FISH) for X and Y chromosomes. Significantly more XY cells could be detected in women with pre-eclampsia (0.61±1.2 XY cells/ml blood) compared to women with uncomplicated pregnancies (0.02±0.04 XY cells/ml blood) (Mann–Whitney U-test, p<0.001). These results suggest that fetal cell trafficking is enhanced in women with pre-eclampsia, and this finding may contribute to the understanding of the pathophysiology of the disease. Copyright © 2001 John Wiley & Sons, Ltd.     

Prenatal foetal diagnosis of partial trisomy 3q and monosomy 13p due to a maternal balanced rearrangement

The authors describe a case of a male foetus whose ultrasound at 20 weeks' gestation revealed cystic hygroma, cleft lip and ventricular septal defect. Amniotic fluid cytogenetics using GTG banding showed a 46,XY,der(13)t(3;13)(q12;p11.1) rearrangement, and fluorescence in situ hybridization (FISH) delineated the relevant breakpoints. Familial studies identified a maternal balanced translocation involving chromosomes 3 and 13. The post-mortem examination confirmed the prenatal ultrasound findings. Copyright © 2005 John Wiley & Sons, Ltd.     

Translocation trisomy 21 in CVS not found in embryoblast: Three different cell lines in CVS,amnion- and placental culture

Chorionic villus samples from a healthy pregnant female were obtained for first-trimester prenatal diagnosis. A translocation trisomy 21 was diagnosed. A consecutive amniocentesis revealed a normal male karyotype. At term a healthy boy was born. Cytogenetic analysis from cord blood showed a regular karyotype of 46,XY, whereas in term placenta a pathological karyotype of 47,XY,+mar was found.     

Trisomy 20 mosaicism confirmed in a phenotypically normal liveborn

Prenatal diagnosis of trisomy 20 mosaicism in this case was based on cytogenetic analysis of cultured amniotic fluid cells (23/52 cells were trisomy 20 representing cells from each of four primary cultures). The pregnancy continued to term and the mosaicism was confirmed in the phenotypically normal male neonate by analysis of cultured foreskin fibroblasts (7/49 cells + 20) and placental cells 20/20 cells + 20) whereas the peripheral lymphocytes were cytogenetically normal (20/20 cells were 46,XY). This represents the first confirmation of trisomy 20 mosaicism in a phenotypically normal full-term neonate.     

Uncommon chromosomal mosaicism in chorionic villi

Three cases of unusual chromosomal mosaicism are reported for which the cytogenetic data show inconsistent findings between CVS and AC or fetal tissue, and which cannot be explained simply by non-disjunction. For case 1, in CVS the karyotype was 46,XY, whereas lymphocytes and fibroblasts revealed 69,XXY. DNA fingerprinting indicated one paternal and two maternal chromosome sets, the latter most probably due to omission of maternal meiosis II. For case 2, in CVS mos 46,XX/47,XX,+mar de novo was observed. Amniotic fluid cells had the karyotype 46,XX. The origin of the marker chromosome might be explained by at least two events of unknown order (a somatic chromosome/chromatid deletion and non-disjunction of the homologous chromosome). In case 3 (CVS: mos 46,XY/46,XY,19q+ de novo; amniotic fluid cells, lymphocytes, and fibroblasts: 46,XY), the surplus of chromosome material in 19q+ might be explained on the basis of a somatic translocation. The idea of a chimera is less convincing, as the mosaic finding is restricted to one tissue. Furthermore, there was no hint of a vanishing twin. Hitherto, no case of structural chromosome mosaicism in CVS has been reconfirmed in fetal tissues.     

Identification of a case of maternal uniparental disomy of chromosome 10 associated with confined placental mosaicism

We report a case of maternal uniparental disomy of chromosome 10 discovered after chorionic villus sampling (CVS). Direct preparations revealed mosaic trisomy 10, while cultured CVS cells, as well as amniotic fluid cells, showed only a normal 46,XY complement. DNA analysis using microsatellite markers showed both chromosomes 10 to have been inherited from the mother. The pregnancy was complicated by polyhydramnios. A phenotypically normal male infant of appropriate size was delivered by Caesarean section at 41 weeks' gestation. Since only the direct preparations showed trisomy 10, this case illustrates the importance of CVS direct preparations in the detection of pregnancies at risk of uniparental disomy (UPD). Although the increased frequency of confined placental mosaicism (CPM) diagnosed when direct preparations are performed has been viewed negatively, identification of both CPM and UPD may have biological and clinical significance for a pregnancy. Even though only a single case of maternal disomy 10 is reported here, the apparently normal phenotype provides evidence that there are no major imprinted loci on chromosome 10 that affect in utero growth and development. However, other potential effects such as mental retardation will require long-term follow-up of this as well as additional cases.     

Fetal karyotype from cystic hygroma fluid

In cystic hygroma (CH) fetuses, hydrops fetalis and anamnios make it difficult or impossible to obtain amniotic fluid or cord blood for cytogenetic analysis. We report six cases of CH in which cytogenetic analysis was simply and successfully performed using nuchal fluid cells. The karyotypes were 47,XY, + 18,46,XY, 46,XX, and 45,X (n = 3).     

Distal partial trisomy 1q: report of two cases and a review of the literature

We report on two cases with partial trisomy 1q syndrome. One case was a mid-trimester fetus with multiple malformations that was prenatally diagnosed with a de novo distal partial trisomy 1q. Prenatal ultrasound at 24th gestational week demonstrated the presence of cleft lip and palate, increased biparietal diameter and decreased abdominal circumference. Cytogenetic analysis (GTG banding) and subsequent fluorescence in situ hybridization (FISH) using whole chromosome paint 1 and multicolor banding (MCB) demonstrated an aberrant karyotype 46,XY,dup(1)(q31q43∼44). The second case was a newborn male infant with multiple congenital malformations. He had a derivative chromosome 18 as a result of a maternal insertion involving chromosomes 1 and 18. Further analyses including MCB showed his karyotype as 46,XY,ins(18;1)(q22;q23q31.1∼32). The present cases and a review of the literature suggest that partial trisomy of the long arm of chromosome 1 is a distinct clinical entity. Copyright © 2007 John Wiley & Sons, Ltd.     

An accessory marker derived from chromosome 20 and its co-existence with a mosaic trisomy 20 cell line

We report a 16-month-old boy with delayed psychomotor development, dysmorphic features, and failure to thrive. He had a mosaic karyotype detected prenatally: mos 46,XY/47,XY,+r(20)/47,XY,+20. After birth, the abnormal cell lines were confirmed in a number of tissues. The small ring chromosome was identified using fluorescence in situ hybridization as derived from chromosome 20. We compared our patient with previously reported cases of mosaic trisomy 20 detected prenatally and associated with an abnormal phenotype. In an attempt to characterize an r(20) syndrome, we also compared our case with two similar reports in the literature.     

Prenatal diagnosis of partial trisomy 12q: clinical presentations and outcome

We present a pregnant woman with a fetus prenatally diagnosed as 46, XY,der(4) t(4;12) (q35.1; q21.2). This defect resulted from the unbalanced segregation of a paternal balanced translocation, t(4;12) (q35.1; q21.2). Prenatal ultrasound revealed borderline ventriculomegaly, a thick nuchal fold, pericardial effusion, arthrogryposis, a single umbilical artery, and micropenis. Fluorescence in situ hybridization (FISH) with whole chromosome painting probe and microarray-based comparative genomic hybridization analysis further confirmed chromosomal gain of terminal 12q. The woman had her pregnancy terminated at 20 weeks of gestational age. When compared with previously reported cases, the proband had characteristics common to the phenotypes of partial trisomy 12q, including an abnormal facial appearance and multiple anomalies. Additionally, this case had previously unreported phenotypes, such as arthrogryposis, a single umbilical artery, and a micropenis. Regarding the outcome of partial trisomy 12q, the fetuses carrying trisomies distal to 12q24 have a good chance of extended postnatal survival. In contrast, the cases with trisomies involving a larger amount of 12q likely die prenatally or within a few days after birth. Copyright © 2005 John Wiley & Sons, Ltd.     

Prenatal diagnosis of complete trisomy 19q

This communication presents the first case of complete trisomy 19q, prenatally detected by ultrasound investigation. Real-time high-resolution ultrasound examination was performed at 19 weeks of gestation. After termination of the pregnancy, autopsy investigation was done. GTG-banding, fluorescence in situ hybridization m-(FISH) analysis, and FISH analysis with a 19q subtelomeric specific probe were used for identification of the fetal karyotype. Sonographic examination revealed an enlarged cisterna magna, cerebellar hypoplasia and aplasia of the inferior part of the vermis, combined and bilateral kidney malformations, significant nuchal fold, absence of fetal nasal bones, and intracardial calcifications. Autopsy confirmed ultrasound findings, but also revealed situs viscerum inversus of the lungs. Fetal karyotype was defined as: 46,XY,der(21)t(19;21)(q11;p13)mat. Our ultrasound and autopsy findings will certainly contribute to better knowledge of phenotype characterization of this rare chromosomal disorder. Copyright © 2007 John Wiley & Sons, Ltd.     

Tetrasomy 12p—unusual presentation in CVS

CVS direct preparations usually achieve limited resolution and are better at detecting numerical rather than structural abnormalities. A CVS direct preparation analyzed using G-banding revealed a 47,XY,+G karyotype in 5 of 11 cells and was reported as mosaic for trisomy 21. Subsequent analysis of the CVS culture found only normal male cells. Amniocentesis revealed both normal male cells and cells with an extra F-group chromosome. Fluorescence in situ hybridization (FISH) identified this chromosome to be an isochromosome from the short arm of chromosome 12 [i(12)(p10)]. The amniocyte karyotype was reported as 47,XY,+i(12)(p10)[12]/46,XY[8].ish i(12)(p10)(wcp12+), which is associated with Pallister–Killian syndrome. Reexamination of the CVS direct preparation by FISH with a chromosome 12 centromere probe confirmed the karyotype of this tissue to be 47,XY,+mar[5]/46,XY[6].nuc ish 12cen(D12Z3 × 3)/12cen(D12Z3 × 2). Thus, multiple studies, including amniocentesis and fluorescence in situ hybridization, may be required to fully and accurately evaluate abnormalities detected by CVS. This case also indicates that mosaicism for supernumerary isochromosomes may have a complex origin. Copyright © 2003 John Wiley & Sons, Ltd.     

Outcome of prenatally diagnosed trisomy 6 mosaicism

We report the prenatal diagnosis of trisomy 6 mosaicism via amniocentesis, in which trisomy 6 cells were identified in three of five culture vessels with 33% (5/15) of colonies showing trisomic cells. The pregnancy was electively terminated and examination revealed minor abnormalities (shortening of the femurs, micrognathia, posterior malrotation of the ears, and bilateral camptomelia of the second digit of the hands and fifth digits of the feet). Cytogenetic analysis of the placenta showed trisomy 6 in 100% of 20 cells studied. Karyotype was 46,XX in 100 cells examined from fetal skin. There are relatively few prenatally diagnosed cases of mosaic trisomy 6 at amniocentesis. Confined placental mosaicism (CPM) has been postulated in other cases where follow-up cytogenetic studies were not available. The present case differs from those previously reported, as it appears to represent CPM of chromosome 6 with phenotypic effects to the fetus. Copyright © 2002 John Wiley & Sons, Ltd.