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.     

Partial trisomy 22q12→qter in prenatal diagnosis

Ultrasound examination of a 27-year-old primigravida at 26 weeks' gestation revealed fetal growth retardation, malformation of the ventricular septum, and a neck fold. Chromosome analysis of the amniotic fluid showed an abnormal 46,XY karyotype with an obvious meta-centric chromosome 17. Chromosome analysis of the mother revealed a balanced t (17;22) (p13;q12) translocation. The fetus thus has a rare familial duplication 22q12→qter. Eight live-born and severely malformed infants with this duplication have been reported in the literature.     

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.     

Mosaic trisomy 17 in amniotic fluid cells not confirmed in the newborn

A case of true fetal mosaicism 46,XY/47,XY, + 17 was diagnosed in amniotic fluid cells. After genetic counselling and unsuccessful periumbilical blood sampling the pregnancy continued to term, and a healthy male infant was born. Lymphocytes of the newborn had a normal karyotype. Follow-up of the child at age 18 months showed normal physical and mental development indicating that the trisomic cell line was restricted most probably to the extra fetal tissue.     

The value of chromosome analysis in cases of neural tube defects: A case of anencephaly associated with fetal DUP(2) (p24→pter)

A family is described in which two anencephalic fetuses were identified in two pregnancies. Autopsy revealed kidney anomalies in both fetuses. Chromosome analysis was performed only on the second fetus, which had a 46,XY,lOq+ karyotype. Parental chromosome analysis showed the maternal karyotype to be 46,XX,t(2;10) (p24;q26) thus demonstrating that the fetus was carrying a duplication 2(p24→pter). Recurrence risks for anencephaly based on the cytogenetic abnormality were much higher than those which would be quoted for isolated anencephaly. This points out the necessity for complete diagnostic studies when a fetus with a neural tube defect is identified. The literature in regard to the 2p duplication phenotype is reviewed. It is possible that the duplication of the distal segment of 2p results in a neural tube defect/kidney anomaly phenotype.     

Prenatal detection of 45,X/46,XX/47,XXX mosaicism through amniocentesis: Mosaicism confirmed in cord blood,amnion, and chorion

Sex chromosome mosaicism in amniotic fluid cells poses a serious dilemma in prenatal diagnosis. Chromosome analysis of 56 primary clones of amniocytes revealed three distinct cell lines. Nine cells (16.1 per cent) demonstrated a 45,X karyotype, 11 cells (19.6 per cent) a 47,XXX karyotype, and the remaining 36 cells (64.3 per cent) had a modal number of 46 chromosomes (46,XX). Cytogenetic evaluation of 100 cells from cord blood, amnion, and chorion following delivery confirmed this triple mosaicism. However, the distribution of the three karyotypes in the pre- and postnatal samples was not found in the same proportions. The cord blood had the most similar frequency to that of the amniotic fluid sample, while the chorion had a significantly increased frequency of 47,XXX cells (41 per cent) and a decreased frequency of 45,X cells (2 per cent). Physical examination of the infant at birth revealed no discernible phenotypic abnormalities. Parental karyotypes were normal. This case highlights the difficulty in determining whether a prenatally detected abnormality will be associated with postnatal phenotypic deviation.     

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.     

Two unbalanced segregation products due to a maternal t(7;16)inv(16)

We report a prenatal case of a maternally inherited abnormal chromosome 16, originally interpreted as a pericentric inversion only, but after family studies re-interpreted as a pericentric inversion (16) accompanied by an unbalanced (7;16) translocation. Because of the inversion 16 and an elder son with developmental delay and craniofacial dysmorphic features, in the past karyotyped as 46,XY, the chromosomes 16 of the mother and son were carefully re-examined. Using a whole chromosome 16 paint and sub-telomere probes of 16p and 16q, the karyotype of the mother was shown to be 46,XX,inv(16)(p11.2q23.2).ish t(7;16)(q36;p13.3)inv(16). Subsequently one chromosome 16 of the elder son appeared to be a der(16)t(7;16)(q36;p13.3). This is probably the result of a meiotic crossover between the chromosomes 16 in the mother. The prenatal karyotype was finally interpreted as 46,XY,inv(16)(p11.2q23.2).ish der(16)t(7;16)(q36;p13.3)inv(16). This is the same cytogenetic imbalance as his elder brother: a partial trisomy of chromosome 7 (q36→qter) and a partial monosomy of chromosome 16 (p13.3→pter). Copyright © 2001 John Wiley & Sons, Ltd.     

A fetus with a chromosome 13 ring and placenta with chromosome 13 rod/ring mosaicism

A fetus was identified by prenatal cytogenetic diagnosis as having a karyotype 46,XY,r(13) (p11q13). Termination of the pregnancy yielded a severely malformed fetus. Fetal abnormalities included anencephaly, imperforate anus and urethral meatus, severe talipes, syndactyly, cardiac defects and other anomalies. Confirmatory studies on cultured placental villi cells indicated a second cell line, 46,XY, −13,+ 13qter→cen::13ql3→qter. This cell line was not detectable in cells derived from the fetus despite extensive studies. It seems likely that the two cell lines arose simultaneously with selection favouring the 46,XY,r(13) line. How the chromosome rearrangements may have arisen is discussed. We are unaware of other cases where a cell line identifiable by a chromosome abnormality appeared to be confined to placental tissue. However, studies on placental tissue may be helpful in understanding the origin of other unbalanced de novo rearrangements.     

Prenatal diagnosis and characterization of an analphoid marker chromosome 16

We report on a fetus with intrauterine growth retardation and multiple malformations diagnosed on ultrasound at 32 weeks. Examination of amniotic fluid cells in culture showed a 47,XY, i(16)(q10), +mar karyotype. Chromosome analysis of both parents was normal. Using spectral karyotyping, we identified the marker chromosome as a mitotically stable acentric marker chromosome derived from chromosome 16. Further studies using subtelomeric fluorescent probes confirmed the presence of an isochromosome for the long arm of chromosome 16 and showed that the acentric marker chromosome derived from the short arm of chromosome 16 leading to a trisomy for the long arm of chromosome 16. After genetic counseling, the parents decided to terminate the pregnancy. Fetal autopsy showed a male fetus with ambiguous external genitalia, cardiac malformation, megacystis and limbs anomalies as observed in other cases of trisomy for the long arm of chromosome 16. In addition, fetal brain examination showed vermian and olfactory bulb hypoplasia. Copyright © 2004 John Wiley & Sons, Ltd.     

Prenatal diagnosis of tetrasomy 12p by in situ hybridization: Varying levels of mosaicism in different fetal tissues

Prenatal diagnosis of tetrasomy 12p is complicated by the discrimination of the 12p isochromosome from the duplication 21q as well as the level of mosaicism demonstrated in the particular tissue sampled. In this disease, a high percentage of chromosomally abnormal cells are generally found in fibroblastic cells, but lymphocyte karyotypes from the same individual may be normal. We report on the pregnancy of a 37-year-old female who presented to our centre at 16 weeks' gestation for genetic amniocentesis. Sonography of the fetus revealed dextrocardia and diaphragmatic hernia. Chromosome analysis of amniocytes demonstrated mosaicism of a 47,XY,+i(12p) line in 80 per cent of cells and a normal male line (20 per cent), consistent with the Pallister-Killian syndrome. Following termination, a 220 g male fetus of 18 weeks was examined. A flattened nose and low-set ears were noted. In situ hybridization with a chromosome 12 centromeric probe in lymphocytes and skin cells unequivocally confirmed the karyotype and showed the presence of a single centromere in the abnormal chromosome, suggesting a true isochromosome. Chromosome analysis of various fetal tissues was performed and the following percentages of abnormal cells were found: skin 100 per cent, chorion 50 per cent, placenta 30 per cent, and blood 80 per cent. The high frequency of tetrasomic cells in fetal blood at this early gestational age is noteworthy, since most reports of this syndrome show a very low percentage of abnormal cells postnatally.     

46,XY/47,XY,+ 17p+ mosaicism in amniocytes associated with fetal abnormalities despite normal fetal blood karyotype

46,XY/47,XY, + 17p + mosaicism was found in two primary amniotic fluid cultures (AFCs). Fetal blood karyotype was normal, but ultrasonography revealed Dandy-Walker malformation and bilateral choroid plexus cysts. Following termination of pregnancy, fetal examination revealed post-axial polydactyly and neuroblastoma-in-situ affecting both adrenals in addition to the cerebellar abnormalities. Mosaicism for the aberrant cell line was confirmed in all fetal tissues sampled and in the placenta.     

A case of paternal uniparental disomy for chromosome 11

We report a case of paternal uniparental disomy for chromosome 11 that presented as severe intrauterine growth retardation. Autopsy following intrauterine death also revealed aberrant intestinal rotation and hypospadias. Chromosome analysis of direct preparations from placental biopsy showed an abnormal 47,XY,+11 karyotype. Analysis of long-term cultures from the placenta revealed 46,XY/47,XY,+11 mosaicism. Fluorescence in situ hybridization (FISH) studies on interphase nuclei confirmed trisomy 11 in multiple placental sites but detected only disomic cells in fetal skin. Investigation using microsatellite polymorphisms demonstrated paternal isodisomy at loci D11S909, D11S956, and D11S488, and paternal heterodisomy at locus D11S928.     

Placental mosaicism in a case of 46,XY, −22, +t(22;22)(p11;q11) or i(22q) diagnosed at amniocentesis

46,XY, −22,+t(22;22)(p11;q11) or i(22q) was diagnosed in 15/15 cells from two cultures from the amniotic fluid culture of a 31-year-old patient whose fetus demonstrated cystic hygroma on ultrasound. Cytogenetic studies performed on fetal skin from the abortus revealed the same karyotype as that seen on amniocentesis, but the placenta demonstrated a 46,XY,46,XY, −22,+t(22;22) or i(22q) mosaicism, with 65 per cent of the cells being 46,XY. This case provides an example of placental mosaicism for a normal male karyotype, while the fetus demonstrated non-mosaic trisomy 22.     

Prenatal diagnosis of familial ring 21 chromosome

Ring chromosome 21 is a rare chromosome anomaly often associated with mental retardation and dysmorphic features. Less commonly, the ring chromosome can be familial and associated with a normal phenotype. Phenotypically normal female carriers, however, are at increased risk of having children with Down syndrome, mosaic monosomy 21, and variable duplication or deletion of chromosome 21. Because of the relative mitotic and meiotic instability of ring chromosomes, abnormal cytogenetic findings encountered during prenatal diagnosis may not reflect the true genetic status of the fetus. This is a report of a phenotypically normal female carrier of a familial ring 21 chromosome. Prenatal diagnosis on her twin pregnancy revealed a mosaic 46,XX,r(21)(p13;q22) (77 per cent)/45,XX, – 21 in one fetus and a normal male karyotype in the second. The pregnancy was carried to term. Both infants are completely normal, with a non-mosaic ring 21 karyotype from the lymphocytes of one twin. The diagnostic uncertainty and problematic genetic counselling related to fetal cytogenetic abnormalities are the subjects of this report.     

Discordance between prenatal cytogenetic diagnosis and outcome of pregnancy

From 1.3.73 to 30.9.80 5580 women had an amniocentesis performed here or elsewhere; fetal chromosome analyses were carried out in this laboratory. We found 112 abnormal karyotypes (2 per cent) out of 5591 chromosome analyses. In 40 women (0.7 per cent) no cytogenetic diagnosis was obtained. Follow-up was successful in 99.5 per cent. Nine cases are reported in detail: Three cases had discrepancy between the karyotype in amniotic fluid and peripheral blood after delivery, two of these cases turned out to be 46,XX (male) while the third was prenatally determined as trisomy 21, but had a 46,XX karyotype at birth. Six cases had discrepancy between the karyotype in amniotic fluid and the phenotypic outcome at birth/abortion. One case was a prenatally undetected 45,X/46,XY mosaicism; one case was an unexplained 45,X male fetus; two cases were prenatally determined as trisomy 21, but at abortion a normal karyotype was determined and in two cases maternal cells were probably examined. The incidence of cytogeneric errors in this study was very low.     

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.     

Normal karyotype in cultured chorionic villus cells,but mosaicism in amniotic and fetal cells

A case with a normal male karyotype in cultured chorionic villus cells, but 46,XY/45,X/ 46,X,i(Yq) mosaicism in amniotic and fetal tissue is reported. The fetus was a phenotypic male. Pathological examination revealed discrete features, which might indicate a syndrome, and histological examination showed large, bright cells in the tubules of the testes. Possible explanations for discordance between the karyotype of embryonic and extraembryonic tissue are discussed.     

Prenatal diagnosis of a de novo unbalanced translocation (4p + ) following in vitro fertilization

We report herein a de novo unbalanced chromosome translocation in a fetus resulting from in vitro fertilization technology. Prenatal diagnostic analysis of an amniotic fluid revealed a 46,XX,4p+ karyotype. The origin of the extra material on the short arm of chromosome 4 could not be identified by a variety of banding techniques. However, examination of fetal parts did reveal some dysmorphic features.     

Familial marker chromosome due to 3:1 Disjunction of t(9;15) in a grandparent

An extra small chromosome detected in amniotic fluid was identified as the product of a translocation [46,XX,t(9;15)(p24;q11.2)]. This case is unusual in that individuals with the unbalanced karyotype resulting from a 3:1 disjunction are phenotypically normal.