Trisomy 20 mosaicism

A further case of trisomy 20 mosaicism found at amniocentesis is presented. Pregnancy was terminated, the fetus showed facial dysmorphia and minor cardial and renal anomalies. 19 published reports of true trisomy 20 mosaicism at amniocentesis are reviewed. Five pregnancies resulted in obviously normal newborns. The significance of mostly minor anomalies found at autopsy of 7 fetuses remains unclear. With regard to genetic counselling the significance of trisomy 20 mosaicism is summarized as follows: (1) true trisomy 20 mosaicism in amniotic fluid cells reflects mosaicism of the fetus; (2) severe malformation is not a major feature of trisomy 20 mosaicism; (3) the risk of mental retardation is still undetermined, due to limited experience. However, there is no definite proof that the condition is harmful at all.     

Trisomy 20 mosaicism in a foetus

A widespread distrust in the significance of the observation of trisomy 20 mosaicism in amniotic fluid cultures has led to an increasing belief that this particular type of aneuploidy is of extra foetal origin and is clinically incosequential. The report presents an example of amnoitic fluid cell mosaicism for trisomy 20 which was ultimately confirmed in the foetus, and proposes that, in spite of the absence of obvious congenital malformation from the foetus, trisomy 20 mosaicism in amnoitic fluid cultures should be regarded with the same deference as mosaicism for any other autosome of unknown effect.     

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.     

Trisomy 20 mosaicism in amniotic fluid cells

The significance of trisomy 20 mosaicism in cultured amniotic fluid cells is still confusing. We report a case of amniotic cell normal/trisomy 20 mosaicism diagnosed prenatally. The pregnancy was carried to term and a normal baby girl was delivered. The authors consider that in cases of amniotic fluid cell normal/trisomy 20 mosaicism the termination of pregnancy may not be advised, however, the parents should be fully informed.     

Prenatal detection of chromosomal mosaicism

A significant problem associated with cytogenetic prenatal diagnosis is distinguishing between true and pseudomosaicism. This becomes a diagnostic dilemma when fetal mosaicism corresponds with a known clinical entity. True mosaicism reportedly occurs with a frequency of 0·2 per cent and pseudomosaicism in 0·7 per cent to 2·7 per cent of cases. In the past 12 months, our laboratory has completed 522 fetal karyotypes. Nine cases were found to demonstrate mosaicism, 4 true mosaics (0·8 per cent) and 6 pseudomosaics (1·1 per cent). One case demonstrated both true and pseudomosaicism. In all cases of true mosaicism, the pregnancy was continued and karyotypes completed at birth. Our results demonstrate a danger of rigid adherence to the criteria for true and pseudomosaicism in the examination of amniotic fluids. It is suggested that the criteria established for true and pseudomosaicism may not be valid when an aberrant cell line is found in a single flask and when that aberrant cell line is compatible with a known clinical entity due to a chromosome anomaly.     

Prenatal diagnosis of chromosome mosaicism

The frequency of mosaicism and pseudomosaicism in the prenatal diagnosis of cytogenetic disorders is reported, based on 3000 pregnancies studied in our laboratory. Diagnosis of true mosaicism was only made when an abnomality was detected in two or more independent cultures established from an amniotic fluid sample. On this basis, 0.37 per cent of all cases were diagnosed as true mosaics. 1.07 per cent of all cases had pseudomosaicism involving more than one cell from the same culture with an identical abnormality. 4.13 per cent of cases had a single abnormal cell with an extra chromosome, loss of a sex chromosome (or part of a sex chromosome), or translocation. Details of the outcome and follow-up of cases is given. Particularly problematical were cases where multiple cells from one culture contained an abnormality which could have been clinically significant. A crude estimate of the extent to which true mosaicism might currently be misinterpreted as pseudomosaicism or entirely missed has been made, based on data from the U.S. survey (Hsu and Perlis, in press). It was concluded that even when two, and if necessary a third culture is extensively analysed with an average of 24 cells per culture counted, at least 4.5 per cent of cases of true mosaicism may be completely missed and at least 7 per cent could be misdiagnosed as pseudomosaicism. There is an urgent need for improved laboratory techniques which allow growth of a greater number of cell colonies and therefore a more broadly based analysis. Detailed long term follow-up of prenatally diagnosed mosaics is also essential for assessing the clinical significance of the laboratory findings.     

Confined placental mosaicism in CVS and pregnancy outcome

The perinatal outcome of 26 patients with confined placental mosaicism (CPM) detected in chorionic villus sampling (CVS) who wished to continue their pregnancies was compared with that of two controls per patient matched for age and parity (n=52). There were no significant differences in birth weight or gestational age at delivery between patients with CPM and controls. There were no cases of intrauterine growth retardation (IUGR) in the CPM patients as compared with two (2/52, 3·8 per cent) in the control group (P>0·05). There was no significant increase in fetal loss between the study group (1/26, 3·6 per cent) and the controls (1/52, 1·9 per cent) (P>0·05).     

Proposed guidelines for diagnosis of chromosome mosaicism in amniocytes based on data derived from chromosome mosaicism and pseudomosaicism studies

Currently, accepted protocol which has been developed at the Prenatal Diagnosis Laboratory of New York City (PDL) requires that when a chromosome abnormality is found in one or more cells in one flask, another 20–40 cells must be examined from one or two additional flasks. Chromosome mosaicism is diagnosed only when an identical abnormality is detected in cells from two or more flasks. In a recent PDL series of 12 000 cases studied according to this protocol, we diagnosed 801 cases (6.68 per cent) of single-cell pseudomosaicism (SCPM), 126 cases (1.05 per cent) of multiple-cell pseudomosaicism (MCPM), and 24 cases (0.2 per cent) of true mosaicism. Pseudomosaicism (PM) involving a structural abnormality was a frequent finding (2/3 of SCPM and 3/5 of MCPM), with an unbalanced structural abnormality in 55 per cent of SCPM and 24 per cent of MCPM. We also reviewed all true mosaic cases (a total of 50) diagnosed in the first 22000 PDL cases. Of these 50 cases, 23 were sex chromosome mosaics and 27 had autosomal mosaicism; 48 cases had numerical abnormalities and two had structural abnormalities. Twenty-five cases of mosaicism were diagnosed in the first 20 cells from two flasks, i.e., without additional work-up, whereas the other 25 cases required extensive work-up to establish a diagnosis (12 needed additional cell counts from the initial two culture flasks; 13 required harvesting a third flask for cell analysis). Our data plus review of other available data led us to conclude that rigorous efforts to diagnose true mosaicism have little impact in many instances, and therefore are not cost-effective. On the basis of all available data, a work-up for potential mosaicism involving a sex chromosome aneuploidy or structural abnormality should have less priority than a work-up for a common viable autosomal trisomy. We recommend revised guidelines for dealing with (1) a numerical versus a structural abnormality and (2) an autosomal versus a sex chromosome numerical aneuploidy. Emphasis should be placed on autosomes known to be associated with phenotypic abnormalities. These new guidelines, which cover both flask and in situ methods, should result in more effective prenatal cytogenetic diagnosis and reduced patient anxiety.     

Confirmation of CVS mosaicism in term placentae and high frequency of intrauterine growth retardation association with confined placental mosaicism

About 2 per cent of specimens from chorionic villus sampling (CVS) analysed either on direct preparation of cytotrophoblast cells or afterculture of mesenchymal stroma reveal confined placental mosaicism (CPM), most commonly involving chromosomal trisomy. A significantly higher rate of prenatal loss (22 per cent) as well as the presence of intrauterine growth retardation (IUGR) has been reported among pregnancies with CPM. To evaluate more precisely the effect of these aneuploid cell lines confined to the placenta on intrauterine fetal growth and fetal survival, we have studied 34 term placentae from pregnancies with CPM diagnosed on CVS and confirmed identical mosaicism in 17 of these placentae. There was a direct correlation between a high number of aneuploid cells present at CVS and a high likelihood of their detection in term placenta. Also, the proportion of aneuploid cells in the mosaic term placentae correlated with that observed in CVS specimens. Among 17 gestations with confirmed CPM at delivery, there were six cases of IUGR identified, five in liveborns and one associated with intrauterine death.     

Prenatal detection of monosomy 21 mosaicism

We report a case of chromosomal mosaicism for monosomy 21 revealed in amniotic fluid cell culture. Ultrasound examination at 19 weeks' gestation showed in utero growth retardation and a complex cardiac malformation. A repeated amniocentesis confirmed the presence of monosomy 21 mosaicism. In view of the sonographically detected fetal abnormalities, termination of pregnancy was elected.     

Complex mosaicism associated with trisomy 9

Fetal karyotypes can be routinely obtained by chorionic villus biopsy, amniocentesis, or fetal blood sampling. Interpretation of results and subsequent counselling can be complicated by pseudomosaicism or mosaicism confined to the placenta or other tissues. We illustrate this by reporting a case of an abnormal fetus with a total of three karyotypically different cell lines (46,XXrpar; 47,XX, + 9; and 47,XX, + del (9) (q11) in different tissues (placenta, lung, gonad, and skin).     

Prenatal detection of trisomy 9 mosaicism

Chromosomal mosaicism in amniotic fluid cells poses a serious dilemma in prenatal diagnosis since the observation may represent: (1) pseudomosaicism—an inconsequential tissue culture artefact; or (2) true mosaicism—occurring in approximately 0.0 per cent of amniocenteses with a significant impact on pregnancy outcome. Mosaicism for trisomy 9 was observed in an amniotic fluid specimen obtained for advanced maternal age with two cell lines [46,XX (46 per cent)/47,XX, + 9 (54 per cent)] present in each of four culture flasks. Since more than 75 per cent of newborns with trisomy 9 mosaicism have complex cardiac malformations, a fetal echocardiogram was obtained at 20 weeks' gestation and interpreted as normal. A fetal blood sample (22 weeks' gestation) disclosed only a single trisomy 9 cell among the 100 metaphases analysed. However, a second fetal echocardiogram performed at the time of blood sampling suggested a non-specific cardiac anomaly. Fetal autopsy following elective pregnancy termination revealed several malformations including severe micrognathia, persistence of the left superior vena cava, and skeletal anomalies. Cytogenetic studies of cell cultures derived from several fetal tissues demonstrated trisomy 9 ranging from 12 to 24 per cent.     

Prenatal diagnosis of trisomy 6 mosaicism

We report on a fetus with multiple congenital anomalies detected at the prenatal ultrasound examination and a trisomy 6 mosaicism in the amniocytes. The pregnancy was interrupted in the 18th gestational week and the autopsy revealed malformations including cleft right hand, arthrogryposis and hypoplasia of the 4th digit of the left hand, syndactylies and overlapping toes, facial dysmorphism with hypertelorism and low-set ears, ventricular septum defect (VSD), intestinal malrotation and scoliosis. Trisomy 6 mosaicism was detected in cultured amniocytes (13.3%), confirmed in umbilical cord fibroblasts (40%) and by fluorescence in situ hybridization on other fetal tissues. Trisomy 6 mosaicism is a very rare finding with only eight cases previously reported to our best knowledge. Copyright © 2005 John Wiley & Sons, Ltd.     

Structural chromosomal mosaicism and prenatal diagnosis

True structural chromosomal mosaicism are rare events in prenatal cytogenetics practice and may lead to diagnostic and prognostic problems. Here is described the case of a fetus carrying an abnormal chromosome 15 made of a whole chromosome 2p translocated on its short arm in 10% of the cells, in association with a normal cell line. The fetal karyotype was 46,XX,add(15)(p10).ish t(2;15)(p10;q10)(WCP2+)[3]/46,XX[27]. Pregnancy was terminated and fetus examination revealed a growth retardation associated with a dysmorphism including dolichocephaly, hypertelorism, high forehead, low-set ears with prominent anthelix and a small nose, which were characteristic of partial trisomy 2p. Possible aetiologies for prenatal mosaicism involving a chromosomal structural abnormality are discussed. Copyright © 2004 John Wiley & Sons, Ltd.     

Prenatal diagnosis of trisomy 18 mosaicism

Trisorny 18 mosaicism was found in multiple primary cultures of amniotic fluid cells and subsequently confirmed by chromosome analysis of several tissues derived from the aborted fetus. The overall frequency of the minority cell line was 25 per cent in the amniotic fluid cultures and 28 per cent in the fetal tissues although much intertissue variations were noted.     

Chromosomal mosaicism confined to chorionic tissue

Chorionic villus samples from two healthy pregnant females were obtained for first trimester fetal diagnosis. The karyotypes were 46, XX/47, XX, +3 and 46, XX/47, XX, +15, respectively. In both cases fibroblast cultures after termination of pregnancy were shown to have normal karyotypes.