Del(18p) syndrome with increased nuchal translucency in prenatal diagnosis

We report a de novo translocation between chromosome 15 and 18 resulting in monosomy 18p in prenatal diagnosis. The patient was referred for amniocentesis due to increased nuchal translucency (INT) (5 mm) at 13.6 weeks of gestation. Karyotype of the fetus revealed 45,XX,der(15;18)(q10;q10) in all metaphases. The targeted fetal ultrasound at 20 weeks of gestation did not show any special physical abnormalities other than 6.4 mm of nuchal fold thickness. Molecular cytogenetic findings using CGH and FISH confirmed the del(18p) with dicentromeres from both chromosome 15 and 18. The present study shows that the INT at first trimester was the only prenatal finding for the fetus with del(18p) syndrome and that molecular cytogenetic methods are useful for detecting chromosomal aberrations precisely. Copyright © 2004 John Wiley & Sons, Ltd.     

Prenatal diagnosis of female monozygotic twins discordant for Turner syndrome: implications for prenatal genetic counselling

We describe a set of monozygotic (MZ) female twins, one of whom presented with a typical Turner syndrome (TS) phenotype and the other a normal female phenotype. Prenatal fetal ultrasonographic examination showed a monochorial diamniotic pregnancy with a hygroma colli and growth delay in Twin A and no anomalies in Twin B. Karyotypic analysis performed on fetal blood samples demonstrated a 46,XX/45,X (23/2) mosaicism in Twin A and a normal 46,XX chromosome constitution in Twin B. At birth, Twin A presented with a typical TS and Twin B had a normal female phenotype. Postnatal cytogenetic investigation of blood lymphocytes showed the same 46,XX/45,X mosaicism in both twins: 46,XX/45,X (40/7) in Twin A and 46,XX/45,X (40/5) in Twin B. Further investigations at the age of 10 months showed in Twin A a 46,XX/45,X (98/2) mosaicism in lymphocytes and 100% of 45,X (50 analysed cells) in fibroblasts, and in Twin B a normal 46,XX (100 analysed cells) chromosome constitution in lymphocytes but a mild 46,XX/45,X (78/2) mosaicism in fibroblasts. Monozygosity was confirmed by molecular analysis. To our knowledge, this is the first report of prenatal diagnosis of MZ female twins discordant for TS. Review of reported sets of MZ female twins (eight cases) or triplets (one case) discordant for TS shows, as in the present case, that the phenotype correlates better with the chromosomal distribution of mosaicism in fibroblasts than in lymphocytes. In the blood of MZ twins chimerism may modify the initial allocation of the mosaicism. These results suggest that, in cases of prenatal diagnosis of MZ female twins discordant for TS, the phenotype of each twin would be better predicted from karyotype analysis of cells from amniotic fluid than from fetal blood. Copyright © 2002 John Wiley & Sons, Ltd.     

An infant with trisomy 9 mosaicism presenting as a complete trisomy 9 by amniocentesis

We present a case in which amniocentesis performed at 33 weeks' gestation because of symmetrical intrauterine growth retardation and decreased amniotic fluid volume led to the prenatal diagnosis of a fetus with a karyotype of 47,XX,+9, t(1;20)(q42;p11.2) pat, i.e., with an extra chromosome 9 and a balanced translocation between chromosomes 1 and 20. At delivery, the baby showed clinical features of trisomy 9, yet chromosome analysis of the cord blood revealed no trisomy 9 cells, a finding confirmed by neonatal blood karyotyping. The balanced translocation was present in all cells. A skin biopsy confirmed trisomy 9 mosaicism with 10 per cent trisomy 9 cells. The baby died at 6 weeks and an autopsy was obtained. Chromosome analysis of different organs demonstrated different frequencies of the mosaicism of trisomy 9. The possible underlying mechanism for the discrepancy between the karyotype results by amniocentesis and those of other tissues is discussed.     

Prenatal diagnosis of a partial 8p

The index patient is a female fetus in which prenatal diagnosis of 8p trisomy was established after amniocentesis at 16 weeks of gestation. This fetus was the unbalanced product of a maternal translocation of 5q/8p (karyotype: 46,XX,t(5;8)(q35;pl 1). Internal malformations include an anomalous lobature of the right lung, a little and high atrio-ventricular communication, and an anomaly in the number and shape of the aortic semilunar valves. The possible relationship between the phenotype and the chromosomal abnormality is briefly discussed.     

Prenatal diagnosis of mosaicism 46, XX/46, XX, −21, +t(21q21q)

Mosaicism for a structural chromosome abnormality in amniotic cell cultures indicative of true fetal mosaicism is a rare event. In addition to the laboratory findings the clinical interpretation for counselling in such cases is based on observation of the same abnormality in liveborns as well as previous experience with prenatal diagnosis of the same or similar abnormalities. We report here the prenatal diagnos is of 46,XX/46,XX,−21,+t(21q21q) which was confirmed in fetal skin cell and amnion cell cultures.     

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.     

Prenatal diagnosis of an isochromosome 5p in a fetus with increased nuchal translucency thickness and pulmonary atresia with hypoplastic right heart at 14 weeks

We report on a fetus presenting with increased nuchal translucency at 11 weeks' gestation, suggesting cystic hygroma. Chorion villous sampling was performed, and cytogenetic analysis revealed a supernumerary isochromosome 5p leading to tetrasomy 5p: 47,XX,+ i(5p)[7]/46,XX[5] after short-term culture and 47,XX,+ i(5p)[20] after long-term culture. Subsequent targeted sonographic follow-up at 12 and 14 weeks revealed further increase of the NT to 6.4 mm and the additional presence of a congenital heart defect (pulmonary atresia with intact ventricular septum). Termination of pregnancy was performed, and the heart defect was confirmed. Isochromosome 5p was found in varying proportions in all examined organs. Only a few cases of mosaic tetrasomy 5p have been reported in the literature, and recent reports on prenatally detected isochromosome 5p showed a possible relationship to increased nuchal translucency in some cases and also a possible role of confined mosaicism in others. Whereas cases with confined mosaicism did not show suspicious signs on ultrasound, true mosaicism conversely showed increased nuchal thickness as well as structural abnormalities. This is the first report on the association of a cardiac defect with this chromosome aberration. Copyright © 2004 John Wiley & Sons, Ltd.     

Prenatal diagnosis,fetal pathology,and cytogenetic analysis of mosaic trisomy 14

While true mosaicism occurs in only 0–25 per cent of genetic amniocenteses, nearly 2–5 per cent of amniotic fluid cell cultures contain a second cell line. In the common practice of prenatal diagnosis, an aberrant cell line confined to a single colony is usually disregarded. We present a case of mosaic trisomy 14 which was not detected on initial chromosome analysis. At birth, multiple malformations were apparent. Newborn cytogenetic studies revealed mosaicism [46,XX/46,XX,-14,+i(14q)] with an isochromosome 14 in 37 per cent of lymphocytes. Additional cells from the initial amniotic fluid culture were analysed post-delivery and the isochromosome 14 identified in only one of 12 total colonies. This case illustrates two important lessons in prenatal diagnosis. First, amniotic fluid cell cultures may not accurately reflect the relative distribution of the normal and abnormal cell lines within a mosaic fetus. Second, while it is generally reasonable to disregard mosaicism confined to a single colony, this policy will, on rare occasion, result in diagnostic error. This should be taken into consideration, particularly when dealing with autosomal trisomies potentially compatible with livebirth.     

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.     

Prenatal diagnosis and post-mortem study of a fetus with mosaic trisomy 14 due to a dic(14)(p11)

Amniocentesis at 17 weeks' gestation revealed a mosaic karyotype—46,XX/46,XX, — 14,+dic(14)(p11). No abnormalities were detected on ultrasound. Growth and placentation were normal. The fetus was examined after termination of pregnancy and micrognathia and pulmonary hyperlobation were the only abnormalities detected. Several tissues were set up for cytogenetics, including fetal skin, kidney, ovary, and placenta. The diagnosis was confirmed by these studies. The level of mosaicism varied between tissues, with the trisomy 14 cell line highest in amniotic fluid.     

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.     

Duplication of chromosome 2 in association with ventriculomegaly — a case report

This is a case report of the prenatal diagnosis of a de novo interstitial duplication of chromosome 2 (46,XX,dup(2)(p13p21) de novo) with an associated phenotypic abnormality. This chromosomal duplication is rare, only one has previously been described prenatally. Postnatal reports of similar duplications in this region have described associated dysmorphic features and significant neurodevelopmental delay. In our case, the only ultrasound finding was moderately severe ventriculomegaly. At post-mortem, ventriculomegaly was confirmed and there was associated macrocephaly (head circumference above the 97th centile) with no dysmorphic features seen. Copyright © 2001 John Wiley & Sons, Ltd.     

Prenatal diagnosis of a homologous Robertsonian translocation involving chromosome 15

We report the prenatal diagnosis of a fetus with a de novo Robertsonian translocation: 45,XY,der(15;15)(q10;q10). Although Robertsonian translocations are common chromosomal rearrangements, those involving homologous chromosomes are infrequent. Since chromosome 15 is imprinted, uniparental disomy (UPD) is a concern when chromosomal rearrangements involving chromosome 15 are identified. In the present case, UPD studies showed normal biparental inheritance. In contrast to the fact that most homologous acrocentric rearrangements are isochromosomes, these results indicate postzygotic formation of a Robertsonian translocation between biparentally inherited chromosomes 15. Copyright © 2001 John Wiley & Sons, Ltd.     

Mosaicism or pseudomosaicism: The problem of hypermodal cells in amniotic fluid cell culture

A series of 2029 consecutive amniotic fluid specimens studied for prenatal genetic diagnosis were reviewed and reassessed so as to evaluate the frequency and clinical significance of hypermodal cells in amniotic fluid cell cultures. Hypermodal cells were defined as those with more than 46 chromosomes, and were characterized by an additional structurally normal or structurally abnormal chromosome. Of 2029 specimens, 47 (2.31 per cent) contained a total of 167 hypermodal cells. True fetal mosaicism was detected in three cases (0.14 per cent). All had hypermodal cells in more than one culture flask or colony which contained the same aberrant chromosome complement. In all but one case the babies were normal when only one cell was hypermodal, or when several cells were hypermodal but present in only one colony or one culture vessel. One case had an extra No. 20 chromosome in one cell. Although the child had multiple anomalies, they were not characteristic of trisomy 20, and subsequent chromosomal study on the baby postnatally revealed a 46,XX karyotype. The in situ coverslip technique is recommended as the preferred method for prenatal diagnosis, and it is useful as an aid in differentiating true mosaicism from pseudomosaicism.     

Fetoplacental discrepancy involving structural abnormalities of chromosome 8 detected by prenatal diagnosis

We describe the finding of three cell lines involving different structural abnormalities of chromosome 8 detected in a prenatal diagnosis. Chorionic villi sampling (CVS) was performed on a pregnant woman because of advanced maternal age. Semidirect cytogenetic analysis showed a mos46,XX,i(8q)/46,XX,del(8)(p11.2) karyotype, confirmed by fluorescence in situ hybridization (FISH). Amniocentesis was subsequently performed, and the karyotype obtained was 46,XX,dup(8)(p23p11.2). The pregnancy was terminated; pathologic findings included clubfeet, clenched left hand, subcutaneous edema and bilateral hydrocephalus. Molecular studies using chromosome 8 microsatellites performed on parents' blood and fetal tissues revealed a maternal meiotic origin of the inv dup(8p) with deletion of the distal p23 region and duplication of the remaining 8p. We propose a model to explain the cytogenetic findings, which includes a first maternal meiotic error giving rise to a large dicentric isochromosome 8 present in the ovum, a second error in one of the first zygote divisions with misdivision of the dicentric 8 giving rise to a cell line with del(8p) confined to the trophoblast and another cell line with inv dup(8p) confined to the fetal tissue and a third error in the trophoblast giving rise to a further cell line with isochromosome 8q. Copyright © 2003 John Wiley & Sons, Ltd.     

Prenatal diagnosis and fetal pathology of partial trisomy 20p–monosomy 4p resulting from paternal translocation

Amniocentesis was performed in view of a paternal balanced chromosomal rearrangement t(4;20)(p16;p12), inv(18)(p11q11). The pregnancy was complicated by severe oligohydramnios. The fetal karyotype was unbalanced: 46XX, der(4), t(4;20)(p16;p12), inv(18) (p11q11)pat., thus resulting in partial trisomy 2Op and monosomy 4p. In addition, the amniotic fluid alpha-fetoprotein (AFP) became increasingly elevated with gestational age. The pregnancy was terminated at 25 weeks. The fetus presented with typical facial dysmorphic features, unilateral cleft lip and palate, severe renal hypoplasia, consistent with the 4p- (Wolf-Hirschhorn) syndrome.     

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.     

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.     

Follow-up and pregnancy outcome after a diagnosis of mosaicism in CVS

In 2103 consecutive diagnostic chorionic villus samples, examined in a 4-year period in our clinical genetics unit, 26 samples (1.2 per cent) presented chromosomal mosaicism in the direct and/or long-term culture preparations. Only once (46,XX/47,XX,+9) was the mosaicism confirmed in the fetus. In the cytogenetic follow-up studies of the remaining 25 pregnancies, in no cases could the aberration be confirmed in amniotic fluid or fetal tissue. One patient requested a termination after the CVS result. Of the remaining 24 pregnancies, four (16.7 per cent) ended in a spontaneous abortion. These findings suggest an association between placental mosaicism and fetal loss.     

Monosomy X rescue explains discordant NIPT results and leads to uniparental isodisomy

Noninvasive prenatal testing accurately detects trisomy for chromosomes 13, 21, and 18, but has a significantly lower positive predictive value for monosomy X. Discordant monosomy X results are often assumed to be due to maternal mosaicism, usually without maternal follow-up. We describe a case of monosomy X-positive noninvasive prenatal testing that was discordant with the 46,XX results from amniocentesis and postnatal testing. This monosomy X pregnancy doubled the single X chromosome, leading to 45,X/46,XX mosaicism in the placenta and uniparental isodisomy X in the amniotic fluid. Thus, at least some discordant monosomy X results are due to true mosaicism in the pregnancy, which has important implications for clinical outcome and patient counseling.