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 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.     

Prenatal diagnosis of 47,XX,der(15)t(15;16)(q13;p13.2)

A case of prenatally detected partial trisomy 15 and 16 is reported. Amniocentesis was performed at 14 weeks' gestation because a 6-mm nuchal translucency was detected on a dating ultrasound evaluation. Karyotype from amniocytes was suspect of an aberration concerning a marker chromosome. FISH analysis demonstrated that this marker chromosome was a der(15). A maternal chromosomal rearrangement t(15;16)(q13;p13.2) was confirmed. At birth, the proband was severely hydropic and had dysmorphic features, which included hypertelorism, micrognathia, incomplete separation of the maxilla and mandible, hyperflexed hands with overlapping fingers, hyposegmented right lung, and a single umbilical artery. Copyright © 2004 John Wiley & Sons, Ltd.     

Prenatal diagnosis of a familial complex chromosomal rearrangement involving chromosomes 5, 10, 16 and 18

We report one case of a familial complex chromosomal rearrangement (CCR) involving four different chromosomes 5, 10, 16 and 18. The CCR was detected prenatally at 20 weeks' gestation because of advanced maternal age and history of recurrent miscarriages. Cytogenetic analysis of cultured amniotic fluid cells with GTG banding showed a 46,XX,t(5;16;10;18)(q13;q22;q11.2;q21) karyotype. Parental cytogenetic study revealed that the mother has the same CCR. RBG banding, high-resolution banding and fluorescence in situ hybridization (FISH) were used to characterize further and confirm the conventional banding data. No physical abnormalities were shown in the targeted fetal ultrasonography examination. The parents decided to continue the pregnancy. The child is now 2 years old and has neither congenital anomalies nor evidence of delayed psychomotor development. The fetal targeted ultrasound and FISH analysis helped us reassure fetal status. Copyright © 2002 John Wiley & Sons, Ltd.     

Fetal phenotype of Prader–Willi syndrome due to maternal disomy for chromosome 15

Prader–Willi syndrome (PWS) results from either paternal deletion of 15q11–q13, or maternal uniparental disomy (UPD) of chromosome 15 or imprinting center mutation. Prenatal diagnosis of PWS is currently indicated for chromosomal parental translocation involving chromosome 15 and for decreased fetal movements during the third trimester of gestation. Here we present the prenatal diagnosis of PWS during the first trimester of gestation and autopsy findings. Chorionic villus sampling (CVS) was performed for advanced maternal age at 13 weeks' gestation. CVS showed mosaicism including cells with a normal karyotype and cells with trisomy 15. Amniocentesis showed cells with a normal karyotype. Molecular analysis demonstrated that the fetus had a typical PWS abnormal methylation profile and maternal disomy for chromosome 15. Fetal ultrasound examination showed slightly enlarged lateral ventricles and hypoplasic male external genitalia without intra-uterine growth retardation. The autopsy showed a eutrophic male fetus with facial dysmorphy, hypoplasic genitalia, abnormal position of both feet and posterior hypoplasia of the corpus callosum. This report points out that in a karyotypically normal fetus with ambiguous male external genitalia and cerebral anomalies, extensive cytogenetic and molecular biology studies are strongly recommended because of risk of PWS. Copyright © 2003 John Wiley & Sons, Ltd.     

Prenatal diagnosis of jumping translocation involving chromosome 22 with ultrasonographic findings

We report on the prenatal diagnosis and ultrasonographic findings of a second-trimester fetus with jumping translocation involving chromosome 22. A 28-year-old gravida 2, partus 1, Turkish woman was referred for genetic counselling and ultrasonographic examination at 18 weeks' gestation because of a high risk of trisomy 21 in triple test. Prenatal ultrasonography showed tetralogy of Fallot with a diverticular dilatation of the pulmonary artery, flattened brow, complete absence of the right upper limb, hypospadias, oligodactyly (three digits) in left hand and in both feet, and hyperechogenic abdominal foci. Amniocentesis revealed a karyotype of 46,XY[4]/46,XY,−8,+ der(8),t(8;22)(q24.3;q11.21)[2]/45, XY,−22,−8,+ der(8)t(8;22)(q24.3;q11.21)[22]/45,XY,−22,−5,+ der(5)t(5;22)(q35.3;q11.21)[44]. A C-banding and FISH study with a specific centromeric probe (D14Z1/D22Z1) for chromosome 22 was made. In our case, partial monosomy for the regions 22q11.21→22pter, 8q24.3→8qter and 5q35.3→5qter may partially explain the fetal malformations. Copyright © 2005 John Wiley & Sons, Ltd.     

Prenatal diagnosis and molecular cytogenetic characterisation of a small de novo interstitial duplication 16q11.2-q13

We describe the first prenatally detected case of a small de novo interstitial duplication of chromosome 16q. This chromosomal aberration is extremely rare. Amniocentesis was indicated by advanced maternal age only. Ultrasound examinations of the foetus showed no abnormalities. Conventional and molecular cytogenetic analyses on cultured amniocytes by comparative genomic hybridisation (CGH) and fluorescence in situ hybridisation (FISH) using partial chromosome paints and a locus-specific YAC clone revealed a de novo direct duplication of the chromosomal region 16q11.2-q13 leading to a partial trisomy 16q (46,XX,dup(16)(q11.2q13)). There are only five postnatal reports of comparable duplications involving this chromosomal region. These patients presented with little or no associated dysmorphic features but with significant neurodevelopmental delay and severe behavioural problems. After genetic counselling, the parents opted for termination of pregnancy. Post-mortem examination showed slight facial dysmorphic signs, minor dysgenesis of the ovaries and an atypical outflow of the arteria thyroidea ima. Copyright © 2006 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.     

Prenatal diagnosis of de novo distal 11q deletion associated with sonographic findings of unilateral duplex renal system,pyelectasis and orofacial clefts

In utero diagnosis of de novo distal 11q deletion associated with renal and orofacial malformations has not been previously described. We present a 35-year-old pregnant woman with prenatal sonographic findings of a unilateral duplex renal system, pyelectasis and orofacial clefts at 20 weeks' gestation. Both genetic amniocentesis and postnatal cytogenetic analysis revealed de novo 46,XX,del(11)(q23). After birth, the fetus manifested a dysmorphic phenotype correlated with del(11q) syndrome. Genetic marker analysis showed a paternally derived distal deletion of chromosome 11q and a breakpoint centromeric to D11S1341. The present case represents the earliest prenatal diagnosis of a duplex renal system, pyelectasis and an additional feature of orofacial clefts associated with distal 11q deletion. Prenatal sonographic detection of a duplex renal system, pyelectasis and orofacial clefts should warrant a careful assessment of fetal anatomy and prompt cytogenetic analysis looking for chromosomal aberrations. Copyright © 2001 John Wiley & Sons, Ltd.     

Prenatal diagnosis of a fetus with partial monosomy 7(q34→qter) and partial trisomy 18(q21→qter)

Ultrasound examination of a 31-year-old woman at 27 weeks' gestation revealed fetal growth retardation, a bilateral cleft lip and palate, and the absence of median cerebral structures. Chromosome analysis after cordocentesis showed an abnormal karyotype with a structural abnormality of the long arm of chromosome 7: 46,XX,—7,+der(7), t(7;18) (q34;q21.3)mat. The pregnancy was terminated at week 29. The ultrasound findings were confirmed by post-mortem examination, which also revealed a semilobar holoprosencephaly.     

Prenatal diagnosis of partial monosomy 18p(18p11.2→pter) and trisomy 21q(21q22.3→qter) with alobar holoprosencephaly and premaxillary agenesis

A prenatal diagnosis of partial monosomy 18p(18p11.2→pter) and trisomy 21q(21q22.3→qter) in a fetus with alobar holoprosencephaly (HPE) and premaxillary agenesis (PMA) but without the classical Down syndrome phenotype is reported. A 27-year-old primigravida woman was referred for genetic counselling at 21 weeks' gestation due to sonographic findings of craniofacial abnormalities. Level II ultrasonograms manifested alobar HPE and median orofacial cleft. Cytogenetic analysis and fluorescence in situ hybridization (FISH) on cells obtained from amniocentesis revealed partial monosomy 18p and a cryptic duplication of 21q,46,XY,der(18)t(18;21)(p11.2;q22.3), resulting from a maternal t(18;21) reciprocal translocation. The breakpoints were ascertained by molecular genetic analysis. The pregnancy was terminated. Autopsy showed alobar HPE with PMA, pituitary dysplasia, clinodactyly and classical 18p deletion phenotype but without the presence of major typical phenotypic features of Down syndrome. The phenotype of this antenatally diagnosed case is compared with those observed in six previously reported cases with monosomy 18p due to 18;21 translocation. The present study is the first report of concomitant deletion of HPE critical region of chromosome 18p11.3 and cryptic duplication of a small segment of distal chromosome 21q22.3 outside Down syndrome critical region. The present study shows that cytogenetic analyses are important in detecting chromosomal aberrations in pregnancies with prenatally detected craniofacial abnormalities, and adjunctive molecular investigations are useful in elucidating the genetic pathogenesis of dysmorphism. Copyright © 2001 John Wiley & Sons, Ltd.     

Prenatal diagnosis of trisomy 4p: a new locus for holoprosencephaly?

Trisomy of the short arm of chromosome 4 is a well-known syndrome, and several observations have been made in the last 30 years. Herein, we report a new observation of trisomy 4p in a fetus with a semi-lobar holoprosencephaly (HPE), dysmorphic features and multiple malformations. The diagnosis of HPE was made, at 33 weeks' gestation, on the fetus of a healthy G1P0 woman. Amniocentesis was performed for chromosome analysis and additional material was found on a chromosome 22. The couple elected to terminate the pregnancy and fetal examination was realized. Conventional and molecular cytogenetic studies were performed on the fetus and the parents, which showed that the additional material found on one chromosome 22 corresponded to the short arm of chromosome 4 and therefore led us to establish a diagnosis of trisomy 4p inherited from the malsegregation of a paternal translocation t(4;22)(q12;q11.1). The etiology of HPE is very heterogeneous; it includes non-genetic factors such as maternal diabetes and genetic causes. HPE cases have been described in association with many chromosomal anomalies, trisomy 13 being the most frequent. However, to our knowledge, HPE has never been previously reported in association with a trisomy involving solely the short arm of chromosome 4. Copyright © 2005 John Wiley & Sons, Ltd.     

Maternal age-specific risks for trisomies at 9—14 weeks' gestation

This study provides data on the incidence of fetal trisomies 21, 18, and 13 at 9–14 weeks' gestation in women aged 35–45 years and estimates of maternal age-specific risks in women aged 20–45 years. Our data from 5814 singleton pregnancies undergoing first-trimester karyotyping for the sole indication of maternal age ⩾ 35 years were combined with those from two previous reports and the incidence of the trisomies was calculated from a total of 15 793 pregnancies. Comparison of incidences at 9–14 weeks' gestation with published data at 15–20 weeks' gestation and in livebirths demonstrated that at birth the maternal age-specific incidence of trisomy 21 is 33 per cent lower than at 15–20 weeks' gestation and 54 per cent lower than at 9–14 weeks' gestation. Furthermore, the relative frequency of trisomies 18 and 13 decreases from 30 per cent at 9–14 weeks to 22 per cent at 15–20 weeks and 14 per cent at birth.     

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.     

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.     

Cornelia de Lange Syndrome in association with a balanced reciprocal translocation involving chromosomes 3 and 5

We present a case report on a fetus with multiple malformations, diagnosed by ultrasound at 20 weeks' gestation. From the combination of intrauterine growth retardation and limb abnormalities that were observed, the most likely diagnosis was considered to be Cornelia de Lange Syndrome (CdLS). Following counselling, the mother opted to terminate the pregnancy. Chromosome analysis of cultured amniotic fluid cells showed a karyotype of 46,XX,t(3;5)(q21;p13). Postmortem examination of the baby confirmed the presence of features consistent with a diagnosis of CdLS. This case provides a report of a definitive diagnosis of Cornelia de Lange Syndrome, suspected on the basis of ultrasound imaging and confirmed by amniocentesis findings. Copyright © 2005 John Wiley & Sons, Ltd.     

Prenatal diagnosis of Pallister–Killian syndrome: Resolution of cytogenetic ambiguity by use of fluorescent in situ hybridization

We report a case of Pallister-Killian syndrome initially diagnosed prenatally as tetrasomy 21. A 33-year-old primiparous woman was noted at 24 weeks' gestation to have moderate polyhydramnios. Ultrasonography showed diminished fetal stomach filling, hydronephrosis, and prominence of the cisterna magna. Cytogenetic analysis of cultured amniocytes was initially interpreted as mosaic tetrasomy 21: 46,XX/47,XX,+i(21q). The patient was then referred to our centre for genetic counselling. At 34 weeks' gestation, a dysmorphic infant was delivered and died within 30 min. Physical features were consistent with the Pallister-Killian syndrome. Renal, gastrointestinal, and central nervous system anomalies were found at post-mortem examination. Analysis of peripheral lymphocytes revealed 5 per cent of cells with a marker chromosome, while 92 per cent of cultured fibroblasts had this same marker. Fluorescent in situ hybridization (FISH) using an alpha-satellite probe for chromosomes 13 and 21 failed to hybridize to the marker, while a chromosome 12 centromeric probe unequivocally identified it as an i(12p). Use of FISH can provide rapid, specific prenatal diagnosis of ambiguous marker chromosomes and improve prenatal counselling.     

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.     

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.