Trisomy 12 mosaicism detected by mid-trimester amniocentesis

Trisomy 12 mosaicism was found in about 15 per cent of cultured amniocytes obtained from a 32-year-old white female at 17.6 weeks of gestation. Termination of pregnancy was elected and multiple tissues were obtained for chromosome analysis. Of 158 cells examined, only 1 cell in placenta was found with an extra number 12 chromosome. Pathological examination of the fetus did not reveal significant physical abnormalities. This report illustrates the difficulty of confirming trisomy 12 mosaicism which has been detected on prenatal diagnosis. The presence of trisomy 12 in one placental cell obtained from the curettage specimen suggests the possibility of confined placental mosaicism in this case.     

Apparent confined placental mosaicism of trisomy 16 and multiple fetal anomalies: case report

Trisomy 16 is frequently found confined to the placenta (confined placental mosaicism (CPM)), with a structurally normal fetus. In some cases of trisomy 16, the fetus has uniparental disomy for chromosome 16 (UPD16) which is associated with intrauterine growth restriction (IUGR) and fetal anomalies. We report a case of apparent confined placental mosaicism for trisomy 16, using standard cytogenetic techniques, but with multiple fetal abnormalities including congenital diaphragmatic hernia in which there was no evidence of UPD in the disomic tissues examined. Subsequent examination of fetal tissues using fluorescent in situ hybridization (FISH) demonstrated low levels of mosaicism for trisomy 16 in all the tissues examined. The use of FISH permits identification of mosaicism which conventional techniques may not identify.     

Mosaicism and accuracy of prenatal cytogenetic diagnoses after chorionic villus sampling and placental biopsies.

Discrepant chromosome findings in placenta and fetus (false negative and false positive) after chorionic villus sampling (CVS) are mainly due to confined mosaicism. Non-mosaic normal or abnormal chromosome counts after direct preparation and culture nearly always correctly reflect the fetal chromosome constitution. False-negative results have almost exclusively been restricted to cytotrophoblast cells not representing a fetal chromosome abnormality. Diagnosis of placental mosaicism definitely requires an adequate follow-up by amniocentesis, fetal blood sampling, or sonography before a pregnancy is terminated. When direct preparations and cultured cells are used for cytogenetic diagnoses and placental mosaicism is not taken as proof for a chromosomal abnormality in the fetus, CVS is an accurate diagnostic tool.     

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.     

嵌合体形成及其对产前筛查及诊断结果的影响

随着细胞分子生物学时代的来临,产前筛查和诊断方法也随之发生改变,更多的数据需要正确解读,这对产前诊断医生无疑是一项挑战。其中,染色体嵌合是影响产前筛查与诊断准确性的重要因素之一,受母亲、父亲以及胎盘等多种因素影响,人类普遍存在染色体嵌合,嵌合形成的主要原因是有丝分裂期染色体错误分离。受多种因素的影响,嵌合的临床表现对每个个体都具有唯一性。嵌合对产前筛查和诊断的影响主要为2个方面：①母血中胎儿游离细胞DNA（cell-free fetal DNA,cfDNA）筛查（无创产前筛查）。虽然大量文献报道无创产前筛查对于２１,１８,１３三体有较高的检出率,但由于其检测的母血中cfDNA来源于胎盘,并非真正的胎儿自身DNA,因此当发生胎盘局限性嵌合时会严重影响无创产前筛查结果的准确性。②绒毛染色体核型分析提示存在嵌合时需要行羊膜腔穿刺进行验证。总之,正确认识染色体嵌合的起源、机制和临床结果,可以为病人提供更多有价值的遗传信息,是做好产前筛查与诊断工作并提供遗传咨询的重要前提。     

A case of confined placental mosaicism with double trisomy associated with stillbirth

We present a case of stillbirth in which the fetus was well grown and karyotypically normal, but the placenta was morphologically abnormal and had confined placental mosaicism (CPM) for a double trisomy of chromosomes 12 and 15. A compilation of published cases of CPM reveals that whilst approximately 80% of pregnancies progress normally, there is an association with abnormal placental morphology, intrauterine growth restriction, fetal abnormalities and stillbirth. This case highlights the potential adverse effects of CPM and the benefit of placental examination in determining the cause of stillbirth.     

Partial molar pregnancy with a chromosomically and phenotypically normal embryo: presentation of an extremely rare case and review of literature

We present an extremely rare case of partial molar pregnancy with a chromosomically and phenotypically normal embryo and review of the literature. A 31-year-old nulliparous was referred to us at 30 weeks of gestation due to absence of fetal movements and subsequent ultrasound examination revealed intrauterine demise. Prenatal amniocentesis due to raised maternal serum α-fetoprotein had shown a karyotypically normal female embryo and second trimester ultrasound demonstrated no anatomic abnormalities. Upon induction of labor with misoprostol, a phenotypically normal embryo was delivered and the placenta showed intermixed areas of marked hydatidiform villous change and normal parenchyma. Pathologic examination of the placenta confirmed the molar change of placenta. Two are the main theories discussed herein that explain the placental molar changes in singleton pregnancies: confined placental mosaicism (one case reported to date) and placental mesenchymal dysplasia (70 cases reported). Differential diagnosis is based on histopathologic features and genetic analysis of placenta.     

Prenatal diagnosis of mosaic tetrasomy 5p

We report the prenatal diagnosis of a fetus with tetrasomy 5p mosaicism resulting from a supernumerary isochromosome for the short arm of chromosome 5. The pregnancy was terminated and fetal autopsy revealed minor facial abnormalities (long philtrum, up-slanting palpebral fissures and a broad nasal bridge). Cultures were established from fetal skin, kidney, and pancreas for cytogenetic analysis; the i(5p) was observed only in the skin fibroblasts. To our knowledge, this is the fourth report of mosaic tetrasomy 5p and the first report of prenatal diagnosis of this abnormality.     

Chromosomal mosaicism in chorionic villus sampling

The observation of multiple, chromosomally distinct cell lines in chorionic villus samples is not an unusual finding and occurs in 1 per 100 samples. This frequency is ten times greater than the level of mosaicism observed in newborn surveys and, thus, must reflect phenomenon other than true fetal mosaicism. Indeed, only 23% of mosaicism detected at CVS is confirmed in the fetus (2.3 per 1,000 CVS), which is much closer to the newborn rate (1 per 1,000). This indicates that most mosaicism encountered in CVS is unrelated to the fetal karyotype and as such is an inaccurate prediction of the fetal genotype, the purpose of prenatal diagnosis. Most of the mosaicism detected in CVS is due to confined placental mosaicism. Either as a result of error-prone cell division generating an excess of abnormal cells in extraembryonic tissues or reduced selection against aneuploid cells in these tissues allowing their persistence, chorionic villi and placenta appear to show much higher levels of mosaicism than seen in fetuses. This explains the more frequent finding of multiple cell lines in CVS than in amniocentesis or liveborn individuals. The discrepancy between levels of mosaicism present in chorionic villi and fetal tissues means that most instances of mosaicism detected in CVS are not associated with a fetal abnormality and should be evaluated by further prenatal testing, i.e., amniocentesis or fetal blood sampling. Because of the frequency of chromosomal mosaicism in CVS and its attendant need for further testing, a discussion of mosaicism should be included in counseling prior to CVS. The higher frequency of discrepant results in direct CVS preparation emphasizes the prudence of delaying decision making until the results of the CVS culture have been obtained. Although the observation of mosaicism clearly complicates genetic counseling and decision making, it does not appear to be associated with an adverse fetal outcome. Whereas most of the mosaicism observed in CVS is the result of confined placental mosaicism, other types of discrepancies also occur. Maternal cell contamination occurs in about 1% of cases, but is easily evaluated by examining the direct preparation and analyzing chromosome polymorphism. The incidence of pseudomosaicism in CVS cultures is unclear but probably low. Interestingly, CVS analysis has suggested that twinning may be a more common phenomenon at conception than reported at birth and that some discrepancies may reflect the nonviability of twins with abnormal karyotypes. Chorionic villi sampling remains a viable alternative to amniocentesis for early prenatal diagnosis. An understanding of the origins of mosaicism in CVS is necessary for     

Prenatal diagnosis of monosomy 18 and ring chromosome 18 mosaicism.

The case of monosomy 18/ring chromosome 18 mosaicism which was detected prenatally by amniocentesis is presented. The pregnancy was terminated in week 18. Autopsy showed complex malformation of the fetus consisting of cebocephaly, hypotelorism, microphthalmia, severe defects of brain development, and arrest of placental maturation.     

Chorionic chromosome abnormalities and intrauterine growth retardation

Chorion, placental membranes, and embryo all arise from the same fertilized oocyte; therefore, chorionic cells are presumed to reflect fetal chromosome status. Progenitor cells of the embryo are selected from the blastocyst, however, at a very early stage of development. If mitotic nondisjunction were to occur in one of the blastocyst cells destined to become trophoblast, the resultant abnormal cell line would be restricted to extraembryonic tissues. Indeed, chromosome mosaicism confined to the placenta has been found repeatedly in diagnostic chorionic villus sampling, and occasionally in third trimester placentas. Cytogenetically abnormal placental cells are morphologically and perhaps functionally abnormal. Such aberrations might result in deficient oxygen or nutrient supply to the fetus, causing intrauterine growth retardation (IUGR). To investigate this hypothesis we studied chorion and cord blood samples after delivery from 11 confirmed IUGR pregnancies. A minimum of 10 cells were analyzed from each cord blood and chorion specimen (mean number of cells from cord blood = 27; from chorion = 17). None of the cases showed true mosaicism for a hyperdiploid line. We conclude from this preliminary study that few, if any, cases of IUGR are likely to be due to chorionic mosaicism.     

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.     

Prenatal diagnosis of a distal 3p deletion associated with fetoplacental chromosomal discrepancy and confined placental mosaicism detected by array comparative genomic hybridization

ObjectiveThis study is aimed at prenatal diagnosis of a distal 3p deletion associated with fetoplacental chromosomal discrepancy and confined placental mosaicism, and providing evidence for the limitation of array comparative genomic hybridization (aCGH) on placental tissues for molecular cytogenetic characterization of prenatally detected aneuploidy.Case ReportA 30-year-old woman underwent amniocentesis at 18 weeks of gestation because of maternal anxiety. Results of amniocentesis revealed a distal deletion of chromosome 3p. A malformed female fetus was delivered at 20 weeks of gestation with brachycephaly and facial dysmorphisms, and a cytogenetic analysis of the cord blood revealed a karyotype of 46,XX,del(3)(p26.1),inv(9)(p12q13). A whole-genome aCGH on uncultured cord blood and placental tissue was performed. The aCGH on cord blood revealed a 7.4-Mb deletion at 3p26.3-p26.1. However, the aCGH on placental tissue revealed a 32.42-Mb gene dosage increase at 3p26.1-p22.1 and a 26.28-Mb gene dosage increase at 1p36.33-p36.11 in addition to a 7.4-Mb deletion at 3p26.3-p26.1, indicating confined placental mosaicism for partial trisomy 3p (3p26.1→p22.1) and mosaicism for partial trisomy 1p (1p36.33→p36.11). The 7.4-Mb deleted region of 3p26.3-p26.1 contained the following genes: CHL1, CNTN4, CRBN, LRRN1, and ITPR1.ConclusionFetal tissue and amniocytes offer more reliable resources for aCGH characterization of prenatally detected aneuploidy compared with placental tissues. A molecular cytogenetic evaluation of prenatally detected aneuploidy using placental tissue should raise concerns of confined placental mosaicism and fetoplacental chromosomal discrepancy.     

Isochromosome 5p mosaicism at prenatal diagnosis: observations and outcomes in six cases at chorionic villus sampling and one at amniocentesis

We present six cases of 47,+i(5p)/46 mosaicism diagnosed at chorionic villus sampling (CVS), this being the first prospective series to be reported. The clinical indication in each was advanced maternal age. Further prenatal studies in four (amniocentesis, plus fetal blood sampling in one) did not show the isochromosome. In one case, subsequent amniocentesis showed 1/48 in situ colonies with the isochromosome, but fetal blood was karyotypically normal. These five pregnancies resulted in phenotypically normal livebirths; further normal follow-up reports (from age 4 months through 4 years) are noted in four of these. Analysis of placental tissue in one case confirmed the presence of the i(5p) mosaicism. In the remaining case, in which 100% of CVS cultured cells had the i(5p), the pregnancy was terminated. Fetal skin fibroblasts did not show the i(5p). Thus, in none of these six cases was true fetal mosaicism detected, nor an abnormal phenotype noted. We suggest that a 47,+i(5p)/46 karyotype, detected at CVS, may frequently reflect confined placental mosaicism. In addition, we report a case of the primary diagnosis of 47,+i(5p)/46 mosaicism at amniocentesis. The infant appeared normal at birth, but a brain malformation was subsequently identified.     

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.     

46,XY,18q+/46,XY,18q- mosaicism in a fragile X prenatal diagnosis

OBJECTIVES: We describe a fetus with confined placental mosaicism for 46,XY,dup(18)(q21q23)/46,XY, del(18)(q21) in which finally the 18q- cell line formed the embryo. This prenatal diagnosis was performed on a pregnant woman carrying a premutation in the FMR1 gene. The purpose of the current study was to characterise the final fetus genotype and to discuss how this chromosomal abnormality was originated. METHODS: Conventional cytogenetic analyses were performed from chorionic villi, amniocytes, and fetal blood samples in order to establish the fetal chromosome constitution. Molecular studies with microsatellite markers and CGH were carried out to this end. PCR and Southern blot were used to analyse the CGG-repeat region of the FMR1 gene. RESULTS: An initial chorionic villi sample analysis showed a normal allele for the fragile X syndrome, but an abnormal 46,XY,dup(18)(q21q23) karyotype. Amniocentesis was subsequently performed, and a different 46,XY,del(18)(q21) cell line was detected. Re-examination of original chorionic villi sample evidenced a mosaicism for 46,XY,dup(18)(q21q23)/46,XY,del(18)(q21). Molecular findings allowed us to determine that the deletion expands at least 20 Mb and that it is paternally inherited. CONCLUSION: Two different cell lines with structural abnormalities on chromosome 18 were formed as a consequence of an unequal sister chromatid exchange during the first post-zygotic division. This case reinforces the necessity of performing a karyotype in all prenatal diagnosis even when the indication is for a monogenic disease.     

Prenatal diagnosis of purine nucleoside phosphorylase deficiency in the first and second trimesters of pregnancy

Prenatal diagnosis was performed in two successive pregnancies of a mother with a previous child with purine nucleoside phosphorylase (PNP) deficiency. In one pregnancy, an affected fetus was diagnosed in the 18th week of gestation after the demonstration of PNP deficiency in cultured amniotic fluid cells. Also an abnormal purine nucleoside profile was found in the amniotic fluid. The diagnosis of an affected fetus was confirmed by the analysis of cultured fetal skin fibroblasts and placental villi. The complete deficiency of PNP activity in placental villi confirms that the prenatal diagnosis of this disorder is possible by the direct investigation of chorionic villi. In the subsequent pregnancy, a heterozygous fetus was predicted in the tenth week of pregnancy by using chorionic villi.     

Prenatal diagnosis and molecular cytogenetic characterization of mosaicism for r(13), monosomy 13 and idic r(13) by amniocentesis

ObjectiveWe present prenatal diagnosis and molecular cytogenetic characterization of mosaicism for ring chromosome 13 [r(13)], monosomy 13 and isodicentric ring chromosome 13 [idic r(13)] by amniocentesis.Case reportA 24-year-old woman underwent amniocentesis at 23 weeks of gestation because of intrauterine growth restriction (IUGR) in the fetus. Amniocentesis revealed a karyotype of 46,XY,r(13)[23]/45,XY,-13[10]/46,XY,idic r(13)[2]. The parental karyotypes were normal. Array comparative genomic hybridization (aCGH) on cultured amniocytes revealed the result of arr 13q11q31.3 (19,436,286–92,284,309) × 1.85, arr 13q31.3q34 (92,288,514–115,107,733) × 1 [GRCh37 (hg19)], indicating a 22.82-Mb 13q31.3-q34 deletion and a 15–20% mosaicism for 13q11-q31.3 deletion. The pregnancy was subsequently terminated, and a malformed fetus was delivered with facial dysmorphism. The placental tissues had a karyotype of 46,XY,r(13)[18]/46,XY,-13,+mar[14]/45,XY,-13[8]. Polymorphic DNA marker analysis confirmed a maternal origin of the 13q deletion.ConclusionFetus with mosaic r(13), monosomy 13 and idic r(13) may present IUGR on prenatal ultrasound, and fetoplacental cytogenetic discrepancy may exist under such a circumstance.     

Rapid karyotyping for prenatal diagnosis in the second and third trimesters of pregnancy

Direct chromosome preparations were performed on placental villi obtained by ultrasound-guided needle aspiration between 18 and 37 weeks of pregnancy in 53 patients. The sampling yielded a sufficient amount of tissue with a maximum of two, and in most cases one, insertions. Placental biopsy is easily performed in cases of severe oligohydrammnios, where fetal blood sampling is usually more difficult. Direct karyotyping of placental villi is faster than chromosome analysis from fetal blood or application of the pipette method on amniotic fluid cells, and currently represents the most rapid approach to prenatal diagnosis of chromosomal abnormalities from the first to the third trimester of pregnancy.     

Management of prenatally detected trisomy 8 mosaicism.

We report on ten pregnancies with trisomy 8 mosaicism. Nine cases were prenatally detected in chorionic villi (n=6), amniotic fluid (AF) cells (n=2) or fetal blood (FB) lymphocytes (n=1). Follow-up laboratory investigations showed confined placental mosaicism (CPM) or pseudomosaicism in eight cases. In one case with ultrasound abnormalities, trisomy 8 mosaicism was detected in FB cells although cultured AF cells showed normal cells only. Another case of mosaic trisomy 8 was prenatally missed; cytogenetic analysis of short-term cultured villi revealed a normal male karyotype, while postnatally, trisomy 8 mosaicism was detected in peripheral blood lymphocytes and skin fibroblasts of the affected child. These findings indicate the difficulties in the prenatal diagnosis of trisomy 8 mosaicism. When found in chorionic villi, it mostly represented CPM, while in a case of true fetal trisomy 8 mosaicism, the cytotrophoblast cells showed a normal karyotype. So, the cytotrophoblast compartment of chorionic villi is a poor indicator of the presence or absence of fetal trisomy 8 mosaicism. Follow-up investigations including amniocentesis and especially fetal blood sampling are required to come to a definite prenatal diagnosis of trisomy 8 mosaicism.