Tetrasomy 12p (Pallister-Killian syndrome): Ultrasound indicators and confirmation by interphase fish

Tetrasomy 12p (Pallister-Killian syndrome) is a mosaic aneuploidy syndrome in which the isochromosome is present in amniocytes with a much greater percentage than fetal lymphocytes. Two new cases identified by prenatal diagnosis are reported. Indications for prenatal diagnosis were advanced maternal age and fetal anomalies. The most consistent reported prenatal ultrasound findings for tetrasomy 12p include polyhydramnios with short femurs and a diaphragmatic hernia. Recognition of congenital malformation patterns prenatally may allow appropriate selection of tissue for chromosome analysis. Molecular cytogenetic analysis using fluorescence in situ hybridization was used retrospectively to confirm the presence of the isochromosome 12p in various formalin-fixed fetal tissues. The levels of mosaicism detected in fetal and placental tissues were lower than those detected prenatally.     

Identification of triploid trophoblast cells in peripheral blood of a woman with a partial hydatidiform molar pregnancy

In a woman with a partial hydatidiform molar pregnancy with 69,XXY karyotype, the presence of male fetal cells of trophoblastic origin was demonstrated in maternal blood by X/Y-chromosome specific PCR and by immunostaining combined with FISH on two cell populations isolated from maternal blood. Blood was obtained three weeks prior to the detection of fetal demise, at 13 weeks' gestation. Results were confirmed on formalin-fixed paraffin-embedded molar tissue, removed at 16 weeks' gestational age for therapeutic reasons. The results indicate that both plasma and cells from maternal peripheral blood might be useful for non-invasive prenatal diagnosis of fetal aneuploidies, as described in the current case with a partial molar pregnancy. 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.     

Factors associated with multiple-pass procedures during chorionic villus sampling: A video analysis

Multiple placental passes during chorionic villus sampling (CVS) increase the risk of fetal loss; however, specific factors that predispose to repeat aspiration have not been delineated. To identify anatomic and technical variables associated with multiple-pass procedures, a detailed review of 205 videotaped CVS procedures (single pass = 163; multiple pass = 42) was performed, blinded to pregnancy outcome. The route of sampling did not influence the need for multiple aspiration attempts (transabdominal—30/ 135; transcervical—12/70), nor was placental location alone discriminatory. However, the combination of a posterior placenta and uterine retroversion was observed more frequently in the multiple-pass cohort (8/42 vs. 9/163; p<0.05). In transabdominal cases, suboptimal needle placement (e.g., perpendicular to the placental long axis) was more common in the initial aspiration of a multiple-pass procedure (21/30 vs. 38/105;p<0.01), while limited penetration of the catheter tip (e.g., just inside the placental edge) characterized a majority of multiple-pass cases in the transcervical subset (7/12 vs. 3/58; p<0.0001). A case-control cohort was constructed to evaluate the impact of these technical variables on sampling efficacy, independent of the influence of uterine position and placental site. In that analysis, suboptimal location and/or orientation of the sampling device remained characteristic of multiple-pass cases. We conclude that further reduction in the frequency of multiple-pass procedures might be achieved by consistent placement of the device tip in the central placental mass. Unlike amniocentesis, where any point of amnion entry will suffice, this technical nuance should be emphasized with CVS to maximize the single-pass success rate.     

Molecular evidence of fetal-derived chromosome 21 markers (STRs) in transcervical samples

Transcervical cells (TCCs), collected by flushing or aspiration at 8–13 weeks of gestation, were analysed for the presence of fetal-derived DNA sequences. DNA extracted from maternal peripheral blood, TCC samples, and placental tissue was amplified by the polymerase chain reaction (PCR) to detect small tandem repeat (STR) markers specific to chromosome 21. STR products of fetal origin could be clearly observed in four TCC samples. TCC samples collected by flushing or aspiration were also analysed by fluorescent in situ hybridization (FISH) using X and Y probes simultaneously: 46,XY cells could be detected in all TCC samples obtained from mothers with male fetuses.     

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. Copyright © 2002 John Wiley & Sons, Ltd.     

Biophysical markers for abnormal placentation: first and/or second trimester

Placental development is a major cause of a successful pregnancy, and in the presence of placental dysfunction, there is a higher risk of pregnancy complications. Doppler technology can be used for screening and detecting the more common pregnancy-associated diseases like preeclampsia, intrauterine growth retardation, and perinatal loss. In this review, the biophysical markers are discussed in the light of the latest information that appeared in the medical literature. © 2014 John Wiley & Sons, Ltd.     

Simultaneous placentacentesis and amniocentesis for prenatal karyotyping: Report on 250 cases

The efficacy and risks of simultaneous transabdominal chorionic villus biopsy (placentacentesis) and amniocentesis in the second and third trimesters were evaluated in 250 singleton pregnancies. The major indications were advanced maternal age (36·0 per cent), abnormal ultrasound findings (23·2 per cent), and low maternal AFP value (17·6 per cent). Nine abnormal karyotypes were found in placental tissue (3·6 per cent). The karyotypes of placental and amniotic cells were different in three cases, including two cases of false-positive mosaicism (08 per cent) and one case of a false-negative result (0·4 per cent) obtained by placental karyotyping. The problem of discrepant karyotypes in embryonic and extra-embryonic tissue does not seem to be restricted to the first trimester. The post-procedure fetal loss rate was estimated as approximately 1·8 per cent. We conclude that the procedure presented here combines the advantages of rapid karyotyping (placentacentesis) and high diagnostic reliability (amniocentesis). It does not seem to be necessary to restrict its use to late presentations and suspicious ultrasound findings.     

Prenatal diagnosis of ornithine transcarbamylase deficiency: Results in SPFASH mice

Ornithine transcarbamylase (OTC) deficiency is a human X-chromosome-linked disease (McKusick 31125). The presence of OTC activity in the human placenta encouraged us to examine the possible diagnosis of the disease in an animal model (Spf^ash mice) by enzymatic assay on placental samples. A significant positive correlation (P< 0·02) was found between placental and hepatic activities; the pH dependence of OTC was similar in the placenta and liver when compared within normal or homozygous mutant mice. The apparent K_m (ornithine) and K_m (carbamoylphosphate) values of the enzyme did not show any significant differences when compared in both placentae and livers of normal fetuses. The use of OTC assay in the placenta for prenatal diagnosis of OTC deficiency in mouse fetuses obtained by the crossbreeding of Spf^ash/+ with +/Y has shown that our method has good diagnostic value. We made the diagnosis of OTC deficiency in male fetuses with a sensitivity and a specificity of 1·0. The + gene from the father in Spf^ash/ + animals is preferentially inactivated in extraembryonic tissues, explaining why very low placental OTC activity was observed in 12 of the 18 female fetuses studied. Because these 12 females have variable OTC activity in their livers, it is not possible to appreciate the true residual activity in their livers by measuring this activity in the placenta.     

Chorionic mosaicism: Association with fetal loss but not with adverse perinatal outcome

Cytogenetic data from the United States NICHD collaborative study of chorionic villus sampling (CVS) were used to evaluate the clinical significance of chorionic mosaicism. The 10 754 patients with normal cytogenetic results were compared wtih 108 patients (1.0 per cent) with placental mosaicism and 181 patients (1.6 per cent) with pseudomosaicism. Of the pregnancies intended to continue, the pregnancy loss rate was significantly greater in patients with placental mosaicism than in the cytogenetically normal cohort (8.6 vs. 3.4 per cent, p <0.05). However, there was no difference in the frequencies of abruptio placenta, preterm labour or delivery, small-for-gestational-age newborns, pregnancy-induced hypertension, or neonates with Apgar scores less than 7.     

Trisomy 16 detected at chorion villus sampling

Trisomy 16 detected at chorion villus sampling (CVS) may reflect the placental but not the fetal karyotype. We describe a case in which the pregnancy continued until intrauterine death at 37 weeks. Cytogenetic study of two placental samples showed 47, +16 and 46,XX; the fetus was morphologically grossly normal, but fetal tissue culture was unsuccessful. Conservative management may be appropriate when trisomy 16 is detected at CVS and the pregnancy is normal ultransonographically.     

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.     

Detection of fetal cells in transcervical samples and prenatal diagnosis of chromosomal abnormalities

Transcervical samples collected by lavage, aspiration, and cytobrush from women between 6 and 13 weeks of gestation were tested for the presence of fetal cells using fluorescence in situ hybridization (FISH) with probes for chromosomes X, Y, 1, and 21, and by polymerase chain reaction (PCR) amplification of DNA sequences derived from chromosomes X, Y, and 21. With a few exceptions, a good correlation was observed between the results of sexing the fetuses using FISH or PCR on transcervical cell (TCC) samples retrieved by lavage and those obtained by testing fetal (placental) tissue. In a comparative study between TCC samples collected by lavage or cytobrush, the sex of the fetus was correctly diagnosed by PCR amplification of a Y-derived DNA sequence. Variable results were observed with samples obtained by aspiration, mainly because this procedure was found to be more prone to failure to remove thick mucus without previous injection of physiological saline. Chromosome 21-derived small tandem repeats (STRs) of fetal origin were successfully detected in about 40 per cent of TCC samples recovered by lavage. Two cases of chromosomal abnormalities, one of trisomy 21 and one of triploidy, were detected in TCC samples in the course of our investigations.     

Mosaicism for trisomy 12: Four cases with varying outcomes

Trisomy 12 observed in chorionic villus sampling (CVS) may reflect generalized mosaicism or indicate mosaicism confined to only the placenta. In this report, four cases of trisomy 12 observed in CVS or cultured placental biopsies with varying outcomes are presented. Seven dinucleotide repeat polymorphisms for chromosome 12 were used to determine the chromosome 12 origins in the fetus or child and to delineate the mechanism(s) that gave rise to the trisomy. In two cases (cases A and C), the mosaicism was confined to the placenta, resulting in normal liveborns. Although, in one case, the molecular results suggested an apparent duplication of one paternal chromosome 12 in the placenta, normal biparental inheritance was found in the diploid fetal cell line in both cases. In two other cases (cases B and D), trisomy 12 was observed in both extraembryonic and fetal tissues. In one of these pregnancies, a child was born by Caesarean section at 37 weeks because of intrauterine growth retardation and oligohydramnios, and resulted in neonatal death. Molecular markers and fluorescence in situ hybridization (FISH) revealed low-level trisomy 12 mosaicism in the spleen. In the fourth case, fetal abnormalities were detected on ultrasound and low-level trisomy 12 mosaicism was observed in amniotic fluid cells using conventional cytogenetics and FISH. Molecular markers revealed a maternal meiosis I non-disjunction of chromosome 12 in DNA from a cultured placental biopsy. Although predicting the outcomes of pregnancies involving confined placental mosaicism remains difficult, molecular techniques are valuable tools for distinguishing uniparental from biparental disomy and mechanisms of mosaicism.     

Stereological quantification of placental villus vascularization and its relation to umbilical artery Doppler flow in intrauterine growth restriction

The aim of this study was to investigate the changes in the number of vessels within tertiary stem villi and intermediate/terminal villi which may be responsible for the abnormalities in placental vascular resistance and Doppler velocity index values in growth-restricted fetuses. The placentas of 20 cases with intrauterine growth restriction and 30 cases which were appropriate for gestational age were studied. The umbilical artery resistance index, pulsatility index and systolic to diastolic ratio were measured in each case. The vessels were quantified by a stereological method described previously and vascular surface density and the volume portion of the villi were calculated. The placentas of preterm and term cases with intrauterine growth restriction displayed significant reductions in the vascular surface density of stem and intermediate/terminal villi and volume portion of intermediate/terminal villi stroma when compared with gestation-matched normally grown cases (p<0.05). There was no significant correlation between Doppler index values of the umbilical artery and the stereological parameters of the intermediate/terminal and stem villi in the intrauterine growth restriction group (p>0.05). Some of the pregnancies with intrauterine growth restriction (six patients) with normal Doppler flow velocity waveforms had reduced vascularization in the placentas, and these pregnancies were found to have no perinatal complications. We conclude that,although the placental villi show reduced vascularization in pregnancies with intrauterine growth restriction, the Doppler indices may be normal and this normal flow pattern is related to reduced complication rate. Copyright © 2002 John Wiley & Sons, Ltd.     

Maternal serum leptin concentration during the second trimester of pregnancy: association with fetal chromosomal abnormalities

Recent studies suggest that leptin, the product of the obese gene, is produced by the placenta during pregnancy. The present study addressed the question whether second trimester maternal serum leptin could be altered by fetal Down syndrome or Edwards syndrome. Maternal serum leptin concentrations were measured in 18 pregnancies complicated with Down syndrome, six pregnancies complicated with Edwards syndrome and 183 uncomplicated pregnancies during the second trimester of pregnancy. The present results demonstrate that leptin concentrations in uncomplicated pregnancies slightly decrease from the 16th week of pregnancy, reaching a minimum of 18.8 ng/ml around the 20th week, and then rapidly increase to 28.2 ng/ml by the 24th week. Leptin correlation with maternal body weight decreases from r=0.695 at 16–17 week of gestation to r=0.544 at >22 weeks of gestation. There was no significant difference between the mean MoMs of Down syndrome- (0.926) or Edwards syndrome- (0.960) affected pregnancies and normal pregnancies (1.002). A weak correlation (r=0.18, p<0.02) was observed between corrected leptin MoMs and human chorionic gonadotrophin (hCG) MoMs in normal pregnancies. It is assumed that around the 20th week of pregnancy placental leptin production is activated or at least is accelerated and it is added to the amount of leptin produced by maternal adipose tissue. Fetal Down syndrome or Edwards syndrome does not seem to alter maternal leptin concentration and therefore leptin cannot be used as a marker for these chromosomal abnormalities in the early second trimester of pregnancy. Copyright © 2002 John Wiley & Sons, Ltd.     

Confined placental mosaicism for 22q11.2 deletion as the etiology for discordant positive NIPT results

22q11.2 deletion, the most common microdeletion syndrome within the general population, is estimated to have a prevalence of 1 in 3000 to 6000. Non-invasive prenatal testing has recently expanded to include screening for several microdeletions including 22q11.2. Given the expansion of prenatal screening options to include microdeletions, it is important to understand the limits of this technology and the variety of reasons that a discordant positive result can occur. Here, we describe a case of a pregnant woman who received a positive non-invasive prenatal maternal plasma screen for 22q11.2 deletion. Maternal and postnatal neonatal peripheral blood cytogenetic, PCR, and fluorescence in situ hybridization studies were normal, but the placenta was mosaic for 22q11.2 deletion in two of three biopsy sites. This case illustrates both the complexities of pre- and post-test counseling for microdeletion screening and the potential for a discordant positive microdeletion result because of confined placental mosaicism. © 2017 John Wiley & Sons, Ltd.     

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.     

Shortened fetal long bones: a possible in utero manifestation of placental function

Shortened fetal long bones (SFLB) are usually indicative of a skeletal dysplasia. Our aim in this observational retrospective study was to describe a new association between SFLB, small for gestational age (SGA) fetuses and placental abnormalities, and to suggest an aetiologic explanation. During the last decade we have evaluated nine cases in which SFLB (more than 2SD below the mean) was associated with SGA, abnormal maternal serum placental hormones and abnormal placental sonography. Six cases had significantly increased second trimester maternal serum βhCG and four developed toxaemia of pregnancy or had chronic hypertension. On histology, mature placentas with vascular abnormalities, including chorangiosis, large infarcts and slightly increased syncytial knots were noted. The combination of SFLB, SGA fetuses and placental abnormalities (sonographic, as well as histological) suggested a possible common pathway in the aetiology of this association. Copyright © 2002 John Wiley & Sons, Ltd.     

Solomon versus selective fetoscopic laser photocoagulation for twin-twin transfusion syndrome: A systematic review and meta-analysis

This meta-analysis aims to compare the perinatal outcome of twin-twin transfusion syndrome (TTTS) pregnancies undergoing selective versus vascular equator (Solomon) fetoscopic laser photocoagulation (FLP). We performed a systematic search in PubMed and Web of Science from inception up to 25 July 2021. Studies comparing the Solomon and selective techniques of FLP for treatment of TTTS pregnancies were eligible. Random-effects or fixed-effect models were used to pool standardized mean differences (SMD) and log odds ratio. Seven studies with a total of 1664 TTTS pregnancies (n = 671 undergoing Solomon and n = 993 selective techniques) were included. As compared to the selective FLP, Solomon was associated with a lower risk of recurrent TTTS compared to the selective technique (Log odds ratio [OR]: −1.167; 95% credible interval [CrI]: −2.01, −0.33; p = 0.021; I²: 67%). In addition, Solomon was significantly associated with a higher risk of placental abruption than the selective technique (Log [OR]: 1.44; 95% CrI: 0.45, 2.47; p = 0.012; I²: 0.0%). Furthermore, a trend for the higher risk of preterm premature rupture of membranes was observed among those undergoing Solomon (Log [OR]: 0.581; 95% CrI: −0.43, 1.49; p = 0.131; I²: 17%). As compared to selective FLP, the Solomon technique for TTTS pregnancies is associated with a significantly lower recurrence of TTTS; however, it significantly increases the risk of placental abruption.