[Management of isolated increased nuchal translucency: survey among the Pluridisciplinary Centers for Prenatal Diagnosis]. / Prise en charge de l'hyperclarté nucale isolée : enquête auprès des Centres pluridisciplinaires de diagnostic prénatal.

OBJECTIVES: The management for isolated increased nuchal translucency (NT) in the first trimester with a normal karyotype and normal Chromosomal Microarray Analysis (CMA) is not consensual. The aim was to perform a survey among the Pluridisciplinary Centers for Prenatal Diagnosis (CPDPN) in France regarding their management of increased NT in the first trimester. METHODS: We conducted a multicenter descriptive survey between September 2021 and October 2021 among the 46 CPDPNs of France. RESULTS: The response rate was 56.5% (n = 26/46). The NT thickness threshold for which invasive diagnosis testing is performed is 3.0mm in 23.1% of centers (n = 6/26) and 3.5mm in 76.9% of centers (n = 20/26). A CMA was performed alone in 26.9% of centers (n = 7/26) while 7.7% of centers (n = 2/26) did not perform a CMA. The gestational age for the first reference ultrasound scan was 16 to 18 WG in 88.5% of centers (n = 23/26), while it was not performed before 22 WG in 11.5% of centers (n = 3/26). Fetal echocardiography is proposed systematically in 73.1% of centers (n = 19/26). CONCLUSION: There is heterogeneity in the management of increased NT in the first trimester among the CPDPNs in France. In case of increased NT on first trimester ultrasound scan, the NT thickness threshold for which invasive diagnosis testing is performed varies from 3.0 mm or 3.5mm depending on the center. Moreover, CMA and early reference morphological ultrasound scan between 16 and 18 WG were not systematically performed, despite the current data suggesting their interest.

[Discordant Down syndrome risk calculation with low maternal serum markers: About five cases of digynic triploidies]. / Risque de trisomie 21 discordant en cas de marqueurs sériques très bas : à propos de cinq cas de triploïdie digynique.

OBJECTIVE: We compare the risk of Down syndrome among five patients carrying a foetus with digynic triploidy and suggest a course of action for these particular serological profiles. METHODS: The concentrations of the different markers used are transformed into multiples of the median by using each of the three software types present on the French market which then determine the risk of Down syndrome. RESULTS: For comparable biochemical and ultrasound profiles, the risk of Down syndrome turns out to be vastly different depending on the type of software employed. The relevance of an immediate diagnostic procedure, of a cell free DNA test or of a basic ultrasound follow-up then arises, leading to a potentially variable care pathway for the patient. CONCLUSIONS: This study confirms that for this type of biochemical profile, the laboratory's advisory service is fundamental, that a control ultrasound is essential and that an invasive procedure must be used almost invariably due to the extremely substantial risk factors.

Clinical, Cognitive and Neurodevelopmental Profile in Tetrasomies and Pentasomies: A Systematic Review.

Background: Sex chromosome aneuploidies (SCAs) are a group of disorders characterised by an abnormal number of sex chromosomes. Collective prevalence rate of SCAs is estimated to be around 1 in 400-500 live births; sex chromosome trisomies (e.g., XXX, XXY, XYY) are most frequent, while tetra- and pentasomies (e.g., XXXX, XXXXX, XXXY, XXXXY) are rarer, and the most common is 48, XXYY syndrome. The presence of additional X and/or Y chromosomes is believed to cause neurodevelopmental differences, with increased risk for developmental delays, language-based learning disabilities, cognitive impairments, executive dysfunction, and behavioural and psychological disorders. Aim of the Study: Our review has the purpose of analysing the neurocognitive, linguistical and behavioural profile of patients affected by sex chromosomes supernumerary aneuploidies (tetrasomy and pentasomy) to better understand the specific areas of weakness, in order to provide specific rehabilitation therapy. Methods: The literature search was performed by two authors independently. We used MEDLINE, PubMed, and PsycINFO search engines to identify sources of interest, without year or language restrictions. At the end of an accurate selection, 16 articles fulfilled the inclusion and exclusion criteria. Results and Conclusions: International literature has described single aspects of the neuropsychological profile of 48, XXYY and 49, XXXXY patients. In 48, XXYY patients, various degrees of psychosocial/executive functioning issues have been reported and there is an increased frequency of behavioural problems in childhood. Developmental delay and behavioural problems are the most common presenting problems, even if anxiety, depression and oppositional defiant disorder are also reported. They also show generalized difficulties with socialization and communication. Cognitive abilities are lower in measures of verbal IQ than in measures of performance IQ. Visuospatial skills are a relative strength compared to verbal skills. In patients with 49, XXXXY, both intellectual and adaptive functioning skills fall into the disability range, with better non-verbal cognitive performance. Speech and language testing reveals more deficits in expressive language than receptive language and comprehension. Anxiety, thought problems, internalizing and externalizing problems, and deficits in social cognition and communication are reported. Behavioural symptoms lessen from school age to adolescence, with the exception of thought problems and anxiety. Individuals affected by sex chromosome aneuploidies show testosterone deficiency, microorchidism, lack of pubertal progression and infertility. Hormone replacement therapy (HRT) is usually recommended for these patients: different studies have found that testosterone-based HRT benefit a wide range of areas initiated in these disorders, affecting not only neuromotor, cognitive and behavioural profile but also structural anomalies of the brain (i.e., increase of volume of grey temporal lobe matter). In conclusion, further studies are needed to better understand the neuropsychological profile with a complete evaluation, including neurocognitive and psychosocial aspects and to establish the real impact of HRT on improving the cognitive and behavioural profile of these patients.

Outcomes following prenatal diagnosis of isolated persistent left superior vena cava.

BACKGROUND: Prenatal diagnosis of persistent left superior vena cava is increasing, but little is known about outcomes of infants with prenatally diagnosed isolated persistent left superior vena cava. OBJECTIVE: To assess the outcomes of infants with isolated persistent left superior vena cava diagnosed prenatally compared with infants with associated malformations. METHODS: All cases of persistent left superior vena cava confirmed by specialized fetal echocardiography in pregnant women were included from a single-centre prospective registry. Unfavourable outcome was defined as termination of pregnancy, in utero death, postnatal death or severe genetic syndrome missed prenatally. RESULTS: A total of 256 infants were included: 113 cases (44.1%) with isolated persistent left superior vena cava and 143 cases (55.9%) with associated malformations; respectively, 111 (98.2%) and 101 (70.6%) had a live birth. The median postnatal clinical follow-up was 3.6 years. Five-year postnatal survival with good outcome was estimated at: 100% (95% confidence interval 90.7% to 100%) in infants with isolated persistent left superior vena cava; 91.0% (74.0% to 98.1%) in infants with associated cardiac anomalies; 87.5% (51.8% to 97.3%) in infants with associated extracardiac anomalies; 81.0% (52.6 to 94.6%) in infants with both cardiac and extracardiac anomalies; and 78.9% (36.7% to 95.9%) in infants with non-structural anomalies. All genetic findings and syndromes were detected in fetuses or infants with non-isolated persistent left superior vena cava. CONCLUSION: Infants with isolated persistent left superior vena cava have good short-term outcomes postnatally, but persistent left superior vena cava is frequently associated with other malformations that have an effect on outcomes, which should be thoroughly searched for prenatally.

Opinion de comité no 406 : Dépistage prénatal après FIV avec test génétique préimplantatoire des aneuploïdies.

OBJECTIFS: Examiner l'approche du dépistage génétique prénatal et du diagnostic des anomalies chromosomiques dans les grossesses conçues par fécondation in vitro à la suite d'un test génétique préimplantatoire des aneuploïdies. PROFESSIONNELS CONCERNéS: Omnipraticiens, médecins de famille, obstétriciens, sages-femmes, infirmières, spécialistes en médecine fœto-maternelle, spécialistes en fertilité, conseillers en génétique, généticiens et autres professionnels de la santé qui participent au dépistage prénatal. POPULATION CIBLE: Toute personne ou tout couple dont la grossesse est issue d'une fécondation in vitro et dont l'embryon a préalablement été soumis à un dépistage génétique préimplantatoire des aneuploïdies. DONNéES PROBANTES: Des recherches ont été effectuées dans les bases de données Medline, PubMed et Cochrane Library pour extraire la littérature publiée au plus tard en septembre 2018. DÉCLARATIONS SOMMAIRES.

[What are the real purpose and scope of screening for aneuploidy?] / Quels sont l'objectif réel et la portée du dépistage des aneuploïdies ?

In France, the recommended method for Down syndrome screening is the first trimester combined test, the risk assessment, based on maternal age, ultrasound measurement of fetal nuchal translucency and maternal serum markers (free ß-hCG and PAPP-A). The Down syndrome detection rate is 78.7% at a screen positive rate of 5%. However, the best screening test is the integrated test using a combination of first trimester combined test and second trimester quadruple test (serum α-fetoprotein, human chorionic gonadotropin, unconjugated E3, and dimeric inhibin-A) and being able to achieve a detection rate for Down syndrome of approximately 96% at a screen-positive rate of 5%. In recent years, the isolation of small fragments of "fetal" cell-free DNA in the maternal blood dramatically changed the screening strategy paradigm allowing a Down syndrome detection rate and false positive rate of 99.2 and 0.09%, respectively. However, aneuploidy screening based on cell-free DNA presents two major limitations which must be taken into account because they considerably limit its benefit: (i) not every woman will receive an interpretable result and that those who fail to receive a result are at increased risk for fetal aneuploidy: whether an inconclusive result is treated as screen positive or screen negative affects the overall detection rate (sensitivity) and false-positive rate (specificity) of the test; (ii) the limited number of targeted aneuploidies (trisomies 21, 18, 13 and common sex chromosome aneuploidies) in contrast to conventional noninvasive screening which is also able to detect rare aneuploidies, duplications, deletions, and other structural rearrangements. Of course, genetic counseling has to include a discussion about benefits and limitations of aneuploidy screening based on cell-free DNA. However, it should not be considered as a new screening test to substitute for conventional noninvasive screening. Moreover, if the ultimate goal is to deliver the most information about potential risk of various chromosomal abnormalities associated with adverse perinatal outcomes, then current cell-free DNA screening strategies may not be the best approach. These data highlight the limitations of cell-free DNA screening and the importance of a clear and fair information during pretest genetic counseling about benefits and limitations of any prenatal noninvasive screening (whether conventional or by cell-free DNA), but also about risks and benefits of invasive diagnostic procedures (in first- or second-line), especially since the cytogenetic analysis with chromosomal microarray analysis has improved the detection of genome microdeletions and microduplications (variants of the copy number) that can not be detected by standard cytogenetic analysis.

Mitotic instability in triploid and tetraploid one-year-old eastern oyster, Crassostrea virginica, assessed by cytogenetic and flow cytometry techniques.

For commercial oyster aquaculture, triploidy has significant advantages. To produce triploids, the principal technology uses diploid × tetraploid crosses. The development of tetraploid brood stock for this purpose has been successful, but as more is understood about tetraploids, it seems clear that chromosome instability is a principal feature in oysters. This paper is a continuation of work to investigate chromosome instability in polyploid Crassostrea virginica. We established families between tetraploids-apparently stable (non-mosaic) and unstable (mosaic)-and normal reference diploids, creating triploid groups, as well as tetraploids between mosaic and non-mosaic tetraploids. Chromosome loss was about the same for triploid juveniles produced from either mosaic or non-mosaic tetraploids or from either male or female tetraploids. However, there was a statistically significant difference in chromosome loss in tetraploid juveniles produced from mosaic versus non-mosaic parents, with mosaics producing more unstable progeny. These results confirm that chromosome instability, as manifested in mosaic tetraploids, is of little concern for producing triploids, but it is clearly problematic for tetraploid breeding. Concordance between the results from cytogenetics and flow cytometry was also tested for the first time in oysters, by assessing the ploidy of individuals using both techniques. Results between the two were non-concordant.

Aneuploid progeny of the American oyster, Crassostrea virginica, produced by tetraploid × diploid crosses: another example of chromosome instability in polyploid oysters.

The commercial production of triploids, and the creation of tetraploid broodstock to support it, has become an important technique in aquaculture of the eastern oyster, Crassostrea virginica. Tetraploids are produced by cytogenetic manipulation of embryos and have been shown to undergo chromosome loss (to become a mosaic) with unknown consequences for breeding. Our objective was to determine the extent of aneuploidy in triploid progeny produced from both mosaic and non-mosaic tetraploids. Six families of triploids were produced using a single diploid female and crossed with three mosaic and non-mosaic tetraploid male oysters. A second set of crosses was performed with the reciprocals. Chromosome counts of the resultant embryos were tallied at 2-4 cell stage and as 6-hour(h)-old embryos. A significant level of aneuploidy was observed in 6-h-old embryos. For crosses using tetraploid males, aneuploidy ranged from 53% to 77% of observed metaphases, compared to 36% in the diploid control. For crosses using tetraploid females, 51%-71% of metaphases were aneuploidy versus 53% in the diploid control. We conclude that somatic chromosome loss may be a regular feature of early development in triploids, and perhaps polyploid oysters in general. Other aspects of chromosome loss in polyploid oysters are also discussed.

Autotetraploid Pacific oysters (Crassostrea gigas) obtained using normal diploid eggs: induction and impact on cytogenetic stability.

We describe two methods of producing viable and fertile autotetraploid Pacific oyster (Crassostrea gigas Thunberg) based on the use of normal-sized oocytes produced by normal diploid females. Our methods showed that the oocyte size is not a limiting factor for the success of the induction to autotetraploidy. These methods offer means of direct introgression of genetic progress from elite diploid lines to tetraploids used as broodstock, avoiding a triploid step with the risk of transferring undesirable traits from highly fecund triploids. High variability in the level of cytogenetic stability was found among the different tetraploid oysters tested, showing that induction method has an important impact on the long-term cytogenetic stability of the tetraploids. It appears that induction method based on the use of triploid females induces a greater cytogenetic instability among tetraploids so obtained, and this compared to tetraploids originating from the two methods described in our present study. As the aneuploidies and reversions observed in tetraploids can have serious consequences for the sustainability of tetraploid broodstock itself, as well as their triploid offspring, the two tetraploid induction methods described in the present work offer means to produce tetraploids with optimal cytogenetic, genetic, and zootechnical performances.

[Second trimester growth restriction and underlying fetal anomalies]. / Retard de croissance intra-utérin du deuxième trimestre : malformations associées et syndromes sous-jacents.

OBJECTIVES: To determine the incidence of chromosomal abnormalities, syndromic association and fetal defects associated with second trimester fetal growth restriction (FGR) in a tertiary referral center. PATIENTS AND METHODS: Retrospective review of all cases referred between 14 and 27 weeks with an abdominal circumference (AC)<5(th) centile between 2008 and 2012. Multiple pregnancies were excluded. Medical records were retrieved to look for the presence of associated malformations, aneuploidy and outcomes. RESULTS: A total of 8626 fetuses had ultrasonographic examination between 14 and 27 weeks. Of these, there were 239 cases (2.8%) with evidence of FGR as based on AC measurement. Thirty-seven fetuses had an abnormal karyotype or an identified syndromic association (15%). The most common chromosomal defect was Trisomy 18 (10 cases, 4.2%), 67 had at least one associated morphological abnormality without aneuploidy or syndromic association (28%). Most common associated abnormalities were relative short femur (5%), omphalocele (5%) and gastroschisis (4%). Last 135 cases were isolated fetal growth retardation (5%). Maternal age was higher (33 yr ± 5 yr versus 31 yr ± 5.6 yr, P < 0.01) and the z-score for the AC lower (2.5 ± 1 versus 2.15 ± 0.6) in the group with abnormal karyotype or syndromic association than in the group without associated malformation. Amniotic fluid was more often increased in the group with an abnormal karyotype or associated malformation (14% and 17%) than in the group without malformations (0%, P < 0.01). DISCUSSION AND CONCLUSION: This study describes abnormalities and outcomes associated with second trimester fetal growth retardation in a large population of patients. Our results suggest that the absence of associated malformation, degree of growth restriction, maternal age and the amniotic fluid index may help in the prenatal management and counseling of this high risk population.

Prevalence of aneuploidies in products of spontaneous abortion: interest of FISH and MLPA.

Spontaneous abortion (SA) is the loss of the conceptus before 22 weeks of gestation when fetal weight is less than 500 g. The genetic etiology accounts for more than two third of SA, and autosomal aneuploidies alone account for up to 70% fetal loss. The aim of this study was to highlight the most common chromosomal causes of fetal loss. In this study, 220 products of abortion and in utero fetal death were analyzed by using FISH (AneuVysion) on interphase nuclei from chorionic villus and by using MLPA (SALSA P036, P070 and P245 kits) on DNA extracted from fetal tissues. The gestational age ranged from the 7th to the 38th week of gestation. Of a total of 151 samples analyzed by using FISH, 10 chromosomal abnormalities were observed: four trisomies 21 (one of them was mosaic), a trisomy 18, a trisomy 13, three triploidies and one monosomy X (Turner). From the additional 69 samples analyzed by using MLPA, two anomalies were found: two monosomies X (Turner). FISH and MLPA are simple, rapid and sensitive tools for the detection of chromosomal aneuploidies. Avoiding the cell culture step necessary for karyotyping, they represent very interesting alternative methods to diagnose genomic disorders in products of abortion in which poor sample quality often leads to cell culture failure.

[Neonatal outcome of fetal hyperechogenic bowel]. / Devenir néonatal des fœtus présentant un intestin hyperéchogène.

OBJECTIVE: Echogenic bowel (EB) represents 1 % of pregnancy and is a risk factor of fetal pathology (infection, cystic fibrosis, aneuploidy). The aim of our study was to determine the fetuses' outcomes with isolated EB. PATIENTS AND METHODS: This is a retrospective study of all patients who presented singleton gestations with a fetal isolated echogenic bowel between 2004 and 2011 in two prenatal diagnosis centers. Search of aneuploidy, infection and cystic fibrosis was systematically proposed as well as an ultrasound monitoring. RESULTS: On 109 fetus addressed for isolate echogenic bowel five had other signs associated and 74 had a real isolated echogenic bowel (without dilatation, calcification, intrauterine growth restriction). In 30 cases, the EB was not found. Eighty-five percent of the patients had in the first trimester a screening for trisomy 21. None fetus with isolated EB had trisomy, infection or cystic fibrosis. One fetus died in utero and one newborn died of a metabolic disease without digestive repercussions. DISCUSSION AND CONCLUSION: The risk of trisomy 21 and the risk to have a serious disease appear low for the fetus with EB. It does not seem necessary to propose a systematic amniocentesis in case of isolated echogenic bowel.