Prenatally Diagnosed Trisomy 21—Reply

To evaluate the value of short tandem repeat polymerase chain reaction (STR-PCR) in identification of zygosity in multiple pregnancy and detection of the common chromosomal trisomies. Amniotic fluid or fetal blood samples were collected from 38 fetuses in 17 multiple pregnant women who had indications for prenatal diagnosis or planed to be performed feticide. Of the 17 cases there were 13 sets of twins (26 fetuses) and 4 sets of triplets (12 fetuses). Parental blood samples were collected. STR-PCR technique was employed to determine the zygosity and detect trisomy 21, trisomy 18, trisomy 13, and trisomy sex chromosomes. Amniotic fluid or blood samples were collected from 18 singleton pregnant fetuses as controls for detecting chromosomal trisomies. All 7 cases with gestation by assisted reproductive techniques were multizygotic. In 7 cases associated with one fetal malformation, only one set of twin was dizygotic. There were no above mentioned trisomies found in the multiple pregnancies while 2 trisomy 21, one trisomy 18 and 13 respectively were detected in the singleton pregnant group. Feticide was performed on 4 multizygotic cases in which 3 were triplets and 1 was twin associated with an abnormal fetus. Following-up showed that there was no any bad effect after procedure. STR-PCR can be used in identifying the zygosity correctly and quickly while being used in detecting chromosomal trisomies. It facilitates monitoring multiple pregnancy as well as selecting appropriate methods of feticide.

To investigate the karyotypes of amniotic fluid cells and compare the incidence of chromosomal abnormality as well as to evaluate the clinical significance of abnormal karyotypes. A total of 13 648 pregnant women came to Shanghai Jiai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University to do amniocentesis from September 1998 to November 2010, and 13 795 amniotic fluid specimens were successfully extracted and cultured, thus 13 795 fetuses received karyotype diagnosis. These fetuses were grouped according to different indications. If maternal age was ≥ 35, the fetuses were grouped into the advanced maternal age group (4065); and if maternal serum screening test revealed high-risk of trisomy 18 or trisomy 21, the fetuses were grouped into the high-risk serum screening group (6462); and those with abnormal signs of ultrasound screening were grouped into the abnormal ultrasound signs group (1539); and if either of the parents was with chromosome abnormalities, the fetus was grouped into the paternal/maternal abnormality group (108); whereas the remainder were grouped in other factors group (1621). The amniotic fluid cells were in-situ cultured on coverslips, harvested by conventional G-banded methods, and then analyzed by two doctors. In order to get rapid diagnosis, some pregnant women whose gestational age ≥ 26 weeks accepted fluorescense in situ hybridization (FISH). FISH was done on 78 uncultured amniotic fluid specimens using probes located at chromosome 13, 18, 21, X, Y. Some parents were required to analyze lymphocyte karyotype to help judging the origin of abnormal karyotype. (1) Classification and composition of abnormal karyotypes in each group: a total of 388 abnormal karyotypes were found among 13 795 fetuses, and the abnormal rate was 2.813% (388/13 795). Of the 388 fetuses, aneuploidy was the most common pattern which was up to 59.8% (232/388); autosomal structural abnormality rate was 24.7% (96/388); mosaicism was 12.4% (48/388). Other uncommon abnormal karyotypes included marker chromosome (5/388, 1.3%), sex chromosomal structural abnormality (4/388, 1.0%) and triploid (3/388, 0.8%). Aneuploidy was the most common in most groups except the paternal/maternal abnormality group. There were four cases of rare aneuploid in the advanced maternal age group, the high-risk serum screening group and the abnormal ultrasound signs group respectively. Every type of abnormality could be found in the abnormal ultrasound signs group, and autosomal structural abnormalities were concentrated in paternal/maternal abnormality group. Mosaicism mainly distributed in the high-risk serum screening group, accounting for 20.0% (29/145) of abnormalities in this group. (2) Abnormal types and the incidence: the most common type was trisomy 21 (138/388, 35.6%), followed by autosomal balanced structural rearrangements (80/388, 20.6%), mosaicism (48/388, 12.4%) and trisomy 18 (44/388, 11.3%). Others included non-balanced autosomal structural rearrangements (16/388, 4.1%), 45, X0 (16/388, 4.1%) and 47, XXY (15/388, 3.9%). (3) Lymphocyte karyotype analysis of the couples: parents of 153 fetuses were analyzed to determine the origin of abnormal karyotype. Fifty-eight familial and 95 de novo abnormalities were found. FISH results were the same with G-banding karyotype, and two of these were trisomy 21. Abnormal karyotype composition is different according to different maternal amniocentisis indications. There is a variety of abnormal karyotypes in the second trimester pregnancy, and the risk of fetal malformation is related with the kind of abnormal karyotype.

Objective To investigate the clinical values of multiple ultrasound soft markers in screening for fetal chromosomal abnormality during first-trimester.Methods Two thousand seven hundred and eighty-nine nulliparas in Department of Obstetrics,the First Affiliated Hospital of Jinan University during early pregnancy (11-13+6 gestational weeks) were selected for this study.Fetalnuchal translucency (NT),facial angle (FA),ductus venosus (DV),fetal heart rate (FHR),tricuspid reverse (TR),nasal bone (NB) and fetal structures were scanned and measured.Risk calculation software (Astraia) was used to calculate the chromosomal abnormal risk (cut-off line:＞1/300) based on ultrasound records.The chorionic villi or amniotic fluid of high risk patients was collected with informed consent for karyotype analysis (prenatal diagnosis).All patients were followed up until six months after delivery.Chi-square test or Fisher exact test was used to compare the difference.Results One hundred and seven cases were high-risk of trisomy 21 among which 96 cases accepted invasive prenatal diagnosis.Sixteen chromosomal anomaly and six trisomy 21 cases were diagnosed out the 96 fetuses.Among 2789 cases,four were high-risk of trisomy 21 according to ultrasound screening.Six cases were diagnosed as trisomy 21.The false positive rate of ultrasound screening was 3.6％(101/2783).There were 196 cases whose NT ≥2.5 mm,in which 66 cases were high risk of chromosomal abnormality,and 16 fetal chromosomal abnormalities were diagnosed after chorionic villus sampling.The invasive procedure rate was 2.3％ (66/2789).Totally,186 pregnant women were older than 35 years,among which 32 cases were high risk.There was no significantly difference on the of rate fetal chromosomal abnormality between the groups of age≥ 35 pregnant women and the general population (P=0.055).But 29.9％ (32/107) high risk cases were detected in the group of age≥35.Five of thirteen fetal malformations cases were associated with abnormal karyotype.Conclusions Multiple ultrasound soft markers screening during early pregnancy could increase the diagnosis rate of chromosomal abnormality and decrease the false positive rate,false negative rate and invasive procedure rate.Early ultrasound screening might be effective in not only identifying chromosomal abnormality,but also diagnosing severe structure deformity of fetus. Key words: Pregnancy, first trimester; ultrasound screening; Chromosomal abnormality

Objective To assess the clinical value of fetal chromosomal aneuploidy diagnosed by free fetal DNA in maternal plasma in 11-13+6 gestational weeks.Methods A total of 2 650 pregnant women who had prenatal care in Tianjin Center Hospital of Obstetrics and Gynecology from January 1,2010 to December 31,2010 were included.Each of them had an ultrasound scan to measure fetal nuchal translucency thickness.Maternal serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein A test was performed as part of screening for chromosomal abnormalities.Results of ultrasound and maternal plasma biochemical analysis were entered into the database,and converted into multiple of median (MoM) by factors such as maternal age,weight,ethnicity,smoking history and mode of conception.The cutoff value was 1 ∶ 270.Meanwhile,20 cases had cell free fetal DNA (cffDNA) test and the ratio of the single nucleotide polymorphism on two alleles of plancenta-specific 4 (PLAC4) were measured in 16 cases.T-test,rank sum test,MannWhitney U test and Chi-square test were used as statistical methods.Results (1) A total of 74 cases were judged as high-risk,among which 35 cases underwent transabdominal chorionic villus sampling (18 cases had cffDNA test),37 cases underwent amniocentesis at the week of 20,and two cases of Rh negative did not receive the invasive examination.Totally 20 cases,including two Rh negative cases,had the cell-free fetal DNA test.(2) By cffDNA test of maternal plasma,two cases of 21 trisomy,one case of 18 trisomy,two cases of 45,XO and one case of balanced translocation were diagnosed.(3) In the two cases of 21 trisomy,maternal plasma G/A ratio ofPL4C4 RNA-single nucleotide polymorphism alleles was 1.00 (0.98,1.02) ; in 14 pregnancies with normal chromosome,the ratio was 1.055 (1.02,1.13,Z=3.5).There was no significant difference (P=0.066).Conclusion Diagnosing of fetal chromosomal aneuploidy by cffDNA in maternal plasma is feasible and noninvasive with high negative predictive value,and can be used in Rh-negative pregnant women for prenatal screening and diagnosis. Key words: Aneuploidy; Prenatal diagnosis; DNA; Pregnancy trimester, first

Congenital leukemia is very rare, diagnosed in first month of life and often associated with Down’s syndrome. Congenital Acute myeloid leukemia (AML) is more common over acute lymphoblastic leukemia (ALL). The hematological parameters such as anemia, low hematocrit, reduced RBC count, reduced platelets are distinct characteristics against normal parameters in very closely associated Transient myeloproliferative disorder (TMD). The immunophenptypic markers such as expression pattern of CD13, CD11b and HLADR in combination can be used for distinguishing two diseases. The morphological discrimination between congenital AML and TMD is little difficult and hence combined results of hematological, cytogenetic and immunophenotyping should be considered while concluding the cases. We here report two cases observed in year 2014 in our hospital, at pune. Both the cases were diagnosed in first week of their life, day 2 (case 1) and day 8 (case2) with distinct features of increased white blood cell count with myeloid blast, reduced Hb, low hematocrit, reduced RBC count and low platelets count with trisomy 21. Both the cases were CD13- and CD11b +, hence we conclude these cases as Congenital Acute myeloid leukemia associated with Down’s syndrome. Both the cases survived for less than 15 days after the birth.

Down syndrome or trisomy 21 is a condition where extra genetic material causes mental and physical delays and deficits. It affects 1 in every 650 babies. Abnormalities of the cardiovascular system are common in down syndrome. Approximately half of all infants born with down syndrome have a heart defect. The most common heart defects in down syndrome are the following: atrioventricular septal defect (45%), ventricular septal defect (35%), atrial septal defects (8%) and patent ductus arteriosus (7%), tetralogy of Fallots (4%). A Two years one-month-old baby was admitted in cardiac surgery department of Dhaka Shishu Hospital, with the diagnosis of Down syndrome with VSD,ASD& PDA with moderate pulmonary arterial hypertension. Clinical examination revealed diastolic murmur over mitral area. The child was treated with face musk oxygen, diuretics and digoxin and was stabilized medically and then was selected for surgery. We used balanced anesthetic technique using oxygen, air, fentanyl, midazolam and vecuronium. Patient was operated under cardiopulmonary bypass (CPB) with moderate hypothermia. Patient tolerated the whole procedure well and was ventilated electively for 4hrs in the intensive care unit. He was discharged on the 8thpostoperative day. Journal of Bangladesh Society of Anaesthesiologists 2015; 28(1): 39-42

Trisomy 18 or Edwards syndrome is the second most common aneuploidy with a prevalence between 1/3000 and 1/10000 live births. The syndrome encompasses malformations of the central nervous, cardiac, respiratory, gastrointestinal, and genitourinary systems. Trisomy 18 carries a poor prognosis with 90% of patients not surviving beyond 1year of age; however, the current trend toward more aggressive supportive care may prolong survival. The limited anesthesia literature highlights the abnormal airway anatomy but generally describes uneventful airway management and perioperative course. Our goal was to review all anesthesia encounters recorded for eleven trisomy 18 patients treated at Children's Wisconsin during the study period to explore the frequency of anesthesia encounters and to improve our understanding of the perioperative risks. We performed a retrospective chart review of all patients with trisomy 18 who were treated at our institution between 2012 and 2017. Records were screened for anesthesia encounters, perioperative critical events and complications, enrollment in palliative care, code status, and time of death. Eleven children were identified. Children were born between 2001 and 2016. Two children never required anesthesia care. Nine patients had a total of 84 anesthesia encounters for 121 surgical or diagnostic procedures or emergent intubations. Critical events and perioperative complications included difficult mask ventilation (n=7), difficult intubation (n=15), and mechanical or pharmacological cardiopulmonary resuscitation (n=6). Five patients presented with difficult peripheral intravenous access. One patient died in the immediate postoperative period. On five occasions, patients required emergent intubation outside of the operating room. Difficult airway management and respiratory compromise were critical concerns during the perioperative period in our patient population, and the inability to ventilate could lead to cardiorespiratory arrest. This case series provides a comprehensive, longitudinal view of complete trisomy 18 patients in the perioperative period and adds information for counseling families and care providers.

Purpose: to conduct a two-stage cluster analysis of clinical and anamnestic data from pediatric patients with different clinical forms of cerebral palsy (CP), along with obstetric and gynecological characteristics of their mothers, to identify pathogenetic phenotypes in children with CP. Methods: A retrospective analysis was conducted on data from the Aktobe Regional Perinatal Center for 2023, covering prenatal screening results from the first trimester of 43,584 pregnant women. This represented 82.5% of those registered for prenatal care before 12 weeks of gestation. The Life Cycle computer program was utilized to calculate individual risk of chromosomal abnormalities. As a result, a high-risk group of 3,343 women (7.7%) was identified, and the course and outcomes of their pregnancies were further analyzed. Following informed consent, invasive prenatal diagnostic procedures were performed on 845 (25.3%) women in this group, including chorionic villus sampling (4.8%), placentocentesis (23.4%), amniocentesis (38.2%), and cordocentesis (33.5%). Results: Cytogenetic and molecular genetic studies confirmed fetal chromosomal abnormalities in 82 cases (10.2%) among those who underwent invasive procedures. The following syndromes were identified: Down syndrome (69.7%), Edwards syndrome (17.4%), Patau syndrome (3.5%), Turner syndrome (4.6%), and structural rearrangements (4.6%). Among the 2,498 women at high risk who declined invasive diagnostics, adverse pregnancy outcomes were observed in 39 cases (1.6%). Conclusion: The retrospective analysis underscores the importance of timely assessment of second-trimester markers, including echographic and biochemical indicators, for early detection of chromosomal abnormalities. Adherence to prenatal diagnostic protocols facilitates timely identification of chromosomal abnormalities, allowing families to make informed decisions about pregnancy continuation. Keywords: children, cerebral palsy, phenotypes, MCP-1, cardiovascular pathology

Variation in the decision to terminate pregnancy in the setting of fetal aneuploidy

Balanced chromosome translocations in either parent increase the risk of recurrent miscarriage, unbalanced chromosome rearrangements, congenital malformations, and mental retardation in liveborn offspring. Chromosome aberrations account for at least 50% of fetal losses prior to 15 weeks’ estimated gestation (EGA). Of these, 60% occur secondary to autosomal trisomies (Gardner and Sutherland, 2004). Prenatal detection of parental chromosome rearrangements provides an opportunity to plan prenatal screening and diagnostic procedures, including chorionic villus sampling (CVS), amniocentesis, early sonographic evaluation, and pre-implantation genetic diagnosis and treatment. We report a familial chromosome translocation involving chromosomes 4 and 18 resulting in multigenerational history of recurrent miscarriage and two offspring with unbalanced chromosome rearrangements and phenotypic and neurodevelopmental sequelae. This case report describes, for the first time, a translocation that resulted in the combination of monosomy 18p and trisomy 4p. The consultand, III-2 (Table 1), a 32-year-old gravida 1, presented at 10 2/7 weeks EGA requesting CVS due to personal and family history of a known chromosome translocation. CVS was not technically possible. Transvaginal fetal ultrasonography showed mid-gut umbilical herniation considered a normal variant given gestational age. Encephalocele was suspected. A protuberant structure from the front of the fetal head consistent with a proboscis was identified. Bilateral clubfeet were suspected. After counseling, given her balanced translocation and ultrasound findings, III-2 elected voluntary pregnancy termination with concomitant fetal karyotype analysis and autopsy. Dilation and evacuation were performed

To perform individual record linkage of women undergoing screening with cell-free DNA (cfDNA), combined first-trimester screening (CFTS), second-trimester serum screening (STSS), and/or prenatal and postnatal cytogenetic testing with the aim to (1) obtain population-based estimates of utilization of prenatal screening and invasive diagnosis, (2) analyze the performance of different prenatal screening strategies, and (3) report the residual risk of any major chromosomal abnormality following a low-risk aneuploidy screening result. This was a retrospective study of women residing in the state of Victoria, Australia, who underwent prenatal screening or invasive prenatal diagnosis in 2015. Patient-funded cfDNA referrals from multiple providers were merged with state-wide results for government-subsidized CFTS, STSS and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12 months of age were obtained to ascertain cases of false-negative screening results and atypical chromosomal abnormalities. Individual record linkage was performed using LinkageWizTM . During the study period, there were 79 140 births and 66 166 (83.6%) women underwent at least one form of aneuploidy screening. Linkage data were complete for 93.5% (n = 61 877) of women who underwent screening, and of these, 73.2% (n = 45 275) had CFTS alone, 20.2% (n = 12 486) had cfDNA alone; 5.3% (n = 3268) had STSS alone, 1.3% (n = 813) had both CFTS and cfDNA, and < 0.1% (n = 35) had both STSS and cfDNA. CFTS had a combined sensitivity for trisomies 21 (T21), 18 (T18) and 13 (T13) of 89.57% (95% CI, 82.64-93.93%) for a screen-positive rate (SPR) of 2.94%. There were 12 false-negative results in the CFTS pathway, comprising 10 cases of T21, one of T18 and one of T13. cfDNA had a combined sensitivity for T21, T18 and T13 of 100% (95% CI, 95.00-100%) for a SPR of 1.21%. When high-risk cfDNA results for any chromosome (including the sex chromosomes) and failed cfDNA tests were treated as screen positives, the SPR for cfDNA increased to 2.42%. The risk of any major chromosomal abnormality (including atypical abnormalities) detected on prenatal or postnatal diagnostic testing after a low-risk screening result was 1 in 1188 for CFTS (n = 37) and 1 in 762 for cfDNA (n = 16) (P = 0.13). The range of chromosomal abnormalities detected after a low-risk cfDNA result included pathogenic copy-number variants (n = 6), triploidy (n = 3), rare autosomal trisomies (n = 3) and monosomy X (n = 2). Our state-wide record-linkage analysis delineated the utilization and clinical performance of the multitude of prenatal screening pathways available to pregnant women. The sensitivity of cfDNA for T21, T18 and T13 was clearly superior to that of CFTS. While there was no statistically significant difference in the residual risk of any major chromosomal abnormality after a low-risk CFTS or cfDNA result, there were fewer live infants diagnosed with a major chromosomal abnormality in the cfDNA cohort. These data provide valuable population-based evidence to inform practice recommendations and health policies. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Background: The diagnosis of a chromosomally abnormal third trimester fetus prior to birth permits optimal obstetrical management and psychological support for the parents when the child is born. Although ultrasound findings may lead to suspicion of Edward syndrome, confirmation of the diagnosis depends on the cytogenetic detection of trisomy 18. Certain obstetrical situations may limit the choice of diagnostic procedures to amniocentesis when a rapid cytogenetic result in required. Case: Fluorescence in situ hybridization in uncultured amniocytes permitted rapid detection of trisomy 18 in one twin following preterm labor, allowing a definitive diagnosis before birth. Conclusion: The technique described enables a rapid, targeted cytogenetic result using uncultured amniocytes. This is a valuable new tool when a specific fetal aneuploidy is strongly suggested by sonography and obstetrical factors preclude the use of procedures other than amniocentesis.