Decoding 22q11.2: prenatal profiling and first-trimester risk assessment in Danish nationwide cohort.

OBJECTIVES: To examine the distribution of nuchal translucency thickness (NT), free ß-human chorionic gonadotropin (ß-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in pregnancies with a fetal 22q11.2 aberration. Furthermore, the performance of combined first-trimester screening (cFTS) and a new risk algorithm targeting 22q11.2 deletions in detecting affected pregnancies was evaluated. Finally, prenatal malformations and pregnancy outcome were assessed. METHODS: This was a nationwide registry-based cohort study of all pregnancies that underwent prenatal screening with a due date between January 2008 and December 2018 in Denmark. All cases with a fetal 22q11.2 deletion or duplication (hg19 chr22:18.9mio-25.0mio) diagnosed pre- or postnatally or following pregnancy loss or termination of pregnancy were retrieved from the Danish Cytogenetic Central Register and linked with pregnancy data from the Danish Fetal Medicine Database. Fetal and maternal characteristics, including cFTS results and pregnancy outcome, of pregnancies with any 22q11.2 deletion or duplication (LCR22-A to -H) and pregnancies with a classic deletion or duplication (LCR22-A to -D) diagnosed by chromosomal microarray were compared with those of a chromosomally normal reference group. A risk algorithm was developed for assessing patient-specific risks for classic 22q11.2 deletions based on NT, PAPP-A and ß-hCG. Detection rates and false-positive rates at different risk cut-offs were calculated. RESULTS: We included data on 143 pregnancies with a fetal 22q11.2 aberration, of which 97 were deletions (54 classic) and 46 were duplications (32 classic). NT was significantly increased in fetuses with a classic deletion (mean, 1.89 mm), those with any deletion (mean, 1.78 mm) and those with any duplication (mean, 1.86 mm) compared to the reference group (mean, 1.65 mm). ß-hCG multiples of the median (MoM) was decreased in all 22q11.2 subgroups compared with the reference group (mean, 1.02) and reached significance in pregnancies with a classic deletion and those with any deletion (mean, 0.77 and 0.71, respectively). PAPP-A MoM was significantly decreased in pregnancies with a classic duplication and those with any duplication (mean, 0.57 and 0.63, respectively), and was significantly increased in pregnancies with a classic deletion and those with any deletion (mean, 1.34 and 1.16, respectively), compared to reference pregnancies (mean, 1.01). The screen-positive rate by cFTS was significantly increased in pregnancies with a classic deletion (13.7%), any deletion (12.5%), a classic duplication (46.9%) or any duplication (37.8%) compared to the reference group (4.5%). A risk algorithm targeting classic 22q11.2 deletions more than doubled the prenatal detection rate of classic 22q11.2 deletions, but with a substantial increase in the false-positive rate. Structural malformations were detected in 41%, 35%, 17% and 25% of the pregnancies with a classic deletion, any deletion, classic duplication or any duplication, respectively. Pregnancy loss occurred in 40% of pregnancies with a classic deletion and 5% of those with a classic duplication diagnosed prenatally or following pregnancy loss. CONCLUSIONS: The distribution of cFTS markers in pregnancies with a classic 22q11.2 duplication resembles that of the common trisomies, with decreased levels of PAPP-A. However, classic 22q11.2 deletions are associated with increased levels of PAPP-A, which likely limits early prenatal detection using the current cFTS risk algorithm. The scope for improving early detection of classic 22q11.2 deletions using targeted risk algorithms based on NT, PAPP-A and ß-hCG is limited. This demonstrates the capability, but also the limitations, of cFTS markers in detecting atypical chromosomal anomalies, which is important knowledge when designing new prenatal screening programs. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Medical imaging utilization and associated radiation exposure in children with down syndrome.

OBJECTIVE: To evaluate the frequency of medical imaging or estimated associated radiation exposure in children with Down syndrome. METHODS: This retrospective cohort study included 4,348,226 children enrolled in six U.S. integrated healthcare systems from 1996-2016, 3,095 of whom were diagnosed with Down syndrome. We calculated imaging rates per 100 person years and associated red bone marrow dose (mGy). Relative rates (RR) of imaging in children with versus without Down syndrome were estimated using overdispersed Poisson regression. RESULTS: Compared to other children, children with Down syndrome received imaging using ionizing radiation at 9.5 times (95% confidence interval[CI] = 8.2-10.9) the rate when age <1 year and 2.3 times (95% CI = 2.0-2.5) between ages 1-18 years. Imaging rates by modality in children <1 year with Down syndrome compared with other children were: computed tomography (6.6 vs. 2.0, RR = 3.1[95%CI = 1.8-5.1]), fluoroscopy (37.1 vs. 3.1, RR 11.9[95%CI 9.5-14.8]), angiography (7.6 vs. 0.2, RR = 35.8[95%CI = 20.6-62.2]), nuclear medicine (6.0 vs. 0.6, RR = 8.2[95% CI = 5.3-12.7]), radiography (419.7 vs. 36.9, RR = 11.3[95%CI = 10.0-12.9], magnetic resonance imaging(7.3 vs. 1.5, RR = 4.2[95% CI = 3.1-5.8]), and ultrasound (231.2 vs. 16.4, RR = 12.6[95% CI = 9.9-15.9]). Mean cumulative red bone marrow dose from imaging over a mean of 4.2 years was 2-fold higher in children with Down syndrome compared with other children (4.7 vs. 1.9mGy). CONCLUSIONS: Children with Down syndrome experienced more medical imaging and higher radiation exposure than other children, especially at young ages when they are more vulnerable to radiation. Clinicians should consider incorporating strategic management decisions when imaging this high-risk population.

Atypicality index: avoiding false reassurance in prenatal screening.

OBJECTIVE: To demonstrate the application of the atypicality index as an adjunct to first-trimester risk assessment for major trisomies by the combined test. METHODS: This was a study of 123 998 Danish women with a singleton pregnancy who underwent routine first-trimester screening, including risk assessment for major trisomies. An atypicality index, which is a measure of the degree to which a profile is atypical, was produced for measurements of fetal nuchal translucency thickness and maternal serum free ß-human chorionic gonadotropin and pregnancy-associated plasma protein-A. The incidence of adverse pregnancy outcome, including miscarriage, intrauterine death and termination of pregnancy, was tabulated according to the screening result and atypicality index. RESULTS: In pregnancies with low risk and those with high risk for major trisomies according to the combined screening test, the incidence of adverse pregnancy outcome increased with increasing atypicality index. In pregnancies with a low risk for trisomies and atypicality index of ≥ 99%, the incidence of adverse outcome was 5.1 (95% CI, 3.4-7.6) times higher compared with that in low-risk pregnancies with a typical measurement profile, reflected by an atypicality index of < 80%. Similarly, in high-risk pregnancies, the incidence of adverse outcome was 7.9 (95% CI, 4.4-14.5) times higher in those with an atypicality index of ≥ 99% compared to those with an atypicality index of < 80%. Using individual profile plots, we were able to demonstrate a transparent and intuitive method for visualization of multiple variables, which can help interpret the individual combination of measurements and level of atypicality. CONCLUSIONS: In pregnancies undergoing first-trimester combined screening and classified as being at low risk for major trisomies, profiles that are typical of pregnancies with normal outcome provide additional reassurance, whereas those with an atypical profile may warrant further investigation. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Características ecográficas y anomalías congénitas en fetos con síndrome de Down / Ultrasound features and congenital anomalies in fetuses with Down syndrome

Resumen Objetivo: Describir y analizar los hallazgos ecográficos en 97 fetos portadores de síndrome de Down (SD) confirmado. Método: Se incluyeron todas las gestantes con diagnóstico prenatal de SD de nuestro centro, realizado por cariograma o reacción en cadena de la polimerasa cuantitativa fluorescente para aneuploidía. Se analizaron los informes genéticos y ecográficos, y se realizó un seguimiento posnatal. Resultados: De los 97 casos de SD, el 73% de los diagnósticos fueron entre las 11 y 14 semanas. El promedio de edad de las madres fue de 35,7 años. El 83% de los fetos con SD, evaluados a las 11-14 semanas, tuvieron una translucencia nucal ≥ 3,5 mm. Del total de los casos analizados, el 33% fueron portadores de una cardiopatía congénita, correspondiendo el 58% de estas a defectos mayores, principalmente anomalías del tabique auriculoventricular. Un 7,6% de los casos terminaron como mortinato, principalmente durante el tercer trimestre. Conclusiones: El ultrasonido es una herramienta muy sensible para la sospecha prenatal de SD y la detección de sus anomalías asociadas. Consideramos que la información aportada será útil para programar estrategias de pesquisa, organizar el control perinatal y precisar el consejo a los padres de fetos portadores de esta condición.

Abstract Objective: To describe and analyze the ultrasound findings in 97 fetuses with confirmed Down syndrome (DS). Method: All pregnant women with prenatal diagnosis of DS in our center, performed by karyotype or quantitative fluorescent polymerase chain reaction for aneuploidy, were included. Genetic and ultrasound reports were analyzed, as well as postnatal follow-up. Results: Of the 97 cases of DS, 73% of the diagnoses were between 11-14 weeks. The average age of the mothers was 35.7 years. 83% of our fetuses with DS, evaluated between 11-14 weeks, had a nuchal translucency ≥ 3.5 mm. Of the total of the fetuses analyzed, 33% were carriers of congenital heart disease, 58% of these correspond to a major defect, mainly anomalies of the atrioventricular septum. 7.6% of cases ended as stillbirth, mainly during the third trimester. Conclusions: Ultrasound is a very sensitive tool for prenatal suspicion of DS and the detection of its associated abnormalities. We believe that the information provided will be useful to program screening strategies, organize perinatal control and to counselling parents of fetuses carrying this condition.

Development and Validation of a Deep Learning Model to Screen for Trisomy 21 During the First Trimester From Nuchal Ultrasonographic Images.

Importance: Accurate screening of trisomy 21 in the first trimester can provide an early opportunity for decision-making regarding reproductive choices. Objective: To develop and validate a deep learning model for screening fetuses with trisomy 21 based on ultrasonographic images. Design, Setting, and Participants: This diagnostic study used data from all available cases and controls enrolled at 2 hospitals in China between January 2009 and September 2020. Two-dimensional images of the midsagittal plane of the fetal face in singleton pregnancies with gestational age more than 11 weeks and less than 14 weeks were examined. Observers were blinded to subjective fetus nuchal translucency (NT) marker measurements. A convolutional neural network was developed to construct a deep learning model. Data augmentation was applied to generate more data. Different groups were randomly selected as training and validation sets to assess the robustness of the deep learning model. The fetal NT was shown and measured. Each detection of trisomy 21 was confirmed by chorionic villus sampling or amniocentesis. Data were analyzed from March 1, 2021, to January 3, 2022. Main Outcomes and Measures: The primary outcome was detection of fetuses with trisomy 21. The receiver operating characteristic curve, metrics of accuracy, area under the curve (AUC), sensitivity, and specificity were used for model performance evaluation. Results: A total of 822 case and control participants (mean [SD] age, 31.9 [4.6] years) were enrolled in the study, including 550 participants (mean [SD] age, 31.7 [4.7] years) in the training set and 272 participants (mean [SD] age, 32.3 [4.7] years) in the validation set. The deep learning model showed good performance for trisomy 21 screening in the training (AUC, 0.98; 95% CI, 0.97-0.99) and validation (AUC, 0.95; 95% CI, 0.93-0.98) sets. The deep learning model had better detective performance for fetuses with trisomy 21 than the model with NT marker and maternal age (training: AUC, 0.82; 95% CI, 0.77-0.86; validation: AUC, 0.73; 95% CI, 0.66-0.80). Conclusions and Relevance: These findings suggest that this deep learning model accurately screened fetuses with trisomy 21, which indicates that the model is a potential tool to facilitate universal primary screening for trisomy 21.

Impact of fetal trisomy 21 on umbilical artery Doppler indices.

OBJECTIVES: Umbilical artery (UA) Doppler indices are surrogate measures of placental function, most commonly used to assess fetal wellbeing in pregnancies with fetal growth restriction. Fetuses with trisomy 21 (t21) are reported to have elevated UA Doppler indices, but reference percentiles are currently lacking for this population. We hypothesized that gestational age-specific values of UA Doppler indices in pregnancies complicated by t21 will be elevated compared to established percentiles based on euploid pregnancies. We aimed to assess UA Doppler indices longitudinally in fetuses with t21 in order to demonstrate Doppler patterns across gestation in this population, compare them with euploid fetuses, and investigate their association with pregnancy outcomes. METHODS: We conducted a retrospective cohort study of singleton pregnancies with confirmed fetal t21 who underwent UA Doppler surveillance antenatally from January 2012 to August 2019. UA Doppler indices, including systolic/diastolic (S/D) ratio, pulsatility index (PI), and resistance index (RI) were extracted from ultrasound reports or directly from ultrasound images. UA S/D, PI, and RI percentiles by gestational week were created from available observations from our cohort via a data-driven approach using a generalized additive model. A secondary analysis was run to statistically compare t21 values to established percentiles based on observations from a historical population of euploid fetuses. RESULTS: UA Doppler measurements from 86 t21 fetuses and 130 euploid fetuses were included in our analysis. Median (IQR) maternal age in t21 pregnancies and euploid pregnancies were 35 years (29-38) and 30 years (27-33), respectively. As in euploid fetuses, we found a negative association between Doppler indices and gestational age in the t21 fetuses. Maternal tobacco use, obesity, or chronic hypertension had no significant effect on UA Doppler indices. As hypothesized, values for UA S/D ratio, PI, and RI at the 2.5th, 5th, 10th, 25th, 50th, 75th, 90th, 95th, and 97.5th percentiles by gestational week were significantly higher in t21 fetuses compared to euploid fetuses (p<.001). Overall, 55.8% (48/86) of the t21 fetuses demonstrated at least one Doppler value above the 95th percentile for gestational age based on euploid reference standard. At birth, eight (9.3%) of the t21 fetuses were small for gestational age. When these pregnancies were removed from analysis, UA Doppler indices remained significantly higher than established percentiles at each week of gestation (p < .001). Only three pregnancies ended in fetal demise in the t21 population, two of which had persistently elevated Dopplers above the 95th percentile per established reference percentiles. CONCLUSIONS: At each week of gestation, UA Doppler indices in t21 fetuses were significantly higher than established percentiles from a euploid population. Reference intervals based on euploid fetuses may therefore not be appropriate for antenatal surveillance of fetuses with t21. Prospective studies are needed to investigate the role and impact of serial UA Doppler velocimetry in the surveillance of pregnancies complicated by fetal t21.

Neurofibrillary tau depositions emerge with subthreshold cerebral beta-amyloidosis in down syndrome.

INTRODUCTION: Adults with Down syndrome are genetically predisposed to develop Alzheimer's disease and accumulate beta-amyloid plaques (Aß) early in life. While Aß has been heavily studied in Down syndrome, its relationship with neurofibrillary tau is less understood. The aim of this study was to evaluate neurofibrillary tau deposition in individuals with Down syndrome with varying levels of Aß burden. METHODS: A total of 161 adults with Down syndrome (mean age = 39.2 (8.50) years) and 40 healthy, non-Down syndrome sibling controls (43.2 (12.6) years) underwent T1w-MRI, [C-11]PiB and [F-18]AV-1451 PET scans. PET images were converted to units of standardized uptake value ratios (SUVrs). Aß burden was calculated using the amyloid load metric (AßL); a measure of global Aß burden that improves quantification from SUVrs by suppressing the nonspecific binding signal component and computing the specific Aß signal from all Aß-carrying voxels from the image. Regional tau was assessed using control-standardized AV-1451 SUVr. Control-standardized SUVrs were compared across Down syndrome groups of Aß-negative (A-) (AßL < 13.3), subthreshold A+ (13.3 ≤ AßL < 20) and conventionally A+ (AßL ≥ 20) individuals. The subthreshold A + group was identified as having significantly higher Aß burden compared to the A- group, but not high enough to satisfy a conventional A + classification. RESULTS: A large-sized association that survived adjustment for chronological age, mental age (assessed using the Peabody Picture Vocabulary Test), and imaging site was observed between AßL and AV-1451 within each Braak region (p < .05). The A + group showed significantly higher AV-1451 retention across all Braak regions compared to the A- and subthreshold A + groups (p < .05). The subthreshold A + group showed significantly higher AV-1451 retention in Braak regions I-III compared to an age-matched sample from the A- group (p < .05). DISCUSSION: These results show that even the earliest detectable Aß accumulation in Down syndrome is accompanied by elevated tau in the early Braak stage regions. This early detection of tau can help characterize the tau accumulation phase during preclinical Alzheimer's disease progression in Down syndrome and suggests that there may be a relatively narrow window after Aß accumulation begins to prevent the downstream cascade of events that leads to Alzheimer's disease.

Doppler de arteria umbilical en fetos con síndrome de Down / Umbilical artery Doppler in fetuses with Down syndrome

INTRODUCCIÓN: La aneuploidía más común entre los recién nacidos vivos es el síndrome de Down (SD). En estos niños el crecimiento está disminuido, con una frecuencia del 25% de restricción del crecimiento intrauterino, pero no se ha establecido el papel de la insuficiencia placentaria. El objetivo es estudiar la resistencia placentaria a través del Doppler de arteria umbilical con índice de pulsatilidad (IP) y el tiempo medio de desaceleración (t/2), y el posible efecto de la insuficiencia placentaria en fetos con SD. MÉTODO: Se realizó Doppler en la arteria umbilical en 78 fetos con SD, se midieron el IP y el t/2, y se compararon los resultados con los pesos de nacimiento. RESULTADOS: Se estudiaron 78 fetos con SD con 214 mediciones Doppler. El t/2 y el IP estaban alterados en el 71,5% y el 65% de las mediciones, respectivamente. La incidencia de t/2 alterado aumenta con la edad gestacional desde un 28,6% a las 15-20 semanas hasta un 89,3% sobre las 36 semanas (p < 0,01); cifras similares se observan para el IP. La clasificación de los pesos fue: 64% adecuados, 12% grandes y 24% pequeños para la edad gestacional. La última medición de t/2 antes del parto era normal en el 17% y estaba alterada en el 83%. En el caso del IP, los valores fueron normales en el 27% y anormales en el 73%. El peso de nacimiento, la edad gestacional y el porcentaje de niños adecuados para la edad gestacional eran significativamente mayores en el grupo con Doppler normal que en el grupo con Doppler alterado. El z-score del t/2 estaba marcadamente alterado (−2.23), pero el del peso de nacimiento solo estaba algo disminuido (−0,39). La mortalidad perinatal fue del 10%, significativamente mayor cuando el flujo diastólico era ausente o reverso. CONCLUSIONES: El estudio demuestra que los fetos con SD tienen una alta incidencia de alteración del Doppler umbilical para el IP y el t/2, lo cual sugiere una insuficiencia placentaria grave. Este deterioro parece iniciarse hacia el final del segundo trimestre y aumenta con la edad gestacional. Sin embargo, en estos fetos, la insuficiencia placentaria produce una ligera caída en el crecimiento fetal. Como hipótesis general pensamos que en los fetos con SD hay datos claros de insuficiencia placentaria, pero habría algún factor que les protegería de una restricción grave del crecimiento.

INTRODUCTION: The most common aneuploidy in live newborns is Down syndrome (DS), in these children growth is decreased, with a frequency of 25-36% of fetal growth restriction (FGR); however, it is not established the role of placental insufficiency. The objective is to study the Doppler of the umbilical artery with pulsatility index (PI) and half peak systolic velocity (hPSV) deceleration time and the possible role of placental insufficiency in fetuses with DS. METHOD: Doppler was performed in fetuses with DS, the umbilical artery and IP and hPSV were measured, and the results were compared with birth weights. RESULTS: 78 fetuses with DS were studied with 214 Doppler measurements. hPSV and the IP were altered in 71.5% and 65% of the measurements; the incidence of abnormal hPSV increases with gestational age from 28.6% between 15 to 20 weeks, to 89.3% over 36 weeks (p < 0.01), similar figures are observed with respect to the PI. The weight classification was: 24% of FGR, 12% of great for age and 64% of adequate for gestational age (AGA). The last measurement of hPSV before delivery was normal in 17% of the fetuses and was abnormal in 83%, in the case of PI the normal and abnormal values were 27 and 73%, respectively. Birth weight, gestational age, and the percentage of AGA children were significantly higher in the normal Doppler group than in the abnormal Doppler group. The hPSV z-score was markedly altered (−2.23), but the birth weight z-score is slightly decreased (−0.39). Perinatal mortality is 10% and is significantly higher when diastolic flow is absent or reverse. CONCLUSIONS: The study shows that DS fetuses have a high incidence of abnormal umbilical Doppler measured with IP and hPSV, which suggests severe placental insufficiency, this deterioration seems to start towards the end of the second trimester and increases with gestational age. However, in these fetuses, placental insufficiency causes a discrete drop in fetal growth. As a general hypothesis, we think that there is clear evidence of placental insufficiency in fetuses with DS, but there would be some factor that would protect these fetuses from severe growth restriction.

A Bayesian risk analysis for Trisomy 21 in isolated choroid plexus cyst: combining a prenatal database with a meta-analysis.

OBJECTIVE: The purpose of this study was to quantify the possible additional risk of a fetus with an isolated choroid plexus cyst (ICPC) for Trisomy 21 by combining a large controlled cohort study with data from existent studies. METHODS: We searched our prenatal database between 2000 and 2014 for all singleton pregnancies between 18 + 0 and 26 + 6 gestational weeks with either an isolated choroid plexus cyst (study group) or no abnormality found in the detailed ultrasound scan (control group). We assessed all prenatal karyotyping results if invasive testing was performed and attempted to collect the postnatal outcome reports of all patients. The prevalence of Down syndrome was calculated. By using previous studies that met our inclusion criteria, a meta-analysis following the Bayesian Independent Model was created. From this meta-analysis, we computed the posterior predictive distribution of the probability (Trisomy 21 | ICPC) = P1 including posterior means, standard deviations, quantiles (2.5, 50, and 97.5%). By calculating the posterior of the difference (Δ) between the probability (Trisomy 21 | ICPC) and the probability (Trisomy 21 | Normal Ultrasound) = P2, we investigated the additional risk of an ICPC (ΔB = P1-P2). RESULTS: Overall, we detected 1220 fetuses with an isolated plexus cyst at 19-27 weeks of gestational age (GA). In our study group, the prevalence of Trisomy 21 was 2/1220 (0.16, 95% CI: 0.1-0.6%). The median of the pooled probability of Trisomy 21 given isolated PC across the studies included in the meta-analysis was 0.2% (CI: 0.1-0.4%). In the given periods (GA and time), 66,606 (74.8%) out of 89,056 investigated fetuses met the inclusion criteria and had a normal ultrasound result without any abnormality. The Δ between our study group and the control group was 0.08% (CIΔA: 0-0.5%). Including the meta-analysis, the median of the posterior distribution of Δ between P1 and P2 was 0.08% (CIΔB: 0-0.4%) (ΔB = P1-P2). CONCLUSION: The posterior distribution of Δ between P1 and P2 including the meta-analysis corresponds to showing no difference between the cases and controls (95% CIΔB: 0-0.4%). The additional risk of a fetus with an ICPC for Trisomy 21 is 97.5% likely to be lower than 0.4% (about 1/250). However, in our collective, the positive predictive value of ICPC for Down syndrome was 0.16% (about 1/625). In prenatal counseling, the additional risk should be added to the individual risk (based on maternal age, earlier screening test results, and sonographic markers) and the diagnostic options including fetal DNA and diagnostic procedures should be discussed according to the posterior individual risk.

Clinical article: screening for trisomy 13 using traditional combined screening versus an ultrasound-based protocol.

AIMS: To compare the screening capability of ultrasonography in detecting trisomy 13 (T13) using a multiparameter sonographic protocol (NT+) with a classical combined screening test (CST) protocol. METHODS: The project was a prospective, multicenter study based on a nonselected mixed-risk population of women referred for a first-trimester screening examination. Each subject was offered a choice between either the gold standard, traditional combined screening test (CSG arm) or the ultrasound-based screening protocol (USG arm). General and MA-based screening performances were checked. RESULTS: The study population comprised 20,887 pregnancies: 12,933 in the CSG arm, including 27 cases of T13, and 7954 in the USG arm, including 30 cases of T13. The DR for T13 was higher in the CSG arm than in the USG arm for all tested cutoff points: 1/50 (88.5 versus 63.3%, respectively), 1/100 (88.5 versus 70%, respectively) and 1/300 (92.3 versus 83.3%, respectively). Using the ROC curves for fixed FPRs of 3 and 5%, the T13 detection rate in our study reached 90 and 93%, respectively, in the USG arm and 92 and 96%, respectively, in the CSG arm. MA influenced the T13 screening performance in the USG arm and reduced the DR in patients <31 years. Such influence was not detected in the CSG arm. CONCLUSIONS: Classic CST was more effective in detecting T13 than the ultrasound-only approach. However, the recommended cutoff of 1/50 showed unsatisfactory results for both traditional CST and the multiparameter sonographic test we proposed.

Prevalence of elevated pulmonary artery systolic pressure in Down Syndrome young patients with and without congenital heart disease.

This study examined the prevalence and distribution of elevated systolic pulmonary arterial pressure, measured by echocardiography, in young patients with down syndrome associated or not with congenital heart disease and surgical correction during childhood. Pulmonary artery systolic pressure, computed by regurgitant tricuspid flow velocity evaluation, is the most frequently used parameter for the screening of pulmonary hypertension. Down syndrome and congenital heart disease often coexist and the probability to detect elevated systolic pulmonary arterial pressure in this setting is high. However, little is known about the evaluation of pulmonary arterial pressure during growth of patients with down syndrome with or without congenital heart disease. We enrolled 47 young patients (55% of male sex; mean age: 18.4 ± 6.0 years), 40 with congenital heart disease and 7 without a cardiac defect. Systolic pulmonary arterial pressure was assessed by echocardiography. No difference was found in the population dichotomized by presence or absence of CHD. Only male sex (p=0.000), highly sensitive troponin-T (P=0.027), tricuspid annular plane systolic excursion (TAPSE, p=0.045) and sPAP (p=0.004) were elevated in surgical group. The ASD was found as, the most common structural abnormality in our patients (50%), followed by VSD (27.5%) and complex CHD (such as complete atrioventricular canal defect, CAVC = 25% and Fallot disease = 15%). Furthermore, about 45% of patients had the combined defect. Only 37.5% of patients underwent to corrective surgery during the first months of life. We observed a significantly increase of sPAP values in patients with complex CHD, such as CAVC (p=0.019) and Fallot disease (p=0.001) but, in the following multivariate analysis performed in the patients with CHD, only Fallot disease remains as independent predictors of elevated values of sPAP (p=0.022). An elevated systolic pulmonary arterial pressure may represent the key screening tool in the diagnostic assessment of suspect pulmonary arterial hypertension in high risk population with down syndrome regardless the presence of congenital heart disease.

Genetic diagnoses and associated anomalies in fetuses prenatally diagnosed with esophageal atresia.

Esophageal atresia (EA) is a congenital anomaly occurring in 2.3 per 10,000 live births. Due to advances in prenatal imaging, EA is more readily diagnosed, but data on the associated genetic diagnoses, other anomalies, and postnatal outcome for fetuses diagnosed prenatally with EA are scarce. We collected data from two academic medical centers (n = 61). Our data included fetuses with suspected EA on prenatal imaging that was confirmed postnatally and had at least one genetic test. In our cohort of 61 cases, 29 (49%) were born prematurely and 19% of those born alive died in the first 9 years of life. The most commonly associated birth defects were cardiac anomalies (67%) and spine anomalies (50%). A diagnosis was made in 61% of the cases; the most common diagnoses were vertebral defects, anal atresia, cardiac anomalies, tracheoesophageal fistula with esophageal atresia, radial or renal dysplasia, and limb anomalies association (43%, although 12% met only 2 of the criteria), trisomy 21 (5%), and CHARGE syndrome (5%). Our findings suggest that most fetuses with prenatally diagnosed EA have one or more additional major anomaly that warrants a more comprehensive clinical genetics evaluation. Fetuses diagnosed prenatally appear to represent a cohort with a worse outcome.

Is there still a role for nuchal translucency measurement in the changing paradigm of first trimester screening?

OBJECTIVES: To give an overview of the genetic and structural abnormalities occurring in fetuses with nuchal translucency (NT) measurement exceeding the 95th percentile at first-trimester screening and to investigate which of these abnormalities would be missed if cell-free fetal DNA (cfDNA) were used as a first-tier screening test for chromosomal abnormalities. METHODS: This is a national study including 1901 pregnancies with NT≥95th percentile referred to seven university hospitals in the Netherlands between 1 January 2010 and 1 January 2016. All cases with unknown pregnancy outcome were excluded. Results of detailed ultrasound examinations, karyotyping, genotyping, pregnancy and neonatal outcomes, investigation by a clinical geneticist and post-mortem investigations were collected. RESULTS: In total, 821 (43%) pregnancies had at least one abnormality. The rate of abnormalities was 21% for fetuses with NT between 95th and 99th percentile and 62% for fetuses with NT≥99th percentile. Prevalence of single-gene disorders, submicroscopic, chromosomal and structural abnormalities was 2%, 2%, 30% and 9%, respectively. CONCLUSION: Although cfDNA is superior to the combined test, especially for the detection of trisomy 21, 34% of the congenital abnormalities occurring in fetuses with increased NT may remain undetected in the first trimester of pregnancy, unless cfDNA is used in combination with fetal sonographic assessment, including NT measurement.

Is Cisterna Magna Width a Useful First-Trimester Marker of Aneuploidy?

OBJECTIVE: To assess whether the cisterna magna (CM) width measured in first-trimester fetuses is a useful marker for aneuploidy detection. METHODS: This was a prospective study in 2 different cohorts in a tertiary referral center. The first cohort comprised 913 fetuses from the general pregnancy population during the period 2012-2016 and was used to construct the CM reference ranges applying the λ-µ-σ (LMS) method. The second cohort included 714 high-risk fetuses undergoing chorionic villus sampling during the period 2012-2016. Mean detection rates using the 95th percentile for CM width observed in chromosomal anomaly groups were compared with those obtained in chromosomally normal fetuses. RESULTS: The 50th percentile for CM ranged from 1.66 to 2.75 mm when crown-rump length (CRL) increased from 45 to 84 mm. Among high-risk fetuses, the following chromosomal anomalies were diagnosed in 125 (17%) fetuses: trisomy 21 (n = 63), trisomy 18 or 13 (n = 21), monosomy X (n = 9), submicroscopic anomalies (n = 11), and other anomalies (n = 22). The mean CM width for euploid fetuses was 2.4 mm (1.13 multiples of the median, MoM). While CM width was significantly increased in trisomy 21 (mean 2.7 mm; 1.23 MoM; p > 0.05), no differences were found in the other anomaly groups. Among the 63 fetuses with trisomy 21, a CM width above the 99th percentile was observed in 23 fetuses (37%). CONCLUSIONS: The new reference range for CM width at 11-13 weeks of gestation did not differ from previous studies. In first-trimester fetuses with trisomy 21, CM width appears to be increased, although its value as an ultrasound marker is limited, because of its detection rate of 37%.

Early striatal amyloid deposition distinguishes Down syndrome and autosomal dominant Alzheimer's disease from late-onset amyloid deposition.

INTRODUCTION: The objective of this study was to evaluate amyloid ß (Aß) deposition patterns in different groups of cerebral ß amyloidosis: (1) nondemented with amyloid precursor protein overproduction (Down syndrome); (2) nondemented with abnormal processing of amyloid precursor protein (preclinical autosomal dominant Alzheimer disease); (3) presumed alteration in Aß clearance with clinical symptoms (late-onset AD); and (4) presumed alterations in Aß clearance (preclinical AD). METHODS: We performed whole-brain voxelwise comparison of cerebral Aß between 23 Down syndrome, 10 preclinical autosomal dominant Alzheimer disease, 17 late-onset AD, and 16 preclinical AD subjects, using Pittsburgh Compound B-positron emission tomography. RESULTS: We found both Down syndrome and preclinical autosomal dominant Alzheimer disease shared a distinct pattern of increased bilateral striatal and thalamic Aß deposition compared to late-onset AD and preclinical AD. CONCLUSION: Disorders associated with early-life alterations in amyloid precursor protein production or processing are associated with a distinct pattern of early striatal fibrillary Aß deposition before significant cognitive impairment. A better understanding of this unique pattern could identify important mechanisms of Aß deposition and possibly important targets for early intervention.

Cerebral vasoreactivity and intima-media thickness in Down syndrome: A case-control study.

Subjects with Down Syndrome (DS) have high prevalence of cerebral vascular amyloidosis, cognitive decline and dementia. In Alzheimer Disease, impaired vasoreactivity has been reported as the results of vascular amyloid deposition. Aim of our study was to verify presence of impaired cerebral vasoreactivity and to study carotid intima media-thickness (IMT) by carotid and transcranial ultrasound. We studied 25 DS and compared them with 25 age- and sex-matched normal controls. Vasomotor reactivity was evaluated by means of breath-holding index (BHI) test. There was no difference in IMT, both considering the two side separately (left: 0.70±0.10 vs 0.69±0.12mm, p=0.6) (right: 0.67±0.13 vs 0.68±0.10mm, p=0.5), and considering the sum of both sides (1.38±0.22 vs 1.38±0.23mm, p=1). There was a significant difference in peak systolic velocities (PSV) (139.75±27.67 vs. 123.89±25.73cm/s, p=0.04) and in pulsatility index (PI) (0.95±0.14 vs. 0.86±0.12, p=0.02). BHI was significantly lower in DS than in controls (1.15±0.38 vs 1.88±0.72, p<0.001). In conclusion, subjects with DS have increased PSV and PI, and show a reduction of BHI, expression of impaired vasomotor reserve, possibly due to micro-vascular impairment. Larger study with longitudinal design is needed to verify our data.

First-trimester ultrasound screening for trisomy 21 based on maternal age, fetal nuchal translucency, and different methods of ductus venosus assessment.

OBJECTIVE: To examine whether combining the dichotomous assessment of the a-wave and the ductus venosus (DV) pulsatility index for veins (PIV) measurement improves first-trimester screening performance. METHODS: Retrospective study performed at the University Hospital of Tuebingen based on singleton pregnancies that underwent first-trimester screening including DV flow assessment. In each case, the risk of trisomy 21 was calculated based on maternal age, fetal nuchal translucency, and DV flow either as dichotomous classification of the a-wave, as measurement of the DV PIV, or both. RESULTS: There were 5280 euploid fetuses and 127 fetuses with trisomy 21. The DV a-wave was reversed in 2.3% and 66.1% in the euploid and trisomy 21 cases, respectively. The DV PIV measurements were above the 95th percentile in 8.3% and 77.2% the euploid and trisomy 21 cases, respectively. For a false positive rate of 3%, the detection rate for trisomy 21 based on maternal age, fetal NT, and DV flow is about 87% irrespective of whether DV is examined as a continuous or dichotomous variable. The combination of both resulted in a small decrease at 3% false positive rate. CONCLUSION: Assessment of the DV a-wave and the DV PIV result in similar DRs. Combining these two approaches does not appear to improve their individual screening performance. © 2017 John Wiley & Sons, Ltd.

First trimester ultrasound tests alone or in combination with first trimester serum tests for Down's syndrome screening.

BACKGROUND: Down's syndrome occurs when a person has three, rather than two copies of chromosome 21; or the specific area of chromosome 21 implicated in causing Down's syndrome. It is the commonest congenital cause of mental disability and also leads to numerous metabolic and structural problems. It can be life-threatening, or lead to considerable ill health, although some individuals have only mild problems and can lead relatively normal lives. Having a baby with Down's syndrome is likely to have a significant impact on family life.Non-invasive screening based on biochemical analysis of maternal serum or urine, or fetal ultrasound measurements, allows estimates of the risk of a pregnancy being affected and provides information to guide decisions about definitive testing.Before agreeing to screening tests, parents need to be fully informed about the risks, benefits and possible consequences of such a test. This includes subsequent choices for further tests they may face, and the implications of both false positive and false negative screening tests (i.e. invasive diagnostic testing, and the possibility that a miscarried fetus may be chromosomally normal). The decisions that may be faced by expectant parents inevitably engender a high level of anxiety at all stages of the screening process, and the outcomes of screening can be associated with considerable physical and psychological morbidity. No screening test can predict the severity of problems a person with Down's syndrome will have. OBJECTIVES: To estimate and compare the accuracy of first trimester ultrasound markers alone, and in combination with first trimester serum tests for the detection of Down's syndrome. SEARCH METHODS: We carried out extensive literature searches including MEDLINE (1980 to 25 August 2011), Embase (1980 to 25 August 2011), BIOSIS via EDINA (1985 to 25 August 2011), CINAHL via OVID (1982 to 25 August 2011), and The Database of Abstracts of Reviews of Effects (the Cochrane Library 2011, Issue 7). We checked reference lists and published review articles for additional potentially relevant studies. SELECTION CRITERIA: Studies evaluating tests of first trimester ultrasound screening, alone or in combination with first trimester serum tests (up to 14 weeks' gestation) for Down's syndrome, compared with a reference standard, either chromosomal verification or macroscopic postnatal inspection. DATA COLLECTION AND ANALYSIS: Data were extracted as test positive/test negative results for Down's and non-Down's pregnancies allowing estimation of detection rates (sensitivity) and false positive rates (1-specificity). We performed quality assessment according to QUADAS criteria. We used hierarchical summary ROC meta-analytical methods to analyse test performance and compare test accuracy. Analysis of studies allowing direct comparison between tests was undertaken. We investigated the impact of maternal age on test performance in subgroup analyses. MAIN RESULTS: We included 126 studies (152 publications) involving 1,604,040 fetuses (including 8454 Down's syndrome cases). Studies were generally good quality, although differential verification was common with invasive testing of only high-risk pregnancies. Sixty test combinations were evaluated formed from combinations of 11 different ultrasound markers (nuchal translucency (NT), nasal bone, ductus venosus Doppler, maxillary bone length, fetal heart rate, aberrant right subclavian artery, frontomaxillary facial angle, presence of mitral gap, tricuspid regurgitation, tricuspid blood flow and iliac angle 90 degrees); 12 serum tests (inhibin A, alpha-fetoprotein (AFP), free beta human chorionic gonadotrophin (ßhCG), total hCG, pregnancy-associated plasma protein A (PAPP-A), unconjugated oestriol (uE3), disintegrin and metalloprotease 12 (ADAM 12), placental growth factor (PlGF), placental growth hormone (PGH), invasive trophoblast antigen (ITA) (synonymous with hyperglycosylated hCG), growth hormone binding protein (GHBP) and placental protein 13 (PP13)); and maternal age. The most frequently evaluated serum markers in combination with ultrasound markers were PAPP-A and free ßhCG.Comparisons of the 10 most frequently evaluated test strategies showed that a combined NT, PAPP-A, free ßhCG and maternal age test strategy significantly outperformed ultrasound markers alone (with or without maternal age) except nasal bone, detecting about nine out of every 10 Down's syndrome pregnancies at a 5% false positive rate (FPR). In both direct and indirect comparisons, the combined NT, PAPP-A, free ßhCG and maternal age test strategy showed superior diagnostic accuracy to an NT and maternal age test strategy (P < 0.0001). Based on the indirect comparison of all available studies for the two tests, the sensitivity (95% confidence interval) estimated at a 5% FPR for the combined NT, PAPP-A, free ßhCG and maternal age test strategy (69 studies; 1,173,853 fetuses including 6010 with Down's syndrome) was 87% (86 to 89) and for the NT and maternal age test strategy (50 studies; 530,874 fetuses including 2701 Down's syndrome pregnancies) was 71% (66 to 75). Combinations of NT with other ultrasound markers, PAPP-A and free ßhCG were evaluated in one or two studies and showed sensitivities of more than 90% and specificities of more than 95%.High-risk populations (defined before screening was done, mainly due to advanced maternal age of 35 years or more, or previous pregnancies affected with Down's syndrome) showed lower detection rates compared to routine screening populations at a 5% FPR. Women who miscarried in the over 35 group were more likely to have been offered an invasive test to verify a negative screening results, whereas those under 35 were usually not offered invasive testing for a negative screening result. Pregnancy loss in women under 35 therefore leads to under-ascertainment of screening results, potentially missing a proportion of affected pregnancies and affecting test sensitivity. Conversely, for the NT, PAPP-A, free ßhCG and maternal age test strategy, detection rates and false positive rates increased with maternal age in the five studies that provided data separately for the subset of women aged 35 years or more. AUTHORS' CONCLUSIONS: Test strategies that combine ultrasound markers with serum markers, especially PAPP-A and free ßhCG, and maternal age were significantly better than those involving only ultrasound markers (with or without maternal age) except nasal bone. They detect about nine out of 10 Down's affected pregnancies for a fixed 5% FPR. Although the absence of nasal bone appeared to have a high diagnostic accuracy, only five out of 10 affected Down's pregnancies were detected at a 1% FPR.

The Down syndrome brain in the presence and absence of fibrillar ß-amyloidosis.

People with Down syndrome (DS) have a neurodevelopmentally distinct brain and invariably developed amyloid neuropathology by age 50. This cross-sectional study aimed to provide a detailed account of DS brain morphology and the changes occuring with amyloid neuropathology. Forty-six adults with DS underwent structural and amyloid imaging-the latter using Pittsburgh compound B (PIB) to stratify the cohort into PIB-positive (n = 19) and PIB-negative (n = 27). Age-matched controls (n = 30) underwent structural imaging. Group differences in deep gray matter volumetry and cortical thickness were studied. PIB-negative people with DS have neurodevelopmentally atypical brain, characterized by disproportionately thicker frontal and occipitoparietal cortex and thinner motor cortex and temporal pole with larger putamina and smaller hippocampi than controls. In the presence of amyloid neuropathology, the DS brains demonstrated a strikingly similar pattern of posterior dominant cortical thinning and subcortical atrophy in the hippocampus, thalamus, and striatum, to that observed in non-DS Alzheimer's disease. Care must be taken to avoid underestimating amyloid-associated morphologic changes in DS due to disproportionate size of some subcortical structures and thickness of the cortex.