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Prenatal genetic diagnosis in euploid fetuses with increased Nuchal Translucency (NT) and persistently increased Nuchal Fold (NF) is challenging. The aims of this study is to evaluate the prevalence of pathogenic copy number variants and Noonan Syndrome (NS) in fetuses with increased NT and persistently increased Nuchal Fold (NF) to provide recommendations for pre-natal diagnostic strategies. This is a prospective study from 118 prenatal samples from fetuses with increased NT (≥3.5mm) in first trimester. Multiplex Ligation Dependent Probe Amplification (MLPA), Chromosomal Microarray Analysis (CMA) and karyotyping were conducted. For fetuses with increased NF (≥6mm) in the second trimester with normal karyotype and CMA, targeted Next-Generation Sequencing (NGS) tests for NS were carried out. A total of 118 fetuses had an NT measurement of ≥3.5mm performed MLPA and karyotyping, 89 euploid fetuses were further investigated with CMA, which yielded eight pathogenic CNVs (size ranged from 0.85Mb to 14.5Mb). Twenty fetuses had persistently increased NF at the second trimester. NS testing revealed 3/20 (15%) fetuses had pathogenic variants, and one (5%) with a novel variant of uncertain clinical significance inherited from the father. Our study suggested that NS targeted sequencing facilitates additional genetic diagnosis in fetuses with high NT and persistently increased NF.

Objective To investigate the performance of the machine learning (ML) model in predicting small-for-gestational-age (SGA) at birth, using second-trimester data. Methods Retrospective data of 347 patients, consisting of maternal demographics and ultrasound parameters collected between the 20th and 25th gestational weeks, were studied. ML models were applied to different combinations of the parameters to predict SGA and severe SGA at birth (defined as 10th and third centile birth weight). Results Using second-trimester measurements, ML models achieved an accuracy of 70% and 73% in predicting SGA and severe SGA whereas clinical guidelines had accuracies of 64% and 48%. Uterine PI (Ut PI) was found to be an important predictor, corroborating with existing literature, but surprisingly, so was nuchal fold thickness (NF). Logistic regression showed that Ut PI and NF were significant predictors and statistical comparisons showed that these parameters were significantly different in disease. Further, including NF was found to improve ML model performance, and vice versa. Conclusion ML could potentially improve the prediction of SGA at birth from second-trimester measurements, and demonstrated reduced NF to be an important predictor. Early prediction of SGA allows closer clinical monitoring, which provides an opportunity to discover any underlying diseases associated with SGA.

Patient: Male, 0 Final Diagnosis: Pallister-Killian syndrome Symptoms: Decidious tooth • flattened nasal bridge • frontal bossing • grooved palate • low-set ears • mid-facial hypoplasia • nuchal fold thickening • right inquinal testis • shortened upper extremities • undescended left intraabdominal testis • widely spaced nipples Medication: — Clinical Procedure: — Specialty: Pediatrics and Neonatology Objective: Congenital defects/diseases Background: Pallister-Killian syndrome (PKS) is a rare, sporadic, polydysmorphic condition that often has highly distinctive features. The clinical features are highly variable, ranging from mild to severe intellectual disability and birth defects. We here report the first case of PKS diagnosed at our institution in a patient in the second trimester of pregnancy. Case Report: A pregnant 43-year-old woman presented for genetic counseling secondary to advanced maternal age and an increased risk for Down syndrome. Ultrasound showed increased fetal nuchal fold thickness, short limbs, polyhydramnios, and a small stomach. The ultrasound evaluation was compromised due to the patient’s body habitus. The patient subsequently underwent amniocentesis and the karyotype revealed the presence of an isochromosome in the short arm of chromosome 12 consistent with the diagnosis of Pallister-Killian syndrome. Postnatally, the infant showed frontal bossing, a flattened nasal bridge, mid-facial hypoplasia, low-set ears, a right upper deciduous tooth, grooved palate, nuchal fold thickening, widely spaced nipples, left ulnar polydactyly, simian creases, flexion contractures of the right middle finger, shortened upper extremities, undescended left intraabdominal testis, and right inguinal testis. Conclusions: The occurrence of PKS is sporadic in nature, but prenatal diagnosis is possible.

Objectives The purpose of this study was to establish gestational age (GA)–specific nomograms for nuchal fold thickness between 16 and 24 weeks. Methods This retrospective cross sectional study included 32,207 women who underwent a second-trimester anomaly scan at the Fetal Care Center of National University Hospital from January 2005 to April 2011. Nomograms were plotted for nuchal fold thickness at each gestation to study its variation with GA. Results Nuchal fold thickness increased with GA in a linear manner from 3.13 ± 0.68 mm (mean ± SD) at 16 weeks to 5.08 ± 0.76 mm at 24 weeks. The 95th percentile measurement at 24 weeks remained less than 6 mm. Conclusions A threshold of 6 mm appears to be appropriate for the diagnosis of a thick nuchal fold even for gestations between 20 and 24 weeks.

The thickness of the nuchal fold is one of the main markers for the detection of Down syndrome during the second trimester of pregnancy. In this paper are reported our preliminary results of the automatic segmentation and measurement of the nuchal fold thickness in ultrasound images of the fetal brain. The method is based on a 2D active shape model used to segment the brain structures involved in the measurement of the nuchal fold: cerebellum; brain midline; the outer edge of the occipital plate; and the outer skin edge. The algorithm was trained and tested in 10 different ultrasound images, using leave one out cross validation. We have obtained an average difference of 0.23 mm from the expert measurement of the nuchal fold, with a standard deviation of 0.1 mm.

Purpose. To compare the measurements of fetal nuchal fold (NF) thickness by two-dimensional (2D) and three-dimensional (3D) ultrasonography using the three-dimensional extended imaging (3DXI).Methods. A cross-sectional study was performed with 60 healthy pregnant women with a gestational age between 16 and 20 weeks and 6 days. The 2D-NF measurements were made as the distance from the outer skull bone to the outer skin surface in the transverse axial image in the suboccipital-bregmatic plane of the head. For the 3D we employed the 3DXI multislice view software, in which3×2tomographic planes was displayed on the screen and the distance between the tomographic slices was 0.5 mm. Maximum, minimum, mean, and standard deviation were calculated for 2D and 3D ultrasonography, as well the maximum and minimum, mean, and standard deviation for the difference between both methods. The Wilcoxon signed-rank test was used to compare the two different techniques.Results. 2D-NF showed a mean of thickness of3.52±0.95 mm (1.69–7.14). The mean of 3D-NF was3.90±1.02 mm (2.13–7.72). The mean difference between the methods was 0.38 mm, with a maximum difference of 3.12 mm.Conclusion. The NF thickness measurements obtained by 3D ultrasonography were significantly larger than those detected with 2D ultrasonography.

We propose to assess the contribution of "modified genetic sonography" (MGS) to the combined test (CT) as a method of stepwise sequential screening (1st step: CT, 2nd step: MGS) for chromosome abnormalities in the general population of pregnant women.Prospective study. During a 4 year study period (July 2005-June 2009) 16,548 pregnancies underwent a CT combined with MGS (major malformation and nuchal fold) as a screening method for chromosome abnormalities. We assessed sensitivity and false positive rate (FPR) (95% CI).We offered a chromosome abnormalities screening test to 96.6% of pregnancies (15,995 cases). 14,160 cases are analyzed (1st step: CT, 2nd step: MGS) including 49 chromosome abnormalities and 35 Down's syndrome (DS). The sensitivity of CT for DS was 77.1% [95% CI, 63.2-91] (27/35) and 77.5% for all chromosome abnormalities [95% CI, 65.8-89.2] (38/49) with a FPR of 4.4% [95% CI, 4.1-4.7]. If MGS was combined with CT, the sensitivity for DS was 91.4% [95% CI, 82.1-99] (32/35) and 93.8% for all chromosome abnormalities [95% CI, 87-99] (46/49) for a FPR of 5.1% [95% CI, 4.7-5.5].The addition of an MGS to combined first-trimester screening test for aneuploidy improved sensitivity by 14.3% while only increasing the FPR by 0.7%.

A case involving a 20-week fetus with Down syndrome is described. Sonographic signs of trisomy 21 included a thickened nuchal fold, heart defect, short femur and humerus length, pyelectasis, hypoplasia of the middle phalanx of the fifth digit, and an abnormal facial profile.

Many studies have shown that a thickened nuchal fold in a second-trimester fetus is a sonographic sign suggestive of a high risk for Down syndrome. These series have included fetuses already at risk for aneuploidy because of advanced maternal age or abnormal maternal serum alpha-fetoprotein (AFP) levels. The authors describe the sonographic and karyotypic findings in 42 women younger than age 35 years whose fetuses were noted to have a thickened nuchal fold. Forty fetuses were not at risk for Down syndrome. Fourteen of the 42 fetuses (33%) had abnormal karyotypes; 11 had Down syndrome and one each had XXX, XO, and XYY. If the five cases with low maternal serum AFP levels are excluded, nine of the 37 fetuses (24%) with thickened nuchal folds had abnormal karyotypes. Amniocentesis would have been performed in one of those nine fetuses because of hydrocephalus. Thus, eight of 36 fetuses (22%) with thickened nuchal folds and no other indications for amniocentesis had abnormal karyotypes. When a thickened nuchal fold is present, the yield of abnormal karyotype is high (22%), making it possible to identify patients who would benefit from cytogenetic evaluation but who would not otherwise be candidates.

Objective: Our purpose was to determine whether ultrasonographic measurements of nuchal fold thickness are affected by the position of the fetal neck. Study Design: Fetal nuchal fold thickness was prospectively measured in 258 women undergoing routine ultrasonography at 15 to 21 completed weeks of gestation. Patients with fetal structural or chromosomal anomalies were excluded. At the time of examination the position of the fetal head was noted as being extended or flexed on the basis of the angle between the spine and the base of the skull. Gestational age was based on menstrual dates or ultrasonographic biometric parameters. Data were tested for normality. Mann-Whitney U test and analysis of covariance were used (significance was considered to be P < .05). Data are presented as median and range. Results: A total of 258 fetuses were examined with 167 (65%) in the flexed and 91 (35%) in the extended neck position. Gestational age was not significantly different between the flexed and extended groups (median, 19.1 weeks; range, 15.5-21.6 weeks; vs median, 19.1 weeks; range, 15.6-22 weeks; P = .23). Nuchal fold thickness was significantly lower in the flexed group than in the extended group (median, 3.5 mm; range, 1.3-6.2 mm; vs median, 3.9 mm; range, 2.2-4.9 mm; P = .0097). Nuchal fold thickness increased significantly with gestational age in both groups. The difference in nuchal fold thickness between the 2 groups persisted even after the increase in nuchal fold thickness was adjusted for with gestational age (P = .002, analysis of covariance). The difference between the 2 groups was higher at earlier gestations. Conclusion: Nuchal fold thickness is affected by gestational age and fetal neck position. Correction for these variables may improve the accuracy of nuchal fold thickness measurements in screening for fetal chromosomal anomalies. (Am J Obstet Gynecol 2000;183:995-7.)

We have determined feasibility and levels of agreement for visualizing the nuchal translucency within a time limit with three-dimensional (3D) and two-dimensional (2D) transvaginal ultrasound. A total of 213 women of median gestational age 13 weeks (range 11-14 weeks) undergoing first-trimester nuchal translucency (NT) thickness measurements with 2D transabdominal ultrasound were included in the study. Additionally all women underwent 2D and 3D transvaginal NT examination within a time limit of 90 s. These two methods were compared with each other and with our standard method (2D transabdominal ultrasound) with respect to visualization of fetal nuchal fold and to the levels of agreement. The nuchal fold was visualized by 3D and 2D transvaginal ultrasound in 85.9% (95% CI: 80.5%, 90.3%) and 25.8% (95% CI: 20.1%, 32.2%), respectively (p

OBJECTIVE: Our purpose was to determine the specific likelihood of different aneuploidies by gestational age in patients with nuchal folds and simple and septated nuchal membranes. STUDY DESIGN: Retrospective database analysis was performed of 158 consecutive patients with a nuchal fold or simple or septated nuchal membrane on either abdominal or vaginal ultrasonography. RESULTS: Thirty-eight patients with nuchal folds, 65 with simple nuchal membranes, and 55 with septated nuchal membranes were evaluated. Septated nuchal membranes were associated with the highest incidence of karyotypic abnormalities (>50%). A peak incidence of trisomy 21 (27%) was found in the early midtrimester, leveling off to 11% by the late midtrimester. The late first trimester had a high incidence of trisomy 18 (22%), occurring more frequently than 45,X. CONCLUSION: Ultrasonographic anomalies in the posterior neck are associated with aneuploidy from 21% to 58% of the patients in this selected population. Each anomaly has different risks for aneuploidy type, varying with gestational age at diagnosis. (Am J Obstet Gynecol 1996;175:995-9.)

Objective To establish normal values of fetal nuchal fold thick-ness at 14–16 weeks of gestation by transvaginal sonography. Methods Transvaginal sonography was used to measure nuchal fold thickness in 182 normal pregnancies at 14–16 weeks of gestation. Nuchal fold thickness was measured as the distance from the outer skull bone to the outer skin surface in the transverse axial image in the suboccipital-bregmatic plane of the head. Results There was no significant association between nuchal fold thickness and gestational age (r = 0.084; P = 0.258). The mean (standard deviation) was 2.2 (0.5) mm and the 95th centile was 3.0 mm. Conclusions The 95th centile of nuchal fold thickness measured by transvaginal sonography at 14–16 weeks is 3.0 mm. Copyright © 2002 ISUOG

Objective: To analyze the methods of prenatal sonographic diagnosis of all kinds of aortic arch anomalies and to improve prenatal sonographic detection rate of aortic arch anomalies. Methods: 73 fetuses with congenital aortic arch anomalies were studied. The results from prenatal ultrasound examination, postnatal examination were compared. Results: 73 cases were with congenital aortic arch anomalies, 33 cases with malposition of aortic arch, 9 cases with normal left aortic arch with aberrant left subclavian artery, 5 cases with interruption of aortic arch, 26 cases with coarctation of aortic arch. The accuracy rate of prenatal sonographic diagnosis was 87.7%. Conclusions: Aortic arch anomalies have typical sonographic image. If we grasp typical sonographic images, we could make accurate diagnosis.

Background The aim of this study was to establish normal values of nuchal fold thickness during 14–16 weeks' gestation by transvaginal sonography (TVS). Method Singleton fetuses of 195 women with normal pregnancies were studied by TVS at 14–16 weeks' gestation. Gestational age was determined by last menstural period and confirmed by biometry. Nuchal fold thickness was measured by the modified axial view of the head, cerebellum and the nuchal fold. All women delivered normal infants with no evidence of anomalies. t-testing was performed to determine any correlation between nuchal fold thickness and gestational age. Results Mean value of nuchal fold thickness during 14–16 weeks' gestation was 2.2 ± 0.5 mm (mean ± SD). The mean values for 14, 15 and 16 weeks' gestation were 2.1 ± 0.5 mm, 2.2 ± 0.4 mm and 2.4 ± 0.9 mm, respectively. There was only a marginally significant increase of the nuchal fold thickness between 15 and 16 weeks' gestation (P = 0.054, t-test). Conclusions Normal values of nuchal fold thickness at 14–16 weeks' gestation for normal fetuses were constructed by TVS. The mean value of nuchal fold thickness only slightly increased during 14–16 weeks' gestation. Therefore, the same mean value (2.2 ± 0.5 mm) may be used throughout this period.

To standardize femur measurement for the identification of fetuses at risk for Down syndrome, sonographers of varying professional experience and background measured the femurs of 20 Down syndrome fetuses and 709 normal control fetuses. A regression analysis performed to compare biparietal diameter to femur length on the 709 control fetuses yielded the following formula: expected femur length = -9.3105 + 0.9028.biparietal diameter. A ratio of measured-to-expected femur length of 0.91 or lower indicated Down syndrome with a sensitivity of 40%, a specificity of 95%, and a positive predictive value of 3.1%. Eight of the 20 fetuses with Down syndrome (40%) also had a thickened nuchal fold (6 mm or larger). If the nuchal fold findings had been considered with the femur length findings, two more of the fetuses with Down syndrome would have been identified, yielding a sensitivity of 45% and a positive predictive value of 4.3%. Because these measurements were made by eight sonographers rather than a single experienced sonologist, these results could be achieved in most ultrasound laboratories where measurements are done primarily by sonographers.