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Introduction: Neonates with D-transposition of the great arteries (dTGA) may die at birth because of the inadequate intracardiac mixing due to a misdiagnosed restrictive foramen ovale. We reviewed our experience in echocardiographic assessment and perinatal management of fetuses with dTGA searching for new features that may predict the need for urgent balloon atrial septostomy (BAS) immediately after birth. Patients and Methods: We included fetuses diagnosed with dTGA between January 2000 and December 2014. We assessed pre- A nd postnatal appearance of the foramen ovale, ductus arteriosus and pulmonary veins. Both the diagnostic findings at the time of last prenatal echocardiogram and those findings deriving from a retrospective reevaluation of stored videos were considered. BAS was defined as urgent if performed in neonates with restrictive foramen ovale and severe hypoxemia. Results: We reviewed 40 fetuses with dTGA. 20/40 fetuses received urgent BAS at birth. Not only the restrictive but also the hypermobile and the redundant appearance of the foramen ovale was significantly associated with urgent BAS (p < 0.0001, p = 0.002 and p = 0.0001, respectively). Conclusions: Prenatal evaluation of the foramen ovale appearance in fetuses with dTGA is still challenging. Based on our experience, also the redundant foramen ovale appearance may need urgent BAS at birth.

Two cases of ultrasound diagnosis of Holt-Oram syndrome are described. Both were characterized by significant right atrial enlargement that was not due to concurrent tricuspid regurgitation or other cardiac anomalies. In both cases the associated skeletal anomaly was subtle and barely visible using ultrasound. Interestingly, despite the fact that Holt-Oram syndrome is also called atriodigital dysplasia, unexplained right atrial enlargement has not been described in this context in the fetus before. When such a finding is detected, we believe a thorough search for upper limb abnormalities should be carried out and genetic testing for Holt-Oram syndrome should be discussed with the parents.

Background RASopathies are a set of relatively common autosomal dominant clinically and genetically heterogeneous disorders. Cardiac outcomes in terms of mortality and morbidity for common heart defects (such as pulmonary valve stenosis and hypertrophic cardiomyopathy) have been reported. Nevertheless, also Atypical Cardiac Defects (ACDs) are described. The aim of the present study was to report both prevalence and cardiac outcome of ACDs in patients with RASopathies. Methods A retrospective, multicentric observational study (CArdiac Rasopathy NETwork-CARNET study) was carried out. Clinical, surgical, and genetic data of the patients who were followed until December 2019 were collected. Results Forty-five patients out of 440 followed in CARNET centers had ACDs. Noonan Syndrome (NS), NS Multiple Lentigines (NSML) and CardioFacioCutaneous Syndrome (CFCS) were present in 36, 5 and 4 patients, respectively. Median age at last follow-up was 20.1 years (range 6.9-47 years). Different ACDs were reported, including mitral and aortic valve dysfunction, ascending and descending aortic arch anomalies, coronary arteries dilation, enlargement of left atrial appendage and isolated pulmonary branches diseases. Five patients (11%) underwent cardiac surgery and one of them underwent a second intervention for mitral valve replacement and severe pericardial effusion. No patients died in our cohort until December 2019. Conclusions Patients with RASopathies present a distinct CHD spectrum. Present data suggest that also ACDs must be carefully investigated for their possible impact on the clinical outcome. A careful longitudinal follow up until the individuals reach an adult age is recommended.

Objectives: The aims of this study were to review systematically literature on and describe the sonographic features and associated anomalies of total (TAPVC) and partial (PAPVC) anomalous pulmonary venous connection and scimitar syndrome (SS). Methods: A retrospective cohort study was carried out of cases of TAPVC, PAPVC and SS that underwent comprehensive ultrasound examination, seen over a 20-year period at two tertiary referral centers. Assessed variables included TAPVC subtype, gestational age at diagnosis, area behind the left atrium, ventricular disproportion, vertical vein, pulmonary venous obstruction, mode of diagnosis, association with cardiac and extracardiac conditions, and pregnancy and fetoneonatal outcomes. The outcome was considered favorable if the individual was alive and well (no functional impairment from surgery or cardiac or extracardiac conditions). Cases associated with right isomerism were excluded from the analysis, as TAPVC in these cases was only one of several major cardiac anomalies affecting sonographic signs. A systematic review was performed in order to obtain a synthesis of characteristics associated with TAPVC, PAPVC and SS. The literature search of PubMed and EMBASE (1970–2016) included reviews, case series and case reports. A meta-analysis was conducted only for TAPVC. Random-effects models were used to obtain pooled estimates of the frequencies of clinical characteristics and sonographic features. Results: For TAPVC, a total of 15 studies involving 71 patients (including 13 from the current cohort study) were included in the systematic review and meta-analysis. The pooled estimate for the association of TAPVC with congenital heart disease was 28.3% (95% CI, 18.1–41.3%) and with extracardiac anomalies it was 18.5% (95% CI, 10.5–30.6%). Of TAPVC cases, obstructed venous return was observed in 34.1% (95% CI, 22.7–47.7%), a favorable outcome in 43.8% (95% CI, 24.0–65.8%), ventricular disproportion in 59.2% (95% CI, 45.1–72.0%), increased area behind the left atrium in 58.1% (95% CI, 41.1–73.5%) and a vertical vein in 59.3% (95% CI, 41.1–75.3%). Diagnosis was established by using color or power Doppler in 84.9% (95% CI, 67.3–93.9%) of cases. For SS, there were only three studies describing eight cases, to which the current study added another five. Ventricular disproportion was present in three out of nine SS cases for which data were available, but for two of these, there was a concurrent heart anomaly. Color Doppler was used for all SS diagnoses, and four-dimensional echocardiography was useful in two out of six cases in which it was used. Outcome for SS cases was generally good. For PAPVC, there were only five studies describing five cases, to which the current study added another two. Major cardiac anomalies were associated in four out of seven of these cases, and extracardiac anomalies in three out of six cases for which data were available. Conclusions: TAPVC can be associated with other cardiac and extracardiac anomalies in a significant percentage of cases. Leading sonographic signs are ventricular disproportion, increased area behind the left atrium and the finding of a vertical vein. Color/power Doppler is the key mode for diagnosis of TAPVC. Obstructed venous return can be expected in roughly one-third of cases of TAPVC and outcome is favorable in less than half of cases. Data for SS and PAPVC are too few to synthesize. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Objective: Vein of Galen aneurysmal malformation (VGAM) is a rare fetal anomaly, the neurological outcome of which can be good with appropriate perinatal management. However, most fetal series are too small to allow reliable statistical assessment of potential prognostic indicators. Our aim was to assess, in a two-center series of 49 cases, the prognostic value of several prenatal variables, in order to identify possible prenatal indicators of poor outcome, in terms of mortality and cerebral disability. Methods: This was a retrospective study involving 49 cases of VGAM diagnosed prenatally and managed at two centers over a 17-year period (1999–2015). All cases had undergone detailed prenatal cerebral and cardiac assessment by grayscale ultrasound, color and pulsed-wave Doppler and magnetic resonance imaging (MRI). Ultrasound and MRI examination reports and images were reviewed and outcome information was obtained from medical reports. Volume of the VGAM (on ultrasound and MRI) was calculated and development of straight-sinus dilatation, ventriculomegaly and other major brain abnormalities was noted. Cardiothoracic ratio, tricuspid regurgitation and reversed blood flow across the aortic isthmus were evaluated on fetal echocardiography. Major brain lesions were considered by definition to be associated with poor outcome in all cases. Pregnancy and fetoneonatal outcome were known in all cases. Fetoneonatal outcome and brain damage were considered as dependent variables in the statistical evaluation. Poor outcome was defined as death, late termination of pregnancy due to association with related severe brain anomalies or severe neurological impairment. Results: At a mean follow-up time of 20 (range, 0–72) months, 36.7% of the whole series and 52.9% of the cases which did not undergo late termination were alive and free of adverse sequelae. Five (10.2%) cases showed progression of the lesion between diagnosis and delivery. On univariate analysis, dilatation of the straight sinus, VGAM volume ≥ 20 000 mm3 and tricuspid regurgitation were all significantly related to poor outcome. However, on logistic regression analysis, the only variables associated significantly with poor outcome were tricuspid regurgitation and, to a lesser extent, VGAM volume ≥ 20 000 mm3. The former was also the only variable associated with brain damage. Conclusions: Major brain lesions, tricuspid regurgitation and, to a lesser extent, VGAM volume ≥ 20 000 mm3 are the only prenatal variables associated with poor outcome in fetal VGAM. Prenatal multidisciplinary counseling should be based on these variables. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Background The pathogenesis of transposition of the great arteries (TGA) is still largely unknown. In general, TGA is not associated with the more common genetic disorders nor with extracardiac anomalies, whereas it can be found in individuals with lateralisation defects, heterotaxy and asplenia syndrome (right isomerism). Objective To analyse genes previously associated with heterotaxy in order to assess mutations in familial TGA unassociated with other features of laterality defects. Methods Probands of seven families with isolated TGA and a family history of concordant or discordant congenital heart disease were screened for mutations in the ZIC3 , ACVR2B , LEFTYA , CFC1 , NODAL , FOXH1 , GDF1 , CRELD1 , GATA4 and NKX2.5 genes. Results Mutation analysis allowed the identification of three sequence variations in two out of seven TGA probands. A FOXH1 (Pro21Ser) missense variant was found in a proband who was also heterozogous for an amino acid substitution (Gly17Cys) in the ZIC3 gene. This ZIC3 variant was also found in another family member with a second sequence variation (Val150Ile) in the NKX2.5 gene homeodomain who was affected by multiple ventricular septal defects. A second proband was found to harbour a splice site variant (IVS2-1G→C) in the NODAL gene. Conclusions The present study provides evidence that some cases of familial TGA are caused by mutations in laterality genes and therefore are part of the same disease spectrum of heterotaxy syndrome, and argues for an oligogenic or complex mode of inheritance in these pedigrees.