Infants with hypoplastic left heart syndrome with severely restrictive or intact atrial septum (R/IAS) have low survival. In-utero creation of an atrial septal communication has been reported, with high complication rates. We performed a retrospective cohort study of fetuses with hypoplastic left heart syndrome, double outlet right ventricle with mitral stenosis/atresia, or mitral valve dysplasia and R/IAS from 2012 to 2024 who underwent evaluation for fetal atrial septal intervention (FASI). Excluding those with comorbidities limiting candidacy, discharge survival and overall survival were compared between (1) those undergoing and not undergoing FASI, and (2) those undergoing technically successful FASI (TS-FASI) and all others. Of 60 fetuses with R/IAS, 18 were considered extremely high risk and excluded from analysis. Among the remaining 42, 25 underwent FASI and 17 did not, with no significant baseline echocardiographic differences. FASI was technically successful in 18 cases, with 13 survivors (6 post-Glenn, 6 post-Fontan, 1 post-Ross). In the 7 unsuccessful FASIs, there were 5 peri-procedural deaths and 1 fetal demise that occurred post-FASI. Technical success rates improved from 58% (first 12) to 85% (last 13). Of 20 FASI patients with fetal magnetic resonance imaging, 15 (75%) had nutmeg lung; of the 9 with nutmeg lung and post-TS-FASI fetal magnetic resonance imaging, 8 improved. Survival to discharge and overall survival were 52% in the FASI group versus 29% in the non-FASI group (P=0.147 and log-rank P=0.376, respectively). When comparing TS-FASI to all others, survival was higher (72% versus 21% for discharge and overall survival, P=0.001 and log-rank P<0.001, respectively). All TS-FASI survivors with catheterization data (11/13) had pulmonary vascular resistance <3 Woods units before Glenn/Fontan. In our cohort, fetuses with R/IAS post-TS-FASI had significantly higher discharge and overall survival rates compared with all other fetuses with R/IAS. Nutmeg lung improved in the majority of TS-FASI cases with post-FASI imaging.

Congenital heart defects (CHDs) represent the leading cause of neonatal mortality among congenital abnormalities. Genetic factors, such as EVC2 gene mutations and other genetic alterations, constitute a major cause of CHD. Thus, determining the genetic etiology of fetal CHDs is crucial for optimizing pregnancy management and informing future reproductive decisions. Here, we describe a male fetus with complex CHD who was diagnosed at 25 weeks of gestation, delivered at full term, and died prematurely within a month due to heart failure. The cardiac abnormalities observed included an atrial septal defect developing from a patent foramen ovale, mitral valve regurgitation, dilated right ventricle and left atrium, aortic stenosis, and aortic arch dysplasia. Novel compound heterozygosity of the EVC2 gene, including a non-sense mutation (p.W828Ter) and two cis missense mutations (p.E87G and p.S217C), was identified by prenatal trio-whole-exome sequencing of amniotic fluid, followed by validation using Sanger sequencing. This novel EVC2 genotype was supposed to potentially affect fetal cardiac development, given the variable clinical heterogeneity of the EVC2 mutation-associated phenotype. This case represents the first identification of the EVC2 p.E87G and p.S217C, and the isolated CHD without visible skeletal dysplasia is an important feature of our case. Our study expands the genotypic and phenotypic spectra of the EVC2 gene. We recommend including the EVC2 gene in preconception carrier screening and prenatal diagnosis for CHDs. The first 2 cases of Costello were described by Costello in 1971, and the condition he described was eponymously named after him. Early literature referred to Costello syndrome as AMICABLE syndrome (amicable personality, mental retardation, impaired swallowing, cardiomyopathy, aortic defects, bulk, large lips and lobules, ectodermal defects) or faciocutaneoskeletal syndrome.  Costello syndrome is an autosomal dominant genetic condition and is one of the rarer RASopathies. RASopathies are a group of conditions that arise from germline mutations in genes that code for any of the components or modulators of the RAS/MAPK pathway. The RAS/MAPK pathway is a signal transduction pathway essential for fundamental cellular functions such as proliferation, differentiation, survival, and metabolism. Costello syndrome is caused by pathogenic variants in the HRAS gene of the RAS/MAPK pathway. Many of the syndromes in this group have many common clinical features, eg, short stature, cardiovascular abnormalities, dysmorphic facial features, and lymphatic involvement. These include syndromes such as Noonan Syndrome, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome-like disorder with loose anagen hair, and together with Costello syndrome, are collectively known as Noonan syndrome-like RASopathies. Costello syndrome has no sex predisposition, so males and females are equally affected. This condition is usually diagnosed in childhood, although Costello syndrome can be suspected prenatally by features including polyhydramnios, increased nuchal thickness, ulnar deviation of the wrists, as well as decreased length of the femur and humeri, which can be detected on sonography. Individuals with Costello syndrome are at risk of developing tumors compared to the general population. Congenital heart defects and hypertrophic cardiomyopathy (HCM) are commonly observed in individuals with Costello syndrome and are significant contributors to morbidity, potentially leading to early mortality. Instances of heart failure and cardiocirculatory collapse have also been documented as causes of death in some infants. Additionally, abnormalities such as pulmonary valve stenosis, valve dysplasia, mitral valve defects, and other valve-related issues have been reported.

Limited data are available on the causes of hydrops fetalis in dogs. Congenital heart defects may be an important contributing factor. Standard autopsy often fails to provide a comprehensive and accurate diagnosis on very small hearts. This study was carried out on five French bulldog puppies all presenting with advanced hydrops fetalis and four diagnosed with pulmonary hypoplasia at autopsy. The body weight of the dogs ranged from 142 to 687 g and the heart with lungs weighed from 4.5 to 23.6 g. The hearts and pulmonary vessels were filled with barium contrast, and micro-CT scans of the physiologically connected heart and lungs were performed. In all five puppies, we confirmed congenital heart defects including: Puppy #1. Perimembranous ventricular septal defect and aortic dextroposition; Puppy #2. Interrupted aortic arch with aortic valve dysplasia and aortic stenosis; Puppy #3. Tricuspid valve dysplasia and bicuspid pulmonary trunk valve; Puppy #4. Aortic stenosis and ventricular septal defect; Puppy #5. Tricuspid valve dysplasia. Additionally, four puppies had pulmonary vascular hypoplasia. Contrast-enhanced micro-CT can provide highly accurate diagnosis of complex congenital heart and lung defects. Examination of the heart in conjunction with the lungs appears to be a rational approach in animals with hydrops fetalis.

Bicuspid aortic valve (BAV) is the most common congenital heart defect, affecting at least 2% of the population. The embryonic origins of BAV remain poorly understood, with few assays for validating patient variants, limiting the identification of causative genes for BAV. In both human and mouse, the left and right leaflets of the arterial valves arise from the outflow tract cushions, with interstitial cells originating from neural crest cells and the overlying endocardium through endothelial-to-mesenchymal transition (EndoMT). In contrast, an EndoMT-independent mechanism of direct differentiation of cardiac progenitors from the second heart field (SHF) is responsible for the formation of the anterior and posterior leaflets. Defects in either of these developmental mechanisms can result in BAV. Although zebrafish have been suggested as a model for human variant testing, their naturally bicuspid arterial valve has not been considered suitable for understanding human arterial valve development. Here, we have set out to investigate to what extent the processes involved in arterial valve development are conserved in zebrafish and, ultimately, whether functional testing of BAV variants could be carried out. Using a combination of live imaging, immunohistochemistry, and Cre-mediated lineage tracing, we show that the zebrafish arterial valve primordia develop directly from SHF progenitors with no contribution from EndoMT or neural crest, in keeping with the human and mouse anterior and posterior leaflets. Moreover, once formed, these primordia share common subsequent developmental events with all three aortic valve leaflets. Our work highlights a conserved ancestral mechanism of arterial valve leaflet formation from the SHF and identifies that development of the arterial valve is distinct from that of the atrioventricular valve in zebrafish. Crucially, this confirms the utility of zebrafish for understanding the development of specific BAV subtypes and arterial valve dysplasia, offering potential for high-throughput variant testing.

Hydrops fetalis (HF) is fluid accumulation in fetus body cavities and subcutaneous tissue. The condition has been described in various farm and companion animal species, including dogs. Most of cases result from a heart defect. Exact nature of this defect is rarely clarified. A newborn, male French bulldog puppy with severe HF underwent a full anatomopathological examination to diagnose the primary cause of HF. Based on the anatomopathological examination, fetal ultrasound, and micro-computed tomography, transposition of the great arteries with hypoplasia of the ascending aorta, aortic arch interruption, ostium secundum atrial septal defect, severe tricuspid valve dysplasia, as well as hypoplasia of pulmonary vessels and lungs were diagnosed. This is the first report of HF caused by severe, complex congenital heart defects with concurrent pulmonary vessel and lung hypoplasia.