Familial Recurrence Patterns in Congenitally Corrected Transposition of the Great Arteries: An International Study.

BACKGROUND: Congenitally corrected transposition of the great arteries (ccTGA) is a rare disease of unknown cause. We aimed to better understand familial recurrence patterns. METHODS: An international, multicentre, retrospective cohort study was conducted in 29 tertiary hospitals in 6 countries between 1990 and 2018, entailing investigation of 1043 unrelated ccTGA probands. RESULTS: Laterality defects and atrioventricular block at diagnosis were observed in 29.9% and 9.3%, respectively. ccTGA was associated with primary ciliary dyskinesia in 11 patients. Parental consanguinity was noted in 3.4% cases. A congenital heart defect was diagnosed in 81 relatives from 69 families, 58% of them being first-degree relatives, including 28 siblings. The most prevalent defects in relatives were dextro-transposition of the great arteries (28.4%), laterality defects (13.6%), and ccTGA (11.1%); 36 new familial clusters were described, including 8 pedigrees with concordant familial aggregation of ccTGA, 19 pedigrees with familial co-segregation of ccTGA and dextro-transposition of the great arteries, and 9 familial co-segregation of ccTGA and laterality defects. In one family co-segregation of ccTGA, dextro-transposition of the great arteries and heterotaxy syndrome in 3 distinct relatives was found. In another family, twins both displayed ccTGA and primary ciliary dyskinesia. CONCLUSIONS: ccTGA is not always a sporadic congenital heart defect. Familial clusters as well as evidence of an association between ccTGA, dextro-transposition of the great arteries, laterality defects and in some cases primary ciliary dyskinesia, strongly suggest a common pathogenetic pathway involving laterality genes in the pathophysiology of ccTGA.

Isoproterenol Challenge Unmasking Dynamic Bulbo-Ventricular Foramen Restriction.

Isoproterenol stress test during cardiac catheterization unmasked dynamic bulbo-ventricular foramen restriction in a 5-year-old boy with bidirectional Glenn anastomosis for tricuspid atresia/transposed great arteries and unexplained syncope.

Cardiovascular events in perimembranous ventricular septal defect with left ventricular volume overload: a French prospective cohort study (FRANCISCO).

The long-term prospective multi-centre nationwide (French) observational study FRANCISCO will provide new information on perimembranous ventricular septal defect with left ventricular overload but no pulmonary hypertension in children older than 1 year. Outcomes will be compared according to treatment strategy (watchful waiting, surgical closure, or percutaneous closure) and anatomic features of the defect. The results are expected to provide additional guidance about the optimal treatment of this specific population, which is unclear at present. BACKGROUND: The management of paediatric isolated perimembranous ventricular septal defect (pmVSD) with left ventricle (LV) volume overload but no pulmonary arterial hypertension (PAH) remains controversial. Three therapeutic approaches are considered: watchful waiting, surgical closure, and percutaneous closure. We aim to investigate the long-term outcomes of these patients according to anatomic pmVSD characteristics and treatment strategy. METHODS: The Filiale de Cardiologie Pediatrique et Congénitale (FCPC) designed the FRANCISCO registry, a long-term prospective nationwide multi-centre observational cohort study sponsored by the French Society of Cardiology, which enrolled, over 2 years (2018­2020), patients older than 1 year who had isolated pmVSD with LV volume overload. Prevalent complications related to pmVSD at baseline were exclusion criteria. Clinical, echocardiographic, and functional data will be collected at inclusion then after 1, 5, and 10 years. A core lab will analyse all baseline echocardiographic data to depict anatomical pmVSD features. The primary outcome is the 5-year incidence of cardiovascular events (infective endocarditis, sub-aortic stenosis, aortic regurgitation, right ventricular outflow tract stenosis, tricuspid regurgitation, PAH, arrhythmia, stroke, haemolysis, heart failure, or death from a cardiovascular event). We plan to enrol 200 patients, given the 10% estimated 5-year incidence of cardiovascular events with a 95% confidence interval of ±5%. Associations linking anatomical pmVSD features and treatment strategy to the incidence of complications will be assessed. CONCLUSIONS: The FRANSCICO study will provide the long-term incidence of complications in patients older than 1 year with pmVSD and LV volume overload. The results are expected to improve guidance for treatment decisions.

Incidence, risk factors, and mortality of neonatal and late-onset dilated cardiomyopathy associated with cardiac neonatal lupus.

BACKGROUND: Dilated cardiomyopathy (DCM), a well-known complication of cardiac neonatal lupus, is associated with high mortality rate. Its risk factors remain unclear. METHODS: We analyzed occurrence of postnatal DCM among children with high-degree congenital heart block (CHB) and mothers with anti-SSA and/or anti-SSB antibodies. RESULTS: Among 187 neonates with CHB, 35 (18.8%, one missing data) had DCM and 22 (11.8%) died during a median follow-up of 7years [range: birth-36years]. On multivariate analysis, factors associated with postnatal DCM were in utero DCM (P=0.0199; HR=3.13 [95% CI: 1.20-8.16]), non-European origin (P=0.0052; HR=4.10 [95% CI: 1.81-9.28]) and pacemaker implantation (P=0.0013; HR=5.48 [95% CI: 1.94-15.47]). Postnatal DCM could be categorized in two subgroups: neonatal DCM (n=13, diagnosed at a median age of 0day [birth-4days]) and late-onset DCM (n=22, diagnosed at a median age of 15.2months [3.6months-22.8years]). Factors associated with neonatal DCM were in utero DCM, hydrops, endocardial fibroelastosis and pericardial effusion, whereas those associated with late-onset DCM were non-European origin, in utero mitral valve insufficiency, and pacemaker implantation. Fluorinated steroids showed no protective effect against late-onset DCM (P=0.27; HR=1.65 [95% CI: 0.63-4.25]). Probability of survival at 10years was 23.1% for newborns diagnosed neonatally with DCM, 53.9% for those who developed late-onset DCM, and 98.6% for those without DCM. CONCLUSION: Neonatal and late-onset DCM appear to be two different entities. None of the known risk factors associated with neonatal DCM predicted late-onset DCM. Long-term follow-up of cardiac function is warranted in all children with CHB.

Neonatal Marfan Syndrome: Report of a Case with an Inherited Splicing Mutation outside the Neonatal Domain.

We report a child and her mother affected by Marfan syndrome. The child presented with a phenotype of neonatal Marfan syndrome, revealed by acute and refractory heart failure, finally leading to death within the first 4 months of life. Her mother had a common clinical presentation. Genetic analysis revealed an inherited FBN1 mutation. This intronic mutation (c.6163+3_6163+6del), undescribed to date, leads to exon 49 skipping, corresponding to in-frame deletion of 42 amino acids (p.Ile2014_Asp2055del). FBN1 next-generation sequencing did not show any argument for mosaicism. Association in the same family of severe neonatal and classical Marfan syndrome illustrates the intrafamilial phenotype variability.

Neurodevelopmental Outcome at 2 Years of Age according to Patent Ductus Arteriosus Management in Very Preterm Infants.

BACKGROUND: Patent ductus arteriosus (PDA) is a condition frequently found in very preterm infants, and its treatment remains a subject of debate. Furthermore, there are only a few studies available that have examined the impact of these treatments on the neurological outcome of the patient. OBJECTIVE: To evaluate the neurodevelopmental outcome of PDA treatment on preterm infants born between 24+0 and 28+6 weeks of gestation. METHODS: We conducted an observational multicentric cohort study (LIFT Cohort). We compared three groups of patients according to their PDA treatment strategy: medical treatment with ibuprofen, surgical ligation, and no treatment. The neurodevelopmental outcome was assessed with a physical examination and cognitive function evaluation at 2 years of age. A propensity score was used to reduce bias in the analysis. RESULTS: Between 2003 and 2011, 857 infants (91.3%) were evaluated at 2 years of corrected age and included in the analysis: 248 received ibuprofen treatment (29%), 104 had PDA surgical ligation (12%), and 505 did not receive any PDA treatment (59%). Surgical ligation of PDA was significantly associated with neurodevelopmental impairment at 2 years of age (adjusted odds ratio = 2.2; 95% confidence interval: 1.4-3.4). CONCLUSION: We found an association between PDA surgical ligation and a nonoptimal neurodevelopmental outcome at 2 years of age for preterm infants born before 29 weeks of gestation. These results suggest that if surgical ligation is unavoidable, particular attention should be given to the patient's neurodevelopmental follow-up.

Search for Rare Copy-Number Variants in Congenital Heart Defects Identifies Novel Candidate Genes and a Potential Role for FOXC1 in Patients With Coarctation of the Aorta.

BACKGROUND: Congenital heart defects are the most frequent malformations among newborns and a frequent cause of morbidity and mortality. Although genetic variation contributes to congenital heart defects, their precise molecular bases remain unknown in the majority of patients. METHODS AND RESULTS: We analyzed, by high-resolution array comparative genomic hybridization, 316 children with sporadic, nonsyndromic congenital heart defects, including 76 coarctation of the aorta, 159 transposition of the great arteries, and 81 tetralogy of Fallot, as well as their unaffected parents. We identified by array comparative genomic hybridization, and validated by quantitative real-time polymerase chain reaction, 71 rare de novo (n=8) or inherited (n=63) copy-number variants (CNVs; 50 duplications and 21 deletions) in patients. We identified 113 candidate genes for congenital heart defects within these CNVs, including BTRC, CHRNB3, CSRP2BP, ERBB2, ERMARD, GLIS3, PLN, PTPRJ, RLN3, and TCTE3. No de novo CNVs were identified in patients with transposition of the great arteries in contrast to coarctation of the aorta and tetralogy of Fallot (P=0.002; Fisher exact test). A search for transcription factor binding sites showed that 93% of the rare CNVs identified in patients with coarctation of the aorta contained at least 1 gene with FOXC1-binding sites. This significant enrichment (P<0.0001; permutation test) was not observed for the CNVs identified in patients with transposition of the great arteries and tetralogy of Fallot. We hypothesize that these CNVs may alter the expression of genes regulated by FOXC1. Foxc1 belongs to the forkhead transcription factors family, which plays a critical role in cardiovascular development in mice. CONCLUSIONS: These data suggest that deregulation of FOXC1 or its downstream genes play a major role in the pathogenesis of coarctation of the aorta in humans.

Late repair of tetralogy of Fallot during childhood in patients from developing countries.

OBJECTIVES: Although the current surgical approach of tetralogy of Fallot (TOF) is primary complete repair in infancy, late diagnosis and lack of surgical facilities in developing countries may delay surgical treatment. Some of these patients exposed to prolonged chronic hypoxaemia are transferred to more privileged countries to undergo surgical repair with the support of non-governmental organizations. The objective of this single-centre retrospective study was to compare the postoperative outcomes of these foreign patients undergoing delayed repair with those of patients born in France undergoing timely repair during the same time period. METHODS: The computer database of our institution was searched for all cases of TOF in foreign patients younger than 15 years, supported by two non-profit organizations, who underwent complete repair between January 2007 and December 2013. The control population consisted of the patients with TOF born in France, who underwent timely complete repair during the same period. RESULTS: The 47 foreign children were older (57.6 ± 38.4 vs 8.3 ± 9.1 months, P < 0.0001), more hypoxaemic (SaO2 79 ± 11 vs 91 ± 8%, P < 0.0001), more growth-retarded (body mass index Z-score -1.35 ± 1.5 vs -0.46 ± 1.3, P = 0.0034), and had higher haematocrit level (52.5 ± 11.7 vs 37.5 ± 6.1%, <0.0001) and worse left ventricular ejection fraction (LVEF 62 ± 8 vs 69 ± 3.8%, P < 0.0001) than the 90 French patients. Postoperative mortality and morbidity (sepsis, arrhythmia, bleeding and need for surgical revision) were similar in the two groups, except for a higher rate of pericardial and/or pleural effusion in foreign children (36 vs 17%, P = 0.02). Length of stay was shorter in foreign than in French patients (11 ± 6 vs 15 ± 15 days, P = 0.0012). CONCLUSIONS: In our experience, despite the presence of several risk factors (growth retardation, chronic hypoxaemia, polycythaemia and left ventricular dysfunction), late repair of TOF was undertaken during childhood in patients from developing countries with no difference in postoperative morbidity and mortality compared with that of timely repair during infancy. These older patients can be discharged sooner. However, patients undergoing late surgery may be at higher risk of complications of right ventricular failure, such as pleural and/or pericardial effusion.

Mechanical circulatory support for infants and small children.

The number of children in need of mechanical circulatory support has increased substantially over the last two decades, due to the technological progress made in surgery and intensive care, leading to improved survival of patients with congenital heart disease. In addition, primary myocardial dysfunction related to myocarditis or dilated cardiomyopathy may cause end-stage cardiac failure in children or infants, although not as frequently as in adults. The need for mechanical circulatory support may be either temporary until spontaneous myocardial recovery, as in postcardiotomy cardiac failure, or prolonged until heart transplantation in the absence of recovery. Two types of mechanical circulatory devices are suitable for the paediatric population: extracorporeal membrane oxygenation for short-term support; and ventricular assist devices for long-term support as a bridge to transplantation. The aim of this review is to describe the specific issues related to paediatric mechanical circulatory support and the different types of devices available, to report on their rapidly growing use worldwide and on the outcomes for each indication and type of device, and to provide a perspective on the future developments and remaining challenges in this field.