Multisystem inflammatory syndrome in children rose and fell with the first wave of the COVID-19 pandemic in France.

AIM: This study determined the influence of the COVID-19 pandemic on the occurrence of multisystem inflammatory syndrome in children (MIS-C) and compared the main characteristics of MIS-C and Kawasaki disease (KD). METHODS: We included patients aged up to 18 years of age who were diagnosed with MIS-C or KD in a paediatric university hospital in Paris from 1 January 2018 to 15 July 2020. Clinical, laboratory and imaging characteristics were compared, and new French COVID-19 cases were correlated with MIS-C cases in our hospital. RESULTS: There were seven children with MIS-C, from 6 months to 12 years of age, who were all positive for the virus that causes COVID-19, and 40 virus-negative children with KD. Their respective characteristics were as follows: under 5 years of age (14.3% vs. 85.0%), paediatric intensive care unit admission (100% vs. 10.0%), abdominal pain (71.4% vs. 12.5%), myocardial dysfunction (85.7% vs. 5.0%), shock syndrome (85.7% vs. 2.5%) and mean and standard deviation C-reactive protein (339 ± 131 vs. 153 ± 87). There was a strong lagged correlation between the rise and fall in MIS-C patients and COVID-19 cases. CONCLUSION: The rise and fall of COVID-19 first wave mirrored the MIS-C cases. There were important differences between MIS-C and KD.

Cardiac MRI in Children with Multisystem Inflammatory Syndrome Associated with COVID-19.

This case series examines cardiac MRI findings in four children and adolescents admitted to intensive care in April 2020 for multisystem inflammatory syndrome and Kawasaki disease-like features related to coronavirus disease 2019 (COVID-19). Acute myocarditis occurred less than 1 week after onset of fever and gastrointestinal symptoms. Physical examination showed rash and cheilitis or conjunctivitis. All patients recovered after intravenous immunoglobulin therapy. Severe acute respiratory syndrome coronavirus 2 reverse transcription polymerase chain reaction was negative in nasopharyngeal, stool, and respiratory samples and was positive on serology. Cardiac MRI showed diffuse myocardial edema on T2 short tau inversion-recovery sequences and native T1 mapping, with no evidence of late gadolinium enhancement suggestive of replacement fibrosis or focal necrosis. These findings favor postinfectious myocarditis in children and adolescents with COVID-19.

Neonatal management and outcomes of prenatally diagnosed CHDs.

OBJECTIVES: The aim of this study was to determine the probability of intervention at birth after prenatal diagnosis of CHD. METHODS: A 10-year retrospective study including all foetuses with a prenatally diagnosed CHD and those delivered in a tertiary-care cardiac centre between January, 2002 and December, 2011 was carried out. Patients were classified into eight groups according to the anticipated risk of neonatal intervention. RESULTS: The need for urgent intervention and/or PGE1 infusion within the first 48 hours of life was 47% (n=507/1080): 72% (n=248) for CHD at risk for a Rashkind procedure, 77% (n=72) for CHD with ductal-dependent pulmonary flow, 13% (n=22) for CHD with potentially ductal-dependent pulmonary flow, 94% (n=62) for CHD with ductal-dependent systemic flow, 29% (n=88) for CHD with potentially ductal-dependant systemic flow, 50% (n=4) for total anomalous pulmonary venous connection, and 17% (n=1) for CHD with atrio-ventricular block. In all, 34% of the patients received PGE1 infusion and 21.4% underwent urgent catheter-based or surgical interventions; 10% of patients without anticipated risk (n=10) underwent an early intervention; 6.7% (n=73) of the patients died; and 55% (n=589) had an intervention before discharge from hospital. CONCLUSION: Half of the neonates with foetal CHD benefited from an urgent intervention or PGE1 infusion at birth. We recommend scheduled delivery and in utero transfer for transposition of the great arteries, double-outlet right ventricle with sub-pulmonary ventricular septal defect, total anomalous pulmonary venous connection, CHD with atrio-ventricular block with heart rate <50, all ductal-dependant lesions, and CHD with potentially ductal-dependant systemic flow.

Coronary stem development in wild-type and Tbx1 null mouse hearts.

BACKGROUND: Coronary artery (CA) stems connect the ventricular coronary tree with the aorta. Defects in proximal CA patterning are a cause of sudden cardiac death. In mice lacking Tbx1, common arterial trunk is associated with an abnormal trajectory of the proximal left CA. Here we investigate CA stem development in wild-type and Tbx1 null embryos. RESULTS: Genetic lineage tracing reveals that limited outgrowth of aortic endothelium contributes to proximal CA stems. Immunohistochemistry and fluorescent tracer injections identify a periarterial vascular plexus present at the onset of CA stem development. Transplantation experiments in avian embryos indicate that the periarterial plexus originates in mesenchyme distal to the outflow tract. Tbx1 is required for the patterning but not timing of CA stem development and a Tbx1 reporter allele is expressed in myocardium adjacent to the left but not right CA stem. This expression domain is maintained in Sema3c(-/-) hearts with a common arterial trunk and leftward positioned CA. Ectopic myocardial differentiation is observed on the left side of the Tbx1(-/-) common arterial trunk. CONCLUSIONS: A periarterial plexus bridges limited outgrowth of the aortic endothelium with the ventricular plexus during CA stem development. Molecular differences associated with left and right CA stems provide new insights into the etiology of CA patterning defects.

The pattern of the coronary arterial orifices in hearts with congenital malformations of the outflow tracts: a marker of rotation of the outflow tract during cardiac development?

Outflow tract defects, including cardiac neural crest defects (so-called conotruncal defects) and transposition of the great arteries, are due to an abnormal rotation of the outflow tract during cardiac development. Coronary orifices are often abnormal in outflow tract defects, particularly in common arterial trunk (CAT). A recent study indicates that abnormal coronary artery pattern in a mouse model with common arterial outlet (Tbx1-/- mouse mutant) could be due to a reduced and malpositioned subpulmonary coronary-refractory myocardial domain. The aim of our study was to demonstrate the relation between coronary orifices pattern in outflow tract defects in human and the abnormal embryonic rotation of the outflow tract. We analyzed 101 heart specimens with outflow tract defects: 46 CAT, 15 tetralogy of Fallot (TOF), 29 TOF with pulmonary atresia (TOF-PA), 11 double-outlet right ventricle with subaortic ventricular septal defect (DORV) and 17 controls. The position of left and right coronary orifices (LCO, RCO) was measured in degrees on the aortic/truncal circumference. The anterior angle between LCO and RCO (α) was calculated. The LCO was more posterior in TOF (31 °), TOF-PA (47 °), DORV (44 °), CAT (63 °), compared with controls (0 °, P < 0.05), and more posterior in CAT than in other outflow tract defects (P < 0.05). The RCO was more anterior in TOF (242 °), TOF-PA (245 °) and DORV (271 °) than in controls (213 °, P < 0.05), but not in CAT (195 °). The α angle was similar in TOF, TOF-PA, DORV and controls (149 °, 162 °, 133 °, 147 °), but significantly larger in CAT (229 °, P < 0.0001). In all outflow tract defects but CAT, the displacement of LCO (anterior) and RCO (posterior), while the α angle remains constant, might be due to incomplete rotation of the myocardium at the base of the outflow tract, leading to an abnormally positioned subpulmonary coronary-refractory myocardial domain. The larger α angle in CAT could reflect its dual identity, aortic and pulmonary.

Antenatal spectrum of CHARGE syndrome in 40 fetuses with CHD7 mutations.

BACKGROUND: CHARGE syndrome is a rare, usually sporadic disorder of multiple congenital anomalies ascribed to a CHD7 gene mutation in 60% of cases. Although the syndrome is well characterised in children, only one series of 10 fetuses with CHARGE syndrome has been reported to date. Therefore, we performed a detailed clinicopathological survey in our series of fetuses with CHD7 mutations, now extended to 40 cases. CHARGE syndrome is increasingly diagnosed antenatally, but remains challenging in many instances. METHOD: Here we report a retrospective study of 40 cases of CHARGE syndrome with a CHD7 mutation, including 10 previously reported fetuses, in which fetal or neonatal clinical, radiological and histopathological examinations were performed. RESULTS: Conversely to postnatal studies, the proportion of males is high in our series (male to female ratio 2.6:1) suggesting a greater severity in males. Features almost constant in fetuses were external ear anomalies, arhinencephaly and semicircular canal agenesis, while intrauterine growth retardation was never observed. Finally, except for one, all other mutations identified in our antenatal series were truncating, suggesting a possible phenotype-genotype correlation. CONCLUSIONS: Clinical analysis allowed us to refine the clinical description of CHARGE syndrome in fetuses, describe some novel features and set up diagnostic criteria in order to help the diagnosis of CHARGE syndrome after termination of pregnancies following the detection of severe malformations.

Comparison of telerobotic and conventional ultrasonography in children: a crossover bicentric pilot study.

Background: The MELODY system allows for performing ultrasonography on a patient remotely and has been proposed to assess disease characteristics in the context of the coronavirus disease 2019 (COVID-19) pandemic. The aim of this interventional crossover study was to address the feasibility of the system in children aged 1 to 10 years old. Methods: Children underwent ultrasonography with a telerobotic ultrasound system followed by a second conventional examination by a different sonographer. Results: In total, 38 children were enrolled, and 76 examinations were performed, with 76 scans analyzed. The mean [standard deviation (SD)] age of participants was 5.7 (2.7) years (range, 1-10 years). We found substantial agreement between telerobotic and conventional ultrasonography [κ=0.74 (95% CI: 0.53-0.94), P<0.005]. The mean (SD) duration was longer for telerobotic than conventional examinations [26.0 (2.5) vs. 13.9 (11.2) min, P<0.0001]. Abdominal organs and abnormalities were similarly visualized on telerobotic and conventional ultrasonography. Cardiac echocardiography provided reliable diagnoses, with non-significantly different measurements with both techniques, although the visualization score was significantly higher with conventional than telerobotic ultrasonography (P<0.05). On lung analysis, both examinations identified consolidations and pleural effusion, whereas visualization and total lung score were similar with the 2 techniques. Overall, 45% of parents reported that their children felt less pressure with the telerobotic system. Conclusions: Telerobotic ultrasonography may be effective, feasible, and well-tolerated in children.

Tbx1, subpulmonary myocardium and conotruncal congenital heart defects.

Conotruncal congenital heart defects, including defects in septation and alignment of the ventricular outlets, account for approximately a third of all congenital heart defects. Failure of the left ventricle to obtain an independent outlet results in incomplete separation of systemic and pulmonary circulation at birth. The embryonic outflow tract, a transient cylinder of myocardium connecting the embryonic ventricles to the aortic sac, plays a critical role in this process during normal development. The outflow tract (OFT) is derived from a population of cardiac progenitor cells called the second heart field that contributes to the arterial pole of the heart tube during cardiac looping. During septation, the OFT is remodeled to form the base of the ascending aorta and pulmonary trunk. Tbx1, the major candidate gene for DiGeorge syndrome, is a critical transcriptional regulator of second heart field development. DiGeorge syndrome patients are haploinsufficient for Tbx1 and present a spectrum of conotruncal anomalies including tetralogy of Fallot, pulmonary atresia, and common arterial trunk. In this review, we focus on the role of Tbx1 in the regulation of second heart field deployment and, in particular, in the development of a specific population of myocardial cells at the base of the pulmonary trunk. Recent data characterizing additional properties and regulators of development of this region of the heart, including the retinoic acid, hedgehog, and semaphorin signaling pathways, are discussed. These findings identify future subpulmonary myocardium as the clinically relevant component of the second heart field and provide new mechanistic insight into a spectrum of common conotruncal congenital heart defects.