Prenatal diagnosis of congenital ventricular aneurysm and diverticulum: Prenatal features and perinatal management.

Congenital ventricular diverticulum (VD) and aneurysm are rare cardiac developmental anomalies and their pathophysiology is still unclear. They present as an anomaly of the four chambers view, cardiomegaly, arrhythmia, pericardial effusion, or hydrops. They are usually isolated anomalies. Differential diagnosis between diverticulum and aneurysm is challenging during the prenatal period. Management policy is not uniform either conservative or repeated pericardial puncture. OBJECTIVE: We wanted to describe prenatal features and post-natal outcomes of fetal cardiac out pouching. METHODS: We retrospectively report 6 cases of VD and aneurysm prenatally managed in our fetal medicine unit between 2010 and 2020. All cases were evaluated from the first or second trimester of pregnancy until postnatal follow-up (3 months to 3 years). RESULTS: All six cases underwent a monthly ultrasound follow-up with spontaneous regression of pericardial effusion, and normal hemodynamics at birth No pericardial puncture was done and postnatal outcome was favorable in all cases. CONCLUSION: Based on our experience and on cases previously published, prenatal counseling should be prudent regarding the final diagnosis. Referral and monthly prenatal ultrasound follow-up, birth in a tertiary center after multidisciplinary evaluation and cardiological evaluation at birth still seem mandatory.

Health-related quality of life and physical activity in children with inherited cardiac arrhythmia or inherited cardiomyopathy: the prospective multicentre controlled QUALIMYORYTHM study rationale, design and methods.

BACKGROUND: Advances in paediatric cardiology have improved the prognosis of children with inherited cardiac disorders. However, health-related quality of life (QoL) and physical activity have been scarcely analysed in children with inherited cardiac arrhythmia or inherited cardiomyopathy. Moreover, current guidelines on the eligibility of young athletes with inherited cardiac disorders for sports participation mainly rely on expert opinions and remain controversial. METHODS: The QUALIMYORYTHM trial is a multicentre observational controlled study. The main objective is to compare the QoL of children aged 6 to 17 years old with inherited cardiac arrhythmia (long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, or arrhythmogenic right ventricular dysplasia), or inherited cardiomyopathy (hypertrophic, dilated, or restrictive cardiomyopathy), to that of age and gender-matched healthy subjects. The secondary objective is to assess their QoL according to the disease's clinical and genetic characteristics, the level of physical activity and motivation for sports, the exercise capacity, and the socio-demographic data. Participants will wear a fitness tracker (ActiGraph GT3X accelerometer) for 2 weeks. A total of 214 children are required to observe a significant difference of 7 ± 15 points in the PedsQL, with a power of 90% and an alpha risk of 5%. DISCUSSION: After focusing on the survival in children with inherited cardiac disorders, current research is expanding to patient-reported outcomes and secondary prevention. The QUALIMYORYTHM trial intends to improve the level of evidence for future guidelines on sports eligibility in this population. Trial registration ClinicalTrials.gov Identifier: NCT04712136, registered on January 15th, 2021 ( https://clinicaltrials.gov/ct2/show/NCT04712136 ).

Association of Intravenous Immunoglobulins Plus Methylprednisolone vs Immunoglobulins Alone With Course of Fever in Multisystem Inflammatory Syndrome in Children.

Importance: Multisystem inflammatory syndrome in children (MIS-C) is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially life-threatening, but the optimal therapeutic strategy remains unknown. Objective: To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone as initial therapy in MIS-C. Design, Setting, and Participants: Retrospective cohort study drawn from a national surveillance system with propensity score-matched analysis. All cases with suspected MIS-C were reported to the French National Public Health Agency. Confirmed MIS-C cases fulfilling the World Health Organization definition were included. The study started on April 1, 2020, and follow-up ended on January 6, 2021. Exposures: IVIG and methylprednisolone vs IVIG alone. Main Outcomes and Measures: The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure. Secondary outcomes included a second-line therapy, hemodynamic support, acute left ventricular dysfunction after first-line therapy, and length of stay in the pediatric intensive care unit. The primary analysis involved propensity score matching with a minimum caliper of 0.1. Results: Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization definition (58 females [52%]; median age, 8.6 years [interquartile range, 4.7 to 12.1]). Five children did not receive either treatment. Overall, 3 of 34 children (9%) in the IVIG and methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to treatment. Treatment with IVIG and methylprednisolone vs IVIG alone was associated with lower risk of treatment failure (absolute risk difference, -0.28 [95% CI, -0.48 to -0.08]; odds ratio [OR], 0.25 [95% CI, 0.09 to 0.70]; P = .008). IVIG and methylprednisolone therapy vs IVIG alone was also significantly associated with lower risk of use of second-line therapy (absolute risk difference, -0.22 [95% CI, -0.40 to -0.04]; OR, 0.19 [95% CI, 0.06 to 0.61]; P = .004), hemodynamic support (absolute risk difference, -0.17 [95% CI, -0.34 to -0.004]; OR, 0.21 [95% CI, 0.06 to 0.76]), acute left ventricular dysfunction occurring after initial therapy (absolute risk difference, -0.18 [95% CI, -0.35 to -0.01]; OR, 0.20 [95% CI, 0.06 to 0.66]), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; difference in days, -2.4 [95% CI, -4.0 to -0.7]). Conclusions and Relevance: Among children with MIS-C, treatment with IVIG and methylprednisolone vs IVIG alone was associated with a more favorable fever course. Study interpretation is limited by the observational design.

Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort.

BACKGROUND: Current data suggest that COVID-19 is less frequent in children, with a milder course. However, over the past weeks, an increase in the number of children presenting to hospitals in the greater Paris region with a phenotype resembling Kawasaki disease (KD) has led to an alert by the French national health authorities. METHODS: Multicentre compilation of patients with KD in Paris region since April 2020, associated with the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ('Kawa-COVID-19'). A historical cohort of 'classical' KD served as a comparator. RESULTS: Sixteen patients were included (sex ratio=1, median age 10 years IQR (4·7 to 12.5)). SARS-CoV-2 was detected in 12 cases (69%), while a further three cases had documented recent contact with a quantitative PCR-positive individual (19%). Cardiac involvement included myocarditis in 44% (n=7). Factors prognostic for the development of severe disease (ie, requiring intensive care, n=7) were age over 5 years and ferritinaemia >1400 µg/L. Only five patients (31%) were successfully treated with a single intravenous immunoglobulin (IVIg) infusion, while 10 patients (62%) required a second line of treatment. The Kawa-COVID-19 cohort differed from a comparator group of 'classical' KD by older age at onset 10 vs 2 years (p<0.0001), lower platelet count (188 vs 383 G/L (p<0.0001)), a higher rate of myocarditis 7/16 vs 3/220 (p=0.0001) and resistance to first IVIg treatment 10/16 vs 45/220 (p=0.004). CONCLUSION: Kawa-COVID-19 likely represents a new systemic inflammatory syndrome temporally associated with SARS-CoV-2 infection in children. Further prospective international studies are necessary to confirm these findings and better understand the pathophysiology of Kawa-COVID-19. Trial registration number NCT02377245.

Calculating the fraction of Kawasaki disease potentially attributable to seasonal pathogens: a time series analysis.

Background: Kawasaki disease is an acute, febrile, systemic vasculitis of children that primarily affects medium-sized blood vessels with a tropism for the coronary arteries. Although the etiological factors remain unknown, infections have been suggested as the trigger of Kawasaki disease. We sought to calculate the fraction of Kawasaki disease potentially attributable to seasonal infections. Methods: This cohort study used a population-based time series analysis from the French hospitalisation database (Programme de Médicalisation des Systèmes d'Information), which includes all inpatients admitted to any public or private hospital in France. We included all children aged 0-17 years hospitalised for Kawasaki disease in France over 13 years. The monthly incidence of Kawasaki disease per 10,000 children over time was analysed by a quasi-Poisson regression model. The model accounted for seasonality by using harmonic terms (a pair of sines and cosines with 12-month periods). The circulation of eight common seasonal pathogens (adenovirus, influenza, metapneumovirus, Mycoplasma pneumoniae, norovirus, rhinovirus, rotavirus, respiratory syncytial virus, and Streptococcus pneumonia) over the same period was included in the model to analyse the fraction of Kawasaki disease potentially attributable to each pathogen. Infections were identified on the basis of polymerase chain reaction or rapid antigen testing in hospital laboratories. Findings: Between Jan 1, 2007, and Dec 31, 2019, we included 10,337 children with Kawasaki disease and 442,762 children with the selected infectious diseases. In the Kawasaki disease cohort, the median age [IQR] was 2 [0-4] years, 6164 [59.6%] were boys. Adenovirus infection was potentially responsible for 24.4% [21.5-27.8] (p < 0.001) of Kawasaki diseases, Norovirus for 6.7% [1.3-11.2] (p = 0.002), and RSV 4.6% [1.2-7.8] (p = 0.022). Sensitivity analyses found similar results. Interpretation: This cohort study of data from a comprehensive national hospitalisation database indicated that approximately 35% of Kawasaki diseases was potentially attributable to seasonal infections. Funding: None.

Development of a score for early identification of children with Kawasaki disease requiring second-line treatment in multi-ethnic populations in Europe: A multicentre retrospective cohort study.

Background: Early identification of high-risk patients is essential to stratify treatment algorithms of Kawasaki disease (KD) and to appropriately select patients at risk for complicated disease who would benefit from intensified first-line treatment. Several scores have been developed and validated in Asian populations but have shown low sensitivity in predicting intravenous immunoglobulin (IVIG) resistance in non-Asian populations. We sought methods to predict the need for secondary treatment after initial IVIG in non-Asian populations. Methods: We conducted a retrospective, multicenter study including consecutive patients with KD admitted to two tertiary pediatric hospitals in France and Italy from 2005 to 2019. We evaluated the performance of the Kawanet-score and compared it with the performances of initial echocardiography findings, and of a newly proposed score combining the Kawanet-score and initial echocardiography findings. For each score, we assessed the AUC, sensitivity and specificity for predicting the need for second-line treatment. Findings: We included 363 children with KD, 186 from France and 177 from Italy, of whom 57 (16%) required second-line therapy after the first IVIG dose. The Kawanet score, coronary artery dilation or aneurysm with maximal Z-score ≥2.0 at baseline, and abnormal initial echocardiography had a sensitivity of 43%, 55% and 65% and a specificity of 73%, 78%, 73%, respectively, for predicting the need for second-line treatment. The Kawanet-score was significantly improved by combining it with initial echocardiography findings. The best predictive performance (Sensitivity 76%, Specificity 54%) was obtained by combining the Kawanet-score with abnormal initial echocardiography, defined by the presence of either coronary artery maximal Z-score ≥2.0, pericarditis, myocarditis and/or ventricular dysfunction. This score predicted the need for second-line treatment in European, African/Afro-Caribbean and Asian ethnicity with a sensitivity of 80%, 65% and 100%, respectively, and a specificity of 56%, 51% and 61%, respectively. Interpretation: Our study proposes a score that we named the Kawanet-echo score, which allows early identification of children with KD who require a second-line treatment in multi-ethnic populations in Europe. Funding: None.

Turner syndrome: French National Diagnosis and Care Protocol (NDCP; National Diagnosis and Care Protocol).

Turner syndrome (TS; ORPHA 881) is a rare condition in which all or part of one X chromosome is absent from some or all cells. It affects approximately one in every 1/2500 liveborn girls. The most frequently observed karyotypes are 45,X (40-50%) and the 45,X/46,XX mosaic karyotype (15-25%). Karyotypes with an X isochromosome (45,X/46,isoXq or 45,X/46,isoXp), a Y chromosome, X ring chromosome or deletions of the X chromosome are less frequent. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins) is to provide health professionals with information about the optimal management and care for patients, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Growth and Developmental Endocrine disorders, is available from the French Health Authority website. Turner Syndrome is associated with several phenotypic conditions and a higher risk of comorbidity. The most frequently reported features are growth retardation with short adult stature and gonadal dysgenesis. TS may be associated with various congenital (heart and kidney) or acquired diseases (autoimmune thyroid disease, celiac disease, hearing loss, overweight/obesity, glucose intolerance/type 2 diabetes, dyslipidemia, cardiovascular complications and liver dysfunction). Most of the clinical traits of TS are due to the haploinsufficiency of various genes on the X chromosome, particularly those in the pseudoautosomal regions (PAR 1 and PAR 2), which normally escape the physiological process of X inactivation, although other regions may also be implicated. The management of patients with TS requires collaboration between several healthcare providers. The attending physician, in collaboration with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are designed to provide such support.

Severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children mimicking Kawasaki disease.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been characterized by high transmission rates and high mortality in adults with predisposing factors, including age>70 years, obesity, diabetes, systemic hypertension and other underlying diseases. During the second week of viral pneumonia, acute respiratory distress syndrome can occur and carries high mortality. Unlike most common respiratory viruses, children seem to be less susceptible to SARS-CoV-2 infection, and generally develop mild disease with low mortality. However, clusters of severe shock associated with high levels of cardiac biomarkers and unusual vasoplegia requiring inotropes, vasopressors and volume loading have recently been described. Both the clinical symptoms (i.e. high and persistent fever, gastrointestinal disorders, skin rash, conjunctival injection and dry cracked lips) and the biological signs (e.g. elevated C-reactive protein/procalcitonin and high levels of ferritinaemia) mimicked Kawasaki disease. In most cases, intravenous immunoglobin therapy improved cardiac function and led to full recovery within a few days. Adjunctive steroid therapy and sometimes biotherapy (e.g. anti-interleukin 1Ra and anti-interleukin 6 monoclonal antibodies) were often necessary. Although almost all children fully recovered within a week, some of them later developed coronary artery dilation or aneurysm. Thus, a new "multisystem inflammatory syndrome in children" related to SARS-CoV-2 has recently been described. Similarities with Kawasaki disease and the physiopathology of this syndrome still need further exploration.

Emergence of Kawasaki disease related to SARS-CoV-2 infection in an epicentre of the French COVID-19 epidemic: a time-series analysis.

BACKGROUND: Kawasaki disease is an acute febrile systemic childhood vasculitis, which is suspected to be triggered by respiratory viral infections. We aimed to examine whether the ongoing COVID-19 epidemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with an increase in the incidence of Kawasaki disease. METHODS: We did a quasi-experimental interrupted time series analysis over the past 15 years in a tertiary paediatric centre in the Paris region, a French epicentre of the COVID-19 outbreak. The main outcome was the number of Kawasaki disease cases over time, estimated by quasi-Poisson regression. In the same centre, we recorded the number of hospital admissions from the emergency department (2005-2020) and the results of nasopharyngeal multiplex PCR to identify respiratory pathogens (2017-2020). These data were compared with daily hospital admissions due to confirmed COVID-19 in the same region, recorded by Public Health France. FINDINGS: Between Dec 1, 2005, and May 20, 2020, we included 230 patients with Kawasaki disease. The median number of Kawasaki disease hospitalisations estimated by the quasi-Poisson model was 1·2 per month (IQR 1·1-1·3). In April, 2020, we identified a rapid increase of Kawasaki disease that was related to SARS-CoV-2 (six cases per month; 497% increase [95% CI 72-1082]; p=0·0011), starting 2 weeks after the peak of the COVID-19 epidemic. SARS-CoV-2 was the only virus circulating intensely during this period, and was found in eight (80%) of ten patients with Kawasaki disease since April 15 (SARS-CoV-2-positive PCR or serology). A second peak of hospital admissions due to Kawasaki disease was observed in December, 2009 (six cases per month; 365% increase ([31-719]; p=0.0053), concomitant with the influenza A H1N1 pandemic. INTERPRETATION: Our study further suggests that viral respiratory infections, including SAR-CoV-2, could be triggers for Kawasaki disease and indicates the potential timing of an increase in incidence of the disease in COVID-19 epidemics. Health-care providers should be prepared to manage an influx of patients with severe Kawasaki disease, particularly in countries where the peak of COVID-19 has recently been reached. FUNDING: French National Research Agency.

Kawasaki disease: abnormal initial echocardiogram is associated with resistance to IV Ig and development of coronary artery lesions.

BACKGROUND: Kawasaki disease (KD) is an acute febrile systemic vasculitis that affects small and medium blood vessels. Intensified treatments for the most severely affected patients have been proposed recently, and the early identification of KD patients at high risk for coronary artery aneurysms (CAA) is crucial. However, the risk scoring systems developed in Japan have not been validated in European populations, and little data is available concerning the link between initial echocardiogram findings other than high z-scores and cardiac prognosis. METHODS: In order to investigate whether the presence of any abnormalities, other than high z-scores in first echocardiogram, are associated with resistance to IV immunoglobulins and/or subsequent development of CAA, we retrospectively analyzed data from children diagnosed with KD between 2006 and 2016 at a tertiary Hospital in Paris, France. RESULTS: A total of 157 children were included. The initial echocardiogram was performed after a median of 7 days of fever and was abnormal in 48 cases (31%). The initial presence of any echocardiographic abnormality (coronary artery dilatation, CAA, pericardial effusion, perivascular brightness of the coronary arteries, left-ventricular dysfunction and mitral insufficiency) was strongly associated with resistance to intravenous immunoglobulin (p = 0.005) and development of coronary artery lesions within the first 6 weeks of disease (p = 0.01). All patients (n = 7) with persistent coronary abnormalities at 1 year already had an abnormal initial echocardiogram. Severity scoring systems from Japan had low sensitivity (0-33%) and low specificity (71-82%) for predicting immunoglobulin resistance or cardiac involvement. CONCLUSIONS: In European populations with mixed ethnic backgrounds, the presence of any abnormalities at the initial echocardiogram may contribute to early identification of patients with severe disease.

A systematic variant screening in familial cases of congenital heart defects demonstrates the usefulness of molecular genetics in this field.

The etiology of congenital heart defect (CHD) combines environmental and genetic factors. So far, there were studies reporting on the screening of a single gene on unselected CHD or on familial cases selected for specific CHD types. Our goal was to systematically screen a proband of familial cases of CHD on a set of genetic tests to evaluate the prevalence of disease-causing variant identification. A systematic screening of GATA4, NKX2-5, ZIC3 and Multiplex ligation-dependent probe amplification (MLPA) P311 Kit was setup on the proband of 154 families with at least two cases of non-syndromic CHD. Additionally, ELN screening was performed on families with supravalvular arterial stenosis. Twenty-two variants were found, but segregation analysis confirmed unambiguously the causality of 16 variants: GATA4 (1 ×), NKX2-5 (6 ×), ZIC3 (3 ×), MLPA (2 ×) and ELN (4 ×). Therefore, this approach was able to identify the causal variant in 10.4% of familial CHD cases. This study demonstrated the existence of a de novo variant even in familial CHD cases and the impact of CHD variants on adult cardiac condition even in the absence of CHD. This study showed that the systematic screening of genetic factors is useful in familial CHD cases with up to 10.4% elucidated cases. When successful, it drastically improved genetic counseling by discovering unaffected variant carriers who are at risk of transmitting their variant and are also exposed to develop cardiac complications during adulthood thus prompting long-term cardiac follow-up. This study provides an important baseline at dawning of the next-generation sequencing era.

Bicuspid pulmonary valve in transposition of the great arteries: impact on outcome.

OBJECTIVE: Long-term evaluation of the impact of bicuspid pulmonary valve on neoaortic valve regurgitation and aortic root dilatation (ARD) after arterial switch operation (ASO) for transposition of the great arteries (TGA). METHODS: Between January 1987 and March 2010, 980 neonates underwent ASO for TGA. A total of 40 patients (4.0%) had a pulmonary bicuspid valve with no significant left ventricular outflow tract obstruction. In this group, 11 patients (28%) had associated ventricular septal defect, three hypoplastic aortic arch, and three had a right ventricular hypoplasia. No pulmonary valvuloplasty was attempted. Mean follow-up was 7.7 ± 5.5 years. Echocardiography evaluations of neoaortic valve function and morphology and aortic root dimensions were performed. RESULTS: There were two hospital deaths (5%) related to hypoplastic right ventricle and left ventricular dysfunction, and no late death yielding an actuarial survival to 95% SD at 1, 5, and 10 years. At last follow-up, five patients (12%) had mild-to-moderate aortic regurgitation (AR). None had aortic valve stenosis. ARD was noted in 28% of the patients (Z-score up to +3). One patient needed a Bentall procedure for significant AR and severe dilatation of the ascending aorta at 11 years of age. As many as four patients underwent reoperation (10%) for stenosis of the left coronary artery. Freedom from reoperation was 95% SD, 88% SD, and 75% SD at 1,5, and 10 years, respectively. CONCLUSIONS: ASO is a safe option for TGA associated with a well-functioning bicuspid pulmonary valve with low morbidity and mortality. Prevalence of AR was not particularly high. Even though ARD was frequent, neoaortic bicuspid valve did not represent a high risk for aortic reoperation. Long-term individual follow-up is mandatory to observe the potential risk of root dilatation and AR.

Nontoxinogenic corynebacterium diphtheriae as a rare cause of native endocarditis in childhood.

We report a pediatric case of negative blood culture pulmonary valve endocarditis caused by a nontoxinogenic Corynebacterium diphtheriae biotype gravis and review the literature on this disease.

Brainstem dysfunction: a possible neuroembryological pathogenesis of isolated Pierre Robin sequence.

UNLABELLED: Pierre Robin sequence (posterior U-shape cleft palate, glossoptosis, retrognathia) (PRS) is a frequent and heterogeneous neonatal condition of obscure origin. We show here that orodigestive and cardiorespiratory functional disorders are very frequent in PRS and that these functional disorders, as well as anatomical and embryological data, argue for the involvement of brainstem dysfunction in the pathogenesis of some cases of isolated PRS. A total of 66 infants consecutively admitted for isolated PRS were followed-up with observations and investigations focused on their orodigestive and cardiorespiratory disorders. Neonatal clinical examination and neonatal anatomical aspects of the three orofacial features of the sequence were evaluated. Feeding difficulties and respiratory disorders were recorded and infants were classified according to three grades of severity. The relation between functional severity grade and neonatal orofacial features was evaluated, as well as the relation between functional severity grade and specific criteria characterising oesophageal and laryngeal motility and cardiac orthoparasympathetic imbalance. In the first weeks of life, sucking and swallowing disorders (100%), excessive regurgitation (94%), upper airways obstruction (50%), and cardiac vagal overactivity (59%) were noted. Correlation of anatomical features with functional severity grades was poor except for extreme forms of glossoptosis and retrognathia. Specific anomalies of oesophageal motility, pharyngolaryngeal tone and parasympathetic cardiac regulation were described. These anomalies were more frequent in children with the two higher grades of functional severity. CONCLUSION: infants with Pierre Robin sequence have early and severe anomalies of orodigestive and cardiorespiratory function which do not appear to be related solely to anatomical features and which require proper medical management. We suggest a prenatal and neonatal brainstem dysfunction as a neuroembryological hypothesis to explain the onset of some cases of Pierre Robin sequence.