Congenital heart defects in CTNNB1 syndrome: Raising clinical awareness.

CTNNB1 [OMIM *116806] encodes ß-catenin, an integral part of the cadherin/catenin complex, which functions as effector of Wnt signaling. CTNNB1 is highly expressed in brain as well as in other tissues, including heart. Heterozygous CTNNB1 pathogenic variations are associated with a neurodevelopmental disorder characterized by spastic diplegia and visual defects (NEDSDV) [OMIM #615075], featuring psychomotor delay, intellectual disability, behavioral disturbances, movement disorders, visual defects and subtle facial and somatic features. We report on a new series of 19 NEDSDV patients (mean age 10.3 years), nine of whom bearing novel CTNNB1 variants. Notably, five patients showed congenital heart anomalies including absent pulmonary valve with intact ventricular septum, atrioventricular canal with hypoplastic aortic arch, tetralogy of Fallot, and mitral valve prolapse. We focused on the cardiac phenotype characterizing such cases and reviewed the congenital heart defects in previously reported NEDSDV patients. While congenital heart defects had occasionally been reported so far, the present findings configure a higher rate of cardiac anomalies, suggesting dedicated heart examination to NEDSDV clinical management.

The heart in RASopathies.

The cardiovascular phenotype associated with RASopathies has expanded far beyond the original descriptions of pulmonary valve stenosis by Dr Jaqueline Noonan in 1968 and hypertrophic cardiomyopathy by Hirsch et al. in 1975. Because of the common underlying RAS/MAPK pathway dysregulation, RASopathy syndromes usually present with a typical spectrum of overlapping cardiovascular anomalies, although less common cardiac defects can occur. The identification of the causative genetic variants has enabled the recognition of specific correlations between genotype and cardiac phenotype. Characterization and understanding of genotype-phenotype associations is not only important for counseling a family of an infant with a new diagnosis of a RASopathy condition but is also critical for their clinical prognosis with respect to cardiac disease, neurodevelopment and other organ system involvement over the lifetime of the patient. This review will focus on the cardiac manifestations of the most common RASopathy syndromes, the relationship between cardiac defects and causal genetic variation, the contribution of cardiovascular abnormalities to morbidity and mortality and the most relevant follow-up issues for patients affected by RAS/MAPK pathway diseases, with respect to cardiac clinical outcomes and management, in children and in the adult population.

Brugada pattern revealed during SARS-COV-2-related multi-systemic inflammatory syndrome in a 6-year-old child.

Rhythm abnormalities are rare during COVID-19-related multisystem inflammatory syndrome in children (MIS-C). We are reporting the detection of type I Brugada pattern in a 6-year-old child with MIS-C. Following the start of treatment (systemic steroids and immunoglobulins), a gradual evolution of cardiac rhythm up to normalisation was observed, concomitantly with a progressive reduction of inflammatory markers.

Genotype-cardiac phenotype correlations in a large single-center cohort of patients affected by RASopathies: Clinical implications and literature review.

Congenital heart disease (CHD) and hypertrophic cardiomyopathy (HCM) are common features in patients affected by RASopathies. The aim of this study was to assess genotype- phenotype correlations, focusing on the cardiac features and outcomes of interventions for cardiac conditions, in a single-center cohort of 116 patients with molecularly confirmed diagnosis of RASopathy, and compare these findings with previously published data. All enrolled patients underwent a comprehensive echocardiographic examination. Relevant information was also retrospectively collected through the analysis of clinical records. As expected, significant associations were found between PTPN11 mutations and pulmonary stenosis (both valvular and supravalvular) and pulmonary valve dysplasia, and between SOS1 mutations and valvular defects. Similarly, HRAS mutations were significantly associated with HCM. Potential associations between less prevalent mutations and cardiac defects were also observed, including RIT1 mutations and HCM, SOS2 mutations and septal defects, and SHOC2 mutations and septal and valve abnormalities. Patients with PTPN11 mutations were the most likely to require both a primary treatment (transcatheter or surgical) and surgical reintervention. Other cardiac anomalies less reported until recently in this population, such as isolated functional and structural mitral valve diseases, as well as a sigmoid-shaped interventricular septum in the absence of HCM, were also reported. In conclusion, our study confirms previous data but also provides new insights on cardiac involvement in RASopathies. Further research concerning genotype/phenotype associations in RASopathies could lead to a more rational approach to surgery and the consideration of drug therapy in patients at higher risk due to age, severity, anatomy, and comorbidities.

Neonatal Life-Threatening Nonoliguric Hyperkalemia Under Therapeutic Hypothermia.

To illustrate our experience with two cases of neonatal life-threatening hyperkalemia during therapeutic hypothermia (TH) despite a normal acid-base status, urine output, and preserved renal function. Clinical cases are presented from Pediatric Intensive Care Unit (PICU) admission to the onset of the hyperkalemia, with related complications and after resolution. Similar cases were not retrieved from a critical review of pertinent literature. Severe hyperkalemia pathophysiology and risk factors have been debated. Two full-term adequate for weight female neonates were admitted to PICU because of perinatal asphyxia who underwent TH. Prenatal history was completely uneventful, nor hereditary genetic conditions were reported; moreover, long-term follow-up ruled out any metabolic or renal disease. Despite an accurate evaluation of previous clinical series and literature on TH and perinatal asphyxia, these hyperkalemic episodes remain unexplained. The hypoxic-ischemic insult may affect multiple organs, mainly central nervous system, heart, lung, and kidneys; acute muscle breakdown and consequent rising of myoglobin may also have a precipitating role in acute kidney failure (AKF) and hyperkalemia. Electrolyte imbalance is a possible finding as a consequence of combined cell injury and AKF. In contrast, an isolated severe hyperkalemia is exceedingly rare in nonoliguric neonates.

Clinical applications of Lung Ultrasound in children in Pediatric Emergency Setting: a lesson from a child with severe heart disease.

BACKGROUND AND AIM: Rheumatic Heart Disease (RHD) often evolves in congestive heart failure with development of pulmonary edema after a period of asymptomatic, latent phase. In the last years, Lung Ultrasound (LUS) has gained a primary role in the diagnosis and management of pleuropulmonary disorders, also in pediatric practice and in the diagnosis and follow-up of pulmonary edema through the qualitative analysis of ultrasound B-lines.Aim of this case report is that to keep high clinicians' attention to the diagnosis that of Rheumatic Heart Disease also in high-income countries and to deepen the role and importance of lung ultrasound, in clinical practice, in diagnosis and follow-up of pediatric lung diseases, especially in emergency settings as happened in our case. METHODS: We present the case of a 14-year-old Italian boy from a medium-low socio-economic and cultural class Italian family, who was diagnosed with severe and advanced stage RHD, which had remained undiagnosed until then. RESULTS AND CONCLUSIONS: In the diagnostic process of our case, LUS played a fundamental role because it quickly directed us, contextually to the clinical and anamnestic evaluation, towards the right diagnosis, in a Pediatric Emergency Department. In clinical practice, the only LUS findings and the only qualitative analysis of the B-lines, does not make clinicians able to make a clear characterization yet. Thus the study of cardiovascular function, laboratory parameters, anamnestic and clinical data continue to be useful tools to assist the LUS in the diagnostic processes of lung diseases, as was the case in our case.

Complications associated with myocardial bridging in four children without underlying cardiac disease: a case series.

BACKGROUND: Myocardial bridging is largely considered to be a benign, symptomless congenital anomaly of the coronary arteries in which the intramyocardial coronary course is partially 'tunnelled' and leads to vessel compression during ventricular systole. There are few data regarding children. OBJECTIVE: To report on myocardial bridging observed in children seeking medical help in the paediatric emergency room. CASE PRESENTATION: A series of four children aged 6-13 years with symptomatic myocardial bridging but no other underlying cardiac abnormalities is reported. They were admitted to the paediatric emergency department during 2013-2016, three with chest pain after physical activity and one with septic shock. RESULTS: Heart computed tomography scan in the first three demonstrated myocardial bridging of the left anterior descendent coronary artery's branches; their 2-year follow-up was uneventful. The fourth patient presented with ventricular fibrillation 24 hours after admission and at autopsy there was an intramyocardial tract 4 cm long on the left anterior descendent coronary artery. CONCLUSIONS: This case series demonstrates that myocardial bridging can be symptomatic in children with no underlying cardiac disorders and should be included in the differential diagnosis of exertional chest pain and/or arrhythmias.Abbreviations: CRP, C-reactive protein; CT, computed tomography; D1, diagonal 1 artery; ECG, electrocardiogram; ED, emergency department; KD, Kawasaki disease; LAD, left anterior descending coronary artery; MB, myocardial bridging; RI, ramus intermedius artery; TN, troponin.

Smith-Magenis syndrome: Report of morphological and new functional cardiac findings with review of the literature.

Smith-Magenis syndrome (SMS) is a genetic disorder characterized by multiple congenital anomalies, sleep disturbance, behavioral impairment, and intellectual disability. Its genetic cause has been defined as an alteration in the Retinoic Acid-Induced 1 gene. Cardiac anomalies have been reported since the first description of this condition in patients with 17p11.2 deletion. Variable cardiac defects, including ventricular septal defects, atrial septal defects, tricuspid stenosis, mitral stenosis, tricuspid and mitral regurgitation, aortic stenosis, pulmonary stenosis, mitral valve prolapse, tetralogy of Fallot, and total anomalous pulmonary venous connection, have been anecdotally reported and systematic case series are still lacking. Herein, we define the spectrum of the cardiac phenotype and describe for the first time the cardiac function in a large cohort of pediatric patients with SMS. Revision of the literature and correlations between genotype and cardiac phenotype was performed.

Role of Troponin Determination to Diagnose Chest Pain in the Pediatric Emergency Department.

OBJECTIVES: Chest pain is a common cause to admission to the pediatric emergency department and often leads to an extensive cardiac evaluation. The objective of this study was to evaluate the usefulness of the troponin (TN) plasma level determination in the initial phase of the differential diagnosis of chest pain in children. METHODS: This is a retrospective observational study on 107 patients, aged 0 to 19 years, admitted for chest pain to the pediatric emergency department of our institution. Demographics, clinical data, and patient outcomes were analyzed. Troponin values of >0.03 ng/mL but <0.1 ng/mL were considered suspected for cardiac pathology, whereas levels of >0.1 ng/mL were indicative of cardiac pathology. In these latter patients, an echocardiographic examination was also performed. RESULTS: Only 99 patients were evaluated with electrocardiogram (ECG). In 91 of 99 patients of our series, both TN determination and ECG recording were performed. Troponin was higher than the cutoff value (0.03 ng/mL) in 9 patients (9.1%). Only 2 of the 9 patients who presented high TN values showed a nonpathological ECG, whereas 16 (17.5%) of 91 patients in whom both ECG and TN determination were performed had ECG abnormalities without a simultaneous elevation of TN. Of the 26 patients who had medical history and suggestive targets of cardiac pathology, only in 6 (23.1%) of them the diagnosis was confirmed. The final diagnosis of the 99 patients was idiopathic chest pain in 45.4% of cases. CONCLUSIONS: Even with the low cost and the relatively easiness for the plasma level determination, TN should be measured only in children with chest pain associated to familiar history suggestive of cardiovascular disease and/or clinical symptoms and/or ECG alterations.

Resolution of Giant Coronary Aneurisms in a Child With Refractory Kawasaki Disease Treated With Anakinra.

Kawasaki disease (KD) is an acute, febrile illness of unknown etiology that mainly affects children under 5 years of age. intravenous immunoglobulin (IVIG), the standard treatment, has reduced coronary involvement to <5%. Patients who do not improve after an initial IVIG have a higher risk of developing coronary arteries aneurysms, and its optimal treatment remains controversial. We present a case of IVIG, steroids, and infliximab-resistant KD in a 9-month-old child, which developed giant aneurysms and was successfully treated with anakinra, a recombinant antagonist of the IL-1 receptor. In our case, the introduction of IL-1 receptor antagonist therapy seems to have blocked the disease from both a clinical and a laboratory point of view. We also noted a very rapid regression of coronary aneurysms passed from giant aneurysms to small ones, or, as in the case of the anterior descending artery, the complete disappearance of the aneurysm formation. We think that our case adds more evidences to the potential role of IL-1RA as therapy in some selected cases of refractory KD, in particular with severe involvement of coronary arteries, although new efficacy trials are needed to better understand the role of Anakinra in these patients.

Outcome of Neonates with Vein of Galen Malformation Presenting with Severe Heart Failure: A Case Series.

BACKGROUND: Neonatal presentation of vein of Galen aneurysmal malformations (VGAMs) complicated by cardiac failure and pulmonary hypertension is frequently associated with a poor prognosis. Interventional neuroradiology with embolization can offer a chance for survival, although neurological damage can represent a limitation. OBJECTIVE: This article determines if aggressive intensive care and drug management of cardiac failure before urgent embolization can influence morbidity and mortality. PATIENTS AND METHODS: Twelve infants (7 boys, 5 girls) were diagnosed with symptomatic vein of Galen malformations in the neonatal period during the period 2000 to 2014. Due to high output cardiac failure, endovascular treatment was attempted as soon as stabilization was achieved. RESULTS: Endovascular procedures successfully reverted cardiac failure in 5 patients who survived without significant neurological damage, while in 7 patients the causes of death were refractory cardiac failure, multiorgan failure, and severe brain damage. Bidimensional echocardiography assessment was performed at presentation and after early embolization procedures. CONCLUSION: Aggressive intensive care approach to heart failure and pulmonary hypertension leading to early neurointervention results in good survival rates with low morbidity even in cases of high-risk neonatal VGAM. Combined hemodynamic treatment can improve outcome in neonates with cardiac failure secondary to VGAM, although there is the risk of precipitating systemic hypoperfusion and renal failure. A moderate prematurity may not prevent both interventional approach and good outcome.

Autoimmunity and autoinflammation as the yin and yang of idiopathic recurrent acute pericarditis.

Autoimmunity and autoinflammation are generally considered as mutually exclusive mechanisms of diseases but may concur to specific syndromes. Idiopathic recurrent acute pericarditis (IRAP) is defined as the recurrence of pericardial symptoms at any point following the prior cessation of acute pericarditis, and the latency is generally 6 weeks. Manifestations of pericarditis such as pericardial friction rub, electrocardiographic changes, and pericardial effusion are less frequent in the subsequent episodes compared to the index attack, and in some cases the only clinical sign is represented by a suggestive chest pain. Several autoimmune diseases may manifest with pericarditis which is often related to viral infections, while postviral pericarditis may in turn display a nonspecific autoimmune background. Similarly, autoinflammatory syndromes such as familial Mediterranean fever and tumor necrosis factor receptor-associated periodic syndrome are characterized by self-limiting pericardial symptoms. Corticosteroids are generally effective, thus supporting the autoimmune nature of IRAP, but dramatic results are obtained with interleukin-1 blocking agents in corticosteroid-dependent cases, pointing to a pathogenic role for the inflammasome. Based on these observations, we submit that IRAP represents a paradigmatic example of the putative coexistence of autoimmunity and autoinflammation: the main aim of this review is to critically discuss the hypothesis as well as the current understanding of this enigmatic clinical condition.

Correlation analysis between echocardiographic flow pattern and N-terminal-pro-brain natriuretic peptide for early targeted treatment of patent ductus arteriosus.

OBJECTIVE: Echocardiographic flow patterns of patent ductus arteriosus (PDA) are useful to predict the development of hemodynamically significant ductus in premature infants. N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations seem to be useful to detect PDA. We investigated how NT-proBNP levels change on the basis of different flow patterns during the first day of life, and whether NT-proBNP might represent a reliable decision tool in PDA management. METHODS: Neonates with gestational age <32 weeks were assessed prospectively, using paired Doppler-echocardiographic evaluation and NT-proBNP values, at T0 (6-24 h of life), and daily until ductal closure. RESULTS: At T0, NT-proBNP concentrations of 41 neonates correlated to the kind of pattern (p = 0.018) with the highest values in neonates with pulsatile or growing patterns. A value <9854 pg/ml identified neonates with spontaneous closure (sensitivity 71.8%, specificity 100%). Overall, 32 infants needed treatment. Pre-treatment NT-proBNP values increased compared to those at T0, significantly in neonates with growing pattern at T0 (p = 0.001). After treatment, NT-proBNP concentrations decreased compared to pre-treatment values (p = 0.0024), more markedly in the responders than in the non-responders (p = 0.042). CONCLUSIONS: NT-proBNP concentrations at T0 show a good agreement with different flow patterns and represent a useful tool to identify neonates at risk of developing hemodynamically significant PDA.

Myocardial performance index and biochemical markers for early detection of doxorubicin-induced cardiotoxicity in children with acute lymphoblastic leukaemia.

BACKGROUND: Despite significant improvements in the prognosis of childhood acute lymphoblastic leukaemia (ALL), the risk of anthracycline-induced cardiovascular disease remains a major concern. This study was designed to investigate the role of the myocardial performance index (MPI) and serum concentrations of biomarkers (cTnT and NT-pro-BNP) in the early detection of subclinical anthracycline-induced functional alterations in children with ALL. METHODS: All children consecutively admitted to our Pediatric Oncologic Department from January 2009 to October 2010 with a diagnosis of ALL were enrolled in this study. cTnT and NT-pro-BNP were evaluated in all patients at diagnosis, before doxorubicin therapy and 2 and 24 h following each anthracycline administration. ECG and echocardiography were performed at diagnosis and 24 h after each anthracycline course. RESULTS: Nineteen children with standard-risk ALL were evaluated. The mean age was 6 years. The cumulative doxorubicin dosage was 240 mg/m(2) according to the AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) ALL 2000 protocol. None of the 19 patients developed congestive heart failure. With increasing cumulative dosages of anthracyclines a significant increase was observed in MPI. This increase was statistically significant starting from the cumulative dosage of 120 mg/m(2) compared to baseline, while the median NT-pro-BNP level did not change significantly during treatment and cTnT levels never exceeded the cut-off value for cardiac injury. CONCLUSION: MPI value is a sensitive and accurate parameter, allowing subclinical cardiac dysfunction to be detected in children receiving anthracyclines. Lifelong cardiac surveillance of these patients is warranted in order to determine the clinical implications of increased MPI on long-term cardiac status.