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.

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.

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.

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.

Hypovitaminosis D and Leukocytosis to Predict Cardiovascular Abnormalities in Children with Kawasaki Disease: Insights from a Single-Center Retrospective Observational Cohort Study.

Introduction: An aberrant immune response involving yet unidentified environmental and genetic factors plays a crucial role in triggering Kawasaki disease (KD). Aims: The aim of this study was to assess general and laboratory data at the onset of KD in a single-center cohort of children managed between 2003 and 2023 and retrospectively evaluate any potential relationship with the development of KD-related cardiovascular abnormalities (CVAs). Patients and methods: We took into account a total of 65 consecutive children with KD (42 males, median age: 22 months, age range: 2-88 months) followed at the Department of Life Sciences and Public Health in our University; demographic data, clinical signs, and laboratory variables at disease onset, before IVIG infusion, including C-reactive protein, hemoglobin, white blood cell (WBC) count, neutrophil count, platelet count, aminotransferases, natremia, albumin, total bilirubin, and 25-hydroxyvitamin D were evaluated. Results: Twenty-one children (32.3% of the whole cohort) were found to have echocardiographic evidence of CVAs. Univariate analysis showed that diagnosis of KD at <1 year or >5 years was associated with CVAs (p = 0.001 and p = 0.01, respectively); patients with CVAs had a longer fever duration and mostly presented atypical or incomplete presentations. Interestingly, all patients with CVAs had lower levels of vitamin D (less than 30 mg/dL, p = 0.0001) and both higher WBC and higher neutrophil counts than those without CVAs (p = 0.0001 and p = 0.01, respectively). Moreover, blood levels of albumin were significantly lower in KD patients with CVAs compared to those without (11/21, 52% versus 13/44, 30%, p = 0.02). Multiple logistic regression with correction for sex showed that serum vitamin D < 30 ng/mL, WBC count > 20.000/mm3, and age > 60 months at KD onset were the only independent factors statistically associated with CVAs. Conclusions: Hypovitaminosis D, WBC count over 20.000/mm3, and age above 5 years at KD onset emerged as independent factors statistically associated with the occurrence of CVAs.

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.

Delayed diagnosis of Kawasaki syndrome and thrombosis of a medium-sized aneurysm of the anterior descending coronary artery: case report and literature review.

A 7-year-old child was first admitted for persistent fever of 15-day duration and suspected meningitis. Kawasaki syndrome was lately diagnosed upon the recognition of an extensive diffuse coronary artery damage characterized by medium-sized aneurysms of the epicardial vessels. An eccentric thrombus along the inferior wall of the left anterior descending artery suspected at transthoracic echocardiography was confirmed by coronary computed tomography angiography scan, without significant segmental stenosis. Strict cardiac surveillance and anticoagulant therapy were maintained, and no ischemic complications occurred at a short-term follow-up. This report emphasizes that thrombosis can be observed even in medium-sized aneurysms when the diagnosis of Kawasaki syndrome is delayed.

Kawasaki syndrome and concurrent Coxsackie virus B3 infection.

We describe two previously healthy children who were hospitalized in the same period in different departments of our University with clinical signs of Kawasaki syndrome, which were treated with intravenous immunoglobulins and acetylsalicylic acid: in both cases, Coxsackie virus infection was concurrently demonstrated by enzyme-linked immunosorbent assay, and complement fixation test identified antibodies to serotype B3. In the acute phase, both patients presented hyperechogenic coronary arteries, but no cardiologic sequels in the mid term. The etiological relationship between Kawasaki syndrome and Coxsackie viruses is only hypothetical; however, the eventual identification of ad hoc environmental triggers is advisable in front of children with Kawasaki syndrome, with the aim of optimizing epidemiological surveillance and understanding the intimate biological events of this condition.

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.

Neurogenic stunned myocardium presenting as left ventricular hypertrabeculation in childhood: a variant of Takotsubo cardiomyopathy?

OBJECTIVE: To report the first case of neurogenic stunned myocardium presenting with heart left ventricle noncompaction requiring intensive care in the perioperative period of tension tumor-induced hydrocephalus. METHODS AND DESIGN: Case report and literature review. Our Institutional Review Board waived the need for consent. PATIENT: A 12-yr-old female with intracranial astrocytoma and hypertensive hydrocephalus presented with severe heart dysfunction and life-threatening ventricular ectopies intraoperatively. A severe heart failure developed requiring hemodynamic and ventilatory support for 10 days. Echocardiography showed a transient noncompaction aspect of the left ventricular wall, further confirmed by a cardiac magnetic resonance image. The noncompaction aspect lasted until 15 days postadmission, as was the case for the QT interval prolongation; no life-threatening ectopies were demonstrated on the subsequent Holter electrocardiogram monitoring. CONCLUSIONS: This report describes a unique presentation of myocardial stunning in association with an intracranial illness, namely, a hypertensive hydrocephalus complicating an intracranial neoplasm.

Tension chylothorax complicating acute malignant airway obstruction.

Acute upper airway obstruction represents one of the most challenging emergencies in pediatric practice. In particular, a tension chylothorax complicating a malignant airway obstruction is a rare and life-threatening complication. We report a rapidly progressing tension chylothorax associated with a cervical mass in a 10-month-old male infant. To our knowledge, the extension of a cervical mass to the supraclavear region resulting in a compressive chylothorax represents an exceptional event in pediatrics. Early recognition and prompt treatment resulted to be essential to relieve the compression and to avoid end-stage hemodynamic and respiratory function derangement.

Neonatal emergencies associated with cardiac rhabdomyomas: an 8-year experience.

During the foetal-neonatal period, rhabdomyomas represent the majority of cardiac tumours and are closely associated with tuberous sclerosis. Cardiac rhabdomyomas may be completely asymptomatic and are incidentally discovered during an echocardiogram, or may cause cardiac dysfunctions requiring medical and/or surgical intervention. During foetal life and the early neonatal period, life-threatening conditions, mostly due to arrhythmias, cardiac failure or obstruction, do occur on rare occasions. We reviewed the medical records of all cases of cardiac rhabdomyomas diagnosed prenatally or postnatally over an 8-year period. The present study reviews 7 cases of life-threatening conditions. Arrhythmic episodes were described in 5 patients, and blood flow obstruction was reported in 2 cases. Antiarrhythmic agents successfully controlled the clinical and electrophysiological conditions. Obstructive conditions were associated with poor outcomes. In conclusion, when prenatal diagnosis of rhabdomyoma is made, appropriate planning at delivery for the management of potential haemodynamic complications may prevent adverse neonatal outcomes. The clinical outcome is more influenced by obstructive rather than by dysrhythmic complications. Appropriate antiarrhythmic treatment is of primary importance. In all cases discovered through prenatal and/or neonatal life-threatening conditions, an accurate follow-up should always be performed to anticipate the development of tuberous sclerosis.

Is the prophylaxis of patent ductus arteriosus useful in extremely premature infants?

This study was aimed to verify the efficacy and safety of ibuprofen prophylaxis of patent ductus arteriosus in very preterm infants, in order to select infants receiving higher benefits from this intervention. Two hundred neonates with gestational age (GA) < or = 28 weeks receiving ibuprofen within the first two hours of life were included. Ductus closure rate was 68%, and results were significantly dependent on GA (48.8% among neonates with GA < 26 weeks vs 73.2% among those with GA > or = 26 weeks, p < 0.01). Neonates with GA < 26 weeks showed a lower ductus closure after the primary course of therapy (20% vs 57.5%, p < 0.01), as well as higher reopening rate (16.2% vs 3.8%, p < 0.05) and need for surgical ligation (38.8% vs 5.8%, p < 0.01). During the prophylaxis period, 11 neonates (5.5%) showed pulmonary hypertension. Considering risks/benefits, we recommend prophylaxis only in infants with GA < 26 weeks.

Isolated pericardial agenesis revealed by bradycardia and heart MRI in a healthy 5-year-old child.

We present a five-year-old boy with an unremarkable medical history who was incidentally found to have bradycardia and electrocardiographic signs of right axial deviation. Initial echocardiogram showed left displacement of the cardiac apex with slight enlargement of the right ventricle, while frontal chest radiograph showed a lucent area between the aorta and pulmonary artery. Cardiac magnetic resonance imaging finally revealed a partial left pericardial agenesis and abnormal displacement of the heart into the left hemithorax.

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.