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.

Smith Magenis syndrome: First case of congenital heart defect in a patient with Rai1 mutation.

Smith Magenis syndrome (SMS) is a rare neurobehavioral disorder caused by 17p11.2 microdeletion encompassing Retinoic Acid-Induced 1 (RAI1) gene (90% of cases) or by RAI1 point mutation (10% of cases). The neuropsychological phenotype of individuals with 17p11.2 deletion and in those with RAI1 variants mostly overlaps. However, cardiac defects have been described only in patients with a deletion so far. Here, we present the first case of a patient affected by SMS caused by RAI1 variant in whom a severe congenital pulmonary valve stenosis was diagnosed at birth, requiring trans catheter dilatation in the first month of life. This case expands the phenotypic spectrum associated with RAI1 variants in SMS, describing a previously unreported association with a congenital heart disease.

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.

Pulmonary artery sling in a 22-month-old boy with 18q deletion syndrome: A rare but possible association.

The 18q deletion syndrome is a rare genetic condition characterized by a large variability in clinical phenotype and severity. Congenital heart diseases have been described by several previous reports, most commonly including pulmonary valve anomalies and septal defects. We describe a new case of a 22-month-old boy affected by 18q del syndrome found to have a symptomatic pulmonary artery sling. This study reports a new case of pulmonary artery sling associated with 18q del syndrome, providing an alert for pediatric cardiologists about less common cardiovascular anomalies, which can easily be missed, allowing for early diagnosis and appropriate care.

COVID-19-Associated Multisystem Inflammatory Syndrome in a Neonate with Atypical Coronary Artery Involvement.

OBJECTIVE: The study aimed to report a novel coronavirus disease 2019 (COVID-19)-associated multisystem inflammatory syndrome in children (MIS-C) in a neonate found to have an atypical diffuse thickening in coronary artery walls whose diagnosis required a multi-imaging approach. STUDY DESIGN: A neonate presented at birth with multiple organ involvement and coronary artery anomalies. A diagnosis of MIS-C associated with COVID-19 was supported by maternal severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection during pregnancy, and by the presence of both immunoglobulin (Ig)-G against SARS-CoV-2 and spike-specific memory B-cells response in the neonatal blood. Other plausible causes of the multiple organ involvement were excluded. RESULT: At admission, a severe coronary artery dilatation was identified on echocardiography, supporting the diagnosis of the MIS-C Kawasaki-like disease; however, coronary artery internal diameters were found to be normal using cardiac computed tomography angiography. At discharge, comparing the two imaging techniques each other, the correct diagnosis resulted to be an abnormal thickening in coronary arterial walls. These findings suggest that the inflammatory process affecting the coronary arterial wall in MIS-C could result not only in typical coronary artery lesions such as dilatation of the lumen or aneurysms development but also in abnormal thickening of the coronary artery wall. CONCLUSION: Our case provides an alert for pediatric cardiologists about the complexity to assess coronary artery involvement in MIS-C and raises the question that whether an abnormal vascular remodeling, with normal inner diameters, is to be considered like coronary artery dilatation for risk stratification. KEY POINTS: · COVID-19 associated MIS-C can present in neonates with multiple organ involvement.. · Coronary artery assessment in neonatal MIS-C could be complex, and a multi-imaging approach could be required.. · Beside the typical coronary artery lesions, such as dilatation of the lumen or aneurysms, also abnormal thickening of the coronary artery wall can occur..

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.

Cardiac function in types II and III spinal muscular atrophy: should we change standards of care?

OBJECTIVE: In the last years, there has been increasing evidence of cardiac involvement in spinal muscular atrophy (SMA). Autonomic dysfunction has been reported in animal models and in several patients with types I and III SMA, these findings raising the question whether heart rate should be routinely investigated in all SMA patients. The aim of our study was to detect possible signs of autonomic dysfunction and, more generally, of cardiac involvement in types II and III SMA. PATIENTS AND METHODS: We retrospectively reviewed 24-hour electrocardiography (ECG) in 157 types II and III SMA patients (age range, 2-74 years). Of them, 82 also had echocardiography. RESULTS: None of the patients had signs of bradycardia, atrial fibrillation, or the other previously reported rhythm disturbances regardless of the age at examination or the type of SMA. Echocardiography was also normal. There were no signs of congenital cardiac defects with the exception of one patient with a history of ventricular septal defects. CONCLUSIONS: Our results suggest that cardiac abnormalities are not common in type II and type III SMA. These findings provide no evidence to support a more accurate cardiac surveillance or changes in the existing standards of care.

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.

Insights into the Cardiac Phenotype in 9p Deletion Syndrome: A Multicenter Italian Experience and Literature Review.

Chromosome 9p deletion syndrome is a rare autosomal dominant disorder presenting with a broad spectrum of clinical features, including congenital heart defects (CHDs). To date, studies focused on a deep characterization of cardiac phenotype and function associated with this condition are lacking. We conducted a multicentric prospective observational study on a cohort of 10 patients with a molecular diagnosis of 9p deletion syndrome, providing a complete cardiological assessment through conventional echocardiography and tissue Doppler imaging echo modality. As a result, we were able to demonstrate that patients with 9p deletion syndrome without major CHDs may display subclinical cardiac structural changes and left-ventricle systolic and diastolic dysfunction. Albeit needing validation in a larger cohort, our findings support the idea that a complete cardiac assessment should be performed in patients with 9p deletion syndrome and should be integrated in the context of a long-term follow-up.

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.

Platelet reactivity and endothelial function in children of patients with early acute myocardial infarction.

AIMS: To assess whether platelet reactivity is increased in offspring of patients with early acute myocardial infarction (AMI) and its possible relation with endothelial dysfunction. METHODS AND RESULTS: We studied 23 healthy children (15±3 years, 13 males) of patients with early AMI (≤50 years old; Group 1) and 21 healthy children of healthy subjects without any history of cardiovascular disease (14±3 years, 10 males; Group 2). Platelet reactivity was assessed by flow cytometry as the increase in monocyte-platelet aggregates (MPA) and CD41 and PAC-1 platelet expression in response to exercise stress test (EST), adenosine diphosphate (ADP) stimulation (10(-7) M), or both. Endothelial function was assessed by measuring brachial artery dilation during post-ischaemic forearm hyperaemia [flow-mediated dilation (FMD)]. Both EST and ADP induced a higher percentage increase in platelet receptor expression in Group 1, compared with Group 2, with the most significant difference being shown for the response to the combined stimuli (e.g. MPA, 23.1±12 vs. 5.63±8%, P<0.001; platelet PAC-1, 57.7±47 vs. 13.2±7%, P<0.001). Compared with Group 2, Group 1 children showed lower FMD (10.7±3.1 vs. 8.0±2.9%, respectively; P=0.007). However, no significant association was found between FMD and platelet reactivity. CONCLUSION: Our results show increased platelet reactivity in children of patients with early AMI; the finding was not significantly correlated with endothelial dysfunction, suggesting that other mechanisms are mainly involved in the enhanced platelet response to agonistic stimuli.

Right ventricle-pulmonary artery coupling in repaired tetralogy of Fallot with pulmonary regurgitation: Clinical implications.

BACKGROUND: Right ventricle-pulmonary artery (RV-PA) coupling is a strong prognostic marker in several clinical settings, but few studies have focused on its role in repaired tetralogy of Fallot (rToF) with pulmonary regurgitation. AIM: To assess whether differences exist in RV-PA coupling, estimated by echocardiography, between patients with rToF and pulmonary regurgitation with or without an indication for pulmonary valve replacement (PVR). METHODS: The study population included 40 patients with rToF, who were allocated to two groups: 20 with an indication for PVR (i-PVR group); and 20 without an indication for PVR (ni-PVR group). Forty healthy controls were also included. All subjects underwent echocardiography, and cardiac magnetic resonance (CMR) was available in 27/40 patients with rToF. RV-PA coupling was assessed by echocardiographic tricuspid annular plane systolic excursion/pulmonary arterial systolic pressure (TAPSE/PASP) and right ventricular stroke volume/right ventricular end-systolic volume (RVSV/RVESV) by CMR. RESULTS: TAPSE was similar in the i-PVR and ni-PVR groups (19.0±3.4 vs 18.8±2.7mm; P=0.97) whereas RV-PA coupling was significantly worse in the i-PVR group versus the ni-PVR group (TAPSE/PASP 0.8±0.3 vs 1.1±0.5mm/mmHg; P=0.001), and in the i-PVR group versus the control group (P=0.02); there was no difference between the ni-PVR and control groups (P=0.29). CMR data confirmed the echocardiography results, with a significant difference in RV-PA coupling between the i-PVR and ni-PVR groups (RVSV/RVESV 0.9±0.2 vs 1.2±0.3mL/min/mL; P=0.01). CONCLUSIONS: This study demonstrates worse RV-PA coupling, despite normal RV systolic function, in patients with rToF with an indication for PVR. RV-PA coupling could be a sensitive marker of a progressive maladaptive RV response to long-standing volume overload in rToF before the onset of clinical symptoms and RV systolic dysfunction.

Impact of severe valvular heart disease in adult congenital heart disease patients.

Background: The clinical impact of valvular heart disease (VHD) in adult congenital heart disease (ACHD) patients is unascertained. Aim of our study was to assess the prevalence and clinical impact of severe VHD (S-VHD) in a real-world contemporary cohort of ACHD patients. Materials and methods: Consecutive patients followed-up at our ACHD Outpatient Clinic from September 2014 to February 2021 were enrolled. Clinical characteristics and echocardiographic data were prospectively entered into a digitalized medical records database. VHD at the first evaluation was assessed and graded according to VHD guidelines. Clinical data at follow-up were collected. The study endpoint was the occurrence of cardiac mortality and/or unplanned cardiac hospitalization during follow-up. Results: A total of 390 patients (median age 34 years, 49% males) were included and S-VHD was present in 101 (25.9%) patients. Over a median follow-up time of 26 months (IQR: 12-48), the study composite endpoint occurred in 76 patients (19.5%). The cumulative endpoint-free survival was significantly lower in patients with S-VHD vs. patients with non-severe VHD (Log rank p < 0.001). At multivariable analysis, age and atrial fibrillation at first visit (p = 0.029 and p = 0.006 respectively), lower %Sat O2, higher NYHA class (p = 0.005 for both), lower LVEF (p = 0.008), and S-VHD (p = 0.015) were independently associated to the study endpoint. The likelihood ratio test demonstrated that S-VHD added significant prognostic value (p = 0.017) to a multivariate model including age, severe CHD, atrial fibrillation, %Sat O2, NYHA, LVEF, and right ventricle systolic pressure > 45 mmHg. Conclusion: In ACHD patients, the presence of S-VHD is independently associated with the occurrence of cardiovascular mortality and hospitalization. The prognostic value of S-VHD is incremental above other established prognostic markers.

Heart rate variability alterations in Dravet Syndrome: The role of status epilepticus and a possible association with mortality risk.

PURPOSE: Preliminary data suggest that patients with Dravet Syndrome (DS) have a reduced heart rate variability (HRV). This seems particularly evident in patients who experienced sudden unexpected death in epilepsy (SUDEP). This study aims at confirming these findings in a larger cohort and at defining clinical, genetic or electroencephalographic predictors of HRV impairment in DS patients. METHODS: DS patients followed at our Institution performed a 24h-ECG Holter to derive HRV parameters. We used as control population patients with epilepsy (PWEs) and healthy controls (HCs). In DS patients, we assessed the impact of different clinical, neurophysiological and genetic features on HRV alterations through multiple linear regression. After a mean follow-up of 7.4 ± 3.2 years since the HRV assessment, all DS patients were contacted to record death or life-threatening events. RESULTS: 56 DS patients had a significantly reduced HRV compared to both HCs and PWEs. A recent history of status epilepticus (SE) was the only significant predictor of lower HRV in the multivariate analysis. At follow-up, only one patient died; her HRV was lower than that of all the controls and was in the low range for DS patients. CONCLUSION: We describe for the first time an association between SE and HRV alterations in DS. Further studies on other SCN1A-related phenotypes and other epilepsies with frequent SE will help clarify this finding. Compared to the literature, our cohort showed better HRV and lower mortality. Although limited, this observation reinforces the role of HRV as a biomarker for mortality risk in DS.

Electrical and autonomic cardiac function in patients with Dravet syndrome.

Dravet syndrome (DS) is an epileptic encephalopathy related mainly to mutations in the SCN1A gene, encoding for neuronal sodium channels. Patients with DS have a high risk of sudden unexpected death in epilepsy (SUDEP). In this study we investigated whether patients with DS present abnormalities in electrical and autonomic cardiac function. To this aim we assessed ventricular repolarization and heart rate variability (HRV) on standard electrocardiography (ECG) and on 24-h ECG Holter monitoring, respectively, in 20 patients affected by DS (6.8 ± 4 years, 11 female). As age- and sex-matched control groups, we also studied 20 patients with other epileptic syndromes receiving antiepileptic drugs (ES/AED, 6.0 ± 5 years, 12 female), 20 patients with other epileptic syndromes without treatment (ES/no-AED, 6.7 ± 4 years, 10 female), and 20 healthy children (HC, 7.2 ± 5 years, 11 females). Data analysis showed that patients with DS had depressed HRV variables compared to both ES patients (ES/AED and ES/no-AED) and HC control group, whereas no significant differences in HRV variables were found between ES patients (with and without treatment) and HC. There was no significant difference between patients with DS and all the other control groups in RR intervals, QT, and QTc interval analysis. In conclusion, DS patients display an imbalance of cardiac autonomic function toward a relative predominance of adrenergic tone compared to both healthy children and patients with other forms of epilepsy, independent of antiepileptic therapy. Follow-up studies should clarify the clinical significance of this autonomic impairment and whether HRV analysis can be helpful in predicting the risk of sudden death in patients with DS.

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.