Congenital Heart Defects in Patients with Molecularly Confirmed Sotos Syndrome.

Sotos syndrome is an autosomal dominant condition characterized by overgrowth with advanced bone age, macrodolicocephaly, motor developmental delays and learning difficulties, and characteristic facial features caused by heterozygous pathogenetic variants in the NSD1 gene located on chromosome 5q35. The prevalence of heart defects (HDs) in individuals with Sotos syndrome is estimated to be around 15-40%. Septal defects and patent ductus arteriosus are the most commonly diagnosed malformations, but complex defects have also been reported. The aim of our study was to analyze the prevalence of HD, the anatomic types, and the genetic characteristics of 45 patients with Sotos syndrome carrying pathogenetic variants of NSD1 or a 5q35 deletion encompassing NSD1, who were followed at Bambino Gesù Children's Hospital in Rome. Thirty-nine of the forty-five patients (86.7%) had a mutation in NSD1, while six of the forty-five (13.3%) had a deletion. Most of the patients (62.2%, 28/45) were male, with a mean age of 14 ± 7 years (range 0.2-37 years). A total of 27/45 (60.0%) of the patients had heart defects, isolated or combined with other defects, including septal defects (12 patients), aortic anomalies (9 patients), mitral valve and/or tricuspid valve dysplasia/insufficiency (1 patient), patent ductus arteriosus (3 patients), left ventricular non-compaction/hypertrabeculated left ventricle (LV) (4 patients), aortic coarctation (1 patient), aortopulmonary window (1 patient), and pulmonary valve anomalies (3 patients). The prevalences of HD in the two subgroups (deletion versus intragenic mutation) were similar (66.7% (4/6) in the deletion group versus 58.91% (23/39) in the intragenic variant group). Our results showed a higher prevalence of HD in patients with Sotos syndrome in comparison to that described in the literature, with similar distributions of patients with mutated and deleted genes. An accurate and detailed echocardiogram should be performed in patients with Sotos syndrome at diagnosis, and a specific cardiological follow-up program is needed.

Is Osteogenesis Imperfecta Associated with Cardiovascular Abnormalities? A Systematic Review of the Literature.

Osteogenesis imperfecta (OI) is a rare genetic disorder caused by abnormal collagen type I production. While OI is primarily characterized by bone fragility and deformities, patients also have extraskeletal manifestations, including an increased risk of cardiovascular disease. This review provides a comprehensive overview of the literature on cardiovascular diseases in OI patients in order to raise awareness of this understudied clinical aspect of OI and support clinical guidelines. In accordance with the PRISMA guidelines, a systematic literature search in PubMed, Embase, Web of Science and Scopus was conducted that included articles from the inception of these databases to April 2023. Valvular disease, heart failure, atrial fibrillation, and hypertension appear to be more prevalent in OI than in control individuals. Moreover, a larger aortic root was observed in OI compared to controls. Various cardiovascular diseases appear to be more prevalent in OI than in controls. These cardiovascular abnormalities are observed in all types of OI and at all ages, including young children. As there are insufficient longitudinal studies, it is unknown whether these abnormalities are progressive in nature in OI patients. Based on these findings, we would recommend referring individuals with OI to a cardiologist with a low-threshold.

Gender differences in congenital heart defects: a narrative review.

Background and Objective: Congenital heart defects (CHD) represent the most frequent human birth defects, occurring in almost 1% of all live newborns. Understanding the effects of gender in the prevalence of CHD has a key role in defining personalized prevention, disease identification, prognosis definition and individualized therapeutic strategies. Recently, the attempt to achieve a holistic approach to patients with CHD cannot be separated from accounting for existing gender differences. The main aim of this narrative review is to provide an overview of gender differences in the epidemiology of CHD. Methods: A standardized research through three electronic databases (PubMed/Scopus/Embase) was performed using a combination of keywords and Medical Subject Headings (MeSH) terms to include congenital heart diseases, gender difference(s), prevalence. Observational, prospective, population based and retrospective studies reporting gender differences in the prevalence of CHD were included. Conference abstracts were excluded as well as studies not written in English language and non-human studies. Further relevant papers were selected by hand-searching of the references list of selected articles. Key Content and Findings: Search results returned 1,904 papers. Screening articles by title and abstracts resulted in 17 articles for full text review. Of these, 10 were included for analysis and additional 11 articles were included after hand searching review of reference lists. A total of 21 articles were included. Conclusions: Our narrative review confirms that there is a significant gender variation in specific CHD subgroups. In particular, we summarized the evidence that there is a significantly greater risk for males to be born with severe CHD and for females with milder CHD subtypes. The etiology of the different distribution of CHD among genders is still under investigation and a deeper understanding of how gender influences the risk for CHD is warranted. In the future, a gender-based management of CHD should become an established medical approach.

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.

COVID-19 Severity, Cardiological Outcome, and Immunogenicity of mRNA Vaccine on Adult Patients With 22q11.2 DS.

BACKGROUND: The contemporaneous presence of immune defects and heart diseases in patients with 22q11.2 deletion syndrome (22q11.3DS) might represent risk factors for severe coronavirus 2019 disease (COVID-19). OBJECTIVE: To analyze severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outcome in 22q11.2DS patients and immunogenicity of different doses of mRNA SARS-CoV-2 vaccine. METHODS: Longitudinal observational study on SARS-CoV-2 outcome in 60 adults with 22q11.2DS (March 2020-June 2022). Anti-Spike, and anti-receptor binding domain (RBD) antibody responses, generation of Spike-specific memory B cells (MBCs) and Spike-specific T cells at different time points before and after the mRNA BNT162b2 vaccination were evaluated in 16 22q11.2DS patients. RESULTS: We recorded a 95% rate of vaccination, with almost all patients being immunized with the booster dose. Twenty-one patients had SARS-CoV-2 infection. Three patients were infected before vaccine availability, 6 after receiving 2 doses of vaccine, and 12 after one booster dose. The SARS-CoV-2- infection had a mild course, except in one unvaccinated patient with several comorbidities who died from acute respiratory distress syndrome (fatality rate 5%). Infected patients had more frequently moderate/severe intellectual disability, lymphopenia, and lower CD4+ count. Despite major congenital heart diseases, COVID-19 did not impact cardiological conditions. The BNT162b2 vaccine induced S1-immunoglobulin G (IgG) responses, low serum S1-IgA, and slightly impaired specific MBCs response. Specific T-cell responses observed were related to lymphocytes and CD4+ T cell counts. CONCLUSIONS: The SARS-CoV-2 infection had a mild course in most patients with 22q11.2DS, even in patients with major cardiovascular diseases. Immunization induced Spike-specific IgG responses and generated specific MBCs and memory T cells. The weaker memory responses in patients with lymphopenia suggested the need for additional doses.

Cardiac function in adolescents and young adults with 22q11.2 deletion syndrome without congenital heart disease.

BACKGROUND: Diagnosis and treatment of 22q11.2 deletion syndrome (22q11.2DS) have led to improved life expectancy and achievement of adulthood. Limited data on long-term outcomes reported an increased risk of premature death for cardiovascular causes, even without congenital heart disease (CHD). The aim of this study was to assess the cardiac function in adolescents and young adults with 22q11.2DS without CHDs. METHODS: A total of 32 patients (20M, 12F; mean age 26.00 ± 8.08 years) and a healthy control group underwent transthoracic echocardiography, including Tissue Doppler Imaging (TDI) and 2-dimensional Speckle Tracking Echocardiography (2D-STE). RESULTS: Compared to controls, 22q11.2DS patients showed a significant increase of the left ventricle (LV) diastolic and systolic diameters (p = 0.029 and p = 0.035 respectively), interventricular septum thickness (p = 0.005), LV mass index (p < 0.001) and aortic root size (p < 0.001). 2D-STE analysis revealed a significant reduction of LV global longitudinal strain (p < 0.001) in 22q11.2DS than controls. Moreover, several LV diastolic parameters were significantly different between groups. CONCLUSIONS: Our results suggest that an echocardiographic follow-up in 22q11.2DS patients without CHDs can help to identify subclinical impairment of the LV and evaluate a potential progression of aortic root dilation over time, improving outcomes, reducing long-term complications and allowing for a better prognosis.

Clinical Risk Factors for Aortic Root Dilation in Patients with 22q11.2 Deletion Syndrome: A Longitudinal Single-Center Study.

BACKGROUND: Aortic root dilation (ARD) has been described in 22q11.2DS, even without congenital heart disease (CHD). However, the clinical implications and longitudinal course are unclear. In this study, we evaluated aortic root (AR) dimensions in 22q112.DS adolescents/adults without major intracardiac CHDs, analyzed the progression over time and investigated correlations with extracardiac comorbidities. METHODS: AR dimensions were evaluated in 74 patients, measuring the sinus of Valsalva (VS) and proximal ascending aorta (AA), using Z-score to define mild, moderate and severe degrees. Changes in AR dimensions during longitudinal echocardiographic follow-up were investigated. Phenotypic characteristics have been collected. RESULTS: Twenty-four patients (32.4%) showed ARD in terms of VS Z-score (2.43; IQR 2.08-3.01), eight (33.3%) of a moderate/severe degree. Thirteen (54.2%) had concomitant AAD (Z-score 2.34; IQR 1.60-2.85). The risk of ARD was significantly directly related to skeletal/connective tissue disorders (OR 12.82, 95% CI 1.43-115.31; p = 0.023) and inversely related to BMI (OR 0.86, 95% CI 0.77-0.97; p = 0.011). A significant increase in AR diameter's absolute value (p = 0.001) over time has been detected. CONCLUSION: Isolated ARD is common in 22q11.2DS. Although some clinical risk factors have been identified, pathogenetic mechanisms and risk of complications are undefined. Regular cardiac evaluations should be part of the 22q11.2DS follow-up, and also in non-CHDs patients, to improve long-term outcome.

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.

22q11.2 Deletion Syndrome: Impact of Genetics in the Treatment of Conotruncal Heart Defects.

Congenital heart diseases represent one of the hallmarks of 22q11.2 deletion syndrome. In particular, conotruncal heart defects are the most frequent cardiac malformations and are often associated with other specific additional cardiovascular anomalies. These findings, together with extracardiac manifestations, may affect perioperative management and influence clinical and surgical outcome. Over the past decades, advances in genetic and clinical diagnosis and surgical treatment have led to increased survival of these patients and to progressive improvements in postoperative outcome. Several studies have investigated long-term follow-up and results of cardiac surgery in this syndrome. The aim of our review is to examine the current literature data regarding cardiac outcome and surgical prognosis of patients with 22q11.2 deletion syndrome. We thoroughly evaluate the most frequent conotruncal heart defects associated with this syndrome, such as tetralogy of Fallot, pulmonary atresia with major aortopulmonary collateral arteries, aortic arch interruption, and truncus arteriosus, highlighting the impact of genetic aspects, comorbidities, and anatomical features on cardiac surgical treatment.

Crossed pulmonary arteries: An underestimated cardiovascular variant with a strong association with genetic syndromes-A report of 74 cases with systematic review of the literature.

Crossed pulmonary arteries (CPAs) represent an uncommon anatomic variant, usually associated with some specific syndromes and conotruncal defects. This finding has been described in 22q11.2 Deletion Syndrome (22q11.2DS). We evaluated the correlation between CPAs and genetic diseases, in order to better define the characteristics of this variant, considered a rare anatomic pattern. An in-depth analysis of CPAs genotype-phenotype correlations was performed via a literature review. We detected 74 CPAs patients through echocardiography. Of these 74 patients, 35.1% of patients showed additional intracardiac malformations, while 29.7% showed extracardiac vascular anomalies, of which 16.2% were associated with intracardiac defects and 13.5% were not. In all, 62.2% of patients were diagnosed with genetic diseases and 52.2% of them were 22q11.2DS patients. In conclusions, CPAs represent a cardiovascular variant, which is detectable in nonsyndromic individuals, but especially in various genetic syndromes and in particular in 22q11.2DS patients. Data on the real prevalence of this morphology is lacking in literature. Knowledge of this anatomic variant is useful to interpret the unusual course of the pulmonary branches and is helpful information before cardiovascular surgical correction. Moreover, due to the strong association of CPAs with some genetic syndromes, the identification of this anatomic pattern can indicate the utility of a genetic assessment of these patients.

Hybrid Single-Stage Repair of Kommerell's Diverticulum in a Right Aortic Arch in a Patient With 22q11.2 Deletion Syndrome.

Hybrid single-stage repair of Kommerell's diverticulum in a right aortic arch.Aortic arch anomalies, isolated or associated with congenital heart defects, are cardiovascular manifestations frequently associated with 22q11.2 deletion syndrome. Kommerell's diverticulum in the context of a right aortic arch is an exceedingly rare congenital anomaly, consisting in aneurysmal degeneration of the origin of an aberrant left subclavian artery. Open surgical repair has been the treatment paradigm, but in recent years, hybrid and endovascular procedures have also been proposed. In this report we present the case of a patient affected by 22q11.2 deletion syndrome successfully treated for Kommerell's diverticulum associated with a right-sided aortic arch through a single-stage hybrid procedure, consisting of bilateral carotid-subclavian bypass, exclusion of the diverticulum by an endovascular thoracic stent graft, and aberrant left subclavian artery plug occlusion. This type of hybrid technique can be an excellent alternative to extensive open surgical repairs or when total endovascular repair is deemed unachievable, also in the context of a complex genetic syndrome.

Congenital heart defects in molecularly confirmed KBG syndrome patients.

Congenital heart defects (CHDs) are known to occur in 9%-25% of patients with KBG syndrome. In this study we analyzed the prevalence and anatomic types of CHDs in 46 personal patients with KBG syndrome, carrying pathogenetic variants in ANKRD11 or 16q24.3 deletion, and reviewed CHDs in patients with molecular diagnosis of KBG syndrome from the literature. CHD was diagnosed in 15/40 (38%) patients with ANKRD11 variant, and in one patient with 16q24.3 deletion. Left ventricular outflow tract obstructions have been diagnosed in 9/15 (60%), subaortic or muscular ventricular septal defect in 5/15 (33%), dextrocardia in 1/15 (8%). The single patient with 16q24.3 deletion and CHD had complete atrioventricular septal defect (AVSD) with aortic coarctation. Review of KBG patients from the literature and present series showed that septal defects have been diagnosed in 44% (27/61) of the cases, left ventricular tract obstructions in 31% (19/61), AVSD in 18% (11/61). Septal defects have been diagnosed in 78% of total patients with 16q24.3 deletion. Valvar anomalies are frequently diagnosed, prevalently involving the left side of the heart. A distinctive association with AVSD is identifiable and could represent a marker to suggest the diagnosis in younger patients. In conclusion, after precise molecular diagnosis and systematic cardiological screening the prevalence of CHD in KBG syndrome seems to be higher than previously reported in clinical articles. In addition to septal defects, left-sided anomalies and AVSD should be considered. Clinical management of KBG syndrome should include accurate and detailed echocardiogram at time of diagnosis.

Clinical Manifestations of 22q11.2 Deletion Syndrome.

DiGeorge syndrome (DGS), also known as "22q11.2 deletion syndrome" (22q11DS) (MIM # 192430 # 188400), is a genetic disorder caused by hemizygous microdeletion of the long arm of chromosome 22. In the last decades, the introduction of fluorescence in situ hybridization assays, and in selected cases the use of multiplex ligation-dependent probe amplification, has allowed the detection of chromosomal microdeletions that could not be previously identified using standard karyotype analysis. The aim of this review is to address cardiovascular and systemic involvement in children with DGS, provide genotype-phenotype correlations, and discuss their medical management and therapeutic options.

Impaction of regurgitation jet on anterior mitral leaflet is associated with diastolic dysfunction in patients with bicuspid aortic valve and mild insufficiency: a cardiovascular magnetic resonance study.

To assess the impact of regurgitant jet direction on left ventricular function and intraventricular hemodynamics in asymptomatic patients with bicuspid aortic valve (BAV) and mild aortic valve regurgitation (AR), using cardiac magnetic resonance (CMR) feature tracking and 4D flow imaging. Fifty BAV individuals were retrospectively selected: 15 with mild AR and posterior regurgitation jet (Group-PJ), 15 with regurgitant jet in other directions (Group-nPJ) and 20 with no regurgitation (Controls). CMR protocol included cine steady state free precession (SSFP) sequences and 4D Flow imaging covering the entire left ventricle (LV) cavity and the aortic root. Cine-SSFP images were analyzed to assess LV volumes, longitudinal and circumferential myocardial strain. Circumferential and longitudinal peak diastolic strain rate (PDSR) and peak diastolic velocity (PDV) were reduced in group PJ if compared to group nPJ and control group (PDSR = 1.10 ± 0.2 1/s vs. 1.34 ± 0.5 1/s vs. 1.53 ± 0.3 1/s, p:0.001 and 0.68 ± 0.2 1/s vs. 1.17 ± 0.2 1/s vs. 1.05 ± 0.4 1/s ; p < 0.001, PDV = - 101.6 ± 28.1 deg/s vs. - 201.4 ± 85.9 deg/s vs. - 221.6 ± 67.1 deg/s; p < 0.001 and - 28.1 ± 8 mm/s vs. - 38.9 ± 11.1 mm/s vs. - 43.6 ± 14.3 mm/s, p < 0.001, respectively), whereas no differences have been found in systolic strain values. 4D Flow images (available only in 9 patients) showed deformation of diastolic transmitral streamlines direction in group PJ compared to other groups. In BAV patients with mild AR, the posterior direction of the regurgitant jet may hamper the complete mitral valve opening, disturbing transmitral flow and slowing the LV diastolic filling.

Cardiac Defects and Genetic Syndromes: Old Uncertainties and New Insights.

Recent advances in understanding the genetic causes and anatomic subtypes of cardiac defects have revealed new links between genetic etiology, pathogenetic mechanisms and cardiac phenotypes. Although the same genetic background can result in different cardiac phenotypes, and similar phenotypes can be caused by different genetic causes, researchers' effort to identify specific genotype-phenotype correlations remains crucial. In this review, we report on recent advances in the cardiac pathogenesis of three genetic diseases: Down syndrome, del22q11.2 deletion syndrome and Ellis-Van Creveld syndrome. In these conditions, the frequent and specific association with congenital heart defects and the recent characterization of the underlying molecular events contributing to pathogenesis provide significant examples of genotype-phenotype correlations. Defining these correlations is expected to improve diagnosis and patient stratification, and it has relevant implications for patient management and potential therapeutic options.

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.

When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort.

PURPOSE: Recent studies have identified suggestive prenatal features of RASopathies (e.g., increased nuchal translucency [NT], cystic hygroma [CH], hydrops, effusions, congenital heart diseases [CHD], polyhydramnios, renal anomalies). Our objective is to clarify indications for RASopathy prenatal testing. We compare genotype distributions between pre- and postnatal populations and propose genotype-phenotype correlations. METHODS: Three hundred fifty-two chromosomal microarray-negative cases sent for prenatal RASopathy testing between 2012 and 2019 were collected. For most, 11 RASopathy genes were tested. Postnatal cohorts (25 patients with available prenatal information and 108 institutional database genotypes) and the NSeuroNet database were used for genotypic comparisons. RESULTS: The overall diagnostic yield was 14% (50/352), with rates >20% for effusions, hydrops, and CHD. Diagnostic yield was significantly improved in presence of hypertrophic cardiomyopathy (HCM), persistent or associated CH, any suggestive finding combined with renal anomaly or polyhydramnios, or ≥2 ultrasound findings. Largest prenatal contributors of pathogenic variants were PTPN11 (30%), RIT1 (16%), RAF1 (14%), and HRAS (12%), which considerably differ from their prevalence in postnatal populations. HRAS, LZTR1, and RAF1 variants correlated with hydrops/effusions, and RIT1 with prenatal onset HCM. CONCLUSION: After normal chromosomal microarray, RASopathies should be considered when any ultrasound finding of lymphatic dysplasia or suggestive CHD is found alone or in association.