ABSTRACT
Advancements in early diagnosis and paediatric cardiac surgery have improved the long-term survival of patients with congenital heart disease, necessitating a thorough assessment of their health-related quality of life (HRQoL). This study aimed to assess HRQoL in paediatric patients with coarctation of the aorta (CoA) (both as reported by patients and caregivers), and to evaluate associated factors. Patients aged 5-18 years diagnosed with CoA and their parents were enrolled at Bambino Gesù Children's Hospital between September 2016 and December 2017. Socio-demographic characteristics were recorded using a family form, and the Pediatric Quality of Life Inventory (PedsQL) 3.0 cardiac module was used to evaluate HRQoL. Clinical data were retrieved from medical chart reviews. In this observational study, sixty-five pediatric patients (39 males, median [IQR] age 12 [9-14]) with CoA and their parents (65 mothers and 65 fathers) were enrolled. These patients exhibited overall good HRQoL. Mothers reported significantly lower total HRQoL scores compared to patient self-reports (p = .037), as well as treatment anxiety (p = .033), and cognitive problems (p = .021). Pediatric patients with CoA perceived their HRQoL better than their mothers did. Female sex and older age were associated with lower HRQoL scores.
ABSTRACT
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.
Subject(s)
Heart Defects, Congenital , Intellectual Disability , Neurodevelopmental Disorders , Humans , Child , beta Catenin/genetics , Heart Defects, Congenital/diagnosis , Syndrome , Intellectual Disability/geneticsABSTRACT
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.
Subject(s)
Ectodermal Dysplasia , Heart Defects, Congenital , Noonan Syndrome , Humans , Noonan Syndrome/genetics , Noonan Syndrome/diagnosis , Heart Defects, Congenital/genetics , Heart Defects, Congenital/diagnosis , Failure to Thrive/genetics , Failure to Thrive/diagnosis , ras Proteins/genetics , Ectodermal Dysplasia/genetics , MutationABSTRACT
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.
Subject(s)
DiGeorge Syndrome , Heart Defects, Congenital , Chromosome Deletion , Chromosomes, Human, Pair 22 , DiGeorge Syndrome/diagnosis , DiGeorge Syndrome/genetics , Heart Defects, Congenital/diagnosis , Humans , Lung , Pulmonary Artery/diagnostic imagingABSTRACT
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.
Subject(s)
Abnormalities, Multiple , Bone Diseases, Developmental , Heart Defects, Congenital , Intellectual Disability , Tooth Abnormalities , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/epidemiology , Abnormalities, Multiple/genetics , Bone Diseases, Developmental/genetics , Chromosome Deletion , Facies , Heart Defects, Congenital/diagnosis , Heart Defects, Congenital/genetics , Heart Septal Defects , Humans , Intellectual Disability/genetics , Tooth Abnormalities/genetics , Transcription FactorsABSTRACT
BACKGROUND: Congenital heart disease (CHD) is the most common congenital anomaly at birth, affecting approximately 1% of live births. In recent decades great medical and surgical advances have significantly increased life expectancy, shifting healthcare professionals' and researchers' interests in patients' Quality of Life (QoL). The main aims of our study were to evaluate generic and condition-specific QoL in a group of Italian children and adolescents with CHD and their parents and examine the level of agreement and directional disagreement between child/adolescent and parents reports on generic and condition-specific QoL. METHODS: A cross-sectional study was designed with CHD children and adolescents and their parents referred to the Cardiology Department of "Bambino Gesù" Children's Hospital. The PedsQL scale was used, including generic (PedsQL 4.0) and cardiac-specific modules (PedsQL 3.0) were administered to patients and caregivers. A Kruskal-Wallis test was used to compare generic and cardiac module scores between patients with different ages, CHD diagnoses, and between patients who underwent surgery interventions and/or are currently taking cardiac medications. RESULTS: 498 families were enrolled in this study. On average, patients reported a good level of generic and condition-specific QoL, as well as their mothers and fathers. Children aged between 5-7 years old reported lower generic and cardiac-specific total QoL levels than children aged 8-12 years and adolescents (13-18 years). With regard to the agreement, patient-parent agreement on condition-specific QoL ranged from 25 to 75% while on generic QoL, it ranged from 19 to 76%. The highest percentage of disagreement between parents and children was found in patients aged 5-7 years old, both for condition-specific and generic QoL rates. CONCLUSIONS: Our study contributed to the growing body of knowledge on QoL in CHD, emphasizing the need for these families to receive support from multidisciplinary standardized care, including psychological consultations and support.
Subject(s)
Heart Defects, Congenital , Quality of Life , Adolescent , Child , Child, Preschool , Cross-Sectional Studies , Female , Heart Defects, Congenital/diagnosis , Heart Defects, Congenital/surgery , Humans , Infant, Newborn , Italy , Parents/psychology , Quality of Life/psychology , Surveys and QuestionnairesABSTRACT
RASopathies are multisystemic disorders caused by germline mutations in genes linked to the RAS/mitogen-activated protein kinase pathway. Diagnosis of RASopathy can be triggered by clinical clues ("red flags") which may direct the clinician toward a specific gene test. Compared with sarcomeric hypertrophic cardiomyopathy, hypertrophic cardiomyopathy in RASopathies (R-HCM) is associated with higher prevalence of congestive heart failure and shows increased prevalence and severity of left ventricular outflow tract obstruction. Biventricular involvement and the association with congenital heart disease, mainly pulmonary stenosis, have been commonly described in R-HCM. The aim of this review is to assess the prevalence and unique features of R-HCM and to define the available therapeutic options.
Subject(s)
Cardiomyopathy, Hypertrophic , Heart Defects, Congenital , Noonan Syndrome , Cardiomyopathy, Hypertrophic/diagnosis , Cardiomyopathy, Hypertrophic/epidemiology , Cardiomyopathy, Hypertrophic/genetics , Genetic Testing , Humans , Noonan Syndrome/genetics , PrognosisABSTRACT
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.
Subject(s)
Heart Defects, Congenital/genetics , Heart/physiopathology , Intellectual Disability/genetics , Smith-Magenis Syndrome/genetics , Abnormalities, Multiple/epidemiology , Abnormalities, Multiple/genetics , Abnormalities, Multiple/physiopathology , Adolescent , Adult , Child , Child, Preschool , Chromosome Deletion , Female , Genotype , Heart Defects, Congenital/epidemiology , Heart Defects, Congenital/physiopathology , Humans , Infant , Infant, Newborn , Intellectual Disability/epidemiology , Intellectual Disability/physiopathology , Male , Phenotype , Precision Medicine , Smith-Magenis Syndrome/epidemiology , Smith-Magenis Syndrome/physiopathology , Young AdultABSTRACT
BACKGROUND: Congenital heart disease (CHD) accounts for nearly a third of all major congenital anomalies. Advances in pediatric cardiology shifted attention from mortality to morbidity and health-related quality of life (HRQOL) of patients with CHD and impact on their families. The purposes of this study were to assess the validity and reliability of the Italian version of the Pediatric Quality of Life (PedsQL) Cardiac Module and to create normative data for the Italian population. METHODS: This was an observational cross-sectional study of pediatric patients (aged 2-18 years) with congenital or acquired Heart Disease (HD) and their parents. Families were asked to complete the cardiac pediatric health-related quality of life questionnaire (the Italian PedsQL™ 3.0 Cardiac Module) and the generic pediatric health-related quality of life questionnaire (PedsQL™ 4.0 Generic Core Scales). The sequential validation procedure of the original United States version of the PedsQL™ 3.0 Cardiac Module was carried out under the instruction of the MAPI Research Institute. To assess construct validity, Pearson's correlation coefficients were assessed between scores on the Cardiac Module scales and scores on the scales of the General Module. To determine agreement between patient self-report and parent proxy-report, we used intraclass correlation coefficients (ICCs). To evaluate Internal consistency of items, we used Cronbach's alpha Coefficient. RESULTS: The study enrolled 400 patients. Construct validity is good between PedsQL Cardiac Module total scores and PedsQL total scores (p < 0.001). The recommended standard value of 0.7 was reached on the Cardiac and General Module core scales. Intercorrelations between PedsQL Cardiac module and PedsQL scores revealed medium to large correlations. In general, correlations between Patient self-reports are poorer than Parent-proxy ones. CONCLUSIONS: Cardiac PedsQL scores are valid and reliable for pediatric patients with congenital and acquired HD and may be useful for future research and clinical management.
Subject(s)
Cardiomyopathies/diagnosis , Heart Defects, Congenital/diagnosis , Quality of Life , Surveys and Questionnaires , Adolescent , Age Factors , Cardiomyopathies/physiopathology , Cardiomyopathies/psychology , Child , Child, Preschool , Cross-Sectional Studies , Female , Health Status , Heart Defects, Congenital/physiopathology , Heart Defects, Congenital/psychology , Humans , Italy , Male , Mental Health , Parents , Predictive Value of Tests , Proxy , Psychometrics , Reproducibility of Results , Self ReportABSTRACT
Morbidity and mortality in Down syndrome (DS) are mainly related to congenital heart defects (CHDs). While CHDs with high prevalence in DS (typical CHDs), such as endocardial cushion defects, have been extensively described, little is known about the impact of less common CHDs (atypical CHDs), such as aortic coarctation and univentricular hearts. In our single-center study, we analyzed, in observational, retrospective manner, data regarding cardiac features, surgical management, and outcomes of a cohort of DS patients. Literature review was performed to investigate previously reported studies on atypical CHDs in DS. Patients with CHDs were subclassified as having typical or atypical CHDs. Statistical analysis was performed for comparison between the groups. The study population encompassed 859 DS patients, 72.2% with CHDs, of which 4.7% were atypical. Statistical analysis showed a significant excess in multiple surgeries, all-cause mortality and cardiac mortality in patients with atypical CHDs (p = .0067, p = .0038, p = .0001, respectively). According to the Kaplan-Meier method, survival at 10 and 40 years was significantly higher in typical CHDs (99 and 98% vs. 91 and 84%, log rank <0.05). Among atypical CHDs, it seems that particularly multiple complex defects in univentricular physiology associate with a worse outcome. This may be due to the surgical difficulty in managing univentricular hearts with multiple defects concurring to the clinical picture or to the severity of associated defects themselves. Further studies need to address this specific issue, also considering the higher pulmonary pressures, infective complications, and potential comorbidities in DS patients.
Subject(s)
Down Syndrome/mortality , Endocardial Cushion Defects/mortality , Heart Defects, Congenital/mortality , Heart Septal Defects, Atrial/mortality , Aortic Coarctation , Child , Child, Preschool , Down Syndrome/complications , Down Syndrome/pathology , Endocardial Cushion Defects/complications , Endocardial Cushion Defects/pathology , Female , Heart Defects, Congenital/complications , Heart Defects, Congenital/pathology , Heart Septal Defects, Atrial/complications , Heart Septal Defects, Atrial/pathology , Humans , Male , Morbidity , Retrospective Studies , Risk FactorsABSTRACT
Noonan syndrome (NS) is caused by mutations in more than 10 genes, mainly PTPN11, SOS1, RAF1, and RIT1. Congenital heart defects and cardiomyopathy (CMP) are associated with significant morbidity and mortality in NS. Although hypertrophic CMP has "classically" been reported in association to RAF1, RIT1, and PTPN11 variants, SOS1 appears to be poorly related to CMP. Patients with NS attending our Center from January 2013 to June 2018 were eligible for inclusion if they carried SOS1 variants and presented with-or developed-CMP. Literature review describing the co-existence of SOS1 mutation and CMP was also performed. We identified six patients with SOS1 variants and CMP (male to female ratio 2:1) including two novel variants. CMP spectrum encompassed: (a) dilated CMP, (b) nonobstructive hypertrophic CMPs, and (c) obstructive hypertrophic CMPs. Survival is 100%. Literature review included 16 SOS1 mutated in CMP. CMP, mainly hypertrophic, has been often reported in association to RAF1, RIT1, and PTPN11 variants. Differently from previous reports, due to the frequent association of SOS1 variants and CMP in our single center experience, we suggest potential underestimated proportion of SOS1 in pediatric CMPs.
Subject(s)
Cardiomyopathies/complications , Cardiomyopathies/genetics , Heart Defects, Congenital/complications , Heart Defects, Congenital/genetics , Mutation/genetics , Noonan Syndrome/complications , Noonan Syndrome/genetics , SOS1 Protein/genetics , Child, Preschool , Female , Humans , Infant , Male , Young AdultABSTRACT
Atrioventricular septal defect (AVSD) may occur as part of a complex disorder (e.g., Down syndrome, heterotaxy), or as isolate cardiac defect. Multiple lines of evidence support a role of calcineurin/NFAT signaling in AVSD, and mutations in CRELD1, a protein functioning as a regulator of calcineurin/NFAT signaling have been reported in a small fraction of affected subjects. In this study, 22 patients with isolated AVSD and 38 with AVSD and heterotaxy were screened for NFATC1 gene mutations. Sequence analysis identified three missense variants in three individuals, including a subject with isolated AVSD [p.(Ala367Val)], an individual with AVSD and heterotaxy [p.(Val210Met)], and a subject with AVSD, heterotaxy, and oculo-auriculo-vertebral spectrum (OAVS) [p.(Ala696Thr)], respectively. The latter was also heterozygous for a missense change in TBX1 [p.(Pro86Leu)]. Targeted resequencing of genes associated with AVSD, heterotaxy, or OAVS excluded additional hits in the three mutation-positive subjects. Functional characterization of NFATC1 mutants documented defective nuclear translocation and decreased transcriptional transactivation activity. When expressed in zebrafish, the three NFATC1 mutants caused cardiac looping defects and altered atrioventricular canal patterning, providing evidence of their functional relevance in vivo. Our findings support a role of defective NFATC1 function in the etiology of isolated and heterotaxy-related AVSD.
Subject(s)
Genetic Association Studies , Genetic Predisposition to Disease , Heart Septal Defects/genetics , Heterozygote , Mutation, Missense , NFATC Transcription Factors/genetics , Alleles , Animals , Chromosome Deletion , Female , Fluorescent Antibody Technique , Gene Expression , Genes, Reporter , Heart Septal Defects/diagnosis , High-Throughput Nucleotide Sequencing , Humans , Male , NFATC Transcription Factors/metabolism , Phenotype , Sequence Analysis, DNA , ZebrafishABSTRACT
Congenital heart diseases (CHDs) and cardiovascular abnormalities are one of the pillars of clinical diagnosis of 22q11.2 deletion syndrome (22q11.2DS) and still represent the main cause of mortality in the affected children. In the past 30 years, much progress has been made in describing the anatomical patterns of CHD, in improving their diagnosis, medical treatment, and surgical procedures for these conditions, as well as in understanding the underlying genetic and developmental mechanisms. However, further studies are still needed to better determine the true prevalence of CHDs in 22q11.2DS, including data from prenatal studies and on the adult population, to further clarify the genetic mechanisms behind the high variability of phenotypic expression of 22q11.2DS, and to fully understand the mechanism responsible for the increased postoperative morbidity and for the premature death of these patients. Moreover, the increased life expectancy of persons with 22q11.2DS allowed the expansion of the adult population that poses new challenges for clinicians such as acquired cardiovascular problems and complexity related to multisystemic comorbidity. In this review, we provide a comprehensive review of the existing literature about 22q11.2DS in order to summarize the knowledge gained in the past years of clinical experience and research, as well as to identify the remaining gaps in comprehension of this syndrome and the possible future research directions.
Subject(s)
DiGeorge Syndrome/etiology , Heart Defects, Congenital/etiology , Cardiovascular Diseases/etiology , Chromosomes, Human, Pair 22 , Counseling , DiGeorge Syndrome/genetics , Female , Heart Defects, Congenital/epidemiology , Heart Defects, Congenital/surgery , Humans , Morbidity , Pregnancy , T-Box Domain Proteins/genetics , Thoracic Surgery/statistics & numerical dataABSTRACT
RASopathies are a heterogeneous group of genetic syndromes characterized by mutations in genes that regulate cellular processes, including proliferation, differentiation, survival, migration, and metabolism. Excluding congenital heart defects, hypertrophic cardiomyopathy is the most frequent cardiovascular defect in patients affected by RASopathies. A worse outcome (in terms of surgical risk and/or mortality) has been described in a specific subset of Rasopathy patients with early onset, severe hypertrophic cardiomyopathy presenting with heart failure. New short-term therapy with a mammalian target of rapamycin inhibitor has recently been used to prevent heart failure in these patients with a severe form of hypertrophic cardiomyopathy.
Subject(s)
Cardiomyopathy, Hypertrophic , Genetic Testing/methods , Mutation , ras Proteins/genetics , Cardiomyopathy, Hypertrophic/diagnosis , Cardiomyopathy, Hypertrophic/genetics , Cardiomyopathy, Hypertrophic/metabolism , Genetic Markers/genetics , Humans , ras Proteins/metabolismABSTRACT
Noonan syndrome (NS) is the second most frequent hereditary syndrome with cardiac involvement. Pulmonary valve stenosis and hypertrophic cardiomyopathy are the most prevalent cardiovascular abnormalities. We report on a 14-year-old girl with NS due to SOS1 mutation with pulmonary stenosis and idiopathic coronary ectasia. To the best of our knowledge, this is the first report describing coronary ectasia in a patient with NS secondary to a SOS1 mutation. We include a literature review of this rare association.
Subject(s)
Cardiomyopathy, Hypertrophic/genetics , Coronary Artery Disease/genetics , Mutation , Noonan Syndrome/genetics , Pulmonary Valve Stenosis/genetics , SOS1 Protein/genetics , Adolescent , Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/diagnosis , Cardiomyopathy, Hypertrophic/pathology , Coronary Artery Disease/complications , Coronary Artery Disease/diagnosis , Coronary Artery Disease/pathology , Female , Gene Expression , Humans , Noonan Syndrome/complications , Noonan Syndrome/diagnosis , Noonan Syndrome/pathology , Pulmonary Valve Stenosis/complications , Pulmonary Valve Stenosis/diagnosis , Pulmonary Valve Stenosis/pathologyABSTRACT
In OHT recipients, pathologic evaluation of the heart during acute rejection can show involvement of both the conduction system and the myocardium. We here describe the cases of a 9-year-old male with DCM and a 13-year-old female with RCM, who developed third-degree PAVB associated with acute rejection 36 months and 24 months after OHT, respectively. We conclude that PAVB could be considered an early sign of acute rejection after OHT in children who exhibit post-transplantation presyncope or syncope.
Subject(s)
Atrioventricular Block , Graft Rejection/diagnosis , Heart Transplantation/adverse effects , Adolescent , Child , Echocardiography , Female , Humans , Male , Myocardium/pathology , Postoperative Complications , Syncope/complications , Treatment OutcomeSubject(s)
Bardet-Biedl Syndrome , Heart Septal Defects , Heterotaxy Syndrome , Situs Inversus , HumansABSTRACT
To date, the role of NODAL in normal and abnormal L-R asymmetry has been well established. In a recent paper, mutations of this gene have been reported in heterotaxy but also in transposition with D- or L-ventricular loop. The effects of NODAL and other laterality genes can be recognized separately in all three cardiac segments: for topology and septation of the atria, for ventricular looping, and for spiralization and alignment of the great arteries.
Subject(s)
Heart Defects, Congenital , Heterotaxy Syndrome , Humans , Heterotaxy Syndrome/genetics , Heart Defects, Congenital/genetics , Nodal Protein/genetics , Nodal Protein/metabolism , Heart , Mutation , AnimalsABSTRACT
BACKGROUND: Despite a successful repair of tetralogy of Fallot (rToF) in childhood, residual lesions are common and can contribute to impaired exercise capacity. Although both cycle ergometer and treadmill protocols are often used interchangeably these approaches have not been directly compared. In this study we examined cardiopulmonary exercise test (CPET) measurements in rToF. METHODS: Inclusion criteria were clinically stable rToF patients able to perform a cardiac magnetic resonance imaging (CMR) and two CPET studies, one on the treadmill (incremental Bruce protocol) and one on the cycle ergometer (ramped protocol), within 12 months. Demographic, surgical and clinical data; functional class; QRS duration; CMR measures; CPET data and international physical activity questionnaire (IPAQ) scores of patients were collected. RESULTS: Fifty-seven patients were enrolled (53% male, 20.5 ± 7.8 years at CPET). CMR measurements included a right ventricle (RV) end-diastolic volume index of 119 ± 22 mL/m2, a RV ejection fraction (EF) of 55 ± 6% and a left ventricular (LV) EF of 56 ± 5%. Peak oxygen consumption (VO2)/Kg (25.5 ± 5.5 vs. 31.7 ± 6.9; p < 0.0001), VO2 at anaerobic threshold (AT) (15.3 ± 3.9 vs. 22.0 ± 4.5; p < 0.0001), peak O2 pulse (10.6 ± 3.0 vs. 12.1± 3.4; p = 0.0061) and oxygen uptake efficiency slope (OUES) (1932.2 ± 623.6 vs. 2292.0 ± 639.4; p < 0.001) were significantly lower on the cycle ergometer compared with the treadmill, differently from ventilatory efficiency (VE/VCO2) max which was significantly higher on the cycle ergometer (32.2 ± 4.5 vs. 30.4 ± 5.4; p < 0.001). Only the VE/VCO2 slope at the respiratory compensation point (RCP) was similar between the two methodologies (p = 0.150). CONCLUSIONS: The majority of CPET measurements differed according to the modality of testing, with the exception being the VE/VCO2 slope at RCP. Our data suggest that CPET parameters should be interpreted according to test type; however, these findings should be validated in larger populations and in a variety of institutions.
ABSTRACT
Hypertrophic cardiomyopathy (HCM) is the major contributor to morbidity and mortality in Noonan syndrome (NS). Gain-of-function variants in RAF1 are associated with high prevalence of HCM. Among these, NM_002880.4:c.770C > T, NP_002871.1:p.(Ser257Leu) accounts for approximately half of cases and has been reported as associated with a particularly severe outcome. Nevertheless, comprehensive studies on cases harboring this variant are missing. To precisely define the phenotype associated to the RAF1:c.770C > T, variant, an observational retrospective analysis on patients carrying the c.770C > T variant was conducted merging 17 unpublished patients and literature-derived ones. Data regarding prenatal findings, clinical features and cardiac phenotypes were collected to provide an exhaustive description of the associated phenotype. Clinical information was collected in 107 patients. Among them, 92% had HCM, mostly diagnosed within the first year of life. Thirty percent of patients were preterm and 47% of the newborns was admitted in a neonatal intensive care unit, mainly due to respiratory complications of HCM and/or pulmonary arterial hypertension. Mortality rate was 13%, mainly secondary to HCM-related complications (62%) at the average age of 7.5 months. Short stature had a prevalence of 91%, while seizures and ID of 6% and 12%, respectively. Two cases out of 75 (3%) developed neoplasms. In conclusion, patients with the RAF1:c.770C > T pathogenic variant show a particularly severe phenotype characterized by rapidly progressive neonatal HCM and high mortality rate suggesting the necessity of careful monitoring and early intervention to prevent or slow down the progression of HCM.