Hidden Y Chromosome Material and Congenital Cardiovascular Malformations in a Cohort of Turner Syndrome Patients with 45,X Blood Karyotype.

INTRODUCTION: Bicuspid aortic valve is the most common congenital cardiac malformation (CCM) in adults and is 30-50 times more frequent in Turner syndrome (TS). We hypothesize that both X and Y chromosome dosages contribute to the prevalence of CCM in TS. The recognition of genotype-phenotype correlations may improve risk stratification of patients with 45,X karyotypes who have cryptic Y chromosome mosaicism. METHODS: Utilizing data and samples from the UTHealth Turner Syndrome Research Registry, we correlated Y chromosome DNA identified by multiplex quantitative PCR and SNP microarrays with the presence of congenital heart lesions. RESULTS: We identified Y chromosome DNA in more than 10% of registry participants, including 2 participants who had no detectable Y DNA by karyotype or SNP microarray. CONCLUSIONS: There were no significant correlations between the presence of Y DNA and CCM.

Prenatal diagnosis in Nevada for patients undergoing cardiovascular surgery in the first six months.

OBJECTIVE: We reviewed our center's experience with prenatal detection in Nevada's general population for young infants undergoing cardiovascular surgery. METHODS: We identified patients born in Nevada that underwent an initial cardiovascular surgery between 0 and 6 months old with birth dates between August 2012 and July 2021. Additionally, we calculated prenatal congenital cardiovascular malformation detection rates for each of the 9 years. RESULTS: We identified 660 patients. For the 660 patients, 649 (98%) mothers underwent prenatal care, which included at least one anatomical-survey obstetric ultrasound. Of the 649 with prenatal care, 395 (61%) had a prenatal diagnosis overall. However, prenatal diagnosis improved over the 9 years from 44% in 2012 to 79% in 2021 (correlation coefficient of 0.93, p = .00024). CONCLUSIONS: Our results demonstrated a progressive rise in prenatal detection rates for young infants undergoing cardiovascular surgery in Nevada.

Surgical treatment of isolated unilateral absence of pulmonary artery with pulmonary hypertension.

A one-and-a-half-month-old patient with isolated unilateral absence of the right proximal pulmonary artery with prominent left pulmonary hypertension was diagnosed using CT. Medication therapy was initiated first. Left pulmonary artery pressure decreased after the initiation of medication therapy, and single-stage reconstruction of the right pulmonary artery was performed. The patient is asymptomatic 14 months postoperatively.

Cdc42 activation by endothelin regulates neural crest cell migration in the cardiac outflow tract.

BACKGROUND: Congenital cardiovascular malformations are the most common birth defects affecting children. Several of these defects occur in structures developing from neural crest cells. One of the key signaling pathways regulating cardiac neural crest cell (CNCC) development involves the endothelin-A receptor (Ednra). However, the exact function of Ednra signaling in CNCC is unknown. RESULTS: The fate mapping of CNCC in Ednra embryos indicated that the migration of these cells is aberrant in the cardiac outflow tract (OFT), but not in the pharyngeal arches. This premature arrest of CNCC migration occurs independently of CNCC proliferation and apoptosis changes and major gene expression changes. Analysis of the Rho family of small GTPases in the mutant embryos revealed that Cdc42 failed to localize normally in the CNCC migrating in the OFT. The inhibition of Cdc42 activity in cultured embryos recapitulated the migratory phenotype observed in Ednra mice. Further analyses revealed that Cdc42 is part of the signaling pathway activated by endothelin specifically in OFT CNCC to control their migration. CONCLUSIONS: These results indicated that the activation of Cdc42 by endothelin signaling is important for CNCC migration in the OFT but this pathway is not involved in mandibular or pharyngeal arch artery patterning.

Heart Failure in Pediatric Patients With Congenital Heart Disease.

Heart failure (HF) is a complex clinical syndrome resulting from diverse primary and secondary causes and shared pathways of disease progression, correlating with substantial mortality, morbidity, and cost. HF in children is most commonly attributable to coexistent congenital heart disease, with different risks depending on the specific type of malformation. Current management and therapy for HF in children are extrapolated from treatment approaches in adults. This review discusses the causes, epidemiology, and manifestations of HF in children with congenital heart disease and presents the clinical, genetic, and molecular characteristics that are similar or distinct from adult HF. The objective of this review is to provide a framework for understanding rapidly increasing genetic and molecular information in the challenging context of detailed phenotyping. We review clinical and translational research studies of HF in congenital heart disease including at the genome, transcriptome, and epigenetic levels. Unresolved issues and directions for future study are presented.

Usefulness of zebrafish in evaluating drug-induced teratogenicity in cardiovascular system.

To confirm the usefulness of zebrafish for evaluating the teratogenic potential of drug candidates, the effect of O-ethylhydroxylamine hydrochloride (OHY), which induces mutagenesis by methylation, was evaluated in teratogenicity studies in rats and zebrafish. In the rat teratogenicity study, OHY-induced cardiovascular malformations such as increased abnormal vascular structures and ventricular septal defects. In the teratogenicity study using zebrafish-injected microspheres and green fluorescent protein-expressing Tg zebrafish (flk1:EGFP), OHY exposure was associated with the loss or malformation of the mandibular arch, opercular artery, and fourth branchial arch. These results suggested that OHY-induced external malformations in zebrafish eleutheroembryos adequately reflect OHY's teratogenicity in rat fetuses. Moreover, the zebrafish teratogenicity study incorporating vascular morphological examinations, including those of blood vessels in the heart, head and trunk, is an easy and reliable screening method to detect potential drug-induced teratogenicity and phenotypic characteristics.

Maternal Exposure to Nitrogen Dioxide, Intake of Methyl Nutrients, and Congenital Heart Defects in Offspring.

Nutrients that regulate methylation processes may modify susceptibility to the effects of air pollutants. Data from the National Birth Defects Prevention Study (United States, 1997-2006) were used to estimate associations between maternal exposure to nitrogen dioxide (NO2), dietary intake of methyl nutrients, and the odds of congenital heart defects in offspring. NO2 concentrations, a marker of traffic-related air pollution, averaged across postconception weeks 2-8, were assigned to 6,160 nondiabetic mothers of cases and controls using inverse distance-squared weighting of air monitors within 50 km of maternal residences. Intakes of choline, folate, methionine, and vitamins B6 and B12 were assessed using a food frequency questionnaire. Hierarchical regression models, which accounted for similarities across defects, were constructed, and relative excess risks due to interaction were calculated. Relative to women with the lowest NO2 exposure and high methionine intake, women with the highest NO2 exposure and lowest methionine intake had the greatest odds of offspring with a perimembranous ventricular septal defect (odds ratio = 3.23, 95% confidence interval: 1.74, 6.01; relative excess risk due to interaction = 2.15, 95% confidence interval: 0.39, 3.92). Considerable departure from additivity was not observed for other defects. These results provide modest evidence of interaction between nutrition and NO2 exposure during pregnancy.

Gain-of-function mutations in SMAD4 cause a distinctive repertoire of cardiovascular phenotypes in patients with Myhre syndrome.

Myhre syndrome is a rare, distinctive syndrome due to specific gain-of-function mutations in SMAD4. The characteristic phenotype includes short stature, dysmorphic facial features, hearing loss, laryngotracheal anomalies, arthropathy, radiographic defects, intellectual disability, and a more recently appreciated spectrum of cardiovascular defects with a striking fibroproliferative response to surgical intervention. We report four newly described patients with typical features of Myhre syndrome who had (i) a mildly narrow descending aorta and restrictive cardiomyopathy; (ii) recurrent pericardial and pleural effusions; (iii) a large persistent ductus arteriosus with juxtaductal aortic coarctation; and (iv) restrictive pericardial disease requiring pericardiectomy. Additional information is provided about a fifth previously reported patient with fatal pericardial disease. A literature review of the cardiovascular features of Myhre syndrome was performed on 54 total patients, all with a SMAD4 mutation. Seventy percent had a cardiovascular abnormality including congenital heart defects (63%), pericardial disease (17%), restrictive cardiomyopathy (9%), and systemic hypertension (15%). Pericarditis and restrictive cardiomyopathy are associated with high mortality (three patients each among 10 deaths); one patient with restrictive cardiomyopathy also had epicarditis. Cardiomyopathy and pericardial abnormalities distinguish Myhre syndrome from other disorders caused by mutations in the TGF-ß signaling cascade (Marfan, Loeys-Dietz, or Shprintzen-Goldberg syndromes). We hypothesize that the expanded spectrum of cardiovascular abnormalities relates to the ability of the SMAD4 protein to integrate diverse signaling pathways, including canonical TGF-ß, BMP, and Activin signaling. The co-occurrence of congenital and acquired phenotypes demonstrates that the gene product of SMAD4 is required for both developmental and postnatal cardiovascular homeostasis. © 2016 Wiley Periodicals, Inc.

Outcome of congenital diaphragmatic hernia with indication for Fontan procedure.

BACKGROUND: The aim of this study was to clarify the outcome of patients with cardiovascular malformation (CVM) among those with congenital diaphragmatic hernia (CDH) who are indicated for the Fontan procedure. METHODS: The subjects included 76 CDH patients with CVM recruited from a national survey of 614 CDH patients. The outcomes were evaluated between two groups divided according to indication for the Fontan procedure. Patients with functional univentricular disease were considered to be candidates for the Fontan procedure. RESULTS: Sixteen (21.1%) of the 76 patients were candidates for the Fontan procedure, accounting for 2.6% of all 614 patients with CDH. None of these patients, however, underwent the Fontan procedure. Among the 16 patients, the absence of obstruction of the left ventricular outflow tract (LVOTO) was significantly associated with better 90 day survival (71.4%, 5/7, for those without LVOTO vs 0.0%, 0/9, for those with LVOTO, P = 0.0007). After excluding 22 patients with chromosomal and/or genetic abnormalities or syndromes, the 90 day survival rate was significantly better in neonates without than with indication for the Fontan procedure (62.5%, 25/40 vs 28.6%, 4/14, P = 0.0271). CONCLUSIONS: Patients with indications for the Fontan procedure are rare, and the outcome of patients with LVOTO among those with CDH is especially poor.

Evaluation of cardiovascular anomalies in patients with asymptomatic turner syndrome using multidetector computed tomography.

Turner syndrome is well known to be associated with significant cardiovascular abnormalities. This paper studied the incidence of cardiovascular abnormalities in asymptomatic adolescent patients with Turner syndrome using multidetector computed tomography (MDCT) instead of echocardiography. Twenty subjects diagnosed with Turner syndrome who had no cardiac symptoms were included. Blood pressure and electrocardiography (ECG) was checked. Cardiovascular abnormalities were checked by MDCT. According to the ECG results, 11 had a prolonged QTc interval, 5 had a posterior fascicular block, 3 had a ventricular conduction disorder. MDCT revealed vascular abnormalities in 13 patients (65%). Three patients had an aberrant right subclavian artery, 2 had dilatation of left subclavian artery, and others had an aortic root dilatation, aortic diverticulum, and abnormal left vertebral artery. As for venous abnormalities, 3 patients had partial anomalous pulmonary venous return and 2 had a persistent left superior vena cava. This study found cardiovascular abnormalities in 65% of asymptomatic Turner syndrome patients using MDCT. Even though, there are no cardiac symptoms in Turner syndrome patients, a complete evaluation of the heart with echocardiography or MDCT at transition period to adults must be performed.

Exploring the Role of Modified Vascular Anatomical Molding (MVAM) in Prenatal Diagnosis Teaching and Prognosis Prediction of Fetal Complex Congenital Heart Disease (CCHD): A Preliminary Study.

Objective: The present study aimed to explore the role of modified vascular anatomical molding (MVAM) in prenatal diagnosis teaching and prognosis prediction of fetal complex congenital heart disease (CCHD). Methods: Step 1, MVAM method was used to cast the micro-blood vessels and trachea of 52 CCHD specimens. Subsequently, 52 MVAMs were analyzed and compared with the prenatal ultrasound to summarize their characteristics, misdiagnosis and MVAM's teaching role. Step 2, the surgical and follow-up data of 206 CCHD cases were retrospectively analyzed. Cases that evolved into critical illnesses or died within 1-3 years after surgery (poor prognosis) were classified into the study group (n = 77) and those with good prognosis into the control group (n = 129), which were split into the training set and the test set in the ratio 7:3 based on the time cut-off. In the training set, the prognosis of CCHD was predicted using the MVAM anatomical soft markers (distortion and narrowing of aorta/pulmonary artery, right ventricular infundibulum, etc.) and the decision curve analysis (DCA) performed. The model was validated using the test set, and a nomogram was finally established. Results: It was observed that all 52 CCHD cases were confirmed using MVAM. A total of 91 cardiac malformations were recorded, among which 41 malformations were misdiagnosed, and 29 malformations were missed by the prenatal echocardiography. The MVAM method has a good teaching/feedback effect on prenatal diagnosis. The combined model exhibited a higher predictive performance in the training- and test-set. Its high clinical net benefit was proved by DCA. Additionally, the nomogram established using the combined model received a favorable response in clinical practice. Conclusion: The research results indicated that MVAM improved the prenatal diagnosis teaching and training performance. The combined model established based on MVAM anatomical soft markers can offer a high clinical significance for prognosis prediction of CCHD.

Trans-arterial Embolization in a Patient with Unilateral Absence of Pulmonary Artery: Treatment Success and the Four-year Prognosis.

Unilateral absence of the pulmonary artery (UAPA) with or without other anomalies in the heart is a rare congenital malformation. A 55-year-old Filipino woman without a remarkable medical history was admitted to our hospital for hemoptysis. Contrast-enhanced chest computed tomography revealed the absence of the left pulmonary artery. Echocardiography and right heart catheterization showed no cardiac malformations or pulmonary hypertension. We diagnosed her with isolated left-sided UAPA and performed transarterial embolization of the left inferior phrenic artery. This resolved the hemoptysis, and there was no recurrence during the four-year follow-up period.

Decreasing Mortality for STAT 4 and 5 Neonatal Heart Surgeries Concurrent With Improving Prenatal Detection: The Nevada Experience.

Objective: Our objective was to investigate whether a relationship existed between our center's STAT 4 and 5 category surgical mortality and general-population prenatal detection rates in Nevada. Methods: We identified patients who underwent STAT 4 and 5 neonatal index cardiovascular surgeries at our center between October 2012 and September 2021. Additionally, we calculated prenatal detection rates for each of the 9 retrospective study years. We used descriptive statistics and nonparametric testing, including the Spearman Rho correlation (R) and the Mann-Whitney U-tests, with a significant P-value set at < .05. Results: We identified 356 patients. We noted a statistically significant increasing trend in prenatal detection percentages (rho = 0.79, P = .01), concurrent with a statistically significant decreasing trend in surgical mortality (rho = -0.82, P = .007). Conclusions: Despite encouraging results, we could not establish a cause-and-effect relationship between concurrent decreased surgical mortality and increased prenatal detection rates for patients undergoing STAT 4 and 5 surgical procedures at our center.

Educational Case: Tetralogy of Fallot and a Review of the Most Common Forms of Congenital Heart Disease.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.1.

Neonatal diagnosis of isolated absence of the right pulmonary artery: a case report and review of the literature.

BACKGROUND: Unilateral absence of the pulmonary artery (UAPA) is a rare congenital malformation often associated with other cardiac anomalies; however it may occur as an isolated lesion. Isolated absence of the right pulmonary artery is twice more frequent than that of the left pulmonary artery. Patients with isolated UAPA are usually asymptomatic at birth; thereafter they may develop a progression of symptoms such as exercise intolerance, dyspnea, chest pain, hemoptysis and recurrent pulmonary infections. As patients may remain asymptomatic or have vague symptoms, the diagnosis of isolated UAPA can be difficult to make in infancy. Indeed, most cases described in literature are adults. Due to the rarity of neonatal presentation, there is no consensus regarding the treatment of this malformation. CASE PRESENTATION: Herein, the case of a two-day-old term female infant, born after uneventful pregnancy, who required a cardiological assessment for a light murmur, is reported; an echocardiogram demonstrated an isolated unilateral absence of the right pulmonary artery, confirmed by means of magnetic resonance imaging (MRI) performed 1 month after child's birth. Besides this finding, MRI showed a slightly increased lumen and size of the main and left pulmonary arteries. The right lung was shown to be perfused by some systemic collateral arteries. In the absence of any other cardiovascular malformation, our patient did not need any treatment. As symptoms may occur later in life, a thorough clinical and cardiological follow up was immediately started. Three years later, she is still asymptomatic, showing adequate growth, without any sign of pulmonary hypertension. CONCLUSIONS: Isolated UAPA is a very rare malformation with a diverse clinical presentation. To the best of our knowledge, this is the second case of neonatal presentation of UAPA reported in literature to date. We believe that our case report supports the opinion that a prompt cardiological evaluation is needed whenever a newborn shows signs and/or symptoms of cardiorespiratory concern. Any missed neonatal diagnosis of UAPA may contribute to the later age at presentation, with resultant higher risk of morbidity and mortality and greater therapeutical difficulties.

Genetics and genetic testing in congenital heart disease.

Congenital heart defects (CHDs) are structural abnormalities of the heart and great vessels that are present from birth. The presence or absence of extracardiac anomalies has historically been used to identify patients with possible monogenic, chromosomal, or teratogenic CHD causes. These distinctions remain clinically relevant, but it is increasingly clear that nonsyndromic CHDs can also be genetic. This article discusses key morphologic, molecular, and signaling mechanisms relevant to heart development, summarizes overall progress in molecular genetic analyses of CHDs, and provides current recommendations for clinical application of genetic testing.

Rationale for the Cytogenomics of Cardiovascular Malformations Consortium: A Phenotype Intensive Registry Based Approach.

Cardiovascular malformations (CVMs) are the most common birth defect, occurring in 1%-5% of all live births. Although the genetic contribution to CVMs is well recognized, the genetic causes of human CVMs are identified infrequently. In addition, a failure of systematic deep phenotyping of CVMs, resulting from the complexity and heterogeneity of malformations, has obscured genotype-phenotype correlations and contributed to a lack of understanding of disease mechanisms. To address these knowledge gaps, we have developed the Cytogenomics of Cardiovascular Malformations (CCVM) Consortium, a multi-site alliance of geneticists and cardiologists, contributing to a database registry of submicroscopic genetic copy number variants (CNVs) based on clinical chromosome microarray testing in individuals with CVMs using detailed classification schemes. Cardiac classification is performed using a modification to the National Birth Defects Prevention Study approach, and non-cardiac diagnoses are captured through ICD-9 and ICD-10 codes. By combining a comprehensive approach to clinically relevant genetic analyses with precise phenotyping, the Consortium goal is to identify novel genomic regions that cause or increase susceptibility to CVMs and to correlate the findings with clinical phenotype. This registry will provide critical insights into genetic architecture, facilitate genotype-phenotype correlations, and provide a valuable resource for the medical community.

Preliminary Evidence for Aortopathy and an X-Linked Parent-of-Origin Effect on Aortic Valve Malformation in a Mouse Model of Turner Syndrome.

Turner syndrome (TS), most frequently caused by X-monosomy (45,X), is characterized in part by cardiovascular abnormalities, including aortopathy and bicuspid aortic valve (BAV). There is a need for animal models that recapitulate the cardiovascular manifestations of TS. Extracellular matrix (ECM) organization and morphometrics of the aortic valve and proximal aorta were examined in adult 39,XO mice (where the parental origin of the single X was paternal (39,XPO) or maternal (39,XMO)) and 40,XX controls. Aortic valve morphology was normal (tricuspid) in all of the 39,XPO and 40,XX mice studied, but abnormal (bicuspid or quadricuspid) in 15% of 39,XMO mice. Smooth muscle cell orientation in the ascending aorta was abnormal in all 39,XPO and 39,XMO mice examined, but smooth muscle actin was decreased in 39,XMO mice only. Aortic dilation was present with reduced penetrance in 39,XO mice. The 39,XO mouse demonstrates aortopathy and an X-linked parent-of-origin effect on aortic valve malformation, and the candidate gene FAM9B is polymorphically expressed in control and diseased human aortic valves. The 39,XO mouse model may be valuable for examining the mechanisms underlying the cardiovascular findings in TS, and suggest there are important genetic modifiers on the X chromosome that modulate risk for nonsyndromic BAV and aortopathy.

Genetic testing practices in infants with congenital heart disease.

OBJECTIVE: Clinical genetic testing is expanding rapidly, but the application of new testing has not been reported in an unselected, comprehensive congenital heart disease (CHD) patient population. This study aims to identify cytogenetic testing practices and diagnostic yield in infants with CHD as an important first step toward understanding clinical utility of dedicated cytogenetic testing. We hypothesized that chromosome microarray analysis (CMA) would identify genetic abnormalities underlying both syndromic and isolated CHD. DESIGN: This is a single institution retrospective study that characterizes cytogenetic testing practices and diagnostic yield for all cytogenetic testing in each infant identified with CHD over a 32-month period. CHD was classified by type, complexity, and presence or absence of extracardiac anomalies. RESULTS: Among the 1087 infants identified with CHD by echocardiogram, 277 infants (25%) had some form of cytogenetic testing, including karyotype, fluorescence in situ hybridization, and/or CMA. Forty-one percent of infants who had cytogenetic testing had more than one test. CMA was performed in 121 patients (11%), and abnormalities (both clinically significant and variants of unknown significance) were identified in 35/121 (29%). Forty-nine percent of CMA abnormalities were in patients with apparently isolated nonsyndromic CHD. CONCLUSIONS: This single institution study identified that only 25% of infants with CHD underwent cytogenetic testing, indicating possible underutilization of testing in this age group. The high multiple testing rate indicates a need for improved guidelines for cost effective testing approaches. The diagnostic yield in this study suggests that CMA is a particularly useful first screening test when a specific syndrome is not clinically identifiable. Larger studies investigating cardiac lesion-specific diagnostic yield in isolated CHD are warranted.

A pediatric approach to family history of cardiovascular disease: diagnosis, risk assessment, and management.

The medical family history is a comprehensive and dynamic record of illnesses and other pertinent health information among family members. Family history is used to facilitate diagnosis, to identify family members at risk for developing a particular disease, and increasingly to manage disease. This article reviews the application of family history to pediatric cardiovascular disease. As more is learned about the genetic basis of cardiovascular disease, the family history will play an increasingly central role in management. Improved understanding of the causes of pediatric cardiovascular disease promises the opportunity to develop new diagnostic and therapeutic strategies.