Search Results (65)

Background/Objectives: Neurodevelopmental disorders (NDDs) represent a clinically diverse group of conditions that affect brain development, often leading to varying degrees of functional impairment. Many NDDs, particularly syndromic forms, are caused by genetic mutations affecting critical cellular pathways. Ribosomopathies, a subgroup of NDDs, are linked to defects in ribosomal function, including those involving the synthesis of diphthamide, a post-translational modification of translation elongation factor 2 (eEF2). Loss-of-function (LoF) mutations in genes involved in diphthamide biosynthesis, such as DPH1, DPH2, and DPH5, result in developmental delay (DD), intellectual disability (ID), and multisystemic abnormalities. DPH5-related diphthamide deficiency syndrome has recently been reported as an ultrarare disorder linked to LoF mutations in DPH5, encoding a methyltransferase required for diphthamide synthesis. Methods: Clinical, neurological, and dysmorphological evaluations were performed by a multidisciplinary team. Brain MRI was acquired on a 3T scanner. Craniofacial abnormalities were assessed using the GestaltMatcher phenotyping tool. Whole exome sequencing (WES) was conducted on leukocyte-derived DNA with a trio-based approach. Bioinformatic analyses included variant annotation, filtering, and pathogenicity prediction using established databases and tools. Results: The affected subject carried a previously reported missense change, p.His260Arg, suggesting the occurrence of genotype–phenotype correlations and a hypomorphic behavior of the variant, likely explaining the overall milder phenotype compared to the previously reported patients with DPH5-related diphthamide deficiency syndrome. Conclusions: Overall, the co-occurrence of short stature, relative macrocephaly, congenital heart defects, variable DD/ID, minor skeletal and ectodermal features, and consistent craniofacial features suggests a differential diagnosis with Noonan syndrome and related phenotypes. Full article

Background: Heart failure in pediatric patients remains a major cause of morbidity and mortality, often associated with congenital heart defects and cardiomyopathies. Mechanical circulatory support (MCS) devices have emerged as critical therapeutic options, particularly as bridges to transplantation or recovery. The complexity of their use in children necessitates highly specialized solutions. This study aimed to evaluate the quality and performance of selected connection technologies between prosthetic vascular grafts and the outflow cannula of the Religa Heart PED^® pediatric pulsatile pump, with a focus on tightness, surface smoothness, and structural integrity. Methods: Mechanical testing was conducted on various connection types, including static tensile strength and long-term durability under pulsatile flow conditions with biological fluid analogs. Macro and microscopic evaluations assessed the surface quality and potential thrombogenic risks, biological testing encompassed permeability analysis in static and dynamic settings, and hemocompatibility was determined by acute thrombogenicity. Additionally, in vivo observations in a large animal model were used for final qualitative validation. Results: All connection types demonstrated sufficient mechanical strength, with no structural degradation or leakage observed in any samples following long-term testing. Thrombus formation was absent in adhesive connections with Dacron and polytetrafluoroethylene (PTFE) grafts but was observed in the mechanical connection with the PTFE prosthesis. In addition, in vivo studies confirmed the tightness, hemocompatibility, and mechanical stability of the adhesive connection with the Dacron prosthesis. Conclusions: The adhesive connection between the outflow cannula and a Dacron prosthesis demonstrated superior mechanical and biological performance, including resistance to thrombogenesis and hemolysis, as well as stable integration under in vivo conditions. This solution shows high potential for safe application in the Religa Heart PED^® system. Full article

Background: The PATHFINDER-CHD Registry is a prospective, multicenter, non-interventional registry across tertiary care centers in Germany. The aim is to analyze real-world data on adults with congenital heart defects (ACHD) or hereditary connective tissue disorders who have manifest heart failure (HF), a history of HF, or are at significant risk of developing HF. This analysis investigates the prevalence and clinical impact of overweight and obesity in this unique population. Methods: As of 1st February, 2025, a total of 1490 ACHD had been enrolled. The mean age was 39.4 ± 12.4 years, and 47.9% were female. Patients were categorized according to Perloff’s functional class and the Munich Heart Failure Classification for Congenital Heart Disease (MUC-HF-Class). Results: The most common congenital heart disease (CHD) in this cohort was Tetralogy of Fallot, transposition of the great arteries, and congenital aortic valve disease. Marfan syndrome was the most common hereditary connective tissue disease. Of the patients, 46.1% were classified as overweight (32.8%) or obese (13.3%), while 4.8% were underweight. The highest prevalence of overweight (47.1%) was observed among patients who had undergone palliative surgery, whereas untreated patients showed the highest proportion of normal weight (57.2%). Cyanotic patients were predominantly of normal weight. Patients with univentricular circulation exhibited significantly lower rates of overweight and obesity (35%; p = 0.001). Overweight and obesity were statistically significantly associated with arterial hypertension, diabetes mellitus, and sleep apnea (all p < 0.001). High BMI was linked to increased use of HF-specific medications, including SGLT2 inhibitors (p = 0.040), diuretics (p = 0.014), and angiotensin receptor blockers (p = 0.005). Conclusions: The data highlight the clinical relevance of overweight and obesity in ACHD with HF, emphasizing the need for individualized prevention and treatment strategies. The registry serves as a critical foundation for the optimization of long-term care in this population. Full article

Background/Objectives: Heart failure (HF) poses a major challenge in managing adults with congenital heart defects (ACHD). Emerging evidence suggests that HF in ACHD increases the risk of underweight due to heightened metabolic demands, gastrointestinal complications, and psychological factors such as anxiety and depression. Despite its critical implications, few studies have examined this association. This study evaluates the relationship between HF and underweight—defined as a body mass index (BMI) < 18.5—in ACHD. Methods: The Pathfinder-CHD Registry is a prospective, observational, web-based HF registry including ACHD with manifest HF, history of HF, or significant risk for HF. It documents congenital diagnoses, HF type, comorbidities, and treatments. Patients were categorized by BMI into mild (17.00–18.49), moderate (16.00–16.99), and severe (<16.00) underweight. Results: As of September 2024, the registry enrolled 1420 adults (mean age 31.8±11.3 years; 49.2% female). Underweight was present in 59 patients (4.2%): 62.7% mild, 18.6% moderate, and 18.6% severe. Among the remaining 1361 patients, 52.8% had normal weight, 32.8% were overweight, and 14.2% were obese. Women had significantly lower metabolic body weight than men (p = 0.002). Underweight correlated with younger age (p < 0.001) and CHD type (p = 0.02). Notably, 42.9% of underweight patients had cyanotic CHD. Conclusions: Underweight is an underrecognized problem in ACHD with HF. Adults with complex CHD or connective tissue disorders are disproportionately affected. Underweight should be seen as an alarm sign requiring personalized, multidisciplinary management, including nutritional support, tailored therapy, and close monitoring to improve outcomes. Full article

Part of the vision of the ISNS is ‘to enhance the quality of neonatal screening and medical services through dissemination of information, guidelines and best practices.’ Although newborn screening encompasses testing in the newborn period for critical congenital heart disease, hearing impairment, birth defects, and congenital biochemical disorders (usually on bloodspots), this guideline is specifically about bloodspot screening. The ISNS has provided neonatal screening guidelines for many years and here presents the renewed 2025 General Guidelines for Neonatal Bloodspot Screening. They are intended to provide a framework for screening programs to develop specific policies around all aspects of the newborn screening system, offering the basic set of items for consideration. These guidelines provide trusted anchors to build, expand, or maintain robustly organized neonatal or newborn screening (NBS) programs and a checklist to evaluate and improve the essential elements of those programs. For starting or developing programs, it is a set of elements for which provisions need to be in place and a checklist of items that the screening program should at a minimum have provisions for. The publication of these guidelines is meant as a starting point for interactive discussion, to further improve this document and expand where necessary. Full article

The relevance of O₃ exposure in critical congenital heart disease (CCHD) remains uncertain and requires further investigation. The present study aims at quantitatively assessing the association between ambient O₃ exposure during the early pregnancy period with fetal CCHD and identifying possible susceptible exposure windows. A retrospective cohort study involving 24,516 pregnant women was conducted using data from the Maternal–Fetal Medicine Consultation Network, which encompassed 1313 medical centers across China from 2013 to 2021. We extracted daily O₃ concentrations from a validated grid dataset with a spatial resolution of 0.1° at each participant’s residential county to assess ambient O₃ exposure, followed by calculating the average exposure levels in the periconceptional period, embryonic period, first trimester, and preconception period. The diagnosis of CCHD was based on fetal echocardiography. Exposure–response analyses were carried out using logistic regression models. During the study period, a total of 1541 (17.4%) subjects were diagnosed with fetal CCHD. Each 10 µg/m³ increase in ambient O₃ exposure in the periconceptional period was associated with a 26.0% increase in the odds of CCHD (odds ratio [OR]: 1.260, 95% confidence interval [CI]: 1.189, 1.335; p < 0.001). Importantly, the association was not modified by factors including maternal age and occupation status, paternal age and smoking status, conception mode, and the presence of risk factors. In the sensitivity analysis, significant associations were observed between O₃ exposure and CCHD in the embryonic period, first trimester, and preconception period, which was consistent with the results of the main analyses. These findings suggest that lowering ambient O₃ exposure in the preconception and early pregnancy periods may be beneficial in reducing the risk of fetal CCHD, especially in regions with elevated O₃ levels. Full article

Background/Objectives: Iron is a fundamental micronutrient. Its deficiency could have a potentially harmful influence on maternal and fetal well-being. Methods: This review synthesizes current evidence on the epidemiology, consequences, and clinical meaning of iron deficiency (ID) and iron deficiency anemia (IDA) in pregnant women. Results: Untreated ID in pregnancy is associated with a wide spectrum of adverse outcomes: maternal clinical symptoms, cardiovascular disturbances, preterm birth, low birth weight, and impaired fetal neurodevelopment. Furthermore, ID has been related to impaired implantation, miscarriage, congenital heart defects, and neurological complications in fetuses. Women with gastrointestinal disorders and low socioeconomic status constitute a high-risk group of developing IDA. ID remains underdiagnosed and suboptimally managed in some clinical practices. Conclusions: This review highlights the critical importance of early detection, individualized supplementation, and public health interventions aimed at reducing iron deficiency during pregnancy. Full article

Advances in surgical and medical management of congenital heart disease have improved survival rates, leading to a growing population of adult congenital heart disease (ACHD) patients requiring specialized perioperative care. Studies indicate that ACHD patients undergoing non-cardiac surgery (NC surgery) have increased mortality and morbidity risks compared to the general population, with complication rates particularly high in those with complex defects, such as Fontan circulation, Eisenmenger syndrome, or cyanotic congenital heart disease. Key perioperative concerns include hemodynamic instability, arrhythmias, thromboembolic events, and bleeding risks. Additionally, comorbidities, such as frailty, chronic inflammation, or respiratory disease, further complicate perioperative management. Multidisciplinary collaboration is critical, involving cardiologists, anesthesiologists, and surgeons to optimize preoperative preparation and perioperative monitoring. Preoperative risk stratification is essential, integrating congenital heart lesion complexity, functional status, and procedural risk. This review underscores the importance of structured preoperative assessment, appropriate risk evaluation, and individualized perioperative strategies to improve surgical outcomes in ACHD patients undergoing NC surgery. Further research is needed to refine risk prediction models and optimize perioperative protocols tailored to this unique patient population. Full article

Advancements in congenital heart disease (CHD) care have significantly improved survival, leading to a growing population of adults with congenital heart disease (ACHDs). Many of these patients require ongoing interventions for residual defects, conduit or valve dysfunction, and arrhythmia management, often performed using transcatheter techniques. Imaging plays a critical role in ensuring procedural success and safety. Intracardiac echocardiography (ICE) has emerged as an essential imaging modality in ACHD interventions. With continuous technological advancements, ICE offers several advantages over transesophageal echocardiography (TEE) and transthoracic echocardiography (TTE), including superior visualization, real-time guidance, and the ability to avoid general anesthesia. These benefits have made ICE the preferred imaging tool for many transcatheter procedures. This review explores the expanding role of ICE in ACHD interventions, highlighting its applications in structural and electrophysiological procedures. By enhancing procedural precision and reducing complications, ICE is transforming the management of ACHD patients, optimizing outcomes, and improving long-term care for this complex and growing population. Full article

Missed or delayed heart disease diagnoses pose a major challenge in pediatric primary care. Many cardiac conditions present with subtle or nonspecific symptoms that resemble benign childhood illnesses, making their prompt recognition difficult. This review describes congenital and acquired heart diseases prone to diagnostic delays, including critical congenital heart disease, coarctation of the aorta, atrial and ventricular septal defects, myocarditis, Kawasaki disease, heart failure, and pulmonary arterial hypertension. The atypical presentations of these disorders and the associated diagnostic pitfalls are emphasized. Furthermore, the importance of alarming symptoms and signs, such as chest pain, palpitations, syncope, and abnormal heart murmurs, is underscored. A structured approach to these red flags is presented to assist primary care pediatricians in identifying children at risk, initiating appropriate management, and referring them for specialized evaluation. The importance of preparticipation screening for athletes is also discussed, highlighting how it can be applied to all children during routine health visits to identify those with heart disease. Appropriate training is essential to increase pediatricians’ ability to recognize and manage cardiac patients. Full article

One out of every hundred live births present with congenital heart abnormalities caused by the aberrant development of the embryonic cardiovascular system. The conserved zinc finger transcription factor proteins, which include GATA binding protein 5 (GATA5) and GATA binding protein (GATA6) play important roles in embryonic development and their inactivation may result in congenital heart defects (CHDs). In this study, we performed genotypic–phenotypic analyses in two families affected by right-sided CHD diagnosed by echocardiography imaging. Proband A presented with pulmonary valve stenosis, and proband B presented with complex CHD involving the right heart structures. For variant detection, we employed whole-genome single-nucleotide polymorphism (SNP) microarray and family-based whole-exome sequencing (WES) studies. Proband A is a full-term infant who was admitted to the neonatal intensive care unit (NICU) at five days of life for pulmonary valve stenosis (PVS). Genomic studies revealed a normal SNP microarray; however, quad WES analysis identified a novel heterozygous [Chr20:g.61041597C>G (p.Arg237Pro)] variant in the GATA5 gene. Further analysis confirmed that the novel variant was inherited from the mother but was absent in the father and the maternal uncle with a history of heart murmur. Proband B was born prematurely at 35 weeks gestation with a prenatally diagnosed complex CHD. A postnatal evaluation revealed right-sided heart defects including pulmonary atresia with intact ventricular septum (PA/IVS), right ventricular hypoplasia, tricuspid valve hypoplasia, hypoplastic main and bilateral branch pulmonary arteries, and possible coronary sinusoids. Cardiac catheterization yielded anatomy and hemodynamics unfavorable to repair. Hence, heart transplantation was indicated. Upon genomic testing, a normal SNP microarray was observed, while trio WES analysis identified a novel heterozygous [Chr18:c.1757C>T (p.Pro586Leu)] variant in the GATA6 gene. This variant was inherited from the father, who carries a clinical diagnosis of tetralogy of Fallot. These findings provide new insights into novel GATA5/6 variants, elaborate on the genotypic and phenotypic association, and highlight the critical role of GATA5 and GATA6 transcription factors in a wide spectrum of right-sided CHDs. Full article

Background: Maternal phenylketonuria (PKU), a metabolic disorder caused by defective phenylalanine hydroxylase activity, requires strict lifelong dietary management to prevent toxic phenylalanine accumulation. During pregnancy, non-adherence to a low-phenylalanine diet can lead to maternal PKU syndrome, resulting in severe neonatal complications, including microcephaly, congenital heart defects, and growth restrictions. Despite advances in metabolic management and preconception care guidelines, adherence remains a significant challenge, particularly among adults transitioning out of pediatric care. This case report examines the clinical consequences of dietary non-adherence in maternal PKU, highlighting the importance of preconception education, metabolic monitoring, and multidisciplinary care in preventing adverse neonatal outcomes. Methods: Using the CARE guidelines, we present the clinical course of a male neonate born to a mother with untreated PKU. Results: The analysis incorporates maternal dietary history, prenatal care details, and neonatal outcomes. Additionally, a review of current literature on maternal PKU management and outcomes contextualizes the findings. The neonate, delivered at 38 weeks via cesarean section, exhibited low birth weight (2150 g), severe microcephaly (head circumference: 28 cm), microphthalmia, and septal heart defects. Maternal dietary non-adherence, beginning in late adolescence, contributed to significantly elevated phenylalanine levels during pregnancy (>20 mg/dL). Prenatal care was initiated in the 23rd week of gestation, delaying dietary intervention. The mother reported limited understanding of the teratogenic risks associated with poor dietary control, which was compounded by gaps in preconception counseling and care continuity. Conclusions: This case underscores the critical need for comprehensive preconception education and lifelong metabolic management for women with PKU. Early and sustained dietary adherence is essential to mitigate neonatal risks. Public health initiatives should prioritize access to preconception care, enhance patient education, and establish robust multidisciplinary support systems to optimize maternal and neonatal outcomes. Addressing barriers such as delayed care initiation and limited dietary support can significantly reduce the burden of maternal PKU syndrome. Full article

Bicuspid Aortic Valve (BAV) is a prevalent congenital heart defect, characterized by the presence of two cusps instead of three, leading to significant clinical implications such as aortic stenosis, regurgitation, and aneurysms. Understanding the genetic underpinnings of BAV is essential for early diagnosis and management, which can prevent severe complications like aortic dissection and heart failure. Recent studies have identified critical genes associated with BAV, including NOTCH1, GATA4, GATA5, SMAD6, NKX2.5, BMP2, and ROBO4, all of which play vital roles in aortic valve development and function. Imaging advancements, particularly in cardiac MRI and echocardiography, have enhanced the assessment of valve morphology and hemodynamics, with Wall Shear Stress emerging as a promising biomarker. This review consolidates current genetic and imaging research, elucidating the contributions of genetic variants to the etiology and progression of BAV, while emphasizing the importance of imaging biomarkers in clinical management. The findings aim to improve genetic screening strategies, facilitate early diagnosis, and guide the development of targeted therapies for individuals with BAV. Full article

Background/Objectives: The failure of physiological left-right (LR) patterning, a critical embryological process responsible for establishing the asymmetric positioning of internal organs, leads to a spectrum of congenital abnormalities characterized by laterality defects, collectively known as “heterotaxy”. MMP21 biallelic variants have recently been associated with heterotaxy syndrome and congenital heart defects (CHD). However, the genotype–phenotype correlations and the underlying pathogenic mechanisms remain poorly understood. Methods: Patients harboring biallelic MMP21 missense variants who underwent diagnostic genetic testing for CHD or heterotaxy were recruited at the Institute for Maternal and Child Health—I.R.C.C.S. “Burlo Garofolo”. Additionally, a literature review on MMP21 missense variants was conducted, and clinical data from reported patients, along with molecular data from in silico and modeling tools, were collected. Results: A total of 18 MMP21 missense variants were reported in 26 patients, with the majority exhibiting CHD (94%) and variable extra-cardiac manifestations (64%). In our cohort, through Whole-Exome Sequencing (WES) analysis, the missense p.(Met301Ile) variant was identified in two unrelated patients, who both presented with heterotaxy syndrome. Conclusions: Our comprehensive analysis of MMP21 missense variants supports the pathogenic role of the p.(Met301Ile) variant and provides significant insights into the disease pathogenesis. Specifically, missense variants are distributed throughout the gene without clustering in specific regions, and phenotype comparisons between patients carrying missense variants in compound heterozygosity or homozygosity do not reveal significant differences. These findings may suggest a potential loss-of-function mechanism for MMP21 missense variants, especially those located in the catalytic domain, and highlight their critical role in the pathogenesis of heterotaxy syndrome. Full article

D-transposition of the great arteries (D-TGA) is a common cyanotic critical congenital heart disease. An arterial switch operation (ASO) with/without a ventricular septal defect (VSD) closure is the preferred surgical approach, with an added challenge when an intramural coronary artery (IMC) is present (1), with a reported increased incidence of postoperative complications and mortality (2,3). We present our recent D-TGA with intramural coronary artery (TGA-IMC) experience, focusing on the salient features identified on echocardiography, computed tomography (CT) angiography, and invasive angiograms, as well as variations in ASO surgical techniques for repair. Diagnostic imaging evaluation allowed for identification of the lesion, as well as planning for and undertaking of two different surgical approaches. While the two patients had differing immediate postoperative courses, both were asymptomatic at discharge, with normal biventricular systolic function. Our experience demonstrates that the suspicion for a coronary anomaly in TGA can be raised prenatally and confirmed postnatally with focused trans-thoracic echocardiography and ECG-gated CT angiogram evaluation while also aiding in operative planning. Moreover, suggesting further exploration of the optimal surgical technique for the repair of TGA-IMC. Full article