Search Results (818)

Background/Objectives: Congenital heart malformations (CHDs) are not rare diseases, and, in many cases, their pathogenic mechanisms are well established. Several conotruncal defects are associated with genetic syndromes such as DiGeorge syndrome and RASopathies, reflecting shared developmental pathways affecting cardiac outflow tract formation. However, even common CHDs may occur within complex syndromic contexts, making early diagnosis essential for optimal management. This review aims to provide a unifying framework linking ciliary dysfunction to CHD phenotypes. Methods: We performed an integrative narrative review of genetic, experimental, and developmental studies focusing on the role of primary and motile cilia in cardiac morphogenesis. Particular attention was given to signaling pathways regulated by cilia and their contribution to disease phenotypes. Results: Emerging evidence indicates that primary and motile cilia act as central regulators of cardiac development, integrating morphogen gradients and mechanical cues into transcriptional programs. Dysfunctions in ciliary structure or signaling are increasingly recognized as important contributors to selected complex CHD phenotypes, particularly in syndromic forms and laterality-associated defects. This cilia-centered model may help explain part of the phenotypic heterogeneity observed in CHD and highlights shared mechanisms across distinct clinical entities. Conclusions: Understanding cilia-dependent mechanisms provides a unifying conceptual framework linking genetic defects to disrupted morphogenesis. This perspective may refine disease interpretation and support future development of precision diagnostics and pathway-informed therapeutic strategies in CHD. Full article

Congenital heart disease (CHD) is the most common anatomical malformation occurring in live-born infants and an increasing cause of morbidity and mortality all over the world. Population-based observations have described associations between maternal cardiometabolic disorders and the risk of CHD in offspring. The present article is a narrative review. The aim of this study was to review the epidemiological evidence and clinical observations relating maternal obesity and diabetes mellitus to the risk of CHD in offspring, with particular attention paid to first trimester disturbances of fetal cardiac development and the influence of genetic, epigenetic and environmental factors. Studies have shown that maternal diabetes is a risk factor associated with nearly all subtypes of CHDs in offspring, while obesity and overweight are associated with increased risk for complex defects and outflow tract obstruction and decreased risk for ventricular septal defects. Diabetes and obesity share several phenotypes, which could be transmissible from mother to fetus via the placenta. This means that an increase in maternal glucose could be responsible for the prevalence of CHD in newborns of obese women. On the other hand, maternal diabetes may induce epigenetic modifications in the developing fetus. DNA methylation changes can impact gene expression patterns relevant to heart development. The abovementioned studies are heterogenous, express different opinions and are often difficult to compare. Therefore, the results from these meta-analyses must be interpreted with caution. Optimal diabetes control is responsible for the prevention of oxidative stress in diabetic pregnancies, and a deeper understanding of maternal risk factors holds the potential to improve both prenatal detection of CHDs by identifying at-risk pregnancies and primary prevention of diseases by improving preconception management. Full article

Background/Objectives: The optimal timing of asymptomatic congenital pulmonary airway malformations (CPAM) is controversial. Early resection may reduce inflammation and scarring secondary to respiratory infections, but contemporary practice patterns are unknown. This study assesses trends in operative timing and approach over the past decade. Methods: A retrospective review was performed of 1934 CPAM patients in NSQIP-P undergoing resection (2012–2021). Trends in surgical approach and age at resection were assessed using Mann–Kendall tests. Multivariable logistic and linear regression were used to model the influence of age at operation on operative length, postoperative complications, and postoperative length of stay. Results: Thoracoscopic approach increased from 47.2% in 2012 to 80.8% in 2021 (p < 0.001). Median age at operation was 7.7 months. There was a downtrend in the open approach in patients ≤ 3 months old (tau = −0.511, p < 0.05) without a corresponding increase in VATS approach (tau = −0.11, p = 0.72). Instead, there was a statistically significant uptrend in all other age cohorts > 3 months old in the VATS approach. After adjusting for confounders there was no difference in complication rates between age cohorts. Conclusions: Adoption of thoracoscopic resection for CPAM has substantially increased. Despite the reported benefits of earlier resection, the timing of surgical resection remains variable with most surgeries still occurring after six months of age. Additionally, the decline in open surgeries in patients ≤ 3 months may reflect a preference towards the VATS approach in a slightly older infant population. Further research is necessary to determine optimal timing for CPAM resection. Full article

Neural tube defects (NTD) are congenital malformations that lead to structural abnormalities of the brain or spine. Mouse embryos deficient in Scavenger Receptor Class B Type 1 (SR-B1 KO), the main receptor for high-density lipoproteins, exhibit a high incidence of anterior NTD, which is associated with vitamin E deficiency and elevated levels of reactive oxygen species (ROS). Maternal supplementation with vitamin E, a micronutrient with antioxidant properties, completely prevents the occurrence of NTD and normalizes ROS levels in SR-B1 KO embryos, suggesting a contribution of oxidative stress to NTD in this model. In this work, we showed that SR-B1 KO embryos at gestational day E9.5 display higher levels of lipoperoxidative damage markers. Analysis of data obtained through shotgun lipidomics evidenced a selective and coordinated reorganization of fatty acid distribution, characterized by altered polyunsaturated and monounsaturated composition, together with reduced phosphatidylcholine and increased lysophosphatidylcholine levels, and diversion of fatty acids into triacylglyceride storage. Transcriptomic analysis revealed a coordinated upregulation of genes involved in phospholipid synthesis and remodeling, consistent with the altered lipid homeostasis observed in SR-B1 KO embryos. Together, these results provide novel information showing a potential link between oxidative stress and disruptions in mammalian embryonic lipid metabolism, highlighting phospholipid remodeling as a potential determinant of susceptibility to NTD. Full article

Extremity vascular malformations in children and adolescents are congenital vascular developmental abnormalities that often present to pediatric orthopedic surgeons with pain, swelling, restricted motion, contracture, gait disturbance, limb asymmetry, and growth-related deformity rather than with an obvious vascular phenotype. The orthopedic importance of these lesions lies less in surface appearance than in their potential to affect muscle balance, joint integrity, osseous development, and peri-procedural safety. This review translates contemporary vascular anomaly classification and multidisciplinary management pathways into a practical orthopedic framework for diagnosis, referral, and longitudinal limb management. The most useful first step is to distinguish low-flow from high-flow lesions and then define lesion depth, periarticular or osseous involvement, coagulopathy risk, and syndromic overgrowth phenotype. Ultrasound is usually the first-line imaging modality for flow characterization, whereas magnetic resonance imaging is the cornerstone for defining extent and planning treatment. Plain radiographs remain highly relevant for identifying phleboliths, osseous remodeling, arthropathy, contracture-related deformity, and limb-length discrepancy. Venous malformations generally warrant pathway-based coagulation assessment, especially D-dimer and fibrinogen, because localized intravascular coagulopathy has direct implications for intervention and surgery. Arteriovenous malformations are best managed within specialist multidisciplinary teams. Fibro-adipose vascular anomaly and syndromic overgrowth phenotypes warrant particular attention because they frequently drive pain, contracture, and progressive limb imbalance. Outcome assessment in this field should extend beyond lesion size and incorporate pain, function, quality of life, and growth-related consequences. For pediatric orthopedic surgeons, management should move from late deformity correction toward early classification, early referral, longitudinal surveillance of joint and growth-related complications, and careful integration of local, surgical, and systemic therapies. Full article

Zika virus (ZIKV) is an emerging flavivirus associated with congenital malformations and ocular complications, representing a significant public health concern. Retinal pigment epithelium (RPE) cells play a key role in maintaining retinal integrity and represent a primary target of ZIKV infection, making them a relevant model for studying host–virus interactions. In this study, we evaluated the antiviral activity of fat- and water-soluble vitamins against ZIKV in hTERT RPE-1 (hRPE1) cells. Particularly, vitamin A was identified as the compound that most effectively inhibited viral replication. Molecular dynamics simulations focusing on the PAS-B domain of the aryl hydrocarbon receptor (AHR) revealed a high affinity of vitamin A for the receptor. In hRPE1 cells, vitamin A treatment reduced viral RNA levels and decreased CYP1A1, TDO, and AHR mRNA expression. In parallel, IFNB1 expression increased, consistent with the involvement of type I interferon (IFN-I), as no antiviral effect was observed in IFN-I-deficient Vero cells. These findings suggest that vitamin A restricts ZIKV replication through host antiviral responses, potentially involving modulation of AHR-associated signaling. The combination of vitamin A and the well-known polyphenol resveratrol further enhanced antiviral activity, showing predominantly additive effects. Together, these results support the potential use of both bioactive compounds as a combined therapeutic strategy. Full article

Hemoptysis is a potentially life-threatening phenomenon with a wide range of underlying causes. While most episodes are linked to common conditions such as infections, malignancy, or pulmonary embolism, a proportion of cases are due to unusual and often unexpected etiologies. This narrative review summarizes published case reports, series, and observational studies describing rare causes of hemoptysis, including vascular malformations, congenital anomalies, benign tumors, systemic diseases, and unusual infections. These conditions are frequently overlooked, which may delay recognition and appropriate management. The reviewed examples highlight the variety of diagnostic challenges and the broad spectrum of therapeutic strategies that may be required, ranging from endovascular procedures and surgery to targeted medical therapy. Despite advances in diagnostic methods, a subset of patients remain classified as having idiopathic or cryptogenic hemoptysis. For this reason, clinicians should keep a broad differential diagnosis in mind and remain aware of rare but clinically important entities. Awareness of these uncommon presentations and individualized patient management are essential for improving outcomes and avoiding missed critical diagnoses. Full article

Background: Congenital cytomegalovirus (CMV) infection is the most common congenital infection worldwide and a leading cause of neurodevelopment impairment. Prenatal imaging plays a central role in diagnosis and prognostic assessment. Methods: We conducted a systematic review of studies evaluating the role of ultrasound, including dedicated fetal neurosonography and magnetic resonance imaging (MRI) in the prenatal detection and assessment of CMV infection. PubMed, Web of Science, and Scopus were searched for relevant studies, and data were synthesized focusing on detected abnormalities and the incremental diagnostic value of MRI. Results: Fifty-nine studies were included. Dedicated neurosonography (NSG) was the primary modality for detecting CMV-related fetal brain abnormalities, particularly ventriculomegaly and cortical malformations. Fetal MRI provided additional diagnostic information, mainly through improved visualization of the brain parenchyma, allowing better detection of white matter abnormalities, migrational disorders and posterior fossa involvement, especially when performed later in gestation. Conclusions: Dedicated neurosonography remains the cornerstone for the evaluation of suspected congenital fetal CMV infection. Fetal MRI represents a complementary tool that can confirm, refine or extend ultrasound findings and may improve prognostic assessment when additional or subtle brain abnormalities are suspected. Full article

Background: Omphalocele is a congenital defect of the anterior abdominal wall frequently associated with additional anomalies that substantially influence neonatal outcomes. Cardiovascular and pulmonary abnormalities are among the most clinically relevant factors affecting survival, yet their relative prognostic contribution remains incompletely characterized in smaller regional cohorts. Methods: This retrospective observational study included 50 neonates with omphalocele treated at a tertiary pediatric surgery center in Northeastern Romania between 2000 and 2025. Demographic characteristics, associated congenital anomalies, surgical management, and clinical outcomes were analyzed. Comparisons were performed between isolated and non-isolated omphalocele cases and according to the presence of cardiac and pulmonary anomalies. Univariate logistic regression was used to evaluate associations between associated anomalies and mortality. Results: Associated congenital anomalies were present in the majority of patients. Cardiac malformations were identified in 68% of cases, pulmonary anomalies in 22%, and combined cardiopulmonary anomalies in 20%. Overall mortality was substantial. Mortality was higher in non-isolated compared with isolated omphalocele, although this difference did not reach statistical significance. Univariate analysis showed that pulmonary anomalies were significantly associated with increased mortality (OR = 4.31, 95% CI: 1.20–15.50, p = 0.025), whereas cardiac anomalies alone were not significantly associated with mortality. Combined cardiopulmonary anomalies were associated with an increased mortality risk without reaching statistical significance. Conclusions: In this cohort, pulmonary anomalies were strongly associated with increased mortality among neonates with omphalocele. These findings suggest that detailed prenatal and postnatal pulmonary assessment may contribute to improved risk stratification and multidisciplinary management in affected neonates. The results should be interpreted in the context of the study’s retrospective design and limited sample size. Full article

MaChiP 1.0 used static magnetic resonance imaging (MRI) to identify coexistent idiopathic intracranial hypertension (IIH) and spontaneous intracranial hypotension (SIH) in Chiari I malformation (CM-I), improving etiologic characterization. This Protocol/Perspective paper presents MaChiP 2.0 as a testable, artificial intelligence (AI)-integrated imaging roadmap for acquired Chiari I malformation (CM-I), intended to support the differentiation between congenital and acquired tonsillar descent and to guide leak-localization imaging in suspected spontaneous intracranial hypotension (SIH). Building on the structural foundation of MaChiP 1.0, this framework outlines how dynamic craniospinal imaging tools, including phase-contrast magnetic resonance imaging (PC-MRI) and displacement encoding with stimulated echoes (DENSE), may be combined with conventional morphologic markers to refine imaging evaluation. It further describes the potential use of currently available artificial intelligence (AI) methods for segmentation, cerebrospinal fluid (CSF) flow quantification, and imaging biomarker assessment. Noninvasive magnetic resonance (MR)-based techniques are proposed as first-line approaches for leak detection, while digital subtraction myelography (DSM) and computed tomography myelography (CTM) remain the reference standards when initial imaging is inconclusive. Full article

Background/Objectives: Congenital gastrointestinal malformations (CGIMs) are important causes of neonatal surgical morbidity with potential long-term consequences. Although some can be suspected on prenatal ultrasound, data on their clinical spectrum, burden, and distribution remain limited in Eastern Europe. This study aimed to describe the diagnostic spectrum, timing of diagnosis, documented prenatal ultrasound suspicion, and the early outcomes of CGIMs managed at a Romanian tertiary referral centre between 2020 and 2024, a period overlapping the COVID-19 pandemic. Methods: We conducted a retrospective, single-centre observational study including all consecutive paediatric patients with a CGIM admitted between January 2020 and December 2024. Cases were analysed by index anatomical diagnosis, phenotypic complexity, and etiologic background. Logistic regression was used to examine factors associated with documented prenatal suspicion and in-hospital mortality, and annual hospital-based CGIM admission rates were modelled with Poisson regression, using the number of paediatric surgical admission as the offset. Results: Among the 231 children (58.9% male), the most frequent diagnoses were persistent omphalomesenteric duct remnants (16%), oesophageal atresia with or without tracheoesophageal fistula (15.6%), and anorectal malformations (13.9%). Documented prenatal ultrasound suspicion was present in 17.7% of pregnancies (41/231) and was likely underestimated because antenatal documentation was unavailable for 17.7% of the cohort. The highest proportions of documented prenatal suspicion were observed in jejuno-ileal and duodenal atresia. Foregut malformations were the most common by embryological grouping (93/231, 40.3%). Most cases were diagnosed during the neonatal period (n = 161, 69.7%). CGIM admission rates per 1000 surgical admissions ranged from 20.8 to 38.2. An exploratory Poisson model yielded a hospital-based rate ratio per calendar year of 0.88 (95% CI 0.81–0.97; p = 0.008). However, given the limited number of annual observations and increasing total surgical admissions, this finding should be considered exploratory and hypothesis-generating only. Complex cases accounted for 8.2% and associated extra-intestinal anomalies were present in 70.1%. In-hospital mortality was 13.0% and occurred predominantly in patients with complex or foregut malformations. In the primary complete-case multivariable model, prematurity remained independently associated with mortality, whereas complex CGIMs were not independently associated with mortality after adjustment. A prespecified multiple-imputation sensitivity analysis yielded a stronger estimate for complex CGIMs, but this finding was interpreted cautiously and not treated as a primary result. Conclusions: In this tertiary referral cohort, documented prenatal suspicion of CGIM was low and strongly diagnosis-dependent, while most cases were identified in the neonatal period. Mortality was concentrated in foregut and clinically complex presentations in the descriptive analysis, while prematurity remained independently associated with death in the primary multivariable model. These findings highlight the need to strengthen prenatal referral pathways and coordinated national surveillance. Full article

A decade has elapsed since the first recognized cluster of congenital anomalies associated with Zika virus (ZIKV) was reported in Brazil in 2015, culminating in the formal delineation of Congenital Zika Syndrome (CZS) as a specific pattern of birth defects. This narrative review examines the ten-year trajectory of CZS as a tropical infectious disease, from its initial emergence and public health emergency declaration by the World Health Organization (WHO) in February 2016, through evolving epidemiological, clinical, and scientific understanding. CZS is characterized by a spectrum of severe neurological manifestations—including microcephaly, subcortical calcifications, malformations of cortical development, ventriculomegaly, and corpus callosum abnormalities—alongside ophthalmic, auditory, and musculoskeletal complications. Transmitted primarily by Aedes aegypti mosquitoes in tropical and subtropical regions, ZIKV disproportionately affects low- and middle-income countries in Latin America, Africa, and Southeast Asia, underscoring its nature as a quintessential tropical disease linked to poverty, inadequate vector control, and health inequity. Over ten years, substantial advances have been made in understanding ZIKV pathogenesis, neurodevelopmental outcomes, diagnostic criteria, and multidisciplinary clinical management of affected children. In the therapeutic and preventive domain, over 45 vaccine candidates have been identified, with 16 reaching Phase 1 or 2 clinical trials by late 2025, though no licensed vaccine or specific antiviral therapy yet exists. This review contextualizes CZS within the broader framework of neglected tropical diseases, evaluates its global and family-level burden, and critically appraises progress and remaining gaps in clinical care, vaccination, and vector control over the past ten years. Full article

Background: Nasal glioma (NG), also known as nasal glial heterotopia, is an extremely rare congenital anomaly characterized by the presence of mature glial tissue outside the cranial cavity. Most patients present with midline craniofacial malformations at birth. However, a small subset of them is entirely intranasal and have no accompanying visible features. We present an unusual case of delayed diagnosis of NG, in tandem with a systematic literature review. Methods: A previously well 2-year-old male presented with obstructive apnea secondary to an intranasal mass. Neuroimaging of his paranasal sinuses demonstrated a bony defect in the anterior cribriform plate with herniation of a soft tissue structure into the right nasal cavity. He underwent craniotomy, total excision of the lesion and repair of skull base defect. His postoperative period was uneventful with resolution of his symptoms. Histology reported infiltrates of mature glial tissue with rare neurons forming the excised nasal mass. We conducted a structured literature review using PRISMA guidelines to evaluate clinical features of NG. Results: A comprehensive search of PubMed and Scopus databases featured 133 published cases of NG relevant to our case. Overall, NG is more common in males, with most cases diagnosed within the first year of life. Clinical presentation usually involved an external nasal mass (82.8%) and/or respiratory symptoms (28.7%), with prenatal detection reported in a subset of cases. Magnetic resonance imaging was the preferred imaging modality. Surgical excision was the mainstay of treatment. Postoperative outcomes were favorable in most patients, with 84.7% showing no complications or recurrence. Incomplete excision was associated with recurrence (10%). Conclusions: We present an intranasal case of NG with late diagnosis that was successfully managed with surgery. Our review underscores the importance of early imaging, accurate diagnosis, and complete surgical resection for best outcomes in affected children. Full article

Sturge–Weber Syndrome (SWS) is a rare congenital disorder presenting with a vascular malformation in the upper face and brain, causing impaired blood–brain barrier function and perfusion, increased calcium signaling, inflammation, and seizures. All these neuropathologic processes result in injury to the brain. The somatic GNAQ R183Q variant, which accounts for the majority of SWS cases, increases signaling through MAPK, PI3K, mTOR, and inflammatory pathways, primarily in endothelial cells. The discovery of this variant enabled the creation of transgenic and genetic animal and cell culture models. Generating in vitro models has been challenging due to the mosaic nature of SWS, and attempts to separate unaffected from mutant cells in primary culture have failed, limiting the utility of in vitro work. Ongoing in vitro work seeks to overcome these limitations, shape our understanding of SWS, and lead to translational advances in treatment and prevention by studying the affected molecular pathways and identifying future targets for therapy. Full article

Hypospadias is a congenital malformation of the male external genitalia resulting from incomplete fusion of the urethral folds during embryonic development. The perineal form represents the most severe phenotype and is frequently associated with abnormalities such as cryptorchidism and penile hypoplasia. Although surgical correction is generally recommended in young dogs, the long-term clinical course of severe hypospadias under conservative management remains poorly documented. In this study, we describe an unusual canine case of severe perineal hypospadias that survived to geriatric age under conservative management and subsequently developed bilateral testicular tumors arising from cryptorchid testes. Despite recurrent urinary tract infections during early life, the patient maintained an acceptable quality of life with long-term supportive care, providing a rare clinical example of extended survival without surgical correction. Because no molecular material was available from the patient, publicly available mouse transcriptomic datasets related to genital tubercle development and Leydig cell differentiation were consulted only as contextual reference. These datasets illustrate established developmental regulators and steroidogenic pathways relevant to genital formation and testicular function but do not represent direct molecular findings from the reported case. This report primarily highlights the clinical course and management of severe hypospadias in a dog, while using existing transcriptomic knowledge solely to provide biological context. The findings should therefore be interpreted as descriptive and hypothesis-generating rather than as evidence of a direct mechanistic link between developmental abnormalities and endocrine tumorigenesis. Full article