Congenital Heart Malformations Masked by Infantile Gangliosidosis-Case Report and Growing Evidence for Metabolic Disease-Associated Aortopathies.

Gangliosidosis (ORPHA: 79255) is an autosomal recessive lysosomal storage disease (LSD) with a variable phenotype and an incidence of 1:200000 live births. The underlying genotype is comprised GLB1 mutations that lead to ß-galactosidase deficiency and subsequently to the accumulation of monosialotetrahexosylganglioside (GM1) in the brain and other organs. In total, two diseases have been linked to this gene mutation: Morquio type B and Gangliosidosis. The most frequent clinical manifestations include dysmorphic facial features, nervous and skeletal systems abnormalities, hepatosplenomegaly, and cardiomyopathies. The correct diagnosis of GM1 is a challenge due to the overlapping clinical manifestation between this disease and others, especially in infants. Therefore, in the current study we present the case of a 3-month-old male infant, admitted with signs and symptoms of respiratory distress alongside rapid progressive heart failure, with minimal neurologic and skeletal abnormalities, but with cardiovascular structural malformations. The atypical clinical presentation raised great difficulties for our diagnostic team. Unfortunately, the diagnostic of GM1 was made postmortem based on the DBS test and we were able to correlate the genotype with the unusual phenotypic findings.

A new approach to explore the correlation between declarative memory and anxiety in animal models of schizophrenia and microplastic pollution.

The discovery of new detrimental effects associated with microplastic pollution is ever-growing and reaching alarming rates worldwide, as it is linked to numerous disorders such as lung diseases, gastrointestinal problems, and cancer. However, a less explored issue is their impact on mental health, more precisely schizophrenia, even though several studies have shown the presence of microplastics in air, water, soil, and even food, thus making them a significant part of our daily dietary intake. It is also well known that declarative memory and anxiety levels are impaired in schizophrenia. However, apart from the novel object recognition test, the possibilities for testing memory in zebrafish are quite limited. For these reasons, we designed a novel memory test based on rewards, a learning period, and zebrafish's natural preference for certain colors. Among the results, our fish preferred the color yellow over red, and we illustrated that ketamine and its combination with methionine provide a robust model that seems to better represent the aspects of schizophrenia in animal models. Moreover, surprisingly, we observed that microplastics (more precisely, polypropylene fibers) ingested by animals through the diet seem to act as a buffer against ketamine toxicity and as an enhancer for methionine exposure. Moreover, according to our results, groups with higher anxiety levels seem to perform better on the memory test.

Nutritional Approach in Selected Inherited Metabolic Cardiac Disorders-A Concise Summary of Available Scientific Evidence.

Inborn errors of metabolism (IMDs) are a group of inherited diseases that manifest themselves through a myriad of signs and symptoms, including structural or functional cardiovascular damage. The therapy of these diseases is currently based on enzyme-replacement therapy, chaperone therapy or the administration of supplements and the establishment of personalized dietary plans. Starting from the major signs identified by the pediatric cardiologist that can indicate the presence of such a metabolic disease-cardiomyopathies, conduction disorders or valvular dysplasias-we tried to paint the portrait of dietary interventions that can improve the course of patients with mitochondrial diseases or lysosomal abnormalities. The choice of the two categories of inborn errors of metabolism is not accidental and reflects the experience and concern of the authors regarding the management of patients with such diagnoses. A ketogenic diet offers promising results in selected cases, although, to date, studies have failed to bring enough evidence to support generalized recommendations. Other diets have been successfully utilized in patients with IMDs, but their specific effect on the cardiac phenotype and function is not yet fully understood. Significant prospective studies are necessary in order to understand and establish which diet best suits every patient depending on the inherited metabolic disorder. The most suitable imagistic monitoring method for the impact of different diets on the cardiovascular system is still under debate, with no protocols yet available. Echocardiography is readily available in most hospital settings and brings important information regarding the impact of diets on the left ventricular parameters. Cardiac MRI (magnetic resonance imaging) could better characterize the cardiac tissue and bring forth both functional and structural information.

Atherosclerosis from Newborn to Adult-Epidemiology, Pathological Aspects, and Risk Factors.

Cardiovascular disease is the leading cause of mortality and morbidity throughout the world, accounting for 16.7 million deaths each year. The underlying pathological process for the majority of cardiovascular diseases is atherosclerosis, a slowly progressing, multifocal, chronic, immune-inflammatory disease that involves the intima of large and medium-sized arteries. The process of atherosclerosis begins in childhood as fatty streaks-an accumulation of lipids, inflammatory cells, and smooth muscle cells in the arterial wall. Over time, a more complex lesion develops into an atheroma and characteristic fibrous plaques. Atherosclerosis alone is rarely fatal; it is the further changes that render fibrous plaques vulnerable to rupture; plaque rupture represents the most common cause of coronary thrombosis. The prevalence of atherosclerosis is increasing worldwide and more than 50% of people with circulatory disease die of it, mostly in modern societies. Epidemiological studies have revealed several environmental and genetic risk factors that are associated with the early formation of a pathogenic foundation for atherosclerosis, such as dyslipidemia, hypertension, diabetes mellitus, obesity, and smoking. The purpose of this review is to bring together the current information concerning the origin and progression of atherosclerosis in childhood as well as the identification of known risk factors for atherosclerotic cardiovascular disease in children.

The Role of Microglial Exosomes and miR-124-3p in Neuroinflammation and Neuronal Repair after Traumatic Brain Injury.

(1) Background: In this study, we aimed to explore the regulatory mechanism of miR-124-3p microglial exosomes, as they were previously reported to modulate neuroinflammation and promote neuronal repair following traumatic brain injury (TBI). (2) Methods: Studies investigating the impact of microglial exosomal miRNAs, specifically miR-124-3p, on injured neurons and brain microvascular endothelial cells (BMVECs) in the context of TBI were reviewed. (3) Results: Animal models of TBI, in vitro cell culture experiments, RNA sequencing analysis, and functional assays were employed to elucidate the mechanisms underlying the effects of miR-124-3p-loaded exosomes on neuroinflammation and neuronal repair. Anti-inflammatory M2 polarization of microglia, mTOR signaling suppression, and BMVECs-mediated autophagy were reported as the main processes contributing to neuroprotection, reduced blood-brain barrier leakage, and improved neurologic outcomes in animal models of TBI. (4) Conclusions: Microglial exosomes, particularly those carrying miR-124-3p, have emerged as promising candidates for therapeutic interventions in TBI. These exosomes exhibit neuroprotective effects, attenuate neuroinflammation, and promote neuronal repair and plasticity. However, further research is required to fully elucidate the underlying mechanisms and optimize their delivery strategies for effective treatment in human TBI cases.

Metacognition in Schizophrenia Spectrum Disorders-Current Methods and Approaches.

Metacognition essentially represents "thinking about thinking", or the individual's capacity to control and monitor their own cognitive processes. Metacognition impairment in schizophrenia represents a core feature of the disease, and, in the last fifteen years, the subject has evolved into a growing study area concentrating on a wide variety of processes, such as clinical insight, autobiographical memory, cognitive beliefs, reasoning, and memory biases. Since metacognition is a complex subject, we wanted to focus on the different nuances of metacognition transposed into the lives of patients diagnosed with either schizophrenia or a schizoaffective disorder. Therefore, this narrative review aims to analyze the literature in order to provide an insight regarding the current methods and approaches in the study of metacognition in schizophrenia or schizoaffective disorders, as well as the results provided. Results from the reviewed studies showed that patients with schizophrenia have a lower metacognitive ability, which is strongly reflected in their lives. Studies to date have highlighted the interaction between schizophrenia symptoms and metacognition, which shows how metacognition impacts work performance, autobiographical memory, motivation, the severity of symptoms, and social cognition.

Post-Traumatic Headache: A Review of Prevalence, Clinical Features, Risk Factors, and Treatment Strategies.

Post-traumatic headache (PTH) is a common and debilitating consequence of mild traumatic brain injury (mTBI) that can occur over one year after the head impact event. Thus, better understanding of the underlying pathophysiology and risk factors could facilitate early identification and management of PTH. There are several factors that could influence the reporting of PTH prevalence, including the definition of concussion and PTH. The main risk factors for PTHs include a history of migraines or headaches, female gender, younger age, greater severity of the head injury, and co-occurring psychological symptoms, such as anxiety and depression. PTH clinical profiles vary based on onset, duration, and severity: tension-type headache, migraine headaches, cervicogenic headache, occipital neuralgia, and new daily persistent headache. Pharmacological treatments often consist of analgesics and non-steroidal anti-inflammatory drugs, tricyclic antidepressants, or antiepileptic medication. Cognitive behavioral therapy, relaxation techniques, biofeedback, and physical therapy could also be used for PTH treatment. Our work highlighted the need for more rigorous studies to better describe the importance of identifying risk factors and patient-centered treatments and to evaluate the effectiveness of the existing treatment options. Clinicians should consider a multidisciplinary approach to managing PTH, including pharmacotherapy, cognitive behavioral therapy, and lifestyle changes.

Foreign Body Aspiration in Children-Retrospective Study and Management Novelties.

Foreign body aspiration (FBA) is a frequent diagnosis in children. In the absence of other lung conditions, such as asthma or chronic pulmonary infections, this manifests as a sudden onset of cough, dyspnea, and wheezing. The differential diagnosis is based on a scoring system which takes into account the clinical picture as well as the radiologic aspects. The treatment that is considered the gold-standard for FBA in children remains to be rigid fibronchoscopy, however it comes with several potentially crucial local complications such as airway edema, bleeding, and bronchospasm, along inherent issues due to general anesthesia. Material and methods: Our study is a retrospective study analyzing the medical files of the cases from our hospital over the span of 9 years. The study group consisted of 242 patients aged 0-16 years diagnosed with foreign body aspiration in the Emergency Clinical Hospital for Children "Sfânta Maria" Iași, between January 2010-January 2018. Clinical and imaging data were extracted from the patients' observation sheets. Results: In our cohort, the distribution of children with foreign body aspiration was uneven, with the highest incidence being reported in children from rural areas (70% of cases), whereas the most affected age group was 1-3 years, amounting to 79% of all cases. The main symptoms which led to emergency admittance were coughing (33%) and dyspnea (22%). The most important factors that determined the unequal distribution were socio-economic status, which relates to a lack of adequate supervision by parents, as well as the consumption of food inappropriate for their age. Conclusions: Foreign body aspiration is a major medical emergency that may be associated with dramatic clinical manifestations. Several scoring algorithms designed to establish the need for bronchoscopy have been proposed, taking into account both the clinical and radiological results. The issue with asymptomatic or mild symptomatic cases, as well as difficulties managing cases with radiolucent foreign bodies, remains a challenge.

A Review of the Most Recent Clinical and Neuropathological Criteria for Chronic Traumatic Encephalopathy.

(1) Background: Chronic traumatic encephalopathy (CTE) is a complex pathological condition characterized by neurodegeneration, as a result of repeated head traumas. Currently, the diagnosis of CTE can only be assumed postmortem. Thus, the clinical manifestations associated with CTE are referred to as traumatic encephalopathy syndrome (TES), for which diagnostic multiple sets of criteria can be used. (2) Objectives: In this study, we aimed to present and discuss the limitations of the clinical and neuropathological diagnostic criteria for TES/CTE and to suggest a diagnostic algorithm enabling a more accurate diagnostic procedure. (3) Results: The most common diagnostic criteria for TES/CTE discriminate between possible, probable, and improbable. However, several key variations between the available diagnostic criteria suggest that the diagnosis of CTE can still only be given with postmortem neurophysiological examination. Thus, a TES/CTE diagnosis during life imposes a different level of certainty. Here, we are proposing a comprehensive algorithm of diagnosis criteria for TES/CTE based on the similarities and differences between the previous criteria. (4) Conclusions: The diagnosis of TES/CTE requires a multidisciplinary approach; thorough investigation for other neurodegenerative disorders, systemic illnesses, and/or psychiatric conditions that can account for the symptoms; and also complex investigations of patient history, psychiatric assessment, and blood and cerebrospinal fluid biomarker evaluation.

Review on the Role of Salivary Biomarkers in the Diagnosis of Mild Traumatic Brain Injury and Post-Concussion Syndrome.

(1) Background: While mild traumatic brain injuries (TBIs) are a major public health issue, post-concussion syndrome (PCS) remains a controversial entity. In both cases, the clinical diagnosis is mainly based on the symptoms and brain imaging evaluation. The current molecular biomarkers were described from blood and cerebrospinal fluid (CSF), yet both fluid collection methods are invasive. Saliva could be preferred in molecular diagnosis due to its non-invasive and non-expensive methods of acquisition, transport, and samples processing. (2) Objectives: In the present study, we aimed to review the latest developments in salivary biomarkers and their potential role in diagnosing mild TBIs, and PCS. (3) Results: In TBIs and PCS, a few novel studies focusing on salivary biomarkers have emphasized their importance in diagnosis. The previous studies mainly focused on micro RNAs, and only a few on extracellular vesicles, neurofilament light chain, and S100B. (4) Conclusions: The combination between salivary biomarkers, clinical history and examination, self-reported symptoms, and cognitive/balance testing can provide a non-invasive alternative diagnostic methodology, as compared to the currently approved plasma and cerebrospinal fluid biomarkers.

Omphalocele and Cardiac Abnormalities-The Importance of the Association.

Omphalocele is the most common ventral abdominal wall defect. Omphalocele is associated with other significant anomalies in up to 80% of cases, among which the cardiac ones are the most frequent. The aim of our paper is to highlight, through a review of the literature, the importance and frequency of association between the two malformations and what impact this association has on the management and evolution of patients with these pathologies. We reviewed the titles, the available abstracts, and the full texts of 244 papers from the last 23 years, from three medical databases, to extract data for our review. Due to the frequent association of the two malformations and the unfavorable effect of the major cardiac anomaly on the prognosis of the newborn, the electrocardiogram and echocardiography must be included in the first postnatal investigations. The timing of surgery for abdominal wall defect closure is mostly dictated by the cardiac defect severity, and usually the cardiac defect takes priority. After the cardiac defect is medically stabilized or surgically repaired, the omphalocele reduction and closure of the abdominal defect are performed in a more controlled setting, with improved outcomes. Compared to omphalocele patients without cardiac defects, children with this association are more likely to experience prolonged hospitalizations, neurologic, and cognitive impairments. Major cardiac abnormalities such as structural defects that require surgical treatment or result in developmental delay will significantly increase the death rate of patients with omphalocele. In conclusion, the prenatal diagnosis of omphalocele and early detection of other associated structural or chromosomal anomalies are of overwhelming importance, contributing to the establishment of antenatal and postnatal prognosis.

Nosocomial Infections Affecting Newborns with Abdominal Wall Defects.

Abdominal wall defects are serious birth defects, with long periods of hospitalization and significant costs to the medical system. Nosocomial infection (NI) may be an additional risk factor that aggravates the evolution of newborns with such malformations. METHODS: in order to analyze the factors that may lead to the occurrence of NI, we performed a retrospective study over a period of thirty-two years (1990-2021), in a tertiary children's hospital; 302 neonates with omphalocele and gastroschisis were eligible for the study. RESULTS: a total of 33.7 % patients were infected with one or more of species of bacteria or fungi. These species were Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp., Staphylococcus spp., Enterococcus spp. or Candida spp., but the rate of NI showed a significant decrease between the 1990-2010 and 2011-2021 period (p = 0.04). The increase in the number of surgeries was associated with the increase in the number of NI both for omphalocele and gastroschisis; in the case of gastroschisis, the age of over 6 h at the time of surgery increased the risk of infection (p = 0.052, marginal statistical significance). Additionally, for gastroschisis, the risk of NI was 4.56 times higher in the presence of anemia (p < 0.01) and 2.17 times higher for the patients developing acute renal failure (p = 0.02), and a hospitalization period longer than 14 days was found to increase the risk of NI 3.46-fold (p < 0.01); more than 4 days of TPN was found to increase the NI risk 2.37-fold (p = 0.015). Using a logistic regression model for patients with omphalocele, we found an increased risk of NI for those in blood group 0 (OR = 3.8, p = 0.02), in patients with a length of hospitalization (LH) of ≥14 days (OR = 6.7, p < 0.01) and in the presence of anemia (OR = 2.5, p = 0.04); all three independent variables in our model contributed 38.7% to the risk of NI. CONCLUSION: although in the past 32 years we have seen transformational improvements in the outcome of abdominal wall defects, there are still many factors that require special attention for corrections.

Unusual Association of Diamond-Blackfan Anemia and Severe Sinus Bradycardia in a Six-Month-Old White Infant: A Case Report and Literature Review.

Diamond-Blackfan anemia is a rare (6-7 million live births), inherited condition manifesting as severe anemia due to the impaired bone marrow production of red blood cells. We present the unusual case of a six month old infant with a de novo mutation of the RPS19 gene causing Diamond-Blackfan anemia who additionally suffers from severe sinus bradycardia. The infant was diagnosed with this condition at the age of four months; at the age of 6 months, she presents with severe anemia causing hypoxia which, in turn, caused severe dyspnea and polypnea, which had mixed causes (hypoxic and infectious) as the child was febrile. After correction of the overlapping diarrhea, metabolic acidosis, and severe anemia (hemoglobin < 3 g/dL), she developed severe persistent sinus bradycardia immediately after mild sedation (before central venous catheter insertion), not attributable to any of the more frequent causes, with a heart rate as low as 49 beats/min on 24 h Holter monitoring, less than the first percentile for age, but with a regular QT interval and no arrhythmia. The echocardiogram was unremarkable, showing a small interatrial communication (patent foramen ovale with left-to-right shunting), mild left ventricular hypertrophy, normal systolic and diastolic function, and mild tricuspid regurgitation. After red cell transfusion and appropriate antibiotic and supportive treatment, the child's general condition improved dramatically but the sinus bradycardia persisted. We consider this a case of well-tolerated sinus bradycardia and foresee a good cardiologic prognosis, while the hematologic prognosis remains determined by future corticoid response, treatment-related complications and risk of leukemia.

Total Anomalous Pulmonary Venous Return in the Time of SARS-CoV-2-Case Report.

The management of children with complex and life-threatening heart malformations became a clinical conundrum during the SARS-CoV-2 pandemic. The pathophysiological features of the new coronavirus infection have raised major dilemmas regarding the postoperative evolution of an infected patient, and the epidemiological limitations have tightened the criteria for selecting cases. We present the case of a newborn diagnosed with total anomalous pulmonary venous return (TAPVR) who underwent surgical repair of the defect with favorable outcome, despite a prior diagnosis of SARS-CoV-2 infection. We discuss the medical and surgical management of TAPVR, highlighting possible management difficulties brought by the SARS-CoV-2 pandemic.

Cardiotoxicity of Electronic Cigarettes and Heat-Not-Burn Tobacco Products-A Problem for the Modern Pediatric Cardiologist.

Electronic nicotine delivery systems (ENDS) have become increasingly popular among adolescents, either as an alternative to conventional cigarettes (CCs) or as a newly acquired recreational habit. Although considered by most users as a safer option for nicotine intake, these devices pose significant health risks, resulting in multisystem damage. Heat-not-burn products, which, unlike ENDS, contain tobacco, are also alternatives to CCs that consumers use based on the idea that their safety profile is superior to that of cigarettes. Recent studies in the USA and EU show that adolescents are particularly prone to using these devices. Pediatric cardiologists, as well as other healthcare professionals, should be aware of the complications that may arise from acute and chronic consumption of these substances, considering the cardiovascular damage they elicit. This article summarized the known data about the impact of ENDS on the cardiovascular system, with emphasis on the pathophysiological and molecular changes that herald the onset of systemic lesions alongside the clinical cardiovascular manifestations in this scenario.

Drug Release from Nanoparticles (Polymeric Nanocapsules and Liposomes) Mimed through a Multifractal Tunnelling-Type Effect.

The present study analyzes (theoretically and experimentally) a drug release process from nanoparticles (polymeric nanocapsules and liposomes). This process is functionalized on the surface with an aptamer. These types of drug release processes can also be included in cream-type formulations. The obtained cream ensures the active targeting of tumor epithelial cells, in the case of skin cancer, because it can be easily administered to the skin by spreading, thus avoiding side effects caused by the toxicity of the drug to healthy cells, increasing both patient compliance and the effectiveness of the treatment. The process of obtaining these formulations is a simple one, easy to use and highly reproductible. The theoretical model, based on the multifractal tunnel effect within the Scale Relativity Theory, considers the system as a complex one. In this model, complexity is replaced with system multifractality, quantified in physical quantities as multifractal dimensions and multifractal functions. The main advantage of this approach consists in the fact that it allows us to obtain information on system behavior at a microscopic level and to evaluate microscopic characteristics of the system, such as intrinsic transparences of the drug molecules, multifractal constants as indicators of the system's complexity, the frequency of interactions within the system and the energy ratio between potential barrier energy and the energy of drug molecules.

Increasing Trends in Obesity-Related Cardiovascular Risk Factors in Romanian Children and Adolescents-Retrospective Study.

Childhood obesity has become a global public health issue and its assessment is essential, as an obese child is a future overweight or obese adult. Obesity is no longer a matter of exercising more and eating less, with several factors coming into play and dictating the pattern of fat accumulation and the ease/difficulty of reducing it. In the current paper, we aimed to analyze the cardiovascular impact of obesity in a large number of patients alongside the paraclinical changes that occur due to weight gain, and to perform an analysis on the increase in prevalence throughout our research. The main cardiovascular conditions identified were hypertension (15.36%), septal or concentric hypertrophic cardiomyopathy (11.15%), atherosclerosis risk (13.04%), and hypercholesterolemia (20.94%). We have used echocardiography to measure the thickness of epicardial adipose tissue (useful for assessing the patient's cardiovascular risk), and we observed that it was greater in children with moderate and severe obesity alongside diastolic dysfunction of the left ventricle in the whole group, without any connection with hypertension or coronary impairment. Obese children will be affected by increased cardiovascular mortality and morbidity in adulthood and they may experience early cardiovascular dysfunction. We want to strongly underline the importance and necessity of programs for the early detection and prevention of obesity and its complications, especially since interesting phenomena such as the "obesity paradox" exist and prove that obesity is far less understood than it is at a first glance.

Ganglioneuroma of the Bladder in Association with Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a genetic disease, with autosomal dominant transmission, related to pathogenic variant of the tumor suppressor gene NF1 (17q11.2), predisposing affected subjects to a variety of benign (neurofibromas and plexiform neurofibromas) and malignant tumors. The lack of the NF1-neurofibromin gene product can cause uncontrolled cell proliferation in the central or peripheral nervous system and multisystemic involvement, and so the disease includes a heterogeneous group of clinical manifestations. Ganglioneuromas are benign tumors developing from the neural crest cells of the autonomic nervous system, considered to be part of neuroblastic tumors. Bladder localization is extremely rare in adults, and only three such cases were reported in children so far. The aim of our study, in addition to a brief review of the literature of these pathologies, is to bring to your attention the case of a sixteen year old patient with a very rare association of NF1 and bladder ganglioneuroma, who presented at the hospital with gross hematuria. Since bladder ganglioneuroma is a rare pathological condition, the differential diagnosis is difficult and imaging investigations and pathological investigations are the ones that elucidate this disease. The clinical approach of the medical multidisciplinary team involved should help the patient in managing her medical and surgical situation.

Current Challenges in the Treatment of the Omphalocele-Experience of a Tertiary Center from Romania.

Omphalocele is a congenital abdominal wall defect with a constant incidence in recent decades, sometimes representing a real burden for neonatal intensive care units due to prolonged hospitalization and the evolution to death. In our study, we aimed to detect the main risk factors of an unfavorable evolution in the case of omphalocele. METHODS: Retrospective cohort study of all neonates with omphalocele treated in our tertiary pediatric hospital during the last three decades; from 158 patients, 139 patients were eligible for the study. We tried to determine the risk of death using logistic regression model. RESULTS: If the neonate develops sepsis, then there is an increased risk (13.03 times) of evolution to death. Similarly, the risk of death is 10.82 times higher in the case of developing acute renal failure, 6.28 times higher in the case of associated abnormalities, 5.54 in the case of developing hemorrhagic disease, and 3.78 in the case of conservative treatment (applied for giant omphalocele or severe chromosomal abnormalities). Prematurity increases by 3.62 times the risk of death. All six independent variables contributed 61.0% to the risk of death. The area under the ROC curve is 0.91, meaning that the diagnostic accuracy of our logistic regression model is very good for predicting the contribution of the six independent variables to the risk of death. CONCLUSION: Although in the past 30 years we witnessed several improvements in the antenatal diagnosis and management of omphalocele, survival rate remained constant, 47.5% overall. Much effort is still needed to eliminate the risk factors for death in this condition.

The Genetic Architecture of Vascular Anomalies: Current Data and Future Therapeutic Perspectives Correlated with Molecular Mechanisms.

Vascular anomalies (VAs) are morphogenesis defects of the vascular system (arteries, capillaries, veins, lymphatic vessels) singularly or in complex combinations, sometimes with a severe impact on the quality of life. The progress made in recent years with the identification of the key molecular pathways (PI3K/AKT/mTOR and RAS/BRAF/MAPK/ERK) and the gene mutations that lead to the appearance of VAs has allowed the deciphering of their complex genetic architecture. Understanding these mechanisms is critical both for the correct definition of the phenotype and classification of VAs, as well as for the initiation of an optimal therapy and the development of new targeted therapies. The purpose of this review is to present in synthesis the current data related to the genetic factors involved in the etiology of VAs, as well as the possible directions for future research. We analyzed the data from the literature related to VAs, using databases (Google Scholar, PubMed, MEDLINE, OMIM, MedGen, Orphanet) and ClinicalTrials.gov. The obtained results revealed that the phenotypic variability of VAs is correlated with genetic heterogeneity. The identification of new genetic factors and the molecular mechanisms in which they intervene, will allow the development of modern therapies that act targeted as a personalized therapy. We emphasize the importance of the geneticist in the diagnosis and treatment of VAs, as part of a multidisciplinary team involved in the management of VAs.