Congenital Research Articles

Concurrent diagnosis of severe haemophilia A and acute lymphoblastic leukemia in a child: First report in Greece

Haemophilia A is a congenital bleeding disorder resulting by deficiency of coagulation factor VIII and Acute Lymphoblastic Leukemia (ALL) Is the most common cancer type in children. The concurrence of hemophilia and ALL in pediatric patients is quite rare. We report a case of a 2.5 year old boy, with an uneventful past history, which presented with pallor, petechiae, ecchymoses and lethargy to the emergency department. A full blood count on admission revealed severe leukocytosis, anemia and thrombocytopenia. Diagnosis of ALL was confirmed and the patient was put on chemotherapy. Excessive bleeding from the site of entry of the central venous catheter led to complementary testing, which revealed very low levels of Factor VIII and severe Haemophilia A was also diagnosed. The patient suffered from minor gastrointestinal bleeds and a severe intrabdominal hemorrhage due to an abcess eruption during his treatment for ALL. To date, very few cases of ALL and Haemophilia have been reported in children, and due to this rarity there are no guidelines concerning the adjustments in treatment in this small population of patients.

Echocardiographic Screening Model for Improved Assessment of Atrial Septal Defect Closure: A Multicenter Retrospective Study.

Atrial septal defect (ASD) is a prevalent congenital heart condition in adults, which finally leads to pulmonary hypertension and right heart failure if left untreated. Right heart catheterization (RHC), the current gold standard for determining ASD closure feasibility, is invasive. Thus, a noninvasive prescreening tool is urgently needed. In a multicenter, retrospective study, we assessed 924 ASD patients (2012-2022) to determine their suitability for ASD closure. Using LASSO regression, we identified predictors for a correctable shunt, enabling us to create the ASD model. The ASD model, comprising of estimated pulmonary artery systolic pressure (ePASP), peak velocity through the pulmonary valve (PV), peak E-wave velocity through the tricuspid valve (TVE), and right atrial longitudinal dimension (RA) by echocardiography, was constructed and exhibited favorable discriminative capability with an area under the curve (AUC) of 0.941 (95% CI: 0.920-0.961) in the derivation group. The model also demonstrated good calibration and discriminative abilities in the validation cohort. When juxtaposed with the earlier congenital heart disease (CHD) model, the newly developed ASD model demonstrated superior predictive capabilities for correctable shunt, supported by the net reclassification index (NRI) [0.063 (95% CI: 0.001-0.127, p = 0.047)] and integrated discrimination improvement (IDI) [0.023 (95% CI: 0.011-0.036, p <0.001)]. In summary, our research advocates the ASD model as a superior tool for screening suitable ASD defect closure candidates.

Young patients in the cardiac intensive care unit: insights from the critical care cardiology trials network registry

Abstract Background Elderly patients treated in the cardiac intensive care unit (CICU) have engendered much warranted investigation. However, little is known about young patients as another distinct population. Purpose: To describe the demographics, clinical profiles, and outcomes of young CICU patients in order to understand any distinct needs and challenges of this population. Methods: We analyzed consecutive admissions to adult CICUs from 2018 to 2023 in the Critical Care Cardiology Trials Network (CCCTN), a multicenter prospective registry of advanced CICUs in North America coordinated by the TIMI Study Group. Patients aged &amp;lt;40 years were classified as "young patients" and compared to patients ≥ 40 years of age. Results: Among 29,035 CICU admissions during the study period, the median age was 67 years (25th, 75th %iles: 56, 70). Admissions 18 to 40 years of age comprised 6.7% (n=1959) of total admissions. The young cohort was more likely to be female (40.0% vs 36.4%, p=0.0015) and non-Caucasian (55.3% vs. 43.0%, p&amp;lt;0.0001). Traditional cardiovascular risk factors were less common among the young, as were prior cardiovascular diagnoses other than congenital heart disease and pulmonary hypertension. Initial SOFA scores and serum lactate levels were similar in the 2 groups (Table). The most common CICU admission diagnoses in the young were heart failure (HF), arrhythmia, and acute coronary syndrome (ACS) (Panel A). Of these, HF was more common in the young (26.4% vs 19.5%, p&amp;lt;0.0001), while arrhythmia (16.8% vs 18.9%, p=0.03) and ACS (10.9% vs 29.4%, p&amp;lt;0.0001) were less common compared to the older group (Panel B). Tamponade, hypertensive emergency, and congenital disease were more common in the young (Panel B). Respiratory insufficiency was the most common indication for admission to CICU in the young (24.6%) followed by cardiogenic shock (22.4%), unstable arrythmia (15.7%), and cardiac arrest (12.7%, Panel C). Critical care resources, other than coronary angiography/PCI, were utilized significantly more often in the young group (Panel D). Overall utilization of mechanical circulatory support (MCS) was modestly higher among the young cohort (13.1% vs. 11.4%, p=0.03, Panel D); however, among those managed with MCS, the % of MCS that was ECMO was higher among the young (29.3% vs 9.9%, p&amp;lt;0.0001). Young admissions had longer CICU stays (2.7 [1.2-5.9] vs 2.3 [1.2-4.9], p&amp;lt;0.0001). CICU mortality (6.5% vs 10.5%, p&amp;lt;0.0001) and hospital mortality (9.5% vs 14.4%, p&amp;lt;0.0001) were significantly lower in the young. Conclusion: Patients under the age of 40 admitted to CICUs presented with similar disease severity to older patients but more often had shock or cardiac arrest, had longer ICU stays, and more use of advanced ICU therapies but with lower in-hospital mortality. This important patient cohort merits continued clinical and research focus.

Decreased left atrial volume and preserved left atrial function in children with congenital Zika syndrome

Abstract Introduction The infection caused by Zika virus during pregnancy leads to congenital Zika syndrome (CZS). In a previous study of our group, we found that the heart is smaller in children with CZS, with few functional alterations. Left atrial strain imaging enables quantitative assessment of left atrial function, and recently its application has also shown promise in the pediatric population. Purpose To evaluate left atrial function in children affected by CZS, using echocardiogram and speckle tracking imaging technique. Methods This observational study was conducted with children with CZS using a two-dimensional speckle tracking technique to measure left atrial reservoir strain (LAS-r), conduit strain (LAS-cd), and contraction strain (LAS-ct). Also, to investigate the relationship between LAS-r and systolic excursion of the septum and lateral mitral annular plane (MAPSE), left atrial volume index and E/e’ ratio. Results A total of 52 patients were included, the median age of the studied population was 5 years (3 to 6), 59.6% male, and the body surface area was 0.66 [0.51, 0.90]. In the echocardiographic evaluation the left atrium volume index (ml/m²) was 13.15 [6.80, 18.00], considered smaller by the reference value. Also, the LAS-r (%) was 40.99 [24-70.5], LAS-cd (%) was 30,94 [32.5-52.5], LAS-cd (%) was 10,91 [5.2-24], values considered normal by the literature. Lateral MAPSE (cm) was 1.25 [0.81, 1.86] and septal MAPSE (cm) was 0.98 [0.78, 1.66] and E/e' ratio was 7.52 [4.57, 10.78]. A positive linear correlation was found between LAS-r and lateral MAPSE (r = 0.51, P = 0.019). Conclusion This original study with children with CZS shows that despite reduced atrial volume, the left atrial function remains normal, and correlates with left ventricular function evaluated by MAPSE. Further studies are needed to prospectively analyze the follow-up of left atrial morphology and function in this population.

Screening for congenital Chagas disease in a non-endemic area: a cost-effectiveness analysis

Abstract Background Due to climate changes, immigration, and globalization, Chagas Disease (CD) also afflicts nations without vector transmission. In Europe, congenital CD (cCD) is a significant public health issue, perpetuating the disease: it is crucial to perform CD screening in pregnant women at risk, as the treatment of infants is effective in eradicating the infection. Only a few European regions have a definite algorithm for diagnosing cCD, but no official guidance has been published at the national or European level. To support policymakers, this study aims to outline a cost-effectiveness analysis of CD screening in non-endemic areas, such as Italy, in pregnant women born or arriving from endemic countries and in their newborns. Methods To measure the economic impact of cCD screening, a decision tree model will be used to compare the test option (screening, diagnosis, treatment, follow-up) with no test option (no screening, progression of disease). Model parameters will be taken from relevant scientific literature. The primary outcome will be the Incremental Cost-Effectiveness Ratio (ICER) between the two options. Sensitivity analyses will be conducted to determine how changes in prevalence, transmission rate, screening adherence, and treatment adherence may affect the ICER. Results We expect the ‘test’ option to be cost-effective even with significant reductions in prevalence, transmission rate, adherence to screening or treatment. Threshold levels of these variables will allow to critically extend the results to areas with reduced immigration, patchy distribution of migrants at risk, health logistical limitations, and limited access to care for immigrants. Conclusions Our findings can help policymakers implement official screening programs and diagnostic algorithms for cCD in Italy and other non-endemic countries. This contributes to SDG 3 by combating the spread and burden of neglected tropical diseases and contributing to maternal, child, and migrant health. Key messages • Screening for congenital Chagas Disease in a non-endemic area may be cost-effective and cost-saving. • Study findings could provide useful information for health policymakers to combat Chagas Disease in Europe.

Variability in patient-reported outcomes among different congenital heart defects: a comparative analysis of 7,498 patients from 32 countries

Abstract Background Patient-reported outcomes (PROs) may not always correlate with the complexity of congenital heart defects (CHDs), as significant variation has been observed between CHDs within complexity levels. Accurate comparisons across various types of CHDs necessitate large sample sizes. Purpose The objective of this study was to compare PROs across different CHDs in a large international sample. Methods ‘Assessment of Patterns of Patient-Reported Outcomes in Adults with Congenital Heart disease – International Study II’ (APPROACH-IS II) was an international cross-sectional investigation, in which 8,415 patients from 32 countries in 6 continents were enrolled (20 high; 7 upper-middle; 4 lower-middle; and 1 low income). For the comparison across different CHDs, conditions with at least 50 patients were included in the analysis. Hence, the sample consisted of 7,498 patients (median age=33y; 53.1% women). Patients completed questionnaires to measure perceived health status (RAND-12 Health Survey; EuroQOL-5D Visual Analog Scale); depressive symptoms (Patient Health Questionnaire-8); anxiety (General Anxiety Disorder-7) and quality of life (Linear Analog Scale). Generalized linear mixed models (GLMMs) were performed with center as random effect. Results Cyanotic heart defects were associated with the lowest scores for physical functioning, mental health, self-rated health, and quality of life (see Figure). Other CHDs found to be associated with poor PRO scores encompassed unrepaired secundum atrial septal defect, Ebstein anomaly, single ventricle, and truncus arteriosus. Conversely, the most favorable scores for all PROs, except for anxiety, were observed with isolated pulmonic stenosis. Other CHDs with favorable PRO scores comprised coarctation of the aorta, isolated small ventricular septal defect, congenital aortic valve disease, and repaired ventricular septal defect. Adjusted for sociodemographic and physiological factors, GLMMs revealed significant differences across defects, using the best score for each PRO as the reference (see Figure). Conclusion Substantial variation in PROs was observed among different types of CHDs. Interestingly, some complex heart defects demonstrated relatively good PRO scores, comparable to some simple defects. On the other hand, unrepaired simple defects or those with residual lesions, were associated with worse PROs.

Congenital partial diaphragmatic eventration presenting with Chilaiditi’s sign: a case report

BackgroundChilaiditi’s sign is an incidental radiographic finding, associated with intestinal disposition located between liver and right diaphragm. It is considered as an acquired rather than a congenital condition and the prevalence ranges from 1.18% to 2.4% according to recent adult retrospective studies. The aspects of this rare entity with regards to a 7-month-old male initially misdiagnosed as diaphragmatic hernia is discussed.Case presentationA 4-month-old Caucasian male was misdiagnosed with a congenital diaphragmatic hernia owing to previous hospitalization with complaints of respiratory tract infection. On admission 3 months later, he was free of any signs and symptoms of intestinal obstruction or respiratory distress. Thorax computed tomography revealed Chilaiditi’s sign. A diagnostic laparoscopy was regarded necessary to evaluate the anatomical details. The most prominent finding was the lack of muscle fibers and almost transparent appearance of the medial aspect of the partially eventrated right hemidiaphragm. Owing to delicate anatomical presentation, diaphragmatic plication was considered hazardous. The patient is doing well and under follow-up.ConclusionsIt is obvious that Chilaiditi’s sign is not always a completely incidental finding of no consequence, and may indicate an underlying congenital diaphragmatic pathology, clearly defined by laparoscopic evaluation in this case.

Overview on Hereditary Spherocytosis Diagnosis.

Hereditary spherocytosis (HS) is a congenital haemolytic disorder, resulting from plasma membrane protein deficiency of red blood cells (RBCs). Typical pathological signs are anemia, jaundice, and splenomegaly; in newborns, jaundice is the main symptom. This study focused on the state of art about the HS diagnosis, from traditional to innovative methods, including diagnostic algorithms that can be applied for pediatric and adult patients, for different laboratory diagnostic levels. The first erythrocyte parameters used for HS diagnosis were the mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), and red blood cell distribution width (RDW); nowadays new parameters are used in blood cell counter. Advia analyzers (Siemens Medical Solutions) supply the hyper-dense cell percentage (% Hyper), which reflects the red blood cells hyperchromia. Sysmex instruments (i.e. XT-4000i, XE-5000, XN-Series) provide the MicroR, that is the percentage of erythrocytes smaller than 60 fL, Hypo-He, which is the percentage of erythrocytes with a content of hemoglobin less than 17 pg and % Hyper-He, which represents the percentage of RBC with cellular hemoglobin content higher than 49 pg. CELL-DYN Sapphire (Abbott Diagnostics) introduced the HPR parameter (% HPR), which represents the erythrocytes with hemoglobin > 410 g/L. Beckman Coulter instruments supply the mean sphered corpuscular volume (MSCV), which is the average volume of all erythrocytes, including mature erythrocytes and reticulocytes. Other reference tests for screening and diagnosis of HS are the acidified glycerol lysis test (AGLT), the eosin-5-maleimide (EMA) binding test and genetic testing by next-generation sequencing. The diagnostic workup of hereditary spherocytosis could be improved thanks to all the available tests, including new molecular tools. However, it requires synergy between clinicians and laboratory staff, evaluating clinical manifestations, all available data related to the disease and the prognosis to fill the diagnostic gaps in the near future.

Mitral valve phenotypes in SMAD3-related thoracic aortic disease: insights from the Montalcino Aortic Consortium

Abstract Background SMAD3 pathogenic variants (PV) predispose to heritable thoracic aortic aneurysms and dissections (HTAD). Mitral annular disjunction (MAD) associated with mitral valve prolapse (MVP) and mitral regurgitation (MR) was identified as a potential new marker of disease severity in Marfan syndrome. The prevalence and prognostic impact of these mitral phenotypes in other forms of HTAD are less known. Purpose We hypothesize that mitral abnormalities are increased in SMAD3-related HTAD and are associated with increased risk for valve and aortic complications. Methods The Montalcino Aortic Consortium (MAC) registry has enrolled participants with PV in 15 HTAD genes. Subjects &amp;gt;16 years old with complete imaging and clinical data were included in this study. MVP was defined according to current guidelines. MR was classified as mild, moderate, or severe. MAD was defined by a &amp;gt;3-millimeter gap between the posterior mitral valve leaflet hinge point and the inferolateral myocardium as confirmed by direct measurement of echocardiogram images. Frequencies of MVP, MR, and MAD were compared between MAC participants with SMAD3 PV and other HTAD PV. Associations between clinical and echo characteristics and the composite outcome of arrhythmia, aortic surgery, aortic dissection, or congestive heart failure was evaluated with multivariable logistic regression. Results In 671 MAC participants (129 with SMAD3 PV, 36 [IQR 19-51] years, 49% female), the prevalence of MVP was 15% and the prevalence of MR was 22%. Both MVP (31/129, 24%, vs. 67/542, 12%, OR 2.2 [1.4-3.6], P&amp;lt;0.001) and MR (40/129, 31%, vs. 108/542, 20%, OR 1.8 [1.2-2.8], P&amp;lt;0.006) were more common in participants with SMAD3 PV compared to other PV and were further enriched in cases with SMAD3 missense PV compared to loss of function PV (MR or MVP: 26/48, 54% vs. 7/30, 23%, OR 3.9 [1.4-10.8], P&amp;lt;0.007). Images were available from 238 MAC participants (67 with SMAD3 PV) to assess for MAD. MAD (29/67, 43%, vs. 28/171, 16%, OR 3.9 [2.1-7.3], P&amp;lt;0.0001), or the composite of MR, MVP, or MAD (42/67, 63%, vs. 69/171, 35%, OR 3.2 [1.8-5.7], P&amp;lt;0.0001) was more common with SMAD3 PV compared to other PV (Figure 1). Twelve participants with SMAD3 PV (18%) had prominent mitral phenotypes (&amp;gt;mild MR, &amp;gt;10 mm MAD, or MAD with MVP) but no significant aortic dilation (Z&amp;lt;3). When controlling for age and sex, MR or MVP, but not MAD, was independently associated with the composite outcome (OR 16 [2.4-110], Figure 2). Conclusion Mitral valve pathology, including MVP, MR, and MAD, is increased in individuals with SMAD3 PV compared to other HTAD PV. Prominent mitral phenotypes related to SMAD3 missense PV may identify a high-risk subgroup with adverse cardiovascular outcomes. Because congenital mitral disease may be the primary presenting feature of SMAD3 PV, genetic testing for HTAD should be considered for such patients, especially if they also have a family history of thoracic aortic disease.

A drug repurposing screen reveals dopamine signaling as a critical pathway underlying potential therapeutics for the rare disease DPAGT1-CDG.

DPAGT1-CDG is a Congenital Disorder of Glycosylation (CDG) that lacks effective therapies. It is caused by mutations in the gene DPAGT1 which encodes the first enzyme in N-linked glycosylation. We used a Drosophila rough eye model of DPAGT1-CDG with an improperly developed, small eye phenotype. We performed a drug repurposing screen on this model using 1,520 small molecules that are 98% FDA/EMA-approved to find drugs that improved its eye. We identified 42 candidate drugs that improved the DPAGT1-CDG model. Notably from this screen, we found that pharmacological and genetic inhibition of the dopamine D2 receptor partially rescued the DPAGT1-CDG model. Loss of both dopamine synthesis and recycling partially rescued the model, suggesting that dopaminergic flux and subsequent binding to D2 receptors is detrimental under DPAGT1 deficiency. This links dopamine signaling to N-glycosylation and represents a new potential therapeutic target for treating DPAGT1-CDG. We also genetically validate other top drug categories including acetylcholine-related drugs, COX inhibitors, and an inhibitor of NKCC1. These drugs and subsequent analyses reveal novel biology in DPAGT1 mechanisms, and they may represent new therapeutic options for DPAGT1-CDG.

Fully automated detection of anomalous aortic origin of the coronary arteries in coronary CT images: a novel artificial intelligence-based screening tool

Abstract Background Anomalous Aortic Origin of the Coronary Artery (AAOCA) is a rare congenital disease that can be easily overlooked during contrast-enhanced Coronary Computed Tomography Angiography (CCTA) image analysis. Objective In this study, we aimed to develop a novel artificial intelligence-based screening tool to automate the detection of AAOCA in CCTA images. Method We enrolled 127 patients from the coronary artery anomaly registry from two centers with AAOCA diagnosis based on CCTA as well as 413 normal cases. A deep learning model was developed to automatically segment the aorta and the left ventricle (LV), after which the images were automatically cropped to the aortic root and LV intersection with a box size of 6 cm3. The images were then clipped to Hounsfield Units ranging from -400 to 750 and normalized to -1 to1. These cropped regions were fed into different residual convolutional neural networks (ResNet, with different depths 10, 18, 34 and 50) to detect AAOCA. Model development (parameter and hyperparameters optimization) was performed on the training and validation sets (70/10%), and finally, it was tested on the 20% untouched test set. Various classification metrics were reported for the detection of AAOCA. Results ResNet-10 achieved an AUC of 0.91 (sensitivity: 0.89, specificity: 0.86), while ResNet-18 showed improved performance with an AUC of 0.95 (sensitivity: 0.89, specificity: 0.95). ResNet-34 achieved an AUC of 0.94 (sensitivity: 0.83, specificity: 0.96), and ResNet-50 excelled with the highest AUC of 0.96 (sensitivity: 0.89, specificity: 0.95), indicating its superior capability in accurately identifying AAOCA. Conclusion We developed a high-performance AI tool for the fully automated detection of AAOCA using CCTA images. This tool can be used to evaluate large patient cohorts and detect AAOCA in extensive databases. Moreover, it can operate seamlessly alongside clinical assessments of CCTA scans, providing real-time alerts to medical personnel about potential AAOCA findings. This enhances diagnostic efficiency and supports early intervention in cardiovascular care.

Klippel-Trénaunay-Weber Syndrome: Prenatal Diagnosis and Review of the Literature.

Klippel-Trénaunay-Weber syndrome (KTW) is a rare congenital disease, representing a challenge in prenatal diagnosis due to overlapping characteristics with other syndromes and no specific genetic markers known to date. We have collected all the cases present in the literature on the prenatal diagnosis of KTW, emphasizing common ultrasound findings that can guide the clinician and genetics to the prenatal counseling. Thus, we collected all the information about the postnatal prognosis and the necessity for treatment. Our review of 44 cases highlights the typical common features: hemihypertrophy, predominantly affecting the right leg, with cystic lesions extending to the trunk or upper limbs and rare internal organ involvement. Prenatal complications, including hydrops and polyhydramnios, emphasize the need for a careful ultrasound follow-up. Despite no identified genetic mutation, genetic counseling and invasive testing are recommended. Mortality rate due to a severe complication known as Kasabach-Merritt syndrome, underlines the importance of early diagnosis and accurate management strategies. Prenatal diagnosis of KTW, guided by ultrasound findings and genetic counseling, could help with informed decision-making and optimal care planning.

Association of non-invasive assessed anatomical features with functional testing in coronary artery anomalies - NARCO trial

Abstract Introduction Anomalous aortic origin of a coronary artery (AAOCA) is a rare congenital condition believed to carry an increased risk for myocardial ischemia. However, correlation between anatomical characteristics and ischemia remains unclear. Therefore, this study aimed to assess: 1. The difference of invasive fractional flow reserve (FFR) and intravascular ultrasound (IVUS)-based minimal lumen area (MLA) between baseline and stress. 2. The association of coronary computed tomography angiography (CCTA)-based anatomical characteristics to invasively measured hemodynamics and IVUS in AAOCA. Methods Consecutive patients with AAOCA and presence of ≥1 anatomical high-risk features (i.e. intramural course (IM), slit-like ostium, acute take-off angle or proximal narrowing), were systematically evaluated as part of the NARCO trial using CCTA, FFR using adenosine (140 µg/kg/min), dobutamine-volume stress (20-40mcg/kg/min, 0.5-1mg atropine and 3L of saline solution) and IVUS- MLA of IM. Anatomic high-risk features were quantified by CCTA including ostial lumen area and IM-MLA, IM-width, IM-height, IM-elliptic ratio, take-off angle, proximal narrowing and IM length of the anomalous coronary segment. Results A total of 94 patients with AAOCA were screened, whereas 48 showed high-risk anatomic features and underwent the complete stress protocol. Mean age was 54±12 years and 36 (75%) were male and 39 (81%) presented with symptoms. FFRstress was significantly lower than FFRadenosine (0.88 [0.81-0.91] vs. 0.91 [0.87-0.94], p&amp;lt;0.001) (Figure 1). FFRadenosine was ≤0.8 in 5 patients (10%), and FFRdobutamine was ≤0.8 in 12 patients (25%), resulting in 7 (15%) with FFRadenosine &amp;gt;0.8 while FFRdobutamine was ≤0.8. IVUS-MLA was decreased from 6.3 (5.4-8.2) mm2 to 5.4 (4.2-7.1) mm2 during stress (p&amp;lt;0.001) (Figure 2), while elliptic ratio increased from 2.6 (2.1-3.4) to 3.3 (2.5-4.4) (p&amp;lt;0.001). Logistic regression analysis for body surface area adjusted CCTA derived high-risk features showed, that only ostial lumen area, IM-MLA, -elliptic ratio and -width could predict FFRstress ≤0.8. Receiver operating curve analysis showed that ostial width had the greatest AUC with 0.86 (accuracy 83%, sensitivity 83%, and specificity 83%). Eight out of 12 (67%) patients with hemodynamic relevance underwent surgery, 2 (17%) underwent stenting and 2 (17%) were treated with medication. Conclusion In patients with AAOCA and anatomic high-risk features, only one quarter are hemodynamic relevant. FFR during dobutamine-volume stress showed to be the more sensitive stress modality as compared to FFRadenosine. CCTA derived ostial and IM anatomical severity is associated with ischemia under stress. Comprehensive functional and anatomical assessment of AAOCA helps to optimize patient management and avoid unnecessary revascularization.Figure 1:FFRadenosine vs FFRstressFigure 2:IVUS-MLArest vs IVUS-MLAstress

An Exoskeleton Design and Numerical Characterization for Children with Duchenne Muscular Dystrophy

This research addresses a feasibility study for validating an exoskeleton with kinematic considerations. The designed exoskeleton will be used for children with congenital disorders, especially for a case study characterized by Duchenne muscular dystrophy (DMD). The research core focuses on virtual simulations carried out through the multibody systems theory under an MSC Adams software environment, with an exoskeleton constructive solution. The designed exoskeleton mechanism is characterized by simplicity, low-cost, and easy-operation features criteria. The results obtained through a numerical processing analysis validate the feasibility study of the proposed prototype.

Satisfactory Clinical Response to Erlotinib in a Patient Diagnosed with Olmsted Syndrome.

Olmsted syndrome is a rare congenital keratinization disorder characterized by mutilating palmoplantar keratoderma (PPK), often accompanied by flexion deformity, periorificial keratotic plaques, and hair abnormalities. The majority of Olmsted syndrome cases are attributed to mutations in the TRPV3 (Transient receptor potential vanillin 3) gene(1). Herein, we aim to present a sporadic case of Olmsted syndrome with a recurrent c1717G&amp;gt;T p.Gly573Cys variant in the TRPV3 gene, demonstrating clinical improvement with the epidermal growth factor inhibitor Erlotinib.

Enhancement of enteric neural stem cell neurogenesis by glial cell-derived neurotrophic factor in experimental Hirschsprung's disease.

Stem cell therapy offers a promising solution for congenital diseases like Hirschsprung's disease (HSCR). Optimizing stem cell efficacy by modifying the cells and their environment is crucial, but in vitro culture conditions need to be further improved. Glial cell-derived neurotrophic factor (GDNF) plays an important role in neuronal survival, proliferation, migration and differentiation during enteric nervous system (ENS) development. In this study, the effects of GDNF on neurites derived from an Ednrb knockout model were investigated with the aim of enhancing the neurogenic potential of enteric neural crest cells (ENCCs). Neurospheres were generated form Ednrb+/+ (control) and Ednrb-/- mice at embryonic day13.5 (E13.5) with Sox10-green fluorescent protein (Venus) transgenic expression. These neurospheres were cultured in control media and neurospheres from Ednrb-/- were cultured with either control media or media supplemented with GDNF. ENCCs differentiation was assessed using immunofluorescence staining after 18days. GDNF-treated Ednrb-/- neurospheres showed increased size and higher density of Sox10-positive ENCCs compared to untreated Ednrb-/- neurospheres. GDNF also enhanced the distribution of both TUJ1-positive neurons and S100-positive glial cells. GDNF effectively enhanced the neurogenic potential of ENCCs from HSCR animal model. This finding is crucial for the development of cell therapy in HSCR.

Minor's Syndrome or Dehiscence of the Superior Semicircular Canal: A Case Report

Semicircular canal dehiscence is a congenital syndrome that mainly affects the superior and, less commonly, the posterior semicircular canal in the temporal bone. This syndrome was first reported by Minor et al. in 1998. The prevalence is about 0.5% in the general population. The most characteristic symptom is the Tullio phenomenon, predominantly vertigo and nystagmus. Hearing loss (in particular conductive loss) often completes overall clinical picture. The dehiscence may be completely asymptomatic, in which case it is seen as an incidental finding on radiological investigations. Audiological evaluation includes audiometry and vestibular evoked myogenic potentials (VEMPs). Clinical symptoms are based on the pathophysiological concept of a third mobile window within the inner ear. Diagnosis is confirmed by high resolution petrous temporal bone CT with multiplanar reconstructions (MPRs) in the plane of the canal (Pöschls’ plane for the superior semicircular canal) and 3-D surface reconstructions. MR findings are less sensitive for this entity. The most common differential diagnosis is otosclerosis. Clinical–radiological correlations have therapeutic applications even though the indication for surgery depends on the severity of the vestibular symptoms.

Risk factors of obstructive sleep apnea syndrome in the developmental age

Background: Obstructive Sleep Apnea Syndrome (OSAS) is a prevalent respiratory sleep disorder in children, associated with severe health consequences, including hypertension, cardiac dysfunction, and neurocognitive impairment. Despite extensive research on OSAS in adults, the risk factors for pediatric OSAS remain underexplored. Objective: This literature review aims to identify and present the key risk factors associated with pediatric OSAS based on contemporary studies. Methods: A systematic search of the PubMed and Scopus databases was conducted for literature published between 2016 and 2024. Search terms included “obstructive sleep apnea,” “children,” and “risk factors.” A total of 93 relevant studies were reviewed after excluding non-pediatric and irrelevant papers from an initial pool of 283. Results: The most commonly identified risk factors for pediatric OSAS include adenoid and tonsillar hypertrophy, obesity, craniofacial abnormalities, and asthma. Additional risk factors such as allergic rhinitis, recurrent upper respiratory infections, nasal stenosis, congenital diseases, low vitamin D levels, and preterm birth were also noted. Conclusion: Pediatric OSAS is influenced by multiple factors, including anatomical, physiological, and genetic components. Further research is required to explore emerging risk factors, such as role of vitamin D deficiency and microbiota, and to clarify the impact of variables like ethnicity and breastfeeding.

Adaptive behavior in primary agenesis of the corpus callosum

Background and aimsPrimary agenesis of the corpus callosum (ACC) is a congenital neurological disorder characterized by the absence, either partial or complete, of the corpus callosum in individuals who do not have intellectual disability and are otherwise neurologically asymptomatic. While mild to moderate neurocognitive deficits have been observed in individuals with primary ACC using neuropsychological assessments, the impact of this syndrome on adaptive behavior remains insufficiently understood. MethodsThis study used self- and informant-ratings on the Adaptive Behavior Assessment System, Second Edition (ABAS-II) to evaluate adaptive behavior in 35 adults diagnosed with primary ACC. ResultsWhile adults with primary ACC reported adaptive functioning comparable to an age-adjusted normative sample, family informants rated their adaptive ability below norms in several skill domains, particularly social skills. ConclusionsThis pattern of lower ratings by informants than self-ratings suggests adults with ACC may have poor understanding of their own behavior and its consequences. This study demonstrates that informants observe significant deficiencies in the conceptual, social, and practical aspects of adaptive behavior in persons with primary ACC, and that these deficiencies are not seen as clearly by the persons themselves.

Adeno-Associated Virus Gene Transfer Ameliorates Progression of Skeletal Lesions in Mucopolysaccharidosis IVA Mice.

Mucopolysaccharidosis type IVA (MPS IVA) is an autosomal congenital metabolic lysosomal disease caused by a deficiency of the N-acetyl-galactosamine-6-sulfate sulfatase (GALNS) gene, leading to severe skeletal dysplasia. The available therapeutics for patients with MPS IVA, enzyme replacement therapy and hematopoietic stem cell transplantation, revealed limitations in the impact of skeletal lesions. Our previous study, a significant leap forward in MPS IVA research, showed that liver-targeted adeno-associated virus (AAV) gene transfer of human GALNS (hGALNS) restored GALNS enzymatic activity in blood and multiple tissues and partially improved the aberrant accumulation of storage materials. This promising approach was further validated in our current study, where we delivered AAV8 vectors expressing hGALNS, under the control of a liver-specific or ubiquitous promoter, into MPS IVA murine disease models. The results were highly encouraging, with both AAV8 vectors leading to supraphysiological enzymatic activity in plasma and improved cytoplasmic vacuolization of chondrocytes in bone lesions of MPS IVA mice. Notably, the ubiquitous promoter constructs, a potential game-changer, resulted in significantly greater enzyme activity levels in bone and improved pathological findings of cartilage lesions in these mice than in a liver-specific one during the 12-week monitoring period, reinforcing the positive outcomes of our research in MPS IVA treatment.