Objective Our objective was to observe the benefits and limitations of WES (Whole Exome Sequencing) in the prenatal setting, in the Romanian population. The scope was to observe the diagnostic yield in comparison to molecular karyotyping testing, which had negative results, as well as a case of consanguinity. Methods The first criteria was selecting pregnancies with abnormal ultrasound findings. These findings would not lead the medical team to a certain known syndrome. Second, we performed SNP-array, which tested negative in all cases, except for Case number 9 which had an abnormal result. The ulterior testing method was WES, using Massive Parallel Sequencing of the whole coding region of the human genome on Next Generation Sequencing Platform, NovaSeq 6000 (average coverage >100X, read length: 2x100bp). The Twist Human Core Exome kit RefSeq & Mitochondrial panel (Twist Bioscience) was used for the library preparation. Bioinformatic analysis was performed by direct comparison of the genome of the test sample with the human reference sequence (hg38). Results Our small cohort of 10 patients, resulted in a 50% diagnostic yield. After receiving the results whether a diagnose or a negative result, 2 couples chose to terminate the pregnancy, 5 were born affirmatively without symptoms, and are still monitored up to date. One of the pregnancies led to a stillbirth. We have also found 3 incidental findings that helped the multidisciplinary team better manage the patient as well as the members at risk. Conclusion In this article we present 10 cases which were tested through prenatal WES, showing the great diagnostic yield in comparison to SNP-array in our selected cases. As a closing remark, we wish to highlight the benefits of WES testing in prenatal cases. Further testing is needed to get a clearer picture of the prenatal diagnostic yield in the Romanian population.

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a rare and inherited vascular disorder, characterized by the development of arteriovenous malformations (AVMs) in various organs and telangiectasia (small AVM) in the mucocutaneous. The majority of HHT patients have haploinsufficiency of genes involved in the transforming growth factor-beta (TGFβ) signaling pathway, including endoglin (ENG), activin receptor-like kinase 1 (ALK1, also known as ACVRL1), or SMAD4. Active angiogenesis is also required for telangiectasia and AVM development. Anti-angiogenic strategies have been tested in patients and animal models extensively. However, the exact mechanisms for telangiectasia and AVM development remain unclear. In this review, we discuss recent advances in identifying disease mechanisms, and potential therapeutic targets.

Congenital malformations are functional and structural alterations in embryonic or foetal development resulting from a variety of factors including maternal health status. This study aimed to investigate the association between maternal birth weight (MBW) and the prevalence of congenital malformations in the offspring using data from a nationwide birth cohort study in Japan including 103,060 pregnancies. A binary logistic regression model with adjustment for various covariates revealed that MBW of <2,500 g (low MBW) was associated with increased risk of congenital heart disease (adjusted odds ratio: 1.388, [95% confidence interval: 1.075–1.792]), angioma (1.491 [1.079–2.059]), and inguinal hernia (1.746, [1.189–2.565]), while MBW of ≥4,000 g (high MBW) with congenital anomalies of the urinary tract (2.194, [1.261–3.819]), and arrhythmia (1.775, [1.157–2.725]), compared with those with MBW of 3,000-3,499 g. Low MBW was associated with cleft lip and/or palate (1.473, [1.052–2.064]), congenital heart disease (1.615, [1.119–2.332]), genital organs(1.648, [1.130–2.405]), hypospadias (1.804, [1.130–2.881]), and inguinal hernia (1.484, [1.189–1.851]) in male infants and CAKUT (1.619, [1.154–2.273]) in female infants, whereas high MBW was associated with congenital heart disease(1.745, [1.058–2.877]) and CAKUT (2.470, [1.350–4.517]) in male infants. The present study is the first to demonstrate a link between MBW and congenital malformations in Japanese children. While these results must be interpreted with caution, MBW should be considered a major predictor of congenital malformation risk.

Fall armyworm Spodoptera frugiperda (J.E. Smith, 1797) is a major pest of corn, rice, and sorghum among other crops usually controlled using synthetic or biological insecticides. Currently, the new invention of nanotechnology is taking root in the agricultural industry as an alternative source of pest management that is target-specific, safe, and efficient. This study sought to determine the efficacy of commercial Zinc Oxide (ZnO) nanoparticles (NPs) towards S. frugiperda under labora-tory conditions. ZnO NPs were diluted into different concentrations (100- 500ppm), where the baby corn used to feed the S. frugiperda larvae was dipped. The development of the insect feeding on food dipped in ZnO solution was significantly (p<0.05) affected, and the number of days that the insect took to complete its life cycle had a significant difference compared to the control. There was a significant difference in the adults’ emergence at all the concentrations of ZnO NPs compared to the control, with over 90% of the eggs successfully going through the cycle until adult emergence. Additionally, several malformations were observed throughout the lifecycle of the insect. Also, the fecundity of the females was greatly affected. The findings of this study suggest the possibility of exploitation of ZnO nanoparticles not only to eradicate S. frugiperda but to significantly reduce their population in the ecosystem through deformations, reduced fecundity, reduced oviposition, and hatchability of eggs. It will be a valuable tool in integrated pest management regimens.

Cerebral cavernous malformations (CCM) or familial cavernomatosis is a rare, autosomal dominant, inherited disease characterized by the presence of vascular malformations consisting of blood vessels with an abnormal structure in the form of clusters. Based on the altered gene (CCM1/Krit1, CCM2, CCM3) and its origin (spontaneous or familial), different types of this dis-ease can be found. In this work we have isolated and cultivated primary endothelial cells (ECs) from peripheral blood of a type 1 CCM patient. Differential functional and gene expression pro-file of these cells were analyzed and compared to primary ECs from a healthy donor. The muta-tion of the familial index case consisted of a heterozygous point mutation in the position +1 splicing consensus between exons 15 and 16, causing failure in RNA processing and in the final protein. Furthermore, gene expression analysis by quantitative PCR revealed a decreased ex-pression of genes involved in intercellular junction formation, angiogenesis, and vascular ho-meostasis. Cell biology analysis showed that CCM1 ECs were impaired in angiogenesis and cell migration. Taken together, the results obtained suggest that the alterations found in CCM1 ECs are already present in the heterozygous condition, suffering from vascular impairment and someway predisposed to vascular damage.

Objectives: Non-adhesive gel-like embolic materials (NAGLEMs) are becoming increasingly dominant in the endovascular treatment of hypervascularised formations in the head and neck due to a combination of their key properties. The main advantages include their lack of adhesion, effective distribution and penetration through pathological vessels, and crucially, their controlla-bility during the process. Our assigned duty was to scrutinise the literature and assess the efficacy and outcomes of administering NAGLEMs, in comparison to other embolizing substances (name-ly, coils, glue, and particles), among patients treated at our clinic. The procedures involved ana-lyzing the technical aspects, efficiency, and safety of endovascular therapy applied to two catego-ries of hypervascular pathological anomalies, surgically managed from 2015 to 2023. Arteriove-nous malformations (AVMs) located in the head, neck, and paragangliomas with jugular/carotid body localization are combined by intense shunting blood flow and shared requirements for em-bolizates used in endovascular treatment (such as penetration, distribution, delayed polymeriza-tion and controllability). An analysis of the literature was also conducted. Results showed 18 pa-tients diagnosed with neck paragangliomas of the carotid body and jugular type. Five patients with arteriovenous malformation (AVM) of the face and neck were included, consisting of 16 fe-males and 7 males with an average age of 55 ± 13 years. Endovascular procedures were conduct-ed using NAGLEMs (ONYX (Medtronic), SQUID (Balt), and PHIL (Microvention)) and dimethyl sulfoxide (DMSO)-compatible balloon catheters. All patients achieved complete or partial embo-lization of hypervascularized formations using one or more stages of endovascular treatment. Additionally, three AVMs of the face and two paragangliomas of the neck were surgically ex-cised following embolization. In other instances, formations were not deemed necessary to be re-moved. The patients' condition upon discharge was assessed by the modified Rankin Scale (mRs) and rated between 0 and 2. Conclusion: Currently, NAGLEMs are predominantly used to treat hypervascularized formations in the neck and head due to their fundamental properties. These properties include a lack of adhesion and a delay in predictable polymerization (after 30-40 minutes). NAGLEMs also exhibit excellent distribution and penetration throughout the vascular bed of the formation. Adequate controllability of the process is largely achieved through the pres-ence of embolism forms of different viscosity, as well as excellent X-ray visualization.

Influenza virus can cause several complications during pregnancy. Therefore, we aimed to inves-tigate the effects of influenza on the development of congenital abnormalities (CAs) by analyzing the database of the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCS-CA). In our multicenter, case-control, population-based study, we processed clinician-reported outcomes and diagnoses collected in the HCCSCA. The case group included newborns with dif-ferent non-chromosomal birth defects, while controls were newborns without CAs. Maternal in-fluenza, as a risk factor for CAs, was analyzed by using a logistic regression model and odds ra-tios with 95% confidence intervals (CIs). Our results showed that maternal influenza in the first trimester was associated with increased odds of developing non-chromosomal CAs (OR: 1.41, CI: 1.28–1.55). There were increased odds of neural tube defects (OR: 2.22, CI: 1.78–2.76), orofacial clefts (OR: 2.28, CI: 1.87–2.78) and congenital heart defects (OR: 1.28, CI: 1.10–1.49) after influenza infection. In all cases, we found a protective effect of folic acid supplementation in the first tri-mester. The odds of non-chromosomal birth defects are higher after maternal influenza in the first -trimester. Folic acid or pregnancy vitamin supplementation and antipyretic therapy may reduce the effect of maternal influenza during the first trimester.

Background: About 10% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. Methods: This retrospective analysis focused on 2927 consecutive patients with WTs registered between 1989 and 2017 in the SIOP/GPOH studies. Results: (GU, N=66, 2,3%), Beckwith-Wiedemann spectrum (BWS, N=32, 1,1%), isolated hemihypertrophy (IHH, N=29, 1,0%), Denys-Drash syndrome (DDS, N=24, 0,8%) and WAGR syndrome (N=20, 0,7%) were reported most frequently. Compared to others, these patients were younger at WT diagnosis (median age 24,5 months vs. 39,0 months), had smaller tumors (334,8mL vs. 496,9mL), less often metastasis (8,2% vs. 18%), but more often nephroblastomatosis (12,9% vs. 1,9%). WT with IHH was associated with blastemal WT and DDS with stromal subtype. Bilateral WTs were common in WAGR (30%), DDS (29%) and BWS (31%). Chemotherapy induced reduction in tumor volume was poor in DDS (7,7% increase) and favorable in BWS (84,6% reduction). The event-free survival (EFS) of patients with BWS was significantly (p=0,002) worse than in others. Conclusions: CPS should be considered in WTs with specific clinical features resulting in referral to a geneticist. Their outcome was not always favorable.

Background: Children with anorectal malformation (ARM) require long-term follow-up, especially for fecal continence and main predictors of longer-term success are the type of ARM, associated anomalies and sacral integrity. Three-Dimensional High Resolution Anorectal Manometry (3D-HRAM) provides an image of the pressure profile of anal sphincter complex. Aim of study was to evaluate the anal sphincter function in ARM patients with 3D HRAM correlating this analysis to clinical outcome and to associated malformations. Methods: Forty ARM patients, were submitted to 3D HRAM: manometric, anatomical and clinical score were correlated to response to bowel management (BM). Results: A positive correlation between all scores and type of ARM was found: in high ARM and in patients with spinal anomalies (regardless to ARM type) lower scores were reported and even after BM they do not achieve good continence. Conclusions: 3D-HRAM provides information on the functional anatomy of the sphincter complex. Our study shows good correlation between the manometric results and clinical outcome, confirming spinal malformations and ARM type as most important prognostic risk factors for poor outcome. Specific sphincteric defects can be explored with manometry, allowing for tailored bowel management strategies.

Background: Congenital Pulmonary Malformations (CPMs) are rare benign lesions potentially causing infective complications and/or malignant transformation requiring surgery even when asymptomatic. CPMs are infrequent in adult but potentially detected at any age. There is not a consensus indicating the correct extent of resection in both adults and paediatrics. This retrospective multicentric study aims to identify the appropriate surgical resection to prevent the recurrence of related respiratory symptoms. Methods: Between 2010 and 2020, a total of 96 patients (adult and pediatric) underwent surgery for CPMs in 4 centers. A 2:1 propensity score matching (considering sex and lesion side) was performed, identifying 2 groups: 50 patients underwent lobectomy (group A) and 25 sub-lobar resections (group B). Clinical and histopathological characteristics, early and late complications and symptom’s recurrence were retrospectively analyzed and compared between the two groups by univariate and multivariate analyses. Results: Patients who underwent lobectomy had a statistically significant lower rate of recurrence (4% vs 24% of group B, p = 0.014) and a lower rate of intraoperative complications (p = 0.014). Logistic regression identified sub-lobar resection (p=0.040), intra- and post-operative complications (p=0.105 and 0.022) and associated developed neoplasm (p=0.062) as possible risk factors for symptoms recurrence after surgery. Conclusions: Pulmonary lobectomy seems to be the most effective surgical treatment for CPMs, guaranteeing stable remission of symptoms and a lower rate of intra- and postoperative complications. To our knowledge this is one of the largest studies comparing lobectomy and sub-lobar resections in patients affected by CPMs, considering the low incidence worldwide.

Viruses are the most common congenital infections and an important cause of fetal malformations, morbidity, and mortality. The effects of these infections, which are transmitted in-utero (transplacentally), during childbirth or in the puerperium depend on the timing of the infections. These vary from miscarriages (usually with infections in very early pregnancy), congenital malformations (where the infections occur during organogenesis) and morbidity (with infections occurring late in pregnancy, during childbirth or after delivery). The most common of these viruses are cytomegalovirus, hepatitis, parvovirus B-19, rubella, varicella and zika. There are currently very few efficacious antiviral agents licensed for use in pregnancy and therefore for most of these infections, prevention by means of immunisation (where there is a vaccine), administration of immunoglobulins to those exposed to the virus to offer passive immunity or appropriate measures to avoid being infected would be options to minimise the infections and their consequences. In this review, we discuss the current understanding of some of the congenital infections and their consequences on both the mother and fetus and their management focusing mainly on prevention.

It is not understood how the numbers and identities of vertebrae are controlled during mammalian development. The remarkable robustness and conservation of segmental numbers may suggest a digital nature of the underlying process. Here I propose a mechanism that allows cells to obtain and store the segmental information in digital form, and to produce a pattern of chromatin accessibility that in turn regulates Hox gene expression specific to the metameric segment. The model requires that a regulatory element be present such that the number of occurrences of the motif between two consecutive Hox genes equals the number of segments under the control of the anterior gene. This is true for the recently discovered HRC3 motif, associated with histone modifications and developmental genes. The finding not only allows correctly predicting the numbers of segments using only sequence information, but also resolves the 40-year-old enigma of the function of temporal and spatial collinearity of Hox genes. The logic of the mechanism is illustrated in an animated video: https://youtu.be/4a3XOQ7Lz28. I also discuss how different aspects of the proposed mechanism can be tested experimentally.