Prevalent Congenital Malformation Research Articles

Periodontal plastic surgery and regenerative periodontal surgery in a forty-seven-year-old patient with cleft lip and palate

Cleft lip and palate represent one of the most prevalent congenital malformations in humans, with an estimated prevalence of 0.45 per 1,000 individuals. During childhood and adolescence, affected patients undergo lengthy and complicated interdisciplinary treatment including treatment from specialists in pediatric medicine, oral and maxillofacial surgery, orthodontics, and otorhinolaryngology. The patient exhibited scarred adhesions with localized mucogingival deformities of the premaxilla (region 12 − 11), bilateral cleft lip and palate, and a complex underlying one-wall intrabony osseous defect on tooth 11, in addition to hard- and soft-tissue deficiencies at the dental implant in region 12. Following the administration of localized anti-infective periodontal therapy, regenerative periodontal surgery, regenerative surgical therapy of periimplantitis, and periodontal plastic surgery were performed. This resulted in a long-term, stable improvement in the clinical situation. Regenerative periodontal therapy and periodontal plastic surgery in patients with palato-alveolar cleft present a significant challenge due to the poor condition of the mucosa and gingiva adjacent to the defect and the insufficient bone dimensions. For this reason, it seems beneficial to include the periodontist in the interdisciplinary treatment team of a patient with cleft lip and palate from the outset. It is recommended that the patient be provided with dental prophylaxis measures and receive individualized oral hygiene instructions in addition to the main maxillofacial and orthodontic treatment. This approach would facilitate the identification of mucogingival issues at an early stage and the implementation of appropriate treatment.

Prenatal exposure to poly/perfluoroalkyl substances and risk for congenital heart disease in offspring

Congenital heart disease (CHD) is the most prevalent congenital malformation worldwide, and the association between per- and polyfluoroalkyl substances (PFASs) exposure and CHD in population has only received limited study. Therefore, we conducted a multicenter case-control study to explore the associations between prenatal exposure to individual PFASs, and also a PFAS mixture, and CHD risk, including 185 CHDs and 247 controls in China from 2016 to 2021. Thirteen PFASs in maternal plasma were quantified using liquid chromatography-tandem mass spectrometry. Logistic regression and two multipollutant models (Bayesian kernel machine regression [BKMR] and quantile g-computation [qgcomp]) were used to assess the potential associations between any individual PFAS, and also a PFAS mixture, and CHD risk. After adjusting for potential confounders, logistic regression indicated significant associations between elevated levels of perfluorononanoic acid (odds ratio [OR]= 1.30, 95% confidence intervals [CI]: 1.07–1.58), perfluorodecanoic acid (OR=2.07, 95%CI: 1.32–3.26), and perfluoroundecanoic acid (OR=2.86, 95%CI:1.45–5.65) and CHD risk. The BKMR model and qgcomp approach identified that a significant positive association between the PFAS mixture and risk for CHD. These findings provide essential evidence that there is indeed a health crisis associated with PFASs and that it is linked to CHD.

Identification of a novel mutation of Platelet-Derived Growth Factor-C (PDGFC) gene in a girl with Non-Syndromic cleft lip and palate

BackgroundCleft lip with or without cleft palate (CL/CP) is a prevalent congenital malformation. Approximately 16 candidate loci for CL/CP have been identified in both animal models and humans through association or genetic linkage studies. One of these loci is the platelet-derived growth factor-C (PDGFC) gene. In animal models, a mutation in the PDGFC gene has been shown to lead to CL/CP, with PDGF-C protein serving as a growth factor for mesenchymal cells, playing a crucial role in embryogenesis during the induction of neural crest cells. In this study, we present the identification of a novel frameshift mutation in the PDGFC gene, which we hypothesize to be associated with CL/CP, within a consanguineous Iranian family. Case presentationThe proband was a 3-year-old girl with non-syndromic CL/CP. A history of craniofacial clefts was present in her family. Following genetic counseling, karyotype analysis and whole-exome sequencing (WES) were performed. Cytogenetic analysis revealed normal results, while WES analysis showed that the proband carried a homozygous c.546dupA (p.L183fs) mutation in the PDGFC gene. Sanger sequencing confirmed that her parents were carriers of the mutation. ConclusionThe c.546dupA (p.L183fs) mutation of PDGFC has not been previously reported and was not found in human genome databases. We speculate that the c.546dupA mutation of the PDGFC gene, identified in the Iranian patient, may be responsible for the phenotype of non-syndromic CL/CP (ns-CL/CP). Further studies are warranted to explore the specific pathogenesis of the PDGFC mutation in ns-CL/CP.

Characterization of genomic variants associated with congenital heart disease in patients from southwestern Colombian

Congenital heart diseases correspond to errors during embryogenesis, generating structural and functional malformations. Congenital heart diseases are the most prevalent congenital malformations and are responsible for the highest infant morbidity and mortality. Among these cases, 8 % can be attributed to variants in genes associated with cardiac development. To establish the population frequency of genomic variants that cause congenital heart disease, a review of the scope of prevalent genes was carried out, complete exome sequencing results of 320 patients without suspicion of congenital heart disease were used, the exome sequencing is a technique based on DNA extraction using a Qiagen kit, with massive sequencing of Nextera TM libraries using an Illumina platform with 100X coverage, alignment with reference genome GRCh38/hg19, and analysis with the CRAVAT program; clinical characterization, significance classification, and gene interaction networks were performed. The scope analysis allowed to determine that the genes NKX2-5, TBX20, GATA4, NOTCH1, PTPN11 are the most prevalent, the variants with the highest allelic frequency were c.63A > G (0.2844), c.39T > C (0.3406), c.1132A > G (0.0406), c.1669+9T > C (0.3531) and c.854-30T > C (0.0875) respectively; 4 variants were reclassified by in silico tools, in the NKX2-5 gene c.335-311_335-303del from benign to probably pathogenic, in the NOTCH1 gene c.2354-24C > T from benign to pathogenic, and in the PTPN11 gene c.2354-24C > T and c.854-30T > C from benign to pathogenic. 17 % of intronic variants and 4.8 % of missense variants were identified. This work contributes to knowledge about the frequency with which genomic variants associated with congenital heart disease are present in the population, generating a tool for early diagnosis, early treatment, thus reducing morbidity and mortality, with a view to future universal molecular neonatal screening of congenital heart disease.

Pediatric Animal Model of Extracorporeal Cardiopulmonary Resuscitation after Prolonged Circulatory Arrest.

Congenital heart disease (CHD) is the most prevalent congenital malformation, with about one million births impacted worldwide per year. Comprehensive investigation of this disease requires appropriate and validated animal models. Piglets are commonly used for translational research due to their analogous anatomy and physiology. This work aimed to describe and validate a neonatal piglet model of cardiopulmonary bypass (CPB) with circulatory and cardiac arrest (CA) as a tool for studying severe brain damage and other complications of cardiac surgery. In addition to including a list of materials, this work provides a roadmap for other investigators to plan and execute this protocol. After experienced practitioners performed several trials, the representative results of the model demonstrated a 92% success rate, with failures attributed to small piglet size and variant vessel anatomy. Furthermore, the model allowed practitioners to select from a wide variety of experimental conditions, including varying times in CA, temperature alterations, and pharmacologic interventions. In summary, this method uses materials readily available in most hospital settings, is reliable and reproducible, and can be widely employed to enhance translational research in children undergoing heart surgery.

Evaluation of Anaesthetic Challenges in Primary Cleft Lip and Palate Surgeries in a Single Center Study

Background: One of the most prevalent congenital malformations and the most frequent craniofacial defects in children is cleft lip and palate. The aim of the study was to investigate the anaesthetic procedures employed and to determine the challenges and postoperative complications associated with cleft lip and palate surgery. Material Methods: A retrospective review of the anaesthetic procedures carried out from January 2022 to December 2022 at the Dhaka Dental College and Hospital. The hospital records were reviewed in order to learn about every occurrence of orofacial cleft surgery. In this study, a total number of 120 cases were reviewed. Results: Among 120 cases, 53 (44.2%) of the patients were female and 67 (55.8%) were male. The bulk of patients came after their first year of life. About 54(45%) of them were younger than five years old. 68(56.67%) underwent cleft lip surgery, 37(30.83%) for cleft palate surgery and rest 15(12.5%) patients under went for combined cleft lip and cleft palate surgeries. Upper Respiratory Tract Infection (URTI) was reported as the most common pre-existing morbidity. Bronchospasm was the main intraoperative complications occurred in 8 (6.67%) of the cases with URTI. After surgey 6(5%) patients experienced bleeding, 3(2.5%) patients needed to be reintubated. In addition, 2 (1.67%) instances had trouble controlling their pain, only 1(0.83%) patient had trouble swallowing and 1(0.83%) recovered slowly. Conclusion: Anaesthesia for surgical repair of cleft lip or palate in children is challenging. After a thorough preoperative evaluation, a trained anaesthesiologist should administer anaesthesia under strict supervision to minimize postoperative complications.

Associated Factors with Congenital Heart Disease in the Most Populated State of Brazil Between 2010 and 2018

Background Cardiac anomalies are the most prevalent congenital malformations among live births in the world. In Brazil, it is estimated that nearly 25,757 new cases occur each year, and the Southeast region presents the highest prevalence, with 10 new cases/1,000 live births. Objective The aim of this study is to evaluate the epidemiology of congenital heart disease (CHD) in the state of São Paulo. Methods This is a cross-sectional and time-series observational study with data from the Brazilian Information [...]

Association of social determinants with the severity of congenital heart disease.

Congenital heart diseases are the most prevalent congenital malformations and cause greater morbi-mortality in newborns and infants. The aim of this study was to analyze the social determinants in families with children with the severity of congenital heart disease. Analytical cross-sectional study in 140 families of children with congenital heart disease to whom a structured survey was applied addressing topics related to family structure, health, economic conditions, exposure factors, and other social conditions relevant to the study, during 1 year. In all, 53.7% of the studied population belonged to low socioeconomic levels. No association was found between the severity of the heart disease and the presence of pathological antecedents in the parents. The families resided in urban areas. Also, 28.3% of the mothers had four or fewer prenatal controls during pregnancy. Only 22% of heart diseases were diagnosed during pregnancy. It was found that exposure to cigarette and wood smoke during pregnancy, in addition to low socioeconomic status, was associated with greater severity of heart disease (RACHS-1 and STS-Score), when evaluated by pathophysiological groups (cyanotic/non-cyanotic/single ventricle). Exposure to cigarette smoke, wood smoke during pregnancy, and low socioeconomic status turned out to be social determinants associated with the severity of heart disease analyzed by pathophysiological groups. The social component has not been well characterized as a cause of congenital heart disease, especially in countries like ours, where the existence of gaps and social inequities have a high impact. The findings of this study could have an impact on public health to the extent that policies are implemented to reduce exposure to cigarettes, especially during pregnancy. Knowledge of these changes and their measurement in this type of pathology could open the door to the creation of policies aimed at their prevention, focusing on the local risk factors found, which can impact the disease.

Leucism: the prevalent congenital malformation in the olive ridley sea turtle of northwestern Mexico

Despite being the most abundant sea turtle in the world, the olive ridley turtle Lepidochelys olivacea is classified as Vulnerable by the IUCN. There is evidence of congenital malformations in hatchlings, and the associated causes are multifactorial, with both genetic and environmental sources. Santuario Playa Ceuta (SPC) is a sanctuary for the olive ridley, located at the northernmost region of its nesting range in the Mexican Pacific. The objective of this study was to identify and quantify the prevalence and severity of congenital malformations in olive ridley embryos/hatchlings in SPC during the 2017 nesting season. We collected 62907 eggs from 643 relocated nests that were moved to a hatchery, of which 4242 eggs with obvious development did not hatch and were analyzed for this study. Hatching success was 53.9%, with 22.5% of nests (n = 145) and 0.54% of eggs (n = 344) showing embryos or hatchlings with malformations. The nest severity index was 2.4 (range: 1-10) malformed embryos or hatchlings per nest, and the organism severity index was 1.4 (range: 1-7) malformations per malformed embryo or hatchling. Leucism was the most prevalent malformation (34.4%; 170/494 total observed), with the craniofacial region showing the greatest diversity of malformations (17/35 types). Given the geographical position of SPC, extreme environmental conditions (e.g. cold, heat, and dryness) could be one of the main causes of teratogenesis in this species. However, more studies are needed regarding the presence of contaminants, genetic factors, health assessments of nesting females, and malformation rates of nests that remain in situ versus those that are relocated.

Expectations of Caregivers of Patients with Cleft Lip and Palate Attending the Cleft Clinic of KATH for the First Time

Background: Cleft lip and palate (CLP) is one of the most prevalent congenital malformations affecting the face worldwide, with high prevalence in Asians, Americans, and Caucasians and low in Africans. Orofacial Clefts (OFCs) are among the causes of perinatal death in Ghana. The children often experience difficulties in swallowing, feeding, and speaking. These children often face problems in cognition, education, and communication. Caregivers’ ignorance of treatment, poverty, and noncompliance with follow-up schedules are obstacles to optimal cleft care. Most studies focus on the incidence of cleft, but not much is known about caregivers’ expectations. Methodology: An exploratory qualitative study design was used for this research between October and November 2020. The study site was the Komfo Anokye Teaching Hospital, (KATH), Kumasi, Ghana. The respondents were recruited from the oral health clinic. Included in the study were all CLP caregivers attending the cleft clinic for the first time. Purposive sampling was used to select fifteen caregivers who met the inclusion criteria. Face-to-face interviews with a semi-structured interview guide were used to collect data. The data were analyzed using NVivo software. Three major themes and six sub-themes emerged from the data analysis using thematic analysis. Ethical clearance was obtained for data collection. Results: Most caregivers were expecting their babies to be operated on, and they were certain that the cleft would be repaired at the end of the treatment, but they were unfamiliar with the process and cost of treatment. Less than half of the caregivers reported that they were oblivious to what to expect the first time visiting but had hopes that the healthcare professionals would be able to close the cleft for their babies. Conclusion: The majority of the caregivers expressed fear and disappointment at the diagnosis of their child. Some caregivers were very scared to the level where they had to hide the babies from the public. Others reported being already in financial difficulties, so their children’s conditions would compound them.

Expectations of Caregivers of Patients with Cleft Lip and Palate Attending the Cleft Clinic of KATH for the First Time

Background: Cleft lip and palate (CLP) is one of the most prevalent congenital malformations affecting the face worldwide, with high prevalence in Asians, Americans, and Caucasians and low in Africans. Orofacial Clefts (OFCs) are among the causes of perinatal death in Ghana. The children often experience difficulties in swallowing, feeding, and speaking. These children often face problems in cognition, education, and communication. Caregivers’ ignorance of treatment, poverty, and noncompliance with follow-up schedules are obstacles to optimal cleft care. Most studies focus on the incidence of cleft, but not much is known about caregivers’ expectations. Methodology: An exploratory qualitative study design was used for this research between October and November 2020. The study site was the Komfo Anokye Teaching Hospital, (KATH), Kumasi, Ghana. The respondents were recruited from the oral health clinic. Included in the study were all CLP caregivers attending the cleft clinic for the first time. Purposive sampling was used to select fifteen caregivers who met the inclusion criteria. Face-to-face interviews with a semi-structured interview guide were used to collect data. The data were analyzed using NVivo software. Three major themes and six sub-themes emerged from the data analysis using thematic analysis. Ethical clearance was obtained for data collection. Results: Most caregivers were expecting their babies to be operated on, and they were certain that the cleft would be repaired at the end of the treatment, but they were unfamiliar with the process and cost of treatment. Less than half of the caregivers reported that they were oblivious to what to expect the first time visiting but had hopes that the healthcare professionals would be able to close the cleft for their babies. Conclusion: The majority of the caregivers expressed fear and disappointment at the diagnosis of their child. Some caregivers were very scared to the level where they had to hide the babies from the public. Others reported being already in financial difficulties, so their children’s conditions would compound them.

Methodology for Free-Floating Organ Culture of Mid-gestation Maxillary Primordial Tissue.

Craniofacial defects, such as cleft palate, are prevalent congenital malformations that present an interesting research challenge due to the complex and multifactorial nature of their etiology. In vitro modeling of craniofacial morphogenesis provides valuable insight into the developmental processes critical to the presentation of these conditions. One such technique, termed a submerged or free-floating organ culture, allows culturing and observation of isolated craniofacial tissue without the need for specialized supporting equipment. Outlined here is a detailed protocol for isolating and culturing maxillary and palatal tissue as a midfacial tissue section. This protocol has been modified from a previously established technique to accommodate culturing tissue from developmental time-points as early as embryonic day 10.5. This allows for greater control over genotypic variance within litters and provides a simplified, accessible methodology.

ДИНАМИКА И СТРУКТУРА ВРОЖДЕННЫХ ПОРОКОВ РАЗВИТИЯ И НАСЛЕДСТВЕННЫХ ЗАБОЛЕВАНИЙ У ДЕТЕЙ В КУРСКОЙ ОБЛАСТИ

The article presents analysis of congenital malformations and hereditary diseases in newborns of Kursk region from the position of public health. Methodology of work includes retrospective analytical study of screening lists and discharge records in case-histories of the Regional perinatal center of Kursk; content-analysis of medical-statistical reports of the medical-genetic consulting center of Kursk regional clinical hospital. In the result of the study there were detected trends in main congenital pathologies of newborns in Kursk region during the years 2015-2019, as well as structure of birth defects by localization. The most prevalent congenital malformations in newborns in Kursk region were cardiovascular pathology, urinary system anomalies, chromosome diseases and central nervous system anomalies. Factors detected as associated with congenital malformations in newborns included low birth weight and living in rural area. The results of the study are applicable for the development of public health programs aimed at improvement of preventive services and organization of medical care for children with birth defects.

Congenital Anomalies in Thi-Qar: A Recent Observational Study during 2019

Background:  congenital anomalies are a significant but under recognized cause of disability and mortality among infants and children under the age of five years. They can be life-threatening conditions, result in long-term disability, and negatively affect health – care system, societies, families and individual (2). Objectives:  to estimate the prevalence of congenital malformations in our locality Thi-Qar province, most common type and any responsible factors for these anomalies. Subjects and methods: a descriptive hospital-based prospective study in one year among newborn delivered baby in Bent Al-Huda Teaching Hospital, Thi-Qar Governorate, Iraq from January 2019 -December 2019. Both the mother and her baby were examined as a unit within 24 hours of birth A medical history was taken including parents age, residency, gestational age, and thorough physical examination of the baby was made. all baby with identified birth defects were admitted to neonatal care unit for observation, investigation, evaluation and management. The data were analyzed by simple statistical techniques recording number and percentage of cases. Results: The overall prevalence of congenital anomalies among neonates was 1.26%. The first most prevalent congenital malformations were anencephaly 7.78%, down syndrome 6.11%, upper and lower limb malformation 6.11% hydrocephalus 9%, heart malformation5%. More than one system involvement was reported in (6.11%) cases. Most congenital malformations occurred in male children 52.73% anomalies, 62% > 2.5 Kg body weight &36.67% in term baby. The highest congenital abnormality is reported among babies delivered by mothers aged 20-45 years of age (i.e.,94%). More than 62 % of urban resident. Conclusion: nervous system anomalies, down syndrome, and musculoskeletal system anomalies  are most prevalent congenital malformations in Thi-Qar while the low birth prevalence of other birth defect 1.26% may be a result of institutional and personal characteristics of the documentation system. Recommendation: The more wide extensive screening programs to detect the exact prevalence, type, causes and distribution of birth defects is needed and implemented as health program.

Signs of Reduced Basal Progenitor Levels and Cortical Neurogenesis in Human Fetuses with Open Spina Bifida at 11-15 Weeks of Gestation.

Open spina bifida (OSB) is one of the most prevalent congenital malformations of the CNS that often leads to severe disabilities. Previous studies reported the volume and thickness of the neocortex to be altered in children and adolescents diagnosed with OSB. Until now, the onset and the underlying cause of the atypical neocortex organization in OSB patients remain largely unknown. To examine the effects of OSB on fetal neocortex development, we analyzed human fetuses of both sexes diagnosed with OSB between 11 and 15 weeks of gestation by immunofluorescence for established neuronal and neural progenitor marker proteins and compared the results with healthy controls of the same, or very similar, gestational age. Our data indicate that neocortex development in OSB fetuses is altered as early as 11 weeks of gestation. We observed a marked reduction in the radial thickness of the OSB neocortex, which appears to be attributable to a massive decrease in the number of deep- and upper-layer neurons per field, and found a marked reduction in the number of basal progenitors (BPs) per field in the OSB neocortex, consistent with an impairment of cortical neurogenesis underlying the neuronal decrease in OSB fetuses. Moreover, our data suggest that the decrease in BP number in the OSB neocortex may be associated with BPs spending a lesser proportion of their cell cycle in M-phase. Together, our findings expand our understanding of the pathophysiology of OSB and support the need for an early fetal therapy (i.e., in the first trimester of pregnancy).SIGNIFICANCE STATEMENT Open spina bifida (OSB) is one of the most prevalent congenital malformations of the CNS. This study provides novel data on neocortex development of human OSB fetuses. Our data indicate that neocortex development in OSB fetuses is altered as early as 11 weeks of gestation. We observed a marked reduction in the radial thickness of the OSB neocortex, which appears to be attributable a decrease in the number of deep- and upper-layer neurons per field, and found a marked reduction in the number of basal progenitors per field, indicating that impaired neurogenesis underlies the neuronal decrease in OSB fetuses. Our findings support the need for an early fetal therapy and expand our understanding of the pathophysiology of OSB.

The prevalence of non-syndromic orofacial clefts and associated congenital heart diseases of a tertiary hospital in Riyadh, Saudi Arabia

BackgroundOrofacial clefts are considered one of the most common birth defects and are frequently associated with other malformations. Congenital heart disease is one of the most prevalent congenital malformation. ObjectiveTo investigate the prevalence of congenital heart diseases associated with non-syndromic orofacial clefts in the Saudi population. MethodsElectronic files of non-syndromic orofacial cleft patients who visited the Oral and Maxillofacial Surgery Department in King Abdulaziz Medical City of Riyadh, Saudi Arabia from January 2015 to December 2018 were retrospectively reviewed. Data were recorded in an excel sheet and analyzed using SPSS via frequency tests. ResultsIn the cleft children identified, the prevalence of non-syndromic orofacial clefts was (77%). Orofacial clefts showed a male predominance (62%). The most common orofacial phenotype was unilateral cleft lip and palate (34%). The prevalence of associated congenital malformations with orofacial clefts was (41%). The most prevalent congenital malformation was congenital heart disease (35%), mainly found in unilateral cleft lip and palate patients (33%). The prevalence of associated congenital heart disease with orofacial clefts was (19%). The most frequent type of congenital heart disease was atrial septal defect (37%). ConclusionThis study highlights the recognition of the associated congenital heart disease with non-syndromic orofacial cleft patients. Global screening protocols designed for newborns with non-syndromic orofacial cleft are needed to eliminate late diagnosis of critical congenital heart diseases which might present operative risks of anesthesia and/or surgical procedures.

Developmental dysplasia of the hip: a systematic literature review of the genes related with its occurrence.

Developmental dysplasia of the hip (DDH) is one of the most prevalent congenital malformations. It has a wide spectrum of anatomical abnormalities of the hip joint and is characterized by mild or incomplete formation of the acetabulum leading to laxity of the joint capsule, secondary deformity of the proximal femur and irreducible hip dislocation. It is the leading cause of early hip osteoarthritis in young individuals.Both genetic and environmental factors have been proposed to play an important role in the pathogenesis of DDH. A high prevalence is present in Asian, Caucasian, Mediterranean and American populations, with females being more frequently affected. We evaluated a variety of genetic studies indexed in the PubMed database.Several susceptive genes, including WISP3, PAPPA2, HOXB9, HOXD9, GDF5, TGF Beta 1, CX3CR1, UQCC, COL1A1, TbX4 and ASPN have been identified as being associated with the development of DDH. Moreover, genetic association has also been reported between hip dysplasia and other comorbidities. Even though genetic components are a crucial part in the aetiology of DDH, several DDH susceptibility genes need further investigation.The purpose of this review is to present current literature evidence regarding genes responsible for DDH development.Cite this article: EFORT Open Rev 2019;4:595-601. DOI: 10.1302/2058-5241.4.190006

Multicenter prospective clinical study to evaluate children short-term neurodevelopmental outcome in congenital heart disease (children NEURO-HEART): study protocol

BackgroundCongenital heart disease (CHD) is the most prevalent congenital malformation affecting 1 in 100 newborns. While advances in early diagnosis and postnatal management have increased survival in CHD children, worrying long-term outcomes, particularly neurodevelopmental disability, have emerged as a key prognostic factor in the counseling of these pregnancies.MethodsEligible participants are women presenting at 20 to < 37 weeks of gestation carrying a fetus with CHD. Maternal/neonatal recordings are performed at regular intervals, from the fetal period to 24 months of age, and include: placental and fetal hemodynamics, fetal brain magnetic resonance imaging (MRI), functional echocardiography, cerebral oxymetry, electroencephalography and serum neurological and cardiac biomarkers. Neurodevelopmental assessment is planned at 12 months of age using the ages and stages questionnaire (ASQ) and at 24 months of age with the Bayley-III test. Target recruitment is at least 150 cases classified in three groups according to three main severe CHD groups: transposition of great arteries (TGA), Tetralogy of Fallot (TOF) and Left Ventricular Outflow Tract Obstruction (LVOTO).DiscussionThe results of NEURO-HEART study will provide the most comprehensive knowledge until date of children’s neurologic prognosis in CHD and will have the potential for developing future clinical decisive tools and improving preventive strategies in CHD.Trial registrationNCT02996630, on 4th December 2016 (retrospectively registered).

Valproic acid effect on neural tube defects is not prevented by concomitant folic acid supplementation: Early chick embryo model pilot study

BackgroundNeural tube defect is one of the most prevalent congenital malformations and it involves a variety of malformations ranging from anencephaly to spina bifida. Folic acid supplementation during pregnancy is known to reduce risk of neural tube defects. Antiepileptic drugs have been associated with neural tube defects, one of which is valproic acid. Protective effect of folic acid on congenital malformations in patients using valproic acid or other antiepileptic medicines during pregnancy has not clearly been delineated uniformly in previous clinical series. In this experimental animal study of early chick embryo model, we would like to determine if there is any dose-response relationship between VA and NTDs and if there is any protective effect of FA on this relationship in early chick embryo period. MethodsOne hundred twenty-two fertile leghorn type chicken eggs were used in this study. Six groups, each of which composed of 20 fertilized eggs, were categorized as: group A-control, group B- folic acid, group C-low-dose valproic acid, group D-high-dose valproic acid, group E-low-dose valproic acid + folic acid, group F-high-dose valproic acid + folic acid. Eggs were hatched for 24 h and injected with destined solutions and hatched till 72th hour. ResultsNo neural tube defect was observed in group A and B. High dose valproic acid led to significantly higher number of embryos with neural tube defects compared to low-dose valproic acid (p = 0.018). This significant difference was also present between low-dose and high dose valproic acid combined with folic acid (p = 0.031). When effect of folic acid was evaluated no significant difference observed between groups. ConclusionsEven though number of embryos with neural tube defects decreased with concomitant folic acid administration, this difference could not reach a statistical level. More experimental animal and large-scaled prospective clinical studies are in need to detect folic acid mechanism in inhibiting antiepileptic drugs, if any present.

MRPL53, a New Candidate Gene for Orofacial Clefting, Identified Using an eQTL Approach

A valuable approach to understand how individual and population genetic differences can predispose to disease is to assess the impact of genetic variants on cellular functions (e.g., gene expression) of cell and tissue types related to pathological states. To understand the genetic basis of nonsyndromic cleft lip with or without cleft palate (NSCL/P) susceptibility, a complex and highly prevalent congenital malformation, we searched for genetic variants with a regulatory role in a disease-related tissue, the lip muscle (orbicularis oris muscle [OOM]), of affected individuals. From 46 OOM samples, which are frequently discarded during routine corrective surgeries on patients with orofacial clefts, we derived mesenchymal stem cells and correlated the individual genetic variants with gene expression from these cultured cells. Through this strategy, we detected significant cis-eQTLs (i.e., DNA variants affecting gene expression) and selected a few candidates to conduct an association study in a large Brazilian cohort (624 patients and 668 controls). This resulted in the discovery of a novel susceptibility locus for NSCL/P, rs1063588, the best eQTL for the MRPL53 gene, where evidence for association was mostly driven by the Native American ancestry component of our Brazilian sample. MRPL53 (2p13.1) encodes a 39S protein subunit of mitochondrial ribosomes and interacts with MYC, a transcription factor required for normal facial morphogenesis. Our study illustrates not only the importance of sampling admixed populations but also the relevance of measuring the functional effects of genetic variants over gene expression to dissect the complexity of disease phenotypes.