Common Malformation Research Articles

Neural crest E-cadherin loss drives cleft lip/palate by epigenetic modulation via pro-inflammatory gene–environment interaction

Gene–environment interactions are believed to play a role in multifactorial phenotypes, although poorly described mechanistically. Cleft lip/palate (CLP), the most common craniofacial malformation, has been associated with both genetic and environmental factors, with little gene–environment interaction experimentally demonstrated. Here, we study CLP families harbouring CDH1/E-Cadherin variants with incomplete penetrance and we explore the association of pro-inflammatory conditions to CLP. By studying neural crest (NC) from mouse, Xenopus and humans, we show that CLP can be explained by a 2-hit model, where NC migration is impaired by a combination of genetic (CDH1 loss-of-function) and environmental (pro-inflammatory activation) factors, leading to CLP. Finally, using in vivo targeted methylation assays, we demonstrate that CDH1 hypermethylation is the major target of the pro-inflammatory response, and a direct regulator of E-cadherin levels and NC migration. These results unveil a gene–environment interaction during craniofacial development and provide a 2-hit mechanism to explain cleft lip/palate aetiology.

Teratogenicity of Dibutyl Phthalate and Polyvinyl Alcohol in Early Developmental Stages of Danio rerio

Dibutyl phthalate (DBP) and polyvinyl alcohol (PVA) are commonly used in manufacturing petroleum-based and biodegradable plastics. Despite being regarded as safe, these chemicals persist as organic pollutants during plastic degradation in aquatic environments and, thus, may pose risks to aquatic organisms and even humans. We performed a 96-h zebrafish embryo test to investigate the toxicity and teratogenicity of DBP and PVA at 25–500 μg/L and 1–3.0% concentrations, respectively. The results showed that exposure to DBP and PVA reduced the survival rate of zebrafish in a concentration and time-dependent manner. In PVA, pericardial edema and heart abnormalities were more common malformations than yolk sack edema and tail deformities in DBP. Reduced body length and hatching rate and elevated heart rates at 400–500 μg/L concentrations were observed in DBP-exposed zebrafish. The same trend was observed in PVA except that decreased heart rate was observed with increasing concentrations. We conclude that DBP and PVA are lethal and teratogenic, even at low concentrations, thus posing questions and concerns about the safety and health, environmental, and ecological risks associated with the use of these chemicals.

A retrospective study of congenital cardiac malformations in 29 goats.

Cardiac malformations are sporadically diagnosed in domestic species; however, little literature is available for this group of developmental anomalies in goats. We performed a retrospective study to catalog congenital cardiac conditions in goats submitted to the University of California-Davis, Veterinary Medical Teaching Hospital, Anatomic Pathology Autopsy Service. From 2000 to 2021, of 1,886 goat autopsies, 29 cases of cardiac malformations were identified (1.5%). Thirteen were ≤ 2-wk-old, 8 were 1-6-mo-old, and 8 were adults 2-9-y-old. The most common malformations were ventricular septal defect (VSD; 21 of 29), atrial septal defect or persistent foramen ovale (10 of 29), and double-outlet right ventricle (3 of 29). Nine cases had > 1 malformation, typically including a VSD. Conditions that had not been reported in the goat included double-outlet right ventricle (3), tetralogy of Fallot (1), cor triatriatum sinister (1), and mitral valve dysplasia (1). Two adult cases were incidental and not suspected clinically. Cardiac malformations occur not uncommonly in goats and should be considered in a wide age range.

Thoracoscopic lobectomy for congenital pulmonary airway malformations before or after 5 months of age: evaluation of pulmonary function.

Congenital pulmonary airway malformation (CPAM) is the most common pulmonary malformation. It can be managed via thoracoscopic lobectomy, which is safe and advantageous over thoracotomy. Some authors advocate the need for early resection to get an advantage over lung growth. Our study aimed to evaluate and compare the pulmonary function in patients who underwent thoracoscopic lobectomy for CPAM before and after 5 months of age. This retrospective study was conducted between 2007 and 2014. Patients younger than 5 months were assigned to group 1 and those over 5 months of age were assigned to group 2. Pulmonary function tests (PFT) were requested for all the included patients. For patients who could not undergo full PFT, the function residual capacity (FRC) was evaluated by the helium dilution technique. The parameters evaluated in full PFT were forced expiratory volume in one second (FEV1), forced vital capacity (FVC), total lung capacity (TLC), and FEV1 to FVC ratio (FEV1/FVC). The Mann Whitney U test was used to compare both groups of patients. Seventy patients underwent thoracoscopic lobectomy during this period, 40 of which had CPAM. Twenty-seven patients tolerated and underwent PFT (group 1: 12 patients; group 2: 15 patients). Among them, 16 patients underwent full PFT and 11 patients had FRC measurement. FRC was similar in both groups (91% vs. 88.2%). FEV1 (83.9% vs. 86.4%), FVC (86.8% vs. 92.6%) and TLC (86.5% vs. 87.8%) were also similar between both groups. FEV1/FVC was slightly higher in group 1 (97.9% vs. 89.4%) but the difference was not statistically significant. PFT for patients who underwent thoracoscopic lobectomy for CPAM before or after 5 months of age is normal and comparable between both groups. Surgical resection of CPAM can be performed safely early in life without any consequences for pulmonary function or more complications when older children undergo surgery.

Classifying and evaluating fetuses with multicystic dysplastic kidney in etiologic studies.

Multicystic dysplastic kidney (MCDK) is one of the most common fetal malformations, but its etiology remains unclear. Identification of the molecular etiology could provide a basis for prenatal diagnosis, consultation, and prognosis evaluation for MCDK fetuses. We used chromosome microarray analysis (CMA) and whole-exome sequencing (WES) to conduct genetic tests on MCDK fetuses and explore their genetic etiology. A total of 108 MCDK fetuses with or without other extrarenal abnormalities were selected. Karyotype analysis of 108 MCDK fetuses showed an abnormal karyotype in 4 (3.7%, 4/108) of the fetuses. However, CMA detected 15 abnormal copy number variations (CNVs) (14 pathogenic CNVs, and one variant of unknown significance [VUS] CNVs), in addition to four cases that were consistent with the results of karyotype analysis. Out of the 14 pathogenic CNVs cases, three were of 17q12 microdeletion, two of 22q11.21 microdeletion, 22q11.21 microduplication uniparental disomy (UPD), and one case of 4q31.3q32.2 microdeletion, 7q11.23 microduplication, 15q11.2 microdeletion, 16p11.2 microdeletion, and 17p12 microdeletion. Of the 89 MCDK fetuses with normal karyotype analysis and CMA, 15 were tested by WES. Two (13.3%, 2/15) fetuses were identified by WES as Bardet-Biedl syndrome (BBS) 1 and BBS2. Combined application of CMA-WES to detect MCDK fetuses can significantly improve the detection rate of genetic etiology, providing a basis for consultation, and prognosis evaluation.

Aberrant adenosine signaling in patients with focal cortical dysplasia.

Focal cortical dysplasia (FCD), a common malformation of cortical development, is frequently associated with pharmacoresistant epilepsy in both children and adults. Adenosine is an inhibitory modulator of brain activity and a prospective anti-seizure agent with potential for clinical translation. Our previous results demonstrated that the major adenosine-metabolizing enzyme adenosine kinase (ADK) was upregulated in balloon cells (BCs) within FCD type IIB lesions, suggesting that dysfunction of the adenosine system is implicated in the pathophysiology of FCD. In our current study, we therefore performed a comprehensive analysis of adenosine signaling in surgically resected cortical specimens from patients with FCD type I and type II via immunohistochemistry and immunoblot analysis. Adenosine enzyme signaling was assessed by quantifying the levels of the key enzymes of adenosine metabolism, i.e., ADK, adenosine deaminase (ADA), and ecto-5'-nucleotidase (CD73). Adenosine receptor signaling was assessed by quantifying the levels of adenosine A2A receptor (A2AR) and putative downstream mediators of adenosine, namely, glutamate transporter-1 (GLT-1) and mammalian target of rapamycin (mTOR). Within lesions in FCD specimens, we found that the adenosine-metabolizing enzymes ADK and ADA, as well as the adenosine-producing enzyme CD73, were upregulated. We also observed an increase in A2AR density, as well as a decrease in GLT-1 levels and an increase in mTOR levels, in FCD specimens compared with control tissue. These results suggest that dysregulation of the adenosine system is a common pathologic feature of both FCD type I and type II. The adenosine system might therefore be a therapeutic target for the treatment of epilepsy associated with FCD.

EEG patterns in Refractory Epilepsy with Focal Cortical Dysplasia and predictors of outcome after surgery (P10-1.003)

<h3>Objective:</h3> To characterize the EEG patterns of type-1 and type-2 FCD with refractory epilepsy, correlate with clinic-radiological features and determine predictors of surgical outcome. <h3>Background:</h3> Focal cortical dysplasia (FCD) is the most common malformation of cortical development (MCD) causing drug refractory epilepsy(DRE) requiring surgical evaluation. Precise characterisation of the FCD and associated epileptogenic zone (EZ) with multimodal evaluation is crucial for surgical success <h3>Design/Methods:</h3> Retrospective analysis data of 188 consecutive patients with FCD operated for DRE and at least two years post-surgery follow-up was analyzed. The clinical features, MRI and interictal and ictal EEG patterns were studied for all patients <h3>Results:</h3> Average age of patients was 17.31±11.26 (2 – 64) years with 48.9% women. Interictal EEG showed regional pattern in 66% of FCD2 patients (p=0.04), while generalised interictal discharges were commonly associated with persistent seizures after surgery (p=0.016). Ictal beta rhythm was significantly associated with FCD2 (p=0.05). Generalised ictal onset was significantly seen in patients with persistent seizures after surgery (p=0.48). MRI showed clear cut FCD in 72.3% patients. At last follow-up 66.0% were seizure free. Patients with FCD type-1 had earlier age at onset (p=0.029) of epilepsy and had multiple seizure patterns (0.034). Patients with FCD type-2 commonly reported aura (p=0.019) and had clear-cut lesion on MRI (p=0.021) and high seizure freedom(p=0.004). Patients with FCD type-1 more often were detected on PET-MRI, underwent multilobar resections and had higher rate of acute postoperative seizures, while complete resection was more frequent in type-2 FCD <h3>Conclusions:</h3> FCD type-1 had early onset of seizures with multiple seizure semiologies, subtle MRI, multi-lobar resection and poor surgical outcome. FCD2 had clear-cut MRI lesion, regional inter-ictal discharges, ictal beta at onset with complete resection at surgery hence favorable post-surgical outcome <b>Disclosure:</b> Dr. Patil has nothing to disclose. Sita Jayalakshmi has nothing to disclose. Dr. Vooturi has nothing to disclose.

Audiological and Speech Outcomes of Cochlear Implantation in Inner Ear Malformation Compared to the Normal Inner Ear.

To compare the overall clinical outcomes of cochlear implantation in children with structural inner ear abnormalities, with results of implantation in children with radiologically 'normal' inner ears. To study the incidence and performance outcomes of cochlear implantation in children with inner ear malformations (IEMs). It is a retrospective case control study of 57 normal and 57 abnormal inner ear patients operated for cochlear implant between Jan 1, 2014 and Aug 1, 2017, by Veria technique. The age range was between 12months and 15years. The prevalence of IEMs was 13.8%. Of the 57 cases with IEMs, 33.3% were of enlarged vestibular acqueduct, 7% were of isolated Incomplete Partition type-2, 21.1% cases were of Mondini's dysplasia, 3.5% of Incomplete partition type-1 and 8.8% of cochlear nerve hypoplasia. Most commonly encountered malformation was EVA while IP-1 was the least common malformation. A CSF gusher was experienced in 11 cases. There was a statistically significant difference between the CAP and SIR scores of both IEM and control groups, both at 1year and at 2years (1year CAP score p value < 0.001, 2year CAP score p value 0.002 and 1year SIR score, p value < 0.001, 2year SIR score, p value 0.013). There was progressive improvement in the scores (of both groups) at the 2year mark, compared to 1year scores. Cochlear implantation is safe and surgically feasible in children with IEMs. However, the hearing outcome and speech perception outcomes are poor than those of patients with normal anatomy, with an exception seen in enlarged vestibular aqueduct.

Distinct patterns of interictal intracranial EEG in focal cortical dysplasia type I and II

ObjectiveFocal cortical dysplasia (FCD) is the most common malformation causing refractory focal epilepsy. Surgical removal of the entire dysplastic cortex is crucial for achieving a seizure-free outcome. Precise presurgical distinctions between FCD types by neuroimaging are difficult, mainly in patients with normal magnetic resonance imaging findings. However, the FCD type is important for planning the extent of surgical approach and counselling. MethodsThis study included patients with focal drug-resistant epilepsy and definite histopathological FCD type I or II diagnoses who underwent intracranial electroencephalography (iEEG). We detected interictal epileptiform discharges (IEDs) and their recruitment into repetitive discharges (RDs) to compare electrophysiological patterns characterizing FCD types. ResultsPatients with FCD type II had a significantly higher IED rate (p < 0.005), a shorter inter-discharge interval within RD episodes (p < 0.003), sleep influence on decreased RD periodicity (p < 0.036), and longer RD episode duration (p < 0.003) than patients with type I. A Bayesian classifier stratified FCD types with 82% accuracy. ConclusionTemporal characteristics of IEDs and RDs reflect the histological findings of FCD subtypes and can differentiate FCD types I and II. SignificancePresurgical prediction of FCD type can help to plan a more tailored surgical approach in patients with normal magnetic resonance findings.

The EDA/EDAR/NF-κB pathway in non-syndromic tooth agenesis: A genetic perspective.

Non-syndromic tooth agenesis (NSTA) is one of the most common dental developmental malformations affected by genetic factors predominantly. Among all 36 candidate genes reported in NSTA individuals, EDA, EDAR, and EDARADD play essential roles in ectodermal organ development. As members of the EDA/EDAR/NF-κB signaling pathway, mutations in these genes have been implicated in the pathogenesis of NSTA, as well as hypohidrotic ectodermal dysplasia (HED), a rare genetic disorder that affects multiple ectodermal structures, including teeth. This review provides an overview of the current knowledge on the genetic basis of NSTA, with a focus on the pathogenic effects of the EDA/EDAR/NF-κB signaling pathway and the role of EDA, EDAR, and EDARADD mutations in developmental tooth defects. We also discuss the phenotypic overlap and genetic differences between NSTA and HED. Ultimately, this review highlights the importance of genetic analysis in diagnosing and managing NSTA and related ectodermal disorders, and the need for ongoing research to improve our understanding of these conditions.

Management and survival of foetuses with trisomy 18 in a French retrospective cohort Prise en charge et survie des fœtus porteurs de trisomie 18 dans une cohorte française rétrospective.

The main objective of this study was to evaluate parents' current demands following the announcement of trisomy 18 and maternal risks. A single-centre retrospective study was performed in the Paris Saclay Foetal Medicine Department from 2018 to 2021. All patients followed up in the department who had cytogenetic confirmation of trisomy 18 were included. 89 patients were recruited. The most common malformations at ultrasound examination were cardiac or brain abnormalities, distal arthrogryposis as well as severe intrauterine growth retardation. 29% of foetuses with trisomy 18 had more than three malformations. 77.5% of patients requested medical termination of pregnancy. Among the 19 patients who chose to continue their pregnancy, 10 (52.6%) presented with obstetrical complications, of which 7 (41.2%) experienced stillbirth; five babies were born alive with no survival at 6 months. In France, in the case of foetal trisomy 18, most women request termination of pregnancy. In the post-natal period, the management of a newborn with trisomy 18 is oriented towards palliative care. The mother's risk of obstetrical complications should be part of counselling. Follow-up, support and safety should be the goal of management of these patients, regardless of the patient's choice.

169 Exome Sequencing Implicates Endothelial Ras Signaling Network in Vein of Galen Aneurysmal Malformation

INTRODUCTION: Early neurovascular development is a complex and intricate process with devastating consequences when impaired. Vein of Galen Aneurysmal Malformations (VGAMs) are the most common and severe neonatal arteriovenous malformation and often present with high-output heart failure, hydrocephalus, neurodevelopmental delay, and brain hemorrhage. Despite their prevalence and severity, little is known regarding their genetic pathomechanism. METHODS: Genetic samples were collected from 114 VGAM probands, including 90 trios, from multiple sites. Collected specimens underwent whole exome sequencing, pathway analysis, and select ACVRL1 and EPHB4 mutations identified via sequencing were then studied in zebrafish models. RESULTS: Exome sequencing revealed a genome-wide significant burden of de novo mutations in Ras suppressor p120 Ras-GAP (RASA1) (enrichment = 324-fold; p = 4.8 x 10-7). Damaging transmitted variants were enriched in p120 Ras-GAP negative regulator Eph-B4 (EPHB4) (odds ratio = 27.4; p = 1.7 x 10-6). Eph-B4 missense variants caused loss of receptor tyrosine kinase activity constitutive Ras activation. Other probands had pathogenic variants in OMIM vascular disease genes PTNPN11, NOTCH1, and ACVRL1; the latter we found mutated in an ultra-rare multi-generational VGAM family. Pathway analysis identified enrichment of rare, damaging de novo and inherited variants in a network of interacting OMIM vascular disease genes involved in axon guidance (FDR = 2.3 x 10-5; enrichment = 3.65-fold). In zebrafish, the functional studies of ACVRL1 and EPHB4 confirmed severe vascular defects in mutant embryos. CONCLUSIONS: These results demonstrate that genetic regulation of a RASA1-centered Ras signaling hub is critical for cerebrovascular development and is impaired in VGAM pathogenesis. This finding has significant implications for the genetic counseling of patient families and the development of targeted therapeutics for VGAM neurovascular disorders.

Inter- and intra-reliability of Cobb angle measurement in pediatric scoliosis using PACS (picture archiving and communication systems methods) for clinicians with various levels of experience

Background: Scoliosis is a common spinal malformation, which is typically diagnosed and assessed for severity by measuring the Cobb angle on a plain radiograph. Although manual methods are still considered the gold standard, recent studies have shown that picture archiving and communication systems (PACS) methods have comparable intraobserver and interobserver reliability levels for experienced clinicians. However, there is limited data for these reliability measures using PACS in less experienced medical personnel and radiologist. The objective of this study was to determine if inter- or intra-reliability differs for clinicians with different experience levels and if PACS provides adequate inter- or intra-reliability.

Symptomatic Developmental Venous Anomaly: State-of-the-Art Review on Genetics, Pathophysiology, and Imaging Approach to Diagnosis.

Developmental venous anomalies (DVAs) are the most common slow-flow venous malformation in the brain. Most DVAs are benign. Uncommonly, DVAs can become symptomatic, leading to a variety of different pathologies. DVAs can vary significantly in size, location, and angioarchitecture, and imaging evaluation of symptomatic developmental venous anomalies requires a systematic approach. In this review, we aimed to provide neuroradiologists with a succinct overview of the genetics and categorization of symptomatic DVAs based on the pathogenesis, which forms the foundation for a tailored neuroimaging approach to assist in diagnosis and management.

Holoprosencephaly: Review of Embryology, Clinical Phenotypes, Etiology and Management.

Holoprosencephaly (HPE) is the most common malformation of the prosencephalon in humans. It is characterized by a continuum of structural brain anomalies resulting from the failure of midline cleavage of the prosencephalon. The three classic subtypes of HPE are alobar, semilobar and lobar, although a few additional categories have been added to this original classification. The severity of the clinical phenotype is broad and usually mirrors the radiologic and associated facial features. The etiology of HPE includes both environmental and genetic factors. Disruption of sonic hedgehog (SHH) signaling is the main pathophysiologic mechanism underlying HPE. Aneuploidies, chromosomal copy number variants and monogenic disorders are identified in a large proportion of HPE patients. Despite the high postnatal mortality and the invariable presence of developmental delay, recent advances in diagnostic methods and improvements in patient management over the years have helped to increase survival rates. In this review, we provide an overview of the current knowledge related to HPE, and discuss the classification, clinical features, genetic and environmental etiologies and management.

Articulation-Function-Associated Cortical Developmental Changes in Patients with Cleft Lip and Palate.

Cleft lip and palate (CLP) is one of the most common craniofacial malformations. Overall, 40-80% of CLP patients have varying degrees of articulation problems after palatoplasty. Previous studies revealed abnormal articulation-related brain function in CLP patients. However, the association between articulation disorders and cortical structure development in CLP patients remains unclear. Twenty-six CLP adolescents (aged 5-14 years; mean 8.88 years; female/male 8/18), twenty-three CLP adults (aged 18-35 years; mean 23.35 years; female/male 6/17), thirty-seven healthy adolescents (aged 5-16 years; mean 9.89 years; female/male 5/16), and twenty-two healthy adults (aged 19-37 years; mean 24.41 years; female/male 19/37) took part in the experiment. The current study aims to investigate developmental changes in cortical structures in CLP patients with articulation disorders using both structural and functional magnetic resonance imaging (MRI). Our results reveal the distinct distribution of abnormal cortical structures in adolescent and adult CLP patients. We also found that the developmental pattern of cortical structures in CLP patients differed from the pattern in healthy controls (delayed cortical development in the left lingual gyrus (t = 4.02, cluster-wise p < 0.05), inferior temporal cortex (z = -4.36, cluster-wise p < 0.05) and right precentral cortex (t = 4.19, cluster-wise p < 0.05)). Mediation analysis identified the cortical thickness of the left pericalcarine cortex as the mediator between age and articulation function (partial mediation effect (a*b = -0.48), 95% confident interval (-0.75, -0.26)). In conclusion, our results demonstrate an abnormal developmental pattern of cortical structures in CLP patients, which is directly related to their articulation disorders.

Vestibular Fistula: A Prospective Follow up Study for the Management of Anorectovestibular Fistula in Neonates

Introduction: Anorectal Malformation (ARM) is one of the common congenital anomalies in the world. Incidence worldwide is 1 in 3000 to 5000 live births. Anorectal malformation is a well-recognized condition since antiquity and represents a wide spectrum of defects. Anorecto-Vestibular fistula (ARVF) is the commonest ARM in female children. Recto‑Vestibular anus is the most common Anorectal Malformation (ARM) in female patients, in which rectum opens immediately behind the hymen in the vestibule. Aim of the Study: The aim of this study was to evaluate and compare the outcome between Trans- Fistula Anorectoplasty (TFARP) and Anterior Sagittal Anorectoplasty (ASARP) in the management of Recto-Vestibular Fistula (RVF) among neonates in a tertiary care hospital .Methods: This was a prospective comparative study and was conducted in the Faculty of Pediatric Surgery of Bangladesh Shishu Hospital &amp; Institute, Dhaka, Bangladesh during the period from February 2017 to January 2021. In our study we took sixty (60) female neonates with vestibular fistula (VF). Among all neonates TFARP was done in 30 neonates and ASARP was done in 30 neonates for definitive correction of RVF. Result: In total 60 patients from both the groups completed the study. In our study we found the mean operation time in TFARP group and ASARP group was 65.97±4.63 minutes and 69.37±4.76 minutes. After operation, 60% neonates in TFARP group and 90% neonates in ASARP group developed complications. Most occurred complication was skin excoriation (20% &amp; 26.67%) in TFARP &amp; ASARP groups respectively. Wound dehiscence was noted significantly more in ASARP group. In TFARP group, 63.3% neonates had good, 33.3% neonates had fair and 3.3% neonates had poor functional score while in ASARP group, 56.7% neonates had good functional score &amp; 43.3% neonates had fair functional score. Conclusion: In conclusion, we found that TFARP may provide the best postoperative cosmetic appearance, parent’s satisfaction, ..........

Variations in the poly-histidine repeat motif of HOXA1 contribute to bicuspid aortic valve in mouse and zebrafish

Bicuspid aortic valve (BAV), the most common cardiovascular malformation occurs in 0.5–1.2% of the population. Although highly heritable, few causal mutations have been identified in BAV patients. Here, we report the targeted sequencing of HOXA1 in a cohort of BAV patients and the identification of rare indel variants in the homopolymeric histidine tract of HOXA1. In vitro analysis shows that disruption of this motif leads to a significant reduction in protein half-life and defective transcriptional activity of HOXA1. In zebrafish, targeting hoxa1a ortholog results in aortic valve defects. In vivo assays indicates that these variants behave as dominant negatives leading abnormal valve development. In mice, deletion of Hoxa1 leads to BAV with a very small, rudimentary non-coronary leaflet. We also show that 17% of homozygous Hoxa1−1His knock-in mice present similar phenotype. Genetic lineage tracing in Hoxa1−/− mutant mice reveals an abnormal reduction of neural crest-derived cells in the valve leaflet, which is caused by a failure of early migration of these cells.

Criss-cross heart: a clinical case of a rare congenital heart defect in a newborn

Introduction. Criss-cross syndrome is a rare congenital heart disease with an incidence of 8 cases per 1 million newborns. The purpose of the work is to demonstrate a rare CHD, a criss-cross heart diagnosed postnatally. The purpose of the work was to demonstrate a rare CHD, a criss-cross heart diagnosed postnatally. Materials and methods. A clinical observation of a newborn child with a rare congenital heart defect is presented. Medical documents with the results of clinical examination (physical examination) and instrumental examinations (X-ray examination, echocardiography, computed tomography) were used for analysis. Results. A child with a rare congenital heart defect (CHD) – criss-cross heart with discordant atrioventricular connections, transposition of the great vessels and preductal aortic coarctation was monitored from the time of delivery until surgical treatment. This malformation was diagnosed postnatally, based on the characteristic clinical symptoms of the detailed segmental analysis of the ultrasound picture of the heart, which is presented as illustrations. Timely diagnosis allowed the choice of adequate medication and surgical tactics of treatment, and the diagnosis was confirmed by computed tomography. Discussion. It is important for the clinician to remember that rare congenital heart diseases cannot always be diagnosed antenatally, and with the results of screening indicating the presence of more common malformations, the real postnatal heart picture may differ significantly. An additional difficulty is the differential diagnosis of the described malformation due to the rare anomalous mutual arrangement of the anatomical structures. Conclusion. Detailed segmental analysis during echocardiography immediately after birth reveals the main diagnostic marker of criss-cross syndrome – inability to simultaneously visualize all four heart chambers and both atrioventricular valves from a four-chamber position.

An integrated genetic analysis of epileptogenic brain malformed lesions

Focal cortical dysplasia is the most common malformation during cortical development, sometimes excised by epilepsy surgery and often caused by somatic variants of the mTOR pathway genes. In this study, we performed a genetic analysis of epileptogenic brain malformed lesions from 64 patients with focal cortical dysplasia, hemimegalencephy, brain tumors, or hippocampal sclerosis. Targeted sequencing, whole-exome sequencing, and single nucleotide polymorphism microarray detected four germline and 35 somatic variants, comprising three copy number variants and 36 single nucleotide variants and indels in 37 patients. One of the somatic variants in focal cortical dysplasia type IIB was an in-frame deletion in MTOR, in which only gain-of-function missense variants have been reported. In focal cortical dysplasia type I, somatic variants of MAP2K1 and PTPN11 involved in the RAS/MAPK pathway were detected. The in-frame deletions of MTOR and MAP2K1 in this study resulted in the activation of the mTOR pathway in transiently transfected cells. In addition, the PTPN11 missense variant tended to elongate activation of the mTOR or RAS/MAPK pathway, depending on culture conditions. We demonstrate that epileptogenic brain malformed lesions except for focal cortical dysplasia type II arose from somatic variants of diverse genes but were eventually linked to the mTOR pathway.