Congenital Research Articles

Molar Incisor Hypomineralization: A Survey of Dental Students from Polish Medical Universities.

Molar incisor hypomineralization (MIH) is a congenital qualitative disorder of the enamel tissue. During examinations, clinicians may observe a range of enamel opacities during examinations. The aim of this study was to assess the knowledge and awareness of dental students in Poland regarding MIH. This study was conducted among dental students who participated in scientific conferences for dental students in Poland. An electronic questionnaire was created for this purpose, accessible via a QR code. The respondents consisted of dental students from the first to the fifth year of study, including 98 fourth-year students and 76 fifth-year students. The students represented 10 medical universities in Poland. Of the 341 respondents, 256 (75.07%) stated that they were familiar with the term MIH, but only 61 (17.89%) correctly indicated the diagnostic criteria of MIH. The most frequently indicated condition resembling MIH was enamel hypoplasia, with 158 (46.33%) respondents identifying it. Dental students at Polish medical universities have basic knowledge of MIH, but it is insufficient and needs to be improved during their educational training.

Sexual Functions in Men with Congenital Bilateral Absence of the Vas Deferens: A Retrospective Cross-sectional Study with Fertile Men.

To examine the sexual and psychological conditions of men with Bilateral Congenital Bilateral Absence of the Vas Deferens (CBAVD), a rare condition that contributes to male infertility, and compare it with healthy fertile men. A total of 52 patients with CBAVD and 66 healthy, fertile men who attended our infertility and andrology clinic were included in the study. Patients with cognitive impairments, language barriers, significant comorbidities, or a history of urogenital surgery were excluded. Reproductive hormone levels and semen volumes were evaluated. In addition, sexual status was investigated with validated questionnaires such as the International Index of Erectile Function, Male Sexual Health Questionnaire, Arabic Index of Premature Ejaculation, Premature Ejaculation Diagnostic Tool, and Premature Ejaculation Profile. In the CBAVD group, median total testosterone, FSH, LH levels, and semen volume were 401 ng/dL, 3.9 mIU/ml, 3.9 mIU/ml, and 0.9 ml, respectively. These parameters were 376 (ng/dL), 4.8 mIU/ml, 5 mIU/ml, and 3 ml in the control group. Semen volume was significantly lower in CBAVD men (p< 0.001). Questionnaires assessing erectile and ejaculatory function have shown that there was no significant difference between the CBAVD and control groups in terms of erectile function, orgasmic function, and sexual relationship satisfaction. However, sexual desire (p=0.006) and overall satisfaction (p=0.028) were found to be higher in the CBAVD group. The study suggests that CBAVD may not be a direct etiological factor for erectile dysfunction or premature ejaculation.

CARDIAC REHABILITATION PROGRAM AS AN EFFORT TO IMPROVE THE QUALITY OF LIFE OF PATIENTS WITH CONgenital HEART DISEASE

ABSTRACT Introduction: Congenital Heart Disease (CHD) is the most common congenital disorder found throughout the world, including Indonesia. Currently, the main treatment for CHD patients is open cardiothoracic surgery. However, its implementation in Indonesia still has some obstacles due to several things which cause the life expectancy of CHD patients in Indonesia is estimated to be not as good as the life expectancy of CHD patients in developed countries. Apart from being related to life expectancy, CHD patients will also experience a decrease in their quality of life, especially those who are not treated properly. The cardiac rehabilitation program is one of the programs to overcome this. Discussion: Cardiac rehabilitation program is able to improve physical and psychosocial quality and ensure that CHD patients' cognitive and socioemotional development is maintained. Cardiac rehabilitation includes physical exercise, psychosocial management, education, risk factor modification, and nutritional management. Several studies have shown that cardiac rehabilitation has many benefits and is safe for CHD patients. In its implementation, cardiac rehabilitation faces several challenges, especially in center-based cardiac rehabilitation (CBCR), so it is recommended to increase home-based cardiac rehabilitation (HBCR) while ensuring that information regarding HBCR is delivered completely and well received by the patients. Conclusion: Based on this literature review, the authors suggest an increase in the implementation of cardiac rehabilitation for CHD patients throughout Indonesia, especially HBCR which can be carried out independently or in the community to improve the patient’s quality of life in the long term. Keywords: congenital, cardiac, rehabilitation, quality of life

Management of Smith-Lemli-Opitz Syndrome Type II associated with Cleft Palate

Rationale: This case report presents the management of a patient with the rare occurrence of SmithLemli-Opitz Syndrome (SLOS) and complete cleft palate Patient Concerns: The patient's cleft palate repair was not done in infancy, and she reported to the dental institution complaining of difficulty with proper food intake and speech. A clinical examination revealed muscle deformity, limited neck mobility, scoliosis, malocclusion, and inadequate oral health. The patient exhibited facial and limb anomalies characteristic of SLOS, in tandem with substantial challenges in speech and nutrition due to the cleft palate. Diagnosis: The patient was referred to the dental wing to manage the cleft palate defect. On dental examination a complete cleft of the hard and soft palate, which had not been surgically corrected during infancy, was confirmed through clinical and radiological investigation. Additional musculoskeletal complications, including scoliosis and muscle deformity, were also identified. Interventions: The treatment plan addressed both SLOS and cleft palate. A prosthodontic appliance was prepared to assist with palatal function and speech therapy. Comprehensive care for SLOS included genetic counselling, nutrition management, and targeted physical therapy. The patient was also referred to an orthodontist, oral surgeon and a speech-language therapist further intervention. Conclusion: This case emphasizes the importance of early diagnosis and intervention in congenital disorders. It advocates for proactive, multidisciplinary care from infancy to enhance the quality of life for individuals with complex syndromes, underscoring the need for ongoing support and resources

Measuring Parental Response Styles to Child Stress in Severe Pediatric Illness: A Validation Study.

Pediatric illnesses not only impose physical challenges on affected children, but also profoundly impact their emotional well-being. Understanding how parents respond to their children's psychological distress during medical experiences is crucial for enhancing the overall support provided to these families. This study evaluated the internal structure of the Parental Response Styles Questionnaire (PRSQ), designed to differentiate parental responses to psychological distress in children with pediatric illnesses. A sample of 701 parents of children with medical issues responded to the PRSQ, reporting their different emotional expressions and responses to their children's expressions of distress during the medical experience. Factor analysis confirmed, in three of the five subsamples, an internal scale structure consisting of four factors: apathy and dysphoria, irritability and rejection, overprotectiveness, and perceived maladjustment. The invariance analyses revealed that congenital heart disease and neurological disorders are more similar in function to each other than pediatric cancer. Parents of children with neurological disorders exhibited a notably insecure pattern of parental responsiveness. In pediatric contexts, parental responses to their children's emotional distress are significant factors in the process of adaptation. These responses can be measured, differentiated, and, ideally, managed by nurses and other healthcare professionals. The Parental Response Styles Questionnaire (PRSQ) is a promising tool for assessing parental reactions during their children's treatment, and its structure appears to be particularly robust across diagnoses such as pediatric cancer, congenital heart disease, and neurological disorders.

Unveiling the Significance of the Androgen Receptor Gene in Disorders of Sex Development

Abstract Disorders of sex development (DSD) encompass a range of congenital conditions where the development of chromosomal, gonadal or anatomical sex is atypical. There are many genes associated with DSD, and one of them is the androgen receptor (AR) gene, which plays a pivotal role in normal sex development. Studies reported numerous genetic variations in the AR gene that lead to 46, XY DSD, including androgen insensitivity syndrome and hypospadias. Identifying and understanding the genetic causes of DSD will aid the healthcare providers design a tailored-made management for DSD patients and optimise patients’ quality of life. This narrative review will explore the significance of the AR gene in DSD while discussing DSD in general.

Fetal Presentation of MYRF-Related Cardiac Urogenital Syndrome: An Emerging and Challenging Prenatal Diagnosis.

MYRF-related cardiac-urogenital syndrome (MYRF-CUGS) is a rare condition associated with heterozygous MYRF variants. The description of MYRF-CUGS phenotype is mostly based on postnatal cases and 36 affected individuals have been published so far. We aim now to delineate the prenatal phenotype of MYRF-CUGS by reporting clinical data from fetuses and neonates with a pathogenic MYRF variant. Detailed radiographic, pathological, clinical, and molecular data from 12 prenatal cases were collected through an international collaborative study. Adding the five fetuses previously published, we were able to study a cohort of 17 cases. Main ultrasound-accessible manifestations of MYRF-CUGS include congenital heart defects (13/17, 76%), congenital diaphragmatic hernia (10/17, 59%) and disorders of sexual differentiation in 46, XY fetuses (7/14; 50%). Postnatal examination and/or autopsy data highlighted additional birth defects and neurological findings with a large spectrum of severity. Molecular results revealed ten previously unpublished variants, one missense and nine predicted truncating variants (three frameshift, three nonsense and three splice site variants). We report the first prenatal cohort of MYRF-CUGS, allowing us to further characterize the variable expressivity of this rare disorder in fetuses. Severe congenital anomalies with a poor prognosis are more frequent than previously described in postnatal cases. Our data suggest that MYRF-CUGS is characterized by a recurrent recognizable malformative association, accessible to prenatal diagnosis, with a significant intrafamilial phenotypic variability making genetic counseling challenging.

Bart syndrome with musculoskeletal deformity: a rare case report

Introduction: Bart syndrome is a rare genetic disorder characterized by epidermolysis bullosa (EB), aplasia cutis congenita i.e., congenital local absence of skin, and nail abnormalities. Case Presentation: We herein present a case of a 14-year old boy with Bart Syndrome. The syndrome was diagnosed clinically. On examination, multiple generalized blisters were present and absence of nails in toes of both feet and middle finger of left hand which was associated with musculoskeletal deformity. Discussion: Bart Syndrome, an inherited autosomal dominant disorder, is an exceedingly rare disorder. Musculoskeletal deformity is an uncommon presentation of this syndrome. It is mostly associated with Dystrophic type of EB. It is mostly a clinical diagnosis however, histopathological study, direct immunofluorescence, and genetic testing helps in diagnosing the type of EB. Conclusion: The absence of skin in a localized area at birth is a crucial indicator for diagnosing Bart Syndrome at birth which later heals and can obscure the diagnosis. Early diagnosis and conservative management prevent the disease progression and complications.

Clinical Characteristics and Mortality Risk Factors of Hospitalized COVID-19 in Children: An Experience of Two Years Pandemic in Regional Referral Hospital

Coronavirus disease 2019 (COVID-19) has spread worldwide rapidly. COVID-19 in children is relatively mild compared to adults. However, several studies showed high mortality rates in children with underlying diseases. This study aimed to describe the clinical characteristics and outcomes of pediatric COVID-19 cases in regional referral hospital. This study was retrospective observational study using data from Medical Record Dr. Moewardi General Hospital between October 1st, 2020 and October 30th, 2022. The epidemiological and clinical data were extracted from the database and were compared with outcomes of patients. All statistical analyses were performed by SPSS software version 27. This study enrolled 371 (19,9%) children with confirmed RT-PCR SARS CoV-2 from 1856 hospitalized suspected children whereas 55% were males, and 63% aged under 5 years old. Moderate-severe patients accounted for 18% of the cases. Cough (74,4%), fever (66,6%) and shortness of breath (22,6) are the most common symptoms while 99 (26,7%) patients who had chronic diseases with the most common diseases being congenital heart disease, hematological malignancy and neurological disorders. Patient outcomes were significantly related to age, degree of severity and chronic disease with p=0.004, p&lt; 0.001, and p&lt; 0.001 respectively. After performing multivariate regression analysis, degree of severity [p&lt;0.001; adjusted OR = 28.03, 95% CI (10.73–73.21)] was found to be significant predictors for mortality. The clinical and epidemiological data revealed that the majority symptom were cough, fever and shortness of breath. Mortality rate during hospitalization was higher in children with moderate-to-severe COVID-19.

Noonan Syndrome: Relation of Genotype to Cardiovascular Phenotype-A Multi-Center Retrospective Study.

Background: Noonan syndrome (NS) is a congenital genetic disorder with a prevalence of 1 in 1000 to 2500 live births, and is characterized by distinctive facial features, short stature, chest deformities, and congenital heart disease. This study aims to evaluate the prevalence of specific genetic mutations and their impact on cardiovascular and other outcomes in NS. Methods: We conducted a retrospective clinical study of 25 pediatric patients diagnosed with NS at two institutions: The Mother and Child Health Care Institute of Serbia and the Clinic for Children Diseases, University Clinical Center of the Republic of Srpska. Patients underwent whole-exome sequencing (WES) to identify genetic mutations. Clinical data, including cardiovascular manifestations, psychomotor development, and stature, were analyzed in relation to mutation types. Results: The cohort comprised 60% male and 40% female patients, with a median age at diagnosis of 7.2 years. Cardiovascular abnormalities were present in 88% of patients. Mutations in PTPN11 were most commonly associated with pulmonary valve stenosis (PVS), while RAF1 mutations were prevalent in patients with hypertrophic cardiomyopathy (HCM). No significant association was found between cardiac disease and delayed psychomotor development (p = 0.755), even though the likelihood ratio showed significance in that regard (p = 0.018). Short stature was observed in 48% of patients but was not significantly correlated with genetic type of disease, presence of cardiac disease, or developmental delay. Conclusions: The study confirms the high prevalence of cardiovascular manifestations in NS and highlights genotype-phenotype correlations. While cardiac abnormalities are common, their impact on psychomotor development and stature is less clear. Further research is needed to explore genetic interactions influencing these outcomes and refine clinical management strategies.

THE CONNECTION OF LOCAL RETINAL DETACHMENT IN THE MACULAR AREA WITH THE FOSSA OF THE OPTIC DISC. DIFFERENTIAL DIAGNOSIS (CLINICAL CASE)

Relevance. The optic nerve pit is a congenital disease manifested by a depression in the disc of the optic nerve, which affects about 0.9% of the population. Complications occur in 25–75% of patients and may include retinal detachment. The causes of detachment remain unclear, but two theories of the occurrence of this complication have been put forward. Fluorescence angiography and optical coherence tomography are used for diagnosis. The treatment of retinal detachment in ONDP is not standardized and includes laser treatment, vitrectomy and other methods for fluid drainage. It is important to differentiate ONDP from other causes of central retinal detachment.Objective. Based on a clinical case, to demonstrate an approach to the diagnosis and treatment of local retinal detachment in the macular area associated with the fossa of the optic disc.Materials and methods. This article presents a clinical case of retinal detachment in the macular area associated with the fossa of the optic disc. Results and discussions. When comparing two clinical cases, the similarity of the ophthalmoscopic picture and the differences in the OCT and FAG images were revealed.Conclusions. The accumulation of fluid under the neuroepithelium is not a pathognomic sign, therefore it is important to carry out differential diagnosis in central serous retinal detachment associated with the fossa of the optic disc.

The efficacy of high pressure liquid chromatography (HPLC) in detecting congenital glycosylation disorders (CDG)

Abstract Objectives Congenital disorders of glycosylation (CDG) are a family of rare inherited metabolic disorders. This study aimed to examine the carbohydrate-deficient transferrin (CDT) screening results of 1,328 patients with suspected CDG by using transferrin- high pressure liquid chromatography (Tf- HPLC) method and to evaluate the performance of the method as a reference diagnostic tool. Methods Relative CDT levels (CDT concentrations expressed as percent of total transferrin) were determined in serum samples by HPLC. The method sensitivity, specificity and positive predictive value (PPV) were further calculated. Results Abnormal transferrin isoform profile consistent with CDG Type-I and CDG Type-II were determined in 50 cases; in 44 cases asiolo-Tf (7.63 ± 5.44 %) and disialo-Tf (36.29 ± 9.04 %), in six cases monosialo-Tf (3.95 ± 0.95 %) and trisialo-Tf (25.05 ± 4.46 %) were determined and decreased tetrasialo-Tf (49.75 ± 11.59 %) was identified in all cases. Two cases having abnormal CDT pattern were molecularly diagnosed with hereditary fructose intolerance and galactosemia and 11 cases diagnosed with CDG based on clinical and molecular analysis showed a normal pattern. The sensitivity, specificity and positive predictive values of Tf-HPLC method were 81.96 %, 99% and 96 %, respectively. Conclusions Tf-HPLC is a useful, highly sensitive, cost-advantageous and reliable method for the detection and preliminary diagnosis of CDG for laboratories working with large sample series.

A Stillborn Baby with Tetra-amelia Syndrome in Jember: A Case Report

Tetra-amelia syndrome is a rare congenital disorder characterized by the absence of all four extremities. This extremity disorder occurs in 1 in 1,300 to 2,000 births. This condition is caused by genetic mutations in the WNT3 and RSPO2 genes. Specific risk factors for tetra-amelia syndrome remain unclear. This is also due to the lack of studies that discuss specific risk factors for tetra-amelia syndrome. In this case report, we discuss a stillborn baby with tetra-amelia syndrome to a mother with various pregnancy risk factors in Jember. This case report aims to examine the presence of several risk factors in the mother and their relationship with congenital disorders, especially tetra-amelia syndrome.

Psychological well-being of women with uterine infertility before considering uterus transplantation as a treatment option.

While uterus transplantation offers a promising treatment option for women with uterine factor infertility (UFI), the potential for graft failure and lack of organ availability could have subsequent psychological repercussions for women. Exploring baseline psychological well-being for women with UFI who could become uterine transplant recipients is essential to identify specific psychological challenges to be considered prior to transplantation. UFI can be congenital uterine absence, namely Mayer-Rokitansky-Küster-Hauser syndrome (MRKH), or acquired uterine absence (hysterectomy). To analyse baseline psychological well-being among women with UFI. A survey including demographic data and two internationally validated psychological questionnaires, Depression, Anxiety and Stress Scale (DASS-21),13 and Fertility Quality of Life (FertiQoL), was disseminated to women with UFI. Data from these instruments was compared between groups and then to data that uses these tools in the general infertility population. The study included 39 women (mean age 29.54 years). Higher scores for moderate symptoms of depression, anxiety, and stress were reported for the entire UFI cohort. More women with congenital UFI showed 'severe' symptoms for depression/anxiety, compared to women with acquired UFI. Women with acquired UFI showed poorer FertiQoL scores compared to both women with congenital UFI and to the general infertility population scores in previously published data. Clinicians should consider accessing increased psychological support for women with UFI when discussing fertility options including uterine transplant, and they may need to tailor this support depending on whether the patient has congenital or acquired UFI.

Expert Opinion for Defining a Severe Bleeding Phenotype to Guide Prophylaxis in Patients with Nonsevere Hemophilia.

Prophylaxis is the standard of care for patients with severe hemophilia, patients with moderate hemophilia, or those with another congenital bleeding disorder that is associated with a severe bleeding phenotype and/or a high risk of spontaneous life-threatening bleeding. Patients with nonsevere hemophilia (factor VIII [FVIII] ≥ 1%) may also have a bleeding phenotype that requires prophylaxis. To date, however, there are no clear criteria as to when prophylaxis is indicated in these patients. Also, the term "severe bleeding phenotype (SBPT)" is neither included in the definitions of the International Society on Thrombosis and Haemostasis (ISTH) nor specified in the World Federation of Hemophilia (WFH) guidelines. Based on our personal experience and available evidence, we propose the criteria we use to define an SBPT and when we consider offering prophylaxis in patients with nonsevere hemophilia. Our proposals can be the basis for discussions in the community about the assessment of SBPT and the initiation of prophylaxis in patients with nonsevere hemophilia without inhibitors.

Abstract 4119744: Evaluation of Neuropsychological development and Factors Affecting it in Children With Cyanotic and Acyanotic Congenital Cardiac Disease After Surgical Treatment

Objective: To evaluate neuropsychological development in children with cyanotic and acyanotic congenital heart diseases (CHDs) after surgical treatment and analyze the risk factors. Methods: 89 children who received follow-up in Fuwai Hospital after surgical treatment of CHDs were recruited in this study and 90 normal children were recruited as the control group. The children with CHDs were divided into cyanotic CHDs group and acyanotic CHDs group. Neuropsychological development was assessed according to Pediatric-psychological mental test scale and statistical analysis was employed. Results: The acyanotic CHDs group achieved better distribution of development quotient than cyanotic CHDs group (p &lt; 0.05) but worse than the normal control group (p = 0.004). The proportion in cyanotic CHDs group with developmental quotient below the moderate level was higher than that of the normal control group (p &lt; 0.001), but there was no significant difference between the cyanotic CHDs group and acyanotic CHDs group (p = 0.055). Multivariate regression analysis indicated that for cyanotic CHDs group, younger age at cardiac surgery, lower body mass, lower preoperative blood glucose level, lower BIS level, and prolonged duration of tracheal intubation after surgery were linked with lower scores in the test scale (p &lt; 0.05); for acyanotic CHDs group, younger age at cardiac surgery, lower body mass, lower temperature during surgery and prolonged duration of tracheal intubation after surgery were linked with lower scores in the test scale(p &lt; 0.05). Conclusion: Distinct neuropsychological impairment could be present in children with cyanotic CHDs. Younger age at cardiac surgery, body mass, preoperative blood glucose level, BIS level during surgery, temperature during surgery and duration of tracheal intubation after surgery were perioperative factors that could influence long-time neuropsychological development in children with CHDs.

Cerebrotendinous Xanthomatosis (CTX) Disease Prevalance in Patients with Autism Spectrum Disorder (ASD): A Prospective Observational Study

Background: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive congenital metabolic disorder which is characterized by the impairment of the enzymatic activity of sterol 27-hydroxylase. CTX, a rare neurodegenerative disease of sterol metabolism, can affect multiple systems, including the nervous system.It has been demonstrated that many congenital metabolic diseases like CTX are associated with Autism Spectrum Disorder (ASD). The aim of this study is to identify the prevalence of CTX disease in patients with ASD. Method: The clinical conditions of all patients were evaluated using the Mignarri Scoring Index. A socio-demographic form and Gilliam Autism Rating Scale-2 were applied to all participants. Results: In total, 101 children and adolescents with ASD were analyzed for genes. Following genetic analyses, four patients with mutations in the CYP27A1 gene, two homozygous variants and two different heterozygous mutations were identified. Most common symptom was diarrhea. 67.3% of all patients and 3 in 4 cases with CYP27A1 gene mutation had gone through psychiatric evaluation. A family history of a psychiatric disorder was present in 19.8% of all cases and in 75% of cases with mutations.Moreover, all mutant cases had comorbid Oppositional Defiant Disorder (ODD). 81.2% of all patients and all mutant patients were diagnosed with a behavioral disorder. Conclusion: psychiatric manifestations ranging from personality changes to behavioral disorders might accompany CTX. Better understanding and knowledge of the CTX disease by distinguishing specific psychiatric and systemic symptoms might help prevent missed diagnoses, progressive neurological deterioration and permanent disability through early initiation of chenodeoxycholic acid treatment.

Evaluation of pitolisant, sodium oxybate, solriamfetol, and modafinil for the management of narcolepsy: a retrospective analysis of the FAERS database.

Narcolepsy, a rare neurological disorder believed to have an autoimmune etiology, necessitates lifelong management. This study aimed to provide evidence supporting the safety of pharmacological treatment for narcolepsy. Five-year data on pitolisant, sodium oxybate, solriamfetol, and modafinil were extracted from the FDA Adverse Event Reporting System (FAERS) self-reporting database for the period spanning from 2019 to 2023. Various statistical methods, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network analysis (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were employed to quantify the signals. Finally, a comparative analysis was conducted between demographic data, outcomes, and inherent associations among the medications and the signals. After data analysis, we obtained 50 signals (a cumulative count of 762 cases) for pitolisant, 640 signals (corresponding to 46,962 cases) for sodium oxybate, 40 signals (equivalent to 1,228 cases) for solriamfetol, and finally, 72 signals (representing 632 cases) for modafinil. The majority of these patients were female. Psychiatric and nervous system disorders were identified as the predominant adverse drug events (ADEs). For sodium oxybate, it is crucial to consider psychiatric disorders (such as suicidal ideation), respiratory disorders (including sleep apnea syndrome and respiratory depression), and signs of pregnancy and congenital familial diseases. For solriamfetol, noteworthy new ADEs include drug inefficacy, suicidal ideation, restless legs syndrome, and somnambulism. Furthermore, a relationship has been observed between modafinil use and restricted fetal growth, spontaneous abortion, cognitive disorders, and drug inefficacy and abuse. The majority of observed adverse reactions in this study were consistent with those listed in the product instructions. However, potential novel or notable ADE signals were identified through real-world pharmacovigilance analysis. It is anticipated that this paper will offer additional information regarding safe and rational medication for narcolepsy.

Manic Fringe promotes endothelial-to-mesenchymal transition mediated by the Notch signalling pathway during heart valve development.

A fundamental event in the formation of heart valves involves the transformation of endocardial cells within the outflow tract (OFT) and atrioventricular canal (AVC) cushions through a process known as endothelial-to-mesenchymal transition (EndMT). Aberrant EndMT is a primary cause of congenital valvular malformations. Manic Fringe (MFNG) has been previously associated with cardiovascular development, although its role in heart valve development remains underexplored. In this study, we seek to enhance our understanding of MFNG's involvement in valve formation and its association with EndMT. Staining results of histological section revealed the expression of MFNG in the AVC and OFT from embryonic day 9.5 to 10.5 (E9.5-E10.5), when EndMT takes place. Cellular data demonstrated that MFNG exerts a positive regulatory influence on the EndMT process, promoting endothelial cell (EC) migration by enhancing the activity of the Notch signalling pathway. MFNG knockdown mediated by antisense morpholino oligonucleotides (MO) injection caused abnormal development of the heart and valves in zebrafish. Furthermore, through whole-exome sequencing (WES), we identified a heterozygous MFNG mutation in patients diagnosed with tetralogy of Fallot-pulmonary valve stenosis (TOF-PS). Cellular and molecular assays confirmed that this deleterious mutation reduced MFNG expression and hindered the EndMT process. In summary, our study verifies that MFNG plays a role in promoting EndMT mediated by the Notch signalling pathway during the heart and valve development. The MFNG deleterious variant induces MFNG loss of function, potentially elucidating the underlying molecular mechanisms of MFNG's involvement in the pathogenesis of congenital heart valve defects. These observations contribute to our current genetic understanding of congenital heart valve disease and may provide a potential target for prenatal diagnosis and treatment. KEY MESSAGES: Our examination revealed, for the first time, that MFNG exhibited high expression levels during EndMT of heart valve development in mice. Our findings provide compelling evidence that MFNG plays a role in promoting EndMT mediated by the Notch signalling pathway. Our results identified, for the first time, a deleterious MFNG p. T77M variant that inhibited the EndMT process by downregulating the activity of the Notch signalling pathway, thereby preventing the normal valve formation. MFNG may serve as an early diagnostic marker and an effective therapeutic target for the clinical treatment of congenital heart valve defects.

A prediction model of echocardiographic variables to screen for potentially correctable shunts in adult ASD-PAH patients.

Atrial septal defect (ASD) is a prevalent congenital heart condition in adults that leads to pulmonary hypertension (PAH) and right heart failure if left untreated. During a routine follow-up of adult ASD-PAH patients, the suitability of shunt closure depends on the invasive right heart catheterization (RHC).Nevertheless, performing RHC at every follow-up is impractical and may be harmful. The present retrospective cross-sectional study was designed to investigate which echocardiographic variables are related to pulmonary vascular resistance (PVR) in adult ASD-PAH patients and proposed a model using these variables to screen for patients with a correctable shunt. A total of 530 adult ASD-PAH patients with pulmonary arterial systolic pressure (PASP) of ≥60 mmHg measured using transthoracic echocardiogram (TTE) were included in the study. All RHCs were performed within 3 months after TTE. The correctable shunt was defined as PVR ≤3 wood units (WU). Multivariate regressions were performed utilizing echocardiographic variables. A scoring system was constructed based on the predictors of PVR ≤3 WU using multivariate logistic regression analysis. The scoring system was then examined using a receiver operating characteristic (ROC) analysis. In addition, clinical utility of the model was determined based on decision curve analysis and a calibration curve was used to evaluate model conformity. Estimated pulmonary arterial systolic pressure, velocity through the pulmonary valve, tricuspid annulus early diastolic velocity, and maximum defect dimension were identified as independent predictors. The area under the ROC curve of the predictive value in the model was 0.905 [95% confidence interval (CI): 0.878-0.931, sensitivity: 84.3%, specificity: 83.6%]. The net benefit of the model was notable in terms of a wide-range probability threshold in decision curve analysis, indicating that the prediction model had good clinical applicability. The model's calibration curve was close to an ideal diagonal line, showing good predictive accuracy between the actual and predictive probabilities. The study model was demonstrated to be valuable in predicting adult ASD-PAH patients with a correctable shunt, which may help clinicians to make appropriate treatment decision for follow-up patients.