Congenital Cardiovascular Anomalies Research Articles

Co-occurrence of patent foramen ovale and Chiari network in a diabetic patient.

The coexistence of congenital cardiovascular anomalies provides valuable insights into the intricate nature of human cardiac anatomy and its potential interactions with underlying health conditions. This case report presents an autopsy analysis of a diabetic patient manifesting both a patent foramen ovale and a Chiari network. A 26-year-old male with a history of type 2 diabetes mellitus was admitted with post cardiac arrest. He died despite resuscitative efforts. Autopsy revealed notable findings including a patent foramen ovale and a Chiari network. Post-mortem biochemical markers indicated elevated HbA1c level and hyperglycaemia. The absence of cryptogenic strokes or paradoxical embolism prompted exploration into potential relationships between these anomalies and metabolic disturbances, and prompts a discussion about whether the observed anatomical variations could potentially serve as risk factors contributing to the patient's death due to complications of diabetes. The co-occurrence of a patent foramen ovale and a Chiari network within a diabetic patient, accompanied by elevated HbA1c level and hyperglycaemia, offers a unique perspective on the convergence of congenital cardiovascular variation and metabolic health. The juxtaposition of these anomalies with biochemical markers underscores the intricate interplay between cardiac morphology and metabolic conditions.

Resection of infected bulla associated with isolated unilateral absence of pulmonary artery: a case report

BackgroundA unilateral absence of the pulmonary artery (UAPA) is a rare congenital anomaly, which in most patients is associated with congenital cardiovascular abnormalities. Some patients with UAPAs do not have associated cardiovascular abnormalities, called isolated UAPA. Patients with isolated UAPA generally have a mild clinical course and may not be diagnosed until adulthood, but repeated complications such as infections may make surgery difficult.Case presentationA 34-year-old female patient with isolated right UAPA was referred to our hospital with a complaint of fever. Chest radiography and computed tomography showed an infectious cavity in the right upper lung. Surgery was scheduled for the patient; however, her preoperative condition needed to be optimized. She was evaluated for pulmonary hypertension and the collateral arteries were mapped out, and a waiting period after treatment of infection was set to avoid perioperative intrathoracic infections. Resection of the infected bulla was performed without any complications. No recurrence of infection was observed two years post-operatively. The residual lung expanded enough to fill the dead intrathoracic space.ConclusionsThis report suggests the importance of adequate preoperative evaluation and perioperative management for patients with isolated UAPA who require surgical resection.

Analysis of genetic variability in Turner syndrome linked to long-term clinical features.

Women with Turner syndrome (TS) (45,X and related karyotypes) have an increased prevalence of conditions such as diabetes mellitus, obesity, hypothyroidism, autoimmunity, hypertension, and congenital cardiovascular anomalies (CCA). Whilst the risk of developing these co-morbidities may be partly related to haploinsufficiency of key genes on the X chromosome, other mechanisms may be involved. Improving our understanding of underlying processes is important to develop personalized approaches to management. We investigated whether: 1) global genetic variability differs in women with TS, which might contribute to co-morbidities; 2) common variants in X genes - on the background of haploinsufficiency - are associated with phenotype (a "two-hit" hypothesis); 3) the previously reported association of autosomal TIMP3 variants with CCA can be replicated. Whole exome sequencing was undertaken in leukocyte DNA from 134 adult women with TS and compared to 46,XX controls (n=23), 46,XX women with primary ovarian insufficiency (n=101), and 46,XY controls (n=11). 1) Variability in autosomal and X chromosome genes was analyzed for all individuals; 2) the relation between common X chromosome variants and the long-term phenotypes listed above was investigated in a subgroup of women with monosomy X; 3) TIMP3 variance was investigated in relation to CCA. Standard filtering identified 6,457,085 autosomal variants and 126,335 X chromosome variants for the entire cohort, whereas a somatic variant pipeline identified 16,223 autosomal and 477 X chromosome changes. 1) Overall exome variability of autosomal genes was similar in women with TS and control/comparison groups, whereas X chromosome variants were proportionate to the complement of X chromosome material; 2) when adjusted for multiple comparisons, no X chromosome gene/variants were strongly enriched in monosomy X women with key phenotypes compared to monosomy X women without these conditions, although several variants of interest emerged; 3) an association between TIMP3 22:32857305:C-T and CCA was found (CCA 13.6%; non-CCA 3.4%, p<0.02). Women with TS do not have an excess of genetic variability in exome analysis. No obvious X-chromosome variants driving phenotype were found, but several possible genes/variants of interest emerged. A reported association between autosomal TIMP3 variance and congenital cardiac anomalies was replicated.

Persistent fifth aortic arch: a comprehensive literature review.

Persistent fifth aortic arch (PFAA) is an extremely rare congenital cardiovascular anomaly resulting from the failure of the fifth aortic arch to degenerate during embryonic development; it is often associated with various other cardiovascular anomalies. Despite being first reported by Van Praagh in 1969, there have been only a few individual case reports. Owing to its rarity and lack of comprehensive understanding, PFAA is often misdiagnosed or missed diagnosed during clinical. Thus, this review aimed to summarise the embryonic development, pathological classification, imaging diagnosis, and clinical treatment of PFAA to improve its overall understanding, ultimately helping in accurate diagnosis and treatment.

Lateral thinking in syndromic congenital cardiovascular disease.

Syndromic birth defects are rare diseases that can present with seemingly pleiotropic comorbidities. Prime examples are rare congenital heart and cardiovascular anomalies that can be accompanied by forelimb defects, kidney disorders and more. Whether such multi-organ defects share a developmental link remains a key question with relevance to the diagnosis, therapeutic intervention and long-term care of affected patients. The heart, endothelial and blood lineages develop together from the lateral plate mesoderm (LPM), which also harbors the progenitor cells for limb connective tissue, kidneys, mesothelia and smooth muscle. This developmental plasticity of the LPM, which founds on multi-lineage progenitor cells and shared transcription factor expression across different descendant lineages, has the potential to explain the seemingly disparate syndromic defects in rare congenital diseases. Combining patient genome-sequencing data with model organism studies has already provided a wealth of insights into complex LPM-associated birth defects, such as heart-hand syndromes. Here, we summarize developmental and known disease-causing mechanisms in early LPM patterning, address how defects in these processes drive multi-organ comorbidities, and outline how several cardiovascular and hematopoietic birth defects with complex comorbidities may be LPM-associated diseases. We also discuss strategies to integrate patient sequencing, data-aggregating resources and model organism studies to mechanistically decode congenital defects, including potentially LPM-associated orphan diseases. Eventually, linking complex congenital phenotypes to a common LPM origin provides a framework to discover developmental mechanisms and to anticipate comorbidities in congenital diseases affecting the cardiovascular system and beyond.

Ondansetron Use During Pregnancy: Birth Defects and Obstetric Outcomes

Ondansetron is a widely administered medication for nausea and vomiting of pregnancy. Further examination of its teratogenic capacity is necessary. This study examines the association between ondansetron treatment during pregnancy and birth defects and adverse obstetric outcomes. Patient data were extracted from Clalit Health Services, Israel. A propensity-score analysis was performed matching those exposed to ondansetron with those who were not. Findings identified 774 women exposed to ondansetron, matched 1:1 with unexposed control patients. No significant differences were found between the groups for: cleft palate, cardiovascular congenital abnormalities, spina bifida occulta, preterm delivery, or small for gestational age. Ondansetron may be a useful and safe alternative as treatment for women who suffer from hyperemesis gravidarum and do not respond to other antiemetic drugs. Notwithstanding, additional prospectively designed research is needed to establish the safety of ondansetron treatment during pregnancy.

Plaque morphology and distribution in patients with and without myocardial bridge – an intravascular ultrasound study

Background Myocardial bridging (MB) is a common congenital cardiovascular anomaly. There are reported associations of MB with different clinical presentations like effort angina, acute coronary syndromes (ACS) and sudden cardiac death. Acceleration of atherosclerosis in proximal vessel is reported in patients with MB, while bridged segments are reported to be free of atherosclerosis Methods We assessed patients who underwent intravascular ultrasound (IVUS) guided percutaneous intervention (PCI) of left anterior descending (LAD) artery. Plaque characteristics derived from IVUS analysis were compared between those who displayed myocardial bridge versus those who did not harbour the anomaly. Results One hundred and forty-seven (147) patients underwent IVUS guided PCI. Incidence of MB was 44/147 (29.9%). Mean age of patients who had MB {+} was higher (62.1 ± 10.3 vs. 57.8 ± 11.2 (p = .03). 142/147 (96.6%) patients presented with ACS. ST elevation myocardial infarction (STEMI) was the most common presenting diagnosis (110/147 to 74.8%). There were no differences in qualitative plaque characteristics – attenuated plaque, calcification or calcium score between two groups. Plaque burden and length of the lesion in the proximal vessel were not different. Among patients with MB {+}, atheromatous extension to segments underlying the bridge was seen in 31/44 (70.5%) cases. Conclusions In a series of patients who presented with advanced clinical atherosclerosis, plaque characteristics were not different in patients who harboured myocardial bridge vs. those who did not have the anomaly. Atheromatous involvement was seen extending into bridged segment contrary to previous reports.

The new prospects for the development of children cardiologic rehabilitation at sanatoriums of Yevpatoria health resort

The article discusses the prospects of rehabilitation of children with congenital cardiovascular anomaly, including those after surgery. The author provides evidence that it is essential to create a system of physical, psychological, and social rehabilitation for this category of patients at all stages of medical care: in hospital, at the sanatorium, and during the follow-up, taking into account the basic principles of rehabilitation (an early start, a stage-by-stage approach, coherence, continuity, consistency, individualization of the rehabilitation plan, etc.). The sanatorium treatment at the famous climatic and balneological children’s health resorts of the Black Sea coast appears to be the most physiologically relevant stage contributing to the improvement of the regulatory processes of cardiac activity and providing optimal results of restorative treatment and rehabilitation for the young patients with congenital heart defects in the remote postoperative period. The creation of the All-Russian Rehabilitation Center for children with cardiovascular pathology, including children after heart surgery, in the Republic of the Crimea should be considered in the context of the further development and implementation of measures in accordance with the List of Instructions of the President of the Russian Federation following the meeting of the Coordinating Council under the President of the Russian Federation on the implementation of the National Strategy of Action in the Interests of Children for 2012–2017 of March 31, 2017.

The influence of prenatal screening on the contemporary operative outcomes and functional alleviation after vascular ring surgery in children

Objective: The impact of prenatal screening on contemporary operative outcomes and functional alleviation during pediatric Vascular Ring Surgery (VRS) is analysed in this research. Methods:All patients who had surgical treatment of an isolated VR at the Texas Children’s Hospitalbetween 1996 and 2018were included in the study. Patients who simultaneously underwent intracardiac repair were disqualified. Other congenital cardiac conditions, clinical symptomatology, contemporary surgical intervention, perioperative outcome, reoperation rates, functional alleviation, and complications were all examined in the data analysis.To examine the data for this investigation, we employed SPSS 13.0.Results: 148 participants were chosen for analysis. Of the 148, 72(48.6%)have a Double Aortic Arch (DAA), 69(47.2%) have a ligamentum and a normal left subclavian artery or Right Aortic Arch (RAA) with a left-sided ductus, 5 (2.7%)have an RAA, Left Descending Aorta (LDA) and 2(1.3%) had RAA, Left Ligamentum Arteriosum (LLA), mirror-image branching. Right aortic arch vascular ring(RAAVR) aregeneral than Double Aortic Arch Vascular Ring (DAAVR): 31 patients had the earlier, with a frequency of 5.7 per 10,000 live births, whereas 6 patients had the latter, with an incidence of 1.1 per 10,000 live births (p = 0.0001).Conclusion: VRs are a prevalent form of congenital cardiovascular abnormality, especially when they affect the right aortic arch. Additionally, prenatal screening reveals a significant percentage of VRs.

Unroofing of an anomalous right coronary artery originating from the left coronary sinus

Coronary abnormalities, including the anomalous aortic origin of a coronary artery, coronary fistula and myocardial bridge, are among the most common congenital cardiovascular anomalies. A left coronary artery arising from the right cusp is less common than the right coronary artery arising from the left cusp but is more often found in autopsy series of sudden cardiac deaths. A slit-like/fish-mouth-shaped orifice, acute angle take-off, intramural course, interarterial course and hypoplasia of the proximal coronary artery have all been proposed as reasons for symptoms, ischaemia and sudden cardiac death. Surgical intervention is recommended for those patients with signs or symptoms of myocardial ischaemia. Intervention in asymptomatic patients with an interarterial/intramural left coronary artery from the right sinus of Valsalva is recommended due to the higher calculated risk of sudden cardiac death. In asymptomatic patients with an intramural right coronary artery from the left sinus of Valsalva, provocative testing is recommended. The slit-like orifice is more commonly seen in an anomalous right coronary artery arising from the left sinus, and we believe it is the major factor responsible for myocardial ischaemia. Our unroofing technique focuses on: (i) transecting the endothelial tissue flap to create a neo-ostium; (ii) limiting the flap resection to the intramural portion to avoid extra-aortic incision; and (iii) marsupialization of a neo-ostium with interrupted sutures to reapproximate the endothelium and prevent aortic dissection.

Seroprevalence and risk factors for rubella infection in pregnant women attending a tertiary hospital in Kano-Nigeria.

rubella is a leading cause of vaccine preventable birth defects especially in developing countries. Acquisition of infection with the rubella virus in early pregnancy exposes the fetus to a very high chance of developing congenital rubella syndrome. The neonate is born with multiple abnormalities with the triad of congenital cataract, deafness and cardiovascular abnormalities like ventricular septal defect or patent ductus arteriosus. Limited data exist on the seroprevalence of rubella antibodies in pregnant women in Nigeria. The aim of this study was to determine the seroprevalence of rubella antibodies in pregnant women attending antenatal clinic in Aminu Kano Teaching Hospital, Kano State. the study was a cross-sectional study involving one hundred and sixty-three pregnant women attending antenatal clinic of Aminu Kano Teaching Hospital in Kano, Nigeria. Interviewer administered questionnaire was used to collect sociodemographic data and risk factors. Blood samples were taken from consenting pregnant women during antenatal care and samples were subjected to antibody testing (IgG and IgM). Descriptive analysis was done for sociodemographic data and seroprevalence of rubella. Chi-square tests were used to determine associations. one hundred and sixty-three pregnant women were recruited for the study. The participants´ age ranged from 18 to 41 years with mean age of 27.60±5.7 years. The overall rubella seroprevalence was found to be 68.7%. The seroprevalence of specific anti-Rubella virus IgM and IgG was found to be 58.4% and 37.3% respectively while prevalence of having both anti-Rubella virus IgG and IgM in the women was found to be 26.4%. Non-formal education and immunodeficiency was found to be associated with rubella infection (P-value of 0.018 and 0.001 respectively). the study found a high prevalence of anti-Rubella virus immunoglobulins in asymptomatic pregnant women attending antenatal care in our facility with immunodeficiency and non-formal education found to be significant risk factors.

Aortic Dissection and COVID-19 Pneumonia in a Pregnant Woman at 34 Weeks of Gestation

Between 0.1% and 0.3% of all aortic dissections occur during pregnancy. Arterial hypertension, connective tissue disorders, and congenital cardiovascular anomalies-including bicuspid aortic valves-are well-known risk factors. The causality between pregnancy and aortic dissection is unclear, but there have been some observations that COVID-19 illness may increase the risk. This report describes a pregnant woman at 34 weeks of gestation who had a bicuspid aortic valve and experienced an acute aortic dissection while ill with COVID-19 pneumonia. Computed tomography confirmed a type A aortic dissection and bilateral patchy pulmonary opacities. Cesarean delivery was performed, followed by replacement of the aortic valve with a mechanical aortic prosthesis and reconstruction of the ascending aorta and hemiarch. The intraoperative course was uneventful, and the patient was successfully weaned from mechanical ventilation after 51 hours. COVID-19 during pregnancy seems to increase the risk for aortic dissection, although there is no evidence base for an association. Because guidelines for diagnosis and treatment in such complex cases are lacking, care from a multidisciplinary team is crucial for successful outcomes.

Ground-glass opacity in a patient with right aortic arch and no left pulmonary artery

BackgroundHere we report a case of patients with mixed ground glass opacity in the left lung combined with congenital right aortic arch, which is only present in 0.01–0.1% of adults.Case presentationA 60-year-old woman was referred to our department with a mixed ground-glass opacity (GGO) in the upper lobe of her left lung. She had congenital right aortic arch, and the left pulmonary artery was absent. Enhanced chest computed tomography, pulmonary perfusion imaging, and three-dimensional reconstruction were performed to confirm the blood supply in the left lung and the exact location of the GGO. Because of the unusual left pulmonary vascular structure, wedge resection was performed to prevent massive hemorrhage. The final pathological examination revealed that the mixed GGO was a well-differentiated pulmonary adenocarcinoma.ConclusionThe surgical options should be evaluated carefully in view of the complications and the prognosis of the patient, when ground glass opacity is combined with congenital cardiovascular anomalies.

898 ROLE OF 3D ECHOCARDIOGRAPHY IN AORTIC VALVE ABNORMALITIES: TWO CASES REPORT

Abstract Introduction Aortic valves with a number of cusps different from two or three are infrequent congenital anomalies that might manifest with valvular disease in young patients. We present two cases of unicuspid and quadricuspid aortic valve diagnosed in our Center. Clinical Cases Case 1. A 23-year-old asymptomatic male was admitted to our Hospital because of the necessity of bone marrow transplantation for Hodgkin lymphoma. He had a previous diagnosis of bicuspid aortic valve and presented a 5/6 mid-systolic harsh murmur, heard best at the right upper sternal border and radiating to the neck. ECG showed sinus rhythm with left ventricular hypertrophy. BNP was in normal range (31 pg/ml). At trans-thoracic echocardiography, there was severe aortic stenosis [peak/mean gradient of 100/67 mmHg with an aortic valve area of 1.04 cm2 (0.54 cm2/m2); V max was 5 m/s] without regurgitation and dilation of the ascending aorta (39 mm), however the morphology of the aortic valve remained undefined. Left ventricle showed hypertrophy (maximum wall thickness = 13 mm) with normal volumes and systolic function. Thus, the patient underwent to 3D-Transesophageal echocardiography, which demonstrated unicuspid aortic valve with a lone commissure between L-NC and anterior calcification. After multidisciplinary discussion, the patient underwent close follow-up and aortic valve replacement was planned after the bone marrow transplantation. Case 2. A 21-year-old male was referred by general practitioner to our outpatient clinic for palpitations. Cardiovascular physical examination and ECG were normal with no evidence of arrhyhtmia or cardiac murmurs. Transthoracic echocardiography revealed central mild aortic valve regurgitation in a suspected quadricuspid aortic valve (i.e., an X-shaped commissure pattern during diastole and a rectangular appearance during systole in the parasternal short-axis view). Left ventricular size and function and ascending aorta dimensions were normal. There was no associated congenital cardiovascular abnormality. 3D-Transesophageal echocardiography confirmed the evidence of a quadricuspid aortic valve. The cusps appeared to be of different size: two equal larger cusps and two equal smaller cusps (Type C, Hurwitz and Robert's classification), thin and mobile. The patient was advised to echocardiographic follow-up at intervals of 12 months. Conclusions We describe two cases of aortic valve congenital anomalies in two coetaneous patients with completely different impacts on hemodynamics. Severe aortic stenosis complicated unicuspid aortic valve whereas quadricuspid aortic valve was associated with mild aortic regurgitation. 3D-Transesophageal echocardiography was essential for accurate morphological characterization of the aortic valves.

Predictors of Disease Progression and Survival in Patients with Myelodysplastic Syndrome Secondary to Inherited Bone Marrow Failure Syndromes

Introduction Inherited bone marrow failure syndromes (IBMFSs) are rare genetic disorders characterized by abnormal hematopoiesis resulting in cytopenias, risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Once patients develop MDS, the only cure is hematopoietic stem cell transplant (HSCT). Proceeding to HSCT before transformation to advanced MDS or AML leads to better outcomes (Smith et al., PBC 2013). The rate of disease progression from early MDS to advanced MDS or AML is variable and risk factors for progression in IBMFS patients are unknown. We hypothesized that certain variables could predict the likelihood of progression, and that the type of disease progression may impact overall survival (OS). Methods Data were collected from patients prospectively enrolled in the Canadian Inherited Marrow Failure Registry (CIMFR), a Canadian collaboration including >95% of pediatric IBMFS patients. Patients were diagnosed with a specific syndrome or unclassified IBMFS (ucIBMFS) based on published criteria. Diagnostic criteria for pediatric MDS defined by Cada et al. (Haematologica 2015) were used, patients with refractory cytopenia (RC) with or without dysplasia or ringed sideroblasts were included. Patients with refractory cytopenia with excess blasts (RCEB) were excluded. MDS progression was defined as 1 or more of: a new cytogenetic abnormality, more advanced cytopathology, worse cytopenias requiring HSCT. Variables evaluated included: involvement of specific organ systems, hematologic parameters within 3 months of cytogenetic clones/MDS diagnosis, type of mutation (as per Waespe et al., Genomic Medicine 2017). Univariate Cox Proportional Hazard modelling was used to estimate association with specific variables and disease progression, Kaplan-Meier analysis was used for survival evaluation. Results Between January 1, 2001 and November 30, 2018, 601 patients were enrolled in the CIMFR, and during this time 59 (9.8%) developed cytogenetic clones/MDS. Four did not meet the pre-defined criteria for IBMFS, 9 had RCEB at diagnosis with MDS and 1 did not have data available; these were excluded from our cohort of 45 patients. Twelve (26%) patients with clones/MDS had Fanconi Anemia (FA), 13 (28.3%) had Shwachman-Diamond Syndrome (SDS), 5 (10.8%) had ucIBMFS, 15 (33.3%) had other IBMFSs. The most common cytogenetic finding at diagnosis was -7/-7q (n=10, 22%). Patients who developed clones/MDS had significantly worse OS compared to those without clones/MDS (HR 3, 95% CI 2-6, p<0.0001). Among patients who developed clones/MDS, 22 (48.9%) underwent HSCT. Twenty one clones/MDS patients (46.7%) had disease progression, with a median time to progression of 7.9 months (1.2-131.4). The majority (68.4%) developed progression within one year of clones/MDS diagnosis. Nine (42.8%) developed more advanced cytopathology, 9 (42.8%) a new cytogenetic abnormality and 5 (23.8%) worsening cytopenias. Most patients with FA (67%) had disease progression, compared to 38.5% of patients with SDS. Mutation types (classified as more vs less deleterious) were similar between the groups with and without progression. The evaluated hematologic parameters (MCV, hemoglobin, platelets and neutrophils within 3 months of diagnosis) were not predictive of disease progression. Patients with disease progression, when compared to those without, were more likely to have congenital malformations of the skin (14.3% vs 0%), cardiovascular system (28.6% vs 4.2%) and kidneys (14.3% vs 4.2%). No specific system involvement predicted disease progression, although congenital malformations of the cardiovascular system had a HR of 2.63 (95% CI 0.93-7.42). Conclusion Development of MDS has a significant adverse impact on the OS of IBMFS patients, with disease progression typically occurring within the first year after MDS diagnosis. Patients with FA have a high risk of disease progression. Hematologic parameters were not predictive of the risk of disease progression, however, the presence of congenital cardiovascular anomalies is suggestive of increased risk of disease progression and warrants further investigation. Our study is limited by the rare nature of IBMFSs and MDS and the collection of additional data will help to guide treatment decisions for this high-risk patient population. Acknowledgment The authors thank Mr. Bryan Maguire for his statistical analysis of data related to this work.

Haploinsufficiencies of FOXF1, FOXC2 and FOXL1 genes originated from deleted 16q24.1q24.2 fragment related with alveolar capillary dysplasia with misalignment of pulmonary veins and lymphedema-distichiasis syndrome: relationship to phenotype

ObjectiveWe describe a fetus with a 2.12-Mb terminal deleted fragment in 16q associated with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) and lymphedema-distichiasis syndrome (LDS) and intend to provide a comprehensive prenatal management strategy for the fetuses with ACDMPV and LDS through reviewing other similar published studies.MethodsThe fetus presented a series of diverse structural malformations including congenital cardiovascular, genitourinary and gastro-intestinal anomalies in ultrasound at 23 + 5 weeks of gestation (GA). Amniocentesis was conducted for karyotype analysis and copy number variation sequencing (CNV-seq) after informed consent.ResultsThe fetal karyotype was 46,XX, however the result of CNV-seq showed an approximately 2.12-Mb deletion in 16q24.1q24.2 (85220000-87340000) × 1 indicating pathogenicity.ConclusionGenomic testing should be recommend as a first line diagnostic tool for suspected ACDMPV and/or LDS or other genetic syndromes for the fetuses with structural abnormalities in clinical practice.

RF26 | PMON326 Medical History of Children Enrolled in PROPEL: A Prospective Clinical Assessment Study in Children with Achondroplasia

Abstract Background Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia, affecting between 1 in 15,000 to 1 in 30,000 live births. People with ACH are at risk for several significant co-morbidities, including foramen magnum stenosis, obstructive sleep apnea, chronic otitis media with conductive hearing loss, spinal stenosis, and a propensity towards obesity. PROPEL is a prospective, non-interventional study designed to examine baseline growth parameters and health status in children being assessed for potential enrollment into interventional studies with infigratinib, an oral FGFR1–3 inhibitor in development as a therapeutic option for ACH. Here we describe the medical complications reported as medical history in the PROPEL study. Methods Children with ACH between the ages of 2.5 and 10 years are eligible for enrollment in PROPEL and are evaluated at screening/baseline, month 3, month 6, and every 6 months thereafter. Medical history collected at screening/baseline is summarized using system organ class and preferred terms. Results A total of 86 children with ACH (60% female, mean±SD age 6.1±2.5 years) have been enrolled to date at 19 sites in Europe, Australia and North America. Fifty-eight children had undergone surgical and medical procedures with a mean of 2.9 procedures per child (1–11 surgeries/subject). The most common procedures were pressure-equalizing ear tube insertion, adenoidectomy and tonsillectomy. Twenty-one (24%) children had undergone at least 1 surgery (1–5 surgeries/child) for spine or cranial decompression. History of infections and respiratory disorders were reported in 46 (53%) and 40 (47%) children, respectively, the most common being ear infections and obstructive sleep apnea. Musculoskeletal disorders were described in 33 (38%) children, with kyphosis being the most common. Hydrocephalus was reported in 2 children, while 4 had ventriculomegaly without intracranial hypertension. Congenital cardiovascular abnormalities were found in 4 children, 2 of whom presented with patent ductus arteriosus and 2 had patent foramen ovale. A comprehensive summary of medical histories will be presented at the conference. Conclusions The PROPEL study has a planned total enrollment of 200 children and seeks to contribute to the deeper understanding of the natural history of ACH. Data described here highlight the significant complications and high number of interventions that children with ACH undergo throughout infancy and childhood. This stresses the importance of expert management of this complex condition. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:05 p.m. - 1:10 p.m.

Myhre syndrome is caused by dominant-negative dysregulation of SMAD4 and other co-factors

Myhre syndrome is a connective tissue disorder characterized by congenital cardiovascular, craniofacial, respiratory, skeletal, and cutaneous anomalies as well as intellectual disability and progressive fibrosis. It is caused by germline variants in the transcriptional co-regulator SMAD4 that localize at two positions within the SMAD4 protein, I500 and R496, with I500 V/T/M variants more commonly identified in individuals with Myhre syndrome. Here we assess the functional impact of SMAD4-I500V variant, identified in two previously unpublished individuals with Myhre syndrome, and provide novel insights into the molecular mechanism of SMAD4-I500V dysfunction. We show that SMAD4-I500V can dimerize, but its transcriptional activity is severely compromised. Our data show that SMAD4-I500V acts dominant-negatively on SMAD4 and on receptor-regulated SMADs, affecting transcription of target genes. Furthermore, SMAD4-I500V impacts the transcription and function of crucial developmental transcription regulator, NKX2-5. Overall, our data reveal a dominant-negative model of disease for SMAD4-I500V where the function of SMAD4 encoded on the remaining allele, and of co-factors, are perturbed by the continued heterodimerization of the variant, leading to dysregulation of TGF and BMP signaling. Our findings not only provide novel insights into the mechanism of Myhre syndrome pathogenesis but also extend the current knowledge of how pathogenic variants in SMAD proteins cause disease.

Detection of Coronary Artery and Aortic Arch Anomalies in Patients with Tetralogy of Fallot Using CT Angiography.

Background: Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease (CHD). Furthermore, the prevalence of anomalous origin of a coronary artery is higher in patients with TOF than in the general population (6% vs. ≤1%). Preoperative assessment of cardiovascular anatomy using computed tomography (CT) angiography enables the adaptation of the surgical approach to avoid potentially overlooked anomalies. Our purpose was to determine the prevalence of coronary artery and aortic arch anomalies in a cohort of TOF patients. Methods: In this retrospective analysis, data were collected from CT reports (2015–2021) of 105 TOF patients. All images were acquired using a 64-slice multi-detector CT (MDCT) scanner. Results: The median age of the patients was 38.7 months, with a male-to-female ratio of 1.39. The overall prevalence of coronary artery anomalies (CAAs) was 7.61% (8 of 105 cases). The anomalous origin and course of coronary arteries across the right ventricular outflow tract (RVOT; prepulmonic course) were defined in 5.71% of cases (six patients). In four of these, the left anterior descending artery (LAD) originated from the right coronary artery (RCA), while in two cases, the RCA arose from the LAD. In the remaining two patients, the coronary arteries followed an interarterial course. The most frequent anomalous aortic arch pattern in the overall TOF population was the right aortic arch (RAA) with mirror image branching, seen in 20% of patients (21 cases). The most frequent anomaly of the supra-aortic trunks was bovine configuration, found in 17.14% (18 cases). Conclusions: The prevalence of CAAs and aortic arch anomalies detected by CT angiography was in line with the data reported in anatomical specimens. Therefore, this technique represents a powerful tool for the evaluation of congenital cardiovascular anomalies.

European epidemiological patterns of cannabis- and substance-related congenital cardiovascular anomalies: geospatiotemporal and causal inferential study

As prenatal and community cannabis exposures have recently been linked with congenital heart disease (CHD), it was of interest to explore these associations in Europe in a causal framework and space-time context. Congenital anomaly data from Eurocat, drug-use data from the European Monitoring Centre for Drugs and Drug Addiction, and income from the World Bank. Countries with rising daily cannabis use had in general higher congenital anomaly rates over time than those without (time: status interaction: β-Est. = 0.0267, P = 0.0059). At inverse probability-weighted panel regression, cannabis terms were positive and significant for CHD, severe CHD, atrial septal defect, ventricular septal defect, atrioventricular septal defect, patent ductus arteriosus, tetralogy of Fallot, vascular disruptions, double outlet right ventricle, transposition of the great vessels, hypoplastic right heart, and mitral valve anomalies from 1.75 × 10−19, 4.20 × 10−11, <2.2 × 10−16, <2.2 × 10−16, 1.58 × 10−12, 4.30 × 10−9, 4.36 × 10−16, 3.50 × 10−8, 5.35 × 10−12, <2.2 × 10−16, 5.65 × 10−5 and 6.06 × 10−10. At spatial regression, terms including cannabis were positive and significant for this same list of anomalies from 0.0038, 1.05 × 10−10, 0.0215, 8.94 × 10−6, 1.23 × 10−5, 2.05 × 10−5, 1.07 × 10−6, 8.77 × 10−5, 9.11 × 10−6, 0.0001, 3.10 × 10−7 and 2.17 × 10−7. 92.6% and 75.2% of 149 E-value estimates and minimum E-values were in high zone >9; 100.0% and 98.7% >1.25. Data show many congenital cardiac anomalies exhibit strong bivariate relationships with metrics of cannabis exposure. Causal inferential modelling for the twelve anomalies selected demonstrated convincing evidence of robust relationships to cannabis which survived adjustment and fulfilled epidemiological criteria for causal relationships. Space-time regression was similarly confirmatory. Epigenomic pathways constitute viable potential mechanisms. Given exponential genotoxic dose-response effects, careful and astute control of cannabinoid penetration is indicated.