Conotruncal Malformations Research Articles

Imaginea de 3 vase şi trahee – marker important în anomaliile de vase mari

Congenital heart malformations are the most common cause of fetal and infant mortality, with an incidence of 4-13 per 1000 live births. Antenatal ultrasound evaluation of the fetal heart has developed over the past 30 years, and has allowed the detection of many abnormalities in the first trimester of pregnancy. Prenatal screening for fetal mal­for­ma­tions is mandatory, allowing a better preg­nan­cy coun­­se­ling and greatly improving the neonatal prog­no­sis. According to the Romanian Society of Obstetrics and Gynecology (SOGR), the evaluation of the fetal heart start­ing from the first trimester of pregnancy is mandatory. Due to technological advances, the fetal heart can be as­ses­sed in detail as early as the first trimester, which al­lows for adequate counseling of the couple facing a mal­for­ma­tive heart pathology in their fetus, allows the ter­mi­na­tion of pregnancy at a legally optimal gestational age, or, when the ultrasound assessment does not reveal any fetal malformation, it assures the couple about the normal course of the pregnancy. The evaluation of the fetal heart using standard plans of examination is per­formed in each tri­mes­ter of pregnancy. We present a series of cardiac mal­for­ma­tions detected antenatally in our clinic, using stan­dard assessment views. The purpose of this study is to em­pha­size that most lesions involving the ejection tracts of the ar­te­ries at the base of the heart are associated with varying de­grees of disruption of the alignment, arrangement, size, or number of the three vessels, thus with an abnormal ap­­pea­rance of the stan­dard cross-section of three vessels. In all cases, the three-vessel view of the heart revealed an abnormal ap­pea­rance, helping us to diagnose major car­diac mal­for­ma­tions. This plan can be easily obtained in all tri­­mes­ters of pregnancy, providing sufficient information to de­tect many major conotruncal malformations.

Results of karyotype analysis and 22q11.2 (DiGeorge Syndrome critical region) deletion investigation in fetal cardiac system anomalies

The results of karyotype analysis and 22q11.2 ( DiGeorge Syndrome critical region) deletion investigation in fetal cardiac system anomalies 
 Objective: We aimed to determine the presence of accompanying chromosomal anomalies and 22q11.2 deletion in patients with cardiac system anomalies.
 Material and Methods: In our retrospective and cross-sectional study, 99 fetuses born with cardiac anomalies were evaluated in terms of chromosomal anomalies. 36 fetuses were evaluated for 22q11.2 deletion. Fetuses who were diagnosed with prenatal congenital heart defect and underwent invasive prenatal diagnostic tests for fetal karyotyping between 01.01.2010 and 30.06.2017 at a tertiary cancer center were included in the study.
 Results: Of 99 cases, 48 (48.4%) had only cardiac anomalies and 51 (51.5%) had non-cardiac anomalies. Chromosomal anomalies were found in 37 (37.4%) of the cases. Autosomal trisomy 18(43.2%) and autosomal trisomy 21(32.4%) were the most common chromosomal anomalies. The study results support the strong association of chromosomal changes and cardiac malformation, especially in septal defects, atrioventricular septal defects, and conotruncal malformations. Deletion was detected in one(2.8%) of 36 cases evaluated for 22q11.2 deletion. The fetus with this deletion had isolated tetralogy of fallot and had no extracardiac anomaly.
 Conclusion: In cases with cardiac anomalies, isolated or accompanied by extracardiac anomalies, investigations should be made in terms of underlying chromosomal diseases in the perinatal evaluation. In addition, the investigation of 22q11.2 deletion in fetuses with conotruncal cardiac anomalies should be included in prenatal genetic examination.
 Keywords: DiGeorge Syndrome, Fetal Anomalies, karyotype, trisomy, 22q11.2 Deletion Syndrome

Prenatally detected aortic arch anomalies and their consequences after birth

Aortic arch anomalies are frequently associated with cardiac or extracardiac malformations, chromosomal aberrations and postpartum esophagus/trachea compression. We aimed to establish the prevalence of associated cardiac and extracardiac malformations, the frequency of chromosomal aberrations in fetuses with the diagnosis of aortic arch anomalies and to assess the pregnancy and the postnatal outcome. Retrospective cohort study of all fetuses with aortic arch anomalies and genetic diagnosis in a tertiary referral obstetric and fetal cardiology centre between 2016 and 2020. Postpartum data were collected within 24 months after birth. In a cohort of 11.380 pregnant women, the prevalence of aortic arch anomalies was 0.25%. Among 28 cases of right aortic arch anomalies, in 27 fetuses prenatal genetic diagnosis was available. We diagnosed 4 fetuses with mirror-image branching (right sided V-sign) and 23 fetuses with U-sign (4 fetuses with complete double aortic arch). 18 cases (66%) were isolated. Associated anomalies were cardiac in 3 cases and extracardiac in 7 cases (33%). The most frequent cardiac anomaly was tetralogy of Fallot (2/27), the extracardiac anomalies were thymus hypoplasia, single umbilical artery and subclavian artery malformations. In 1 case (3.7%), fluorescent in situ hybridization diagnosed 22q11.2 microdeletion. 75% of fetuses with right sided V-sign were associated with conotruncal malformations. Pregnancy and postpartum outcome were known in 24 pregnancies. Postnatal diagnosis was different from prenatal in 2 cases, the concordance rate was 93%. Isolated cases resulted in live birth in 17/18 pregnancies (93%). The frequency of postpartum trachea/esophagus compression was 42,9% (9 cases) due to vascular ring, in 6 children (28,6%) operation was necessary. Fetal aortic arch anomalies are multidisciplinary diseases to be diagnosed by proper prenatal ultrasound examination. Associated fetal anomalies necessitate extended obstetric and cardiac sonography, invasive prenatal testing should be offered, and thorough postnatal long-term follow-up is recommended. Orv Hetil. 2023; 164(28): 1111-1120.

Transpositions of the great arteries versus aortic dextropositions. A review of some embryogenetic and morphological aspects.

This review examines and discusses the morphology and embryology of two main groups of conotruncal cardiac malformations: (a) transposition of the great arteries (complete transposition and incomplete/partial transposition namely double outlet right ventricle), and (b) aortic dextroposition defects (tetralogy of Fallot and Eisenmenger malformation). In both groups, persistent truncus arteriosus was included because maldevelopment of the neural crest cell supply to the outflow tract, contributing to the production of the persistent truncus arteriosus, is shared by both groups of malformations. The potentially important role of the proximal conal cushions in the rotatory sequence of the conotruncus is emphasized. Most importantly, this study emphasizes the differentiation between the double-outlet right ventricle, which is a partial or incomplete transposition of the great arteries, and the Eisenmenger malformation, which is an aortic dextroposition. Special emphasis is also given to the leftward shift of the conoventricular junction, which covers an important morphogenetic role in both aortic dextropositions and transposition defects as well as in normal development, and whose molecular genetic regulation seems to remain unclear at present. Emphasis is placed on the distinct and overlapping roles of Tbx1 and Pitx2 transcription factors in modulating the development of the cardiac outflow tract.

Aortic Arch Laterality in Chromosome 22q11.2 Deletion Syndrome: Male-Female Difference.

We reviewed patients with chromosome 22q11.2 deletion syndrome. We analyzed cardiovascular findings in patients with confirmed chromosome 22q11.2 deletion syndrome live-born in Nevada between March 2007 and September 2020. We identified 60 patients. Of the 60 patients, 32 (53%) were female. Of the 60, 48 (80%) had a conotruncal abnormality (including isolated vascular rings): 23 of 32 (72%) for females versus 25 of 28 (89%) for males, P = .41. However, 11 (34%) of 32 females had a right aortic arch; whereas, 21 (75%) of 28 males had a right aortic arch, P = .007. In conclusion, in our patient cohort, we found conotruncal malformations were common. However, we noted males were statistically more likely to have a right aortic arch than females. To the best of our knowledge, this male-female aortic arch laterality difference in patients with chromosome 22q11.2 deletion syndrome has not been previously noted.

Screening Method for 22q11 Deletion Syndrome Involving the Use of TaqMan qPCR for TBX1 in Patients with Conotruncal Congenital Heart Disease

22q11.2 deletion syndrome is a phenotypic spectrum that encompasses DiGeorge syndrome (OMIM: 188400) and velocardiofacial syndrome (OMIM: 192430). It is caused by a 1.5–3.0 Mb hemizygous deletion of locus 22q11.2, which leads to characteristic facies, conotruncal cardiovascular malformations, velopharyngeal insufficiency, T-lymphocyte dysfunction due to thymic aplasia, and parathyroid hypoplasia, and, less frequently, neurological manifestations such as delayed psychomotor development or schizophrenia. This study aimed to describe a screening method for the diagnosis of 22q11.2 deletion syndrome in patients with Conotruncal Congenital Heart Disease (CCHD), using qPCR to detect the copy number of the TBX1 gene in a single DNA sample. A total of 23 patients were included; 21 with a biallelic prediction of the TBX1 copy number gene and 2 with a monoallelic prediction who were suspected to be positive and subjected to MLPA confirmation. One patient (4.34%) with truncus arteriosus CCHD was confirmed to have 22q11.2 deletion syndrome. We propose this approach as a possible newborn screening method for 22q11.2 deletion syndrome in CCHD patients.

Chromosomal Microarray Analysis in Fetuses Detected with Isolated Cardiovascular Malformation: A Multicenter Study, Systematic Review of the Literature and Meta-Analysis.

Cardiovascular malformations (CVM) represent the most common structural anomalies, occurring in 0.7% of live births. The CVM prenatal suspicion should prompt an accurate investigation with fetal echocardiography and the assessment through genetic counseling and testing. In particular, chromosomal microarray analysis (CMA) allows the identification of copy number variations. We performed a systematic review and meta-analysis of the literature, studying the incremental diagnostic yield of CMA in fetal isolated CVM, scoring yields for each category of heart disease, with the aim of guiding genetic counseling and prenatal management. At the same time, we report 59 fetuses with isolated CVM with normal karyotype who underwent CMA. The incremental CMA diagnostic yield in fetuses with isolated CVM was 5.79% (CI 5.54–6.04), with conotruncal malformations showing the higher detection rate (15.93%). The yields for ventricular septal defects and aberrant right subclavian artery were the lowest (2.64% and 0.66%). Other CVM ranged from 4.42% to 6.67%. In the retrospective cohort, the diagnostic yield was consistent with literature data, with an overall CMA diagnostic yield of 3.38%. CMA in the prenatal setting was confirmed as a valuable tool for investigating the causes of fetal cardiovascular malformations.

Psychopathology in adults with copy number variants.

Copy number variants (CNVs) have been associated with the risk of schizophrenia, autism and intellectual disability. However, little is known about their spectrum of psychopathology in adulthood. We investigated the psychiatric phenotypes of adult CNV carriers and compared probands, who were ascertained through clinical genetics services, with carriers who were not. One hundred twenty-four adult participants (age 18-76), each bearing one of 15 rare CNVs, were recruited through a variety of sources including clinical genetics services, charities for carriers of genetic variants, and online advertising. A battery of psychiatric assessments was used to determine psychopathology. The frequencies of psychopathology were consistently higher for the CNV group compared to general population rates. We found particularly high rates of neurodevelopmental disorders (NDDs) (48%), mood disorders (42%), anxiety disorders (47%) and personality disorders (73%) as well as high rates of psychiatric multimorbidity (median number of diagnoses: 2 in non-probands, 3 in probands). NDDs [odds ratio (OR) = 4.67, 95% confidence interval (CI) 1.32-16.51; p = 0.017) and psychotic disorders (OR = 6.8, 95% CI 1.3-36.3; p = 0.025) occurred significantly more frequently in probands (N = 45; NDD: 39[87%]; psychosis: 8[18%]) than non-probands (N = 79; NDD: 20 [25%]; psychosis: 3[4%]). Participants also had somatic diagnoses pertaining to all organ systems, particularly conotruncal cardiac malformations (in individuals with 22q11.2 deletion syndrome specifically), musculoskeletal, immunological, and endocrine diseases. Adult CNV carriers had a markedly increased rate of anxiety and personality disorders not previously reported and high rates of psychiatric multimorbidity. Our findings support in-depth psychiatric and medical assessments of carriers of CNVs and the establishment of multidisciplinary clinical services.

Structural heart defects associated with ETB mutation, a cause of Hirschsprung disease

BackgroundHSCR, a colonic neurocristopathy affecting 1/5000 births, is suggested to associate with cardiac septal defects and conotruncal malformations. However, we question subtle cardiac changes maybe more commonly present due to multi-regulations by HSCR candidate genes, in this instance, ETB. To investigate, we compared the cardiac morphology and quantitative measurements of sl/sl rat to those of the control group.MethodsEleven neonatal rats were generated from heterozygote (ETB+/−) crossbreeding. Age and bodyweight were recorded at time of sacrifice. Diffusion-staining protocols with 1.5% iodine solution was completed prior to micro-CT scanning. All rats were scanned using an in vivo micro-CT scanner, Caliper Quantum FX, followed by two quality-control scans using a custom-built ex vivo micro-CT system. All scans were reviewed for gross cardiac dysmorphology. Micro-CT data were segmented semi-automatically post-NLM filtering for: whole-heart, LV, RV, LA, RA, and aortic arch. Measurements were taken with Drishti. Following image analysis, PCR genotyping of rats was performed: five sl/sl rats, three wildtype, and three heterozygotes. Statistical comparisons on organ volume, growth rate, and organ volume/bodyweight ratios were made between sl/sl and the control group.ResultsCardiac morphology and constituents were preserved. However, significant volumetric reductions were recorded in sl/sl rats with respect to the control: whole heart (38.70%, p value = 0.02); LV (41.22%, p value = 0.01), RV (46.15%, p value = 0.02), LA (44.93%, p value = 0.06), and RA (39.49%, p value = 0.02). Consistent trend was observed in growth rate (~ 20%) and organ-volume/bodyweight ratios (~ 25%). On the contrary, measurements on aortic arch demonstrated no significant difference among the two groups.ConclusionDespite the presence of normal morphology, significant cardiac growth retardation was detected in sl/sl rat, supporting the likely association of cardiac anomalies with HSCR, at least in ETB−/− subtype. Structural reduction was likely due to a combination of failure to thrive from enteric dysfunction, alterations to CaNCC colonization, and importantly coronary hypoperfusion from elevated ET-1/ETA-mediated hypervasoconstriction. Little correlation was detected between aortic arch development and sl/sl rat, supporting minor ETB role in large vessels. Although further clinical study is warranted, HSCR patients may likely require cardiac assessment in view of potential congenital cardiac defects.

Long Noncoding RNA lnc-TSSK2-8 Activates Canonical Wnt/β-Catenin Signaling Through Small Heat Shock Proteins HSPA6 and CRYAB.

Congenital heart defects (CHDs) are the most common birth defects worldwide. 22q11.2 deletion syndrome is the most common microdeletion disorder that has been frequently associated with conotruncal malformations. By now, the dosage-sensitive gene TBX1 has been adopted as the major pathogenic gene responsible for 22q11.2 deletion, which is regulated by canonical Wnt/β-catenin signaling pathway in heart outflow tract development. Here, we report the long noncoding RNA (lncRNA) lnc-TSSK2-8, which is encompassed in the 22q11.2 region, that can activate canonical Wnt/β-catenin signaling by protecting β-catenin from degradation, which could result from decreased ubiquitination. Such effects were mediated by two short heat shock proteins HSPA6 and α-β-crystallin (CRYAB), whose expression was regulated by lnc-TSSK2-8 through a competing endogenous RNA (ceRNA) mechanism. In clinical practice, the pathogenesis of copy number variation (CNV) was always attributed to haploinsufficiency of protein-coding genes. Here, we report that the 22q11.2 lncRNA lnc-TSSK2-8 significantly activated canonical Wnt/β-catenin signaling, which has major roles in cardiac outflow tract development and should act upstream of TBX1. Our results suggested that lncRNAs should contribute to the etiology of CNV-related CHD.

LRP2 controls sonic hedgehog-dependent differentiation of cardiac progenitor cells during outflow tract formation.

Conotruncal malformations are a major cause of congenital heart defects in newborn infants. Recently, genetic screens in humans and in mouse models have identified mutations in LRP2, a multi-ligand receptor, as a novel cause of a common arterial trunk, a severe form of outflow tract (OFT) defect. Yet, the underlying mechanism why the morphogen receptor LRP2 is essential for OFT development remained unexplained. Studying LRP2-deficient mouse models, we now show that LRP2 is expressed in the cardiac progenitor niche of the anterior second heart field (SHF) that contributes to the elongation of the OFT during separation into aorta and pulmonary trunk. Loss of LRP2 in mutant mice results in the depletion of a pool of sonic hedgehog-dependent progenitor cells in the anterior SHF due to premature differentiation into cardiomyocytes as they migrate into the OFT myocardium. Depletion of this cardiac progenitor cell pool results in aberrant shortening of the OFT, the likely cause of CAT formation in affected mice. Our findings identified the molecular mechanism whereby LRP2 controls the maintenance of progenitor cell fate in the anterior SHF essential for OFT separation, and why receptor dysfunction is a novel cause of conotruncal malformation.

Oral fluconazole use in the first trimester and risk of congenital malformations: population based cohort study.

ObjectiveTo examine the risk of congenital malformations associated with exposure to oral fluconazole at commonly used doses in the first trimester of pregnancy for the treatment of vulvovaginal candidiasis.DesignPopulation based cohort study.SettingA cohort of pregnancies publicly insured in the United States, with data from the nationwide Medicaid Analytic eXtract 2000-14.ParticipantsPregnancies of women enrolled in Medicaid from three or more months before the last menstrual period to one month after delivery, and infants enrolled for three or more months after birth.InterventionsUse of fluconazole and topical azoles was established by requiring one or more prescriptions during the first trimester of pregnancy.Main outcome measuresRisk of musculoskeletal malformations, conotruncal malformations, and oral clefts (primary outcomes), associated with exposure to oral fluconazole, diagnosed during the first 90 days after delivery, were examined.ResultsThe study cohort of 1 969 954 pregnancies included 37 650 (1.9%) pregnancies exposed to oral fluconazole and 82 090 (4.2%) pregnancies exposed to topical azoles during the first trimester. The risk of musculoskeletal malformations was 52.1 (95% confidence interval 44.8 to 59.3) per 10 000 pregnancies exposed to fluconazole versus 37.3 (33.1 to 41.4) per 10 000 pregnancies exposed to topical azoles. The risks of conotruncal malformations were 9.6 (6.4 to 12.7) versus 8.3 (6.3 to 10.3) per 10 000 pregnancies exposed to fluconazole and topical azoles, respectively; risks of oral clefts were 9.3 (6.2 to 12.4) versus 10.6 (8.4 to 12.8) per 10 000 pregnancies, respectively. The adjusted relative risk after fine stratification of the propensity score was 1.30 (1.09 to 1.56) for musculoskeletal malformations, 1.04 (0.70 to 1.55) for conotruncal malformations, and 0.91 (0.61 to 1.35) for oral clefts overall. Based on cumulative doses of fluconazole, the adjusted relative risks for musculoskeletal malformations, conotruncal malformations, and oral clefts overall were 1.29 (1.05 to 1.58), 1.12 (0.71 to 1.77), and 0.88 (0.55 to 1.40) for 150 mg of fluconazole; 1.24 (0.93 to 1.66), 0.61 (0.26 to 1.39), and 1.08 (0.58 to 2.04) for more than 150 mg up to 450 mg of fluconazole; and 1.98 (1.23 to 3.17), 2.30 (0.93 to 5.65), and 0.94 (0.23 to 3.82) for more than 450 mg of fluconazole, respectively.ConclusionsOral fluconazole use in the first trimester was not associated with oral clefts or conotruncal malformations, but an association with musculoskeletal malformations was found, corresponding to a small adjusted risk difference of about 12 incidents per 10 000 exposed pregnancies overall.

The 3-vessel view as a means of screening for conotruncal malformations

Prenatal detection of fetal anomalies allows the adequate counseling of the parents regarding the pregnancy and the neonatal prognosis. This is especially true in the case of congenital heart defects where counseling the parents is essential, given the high neonatal mortality of such anomalies. Conotruncal malformations are made up of a wide variety of congenital heart defects with abnormal ventriculoarterial connections and represent up to 30% of all cases of congenital heart defects. The most common types of conotruncal malformations are tetralogy of Fallot, transposition of great arteries, double outlet right ventricle, common arterial trunk, but numerous anatomical variants exist. The 3-vessel view can be used as an alternative to the ventricular outflow tract views to detect conotruncal malformations and may be used as a screening test. To test this hypothesis, we evaluated the 3-vessel view in both normal cases and cases of conotruncal malformations. As expected, in the 30 normal cases we reviewed, all the criteria for a normal 3-vessel view were met. In the 15 cases of conotruncal malformations (tetralogy of Fallot, transposition of great arteries, double outlet right ventricle, common arterial trunk) that we investigated, at least one criterion for a normal 3-vessel view was not met. This goes to show the utility the 3-vessel view can have in the screening for conotruncal malformations

EFFECTS OF FEMALE BLOOD AUTOSERUM ON ALLOGENIC INTERACTIONS IN SHORT-TERM LYMPHOCYTE CULTURES OF PARENTS HAVING CHILDREN WITH CONOTRUNCAL HEART MALFORMATIONS

Highlights The findings of this original study ensure the detection of violations in the humoral regulation of the maternal immune interactions with semiallogeneic fetus, considered as a risk factor for developing sporadic conotruncal heart malformations in the next generation.Aim To study the role of female autoserum blood in limiting allogeneic interactions in short-term lymphocyte cultures of parents having children with conotruncal heart malformations.Methods 21 married couples (the study group) with children suffering from conotrucnal heart malformations (Tetralogy of Fallot) without chromosomal diseases were examined. The control group consisted of 21 families with three or more healthy children. The immune response in a mixed lymphocyte culture of parents was assessed by the increase in HLA-DR expression in the mixed culture with respect to spontaneous lymphocyte cultures. Primary staining of female and male lymphocytes with monoclonal antibodies to CD45, conjugated with various fluorescent dyes (PC-5 and PC-7), allowed assessing the immune response of female lymphocytes to male and vice versa.Results The effects of female autoserum on the mixed lymphocyte culture of parents were assessed. The obtained results reported that the birth of children with conotruncal heart malformations is associated with the interfering effect of female autoserum on HLA-DR expression on subpopulations of female lymphocytes (CD3+, HLA-DR+) and the activating effect on subpopulations of female lymphocytes (CD3-, HLA-DR+). The observed role of female autoserum in the study group may be associated with the absence of HLA-DR-blocking autoantibodies and high synthesis of cytokines by T2 and T3 helper lymphocytes.Conclusion The effects of female autoserum on allogeneic lymphocyte interactions of parents may be observed in short-term mixed lymphocyte cultures. The evaluation of the activating and interfering effects ensures timely identification of any violations in the humoral regulation of the maternal immune interactions with the HLA semiallogenic fetus, considered as a risk factor for developing sporadic conotruncal heart malformations in the next generation.

Exploring Shared Susceptibility between Two Neural Crest Cells Originating Conditions: Neuroblastoma and Congenital Heart Disease.

In the past years, genome wide association studies (GWAS) have provided evidence that inter-individual susceptibility to diverse pathological conditions can reveal a common genetic architecture. Through the analysis of congenital heart disease (CHD) and neuroblastoma (NB) GWAS data, we aimed to dissect the genetic susceptibility shared between these conditions, which are known to arise from neural crest cell (NCC) migration or development abnormalities, via identification and functional characterization of common regions of association. Two loci (2q35 and 3q25.32) harbor single nucleotide polymorphisms (SNPs) that are associated at a p-value < 10−3 with conotruncal malformations and ventricular septal defect respectively, as well as with NB. In addition, the lead SNP in 4p16.2 for atrial septal defect and the lead SNP in 3q25.32 for tetralogy of Fallot are less than 250 Kb distant from the lead SNPs for NB at the same genomic regions. Some of these shared susceptibility loci regulate the expression of relevant genes involved in NCC formation and developmental processes (such as BARD1, MSX1, and SHOX2) and are enriched in several epigenetic markers from NB and fetal heart cell lines. Although the clinical correlation between NB and CHD is unclear, our exploration of a possible common genetic basis between NB and a subset of cardiac malformations can help shed light on their shared embryological origin and pathogenetic mechanisms.

Fetal MRI and prenatal diagnosis of congenital heart defects

Fetal MRI and prenatal diagnosis of congenital heart defects

Edwards SAPIEN Transcatheter Pulmonary Valve Implantation: Results From a French Registry

ObjectivesThe aim of this study was to describe and analyze data from patients treated in France with the Edwards SAPIEN transcatheter heart valve (Edwards Lifesciences LLC, Irvine, California) in the pulmonary position. BackgroundThe Edwards SAPIEN valve has recently been introduced for percutaneous pulmonary valve implantation (PPVI). MethodsFrom April 2011 to May 2017, 71 patients undergoing PPVI were consecutively included. ResultsThe median age at PPVI was 26.8 years (range 12.8 to 70.1 years). Primary underlying diagnoses were conotruncal malformations (common arterial trunk, tetralogy of Fallot and variants; n = 45), Ross procedure (n = 18), and other diagnoses (n = 8). PPVI indication was pure stenosis in 33.8% of patients, pure regurgitation in 28.1%, and mixed lesions in 38.1%. PPVI was successfully implemented in 68 patients (95.8%). Pre-stenting of the right ventricular outflow tract was performed in 70 patients (98.6%). Early major complications occurred in 4 subjects (5.6%), including 1 death, 1 coronary compression, and 2 pulmonary valve embolizations. Three of the 4 major complications occurred in the first 15 operated patients. No significant regurgitation was recorded after the procedure. Transpulmonary gradient was significantly reduced from 34.5 to 10.5 mm Hg (p < 0.0001). No patient died during a 1-month follow-up period. At 1-year follow-up, the death rate was 2.9%, and 3 patients had undergone surgical reintervention (44%). ConclusionsEarly results with the Edwards SAPIEN valve in the pulmonary position demonstrate an ongoing high rate of procedural success.

Rheumatic “Taussig-Bing Heart”: A Case Report

Aim: To report a case of acyanotic Taussig-Bing heart, anatomically consistent with L-transposition and rheumatic Left AV valve regurgitation associated with complete AV block in an adolescent male. Introduction: Taussig-Bing heart is one of the conotruncal malformation, characterized by double-outlet right ventricle (DORV) and a subpulmonary VSD. Embryologically, abnormal cardiac looping with malalignment of conotruncal septum result its complexity and great artery relationships. Case Report: A 14-year old acyanotic boy presented with severe left-sided AV valve regurgitation and bradycardia. ECG revealed left sided morphologic right ventricular hypertrophy (RVH) as evidenced by a loss of septal Q waves in left precordial leads suggesting ventricular inversion. X-ray chest revealed a straight upper right cardiac border due to loss of normal relationship of great vessels and cardiomegaly due to both left atrial and morphologic right ventricular enlargements suggesting a left-sided regurgitant lesion. Echocardiography revealed the ventricular inversion, primary origin of both L-transposed great arteries from the left-sided morphologic right ventricle suggesting a “double-outlet morphologic right ventricle” with “double discordance” and a subpulmonary VSD of Taussig-Bing type. The left-sided morphologic tricuspid valve is severely regurgitant due to rheumatic process resulting in heart failure which was improved with anti-failure measures and penicillin prophylaxis. Conclusion: The presence of left-sided regurgitation associated with bradycardia is a suspicion of “double discordance” and “double switch” procedure remains the mainstay of its surgical correction. Left AV valve replacement with intraventricular repair is preferred in this child since the malformation is consistent with Taussing-Bing type of DORV with L-transposition.

In Silico Analyses Reveal the Relationship Between SIX1/EYA1 Mutations and Conotruncal Heart Defects.

Conotruncal heart defects (CTDs) represent a group of severe and complicated congenital cardiovascular malformations and require opportune clinical interventions once diagnosed. Occurrence of CTD is related to the functional abnormality of the second heart field (SHF), and variants of genes which regulate the development of the second heart field have been recognized as the main genetic factors leading to CTDs. Previous studies indicated that transcriptional complex SIX1/EYA1 may contribute to SHF development, and SIX1/EYA1 knockout mice exhibited a series of conotruncal malformations. Here, we recruited and sequenced 600 Chinese conotruncal heart defect patients and 300 controls. We screened out one novel SIX1 mutation (SIX1-K134R) and four EYA1 rare mutations (EYA1-A227T, EYA1-R296H, EYA1-Q397R, EYA1-G426S), all variants were present only in the case cohort, and the mutated sites were highly conserved. We then analyzed mutations by software including Sift, PolyPhen-2, PROVEAN, Mutation Taster, HOPE, and SWISS-PdbViewer. The results showed that the mutations had varying degrees of pathogenic risk, protein properties, spatial conformations, and domain functions which might be altered or influenced. Through biological and in silico analyses, our study suggests an association between SIX1/EYA1 mutations and cardiovascular malformations, SIX1/EYA1 mutations might be partially responsible for CTDs.

Syndrome de microdélétion 22q11.2 : analyse du parcours patient avant le diagnostic génétique

22q11.2 deletion syndrome (22q11.2DS) is a very broad phenotypic spectrum disorder. It can affect many organs or systems. 22q11.2DS is the most common microdeletion syndrome in humans, with a prevalence ranging from one in every 2000 to one in 4000 newborns. It seems to be more prevalent than reported and under-recognized or undiagnosed because of its inherent clinical variability and heterogeneity. In France, 15,000 patients may be affected by this disease, more than half without knowing it. The aim of this study was to analyze the care pathway before the genetic diagnosis of 22q11.2DS.We conducted a single-center, retrospective analysis of postnatally diagnosed patients recruited by the cytogenetic laboratory of Nancy (France) from January 2000 to December 2015. Clinical data were first collected by consulting the medical files of patients and then by calling them directly. Written informed consent was obtained and the study was approved by local research ethics boards. Data concerned only clinical features before the diagnosis.The cohort consisted of 32 individuals with 22q11.2DS. The average age at diagnosis was 9 years and 2 months and the median age was 2 years and 11 months. Fetal echography was abnormal in 15 pregnancies. During the neonatal period, the most important features were eating difficulties and congenital malformations (n=20), with a majority of complex heart diseases (n=16), dominated by conotruncal malformations (n=6). In case of malformation, the average age at diagnosis decreased to 2 years and 6 months. A congenital heart disease brought the average age of diagnosis down to 2 years and 6 months. Hypocalcemia and dysmorphism were also classical features (n=14). Before the age of 3 years, speech delay occurred in nine patients. After 3 years of age, rhinolalia was predominant (n=11). Academic disabilities were present in all subjects. At least 14 patients had a de novo deletion. Five patients were diagnosed within genetic counseling, with the deletion was inherited from the mother in three out of four cases. One was the monozygotic twin of a patient. Seven patients were diagnosed as adults. Four of them were diagnosed only because of the clinical presentation of their children or fetuses. Retrospectively, all adult patients had clinical signs suggesting the 22q11.2DS diagnosis. Relational disorders affected eight patients. None of them had been referred to the geneticist for this reason. In most cases, the pediatric cardiologist referred patients to the geneticist (n=9). Physiotherapists (n=15) and speech-language pathologists (n=12) were frequently requested but did not participate in the diagnosis.The present study highlights the difficulty of establishing the diagnosis when the major features of the 22q11.2DS are absent during the 1st months of life. This is particularly true when there is no congenital defect. Special attention must be given to speech disorders in childhood and neuropsychological disorders later in life. The association between 22q11.2DS and early-onset parkinson disease implies that adult neurologists should be aware of this diagnosis. For adult patients, familial occurrence is the most frequent cause of diagnosis in spite of clinical signs suggestive of 22q11.2DS. The management of these patients involves better information of medical and paramedical staff in order to refer them to the geneticist earlier in life.