Conotruncal Heart Malformations Research Articles

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.

Do toxic metals and trace elements have a role in the pathogenesis of conotruncal heart malformations?

The aim of the present study was to determine the role of toxic elements and trace elements in the pathogenesis of conotruncal heart defects by measuring their concentrations in the first meconium specimens of the affected newborns. Concentrations of lead, cadmium, iron, zinc, and copper were measured in 1st-day meconium specimens that were collected from 60 newborns with conotruncal heart defects (Group I) and 72 healthy newborns (Group II). The newborns with conotruncal defects and the healthy newborns had statistically similar demographic and clinical characteristics. When compared with healthy newborns, mean concentrations of lead, cadmium, iron, zinc, and copper were significantly higher in newborns with conotruncal heart defects (p=0.001 for each). In total, 51 newborns with conotruncal heart defects had normal karyotype. These newborns had significantly higher concentrations of lead, cadmium, iron, zinc, and copper when compared with healthy newborns. There were significant and positive correlations between the concentrations of lead and cadmium (r=0.618, p=0.001), lead and iron (r=0.368, p=0.001), lead and zinc (r=0.245, p=0.005), lead and copper (r=0.291, p=0.001), cadmium and iron (r=0.485, p=0.001), cadmium and zinc (r=0.386, p=0.001), and cadmium and copper (r=0.329, p=0.001). Toxic metals and trace elements may disturb DNA repair mechanisms by impairing DNA methylation profiles, and thus have a role in the pathogenesis of conotruncal heart defects.

Parental perceptions of congenital cardiovascular malformations in their children.

We assessed parental attitudes towards congenital cardiovascular malformations in their children in a cross-sectional study in Egypt. Parents face many problems related to concerns about their child's prognosis, but these associations with parental stress have never been evaluated in Egypt or examined in relation to religiosity in a predominantly Muslim society. Accordingly, we conducted interviews in Cairo with mothers of 99 sequential infants born with conotruncal heart malformations (cases) and 65 mothers of age-matched controls. The survey assessed healthcare access and usage, knowledge of congenital cardiovascular malformations, religiosity, the Locus of Control Scale, and the Parenting Stress Index. Results showed that 45% of the mothers of cases had correct knowledge about their child's diagnosis; 85% were satisfied with the clinical care; and 79% reported that the cost of care was burdensome. Compared with parents of cases, parents of controls were more likely to report stress overall and all its subscales. Regarding belief about locus of control over health, God as a determining factor was given the highest endorsement. Mothers in the congenital cardiovascular malformations group reported a higher level of parental locus of control than did those in the control group. The correlations between stress and locus of control were stronger in the control than in the case group. Religiosity was related neither to stress nor to locus of control. Future studies can explore the roles that personal, familial, and societal factors play in exacerbating or reducing stress levels among parents of sick children, particularly in developing countries where economic pressures are acute.

Chromosome 22q11.2 deletion syndrome: prenatal diagnosis, array comparative genomic hybridization characterization using uncultured amniocytes and literature review

We present prenatal diagnosis of de novo 22q11.2 microdeletion syndrome using uncultured amniocytes in a pregnancy with conotruncal heart malformations in the fetus. We discuss the genotype–phenotype correlation and the consequence of haploinsufficiency of TBX1, COMT, UFD1L, GNB1L and MED15 in the deleted region. We review the literature of chromosomal loci and genes responsible for conotruncal heart malformations and tetralogy of Fallot.

Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry

BackgroundWHIM syndrome (WS), a rare congenital neutropenia due to mutations of the CXCR4 chemokine receptor, is associated with Human Papillomavirus (HPV)-induced Warts, Hypogammaglobulinemia, bacterial Infections and Myelokathexis. The long term follow up of eight patients highlights the clinical heterogeneity of this disease as well as the main therapeutic approaches and remaining challenges in the light of the recent development of new CXCR4 inhibitors.ObjectiveThis study aims to describe the natural history of WS based on a French cohort of 8 patients.MethodsWe have reviewed the clinical, biological and immunological features of patients with WS enrolled into the French Severe Chronic Neutropenia Registry.ResultsWe identified four pedigrees with WS comprised of eight patients and one foetus. Estimated incidence for WS was of 0.23 per million births. Median age at the last visit was 29 years. Three pedigrees encompassing seven patients and the fetus displayed autosomal dominant heterozygous mutations of the CXCR4 gene, while one patient presented a wild-type CXCR4 gene. Two subjects exhibited congenital conotruncal heart malformations. In addition to neutropenia and myelokathexis, all patients presented deep monocytopenia and lymphopenia. Seven patients presented repeated bacterial Ears Nose Throat as well as severe bacterial infections that were curable with antibiotics. Four patients with late onset prophylaxis developed chronic obstructive pulmonary disease (COPD). Two patients reported atypical mycobacteria infections which in one case may have been responsible for one patient’s death due to liver failure at the age of 40.6 years. HPV-related disease manifested in five subjects and progressed as invasive vulvar carcinoma with a fatal course in one patient at the age of 39.5 years. In addition, two patients developed T cell lymphoma skin cancer and basal cell carcinoma at the age of 38 and 65 years.ConclusionsContinuous prophylactic anti-infective measures, when started in early childhood, seem to effectively prevent further bacterial infections and the consequent development of COPD. Long-term follow up is needed to evaluate the effect of early anti-HPV targeted prophylaxis on the development of skin and genital warts.

Angeborene Herzfehlbildungen von Septen, Endokardkissen und Konotrunkus

During embryological development the heart develops from a simple tube into a complex fully developed heart with four chambers. Hence all congenital heart defects develop before the ninth week of gestation. Currently a steadily increasing number of genetic mutations have been found to be responsible for congenital heart defects. Nevertheless, up to now it has been impossible to diagnose a heart defect just on the basis of molecular pathology. Despite the current excellent prenatal and postnatal ultrasound diagnostics, the post-mortem examination is still the gold standard for the diagnosis of complex heart malformations. However, this requires knowledge of the pathomorphology of the heart malformation in question. Therefore, characteristic and distinguishing features of septal defects including atrioventricular septal defects are presented, especially as the latter are part of complex heart defects, such as conotruncal heart malformations.

Polimicrogiria cerebral y síndrome de deleción 22q11

Chromosome 22q11 microdeletion syndrome, DiGeorge syndrome or CATCH 22 spectrum, is characterised by conotruncal heart malformations, facial dysmorphisms, cleft palate, velopharyngeal insufficiency, transient hypocalcemia and T cell disorders. Furthermore, a significant number of patients may present autism-type developmental disorders, learning disabilities, attention deficit hyperactivity disorder or schizophrenia-like psychiatric problems. A girl with congenital heart disease that had been treated surgically in the neonatal period, who presented psychomotor retardation, dysmorphic features and microcephaly. The conventional karyotype study that was performed at birth was normal. The physical examination revealed subtle signs of left hemiparesis. A neuroimaging study showed polymicrogyria-type cortical dysplasia that involved the right frontotemporal cortex. A chromosomal study was conducted and findings showed a 22q11.2 chromosome deletion. Brain malformations in children with deletion of the 22q11.2 chromosome have been reported previously, but their real prevalence and the most frequent type of malformation have not been properly determined. The authors conclude that brain malformations should be studied in all patients with 22q11.2 deletion and it should be borne in mind that all patients with cortical dysplasias may present this deletion.

Chromosomal abnormalities among children born with conotruncal cardiac defects

Conotruncal heart defects compose 25% to 30% of nonsyndromic congenital heart defects. This study describes the frequency of chromosome abnormalities and microdeletion of 22q11 associated among infants and fetuses delivered with conotruncal heart malformations. From a population base of 974,579 infants/fetuses delivered, 622 California infants/fetuses were ascertained with a defect of aortopulmonary septation. Infants whose primary cardiac defect was tetralogy of Fallot (n = 296) or d-transposition of the great arteries (n = 189) were screened for microdeletion of 22q11. Of the infants who had routine karyotypes, 5% had chromosomal abnormalities, including four with extra sex chromosomes. Thirty infants had chromosome 22q11 microdeletions, providing a cause for 10% of infants whose primary defect was tetralogy of Fallot. Right aortic arch, abnormal branching patterns of the major arteries arising from the thoracic aorta, and pulmonary artery abnormalities were observed more frequently among infants with tetralogy of Fallot caused by 22q11 microdeletion. We found an unusual number of infants with an extra sex chromosome and a conotruncal defect. Infants with tetralogy of Fallot owing to 22q11 microdeletion showed more associated vascular anomalies than infants with tetralogy without a 22q11 microdeletion. Although these associated vascular anomalies provide clues as to which infants with tetralogy of Fallot are more likely to carry the microdeletion, the overall risk of 10% among infants with tetralogy of Fallot warrants chromosome analysis and fluorescent in situ hybridization (FISH) testing routinely, which may be supplanted by genome-wide copy number testing as it becomes more widely utilized.

D-Transposition of the Great Arteries in a Case of Microduplication 22q11.2

The 22q11.2 deletion syndrome is one of the most frequent genetic syndromes, mainly characterized by cleft palate, facial dysmorphism, conotruncal heart malformations and immune deficiencies. Microduplication of the 22q11.2 region is a quite recently characterized genetic entity comprising a variable phenotype including some overlapping features with the 22q11.2 deletion syndrome. So far only few reports of patients with this microduplication and heart defects have been published. To our knowledge this is the first description of a patient with genetically confirmed duplication of the 22q11.2 region and d-transposition of the great arteries (d-TGA) as well as Ebstein's anomaly.

Ocular findings in children with a microdeletion in chromosome 22q11.2

A microdeletion in chromosome 22q11.2 is one of the most frequent genetic syndromes. The phenotypic manifestations vary widely, which has led to its initial description as apparently different clinical entities, such as the velocardiofacial syndrome (VCFS) and DiGeorge syndrome. Characteristic features include cleft palate, conotruncal heart malformations, thymus hypoplasia, hypoparathyroidism, a characteristic facial phenotype and learning difficulties. Ocular abnormalities are frequently seen in this patient population. We describe the ophthalmological findings in 36 children between the age of 3 and 14 years with a microdeletion in chromosome 22q11.2. They underwent a full ophthalmological examination with assessment of visual acuity, eye position and motility, stereoscopic vision, biomicroscopic examination, refraction and fundoscopy. If necessary amblyopia treatment was started and follow-up was planned. The presence of a cardiovascular malformation was noted. In conclusion, refractive errors, strabismus, amblyopia and structural ocular abnormalities are frequently encountered in children with a microdeletion in chromosome 22q11.2. Ophthalmological examination at a young age and refractive correction in those children is warranted. On the other hand, ocular findings can give a clue to the diagnosis of del 22q11.2.

D-Transposition of the Great Arteries and Ebstein's Anomaly in a Case with Microduplication 22q11.2

The Velo-cardio-facial syndrome has become one of the most researched and most common genetic syndromes, mainly characterized by cleft palate and conotruncal heart malformations. In contrast, microduplication of the 22q11.2 region is a quite recently described new genetic entity comprising variable anomalies and also conotruncal heart defects. So far only few reports on this microduplication have been published. To our knowledge the present case is the first description of a patient with genetically confirmed duplication of the 22q11.2 region with d-transposition of the great arteries (d-TGA) and Ebsteinrsquor;s anomaly.

Velo-cardio-facial syndrome

Velo-cardio-facial syndrome has emerged from obscurity to become one of the most researched disorders this past decade. It is one of the most common genetic syndromes in humans, the most common contiguous gene syndrome in humans, the most common syndrome of cleft palate, and the most common syndrome of conotruncal heart malformations. Velo-cardio-facial syndrome has an expansive phenotype, a factor reflected in the wide range of studies that cover both clinical features and molecular genetics. In this review, we cover multiple areas of research during the past year, including psychiatric disorders, neuroimaging, and the delineation of clinical features. The identification of candidate genes for heart anomalies, mental illness, and other clinical phenotypes has been reported in the past year with a focus on TBX1 for cardiac and craniofacial phenotypes and COMT and PRODH for psychiatric disorders. The expansive phenotype of velo-cardio-facial syndrome continues to grow with new behavioral and structural anomalies reported. Treatment issues are beginning to draw attention, although most authors continue to focus on diagnostic issues. Its high population prevalence, estimated to be as common as 1:2000 has sparked a large amount of research, as has the model the syndrome serves for identifying the causes of mental illness and learning disabilities, but it is obvious that more information is needed. Intensive scrutiny of velo-cardio-facial syndrome will undoubtedly continue for many years to come with the hope that researchers will turn more of their attention to treatment and treatment outcomes.

Increased incidence of renal anomalies in patients with chromosome 22q11 microdeletion.

A well-known association exists between the presence of a chromosome 22q11 micro-deletion and conotruncal heart malformations. Recently, there has been an increased appreciation of the expanded clinical phenotype associated with this chromosome abnormality. We performed a medical record review to evaluate the incidence of renal anomalies in a group of 15 patients ascertained in a single medical center over a 33-month period. Of the 15 patients, 13 had a renal sonogram performed. Five of 13 patients studied (38.4%) had a renal anomaly. The specific abnormalities identified included: bilateral duplex kidneys (1 patient), unilateral renal agenesis (1 patient), unilateral multicystic dysplastic kidneys (2 patients, including 1 ascertained prenatally), and bilateral, extremely small (less than 2 SD below mean) kidneys (1 patient). The incidence of renal anomalies in our patient population (38.4%) was higher than expected, and agrees with a recent European collaborative study. The present report and the European study both demonstrate a higher percentage of renal abnormalities than the 10% previously reported in the literature. Because patients affected with chromosome 22q11 micro-deletion often have multiple medical and surgical problems, we recommend obtaining a baseline renal ultrasound examination to identify renal anomalies before they become symptomatic.

Gap junction-mediated cell-cell communication modulates mouse neural crest migration.

Previous studies showed that conotruncal heart malformations can arise with the increase or decrease in alpha1 connexin function in neural crest cells. To elucidate the possible basis for the quantitative requirement for alpha1 connexin gap junctions in cardiac development, a neural crest outgrowth culture system was used to examine migration of neural crest cells derived from CMV43 transgenic embryos overexpressing alpha1 connexins, and from alpha1 connexin knockout (KO) mice and FC transgenic mice expressing a dominant-negative alpha1 connexin fusion protein. These studies showed that the migration rate of cardiac neural crest was increased in the CMV43 embryos, but decreased in the FC transgenic and alpha1 connexin KO embryos. Migration changes occurred in step with connexin gene or transgene dosage in the homozygous vs. hemizygous alpha1 connexin KO and CMV43 embryos, respectively. Dye coupling analysis in neural crest cells in the outgrowth cultures and also in the living embryos showed an elevation of gap junction communication in the CMV43 transgenic mice, while a reduction was observed in the FC transgenic and alpha1 connexin KO mice. Further analysis using oleamide to downregulate gap junction communication in nontransgenic outgrowth cultures showed that this independent method of reducing gap junction communication in cardiac crest cells also resulted in a reduction in the rate of crest migration. To determine the possible relevance of these findings to neural crest migration in vivo, a lacZ transgene was used to visualize the distribution of cardiac neural crest cells in the outflow tract. These studies showed more lacZ-positive cells in the outflow septum in the CMV43 transgenic mice, while a reduction was observed in the alpha1 connexin KO mice. Surprisingly, this was accompanied by cell proliferation changes, not in the cardiac neural crest cells, but in the myocardium- an elevation in the CMV43 mice vs. a reduction in the alpha1 connexin KO mice. The latter observation suggests that cardiac neural crest cells may have a role in modulating growth and development of non-neural crest- derived tissues. Overall, these findings suggest that gap junction communication mediated by alpha1 connexins plays an important role in cardiac neural crest migration. Furthermore, they indicate that cardiac neural crest perturbation is the likely underlying cause for heart defects in mice with the gain or loss of alpha1 connexin function.

Heart Malformations in Transgenic Mice Exhibiting Dominant Negative Inhibition of Gap Junctional Communication in Neural Crest Cells

Transgenic mice were generated expressing an α1 connexin/β-galactosidase fusion protein previously shown to exert dominant negative effects on gap junctional communication. RNase protection analysis and assays for β-galactosidase enzymatic activity showed that the transgene RNA and protein are expressed in the embryo and adult tissues.In situhybridization analysis revealed that in the embryo, expression was predominantly restricted to neural crest cells and their progenitors in the dorsal neural tube, regions where the endogenous α1 connexingene is also expressed. Dye-coupling analysis indicated that gap junctional communication was inhibited in the cardiac neural crest cells. All of the transgenic lines were homozygote inviable, dying neonatally and exhibiting heart malformations involving the right ventricular outflow tract—the same region affected in the α1 connexinknockout mice. As in the knockout mice, the conotruncal heart malformations were accompanied by outflow tract obstruction. Histological analysis showed that this was associated with abnormalities in the differentiation of the conotruncal myocardium. These results suggest that the precise level of gap junctional communication in cardiac neural crest cells is of critical importance in right ventricular outflow tract morphogenesis. Consistent with this possibility is the fact that cardiac crest cells from the α1 connexinknockout mice also exhibited a greatly reduced level of gap junctional communication. These studies show the efficacy of a dominant negative approach for manipulating gap junctional communication in the mouse embryo and demonstrate that targeted expression of this fusion protein can be a powerful tool for examining the role of gap junctions in mammalian development.

Microsatellite DNA markers detects 95% of chromosome 22q11 deletions

Cono-truncal cardiac malformations account for some 50% of congenital heart defects in newborn infants. Recently, hemizygosity for chromosome 22q11.2 was reported in patients with the DiGeorge/Velo-cardio-facial syndromes (DGS/VCFS) and causally related disorders. We have explored the potential use of microsatellite DNA markers for rapid detection of 22q11 deletions in 19 newborn infants referred for cono-truncal heart malformations with associated DGS/VCFS anomalies. A failure of parental inheritance was documented in 84.2% of cases (16/19). PCR-based genotyping using microsatellite DNA markers located within the commonly deleted region allowed us either to confirm or reject a 22q11 microdeletion in 94.3% of cases (18/19) within 24 hours. This test is now currently performed in the infants referred to us for a cono-truncal heart malformation as a first intention screening for 22q11 microdeletion. Am. J. Med. Genet. 68:182–184, 1997 © 1997 Wiley-Liss, Inc.

Microsatellite DNA markers detects 95% of chromosome 22q11 deletions

Cono-truncal cardiac malformations account for some 50% of congenital heart defects in newborn infants. Recently, hemizygosity for chromosome 22q11.2 was reported in patients with the DiGeorge/Velo-cardio-facial syndromes (DGS/VCFS) and causally related disorders. We have explored the potential use of microsatellite DNA markers for rapid detection of 22q11 deletions in 19 newborn infants referred for cono-truncal heart malformations with associated DGS/VCFS anomalies. A failure of parental inheritance was documented in 84.2% of cases (16/19). PCR-based genotyping using microsatellite DNA markers located within the commonly deleted region allowed us either to confirm or reject a 22q11 microdeletion in 94.3% of cases (18/19) within 24 hours. This test is now currently performed in the infants referred to us for a cono-truncal heart malformation as a first intention screening for 22q11 microdeletion.