The pathogenesis of hereditary congenital malformations of the anorectum in the pig

The pathogenesis of anorectal malformations was studied in 41 abnormal embryos, foetuses and newborn pigs descended from a herd in which this anomaly was caused by a hereditary trait. The principal development error was found to be situated in the cloacal plate, of which a dorsal part of variable size was missing. This defect impeded the normal migration of the dorsal cloaca and adjacent structures along the dorsal border of the plate to the body surface of the tailgroove. Correlated to the size of the cloacal plate defect diverse types of anorectal malformations may develop ranging from slight abnormalities such as anal stenosis and perineal or vulvar ectopic anus to more serious anomalies such as imperforate anus of low, intermediate and high types. In the cases with imperforate anus a communication with the urogenital system is always formed, although it may disappear later in some animals. This communication which represents a persistent cloaca, has to be considered as an ectopic anorectal canal according to its origin and structure. The abnormalities of the internal and external sphincter ani muscles and puborectal muscles are secondary although distinctly correlated to the malformations of the epithelial structures.     

Imprinting aberrations of SNRPN,ZAC1 and INPP5F genes involved in the pathogenesis of congenital heart disease with extracardiac malformations

Congenital heart disease (CHD) with extracardiac malformations (EM) is the most common multiple malformation, resulting from the interaction between genetic abnormalities and environmental factors. Most studies have attributed the causes of CHD with EM to chromosomal abnormalities. However, multi‐system dysplasia is usually caused by both genetic mutations and epigenetic dysregulation. The epigenetic mechanisms underlying the pathogenesis of CHD with EM remain unclear. In this study, we investigated the mechanisms of imprinting alterations, including those of the Small nuclear ribonucleoprotein polypeptide N (SNRPN), PLAG1 like zinc finger 1 (ZAC1) and inositol polyphosphate‐5‐phosphatase F (INPP5F) genes, in the pathogenesis of CHD with EM. The methylation levels of SNRPN, ZAC1, and INPP5F genes were analysed by the MassARRAY platform in 24 children with CHD with EM and 20 healthy controls. The expression levels of these genes were detected by real‐time polymerase chain reaction (PCR). The correlation between methylation regulation and gene expression was confirmed using 5‐azacytidine (5‐Aza) treated cells. The methylation levels of SNRPN and ZAC1 genes were significantly increased in CHD with EM, while that of INPP5F was decreased. The methylation alterations of these genes were negatively correlated with expression. Risk analysis showed that abnormal hypermethylation of SNRPN and ZAC1 resulted in 5.545 and 7.438 times higher risks of CHD with EM, respectively, and the abnormal hypomethylation of INPP5F was 8.38 times higher than that of the control group. We concluded that abnormally high methylation levels of SNRPN and ZAC1 and decreased levels of INPP5F imply an increased risk of CHD with EM by altering their gene functions. This study provides evidence of imprinted regulation in the pathogenesis of multiple malformations.     

Epidemiology of congenital heart disease in Louisiana: an association between race and sex and the prevalence of specific cardiac malformations.

We hypothesized that susceptibility to the genetic and environmental factors that disrupt cardiac development is associated with race and sex. To evaluate this hypothesis, we asked whether the prevalence of specific cardiac malformations differs by race and sex. We attempted to include all infants born alive in the State of Louisiana from January 1, 1988, through December 31, 1989, and diagnosed by echocardiography, catheterization and/or autopsy within a year of birth as having one of ten specific cardiac malformations. The prevalence of atrioventricular canal defects (AVCD) per 1,000 live births was significantly higher for black females (.744) compared to black males (.198) and for white females (.414) compared to white males (.116). Complete transposition of the great arteries (TGA) was significantly higher for white males (.559) compared to white females (.122); in contrast, TGA was not significantly different for black males (.198) and black females (.169). Obstructive left heart syndrome (OLHS)--aortic stenosis and/or coarctation of the aorta--was significantly higher for white males (.652) compared to white females (.317); in contrast, OLHS was not significantly different for black males (.264) and black females (.169). Single ventricle (SV) was significantly higher for whites (.202) compared to blacks (.067). We did not find that race and sex were associated with differences in the prevalence of tetralogy of Fallot and hypoplastic left heart syndrome. The numbers of infants with anomalous pulmonary venous return, tricuspid atresia, double outlet right ventricle, or truncus arteriosus were too small to measure an association with race and sex. These results demonstrate that the prevalence of a subset of cardiac malformations differs by race and sex.(ABSTRACT TRUNCATED AT 250 WORDS)     

Etiologic heterogeneity in the familial aggregation of congenital cardiovascular malformations.

Recent data indicate that there is increased risk of congenital cardiovascular malformations (CCVM) within families of probands diagnosed with congenital cardiovascular malformations that are due to altered embryonic blood flow (flow lesions). In the present study, regressive models recently developed by Bonney were used to compare specific models of inheritance and to test for etiologic heterogeneity among three subgroups of 375 flow-lesion families identified by the Baltimore-Washington Infant Study. When all families were analyzed as a single group, the best-fitting model was a simple recessive model with Mendelian transmission; race did not have a significant effect on estimated risk. Separate analyses of families of probands with left heart defects, right heart defects, and ventricular septal defects (VSD) confirmed this simple Mendelian recessive model as the model of choice. However, when race was included as a covariate in these genetic models, there was evidence for significant heterogeneity among the three subgroups. There was an increased risk to relatives of white probands with right heart defects and to relatives of black probands with VSD, while there was no effect of race among relatives of probands with left heart defects. These results strongly suggest that there is etiologic heterogeneity in the control of CCVM among flow-lesion families and that the patterns of familial aggregation differ among the races.     

Cytokine polymorphisms and histologic expression in autopsy studies: contribution of TNF-alpha and TGF-beta 1 to the pathogenesis of autoimmune-associated congenital heart block

Although Abs to SSA/Ro-SSB/La are necessary for the development of congenital heart block (CHB), the low frequency suggests that fetal factors are contributory. Because CHB involves a cascade from inflammation to scarring, polymorphisms of the TNF-alpha promoter region and codons 10 and 25 of the TGF-beta gene were evaluated in 88 children (40 CHB, 17 rash, 31 unaffected siblings) and 74 mothers from the Research Registry for Neonatal Lupus (NL). Cytokine expression was assessed in autopsy material from two fetuses with CHB. Significantly increased frequency of the -308A (high-producer) allele of TNF-alpha was observed in all NL groups compared with controls. In contrast, the TGF-beta polymorphism Leu(10) (associated with increased fibrosis) was significantly higher in CHB children (genotypic frequency 60%, allelic frequency 78%) than unaffected offspring (genotypic frequency 29%, p = 0.016; allelic frequency 56%, p = 0.011) and controls, while there were no significant differences between controls and other NL groups. For the TGF-beta polymorphism, Arg(25), there were no significant differences between NL groups and controls. In fetal CHB hearts, protein expression of TGF-beta, but not TNF-alpha, was demonstrated in septal regions, extracellularly in the fibrous matrix, and intracellularly in macrophage infiltrates. Age-matched fetal hearts from voluntary terminations expressed neither cytokine. TNF-alpha may be one of several factors that amplify susceptibility; however, the genetic studies, backed by the histological data, more convincingly link TGF-beta to the pathogenesis of CHB. This profibrosing cytokine and its secretion/activation circuitry may provide a novel direction for evaluating fetal factors in the development of a robust animal model of CHB as well as therapeutic strategies in humans.     

The anti-infection resistance system and the pathogenesis of bacterial endocarditis in patients with congenital heart defects

The clinico-immuno-microbiological study of 24 patients with congenital heart diseases was made. Clinically, the patients were subdivided into two groups: 8 patients with diagnosed bacterial endocarditis (BE) prior to the operation and 16 patients without BE. The analysis of the results of investigation carried out prior to the operation showed that age, the form of the disease and its duration did not affect the level of anti-infectious resistance factors (AIRF): in both groups a decrease in the level of AIRF characteristics (cell-mediated and humoral) was noted and no characteristic differences were determined. The results of the study of microflora from the nasal and laryngeal mucosa showed no difference in both groups of the patients. At the same time the detailed analysis of the results made it possible to suggest that BE caused by Streptococcus epidermidis and Streptococcus aureus inhabiting the mucous membrane of the anterior sections of the nasal cavity, alpha-hemolytic streptococci and S. epidermidis inhibiting the laryngeal mucosa. The results of the analysis made 3-6 months after the operation were also indicative of the absence of essential differences between AIRF characteristics observed in patients with confirmed and clinically unconfirmed BE. The clinical manifestation of this fact was an increase in the percentage of diagnosed BE cases up to 70% as compared with that before the operation (33%). This clinico-immuno-microbiological study made it possible to come to the conclusion that any form of congenital heart disease develops in combination with BE and/or is its prodrome.     

The significance of the lung biopsy in congenital cardiovascular malformations

The microscopic changes of pulmonary arteries in 18 patients with congenital cardiovascular malformations were studied on lung biopsies and appreciated by the Heath-Edwards' scale. A correlation between the nature of the malformation and the patient's age on the one hand, and the severity of arterial lesions on the other hand, was observed, suggesting the utility of the lung biopsy for a better prognosis of the surgical corrective intervention. The role of inflammatory factors in the genesis of arterial changes leading to hypertension is also discussed.     

Incidence of congenital heart disease in Hungary.

A survey was planned for establishing the point prevalence at birth of congenital heart disease and for assessing at the same time the efficacy of a screening for such anomalies. This model included: (1) exact determination of the population under survey; (2) approximately complete ascertainment of all persons in the population studied; (3) identical principles of cardiologic screening; (4) application of modern cardiologic diagnostic methods, and (5) a sample of over 2,000 persons. 23 cases of congenital heart diseases were found among 2,259 children born 1963 in a defined Hungarian territory. This means a point prevalence of 10.2+/-2.1% live births. (An additional 6 doubtful cases were not taken into account.) From the 12 cases diagnosed in vivo, 10 were detected by the screening.