Atrioventricular Canal Malformations Research Articles

Atrioventricular Septal Defect: What Is in a Name?

Robert Anderson has made a huge contribution to almost all aspects of morphology and understanding of congenital cardiac malformations, none more so than the group of anomalies that many of those in the practice of paediatric cardiology and adult congenital heart disease now call ‘Atrioventricular Septal Defect’ (AVSD). In 1982, with Anton Becker working in Amsterdam, their hallmark ‘What’s in a name?’ editorial was published in the Journal of Thoracic and Cardiovascular Surgery. At that time most described the group of lesions as ‘atrioventricular canal malformation’ or ‘endocardial cushion defect’. Perhaps more significantly, the so-called ostium primum defect was thought to represent a partial variant. It was also universally thought, at that time, that the left atrioventricular valve was no more than a mitral valve with a cleft in the aortic leaflet. In addition to this, lesions such as isolated cleft of the mitral valve, large ventricular septal defects opening to the inlet of the right and hearts with straddling or overriding tricuspid valve were variations of the atrioventricular canal malformation. Anderson and Becker emphasised the differences between the atrioventricular junction in the normal heart and those with a common junction for which they recommended the generic name, ‘atrioventricular septal defect’. As I will discuss, over many years, they continued to work with clinical cardiologists and cardiac surgeons to refine diagnostic criteria and transform the classification and understanding of this complex group of anomalies. Their emphasis was always on accurate diagnosis and communication, which is conveyed in this review.

Biallelic ERBB3 loss-of-function variants are associated with a novel multisystem syndrome without congenital contracture

BackgroundGain-of-function pathogenic variants of the Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene contribute to the occurrence and development of a variety of human carcinomas through activation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) signaling. ERBB3 gene homozygous germline variants, whose loss of function may cause autosomal recessive congenital contractural syndrome, were recently identified. This study aims to identify the disease-causing gene in a Chinese pedigree with variable phenotypes involving multiple systems, including developmental delay, postnatal growth retardation, transient lower limb asymmetry, facial malformations, atrioventricular canal malformation, bilateral nystagmus and amblyopia, feeding difficulties, immunodeficiency, anemia, and liver damage, but without congenital contracture.MethodsTrio-whole exome sequencing (WES) was performed to identify the disease-causing gene in a 24-month-old Chinese female patient. The pathogenicity of the identified variants was evaluated using in silico tools and in vitro functional studies.ResultsTrio-WES revealed compound heterozygous variants of c.1253 T > C (p.I418T) and c.3182dupA (p.N1061Kfs*16) in the ERBB3 gene. Functional studies showed that p.I418T resulted in normal expression of ERBB3, which was capable of interacting with ERBB2. However, the variant impaired ERBB3 phosphorylation, consequently blocking ERBB2 phosphorylation and AKT and ERK activation. The truncated protein resulting from the c.3182dupA variant also lacked the capacity to activate downstream signaling pathways.ConclusionsWe report the first patient with a novel multisystem syndrome disorder without congenital contracture resulting from biallelic loss-of-function variants of ERBB3.

16q24.1 microdeletion in a premature newborn: Usefulness of array-based comparative genomic hybridization in persistent pulmonary hypertension of the newborn

Report of a 16q24.1 deletion in a premature newborn, demonstrating the usefulness of array-based comparative genomic hybridization in persistent pulmonary hypertension of the newborn and multiple congenital malformations. Descriptive case report. Genetic department and neonatal intensive care unit of a tertiary care children's hospital. None. We report the case of a preterm male infant, born at 26 wks of gestation. A cardiac malformation and bilateral hydronephrosis were diagnosed at 19 wks of gestation. Karyotype analysis was normal, and a 22q11.2 microdeletion was excluded by fluorescence in situ hybridization analysis. A cesarean section was performed due to fetal distress. The patient developed persistent pulmonary hypertension unresponsive to mechanical ventilation and nitric oxide treatment and expired at 16 hrs of life. An autopsy revealed partial atrioventricular canal malformation and showed bilateral dilation of the renal pelvocaliceal system with bilateral ureteral stenosis and annular pancreas. Array-based comparative genomic hybridization analysis (Agilent oligoNT 44K, Agilent Technologies, Santa Clara, CA) showed an interstitial microdeletion encompassing the forkhead box gene cluster in 16q24.1. Review of the pulmonary microscopic examination showed the characteristic features of alveolar capillary dysplasia with misalignment of pulmonary veins. Some features were less prominent due to the gestational age. Our review of the literature shows that alveolar capillary dysplasia with misalignment of pulmonary veins is rare but probably underreported. Prematurity is not a usual presentation, and histologic features are difficult to interpret. In our case, array-based comparative genomic hybridization revealed a 16q24.1 deletion, leading to the final diagnosis of alveolar capillary dysplasia with misalignment of pulmonary veins. It emphasizes the usefulness of array-based comparative genomic hybridization analysis as a diagnostic tool with implications for both prognosis and management decisions in newborns with refractory persistent pulmonary hypertension and multiple congenital malformations.

Morphology and Morphogenesis of Atrioventricular Septal Defect With Common Atrioventricular Junction

For many years, the lesions now often described as atrioventricular septal defects were considered to represent atrioventricular canal malformations or endocardial cushion defects. It was also long recognized that patients with the so-called ostium primum defect should be included in this category. The phenotypic feature of these hearts is the presence of a common atrioventricular junction, as opposed to separate right and left atrioventricular junctions. The presence of the common atrioventricular junction underscores the associated phenotypic features, such as the presence of a trifoliate left atrioventricular valve, which has no resemblance to a cleft mitral valve; unwedging of the subaortic outflow tract; and disproportion between the inlet and outlet dimensions of the left ventricle. These features are comparable in patients having the so-called partial, intermediate, and complete variants of the malformation. Anatomical differentiation depends on the morphology of the leaflets of the common atrioventricular valve that bridge the ventricular septum. If these bridging leaflets are fused one to the other, then there are dual orifices, rather than a common orifice, within the common atrioventricular junction. The relationships of the bridging leaflets to the septal structures determine the potential for shunting across the atrioventricular septal defect, which can occur at atrial and ventricular levels or exclusively at either atrial or ventricular level. Rarely, the atrioventricular septal defect may close spontaneously. Recent evidence from studies of cardiac development shows that rather than being an endocardial cushion defect, the malformation results from failure of ingrowth into the developing heart from the dorsal mesenchymal tissues.

Establishing the anatomic hallmarks of congenitally malformed hearts

A detailed knowledge of the precise morphology of the congenitally malformed heart has never been more important. In fields as diverse as clinical genetic counseling, epidemiology, surgery, and development biology, a proper description of morphology is essential to understand the cause and prevention of cardiac malformations. There has been a tendency in the past to categorize malformed hearts on the basis of putative developmental faults that are deduced from abnormal morphology, for example “endocardial cushion” or “looping” defects. We consider that this is potentially misleading. A better approach is exactly to determine cardiac structure so as to identify the “hallmark” (or “prototype”) morphology of a given lesion. The hallmark will constitute those features, among all the changes in a malformed heart, that best define its fundamental character. As an example of the confusion produced by mechanistic extrapolation, consider the cleft in the anterior leaflet of an otherwise normal mitral valve, compared with the space between the leaflets bridging the ventricular septum in hearts with common atrioventricular junctions and deficient atrioventricular septation (“atrioventricular canal malformations”). It is probably correct to presume that both of these entities result from failure of fusion of the atrioventricular endocardial cushions. It is quite inappropriate, in contrast, to group these two lesions together morphologically, given the major anatomical differences seen in the formed hearts (Sigfússon et al. 1995). Therefore it is also important from the stance of developmental biology that the precise morphology of a genetically or chemically induced lesion be recognized if appropriate inferences are to be drawn for consideration of morphogenetic mechanisms and of comparable lesions in humans.

The surgical treatment of Ebstein's malformation

THE MOST APPROPRIATE SURGICAL TREATMENT FOR Ebstein's malformation and, indeed, the very nature of the lesion itself, remain contentious issues. The long experience of the group from Hopital Broussais has proved invaluable in directing surgeons towards the best techniques for conservative repair and in pointing anatomists towards the most appropriate description of the deranged valvar structure. This is exemplified by the advances made in the understanding of the left atrioventricular valve in hearts with deficient atrioventricular septation (atrioventricular canal malformations) . It was the beautifully explicit diagrams of Carpentier which, for me at least, first focused attention on the unequivocal trifoliate arrangement of this left atrioventricular valve, although the information required was also provided by Van Mierop and his colleagues in their earlier studies.' The impact of all these excellent investigations, however, was dissipated by continued use of the adjective mitral to describe the trifoliate valve, together with arguments which continued concerning the optimal surgical treatment of the zone of apposition between the edges of the two leaflets of the trifoliate valve which bridge the ventricular septum (the commissure or cleft). It is now becoming appreciated that it is better to avoid nominative terms for this structure and simply describe the zone of apposition between the leaflets. In the accompanying paper, Chauvaud and his colleagues describe the continuing evaluation of their surgical management of Ebstein's malformation. At the same time, (for me, at any rate) they continue to clarify the morphology of this fascinating lesion. I had thought that I understood well the anomaly, having published several accounts of its structure which, over time, illustrated my own increasing appreciation of its morphology. When preparing a chapter from a presentation for a meeting also attended by both Chauvaud and Carpentier, however, elements of my continuing ignorance were highlighted by the comments of these skilled surgeons. Much of the impetus for my own chapter had itself been provided by an editorial comment by Becker

Aberrant right subclavian artery with left aortic arch: associated cardiac anomalies.

Anomalous origin of the right subclavian artery (ARSA) from the aorta distal to the normally positioned left subclavian artery is a relatively frequent congenital anomaly in subjects with left aortic arch. The purpose of this study was to determine the relative frequency of associated cardiovascular anomalies in individuals with this anomaly. From the records of approximately 11,000 pathologic specimens in the Registry of Cardiovascular Disease of United Hospital (St. Paul, MN, USA), we found 128 (1.2%) with ARSA. Of the 128 ARSA, 117 (2.9%) occurred among 4102 instances of congenital heart disease. The 117 cases with congenital heart disease and ARSA were conotruncal anomalies in 38%, septal defects in 28%, obstructive anomalies of the left side of the heart in 21%, right heart anomalies in 5%, and miscellaneous conditions in the other 8%. Down syndrome existed in 14 (12%) of the 117 specimens with ARSA and some congenital cardiac anomaly; nine of the latter had an atrioventricular canal (AVC) malformation.

Prenatal Diagnosis of Atrioventricular Canal Malformations with Up-to-Date Echocardiographic Technology: Report of 14 Cases

Prenatal Diagnosis of Atrioventricular Canal Malformations with Up-to-Date Echocardiographic Technology: Report of 14 Cases

Prenatal diagnosis of atrioventricular canal malformations with up-to-date echocardiographic technology: report of 14 cases

Fourteen fetuses with atrioventricular canal malformations were examined by two-dimensional echocardiography, pulsed-wave Doppler echocardiography, and color Doppler flow mapping. Eleven fetuses had complete and three fetuses had partial atrioventricular canal malformations. Nonimmune hydrops fetalis was associated with six cases, and fetal arrhythmia was seen in three cases. With two-dimensional echocardiography, the atrioventricular canal malformations could be diagnosed accurately. The inclusion of color Doppler flow mapping, however, provided additional hemodynamic information that was important from the prognostic point of view. Incompetence of atrioventricular valves could be demonstrated in 10 of 14 cases by Doppler echocardiography. In nine cases, detailed Doppler echocardiographic evaluation of the regurgitation jet was possible. The proportion of systolic time during which atrioventricular valve insufficiency was demonstrated was related to the occurrence of nonimmune hydrops fetalis. When insufficiency of atrioventricular valves was associated with hydrops (four cases), a pansystolic insufficiency was always present. In cases without hydrops (five), regurgitation was confined to early systole. Thus a reliable method for semiquantitative evaluation of the degree of insufficiency seems to have been found. Moreover, an association appeared to exist between the occurrence of hydrops tetalis and the proportion of atrial area that was taken up by regurgitant jet area, as determined by planimetry in the four-chamber view. Prenatal diagnosis was confirmed by autopsy or neonatal cardiac evaluation. Only one neonate survived in our series. Two were stillborn, four died during the neonatal period, two died during infancy, and pregnancy was electively terminated prematurely in five cases. Eight fetuses were found to have a karyotypic abnormality.

Ethical Dilemmas in Fetal Echocardiography

Recent technology permits detection of congenital heart diseases as early as the 17th or 18th week of gestation. These detectable defects include hypoplastic left heart syndrome, Ebstein anomaly, and atrioventricular canal malformation. Surgical treatments for these problems raise ethical as well as medical questions regarding patients whose prenatal diagnosis reveals congenital heart disease. We report six cases of in utero diagnosis of hypoplastic left heart syndrome and other complex congenital heart anomalies. Empirical factors relevant to our management were gestational age, severity of the anomaly, degree of certainty of diagnosis and prognosis, possibilities for treatment, and parental wishes regarding the fetus or newborn. Each of these factors was examined in the context of the reported cases and correlated with ethical principles applicable to obstetrics and neonatology: 1) respect for parental autonomy, 2) promotion of the infant's welfare, and 3) fairness in distributing scarce medical resources. We maintain that the first two principles are paramount in ethical decisions regarding individual patients, while the third is foremost in policy decisions affecting others as well.

Surgical Treatment of Atrioventricular Canal Malformations

This study reports our experience with a consecutive series of 106 patients with atrioventricular (AV) canal malformations operated on between March, 1972, and June, 1985. There were 11 ostium primum defects, 90 partial forms of AV canal, and 5 complete forms of AV canal. Associated cardiovascular lesions were found in 26 patients. Operation was performed under total-body perfusion. There were 5 postoperative deaths, and the overall mortality was 4.7%. Eighty-seven patients were followed up. Follow-up averaged 6 years 7 months. The study shows that the long-term results in patients with mild preoperative mitral insufficiency are better than those with severe mitral insufficiency, and suggests that partial approximation of the mitral cleft is probably the method of choice in most patients.

Further observations on the morphology of atrioventricular septal defects

Certain morphologic aspects of atrioventricular septal defects ("endocardial cushion defects," "atrioventricular canal malformations") remain controversial. It is still not clear which precise lesions should not be placed in this category. For example, is an "isolated" cleft of the mitral valve or a perimembranous inlet ventricular septal defect to be so described? It is also not fully accepted that the left atrioventricular valve in these lesions bears little resemblance to a morphologically mitral valve. We have investigated these problems by both observation and mensuration. We determined the junctional circumference of the left atrioventricular valve leaflets and the ventricular dimensions in 130 atrioventricular septal defects (95 with common valve orifice and 35 with separate right and left atrioventricular orifices); in 50 hearts with perimembranous ventricular septal defects (20 extending into the inlet septum and 30 with outlet or trabecular extensions); in seven hearts with isolated cleft of the mitral valve, and in 10 normal hearts. All specimens came from the cardiopathological collection of Children's Hospital of Pittsburgh. The measurements showed conclusively that the atrioventricular septal defects were all directly comparable irrespective of the detailed morphology of the atrioventricular valve or valves. The group of atrioventricular septal defects was totally discrete as compared with all the other specimens that had normal atrioventricular septation. The left atrioventricular valve in atrioventricular septal defects is basically a three-leaflet valve which differs from the normal mitral valve in terms of its leaflet, its chordal support, and the arrangement of its papillary muscle. Its only similarity with the normal mitral valve is that it resides in the morphologically left ventricle and guards the left atrioventricular junction.

Of clefts, commissures, and things

A full understanding of the morphology of atrioventricular septal defects ("endocardial cushion defects," "atrioventricular canal malformations") demands knowledge of the exact nature of three specific breaches in the skirt of valve leaflet tissue guarding the atrioventricular junction. One of these is the space between the left ventricular components of the two leaflets that are enclosed in both the right and left ventricles (the bridging leaflets). Traditionally described as a cleft, it has been suggested more recently that this gap functions as a commissure. The second space is that which is found anteriorly and superiorly in the so-called Rastelli type A malformation. This is also called a cleft in a common anterior leaflet, but it has been suggested that it too is a commissure. The final breach is that produced by the surgeon when he divides the free-floating superior bridging leaflet if repairing the so-called Rastelli type C malformation with a one-patch technique. It is generally agreed that this breach be considered a division. To adjudicate the nature of the other breaches, it is necessary to compare them with commissures in atrioventricular and arterial valves and with the isolated cleft that exists in the aortic leaflet of a normal mitral valve. These considerations show that the gap between the left ventricular components of the bridging leaflets functions as a commissure even though it is not supported by a papillary muscle. This would not be expected, since the commissural attachments of the leaflets are in the left and right ventricle, respectively. The gap seen anteriorly in the Rastelli type A malformation is also a commissure, being supported in typical fashion by the medial papillary muscle of the right ventricle.

Increased adhesiveness of trisomy 21 cells and atrioventricular canal malformations in Down syndrome: a stochastic model.

Based on the finding that fetal trisomy 21 fibroblasts explanted from lungs and endocardial-cushion-derived structures appear more adhesive in vitro than those from normal control individuals, we present a stochastic model for atrioventricular (AV) canal malformations in Down syndrome (DS). Computer simulations were performed to model the normal anatomic sequences of cushion-to-cushion and cushion-to-septum fusion in AV canal development. In these simulations, random-walking endocardial cells were allowed to migrate, divide, and adhere with programmable probabilities. Low values of intercellular adhesiveness engendered simulations resembling normal AV canal development; higher values of adhesiveness yielded deficiencies of AV canal development as seen in DS. Moderately high levels of adhesiveness resulted in abnormalities in only a proportion of multiple, independently performed simulations. The model successfully predicts the temporospatial sequence of anatomic events in cushion-to-septum fusion, clinical variability among individuals with the same genotype based on chance alone, and amplified developmental instability as observed in individuals with DS.

大動脈弁下狭窄をともなう不完全型房室管奇形の豚の一例

大動脈弁下狭窄をともなう不完全型房室管奇形の豚の一例

Asplenia and Polysplenia Malformation Complexes Explained by Abnormal Embryonic Body Curvature

Asplenia and polysplenia malformation complexes characteristically have severe cardiovascular defects and visceral heterotaxy. We examined the hypothesis that the conditions may arise from an altered timing of development of embryonic body curvature: delayed in asplenia, accelerated in polysplenia. The morphologic features of the 25 patients with asplenia and 15 with polysplenia autopsied at The Johns Hopkins Hospital were determined. The time of appearance of various morphologic features and the evolution of body curvature was studied in 351 staged serially sectioned human embryos of The Carnegie Embryological Collection. All asplenia patients had severe atrioventricular canal malformations. Bilateral trilobed lungs were found in 12 patients. The polysplenia patients had severe interatrial septal defects in 10 patients; but ventricular septal defects in only six. Bilateral bilobed lungs were seen in five patients. Comparison of the time of appearance of anatomic structures in normal embryos with the observed malformations suggest that asplenia and polysplenia complexes originate in stages 13 to 15. The observations are consistent with the concept that the malformations in asplenia and polysplenia can be explained by minor alterations in the sequence of development of embryonic body curvature relative to organ maturation.

Atrio-ventricular Canal Malformations. Recent Surgical Techniques

Twenty patients with atrio-ventricular canal malformations (5 complete and 15 partial forms) were operated upon during the last two years, using new surgical techniques. The repair of the complete form based on a three-leaflet three-commissure mitral valve concept, was accomplished by: a) Two separate partitioning patches (one ventricular, one atrial), b) mitral and tricuspid valve attachment in between, c) no cleft sutures, d) correction of subvalvular apparatus abnormalities, e) commissuroplasty. The repair of the partial form was obtained by: a) Valvular and subvalvular repair of the lesions when present, b) patch closure of the ostium primum defect suturing on the tricuspid side. All patients survived operation and exhibited normal sinus rhythm. Residual mitral incompetence proved to be less frequent as compared to previous techniques.

TWO‐DIMENSIONAL ECHOCARDIOGRAPHY IN ATRIOVENTRICULAR CANAL MALFORMATION: A DIAGNOSTIC APPROACH

Two-dimensional echocardiographic studies were performed in 20 children with various forms of atrio-ventricular canal malformation. Both sagittal and transverse cross-sections were evaluated. The most typical finding in all patients was the visualization of the cleft anterior mitral leaflet (AML) represented by a diastolic break of AML echoes in the sagittal cross-section. - In cases where the AML is attached to the interventricular septum, varying degrees of left ventricular outflow tract narrowing and elongation were observed. In the transverse cross-section mitral-tricuspid alignment could be observed at the level of the aortic root. The ventricular septal defect in complete AVC was visualized as an echo-free space between the common anterior leaflet and the interventricular septum.

Complete Atrioventricular Canal Malformation: Further Clarification of the Anatomy of the Common Leaflet and Its Relationship to the VSD in Surgical Correction

Thirty-four heart specimens showing complete atrioventricular (AV) canal malformation were studied. The size of defects underneath the anterior common leaflet was compared with the size of those beneath the posterior common leaflet. Wherever such defects were present, they were either of the same size or larger underneath the anterior leaflet. There was no correlation between the type of posterior common leaflet and the size of ventricular communication. The importance of the location of the ventricular defect in relation to surgical correction, especially in small infants, is discussed.

Further observations on the pathology of the atrioventricular canal malformation.

THIRTY-TWO human hearts having atrioventricular (AV) canal malformation were recently studied. The attention was drawn to the anatomical and geometric aspects of the diseased hearts. It was noted that the defect included a significant portion of the muscular septum as far as its junction with the diaphragmatic wall and significant deficiency in the posterior base of the heart. Also, there were major anomalies of the right ventricle, mainly hypoplasia of the septal portion of the right ventricular sinus, and hyperdevelopment of the conal portion of the right ventricle. To the best of our knowledge, the anomalies involving the base of the heart and the ventricles were not described before and they may have some implication as to the surgical approach as well as to the developmental anomaly. The purpose of this communication is to give an anatomic description of the AV canal heart and to define the involved structures, morphologically.