It has long been recognised that congenital absence of the spleen, or the presence of multiple spleens, is associated with severe congenital malformations of the heart. 1–3 Some of the most complex forms of congenital cardiac disease are associated with these splenic abnormalities, and the prognosis for many patients with these lesions remains poor, even in the modern era of congenital cardiovascular surgery. If progress is to continue in the care of these children, the cardiac abnormalities need to be determined with precision in each case, and their nature be conveyed in unambiguous fashion to the surgeon attempting correction or palliation. Description of the cardiac malformations found in association with splenic abnormalities, however, has been the cause of much confusion and controversy. It is now established that cardiac structures are best identified on the basis of their most constant components, following the so-called morphological method. 4 When considering the atriums, it is the appendage which is most constantly present (see Chapter 1 ). It is then the presence of isomeric atrial appendages that is the most accurate feature with which to stratify the patients previously labeled as having splenic syndromes, 5 or more recently as having visceral heterotaxy. 6–8 In the first part of this chapter, we review some of the historical landmarks in the recognition of the cardiac malformations seen in the presence of isomeric atrial appendages, and attempt to clarify some of the confusing nomenclature that has evolved over the last few decades. Subsequently, we describe in detail the morphological and clinical features of these cardiac malformations. We then focus attention on the progress made in recent years in the diagnosis and surgical treatment of these generally highly complex malformations.
HISTORICAL NOTES AND DEFINITIONS
Absence of the spleen is an obvious autopsy finding, which is unlikely to be missed, being noted as long ago as the 16th century, but very likely then as the consequence of tuberculous infection. The earliest recorded examples of congenital absence of the spleen are probably those appearing in 1826. 2 Multiple spleens occurring as a congenital malformation had been recorded more than 30 years previously. 1 These early accounts recognised not only the splenic anomalies, but also abnormal arrangements of other organs, as well as the cardiac malformations. Over the last five decades, there has been a more systematic analysis of the cardiac and extracardiac malformations seen in patients with congenital splenic anomalies. This has resulted in recognition that the entire bodily arrangement of patients, now often described as visceral heterotaxy, 6–8 differs from the usual arrangement, or situs solitus, and also from the mirror-imaged variant, typically described as situs inversus. Those observing the abnormal arrangement of the abdominal organs 3,9 had noted the association with congenital cardiac disease. They had also noted the symmetrical nature of the lungs. Ivemark, in his classical description, introduced the phrase ‘asplenia, a teratologic syndrome of visceral symmetry’. 3 Putschar and Mannion, 9 with remarkable prescience, stated: ‘The relationship of agenesis of the spleen to disturbed development of laterality, however, goes beyond the manifestations of obvious situs inversus. Between the normal situs, which is asymmetrical, and the situs inversus, which is the asymmetrical mirror-image of normality, a symmetrical situs sometimes exists, exhibiting symmetrical rightness or leftness on both sides’. It is hard to find any subsequent account that so well expresses the concept of biological isomerism, namely, lack of normal lateralisation leading to visceral symmetry.
Others had also emphasised this symmetry, with note taken of isomerism of the right atrial appendages and sinus nodes in patients having absence of the spleen, 10 and bilateral left-sidedness in patients with multiple spleens. 11 Despite such long-standing recognition of isomerism of the organs and atriums as the essence of these malformations, others had argued that the concept of isomerism had no scientific foundation, 12 and continued to stratify the cardiac malformations found in these settings under the headings of asplenia and polysplenia, grouping them together as situs ambiguus. 13 This approach is less than ideal at a time when most centres dealing with congenital cardiac disease use a sequential segmental approach to diagnosis, a form of analysis which must start with accurate identification of the arrangement of the atrial chambers. When the essence of the malformations is isomerism, rather than lateralisation, of the atrial appendages, there is nothing ambiguous, or uncertain, concerning the atrial morphology. In terms of the scientific rigour, it is also the case that molecular advances have made it possible to generate knock-out mice with unequivocal isomerism of the atrial appendages. 14 We urge strongly, therefore, that the term situs ambiguus be abandoned, even though a definition for the entity was suggested by the International Working Group dealing with nomenclature. 7
We find it difficult to understand why so many authors continued to use the terms asplenia and polysplenia to characterise the congenital anomalies of this group of patients. For the cardiologist, it is hard to believe that knowledge of the state of the spleen, even recognising the risk of overwhelming sepsis in its absence, takes precedence over precise description of the complex cardiac malformations. When the cardiac malformations were first emphasised as a feature of patients having congenital absence of the spleen, a sequential segmental approach to the description of congenitally malformed hearts had yet to be developed. At that time, a short, but limited, diagnostic label, such as asplenia syndrome, sufficed to describe a condition then considered prognostically hopeless. These labels now surely seem obsolete for the fundamental description of the complex cardiac malformations associated with abnormalities of lateralisation. Furthermore, discordance between splenic status and the arrangement of the atrial appendages is far from rare. 5 The first step in the sequential diagnosis of any patient suspected of having congenital cardiac disease is now the identification of bodily and atrial arrangement, irrespective of the state of the spleen. This should be followed by a systematic description of the cardiac malformations, using the principles of sequential segmental analysis (see Chapter 1 ). This approach can include description of the state of the spleen, when pertinent, and listing of other extracardiac anomalies. It simply emphasises that analysis starts within the heart, and is based on the arrangement of the atrial appendages.
As we have already discussed, the background to some of the more complex and confusing terminology used previously to describe the hearts and organs of patients with isomeric atrial appendages was reviewed in the recent report from the International Nomenclature Group. 7 In this respect, it should be noted that the term isomerism has been widely accepted as short-hand for the overall description of hearts with isomeric atrial appendages. The atriums themselves, of course, are not literally isomeric, nor are the appendages identical in all respects. Both atrial appendages, in the setting of visceral heterotaxy, nonetheless, have morphologic features characteristic of either the typical right or left structures. It is this feature that should be used to stratify the syndrome when assessing its cardiac aspects.
ANATOMY
Atrial Anatomy
Structural isomerism, strictly enantiomerism, is seen when entities are mirror-images of each other ( Fig. 22-1 ). In this respect, the usual arrangement of the organs within the body, when compared to its mirror-imaged variant, represents biological enantiomerism ( Fig. 22-2 ). As applied to those with visceral heterotaxy, however, the concept of isomerism implies that the mirror-imaged structures are present in the same individual ( Fig. 22-3 ). Within the heart, it is the atrial appendages, when assessed according to the extent of the pectinate muscles relative to the atrioventricular junctions, 6 which show the enantiomeric features. It should not be thought that the hearts from patients having isomeric right atrial appendages also exhibit bilateral superior and inferior caval veins, along with a coronary sinus draining to each atrium. As we will see, absence of the coronary sinus is a defining feature of those having isomeric right atrial appendages. Nor do hearts with left atrial appendages bilaterally have two normal left atriums, each receiving four pulmonary veins. The presence of isomerism within the atrial segment simply means that there is duplication of those parts of the appendages exhibiting the characteristic anatomical features of rightness or leftness. Emphasis is placed on the appendages because venous connections, vestibular morphology, and septal structure are all variable. For example, the pulmonary veins may be connected to the morphologically right atrium, or to an extracardiac site (see Chapter 24 ). The atrioventricular junction may be absent, as in tricuspid or mitral atresia. Although the atrial septum has typical morphologically right and morphologically left sides, it is not always there. These variable features, therefore, following the precepts established in the morphological method, 4 cannot be used as reliable indicators of morphologically rightness or leftness. Instead, the heart with right isomerism will be characterised by the presence of appendages each having the morphology of the normal right appendage. The uniformly characteristic feature of rightness is the extent of the pectinate muscles around the atrioventricular junctions, so that they meet at the crux ( Fig. 22-4 ). In contrast, in the heart showing left isomerism, each of the appendages will have the characteristic morphology of the normal left appendage, with the pectinate muscles contained within the tubular appendages, the posterior vestibular areas being smooth on both sides, and directly confluent with the venous components ( Fig. 22-5 ). The major morphological features of rightness of the isomeric appendages, as shown in Figure 22-4 , are to be found internally. External features are also usually distinctive. In most hearts, each triangular appendage is separated along its entire border with the smooth‑walled part of the atrium by an extensive groove, marked internally by a prominent terminal crest ( Fig. 22-6 ). Although seen in most cases, this feature is not universally present. Similarly, the external shape of the appendages is usually but not constantly characteristic. Morphologically right appendages are almost always triangular, but the triangle can have a narrow base. It is the extent of the pectinate muscles which is the universal criterion for morphologically rightness on both sides of the atriums (see Fig. 22-4 ).
We have usually found it possible, when examining hearts from patients with left isomerism, to recognise morphologically left appendages bilaterally because of their narrow shape, along with their constricted junction with the smooth‑walled atrial portions ( Fig. 22-7 ). It is the internal characteristics which have again proved to be constant (see Fig. 22-5 ). Although the pectinate ridges may extend more laterally than the constricted junction of appendage and atrium, they are always significantly more limited in their extent than in the morphologically right atrium (compare Figs. 22-4 and 22-5 ). Using the criterion of the extent of the pectinate muscles, we have found it possible uniformly to distinguish morphologically right from left appendages, thus permitting the distinction of isomeric and lateralised arrangements, even when we studied each individual atrium in isolation. 6
The arrangement of the appendages in patients with visceral heterotaxy is usually, but not universally, harmonious with the arrangement of the thoracic organs. Discordance between thoracic and atrial arrangement can also be found in patients with normal hearts, typically in the syndrome of biliary atresia with multiple spleens, bronchial isomerism, but usual atrial arrangement. 15,16 We discuss this discordance, and the arrangement of the other systems of organs, in greater detail in the sections that follow.
Venoatrial Connections
Anomalous venoatrial connections are the rule in patients with isomeric atrial appendages. Although a small proportion of cases have an overall pattern of drainage which can be considered usual, or mirror-imaged, even in these hearts the patterns are never morphologically normal. In each individual, any pattern must be anticipated, but certain features are sufficiently common to permit the differentiation of right and left isomerism. It is the connection of the pulmonary veins which is most reliable in permitting this distinction. In right isomerism, because the pectinate muscles extend to the crux on both sides, the pulmonary venous connections are always anatomically abnormal. Even when all the pulmonary veins connect to one of the morphologically right atrial chambers, be the chamber right- or left-sided, the anatomy is abnormal when compared to the normal connections of the pulmonary veins to the morphologically left atrium. This is because the morphologically left atrium never exhibits pectinate muscles extending to the crux ( Fig. 22-8 ). Most usually, if the pulmonary veins do return to the heart, they make their connection via a fibrous confluence, typically opening centrally ( Fig. 22-9 ). When there are morphologically right appendages bilaterally, therefore, the connections of the pulmonary veins will always be anomalous anatomically, even if the atrium receiving the veins is itself left‑sided. In about half the patients having isomeric right appendages, such semantic pitfalls do not arise, because the pulmonary venous drainage is exclusively to an extracardiac source. The site of anomalous connection is then as varied as when totally anomalous pulmonary venous connection is seen with usual atrial arrangement (see Chapter 24 ). The problems of obstruction within the anomalous pulmonary venous pathway are the same. Indeed, clinical experience suggests that an obstructed supracardiac pathway is more frequent in the setting of right isomerism than in usual arrangement. 17
The other universally constant feature of the venoatrial connections in the presence of isomeric right atrial appendages is absence of the coronary sinus, this channel being a component of the morphologically left atrioventricular junction. When the pectinate muscles extend bilaterally to the crux, there is no room to enclose the sinus within the junctions (see Fig. 22-4 ). It may be anticipated, nonetheless, that some patients with absence of the spleen may possess a coronary sinus, since not all patients with asplenia have isomeric right atrial appendages.
If totally anomalous pulmonary venous connection, together with absence of the coronary sinus, are the distinguishing atrial features of hearts with isomeric right atrial appendages, then it is an anomalous connection of the inferior caval vein which draws attention to the potential presence of isomeric left atrial appendages. Most frequently, the suprarenal segment of the inferior caval vein is totally absent. The abdominal segment of the caval vein continues through the azygos venous system to drain to either the right- or the left-sided superior caval vein ( Fig. 22-10 ). In patients with left isomerism, both accessory venous systems are strictly hemiazygos, since the hemiazygos vein is a morphologically left structure. It is simpler, nonetheless, to describe communication via the azygos venous system, and then to account for the right- or left-sided location of the anomalous venous channel. Although right-sided azygos continuation has been noted in the setting of right isomerism, albeit rarely, 18 continuation through the left-sided azygos veins has been reported only in association with left isomerism, or very rarely, in patients with usual atrial arrangement or mirror-imaged arrangement. In terms of connection of the hepatic veins, a confluent suprahepatic channel was present in one-third of cases with isomeric left atrial appendages in the case material of the Children’s Hospital of Pittsburgh (see Fig. 22-10 ). The presence of separate connection of the hepatic veins, when combined with the relationship of the abdominal great vessels relative to the spine, had been considered a reliable means of distinguishing non-invasively the presence of right and left isomerism. 19 We now know this not to be strictly accurate. It is difficult, if not impossible, to distinguish with certainty cases as having isomerism simply by studying the relationships of the abdominal great vessels to the spine. This is not to detract from the immense value of this feature when used as the initial step in the ultrasonographic assessment of sequential segmental anatomy. 19 When note is taken of the overall connections of the pulmonary veins, the inferior caval vein, and the drainage of the hepatic veins to the atriums, along with the arrangement of the coronary sinus, it should always be possible to distinguish between the right and left forms of isomerism. This is certainly not the case with the connections of the superior caval veins. Bilateral connections to the roofs of the right- and left-sided atriums are frequent in either setting. In those with isomeric left appendages, these connections are anomalous on each side. In those with isomeric right atrial appendages, in contrast, they are anatomically normal, with each caval vein appropriately related to a terminal crest, and with sinus nodes present subepicardially in the bilateral terminal grooves ( Fig. 22-11 ).
The drainage of the veins from the heart itself is also abnormal in both right and left isomerism. This is no more than to be expected in right isomerism since, in the universal absence of the coronary sinus, there is no transverse channel within the atrioventricular groove to collect the venous return from the heart. The variability in termination of the individual cardiac veins is surprising. The veins can terminate directly, take a crooked course for a short distance along the atrioventricular groove, or traverse the atrial wall for some distance before draining into the atrium well away from the atrioventricular groove, often adjacent to the opening of a pulmonary or systemic vein ( Fig. 22-12 ). Such direct, crooked, or distant venous terminations are also to be found in hearts with isomeric left appendages, but a coronary sinus receiving all the coronary venous return is more frequent in cases with left isomerism. 20
Atrial Septum
The degree of atrial septal deficiency also fails positively to discriminate between patients having isomeric right or left atrial appendages. In those with right atrial appendages bilaterally, most frequently there is simply a strand of atrial tissue which spans a common atrial cavity (see Fig. 22-4 ). It is rare to find the atrial septum completely lacking, but in most cases there is, effectively, a common atrium. In about a quarter of cases, the septum is well-formed superiorly in association with an atrioventricular septal defect, while very rarely the septum can be intact, or else the oval foramen be probe patent. An effectively common atrium is to be expected in about one‑half of cases with left isomerism (see Fig. 22-5 ). An atrioventricular septal defect is also present in nearly half, while the septum can be virtually intact in nearly one-fifth.
Atrioventricular Junctions
As with hearts in which the atrial appendages are lateralised, chambers with isomeric appendages can each be connected to their own ventricles, or else the atriums can be connected to only one ventricle. When the atrioventricular connections are biventricular, it is essential also to describe the ventricular topology. This is because there are two patterns to be found, irrespective of whether the isomeric appendages are of right or left morphology. In the first pattern, the right-sided atrium, be it associated with a morphologically right or left appendage, will be connected to the morphologically right ventricle ( Fig. 22-13 A), and the left-sided atrium to the morphologically left ventricle. This ventricular topology is right-handed. In the second arrangement, the right-sided atrial chamber, which again may possess either a morphologically right or left atrial appendage, will be connected to a morphologically left ventricle, and the left-sided atrium will be connected to a morphologically right ventricle. In this second pattern, the ventricular topology is left-handed (see Fig. 22-13 B). When we initially defined such atrioventricular connections, we described them as ambiguous. We now recognise that it is better to describe them as biventricular and mixed (see Fig. 22-13 ), proceeding always to describe the ventricular topology present and, if necessary, any abnormal and unexpected ventricular relationships. Biventricular and mixed atrioventricular connections are much more frequent in the setting of isomeric left atrial appendages, and most of these patients should be anticipated to have right hand pattern ventricular topology.
Univentricular atrioventricular connections, typically with double inlet via a common atrioventricular valve, are significantly more frequent in hearts with right rather than left isomerism. In about one-third of such instances, the univentricular connection will be to a morphologically right ventricle, usually left-sided, but in some it will not be possible to find a second ventricle. The majority of hearts will have double inlet to a dominant morphologically left ventricle, but solitary and indeterminate ventricles are more frequent with isomerism than in any other setting. Absence of the left-sided or right-sided atrioventricular connection is rare, but can be found with any ventricular morphology. Thus, when the atrial appendages are isomeric, any type of univentricular atrioventricular connection must be anticipated, along with any possible ventricular morphology. Fewer hearts with left isomerism have univentricular atrioventricular connections, but the same variability must be expected.
Irrespective of the presence of biventricular or univentricular atrioventricular connections, most hearts with right isomerism have a common atrioventricular junction guarded by a common valve (see Fig. 22-4 ). In autopsy series, the finding of normally located and unobstructed mitral and tricuspid valves is rare. In hearts with double inlet, a common valve is to be expected irrespective of the morphology of the dominant ventricle.
As would be expected, with such a high incidence of atrioventricular septal defects, the ventricular septum in the majority of hearts with biventricular atrioventricular connections is deformed in the anticipated fashion. In the very rare cases with right isomerism but without an atrioventricular septal defect, ventricular septal defects are the rule, and typically are perimembranous or muscular. In those with left isomerism, however, the ventricular septum is more frequently intact, including those having an atrioventricular septal defect with shunting exclusively at atrial level. In all hearts with univentricular atrioventricular connection, be there right or left isomerism, those with incomplete ventricles have interventricular communications as anticipated for the ventricular morphology present (see Chapter 31 ).
Ventriculo-arterial Junctions
Amongst the entire group of hearts with isomeric atrial appendages, there is just as much variability in type and mode of ventriculo-arterial connection, infundibular morphology, and arterial relationships as encountered in congenital cardiac disease as a whole. 21 Certain patterns occur with significantly different frequencies in hearts with isomeric right as opposed to left appendages. Pulmonary obstruction or atresia is significantly more common in association with right than with left isomerism. When there is pulmonary atresia, almost always the pulmonary supply is duct-dependent, although supply through systemic-to-pulmonary collateral arteries can sometimes be found. Obstruction of the left ventricular outflow tract, with aortic coarctation or atresia, is much commoner with left isomerism. Analysis of the ventriculo-arterial junctions as a whole shows significant differences between the two isomeric arrangements. An anterior right-sided aorta, along with subaortic or bilateral infundibulums, is commoner with right isomerism, while concordant ventriculo‑arterial connections are more frequent in left isomerism.
Conduction Tissues
The morphology of the sinus node reflects the arrangement of the atrial appendages. In right isomerism, there are bilateral sinus nodes, each related to the terminal crest and the cavoatrial junction in normal fashion. 10,22 In left isomerism, in contrast, there are no terminal crests, and no right atrial appendages. The sinus node, therefore, cannot occupy its normal position. Indeed, in most hearts studied, it has not proved possible to identify with certainty the sinus node. 22 When a candidate for the sinus node is discovered, it tends to be grossly hypoplastic and located in the atrial wall adjacent to the atrioventricular junctions.
The disposition of the atrioventricular conduction axis reflects both the atrioventricular connection present and the ventricular topology. 22 When there are biventricular atrioventricular connections, the dominant feature is the ventricular topology. An atrioventricular node in its regular position, with a postero-inferior penetrating atrioventricular bundle, is found with right hand topology, the axis of conduction tissue being deviated posteriorly in presence of an atrioventricular septal defect. When there is left hand pattern ventricular topology, there is either an anterior atrioventricular node and the conduction system is found as is typical for congenitally corrected transposition, or else a sling of conduction tissue is present running along the crest of the ventricular septum, producing a connection with two atrioventricular nodes. With univentricular atrioventricular connection, ventricular morphology becomes the dominant feature. When the left ventricle is dominant, the atrioventricular node is found in anterior position, with the bundle varying its relationship to the outflow tract of the left ventricle according to the position of the incomplete right ventricle (see Chapter 31 ). With connection to a dominant right ventricle, the conduction system is normally situated when the incomplete left ventricle is left-sided, but an anterior node or sling may be found when the incomplete left ventricle is right-sided. The atrioventricular conduction tissues are bizarre when there is a solitary and indeterminate ventricle. 22
Cardiac Position
An unusual position of the heart should always alert to the presence of isomerism. As reported in one extensive autopsy series 5 , the heart was left-sided in three-fifths, right-sided in three-tenths, with one-tenth showing a midline arrangement. The location of the heart, and the position of its apex, however, failed to discriminate between right and left isomerism.
Arrangement of the Thoraco-abdominal Organs
Jumbled-up arrangement of the abdominal organs, or visceral heterotaxy, has long been recognised as the hallmark of the splenic syndromes. For some time, a midline liver was also considered a marker, but more recent experience shows this often not to be the case, the abdominal organs not typically being arranged in symmetrical fashion. Our own experience 5 confirms that thoracic isomerism cannot reliably be diagnosed on the basis of the disposition of the abdominal organs, particularly with regard to the morphology of the spleen. Should splenic tissue be absent, this should be documented, since this feature carries connotations for the immune state of the patient. The spleen, nonetheless, whilst expected to be absent in those with right isomerism, can also be absent in those with isomeric left atrial appendages. The arrangement of the remaining abdominal organs is also of significance. A short mesentery can lead to intestinal volvulus, and occurs in right or left isomerism. 8 The pancreas tends to be short or annular only in the presence of left isomerism.
The morphology of the thoracic organs, specifically the bronchial tree, is a much better guide to the presence of isomerism of the atrial appendages. Bilateral long and hyparterial bronchuses are indicative of left isomerism, and bilateral short and eparterial bronchuses of right isomerism, respectively. Not all cases with isomeric atrial appendages have bronchial isomerism. Thus, while examination of the penetrated chest radiograph was considered a useful step in the evaluation of the infant or child suspected of having isomeric atrial appendages, it is now rarely used as a diagnostic tool.
Visceral Symmetry without Isomeric Atrial Appendages
Whilst the focus of this chapter is on isomerism of the atrial appendages, there is increasing evidence to suggest that varying degrees of visceral symmetry may occur in the presence of usual atrial arrangement. Indeed, a symmetrical arrangement of some of the organs appears to occur with significantly greater frequency than does isomerism of the atrial appendages. Abnormal arrangement of the abdominal organs, and pulmonary isomerism, appear to be the most common abnormalities. In our reviews of the autopsy data from Children’s Hospital of Pittsburgh, we noted a number of instances in which a tendency to visceral symmetry occurred with usual atrial arrangement. 16,23 In a genetic analysis of isomerism, a healthy sibling of a proband with right isomerism was noted to have left bronchial isomerism. 24 Abnormal lateralisation, with a tendency to visceral symmetry, can be found, therefore, in patients with structurally normal hearts. These observations have important implications for research into the aetiology of abnormal lateralisation, and for genetic counselling. 25 For the purposes of genetic studies, cases showing any degree of abnormal lateralisation should be distinguished from the normal. External phenotype, and cardiac morphology, is an inadequate indicator of the overall arrangement of the organs. Thus, each system of organs requires individual and specific analysis. It is best to avoid inferring the morphology of one group of organs based on observations in another. At the same time, for these purposes above all, it is necessary to stratify visceral heterotaxy into the subsets of right and left isomerism.
EXTRACARDIAC ANOMALIES
Malformations of the bodily organs, in addition to splenic anomalies and abnormal arrangements, occur with significant frequency in patients with isomeric atrial appendages. 8,9,26–28 The malformations, present in at least one-fifth of cases, included lesions involving the central nervous system, skeletal anomalies, and genitourinary anomalies. Gastrointestinal abnormalities can produce intestinal obstruction, either because of an annular pancreas or fibrous bands, 27 or subsequent to volvulus. 8 Abnormal dilated pulmonary and pleural lymphatics have been described in patients with asplenia syndrome, with the reported changes considered unrelated to any obstruction to pulmonary venous return. 29
A wide range of anomalies is also observed in those having left isomerism. The most specific association between left isomerism, or polysplenia, and anomalies of other organ systems is biliary atresia, with or without hypoplasia or agenesis of the gallbladder. While this finding is seen in some patients with isomeric left atrial appendages, the combination of biliary atresia and multiple spleens often occurs in the setting of a structurally normal heart. 15,16 The fact that many of these patients have usual atrial arrangement does not imply the normal development of left-right asymmetry, since left bronchial and left pulmonary isomerism, intestinal malrotation, and interruption of the suprarenal portion of the inferior caval vein are frequently observed when polysplenia accompanies biliary atresia. 16 Although extracardiac anomalies are common in patients with isomeric atrial appendages, recognisable patterns of malformations that would lead to the designation of a specific syndrome or malformation sequence are rare. 27
ISOMERISM AND CONJOINED TWINNING
There is a fascinating association between conjoined twins and disruption of normal left-right asymmetry. Complex cardiac malformations, and absence of the spleen in one of the twins, have been well described. 27,30–32 The most complex cardiac anomalies are usually, but not always, observed in the right hand twin. Features of left isomerism, in contrast, are rarely observed.
MORPHOGENESIS
Most early studies of the development of the splenic syndromes concentrated their attention upon the spleen. 3,9 While of undoubted value in terms of knowledge of splenic development, this approach does little to clarify the grossly abnormal cardiac development associated with isomerism. Here, as with the analysis of the heart itself, the significant feature is the isomeric nature of the atrial appendages. The significant point from the stance of development is that the apical parts of the ventricles, which confer morphological rightness or leftness, balloon in series from the inlet and outlet parts of the ventricular component of the primary heart tube, while the atrial appendages balloon in parallel from the atrial component (see Chapter 3 ). It is not surprising, therefore, that the isomeric malformation should produce duplication of the atrial appendages, without producing symmetry of the ventricles. The venous malformations are then equally well explained. With bilateral morphologically right atrial appendages, there will be no focus for incorporation of the pulmonary venous component. In normal development, this occurs by lumenisation of the pulmonary vein in the developing mediastinum, the vein using the dorsal mesocardial connection between the heart tube and the body as its entrance to the heart (see Chapter 3 ). These connections are grossly abnormal when both appendages develop with right morphology. The intrapulmonary venous plexuses developing in the mediastinum will, therefore, join up with suitable systemic channels to form totally anomalous connections, or else will connect directly but anomalously to the roof of the atrial chambers. Persistence of the initial bilateral symmetry of the systemic venous tributaries accounts for the usual finding of bilateral superior caval veins and absence of the coronary sinus. The bilateral formation of the terminal crests accounts for the development of bilateral sinus nodes. Since the inferior caval vein is able to drain in normal fashion to the atrial chamber, the hepatic veins will also develop normally.
When both the atrial appendages develop morphologically left characteristics, the pulmonary venous channels can be incorporated into either side of the atrium, accounting for the common finding of bilateral pulmonary venous connections. Because the terminal crest develops from the morphologically right side, the superior caval venous channels will never drain in normal fashion in hearts with left isomerism, and there will be no potential for formation of a normal sinus node. Since the ventricles develop in series, they can form in any fashion as occurs in malformations without isomerism. This is reflected in the variation seen in ventricular morphology. It is not clear why isomerism of the right appendages should more frequently be associated with a univentricular atrioventricular connection, nor with either pulmonary atresia or stenosis.
Much has now been learned concerning the genetic pathways producing these changes, with experiments confirming the reality of isomerism of the atrial appendages. Thus, it is known that cilia in the primitive node create a wave that drives molecules in one specific direction across the cells of the developing embryo, with expression of the gene Nodal mostly confined to the left side. 33 The wave of molecular material produced from the node that influences development of lateralised features is stopped from crossing the midline of the embryo, this process known to be under the influence of the gene Sonic hedgehog 34 Because of this midline barrier, other genes, such as Lefty , and Pitx2 , along with the gene Cited2 , also known to be part of the genetic cascade, 14 have their expression confined to the left side of the body, thus producing the morphologically left characteristics ( Fig. 22-14 ). Knocking out genes such as Pitx2 or Cited2 in mice then produces animals with unequivocal right isomerism ( Fig. 22-15 ), 14,35 while knocking out Sonic hedgehog permits the left-forming genes to occupy the right side of the body, and produces left isomerism 34,36 ( Fig. 22-16 ).
INCIDENCE
It is difficult to calculate precisely the incidence of isomerism. This is because, until recently, the malformation has been described under a bewildering plethora of titles, and has been recognised most frequently at postmortem rather than during life. In the New England survey, 37 95 of the 2251 infants presenting with congenital heart disease had visceral heterotaxy. Another study 38 estimated the incidence at around 1 in 40,000 live births. In a population-based study of all infants born with congenital asplenia in British Columbia, we calculated an incidence for right isomerism of 1 in 22,000 live births. 17 The Baltimore–Washington Infant Study 39 identified heterotaxy as representing 2.3% of congenital cardiac disease seen in infants, giving an incidence of 1 in 9158 live births. In the Active Malformation Surveillance Program at the Brigham and Women’s Hospital, Boston, 40 prevalence of heterotaxy among the offspring of mothers who had planned delivery at that hospital was approximately 1 per 10,000 total births. The degree of potential underestimation of incidence and prevalence given by these studies is difficult to establish. It seems likely that most cases of right isomerism are recognised in infancy because of the presence of severe forms of cyanotic heart disease. Failure to recognise left isomerism is more likely because of the wider range of associated heart disease, including mild forms that may not even warrant surgical intervention. We have observed patients with isomerism of the left atrial appendages with interruption of the inferior caval vein and no other cardiac anomalies. Such patients are unlikely to be identified in life unless extracardiac anomalies, such as biliary atresia, lead to cardiac evaluation. It may be that patients with isomeric atrial appendages represent only the tip of the iceberg of the total population with abnormal lateralisation.
AETIOLOGY
There is compelling evidence that there is no single aetiology responsible for the development of abnormal lateralisation and isomerism. Evidence for causal heterogeneity comes from studies of humans and from animal models. Chromosomal anomalies are only rarely associated with visceral heterotaxy. We found no karyotypic abnormalities among infants with right isomerism and asplenia. 17 In the Baltimore–Washington Infant Study, 1 of 99 infants with heterotaxia had trisomy 13, and two other infants had unspecified chromosomal abnormalities. 39 An association between trisomy 13 and abnormalities of left-right development, nonetheless, has been noted, 41 as had a case of balanced translocation of chromosomes 12 and 13 associated with right isomerism and asplenia. 42 This latter observation suggests that a gene at break points 12q13.1 or 13p13 might be important in development of normal asymmetry. A patient with heterotaxy was also noted to have a new, apparently balanced, reciprocal translocation with breakpoints at 6q21 and 20p13. 43 Because another patient with heterotaxy was previously reported with such a new balanced translocation involving chromosome band 6q21, the authors speculated that a critical gene, or genes, in this region may be important in the development of heterotaxy. Several studies of families also suggest that hereditable single gene defects may be important aetiological factors. 44–46 Probable autosomal dominant inheritance has been described in more than one family. 47,48 Another family with heterotaxy provides clear evidence of X-linked recessive inheritance. 49 Linkage analysis in a second family with this mode of inheritance mapped the abnormal gene or genes to the region Xq24–q27.1. 50 More recently, mutations in the zinc finger transcription factor ZIC3 have been demonstrated to cause at least some cases of X-linked heterotaxy. 51 Molecular cytogenetic investigations in another patient identified a breakpoint spanning a small region on the X chromosome containing the ZIC3 gene. 52 Although distinct anatomical differences of the heart and other organs distinguish patients with left and right isomerism, it is interesting to note that patients have been identified with both right and left isomerism, along with multiple or absent spleens, in several familial cases of visceral heterotaxy. 47,53,54 Anatomical variations, therefore, do not necessarily reflect genetic differences.
At present, we do not know the proportion of cases of human isomerism caused by inheritable single gene defects. The finding of three pairs of siblings in 60 cases of asplenia or polysplenia gives a recurrence risk of just under 5%, 38 which is much too low for simple autosomal recessive transmission, yet much higher than would be predicted from the multi-factorial threshold model. We found no familial cases among 43 examples of congenital asplenia. 17 Others calculated a risk of recurrence of 3% to 4%. 24 Despite this, the Ivemark syndrome is listed as an autosomal recessive condition. 55,56 The lower than expected risk of recurrence is explained in various ways, including causal heterogeneity, low fertility of affected patients, reduced penetrance of some recessive traits, and fetal loss. We observed only one case of right isomerism, nonetheless, amongst 5000 postmortems performed on early fetuses and stillbirths over a 21-year period in British Columbia. 17
While the study of family kindreds may supply important information about modes of human inheritance, animal models, including knock-out and knock-in models, are a more potent tool for studying the molecular pathways that lead to abnormal lateralisation. Fortunately, several animal models of visceral heterotaxy exist, and have been studied in detail. The iv/iv mouse has been studied most comprehensively. 57 This recessive trait was initially considered to be a model of mirror imagery, in which homozygous animals exhibit random lateralisation, with half manifesting mirror-imaged arrangement. 58 Subsequent, more detailed anatomical studies showed that a minority of the affected animals had visceral heterotaxy, with isomerism of the atrial appendages, along with both splenic abnormalities and complex cardiac defects strongly reminiscent of human hearts with isomerism. 59 Other mutations in the mouse, the result of insertion of transgenes, have resulted in abnormalities of lateralisation. Individual inv/inv mice show evidence of isomerism as well as mirror imagery, 60 and the insertional mutation has been mapped to mouse chromosome 4. The legless mice represent another insertional mutation associated with partial deletion of chromosome 12. The genetic defect appears to involve the iv/iv locus. Molecular genetic studies of these models have helped bridge the gap between genetics and our understanding of the molecular pathways involved in normal and abnormal lateralisation, as discussed earlier. Abnormalities in nodal cilia and nodal flow are a common theme in several animal models of abnormal lateralisation with visceral heterotaxy, including the iv/iv and inv/inv models. For more detailed understanding of the molecular pathways involved in abnormal lateralisation, the reader is referred to several excellent reviews. 8,61,62 When the genes involved in lateralisation abnormalities have been fully localised within the mouse genome, analysis of syntenic regions on human chromosomes and studies of affected human kindreds should result in characterisation of the genes involved in human syndromes associated with isomerism and abnormal lateralisation. 63
Other animal studies suggest that non-genetic factors may result in abnormal lateralisation. In the non-obese diabetic mouse, visceral heterotaxy and isomerism of the atrial appendages are frequently seen when diabetes develops early in pregnancy. 64 Retinoic acid has also been reported to cause heterotaxy in rat embryos, 65 and isomerism has been produced in offspring of pregnant rats kept at warm temperatures. 66 At the present time, no specific environmental factors have been implicated in the aetiology of human heterotaxy.
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