Introduction It has long been recognized that congenital absence of the spleen, or the presence of multiple spleens, is associated with severe congenital malformations of the heart.1 Some of the most complex forms of congenital cardiac disease are associated with these splenic abnormalities 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 More importantly, they need to be described in unambiguous fashion to the surgeon attempting correction or palliation Description of the so-called “splenic syndromes,” however, continues to be 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 morphologic method.2 When considering the atriums, it is the appendage that is most constantly present (see Chapter 1) The presence of isomeric atrial appendages is the most accurate feature with which to stratify the patients previously labeled as having “splenic syndromes,” or more recently as having either “situs ambiguous,” or “visceral heterotaxy.”3–5 To set the scene for clarification, we begin this account by reviewing some of the historical landmarks in the recognition of the cardiac malformations seen in the syndromes We then seek to clarify some of the confusing nomenclature that has evolved over the last few decades We then describe in detail the morphologic and clinical features of these cardiac malformations, taking advantage of our own extensive recent researches, correlating the cardiac features with the findings within the other systems of organs We then focus attention on the progress made in recent years in the diagnosis and treatment of patients with these complex malformations Historical Notes and Definitions Absence of the spleen is an obvious autopsy finding It is unlikely to be missed, and was noted as long ago as the 16th century, but very likely as the consequence of tuberculous infection The earliest recorded examples of congenital absence are probably those appearing in 1826 Multiple spleens occurring as a congenital malformation had been recorded over 30 years previously These early accounts recognized not only the splenic anomalies, but also the abnormal arrangements of other organs, including the cardiac malformations Over recent 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 involved patients differs from both the usual arrangement, or “situs solitus,” and its mirror-imaged variant, typically described as “situs inversus.” It is of note that in his classical description, Ivemark introduced the phrase “asplenia, a teratologic syndrome of visceral symmetry.”1 Shortly after, Putschar and Mannion, 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 biologic isomerism that is the essence of the “splenic syndromes.”6 This fact is the more surprising, since note had been taken not only of isomerism of the right atrial appendages and sinus nodes in patients having absence of the spleen, but also the obvious bilateral left sidedness in patients with multiple spleens.7 The approach in which the cardiac malformations continue to be grouped under the headings of “asplenia” and “polysplenia” by some, within an overall grouping of “situs ambiguous,” is less than ideal at a time when most centers dealing with congenital cardiac disease use a sequential segmental approach to diagnosis.7,8 Such analysis, of necessity, must start with accurate identification of the arrangement of the atrial chambers When the essence of the malformations is now proven to be isomerism, rather than lateralization, of the atrial appendages, there is nothing ambiguous, or uncertain, concerning the atrial morphology In terms of the scientific rigor, it is also the case that molecular advances have made it possible to generate knockout mice with unequivocal isomerism of the atrial appendages.9 We see no reason for continuing to use “situs ambiguous,” even though a definition for the entity was suggested by the international working group dealing with nomenclature.5 We recognize that isomerism is not uniformly present Indeed, it is the case that only the thoracic organs show evidence of isomerism Providing each system of organs is described separately, all questions of ambiguity are removed by accurate description