The Heterotaxy Syndromes: Asplenia, Polysplenia, and With Normally Formed but Right-Sided Spleen

What are the Heterotaxy Syndromes?

Heterotaxy is derived from two Greek words: heteros, “other,” and taxis, “arrangement.” Hence, heterotaxy is an arrangement of the viscera that is other than normal (situs solitus) or its mirror image (situs inversus).

Although there is now much literature relevant to the understanding of the heterotaxy syndromes(s), from very early in their recognition and delineation, anomalies of the spleen were identified as important markers of these syndromes, namely, congenital asplenia and congenital polysplenia.

Later it was realized that visceral heterotaxy (scrambling of the situs) could also occur with a normally formed spleen. Consequently, the heterotaxy syndromes cannot be satisfactorily designated in terms of asplenia or polysplenia (because the spleen can be normally formed).

Thus, as the title of this chapter indicates, there are three different types of heterotaxy syndrome in terms of the status of the spleen: (1) the heterotaxy syndrome with asplenia; (2) the heterotaxy syndrome with polysplenia; and (3) the heterotaxy syndrome with a normally formed, but often right sided, spleen.

Other efforts have been made to characterize these syndromes in terms of bilateral right-sidedness (right isomerism) and bilateral left-sidedness (left isomerism). The asplenia syndrome was said, as a teaching mnemonic, to have bilateral right-sidedness: a bilaterally symmetrical liver, with a large lobe on both right and left sides; the inferior vena cava (IVC) was almost always intact (not interrupted), this being a right-sided feature; bilateral superior venae cavae (SVCs) (an SVC bilaterally also may be regarded as a bilaterally right-sided feature); the lungs are often bilaterally trilobed; both bronchi frequently eparterial; and both atrial appendages often being abnormally broad and triangular (resembling right atrial appendages bilaterally).

Conversely, the polysplenia syndrome may be regarded as having bilateral left-sidedness (left isomerism) ^, ; the lungs are often bilaterally bilobed; both bronchi are frequently hyparterial; the pulmonary veins may be ipsilateral, with the right veins draining into the right-sided atrium and the left veins draining into the left-sided atrium, suggesting that the left atrium (LA) is present bilaterally; the tips of the atrial appendages are often long and thin, like pointing fingers, resembling left atrial appendages bilaterally; and the gallbladder can be absent (absence of the gallbladder being remembered as a bilaterally left-sided feature because the gallbladder normally is a right-sided structure).

Initially, we thought these were wonderful and helpful mnemonics (memory aids), until we realized that some of our friends and colleagues thought them literal. Some people thought that the right atrium (RA) really could be bilateral, and that the LA also really could be bilateral. It was at this juncture that we started whispering into influential ears that right atrial “isomerism” and left atrial “isomerism” were just memory aids, not accurate anatomy. We were telling any who would listen that bilaterally RAs and bilaterally LAs in fact have never been documented.

Accurately speaking, we said, for the morphologically RA to be bilateral, there would have to be an IVC bilaterally, a coronary sinus bilaterally, a SVC bilaterally, a septum secundum with superior and inferior limbic band bilaterally, and a broad triangular atrial appendage bilaterally. This situation has never been documented in a single human being (conjoined twins excluded).

Accurately speaking, we added, for the morphologically left atrium to be bilateral, there would have to be four pulmonary veins bilaterally, septum primum bilaterally, and a long, thin, finger-like appendage bilaterally. Again, this situation has never been documented in a single human being (conjoined twins excluded).

To their credit, our colleagues listened, pondered, and agreed. However, some of them then retreated from atrial “isomerism” (an untenable position), to atrial appendage isomerism. Again, we whispered in influential ears that this position also is untenable, both factually and conceptually.

Factually, one does not always have a large triangular atrial appendage bilaterally in the asplenia syndrome; nor does one always have a long thin atrial appendage bilaterally in the polysplenia syndrome, as will be documented subsequently.

Conceptually, the idea of partial atrial isomerism—involving the atrial appendages only or the pectinate muscles only—is not isomerism. By analogy, consider the molecules of 0-glucose and L-glucose, which really are isomers. These molecules are isomers because each of the asymmetrical atoms in L-glucose is a mirror-image of the corresponding asymmetrical atoms in 0-glucose. If a molecule had only a few atoms that were mirror images of those in 0-glucose, such a molecule would not be considered a “partial” isomer of 0-glucose. Isomerism must involve the whole structure (the whole atrium, or the whole molecule). Partial isomerism is a contradiction in terms. Isomerism is binary: either it is present or it is not present. Conceptually and logically, isomerism cannot be partial. Or to put in another way, “partial” isomerism (appendages only or pectinate muscles only) is not isomerism.

At a less abstract level, consider a patient with right sided polysplenia. The left-sided IVC was interrupted. A large left-sided azygos vein connected with a left-sided SVC that drained into the left-sided atrium. The suprahepatic segment of the IVC also connected with the left-sided atrium, as did the coronary sinus.

The left-sided atrium had septum secundum’s superior and inferior limbic bands on its septal surface. The right-sided atrium received all of the pulmonary veins, and the septal surface of the right-sided atrium displayed a well-formed septum primum. The appendage of the left-sided atrium was broad, triangular, and anterior, whereas the appendage of the right-sided atrium was long, thin, and posterior.

This case was actually presented to one of us (RVP) at an international symposium in Tokyo. One final detail: The left-sided atrial appendage (that was broad, triangular, and anterior) also had at its tip a long, thin, projecting point.

What was the Atrial Situs?

We replied with no hesitation: situs inversus. But what about the finger-like tip of this right atrial appendage (RAA)? True, this part of the left-sided atrial appendage looks a little “leftish,” but it is not really the left atrial appendage (LAA). (The morphologically LAA was right-sided in this patient with visceroatrial situs inversus.) To insist that this pointed tip of the left-sided atrial appendage really is the LAA would be to state that this morphologically RA is a composite structure consisting mostly of the morphologically RA, but having an atrial appendage tip consisting of morphologically LAA.

Briefly, we think that the latter interpretation is both erroneous and absurd. To insist on LAA isomerism (literally) is to assert that this left-sided morphologically RA really does have the tip of its appendage composed of morphologically LAA myocardium. The assertion that this left-sided atrium really is composed of both right and left atrial myocardium is to say that it is a chimera. (In Greek mythology, Chimera was a fire-breathing female monster usually represented as a composite of a lion, a goat, and a serpent.) We think that such a composite atrium, literally composed of both morphologically right and left atrial myocardium, is highly improbable (and amusing). (We cannot imagine how one could literally have a morphologically RA, with the tip of its appendage composed of morphologically left atrial myocardium. Biologically, we think this is a joke. We hope that you too will see how funny this concept of atrial appendage isomerism really is.)

The foregoing, then, are the main reasons why we are presenting these cases as follows: (1) as the heterotaxy syndromes, because visceral heterotaxy is the only accurate anatomic common denominator (the spleen is not always abnormally formed); and (2) bearing in mind the status of the spleen—asplenia, or polysplenia, or occasionally with a normally formed spleen. Not only do the asplenia and the polysplenia syndromes have statistically significant anatomic differences (as will be shown), but also the clinical importance of the status of the spleen merits emphasis concerning susceptibility to fulminating and rapidly fatal infection by encapsulated gram-negative coliform bacilli during the first 6 months of life and by encapsulated gram-positive bacteria— mainly pneumococcus—thereafter. Another advantage of this approach is avoidance of the assertion that either right or left atrial isomerism or atrial appendage isomerism is present, thereby sidestepping these morphologic anatomic and conceptual errors.

What structures are Involved?

Normally asymmetrical structures are typically involved: bronchi, lungs, liver, stomach, spleen, pancreas, gastrointestinal (GI) tract, IVC, SVC, azygos vein, coronary sinus, pulmonary veins, septum primum, septum secundum, atrioventricular (AV) valves, ventricles, conus arteriosus, great arteries, and the aortic arch. These normally asymmetrical structures do not necessarily become symmetrical in the heterotaxy syndromes, although they often do become less asymmetrical than normal.

What is the Morphologically Right Atrium?

As is presented in Chapter 3 , the key gross anatomic features are the IVC, the ostium of the coronary sinus, the septum secundum (superior and inferior limbic bands), and a large, triangular, anterior atrial appendage.

The key to diagnosing the atrial situs is to figure out which is the morphologically right atrium (RA). The connection of the IVC is a very highly reliable diagnostic marker of the RA. The IVC works even with interruption of the IVC, which is sometimes called absence of the IVC, because the suprahepatic segment of the IVC that connects with and identifies the RA is always present. The ostium of the coronary sinus is not always present; it can be atretic, or unidentifiable (absent), as is frequent with common AV canal because of associated unroofing of the coronary sinus. But when the ostium of the coronary sinus is present, it too is a highly reliable diagnostic marker of the RA, as is the large triangular anterior atrial appendage.

What is the Morphologically Left Atrium?

The morphologically LA is the other atrium, which has a small, finger-like, posterior atrial appendage. Typically (but not always), the LA has a septum primum—the flap valve of the foramen ovale—on its septal surface, and, normally, it receives the pulmonary veins.

When can we not Diagnose the Atrial Situs?

We cannot diagnose the atrial situs with confidence when the IVC and the atrial appendages appear to tell two different stories: for example, when the IVC is right-sided, and the large triangular atrial appendage is left sided, or vice versa. A right-sided IVC suggests visceroatrial situs solitus; but a left-sided morphologically right atrial appendage suggests atrial situs inversus. Which should one believe, the IVC or the appendages? From the scientific standpoint, we are not sure how to answer this question. From the practical hemodynamic standpoint, there is no doubt that the connections of the great veins (e.g., the IVC) are more important than the shape of the atrial appendages.

Consequently, we make the diagnosis of atrial situs ambiguus when we are not sure whether the atrial situs is solitus or inversus. Note that atrial situs ambiguus is not a specific third type of atrial situs. It may be a “scrambled” atrial situs solitus or a “scrambled” atrial situs inversus. Atrial situs ambiguus means nothing more.

Septum Primum Can Be Malpositioned

The septum primum—the flap valve of the foramen ovale—can be displaced into the morphologically LA. Then septum primum can lie to the left of the right pulmonary veins ( Fig. 29.1 ), resulting in partially anomalous pulmonary venous drainage into the RA, also known as ipsilateral pulmonary veins, which are quite frequent in the heterotaxy syndrome with polysplenia. Ipsilateral pulmonary veins means that the pulmonary veins are same-sided (Latin: ipse, “self,” latus, “side”).

The right pulmonary veins drain into the right-sided atrium, and the left pulmonary veins drain into the left-sided atrium. This is part of the mnemonic that characterizes the polysplenia syndrome—“bilateral left-sidedness”: the presence of pulmonary veins entering both atria is somewhat suggestive of a LA bilaterally (not really, but as an aide memoire).

Displacement of the septum primum to the left of the right pulmonary veins is, we think, what produces so-called ipsilateral pulmonary veins. The septum primum can be malaligned further to the left, lying to the left of the left pulmonary veins ( Fig. 29.2 ), resulting in totally anomalous pulmonary venous drainage (TAPVD) into the RA. Such marked leftward malalignment of the septum primum may erroneously suggest a common atrium with a supramitral stenosing membrane (see Fig. 29.2 ).

Understanding of the pathologic anatomy of leftwardly displaced septum primum ( Figs. 29.1 to 29.3 ) suggests its appropriate surgical management: excision of the malaligned septum primum and construction of a normally positioned atrial septum. Malalignment of the septum primum is associated with a newly recognized type of atrial septal defect (ASD): a septum primum malposition ASD. ^15,46,153 Malposition of the septum primum into the morphologically LA is associated with leftward malalignment in visceroatrial situs solitus, and with rightward malalignment in visceroatrial situs inversus.

Whenever the pulmonary veins connect at the atrial level (except with the sinus), we think that the pulmonary veins are normally connected, because the relationships of the pulmonary veins with the sinus venosus are normal. The pulmonary veins connect within a horseshoe of sinus venosus tissue, typically composed of the right horn of the sinus venosus to the right (the medial venous part of the morphologically RA), and the left horn of the sinus venosus to the left and below (the persistent left SVC or the ligament of Marshall to the left, and the coronary sinus below). (The normal development of the sinus venosus and the pulmonary veins is presented diagrammatically in Fig. 29.4 .)

The realization that these partially or totally anomalously draining pulmonary veins are normally connected relative to both the right and left sinus horns, but not relative to the leftwardly malpositioned septum primum, leads us to realize the important distinction that exists between anomalous pulmonary venous drainage and anomalous pulmonary venous connection. In these cases (see Figs. 29.1 and 29.2 ), normally connected pulmonary veins drain anomalously because of malposition of the septum primum into the LA.

From the anatomic standpoint, the septum primum can be clearly seen from the right atrial view, because the superior limbic band of septum secundum is very deficient or absent (see Fig. 29.3 ). Indeed, our understanding of septum primum malposition and its importance began with a question from Dr. Luis Alday of Cordoba, Argentina: In a case of polysplenia with all pulmonary veins draining into the RA, why is the septum primum so well seen from within the right atrium? Normally, the septum primum is well seen only from within the left atrium. This question led to a surprising voyage of discovery.

In our experience, septum primum malposition has occurred predominantly in patients with the heterotaxy syndrome with polysplenia but can occur, rarely, in association with asplenia or with a right-sided but otherwise normally formed spleen.

The following study of the heterotaxy syndromes was first presented in part at the meeting of the American Heart Association in Dallas, Texas, November 8, 1998, and has not been published previously. In the interests of clarity and brevity, the findings are presented mainly in tables and figures ( Table 29.1 )

TABLE 29.1

Material (n = 168)

Status of the Spleen	No. of Patients	% of Series
1. Asplenia	95	57
2. Polysplenia	68	40
3. Right-sided spleen	5	3