Heterotaxy is defined as any arrangement of the body organs that deviates from complete situs solitus with levocardia and dextrocardiac loop (the normal arrangement) or from complete situs inversus with dextrocardia and a levocardiac loop. During development there is a failure to form asymmetry along the left–right axis in the heterotaxy syndrome. In normal development, this asymmetry is first manifested at 2 to 23 days of gestation, with looping of the cardiac tube to the right (Gutgesell, 1990). During this same period, abdominal situs is determined (Chandra, 1974; Gray et al., 1994). The 270-degree counterclockwise rotation of the intestine about the axis of the superior mesenteric artery is completed by 10 weeks. Because looping of the cardiac tube and intestinal rotation both occur during the 4th week of gestation, defects of the cardiac situs are frequently associated with abnormal intestinal rotation. Because development of the heart is dependent on the formation of a normal left–right relationship, heterotaxy is associated with congenital heart disease in the majority of cases (Chandra, 1974; Gutgesell, 1990; Cohen et al., 2007).

There is a spectrum of defects in heterotaxy syndrome, varying from isolated levocardia with abdominal situs inversus or isolated dextrocardia with abdominal situs solitus to total absence of asymmetry along the left–right axis. The most significant forms of heterotaxy syndrome are seen in left isomerism (also known as the polysplenia syndrome) or right isomerism (also known as asplenia syndrome). The term asplenia originated from Ivemark’s (1955) initial description of cardiac malformations associated with congenital asplenia. Moller et al. (1967) subsequently reported another syndrome, also with cardiac and visceral abnormalities, but because it was associated with multiple splenic masses, it was called “polysplenia syndrome.”

Sapire et al. (1986) further described these syndromes in relation to anatomic features of the atria, such as right atrial isomerism (asplenia syndrome) and left atrial isomerism (polysplenia syndrome). This distinction was suggested because the anatomic features of the atria more reliably reflect the visceral abnormalities than does the spleen. Usually asplenia occurs in right atrial isomerism and polysplenia occurs in left atrial isomerism, but discrepancies have been reported (Caruso and Becher, 1979). In addition, each condition has been described with both the presence of a normal spleen (Laman et al., 1967; Landing et al., 1971) and normal cardiac anatomy (Peoples et al., 1983). Left atrial isomerism accounts for most cases of “polysplenia syndrome” (Moller et al., 1967; Van Mierop et al., 1972; Rose et al., 1975; Peoples et al., 1983). Polysplenia is usually manifested as multiple splenic masses along the greater curvature of the stomach. The combined weight of the splenic tissue is approximately equivalent to a normal spleen. Left atrial isomerism usually has absent right-sided organs and bilaterally placed left-sided organs. Left atrial isomerism is usually associated with less severe cardiac anomalies and better survival than right atrial isomerism (Peoples et al., 1983; Sapire et al., 1986).

Left Atrial Isomerism

The organs most involved in left atrial isomerism are the lungs, liver, heart, and intestines. The lungs are symmetric mirror images of the left lung with only two lobes. Each side has left-sided relationships between the pulmonary artery and the mainstem bronchi (Moller et al., 1967). The pulmonary artery courses over and behind the mainstem bronchus on both sides, as in a normal left lung. The bronchi branch in a pattern similar to the left tracheobronchial tree and there is no horizontal minor fissure on the right because there are only two lobes.

The liver usually is abnormal in shape and position and typically has a central globular appearance, as it is symmetric. The gallbladder may be midline, hypoplastic, or absent. In 10% of the cases, biliary anomalies can also be seen (Peoples et al., 1983). Several cases of biliary atresia have been reported in left atrial isomerism (Mayo et al., 1949; Teichberg et al., 1982).

The intestines demonstrate nonrotation or reverse rotation of the midgut loop. The initial 90-degree counterclockwise rotation occurs, but the final 180-degree rotation about the superior mesenteric artery does not occur. The result is that the small intestine is on the right side of the abdomen and the colon is on the left. In severe reverse rotation, the midgut rotates clockwise instead of counterclockwise. The result is that the duodenum lies inferior to the superior mesenteric artery and the transverse colon behind it. These rotational abnormalities are prone to proximal intestinal obstruction or midgut volvulus.

Cardiac anomalies in the left atrial isomerism can occur at every level of the heart (Moller et al., 1967; Van Mierop et al., 1972; Rose et al., 1975; Tommasi et al., 1981; Peoples et al., 1983). In 50% of the cases, there are bilateral venae cavae connecting to the superior posterior aspect of the ipsilateral atrium. In rare cases, a single superior vena cava (SVC) connects to the coronary sinus, but the coronary sinus is usually absent. In 65% of the cases, the intrahepatic inferior vena cava (IVC) is interrupted. The IVC above the renal veins connects to the azygous system. The hepatic veins connect directly to the floor of the atrium. Anomalous pulmonary venous return occurs in 40% of the patients (Ware et al., 2004). This is usually partial, with the veins from each lung entering the ipsilateral atrium on the opposite sides of the midline. The atria each show features of the left atrium with a long narrow atrial appendage. The atrial septum is usually absent, with an ostium primum defect in 65% of the cases.

Peoples et al. (1983) reviewed the ventricular anatomy of 127 cases of left atrial isomerism and found that in 38 the ventricular septum was intact, in 80 a ventricular septal defect (VSD) was present, and in 9 there was a univentricular heart. The VSD was either a form of endocardial cushion defect or a VSD in one of the typical locations. The atrioventricular connection is ambiguous through either a common or two-leaflet valve (Tommasi et al., 1981). In a univentricular heart, there is usually a double inlet ventricle to a chamber of right or left ventricular morphology.

The great vessels in the left atrial isomerism are concordant in 69% (Peoples et al., 1983). The remainder are equally divided between discordant atrioventricular connection and double outlet ventricle (usually of the right, but sometimes double outlet left ventricle can be seen). In 20% of the cases, the side of the aortic arch is opposite the side of the cardiac apex.

The pulmonary valve of the right ventricular outflow area is normal in 65% of the cases. In the remaining cases, the pulmonic valve is stenotic (20%) or atretic (10%) with isolated subpulmonic stenosis in the remainder. In the left side of the heart, Peoples et al. (1983) found obstructive lesions in 22% of cases. These included valvular or subvalvular aortic stenosis (11 cases), coarctation of the aorta (7), hypoplastic left heart, hypoplastic left ventricle (6), mitral stenosis (3), and cor triatriatum (1).

Right Atrial Isomerism

The asplenia syndrome is now best described, in terms of the visceral asymmetry, as right atrial isomerism. Although most patients will lack a spleen, some patients will have a normal spleen or multiple spleens. These patients usually come to the attention of a pediatric cardiologist early in life, secondary to severe associated congenital heart disease. Although historically 90% of the patients with the asplenia syndrome died by 1 year of age, survival has significantly improved due to advances in cardiac diagnosis, the use of prostaglandin E₁ in duct-dependent lesions, and improvements in cardiac surgery (Ivemark, 1955; Van Mierop et al., 1972; Chang et al., 1993).

In right atrial isomerism, there are multiple visceral abnormalities that affect the heart, lungs, liver, and gastrointestinal tract. The lungs are both trilobed and the pulmonary arterial relationships with the tracheobronchial tree may be obscured by proximal pulmonary atresia. The lungs often derive significant blood flow from systemic vessels. The liver occupies a central position in the upper abdomen with the globular transverse lie.

Some take exception to the concept of atrial isomerism in heterotaxy (Van Praagh, 1985; Van Praagh and Van Praagh, 1990). Van Praagh has written that the concept of atrial isomerism is conceptually and anatomically flawed, as the atrial appendages are not mirror images of each other. The heart is organized initially as a cephalocaudally oriented blood vessel. In contrast to other viscera, in the heart left–right organization is not initially present in the embryo but is acquired later in development. This group suggested criteria to define the morphologic right atrium as one that receives: (1) all of the systemic veins, while a separate atrium receives all of the pulmonary veins; or (2) all of the systemic veins and some or all of the pulmonary veins, without losing a common atrium because a second atrium is present; or (3) the orifice of a normal coronary sinus. In contrast, the morphologically left atrium can be defined as the atrium that receives: (1) all or half of the pulmonary veins, but none of the systemic veins (except for a persistent SVC associated with an unroofed coronary sinus in cases with bilateral SVC); or (2) none of the pulmonary veins and none of the systemic veins. In addition, the left atrial appendage is usually smaller and more posterior than the right atrial appendage.

It is difficult to estimate the incidence of heterotaxy, because birth defect registries track each anomaly separately. A recent study with strict diagnostic criteria estimated the prevalence of heterotaxy to be 1 in 10,000 birth (Lin et al., 2000). The observed male-to-female ratio is 2 to 1. Overall, heterotaxy account for 3% of cases of congenital heart disease (Ware et al., 2004).

Accurate prenatal diagnosis in heterotaxy is not only possible but offers the advantage of assisting postnatal management (Allan et al., 1994; Copel et al., 1997; Lin et al., 2002; Taketazu et al., 2006).