INTRODUCTION — Heterotaxy, also referred to as isomerism of the atrial appendages, is defined as an abnormal assembly of the thoracic and abdominal organs from the normal arrangement known as "situs solitus." It is caused by disruption of left-right axis orientation during early embryonic development. Cardiac malformations are a major component of heterotaxy syndrome and can be associated with considerable morbidity and mortality.
Abnormal cardiac development typically leads to atrial appendage isomerism, resulting in either bilateral paired right atria (right atrial isomerism) or paired left atria (left atrial isomerism).
This topic will review the anatomical variation, clinical manifestations, and diagnosis of heterotaxy (isomerism). The management and outcome of patients with heterotaxy are discussed separately. (See "Heterotaxy (isomerism of the atrial appendages): Management and outcome".)
Heterotaxy — Heterotaxy, derived from Greek (hetero, meaning "different," and taxy, meaning "arrangement"), is also referred to as visceral heterotaxy or heterotaxy syndrome. It is defined as an abnormal arrangement of the internal thoracic-abdominal organs across the left-right axis of the body. Patients with heterotaxy have been historically stratified into either the subsets of asplenia syndrome or polysplenia syndrome [1-3]. However, this classification is not useful in describing the cardiac malformations associated with heterotaxy.
Isomerism — In patients with heterotaxy, the normal asymmetry of the thoracic and abdominal organs is lost, resulting in an unusual degree of symmetry of organs and veins. The term "isomerism," derived from Greek (iso, meaning "equal," and meros, meaning "part"), refers to this abnormal developmental symmetry in which morphologic structures that normally develop on one side are found on both sides of the body and is the currently accepted term used to describe hearts with isomeric atria and atrial appendages . So, in affected patients, instead of distinct left and right sides, individuals with isomerism will have either two right sides or two left sides resulting in either two right atria or two left atria (atrial isomerism) . Atrial isomerism is a major component of heterotaxy and causes significant morbidity and mortality because of discordance among the heart, systemic and pulmonary vessels, and other organs, and also among components of the heart.
Right atrial appendage isomerism, also referred to as right atrial isomerism (RAI), results in two right sides with bilateral right atria and atrial appendages and an absence of left-sided structures (eg, coronary sinus). These patients usually have pulmonary venous anomalies, such as anomalous pulmonary venous connections or small pulmonary veins. Single ventricle physiology is predominant in RAI. These patients also typically have asplenia, as the spleen is a left-side abdominal organ. (See 'Right atrial isomerism' below.)
Left atrial appendage isomerism, also referred to as left atrial isomerism (LAI), results in two left sides with bilateral left atria and atrial appendages. In these cases, systemic venous abnormalities, such as interruption of the inferior vena cava, are common. The cardiac anatomy is more variable in LAI than in RAI. Polysplenia also occurs more often, as left-sided organs are more frequently duplicated in patients with LAI. (See 'Left atrial isomerism' below.)
EMBRYOLOGY AND ANATOMY
Visceral arrangement (situs) — The arrangement of the viscera and atria in the first weeks of gestation results in one of three arrangements of the abdominal and thoracic organs:
●Situs solitus – Normal asymmetrical arrangement of abdominal and thoracic organs and vessels with unique right and left concordant structures including a right-sided liver, left-sided stomach, right-sided inferior vena cava (IVC) that flows into the right atrium (RA), and right- and left-sided atrial morphology.
●Situs inversus – The mirror image of situs solitus, in which there is a reversal of placement of the abdominal and thoracic structures resulting in a left-sided liver, right-sided stomach, left-sided IVC, right atria on the left side, and the left atria on the right side. With this arrangement, concordance among organs, vessels, and cardiac components is generally conserved.
●Situs ambiguus – Situs ambiguus is defined as abnormal arrangements of abdominal and thoracic organs that do not include situs inversus. Most cases of situs ambiguus are due to heterotaxy. In these patients, disruption of the left and right axis differentiation occurs in early development, resulting in a variety of cardiac and noncardiac anomalies. This results in different combinations of defects between patients with right versus left atrial isomerisms (table 1). These patients may have significant complications because of discordance among the heart, systemic and pulmonary vessels, and other organs.
Whenever heterotaxy is diagnosed, it is important to independently assess the arrangement of each organ system [6,7]. In a study of 114 children with heterotaxy who underwent evaluation with computed tomography and magnetic resonance imaging (MRI), >20 percent were found to have discordance between bronchopulmonary branching, atrial appendage arrangement, and splenic status .
The heart's position in the thorax and the direction in which the apex points (rightward versus leftward) do not correlate with the isomerism of any particular side. However, a malpositioned heart should always alert the clinician to the possibility that isomerism might be present. Overall, in heterotaxy, 50 to 70 percent of the patients have levocardia, 25 to 50 percent have dextrocardia, and 5 to 10 percent have mesocardia [8-16].
Cardiac — The heart is divided into three embryonic anatomical segments:
●Viscera and atria, which form the atria, including the atria septa, and systemic (superior and inferior vena cava) and pulmonary venous returns
●Ventricular loop, which forms the ventricles, including the ventricular septa
●Truncus arteriosus, which forms the main pulmonary artery and aorta
These segments are connected by two junctional cardiac segments (the atrioventricular [AV] canal and the infundibulum [also referred to as the conus arteriosus]). In normal development, the anatomic segments develop into unique right and left concordant structures (eg, morphologic RA aligned with the right ventricle [RV]) that are connected through the junctional (connecting) segments (figure 1).
In patients with heterotaxy, the early disruption of cardiac development typically causes right or left atrial isomerism, which often results in discordance among cardiac segments. Thus, systemic and pulmonary venous returns and ventricles are not reliably aligned with the morphologically correct atrium, resulting in the clinical features of the anatomic variants of heterotaxy. Although any pattern of cardiac defects can be seen, particular combinations of anatomic lesions of various cardiac segments are commonly observed, which differentiate right and left isomerism, as discussed in the following sections (table 1).
Right atrial isomerism — Right atrial isomerism (RAI) results in two right sides with bilateral right atria and atrial appendages, and an absence of left-sided structures, such as the coronary sinus. In general, patients with RAI have a consistent pattern of cardiac lesions that include anomalous pulmonary venous drainage, which often results in some degree of pulmonary outflow tract obstruction, and single ventricle physiology. The combination of the following anatomic features results in significant right-to-left shunting and cyanosis. (See 'Clinical features' below.)
●Atrial anatomy – In cases of RAI, there are two broad-based appendages with a terminal crest (crista terminalis). In addition, the atrial septum is typically absent and there are large primum and secundum defects separated by a thin muscular strand [8,9].
●Systemic and pulmonary venous returns – The coronary sinus (left-sided structure) is often absent. In addition, bilateral superior venae cavae (SVCs) occur in 50 to 80 percent of the patients, but it is rare to encounter interruption of the IVC in RAI [10,17]. In contrast, interruption of the IVC is a characteristic finding of left atrial isomerism (LAI).
In patients with RAI, pulmonary venous return typically drains to extracardiac structures due to the absence of the left atria, mainly to the SVC and the portal system. This occurs in 60 to 87 percent of patients with RAI [8,9,14,15,18,19]. Approximately one-half of these anomalous pulmonary veins become obstructed.
●AV junction and ventricles – The AV valve is almost always a complete AV canal type and there are rarely two separate AV rings (image 1) [20-22]. Complete AV canal defect generally occurs in RAI but can also be seen less frequently in cases of LAI. The AV valve commonly tends to be thickened, with rudimentary leaflets, deformed papillary muscles, and abnormal chordal attachments [23,24]. The inlet septum is hypoplastic with a large inlet ventricular septal defect (VSD). Patients with RAI usually have single RV morphology with a hypoplastic left ventricle (LV) [9,10,14,18,25]. Single left and biventricular morphologies are also seen.
Normal D-looping of the ventricles, in which the morphologic RV is on the right side of the patient and the morphologic LV is on the left side of the patient, occurs in 62 to 78 percent of patients with RAI [26,27]. The remaining patients have L-looping of the ventricles with the RV on the left side and vice versa. As with normal hearts, patients with heterotaxy have a subpulmonary conus and aortomitral continuity [12,28].
●Great arteries and semilunar valves – Approximately 85 percent of patients with RAI have significant pulmonary artery stenosis or atresia. In neonates with either critical pulmonary stenosis or pulmonary atresia, survival is dependent on pulmonary blood flow through a patent ductus arteriosus. (See "Pulmonary atresia with intact ventricular septum (PA/IVS)" and "Pulmonic stenosis in infants and children: Clinical manifestations and diagnosis", section on 'Severe and critical pulmonic stenosis'.)
The ventricle is most often of univentricular morphology and has either a single or a double outlet with discordant connections in more than 90 percent of cases [8-10,13,14,18,25]. An anterior right-sided aortic valve with subaortic or bilateral infundibulum is most often seen.
Left atrial isomerism — LAI results in bilateral left atria and atrial appendages. The characteristic cardiac lesion in LAI is an interrupted IVC because the two morphologic left atria usually do not have an IVC connection. Otherwise, there is greater variability of cardiac anomalies in LAI compared with RAI.
●Atrial anatomy – In patients with LAI, the atrial septum anatomy is highly variable: from an intact septum with a fossa ovalis to a common atrium with no septum [8,9].
●Systemic and pulmonary venous returns – The coronary sinus is absent in only 30 to 55 percent of patients, and 40 to 50 percent have bilateral SVCs [11,12]. The characteristic anatomic feature of an interrupted IVC occurs in 80 percent of patients, who have subsequent drainage of the interrupted IVC into the azygos vein and, from there, to the atrium via the SVC [2,8,9,12,13].
Partial pulmonary anomalous return is observed in approximately 50 percent of cases with drainage of the pulmonary veins into the ipsilateral atrium since the pulmonary veins tend to drain into the morphologic left atrium. (See "Partial anomalous pulmonary venous return".)
●AV junction and ventricles – Approximately 50 percent of patients with LAI have a common AV valve [8,9,11-13,15]. Atresia, or absence, of an inlet septum occurs in approximately 10 percent of patients . Only one-third of patients have an intact ventricular septum, with the rest having an isolated VSD or a VSD that is part of an AV canal defect [8,12,13,15,18]. Normal D-looping occurs in 70 to 88 percent of cases with LAI [26,27]. As is true for normal hearts and RAI, patients with LAI also have a subpulmonary conus and aortomitral continuity [12,28].
●Great arteries and semilunar valves – Pulmonary stenosis or atresia is much less common in LAI than in RAI, occurring in approximately 20 percent of cases. Left-sided obstruction, including aortic atresia or coarctation of the aorta, has been reported in 20 to 45 percent of cases with LAI. Concordant connections are more frequent between the ventricles and great vessels than in patients with RAI, occurring in 40 to 64 percent of cases of LAI. Discordant connections occur in 16 percent, and double outlet ventricles occur in 15 to 37 percent [2,8,9,11-13,15,16,18,29].
Conduction tissues — In patients with heterotaxy, sinus node and AV node abnormalities occur, as well as propagation of electrical depolarization through the ventricles because of conduction tissue defects. (See "ECG tutorial: Physiology of the conduction system".)
When isomerism of the atrial appendages is present, the sinus node may either be duplicated (RAI) or absent/hypoplastic (LAI) (figure 2) [15,16,30,31]. As a result, patients with LAI are more susceptible to "sinus node dysfunction," atrial fibrillation, and atrial flutter . In systematic review including 36 observational studies of patients with heterotaxy, those with RAI were found to be more likely to have atrial flutter, atrial tachycardia, junctional tachycardia, and ventricular tachycardia; and those with LAI were more likely to have atrioventricular block, intraventricular conduction delay, sinus node dysfunction, and atrioventricular nodal reentry tachycardia .
The anatomy and function of the AV node and the bundle of His depend on the ventricular topology and the AV connection. In D-looped ventricles, the AV node is in its usual position unless there is an AV septal defect, in which case the AV node will be displaced posteroinferiorly. In L-looped ventricles, the AV node position will be either anterior or both anterior and posterior, and connected by a sling of tissue, resulting in a tenuous connection prone to the development of AV block [30,34,35]. It is not clear why complete heart block is more common in LAI, as the incidence of L-looping is roughly equal between LAI and RAI.
Indeterminate univentricular connections will yield unconventional and bizarre AV conduction pathways . When attempting to map and ablate arrhythmias in these patients, special challenges arise, such as problematic access to the atria. For example, in neonates with an interrupted IVC, transvenous access to the atria can only be achieved through neck vessels . In addition, normal conduction tissue may be present with AV discordance. Technical advances in cardiac catheterization have resulted in successful ablation in patients with AV discordance .
Bronchial tree and lung — Normally (situs solitus), lung lobulation is asymmetrical with trilobulation on the right and bilobulation on the left. In addition, the right mainstem bronchus has a short course from the carina to its first branch (right upper lobar bronchus), which is located above the right pulmonary artery (eparterial bronchus), whereas the left bronchus has a longer course from the carina below the left pulmonary artery (hyparterial bronchus) to its bifurcation.
In patients with atrial isomerism, one would anticipate concordance between cardiac and pulmonary defects, so that patients with RAI would be expected to have symmetrical trilobed lungs with bilateral short eparterial bronchi, and those with LAI would have symmetrical bilobed lungs with bilateral longer hyparterial bronchi (figure 3 and figure 4 and figure 5). However, a postmortem autopsy series of 56 cases of heterotaxy, which assessed features of bronchial and lung situs, found a minority, but significant number, of cases of discordance between cardiac and pulmonary morphology as follows :
●Lung lobation, concordance in 40 of 56 cases (71 percent); there were six additional cases of extra lobes
●Length of the bronchi, concordance in 43 of 56 cases (77 percent)
●Ratio of right/left bronchi, concordance in 47 of 56 cases (84 percent)
●Bronchial to pulmonary relationship (eparterial versus hyparterial bronchus), concordance in 54 of 56 cases (93 percent)
●Number of branch pulmonary artery cartilages, concordance in 36 of 56 cases (64 percent)
However, bronchial tree isomerism and discordance with atrial morphology typically do not have any significant clinical implications .
Abdominal organs — Patients with heterotaxy may display right- or left-sidedness of the abdominal organs including the liver, stomach, and spleen, which may impact clinical findings and evaluation. (See 'Noncardiac' below and 'Noncardiac evaluation' below.)
Spleen — The embryologic spleen forms in the dorsal mesogastrium resulting in the normal location of a single spleen at the greater curvature of the stomach. However, in patients with heterotaxy, normal splenic development is almost always disrupted.
●Absence of the spleen is most often seen in RAI (asplenia) with occasional reports of a hypoplastic spleen; splenic function is usually absent [38-40].
●In LAI, approximately 90 percent of patients have more than one splenic mass (polysplenia). However, in a smaller proportion of patients with LAI, the spleen is normal and single.
It is important to stress that the terms asplenia and polysplenia are not constant features of RAI and LAI, because there are many instances of discordance between bronchial-atrial arrangement and the status of the spleen. As a result, these terms should only be used after appropriate radiologic and laboratory evaluation have confirmed asplenia or polysplenia . (See 'Splenic function' below.)
Liver — The liver is abnormally symmetrical in most cases of RAI and LAI [1,10,11,40]. Of more important clinical significance is that 10 percent of patients with LAI have biliary tract anomalies, with a majority being extrahepatic biliary atresia with or without hypoplasia or agenesis of the gallbladder [15,42-47]. Conversely, approximately 8 percent of patients with biliary atresia have LAI. In RAI, biliary abnormalities are absent.
Stomach and intestinal tract — Any abnormal position of the stomach within the abdominal cavity should raise the question of isomerism. Although malrotation of the intestines and possible intestinal obstruction occur in both RAI and LAI, one case series of 38 patients from a single center in the United States reported a higher prevalence in patients with RAI . In this series, malrotation was detected in 8 of 18 patients who underwent abdominal exploration; seven malrotations were detected in patients with RAI and one in a patient with LAI. (See 'Intestinal rotation abnormality' below.)
EPIDEMIOLOGY — Among the various kinds of congenital heart disease (CHD), atrial isomerism is rare. It occurs in approximately 1 per 10,000 to 40,000 live births [49-52]. Several case series of fetal electrocardiographic studies report that atrial isomerism accounts for approximately 3 to 6 percent of all CHD [53-56].
Atrial isomerism is the cardiac condition with the highest familial recurrence rate of all cardiovascular malformations . While most cases of isomerism are nonsyndromic, some are related to genetic syndromes and aneuploidies with inheritance being X-linked, autosomal dominant, autosomal recessive, or sporadic [58-60].
PATHOGENESIS — The molecular and cellular mechanisms leading to normal right-left asymmetry have been and remain an extensive area of research [61,62]. Although several gene mutations in left-right patterning have been associated with atrial isomerism, a full understanding of the underlying mechanisms that induce normal human cardiovascular development from left-right patterning signals early in fetal development remains unclear.
Mutations of genes that encode proteins that are components of the TGF-beta pathway have been identified in children with atrial isomerism [63-65]. These genes include NODAL, NKX2-5, CRELD1, LEFTY2, ZIC3, and ACVR2B. Of particular interest, mutations of the ZIC3 gene, which encodes the Zinc finger transcription factor, account for approximately 75 percent of X-linked familial cases and 5 percent of sporadic cases. Some experts in the field suggest that affected males should undergo genetic testing for ZIC3 mutations; if found positive, the relative risk for family recurrence is 50 percent versus 5 to 10 percent for families with a negative result [66-68].
Although not confirmed in humans, animal studies using mice, zebrafish, and rabbits have shown that motile cilia at the embryonic node are crucial for correct left-right patterning [60,61,67,69,70]. Cilia at the embryonic node move in a clockwise rotary motion that causes a leftward nodal flow: the first physical sign of left-right asymmetry. It is thought that this motion generates a gradient that breaks symmetry and provides the left-sided activation of the nodal-signaling cascade. The transmission of these asymmetric signals to the lateral plate mesoderm provokes an asymmetrical increased influx of calcium ion in the sensory cilia cells through the gene product of PKD2. This calcium influx is linked to the activation of the NODAL gene in the left-side perinodal cells of a midline structure (Hensen nodes) at the distal tip of the primitive streak and leads to expression of other gene products including PITX2, LEFTY1, and LEFTY2. Situs-specific morphogenesis is mediated by asymmetric expression of PITX2, which encodes a transcription factor and is regulated by NODAL signaling.
Antenatal presentation — Heterotaxy is among the congenital heart conditions that have the highest detection rate by prenatal echocardiography (movie 1 and movie 2 and movie 3) . Fetal complete heart block, especially in the absence of SS-A and SS-B maternal antibodies, should raise the possibility of left atrial isomerism (LAI) [72-74], whereas the presence of an atrioventricular (AV) canal defect, especially when there is ventricular asymmetry as a result of an unbalanced AV canal, should raise the possibility of right atrial isomerism (RAI). Unbalanced canal is defined as the favoring of the common AV valve for one ventricle over the other, resulting in an unbalance or hypoplasia of the unfavored ventricle. Complete heart block is a poor prognostic indicator in fetuses with heterotaxy.
The survival rate for fetuses with either single ventricle physiology or complete heart block ranges from 50 to 67 percent through the first year of life [54,72,75]. Because of the poor postnatal outcome, prenatal detection has resulted in elective termination.
In a systematic review of 16 observational studies including 647 fetuses with prenatally diagnosed heterotaxy, the mean gestational age at diagnosis ranged from 18 to 29 weeks (22 to 24 weeks in most larger series) . AV canal defect was the most common associated cardiac anomaly both in fetuses with LAI and RAI (present in 59 and 73 percent, respectively). Right ventricular outflow tract obstruction was present in 35 percent of fetuses with LAI and 67 percent of fetuses with RAI. Complete heart block occurred in 27 percent of fetuses with LAI and only 1 percent of those with RAI. Polysplenia was noted in 56 percent of fetuses with LAI; asplenia was noted in 87 percent of fetuses with RAI.
Pregnancy outcomes were as follows :
●Termination of pregnancy – 25 percent for LAI, 33 percent for RAI
●Fetal demise – 7 percent for LAI, 2 percent for RAI
●Live birth – 68 percent for LAI, 65 percent for RAI
●Neonatal death – 11 percent for LAI, 18 percent for RAI
●Late death – 6 percent for LAI, 15 percent for RAI
Among studies reporting surgical outcomes in live-born infants prenatally diagnosed with LAI (three studies; n = 109), 78 percent underwent biventricular repair and 17 percent underwent univentricular repair . Intraoperative/early postoperative mortality was 27 percent. Among studies reporting surgical outcomes in live-born infants with RAI (three studies; n = 62), 7 percent underwent biventricular repair and 93 percent underwent univentricular repair. Intraoperative/early postoperative mortality was 28 percent.
Postnatal presentation and findings — Postnatal findings are highly variable and are based on the wide range of anatomic lesions, which lead to a spectrum of clinical presentations that extend from the asymptomatic newborn with isolated interruption of the inferior vena cava to the gravely ill cyanotic neonate with life-threatening obstructed anomalous pulmonary venous return. In some of these patients, survival is dependent on maintaining patency of the ductus arteriosus.
Cardiac — The primary findings are generally due to cardiac manifestations, which can be grouped based on whether heterotaxy is due to right versus left atrial isomerism.
●RAI – RAI most often presents during the neonatal period with cyanosis due to right-to-left shunting as a result of pulmonary arterial outflow obstruction. These patients may also have increasing respiratory distress from pulmonary congestion secondary to obstructed pulmonary veins. Physical findings may include an increased palpable right-sided heave and a pulmonary ejection murmur.
●LAI – LAI has an even more varied presentation due to a wider range of anatomical findings. Patients with LAI tend to present later in life than do patients with RAI because the degree of pulmonary artery outflow obstruction is of lesser magnitude than that seen in RAI. Tachypnea, when present, is usually secondary to heart failure and not due to pulmonary venous obstruction. The clinical examination is not specific for this group of lesions.
Noncardiac — Noncardiac findings vary and are dependent on specific anatomic lesions, especially those affecting the abdominal organs. They include the following:
●Sepsis – Patients with asplenia and/or hypoplastic spleen are at risk for sepsis . Patients with RAI often will have no spleen or severe splenic hypoplasia, whereas multiple spleens are frequently present in patients with LAI. (See 'Splenic function' below.)
●Jaundice – Jaundice is the presenting symptom of biliary atresia, which occurs in 10 percent of patients with LAI. Conversely, approximately 10 to 15 percent of infants with biliary atresia have laterality malformations, referred to as biliary atresia splenic malformation or "embryonal biliary atresia." (See 'Liver' above and "Biliary atresia".)
●Symptoms of bowel obstruction, such as bilious vomiting – Malrotation of the gut, with possible ensuing volvulus leading to obstruction of the bowel, has been described in patients with either RAI or LAI . (See 'Intestinal rotation abnormality' below.)
●Anal atresia has been reported in patients with RAI.
●Other rarer extracardiac anomalies associated with isomerism of the atrial appendages include :
•RAI has been associated with tracheoesophageal fistula, meningomyelocele, encephalocele, cerebellar agenesis, cleft lip, cleft palate, and horseshoe kidney [78,79]
•LAI has also been rarely associated with esophageal atresia and congenital short pancreas 
•Renal abnormalities have been described in both RAI and LAI [49,78]
•There is a risk for respiratory disease because of airway ciliary dysfunction in both RAI and LAI 
Initial testing — Most patients will undergo initial testing generally performed in cyanotic neonates or in those with evidence of heart failure. This includes pulse oximetry screening, electrocardiogram, and chest radiograph. However, the diagnosis of atrial isomerism is typically made by echocardiography. (See "Approach to cyanosis in the newborn", section on 'Evaluation'.)
Pulse oximetry screening — Pulse oximetry screening detects most neonates with RAI who have a significant right-to-left shunt. However, the amount of right-to-left shunting depends on the degree of pulmonary artery outflow obstruction, and not all affected neonates have appreciable cyanosis. (See "Newborn screening for critical congenital heart disease using pulse oximetry".)
Electrocardiogram — The electrocardiogram is generally abnormal due to anatomic defects of the conduction tissues. For example, sinus node abnormalities are common because patients either have two right or left morphologic atria (figure 2). As a result, patients may have no sinus node, a single sinus node, or two sinus nodes, which may result in ectopic atrial rhythm and/or multiple P wave morphologies in the same patient .
In RAI, the electrocardiogram is usually abnormal, with an inferiorly- and rightward-directed P wave axis in patients with levocardia and leftward-directed P wave axis in those with dextrocardia . The QRS axis is usually superior in those with an AV canal defect. Supraventricular tachycardia has been associated with RAI in up to 25 percent of patients .
In LAI, due to the possible absence of the sinus node, a leftward- and superiorly-directed P wave axis and an ectopic atrial rhythm are often present . As in RAI, the QRS axis is usually superior in those with an AV canal defect.
Complete AV block might also be present in approximately 10 percent of the patients with LAI but is almost never present in patients with RAI [35,83].
Chest radiograph — Chest radiograph is often the first clue to abnormal situs (image 2). Differentiating among normal situs (situs solitus) or abnormal situs (inversus and ambiguus) can be determined by the positions of the heart (levo-, dextro-, or mesocardia), stomach bubble, and bronchi. (See 'Embryology and anatomy' above.)
DIAGNOSIS — The diagnosis of heterotaxy is typically made by echocardiography both in the prenatal and postnatal settings.
Prenatal diagnosis — Isomerism is reliably detected by routine prenatal screening ultrasonography by the discrepancy between stomach location and cardiac apex direction. However, assessment of the atrial appendage morphology is difficult and unreliable because of its size, and standard views do not visualize this cardiac region. Even when cardiac abnormalities are not detected, the presence of abnormal arrangement of the abdominal organs (eg, abnormal stomach location, absent spleen, multiple spleens, and/or a midline liver) should prompt referral for fetal cardiac echocardiography. (See "Congenital heart disease: Prenatal screening, diagnosis, and management".)
Isomerism can be diagnosed accurately by fetal echocardiography . We and others in the field prefer to assess atrial arrangement through a transverse section of the upper abdomen, as it has been shown that there is a close relationship between position of the descending aorta and the great veins with the atrial arrangement at the level of the diaphragm [84-86]. In this view, the aorta and inferior vena cava (IVC) are on the same side of the spine in fetuses with right atrial isomerism (RAI) (movie 3). In contrast, because of the prevalence of an interrupted IVC in cases of left atrial isomerism (LAI), the azygos and hemiazygos veins are prominent and are seen posterior to the aorta and usually midline (movie 1 and movie 2). Both pulmonary and systemic venous abnormalities are often seen in isomerism, although these might be missed in the fetus if there are no major intracardiac clues of isomerism . Other experts have proposed evaluating atrial morphology using a four chamber view .
With technologic advancements, three-dimensional fetal echocardiography may assist in diagnosing complex fetal congenital heart diseases such as heterotaxy in the future . Fetal magnetic resonance imaging (MRI) has been shown to be a useful complementary tool to define cardiac malposition in complex cases . This can inform prenatal counseling and planning.
Postnatal diagnosis — Transthoracic echocardiography is the primary tool for postnatal diagnosis of isomerism [90,91]. As early as 1974, studies showed that echocardiography accurately defined important anatomic relations in patients with cardiac malposition [90,92]. Echocardiography easily differentiates individuals with situs solitus (normal thoracic and abdominal arrangement) (image 3) from those with situs inversus (mirror image of the situs solitus pattern) or those with isomerism, referred to as situs ambiguus (image 4). (See 'Embryology and anatomy' above.)
Right or left isomerism is diagnosed by the abnormal position of the IVC and aorta in the abdomen. In RAI, the aorta and IVC run adjacent and parallel to each other (they are "juxtaposed"), with the aorta posterior to either the right or the left of the spine. In LAI, the aorta is often midline. No normal IVC is seen, but azygos continuation of the IVC courses posterior to the aorta, either to the left or right of the spine (image 4). More rarely, the azygos vein is not visualized and only the midline aorta is seen.
An unbalanced atrioventricular canal defect should raise the suspicion of isomerism (movie 4 and movie 5). The finding of situs solitus on the subcostal imaging (image 3) does not rule out isomerism, and an atrioventricular septal defect with normal situs could be LAI.
Other cardiac imaging modalities — As noted above, other imaging modalities are not typically necessary to make the diagnosis of isomerism. However, they may be used to further delineate anatomical details needed for surgical management decisions or postsurgical intervention.
Magnetic resonance imaging — Cardiac magnetic resonance imaging (CMRI) is used as an adjunct to echocardiography to provide further anatomic details. Some have proposed that CMRI may be superior to echocardiography for looking for pulmonary and systemic venous abnormalities prior to surgical palliation of these patients [93-95].
Cardiac catheterization and angiography — Historically, angiography was used to make the diagnosis and delineate the anatomy in those with suspected isomerism ; however, it is now rarely performed, as less invasive studies, such as echocardiography and CMRI, typically provide the necessary anatomic details needed for surgical intervention. In rare cases, when data from echocardiography or CMRI are insufficient, cardiac catheterization may be performed. As an example, in patients with right atrial isomerism (RAI) and pulmonary atresia, angiocardiography may be needed to assess pulmonary arterial blood supply and pulmonary artery anatomy [97-99]. It may also assist in delineating pulmonary venous connection and degree of obstruction.
If angiography is performed in patients with left atrial isomerism (LAI) with interruption of the inferior vena cava with azygos continuation, a percutaneous approach from the neck may be needed to reach the heart directly and to avoid "looping" the catheter in the azygos vein and superior vena cava.
Angiographic evaluation is often performed after initial surgical palliation in patients with single ventricle physiology who require further surgical intervention. This provides a more complete hemodynamic evaluation and information for planning of future partial and total cavopulmonary connections.
Noncardiac evaluation — Noncardiac evaluation includes evaluation of splenic function in all patients with isomerism. Other assessment is based on symptoms and clinical manifestations of individual patients.
Splenic function — Patients with isomerism, especially RAI, are at risk for overwhelming sepsis because of asplenia or hyposplenia. As a result, in all patients with suspected isomerism, splenic function and number need to be assessed because there are instances of discordance between bronchial-atrial arrangement and splenic status. Anatomical identification of the spleen, or the lack thereof, may be accomplished with multiple imaging modalities such as echocardiography, radionuclide scintigraphy, computed tomography, or MRI. In the absence of splenic function, Howell-Jolly bodies are usually present on a smear of peripheral blood . (See "Clinical features, evaluation, and management of fever in patients with impaired splenic function".)
Biliary tree — In patients with jaundice and isomerism, the biliary anatomy should be assessed, especially in patients with LAI. The diagnosis and evaluation for biliary atresia are discussed separately. (See "Biliary atresia", section on 'Evaluation'.)
Intestinal rotation abnormality — Malrotation of the gut, with possible ensuing volvulus leading to obstruction of the bowel, has been described in both RAI and LAI [42,48]. Patients with signs of obstruction (eg, bilious vomiting) need to be screened by an upper gastrointestinal contrast study to detect intestinal rotation abnormality and midgut volvulus. It remains uncertain whether or not screening asymptomatic patients is beneficial, as there is a high rate of surgical complications after elective surgical correction in asymptomatic patients with malrotation [1,10,15,49,101-110]. This issue is discussed separately. (See "Heterotaxy (isomerism of the atrial appendages): Management and outcome", section on 'Surgical repair for intestinal malrotation'.)
Anal atresia — Neonates with anal atresia need to be referred to a pediatric surgeon and center experienced in managing patients with this congenital anomaly.
Genetic testing — As previously discussed, several gene mutations have been identified in children with atrial isomerism (see 'Pathogenesis' above). In particular, patients with respiratory ciliary dysfunction and heterotaxy are at risk for genetic mutations . Information is available from the National Center for Biotechnology Information (Genetic Testing Registry).
DIFFERENTIAL DIAGNOSIS — The differential diagnosis includes other complex congenital heart conditions (atrioventricular canal). However, these are differentiated from atrial isomerism by echocardiography.
SUMMARY AND RECOMMENDATIONS
●Definition – Heterotaxy, also referred to as isomerism of the atrial appendages, is defined as an abnormal arrangement of the internal thoracic-abdominal organs across the left-right axis of the body. Cardiac malformations are a major component of heterotaxy syndrome and are associated with considerable morbidity and mortality. (See 'Definitions' above.)
●Prevalence – Atrial isomerism is rare, occurring in approximately 1 per 10,000 to 40,000 live births. (See 'Epidemiology' above.)
●Cardiac anatomy – Heterotaxy can involve right or left atrial isomerism (see 'Cardiac' above):
•Right atrial isomerism (RAI) – Right atrial appendage isomerism, also referred to as right atrial isomerism (RAI), results in two right sides with bilateral right atria and atrial appendages and an absence of left-sided structures (eg, coronary sinus). These patients usually have pulmonary venous anomalies, such as anomalous pulmonary venous connections or small pulmonary veins. Single ventricle physiology is predominant in RAI as there are often atrioventricular canal defects. (See 'Right atrial isomerism' above.)
•Left atrial isomerism (LAI) – Left atrial appendage isomerism, also referred to as left atrial isomerism (LAI), results in two left sides with bilateral left atria and atrial appendages. In these cases, systemic venous abnormalities, such as interruption of the inferior vena cava, are common. The cardiac anatomy is more variable in LAI than in RAI. Patients with LAI are more likely to have arrhythmias and/or complete heart block because of the absence of a sinus node, which is located in the right atrium. (See 'Left atrial isomerism' above and 'Conduction tissues' above.)
●Noncardiac anatomy – Patients with heterotaxy display right- or left-sidedness of other thoracic and abdominal organs, which may be discordant from atrial isomerism. (See 'Bronchial tree and lung' above and 'Abdominal organs' above.)
•Splenic abnormalities include asplenia (usually associated with RAI) or polysplenia (usually associated with LAI).
•Biliary atresia is present in approximately 10 percent of patients with LAI. The liver is usually midline and symmetrical in patients with either RAI or LAI.
•Malrotation of the intestines and possible intestinal obstruction occur in both RAI and LAI.
•Prenatal diagnosis – Many affected patients are diagnosed prenatally, as routine antenatal screening ultrasound will usually detect isomerism and fetal echocardiography can accurately confirm the diagnosis. (See 'Antenatal presentation' above and 'Prenatal diagnosis' above and "Congenital heart disease: Prenatal screening, diagnosis, and management".)
•Postnatal presentation – Since the spectrum of anatomic abnormalities in heterotaxy syndrome is highly variable, the presentation can range from an asymptomatic newborn to a gravely ill cyanotic neonate. In general, patients with RAI most often present during the neonatal period with cyanosis and respiratory distress, whereas the presentation of LAI is more varied and includes asymptomatic patients. (See 'Postnatal presentation and findings' above.)
Other noncardiac findings can include (see 'Noncardiac' above):
-Overwhelming sepsis (due to asplenia or hyposplenia)
-Jaundice (due to biliary atresia)
-Bilious vomiting (due to malrotation of the gut)
●Initial evaluation – Initial testing that is generally performed in all neonates who present with cyanosis and/or heart failure includes (see 'Initial testing' above and "Diagnosis and initial management of cyanotic heart disease in the newborn"):
•Pulse oximetry may reveal oxygen desaturation in patients with RAI. (See 'Pulse oximetry screening' above and "Newborn screening for critical congenital heart disease using pulse oximetry".)
•Electrocardiogram may show sinus node abnormalities (eg, ectopic atrial rhythm, abnormal P wave axis, multiple P wave morphologies, or even complete heart block) due to anatomic defects of the conduction system. However, these findings are not diagnostic. (See 'Electrocardiogram' above.)
•Chest radiograph will often show an abnormal position of the heart, stomach bubble, and/or bronchi. (See 'Chest radiograph' above.)
●Diagnosis – The diagnosis of heterotaxy is made by echocardiography, which can be performed prenatally or postnatally. Once the diagnosis is made, further evaluation includes other imaging studies (if echocardiogram did not provide sufficient anatomical detail) and assessment of spleen location, number, and function. Other tests are done based on symptoms and findings for individual patients. (See 'Diagnosis' above and 'Further evaluation' above.)
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