Heterotaxia Isomerism

Summary of Heterotaxia and Isomerism

Heterotaxy syndrome refers to an abnormality of situs or left–right patterning within the body. Structures that are typically asymmetrical are positioned ambiguously. Heterotaxy is frequently associated with congenital heart disease (CHD) and/or arrhythmias. Understanding these complex arrangements is crucial in neonatal cardiovascular care and diagnostic imaging. In the context of heterotaxy, one should rule out primary ciliary dyskinesia. The definition of heterotaxia describes the abnormal disposition of organs of the thorax and abdomen relative to the left-right axis. Fundamentally, heterotaxia involves anomalies of laterality that concern the heart, lungs, bronchi, and intra-abdominal organs. While the term’s strict definition encompasses all laterality issues, in common use, it refers to conditions that are neither situs solitus (normal position) nor complete situs inversus (mirror image of normal). Situs inversus is often excluded from the clinical categorization of heterotaxia because, despite being an abnormal laterality, it usually does not involve associated cardiac pathology (Ref). Heterotaxia highlights a problem with the fundamental process of side determination, and in rare instances, heterotaxia can even occur without any associated cardiac or vascular anomalies. Heterotaxia is characterized as non-binary by nature, representing a combination of anomalies of the right and left sides of the body. Rather than following a mirror-image symmetry or strict normal alignment, the condition may manifest as a random distribution of intra-thoracic and intra-abdominal organs. A practical clinical definition relies on the identification of abnormal asymmetry of certain viscera or normally asymmetric channels (such as the bronchi), or the presence of a discordant situs among various organs and/or cardiac segments. Specifically, heterotaxia is defined by the disharmony between the situs of the atria, the bronchi, and the intra-abdominal organs. For example, a definitive diagnosis of heterotaxia can be made when there is discordance between segments, such as having a situs solitus arrangement of the atria but a situs inversus arrangement of the abdominal organs. Historically, attempts to categorize these highly complex anomalies led to the creation of terms like "right isomerism" and "left isomerism", but these concepts are now considered inaccurate and misleading because there is almost never true isomerism across all abdominal organs, and the corresponding algorithms are incorrect in nearly half of cases.

Situs Abnormalities 

Situs describes the arrangement of internal thoracic and abdominal organs along the left–right axis. It is determined by evaluating abdominal situs, bronchopulmonary situs, and atrial situs. The main types of situs are:

• Situs Solitus: The usual arrangement where the left atrium (LA) and left-sided organs are on the left, and the right atrium (RA) and right-sided organs are on the right.

• Situs Inversus: A mirror-image arrangement where the LA and left-sided organs are on the right, and the RA and right-sided organs are on the left. This usually involves a mirror image of the entire body.

• Heterotaxy (Situs Ambigus): An arrangement that is neither situs solitus nor situs inversus. The position of the atrium, pulmonary artery, bronchus, and abdominal viscera does not follow a regular rule. This is often associated with complex cardiac malformations.

Atrial Isomerism Isomerism is a form of heterotaxy where structures that are normally dissimilar appear bilaterally similar. It is specifically defined by the morphology of the atrial appendages; in isomerism, both the right and left atrial appendages have the same morphology. There are two main types of classic isomerism:

• Right Isomerism (Asplenia Syndrome): Characterized by bilateral morphologic right atrial appendages. This is also known as bilateral right sidedness or Ivemark syndrome. It is usually associated with the absence of the spleen. Previously known as "Ivemark syndrome".

• Left Isomerism (Polysplenia Syndrome): Characterized by bilateral morphologic left atrial appendages. This is also known as bilateral left sidedness. It is usually associated with multiple spleens.

Approximately 20% of heterotaxy cases show mixed or disharmonious patterns that are not classifiable into classic right or left isomerism.

Key Features in Isomerism 

The type of isomerism is inferred from specific anatomical features, often visualized by imaging modalities like echocardiography and CT/MRI.

• Right Isomerism:

  • Atrial Appendages: Bilateral appendages are broad and triangular with wide junctions to the atrium, and extensive pectinate muscles extend around both atrioventricular junctions.

  • Bronchi/Lungs: Bilateral symmetrical right bronchi, resulting in bilateral trilobed lungs. Pulmonary arteries pass into the lungs anterior to the bronchi (bilateral eparterial bronchi).

  • Viscera: Frequently associated with absence of the spleen and a midline liver. The abdominal aorta and inferior vena cava (IVC) are typically located on the same side of the spine (juxtaposition), with the IVC anterior to the aorta. This juxtaposition is observed in about 95% of patients. Bilateral superior vena cava (SVC) is seen in 50–80%, and the coronary sinus is often absent. A common atrium with a characteristic central strand is often seen.

• Left Isomerism:

  • Atrial Appendages: Bilateral appendages are hooked and tube-like with narrow junctions, and the pectinate muscles are limited in extent, not reaching the crux.

  • Bronchi/Lungs: Bilateral symmetrical left bronchi, which are longer before branching, resulting in bilateral bilobed lungs. Main pulmonary arteries pass over the major bronchi (bilateral hyparterial bronchi).

  • Viscera: Characterized by polysplenia. The IVC is typically interrupted with azygos or hemiazygos continuation into the SVC in over 80% of cases. The azygos or hemiazygos vein is usually posterior to the aorta. The liver can be symmetric or asymmetric, and the stomach can be on either side, often closer to the midline. Bilateral SVC is seen in 40–50%. Hepatic veins often connect bilaterally to the atriums. The atrial septum tends to be better formed than in right isomerism.

Associated Cardiac Anomalies 

Congenital heart defects are almost always present in right isomerism (nearly 100%) and in about 75% of left isomerism cases (25% have a normal heart). The cardiac anomalies associated with isomerism are often complex and highly variable.

• Right Isomerism: Typically involves complex CHD.

  • Atrioventricular Septal Defect (AVSD): Very common (70–81%), often complete. Frequently associated with unbalanced ventricles, commonly a large morphologic right ventricle and a hypoplastic morphologic left ventricle, often resulting in a functionally single ventricle.

  • Ventriculo-arterial Connections: Abnormal in 96%, including complete transposition of the great arteries (TGA) or double outlet right ventricle (DORV).

  • Pulmonary Obstruction: Pulmonary stenosis or atresia is very common (often multi-level).

  • Pulmonary Venous Connection: Total anomalous pulmonary venous connection (TAPVC) is common (60–87%), and obstructed TAPVC (up to 25%) portends a worse outcome. Pulmonary vein stenosis is also common.

  • Arrhythmias: Less common than in left isomerism. Bilateral SA nodes may be present, sometimes with different P wave origins, and dual AV nodes are possible, increasing the risk of re-entrant supraventricular tachycardia (SVT).

• Left Isomerism: CHD is typically less severe, and a biventricular repair is commonly possible.

  • AVSD: Common (70%), with partial AVSD being more frequent than complete AVSD.

  • Ventricles: Most patients have two balanced ventricles (90%). Functional single ventricle is much less common (10%).

  • Ventriculo-arterial Connections: Concordant ventriculo-arterial connections are seen in up to 70%. Ventricular outflow tract obstruction is present in two thirds, with pulmonary obstruction in one third and systemic obstruction (like coarctation of the aorta, aortic stenosis, or interrupted aortic arch) in one third. TGA is rare.

  • Pulmonary Venous Connection: TAPVC is rare, while partial anomalous pulmonary venous connection (PAPVC) is common. Pulmonary vein stenosis is rare.

  • Arrhythmias: Common and potentially life-threatening, particularly bradyarrhythmias and complete heart block (CHB). Sinus rhythm is rare due to the absence of the SA node. Ectopic atrial or junctional rhythms are common. CHB occurs in about 40% due to the absence of the AV node. Fetal CHB or bradycardia is a risk factor for poor prognosis.

Associated Non-Cardiac Anomalies 

Extracardiac manifestations are common in heterotaxy, occurring in about 15% of cases with a prenatal diagnosis, and are often more severe with left isomerism. Comprehensive management requires attention to these issues.

• Splenic Abnormalities: Asplenia (right isomerism) or polysplenia (left isomerism) are typical associations. Splenic function must be confirmed but frequently not efficient (even in polysplenia). Patients with asplenia are at high risk for severe bacterial infection, particularly after 6 months of age. Patients with polysplenia generally have no functional splenic abnormality. These patients generally require some degree of antibiotics prophylaxis and adequate adapted vaccination protection. 

• Intestinal Malrotation: Common in both forms of isomerism, but reported as a rule rather than exception in left isomerism. Predisposes to volvulus. However, it is not necessarily recommended to do a systemic upper GI and/or surgical intervention in these patients. 

• Biliary Atresia: Occurs in up to 10–20% of patients with heterotaxy and left isomerism. Parental information should be provided to be sensitive at early signs such as acholic stools. Some centers will obtain a direct biluribin level in the first 2 weeks of life to ascertain no presence of a rise. 

• Pulmonary Anomalies: Bilateral lung lobe morphology (trilobed in right, bilobed in left) corresponding to bronchial anatomy is characteristic. Bilateral tracheal bronchi are relatively common in right isomerism.

• Other: Partial ectopic stomach (hiatal hernia) in up to 15% of right isomerism cases. Extrahepatic portosystemic shunt reported. Primary ciliary dyskinesia in up to 25% of heterotaxy.

Diagnostic Studies 

Accurate diagnosis is essential for appropriate counseling, delivery planning, and postnatal management.

• Fetal Echocardiography: Accurate diagnosis is possible prenatally. It is the gold standard to delineate cardiac position, atrial and ventricular anatomy, connections, and flow patterns. It is crucial for assessing systemic and pulmonary venous anomalies and diagnosing arrhythmias like CHB.

• Neonatal Echocardiography: Remains the gold standard postnatally. Provides detailed assessment of cardiac anatomy, valve function, ventricular function, and shunts. Can infer visceral situs indirectly by evaluating the relationship of the aorta and IVC. Essential for evaluating associated lesions such as AVSDs, outflow tract obstructions, and venous anomalies. Functional echocardiography assesses myocardial function, blood flow (LVO, RVO, SVC flow), and pressure gradients.

• Chest X-ray: Can show dextrocardia (35–40%), cardiomegaly, pulmonary vascular markings, and is particularly useful for demonstrating bronchial anatomy.

• Cross-Sectional Imaging (CT or MRI): Valuable for detailed depiction of complex systemic and pulmonary venous anatomy, bronchial anatomy, and visceral situs, especially when echocardiography views are limited. Used to guide surgical planning.

• Abdominal Ultrasound: Can establish visceral situs and the presence or absence of spleens, and assess for intestinal malrotation.

• Electrocardiography (ECG): Findings vary depending on isomerism type and associated anomalies. Right isomerism may show evidence of bilateral SA nodes. Left isomerism typically shows absent sinus rhythm, ectopic rhythms, and potential for CHB. May show abnormal P wave axis.

• Peripheral Blood Smear: Checks for Howell-Jolly bodies or pitted RBCs to assess splenic function, particularly relevant in suspected asplenia (right isomerism).

Clinical Presentation and Outcomes 

Presentation varies depending on the specific anomalies. Right isomerism often presents with cyanosis. Left isomerism may present early with bradyarrhythmias or CHB. Outcomes for patients with heterotaxy are generally worse than for those with comparable isolated CHD. Overall 25-year survival is around 60%. Right isomerism has a poorer prognosis (50% 25-year survival) compared to left isomerism (75% 25-year survival), especially if early intervention is needed. Risk factors for poor outcomes from birth include right isomerism/asplenia, obstructed pulmonary venous return, complete AVSD, and common AV valve regurgitation. Heterotaxy and isomerism represent a spectrum of complex anatomical variations impacting both cardiac and extracardiac systems. Comprehensive evaluation, heavily relying on echocardiography and other imaging modalities, is essential for accurate diagnosis, risk stratification, and planning of often multidisciplinary care in the neonatal period.

"Isomerism"

The terminology of "isomerism," particularly in the context of complex congenital anomalies known as heterotaxia, is increasingly viewed as an erroneous concept and misleading, serving more as a mnemonic device. Historically, attempts to categorize these complex laterality issues led to the distinction between "right isomerism" (or dextro isomerism) and "left isomerism" (or levo isomerism). This approach relies on algorithms suggesting that structures throughout the body are symmetrically duplicated, such as having all organs of right morphology (e.g., two right-sided lungs/bronchi, widespread pectinate muscles) for "right isomerism". However, the foundational critique is that heterotaxia, by its very nature, is non-binary. It represents a combination of anomalies involving both right and left structures, resulting in a random distribution of organs within the thorax and abdomen. Therefore, relying on "isomerism" to imply an organized, mirror-like symmetry is inaccurate because heterotaxia is defined by a total disorganization (désorganisation totale). The conceptual failure of isomerism is confirmed by empirical data demonstrating that the established diagnostic algorithms are unreliable for describing actual patient anatomy. When investigators classified specimens based on isomerism, they found that nearly half of cases did not respond to the expected algorithms (non-classic forms). Even in cohorts classified as having "classic" isomerism, the criteria failed almost universally. Discordant findings are noted frequently across different organs, with the spleen being described as a highly discordant and unreliable criterion. Furthermore, even fundamental anatomical elements cited to define isomerism, such as the supposed isomerism of the pectinate muscles, are often found to be lateralized (i.e., lacking isomerism) in 18% of cases within one study cohort, leading to the conclusion that heterotaxia is not synonymous with isomerism of the pectinate muscles. Consequently, rather than trying to fit complex anatomy into the simplifying and frequently incorrect "isomerism" categories, the preferred approach is through individual analysis of each segment and organ (see Morphological approach section), specifically noting the disharmony or discordance between the situs of the atria, the bronchi, and the intra-abdominal organs.

• References:

  • Freud LR, Yoo S-J. Heterotaxy and Isomerism. In: Dipchand AI, et al., editors. Manual of Cardiac Care in Children. Springer Nature Switzerland AG; 2024. p. 391-400.

  • Balasubramanian S, Punn R. Dextrocardia and the Heterotaxy Syndromes. In: Alboliras ET, et al., editors. Visual Guide to Neonatal Cardiology. Wiley; 2018. p. 292-296.

  • Rudolph AM. Congenital Diseases of the Heart: Clinical-Physiological Considerations. 3rd ed. Wiley-Blackwell; 2009.

  • Pediatric Electrocardiography. 2016. Axis Abnormalities in Heterotaxy.

  • Vanderlaan RD, Dragulescu A. Total Anomalous Pulmonary Venous Connection. In: Dipchand AI, et al., editors. Manual of Cardiac Care in Children. Springer Nature Switzerland AG; 2024. p. 206-208.

  • Agarwal R, Varghese R, Jesudian V, Moses J. The heterotaxy syndrome: associated congenital heart defects and management. Indian J Thorac Cardiovasc Surg. 2021 Jan;37(Suppl 1):67-81. doi: 10.1007/s12055-020-00935-y. Epub 2020 Mar 27. PMID: 33603285; PMCID: PMC7859150.

  • Buca DIP, Khalil A, Rizzo G, Familiari A, Di Giovanni S, Liberati M, Murgano D, Ricciardulli A, Fanfani F, Scambia G, D'Antonio F. Outcome of prenatally diagnosed fetal heterotaxy: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2018 Mar;51(3):323-330. doi: 10.1002/uog.17546. PMID: 28603940.

  • Les malformations cardiaques peuvent elles se décrire comme des algorithmes by Dr Lucile Houyel - M3C Academy

  • DIU CPC Lucile Houyel Anatomie des cardiopathies congénitales et embryologie 2021

Echocardiography outlining LA isomerism with interrupted IVC with azygous continuation to left SVC

One may appreciate from this view the left SVC draining to the coronary sinus by B-Mode

Subcostal short axis view outlining the absence of a "Bicaval" view . Subhepatic veins are seen connecting to the right atrium, but not the inferior vena cava. 

Interruption of the hepatic IVC. Rerouting of the blood flow to the azygos vein. See with colour.