Heterotaxy syndrome is a rare disorder characterized by abnormal laterality in the body's organs. The incidence is reported to be about 1 in 10,000 live births and accounts for approximately 3% of all congenital heart disease (CHD) but numbers may increase as diagnostic testing improves. Gene loci associated with heterotaxy have been identified and genetic screening should be offered to patients in whom heterotaxy is suspected.

Cardiac Anatomical Diagnosis and Management

The manifestations of cardiac defects may be very severe in infancy. Echocardiography and cross-sectional imaging with computed tomography angiography (CTA) or magnetic resonance imaging (MRI) are often required for comprehensive diagnoses. Though not 100% specific, patients can be categorized into right and left atrial isomerism as their cardiac defects follow the "duplicated"/"missing" atria. In right atrial isomerism, the incidence of associated pulmonary venous abnormalities and tachyarrhythmias are higher, while bradyarrhythmia are more common in cases of left atrial isomerism with absent sinus and AV nodes. These patients are also more likely to have an interrupted inferior vena cava (IVC) with atypical hepatic vein drainage.

Initial management of these neonates ensures unobstructed systemic and pulmonary blood flow. Frequently, these patients have physiologic single ventricle lesions. Unbalanced atrioventricular canal defects with double outlet right ventricle and malposed great vessels are common. For those without systemic blood flow obstruction, initial management is determined by the degree of pulmonary blood flow  ̶  whether the patient is balanced (just the right degree of pulmonary stenosis) or over-circulated, (i.e., requiring pulmonary artery band placement) or too cyanotic (ductal dependent requiring stabilization with prostaglandins [PGE] and provision of a stable source of pulmonary blood flow). Anomalous pulmonary venous return is not uncommon and requires urgent repair if obstructed. Neonates with obstructed pulmonary venous return will be more cyanotic due to elevated pulmonary vascular resistance. Thus, determining the degree of pulmonary stenosis should be based on its anatomical features, and less dependent on the gradient obtained by Doppler echocardiography. Many of these patients have a single right ventricle and canal type atrioventricular valve. These features render them less able to handle excessive pulmonary blood flow, leading to ventricular dilation and progressive atrioventricular valve regurgitation. Care should be taken to ensure adequate afterload reduction and diuresis.

Systemic outflow tract obstruction (aortic stenosis/atresia with or without coarctation of the aorta) is much less frequent in heterotaxy syndrome than stenotic or atretic pulmonary outflow. If present, these patients may need a Norwood type operation. Outcomes are less favorable due to a higher risk of significant atrioventricular valve regurgitation and bradyarrhythmia (preponderance of left atrial isomerism) which are poorly  tolerated in Norwood physiology. Only 3% of patients included in the ongoing Texas Children's Hospital (TCH) series have required a Norwood procedure.

Arrhythmias

Patients with heterotaxy syndrome are prone to arrhythmias.¹ Those with right atrial isomerism often have dual sinus and atrioventricular nodes that can lead to reentrant supraventricular tachycardia. Many also will have atrial suture lines after pulmonary vein repair that places them at risk for atrial tachycardias. Those with left atrial isomerism can present with complete heart block that may need prompt pacing as their associated anatomic cardiac abnormalities may put them at higher risk for early heart failure. Fetuses with complex CHD and complete heart block may present with irreversible, fatal hydrops fetalis.

Infectious Concerns

Patients with heterotaxy syndrome also have other organ system involvement. All patients should be assumed to be functionally, if not anatomically, asplenic. Even those with polysplenia may benefit from prophylactic antibiotics as splenules may be hypofunctional. Patients are especially susceptible to infections with encapsulated organisms. The literature supports prophylactic antibiotics through 5 years of age and immunizations to protect against encapsulated organisms. Some clinicians opt to prolong asplenia prophylaxis beyond childhood.

Gastrointestinal Diagnosis and Management

Initial radiography should be used to evaluate for abdominal situs inversus based on the location of the hepatic mass and stomach bubble. Malrotation is common, and patients should have an upper gastrointestinal (GI) series to confirm this. Our previous practice at TCH was to perform an elective Ladd's procedure on all patients with heterotaxy and malrotation, but this approach had been modified after a review of outcomes and postoperative complications (mainly bowel obstruction) showed that the risk of "prophylactic" surgery exceeded the risk of volvulus.² All patients with abdominal pain or obstructive symptoms, such as protracted vomiting, should be evaluated to rule out volvulus. It is also important to remember that the appendix may not be in the "normal" position and thus the typical right lower quadrant pain of appendicitis may not be seen. Any abdominal pain associated with fever should be worked up for appendicitis and/or volvulus. It is recommended that patients with heterotaxy that have any intra-abdominal surgery have an incidental appendectomy.

Pulmonary Concerns

Bronchial anatomy follows atrial isomerism. Right isomerism is characterized by bilateral tri-lobed lungs and eparterial bronchi, while bilateral bilobed lungs and hyparterial bronchi are seen in left isomerism. Lung anatomy is generally not clinically relevant, but patients with heterotaxy syndrome can have problems with ciliary dyskinesia and should be evaluated for this, especially in the presence of recurrent pulmonary infections. Treatment can improve lung mechanics which is especially important in those with single ventricle physiology.

Long Term Management of Cardiac Disease

Long term follow-up of patients with heterotaxy syndrome needs to consider multiple organ system involvement. In patients after pulmonary vein repair, it is important to evaluate for evolving obstruction with early intervention if recognized. Afterload reduction must be considered in patients with common atrioventricular valves that are more likely to become regurgitant. Periodic Holter monitoring to evaluate for occult arrhythmias and prompt therapy for clinically relevant findings should be performed. Timing of promotion to bidirectional Glenn anastomosis should be based on saturations and the presence of ventricular dysfunction and/or atrioventricular valve regurgitation, as these may improve with ventricular "offloading". Pre-Fontan considerations include not only hemodynamics but also anatomic factors that can complicate the total Cavo pulmonary completion. The site of pulmonary vein drainage must be taken into account to determine placement of the Fontan circuit and avoid inadvertently causing pulmonary venous obstruction. Fontan completion in patients with dextrocardia should be carefully planned to avoid compromise of the Fontan circuit by the ventricular mass. In patients with an interrupted IVC, hepatic veins require direct anastomosis into the "Fontan" circuit whether via a connection to the underside of the pulmonary artery (this may result in preferential streaming of hepatic factor to one lung) or by anastomosing them with a graft into the azygous vein to avoid the late development of arteriovenous malformations. Pre-operative assessment should identify arteriovenous malformations and portosystemic shunts that can lead to post-Fontan cyanosis. Portosystemic shunts should be occluded as much as possible. As a last resort, cardiac transplantation is not precluded even in patients with abnormal venous anatomy, as good post-transplant outcomes have been demonstrated in these patients.

Conclusions

Management of patients with heterotaxy syndrome involves early anatomic delineation and staged cardiac surgical palliations. Appropriate surveillance for the development of rhythm disturbances, ventricular dysfunction, significant atrioventricular valve regurgitation or pulmonary venous obstruction is imperative.^3,4 In addition, the clinician should be aware of the associated multisystem organ abnormalities that can impact these patients' lives.

References

1. Niu MC, Dickerson HA, Moore JA, et al. Heterotaxy syndrome and associated arrhythmias in pediatric patients. Heart Rhythm 2018;15:548-54.
2. Abbas PI, Dickerson HA, Wesson DE. Evaluating a management strategy for malrotation in heterotaxy patients. J Pediatr Surg 2016:51:859-62.
3. Marathe SP, Zannino D, Cao JY, et al. Heterotaxy is not a risk factor for adverse long-term outcomes after Fontan completion. Ann Thorac Surg 2020;110:646-53.
4. Broda CR, Salciccioli KB, Lopez KN, Ermis PR, Moodie DS, Dickerson HA. Outcomes in adults with congenital heart disease and heterotaxy syndrome: a single-center experience. Congenit Heart Dis 2019;14:885-94.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Cardiovascular Care Team, Congenital Heart Disease and Pediatric Cardiology, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Valvular Heart Disease, Vascular Medicine, Implantable Devices, EP Basic Science, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and CHD and Pediatrics, Cardiac Surgery and Heart Failure, Cardiac Surgery and VHD, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Imaging, CHD and Pediatrics and Interventions, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Lipid Metabolism, Acute Heart Failure, Heart Transplant, Interventions and Imaging, Interventions and Structural Heart Disease, Interventions and Vascular Medicine, Computed Tomography, Echocardiography/Ultrasound, Magnetic Resonance Imaging, Nuclear Imaging

Keywords: Heterotaxy Syndrome, Atrioventricular Node, Hepatic Veins, Fontan Procedure, Pulmonary Veins, Double Outlet Right Ventricle, Pulmonary Artery, Aortic Coarctation, Pulmonary Circulation, Intestinal Volvulus, Appendicitis, Appendix, Bradycardia, Appendectomy, Heart Ventricles, Computed Tomography Angiography, Prostaglandins, Electrocardiography, Ambulatory, Hydrops Fetalis, Vena Cava, Inferior, Follow-Up Studies, Dilatation, Isomerism, Isomerism, Portasystemic Shunt, Transjugular Intrahepatic, Scimitar Syndrome, Situs Inversus, Ciliary Motility Disorders, Pulmonary Valve Stenosis, Arteriovenous Malformations, Tachycardia, Supraventricular, Magnetic Resonance Imaging, Tachycardia, Heart Transplantation, Abdominal Pain, Abdominal Pain, Ventricular Dysfunction, Hemodynamics, Echocardiography, Doppler, Postoperative Complications, Heart Failure, Echocardiography, Vascular Resistance, Aortic Valve Stenosis, Dextrocardia, Heart Block, Anti-Bacterial Agents

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