The heterotaxy syndrome: associated congenital heart defects and management

Abstract

Heterotaxy syndrome (HS) constitutes a spectrum of anomalies arising from embryological errors that result in abnormalities of lateralization involving thoraco-abdominal viscera and culminate in loss of normal asymmetric arrangement of these organs. Besides the unique challenges involved in planning and execution of surgical procedures aimed at correction or palliation of these anomalies, they have the potential to cause profound physiological and immunological consequences in the individual patient due to their cardiac and extra-cardiac manifestations. This article aims to review the literature on this rare and extraordinary subset of developmental anomalies with the intention of familiarizing the reader on the modes of presentation, manifestations, and the variations thereof while dealing with this anomaly. In our institutional experience with HS, 75 consecutive patients were seen between January 2011 and September 2018. Of these, 48 (64%) were confirmed to have isomerism of right atrial appendages (IRAA) and the rest had isomerism of left atrial appendages (ILAA). The cardiac and extra-cardiac manifestations of these patients were listed out. Fifty-four patients (34 with IRAA and 20 with ILAA) underwent 83 surgical procedures. While 49 patients were palliated on the univentricular pathway, 5 underwent biventricular repair. The in-hospital mortality was 7 (13%) in both groups combined (5 for patients with IRAA and 2 for ILAA). In conclusion, the surgical management of HS is associated with satisfactory outcomes in current era.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 1.

    Jacobs JP, Anderson RH, Weinberg PM, et al. The nomenclature, definition, and classification of cardiac structures in the setting of heterotaxy. Cardiol Young. 2007;17:1–28.

    PubMed  Google Scholar 

  2. 2.

    Sutherland MJ, Ware SM. Disorders of left–right asymmetry: heterotaxy and situs inversus. Am J Med Genet C: Semin Med Genet. 2009;151C:307–17.

    CAS  Google Scholar 

  3. 3.

    Shiraishi I, Ichikawa H. Human heterotaxy syndrome—from molecular genetics to clinical features, management and prognosis. Circ J. 2012;76:2066–75.

  4. 4.

    Belmont JW, Mohapatra B, Towbin JA, Ware SM. Molecular genetics of heterotaxy syndromes. Curr Opin Cardiol. 2004;19:216–20.

    PubMed  Google Scholar 

  5. 5.

    Kuehl KS, Loffredo C. Risk factors for heart disease associated with abnormal sidedness. Tetralogy. 2002;66:242–8.

    CAS  Google Scholar 

  6. 6.

    Van Praagh R. Terminology of congenital heart disease: glossary and commentary. Circulation. 1977;56:139–43.

    PubMed  Google Scholar 

  7. 7.

    Anderson RH, Becker AE, Freedom RM, et al. Sequential segmental analysis of congenital heart disease. Pediatr Cardiol. 1984;5:281–7.

    CAS  PubMed  Google Scholar 

  8. 8.

    Anderson RH, Ho SY. Sequential segmental analysis—description and categorization for the millennium. Cardiol Young. 1997;7:98–116.

    Google Scholar 

  9. 9.

    Uemura H, Ho SY, Devine WA, Kilpatrick LL, Anderson RH. Atrial appendages and venoatrial connections in hearts with patients with visceral heterotaxy. Ann Thorac Surg. 1995;60:561–9.

    CAS  PubMed  Google Scholar 

  10. 10.

    Van Praagh R, Van Praagh S. Atrial isomerism in the heterotaxy syndrome with asplenia, or polysplenia, or normally formed spleen: an erroneous concept. Am J Cardiol. 1990;66:1504–6.

    PubMed  Google Scholar 

  11. 11.

    Ticho BS, Goldstein AM, Van Praagh R. Extracardiac anomalies in the heterotaxy syndrome with focus on anomalies of midline-associated structures. Am J Cardiol. 2000;85:729–34.

    CAS  PubMed  Google Scholar 

  12. 12.

    Price VE, Blanchette VS, Ford-Jones EL. Prevention and management of infections in children with asplenia or hyposplenia. Infect Dis Clin N Am. 2007;21:697–710.

    Google Scholar 

  13. 13.

    Barker GM, O’Brien SM, Welke KF, et al. Major infection after pediatric cardiac surgery: a risk estimation model. Ann Thorac Surg. 2010;89:843–50.

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Nakhleh N, Francis R, Giese RA, et al. High prevalence of respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy. Circulation. 2012;125:2232–42.

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Yamamura K, Joo K, Ohga S, et al. Thrombocytosis in asplenia syndrome with congenital heart disease: a previously unrecognized risk factor for thromboembolism. Int J Cardiol. 2013;167:2259–63.

    PubMed  Google Scholar 

  16. 16.

    McElhinney DB, Marx GR, Newbeuger JW. Congenital portosystemic venous connections and other abdominal venous abnormalities in patients with polysplenia and functionally univentricular heart disease: a case series and literature review. Congenit Heart Dis. 2011;6:28–40.

    PubMed  Google Scholar 

  17. 17.

    Lin JH, Chang CI, Wang JK, et al. Intrauterine diagnosis of heterotaxy syndrome. Am Heart J. 2002;143:1002–8.

    PubMed  Google Scholar 

  18. 18.

    Yan YL, Tan KB, Yeo GS. Right atrial isomerism: preponderance in Asian fetuses. Using the stomach-distance ratio as a possible diagnostic tool for prediction of right atrial isomerism. Ann Acad Med Singap. 2008;37:906–12.

    PubMed  Google Scholar 

  19. 19.

    Yim D, Nagata H, Lam CZ, et al. Disharmonious patterns of heterotaxy and isomerism: how often are the classic patterns breached? Circ Cardiovasc Imaging. 2018. https://doi.org/10.1161/CIRCIMAGING.117.006917.

  20. 20.

    Sanders SP, Geva T. Classifying heterotaxy syndrome: time for a new approach. Circ Cardiovasc Imaging. 2018. https://doi.org/10.1161/CIRCIMAGING.118.007490.

  21. 21.

    Loomba R, Shah PH, Anderson R, Arora Y. Radiologic considerations in Heterotaxy: need for detailed anatomic evaluation. Cureus. 2016. https://doi.org/10.7759/cureus.470.

  22. 22.

    Blieden LC, Moller JH. Analysis of the P wave in congenital cardiac malformations associated with splenic anomalies. Am Heart J. 1973;85:439–44.

    CAS  PubMed  Google Scholar 

  23. 23.

    Ho SY, Seo JW, Brown NA, Cook AC, Fagg NL, Anderson RH. Morphology of the sinus node in human and mouse hearts with isomerism of the atrial appendages. Br Heart J. 1995;74:437–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Frogoudaki A, Sutton R, Gatzoulis MA. Pacing for adult patients with left atrial isomerism: efficacy and technical considerations. Europace. 2003;5:189–93.

    CAS  PubMed  Google Scholar 

  25. 25.

    Suman-Horduna I, Babu-Narayan SV, Ueda A, et al. Magnetic navigation in patients with atrial isomerism (heterotaxy syndrome) and supraventricular arrhythmias. EP Europace. 2013;15:877–85.

    Google Scholar 

  26. 26.

    Marx GR. Echocardiography in heterotaxy syndrome. World J Pediatr Congenit Heart Surg. 2011;2:253–7.

    PubMed  Google Scholar 

  27. 27.

    Berg C, Geipel A, Smrcek J, et al. Prenatal diagnosis of cardiosplenic syndromes: a 10 year experience. Ultrasound Obstet Gynecol. 2003;22:451–9.

    CAS  PubMed  Google Scholar 

  28. 28.

    Hamasaka N, Matsushita M, Takeda S, et al. Prenatal diagnosis of heterotaxy syndrome: an 11 year experience. Ultrasound Obstet Gynecol. 2010;36:179.

    Google Scholar 

  29. 29.

    Loomba R, Shah PH, Anderson RH, et al. Fetal magnetic resonance imaging of malformations associated with heterotaxy. Cureus. 2015;7:e269.

  30. 30.

    Uemura H, Yagihara T, Kawahira Y, Yoshikawa Y. Anatomic biventricular repair by intraatrial and intraventricular re-routing in patients with left isomerism. Cardiol Young. 2001;11:12–6.

    CAS  PubMed  Google Scholar 

  31. 31.

    Koh M, Yagihara T, Uemura H, et al. Biventricular repair for right atrial isomerism. Ann Thorac Surg. 2006;81:1808–16.

    PubMed  Google Scholar 

  32. 32.

    Lim HG, Bacha EA, Marx GR, et al. Biventricular repair in patients with heterotaxy syndrome. J Thorac Cardiovasc Surg. 2009;137:371–9.

    CAS  PubMed  Google Scholar 

  33. 33.

    Makhija Z, Marwah A, Mishra S, Kumar J, Goel A, Sharma R. Biventricular repair in heterotaxy patients. World J Pediatr Congenit Heart Surg. 2015;6:195–202.

    PubMed  Google Scholar 

  34. 34.

    Heinemann MK, Hanley FL, Van Praagh S, et al. Total anomalous pulmonary venous drainage in newborns with visceral heterotaxy. Ann Thorac Surg. 1994;57:88–91.

    CAS  PubMed  Google Scholar 

  35. 35.

    Sadiq M, Stumper O, De Giovanni JV, et al. Management and outcome of infants and children with right atrial isomerism. Heart. 1996;75:314–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Jacobs ML. Complications associated with heterotaxy syndrome in Fontan patients. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2002;5:25–35.

    PubMed  Google Scholar 

  37. 37.

    Khan MS, Bryant R 3rd, Kim SH, et al. Contemporary outcomes of surgical repair of total anomalous pulmonary venous connection in patients with heterotaxy syndrome. Ann Thorac Surg 2015;99:2134–9.

  38. 38.

    Brown JW, Ruzmetov M, Vijay P, Rodefeld MD, Turrentine MW. Pulmonary arteriovenous malformations in children after the Kawashima operation. Ann Thorac Surg. 2005;80:1592–6.

    PubMed  Google Scholar 

  39. 39.

    Kim SJ, Bae EJ, Lee JY, Lim HG, Lee C, Lee CH. Inclusion of hepatic venous drainage in patients with pulmonary arteriovenous fistulas. Ann Thorac Surg. 2009;87:548–53.

    PubMed  Google Scholar 

  40. 40.

    Vouhe PR. Kawashima procedure: can pulmonary arteriovenous malformations be avoided? Eur J Cardiothorac Surg. 2012;41:579–80.

    PubMed  Google Scholar 

  41. 41.

    Jonas RA. Three-stage management of single ventricle. In: Jonas RA. Comprehensive surgical management of congenital heart disease. 2nd edition. CRC Press 2014. pp 501.

  42. 42.

    Alsoufi B, McCracken C, Schlosser B, et al. Outcomes of multistage palliation of infants with functional single ventricle and heterotaxy syndrome. J Thorac Cardiovasc Surg. 2016;151:1369–77.

    PubMed  Google Scholar 

  43. 43.

    Swisher M, Jonas R, Tian X, Lee ES, Lo CW, Leatherbury L. Increased postoperative and respiratory complications in patients with congenital heart disease associated with heterotaxy. J Thorac Cardiovasc Surg. 2011;141:637–44.

    PubMed  Google Scholar 

  44. 44.

    Anagnostopoulos PV, Pearl JM, Octave C, et al. Improved current era outcomes in patients with heterotaxy syndromes. Eur J Cardiothorac Surg. 2009;35:871–7.

  45. 45.

    Azakie A, Merklinger SL, Williams WG, Van Arsdell GS, Coles JG, Adatia I. Improving outcomes of the Fontan operation in children with atrial isomerism and heterotaxy syndromes. Ann Thorac Surg. 2001;72:1636–40.

    CAS  PubMed  Google Scholar 

  46. 46.

    Bartz PJ, Driscoll DJ, Dearani JA, et al. Early and late results of the modified Fontan operation for the heterotaxy syndrome 30 years of experience in 142 patients. J Am Coll. 2006;48:2301–5.

    Google Scholar 

  47. 47.

    Kim SJ, Kim WH, Lim HG, Lee CH, Lee JY. Improving results of the Fontan procedure in patients with heterotaxy syndrome. Ann Thorac Surg. 2006;82:1245–51.

    PubMed  Google Scholar 

  48. 48.

    Atz Am, Cohen MS, Sleeper LA, et al. Functional state of patients with heterotaxy syndrome following the Fontan operation. Cardiol Young. 2007;17:44–53.

    Google Scholar 

  49. 49.

    Kulkarni A, Patel N, Singh TP, Mossialos E, Mehra MR. Risk factors for death or heart transplantation in single-ventricle physiology (tricuspid atresia, pulmonary atresia and heterotaxy): a systematic review and meta-analysis. J Heart Lung Transplant. 2019;38:739–47.

    PubMed  Google Scholar 

Download references

Summary

To summarize, HS is a generalized somatic laterality disorder characterized by abnormal arrangement of thoracic and abdominal viscera. It is associated with complex congenital cardiac malformations which are usually grouped as isomerism of right or left atrial appendages. Most of the cardiac anomalies associated with HS are managed by univentricular pathway, albeit some are amenable for biventricular repair; more so in patients with left atrial isomerism. Biventricular repair strategy provides excellent long-term functional outcome but with a higher incidence of reinterventions and reoperations. The results of univentricular palliation in this setting have improved due to thoughtful early preparation and careful conduct of modified Fontan procedure. Presence of obstructed TAPVC and significant atrioventricular valve incompetence has been associated with poor outcome in patients with single ventricle physiology and aggressive approach towards their repair is recommended.

Funding

The authors declare they have not received any funding.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Ravi Agarwal.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical statements, human and animal rights consent

Not applicable being a review article.

Informed consent

Not applicable being a review article.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Agarwal, R., Varghese, R., Jesudian, V. et al. The heterotaxy syndrome: associated congenital heart defects and management. Indian J Thorac Cardiovasc Surg 37, 67–81 (2021). https://doi.org/10.1007/s12055-020-00935-y

Download citation

Keywords

  • Heterotaxy syndrome
  • Right atrial isomerism
  • Left atrial isomerism
  • Single ventricle
  • Biventricular repair