Skip to main content

Controversies, genetics, diagnostic assessment, and outcomes relating to the heterotaxy syndrome

  • Meryl S. Cohen (a1), Robert H. Anderson (a2), Mitchell I. Cohen (a3), Andrew M. Atz (a4), Mark Fogel (a1), Peter J. Gruber (a1), Leo Lopez (a5), Jonathan J. Rome (a1) and Paul M. Weinberg (a1)...

How best to analyse and describe the features of the situation commonly known as “visceral heterotaxy” remains controversial. Much of the disagreement devolves on how to deal with the concept of isomerism. In the opinion of some, the concept of bilateral right-sidedness and bilateral left-sidedness, while useful in helping to remember which abnormalities are likely to occur in asplenia or polysplenia, should not be granted the status of a specific “situs”, since there are numerous examples of exceptions to these patterns. On the other hand, those who favour the concept of isomerism point out that, when describing only the heart, and taking the structure of the atrial appendages as the starting point for analysis, basing this on the extent of the pectinate muscles relative to the atrioventricular junctions, then the only possible arrangements for the appendages are the usual one, its mirror-image, and the two situations in which appendages of comparable morphology are found on both sides of the heart, these being the arrangements of right or left isomerism. It is certainly the case that the arrangement of the organs is not always in harmony with the arrangement of the atrial appendages, but those circumstances, in which there is disharmony, can readily be described by paying specific attention to each series of organs. On this basis, in this review, we describe the approach to heterotaxy, and isomerism of the atrial appendages, in terms of the genetic background, the diagnosis, and outcomes after cardiac surgery. Attention is given to the various diagnostic modalities, including fetal and postnatal echocardiography, recent tomographic and magnetic resonance imaging techniques, and the time-honoured approach using angiography.

Corresponding author
Correspondence to: Meryl S. Cohen, MD, Division of Cardiology, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Blvd., Philadelphia, Pennsylvania 19104, USA. Tel: (215) 590 3354; Fax: (215) 590 3788; E-mail:
Hide All
1. Van Praagh R. The segmental approach to diagnosis in congenital heart disease. In: Bergsma D (ed). Birth Defects: Original Article Series, vol. VIII, No. 5. The National Foundation – March of Dimes. Williams and Wilkins, Baltimore, 1972, pp 423.
2. Van Praagh R, David I, Wright GB, Van Praagh S. Large RV plus small LV is not single LV. Circulation 1980; 61: 10571058.
3. Keeton BR, Macartney FJ, Hunter S, et al. . Univentricular heart of right ventricular type with double or common inlet. Circulation 1979; 59: 403411.
4. 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: 561569.
5. Van Mierop LHS, Gessner IH, Schiebler GL. Asplenia and polysplenia syndromes. Birth Defects: Original Article Series 1972; 8: 3652.
6. Uemura H, Ho SY, Devine WA, Anderson RH. Analysis of visceral heterotaxy according to splenic status, appendage morphology, or both. Am J Cardiol 1995; 76: 846849.
7. Smith A, Ho SY, Anderson RH, Connell MG, Arnold R, Wilkinsion JL. The diverse cardiac morphology seen in hearts with isomerism of the atrial appendages with reference to the disposition of the specialized conduction system. Cardiol Young 2006; 16: 437454.
8. Harh JY, Paul MH, Gallen WJ, Friedberg DZ, Kaplan S. Experimental production of hypoplastic left heart syndrome in the chick embryo. Am J Cardiol 1973; 31: 5156.
9. Gruber PJ, Epstein JA. Development gone awry: congenital heart disease. Circ Res 2004; 94: 273283.
10. Pehlivan T, Pober BR, Brueckner M, et al. . GATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease. Am J Med Genet 1999; 83: 201206.
11. Hummel KP, Chapman DB. Situs viscerum inversus. Mouse News letter 1956; 14-21.
12. Hummel KP, Chapman DB. Visceral inversion and associated anomalies in the mouse. J Hered 1959; 50: 913.
13. Icardo JM, Sanchez de Vega MJ. Spectrum of heart malformations in mice with situs solitus, situs inversus, and associated visceral heterotaxy. Circulation 1991; 84: 25472558.
14. Supp DM, Brueckner M, Kuehn MR, et al. . Targeted deletion of the ATP binding domain of left-right dynein confirms its role in specifying development of left-right asymmetries. Development 1999; 126: 54955504.
15. Supp DM, Witte DP, Potter SS, Brueckner M. Mutation of an axonemal dynein affects left-right asymmetry in inversus viscerum mice. Nature 1997; 389: 963966.
16. Watanabe D, Saijoh Y, Nonaka S, et al. . The left-right determinant Inversin is a component of node monocilia and other 9+0 cilia. Development 2003; 130: 17251734.
17. Afzelius BA. A human syndrome caused by immotile cilia. Science 1976; 193: 317319.
18. Marszalek JR, Ruiz-Lozano P, Roberts E, Chien KR, Goldstein LS. Situs inversus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II. Proc Natl Acad Sci USA 1999; 96: 50435048.
19. Levin M, Johnson RL, Stern CD, Kuehn M, Tabin C. A molecular pathway determining left-right asymmetry in chick embryogenesis. Cell 1995; 82: 803814.
20. Heymer J, Kuehn M, Ruther U. The expression pattern of nodal and lefty in the mouse mutant Ft suggests a function in the establishment of handedness. Mech Dev 1997; 66: 511.
21. Tsukui T, Capdevila J, Tamura K, et al. . Multiple left-right asymmetry defects in Shh(−/−) mutant mice unveil a convergence of the shh and retinoic acid pathways in the control of Lefty-1. Proc Natl Acad Sci 1999; 96: 1137611381.
22. Ryan AK, Blumberg B, Rodriguez-Esteban C, et al. . Pitx2 determines left-right asymmetry of internal organs in vertebrates. Nature 1998; 394: 545551.
23. Piedra ME, Icardo JM, Albajar M, Rodriguez-Rey JC, Ros MA. Pitx2 participates in the late phase of the pathway controlling left-right asymmetry. Cell 1998; 94: 319324.
24. Afzelius BA. Asymmetry of cilia and of mice and men. Int J Dev Biol 1999; 43: 283286.
25. McGrath J, Somlo S, Makova S, Tian X, Brueckner M. Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell 2003; 114: 6173.
26. Okada Y, Nonaka S, Tanaka Y, Saijoh Y, Hamada H, Hirokawa N. Abnormal nodal flow precedes situs inversus in iv and inv mice. Mol Cell 1999; 4: 459468.
27. Hirokawa N, Tanaka Y, Okada Y, Takeda S. Nodal flow and the generation of left-right asymmetry. Cell 2006; 125: 3345.
28. Cohen MS. Clarifying anatomical complexity: Diagnosing heterotaxy syndrome in the fetus. Prog Pediatr Cardiol 2006; 22: 6170.
29. Gilljam T, McCrindle BW, Smallhorn JF, Williams WG, Freedom RM. Outcomes of left atrial isomerism over a 28-year period at a single institution. J Am Coll Cardiol 2000; 36: 908916.
30. Anderson RH, Webb S, Brown NA. Defective lateralization in children with congenitally malformed hearts. Cardiol Young 1998; 8: 512531.
31. Jacobs ML, Mayer JE. Congenital heart surgeon nomenclature and database project: Single ventricle. Ann Thorac Surg 2000; 69: S197S204[Suppl].
32. Cohen MS, Schultz AH, Tian ZY, et al. . Heterotaxy syndrome with functional single ventricle: Does prenatal diagnosis improve survival? Ann Thorac Surg 2006; 82: 16291636.
33. Tworetzky W, McElhinney DB, Reddy VM, Brook MM, Hanley FL, Silverman NH. Improved surgical outcome after fetal diagnosis of hypoplastic left heart syndrome. Circulation 2001; 103: 12691273.
34. Bonnet D, Coltri A, Butera G, et al. . Prenatal diagnosis of transposition of great vessels reduces neonatal morbidity and mortality. Arch Mal Couer Vaiss 1999; 92: 637640.
35. Kumar RK, Newburger JW, Gauvreau K, Kamenir SA, Hornberger LK. Comparison of outcome when hypoplastic left heart syndrome and transposition of the great arteries are diagnosed prenatally versus when diagnosis of these two conditions is made only postnatally. Am J Cardiol 1999; 83: 16491653.
36. Mahle WT, Clancy RR, McGaurn SP, Goin JE, Clark BJ. Impact of prenatal diagnosis on survival and early neurologic morbidity in neonates with the hypoplastic left heart syndrome. Pediatrics 2001; 107: 12771282.
37. Verheijen PM, Lisowski LA, Stoutenbeek P, et al. . Prenatal diagnosis of congenital heart disease affects preoperative acidosis of the newborn patient. J Thorac Cardiovasc Surg 2001; 121: 798803.
38. Lim JS, McCrindle BW, Smallhorn JF, et al. . Clinical features, management, and outcome of children with fetal and postnatal diagnoses of isomerism syndromes. Circulation 2005; 112: 24542461.
39. Rose V, Izukawa T, Moes CA. Syndromes of asplenia and polysplenia. A review of cardiac and non-cardiac malformations in 60 cases with special reference to diagnosis and prognosis. Br Heart J 1975; 37: 840852.
40. Van Praagh S. Cardiac malpositions and the heterotaxy syndromes. In: Keane JF, Lock JE, Fyler DC (eds). Nadas’ Pediatric Cardiology, 2006, pp 589–608.
41. Rubino M, Van Praagh S, Kadoba K, Pessotto R, Van Praagh R. Systemic and pulmonary venous connections in visceral heterotaxy with asplenia. Diagnostic and surgical considerations based on seventy-two autopsied cases. J Thorac Cardiovasc Surg 1995; 110: 641650.
42. Webber SA, Uemura H, Anderson RH. Isomerism of the atrial appendages. In: Anderson RH, Baker EJ, Macartney FJ, Rigby ML, Shinebourne EA, Tynan M (eds). Paediatric Cardiology. Churchill Livingstone, London, 2002, pp 813850.
43. Ruscazio M, Van Praagh S, Marrass AR, Catani G, Iliceto S, Van Praagh R. Interrupted inferior vena cava in asplenia syndrome and a review of the hereditary patterns of visceral situs abnormalities. Am J Cardiol 1998; 81: 111116.
44. Van Praagh S, Carrera ME, Sanders S, JrMayer JE, Van Praagh R. Partial or total direct pulmonary venous drainage to right atrium due to malposition of septum primum. Anatomic and echocardiographic findings and surgical treatment: a study based on 36 cases. Chest 1995; 107: 14881498.
45. De Tommasi S, Daliento L, Ho SY, Macartney FJ, Anderson RH. Analysis of atrioventricular junction, ventricular mass, and ventriculoarterial junction in 43 specimens with atrial isomerism. Br Heart J 1981; 45: 236247.
46. Masui T, Seelos KC, Kersting-Sommerhoff BA, Higgins CB. Abnormalities of the pulmonary veins: Evaluation with MR imaging and comparison with cardiac angiography and echocardiography. Radiology 1991; 181: 645649.
47. Geva T, Vick W, Wendt RE, Rockey R. Role of spin echo and cine magnetic resonance imaging in presurgical planning of heterotaxy syndrome. Comparison with echocardiography and catheterization. Circulation. 1994; 90: 348356.
48. Hong YK, Park YW, Ryu SJ, et al. . Efficacy of MRI in complicated congenital heart disease with visceral heterotaxy syndrome. J Comput Assist Tomogr 2000; 24: 671682.
49. Webber SA, Uemura H, Anderson RH. Isomerism of the atrial appendages. In: Anderson RH, Baker EJ, Macartney FJ, Rigby ML (eds). Paediatric Cardiology, 2nd edn. Churchill-Livingstone, London, 2002, p 822.
50. Ho SY, Fagg N, Anderson RH, Cook A, Allan L. Disposition of the atrioventricular conduction tissues in the heart with isomerism of the atrial appendages: its relation to congenital complete heart block. J Am Coll Cardiol 1992; 20: 904910.
51. Cheung YF, Yan-wah C, Yung TC, Chau AK. Cardiac rhythm and symptomatic arrhythmia in right atrial isomerism. Am Heart J 2002; 144: 159164.
52. Wren C, Macartney FJ, Deanfield JE. Cardiac rhythm in atrial isomerism. Am J Cardiol 1987; 59: 11561158.
53. Wu MH, Wang JK, Lin JL, et al. . Supraventricular tachycardia in patients with right atrial isomerism. J Am Coll Cardiol 1998; 32: 773778.
54. Epstein MR, Saul JP, Weindling SN, Triedman JK, Walsh EP. Atrioventricular reciprocating tachycardia involving twin atrioventricular nodes in patients with complex congenital heart disease. J Cardiovasc Electrophysiol 2001; 12: 671679.
55. Wu MH, Wang JK, Lin JL, Lai LP, Lue HC, Hsieh FJ. Cardiac rhythm disturbances in patients with left atrial isomerism. PACE 2001; 24: 16311638.
56. Garcia OL, Mehta AV, Pickoff AS, et al. . Left isomerism and complete atrioventricular block: A report of six cases. Am J Cardiol 1981; 48: 11031107.
57. Roguin N, Pelled B, Freundlich E, Yahalom M, Riss E. Atrioventricular block in situs ambiguous and left isomerism (polysplenia syndrome). PACE 1984; 7: 1822.
58. Waldman JD, Rosenthal A, Smith AL, Shurin S, Nadas AS. Sepsis and congenital asplenia. J Pediatr 1977; 99: 555559.
59. Choi M, Borenstein SH, Hornberger L, Langer JC. Heterotaxia syndrome: The role of screening for intestinal rotation abnormalities. Arch Dis Child 2005; 90: 813815.
60. Ferdman B, States L, Gaynor JW, Hedrick HL, Rychik J. Abnormalities of intestinal rotation in patients with congenital heart disease and the heterotaxy syndrome. Congenit Heart Dis 2007; 2: 1218.
61. Applegate KE, Goske MJ, Pierce G, Murphy D. Situs revisited: Imaging of the heterotaxy syndrome. Radiographics 1999; 19: 837852.
62. Ticho BS, Goldstein AM, Van Praagh R. Extracardiac anomalies in the heterotaxy syndromes with focus on anomalies of midline-associated structures. Am J Cardiol 2000; 85: 729734.
63. Hsu JY, Chen SJ, Wang JK, Ni YH, Chang MH, Wu MH. Clinical implication of hiatal hernia in patients with right isomerism. Acta Paediatr 2005; 94: 12481252.
64. Strouse PJ, Haller JO, Berdon WE, Rosovsky MA, Bellah RD, JrBarr M. Horseshoe adrenal gland in association with asplenia. Pediatr Radiol 2002; 32: 778782.
65. Chandra RS. Biliary atresia and other structural anomalies in the congenital polysplenia syndrome. J Pediatr 1974; 85: 649655.
66. Hashmi A, Abu-Sulaiman R, McCrindle BW, Smallhorn JF, Williams WG, Freedom RM. Management and outcomes of right atrial isomerism: a 26-year experience. J Am Coll Cardiol 1998; 31: 11201126.
67. Gaynor JW, Collins MH, Rychik J, Gaughan JP, Spray TL. Long-term outcome of infants with single ventricle and total anomalous pulmonary venous connection. J Thorac Cardiovasc Surg 1999; 117: 506513.
68. Morales DL, Braud BE, Booth JH, et al. . Heterotaxy patients with total anomalous pulmonary venous return: improving surgical results. Ann Thorac Surg 2006; 82: 16211627.
69. 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: 16361640.
70. Bartz PJ, Driscoll DJ, Dearani JA, et al. . Early and late results of the modified Fontan operation for heterotaxy syndrome. J Am Coll Cardiol 2006; 48: 23012305.
71. Gentles TL, Gauvreau K, Jr.Mayer JE, et al. . Functional outcome after the Fontan operation: factors influencing late morbidity. J Thorac Cardiovasc Surg 1997; 114: 392403.
72. Stamm C, Friehs I, Duebener LF, et al. . Improving results of the modified Fontan operation in patients with heterotaxy syndrome. Ann Thorac Surg 2002; 74: 19671977.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Cardiology in the Young
  • ISSN: 1047-9511
  • EISSN: 1467-1107
  • URL: /core/journals/cardiology-in-the-young
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 8
Total number of PDF views: 64 *
Loading metrics...

Abstract views

Total abstract views: 528 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 20th November 2017. This data will be updated every 24 hours.