Skip to main content
    • Aa
    • Aa
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 6
  • Cited by
    This article has been cited by the following publications. This list is generated based on data provided by CrossRef.

    van Veenendaal, Nicole R. Kusters, Cynthia D.J. Oostra, Roelof-Jan Bergman, Jorieke E.H. and Cobben, Jan-Maarten 2016. When the right (Drug) should be left: Prenatal drug exposure and heterotaxy syndrome. Birth Defects Research Part A: Clinical and Molecular Teratology, Vol. 106, Issue. 7, p. 573.

    Vandenberg, Laura N Lemire, Joan M and Levin, Michael 2013. It’s never too early to get it Right. Communicative & Integrative Biology, Vol. 6, Issue. 6, p. e27155.

    El Guindi, W. Dreyfus, M. Carles, G. Lambert, V. Herlicoviez, M. and Benoit, G. 2012. L’apport de l’échographie 3D dans les syndromes d’hétérotaxie : à propos de quatre cas et revue de la littérature. Journal de Gynécologie Obstétrique et Biologie de la Reproduction, Vol. 41, Issue. 5, p. 489.

    O’Connor, Matthew J. Ravishankar, Chitra Ballweg, Jean A. Gillespie, Matthew J. Gaynor, J. William Tabbutt, Sarah and Dominguez, Troy E. 2011. Early systemic-to-pulmonary artery shunt intervention in neonates with congenital heart disease. The Journal of Thoracic and Cardiovascular Surgery, Vol. 142, Issue. 1, p. 106.

    Katsuya, Satoko Yamada, Shigehito Ukita, Masayo Nishimura, Hiromi Matsumura, Noriomi Fukuhara, Ken Sato, Yukiyasu Shiota, Kohei and Konishi, Ikuo 2009. Isolated levocardia: Prenatal diagnosis and management. Congenital Anomalies, Vol. 49, Issue. 2, p. 56.

    Thacker, Deepika Gruber, Peter J. Weinberg, Paul M. and Cohen, Meryl S. 2009. Heterotaxy Syndrome with Mirror Image Anomalies in Identical Twins. Congenital Heart Disease, Vol. 4, Issue. 1, p. 50.


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)
  • DOI:
  • Published online: 01 September 2007

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:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

3.BR Keeton , FJ Macartney , S Hunter , . Univentricular heart of right ventricular type with double or common inlet. Circulation 1979; 59: 403411.

4.H Uemura , SY Ho , WA Devine , LL Kilpatrick , RH Anderson . Atrial appendages and venoatrial connections in hearts with patients with visceral heterotaxy. Ann Thorac Surg 1995; 60: 561569.

6.H Uemura , SY Ho , WA Devine , RH Anderson . Analysis of visceral heterotaxy according to splenic status, appendage morphology, or both. Am J Cardiol 1995; 76: 846849.

7.A Smith , SY Ho , RH Anderson , MG Connell , R Arnold , JL Wilkinsion . 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.JY Harh , MH Paul , WJ Gallen , DZ Friedberg , S Kaplan . Experimental production of hypoplastic left heart syndrome in the chick embryo. Am J Cardiol 1973; 31: 5156.

9.PJ Gruber , JA Epstein . Development gone awry: congenital heart disease. Circ Res 2004; 94: 273283.

10.T Pehlivan , BR Pober , M Brueckner , . GATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease. Am J Med Genet 1999; 83: 201206.

13.JM Icardo , MJ Sanchez de Vega . Spectrum of heart malformations in mice with situs solitus, situs inversus, and associated visceral heterotaxy. Circulation 1991; 84: 25472558.

15.DM Supp , DP Witte , SS Potter , M Brueckner . Mutation of an axonemal dynein affects left-right asymmetry in inversus viscerum mice. Nature 1997; 389: 963966.

16.D Watanabe , Y Saijoh , S Nonaka , . The left-right determinant Inversin is a component of node monocilia and other 9+0 cilia. Development 2003; 130: 17251734.

17.BA Afzelius . A human syndrome caused by immotile cilia. Science 1976; 193: 317319.

18.JR Marszalek , P Ruiz-Lozano , E Roberts , KR Chien , LS Goldstein . 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.M Levin , RL Johnson , CD Stern , M Kuehn , C Tabin . A molecular pathway determining left-right asymmetry in chick embryogenesis. Cell 1995; 82: 803814.

20.J Heymer , M Kuehn , U Ruther . 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.T Tsukui , J Capdevila , K Tamura , . 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.

23.ME Piedra , JM Icardo , M Albajar , JC Rodriguez-Rey , MA Ros . Pitx2 participates in the late phase of the pathway controlling left-right asymmetry. Cell 1998; 94: 319324.

25.J McGrath , S Somlo , S Makova , X Tian , M Brueckner . Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell 2003; 114: 6173.

26.Y Okada , S Nonaka , Y Tanaka , Y Saijoh , H Hamada , N Hirokawa . Abnormal nodal flow precedes situs inversus in iv and inv mice. Mol Cell 1999; 4: 459468.

27.N Hirokawa , Y Tanaka , Y Okada , S Takeda . Nodal flow and the generation of left-right asymmetry. Cell 2006; 125: 3345.

28.MS Cohen . Clarifying anatomical complexity: Diagnosing heterotaxy syndrome in the fetus. Prog Pediatr Cardiol 2006; 22: 6170.

29.T Gilljam , BW McCrindle , JF Smallhorn , WG Williams , RM Freedom . Outcomes of left atrial isomerism over a 28-year period at a single institution. J Am Coll Cardiol 2000; 36: 908916.

30.RH Anderson , S Webb , NA Brown . Defective lateralization in children with congenitally malformed hearts. Cardiol Young 1998; 8: 512531.

31.ML Jacobs , JE Mayer . Congenital heart surgeon nomenclature and database project: Single ventricle. Ann Thorac Surg 2000; 69: S197S204[Suppl].

32.MS Cohen , AH Schultz , ZY Tian , . Heterotaxy syndrome with functional single ventricle: Does prenatal diagnosis improve survival? Ann Thorac Surg 2006; 82: 16291636.

33.W Tworetzky , DB McElhinney , VM Reddy , MM Brook , FL Hanley , NH Silverman . Improved surgical outcome after fetal diagnosis of hypoplastic left heart syndrome. Circulation 2001; 103: 12691273.

35.RK Kumar , JW Newburger , K Gauvreau , SA Kamenir , LK Hornberger . 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.WT Mahle , RR Clancy , SP McGaurn , JE Goin , BJ Clark . Impact of prenatal diagnosis on survival and early neurologic morbidity in neonates with the hypoplastic left heart syndrome. Pediatrics 2001; 107: 12771282.

37.PM Verheijen , LA Lisowski , P Stoutenbeek , . Prenatal diagnosis of congenital heart disease affects preoperative acidosis of the newborn patient. J Thorac Cardiovasc Surg 2001; 121: 798803.

38.JS Lim , BW McCrindle , JF Smallhorn , . Clinical features, management, and outcome of children with fetal and postnatal diagnoses of isomerism syndromes. Circulation 2005; 112: 24542461.

39.V Rose , T Izukawa , CA Moes . 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.

43.M Ruscazio , S Van Praagh , AR Marrass , G Catani , S Iliceto , R Van Praagh . 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.S Van Praagh , ME Carrera , S Sanders , JE Mayer Jr, R Van Praagh . 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.S De Tommasi , L Daliento , SY Ho , FJ Macartney , RH Anderson . Analysis of atrioventricular junction, ventricular mass, and ventriculoarterial junction in 43 specimens with atrial isomerism. Br Heart J 1981; 45: 236247.

46.T Masui , KC Seelos , BA Kersting-Sommerhoff , CB Higgins . Abnormalities of the pulmonary veins: Evaluation with MR imaging and comparison with cardiac angiography and echocardiography. Radiology 1991; 181: 645649.

47.T Geva , W Vick , RE Wendt , R Rockey . 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.YK Hong , YW Park , SJ Ryu , . Efficacy of MRI in complicated congenital heart disease with visceral heterotaxy syndrome. J Comput Assist Tomogr 2000; 24: 671682.

50.SY Ho , N Fagg , RH Anderson , A Cook , L Allan . 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.YF Cheung , C Yan-wah , TC Yung , AK Chau . Cardiac rhythm and symptomatic arrhythmia in right atrial isomerism. Am Heart J 2002; 144: 159164.

52.C Wren , FJ Macartney , JE Deanfield . Cardiac rhythm in atrial isomerism. Am J Cardiol 1987; 59: 11561158.

53.MH Wu , JK Wang , JL Lin , . Supraventricular tachycardia in patients with right atrial isomerism. J Am Coll Cardiol 1998; 32: 773778.

54.MR Epstein , JP Saul , SN Weindling , JK Triedman , EP Walsh . Atrioventricular reciprocating tachycardia involving twin atrioventricular nodes in patients with complex congenital heart disease. J Cardiovasc Electrophysiol 2001; 12: 671679.

55.MH Wu , JK Wang , JL Lin , LP Lai , HC Lue , FJ Hsieh . Cardiac rhythm disturbances in patients with left atrial isomerism. PACE 2001; 24: 16311638.

56.OL Garcia , AV Mehta , AS Pickoff , . Left isomerism and complete atrioventricular block: A report of six cases. Am J Cardiol 1981; 48: 11031107.

57.N Roguin , B Pelled , E Freundlich , M Yahalom , E Riss . Atrioventricular block in situs ambiguous and left isomerism (polysplenia syndrome). PACE 1984; 7: 1822.

59.M Choi , SH Borenstein , L Hornberger , JC Langer . Heterotaxia syndrome: The role of screening for intestinal rotation abnormalities. Arch Dis Child 2005; 90: 813815.

60.B Ferdman , L States , JW Gaynor , HL Hedrick , J Rychik . Abnormalities of intestinal rotation in patients with congenital heart disease and the heterotaxy syndrome. Congenit Heart Dis 2007; 2: 1218.

61.KE Applegate , MJ Goske , G Pierce , D Murphy . Situs revisited: Imaging of the heterotaxy syndrome. Radiographics 1999; 19: 837852.

62.BS Ticho , AM Goldstein , R Van Praagh . Extracardiac anomalies in the heterotaxy syndromes with focus on anomalies of midline-associated structures. Am J Cardiol 2000; 85: 729734.

63.JY Hsu , SJ Chen , JK Wang , YH Ni , MH Chang , MH Wu . Clinical implication of hiatal hernia in patients with right isomerism. Acta Paediatr 2005; 94: 12481252.

64.PJ Strouse , JO Haller , WE Berdon , MA Rosovsky , RD Bellah , M Barr Jr. Horseshoe adrenal gland in association with asplenia. Pediatr Radiol 2002; 32: 778782.

65.RS Chandra . Biliary atresia and other structural anomalies in the congenital polysplenia syndrome. J Pediatr 1974; 85: 649655.

66.A Hashmi , R Abu-Sulaiman , BW McCrindle , JF Smallhorn , WG Williams , RM Freedom . Management and outcomes of right atrial isomerism: a 26-year experience. J Am Coll Cardiol 1998; 31: 11201126.

67.JW Gaynor , MH Collins , J Rychik , JP Gaughan , TL Spray . Long-term outcome of infants with single ventricle and total anomalous pulmonary venous connection. J Thorac Cardiovasc Surg 1999; 117: 506513.

68.DL Morales , BE Braud , JH Booth , . Heterotaxy patients with total anomalous pulmonary venous return: improving surgical results. Ann Thorac Surg 2006; 82: 16211627.

69.A Azakie , SL Merklinger , WG Williams , GS Van Arsdell , JG Coles , I Adatia . Improving outcomes of the Fontan operation in children with atrial isomerism and heterotaxy syndromes. Ann Thorac Surg 2001; 72: 16361640.

70.PJ Bartz , DJ Driscoll , JA Dearani , . Early and late results of the modified Fontan operation for heterotaxy syndrome. J Am Coll Cardiol 2006; 48: 23012305.

71.TL Gentles , K Gauvreau , JE Mayer Jr., . Functional outcome after the Fontan operation: factors influencing late morbidity. J Thorac Cardiovasc Surg 1997; 114: 392403.

72.C Stamm , I Friehs , LF Duebener , . 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? *