Hostname: page-component-77f85d65b8-pkds5 Total loading time: 0 Render date: 2026-04-12T19:13:50.608Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  26 November 2007

Meryl S. Cohen ,
Robert H. Anderson ,
Mitchell I. Cohen ,
Andrew M. Atz ,
Mark Fogel ,
Peter J. Gruber ,
Leo Lopez ,
Jonathan J. Rome  and
Paul M. Weinberg
Meryl S. Cohen*
Affiliation:
Divisions of Cardiology and Cardiothoracic Surgery, The Cardiac Center at The Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
Robert H. Anderson
Affiliation:
Cardiac Unit, Institute of Child Health, University College London, London, United Kingdom
Mitchell I. Cohen
Affiliation:
Division of Cardiology, Phoenix Children’s Hospital, Phoenix, Arizona, United States of America
Andrew M. Atz
Affiliation:
Division of Cardiology, Medical University of South Carolina Children’s Hospital, Charleston, South Carolina, United States of America
Mark Fogel
Affiliation:
Divisions of Cardiology and Cardiothoracic Surgery, The Cardiac Center at The Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
Peter J. Gruber
Affiliation:
Divisions of Cardiology and Cardiothoracic Surgery, The Cardiac Center at The Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
Leo Lopez
Affiliation:
Division of Cardiology, Miami Children’s Hospital, Miami, Florida, United States of America
Jonathan J. Rome
Affiliation:
Divisions of Cardiology and Cardiothoracic Surgery, The Cardiac Center at The Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
Paul M. Weinberg
Affiliation:
Divisions of Cardiology and Cardiothoracic Surgery, The Cardiac Center at The Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
*
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: cohenm@email.chop.edu
Get access Rights & Permissions [Opens in a new window]

Abstract

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.

Keywords

Situs ambiguousisomerism of atrial appendagesmorphologyechocardiography

Information

Type
Original Article
Information
Cardiology in the Young , Volume 17 , Supplement S4 , September 2007 , pp. 29 - 43
Copyright
Copyright © Cambridge University Press 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

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 4–23.Google Scholar
2. Van Praagh, R, David, I, Wright, GB, Van Praagh, S. Large RV plus small LV is not single LV. Circulation 1980; 61: 1057–1058.CrossRefGoogle Scholar
3. Keeton, BR, Macartney, FJ, Hunter, S, et al. . Univentricular heart of right ventricular type with double or common inlet. Circulation 1979; 59: 403–411.Google Scholar
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: 561–569.Google Scholar
5. Van Mierop, LHS, Gessner, IH, Schiebler, GL. Asplenia and polysplenia syndromes. Birth Defects: Original Article Series 1972; 8: 36–52.Google Scholar
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: 846–849.Google Scholar
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: 437–454.Google Scholar
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: 51–56.CrossRefGoogle ScholarPubMed
9. Gruber, PJ, Epstein, JA. Development gone awry: congenital heart disease. Circ Res 2004; 94: 273–283.CrossRefGoogle ScholarPubMed
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: 201–206.Google Scholar
11. Hummel, KP, Chapman, DB. Situs viscerum inversus. Mouse News letter 1956; 14-21.Google Scholar
12. Hummel, KP, Chapman, DB. Visceral inversion and associated anomalies in the mouse. J Hered 1959; 50: 9–13.CrossRefGoogle Scholar
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: 2547–2558.CrossRefGoogle ScholarPubMed
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: 5495–5504.CrossRefGoogle ScholarPubMed
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: 963–966.Google Scholar
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: 1725–1734.CrossRefGoogle Scholar
17. Afzelius, BA. A human syndrome caused by immotile cilia. Science 1976; 193: 317–319.CrossRefGoogle ScholarPubMed
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: 5043–5048.Google Scholar
19. Levin, M, Johnson, RL, Stern, CD, Kuehn, M, Tabin, C. A molecular pathway determining left-right asymmetry in chick embryogenesis. Cell 1995; 82: 803–814.CrossRefGoogle ScholarPubMed
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: 5–11.Google Scholar
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: 11376–11381.Google Scholar
22. Ryan, AK, Blumberg, B, Rodriguez-Esteban, C, et al. . Pitx2 determines left-right asymmetry of internal organs in vertebrates. Nature 1998; 394: 545–551.Google Scholar
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: 319–324.Google Scholar
24. Afzelius, BA. Asymmetry of cilia and of mice and men. Int J Dev Biol 1999; 43: 283–286.Google Scholar
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: 61–73.Google Scholar
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: 459–468.CrossRefGoogle ScholarPubMed
27. Hirokawa, N, Tanaka, Y, Okada, Y, Takeda, S. Nodal flow and the generation of left-right asymmetry. Cell 2006; 125: 33–45.CrossRefGoogle ScholarPubMed
28. Cohen, MS. Clarifying anatomical complexity: Diagnosing heterotaxy syndrome in the fetus. Prog Pediatr Cardiol 2006; 22: 61–70.Google Scholar
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: 908–916.CrossRefGoogle Scholar
30. Anderson, RH, Webb, S, Brown, NA. Defective lateralization in children with congenitally malformed hearts. Cardiol Young 1998; 8: 512–531.CrossRefGoogle ScholarPubMed
31. Jacobs, ML, Mayer, JE. Congenital heart surgeon nomenclature and database project: Single ventricle. Ann Thorac Surg 2000; 69: S197–S204[Suppl].CrossRefGoogle Scholar
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: 1629–1636.Google Scholar
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: 1269–1273.CrossRefGoogle ScholarPubMed
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: 637–640.Google Scholar
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: 1649–1653.Google Scholar
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: 1277–1282.Google Scholar
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: 798–803.CrossRefGoogle ScholarPubMed
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: 2454–2461.Google Scholar
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: 840–852.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
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: 641–650.Google ScholarPubMed
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 813–850.Google Scholar
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: 111–116.Google Scholar
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: 1488–1498.Google Scholar
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: 236–247.CrossRefGoogle ScholarPubMed
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: 645–649.CrossRefGoogle ScholarPubMed
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: 348–356.CrossRefGoogle ScholarPubMed
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: 671–682.Google Scholar
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.Google Scholar
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: 904–910.Google Scholar
51. Cheung, YF, Yan-wah, C, Yung, TC, Chau, AK. Cardiac rhythm and symptomatic arrhythmia in right atrial isomerism. Am Heart J 2002; 144: 159–164.Google Scholar
52. Wren, C, Macartney, FJ, Deanfield, JE. Cardiac rhythm in atrial isomerism. Am J Cardiol 1987; 59: 1156–1158.CrossRefGoogle ScholarPubMed
53. Wu, MH, Wang, JK, Lin, JL, et al. . Supraventricular tachycardia in patients with right atrial isomerism. J Am Coll Cardiol 1998; 32: 773–778.Google Scholar
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: 671–679.CrossRefGoogle ScholarPubMed
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: 1631–1638.Google Scholar
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: 1103–1107.CrossRefGoogle ScholarPubMed
57. Roguin, N, Pelled, B, Freundlich, E, Yahalom, M, Riss, E. Atrioventricular block in situs ambiguous and left isomerism (polysplenia syndrome). PACE 1984; 7: 18–22.CrossRefGoogle Scholar
58. Waldman, JD, Rosenthal, A, Smith, AL, Shurin, S, Nadas, AS. Sepsis and congenital asplenia. J Pediatr 1977; 99: 555–559.Google Scholar
59. Choi, M, Borenstein, SH, Hornberger, L, Langer, JC. Heterotaxia syndrome: The role of screening for intestinal rotation abnormalities. Arch Dis Child 2005; 90: 813–815.Google Scholar
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: 12–18.Google Scholar
61. Applegate, KE, Goske, MJ, Pierce, G, Murphy, D. Situs revisited: Imaging of the heterotaxy syndrome. Radiographics 1999; 19: 837–852.Google Scholar
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: 729–734.Google Scholar
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: 1248–1252.Google Scholar
64. Strouse, PJ, Haller, JO, Berdon, WE, Rosovsky, MA, Bellah, RD, JrBarr, M. Horseshoe adrenal gland in association with asplenia. Pediatr Radiol 2002; 32: 778–782.Google Scholar
65. Chandra, RS. Biliary atresia and other structural anomalies in the congenital polysplenia syndrome. J Pediatr 1974; 85: 649–655.Google Scholar
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: 1120–1126.CrossRefGoogle ScholarPubMed
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: 506–513.Google Scholar
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: 1621–1627.Google Scholar
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: 1636–1640.Google Scholar
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: 2301–2305.Google Scholar
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: 392–403.Google Scholar
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: 1967–1977.Google Scholar