Medscape is available in 5 Language Editions – Choose your Edition here.


Heterotaxy Syndrome and Primary Ciliary Dyskinesia Treatment & Management

  • Author: Alvin J Chin, MD; Chief Editor: Stuart Berger, MD  more...
Updated: May 09, 2014

Medical Care

For ductal-dependent pulmonary blood flow or ductal-dependent systemic blood flow, prostaglandin E1 infusion is life-saving. For common atrioventricular valve regurgitation, vasodilator therapy (eg, ACE inhibition) can be palliative. Arrhythmias, predominantly supraventricular, frequently complicate the preoperative and postoperative management.


Surgical Care

This depends on the underlying cardiovascular phenotype, with the most severe individuals typically being staged toward Fontan-type circulatory configurations. Pacing may be indicated in patients with third-degree atrioventricular block or sinus node dysfunction.

Cardiothoracic surgeons tend to use cavopulmonary connections rather than complicated intra-atrial baffles; thus, early survival after the Fontan operation has improved. However, survival is still clearly lower than for other patients without heterotaxy. Although part of this disparity can be attributed to the propensity of atrioventricular valve regurgitation to progress in heterotaxy patients, whether this is actually primarily due to ventricular deterioration (rather than the presence of an inherently different atrioventricular valve) is unclear.



Patients with presumptive heterotaxy should have a comprehensive evaluation by a pediatric cardiologist, a geneticist, and a cardiac surgeon.

Contributor Information and Disclosures

Alvin J Chin, MD Emeritus Professor of Pediatrics, University of Pennsylvania School of Medicine

Alvin J Chin, MD is a member of the following medical societies: American Association for the Advancement of Science, Society for Developmental Biology, American Heart Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Julian M Stewart, MD, PhD Associate Chairman of Pediatrics, Director, Center for Hypotension, Westchester Medical Center; Professor of Pediatrics and Physiology, New York Medical College

Julian M Stewart, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Autonomic Society, American Physiological Society

Disclosure: Received grant/research funds from Lundbeck Pharmaceuticals for none.

Chief Editor

Stuart Berger, MD Medical Director of The Heart Center, Children's Hospital of Wisconsin; Associate Professor, Department of Pediatrics, Section of Pediatric Cardiology, Medical College of Wisconsin

Stuart Berger, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, American College of Chest Physicians, American Heart Association, Society for Cardiovascular Angiography and Interventions

Disclosure: Nothing to disclose.

Additional Contributors

Charles I Berul, MD Professor of Pediatrics and Integrative Systems Biology, George Washington University School of Medicine; Chief, Division of Cardiology, Children's National Medical Center

Charles I Berul, MD is a member of the following medical societies: American Academy of Pediatrics, Heart Rhythm Society, Cardiac Electrophysiology Society, Pediatric and Congenital Electrophysiology Society, American College of Cardiology, American Heart Association, Society for Pediatric Research

Disclosure: Received grant/research funds from Medtronic for consulting.

  1. Kartagener M. Zur Pathogenese der Bronchiektasien: Bronchiektasien bei Situs viscerum inversus. Beitrage zur Klinik der Tuberkulose. 1933. 83:489-501.

  2. Martin G. Observation d'une deviation organique de l'estomac, d'une anomalie dans la situation et dans le configuration du coeur et des vaisseaux qui en partent ou qui s'y rendant. Bull Soc Anat Paris. 1826. 1:40-48.

  3. Kennedy MP, Omran H, Leigh MW, et al. Congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia. Circulation. 2007 Jun 5. 115(22):2814-21. [Medline].

  4. Shapiro AJ, Davis SD, Ferkol T, Dell SD, Rosenfeld M, Olivier KN, et al. Laterality Defects other than Situs Inversus Totalis in Primary Ciliary Dyskinesia: Insights into Situs Ambiguus and Heterotaxy. Chest. 2014 Feb 27. [Medline].

  5. Polhemus DW, Schafer WB. Congenital absence of the spleen; syndrome with atrioventricularis and situs inversus; case reports and review of the literature. Pediatrics. 1952 Jun. 9(6):696-708. [Medline].

  6. Zlotogora J, Elian E. Asplenia and polysplenia syndromes with abnormalities of lateralisation in a sibship. J Med Genet. 1981 Aug. 18(4):301-2. [Medline].

  7. Ivemark BI. Implications of agenesis of the spleen on the pathogenesis of conotruncus anomalies in childhood; an analysis of the heart malformations in the splenic agenesis syndrome, with fourteen new cases. Acta Paediatr Suppl. 1955 Nov. 44(Suppl 104):7-110. [Medline].

  8. Hummel K, Chapman D. Visceral inversion and associated anomalies in the mouse. Journal of Heredity. 1959. 50:9-13.

  9. Layton WM Jr. Random determination of a developmental process: reversal of normal visceral asymmetry in the mouse. J Hered. 1976 Nov-Dec. 67(6):336-8. [Medline].

  10. Icardo JM, Sanchez de Vega MJ. Spectrum of heart malformations in mice with situs solitus, situs inversus, and associated visceral heterotaxy. Circulation. 1991 Dec. 84(6):2547-58. [Medline].

  11. Seo JW, Brown NA, Ho SY, Anderson RH. Abnormal laterality and congenital cardiac anomalies. Relations of visceral and cardiac morphologies in the iv/iv mouse. Circulation. 1992 Aug. 86(2):642-50. [Medline].

  12. Nonaka S, Tanaka Y, Okada Y, et al. Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell. 1998 Dec 11. 95(6):829-37. [Medline].

  13. Hirokawa N, Tanaka Y, Okada Y. Left-right determination: involvement of molecular motor KIF3, cilia, and nodal flow. Cold Spring Harb Perspect Biol. 2009 Jul. 1(1):a000802. [Medline]. [Full Text].

  14. Gros J, Feistel K, Viebahn C, Blum M, Tabin CJ. Cell movements at Hensen's node establish left/right asymmetric gene expression in the chick. Science. 2009 May 15. 324(5929):941-4. [Medline].

  15. Lin AE, Ticho BS, Houde K, Westgate MN, Holmes LB. Heterotaxy: associated conditions and hospital-based prevalence in newborns. Genet Med. 2000 May-Jun. 2(3):157-72. [Medline].

  16. Ferencz C. C Ferencz, CA Loffredo, A Correa-Villasenor and PD Wilson, Eds. Defects of laterality and looping. Armonk, NY: Futura Publishing; 1997.

  17. Bartoloni L, Blouin JL, Pan Y, Gehrig C, Maiti AK, Scamuffa N. Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely primary ciliary dyskinesia. Proc Natl Acad Sci U S A. 2002 Aug 6. 99(16):10282-6. [Medline].

  18. Kosaki K, Bassi MT, Kosaki R, et al. Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine genes implicated in left-right axis development. Am J Hum Genet. 1999 Mar. 64(3):712-21. [Medline].

  19. Bamford RN, Roessler E, Burdine RD, et al. Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects. Nat Genet. 2000 Nov. 26(3):365-9. [Medline].

  20. Hornef N, Olbrich H, Horvath J, Zariwala MA, Fliegauf M, Loges NT. DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects. Am J Respir Crit Care Med. 2006 Jul 15. 174(2):120-6. [Medline]. [Full Text].

  21. Tan SY, Rosenthal J, Zhao XQ, et al. Heterotaxy and complex structural heart defects in a mutant mouse model of primary ciliary dyskinesia. J Clin Invest. 2007 Dec. 117(12):3742-52. [Medline].

  22. Karkera JD, Lee JS, Roessler E, Banerjee-Basu S, Ouspenskaia MV, Mez J. Loss-of-function mutations in growth differentiation factor-1 (GDF1) are associated with congenital heart defects in humans. Am J Hum Genet. 2007 Nov. 81(5):987-94. [Medline].

  23. Pennarun G, Escudier E, Chapelin C, Bridoux AM, Cacheux V, Roger G. Loss-of-function mutations in a human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia. Am J Hum Genet. 1999 Dec. 65(6):1508-19. [Medline].

  24. Ware SM, Peng J, Zhu L, et al. Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects. Am J Hum Genet. 2004 Jan. 74(1):93-105. [Medline].

  25. Mohapatra B, Casey B, Li H, et al. Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations. Hum Mol Genet. 2009 Mar 1. 18(5):861-71. [Medline]. [Full Text].

  26. Roessler E, Ouspenskaia MV, Karkera JD, et al. Reduced NODAL signaling strength via mutation of several pathway members including FOXH1 is linked to human heart defects and holoprosencephaly. Am J Hum Genet. 2008 Jul. 83(1):18-29. [Medline]. [Full Text].

  27. Kosaki R, Gebbia M, Kosaki K, et al. Left-right axis malformations associated with mutations in ACVR2B, the gene for human activin receptor type IIB. Am J Med Genet. 1999 Jan 1. 82(1):70-6. [Medline].

  28. Nakhleh N, Francis R, Giese RA, Tian X, Li Y, Zariwala MA, et al. High Prevalence of Respiratory Ciliary Dysfunction in Congenital Heart Disease Patients with Heterotaxy. Circulation. 2012 Apr 12. [Medline].

  29. Zariwala MA, Omran H, Ferkol TW. The emerging genetics of primary ciliary dyskinesia. Proc Am Thorac Soc. 2011 Sep. 8(5):430-3. [Medline]. [Full Text].

  30. Merveille AC, Davis EE, Becker-Heck A, Legendre M, Amirav I, Bataille G, et al. CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nat Genet. 2011 Jan. 43(1):72-8. [Medline].

  31. Becker-Heck A, Zohn IE, Okabe N, et al. The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation. Nat Genet. 2011 Jan. 43(1):79-84. [Medline]. [Full Text].

  32. Norris DP, Grimes DT. Mouse models of ciliopathies: the state of the art. Dis Model Mech. 2012 May. 5(3):299-312. [Medline]. [Full Text].

  33. Saunders CJ, Miller NA, Soden SE, Dinwiddie DL, Noll A, Alnadi NA, et al. Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. Sci Transl Med. 2012 Oct 3. 4(154):154ra135. [Medline].

  34. Boskovski MT, Yuan S, Pedersen NB, Goth CK, Makova S, Clausen H, et al. The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality. Nature. 2013 Dec 19. 504(7480):456-9. [Medline]. [Full Text].

  35. Zariwala MA, Gee HY, Kurkowiak M, Al-Mutairi DA, Leigh MW, Hurd TW, et al. ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6. Am J Hum Genet. 2013 Aug 8. 93(2):336-45. [Medline]. [Full Text].

  36. Tarkar A, Loges NT, Slagle CE, Francis R, Dougherty GW, Tamayo JV, et al. DYX1C1 is required for axonemal dynein assembly and ciliary motility. Nat Genet. 2013 Sep. 45(9):995-1003. [Medline].

  37. Hjeij R, Lindstrand A, Francis R, Zariwala MA, Liu X, Li Y, et al. ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry. Am J Hum Genet. 2013 Aug 8. 93(2):357-67. [Medline]. [Full Text].

  38. Daniels ML, Leigh MW, Davis SD, Armstrong MC, Carson JL, Hazucha M, et al. Founder mutation in RSPH4A identified in patients of Hispanic descent with primary ciliary dyskinesia. Hum Mutat. 2013 Oct. 34(10):1352-6. [Medline]. [Full Text].

  39. Knowles MR, Ostrowski LE, Loges NT, Hurd T, Leigh MW, Huang L, et al. Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms. Am J Hum Genet. 2013 Oct 3. 93(4):711-20. [Medline]. [Full Text].

  40. Knowles MR, Leigh MW, Ostrowski LE, Huang L, Carson JL, Hazucha MJ, et al. Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia. Am J Hum Genet. 2013 Jan 10. 92(1):99-106. [Medline]. [Full Text].

  41. Horani A, Druley TE, Zariwala MA, Patel AC, Levinson BT, Van Arendonk LG, et al. Whole-exome capture and sequencing identifies HEATR2 mutation as a cause of primary ciliary dyskinesia. Am J Hum Genet. 2012 Oct 5. 91(4):685-93. [Medline]. [Full Text].

  42. Harden B, Tian X, Giese R, Nakhleh N, Kureshi S, Francis R, et al. Increased postoperative respiratory complications in heterotaxy congenital heart disease patients with respiratory ciliary dysfunction. J Thorac Cardiovasc Surg. 2014 Apr. 147(4):1291-1298.e2. [Medline].

The structure and function of cilia is shown here. (A) Most motile cilia are organized with 9 microtubule doublets surrounding a core pair of doublets (9+2 configuration). Outer dynein arms (green) and inner dynein arms (blue) are shown. Cilia on the cells of the ventral node in the normal mouse embryo have no core doublet (a 9+0 configuration) and were initially thought to be nonmotile; however, upon closer scrutiny, node cilia were seen to have a rotatory motion (600 rpm). [Figure A is from Hirokawa N, Tanaka Y, Okada Y. Left-right determination: involvement of molecular motor KIF3, cilia, and nodal flow. Cold Spring Harb Perspect Biol. Jul 2009;1(1):a000802 and is reprinted with permission of Cold Spring Harbor Press](B) lrd (left-right dynein), the protein (green) mutated by the iv mutation, is also known as DNAH11, DNAHC11, and DLP11. [Figure B is from the United States Department of Energy Genomes to Life Program](C) The rotatory cone of each cilium is tilted posteriorly. Hence, the cilia make a leftward swing at the fluid surface and a rightward swing at the cellular surface. Because more viscous drag is present at the cellular surface, the rightward sweep is less effective at generating fluid movement than is the leftward sweep.[Figure C is from Hirokawa N, Tanaka Y, Okada Y, Takeda S. Nodal flow and the generation of left-right asymmetry. Cell 2006; 125:33-45 and is reproduced with permission from Cell Press]A = Anterior; L = Left; P = Posterior; R = Right.
Three phases of elaboration of LR asymmetry are shown. The first step consists of differentiating the left and right sides on the cellular level. This probably takes place by means of a chiral molecule. (A) A subset of the cells (yellow) of the fairly early embryo undergo this process.(B) Localized cellular asymmetry is propagated between cells to cause LR determinants to accumulate on one side of the embryonic midline, possibly by a process involving transport through gap junctions. These determinants would then induce cascades of factors in multicellular fields of the embryo. (C) Finally, the asymmetric presence of these factors induces or suppresses asymmetrically located organs such as the spleen and regulates asymmetric morphogenesis of other organs such as the heart tube.Courtesy of Levin M, Mercola M. The compulsion of chirality: toward an understanding of left-right asymmetry. Genes Dev. Mar 15 1998;12(6):763-9.
Genes required for proper left-right asymmetry are shown. Genes are presented in 5 columns, according to the developmental phase in which they are currently thought to function. The leftmost column has the earliest functioning genes. The second column has genes required for the development of the node (or its equivalent). The third and fourth column have genes that are required for normal node cilia function. Genes in white, green, or blue denote those in which the proof came from studies of fruit fly (Drosophila melanogaster), zebrafish (Danio rerio), or frog (Xenopus laevis), respectively. Genes in brown are those studied in mouse (Mus musculus), whereas those discovered in human (Homo sapiens) are shown in red.
Axial MRI of a case of heterotaxy with polysplenia. (A) The abdominal aorta (abd ao) is on the left side of the spine (S), as is the left-sided azygos (L Azy). Two right-sided spleens (spl) are visible. LHV = Left hepatic vein; RHV = Right hepatic vein.(B) A common atrioventricular valve (black unlabelled arrows) is markedly malaligned to the right ventricle (RV). A diminutive left atrium (LA) is represented by only an appendage. The patient had an extracardiac conduit (EC) type of Fontan operation. No fenestration is noted between the EC and the neo-left atrium (neoLA). (C) Because this patient had subaortic stenosis, a proximal pulmonary artery-to-ascending aortic anastomosis was performed early in life, along with augmentation of the aortic arch. The L Azy connects to the left superior vena cava (LSVC). LU DAo = Left upper descending aorta; Prox = Proximal. (D) The LSVC connected originally to the coronary sinus (CS) and then to the right atrium. Despite the fact that the LSVC has been disconnected from the heart and anastomosed end-to-side to the left pulmonary artery, the CS remains large. The narrowed left ventricular outflow tract (LVOT) is seen. Ao = Aorta; PA = Pulmonary root; RLL PV = Right lower lobe pulmonary vein. (E) Because this patient had absence of the hepatic segment of the inferior vena cava, the left-sided SVC-to-left pulmonary artery (LPA) anastomosis is referred to a left-sided Kawashima (LK). The anastomosis of the right superior vena cava to the right pulmonary artery is a right-sided bidirectional Glenn (R BDG) shunt. (F) The left lower lobe pulmonary vein (LLL PV), as part of this patient's totally anomalous pulmonary venous connection, connects to the original right atrium, which is now the neoLA.
Coronal MRI of the patient shown in media file 4. (A) Both superior vena cava (SVC)–to–pulmonary artery (PA) anastomoses can be seen. LCCA = Left common carotid artery. (B) Three dimensional surface rendering. RIA = Right innominate artery. (C) Three-dimensional reconstruction of only the systemic venous pathway.
Malrotation of the gut. This upper GI barium study of the heterotaxy patient shown in media files 4 and 5 shows a right-sided stomach (St), opposite of normal. The duodenum heads to the left, the duodenal-jejunal junction is to the left of the spine (opposite to what would be expected for situs inversus totalis), and the jejunum (J) stays left-sided.
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.