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Primary Ciliary Dyskinesia and the HeartCilia Breaking Symmetry: Cilia Breaking Symmetry FREE TO VIEW

Marcus P. Kennedy, MD, FCCP; Barry J. Plant, MD
Author and Funding Information

From the Department of Respiratory Medicine, Cork University Hospital.

CORRESPONDENCE TO: Marcus P. Kennedy, MD, FCCP, Cork University Hospital, Wilton, Cork, Republic of Ireland; e-mail: Marcus.kennedy@hse.ie


FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(5):1136-1138. doi:10.1378/chest.14-0722
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The prospective study by Shapiro et al1 in this issue of CHEST (see page 1176) has enhanced our previous knowledge of the incidence of laterality defects, including congenital heart disease (CHD), in patients with primary ciliary dyskinesia (PCD), an inherited, usually autosomal recessive disorder with impaired ciliary function leading to unexplained neonatal respiratory distress, recurrent otitis media, chronic nasal drainage and sinusitis, and chronic bronchitis leading to bronchiectasis.2 The nomenclature for abnormal thoracoabdominal asymmetry varies. In keeping with the article by Shapiro et al,1 this editorial refers to the mirror image of normal as “situs inversus” and any other organ distribution as “situs ambiguus” with combined situs ambiguus and CHD benign referred to as “heterotaxy.” Although traditionally, knowledge of abnormal thoracoabdominal asymmetry is important in trauma and surgery, and patients with asplenia (a subset of heterotaxy) may be at increased risk of infection, it is the cardiovascular defects that lead to morbidity in patients with heterotaxy. Another study looking for ciliary dysfunction in patients with heterotaxic CHD also pointed toward a significant overlap with 18 of 43 patients with heterotaxic CHD (41%) having abnormal ciliary motion and nasal nitric oxide levels below or near the PCD cutoff values.3 Learning points from both these studies are that a PCD-CHD overlap phenotype exists and that we should consider screening for CHD in patients with PCD and for PCD in patients with CHD, especially if they have certain phenotypic features (eg, productive cough and neonatal respiratory compromise in patients with CHD, evidence of heart failure and cardiac murmur in patients with PCD, or relevant family history in either group). However, questions remain, including (1) the precise incidence of this PCD-CHD overlap, (2) why it is more common in animal models of PCD, and (3) how much CHD could be attributed to ciliary dysfunction.

The main obstacle to the first question is the lack of clarity of the precise incidence of PCD. In fact, our limited knowledge of the incidence of PCD relies on cilia breaking symmetry. In evolution, the separation of pulmonary and systemic circulation led to the development of air-breathing crocodilians, birds, and mammals. This breaking of symmetry is a complex process that commences in the embryonic node. Both primary motile cilia and sensory cilia are involved in breaking symmetry; however, defects in many other genes are associated with abnormal thoracoabdominal asymmetry.4 Approximately one in five of the genes identified as associated with heterotaxy are ciliary genes.4 In the majority, this separation leads to normal thoracoabdominal asymmetry (situs solitus) with a left-sided heart and spleen, right-sided liver and larger trilobed lung, and vascular distribution to match supply and drainage of these organs.

The question of how frequent (Table 1) these abnormal distributions are has been estimated through the analysis of chest radiographs in large series, with a Norwegian series of 1.8 million chest radiographs in subjects aged > 15 years identifying 200 cases of situs inversus (one in 10,000) and two cases of isolated dextrocardia (a subset of situs ambiguus) (one in 1,000,000).6 A Japanese study identified a higher incidence of situs inversus (one in 4,100) and identified through radiography that 25% of these patients had bronchiectasis, thus, extrapolating that the incidence of Kartagener syndrome (bronchiectasis, sinusitis, and situs inversus) was one in 16,000 in the study population.7 Because approximately one-half of patients with PCD have Kartagener triad,1,2 the incidence of PCD from these studies is estimated at one in 8,000 to one in 20,000.6,7 It is also hypothesized from these studies that 75% of patients with situs inversus do not have PCD; however, many authors have postulated that the percentage of situs inversus associated with ciliary defects is probably higher.8 There are clearly limitations to these estimations. These are selected populations of mostly adult patients (and, thus, require survival to adulthood) and involve chest radiography alone and not CT scanning or other imaging. Unlike cystic fibrosis, screening of all live births for PCD would not be feasible or cost-effective at present for a number of reasons, including lower incidence, milder phenotype, and less readily available and more complex testing. However, for those who have symptoms or a family history, improvements in diagnostic testing have occurred through better understanding of phenotype-genotype correlations, research networks, and centers of excellence.9-11 Genetic testing may ultimately lead to a better assessment of the incidence of PCD through testing for genetic mutations in large unselected populations, but the exciting and exponential increase in genes associated with PCD phenotype (21 published and increasing) also will require more complex genetic analysis.9

Table Graphic Jump Location
TABLE 1 ]  Incidence of PCD, Thoracoabdominal Asymmetry Subgroups, and PCD-CHD Overlap

CHD = congenital heart disease; PCD = primary ciliary dyskinesia.

a 

Twenty-five percent or more may have PCD.

b 

Unknown percentage associated with PCD.

Comparing the incidence of situs inversus, situs solitus, and situs ambiguus in animal models of PCD to human studies generates another question that is yet to be answered: Why is heterotaxic CHD more common in animal models than in humans? The axonemal structure is highly conserved, and murine ciliary genes invariably have human orthologs. Murine models of defective ciliary genes display PCD-like phenotypes.12-15 However, the distribution of thoracoabdominal asymmetry differs in that there is often a near equal distribution of situs inversus, situs solitus, and situs ambiguus in litters with early loss of many situs ambiguus fetuses due to CHD. This raises the question of whether the lower incidence of human situs ambiguus in the study by Shapiro et al1 could be associated with in utero loss. This is also reflected by the fact that most patients with PCD with situs ambiguus do not have heterotaxic CHD but, rather, mild and isolated laterality defects.1,2 Further insight is required to answer why the majority of patients with PCD have situs solitus despite defective embryonic nodal ciliary function.

The final question of how much human CHD could be attributed to defective ciliary function should be easier to address. By virtue of the severity of the defects in heterotaxic CHD, it is usually symptomatic and, thus, is identified either before or soon after birth.7 It is estimated that heterotaxic CHD comprises approximately 3% of congenital heart defects and has an estimated prevalence of one in 10,000 live births.5 Given that currently, approximately one in five genes identified as associated with heterotaxic CHD are ciliary genes4 and the number of genes identified as associated with PCD is growing exponentially and now includes genes expressed in the cytoplasm involved in preassembly of cilia,9 the initial study reporting ciliary dysfunction in > 40% patients with heterotaxic CHD may be an underestimation.3 With better genetic testing, it may be feasible and inexpensive to screen all patients with CHD for PCD-related genes, which may improve outcomes through early detection and treatment of respiratory disease associated with PCD.

References

Shapiro AJ, Davis SD, Ferkol T, et al; on behalf of the Genetic Disorders of Mucociliary Clearance Consortium. Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy. Chest. 2014;146(5):1176-1186.
 
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;115(22):2814-2821. [CrossRef] [PubMed]
 
Nakhleh N, Francis R, Giese RA, et al. High prevalence of respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy. Circulation. 2012;125(18):2232-2242. [CrossRef] [PubMed]
 
Brueckner M. Impact of genetic diagnosis on clinical management of patients with congenital heart disease: cilia point the way. Circulation. 2012;125(18):2178-2180. [CrossRef] [PubMed]
 
Lin AE, Ticho BS, Houde K, Westgate MN, Holmes LB. Heterotaxy: associated conditions and hospital-based prevalence in newborns. Genet Med. 2000;2(3):157-172. [CrossRef] [PubMed]
 
Torgersen J. Situs inversus, asymmetry, and twinning. Am J Hum Genet. 1950;2(4):361-370. [PubMed]
 
Katsuhara K, Kawamoto S, Wakabayashi T, Belsky JL. Situs inversus totalis and Kartagener’s syndrome in a Japanese population. Chest. 1972;61(1):56-61. [CrossRef] [PubMed]
 
Zhu L, Belmont JW, Ware SM. Genetics of human heterotaxias. Eur J Hum Genet. 2006;14(1):17-25. [PubMed]
 
Knowles MR, Daniels LA, Davis SD, Zariwala MA, Leigh MW. Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. Am J Respir Crit Care Med. 2013;188(8):913-922. [CrossRef] [PubMed]
 
Strippoli MP, Frischer T, Barbato A, et al; ERS Task Force on Primary Ciliary Dyskinesia in Children. Management of primary ciliary dyskinesia in European children: recommendations and clinical practice. Eur Respir J. 2012;39(6):1482-1491. [CrossRef] [PubMed]
 
Barbato A, Frischer T, Kuehni CE, et al. Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children. Eur Respir J. 2009;34(6):1264-1276. [CrossRef] [PubMed]
 
Supp DM, Witte DP, Potter SS, Brueckner M. Mutation of an axonemal dynein affects left-right asymmetry in inversus viscerum mice. Nature. 1997;389(6654):963-966. [CrossRef] [PubMed]
 
Ibañez-Tallon I, Gorokhova S, Heintz N. Loss of function of axonemal dynein Mdnah5 causes primary ciliary dyskinesia and hydrocephalus. Hum Mol Genet. 2002;11(6):715-721. [CrossRef] [PubMed]
 
Ibañez-Tallon I, Pagenstecher A, Fliegauf M, et al. Dysfunction of axonemal dynein heavy chain Mdnah5 inhibits ependymal flow and reveals a novel mechanism for hydrocephalus formation. Hum Mol Genet. 2004;13(18):2133-2141. [CrossRef] [PubMed]
 
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;117(12):3742-3752. [PubMed]
 

Figures

Tables

Table Graphic Jump Location
TABLE 1 ]  Incidence of PCD, Thoracoabdominal Asymmetry Subgroups, and PCD-CHD Overlap

CHD = congenital heart disease; PCD = primary ciliary dyskinesia.

a 

Twenty-five percent or more may have PCD.

b 

Unknown percentage associated with PCD.

References

Shapiro AJ, Davis SD, Ferkol T, et al; on behalf of the Genetic Disorders of Mucociliary Clearance Consortium. Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy. Chest. 2014;146(5):1176-1186.
 
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;115(22):2814-2821. [CrossRef] [PubMed]
 
Nakhleh N, Francis R, Giese RA, et al. High prevalence of respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy. Circulation. 2012;125(18):2232-2242. [CrossRef] [PubMed]
 
Brueckner M. Impact of genetic diagnosis on clinical management of patients with congenital heart disease: cilia point the way. Circulation. 2012;125(18):2178-2180. [CrossRef] [PubMed]
 
Lin AE, Ticho BS, Houde K, Westgate MN, Holmes LB. Heterotaxy: associated conditions and hospital-based prevalence in newborns. Genet Med. 2000;2(3):157-172. [CrossRef] [PubMed]
 
Torgersen J. Situs inversus, asymmetry, and twinning. Am J Hum Genet. 1950;2(4):361-370. [PubMed]
 
Katsuhara K, Kawamoto S, Wakabayashi T, Belsky JL. Situs inversus totalis and Kartagener’s syndrome in a Japanese population. Chest. 1972;61(1):56-61. [CrossRef] [PubMed]
 
Zhu L, Belmont JW, Ware SM. Genetics of human heterotaxias. Eur J Hum Genet. 2006;14(1):17-25. [PubMed]
 
Knowles MR, Daniels LA, Davis SD, Zariwala MA, Leigh MW. Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. Am J Respir Crit Care Med. 2013;188(8):913-922. [CrossRef] [PubMed]
 
Strippoli MP, Frischer T, Barbato A, et al; ERS Task Force on Primary Ciliary Dyskinesia in Children. Management of primary ciliary dyskinesia in European children: recommendations and clinical practice. Eur Respir J. 2012;39(6):1482-1491. [CrossRef] [PubMed]
 
Barbato A, Frischer T, Kuehni CE, et al. Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children. Eur Respir J. 2009;34(6):1264-1276. [CrossRef] [PubMed]
 
Supp DM, Witte DP, Potter SS, Brueckner M. Mutation of an axonemal dynein affects left-right asymmetry in inversus viscerum mice. Nature. 1997;389(6654):963-966. [CrossRef] [PubMed]
 
Ibañez-Tallon I, Gorokhova S, Heintz N. Loss of function of axonemal dynein Mdnah5 causes primary ciliary dyskinesia and hydrocephalus. Hum Mol Genet. 2002;11(6):715-721. [CrossRef] [PubMed]
 
Ibañez-Tallon I, Pagenstecher A, Fliegauf M, et al. Dysfunction of axonemal dynein heavy chain Mdnah5 inhibits ependymal flow and reveals a novel mechanism for hydrocephalus formation. Hum Mol Genet. 2004;13(18):2133-2141. [CrossRef] [PubMed]
 
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;117(12):3742-3752. [PubMed]
 
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