Published Online
on May 21, 2007

A more recent version of this article appeared on June 5, 2007

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Submitted on June 30, 2006
Accepted on February 22, 2007

Congenital Heart Disease and Other Heterotaxic Defects in a Large Cohort of Patients With Primary Ciliary Dyskinesia

Marcus P. Kennedy MD, Heymut Omran MD, Margaret W. Leigh MD, Sharon Dell MD, Lucy Morgan MD, Paul L. Molina MD, Blair V. Robinson MD, Susan L. Minnix RN, Heike Olbrich PhD, Thomas Severin MD, Peter Ahrens MD, Lars Lange MD, Hilda N. Morillas MD, Peadar G. Noone MD, Maimoona A. Zariwala PhD, and Michael R. Knowles MD^*

From the University of North Carolina (M.P.K., M.W.L., P.L.M., B.V.R., S.L.M., H.N.M., P.G.N., M.A.Z., M.R.K.), Chapel Hill; University Hospital Freiburg (H. Omran, H. Olbrich, T.S.), Freiburg, Germany; The Toronto Hospital for Sick Children (S.D.), Toronto, Canada; Concord Hospital (L.M.), New South Wales, Australia; Darmstädter Kinderkliniken Prinzessin Margaret (P.A.), Darmstädt, Germany; and University Hospital Cologne (L.L.), Cologne, Germany.

^* To whom correspondence should be addressed. E-mail: knowles{at}med.unc.edu.

Background--Primary ciliary dyskinesia (PCD) is a recessive genetic disorder that is characterized by sinopulmonary disease and reflects abnormal ciliary structure and function. Situs inversus totalis occurs in 50% of PCD patients (Kartagener’s syndrome in PCD), and there are a few reports of PCD with heterotaxy (situs ambiguus), such as cardiovascular anomalies. Advances in diagnosis of PCD, such as genetic testing, allow the systematic investigation of this association.

Methods and Results--The prevalence of heterotaxic defects was determined in 337 PCD patients by retrospective review of radiographic and ultrasound data. Situs solitus (normal situs) and situs inversus totalis were identified in 46.0% and 47.7% of patients, respectively, and 6.3% (21 patients) had heterotaxy. As compared with patients with situs solitus, those with situs abnormalities had more ciliary outer dynein arm defects, fewer inner dynein arm and central apparatus defects (P<0.001), and more mutations in ciliary outer dynein arm genes (DNAI1 and DNAH5; P=0.022). Seven of 12 patients with heterotaxy who were genotyped had mutations in DNAI1 or DNAH5. Twelve patients with heterotaxy had cardiac and/or vascular abnormalities, and most (8 of 12 patients) had complex congenital heart disease.

Conclusions--At least 6.3% of patients with PCD have heterotaxy, and most of those have cardiovascular abnormalities. The prevalence of congenital heart disease with heterotaxy is 200-fold higher in PCD than in the general population (1:50 versus 1:10 000); thus, patients with PCD should have cardiac evaluation. Conversely, mutations in genes that adversely affect both respiratory and embryological nodal cilia are a significant cause of heterotaxy and congenital heart disease, and screening for PCD is indicated in those patients.

Key words: defects • heart defects, congenital • lung • pediatrics • transposition of great vessels

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