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Original Research: Genetic and Developmental Disorders |

Laterality Defects Other Than Situs Inversus Totalis in Primary Ciliary DyskinesiaLaterality Defects in Primary Ciliary Dyskinesia: Insights Into Situs Ambiguus and Heterotaxy

Adam J. Shapiro, MD; Stephanie D. Davis, MD; Thomas Ferkol, MD; Sharon D. Dell, MD; Margaret Rosenfeld, MD; Kenneth N. Olivier, MD; Scott D. Sagel, MD; Carlos Milla, MD; Maimoona A. Zariwala, PhD; Whitney Wolf, BS; Johnny L. Carson, PhD; Milan J. Hazucha, MD, PhD; Kimberlie Burns; Blair Robinson, MD; Michael R. Knowles, MD; Margaret W. Leigh, MD on behalf of the Genetic Disorders of Mucociliary Clearance Consortium
Author and Funding Information

From the Department of Pediatrics (Dr Shapiro), Montreal Children’s Hospital, McGill University, Montreal, QC, Canada; Department of Pediatrics (Dr Davis), Riley Hospital for Children, Indiana University, Indianapolis, IN; Department of Pediatrics (Dr Ferkol), Washington University School of Medicine, St. Louis, MO; Department of Pediatrics (Dr Dell), The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada; Department of Pediatrics (Dr Rosenfeld), Seattle Children’s Hospital and University of Washington, Seattle, WA; National Institute of Allergy and Infectious Diseases (Dr Olivier), Bethesda, MD; Department of Pediatrics (Dr Sagel), Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora, CO; Department of Pediatrics (Dr Milla), Stanford University, Palo Alto, CA; and Department of Pathology and Laboratory Medicine (Dr Zariwala), Department of Medicine (Mss Wolf and Burns and Drs Hazucha and Knowles), and Department of Pediatrics (Drs Carson, Robinson, and Leigh), University of North Carolina School of Medicine, Chapel Hill, NC.

CORRESPONDENCE TO: Adam J. Shapiro, MD, Department of Pediatrics, Montreal Children’s Hospital, McGill University, 2300 Tupper, D-380, Montreal, QC H3H 1P3, Canada; e-mail: adam.shapiro@muhc.mcgill.ca


FOR EDITORIAL COMMENT SEE PAGE 1136

Dr Shapiro was affiliated with the University of North Carolina when this research began.

FUNDING/SUPPORT: Funding for this research was provided to Drs Shapiro, Davis, Ferkol, Dell, Rosenfeld, Olivier, Sagel, Milla, Zariwala, Carson, Hazucha, Knowles, and Leigh and Mss Wolf and Burns by National Institutes of Health (NIH), Office of Rare Diseases Research, National Heart, Lung, and Blood Institute (NHLBI) [Grant 5US54HL096458-06] and to Drs Zariwala and Knowles by NIH, NHLBI [Grant 5R01HL071798] and NIH, National Center for Advancing Translational Science (NCATS) [Grant UL1TR000083]. Funding for Dr Rosenfeld was provided by NIH/NCATS [Grant UL1TR000423]. Funding for Dr Olivier was provided by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. Funding for Dr Sagel was by NIH/NCATS Colorado Clinical and Translational Sciences Institute [Grant UL1TR000154]. The Genetic Disorders of Mucociliary Clearance Consortium [U54HL096458] is a part of the NIH Rare Diseases Clinical Research Network supported through collaboration between the NIH Office of Rare Diseases Research at the NCATS and the National Heart, Lung, and Blood Institute.

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):1176-1186. doi:10.1378/chest.13-1704
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BACKGROUND:  Motile cilia dysfunction causes primary ciliary dyskinesia (PCD), situs inversus totalis (SI), and a spectrum of laterality defects, yet the prevalence of laterality defects other than SI in PCD has not been prospectively studied.

METHODS:  In this prospective study, participants with suspected PCD were referred to our multisite consortium. We measured nasal nitric oxide (nNO) level, examined cilia with electron microscopy, and analyzed PCD-causing gene mutations. Situs was classified as (1) situs solitus (SS), (2) SI, or (3) situs ambiguus (SA), including heterotaxy. Participants with hallmark electron microscopic defects, biallelic gene mutations, or both were considered to have classic PCD.

RESULTS:  Of 767 participants (median age, 8.1 years, range, 0.1-58 years), classic PCD was defined in 305, including 143 (46.9%), 125 (41.0%), and 37 (12.1%) with SS, SI, and SA, respectively. A spectrum of laterality defects was identified with classic PCD, including 2.6% and 2.3% with SA plus complex or simple cardiac defects, respectively; 4.6% with SA but no cardiac defect; and 2.6% with an isolated possible laterality defect. Participants with SA and classic PCD had a higher prevalence of PCD-associated respiratory symptoms vs SA control participants (year-round wet cough, P < .001; year-round nasal congestion, P = .015; neonatal respiratory distress, P = .009; digital clubbing, P = .021) and lower nNO levels (median, 12 nL/min vs 252 nL/min; P < .001).

CONCLUSIONS:  At least 12.1% of patients with classic PCD have SA and laterality defects ranging from classic heterotaxy to subtle laterality defects. Specific clinical features of PCD and low nNO levels help to identify PCD in patients with laterality defects.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT00323167; URL: www.clinicaltrials.gov

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