title: Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy.
abstract: 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.
  
  
  BACKGROUND
  ClinicalTrials.gov; No.: NCT00323167; URL: www.clinicaltrials.gov.
authors.affiliation: From the Department of Pediatrics, Montreal Children's Hospital, McGill University, Montreal, QC, Canada. Electronic address: adam.shapiro@muhc.mcgill.ca.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Shapiro
authors.affiliation: Department of Pediatrics, Riley Hospital for Children, Indiana University, Indianapolis, IN.
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Davis
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ferkol
authors.affiliation: Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada.
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Dell
authors.affiliation: Department of Pediatrics, Seattle Children's Hospital and University of Washington, Seattle, WA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Rosenfeld
authors.affiliation: National Institute of Allergy and Infectious Diseases, Bethesda, MD.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Olivier
authors.affiliation: Department of Pediatrics, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Sagel
authors.affiliation: Department of Pediatrics, Stanford University, Palo Alto, CA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Milla
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC.
authors.forename: Maimoona A
authors.initials: MA
authors.lastname: Zariwala
authors.affiliation: Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC.
authors.forename: Whitney
authors.initials: W
authors.lastname: Wolf
authors.affiliation: Department of Pediatrics, University of North Carolina School of Medicine, on behalf of the Genetic Disorders of Mucociliary Clearance Consortium, Chapel Hill, NC.
authors.forename: Johnny L
authors.initials: JL
authors.lastname: Carson
authors.affiliation: Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC.
authors.forename: Milan J
authors.initials: MJ
authors.lastname: Hazucha
authors.affiliation: Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC.
authors.forename: Kimberlie
authors.initials: K
authors.lastname: Burns
authors.affiliation: Department of Pediatrics, University of North Carolina School of Medicine, on behalf of the Genetic Disorders of Mucociliary Clearance Consortium, Chapel Hill, NC.
authors.forename: Blair
authors.initials: B
authors.lastname: Robinson
authors.affiliation: Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
authors.affiliation: Department of Pediatrics, University of North Carolina School of Medicine, on behalf of the Genetic Disorders of Mucociliary Clearance Consortium, Chapel Hill, NC.
authors.forename: Margaret W
authors.initials: MW
authors.lastname: Leigh
mesh_terms: D000293:Adolescent; D000328:Adult; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D002923:Cilia / Q000648:ultrastructure*; D004247:DNA / Q000032:analysis*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007619:Kartagener Syndrome / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009154:Mutation; D015995:Prevalence; D011446:Prospective Studies; D014057:Tomography, X-Ray Computed; D014481:United States / Q000453:epidemiology; D055815:Young Adult
chemical_list: D004247:DNA