title: Clinical Features and Associated Likelihood of Primary Ciliary Dyskinesia in Children and Adolescents.
abstract: Primary ciliary dyskinesia (PCD), a genetically heterogeneous, recessive disorder of motile cilia, is associated with distinct clinical features. Diagnostic tests, including ultrastructural analysis of cilia, nasal nitric oxide measurements, and molecular testing for mutations in PCD genes, have inherent limitations.
  
  
  
  To define a statistically valid combination of systematically defined clinical features that strongly associates with PCD in children and adolescents.
  
  
  
  Investigators at seven North American sites in the Genetic Disorders of Mucociliary Clearance Consortium prospectively and systematically assessed individuals (aged 0-18 yr) referred due to high suspicion for PCD. The investigators defined specific clinical questions for the clinical report form based on expert opinion. Diagnostic testing was performed using standardized protocols and included nasal nitric oxide measurement, ciliary biopsy for ultrastructural analysis of cilia, and molecular genetic testing for PCD-associated genes. Final diagnoses were assigned as "definite PCD" (hallmark ultrastructural defects and/or two mutations in a PCD-associated gene), "probable/possible PCD" (no ultrastructural defect or genetic diagnosis, but compatible clinical features and nasal nitric oxide level in PCD range), and "other diagnosis or undefined." Criteria were developed to define early childhood clinical features on the basis of responses to multiple specific queries. Each defined feature was tested by logistic regression. Sensitivity and specificity analyses were conducted to define the most robust set of clinical features associated with PCD.
  
  
  
  From 534 participants 18 years of age and younger, 205 were identified as having "definite PCD" (including 164 with two mutations in a PCD-associated gene), 187 were categorized as "other diagnosis or undefined," and 142 were defined as having "probable/possible PCD." Participants with "definite PCD" were compared with the "other diagnosis or undefined" group. Four criteria-defined clinical features were statistically predictive of PCD: laterality defect; unexplained neonatal respiratory distress; early-onset, year-round nasal congestion; and early-onset, year-round wet cough (adjusted odds ratios of 7.7, 6.6, 3.4, and 3.1, respectively). The sensitivity and specificity based on the number of criteria-defined clinical features were four features, 0.21 and 0.99, respectively; three features, 0.50 and 0.96, respectively; and two features, 0.80 and 0.72, respectively.
  
  
  
  Systematically defined early clinical features could help identify children, including infants, likely to have PCD. Clinical trial registered with ClinicalTrials.gov (NCT00323167).
authors.affiliation: 1 Department of Pediatrics.|2 Marsico Lung Institute.
authors.forename: Margaret W
authors.initials: MW
authors.lastname: Leigh
authors.affiliation: 3 Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Ferkol
authors.affiliation: 4 Department of Pediatrics, Riley Children's Hospital, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Davis
authors.affiliation: 5 Department of Pediatrics, University of South Florida, Tampa, Florida.
authors.forename: Hye-Seung
authors.initials: HS
authors.lastname: Lee
authors.affiliation: 6 Seattle Children's Hospital, Seattle, Washington.
authors.forename: Margaret
authors.initials: M
authors.lastname: Rosenfeld
authors.affiliation: 7 Department of Paediatrics, The Hospital for Sick Children, and.|8 Institute for Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Dell
authors.affiliation: 9 Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Sagel
authors.affiliation: 10 Department of Pediatrics, Stanford University, Palo Alto, California; and.
authors.forename: Carlos
authors.initials: C
authors.lastname: Milla
authors.affiliation: 11 National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Olivier
authors.affiliation: 2 Marsico Lung Institute.|12 Department of Medicine.
authors.forename: Kelli M
authors.initials: KM
authors.lastname: Sullivan
authors.affiliation: 2 Marsico Lung Institute.|13 Department of Pathology and Laboratory Medicine, and.
authors.forename: Maimoona A
authors.initials: MA
authors.lastname: Zariwala
authors.affiliation: 3 Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Pittman
authors.affiliation: 1 Department of Pediatrics.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Shapiro
authors.affiliation: 1 Department of Pediatrics.|14 Center for Environmental Medicine, Asthma and Lung Biology, UNC School of Medicine, Chapel Hill, North Carolina.
authors.forename: Johnny L
authors.initials: JL
authors.lastname: Carson
authors.affiliation: 5 Department of Pediatrics, University of South Florida, Tampa, Florida.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Krischer
authors.affiliation: 12 Department of Medicine.|14 Center for Environmental Medicine, Asthma and Lung Biology, UNC School of Medicine, Chapel Hill, North Carolina.
authors.forename: Milan J
authors.initials: MJ
authors.lastname: Hazucha
authors.affiliation: 2 Marsico Lung Institute.|12 Department of Medicine.
authors.forename: Michael R
authors.identifier: 0000-0002-4672-5969
authors.initials: MR
authors.lastname: Knowles
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002923:Cilia / Q000648:ultrastructure; D003955:Diagnostic Tests, Routine / Q000592:standards*; D005260:Female; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007619:Kartagener Syndrome / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology*; D016015:Logistic Models; D008297:Male; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D009569:Nitric Oxide / Q000032:analysis; D009864:Ontario / Q000453:epidemiology; D010641:Phenotype; D011336:Probability; D011446:Prospective Studies; D012127:Respiratory Distress Syndrome, Newborn / Q000209:etiology; D012680:Sensitivity and Specificity; D014481:United States / Q000453:epidemiology
chemical_list: D009569:Nitric Oxide
keywords: clinical features; laterality defects; neonatal respiratory distress; primary ciliary dyskinesia