Clinical features and associated likelihood of primary ciliary dyskinesia in children and adolescents

Margaret W. Leigh, Thomas W. Ferkol, Stephanie Davis, Hye Seung Lee, Margaret Rosenfeld, Sharon D. Dell, Scott D. Sagel, Carlos Milla, Kenneth N. Olivier, Kelli M. Sullivan, Maimoona A. Zariwala, Jessica E. Pittman, Adam J. Shapiro, Johnny L. Carson, Jeffrey Krischer, Milan J. Hazucha, Michael R. Knowles

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Rationale: 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. Objectives: To define a statistically valid combination of systematically defined clinical features that strongly associates with PCD in children and adolescents. Methods: 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. Measurements and Main Results: 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. Conclusions: Systematically defined early clinical features could help identify children, including infants, likely to have PCD.

Original languageEnglish (US)
Pages (from-to)1305-1313
Number of pages9
JournalAnnals of the American Thoracic Society
Volume13
Issue number8
DOIs
StatePublished - 2016

Fingerprint

Kartagener Syndrome
Nose
Cilia
Nitric Oxide
Mutation
Genes
Research Personnel
Mucociliary Clearance
Sensitivity and Specificity
Inborn Genetic Diseases

Keywords

  • Clinical features
  • Laterality defects
  • Neonatal respiratory distress
  • Primary ciliary dyskinesia

ASJC Scopus subject areas

  • Medicine(all)
  • Pulmonary and Respiratory Medicine

Cite this

Clinical features and associated likelihood of primary ciliary dyskinesia in children and adolescents. / Leigh, Margaret W.; Ferkol, Thomas W.; Davis, Stephanie; Lee, Hye Seung; Rosenfeld, Margaret; Dell, Sharon D.; Sagel, Scott D.; Milla, Carlos; Olivier, Kenneth N.; Sullivan, Kelli M.; Zariwala, Maimoona A.; Pittman, Jessica E.; Shapiro, Adam J.; Carson, Johnny L.; Krischer, Jeffrey; Hazucha, Milan J.; Knowles, Michael R.

In: Annals of the American Thoracic Society, Vol. 13, No. 8, 2016, p. 1305-1313.

Research output: Contribution to journalArticle

Leigh, MW, Ferkol, TW, Davis, S, Lee, HS, Rosenfeld, M, Dell, SD, Sagel, SD, Milla, C, Olivier, KN, Sullivan, KM, Zariwala, MA, Pittman, JE, Shapiro, AJ, Carson, JL, Krischer, J, Hazucha, MJ & Knowles, MR 2016, 'Clinical features and associated likelihood of primary ciliary dyskinesia in children and adolescents', Annals of the American Thoracic Society, vol. 13, no. 8, pp. 1305-1313. https://doi.org/10.1513/AnnalsATS.201511-748OC
Leigh, Margaret W. ; Ferkol, Thomas W. ; Davis, Stephanie ; Lee, Hye Seung ; Rosenfeld, Margaret ; Dell, Sharon D. ; Sagel, Scott D. ; Milla, Carlos ; Olivier, Kenneth N. ; Sullivan, Kelli M. ; Zariwala, Maimoona A. ; Pittman, Jessica E. ; Shapiro, Adam J. ; Carson, Johnny L. ; Krischer, Jeffrey ; Hazucha, Milan J. ; Knowles, Michael R. / Clinical features and associated likelihood of primary ciliary dyskinesia in children and adolescents. In: Annals of the American Thoracic Society. 2016 ; Vol. 13, No. 8. pp. 1305-1313.
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T1 - Clinical features and associated likelihood of primary ciliary dyskinesia in children and adolescents

AU - Leigh, Margaret W.

AU - Ferkol, Thomas W.

AU - Davis, Stephanie

AU - Lee, Hye Seung

AU - Rosenfeld, Margaret

AU - Dell, Sharon D.

AU - Sagel, Scott D.

AU - Milla, Carlos

AU - Olivier, Kenneth N.

AU - Sullivan, Kelli M.

AU - Zariwala, Maimoona A.

AU - Pittman, Jessica E.

AU - Shapiro, Adam J.

AU - Carson, Johnny L.

AU - Krischer, Jeffrey

AU - Hazucha, Milan J.

AU - Knowles, Michael R.

PY - 2016

Y1 - 2016

N2 - Rationale: 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. Objectives: To define a statistically valid combination of systematically defined clinical features that strongly associates with PCD in children and adolescents. Methods: 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. Measurements and Main Results: 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. Conclusions: Systematically defined early clinical features could help identify children, including infants, likely to have PCD.

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KW - Clinical features

KW - Laterality defects

KW - Neonatal respiratory distress

KW - Primary ciliary dyskinesia

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