Clinical Features and Associated Likelihood of Primary Ciliary Dyskinesia in Children and Adolescents

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. Clinical trial registered with ClinicalTrials.gov (NCT00323167).

Keywords: clinical features; laterality defects; neonatal respiratory distress; primary ciliary dyskinesia.

Figures

Figure 1.

Schematic diagram showing general clinical features and series of questions to define criteria-defined clinical features. The four criteria-defined clinical features most predictive of primary ciliary dyskinesia were unexplained neonatal respiratory distress, early onset, year-round wet cough, early onset, year-round nasal congestion, and laterality defects. The sensitivity and specificity to identify children and adolescents with primary ciliary dyskinesia are shown for each general clinical feature and its respective criteria-defined clinical feature. Early onset is defined as onset before 6 months of age; year-round is defined as occurring in all 12 months of the year; and wet cough is defined as sounds productive even if unable to expectorate sputum.

Figure 2.

Receiver operating characteristic curves for the criteria-defined clinical features. The unweighted receiver operating characteristic curve (solid curved line) uses a uniform weight for each of the four significant criteria-defined clinical features. For the weighted curve (dashed line), each clinical feature is weighted by its logistic regression parameter estimate from Table 3 (2.05 for laterality defect, 1.89 for neonatal respiratory distress, 1.28 for nasal congestion, 1.13 for chronic cough and 0.01 for multiple ear infections). The areas under the curve were 0.86 (95% confidence interval, 0.82–0.89) for the weighted receiver operating characteristic curve and 0.84 (95% confidence interval, 0.81–0.88) for the unweighted receiver operating characteristic curve. The weighted curve was minimally better than the unweighted curve (P = 0.019), but the shape was similar except for the region of sensitivity (50–80%).