Clinical features of childhood primary ciliary dyskinesia by genotype and ultrastructural phenotype

Abstract

Rationale: The relationship between clinical phenotype of childhood primary ciliary dyskinesia (PCD) and ultrastructural defects and genotype is poorly defined.

Objectives: To delineate clinical features of childhood PCD and their associations with ultrastructural defects and genotype.

Methods: A total of 118 participants younger than 19 years old with PCD were evaluated prospectively at six centers in North America using standardized procedures for diagnostic testing, spirometry, chest computed tomography, respiratory cultures, and clinical phenotyping.

Measurements and main results: Clinical features included neonatal respiratory distress (82%), chronic cough (99%), and chronic nasal congestion (97%). There were no differences in clinical features or respiratory pathogens in subjects with outer dynein arm (ODA) defects (ODA alone; n = 54) and ODA plus inner dynein arm (IDA) defects (ODA + IDA; n = 18) versus subjects with IDA and central apparatus defects with microtubular disorganization (IDA/CA/MTD; n = 40). Median FEV1 was worse in the IDA/CA/MTD group (72% predicted) versus the combined ODA groups (92% predicted; P = 0.003). Median body mass index was lower in the IDA/CA/MTD group (46th percentile) versus the ODA groups (70th percentile; P = 0.003). For all 118 subjects, median number of lobes with bronchiectasis was three and alveolar consolidation was two. However, the 5- to 11-year-old IDA/CA/MTD group had more lobes of bronchiectasis (median, 5; P = 0.0008) and consolidation (median, 3; P = 0.0001) compared with the ODA groups (median, 3 and 2, respectively). Similar findings were observed when limited to participants with biallelic mutations.

Conclusions: Lung disease was heterogeneous across all ultrastructural and genotype groups, but worse in those with IDA/CA/MTD ultrastructural defects, most of whom had biallelic mutations in CCDC39 or CCDC40.

Keywords: Kartagener syndrome; X-ray computed tomography scanners; cilia; respiratory function tests; ultrastructure.

Figure 1.

Pulmonary function measures (A) FEV₁ and (B) forced expiratory flow, midexpiratory phase (FEF_25–75) % predicted plotted as a function of age in pediatric subjects with primary ciliary dyskinesia (n = 82). Circles represent subjects with primary ciliary dyskinesia who have outer dynein arm (ODA) defects that include absent or truncated ODA and combined absence of ODA and inner dynein arm (IDA) (groups 1 and 2). Squares represent individuals who have microtubular disorganization (MTD) associated with IDA and central apparatus (CA) defects (IDA/CA/MTD, group 3). Filled symbols identify subjects who have known biallelic genetic defects, whereas open symbols indicate those subjects for whom the genetic basis of their disease is yet unknown. In this cross-sectional study, the association of both FEV₁ and FEF_25–75 with age declines for subjects with IDA/CA/MTD derangements (group 3) compared with the combined ODA groups, ODA (group 1) and ODA + IDA (group 2) (P = 0.003 and 0.010, respectively). The slope of FEV₁ change in the IDA/CA/MTD group was −3.88% predicted per year (dashed line), or −3.90% predicted per year for subjects with known genetic defects. The FEV₁ slope of the combined ODA and ODA + IDA groups was 0.085% predicted per year (solid line), or 0.64% predicted per year in known genetic defects. The slope of FEF_25–75 change was −4.09% predicted per year (dashed line), or −5.03% predicted per year in known genetic defects, in the IDA/CA/MTD cohort, and 0.30% predicted per year (solid line), or 0.70% predicted per year in known genetic defects, for the combined ODA and ODA + IDA groups.

Figure 2.

Radiographic findings of (A) bronchiectasis and (B) alveolar consolidation in individual lobes and lingula in pediatric subjects with primary ciliary dyskinesia (n = 112), segregated into different age groups (<5 yr, 5–11 yr, and 12–18 yr of age). Circles represent subjects with primary ciliary dyskinesia who have outer dynein arm (ODA) defects, which include absent or truncated ODA and complete absence of both ODA and inner dynein arm (IDA) (groups 1 and 2). Squares represent individuals who have microtubular disorganization (MTD) associated with IDA and central apparatus (CA) defects (IDA/CA/MTD, group 3). The vertical lines represent median and first and third quartile. Subjects with IDA/CA/MTD defects between the ages of 5 and 11 years have increased bronchiectasis (P = 0.0008) and alveolar consolidation (P = 0.0001) compared with the combined ODA groups, ODA (group 1) and ODA + IDA defects (group 2).