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High-speed Video Microscopy Analysis for First-line Diagnosis of Primary Ciliary Dyskinesia
Published on: January 19, 2022
Clinical features of childhood primary ciliary dyskinesia by genotype and ultrastructural phenotype
Stephanie D Davis1, Thomas W Ferkol, Margaret Rosenfeld
11 Department of Pediatrics and.
Insights
Childhood primary ciliary dyskinesia (PCD) lung disease varies by defect type. Inner dynein arm/central apparatus defects with microtubular disorganization (IDA/CA/MTD) show worse lung function and imaging compared to outer dynein arm (ODA) defects.
Area of Science:
- Pediatric Pulmonology
- Genetics
- Cell Biology
Background:
- Primary ciliary dyskinesia (PCD) is a rare genetic disorder affecting cilia function.
- The correlation between PCD's clinical presentation, ciliary ultrastructure, and genetic mutations is not well understood.
- Understanding these relationships is crucial for accurate diagnosis and management of childhood PCD.
Purpose of the Study:
- To investigate the clinical characteristics of childhood PCD.
- To determine associations between clinical phenotypes, ciliary ultrastructural defects, and specific genotypes in pediatric PCD patients.
- To provide a comprehensive overview of PCD heterogeneity in children.
Main Methods:
- Prospective evaluation of 118 children (<19 years) with PCD across six North American centers.
- Standardized diagnostic testing, including spirometry, chest CT scans, and respiratory cultures.
- Detailed clinical phenotyping and correlation with ultrastructural defect analysis and genetic data.
Main Results:
- Common clinical features include neonatal respiratory distress, chronic cough, and nasal congestion.
- No significant differences in clinical features or pathogens were found between outer dynein arm (ODA) defects and combined ODA/inner dynein arm (IDA) defects.
- Subjects with IDA and central apparatus defects with microtubular disorganization (IDA/CA/MTD) exhibited worse FEV1, lower BMI, and more extensive bronchiectasis and consolidation, particularly in younger children.
- These findings were consistent in participants with biallelic mutations.
Conclusions:
- Childhood PCD presents with heterogeneous lung disease across different ultrastructural and genetic groups.
- IDA/CA/MTD defects are associated with more severe lung disease manifestations compared to ODA defects.
- Mutations in CCDC39 or CCDC40 are frequently observed in patients with IDA/CA/MTD defects and severe PCD.
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.
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