Overlapping Clinical Phenotypes in Patients With Primary Ciliary Dyskinesia or Activated Phosphoinositide 3-Kinase Delta Syndrome

To examine the overlap between primary ciliary dyskinesia (PCD) and activated phosphoinositide 3-kinase delta syndrome type 1 (APDS1). PCD and APDS1 are genetically distinct, but they may present with similar features, including recurrent respiratory infections and a decreased nasal nitric oxide (nNO).The study included 8 participants with chronic respiratory infections who were referred for evaluation of PCD. Participants were from 5 countries (Great Britain, Germany, Mexico, Canada, and the United States). The median age was 10 years at research enrollment (range 4-19 years) and 4 were male.Study participants were identified via their participation in international PCD research networks. These include the Genetic Disorders of Mucociliary Clearance Consortium, Vanderbilt University, the Rare Lung Disease of Latin America Foundation, and the Clinical Genetics and Genomics Laboratory at the Royal Brompton Hospital. nNO measurements were done using chemiluminescence devices. Transmission electron microscopy analysis of respiratory epithelial cells was performed and interpreted using European Respiratory Society consensus guidelines. Genetic analysis was done through next-generation sequencing panels or whole-exome sequencing. Immunophenotyping and in vitro functional immune assays were performed in select patients.All participants were found to have heterozygous, pathogenic, activating PIK3CD variants causing APDS1. Six of the 8 participants shared a common known pathogenic PIK3CD variant, c.3061 G>A, p.(Glu1021Lys) in exon 24 (dbSNP: rs397518423). Two unrelated participants had a variant at c.1574 A>G, (p.Glu525Gly) in exon 13 (dbSNP: rs1557669079). This variant initially was classified as having uncertain significance, but in vitro functional testing confirmed pathogenicity. Five of the 8 participants had low levels of nNO (<77 nL/min), which is highly suggestive of PCD. Ciliary electron microscopy was normal in 2 patients. One hundred percent of patients had recurrent otitis media, 88% had recurrent sinusitis, 88% had bronchiectasis, 75% had nodular lymphoid hyperplasia of airway mucosa, and 75% had previously been hospitalized for respiratory symptoms. In addition, 100% of patients had chronic cough, 75% had persistent nasal congestion, 13% had neonatal respiratory distress, and 13% had an organ laterality defect, all symptoms that, when combined, are highly specific for PCD.Children with PCD and APDS1 share considerable overlap in their clinical presentations. Both conditions present with upper and lower respiratory tract infections with encapsulated organisms in early childhood. In addition, screening nNO may also be low in both conditions. Both PCD and APDS1 should be considered in patients with this clinical phenotype.This study emphasizes the need for heightened awareness among pediatricians and pediatric subspecialists regarding the clinical overlap between APDS1 and PCD. The identification of pathogenic PIK3CD variants in all participants referred for PCD evaluation underscores the importance of early genetic testing in patients with a PCD-like phenotype, particularly when traditional diagnostics yield inconclusive results. The authors’ findings further highlight the clinical value of genetic testing, especially given the availability of targeted therapies such as leniolisib, a selective PI3Kδ inhibitor, for patients with APDS1.

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