RESUMEN
RATIONALE: Bronchiectasis is a pathological dilatation of the bronchi in the respiratory airways associated with environmental or genetic causes (e.g., cystic fibrosis, primary ciliary dyskinesia and primary immunodeficiency disorders), but most cases remain idiopathic. OBJECTIVES: To identify novel genetic defects in unsolved cases of bronchiectasis presenting with severe rhinosinusitis, nasal polyposis, and pulmonary Pseudomonas aeruginosa infection. METHODS: DNA was analyzed by next-generation or targeted Sanger sequencing. RNA was analyzed by quantitative PCR and single-cell RNA sequencing. Patient-derived, cells, cell cultures and secretions (mucus, saliva, seminal fluid) were analyzed by Western blotting and immunofluorescence microscopy, and mucociliary activity was measured. Blood serum was analyzed by electrochemiluminescence immunoassay. Protein structure and proteomic analyses were used to assess the impact of a disease-causing founder variant. MEASUREMENTS AND MAIN RESULTS: We identified bi-allelic pathogenic variants in WFDC2 in 11 individuals from 10 unrelated families originating from the United States, Europe, Asia, and Africa. Expression of WFDC2 was detected predominantly in secretory cells of control airway epithelium and also in submucosal glands. We demonstrate that WFDC2 is below the limit of detection in blood serum and hardly detectable in samples of saliva, seminal fluid, and airway surface liquid from WFDC2-deficient individuals. Computer simulations and deglycosylation assays indicate that the disease-causing founder variant p.Cys49Arg structurally hampers glycosylation and thus secretion of mature WFDC2. CONCLUSIONS: WFDC2 dysfunction defines a novel molecular etiology of bronchiectasis characterized by the deficiency of a secreted component of the airways. A commercially available blood test combined with genetic testing allows its diagnosis. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
RESUMEN
We report the case of a 6-year-old boy who presented with a 2-month history of stridor and respiratory difficulty, preceded 1 month earlier by dry cough. The evaluation before admission revealed glottic narrowing due to diffuse inflammatory changes. On examination, the patient was seen to have biphasic stridor and respiratory distress with diminished breath sounds throughout both lung fields. Laryngoscopy revealed multiple polyps and granulation tissue causing marked laryngeal narrowing. No foreign body was detected in the larynx. Elective tracheostomy was performed before proceeding to bronchoscopy. The latter procedure revealed a foreign body in the left main bronchus. One week after the foreign body extraction, repeat bronchoscopy revealed nearly total disappearance of polyps and granulation tissues. The tracheostomy tube was removed and the patient recovered uneventfully. To our knowledge, this is the first reported case of stridor caused by a migrating laryngeal foreign body. A thorough endobronchial examination should be carried out in patients with unexplained laryngeal polyps and granulation tissue.