A 17-year-old boy presents with chronic productive cough, recurrent pneumonias, pancreatic insufficiency, and failure to thrive. Spirometry shows FEV1 45%, FVC 60%, FEV1/FVC 0.62. The flow-volume loop demonstrates the pattern marked **A** — scooped expiratory limb indicating airway obstruction — along with reduced overall lung volumes. Which of the following CFTR mutations is most commonly responsible for this mixed obstructive-restrictive pattern in advanced cystic fibrosis?

Explanation

## Why ΔF508 is right ΔF508 is the most common CFTR mutation worldwide, accounting for ~70% of CF alleles in European populations and ~50% in Indian CF cohorts. This mutation causes misfolding of the CFTR chloride channel protein, leading to impaired trafficking to the apical membrane and loss of function. The resulting defective chloride secretion produces dehydrated, viscous airway secretions that impair mucociliary clearance, driving chronic Pseudomonas aeruginosa infection and progressive bronchiectasis. The scooped expiratory limb (**A**) reflects small airway obstruction from bronchial wall thickening and mucus plugging, while reduced FVC reflects restrictive changes from bronchiectasis and parenchymal fibrosis — the hallmark mixed pattern of advanced CF. ΔF508 homozygotes typically develop this severe phenotype by adolescence (Nelson Textbook of Pediatrics, 21st ed; CFF Patient Registry 2024). ## Why each distractor is wrong - **G551D**: This is a gating mutation (channel opens but conducts poorly) found in ~5% of CF patients. It causes a milder phenotype and is specifically targeted by IVACAFTOR monotherapy. Patients with G551D typically have better lung function than ΔF508 homozygotes and would not present with FEV1 of 45% at age 17 without additional mutations. - **R117H**: This is a rare, often benign variant associated with mild or atypical CF (e.g., isolated CBAVD or pancreatitis). It does not cause the severe mixed obstructive-restrictive pattern with pancreatic insufficiency and failure to thrive seen in this patient. - **W1282X**: This nonsense mutation produces a truncated, non-functional CFTR protein. While severe, it is much less common than ΔF508 globally and in Indian populations, making it statistically unlikely in this clinical presentation. **High-Yield:** ΔF508 (most common CF mutation) → misfolded CFTR → impaired Cl⁻ secretion → viscous secretions → bronchiectasis → mixed obstructive-restrictive spirometry pattern + pancreatic insufficiency. [cite: Nelson Textbook of Pediatrics 21st ed; CFF Patient Registry 2024]