Autosomal recessive; defect in CFTR gene on chromosome 7; commonly a deletion of Phe508.Most common lethal genetic disease in Caucasian population.

- CFTR encodes an ATP-gated Cl^- channel that secretes Cl^- in lungs and GI tract, and reabsorbs Cl^- in sweat glands.- Most common mutation → misfolded protein → retained in RER and not transported to cell membrane → ↓ Cl^- and H₂O secretion; ↑ intracellular Cl^- results in compensatory ↑ Na⁺ reabsorption via epithelial Na⁺ channels → ↑ H₂O reabsorption → abnormally thick mucous. ↑ Na⁺ reabsorption also causes more negative transepithelial potential difference.

- ↑ Cl^- concentration (>60 mEq/L) in sweat is diagnostic- Can present with contraction alkalosis and hypocalemia (ECF effects analogous to a patient taking a loop diuretic) because of ECF H₂O/Na⁺ losses and concomitant renal K⁺/H⁺ wasting.- ↑ immunoreactive trypsinogen (newborn screening).

- Recurrent pulmonary infection (eg, S aureus [early infancy], P aeruginosa [adolescence]), chronic bronchitis and bronchiectasis → reticulonodular pattern on CXR, opacification of sinuses.- Pancreatic insufficiency, malabsorption with steatorrhea, fat-soluble vitamin deficiencies (ADEK), biliary cirrhosis, liver disease. Meconium ileus in newborns.- Infertility in men (absence of vas deferens, spermatogenesis may be unaffected) and subfertility in women (amenorrhea, abnormally thick cervical mucus).- Nasal polyps, clubbing of nails

Treatment: Chest physiotherapy, albuterol, aerosolized dornase alfa (DNase), and hypertonic saline facilitate mucus clearance. Azithromycin used as anti-inflammatory agent. Ibuprofen slows disease progression.- In patients with Phe508 deletion: combination of lumacaftor (corrects misfolded proteins and improves their transport to cell surface) and ivacaftor (opens Cl^- channels → improve chloride transport).