Definition

• An inherited disorder caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Epidemiology

• the most common lethal genetic disease in Caucasian populations.

 • About 1 in 2500 live births in Caucasian populations.

 Genetics

 • Inherited in an autosomal recessive manner.

• CFTR is on chromosome 7q and codes for an anion channel that regulates multiple cellular ion channels.

 • Over 1400 mutations have been described, though the most common is a deletion at position 508 that leads to loss of a phenylalanine amino acid (the ΔF508 mutation).

 Pathogenesis

 • the ΔF508 mutation is a processing mutation that causes abnormal folding of the CFTR protein and its subsequent degradation in the cell.

• In sweat ducts, abnormal CFTR function causes reduced absorption of sodium chloride with production of salty sweat.

 • In the lungs and gut, abnormal CFTR function result in reduced chloride secretion and increased sodium absorption. As a result, passive water reabsorption increases lowering surface water content of epithelial cells.

 • In the lungs, this causes viscid secretions that obstruct the airways and predispose to recurrent infections.

 Presentation

• Most patients present with pulmonary disease due to recurrent infections. Initially, common bacteria colonize the lungs, but eventually Pseudomonas aeruginosa often becomes the dominant organism.

• Pancreatic insufficiency is also common.

 • Bowel obstruction may occur in the neonatal period due to thick meconium (meconium ileus) or develop later in childhood.

• Liver disease develops late.

• Some cases may be diagnosed when a raised serum immunoreactive trypsin is picked up on neonatal screening.

Macroscopy

• Lungs from older children usually show widespread bronchiectasis.

 • the liver may appear fatty and, in severe cases, may be cirrhotic.

 Histopathology

 • Lungs show bronchiectatic airways containing thick mucus. Acute inflammation may be seen if there is active infection.

 • the liver shows inspissated bile in intrahepatic bile ducts. there may be periportal fibrosis and, in more severe cases, cirrhosis.

Prognosis

 • Major improvements in management have extended average life expectancy to 50 years.

• Most patients die as a result of pulmonary disease.

 • novel genetic treatments for restoring CFTR function are being investigated in clinical trials