Cystic fibrosis (CF) is the most common, inherited disease of Caucasians, found in roughly 1 in 3,000 live births based on epidemiologic data, and a multisystem disease of exocrine gland function that typically involves the lungs, paranasal sinuses, skin, pancreas, male reproductive tract (vas deferens), intestines, and biliary tract.
An autosomal recessive defect, the life expectancy of a child born with CF in the United States has gradually improved and is now extending well into adulthood. Nevertheless, much of the morbidity in the "classic" disease still results from progressive lung disease, characterized by airway infection and inflammation that ultimately leads to bronchiectasis, respiratory failure, and death. Defective function of the cystic fibrosis transmembrane conductance regulator (CFTR) and associated channels in airway epithelial cells and submucosal glands results in dehydration of endobronchial secretions. These desiccated secretions obstruct the airways and prevent the elimination of bacteria from the lung, thus allowing infection to become established. Current management of pulmonary disease in CF has been directed at the downstream consequences of CFTR dysfunction, focusing on the treatment of airway infection and inflammation.
Historically, CF has been divided into distinct, clinical phenotypes, but with the advent of genetic testing for CF, milder or variant forms of the disease have been recognized. Indeed, it has become increasingly clear that the disease exists as a continuum and clinical manifestations correlate with levels of CFTR activity. The course of pulmonary disease in these milder variants has not been well defined in terms of microbial colonization of the lower respiratory tract and the development of bronchiectasis.
A common problem for physicians is the presentation of children with CF-like pulmonary disease, but normal or equivocally elevated sweat electrolyte concentrations but negative for mutant CFTR alleles. These patients are a difficult, diagnostic conundrum for clinicians. We plan to characterize and better define atypical or variant forms of CF in this consortium and determine mechanisms by which mutant CFTR expression contributes to pathogenesis and pulmonary outcomes in variant forms of the disease.