CHAPTER 6: CYSTIC FIBROSIS AND SWEAT TESTING

LEARNING OBJECTIVES

INTRODUCTION

Cystic fibrosis (CF) is an autosomal recessive disease that primarily affects young children. CF is considered one of the most common life-shortening genetic diseases in Caucasians. In the classical description of the disease, it usually presents itself with a classic clinical pattern of exocrine pancreatic insufficiency, chronic pulmonary disease, and congenital bilateral absence of the vas deferens in males. Other systems are affected as well including the gastrointestinal and endocrine systems. Upon sweat testing, these patients exhibit chloride concentrations ≥60 mmol/L. Patients with mutations in the CF gene detected by newborn screening programs typically represent the classical form of CF. Many other mutations exhibit a milder, non-classic form of CF in which only one organ system is affected. In these cases, symptoms may or may not develop until beyond the newborn period.

Cystic Fibrosis Transmembrane Conductance Regulator

Cystic fibrosis is caused by mutations found in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a 250 kb gene composed of 27 exons encoding 1,480 amino acids found on the long arm of chromosome 7. CFTR belongs to a family of ATP-binding cassette subfamily C.¹ The protein is found in all exocrine tissue and commonly in the apical portion of mucosal epithelial cells and functions as a chloride channel regulated by cyclic AMP-dependent phosphorylation. The protein contains three primary domains. One domain interacts with ATP and is identified as nucleotide-binding domain 1 (NBD-1) and NBD-2. The second domain is responsible for anchoring the protein in the membrane and is termed membrane-spanning domain 1 (MSD-1) and MSD-2. The final domain is a regulatory domain, termed the R domain, and contains multiple sites for phosphorylation. Mutations affecting the chloride channel result in changes to the transport of ions such as chloride, sodium, and bicarbonate. The functional outcome is the presence of thick, viscous secretions and an overt inflammatory response in the lungs resulting in the inability to clear microorganisms and severe lung disease.

The incidence of clinical CF in the US population is approximately 1:2,500 for Caucasians, 1:13,500 in Hispanics, 1:15,000 in African Americans, and 1:31,000 in Asian Americans, though the incidence in the Asian American population may be influenced by mixing with other ethnic populations.² It is expected that the incidence will continue to increase due to increased detection of CF as inclusion of CF into newborn screening programs increases. Over 2000 mutations are listed in the Cystic Fibrosis Mutation Database with the most common occurring approximately 70% of the time. This mutation results in the deletion of phenylalanine at position 508 (F508del). Due to the founder effect, a high frequency gene mutation found in a specific population due to its presence in ...