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Previous Volume 347:401-407 August 8, 2002 Number 6 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Editorial by Knowles, M. R. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Cystic fibrosis is a life-limiting autosomal recessive disorder with a highly variable clinical presentation. The classic form involves characteristic findings in the respiratory tract, gastrointestinal tract, male reproductive tract, and sweat glands and is caused by loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR ) gene. Nonclassic forms of cystic fibrosis have been associated with mutations that reduce but do not eliminate the function of the CFTR protein. We assessed whether alteration in CFTR function is responsible for the entire spectrum of variant cystic fibrosis phenotypes.

Methods Extensive genetic analysis of the CFTR gene was performed in 74 patients with nonclassic cystic fibrosis who had been referred by 34 medical centers. We evaluated two families that each included a proband without identified mutations and a sibling with nonclassic cystic fibrosis to determine whether there was linkage to the CFTR locus and to measure the extent of CFTR function in the sweat gland and nasal epithelium.

Results Of the 74 patients studied, 29 had two mutations in the CFTR gene, 15 had one mutation, and 30 had no mutations. A final genotype of two mutations was more common among patients who had been referred after screening for common cystic fibrosis–causing mutations identified one mutation than among those who had been referred after screening had identified no such mutations (26 of 34 patients vs. 3 of 40 patients, P<0.001). Comparison of clinical features and sweat chloride concentrations revealed no significant differences among patients with two, one, or no CFTR mutations. Haplotype analysis in the two families revealed no linkage to CFTR. Although each of the affected siblings had elevated sweat chloride concentrations, measurements of cyclic AMP–mediated ion and fluid transport in the sweat gland and nasal epithelium demonstrated the presence of functional CFTR.

Conclusions Factors other than mutations in the CFTR gene can produce phenotypes clinically indistinguishable from nonclassic cystic fibrosis caused by CFTR dysfunction.

Source Information

From the McKusick–Nathans Institute of Genetic Medicine and Cystic Fibrosis Foundation Genotyping Center (J.D.G., M.E.M., G.R.C.), the Predoctoral Training Program in Human Genetics (J.D.G.), and the Department of Pediatrics (P.L.Z., G.R.C.), Johns Hopkins University School of Medicine, Baltimore; and the Department of Pediatrics, Saint Louis University School of Medicine, St. Louis (R.W.W.).

Address reprint requests to Dr. Cutting at Childrens Medical Surgical Center 9-125, 600 N. Wolfe St., Baltimore, MD 21287, or at gcutting{at}jhmi.edu.

Full Text of this Article

Related Letters:

Variant Cystic Fibrosis Phenotypes in the Absence of CFTR Mutations
Couper R. T.L., Groman J. D., Cutting G. R.
Extract | Full Text | PDF  
N Engl J Med 2002; 347:1892-1893, Dec 5, 2002. Correspondence

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