Correspondence

A Cystic Fibrosis Mutation Associated with Mild Lung Disease

N Engl J Med 1995; 333:1644December 14, 1995

Article

To the Editor:

Gan et al. (July 13 issue)1 report an association between a cystic fibrosis mutation that is common in the Netherlands (A455E) and mild pulmonary disease; this mutation has also been associated with relatively mild pancreatic involvement.2 Milder disease in patients with the A455E mutation is presumably related to the residual ability of cells to secrete chloride, which has been found in rectal-biopsy specimens.3 We wonder whether, as a result of residual chloride secretion, the sweat chloride values in the compound heterozygotes with the A455E mutation were lower than those in patients with more severe disease (ΔF508 homozygotes) and whether there were some initial difficulties in confirming the diagnosis of cystic fibrosis (before the genotype analysis had been done), if the values were below the generally accepted cutoff value of 60 mmol per liter.

Recent reports4,5 have clearly shown that normal sweat chloride values, and even those as low as 16 mmol per liter, do not absolutely rule out the diagnosis of cystic fibrosis. In the case of a patient with a constellation of signs and symptoms suggestive of cystic fibrosis but in whom the results of sweat testing are not clearly positive, no known cystic fibrosis mutations can be identified, and electrophysiologic testing is not practical, making a definitive diagnosis remains a troublesome problem for clinicians.

Lee S. Rusakow, M.D.
Margarita Guarín, M.D.
Children's Hospital of Wisconsin, Milwaukee, WI 53226

5 References

1
Gan K-H, Veeze HJ, van den Ouweland AMW, et al. A cystic fibrosis mutation associated with mild lung disease. N Engl J Med 1995;333:95-99
Full Text | Web of Science | Medline

2
Kristidis P, Bozon D, Corey M, et al. Genetic determination of exocrine pancreatic function in cystic fibrosis. Am J Hum Genet 1992;50:1178-1184
Web of Science | Medline

3
Veeze HJ, Halley DJ, Bijman J, de Jongste JC, de Jonge HR, Sinaasappel M. Determinants of mild clinical symptoms in cystic fibrosis patients: residual chloride secretion measured in rectal biopsies in relation to the genotype. J Clin Invest 1994;93:461-466
CrossRef | Web of Science | Medline

4
Highsmith WE, Burch LH, Zhou Z, et al. A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations. N Engl J Med 1994;331:974-980
Full Text | Web of Science | Medline

5
Stewart B, Zabner J, Shuber AP, Welsh MJ, McCray PB Jr. Normal sweat chloride values do not exclude the diagnosis of cystic fibrosis. Am J Respir Crit Care Med 1995;151:899-903
Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: The diagnosis of cystic fibrosis is usually confirmed by a positive sweat test (a chloride concentration above 60 mmol per liter). However, the diagnosis of cystic fibrosis may still be suspected in the presence of a normal sweat-test result. The sweat tests in the patients with cystic fibrosis described in our study were performed at various clinics with different techniques and were therefore not directly comparable.

We collected data on sweat tests performed by pilocarpine iontophoresis in all patients with newly diagnosed cystic fibrosis (age range, 0.3 to 68 years) and the A455E mutation who came to Sophia Children's Hospital for evaluation. In 8 of 18 patients, the highest sweat sodium concentration was less than 70 mmol per liter (the cutoff value for a positive test) (Figure 1Figure 1Sweat Sodium and Chloride Values in 18 Compound Heterozygotes with the A455E Mutation.). Although sweat chloride, with the cutoff value of 60 mmol per liter, is a more sensitive indicator, in three patients with cystic fibrosis and the A455E mutation, the sweat test was negative. The ratio of sweat sodium to sweat chloride may be helpful, but in patients with the A455E mutation, the chloride level is not always in excess of the sodium level. The most likely reason is that chloride transport is preserved in such patients. It is our experience that characteristic clinical symptoms, such as nasal polyps, bronchiectasis, colonization with pseudomonas, and male infertility, in combination with elevated values on sweat tests (in general, >30 mmol of chloride per liter), warrant further diagnostic evaluation. The A455E mutation may be particularly common in Dutch patients with cystic fibrosis, although the current results demonstrate that a considerable proportion of these patients have normal sweat-test results.