Correspondence

Mutations of the Cystic Fibrosis Gene and Pancreatitis

N Engl J Med 1999; 340:238-239January 21, 1999

Article

To the Editor:

In the September 3 issue, Sharer et al.1 and Cohn et al.2 reported an association between chronic pancreatitis and mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Sharer et al. concluded that none of their patients met the diagnostic criteria for cystic fibrosis, whereas Cohn et al. identified one patient as having an “atypical cystic fibrosis phenotype.” The diagnostic criteria established by a consensus panel of the Cystic Fibrosis Foundation3 require one or more characteristic phenotypic features and one of three laboratory findings: an elevated sweat chloride concentration on two occasions, the identification of two known CFTR mutations, and the demonstration of abnormal nasal epithelial ion transport.3 Any one of these three laboratory findings is sufficient for the diagnosis, and recurrent pancreatitis is listed as a phenotypic feature. According to these criteria, two of the patients in the study by Sharer et al. (Patients 9 and 15) and one of the patients in the study by Cohn et al. (Patient 1) had cystic fibrosis.

If CFTR mutations affect the sweat ducts, the func-tion of CFTR in the lung will also be affected.4 The ΔF508/A455E genotype in particular is associated with elevated sweat chloride concentrations and delayed onset of pulmonary disease4; Sharer et al. did not screen for this mutation. The absence of clinical lung disease does not rule out pulmonary involvement secondary to cystic fibrosis, and there should be close follow-up of these study patients.

Clement L. Ren, M.D.
State University of New York at Stony Brook, Stony Brook, NY 11794-8111

4 References

1. 1

   Sharer N, Schwarz M, Malone G, et al. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 1998;339:645-652
   Full Text | Web of Science | Medline

2. 2

   Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 1998;339:653-658
   Full Text | Web of Science | Medline

3. 3

   Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr 1998;132:589-595
   CrossRef | Web of Science | Medline

4. 4

   Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care Med 1996;154:1229-1256
   Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: The definition of cystic fibrosis has become progressively more hazy since the CFTR gene was characterized and cloned. Because the phenotypic spectrum that may now legitimately be called cystic fibrosis has become so large, it is unhelpful in the clinical context. Dr. Ren's comments concerning two patients in our cohort exemplify this point. Although we acknowledge that a sweat chloride concentration of more than 80 mmol per liter in a patient with pancreatic insufficiency meets recent consensus diagnostic criteria,1 the absence of any suppurative lung disease and the presence of an isolated CFTR mutation and a base-line nasal potential difference that is within the normal range militated against the diagnosis. An abnormal nasal potential difference is arguably a more reliable demonstrator of CFTR function than sweat testing,2 and indeed, patients with the 3849+10Kb (C→T) mutation may have normal sweat chloride concentrations but abnormal nasal-potential-difference properties.3

We did not test for the A455E mutation, since it does not seem to occur in our population.4 This mutation is associated with mild pulmonary disease, pancreatic sufficiency, and as far as we are aware, normal glucose tolerance.5 In our study, Patients 9 and 15 both had pancreatic insufficiency, with the latter also having insulin-dependent diabetes mellitus.

Rather than encourage further pedantic debate, we propose that the time is now right to recognize that the diagnosis of cystic fibrosis is too nebulous to preserve in clinical practice and that perhaps, as is the case for Cushing's disease and syndrome, we need to have both a cystic fibrosis “disease” (defined as the progressive suppurative respiratory tract condition irrespective of other phenotypic features) and a cystic fibrosis “syndrome” (which would include the pancreatic manifestations, congenital absence of the vas deferens, and lesser pulmonary manifestations).

Nicholas Sharer, M.R.C.P.
Poole Hospital National Health Service Trust, Poole, Dorset BH15 2JB, United Kingdom

Martin Schwartz, Ph.D., M.R.C.Path.
Royal Manchester Children's Hospital, Manchester M27 4HA, United Kingdom

5 References

1. 1

   Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr 1998;132:589-595
   CrossRef | Web of Science | Medline

2. 2

   Stern RC. The diagnosis of cystic fibrosis. N Engl J Med 1997;336:487-491
   Full Text | Web of Science | Medline

3. 3

   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

4. 4

   Super M, Schwarz MJ. Mutations of the cystic fibrosis gene locus within the population of the Northwest of England. Eur J Pediatr 1992;151:108-111
   CrossRef | Web of Science | Medline

5. 5

   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

Author/Editor Response

Dr. Ren calls attention to an important issue. To make a diagnosis of cystic fibrosis, the consensus panel requires the presence of compatible clinical disease and at least one of three laboratory findings: an abnormal sweat chloride concentration, an abnormal nasal potential difference, and two cystic fibrosis–causing mutations.1 The case of Patient 1 in our series illustrates that some patients remain in a borderline category when evaluated according to these criteria. His sweat chloride and base-line potential-difference values were normal, and he had one mutation that causes cystic fibrosis (ΔF508, 9T) and one mutation that ordinarily does not (R117H, 7T).1,2 None of these findings establish a firm diagnosis of cystic fibrosis. In spite of this, we believe that this patient's condition was related to an inherited abnormality of CFTR on the basis of his genotype, more detailed nasal bioelectric studies, and the involvement of multiple epithelial tissues. This was our rationale for concluding that he had an atypical cystic fibrosis phenotype.

Jonathan A. Cohn, M.D.
Duke University Medical Center, Durham, NC 27710

Lawrence M. Silverman, Ph.D.
Michael R. Knowles, M.D.
University of North Carolina, Chapel Hill, NC 27599

2 References

1. 1

   Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr 1998;132:589-595
   CrossRef | Web of Science | Medline

2. 2

   Kiesewetter S, Macek M Jr, Davis C, et al. A mutation in CFTR produces different phenotypes depending on chromosomal background. Nat Genet 1993;5:274-278
   CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   Patrick Maisonneuve, Preston Campbell, Peter Durie, Albert B. Lowenfels. (2004) Pancreatitis in hispanic patients with cystic fibrosis carrying the R334W mutation. Clinical Gastroenterology and Hepatology 2:6, 504-509
   CrossRef

2. 2

   (1999) Correction: Mutations of the Cystic Fibrosis Gene in Patients with Chronic Pancreatitis. New England Journal of Medicine 340:20, 1592-1593
   Full Text