Correspondence

Variant Cystic Fibrosis Phenotypes in the Absence of CFTR Mutations

N Engl J Med 2002; 347:1892-1893December 5, 2002

Article

To the Editor:

The best interpretation of the data presented by Groman et al. (Aug. 8 issue)1 is not that their patients had variant cystic fibrosis phenotypes in the absence of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene but that these patients had similar but different diagnoses. In their accompanying editorial, Knowles and Durie2 allude to this when they comment on the lack of phenotypic information and make a number of suggestions that could unify a cystic fibrosis–like phenotype and laboratory abnormalities with other disorders, including malnutrition, adrenal disorders, and hypergammaglobulinemia with skin changes. Pseudohypoaldosteronism type 1 is an autosomal recessive disorder caused by mutations in the genes for the alpha, beta, and gamma subunits of the epithelial sodium channel (Online Mendelian Inheritance in Man [OMIM] number 264350). This condition results in disordered sweat and salivary electrolytes as well as renal tubular salt wastage and should also, at least theoretically, result in potential changes similar to those in cystic fibrosis. Patients have excess liquid in the airways and cystic fibrosis–like symptoms, including chest congestion, coughing, and wheezing.3 Recurrent lower respiratory tract infections4 may result, and Pseudomonas aeruginosa bronchopneumonia has occasionally been reported.5 It is possible that this condition or a variant form of it acts as a doppelgänger for cystic fibrosis. More clinical information is required, including data on urinary electrolytes and circulating aldosterone levels, before it can be concluded that the patients described by Groman et al. had a variant form of cystic fibrosis.

Richard T.L. Couper, M.B., Ch.B.
University of Adelaide, Adelaide 5006, Australia
richard.couper@adelaide.edu.au

5 References

1. 1

   Groman JD, Meyer ME, Wilmott RW, Zeitlin PL, Cutting GR. Variant cystic fibrosis phenotypes in the absence of CFTR mutations. N Engl J Med 2002;347:401-407
   Full Text | Web of Science | Medline

2. 2

   Knowles MR, Durie PR. What is cystic fibrosis? N Engl J Med 2002;347:439-442
   Full Text | Web of Science | Medline

3. 3

   Kerem E, Bistritzer T, Hanukoglu A, et al. Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism. N Engl J Med 1999;341:156-162
   Full Text | Web of Science | Medline

4. 4

   Hanukoglu A, Bistritzer T, Rakover Y, Mandelberg A. Pseudohypoaldosteronism with increased sweat and saliva electrolyte values and frequent lower respiratory tract infections mimicking cystic fibrosis. J Pediatr 1994;125:752-755
   CrossRef | Web of Science | Medline

5. 5

   Marthinsen L, Kornfalt R, Aili M, Andersson D, Westgren U, Schaedel C. Recurrent Pseudomonas bronchopneumonia and other symptoms as in cystic fibrosis in a child with type 1 pseudohypoaldosteronism. Acta Paediatr 1998;87:472-474
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Both Dr. Couper and Drs. Knowles and Durie in their editorial suggest that patients in our study who had nonclassic cystic fibrosis without CFTR mutations may have had variant forms of known disorders with organ-system involvement similar to that in cystic fibrosis. However, we would like to emphasize that patients who had nonclassic cystic fibrosis without mutations could not be distinguished from those who had nonclassic cystic fibrosis with mutations by clinicians who routinely differentiate cystic fibrosis from other disorders. Our results highlight the usefulness of genetic analysis for segregating patients into groups with disorders that have known causes (e.g., CFTR dysfunction) versus groups with disorders that have uncertain causes and that warrant further clinical evaluation.

Dr. Couper specifically sites pseudohypoaldosteronism type 1 as a possible cause of the nonclassic cystic fibrosis phenotype,1 yet none of our patients were reported to have had the profound hyponatremic or hyperkalemic dehydration in the neonatal period that uniformly results from loss-of-function mutations in the epithelial sodium channel (EnaC) genes resulting in pseudohypoaldosteronism.1,2 It is possible that “mild” EnaC mutations result in an attenuated pseudohypoaldosteronism phenotype that has yet to be recognized, and it is also possible that the variant pseudohypoaldosteronism phenotype overlaps with nonclassic cystic fibrosis. Dr. Couper's suggestion is worthy of investigation now that the constellation of clinical features currently recognized as nonclassic cystic fibrosis has been shown to have causes other than CFTR dysfunction. Thus, we agree that extensive clinical investigation may reveal variant forms of diseases with known causes (e.g., the Shwachman–Diamond syndrome, primary ciliary dyskinesia, or pseudohypoaldosteronism), but we also suggest that these investigations will lead to the recognition of nonclassic cystic fibrosis with novel causes.

Joshua D. Groman, M.S.
Garry R. Cutting, M.D.
Johns Hopkins University School of Medicine, Baltimore, MD 21287
gcutting@jhmi.edu

2 References

1. 1

   Kerem E, Bistritzer T, Hanukoglu A, et al. Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism. N Engl J Med 1999;341:156-162
   Full Text | Web of Science | Medline

2. 2

   Schaedel C, Marthinsen L, Kristofferson AC, et al. Lung symptoms in pseudohypoaldosteronism type 1 are associated with deficiency of the alpha-subunit of the epithelial sodium channel. J Pediatr 1999;135:739-745
   CrossRef | Web of Science | Medline