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Vol. 50. Issue 11.
Pages 499-500 (November 2014)
Vol. 50. Issue 11.
Pages 499-500 (November 2014)
Letter to the Editor
DOI: 10.1016/j.arbr.2014.09.006
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S1455X CFTR Mutation and Upper Airway Colonization With Pseudomonas aeruginosa
Mutación S1455X del CFTR y colonización de vías aéreas altas por Pseudomonas aeruginosa
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Efthimia Kalampoukaa, Argyri Petrocheiloua,
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apetroch@gmail.com

Corresponding author.
, Athanasios G. Kaditisb, Stavros-Eleftherios Doudounakisa
a Cystic fibrosis Center, Agia Sophia Children's Hospital, Atenas, Greece
b First Department of Pediatrics, University of Athens Medical School, Agia Sophia Children's Hospital, Atenas, Greece
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To the Editor:

Cystic fibrosis (CF) is a classic example of an autosomal recessive genetic disorder, and multiple variant forms of this disease have been identified. It is caused by CF transmembrane conductance regulator (CFTR) dysfunction resulting from CFTR gene mutations. Not all CFTR mutations are associated with disease expression. The S1455X mutation is very uncommon (0.22% prevalence in our patient population). Individuals with this mutation have only very mild symptoms, if any. We present the first report of twin brothers, both S1455X mutation-carriers, with Pseudomonas aeruginosa colonization of the upper airways.1–4

Patients A and B are 2-year-old monozygotic twin brothers. After birth, patient A was admitted to the neonatal intensive care unit for 7 days due to mild breathing difficulties. Routine neonatal immunoreactive trypsinogen screening results were close to the upper limit of normal (65mcg/l; normal value<77mcg/l). When patient A was 7 months old he suffered bronchitis, for which he received inhaled albuterol and fluticasone. At the age of 13 months, he was admitted to a pediatric intensive care unit with lethargy due to severe hyponatremic dehydration and hypochloremic and hypokalemic metabolic alkalosis. At that time a definitive diagnosis of CF was given (chloride sweat levels of 101.6mEq/l and 105.8mEq/l; mutations: F508del and S1455X). The patient has pancreatic sufficiency and normal growth (weight: 75th–90th percentile; height: 90th percentile). Serial pharyngeal swab cultures grew Pseudomonas aeruginosa.

Following his brother's diagnosis, at the age of 13 months patient B was also diagnosed with CF (chloride sweat levels: 80.7mEq/l and 81.7mEq/l, mutations: F508del and S1455X). Similarly, he has pancreatic sufficiency and good growth (weight, 50th percentile; height: 75th percentile). Repeated pharyngeal swab cultures grew Pseudomonas aeruginosa.

The case of these two brothers suggests that the S1455X mutation of the CFTR gene in combination with the F508del mutation may be associated with early Pseudomonas aeruginosa colonization of the upper airways. This observation has not been previously reported in the literature. In other reported cases of S1455X CFTR mutation, the sweat test was abnormal, but no respiratory disorders were detected.1,2 Only one case of a child with mild pulmonary disease due to Haemophilus influenza infection and persistent hyponatremia during a heat wave has been described.3

S1455X is a nonsense mutation causing premature transcriptional termination of CFTR. More specifically, the codon for serine at residue 1455 is replaced by a stop codon, hence the designation S1455X.1 In the initial description from Mickle et al.,1 the S1455X mutation was associated with isolated elevated chloride levels in sweat. In vitro testing predicted preserved CFTR function in lung and pancreatic cells.1 Subsequently, Moyer et al.4 suggested that the CFTR-S1455 chloride channel defect was caused by mispolarization to the lateral membrane instead of to the apical membrane.

The two cases previously described in the literature as compound heterozygotes for the F508del and S1455X mutations presented a mild phenotype in the sense that S1455X was associated with minor symptoms and a favorable prognosis, even when accompanied by such a severe mutation as F508del.2,3 Although our pediatric patients are carriers of this same genotype, they appear to have a more severe clinical presentation than that predicted by other authors, leading us to speculate on the possibility of a predominant F508del mutation. Our cases underline the concept of a variable correlation between the CF genotype and phenotype.

Authorship

Efthimia Kalampouka and Argyri Petrocheilou participated equally in the authorship of this letter.

References
[1]
J.E. Mickle, M. Macek Jr., S.B. Fulmer-Smentek, M.M. Egan, E. Schwiebert, W. Guggino, et al.
A mutation in the cystic fibrosis transmembrane conductance regulator gene associated with elevated sweat chloride concentrations in the absence of cystic fibrosis.
Hum Mol Genet, 7 (1998), pp. 729-735
[2]
D. Salvatore, R. Tomaiuolo, B. Vanacore, A. Elce, G. Castaldo, F. Salvatore.
Isolated elevated sweat chloride concentrations in the presence of the rare mutation S1455X: an extremely mild form of CFTR dysfunction.
Am J Med Genet A, 133A (2005), pp. 207-208
[3]
R. Epaud, E. Girodon, H. Corvol, F. Niel, V. Guigonis, A. Clement, et al.
Mild cystic fibrosis revealed by persistent hyponatremia during the French 2003 heat wave, associated with the S1455X C-terminus CFTR mutation.
Clin Genet, 68 (2005), pp. 552-553
[4]
B.D. Moyer, J. Denton, K.H. Karlson, D. Reynolds, S. Wang, J.E. Mickle, et al.
A PDZ-interacting domain in CFTR is an apical membrane polarization signal.
J Clin Investig, 104 (1999), pp. 1353-1361

Please cite this article as: Kalampouka E, Petrocheilou A, Kaditis AG, Doudounakis SE. Mutación S1455X del CFTR y colonización de vías aéreas altas por Pseudomonas aeruginosa. Arch Bronconeumol. 2014;50:499–500.

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