Radiological analysis of children with cystic fibrosis who are homozygous for cystic fibrosis transmembrane conductance regulator mutation S549R (T->G)

Abstract

Genotype-phenotype analyses in cystic fibrosis (CF) have shown that cystic fibrosis transmembrane conductance regulator (CFTR) genotypes can predict pancreatic status but that correlations with pulmonary status remain elusive. We investigated the extent and severity of lung disease associated with CFTR mutation S549R (T-->G). This mutation is localized in intron 11 (nucleotide-binding fold 1 of the CFTR protein) and had so far been described as a private mutation only. It is associated with an extremely severe overall CF phenotypic expression. Detailed radiological analyses were performed by a single observer in 12 children with CF from the United Arab Emirates who were homozygous for CFTR mutation S549R (T-->G). A diversity of pulmonary changes included marked hyperinflation in early infancy in conjunction with inflammation of the interstitium. After 2 years of age, signs of central airway involvement occurred in association with early signs of pulmonary hypertension. In conclusion, although there is some diversity in the radiological findings of these CF patients, R549 is a very severe allele associated with extreme lung disease and rapid pulmonary decline.

Mild clinical phenotype associated with R1158X/S549R(T→G) CFTR genotype

“…Thus, although a patient with an R1158X/S549R(T→G) genotype could have been expected to present with severe clinical manifestations, we find here that it is not the case. The fact that the Emirati patient investigated here lives in the same environmental and medical conditions as the subjects that we have studied before [4–6] prompts us to believe that there must be attenuating genetic factors. Indeed, Duarte et al [9] have reported that a complex allele containing two mutations, R334W and R1158X, is associated with reduced levels of correctly processed mRNA, and that a patient with the complex genotype R334W–R1158X/ΔF508 presented with pancreatic sufficiency and an atypical course of CF.…”

“…We had so far observed that, in the UAE, mutations ΔF508 and S549R(T→G) account for 88% of CF chromosomes, and that CF patients were homozygous for either of the two mutations – a phenomenon that reflects the high level of consanguinity among Emirati [4]. Moreover, the clinical phenotypes associated with both mutations are quite homogeneous and extremely severe [5], including dramatic losses of pulmonary function [6].…”

“…All patients that we investigated were homozygous for either of the two mutations: 16 CF patients (who were of Bedouin origin) were S549R(T→G) homozygotes and 7 patients (who were of Baluch lineage) were ΔF508 homozygotes [4]. Moreover, the clinical presentation associated with S549R homozygosity is quite homogeneous and shows an extreme degree and course of CF severity – at least as much as those associated with ΔF508 [5,6]. We report here the identification of the first compound heterozygote patient in the UAE, who harbours mutations S549R/R1158X in his CFTR gene.…”