There has been a huge improvement in survival of cystic fibrosis (CF) patients in the developed world over the last two decades; they are likely to survive into the fifth decade of life. There are promises of even further improvements in survival and quality of life with newer therapies that are mutation-specific. Recognition of electrolyte abnormalities in the sweat in the fifties by di Sant’Agnese, et al. [1] led to the development of the ‘sweat test’ to diagnose CF that continues to be the gold standard in its diagnosis. In 1989, the gene that encodes the CF transmembrane conductance regulator (CFTR) protein on the long (q) arm of chromosome 7, was first identified. To date, more than 1500 CFTR gene mutations with the potential to cause cystic fibrosis disease have been described. Genotype-phenotype correlations remain poor (except in pancreatic insufficiency) and there is variation in the severity of illness even in siblings carrying the same mutation profile.

Cystic fibrosis remains a clinical diagnosis with classical phenotypic features in the presence of either: a) evidence of CFTR dysfunction, mostly in the form of elevated sweat chloride; or b) demonstration of two disease-causing mutations. Mutational analysis has especially been useful in the context of newborn screening and when sweat tests are equivocal. Knowledge of the common mutations in a population is important in the diagnostic armamentarium as well as for prognosis.

Much of the progress in cystic fibrosis survival has been achieved incrementally in small steps rather than a huge leap or cure. Proactive management through specialist centers, pancreatic replacement therapy, inhaled antibiotics and mucolytics have contributed to this improvement. Newborn screening has minimized the diagnostic delay, and early nutritional treatment contributes to improved growth and cognition. Early recognition may also help to delay the onset of established lung disease although the evidence for this is mixed. Prolific research into the molecular basis of the disease and clinical trials has complemented the clinical care available to CF patients in developed countries.

While most treatments are ‘symptomatic’, development of small molecule compounds that directly target the underlying CFTR defects has the potential of being disease-modifying. Ivacaftor is the first such treatment which targets the CFTR-gating mutation Gly551Asp (previously termed G551D). Clinical trials have demonstrated benefit in terms of an increase in lung function, decreased sweat chloride, weight gain, improvement in patient-reported quality of life, and reduction in number of respiratory exacerbations with Ivacaftor [2].

As mutation-specific therapies such as Ivacaftor become available, correct genotyping of CF patients will become increasingly important for targeted therapy. In this context, Kawoosa and colleagues [3] present an intriguing clinical and genetic (mutational) description of 18 cases of cystic fibrosis from the Indian state of Jammu and Kashmir. Remarkably within a high risk group of 100, almost a fifth of children were found to have CF based on sweat testing and mutation analysis. This relatively high proportion underscores the importance of awareness of CF in South Asian populations who were previously thought to have low prevalence of the condition.

Although a limited number of mutations were looked at in the patients with suggestive sweat tests, most patients with CF were found to have either Phe508del or 3849+10kb C>T mutations. Both these mutations are associated with relatively severe phenotype, and patients presented with the classic symptoms of failure to thrive and pulmonary involvement (although the children with 3849+10kb C>Tt ended to have later onset of symptoms).

Difficulties mastered are opportunities won. Diagnosis of CF in developing countries is impeded by lack of awareness, poor healthcare access and financial constraints. While diagnosis of CF in South Asia must primarily rely on high diagnostic suspicion and availability of sweat electrolyte analysis, CFTR mutation analysis can also be complementary to an early diagnosis in these children. In addition, knowledge of the genotype provides an opportunity to benefit from genotype-specific treatment in the future.

Funding: None; Competing interest: None stated.

1. di Sant’Agnese PA, Darling RC, Perera GA, Shea E. Sweat electrolyte disturbances associated with childhood pancreatic disease. Am J Med. 1953;15:777-84.

2. Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR,　 et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010;363:1991-2003.