To the Editor: The original understanding of cystic fibrosis (CF) as a well-defined, severe disorder has changed dramatically with the recent description of a wide range of clinical presentations. Correlations between genotype and phenotype have been reported, although the genotype–phenotype relationship is not a simple one.1

We report on a patient, now a 39-year-old woman, who had a single episode of distal intestinal obstruction (meconium ileus equivalent) at the age of 5 years, leading to a diagnosis of CF. She had a lower respiratory tract infection (caused by Klebsiella species) at the age of 10 years, but has otherwise been well, and is now asymptomatic, despite not being treated for CF since her teenage years. Her two pregnancies have been uncomplicated.

She presented wishing to clarify the previous diagnosis of CF and to determine the health implications for her, if any. Her sweat chloride level was 93 mmol/L. Levels above 70 mmol/L are abnormal in adults, and this cutoff value reliably distinguishes people with CF from controls.2 Lung function testing and a chest x-ray were normal.

Genetic testing revealed a genotype consistent with a diagnosis of CF. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7. The most common mutation is ΔF508, which produces misfolding of the CFTR protein. The polythymidine tract is a region in the CFTR gene that varies in size depending on the number of thymidine bases present — most commonly 5, 7 or 9. The 5T variant causes a reduction in functional CFTR protein, but is not of itself associated with classic CF. In this case, testing for 30 CFTR mutations showed heterozygosity for ΔF508. Testing for the poly-T polymorphism showed the presence of 9T and 5T alleles. As ΔF508 is essentially always found in cis (on the same chromosome) with 9T,3 we conclude that the patient’s genotype is ΔF508(9T)/5T.

The symptoms a patient develops and their severity are thought to be related to the amount of functional CFTR protein produced. If this is above 10% of normal, an abnormal phenotype is unlikely. Levels < 10% are associated with congenital bilateral absence of the vas deferens (CBAVD), levels < 4.5% with progressive pulmonary disease, and levels < 1% with pancreatic exocrine deficiency.4

Homozygosity for ΔF508 is associated with a severe phenotype, whereas the genotype ΔF508(9T)/5T has been associated with a range of clinical phenotypes, including CBAVD, atypical CF, or no clinical features.5

Currently, our patient has no symptoms attributable to CF. She is presumably at increased risk of chronic lung disease, and has been advised to have her lung function monitored. Giving a long-term prognosis for individuals with mild variants of CF is challenging, and a normal outcome should be considered. In future, it may be possible to predict which patients with ΔF508(9T)/5T are likely to develop symptoms.

CF and its variants need to be considered in an increasingly wide range of clinical presentations. Testing for CF mutations is available from a number of Australian laboratories (listed on the Human Genetics Society of Australasia website, www.hgsa.com.au) and should be conducted in the setting of appropriate genetic counselling.