In the past, cystic fibrosis patients rarely lived past their second decade, but those with atypical cystic fibrosis tend to have milder disease, including less severe respiratory signs and symptoms. The good news is that often translates into a long lifespan.1 As recently as 2005, the Cystic Fibrosis Foundation had listed a median survival age of 37.2 Advances in respiratory, gastrointestinal, and nutritional therapies have significantly contributed to the increased survival of these patients. Unfortunately, such milder cases can easily go undetected.
Sweat chloride testing remains a gold standard for the diagnosis of cystic fibrosis. As previously mentioned, classic cystic fibrosis patients are typically diagnosed during childhood and have a sweat chloride concentration ≥60 mmol/L and more severe multiorgan involvement (sinopulmonary and gastrointestinal disease with failure to thrive).
There are 5 classes of CFTR mutations that result in compromised CFTR function: The presence of 2 severe CFTR mutations (classes I-III) completely abolishes CFTR function. It is diagnosed in childhood and usually results in the classic clinical features of pancreatic insufficiency and failure to thrive. However, patients who are compound heterozygous for the milder CFTR mutations (classes IV and V) experience partial CFTR function, which in turn results in atypical features such as pancreatic sufficiency and normal or borderline sweat chloride concentrations. That makes the diagnosis more elusive during early childhood.1,3
The severity of sweat gland and exocrine pancreatic dysfunction produced by a cystic fibrosis mutation depends on the class of CFTR gene mutation and the level of CFTR gene and protein expression.4,5 In certain genetic backgrounds, the 5T allele associated with a high number of TG (thymine/guanine) repeats found in compound heterozygosity with a disease-causing CFTR mutation acts as a “mild CFTR mutation,” resulting in the nonclassic cystic fibrosis phenotype.3 Individuals with atypical cystic fibrosis diagnosed later in life may have single organ involvement, such as mild lung disease, nasal polyposis, recurrent pancreatitis, biliary cirrhosis, portal hypertension, or obstructive azoospermia.1
Lauren had several classic cystic fibrosis features, including recurrent lung disease, pancreatic insufficiency, and sweat gland dysfunction, but it’s likely that her relatively mild pulmonary presentation, normal body mass index, and lack of failure to thrive led to a delay in her diagnosis.
Some patients with atypical cystic fibrosis seek care for idiopathic chronic pancreatitis (ICP), and researchers have found a link between ICP and CFTR gene mutations. For instance, recent studies of ICP patients compared with geographically and ethnically matched controls revealed a higher frequency of abnormal CFTR alleles in the ICP population.6,7 Milder CFTR mutations resulting in partial CFTR function have also been associated with ICP.7,8
Zack was heterozygous for Δ F508, a common CFTR mutation in the Caucasian population. Cohn et al found a higher frequency of this mutation in ICP patients from Europe (mostly English, Italian, and Czech).9 Poly T allele variants such as 5T, 7T, and 9T have not been associated with a higher frequency of ICP.6,7
Early detection may translate into better treatment
Although patients diagnosed with cystic fibrosis as adults are less likely to present with classic clinical features, they may develop bronchiectasis and advanced lung disease.10,11 Those who are identified early on—including those who are asymptomatic and have normal lung function—may benefit from respiratory therapy to prevent or delay lung disease.12 Several studies have shown that patients with mild cystic fibrosis disease and stable spirometry results have evidence of bronchiectasis on their x-rays and advanced lung disease that appears on high-resolution CT.13,14
Judge et al have suggested that mucus plugging occurs early in cystic fibrosis lung disease and at a milder stage of lung function impairment, and that bronchiectasis may be an end result of such abnormalities.14 Nonclassic cystic fibrosis patients often have episodes of “bronchitis,” and once the practitioner becomes concerned, the radiographic image may already show evidence of bronchiectasis. Once again, this emphasizes the importance of early detection and prompt treatment.15
CASE 1: Lauren
Unfortunately, Lauren was unable to benefit from early use of respiratory therapies like tobramycin, hypertonic saline, and recombinant human DNase. She began these treatments after developing advanced lung disease. Studies have shown that tobramycin, long-term inhaled hypertonic saline, and recombinant human DNase can reduce the number of pulmonary exacerbations and increase both FVC and FEV1 values in previously stable cystic fibrosis patients.16-18
Similarly, because Lauren’s pancreatitis was due to pancreatic insufficiency, early recognition of pancreatic insufficiency and enzyme therapy may have greatly reduced the number and severity of her pancreatic episodes.19