Cystic fibrosis (CF) is the most common life-threatening autosomal recessive disease in the United States, occurring in approximately 1 in 3500 newborns.1–3
Treatment advances over the past several decades have raised the median predicted survival age in the United States from the mid-teens in the 1970s to more than 36 years old today;4
optimal outcomes depend on timely and accurate diagnosis, however.5–8
Although the vast majority of persons with CF are diagnosed through classic signs and symptoms of the disease () and corroborative laboratory results, the diagnosis is not as clear-cut in approximately 5% to 10% of individuals with CF.4,9–11
To facilitate the diagnostic process and thereby improve access to vital medical services, in 1996 the Cystic Fibrosis Foundation convened a panel of experts to develop criteria for the diagnosis of CF. The panel’s consensus was that the diagnosis of CF should be based on the presence of 1 or more characteristic clinical features, a history of CF in a sibling, or a positive newborn screening (NBS) test, plus
laboratory evidence of an abnormality in the CF transmembrane conductance regulator (CFTR) gene or protein.12
Acceptable evidence of a CFTR abnormality included biological evidence of channel dysfunction (ie, abnormal sweat chloride concentration or nasal potential difference) or identification of a CF disease-causing mutation in each copy of the CFTR gene (ie, on each chromosome). Nevertheless, some patients remain difficult to classify due to the presence of only limited clinical features of CF and inconclusive diagnostic test results.
Phenotypic features consistent with a diagnosis of CF
The significant advances in the diagnosis and treatment of CF over the past decade have increased our understanding of the disease, making this an opportune time to reexamine the criteria for a diagnosis of CF. For example, the age of onset of symptoms is increasingly recognized as being highly variable, ranging from prenatal evidence of echogenic bowel to onset of symptoms in late adolescence or adulthood that nevertheless can cause major morbidity and premature mortality. Our knowledge of the scope and complexity of CFTR gene mutations also has expanded greatly. In 1996, approximately 500 mutations had been identified, with typical commercial panels screening for only 30 of them. Today, more than 1500 mutations have been identified (http://www.genet.sickkids.on.ca/cftr
), and comprehensive analysis of the CFTR gene, including sequence determination of the exons and intron splice sites, as well as detection of gross deletions and duplications, is readily available. Extensive genetic studies have produced both greater awareness of the spectrum of mutations in specific population groups13
and increased understanding of genotype–phenotype relationships,14,15
illuminating distinctions between CFTR mutations with limited or no functional effects and those known or predicted to cause CF disease. For the purposes of this article, here “CF mutation” refers only to a CF disease-causing mutated allele, although it is recognized that mutations in the CFTR gene can result in various pathologies, ranging from chronic sinusitis16
to extensive hepatobiliary17
and lung disease.15
Our increased understanding of the wide range of phenotypes in individuals diagnosed with CF is helping to establish a breakpoint for the diagnosis of CF. In addition to the progress in these areas, important advances in defining reference and abnormal ranges of sweat chloride concentrations more clearly also may help improve the accuracy of CF diagnosis.
One of the greatest changes over the past decade has been the way in which individuals with CF come to recognition. In 1996, most people in the United States who presented for diagnostic testing did so based on clinical features or a positive family history; at the time, NBS for CF was routinely operational in only 2 states. Today, CF NBS is in various stages of implementation in 40 states and is likely to be implemented in all states by 2010. Such widespread NBS is rapidly changing the diagnostic paradigm. In contrast to individuals who are diagnosed due to clinical features suggestive of CF, infants referred for diagnostic testing after a positive screen, though they may be underweight,18
often have no clear clinical manifestations of the disease. NBS for CF depends instead on the initial identification of high values of immunoreactive trypsinogen (IRT) in the blood of the newborn (). Because normal IRT reference values vary slightly, the individual NBS program in the state in which the newborn is being tested sets the specific cutoff value that defines an elevated IRT. After an abnormal IRT value is identified, most NBS programs perform DNA testing to identify known CFTR gene mutations (IRT/DNA strategy), while other programs repeat the IRT measurement in a second blood sample obtained from the infant at age approximately 2 weeks (IRT/IRT strategy).19
Both strategies have been reported to provide approximately 90% to 95% sensitivity,20,21
and both identify newborns at risk for a wide spectrum of disease severity.22,23
The CF diagnostic process for screened newborns.
CF NBS is a screen, not a diagnostic test, and thus identifies only newborns at risk for CF. A positive screening result, indicating persistent hypertrypsinogenemia, must be followed by referral for direct diagnostic testing (ie, sweat chloride test) to confirm a diagnosis of CF. With sufficient experience, sweat testing can be performed adequately in infants, but interpreting the results can be problematic. Some infants have been particularly difficult to classify, such as those with 2 CF mutations and a sweat chloride value <40 mmol/L and those with only 1 CF mutation and a slightly elevated sweat chloride value. Although such infants represent only a small fraction of patients, they may be at risk for developing complications of CF and thus should be identified and followed.
The opportunity provided by NBS to diagnose individuals before symptoms appear and the ability to apply recently acquired knowledge of CF genotype and phenotype relationships to the diagnostic process clearly demonstrate the need for an improved algorithm for diagnosis. Toward this end, in 2007 the Cystic Fibrosis Foundation convened another diagnosis consensus committee of experts, including some members of the panel from 1996 together with representatives from the United States, Canada, Europe, and Australia. In addition to addressing the needs of the clinician faced with the infant with a positive screen, the meeting also provided an opportunity to apply the newly acquired tools to older patients with diagnostic uncertainty. This article presents consensus recommendations for a diagnosis of CF developed by the committee after reviewing recent data, including a diagnostic algorithm formulated by an international group of experts following a European consensus conference.10
In addition, it is intended to present guidance to physicians who are faced with disorders that are related to the partial loss of CFTR function but do not clearly meet the diagnostic criteria for CF. In the end, the diagnosis of CF must be based on good clinical judgment and, in rare cases, may become apparent only over time.