CF is a genetic condition caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (\(CFTR\)) gene. These mutations impair the movement of salt and water, leading to the production of thick, sticky mucus that obstructs and damages organs, most notably the lungs and pancreas. While classic CF is typically identified in infancy through newborn screening, it is possible to be diagnosed later in adolescence or adulthood. This late diagnosis, often termed atypical CF, occurs because the disease can manifest with symptoms far milder or more localized than the severe, multi-system involvement seen in traditional cases.
The Spectrum of Cystic Fibrosis
The reason some individuals live for years without a diagnosis lies in the wide spectrum of \(CFTR\) gene mutations and their effect on protein function. The \(CFTR\) protein regulates the flow of chloride ions across cell membranes, which is important for maintaining the proper hydration of mucus. More than 2,000 different mutations have been identified in the \(CFTR\) gene, categorized into classes based on how they affect the protein’s production or function.
Individuals must inherit two copies of a mutated gene, one from each parent, to develop the condition. Classic, severe CF is usually associated with inheriting two copies of mutations (e.g., Class I, II, or III) that result in little to no functional \(CFTR\) protein. These severe defects lead to profound organ damage early in life, often including pancreatic insufficiency and progressive lung disease.
Atypical or non-classic CF results from inheriting a combination of mutations that allow for some residual \(CFTR\) function. For example, a person might inherit one severe mutation and one milder mutation (e.g., Class IV or V). These milder mutations allow the \(CFTR\) protein to retain a small amount of function. This residual function is enough to prevent the severe, life-threatening symptoms that prompt early diagnosis, leading to a milder phenotype where symptoms may be intermittent or affect only a single organ.
Why Diagnosis Can Be Delayed
Diagnosis is often delayed because the subtle or single-organ symptoms of atypical CF mimic common conditions, causing healthcare providers to overlook the possibility of a genetic disorder. In adults, the presentation is frequently limited to a single organ system. For instance, respiratory symptoms might be limited to chronic sinusitis, recurrent nasal polyps, or persistent coughs often misdiagnosed as asthma or chronic bronchitis.
A highly specific presentation that delays diagnosis is Congenital Bilateral Absence of the Vas Deferens (CBAVD) in men, characterized by male infertility. This condition, where the tubes that transport sperm are absent or blocked, is often the first and only symptom that prompts genetic testing in adulthood.
Gastrointestinal issues in atypical CF can manifest as recurrent or chronic pancreatitis. Unlike classic CF, where pancreatic insufficiency is present from infancy, this organ dysfunction can be the primary reason for a later clinical evaluation.
The effectiveness of newborn screening programs is directly related to the severity of the mutations. Individuals with milder mutations may have initial screening results that fall within the normal range, meaning they are not flagged for further diagnostic testing in infancy. This oversight, combined with a lack of awareness regarding adult-onset CF, contributes significantly to a delayed diagnosis, sometimes into a person’s 40s or 50s.
Diagnostic Pathways for Adults
When cystic fibrosis is suspected in an older child or an adult, the diagnostic process follows a multi-step pathway to confirm \(CFTR\) dysfunction. The initial and most established test is the Sweat Chloride Test, which measures the concentration of chloride in sweat. Individuals with CF have significantly higher levels because the faulty \(CFTR\) protein does not properly reabsorb salt.
A chemical is applied to the skin to induce sweating, and the collected sweat is analyzed. A positive result, indicating elevated chloride levels, strongly suggests CF when combined with compatible clinical symptoms. However, for those with atypical CF, the sweat chloride level may be intermediate or even within the normal range, necessitating further investigation.
If the sweat test is inconclusive, comprehensive genetic testing is performed to analyze the \(CFTR\) gene. This involves sequencing the gene to identify the specific combination of mutations present, which is crucial since there are over 2,000 known variants. Genetic analysis is particularly important for identifying rarer, milder mutations that might explain a late-onset or single-organ presentation. In cases where all other tests are inconclusive, a specialized procedure called the Nasal Potential Difference test may be used to directly measure the electrical activity of the nasal lining.