Clinical Suspicion

The majority of unscreened children with CF present with a history of bulky fatty stools, failure to thrive, and recurrent chest infections. Shortly after birth, 10%–15% will present with intestinal obstruction as meconium ileus. However, there is a wide range of less common presenting features ( Box 50.2 ). Any children or adults presenting with suspicious features of CF should be investigated further, even if they have undergone newborn screening. A possible diagnosis of CF in a child with suggestive clinical findings should not be discounted just because the child appears too well or is thought to be too old. Although the diagnosis is established in most children by the age of 1 year—and earlier if screened—in approximately 10% of children the diagnosis is delayed until after 7 years of age. Patients with pancreatic sufficiency and non-Caucasian patients are particularly vulnerable to delays in diagnosis.

The Sweat Test

The sweat test was first described in 1959 and remains a gold standard for the diagnosis of CF. In the appropriate clinical setting, whether the child has entered the diagnostic algorithm via clinical suspicion or newborn screening, a positive sweat chloride test is diagnostic of CF. There are a number of other rare conditions (sometimes single case reports) that have been associated with a positive sweat test, but these are usually clearly distinguishable by their clinical features ( Box 50.3 ).

The standard sweat test (Gibson and Cooke technique) requires skill and care, and should be undertaken by accredited laboratories. Localized sweating is stimulated by the iontophoresis of pilocarpine into the skin. Sweat is collected on filter paper, gauze, or in microbore tubing over a controlled period of time to ensure that the rate of sweating and the total sweat collected are sufficient and standardized. Guidelines for sweat testing procedures and precautions are available in published and electronic format ( http://www.acb.org.uk/docs/sweat.pdf ).

Chloride is the analyte of choice. The sodium levels and osmolality of sweat are less reliable and should never be used in isolation. A sweat chloride concentration of more than 60 mmol/L is considered positive, and levels below 30 mmol/L are likely to be in the normal range. This lower limit of 30 mmol/L was previously set at 40 mmol/L in children older than 6 months, but recent consensus guidelines have revised to a chloride level of less than 30 mmol/L for all age groups. Results between 30 and 60 mmol/L have traditionally been considered intermediate and require further evaluation. A high proportion of patients with chloride concentrations in this intermediate range will have two CFTR mutations—usually one at least that is not defined as disease causing, a situation found with increasing frequency with the advent of more detailed CFTR mutation testing.

Following the introduction of newborn screening (NBS) for CF, sweat tests are increasingly performed on infants. It is recommended that sweat chloride testing in asymptomatic newborns with a positive NBS test be performed when the infant is older than 2 weeks of age and more than 2 kg. The vast majority of affected infants will have a chloride level greater than 60 mmol/L. A sweat chloride value between 30 and 59 mmol/L should be considered intermediate and trigger further patient evaluation, including repeat testing when older. Certain CFTR mutations (such as R117H, R334W, 3849+10kbC>T) associated with a milder CF phenotype may also demonstrate a normal sweat chloride.

Some normal adolescents and adults can have sweat chloride values in the intermediate range, and sweat chloride levels alone may be insufficient to diagnose CF in the older adolescent. A false-positive sweat test in the severely malnourished child or the critically ill child in intensive care needs cautious interpretation and follow-up.

Research continues to explore the development of an easier sweat test. Collecting systems such as the Macroduct and Nanoduct simplify collection and are now in routine practice. The role of sweat conductivity as a diagnostic tool in CF is debated. In one large trial, the best conductivity cutoff value to diagnose CF was ≥90 mmol/L, and the best conductivity cutoff value to exclude CF was less than 75 mmol/L. However, most clinicians and laboratories will chose to confirm a positive sweat conductivity result with a formal measurement of chloride concentration.

Mutation Analysis

The 1989 identification of the CF gene and the characterization of its protein product (CFTR) held the promise that the diagnostic dilemmas for the condition were over. If you had two CFTR mutations, you had CF—if not, you did not. Unfortunately it has not worked out that simply. Even though the presence of two mutations is very supportive of the diagnosis of CF in the appropriate clinical setting, two alterations in the gene that encodes CFTR does not necessarily mean that you will develop classic CF disease, as outlined later.

There are more than 2000 different CF gene mutations documented, although the clinical impact of these mutations is frequently uncharacterized. A valuable online resource lists identified mutations at http://www.genet.sickkids.on.ca/app .

Clinically available techniques do not routinely allow a full screen of the entire CF genome, and most laboratories will only search for the most common mutations within their geographical region—focusing on those known to be disease causing. Examples of disease-causing CFTR mutations are listed in Table 50.1 , highlighting the dominance of the ΔF508 mutation (present in >70% of CF alleles in Caucasian populations). Customizing mutation panels to match the patient’s ethnic background and clinical presentation can enhance the sensitivity of DNA testing in CF.

Second, there is a range of mutation types that have been classified into classes according to the functional impact on the CFTR. The final protein product may be incomplete, complete but incorrectly packaged and processed, or a final CFTR molecule that is unstable or incapable of reaching the cell surface in sufficient quantity to be physiologically effective. This is discussed further in Chapter 49 .

In addition to the “disease-causing” mutations, there are also recognizable polymorphisms that do not necessarily result in a clinical phenotype but may influence the structure of the final protein product when associated with another mild mutation. The thymidine run in intron 8 is a well-described example where the 5T allele leads to a substantial reduction in functional protein compared with the 9T allele; the 7T allele is intermediate in its effect. The clinical phenotype associated with two CFTR mutations is far broader than previously anticipated ( Box 50.4 ). Caregivers should avoid making prognostic predictions based on genotype alone. Examples of the potential clinical impact of selected CFTR mutations is shown in Table 50.2 and can also be researched on the CFTR2 website ( http://www.cftr2.org/ ), which also regularly updates the growing list of disease causing mutations.

Table 50.2

Examples of CFTR Mutations With Regard to Their Clinical Consequences

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