Advanced laboratory services

INTRODUCTION 

The classic or typical form of CF is diagnosed if a patient demonstrates clinical disease in one or more organ systems (pancreas, upper and lower respiratory tract, and male reproductive tract) and has elevated sweat chloride (≥60 mmol/L). A CFTR-related disorder is defined as clinical disease limited to only one organ system associated with some evidence of CFTR dysfunction that does not meet full genetic or functional criteria for a CF diagnosis. In such patients, testing may identify only one disease-causing mutation in CFTR and intermediate sweat chloride measurements. (CFTR: cystic fibrosis transmembrane conductance regulator)

CLINICAL MANIFESTATIONS

Prenatal findings

Some cases of CF present with abnormal findings on routine prenatal ultrasonography, including hyperechogenic bowel. The risk of CF is highest if there is evidence of meconium peritonitis (scattered calcifcations are seen throughout the fetal peritoneum), bowel dilatation, or absent gallbladder. If these findings are present on fetal ultrasonography, we suggest offering the parents prenatal CF carrier screening.

Symptomatic presentation in infants and children

Prior to widespread newborn screening infants and children were typically diagnosed with CF after presenting with one or more of the following symptoms:

● Meconium ileus – 20 percent of patients

● Respiratory symptoms – 45 percent of patients

● Failure to thrive – 28 percent of patients

Symptomatic presentation in adulthood

Patients presenting with CF later in life are more likely to have atypical symptoms. Patients diagnosed in adulthood are more likely than children to present with gastrointestinal symptoms, diabetes mellitus, and infertility and to have unusual genetic mutations, normal pancreatic function, and equivocal results on sweat chloride tests.

DIAGNOSIS

Both of the following criteria must be met to diagnose CF:

● Clinical symptoms consistent with CF in at least one organ system, or positive newborn screen or having a sibling with CF

AND

● Evidence of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction (any of the following):

 • Elevated sweat chloride ≥60 mmol/L

 • Presence of two disease-causing mutations in the CFTR gene, one from each parental allele

 • Abnormal nasal potential difference (NPD) 

Sweat chloride

The sweat chloride test remains the primary test for the diagnosis of CF; sweat testing is performed by the collection of sweat with pilocarpine iontophoresis and by determination of the chloride concentration.

Indications

Patients with the following characteristics should undergo sweat testing to clarify a diagnosis of CF:

● Infants with positive CF newborn screening results (perform after two weeks of age and >2 kg if asymptomatic)

● Infants with symptoms suggestive of CF (eg, meconium ileus)

● Older children and adults with symptoms suggestive of CF (eg, male infertility, chronic respiratory infections, or chronic sinusitis)

● Siblings of a patient with confirmed CF, if the diagnosis cannot be established based on genetic testing

Interpretation

Normal – Sweat chloride ≤29 mmol/L is normal. This result is sufficient to rule out CF in most

individuals. Nonetheless, in patients with symptoms strongly suggesting CF, repeating sweat chloride and/or DNA testing may be warranted.

Intermediate – Sweat chloride 30 to 59 mmol/L is intermediate. This result suggests possible CF and calls for further evaluation by repeating sweat chloride testing and also CFTR sequencing. Approximately 20 percent of children with intermediate sweat chloride results will have DNA evidence of CF on expanded analysis.

Abnormal – Sweat chloride ≥60 mmol/L is abnormal. If confirmed on a second occasion, this is sufficient to confirm the diagnosis of CF in patients with clinical symptoms of CF. Clinical symptoms are not required for infants who were identified by newborn screening. Very rarely, apparently healthy individuals have sweat chloride values ≥60 mmol/L. Therefore, positive results of sweat testing should be further evaluated by CFTR sequencing and repeat sweat chloride testing

Molecular Diagnosis

If two CF-causing mutations are detected and the sweat test is intermediate or positive, the diagnosis of CF is confirmed. If two CF-causing mutations are not identified, the sweat test should be repeated. 

Genetic screening panels: Screening of newborn infants is typically performed with panels of CFTR gene mutations. The mutations included in the panel vary depending on the ethnic diversity of the target populations. In Farabi Medical Laboratory a panel of 18 mutations is used which is verified for Mediterranean populations.

Gene sequencing – CFTR sequencing should be performed in individuals with any uncertainty in the diagnosis, including:

• Patients with intermediate sweat chloride results (in addition to repeat sweat chloride testing).

• Patients with confirmed or suspected CF, if the genotype is not yet known. In these patients, the gene sequencing confirms the diagnosis and knowledge of the specific CFTR mutation also has important implications for treatment and prognosis.

• Patients with normal sweat chloride results if there is a strong clinical suspicion of CF.

CFTR sequencing is not mandatory for infants with positive results of sweat chloride testing if their genotype was definitively determined on the newborn screen panels.

Source: Julie P Katkin, MD; Cystic fibrosis: Clinical manifestations and diagnosis; Uptodate; Last updated Oct 2021