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Cystic fibrosis (CF), a serious autosomal recessive disease, affects approximately one in every 4,000 newborns in the United States, but individuals may also be diagnosed later in childhood or adulthood. Symptoms of CF include lung disease, liver disease, and exocrine and endocrine pancreatic insufficiency. Age of onset, severity of symptoms, and manifestations of CF vary widely. CF is caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR) gene. More than 2,000 CFTR variants have been reported but most are very rare and of unknown significance, which presents a diagnostic challenge. Sweat chloride testing is the gold standard diagnostic test for CF. The immunoreactive trypsinogen (IRT) test is a preliminary assay used for newborn screening. Molecular testing (ie, DNA analysis) can be used for carrier screening, newborn screening, and diagnostic testing.
Quick Answers for Clinicians
Testing recommendations for adult and pediatric populations are the same, regardless of whether the suspicion for cystic fibrosis (CF) arises from newborn screening or symptomatic presentation. Both the Cystic Fibrosis Foundation and the European Cystic Fibrosis Society recommend sweat chloride testing. , Two elevated (positive) sweat chloride test results on two different days are diagnostic for CF; if sweat chloride values are borderline, CFTR genetic testing is recommended. , The identification of two severe pathogenic CFTR variants on opposite chromosomes is also diagnostic for CF; however, the absence of a positive genetic result does not exclude CF. ,
If carrier screening reveals that both members of a couple are carriers of cystic fibrosis (CF), the couple should be offered the option of preimplantation genetic diagnosis or prenatal diagnosis.
CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID) refers to the combination of a positive newborn screen (high immunoreactive trypsinogen [IRT]), inconclusive sweat chloride test, and inconclusive genetic testing results. Newborns with CRMS/CFSPID may never develop any symptoms of CF but are at risk for CFTR-related disorders such as bilateral absence of the vas deferens, lung disease, and pancreatic insufficiency.
Indications for Testing
Molecular testing for CF is indicated for the following - :
- Carrier screening in individuals who are pregnant or planning a pregnancy
- Carrier screening in individuals with a family history of CF or CFTR-related conditions
- Diagnosis in newborns with a positive newborn screening result
- Diagnosis in adult or pediatric patients with signs or symptoms or a family history of CF
- Confirmation of the causative CFTR gene variants in a known affected individual to determine eligibility for CFTR variant-specific treatment
Laboratory testing is also used to monitor complications in patients with an established diagnosis of CF.
Criteria for Diagnosis
The Cystic Fibrosis Foundation proposes the following diagnostic criteria for CF in an individual with a positive newborn screening test, signs and/or symptoms of CF, or a family history of CF:
- A positive sweat chloride test result ≥60 mmol/L
- Identification of two CF-causing variants on separate chromosomes and a sweat chloride value of ≥30 mmol/L
- Demonstrated CFTR dysfunction (ie, a sweat chloride test result of ≥60 mmol/L or CF-typical nasal potential difference or intestinal current measurement), regardless of whether or not two molecular pathogenic variants can be identified
Laboratory Testing
Carrier Screening
Carrier screening for CF is recommended for all individuals who are pregnant or planning a pregnancy, individuals with a family history of CF, and individuals with isolated congenital bilateral absence of the vas deferens. , , A targeted CFTR variant panel test or a more comprehensive testing method (eg, next generation sequencing) may be used. When a targeted variant approach is used for carrier screening, it is now recommended to test for a minimum of 100 specific known CF-causing variants, an increase from the previously recommended 23 variants (ie, “ACMG-23”). This update aims to enhance variant detection rates across varied biogeographic populations.
Newborn Screening
Screening for CF is recommended for all newborns in the U.S. Screening is performed using a measurement of IRT in blood spots; depending on the results, a reflex test for a panel of common pathogenic CFTR gene variants may be performed. , False-negative results occur at an increased rate in infants with meconium ileus.
Diagnosis
In individuals with a positive IRT test, positive CFTR genetic test, or suggestive symptoms, sweat chloride testing is recommended. A sweat chloride test result of ≥60 mmol/L is diagnostic for CF, and no further testing is required. A sweat chloride test result of <30 mmol/L suggests that CF is unlikely, and further testing is not indicated unless clinical suspicion persists. An intermediate sweat chloride test result of 30-59 mmol/L should be clarified with CFTR genetic analysis. CFTR gene sequencing and deletion/duplication analysis should be performed if one or no pathogenic variants are identified on a CF panel of selected variants. If CFTR sequencing and deletion/duplication testing fails to identify two causative variants, functional analysis (nasal potential difference and intestinal current measurement) is recommended. If results are inconclusive, a diagnosis of CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID) is appropriate.
Monitoring
CF has numerous complications that require careful monitoring.
Complication | Laboratory Tests | Recommended Frequency |
---|---|---|
Liver disease | Liver enzyme tests (and liver function tests in patients with cirrhosis) | Periodically |
Exocrine pancreatic insufficiency | Fecal pancreatic elastase-1 | Annually during infancy and childhood; testing should also be performed during periods of failure to thrive, weight loss, or diarrhea |
Pancreatitis | Lipase and amylase tests | On presentation with recurrent unexplained pain and associated nausea/vomiting |
Diabetes mellitus | Oral glucose tolerance test (confirm with second test) | Annually beginning at 10 yrs of age; more frequently if the individual is symptomatic or in cases of pulmonary exacerbation, initiation of glucocorticoids, enteral tube feeding, planning for pregnancy, pregnancy, and planned organ transplantation |
Nutritional deficiency | Essential fatty acid status (if testing is available), fat-soluble vitamin testing | Annually |
Allergic bronchopulmonary aspergillosis | Allergy skin testing, serum IgE, Aspergillus-specific IgE, Aspergillus serum precipitins tests | On presentation with symptoms |
Airway fungal infections | Airway cultures | Every clinic visit |
Bacterial infection (eg, with Pseudomonas aeruginosa or Staphylococcus aureus) | Cultures | On presentation with acute exacerbation of lung function and after treatment to ensure eradication |
Nephrolithiasis | Urinalysis | On presentation with signs and symptoms |
Medication toxicity | According to standard therapeutic drug monitoring protocols | When taking aminoglycosides |
IgE, immunoglobulin E |
ARUP Laboratory Tests
Matrix-Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) Mass Spectrometry
Massively Parallel Sequencing/Sequencing
Matrix-Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) Mass Spectrometry/Fragment Analysis
Massively Parallel Sequencing
Quantitative Enzymatic Assay/Quantitative Spectrophotometry
Quantitative Chemiluminescent Immunoassay (CLIA)
Quantitative Enzymatic Assay
Quantitative Enzymatic Assay
Quantitative Chemiluminescent Immunoassay
Quantitative ImmunoCAP Fluorescent Enzyme Immunoassay/Qualitative Immunodiffusion
References
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Deignan JL, Gregg AR, Grody WW, et al. Updated recommendations for CFTR carrier screening: a position statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2023;25(8):100867.