Cystic Fibrosis - CF

Clinical Background

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene; over 1,600 different CFTR mutations have been reported.

Epidemiology

Incidence
- Classic CF affects 1/3,000 Caucasians and Ashkenazi Jews, 1/8,000 Hispanics, 1/15,000 African Americans, 1/32,000 Asians; incidence of nonclassic CF is unknown
- 4% of Caucasians are carriers
Age – usually diagnosed in childhood
Ethnicity – >90% are Caucasian

Inheritance

Autosomal recessive
- 2 pathogenic CFTR mutations on different chromosomes
  - Classic symptoms of CF – 2 severe mutations
  - Nonclassic symptoms of CF – 1 severe/moderate and 1 mild/moderate mutations
- Penetrance – high for severe mutations, variable for mild/moderate mutations

Pathophysiology

CFTR codes for a cAMP-regulated chloride channel in the apical membrane of epithelial cells
- Without enough functional CFTR, the salt concentration in sweat is elevated and the viscosity of the mucous in the lungs and pancreas is increased, leading to obstruction
- Obstruction sets the stage for chronic infection, inflammation and eventual epithelial injury
Death typically results from obstructive airway disease in the 40s

Clinical Presentation

Classic – chronic sinopulmonary disease, gastrointestinal malabsorption, pancreatic insufficiency and obstructive azoospermia
Atypical – monosymptomatic disease such as chronic pancreatitis, bilateral absence of the vas deferens, nasal polyps or bronchiectasis
Sinopulmonary disease
- Chronic lung infections – bronchiectasis, dyspnea, wheezing, chest pain, nasal polyps, clubbing
- Infectious organisms
  - Pseudomonas aeruginosa
  - Staphylococcus aureus
  - Burkholderia cepacia
Pancreas/liver/gallbladder/gastrointestinal (GI) disease
- Pancreas
  - 85% or more have pancreatic insufficiency
  - Absorption of lipids and fat soluble vitamins is reduced
  - Chronic or recurrent abdominal pain from pancreatitis
  - Steatorrhea and malnutrition result
  - 25% of adults develop diabetes
- Liver
  - Clogging of biliary ducts leads to liver and biliary cirrhosis
  - Congestion of liver secondary to hypoxia-induced cor pulmonale
  - Gallbladder
  - Fecal loss of bile acids leads to reduction in bile-salt pool
  - Reduction may lead to gallstones
- GI
  - Distal intestinal obstruction (meconium ileus equivalent)
  - Constipation, intussusception, colonic strictures, hypotonic colon
  - Meconium ileus in 15% of infants
Endocrine systems dysfunctions
- Male – azoospermia due to congenital bilateral absence of vas deferens (CBAVD) in >95%
- Female – modest reduction in fertility

Treatment

Respiratory therapy – chest physiotherapy
Antibiotic treatment of infections
Inhalant treatment – Dornase alfa
Pancreatic enzymes taken with meals to increase nutrient absorption
Lung transplantation
- Improves quality of life but not survival

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations
Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Recommended Use	Limitations
Cystic Fibrosis (CFTR) 32 Mutations 2001933 Method: Polymerase Chain Reaction/Oligonucleotide Ligation/Fragment Analysis	Tests for 32 common CFTR gene mutations Order for any of the following indications: Carrier testing in a healthy patient Patient with symptoms of CF Patient with family history of CF Clinical sensitivity varies with ethnicity	Mutations other than the 32 tested will not be detected Primer site mutations may affect this assay
Cystic Fibrosis (CFTR) 32 Mutations with Reflex to Sequencing 2001968 Method: Polymerase Chain Reaction/Oligonucleotide Ligation/Fragment Analysis/Sequencing	Tests for 32 common CFTR gene mutations; if two CFTR mutations are not identified, sequencing is performed to detect 97% of the over 1,600 described CF mutations Order for patients with either of the following indications if not previously tested using the CF mutation panel: Patients with symptoms of classic CF Patients with a positive sweat chloride Clinical sensitivity: 97% in all ethnicities	CFTR promoter mutations, deep intronic mutations and large gene deletions/duplications will not be detected
Cystic Fibrosis (CFTR) 32 Mutations with Reflex to Sequencing and Reflex to Deletion/Duplication 2001967 Method: Polymerase Chain Reaction/Oligonucleotide Ligation/Fragment Analysis/Sequencing/Multiplex Ligation-dependent Probe Amplification	Tests for 32 common CFTR gene mutations; sequencing is performed if two CFTR mutations are not identified; deletion/duplication testing is performed if two CFTR mutations are not identified by sequencing Clinical sensitivity is 99% Order for patients with a clinical diagnosis of CF as a cost-effective method for determining the causative mutations present	CFTR promoter mutations and deep intronic mutations will not be detected
Cystic Fibrosis (CFTR) 32 Mutations, Fetal 2001970 Method: Polymerase Chain Reaction/Oligonucleotide Ligation/Fragment Analysis	Test amniocytes for 32 common CF gene mutations Order in fetal samples for the following indications: One or both parents have CFTR mutations included on the panel Echogenic or cystic dilatation of the fetal bowel on ultrasound Clinical sensitivity varies with ethnicity	Only the 32 mutations tested will be detected; further mutations within the primer/probe regions could affect this assay
Cystic Fibrosis (CFTR) Deletion/Duplication 0051642 Method: Multiplex Ligation Probe Amplification	Detects large CFTR duplications and deletions within the exons and intron/exon borders Order for patients who have a positive sweat chloride or atypical CF but only one or no detectable mutations upon CFTR sequencing Approximately 1-2% of CFTR mutations are large deletions or duplications	Deletion/duplication breakpoints will not be determined CFTR single-base pair substitutions, small deletions/duplications, and deep intronic and promoter mutations will not be detected Mutations within the primer/probe regions could affect this assay
Cystic Fibrosis (CFTR) Sequencing 0051110 Method: Polymerase Chain Reaction/Scanning/Sequencing	Detects 97% of the over 1,600 described CFTR gene mutations Order for patients with symptoms of classic or atypical CF but without two mutations identified by the CF mutation panel	Rare diagnostic errors can occur due to primer site mutations Regulatory region mutations, large gene deletions/duplications and some deep intronic mutations will not be detected
Cystic Fibrosis (CFTR) Sequencing with Reflex to Deletion/Duplication 0051640 Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation Probe Amplification	Tests for over 1,600 CFTR gene mutations If two CFTR mutations are not identified by sequencing, deletion/duplication testing is performed Order for patients with symptoms of classic or atypical CF but without two mutations identified using the CF mutation panel Clinical sensitivity: 99%	Rare diagnostic errors can occur due to primer and probe site mutations Breakpoints for large deletions/duplications will not be determined Regulatory region and some deep intronic mutations will not be detected
Cystic Fibrosis Cis-Trans (CFTR) R117H & 5T Mutations 0056006 Method: Polymerase Chain Reaction/Oligonucleotide Ligation	Tests whether the R117H mutation and 5T variant are on the same chromosome Order only for patients who have a previously identified R117H mutation and 5T variant
Cystic Fibrosis (CFTR) 32 Mutations, Atypical 2001969 Method: Polymerase Chain Reaction/Oligonucleotide Ligation/Fragment Analysis	Tests for 33 common CFTR gene mutations, including 5T Order in patients with one or more of the following symptoms: Bilateral absence of the vas deferens Nasal polyps Bronchiectasis	Mutations other than the 33 tested will not be detected Primer site mutations may affect the analytic sensitivity of this assay
Cystic Fibrosis 3199del6 Only (ARUP Medical Director or Genetic Counselor approval required prior to testing) 0050098 Method: Polymerase Chain Reaction/Fluorescence Monitoring	Tests for 3199del6 mutation only Order only for patients who have a previously identified I148T mutation	ARUP Medical Director or Genetic Counselor approval required prior to testing
Pancreatic Elastase, Fecal 0080526 Method: Enzyme-Linked Immunosorbent Assay	Screen for pancreatic insufficiency caused by cystic fibrosis	Watery stool samples may produce falsely decreased results due to a dilution effect

Additional Tests Available

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Cystic Fibrosis (CFTR) 5T Mutation 0056003 Method: Polymerase Chain Reaction/Fragment Analysis	Do not order without ARUP's genetic counselor approval
Cystic Respiratory Culture 0060130 Method: Standard reference procedure for aerobic bacterial culture and identification