CF is inherited in an autosomal recessive pattern. Normally a person has two working CFTR genes. In people with cystic fibrosis, both genes have variants that affect the normal function of the gene. Each parent of a newborn with CF typically has one functional and one variant gene and is considered a carrier. When both parents are carriers, the chance for each baby to inherit two variant genes is 25%, or 1 in 4.
Many women have genetic testing for CF during pregnancy or when they are planning a pregnancy. If a CF variant is identified in the woman, carrier testing is recommended for her partner. If her partner has a negative carrier test and the baby has a positive newborn screen, follow-up testing is still needed, because the baby could still have CF. CF carrier testing could be negative for a person with a rare variant, because carrier testing is not usually performed for all possible, rare CF variants.
Carriers of CF do not typically have symptoms.
Lungs – Thickened mucus builds up in the lungs of people with CF. They often have breathing problems and lung infections. There is eventually permanent damage to the lungs.
Pancreas – The pancreas produces enzymes that aid in digestion, and insulin, which controls blood sugar. The lack of pancreatic enzymes affects the GI tract’s ability to break down and use nutrients from food. People with CF may develop a form of diabetes called CF-related diabetes mellitus.
Gastrointestinal tract – Malnutrition and poor growth are concerns for people with CF. Babies with CF may also have an intestinal blockage at birth called meconium ileus.
Congenital absence of the vas deferens (CAVD) in males – Males with CF are usually infertile. The tube that carries sperm out of the body (vas deferens) does not develop. Some men with variants in the CFTR gene have no other symptoms of CF except infertility.
CFTR-related metabolic syndrome (CRMS) – Many people with CRMS never develop symptoms. Others may develop some of the symptoms of CF, but they are usually milder.
Incidence: The overall incidence of CF is approximately 1 in 2,500 Caucasian births. The disease is less common in other race/ethnic groups.
New York State Method of Screening: Screening for CF is accomplished using a three-tier algorithm commonly referred to as an “IRT-DNA-SEQ algorithm”.
- First Tier Screening (IRT): First, immunoreactive trypsinogen (IRT) is tested in all babies. Trypsinogen is produced in the pancreas and is the precursor of trypsin, which is required for protein digestion. IRT is elevated in most people with CF due to abnormal pancreatic function. Even though this assay is designed to detect CF, newborns with CF-related metabolic syndrome (CRMS), congenital absence of the vas deferens (CAVD), and even carriers with no CF disease may also screen positive.
- Second Tier Screening (DNA): Specimens with IRT levels in the top 5% are then tested for a panel of the most common CF-causing gene variants. If two CF-causing variants are identified, the baby is referred.
- Third Tier Screening (SEQ): Specimens with one variant on the DNA panel or extremely elevated IRT (top 0.1%) are more comprehensively analyzed by sequencing the coding region of the CF gene. If two CF-causing variants are identified, the baby is referred.
Testing can be affected by: Factors affecting IRT concentration, for example, IRT may be normal in some patients with CF, including some babies with meconium ileus, and this situation yields a false negative result. IRT may also be elevated within the first 24 hours after birth in healthy newborns, and this situation yields a false positive result. Most CF-causing variants will be identified in CF patients using the IRT-DNA-SEQ strategy, but in rare cases, a variant may be missed by the technology used. Due in part to the tiered approach, parents should not be told that a negative screen rules out CF carrier status or CF disease and should be educated about CF symptoms.
Interpretation/reporting of data: Results are reported as within acceptable limits, CF carrier (“one variant”), or as a referral (“two variants”). Prompt consultation with a specialist is required for a referral.
When two CF-causing gene variants are identified, this is usually consistent with a diagnosis of CF and the baby must be referred to an accredited Cystic Fibrosis Specialty Care Center.
When the screen identifies one variant or no variants, the risk of CF is low and further testing is not required, unless there is clinical suspicion of CF.
Referral to Specialty Care Center: Infants with an abnormal newborn screen for CF are referred to a Cystic Fibrosis Specialty Care Center for an evaluation by a pulmonologist trained in the diagnosis and treatment of CF.
Any baby who has a positive CF newborn screen result must be referred for a sweat test and assessed for symptoms such as malabsorption and respiratory problems. The sweat test measures the amount of salt in the sweat. The sweat test takes about one hour from start to finish. A special machine causes a small part of the baby's arm or leg to sweat. The skin may feel warm and tingly for 5 minutes while the machine is on. The baby may cry during this part of the test, but the test does not inflict pain. The sweat is collected on a gauze pad or disc. After 30 minutes, the gauze or disc is removed, and the collected sweat is tested in the lab.
The possible outcomes of the sweat test are:
- Negative result: This means that a normal amount of salt was found in the sweat. It is very rare for a person to have CF if the sweat test result is negative. The baby should continue to receive regular healthcare.
- Positive result: A positive sweat test means that the baby probably has CF. The baby should have a second sweat test shortly thereafter and a check-up with a doctor who specializes in treating people with CF.
- Borderline result: Sometimes the sweat test result will be in-between positive and negative. The baby will need to return for another sweat test in 1-2 months, and perhaps an exam by a pulmonologist trained in the diagnosis of CF.
QNS: means Quantity Not Sufficient (there was not enough sweat on the gauze or disc). The baby will need to return for another test as soon as possible.
Lungs – Antibiotics to prevent infections, medications to improve breathing and lung function (bronchodilators, mucolytic agents), chest physiotherapy to remove fluid and mucus from the lungs) and lung transplant in later stages of disease
Pancreas – Oral pancreatic enzymes and monitoring and treatment for diabetes
Digestion – Enemas or surgery for meconium ileus and vitamins and supplemental feedings with high calorie formula
There are new treatments available and in development to target specific CFTR variant types in the CFTR gene to restore function. Because these treatments are variant dependent, they will not work for all people with CF.
Prognosis is variable and dependent on multiple factors, including the severity of disease and response to treatments.
Cystic fibrosis (CF) is a genetic disorder caused by variants (sometimes referred to as mutations) in the CFTR gene. Variants in the CFTR gene may also cause CFTR-related metabolic syndrome (CRMS) and congenital absence of the vas deferens (CAVD).
The CFTR protein plays an important role in moving sodium and chloride across the cell wall. In CF patients, symptoms can develop in the lungs, pancreas, liver and intestines. When the CFTR protein is not functioning correctly, there is mucus build-up and inflammation in the lungs, blockage in the intestines, blockage of the biliary duct in the liver, and blockage in the pancreas. In addition, people with CF are often afflicted with malnutrition and infertility.