Cystic fibrosis

An autosomal recessive condition caused by one broken channel. Here's how that one channel failing dehydrates organs across the entire body.

If you haven't covered the six inheritance patterns yet, read our genetics basics article first. The rest of this page assumes you know what autosomal recessive and carrier mean.

Inheritance: a quick recap

Cystic fibrosis, usually shortened to CF, is autosomal recessive. The gene sits on chromosome 7 and codes for a protein called CFTR. A person needs two altered copies to be affected, written aa. One altered copy and one normal copy, written Aa, makes someone a carrier. Carriers show no symptoms, because the one working copy makes enough functional protein.

This is why CF can appear with no family history at all. Two unaffected carrier parents, both Aa, have no symptoms and often don't know they carry anything. Each child has a 25 percent chance of inheriting the altered copy from both parents and being affected, a 50 percent chance of inheriting one altered copy and becoming a carrier, and a 25 percent chance of inheriting neither.

Unlike X-linked recessive conditions, CF affects males and females equally, since the gene sits on an autosome, not the X chromosome. There's no father to son exception here. Either parent can pass the altered allele to a child of either sex.

What CFTR actually does

CF is caused by mutations in the gene for CFTR, a channel protein. CFTR sits in the membrane of epithelial cells, the cells that line the lungs, pancreas, intestines, sweat glands, and reproductive tract, and its job is to let chloride ions pass out of the cell onto the surface. Sodium ions follow chloride passively, and water follows sodium by osmosis. The result, in healthy tissue, is a thin layer of salty water sitting on the cell surface, keeping mucus loose enough to move.

Without working CFTR, chloride stays inside the cell instead of moving out. Sodium gets pulled back in along with it, and water follows sodium back into the cell instead of staying on the surface. The surface dries out.

From a dry surface to a failing body

This is the chain worth understanding, because it explains everything else in this article.

A dehydrated cell surface means dehydrated mucus. Mucus that should be thin and easy to move becomes thick and sticky instead. This single change in fluid physics, not a separate problem in each organ, is the root cause of nearly every symptom of CF. Thick mucus behaves the same way everywhere it forms. It just causes a different problem depending on which duct it blocks.

In the lungs, thick mucus can't be cleared by the lining's normal cleaning motion, so it sits in the airways and traps bacteria. The result is chronic infection and progressive inflammation, which over years damages the airway walls and ends in irreversible lung damage. In the pancreas, the same thick mucus blocks the small ducts that carry digestive enzymes into the intestine. Those enzymes back up and start damaging the pancreas itself, and without them reaching the gut, food can't be properly digested or absorbed, which leads to malnutrition and poor growth, especially in children. The pancreas can also lose the ability to produce insulin over time, leading to a distinct form of diabetes specific to CF.

One organ shows the mechanism in an almost diagnostic way: sweat glands. CFTR normally reabsorbs chloride and sodium from sweat as it travels through the duct to the skin, so that you don't lose too much salt when you sweat. In CF, that reabsorption fails, and sweat comes out abnormally salty. This is consistent enough that a sweat chloride test remains one of the standard ways to diagnose CF today.

Symptoms and how the disease progresses

Symptoms often appear in infancy: salty tasting skin, poor weight gain despite a normal appetite, greasy or bulky stools from poor fat absorption, and frequent respiratory infections. In many countries, newborn screening now identifies CF before symptoms appear at all.

Lung disease is progressive. Repeated infection and inflammation gradually scar and widen the airways, a process called bronchiectasis, and lung function declines over years. Pancreatic involvement is often present from birth in the more severe forms of CF and contributes to lifelong digestive and nutritional challenges. Most adult men with CF are infertile, since the same duct blocking process affects the tube that carries sperm.

Prevalence

CF is one of the most common life shortening genetic conditions in people of Northern European descent, with birth incidence in recent registry data ranging from roughly 1 in 3,000 to 1 in 7,000 live births in the United States and Canada. Carrier frequency in that population is approximately 1 in 31. CF is less common in people of African, Asian, and Hispanic descent, though it occurs in every population studied and is likely underdiagnosed in regions without routine newborn screening. Incidence has been gradually declining in places with widespread carrier screening, since couples who learn they are both carriers can make informed choices about family planning.

Why life expectancy was shortened, and how that's changing

In the 1950s, most children with CF didn't survive past their first few years. The damage described above, recurring lung infection and pancreatic failure, was essentially unmanaged. There was no way to clear the mucus, fight the chronic infection, or replace the missing digestive enzymes.

That has changed more dramatically for CF than for almost any other genetic condition. According to the most recent Cystic Fibrosis Foundation registry data, the predicted median survival age for a child born with CF between 2021 and 2025 is 66 years. That figure was in the 30s as recently as the 1990s. The disease itself hasn't changed. What changed is decades of incremental improvement in airway clearance techniques, antibiotics for chronic infection, pancreatic enzyme replacement, and, most recently, drugs that act directly on the defective CFTR protein itself.

Current treatment

Care for CF for decades focused entirely on managing the downstream effects of thick mucus: physical therapy techniques to clear the lungs, inhaled and oral antibiotics to control infection, and pancreatic enzyme supplements taken with food to replace what the pancreas can no longer deliver.

The more recent and more significant development is a class of drugs called CFTR modulators. Rather than treating the consequences of a broken channel, these drugs target the channel itself, either by helping a misfolded CFTR protein reach the cell surface correctly or by holding the channel open longer once it's there. They aren't effective for every CFTR mutation, since different mutations break the protein in different ways, but for the mutations they do target, modulators have measurably improved lung function and quality of life, and they are a major contributor to the rising survival figures described above. They do not cure CF or reverse existing organ damage, and they need to be taken for life.

For how X-linked recessive conditions behave differently on a pedigree, including the father to son rule that doesn't apply here, read our article on Duchenne muscular dystrophy.