Lung collapse is more common than you think

As many of us know, lungs can collapse. It usually happens in everyday situations, without any warning or injury. You could be sitting in class, at work, or even just watching TV when you suddenly feel a sharp pain and shortness of breath. Doctors call this a pneumothorax, and while it can happen by chance, sometimes it’s a red flag for something happening to your DNA.

One rare culprit is Birt-Hogg-Dubé syndrome (BHDS), a mouthful of a condition that links together three seemingly unrelated problems: skin bumps, lung cysts that can burst, and kidney cancer. For years, BHDS has been thought of as a medical zebra, so rare that only about one in 200,000 people were believed to have it.

But new research from the University of Cambridge, Birmingham Women’s and Children’s Hospitals, and Queen Mary University of London, published in Thorax in April 2025, suggests that BHDS may not be rare at all. In fact, it might be surprisingly common: more like one in 3,000 people.

What exactly is BHDS?

BHDS is caused by mutations in a gene called FLCN, which makes a protein known as folliculin. When this gene breaks down, it sets off a cascade of problems, including skin growths (benign but often overlooked bumps called fibrofolliculomas, usually on the face and upper body), Lung cysts, which are harmless until they suddenly pop, causing a lung to collapse, and kidney cancer (especially rare and unusual forms that can appear in both kidneys at once).

Doctors first described the syndrome in the late 1970s, naming it after the Canadian physicians Arthur Birt, Georgina Hogg, and William Dubé. Since then, over 190 different mutations in the FLCN gene have been linked to the condition.

For decades, textbooks repeated the line: “BHDS affects about 1 in 200,000 people.” That made it sound almost vanishingly rare, something a general doctor might never see in their career.

But what if that number was wrong? Enter Bryndis Yngvadottir, Lucy Richman, Avgi Andreou, Jessica Woodley, Anita Luharia, Derek Lim, Eamonn Maher, and Stefan Marciniak of Cambridge. Their team decided to test the old assumption by turning to modern genomic treasure troves.

They drew on three enormous DNA datasets, the UK Biobank, which includes half a million British volunteers, the 100,000 Genomes Project, a pioneering NHS effort to decode genomes of patients with rare diseases, and Genes & Health, a large-scale community-based study of British Bangladeshi and Pakistani populations in East London. Altogether, they analyzed the DNA of over 556,000 people, an unprecedented chance to spot patterns invisible in small family studies.

Here's what they found. Across these databases, they discovered 155 people carrying clearly harmful FLCN mutations. When they crunched the numbers, that worked out to somewhere between 1 in 2,710 and 1 in 4,190 individuals. Tens of times higher than the old 1-in-200,000 estimate. In East London’s Genes & Health group, the numbers were even higher: about 1 in 1,490. So, this is not rare. This is common.

How dangerous are these mutations?

Finding out that a gene mutation is common is one thing. But how risky is it? The researchers compared people with FLCN mutations in the UK Biobank to a group of BHDS patients who had been diagnosed clinically. By age 65, about 28% of Biobank carriers had experienced a collapsed lung (pneumothorax), compared to 37% of diagnosed BHDS patients. Both groups had a substantial risk, but the Biobank numbers suggest some carriers live long without ever having lung problems. For kidney cancer patients, this was where things really diverged. In diagnosed BHDS patients, the lifetime risk of kidney cancer was about 32%. But in the general-population Biobank carriers, the risk was only 1%. In other words, the same mutation can play out very differently depending on the person’s background, family history, and perhaps environment.

Why the difference?

One idea is that when BHDS is discovered in families, it’s because the syndrome is severe: lots of lung collapses, or multiple cases of kidney cancer. Those families, by definition, show the “worst-case scenario.” But in the general population, many people with the mutation may never even know they have it. They might live their whole lives without a collapse or a tumor. This doesn’t mean the mutation is harmless. It just means it isn’t destiny. Genes load the gun, as the saying goes, but environment and chance pull the trigger.

The findings of the study raise big questions for doctors and genetic counselors. If FLCN mutations are as common as 1 in 3,000, then tens of thousands of people in the UK alone may carry them. With genetic testing becoming more routine, many of these cases will turn up as “incidental findings”, a mutation spotted when someone gets their DNA sequenced for another reason.

So what do you do if you find out you carry one? For lung risks, it may mean being alert to symptoms of a collapsed lung and warning doctors if it runs in the family. For kidneys, the answer is trickier. Right now, people diagnosed with BHDS are often given regular MRI scans to check for kidney tumors, sometimes every year. But if the cancer risk in the general population is as low as this study suggests, maybe less intensive screening, like ultrasound every two years, could be enough.

The study points to the need for prospective follow-up, and tracking people with incidental mutations over time to see how their health plays out.

Behind the statistics are real families. For some, BHDS is devastating. Multiple siblings with collapsed lungs, parents facing kidney surgery, and young people learning they carry a lifelong risk. For others, the mutation may stay in the background, never making itself known. The message from the authors is clear: doctors shouldn’t dismiss BHDS as vanishingly rare. Instead, they should think of it whenever a young, healthy person shows up with a spontaneous pneumothorax, or when kidney cancers crop up in multiple family members. Furthermore, early diagnosis matters. Catching kidney cancer early can be lifesaving. And understanding the genetic cause of a collapsed lung can help prevent recurrences and guide family testing.

The story of BHDS is part of a larger shift in medicine. As we collect data from hundreds of thousands of genomes, we’re realizing that many so-called “rare diseases” may not be rare at all. They’ve just been underdiagnosed, hiding in plain sight. And while genes like FLCN can increase risk, they don’t tell the whole story. Family context, lifestyle, and plain luck still play huge roles.

If you want to learn more, the original article titled "A prospective code for value in the serotonin system" on Thorax at https://doi.org/10.1136/thorax-2024-221738