The Genetic Thread Connecting Skin, Lungs, and Kidneys
Imagine a family where multiple members, across different generations, experience seemingly unrelated health problems: some develop benign skin growths on their faces, others suffer from collapsed lungs without warning, and a few are diagnosed with kidney cancer. For decades, these conditions appeared unrelated until the discovery of Birt–Hogg–Dubé syndrome (BHDS) revealed their common genetic origin 1 6 .
Fibrofolliculomas, trichodiscomas
Lung cysts, pneumothorax
Increased lifetime risk
BHDS has long been considered exceptionally rare, with initial estimates suggesting just 1-2 cases per million people 7 . However, groundbreaking recent research suggests this genetic mutation may be far more common than previously thought 9 .
The history of BHDS begins with dermatology. Birt, Hogg, and Dubé documented a family with distinctive facial papules—small, dome-shaped skin growths—which they classified as fibrofolliculomas, trichodiscomas, and acrochordons (skin tags) 1 6 .
The genetic breakthrough came when researchers identified mutations in the FLCN gene on chromosome 17p11.2 as the underlying cause of BHDS 6 . This discovery revealed BHDS as an autosomal dominant disorder, meaning each child of an affected parent has a 50% chance of inheriting the condition 1 .
Today, BHDS is recognized as a multisystem disorder connecting dermatology, pulmonology, and oncology through a common genetic pathway.
The FLCN gene encodes the folliculin protein, which plays a crucial role in regulating cell growth and division. Though its exact functions are still being unraveled, folliclin interacts with several key cellular pathways 1 6 7 .
| Mutation Type | Frequency | Functional Impact |
|---|---|---|
| Frameshift | Most common | Truncated, nonfunctional protein |
| Nonsense | Less common | Premature stop codon |
| Large deletions | Rare | Complete loss of gene segments |
| Missense | Rare | Altered protein structure |
The most recognizable sign of BHDS is fibrofolliculomas—small, whitish, dome-shaped papules that typically appear on the face, neck, and upper torso 1 .
A 2025 study published in BMJ Open Respiratory Research dramatically challenged previous assumptions, revealing that the genetic basis of BHDS might be far more common than previously recognized 3 5 9 .
New estimated prevalence of FLCN mutations
Almost 100 times more common than previous estimates 9
| Clinical Feature | Percentage of Patients | Additional Details |
|---|---|---|
| Lung cysts on CT | 94% | Bilateral in nearly all cases (93%) |
| History of pneumothorax | 56% | Multiple episodes in 70% of these |
| Fibrofolliculomas | 65% | Biopsy-proven in 34% |
| Renal tumors | 26% | All biopsy-proven |
| Family history of BHD | 66% | Supports autosomal dominant inheritance |
| Never smokers | 70% | Suggests cysts not related to smoking |
These findings suggest that many people carrying FLCN mutations may never receive a BHDS diagnosis because they don't develop the full clinical syndrome. As lead researcher Professor Marciniak noted, "There must be something else about their genetic background that's interacting with the gene to cause the additional symptoms" 9 .
The future of BHDS research looks promising as scientists work to develop targeted therapies based on the molecular pathways disrupted by folliculin deficiency.
"If an individual has Birt-Hogg-Dubé syndrome, then it's very important that we're able to diagnose it, because they and their family members may also be at risk of kidney cancer. The good news is that the collapsed lung usually happens 10 to 20 years before the individual shows symptoms of kidney cancer, so we can keep an eye on them, screen them every year, and if we see the tumour it should still be early enough to cure it."
The story of Birt–Hogg–Dubé syndrome continues to evolve. What began as a dermatological curiosity has transformed into a multifaceted genetic condition that connects specialists across medicine—from dermatologists to pulmonologists, oncologists to genetic counselors.
The recent discovery that FLCN mutations are far more common than previously thought opens new chapters in our understanding of this syndrome and highlights the complex interplay between our genetic blueprint and its clinical expression.
As genetic testing becomes more widespread, the medical community faces the challenge of appropriately counseling and managing a growing population of individuals with FLCN mutations, many of whom may never develop the classic triad of BHDS symptoms. Through continued research and clinical collaboration, we move closer to unraveling the remaining mysteries of this fascinating syndrome and improving care for those affected by it.