Birt-Hogg-Dubé syndrome is a rare inherited condition caused by mutations in a single gene that can affect the skin, lungs, and kidneys. First described in 1977 in a family from Winnipeg, Manitoba, the syndrome was originally identified through unusual skin growths that ran through multiple generations in a pattern suggesting dominant inheritance.1CMAJ. Birt–Hogg–Dubé syndrome: an inherited cause of spontaneous pneumothorax The condition turns out to be far more than a skin disease, though. Lung cysts, collapsed lungs, and kidney tumors all belong to the same syndrome, and recognizing the pattern early can make a real difference in outcomes.
The Gene Behind It
Birt-Hogg-Dubé syndrome stems from mutations in the folliculin gene, known as FLCN, located on chromosome 17.2PubMed Central. Birt-Hogg-Dubé Syndrome: A Mini Review of the Clinical Manifestations, Investigation, and Management Inheritance follows an autosomal dominant pattern, meaning a person only needs one faulty copy of the gene to be affected. Each child of someone carrying the mutation has a fifty-fifty chance of inheriting it.
The FLCN protein normally helps regulate cell growth and energy metabolism. It interacts with a key growth-signaling hub called mTOR and with the energy sensor AMPK. When folliculin is missing or broken, certain transcription factors that control cell growth become permanently switched on, and the cell’s metabolic balance shifts.3PubMed Central. Folliculin: A Regulator of Transcription Through AMPK and mTOR Signaling Pathways That disruption sits at the root of the cysts, skin growths, and tumors that define the syndrome.
One complicating factor is that not everyone with a FLCN mutation looks the same clinically. Penetrance is incomplete, meaning some mutation carriers develop all three classic features while others show only one or two. In one study of families carrying confirmed FLCN mutations, the typical skin lesions appeared in fewer than half of mutation carriers over 20.4PubMed. Constitutional FLCN mutations in patients with suspected Birt-Hogg-Dubé syndrome ascertained for non-cutaneous manifestations This variability means some affected individuals go undiagnosed for years, especially if they present with lung or kidney problems rather than skin findings.
Skin Growths and What They Look Like
The hallmark skin lesion of Birt-Hogg-Dubé syndrome is the fibrofolliculoma, a small benign tumor that forms around hair follicles. Clinically, these growths show up as multiple whitish, dome-shaped bumps a few millimeters across, concentrated on the nose, forehead, cheeks, neck, and sometimes the trunk. They tend to appear during a person’s twenties or thirties and gradually multiply with age.5Actas Dermo-Sifiliográficas. Birt–Hogg–Dubé Syndrome: An Update The bumps are painless and medically harmless, but they can be cosmetically bothersome, especially when they cluster on the face.
The original description of the syndrome referred to a “triad” of skin growths: fibrofolliculomas, trichodiscomas, and skin tags. Current understanding, though, is that trichodiscomas are really just a later-stage version of the same fibrofolliculoma process, and the three lesion types exist along a single spectrum rather than being truly separate conditions.6Actas Dermo-Sifiliográficas. Birt–Hogg–Dubé Syndrome: An Update Under the microscope, fibrofolliculomas show a characteristic pattern: thin strands of tissue radiating out from a central hair follicle, surrounded by loose connective tissue.7PubMed Central. Birt–Hogg–Dubé Syndrome: A Rare Genodermatosis Presenting as Skin Papillomas That microscopic appearance is often what clinches the diagnosis, since the bumps themselves can look unremarkable to the naked eye.
Lung Cysts and Collapsed Lungs
Pulmonary involvement is actually more common than the skin findings. In a study of over 100 patients with confirmed Birt-Hogg-Dubé syndrome, lung cysts were present in about 85%. Roughly three-quarters had experienced at least one spontaneous pneumothorax (collapsed lung), and of those, more than 80% had multiple episodes.8PubMed Central. Spontaneous Pneumothoraces in Patients with Birt-Hogg-Dubé Syndrome A collapsed lung is often what brings someone to medical attention in the first place, sometimes years before any skin bumps appear.
The cysts in Birt-Hogg-Dubé syndrome have a distinctive look on chest imaging. They tend to cluster in the lower portions of the lungs, sit along the edges and near blood vessels, and frequently have an oval or lens-like shape rather than the round cysts seen in other cystic lung diseases.9PubMed Central. Pulmonary manifestations of Birt-Hogg-Dubé syndrome An experienced radiologist can sometimes suspect the syndrome based on a chest CT alone, before genetic testing is ordered. The cysts themselves rarely cause breathing difficulty on their own; the problem is their tendency to rupture and cause pneumothorax.
Because recurrences are so frequent, early surgical intervention is generally recommended after a first or second pneumothorax. The preferred approach is video-assisted thoracoscopic surgery, a minimally invasive procedure that typically involves removing the ruptured area of lung and performing pleurodesis, which is essentially getting the lung surface to stick to the chest wall so air leaks cannot accumulate.10PubMed Central. Recurrent spontaneous pneumothorax and surgical management in Birt–Hogg–Dubé syndrome: a case report This does not eliminate the underlying cysts, but it substantially reduces the chance of another collapse on the treated side.
Kidney Tumors
The most medically serious aspect of Birt-Hogg-Dubé syndrome is the elevated risk of kidney cancer. The tumors that develop tend to be unusual types. A landmark pathology study found that among 130 resected kidney tumors from BHD patients, about half were hybrid oncocytic tumors (a mix of two cell types), about a third were chromophobe renal cell carcinomas, and roughly 9% were clear cell carcinomas.11PubMed. Renal tumors in the Birt-Hogg-Dubé syndrome The tumors are often multiple and can appear in both kidneys, a pattern that in a young person should raise suspicion for an inherited syndrome.12PubMed. The ABCs of BHD: An In-Depth Review of Birt-Hogg-Dubé Syndrome
The good news is that most BHD-associated kidney tumors grow slowly. The standard management approach is active surveillance with regular imaging, intervening surgically only when a tumor reaches about 3 cm. At that point, surgeons aim for nephron-sparing surgery, removing the tumor while preserving as much healthy kidney tissue as possible. This is especially important because tumors can recur in both kidneys over a lifetime, and losing too much kidney tissue early on could lead to chronic kidney disease down the road. When tumors are caught while still confined to the kidney, the vast majority of patients achieve a cure.13PubMed Central. Diagnosis and management of BHD-associated kidney cancer
One area of ongoing investigation is whether the location of the mutation within the FLCN gene affects kidney cancer risk. Researchers have noticed a trend suggesting mutations in the earlier portion of the gene may carry somewhat higher risk than mutations in the later portion, but the difference has not reached statistical significance in the studies done so far. Larger patient registries are needed before genotype can reliably guide screening intensity.14PLoS ONE. Kidney cancer characteristics and genotype-phenotype-correlations in Birt-Hogg-Dubé syndrome
How the Diagnosis Is Made
A definitive diagnosis requires finding a disease-causing mutation in the FLCN gene. Genetic testing picks up the mutation in an estimated 88% to 96% of people who have the clinical syndrome.15European Journal of Human Genetics. ERN GENTURIS clinical practice guidelines for the diagnosis, surveillance and management of people with Birt-Hogg-Dubé syndrome Most mutations are the type that truncate the protein, and one particular mutation in exon 11 recurs across unrelated families around the world. Genetic testing is typically done through a multigene panel rather than a single-gene test, since the clinical picture can overlap with several other hereditary conditions.
When genetic testing comes back negative but clinical suspicion remains high, a diagnosis can still be made using clinical criteria established by European expert guidelines. The major criterion is having more than five fibrofolliculomas or trichodiscomas, with at least one confirmed under the microscope. Alternatively, two of the following minor criteria can clinch it: bilateral lung cysts in the lower zones with no other explanation, kidney cancer that is early-onset or bilateral or of the characteristic hybrid histology, or a first-degree relative already diagnosed with BHD.16PubMed Central. ERN GENTURIS clinical practice guidelines for the diagnosis, surveillance and management of people with Birt-Hogg-Dubé syndrome
The same guidelines also spell out a list of “red flags” that should prompt FLCN testing even when BHD is not the first thing on a clinician’s mind. These include recurrent spontaneous pneumothorax (especially if it runs in the family), bilateral lung cysts without a known cause, bilateral or multifocal kidney tumors, kidney cancer before age 45, and the characteristic facial papules. A combination of any of these in the same person or across family members should raise the question.17PubMed Central. ERN GENTURIS clinical practice guidelines for the diagnosis, surveillance and management of people with Birt-Hogg-Dubé syndrome
Distinguishing BHD From Similar Conditions
Several other hereditary syndromes can involve kidney tumors, lung cysts, or both, creating diagnostic overlap. BHD is one of seven hereditary kidney cancer syndromes recognized by major cancer guidelines, alongside conditions like Von Hippel-Lindau disease, tuberous sclerosis complex, and hereditary leiomyomatosis and renal cell cancer.18PubMed. Hereditary syndromes and RCC: what radiologists need to know Each of these syndromes favors different tumor types and has distinct associated features, but from an imaging standpoint, telling apart a chromophobe renal cell carcinoma from a benign oncocytoma can be genuinely difficult. That ambiguity is one reason BHD patients are followed with serial imaging rather than biopsied at every turn.
Tuberous sclerosis complex deserves special mention because its skin and kidney findings can mimic BHD. Both produce benign skin growths and renal tumors, and under the microscope, some BHD skin lesions share features with the fibromas seen in tuberous sclerosis.19The American Journal of Dermatopathology. Syndrome of Birt–Hogg–Dubé, a Histopathological Pitfall With Similarities to Tuberous Sclerosis Genetic testing resolves the confusion, since the two conditions involve entirely different genes, but the clinical overlap underscores why a biopsy of a skin lesion can be so diagnostically useful when someone presents with unexplained lung cysts or kidney tumors.
There are also rare reports of a BHD-like condition caused by mutations in a different gene called PRDM10 rather than FLCN. This is a recent discovery and appears to be uncommon, but it means that a negative FLCN test does not completely rule out a BHD-like syndrome.20European Journal of Human Genetics. ERN GENTURIS clinical practice guidelines for the diagnosis, surveillance and management of people with Birt-Hogg-Dubé syndrome
Treating the Skin Bumps
Fibrofolliculomas do not become cancerous and do not require treatment for medical reasons. But for people with dozens of them clustered across their face, the cosmetic impact can be significant, and removal is a reasonable choice. The options that have been tried include electrosurgery (using heat from an electrical current), shave removal, dermabrasion, surgical excision, and laser ablation.21PubMed Central. Fibrofolliculomas in Birt-Hogg-Dubé syndrome treated with nonfractionated ablative CO 2 laser
No randomized controlled trials have compared these approaches head to head, so the evidence comes from case reports and small series. Electrosurgery has shown good tolerability with limited recurrence over a few years. CO2 laser and erbium:YAG laser treatments are popular because they can address many lesions quickly in a single session. Recurrence after laser treatment has been reported anywhere from a few months to several years later, and some practitioners combine laser with topical rapamycin to try to slow regrowth.22PubMed. Cutaneous Fibrofolliculomas and Trichodiscomas in Birt-Hogg-Dubé Syndrome: A Review of Therapeutic Surgical Strategies None of these treatments address the underlying genetic cause, so new lesions can continue to appear over time. Most people who opt for treatment expect to need periodic maintenance sessions rather than a one-time fix.
Living With the Diagnosis
Beyond the medical management, a BHD diagnosis carries a range of psychosocial burdens that physicians do not always think to address. The threat of recurrent pneumothorax can create anxiety around physical activity and air travel. The awareness that kidney tumors could develop at any time means committing to lifelong imaging surveillance. And because the condition is inherited, the diagnosis ripples through families, sometimes disrupting relationships when relatives disagree about whether to get tested or how seriously to take the findings.23PubMed Central. Birt-Hogg-Dubé: beyond the clinical manifestations
Economic concerns are real as well. Regular imaging, potential surgeries, genetic counseling for family members, and dermatological treatments all add up. For people in healthcare systems without strong genetic-disease coverage, these costs can be a barrier to the kind of proactive surveillance that makes the syndrome manageable. Physicians who are aware of these non-medical dimensions can connect patients with genetic counselors, support groups, and financial assistance programs, all of which improve quality of life beyond what clinical management alone can offer.
Colorectal Cancer and Other Possible Associations
Whether Birt-Hogg-Dubé syndrome raises the risk of cancers outside the kidney has been debated. One interesting finding involves colorectal tumors. Analysis of families carrying two different recurrent FLCN mutations showed that one specific mutation (a duplication in exon 11) was associated with a significantly higher rate of colorectal growths than another common mutation.24PubMed. Investigation of the Birt-Hogg-Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer This is one of the clearest examples of a genotype-phenotype link in BHD, and it raises the question of whether certain mutation carriers might benefit from earlier or more frequent colorectal screening. The evidence is still limited, and current guidelines do not mandate colonoscopy for all BHD patients, but this is an area many specialists watch closely.
Other tumor types have been reported in BHD families at rates that seem higher than expected, including thyroid tumors and parotid gland tumors, but these associations are not firmly established. The rarity of the syndrome makes it genuinely difficult to tell whether a given cancer occurring in a BHD family is related to the FLCN mutation or is just coincidence. For now, kidney surveillance remains the primary cancer-focused component of BHD management.
Where Research Is Headed
The discovery of FLCN’s role in growth-signaling pathways has opened up possibilities for targeted therapy. Mouse models in which the BHD gene has been knocked out develop enlarged, cystic kidneys and die of kidney failure within weeks. But when those mice were treated with rapamycin, an mTOR inhibitor, their kidneys were significantly smaller and they survived roughly twice as long as untreated animals.25PubMed Central. Kidney-Targeted Birt-Hogg-Dube Gene Inactivation in a Mouse Model: Erk1/2 and Akt-mTOR Activation, Cell Hyperproliferation, and Polycystic Kidneys That result is encouraging because mTOR inhibitors already exist as approved drugs for other conditions, which could shorten the path to clinical trials in BHD patients.
Drug screening in BHD cell lines has also turned up compounds that selectively target cells lacking folliculin. One study found that mithramycin, an older antibiotic with anti-cancer properties, was roughly tenfold more effective at inhibiting growth in FLCN-deficient cells compared to cells with normal folliculin expression.26Molecular Cancer Therapeutics. Therapeutic Targeting the Loss of the Birt-Hogg-Dubé Suppressor Gene These are still very early laboratory findings, not treatments ready for human use. But they show that the metabolic vulnerabilities created by FLCN loss are real and potentially exploitable.
Researchers are also unraveling FLCN’s broader biological roles using organisms far simpler than mice. In the roundworm C. elegans, losing the equivalent of the FLCN gene actually extended lifespan and improved stress resistance, through a pathway involving the same oxygen-sensing system (HIF-1) that plays a role in kidney tumors when the closely related VHL gene is lost.27PubMed. Loss of the Birt-Hogg-Dubé gene product folliculin induces longevity in a hypoxia-inducible factor-dependent manner The fact that a human tumor-suppressor gene affects aging in worms underscores how deeply embedded FLCN is in basic cellular housekeeping. Understanding exactly how folliculin loss leads to cysts in the lungs, tumors in the kidneys, and benign growths in the skin remains one of the open puzzles in BHD research, and the answer will likely come from continued work across these diverse model systems.28PubMed Central. Birt-Hogg-Dubé syndrome: from gene discovery to molecularly targeted therapies