Which are the causes of Birt-Hogg-Dubé syndrome?

TL;DR: Birt-Hogg-Dubé syndrome is a rare genetic condition caused by pathogenic variants in the FLCN gene, which provides instructions for making the protein folliculin. This mutation disrupts the body's ability to regulate cell growth and metabolism, leading to the development of characteristic skin lesions, pulmonary cysts, and an increased risk of specific kidney tumors.

What causes Birt-Hogg-Dubé syndrome at a genetic level?

Birt-Hogg-Dubé syndrome is caused by mutations in the FLCN gene, located on chromosome 17 (specifically at 17p11.2). This gene is responsible for producing a protein called folliculin. Think of the folliculin protein as a "cellular traffic controller"; in a healthy body, it helps regulate the mTOR pathway, which is a signaling network that controls cell growth, proliferation, and survival. When a person has Birt-Hogg-Dubé syndrome, the mutated FLCN gene produces a non-functional or missing protein, causing the "traffic controller" to stop working correctly. This leads to unchecked cell growth, which manifests as the benign skin tumors (fibrofolliculomas), lung cysts, and renal neoplasms associated with the condition.

Is Birt-Hogg-Dubé syndrome hereditary?

Yes, Birt-Hogg-Dubé syndrome is inherited in an autosomal dominant pattern. This means that an individual only needs to inherit one copy of the mutated FLCN gene from one affected parent to develop the disorder. If a parent has Birt-Hogg-Dubé syndrome, each child has a 50% chance of inheriting the mutation. However, it is important to note that the syndrome exhibits "variable expressivity," meaning that even within the same family, some individuals may have severe symptoms while others may show very few signs of the disease. Currently, 114 people with Birt-Hogg-Dubé syndrome have joined the DiseaseMaps community, sharing diverse experiences that highlight how this genetic inheritance affects individuals differently.

Are there environmental triggers or other metabolic factors?

Unlike some conditions, Birt-Hogg-Dubé syndrome is not caused by environmental triggers, diet, or lifestyle choices. It is strictly a genetic condition present from conception. While researchers are actively studying the metabolic role of the FLCN gene, there is no evidence that external factors like infections or toxins cause the disease. The primary risk factor for developing the clinical features of Birt-Hogg-Dubé syndrome is simply the presence of the germline mutation in the FLCN gene.

How does current research aim to better understand the syndrome?

Researchers are focused on understanding the exact molecular functions of folliculin to develop targeted therapies. Because the mTOR pathway is involved in many cancers, current research into Birt-Hogg-Dubé syndrome is exploring whether drugs that inhibit mTOR could potentially manage the kidney tumors associated with the condition. Scientists are also investigating why some people with the mutation develop severe lung cysts (leading to pneumothorax) while others do not, which may involve "modifier genes" that influence how the body compensates for the missing folliculin protein.

Key facts about the genetics of Birt-Hogg-Dubé syndrome

• Gene Involved: FLCN (Folliculin).


• Inheritance Pattern: Autosomal dominant.


• Location: Chromosome 17p11.2.


• Primary Mechanism: Dysregulation of the mTOR signaling pathway, leading to abnormal cell growth.


• Clinical Variability: High; symptoms vary significantly even among family members with the exact same mutation.

Next steps

• Consult with a clinical geneticist to discuss genetic testing and family screening options.


• Schedule regular renal imaging (such as MRI) as recommended by your specialist to monitor for kidney tumors.


• Connect with the 114 members of the DiseaseMaps community who share your journey with Birt-Hogg-Dubé syndrome.


• Review the latest clinical trial information through the NIH ClinicalTrials.gov database.

Medical disclaimer: This information is for educational purposes only and does not constitute medical advice; please consult with a qualified healthcare professional regarding any medical condition or treatment.

References

• NIH Genetic and Rare Diseases Information Center (GARD): Birt-Hogg-Dubé syndrome overview.


• Orphanet: Rare disease database entry for Birt-Hogg-Dubé syndrome (ORPHA125).


• OMIM (Online Mendelian Inheritance in Man): FLCN Gene and Birt-Hogg-Dubé syndrome (Entry #135150).


• The BHD Foundation: International resources for patients and researchers.