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

Birt-Hogg-Dubé syndrome (BHD) is a rare genetic disorder that is inherited in an autosomal dominant manner. It is caused by mutations in the Folliculin (FLCN) gene, which is located on chromosome 17. The FLCN gene provides instructions for producing a protein called folliculin, which is involved in regulating cell growth and division.

Individuals with BHD have a mutation in one copy of the FLCN gene, which leads to a loss of function of the folliculin protein. This loss of function disrupts the normal cellular processes and can result in the development of various symptoms and manifestations associated with BHD.

One of the primary features of BHD syndrome is the development of multiple benign skin tumors called fibrofolliculomas. These small, dome-shaped growths typically appear on the face, neck, and upper body. Fibrofolliculomas are usually harmless, but their presence can be a characteristic sign of BHD.

Pulmonary manifestations are also common in individuals with BHD. They may develop multiple lung cysts, which are small air-filled sacs in the lungs. These cysts can vary in size and number and may increase the risk of pneumothorax (collapsed lung) or other respiratory complications. Some individuals with BHD may also develop a lung condition called pneumothorax, which occurs when air leaks into the space between the lung and chest wall, causing the lung to collapse.

Renal manifestations are another significant aspect of BHD syndrome. Individuals with BHD have an increased risk of developing kidney tumors, particularly a type called renal cell carcinoma (RCC). RCC is a malignant tumor that originates in the cells of the kidney and can potentially spread to other parts of the body. The risk of developing RCC in BHD syndrome is higher compared to the general population.

Other features associated with BHD syndrome include the development of spontaneous pneumothorax (collapsed lung) in individuals without lung cysts, as well as the presence of renal cysts and renal cancer in family members without skin lesions. Additionally, some individuals with BHD may experience gastrointestinal polyps, which are noncancerous growths in the digestive tract.

The exact mechanisms by which FLCN gene mutations lead to the development of BHD manifestations are not fully understood. However, it is believed that the loss of folliculin protein function disrupts cellular signaling pathways involved in cell growth, division, and tumor suppression. This disruption can result in the formation of fibrofolliculomas, lung cysts, and kidney tumors.

Genetic testing is available to confirm a diagnosis of BHD syndrome. It involves analyzing the FLCN gene for mutations or deletions. Genetic testing can help identify individuals at risk of developing BHD-related manifestations and enable early detection and management of associated conditions.

In conclusion, Birt-Hogg-Dubé syndrome is caused by mutations in the FLCN gene, which disrupts normal cellular processes involved in cell growth and division. This genetic disorder leads to the development of fibrofolliculomas, lung cysts, and an increased risk of kidney tumors. Genetic testing plays a crucial role in diagnosing BHD and managing associated manifestations.