Birt-Hogg-Dubé syndrome is a rare, inherited genetic condition that primarily affects the skin and lungs, and it increases a person’s risk of developing kidney tumors. First described in 1977 by Canadian physicians Arthur R. Birt, Georgina R. Hogg, and W. J. Dubé, the disorder presents with a distinct combination of symptoms. These manifestations often include non-cancerous skin lesions, the formation of cysts in the lung tissue, and a predisposition for certain types of kidney growths. The expression of these signs can vary significantly among individuals, even within the same family, and symptoms typically begin to appear in early adulthood.
Genetic Origins of Birt-Hogg-Dubé Syndrome
Birt-Hogg-Dubé (BHD) syndrome is caused by a mutation in the Folliculin (FLCN) gene. This gene provides instructions for making a protein called folliculin, which acts as a tumor suppressor. The folliculin protein helps regulate cell growth, preventing cells from dividing too rapidly or in an uncontrolled way. When a mutation occurs in the FLCN gene, the production of functional folliculin is disrupted, leading to the uncontrolled cell growth that forms the tumors and cysts of BHD.
The inheritance pattern for BHD syndrome is autosomal dominant, meaning an individual needs to inherit only one copy of the mutated gene to develop the condition. A parent with BHD has a 50% chance of passing the mutated gene to each child. While most individuals with BHD inherit the condition, the mutation can occur spontaneously in a person with no family history of the syndrome.
Key Signs and Associated Health Risks
Skin Manifestations
A common sign of Birt-Hogg-Dubé syndrome is the development of multiple, benign skin bumps called fibrofolliculomas. These small, dome-shaped, whitish papules arise from hair follicles. They begin to appear during a person’s 20s or 30s and increase in number with age. The fibrofolliculomas are most commonly found on the face, neck, and upper torso, and their appearance is a primary indicator for diagnosis.
Lung Cysts and Pneumothorax
Individuals with BHD syndrome often develop multiple cysts within their lung tissue. These air-filled sacs do not usually affect lung function but create a structural weakness in the lung wall. The presence of these cysts increases the risk for a spontaneous pneumothorax, or a collapsed lung.
A pneumothorax occurs when a cyst ruptures, allowing air to leak from the lung into the space between the lung and chest wall, causing it to deflate. This medical event requires immediate attention and its symptoms include sudden sharp chest pain and shortness of breath. Individuals with BHD may have recurrent episodes.
Kidney Abnormalities
BHD syndrome increases the lifetime risk of developing kidney tumors. These tumors typically appear later than the skin and lung signs, with an average age of onset around 50. The growths can be multifocal, meaning multiple tumors can appear, and they can affect both kidneys, being either benign or malignant.
The most common kidney tumor in BHD is a benign growth called a renal oncocytoma. However, the syndrome also elevates the risk for cancerous tumors, most notably chromophobe renal cell carcinoma. A mix of chromophobe and oncocytic cells in a tumor is a hallmark of BHD. Not everyone with BHD will develop kidney cancer; estimates suggest 15% to 30% of individuals will.
The Diagnostic Process
Diagnosis of Birt-Hogg-Dubé syndrome often begins with a clinical evaluation based on physical signs and family history. Specific diagnostic criteria guide this process, requiring either one major criterion or two minor criteria to be met.
Following this assessment, imaging studies identify internal manifestations. A high-resolution computed tomography (CT) scan of the chest is used to detect lung cysts. An abdominal CT or magnetic resonance imaging (MRI) scan can reveal the characteristic kidney cysts and tumors.
While clinical signs and imaging are strong indicators, genetic testing provides a definitive diagnosis. A blood test analyzes the FLCN gene to identify a pathogenic mutation. This confirmation provides a conclusive diagnosis and allows for predictive testing for at-risk family members.
Management and Surveillance Strategies
As there is no cure for Birt-Hogg-Dubé syndrome, management focuses on surveillance and treating complications. The primary goal is to monitor for kidney tumors, which pose the most significant health risk. Individuals with BHD are advised to undergo regular kidney imaging with MRI or CT scans to detect tumors early.
For skin manifestations, treatment is cosmetic and may involve laser ablation or surgical removal of the fibrofolliculomas, though lesions often recur. When a spontaneous pneumothorax occurs, treatment involves removing air from the chest cavity to allow the lung to re-inflate, often by inserting a chest tube.
Lifestyle adjustments are also part of managing BHD. Patients are advised to avoid activities that increase the risk of a collapsed lung due to air pressure changes, like scuba diving. Genetic counseling is recommended to help families understand the inheritance pattern and make informed decisions about testing for relatives.