The FLCN gene is a segment of human DNA, found on chromosome 17, that carries instructions for producing a particular protein. Understanding the FLCN gene provides insight into certain health conditions linked to its variations.
Role of the FLCN Gene
The FLCN gene directs the creation of a protein known as folliculin. This protein is found in many bodily tissues, including the brain, heart, skin, lungs, and kidneys. Folliculin functions as a tumor suppressor, regulating cell growth and division to prevent uncontrolled cell proliferation.
Beyond its role in tumor suppression, folliculin is thought to participate in other cellular processes. It may be involved in the uptake of foreign particles by cells, such as through endocytosis or phagocytosis. The protein also contributes to the cell’s structural framework, known as the cytoskeleton, which helps define cell shape and movement. In the lungs, folliculin supports the repair and regeneration of lung tissue after injury. Furthermore, folliculin interacts with other proteins and plays a part in regulating metabolic pathways, including those controlled by mTORC1 and AMPK, which are important for cellular energy balance.
Understanding Birt-Hogg-Dubé Syndrome
Birt-Hogg-Dubé (BHD) syndrome is a rare, inherited genetic disorder caused by mutations in the FLCN gene. These germline mutations are present in all cells of the body and can be passed down from a parent to their child. The syndrome follows an autosomal dominant inheritance pattern, meaning a person needs to inherit only one copy of the mutated FLCN gene from either parent to develop the condition.
The mutations in the FLCN gene often result in the production of an abnormally short or non-functional folliculin protein. Without a properly functioning folliculin protein, cells may lose their ability to control growth and division, contributing to the formation of both non-cancerous and cancerous tumors. BHD syndrome affects multiple organ systems, with its main manifestations appearing in the skin, lungs, and kidneys. Symptoms emerge between the second and fourth decades of life.
Specific Health Concerns
BHD syndrome presents with characteristic health manifestations affecting the skin, lungs, and kidneys.
Skin Manifestations
Skin lesions are a common feature, often appearing as multiple, small, dome-shaped papules, typically on the face, neck, and upper chest. These benign skin tumors include fibrofolliculomas, which are hamartomas of the hair follicle, and trichodiscomas. Acrochordons, also known as skin tags, can also be present.
Lung Manifestations
Lung issues are a frequent concern for individuals with BHD. Most affected individuals develop multiple lung cysts, also known as pneumatoceles, which are air-filled sacs in the lung tissue. These cysts are often found in both lungs and can increase the risk of spontaneous pneumothorax, a condition where air leaks into the space between the lung and chest wall, leading to a collapsed lung. While lung cysts are common, BHD syndrome typically does not lead to a progressive loss of lung function or chronic respiratory insufficiency.
Kidney Manifestations
Individuals with BHD syndrome have an increased risk of developing kidney tumors. These tumors are often multiple and can appear in both kidneys. The types of kidney tumors commonly seen in BHD syndrome include oncocytomas, which are benign but can grow large, as well as oncocytic hybrid tumors and chromophobe renal cell carcinomas (RCCs), which tend to be slow-growing forms of kidney cancer. Renal tumors typically develop in the fourth and fifth decades of life.
Identifying and Living with the Syndrome
Diagnosing Birt-Hogg-Dubé syndrome often involves a combination of clinical evaluation and genetic testing. Clinical criteria, such as the presence of characteristic skin lesions, multiple lung cysts, or specific types of kidney tumors, can suggest the diagnosis. A family history of BHD syndrome or its associated symptoms also supports the diagnosis.
Genetic testing for mutations in the FLCN gene (OMIM: 607273) is the definitive method to confirm the diagnosis. Once a pathogenic FLCN variant is identified in an affected family member, predictive testing can be offered to at-risk relatives to determine if they have inherited the mutation.
Management of BHD syndrome focuses primarily on surveillance and early detection of potential complications, particularly kidney tumors and lung issues. Regular screenings are recommended, typically beginning around age 20. This often includes periodic magnetic resonance imaging (MRI) of the kidneys, usually every one to two years, to monitor for tumor development. Computed tomography (CT) scans of the chest are also performed to evaluate lung cysts and assess the risk of pneumothorax.
While there is no cure for BHD syndrome, proactive management aims to prevent severe outcomes. Treatment for skin lesions, such as fibrofolliculomas, may involve surgical removal or laser ablation. For kidney tumors, nephron-sparing surgery is the preferred approach for larger tumors, preserving as much healthy kidney tissue as possible. Individuals with BHD syndrome are advised to avoid activities that may increase the risk of pneumothorax, such as smoking and scuba diving. Genetic counseling is also recommended for affected individuals and their families.