Years published: 2007, 2012, 2015, 2018, 2023
NORD gratefully acknowledges Laura S. Schmidt, PhD, Principal Scientist, Urologic Oncology Branch, National Cancer Institute, and BSP, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, for assistance in the preparation of this report.
Birt-Hogg-Dubé (BHD) syndrome is a rare complex genetic skin disorder (genodermatosis) characterized by the development of skin papules generally located on the head, face and upper torso. These benign (noncancerous) tumors of the hair follicle are called fibrofolliculomas. BHD syndrome also predisposes individuals to the development of benign cysts in the lungs, repeated episodes of a collapsed lung (pneumothorax) and increased risk for developing kidney neoplasia. BHD syndrome is caused by changes (pathogenic variants or mutations) in the FLCN gene and is inherited in an autosomal dominant pattern.
BHD syndrome was first described in the medical literature in 1977 by three Canadian physicians (Drs. Birt, Hogg and Dubé) for whom the disease was named.
The symptoms of Birt-Hogg-Dubé syndrome vary from person to person. The most common symptoms are multiple, benign skin lesions, lung (pulmonary) cysts, increased risk of repeated collapsed lungs (pneumothorax) and kidney (renal) neoplasia (malignant and benign tumors). Skin papules are the most frequent symptom occurring in up to 85% of individuals with BHD, but some affected individuals may develop lung cysts/pneumothorax and renal neoplasia without skin lesions. Symptoms of BHD may vary in affected members of a single BHD family who inherit the same FLCN gene variant, and patients may develop one, two or all three of the characteristic features in any combination.
The skin papules known as fibrofolliculomas that are associated with BHD syndrome commonly occur on the scalp, face and neck, but can also be found on the ear lobes and in the oral mucosa. They are generally 2-3mm in size, dome shaped, flesh-colored and are not associated with any pain or discomfort. The onset is usually after the age of 20. Skin lesions may increase in number as affected individuals age. The number of skin lesions can vary dramatically; some individuals may only have a few skin lesions, while others may have a hundred or more.
In the original description of BHD syndrome, two other skin lesions were noted: trichodiscomas, benign tumors of the hair disc, and acrochordons or skin tags that appear as soft small growths that hang off the skin and are common in the general population. Some researchers believe that trichodiscomas and fibrofolliculomas are the same lesion despite different surface appearances.
Individuals with BHD syndrome may also develop multiple lung (pulmonary) cysts in both lungs, which occur in greater than 80% of individuals affected with BHD. These cysts usually do not cause symptoms (asymptomatic) and lung function is generally normal, but up to one-third of affected individuals may experience repeated occurrences of a collapsed lung (spontaneous pneumothorax). A collapsed lung occurs when air or gas is trapped in the space surrounding the lungs. When the cause is not known (e.g., trauma, injury), it is referred to as spontaneous. Pneumothorax in BHD syndrome occurs more often in younger individuals and has been reported in children as young as 7 years old. Individuals in a BHD family who inherit the diseae-causing FLCN variant have a 50-fold greater risk of developing spontaneous pneumothorax than their unaffected siblings.
Approximately 15-30 % of individuals with BHD syndrome may develop multiple kidney (renal) neoplasms. These are usually slow growing and can affect both kidneys (bilateral). The mean age of diagnosis for renal neoplasia is 48-50 years old. The most common tumor types are the hybrid oncocytic tumor (a hybrid consisting of both oncocytoma and chromophobe histologic cell types), and chromophobe renal cell carcinoma, both of which are malignant (cancerous). Renal oncocytomas, which are benign tumors, can also develop but occur only rarely. Individuals affected with BHD have a 7-fold greater risk of developing renal neoplasia than siblings who do not inherit the FLCN variant.
In 1975, two researchers reported on a disorder that became known as Hornstein-Knickenberg syndrome. This disorder is now considered to be the same as BHD syndrome. Affected individuals with Hornstein-Knickenberg syndrome had polyps in the colon in addition to skin lesions. Some researchers believe that colonic polyps are a coincidental finding in individuals with BHD syndrome and not part of the disorder; more family studies are needed to determine whether colon polyps are an additional symptom of BHD.
Other findings have been reported in a few cases of BHD syndrome including oral papules in the mouth, benign tumors consisting of fatty tissue (lipomas), benign tumors consisting of fatty tissue and an abnormally large number of blood vessels (angiolipomas), a benign tumor of the parathyroid glands (parathyroid adenoma), a benign tumor of the salivary gland (parotid oncocytoma) and a lesion or birthmark consisting of thickened, abnormally firm connective tissue (connective tissue nevus). Researchers do not know whether these findings are incidental or true manifestations of BHD syndrome.
BHD syndrome is caused by changes (pathogenic variant or mutations) in the FLCN gene. The FLCN gene carries the instructions to produce (encode) folliculin, a protein whose precise function is not known, but which interacts with proteins that function in cellular pathways involved in cell growth, energy production and metabolism. The FLCN gene is a tumor suppressor gene, a gene that keeps cell growth in check or slows its growth, repairs damage to the DNA of cells and tells cells when to die, a normal process called apoptosis. Variants in a tumor suppressor gene often predispose individuals to develop cancer, but having a gene variant does not absolutely guarantee development of the disease.
The predisposition to develop Birt-Hogg-Dubé syndrome is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new gene change in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
In some individuals, the predisposition to the disorder is due to a spontaneous (de novo) gene change that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
Birt-Hogg-Dubé syndrome is a rare disorder that affects males and females in equal numbers. About 600 families (kindreds) affected with BHD have been described to date in the medical literature. Some researchers believe BHD syndrome is under-diagnosed, making it difficult to determine its true frequency in the general population.
A diagnosis of Birt-Hogg-Dubé syndrome is made based upon a thorough clinical evaluation, detailed patient history and identification of characteristic symptoms including two or more fibrofolliculomas, history of spontaneous pneumothorax or bilateral, multiple chromophobe or hybrid oncocytic renal tumors.
Surgical removal and microscopic evaluation (biopsy) of affected skin tissue is performed to determine the type of skin lesion present. Detection of a pathogenic (disease-causing) FLCN variant in a DNA-based genetic test confirms the diagnosis of BHD. Since renal neoplasia has been reported in individuals with BHD as young as 14, genetic testing is recommended starting at age 21 in at-risk family members.
Clinical Testing and Work-up
If a diagnosis of BHD syndrome is made, computed tomography (CT) scans of the lungs are recommended to detect pulmonary cysts/pneumothorax. Individuals with BHD have a lifelong risk for developing renal tumors and therefore, should undergo periodic surveillance by abdominal imaging (CT or magnetic resonance imaging to reduce radiation exposure is recommended) for early detection of renal tumors.
The treatment of BHD syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may include the use of a laser beam to destroy affected skin tissue (laser ablation). This treatment is highly successful in treating the skin lesions associated with BHD syndrome, but the lesions often return (relapse).
Some instances of a lung collapse do not require treatment and the air is absorbed over several days. In some patients, treatment is necessary. Treatment of a collapsed lung is intended to remove the air surrounding the lungs, allowing the lungs to re-inflate. A tube is inserted into the chest to allow the air or gas to escape (aspiration). In cases where repeated lung collapses occur, surgery may be necessary.
Surgery may also be necessary in individuals with renal neoplasia. Surgeons need to remove the kidney neoplasm, so it does not grow larger and spread (metastasis). They may also remove part or all of a kidney (nephrectomy) if the tumor burden is extensive. The main objective of surgery in individuals with renal neoplasia is to preserve as much kidney tissue as possible, thereby preserving as much of the kidney function as possible. Since individuals with BHD may have multiple surgeries for multiple tumors over their lifetime, one effective management practice has been to wait and remove the largest tumor when it reaches 3 cm in diameter by nephron-sparing surgery.
Individuals with BHD syndrome without renal neoplasia should be periodically imaged to monitor tumor development (recommended at 2-to-3-year intervals).
Genetic counseling is recommended for affected individuals and their families.
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Contact for additional information about Birt-Hogg-Dubé syndrome:
Laura S. Schmidt, PhD
Principal Scientist, BSP, Leidos Biomedical Research, Inc. and
Urologic Oncology Branch
National Cancer Institute
10 Center Drive MSC 1107
BLDG 10 CRC Room 1-3961
Bethesda, MD 20892
E-mail: [email protected]
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Schmidt LS, Linehan WM. FLCN: The causative gene for Birt-Hogg-Dubé syndrome.Gene. 2018;640:28-42.
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