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.
The symptoms of Birt-Hogg-Dubé syndrome vary from case to case. 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 lesions 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 within affected members of a single BHD family who inherit the same FLCN mutation, with patients developing one, two or all three of the features.
The skin lesions associated with BHD syndrome are known as fibrofolliculomas and commonly occur on the scalp, face and neck, but can also be found on the ear lobes and in the oral mucosa. 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.
Fibrofolliculomas are small, firm, flesh-colored, dome-shaped growths or benign tumors. 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, which are common, soft small growths that hang off the skin. Some researchers believe that trichodiscomas and fibrofolliculomas despite different surface appearances are actually the same lesion.
Individuals with BHD syndrome may also have 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 and 16 years old. Individuals in a BHD family who inherit the FLCN mutation 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 renal neoplasms. These are usually slow growing and affect both kidneys (bilateral). The mean age of diagnosis for renal neoplasia is 48-50. 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 mutation.
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; additional family studies are needed to determine whether or not colon polyps are a manifestation of BHD.
Additional findings have been reported in a few cases of BHD syndrome including lesions in the mouth (oral papules), 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). Researches do not know whether these findings are incidental or part of BHD syndrome.
Birt-Hogg-Dubé syndrome is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Some cases of Birt-Hogg-Dubé syndrome occur as a result of a spontaneous genetic change (i.e., new mutation) in an individual with no family history of BHD symptoms.
Investigators have determined that BHD syndrome is caused by disruptions or changes (mutations) in the FLCN gene located on the short arm (p) of chromosome 17 (17p11.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 17p11.2” refers to band 11.2 on the short arm of chromosome 17. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The FLCN gene carries the instructions to produce (encode) folliculin, a protein whose precise function is not known, but which interacts in cellular pathways involved in cell growth, energy production, and metabolism. The FLCN gene is a tumor suppressor gene, a gene that slows down cell growth, repairs damage to the DNA of cells, and tells cells when to die, a normal process called apoptosis. Mutations in a tumor suppressor gene often predispose individuals to develop cancer.
Birt-Hogg-Dubé syndrome is a rare disorder that affects males and females in equal numbers. Less than 300 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.
BHD syndrome was first described in the medical literature in 1977 by three Canadian physicians (Drs. Birt, Hogg and Dubé).
A diagnosis of Birt-Hogg-Dubé syndrome is made based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic manifestations (symptoms) including 2 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 mutation in a DNA-based genetic test confirms the definitive diagnosis of BHD. Since renal neoplasia has been reported in BHD affected individuals as young as 24, genetic testing is recommended starting at age 21 in at-risk family members.
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 cases, 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 and may also remove part of or all of a kidney (nephrectomy). 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 BHD affected individuals 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 3cm in diameter by nephron-sparing surgery.
Individuals with BHD syndrome without renal neoplasia should be periodically imaged to monitor tumor development. Genetic counseling may be of benefit 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
Tel: (301) 402-4707
Fax: (301) 480-3195
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Stamatakis L, Metwalli AR, Middelton LA, Linehan WM. Diagnosis and management of BHD-associate kidney cancer. Fam Cancer. 2013; 12(3):397-402.
Schmidt LS. Birt-Hogg-Dubé syndrome: from gene discovery to molecularly targeted therapies. Fam Cancer. 2013;12(3):357-64.
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Adley BP, Smith ND, Nayar R, Yang XJ. Birt-Hogg-Dubé syndrome. Clinicopathologic findings and genetic alterations. Arch Pathol Lab Med. 2006;130(12):1865-70.
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Schaffer JV, Gohara MA, McNiff JM, et al. Multiple facial angiofibromas: a cutaneous manifestation of Birt-Hogg-Dubé syndrome. J Am Acad Dermatol. 2005; 53(2 Suppl 1):S108-11.
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Vincent A, Farley M, Chan, E, James WD. Birt-Hogg-Dubé syndrome: a review of the literature and the differential diagnoses of firm facial papules. J Am Acad Dermatol. 2003;49(4):698-705.
Zbar B, Alvord WG, Glenn G, Turner M, Pavlovich CP, Schmidt L, Walther M, Choyke P, Weirich G, Hewitt SM, Duray P, Gabril F, Greenberg C, Merino MJ, Toro J, Linehan WM. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer Epidemiol Biomarkers Prev. 2002;11(4):393-400.
Nickerson ML, Warren MB, Toro JR, et al.. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. Cancer Cell. 2002;2(2):157-64.
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