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Birt-Hogg-Dubé Syndrome

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Copyright 2007, 2012

NORD is very grateful to Laura S. Schmidt, PhD, Principal Scientist, BRP, SAIC-Frederick, Inc., Urologic Oncology Branch, National Cancer Institute, for assistance in the preparation of this report.

Synonyms of Birt-Hogg-Dubé Syndrome

Disorder Subdivisions

General Discussion

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 tumors (hamartomas) 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 renal neoplasia. BHD syndrome is caused by mutations in the FLCN (alias BHD) gene and is inherited as an autosomal dominant trait.

Symptoms

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 occur most frequently, 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 BHD 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, forehead and neck. Onset is usually in the third or fourth decade. 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. These cysts usually do not cause symptoms (asymptomatic), but 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.

Approximately 15-25 percent of individuals with BHD syndrome may develop multiple renal neoplasia. These are usually slow glowing and affect both kidneys (bilateral). The mean age of diagnosis for renal neoplasia is 48. The most common tumor types are the so-called hybrid oncocytic tumor (a hybrid consisting of both oncocytoma and chromophobe histologic cell types), chromophobe renal cell carcinoma and renal oncocytoma. The first two tumors are malignant (cancerous), the third is considered benign.

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-Knickeberg 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 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) 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.

Causes

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) with no family history.

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 create (encode) folliculin, a protein whose precise function is not known. The FLCN gene is a tumor suppressor gene, a gene that slows down cell division, 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.

Affected Populations

Birt-Hogg-Dubé syndrome is a rare disorder that affects males and females in equal numbers. Approximately 250 BHD families (kindreds) 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).

Related Disorders

Symptoms of the following disorders can be similar to those of Birt-Hogg-Dubé syndrome. Comparisons may be useful for a differential diagnosis.

The PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders caused by mutations of the PTEN gene. These disorders are characterized by multiple hamartomas that can affect various areas of the body. Hamartoma is a general term for benign tumor-like malformations that can affect any area of the body. Hamartomas are composed of mature cells and tissue normally found in the affected area. PHTS includes virtually all cases of Cowden syndrome (also known as multiple hamartoma syndrome) and a percentage of cases of Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome and Proteus-like syndrome (i.e., those associated with mutations of the PTEN gene). Cowden syndrome is a difficult to recognize, under-diagnosed genetic disorder characterized by the development of multiple, benign tumor-like malformations (hamartomas) in various areas of the body. Affected individuals also have a predisposition to developing certain cancers, especially cancer of the breast, thyroid or mucous membrane lining the uterus (endometrium). The specific symptoms of Cowden syndrome vary from case to case. (For more information on this disorder, choose "PTEN hamartoma tumor syndrome" as your search term in the Rare Disease Database.)

Some researchers think symptoms of tuberous sclerosis including skin and lung hamartomas and angiolipomas of the kidney (and rare renal neoplasia) are similar to BHD.

Recently germline mutations in the FLCN gene have been identified in Familial Spontaneous Pneumothorax families, in which individuals develop frequent lung collapse without other typical BHD skin lesions or renal neoplasia.

Standard Therapies

Diagnosis
A diagnosis of Birt-Hogg-Dubé syndrome is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and several specialized tests. Surgical removal and microscopic evaluation (biopsy) of affected skin tissue is performed to determine the type of skin lesion present.

If a diagnosis of BHD syndrome is made, computed tomography (CT) scans of the lungs is recommended to detect pulmonary cysts. Additional tests should be performed to detect whether renal neoplasms are present.

Treatment
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.

Individuals with BHD syndrome without renal neoplasia should be periodically monitored for their possible development. Genetic counseling may be of benefit for affected individuals and their families.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Contact for additional information about Birt-Hogg-Dubé syndrome:

Laura S. Schmidt, PhD
Principal Scientist, BRP, SAIC-Frederick, Inc.
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
E-mail: schmidtl@mail.nih.gov

Organizations related to Birt-Hogg-Dubé Syndrome

References

JOURNAL ARTICLES
Menko FH, van Steensel MA, Giraud S, et al. Birt-Hogg-Dubé syndrome: diagnosis and management. Lancet Oncol. 2009;10(12):1199-206.

Gunji Y, Akiyoshi T, Sato T, et al. Mutations of the Birt-Hogg-Dubé gene in patients with multiple lung cysts and recurrent pneumothorax. J Med Genet. 2007;44(9):588-93.

Murakami T, Sano F, Huang Y, et al., Identification and characteristic of Birt-Hogg-Dubé associated with renal carcinoma. J Pathol. 2007;211(5):524-31.

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.

Schmidt LS, Nickerson ML, Warren MB, et al. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. Am J Hum Genet. 2005;76(6):1023-33.

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.

Schmidt LS. Birt-Hogg-Dubé syndrome, a genodermatosis that increases risk for renal carcinoma. Curr Mol Med. 2004;4(8):877-85.

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.

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.

Birt AR, Hogg GR, Dube WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol. 1977;113(12):1674-7.

INTERNET
Toro JR . (Updated September 9, 2008). Birt-Hogg-Dubé Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2012. Available at http://www.genetests.org. Accessed March 13, 2012.

Buckley KK, Meffert J. Birt-Hogg-Dubé Syndrome. Emedicine. http://emedicine.medscape.com/article/1060579-overview. Edited November 7, 2011. Accessed March 13, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Birt-Hogg-Dube Syndrome; BHD. Entry No: 135150. Last Edited May 31, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 13, 2012.

Report last updated: 2012/04/03 00:00:00 GMT+0