Birt–Hogg–Dubé syndrome
| Birt–Hogg–Dubé syndrome | |
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| Classification and external resources | |
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| OMIM | 135150 |
| DiseasesDB | 33274 |
| eMedicine | derm/622 |
| GeneReviews | Birt-Hogg-Dubé Syndrome |
Birt–Hogg–Dubé syndrome (BHD) is a human genetic disorder that involves susceptibility to renal cancer, renal and pulmonary cysts, and noncancerous tumors of the hair follicles.[1]:674 The disorder has been reported in more than 100 families worldwide, and it is inherited in an autosomal dominant pattern. The pattern of mutations and spectrum of symptoms are heterogeneous between individuals.[2]
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[edit] Signs and symptoms
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Individual with Birt–Hogg–Dubé syndrome.
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Birt–Hogg–Dubé syndrome affects the skin and increases the risk of certain types of tumors. The condition is characterized by multiple noncancerous tumors of the hair follicles, particularly on the face, neck, and upper chest. These growths typically first appear in a person's twenties or thirties. People with Birt–Hogg–Dubé syndrome also have an increased risk of developing cancerous or noncancerous kidney tumors (chromophobe renal cell carcinoma and oncocytoma, respectively) and possibly tumors in other organs and tissues. Additionally, affected individuals frequently develop cysts in the lungs that are at risk to rupture and cause an abnormal collection of air in the chest cavity (pneumothorax) that may result in the collapse of a lung.
[edit] Cause
Mutations in the FLCN gene, located on the short arm of chromosome 17 (17p11.2), cause Birt–Hogg–Dubé syndrome.[3] These mutations are often passed from one generation to the next in an autosomal dominant fashion but can occur as a new mutation in an individual with no prior family history.
[edit] Pathophysiology
The FLCN gene eates a protein called folliculin. The normal function of this protein is still being investigated, but it appears to act as a tumor suppressor. Tumor suppressors normally prevent cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in the FLCN gene may interfere with the ability of folliculin to restrain cell growth and division, leading to the formation of noncancerous and cancerous tumors. Recent studies suggest that folliculin accomplishes this function through its involvement with cellular metabolism, possibly through modulation of the mTOR pathway and/or oxidative phosphorylation in mitochondria [4].
People with BHD are born with one mutated copy of the FLCN gene in each cell. During their lifetime, random mutations might inactivate the normal copy of the gene in a subset of cells. When this occurs, the result is that these cells have no functional copies of the FLCN gene, allowing the cells to divide uncontrollably and form tumors. This loss of heterozygosity is a common mechanism in cancer, and it is frequently detected in the renal cancers associated with BHD [5]. The molecular genetic defects in renal tumors of people with BHD are different from two other similar kidney tumors, chromophobe renal cell carcinoma and renal oncocytoma [4].
[edit] Diagnosis
BHD can be suggested by clinical findings but is definitively diagnosed by molecular genetic testing to detect mutations in the FLCN gene. The classical clinical triad includes: 1) benign growths of the hair follicles, 2) pulmonary cysts and spontaneous pneumothorax, and 3) bilateral, multifocal renal tumors.
[edit] Clinical triad
- 1. The cutaneous manifestations of BHD were originally described as fibrofolliculomas (abnormal growths of a hair follicle), trichodiscomas (hamartomatous lesions with a hair follicle at the periphery, often found on the face), and acrochordons (skin tags). Cutaneous manifestations are confirmed by histology.
- 2. Most individuals (89%) with BHD are found to have multiple cysts in both lungs, and 24% have had one or more episodes of pneumothorax. The cysts can be detected by chest CT scan.
- 3. Renal tumors can manifest as multiple types of renal cell carcinoma, but certain pathological subtypes (including chromophobe, oncocytoma, and oncocytic hybrid tumors) are more commonly seen in BHD.
Although the original syndrome was discovered on the basis of cutaneous findings, it is now recognized that individuals with BHD may only manifest the pulmonary and/or renal findings, without any skin lesions.[6]
[edit] Genetic testing
FLCN mutations are detected by sequencing in 88% of probands with BHD. This means that some people with the clinical diagnosis of BHD have mutations that are not detectable by current technology, or that mutations in another currently unknown gene could be responsible for a minority of BHD cases. Genetic testing can be useful to confirm the clinical diagnosis of BHD and to provide a means of determining other at-risk individuals in a family.
[edit] Management
Menko et al, 2009: Birt-Hogg-Dubé syndrome: diagnosis and management. The Lancet Oncology, Volume 10, Issue 12, Pages 1199 - 1206, December.
[edit] Epidemiology
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[edit] History
The syndrome was first well described in 1977.[7] The earliest case of possible BHD in the medical literature was published by Burnier and Rejesk in 1927.[8]
The BHD Foundation supports research into BHD syndrome and holds regular symposia in BHD and related disorders for researchers, clinicians, and family members. 47 researchers attended the Inaugural Symposium in 2008. The Second Symposium welcomed an increased number of delegates and was sponsored in part by the Office of Rare Disease Research at the NIH. The Third BHD Symposium took place in May 2011. The Fourth BHD Symposium will be on 28-30 March 2012. More information about BHD syndrome is available at the world's first website dedicated to BHD syndrome - BHDSyndrome.org
[edit] Research directions
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[edit] References
- ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: Clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0.
- ^ Toro, J.R.; Wei, MH; Glenn, GM; Weinreich, M; Toure, O; Vocke, C; Turner, M; Choyke, P et al (2008). "BHD mutations, clinical and molecular genetic investigations of Birt–Hogg–Dubé syndrome: a new series of 50 families and a review of published reports". J Med Genet 45 (6): 321–331. doi:10.1136/jmg.2007.054304. PMC 2564862. PMID 18234728. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2564862.
- ^ Nickerson, M. L.; Warren, MB; Toro, JR; Matrosova, V; Glenn, G; Turner, ML; Duray, P; Merino, M et al (2002). "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 2 (2): 157–164. doi:10.1016/S1535-6108(02)00104-6. PMID 12204536.
- ^ a b Klomp, JA; Petillo, D; Niemi, NM; Dykema, KJ; Chen, J; Yang, XJ; Saaf, A; Zickert, P et al (2010). "Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression". BMC Med Genomics: 3–59. doi:10.1186/1755-8794-3-59. PMID 21162720.
- ^ Linehan, WM; Pinto, PA; Srinivasan, R; Merino, M; Choyke, P; Choyke, L; Coleman, J; Toro, J et al (2007). "Identification of the genes for kidney cancer: opportunity for disease-specific targeted therapeutics". Clinical cancer research : an official journal of the American Association for Cancer Research 13 (2 Pt 2): 671s–679s. doi:10.1158/1078-0432.CCR-06-1870. PMID 17255292.
- ^ Toro, Jorge R. (2008). Birt-Hogg-Dubé Syndrome. NCBI. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=bhd.
- ^ Birt, A. R.; Hogg, G. R.; Dubé, W. J. (1977). "Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons". Arch. Derm. 113 (12): 1674–1677. doi:10.1001/archderm.113.12.1674. PMID 596896.
- ^ "Birt-Hogg-Dube : In Familial Cancer Syndromes. DL Riegert-Johnson and others. NCBI 2009". http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=famcan&part=bhd_appendix. Retrieved 2009-07-21.
[edit] Useful Links
Several Information Pamphlets are available from BHDSyndrome.org
Cancer.Net: Birt-Hogg-Dubé Syndrome
