Birt–Hogg–Dubé syndrome
Classification and external resources
OMIM	135150
DiseasesDB	33274
eMedicine	derm/622

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]

Contents 1 Signs and symptoms 2 Cause 3 Pathophysiology 4 Diagnosis 4.1 Clinical triad 4.2 Genetic testing 5 Management 6 Epidemiology 7 History 8 Research directions 9 References

[edit] Signs and symptoms

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 makes 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 interaction with the mTOR pathway.

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 ^[4]

[edit] Diagnosis

BHD can be diagnosed by clinical findings and/or 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). The dermatologic diagnosis of BHD can be made in an individual five or more skin lesions, at least one of which must be confirmed as a fibrofolliculoma 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.^[5]

[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

[edit] Epidemiology

[edit] History

The syndrome was first described in 1977.^[6] The Myrovlytis Trust has recently started supporting research into BHD syndrome. The Inaugural BHD syndrome Symposium was held in Roskilde, Denmark, in September 2008: 47 of the worlds leading BHD researchers and clinicians, as well as family members affected by BHD, attended this scientific meeting. More information about BHD syndrome is available at the world's first website dedicated to BHD syndrome - BHDSyndrome.org

[edit] Research directions

[edit] References