Birt-Hogg-Dubé syndrome
Encyclopedia
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. 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.
and increases the risk of certain types of tumor
s. The condition is characterized by multiple noncancerous tumors of the hair follicle
s, 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 cancer
ous or noncancerous kidney
tumors (chromophobe renal cell carcinoma
and oncocytoma
, respectively) and possibly tumors in other organs and tissues. Additionally, affected individuals frequently develop cyst
s in the lung
s 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.
. 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 .
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 . 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
.
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.
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.
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.
The earliest case of possible BHD in the medical literature was published by Burnier and Rejesk in 1927.
The Myrovlytis Trust has recently started supporting 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 will take place in May 2011. More information about BHD syndrome is available at the world's first website dedicated to BHD syndrome - BHDSyndrome.org
Cancer.Net: Birt-Hogg-Dubé Syndrome
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
that involves susceptibility to renal cancer, renal and pulmonary cysts, and noncancerous tumors of the hair follicles. The disorder has been reported in more than 100 families worldwide, and it is inherited
Heredity
Heredity is the passing of traits to offspring . This is the process by which an offspring cell or organism acquires or becomes predisposed to the characteristics of its parent cell or organism. Through heredity, variations exhibited by individuals can accumulate and cause some species to evolve...
in an autosomal dominant pattern. The pattern of mutations and spectrum of symptoms are heterogeneous between individuals.
Signs and symptoms
Birt–Hogg–Dubé syndrome affects the skinSkin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
and increases the risk of certain types of tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s. The condition is characterized by multiple noncancerous tumors of the hair follicle
Hair follicle
A hair follicle is a skin organ that produces hair. Hair production occurs in phases, including a growth phase , and cessation phase , and a rest phase . Stem cells are principally responsible for the production of hair....
s, 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 cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
ous or noncancerous kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
tumors (chromophobe renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases...
and oncocytoma
Oncocytoma
An oncocytoma is a tumor made up of oncocytes, a special kind of cells. -Presentation:An oncocytoma is an epithelial tumor composed of oncocytes, large eosinophilic cells having small, round, benign-appearing nuclei with large nucleoli....
, respectively) and possibly tumors in other organs and tissues. Additionally, affected individuals frequently develop cyst
Cyst
A cyst is a closed sac, having a distinct membrane and division on the nearby tissue. It may contain air, fluids, or semi-solid material. A collection of pus is called an abscess, not a cyst. Once formed, a cyst could go away on its own or may have to be removed through surgery.- Locations :* Acne...
s in the lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s that are at risk to rupture and cause an abnormal collection of air in the chest cavity (pneumothorax
Pneumothorax
Pneumothorax is a collection of air or gas in the pleural cavity of the chest between the lung and the chest wall. It may occur spontaneously in people without chronic lung conditions as well as in those with lung disease , and many pneumothoraces occur after physical trauma to the chest, blast...
) that may result in the collapse of a lung.
Cause
Mutations in the FLCN gene, located on the short arm of chromosome 17 (17p11.2), cause Birt–Hogg–Dubé syndrome. 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.Pathophysiology
The FLCN gene makes a protein called folliculinFolliculin
Folliculin also known as FLCN, BHD, FLCL, FLCN_HUMAN, MGC17998, or MGC23445 is a tumor-suppressor protein associated with Birt-Hogg-Dubé syndrome...
. 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
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
in mitochondria .
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
Loss of heterozygosity
Loss of heterozygosity in a cell is the loss of normal function of one allele of a gene in which the other allele was already inactivated. This term is mostly used in the context of oncogenesis; after an inactivating mutation in one allele of a tumor suppressor gene occurs in the parent's germline...
is a common mechanism in cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, and it is frequently detected in the renal cancers associated with BHD . The molecular genetic defects in renal tumors of people with BHD are different from two other similar kidney tumors, chromophobe
Chromophobe
The term chromophobe refers to histological structures which do not stain readily, and thus appear more relatively pale under the microscope—hence their "fear" of "color" .-Cancer:...
renal cell carcinoma and renal oncocytoma
Oncocytoma
An oncocytoma is a tumor made up of oncocytes, a special kind of cells. -Presentation:An oncocytoma is an epithelial tumor composed of oncocytes, large eosinophilic cells having small, round, benign-appearing nuclei with large nucleoli....
.
Diagnosis
BHD can be diagnosed by clinical findings and/or molecular genetic testingGenetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
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.
Clinical triad
- 1. The cutaneous manifestations of BHD were originally described as fibrofolliculomaFibrofolliculomaFibrofolliculomas are 2 to 4mm in diameter, dome-shaped, yellowish or skin-colored papules usually located on the head, neck, and upper trunk. They are characteristically seen in Birt–Hogg–Dubé syndrome....
s (abnormal growths of a hair follicle), trichodiscomaTrichodiscomaA trichodiscoma is a cutaneous condition, a benign tumor usually skin colored, most often affecting the face and upper trunk....
s (hamartomatous lesions with a hair follicle at the periphery, often found on the face), and acrochordonAcrochordonAn acrochordon An acrochordon An acrochordon (plural acrochorda, and also known as a (cutaneous) skin tag, or fibroepithelial polyp, is a small benign tumour that forms primarily in areas where the skin forms creases, such as the neck, armpit, and groin. They may also occur on the face, usually on...
s (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 histologyHistologyHistology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
. - 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 scanComputed tomographyX-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
. - 3. Renal tumors can manifest as multiple types of renal cell carcinomaRenal cell carcinomaRenal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases...
, but certain pathological subtypes (including chromophobeChromophobeThe term chromophobe refers to histological structures which do not stain readily, and thus appear more relatively pale under the microscope—hence their "fear" of "color" .-Cancer:...
, oncocytomaOncocytomaAn oncocytoma is a tumor made up of oncocytes, a special kind of cells. -Presentation:An oncocytoma is an epithelial tumor composed of oncocytes, large eosinophilic cells having small, round, benign-appearing nuclei with large nucleoli....
, 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.
Genetic testing
FLCN mutations are detected by sequencingSequencing
In genetics and biochemistry, sequencing means to determine the primary structure of an unbranched biopolymer...
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.
Management
Menko et al, 2009: Birt-Hogg-Dubé syndrome: diagnosis and management. The Lancet Oncology, Volume 10, Issue 12, Pages 1199 - 1206, December.History
The syndrome was first well described in 1977.The earliest case of possible BHD in the medical literature was published by Burnier and Rejesk in 1927.
The Myrovlytis Trust has recently started supporting 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 will take place in May 2011. More information about BHD syndrome is available at the world's first website dedicated to BHD syndrome - BHDSyndrome.org
Useful Links
Several Information Pamphlets are available from BHDSyndrome.orgCancer.Net: Birt-Hogg-Dubé Syndrome