NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Birt-Hogg-Dubé Syndrome

, MD
Genetic Epidemiology Branch
Division of Cancer Epidemiology and Genetics
National Cancer Institute
National Institutes of Health
Bethesda, Maryland

Initial Posting: ; Last Update: August 7, 2014.

Summary

Disease characteristics. The clinical characteristics of Birt-Hogg-Dubé syndrome (BHDS) include cutaneous manifestations (fibrofolliculomas, trichodiscomas/angiofibromas, perifollicular fibromas, and acrochordons), pulmonary cysts/history of pneumothorax, and various types of renal tumors. Disease severity can vary significantly even within the same family. Skin lesions typically appear during the third and fourth decades of life and typically increase in size and number with age. Lung cysts are mostly bilateral and multifocal; most individuals are asymptomatic but at high risk for spontaneous pneumothorax. Individuals with BHDS are at a sevenfold increased risk for renal tumors that are typically bilateral and multifocal and usually slow growing; median age of tumor diagnosis is 48 years. The most common renal tumors are a hybrid of oncocytoma and chromophobe histologic cell types (so-called oncocytic hybrid tumor) and chromophobe histologic cell types. Some families have renal tumor and/or autosomal dominant spontaneous pneumothorax without cutaneous manifestations.

Diagnosis/testing. BHDS is diagnosed by clinical findings and by molecular genetic testing. FLCN (also known as BHD) is the only gene known to be associated with BHDS. Sequence analysis detects pathogenic variants in FLCN in 88% of affected families, whereas 3%-5% have partial- or whole-gene deletions identified by other methods. Therefore, approximately 7%-9% of affected individuals who fulfill clinical diagnostic criteria do not have an identifiable FLCN pathogenic variant.

Management. Treatment of manifestations: Laser ablation of folliculoma/trichodiscoma results in substantial improvement for a period of time, but relapse usually occurs. Pneumothoraces are treated as in the general population. When possible, nephron-sparing surgery is the treatment of choice for renal tumors, depending on their size and location.

Surveillance: Periodic MRI of the kidneys is the optimal screening modality to assess for kidney lesions; abdominal/pelvic CT scan with contrast is an alternative when MRI is not an option, but the long term effects of cumulative radiation exposure is unknown; full body skin examination at routine intervals to evaluate for melanoma should be considered.

Agents/circumstances to avoid: Cigarette smoking, high ambient pressures, and radiation.

Evaluation of relatives at risk: Molecular genetic testing for the family-specific pathogenic variant for early identification of at-risk family members improves diagnostic certainty and reduces costly screening procedures in at-risk relatives who have not inherited the family-specific pathogenic variant.

Genetic counseling. BHDS is inherited in an autosomal dominant manner. The offspring of an individual with BHDS have a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the FLCN pathogenic variant of an affected family member has been identified.

Diagnosis

Clinical Diagnosis

Three major features characterize Birt-Hogg-Dubé syndrome (BHDS):

  • Cutaneous manifestations. Individuals with BHDS usually present with multiple, small, skin-colored, dome-shaped papules distributed over the face, neck, and upper trunk. The original characteristic dermatologic triad was fibrofolliculomas, trichodiscomas, and acrochordons [Toro et al 1999]; however, only fibrofolliculomas are specific for BHDS. Perifollicular fibromas and angiofibromas have also been associated with BHDS. Trichodiscomas are essentially histologically and clinically indistinguishable from angiofibromas; the term trichodiscoma has been used to describe angiofibromas when they occur in the setting of BHDS.

    The dermatologic diagnosis of BHDS is made in individuals who have five or more facial or truncal papules with at least one histologically confirmed fibrofolliculoma [Toro et al 1999]:
    • Fibrofolliculomas are defined as multiple anastomosing strands of two to four epithelial cells extending from a central follicle. Sometimes a well-demarcated, mucin-rich, or thick connective tissue stroma encapsulates the epithelial component. Biopsy is required to make the diagnosis.

      Note: Shave biopsy is usually not adequate. More than one skin-punch biopsy and sectioning of the paraffin-embeded block is sometimes needed to make the diagnosis of fibrofolliculoma.
    • Trichodiscomas are hamartomatous lesions comprising a round to elliptically shaped well-demarcated proliferation of thick fibrous and vascular stroma in the reticular dermis with a hair follicle at the periphery. Because of the high density of hair follicles in the face, hair follicles are commonly found at the periphery of these lesions. Angiofibromas are clinically and histologically essentially the same as trichodiscomas.

      Note: Trichodiscomas/angiofibromas are suggestive for the diagnosis of BHDS but not diagnostic. Angiofibromas are commonly also found in tuberous sclerosis complex (TSC) and multiple endocrine neoplasia type 1 (MEN1).
    • Acrochordons, or skin tags, are soft pedunculated papules that histologically are characterized by acanthotic and mild papillomatous epidermis with loose connective tissue stroma and blood vessels.
    • Perifollicular fibromas are well-demarcated proliferations of fibrous and vascular stroma in the reticular dermis surrounding a hair follicle.
  • Lung cysts and spontaneous pneumothorax. Most individuals (89%) with BHDS have multiple bilateral lung cysts, identified by high-resolution chest CT. The total number of lung cysts per individual ranges from 0 to 166 (mean 16). Forty-eight (24%) of 198 individuals with BHDS had a history of one or more pneumothoraces [Toro et al 2007].
    • All individuals with a history of pneumothorax had multiple lung cysts identified by high-resolution chest CT imaging. BHDS-related lung cysts abutted on interlobular septa (88.2%) and had intracystic septa (13.6%) or protruding venules (39.5%) without cell proliferation or inflammation. BHDS-related lung cysts are likely to develop in the periacina region where alveoli attach to connective tissue [Kumasaka et al 2014].
  • Renal tumors. The renal tumors are usually bilateral and multifocal. Histologic tumor types include: hybrid oncocytic renal cell carcinoma, oncocytoma, chromophobe renal cell carcinoma, and a minority of clear cell renal cell carcinoma. Note: FLCN nucleotide variants have been identified in certain tumors, see Molecular Genetics, Cancer and Benign Tumors.

Note: The original description and diagnosis of BHDS is based on skin pathology. However, recent investigations have shown that some individuals with BHDS could present with pulmonary involvement and/or renal tumors without skin lesions.

Molecular Genetic Testing

Gene. FLCN is the only gene in which pathogenic variants are known to cause BHDS.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Birt-Hogg-Dubé Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method 2
FLCNSequence analysis of exon 11 3, 4~53% 5
Sequence analysis of entire coding region 3~88%
Deletion/duplication analysis 6~3%-5%

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2. Schmidt et al [2005], Toro et al [2008]

3. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4. Pathogenic variants detected: Polycytosine tract deletion (c.1285delC) / duplication (c.1285dupC)

5. Twenty-seven (53%) of 51 families with BHDS were found to have deletion (c.1285delC) or duplication (c.1285dupC) of a C nucleotide in the polycytosine tract in exon 11, which is a mutational hot spot (see Table 2).

6. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To confirm/establish the diagnosis in a proband. Molecular genetic testing is indicated in all individuals known to have or suspected of having BHDS, including individuals with one of the following:

  • Five or more facial or truncal papules with at least one histologically confirmed fibrofolliculoma [Toro et al 1999], with or without a family history of BHDS
  • Facial papules histologically confirmed to be angiofibroma in an individual who does not fit the clinical criteria of tuberous sclerosis complex (TSC) or multiple endocrine neoplasia type 1 (MEN1)
  • Multiple and bilateral chromophobe, oncocytic, and/or hybrid renal tumors
  • A single oncocytic, chromophobe, or oncocytic hybrid renal tumor and a family history of renal cancer with any of the above renal cell tumor types
  • A family history of autosomal dominant primary spontaneous pneumothorax without a history of smoking or COPD

Single gene testing. One strategy for molecular diagnosis of a proband suspected of having BHDS is cascade testing of FLCN:

1.

Molecular genetic testing may start with sequence analysis of exon 11, as a majority of affected individuals have one of two pathogenic variants found in exon 11 (see Table 1).

2.

If targeted sequence analysis of exon 11 does not identify a pathogenic variant, sequencing of the entire coding region of FLCN should be considered.

3.

If full-gene sequence analysis does not identify a pathogenic variant, deletion/duplication analysis of FLCN may be considered.

Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having BHDS is a multi-gene panel that includes genes known to cause various features of the condition (see Differential Diagnosis). These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation in any given individual with features of BHDS also varies.

One type of multigene panel is whole-exome sequencing; in individuals with a clinical diagnosis of BHDS but in whom no pathogenic variant in FLCN is identified, whole-exome sequencing may be considered.

Clinical Description

Natural History

The clinical characteristics of Birt-Hogg-Dubé syndrome (BHDS) include fibrofolliculomas (specific cutaneous lesions), pulmonary cysts/history of pneumothorax, and various types of renal tumors. Disease severity can vary significantly among family members and between families.

Cutaneous lesions. BHDS is associated with a spectrum of cutaneous hamartomas ranging from angiofibroma to perifollicular fibromas to fibrofolliculomas [Toro et al 2008]. Families with germline mutations in FLCN can have angiofibromas (i.e., trichodiscomas), perifollicular fibroma, or both angiofibroma and perifollicular fibromas as their only cutaneous manifestations of BHDS [Toro et al 2008]. Other individuals with BHDS develop oral papules and cutaneous collagenomas [Nadershahi et al 1997, Toro et al 1999]. Multiple epidermal cysts have been found in approximately 14% of individuals with BHDS [Kluger et al 2010].

The onset of skin lesions is typically during the third or fourth decade of life. Skin lesions tend to increase in size and number with age. Later onset of cutaneous lesions tends to correlate with a milder skin phenotype. Women tend to have smaller and fewer lesions than men.

BHDS has been reported to be associated with cutaneous melanoma, including multiple desmoplastic melanomas [Lindor et al 2001, Khoo et al 2002, Welsch et al 2005, Toro et al 2008, Sempau et al 2010, Cocciolone et al 2010, Mota-Burgos et al 2013] and choroidal melanoma [Fontcuberta et al 2011]. Whether individuals with BHDS are at increased risk of developing melanoma compared to the general population requires further investigation.

A family with BHDS in which one sib developed a dermatofibrosarcoma protuberans (DFSP) and another sib had a cutaneous leiomyosarcoma has also been described [Toro et al 2008].

Pulmonary cysts and spontaneous pneumothorax. Lung cysts are mostly bilateral and multifocal. Most individuals with BHDS and lung cysts are asymptomatic, but they have a high risk of developing spontaneous, often recurrent, pneumothorax. Clinical presentation of pneumothorax ranges from asymptomatic to dyspnea and chest pain. Clinical findings include tachypnea or decreased or absent breath sounds. Radiographic investigation may require a high-resolution CT of the chest to confirm the diagnosis of pneumothorax as chest x-ray may not be sensitive enough to detect a loculated pneumothorax.

In the recent study of Toro et al [2008], 89% of individuals with a FLCN germline mutation were found to have pulmonary cysts on chest CT, a rate that is higher than the 77% observed in all earlier reports combined.

In the same study of Toro et al [2008], 38% of individuals with a FLCN germline mutation were found to have a history of spontaneous pneumothorax, a rate similar to the 33% in all earlier reports combined.

Individuals with BHDS and a family history of pneumothorax have a statistically significant increased risk of pneumothorax compared to individuals with BHDS without a family history of spontaneous pneumothorax.

Individuals with BHDS have a 50-fold increased risk for spontaneous pneumothorax compared to family members who do not have BHDS [Zbar et al 2002].

Renal cysts and tumors. In a French case series, renal ultrasound, CT scan and/or MRI revealed renal cysts in ten (45%) of 22 individuals with BHDS who did not have renal carcinoma diagnosed at the time of screening [Kluger et al 2010].

Approximately 70 individuals with FLCN germline mutation and kidney tumors have been reported [Toro et al 2008]. The most common tumors are a hybrid of oncocytoma and chromophobe histologic cell types, so-called oncocytic hybrid tumor (67%), chromophobe renal cell carcinoma (23%), and renal oncocytoma (3%). Only renal oncocytoma is considered a benign tumor [Pavlovich et al 2005]. Other types of renal tumors reported in lower frequency include clear cell renal cell carcinoma and papillary renal carcinoma.

Most renal tumors associated with BHDS are bilateral, multifocal, and slow growing. Median age of diagnosis is 48 years, with a range from 31 to 71 years [Schmidt et al 2005].

Individuals with BHDS were at a sevenfold increased risk for renal tumors compared with their unaffected sibs [Zbar et al 2002]. Using combined ascertainment in dermatologic and urologic oncology clinics at the National Cancer Institute (NCI) at the National Institutes of Health (NIH), the overall prevalence of kidney tumors among individuals with germline FLCN mutations was 29%-34% [Toro et al 2008]. This high frequency – compared to the 6.5% frequency of kidney tumors in BHDS cases determined from a combination of other investigators – may reflect ascertainment bias.

The renal tumors associated with BHDS may affect morbidity more than mortality in persons with BHDS. Nephron-sparing surgery may decrease the morbidity associated with renal tumors by preserving functioning renal tissue because affected individuals usually develop multifocal and bilateral kidney tumors.

Renal oncocytosis observed at surgery or at postmortem examination is evidence of the potential of persons with BHDS to develop kidney tumors [Toro et al 2008].

Parotid oncocytoma. The first case of an individual with BHDS who developed a parotid oncocytoma was reported in 2000 [Liu et al 2000]. Subsequently multiple cases have been reported [Schmidt et al 2005, Toro et al 2008]. Additionally, one person with BHDS has been reported with a pleomorphic adenoma [Palmirotta et al 2008] and another individual with BHDS has been reported with a Warthin parotid tumor [Maffe et al 2011]. Two cases of bilateral parotid tumors have also been reported [Maffe et al 2011, Lindor et al 2012]. The frequency and the bilateral, multifocal nature of these tumors in individuals with BHDS who have not undergone specific screening for parotid tumors suggest that parotid tumors are a manifestation of BHDS.

Oral papules have been reported in nine (43%) of 21 individuals with BHDS in a large French case series [Kluger et al 2010] and in several other reports [Nadershahi et al 1997, Toro et al 1999].

Other findings

Genotype-Phenotype Correlations

Genotype-phenotype correlations have been reported; whether these manifestations are truly associated with BHDS remains to be determined through larger studies.

No correlation is observed between the type of FLCN mutation and pulmonary and cutaneous manifestations.

A previous study suggested that individuals with the c.1285delC pathogenic variant may be at lower risk of developing renal cancers than individuals with other FLCN pathogenic variants; this needs to be evaluated in large studies.

Analysis of genotype-phenotype correlations for two recurrent FLCN pathogenic variants identified in a subset of 51 families with BHDS demonstrated a significantly higher risk of colorectal neoplasia in those with the c.1285dupC pathogenic variant (within the exon 11 C(8) mononucleotide tract) than in those with the c.610delGCinsTA pathogenic variant (chi(2)=5.78, p=0.016) [Nahorski et al 2010].

Penetrance

Based on the three major clinical manifestations, penetrance of BHDS is considered to be very high.

Anticipation

Anticipation is not known to occur in BHDS.

Nomenclature

Hornstein-Knickenberg syndrome (HK), which describes familial multiple perifollicular fibromas, is considered to fall within the spectrum of BHDS [Schulz & Hartschuh 1999].

Prevalence

More than 100 affected families from various populations have been described.

Differential Diagnosis

Cutaneous lesions. Fibrofolliculomas are rare and specific for Birt-Hogg-Dubé syndrome (BHDS). Because fibrofolliculomas are clinically similar to various cutaneous lesions, histologic diagnosis is required.

Acrochordons, or skin tags, are nonspecific and are found in the general population.

BHDS-associated hamartomas should be distinguished from other genodermatoses with an increased risk for internal malignancy, including tuberous sclerosis complex (TSC), familial trichoepitheliomas, MEN1, and Cowden syndrome (see PTEN hamartoma tumor syndrome).

Pulmonary manifestation. Several inherited and noninherited conditions can present with lung cysts and/or pneumothorax. A thorough history and physical examination help to differentiate these conditions from BHDS. These conditions include the following:

Renal tumor. Unlike BHDS, most familial renal cancer syndromes are associated with different types of renal pathology [Linehan et al 2005]. Familial renal cancer syndromes and their renal pathology include the following:

  • von Hippel-Lindau syndrome (VHL syndrome). Bilateral and multifocal clear cell renal cell carcinomas. Individuals with VHL syndrome are also at risk for central nervous system hemangioblastoma, retinal angioma, pheochromocytoma, and endolymphatic sac tumors.
  • Hereditary papillary renal cancer (HPRC). Bilateral and multifocal type 1 papillary renal cell carcinomas
  • Hereditary leiomyomatosis and renal cell cancer (HLRCC). Usually solitary renal tumors with a histologic spectrum ranging from tubo-papillary renal cell cancer to type 2 papillary renal cancer to collecting duct renal cell cancer. Individuals with HLRCC can present with cutaneous leiomyoma and/or with early-onset and aggressive uterine fibroids.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Birt-Hogg-Dubé syndrome (BHDS), the following evaluations are recommended:

  • Detailed dermatologic examination and punch biopsy of suspected cutaneous lesion
  • High-resolution computed tomography (HRCT) or CT of the chest highly recommended for visualization of pulmonary cysts. Individuals who have symptoms/signs of pneumothorax should immediately undergo chest x-ray and CT of the chest and appropriate treatment.
  • Baseline abdominal/pelvic CT scan with contrast or MRI to screen for renal tumor. Renal ultrasound examination may distinguish cystic from solid renal lesions.
  • Medical genetics consultation

Treatment of Manifestations

In general, fibrofolliculomas and trichodiscomas are benign lesions for which no treatment is required; however, affected individuals may seek treatment for such lesions for cosmetic purposes, particularly when multiple cutaneous lesions are located on the face. Treatment of fibrofolliculomas and trichodiscomas is difficult, as they tend to be numerous and recurring. Erbium-YAG or fractional CO2 laser ablation may result in substantial improvement, but relapse can occur [Gambichler et al 2000, Jacob & Dover 2001, Kahle et al 2001]. Shaving or other ablative methods have been used with variable results.

Treatment of pneumothorax is the same as in the general population.

Nephron-sparing surgery is the treatment of choice for renal tumors whenever possible, depending on the size and location of the tumors [Pavlovich et al 2005]. Because of the bilateral, multifocal nature of BHDS-associated kidney cancer, a management approach involving observation of small tumors until they reach 3 cm in size is often recommended [Pavlovich et al 2005]. Therefore, renal tumors greater than 3.0 cm and/or rapidly growing tumors usually require partial nephrectomy. When surgical intervention is recommended, an attempt is made to remove all or most of the visible tumors. Although surgical management is not considered “curative” for BHDS-associated renal cell carcinoma (RCC), BHDS-associated renal tumors often are slow growing, and only infrequently are multiple surgical procedures required during a an affected individual’s lifetime to control the tumor burden and prevent the development of metastasis.

Prevention of Primary Manifestations

No preventive or curative treatment is available for BHDS. However, development of renal cell carcinoma has the strongest positive association with cigarette smoking [Moore et al 2005].

Surveillance

There is no consensus on clinical surveillance; the recommendations given are provisional until a consensus conference is conducted.

Individuals with known BHDS, individuals known to have a pathogenic variant in FLCN without clinical manifestations, and at-risk family members who have not undergone genetic testing should have regular monitoring by physicians familiar with the spectrum of BHDS.

Renal tumor screening

  • Renal imaging is appropriate for individuals age 18 years or older when the clinical diagnosis of BHDS is established or if a pathogenic variant in FLCN is confirmed. However, earlier testing and surveillance for renal tumors should be personalized based on family history of renal tumor development, when available.
  • Yearly MRI of the kidneys is the optimal screening modality to assess for kidney lesions.
    • Abdominal/pelvic CT scan with contrast is an alternative when MRI is not an option. However, the long-term effects of cumulative radiation exposure in individuals with BHDS is unknown and has not been studied.
  • As a result of the low aggressiveness of kidney tumors and the 3.0-cm rule used by surgeons in treating renal tumors [Pavlovich et al 2005], affected individuals without a family history of kidney tumors who have had two to three consecutive annual MRI examinations without the detection of kidney lesions may be screened every two years until a suspicious lesion is identified.
    Note: The use of renal ultrasound examination is helpful in further characterization of kidney lesions but should not be used as a primary screening modality.
  • If any suspicious lesion (<1.0 cm in diameter, indeterminate lesion, or complex cysts) is noted on screening examination, annual MRI should be instituted. Abdominal/pelvic CT scan with contrast may be used as an alternative in those for whom MRI is not an option.
  • Renal tumors less than 3.0 cm in diameter are monitor by periodic imaging. When the largest renal tumor reaches 3 cm in maximal diameter evaluation by a urologic surgeon is appropriate with consideration of nephron-sparing surgery [Stamatakis et al 2013].
  • Rapidly growing lesions and/or symptoms including pain, blood in the urine, or atypical presentations require a more individualized approach. PET-CT scan is an option for evaluation of these lesions.

Melanoma. Because of a concern for a possible increased risk of melanoma in those with BHDS, full body skin examination at routine intervals to evaluate for suspicious pigmented lesions should be considered.

Agents/Circumstances to Avoid

The following should be avoided:

  • Cigarette smoking
  • High ambient pressures, which may precipitate spontaneous pneumothorax
  • Radiation exposure

Evaluation of Relatives at Risk

When the family-specific pathogenic variant is known, use of molecular genetic testing for early identification of at-risk family members improves diagnostic certainty and reduces costly screening procedures in at-risk members who have not inherited the pathogenic variant.

Early recognition of clinical manifestations may allow timely intervention and improve outcome. Therefore, clinical surveillance of asymptomatic at-risk relatives for early detection is appropriate.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Birt-Hogg-Dubé syndrome (BHDS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Some individuals with BHDS have an affected parent, and some have BHDS as a result of de novo mutation of FLCN.
  • The proportion of cases caused by de novo mutation is unknown because a sufficient number of parents have not been evaluated for subtle manifestation, nor are there sufficient data on clinically unaffected parents who have been evaluated by molecular genetic testing.
  • Recommendations for the evaluation of parents of a proband with suspected de novo mutation include molecular genetic testing if the pathogenic variant in FLCN in the proband is identified.

Note: Although some individuals diagnosed with BHDS have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of a proband is clinically affected or has an FLCN pathogenic variant, the sibs of the proband are at a 50% risk of inheriting the pathogenic variant.
  • If neither parent has the FLCN pathogenic variant identified in the proband, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with BHDS is at a 50% risk of inheriting the FLCN pathogenic variant. The degree of clinical severity is not predictable.

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with BHDS has the FLCN pathogenic variant or clinical evidence of the disorder, it is likely that mutation of FLCN occurred de novo in the proband. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Testing at-risk asymptomatic family members. Molecular genetic testing of at-risk family members is appropriate in order to identify the need for continued lifelong clinical surveillance. Interpretation of the result is most accurate when an FLCN pathogenic variant has been identified in an affected family member. Those who have the pathogenic variant require lifelong, regular surveillance. Family members who have not inherited the pathogenic variant and their offspring have risks similar to the general population.

Early detection of at-risk individuals affects medical management. However, in the absence of an increased risk of developing childhood malignancy, the American Society of Clinical Oncology (ASCO) recommends delaying genetic testing in at-risk individuals until they reach age 18 years and are able to make informed decisions regarding genetic testing [American Society of Clinical Oncology 2003 (full text)].

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the FLCN pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the FLCN pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Kidney Cancer Association
    PO Box 96503
    Washington DC 20090
    Phone: 800-850-9132 (toll-free); 312-436-1455
    Fax: 847-332-2978
    Email: kidney.cancer@hotmail.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Birt-Hogg-Dube Syndrome: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
FLCN17p11​.2FolliculinThe Folliculin Mutation Database
Folliculin (FLCN) @ LOVD
FLCN

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Birt-Hogg-Dube Syndrome (View All in OMIM)

135150BIRT-HOGG-DUBE SYNDROME; BHD
607273FOLLICULIN; FLCN

Gene structure. FLCN (BHD) was identified by positional cloning by Nickerson et al [2002]. The gene is highly conserved across species. Human FLCN consists of 14 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table 2. Various pathogenic variants have been identified in families with Birt-Hogg-Dubé syndrome (BHDS). All pathogenic variants predict protein truncation. The most common pathogenic variants are c.1285dupC and c.1285delC, which duplicate or delete a single C nucleotide in a polycytosine tract in exon 11, suggesting the presence of a hypermutable site [Schmidt et al 2005].

Table 2. FLCN Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.610_611delGCinsTAp.Ala204TerNM_144997​.4
NP_659434​.2
c.1285dupC
(1733insC)
p.His429ProfsTer26
c.1285delC
(1733delC)
p.His429ThrfsTer38

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

For more information, see Table A.

Normal gene product. Folliculin (FLCN) has 579 amino acid residues. A role for folliculin is suggested in regulation of 5' AMP-activated protein kinase (AMPK) and activation of the mTOR signalling pathway. Specifically, folliculin forms a complex with folliculin interacting protein 1 or 2 (encoded by FNIP1 or FNIP2) and the FLCN-FNIP complex binds to AMPK [Baba et al 2006, Hasumi et al 2008, Takagi et al 2008]. Recent studies suggest that loss of FLCN expression leads to activation of the AMPK/PGC-1α/OXPHOS/HIF signaling axis [Klomp et al 2010]. Loss of FLCN constitutively activates AMPK, resulting in PGC-1α-mediated mitochondrial biogenesis and increased ROS production [Yan et al 2014]. It is hypothesized that FLCN inhibits tumorigenesis by preventing AMPK-dependent HIF activation and the subsequent Warburg metabolic transformation [Yan et al 2014]. Loss of FLCN induces an AMPK-HIF-dependent metabolic reprogramming favoring tumor progression.

FLCN is highly expressed in a variety of tissues including skin and skin appendages, type 1 pneumocytes, and distal nephrons of the kidney [Warren et al 2004].

Abnormal gene product. Germline mutations in FLCN – as well as somatic mutations and loss of heterozygosity in tumor tissue – suggest that loss of function of the folliculin protein is the basis of tumor formation in BHDS [Vocke et al 2005]. Reduced expression of folliculin in renal tumors from individuals with BHDS supports its role in tumor suppression [Warren et al 2004].

Cancer and Benign Tumors

Acquired nucleotide variants in FLCN have been identified in sporadic clear cell renal cell carcinoma [da Silva et al 2003, Khoo et al 2003] and colon cancer [Kahnoski et al 2003, Shin et al 2003], without other associated tumors characteristic of the heritable disease.

  • FLCN pathogenic variants have been identified in two cell lines with MSI [Shin et al 2003].
  • In one study, 16% of MSI sporadic colorectal carcinoma harbored pathogenic variants in the poly C8 track of FLCN [Shin et al 2003].
  • An independent English study found that somatic frameshifting variants in the exon 11 C(8) mononucleotide tract of FLCN were detected in 23% of sporadic colorectal cancers with microsatellite instability [Nahorski et al 2010].
  • Two heterozygous FLCN missense variants have been reported in colorectal cancer cell lines.

Further studies are needed to investigate the role of folliculin in colorectal carcinogenesis.

Molecular Pathogenesis

BHDS-associated renal tumors have distinct gene expression and cytogenetic characteristics as compared to sporadic renal oncocytoma and chromophobe RCC [Klomp et al 2010]. BHDS-derived kidney tumors have high expression of mitochondria- and oxidative phosphorylation-associated genes and deregulation of the PGC-1α-TFAM signaling axis. In addition, loss of FLCN expression is also associated with increased nuclear mitochondrial gene expression [Klomp et al 2010].

References

Published Guidelines/Consensus Statements

  1. American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2003. Accessed 10-17-12.

Literature Cited

  1. American Society of Clinical Oncology; American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. 2003;21:2397–406. [PubMed: 12692171]
  2. Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins RF, Hartley JL, Furihata M, Oishi S, Zhen W, Burke TR, Linehan WM, Schmidt LS, Zbar B. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci USA. 2006;103:15552–7. [PMC free article: PMC1592464] [PubMed: 17028174]
  3. Chung JY, Ramos-Caro FA, Beers B, Ford MJ, Flowers F. Multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with Birt-Hogg-Dube syndrome. Int J Dermatol. 1996;35:365–7. [PubMed: 8734663]
  4. Claessens T, Weppler SA, van Geel M, Creytens D, Vreeburg M, Wouters B, van Steensel MA. Neuroendocrine carcinoma in a patient with Birt-Hogg-Dubé syndrome. Nat Rev Urol. 2010;7:583–7. [PubMed: 20842188]
  5. Cocciolone RA, Crotty KA, Andrews L, Haass NK, Moloney FJ. Multiple desmoplastic melanomas in Birt-Hogg-Dubé syndrome and a proposed signaling link between folliculin, the mTOR pathway, and melanoma susceptibility. Arch Dermatol. 2010;146:1316–8. [PubMed: 21079084]
  6. da Silva NF, Gentle D, Hesson LB, Morton DG, Latif F, Maher ER. Analysis of the Birt-Hogg-Dubé (BHD) tumour suppressor gene in sporadic renal cell carcinoma and colorectal cancer. J Med Genet. 2003;40:820–4. [PMC free article: PMC1735328] [PubMed: 14627671]
  7. Daniel R, Teba L. Spontaneous pneumothorax and alpha 1-antitrypsin deficiency. Respir Care. 2000;45:327–9. [PubMed: 10771802]
  8. Drummond C, Grigoris I, Dutta B. Birt-Hogg-Dubé syndrome and multinodular goitre. Australas J Dermatol. 2002;43:301–4. [PubMed: 12423440]
  9. Flume PA, Strange C, Ye X, Ebeling M, Hulsey T, Clark LL. Pneumothorax in cystic fibrosis. Chest. 2005;128:720–8. [PubMed: 16100160]
  10. Fontcuberta IC, Salomão DR, Quiram PA, Pulido JS. Choroidal melanoma and lid fibrofoliculomas in Birt-Hogg-Dubé syndrome. Ophthalmic Genet. 2011;32:143–6. [PubMed: 21401403]
  11. Gambichler T, Wolter M, Altmeyer P, Hoffman K. Treatment of Birt-Hogg-Dubé syndrome with erbium:YAG laser. J Am Acad Dermatol. 2000;43:856–8. [PubMed: 11050594]
  12. Godbolt AM, Robertson IM, Weedon D. Birt-Hogg-Dubé syndrome. Australas J Dermatol. 2003;44:52–6. [PubMed: 12581083]
  13. Graham RB, Nolasco M, Peterlin B, Garcia CK. Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults. Am J Respir Crit Care Med. 2005;172:39–44. [PubMed: 15805188]
  14. Hasumi H, Baba M, Hong SB, Hasumi Y, Huang Y, Yao M, Valera VA, Linehan WM, Schmidt LS. Identification and characterization of a novel folliculin-interacting protein FNIP2. Gene. 2008;415:60–7. [PMC free article: PMC2727720] [PubMed: 18403135]
  15. Jacob CI, Dover JS. Birt-Hogg-Dube syndrome: treatment of cutaneous manifestations with laser skin resurfacing. Arch Dermatol. 2001;137:98–99. [PubMed: 11176677]
  16. Kahle B, Hellwig S, Schulz T. Multiple mantleomas in Birt-Hogg-Dubé syndrome: successful therapy with CO2 laser. Hautarzt. 2001;52:43–6. [PubMed: 11220238]
  17. Kahnoski K, Khoo SK, Nassif NT, Chen J, Lobo GP, Segelov E, Teh BT. Alterations of the Birt-Hogg-Dubé gene (BHD) in sporadic colorectal tumours. J Med Genet. 2003;40:511–5. [PMC free article: PMC1735520] [PubMed: 12843323]
  18. Khoo SK, Giraud S, Kahnoski K, Chen J, Motorna O, Nickolov R, Binet O, Lambert D, Friedel J, Levy R, Ferlicot S, Wolkenstein P, Hammel P, Bergerheim U, Hedblad MA, Bradley M, Teh BT, Nordenskjold M, Richard S. Clinical and genetic studies of Birt-Hogg-Dubé syndrome. J Med Genet. 2002;39:906–12. [PMC free article: PMC1757219] [PubMed: 12471204]
  19. Khoo SK, Kahnoski K, Sugimura J, Petillo D, Chen J, Shockley K, Ludlow J, Knapp R, Giraud S, Richard S, Nordenskjold M, Teh BT. Inactivation of BHD in sporadic renal tumors. Cancer Res. 2003;63:4583–7. [PubMed: 12907635]
  20. Klomp JA, Petillo D, Niemi NM, Dykema KJ, Chen J, Yang XJ, Sääf A, Zickert P, Aly M, Bergerheim U, Nordenskjöld M, Gad S, Giraud S, Denoux Y, Yonneau L, Méjean A, Vasiliu V, Richard S, MacKeigan JP, Teh BT, Furge KA. 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. 2010;3:59. [PMC free article: PMC3012009] [PubMed: 21162720]
  21. Kluger N, Giraud S, Coupier I, Avril MF, Dereure O, Guillot B, Richard S, Bessis D. Birt-Hogg-Dubé syndrome: clinical and genetic studies of 10 French families. Br J Dermatol. 2010;162:527–37. [PubMed: 19785621]
  22. Kumasaka T, Hayashi T, Mitani K, Kataoka H, Kikkawa M, Tobino K, Kobayashi E, Gunji Y, Kunogi M, Kurihara M, Seyama K. Characterization of pulmonary cysts in Birt-Hogg-Dubé syndrome: histopathological and morphometric analysis of 229 pulmonary cysts from 50 unrelated patients. Histopathology. 2014;65:100–10. [PubMed: 24393238]
  23. Kunogi M, Kurihara M, Ikegami TS, Kobayashi T, Shindo N, Kumasaka T, Gunji Y, Kikkawa M, Iwakami S, Hino O, Takahashi K, Seyama K. Clinical and genetic spectrum of Birt–Hogg–Dubé syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature. J Med Genet. 2010;47:281–7. [PMC free article: PMC2981024] [PubMed: 20413710]
  24. Lindor NM, Hand J, Burch PA, Gibson LE. Birt-Hogg-Dube syndrome: an autosomal dominant disorder with predisposition to cancers of the kidney, fibrofolliculomas, and focal cutaneous mucinosis. Int J Dermatol. 2001;40:653–6. [PubMed: 11737429]
  25. Lindor NM, Kasperbauer J, Lewis JE, Pittelkow M. Birt-Hogg-Dube syndrome presenting as multiple oncocytic parotid tumors. Hered Cancer Clin Pract. 2012;10:13. [PMC free article: PMC3492097] [PubMed: 23050938]
  26. Linehan WM, Grubb RL, Coleman JA, Zbar B, Walther MM. The genetic basis of cancer of kidney cancer: implications for gene-specific clinical management. BJU Int. 2005;95 Suppl 2:2–7. [PubMed: 15720328]
  27. Liu V, Kwan T, Page EH. Parotid oncocytoma in the Birt-Hogg-Dubé syndrome. J Am Acad Dermatol. 2000;43:1120–2. [PubMed: 11100034]
  28. Maffé A, Toschi B, Circo G, Giachino D, Giglio S, Rizzo A, Carloni A, Poletti V, Tomassetti S, Ginardi C, Ungari S, Genuardi M. Constitutional FLCN mutations in patients with suspected Birt-Hogg-Dubé syndrome ascertained for non-cutaneous manifestations. Clin Genet. 2011;79:345–54. [PubMed: 20618353]
  29. Mendez JL, Nadrous HF, Vassallo R, Decker PA, Ryu JH. Pneumothorax in pulmonary Langerhans cell histiocytosis. Chest. 2004;125:1028–32. [PubMed: 15006964]
  30. Moore LE, Wilson RT, Campleman SL. Lifestyle factors, exposures, genetic susceptibility, and renal cell cancer risk: a review. Cancer Invest. 2005;23:240–55. [PubMed: 15945510]
  31. Mota-Burgos A, Acosta EH, Márquez FV, Mendiola M, Herrera-Ceballos E. Birt-Hogg-Dubé syndrome in a patient with melanoma and a novel mutation in the FCLN gene. Int J Dermatol. 2013;52:323–6. [PubMed: 23414156]
  32. Nadershahi NA, Wescott WB, Egbert B. Birt-Hogg-Dubé syndrome: a review and presentation of the first case with oral lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;83:496–500. [PubMed: 9127384]
  33. Nahorski MS, Lim DH, Martin L, Gille JJ, McKay K, Rehal PK, Ploeger HM, van Steensel M, Tomlinson IP, Latif F, Menko FH, Maher ER. Investigation of the Birt-Hogg-Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer. J Med Genet. 2010;47:385–90. [PubMed: 20522427]
  34. Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, Duray P, Merino M, Choyke P, Pavlovich CP, Sharma N, Walther M, Munroe D, Hill R, Maher E, Greenberg C, Lerman MI, Linehan WM, Zbar B, Schmidt LS. 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;2:157–64. [PubMed: 12204536]
  35. Painter JN, Tapanainen H, Somer M, Tukiainen P, Aittomaki K. A 4-bp deletion in the Birt-Hogg-Dubé gene (FLCN) causes dominantly inherited spontaneous pneumothorax. Am J Hum Genet. 2005;76:522–7. [PMC free article: PMC1196403] [PubMed: 15657874]
  36. Palmirotta R, Donati P, Savonarola A, Cota C, Ferroni P, Guadagni F. Birt-Hogg-Dubé (BHD) syndrome: report of two novel germline mutations in the folliculin (FLCN) gene. Eur J Dermatol. 2008;18:382–6. [PubMed: 18573707]
  37. Pavlovich CP, Grubb RL, Hurley K, Glenn GM, Toro J, Schmidt LS, Torres-Cabala C, Merino MJ, Zbar B, Choyke P, Walther MM, Linehan WM. Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome. J Urol. 2005;173:1482–6. [PubMed: 15821464]
  38. Renfree KJ, Lawless KL. Multiple neurilemmomas in Birt-Hogg-Dubé syndrome: case report. J Hand Surg Am. 2012;37:792–4. [PubMed: 22326190]
  39. Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, Turner ML, Choyke PL, Sharma N, Peterson J, Morrison P, Maher ER, Walther MM, Zbar B, Linehan WM. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. Am J Hum Genet. 2005;76:1023–33. [PMC free article: PMC1196440] [PubMed: 15852235]
  40. Schulz T, Hartschuh W. Birt-Hogg-Dubé syndrome and Hornstein-Knickenberg syndrome are the same. Different sectioning technique as the cause of different histology. J Cutan Pathol. 1999;26:55–61. [PubMed: 10189247]
  41. Sempau L, Ruiz I, González-Morán A, Susanna X, Hansen TV. New mutation in the Birt Hogg Dube gene. Actas Dermosifiliogr. 2010;101:637–40. [PubMed: 20858390]
  42. Shin JH, Shin YK, Ku JL, Jeong SY, Hong SH, Park SY, Kim WH, Park JG. Mutations of the Birt-Hogg-Dubé (BHD) gene in sporadic colorectal carcinomas and colorectal carcinoma cell lines with microsatellite instability. J Med Genet. 2003;40:364–7. [PMC free article: PMC1735471] [PubMed: 12746401]
  43. Stamatakis L, Metwalli AR, Middelton LA, Marston Linehan W. Diagnosis and management of BHD-associated kidney cancer. Fam Cancer. 2013;12:397–402. [PMC free article: PMC4175415] [PubMed: 23703644]
  44. Takagi Y, Kobayashi T, Shiono M, Wang L, Piao X, Sun G, Zhang D, Abe M, Hagiwara Y, Takahashi K, Hino O. Interaction of folliculin (Birt-Hogg-Dube gene product) with a novel Fnip1-like (FnipL/Fnip2) protein. Oncogene. 2008;27:5339–47. [PubMed: 18663353]
  45. Toro JR, Glenn G, Duray P, Darling T, Weirich G, Zbar B, Linehan M, Turner ML. Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia. Arch Dermatol. 1999;135:1195–202. [PubMed: 10522666]
  46. Toro JR, Pautler SE, Stewart L, Glenn GM, Weinreich M, Toure O, Wei MH, Schmidt LS, Davis L, Zbar B, Choyke P, Steinberg SM, Nguyen DM, Linehan WM. Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome. Am J Respir Crit Care Med. 2007;175:1044–53. [PMC free article: PMC1899269] [PubMed: 17322109]
  47. Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, Turner M, Choyke P, Merino MJ, Pinto PA, Steinberg SM, Schmidt LS, Linehan WM. 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. 2008;45:321–31. [PMC free article: PMC2564862] [PubMed: 18234728]
  48. Vincent A, Farley M, Chan E, James WD. Birt-Hogg-Dubé syndrome: two patients with neural tissue tumors. J Am Acad Dermatol. 2003;49:717–9. [PubMed: 14512924]
  49. Vocke CD, Yang Y, Pavlovich CP, Schmidt LS, Nickerson ML, Torres-Cabala CA, Merino MJ, Walther MM, Zbar B, Linehan WM. High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors. J Natl Cancer Inst. 2005;97:931–5. [PubMed: 15956655]
  50. Walter P, Kirchhof B, Korge B, Heimann K. Flecked chorioretinopathy associated with Birt-Hogg-Dubé syndrome. Graefes Arch Clin Exp Ophthalmol. 1997;235:359–61. [PubMed: 9202964]
  51. Warren MB, Torres-Cabala CA, Turner ML, Merino MJ, Matrosova VY, Nickerson ML, Ma W, Linehan WM, Zbar B, Schmidt LS. Expression of Birt-Hogg-Dubé gene mRNA in normal and neoplastic human tissues. Mod Pathol. 2004;17:998–1011. [PubMed: 15143337]
  52. Welsch MJ, Krunic A, Medenica MM. Birt-Hogg-Dubé Syndrome. Int J Dermatol. 2005;44:668–73. [PubMed: 16101870]
  53. Yan M, Gingras MC, Dunlop EA, Nouët Y, Dupuy F, Jalali Z, Possik E, Coull BJ, Kharitidi D, Dydensborg AB, Faubert B, Kamps M, Sabourin S, Preston RS, Davies DM, Roughead T, Chotard L, van Steensel MA, Jones R, Tee AR, Pause A. The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. J Clin Invest. 2014;(Apr):24. [PMC free article: PMC4038567] [PubMed: 24762438]
  54. 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;11:393–400. [PubMed: 11927500]

Suggested Reading

  1. Schmidt LS. The Birt-Hogg-Dubé syndrome. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID), New York, NY: McGraw-Hill. Chap 41.1. Available online. 2014. Accessed 7-30-14.

Chapter Notes

Author History

Manop Pithukpakorn, MD; Mahidol University (2006-2008)
Jorge R Toro, MD (2006-present)

Revision History

  • 7 August 2014 (me) Comprehensive update posted live
  • 9 September 2008 (me) Comprehensive update posted live
  • 27 February 2006 (me) Review posted to live Web site
  • 30 November 2005 (jt) Original submission

Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview ‘Birt-Hogg-Dubé Syndrome’ is in the public domain in the United States of America.

Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1522PMID: 20301695
PubReader format: click here to try

Views

Tests in GTR by Gene

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...