Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominantly inherited hamartomatous disorder caused by germline pathogenic variants in the FLCNgene.[
Disease severity can vary significantly. Skin lesions typically appear during the third or fourth decade of life and increase in size and number with age. Lung cysts are usually bilateral and multifocal; most individuals are asymptomatic but have a high risk of developing spontaneous pneumothorax.
Approximately 15% to 30% of individuals with BHD develop renal tumors, which are typically bilateral, multifocal, and slow growing; the median age at tumor diagnosis is 46 to 50 years.[
The clinical characteristics of BHD include specific cutaneous hamartomas of the skin, called fibrofolliculomas/trichodiscomas; pulmonary cysts/history of pneumothorax; and various histologic types of renal tumors. BHD is characterized by phenotypic heterogeneity, and disease severity can vary significantly among family members and between families. To date, there is no evidence of increased risk of skin cancer or malignant transformation of these hamartomatous lesions.
In 2001, a family-based study showed that patients with the clinical diagnosis of BHD were seven times more likely than clinically unaffected family members to develop renal tumors.[
FLCN, a novel tumor suppressor gene, comprises 14 exons located at chromosome 17p11.2.[
More than 200 families affected with BHD from various populations have been described in various countries, including the United States, United Kingdom, Japan, Denmark, Spain, Italy, Australia, Canada, and the Netherlands.[
No correlation has been established between specific FLCNvariants and renal, pulmonary, and cutaneous manifestations. However, it was reported that individuals who have a deletion in the polycytosine tract of exon 11 may have a lower risk of developing renal cancers than do individuals with other variants,[
The identification of a somatic "second hit" in most Birt-Hogg-Dubé syndrome (BHD)-associated renal tumors strongly suggests that FLCN functions as a tumor suppressor. Both somatic point mutations (variants) in the wild-type FLCNallele and loss of heterozygosity at chromosome 17p have been identified, although the former appears to be the more common mechanism of inactivation of the second FLCN allele.[
The precise mechanisms by which inactivation of FLCN leads to tumorigenesis remain to be elucidated. However, folliculin, the protein product of FLCN, has been implicated as a component of the cellular energy–sensing system. Folliculin, in association with either of two novel folliculin-interacting proteins, FNIP1 and FNIP2, interacts with AMPK.[
The effects of folliculin loss on mTOR activity have been studied by several groups. Tissue-specific activation of mTORC1 was demonstrated in a kidney-specific FLCN knockout mouse model.[
The three major features of Birt-Hogg-Dubé syndrome (BHD) include fibrofolliculomas /trichodiscomas, pulmonary cysts and spontaneous pneumothorax, and renal tumors.[
Individuals with BHD usually present with multiple, small, skin-colored, dome-shaped papules distributed over the face, neck, and upper trunk. The characteristic dermatologic manifestation is a fibrofolliculoma or trichodiscoma (hamartoma of the hair follicle).[
Histologically, fibrofolliculomas/trichodiscomas are characterized by multiple anastomosing epithelial strands emanating from a central follicle. Mucin-rich or thick connective tissue stroma may encapsulate the epithelial component.[
Pulmonary Cysts and Spontaneous Pneumothorax
Computed tomography (CT) imaging results showed that lung cysts are present in 85% to 87% of patients with BHD.[
In a study of 198 BHD-affected patients, the occurrence of spontaneous pneumothorax was comparable between men (20%) and women (29%). The age range for initial pneumothorax was 22 to 75 years, but the median age for first occurrence was 38 years [
The clinical presentation of spontaneous pneumothorax ranges from asymptomatic to dyspnea and chest pain. Clinical findings include tachypnea or decreased-to-absent breath sounds. Radiographic investigation may require a high-resolution chest CT to confirm the diagnosis because a chest x-ray may not be sensitive enough to detect a loculated pneumothorax. Up to 75% of patients with a history of spontaneous pneumothorax experience a second one. Differences in reported spontaneous pneumothorax recurrence may reflect the efficacy of different treatment modalities.
Histologic findings of pleuropulmonary lesions associated with BHD patients include thin-walled pleural and subpleural cysts and bullae, intraparenchymal air cysts, pleural blebs and changes consistent with spontaneous pneumothorax, and underlying emphysematous changes in lung tissue parenchyma adjacent to the bullae.[
Approximately 25% to 35% of individuals with BHD develop renal tumors,[
Figure 1. Birt-Hogg-Dubé syndrome–associated renal tumors are commonly multifocal and bilateral. Arrows indicate the locations of the tumors.
The most common tumors are a hybrid of oncocytoma and chromophobe histologic cell types, so-called oncocytic hybrid tumors, chromophobe RCC, and renal oncocytoma. Only renal oncocytoma is considered a benign tumor.[
Among 70 BHD patients with renal tumors and an FLCN pathogenic variant seen at the National Institutes of Health and identified through a literature review, 5 (7%) reportedly died from metastatic RCC.[
Bilateral multifocal parotid oncocytomas [
It should be noted that germline FLCNvariants were also found in patients without cutaneous findings but suspected of having BHD because of their specific renal and pulmonary manifestations.[
Although initial epidemiologic observations linked BHD with an increased risk of colonic polyps, subsequent epidemiologic studies did not appear to confirm this association.[
Risk Assessment for BHD Syndrome
FLCN is the only gene known to be associated with Birt-Hogg-Dubé syndrome (BHD). It is located on chromosome 17p11.2.[
Genetic testing performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory is indicated for all individuals known to have or suspected of having BHD, including individuals with the following:
BHD syndrome is inherited in an autosomal dominant manner. If a parent of a proband is clinically affected or has a pathogenic variant, the siblings of the proband are at 50% risk of inheriting the variant. The degree of clinical severity is not predictable. Prenatal diagnosis for pregnancies at 50% risk is possible if the disease-causing allele of an affected family member has been identified. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)
The three major features of BHD include cutaneous lesions, lung cysts and spontaneous pneumothorax, and renal tumors.[
The dermatologic diagnosis of BHD is made in individuals who have five or more facial or truncal papules with at least one histologically confirmed fibrofolliculoma.[
It is important to distinguish between BHD-associated RCC and sporadic RCC because this may have implications for management. Genetic testing for a pathogenic variant in FLCN, a family history of BHD, or the presence of extrarenal manifestations associated with BHD are helpful in establishing a diagnosis of this condition. Because a variety of histologic variants of kidney cancer can be seen in association with BHD, it is often necessary to make a histologic diagnosis to help differentiate between the benign tumors (oncocytomas) and those with a malignant potential (chromophobe, clear cell, and papillary RCC).[
The differential diagnosis of pulmonary cysts includes lymphangioleiomyomatosis (LAM); distinguishing this from BHD can be clinically challenging. One study proposed a set of findings that permit differentiation between BHD and LAM.[
BHD patients display two main clinical presentations. Most commonly, individuals present with a documented family history of BHD. Other presentations include individuals without a BHD family history or one that is unknown. In the former clinical scenario, if the patient's biological relative has a genetic diagnosis with an identified FLCN pathogenic variant, the patient may choose to begin evaluation with genetic counseling and pathogenic variant testing.
Clinical surveillance for individuals at risk of BHD includes dermatologic, radiological, and histological examinations to identify characteristic cutaneous lesions, renal tumors, and lung cysts, with or without a history of spontaneous pneumothorax. Not all features are present in each at-risk individual, and some BHD family members may have no discernible phenotypic findings (i.e., they are clinically unaffected carriers of deleterious FLCN variants). This clinical scenario is being encountered with increasing frequency as the number of syndrome-associated genes for which pathogenic variant testing can be offered clinically expands. In most disorders, the natural history of genetically abnormal/clinically normal individuals has not yet been well characterized. These major features of BHD are described in the Clinical diagnosis section.
Decisions regarding the use of lifelong surveillance for hereditary RCC syndromes must consider both risks and benefits. Approximately 15% to 29% of individuals with BHD have renal tumors,[
Contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) are both useful modalities for the detection of BHD-associated renal tumors.[
Level of evidence: 5
Cryotherapy, electrodessication, surgery, and laser therapy have been used with good cosmetic results, but relapse usually occurs because the cutaneous lesions are a manifestation of an inherited skin condition.[
Level of evidence: 5
Partial nephrectomy is the treatment of choice in the management of BHD-related kidney neoplasms, to preserve optimal long-term kidney function in patients at risk of multiple primary renal tumors. However, this renal-sparing surgery depends on the size and location of the tumors found during surgery. It is important to incorporate knowledge of the high cumulative risk of multifocal and bilateral kidney tumors in this syndrome, as surgical management is planned. In general, renal tumors smaller than 3 cm in diameter may be monitored radiologically under the close supervision of the urologic oncology surgeon; immediate surgery may not be required.[
Surveillance of at-risk individuals and relatives includes abdominal/pelvic MRI or CT scans and evaluation of renal tumors by urologic surgeons and radiologists experienced in the management of these complicated patients. Use of genetic testing for early identification of at-risk family members improves diagnostic certainty and eliminates costly and stressful screening procedures in at-risk relatives who have not inherited their family's disease-causing variant.
Level of evidence: 4
The management of spontaneous pneumothorax in patients with BHD is similar to that employed in the general population.[
The clinical presentation of spontaneous pneumothorax in patients with BHD is variable. Therapy is dictated by the underlying lung condition and general health of the patient. One study reported that of 101 patients with spontaneous pneumothoraces, 78 required medical intervention, and 23 were managed by observation alone.[
Level of evidence: 4
The major cause of morbidity and mortality in Birt-Hogg-Dubé syndrome (BHD) is related to renal lesions. Because of the rarity of BHD, it is difficult to generate robust overall survival data on populations of patients with the syndrome; however, when patients are managed with an appropriate surveillance and intervention strategy, their life expectancy should not be significantly different from that of matched individuals in the general population.
While a majority of patients have excellent outcomes when tumors are detected early and removed surgically, there is a risk of metastasis with larger tumors; the optimal management for metastatic disease is unclear.[
Since FLCN, the gene responsible for Birt-Hogg-Dubé syndrome, was identified in 2001, a number of studies have elucidated its function and possible genotype -phenotype correlations. Although surveillance followed by surgical resection remains the mainstay of disease management, improvements in early detection and in molecularly targeted early intervention may alter the course of this disease in the kidney and decrease the incidence of overt and/or lethal renal manifestations. A better understanding of the biochemical function of the FLCN protein should provide insights into target identification and validation of medical therapy for localized, locally advanced, and metastatic disease.
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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of Birt-Hogg-Dubé syndrome. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
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Last Revised: 2022-04-13
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