Birt-Hogg-Dube syndrome is an autosomal dominant genodermatosis characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax (Nickerson et al., 2002).
BHD is similar to, but histologically and genetically distinct from, familial multiple discoid fibromas (FMDF; ... Birt-Hogg-Dube syndrome is an autosomal dominant genodermatosis characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax (Nickerson et al., 2002). BHD is similar to, but histologically and genetically distinct from, familial multiple discoid fibromas (FMDF; 190340).
Hornstein and Knickenberg (1975) first described this disorder as 'perifollicular fibromatosis cutis with polyps of the colon' in 2 sibs. Their father was reportedly similarly affected, indicating an inherited condition. The proband was a 47-year-old woman who developed ... Hornstein and Knickenberg (1975) first described this disorder as 'perifollicular fibromatosis cutis with polyps of the colon' in 2 sibs. Their father was reportedly similarly affected, indicating an inherited condition. The proband was a 47-year-old woman who developed multiple perifollicular fibromas and skin tags affecting the neck, face, back, axillae, and groin. The skin lesions were 2 to 4 mm in diameter, flat-topped, solid, and skin-colored. Most had a central pit or plug. Histologic analysis showed whorl-shaped connective tissue fibers surrounding atrophic sebaceous glands. She also was found to have several colonic polyps, one of which showed malignant degeneration. The brother had similar adult onset of the skin lesions, but refused gastrointestinal examination. The patients' father also had renal and lung cysts. The disorder was distinguished from Gardner syndrome (FAP1; 175100). Hornstein and Knickenberg (1975) suggested that patients with follicular fibromatosis be examined for intestinal polyps. Hornstein (1976) reviewed the condition in this family and considered the disorder a genodermatosis. Birt et al. (1977) described fibrofolliculomas with trichodiscomas (see 190340) and acrochordons in a family. Onset of this dermatologic condition was invariably in adulthood. A central hair was often visible in the lesions. Hereditary medullary carcinoma of the thyroid was also segregating, apparently independently, in the kindred. In a sibship of 9, 6 had medullary carcinoma of the thyroid. Two of those with thyroid cancer and 2 without had numerous small papular skin lesions that Birt et al. (1977) labeled fibrofolliculoma. The lesion was characterized by abnormal hair follicles with epithelial strands extending from the infundibulum of the hair follicle into a hyperplastic mantle of specialized fibrous tissue. Associated skin lesions were trichodiscomas (tumor of the hair disc) and acrochordons ('wart with a thin neck;' skin tag). Fujita et al. (1981) reported the cases of 2 brothers and the son of one of them. By history the father of the 2 brothers was considered affected. Clinically the disorder was characterized by asymptomatic dome-shaped papules primarily involving the head, neck, chest, back, and arms. Ubogy-Rainey et al. (1987) likewise reported a family with 3 affected: a mother and her daughter and son. They discussed the clinical differential diagnosis of multiple firm, skin-colored papules. They diagrammed the histogenesis of benign follicular neoplasms, indicating that trichodiscomas are derived from the mesenchymal component of the pilar complex, trichofolliculomas, trichodiscomas, and trichoepitheliomas from epithelial components, and fibrofolliculomas from both epithelial and mesenchymal proliferation. Shapiro and Kopf (1991) described a family in which a mother and son had multiple desmoplastic trichoepitheliomas. The grandmother had a single cylindroma of the scalp. Rongioletti et al. (1989) and Le Guyadec et al. (1998) described association of Birt-Hogg-Dube syndrome with intestinal polyposis. Roth et al. (1993) observed bilateral renal cell carcinoma in association with BHD. Chung et al. (1996) described multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with BHD. Toro et al. (1999) evaluated kindreds with familial renal tumors for cutaneous manifestations of BHD. They performed complete oral and skin examinations of 152 patients from 49 families. In this way, they identified 3 extended kindreds in whom renal neoplasms and BHD appeared to segregate together. Two kindreds had renal oncocytomas and a third had a variant of papillary renal cell carcinoma. Thirteen patients exhibited BHD. Seven individuals, including a set of identical twins, had renal neoplasms and BHD. An additional 4 patients (3 deceased and not examined) in these families had renal neoplasms but not BHD. BHD without renal neoplasms was present in 6 individuals. Thirteen patients with fibrofolliculomas and trichodiscomas presented clinically with multiple smooth skin-colored to grayish-white papules located on the face, auricles, neck, and upper trunk. Oral papules were present in 9 of 28 and acrochordons in 11 of 28 patients. Features of BHD not previously appreciated included deforming lipomas in 5, collagenomas in 4, and pulmonary cysts in 4 of 28 patients. Families with BHD did not display germline mutations in the von Hippel-Lindau gene (608537) or in the tyrosine kinase domain of the MET protooncogene (164860), which are known to be associated with renal neoplasms. The pedigree pattern was entirely consistent with autosomal dominant inheritance; for example, a father and both of his twin sons had renal tumor and BHD. Weirich et al. (1998) described 5 families in which multiple members had multiple bilateral renal oncocytomas. On dermatologic examination, 13 members of 3 of these families were found to have cutaneous BHD lesions (Toro et al., 1999). Subsequently, through mass mailings to dermatologists, Schmidt et al. (2001) identified 33 families with BHD skin lesions and associated renal tumors, lung cysts, or pneumothorax, and/or colonic polyps, including the original Canadian family described by Birt et al. (1977). Zbar et al. (2002) showed that BHD confers an increased risk for the development of renal tumors and lung cysts or spontaneous pneumothorax but not for the development of colonic polyps. Kidney cancer may be classified into 4 histologic types: clear cell (CCRC, 75%), papillary (PRC, 15%), oncocytoma (5%), and chromophobe (5%) (Kovacs et al., 1997). In a study of 130 renal tumors found in 30 BHD patients, the spectrum of renal histology included 34% chromophobe, 5% oncocytoma, 50% chromophobe/oncocytic hybrid, 9% clear cell, 2% papillary (Pavlovich et al., 2002). Toro et al. (2008) reported the clinical features of 89 individuals from 51 families with BHD syndrome. Forty-six (90%) of 51 families had individuals with multiple fibrofolliculomas, and 26 (57%) of 46 BHD families had individuals with a second histologically confirmed cutaneous lesion, including angiofibroma, trichodiscoma, and perifollicular fibroma. Thirty (34%) of 89 individuals and 25 (49%) of 51 families had kidney tumours. Forty-five (88%) of 51 families and 75 (84%) of 89 individuals had lung cysts on CT imaging. Twenty-seven (53%) of 51 families and 34 (38%) of 89 individuals had a history of spontaneous pneumothorax, most often associated with lung cysts. Eighteen (58%) of 31 individuals with a family history of pneumothorax developed pneumothoraces compared to 16 (28%) of 57 individuals without family history (p = 0.011). Toro et al. (2008) noted inter- and intrafamilial phenotypic variation. Kluijt et al. (2009) reported a large Dutch family with BHD syndrome confirmed by genetic analysis (607273.0015). The proband was a 27-year-old man with metastatic high-grade clear cell carcinoma of the kidney. His 32-year-old brother had high-grade papillary renal cell carcinoma, and a deceased sister of the maternal grandmother had a hybrid chromophobe/oncocytic renal carcinoma at age 71. She also had a history of recurrent pneumothorax. Six of 13 mutation carriers in the family who had a renal MRI scan showed unilateral or bilateral renal cysts; all were 55 years or older. Pneumothorax occurred in 8 mutation carriers at a relatively advanced age (third through sixth decades), and 5 had lung cysts and bullous lung disease. Eleven carriers had facial papules, most with onset after age 40. Kluijt et al. (2009) suggested that the relatively early age of renal cancer in some family members may be due to a modifier gene. Importantly, the clinical features of the family also illustrated that skin anomalies and/or lung disease are not mandatory for considering BHD in patients with renal cancer. - Pathologic Findings The Hornstein-Knickenberg syndrome had been thought to be characterized by perifollicular fibromas, whereas BHD was characterized by fibrofolliculomas and trichodiscomas. Schulz and Hartschuh (1999) reported a father and daughter with a diagnosis of BHD. Extensive histologic examination of papular skin lesions indicated that histologic differences between the skin lesions are artificial and caused by interpretation of different sectioning planes; thus, fibrofolliculoma, perifollicular fibroma, and so-called trichodiscoma are in fact the same lesion. Similarly, some think that acrochordons are in fact fibrofolliculomas (Happle, 2012). Starink et al. (2012) favored use of the term 'discoid fibroma' rather than 'trichodiscoma,' and suggested that most lesions described as 'trichodiscoma' in BHD were in fact 'fibrofolliculomas.' - Clinical Variability Maffe et al. (2011) found FLCN mutations in 9 (47%) of 19 probands who presented initially with extracutaneous tumors suggestive of BHD syndrome, either a renal tumor or pneumothorax/lung cysts. Five (56%) of the 9 probands were found to have cutaneous hamartomas. Family history showed that 8 of the patients had affected relatives; however, 7 (44%) of 16 heterozygous relatives over the age of 20 years were asymptomatic. One patient had bilateral parotid oncocytomas, and tumor tissue showed loss of heterozygosity (LOH) for the wildtype FLCN allele. Maffe et al. (2011) noted that although most patients with BHD are ascertained on the basis of skin lesions, the diagnosis should be suspected in those who present with extracutaneous manifestations.
By positional cloning, Nickerson et al. (2002) identified a novel gene (FLCN) in this region encoding a protein called folliculin. In several BHD families, they identified protein-truncating mutations in the FLCN gene (607273.0001-607273.0005). Nickerson et al. (2002) stated ... By positional cloning, Nickerson et al. (2002) identified a novel gene (FLCN) in this region encoding a protein called folliculin. In several BHD families, they identified protein-truncating mutations in the FLCN gene (607273.0001-607273.0005). Nickerson et al. (2002) stated that their identification of this novel kidney cancer gene associated with renal oncocytoma or chromophobe renal cancer could contribute to understanding the role of folliculin in pathways common to skin, lung, and kidney development. Khoo et al. (2002) studied 4 sporadic BHD cases and 4 families with a total of 23 affected subjects. Haplotype analysis of these families using BHD-linked markers showed that they did not share the same affected alleles, excluding common ancestry. Mutation analysis of the BHD gene identified 2 germline mutations on exon 11 in 3 of 4 families as well as 2 of 4 sporadic cases. A novel somatic mutation was detected in a BHD-related chromophobe renal carcinoma. Schmidt et al. (2005) performed direct sequencing of the BHD gene in 30 families with BHD and reported that combined with their previous data (Nickerson et al., 2002), they had identified germline BHD mutations in 51 (84%) of 61 families with BHD. Each family's mutation cosegregated with disease and was not found in at least 160 unaffected individuals. Of the 51 families with a germline BHD mutation, 27 (53%) had a cytosine insertion or deletion in the mononucleotide tract of 8 cytosines in exon 11 (1285insC, 607273.0001; 1285delC, 607273.0002, respectively), which appears to represent a mutation hotspot. Two large families with BHD, one of them the original family reported by Birt et al. (1977), showed linkage to 17p11.2 but had no mutation in the BHD gene by direct sequencing. Schmidt et al. (2005) noted that most reported mutations were predicted to terminate folliculin prematurely and to result in loss of function and suggested that BHD may act as a tumor suppressor gene. In affected individuals from 51 (88%) of 58 families with BHD, Toro et al. (2008) identified 23 different mutations in the FLCN gene, including 13 novel mutations (see, e.g., 607273.0014). The 1285insC or 1285delC mutations were most common, occurring in 14 and 5 families, respectively. All mutations except one were predicted to result in a truncated protein. There were no apparent genotype/phenotype correlations. Kunogi et al. (2010) screened the FLCN gene by DHPLC in 36 Japanese patients with multiple lung cysts of undetermined causes, all but 1 of whom had suffered at least 1 pneumothorax, and identified 13 different germline mutations in 23 of the patients, respectively. The remaining 13 patients were further analyzed by quantitative PCR, and large genomic deletions (see, e.g., 607273.0017) were found in 2; thus 25 (69.4%) of the 36 patients had germline FLCN mutations. Only 6 of the mutation-positive patients had skin lesions, and 2 others had renal tumors, 1 of which was an angiomyolipoma and the other a renal cancer (histopathologic information unavailable). Kunogi et al. (2010) noted that 13 (52%) of the 25 mutations were located in the 3-prime end of the FLCN gene, and that these Japanese patients with FLCN mutations had a very low incidence of skin and renal involvement.
The three major features of Birt-Hogg-Dubé syndrome (BHDS) are the presence of the following:...
DiagnosisClinical DiagnosisThe three major features of Birt-Hogg-Dubé syndrome (BHDS) are the presence of the following: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 been also described 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 is sometimes needed to make the diagnosis of fibrofolliculomas.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 suspicious for the diagnosis of BHDS, but are 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 chest CT. The total number of lung cysts per individual ranges from 0 to 166 (mean 16). Twenty-four percent (48/198) of 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 chest CT imaging.Renal tumors. The renal tumors are usually bilateral and multifocal. Tumor types include renal oncocytoma, chromophobe renal cell carcinoma, oncocytic hybrid tumor, and a minority of clear cell renal cell carcinoma.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 TestingGene. FLCN is the only gene known to be associated with BHDS.Clinical testingSequence analysis of select exons. Fifty-three percent (27 of 51) of 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).Sequence analysis of the entire coding region, including coding exons 4 through 14, increases the mutation detection in probands to 88%.Table 1. Summary of Molecular Genetic Testing Used in Birt-Hogg-Dubé SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1, 2Test AvailabilityFLCNSequence analysis of exon 11Polycytosine tract deletion (c.1285delC) / duplication (c.1285dupC)~53%ClinicalSequence analysis of entire coding regionSequence variants 3~88%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Schmidt et al [2005], Toro et al [2008]3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm 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 BHDSFacial 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 tumorsA single oncocytic, chromophobe, or oncocytic hybrid renal tumor and a family history of renal cancer with any of the above renal cell tumor typesA family history of autosomal dominant primary spontaneous pneumothorax without a history of smoking or COPDPrenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersAutosomal dominant primary spontaneous pneumothorax. Germline mutations in FLCN were found in families with dominantly inherited spontaneous pneumothorax. Pulmonary involvement appears to be the only manifestation; penetrance is 100% [Graham et al 2005, Painter et al 2005].Somatic mutation. Acquired mutations 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.
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....
Natural HistoryThe 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 BHDS cutaneous phenotype [Toro et al 2008]. In addition, some individuals with BHDS develop oral papules and cutaneous collagenomas [Nadershahi et al 1997, Toro et al 1999].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. In addition, women tend to have smaller and fewer lesions than men.Recently, three individuals with germline FLCN mutations who also had a history of malignant melanoma were reported [Khoo et al 2002, Toro et al 2008].A family with BHDS in which one sib developed a dermatofibrosarcoma protuberans (DFSP) and another sib had a cutaneous leiomyosarcoma was also recently 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 a 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 because 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 tumors. 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 had a sevenfold increased risk of 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].Other manifestationsOral papules [Nadershahi et al 1997, Toro et al 1999] and parotid oncocytoma [Liu et al 2000, Schmidt et al 2005, Toro et al 2008] have been seen in increased frequency in BHD syndrome.Non-renal tumors recently reported in BHDS include [Toro et al 2008]:Two cases of thyroid cancerTwo cases of Colon cancer The evidence associating colonic neoplasm and BHDS is conflicting [Khoo et al 2002, Zbar et al 2002].Single cases of the following:Squamous cell carcinoma of the head and neckHodgkin’s diseaseUterine cancerProstate cancerBreast cancerSquamous cell carcinoma of the cervixRhabdomyomaAn adrenal massSingle cases of the following have also been reported: Lipoma, angiolipoma, and collagenoma [Toro et al 1999]Cutaneous neurothekeoma (benign myxoma of cutaneous nerve sheath origin) and meningioma [Vincent et al 2003]Multinodular goiter [Drummond et al 2002, Welsch et al 2005]Ovarian cyst [Godbolt et al 2003]Parathyroid adenomaChorioretinal lesions [Walter et al 1997, Godbolt et al 2003]
Genotype-phenotype correlations have been reported; however, whether these manifestations are truly associated with BHDS remains to be determined through larger studies....
Genotype-Phenotype CorrelationsGenotype-phenotype correlations have been reported; however, 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 who have a c.1285delC mutation may have a lower risk of developing renal cancers than individuals with other FLCN mutations, but this needs to be evaluated in large studies.
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....
Differential DiagnosisCutaneous 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:Marfan syndromeEhlers-Danlos syndrome, vascular typeTSCAlpha1-antitrypsin deficiency [Daniel & Teba 2000]Cystic fibrosis [Flume et al 2005]Langerhan cell histiocytosis [Mendez et al 2004]Pulmonary lymphangioleiomyomatosis (LAM), which can occur as an isolated finding or as part of TSCRenal 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 carcinomasHereditary 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.
To establish the extent of disease in an individual diagnosed with Birt-Hogg-Dubé syndrome (BHDS), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Birt-Hogg-Dubé syndrome (BHDS), the following evaluations are recommended:Detailed dermatologic examination and punch biopsy of suspected cutaneous lesionHigh-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.Treatment of ManifestationsTreatment of fibrofolliculomas and trichodiscomas is difficult. Laser ablation shows substantial improvement, but relapse can occur [Gambichler et al 2000].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]. Renal tumors greater than 3.0 cm and/or rapidly growing tumors usually require partial nephrectomy. Total nephrectomy may be necessary in some cases. The main objective is to preserve as much of the kidney as possible to help preserve long-term kidney function because affected individuals usually develop multifocal and bilateral kidney tumors.Prevention of Primary ManifestationsNo 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].SurveillanceThere 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 disease-causing mutation 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. In particular, surveillance for and monitoring of renal tumors include the following:If normal at baseline, abdominal/pelvic CT scan with contrast or MRI (if CT is not possible) every two to three years are the optimal studies for complete assessment of kidney lesions. However, 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], the use of renal ultrasound examination for screening individuals with BHDS and/or a FLCN germline mutation may be adequate in some patients, while avoiding long-term cumulative radiation exposure. Note: The use of renal ultrasound examination is especially applicable to individuals who have had two normal CT examinations or MRI examinations and individuals without a family history of kidney cancer.If any suspicious lesion (<1.0 cm in diameter, indeterminate lesion, or complex cysts) is noted on a previous examination, annual abdominal/pelvic CT scan with contrast alternating every other year with renal MRI or abdominal ultrasound examination to reduce lifetime exposure to radiation is recommended.Evaluation of renal tumors by a urologic surgeon is appropriateMonitor tumors less than 3.0 cm in diameter by periodic imaging; they may not require surgical intervention while this small.Rapidly growing lesions and/or symptoms including pain, blood in the urine, or atypical presentations require a more individualized approach.Agents/Circumstances to AvoidThe following should be avoided:Cigarette smokingHigh ambient pressures, which may precipitate spontaneous pneumothoraxEvaluation of Relatives at RiskWhen the family-specific mutation 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 disease-causing mutations.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 InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFLCN17p11.2FolliculinFolliculin (FLCN) @ LOVD The Folliculin Mutation DatabaseFLCNData 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) View in own window 135150BIRT-HOGG-DUBE SYNDROME; BHD 607273FOLLICULIN; FLCNNormal allelic variants. 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.Pathologic allelic variants. See Table 2. Various mutations have been identified in families with Birt-Hogg-Dubé syndrome (BHDS). All mutations predict protein truncation. The most common mutations 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 Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid ChangeReference Sequencesc.1285dupC (1733ins C)p.His429Profs*26NM_144997.4 NP_659434.2c.1285delC (1733delC)p.His429Thrfs*38See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventionsFor more information, see Table A.Normal gene product. Folliculin, the product of FLCN, has 579 amino acid residues. It has no known function, but 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, plus 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].