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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Birt-Hogg-Dubé Syndrome - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="GeneReviews® [Internet]">
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<meta name="citation_title" content="Birt-Hogg-Dubé Syndrome">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2024/12/05">
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<meta name="citation_author" content="Elke C Sattler">
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<meta name="citation_author" content="Ortrud K Steinlein">
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<meta name="citation_pmid" content="20301695">
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<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1522/">
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<meta name="citation_keywords" content="Hornstein-Knickenberg Syndrome">
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<meta name="citation_keywords" content="Hornstein-Knickenberg Syndrome">
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<meta name="citation_keywords" content="Folliculin">
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<meta name="citation_keywords" content="FLCN">
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<meta name="citation_keywords" content="Birt-Hogg-Dube Syndrome">
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<meta name="DC.Title" content="Birt-Hogg-Dubé Syndrome">
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<meta name="DC.Publisher" content="University of Washington, Seattle">
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<meta name="DC.Contributor" content="Elke C Sattler">
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<meta name="DC.Contributor" content="Ortrud K Steinlein">
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<meta name="DC.Date" content="2024/12/05">
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<meta name="description" content="The clinical characteristics of Birt-Hogg-Dubé syndrome (BHDS) include cutaneous manifestations (fibrofolliculomas, acrochordons, angiofibromas, oral papules, cutaneous collagenomas, and epidermal cysts), pulmonary cysts / history of pneumothorax, renal cysts, and various types of renal tumors. Disease severity can vary significantly even within the same family. Skin lesions typically appear between the second and fourth decades of life and typically increase in size and number with age. Lung cysts are mainly in the basal lung regions; most individuals are asymptomatic but at high risk for spontaneous pneumothorax. Renal tumors can be bilateral and multifocal. The most common renal tumors are a hybrid of oncocytoma and chromophobe histologic cell types (oncocytic hybrid tumor); clear cell carcinoma and oncocytoma are also common.">
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<meta name="og:title" content="Birt-Hogg-Dubé Syndrome">
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<meta name="og:description" content="The clinical characteristics of Birt-Hogg-Dubé syndrome (BHDS) include cutaneous manifestations (fibrofolliculomas, acrochordons, angiofibromas, oral papules, cutaneous collagenomas, and epidermal cysts), pulmonary cysts / history of pneumothorax, renal cysts, and various types of renal tumors. Disease severity can vary significantly even within the same family. Skin lesions typically appear between the second and fourth decades of life and typically increase in size and number with age. Lung cysts are mainly in the basal lung regions; most individuals are asymptomatic but at high risk for spontaneous pneumothorax. Renal tumors can be bilateral and multifocal. The most common renal tumors are a hybrid of oncocytoma and chromophobe histologic cell types (oncocytic hybrid tumor); clear cell carcinoma and oncocytoma are also common.">
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class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK1522_"><span class="title" itemprop="name">Birt-Hogg-Dubé Syndrome</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: Hornstein-Knickenberg Syndrome</div><p class="contribs">Sattler EC, Steinlein OK.</p><p class="fm-aai"><a href="#_NBK1522_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 32 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="bhd.Summary" itemprop="description"><h2 id="_bhd_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>The clinical characteristics of Birt-Hogg-Dubé syndrome (BHDS) include cutaneous manifestations (fibrofolliculomas, acrochordons, angiofibromas, oral papules, cutaneous collagenomas, and epidermal cysts), pulmonary cysts / history of pneumothorax, renal cysts, and various types of renal tumors. Disease severity can vary significantly even within the same family. Skin lesions typically appear between the second and fourth decades of life and typically increase in size and number with age. Lung cysts are mainly in the basal lung regions; most individuals are asymptomatic but at high risk for spontaneous pneumothorax. Renal tumors can be bilateral and multifocal. The most common renal tumors are a hybrid of oncocytoma and chromophobe histologic cell types (oncocytic hybrid tumor); clear cell carcinoma and oncocytoma are also common.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The clinical diagnosis of BHDS is established in a proband with either one major criteria (>5 fibrofolliculomas/trichodiscomas; one histologically confirmed) or two minor criteria (bilateral basally located lung cysts without other cause, early-onset renal cell cancer [age <50 years], multifocal/bilateral renal cell cancer, renal cell cancer with mixed chromophobe/oncocytic histology, and/or a first-degree relative with BHDS). The molecular diagnosis is established in a proband with any suggestive findings and a germline heterozygous pathogenic variant in <i>FLCN</i> identified by molecular genetic testing.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Surgical and laser treatment can lead to temporary improvement of fibrofolliculomas, but lesions often recur. Pneumothoraces are treated as in the general population; consider surgical intervention for recurrent pneumothoraces. Renal tumors less than 3.0 cm in diameter can be monitored with imaging; when possible, nephron-sparing surgery is the treatment of choice for larger renal tumors, depending on their size and location.</p><p><i>Surveillance:</i> Assess for pulmonary signs/symptoms of lung cysts/pneumothorax; discuss activities that might increase pneumothorax risk (e.g., working as a pilot, flying in unpressurized aircraft, diving). Annual abdominal/pelvic MRI to assess for renal lesions beginning at age 20 years or earlier in those with a family history of renal tumors before age 30 years; abdominal/pelvic CT with contrast is an alternative when MRI is not an option, but the long term-effects of cumulative radiation exposure are unknown.</p><p><i>Agents/circumstances to avoid:</i> Cigarette smoking, high ambient pressures, and radiation exposure.</p><p><i>Evaluation of relatives at risk:</i> Molecular genetic testing for the family-specific <i>FLCN</i> 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. Screening for lung cysts, fibrofolliculomas, and trichodiscomas can be performed if the pathogenic variant in the family is not known.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>BHDS is inherited in an autosomal dominant manner. Most individuals diagnosed with BHDS have an affected parent; some individuals have a <i>de novo</i>
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<i>FLCN</i> pathogenic variant. Each child of an individual with BHDS is at a 50% risk of inheriting the <i>FLCN</i> pathogenic variant. Once the <i>FLCN</i> pathogenic variant has been identified in an affected family member, predictive testing for at-risk family members and prenatal/preimplantation genetic testing for BHDS are possible.</p></div></div><div id="bhd.Diagnosis"><h2 id="_bhd_Diagnosis_">Diagnosis</h2><p>Clinical diagnostic criteria for the diagnosis of Birt-Hogg-Dubé syndrome (BHDS) have been published [<a class="bibr" href="#bhd.REF.geilswijk.2024" rid="bhd.REF.geilswijk.2024">Geilswijk et al 2024</a>].</p><div id="bhd.Suggestive_Findings"><h3>Suggestive Findings</h3><p>BHDS <b>should be suspected</b> in individuals with any of the following clinical findings and/or family history.</p><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div>
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<b>Pulmonary</b>
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</div><ul><li class="half_rhythm"><div>Primary spontaneous pneumothorax</div></li><li class="half_rhythm"><div>Multiple lung cysts (particular in the lower lung zone) without known cause</div></li></ul></li><li class="half_rhythm"><div>
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<b>Renal</b>
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</div><ul><li class="half_rhythm"><div>Early-onset renal cell cancer (age <50 years)</div></li><li class="half_rhythm"><div>Multifocal or bilateral renal cell cancer or oncocytoma</div></li><li class="half_rhythm"><div>≥2 family members with renal cancer</div></li></ul></li><li class="half_rhythm"><div><b>Cutaneous.</b> Multiple fibrofolliculomas/trichodiscomas</div></li></ul><p><b>Family history</b> is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.</p></div><div id="bhd.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><div id="bhd.Clinical_Diagnosis"><h4>Clinical Diagnosis</h4><p>The clinical diagnosis of BHDS <b>is established</b> in a proband with one major or two minor criteria.</p><p><b>Major criteria.</b> More than five fibrofolliculomas/trichodiscomas, one histologically confirmed</p><p>
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<b>Minor criteria</b>
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</p><ul><li class="half_rhythm"><div>Bilateral basally located lung cysts without other cause</div></li><li class="half_rhythm"><div>Early-onset renal cell cancer (at age <50 years)</div></li><li class="half_rhythm"><div>Multifocal or bilateral renal cell cancer</div></li><li class="half_rhythm"><div>Chromophobe/oncocytic mixed renal cell cancer</div></li><li class="half_rhythm"><div>First-degree relative with BHDS</div></li></ul></div><div id="bhd.Molecular_Diagnosis"><h4>Molecular Diagnosis</h4><p>The molecular diagnosis of BHDS <b>is established</b> in a proband with <a href="#bhd.Suggestive_Findings">suggestive findings</a> and a heterozygous pathogenic (or likely pathogenic) variant in <i>FLCN</i> identified by molecular genetic testing (see <a href="/books/NBK1522/table/bhd.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobbhdTmoleculargenetictestingusedin">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bibr" href="#bhd.REF.richards.2015.405" rid="bhd.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (2) Identification of a heterozygous <i>FLCN</i> variant of uncertain significance does not establish or rule out the diagnosis.</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (single gene testing, multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see <a href="#bhd.Option_1">Option 1</a>), whereas comprehensive genomic testing does not (see <a href="#bhd.Option_2">Option 2</a>).</p><div id="bhd.Option_1"><h5>
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<b>Option 1</b>
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</h5><p>When the phenotypic findings suggest the diagnosis of BHDS, molecular genetic testing approaches can include <b>single-gene testing</b> or use of a <b>multigene panel</b>.</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-gene testing.</b> Sequence analysis of <i>FLCN</i> is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A multigene panel</b> that includes <i>FLCN</i> and other genes of interest (see <a href="#bhd.Differential_Diagnosis">Differential Diagnosis</a>) may be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul></div><div id="bhd.Option_2"><h5>
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<b>Option 2</b>
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</h5><p>When the phenotype is indistinguishable from many other inherited disorders characterized by facial papules and renal tumors, <b>comprehensive</b>
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<b>genomic testing</b> does not require the clinician to determine which gene is likely involved. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible.</p><p>For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figbhdTmoleculargenetictestingusedin"><a href="/books/NBK1522/table/bhd.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobbhdTmoleculargenetictestingusedin"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="bhd.T.molecular_genetic_testing_used_in"><a href="/books/NBK1522/table/bhd.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobbhdTmoleculargenetictestingusedin">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in Birt-Hogg-Dubé Syndrome </p></div></div></div></div></div></div><div id="bhd.Clinical_Characteristics"><h2 id="_bhd_Clinical_Characteristics_">Clinical Characteristics</h2><div id="bhd.Clinical_Description"><h3>Clinical Description</h3><p>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. Intra- as well as interfamilial variation in disease severity can be significant. To date, more than 1,000 individuals have been identified with a pathogenic variant in <i>FLCN</i>. The following description of the phenotypic features associated with this condition is based on these reports.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figbhdTbirthoggdubsyndromefrequencyof"><a href="/books/NBK1522/table/bhd.T.birthoggdub_syndrome_frequency_of/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobbhdTbirthoggdubsyndromefrequencyof"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="bhd.T.birthoggdub_syndrome_frequency_of"><a href="/books/NBK1522/table/bhd.T.birthoggdub_syndrome_frequency_of/?report=objectonly" target="object" rid-ob="figobbhdTbirthoggdubsyndromefrequencyof">Table 2. </a></h4><p class="float-caption no_bottom_margin">Birt-Hogg-Dubé Syndrome: Frequency of Select Features </p></div></div><div id="bhd.Cutaneous_Manifestations"><h4>Cutaneous Manifestations</h4><p>Individuals with BHDS usually present with multiple small skin-colored, opaque, whitish or yellowish dome-shaped papules known as fibrofolliculomas. These noncancerous skin lesions start to appear between the second and fourth decade of life. They are the most common cutaneous manifestation in individuals with BHDS by age 70 years. In early stages they are typically found centrofacially (nasal and paranasal) and in a retroauricular location. They often increase in size, number, and distribution with age, eventually involving the face, neck, and upper trunk. Later onset of cutaneous lesions tends to correlate with a milder skin phenotype. Women tend to have smaller and fewer lesions than men. The large variability in age of onset and expression often limits their usefulness for clinical diagnosis, especially in younger individuals. If present, however, they are a helpful indicator of BHDS. Histopathologically circumscribed fibrosis is seen, which, depending on the location, is described as: perifollicular fibroma, often replacing the entire hair follicle in the corium; as fibrofolliculoma, with elongated fingerlike extensions; or as trichodiscoma, located subepidermally, mostly parallel to the skin surface.</p><p>Note: Trichodiscomas, formerly described as tumors of the hair disc, are now considered to be scarred remnants of fibrofolliculomas [<a class="bibr" href="#bhd.REF.tellechea.2015.780" rid="bhd.REF.tellechea.2015.780">Tellechea et al 2015</a>].</p><p>Additional benign adnexal tumors have been described as achrocordons (skin tags) [<a class="bibr" href="#bhd.REF.toro.2008.321" rid="bhd.REF.toro.2008.321">Toro et al 2008</a>]. Achrocordons are also common skin lesions found in 25% of the general population and are more common in individuals with obesity and/or advanced age. Achrocordons are typically located on the neck, axillae, and larger skin folds. Angiofibromas have also been reported in individuals with BHDS but are more common in individuals with <a href="/books/n/gene/tuberous-sclerosis/?report=reader">tuberous sclerosis</a>. Individuals with BHDS may also develop oral papules (located on the buccal mucosa, tongue, gums, or lips) and cutaneous collagenomas [<a class="bibr" href="#bhd.REF.nadershahi.1997.496" rid="bhd.REF.nadershahi.1997.496">Nadershahi et al 1997</a>, <a class="bibr" href="#bhd.REF.toro.1999.1195" rid="bhd.REF.toro.1999.1195">Toro et al 1999</a>]. Multiple epidermal cysts have been found in approximately 14% of individuals with BHDS [<a class="bibr" href="#bhd.REF.kluger.2010.527" rid="bhd.REF.kluger.2010.527">Kluger et al 2010</a>].</p><p>BHDS has been reported to be associated with cutaneous melanoma, including multiple desmoplastic melanomas [<a class="bibr" href="#bhd.REF.lindor.2001.653" rid="bhd.REF.lindor.2001.653">Lindor et al 2001</a>, <a class="bibr" href="#bhd.REF.khoo.2002.906" rid="bhd.REF.khoo.2002.906">Khoo et al 2002</a>, <a class="bibr" href="#bhd.REF.welsch.2005.668" rid="bhd.REF.welsch.2005.668">Welsch et al 2005</a>, <a class="bibr" href="#bhd.REF.toro.2008.321" rid="bhd.REF.toro.2008.321">Toro et al 2008</a>, <a class="bibr" href="#bhd.REF.cocciolone.2010.1316" rid="bhd.REF.cocciolone.2010.1316">Cocciolone et al 2010</a>, <a class="bibr" href="#bhd.REF.sempau.2010.637" rid="bhd.REF.sempau.2010.637">Sempau et al 2010</a>, <a class="bibr" href="#bhd.REF.motaburgos.2013.323" rid="bhd.REF.motaburgos.2013.323">Mota-Burgos et al 2013</a>, <a class="bibr" href="#bhd.REF.sattler.2018a.e132" rid="bhd.REF.sattler.2018a.e132">Sattler et al 2018a</a>] and choroidal melanoma [<a class="bibr" href="#bhd.REF.fontcuberta.2011.143" rid="bhd.REF.fontcuberta.2011.143">Fontcuberta et al 2011</a>]. In one study an overall rate of 6% was observed for melanoma, which would be significantly higher than the lifetime risk of melanoma in the general population of 1.8%-2.4%. Whether individuals with BHDS are indeed at increased risk of developing melanoma compared to the general population requires further investigation.</p></div><div id="bhd.Pulmonary_Cysts_and_Spontaneous_Pneu"><h4>Pulmonary Cysts and Spontaneous Pneumothorax</h4><p>Lung cysts, located mainly in the basal lung regions (subpleural and intrapulmonary areas), are common in adults with BHDS. The total number of lung cysts per individual ranges from zero to 166 (mean: 16). They are of irregular shape and variable size (1.0-30 mm). The cysts are usually embedded in normal parenchyma that does not exhibit signs of proliferation (as seen in tuberous sclerosis), inflammation (as seen in <a href="/books/n/gene/cf/?report=reader">cystic fibrosis</a>), or matrix deposition (as occurs in amyloidosis).</p><p>With an average age of onset of 30.2 years in females and 38.4 years in males, spontaneous pneumothorax is often the first manifestation in individuals with BHDS (onset range: age 13-69 years). In most individuals the risk of pneumothorax decreases in later adulthood. This could indicate that the formation of lung cysts is a process mainly restricted to younger individuals. Chest CT examination to screen for lung cysts is not feasible in healthy children from families with BHDS; thus, the age at which the lung cysts start to develop is unknown.</p></div><div id="bhd.Renal_Cysts_and_Tumors"><h4>Renal Cysts and Tumors</h4><p>Renal tumors associated with BHDS tend to be bilateral and multifocal, but isolated tumors are also common. The reported overall prevalence of renal tumors among individuals with a germline <i>FLCN</i> pathogenic variant varies between 19% and 35%. These differences may reflect ascertainment bias as well as the inclusion or exclusion of benign renal tumors. No sex differences are observed in the median age of diagnosis (females: 54.5 years, range 37-79 years; males: 57.0 years, range 30-80 years). The median age of onset is well below that of sporadic renal cell carcinoma (61.8 years) [<a class="bibr" href="#bhd.REF.furuya.2016.403" rid="bhd.REF.furuya.2016.403">Furuya et al 2016</a>, <a class="bibr" href="#bhd.REF.sattler.2018b.e0209504" rid="bhd.REF.sattler.2018b.e0209504">Sattler et al 2018b</a>]. Adolescent onset of renal cell carcinoma in individuals with BHDS has been reported [<a class="bibr" href="#bhd.REF.schneider.2018.135" rid="bhd.REF.schneider.2018.135">Schneider et al 2018</a>].</p><p>The most typical renal tumor in BHDS is a hybrid of oncocytoma and chromophobe histologic cell types, the so-called oncocytic hybrid tumor or hybrid oncocytoma/chromophobe tumor. It has been previously described as the most common tumor type in BHDS, but this could be an ascertainment artifact. Other common renal tumor types are clear cell carcinoma and oncocytoma; papillary carcinoma is less common. Discordance of histologic subtypes in bilateral and multifocal tumors is common.</p><p>Multifocal renal oncocytosis, a rare pathologic condition characterized by numerous oncocytic nodules, is found in the renal parenchyma surrounding tumors in 50%-58% of individuals with BHDS [<a class="bibr" href="#bhd.REF.kuroda.2014.93" rid="bhd.REF.kuroda.2014.93">Kuroda et al 2014</a>]. It is still unclear if renal oncocytosis represents a precursor lesion of renal cell carcinoma or a benign condition.</p></div><div id="bhd.Other_Findings"><h4>Other Findings</h4><p><b>Parotid tumors.</b> Parotid oncocytoma has been reported in several individuals with BHDS [<a class="bibr" href="#bhd.REF.toro.2008.321" rid="bhd.REF.toro.2008.321">Toro et al 2008</a>, <a class="bibr" href="#bhd.REF.yoshida.2018.6265175" rid="bhd.REF.yoshida.2018.6265175">Yoshida et al 2018</a>]. Additionally, pleomorphic adenoma [<a class="bibr" href="#bhd.REF.palmirotta.2008.382" rid="bhd.REF.palmirotta.2008.382">Palmirotta et al 2008</a>] and Warthin parotid tumor [<a class="bibr" href="#bhd.REF.maff_.2011.345" rid="bhd.REF.maff_.2011.345">Maffé et al 2011</a>] have been described. Bilateral parotid tumors have been reported in two individuals [<a class="bibr" href="#bhd.REF.maff_.2011.345" rid="bhd.REF.maff_.2011.345">Maffé et al 2011</a>, <a class="bibr" href="#bhd.REF.lindor.2012.13" rid="bhd.REF.lindor.2012.13">Lindor et al 2012</a>]. The frequency and the sometimes 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.</p><p><b>Thyroid pathology.</b> Several instances of thyroid cancer in individuals with BHDS have been reported [<a class="bibr" href="#bhd.REF.toro.2008.321" rid="bhd.REF.toro.2008.321">Toro et al 2008</a>, <a class="bibr" href="#bhd.REF.kunogi.2010.281" rid="bhd.REF.kunogi.2010.281">Kunogi et al 2010</a>, <a class="bibr" href="#bhd.REF.benusiglio.2014a.159" rid="bhd.REF.benusiglio.2014a.159">Benusiglio et al 2014a</a>, <a class="bibr" href="#bhd.REF.dong.2016.e3695" rid="bhd.REF.dong.2016.e3695">Dong et al 2016</a>, <a class="bibr" href="#bhd.REF.p_rez_garc_a.2017.528" rid="bhd.REF.p_rez_garc_a.2017.528">Pérez García et al 2017</a>, <a class="bibr" href="#bhd.REF.panagiotidis.2018.123" rid="bhd.REF.panagiotidis.2018.123">Panagiotidis et al 2018</a>]. Multinodular goiter [<a class="bibr" href="#bhd.REF.drummond.2002.301" rid="bhd.REF.drummond.2002.301">Drummond et al 2002</a>, <a class="bibr" href="#bhd.REF.welsch.2005.668" rid="bhd.REF.welsch.2005.668">Welsch et al 2005</a>], thyroid nodules, and/or cysts have also been reported. In a French series, thyroid nodules and/or cysts were detected by ultrasonography in 13/20 individuals (65%) with BHDS; no medullary carcinoma or other thyroid carcinomas were detected. None of the affected individuals with thyroid nodules and/or cysts had a familial history of thyroid cancer. Overall, individuals with thyroid nodules were found in nine of ten families (90%) with <i>FLCN</i> germline pathogenic variants [<a class="bibr" href="#bhd.REF.kluger.2010.527" rid="bhd.REF.kluger.2010.527">Kluger et al 2010</a>].</p><p><b>Colon cancer.</b>
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<a class="bibr" href="#bhd.REF.hornstein.1975.161" rid="bhd.REF.hornstein.1975.161">Hornstein & Knickenberg [1975]</a> described a family with fibrofolliculoma and colorectal polyps. Hornstein-Knickenberg syndrome is now believed to be identical to BHDS. Several instances of colon cancer or colon polyps have been described in affected individuals and family members [<a class="bibr" href="#bhd.REF.kayhan.2017.632" rid="bhd.REF.kayhan.2017.632">Kayhan et al 2017</a>, <a class="bibr" href="#bhd.REF.motegi.2018.720" rid="bhd.REF.motegi.2018.720">Motegi et al 2018</a>], but the evidence associating colonic neoplasm and BHDS is conflicting. It has been suggested that only certain pathogenic variants are associated with an increased risk for colon cancer, but other studies were not able to confirm this [<a class="bibr" href="#bhd.REF.khoo.2002.906" rid="bhd.REF.khoo.2002.906">Khoo et al 2002</a>, <a class="bibr" href="#bhd.REF.zbar.2002.393" rid="bhd.REF.zbar.2002.393">Zbar et al 2002</a>, <a class="bibr" href="#bhd.REF.nahorski.2010.385" rid="bhd.REF.nahorski.2010.385">Nahorski et al 2010</a>] (see <a href="#bhd.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a> and <a href="#bhd.Molecular_Genetics">Molecular Genetics</a>). Early-onset colon cancer (age >50 years) might be more common in individuals with BHDS compared to the general population [<a class="bibr" href="#bhd.REF.sattler.2021.168" rid="bhd.REF.sattler.2021.168">Sattler et al 2021</a>].</p><p><b>Other tumor types</b> have been reported rarely in individuals with BHDS [<a class="bibr" href="#bhd.REF.tong.2018.87" rid="bhd.REF.tong.2018.87">Tong et al 2018</a>]:</p><ul><li class="half_rhythm"><div><b>Skin.</b> Basal cell carcinoma, dermatofibrosarcoma protuberans, Koenen tumor, squamous cell carcinoma, trichoblastoma</div></li><li class="half_rhythm"><div><b>Soft tissue.</b> Angiolipoma, leiomyoma, leiomyosarcoma, lipoma</div></li><li class="half_rhythm"><div><b>Musculoskeletal.</b> Cardiac rhabdomyoma, fibrosarcoma, osteoma, rhabdomyoma, sarcoma</div></li><li class="half_rhythm"><div><b>Gastrointestinal.</b> Gastric cancer, hepatic cysts, hepatic angioma, peritoneal mesothelioma</div></li><li class="half_rhythm"><div><b>Head and neck.</b> Parathyroid adenoma, squamous cell carcinoma, throat cancer</div></li><li class="half_rhythm"><div><b>Endocrine.</b> Adrenal adenoma, oncocytic adrenal tumor, pheochromocytoma</div></li><li class="half_rhythm"><div><b>Hematologic/lymphatic.</b> Hodgkin lymphoma, leukemia, and non-Hodgkin lymphoma</div></li><li class="half_rhythm"><div><b>Nervous system.</b> Astrocytoma, cerebral hemangioma, choroidal melanoma, meningioma, neurothekeoma, oncocytic pituitary adenoma, schwannoma</div></li><li class="half_rhythm"><div><b>Lung.</b> Adenocarcinoma, bronchoalveolar carcinoma, clear cell sugar tumor, histiocytoma</div></li><li class="half_rhythm"><div><b>Renal/urinary tract.</b> Neuroendocrine tumor, prostate cancer, renal angiomyolipoma</div></li><li class="half_rhythm"><div><b>Reproductive system.</b> Breast cancer including sarcoma, endometrial carcinoma, fibroadenomatosis, uterine cancer</div></li></ul></div></div><div id="bhd.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No genotype-phenotype correlations for <i>FLCN</i> have been confirmed. The following correlations are preliminary:</p><ul><li class="half_rhythm"><div><b>c.1285delC</b> or <b>c.1285dupC.</b> A lower renal tumor frequency was observed in individuals with either of the two most common <i>FLCN</i> pathogenic variants in a study including 50 families [<a class="bibr" href="#bhd.REF.sattler.2018b.e0209504" rid="bhd.REF.sattler.2018b.e0209504">Sattler et al 2018b</a>] (see <a href="/books/NBK1522/table/bhd.T.flcn_pathogenic_variants_reference/?report=objectonly" target="object" rid-ob="figobbhdTflcnpathogenicvariantsreference">Table 7</a>).</div></li><li class="half_rhythm"><div><b>c.1285dupC.</b> Analysis of a subset of 51 families with BHDS demonstrated a significantly higher risk of colorectal neoplasia in those with the common <i>FLCN</i> pathogenic variant c.1285dupC compared to those with the c.610delGCinsTA pathogenic variant [<a class="bibr" href="#bhd.REF.nahorski.2010.385" rid="bhd.REF.nahorski.2010.385">Nahorski et al 2010</a>] (see <a href="/books/NBK1522/table/bhd.T.flcn_pathogenic_variants_reference/?report=objectonly" target="object" rid-ob="figobbhdTflcnpathogenicvariantsreference">Table 7</a>).</div></li></ul></div><div id="bhd.Penetrance"><h3>Penetrance</h3><p>Based on the three major clinical manifestations, penetrance of BHDS is considered to be very high. Up to 97% of individuals with a heterozygous germline <i>FLCN</i> pathogenic variant develop at least one feature of BHDS during their lifetime [<a class="bibr" href="#bhd.REF.bruinsma.2023.317" rid="bhd.REF.bruinsma.2023.317">Bruinsma et al 2023</a>].</p></div><div id="bhd.Nomenclature"><h3>Nomenclature</h3><p>Hornstein-Knickenberg syndrome, which describes familial multiple perifollicular fibromas and fibromata pendulantia [<a class="bibr" href="#bhd.REF.hornstein.1975.161" rid="bhd.REF.hornstein.1975.161">Hornstein & Knickenberg[1975]</a>, is now believed to be identical to BHDS and is thought by some authors to represent the more appropriate designation for the disorder [<a class="bibr" href="#bhd.REF.happle.2020.885" rid="bhd.REF.happle.2020.885">Happle 2020</a>].</p></div><div id="bhd.Prevalence"><h3>Prevalence</h3><p>More than 1,000 affected families from various populations have been described.</p></div></div><div id="bhd.Genetically_Related_Allelic_Disorder"><h2 id="_bhd_Genetically_Related_Allelic_Disorder_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with germline pathogenic variants in <i>FLCN</i>.</p><p><b>Sporadic tumors</b> (including renal cancer and colorectal cancer) occurring as single tumors in the absence of any other findings of Birt-Hogg-Dubé syndrome can contain a somatic variant in <i>FLCN</i> that is not present in the germline. Two missense variants (p.Ala444Ser, p.Ala238Val) have been detected in a sample of 30 renal cancer cell lines. Somatic frameshift variants in the <i>FLCN</i> exon 11 C(8) mononucleotide tract were detected in 23% of sporadic colorectal cancers with microsatellite instability, suggesting that <i>FLCN</i> inactivation could contribute to colorectal tumorigenesis. A non-frameshift deletion and <i>FLCN</i> loss of heterozygosity was found in a pancreatic neuroendocrine tumor [<a class="bibr" href="#bhd.REF.da_silva.2003.820" rid="bhd.REF.da_silva.2003.820">da Silva et al 2003</a>, <a class="bibr" href="#bhd.REF.khoo.2003.4583" rid="bhd.REF.khoo.2003.4583">Khoo et al 2003</a>, <a class="bibr" href="#bhd.REF.nahorski.2010.385" rid="bhd.REF.nahorski.2010.385">Nahorski et al 2010</a>, <a class="bibr" href="#bhd.REF.lawrence.2018.18" rid="bhd.REF.lawrence.2018.18">Lawrence et al 2018</a>]. In these circumstances predisposition to these tumors is not hereditary.</p></div><div id="bhd.Differential_Diagnosis"><h2 id="_bhd_Differential_Diagnosis_">Differential Diagnosis</h2><p>Genes of interest in the differential diagnosis of Birt-Hogg-Dubé syndrome (BHDS) are listed in <a href="/books/NBK1522/table/bhd.T.genes_of_interest_in_the_different/?report=objectonly" target="object" rid-ob="figobbhdTgenesofinterestinthedifferent">Table 3</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figbhdTgenesofinterestinthedifferent"><a href="/books/NBK1522/table/bhd.T.genes_of_interest_in_the_different/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobbhdTgenesofinterestinthedifferent"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="bhd.T.genes_of_interest_in_the_different"><a href="/books/NBK1522/table/bhd.T.genes_of_interest_in_the_different/?report=objectonly" target="object" rid-ob="figobbhdTgenesofinterestinthedifferent">Table 3. </a></h4><p class="float-caption no_bottom_margin">Genes of Interest in the Differential Diagnosis of Birt-Hogg-Dubé Syndrome </p></div></div><p>
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<b>Other conditions to consider in the differential diagnosis of BHDS</b>
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</p><ul><li class="half_rhythm"><div><b>Pulmonary Langerhans cell histiocytosis</b> is a rare, acquired smoking-related interstitial lung condition characterized by abnormal proliferation of histiocytes that predisposes individuals to pneumothorax. Chest radiographs often show micronodular and interstitial pulmonary infiltrates, and individuals may develop pulmonary fibrosis and pulmonary hypertension. These symptoms are not typical for BHDS [<a class="bibr" href="#bhd.REF.yang.2022.22" rid="bhd.REF.yang.2022.22">Yang et al 2022</a>].</div></li><li class="half_rhythm"><div><b>Sporadic pulmonary lymphangioleiomyomatosis (LAM)</b> is a condition characterized by multiple lung cysts and pneumothorax and is usually associated with either tuberous sclerosis (15%) or somatic <i>TSC1</i>/<i>TSC2</i> pathogenic variants. It affects mainly woman of childbearing age. Spontaneous pneumothorax is often the first manifestation. Features atypical for BHDS are an even distribution of cysts throughout the lung, dyspnea on exertion, hemoptysis, and chylothorax.</div></li></ul></div><div id="bhd.Management"><h2 id="_bhd_Management_">Management</h2><p>The following recommendations are based on published practice guidelines [<a class="bibr" href="#bhd.REF.geilswijk.2024" rid="bhd.REF.geilswijk.2024">Geilswijk et al 2024</a>].</p><div id="bhd.Evaluations_Following_Initial_Diagno"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with BHDS, the evaluations summarized in <a href="/books/NBK1522/table/bhd.T.birthoggdub_syndrome_recommended_e/?report=objectonly" target="object" rid-ob="figobbhdTbirthoggdubsyndromerecommendede">Table 4</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figbhdTbirthoggdubsyndromerecommendede"><a href="/books/NBK1522/table/bhd.T.birthoggdub_syndrome_recommended_e/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobbhdTbirthoggdubsyndromerecommendede"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="bhd.T.birthoggdub_syndrome_recommended_e"><a href="/books/NBK1522/table/bhd.T.birthoggdub_syndrome_recommended_e/?report=objectonly" target="object" rid-ob="figobbhdTbirthoggdubsyndromerecommendede">Table 4. </a></h4><p class="float-caption no_bottom_margin">Birt-Hogg-Dubé Syndrome: Recommended Evaluations Following Initial Diagnosis </p></div></div></div><div id="bhd.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see <a href="/books/NBK1522/table/bhd.T.birthoggdub_syndrome_treatment_of/?report=objectonly" target="object" rid-ob="figobbhdTbirthoggdubsyndrometreatmentof">Table 5</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figbhdTbirthoggdubsyndrometreatmentof"><a href="/books/NBK1522/table/bhd.T.birthoggdub_syndrome_treatment_of/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobbhdTbirthoggdubsyndrometreatmentof"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="bhd.T.birthoggdub_syndrome_treatment_of"><a href="/books/NBK1522/table/bhd.T.birthoggdub_syndrome_treatment_of/?report=objectonly" target="object" rid-ob="figobbhdTbirthoggdubsyndrometreatmentof">Table 5. </a></h4><p class="float-caption no_bottom_margin">Birt-Hogg-Dubé Syndrome: Treatment of Manifestations </p></div></div></div><div id="bhd.Surveillance"><h3>Surveillance</h3><p>The recommendations summarized in <a href="/books/NBK1522/table/bhd.T.birthoggdub_syndrome_recommended_s/?report=objectonly" target="object" rid-ob="figobbhdTbirthoggdubsyndromerecommendeds">Table 6</a> are based on the current clinical practice guidelines [<a class="bibr" href="#bhd.REF.geilswijk.2024" rid="bhd.REF.geilswijk.2024">Geilswijk et al 2024</a>].</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figbhdTbirthoggdubsyndromerecommendeds"><a href="/books/NBK1522/table/bhd.T.birthoggdub_syndrome_recommended_s/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobbhdTbirthoggdubsyndromerecommendeds"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="bhd.T.birthoggdub_syndrome_recommended_s"><a href="/books/NBK1522/table/bhd.T.birthoggdub_syndrome_recommended_s/?report=objectonly" target="object" rid-ob="figobbhdTbirthoggdubsyndromerecommendeds">Table 6. </a></h4><p class="float-caption no_bottom_margin">Birt-Hogg-Dubé Syndrome: Recommended Surveillance </p></div></div></div><div id="bhd.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Avoid the following:</p><ul><li class="half_rhythm"><div>Cigarette smoking</div></li><li class="half_rhythm"><div>High ambient pressures, which may precipitate spontaneous pneumothorax. Air travel increases pneumothorax risk [<a class="bibr" href="#bhd.REF.johannesma.2016.1506" rid="bhd.REF.johannesma.2016.1506">Johannesma et al 2016</a>, <a class="bibr" href="#bhd.REF.gupta.2017.706" rid="bhd.REF.gupta.2017.706">Gupta et al 2017</a>].</div></li><li class="half_rhythm"><div>Radiation exposure</div></li></ul></div><div id="bhd.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to evaluate apparently asymptomatic at-risk sibs, parents, and relatives of individuals with BHDS in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include:</p><ul><li class="half_rhythm"><div>Molecular genetic testing if the familial <i>FLCN</i> pathogenic variant is known (use of molecular genetic testing for a known familial <i>FLCN</i> pathogenic variant improves diagnostic certainty and reduces costly screening procedures in at-risk members who have not inherited the pathogenic variant);</div></li><li class="half_rhythm"><div>Screening for lung cysts, fibrofolliculomas, and trichodiscomas if the pathogenic variant in the family is not known.</div></li></ul><p>Genetic testing should be considered in family members of a proband with BHDS starting at age 18 years [<a class="bibr" href="#bhd.REF.geilswijk.2024" rid="bhd.REF.geilswijk.2024">Geilswijk et al 2024</a>]. However, in families with a history of juvenile or adolescent onset of manifestations and/or hobbies (e.g., scuba diving [<a class="bibr" href="#bhd.REF.van_riel.2023.1003" rid="bhd.REF.van_riel.2023.1003">van Riel et al 2023</a>]) or career plans involving potentially increased risks for pneumothorax, testing may be recommended at an earlier age.</p><p>See <a href="#bhd.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="bhd.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe 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.</p></div></div><div id="bhd.Genetic_Counseling"><h2 id="_bhd_Genetic_Counseling_">Genetic Counseling</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><div id="bhd.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Birt-Hogg-Dubé syndrome (BHDS) is inherited in an autosomal dominant manner.</p></div><div id="bhd.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>Most individuals diagnosed with BHDS have an affected parent.</div></li><li class="half_rhythm"><div>Some individuals diagnosed with BHDS have the disorder as a result of a <i>de novo</i> pathogenic variant. The percentage of individuals with BHDS caused by a <i>de novo</i> pathogenic variant is unknown but is most likely in the lower single-digit range.</div></li><li class="half_rhythm"><div>If an <i>FLCN</i> pathogenic variant has been identified in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and assess their need for clinical evaluation and surveillance. Note: A proband may appear to be the only affected family member 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. Therefore, <i>de novo</i> occurrence of an <i>FLCN</i> pathogenic variant in the proband cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has the <i>FLCN</i> pathogenic variant.</div></li><li class="half_rhythm"><div>If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>The proband has a <i>de novo</i> pathogenic variant.</div></li><li class="half_rhythm"><div>The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. (Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ [gonadal] cells only.)</div></li></ul></li><li class="half_rhythm"><div>If a molecular diagnosis has not been established in the proband, the parents should be offered screening for common BHDS manifestations (i.e., lung cysts, fibrofolliculomas, and trichodiscomas).</div></li></ul><p><b>Sibs of a proband.</b> The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:</p><ul><li class="half_rhythm"><div>If a parent of a proband is clinically affected and/or is known to have the <i>FLCN</i> pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%.</div></li><li class="half_rhythm"><div>The degree of clinical severity in sibs who inherit an <i>FLCN</i> pathogenic variant cannot be predicted; significant clinical variability has been observed among affected family members.</div></li><li class="half_rhythm"><div>If the proband has a known <i>FLCN</i> pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [<a class="bibr" href="#bhd.REF.rahbari.2016.126" rid="bhd.REF.rahbari.2016.126">Rahbari et al 2016</a>].</div></li><li class="half_rhythm"><div>If the parents are clinically unaffected but their genetic status is known, sibs are still presumed to be at increased risk for BHDS because of the possibility of reduced penetrance in a parent and the possibility of parental gonadal mosaicism.</div></li></ul><p><b>Offspring of a proband.</b> Each child of an individual with BHDS is at a 50% risk of inheriting the <i>FLCN</i> pathogenic variant.</p><p><b>Other family members.</b> The risk to other family members depends on the status of the proband's parents: if a parent has the <i>FLCN</i> pathogenic variant, the parent's family members may be at risk.</p></div><div id="bhd.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#bhd.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p>
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<b>Predictive testing (i.e., testing of asymptomatic at-risk individuals)</b>
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</p><ul><li class="half_rhythm"><div>Predictive testing for at-risk family members is possible once an <i>FLCN</i> pathogenic variant has been identified in an affected family member.</div></li><li class="half_rhythm"><div>Molecular genetic testing of at-risk family members is appropriate in order to identify the need for continued lifelong clinical surveillance. Individuals who have the <i>FLCN</i> 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 and can be discharged from surveillance for BHDS-related manifestations.</div></li></ul><p>In a family with an established diagnosis of BHDS, it is appropriate to consider testing of symptomatic individuals regardless of age.</p><p>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>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.</div></li></ul><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see <a class="bibr" href="#bhd.REF.huang.2022.389" rid="bhd.REF.huang.2022.389">Huang et al [2022]</a>.</p></div><div id="bhd.Prenatal_Testing_and_Preimplantation"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>FLCN</i> pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for BHDS are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="bhd.Resources"><h2 id="_bhd_Resources_">Resources</h2><p>
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<i>GeneReviews staff has selected the following disease-specific and/or umbrella
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support organizations and/or registries for the benefit of individuals with this disorder
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and their families. GeneReviews is not responsible for the information provided by other
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organizations. For information on selection criteria, click <a href="/books/n/gene/app4/?report=reader">here</a>.</i></p>
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<ul><li class="half_rhythm"><div>
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<b>BHD Foundation</b>
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</div><div>London </div><div>United Kingdom</div><div>
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<a href="https://www.bhdsyndrome.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">bhdsyndrome.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Kidney Cancer Association</b>
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</div><div><b>Phone:</b> 800-850-9132</div><div><b>Email:</b> office@kidneycancer.org</div><div>
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<a href="http://www.kidneycancer.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">kidneycancer.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>MedlinePlus</b>
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</div><div>
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<a href="https://medlineplus.gov/genetics/condition/birt-hogg-dube-syndrome/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Birt-Hogg-Dubé syndrome</a>
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</div></li></ul>
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</div><div id="bhd.Molecular_Genetics"><h2 id="_bhd_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figbhdmolgenTA"><a href="/books/NBK1522/table/bhd.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobbhdmolgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="bhd.molgen.TA"><a href="/books/NBK1522/table/bhd.molgen.TA/?report=objectonly" target="object" rid-ob="figobbhdmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">Birt-Hogg-Dube Syndrome: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figbhdmolgenTB"><a href="/books/NBK1522/table/bhd.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobbhdmolgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="bhd.molgen.TB"><a href="/books/NBK1522/table/bhd.molgen.TB/?report=objectonly" target="object" rid-ob="figobbhdmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for Birt-Hogg-Dube Syndrome (View All in OMIM) </p></div></div><div id="bhd.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p>The tumor suppressor gene responsible for Birt-Hogg-Dubé syndrome (BHDS), <i>FLCN</i>, encodes the protein folliculin (FLCN). FLCN is ubiquitously expressed, evolutionarily highly conserved, and believed to control several important pathways of cell physiology. It was shown to act as a cytoplasmic guanine exchange factor and has been linked to different signaling pathways that are crucial for both tumorigenesis and normal cellular metabolism, including mTOR, AMPK, EGFR signaling, and HIF1α [<a class="bibr" href="#bhd.REF.yan.2014.2640" rid="bhd.REF.yan.2014.2640">Yan et al 2014</a>, <a class="bibr" href="#bhd.REF.laviolette.2017.15866" rid="bhd.REF.laviolette.2017.15866">Laviolette et al 2017</a>, <a class="bibr" href="#bhd.REF.haley.2018.e1007558" rid="bhd.REF.haley.2018.e1007558">Haley et al 2018</a>, <a class="bibr" href="#bhd.REF.zhao.2018.jcs218792" rid="bhd.REF.zhao.2018.jcs218792">Zhao et al 2018</a>, <a class="bibr" href="#bhd.REF.collodet.2019.12374" rid="bhd.REF.collodet.2019.12374">Collodet et al 2019</a>, <a class="bibr" href="#bhd.REF.mart_nezcarreres.2019.5245" rid="bhd.REF.mart_nezcarreres.2019.5245">Martínez-Carreres et al 2019</a>]. FLCN appears to have various roles, participating in (among others) ciliogenesis, autophagy, and lysosomal biogenesis. Several interacting proteins have been identified, including FLCN interacting proteins 1 and 2 (FNIP1/FNIP2), TOR signaling pathway regulator (TIPRL), SIN1, and Rag GTPase. In amino acid-starved cells the FLCN-FNIP complex is recruited to lysosomes, a nutrient-dependent mechanism controlled by GATOR1 and RagA/B GAP [<a class="bibr" href="#bhd.REF.meng.2018.2765" rid="bhd.REF.meng.2018.2765">Meng & Ferguson 2018</a>]. This enables FLCN to control the amino acid-dependent activation of mTOR, a key process both in a physiologic cell state and in tumorigenesis. FLCN also appears to have a context-dependent role in the exit of cells from pluripotency, another mechanism that can become important in tumor development [<a class="bibr" href="#bhd.REF.mathieu.2019.632" rid="bhd.REF.mathieu.2019.632">Mathieu et al 2019</a>].</p><p><b>Mechanism of disease causation.</b> Loss of function</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figbhdTflcnpathogenicvariantsreference"><a href="/books/NBK1522/table/bhd.T.flcn_pathogenic_variants_reference/?report=objectonly" target="object" title="Table 7. " class="img_link icnblk_img" rid-ob="figobbhdTflcnpathogenicvariantsreference"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="bhd.T.flcn_pathogenic_variants_reference"><a href="/books/NBK1522/table/bhd.T.flcn_pathogenic_variants_reference/?report=objectonly" target="object" rid-ob="figobbhdTflcnpathogenicvariantsreference">Table 7. </a></h4><p class="float-caption no_bottom_margin"><i>FLCN</i> Pathogenic Variants Referenced in This <i>GeneReview</i> </p></div></div></div></div><div id="bhd.Chapter_Notes"><h2 id="_bhd_Chapter_Notes_">Chapter Notes</h2><div id="bhd.Author_History"><h3>Author History</h3><p>Manop Pithukpakorn, MD; Mahidol University (2006-2008)<br />Elke C Sattler, MD (2020-present)<br />Ortrud K Steinlein, MD (2020-present)<br />Jorge R Toro, MD; National Cancer Institute, NIH (2006-2020)</p></div><div id="bhd.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>5 December 2024 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>30 January 2020 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>7 August 2014 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>9 September 2008 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>27 February 2006 (me) Review posted live</div></li><li class="half_rhythm"><div>30 November 2005 (jt) Original submission</div></li></ul></div></div><div id="bhd.References"><h2 id="_bhd_References_">References</h2><div id="bhd.Published_Guidelines__Consensus_Stat"><h3>Published Guidelines / Consensus Statements</h3><ul class="simple-list"><li class="half_rhythm"><div>American Society of Clinical Oncology. 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[<a href="https://pubmed.ncbi.nlm.nih.gov/30446510" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30446510</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1522_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Elke C Sattler</span>, MD<div class="affiliation small">Department of Dermatology and Allergology<br />University Hospital<br />LMU Munich<br />Munich, Germany<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ed.nehcneum-inu.dem@relttas.ekle" class="oemail">ed.nehcneum-inu.dem@relttas.ekle</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Ortrud K Steinlein</span>, MD<div class="affiliation small">Institute of Human Genetics<br />University Hospital<br />LMU Munich<br />Munich, Germany<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ed.nehcneum-inu.dem@nielniets.durtro" class="oemail">ed.nehcneum-inu.dem@nielniets.durtro</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">February 27, 2006</span>; Last Update: <span itemprop="dateModified">December 5, 2024</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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a registered trademark of the University of Washington, Seattle. All rights
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reserved.<p class="small">GeneReviews® chapters are owned by the University of Washington. Permission is
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hereby granted to reproduce, distribute, and translate copies of content materials for
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Washington) are included with each copy; (ii) a link to the original material is provided
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whenever the material is published elsewhere on the Web; and (iii) reproducers,
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use.</p><p class="small">For more information, see the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
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Disclaimer</a>.</p><p class="small">For questions regarding permissions or whether a specified use is allowed,
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Sattler EC, Steinlein OK. Birt-Hogg-Dubé Syndrome. 2006 Feb 27 [Updated 2024 Dec 5]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gene/biotin/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/bpes/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobbhdTmoleculargenetictestingusedin"><div id="bhd.T.molecular_genetic_testing_used_in" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Birt-Hogg-Dubé Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1522/table/bhd.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__bhd.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_bhd.T.molecular_genetic_testing_used_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_bhd.T.molecular_genetic_testing_used_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Proportion of BHDS Attributed to Pathogenic Variants in Gene</th><th id="hd_h_bhd.T.molecular_genetic_testing_used_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_bhd.T.molecular_genetic_testing_used_in_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Identified by Method</th></tr></thead><tbody><tr><td headers="hd_h_bhd.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>FLCN</i>
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</td><td headers="hd_h_bhd.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">96%</td><td headers="hd_h_bhd.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_bhd.T.molecular_genetic_testing_used_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~88%-96% <sup>4, 5</sup></td></tr><tr><td headers="hd_h_bhd.T.molecular_genetic_testing_used_in_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>6</sup></td><td headers="hd_h_bhd.T.molecular_genetic_testing_used_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><8% <sup>4</sup></td></tr><tr><td headers="hd_h_bhd.T.molecular_genetic_testing_used_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown</td><td headers="hd_h_bhd.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~4% <sup>4</sup></td><td headers="hd_h_bhd.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_bhd.T.molecular_genetic_testing_used_in_1_1_1_4" colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;">NA</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">BHDS = Birt-Hogg-Dubé syndrome; NA = not applicable</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="bhd.TF.1.1"><p class="no_margin">See <a href="/books/NBK1522/?report=reader#bhd.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="bhd.TF.1.2"><p class="no_margin">See <a href="#bhd.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="bhd.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="bhd.TF.1.4"><p class="no_margin"><a class="bibr" href="#bhd.REF.schmidt.2005.1023" rid="bhd.REF.schmidt.2005.1023">Schmidt et al [2005]</a>, <a class="bibr" href="#bhd.REF.toro.2008.321" rid="bhd.REF.toro.2008.321">Toro et al [2008]</a>, <a class="bibr" href="#bhd.REF.sattler.2018b.e0209504" rid="bhd.REF.sattler.2018b.e0209504">Sattler et al [2018b]</a>, and data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bibr" href="#bhd.REF.stenson.2020.1197" rid="bhd.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="bhd.TF.1.5"><p class="no_margin">20%-24% 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 <a href="/books/NBK1522/table/bhd.T.flcn_pathogenic_variants_reference/?report=objectonly" target="object" rid-ob="figobbhdTflcnpathogenicvariantsreference">Table 7</a>) [<a class="bibr" href="#bhd.REF.sattler.2018b.e0209504" rid="bhd.REF.sattler.2018b.e0209504">Sattler et al 2018b</a>].</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="bhd.TF.1.6"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobbhdTbirthoggdubsyndromefrequencyof"><div id="bhd.T.birthoggdub_syndrome_frequency_of" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Birt-Hogg-Dubé Syndrome: Frequency of Select Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1522/table/bhd.T.birthoggdub_syndrome_frequency_of/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__bhd.T.birthoggdub_syndrome_frequency_of_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_bhd.T.birthoggdub_syndrome_frequency_of_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_bhd.T.birthoggdub_syndrome_frequency_of_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Persons w/Feature<br />(lifetime risk)</th><th id="hd_h_bhd.T.birthoggdub_syndrome_frequency_of_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_bhd.T.birthoggdub_syndrome_frequency_of_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cutaneous manifestations (e.g., fibrofolliculoma, acrochordons)</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_frequency_of_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">87%-97% <sup>1</sup></td><td headers="hd_h_bhd.T.birthoggdub_syndrome_frequency_of_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cutaneous manifestations are unusual in persons age <20 yrs.</td></tr><tr><td headers="hd_h_bhd.T.birthoggdub_syndrome_frequency_of_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pulmonary cysts</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_frequency_of_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">70%-85% <sup>2</sup></td><td headers="hd_h_bhd.T.birthoggdub_syndrome_frequency_of_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">The age when cysts start to appear is unknown; childhood onset is likely.</td></tr><tr><td headers="hd_h_bhd.T.birthoggdub_syndrome_frequency_of_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Spontaneous recurrent pneumothorax</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_frequency_of_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">24%-48% <sup>3</sup></td><td headers="hd_h_bhd.T.birthoggdub_syndrome_frequency_of_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_bhd.T.birthoggdub_syndrome_frequency_of_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Renal cell carcinoma</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_frequency_of_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15%-30% <sup>4, 5</sup></td><td headers="hd_h_bhd.T.birthoggdub_syndrome_frequency_of_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="bhd.TF.2.1"><p class="no_margin"><a class="bibr" href="#bhd.REF.schmidt.2015.558" rid="bhd.REF.schmidt.2015.558">Schmidt & Linehan [2015]</a>, <a class="bibr" href="#bhd.REF.bruinsma.2023.317" rid="bhd.REF.bruinsma.2023.317">Bruinsma et al [2023]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="bhd.TF.2.2"><p class="no_margin">
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<a class="bibr" href="#bhd.REF.kunogi.2010.281" rid="bhd.REF.kunogi.2010.281">Kunogi et al [2010]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="bhd.TF.2.3"><p class="no_margin">
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<a class="bibr" href="#bhd.REF.zbar.2002.393" rid="bhd.REF.zbar.2002.393">Zbar et al [2002]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="bhd.TF.2.4"><p class="no_margin">
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<a class="bibr" href="#bhd.REF.houweling.2011.1912" rid="bhd.REF.houweling.2011.1912">Houweling et al [2011]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="bhd.TF.2.5"><p class="no_margin">
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<a class="bibr" href="#bhd.REF.bruinsma.2023.317" rid="bhd.REF.bruinsma.2023.317">Bruinsma et al [2023]</a>
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</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobbhdTgenesofinterestinthedifferent"><div id="bhd.T.genes_of_interest_in_the_different" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Genes of Interest in the Differential Diagnosis of Birt-Hogg-Dubé Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1522/table/bhd.T.genes_of_interest_in_the_different/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__bhd.T.genes_of_interest_in_the_different_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_1" style="text-align:left;vertical-align:middle;">Phenotype</th><th id="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_2" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_3" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_4" rowspan="2" scope="col" colspan="1" headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_4" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Key Features of Disorder</th></tr><tr><th headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5" id="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/BHDS</th><th headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5" id="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from BHDS</th></tr></thead><tbody><tr><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cutaneous manifestations <sup>1</sup></b>
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>CYLD</i> <sup>2</sup></td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multiple familial trichoepithelioma (See <a href="/books/n/gene/cyld-cs/?report=reader"><i>CYLD</i> Cutaneous Syndrome</a>.)</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cutaneous manifestations may appear similar on clinical exam.</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Trichoepitheliomas (must be distinguished histopathologically)</td></tr><tr><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<i>MEN1</i>
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/men1/?report=reader">Multiple endocrine neoplasia type 1</a>
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Facial angiofibromas & collagenomas</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ependymomas, meningiomas</td></tr><tr><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<i>PTEN</i>
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cowden syndrome (See <a href="/books/n/gene/phts/?report=reader"><i>PTEN</i> Hamartoma Tumor Syndrome</a>.)</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Uterine & renal cancers</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Trichilemmomas, acral keratoses (must be distinguished histopathologically), mucosal lesions</td></tr><tr><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_1" rowspan="5" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Lung cysts &/or pneumothorax</b>
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CFTR</i>
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/cf/?report=reader">Cystic fibrosis</a>
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Only lung cysts</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Progressive obstructive lung disease w/bronchiectasis & inflammation</td></tr><tr><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<i>COL3A1</i>
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/eds4/?report=reader">Vascular Ehlers-Danlos syndrome</a>
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD<br />(AR)</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Only lung cysts</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Spontaneous pneumothoraces may be 1st significant presenting feature; hemothorax, hemopneumothorax, pulmonary blebs, cystic lesions, & hemorrhagic or fibrous nodules</td></tr><tr><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<i>FBN1</i>
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/marfan/?report=reader"><i>FBN1</i>-related Marfan syndrome</a>
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lung cysts & spontaneous pneumothorax</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lung bullae typically in upper lobes</td></tr><tr><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<i>SERPINA1</i>
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/alpha1-a/?report=reader">Alpha-1 antitrypsin deficiency</a>
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 3.</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Only lung cysts</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Chronic obstructive pulmonary disease; emphysema, sometimes w/bronchiectasis</td></tr><tr><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<i>TSC1</i>
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<br />
|
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<i>TSC2</i>
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/tuberous-sclerosis/?report=reader">Tuberous sclerosis complex</a>
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lung cysts & skin papules (facial angiofibromas)</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Additional skin lesions: hypomelanotic macules, confetti skin lesions, shagreen patches, fibrous cephalic plaques, ungual fibromas; pulmonary lymphangioleiomyomatosis</td></tr><tr><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_1" rowspan="6" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Renal cancer <sup>4</sup></b>
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>BAP1</i>
|
|
</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/bap1-tpds/?report=reader"><i>BAP1</i> tumor predisposition syndrome</a>
|
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Various types of RCC, cutaneous melanoma</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mesothelioma, uveal melanoma</td></tr><tr><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<i>FH</i>
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<a href="/books/n/gene/hlrcc/?report=reader"><i>FH</i> tumor predisposition syndrome</a>
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</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Various types of renal cancer, cutaneous leiomyoma, uterine fibroids</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Renal tumors are usually solitary & less likely to be oncocytoma or chromophobe type.</td></tr><tr><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<i>MAX</i>
|
|
<br />
|
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<i>SDHA</i>
|
|
<br />
|
|
<i>SDHAF2</i>
|
|
<br />
|
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<i>SDHB</i>
|
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<br />
|
|
<i>SDHC</i>
|
|
<br />
|
|
<i>SDHD</i>
|
|
<br />
|
|
<i>TMEM127</i>
|
|
</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<a href="/books/n/gene/paragangliomas/?report=reader">Hereditary paraganglioma-pheochromocytoma syndromes</a>
|
|
</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↑ risk for paragangliomas, pheochromocytomas, & RCCs incl oncocytic renal tumors</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gastrointestinal stromal tumors</td></tr><tr><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
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<i>MET</i>
|
|
</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hereditary papillary renal cancer (OMIM <a href="https://omim.org/entry/605074" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">605074</a>)</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Bilateral & multifocal type 1 papillary RCC</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<i>PTEN</i>
|
|
</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cowden syndrome (See <a href="/books/n/gene/phts/?report=reader"><i>PTEN</i> Hamartoma Tumor Syndrome</a>.)</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Uterine & renal cancers, skin papules</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Benign hamartomas & ↑ risks of breast, thyroid, & other cancers; other dermatologic features (e.g., lipomas, trichilemmomas, oral papillomas, penile freckling)</td></tr><tr><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<i>VHL</i>
|
|
</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/vhl/?report=reader">Von Hippel-Lindau syndrome</a>
|
|
</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Bilateral & multifocal clear cell RCC; ↑ risk for pheochromocytoma</td><td headers="hd_h_bhd.T.genes_of_interest_in_the_different_1_1_1_5 hd_h_bhd.T.genes_of_interest_in_the_different_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↑ risk for CNS hemangioblastoma, retinal angioma, & endolymphatic sac tumors</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; AR = autosomal recessive; BHDS = Birt-Hogg-Dubé syndrome; CNS = central nervous system; MOI = mode of inheritance; RCC = renal cell carcinoma</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="bhd.TF.3.1"><p class="no_margin">Fibrofolliculomas are rare and specific for 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.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="bhd.TF.3.2"><p class="no_margin">Multiple familial trichoepithelioma 1 is caused by pathogenic variants in <a href="/books/n/gene/cyld-cs/?report=reader"><i>CYLD</i></a>; the genetic basis of multiple familial trichoepithelioma 2 is unknown (OMIM <a href="https://omim.org/entry/612099" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">612099</a>).</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="bhd.TF.3.3"><p class="no_margin">Alpha-1 antitrypsin deficiency is inherited in an autosomal codominant manner.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="bhd.TF.3.4"><p class="no_margin">Most syndromes with an increased risk of renal cancer are associated with renal pathology that is distinct from that seen in individuals with BHDS-related renal tumors [<a class="bibr" href="#bhd.REF.benusiglio.2014b.163" rid="bhd.REF.benusiglio.2014b.163">Benusiglio et al 2014b</a>].</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobbhdTbirthoggdubsyndromerecommendede"><div id="bhd.T.birthoggdub_syndrome_recommended_e" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Birt-Hogg-Dubé Syndrome: Recommended Evaluations Following Initial Diagnosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1522/table/bhd.T.birthoggdub_syndrome_recommended_e/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__bhd.T.birthoggdub_syndrome_recommended_e_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_bhd.T.birthoggdub_syndrome_recommended_e_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_bhd.T.birthoggdub_syndrome_recommended_e_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_bhd.T.birthoggdub_syndrome_recommended_e_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_e_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Integument</b>
|
|
</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_e_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Detailed dermatologic exam</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_e_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Beginning at age 20 yrs</td></tr><tr><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_e_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Pulmonary</b>
|
|
</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_e_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Discuss avoiding activities that might ↑ pneumothorax risk (e.g., working as a pilot, flying in unpressurized aircraft, diving)</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_e_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_e_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">HRCT or CT of chest for visualization of pulmonary cysts & evidence for pneumothorax</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_e_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>In adults at diagnosis</div></li><li class="half_rhythm"><div>Note: Persons w/manifestations of pneumothorax should immediately undergo chest radiograph & chest CT.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_e_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Renal</b>
|
|
</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_e_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Abdominal/pelvic MRI to screen for renal tumor(s)</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_e_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Beginning at age 20 yrs</td></tr><tr><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_e_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Genetic counseling</b>
|
|
</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_e_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_e_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of BHDS to facilitate medical & personal decision making</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">BHDS = Birt-Hogg-Dubé syndrome; HRCT = high-resolution computed tomography; MOI = mode of inheritance</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="bhd.TF.4.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobbhdTbirthoggdubsyndrometreatmentof"><div id="bhd.T.birthoggdub_syndrome_treatment_of" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Birt-Hogg-Dubé Syndrome: Treatment of Manifestations</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1522/table/bhd.T.birthoggdub_syndrome_treatment_of/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__bhd.T.birthoggdub_syndrome_treatment_of_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_bhd.T.birthoggdub_syndrome_treatment_of_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_bhd.T.birthoggdub_syndrome_treatment_of_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_bhd.T.birthoggdub_syndrome_treatment_of_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_bhd.T.birthoggdub_syndrome_treatment_of_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Fibrofolliculomas</b>
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</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_treatment_of_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Fibrofolliculomas are benign lesions for which no treatment is required; however, affected persons may seek treatment for cosmetic purposes, particularly for facial lesions.</div></li><li class="half_rhythm"><div>Surgical & laser treatment can provide temporary improvement, but lesions often recur. <sup>1</sup></div></li></ul>
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</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_treatment_of_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Topical treatment of fibrofolliculomas w/mTOR inhibitor rapamycin in persons w/BHDS in a double-blinded placebo-controlled randomized split-face study showed no effect. <sup>2</sup></td></tr><tr><td headers="hd_h_bhd.T.birthoggdub_syndrome_treatment_of_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Lung cysts</b>
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</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_treatment_of_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Often no treatment is needed.</div></li><li class="half_rhythm"><div>Some persons develop mild signs of airway obstruction, which are treated conservatively.</div></li></ul>
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</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_treatment_of_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_bhd.T.birthoggdub_syndrome_treatment_of_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Pneumothorax</b>
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</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_treatment_of_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per pulmonologist</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_treatment_of_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Surgical intervention should be considered for recurrent pneumothoraces.</td></tr><tr><td headers="hd_h_bhd.T.birthoggdub_syndrome_treatment_of_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Renal tumors</b>
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</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_treatment_of_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><b>Renal tumors <3.0 cm in diameter:</b> Monitor w/imaging.</div></li><li class="half_rhythm"><div><b>At least 1 renal tumor ≥3.0 cm:</b> Eval by urologic surgeon. Nephron-sparing surgery of tumors should be used whenever possible. Rapidly growing lesions, pain, hematuria, or atypical presentations require a more individualized approach. PET-CT scan is an option for eval of these lesions.</div></li></ul>
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</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_treatment_of_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>It is crucial to detect renal tumors before they exceed 3.0 cm in diameter because nephron-sparing surgery is the treatment of choice whenever possible, depending on size & location of tumors. <sup>3</sup></div></li><li class="half_rhythm"><div>It has been previously reported that renal tumors in BHDS tend to be slow growing & metastasize late. This is most likely not accurate for all tumor subtypes, & metastatic disease has been reported in several persons. <sup>4</sup></div></li></ul>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">BHDS = Birt-Hogg-Dubé syndrome</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="bhd.TF.5.1"><p class="no_margin"><a class="bibr" href="#bhd.REF.gambichler.2000.856" rid="bhd.REF.gambichler.2000.856">Gambichler et al [2000]</a>, <a class="bibr" href="#bhd.REF.jacob.2001.98" rid="bhd.REF.jacob.2001.98">Jacob & Dover [2001]</a>, <a class="bibr" href="#bhd.REF.kahle.2001.43" rid="bhd.REF.kahle.2001.43">Kahle et al [2001]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="bhd.TF.5.2"><p class="no_margin">
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<a class="bibr" href="#bhd.REF.gijezen.2014.e99071" rid="bhd.REF.gijezen.2014.e99071">Gijezen et al [2014]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="bhd.TF.5.3"><p class="no_margin">
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<a class="bibr" href="#bhd.REF.johannesma.2019.e0212952" rid="bhd.REF.johannesma.2019.e0212952">Johannesma et al [2019]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="bhd.TF.5.4"><p class="no_margin">
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<a class="bibr" href="#bhd.REF.houweling.2011.1912" rid="bhd.REF.houweling.2011.1912">Houweling et al [2011]</a>
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</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobbhdTbirthoggdubsyndromerecommendeds"><div id="bhd.T.birthoggdub_syndrome_recommended_s" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Birt-Hogg-Dubé Syndrome: Recommended Surveillance</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1522/table/bhd.T.birthoggdub_syndrome_recommended_s/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__bhd.T.birthoggdub_syndrome_recommended_s_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_bhd.T.birthoggdub_syndrome_recommended_s_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_bhd.T.birthoggdub_syndrome_recommended_s_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_bhd.T.birthoggdub_syndrome_recommended_s_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_s_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Lung cysts / Pneumothoraces</b>
|
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</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_s_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Assess for pulmonary signs/symptoms of lung cysts / pneumothorax.</div></li><li class="half_rhythm"><div>Discuss avoidance of activities that might ↑ pneumothorax risk (e.g., working as a pilot, flying in unpressurized aircraft, diving)</div></li></ul>
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</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_s_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_s_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Lung CT</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_s_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Only as needed</div></li><li class="half_rhythm"><div>No routine screening in those w/o signs/symptoms to avoid cumulative radiation exposure</div></li></ul>
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</td></tr><tr><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_s_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Renal tumors</b>
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</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_s_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Abdominal/pelvic MRI is optimal. <sup>1</sup></div></li><li class="half_rhythm"><div>Abdominal/pelvic CT w/contrast (if MRI is not an option) <sup>2</sup></div></li></ul>
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</td><td headers="hd_h_bhd.T.birthoggdub_syndrome_recommended_s_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Annually starting at age 20 yrs <sup>3</sup></div></li><li class="half_rhythm"><div>Continue annually in those w/suspicious lesion(s) (<1.0 cm in diameter, indeterminate lesion, or complex cysts)</div></li><li class="half_rhythm"><div>In those w/o family history of renal tumors, after 2-3 consecutive normal MRIs, continue screening every 2 yrs <sup>4</sup></div></li></ul>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="bhd.TF.6.1"><p class="no_margin">The use of renal ultrasound examination is helpful in further characterization of kidney lesions but should not be used as a primary screening modality due to its unreliability in detecting tumors <3 cm in diameter [<a class="bibr" href="#bhd.REF.johannesma.2019.e0212952" rid="bhd.REF.johannesma.2019.e0212952">Johannesma et al 2019</a>]. Renal ultrasound can be considered in the 12-month interval between MRI screenings.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="bhd.TF.6.2"><p class="no_margin">The long-term effect of cumulative radiation exposure in individuals with BHDS is unknown and has not been studied.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="bhd.TF.6.3"><p class="no_margin">Surveillance can start earlier in those with a family history of renal tumors before age 30 years.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="bhd.TF.6.4"><p class="no_margin">According to the 3 cm rule used by surgeons in treating renal tumors [<a class="bibr" href="#bhd.REF.pavlovich.2005.1482" rid="bhd.REF.pavlovich.2005.1482">Pavlovich et al 2005</a>], affected individuals without a family history of renal tumors who have had two to three consecutive annual MRI examinations without the detection of renal lesions may be screened every two years until a suspicious lesion is identified.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobbhdmolgenTA"><div id="bhd.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Birt-Hogg-Dube Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1522/table/bhd.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__bhd.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_bhd.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_bhd.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_bhd.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_bhd.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_bhd.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_bhd.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_bhd.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<a href="/gene/201163" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>FLCN</i>
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</a>
|
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</td><td headers="hd_b_bhd.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=201163" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">17p11<wbr style="display:inline-block"></wbr>​.2</a>
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</td><td headers="hd_b_bhd.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/Q8NFG4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Folliculin</a>
|
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</td><td headers="hd_b_bhd.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<a href="http://www.LOVD.nl/FLCN" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Folliculin (FLCN) @ LOVD</a>
|
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</td><td headers="hd_b_bhd.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=FLCN" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FLCN</a>
|
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</td><td headers="hd_b_bhd.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=FLCN[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FLCN</a>
|
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="bhd.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
|
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
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chromosome locus from
|
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
|
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
|
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
|
<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobbhdmolgenTB"><div id="bhd.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Birt-Hogg-Dube Syndrome (<a href="/omim/135150,607273" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1522/table/bhd.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__bhd.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<a href="/omim/135150" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">135150</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">BIRT-HOGG-DUBE SYNDROME 1; BHD1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<a href="/omim/607273" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">607273</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">FOLLICULIN; FLCN</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobbhdTflcnpathogenicvariantsreference"><div id="bhd.T.flcn_pathogenic_variants_reference" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p><i>FLCN</i> Pathogenic Variants Referenced in This <i>GeneReview</i></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1522/table/bhd.T.flcn_pathogenic_variants_reference/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__bhd.T.flcn_pathogenic_variants_reference_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_bhd.T.flcn_pathogenic_variants_reference_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_bhd.T.flcn_pathogenic_variants_reference_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_bhd.T.flcn_pathogenic_variants_reference_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_bhd.T.flcn_pathogenic_variants_reference_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_bhd.T.flcn_pathogenic_variants_reference_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_144997.7" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_144997<wbr style="display:inline-block"></wbr>​.7</a>
|
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<br />
|
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_659434.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_659434<wbr style="display:inline-block"></wbr>​.2</a>
|
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</td><td headers="hd_h_bhd.T.flcn_pathogenic_variants_reference_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1285delC</td><td headers="hd_h_bhd.T.flcn_pathogenic_variants_reference_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.His429ThrfsTer39</td><td headers="hd_h_bhd.T.flcn_pathogenic_variants_reference_1_1_1_4" rowspan="2" colspan="1" style="text-align:left;vertical-align:top;">Most common pathogenic variants, reported in 20%-24% of families [<a class="bibr" href="#bhd.REF.sattler.2018b.e0209504" rid="bhd.REF.sattler.2018b.e0209504">Sattler et al 2018b</a>]</td></tr><tr><td headers="hd_h_bhd.T.flcn_pathogenic_variants_reference_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1285dupC</td><td headers="hd_h_bhd.T.flcn_pathogenic_variants_reference_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.His429ProfsTer27</td></tr><tr><td headers="hd_h_bhd.T.flcn_pathogenic_variants_reference_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1347_1353dupCCACCCT</td><td headers="hd_h_bhd.T.flcn_pathogenic_variants_reference_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Val452ProfsTer6</td><td headers="hd_h_bhd.T.flcn_pathogenic_variants_reference_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Frequency of 16%-32% in persons of Japanese ancestry [<a class="bibr" href="#bhd.REF.furuya.2016.403" rid="bhd.REF.furuya.2016.403">Furuya et al 2016</a>, <a class="bibr" href="#bhd.REF.iwabuchi.2018.77" rid="bhd.REF.iwabuchi.2018.77">Iwabuchi et al 2018</a>]</td></tr><tr><td headers="hd_h_bhd.T.flcn_pathogenic_variants_reference_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_144997.7" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_144997<wbr style="display:inline-block"></wbr>​.7</a>
|
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</td><td headers="hd_h_bhd.T.flcn_pathogenic_variants_reference_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1062+2T>G</td><td headers="hd_h_bhd.T.flcn_pathogenic_variants_reference_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">--</td><td headers="hd_h_bhd.T.flcn_pathogenic_variants_reference_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Danish founder variant (7.7% of affected persons/families) [<a class="bibr" href="#bhd.REF.rossing.2017.151" rid="bhd.REF.rossing.2017.151">Rossing et al 2017</a>]</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>​.hgvs.org</a>). See <a href="/books/n/gene/app3/?report=reader">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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