Familial Birt-Hogg-Dubé Syndrome diagnosed with the rare FLCN exon 6 mutation: a case series of three related patients

Familial Birt-Hogg-Dubé Syndrome diagnosed with the rare FLCN exon 6 mutation: a case series of three related patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Familial Birt-Hogg-Dubé Syndrome diagnosed with the rare FLCN exon 6 mutation: a case series of three related patients Mustafa Nadir Tantay, Mutlu Onur Gucsav, Mehmet Berkay Akcan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7899579/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 13 You are reading this latest preprint version Abstract Birt-Hogg-Dubé Syndrome (BHDS) is a rare, autosomal dominant genodermatosis characterized by a triad of benign cutaneous lesions, pulmonary cysts or spontaneous pneumothorax, and renal tumors. The clinical presentation is heterogeneous and often underrecognized, leading to diagnostic delays. We present a case series of three genetically related individuals diagnosed with BHDS. All patients demonstrated characteristic dermatological findings, including multiple fibrofolliculoma-like lesions on the face and trunk. Pulmonary involvement varied: one case was incidentally detected on imaging, while two patients presented with spontaneous pneumothorax requiring surgical intervention. Renal involvement ranged from benign renal cysts to a history of nephrectomy for oncocytoma. Although FLCN mutation was confirmed in one patient, the other two were diagnosed clinically based on typical findings and family history. This case series highlights the broad clinical spectrum of BHDS and underscores the importance of clinician and radiologist awareness to facilitate early diagnosis. Multidisciplinary management and screening of first-degree relatives are critical to prevent morbidity and mortality associated with renal tumors and pneumothorax. Birt-Hogg-Dube Syndrome Fibrofolliculoma Renal oncocytoma cystic lung disease Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Birt-Hogg-Dubé syndrome (BHDS) is a rare, autosomal dominant genodermatosis characterized by benign cutaneous lesions, pulmonary cysts or pneumothorax, and renal tumors ( 1 ). First described in 1977 by dermatologist Dr. Hogg and internist Dr. Dubé, the syndrome is caused by mutations in the FLCN gene. Due to diagnostic challenges, the true incidence of BHDS remains undetermined. To date, approximately 430 families with FLCN mutations have been reported in the literature ( 2 , 3 ). BHDS manifests with dermatologic, pulmonary, and renal components. Benign cutaneous lesions being the most frequent and often earliest manifestation, observed in approximately 85% of patients. These typically appear after the age of twenty. Pulmonary involvement typically presents as bilateral, thin-walled cysts of variable size. Patients usually remain asymptomatic unless spontaneous pneumothorax occurs. Renal manifestations are also notable, particularly in individuals aged 40 to 70. Although many renal tumors are benign, malignant lesions, such as renal cell carcinoma (RCC), may also occur ( 4 ). The diagnosis of BHDS is based on clinical and genetic criteria, with the most widely accepted guidelines proposed by the European Birt-Hogg-Dubé Consortium in 2009 and included in the most recent diagnostic recommendations. The presence of one major or two minor criteria is considered sufficient for diagnosis (Table 1 ) ( 5 ). In this report, we present a case series of three genetically related patients diagnosed with Birt-Hogg-Dubé syndrome. This case series aims to raise awareness of the syndrome's clinical spectrum and highlight the importance of considering BHDS in patients with characteristic cutaneous lesions and suggestive family history. Table 1 Diagnostic Criteria for Birt-Hogg-Dubé Syndrome Major Criteria Minor Criteria ≥ 5 fibrofolliculomas or trichodiscomas, at least one histologically confirmed, diagnosed in adulthood Multiple lung cysts (bilateral and basally located) with or without a history of spontaneous pneumothorax Pathogenic mutation in the FLCN gene Renal cancer (diagnosed before age 50, or multifocal, bilateral, or with chromophobe, oncocytic, or hybrid oncocytic/chromophobe histology) First-degree relative with confirmed Birt-Hogg-Dubé syndrome Case-1 A 62-year-old male patient with a chronic obstructive pulmonary disease (COPD) presented for routine follow-up. His medical history included hypertension (HT), diabetes mellitus (DM), coronary artery disease (CAD), and COPD. He had undergone right nephrectomy five years earlier due to a renal mass, colectomy three years ago for colon adenocarcinoma, and bullectomy one year ago for a giant bulla in the right lung. Additionally, he had a history of spontaneous pneumothorax approximately 40 years prior. Although he had quit smoking two years ago, he had a 50 pack-year smoking history. His family history was notable for multiple relatives with spontaneous pneumothorax. On physical examination, his vital signs were stable. Pulmonary auscultation revealed decreased breath sounds in the mid-to-upper zones of the right lung. Dermatological examination showed multiple dome-shaped, skin-colored papular lesions on the face, particularly in the infraorbital region, and on the anterior trunk (Fig. 1 ). Laboratory tests were within normal limits. Chest computer tomography (CT) revealed numerous irregularly shaped cystic lesions, more prominent in the basal regions of both lungs. These cysts were frequently located in perifissural areas (Fig. 2). The patient’s previous chest CT scans supported these findings. The papular skin lesions were evaluated by a dermatologist. Histological assessment confirmed the diagnosis of fibrofolliculomas. Pathology reports from the prior nephrectomy were reviewed, revealing oncocytic morphology of the renal lesion, as well as multiple cystic structures causing atrophy of the renal parenchyma. Based on the presence of perifissural and irregularly shaped pulmonary cysts, fibrofolliculomas, and renal oncocytoma, the patient was diagnosed with BHDS. He was subsequently enrolled in clinical follow-up. Case-2 A 76-year-old female patient presented to the outpatient clinic with worsening of her chronic symptoms of cough, non-purulent sputum, and dyspnea over the past two weeks. Her medical history included COPD, DM, HT, and heart failure. She had been receiving long-term oxygen therapy and home-based noninvasive mechanical ventilation (NIMV) due to COPD. Additionally, she had experienced a spontaneous pneumothorax two years prior. The patient had no history of tobacco use, but she reported exposure to biomass smoke. Her family history revealed that her brother (Case 1) had also experienced spontaneous pneumothorax and was diagnosed with BHDS following clinical investigations. On physical examination, her vital signs were stable. Pulmonary auscultation revealed rhonchi in the mid-to-lower zones bilaterally and fine crackles in the lower zone of the right lung. Moreover, multiple dome-shaped, skin-colored papular lesions were observed on her face—particularly around the eyes—and on the anterior trunk (Fig. 3). Laboratory findings showed leukocytosis and elevated C-reactive protein (CRP) levels. Chest CT revealed a newly developed consolidation in the posterobasal segment of the right lung, along with multiple air-filled cysts of varying sizes predominantly distributed in the perifissural areas of the bilateral lower lobes, as well as pleural thickening, calcifications, and areas of atelectasis (Fig. 4 ). The patient was hospitalized with a preliminary diagnosis of pneumonia and infective COPD exacerbation, and appropriate treatment was initiated. After treatment was completed, the patient was evaluated for BHDS due to her brother’s diagnosis and the presence of pulmonary cysts. A consultation was obtained due to her cutaneous lesions. Multiple follicular-based papules were noted on the anterior trunk, and acrochordon-like lesions were detected in the infraorbital regions. Although a skin biopsy was recommended, the patient declined the procedure. Renal ultrasound demonstrated bilateral increased parenchymal echogenicity (Grade 1) and multiple cystic lesions, the largest measuring 2 cm. Given the presence of typical pulmonary and cutaneous findings, along with a first-degree relative previously diagnosed with BHDS, the patient was diagnosed with Birt-Hogg-Dubé syndrome. She was subsequently enrolled in clinical follow-up. Case-3 A 50-year-old female patient presented to the outpatient clinic with a one-month history of chest pain, which had worsened in recent days. Her medical history was unremarkable, and she was an active smoker with a 20 pack-year smoking history. Her family history was notable for multiple relatives with a history of spontaneous pneumothorax. On physical examination, her vital signs were stable. Pulmonary auscultation revealed markedly decreased breath sounds in the upper zone of the left hemithorax. Additionally, inspection revealed millimetric, white-colored papular lesions around the nose, infraorbital regions, and anterior trunk (Fig. 5 ). Laboratory investigations were unremarkable. A posteroanterior chest radiograph revealed a left-sided pneumothorax, and the patient was admitted to the thoracic surgery ward with a diagnosis of spontaneous pneumothorax. Oxygen therapy was initiated, and as the pneumothorax resolved with treatment, further investigations were planned. Chest CT demonstrated thin-walled cystic lesions in both lungs, predominantly in the lower lobes, often associated with the fissures and centrally located, as well as a residual pneumothorax line in the left lung (Fig. 6). The patient was referred for dermatologic evaluation of her cutaneous lesions. The lesions were considered consistent with fibrofolliculomas, and a diagnostic biopsy was recommended. Renal ultrasound was performed to evaluate for renal involvement but revealed no pathology. The Screening for FLCN gene mutations was performed, and a heterozygous frameshift variant was detected in exon 6 of FLCN. The identified variant was considered pathogenic. The patient was diagnosed with BHDS because family members (Cases 1 and 2) had been diagnosed with BHDS and because chest CT revealed perifissural lung cysts, fibrofolliculoma-like skin lesions, and positive FLCN gene mutation findings. Discussion BHDS (Birt-Hogg-Dubé syndrome) is a rare autosomal dominant genodermatosis characterized by benign cutaneous lesions, pulmonary cysts or pneumothorax, and renal tumors ¹. BHDS results from mutations in the FLCN gene, a novel tumor suppressor located on chromosome 17p11.2, which consists of 14 exons. Pathogenic variants have been identified in various exons of the gene, and mutations in exons 9 and 12 have been reported to be more frequently associated with the development of spontaneous pneumothorax. The FLCN gene encodes the protein folliculin, which interacts with folliculin-interacting proteins (FNIP1, FNIP2) and AMPK, playing a critical role in the regulation of cell growth and other cellular processes ( 6 , 7 ) Diagnosis of BHDS is based on clinical and genetic criteria, with the demonstration of an FLCN mutation being one of the major diagnostic criteria ( 5 ). In our third case, next-generation sequencing (NGS) analysis was performed on genomic DNA obtained from peripheral blood, covering all exons and exon–intron boundaries of the FLCN gene. The analysis revealed a heterozygous c.479_480insAGGA (p.Asp160GlufsTer41) variant in exon 6 of the FLCN gene, according to the reference transcript ENST00000285071.9. This variant causes a frameshift, resulting in a premature stop codon and is expected to lead to loss of functional protein. This variant has not been reported in the gnomAD population database and is classified as pathogenic in the ClinVar database (ClinVar Variant ID: 1361582). According to ACMG/AMP criteria, with evidence codes PVS1, PM2, and PP5, it was evaluated as pathogenic. This finding was interpreted as a pathogenic germline variant consistent with Birt–Hogg–Dubé syndrome (BHDS). Following confirmation of the FLCN gene mutation, the other two family members were clinically diagnosed without genetic testing due to the autosomal dominant inheritance pattern and the presence of characteristic clinical findings. Given this inheritance pattern, screening of at-risk relatives is recommended to facilitate early diagnosis and management. Pulmonary and renal manifestations in BHDS often have an insidious course, contributing to diagnostic delays. In contrast, cutaneous lesions may serve as an early diagnostic clue. The most specific cutaneous lesions are fibrofolliculomas, which are benign, dome-shaped, skin-colored, soft papules measuring 2–4 mm, typically located on the face, neck, and upper trunk. Trichodiscomas and acrochordons are among the other common cutaneous lesions observed in BHDS. The presence of five or more trichodiscomas and/or fibrofolliculomas, with at least one histologically confirmed, emerging during adulthood, constitutes a major diagnostic criterion. In addition, other cutaneous tumors such as angiofibromas, lipomas, angiomyolipomas, oral polyps, and collagenomas may also occur, although less frequently ( 8 ). Notably, in our series, all patients exhibited these characteristic skin lesions and one of them histological confirmation was obtained due to biopsy. Pulmonary involvement in BHDS is typically characterized by bilateral, thin-walled cysts of varying sizes, predominantly located in the lower lobes and often distributed in subpleural or perifissural regions. These radiological features are helpful in distinguishing BHDS from other cystic lung diseases, such as lymphocytic interstitial pneumonia (LIP) and Langerhans cell histiocytosis (LCH) ( 9 ). Patients generally remain asymptomatic until the occurrence of spontaneous pneumothorax, with pulmonary cysts frequently identified incidentally on high-resolution computed tomography (HRCT). Approximately 24% to 37% of individuals with BHDS experience at least one episode of pneumothorax during their lifetime, with the risk decreasing with advancing age ( 10 , 11 ). Therefore, establishing an accurate diagnosis based on pulmonary findings requires a high index of suspicion among radiologists and pulmonologists. In our case series, one patient presented with spontaneous pneumothorax requiring surgical intervention, while cystic lung disease was incidentally detected in two patients. Accordingly, BHDS should be considered in the differential diagnosis of patients presenting with spontaneous pneumothorax. Given the considerable morbidity and potential for recurrence associated with pneumothorax in BHDS, patient education, smoking cessation counseling, and close clinical surveillance are essential following diagnosis. Renal tumors are the primary contributors to long-term morbidity and mortality in BHDS. Although many renal tumors are benign, malignant lesions such as renal cell carcinoma (RCC) can also occur. Studies have shown that most renal tumors in BHDS are oncocytomas or RCCs with chromophobe or hybrid chromophobe-oncocytoma histology. The risk of renal tumors in BHDS is approximately 16 times higher than in the general population, with advanced age and male sex identified as additional risk factors ( 12 ). Although renal involvement was not observed at the time of diagnosis in two of our patients, one patient had a prior history of nephrectomy for oncocytoma. Therefore, routine renal imaging surveillance with ultrasonography or MRI is recommended for all patients diagnosed with BHDS, regardless of findings at initial evaluation. One patient in our series had a history of colon adenocarcinoma. While colorectal cancer is not part of the BHDS diagnostic criteria, a potential link between FLCN mutations and colorectal cancer has been suggested but remains inconclusive due to insufficient evidence ( 13 ). Further research and larger cohorts are needed to clarify this association. A limitation of this case series is that skin biopsies were not performed in two patients, as both declined the procedure despite dermatological recommendation. While histopathological confirmation of fibrofolliculomas is considered a major diagnostic criterion for BHDS, clinical diagnosis was made based on the presence of characteristic skin lesions, typical pulmonary findings, and a positive family history. Although the lack of pathological confirmation limits diagnostic certainty, the combination of these features is widely accepted in clinical practice as sufficient evidence for diagnosing BHDS when biopsy is not feasible. In summary, this case series highlights the variable clinical spectrum of BHDS, which can result in delayed or missed diagnoses. Raising awareness among clinicians and radiologists is essential to improve recognition and reduce diagnostic delays. Multidisciplinary care involving dermatology, pulmonology, nephrology, and genetics specialists, along with screening of first-degree relatives, are key components of comprehensive patient management Declarations Acknowledgments In our study, AI- assisted Technologies were used only for improve readability and language. AI-assisted technologies were not involved in authorship, or editorial decision-making processes. Consent to publish: Written informed consent was obtained from all patients mentioned in the manuscript for the publication of their clinical data and images. The purpose and scope of the manuscript were clearly explained to the patients in a language they could understand. The privacy of all participants was ensured, and their identities were kept confidential. Funding declaration: The authors received no financial support for the research, authorship, and/or publication of this article. Conflict of Interest: The authors have no conflicts of interest to declare. Availability of data and material: All review data are publicly available. References Bajpai J, Roy S, Zanwar V, Kant S. Birt-Hogg-Dubé syndrome presenting with bilateral pneumothorax, skin, kidney, liver, and brain lesions. J Family Med Prim Care. 2024;13(5):2164–7. https://doi.org/10.4103/jfmpc.jfmpc_1451_23 Dal Sasso AA, Belém LC, Zanetti G, Souza CA, Escuissato DL, Irion KL, et al. Birt-Hogg-Dubé syndrome: state-of-the-art review with emphasis on pulmonary involvement. Respir Med. 2015;109(3):289–96. https://doi.org/10.1016/j.rmed.2014.11.008 Escalon JG, Richards JC, Koelsch T, Downey GP, Lynch DA. Isolated cystic lung disease: an algorithmic approach to distinguishing Birt-Hogg-Dubé syndrome, lymphangioleiomyomatosis, and lymphocytic interstitial pneumonia. AJR Am J Roentgenol. 2019;212(6):1260–4. https://doi.org/10.2214/AJR.18.20920 Shin WW, Baek YS, Oh TS, Heo YS, Son SB, Oh CH, et al. Birt-Hogg-Dubé syndrome: a rare case in Korea confirmed by genetic analysis. 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Orphanet J Rare Dis. 2014;9:163. https://doi.org/10.1186/s13023-014-0163-z Nahorski MS, Lim DH, Martin L, Gille JJP, McKay K, Rehal PK, et al. Investigation of the Birt-Hogg-Dubé tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer. J Med Genet. 2010;47(6):385–90. https://doi.org/10.1136/jmg.2009.073304 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 04 Feb, 2026 Reviews received at journal 04 Feb, 2026 Reviews received at journal 26 Jan, 2026 Reviewers agreed at journal 26 Jan, 2026 Reviewers agreed at journal 21 Jan, 2026 Reviewers agreed at journal 19 Jan, 2026 Reviewers agreed at journal 12 Jan, 2026 Reviews received at journal 20 Nov, 2025 Reviewers agreed at journal 13 Nov, 2025 Reviewers invited by journal 11 Nov, 2025 Editor assigned by journal 28 Oct, 2025 Submission checks completed at journal 28 Oct, 2025 First submitted to journal 19 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7899579","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":548346841,"identity":"f2609613-150a-4f2c-805c-ed4e95bd7daa","order_by":0,"name":"Mustafa Nadir 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19:36:56","extension":"xml","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":54044,"visible":true,"origin":"","legend":"","description":"","filename":"75aade1f18224e7cb81151d8bee1e46c1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7899579/v1/c4b6c5fd1ae810ef4acbbbf8.xml"},{"id":96709884,"identity":"6f837fee-5ede-4b49-b13d-12ddf917ea53","added_by":"auto","created_at":"2025-11-25 10:09:45","extension":"html","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":62376,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7899579/v1/b976b9ce2682c9692f5408d3.html"},{"id":96664099,"identity":"f7a942fa-4c20-4333-9524-79389786b63f","added_by":"auto","created_at":"2025-11-24 19:36:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":392720,"visible":true,"origin":"","legend":"\u003cp\u003eMultiple dome-shaped, skin-colored papular lesions on the face, particularly in the infraorbital region, and on the anterior trunk\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7899579/v1/72eb036ae6d953bfd7ed89ed.png"},{"id":96709588,"identity":"90cfb38a-d921-4433-a634-3e50204df703","added_by":"auto","created_at":"2025-11-25 10:09:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":248404,"visible":true,"origin":"","legend":"\u003cp\u003eChest CT demonstrating multiple irregularly shaped pulmonary cysts, predominantly located in the basal regions of both lungs, most of which are perifissural in distribution.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7899579/v1/cd21f481a8bb7c9fbfe6f088.png"},{"id":96709967,"identity":"013ebbd7-a9dc-43f7-8579-4b2ed11c3296","added_by":"auto","created_at":"2025-11-25 10:09:50","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":386481,"visible":true,"origin":"","legend":"\u003cp\u003eMultiple dome-shaped, skin-colored papular lesions observed on the patient's face, particularly in the periorbital region, and on the anterior trunk.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7899579/v1/2e62f1dc40d2cd0f5fbc54fc.png"},{"id":96710263,"identity":"bf9979c7-562f-49ed-a492-32ce8d619305","added_by":"auto","created_at":"2025-11-25 10:10:21","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":287456,"visible":true,"origin":"","legend":"\u003cp\u003eChest CT showing numerous air cysts of varying sizes, predominantly distributed in the perifissural regions of the bilateral lower lobes.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7899579/v1/47d88410b23d0e92a2d450b1.png"},{"id":96710427,"identity":"a0d7d652-8465-4e73-a51d-d4b5617d46ab","added_by":"auto","created_at":"2025-11-25 10:10:37","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":387243,"visible":true,"origin":"","legend":"\u003cp\u003eThe patient demonstrates millimetric, white papular lesions on the nose, infraorbital regions, and anterior trunk\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7899579/v1/951c6b00a5fdd29d524e37b2.png"},{"id":96710777,"identity":"b0366e33-4104-4e0b-bedb-2d44c617125e","added_by":"auto","created_at":"2025-11-25 10:11:10","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":206729,"visible":true,"origin":"","legend":"\u003cp\u003eChest CT demonstrating thin-walled cystic lesions in both lungs, predominantly in the lower lobes, often perifissural and centrally located.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7899579/v1/4ad6adc90694fcdc473f009d.png"},{"id":96913417,"identity":"acdad1a5-8055-4eb5-bf47-d4b621346554","added_by":"auto","created_at":"2025-11-27 14:01:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3034292,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7899579/v1/414aa1bb-9ce4-4117-94c4-2ce21f1429b2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eFamilial Birt-Hogg-Dubé Syndrome diagnosed with the rare FLCN exon 6 mutation: a case series of three related patients\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBirt-Hogg-Dub\u0026eacute; syndrome (BHDS) is a rare, autosomal dominant genodermatosis characterized by benign cutaneous lesions, pulmonary cysts or pneumothorax, and renal tumors (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). First described in 1977 by dermatologist Dr. Hogg and internist Dr. Dub\u0026eacute;, the syndrome is caused by mutations in the \u003cem\u003eFLCN\u003c/em\u003e gene. Due to diagnostic challenges, the true incidence of BHDS remains undetermined. To date, approximately 430 families with \u003cem\u003eFLCN\u003c/em\u003e mutations have been reported in the literature (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eBHDS manifests with dermatologic, pulmonary, and renal components. Benign cutaneous lesions being the most frequent and often earliest manifestation, observed in approximately 85% of patients. These typically appear after the age of twenty. Pulmonary involvement typically presents as bilateral, thin-walled cysts of variable size. Patients usually remain asymptomatic unless spontaneous pneumothorax occurs. Renal manifestations are also notable, particularly in individuals aged 40 to 70. Although many renal tumors are benign, malignant lesions, such as renal cell carcinoma (RCC), may also occur (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe diagnosis of BHDS is based on clinical and genetic criteria, with the most widely accepted guidelines proposed by the European Birt-Hogg-Dub\u0026eacute; Consortium in 2009 and included in the most recent diagnostic recommendations. The presence of one major or two minor criteria is considered sufficient for diagnosis (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn this report, we present a case series of three genetically related patients diagnosed with Birt-Hogg-Dub\u0026eacute; syndrome. This case series aims to raise awareness of the syndrome's clinical spectrum and highlight the importance of considering BHDS in patients with characteristic cutaneous lesions and suggestive family history.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDiagnostic Criteria for Birt-Hogg-Dub\u0026eacute; Syndrome\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMajor Criteria\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMinor Criteria\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;5 fibrofolliculomas or trichodiscomas, at least one histologically confirmed, diagnosed in adulthood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMultiple lung cysts (bilateral and basally located) with or without a history of spontaneous pneumothorax\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePathogenic mutation in the \u003cem\u003eFLCN\u003c/em\u003e gene\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRenal cancer (diagnosed before age 50, or multifocal, bilateral, or with chromophobe, oncocytic, or hybrid oncocytic/chromophobe histology)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFirst-degree relative with confirmed Birt-Hogg-Dub\u0026eacute; syndrome\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Case-1","content":"\u003cp\u003eA 62-year-old male patient with a chronic obstructive pulmonary disease (COPD) presented for routine follow-up. His medical history included hypertension (HT), diabetes mellitus (DM), coronary artery disease (CAD), and COPD. He had undergone right nephrectomy five years earlier due to a renal mass, colectomy three years ago for colon adenocarcinoma, and bullectomy one year ago for a giant bulla in the right lung. Additionally, he had a history of spontaneous pneumothorax approximately 40 years prior. Although he had quit smoking two years ago, he had a 50 pack-year smoking history. His family history was notable for multiple relatives with spontaneous pneumothorax.\u003c/p\u003e\n\u003cp\u003eOn physical examination, his vital signs were stable. Pulmonary auscultation revealed decreased breath sounds in the mid-to-upper zones of the right lung. Dermatological examination showed multiple dome-shaped, skin-colored papular lesions on the face, particularly in the infraorbital region, and on the anterior trunk (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Laboratory tests were within normal limits. Chest computer tomography (CT) revealed numerous irregularly shaped cystic lesions, more prominent in the basal regions of both lungs. These cysts were frequently located in perifissural areas (Fig. 2). The patient\u0026rsquo;s previous chest CT scans supported these findings.\u003c/p\u003e\n\u003cp\u003eThe papular skin lesions were evaluated by a dermatologist. Histological assessment confirmed the diagnosis of fibrofolliculomas. Pathology reports from the prior nephrectomy were reviewed, revealing oncocytic morphology of the renal lesion, as well as multiple cystic structures causing atrophy of the renal parenchyma. Based on the presence of perifissural and irregularly shaped pulmonary cysts, fibrofolliculomas, and renal oncocytoma, the patient was diagnosed with BHDS. He was subsequently enrolled in clinical follow-up.\u003c/p\u003e"},{"header":"Case-2","content":"\u003cp\u003eA 76-year-old female patient presented to the outpatient clinic with worsening of her chronic symptoms of cough, non-purulent sputum, and dyspnea over the past two weeks. Her medical history included COPD, DM, HT, and heart failure. She had been receiving long-term oxygen therapy and home-based noninvasive mechanical ventilation (NIMV) due to COPD. Additionally, she had experienced a spontaneous pneumothorax two years prior. The patient had no history of tobacco use, but she reported exposure to biomass smoke. Her family history revealed that her brother (Case 1) had also experienced spontaneous pneumothorax and was diagnosed with BHDS following clinical investigations.\u003c/p\u003e\n\u003cp\u003eOn physical examination, her vital signs were stable. Pulmonary auscultation revealed rhonchi in the mid-to-lower zones bilaterally and fine crackles in the lower zone of the right lung. Moreover, multiple dome-shaped, skin-colored papular lesions were observed on her face\u0026mdash;particularly around the eyes\u0026mdash;and on the anterior trunk (Fig.\u0026nbsp;3).\u003c/p\u003e\n\u003cp\u003eLaboratory findings showed leukocytosis and elevated C-reactive protein (CRP) levels. Chest CT revealed a newly developed consolidation in the posterobasal segment of the right lung, along with multiple air-filled cysts of varying sizes predominantly distributed in the perifissural areas of the bilateral lower lobes, as well as pleural thickening, calcifications, and areas of atelectasis (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). The patient was hospitalized with a preliminary diagnosis of pneumonia and infective COPD exacerbation, and appropriate treatment was initiated.\u003c/p\u003e\n\u003cp\u003eAfter treatment was completed, the patient was evaluated for BHDS due to her brother\u0026rsquo;s diagnosis and the presence of pulmonary cysts. A consultation was obtained due to her cutaneous lesions. Multiple follicular-based papules were noted on the anterior trunk, and acrochordon-like lesions were detected in the infraorbital regions. Although a skin biopsy was recommended, the patient declined the procedure. Renal ultrasound demonstrated bilateral increased parenchymal echogenicity (Grade 1) and multiple cystic lesions, the largest measuring 2 cm.\u003c/p\u003e\n\u003cp\u003eGiven the presence of typical pulmonary and cutaneous findings, along with a first-degree relative previously diagnosed with BHDS, the patient was diagnosed with Birt-Hogg-Dub\u0026eacute; syndrome. She was subsequently enrolled in clinical follow-up.\u003c/p\u003e"},{"header":"Case-3","content":"\u003cp\u003eA 50-year-old female patient presented to the outpatient clinic with a one-month history of chest pain, which had worsened in recent days. Her medical history was unremarkable, and she was an active smoker with a 20 pack-year smoking history. Her family history was notable for multiple relatives with a history of spontaneous pneumothorax. On physical examination, her vital signs were stable. Pulmonary auscultation revealed markedly decreased breath sounds in the upper zone of the left hemithorax. Additionally, inspection revealed millimetric, white-colored papular lesions around the nose, infraorbital regions, and anterior trunk (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e). Laboratory investigations were unremarkable.\u003c/p\u003e\n\u003cp\u003eA posteroanterior chest radiograph revealed a left-sided pneumothorax, and the patient was admitted to the thoracic surgery ward with a diagnosis of spontaneous pneumothorax. Oxygen therapy was initiated, and as the pneumothorax resolved with treatment, further investigations were planned. Chest CT demonstrated thin-walled cystic lesions in both lungs, predominantly in the lower lobes, often associated with the fissures and centrally located, as well as a residual pneumothorax line in the left lung (Fig. 6).\u003c/p\u003e\n\u003cp\u003eThe patient was referred for dermatologic evaluation of her cutaneous lesions. The lesions were considered consistent with fibrofolliculomas, and a diagnostic biopsy was recommended. Renal ultrasound was performed to evaluate for renal involvement but revealed no pathology. The Screening for FLCN gene mutations was performed, and a heterozygous frameshift variant was detected in exon 6 of FLCN. The identified variant was considered pathogenic. The patient was diagnosed with BHDS because family members (Cases 1 and 2) had been diagnosed with BHDS and because chest CT revealed perifissural lung cysts, fibrofolliculoma-like skin lesions, and positive FLCN gene mutation findings.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eBHDS (Birt-Hogg-Dub\u0026eacute; syndrome) is a rare autosomal dominant genodermatosis characterized by benign cutaneous lesions, pulmonary cysts or pneumothorax, and renal tumors \u0026sup1;. BHDS results from mutations in the FLCN gene, a novel tumor suppressor located on chromosome 17p11.2, which consists of 14 exons. Pathogenic variants have been identified in various exons of the gene, and mutations in exons 9 and 12 have been reported to be more frequently associated with the development of spontaneous pneumothorax. The FLCN gene encodes the protein folliculin, which interacts with folliculin-interacting proteins (FNIP1, FNIP2) and AMPK, playing a critical role in the regulation of cell growth and other cellular processes (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eDiagnosis of BHDS is based on clinical and genetic criteria, with the demonstration of an FLCN mutation being one of the major diagnostic criteria (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In our third case, next-generation sequencing (NGS) analysis was performed on genomic DNA obtained from peripheral blood, covering all exons and exon\u0026ndash;intron boundaries of the \u003cem\u003eFLCN\u003c/em\u003e gene. The analysis revealed a heterozygous c.479_480insAGGA (p.Asp160GlufsTer41) variant in exon 6 of the \u003cem\u003eFLCN\u003c/em\u003e gene, according to the reference transcript ENST00000285071.9. This variant causes a frameshift, resulting in a premature stop codon and is expected to lead to loss of functional protein.\u003c/p\u003e\u003cp\u003eThis variant has not been reported in the gnomAD population database and is classified as pathogenic in the ClinVar database (ClinVar Variant ID: 1361582). According to ACMG/AMP criteria, with evidence codes PVS1, PM2, and PP5, it was evaluated as pathogenic. This finding was interpreted as a pathogenic germline variant consistent with Birt\u0026ndash;Hogg\u0026ndash;Dub\u0026eacute; syndrome (BHDS).\u003c/p\u003e\u003cp\u003eFollowing confirmation of the FLCN gene mutation, the other two family members were clinically diagnosed without genetic testing due to the autosomal dominant inheritance pattern and the presence of characteristic clinical findings. Given this inheritance pattern, screening of at-risk relatives is recommended to facilitate early diagnosis and management.\u003c/p\u003e\u003cp\u003ePulmonary and renal manifestations in BHDS often have an insidious course, contributing to diagnostic delays. In contrast, cutaneous lesions may serve as an early diagnostic clue. The most specific cutaneous lesions are fibrofolliculomas, which are benign, dome-shaped, skin-colored, soft papules measuring 2\u0026ndash;4 mm, typically located on the face, neck, and upper trunk. Trichodiscomas and acrochordons are among the other common cutaneous lesions observed in BHDS. The presence of five or more trichodiscomas and/or fibrofolliculomas, with at least one histologically confirmed, emerging during adulthood, constitutes a major diagnostic criterion. In addition, other cutaneous tumors such as angiofibromas, lipomas, angiomyolipomas, oral polyps, and collagenomas may also occur, although less frequently (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Notably, in our series, all patients exhibited these characteristic skin lesions and one of them histological confirmation was obtained due to biopsy.\u003c/p\u003e\u003cp\u003ePulmonary involvement in BHDS is typically characterized by bilateral, thin-walled cysts of varying sizes, predominantly located in the lower lobes and often distributed in subpleural or perifissural regions. These radiological features are helpful in distinguishing BHDS from other cystic lung diseases, such as lymphocytic interstitial pneumonia (LIP) and Langerhans cell histiocytosis (LCH) (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Patients generally remain asymptomatic until the occurrence of spontaneous pneumothorax, with pulmonary cysts frequently identified incidentally on high-resolution computed tomography (HRCT). Approximately 24% to 37% of individuals with BHDS experience at least one episode of pneumothorax during their lifetime, with the risk decreasing with advancing age (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Therefore, establishing an accurate diagnosis based on pulmonary findings requires a high index of suspicion among radiologists and pulmonologists. In our case series, one patient presented with spontaneous pneumothorax requiring surgical intervention, while cystic lung disease was incidentally detected in two patients. Accordingly, BHDS should be considered in the differential diagnosis of patients presenting with spontaneous pneumothorax. Given the considerable morbidity and potential for recurrence associated with pneumothorax in BHDS, patient education, smoking cessation counseling, and close clinical surveillance are essential following diagnosis.\u003c/p\u003e\u003cp\u003eRenal tumors are the primary contributors to long-term morbidity and mortality in BHDS. Although many renal tumors are benign, malignant lesions such as renal cell carcinoma (RCC) can also occur. Studies have shown that most renal tumors in BHDS are oncocytomas or RCCs with chromophobe or hybrid chromophobe-oncocytoma histology. The risk of renal tumors in BHDS is approximately 16 times higher than in the general population, with advanced age and male sex identified as additional risk factors (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Although renal involvement was not observed at the time of diagnosis in two of our patients, one patient had a prior history of nephrectomy for oncocytoma. Therefore, routine renal imaging surveillance with ultrasonography or MRI is recommended for all patients diagnosed with BHDS, regardless of findings at initial evaluation.\u003c/p\u003e\u003cp\u003eOne patient in our series had a history of colon adenocarcinoma. While colorectal cancer is not part of the BHDS diagnostic criteria, a potential link between \u003cem\u003eFLCN\u003c/em\u003e mutations and colorectal cancer has been suggested but remains inconclusive due to insufficient evidence (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Further research and larger cohorts are needed to clarify this association.\u003c/p\u003e\u003cp\u003eA limitation of this case series is that skin biopsies were not performed in two patients, as both declined the procedure despite dermatological recommendation. While histopathological confirmation of fibrofolliculomas is considered a major diagnostic criterion for BHDS, clinical diagnosis was made based on the presence of characteristic skin lesions, typical pulmonary findings, and a positive family history. Although the lack of pathological confirmation limits diagnostic certainty, the combination of these features is widely accepted in clinical practice as sufficient evidence for diagnosing BHDS when biopsy is not feasible.\u003c/p\u003e\u003cp\u003eIn summary, this case series highlights the variable clinical spectrum of BHDS, which can result in delayed or missed diagnoses. Raising awareness among clinicians and radiologists is essential to improve recognition and reduce diagnostic delays. Multidisciplinary care involving dermatology, pulmonology, nephrology, and genetics specialists, along with screening of first-degree relatives, are key components of comprehensive patient management\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn our study, AI- assisted Technologies were used only for improve readability and language. AI-assisted technologies were not involved in authorship, or editorial decision-making processes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish:\u0026nbsp;\u003c/strong\u003eWritten informed consent was obtained from all patients mentioned in the manuscript for the publication of their clinical data and images. The purpose and scope of the manuscript were clearly explained to the patients in a language they could understand. The privacy of all participants was ensured, and their identities were kept confidential.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding declaration:\u0026nbsp;\u003c/strong\u003eThe authors received no financial support for the research, authorship, and/or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u0026nbsp;\u003c/strong\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material:\u003c/strong\u003e All review data are publicly available.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBajpai J, Roy S, Zanwar V, Kant S. Birt-Hogg-Dub\u0026eacute; syndrome presenting with bilateral pneumothorax, skin, kidney, liver, and brain lesions. J Family Med Prim Care. 2024;13(5):2164\u0026ndash;7. https://doi.org/10.4103/jfmpc.jfmpc_1451_23\u003c/li\u003e\n\u003cli\u003eDal Sasso AA, Bel\u0026eacute;m LC, Zanetti G, Souza CA, Escuissato DL, Irion KL, et al. Birt-Hogg-Dub\u0026eacute; syndrome: state-of-the-art review with emphasis on pulmonary involvement. Respir Med. 2015;109(3):289\u0026ndash;96. https://doi.org/10.1016/j.rmed.2014.11.008\u003c/li\u003e\n\u003cli\u003eEscalon JG, Richards JC, Koelsch T, Downey GP, Lynch DA. Isolated cystic lung disease: an algorithmic approach to distinguishing Birt-Hogg-Dub\u0026eacute; syndrome, lymphangioleiomyomatosis, and lymphocytic interstitial pneumonia. AJR Am J Roentgenol. 2019;212(6):1260\u0026ndash;4. https://doi.org/10.2214/AJR.18.20920\u003c/li\u003e\n\u003cli\u003eShin WW, Baek YS, Oh TS, Heo YS, Son SB, Oh CH, et al. Birt-Hogg-Dub\u0026eacute; syndrome: a rare case in Korea confirmed by genetic analysis. Ann Dermatol. 2011;23(Suppl 2):S193\u0026ndash;6. https://doi.org/10.5021/ad.2011.23.S2.S193\u003c/li\u003e\n\u003cli\u003eGeilswijk M, Genuardi M, Woodward ER, Nightingale K, Huber J, Madsen MG, et al. ERN GENTURIS clinical practice guidelines for the diagnosis, surveillance and management of people with Birt-Hogg-Dub\u0026eacute; syndrome. Eur J Hum Genet. 2024;32(12):1542\u0026ndash;50. https://doi.org/10.1038/s41431-024-01671-2\u003c/li\u003e\n\u003cli\u003eSchmidt LS, Linehan WM. Molecular genetics and clinical features of Birt-Hogg-Dub\u0026eacute; syndrome. Nat Rev Urol. 2015;12(10):558\u0026ndash;69. https://doi.org/10.1038/nrurol.2015.206\u003c/li\u003e\n\u003cli\u003eSchmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, et al. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dub\u0026eacute; syndrome. Am J Hum Genet. 2005;76(6):1023\u0026ndash;33. https://doi.org/10.1086/430842\u003c/li\u003e\n\u003cli\u003e\u0026Ouml;mer D, Dilektaşlı AG, Başkan EB, Temel ŞG, Uzaslan E, Sağ Ş\u0026Ouml;. A rare cystic lung disease: Birt-Hogg-Dub\u0026eacute; syndrome. Turkiye Klinikleri Arch Lung. 2021;20(2):62\u0026ndash;7. https://doi.org/10.5336/archlung.2020-79774\u003c/li\u003e\n\u003cli\u003eAgarwal PP, Gross BH, Holloway BJ, Seely J, Stark P, Kazerooni EA. Thoracic CT findings in Birt-Hogg-Dub\u0026eacute; syndrome. AJR Am J Roentgenol. 2011;196(2):349\u0026ndash;52. https://doi.org/10.2214/AJR.10.4757\u003c/li\u003e\n\u003cli\u003eEscalon JG, Richards JC, Koelsch T, Downey GP, Lynch DA. Isolated cystic lung disease: an algorithmic approach to distinguishing Birt-Hogg-Dub\u0026eacute; syndrome, lymphangioleiomyomatosis, and lymphocytic interstitial pneumonia. AJR Am J Roentgenol. 2019;212(6):1260\u0026ndash;4. https://doi.org/10.2214/AJR.18.20920\u003c/li\u003e\n\u003cli\u003eSkolnik K, Tsai WH, Dornan K, Perrier R, Burrowes PW, Davidson WJ. Birt-Hogg-Dub\u0026eacute; syndrome: a large single family cohort. Respir Res. 2016;17(1):22. https://doi.org/10.1186/s12931-016-0339-2\u003c/li\u003e\n\u003cli\u003eBenusiglio PR, Giraud S, Deveaux S, M\u0026eacute;jean A, Correas JM, Joly D, et al. Renal cell tumour characteristics in patients with the Birt-Hogg-Dub\u0026eacute; cancer susceptibility syndrome: a retrospective, multicentre study. Orphanet J Rare Dis. 2014;9:163. https://doi.org/10.1186/s13023-014-0163-z\u003c/li\u003e\n\u003cli\u003eNahorski MS, Lim DH, Martin L, Gille JJP, McKay K, Rehal PK, et al. Investigation of the Birt-Hogg-Dub\u0026eacute; tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer. J Med Genet. 2010;47(6):385\u0026ndash;90. https://doi.org/10.1136/jmg.2009.073304\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Journal of Rare Diseases](https://link.springer.com/journal/44162)","snPcode":"44162","submissionUrl":"https://submission.nature.com/new-submission/44162/3","title":"Journal of Rare Diseases","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Birt-Hogg-Dube Syndrome, Fibrofolliculoma, Renal oncocytoma, cystic lung disease","lastPublishedDoi":"10.21203/rs.3.rs-7899579/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7899579/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBirt-Hogg-Dub\u0026eacute; Syndrome (BHDS) is a rare, autosomal dominant genodermatosis characterized by a triad of benign cutaneous lesions, pulmonary cysts or spontaneous pneumothorax, and renal tumors. The clinical presentation is heterogeneous and often underrecognized, leading to diagnostic delays.\u003c/p\u003e\u003cp\u003eWe present a case series of three genetically related individuals diagnosed with BHDS. All patients demonstrated characteristic dermatological findings, including multiple fibrofolliculoma-like lesions on the face and trunk. Pulmonary involvement varied: one case was incidentally detected on imaging, while two patients presented with spontaneous pneumothorax requiring surgical intervention. Renal involvement ranged from benign renal cysts to a history of nephrectomy for oncocytoma. Although FLCN mutation was confirmed in one patient, the other two were diagnosed clinically based on typical findings and family history.\u003c/p\u003e\u003cp\u003eThis case series highlights the broad clinical spectrum of BHDS and underscores the importance of clinician and radiologist awareness to facilitate early diagnosis. Multidisciplinary management and screening of first-degree relatives are critical to prevent morbidity and mortality associated with renal tumors and pneumothorax.\u003c/p\u003e","manuscriptTitle":"Familial Birt-Hogg-Dubé Syndrome diagnosed with the rare FLCN exon 6 mutation: a case series of three related patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-24 19:36:52","doi":"10.21203/rs.3.rs-7899579/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-04T07:24:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-04T06:57:34+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-26T08:19:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"333697428239438591736936660828851279645","date":"2026-01-26T05:33:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"181065914001109366586485214376270876627","date":"2026-01-21T12:57:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"31047396016779627133733353796118251508","date":"2026-01-19T14:05:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"256745274965715179225699507735093179730","date":"2026-01-12T10:29:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-20T20:34:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"238657665923014497357922008906391053264","date":"2025-11-13T14:42:21+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-11T12:11:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-28T07:50:28+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-28T07:49:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Rare Diseases","date":"2025-10-19T15:24:09+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Journal of Rare Diseases](https://link.springer.com/journal/44162)","snPcode":"44162","submissionUrl":"https://submission.nature.com/new-submission/44162/3","title":"Journal of Rare Diseases","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9e855240-b331-4f99-9d01-43eeaa0851e5","owner":[],"postedDate":"November 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-20T10:08:11+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-24 19:36:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7899579","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7899579","identity":"rs-7899579","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}